WO1998009956A1

WO1998009956A1 - 2,3-dihydrobenzofuran derivative and hepatopathy remedy comprising the same as active ingredient

Info

Publication number: WO1998009956A1
Application number: PCT/JP1997/003168
Authority: WO
Inventors: Mikio Kurokawa; Takayuki Yoshida; Huminori Sato; Nobuo Matsuoka; Kunihisa Satomura
Original assignee: Dainippon Pharmaceutical Co., Ltd.
Priority date: 1996-09-09
Filing date: 1997-09-09
Publication date: 1998-03-12
Also published as: AU4136897A

Abstract

3-Amino- or imino-2,3-dihydrobenzofuran (or benzothiophene) derivatives represented by general formula (I), pharmaceutically acceptable acid-addition salt thereof, and a hepatopathy remedy comprising the same as the active ingredient, wherein R?1 and R2¿, which may be the same or different, each represents H, a lower alkyl group, or an acryl group, or R?1 and R2¿ combine with each other to form a methylene group or the like; R?3 and R4¿, which may be the same or different, each represents H, OH, an acyloxy group, or a lower alkoxy group; R?5a and R5b¿, which may be the same or different, each represents H, a lower alkyl or the like; ...A-R6 represents =N-R?6 or -NR6R7; R6¿ represents H, -OR8, a substituted or unsubstituted C¿1?-C8 alkyl group, -CO-R?9¿, or -SO¿2R?11; and X represents O or S.

Description

2,3-dihydrobenzobenzofuran derivatives and

A therapeutic drug for liver disease containing it as an active ingredient

The present invention relates to 2,3-dihydrobenzene diazofuran (or benzothiophene) derivatives. See 3-Amino or Iminnow 2, 3-Jihi Droben

The present invention relates to a zofuran (or benzothiophene) derivative and a therapeutic agent for liver disease containing the same as an active ingredient.

Liver diseases include acute hepatitis, chronic hepatitis, fulminant hepatitis, cirrhosis, hepatic failure, liver cancer, fatty liver, etc. The causes are also various, including hepatitis virus, alcohol, drugs, autoimmunity, and metabolic abnormalities. It is said that these cause the disease and eventually lead to liver cancer. It has become clear that cirrhosis is the basis for most liver cancers, and treatment of acute hepatitis may prevent irritation and prevent chronic hepatitis from progressing to cirrhosis. Treatment is considered clinically important. Currently, a representative drug clinically evaluated as a therapeutic agent for the above-mentioned liver diseases is an interferon preparation *. Interferon preparations have been shown to be effective for chronic viral hepatitis, but the efficacy rate is relatively low. In addition, interferon preparations have a high incidence of side effects such as fever and leukopenia, and long-term treatment with interstitial pneumonia (pulmonary fibrosis), autoimmune diseases (thyroiditis), psychiatric neuropathy, cardiomyopathy This is a problem because serious side effects such as these occur. Ma In addition, since the administration method is intravenous injection and is not effective orally, there are restrictions on the administration form. Other drugs include corticosteroids, liver protectants, branched-chain amino acids, glucagon and insulin. Examples of hepatoprotective agents include glycyrrhizin preparations (injection for intravenous injection), germanium preparations (propagermanium, etc.), herbal medicine Sho-saiko-to, gallstone dissolving agent ursodeoxycholic acid, tiopronin, maloylate, polyenphosphatidylcholine and so on. But force ^s et al, although in their indications also look for these agents are listed certain results, or have intravenous limited to dosage forms, or a drug efficacy is insufficient, the serious side effects There is a problem that it often occurs. Under such circumstances, there is a demand for the development of an excellent therapeutic agent for liver disease that is highly safe in the therapeutic field and effective orally.

In view of such circumstances, the present inventors have conducted intensive studies to develop a new therapeutic agent for liver disease. We found that it fit this purpose.

The following compounds are disclosed as 3-amino or imino-1,2,3-dihydrobenzofuran derivatives in Chim. Acta. Turc., 13, 403-412 (1985). Are different. In addition, the literature describes that these compounds are useful as synthetic intermediates for adrenergic blocking agen, but does not disclose their pharmacological actions at all.

The following compounds are disclosed in U.S. Pat. No. 2,855,406. The U.S. patent discloses these compounds as coronary vasodilators.

It is described as useful as a synthetic intermediate of (coronary vasodilator), but its pharmacological action is not described at all.

Disclosure of the invention

An object of the present invention is to provide an excellent therapeutic agent for liver disease which is highly safe and is effective orally. The present invention relates to a novel 2,3-dihydrobenzozofuran (or benzothiophene) derivative represented by the following general formula (I) or a physiologically acceptable acid thereof, which is useful as a medicament, particularly as a therapeutic drug for liver disease. The present invention relates to an addition salt and a use thereof as a therapeutic agent for liver disease containing the active ingredient as an active ingredient.

Wherein R i and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an aryl group, a hydroxy lower alkyl group, an aceethoxy lower alkyl group, a lower alkoxy lower alkyl group; A lower alkyl group, a lower alkylsulfonyl group, or a combination of R 1 and R ² may form a methylene group;

R ³ and R ⁴ are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a halo Gen atom, hydroxy group, acyloxy group, lower alkylsulfonyl group, lower alkoxy group, cyclo lower alkyloxy group, aralkyloxy group, nitro group, amino group, cyano group, carbamoyl group, sulfamoyl group, carboxyl group or lower alkoxycarbo means alkenyl group, R ⁵ a and R 5 b is a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, Ararukiru group or R ⁵ a and R 5 b forms a connexion ring such together the same or different ^ A—R 6 means (i) = N—R 6 when 1 ^ 1 is a double bond, and one NR ⁶ R ⁷ when (ii) is a single bond Means

R ⁶ is a hydrogen atom; R ⁸ (where R 8 is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or an acyl group), substituted or unsubstituted C ₈ alkyl group (substituent is cyclo lower § alkyl group of the alkyl group, Ariru group, Heteroariru group, arsenate Dorokishi group, a lower alkoxy group, Ararukiruokishi group, Ariruokishi group, Ashiruokishi group, amino group, mono-lower alkyl Wakashi Ku Di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkylsulfonyl group, arylsulfonyl group, acyl Group, carboxyl group or lower alkoxycarbonyl group One or two or more), lower alkyl group, aryl group, heteroaryl group, CO—R ⁹ (where R ⁹ is a hydrogen atom, cyclo lower alkyl group, aryl group, heteroaryl group, lower alkoxy) group, Ariruokishi group, an amino group, a mono (lower alkyl) Broiler Shikuji substituents lower alkyl amino group or a substituted or unsubstituted C i~CI ₂ alkyl group (the alkyl group is a lower cycloalkyl group, Ariru group, Heteroa Reel group, hydroxy group, acyloxy group, aryloxy group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino One or more selected from a group, a mercapto group, a lower alkylthio group, an arylthio group, a lower alkylsulfinyl group, an arylsulfinyl group, a lower alkylsulfonyl group, an arylsulfonyl group and a sulfamoyl group )), One CO—CH = CHR 10 (where Rio is a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, an acyl group, a cyano group, a lower alkoxycarbonyl group, a carboxyl group, or a carbamoyl group) or a S 0 ₂ R 1 1 (wherein, Ri i is Means grade alkyl group, triflate Ruoromechiru group, Ararukiru group, a a a) Ariru group or heteroaryl group,

R 7 represents a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group,

X represents an oxygen atom or a sulfur atom. However, when ^: Α—R ⁶ is —NH ₂ or = N—OH, R 10— and R ² 〇 are 4-1CH ₃ and 7—0 CH ₃ and R 3 and R 4 Except when one is a hydrogen atom and the other is 6-0 H)

Or a physiologically acceptable acid addition salt thereof.

The compound of the present invention is represented by the above general formula (I), and is specifically represented by the following general formula (II) or general formula (III).

Wherein R i and R 2 are the same or different from each other and are a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an aryl group, a hydroxy lower alkyl group, an acetyloxy lower alkyl group, a lower alkoxy lower alkyl group, Roxy lower alkyl group, acyl group, lower alkylsulfonyl group or R 1 and R ² may be combined to form a methylene group,

R 3 and R ⁴ are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkyl sulfonyl group A xy group, a lower alkoxy group, a cyclo-lower alkyloxy group, an aralkyloxy group, a nitro group, an amino group, a cyano group, a carbamoyl group, a sulfamoyl group, a carboxyl group or a lower alkoxycarbonyl group;

R ⁵ a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a cyclo-lower Arukiru group, Ararukiru group or R ⁵ a and R 5 b is may form a connexion ring such together,

R ⁶ is a hydrogen atom, one OR ⁸ (where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, an aralkyl group, an aryl group or an acyl group), substituted or unsubstituted C i -C 8 alkyl group (substituents of the alkyl group are cyclo lower alkyl group, aryl group, heteroaryl group, hydroxy group, lower alkoxy group, aralkyloxy group, aryloxy group, acyloxy group, amino group, Mono-lower alkyl or di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkyl sulfonyl group , An arylsulfonyl group, an acyl group, a carboxyl group or a lower alkoxycarbonyl group), a cycloalkyl group, an aryl group, a heteroaryl group, a CO—R 9 ( Here, R ⁹ is a hydrogen atom, a cyclo-lower alkyl group, an aryl group, a heteroaryl group, a lower alkoxy group, an aryloxy group, an amino group, a mono-lower alkyl or di-lower alkylamino group or a substituted or unsubstituted C 1 -C 1 ₂ alkyl group (the substituent is a lower cycloalkyl group and the alkyl group Aryl group, heteroaryl group, hydroxy group, acyloxy group, aryloxy group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono-lower alkyl or di-lower Selected from an alkylamino group, an acylamino group, a mercapto group, a lower alkylthio group, an arylthio group, a lower alkylsulfinyl group, an arylsulfinyl group, a lower alkylsulfonyl group, an arylsulfonyl group and a sulfamoyl group One or two or more)), one CO—CH = CHR 10 (where R io is a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl group, an acyl group, a cyano group, a lower alkoxycarbonyl group, Carboxyl or levamoyl) or S 0 ₂ R i 1 (wherein, R 1 1 is a lower alkyl group, triflate Ruoromechiru group, Ararukiru group, a is Ariru group or heteroaryl group) means,

X represents an oxygen atom or a sulfur atom. However, when R ⁶ is OH, R 1 0- and R 2〇— are 4-0 CH ₃ and 7— OCH ₃ , unless one of R 3 and R 4 is a hydrogen atom and the other is 6-0 H)

2,3-dihydrobenzofuran derivative represented by or a physiologically acceptable acid addition salt thereof.

Wherein R 1 and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, an aralkyl group, an aryl group, a hydroxy lower alkyl group, an aceethoxy lower alkyl group, a lower alkoxy lower alkyl group; R 1 and R ² may be combined with each other to form a methylene group, or a lower alkoxyl alkyl group, an acyl group, a lower alkyl sulfonyl group, or

R ³ and R ⁴ are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy Group, lower alkoxy group, cyclo-lower alkyloxy group, aralkyloxy group, nitro group, amino group, cyano group, carbamoyl group, sulfamoyl group, carboxyl group or quaternary alkoxycarbonyl group, R 5a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, Ararukiru group or R ⁵ a and R 5 b is may form a connexion ring such together,

R ⁶ is a hydrogen atom, —OR ⁸ (where R ⁸ is a hydrogen atom, a lower alkyl group, Mouth lower alkyl group, Ararukiru group, a Ariru group or Ashiru group), substitution or unsubstituted C. 1 to C ₈ substituent of the alkyl group (the alkyl group is a cyclo-lower § alkyl group, Ariru group, Heteroari Ichiru group , Hydroxy group, lower alkoxy group, aralkyloxy group, aryloxy group, acyloxy group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, α One or more selected from a arylthio group, a lower alkylsulfinyl group, an arylsulfinyl group, a lower alkylsulfonyl group, an arylsulfonyl group, an acyl group, a carboxyl group and a lower alkoxycarbonyl group) , Lower mouth alkyl group, aryl group, hete Ariru group, -CO- R 9 (wherein, R ⁹ is a hydrogen atom, a lower cycloalkyl group, Ariru group, Heteroariru group, a lower alkoxy group, Ariruokishi group, an amino group, a mono (lower alkyl) Broiler Shikuji lower Arukiruamino group or a substituted or unsubstituted C 1 through C 1 ₂ substituents alkyl group (the alkyl group is a lower cycloalkyl group, Ariru group, Heteroa aryl group, arsenate Dorokishi group, Ashiruokishi group, Ariruokishi group, a lower alkoxy group, a carboxyl group, a lower Alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino group, mercapto group, lower alkylthio group, aryloxy group, lower alkylsulfinyl group, arylsulfinyl Group, lower alkyl sulfo Or one or more selected from an aryl group, an arylsulfonyl group or a sulfamoyl group)), one CO—CH = CHR io (where R io is a hydrogen atom, a lower alkyl group, an aryl group, a heteroaryl) Group, acyl group, cyano group, lower alkoxycarbonyl group, carboxyl group or carbamoyl Or SOSOzR ¹¹ (where RH is a lower alkyl group, a trifluoromethyl group, an aralkyl group, an aryl group or a heteroaryl group),

R ⁷ represents a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and X represents an oxygen atom or a sulfur atom. However, when R ⁶ and R ⁷ are both hydrogen atom, R 10- and R20- is 4 one 〇_CH ₃ and 7 0 (: 11 ₃ a and the other while the hydrogen atoms of R ³ and R 4 6-3 except H), or a physiologically acceptable acid addition salt thereof.

Among the compounds of the present invention, preferred compounds are those in which X is an oxygen atom and R ¹ and R ² are the same or different from each other and are a hydrogen atom, a lower alkyl group, an acyl group, a lower alkyl group. Sulfonyl group or R ¹ and R ^2- a methylene group connected together and R ³ and R ⁴ are the same or different from each other and are a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkyl group a Suruhoniruokishi or a lower alkoxy group, R ⁵ a and R

5 b is the same or different and is a hydrogen atom or a lower alkyl group, R ⁶ is a hydrogen atom, a lower alkyl group, —OR ⁸ (where R ⁸ is a lower alkyl group), —C0—R 9 ( Here, R 9 is a substituted or unsubstituted ^ 〜 (: an alkyl group (the substituent of the alkyl group is one or more selected from a hydroxy group, an acyloxy group or a lower alkoxy group); -CHR 10 (where R 10 is a hydrogen atom, a lower alkyl group or an aryl group) or one SOR 11 (where R 11 is a lower alkyl group or an aryl group) or a compound thereof or its physiology And acid addition salts which are chemically acceptable. As more preferred compounds, in the general formula (II), R 1 and R ² are the same or different from each other and are a hydrogen atom, a C! C ^ alkyl group, an acyl group;

3 and R ⁴ are the same or different from each other and are a hydrogen atom, a hydroxy group, an acyloxy group or a C i Cg alkoxy group, and R 5a and R 5b are one or different hydrogen atoms or C—C ₃ A compound wherein R ⁶ is a hydrogen atom or one OR ⁸ (where R ⁸ is a C i -C ₃ alkyl group) or a physiologically acceptable acid addition salt thereof.

Specific preferred compounds represented by the general formula (II) include:

3-imino_4-hydroxy-1 6-methoxy-2,2-dimethyl-2,3-dihydroxybenzofuran hydrochloride,

3-Iminnow 4-Hydroxy-5,6-dimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran hydrochloride,

3—Methoxyminnow 5—Hydroxy 4,6—Dimethoxy 2,3—Dihydro benzofuran,

3—Methoxyimino 5—Hydroxy 1,6,7—Dimethoxy 1,2,3-Dihydro πbenso ', furan,

3-Methoxyimino 5-Hydroxy 6,7-Dimethoxy 1,2,2-Dimethyl 2,3, Dihydrobenzoben

3-Methoxyimino-1 7-Hydroxy-5,6-dimethoxy 2,3-dihydric benzofuran.

Other preferred compounds of the present invention include a compound represented by the above general formula (III) wherein X is an oxygen atom, and R 1 and R 2 are the same or different from each other and are a hydrogen atom, a lower alkyl group, an acyl group, a lower alkyl group. A sulfonyl group or R] and R ² — Represents a methylene group, and R ³ and R ⁴ are the same or different and are each a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy or a lower alkoxy group, R ^{5 a} and R ⁵ b are the same or different connexion hydrogen atom or a lower alkyl group, R ⁶ is water atom, a substituted or unsubstituted C. 1 to C ₈ substituent of the alkyl group (said alkyl group arsenide Dorokishi group , An acyloxy group, a lower alkoxy group, a carboxyl group or a lower alkoxycarbonyl group, which is at least one member selected from the group consisting of —CO—R ⁹ (where R 9 is a hydrogen atom or a substituted or unsubstituted C! ₂ alkyl group (the substituent of the alkyl group is one or more selected from a hydroxy group, an acyloxy group, an aryloxy group and a lower alkoxy group. )), One CO—CH2 CHR 10 (where R 10 is a hydrogen atom, a lower alkyl group or an aryl group) or one S〇 ₂ R 11 ¹ (where Ri 1 is a lower alkyl group) a group or Ariru a group), compounds wherein R ⁷ is hydrogen atom or a lower § Le kill group (provided that when R ⁶ and R ⁷ are both hydrogen atom, R 10- and R ² 0- is 4 _0 (11 _{3 and} 7— 0 CH ₃ and R 3 and R

(Unless one of 4 is a hydrogen atom and the other is 6-0H) or a physiologically acceptable acid addition salt thereof.

More preferred compounds are those in which R ¹ and R ² in formula (III) are the same or different from each other and are a hydrogen atom, a CiC ^ alkyl group or an acyl group, and R ³ and R ⁴ are the same or different from each other. hydrogen atom, hydroxy group, an Ashiruoki shea group or C i C ^ alkoxy group, R ^{5 a} and R 5 b are taken the same or different hydrogen atom or a C] -C ₃ alkyl group, R ⁶ is a hydrogen atom , Replace Or an unsubstituted C〗 -C3 alkyl group (the substituent of the alkyl group is one or more selected from a hydroxy group, an acyloxy group or a carboxyl group), and one CO—R ⁹ (where R ⁹ is a hydrogen atom or a substituted or unsubstituted C

A C ₃ alkyl group (substituent of the alkyl group is a hydroxy group or an acyloxy group)) or one S〇 ₂ R ¹¹ (where R ¹¹ is C) to a C ₃ alkyl group or a phenyl group And R ⁷ is a hydrogen atom (provided that when R ⁶ and R ⁷ are both hydrogen atoms, R 10 — and R ²⁰ — are 4-—CH ₃ and 7—OCH ₃ and one of R 3 and R 4 is a hydrogen atom and the other is 6—

〇H) or a physiologically acceptable acid addition salt thereof.

Still another preferred compound of the present invention has the following general formula (III-A):

(Wherein R 1 and R ² are the same or different from each other and represent a hydrogen atom, a lower alkyl group, an acyl group,

R ³ represents a hydrogen atom, a lower alkyl group, an acyloxy group, a lower alkylsulfonyloxy group or a lower alkoxy group,

R ⁴ represents a hydrogen atom, a lower alkyl group, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy group or a lower alkoxy group,

R ⁵ a and R ⁵ b are the same or different, represent a hydrogen atom or a lower alkyl group And

R ⁶ is a hydrogen atom, a substituted or unsubstituted C-C ₈ alkyl group (substituted with an alkyl group is a hydroxy group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, an acyloxy group, One or more selected from a carboxyl group or a lower alkoxycarbonyl group), —CO—R 9 (where R 9 is a hydrogen atom, a substituted or unsubstituted Ci Ciz alkyl group (substituted alkyl group) The group is one or more selected from a hydroxy group, an acyloxy group, a substituted or unsubstituted aryloxy group or a lower alkoxy group)), or one S 0 ₂ R 11 (where R 11 is Lower alkyl or substituted or unsubstituted aryl).

R ⁷ represents a hydrogen atom or a lower alkyl group)

And a physiologically acceptable acid addition salt thereof.

Specific preferred compounds of the general formulas (III) and (III-A) include 3-amino-4-hydroxy-15,6-dimethoxy-1,2,3-dihydrobenzofuran hydrochloride,

3-amino-4-hydroxy-5,6-dimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran hydrochloride,

3-methylamino-4-hydroxy-1,5,6-dimethoxy-2,2-dimethyl-1,2,3-dihydrobenzofuran hydrochloride,

3— (2-Hydroxyshetyl) amino 4-Hydroxy 6—Methoxy 2,

2-dimethyl-1,2,3-dihydrobenzofuran hydrochloride,

3- (2-Hydroxyshetyl) amino-4-hydroxy-5,6-dimethoxy -2,2-Dimethyl-2,3-dihydrobenzofuran hydrochloride,

3 1-carboxymethylamino-4-hydroxy-1 6-methoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran,

3—carboxymethylamino-4-hydroxy-5,6-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran,

3 _ methanesulfonylamino-4-hydroxy-1 6-methoxy 2,3-dihydroxybenzofuran,

3-Methanesulfonylamino 4-Acetoxy 6-Methoxy 2,3-Dihydrobenso * furan,

3—Methanesulfonylamino-4-hydroxy-6-methoxy-2,2-dimethyl-1,3,3-dihydroxybenzofuran,

3—methanesulfonylamino-4—acetoxy-1 6—methoxy-1,2,2-dimethyl-1,2,3-dihidrobenzofuran,

3 — methanesulfonylamino 4-hydroxy-5, 6 — dimethoxy 2,3 — dihydroxybenzofuran,

3-methanesulfonylamino 4-hydroxy-5,6-dimethoxy-2,2-dimethyl-1,2,3-dihydrobenzofuran,

3-methansulfonylamino-5-hydroxy-6,7-dimethoxy-1,2 dihydrobenzofuran,

3—Methanesulfonylamino 4,4,6-Diacetoxy-1,2,2-dimethyl-2,3-dihidrobenzofuran,

3-benzenesulfonylamino-6,7-dimethoxy-1,2,3-dihydrobenzoben,

3-benzenesulfonylamino-4-hydroxy-1 6-methoxy 2,3— Jihi Drobenzofuran,

3—benzenesulfonylamino-4-hydroxy-6—methoxy 2,2—dimethyl 2,3-dihydrobenzofuran,

3—benzenesulfonylamino-4—hydroxy-5,6-dimethoxy-1,2,3-dihydroxybenzene,

3 1-benzenesulfonylamino-4-hydroxy-5,6-dimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran,

3-formylamino-1-hydroxy-6-methoxy-2,2-dimethyl-2,3-dihidrobenzofuran,

3 1-formylamino-4-hydroxy-5,6-dimethoxy-1,2,2-dimethyl-2-, 3-dihydrobenzofuran,

3—Hydroxymethylcarbonylamino 1,4,6—Dimethoxy 2,2—Dimethyl 1,2,3—Dihydroxy benzofuran,

3—Hydroxymethylcarbonylamine 4—Hydroxy-1- 6-Methoxy 2,3—Dihydrobenzofuran,

3-hydroxymethylcarbonylamino-1-acetoxy-6-methoxy-1,2,3-dihydroxybenzofuran,

3-hydroxymethylcarbonylamino 4-hydroxy-1 6-methoxy-2,2-dimethyl-2,3-dihydroxybenzofuran,

3-hydroxymethylcarbonylamino 4-acetoxy-6-methoxy-2,2-dimethyl-2,3-dihydroxybenzofuran,

3-hydroxymethylcarbonylamine 4 -hydroxy-5,6-dimethoxy-1,2,3-dihydroxybenzofuran,

3-hydroxymethylcarbonylamino-4-acetoxy-1,5,6-dimethyl Xy 2,3-dihydrobenzofuran and

3-Hydroxymethylcarbonylamino 4-acetoxy-5,6-dimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran

Is mentioned.

Examples of the physiologically acceptable acid addition salts of the compound of the present invention include salts with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, oxalic acid, and maleic acid. Acid, fumaric acid, malonic acid, lactic acid, malic acid, citric acid, tartaric acid, benzoic acid, salts with organic acids such as methanesulfonic acid, tosylic acid, gluconic acid, and salts with amino acids such as glycine and alanine. .

In the present specification, the “lower alkyl group” and the “lower alkyl” portion mean a linear or branched alkyl group having 1 to 5 carbon atoms, for example, a methyl group, an ethyl group, a propyl group, a butyl group, an isobutyl group. And a pentyl group. The “substituted or unsubstituted C i C g alkyl group” refers to a straight-chain or branched-chain alkyl group having 1 to 8 carbon atoms including a hexyl group, a heptyl group, an octyl group and the like in addition to the lower alkyl group. Wherein the substituent is a cyclo lower alkyl group, an aryl group, a heteroaryl group, a hydroxy group, a lower alkoxy group, an aralkyloxy group, an aryloxy group, an acyloxy group, an amino group, a mono-lower alkyl or di-lower alkylamino group, Acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, arylthio group, lower alkylsulfinyl group, arylsulfinyl group, lower alkyl sulfoninole group, arylsulfonyl group, acyl Group, carboxyl group or lower alkoxycarbonyl group. Or may have two or more types. The "substituted or unsubstituted C i~C _{1 2} alkyl group", the (~ Ji _{8 In} addition to the alkyl group, a linear or branched alkyl group having 1 to 12 carbon atoms, including a nonyl group, a decyl group, a decyl group, a dodecyl group, etc., and a cyclo lower alkyl group as a substituent , Aryl group, heteroaryl group, hydroxy group, acyloxy group, aryloxy group, lower alkoxy group, carboxy group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono-lower alkyl group One or two selected from di-lower alkylamino, acylamino, mercapto, lower alkylthio, arylthio, lower alkylsphinyl, arylsulfinyl, lower alkylsulfonyl, arylsulfonyl and sulfamoyl; It may have more than one species. Among these substituents, a hydroxy group, an acyloxy group, an aryloxy group or a lower alkoxy group is preferred. “Cyclo-lower alkyl group” means a cycloalkyl group having 3 to 7 carbon atoms, and examples thereof include a propyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, and a cycloheptyl group. The “aryl group” and the “aryl group” mean a phenyl group, a naphthyl group and the like, and the ring may have a substituent. Preferred substituents on the ring include a halogen atom, a lower alkyl group, a trifluoromethyl group, a lower alkoxy group, a hydroxy group, an amino group and a nitro group. The “aralkyl group” and the “aralkyl” portion mean a straight-chain or branched alkyl group having 1 to 3 carbon atoms substituted by the above “aryl group”, for example, phenylmethyl group, 1-phenylethyl group, 2-phenylethyl group. And 3-phenylpropyl group, naphthylmethyl group, 2-naphthylethyl group and the like. These phenyl group or naphthyl group may have the same substituent as described above. The “lower alkoxy” and “lower alkoxy” moieties mean a straight-chain or branched-chain alkoxy group having 1 to 5 carbon atoms, for example, methoxy, ethoxy, propoxy, isopropyloxy, butoxyl, Examples include an isoptyloxy group, a tert-butyloxy group, and a pentyloxy group. “Acyl group” means a lower alkanoyl group, a benzoyl group, or a naphthoyl group. “Lower alkanoyl group” means an alkanoyl group having 1 to 3 carbon atoms, and examples include a formyl group, an acetyl group and a propionyl group. "Heteroaryl group" means a 5- or 6-membered aromatic heterocyclic ring containing one or two heteroatoms selected from a nitrogen atom, an oxygen atom and a sulfur atom. Examples thereof include phenyl, pyrrolyl, oxazolyl, isoxazolyl, pyridyl, pyridazinyl, and pyrimidinyl.The heterocyclic group is one or two selected from a halogen atom, a lower alkyl group, a lower alkoxy group, a hydroxy group, and an amino group. May have a substituent. “Halogen atom” means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The compounds of the present invention and their physiologically acceptable acid addition salts may exist as hydrates and Z or solvates. Therefore, such forms are naturally included in the compounds of the present invention. The compounds of the present invention have two asymmetric carbon atoms on the dihydrobenzofuran or dihydrobenzothiophene ring, which can exist as different stereoisomers. Therefore, these stereoisomers are also included in the compounds of the present invention. Compound Okishimu derivatives der Rutoki of the present invention, geometrical isomers force of ^{anti-single-core?} Are present, these geometric isomers are also encompassed in the compound of the present invention. Further, the compounds of the present invention include those having an asymmetric carbon atom in the side chain substituent thereof, and they may exist as stereoisomers. These stereoisomers are also included in the compounds of the present invention. In addition, the present invention The compounds of the formula (1) include those having a double bond in the side chain substituent thereof, and there are geometrical isomers of cistran. These geometrical isomers are also included in the compound of the present invention.

Next, a method for producing the compound of the present invention will be described below.

(Production method 1)

In the compound of the present invention represented by a one-branch formula (Π) in which A—shake 6 is 1——R 6 in the general formula (I), R ⁶ is a hydrogen atom, a substituted or unsubstituted _salkyl group, lower alkyl group, Ararukiru group, Ariru group, hetero Ariru group or compound is an 0 R ⁸ is a hydroxylamine derivative or an amine derivative corresponding to the compound represented by the following general formula (IV), by methods known It can be produced by reacting.

(Where R i R S a R 5 b and X are the same as above)

The compound of the present invention produced by the above method or derived from the compound of the present invention (for example, R ⁶ = benzyloxy group, benzyl group) produced by the above method is an oxime (R 6 = 0 H) or imine (R 6 = H), the oxime or imine is further alkylated, acylated or sulfonylated by a conventional method to obtain another compound of the present invention (for example, when R ^{6 is} —CO— R 9 or — so 2 R 1 1). Examples of the alkylation method include a substitution reaction with an alkylating agent in a suitable solvent in the presence of a base. Examples thereof include reactive derivatives of alcohol (eg, alkyl halide, alkyl tosylate, alkyl methanesulfonate). Examples of the acylation method include a reaction with a corresponding reactive derivative of a carboxylic acid, for example, a substitution reaction with an acylating agent such as an active ester, an acid anhydride or an acid halide. Examples of the sulfonylation method 'include a reaction of a corresponding sulfonic acid with a reactive derivative, for example, a substitution reaction with an acylating agent such as an active ester, an acid anhydride or an acid halide. The method of sulfonylation includes reaction with the corresponding reactive derivative of sulfonic acid, for example, lower alkane sulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride and the like. Substitution reaction with a sulfonylating agent can be mentioned.

(Production method 2)

Further, in the general formula (II), the compound (lib) in which R 6 is —0 R ⁸ (R 8 is the above R 8 group other than a hydrogen atom) and R 1 is a hydrogen atom can also be produced by the method of Production Method 1. As shown in the following reaction formula, the compound can be produced by treating the compound of the present invention represented by the general formula (Ila) with lysic acid in a suitable inert solvent. Examples of the Lewis acid include anhydrous sodium chloride, anhydrous aluminum chloride, boron trichloride, boron tribromide and boron trifluoride. Examples of the solvent include methylene chloride, benzene and nitrobenzene.

(In the reaction formula, R, R ² and R ⁸ are the same groups as described above except for a hydrogen atom;

3-R5a, R5b and X are the same as above)

(Production method 3)

Further, in the general formula (II), 1¾ ⁶ ^months? Hydrogen atom, a group other than hydroxy group, certain compounds of the compound which is the R ¹ other than R 1 forces a hydrogen atom is the R i force a hydrogen atom The compound represented by the following general formula (lie) can be produced by alkylating, acylating, or sulfonylating the hydroxyl group in a suitable solvent in a conventional manner.

(Wherein, R ⁶ is the same group as cited above other than a hydrogen atom, a hydroxyl group, R ² ~

R5a, R5b and X are the same as above)

Examples of the alkylation method include a substitution reaction with an alkylating agent in a suitable solvent in the presence of a base. As the alkylating agent, for example, a reactive derivative of an alcohol (an alkyl halide, an alkyl tosylate, an alkyl Methanesulfonate). The acylation method includes reaction with a corresponding reactive derivative of rubonic acid, for example, active ester, acid anhydride, or acid halide. And a substitution reaction with an acylating agent such as an id. The method of sulfonylation includes reaction with the corresponding reactive derivative of sulfonic acid, for example, lower alkane sulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride. Reaction with a sulfonylating agent such as a product.

(Production method 4)

In the compound of the present invention represented by the general formula (III), in which the ninini A—R 6 is —NR 6 R 7 in the general formula (I), R ⁷ is a hydrogen atom, R ⁶ is a hydrogen atom, — oR 8, substituted or unsubstituted C i~C ₈ alkyl group, a lower cycloalkyl group, Ariru group or to Teroari - a le radical compound is represented by the following general formulas manufacturing by the manufacturing method 1 (II) Can be produced by reducing the compound of the present invention with a suitable reducing agent in an inert solvent by a method known in the literature or a method analogous thereto.

(Wherein, R ⁶ is a hydrogen atom, —OR8, a substituted or unsubstituted Ci Cg alkyl group, a cyclo-lower alkyl group, a CO—R ⁹ , an aryl group or a heteroaryl group, and R] to R 5a , R5b and X are the same as above)

The reduction method is appropriately selected from known reduction methods depending on the type of the substituent of the compound represented by the general formula (Π) or the properties of other functional groups. For example, platinum oxide, palladium-carbon, Atmospheric pressure using a catalyst such as nickel Is catalytic hydrogen reduction in a hydrogen atmosphere under pressure, reduction with metallic sodium in an alcohol solvent such as ethanol or propanol, sodium mouma gum / acetic acid, aluminum-amalgam Z water, borane-tetrahydrofuran complex, hydrogenation Sodium borohydride Z tetrachloride titanium, sodium borohydride Z nickel dichloride hexahydrate, sodium borohydride molybdenum oxide, sodium trifluoroacetoxyborohydride, lalancet reagent

(Lalancette's Reagent; NaBH ₂ S ₃ ), a method using a reducing agent such as sodium bismethoxetoxy aluminum hydride, lithium aluminum hydride and the like.

Compounds in which R ^{6 is} —OR 8 may be replaced with the above-described reduction method, for example, in Journal of Chemical Society, Perkin I, vol. 64, p. 643 (1979 ) Or a method analogous thereto, the compound of the present invention (R ⁶ = —0 R ⁸ ) represented by the general formula (Π) is converted to an amine-borane complex (for example, a pyridine-borane complex) in an inert solvent. It can also be produced by reduction with.

(Production method 5)

In the general formula (III), R ⁷ is a hydrogen atom, a lower alkyl group or a consequent opening lower alkyl group, R ⁶ gar CO- R ^9, one CO- CH = CHR io or a -S0 ₂ Rii A certain compound can be produced by acylating or sulfonylating a compound represented by the following general formula (V) produced by the above-mentioned production method by a conventional method.

(In the formula, R ⁷ is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R i to R 5a, R 5b and X are the same as described above.) As a method of acylation, the corresponding carboxylic acid Reaction with a reactive derivative, for example, a substitution reaction with an acylating agent such as an alkyl ester, an active ester, an acid anhydride or an acid halide, or condensation with the corresponding carboxylic acid itself in the presence of a condensing agent Reaction. Examples of the condensing agent include Ν, Ν'-dicyclohexylcarbodiimide, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimid hydrochloride, Ν, Ν'-carbonyldiimidazole, Ν, Ν, 1-carbodilsuccinic acid imid, 1—ethoxycarboryl 2-ethoxy-1,2, -dihydroquinoline, diphenylphosphorylazide, propanephosphonic anhydride, benzotriazole-1-yloxystris ( Dimethylamino) phosphodium hexafluorophosphate. The method of sulfonylation includes reaction with a corresponding reactive derivative of sulfonic acid, for example, lower alkylsulfonyl halide, arylsulfonyl halide, trifluoromethanesulfonyl halide, trifluoromethanesulfonic anhydride and the like. And a substitution reaction with a sulfonylating agent.

(Production method 6)

In the general formula (III), R ⁷ is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R ⁶ is a substituted or unsubstituted C 1 -C ₈ alkyl group. Compound is may force ⁵ also be produced by a method represented by the following Method A or Method B.

(Method A) The compound represented by the following general formula (VI) produced by the above-mentioned production method is produced by reducing with a suitable reducing agent in an inert solvent by a method known in the literature or a method analogous thereto. be able to.

(In the formula, R 7 is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R 1 to R 5a, R 5b, R 9 and および are the same as described above.)

As the reduction method, a force appropriately selected from known methods according to the type of the substituent of the compound represented by the general formula (III) or the properties of the other functional groups, for example, oxidized platinum, noradium monocarbon, Catalytic hydrogen reduction in a hydrogen atmosphere at normal pressure or under pressure using a catalyst such as Raney Nickel, borane-tetrahydrofuran complex, sodium borohydride / titanium tetrachloride, sodium borohydride nickel nickel dichloride, sodium borohydride / molybdenum oxide, hydrogenated triflumizole Ruo b acetoxy boron sodium, Raranse' preparative reagent _{(Lalancette 's reagent; NaBH 2} S 3), hydrogenated Bisume Toki Chez butoxy aluminum two © beam sodium, such as lithium aluminum hydride Examples thereof include a method using a reducing agent.

(Method B) Also, the compound represented by the following general formula (V) produced by the above-mentioned production method is alkylated by a conventional method or CH ₂ == CH—Z (where Z is cyano). Group, carbamoyl group, lower alkoxycarbonyl group, etc.).

(In the formula, R ⁷ is a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and R 1 to R 5a, R 5b and X are the same as described above.)

Examples of the alkylation method include a substitution reaction with an alkylating agent in a suitable solvent in the presence of a base. As the alkylating agent, for example, a reactive derivative of a corresponding alcohol (eg, an alkyl halide or an alkyl tosylate) is used. Rates, alkyl methanesulfonates, etc.).

(Production method 7)

Certain of the compounds of the present invention represented by the general formula (III), for example, a compound in which R 1 or R ² is a hydrogen atom, a compound in which R ³ or R ⁴ is a hydroxyl group, or a side chain R ^The compound containing a functional group in ⁶ can be led to another compound of the present invention by chemical modification according to a conventional method. Chemical modifications include, for example, alkylation, acylation, sulfonylation, hydrolysis, oxidation and reduction methods.

The compound of the present invention produced by the above production methods 1 to 7 is isolated and purified by a conventional method such as various chromatographic methods, recrystallization, and reprecipitation.

Some of the compounds of the present invention can be obtained in the form of a free base or an acid addition salt depending on the selection of starting compounds, reaction and treatment conditions, and the like. The acid addition salt can be prepared by a conventional method, for example, treatment with a base such as alkali carbonate or alkali hydroxide to give a free salt. Can be changed to base. The free base can be converted to an acid addition salt by treating it with various acids according to a conventional method. When the compound of the present invention is obtained in the form of a complex with borane, it can be converted to an acid addition salt by treating with an acid.

(Production method of raw material compounds)

Next, the method for producing the 2,3-dihydrobenzofuran (or benzothiophene) -13-one derivative used as the raw material for producing the compound of the present invention in the above-mentioned production method 1 will be described.

The 2,3-dihydrobenzofuran-3-one derivative can be obtained from commercially available gas or starting materials that can be synthesized by known methods. Male supervision, Asakura Shoten Publishing First Edition, Tokyo, 1959, and THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS Vol. 29, pp 210-219, written by M. Ahmed, John Wiley and Sons IN Publishing, ew York 1954) It can be produced by a known method or a method analogous thereto. For example, (i) a method of intramolecular ring closure of a 0-oxy-a-haloacetophenone derivative in the presence of a base such as sodium acetate; Intramolecular ring closure by Friedel-Crafts reaction, or (iii) o-Methoxy-ω-diazoacetophenone under acidic conditions (eg glacial acetic acid, hydrochloric acid) According to the method, 2,3-dihydrobenzofuran-1-one derivative can be produced. The 2,3-dihydrobenzofuran-3-one derivative can also be converted from other 2,3-dihydrobenzofuran-3-one derivatives. For example, the introduction of a hydroxyl group at the 7-position of certain 2,3-dihydrobenzofuran-13-one derivatives requires the use of η-butyl lithium notrimethoxyborane reagent. Can be done. The introduction of a lower alkyl group at the 2-position of a certain 2,3-dihydrobenzofuran-13-one derivative can be carried out by alkylation with an alkylating agent in the presence of a strong base.

The 2,3-dihydrobenzothiophene-3-one derivative can also be prepared from commercially available catalysts or starting materials that can be synthesized by known methods, for example, as described in “THE CHEMISTRY OF HETEROCYCLIC COMPOUNDS, pp66-75, HD Hartough. Published by Interscience Publhers, INC., New York 1974 and Advances in HETEROCYCLIC CHEMISTRY Vol. 11, p.225, edited by AR Katritzky et al., Published by Academic Press, New York and London, 1970. Or a method analogous thereto, for example, a method of intramolecularly closing an S- (o-carboxylphenyl) thioglycolic acid derivative followed by decarboxylation, or an S-polysubstituted phenyl A 2,3-dihydrobenzothiothiophene-3-one derivative can be produced by a method utilizing an intramolecular ring closure reaction of a dithioglycolic acid derivative.

Pharmacological test

Next, the pharmacological test method, the pharmacological test results and the toxicity test results for the compound of the present invention are shown, and the characteristics of the action of the compound of the present invention will be described below. As a test method, each test compound was tested using a D-(+)-galactosamine-induced liver injury model in rats and a D-(+)-galactosamine-nolipopolysaccharide-induced liver injury model in mice. They were screened and their inhibitory effects were evaluated.

Test Example 1 Inhibitory effect on D-galactosamine-induced liver injury model:-s1c: Dissolved and diluted in a male male Wistar rat (about 200 g body weight, 7-9 weeks old) with physiological saline for injection. D — (+) — Galactosamine (250 mg Z kg) was administered subcutaneously once a day for 4 consecutive days to induce liver damage. The test compound (dose: 3 Omg / kg) was suspended or dissolved in 0.5% methylcellulose solution or olive oil and orally administered 1 hour after each induction for 4 consecutive days. 24 hours after the final administration of D-galactosamine, heart blood was collected under pentobarbital anesthesia, and AST (G0T) and ALT (GPT) in plasma were measured. The inhibition rate (%) was calculated by the following formula (where the inducer means D — (+) galactosamine). The results are shown in Tables 1 and 2. Induced agent treated group actual value-each test compound administration group actual measured value

Inhibition rate (%) = X 100

D—Inhibitory effect on galactosamine-induced liver injury model Inhibition rate (%)

Compound No A S T A L T

3 4 0 4 0

7 6 8 6 9

29 5 3 5 0

60 4 1 5 3

69 7 0 7 5

72 7 8 7 8

74 5 6 5 7

80 5 6 4 5

83 3 6 3 2

85 5 7 4 5

88 4 2 4 8

89 7 2 7 6

90 5 6 5 6

103 3 2 2 4

119 4 0 4 9

121 5 1 5 2

124 5 8 4 7

131 4 5 5 3

139 4 4 3 4

160 3 3 4 8 Table 2 Continued from Table 1 Suppression rate (%)

Compound No AST ALT

162 49 33

172 73 62

201 7 1 66

203 3 1 30

205 60 58

206 4 1 47

225 64 70

238 4 5 30

όοί 0 u 丄

284 67 73

297 38 47

301 7 1 76

305 60 39

308 59 53

321 68 64

326 76 72

344 72 7 1

346 74 57 Test Example 2 Inhibitory effect on D-galactosamine nolipopolysaccharide-induced liver injury model: The efficacy screening was performed using mouse D-(+)-galactosamine (Ga1N) / lipopolysaccharide (LPS). ) The induced liver injury model was used. 0.1% of male BALBZc mice (weight around 20 g, 7 weeks old) fasted for 15 to 17 hours G1N (14 mg / mouse) and LPS (40 _ng // mouse) dissolved in physiological saline containing serum albumin were simultaneously administered to the tail vein to induce liver damage. The test compound (dose: 10 OmgZkg) was suspended or dissolved in 0.5% carboxymethylcellulose solution 2 hours before induction of hepatic injury and 3 times.

Oral administration was performed 0 minutes before. Six hours after administration of D-(+)-galactosamine Z lipopolysaccharide, heart blood was collected under Nembutal anesthesia, and AST (GOT) and ALT (GPT) in plasma were measured. The inhibition rate (%) was calculated by the following formula (where the inducer means D-(+)-galactosamine nolipopolysaccharide). The results are shown in Tables 3 and 4. Inducer treatment group actual value-Actual value of each test compound administration group

Inhibition rate (%) =; X 100 Inducer treated group actual value-solvent control group actual value

D—galactosamin / lipopolysaccharide-induced inhibitory effect on liver injury model Inhibition rate (%)

Compound No A S T A L T

3 8 5 9 3

49 5 0 6 1

60 5 8 6 2

74 8 4 9 4

77 8 0 8 4

85 9 1 9 3

90 7 7 9 3

93 9 0 9 6

97 6 6 6 6

106 9 1 9 6

121 6 5 6 4

164 6 2 6 8

172 4 9 5 1

178 5 0 5 6

184 4 4 3 7

186 6 7 6 9

257 9 9 8 9

282 5 9 5 7 Table 4 Continuation of Table 3 (%)

Compound No AST ALT

302 78 84

305 72 85

310 39 3 5

317 39 53

322 76 72

326 3 1 34

337 59 6 1

340 45 46

346 45 53

359 46 47 Test Example 3 Toxicity test:

Test compounds (compound Nos. 3, 85, 164, 172 and 305) were orally administered for 2 consecutive weeks using ICR female mice (7-week old) (Dose: 30 OmgZk gZl once daily) ). As a result, none of the test compounds died. As is clear from the above test results, the compound of the present invention has an inhibitory effect on the D-(+)-galactosamine-induced hepatic injury model and the D-galactosamine / ribopolysaccharide-induced hepatic injury model. It showed extremely low toxicity and high safety. Therefore, the compound of the present invention is useful as a therapeutic drug for liver diseases and can be used as a therapeutic / prophylactic drug for various liver disorders in animals including humans. Specifically, for example, acute hepatitis, chronic hepatitis, drug-toxic liver injury, It can be used to treat or prevent viral hepatitis, alcoholic hepatitis, jaundice, and cirrhosis.

When the compound of the present invention is used as a therapeutic agent for liver disease, the dosage form is orally administered as tablets, capsules, granules, fine granules, powders, syrups, suspensions, etc. It is administered parenterally or rectally as drops, suppositories, gels, tablets, etc. These preparations are prepared according to a conventional method. In the case of liquid preparations, they may be dissolved or suspended in water or other suitable medium at the time of use. Tablets and granules may be coated by a known method. In the case of injections, the drug is prepared by dissolving the drug in water for injection, but if necessary, add a pH regulator, buffer, isotonic agent, stabilizer, solubilizer, etc. It can be used as a subcutaneous, intramuscular, or intravenous injection by a conventional method. The dosage depends on the administration method, the patient's symptoms, age, treatment type (prevention or treatment), etc., usually 0.1 mg to 200 mg per adult per day, preferably 2 mg to 8 mg. 0 mg is administered once or several times a day.

When the compound of the present invention is administered in the form of a preparation prepared by mixing the compound of the present invention with a conventional pharmaceutically acceptable carrier for pharmaceuticals, the carrier for pharmaceuticals includes an excipient, a binder, a disintegrant, and a lubricant. Carriers that do not react with the compound of the present invention, such as antioxidants, coating agents, surfactants, fluidity enhancers, flavoring agents, coloring agents, plasticizers, fragrances, etc. Is appropriately selected and used.

Specifically, excipients such as glucose, sucrose, lactose, mannitol, xylitol, sorbitol, crystalline cellulose, sodium carboxymethyl cellulose, calcium hydrogen phosphate, starch, sodium carboxymethyl starch, dextrin ,. One cyclodextrin, β-cyclodextrin Examples include xistrin, carboxyvinyl polymer, light caustic anhydride, titanium oxide, magnesium aluminate metasilicate, polyethylene glycol, and medium-chain fatty acid triglycerides.

Examples of the binder include crystalline cellulose, methylcellulose, Echiruseru loin, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, polyethylene-vinyl pyrrolidone, polyvinyl alcohol, gum arabic, _alpha starch, pullulan, gelatin, agar, Taraganto, alginic acid sodium And propylene glycol alginate.

Disintegrators include, for example, crystalline cellulose, carboxymethylcellulose, low-substituted hydroxypropylcellulose, carboxymethylcellulose sodium, carboxymethylcellulose calcium, croscarmellose sodium, starch, hydroxypropyl starch, partially modified starch Can be

Examples of the lubricant include stearic acid, aluminum stearate, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated vegetable oil, sucrose fatty acid ester, dimethylpolysiloxane, polyethylene glycol, waxes, Hydrogenated vegetable oils;

Examples of the antioxidant include propyl gallate, dibutyl hydroxytoluene, butylhydroxyanisole, _α -tocopherol, and citric acid.

Examples of the coating agent include methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxypropylmethylcellulose phthalate, and hydroxypropylmethyl. Cellulose acetate succinate, cellulose acetate phthalate, cellulose acetate phthalate, polyvinyl acetate, uretyl amino acetate, aminoalkyl methacrylate copolymer, methacrylate copolymer, cellulose acetate phthalate, cellulose Examples include acetate trimellitate, polyvinyl acetate saphthalate, and shellac. Examples of surfactants include polyoxyethylene hard castor oil, glycerin monostearate, sorbitan monostearate, sorbitan monopalmitate, sorbitan monolaurate, polysorbates, sodium lauryl sulfate, macrogols Sucrose fatty acid esters and soybean lecithin.

Examples of the fluidity promoter include light caustic anhydride, dried palm hydroxide gel, synthetic aluminum silicate, and magnesium silicate. Examples of the flavoring agent include citric acid, adipic acid, ascorbic acid, and menthol. Examples of the colorant include a tar dye and titanium oxide. Examples of the plasticizer include trimethyl citrate, triacetin, and ethanol.

These preparations can contain the compound of the present invention in an amount of 0.01% or more, preferably 0.05 to 70%. These formulations may also contain other therapeutically active ingredients.

The best form bear to carry out Ming

Examples and Reference Examples below, the force ^s to specifically describes compounds of the present invention, the present invention is not limited to these examples. The compounds were identified by elemental analysis, mass spectrum, infrared absorption spectrum, hydrogen nuclear magnetic resonance absorption spectrum, and the like. For simplicity of description, The following abbreviations may be used in Examples and Reference Examples.

M e: methyl group; E t: ethyl group; i—P r: isopropyl group;

Pr: cyclopropyl group; i-Bu: isobutyl group; cPen: cyclopentyl group; Phe: phenyl group; Bz: benzyl group; Ac: acetyl group;

M s: Mesyl group

Example 1

3—Hydroxyiminot 4,5,6—Trimethoxy-1,2,3-dihydrobenzene production

4,5,6-Trimethoxy-2,3-dihydrobenzofuran-13-one To a solution of 30 g of methanol in 35 Om1 were added 18.7 g of hydroxylamine hydrochloride and 32 g of pyridine in turn. Heat to reflux for 1 hour with stirring. The reaction mixture is concentrated to dryness under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-ethyl acetate to obtain 11 g of the title compound (Compound No. 1). Mp 1 94.

Example 2

Production of 3-Methoxyimino-6,7-dimethoxy-1,2,3-dihydrobenzofuran

6,7-Dimethoxy-1,2,3-Dihydrobenzofuran-13-one To a solution of 10 g of methanol in 150 ml of methanol, add 8.6 g of 0-methylhydroxylamine hydrochloride and 20 g of pyridine in turn. Heat to reflux for 1 hour with stirring. The reaction mixture is concentrated to dryness under reduced pressure, water is added to the obtained residue, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were added to ethyl acetate-ethyl ether ether. Recrystallize from xan to obtain 10 g of the title compound (Compound No. 2). Mp 109-111.

删 3

3-Methoxyminoh 5-hydroxy-6,7-Dimethoxy-1,2,3-Dihydrobenzobenzofuran

To a solution of 17 g of 5-hydroxy-6,7-dimethoxy-1,3-dihydroxybenzofuran-13-one in 17 ml of methanol was added 20 g of 0-methylhydroxylamine hydrochloride and 32 g of pyridine. Heat to reflux for 1 hour. The reaction mixture is concentrated to dryness under reduced pressure, water is added to the residue and extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with n-hexane monoethyl acetate (2: 1) ', and purified to give 14 g of the title compound (Compound No. 3). obtain. Melting point 88-92 (recrystallized from ethyl acetate-n-hexane-ether).

Lonely.Example 4

Production of 3-methoxyminnow 4,5,6-trimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran

2,2-Dimethyl-4,5,6-trimethoxy-1,2,3-dihydrobenzofuran-13-one 4 In a 500 ml solution of 1 g of methanol, 27.1 g of 0-methylhydroxylamine hydrochloride and 51.5 g of pyridine And heat to reflux all day. The reaction mixture is concentrated to dryness under reduced pressure, water is added to the residue, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from getyl ether-n-hexane to obtain 45.7 g of the title compound (Compound No. 4). Melting point 86-87 ° C.

Example

Production of 3-Methoxyimino-1-hydroxy-5,6-dimethoxy-2,2-dimethyl-2-, 3-dihydrobenzofuran

3-Methoxyimino-1,4,5,6-trimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran To a solution of 46 g of benzene in 800 ml of benzene, add 37 g of anhydrous aluminum chloride, and stir at room temperature for 1.5 hours. . Add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to obtain 27 g of the title compound (Compound No. 5). Mp 125-126.

Example 6

Production of 3-methoxyminnow 4-benzyloxy-5,6-dimethoxy-1,2,2-dimethyl-1,2,3-dihydrobenzofuran

3-methoxyminnow 4-hydroxy-5,6_dimethoxy-2,2-dimethyl-1,2,3-dihydrobenzofuran 26 g of dimethylformamide (DMF) 55 Om 1 solution of 25.6 g of benzyl zirconate and carbonic acid Add 41.5 g of potassium and stir at room temperature for 1 hour. Add water and extract with toluene. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with ethyl acetate- _n- hexane (13: 1) and purified to obtain 36.6 g of the title compound (Compound No. 6). . Melting point 84-85 (recrystallized from ethyl acetate-n-hexane).

Example 7

3-isobutylimino 4,6-dimethoxy-1,2,3-dihydrobenzofura Of hydrochloride

4,6-Dimethoxy-2,3-dihydrobenzofuran-3-one Add 1.3 g of isobutylamine to 1.3 g of toluene 20 Om 1 and heat to reflux for 24 hours. The reaction mixture is concentrated to dryness under reduced pressure. 20 OmI of ether is added to the residue, and the precipitated insoluble matter is removed by filtration. Ethyl acetate is added to the filtrate, and 3% (vZv) ethanol hydrochloride is added dropwise under ice cooling. The precipitated crystals are collected by filtration, and recrystallized from methanol-ether to give 0.35 g of the title compound (Compound No. 7). Melting point 1 62 ° C. Using the corresponding starting compounds, the compounds of compound numbers 8 to 73 listed in Tables 5 to 7 are obtained in the same manner as in the production methods of Examples 1 to 7.

Five

Compound

No.Ra R _b Rc R5a R5b R6 mp (° C)

8 H -OCH ₂ 0- HHH OH

Q H H OMe UIVIc n u Π un ί

10 OH H OMe OMe H H OH

O e OH OMe H H H OH 1 ^ -1 7 ί 0

O e OMe H H H H H

13 -0CH _20- HHHH OMe

u

14 OMe H OMe H Π Π UMe

OMe H OMe n M6

OBz H OMe H H H OMe 100—101

17 OBz H OMe H Me Me OMe oi l

18 OH H OMe H H H OMe

19 OBz H OBz H H H OMe

20 OH H OH H H H OMe

21 OMs H OMs H H H OMe 143-144

22 OBz H OBz H Me Me OMe 92-95

23 OH H OH H Me Me OMeoi l

24 OAc H OAc H Me Me OMe

25 OMs H OMs H Me Me OMe o i l

26 OMe H H OMe H H OMe 140-141

27 H OMe OMe H H H OMe

28 H OMe OMe H Me Me OMe 6 Compounds following Table 5

No.Rc Rd R5a R5b R6 mp ()

29 H -0CH ₂ 0- HHH OMe

u

Π 0H OH H u n n u 1 1

丄 DID— 丄 θδ dec.

on

L Π H OMe OMe «: 1

Me M6 uivie 0 1 1 u

Π H OMe OMe Π u n 0 1 4 n H OMe OMe u n UDZ

o u

OD n H -0CH ₂ 0-u

Π u Π uivie

*

36 H H OBz OMe H H OMe

37 H H OH OMe H H OMe 84-86

38 H H OMe OH H H OMe 108-110

39 H H OMe OAc H H OMe 131-134

40 H H OH OH H n OMe 150 dec.

r \ i

41 H H OAc OAc H H 102-105

42 OMe OMe OMe H H H OMe 83-85

OMe OMe H u n u n

44 OMe OMe OMe H H H OBz 103

45 OMe OMe OMe H Me H OMe 90-92

46 OH OMe OMe H H H OMe 108-110

47 OMs OMe OMe H H H OMe 139-142

48 OBz OMe OMe H H H OMe 94-96

49 OMe OH OMe H H H OMe 113-115

50 OMe OMs OMe H H H OMe 147-152

51 OMe OMe H OMe HH OMe Table 7 Compounds following Table 5

¾ R5a R5b R6 mp (° C)

52 O e H OMe OMe H H OMe 142-143

53 OH H OMe OMe H H OMe 157-158

54 OBz H OMe OMe H H OBz _

55 H OMe OMe OMe H H OMe ―

_{56 H -0CH 2 0- OMe HH OMe} -

57 H OH OMe OMe Me Me OMe o i l

58 H OAc OMe OMe H H OMe

59 H-0CH ₂ CH ₂ 0H OMe OMe HH OMe

60 H OMe OMe OH H H OMe 109-112

61 OMe OMe OMe OMe H H OMe

β9 OH OMe OMe OMe H H OMe

63 OMe OH OMe OMe H H OMe 89-93

64 OMe OMe OH OMe H H OMe 127-130

65 OMe OMe OMe OH H H OMe 119-122

66 OMe H OMe H H H Me / HCl salt 195-197 dec.

67 OMe OMe OMe H H H Me / HCl salt 181 dec.

68 OMe OMe OMe H H H Et / HCl salt 174 dec.

69 OMe OMe OMe H H H G WH I I 151 dec.

70 OMe OMe OMe H H H-CH (Me) Et HCl salt 94 dec.

71 OMe OMe OMe HHH - (CH 2) 2 0H / HC1 salt 104

72 OMe OMe OMe HHH-(CH ₂ ) ₂ OMe / HCl salt 141

73 HH OMe OMe Me Me Bz Example 8 Production of 3-imino-6,7-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran hydrochloride 3-benzylimino 6,7-dimethoxy 2,2-dimethyl-2,3-dihydrobenzofuran 1.0 g of ethyl acetate (100 ml) -ethanol (30 m 1) mixed with palladium hydroxide 0.3 g, and catalytic hydrogen reduction is performed under a hydrogen atmosphere at normal temperature and normal pressure. After the reaction, the catalyst is removed, and the solvent is distilled off under reduced pressure. The residue is subjected to silica gel column chromatography and eluted with n-hexane monoacetate (3: 1). 10% (vZv) ethanol / hydrochloric acid was gradually added to 10 ml of ethyl oily ethyl acetate obtained, and the precipitated crystals were cooled and collected by filtration. The crystals were recrystallized from methanol / lugetyl ether to give the title compound ( Compound number 74) 43 Om is obtained. Mp 168-173 ° C.

The following compounds were obtained in the same manner as in Example 8 using the corresponding starting compounds.

3-Iminor 4-Hydroxy-1-6-Methoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran hydrochloride (Compound No. 75)

3-Imino-1-4-hydroxy-5,6-dimethoxy-1,2-dimethyl-2,3-dihydrobenzofuran hydrochloride (Compound No. 76)

Example 9

Production of 3-methanesulfonylimino 6,7-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran

3-Iminnow 6,7-Dimethoxy 2,2-Dimethyl-1,2,3-dihydrobenzofuran 260 mg was reacted with methylbenzenesulfonyl chloride in the presence of Triethylamine 310 mg to give the title compound (Compound No. 77) Get. Melting point 121-124 (recrystallized from ethyl acetate-n-hexane).

Using 3-imino-6,7-dimethoxy-2,2-dimethyl-1,2,3-dihydrobenzofuran, the methanesulfonyl chloride of Example 9 was changed to salidazoacetoxymethylcarbonyl and reacted. Acetylation to give the following compound Get each.

3-acetoxymethylcarbonilimino-1,6,7-dimethoxy-1,2,2-dimethyl-1,2,3-dihydrobenzofuran (Compound No. 78) Melting point 107-109 ° C (ethyl acetate n- Recrystallized from hexane).

3-Hydroxymethylcarbonilimino_6,7-dimethoxy-1,2,2-dimethyl-1,2,3-dihydrobenzofuran (Compound No. 79). 143-145 ° C (recrystallized from ethyl acetate-n-hexane).

, Ten

Production of 3-amino-4,5,6-trimethoxy 2,3-dihydrobenzofuran hydrochloride

3-Hydroxyimino-1,4,5,6-trimethoxy-1,2,3-dihydrobenzofuran 1.0 g of ethanol 1 50 ml suspension of 50 mg of platinum oxide and 30% (v / v) ethanol lm 1 of hydrochloric acid in succession In addition, catalytic reduction is performed in a hydrogen atmosphere at room temperature and atmospheric pressure. After absorbing the theoretical amount of hydrogen, the catalyst is removed, and the reaction solution is concentrated to dryness under reduced pressure. The residue is crystallized by adding getyl ether, and the obtained crystals are recrystallized from methanol-ethyl ether to give 352 mg of the title compound (I-do Compound No. 80). Melting point 187-: L 93

删 1 1

3-amino-6,7-dimethoxy-1,3-dihydrobenzobenzofuran hydrochloride

(Method a) Borane-THF complex (1 molar THF solution) was stirred at room temperature in a solution of 7 g of 3-methoximino-1,6,7-dimethoxy-2,3-dihydrobenzofuran in 7 g of tetrahydrofuran (THF) l O Oml. ) Add 220 ml dropwise. Heat to reflux for 3 hours after dropping. After cooling, ice water is added to the reaction solution, and a 10% hydrochloric acid aqueous solution 50 is stirred. Add m 1 slowly. The solution is heated under reflux for 20 minutes to decompose the amine-borane complex, and then added with a 10% aqueous sodium hydroxide solution under ice-cooling to make the solution more viscous. The mixture is extracted with ethyl acetate, and the organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is dissolved in ethyl acetate, and 30% (v / v) ethanol hydrochloride is added under ice-cooling and stirring. The precipitated crystals are collected by filtration and recrystallized from ethanol-ethyl ether to give 3.1 g of the title compound (Compound No. 81). Melting point 1 98 ° (:.

(Method b) In the same manner as in Example 10, 1.0 g of 3-methoximino-1,6,7-dimethoxy-1,2,3-dihydrobenzofuran was used to obtain 246 mg of the title compound.

Example 1 2

Production of 3-amino-5-hydroxy 6,7-dimethoxy 2,3-dihydroxy benzofuran

5-Hydroxy-1,6,7-dimethoxy-3-minoxyminnow 2,3-Dihydroxybenzofuran To a solution of 6.0 g of THF 3 Om 1 was added 176 ml of borane-THF complex (1 M solution in THF), and 4 Heat to reflux for hours. After ice cooling, add ice water little by little until firing stops. Next, 100 ml of a 10% hydrochloric acid aqueous solution is added, and the mixture is again heated under reflux for 20 minutes. After cooling with ice, add 10% aqueous solution of potassium hydroxide to make it neutral, and then concentrate the reaction solution under reduced pressure to 1Z2. Add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate-ethyl ether to obtain 4.8 g of the title compound (Compound No. 82). With a melting point of 1 37 to 140.

Example 13

3-Methoxyamino-6,7-Dimethoxy-1,2,3-Dihydrobenzofuran Production of hydrochloride

6 ml of a pyridine-borane complex (8 molar solution) is added dropwise to a suspension of 3 g of 3-methoxyimino-6,7-dimethoxy-2,3-dihydrobenzofuran in 20 ml of ethanol under ice-cooling and stirring. Next, slowly add 45 ml of ethanol (1 Οο / οίνΖν) hydrochloric acid. After the addition, continue stirring for another 15 minutes. To the reaction mixture is added a saturated carbonated aqueous solution to make it alkaline. The mixture is extracted with ethyl acetate, and the organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, getyl ether is added to the obtained residue, and the insoluble matter is filtered off. Ethyl acetate is added to the filtrate, and 30% (v / v) hydrochloric ethanol is slowly added dropwise while stirring with water. The precipitated crystals are collected by filtration and recrystallized from methanol-ethyl ether to give 2.2 g of the title compound (Compound No. 83). Melting point 1 4 7. C.

Example 14

Production of 3-amino-4-benzyloxy-1,5,6-dimethoxy-2,2-dimethyl-1,2,3-dihydrobenzofuran

3-Methoxyimino-1,4-benzyloxy-5,6-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran To a solution of 35 g of THF 10 Om 1 was added borane-THF complex (1 M THF) under stirring at room temperature. Add 1.8 L of solution and heat to reflux overnight. After ice cooling, add ice water little by little until firing stops, causing excess borane complex. Next, 2 L of a 10% aqueous hydrochloric acid solution is added, and the mixture is stirred for 2 hours under ice cooling. 15 Add 5% aqueous potassium hydroxide solution to make it alkaline, and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 14 g of the title compound (Compound No. 84) as an oil. Well 1 5

Preparation of 3-amino-1-hydroxy-5,6-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran hydrochloride

3-Amino-4-benzyloxy-1,5,6-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran To a solution of 2.8 g of ethanol in 200 ml of ethanol, add a catalytic amount of 10% palladium-carbon and add a hydrogen atmosphere. Catalytic hydrogen reduction at room temperature. After completion of the reaction, the catalyst is removed, 30% (vZv) ethanol hydrochloride is added, and the mixture is concentrated under reduced pressure. After cooling, the precipitated crystals are collected by filtration and recrystallized from ethanol to give 2.3 g of the title compound (Compound No. 85). Mp 189-190 ° C.

Using the corresponding starting compounds, in the same manner as in the production method of Examples 10 to 15 and the compound numbers 86 to 141 shown in Tables 8 to 10, represented by the following formulas: Get the compound.

Α »Ηπ

ap (° C) No.Rc R5a R5b Arm ⁷ r

86 OMe OMe HHHH NH ₂ / HC1 salt 220-225

_{_{87 -0CH 2 0- HHHH NH 2 /}} HC1 salt 240 dec.

88 H OMe HHH NH ₂ / HC1 salt 194

89 OMe H OMe H H H Orchid Me / HCl salt 121

_{90 H OMe H Me Me NH 2} / HC1 salt 197-206

91 UDZ H OMe HHHH ₂ oi l

92 UDZ H OMe H Me Me NH ₂ oil

93 H OMe HHH NH ₂ / HCi salt 146-147

_{94 OMs H OMe HHH NH 2 /} HCi salt 187-194

95 OBz H OBz HHH NH ₂ 54-56

96 OBz H OBz H Me Me NH ₂ 100-101

97 OH H OH H Me Me NH 2 / HC1 salt 220 dec.

_{98 OMe HH OMe HH NH 2 /} HC1 salt 204

_{99 H OMe OMe HHH NH 2 /} HC1 salt 174-75

100 H OH OMe HHH NH ₂

101 H -0CH ₂ 0- HHH NH ₂ / HC1 salt 175

102 H OMe OMe H H H painting H / HC1 salt 115-17

103 H OMe OMe H H H Excited Me / HCl salt 98

104 H -0CH ₂ 0- HHH NHOH / Mo / maleate

105 H OMe H OMe HH NH ₂

_{106 H OMe H OMe HH NH 2} / HC1 salt 195-202

107 HH OMe OMe HH NH ₂ / Monomaleate 176

10S HH OMe OMe HH NH0H 146 9 Continued in Table 8

Compound ρ D5a R5b MR6R7

Rc mp sino number

_{109 HH OMe OMe Me Me NH 2} / HC1 salt 181

110 H H OMe OMe H H NHOEt HCl salt 154 u u u

丄丄丄 n Π OMe OMe Π n Ν 1ΠπΠϋΓ1Γΐ2 PΓΩVi 140 u MU / DU

11ό u u

H Π -OCH ₂ 0- H n iit / Jr loo dec. Uu 1 AO 111 丄丄 3 Π rl OH OMe Π Π 丄 8 8— 丄丄丄 4 u Π n OBz OMe U u

Π Π l,

1 丄丄 1 ϋ

1 Ifi H OMe OH H

1 1 LI

丄丄 7 u

/ nn OH OH u Π u Π ^m 2

l ie

Uivl6 UM6 OMe H u ₀

Μθ u n Ι Π2 Π i 丄丄 34

11Q UlVlc OMe H Up IVlc H / Η 1Π i ± ^ 17 ί4

1 丄? 0 ivie OMe H i H Η / ίNomalain west: ^ 1 3

_{121 OH OMe OMe HHH NH 2 /} HC1 salt 162-166

122 OBz OMe OMe HHH NH ₂

_{123 OMs OMe OMe HHH NH 2 /} HC1 salt 185-187

124 OMe OH OMe HHH NH ₂ 143-149

_{125 OMe OMs OMe HHH NH 2 /} HC1 salt 183-186

126 OMe OBz OMe H H H N HC1 salt 156-159

_{127 OMe OMe H OMe HHH 2 /} HC1 salt 176-179

128 -0CH _20- H OMe HH ₂ / ¾¾ complex 147 Table 10 Compounds following Table 8 R5a R5b NR6R7 mpC)

129 OMe H OMe OMe HH NH ₂ HC1 salt 181

_{130 OH H OMe OMe HHH 2 /} HC1 salt

131 H OMe OMe OMe HHH ₂ HC1 salt 180-185

_{132 H -0CH 2 0- OMe HH NH} 2 / HC1 salt 160

133 H -0CH ₂ 0- OH HH NH ₂ / B complex 173 dec.

134 H-0CH _20- Me HH NH ₂ / HC1 salt 159

135 H -0CH _20- Br HH NH ₂ / HC1 salt 180

136 H OH OMe OMe Me Me NH ₂

137 H OMe OMe OH HH! ^ ₂ / ¾ complex> 250

_{138 OMe OMe OMe OMe HH NH 2} / HC1 salt 161

139 OMe OH OMe OMe HH NH ₂ 117-121

_{140 OMe OMe OH OMe HH NH 2} / HC1 salt 136-139

141 OMe OMe OMe OH HH NH ₂ 133-135 mm 1 6

Production of 3-methylamino-4,5,6-trimethoxy-1,2,3-dihydrobenzozofuran hydrochloride

To a solution of 1-g of 3-formylamino-1,4,5,6-trimethoxy-2,3-dihydrobenzofuran in 30 ml of THF was added 27.7 ml of a borane-THF complex (1M THF solution) under stirring at room temperature. Drip. After the addition, reflux for 3 hours. 20 ml of a 10% salt solution is gradually added to the reaction solution while stirring with water cooling. The solution is heated under reflux for 20 minutes, and then added with an aqueous solution of sodium hydroxide under ice cooling to make the solution more viscous. After extraction with ethyl acetate, the organic layer was washed successively with water and saturated saline, and then dried. Dry over magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained residue is dissolved in geethyl ether, and 30% (vZv) ethanol hydrochloride is added under ice-cooling. The precipitated crystals are collected by filtration and recrystallized from ethanol-ethyl ether to give 1.1 g of the title compound (Compound No. 142). Melting point 1 59.

Example 1 7

Preparation of 3-dimethylamino-4,5,6-trimethoxy-1,2,3-dihydrobenzofuran

To a solution of 1-g of 3-amino-4,5,6-trimethoxy-1,2,3-dihydrobenzofuran in anhydrous 5Om1 of THF was added 60 Omg of sodium hydride (60% dispersion in mineral oil) with stirring under ice-cooling. Add each. Then 2.8 g of methyl iodide are slowly added dropwise. After the addition, stir at room temperature for another 1 hour. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluted with 1-hexane monoethyl acetate (3: 1), purified, and then recrystallized from ethyl acetate-n-hexane. Thus, 1.3 g of the title compound (Compound No. 143) is obtained. Melting point 91.

1 8

Preparation of 3 _ (2-ethoxycarbonylethyl) amino-1,6,7-dimethoxy-2,3-dihydrobenzofuran hydrochloride

1.5 g of ethyl acrylate is added to a solution of 2 g of 3-amino-1,6,7-dimethoxy_2,3-dihydrobenzofuran in 3 Om1 of ethanol, and the mixture is heated under reflux overnight with stirring. The reaction solution is concentrated to dryness under reduced pressure, and the obtained residue is dissolved in ethyl ether, and 10% (v / v) ethanol hydrochloride is added under cooling with water. The precipitated crystals were collected by filtration and recrystallized from ethanol-ethyl ether to give the title compound (Compound No. 144) 0.8 g is obtained. Using the corresponding starting compounds, melting point 1 69 ° C, Compound No. 1 4 5 1 shown in Table 11 and represented by the following formula in the same manner as in the production method of Examples 16 to 18: Obtain 5 8 compounds.

Table 11

Compound

¾ Rc NR6R7 mp (° C)

U n

n Ιχπΐνΐθ / Π 1 oy Ι Ό

147 OH H OMe H Me Me NHCH ₂ C00H

148 H -0CH ₂ 0-HHH Awake e 50

149 H-0CH ₂ O-HHHN (e) ₂ 156-158

150 H -0CH ₂ 0- HHH NHCH _2-3 -Pirile 79-80

151 OMe OMe OMe HHH NH (CH ₂ ) ₂ C00Et / HCl salt 138

152 OMe OMe OMe H H H NHC¾- c-Pen / HCl salt 166

153 OMe OMe OMe HHH NH (CH 2) 2 0H HC1 salt 131

154 OMe OMe OMe HHH NH (CH ₂ ) ₂ O e 133

155 OMe OMe OMe HHH NH (CH 2) 2 N (Me) 2/2 HC l salt 127

156 OH OMe OMe H Me Me brain e / HCl salt

157 OH OMe OMe H Me Me H (CH 2) 2 0H / HC1 salt

158 OH OMe OMe H Me Me NHCH ₂ C00H Example 1 9

3-formylamino-1,4,56-trimethoxy-1,2,3-dihydrobenzene Production of furan

100 ml of ethyl formate is added to a 200 ml solution of 5 g of 3-amino-1,4,5,6-trimethoxy-1,2,3-dihydrobenzofuran in toluene and heated to reflux for 16 hours. The reaction solution was concentrated to dryness under reduced pressure, and the obtained residue was subjected to silica gel column chromatography, eluted with n-hexaneethyl acetate (1: 2), purified, and purified to give the title compound (compound Number 1 5 9) 4.2 g are obtained. Melting point: 106-109 ° C (recrystallized from ethyl acetate-n-hexane).

Example 20

Preparation of 3-cyclopentylcarbonylamine 4,5,6-trimethoxy 2,3—dihydrobenzofuran

10 g of pyridine was added to a solution of 6 g of 3-amino-1,4,5,6-trimethoxy-1,2,3-dihydrobenzofuran hydrochloride in 50 ml of methylene chloride under ice-cooling and stirring, followed by cyclopentylcarbonyl chloride. 5 g are dropped. After the addition, continue stirring for 8 hours. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 1.25 g of the title compound (Compound No. 160). Melting point 176.

Example 2 1

Production of 3-acetylamino 7-acetoxy 6-methoxy 2,3-dihydrobenzofuran

1.0 g of 3-amino-7-hydroxy-1,6-methoxy-2,3-dihydrobenzozofuran is reacted with acetic anhydride in pyridine to obtain 0.9 g of the title compound (Compound No. 161). Melting point 142-144 (recrystallized from ethyl acetate).

Example 22 Production of 3-acetoxyacetylamino-4,5,6—trimethoxy-2,3-dihydrobenzofuran

10 g of pyridine is added to a suspension of 5 g of 3-amino-1,4,5,6-trimethoxy-2,3-dihydrobenzofuran hydrochloride in 200 ml of methylene chloride at room temperature. Next, 10 g of acetooxyacetic acid 6 and 1-ethyl-13- (3-dimethylaminopropyl) carbodiimide (WSC) hydrochloride are added, and the mixture is stirred for 1.5 hours. Water is added to the reaction solution, and the mixture is extracted with methylene chloride. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 3.8 g of the title compound (Compound No. 162). Melting point 118-120 t :.

Example 23

3 Production of 1-benzyloxyacetylamino-4,1-benzyloxy-5,6-dimethoxy-1,2,3-dihydroxybenzofuran

To a solution of 9.0 g of 3-amino-4,1-benzyloxy-5,6-dimethoxy-1,2,3-dihydrobenzofuran in 50 ml of methylene chloride was added 9.1 g of triethylamine and benzyloxy chloride under ice-cooling and stirring. Add xiacetyl 6.7. After stirring for 30 minutes, add water and extract with methylene chloride. The organic layer is washed successively with water and a saturated food, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate to obtain 12.8 g of the title compound (Compound No. 1663). Melting point 117-118 ° C.

twenty four

Production of 3-hydroxymethylcarbonylamino-4-hydroxy-5,6-dimethoxy-2,3-dihydrobenzofuran

3 Benzyloxycetylamine 4 Benzyloxy 5, 6-dimethyl Toxic 2,3-dihydrobenzofuran A catalyst palladium hydroxide 3 is added to a mixed solvent of 12.8 g of ethanol (100 ml) and ethyl ethyl acetate (100 ml), and the mixture is subjected to catalytic hydrogen reduction under a hydrogen atmosphere. After the reaction, the catalyst was removed, the solvent was distilled off, and the obtained crude crystals were recrystallized from getyl ether to obtain 7.1 g of the title compound (Compound No. 164). Mp 189-194 ° C.

Fine 2 5

Preparation of 3-acetoxyacetylamino-4-acetoxy 5,6-dimethoxy 2,3-dihydrobenzofuran

3-Hydroxymethylcarbonylamino-4-hydroxy-5,6-dimethoxy-2,3-dihydroxybenzofuran 1.0 g was reacted with acetic anhydride in pyridine to give the title compound (Compound No. 165) 0.9 g Get. Melting point 109-111 ° C (recrystallized from getyl ether).

Using the corresponding starting compounds, in the same manner as in the production methods of Examples 19 to 25, compounds represented by the following formulas and represented by the compound numbers 166 to 300 listed in Tables 12 to 18 Get.

Compound

(¾ Rc RBa R5b NR6R ⁷ m CC)

-0CH ₂ 0- n HHHH ΝΗΓΗΟ

丄ゎ ί OMe H U U

Π Π Π Ι uΠrνuΓΐnυ I a oao I C oQo

168 OMe H OMe H H H NHAc 196-197

169 O e H OMe HHH NHCOCH ₂ O e 119-120

170 OMe H OMe H H H NHCO-c- Pen 170-172

171 OH H OMe HHH NHCOCH ₂ OAc 121-122

172 OH H OMe HHH NHCOCH ₂ OH 137-141

_{173 OAc H OMe HHH NHCOCH 2 0H} -

174 OAc H OMe H H H NHAc-

175 OAc H OMe H Me Me NHAc-

176 OAc H OMe HHH NHCOCH ₂ OAc 98-100

177 OH H OH HHH HCOCH ₂ OAc 155-158

178 OH H OH HHH stroke CH ₂ OH 164-166

179 OBz H OBz HHH NHCOCH ₂ OAc 166

180 OBz H OBz HHH Picture CH ₂ 0Bz

181 O s H OMs HHH NHCOCH ₂ 0Ac 92-94

182 OAc H OAc HHH NHCOCH ₂ OAc 90-92

183 OMe H OMe H Me Me NHCOCH ₂ OAc 132-133

184 OMe H OMe H Me Me NHCOCH ₂ OH 162-163

185 OH H OMe H Me Me NHCHO

186 OH H OMe H Me Me NHCOCH ₂ 0Ac 149-152

187 OH H OMe H Me Me NHC0CH ₂ 0H 159-161

188 OBz H OMe H Me Me picture CH ₂ OAc 126-129

189 OAc H OMe H Me Me NHCOCH ₂ OH 121-125 Table 13 Compounds following Table 12

Ra ^R b R ^5a R5b NR6R7 rap (° C)

190 OBz H OMe H Me Me NHC0CH ₂ 0Bz 127-129

191 OBz H OBz H Me Me NHC0CH ₂ 0Ac 163-164

192 O s H OMe H Me Me NHCOCH OAc 105-109

193 OH H OMe H Me Me NHC0CH ₂ 0Bz 128-131

194 OBz H OMe H Me Me NHC0CH ₂ 0Bz

195 OAc H OMe H Me Me NHC0CH ₂ 0Bz 98-101

196 OMs H OMe H Me Me NHC0CH 2 0H 109-111

197 OAc H OAc H Me Me NHC0CH 2 0Ac 133-135

198 OH H OH H Me Me NHC0CH ₂ 0Ac oil

199 H OMe OMe H H H NHCH0 146-147

200 H OMe OMe HHH NHC0CH ₂ 0Ac 162-165

201 H 100 ΟΓΗ 0-H H H NHCH0 208-209

202 H -OCHoO- H H H N (Me) CH0 102-104

203 H -ΟΓΗ Ο- H H H Marauder C 200 n Π9 H

_{_{205 H -0CH 2 0- HHH NHC0CH 2}} 0H 160-162

_{_{206 H -0CH 2 0- HHH NHC0CH 2}} 0Ac 164-166

_{207 H - 0CH 2 0 - HHH} NHC0CH 2 0Me 127-128

_{208 H -0CH 2 0- HHHN (Me} ) C0CH 2 0Me 76-78

209 H -0CH ₂ 0- HHH image CH ₂ SPh 148-150

_{_{210 H -0CH 2 0- HHH NHCOCH 2}} S0 2 Ph

211 H -0CH ₂ 0- HHH NHC0CH ₂ NHCH0 232-234

212 H -0CH _20- HHH NHCOCH (Me) OAc 152-153 Table 14 Continued from Table 12

^^

R _a Rc ¾ R5a R5b 7 mp CC)

_{H -0CH 2 0- HHH HC0 (CH} ,)? C00H 182-185

214 H-0CH ₂ 0- HHH NHCO (CH ₂ ) ₂ COOMe 146-149

215 H-0CH ₂ 0- HHH NHC0 (CH ₂ ) ₂ C0NH ₂ 158-159

H -0CH _20- HHH NHC0 (CH ₂ ) ₂₀ Me 140-142

UC 1 C Π-0CH ₂ 0- yuu

n n Π ノ 2 1

丄 13 丄 8 Π-0CH ₂ 0- H uu

nn

Up / D- 丄 / 8

_{219 H -0CH 2 0- HHH NHC0 (} CH 2) 2 S0 2 Me 217-219

220 H-0CH ₂ 0- HHH NHC0 (CH ₂ ) ₈ C00 e 126

221 H -0CH ₂ 0- HHH NHCOCOCH3 157

222 H -0CH ₂ 0- HHH NHCO- 3-pyridyl 181-183

_{223 H - 0CH 2 0 - HHH} NHC0CH 2 - 3 - pyridyl Le -

224 H H OMe OMe H H NHCH0 117

_{225 HH - 0CH 2 0- HH NHCH0} 176

NHC0CH = CH- (3, 4-

226 H H OMe OMe H H 158 n MeOPh)

997 n H OMe OMe u n u n NHC0CH OAr 丄 UO ー丄

228 HH OMe OMe HH NHC0CH ₂ OH 137-140

229 HH OH OMe HH image CH ₂ 0Ac 158-160

230 HH OMe OMe Me Me NHC0CH ₂ 0Ac 81-82

231 OMe OMe OMe H H H NHAc 147-149

232 OMe OMe OMe H H H NHCOCOOEt 87

_{233 OMe OMe OMe HHH NHC0CH 2 0H} 126-127

234 OMe OMe OMe HHH HC0CH ₂₀ e 88-90 Table 15 Compounds following Table 12

No.¾ ¾ Rc Rd R5a R5b N 6R7 mp (° C)

235 OMe OMe OMe HHH NHCOCH ₂ NHCHO 193

236 OMe OMe OMe HHH HCOCH ₂ C00H 143-144

237 OMe OMe OMe HHH NHCOCH ₂ COOEt 167

238 OMe OMe OMe HHH NHCOCH ₂ SMe 145

239 OMe OMe OMe HHH NHCOCH ₂ S0 ₂ e 164

240 OMe OMe OMe HHH Hidden CH = CH ₂ 132

HC0CH = CH- (3,4- 4 丄 UMe UMe UMe u U LI N

Π ΙΊ Π 丄丄丄

· MeOPh)

242 OMe OMe OMe HHH NHCOC oH ₂ CH ₂ CN 125-126

243 OMe OMe OMe HHH NHCO (CH ₂ ) ₂ COOEt 113

244 OMe OMe OMe HHH NHCOCH ₂ NHAc 151

245 OMe OMe OMe HHH HCOCH ₂ N (e) ₂ 88

246 OMe OMe OMe HHH NHCO (CH ₂ ) ₃ C0CH ₃ 116

247 OMe OMe OMe H H H 162

248 OMe OMe OMe H H H NHCO-c-Pr 155

249 OMe OMe OMe HHH HCO (CH ₂ ) ₂ Se 131

NHC0CH ₂₀ (3,4,5-

250 OMe OMe OMe H H H 154-155 Tri MeOPh)

251 OMe OMe OMe HHH NHCOCH ₂₀ (CH ₂ ) ₂ OMe oil

252 OMe OMe OMe H H H NHCOCH (Me) OAc 139-140

253 OMe OMe OMe H H H NHCOCH = CHC0OEt 153-154

254 OMe OMe OMe H H H NHCO-2-tetrahydrid n-furyl 135

255 OMe OMe OMe HHH NHCO- 5-Isoxaso'lyl 146-151 Table 麵 16 Continued from Table 12

¾ R5a R5b NR6R7

OMe OMe OMe H Me Me NHCOCH ₂ OAc 137-138 ά 1 OMe OMe OMe H Me Me NHCOCH ₂ OH 146-148

OMe OMe OMe H H H HCO-5- (2-year-old Kisop α Rishi ':: R) 221

259 OMe OMe OMe H H H NHCO- 4- (5-Me isoxazolyl) 169-172

260 OAc OMe OMe H H H Thigh c

261 OAc OMe OMe H Me Me NHAc

262 Un UMe UMe n Me Me H HU

263 OH OMe OMe H H H NHCOCHoOAc

264 OAc OMP OMP H H H NHCOCH OH

265 OBz OMe OMe H H H NHCOCHoOAc 96-100

266 OMs OMe OMe H H H NHCOCH7OAC 144-149

267 OMs OMe OMe H H H NHCOCHoOH 1 12-1 14

268 0R ₇ OMP OMe H Up Up NHCOCHoOAc 1 12

269 OH OMe OMe H Me Me NHCOCH ₂ OAc 148-149

270 OH OMe OMe H Me Me NHCOCH ₂ OH 118-119

271 OMs OMe OMe H Me Me NHCOCH ₂ OAc 96-97

272 OMs OMe OMe H Me Me NHC0CH ₂ OH 117-118

273 OAc OMe OMe H Me Me NHC0CH 2 0Ac 113-116

274 OAc OMe OMe H Me Me NHCOCH ₂ OH

275 OMe OH OMe HHH picture CH ₂ 0Ac 167-170

276 OMe OMs OMe HHH NHCOCH ₂ OAc 155-158 Table 17 Compounds following Table 12

^-l R .R5a R5b NR6R7 ⁱⁱⁱ

277 OMe OMs OMe HHH NHCOCH ₂ OH 166-168

278 OMe OBz OMe HHH NHCOCH ₂ OAc 120-123

279 OMe OBz OMe HHH NHCOCH ₂ OH ―

280 OMe OBz OMe HHH NHCOCH ₂ OBz

281 OMe OAc OMe HHH NHCOCH ₂ OAc 144-149

282 OMe OH OMe HHH NHCOCH ₂ OH 157-160

283 OMe OMe H OMe H H NHCHO 125-126

284 OMe H OMe OMe H H NHCHO 132-133

285 OMe H OMe OMe HH NHCOCH ₂ OAc 154-155

286 OMe H OMe OMe H H NHCO- c- Pen 146-151

287 OMe H OMe OMe H II NHCO- 5- (2-year-old oxopi n-ricinyl) 136-143

H OMP H H NHCO-4- (5-CH soxazo'lyl)

289 H OMe OMe OMe H H NHCHO 100-101

290 H OMe OMe OMe HH NHCOCH ₂ OAc 76-80

291 H OH OMe OMe HH NHCOCH ₂ 0Ac 138-143

292 H OH OMe OMe Me Me NHCOCH ₂ OH

293 H OH OMe OMe Me Me NHCOCH ₂ OAc

294 H OAc OMe OMe Me Me HC0CH 2 0H

295 H OAc OMe OMe Me Me Oki CH ₂ OAc Table 18 Compound _R 5a R5b NR6R7 mp (° C) following Table 12

296 H-0CH _20- OMe HH NHCHO 179-180

297 H -0CH ₂ 0- Me HH NHCHO 170 dec.

298 H -0CH ₂ 0- Br HH NHCHO

299 H -0CH ₂ 0- CH ₂ 0H HH NHCHO 136-137

300 O e O e OMe OMe H H NHCHO 63-65 .. Example 2 6

3 —Methanesulfonylamino-6,7—Dimethoxy 23 3 —Production of dihydrobenzofuran

To a suspension of 3-amino-1,6,7-dimethoxy2,3-dihydrobenzofuran hydrochloride 4 in 200 ml of methylene chloride was added 8 g of triethylamine while stirring under ice-cooling. Then 3.3 g of methanesulfonyl chloride are added dropwise and stirring is continued for another 10 minutes. Water is added to the reaction solution, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-ethyl ether to obtain 1.3 g of the title compound (Compound No. 301). Melting point 1 2 4 ° C Example 2 7

5 —Hydroxy-6,7-dimethoxy-3 —Methanesulfonylamino-23 —Dihydrobenzobenfuran

3 -Amino-5-hydroxy-1,6,7-dimethoxy2,3 -Dihydrobenzofuran 3.8 g of methylene chloride in 500 ml of methylene chloride under stirring at room temperature Slowly add 4.1 g of sulfonyl dropwise. After stirring for 15 minutes, add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with n-hexane monoethyl acetate (1: 1) to obtain 0.7 g of the title compound (Compound No. 302). Melting point: 134-136 x: (recrystallized from ethyl acetate-n-hexane monoether).

Example 2 $

5-Methanesulfonyloxy-6,7-Dimethoxy-3-Methanesulfonylamine Production of 2,3-dihydrobenzofuran

3.2 g of methanesulfonyl chloride in a solution of 2.0 g of 3-amino-5-hydroxy-6,7-dimethoxy-1,2,3-dihydroxybenzofuran in 200 ml of methylene chloride with stirring at room temperature in the presence of 4.8 g of triethylamine Drip. After stirring for 15 minutes, add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated food ^ J, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (1: 1). Purification was performed to obtain 2.3 g of the title compound (Irido Compound No. 303). obtain. Melting point 130 to 132 C (recrystallized from ethyl acetate-n-hexane)

Example 29

4-Benzyloxy 6-methoxy 3-methanesulfonylamino 1,2

Production of 2-dimethyl-2,3-dihydrobenzofuran

3-amino-1 4-benzyloxy 6-methoxy2,2-dimethyl-2,

To a solution of 12 g of 3-dihydrobenzofuran in 300 ml of methylene chloride was added 16.2 g of triethylamine while stirring at room temperature, and then methanesulfonyl chloride 6.9 Add g slowly. After stirring for 30 minutes, add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the obtained crystal is recrystallized from ethanol-n-hexane-ethyl ether to obtain the title compound (Compound No. 304) 6.5. Melting point 141-14-143x :.

Example 3 0

4—Hydroxy-1 6-Methoxy-1 3-Methanesulfonylamino-1,2,2-dimethyl-2,3-Dihydrobenzofuran

4 Addition of a catalytic amount of 10% palladium-carbon to a solution of 6.2 g of ethyl acetyl acetate in 6.2 g of monobenzyloxy 6-methoxy 3 -methanesulfonylamino 2,2-dimethyl-2,3-dihydrobenzofuran 6.2 g And catalytic hydrogen reduction at room temperature in a hydrogen atmosphere. After completion of the reaction, the catalyst is removed, and the solvent is distilled off under reduced pressure. The obtained crystals are recrystallized from ethanol_n-hexane-monoether to obtain 4.1 g of the title compound (Compound No. 305). Melting point 167-170 ° C.

m 3 1

Preparation of 4-acetoxy 6-methoxy 3-methanesulfonylamino-1,2,2-dimethyl-2,3-dihydrobenzofuran

4-Hydroxy 6-methoxy 3 -Methanesulfonylamino-1,2,2-dimethyl-1,2,3 -dihydrobenzofuran is acetylated with acetic anhydride in pyridine to give the title compound (Compound No.306). obtain. Melting point 89-93 (recrystallized from ethyl acetate-n-hexane).

Using the corresponding starting compounds, in the same manner as in the production method of Examples 26 to 31 and the compound numbers of 307 to 361 listed in Tables 19 to 21 represented by the following formulas: Obtain the compound. 1 9

Compound

Number ¾ Rc ¾ R5a R5b ⁷ mp (° C)

307 OMe OMe HHHH -NHS0 ₂ Me 104

308 OMe H OMe HHH -NHS0 ₂ e 166

309 OMe H OMe H Me Me -NHS0 ₂ Me 167-172

310 OH H OMe HHH -NHS0 ₂ Me 125-131

311 OH H OMe H Me Me -NHS0 ₂ Me ―

312 OH H OMe HHH -NHS0 ₂ Ph ―

313 OMs H OMe HHH-Solid ₂ Me 164-167

314 O s H OMs H Me Me -NHS0 ₂ Me 121-123

315 OBz H OBz H Me Me -NHS0 ₂ Me oi l

316 OH H OH H Me Me-Awake ₂ Me oil

317 OAc H OAc H Me Me -Sleep ₂ Me 156-157

318 OAc H OAc H Me Me -Sleep ₂ Ph

319 OMe HH OMe HH -Drop ₂ Me 177

320 H OMe OMe HHH-recitation ₂ Me 137-140

321 H -OCH ₂ 0- HHH-NHS0 ₂ Me 145-147

322 H OMe H OMe HH -NHS0 ₂ e 124

323 H H OMe OMe Me Me-Picture 124-128

324 HH OMe OMe HH -Fuji ₂ Et 96-98

325 HH OMe OMe HH -NHS0 ₂ i -Pr 76-77

326 HH OMe OMe HH-瞧₂ Ph 158-159

327 HH OMe OH HH -NHS0 ₂ Me 162-166

328 OMe OMe OMe HHH -NHS0 ₂ Me 127 20 Compounds following Table 19

¾ ：-& ¾ ^R 5a ^R 5b finished 7 mp C)

329 OMe O Me (Me H Me Me -NHS0 ₂ Me 144

H H H -NHSO i -Pr o o

VJlVlc UIVlC n n -NHSO D-MePh i

332 OBz OMe OMe HHH -NHS0 ₂ Me 145- 147

333 OBz OMe OMe H Me Me -NHS0 ₂ e 1 30-132

334 OMs OMe OMe HHH -NHS0 ₂ Me 135-138

336 OH OMe OMe HHH -NHS0 ₂ Me 1 70-171

337 OH OMe OMe H Me Me -NHS0 ₉ Me 195-203

338 OH OMe OMe HHH -NHS0 ₂ Ph

339 OH OMe OMe H Me Me-Picture ₂ Ph

340 OAc OMe O ReMe HHH -NHS0 ₂ e 123-1 27

341 OAc OMe OMe H Me Me -NHS0 ₂ Me 164-166

342 OMe OBz OMe HHH -NHS0 ₂ e

343 OMe OMs OMe HHH-瞧₂ Me 135-137

344 OMe OH OMe HHH -NHS0 ₂ Me 157-159

345 OMe OAc OMe HHH -Image ₂ Me 122-125

346 OMe OMe H OMe HH -NHS0 ₂ Me 115-118

347 OH OMe H OMe HH-Picture ₂ Me

348 OH OMe H OMe Me Me -NHS0 ₂ Me

349 OMe H OMe OMe HH -Image ₂ Me 138-140 Table 21 Compounds R R5a R5b M 6R7 (. () No. H following Table 19)

350 OH H OMe O e HH -NHS0 ₂ Me

35 丄 OH H OMe OMe Me Me -NHS0 ₂ Me

352 H OMe OMe OMe H H-NHS (¾Me 120

353 H OH UMe UMe Me Me-NH ^ Me

-NH OnPh

355 OMe OMe OMe OMe HH -NHS0 ₂ Me 116-117

356 OH OMe OMe OMe HH -NHS0 ₂ Me

357 OH OMe OMe OMe Me Me -NHS0 ₂ Me

358 OMe O s OMe OMe HH -NHS0 2 Me 127-129

359 OMe OH OMe OMe HH -NHS0 ₂ Me 154-157

360 OMe OMe OH OMe HH -Image ₂ Me

361 OMe OMe OMe OH HH -NHS0 ₂ e 133-136

Reference example 1

4,5,6—trimethoxy-1 23-dihydrobenzofuran 1-3-one

(1) To a commercially available solution of 25 g of 3,4,5-trimethoxyphenol in 150 g of dimethylformamide is added 37.5 g of potassium carbonate. To this mixture, 27.2 g of ethyl bromoacetate was added dropwise while stirring at room temperature, and the mixture was heated and stirred at 80 for 3.5 hours. After cooling, add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, the obtained residue is dissolved in 100 ml of ethanol, 200 ml of a 10% aqueous sodium hydroxide solution is added, and the mixture is stirred at room temperature for 1 hour. Add concentrated hydrochloric acid while stirring on ice Neutralize. The precipitated crystals are collected by filtration, washed with water and dried to give 26 g of 3,4,5-trimethoxyphenoxyacetic acid. With a melting point of 114 to 115.

(2) 47 g of trifluoroacetic anhydride is added dropwise to a suspension of 36.4 g of the above compound in 500 ml of methylene chloride while stirring at room temperature. Next, 32 g of trifluoroborane-getyl ether complex (1 molar solution) is added dropwise, and the mixture is further stirred at room temperature for 4 hours. Add water to the reaction mixture and extract with methylene chloride. The organic layer is washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 16.4 g of the title compound. Melting point 144 ° (:.

Participant example 2

5, 7-Dimethoxy-1,2,3-Dihidrobenzofuran 3-Production

(1) Literature (Pharmaceutical Journal, 99 (6), 657-662 (1979)) Known 2-hydroxy-3,5-dimethoxyacetophenone 37 g of pyridine in a 60 ml solution of acetic anhydride was stirred under ice-cooling with acetic anhydride. After adding 53 ml, leave at room temperature overnight. Pour the reaction solution into ice water, stir for 30 minutes, and extract with ethyl acetate. The organic layer is washed sequentially with water and a saturated aqueous solution of sodium hydrogen, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with n-hexane-ethyl acetate (2: 1) 'Purified, and colorless crystals of 2-acetoxy-1,3,5-dimethyl 37 g of Toxiacetophenone are obtained.

(2) To a mixed solution of 37 g of the above compound in form-form (800 ml) -ether (1.5 L), slowly add dropwise 28 g of bromine over 1 hour while stirring at room temperature. After dropping, continue stirring for another 40 minutes. Pour the anti-IS solution into permanent water and extract with black-mouthed form. The organic layer is washed with water and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give colorless crystalline 2-acetoxy-1,3-dimethoxy. One bromo 30 g of acetophenone was obtained and used for the next reaction without further purification.

(3) To a solution of 30 g of the above compound in 1 L of methanol was added 330 ml of 48% hydrobromic acid, and the mixture was heated and refluxed for 80 hours and 2 hours. After cooling, pour the reaction solution into water and stir for a while. After methanol is distilled off under reduced pressure, extraction is performed with ethyl acetate. The organic layer is washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 2-hydroxy-3,5-dimethyl. Obtain 20 g of 1-bromoacetophenone and use it for the next reaction without further purification.

(4) To a solution of 20 g of the above compound in 400 ml of methanol was added 7.2 g of sodium acetate, and the mixture was heated under reflux at 80 for 1.5 hours. After cooling, pour the reaction solution into water, stir for a while, and extract with ethyl acetate. The organic layer is washed successively with water and a saturated aqueous solution of sodium hydrogen carbonate, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 7.1 g of the title compound. Mp 138-139 ° C.

Reference example

5-hydroxy-1,6,7-dimethoxy 2,3-dihydroxybenzofuran

(1) Literature (). Chem. So, 662 (1941)) A solution of 102 g of 2,5-dihydroxy-1,4,4-dimethoxyacetophenone, known in the art, in pyridine (233 g) was added to a solution of 200 g of acetic anhydride under stirring at room temperature. Add g and stir for 3 hours. Add ice water to the reaction solution under ice cooling and stir for 30 minutes. Add 500 ml of water and extract with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (3: 1). Toxic 3,4-dimethoxyacetophenone (140 g) is obtained as a colorless oil and used for the next reaction without further purification.

(2) To a mixed solution of 140 g of the above compound (140 g) in chloroform (450 ml) -ether (1.6 L), slowly add 83 g of bromine under stirring at room temperature. After dropping, continue stirring for another 30 minutes. A saturated aqueous solution of sodium thiosulfate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer is washed successively with water and saturated food, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and 2,5-diacetoxy-1,3,4-dimethoxy-1-α-bromoacetophenone is obtained as an oil, which is used for the next reaction without further purification.

(3) To a solution of the above compound in 600 ml of methanol is added 320 ml of 48% hydrobromic acid, and the mixture is heated under reflux for 1 hour. After cooling, pour the reaction solution into water and extract with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to give 2,5-dihydroxy-1,3,4-dimethoxy. Obtain 1-bromoacetophenone and use it for the next reaction without further purification.

(4) 78 g of sodium acetate is added to a 500 ml solution of the above compound in methanol, and the mixture is heated and refluxed for 30 minutes. After cooling, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with n-hexane monoethyl acetate (2: 1). Purification was performed to obtain 44 g of the title compound. Melting point: 123-125 (recrystallized from n-hexane monoacetate) ₀

Reference example 4

5—Hydroxy-1,4—Dimethoxy 2,3—Dihydrobenzofuran 3 One on

(1) To a solution of 2,5-dihydroxy-4,6-dimethoxyacetophenone (175 g) in pyridine (521 g) was added 421 g of acetic anhydride with stirring at room temperature, followed by stirring for 2 hours. Add ice water to the reaction solution under ice cooling, stir for 30 minutes, and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crude crystals were recrystallized from ethyl acetate-n-hexane to obtain 185 g of 2,5-diacetoxy-4,6-dimethoxyacetophenone. Melting point 101-103 ° C.

(2) To a mixed solution of 183 g of the above compound in chloroform (2.1 L) ether (580 ml) was slowly added dropwise 109 g of bromine while stirring at room temperature. After the dropwise addition, the mixture was further stirred for 30 minutes, then 1 L of a saturated aqueous solution of sodium thiosulfate was added, and the mixture was extracted with ethyl ether. The organic layer is washed successively with a saturated aqueous solution of sodium thiosulfate, water and a saturated food, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to give 2,5-diacetoxy-1,4,6-dimethoxy-1-α-bromoacetophenone as an oil, which is used for the next reaction without further purification.

(3) To a 1 L solution of the above-mentioned compound in methanol is added 421 ml of 48% hydrobromic acid, and the mixture is heated under reflux for 70 minutes. After cooling, the reaction solution is poured into water, and the precipitated crystals are collected by filtration. The obtained crude crystals were recrystallized from ethyl acetate-n-hexane to give 2,5-dihydroxy-4,6-dimethoxy-1. Obtain 130 g of 1-bromoacetophenone. Mp 148-151.

(4) 73 g of sodium acetate is added to a 1.3 L solution of the above compound (130 g) in methanol, and the mixture is heated under reflux for 30 minutes. After cooling, add water and extract with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate and a shim. The solvent was distilled off under reduced pressure, and the obtained crude crystals were purified from ethyl acetate-n-hexane. Recrystallize to give 51 g of the title compound. With a melting point of 145-147.

Participant example 5

Production of 5-hydroxy 4, 6, 7-trimethoxy 2, 3-dihydroxybenzofuran-3-one

(1) Literature 0. Chem. So, 662 (1941)) Known 2,5-dihydroxy-3,4,6-trimethoxyacetophenone 70 g, acetic anhydride 126 g, pyridine

A mixture of 1 47 g and 6 g of 4-dimethylaminopyridine is stirred overnight at room temperature. Pour the reaction solution into ice water and extract with ethyl acetate. The organic layer is washed successively with a saturated aqueous solution of copper sulfate, water, and a saturated saline solution, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 66 g of 2,5-diacetoxy-3,4,6-trimethoxyacetophenone, which is used for the next reaction without further purification.

(2) To a mixed solution of 66 g of the above compound in chloroform (2 12 ml) -ether (774 m 1), 35.6 g of bromine was slowly added dropwise over 1 hour while stirring at room temperature. After the dropwise addition, the mixture is further stirred for 30 minutes. Pour the reaction solution into ice water, add 800 ml of a saturated aqueous solution of sodium thiosulfate, and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with n-hexane-ethyl acetate (2: 1) 'purified, and purified with 2,5-diacetoxie 3,4,6-trimethyl Obtain 50 g of toxic α-bromoacetophenone and use it for the next reaction without further purification.

(3) A solution of 50 g (0.09 mol) of the above compound in 375 ml of methanol

Add 8% hydrobromic acid (125 ml) and heat to reflux for 1 hour. After cooling, pour the reaction solution into water and extract with ethyl acetate. The organic layer was washed sequentially with water and saturated food ^ 7] C Then, it is dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to give 2,5-dihydroxy 3,4,6-trimethoxy. -39 g of bromoacetophenone is obtained and used for the next reaction without further purification.

(4) To a solution of 39 g (0.084 mol) of the above compound in 830 ml of methanol, add 38 g (0.252 mol) of sodium acetate and heat to reflux for 1 hour. After cooling, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate (1 LX 2). The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with n-hexane-ethyl acetate (2: 1) to obtain 13 g of the title compound. Melting point: 103 ° C (recrystallized from getyl ether).

Reference example Q

Preparation of 6-hydroxy-1,4,5,7-trimethoxy-1,2,3-dihydroxybenzofuran-1-one

(1) 2,4-Diacetoxy-1,3,5,6-trimethoxyacetophenone 18.7 g of bromine was stirred for 1 hour under stirring at room temperature in a mixed solution of 30 g of formaldehyde (96 ml) -ether (345 ml). Apply slowly and drop. Stir for an additional 30 minutes after the addition. The reaction solution was poured into ice water, 600 ml of a saturated aqueous solution of sodium thiosulfate was added, and the mixture was extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted and purified with n-hexane monoacetate (2: 1), and purified with 2,4-diacetoxy-1,3,5. 36.5 g of, 6-trimethoxy-1- _α -bromoacetophenone are obtained as an oil which is used without further purification in the next reaction.

(2) 48% hydrogen bromide in a solution of 36.5 g of the above compound in 70 ml of methanol Add 89 ml of acid and heat to reflux for 1.5 hours. After cooling, pour the reaction solution into water and extract with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over magnesium sulfate anhydride. The solvent was distilled off under reduced pressure to give 2,4-dihydroxy-

3, 5, 6-Trimethyoxy 1-bromoacetophenone 27 g. Mp 1

13 to; I 14 ° C.

(3) To a solution of 27 g of the above compound in 500 ml of methanol is added 20.7 g of sodium acetate, and the mixture is heated under reflux for 1 hour. After cooling, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layer was washed successively with water and saturated food D, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from ethyl acetate to obtain 13.5 g of the title compound. Mp 136-138.

Participant example 7

7-Hydroxy 6-Methoxy 2-, 3-Dihydro-benzobenzofuran production

(1) 2,3-Dihydroxy-14-methoxyacetophenone 12.5 g, obtained by acetylating acetic acid in pyridine with acetic anhydride in 2,3-diacetoxy-4-methoxyacetophenone To a mixed solution of (80 ml) and ether (250 ml), 7.4 g of bromine is slowly added dropwise over 1 hour while stirring at room temperature. After dropping, stir for another 30 minutes. Pour the reaction solution into ice water, add a saturated aqueous solution of sodium thiosulfate, and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with n-hexane monoethyl acetate (2: 1) 'purified, and purified with 1,3-diacetoxy-4-methoxy-c-1 13.3 g of bromoacetophenone are obtained as an oil and used for the next reaction without further purification. (2) To a solution of the above compound (13.lg) in methanol (130 ml) was added 48% hydrobromic acid (13 ml), and the mixture was heated under reflux for 2 hours. After cooling, pour the reaction solution into water and extract with ethyl acetate. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 9.6 g of 2,3-dihydroxy-14-methoxyα-bromoacetophenone. Use for the next reaction without further purification.

(3) To a solution of 9.6 g of the above compound in 100 ml of methanol was added 12 g of sodium acetate, and the mixture was heated under reflux for 1 hour. After cooling, the solvent is distilled off under reduced pressure, water is added, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the obtained crystals were recrystallized from methanol to obtain 4.4 g of the title compound. 224-225 ° C (decomposition).

Reference Example 8

Preparation of 7-hydroxy-5,6-dimethoxy2,3-dihydrobenzofuran-3-one:

(1) 5,6-Dimethoxy-2,3-dihydrobenzofuran-3-one 26 g of triethylamine was added to a solution of 28 g of methylene chloride in 500 ml of methylene chloride, and then t-butyldimethylsilyl trifure was added under ice-cooling and stirring. Slowly add 50 g of dichloromethane. After the addition, the mixture is further stirred for 15 minutes. Add water and extract with ether. The organic layer is washed successively with water and a saturated diet ^ 7, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with n-hexane monoacetate (3: 1).-Purified, 3- (t-butyldimethylsilyloxy)- 43 g of 5,6-dimethoxybenzofuran are obtained as a colorless oil and used in the next reaction without further purification. (2) To a solution of 43 g of the above compound in 300 ml of THF, slowly add 96 ml of n-butyllithium (1.6 molar hexane solution) dropwise under a nitrogen stream. After dropping, stir for 30 minutes under ice cooling. Cool again to -78 ° C, and slowly add dropwise 16 g of trimethoxyborane to the reaction solution. After the dropwise addition, return to room temperature and stir for 20 minutes. Then, the mixture is cooled to 10 and 17.4 g of aqueous hydrogen peroxide is added dropwise to the reaction solution over 30 minutes. After the dropwise addition, return to room temperature and stir for 30 minutes. Add 80 ml of a saturated aqueous solution of sodium sulfite dropwise over 30 minutes under ice-cooling. After dropping, add ice water and extract with ether. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, eluted with n-hexane monoethyl acetate (5: 1), purified and purified with 7-hydroxy-3- (t-butyldimethylsilyl). 12 g of 5,6-dimethoxybenzofuran are obtained as a yellow oil. Use in the next reaction without further purification o

(3) To a solution of 12 g of the above compound in 1 L of THF, slowly add 20 ml of tetrabutylammonium fluoride (1M in THF) dropwise under ice-cooling. After stirring for 5 minutes, ice water and a saturated aqueous solution of sodium chloride are sequentially added, and the mixture is extracted with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 10.5 g of the title compound, which was used for the next reaction without further purification.

Participant example 9

Preparation of 4-benzyloxy-6-methoxy-1,2,2-dimethyl-12,3-dihydrobenzofuran-1-one

4-Benzyloxy-6-dimethoxy 2,3-dihydrobenzofuran To a solution of 40 g of 3-one in 800 ml of toluene was added 36.5 g of t-butoxylium under ice-cooling and stirring. Next, 92.2 ml of methyl iodide is added dropwise over 15 minutes. After stirring at room temperature for another 15 minutes, add water and extract with black hole form. The organic layer is washed sequentially with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography, and eluted with n-hexane-ethyl acetate (4: 1) 'purified to obtain the title compound 38.3 as an oil.

Reference example 10

Production of 4,5,6-trimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran-3-one

4,5,6-Trimethoxy-1,2,3-dihydrobenzofuran-3-one To a solution of 100 g of toluene in 1.5 L of toluene, add 433 g of potassium t-butoxy under ice-cooling and stirring. Next, 999 g of methyl iodide was added, and the mixture was stirred for 1.5 hours. Add water and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure, and the residue is subjected to silica gel column chromatography, eluted with n-hexane monoethyl acetate (3: 1) and purified to obtain 71 g of the title compound. 70-73 ° C (recrystallized from ethyl acetate-n-hexane).

Participant example 1 1

Preparation of 4-hydroxy-5,6-dimethoxy-1,2,2-dimethyl-2,3-dihydrobenzobenzofuran-3-one

4,5,6-Trimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran-13-one To a solution of 20 g of benzene in 400 ml of benzene, add anhydrous aluminum chloride 21 and stir at 5 Ot for 3 hours. Add 10% hydrochloric acid aqueous solution to the reaction mixture under ice-cooling Calculate 400 m 1 and extract with ethyl acetate. The organic layer is washed successively with water and saturated saline, and then dried over anhydrous magnesium sulfate. The solvent is distilled off under reduced pressure to obtain 8.5 g of the title compound as a pale yellow oil. Use for the next reaction without further purification.

From the corresponding starting compounds, the compounds listed in Tables 22 to 23 can be produced in the same manner as in the corresponding methods of Reference Examples 1 to 11.

2, 3—Jihi Drovenzofuran 3—On

¾ K ¾ R5a _R 5b Reconstituted solvent ^a )

OMe OMe H H H H 99 H / AC

OH OMe H H H H

OMe OH H H H H I

OH H OH H H H I

OBz H OBz H H H I

OBz H OBz H Me Me o i l

OMe H OMe H H H

OMe H OMe H Me Me 124-126 H / AC

OH H OMe H H H

OBz H OMe H H H

OMe H OH H H H

OMe H OBz H H H

OMe H H OMe H H 161-162 H / AC

OH H H OMe H H

OMe H H OH H H

H OMe OMe H H H

H OH OMe H H H

H OMe OH H H H

H OH OH H H H> 250

H H OMe OMe H H

HH OMe OMe Me Me 101-103 H / AC 2 3 Continued from Table 22

¾ Rc ¾ R2a R2 mp CC) Reconstituted solvent ^a )

H H OH OMe H H ―

H H OH OH H H ―

-0CH _20- HHHH ―

H -OCH ₂ 0- HHH one

HH OCH ₂ 0- HH one

OMe OMe OMe H Me H I

OH OMe OMe H H H ―

OMe OBz OMe H H H ―

OMe OMe H OMe H H 85-86 H / AC

OH OMe H OMe H H ―

-OCH _20- H Me HH one

- OCH ₂ 0- H OMe HH -

-OCH _20- H Br HH ―

-OCH ₂ 0- H CH ₂ OH HH

O e H OMe OMe H H 143-144 H / AC

OMe H OMe OMe Me Me 79-80 H / AC

OH H OMe OMe H H

OMe H OH OMe H H ―

H OMe OMe OMe H H

H OH OMe OMe Me Me oi l

H OBz OMe OMe H H 82-83

H OBz OMe OMe Me Me oi l

H -OCH ₂ 0- OMe HH

OMe OMe OMe OMe H H

OH OMe OMe OMe H H

OMe OMe OMe OH H H 88-91 H / AC Footnotes: a) Abbreviations: H = n-hexane; AC = ethyl acetate

Claims

1. The following general formula (I)

Chief

of

[Wherein, R 1 and R ² are the same or different and are each a hydrogen atom, a lower alkyl

0

Group, cyclo-lower alkyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aralkyl group, hydroxy lower alkyl group, acetooxy lower alkyl group, lower alkoxy lower alkyl group, carboxy lower alkyl group, acyl group, lower alkyl sulfonyl The group or R ¹ and R ² may together form a methylene group,

R 3 is the same or different from each other and is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a nitrogen atom, a hydroxy group, an acyloxy group, or a lower alkyl sulfonyl group; Roxy group, lower alkoxy group, cyclo-lower alkyloxy group, substituted or unsubstituted aralkyloxy group, nitro group, amino group, cyano group, sulfamoyl group, sulfamoyl group, carboxyl group or lower alkoxycarbonyl group,

R 5 a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, optionally substituted or unsubstituted Ararukiru group or R ⁵ becomes a and R 5 b gar cord to form a ring Well, Eight _ shaku 6 means (1 ^-1 ^ 6 when (0 ^ ^: is a double bond), and means one NR 6 R ⁷ when (ii) is a single bond,

R ⁶ is a hydrogen atom, —OR ⁸ (where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group or an acyl group), Substituted or unsubstituted C! -C _s alkyl group (the substituent is a lower cycloalkyl group of the alkyl group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted heteroaryl group, a hydroxy group, a lower alkoxy group, a substituted or unsubstituted Ararukiruokishi group, a substituted or unsubstituted Substituted aryloxy group, acyloxy group, amino group, mono-lower alkyl or di-lower alkyl amino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, substituted or unsubstituted arylthio group, One or two selected from a lower alkylsulfinyl group, a substituted or unsubstituted arylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, an acyl group, a carboxy group and a lower alkoxycarbonyl group Species or more), cyclo lower al , A substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, —CO—R 9 (where R 9 is a hydrogen atom, a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted Heteroaryl group, lower alkoxy group, substituted or unsubstituted aryloxy group, amino group, mono-lower alkyl or di-lower alkylamino group or substituted or unsubstituted Ci-C! ₂ alkyl group (substituent of the alkyl group Is a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy group, a hydroxy group, a substituted or unsubstituted aryloxy group, a lower alkoxy group, a carboxyl group, a lower alkoxycarbonyl group, Group, Cyano group, acyl group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino group, mercapto group, lower alkylthio group, substituted or unsubstituted arylaryl group, lower alkylsulfinyl group, substituted or unsubstituted arylsulfinyl group , Lower alkylsulfonyl, one or more selected from substituted or unsubstituted arylsulfonyl or sulfamoyl)), —CO—CH2CHR10 (where Rio is a hydrogen atom, A lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an acyl group, a cyano group, a lower alkoxycarbonyl group, a carboxyl group or a carbamoyl group) or one of S0 ₂ R ¹ , R ^{1 1} is lower alk kill groups, trifluoperazine Ruo Russia methyl group, a substituted or unsubstituted Araru Group, a substituted or an a is) unsubstituted § Li Ichiru group or a substituted or unsubstituted heteroaryl group and meaning taste,

R ⁷ represents a hydrogen atom, a lower alkyl group or a cyclo lower alkyl group, and X represents an oxygen atom or a sulfur atom. However, when i ^ A—R ⁶ is —NH ₂ or N—OH, R ¹⁰ — and R 2 — are 4-OCH ₃ぉ and 7—〇 CH ₃ and R ³ and R ⁽ Unless one of ⁴ is a hydrogen atom and the other is 6-0 H)

A 2,3-dihydrobenzofuran derivative represented by the formula or a physiologically acceptable acid addition salt thereof.

2. The following general formula (II)

(In the formula, R 1 and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a hydroxy lower alkyl group, an aceethoxy lower alkyl group. A lower alkoxy lower alkyl group, a carboxy lower alkyl group, an acyl group, a lower alkylsulfonyl group or R ¹ and R ² may together form a methylene group;

R 3 and R ⁴ are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclic lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a nitrogen atom, a hydroxy group, an acyloxy group, or a lower alkyl sulfo group; Dioxy group, lower alkoxy group, cyclo lower alkyloxy group, substituted or unsubstituted aralkyloxy group, nitro group, amino group, cyano group, carbamoyl group, sulfamoyl group, carboxyl group or lower alkoxycarbonyl group;

R 5 a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, Ararukiru group or R ⁵ a and R 5 b is may form a connexion ring such together,

R ⁶ is a hydrogen atom, OR ⁸ (where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group or an acyl group), substituted or unsubstituted C i~C ₈ alkyl group ( The substituent of the alkyl group may be a cyclo lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryl group. —Roxy group, acyloxy group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino group, cyano group, carbamoyl group, mercapto group, lower alkylthio group, substituted or unsubstituted arylthio group, One or more selected from a lower alkylsulfinyl group, a substituted or unsubstituted arylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, an acyl group, a carboxy group and a lower alkoxycarbonyl group; 2 or more), cyclo-lower alkyl, substituted or Unsubstituted Ariru group, a substituted or unsubstituted heteroaryl group, one CO- R ⁹ (wherein, R ⁹ is a hydrogen atom, a cycloalkyl lower alkyl group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted to Teroa aryl group, Lower alkoxy group, substituted or unsubstituted aryloxy group, amino group, mono-lower alkyl or di-lower alkylamino group or substituted or unsubstituted ~ C! ₂ alkyl group (the substituent of the alkyl group is a cyclo-lower alkyl group, Substituted or unsubstituted arylyl, substituted or unsubstituted heteroaryl, hydroxy, acyloxy, substituted or unsubstituted aryloxy, lower alkoxy, carboxyl, lower alkoxycarbonyl, alkamoyl, cyano, acyl Group, amino group, mono-lower alkyl or di-lower alkylamino group, Selected from a lumino group, a mercapto group, a lower alkylthio group, a substituted or unsubstituted arylylthio group, a lower alkylsulfinyl group, a substituted or unsubstituted arylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group or a sulfamoyl group 1 or 2 or more Above)), one CO—CH = CHR io (where Rio is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, an acyl group, a cyano group, a lower alkoxy group) A carbonyl group, a carboxyl group or a carbamoyl group) or one S 0 ₂ R ¹¹ (where R ¹¹ is a lower alkyl group, a trifluoromethyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aralkyl group, Is an unsubstituted aryl group or a substituted or unsubstituted heteroaryl group)

X represents an oxygen atom or a sulfur atom. However, when R ⁶ is OH, Ri and R20 are forty-one OCH ₃ and 7- OCH ₃ and one of R 3 and R 4 is a hydrogen atom and the other is 6-0 H ]

The compound according to claim 1, which is represented by the following, or a physiologically acceptable acid addition thereof:

3. In the general formula (II), 1 ^ ⁶ hydrogen atoms, one OR ⁸ (where R ⁸ is a lower alkyl group or an aralkyl group), substituted or unsubstituted C! -C ₈ alkyl group (the substituent is a cyclo-lower Arukiru of the alkyl group, a substituted or unsubstituted § aryl group, a substituted or unsubstituted heteroaryl group, hydroxy group, lower alkoxycarbonyl group, a substituted or unsubstituted Ararukiruokishi group, a substituted Or unsubstituted aryloxy, acyloxy, amino, mono-lower alkyl or di-lower alkylamino, acylamino, cyano, carbamoyl, mercapto, lower alkylthio, substituted or unsubstituted arylthio, lower alkyl One or more selected from a sulfinyl group, a substituted or unsubstituted arylsulfinyl group, a lower alkyl sulfonyl group, a substituted or unsubstituted arylsulfonyl group, an acyl group, a carboxyl group and a lower alkoxycarbonyl group Above), one CO—R ⁹ (where R 9 is a hydrogen atom, a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a lower alkoxy group, a substituted or unsubstituted aryloxy group) Group, amino group, mono-lower alkyl or di-lower alkylamino group or substituted or unsubstituted C f-C i

2 alkyl group (the substituent of the alkyl group is a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy group, an acyloxy group, a substituted or unsubstituted aryloxy group, a lower alkoxy group, Ruboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono-lower alkyl or di-lower alkylamino group, acylamino group, mercapto group, lower alkylthio group, substituted or unsubstituted arylthio group , A lower alkylsulfinyl group, a substituted or unsubstituted arylsulfinyl group, a lower alkylsulfonyl group or a substituted or unsubstituted arylsulfonyl group, which is one or more selected from a)), -CO-CH = CHR io (where R 10 is a hydrogen atom, a lower alkyl group, Substituted or unsubstituted Ariru group, a substituted or unsubstituted heteroaryl group, Ashiru group, Shiano group, low-grade alkoxy force carbonyl group, a force carboxyl group or force Rubamoiru group) or a S 0 ₂ R ^{1 1} (wherein, R ¹¹ is a lower alkyl group, a trifluoromethyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group), and X is an oxygen atom. Or a physiologically acceptable acid addition salt thereof.

4. General formula (II) in R ¹ and R ² are each the same or different and each is hydrogen atom, lower alkyl group, a Ashiru group, a lower alkylsulfonyl group, or R ¹ and R 2 gar turned cord methylene group , R 3 and R 4 are the same or different and each represents a hydrogen atom, a lower alkyl group, a halogen atom, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy group or a lower alkoxy group.

R ⁵ a and R ⁵ b are the same or different and each represents a hydrogen atom or a lower alkyl group,

4. The compound according to claim 3, wherein R ⁶ is a hydrogen atom or one OR ⁸ (where R s is a lower alkyl group), or a physiologically acceptable acid addition salt thereof.

5. In the general formula (Π), R ¹ and R ² are the same or different from each other and are a hydrogen atom, Ci to c, an alkyl group or an acyl group;

R ³ and R ⁴ are the same or different from each other and are a hydrogen atom, a hydroxy group, an acyloxy group or a C: ^ alkoxy group;

5. The compound according to claim 4, wherein R ⁶ is a hydrogen atom or one OR ⁸ (where R i C 1 -C ₃ alkyl group) or a physiologically acceptable acid addition salt thereof.

6. The following Koko formula (III)

Wherein R 1 and R ² are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclo lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, a hydroxy lower alkyl group, an acetyloxy lower alkyl group. A lower alkoxy lower alkyl group, a carboxy lower alkyl group, an acyl group, a lower alkylsulfonyl group, or R 1 and R ² may together form a methylene group, R 3 and R ⁴ may be the same or different from each other and represent a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a hydroxy-lower alkyl group, a trifluoromethyl group, a nitrogen atom, a hydroxy group, an acyloxy group, a lower alkyl sulfo group; A dioxo group, a lower alkoxy group, a cyclo-lower alkyloxy group, a substituted or unsubstituted aralkyloxy group, a nitro group, an amino group, a cyano group, a carbamoyl group, a sulfamoyl group, a carboxyl group or a lower alkoxy carboxy group. ,

R ⁵ a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a lower cycloalkyl group, optionally substituted or unsubstituted Ararukiru group or R ⁵ becomes a and R 5 b gar cord to form a ring Well,

R ⁶ is a hydrogen atom, OR ⁸ (where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group, or an acyl group. there), substituted or unsubstituted C. 1 to C ₈ alkyl group

(The substituent of the alkyl group is a cyclo lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryl group. Roxoxy, acyloxy, amino, mono-lower alkyl or di-lower alkyl amino, acylamino, cyano, carbamoyl, mercapto, lower alkylthio, substituted or unsubstituted arylthio, lower alkylsulfinyl One or more selected from a group, a substituted or unsubstituted arylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, an acyl group, a carboxy group and a lower alkoxycarbonyl group ), Cyclo-lower alkyl, substituted or Is an unsubstituted aryl group, substituted or An unsubstituted heteroaryl group, —CO—R ⁹ (where R 9 is a hydrogen atom, a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a lower alkoxy group, a substituted or unsubstituted substituted Ariruokishi group, amino groups, mono-lower alkyl Wakashikuji substituents lower alkyl amino group or a substituted or Hi置conversion Ci～C ₂ alkyl group (the alkyl group is a lower cycloalkyl group, a substituted or unsubstituted Ariru group, a substituted Or unsubstituted heteroaryl group, hydroxy group, acyloxy group, substituted or unsubstituted aryl group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono Lower alkyl or di-lower alkylamino, acylamino, mercapto, lower amino Selected from alkylthio group, substituted or unsubstituted arylthio group, lower alkylsulfinyl group, substituted or unsubstituted arylsulfinyl group, lower alkylsulfonyl group, substituted or unsubstituted arylsulfonyl group and sulfamoyl group is on the one or more kinds)), - CO- CH = CHR 1 0 ( wherein, R ¹⁰ is a hydrogen atom, a lower § alkyl group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted heteroaryl group, A sulfo group, a cyano group, a lower alkoxycarbonyl group, a carboxyl group or a carbamoyl group) or one S 0 ₂ R ¹¹ (where R ¹¹ is a lower alkyl group, a trifluoromethyl group, Or an unsubstituted aralkyl group, a substituted or unsubstituted aryl group or a substituted or unsubstituted heteroaryl group)

X represents an oxygen atom or a sulfur atom. However, when R ⁶ and R ⁷ are both hydrogen atoms, R 1 Q— and R 2 Q— are 4— OCH ₃ and 7— OCH ₃ Except that one of R ³ and R 4 is a hydrogen atom and the other is 6-0 H) or a physiologically acceptable acid addition thereof.

7, — In the general formula (III), R ⁶ is a hydrogen atom, one OR 8 (where R 8 is a hydrogen atom, a lower alkyl group, a cyclo-lower alkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group A substituted or unsubstituted C i -C s alkyl group (substituent of the alkyl group is a cyclo lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a hydroxy group) A lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, an acyloxy group, an amino group, a mono-lower alkyl or di-lower alkylamino group, an acylamino group, a cyano group, a valvamoyl group, Mercapto group, lower alkylthio group, substituted or unsubstituted arylthio group, lower alkylsulfinyl group, substituted or unsubstituted Selected from a substituted arylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, an acyl group, a carboxyl group or a lower alkoxycarbonyl group

A cycloalkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, and X is an oxygen atom. Acceptable acid addition salts.

8. In the general formula (III), R ¹ and R ² are the same or different from each other and are a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, or a methylene group obtained by combining R ¹ and R 2 together; R ³ and R ⁴ are mutually the same or different dates Te hydrogen atom, a lower alkyl group, hydroxy group, Ashiruokishi group, a lower alkyl sulfonyl O alkoxy group or a lower alkoxy group, R ⁵ a and R ⁵ b are the same Or differently a hydrogen atom or a lower alkyl group, and R ⁶ is a hydrogen atom or a substituted or unsubstituted C i C g alkyl group (the substituent of the alkyl group is selected from a hydroxy group, an acyloxy group and a carboxyl group. Or a combination thereof, and R ⁷ is a hydrogen atom or a lower alkyl group, or a physiologically acceptable acid addition salt thereof.

9. In the general formula (III), R 1 and R ² are the same or different from each other and are a hydrogen atom, a lower alkyl group, an acyl group, a lower alkylsulfonyl group, or R 1 and R ² together form a methylene group;

R ³ is the same or different and is a hydrogen atom, a lower alkyl group, a hydroxy group, an acyloxy group, a lower alkylsulfonyloxy group or a lower alkoxy group,

R ⁵ a and R 5 b are the same or different and each represents a hydrogen atom or a lower alkyl group,

R ⁶ is CO—R 9 (where R ⁹ is a hydrogen atom, a cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, a lower alkoxy group, a substituted or unsubstituted aryl group Ruokishi group, an amino group, a mono (lower alkyl) Broiler Shikuji lower alkylamino group or a substituted or unsubstituted C. 1 to (: 1 ₂ substituent alkylene Le group (the alkyl group is a lower cycloalkyl group, a substituted or unsubstituted § reel Group, substituted or unsubstituted heteroaryl group, hydroxyl group, acyloxy group, substituted or unsubstituted aryloxy group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, Mono-lower alkyl or di-lower alkylamino group, acylamino group, mercapto group, lower alkylthio group , Substituted or unsubstituted arylthio group, lower alkylsulfinyl group, substituted or unsubstituted arylsulfinyl group Or at least one selected from a substituted or unsubstituted arylsulfonyl group or a sulfamoyl group), or — SC ^ R ¹¹ (where R ¹¹ is lower alkyl) Group, trifluoromethyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aryl group or substituted or unsubstituted heteroaryl group),

R 7 is a hydrogen atom or a lower alkyl group,

7. The compound according to claim 6, wherein X is an oxygen atom, or a physiologically acceptable acid addition salt thereof.

10. - In general formula (ΠΙ) R 6 in one C_〇 one R 9 (wherein, R 9 is hydrogen atom, the substituent of the substituted or unsubstituted C i~C 1 ₂ alkyl group (the alkyl group hydrate One or more selected from a roxy group, an acyloxy group, a substituted or unsubstituted aryloxy group or a lower alkoxy group, or one S0 ₂ R 1 ι (where Ri〗 is a lower alkyl group or 10. The compound according to claim 9, wherein R ⁷ is a hydrogen atom, or a physiologically acceptable acid addition salt thereof.

1 1. In the general formula (III), R ¹ and R ² are the same or different from each other and are a hydrogen atom, a C〜alkyl group or an acyl group, and R ³ and R ⁴ are the same or different from each other and atom, hydroxy group, Ashiruokishi group or C. 1 to (: ₃ a § alkoxy group, R ⁶ an CO- R ⁹ (wherein, R ⁹ is a hydrogen atom or a substituted or unsubstituted C i ^ alkyl group (the alkyl substituent groups were or hydroxy group is Ashiruokishi group)), or a S_〇 ₂ R 1 1 (wherein, R iCi~ C 3 alkyl group or Fuweniru a group) compound of claim 10 wherein the Ma Or a physiologically acceptable acid addition salt thereof.

12. The following general formula (III-A)

R 5a and R 5b are the same or different and represent a hydrogen atom or a lower alkyl group,

R 6 is a hydrogen atom, a substituted or unsubstituted C 1 -C ₈ alkyl group (the substituent of the alkyl group is a hydroxy group, a lower alkoxy group, a substituted or unsubstituted aralkyloxy group, a substituted or unsubstituted aryloxy group, an acyloxy group , A carboxyl group or a lower alkoxycarbonyl group) or one or more selected from the group consisting of CO-R, wherein R 9 is a hydrogen atom, a substituted or unsubstituted CiC ^ z alkyl group (of the alkyl group) The substituent is one or more selected from a hydroxy group, an alkoxy group, a substituted or unsubstituted aryloxy group or a lower alkoxy group)), or one SOsR ¹¹ (where Rii is a lower alkyl group) , Or a substituted or unsubstituted aryl group); R ⁷ represents a hydrogen atom or a lower alkyl group)

10. The compound according to claim 7 or 9 or a physiologically acceptable acid addition salt thereof.

1 3. —In the general formula (ΙΠ— R), R ¹ and R ² are the same or different and each represent a hydrogen atom, a C ₃ -alkyl group or an acyl group, and R ³ represents a hydrogen atom, an acyloxy group or C J～C a ₃ alkoxy group, R ⁴ is a hydrogen atom, hydrate proxy group, the compound or a physiologically acceptable acid addition salt according to claim 1 wherein a Ashiruokishi group or C I～C ₃ alkoxy groups .

1 4. 3 —Iminnow 4 —Hydroxy-1 6 —Methoxy 2, 2 —Dimethyl

2,3—dihydrobenzofuran hydrochloride,

3—Iminnow 4—Hydroxy-5,6—Dimethoxy-1,2,2-dimethyl-2,3-Dihydroxybenzofuran hydrochloride,

3—Methoxymino 5—Hydroxy 4, 6—Dimethoxy 1,2,3—Dihydro benzofuran

3—Methoxyminnow 5—Hydroxy-6,7—Dimethoxy 2,3—Dihydroxy Mouth Benzofuran,

3-methoxyminnow 5—hydroxy 6,7—dimethoxy-1,2,2-dimethyl 2,3—dihidrobenzofuran,

3-methoxyminnow 7-hydroxy-5,6-dimethoxy-1,2,3-dibenzo

3-amino-4, hydroxy-1,5,6-dimethoxy-1,2,3-dihydrobenzofuran hydrochloride,

3-Amino-4-hydroxy-5,6-dimethoxy-1,2,2-Dimethyl-2, 3-dihydrobenzofuran hydrochloride,

3-methylamino-4-hydroxy-5,6-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran hydrochloride,

3— (2-Hydroxyshetyl) amino-4—Hydroxy-6-Methoxy-2,

2—Dimethyl-2,3—dihydrobenzofuran hydrochloride,

3— (2-Hydroxitytyl) amino-4—Hydroxy-5,6-dimethoxy-2,2—dimethyl-2,3—Dihydrobenzobenzofuran hydrochloride,

3-carboxymethylamino-4-hydroxy-6-methoxy-2,2-dimethyl-2,3-dihydrobenzofuran,

3-carboxymethylamino-4-hydroxy-5,6-dimethoxy-2,2-dimethyl-2,3-dihydrobenzofuran,

3—Methanesulfonylamino 4-hydroxy-1 6-Methoxy 2,3-Dihydroxybenzofuran,

3—Methanesulfonylamino-4-acetoxy-6-methoxy 2,3—dihydrobenzofuran,

3—methanesulfonylamino 1—4—hydroxy 6—methoxy 2,2—dimethyl-2,3-dihydrobenzofuran,

3-methanesulfonylamino 1-4-acetoxy 6-methoxy 2,2-dimethyl-2,3-dihydrobenzozofuran,

3—Methanesulfonylamino-1-hydroxy-5,6-dimethoxy 2,3—dihydrobenzofuran,

3—methanesulfonylamino-4—hydroxy-5,6-dimethoxy-2,2-dimethyl-1,2,3—dihydrobenzofuran,

3-Methanesulfonylamino-5-Hydroxy-6,7-Dimethoxy-1,2,3 —Jihi Drobenzofuran,

3-methanesulfonylamino-1,4,6-diacetoxy-2,2-dimethyl-2,3-dihydrobenzofuran,

3-benzenesulfonylamino _ 6, 7-dimethoxy 2, 3-dihydrobenzofuran,

3—benzenesulfonylamino 1 4—hydroxy 6-methoxy 2,3, dihydroxybenzofuran,

3 — benzenesulfonylamino 1 4 — hydroxy 6 — methoxy-2,2-dimethyl-2,3-dihydrobenzofuran,

3 1-benzenesulfonylamino 4-hydroxy-5,6-dimethoxy-2,3-dihydroxybenzofuran,

3 1-benzenesulfonylamino 1 4 —hydroxy 5, 6 —dimethoxy 2,

2—Dimethyl 2,3 dihydrobenzofuran),

3 —Formylamino-4 —Hydroxy-1 6-Methoxy-1 2,2, Dimethyl-1

2, 3 — Jihi Drobenzofuran,

3—formylamino-1-hydroxy-5,6-dimethoxy 2,2—dimethyl 2,3—dihydrobenzozofuran,

3—Hydroxymethylcarbonylamine 4,6—Dimethoxy-1,2,2-Dimethyl-2,3-Dihydrobenzofuran,

3-hydroxymethylcarbonylamino-4-hydroxy-6-methoxy2.3-dihydroxybenzofuran,

3-Hydroxymethylcarbonylamino _ 4-acetoxy 6-Methoxy

2, 3—Jihi Drobenzofuran,

3-hydroxymethylcarbonylamino 4-hydroxy-6-methoxy 2,2-dimethyl-2,3-dihydrobenzofuran,

3-hydroxymethylcarbonylamino 4-acetoxy 6-methoxy

2,2-dimethyl-2,3-dihydrobenzofuran,

3-hydroxymethylcarbonylamino-4-hydroxy-5,6 dimethoxy-1,2,3-dihydroxybenzofuran,

3-Hydroxymethylcarbonylamino 4- 4-acetoxy-5,6-dimethoxy 2,3-dihydrobenzofuran and

A compound selected from the group consisting of 3-hydroxymethylcarbonylamino-4-acetoxy-1,5,6-dimethoxy-1,2,2-dimethyl-2,3-dihydrobenzofuran.

1 5.3 3-Methoxymino 1 5-Hydroxy 6, 7-Dimethoxy 2, 3—Dihydrobenzofuran

1 6.3_Amino-4-hydroxy-1,5,6-dimethyl-1,2-dimethyl-1,2,3-dihydrobenzofuran hydrochloride

17.3-Methanesulfonylamino-1-hydroxy-6-methoxy-2,2-dimethyl-1,2,3-dihydroxybenzofuran

1 8.3—Hydroxymethylcarbonylamine 4-Hydroxy-6-methoxy-1,2,3-dihydrobenzofuran

1 9. The following general formula (I)

[Wherein, R ¹ and R ² are the same or different and are each a hydrogen atom, a lower alkyl Group, cyclo-lower alkyl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aralkyl group, hydroxy lower alkyl group, acetooxy lower alkyl group, lower alkoxy lower alkyl group, carboxy lower alkyl group, acryl group, lower alkyl sulfonyl The group or R 1 and R ² may together form a methylene group,

R 3 and R ⁴ are the same or different and are each a hydrogen atom, a lower alkyl group, a cyclic lower alkyl group, a hydroxy lower alkyl group, a trifluoromethyl group, a nitrogen atom, a hydroxy group, an acyloxy group, or a lower alkyl sulfo group; Niloxy, lower alkoxy, cyclo-lower alkyloxy, substituted or unsubstituted aralkyloxy, nitro, amino, cyano, carbamoyl, sulfamoyl, carboxyl or lower alkoxyl And

R 5 a and R 5 b are the same or different and each represents a hydrogen atom, a lower alkyl group, a cyclo-lower Arukiru group, to form a琛turned substituted or unsubstituted Ararukiru group or R ⁵ a and R ⁵ b gar cord Well,

z ^: A—R6 means (N) -N—R6 when (i) ^^ is a double bond, ()

When ^^ is a single bond, it means one N R 6 R 7,

R ⁶ is a hydrogen atom, OR ⁸ (where R ⁸ is a hydrogen atom, a lower alkyl group, a cycloalkyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group or an acyl group), substituted or unsubstituted C i~C ₈ substituent of the alkyl group (the alkyl group is a lower cycloalkyl group, a substituted or unsubstituted Ariru group, a substituted or unsubstituted heteroaryl group, a hydroxy group, a lower alkoxy group, a substituted or unsubstituted Aralkyloxy, substituted or unsubstituted aryloxy Di-, acyloxy, amino, mono-lower or di-lower alkyl amino, acylamino, cyano, carbamoyl, mercapto, lower alkylthio, substituted or unsubstituted arylthio, lower alkyl One or more selected from a sulfinyl group, a substituted or unsubstituted arylsulfinyl group, a lower alkylsulfonyl group, a substituted or unsubstituted arylsulfonyl group, an acyl group, a carboxy group and a lower alkoxycarbonyl group ), A cyclo-lower alkyl group, a substituted or unsubstituted aryl group, a substituted or unsubstituted heteroaryl group, one CO—R ⁹ (where R 9 is a hydrogen atom, a cyclo-lower alkyl group, a substituted or unsubstituted Unsubstituted aryl, substituted or unsubstituted heteroaryl, lower alkoxy, substituted or unsubstituted Conversion Ariruokishi group, Amino groups, mono-lower alkyl Wakashikuji substituents lower alkyl amino group or a substituted or Hi置conversion 〇 ~C Interview ₂ alkyl group (the alkyl group is a lower cycloalkyl group, a substituted or unsubstituted Ariru group, Substituted or unsubstituted heteroaryl group, hydroxy group, acyloxy group, substituted or unsubstituted aryloxy group, lower alkoxy group, carboxyl group, lower alkoxycarbonyl group, carbamoyl group, cyano group, acyl group, amino group, mono-lower group Alkyl or di-lower alkylamino, acylamino, mercapto, lower alkylthio, substituted or unsubstituted arylthio, lower alkylsulfinyl, substituted or unsubstituted arylsulfinyl, lower alkylsulfonyl, substituted or unsubstituted Reel through One or two or more selected from a benzyl group or a sulfamoyl group)), one CO—CH—CHR 10 (where R 10 is a hydrogen atom, a lower alkyl group, a substituted or unsubstituted aryl group) , Substituted or unsubstituted heteroaryl, acyl, cyano, lower alkoxycarbonyl, carboxyl, etc. Or R ₂ li (where R ¹¹ is a lower alkyl group, a trifluoromethyl group, a substituted or unsubstituted aralkyl group, a substituted or unsubstituted aryl group) Group or substituted or unsubstituted heteroaryl group).

R ⁷ represents a hydrogen atom, a lower alkyl group or a cyclo-lower alkyl group, and X represents an oxygen atom or a sulfur atom.]

A therapeutic agent for liver disease, comprising a 2,3-dihydrobenzofuran derivative represented by the following formula or a physiologically acceptable acid addition salt thereof as an active ingredient.

20. A therapeutic agent for liver disease, comprising the compound according to any one of claims 1 to 18 or a physiologically acceptable acid addition salt thereof as an active ingredient.

21. A pharmaceutical composition comprising the compound according to any one of claims 1 to 18 and a carrier for pharmaceutical preparation.