WO1995002589A1

WO1995002589A1 - Novel chroman compound, intermediate thereof, and medicinal use thereof

Info

Publication number: WO1995002589A1
Application number: PCT/JP1993/000992
Authority: WO
Inventors: Susumu Kato; Hidetsura Cho; Shinsuke Sayama; Yasuyuki KAJIMOTO; Saizo Shibata; Atsushi Mizushima; Tukuo YAMAKI; Itsuo Uchida
Original assignee: Japan Tobacco Inc.
Priority date: 1993-07-16
Filing date: 1993-07-16
Publication date: 1995-01-26

Abstract

A chroma compound represented by general formula (I), the use thereof as a coronary vasodilator, and intermediates thereof including 4-oxochroman, 4-hydroxychroman, chromene and 3,4-epoxychroman compounds wherein R1 represents cyano, nitro or halogen; R2 represents lower alkoxyalkyl, lower alkoxycarbonyl, hydroxyalkyl, aryloxyalkyl or t-butyldimethylsilyloxyalkyl; R3 represents H, lower alkyl, etc.; R4 represents H, OH, etc.; R5 represents H, etc.; A represents (a); R6 represents substituted aryl, heteroaryl, arylamino, aryloxy or lower alkyl; X represents N-CN, O or S; and R7 represents H or lower alkyl.

Description

Specification

Novel chroman compounds, their intermediates and pharmaceutical uses

"Technical field"

The present invention relates to a novel Kuguchiman compound, an intermediate thereof and a medicinal use thereof, and more specifically, has a selective and excellent vasodilatory effect on the coronary artery system, The present invention relates to a novel chroman compound useful as an agent for treating or preventing heart failure and an intermediate for producing the compound.

`` Background technology J

Potassium channels are involved in resting membrane potential. When this potassium channel is activated, the resting membrane potential changes more negatively (hyperpolarization) and approaches the equilibrium potential of potassium ion. In addition, activation of potassium channels inhibits activation of voltage-gated calcium channels, suppresses the influx of calcium in the cells, and reduces intracellular calcium due to sodium calcium exchange reaction. Pumping is promoted. As a result of the hyperpolarization of these membranes and the subsequent decrease in intracellular free calcium concentration, smooth muscle is relaxed, and the blood vessels are dilated, resulting in a hypotensive effect and a coronary vasodilatory effect. Potassium channels are also widely distributed in other smooth muscles (trachea, intestinal tract, uterus, etc.) and are known to have an action of relaxing these. Therefore, these compounds having a potassium channel activating action are useful as therapeutic or preventive agents for hypertension, angina pectoris, heart failure, asthma and the like. There have already been reported some compounds that activate the potassium channel. For example, JP-A-2-300182 and JP-A-3-2797377 disclose 6 compounds. —Cyano 3,4—dihydro-2,2-dimethyltrans-141-[(N-cyanoacetimidoyl) amino] -12H-benzo [b] pyran-3-ol, 6-cyano 3,4 —Dihydro-2,2-dimethyl-trans-1-41 [(N-cyanobenzimidyl) amino] -12H-benzo [b] A lower alkyl group such as pyran-13-ol, etc. A chroman derivative modified with a phenyl group is disclosed, and European Patent Publication No. 514,935 and European Patent Publication No. 514,942 disclose 2-dimethoxymethyl-2. —Methyl-41 A chroman derivative in which a 2-methyl group such as (3'-N-oxopyridyl) -16-cyano-12H-1-benzopyran is modified with a dimethoxymethyl group is disclosed. Further, Japanese Patent Application Laid-Open No. 3-66681 discloses 2-methoxymethyl-2-methyl 4- (1,2-dihydro-2-oxofu-1-pyridyl) -16-cyano-3-chromanol and the like. A chroman derivative obtained by modifying a methyl group at the -position with a methoxymethyl group is disclosed. The above-mentioned Japanese Patent Application Laid-Open No. 3-66681 also states that such a compound reduces blood flow resistance and increases blood flow while maintaining a low effect on heart rate in coronary arteries. is there. However, such known compounds do not always have a sufficient effect on coronary vascular diseases such as heart failure, and the emergence of better drugs has been desired.

"Disclosure of the invention"

The present inventors have conducted intensive studies to find a compound having a safer and superior coronary vasodilatory effect. As a result, the present inventors have found that the compound is effective in preventing or treating cardiovascular disorders such as the aforementioned diseases, angina pectoris, and heart failure. In addition, a novel chroman compound and a pharmaceutically acceptable salt thereof, which do not cause a high blood pressure drop which should cause tachycardia, that is, have a selective and excellent coronary vasodilator action, are to be found. The invention has been completed.

That is, the present invention provides the following general formula [I]

Wherein R ¹ is a cyano group, a nitro group or a halogen atom;

R ² is a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group, an aryloxyalkyl group or a tert-butyldimethylsilyloxyalkyl group,

R ³ is a hydrogen atom, a lower alkyl group, lower alkoxy Ryo alkyl group, a lower alkoxycarbonyl group, hydroxyalkyl group or tert one heptyl dimethylsilyl Okishiarukiru group, or that the R ³ together, one (CH ₂ ), — 0— (CH ₂ ) _ffl — 0— (CH ₂ ) _n — ( _where 1, and n are each independently 0 or an integer of 1-2, and m is an integer of 1-2) Form a group that is

R is a hydrogen atom, a hydroxyl group, a formyloxy group or a lower alkanoyloxy group,

R ⁵ is a hydrogen atom, or R ⁴ and R ⁵ together represent a bond,

A is

R ^fi is an aryl group optionally substituted with a lower alkyl group or a halogen atom, a heteroaryl group optionally substituted with a lower alkyl group or a halogen atom, a substituent substituted with a lower alkyl group or a halogen atom. An aryloxy group or a lower alkyl group which may be substituted with a lower alkyl group or a halogen atom;

X is N—CN, an oxygen atom or a zeo atom,

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

Or a pharmaceutically acceptable salt thereof (hereinafter, also referred to as chroman compound '[I] or compound [I]).

The present invention also provides an intermediate useful for producing the above chroman compound [I]. These intermediates are represented by the following general formulas [3 '], [4'], [5 '], [8'] or [9].

Wherein R ′ and R ⁷ are as described above,

R ² ′ is a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group, an aryloxyalkyl group or a tert-butyldimethylsilyloxyalkyl group,

R ³ ′ is a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group, or a tert-butyldimethylsilyloxyalkyl group, or R ³ ′ and R ³ ′ together , — (CH2), — 0— (CH ₂ ) _m — 0— (CH ₂ ) _n — (wherein, 1 and n are each independently 0 or an integer of 1 to 2, and m is 1 to 2 Where R ² ′ is a lower alkoxyalkyl group, then R ³ ′ is a lower alkoxyalkyl group or a lower alkoxyalkyl group. A carbonyloxy group, a hydroxyalkyl group or a tert-butyldimethylsilyloxyalkyl group.)

Furthermore, the present invention provides a coronary vasodilator comprising the above chroman compound [I] or a pharmaceutically acceptable salt thereof as an active ingredient.

"Brief description of the drawings"

FIG. 1 shows the compound of the present invention (Example 39), remacalim (control compound a), and 2-methoxymethyl-2-methyl-4_ (1,2-dihydro-12-oxo-1-1-pyridyl) -16-cyano. 3 is a graph showing the relationship between the change in mean blood pressure (%) (horizontal axis) and the change in coronary blood flow () (vertical axis) for each of 3-chromanol (control compound b).

"Detailed description of the invention"

In this specification, the meanings of the terms used in the various definitions are as follows.

"Lower alkyl group" means a straight-chain or branched alkyl having 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. Tert-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and benzyl group.

The term “lower alkoxyalkyl group” means an alkoxyalkyl group having a total of 2 to 6, preferably 2 to 5, carbon atoms in the alkoxy moiety and the alkyl moiety, wherein the alkoxy moiety and the alkyl moiety are linear or branched. It may be either of the face. Specifically, methoxymethyl group, 1-methoxyethyl group, 2-methoxyethyl group, 3-methoxypropyl group, 2-methoxypropyl group, 1-methoxy-1-methylethyl group, ethoxymethyl group, propoxymethyl group, It means a propoxymethyl group, a butoxymethyl group, an isobutoxymethyl group, a sec-butoxymethyl group, a tert-butoxymethyl group, a pentoxymethyl group and the like.

The term "lower alkanoyloxy group" means an alkanoyloxy group having 2 to 6, preferably 2 to 4 carbon atoms, and specifically includes an acetyloxy group, a propionyloxy group, a petyryloxy group and the like. means.

ΓLower alkoxycarbonyl group J means an alkoxycarbonyl group having 2 to 6, preferably 2 to 5 carbon atoms, specifically, methoxycarbonyl group, ethoxy group It means a cicarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxydicarbonyl group, a tert-butoxycarbonyl group, a pentoxycarbonyl group or the like.

ΓHalogen atom j specifically means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

The term "aryl group" specifically means a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 0-biphenyl group, an m_biphenyl group, a P-biphenyl group, or the like, preferably a phenyl group. It is.

Further, "the lower alkyl group J which may be substituted with a lower alkyl group or a halogen atom" is the same as the above-mentioned "lower alkyl group J and 1 or 3 substituents selected from a halogen atom j. “Aryl group j, specifically, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-bromopyrphenyl Phenyl, 3-propylphenyl, 4-propylphenyl, 2-fluorophenyl, 3-fluoroα-phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl , 4-monophenyl, 2-bromophenyl, 3-bromophenyl, 4-morphophenyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 4 Methyl-1-naphthyl, 5-methyl-1-naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 8-methyl-1-naphthyl, 2-ethyl-1-naphthyl, 3 —Ethyl 1-naphthyl, 4-ethyl—1-naphthyl, 5-ethyl 1-naphthyl, 6-ethyl 1-naphthyl, 7-ethyl 1-naphthyl, 8-ethyl 1-naphthyl, 2-Propyl 1-naphthyl group, 3-Pp sigma-pyl 1-naphthyl group, 4-propyl-11-naphthyl group, 5-propyl-11-naphthyl group, 6-propyl-11-naphthyl group, 7- Propyl-1-naphthyl, 8-propyl-11-naphthyl, 2-fluoro-1-naphthyl, 3-fluoro-1-naphthyl, 4-fluoro-11-naphthyl, 5-fluoro-1-naphthyl, 6 —Fluoro-1-naphthyl group 7- Furuoro 1 one naphthyl group, 8-Furuoro 1 one-naphthyl group, 2-chloro 1-naphthyl group, 3-chloro-1-naphthyl group, 4-chloro-11-naphthyl group, 5-chloro-1-naphthyl group, 6-chloro-1-naphthyl group, 7-chloro-11-naphthyl group, 8-chloro-1-1 Naphthyl group, 2-butophone 1-naphthyl group, 3-buth-D 乇 -1-naphthyl group, 4-bromo-1-naphthyl group, 5-bromo-1-naphthyl group, 6-bromo-naphthyl group Group, 7-butane 1-naphthyl, 8-bromo 1-naphthyl, 1-methyl-2-naphthyl, 3-methyl-2-naphthyl, 4-methyl-1-naphthyl, 5-methyl-1 2 —Naphthyl group, 6-methyl-2-naphthyl group, 7-methyl-2-naphthyl group, 8-methyl-2-naphthyl group,

1-ethyl 2-naphthyl, 3-ethyl 2-naphthyl, 4-ethyl 2-naphthyl, 5-ethyl 2-naphthyl, 6-ethyl 1-2-naphthyl, 7-ethyl 2-naphthyl, 8 —Ethyl-2-naphthyl group, 1-propyl-12-naphthyl group, 3-propyl-12-naphthyl group, 4-propyl-12-naphthyl group, 5-propyl-12-naphthyl group, 6-propyl) 2- Naphthyl group, 7-butyl α-pill

2-naphthyl group, 8-propyl-2-naphthyl group, 1-fluoro-2-naphthyl group, 3-fluoro-2-naphthyl group, 4-fluoro-2-naphthyl group, 5-fluoro-2-naphthyl group, 6-fluoro ο— 2-naphthyl, 7-fluoro-2-naphthyl, 8-fluoro π—2-naphthyl, 1-chloro-2-naphthyl, 3-chloro-2-naphthyl, 4-chloro-2naphthyl , 5-π π _ 2-naphthyl group, 6-chloro-1-naphthyl group, 7-chloro-2-naphthyl group, 8-chloro-2-naphthyl group, 1-bromo-1-naphthyl group, 3-promo 2-naphthyl, 4-bromo-2-naphthyl, 5-promo 2-naphthyl, 6-bromo-2-naphthyl, 7-bromo-2-naphthyl, 8-bromo-2-naphthyl, 2-methyl-0-biphenyl group, 3-methyl-1-0-biph Enyl group, 4-methyl-0-biphenyl group, 2-ethyl-0-biphenyl group, 3-ethyl-0-biphenyl group, 4-ethyl-0-piphenyl group, 2-propyl-1 0-biphenyl group, 3-propyl-1 0-biphenyl group, 4-propyl-10-biphenyl group, 2-butyl-0-biphenyl group, 3-butyl-0-biphenyl; phenyl group, 4-butyl-1-0-biphenyl group, 2-fluoro-ο- Biphenyl group, S-fluoro-0-biphenyl group, —Fluoro-o-biphenyl tomb, 2-chloro n—o-biphenyl group, 3-cycloπ σ—ο—biphenyl group, 4-chloro-0-biphenyl group, 2-promo 0—biphenyl group, 3-bromo-0-biphenyl group, 4-bromo-10-biphenyl group, 2-methyl-1-m-biphenyl group, 3-methyl-biphenyl group, 4-methyl-1m-biphenyl group, 2-ethyl- m-biphenyl group, 3-ethyl-m-biphenyl group, 4-ethyl_m-biphenyl group, 2-propyl-1-m-biphenyl group, 3-propyl-m-biphenyl group, 4-propyl-1-m nibiphenyl group , 2-butyl-m-biphenyl group, 3-butyl-: m-biphenyl group, 4-butyl-m-biphenyl group, 2-fluoro-m-biphenyl group, 3-fluoro-m-biphenyl group, 4-fluoro m-biphenyl group, 2-chloro-m biphenyl Group, 3-chloro-m-biphenyl group, 4-chloro-m-biphenyl group, 2-bromo-m-biphenyl group, 3-bromo-1-m-biphenyl group, 4-promo m-biphenyl group, 2-methyl- p-biphenyl, 3-methyl-1-p-biphenyl, 2-ethyl-ρ-biphenyl, 3-ethyl-p-biphenyl, 2-propyl! ) 1-biphenyl, 3-propyl-1p-biphenyl, 2-butyl-biphenyl, 3-butyl-1p-biphenyl, 2-fluoro-p-biphenyl, 3-fluoro-p-biphenyl, 2-chloro-one: -biphenyl, 3-chloro π- ρ-biphenyl, 2-bromo-; -biphenyl, 3-bromo-p-biphenyl, 2,3-dimethylphenyl, 2,4-dimethyl Phenyl group, 2,5-dimethylphenyl: cenyl group, 2,6-dimethylphenyl group, 3,4-dimethylphenyl group, 3,5-dimethylphenyl group, 2,3-dimethylphenyl group, 2,4 -Jetylphenyl group, 2,5-Jetylphenyl group, 2,6-Jetylphenyl group, 3,4-Jetylphenyl group, 3,5-Jetylphenyl group, 2,3-Difluorophenyl group, 2,4 Difluorophenyl group, 2,5-di Fluorophenyl group, 2,6-difluorophenyl group, 3,4-difluorophenyl group, 3,5-difluorophenyl group, 2,3-dichlorophenyl group, 2,4-dichlorophenyl group, 2,5-dichlorophenol Nyl, 2,6-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl Group, 2,5-dibromophenyl group, 2,6-dibromophenyl group, 3,4-dibromophenyl group, 3,5-dibromophenyl group, methylethyl-substituted phenyl group, Fluoro sigma-substituted phenyl group, Fluorob Mouth-substituted phenyl, chlorobromo-substituted phenyl, 2,3,4-trimethylphenyl, 2,3,5-trimethylphenyl, 2,3,6-trimethylphenyl, 2,4,5-trimethyl Phenyl group, 2,4,6-trimethylphenyl group, 3,4,5-trimethylphenyl group, 2,3,4-triethylphenyl group, 2,3,5-triethylphenyl group, 2,3,6-triethylphenyl group, 2,4,5-triethylphenyl group, 2,4,6-triethylphenyl group, 3,4,5-triethylphenyl group, 2, 3, 4-trifluorophenyl, 2, 3, 5-trifluorophenyl, 2, 3, 6-triphenyl Fluorophenyl group, 2,4,5-trifluorophenyl group, 2,4,6-trifluoroα-phenyl group, 3,4,5-trifluorophenyl group, 2,3,4-trichloromethylphenyl group, 2, 3,5-trichlorophenyl, 2,3,6-trichlorophenyl, 2,4,5-trichlorophenyl, 2,4,6-triphenylphenyl, 3,4,5-trichloro tiphenyl, 2,3,4-triphenyl, 2,3,5-tripromophenyl, 2,3,6-tribromophenyl, 2,4,5-tribromophenyl, 2 , 4,6-Tribu D mophenyl group, 3,4,5-Tribromophenyl group, Dimethylethyl substituted phenyl group, Dimethylmethyl substituted phenyl group, Difluorochloro substituted phenyl group, Difluorobromo substituted phenyl group, Dichlorofluoro group Phenyl, dichlorobromo-substituted Phenyl group, dibromodifluoro-substituted phenyl group, dichloro-mochloro-substituted phenyl group, etc., preferably 2-methylphenyl group, 3-methylphenyl go, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl Group, 4-ethylphenyl group, 2-propylphenyl group, 3-propylphenyl group, 4-propylphenyl group, 2-fluorophenyl group, 3-fluorophenyl group, 4-fluorophenyl group, 2-chlorophenyl group Methylphenyl, 3-chlorophenyl, 4-chlorophenyl, 2-bromophenyl, 3-bromophenyl, 4-promophenyl, particularly preferably 2-fluoroalphaphenyl, 3 —Fluorophenyl group, 4-fluorophene And a nyl group.

"Heteroaryl group j is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, birazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl Group, 2-furanyl group, 3-furanyl group, 2-thenyl group, 3-thenyl group, 2-pyrrolyl group, 3-pyrrolyl group, pyridine-N-oxydoxy-2-yl group, pyridine-N-oxydol 3 —Yl group, pyridine-N-oxydoxy 4-yl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl ¾, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group , 2-Imidazolyl group, 4-Imidabrile group, 5-Imidabril group, 1-Vilabryl group, 3-Pyrazolyl group, 3-Isothiazolyl group, 4-Isothiazolyl group, 3-Ixoxabril group, 4-Isoxa Lil group, 1 one indolizinyl group, 2-I Ndorijiniru group, 3-indolizinyl group, 4 one indolizinyl group, 5-indol Jiniru group, 6-indolizinyl group, 7-indolizinyl group, 1-indolyl group,

2-Indolyl tomb, 3-Indolyl, 4-Indolyl, 5-Indolyl, 1,8-Naphthyridine-1-yl, 1,8-Naphthyridine-1-yl, 1,8-Naphthyridine-1 Represents a 4-yl group, a 2-quinoxalinyl group, a 3-cinnolinyl group, a 4-cinnolinyl group, a 5-cinnolinyl group, a 6-cinnolinyl group, a 7-cinnolinyl group, an 8-cinnolinyl group, and the like; Pyridinyl group, 3-pyridinyl group, 4-pyridinyl group, birazinyl group, 2-phenyl group, 3-phenyl group, pyridine-1-N-oxyd-2-yl group, pyridine-N-oxyd-3-yl group ,

Represents a 3-quinolyl group.

Further, Γheteroaryl group J optionally substituted with a lower alkyl group or a halogen atom is a group substituted with 1 to 3 substituents selected from the above-mentioned `` lower alkyl group '' and Γhalogen atom. May mean "heteroyl group J", specifically, 3-methyl-2-pyridinyl group, 4-methyl-2-pyridinyl group, 5-methyl-2-pyridinyl group, 6-methyl-2-pyridinyl group, 3 —Ethyl-2-pyridinyl, 4-ethyl-2-pyridinyl, 5-ethyl-2-pyridinyl, 6-ethyl-2-pyridinyl, 3-pro: pyr-2-pyridinyl, 4-propynyl Rue 2-pyridinyl, 5-propyl-12-pyridinyl, 6-propyl-12-pyridinyl, 3-fluoro-2-pyridinyl, 4-fluoro-2-pyridinyl, 5-fluoro-2-pyridinyl, 6 —Fluoro-2-pyridinyl group, 3-chloro-2-pyridinyl group, 4-chloro-2-pyridinyl group, 5-chloro-2-pyridinyl group, 6-chloro-2-pyridinyl group, 3-promo-2-pyridinyl group , 4-bromo-2-pyridinyl, 5-promo-2-pyridinyl, 6-bromo-2-pyridinyl, 2-methyl-3-pyridinyl, 4-methyl-3-pyridinyl, 5-methyl-3-pyridinyl , 6-methyl-3-pyridinyl, 2-ethyl-3-pyridinyl, 4-ethyl-3-pyridinyl, 5-ethyl-3-pyridinyl, 6-ethyl-3-pyridinyl , 2-propyl-13-pyridinyl, 4-propyl-13-pyridinyl, 5-propyl-13-pyridinyl, 6-propyl-13-pyridinyl, 2-fluoro-3-pyridinyl, 4-fluoro 1 3-pyridinyl group, 5-fluoro-3-pyridinyl group, 6-fluoro-3-pyridinyl group, 2-chloro-3-pyridinyl group, 4-chloro-3-pyridinyl group, 5-chloro-3-pyridinyl group, 6-chloroidyl group 1,3-pyridinyl, 2-bromo-3-pyridinyl, 4-bromo-3-pyridinyl, 5-bromo-3-pyridinyl, 6-bromo-3-pyridinyl, 2-methyl-4-pyridinyl, 3-methyl 4-Pyridinyl group, 2-Ethyl-4-Pyridinyl group, 3-Ethyl-4-Pyridinyl group, 2-Bropropyl-1-Pyridinyl group, 3-Bopyryl-4-Pyridinyl group, 2-Full Ollow 4-pyridinyl, 3-fluoro-4-pyridinyl, 2-chloro-4-pyridinyl, 3-chloro-4-pyridinyl, 2-bromo-4-pyridinyl, 3-bromo-4-pyridinyl, 3- Methyl virazinyl group, 5-methyl virazinyl group, 6-methyl vilazinyl group, 3-ethyl virazinyl group, 5-ethyl vilazinyl group, 6-ethyl vilazinyl group, 3-propyl virazinyl group, 5-propyl pyrazyl group, 6-propyl virazinyl Group, 3-fluorovirazinyl group, 5-fluorobiradinyl group, 6-fluorovirazinyl group, 3-chlorovirazinyl group, 5-chlorovirazinyl group, 6-chlorovirazinyl group, 3-bromopyrazinyl group , 5-bromopyrazinyl group, 6-bromopyrazinyl group, 4-methyl-2- Pyrimidinyl, 5-methyl-2-pyrimidinyl, 6-methyl-2-pyrimidinyl, 4-ethyl-2-pyrimidinyl, 5-ethyl-2-pyrimidinyl, 6-ethyl-2-pyrimidinyl, 4 Σ pil-1 2-pyrimidinyl group, 5-pulpyl-2-pyrimidinyl group, 6-propyl-12-pyrimidinyl group, 4-fluoro-2-pyrimidinyl group, 5-fluoro-2-pyrimidinyl Group, 6-fluoro-2-pyrimidinyl group, 4-chloro-2-pyrimidinyl group, 5-chloro-2-pyrimidinyl group, 6-chloro-2-pyrimidinyl group, 4-bromo-2-pyrimidinyl group, 5- Bromo-2-pyrimidinyl group, 6-promo 2-pyrimidinyl group, 2-methyl-4-pyrimidinyl group, 5-methyl-4-pyrimidinyl group, 6-methyl-4-pyrimidinyl group, 2-ethyl -4-Pyrimidinyl group, 5-Ethyl-4-Pyrimidinyl group, 6-Ethyl-4-1Pyrimidinyl group, 2-Propyl-41-Pyrimidinyl group, 5-Bropyl- 4-Pyrimidinyl group, 6-Propyl- 4-Pyrimidinyl group, 2-fluoro-4-pyrimidinyl group, 5-fluoro-4-pyrimidinyl group, 6-fluoro-1-pyrimidinyl group, 2-chloro-4-pyrimidinyl group, 5-chloro-4-pyrimidinyl group 6-chloro-4-pyrimidinyl group, 2-bromo-4-pyrimidinyl group, 5-bromo-4-pyrimidinyl group, 6-bromo-4-pyrimidinyl group, 2-methyl-5-pyrimidinyl group, 4-methyl-5-pyrimidinyl group, 6-methyl-5-pyrimidinyl group, 2-ethyl-5-pyrimidinyl group, 4-ethyl-5-pyrimidinyl group, 6-ethyl-5-pyrimidinyl group, 2- Ropyr-5-pyrimidinyl, 4-propyl-15-pyrimidinyl, 6-propyl-15-pyrimidinyl, 2-fluoro-5-pyrimidinyl, 4-fluoro-5-pyrimidinyl, 6-fluoro-5 —Pyrimidinyl group, 2-chloro-5-pyrimidinyl group, 4-chloro-5-pyrimidinyl group, 6-chloro—5-pyrimidinyl group, 2-bromo-5-pyrimidinyl group, 4-bromo-5-pyrimidinyl Group, 6-bromo-5-pyrimidinyl group, 4-methyl-3-pyridazinyl group, 5-methyl-3-pyridazinyl group, 6-methyl-3-pyridazinyl group, 4-ethyl-3-pyridazinyl group, 5-ethyl-3-pyridazinyl group, 6-Ethyl-3-pyridazinyl, 4-propyl-13-pyridazinyl, 5-propyl-13-pyridazinyl, 6-propyl 1-Pyridazinyl group, 4-Fluoro-3-pyridazinyl group, 5-Fluoro-3-pyridazinyl group, 6-Fluoro-3-pyridazinyl group, 4-Chloro-3-pyridazinyl group, 5-Chloro-3-pyridazinyl group, 6— Chloro-3-pyridazinyl, 4-bromo-3-pyridazinyl, 5-promo 3-pyridazinyl, 6-bromo-3-pyridazinyl, 3-methyl-4-pyridazinyl, 5-methyl-4-pyridazinyl, 6-methyl-4-pyridazinyl , 3-Ethyl-4-1-pyridazinyl group, 5-Ethyl-4-pyridazinyl group, 6-Ethyl-4-pyridazinyl group, 3-propyl-14-pyridazinyl group, 5-propyl-14-pyridazinyl group, 6-propyl-4-pyridazinyl group , 3-fluoro-4-pyridazinyl group, 5-fluoro-4-pyridazinyl group, 6-fluoro 4-pyridazinyl group, 3-chloro 4-pyridazinyl group, 5-chloro-4-pyridazinyl group, 6-chloro-4-pyridazinyl group, 3-bromo-4-pyridazinyl group, 5-bromo-4-pyridazinyl group, 6-bromo-4-pyridazinyl Group, 3-methyl-2-furanyl group, 4-methyl-2-furanyl group, 5-methyl-2-furanyl group, 3-ethyl-2-furanyl group, 4-ethyl-2-furanyl group, 5-ethyl-2-furanyl group, 3 —Propyl-2-furanyl group, 4-propyl-12-furanyl group, 5-propyl-12-furanyl group, 3-fluoro-2-furanyl group, 4-fluoro-2-furanyl group, 5-fluoro-2-furanyl group , 3-Chloro-2-furanyl, 4-Chloro-2-furanyl, 5-Chloro-2-furanyl, 3-Promo-2-furanyl, 4-Bromo-2-furan 5-, 2-bromo-2-furanyl, 2-methyl-3-furanyl, 4-methyl-3-furanyl, 5-methyl-3-furanyl, 2-ethyl-3-furanyl, 4-ethyl-3 Furanyl group, 5-ethyl-3-furanyl group, 2-propyl-13-furanyl group, 4-propyl-13-furanyl group, 5-propyl-13-furanyl group, 2-fluoro-13-furanyl group, 4 Monofluoro-3-furanyl group, 5-fluoro-3-furanyl group, 2-chloro-3-furanyl group, 4-chloro-3-furanyl group, 5-chloro-3-furanyl group, 2-bromo-3-furanyl group, 4 -Bromo-3-furanyl group, 5-promo 3-furanyl group, 3-methyl-2-phenyl group, 4-methyl-2-phenyl group, 5-methyl-2-phenyl group Group, 3-ethyl-2-enyl, 4-ethyl-2-phenyl, 5-ethyl

2-Chenyl group, 3-Propyl-2-Chenyl group, 4-Propyl-12-Cenyl group, 5-Propyl-2-Cenyl group, 3-Fluoro-2-Cenyl group, 4-Fluoro-2-Cenyl group, 5 —Fluoro-2-Chenyl group, 3-Chloro—2-Chenyl, 4-Chloro—2-Chenyl, 5-Chloro—2-Chenyl, 3-bromo-2-Chenyl, 4-Bromo — 2-Chenyl group, 5-promo 2-Chenyl group, 2-Methyl-3-Chenyl group, 4-Methyl-3-Cenyl group, 5-Methyl-

3-Chenyl group, 2-Ethyl 3-Chenyl group, 4-Ethyl 3-Cenyl group, 5-Ethyl 3-Chenyl group, 2-Propyl 3-Cenyl group, 4-Propyl 3-Cenyl group, 5-Propyl 3-Chenyl group, 2-Fluoro-3-Chenyl group, 4-Fluoro-3-Chenyl group, 5-Fluoro-3-Cenyl group, 2-Chloro3-Chenyl group, 4-Chloro-3-Cenyl group, 5-Chloro-3 —Chenyl, 2-bromo-3-Chenyl, 4-bromo-3-Cenyl, 5-bromo-3-Cenyl, 3-methyl-2-pyrrolyl, 4-Methyl-2-pyrrolyl, 5-Methyl-2-pyrrolyl , 3-ethyl-2-pyrrolyl, 4-ethyl-2-pyrrolyl, 5-ethyl-2-pyrrolyl, 3-propyl-12-pyrrolyl, 4-propyl-12-pyrrolyl, 5-propyl-12-pi Lil group, 3- Furuoro 2-pyrrolyl group, 4 one Furuoro 2-pyrrolyl group, 5- Furuoro 2-pyrrolyl group, 3-chloro-2-pyrrolyl group, 4 one black port one 2-pyrrolyl group, 5- chloro

2-pyrrolyl group, 3-bromo-2-pyrrolyl group, 4-bromo-2-pyrrolyl group, 5-bromo-2-pyrrolyl group, 2-methyl-3-pyrrolyl group, 4-methyl-3-pyrrolyl group, 5-methyl-3-pyrrolyl group , 2-ethyl-3-pyrrolyl, 4-ethyl-3-pyrrolyl, 5-ethyl-3-pyrrolyl, 2-propyl-13-pyryl, 4-propyl-13-pyrrolyl, 5-propyl-13- Pyrrolyl group, 2-fluoro-3-pyrrolyl group, 4-fluoro-3-pyrrolyl group, 5-fluoro-

3-pyrrolyl, 2-chloro-3-pyrrolyl, 4-chloro-3-pyrrolyl, 5-chloro-3-pyrrolyl, 2-bromo-3-pyrrolyl, 4-bromo-3-pyrrolyl, 5-promol3 -Pyrrolyl group, 3-methyl-pyridine-N-oxy DO-2-yl group, 4-methyl-pyridine-1-N-oxide-2-yl group, 5-methylthiopyridine-1-N-oxyd-2-yl group, 6-methyl-pyridine-1-N-oxydoxy-2 3-, ethyl-pyridine-N-oxide 2-yl group, 4-ethyl-pyridine-N-oxide 2-yl group, 5-ethyl-pyridine-N-oxydoxy-2-yl group, 6-ethyl-pyridine-N —Oxide— 2-yl group, 3-propyl-pyridine—N-oxide 2-yl group, 4-propyl-pyridine-N—year-old Oxide-2-yl group, 5-propyl-pyridine—N— 2-oxyl group, 6-propyl-1-pyridine-1-N-oxydyl-2-yl group, 3-fluoro-pyridine-1-N-oxid-2-yl group, 4-fluoro-pyridine-1-N-oxyd-2-yl group Group, 5-fluoro-pyridine-N-oxide 2-yl group, 6-fluoro-pyridine-N-oxide 2-yl group, 3-chloro-pyridine-N-oxide 2-yl group, 4-chloro-pyridine-N-oxide--2-yl group , 5-chloro-pyridin-1-N-oxydoxy-2-yl group, 6-chloro-pyridine-N-oxydoxy-2-yl group, 3-bromo-pyridine-N-oxydoxy-2-yl group, 4-bromo-pyridin-1-N —Oxido 2-yl group, 5-Bromo-pyridine-1-N-oxydyl 2-yl group, 6-Promopyridine-N-oxoxide 2-yl group, 2-methyl-pyridine-1-N-oxide-13-yl Group, 4-methyl-pyridine-1-N-oxide-3-yl group, 5-methyl-pyridine-1-N-oxide-3-yl group, 6-methyl-pyridine-1-N-oxide-3-yl group, 2-ethyl-pyridine-1 N-Oxido 3-yl group, 4 Ethyl-pyridine-1-N-oxide-3-yl group, 5-ethyl-pyridin-1-N-oxide-3-yl group, 6-ethyl-pyridine-1-N-oxide-3-yl group, 2-propyl-1-pyridine-N-oxide-3 —Yl group, 4-propyl-1-pyridine-1-N-oxide 3-yl group, 5-propyl-1-pyridine-1-N-oxide-13-yl group, 6-propyl-1-pyridine—N-oxyd-3-yl group , 2-Fluoropyridine-1-N-oxyd-3-yl group, 4-Fluoro-pyridine-1-N-hydroxydyl-3-yl group, 5-Fluoro-pyridine-1-N-oxydoxy-3-yl group, 6-fluoro- Pyridine-1-N-oxide-3-yl group, 2-chloro-pyridine-1-N-oxide-3-yl group, 4-chloro-pyridine-1-N-oxide-3-yl group, 5-Chloro-pyridine-1-N-oxide-3-yl group, 6-Chloro-pyridine-1-N-oxyd-3-yl group, 2-Bromo-pyridine-1-N-oxide 3-yl group, 4-bromo- Pyridine-1-N-oxide-3-yl group, 5-bromo-pyridine-N-oxide-3-yl group, 6-bromo-pyridine-1-N-oxide-3-yl group, 2-methyl-pyridine-1-N— Oxido 4-yl group, 3-methyl-pyridine-1-N-oxydoxy 4-yl group, 1-ethyl-pyridine-l N-oxide 4-yl group, 3-ethyl-pyridine-N-oxoxide 4-yl group, 2-propyl-one Pyridine-1-N-oxide-4-yl group, 3-propyl-1-pyridine-1-N-oxide-4-yl group, 2-Fluoro-pyridine-1-N-oxide-4-yl group, 3-Fluoro-pyridin-1-N-oxide-4-yl group, 2 —Chloropie Gin-N-oxydoxy 4-yl group, 3-Cross-pyridine-N-oxydoxy 4-yl group, 2-Bromo-pyridine-N-oxydoxy 4-yl group, 3-Promopyridine-N-oxydoxy 4-yl group , 2,3-dimethylthenyl, 2,4-dimethylthenyl, 2,5-dimethylthenyl, 2,3-difluorocenyl, 2,4-difluorocenyl, 2,5-difluro Orochenyl, 2,3-dichlorophenyl, 2,4-dichlorophenyl, 2,5-dichlorophenyl, 2,3-dibromophenyl, 2,4-dibromophenyl, 2 5,5-dibromothenyl group, methylethyl-substituted phenyl group, 2,3-dimethylfuranyl group, 2,4-dimethylfuranyl group, 2,5-dimethylfuranyl group, 2,3-difluorofurer group, 2,4-difluorofuranyl group, 2,5-difluorofuran 2,3-dichlorofuranyl, 2,4-dichlorofuranyl, 2,5-dichlorofuranyl, 2,3-dibromofuranyl, 2,4-dibromofuranyl, 2,5 —Dibromofuranyl group, methylethyl-substituted furanyl group, 2,3-dimethylpyrrolyl group, 2,4-dimethylpyrrolyl group, 2,5-dimethylpyrrolyl group, 2,3-difluoropyrrolyl group, 2 2,4-difluoropyrrolyl, 2,5-difluoropyrrolyl, 2,3-dichloropyrrol, 2,4-dichloropyrrolyl, 2,5-dichloropyrrolyl, 2, 3 dibromopyrrolyl, 2,4-dibromopyrrolyl, 2,5-dibromopyrrolyl, methylethyl-substituted pyrrolyl, 2- (4,5-dimethyl) imidazolyl, 2- (4,5-difluoro) imidazolyl group, 2- (4,5-dichloro mouth) imidazolyl group, 2- (3,4-dibromo) imidazolyl group, methylethyl-substituted imidabryl group, 1-1 (3,4 —Dimethyl) pyrazolyl group, 1- (3,4-difluoro) pyrazolyl group, 1- (3,4-dichloro opening) pyrazolyl group, 1- (3,4-dibu opening) pyrazolyl group, methylethyl-substituted pyrazolyl group, 3 — (4,5-dimethyl) isothiabril group, 3— (4,5-difluoro) isothiabril group, 3— (4,

5-dichloro) isothiazolyl group, 3- (4,5-dibromo) isothiabril group, methylethyl-substituted isothiazolyl group, 3- (4,5-dimethyl) isoxazolyl group, 3- (4,5-difluoro) isoxazolyl group, 3 — (4,5-dichloro mouth) isoxazolyl group, 3- (4,5-dibromo) isoxazolyl group, methylethyl-substituted isoxazolyl group, 2-C3,4-dimethyl) pyridyl group, 2- (3,5-dimethyl) pyridyl Group, 2- (3,6-dimethyl) pyridyl group, 3- (2,4-dimethyl) pyridyl group, 3- (2,5-dimethyl) pyridyl group, 3- (2,6-dimethyl) pyridyl group, 3- (4,5-dimethyl) pyridyl group, 3- (4,6-dimethyl) pyridyl group, 3- (5,6-dimethyl) pyridyl group, 4- (2,3-dimethyl) pyridyl group, 4- (2,5-dimethyl) pyridyl group, 4- (2,6-dimethyl) pyridyl group, 4- (3,5-dimethyl) pyridyl group, 2- (3,4-difluoro) pyridyl group, 2- (3,5-difluoro) pyridyl group, 2- (3,6-difluoro) pyridyl group, 3- (2,4-difluoro) pyridyl group, 3- (2,5-difluoro) pyridyl group, 3- (2,6-difluoro) pyridyl group, 3-1 (4 , 5—difluoro) pyridyl group, 3— (4, 6—difluoro) pyridyl group,

3- (5,6-difluoro) pyridyl group, 4- (2,3-difluoro) pyridyl group, 4- (2,5-difluoro) pyridyl group, 4- (2,6-difluoro) pyridyl group, 4 One (3,5-difluoro) pyridyl group, 2- (3,4-dichloro mouth) pyridyl group, 2- (3,5-dichloro mouth) pyridyl group, 2— (3,6-dichloro mouth) pyridyl Group, 3- (2.4 dichloro mouth) pyridyl group, 3- (2,5-dichloro mouth) pyridyl group, 3- (2,6-dichloro) pyridyl group, 3— (4,5-dichloro mouth) Pyridyl group, 3— (4, 6-dichro mouth) pyridyl group, 3— (5, 6-dichro mouth) Lysyl group, 4- (2,3-dichro) Pyridyl group, 4- (2,5-dichro) Pyridyl group, 4- (2,6-dichro) Pyridyl group, 4- (3,5-) Dichloro mouth) pyridyl group, 2- (3,4-dibromo) pyridyl group, 2- (3,5-dibromo) pyridyl group, 2- (3,6-dibromo) pyridyl group, 3- (2,4 1-dibromo) pyridyl group, 3- (2,5-dibromo) pyridyl group, 3- (2,6-dibromo) pyridyl group, 3- (4,5-dibromo) pyridyl group, 3- (4,6 —Dibromo) pyridyl group, 3- (5,6-dibromo) pyridyl group, 4- (2,3-dibromo) pyridyl group, 4- (2,5-dibromo) pyridyl group, 4- (2,6 —Dibromo) pyridyl group, 4- (3,5-dibromo) pyridyl group, 2- (3,5-dimethyl) pyrazinyl group, 2- (3,6-dimethyl) birazinyl group, 2— (5,6 Dimethyl) virazinyl group, 2- (3,5-difluoro) bilazinyl group, 2- (3,6-difluoro mouth) virazinyl group, 2- (5,6-difluoro) virazinyl group, 2- (3,5— Diclo mouth) bilazinyl group, 2- (3,6-dichro mouth) bilazinyl group, 2- (5,6-dichro mouth) vilazinyl group, 2- (3,5-dibromo) pyrazinyl group, 2- (3,6 —Dibromo) birazinyl group, 2— (5,6-dibromo) birazinyl group, 2— (4,5-dimethyl) pyrimidinyl group, 2— (4,6-dimethyl) pyrimidinyl group, 2— (5, 6-dimethyl) pyrimidinyl group, 2- (4,5-difluoro) pyrimidinyl group, 2- (4,6-difluoro) pyrimidinyl group, 2- (5,6-difluoro) pyrimidinyl group, 2— ( 4,5-dichro) pyrimidinyl group, 2- (4,6-dichro) pyrimidinyl group, 2- (5,6-dichloro) pyrimidinyl group, 2- (4,5-dibromo) pyrimidinyl group, 2- (4,6-dibromo) pyrimidinyl group, 2- (5,6-dibromo) pyrimidinyl Capped, 3- (4,5-dimethyl) pyridazinyl group, 3- (4,6-dimethyl) pyridazinyl group, 3- (5,6-dimethyl) pyridazinyl group, 3- (4,5-difluoro) pyridazinyl group, 3- (4,6-difluoro) pyridazinyl group, 3- (5,6-difluoro) pyridazinyl group, 3- (4,5-dichloro opening) pyridazinyl group, 3- (4,6-dichloro) pyridazinyl group, 3- (5,6-dichloro) pyridazinyl group, 3- (4,5-dipromo) pyridazinyl group, 3- (4,6-dibromo) pyridazinyl group, 3- (5, 6-dibromo) pyridazinyl group, 2- (1,3-dimethyl) indridinyl group, 2- (1,5-dimethyl) indolidinyl group, 2- (1,6-dimethyl) indolidinyl group, 2- (1,7 —Dimethyl) indolizinyl group, 2— (1,8-dimethyl) indolizinyl group, 2— (3,5-dimethyl) indolizinyl group, 2— (3,6-dimethyl) indolizinyl group, 2— (3, 7— Dimethyl) indolizinyl group, 2- (3,8-dimethyl) indolizinyl group, 2- (5,6-dimethyl) indolizinyl group, 2- (5,7-dimethyl) indolizinyl group, 2- (5,8-dimethyl) Indolizinyl group, 2- (6,8-dimethyl) indolizinyl group, 2- (7,8-dimethyl) indolizinyl group, 2- (1,3-difluoro) in dridinyl group, 2- (1,5-difluoro) in Lysinyl group, 2- (1,6-difluoro) indolidinyl group, 2- (1,7-difluoro) indolidinyl group, 2- (1,8-difluoro) indolidinyl group, 2- (3,5-difluoro) indridinyl Group, 2- (3,6-difluoro) indolizinyl group, 2- (3,7-difluoro) indolizinyl group, 2- (3,8-difluoro) indolizinyl group, 2- (5,6-difluoro) indolizinyl group, 2 — (5,7-difluoro) indolidinyl group, 2- (5,8-difluoro) indolidinyl group, 2- (6,8-difluoro) indolidinyl group, 2- (7,8-difluoro) indolidinyl group, 2— (1,3-dichloro mouth) indolidinyl group, 2- (1,5-dichloro) indolizinyl group, 2- (1,6-dichloro mouth) indolizinyl group, 2— (1,7-dichloro mouth) Inn Lysinyl group, 2- (1,8-dichloro) indolizinyl group, 2- (3,5-dichloro mouth) indolizinyl group, 2- (3,6-dichloro mouth) indolizinyl group, 2- (3,7-dichloro mouth Mouth) Indolizinyl group, 2- (3,8-dicloro) Indolizinyl group, 2- (5,6-dichloro mouth) Indolizinyl group, 2— (5,7-diclo mouth) Indolizinyl group, 2- —Dichro mouth) Indolizinyl group, 2— (6,8—Dichro mouth) Indolizinyl group, 2— (7,8-dichloro) Indolizinyl group, 2— (1,3-Dibromo) indolizinyl group, 2— (1, 5 Idibro 乇) Indolidinyl group, 2- (1,6-dibromo) indolizinyl group, 2- (1,7-dibu) 乇 Indolizinyl group, 2— (1,8-dibromo) India

1 θ Lysinyl group, 2- (3,5-dibromo) indolidinyl group, 2- (3,6-dibromo) indolidinyl group, 2- (3,7-dibromo) indolidinyl group, 2- (3,8-dibromo) indolidinyl Group, 2- (5,6-dibromo) indolizinyl group, 2- (5,7-dibromo) indolizinyl group, 2- (5,8-dibromo) indolizinyl group, 2- (6,8-dibromo) indolizinyl group , 2- (7,8-dibromo) indolidinyl group, 1-1 (2,3-dimethyl) indolyl group, 1-1 (2,4-dimethyl) indolyl group, 1-1 (2,5-dimethyl) indolyl group, 1 1- (2,6-dimethyl) indolyl group, 1- (2,7-dimethyl) indolyl group, 1- (2,3-difluoro) indolyl group, 1- (2,4-difluoro) indrill group, 1- (2,5-difluoro) indolyl group, 1 1 (2,6-difluoro) indolyl group, 1 1 (2,7-difluoro) indolyl group, 1— (2,3 dichloro mouth) indolyl group, 1 1 (2,4-dichloro) indolyl group, 1 1 (2,5-dichloro) indolyl, 1 1 (2,6-dichloro) indolyl, 1 (2,7-dichloro) indolyl, 1- (2,3-dibromo) indolyl, 1 1- (2,4-dibromo) indolyl group, 1- (2,5-dibromo) indolyl group, 1- (2,6-dibromo) indolyl group, 1- (2,7-dibromo) indolyl group, 2— ( 3,4-dimethyl) quinolyl group, 2- (3,5-dimethyl) quinolyl group, 2- (3,6-dimethyl) quinolyl group, 2- (3,7-dimethyl) quinolyl group, 2- (3 , 8-dimethyl) quinolyl group, 2- (4,5-dimethyl) quinolyl group, 2- (4,6-dimethyl) quinolyl group 2- (4,7-dimethyl) quinolyl group, 2- (4,8-dimethyl) quinolyl group, 2- (5,6-dimethyl) quinolyl group, 2- (5,7-dimethyl) quinolyl group , 2- (5,8-dimethyl) quinolyl group, 2- (6,7-dimethyl) quinolyl group, 2- (6,8-dimethyl) quinolyl group, 2- (7,8-dimethyl) quinolyl group, 2- (3,4-difluoro) quinolyl group, 2- (3,5-difluoro) quinolyl group, 2- (3,6-difluoro) quinolyl group, 2- (3,7-difluoro) quinolyl Group, 2- (3,8-difluoro) quinolyl group, 2- (4,5-difluoro) quinolyl group, 2- (4,6-difluoro) quinolyl group, 2- (4,7-difluoro) quinolyl Group, 2— (4,8—jifu Quinolyl group, 2- (5,6-difluoro) quinolyl group, 2- (5,7-difluoro) quinolyl group, 2_ (5,8-difluoro) quinolyl group, 2— (6 , 7-difluoro) quinolyl group, 2- (6,8-difluoro) quinolyl group, 2— (

7,8 difluoro) quinolyl group, 2- (3,4 dichloro mouth:) quinolyl group, 21

(3,5-dichloro mouth) quinolyl group, 2- (3,6-dichloro mouth:) quinolyl group, 21

(3,7-dichloro mouth) quinolyl group, 2- (3,8-dichloro mouth) quinolyl group, 21

(4,5-dichloro mouth) quinolyl group, 2- (4,6-dichloro mouth) quinolyl group, 2-

(4,7 dichloro o) quinolyl group, 2- (4,8-dichloro mouth:) quinolyl group, 2-

(5,6 dichloro mouth) quinolyl group, 2- (5,7-dichloro:) quinolyl group, 21

(5,8-dichrolic mouth) quinolyl group, 2- (6,7-dichrolic mouth) quinolyl group, 2-

(6,8 dichloro mouth) quinolyl group, 2- (7,8-dichloro:) quinolyl group, 21

(3,4-dibromo) quinolyl group, 2- (3,5-dibromo:) quinolyl group,

(3,6-dibromo) quinolyl group, 2- (3,7-dibromo:) quinolyl group,

8-dibromo) quinolyl group, 2- (4,5-dibromo:) quinolyl group, 21

(4,6-dibromo) quinolyl group, 2- (4,7-dibromo:) quinolyl group, 21-

(4,8-dibromo) quinolyl group, 2- (5,6-dibromo:) quinolyl group, 2-

(5,7-dibromo) quinolyl group, 2- (5,8-dibromo:) quino'J group, 21-

(6,7-dibromo) quinolyl group, 2- (6,8-dibromo:) quinolyl group, 21-

(7,8-dibromo) quinolyl group, 3- (4,5-dimethyl:

3- (4,6-dimethyl) cinnolinyl group, 3- (4,7-dimethyl) cinnolinyl group, 3- (4,8-dimethylcinnolinyl group, 3- (5,6-dimethyl) cinno Linyl group, 3- (5,7-dimethyl) cinnolinyl group, 3- (5,8-dimethyl) cinnolinyl group, 3- (6,7-dimethylcinnolinyl group, 3- (6,8-dimethyl) cinno Linyl group, 3- (7,8-dimethylcinnolinyl group, etc., preferably 3-methyl-2-pyridinyl group, 4-methyl-2-pyridinyl group, 5-methyl-2-pyridinyl group, 6-methyl-2 —Pyridinyl, 3-fluoro—2-pyridinyl, 4-fluoro-2-pyridinyl, 5-fluoro-2-pyridinyl, 6-fluoro-2-pyridinyl, 2-fluoro-3-pyridinyl A 4-fluoro-3-pyridinyl group, a 5-fluoro-3-pyridinyl group, a 6-fluoro-3-pyridinyl group, and the like.

The term “hydroxydialkyl group” means an alkyl group having 1 to 5 carbon atoms having a hydroxy group, specifically, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, and the like. Represents a hydroxymethyl group, a hydroxyethyl group or the like.

The “aryloxyalkyl group” means an alkyl group having 1 to 5 carbon atoms having an aryloxy group, and specifically includes a phenyloxymethyl group, a phenyloxyethyl group, a nailoxypropyl group, and a phenyloxyalkyl group. Phenyloxyisopropyl group, 1-naphthyloxymethyl group, 1-naphthyloxyshethyl group, 1-naphthyloxypropyl group, 1-naphthyloxyisopropyl group, 2-naphthyloxymethyl group, 2-naphthyl Oxyshetyl group, 2-naphthyloxyquinpropyl group, 2-naphthyloxyisopropyl group, 0-biphenyloxymethyl group, 0-biphenyloxyxetyl group, 0-biphenyloxypropyl group, 0-biphenyl M-biphenyloxymethyl group, m-biphenyloxyshethyl group, m-biphenyloxypropyl group, m- A biphenyloxyisopropyl group, a p-biphenyloxymethyl group, a p-biphenyloxyshethyl group, a p-biphenyloxypropyl group, a p-biphenyloxyisopropyl group, and the like, and preferably a phenyloxymethyl group and a phenyloxymethyl group. It is an eniloxhetyl group.

Specific examples of the "aryl amino group" include phenyl amino group, 1-naphthylamino group, 2-naphthylamino group, 0-biphenylamino group, m-biphenylamino group, p-biphenylamino group, and the like, and are preferable. Is a phenylamino group.

The “lower alkyl group or an arylamino group optionally substituted with a halogen atom” is the “lower alkyl group” and the “arylamino group which may be substituted with one to three substituents selected from“ halogen atoms ”as described above. For specific examples of the substituted aryl group, refer to those described above as the substituted aryl group.

The term "aryloxy group" refers specifically to phenyloxy, 1-naphthyloxy, 2-naphthyloxy, 0-biphenyloxy, m-biphenyloxy. And a p-biphenyloxy group and the like, and preferably a phenyloxy group.

"An aryloxy group optionally substituted with a lower alkyl group or a halogen atom

'' Means an `` aryloxy group '' which may be substituted with 1 to 3 substituents selected from the above-mentioned `` lower alkyl group '' and `` halogen atom '', and specific examples of the substituted aryl group are substitution. As the aryl group, reference is made to those exemplified above.

The group J represented by {one (CHz), one 0— CCH ₂ ) _B- 1 0— (CH ₂ )} — is specifically — CH ₂ -0-CH ₂ -0—, one CH ₂ -0-CH ₂ 1 0— CH ₂ —, — (CH ₂ ) ₂ — 0— CH ₂ — 0— CH ₂ —, 1 CH ₂ — 0— (CH ₂ ) ₂ — 0— CH ₂ (CH ₂ ) ₂ -0-CH, one 0— (CH ₂ ) ₂ —, one (CH ₂ ) ₂ — 0— (CH ₂ ) ₂ -0- (CH ₂ ) ₂ — and the like, preferably — CH ₂ -0-CH ₂ 1 0 1 CH ₂ —.

“Pharmaceutically acceptable salt” means, for example, various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; acetate, propionate, succinate, and glycol. Various organic acid addition salts such as acid, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; aspartic acid Salts and salts with various amino acids such as glutamate are included, but are not limited thereto. The general formula [I],

The compound represented by [3 '], [4'], [5 '], [8'] or [9 '] may have one or more asymmetric carbons, In the case of one, a pure optically active substance, a mixture thereof in an arbitrary ratio or a racemic form is present, and in the case of two or more asymmetric carbons, an optically pure diastereomer, its racemic form, Alternatively, mixtures thereof may be present in any combination and ratio. Further, compound [I] has E-isomer and Z-isomer depending on the arrangement of the double bond in the amidine moiety. Further, a resonance structure may exist in the amidine moiety of the compound [I]. The present invention includes all these isomeric forms.

When compound [I] is used as a pharmaceutical preparation, it is usually a pharmacologically acceptable carrier, excipient, diluent, bulking agent, disintegrant, stabilizer, preservative, buffer, emulsifier known per se. , Fragrance, colorant, sweetener, thickener, flavoring agent, solubilizer, other additives Agents, specifically water, vegetable oils, alcohols such as ethanol, benzyl alcohol or hydroxypropyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, etc., magnesium stearate, talc, Lanolin, Vaseline, lactose, lactose, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, gum arabic, dextrin, pullulan, aluminum gayate, calcium phosphate, waxes, boric acid, DL-isocyanate, sodium fatty acid, magnesium lauryl sulfate, Dextrin, hydroxypropyl methylcellulose, polyvinylpyrrolidone, macrogol, carnauba wax, polyoxyethylene polyoxypropylene glycol, cacao Fats, lactic acid, lecithin, glycerin, sodium parahydroxybenzoate, sodium benzoate, salicylic acid, potassium sorbate, etc., mixed with tablets, pills, powders, granules, suppositories, suppositories, injections, eye drops, It can be administered orally or parenterally in the form of solutions, capsules, troches, aerosols, elixirs, suspensions, emulsions, syrups and the like. The dose may vary depending on the type and degree of the disease, the compound to be administered, the route of administration, the age, sex, weight, etc. of the patient. In the case of oral administration, the compound [I] is usually used in an adult at a dose of 0.001 per day. It is preferred to administer from 1 to 100 mg, especially from 0.1 to 100 mg.

Next, methods for producing these chroman compounds will be described. However, it goes without saying that the method for producing the compound of the present invention is not limited to the exemplified production methods.

Hereinafter, the flow will be shown and described in further detail.

Manufacturing method 1

O

[1] [3] [4] Process 3

Process 5

C6) [7] [5]

(5) (8) (9)

Manufacturing method 1 (continued)

B'-N

C = X "

[10-4]

Process 8-1 v

¾ ¾9

(Ib) (Ia)

^R ,. [Ic] R '[10-1]

Process 12-

General manufacturing method

Process 1

2-hydroxyacetophenone (compound [1]) (R ¹ is as described above) and compound [2] (R ² and R ³ are as described above) are combined with pyrrolidine, piperidine, morpholine, etc. In a solvent such as benzene, toluene or xylene in the presence of a secondary amine, the mixture is heated to reflux using a Dean-stark apparatus while removing liberated water, thereby obtaining a solution of 4-chromanone. Compound [3]) (R ¹ , R ² and R ³ are as described above) can be produced. In this reaction, more preferable results are often obtained by adding a small amount of an acid catalyst such as acetic acid, benzoic acid or P-toluenesulfonic acid. In addition, enamine is prepared from compound [2] and secondary amamine by a conventional method, and is reacted with compound [1] to give compound [1].

[3] can also be manufactured. The compound [1] used is commercially available in many cases, but if it is not commercially available, it can be prepared by acetylating the ortho-position from p-substituted phenol by Friedel 'Kraft reaction or Fries rearrangement. .

Process 2

The compound [3] is reduced with a reducing agent such as sodium borohydride in an alcoholic solvent such as methanol, ethanol, tetrahydrofuran, preferably methanol or ethanol, under cooling or at room temperature, to give 4-chromanol (compound

[4]) (R ¹ , R ² and R ³ are as described above).

Process 3

Compound [4] is removed using a Dean-stark apparatus in a solvent such as benzene, toluene, or xylene in the presence of an acidic catalyst such as ρ-toluenesulfonic acid or camphorsulfonic acid to remove free water. While heating and refluxing, or using acetic anhydride, trifluoroacetic acid, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, P-toluenesulfonyl chloride, etc., the hydroxyl group of compound [4] is changed to an acetyl group, a trifluoromethyl group. Roacetyl, methanesulfonyl, trifluoromethanesulfonyl, p-toluenesulfonyl, etc. The chromene (compound [5]) (R) can be obtained by activating and releasing with a base such as triethylamine, N-methylmorpholine, or diazabicycloundecene, and particularly preferably with diazabicycloundecene. ¹ , R ² and R ³ are as described above).

Compound [5] can also be produced as follows. (Process 4-Process 5)

Process 4

Known methods from compound [2] and lithium metal acetylide such as lithium acetylide or sodium acetylide (for example, Journal of Organic Chemistry (J. Org. Chem) 33, 778 (1968), Synthetic Communique) one Chillon (Synth. Commun.) 18, 131 (1988) propargyl alcohol (compound made mutatis mutandis regulating how) described in such [6]) (R ² and R ³ are as defined above) And p-substituted fluorobenzene in the presence of a base such as sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, etc. in a solvent such as dioxane, acetonitrile, dimethyl sulfoxide, dimethylformamide, etc. at room temperature or under heating, particularly preferably reacted with 6 0 a to 1 4 0 ° C § acetylene derivative (compound ^{[7]) (R 1,} R 2 and R ³ It can be produced in a) above. In addition, the hydroxyl group of compound [6] may be substituted with an acetyloxy group, a trifluoroacetyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or an activity such as a chlorine atom or a bromine atom. A nonprotonic solvent such as benzene, toluene, methylene chloride, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, etc. Reaction in an alcoholic solvent such as methanol or ethanol, or a mixed solvent thereof in the presence of a base such as pyridine, N-methylmorpholine, triethylamine, sodium hydride, caustic soda, sodium bicarbonate, or sodium carbonate. Compound [7] It is.

Process 5 Compound [7] is heated in a solvent that does not inhibit the reaction itself, such as benzene, toluene, acetonitrile, N, N-dimethylaniline, dimethylformamide, dimethylsulfoxide, etc., particularly preferably in dimethylaniline or dimethylsulfoxide. The compound [5] can be produced preferably by heating to 100 to 18 (TC. The compound [5] is described in JP-A-3-66681. As described above, there are known ones, and in that case, they can be produced according to the method described therein.

Process 6

Compound [5] can be obtained by cooling m-chloroperbenzoic acid, peracetic acid, etc., in a solvent such as chloroform, methylene chloride or ether, under cooling or heating, particularly preferably under ice-cooling or room temperature. 3 by oxidizing the oxidation agent, 4-epoxychroman (compound ^{[8]) (R 1,} R 2 and R ³ are as defined above) as possible out to produce. Further, the conversion of compound [5] to compound [8] can also be performed in a plurality of steps. That is, compound [5] is treated with N-butyl moss imide in a mixed solvent of water and a solvent such as methylene chloride, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, or the like. The compound [8] can be obtained by converting the compound into a bromohydrin compound by removing the hydrogen bromide with a base such as caustic soda. Furthermore, the production of optically active compounds [8] is described in Journal of American Chemical Society (J. Am. Chenj. Soc.) 1991, 113, 7063. It can be produced by stereoselectively oxidizing compound [5] with a (Salen) complex or the like.

Process "7

Compound [8] is ring-opened with aqueous ammonia or lower alkylamine in an organic solvent such as methanol, ethanol, tetrahydrofuran or dioxane, particularly preferably in an alcoholic solvent such as methanol or ethanol under cooling or heating. Amino-3-chromanol (compound [9]) (R], R ² , R ³ and R ⁷ can be obtained as described above.

2 Θ Step 8—i

The method described in European Patent Publication (EP0388528A), Organic Functional Group Preparations (Organic Functional group preparations) 2nd. Vol.3, chap.8, ACADEMIC PRESS, INC. (Compound [10-1]) (R ^s is as described above, X ′ is N—CN, and R is a halogen atom, a lower alkoxy group or a methylthio group, an ethylthio group, etc. Compound (9) was synthesized with Compound [9] by Synthesis, 1978. 673 ·, Synthesis, 1980, 213., Journal of Organic Chemistry U. Org. Chem.), 26, 412 ( 1961). Compound [Ia] can be synthesized by reacting according to the method disclosed in US Pat. That is, aprotic solvents such as benzene, toluene, methylene chloride, triethylamine, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, and dimethyl sulfoxide; and alcohols such as methanol and ethanol. Reaction in an aprotic solvent or a mixed solvent thereof, particularly preferably in an alcoholic solvent such as methanol or ethanol, at room temperature to under heating, particularly preferably at room temperature to 8 O'C to obtain compound [la]. Can be.

Step 8-ii

The compound [Ia] is a amide (compound [10-2]) (R ⁶ is as described above, X ″ is an oxygen atom or a zeo atom, and R is as described above). Ester, acid halide or acid anhydride and compound [9] with or without a solvent such as chloroform or methylene chloride in the presence or absence of a base such as gin, lutidine, and triethylamine, and the compound [9] under ice-cooling Alternatively, it can be obtained by reacting under heating.

Process 8-i

Compound [Ia] is prepared by combining thiourea compound [10-3] (R ^e 'is a lower alkyl group or an aryl group which may be substituted with a halogen atom) and compound [9] with dimethylformamide and tetrahydrofuran. Carbodiimide, preferably in an organic solvent such as acetonitrile or dichloromethane, preferably 1- (3-dimethylaminopropyl) It can be obtained by reacting in the presence of 1-3-ethylcarbodimid.

Step 8-iv

Compound [la] is an isocyanate (compound [10-4]) (R ⁶ 'and X "are as described above) and compound [9] are converted to an alcohol such as methanol and ethanol, or an organic compound such as tetrahydrofuran or dioxane. It can be obtained by reacting in a solvent, particularly preferably in an alcohol such as methanol or ethanol, at room temperature or under heating.

Process 9

Compound [Ib] was prepared from compound [Ia] by applying the method described in Journal of Medicinal Chemistry (J. Med. Chem.) 1990, 33. 2667. By the normal dehydration method using Dean-Stark equipment in a solvent such as benzene, toluene, or xylene in the presence of an acid catalyst such as an acid, or the 3-position hydroxyl group can be converted to methanesulfonyl, trifluoromethanesulfonyl, etc. It can be synthesized by activating with elimination under basic conditions. Step 1 0

Compound [I c] (R ⁸ is an alkanoyloxy group or a formyloxy group) can be produced by alkanoylation or formylation of a hydroxyl group of the compound [I a] by a conventional method. That is, the alkanoylation of the compound [Ia] can be carried out in the presence of a base such as pyridine, lutidine or triethylamine in a solvent such as chloroform or methylene chloride, or without using a solvent. By reacting the compound with the compound [Ia] at ice-cooling to room temperature. The formylation of the compound [la] can be achieved by treating with refluxing formic acid and acetic anhydride in a solvent such as methylene chloride or chloroform which does not inhibit the reaction itself.

Process 1 1

4-aminochroman wherein R ⁷ is a hydrogen atom (compound [11]) (R ¹ , R ² and R ³ are as described above) is described in JP-A-2-134357 from compound [4]. It is synthesized using the above method mutatis mutandis, or using a modification of this method. That is, The hydroxyl group of the compound [4] is converted to an active leaving group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a chlorine atom or a bromine atom, and is converted to an azide It is manufactured by reacting sodium and further reducing it with zinc dust, iron powder, and the like.

The compound [11] in which R ⁷ is a lower alkyl group (R ¹ , R ² and R ³ are as described above) corresponds to the compound [11] in which R ⁷ is a hydrogen atom and a lower alkyl group By producing an imine by reacting the aldehyde with a solvent such as benzene, toluene, methanol, and ethanol that does not hinder the reaction itself, and producing the imine by reducing it. The reduction is carried out in the presence of a palladium catalyst, a nickel catalyst, a platinum catalyst or the like, preferably at a pressure of 1 to 10 atm, preferably 1 to 3 atm using palladium carbon as a catalyst, in the presence or absence of an acid such as acetic acid or hydrochloric acid. The reaction can be carried out in a solvent that does not hinder the reaction itself, preferably in an alcoholic solvent such as methanol or ethanol. The imine can be reduced using a hydride reducing agent, preferably sodium borohydride or sodium cyanoborohydride, in an alcoholic solvent such as methanol or ethanol, in a non-protonic solvent such as tetrahydrofuran, acetic acid, The reaction can be carried out under cooling or heating in the presence or absence of an acid such as trifluoroacetic acid or hydrochloric acid.

Process 1 2

Compound [Id] (R ¹ , R ² , R ³ , Rs, and R ⁷ are as described above) is obtained by converting compound [11] with compounds [10-i] to compound [10-iv]. It is produced by reacting. This reaction is basically the same as the reaction from compound [9] to compound [Ia], and each reaction shown in step 8 can be applied.

Hereinafter, the present invention will be described more specifically with reference to examples.

Example 1

i) 3.253 g of a diastereomeric mixture of 6-cyano 3,4-dihydro-3,4-epoxy-12-methoxymethyl-2-methyl-2H-1-1-benzopyran described in JP-A-3-66681. The mixture was dissolved in 50 ml of ethanol, and 50 ml of a 28% aqueous ammonia solution was added under ice-cooling. After stirring at room temperature for 4 days, the solvent Was distilled off under reduced pressure to obtain 3.5 g of a diastereomer mixture of t-14-amino-6-cyano-3,4-dihydro-r-3-hydroxyl-2-methoxymethyl-2-methyl-2H-1-benzopyran. Was.

ii) t-41-amino-6-cyano_3,4-dihydro-r-3-hydroxy-2-methoxymethyl-2-methyl-1H-dibenzo-pyran diastereomeric mixture 2 g of dioxane 8 m 1-water 6 m The resulting mixture was dissolved in 1 and added with 44 Omg of sodium hydrogencarbonate, and 2.2 ml of carbobenzoxychloride was added with stirring under ice-cooling. After stirring at room temperature for 4 hours, ethyl acetate was added to the reaction solution, and the mixture was washed successively with aqueous sodium hydrogen carbonate and brine. After drying over magnesium sulfate, the solvent is distilled off, and the residue obtained is purified and separated by silica gel column chromatography (ethyl acetate: hexane = 3: 7) to obtain a low-polarity t-substance. N-dioxycarbonylamino-6-cyano 3,4-dihydro-c-13-hydroxy-r-2-methoxymethyl-2-methyl-2H-1 1 Benzopyran (A isomer) 07 g, and high polarity C-14-benzyloxycarbonylamino 6-cyano 3,4-dihydro-t-3-hydroxy-r-12-methoxymethyl-2-methyl-2H-1-1-benzopyran (B isomer) 1.13 was obtained.

A isomer

^{_{J H NMRCCDCl 3 / ppm) 5}} 1.55 (s. 3H), 3.33 (s, 3H), 3.5-3.7 (4H), 4.9-5 · 1 (2Η), 5.2K2H), 6.87Cd. 1H). 7.3- 7.5C7H), 7.58 (d, 1H).

B isomer

'Η NM (CDCl ₃ / ppm) <5 1.22 (s.3H), 3.4-3.8C3H) .3.42 (s, 3H).

4.01 (d, J = 9.0Hz.1H), 4.86 (t, J = 9.0Hz.1H) .5.1-5.3C3H) .6.88 (d.1H), 7.3-7.6C7H).

iii) t-14-Benzyloxycarbonylamino-6-cyano 3,4-dihydroxy c-13-hydroxyr-12-methoxymethyl-2-methyl-2H-1-1-benzopyran (A isomer) 1 0.5 g was dissolved in 15 ml of methanol, and 105 mg of 10% dispersion carbon was added thereto, followed by stirring under a hydrogen atmosphere at normal temperature and normal pressure for 4 hours. The catalyst was removed by filtration and the solvent was distilled off under reduced pressure to obtain t-amino-6-cyano-3,4. Dihydro-c-3-hydroxy-r-1-2-methoxymethyl-2-methyl-2H

— 1 Benzopyran (A isomer) 67 Omg was obtained.

lH NR (CDCl ₃ / ppni) 5 1.60 (s, 3H) .3.34 (s, 3Η), 3.37 (d.1H).

3.52 (d, J = 9.7Hz.1H), 3.63 (d.J = 9.7Hz, 1H), 3.84 (d.1H), 6.85 (d, 1H),

7.43C1H), 7.86C1H).

In the same way, c-14-benzyloxycarbonylamino 6-cyano-3,4-dihydrot-13-hydroxy-r-12-methoxymethyl-2-methyl-2H-1-1-benzopyran (B isomer) 1.13 g of c-41-amino-6-cyano 3,4-dihydro-t-3-hydroxy-r-2-methoxymethyl-2-methyl-2H-1-1-benzopyran (isomer B) 69 Omg was obtained. .

JH NMR (CDCl ₃ / ppm) 5 1.22 (s, 3H), 3.47 (s, 3H) .3.6-3.8 (4H), 6.87 (d, 1H),

7.43 (dd.1H), 7.84 (d, 1H).

Example 2

508 mg of methyl N-cyano 3-pyridine carboxymidate and t-14-amino-6-shiryono-1,4-dihydro-r-13-hydroxy-2-methoxymethyl- obtained in Example 1-i) 804 mg of an isomer mixture of 2-methyl-1H-1-benzopyran was added to 1 ml of methanol, and the mixture was stirred at room temperature for 3 days. The precipitated precipitate is collected and purified by silica gel column chromatography (form: methanol-99: 1 to 9: 1) to form a low-polarity N'-cyano N- (6 —Cyanol 3,4-dihydro-c-1-3-hydroxy-r-1 2—Methoxymethyl-2-methyl-2H—1-benzopyran—t1—41-yl) 1-3—Pyridinecarboxamidine (A isomer) Methanol addition 64 mg, and highly polar N'-cyano N- (6-cyano 3,4-dihydro-t-3-hydroxy-r-1-2-methoxymethyl-2-methyl-2H-1-benzo-pyran-1 c-1 4- (Yl) 1-3-pyridinecarboxamidine (B isomer) 72 mg of a methanol adduct was obtained.

A isomer

Melting point 2 16.1-2 17.2. C 'Η NMR (DMS0-d ₈ / ppm) 5 1.40 (s. 3H), 3.16 (d. J = 5.3 Hz. 3H methanol),

3.21 (s, 3H), 3.48 (d.J = 10.7Hz.IH), 3.68 (d, J = 10.7Hz, IH).

3.84 (dd, J = 5.7Hz. IH). 4.10 (q, J = 5.3Hz, IH methanol), 5.33 (t, J = 8.3Hz, IH), 6.21 (d, J = 5.7Hz, IH). 6.97 (d, IH), 7.6_7.7 (2H), 7.81 (s, IH),

8.21 (dd, IH), 8.79 (dd, 1H), 8.9 (d, IH). 9.55d, J = 8.3Hz, IH).

B isomer

Melting point 235.3-236.1 ° C

^! H NMR (DMSO-d ₆ / ppm) d 1.17 (s, 3H), 3.16 (d. J = 5.3Hz. 3H (tagle),

3.34 (s, 3H), 3.47 (d, J = 10.7Hz, IH), 3.63 (d, J = 10.7Hz. IH),

4.1-4.2 (1H + 1H methanol), 5.26 (t, IH), 6.11 (d, 1H), 6.98 (d, IH),

7.6-7.7C2H), 7.83 (s, IH), 8.25 (d, IH). 8.80 (d, IH), 9.00 (s, IH),

9.61 (d, IH).

Example 3

Example 11 t-14-amino-6-cyano 3,4-dihydro-1c-13-hydroxyr-12-methoxymethyl-2-methyl-2H-1-1-benzopyran (A isomer) obtained in 1 iii) 0.5 ml of methanol was added to 203 mg and 157 mg of methyl N-cyano 4-fluorobenzimidate, and the mixture was stirred at room temperature for 5 days, and then the solvent was distilled off under reduced pressure. The resulting residue was subjected to silica gel column chromatography (form: methanol = 97: 3), and further crystallized from methanol to give N'-cyano N- (6-cyano-1,3,4-dihydro-c-3-hydroxy). —R-12-Methoxymethyl-2-methyl-2H—1 benzozopyran—t-14 4-yl) 4-fluorobenzamidine (A isomer) (189 mg) was obtained.

Melting point: 1 40— 1 69

^{_{J H NMR (DMS0-d 6}} /ppra)dl.39(s. 3H), 3.20 (s, 3H). 3.48 (d. J = 10.7Hz. IH), 3.66 (1 J = 10.7Hz, IH). 3.84 (dd, IH). 5.30 (t, IH), 6.18 (d, IH),

6.97 (d, IH). 7.45 (t, 2H), 7.63 (d.IH), 7.72 (s.IH). 7.85 (dd, 2H),

9.37 (d, IH).

In the same way, c-14-amino-6-cyano 3,4-dihydrot-1-3-hydroxy From r-2-Methoxymethyl-2-methyl-2-H-1-1-benzopyran (isomer B) 206 mg and methyl N-cyano-4-fluorobenzimidate 157 mg from N'-cyano N- (6-cyano 3,4-dihydro-1t-3-hydroxy-1r-12-methoxymethyl-12-methyl-2H-1-benzopyran-1c-14-yl) 1-4-fluoro alpha benzamidine (Β isomer ) 248 mg were obtained.

Melting point: 25 0.4-251.0 ° C

Ή NM (DMS0-d _{6 /} ppm) 51.16Cs, 3H), 3.34 (s, 3H). 3.47 (d, J = 10.7Hz, 1H), 3.62 (d, J = 10.7Hz.1H), 4.1-4.2 (1H), 5.24 (t, 1H). 6.07 (d. 1H),

6.98 (d.1H), 7.45 (t.2H), 7.64 (dd.1H), 7.72 (s, 1H), 7.90 (dd.2H).

9.3 (d. 1H).

Example 4

1-5.77 g of 5-cyano-2-hydroxyacetophenone was dissolved in 120 ml of toluene, and 6 ml of pyrrolidine and 15 ml of 1.3-dimethoxy-2-propanone were added, followed by refluxing for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate, washed sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate, and brine, and dried over magnesium sulfate. The solvent was distilled off, and the resulting residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 8) to give 6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) -1. 2H—1—Venzopyran-14.0 g was obtained.

^{_{J H NMR (CDCl 3 /ppm)(52.95(s,}} 2H), 3.35 (s, 6H). 3.55 (d. J = 10.3Hz, 2H), 3.60 (d, J = 10.3Hz, 2), 7.07 ( d, 1H), 7.68C1H), 8.140H).

Example 5

6-cyanoh 3,4-dihydro-2,2-di (methoxymethyl) -12H-1-benzopyran-14one 12.1 g was dissolved in methanol 150 ml and hydrogenated under ice-cooled stirring. 1.96 g of sodium borohydride was added in small portions. After stirring for 1.5 hours, the mixture was concentrated, and the residue was added with ice and ethyl acetate, and washed with water, diluted hydrochloric acid, aqueous sodium bicarbonate, and brine in that order. After drying over magnesium sulfate, the solvent was distilled off to obtain 11.5 g of 6-cyano-1,3,4-dihydro-2,2-di (methoxymethyl) -12H-1-benzobenzoylan-1-ol. . Ή NMR (CDCl ₃ / ppm) d 2.12 (dd, J = 5.3Hz, J = 14.5Hz, 1H) .2.33 (d.J = 5.6Hz.

14.5Hz.1H), 3.36 (s.3H) .3.41 (s, 3H) .3.4-3.7C4H). 4.77 (m, 1H),

6.92Cd.1H), 7.44 (dd.1H). 7.72 (d, 1H).

Example 6

Dissolve 6.5 g of 6-cyano-1,4-dihydro-2,2-di (methoxymethyl) -12H-1-1benzopyran-1-ol in 60 ml of toluene and dissolve 0.6 g of p-toluenesulfonic acid. The mixture was heated under reflux for 1 hour while distilling free water off. The reaction solution was concentrated, ethyl acetate was added, and the mixture was washed with water, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography.

(Ethyl acetate: Hexane = 15:85) to give 4.91 g of 6-cyano 2,2-di (methoxymethyl) -1-2H- 1-benzophenane.

! H

2). 3.60 (d, J = 10.2Hz,

2H), 5.76 (d, J = 10.1Hz.1H). 6.49 (1 J = 10.1Hz.1H). 6.87 (d.1H),

7.25 (d.1H), 7.39 (dd.1H).

Example 7

Dissolve 4.3 g of 6-cyano 2,2-di (methoxymethyl) 1-2H-1 benzopyran in 50 ml of methylene chloride, add 4.75 g of m-chloroperbenzoic acid under ice cooling, and add room temperature. And stirred. After 1 hour, add 2.2 g of m-chloroperbenzoic acid, and 1.5 g after 18 hours, and add 2 ml of form after 21 hours, and wash with 1N aqueous sodium hydroxide, sodium bicarbonate, and brine. did. After drying over magnesium sulfate, the solvent was distilled off, and the residue was purified by silica gel column chromatography (ethyl acetate: hexane = 2: 8) to give 6-cyano 3,4-epoxy-1,3,4-dihydro-1. There were obtained 4.05 g of 2,2-di (methoxymethyl) -1H-1-1-benzopyran.

JH MR (CDCl ₃ / ppm) <5 3.27 (s.3H), 3.48 (s.3H) .3.57 (d, J = 10.3Hz.1H),

3.70 (d.J = 10.3Hz, 1H), 3.71 (s, 1H) .3.82 (d, J = 4.4Hz, 1H), 3.94 (d,

J = 4.4Hz, 1H), 6.91 (d, 1H), 7.53 (dd, 1H), 7.65 (d.1H).

Example 8

6-cyano 3,4-epoxy-1,3,4-dihydro-2,2-di (methoxymeth (Chill) 3.04 g of 12H-1 benzopyran was dissolved in 25 ml of ethanol, 25 ml of a 28% aqueous ammonia solution was added under ice cooling, and the mixture was stirred at room temperature. After 24 hours, add 10 ml of aqueous ammonia solution, stir for another 15 hours, concentrate, and purify the residue by silica gel chromatography (chloroform: methanol = 95: 5) to obtain trans-1-amino-6. —Cyanol 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H-1-benzopyran 2.87 g was obtained.

H NMR (CDCl ₃ / ppra) 5 3.33 (s.3H), 3.48 (s.3H), 3.6-3.9 (6H) .6.91 (d, 1H) .7.43 (dd.1H). , 1H).

Example 9

Trans-4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-12H-1 benzopyran 5.55 mg and ethyl N-cyano-3-pyridinecarboxymidate 5 From 24 mg, N'-cyano N- [trans-6-cyano-1,3,4-dihydro 2,2-di (methoxymethyl) -1,3-hydroxy-12 H-1 Benzopyran-14-yl] -13-pyridinecarboxamidine was obtained in an amount of 577 mg.

Melting point: 23 9 ^e C <decomposition

^! H NMR (DMS0-d _B / ppm) δ 3.20 (s, 3H), 3.32 (s.3H), 3.5-3.8 (4H), 4.19 (d, 1H), 5.36 (t, IH), 6.3QH 7.6_7.7 (2H). 7.78 (s, 1H), 8.25C1H), 8.79 (dd, IH). 8.99 (d, IH), 8.54 (d.IH).

Example 10

Dissolve 1.7 g of 6-cyano-1,3-dihydro-2,2-di (methoxymethyl) 1-2H-1-benzopyran-14-ol obtained in Example 5 in 50 ml of methylene chloride Then, 1.7 ml of triethylamine and 1 ml of methyl sulfonyl chloride were added under ice-cooling and stirring, and the mixture was stirred at room temperature for 1 day. The reaction water, aqueous sodium bicarbonate, washed successively dimethylformamide and oil 1. 8 g obtained _c to give an oil Fushimi of 1. 9 g by distilling off the dried solvent with sulfuric acid Maguneshiumu brine The solution was dissolved in 20 ml of an amide, and 0.41 g of sodium azide was added thereto under ice-cooling and stirring, followed by stirring at room temperature for 1 day. Reaction solution in water After pouring, the product was extracted with ethyl acetate, washed and dried, and then the solvent was distilled off under reduced pressure to obtain 1.79 g of an oily substance.

1.68 g of the obtained oil was dissolved in 15 ml of acetone, and 1.2 ml of concentrated hydrochloric acid and 1 g of zinc powder were added thereto under ice-cooling, followed by stirring at room temperature for 2 hours. The solid was separated by filtration, and the residue obtained by concentration was dissolved in a 1N aqueous hydrochloric acid solution. After washing with ethyl acetate, the aqueous layer was made basic with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate layer was washed with brine, dried and concentrated, and the residue was subjected to silica gel column chromatography (form: methanol-97

: 3) to give 853 mg of 4-amino-6-cyano-3,4-dihydro-2,2-di (methoxymethyl) -12H-1benzopyran.

^J H NM (CDCl ₃ / ppm) d 1.73 (dd, J = ll.lfiz.13.6Hz.1H) .2.31 (dd, J = 5.8Hz.

13.6Hz, 1H), 3.35 (s, 3H). 3.40 (d.J = 9.8Hz, 1H) .3.43 (s, 3H),

3.49 (d, J = 9.8Hz, 1H). 3.56 (s.2H), 4.03 (dd.J = 5.8Hz, 11.1Hz, 1H).

6.90 (d.1H), 7.41 (dd, 1H), 7.87 (d, 1H).

Example 1 1

Example 4 from 4-amino-6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) -12H-1 monobenzopyran 246 mg and methyl N-cyano 3-pyridine power lipoximidate 253 mg N'-Cyanone-N- [6-cyano-3,4-dihydro-2,2-di (methoxymethyl) -12H-1-1-benzopyran-14-yl] -13-pyridine 259 mg of carboxamidine were obtained.

^J H NMR (CDCl ₃ / ppm) d 2.29 (dd, J = 4.4Hz.14.8Hz.1H), 2.43 (dd, J = 6.0Hz.14.8Hz, 1H), 3.32 (s, 3H). 3.40 (s , 3H), 3.4-3.5C2H), 3.67 (s, 2H), 5.48 (dd.1H), 6.98 (d, J = 8.5Hz.1H), 7.4-7.5 (2H), 7.80 (1 1H),

8.1-8.2C2H) .8.7-8.8C2H).

Example 1 2

6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2H-1-benzopyran isomer mixture 4 prepared according to the method described in JP-A-3-66681. From 3 g, 4-amino- in the same manner as in Example 10 2.7 g of a mixture of isomers of 6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2H-11-benzopyran was obtained. Dissolve 2.4 g of this isomer mixture in a mixed solvent of dioxane 2 Om 1-water 1 ml, add 2.3 g of dibutyl dicarbonate under ice-cooling and stir, and stir at room temperature for 1 hour. did. The reaction mixture is concentrated, and the resulting residue is separated and purified by silica gel column chromatography (ethyl acetate: hexane = 1: 5: 85-20: 80) to give 4-tert-butyloxycarbonylamino-6- 1,3-Dihydro-2-methoxymethyl-2-methyl-2H-1 low-polar isomer of 1-benzopyran (A isomer) 0.67 g and high-polar isomer (B isomer) 0.6 6 g were obtained.

This O isomer (62 Omg) was dissolved in dioxane (4 ml), and thereto was added 4N hydrochloric acid (dioxane solution) (5 ml), and the mixture was stirred at room temperature for 15 hours. The residue obtained by evaporating the solvent was dissolved in a 1 N aqueous hydrochloric acid solution, and washed with ethyl acetate. The product was extracted from the aqueous layer basified with 1N aqueous sodium hydroxide solution with ethyl acetate, dried and concentrated to give 4-amino-6-cyano 3,4-dihydro-2-methoxymethyl-12- Methyl-2H-1 monobenzopyran (A isomer) 42 Omg was obtained as crystals.

'Η

1.44 (s, 3H) .1.56 (br, 2H), 1.58 (dd, J = 11.2Hz,

13.5Hz, 1H), 2.39 (dd, J = 5.9Hz, 13.5Hz. 1H), 3.31 (d. J = 9.5Hz. 1H).

3.34 (s, 3H), 3.39Cd. J = 9.5Hz. 1H). 4.00 (dd, J = 5.9Hz. 11.2Hz, 1H).

6.84 (d. 1H), 7.41 (dd, 1H). 7.860H).

Similarly, 4-tert-butyroxycarbonylamino 6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-211-highly polar isomer of benzopyran (B isomer) 62 Omg to oil 41 Amino-6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2H-1 monobenzopyran (B isomer) 3 74 mg was obtained.

^J H NMR (CDCl ₃ / ppm) 5 1.30 (s, 3H). 1.64 (br, 2H), 1.84 (dd, J = 11.4 Hz,

13.3Hz, 1H), 2.07 (dd, J = 5.9Hz, 13.3Hz, 1H) .3.44 (s.3H), 3.43 (d.

J = 10.0Hz.1H), 3.50 (d, J = 10.0Hz, 1H), 4.05Cdd, J = 5.9Hz.11.4Hz, 1H), 6.86 (d, IH), 7.41 (dd.IH), 7.87 (1H).

Example 13

4-amino-6-cyano-3,4-dihydro-2-methoxymethyl-2-methyl-2H-1 monobenzopyran (A isomer) 320 mg and ethyl N-cyano 3-pyridinecarboximidate 3201113 The mixture was stirred at room temperature for 5 days. Ethyl acetate was added to the reaction solution, washed sequentially with 10% citrate, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The residue obtained by concentrating the solvent was subjected to silica gel column chromatography (ethyl acetate), and further crystallized from methanol to give N'-cyano-N- (6-cyano 3,4-dihydro-2-methoxymethyl-2-). Methyl-2H-1-1-benzopyran-14-yl-13-pyridincarboxamidine (A isomer) 154 mg was obtained.

Melting point: 20 5.3-20 6.7

^: H NMR (CDCl _s / ppm) d 1.48 (s.3H), 1.89 (dd.IH), 2.66 (dd.IH).

3.39 (s.3H), 3.44 (d, J = 9.9Hz, IH), 3.49 (1 J = 9.9Hz, IH), 5.55 (dd, IH).

6.74 (d, IH), 6.93 (d, IH) .7.4-7.6C3H), 8.11QH), 8.7-8.8 (2H).

Similarly, from 4-amino-6-cyano 3,4-dihydro-12-methoxymethyl-2-methyl-2H-1 monobenzopyran (B isomer) 2 95 mg and ethyl N-cyano 1-3-pyridinecarboxymidate 3 00111 '-Cyaneau N— (

6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2H-1-benzopyran-4-yl-13-pyridinecarboxamidine (B isomer) 246 mg was obtained.

^J H NMR (CDCl ₃ / ppm) 5 1.40 (s, 3H), 2.31 (m, 2H), 3.32 (s.3H), 3.52 (d.

J = 10.5Hz, IH), 3.58 (d, J = 10.5Hz, IH). 5.50 (dd.1H). 6.94 (d.IH).

7.4-7.5C2H), 7.74 (d.IH). 7.95 Cd, IH) .8.12C1H) .8.7_8.8 (2H).

Example 14

468 mg of 6-cyano 2,2-di (methoxymethyl)-1H-benzopyran obtained in Example 6 was treated with 0.05M phosphate buffer and 1M aqueous sodium hydroxide solution to pH = ll.5. 0.5 M sodium hypochlorite aqueous solution adjusted to In addition to 8 ml, it is described as Compound 5 in J. Am. Chem. Soc. Mil (III) —sa 1 en (1 ^, 10 complex 25.5 mg of methylene chloride 2 ml solution was added. After stirring for 17 hours under ice-cooling, extraction with methylene chloride (3 Times), and then dried and concentrated, and then subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4), which is the enantiomer of the compound described in Example 7 (3R, 4R) — 6-cyano 3,4-epoxy 1,3,4-Dihydro-1,2,2-di (methoxymethyl) -1,2H-1 benzopyran (89% ee) 398 mg was obtained Similarly, 45 lmg of 6-cyano 2,2-di By oxidizing (methoxymethyl) 1-2H-1 benzopyran using Mn (III) -salen (sa 1 en) (S, S) complex as a catalyst, (3 (3, 4 S) — 6-Cyanoh 3,4-epoxy-1,3,4-dihydro-2,2-di (methoxymethyl) -1,2H—1 benzopyran (94% ee) was obtained.

Example 15

6-cyano 3,4-epoxy-1,3,4-dihydro-2,2-di (methoxymethyl) -1,2H-1-benzopyran obtained in Example 14 (3R, 4R) -form 36 6 mg and (3 (S, 4 S) A total of 355 mg was subjected to the same reaction procedure as in Example 8 to give the enantiomer of the compound described in Example 8, 4-amino-6-cyano-1,3,4-dihydro-2,2-di (methoxymethyl). There were obtained 346 mg of (3R, 4S) -isomer and 278 mg of (3S, 4R) -isomer of 1-3-hydroxy-2H-1-benzopyran.

Example 16

(3 R, 4 S) — 4-Amino-6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) 1,3-hydroxy-2 Η—1 Benzopyran 32 Omg and methyl N-cyano 3-pyridine 0.3 ml of methanol was added to 28 mg of carboximidate, and the mixture was stirred at room temperature for 1 day. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (form: chloroform: 97: 3) to give N'-cyano N-[(3R, 4S) -6-cyano 3, 4-dihydro There were obtained 384 mg of 2,2-di (methoxymethyl) -13-hydroxy-2H-1-benzopyran-14-yl] -13-pyridinecarboxamidine.

[a] g ⁵ = + 1 31.7 ° (c = l. 0 1; methanol)

Similarly, (3S, 4R) — 4-amino-6-cyano 3,4 dihydro-2,

N-cyano N— [(3 S, 4R) from 278 mg of 2-di (methoxymethyl) 1-3-hydroxy-1 2H-1 benzopyran and 246 mg of methyl N-cyano-3-pyridinecarboxymidate — 6—Cyaneau 3, 4-dihydro-2,2-di

(Methoxymethyl) 1-3-Hydroxy-2H-1 Benzopyran 1-4yl] One

348 mg of 3-pyridinecarboxamidine was obtained.

ial g ⁵ =-1 39.6 ° (c = l. 0 1; methanol)

Example 17

Dissolve 7.0 g of 5-bromo-2-hydroxyacetophenone and 5.0 g of 1,3-dimethoxyacetone in 70 ml of toluene and add 2.7 ml of pyrrolidine to remove free water The mixture was heated under reflux for 1 hour. After cooling, the reaction mixture was diluted with ethyl acetate, washed successively with 1N hydrochloric acid, aqueous sodium bicarbonate and brine, dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 9). —Bromo-3,4-dihydro-2,2-di (methoxymethyl) -12H-1-1-benzopyran-14one 4.8 g was obtained.

NR NR (CDCl ₃ / ppin) 5 2.89 (s, 2H), 3.36 (s, 6H) .3.56 (s.4H), 6.89 (d,

J = 8.8Hz, 1H), 7.53Cdd. J = 2.6Hz. 8.8Hz, 1H), 7.94 (d. J = 2.6Hz. 1H).

Example 18

6-Promo 3,4-dihydro-2,2-di (methoxymethyl) -1-2H-1-1-benzopyran-4-one 5.05 g was dissolved in 50 ml of methanol, and 0.67 g under ice-cooling and stirring. Of sodium borohydride was added little by little and stirred for 1.5 hours. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the mixture was washed successively with 1 N hydrochloric acid, aqueous sodium bicarbonate, and brine, dried, and evaporated under reduced pressure to give an oily 6-promo 3,4-dihydro-2,2. There were obtained 5.35 g of 2-di (methoxymethyl) 1-2H-1-benzopyran-1-ol. ^J H NMR (CDCl ₃ ppm) 5 2.07 (dd, J = 5.Hz.14.4Hz, 1H). 2.28 (dd.J = 5.4Hz.

14.4Hz, 1H), 3.30 Cd, 1H). 3.36 (s, 3H). 3.39 (s, 3H). 3.42 (d.J = 10.0Hz.

1H). 3.48 (d, J = 10. OHz.1H) .3.58 (d.J = 10.4Hz, 1H), 3.62 (d, J = 10.4Hz.

1H), 4.74Ct. J = 5.4Hz, 1H), 6.76 (d, 1H). 7.25 (dd, 1H). 7.51 (d, 1H).

Example 19

6.05 g of 6-bromo-3,4-dihydro-2,2-di (methoxymethyl) -1-2H-1-1-benzopyran-1-ol and 0.55 g of p-toluenesulfonic acid were added to 5 Om 1 of benzene. The mixture was heated under reflux for 1.5 hours while removing free water. After cooling, the reaction mixture was concentrated, ethyl acetate was added to the residue, and the mixture was washed with aqueous sodium bicarbonate and brine in that order. After drying, the solvent was distilled off under reduced pressure to give oily 6-promo 2,2-di (methoxymethyl) 1-2H 1—Benzopyran 4.4 g was obtained.

^{_{3 H NMR (CDCl 3 / ppm}} ) d 3.39 (s, 6H), 3.53 (d, J = 10.2Hz. 1H), 3.60 (d,

J = 10.2Hz, 1H), 5.70 (d, J = 10.0Hz, 1H), 6.44 (d, J = 10.OHz.1H),

6.72 (d.1H). 7.09 (d, 1H). 7.19 (dd.1H), 7.27 (d, 1H).

Example 20

Dissolve 3.45 g of 6-bromo-2,2-di (methoxymethyl) -12H-1 benzopyran in a mixed solvent of 10 ml of dimethyl sulfoxide and 0.6 ml of water, and add N-promosuccinimide under ice-cooling. .43 g were added. After stirring at room temperature for 1.5 hours, the reaction solution was poured into ice water, extracted with ethyl acetate, and dried and concentrated to obtain 4.9 g of an oil. This oil was dissolved in 25 ml of dioxane, 2 ml of a 2N aqueous solution of caustic soda was added, and the mixture was stirred at room temperature. After 19 hours, 2 ml of aqueous sodium hydroxide solution was added, and the mixture was further stirred for 8 hours, and then the solvent was distilled off. Ethyl acetate was added to the residue, and the mixture was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure to give an oily 6-butyl α-mo 3,4-epoxy-3,4-dihydro-1,2,2-di (methoxymethyl 3.4 g of 1 2Η— 1-benzopyran was obtained.

^{_{J H NMR (CDCl 3 / ppm}} ) 5 3.29 (s. 3H). 3.48 (s, 3H), 3.5-3.9 (6H). 6.74 (d. 1H), 7.33 (dd, 1H), 7.46 (d. 1H ).

Example 2 1 Dissolve 2.4 g of 6-bromo-1,4-epoxy-1,4-dihydro-2,2-di (methoxymethyl) —2H-1-benzopyran in 25 ml of ethanol and 28% ammonia under ice-cooling An aqueous solution (25 ml) was added, and the mixture was stirred at room temperature. After stirring for 3 days, the mixture was concentrated, and the residue was purified by silica gel chromatography (chloroform: methanol = 98: 2) to give trans-41-amino-6-butane D-mo 3,4-dihydro-2,2 as crystals. 2.23 g of —di (methoxymethyl) -13-hydroxy-1 2H-1-benzopyran were obtained.

NMR (CDCl ₃ / ppn05 3.34 (s, 3H), 3.49 (s, 3H) .3.6-3.9 (6Η), 6.74 (d, 1H), 7.24 (ddd, 1H), 7.68 (dd, 1H).

Example 22

Trans-4-amino-6-bromo-3,4-dihydro-2,2-di (methoxymethyl) -1-hydroxy-2H-1 benzopyran 304 mg and methyl N-cyano 3-pyridinecarboxymidate 23 Omg Following the same reaction procedure as in Example 3, N- [trans-6-bromo-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H-1-1-benzopyran-14-yl] -1 27 Omg of N'-Icyan-3-pyridinecarboxamidine was obtained.

Melting point: 1 68.4-1 69.2'C

^] HNR (CDCl ₃ / ppm) 5 3.36 (s.3H), 3.39 (s, 3H), 3.6-3.8 (3H). 3.85 (d, 1H).

4.01 (d, 1H), 4.22 (t, 1H), 5.53 (t.1H). 6.78 (d, 1H), 7.3-7.5C4H),

8.140H), 8.70 (dd, 1H), 8.80 (d, 1H).

Example 23

Dissolve 5.5 g of 2-hydroxy-5-nitroacetophenone and 6.0 g of 1,3-dimethoxyacetone in 63 ml of benzene, add 2.8 ml of pyrrolidine and release water. The mixture was heated under reflux for 3 hours while removing the solvent. After cooling, the reaction solution was washed with 2N hydrochloric acid, and the water bath was extracted with ethyl acetate. The mixed organic layer was washed with brine, dried and concentrated, and then purified by silica gel column chromatography (ethyl acetate: hexane = 1: 2) to give 3,4-dihydro-2,2-di (methoxymethyl) 16. — Nitro-2H-1-1 Benzopyran-1 4-one 4.4 g was obtained. ^J HNR (CDCl ₃ / ppm) <5 2.97 (s, 2H). 3.35 (s, 6H), 3.56 (d.J = 10.3Hz.2H), 3.62 (d.J = 10.3Hz.2H), 7.09 ( d, J = 9.0Hz.1H) .8.03 (dd.J = 2.8Hz, 9.0Hz.1H), 8.72 (d, J = 2.8Hz.1H).

Example 24

3,4-dihydro-1,2,2-di (methoxymethyl) -1-6-nitro-2H-11-benzopyran-4-one 5. Dissolve Og in 50 ml of methanol and add 0.0 g of sodium borohydride was added in small portions. After stirring overnight, the solvent was distilled off, diluted hydrochloric acid was added to the residue, and the mixture was extracted with ethyl acetate. After drying and concentration, it was purified by silica gel column chromatography (form: methanol = 98: 2) and the oily 3,4-dihydro-2,2-di (methoxymethyl) 16-two-trough 2H-1 —5.0 g of benzopyran-1-ol were obtained.

_{JH NM (CDC1 3 / PPDI)} <5 2.15 (dd, J = 5.5Hz, 14.5Hz. 1H). 2.37 (dd, J = 5.5Hz, 14.5Hz. 1H). 3.36 (s, 3H), 3.40 (s 3H), 3.45-3.7 (m, 4H), 4.83 (m, 1H), 6.94 (d.J = 9.0Hz, 1H), 8.06 (dd, J = 2.9Hz.9.0Hz.1H), 8.35 (d (J = 2.9Hz, 1H). Example 25

3,4-Dihydro-2,2-di (methoxymethyl) -16-twotrough 2H-1-benzopyran-4-iol 5.0 g and p-toluenesulfonic acid 26 Omg were added to 70 ml of benzene and released The mixture was heated under reflux for 8 hours while removing water. After cooling, the reaction solution was washed with aqueous sodium bicarbonate, and the water tank was extracted with ethyl acetate. The mixed organic layer was washed with brine, dried and concentrated, and then purified by silica gel column chromatography (black-mouthed form) to give yellow crystalline 2,2-di (methoxymethyl) -16-nitro-12H- 4.4 g of 1 Benzopyran were obtained.

^J H NMR (CDCl ₃ / ppm) 5 3.39 (s, 6H), 3.56dd.J = 10.2Hz, 2H), 3.61 (d,

J-10.2HZ, 2H), 5.81 (d, J = 10.lHz, 1H) .6.55 (d.J = 10.lHz, 1H). 6.88 (d, J = 8.9Hz.1H), 7.88 (d. J = 2.7Hz, 1H), 8.02Cdd, J = 2.7Hz, 8.9Hz, 1H).

Example 26

Mn (III) -salen (sa 1 en) (S, S) complex described in Example 14 with 4.1 g of 2,2-di (methoxymethyl) -1-6-nitro-2H-1-benzobenzopyran The same reaction procedure was performed using 25 Omg as a catalyst. 2.62 (33,4S) -3,4-epoxy-1,3,4-dihydro-2,2-di (methoxymethyl) -16-nitro -2H-1-benzopyran (96% ee) was obtained.

^J H NMR (CDCl ₃ / ppm) (5 3.26 (s, 3H). 3.48 (s, 3H) .3.58 (d, J = 10.3Hz, 1H), 3.71 (s, 2H), 3.74 Cd.J = 10.3 Hz.1H) .3.84 (d, J = 4.4Hz.1H) .4.01 (d,

J = 4.4 Hz.1H), 6.92Cd, J = 9.0Hz, 1H), 8.13 (dd.J = 2.7Hz, 9.0Hz.1H), 8.29 (d, J = 2.7Hz.1H).

Example 27

(3S, 4S) -3,4-epoxy-1,3,4-dihydro-2,2-di (methoxymethyl) -1-6-nitro-1H-benzopyran 3.1 g ethanol 6 Om 1 Then, 6 Oml of a 28% aqueous ammonia solution was added thereto under ice cooling, followed by stirring at room temperature. After 16 hours, the reaction solution was concentrated, and the residue was purified by silica gel chromatography (chloroform: methanol = 97: 3) to give (3S, 4R) —4-amino-3,4-dihydro-2, 2.5 g of 2-di (methoxymethyl) -13-hydroxy-6-12throw 2H-1-benzopyran was obtained.

Ή NMR (CDCl ₃ / ppm) 5 3.33 (s.3H). 3.49 (s, 3H) .3.65-4.00 (6H), 6.92 (d, J = 9.0Hz, 1H) .8.04 (dd.J = 2.8Hz) 9.0Hz. 1H), 8.49 (d, J = 2.8Hz. 1H).

Example 28

(3 S, 4R) — 4-Amino-3,4-dihydro-2,2-di (methoxymethyl) 1-3-hydroxy-6-two-row 2 H-1 Benzopyran 37 Omg and Methyl N-cyano 3-pyridine To 302 mg of carboxymidate was added 0.4 mL of methanol, and the mixture was stirred at room temperature for 1 day. The residue obtained by evaporating the solvent under reduced pressure was subjected to silica gel column chromatography (chloroform: methanol-98: 2) to give N'—cyano N — [(3S, 4R) —3,4-dihydro-2 There were obtained 399 mg of 2,2-di (methoxymethyl) -1-hydroxy-6-twotrough 2H-1-benzopyran-141-yl] -13-pyridinecarboxamidine.

[a] g ^s =-14.5 ° (c = 0.99: methanol)

Ή NMR (CDCl ₃ / ppm) 5 3.37 (s.3H), 3.38 (s, 3H), 3.7-3.9C4H), 4.32 (d, J = 8.5Hz IH), 5.60Ct, J = 8.5Hz, IH), 6.99 (d, J = 9.0Hz.IH). 7.45Cra.IH). 7.95-8.15Cra.4H), 8.62 (d, J = 4.5Hz, IH), 8.76 (s, IH).

Example 2 9

In the same manner as in Example 28, (3S, 4R) —4-amino-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-twotrough 2 H—1-benzopyran mg and methyl N-cyano 2-pyridinecarboxymidate 20711 from 1 ^ '-cyano N — [(3S, 4R) —3,4-dihydro-2,2-di (methoxymethyl) -1-hydroxy-6— Two-row 2H-1-1-benzopyran-4-yl]-1 -2-pyridinecarboxamidine 358 mg was obtained.

La] =-1 48.7. (C = l. 00; methanol)

JH NMR (CDCl ₃ / ppm) 5 3.42 (s, 3H), 3.45 (s, 3H) .3.7-3.9 (5H), 4.31 (dd, IH),

6.0 (br.IH) .7.02 (d.IH) .7.55 (m.IH). 7.98 (dt, IH), 8.1-8.2C2H).

8.6 (d, IH) .8.7-8.9C2H).

Example 30

In the same manner as in Example 28, (3S, 4R)-4-amino-3,4-dihydro-2,2-di (methoxymethyl) -l-hydroxy-l-6-trow 2H-l-benzopyran 30 1 mg And ethyl N-cyanoacetimidate 152 mg from N'-cyano N — [(3S, 4R) -3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-nitro-1H— [1 Benzopyran-1 4 1]] acetamidine 233 mg was obtained.

[a] g = -2 19.2 ° (c = l. 0 1; methanol)

Ή NR (CDCl ₃ / ppm) <5 2.47 (s, 3H), 3.35 (s.3H) .3.44 (s, 3H), 3.6-3.9 (4H),

3.94 (d, J = 6.4Hz.IH), 4.18Cdd, IH), 5.45 (t, IH), 6.96 (d.IH),

7.16 (d, IH) .8.0-8.K2H).

Example 3 1

In the same manner as in Example 28, (3S, 4R) —4-amino-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-twotrough 2 H—1-benzopyran 31 Omg And etil N—cyano—3—fluo mouth benzimidate 255 mg to N '—Cyanore N- [(3 S, 4R) — 3,4-Dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-1 6-nitro-2H—1 Benzopyran-1

4-yl] 1-3-Fluorobenzamidine 284 mg was obtained.

[α] ⁵ = — 1 49.0 ° (c = l. 0 0; methanol)

^J H NM (CDCl ₃ / ppm) d 3.33 (s, 3H), 3.39 (s, 3H), 3.6- 3.9 (4H), 4.12 (d,

J = 6.6Hz, 1H), 4.26 (dd, J = 6.6Hz, 8.3Hz, 1H) .5.59 (t, J-8.3Hz, 1H),

6.96 (d, IH), 7.17 (d.1H), 7.29 (m.IH), 7.38 (dt.1H) .7.5-7.6C2H).

8.07 (dd, IH), 8.15 (dd.IH).

Example 32

In the same manner as in Example 28, (3S, 4R) —4-amino-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-two-row 2 H—1-benzopyran 3 3 9 mg and methyl 278 mg of N-cyano 2-thiophene carboximide N'-cyano N — [(3S, 4R) -3,4-dihydro-1,2,2-di (methoxymethyl) There were obtained 308 mg of 3-hydroxy-6-nitro-1H-2-1-benzo [4-yl] -12-thiophencarboxamidine.

Melting point: 2 1 3.7-2 1 4.3. C

[α] ^Β =-162.0. (c = 0.5; methanol)

^{_{J H NMR (DMS0-d e}} / ppm) δ 3.19 (s, 3H), 3.33 (s. 3H), 3.45-3.80 (4H), 4.31 (1H), 5.460H). 6.16 (d. J = 5.8Hz , IH), 7.06 (d. J = 9.0Hz, 1H), 7.32 (1H).

7.90-8.15C4H), 9.38 (d.J = 8.4Hz, IH).

Example 33

In the same manner as in Example 16, (3S, 4R) -4-1-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H-1-1-benzopyran 3 1 Omg and ethyl N-cyanacetimidate 1 8201 from 1N-[(3S, 4R)-6-cyano 3,4-dihydro-2,2-di

(Methoxymethyl) -3-hydroxy-2H-1-benzopyran-14-yl] acetamidine was obtained in an amount of 263 mg.

[a] E ^s =-208.8. (C = l. 02; methanol) Ή NMR (DMS0-d ₆ / ppm) d 2.32 (s, 3H). 3.17 (s, 3H) .3.31 (s.3H), 3.48 (d, J = 10.8Hz, IH), 3.56 (dd, 2H ), 3.65 (d.J = 10.8Hz, IH) .4.05Cdd.J = 5.4Hz.lH) .5.12 (t, IH), 5.93 (d.J = 5.4Hz.IH), 6.98 (1 IH). 7.6-7.7 (m, 2H), 9.06 (d.IH).

Example 34

In the same manner as in Example 16, (3S, 4R) —4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-1 2H—1-benzopyran 33 Omg And methyl N-cyano 2-pyridinecarboximidate 2201118 1 ^ '-cyano-N-[(3S, 4R) -6-cyano 3,4-dihydro-2,2-di (methoxymethyl) 13 —Hydroxy-2H—1-benzopyran-14-yl] -12-pyridinecarboxamidine 383 mg was obtained.

[a] g ⁵ =-1 48.7 '(c = 1.01; methanol)

JH N R (DMS0-de / ppm) 5 3.20 (s, 3H) .3.31 (s.3H) .3.5_3.7 (m, 3H),

3.73 (d, IH), 4.29 (dd, J = 5.9Hz.IH), 5.44 (br, IH), 6.07 (d.J = 5.9Hz. IH),

7.01 (d, IH), 7.56 (s, IH), 7.6-7.7 (m, 2H), 8.1-8.2 (m, 2H), 8.77 (d, IH),

9.62 (d.IH).

Example 35

In the same manner as in Example 16, (3S, 4R) —4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydrochidi-2H—1-benzopyran 3 0 Omg and methyl N-cyano-41-pyridinecarboximidate 2 6 01112 to 1 ^ '-cyano N-[(3S, 4R) -6-cyano 3,4-dihydro-2,2-di (methoxymethyl ) 1-Hydroxy-2H-1 benzopyran-14yl] 414 mg of pyridinecarboxamidine was obtained.

[Hi] ⁵ =-1 38. 7. (C = 0.99; methanol)

JH NMR (DMS0-d _e / ppiD) 5 3.20 (s, 3H), 3.32 (s, 3H) .3.52 (d.J = 10.8Hz, IH),

3.60 (dd, J = 10.8Hz, 18.6Hz, 2H) .3.73 (d, J = 10.8Hz.IH), 4.19 (dd, J = 5.8Hz,

IH), 5.35 (t, IH) .6.22 (d, J = 5.8Hz, IH), 7.01 (d, IH). 7.64 (dd, IH),

7.7-7.800, 3H), 8.8-8.9 (m.2H), 9.59 (d.IH). Example 3 6

(3S, 4R) -4-amino-6-cyano-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxydi-2H-1-benzopyran 2 64 in the same manner as in Example 16 mg and ethyl N-cyanobenzenecarboximidate From 242 mg N '-cyano N- [(3 S, 4R)-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) 1-3 Hydroxy- 1 2 H— 1-benzopiran- 4-yl] benzene (252 mg) was obtained.

[a] g ⁵ = -144.0. (c = 1.03; methanol)

'Η N R (DMS0-ds / ppm) 5 3.20 (s.3H) .3.32 (s, 3H), 3.53 (d, J = 10.8Hz, IH).

3.61 (dd, J = 10.8Hz, 17.1Hz, 2H), 3.71 (d, J = 10.8Hz.IH), 4.23 (dd, J = 6.0Hz.

IH) .5.34 (t.IH), 6.16 (d.J = 6.OHz.IH), 7.00 (d, IH) .7.5-7.6 (m, 5H),

7.8-7.9 (m.2H), 9.35 (d, IH).

Example 3 7

Methyl N-cyano 2-thiophene carboximidate 37 Omg and (

3S, 4R) — 4-Amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -3-hydroxy-2H-1-benzopyran 48 Omg was reacted in the same manner as in Example 16. By treatment with N'-cyano N — [(3S, 4R) -6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) -1,3-hydroxy-2H—1 benzopyran-1 41 1) 2-thiophenecarboxamidine to obtain 210 mg.

[a] = ~ 1 46.4 ° (c = 0.50; methanol)

JH NMR (CDCl ₃ / ppm) d 3.39Cs, 6H), 3.65-3.80 (3H). 3.86 (d, J = 11.0Hz.IH),

4.05 (1H). 4.27C1H) .5.55C1H), 6.95 (d.J = 8.6Hz, 1H). 7.15-7.25 (ra.2H).

7.46 (d, J = 8.6Hz. IH), 7.55GH). 7.62C1H), 8.02 (1H).

Example 38

Etil N—Cyaneau 2-Fluorobenzimidate 77 Omg and (3 S,

4 R) — 4-Amino-6-cyno-1,3,4-dihydro-1,2-di (methoxymethyl) -1,3-hydroxy-1 2H—1 Benzopyran 48 Omg was applied as in Example 16 same By the same reaction procedure, N'-cyano-N-[(3S, 4R) -6-cyano3,4-dihydro-2,2-di (methoxymethyl) -13-hydroquinone-2H — 1-benzopyran-41-yl] 1-2-Fluorobenzamidine 18 Obtain 1 mg 0

[a] V =-1 21.0 ° (c = 0.50; methanol)

: HN RCCDCl ₃ / ppm) 5 3.29 (s, 3H), 3.37 (s, 3H), 3.55-3.80 (m.4H),

3,96 (d, J = 6.7Hz.1H), 4.16C1H), 5.59QH), 6.93 (d, J = 8.6Hz, 1H),

7.1-7.4 (m, 3H) .7.5 (dd.J = 1.8Hz.8.6Hz.1H), 7.5-7.7Cm.3H).

Example 3 9

Ethyl N-Cyanol 3-Fluorobenzimidate 41 Omg and (3S, 4R) — 4-Amino-6-Cyanor 3,4 dihydro-2,2-di (methoxymethyl) -13-Hydroxy-2 By subjecting 40 mg of H-1 benzopyran to the same reaction procedure as in Example 16, N′-cyano-N — [(3S, 4R) —6-cyano 3,4 dihydro-2,2 —Di (methoxymethyl) -13-hydroxy-2H-1-1-benzopyran-14yl] -13-fluorobenzamidine is obtained in an amount of 428 mg.

[a] V =-1 27.8 ° (c = l. 00; methanol)

JH NMR (CDCl ₃ / ppm) 5 3.31 (s.3H), 3.38 (s.3H), 3.63 (d, J = ll.lHz.1H),

3.69 (s.2H). 3.79 (d, J = ll.lHz.1H), 4.05 (1H), 4.22QH) .5.53C1H),

6.94 (d.J = 8.6Hz.1H), 7.18 (d, J = 8.6Hz.1H), 7.25-7.35 (m, 1H) 7.38 (d,

J = 8.6Hz, d), 7.4-7.6 (m, 4H).

Example 40

Methyl N-cyano 3-quinoline carboximidate 35 5 mg and (3S, 4R)-4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -3-hydroxy By subjecting 2H—1 benzopyran 35 Omg to the same reaction procedure as in Example 16, N′—cyano N — [(3S, 4R) -6-cyano 3,4-dihydro-2,2-di Toximethyl) 1-3-Hydroxy-12H-1 Benzopyran-14yl] — 3-Quinolinecarboxamidine 4 44 get mg.

[a] ^s = -87. 0 ° (c = l. 0 1; methanol)

^{_{J H NMR (CDCl 3 / ppm}} ) 5 3.31 (s, 3H), 3.36 (s, 3H), 3,6-3.9 (m, 4H), 4.34C1H).

4.59C1H), 5.58C1H), 6.90 (d.J = 8.6Hz, 1H), 7.38 (1H) .7.50-7.65 (ra.2H).

7.73 (1H), 7.79 (2H), 8.50 (1H), 8.97 (1H).

Example 4 1

Ethyl N-cyano 2-naphthylene carboximidate 3 85 mg and (3S, 4R) — 4-amino-6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) 13 —Hydroxy-2H—1 Benzopyran 30 Omg was subjected to the same reaction procedure as in Example 16 to give N′—cyano N — [(3S, 4R) -16-cyano-1,3,4-dihydro. 1,2,2-di (methoxymethyl) -1,3-hydroxy2H-1,1-benzopyran-4-yl] -12-naphthylene carboxamidine 326 mg was obtained.

[Na] § ⁵ = — 94.2 ^e (c = l. 00; methanol)

JH MR (CDCI ₃ / ppm) d 3.26 (s, 3H) .3.34 (s, 3H), 3.59 (d, J = ll.lHz, 1H), 3.67C2H), 3.75 (d, J = ll.lHz, 1H). 4.15-4.35 On, 2H), 5.58QH),

6.93 (d, J = 8.6Hz, lHz), 7.08 (d, J = 8.6Hz, 1H), 7.44 (d.J = 8.6Hz.1H),

7.50-7.65 Cm, 3H), 7.68 (d, J = 6.8Hz.1H) .7.8-7.9 (3H) .8.170H).

Example 42

In the same manner as in Example 16, (3S, 4R) —4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H—1-benzopyran 281 mg and diphenylcyanocarbonimidate 2 9 2111 £ to 1 ^ '-Cyanaw N — [(3S, 4R) —6-Cyanaw 3,4-dihydro-2,2-di

(Methoxymethyl) -3-hydroxy-2H-11-benzopyran-4-yl] -1-phenoxycarboxamidine 0.15 g was obtained.

[a] g ⁵ =-47.7. (C = 0.83; methanol)

_{JH NMRCDMS0-d 6 / ppm,} 353) d 3.19 (s. 3H), 3.36 (s, 3H), 3.54 (d. J = 11.0Hz,

1H) .3.62 (dd.J = 11.0Hz.17.1Hz.2H), 3.74 (d, J = 11.0Hz.1H), 4.2 (br.1H), 5.2 (br.1H), 5.8 (br, 1H) .6.96 (d.1H), 7.2-7.3 Cm.3H) .7.46Ct.2H) .7.58 (dd.1H), 7.7 (br.1H) .8.7 (br. 1H).

Example 4 3

(3 S, 4 R) — 4-Amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2 H—1 Benzopyran 25 3111 and Cyanone N ′ —phenylthiodiarea Dissolve 196 mg in dimethylformamide, add 192 mg of 11- (3-dimethylaminopropyl) -13-ethylcarposimid hydrochloride (WSC · HC1) and stir. After 3 hours, add 34 mg of N-cyano N'-phenylthiourea and 34 mg of WSC / HC.After 3 hours, add ethyl acetate, wash with hydrochloric acid, aqueous sodium bicarbonate and brine, dry over magnesium sulfate, and evaporate the solvent. The residue was purified by silica gel chromatography, and N "—cyano N — [(3S, 4R) —6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-2H—11 Benzopyran-1 4 '] 1 N'-Fenirguanidin 20 Om was obtained.

[a] g ^s =-43.1 ^β (c- 0.99; methanol)

Ή N RCDMS0-de / ppra) 5 3 ・ 17 (s, 3Η). 3.30 (s, 3H) .3.5-3.7 (m.4H).

4.17 (dd.1H), 5.07 (t.1H). 6.0 (br.1H), 6, 95 (d, 1H), 7.1-7.2 (m.1H).

7.3-7.4 (m.4H). 9.28 (s.1H).

Example 44

Dissolve 500 mg of trans-4-amino-6-cyano-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H-1 benzopyran obtained in Example 8 in 2 ml of ethanol. , added phenylene Ruisoshianeto 0. 22m l, after stirring 1 7.5 hour at 9 0 ^D C, add a phenylene Ruisoshianeto 0. l _m l, and stirred 0.5 hours at 9 0 ^e C . The solvent was distilled off, and the residue was roughly purified by silica gel column chromatography (chloroform: methanol = 96: 4) and crystallized from methanol to give N- [trans-6-cyano-3,4-] Dihydro-1,2,2-di (methoxymethyl) -1,3-hydroxy-2H-1-benzopyran-14yl] —N′-phenylperrea 35 9 mg was obtained. Melting point: 18.6.7-1.87.7 "C

Ή N (DMSO-de / ppm) J 3.19 (s, 3H) .3.23 (s, 3H), 3.5-3.7 (m.4H), 4.01 (dd, J = 5.7HZ.9.6Hz.1H), 4.84C1H ), 5.74 (d. J = 5.7Hz. 1H), 6.57Cd, J = 8.3Hz). 6.9-7.0 (m, 2H), 7.25 (2H), 7.47 (2H), 7.54-7.65 (m, 2H) 8.52Cs, 1H).

Example 4 5

(3S, 4R) -4-amino-6-cyano-3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-2H-1 in Benzene methylene chloride 1 Benzopyran 25 Omg in triethylamine 0 Add 13 ml and add dropwise 70 mg of cetyl chloride in methylene chloride under ice-cooling. Two hours later, the mixture was added to aqueous sodium hydrogen carbonate, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and the solvent was distilled off. The residue was purified by silica gel column chromatography to give (3S, 4R) -14-acetylamino- 6-Cyanol 3,4-dihydro-2,2-di (methoxymethyl) -12H-1-1-benzopyran-3-ol 208 mg was obtained.

i l § =-8 7.3. (C = l. 035; methanol)

] H NMRCDMSO-de / ppra) 5 1.95 (s, 3H). 3.17 (s.3H), 3.31 (s, 3H),

3.4-3.7 (m.4H), 3.98 (dd.J = 5.6Hz.1H), 4.91 (t, 1H), 5.73 (d, J = 5.6Hz.

1H), 6.95 (d, 1H), 7.43 (t, 1H), 7.59 (dd.1H), 8.19 (d, 1H).

Example 4 6

(3 S, 4 R) — 4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H-1 Benzopyran (306 mg) was dissolved in dichloromethane (4 ml). Add 0.4 ml of triethylamine and 236 mg of nicotinic acid chloride hydrochloride, and stir at room temperature for 3 days. Water is added to the reaction solution, and the mixture is extracted with chloroform and washed with brine. After drying and concentration with magnesium sulfate, the product was purified by silica gel gel chromatography (clo-form: methanol-98: 2) to give (3 S, 4R) — 6-cyano 3, 4-dihydro-2, 2-di (methoxymethyl) -1-hydroxy-4-1 (3-pyridinecarboxamide) -2H-1 benzopyran 24 Omg is obtained.

[alpha]-out ^{5 - 4 6. 0 ° (c} = 0. 50; methanol) ^J HNR (CDCl ₃ / ppm) (5 3.36 (s, 3H), 4.42 (s, 3H), 3.73 Cd.J-ll.OHz, 1H), 3.74 (s.2H), 3.88Cd, J = 11.0Hz 1H), 4.25 (d. J = 8.7Hz, 1H) .5.52C1H). 6.90 (d, J = 8.5Hz, 1H). 7.30 Cd. J = 8.5Hz, 1H). 7.35-7.50Cm, 2H) 7.59 (s, 1H), 8.17C1H), 8.71 OH), 9.02 (1H).

Example 4 7

In the same manner as in Example 45, (3S, 4R) —4-amino-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H—1-benzopyran 20 5 mg and benzoyl chloride 8 01112 to (33,4R) 1-4 benzenecarboxamide 6-cyano 3,4-dihydro-2,2-di (methoxymethyl) 1-2H-1 benzopyran-1 3-ol 202 mg were obtained.

[α] δ ⁵ = -5 1.0 ”(c = 1.04; methanol)

NMR (DMSO-de / ppm) 5 3.20 (s, 3H) .3.33 (s.SH), 3.5-3.7 (ra, 4H),

4.26 (dd, J = 5.8Hz.1H) .5.21 (t, 1H), 5.85 Cd.J = 5.8Hz.1H), 7.00 (d, 1H), 7.39 (s.1H), 7.5-7.7 (m. 4H), 7.97 (d.1H), 8.75 (d, 1H).

Example 4 8

In the same manner as in Example 45, (3S, 4R) -4-1-amino-6-cyanore 3,4 dihydro-1,2,2-di (methoxymethyl) -13-hydroxy-2H-1 1-benzopyran was obtained in an amount of 299 mg. Dissolve in 3 ml of dichloromethane, add 0.35 ml of triethylamine and 0.13 ml of thenoyl chloride and stir at room temperature for 3 hours. To the reaction mixture is added 0.1 N aqueous hydrochloric acid, extracted with dichloromethane, and washed with aqueous sodium bicarbonate and brine. After drying and concentrating with magnesium sulfate, purification by silica gel column chromatography (chloroform: methanol = 98: 2) yields (3S, 4R) -6-cyano 3,4-dihydro-2,2-diene. (Methoxymethyl) 1-hydroxy-41- (2-thiophenecarboxamide) 1-2H-1 Benzopyran 3389 mg was obtained.

[α] δ ⁵ = -5 9.4 ° (c = 0.50; methanol)

! H NM (CDCl ₃ / ppm) d 3.33 (s.3H). 3.42 (s, 3H), 3.70C2H), 3.83 (1H), 3.92 (1H), 4.20 (1H), 5.420H), 6.79 (d , J = 8.5Hz, 1H), 6.93 (d, J = 8.5Hz. IH), 7.07C1H), 7.41 (d, J = 8.5Hz, IH), 7.52 (d, J = 4, 7Hz. IH), 7.58 (2H).

Example 49

In the same manner as in Example 28, 675 mg of ethyl N-cyanobenzimidate and (3S, 4R) -4-1-amino-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6- N-Tro 2H— 1—Benzopyran 377 mg, N′-Shi-no N — [(3S, 4R) —3,4-dihydro-2,2-di (methoxymethyl) 1-3-Hydroxy 6—2-Trow 2 H—1 benzopyran—41 yl] Benzamidine 46 Omg is obtained.

[] § ⁵ = — 1 42. 9. (C = l. 005; methanol)

^ NMR (CDCl ₃ / ppm) d 3.26 (s, 3H), 3.38 (s, 3Η), 3.60-3.90 (m.4H), 3.95C1H), 4.250H), 5.62C1H), 6.79 (d, J = 8.6Hz, IH). 6.98 (1 J = 9.2Hz, IH),

7.45-7.65 (m, 2H), 7.71 (d, J = 8.6Hz, IH), 8.08 (IH), 8.19C IH).

Example 50

(3 S, 4R) — 4-Amino-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-nitro-12H-1 1 Benzopyran (299 mg) was dissolved in dichloromethane (3 ml). Add 0.3 ml of triethylamine and 20 Omg of nicotinic acid chloride hydrochloride, and stir at room temperature for 3.5 days. Add water to the reaction mixture, extract with chloroform, and wash with brine. After drying and concentrating with magnesium sulfate, silica gel column chromatography (form: methanol = 98.

: Purified in 2), (3S, 4R) — 3,4 dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-6-nitro-1,41 (3-pyridinecarboxamide) 1-2H—1 —Get 305 mg of Benzopyran.

[a] g ⁵ = — 36.2 ^e (c = l. 005; methanol)

! HNR (CDCl ₃ / ppm) 5 3.37 (s, 3H), 3.43Cs.3H), 3.70-3.85 (m, 2H).

3.88 (d, J = 11.0Hz, IH), 4.27 (d, J = 8.6Hz, IH) .5.57C1H), 6.98 (d, J = 9.0Hz,

IH), 7.23 (d.J = 8.6Hz, IH) .7.0 (1H), 8.04 (1H), 8.15-8.19Cm, IH),

8.72C1H), 9.03 (s.IH). Example 5 1

4-Amino-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-1-6-nitro-2H-1-1-benzopyran 334 mg and methyl 2-pyridinecarboxylate 27 Omg in methanol 0 Dissolve in 6 ml, stir at room temperature for 14.5 hours, and then stir at 60 ° C for 23.5 hours. Furthermore, 273 mg of methyl 2-pyridinecarboxylate and 1.2 ml of methanol were added, and the mixture was stirred at 60 "C for 3 days, 8 (9 hours at TC, and then 19 hours at reflux). The solvent was distilled off and the silica gel column was removed. Purify by chromatography (form: methanol = 98: 2) and (3S, 4R) —3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-6-nitro-1 (2-Pyridinecarboxamide) 1 2H-1 1 Benzopyran 179 mg is obtained.

ί ΐ ^ζ =-25.94. (C = 0.505; methanol)

_{»H NMR (CDC1 3 / PPID} ) (5 3.38 (s, 3H), 3.48 (s. 3H). 3.70-3.95 (m. 4H),

4.24QH) .5.57C1H) .7.01 (d, J = 9.0Hz.IH). 8.09 (1H), 8.19C1H), 8.22 (1H) .8.54GH) .8.8K1H). 9.49C1H).

Example 5 2

In the same manner as in Example 4-17, 5-cyano-2-hydroxyacetophenone and phenoxy-12-propanone were converted to 6-cyano 3,4-dihydro-1,4-epoxy 2-methyl-2-phenoxime. A mixture of isomers of Chill 2 H-1 Benzopyran was obtained.

^! HN RCCDCh / ppm) ^ (1: 1 isomer) 1.47, 1.68 (each s, 3H), 3.8-4.3 (m, 4H), 6.63 (dd, IH), 6.8-7.0 (m, 3H), 7.2- 7.4 (m.2H), 7.5-7.6 (in, IH), 7.68 (dd, IH) Example 53

In the same manner as in Example 8, 6-cyano 3,4-dihydro-3,4-epoxy-2-methyl-2-phenoxymethyl-2H-1 isomer mixture of benzopyran-1.65 g to t-14-amino-6 1.8 g of an isomer mixture of -cyano-1,4-dihydro-1-r-3-hydroxy-2-methyl-2-phenoxymethyl-2H-1-benzopyran was obtained. ^J H NMR (CDCl ₃ / ppm) <5 (1: 1 isomer) 1.22, 1.52 (each s.3H), 2.3 (br), 3.45, 3.85 (each d.J = 9.3Hz, IH), 3.72 (dd 2H), 4.0-4.Km, IH). 4.l-4.2Cm, IH), 5.7 (br) .6.7-7.0 (m.4H). 7.l-7.3 (m.2H), 7.5- 7.6 (m.IH), 8.01 (d.IH).

In the same manner as in Example 2, methyl l-cyano 3-pyridinecarboxymidate 64 lmg and t-14-amino-6-cyano-1,3,4-dihydro-1r-13-hydroxy-12-methyl-2-phenoxy From 660 mg of a mixture of isomers of cimethyl-2H- 1-benzopyran N'-cyano N- (6-cyano 3,4-dihydro-r-3-hydroxy-12-methyl-2-phenoxymethyl-12H-1-benzopyran-t 341 mg) Low-polar A isomer of 346 mg of 1,3-pyridinecarboxamidine and 253 mg of high-polar B isomer were obtained.

A isomer

Melting point: 1 35. 1-14 1.5

^! H NMR (DMS0-d _e / ppra) δ 1.33 (s.3H), 4.12 (d, IH), 4.2-4.4 (m, 2H),

5.35Ct, IH). 6.24 (d, IH), 6.9-7.Km, 4H), 7.31 (t.2H), 7.6-7.7 (m, 2H), 7.87 (s, 1H). 8.25 (d.IH) ), 8.80Cdd. IH), 8.99Cd, IH). 9.68 (1 IH).

B isomer

Melting point: 1 75.4-177.5 "C

Ή NMR (DMS0-d ₆ / ppra) ά 1.54 (s.3H), 3.97 (dd, J = 5.8, 8.5Hz, IH), 4.13 (d, J = llHz, IH), 4.34 (d.J = llHz , IH) .5.53 (t, J = 8.5Hz, 1H), 6.36 (d, J = 5.8Hz, IH), 6.81 (d, 2H), 6.9-7.0 (m, 2H), 7.24 (t.2H) 7.6-7.7 (m, 2H), 7.88 (s, IH), 8.23 (d, IH), 8.80 (dd, IH), 8.96 (d, IH), 9.61 (d, IH).

Example 55

In the same manner as in Examples 4, 5, and 6, 13.3 g of 5-cyano 2-hydroxyacetophenone and 19.9 g of 1,3-di (tert-butoxy) -1-propanone were added to 1-g of 6-cyano. 5.2 g of 2,2-di (tert-butoxymethyl) -1-2H-1-benzopyran was obtained.

^: H NMR (CDCl ₃ / ppm) 5 1.14 (s, 18H) .3.6 (d, J = 9.3Hz.2H), 3.57 (d, J = 9.3Hz, 2H), 5.84 (d, J = 10.1Hz, 1H). 6.42 (d, J = 10.1Hz.1H), 6.81 (d.1H),

7.22 (d, 1H), 7.36 (dd, 1H).

Example 5 6

Dissolve 4.8 g of 6-cyano-1,2-di (tert-butoxymethyl) -1H-one-benzopyran with methylene chloride, add trifluoroacetic acid 2 Om 1 under ice cooling, and distill off after 5 hours. . The residue is added to aqueous sodium bicarbonate, extracted with ethyl acetate, washed with brine, dried over magnesium sulfate, and then the solvent is distilled off to give 6-cyano 2,2-di (hydroxymethyl) -12H-1-1-benzopyran. 2.7 g were obtained.

JH NMR (DMSO- _ds / ppm) d 3.4-3.6 (m, 4H) .4.99 (t, J = 5.9Hz, 2H), 5.79 (d, J = 10.1Hz, 1H), 6.57 (d, J = 10.1Hz.1H). 6.65 (d.1H), 7.5-7.6 (ra, 2H) Example 57

To 1 g of 6-cyano 2,2-di (hydroxymethyl) -12H-11-benzopyran in methylene chloride, add 2 ml of diisopropylethylamine, and add 0.8 ml of chloromethyl methyl ether under ice cooling. Stir at room temperature. After 3 hours, add 1 ml of diisopropylethylamine and 0.4 ml of chloromethyl methyl ether, and stir at 40 degrees for 3 hours. The solvent is distilled off, the residue is added to 10% citric acid, extracted with ethyl acetate, and further washed with aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent is distilled off to obtain an oil. This oily substance is dissolved in benzene to form a boron trifluoride ether complex.

1. Add 4 ml and stir for 2 hours. The reaction solution is added to aqueous sodium bicarbonate solution, extracted with methylene chloride, and further washed with aqueous sodium bicarbonate solution and brine. After drying over magnesium sulfate, the solvent was distilled off, and the residue was washed with methanol to obtain 0.74 g of 6-cyano 2-spiro 5 '-(Γ, 3'-dioxacyclohexyl) -1-2H-1-benzobenzopyran. . ^! H NMR (CDCl ₃ / ppm) (5 3.83 (d, J = 11.8Hz, 2H). 4.02Cd, J = 11.8Hz, 2H),

4.85 (d.J = 6.2Hz, 1H). 4.98 (d.J = 6.2Hz, 1H). 5.76 (d.J = 10.0Hz. 1H).

6.52 (d.J = 10.0Hz.1H), 6.99 (d.1H), 7.29 (d.1H), 7.44 (dd.1H).

Example 58

In the same manner as in Example 7, 6-cyano 2-spiro-5 '-(Γ, 3'-dioxocyclohexyl) -1 2H-1 1-benzopyran 0.74 g to 6-cyano 3, 4-epoxy-1,3,4-dihydro-2-spiro-5 '-(1', 3'-dioxacyclohexyl) 1-2H-1-benzopyran 0.73 g was obtained.

JH N RCCDCl ₃ / ppm) d 3.71 (d, J = l 1.3Hz, IH). 3.86 (d.J = 11.3Hz. IH),

3.9-4.Km, 2H), 4.18 (d, IH). 4.29 (dd, IH). 4.77 (d.J = 6.2Hz. IH),

5.06 (d, J = 6.2Hz. IH), 6.93 (d, IH), 7.55 (dd, IH). 7.69 (d, IH).

Example 59

In the same manner as in Example 8, 6-cyano 3,4-epoxy-1,3,4-dihydro-2-spiro-5 '-(2,3'-dioxacyclohexyl) -12H-1 benzopyran Amino-6-cyano 3,4-dihydro-3-hydroxy-2-spiro-5 '-(1', 3, dioxacyclohexyl) -1H-1 benzopyran 59 Omg was obtained.

^{J H NMRCDMSO-de / ppm)} ά 2.05 (s, 2H). 3.32C1H), 3.60 (d, 1H), 3.8-4.0 (ra.

3H). 4.10 (d.1H). 4.64 (d.J = 6.lHz, IH). 4.95 (d.J = 6.1Hz, IH).

5.77 (d.IH), 7.02 (d.IH), 7.60 (dd, IH). 7.94Cd.IH).

Example 60

0.6 1 g of methyl N-cyano 3-pyridinecarboximidate and 4-amino-6-cyano 3,4-dihydro-3-hydroxy-12-spiro-5 '-(1', 3) were obtained in the same manner as in Example 3. '-Dioxacyclohexyl) 1 2H-1 1 Benzopyran 31 71 118 1 ^'-cyano N- [trans-6-cyano-1,3,4-dihydro-1-hydroxy-2H-1 -benzopyran-1 2-spiro-1 5 '— (1', 3'-Dioxacyclohexyl) -14-yl] -1-3-Pyridinecarboxamidine 15 Omg was obtained.

^J H NMRCDMSO-de / ppm) 5 3.9-4.Km, 5H), 4.69 (d, IH), 4.9-5.0 (m, 2H), 6.21 (d, IH), 7.12 (d, IH), 7.63 ( dd, IH), 7.71 (dd, IH), 7.99 (s.IH), 8.12 (d, IH), 8.78 (dd.IH). 8.88Cd, IH), 9.57 (d, IH),

Example 61

6-Cyan-1,2-di (hydroxymethyl) -1H-2 Benzopyran lg is dissolved in dimethylformamide, imidabul 793 mg is added, and the mixture is cooled under ice cooling. Add 1.52 g of t-butyldimethylsilyl chloride, stir at room temperature for 6 hours, and add the reaction solution to water. Extract with ethyl acetate, wash with water and brine, dry with magnesium sulfate, and evaporate the solvent to obtain 1.99 g of a solid. 1.88 g of the solid was treated in the same manner as in Example 7 to give 6-cyano 3,4-epoxy-1,2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-2H-1. 1.87 g of nzopyran were obtained.

^! H

-0.17 (s, 3H), -0.05Cs.3H), 0.12 (s, 6H), 0.68 (s, 9H) .0.93 (s, 9H), 3.8-4.Km, 6H), 6.82 (d, 1H ). 7.50 (dd. 1H). 7.62 (d, 1H).

6-cyanore 3,4-epoxy-1,2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-2H-1-benzopyran 1.76 g of 4-amino-amino acid was prepared in the same manner as in Example 8. 1.18 g of 6-cyano-2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-3-hydroxy-2H-11-benzopyran was obtained.

^{_{J H NMR (CDC1 3 / PPID}} ) 5 -0.07 (s. 3H), 0.00 (s, 3H), 0.10 (s. 3H), 0.13 (s, 3H).

0.79 (s, 9H), 0.91 (s.9H). 3.67 (d, 1H), 4.8-5.Km.5H), 6.81 (d.1H),

7.42 (dd.1H), 7.91 (d, 1H).

Example 6 3

4-Amino-6-cyano 2,2-di (tert-butyldimethylsilyloxymethyl) 1,3,4-dihydro-3-hydroxy-2H-1 Benzopyran 1 g and methyl N-cyano 3-pyridinecarboximidate 0.55 g of N'-cyano-N- [trans-6-cyano 2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-3-hydroxy] was prepared in the same manner as in Example 9. [2H-1 1-benzopyran-14-yl] -1 3-pyridinecarboxamidine 1 g was obtained.

Ή NMR (CDCl ₃ / ppm) (5 -0.04 (s, 3H), O.OKs, 3H), 0.07 (s, 3H), 0.08 (s, 3H), 0.77 (s, 9H), 0.82 (s, 9H) .3.84 (d, J = 10.9Hz.1H), 3.94 (dd, J = 11.3Hz, 20.8Hz, 2H) .4.06 (d.J = 10.9Hz.IH), 4.24 (dd.1H). 4.47 (br, 1H), 5.72 (t, IH). 6.90 (d, IH), 7.4-7.5 (m, 3H). 7.75 (d, IH), 8.13 (dt.IH), 8.69 (dd, IH), 8.80 (1 IH).

Example 64

N'-cyano N— [trans-6-cyano 2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-13-hydroxy-2H-1-1-benzopyran-14-yl] 1.1 g of 3-pyridinecarboxamidine is dissolved in tetrahydrofuran, and under water cooling, 4.3 ml of a 1M tetrabutylammonium fluoride tetrahydrofuran solution is added, followed by stirring at room temperature for 1 hour. Evaporate the solvent, add water to the residue, wash with ethyl acetate and concentrate the aqueous layer. The residue was purified by silica gel column chromatography followed by crystallization with ethanol to give N'-cyano N- [trans-6-cyano 3,4-dihydro-2,2-di (hydroxymethyl) -13-hydroxy- 2H—1 Benzopyran 1-4yl] -13-Pyrenecarboxamidine 51 2m was obtained.

Melting point: 208'C <decomposition

^J H NMR (DMS0-d ₆ / ppm) d 3.53 (dd, J = 5.2Hz, 11.6Ηζ, IH), 3.6-3.7Cm.2H), 3.81 (dd, J = 5.2Hz, 11.6Hz, IH) , 4.21 (dd, J = 5.8Hz, IH), 4.92 (t, J = 5.2Hz, IH), 4.97 (t, IH) .5.51 (t, IH). 5.96 (d.J = 5.8Hz, IH) 6.95 (d, IH).

7.6-7.7 (m, 2H), 7.71 (s.IH), 8.25 (1 IH), 8.79Cdd.IH), 8.99Cd.IH), 9.53 (d, IH).

Example 65

3.40 g of 5-cyano-2-hydroxyacetophenone was dissolved in 50 ml of benzene, and 1.8 ml of pyrrolidine and 15 ml of 1,3-diethoxy-2-propanone were added and refluxed for 1 hour. After cooling, the reaction solution was diluted with ethyl acetate, washed sequentially with dilute hydrochloric acid, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The solvent is distilled off, and the resulting residue is roughly purified by silica gel column chromatography (ethyl acetate: hexane == 1: 6) to give 6-cyano-1,3,4-dihydro-2,2-di (ethoxymethyl). 2.96 g of 1 2H— 1-benzopyran-1 4-one was obtained. It was used for the next reaction without further purification. ^J H NM (CDCl ₃ / ppm) 5 l.lKt, J = 7.0Hz, 6H), 2.96 (s.2H). 3.40-3.70 (m.8H), 7.05 (d.J = 8.6Hz, 1H). 7.66Cdd. J = 2. LHz, 8.6Hz. 1H). 8.13 (d, J = 2.1Hz, 1H).

Dissolve 3.7 g of 6-cyano-1,4-dihydro-2,2-di (ethoxymethyl) -12H-1-benzopyran-14-one in 37 ml of methanol and add sodium borohydride under ice-cooling and stirring. Omg was added in small portions. After stirring for 2.5 hours, the mixture was concentrated, water and ethyl acetate were added to the residue, and the mixture was washed with brine. After drying over magnesium sulfate, the solvent was distilled off, and the resulting residue was roughly purified by silica gel column chromatography (chloroform) to give 6-cyano 3,4-dihydro-2,2-di (ethoxymethyl) -12H — 1 Benzopiran 4-ol 2.92 g was obtained. It was used for the next reaction without further purification.

JH NMR (CDCl ₃ / ppm) 5 1.06Ct.J = 7.OHz.3H), 1.90 (t.J = 7.OHz.3H),

2.18GH). 2.35 (dd, J = 5.5Hz, 14.7Hz, 1H), 3.4-3.8 (m, 8H), 3.95 (1H),

4.73C1H). 6.90 (d. J = 8.6Hz. 1H), 7.43 (dd, J = 2. LHz. 8.6Hz, 1H),

7.71 (d, J = 2.1Hz, J = 1H).

Example 67

Dissolve 2.85 g of 6-cyano 3,4-dihydro-2,2-di (ethoxymethyl) -1-2H- 1-benzopyran-1-ol in 42 ml of benzene, add 184 mg of p-toluenesulfonic acid, and incubate The mixture was heated under reflux for 3.5 hours while distilling off water. Ethyl acetate was added to the reaction solution, washed with water, aqueous sodium bicarbonate and brine, and dried over magnesium sulfate. The residue obtained by distilling off the solvent is subjected to silica gel column chromatography.

(Ethyl acetate: hexane = 1: 4) to give 1.68 g of 6-cyano 2,2-di (ethoxymethyl) 1-2H-1-benzobenzopyran.

JH NMRCCDCl ₃ / ppm) d 1.15 (t, J = 7.OHz.6H), 3.4-3.7 (m.4H) .5.79 (d,

J = 10.OHz, 1H), 6.46 (d, J = 10.OHz, 1H), 6.85 (d.J = 8.4Hz.1H), 7.24 (d.

J = 2. OHz. 1H). 7.38 (dd, J = 2. OHz. 8.4Hz, 1H).

Example 6 8

6-cyano 2,2-di (ethoxymethyl) -2H-1 obtained in Example 6 7 1-Benzopyran (1.66) was adjusted to pH = 11.5 with 0.05 M phosphate buffer and 1 M aqueous sodium hydroxide solution, and added to 0.5 M sodium hypochlorite aqueous solution (45 ml). The solution of Mn (III) -salen (S, S) complex (355 mg) and methylene chloride (15m) described in Example 14 was added thereto under ice cooling. After stirring for 16.5 hours under ice-cooling, the mixture was extracted with methylene chloride, washed with brine, dried and concentrated over magnesium sulfate, and then subjected to silica gel column chromatography (ethyl acetate: hexane = 1: 4). , (3 S, 4 S) — 6—Cyanoh 3,4—Epoxy-1,3,4-dihydro-2,2-di (ethoxymethyl) -1 2H— 1—Benzopyran (96% ee) 1.2 1 g I got

^J H NMR (CDCl ₃ / ppm) (5 0.97 (t.J = 7.OHz, 3H), 1.24 (t, J = 7.OHz, 3H),

3.25-3.95 (m.10H), 6.88 (d, 8.5Hz, 1H) .7.53 (dd.J = 2.OHz, 8.5Hz, 1H). 7.63 (d, J = 2.OHz, 1H).

Example 6 9

(3 S, 4 S) — 6-cyanore 3,4-epoxy-1,3,4-dihydro-2,2-di (ethoxymethyl) 1-2 H—1-benzobenzopyran 1.12 g dissolved in ethanol 16 ml Then, add 16 ml of a 28% aqueous ammonia solution under ice-cooling, stir at room temperature for 2.5 days, concentrate, and evaporate the solvent to remove (3S, 4R) 14-minamino 6-. 1.24 g of 3,4-dihydro-1,2,2-di (methoxymethyl) -1,3-hydroxy-2H-1-benzopyran were obtained. It was used for the next reaction without further purification.

^J H NM (CDCl3 / ppm) 5 1.13 (t.J = 7.OHz, 1H) .1.23 (t, J = 7.OHz, 1H),

3.4-4.0 (m, 10H), 6.89 (d, J = 8.5Hz, 1H), 7.43 (dd, J = 1.5Hz, 8.5Hz, 1H), 7.94C1H).

Example 7 0

Methyl N-cyano-3-pyridinecarboximidate 295mg and (3S, 4R) -4-amino-6-cyano 3,4-dihydro-2,2-di (ethoxymethyl) -13-hydroxy-2H-1 Dissolve 42 lmg of Benzopyran in 0.5 ml of methanol and stir at room temperature for 23 hours. Solvent is distilled off and silica After purification by gel column chromatography (cloth form: methanol = 98: 2), crystallization from dichloromethane yields N'-cyano-N-[(3S, 4R) -16-cyano 3, 4-Dihydro-2,2-di (ethoxymethyl) -1,3-hydroxy2H-1,1-benzopyran-1,4-yl] -13-pyridinecarboxamidine 16 1 mg are obtained.

Melting point 72.3-86.9 'C

[α] | ⁵ =-1 52.6 ° (c = 0.50; methanol)

! H NMR (CDCl ₃ / ppm) 5 1.02 (t.J = 7.OHz.3H), 1.17 (t, J = 7.0Hz.3H),

3.4-3.9 (m.8H), 4.2-4.4 (m.2H), 5.5K1H). 6.96 (1 J = 8.6Hz, 1H).

7.40-7.52 (m, 2H) .7.57C1H). 7.77Cd.J = 8.6Hz, 1H) .8.12 (1H), 8.70QH),

8.80QH).

Example 7 1

In the same manner as in Example 70, ethyl ethyl N-cyanoacetimidate 118 mg and (3S, 4R) -4-amino-6-cyano 3,4-dihydro-2,2-di (ethoxymethyl) 13 —Hydroxy-2H—1 Benzopyran (40 Omg) is dissolved in ethanol (0.4 ml) and stirred at room temperature for 27 hours. Further, 118 mg of ethyl N-cyanoacetimidate is added, and the mixture is stirred at room temperature for 38.5 hours. The solvent was distilled off, the residue was subjected to silica gel column chromatography (cloth form: methanol = 98: 2), and further purified by silica gel column chromatography (ethyl acetate: hexane = 2: 1) again. , N'—Cyanor N — [(3S, 4R) -1-6-Canoh 3,4-dihydro-2,2-di (ethoxymethyl) -13-hydroxy 2H—1-Venzopyran-1 4-yl] 196 mg of acetamidine are obtained.

[α] § ⁵ =-20 9.6. (C = 0.50: methanol)

NR NR (CDCl ₃ / ppm) 5 1.15 (t, J = 7.OHz, 3H). 1.16 (t, J = 7.0Hz, 3H),

2.46 (s, 3H), 3.45-3.80 Cm.7H), 3.80-4.00 (m, 2H), 4.10-4.20 (m, 1H), 5.46QH), 6.93 (d, J = 8.5Hz, 1H), 6.98 (d, J = 8.3Hz, 1H), 7.45 (dd.J = 1.9Hz, 8.5Hz, 1H), 7.50 (1H). Example 72

N′-Cyanone N — [(3S, 4R) —6-Cyanoh-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H—1-benzopyran obtained in Example 16 1.41] 1-3-pyridinecarboxamidine (2.1 g) is dissolved in pyridine (4.7 ml), and formic acid-acetic anhydride (2; 1) is stirred at 50 ° C for 15 minutes. Add 4.7 ml of the acetate formic acid reagent under ice cooling, stir for 1.5 hours, then add 4.7 ml of the acetate formic acid reagent and stir for 50 minutes. The reaction solution is added to ice water, extracted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate and brine. After drying and concentration with sodium sulfate, recrystallization from ethyl acetate gave N'-cyano N-[(3S, 4R) -6-cyano-1,3,4-dihydro-2,2-di (methoxymethyl) 13- Formyloxy-2H-1-1-benzopyran-14-yl] -13-pyridinecarboxamidine 73 lmg is obtained.

[a] g ⁵ = -52.0 ^β (c = 0.50; methanol)

Ή NMRCDMSO-de / ppm) δ 3,23 (s, 3H), 3.27 (s, 3H), 3.45-3.70 (m, 3H),

3.79 (d, 1H) .5.50-5.75 (m.2H), 7.07 (d.J = 8.6Hz.1H), 7.6-7.75 (m, 2H),

7.92GH), 8.10 (d.J = 8.0Hz, 1H), 8.43 (s.1H), 8.75-8.85 (m, 2H),

9.74 (d, J = 8.0Hz, 1H).

The structural formulas of the compounds of the examples are shown in Tables 1 to 8 below.

Table 2

Table 3

O

Table 4

Table 5

Table 6

Table 7

Table 8

ϋΐ

The present invention is not limited only to the compounds shown in the examples, but includes the following compounds, for example.

Example of structural formula

Compound R ¹ R ² R ³ R ⁵ R ⁷

28 CN CH ₂ OCH ₃ CH ₂ OCHj OCHO

29 N0 ₂

30 'Br *,

31 CN ', OCOCH3',

32 N0 ₂ *, ',

33 Br ''

34 CN ', H CHi

35 N0 ₂ '

36 Br,

37 CN · »R 'and R ^s mixed H

38 N0 ₂ ·,

39 Br · '*,',

40 CN *, 'CH ₃

41 N0 _2, ♦ *,

42 Br · '· ，

43 CN CzH ₄ OCH _s C2H4OCH3 HHH

44 N0 ₂

45 Br

46 N0 ₂ ··· OH

47 Br ···

48 CN OCHO,

49 N0 ₂

50 Br, ··· ', ·,,

51 CN OCOCH ₃ *

52 NO, "'·' ·

53 Br '·',

54 CN H CH ₃

55 N0 ₂ '

Example formula

■ p i it Γν

56 Br *, *

57 CN, / R <and R ^s for H

58 N0 ₂ '//''

59 Br

60 CN '/ CH ₃

61 0 ₂ ❖ *,

62 Br '

63 CN COOCH ₃ COOCH ₃ HHH

64 N0 ₂

65 Br

66 CN ·, OH

67 N0 ₂ ', *,

68 Br · '

69 CN

70 N0 ₂ ·, ,,

71 Br ···,

72 CNOCOCH3

73 N0 ₂ ', ... //',

74 Br "

/ 0 CN H ·, CH ₃

76 N0 ₂

77 Br '·' /

78 CN 'Single bond at R <and R ⁵ H

79 N0 ₂

80 Br //

81 CN ** CH ₃

82 N0 ₂

S3 Br

Table 13

Example structural formula

^^ R ³ R ⁷

111 N0 ₂ CH2D H3 CH2OCH3

112 Br

113 CN OCOCH ₃

114 N0 ₂

115 Br,

116 CN », 'H' / CH ₃

117 N0 ₂ '/

118 Br '/

Mixed with 119 CN and R ⁵ H

120 N0 ₂ ',

121 Br *

122 CN ·, '/ CH ₃

123 N0 ₂ '/' / //

124 B ·, ·, ** '/ * »

125 CN C2H4OCH3 then Us H H H

126 N0 ₂

127 Br ,,

128 CN, '·, OH'

129 N0 ₂

130 Br * _f *

131 CN 'OCHO /

132 N0 ₂ »

133 Br ', /'

134 CN ···· OCOCH ₃ », ···

135 N0 ₂ · * »* ,,»

136 Br · '

137 CN ·, H CH ₃

138 N0 ₂

Structural formula of embodiment ^) R ² R ³ R ⁴ R ⁵ R ⁷

139 Br *, //

140 CN * R <and R ^s ^^ H

141 N0 ₂

142 Br

143 CN '/ CH ₃

144 N0 ₂ //

145 Br /,

146 CN COOCH ₃ COOCH3 Π Π H

147 N0 ₂

148 Br

149 CN // OH '/

150 N0 ₂ **

151 Br ** '

152 CN OCHO

153 N0 ₂ ·,, '', *,

154 Br · · · · *

155 CN OCOCH ₃

156 N0 ₂ * · ,, *,

157 Br ',

156 CN ·, H ', CH ₃

159 NO ',

.160 Br *, ·, ', *, ·,

161 CN '/ R * and R ^s single H

162 N0 ₂ '

163 Br '

164 CN '/' CH ₃

165 O: ·, *,, ·

166 Br * Structural formula of embodiment ^! R ¹ R ³ RR ⁷

1 3 1 3

/, * /, /,

NO2 OH

170 Br

171 CN OCHO ',

172 O2 /

17ο Br

, CN OCOCH3 '/ ·,

1 (ο NO2 *, ·,

Br

丄 / / CN H CH3

Ten ·,

丄 Br ·,

Single combination of n an ,, _{R <} and _RS

181 N0 ₂ ,,

182 Br *

183 CN 'CH ₃

184 N0 ₂ ,, *,

185 Br ·,

186 N0 ₂ CH20CH3 CH20CH3 HH Η

187 Br

188 Br * OH ',

189 CN ·, ·, OCHO *,

190 N0 ₂ ·, '/', ',

191 Br ,, ','

Example structural formula

^^ R ¹ R ² R ³ R ⁴ R ⁵ R ⁷

192 CN CH2OCK3 CH ₂ OCH ₃ OCOCH3 *

193 N0 ₂ ', ·, · * ♦,

194 'Br ·,,' *,

195 CN H CH ₃

196 N0 ₂ ``

197 Br,

198 CN H H H

199 NO? *, /

200 Br

201雜合CH ₃ CN, and R ^s

202 NO; '

203 Br '/', * / '

204 CN CzHiOCH, C ₂ H «OCH ₃ HHH

205 N0 ₂

206 Bi- '

207 CN OH '

208 N0 ₂

209 Br ·······, ',

210 CN ·, OCHO * '*,

211 N0 ₂ '

212 Br ,,, '

213 CN OCOCH3

214 NO; '/ ,,'

215 Br ·, '/

216 CN ·, H * »CHi

217 N0 ₃ ·,, '

Example structural formula

R! R ¹ R ² R ³ R ⁷

218 Br

219 CN ·, single bond in R ⁵ and R 'H

220 N0 ₂

221 Br '/ /,

222 CN ,, CH ₃

223 N0 ₂ '···', ,,

224 • Br

225 CN COOCH ₃ COOCH3 n H

226 N0 ₂ ,

227 Br '

228 CN * OH

229 N0 ₂ ',

230 Br

231 CN ·, OCHO

232 N0 ₂

233 Br

234 CN, OCOCH ₃

235 N0 ₂ ···, ·, '/

236 Br

237 CN *, H CH ₃

23B NO;

239 Br

240 CN, 'hybrid with R <and Rs Η

241 N0 ₂ '/

242 Br ',', ·· »

243 j CN, CH ₃

244 N0 ₂

245 Br, The pharmacological evaluation results of this compound are shown below.

Effects on coronary blood flow

Adult male and female hybrid dogs (9.5 to 15 kg) were anesthetized intravenously with pentobarbitil sodium (25 mg / kg), tracheal force was introduced, and a respirator (Shinano Seisakusho, SN-408-4) Artificial respiration (20 ml / kg body weight, 18 times Z minutes). Pentobarbital sodium (5 mg / kg / hour) was continuously infused from a catheter inserted into the right femoral vein to maintain anesthesia. The blood pressure was measured from a Kiefer catheter (17-867-1, Siemens' Elema, Sweden) inserted into the abdominal artery from the right femoral artery into a pressure transducer (Nihon Kohden, TP-400T). The coronary blood flow is measured using an electromagnetic blood flow probe (Nihon Kohden, FJ-020T and FJ-025T) installed in the extracorporeal circuit leading from the femoral artery to the origin of the coronary artery when administering the drug into the artery. When administering the drug intravenously, open the chest between the left five ribs and use an electromagnetic blood flow probe (Nihon Kohden, FJ-020T and FJ-025T) attached to the left circumflex branch of the left coronary artery. Connected and measured. Each of these parameters was recorded on a hot pen reticule coder (Nihon Kohden, RJG-4128). The test drug solution was prepared by dissolving the sample in a mixture of N, N-dimethylformamide (30%) and physiological saline (70) and appropriately diluting with physiological saline. The test drug solution was prepared in the extracorporeal circulation circuit. The control compounds were remacarim (control compound a) and 2-methoxymethyl-2-methyl--(1,2-) disclosed in JP-A-3-66681. Dihydro-l-oxo-l-l-pyridyl) -l-6-cyano 3-chromanol (low-polar isomer) (control compound b) was used, and the dose was 10 for the compound of the present invention (Example 39). , 30, 100 zgZkg, remacarim (control compound a) at 0.3, 1, 3 g / kg, and control compound b at 10, 30, 100〃gZkg.

The results are shown in FIG.

According to the figure, when the coronary blood flow is to be increased by 100%, the compound of the present invention shows only about a 3% decrease in blood pressure, whereas the control compound a has twice the blood pressure. Above about 8% decrease in blood pressure was observed. In addition, when trying to increase coronary blood flow by 50%, this compound causes only about 2% decrease in blood pressure. On the other hand, control compound a showed a drop in blood pressure of more than twice that of 5%, and control compound b showed a drop of blood pressure of more than three times that of about 7%.

効果 Effect of the invention ''

As is clear from the above test results, the compound of the present invention and a pharmaceutically acceptable salt thereof have a selective and excellent effect of increasing coronary blood flow, but have a very weak effect of lowering blood pressure. Therefore, it is possible to selectively increase coronary blood flow without causing a rapid drop in blood pressure that causes tachycardia that adversely affects the heart, and this compound is a prophylactic or therapeutic agent for angina pectoris, heart failure, etc. Useful as

In addition, since it is expected to have a relaxing effect on smooth muscles other than coronary vascular smooth muscle, treatment of gastrointestinal tumors, irritable bowel group and diverticulum disease, reversible tracheal obstruction and asthma, premature birth, urinary incontinence, and cerebrovascular disease It is also expected to be useful as an agent.

Furthermore, if applied topically to the scalp, it is expected to be used as an agent for preventing or treating alopecia such as alopecia areata.

Claims

The scope of the claims

1. —general formula

Wherein R ¹ is a cyano group, a nitro group or a halogen atom;

R ³ is a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group or a tert-butyldimethylsilyloxyalkyl group, or R ² and R ³ together form one ( CHz), — 0— (CH ₂ ) _m — 0— (CH ₂ ) „-(where, 1 and n are each independently 0 or an integer of 1 to 2, and m is an integer of 1 to 2 To form a group represented by

R ⁴ is a hydrogen atom, a hydroxyl group, a formyloxy group or a low-handling alkanoyloxy group;

R ⁵ is a hydrogen atom, or R ⁴ and R ^s together represent a bond,

A is

R ^e is an aryl group optionally substituted with a lower alkyl group or a halogen atom, a heteroaryl group optionally substituted with a lower alkyl group or a halogen atom, and optionally substituted with a lower alkyl group or a halogen atom. An arylamino group, a lower alkyl group or an aryloxy group or a lower alkyl group which may be substituted with a halogen atom, X is N—CN, an oxygen atom or a zeo atom,

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

Or a pharmaceutically acceptable salt thereof.

2. R ² is a lower alkoxyalkyl group, a hydroquinalkyl group or a tert-butyldimethylsilyloxyalkyl group,

R ³ is a lower alkyl group, a lower alkoxyalkyl group, a hydroxyalkyl group or a tert-butyldimethylsilyloxyalkyl group, or R ² and R ³ together form one (〇Η ₂ ), -0- (CH ₂ ) »one 0— (CH ₂ ) n one (wherein, 1 and n are each independently 0 or an integer of 1-2, and m is an integer of 1-2) The chroman compound according to claim 1, which forms a group represented by the formula, or a pharmaceutically acceptable compound thereof 0

3. N'-cyano-N- (6-cyano 3,4-dihydro-t-l-hydroxyl-r-l-methoxymethyl-2-methyl- 2H-l-benzopyran-c-l-yl) 3-pyridine power lipoxamidine,

N, cyano N— (6-cyano 3,4-dihydro-c-13-hydroxyr-12-methoxymethyl-2-methyl-2H—1 benzopyran-1 t4-1yl) 14-fluorene benzomidine ,

N'-cyano N- [trans-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H-1-1benzopyran-1-4-yl] -13-pyridine-potassium lipoxamidine,

N '—Cyanaw N— [6-Cyannow 3,4-dihydro-2,2-di (methoxymethyl) 1-2H—1-benzopyran-14-yl] -13-pyridinecarboxamidine,

Ν'-cyano Ν— (6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2Η—1-benzopyran-1 4-yl) 1-3-pyridinecarboxamidine,

N'-cyano Ν— [(3R, 4S) — 6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-2 Η— 1-benzopyran

8 g L] 3-pyridine power lipoxamidine,

N- [trans-6-bromo-3,4-dihydro-1,2,2-di (methoxymethyl) -13-hydroquin-1H-1 benzobenzopyran-14-yl] N'-cyano 3-pyridine Carboxamidine,

N'-Cyano-N-[(3S.4R) -3,4-Dihydro-1,2,2-di (methoxymethyl) -1,3-hydroxy-6-two-trough 2H-1-Venzopyran-1,4-yl ] 1-Pyridinecarboxamidine,

N '—Cyanaw N— [(3 S, 4 R) -3,4 dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-1-6-nitro-2 H—1-benzopyran 1-4 L] 2-pyridinecarboxamidine,

N "-cyano N-[(3S, 4R) -3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-6-nitro-2H-1-1-benzopyran-1-4-inole] Seyuu Midine,

Ν'-cyano Ν— [(3 S, 4R) — 3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-6-nitro-1 2 Η-1-benzopyran-1 4-yl] 3—Fluorobenzamidine,

N '—Cyaneau Ν— [(3S, 4R) -3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-1-6-two-row 2Η-1 Benzopyran-1 4-yl] 2-thiophencarboxamidine,

N '—Cyanaw Ν— [(3 S, 4R) — 6—Cyanaw 3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydrokidi-1 2 Η—1 Benzopyran-1 4-yl] 1 Casey Midin,

N'-cyano Ν— [(3 S, 4 R) — 6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) -1,3-hydroxy-2 Η—11-benzopyran-14-yl] 1,2— Pyridine-powered lipoxamidine,

Ν '1-cyanone Ν— [(3 S, 4 R) — 6-cyanone 3,4-dihydro-2,2-di (methoxymethyl) -1-hydroxy-2 Η—1-benzopyran-1 4-yl] One 41-pyridinecarboxamidine, N '—Cyanone N_ [(3 S, 4 R) — 6—Cyanore 3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-2H—1 Benzopyran-1 4-yl] Nzamidine,

Ν'-cyano Ν— [(3S, 4R) —6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-2 2—1 benzopyran-1 4-yl] 1-2 —Thiondin carboxamidine,

N '—Cyanaw Ν— [(3 S, 4 R) — 6—Cyanaw 3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-2 Η- 1-benzopyran-14-yl] 1-2 Fluo mouth benzamidine,

N '—Cyanaw Ν— [(3 S, 4 R) — 6—Cyanaw 3,4-dihydro-2,2-di (methoxymethyl) -1 3-hydroxy-2 Η—1 Benzopyran-1 4-yl] One 3—Fluorobenzamidine,

N '—Syno Ν— [(3S, 4R) -1-6-Cano-3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-2 Η—1 Benzopyran-14-yl] One 31-quinolinecarboxamidine,

N '—Cyanone Ν— [(3 S, 4 R) — 6—Cyanaw 3,4 dihydro-2,2-di (methoxymethyl) -1 3-hydroxy-2 Η—1 Benzopyran-1 4-yl] 2-naphthalenecarboxamidine,

N '—Cyanaw Ν— [(3S, 4R) -1-6-Cyanaw 3,4-dihydro-2,2-di (methoxymethyl) -1-3-hydroxy-2 ー —1-benzopyran-1-4-yl]ヱ Noxycarboxamidine,

Ν "—Cyanaw Ν— [(3 S, 4R) — 6—Cyanaw 3,4-dihydro-2,2-di (methoxymethyl) -1 3-hydroxy-2 H—1 Benzopyran-1 4-yl] 1 N '—Fujirung Ryojijin,

N— [trans-6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H—1-benzopyran-14-yl] 1-N'—phenylphenyl

(3 S, 4 R) — 4-acetylamino-6-cyano 3, 4-dihydro-2 2-di (methoxymethyl) 1 2H-1 1 benzopyran 1 3-ol,

(3 S, 4 R) — 6-cyanore 3,4-dihydro-1,2,2-di (methoxymethyl) -1,3-hydroxy-4- (3-pyridinecarboxamide) 1 2 H— 1—benzopyran ,

(3 S, 4 R) — 4-benzenecarboxamido 6-cyano 3,4-dihydric □-2,2-di (methoxymethyl) -1 2H— 1—benzopyran-1 3-ol,

(3 S, 4R) — 6-cyanore 3,4-dihydro-2,2-di (methoxymethyl) 1-3-hydroxy 41- (2-thiophenecarboxamide) 1 2 H—1 Benzovirane,

Ν'-cyano Ν— [(3S, 4R) —3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-twotrough 2Η—1 benzopyran-14-yl] benzamidine,

(3S, 4R) — 3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-16,2-trough 41,3- (3-pyridinecarboxamide) 1,2Η-1,1-benzopyran,

(3 S, 4 R) -3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-6-two-row 41- (2-pyridinecarboxamide) one 2Η-1-benzopyran,

N'-cyano-I- (6-cyano 3,4-dihydro-r-3-hydroxy-2-methyl-2-phenoxymethyl-2H-1 benzopyran-1t-4-yl) 1-3-pyridinecarbo Xamidine,

N '—Cyanaw N- [Trans-6-Cyanaw 3,4-dihydro-3-Hydroxy-2 H-1 1-Benzopyran-1 2-Spi 5' — (1 ', 3'-Dioxacyclohexyl) 1-41 1] 3-pyridinecarboxamidine,

N'-cyano N- [trans-6-cyano 2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-13-hydroxy-2H-1 1-benzopyran-1 4-yl] 3—pyridinecarboxamidine,

N'-cyano N— [trans-6-cyano 3,4-dihydro-2,2-di (Hydroxymethyl) 1-3-hydroxy-2H-1-benzopyran-14-yl] -13-pyridinecarboxamidine,

N '—Cyanaw N— [(3 S, 4 R) — 6—Cyanaw 3,4-dihydro-2,2-di (ethoxymethyl) -1 3-hydroxy-2 H— 1 Benzopyran-1 4-yl] One 3-pyridine power lipoxamidine,

N'—Cyanor N — [(3S, 4R) -1-6-Cyanor-3,4-dihydro-2,2-di (ethoxymethyl) -1-3-hydroxy-2H—1-benzopyran-1-4-yl] ase Evening Midine, and

N '—Cyanaw N— [(3 S, 4 R) — 6—Cyanaw 3,4-dihydro-2,2-di (methoxymethyl) -13-formyloxy-1 2H—11-benzopyran-4-yl] 1-3 2. The chroman compound according to claim 1, which is selected from pyridinecarboxamidine, or a pharmaceutically acceptable salt thereof.

4. General formula

Wherein R ¹ is a cyano group, a nitro group or a halogen atom;

R ³ ′ is a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group or a tert-butyldimethylsilyloxyalkyl group, or R ³ ′ and R ³ ′ together , — (CH ₂ ), — 0— (CH ₂ ) _m —0— (CH ₂ ) _n — (wherein, 1 and n are each independently 0 or an integer of 1 to 2, and m is 1 to Where R ² ′ is a lower alkoxyalkyl group, R ³ ′ is a lower 极 alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group or a tert-alkyl group. Butyldimethyl A lyloxyalkyl group)

A 4-oxochroman compound represented by or a salt thereof c

5. General formula

(Wherein, R ¹ , R ² ′, and R ³ ′ are as defined in claim 4) or a 4-hydroxychroman compound or a salt thereof.

6. ―

(Wherein, R], R ² ′ and R ³ ′ are as described in claim 4) or a salt thereof.

7. General formula

(Wherein R ¹ , R ² \ R ³ ′ are as defined in claim 4) or a salt thereof, or a salt thereof.

8. General formula

(Wherein, R ¹ , R ² ′, and R ³ ′ are as described in claim 4, and R ⁷ is a hydrogen atom or a lower alkyl group). A hydroxychromane compound or a salt thereof.

9. A coronary vasodilator comprising the chroman compound according to claim 1 or a pharmaceutically acceptable salt thereof.