KR20180064130A - Novel homoisoflavanone derivatives, preparation method thereof, and pharmaceutical composition for use in preventing or treating ischemic brain damage and multiple sclerosis containing the same as an active ingredient - Google Patents

Abstract

The present invention relates to: a homoisoflavanone compound; a manufacturing method thereof; and a pharmaceutical composition for preventing or treating ischemic brain damage and multiple sclerosis containing the homoisoflavanone compound as an active ingredient, wherein the novel homoisoflavanone compound decreases the extent of the brain damage caused by ischemic stroke, reduces neurodegeneration and increases the expression of NGF which promotes neural cell regeneration to be used as a pharmaceutical composition for preventing or treating the brain damage due to ischemia, and to be used as a pharmaceutical composition for preventing or treating the multiple sclerosis.

Description

TECHNICAL FIELD [0001] The present invention relates to a novel homoisoflavanone compound, a process for producing the same, and a pharmaceutical composition for preventing or treating ischemic brain damage and multiple sclerosis containing the compound as an active ingredient. or treating ischemic brain damage and multiple sclerosis comprising the same as an active ingredient}

The present invention relates to a homoisoflavanone compound, a process for producing the same, and a pharmaceutical composition for preventing or treating ischemic brain damage and multiple sclerosis containing the compound as an active ingredient.

Cerebral infarction and myocardial infarction, which are representative ischemic diseases, are caused by arterial sclerosis in which blood vessels become narrow due to hypertension, hyperlipemia, diabetes, smoking, etc., and a cerebral artery supplying blood to the brain by thrombus or the like, or a coronary artery supplying blood to the heart is blocked It is caused by necrosis of tissue.

Cardiovascular disease accounts for 30% of all deaths globally and is the number one cause of death. 75% of these are ischemic diseases such as myocardial infarction and cerebral infarction. Myocardial infarction and cerebral infarction each account for the highest mortality rate with cancer. Methods to reduce mortality from myocardial infarction and stroke include treatment of hypertension and hyperlipidemia to prevent occlusion of blood vessels and reduction of necrosis of surrounding tissues during vascular occlusion.

Of these, the best way to reduce the necrotic area is to quickly re-perfuse the blood vessels with a thrombolytic agent or the like through the clogged blood vessels in a short period of time. However, the heart and the brain, which receive energy by respiration, It is impossible to expect the therapeutic effect even if perfusion is performed afterwards. However, it is difficult to get reperfusion by receiving the treatment within 3-6 hours of occlusion, which is the time needed to increase the therapeutic effect. Also, the heart and brain are not well regenerated once damaged. Therefore, it is possible to improve the therapeutic effect by improving the cell viability in the ischemic state until reperfusion in the hospital. At this time, one of the causes of tissue necrosis is apoptosis of cell, and it can improve cell viability by inhibiting it.

In addition, damage to tissue implanted in kidney transplantation or plastic surgery is also caused by ischemia-induced apoptosis and cell suicide. In the case of operation in which the heart is stopped and performed, the amount of oxygen required is higher than the amount of oxygen supplied by the cardiopulmonary apparatus And brain damage due to myocardial damage or hypotension may occur. For example, it can be used for bypass graft surgery for coronary artery occlusion, aneurysm surgery for a cerebral artery or aorta, myocardial damage due to ischemia, Side effects such as half-life may occur. In fact, in the surgical or interventional treatment of aortic aneurysms, side effects such as myocardial ischemia, renal failure, and paralysis occur in 3-16% of patients.

Although the cause of ischemic brain damage has not yet been elucidated, in the case of transient cerebral ischemia in the cerebrum, the supply of oxygen and glucose is blocked, resulting in decreased adenosine triphosphate (ATP) and edema It is known that cell suicide is induced. Brain damage caused by cerebral ischemia, neuronal cell suicide mechanism, is caused by excessive accumulation of glutamate outside the cell by ischemia and glutamate is introduced into the cell, resulting in excessive accumulation of calcium in the cell nerve cell suicide is triggered excitatory nerve cell There is an oxidative nerve cell suicide mechanism in which the increase of in vivo radicals due to abrupt oxygen supply during suicide and ischemia-reperfusion causes damage to DNA and cytoplasm and induces neuronal cell death (Non-Patent Document 1). Based on these meticulous studies, many researches have been conducted to search for substances that effectively inhibit neuronal cell suicide due to cerebral ischemia, and to elucidate the mechanisms of substances. However, substances that effectively inhibit ischemic brain damage and nerve cell suicide Little was found.

Traditionally, only drugs that show therapeutic effects against ischemic brain damage include radicul ^® (Mitsubishi Tanabe Pharma Cp.), And treatment of cerebral infarction (atherothrombotic stroke, lacuna infarction, . Recently, food ingredients such as carnosine, ellagic acid derivatives, carotene derivatives, and Socysteinyl derivatives have been reported to be effective in secondary prevention as well as primary prevention of ischemic brain injury. Studies to develop a therapeutic agent for stroke mainly focused on the development of a glutamate receptor blocker and an antioxidant as an attempt to prevent primary brain damage, but failed in clinical trials and failed due to toxicity. NMDA receptor antagonists are not used as serious toxicities and are largely rejected in clinical trials.

Therefore, it is necessary to develop therapeutic agents and foods that can prevent or treat brain damage caused by ischemia substantially.

Multiple sclerosis (MS) is the most common chronic inflammatory dehydration disease of the central nervous system (brain, spinal cord, optic nerve). It is characterized mainly by multiple inflammation and dehydration in the central nervous system, Although the cause of the disease is not yet clear, it is thought to be an autoimmune disease caused by the environment in a genetically susceptible patient.

Accordingly, the inventors of the present invention completed the present invention upon discovering a compound capable of preventing or treating brain damage caused by ischemia, confirming that the compound of the present invention is excellent in the treatment and prevention of brain injury due to multiple sclerosis and ischemia .

Kang TC, et al., J. Neurocytol., 30 (12): 945-955, 2001.

It is an object of the present invention to provide a novel homoisoflavanone compound, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

Another object of the present invention is to provide a process for preparing the novel homoisoflavanone compound.

It is still another object of the present invention to provide a pharmaceutical composition for preventing or treating brain damage due to ischemia comprising the novel homoisoflavanone compound as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for preventing or treating multiple sclerosis containing the novel homoisoflavanone compound as an active ingredient.

Yet another object of the present invention is to provide a health food for preventing or ameliorating brain damage due to ischemia, which contains the novel homoisoflavanone compound as an active ingredient.

Another object of the present invention is to provide a health food for preventing or ameliorating multiple sclerosis containing the novel homoisoflavanone compound as an active ingredient.

In order to achieve the above object,

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ¹ , R ² and R ³ are independently -H, -OH, or straight or branched C _1-5 alkoxy,

또는

를 형성하되, 상기

가 이중결합일 경우 Z¹ 및 Z²는 함께 연결되어

를 형성하지 않고,Z ¹ and Z ² are independently -H or -OH, or Z ¹ and Z ² are linked together

or

,

Is a double bond, Z < ^{1 >} and Z < ^{2 >}

. However,

가 이중결합일 경우 부재이고, 상기

가 단일결합일 경우 -H 또는 -CH₂OH이되, 상기

가 단일결합이고 상기 Z¹ 및 Z²가 함께 연결되어

를 형성할 경우 Z³는 부재이고,Z < ^{3 &}

Member is a double bond,

If the work -H single bond or -CH ₂ OH, provided the

Is a single bond and Z < ¹ > and Z < ² &

, Z ³ is a member,

E, G and M are independently C or N,

R ⁴ is a member when E is N and is -H when E is C, C _1-5 alkoxy, straight or branched chain, or halogen, or is connected with R ⁵ to form unsubstituted phenyl,

또는

이거나, R⁶과 함께 연결되어

를 형성하고,R ⁵ is a member when G is N and is -H when G is C, straight or branched C _1-5 alkoxy, halogen, unsubstituted or substituted straight or branched C _1-5 Alkyl, -OH,

or

Or, together with R ⁶ is connected

Lt; / RTI >

R ⁶ is a member when M is N and is -H when M is C, straight or branched C _1-5 alkoxy, halogen, -OH, or straight or branched chain unsubstituted or substituted with one or more halogens _{Lt; /} RTI > alkyl, and

R ⁷ and R ⁸ are independently -H, or a linear or branched C _1-5 alkoxy.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1) (step 2) ≪ / RTI >

[Reaction Scheme 1]

In the above Reaction Scheme 1,

, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, Z¹, Z², Z³, E, G 및 M은 독립적으로 상기 화학식 1에서 정의한 바와 같다.

, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z ¹ , Z ² , Z ³ , And M are independently as defined in the above formula (1).

The present invention also relates to a pharmaceutical composition for preventing or treating brain damage caused by ischemia comprising the compound represented by the formula (1), an optical isomer thereof or a pharmaceutically acceptable salt thereof as an active ingredient, and a method for preventing or treating multiple sclerosis A pharmaceutical composition is provided.

Furthermore, the present invention relates to a method for preventing or ameliorating health food and multiple sclerosis for preventing or ameliorating brain damage due to ischemia, which comprises the compound represented by the above-mentioned formula (1), its optical isomer and its pharmaceutically acceptable salt as an active ingredient Provide health food.

The novel homoisoflavanone compound according to the present invention reduces the extent of brain damage caused by ischemia, reduces neurodegeneration and increases the expression of NGF that promotes regeneration of neurons, thereby preventing or treating brain damage due to ischemia There is an effect that it can be used as a pharmaceutical composition and can be used as a pharmaceutical composition for the prevention or treatment of multiple sclerosis.

Figure 1 shows that treatment of Example 21 (SH-88) with M / R resulted in a reduction in cerebral infarcted areas compared to the control.
Figure 2 shows that treatment of Example 21 (SH-88) with M / R resulted in a lower cerebral infarct volume percentage compared to the control and a reduction in neurological sequelae.
FIG. 3 shows that when Example 1 (SH-66) was treated with M / R, the cerebral infarct area was reduced as compared with the control group.
Figure 4 shows that treatment of Example 1 (SH-66) with M / R resulted in a lower percentage of cerebral infarct volume compared to the control group and a decrease in neurological sequelae.
Figure 5 shows that treatment of Example 19 (HJ-16) with M / R resulted in a reduction in cerebral infarcted areas compared to the control.
Figure 6 shows that treatment of Example 19 (HJ-16) with M / R resulted in a decrease in cerebral infarct volume percent compared to the control and a decrease in neurological sequelae.
Figure 7 shows that treatment of Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) resulted in a decrease in cerebral infarct volume percentage and a decrease in neurological sequelae .
8 is a photograph of brain cell death in a brain tissue slice through FJB staining.
FIG. 9 shows the results of treatment of Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) in M / R, The results are shown in Fig.
FIG. 10 shows the results of treatment of Example 21 (SH-88), Example 1 (SH-66) and Example 19 (HJ-16) in M / R, And the decrease in cell activity was observed at 1 dpi.
FIG. 11 shows the results of treatment of Example 21 (SH-88), Example 1 (SH-66) and Example 19 (HJ-16) in M / R, The results are shown in FIG.
12 shows the results of treatment of Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) in M / R, And the decrease in cell activity was observed in 3 dpi units.
FIG. 13 shows that the treatment of Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) in M / R resulted in inhibition of proliferation of microglia It shows.
14 compares the inhibition of microbial cell proliferation compared to the control group in Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) .
FIG. 15 shows that the treatment of LPS with the compound of Example 1 (SH-66) inhibited the production of Nitrite compared with the treatment with LPS alone and the treatment with L-NMMA.
FIG. 16 shows that treatment of LPS with the compound of Example 1 (SH-66) inhibited the production of Nitrite compared to that of LPS alone treatment and LPS treatment with 6-shogaol .
Figure 17 shows that LPS treated with Example 1 (SH-66) increased cell survival compared to LPS-treated and L-NMMA treated.
Figure 18 shows the expression of iNOS, COX-2, and TNF- [alpha] by treatment of Example 1 (SH-66) with LPS (0.1 [mu] g / ml) compared to the control and LPS .
Figure 19 shows that LPS treated with the Example 1 (SH-66) compound reduced PGE2 compared with LPS alone treatment and L-NMMA treatment.
Figure 20 shows that treatment of LPS with Example 1 (SH-66) resulted in reduction of IL-6 compared with LPS alone treatment and L-NMMA treatment.
Figure 21 shows that treatment of LPS with Example 1 (SH-66) resulted in a reduction of TNF-a compared with LPS alone treatment and L-NMMA treatment.
22 shows the results of comparing the reduction of nitrite by treating the compound of Example 1 (SH-66) with LPS (TLR 4 agonist), Pam (TLR 1,2 agonist) and poly (TLR 3 agonist) SH-66) compounds are nonspecific in the type of TLRs (tall-like analogues in innate immunity).
Figure 23 compares the expression of MAPKs in the control and LPS alone treated and in Example 1 (SH-66) treated with LPS.
Figure 24 compares AP-1 expression of control and LPS treated alone versus LPS treated with Example 1 (SH-66) compound.
Figure 25 shows that treatment of LPS with Example 1 (SH-66) increased the survival of N2a cells compared to LPS alone.
FIG. 26 shows the protective effects of Bax, Bcl2, Cleaved caspase 3 and Tublin compared to LPS alone treatment of LPS with Example 1 (SH-66) compound.
FIG. 27 shows COX2, INOS, and tubulin observed when LPS (2.5 μg / ml) was treated with the compound of Example 1 (SH-66) and LPS alone.
FIG. 28 shows TLR4, Ninjurin1, and Tubulin observed in comparison with the treatment of Example 1 (SH-66) with LPS (2.5 μg / ml) and LPS alone treatment.
FIG. 29 shows Ninjurin 1, P53, TNF-α, and Tubulin observed in comparison with LPS alone (2.5 μg / ml) treated with Example 1 (SH-66) and LPS alone.
FIG. 30 is a comparison of the cell survival of N2a cells on the control group in the control and RA (retinoic acid) -treated and Example 1 (SH-66) treated groups.
Figure 31 compares the neurite length of N2a cells treated with control and RA (Retinoic acid) treated and with Example 1 (SH-66) treated.
FIG. 32 is a graph showing the changes in the number of N2a cells (control), 10 mu m of retinoic acid (RA), 20 mu m of shogaol, 20 mu m of NMMA and 1 mu m, 5 mu m, 10 mu m, And the neurite length was observed with the passage of time.
FIG. 33 shows the results of the measurement of the nerve fibers in the control, RA (retinoic acid) 10 .mu.m, shogaol 20 .mu.m, NMMA 20 .mu.m, Example 1 (SH-66) compounds 1 .mu.m, 5 .mu.m, 10 .mu.m and 20 .mu.m The length of the projection is observed.
Figure 34 compares the cell survival of 6-shogaol treated C6 cells with the control and LPS treated Example 1 (SH-66) compound.
FIG. 35 compares the production of neural cell growth factors of 6-shogaol-treated C6-cells with the control and LPS treated with Example 21 (SH-88).
Figure 36 shows that treatment of Example 21 (SH-88) with LPS resulted in a reduction in the production of nitrite compared with LPS alone treatment and L-NMMA treatment of LPS.
Figure 37 shows that the cell viability was increased compared with LPS-treated LPS and L-NMMA treated LPS treated with LPS (Example 21 (SH-88)) on the basis of LPS treatment .
FIG. 38 shows INOS, COX-2, and? -Tubulin compared to LPS (100 ng / ml) treated with 5, 10 and 20 占 퐉 of Example 21 (SH-88) It is.
Figure 39 shows that PGE2 was reduced compared to LPS treated with 5, 10 and 20 [mu] m of Example 21 (SH-88), LPS alone treated with LPS and L-NMMA treated with LPS.
Figure 40 shows a decrease in IL-6 compared to LPS treated with 5, 10 and 20 [mu] m of Example 21 (SH-88) and LPS treated with LPS alone and LPS treated with L-NMMA .
Figure 41 shows that TNF-alpha was reduced compared to LPS treated with 5, 10 and 20 [mu] m of Example 21 (SH-88), LPS alone, and L-NMMA treated with LPS .
FIG. 42 shows the results of comparing the reduction of nitrite by treating Example 21 (SH-88) with LPS (TLR 4 agonist), Pam (TLR 1,2 agonist) and poly (TLR 3 agonist) -88) are nonspecific in the type of TLRs (tall analogues in connexin immunity)
Figure 43 shows the effect of Example 21 (SH-88) on MAPK 'S expression.
Figure 44 compares the survival rate of N2a cells treated with LPS alone and LPS with 5, 10 and 20 [mu] m of Example 21 (SH-88), respectively, on the basis of LPS.
Figure 45 shows the results of BAX, BCL-2, Cleaved caspase-3 and tubulin treated with 5, 10 and 20 [mu] m of Example 21 (SH-88) in LPS alone and LPS, respectively.
46 shows the cell survival rate of N2a cells treated with the control, RA (retinoic acid), and Example 21 (SH-88) treated with 5, 10 and 20 [mu] .
FIG. 47 compares the lengths of neurites of N2a cells treated with the control, RA (retinoic acid), and Example 21 (SH-88) treated with 5, 10 and 20 μm, respectively.
48 shows the results of the addition of a control group, 10 μM RA (retinoic acid), 20 μM shogaol and 1 μM, 5 μM, 10 μM and 20 μM of Example 21 (SH-88) Observation of neurite length over time.
FIG. 49 shows the distribution of the neurite outgrowth in the control group, retinoic acid (retinoic acid) 10 .mu.m, shogaol 20 .mu.m, NMMA 20 .mu.m, Example 21 (SH-88) 1 .mu.m, 5 .mu.m, 10 .mu.m, Observing the length.
Figure 50 compares the cell survival of 6-shogaol treated C6 cells with control and Example 21 (SH-88).
FIG. 51 compares the percentage of control group with that of control group and Example 21 (SH-88) in C6 cells and the production of neural cell growth factor in 6-shogaol treated groups.
52 shows the EAE test results of Example 21 (SH-88).

Hereinafter, the present invention will be described in detail.

The present invention provides a compound represented by the following general formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof.

[Chemical Formula 1]

In Formula 1,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ¹ , R ² and R ³ are independently -H, -OH, or straight or branched C _1-5 alkoxy,

또는

를 형성하되, 상기

가 이중결합일 경우 Z¹ 및 Z²는 함께 연결되어

를 형성하지 않고,Z ¹ and Z ² are independently -H or -OH, or Z ¹ and Z ² are linked together

or

,

Is a double bond, Z < ^{1 >} and Z < ^{2 >}

. However,

가 이중결합일 경우 부재이고, 상기

가 단일결합일 경우 -H 또는 -CH₂OH이되, 상기

가 단일결합이고 상기 Z¹ 및 Z²가 함께 연결되어

를 형성할 경우 Z³는 부재이고,Z < ^{3 &}

Member is a double bond,

If the work -H single bond or -CH ₂ OH, provided the

Is a single bond and Z < ¹ > and Z < ² &

, Z ³ is a member,

E, G and M are independently C or N,

R ⁴ is a member when E is N and is -H when E is C, C _1-5 alkoxy, straight or branched chain, or halogen, or is connected with R ⁵ to form unsubstituted phenyl,

또는

이거나, R⁶과 함께 연결되어

를 형성하고,R ⁵ is a member when G is N and is -H when G is C, straight or branched C _1-5 alkoxy, halogen, unsubstituted or substituted straight or branched C _1-5 Alkyl, -OH,

or

Or, together with R ⁶ is connected

Lt; / RTI >

R ⁶ is a member when M is N and is -H when M is C, straight or branched C _1-5 alkoxy, halogen, -OH, or straight or branched chain unsubstituted or substituted with one or more halogens _{Lt; /} RTI > alkyl, and

R ⁷ and R ⁸ are independently -H, or a linear or branched C _1-5 alkoxy.

Preferably,

는 단일결합 또는 이중결합이고,

Is a single bond or a double bond,

R ¹ , R ² and R ³ are independently -H, -OH, or a straight or branched C _1-3 alkoxy,

또는

를 형성하되, 상기

가 이중결합일 경우 Z¹ 및 Z²는 함께 연결되어

를 형성하지 않고,Z ¹ and Z ² are independently -H or -OH, or Z ¹ and Z ² are linked together

or

,

Is a double bond, Z < ^{1 >} and Z < ^{2 >}

. However,

가 이중결합일 경우 부재이고, 상기

가 단일결합일 경우 -H 또는 -CH₂OH이되, 상기

가 단일결합이고 상기 Z¹ 및 Z²가 함께 연결되어

를 형성할 경우 Z³는 부재이고,Z < ^{3 &}

Member is a double bond,

If the work -H single bond or -CH ₂ OH, provided the

Is a single bond and Z < ¹ > and Z < ² &

, Z ³ is a member,

E, G and M are independently C or N,

R ⁴ is a member when E is N and is -H when E is C, C _1-3 alkoxy, straight or branched chain, or halogen, or is connected with R ⁵ to form unsubstituted phenyl,

또는

이거나, R⁶과 함께 연결되어

를 형성하고,R ⁵ is a member when G is N and is -H when G is C, straight or branched C _1-3 alkoxy, halogen, unsubstituted or straight-chain or branched C _1-4 Alkyl, -OH,

or

Or, together with R ⁶ is connected

Lt; / RTI >

R ⁶ is a member when M is N and is -H when M is C, straight or branched C _1-3 alkoxy, halogen, -OH, or straight or branched chain unsubstituted or substituted with one or more halogens C _1-4 alkyl; And

R ⁷ and R ⁸ are independently -H, or a linear or branched C _1-3 alkoxy.

More preferably,

는

,

,

,

,

,

,

,

또는

이되,

The

,

,

,

,

,

,

,

or

However,

가

또는

일 경우,

는 단일결합이다.remind

end

or

If it is,

Is a single bond.

Most preferably,

The compound represented by the formula (1) is any one selected from the following group of compounds.

(1) (E) -3- (3-hydroxy-4-methoxybenzylidene) -5,7-dimethoxychroman-4-one;

(2) (E) -3- (4-hydroxy-3-methoxybenzylidene) -5,7-dimethoxychroman-4-one;

(3) (E) -3-Benzylidene-5,7-dimethoxychroman-4-one;

(4) (E) -3- (4-tert-Butylbenzylidene) -5,7-dimethoxychroman-4-one;

(5) (E) -5,7-Dimethoxy-3- (4-methoxybenzylidene) chroman-4-one;

(6) (E) -3- (4-Chloro-3- (trifluoromethyl) benzylidene) -5,7-dimethoxychroman-4-one;

(7) (E) -3- (Benzo [d] [1,3] dioxol-5-ylmethylene) -5,7-dimethoxychroman-4-one;

(8) (E) -5,7-Dimethoxy-3- (naphthalen-1-ylmethylene) chroman-4-one;

(9) (E) -5,7-Dimethoxy-3- (3,4,5-trimethoxybenzylidene) chroman-4-one;

(10) (E) -3- (4-fluorobenzylidene) -5,7-dimethoxychroman-4-one;

(11) (E) -3- (4-hydroxybenzylidene) -5,7-dimethoxychroman-4-one;

(12) (E) -3- (3-Fluorobenzylidene) -5,7-dimethoxychroman-4-one;

(13) (E) -5,7-Dimethoxy-3 - ((6-methoxypyridin-2-yl) methylene) chroman-4-one;

(14) (E) -3- (4-Chloro-3-fluorobenzylidene) -5,7-dimethoxychroman-4-one;

(15) (E) -3- (3,4-dimethoxybenzylidene) -5,7-dimethoxychroman-4-one;

(16) (E) -3- (4-Bromo-2-fluorobenzylidene) -5,7-dimethoxychroman-4-one;

(17) (E) -5,7-Dimethoxy-3- (2,4,6-trimethoxybenzylidene) chroman-4-one;

(18) (E) -5,7-Dimethoxy-3- (pyridin-2-ylmethylene) chroman-4-one;

(19) (E) -5,7-Dimethoxy-3- (pyridin-3-ylmethylene) chroman-4-one;

(20) (E) -5,7-Dimethoxy-3- (pyridin-4-ylmethylene) chroman-4-one;

(21) 3- (3-hydroxy-4-methoxybenzyl) -5,7-dimethoxychroman-4-one;

(22) 3- (4-hydroxy-3-methoxybenzyl) -5,7-dimethoxychroman-4-one;

(23) 3-benzyl-5,7-dimethoxychroman-4-one;

(24) 3- (4-tert-Butylbenzyl) -5,7-dimethoxychroman-4-one;

(25) 5,7-Dimethoxy-3- (4-methoxybenzyl) chroman-4-one;

(26) 3- (4-Chloro-3- (trifluoromethyl) benzyl) -5,7-dimethoxychroman-4-one);

(27) 3- (Benzo [d] [1,3] dioxol-5-ylmethyl) -5,7-dimethoxychroman-4-one;

(28) 5,7-Dimethoxy-3- (naphthalen-1-ylmethyl) chroman-4-one;

(29) 5,7-Dimethoxy-3- (3,4,5-trimethoxybenzyl) chroman-4-one;

(30) 3- (4-fluorobenzyl) -5,7-dimethoxychroman-4-one;

(31) 3- (4-hydroxybenzyl) -5,7-dimethoxychroman-4-one;

(32) 3- (3-fluorobenzyl) -5,7-dimethoxychroman-4-one;

(33) 5,7-Dimethoxy-3 - ((6-methoxypyridin-2-yl) methyl) chroman-4-one;

(34) 3- (4-Chloro-3-fluorobenzyl) -5,7-dimethoxychroman-4-one;

(35) 3- (3,4-dimethoxybenzyl) -5,7-dimethoxychroman-4-one;

(36) 3- (4-Bromo-2-fluorobenzyl) -5,7-dimethoxychroman-4-one;

(37) 5,7-Dimethoxy-3- (2,4,6-trimethoxybenzyl) chroman-4-one;

(38) 5,7-Dimethoxy-3- (pyridin-2-ylmethyl) chroman-4-one;

(39) 5,7-Dimethoxy-3- (pyridin-3-ylmethyl) chroman-4-one;

(40) 5,7-Dimethoxy-3- (pyridin-4-ylmethyl) chroman-4-one;

(41) (E) -3- (3-hydroxy-4-methoxybenzylidene) -5,6,7-trimethoxychroman-4-one;

(42) 3- (3-hydroxy-4-methoxybenzyl) -5,6,7-trimethoxy-4H-chromen-4-one;

(43) Synthesis of (E) -3- (3- (benzyloxy) -4-methoxyphenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) prop- 1-one;

(44) 3- (3-hydroxy-4-methoxybenzyl) -5,6,7-trimethoxychroman-4-one;

(45) 3-benzyl-5,6,7-trimethoxychroman-4-one;

(46) 3-Benzyl-5-hydroxy-6,7-dimethoxychroman-4-one;

(47) 5 - ((5,7-dihydroxy-6-methoxy-4-oxochroman-3-yl) methyl) -2-methoxyphenyl benzoate;

(48) 5,7-Dihydroxy-3- (3-hydroxy-4-methoxybenzyl) -3- (hydroxymethyl) -6-methoxychroman-4-one;

(49) 1- (6-Hydroxy-2,3,4-trimethoxyphenyl) -3- (3-hydroxy-4-methoxyphenyl) propan-1-one;

(50) 3- (3,4-dimethoxyphenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) propan-1-one; And

(51) 1- (6-Hydroxy-2,3,4-trimethoxyphenyl) -3-phenylpropan-1-one.

The compound represented by the formula (1) of the present invention can be used in the form of a pharmaceutically acceptable salt, and as the salt, an acid addition salt formed by a pharmaceutically acceptable free acid is useful. Acid addition salts include those derived from inorganic acids such as hydrochloric acid, nitric acid, phosphoric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, nitrous acid, phosphorous acid and the like, aliphatic mono- and dicarboxylates, phenyl-substituted alkanoates, Derived from organic acids such as acetic acid, benzoic acid, citric acid, lactic acid, maleic acid, gluconic acid, methanesulfonic acid, 4-toluenesulfonic acid, tartaric acid, fumaric acid and the like. Examples of such pharmaceutically innocuous salts include, but are not limited to, sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, nitrate, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate chloride, bromide, But are not limited to, but are not limited to, but are not limited to, but are not limited to, but are not limited to, halides, halides, halides, halides, halides, halides, But are not limited to, lactose, sebacate, fumarate, maleate, butyne-1,4-dioate, hexane-1,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, Methoxybenzoate, phthalate, terephthalate, benzene sulfonate, toluene sulfonate, chloro Such as benzenesulfonate, benzenesulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate,? -Hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1-sulfonate, naphthalene-2-sulfonate, mandelate and the like.

The acid addition salt according to the present invention can be prepared by a conventional method, for example, by dissolving the derivative of Chemical Formula 1 in an organic solvent such as methanol, ethanol, acetone, dichloromethane, acetonitrile and the like, Followed by filtration and drying, or by distillation of the solvent and excess acid under reduced pressure, followed by drying and crystallization in an organic solvent.

In addition, bases can be used to make pharmaceutically acceptable metal salts. The alkali metal or alkaline earth metal salt is obtained, for example, by dissolving the compound in an excess amount of an alkali metal hydroxide or an alkaline earth metal hydroxide solution, filtering the insoluble compound salt, and evaporating and drying the filtrate. At this time, it is preferable for the metal salt to produce sodium, potassium or calcium salt. In addition, the corresponding salt is obtained by reacting an alkali metal or alkaline earth metal salt with a suitable salt (such as silver nitrate).

Furthermore, the present invention includes all the solvates, stereoisomers, hydrates, and the like, which can be prepared therefrom, as well as the compound represented by Formula 1 and pharmaceutically acceptable salts thereof.

The present invention also relates to a process for producing a compound represented by the formula (1)

Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And

Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1) (step 2) ≪ / RTI >

[Reaction Scheme 1]

In the above Reaction Scheme 1,

, R¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, Z¹, Z², Z³, E, G 및 M은 독립적으로 상기 화학식 1에서 정의한 바와 같다.

, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z ¹ , Z ² , Z ³ , And M are independently as defined in the above formula (1).

Hereinafter, a method for preparing the compound represented by Formula 1 according to the present invention will be described in detail.

In the process for preparing the compound represented by the formula (1) according to the present invention, the step (1) is a step of reacting the compound represented by the formula (2) with the compound represented by the formula (3) to prepare the compound represented by the formula (4).

The compound represented by Formula 2 is dissolved in toluene, and the compound represented by Formula 3 is added thereto. The compound is reacted under reflux conditions for 15 hours. If all the starting materials disappeared, the reaction mixture was cooled to 0 ° C and conc.HCl was added, followed by stirring at 50 ° C for 5 hours.

Alternatively, after the above-mentioned stirring, the compound is dissolved in anhydrous methanol, Pd / C is added in an amount of 10 mol%, and the hydrogenation reaction is carried out to prepare a compound represented by the formula (4).

In the process for preparing the compound represented by the formula (1) according to the present invention, the step (2) may be carried out by reacting the compound represented by the formula (4) prepared in the step 1 with the compound represented by the formula (5) .

The compound represented by the general formula (4) can be produced by subjecting the compound represented by the general formula (4) to an aldol condensation reaction with the compound represented by the general formula (5).

Furthermore, the present invention provides a pharmaceutical composition for preventing or treating brain damage caused by ischemia, which comprises the compound represented by the above-mentioned formula (1), its optical isomer or a pharmaceutically acceptable salt thereof as an active ingredient. Here, the cerebral damage due to the ischemia is cerebral infarction, occlusion and stenosis of cerebral artery, occlusion and stenosis of the cerebral artery, and cerebral hemorrhage.

The present invention also provides a pharmaceutical composition for preventing or treating multiple sclerosis comprising the compound represented by the formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

In the pharmaceutical composition according to the present invention, the compound represented by the formula (1), or a pharmaceutically acceptable salt thereof, can be administered in various forms of oral and parenteral administration at the time of clinical administration. Such as fillers, extenders, binders, wetting agents, disintegrants, surfactants, and the like.

Examples of formulations for oral administration include tablets, pills, light / soft capsules, liquids, suspensions, emulsions, syrups, granules, elixirs and troches, , Dextrose, sucrose, mannitol, sorbitol, cellulose and / or glycine), lubricants (such as silica, talc, stearic acid and its magnesium or calcium salts and / or polyethylene glycols). The tablets may contain binders such as magnesium aluminum silicate, starch paste, gelatin, methylcellulose, sodium carboxymethylcellulose and / or polyvinylpyrrolidine and may optionally contain binders such as starch, agar, alginic acid or sodium salts thereof Release or boiling mixture and / or absorbent, colorant, flavor, and sweetening agent.

The pharmaceutical composition containing the compound represented by the formula (1) as an active ingredient may be administered parenterally, and the parenteral administration may be by subcutaneous injection, intravenous injection, intramuscular injection, or intrathoracic injection.

In this case, in order to formulate the composition for parenteral administration, the compound represented by the formula (1) or a pharmaceutically acceptable salt thereof may be mixed with water or a stabilizer or a buffer to prepare a solution or suspension, . The compositions may contain sterilized and / or preservatives, stabilizers, wettable or emulsifying accelerators, adjuvants such as salts and / or buffers for the control of osmotic pressure, and other therapeutically useful substances, Or may be formulated according to the coating method.

Furthermore, the dose of the compound of the present invention represented by the formula (1) or a pharmaceutically acceptable salt thereof in the human body may vary depending on the patient's age, weight, sex, dosage form, health condition and disease severity, The dose is usually 0.1-1000 mg / day, preferably 1-500 mg / day, based on an adult patient of 70 Kg, and may be once or twice a day at certain intervals according to the judgment of a doctor or pharmacist It may be administered in divided doses.

The present invention provides a health food for preventing or ameliorating brain damage due to ischemia comprising the compound represented by the above-mentioned formula (1), its optical isomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

Also provided is a health food for preventing or ameliorating multiple sclerosis comprising the compound represented by the above-mentioned formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

It is supported by the following experimental examples that the compound of Example 1-51, which is a homoisoflavanone derivative compound according to the present invention, can be used as a pharmaceutical composition for preventing or treating brain damage and multiple sclerosis.

Hereinafter, the present invention will be described in detail with reference to Examples and Experimental Examples.

However, the following examples and experimental examples are illustrative of the present invention, and the present invention is not limited by the following examples and experimental examples.

< Example  1 (E) -3- (3 &apos; - Hydroxy -4'- Methoxybenzylidene ) -5,7- Dimethoxychroman (13a, SH-66) &lt; RTI ID = 0.0 &gt;

step 1: 5 , 7- Dimethoxy -4H- Kromen -4-one

After dissolving 1- (2-hydroxy-4,6-dimethoxyphenyl) ethanone in toluene, (CH ₃ ) ₂ NCH (OCH ₃ ) ₂ was added and reacted for 15 hours under reflux conditions. When all of the starting material disappeared, the mixture was cooled to 0 ° C and conc. HCl was added followed by stirring at 50 &lt; 0 &gt; C for 5 hours to give the title compound.

step 2: 5 , 7- Dimethoxychroman -4-one

The 5,7-dimethoxy-4H-chromen-4-one prepared in the above step 1 was dissolved in anhydrous methanol, Pd / C was added in an amount of 10 mol%, and hydrogenation was carried out to prepare the title compound Respectively.

Step 3: (E) -3- (3'- Hydroxy -4'- Methoxybenzylidene ) -5,7- Dimethoxychroman -4-one

(71 mg, 0.34 mmol), 3-hydroxy-4-methoxybenzaldehyde (62 mg, 0.041 mmol) and para-toluenesulfonic acid (7 mg , 0.03 mmol) were dissolved in benzene (2 ml) at 0 ° C and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (72 mg, 62% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.72 (s, 1H), 6.89-6.87 (m, 2H), 6.83 (d, 1H, J = 8.4Hz), 6.11 (s, 1H), 6.06 (s , 5.23 (s, 2H), 3.93 (s, 3H), 3.90 (s, 3H), 3.82 (s, 3H);

¹³ C-NMR (150 MHz, CDCl ₃ ) δ 179.5, 165.6, 164.6, 162.7, 147.4, 145.5, 135.7, 130.5, 128.3, 123.0, 115.8, 110.5, 107.3, 9305, 93.5, 67.6, 56.1, 56.0, 55.5;

HRMS (EI): mass calcd for C19H18O6 [M +], 342.1103; found, 342.1101.

< Example  2 >. (E) -3- (4- Hydroxy -3- Methoxybenzylidene ) -5,7- Dimethoxychroman -4-one (13b, SH-90)

3-methoxybenzaldehyde (27 mg, 0.173 mmol) and para-toluenesulfonic acid (3 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- Was dissolved in benzene (2 mL) at 0 ° C and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (31 mg, 63% .

¹ H-NMR (600 MHz, CDCl ₃ )? 7.74 (s, 1H), 6.96-6.95 (m, 2H), 6.83 (d, (D, 2H, J = 1.8 Hz), 6.13 (d, 2H, J = 2.4 Hz), 6.07 , &Lt; / RTI &gt; 3H), 3.83 (s, 3H).

< Example  3> (E) -3- Benzylidene -5,7- Dimethoxychroman (13c, &lt; RTI ID = 0.0 &gt; SH -92)

Benzene (2 mL) was added to a solution of 5,7-dimethoxychroman-4-one (30 mg, 0.144 mmol), benzaldehyde (15 mg, 0.144 mmol) and para- toluenesulfonic acid (3 mg, 0.014 mmol) And reacted for 12 hours under reflux conditions. After lowering the temperature to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (17 mg, 35% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.79 (s, 1H), 7.40-7.38 (m, 2H), 7.35-7.33 (m, 2H), 7.25 (d, 2H, J = 8.4 hz), 6.10 (d, 2H, J = 1.8 Hz), 6.07 (d, 1H, J = 2.4 Hz), 5.19 (d, 2H, J = 1.8 Hz), 3.89 (s, 3H), 3.80 ¹³ C-NMR (150 MHz, CDCl ₃ )? 179.5, 165.8, 164.7, 162.8, 135.9, 134.8, 131.9, 129.7, 128.9, 128.6, 107.2, 93.6, 67.4, 56.1, 55.6.

< Example  4 >. (E) -3- (4- Rat - Butyl benzylidene ) -5,7- Dimethoxychroman One (13d, &lt; RTI ID = 0.0 &gt; HJ -006)

Tert-butylbenzaldehyde (36 μL, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- Was dissolved in benzene (2 ml) and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (29 mg, 56% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.80 (s, 1H), 7.45-7.43 (m, 2H), 7.23 (d, 2H, J = 8.4Hz), 6.12 (d, 2H, J = 2.4Hz ), 6.07 (d, 1H, J = 2.4Hz), 5.24 (d, 2H, J = 2.4Hz), 3.91 (s, 3H), 3.82 (s, 3H), 1.34 (s, 9H).

< Example  5> (E) -5,7- Dimethoxy -3- (4- Methoxybenzylidene ) Croix One (13e, &lt; RTI ID = 0.0 &gt; HJ -003)

4-methoxybenzaldehyde (26 μL, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- Benzene (2 ml) and reacted under reflux conditions for 12 hours. After lowering the temperature to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (26 mg, 55% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.24 (d, 2H, J = 8.4Hz), 6.94 (d, 2H, J = 9.0Hz), 6.11 (d, 1H, J = 1.8Hz), 6.06 ( (d, 1H, J = 2.4Hz), 5.23 (d, 2H, J = 1.8Hz), 3.90 (s, 3H), 3.84 (s, 3H), 3.82

< Example  6 >. (E) -3- (4- Chloro -3- ( Trifluoromethyl ) Benzylidene ) -5,7- Dimethoxychroman (13f, &lt; RTI ID = 0.0 &gt; HJ -010)

4-chloro-3-trifluoromethylbenzaldehyde (45 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- mmol) were dissolved in benzene (2 ml) at 0 ° C and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (23 mg, 40% .

¹ H-NMR (600 MHz, CDCl ₃ )? 7.72 (s, 1H), 7.57-7.55 (m, 2H), 7.37 (dd, 1H, J = 8.4 and 6.6Hz) (D, 2H, J = 1.8 Hz), 3.92 (s, 3H), 3.83 (s, 3H).

< Example  7> (E) -3- ( Benzo [d] [1,3] dioxole -5- Ylmethylene ) -5,7- Dimethoxychroman One (13 g, HJ -007)

(32 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman-4-one (30 mg, 0.144 mmol) 2 ml) and reacted for 12 hours under reflux conditions. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (26 mg, 54% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.71 (s, 1H), 6.87 (d, 2H, J = 7.8Hz), 6.79-6.78 (m, 1H), 6.76 (d, 1H, J = 1.8Hz 2H), 6.21 (d, 1H, J = 2.4 Hz), 6.07 (d, ), 3.83 (s, 3H).

< Example  8> (E) -5,7- Dimethoxy -3- (naphthalene-1- Ylmethylene ) Croix One (13h, &lt; RTI ID = 0.0 &gt; HJ -005)

(29 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman-4-one (30 mg, 0.144 mmol) (2 ml) and allowed to react for 12 hours under reflux conditions. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (38 mg, 77% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.98 (d, 1H, J = 3.6Hz), 7.97 (m, 1H), 7.89-7.87 (m, 2H), 7.54-7.53 (m, 2H), 7.49 1H, J = 2.4 Hz), 5.09 (d, 1H, J = 15.6 and 7.2 Hz), 7.19 (d, 2H, J = 1.8 Hz), 3.95 (s, 3H), 3.82 (s, 3H).

< Example  9> (E) -5,7- Dimethoxy -3- (3,4,5- Trimethoxybenzylidene ) Croix One (13i, &lt; RTI ID = 0.0 &gt; HJ -004)

(43 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman-4-one (30 mg, 0.144 mmol) Was dissolved in benzene (2 ml) at 0 ° C and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (32 mg, 58% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.73 (s, 1H), 6.48 (s, 1H), 6.13-6.12 (d, 2H, J = 2.4Hz), 6.07-6.06 (d, 1H, J = (S, 3H), 3.88 (s, 3H), 3.88 (s, 6H), 3.83 (s, 3H).

< Example  10 (E) -3- (4- Fluorobenzylidene ) -5,7- Dimethoxychroman One (13j, &lt; RTI ID = 0.0 &gt; HJ -001)

4-Fluorobenzaldehyde (23 μL, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- Benzene (2 ml) and reacted under reflux conditions for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (72 mg, 62% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.75 (s, 1H), 7.26-7.24 (m, 2H), 7.12-7.09 (t, 2H, J = 8.4Hz), 6.12-6.11 (d, 1H, J = 1.8Hz), 6.06 (d, 1H, J = 2.4Hz), 5.18-5.17 (d, 2H, J = 1.2Hz), 3.91 (s, 3H), 3.82 (s, 3H).

< Example  11 >. (E) -3- (4- Hydroxybenzylidene ) -5,7- Dimethoxychroman One (13k, &lt; RTI ID = 0.0 &gt; HJ -002)

4-Hydroxybenzaldehyde (26.4 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- Benzene (2 ml) and reacted under reflux conditions for 12 hours. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (15 mg, 33% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.77 (s, 1H), 7.19-7.18 (d, 2H, J = 8.4Hz), 6.93-6.91 (d, 2H, J = 8.4Hz), 6.12-6.11 (d, 2H, J = 2.4 Hz), 6.07 (d, 2H, J = 2.4 Hz), 5.24-5.23 .

< Example  12> (E) -3- (3- Fluorobenzylidene ) -5,7- Dimethoxychroman One (13 l, HJ-008)

3-Fluorobenzaldehyde (23 μL, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- Benzene (2 ml) and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (21 mg, 47% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.74 (s, 1H), 7.40-7.37 (m, 1H), 7.09-7.04 (m, 2H), 6.98 (dd, 1H, J = 9.6 and 1.8Hz) , 5.13 (d, 2H, J = 1.8 Hz), 3.91 (s, 3H), 3.82 (s, 3H) .

< Example  (E) -5,7- Dimethoxy -3 - ((6- Methoxypyridine Yl) methylene) Croix One (13m, &lt; RTI ID = 0.0 &gt; HJ -009)

(26 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman-4-one Benzene (2 ml) and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (20 mg, 47% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.61 (dd, 1H, J = 8.4 and 7.2Hz), 7.57 (t, 1H, 1.8Hz), 7.11 (d, 1H, J = 1.2Hz), 6.71 ( (d, 1H, J = 7.8 Hz), 6.12 (d, 1H, J = 2.4 Hz), 6.09 3H), 3.91 (s, 3H), 3.84 (s, 3H).

< Example  14> (E) -3- (4- Chloro -3- Fluorobenzylidene ) -5,7- Dimethoxychroman One (13n, &lt; RTI ID = 0.0 &gt; HJ -011)

Chloro-3-fluorobenzaldehyde (34 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) were added to a solution of 5,7-dimethoxychroman- The solution was dissolved in benzene (2 ml) at 0 ° C and reacted under reflux conditions for 12 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (23 mg, 40% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.68 (s, 1H), 7.45 (t, 1H, J = 7.8Hz), 7.06 (dd, 1H, J = 9.6 and 1.8Hz), 7.00-6.99 (m , 5.13 (d, 2H, J = 1.8 Hz), 3.91 (s, 3H), 3.83 (s, 1H), 6.13 , 3H).

< Example  15 (E) -3- (3,4- Dimethoxybenzylidene ) -5,7- Dimethoxychroman One (13o, HJ-012)

(50 mg, 0.240 mmol), 3,4-dimethoxybenzaldehyde (60 mg, 0.360 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) (2 ml) and reacted under reflux condition for 12 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (49 mg, 57% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.75 (s, 1H), 6.91 (d, 1H, J = 9.0Hz), 6.84 (t, 2H, J = 4.2Hz), 6.12 (d, 1H, J 2H), 3.92 (s, 3H), 3.91 (s, 3H), 3.90 (s, 3H) 3.82 (s, 3 H).

< Example  (E) -3- (4- Bromo -2- Fluorobenzylidene ) -5,7- Dimethoxychroman (13p, HJ-015) &lt; RTI ID = 0.0 &gt;

(30 mg, 0.144 mmol), 4-bromo-2-fluorobenzaldehyde (35.7 mg, 0.216 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol ) Was dissolved in benzene (2 ml) at 0 ° C and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (18 mg, 32% Respectively.

¹ H-NMR (600 MHz, CDCl ₃ )? 7.66 (s, 1H), 7.34-7.31 (m, 2H), 7.06 ), 6.06 (d, IH, J = 2.4 Hz), 5.00 (s, 2H), 3.91 (s, 3H), 3.82 (s, 3H).

< Example  17> (E) -5,7- Dimethoxy -3- (2,4,6- Trimethoxybenzylidene ) Croix -4-one (13q, HJ-014)

(30mg, 0.144mmol), 2,4,6-trimethoxybenzaldehyde (34.2mg, 0.216mmol) and para-toluenesulfonic acid (5mg, 0.02mmol) were added to a solution of 5,7-dimethoxychroman- ) Was dissolved in benzene (2 ml) at 0 ° C and reacted under reflux conditions for 12 hours. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (33 mg, 59% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.64 (s, 1H), 6.13 (s, 2H), 6.09 (d, 1H, J = 1.8Hz), 6.03 (d, 1H, J = 2.4Hz), (D, 2H, J = 0.6 Hz), 3.89 (s, 3H), 3.84 (s, 3H), 3.80 (s, 3H), 3.77

< Example  18 (E) -5,7- Dimethoxy -3- (pyridin-2- Ylmethylene ) Croix (13r, HJ-013) &lt; RTI ID = 0.0 &gt;

(50 mg, 0.240 mmol), 2-pyridinecarboxaldehyde (34 μL, 0.360 mmol) and para-toluenesulfonic acid (5 mg, 0.02 mmol) Was dissolved in benzene (2 ml) and reacted under reflux conditions for 12 hours. After the reaction mixture was cooled to room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (32 mg, 45% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.66 (dd, 1H, J = 4.2 and 0.6Hz), 7.71-7.68 (m, 1H), 7.63 (t, 1H, J = 1.8Hz), 7.46 (d 2H, J = 7.8 Hz), 7.90-7.18 (m, 1H), 6.09 (dd, 2H, J = 10.2 and 2.4 Hz), 5.75 , &Lt; / RTI &gt; 3.82 (s, 3H).

< Example  (E) -5,7- Dimethoxy -3- (pyridin-3- Ylmethylene ) Croix -4-one (13s, HJ-016)

(15 mg, 0.116 mmol) and 3-pyridinecarboxaldehyde (16 μL, 0.216 mmol) were dissolved in ethanol (3 mL), and a 5% aqueous NaOH solution (0.15 ml) Was added at 0 &lt; 0 &gt; C. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (ethyl acetate: n-hexane = 1: 1) on silica gel to give the title compound (26 mg, 61% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.61 (dd, 2H, J = 4.8 and 1.8Hz), 8.54 (d, 1H, J = 2.4Hz), 7.75 (s, 1H), 7.62-7.60 (m J = 2.4 Hz), 5.19 (d, 2H, J = 2.4 Hz), 7.38 (dd, 1H, J = 7.8 and 4.8 Hz), 6.14 1.8 Hz), 3.92 (s, 3H), 3.84 (s, 3H).

< Example  (E) -5,7- Dimethoxy -3- (pyridin-4- Ylmethylene ) Croix One (13t, &lt; RTI ID = 0.0 &gt; HJ -017)

4-pyridinecarboxaldehyde (16 μL, 0.216 mmol) was dissolved in ethanol (3 mL), and a 5% aqueous solution of NaOH (0.15 ml) Was added at 0 &lt; 0 &gt; C. After reaction for 1 hour at room temperature, the reaction mixture was concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 1) to give the title compound (23 mg, 53% .

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.68 (d, 2H, J = 6.0Hz), 7.69 (s, 1H), 7.15 (d, 2H, J = 5.4Hz), 6.14 (d, 1H, J = 2.4 Hz), 6.08 (d, IH, J = 2.4 Hz), 5.16 (d, 2H, J = 1.8 Hz), 3.92 (s, 3H), 3.84 (s,

< Example  21> 3- (3'- Hydroxy -4'-methoxybenzyl) -5,7- Dimethoxychroman (14a, &lt; RTI ID = 0.0 &gt; SH -88)

(E) -3- (3-hydroxy-4-methoxybenzylidene) -5,7-dimethoxychroman-4-one (12 mg, 0.04 mmol) prepared in Example 1 was dissolved in anhydrous After dissolving in methanol, 10% Pd / C (4 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (10 mg, 73%).

^{1 H-NMR (600 MHz,} CDCl3) δ 6.81-6.77 (m, 2H), 6.71 (d, 1H, J = 8.4 Hz), 6.06 (d, 1H, J = 8.4 Hz), 5.58 (s, 1H) , 4.27 (dd, 1H, J = 11.4 and 4.2 Hz), 4.10 (dd, 1H, J = 10.8 and 7.2 Hz), 3.88 (s, 3H), 3.87 3.19 (dd, 1H, J = 13.8 and 4.2 Hz), 2.75-2.72 (m, 1H), 2.58 (t, 1H, J = 12.6 Hz);

¹³ C-NMR (150 MHz, CDCl ₃ ) δ 191.3, 165.7, 164.9, 162.5, 145.6, 145.2, 131.9, 120.6, 115.2, 110.7, 105.4, 93.1, 92.9, 68.9, 56.1, 56.0, 55.5, 48.4, 32.2;

HRMS (EI): mass calcd for C19H20O6 [M +], 344.1260; found, 344.1267.

< Example  22 > 3- (4- Hydroxy -3-methoxybenzyl) -5,7- Dimethoxychroman (14b, &lt; RTI ID = 0.0 &gt; SH -91)

(E) -3- (4-hydroxy-3-methoxybenzylidene) -5,7-dimethoxychroman-4-one (28 mg, 0.083 mmol) prepared in Example 2 was dissolved in anhydrous methanol (4 mL), 10% Pd / C (9 mg, 0.083 mmol) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (16 mg, 57%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.83 (d, 2H, J = 8.4 Hz), 6.72 (m, 1H) 6.71 (m, 1H), 6.05 (dd, 2H, J = 7.8 and 2.4 Hz) , 5.51 (bs, 1H) 4.26-4.23 (dd, 1H, J = 11.4 and 4.2 Hz), 4.10-4.07 (m, 1H), 3.87 (s, ), 3.17 (dd, 1H, J = 13.8 and 4.2 Hz), 2.72-2.68 (m, 1H), 2.61 (dd, 1H, J = 14.4 and 11.4 Hz); ¹³ C-NMR (150 MHz, CDCl ₃ ) δ 191.4, 165.8, 164.9, 162.5, 146.6, 144.2, 130.4, 121.9, 114.3, 111.4, 105.4, 93.2, 93.0, 68.8, 56.1, 55.9, 55.5, 48.7, 32.7.

< Example  23> 3- benzyl -5,7- Dimethoxychroman (14c, &lt; RTI ID = 0.0 &gt; SH -93)

(E) -3-benzylidene-5,7-dimethoxychroman-4-one (10 mg, 0.03 mmol) prepared in Example 3 was dissolved in anhydrous methanol (4 mL) / C (4 mg, 0.003 mmol) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (10 mg, 94%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.30-7.27 (m, 2H), 7.22-7.19 (m, 3H) 6.05 (d, 1H, J = 2.4 hz), 6.04 (d, 1H, J = 2.4 3H), 3.80 (s, 3H), 3.27 (dd, 1H, J = 14.4 and 4.2 Hz), 2.78 (s, -2.74 (m, 1 H), 2.65 (dd, 1 H, J = 13.8 and 10.8 Hz); ¹³ C-NMR (150 MHz, CDCl ₃ ) δ 191.2, 165.7, 164.9, 162.5, 138.7, 129.1, 128.6, 126.4, 105.4, 93.1, 93.0, 68.9, 56.1, 55.5, 48.3, 32.8.

< Example  24 > 3- (4- ( Rat -Butyl) benzyl ) -5,7- Dimethoxychroman -4-one (14d, HJ-023)

(E) -3- (4-tert-butylbenzylidene) -5,7-dimethoxychroman-4-one (25 mg, 0.07 mmol) prepared in Example 4 was dissolved in anhydrous methanol 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (15 mg, 60%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.33 (d, 2H, J = 8.4 Hz), 7.17 (d, 2H, J = 7.8 Hz), 6.07 (dd, 2H, J = 9.0 and 1.8 Hz), J = 11.4 and 7.2 Hz), 3.89 (s, 3H), 3.82 (s, 3H), 3.25 (dd, 13.8 and 4.2 Hz), 2.79-2.74 (m, 1H), 2.64 (dd, 1H, J = 14.4 and 11.4 Hz), 1.30 (s, 9H).

< Example  25> 5,7- Dimethoxy -3- (4-methoxybenzyl) Croix One (14e, &lt; RTI ID = 0.0 &gt; HJ -020)

(E) -5,7-dimethoxy-3- (4-methoxybenzylidene) chroman-4-one (17 mg, 0.05 mmol) prepared in Example 5 was dissolved in anhydrous methanol, % Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (12 mg, 69%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.15 (d, 2H, J = 8.4 Hz), 6.85 (d, 2H, J = 1.8 Hz), 6.07 (dd, 2H, J = 9.6 and 2.4 Hz), 3H), 3.81 (s, 3H), 3.78 (s, 3H), 3.20 (d, 1H, J = (dd, 1H, J = 13.8 and 4.2 Hz), 2.74-2.70 (m, 1H), 2.64 (dd, 1H, J = 13.8 and 10.8 Hz).

< Example  26 > 3- (4- Chloro -3- ( Trifluoromethyl ) benzyl ) -5,7- Dimethoxychroman One (14f, &lt; RTI ID = 0.0 &gt; HJ -027)

(E) -3- (4-chloro-3- (trifluoromethyl) benzylidene) -5,7-dimethoxychroman-4-one prepared in Example 6 (15 mg, 0.04 mmol ) Was dissolved in anhydrous methanol, and then 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (6 mg, 45%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.48 (t, 1H, J = 7.2 Hz), 6.79 (d, 1H, J = 7.2 Hz), 6.57 (d, 1H, J = 8.4 Hz), 6.07 ( (d, 2H, J = 9.6 and 1.8 Hz), 4.50 (dd, 1H, J = 11.4 and 4.8 Hz), 4.23 ), 3.38 (dd, 1H, J = 14.4 and 4.2 Hz), 3.29-3.24 (m, 1H), 2.75 (dd, 1H, J = 15.0 and 9.6 Hz).

< Example  27> 3- ( Benzo [d] [1,3] dioxole -5- Yl methyl ) -5,7- Dimethoxychroman -4-one (14 g, HJ-024)

(E) -3- (benzo [d] [1,3] dioxol-5-ylmethylene) -5,7-dimethoxychroman-4-one prepared in Example 7 0.07 mmol) was dissolved in anhydrous methanol, 10% Pd / C (5 mg) was added, and the solution was placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (20 mg, 82%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.75 (m, 2H), 6.68 (dd, 1H, J = 7.8 and 1.2 Hz), 6.07 (dd, 2H, J = 9.6 and 2.4 Hz), 5.93 (s 3H), 3.82 (s, 3H), 3.18 (dd, 2H), 4.28 (dd, 1H, J = 10.8 and 4.2 Hz), 4.11 1H, J = 13.8 and 4.2 Hz), 2.74-2.69 (m, 1H), 2.61 (dd, 1H, J = 13.8 and 10.2 Hz).

< Example  28> 5,7- Dimethoxy -3- (naphthalene-1- Yl methyl ) Croix One (14h, HJ-022)

(E) -5,7-dimethoxy-3- (naphthalen-1-ylmethylene) chroman-4-one (13 mg, 0.04 mmol) prepared in Example 8 was dissolved in anhydrous methanol, % Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (6 mg, 47%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.17 (d, 1H, J = 8.4 Hz), 7.87 (d, 1H, J = 9.0 Hz), 7.77 (d, 1H, J = 7.8 Hz), 7.55- 1H), 7.50 (m, 1H), 7.50-7.49 (m, 1H), 7.43-7.40 (d, 1H, J = 2.4 Hz), 4.25 (dd, IH, J = 11.4 and 3.6 Hz), 4.16-4.12 2.90 (m, 3 H).

< Example  29> 5,7- Dimethoxy -3- (3,4,5- Trimethoxybenzyl ) Croix -4-one (14i, HJ-021)

(E) -5,7-dimethoxy-3- (3,4,5-trimethoxybenzylidene) chroman-4-one (13 mg, 0.03 mmol) prepared in Example 9 was dissolved in anhydrous After dissolving in methanol, 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (6 mg, 48%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.44 (s, 2H), 6.07 (dd, 2H, J = 7.2 and 1.8 Hz), 4.30 (dd, 1H, J = 11.4 and 4.2 Hz), 4.14-4.10 (d, 1H, J = 13.8 and 4.2 Hz), 2.77 (s, 3H), 3.82 (s, 3H) 2.73 (m, 1H), 2.61 (dd, 1H, J = 13.8 and 11.4 Hz).

< Example  30> 3- (4- Fluorobenzyl ) -5,7- Dimethoxychroman (14j, &lt; RTI ID = 0.0 &gt; HJ -018)

(E) -3- (4-fluorobenzylidene) -5,7-dimethoxychroman-4-one (6 mg, 0.02 mmol) prepared in Example 10 was dissolved in anhydrous methanol, % Pd / C (2 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (5 mg, 87%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.20-7.17 (m, 2H), 7.00-6.96 (m, 2H), 6.07 (dd, 2H, J = 13.2 and 2.4 Hz), 4.27 (dd, 1H, J = 15.6 and 4.2 Hz), 4.07 (dd, IH, J = 10.8 and 6.0 Hz), 3.88 (s, 3H), 3.81 2.76 - 2.72 (m, 1H), 2.67 (dd, 1H, J = 13.8 and 10.8 Hz).

< Example  31> 3- (4- Hydroxybenzyl ) -5,7- Dimethoxychroman One (14k, HJ-019)

(E) -3- (4-hydroxybenzylidene) -5,7-dimethoxychroman-4-one (6 mg, 0.02 mmol) prepared in Example 11 was dissolved in anhydrous methanol, % Pd / C (2 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (3 mg, 56%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.10 (d, 2H, J = 5.4 Hz), 6.78 (d, 2H, J = 11.4 Hz), 6.07 (dd, 2H, J = 9.0 and 2.4 Hz), 1H, J = 8.4 and 4.2 Hz), 2.88 (s, 3H), 3.82 (s, 3H), 3.18 (dd, , 2.64 (dd, 1H, J = 16.8 and 10.8 Hz).

< Example  32> 3- (3- Fluorobenzyl ) -5,7- Dimethoxychroman One (14 l, &lt; RTI ID = 0.0 &gt; HJ -025)

(E) -3- (3-fluorobenzylidene) -5,7-dimethoxychroman-4-one (5 mg, 0.01 mmol) prepared in Example 12 was dissolved in anhydrous methanol, % Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (3 mg, 75%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.26-7.24 (m, 1H), 7.00 (d, 1H, J = 7.8 Hz), 6.94-6.90 (m, 2H), 6.06 (dd, 2H, J = J = 11.4 and 7.8 Hz), 3.87 (s, 3H), 3.80 (s, 3H), 3.26 (dd, dd, 1H, J = 13.8 and 4.2 Hz), 2.79-2.75 (m, 1H), 2.65 (dd, 1H, J = 13.8 and 10.8 Hz).

< Example  33> 5,7- Dimethoxy -3 - ((6- Methoxypyridine -2 days) methyl ) Croix One (14m, &lt; RTI ID = 0.0 &gt; HJ -026)

(E) -5,7-dimethoxy-3 - ((6-methoxypyridin-2-yl) methylene) chroman-4-one (3 mg, 0.01 mmol) prepared in Example 13 After dissolving in anhydrous methanol, 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (3 mg, 88%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.48 (dd, 1H, J = 7.8 and 7.2 Hz), 6.79 (d, 1H, J = 7.2 Hz), 6.57 (d, 1H, J = 8.4 Hz), (Dd, 2H, J = 9.6 and 2.4 Hz), 4.50 (dd, 1H, J = 10.8 and 4.8 Hz), 4.22 (s, 3H), 3.82 (s, 3H), 3.38 (dd, 1H, J = 15.0 and 4.8 Hz), 3.28-3.24 (m, 1H), 2.75 (dd, 1H, J = 15.0 and 10.2 Hz).

< Example  34> 3- (4- Chloro -3- Fluorobenzyl ) -5,7- Dimethoxychroman (14n, &lt; RTI ID = 0.0 &gt; HJ-028)

(E) -3- (4-chloro-3-fluorobenzylidene) -5,7-dimethoxychroman-4-one (5 mg, 0.01 mmol) prepared in Example 14 was dissolved in anhydrous methanol , 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (3 mg, 55%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.32 (t, 1H, J = 7.8 Hz), 6.99-6.96 (m, 1H), 6.92-6.89 (m, 1H), 6.03 (dd, 2H, J = 3H), 2.70-2.60 (m, 2H), 2.26-2.21 (m, IH) (m, 1H).

< Example  35> 3- (3,4- Dimethoxybenzyl ) -5,7- Dimethoxychroman -4-one (14o, HJ-029)

(E) -3- (3,4-dimethoxybenzylidene) -5,7-dimethoxychroman-4-one (24 mg, 0.07 mmol) prepared in Example 15 was dissolved in anhydrous methanol After 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (15 mg, 67%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.81-6.75 (m, 3H), 6.07 (dd, 2H, J = 8.4 and 2.4 Hz), 4.28 (dd, 1H, J = 10.8 and 3.6 Hz), 4.11 (d, 1H, J = 11.4 and 7.2 Hz), 3.89 (s, 3H), 3.87 (s, 3H), 3.86 and 4.2 Hz), 2.76-2.71 (m, 1H), 2.64 (dd, 1H, J = 13.8 and 10.8 Hz).

< Example  36> 3- (4- Bromo -2- Fluorobenzyl ) -5,7- Dimethoxychroman One (14p, HJ-032)

(E) -3- (4-bromo-2-fluorobenzylidene) -5,7-dimethoxychroman-4-one (7 mg, 0.02 mmol) prepared in Example 16 was dissolved in anhydrous After dissolving in methanol, 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (6 mg, 70%).

¹ H-NMR (600 MHz, CDCl ₃ )? 7.22-7.18 (m, IH), 7.09-7.00 (m, 2H), 7.61-7.59 (d, 2H, J = 13.8 and 2.4 Hz), 4.32 (dd, 1H, J = 11.4 and 4.8 Hz), 4.11-4.08 (dd, 1H, J = 14.4 and 4.8 Hz), 3.23-3.19 (m, 1H), 2.74 (dd, 1H, J = 13.8 and 10.2 Hz).

< Example  37> 5,7- Dimethoxy -3- (2,4,6- Trimethoxybenzyl ) Croix One (14q, &lt; RTI ID = 0.0 &gt; HJ -031)

(E) -5,7-dimethoxy-3- (2,4,6-trimethoxybenzylidene) chroman-4-one (20 mg, 0.05 mmol) prepared in Example 17 was dissolved in anhydrous After dissolving in methanol, 10% Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (14 mg, 72%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 6.11 (s, 2H), 6.05-6.00 (m, 2H), 4.20-4.11 (m, 2H), 3.87 (s, 3H), 3.80 (s, 6H) , 3.74 (s, 6H), 3.30 (dd, 1H, J = 13.8 and 4.8 Hz), 2.88-2.71 (m, 1H), 2.67 (dd, 1H, J = 13.2 and 10.2 Hz).

< Example  38> 5,7- Dimethoxy -3- (pyridin-2- Yl methyl ) Croix One (14r, &lt; RTI ID = 0.0 &gt; HJ -030)

(E) -5,7-dimethoxy-3- (pyridin-2-ylmethylene) chroman-4-one (27 mg, 0.09 mmol) prepared in Example 18 was dissolved in anhydrous methanol, % Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (11 mg, 42%).

¹ H-NMR (600 MHz, CDCl ₃ )? 8.53-8.52 (m, IH), 7.61-7.59 (m, IH), 7.61-7.59 (dd, 2H, J = 4.8 and 2.4 Hz), 4.46 (dd, 1H, J = 10.8 and 4.8 Hz), 4.20 , 3.44 (dd, 1H, J = 14.4 and 4.8 Hz), 3.23-3.19 (m, 1H), 2.84 (dd, 1H, J = 14.4 and 9.6 Hz).

< Example  39> 5,7- Dimethoxy -3- (pyridin-3- Yl methyl ) Croix One (14s, &lt; RTI ID = 0.0 &gt; HJ -033)

(E) -5,7-Dimethoxy-3- (pyridin-3-ylmethylene) chroman-4-one (15 mg, 0.05 mmol) prepared in Example 19 was dissolved in anhydrous methanol, % Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (11 mg, 72%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.48-8.46 (m, 2H), 7.59-7.58 (m, 1H), 7.24 (dd, 1H, J = 7.8 and 4.8 Hz), 6.07 (dd, 2H, J = 13.8 and 2.4 Hz), 4.30 (dd, 1H, J = 11.4 and 4.2 Hz), 4.08 (dd, (Dd, 1H, J = 13.8 and 4.2 Hz), 2.81-2.77 (m, 1H), 2.71 (dd, 1H, J = 14.4 and 10.2 Hz).

< Example  40> 5,7- Dimethoxy -3- (pyridin-4- Yl methyl ) Croix One (14t, &lt; RTI ID = 0.0 &gt; HJ -034)

(E) -5,7-dimethoxy-3- (pyridin-4-ylmethylene) chroman-4-one (15 mg, 0.05 mmol) prepared in Example 20 was dissolved in anhydrous methanol, % Pd / C (5 mg) was added and placed in a hydrogen atmosphere. After stirring for one hour, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (10 mg, 70%).

^{1 H-NMR (600 MHz,} CDCl 3) δ 8.53 (dd, 2H, J = 4.2 and 1.8 Hz), 7.18 (d, 1H, J = 6.0 Hz), 6.08 (dd, 2H, J = 16.2 and 1.8 Hz ), 4.30 (dd, 1H, J = 11.4 and 4.2 Hz), 4.07 (dd, 1H, J = 10.8 and 8.4 Hz), 3.89 (s, 3H), 3.82 J = 13.8 and 4.8 Hz), 2.87-2.82 (m, 1H), 2.67 (dd, 1H, J = 13.8 and 9.6 Hz).

< Example  (E) -3- (3- Hydroxy -4- Methoxybenzylidene ) -5,6,7- Trimethoxys (SH-25) &lt; RTI ID = 0.0 &gt;

Benzene (2 mL) was added to a solution of 5,6,7-trimethoxychroman-4-one (238 mg, 1 mmol), isovaniline (170 mg, 1.1 mmol) and para- toluenesulfonic acid (20 mg, And reacted for 12 hours under reflux conditions. After cooling to room temperature, the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 1) to give the title compound (215 mg, 58% Respectively.

^{1 H-NMR (600 MHz,} CDCl 3) δ 7.74 (s, 1H), 6.91-6.84 (m, 3H), 6.26 (s, 1H), 5.67 (s, 1H), 5.24 (d, 2H, J = 1.8 Hz); 3.98 (s, 3H), 3.94 (s, 3H), 3.88 (s, 3H), 3.83 (s, 3H); (100 MHz, CDCl 3) δ 179.5, 159.3, 159.1, 154.7, 147.5, 145.5, 137.8, 136.2, 130.1, 128.1, 123.2, 115.7, 110.5, 96.1, 67.6, 61.6, 61.3, 60.3, 60.3, 56.0, 55.9; LRMS (ESI) m / z 373 (M + H).

< Example  42> 3- (3- Hydroxy -4-methoxybenzyl) -5,6,7- Trimethoxy -4H- Kromen 4-one ( GS -09)

PCl ₅ (180mg, 0.86mmol) and then at 20 ℃ conditions, dissolved in DMF (2.5mL) was stirred for 20 minutes _{BF 3 -Et 2 O (0.22mL,} 1.73mmol) and into the die high drone chalkon (200mg, 0.58mmol) And reacted for 4 hours. 1 N HCl (2 mL) and ethyl acetate were added and the reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 4) to give the title compound , 51%). %).

^{1 H-NMR (400 MHz,} CDCl 3) δ 7.34 (s, 1H), 6.83-6.79 (m, 2H), 6.74-6.73 (m, 1H), 6.59 (s, 1H), 5.49 (s, 1H) , 3.94 (s, 3H), 3.90 (s, 3H), 3.86 (s, 3H), 3.67 (s, 2H); 13 C-NMR (100 MHz, CDCl 3) 隆 175.9, 157.5, 154.7, 152.6, 151.0, 146.5, 144.1, 140.2, 130.6, 125.2, 121.6, 114.3, 112.9, 111.7, 95.9, 62.0, 61.4, 56.2, 55.9, 31.1. LRMS (ESI) m / z 373 (M + H).

< Example  (E) -3- (3- ( Benzyloxy )-4- Methoxyphenyl ) -1- (6- Hydroxy -2,3,4- Trimethoxyphenyl ) Prop-2-en-1-one GS -07)

To a solution of 1- (6-hydroxy-2,3,4-trimethoxyphenyl) ethan-1-one (1.5 g, 6.5 mmol) in methanol (10 mL) was added 3-benzyloxy-4-methoxybenzaldehyde 2.0 g, 8.0 mmol) and potassium hydroxide (1.5 g, 25 mmol) at 0 ° C and the temperature was raised to room temperature. The reaction was then stirred at 35 &lt; 0 &gt; C for 72 h and then concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: ).

^{1 H-NMR (600 MHz,} CDCl 3) δ 13.7 (s, 1H), 7.74 (s, 2H), 7.47 (d, 2H, J = 7.2 Hz); 7.40 (t, 2H, J = 7.2 Hz); 7.33 (d, 1 H, J = 7.2 Hz); 7.24 (dd, 1H, J = 8.4 and 2.4 Hz); 7.17 (d, 1 H, J = 1.2 Hz); 6.92 (d, 1 H, J = 8.4 Hz); 2H), 3.84 (s, 3H), 3.84 (s, 3H), 3.84 (s, 3H), 3.83 (s, 3H); 128.9, 128.0, 127.2, 124.2, 123.5, 113.0, 111.5, 108.7, 96.6, 71.12, 61.9, 61.32, 56.12, 29.7; LRMS (ESI) m / z 315 (M + H).

< Example  44> 3- (3- Hydroxy -4-methoxybenzyl) -5,6,7- Trimethoxy chroman -4- Manufacture of onions  ( GS -06)

Methoxyphenyl) ethyl) -5,6,7-trimethoxychroman-4-one (100 mg, 0.25 mmol) and potassium hydroxide (54 mg, 0.49 mmol) dissolved in ethanol (2 mL) and stirred at 90 ° C for 3 hours. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (45 mg, 49%).

^{1 H-NMR (400 MHz,} CDCl 3) δ 7.24 (s, 1H), 6.83 (d, 1H, J = 7.8 Hz); 6.71 (d, 2H, J = 1.9 Hz); 1H), 6.23 (s, 1H), 5.53 (s, 1H), 4.23 (m, 1H), 4.10 (m, 1H), 3.91 (s, 3H), 3.85 (d, 6H, J = 1.9 Hz); 3.79 (s, 3H), 3.16 (m, IH), 2.70 (m, IH), 2.63 (m, IH); 13 C-NMR (100 MHz, CDCl 3) δ 191.3, 159.6, 159.2, 154.4, 146.5, 144.2, 137.4, 130.2, 121.8, 114.3, 111.4, 108.6, 95.9, 69.0, 61.5, 61.2, 56.0, 55.9, 48.5, 32.5; LRMS (ESI) m / z 375 (M + H).

< Example  45> 3- benzyl -5,6,7- Trimethoxy chroman 4-one ( GS -03)

Dissolve dihydrochalcone (100 mg, 0.31 mmol) in 50% aqueous sodium hydroxide (2 mL) and distilled water (6 mL), then add formalin (0.04 mL, 1.61 mmol) and stir at 60 ° C for three hours. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 4) to give the title compound (44 mg, 42%).

¹ H-NMR (400 MHz, CDCl ₃ )? 7.31-7.28 (m, 2H), 7.22-7.20 (m, 3H), 6.23 3H), 3.79 (s, 3H), 3.28 (dd, 1H, J = 14 and 3.9 Hz), 4.09 (dd, 2.80-2.73 (m, 1H), 2.68 (dd, 1H, J = 14 and 11 Hz); 13 C-NMR (100 MHz, CDCl 3)? 191.1, 159.6, 159.2, 154.4, 138.5, 137.4, 129.1, 128.6, 126.5, 108.6, 95.9, 69.0, 61.5, 61.3, 56.0, 48.2, 32.7.

< Example  46> 3- benzyl -5- Hydroxy -6,7- Dimethoxychroman 4-one ( GS -04)

3-Benzyl-5,6,7-trimethoxychromanone (15 mg, 0.046 mmol) prepared in Example 45 was dissolved in acetic acid (0.75 mL), and HBr (0.5 mL) And the mixture is refluxed for two hours. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (5 mg, 35%).

¹ H-NMR (400 MHz, CDCl ₃ )? 11.96 (s, 1 H), 7.35-7.31 (m, 2H), 7.27-7.22 J = 11 and 4.4 Hz), 4.13 (dd, 1H, J = 11 and 7.3 Hz), 3.88 (s, 3H), 3.83 2.90 - 2.83 (m, 1H), 2.76 (dd, 1H, J = 14 and 11 Hz); LRMS (ESI) m / z 315 (M + H).

< Example  47> 5 - ((5,7- Dihydroxy -6- Methoxy -4- Oxochroman -3 days) methyl )-2- Methoxyphenyl Benzoate  Produce ( GS -10)

Phenylbenzoate (50 mg, 0.104 mmol) was dissolved in chloroform (1 mL), followed by the addition of 2-methoxy-5 - ((5,6,7- trimethoxy-4-oxochroman- TMSI (60 μL, 0.4 mmol) is added at 0 ° C and the mixture is stirred at 60 ° C for 12 hours. The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (18 mg, 38%).

^{1 H-NMR (400 MHz,} CDCl 3) δ 8.22 (m, 2H), 7.65 (m, 1H), 7.53-7.49 (m, 2H), 7.11 (d, 1H, J = 7.8 Hz), 6.89 (dt 1H, J = 7.8 and 2.0 Hz), 6.08 (s, 1H), 4.34 (dd, 1H, J = 11 and 3.9 Hz), 4.18 3H), 3.82 (s, 3H), 3.28 (dd, 1H, J = 13 and 3.9 Hz), 2.91-2.86 (m, 1H), 2.80 (dd, 1H, J = 13 and 11 Hz); 13 C-NMR (100 MHz, CDCl 3) δ 198.4, 164.7, 155.9, 154.7, 151.4, 148.1, 138.8, 136.8, 133.4, 130.2, 128.5, 127.3, 123.0, 121.3, 113.2, 102.4, 91.0, 69.2, 56.3, 55.9, 46.8 , 32.7, 30.9; LRMS (ESI) m / z 451 (M + H).

< Example  48> 5,7- Dihydroxy -3- (3- Hydroxy Methoxybenzyl) -3- ( Hydroxymethyl ) -6-methoxychroman-4-one ( GS -11)

The dihydrochalcone (700 mg, 1.9 mmol) prepared in Example 49 was dissolved in 50% aqueous sodium hydroxide (0.96 mL) and distilled water (3.8 mL), formalin (0.16 mL, 5.8 mmol) Mix for 3 hours at < RTI ID = 0.0 > The reaction was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (383 mg, 54%).

^{1 H-NMR (400 MHz,} CDCl 3) δ 6.83-6.80 (m, 2H), 6.75-6.73 (m, 1H), 6.28 (s, 1H), 5.78 (bs, 1H), 4.04-4.03 (m, 2H), 3.91 (s, 3H), 3.88 (s, 3H), 3.84 (s, 3H), 3.79 (s, 2H), 3.58-3.50 , &Lt; / RTI &gt; 1H, J = 13 Hz); 2.85 (d, 1 H, J = 14 Hz); (100 MHz, CDCl 3) δ 196.1, 159.7, 159.4, 154.5, 146.3, 144.5, 137.5, 126.7, 123.3, 114.1, 113.0, 107.8, 95.9, 69.6, 62.2, 61.4, 61.2, 56.0, 55.8, 49.9, 34.8. LRMS (ESI) m / z 405 (M + H).

< Example  49> 1- (6- Hydroxy -2,3,4- Trimethoxyphenyl ) -3- (3- Hydroxy -4- Me Ethoxyphenyl) propan-1-one (GS-05)

(850 mg, 1.9 mmol), sodium formate (513 mg, 7.5 mmol), Pd / C (195 mg, 1.8 mmol) and formaldehyde (1 mL) prepared in Example 43 were dissolved in isopropanol mL) and stirred at 0 ° C for 6 h, then the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 3) to give the title compound (517 mg, 79%).

¹ H-NMR (400 MHz, CDCl ₃ )? 13.38 (s, 1H), 6.82 (d, 1H, J = 8.28 Hz); 6.73 (s, 2H), 6.21 (s, 1H), 5.53 (s, 1H), 3.93 (s, 3H), 3.85 (d, 6H, J = 1.96 Hz); 3.74 (s, 3H), 3.31 (m, 2H), 2.94 (d, 2H, J = 7.8 Hz); 13 C-NMR (100 MHz, CDCl 3)? 204.8, 161.7, 159.8, 155.0, 146.3, 143.7, 134.6, 133.3, 120.7, 114.2, 111.1, 108.1, 96.1, 61.0, 60.9, 55.9, 55.7, 45.1, 30.2; LRMS (ESI) m / z 317 (M + H).

< Example  50> 3- (3,4- Dimethoxyphenyl ) -1- (6- Hydroxy -2,3,4- Trimethoxyphenyl ) Propane-1-one (GS-08)

(E) -3- (3,4-dimethoxyphenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) prop- 0.152 mmol) was dissolved in absolute ethanol (1.5 mL), 10% Pd / C (10 mg) was added, and the solution was placed in a hydrogen atmosphere. After stirring for four hours, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (38 mg, 66%).

¹³ C-NMR (100 MHz, CDCl ₃ )? 204.8, 161.8, 159.9, 155.0, 148.8, 147.3, 134.7, 134.1, 120.4, 111.8, 111.2, 108.2, 96.2, 61.1, 60.9, 56.0, 55.9, 55.8, 45.1, 30.1.

< Example  51 > 1- (6- Hydroxy -2,3,4- Trimethoxyphenyl ) -3- Phenylpropane -1-one ( GS -02)

(E) -3- (3,4-dimethoxyphenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) prop- 0.152 mmol) was dissolved in absolute ethanol (1.5 mL), 10% Pd / C (10 mg) was added, and the solution was placed in a hydrogen atmosphere. After stirring for four hours, the reaction was diluted with ethyl acetate, filtered through a pad of celite, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (ethyl acetate: n-hexane = 1: 2) to give the title compound (38 mg, 66%).

¹³ C-NMR (100 MHz, CDCl ₃ )? 204.8, 161.8, 159.9, 155.0, 148.8, 147.3, 134.7, 134.1, 120.4, 111.8, 111.2, 108.2, 96.2, 61.1, 60.9, 56.0, 55.9, 55.8, 45.1, 30.1.

The specific structures of the compounds prepared in Examples 1 to 51 are shown in Table 1 below.

Example Chemical structure Example Chemical structure (One)
(SH-66, 13a)

(27)
(HJ-024,14 g)

(2)
(SH-90, 13b)

(28)
(HJ-022,14h)

(3)
(SH-92, 13c)

(29)
(HJ-021,14i)

(4)
(HJ-006,13d)

(30)
(HJ-018,14j)

(5)
(HJ-003,13e)

(31)
(HJ-019,14k)

(6)
(HJ-010,13f)

(32)
(HJ-025,141)

(7)
(HJ-007, 13g)

(33)
(HJ-026,14m)

(8)
(HJ-005,13h)

(34)
(HJ-028,14n)

(9)
(HJ-004, 13i)

(35)
(HJ-029,14o)

(10)
(HJ-001, 13j)

(36)
(HJ-032,14p)

(11)
(HJ-002,13k)

(37)
(HJ-031,14q)

(12)
(HJ-008,131)

(38)
(HJ-030,14r)

(13)
(HJ-009,13m)

(39)
(HJ-033,14s)

(14)
(HJ-011, 13n)

(40)
(HJ-034,14t)

(15)
(HJ-012,13o)

(41)
(SH-25)

(16)
(HJ-015, 13p)

(42)
(GS-09)

(17)
(HJ-014,13q)

(43)
(GS-07)

(18)
(HJ-013, 13r)

(44)
(GS-06)

(19)
(HJ-016,13s)

(45)
(GS-03)

(20)
(HJ-017,13t)

(46)
(GS-04)

(21)
(SH-88, 14a)

(47)
(GS-10)

(22)
(SH-91, 14b)

(48)
(GS-11)

(23)
(SH-93, 14c)

(49)
(GS-05)

(24)
(HJ-023,14d)

(50)
(GS-08)

(25)
(HJ-020,14e)

(51)
(GS-02)

(26)
(HJ-027,14f)

< Experimental Example  1> BV -2 Production of NO in Microglial Cells

1-1 Experimental Method

NO production in rat microglia (BV-2 microglia) of Example 1-51, a compound according to the present invention, was measured as the IC ₅₀ and percent survival of the cells.

First, BV-2 cells induced with LPS were used to assess the inhibitory effect of NO on the inflammation-related factors, which are the respective compounds. BV-2 cells were plated at 4 × 10 ⁴ cells / well in a 96-well plate and treated with LPS at 100 ng / ml for 24 hours. After 30 minutes, the compounds were treated at different concentrations and cultured for 24 hours. NO production was measured by Griess assay. 100 μl of the supernatant was collected from each well and incubated with 100 μl of Griess reagent (0.1% N-1-napthylethylenediamine dihydrochloride (N) and 1% sulfanilamide in 5% phosphoric acid (SP) . The absorbance was measured using an ELISA reader (570 nm) and the NO concentration was calculated based on the standard curve of sodium nitrite (NaNO 2).

One- 2. Experimental results

The results are shown in Table 2 below.

As shown, homoisoflavanone derivatives did not show cytotoxicity in murine microglia induced by LPS but decreased NO production. The compounds of Example 22 (SH 91 (14b)), Example 23 (SH91 (14c)) and Example 19 (HJ-016 (13s)) showed the highest inhibition of NO production with IC _{50 values} of 0.65, 3.3 and 3.63 .

Example 13 (HJ-013 (13r)), Example 8 (HJ-005 (13h)), Example 1 (SH- example 12 (HJ-008 (13l) ), example 10 (HJ-001 (13J) ), example 21 (SH-88 (14a) ) as in example 16 (HJ-O15 (13p) ) compounds also IC ₅₀ Were 5.60, 6.69, 6.73, 7.06, 7.33, 8.51, 8.85 and 9.48, respectively. These compounds showed no cytotoxicity in BV2 cells.

Example NO production in BV-2 microglia cells.
IC50 ([mu] M) NO production in BV-2 microglia cells.
Cell Viability (%) Example NO production in BV-2 microglia cells.
IC50 ([mu] M) NO production in BV-2 microglia cells.
Cell Viability (%) (One)
(SH-66, 13a) 6.73 170.77 + - 4.25 (27)
(HJ-024,14 g) 127 86.44 + - 3.89 (2)
(SH-90, 13b) 14.4 173.42 + - 7.30 (28)
(HJ-022,14h) 51.15 144.01 + - 10.95 (3)
(SH-92, 13c) 17.57 132.9 ± 5.39 (29)
(HJ-021,14i) 59.6 125.19 + - 6.87 (4)
(HJ-006,13d) 11.78 124.20 ± 2.80 (30)
(HJ-018,14j) 55.95 101.73 + - 2.75 (5)
(HJ-003,13e) 11.7 139.41 + - 4.96 (31)
(HJ-019,14k) 26.8 132.06 + - 4.70 (6)
(HJ-010,13f) 40.97 100.88 + - 3.33 (32)
(HJ-025,141) 48.44 116.12 ± 7.69 (7)
(HJ-007, 13g) 17.51 113.23 + - 8.78 (33)
(HJ-026,14m) 132.02 109.02 + - 3.95 (8)
(HJ-005,13h) 6.69 135.87 ± 9.08 (34)
(HJ-028,14n) > 500 112.64 + 9.38 (9)
(HJ-004, 13i) 7.06 148.43 + - 7.45 (35)
(HJ-029,14o)  107.9 126.64 + 9.38 (10)
(HJ-001, 13j) 8.51 123.97 + - 3.42 (36)
(HJ-032,14p) 53.77 139.64 ± 6.15 (11)
(HJ-002,13k) 18.3 121.37 + - 4.27 (37)
(HJ-031,14q)
101.76 147.73 + - 11.6 (12)
(HJ-008,131) 7.33 125.51 + - 4.19 (38)
(HJ-030,14r) 156.92 122.22 + - 6.68 (13)
(HJ-009,13m) 29.4 108.88 + - 5.31 (39)
(HJ-033,14s) ND ND (14)
(HJ-011, 13n) 21.27 110.62 + 5.03 (40)
(HJ-034,14t) ND ND (15)
(HJ-012,13o) 12.41 150.80 ± 9.01 (41)
(SH-25) 48.59 165.10 ± 1.54 (16)
(HJ-015, 13p) 9.48 132.96 + - 2.70 (42)
(GS-09) ND ND (17)
(HJ-014,13q) 41.21 120.50 ± 3.70 (43)
(GS-07) ND ND (18)
(HJ-013, 13r) 5.6 152.99 + - 4.57 (44)
(GS-06) ND ND (19)
(HJ-016,13s) 3.63 148.06 ± 8.90 (45)
(GS-03) ND ND (20)
(HJ-017,13t) 7.56 148.94 + 9.13 (46)
(GS-04) ND ND (21)
(SH-88, 14a) 8.85 163.79 + - 6.44 (47)
(GS-10) ND ND (22)
(SH-91, 14b) 0.65 170.90 ± 6.26 (48)
(GS-11) ND ND (23)
(SH-93, 14c) 3.3 168.05 ± 5.91 (49)
(GS-05) ND ND (24)
(HJ-023,14d) 75.51 80.29 + 2.81 (50)
(GS-08) ND ND (25)
(HJ-020,14e) 64.74 111.41 + - 5.47 (51)
(GS-02) ND ND (26)
(HJ-027,14f) 50.86 115.82 + - 3.71

In Table 2,

ND means Not Determined.

< Experimental Example  2> Secretion of nerve growth factor in C6 cells

2-1 Experimental Method

The secretion of nerve growth factor (NGF) in mouse derived glioma cells (C6 Cell) of the compound of the present invention, which is a compound according to the present invention, was measured by the percent of NGF secretion and the survival percentage of cells.

First, to evaluate the secretion effect of nerve growth factor (NGF) on each compound, C6 cells were divided into 1 × 10 ⁵ cells / well in 24-well plates, and after 24 hours, 1% of antibiotics and FBS The DMEM medium containing 10% of the compound was treated with the compound for each concentration and incubated for 24 hours. Cells were harvested from the wells cultured by the above method and assayed using an NGF ELISA kit. 6-Shogaol was used as a positive control.

2-2 Experimental results

The results are shown in Table 3 below.

As shown, Homoisoflavanone derivatives increased NGF production and showed protective effects on nerve cells. In particular, the HJ-008 (3l) and SH-88 (14a) compounds showed the highest activity by increasing NGF production to 213.59 ± 14.40 and 189.36 ± 2.44%. (HJ-015 (13p)), Example 9 (HJ-004 (13i)), Example 5 (HJ- The compound of Example 23 (SH-93 (14c)) was also 178.82 ± 10.65, 177.30 ± 7.93, 175.13 ± 22.9, 174.27 ± 2.22 and 171.32 ± 5.77%. All of these compounds were not cytotoxic up to 20 μM concentration in C6 cell line.

Example NGF production in C6 cells NGF secretion a / NGF secretion in C6 cells
Cell viability /% Example NGF production in C6 cells NGF secretion a / NGF secretion in C6 cells
Cell viability /% (One)
(SH-66, 13a) 174.27 ± 2.22 101.36 ± 9.2 (27)
(HJ-024,14 g) ND ND (2)
(SH-90, 13b) 155.00 ± 0.56 91.44 ± 2.9 (28)
(HJ-022,14h) ND ND (3)
(SH-92, 13c) 152.86 + - 6.95 94.27 + - 4.8 (29)
(HJ-021,14i) ND ND (4)
(HJ-006,13d) 149.64 ± 13.98 121.24 + 0.26 (30)
(HJ-018,14j) ND ND (5)
(HJ-003,13e) 175.13 + - 22.9 104.74 + - 4.36 (31)
(HJ-019,14k) ND ND (6)
(HJ-010,13f) ND ND (32)
(HJ-025,141) ND ND (7)
(HJ-007, 13g) ND ND (33)
(HJ-026,14m) ND ND (8)
(HJ-005,13h) 168.99 + - 10.70 90.01 ± 0.29 (34)
(HJ-028,14n) ND ND (9)
(HJ-004, 13i) 177.30 ± 7.93 112.89 ± 0.83 (35)
(HJ-029,14o) ND ND (10)
(HJ-001, 13j) 159.94 + - 11.43 ND (36)
(HJ-032,14p) ND ND (11)
(HJ-002,13k) ND ND (37)
(HJ-031,14q) ND ND (12)
(HJ-008,131) 213.59 ± 14.40 110.06 + 4.08 (38)
(HJ-030,14r) ND ND (13)
(HJ-009,13m) ND ND (39)
(HJ-033,14s) ND ND (14)
(HJ-011, 13n) ND ND (40)
(HJ-034,14t) ND ND (15)
(HJ-012,13o) 139.27 + - 8.14 120.41 + - 0.27 (41)
(SH-25) 148.65 ± 3.84 97.69 + - 7.08 (16)
(HJ-015, 13p) 178.82 ± 10.65 104.00 ± 2.02 (42)
(GS-09) ND ND (17)
(HJ-014,13q) ND ND (43)
(GS-07) ND ND (18)
(HJ-013, 13r) 120.91 ± 5.29 119.16 ± 1.85 (44)
(GS-06) ND ND (19)
(HJ-016,13s) 141.04 + - 1.26 108.49 + 1.68 (45)
(GS-03) ND ND (20)
(HJ-017,13t) ND ND (46)
(GS-04) ND ND (21)
(SH-88, 14a) 189.36 + - 2.44 98.12 ± 6.5 (47)
(GS-10) ND ND (22)
(SH-91, 14b) 160.62 + 1.81 95.08 + - 4.6 (48)
(GS-11) ND ND (23)
(SH-93, 14c) 171.32 + - 5.77 85.50 ± 10.10 (49)
(GS-05) ND ND (24)
(HJ-023,14d) ND ND (50)
(GS-08) ND ND (25)
(HJ-020,14e) ND ND (51)
(GS-02) ND ND (26)
(HJ-027,14f) ND ND

In Table 3,

ND means Not Determined.

< Experimental Example  3> Example 21 ( SH -88), Example 1 ( SH -66), Example 19 (HJ-16) On cerebral ischemia  Evaluation of drug efficacy

3-1 Experimental Method

The compounds of Example 21 (SH-88), Example 1 (SH-66) and Example 19 (HJ-16) according to the present invention were tested for MCAO (middle cerebral artery occlusion) middle cerebral artery stenosis / (7 to 8 weeks old) were evaluated for their symptoms and efficacy.

MCAO cerebral artery stenosis / reperfusion (M / R) induces reperfusion (M / R) in male rat (7th birthday, Orient Co., Ltd) after 90 minutes of MCAO, 88, SH-66, and HJ-16, respectively. Each compound was dosed (1, 5, 10, 20 mg / kg) to evaluate the efficacy of each compound.

Specifically, the occlusion was caused by paralysis of the right midbrain artery by inserting a silicone-coated staple fiber (9 mm long 5-0 nylon staple fiber) from the branch of the cerebral artery of the rat, (1, 5, 10, 20 mg / kg, po (10% Tween 80, po) was administered to the mice ), And the degree of damage was shown numerically after 22 hours of reperfusion. The compounds of SH-66 and HJ-16 were also divided into five groups, respectively, and the efficacy was evaluated in the same manner.

The neurological sequela was first quantified on the basis of the modified neurological severity score scale (mNSS) as follows: The total score for neurological sequelae was 18 points, (Total 6 points), sensory function (total 2 points), balance sensory function (total 6 points), and reflection function (total 4 points). The described modified neurological severity score scales are described in the prior art (Chen et al., 2001. Intravenous administration of human umbilical cord blood reduced behavioral deficits after stroke in rats. Stroke, a journal of cerebral circulation 32: 2682-2688. Were used.

In addition, brains were removed from rats that had undergone neurological sequelae and stained with 2,3,5-triphenyltetrazolium (TTC), and the infarct volume was measured. Using ImageJ (NIH, Bethesda, MD, USA) Respectively.

Histological evaluation was performed by evaluating the efficacy of SH-88, SH-66, and HJ-16 compounds according to the present invention for cerebral ischemia separately from cerebral infarction volume measurement and neurological sequelae test. (M / R) after MCAO for 90 min in the same manner as in the above experiment. The M / R mice were randomly divided into five groups to prepare vehicle (10% Tween 80, po) (10 mg / kg, po), SH-66 (10 mg / kg, po) and HJ-16 The experiment was completed after 22 hours or 3 days of reperfusion. After 22 hours or 3 days of reperfusion, the mice were anesthetized with an intramuscular injection of anesthetics (Zoletil 50 10 mg / kg + Rompun 3 mg / kg), followed by perfusion through the heart. The needle was inserted in the left ventricle of the heart in the direction of the aorta, and perfused with phosphate buffer saline (PBS) using a peristaltic pump. After the blood was completely removed, the tissue was fixed by perfusion with 4% paraformaldehyde. After fixation, the brain was removed and immersed in 4% paraformaldehyde solution. The cells were stored at 4 ° C for additional 16 hours, washed with PBS, and left in a 30% sucrose solution for more than one day to prevent tissue damage during freezing. Brains completely submerged in sucrose were prepared by freezing tissue samples using OCT solution, and then frozen sections of 20 μm thickness were attached to slides for tissue sections using a microtome and then used in the experiment.

The degree of neurodegeneration was determined by analyzing the death of brain cells in prepared tissue sections. The brain cell death was photographed by fluorescence microscopy (Olympus BX53 fluorescence microscope) for each cortex (Cx) and striatum (St) region by Fluroro-Jade B (FJB) staining.

3-2 Experimental results

The results are shown in Figs. 1-8.

Figures 1 and 2 show that after the reperfusion, the compound of Example 21 (SH-88) was immediately dosed (1, 5, 10, 20 mg / kg, po) , The graphs A in FIGS. 1 and 2 show photographs and numerical values of the infarcted regions in the brain, respectively, and the graph B in FIG. 2 shows numerical values of neurological sequelae.

As shown, the administration of the compound of Example 21 (SH-88) showed that the volume of cerebral infarction was reduced in a dose-dependent manner, and neuroprotective effect could be confirmed through the dose-dependent decrease in neurological sequelae.

Figures 3 and 4 show that after the reperfusion, the compound of Example 1 (SH-66) was immediately dosed (1, 5, 10, 20 mg / kg, po) , Graphs A and B in FIGS. 3 and 4 respectively show photographs and numerical values of infarct volume on the brain, and graph B in FIG. 4 shows numerical values of neurological sequelae.

As shown, the neuroprotective effect can be confirmed by dose-dependent reduction of cerebral infarction volume and neurological sequelae by compound administration of Example 1 (SH-66).

Figures 5 and 6 show that after the reperfusion, rats were immediately dosed with the compound of Example 19 (HJ-16) by dose (1, 5, 10, 20 mg / kg, po) , The graph A of FIG. 5 and FIG. 6 shows photographs and numerical values of the infarct volume on the brain, and the graph B of FIG. 6 shows numerical values of the neurological sequelae.

As shown, the neuroprotective effect can be confirmed by dose-dependent reduction of the volume of cerebral infarction and neurological sequelae by the compound administration of Example 19 (HJ-16).

FIG. 7 is a graph comparing the changes in the dose of each compound of the cerebral infarction volume and the neurological sequelae according to the dose. Examples 21 (SH-88), 1 (SH-66) and 19 ) Compounds showed neuroprotective effects against cerebral ischemia, and it was confirmed that the neuroprotective effect of Example 21 (SH-88) was the most excellent.

8 is a photograph of brain cell death in a brain tissue slice through FJB staining. The above five photographs are of a size of 200 탆, and the middle and lower photographs are of a size of 50 탆. Thus, it was confirmed that brain cell death was reduced by administering the compound of Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16).

As a result, Compound Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) according to the present invention effectively reduce cerebral infarction and neurological sequelae resulting from cerebral ischemia, It is possible to effectively treat cerebral ischemia by reducing death, and thus it can be usefully used as a pharmaceutical composition containing it as an active ingredient.

< Experimental Example  4> Example 21 ( SH -88), Example 1 ( SH -66), Example 19 (HJ-16) Compound  Effect on activation of microglia

4-1 Experimental Method

Microglial activation was confirmed by immunohistochemical staining using a specific antibody. The specific antibody used for the measurement of microglial activation was anti-Iba-1 (an indicator of activation of microglia), and immunohistochemical staining proceeded as follows. The slides with frozen tissue sections were washed with 0.05 M PBS and then fixed with 4% paraformaldehyde solution and reacted with 1% H2O2 for 15 minutes to block the non-specific reaction of hydrogen peroxide in the tissues. After the addition of 5% normal donkey serum for 1 hour at room temperature, the nonspecific immune response was removed and then the primary antibody anti-Iba1 (Iba1 1: 500, Abcam plc, UK) was added and reacted at 4 ° C for 16 hours or longer. After the tissue was washed again, biotin-labeled secondary antibody was added for 2 hours and then washed. The avidin-biotin peroxidase complex (Vector Laboratories) was added to the tissues for 90 minutes, then washed, and developed with 0.02% 3,3'-diaminobenzidine tetrahydrochloride (DAB; Sigma, St. Louis, MO, USA) containing 0.01% The developed tissue sections were dehydrated, clarified with xylene, and sealed with mounting solution. After staining the stained tissue with a microscope, the photographs were taken with a periischemic region and an ischemic core region based on the hemisphere with stroke stimulus, and the number of stained cells in each region was calculated Respectively.

In addition, in order to histologically assess whether or not microglial cell proliferation, which is another indicator of micrographic cell activation, reperfusion (M / R) occurs after MCAO for 90 minutes, and the M / (10 mg / kg, po), SH-66 (10 mg / kg, po) and vehicle (10% Tween80, po) And the tissue sections used in the histological method were obtained after 3 days of reperfusion after all experiments. The detailed experimental method is as follows. After reperfusion, 5-bromodeoxyuridine (BrdU, Sigma-Aldrich) was intraperitoneally injected into the rats at a dose of 50 mg / kg twice a day at 12-hour intervals. The first BrdU injection was performed 12 hours after reperfusion, the last BrdU injection was performed 12 hours before brain tissue extraction, and the brain tissue extraction was performed 3 days after reperfusion. Experimental methods for anesthesia, perfusion fixation, brain excision, and acquisition of frozen tissue samples for obtaining brain tissue sections were obtained in the same manner as the above-described microcytotoxic activation assay.

Microglial cell proliferation was confirmed by applying a frozen tissue section to a double immunofluorescence method using a specific antibody. The specific antibodies used for microcellular activation and proliferated cell count were anti-Iba-1 (small cell activation markers) and anti-BrdU (proliferating cell markers), and immunohistochemical staining was performed as follows . The slides with frozen sections were washed with 0.05 M PBS, and the plates were incubated with 4% paraformaldehyde solution. After incubation at 37 ° C for 1 hour with 2N HCl, the slides were incubated with borate buffer (0.1 M, pH 8.5) And neutralized by washing three times. Then, 1% fetal bovine serum was added and reacted at room temperature for 1 hour to remove the nonspecific immune response. Then, primary antibody anti-BrdU (1: 200, Abcam) and anti-Iba1 (1: 500, Abcam plc, UK) was added and reacted at 4 ° C for 16 hours or longer. After washing the tissue again, the secondary antibody labeled with AF488 fluorescence and Cy3 fluorescence was applied for 2 hours and then washed and sealed with a mounting solution for fluorescence observation (Vectashield). The green and red fluorescence signals of the labeled tissue were observed with a confocal microscope (Nikon), and the number of cells labeled with BrdU, the number of labeled with Iba1, and the number of cells labeled with BrdU and Iba1 were calculated .

4-2 Experimental results

The results are shown in Figs.

FIGS. 9 and 10 are statistical images of microsomal cells activated in the hemisphere of the brain 1 day after cerebral ischemia. The number of activated macrophages in the cerebral ischemia was increased, and the number of the microcystic cells in the cerebral ischemia was increased, and the number of the microcytic cells in the cerebral ischemia was statistically decreased by treating the compounds of the present invention.

11 and 12, in which microphotographs and numbers of microcytes activated in the hemispheres of the brain 3 days after cerebral ischemia were statistically treated, the compounds of the present invention were treated by treating the compounds of the present invention in the hemispheres of the brain subjected to stimulation three days after cerebral ischemia The number of microglial cells was decreased statistically and the decrease by compound treatment was observed in both observed sites. In addition, analysis of the shape of the microglobulin showed that the number of microglobulin cells of the amoeboid type mediating the damage of the cerebral ischemia was significantly reduced by the compound treatment

FIGS. 13 and 14 are statistical images of microglial cell proliferation photographs and numbers thereof activated in the hemisphere of the brain 3 days after cerebral ischemia. As shown, the number of proliferating activated macrophages in the cerebral ischemia was increased, and it was confirmed that the number of the activated macrophages was significantly reduced by treating the compounds of the present invention.

Thus, Compound Example 21 (SH-88), Example 1 (SH-66), and Example 19 (HJ-16) according to the present invention are useful for the treatment of micro- Cell proliferation is effectively reduced, thereby effectively treating cerebral ischemia.

< Experimental Example  5> NO production inhibition experiment

5-1 Experimental Method

Example 1 To evaluate the inhibitory effect of NO on the secretion-related factor (SH-66), LPS-induced BV-2 cells were used. BV-2 cells were plated at 4 × 10 ⁴ cells / well in a 96-well plate and treated with LPS at 100 ng / ml for 24 hours. After 30 minutes, the compounds were treated by concentration and incubated for 24 hours. NO production was measured by Griess assay. 100 μl of the supernatant was collected from each well and incubated with 100 μl of Griess reagent (0.1% N-1-napthylethylenediamine dihydrochloride (N) and 1% sulfanilamide in 5% phosphoric acid (SP) The absorbance was measured using an ELISA reader (570 nm) and the NO concentration was calculated based on the standard curve of sodium nitrite (NaNO 2).

5-2 Experimental results

The results are shown in Fig. 15 and Fig.

As shown, the inhibitory effect of NO secretion, which is an inflammation-related factor, on the compound of Example 1 (SH-66) was evaluated by microglia cells. As a result, the compound of Example 1 (SH-66) inhibited NO production in a concentration- NMDA compounds, which are well known as NO production inhibitors, exhibit higher inhibitory effect on NO production. In addition, the inhibitory effect of NO production was higher than that of 6-shogaol

< Experimental Example  6> MTT  Experiment

6-1 Experimental Method

In order to evaluate the cytotoxicity of the compound of Example 1 (SH-66), BV2 cells were divided into 4 × 10 ⁴ cells / well in a 6-well plate for cell culture and stabilized for 24 hours. -66) compounds were pre-treated for 24 hours at each concentration, and post-treated with LPS for 24 hours. The medium was then removed, and tetrazolium bromide salt (MTT) was diluted to a concentration of 0.5 g / ml and dispensed. After incubation for 2 hours, the supernatant was removed, and formazin was completely dissolved in dimethylsulfoxide (DMSO). Then, 200 μl of the solution was transferred to a 96-well plate and measured with an ELISA reader at 570 nm absorbance.

6-2 Experimental results

The results are shown in Fig.

As shown, the Example 1 (SH-66) compound was determined to be non-cytotoxic.

< Experimental Example  7> Example 1 (SH-66) Compound BV - 2 cells iNOS , COX-2, TNF -α expression

7-1 Experimental Method

Example 1 In order to evaluate the inhibitory effect of iNOS, COX-2 and TNF-α, which are inflammatory factors, on SH-66 compounds, LPS-induced BV-2 cells were treated with SH66 compounds at various concentrations, analysis method. BV2 cells were plated at 6 × 10 ⁵ cells / well in 6-well plates, washed twice with PBS, and lysed in 1 M Tris-HCl, 5 M NaCl, 0.5% Triton X-100, protease inhibitor The cells were lysed using a cocktail. The supernatant was recovered by centrifugation at 14,000 rpm for 15 min. The amount of protein was quantified using Bradford's solution and BSA standard solution, and 50 μg of protein was electrophoresed using 9-12% polyacrylamide gel. Gel was separated, transferred to nitrocellulose membrane, blocked with 5% skim milk for 1 hour at room temperature, antibody was added to each target protein, reacted overnight at 4 ° C, washed three times with PBS-T solution Anti-IgG conjugated HRP antibody was added and reacted at room temperature for 1 hour. The cells were washed three times with PBS-T and sensitized to X-ray film using a solution of enhanced chemiluminescence (ECL) Western blotting detection reagents (SuperSignal, Thermo Scientific, Rockford, Ill., USA).

7-2 Experimental Results

The results are shown in Fig.

As shown, the Example 1 (SH-66) compound decreased inflammation-related factors (iNOS, Cox-2, TNF-a) in a concentration-dependent manner.

< Experimental Example  8> Example 1 (SH-66) Compound PGE2 , IL- 6, TNF Effect on -α

8-1 Experimental Method

Example 1 In order to measure the inhibitory effect of PGE2, IL-6, and TNF-a on the inflammation-related factors (SH-66), ELISA assay kit was used.

8-2 Experimental results

The results are shown in Figs. 19, 20 and 21. Fig.

As shown, the Example 1 (SH-66) compound reduced PGE2, IL-6, and TNF-a secretion in a concentration-dependent manner, especially in the PGE2 and TNF- Showed high inhibition.

Experimental Example 9 Example 1 (SH-66) Non-specificity by type of TLR

9-1 Experimental Method

Example 1 To confirm that the compound (SH-66) is selective for a specific TLR, TLR4 antagonist LPS and TLR1,2 antagonist PamCSK and TLR3 antagonist poly Lt; / RTI &gt; Example 1 (SH-66) After 24 hours of compound treatment, the NO production inhibitory effect was measured using the Griess reagent method described above.

9-2 Experimental results

The results are shown in FIG.

As shown, the Example 1 (SH-66) compound was not specific for a particular TLR. Dose-dependently reduced NO production in each TLR antagonist.

< Experimental Example  10> Example 1 (SH-66) Compound MAPK's  And AP-1

10-1 Experimental method

The expression levels of MAPKs (P38, ERK and JNK) and AP-1 (C-JUN, C-FOS) protein were determined by the Western blot analysis method in order to investigate the neuroinflammatory mechanism of the compound of Example 1 (SH- .

10-2 Experimental results

The results are shown in Figs. 23 and 24.

As shown, the Example 1 (SH-66) compound reduced the phosphorylation protein expression of MAPKs (P38, ERK, JNK) and AP-1 (C-JUN, C-FOS) in a concentration-dependent manner.

< Experimental Example  11> Example 1 Synthesis of (SH-66) Compound  Neuroprotective effect

11-1 Experimental Method

Example 1 N2a cells were used to confirm the ability of (SH-66) compounds to protect against apoptotic neuronal cell death. BV2 cells were plated at 4 × 10 ⁴ cells / well in a 6-well plate for cell culture, and then conditioned medium (CM) was cultured for 24 hours in LPS (100 ng / ml) And the cytotoxicity was measured 24 hours after the MTT assay. Bax, Bcl2, and Cleaved caspase-3 protein expression levels were also measured by western blot analysis to determine the expression level of neuronal cell apoptosis-related protein.

11-2 Experimental Results

The results are shown in Fig. 25 and Fig. 26.

Example 1 (SH-66) compound increased cell survival rate in neuronal N2a cells in a concentration-dependent manner, in contrast to cytotoxicity induced by microglia conditioned medium induced by LPS. In addition, it decreased the amount of Bax and Cleaved caspase-3 protein, which is a neuronal cell apoptosis related protein, and increased the amount of Bcl2 protein expression.

< Experimental Example  12> BV - 2 cells Example 1 (SH-66) Compound  Effect on protein expression

12-1 Experimental method

The expression level of COX-2, iNOS, TLR4, Ninjurin1, P53 and TNF-α was determined by western blot analysis by increasing the concentration of LPS to 100 ng / ml to 2.5 μg / ml in order to confirm the reduction of ninjurin1 production in BV2 cells Lt; / RTI &gt;

12-2 Experimental results

The results are shown in Fig. 27, Fig. 28 and Fig. 29.

LPS treatment in BV2 cells increased COX-2, iNOS, TLR4 and Ninjurin1 protein expression as opposed to Example 1 (SH-66) compound treatment. In addition, Ninjurin 1, P53 and TNF-? Were reduced in the same time and under the same conditions in Example 1 (SH-66) compound treatment. These results suggest that LPS increases Ninjurin1, P53 and TNF-α protein expression.

< Experimental Example  13> In N2a cells Example 1 (SH-66) Compound  Effect on cell survival and neurite length

13-1 Experimental method

N2a cells were treated with the compound of Example 1 (SH-66) and retinoic acid (RA) as a positive control for 24 hours to measure neurite outgrowth and cell viability. Cell viability was measured by MTT assay and neurite growth was measured by incucyte To measure the extent of this.

13-2 Experimental results

The results are shown in Fig. 30, Fig. 31, Fig. 32, and Fig.

The compound of Example 1 (SH-66) showed cytotoxicity when treated at a concentration of 10, 20 μM in N2a cells, and was not toxic at a concentration as low as 1,5 μM. At 5, 10 and 20 μM concentrations, the neurite length was significantly increased, and at 5 μM concentration, it was nearly double that of the positive control group, Retinoic acid (RA) 20 μM. Although toxic at 10 and 20 μM concentrations, the effect was higher than the positive control RA. Neurite length graphs were also measured in the same manner.

< Experimental Example  14> In astrocytes  Neuroprotective effect observation

14-1 Experimental Method

C6 glioma cells were assayed for release of NGF liberated in the medium. For the measurement of NGF levels, C6 cells were plated at 1 × 10 ⁵ cells / well in a 24-well plate. After 24 hours, the compounds were treated with different concentrations of serum free DMEM and antibiotics and cultured for 24 hours. The supernatant was used for NGF assay and the degree of NGF was measured by ELISA kit. Cell viability was measured by MTT assay.

14-2 Experimental results

The results are shown in Figs. 34 and 35.

The Example 1 (SH-66) compound did not show cytotoxicity in C6 cells, and it is thought that it may be helpful in treating brain inflammation in brain by increasing NGF production in astrocyte cells.

< Experimental Example  15> NO production inhibition experiment

15-1 Experimental method

To evaluate the inhibitory effect of NO, which is an inflammation-related factor, to the compound of Example 21 (SH-88), LPS-induced BV-2 cells were used. BV-2 cells were plated at 4 × 10 ⁴ cells / well in a 96-well plate and treated with LPS at 100 ng / ml for 24 hours. After 30 minutes, the compounds were treated by concentration and incubated for 24 hours. NO production was measured by Griess assay. 100 μl of the supernatant was collected from each well and incubated with 100 μl of Griess reagent (0.1% N-1-napthylethylenediamine dihydrochloride (N) and 1% sulfanilamide in 5% phosphoric acid (SP) The absorbance was measured using an ELISA reader (570 nm) and the NO concentration was calculated based on the standard curve of sodium nitrite (NaNO 2).

15-2 Experimental results

The results are shown in Fig.

Example 21 (SH-88) The inhibitory effect of NO on secretion of the compound was evaluated by microglia cells. As a result, the compound of Example 21 (SH-88) inhibited NO production in a concentration- Compared with the well-known L-NMMA compound, the inhibitory effect on NO production was more pronounced at the same concentration of 20M. Also, NO production inhibition effect was higher than 6-shogaol.

< Experimental Example  16> MTT experiment

16-1 Experimental Method

In order to evaluate cytotoxicity against the compound of Example 21 (SH-88), BV2 cells were divided into 4 × 10 ⁴ cells / well in a 6-well plate for cell culture and stabilized for 24 hours. 88) were pretreated with LPS for 24 hours, and cultured for 24 hours. The medium was then removed, and tetrazolium bromide salt (MTT) was diluted to a concentration of 0.5 g / ml and dispensed. After incubation for 2 hours, the supernatant was removed, and formazin was completely dissolved in dimethylsulfoxide (DMSO). Then, 200 μl of the solution was transferred to a 96-well plate and measured with an ELISA reader at 570 nm absorbance.

16-2 Experimental results

The results are shown in Fig.

As shown, the Example 21 (SH-88) compound was determined to be non-cytotoxic.

< Experimental Example  17> Example 21 (SH-88) Compound iNOS , COX-2 Expression

17-1 Experimental method

Example 21 To evaluate the inhibitory effect of iNOS and COX-2 on the inflammation-related factors (SH-88), BV-2 cells induced by LPS were treated with the compound of Example 21 (SH-88) Were measured by Western blot analysis. BV2 cells were plated at 6 × 10 ⁵ cells / well in 6-well plates, washed twice with PBS, and lysed in 1 M Tris-HCl, 5 M NaCl, 0.5% Triton X-100, protease inhibitor The cells were lysed using a cocktail. The supernatant was recovered by centrifugation at 14,000 rpm for 15 minutes. The amount of protein was quantified using Bradford's solution and BSA standard solution, and 50 μg of protein was electrophoresed using 9-12% polyacrylamide gel. Gel was separated, transferred to nitrocellulose membrane, blocked with 5% skim milk for 1 hour at room temperature, antibody was added to each target protein, reacted overnight at 4 ° C, washed three times with PBS-T solution Anti-IgG conjugated HRP antibody was added and reacted at room temperature for 1 hour. The cells were washed three times with PBS-T and sensitized to X-ray film using a solution of enhanced chemiluminescence (ECL) Western blotting detection reagents (SuperSignal, Thermo Scientific, Rockford, Ill., USA).

17-2 Experimental results

The results are shown in Fig.

Example 21 (SH-88) compound decreased the expression of inflammation-related proteins iNOS and COX-2 protein in a concentration-dependent manner.

< Experimental Example  18> Example 21 (SH-88) Compound PGE2 , IL-6, TNF Effect on -α

18-1 Experimental method

Example 21 In order to measure the inhibitory effect of PGE2, IL-6, and TNF-α secretion-related factors on the SH-88 compound, ELISA assay kit was used.

18-2 Experimental results

The results are shown in FIG. 39, FIG. 40, and FIG.

Example 21 (SH-88) decreased PGE2, IL-6, and TNF-α secretion, and PGE2 and TNF-α inhibition showed higher inhibition than the positive control L-NMMA compound.

< Experimental Example  19> Example 21 Synthesis of (SH-88) Compound TLR  Non-specific

19-1 Experimental method

Example 21 (SH-88) TLR4 antagonist LPS and TLR1,2 antagonist PamCSK and TLR3 antagonist poly were treated for 30 minutes before compound 21 (SH-88) compound treatment to confirm that the compound was specific for TLR Respectively. Example 21 (SH-88) Compound treatment After 24 hours, the inhibitory effect of NO production was measured using the Griess reagent method.

19-2 Experimental Results

The results are shown in Fig.

As shown, the Example 21 (SH-88) compound was not specific for a particular TLR. Dose-dependently reduced NO production in each TLR antagonist.

< Experimental Example  20> Example 21 (SH-88) Compound In MAPK's expression  Effect

20-1 Experimental Method

Example 21 The expression level of MAPK's (P38, ERK and JNK) protein was measured by the Western blot analysis method to identify the neuroinflammatory mechanism for the compound (SH-88).

20-2 Experimental results

The results are shown in FIG.

As shown, the compound of Example 21 (SH-88) significantly decreased the expression of P38 phosphorylation protein in the MAPKs sinal pathway in a concentration-dependent manner, and the amount of phosphorylation protein expression of ERK and JNK did not change.

< Experimental Example  21> At N2a  Neuroprotective effect

21-1 Experimental Method

Example 21 N2a cells were used to determine the apoptotic neuronal cytotoxicity of (SH-88) compounds. BV2 cells were plated at 4 × 10 ⁴ cells / well in a 6-well plate for cell culture, and then conditioned medium (CM) was cultured for 24 hours in LPS (100 ng / ml) And the cytotoxicity was measured 24 hours after the MTT assay. Bax, Bcl2, and Cleaved caspase-3 protein expression levels were also measured by western blot analysis to determine the expression level of neuronal cell apoptosis-related protein.

21-2 Experimental results

The results are shown in Figs. 44 and 45

As shown, the compound of Example 21 (SH-88) increased cell survival rate in neuronal cells, N2a cells, in a concentration-dependent manner, in contrast to cytotoxicity of LPS-induced microglia. In addition, it decreased the amount of Bax and Cleaved caspase-3 protein, which is a neuronal cell apoptosis related protein, and increased the amount of Bcl2 protein expression.

< Experimental Example  22> In N2a cells Example 21 (SH-88) Compound  Effect on cell survival and neurite length

22-1 Experimental Method

For the measurement of neurite outgrowth and cell viability in N2a cells, the compound of Example 21 (SH-88) and retinoic acid (RA) as a positive control were treated for 24 hours. Cell viability was measured by MTT assay, Was measured by incucyte.

22-2 Experimental Results

The results are shown in Figures 46-49.

The compound of Example 21 (SH-88) showed no toxicity at the concentrations of 1, 5, 10, and 20 uM in N2a cells. In Figure 46, retinoic acid (RA) was used as a positive control. When the compound of Example 21 (SH-88) was treated in N2a cells for 24 hours, the length of neurite increased in a concentration-dependent manner. As a result of a similar pattern, the length of the neurite was observed as shown in FIG. Example 21 (SH-88) compounds induced neurite outgrowth more than RA and 6-shogaol.

< Experimental Example  23> In astrocytes  Neuroprotective effect

23-1 Experimental Method

C6 glioma cells were used to measure the amount of NGF secreted by the culture medium. For the measurement of NGF levels, C6 cells were plated at 1 × 10 ⁵ cells / well in a 24-well plate. After 24 hours, the compounds were treated with different concentrations of serum free DMEM and antibiotics and cultured for 24 hours. The supernatant was used for NGF assay and the degree of NGF was measured by ELISA kit. Cell viability was measured by MTT assay.

23-2 Experimental results

The results are shown in Fig. 50 and Fig. 51 .

The compound of Example 21 (SH-88) did not show cytotoxicity in C6 cells. This shows that NGF production in astrocyte can be induced when compared to 6-shogaol. Thus, Example 21 (SH-88) was found to have a very high potential for neuroprotection.

< Experimental Example  24> In multiple sclerosis  About Example 21 Synthesis of (SH-88) Compound  Efficacy evaluation

24-1 Experimental Method

(SH-88) compound according to the present invention was administered to experimental rats (7-8 weeks old) induced EAE by using an experimental autoimmune encephalomyelitis (EAE) model, which is a representative animal model of multiple sclerosis And drug efficacy were evaluated.

Specifically, the EAE experiment was performed by preparing a myelin spindle-cell glial cell glycoprotein (MOG) amino acid 35-55 (MEVGWYRSPFSRVVHLYRNGK; Peptron, Republic of Korea, 96% purity) in a laboratory mouse (C57BL / 200 μg (MOG / CFA) was subcutaneously injected as a pertussis toxin (PTX, 400 ng / mouse, ip) with Complete Freund's Adjuvant (CFA) Respectively. (1% DMSO in 10% Tween 80, po) and Example 21 (SH-88) compound (2 or 10) after the symptoms of the disease reached a peak (antigen challenge 21 days) mg / kg in 10% Tween 80, po) for 14 days in rats with EAE symptoms.

The mice were weighed daily and the symptoms of the disease were measured and the symptoms of the disease according to progression were shown using the following values (0, healthy state: 1, exhaustion state: 2, weakness of hind limb movement: 3 , Complete paralysis of the hind limb; 4, two or more limb paralysis; 5, death due to illness).

24-2 Experimental results

The results are shown in Fig.

Fig. 52 shows the results of EAE-induced rats receiving vehicle (10% Tween 80, po), Example 21 (SH-88) compound 2 mg / kg (po) or Example 21 (SH- ), And the boxed period is the period of drug administration (start of administration after 21 days of antigen injection, final administration of 33 days, end of 34 days of experiment) .

As shown, 2 mg / kg of the compound of Example 21 (SH-88) shows that the clinical score begins to decrease after 3 days of dosing. From this, it was confirmed that the compound of Example 21 (SH-88) according to the present invention can prevent or treat multiple sclerosis by effectively reducing nerve damage resulting from multiple sclerosis, and is useful as a pharmaceutical composition containing it as an active ingredient It is confirmed that

Claims (10)

Claims 1. A compound represented by the following formula (1), an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
[Chemical Formula 1]

(In the formula 1,

Is a single bond or a double bond;

R ¹ , R ² and R ³ are independently -H, -OH, or a straight or branched C _1-5 alkoxy;

Z ¹ and Z ² are independently -H or -OH, or Z ¹ and Z ² are linked together

or

,

Is a double bond, Z &lt; ^{1 &gt;} and Z &lt; ^{2 &gt;}

&Lt; / RTI &gt;

Z &lt; ^{3 &}

Member is a double bond,

If the work -H single bond or -CH ₂ OH, provided the

Is a single bond and Z &lt; ¹ &gt; and Z &lt; ² &

Z &lt; ³ &gt; is a member;

E, G and M are independently C or N;

R ⁴ is member when E is N, -H when E is C, C _1-5 alkoxy of straight chain or branched chain, or halogen, or is connected with R ⁵ to form unsubstituted phenyl;

R ⁵ is a member when G is N and is -H when G is C, straight or branched C _1-5 alkoxy, halogen, unsubstituted or substituted straight or branched C _1-5 Alkyl, -OH,

or

Or, together with R ⁶ is connected

&Lt; / RTI &gt;

R ⁶ is a member when M is N and is -H when M is C, straight or branched C _1-5 alkoxy, halogen, -OH, or straight or branched chain unsubstituted or substituted with one or more halogens C _1-5 alkyl; And

R ⁷ and R ⁸ are independently -H, or a linear or branched C _1-5 alkoxy.
The method according to claim 1,

Is a single bond or a double bond;

R ¹ , R ² and R ³ are independently -H, -OH, or a linear or branched C _1-3 alkoxy;

Z ¹ and Z ² are independently -H or -OH, or Z ¹ and Z ² are linked together

or

,

Is a double bond, Z &lt; ^{1 &gt;} and Z &lt; ^{2 &gt;}

&Lt; / RTI &gt;

Z &lt; ^{3 &}

Member is a double bond,

If the work -H single bond or -CH ₂ OH, provided the

Is a single bond and Z &lt; ¹ &gt; and Z &lt; ² &

Z &lt; ³ &gt; is a member;

E, G and M are independently C or N;

R ⁴ is member when E is N, -H when E is C, C _1-3 alkoxy of straight chain or branched chain, or halogen, or R ⁸ together with R ⁵ forms unsubstituted phenyl;

R ⁵ is a member when G is N and is -H when G is C, straight or branched C _1-3 alkoxy, halogen, unsubstituted or straight-chain or branched C _1-4 Alkyl, -OH,

or

Or, together with R ⁶ is connected

&Lt; / RTI &gt;

R ⁶ is a member when M is N and is -H when M is C, straight or branched C _1-3 alkoxy, halogen, -OH, or straight or branched chain unsubstituted or substituted with one or more halogens C _1-4 alkyl; And

R ⁷ and R ⁸ are independently -H, or a linear or branched C _1-3 alkoxy, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,

The

,

,

,

,

,

,

,

or

However,

remind

end

or

If it is,

Is a single bond, an optical isomer thereof, or a pharmaceutically acceptable salt thereof.
The method according to claim 1,
The compound represented by the formula (1) is any one selected from the group consisting of the following compounds, an optical isomer thereof, or a pharmaceutically acceptable salt thereof:
(1) (E) -3- (3-hydroxy-4-methoxybenzylidene) -5,7-dimethoxychroman-4-one;
(2) (E) -3- (4-hydroxy-3-methoxybenzylidene) -5,7-dimethoxychroman-4-one;
(3) (E) -3-Benzylidene-5,7-dimethoxychroman-4-one;
(4) (E) -3- (4-tert-Butylbenzylidene) -5,7-dimethoxychroman-4-one;
(5) (E) -5,7-Dimethoxy-3- (4-methoxybenzylidene) chroman-4-one;
(6) (E) -3- (4-Chloro-3- (trifluoromethyl) benzylidene) -5,7-dimethoxychroman-4-one;
(7) (E) -3- (Benzo [d] [1,3] dioxol-5-ylmethylene) -5,7-dimethoxychroman-4-one;
(8) (E) -5,7-Dimethoxy-3- (naphthalen-1-ylmethylene) chroman-4-one;
(9) (E) -5,7-Dimethoxy-3- (3,4,5-trimethoxybenzylidene) chroman-4-one;
(10) (E) -3- (4-fluorobenzylidene) -5,7-dimethoxychroman-4-one;
(11) (E) -3- (4-hydroxybenzylidene) -5,7-dimethoxychroman-4-one;
(12) (E) -3- (3-Fluorobenzylidene) -5,7-dimethoxychroman-4-one;
(13) (E) -5,7-Dimethoxy-3 - ((6-methoxypyridin-2-yl) methylene) chroman-4-one;
(14) (E) -3- (4-Chloro-3-fluorobenzylidene) -5,7-dimethoxychroman-4-one;
(15) (E) -3- (3,4-dimethoxybenzylidene) -5,7-dimethoxychroman-4-one;
(16) (E) -3- (4-Bromo-2-fluorobenzylidene) -5,7-dimethoxychroman-4-one;
(17) (E) -5,7-Dimethoxy-3- (2,4,6-trimethoxybenzylidene) chroman-4-one;
(18) (E) -5,7-Dimethoxy-3- (pyridin-2-ylmethylene) chroman-4-one;
(19) (E) -5,7-Dimethoxy-3- (pyridin-3-ylmethylene) chroman-4-one;
(20) (E) -5,7-Dimethoxy-3- (pyridin-4-ylmethylene) chroman-4-one;
(21) 3- (3-hydroxy-4-methoxybenzyl) -5,7-dimethoxychroman-4-one;
(22) 3- (4-hydroxy-3-methoxybenzyl) -5,7-dimethoxychroman-4-one;
(23) 3-benzyl-5,7-dimethoxychroman-4-one;
(24) 3- (4-tert-Butylbenzyl) -5,7-dimethoxychroman-4-one;
(25) 5,7-Dimethoxy-3- (4-methoxybenzyl) chroman-4-one;
(26) 3- (4-Chloro-3- (trifluoromethyl) benzyl) -5,7-dimethoxychroman-4-one);
(27) 3- (Benzo [d] [1,3] dioxol-5-ylmethyl) -5,7-dimethoxychroman-4-one;
(28) 5,7-Dimethoxy-3- (naphthalen-1-ylmethyl) chroman-4-one;
(29) 5,7-Dimethoxy-3- (3,4,5-trimethoxybenzyl) chroman-4-one;
(30) 3- (4-fluorobenzyl) -5,7-dimethoxychroman-4-one;
(31) 3- (4-hydroxybenzyl) -5,7-dimethoxychroman-4-one;
(32) 3- (3-fluorobenzyl) -5,7-dimethoxychroman-4-one;
(33) 5,7-Dimethoxy-3 - ((6-methoxypyridin-2-yl) methyl) chroman-4-one;
(34) 3- (4-Chloro-3-fluorobenzyl) -5,7-dimethoxychroman-4-one;
(35) 3- (3,4-dimethoxybenzyl) -5,7-dimethoxychroman-4-one;
(36) 3- (4-Bromo-2-fluorobenzyl) -5,7-dimethoxychroman-4-one;
(37) 5,7-Dimethoxy-3- (2,4,6-trimethoxybenzyl) chroman-4-one;
(38) 5,7-Dimethoxy-3- (pyridin-2-ylmethyl) chroman-4-one;
(39) 5,7-Dimethoxy-3- (pyridin-3-ylmethyl) chroman-4-one;
(40) 5,7-Dimethoxy-3- (pyridin-4-ylmethyl) chroman-4-one;
(41) (E) -3- (3-hydroxy-4-methoxybenzylidene) -5,6,7-trimethoxychroman-4-one;
(42) 3- (3-hydroxy-4-methoxybenzyl) -5,6,7-trimethoxy-4H-chromen-4-one;
(43) Synthesis of (E) -3- (3- (benzyloxy) -4-methoxyphenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) prop- 1-one;
(44) 3- (3-hydroxy-4-methoxybenzyl) -5,6,7-trimethoxychroman-4-one;
(45) 3-benzyl-5,6,7-trimethoxychroman-4-one;
(46) 3-Benzyl-5-hydroxy-6,7-dimethoxychroman-4-one;
(47) 5 - ((5,7-dihydroxy-6-methoxy-4-oxochroman-3-yl) methyl) -2-methoxyphenyl benzoate;
(48) 5,7-Dihydroxy-3- (3-hydroxy-4-methoxybenzyl) -3- (hydroxymethyl) -6-methoxychroman-4-one;
(49) 1- (6-Hydroxy-2,3,4-trimethoxyphenyl) -3- (3-hydroxy-4-methoxyphenyl) propan-1-one;
(50) 3- (3,4-dimethoxyphenyl) -1- (6-hydroxy-2,3,4-trimethoxyphenyl) propan-1-one; And
(51) 1- (6-Hydroxy-2,3,4-trimethoxyphenyl) -3-phenylpropan-1-one.
As shown in Scheme 1 below,
Reacting a compound represented by the formula (2) with a compound represented by the formula (3) to prepare a compound represented by the formula (4) (step 1); And
Reacting the compound represented by the formula (4) and the compound represented by the formula (5) prepared in the step 1 to prepare a compound represented by the formula (1) (step 2) : &Lt;
[Reaction Scheme 1]

(In the above Reaction Scheme 1,

, R ¹ , R ² , R ³ , R ⁴ , R ⁵ , R ⁶ , R ⁷ , R ⁸ , Z ¹ , Z ² , Z ³ , And M are independently as defined in formula (1) of claim 1).
A pharmaceutical composition for preventing or treating brain injury caused by ischemia comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
The method according to claim 6,
Wherein the brain injury caused by ischemia is brain damage caused by cerebral infarction, occlusion and stenosis of cerebral artery, occlusion and stenosis of cerebral artery, and cerebral hemorrhage.
A pharmaceutical composition for preventing or treating multiple sclerosis comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
A health food for preventing or ameliorating brain damage caused by ischemia comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.
A health food for preventing or ameliorating multiple sclerosis comprising the compound represented by the general formula (1) of claim 1, an optical isomer thereof, or a pharmaceutically acceptable salt thereof as an active ingredient.

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