Drug for Treating Circulatory Insufficiency

Information

  • Patent Application
  • 20090099256
  • Publication Number
    20090099256
  • Date Filed
    October 23, 2006
    18 years ago
  • Date Published
    April 16, 2009
    15 years ago
Abstract
The present invention relate to a drug for treating circulatory insufficiency containing a benzopyran derivative represented by the following general formula (I):
Description
TECHNICAL FIELD

The present invention relates to a drug for treating circulatory insufficiency containing a benzopyran derivative and/or a physiologically acceptable salt thereof as an active ingredient.


BACKGROUND ART

An anti-allergy agent containing as an active ingredient a benzopyran derivative represented by the following general formula is known:







(wherein R1 is an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms; and any one of R2, R3, R4 and R5 is an alkoxy group substituted with a hydroxyl group or an alkoxy group substituted with a carboxy group, and the others are hydrogen atoms) (see Patent Publication No. 1).


There is also a publication disclosing an agent for treating heart disease containing as an active ingredient a benzopyran derivative represented by the following general formula:







(wherein R1 is an alkyl group or an alkenyl group; and R2 is a hydrogen atom, an alkyl group, an alkyl group having a hydroxyl group, an alkenyl group, an acyl group or a glycosyl group) (see Patent Publication No. 2).


However, there was no a suggestion or a teaching at all in either Patent Publication No. 1 or No. 2 that the benzopyran derivatives could be effective in the treatment of circulatory insufficiency and be extremely useful drugs for treating circulatory insufficiency.


Furthermore, it has been disclosed that the benzopyran derivatives represented by the following formulas have a platelet anti-aggregating effect, and are useful for treating or preventing thrombosis (for example, see Non-patent Publication No. 1 and Patent Publication No. 3).







However, there was no specific description with regard to stability or bioabsorption of these compounds in these publications, and whether these compounds had favorable characteristics as pharmaceutical agents had been totally unknown.


Additionally, aspirin cilostazol, beraprost sodium, ticlopidine hydrochloride, among others have been used as an antiplatelet drug, anticoagulant drug or the like (for example, see Non-patent Publication No. 2). However, the use of aspirin cilostazol, beraprost sodium, or ticlopidine hydrochloride for treatment of peripheral circulation insufficiency exhibits a bleeding tendency as a side effect derived from its antithrombotic effect. Therefore, such drugs are contraindicated in patients with haemorrhage, potential haemorrhage, congestive heart failure, serious haemological abnormality, or serious hepatopathy, or postoperative patients.


Patent Document 1: Japanese Unexamined Patent Application, Publication No. 2003-81827


Patent Document 2: Japanese Unexamined Patent Application, Publication No. Hei 9-315967


Patent Document 3: U.S. Pat. No. 4,845,121


Non-patent Document 1: Donald. T. Witiak, J. Med. Chem., vol. 31, p. 1437-1445, 1988


Non-patent Document 2: Kyou no chiryouyaku (Today's medicine), Nankodo, P. 476-478, 2002


DISCLOSURE OF INVENTION

The object of the present invention is to provide very useful drugs for treating circulatory insufficiency which have excellent safety, stability and absorption, and which have an extremely low haemorrhagic adverse reaction, and which are effective in treatment of circulatory insufficiency.


In order to achieve the object of the present invention described above, the inventors synthesized numerous types of compounds and evaluated these for their effectiveness in improving circulatory insufficiency and their safety, stability, absorption and bleeding effect, whereupon they discovered that the benzopyran derivatives shown by the above-mentioned general formula (I) were extremely effective in treating circulatory insufficiency. Specifically, they discovered that the benzopyran derivatives had excellent characteristics such as excellent improving effects in circulatory insufficiency, and that the benzopyran derivatives had superior safety, stability and absorption, compared to the existing drugs, and that the benzopyran derivatives had an extremely low haemorrhagic adverse reaction.


In other words, the present invention provides a drug for treating circulatory insufficiency containing a benzopyran derivative represented by the following general formula (I):







and/or a physiologically acceptable salt thereof as an active ingredient, wherein R1 is an alkyl group having 1 to 10 carbon atoms, or an alkenyl group having 2 to 10 carbon atoms; and any one of R2, R3, R4 and R5 is a hydroxyl group, an alkoxy group, an alkenyloxy group, an alkoxy group substituted with a hydroxyl group, or an alkoxy group substituted with a carboxy group, and the others are hydrogen atoms.


Moreover, the present invention relates to use of the aforementioned drug for treating circulatory insufficiency.


Furthermore, the present invention also provides a method for treating circulatory insufficiency, the method including: using the aforementioned drug for treating circulatory insufficiency.


The present invention can provide an excellent drug for treating circulatory insufficiency which has high safety, stability and absorption, and which has an extremely low haemorrhagic adverse reaction because a benzopyran derivative represented by the general formula (I) is contained therein as an active ingredient.


Furthermore, according to the present invention, the use of the aforementioned drug for treating circulatory insufficiency enables effective and safe treatment for circulatory insufficiency without causing a haemorrhagic side effect.


Additionally, according to the aforementioned method for treating circulatory insufficiency, circulatory insufficiency can be effectively and safely treated by using the aforementioned drug for treating circulatory insufficiency without causing a haemorrhagic side effect.







BEST MODE FOR CARRYING OUT THE INVENTION

In the benzopyran derivative represented by the general formula (I) of the present invention, the alkyl group having 1 to 10 carbon atoms of R1 can be either a straight-chain alkyl group or a branched alkyl group. Examples of such alkyl groups include a methyl group, ethyl group, propyl group, isopropyl group, n-butyl group, n-pentyl group, 2-ethyl-propyl group, n-hexyl group, 4-methylpentyl group, n-heptyl group, 2-ethylhexyl group, n-octyl group, n-nonyl group and n-decyl group.


And the alkenyl group having 2 to 10 carbon atoms of R1 can be either a straight-chain or branched alkenyl group. Examples of such alkenyl groups include a vinyl group, 2-propenyl group, 2-butenyl group, prenyl group, octenyl group and geranyl group.


For example, the alkoxy group represented by any one of R2, R3, R4 and R5 in the general formula (I) of the present invention can be an alkoxy group having 1 to 10 carbon atoms. More specific examples of such alkoxy groups include a methoxy group, ethoxy group, propoxy group, butoxy group, pentyloxy group, 2-ethylpropoxy group, hexyloxy group, 4-methylpentyloxy group, heptyloxy group, octyloxy group, 2-ethylhexyloxcy group, nonyloxy group, and decyloxy group. The alkoxy groups having 2 to 8 carbon atoms are particularly preferable among these groups.


Additionally, examples of alkenyloxy groups include a vinyloxy group, 2-propenyloxy group, 2-butenyloxy group, prenyloxy group, octenyloxy group, and geranyloxy group.


For example, the alkoxy group substituted with a hydroxyl group, represented by any one of R2, R3, R4 or R5, may be an alkoxy group having 1 to 10 carbon atoms, preferably having 1 to 4 carbon atoms, which is substituted with a hydroxyl group. More specific examples of such alkoxy groups include a 2-hydroxyethoxy group, 3-hydroxypropoxy group, 4-hydroxybutoxy group, 2,3-dihydroxypropoxy group, and 3,4-dihydroxybutoxy group. The aforementioned alkoxy groups substituted with 1 or 2 hydroxyl groups are particularly preferable among these groups.


For example, the alkoxy group substituted with a carboxy group, represented by any one of R2, R3, R4 and R5, may be an alkoxy group having 1 to 4 carbon atoms substituted with a carboxy group. More specific examples of such alkoxy groups include a carboxymethoxy group, 2-carboxyethoxy group, 3-carboxypropoxy group, and 4-carboxybutoxy group. The alkoxy groups substituted with 1 carboxy group are particularly preferable among these groups.


Production of the benzopyran derivatives represented by the general formula (I) can be achieved by selecting a preferable method, depending on the structure of desired benzopyran derivative is planned on. For example, the benzopyran derivative can be produced by the following method disclosed in Japanese Patent Application, First Publication No. 2003-81827. Specifically, the method is conducted as shown in the following reaction path.










In the reaction path, at first, the hydroxyl groups of dihydroxyacetophenone (a) are protected with a benzyl group to obtain compound (b). Next, a condensation reaction between compound (b) and dimethyl carbonate is carried out to obtain a keto ester compound (c) which is subsequently reacted with benzoyl peroxide to obtain compound (d). At this stage, the benzyl groups used as a protecting group for the hydroxyl group are deprotected by hydrocracking, and then treated with an acid to obtain a benzoyloxy compound (f).


Subsequently, the hydroxyl group on the aromatic ring of this benzoyloxy compound (f) is protected with a benzyl group to obtain compound (g), and then a methoxymethyl group is added to the 4-position to obtain compound (h). After removing the benzoyl group from compound (h), the hydroxyl group at the 3-position is alkylated to obtain compound (j). The alkylation of the hydroxyl group can be performed by a conventional alkylation reaction such as a reaction with an alkyl halide, a sulfate ester, an arylsulfonate ester or the like. Then, the protective group of the hydroxyl group on the aromatic ring is deprotected to obtain compound (k).


In order to obtain the benzopyran derivatives represented by the general formula (I), wherein any one of R2, R3, R4 and R5 is an alkoxy group, an alkenyloxy group, or an alkoxy group substituted with a hydroxyl group or a carboxy group, the hydroxyl group on the aromatic ring of the compound (k) or compound (m) is alkylated with alkylating agents (such as alkyl halide, sulfate ester or arylsulfonate ester); alkenylating agents (such as alkenyl halide, sulfate ester or arylsulfonate ester); or alkylating agents wherein the hydroxyl or carboxy group is protected (such as alkyl halide, sulfate ester or arylsulfonate ester), and then the protected hydroxyl or carboxy group is deprotected.


Furthermore, in order to explain the process of producing the benzopyran derivatives represented by the general formula (I), a method of producing a benzopyran derivative wherein any one of R2, R3, R4 and R5 is a 2-hydroxyethoxy group is specifically explained below.


First, an alkoxylation reaction is performed where 2-acetoxyethyl bromide is reacted with compound (k) in an organic solvent in the presence of a basic compound.


As examples of the basic compounds used in this reaction, there are inorganic salts such as sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, sodium hydroxide and potassium hydroxide; metal alcoholates such as sodium methoxide, sodium ethoxide, sodium t-butoxide and potassium t-butoxide; and metallic hydrides such as sodium hydride and potassium hydride.


Examples of organic solvents used in the reaction include hydrocarbons such as benzene, toluene and xylene; ethers such as diethyl ether, tetrahydrofuran and 1,2-dimethoxyethane; and amides such as N,N-dimethylformamide, N,N-dimethylacetoamide and 1-methyl-2-pyrrolidinone.


The reaction temperature is preferably 0° C. to 100° C., and more preferably 20° C. to 50° C., and the reaction time is normally 1 to 5 hours.


Next, if necessary, the acetyl group which is a protective group may be removed, and this reaction can be a de-acetylation reaction conducted under ordinary alkaline conditions. In this way, the objective benzopyran derivatives substituted with a 2-hydroxyethoxy group can be produced.


The following compounds are illustrative examples of the benzopyran derivatives of the present invention, represented by the general formula (I), however these examples are intended to illustrate the invention and not to be construed to limit the scope of the invention.














TABLE 1





Compound







No.
R1
R2
R3
R4
R5




















1
methyl
hydroxyl
H
H
H


2
ethyl
hydroxyl
H
H
H


3
propyl
hydroxyl
H
H
H


4
isopropyl
hydroxyl
H
H
H


5
butyl
hydroxyl
H
H
H


6
s-butyl
hydroxyl
H
H
H


7
pentyl
hydroxyl
H
H
H


8
1-ethylpropyl
hydroxyl
H
H
H


9
hexyl
hydroxyl
H
H
H


10
2-methylpentyl
hydroxyl
H
H
H


11
heptyl
hydroxyl
H
H
H


12
1-ethylpentyl
hydroxyl
H
H
H


13
4-methylpentyl
hydroxyl
H
H
H


14
4-ethylbutyl
hydroxyl
H
H
H


15
octyl
hydroxyl
H
H
H


16
1-ethylhexyl
hydroxyl
H
H
H


17
decyl
hydroxyl
H
H
H


18
vinyl
hydroxyl
H
H
H


19
1-propenyl
hydroxyl
H
H
H


20
2-butenyl
hydroxyl
H
H
H


21
1-hexenyl
hydroxyl
H
H
H


22
1-octenyl
hydroxyl
H
H
H


23
1-decenyl
hydroxyl
H
H
H


24
3-methyl-2-butenyl
hydroxyl
H
H
H


25
geranyl
hydroxyl
H
H
H


26
prenyl
hydroxyl
H
H
H


27
methyl
methoxy
H
H
H


28
ethyl
methoxy
H
H
H


29
butyl
methoxy
H
H
H


30
hexyl
ethoxy
H
H
H


31
2-methylpentyl
ethoxy
H
H
H


32
octyl
ethoxy
H
H
H


33
decyl
ethoxy
H
H
H


34
1-propenyl
isopropoxy
H
H
H


35
1-octenyl
isopropoxy
H
H
H





















TABLE 2





Compound







No.
R1
R2
R3
R4
R5







36
geranyl
isopropoxy
H
H
H


37
ethyl
butoxy
H
H
H


38
butyl
butoxy
H
H
H


39
s-butyl
butoxy
H
H
H


40
hexyl
butoxy
H
H
H


41
1-ethylpentyl
hexyloxy
H
H
H


42
octyl
hexyloxy
H
H
H


43
2-butenyl
hexyloxy
H
H
H


44
prenyl
hexyloxy
H
H
H


45
ethyl
octyloxy
H
H
H


46
butyl
octyloxy
H
H
H


47
hexyl
octyloxy
H
H
H


48
octyl
octyloxy
H
H
H


49
decyl
decyloxy
H
H
H


50
1-hexenyl
decyloxy
H
H
H


51
3-methyl-2-butenyl
decyloxy
H
H
H


52
methyl
1-octenyloxy
H
H
H


53
ethyl
1-octenyloxy
H
H
H


54
hexyl
1-octenyloxy
H
H
H


55
octyl
1-octenyloxy
H
H
H


56
1-propenyl
1-octenyloxy
H
H
H


57
1-octenyl
1-octenyloxy
H
H
H


58
geranyl
geranyloxy
H
H
H


59
methyl
H
hydroxyl
H
H


60
ethyl
H
hydroxyl
H
H


61
propyl
H
hydroxyl
H
H


62
isopropyl
H
hydroxyl
H
H


63
butyl
H
hydroxyl
H
H


64
s-butyl
H
hydroxyl
H
H


65
pentyl
H
hydroxyl
H
H


66
1-ethylpropyl
H
hydroxyl
H
H


67
hexyl
H
hydroxyl
H
H


68
2-methylpentyl
H
hydroxyl
H
H


69
heptyl
H
hydroxyl
H
H


70
1-ethylpentyl
H
hydroxyl
H
H





















TABLE 3





Compound







No.
R1
R2
R3
R4
R5




















71
4-methylpentyl
H
hydroxyl
H
H


72
4-ethylbutyl
H
hydroxyl
H
H


73
octyl
H
hydroxyl
H
H


74
1-ethylhexyl
H
hydroxyl
H
H


75
decyl
H
hydroxyl
H
H


76
vinyl
H
hydroxyl
H
H


77
1-propenyl
H
hydroxyl
H
H


78
2-butenyl
H
hydroxyl
H
H


79
1-hexenyl
H
hydroxyl
H
H


80
1-octenyl
H
hydroxyl
H
H


81
1-decenyl
H
hydroxyl
H
H


82
3-methyl-2-butenyl
H
hydroxyl
H
H


83
geranyl
H
hydroxyl
H
H


84
prenyl
H
hydroxyl
H
H


85
methyl
H
methoxy
H
H


86
ethyl
H
methoxy
H
H


87
butyl
H
methoxy
H
H


88
hexyl
H
ethoxy
H
H


89
2-methylpentyl
H
ethoxy
H
H


90
octyl
H
ethoxy
H
H


91
decyl
H
ethoxy
H
H


92
1-propenyl
H
isopropoxy
H
H


93
1-octenyl
H
isopropoxy
H
H


94
geranyl
H
isopropoxy
H
H


95
ethyl
H
butoxy
H
H


96
butyl
H
butoxy
H
H


97
s-butyl
H
butoxy
H
H


98
hexyl
H
butoxy
H
H


99
1-ethylpentyl
H
hexyloxy
H
H


100
octyl
H
hexyloxy
H
H


101
2-butenyl
H
hexyloxy
H
H


102
prenyl
H
hexyloxy
H
H


103
ethyl
H
octyloxy
H
H


104
butyl
H
octyloxy
H
H


105
hexyl
H
octyloxy
H
H





















TABLE 4





Compound







No.
R1
R2
R3
R4
R5







106
octyl
H
octyloxy
H
H


107
decyl
H
decyloxy
H
H


108
1-hexenyl
H
decyloxy
H
H


109
3-methyl-2-butenyl
H
decyloxy
H
H


110
methyl
H
1-octenyloxy
H
H


111
ethyl
H
1-octenyloxy
H
H


112
hexyl
H
1-octenyloxy
H
H


113
octyl
H
1-octenyloxy
H
H


114
1-propenyl
H
1-octenyloxy
H
H


115
1-octenyl
H
1-octenyloxy
H
H


116
geranyl
H
geranyloxy
H
H


117
methyl
H
H
hydroxyl
H


118
ethyl
H
H
hydroxyl
H


119
propyl
H
H
hydroxyl
H


120
isopropyl
H
H
hydroxyl
H


121
butyl
H
H
hydroxyl
H


122
s-butyl
H
H
hydroxyl
H


123
pentyl
H
H
hydroxyl
H


124
1-ethylpropyl
H
H
hydroxyl
H


125
hexyl
H
H
hydroxyl
H


126
2-methylpentyl
H
H
hydroxyl
H


127
heptyl
H
H
hydroxyl
H


128
1-ethylpentyl
H
H
hydroxyl
H


129
4-methylpentyl
H
H
hydroxyl
H


130
4-ethylbutyl
H
H
hydroxyl
H


131
octyl
H
H
hydroxyl
H


132
1-ethylhexyl
H
H
hydroxyl
H


133
decyl
H
H
hydroxyl
H


134
vinyl
H
H
hydroxyl
H


135
1-propenyl
H
H
hydroxyl
H


136
2-butenyl
H
H
hydroxyl
H


137
1-hexenyl
H
H
hydroxyl
H


138
1-octenyl
H
H
hydroxyl
H


139
1-decenyl
H
H
hydroxyl
H


140
3-methyl-2-butenyl
H
H
hydroxyl
H





















TABLE 5





Compound







No.
R1
R2
R3
R4
R5







141
geranyl
H
H
hydroxyl
H


142
prenyl
H
H
hydroxyl
H


143
methyl
H
H
methoxy
H


144
ethyl
H
H
methoxy
H


145
butyl
H
H
methoxy
H


146
hexyl
H
H
ethoxy
H


147
2-methylpentyl
H
H
ethoxy
H


148
octyl
H
H
ethoxy
H


149
decyl
H
H
ethoxy
H


150
1-propenyl
H
H
isopropoxy
H


151
1-octenyl
H
H
isopropoxy
H


152
geranyl
H
H
isopropoxy
H


153
ethyl
H
H
butoxy
H


154
butyl
H
H
butoxy
H


155
s-butyl
H
H
butoxy
H


156
hexyl
H
H
butoxy
H


157
1-ethylpentyl
H
H
hexyloxy
H


158
octyl
H
H
hexyloxy
H


159
2-butenyl
H
H
hexyloxy
H


160
prenyl
H
H
hexyloxy
H


161
ethyl
H
H
octyloxy
H


162
butyl
H
H
octyloxy
H


163
hexyl
H
H
octyloxy
H


164
octyl
H
H
octyloxy
H


165
decyl
H
H
decyloxy
H


166
1-hexenyl
H
H
decyloxy
H


167
3-methyl-2-butenyl
H
H
decyloxy
H


168
methyl
H
H
1-octenyloxy
H


169
ethyl
H
H
1-octenyloxy
H


170
hexyl
H
H
1-octenyloxy
H


171
octyl
H
H
1-octenyloxy
H


172
1-propenyl
H
H
1-octenyloxy
H


173
1-octenyl
H
H
1-octenyloxy
H


174
geranyl
H
H
geranyloxy
H


175
methyl
H
H
H
hydroxyl





















TABLE 6





Compound







No.
R1
R2
R3
R4
R5







176
ethyl
H
H
H
hydroxyl


177
propyl
H
H
H
hydroxyl


178
isopropyl
H
H
H
hydroxyl


179
butyl
H
H
H
hydroxyl


180
s-butyl
H
H
H
hydroxyl


181
pentyl
H
H
H
hydroxyl


182
1-ethylpropyl
H
H
H
hydroxyl


183
hexyl
H
H
H
hydroxyl


184
2-methylpentyl
H
H
H
hydroxyl


185
heptyl
H
H
H
hydroxyl


186
1-ethylpentyl
H
H
H
hydroxyl


187
4-methylpentyl
H
H
H
hydroxyl


188
4-ethylbutyl
H
H
H
hydroxyl


189
octyl
H
H
H
hydroxyl


190
1-ethylhexyl
H
H
H
hydroxyl


191
decyl
H
H
H
hydroxyl


192
vinyl
H
H
H
hydroxyl


193
1-propenyl
H
H
H
hydroxyl


194
2-butenyl
H
H
H
hydroxyl


195
1-hexenyl
H
H
H
hydroxyl


196
1-octenyl
H
H
H
hydroxyl


197
1-decenyl
H
H
H
hydroxyl


198
3-methyl-2-butenyl
H
H
H
hydroxyl


199
geranyl
H
H
H
hydroxyl


200
prenyl
H
H
H
hydroxyl


201
methyl
H
H
H
methoxy


202
ethyl
H
H
H
methoxy


203
butyl
H
H
H
methoxy


204
hexyl
H
H
H
ethoxy


205
2-methylpentyl
H
H
H
ethoxy


206
octyl
H
H
H
ethoxy


207
decyl
H
H
H
ethoxy


208
1-propenyl
H
H
H
isopropoxy


209
1-octenyl
H
H
H
isopropoxy


210
geranyl
H
H
H
isopropoxy





















TABLE 7





Com-







pound


No.
R1
R2
R3
R4
R5







211
ethyl
H
H
H
butoxy


212
butyl
H
H
H
butoxy


213
s-butyl
H
H
H
butoxy


214
hexyl
H
H
H
butoxy


215
1-ethylpentyl
H
H
H
hexyloxy


216
octyl
H
H
H
hexyloxy


217
2-butenyl
H
H
H
hexyloxy


218
prenyl
H
H
H
hexyloxy


219
ethyl
H
H
H
octyloxy


220
butyl
H
H
H
octyloxy


221
hexyl
H
H
H
octyloxy


222
octyl
H
H
H
octyloxy


223
decyl
H
H
H
decyloxy


224
1-hexenyl
H
H
H
decyloxy


225
3-methyl-2-butenyl
H
H
H
decyloxy


226
methyl
H
H
H
1-octenyloxy


227
ethyl
H
H
H
1-octenyloxy


228
hexyl
H
H
H
1-octenyloxy


229
octyl
H
H
H
1-octenyloxy


230
1-propenyl
H
H
H
1-octenyloxy


231
1-octenyl
H
H
H
1-octenyloxy


232
geranyl
H
H
H
geranyloxy


233
methyl
2-hydroxyethoxy
H
H
H


234
ethyl
2-hydroxyethoxy
H
H
H


235
propyl
2-hydroxyethoxy
H
H
H


236
isopropyl
2-hydroxyethoxy
H
H
H


237
butyl
2-hydroxyethoxy
H
H
H


238
s-butyl
2-hydroxyethoxy
H
H
H


239
pentyl
2-hydroxyethoxy
H
H
H


240
1-ethylpropyl
2-hydroxyethoxy
H
H
H


241
hexyl
2-hydroxyethoxy
H
H
H


242
2-methylpentyl
2-hydroxyethoxy
H
H
H


243
heptyl
2-hydroxyethoxy
H
H
H


244
1-ethylpentyl
2-hydroxyethoxy
H
H
H


245
4-methylpentyl
2-hydroxyethoxy
H
H
H





















TABLE 8





Compound







No.
R1
R2
R3
R4
R5







246
4-ethylbutyl
2-hydroxyethoxy
H
H
H


247
octyl
2-hydroxyethoxy
H
H
H


248
1-ethylhexyl
1-hydroxymethoxy
H
H
H


249
decyl
1-hydroxymethoxy
H
H
H


250
vinyl
1-hydroxymethoxy
H
H
H


251
1-propenyl
1-hydroxymethoxy
H
H
H


252
2-butenyl
1-hydroxymethoxy
H
H
H


253
1-hexenyl
1-hydroxymethoxy
H
H
H


254
1-octenyl
1-hydroxymethoxy
H
H
H


255
1-decenyl
1-hydroxymethoxy
H
H
H


256
3-methyl-2-butenyl
1-hydroxymethoxy
H
H
H


257
geranyl
1-hydroxymethoxy
H
H
H


258
prenyl
1-hydroxymethoxy
H
H
H


259
methyl
3-hydroxypropoxy
H
H
H


260
ethyl
3-hydroxypropoxy
H
H
H


261
butyl
3-hydroxypropoxy
H
H
H


262
hexyl
3-hydroxypropoxy
H
H
H


263
2-methylpentyl
3-hydroxypropoxy
H
H
H


264
octyl
3-hydroxypropoxy
H
H
H


265
decyl
3-hydroxypropoxy
H
H
H


266
1-propenyl
3-hydroxypropoxy
H
H
H


267
1-octenyl
3-hydroxypropoxy
H
H
H


268
geranyl
3-hydroxypropoxy
H
H
H


269
ethyl
4-hydroxybutoxy
H
H
H


270
butyl
4-hydroxybutoxy
H
H
H


271
s-butyl
4-hydroxybutoxy
H
H
H


272
hexyl
4-hydroxybutoxy
H
H
H


273
1-ethylpentyl
4-hydroxybutoxy
H
H
H


274
octyl
4-hydroxybutoxy
H
H
H


275
2-butenyl
4-hydroxybutoxy
H
H
H


276
prenyl
4-hydroxybutoxy
H
H
H


277
ethyl
2,3-dihydroxypropoxy
H
H
H


278
butyl
2,3-dihydroxypropoxy
H
H
H


279
hexyl
2,3-dihydroxypropoxy
H
H
H


280
octyl
2,3-dihydroxypropoxy
H
H
H





















TABLE 9





Compound







No.
R1
R2
R3
R4
R5







281
decyl
2,3-dihydroxypropoxy
H
H
H


282
1-hexenyl
2,3-dihydroxypropoxy
H
H
H


283
3-methyl-2-butenyl
2,3-dihydroxypropoxy
H
H
H


284
methyl
3,4-dihydroxybutoxy
H
H
H


285
ethyl
3,4-dihydroxybutoxy
H
H
H


286
hexyl
3,4-dihydroxybutoxy
H
H
H


287
octyl
3,4-dihydroxybutoxy
H
H
H


288
1-propenyl
3,4-dihydroxybutoxy
H
H
H


289
1-octenyl
3,4-dihydroxybutoxy
H
H
H


290
geranyl
3,4-dihydroxybutoxy
H
H
H


291
methyl
carboxymethoxy
H
H
H


292
ethyl
carboxymethoxy
H
H
H


293
propyl
carboxymethoxy
H
H
H


294
isopropyl
carboxymethoxy
H
H
H


295
butyl
carboxymethoxy
H
H
H


296
s-butyl
carboxymethoxy
H
H
H


297
pentyl
carboxymethoxy
H
H
H


298
hexyl
carboxymethoxy
H
H
H


299
2-methylpentyl
carboxymethoxy
H
H
H


300
heptyl
carboxymethoxy
H
H
H


301
1-ethylpentyl
carboxymethoxy
H
H
H


302
4-methylpentyl
carboxymethoxy
H
H
H


303
1-ethylhexyl
carboxymethoxy
H
H
H


304
octyl
carboxymethoxy
H
H
H


305
1-ethylhexyl
carboxymethoxy
H
H
H


306
decyl
carboxymethoxy
H
H
H


307
vinyl
carboxymethoxy
H
H
H


308
1-propenyl
carboxymethoxy
H
H
H


309
2-butenyl
carboxymethoxy
H
H
H


310
1-hexenyl
carboxymethoxy
H
H
H


311
1-octenyl
carboxymethoxy
H
H
H


312
1-decenyl
carboxymethoxy
H
H
H


313
3-methyl-2-butenyl
carboxymethoxy
H
H
H


314
geranyl
carboxymethoxy
H
H
H


315
prenyl
carboxymethoxy
H
H
H





















TABLE 10





Com-







pound


No.
R1
R2
R3
R4
R5







316
methyl
2-carboxyethoxy
H
H
H


317
ethyl
2-carboxyethoxy
H
H
H


318
butyl
2-carboxyethoxy
H
H
H


319
hexyl
2-carboxyethoxy
H
H
H


320
octyl
2-carboxyethoxy
H
H
H


321
1-propenyl
2-carboxyethoxy
H
H
H


322
1-octenyl
2-carboxyethoxy
H
H
H


323
geranyl
2-carboxyethoxy
H
H
H


324
ethyl
3-carboxypropoxy
H
H
H


325
butyl
3-carboxypropoxy
H
H
H


326
hexyl
3-carboxypropoxy
H
H
H


327
octyl
3-carboxypropoxy
H
H
H


328
2-butenyl
3-carboxypropoxy
H
H
H


329
prenyl
3-carboxypropoxy
H
H
H


330
ethyl
4-carboxybutoxy
H
H
H


331
butyl
4-carboxybutoxy
H
H
H


332
hexyl
4-carboxybutoxy
H
H
H


333
octyl
4-carboxybutoxy
H
H
H


334
1-octenyl
4-carboxybutoxy
H
H
H


335
methyl
H
2-hydroxyethoxy
H
H


336
ethyl
H
2-hydroxyethoxy
H
H


337
propyl
H
2-hydroxyethoxy
H
H


338
isopropyl
H
2-hydroxyethoxy
H
H


339
butyl
H
2-hydroxyethoxy
H
H


340
s-butyl
H
2-hydroxyethoxy
H
H


341
pentyl
H
2-hydroxyethoxy
H
H


342
1-
H
2-hydroxyethoxy
H
H



ethylpropyl


343
hexyl
H
2-hydroxyethoxy
H
H


344
2-
H
2-hydroxyethoxy
H
H



methylpentyl


345
heptyl
H
2-hydroxyethoxy
H
H


346
1-ethylpentyl
H
2-hydroxyethoxy
H
H


347
4-
H
2-hydroxyethoxy
H
H



methylpentyl


348
1-ethylhexyl
H
2-hydroxyethoxy
H
H


349
octyl
H
2-hydroxyethoxy
H
H


350
1-ethylhexyl
H
1-hydroxymethoxy
H
H





















TABLE 11





Compound







No.
R1
R2
R3
R4
R5







351
decyl
H
1-hydroxymethoxy
H
H


352
vinyl
H
1-hydroxymethoxy
H
H


353
1-propenyl
H
1-hydroxymethoxy
H
H


354
2-butenyl
H
1-hydroxymethoxy
H
H


355
1-hexenyl
H
1-hydroxymethoxy
H
H


356
1-octenyl
H
1-hydroxymethoxy
H
H


357
1-decenyl
H
1-hydroxymethoxy
H
H


358
3-methyl2-butenyl
H
1-hydroxymethoxy
H
H


359
geranyl
H
1-hydroxymethoxy
H
H


360
prenyl
H
1-hydroxymethoxy
H
H


361
methyl
H
3-hydroxypropoxy
H
H


362
ethyl
H
3-hydroxypropoxy
H
H


363
butyl
H
3-hydroxypropoxy
H
H


364
hexyl
H
3-hydroxypropoxy
H
H


365
2-methylpentyl
H
3-hydroxypropoxy
H
H


366
octyl
H
3-hydroxypropoxy
H
H


367
decyl
H
3-hydroxypropoxy
H
H


368
1-propenyl
H
3-hydroxypropoxy
H
H


369
1-octenyl
H
3-hydroxypropoxy
H
H


370
geranyl
H
3-hydroxypropoxy
H
H


371
ethyl
H
4-hydroxybutoxy
H
H


372
butyl
H
4-hydroxybutoxy
H
H


373
s-butyl
H
4-hydroxybutoxy
H
H


374
hexyl
H
4-hydroxybutoxy
H
H


375
1-ethylpentyl
H
4-hydroxybutoxy
H
H


376
octyl
H
4-hydroxybutoxy
H
H


377
2-butenyl
H
4-hydroxybutoxy
H
H


378
prenyl
H
4-hydroxybutoxy
H
H


379
ethyl
H
2,3-dihydroxypropoxy
H
H


380
butyl
H
2,3-dihydroxypropoxy
H
H


381
hexyl
H
2,3-dihydroxypropoxy
H
H


382
octyl
H
2,3-dihydroxypropoxy
H
H


383
decyl
H
2,3-dihydroxypropoxy
H
H


384
1-hexenyl
H
2,3-dihydroxypropoxy
H
H


385
3-methyl-2-butenyl
H
2,3-dihydroxypropoxy
H
H





















TABLE 12





Compound







No.
R1
R2
R3
R4
R5







386
methyl
H
3,4-dihydroxybutoxy
H
H


387
ethyl
H
3,4-dihydroxybutoxy
H
H


388
hexyl
H
3,4-dihydroxybutoxy
H
H


389
octyl
H
3,4-dihydroxybutoxy
H
H


390
1-propenyl
H
3,4-dihydroxybutoxy
H
H


391
1-octenyl
H
3,4-dihydroxybutoxy
H
H


392
geranyl
H
3,4-dihydroxybutoxy
H
H


393
methyl
H
carboxymethoxy
H
H


394
ethyl
H
carboxymethoxy
H
H


395
propyl
H
carboxymethoxy
H
H


396
isopropyl
H
carboxymethoxy
H
H


397
butyl
H
carboxymethoxy
H
H


398
s-butyl
H
carboxymethoxy
H
H


399
pentyl
H
carboxymethoxy
H
H


400
hexyl
H
carboxymethoxy
H
H


401
2-methylpentyl
H
carboxymethoxy
H
H


402
heptyl
H
carboxymethoxy
H
H


403
1-ethylpentyl
H
carboxymethoxy
H
H


404
4-methylpentyl
H
carboxymethoxy
H
H


405
1-ethylhexyl
H
carboxymethoxy
H
H


406
octyl
H
carboxymethoxy
H
H


407
1-ethylhexyl
H
carboxymethoxy
H
H


408
decyl
H
carboxymethoxy
H
H


409
vinyl
H
carboxymethoxy
H
H


410
1-propenyl
H
carboxymethoxy
H
H


411
2-butenyl
H
carboxymethoxy
H
H


412
1-hexenyl
H
carboxymethoxy
H
H


413
1-octenyl
H
carboxymethoxy
H
H


414
1-decenyl
H
carboxymethoxy
H
H


415
3-methyl-2-butenyl
H
carboxymethoxy
H
H


416
geranyl
H
carboxymethoxy
H
H


417
prenyl
H
carboxymethoxy
H
H


418
methyl
H
2-carboxyethoxy
H
H


419
ethyl
H
2-carboxyethoxy
H
H


420
butyl
H
2-carboxyethoxy
H
H





















TABLE 13





Com-







pound


No.
R1
R2
R3
R4
R5







421
hexyl
H
2-carboxyethoxy
H
H


422
octyl
H
2-carboxyethoxy
H
H


423
1-propenyl
H
2-carboxyethoxy
H
H


424
1-octenyl
H
2-carboxyethoxy
H
H


425
geranyl
H
2-carboxyethoxy
H
H


426
ethyl
H
3-carboxypropoxy
H
H


427
butyl
H
3-carboxypropoxy
H
H


428
hexyl
H
3-carboxypropoxy
H
H


429
octyl
H
3-carboxypropoxy
H
H


430
2-butenyl
H
3-carboxypropoxy
H
H


431
prenyl
H
3-carboxypropoxy
H
H


432
ethyl
H
4-carboxybutoxy
H
H


433
butyl
H
4-carboxybutoxy
H
H


434
hexyl
H
4-carboxybutoxy
H
H


435
octyl
H
4-carboxybutoxy
H
H


436
1-octenyl
H
4-carboxybutoxy
H
H


437
methyl
H
H
2-hydroxyethoxy
H


438
ethyl
H
H
2-hydroxyethoxy
H


439
propyl
H
H
2-hydroxyethoxy
H


440
isopropyl
H
H
2-hydroxyethoxy
H


441
butyl
H
H
2-hydroxyethoxy
H


442
s-butyl
H
H
2-hydroxyethoxy
H


443
pentyl
H
H
2-hydroxyethoxy
H


444
1-
H
H
2-hydroxyethoxy
H



ethylpropyl


445
hexyl
H
H
2-hydroxyethoxy
H


446
2-
H
H
2-hydroxyethoxy
H



methylpentyl


447
heptyl
H
H
2-hydroxyethoxy
H


448
1-ethylpentyl
H
H
2-hydroxyethoxy
H


449
4-
H
H
2-hydroxyethoxy
H



methylpentyl


450
4-ethylbutyl
H
H
2-hydroxyethoxy
H


451
octyl
H
H
2-hydroxyethoxy
H


452
1-ethylhexyl
H
H
1-hydroxymethoxy
H


453
decyl
H
H
1-hydroxymethoxy
H


454
vinyl
H
H
1-hydroxymethoxy
H


455
1-propenyl
H
H
1-hydroxymethoxy
H





















TABLE 14





Compound







No.
R1
R2
R3
R4
R5







456
2-butenyl
H
H
1-hydroxymethoxy
H


457
1-hexenyl
H
H
1-hydroxymethoxy
H


458
1-octenyl
H
H
1-hydroxymethoxy
H


459
1-decenyl
H
H
1-hydroxymethoxy
H


460
3-methyl-2-butenyl
H
H
1-hydroxymethoxy
H


461
geranyl
H
H
1-hydroxymethoxy
H


462
prenyl
H
H
1-hydroxymethoxy
H


463
methyl
H
H
3-hydroxypropoxy
H


464
ethyl
H
H
3-hydroxypropoxy
H


465
butyl
H
H
3-hydroxypropoxy
H


466
hexyl
H
H
3-hydroxypropoxy
H


467
2-methylpentyl
H
H
3-hydroxypropoxy
H


468
octyl
H
H
3-hydroxypropoxy
H


469
decyl
H
H
3-hydroxypropoxy
H


470
1-propenyl
H
H
3-hydroxypropoxy
H


471
1-octenyl
H
H
3-hydroxypropoxy
H


472
geranyl
H
H
3-hydroxypropoxy
H


473
ethyl
H
H
4-hydroxybutoxy
H


474
butyl
H
H
4-hydroxybutoxy
H


475
s-butyl
H
H
4-hydroxybutoxy
H


476
hexyl
H
H
4-hydroxybutoxy
H


477
1-ethylpentyl
H
H
4-hydroxybutoxy
H


478
octyl
H
H
4-hydroxybutoxy
H


479
2-butenyl
H
H
4-hydroxybutoxy
H


480
prenyl
H
H
4-hydroxybutoxy
H


481
ethyl
H
H
2,3-dihydroxypropoxy
H


482
butyl
H
H
2,3-dihydroxypropoxy
H


483
hexyl
H
H
2,3-dihydroxypropoxy
H


484
octyl
H
H
2,3-dihydroxypropoxy
H


485
decyl
H
H
2,3-dihydroxypropoxy
H


486
1-hexenyl
H
H
2,3-dihydroxypropoxy
H


487
3-methyl-2-butenyl
H
H
2,3-dihydroxypropoxy
H


488
methyl
H
H
3,4-dihydroxybutoxy
H


489
ethyl
H
H
3,4-dihydroxybutoxy
H


490
hexyl
H
H
3,4-dihydroxybutoxy
H





















TABLE 15





Compound







No.
R1
R2
R3
R4
R5







491
octyl
H
H
3,4-dihydroxybutoxy
H


492
1-propenyl
H
H
3,4-dihydroxybutoxy
H


493
1-octenyl
H
H
3,4-dihydroxybutoxy
H


494
geranyl
H
H
3,4-dihydroxybutoxy
H


495
methyl
H
H
carboxymethoxy
H


496
ethyl
H
H
carboxymethoxy
H


497
propyl
H
H
carboxymethoxy
H


498
isopropyl
H
H
carboxymethoxy
H


499
butyl
H
H
carboxymethoxy
H


500
s-butyl
H
H
carboxymethoxy
H


501
pentyl
H
H
carboxymethoxy
H


502
1-ethylpropyl
H
H
carboxymethoxy
H


503
hexyl
H
H
carboxymethoxy
H


504
2-methylpentyl
H
H
carboxymethoxy
H


505
heptyl
H
H
carboxymethoxy
H


506
1-ethylpentyl
H
H
carboxymethoxy
H


507
4-methylpentyl
H
H
carboxymethoxy
H


508
1-ethylhexyl
H
H
carboxymethoxy
H


509
octyl
H
H
carboxymethoxy
H


510
1-ethylhexyl
H
H
carboxymethoxy
H


511
decyl
H
H
carboxymethoxy
H


512
vinyl
H
H
carboxymethoxy
H


513
1-propenyl
H
H
carboxymethoxy
H


514
2-butenyl
H
H
carboxymethoxy
H


515
1-hexenyl
H
H
carboxymethoxy
H


516
1-octenyl
H
H
carboxymethoxy
H


517
1-decenyl
H
H
carboxymethoxy
H


518
3-methyl2-butenyl
H
H
carboxymethoxy
H


519
geranyl
H
H
carboxymethoxy
H


520
prenyl
H
H
carboxymethoxy
H


521
methyl
H
H
2-carboxyethoxy
H


522
ethyl
H
H
2-carboxyethoxy
H


523
butyl
H
H
2-carboxyethoxy
H


524
hexyl
H
H
2-carboxyethoxy
H


525
octyl
H
H
2-carboxyethoxy
H





















TABLE 16





Com-







pound


No.
R1
R2
R3
R4
R5







526
1-propenyl
H
H
2-carboxyethoxy
H


527
1-octenyl
H
H
2-carboxyethoxy
H


528
geranyl
H
H
2-carboxyethoxy
H


529
ethyl
H
H
3-carboxypropoxy
H


530
butyl
H
H
3-carboxypropoxy
H


531
hexyl
H
H
3-carboxypropoxy
H


532
octyl
H
H
3-carboxypropoxy
H


533
2-butenyl
H
H
3-carboxypropoxy
H


534
prenyl
H
H
3-carboxypropoxy
H


535
ethyl
H
H
4-carboxybutoxy
H


536
butyl
H
H
4-carboxybutoxy
H


537
hexyl
H
H
4-carboxybutoxy
H


538
octyl
H
H
4-carboxybutoxy
H


539
1-octenyl
H
H
4-carboxybutoxy
H


540
methyl
H
H
H
2-hydroxyethoxy


541
ethyl
H
H
H
2-hydroxyethoxy


542
propyl
H
H
H
2-hydroxyethoxy


543
isopropyl
H
H
H
2-hydroxyethoxy


544
butyl
H
H
H
2-hydroxyethoxy


545
s-butyl
H
H
H
2-hydroxyethoxy


546
pentyl
H
H
H
2-hydroxyethoxy


547
hexyl
H
H
H
2-hydroxyethoxy


548
2-
H
H
H
2-hydroxyethoxy



methylpentyl


549
heptyl
H
H
H
2-hydroxyethoxy


550
1-ethylpentyl
H
H
H
2-hydroxyethoxy


551
4-
H
H
H
2-hydroxyethoxy



methylpentyl


552
1-ethylhexyl
H
H
H
2-hydroxyethoxy


553
octyl
H
H
H
2-hydroxyethoxy


554
1-ethylhexyl
H
H
H
1-hydroxymethoxy


555
decyl
H
H
H
1-hydroxymethoxy


556
vinyl
H
H
H
1-hydroxymethoxy


557
1-propenyl
H
H
H
1-hydroxymethoxy


558
2-butenyl
H
H
H
1-hydroxymethoxy


559
1-hexenyl
H
H
H
1-hydroxymethoxy


560
1-octenyl
H
H
H
1-hydroxymethoxy





















TABLE 17





Compound







No.
R1
R2
R3
R4
R5







561
1-decenyl
H
H
H
1-hydroxymethoxy


562
3-methyl-2-butenyl
H
H
H
1-hydroxymethoxy


563
geranyl
H
H
H
1-hydroxymethoxy


564
prenyl
H
H
H
1-hydroxymethoxy


565
methyl
H
H
H
3-hydroxypropoxy


566
ethyl
H
H
H
3-hydroxypropoxy


567
butyl
H
H
H
3-hydroxypropoxy


568
hexyl
H
H
H
3-hydroxypropoxy


569
2-methylpentyl
H
H
H
3-hydroxypropoxy


570
octyl
H
H
H
3-hydroxypropoxy


571
decyl
H
H
H
3-hydroxypropoxy


572
1-propenyl
H
H
H
3-hydroxypropoxy


573
1-octenyl
H
H
H
3-hydroxypropoxy


574
geranyl
H
H
H
3-hydroxypropoxy


575
ethyl
H
H
H
4-hydroxybutoxy


576
butyl
H
H
H
4-hydroxybutoxy


577
s-butyl
H
H
H
4-hydroxybutoxy


578
hexyl
H
H
H
4-hydroxybutoxy


579
1-ethylpentyl
H
H
H
4-hydroxybutoxy


580
octyl
H
H
H
4-hydroxybutoxy


581
2-butenyl
H
H
H
4-hydroxybutoxy


582
prenyl
H
H
H
4-hydroxybutoxy


583
ethyl
H
H
H
2,3-dihydroxypropoxy


584
butyl
H
H
H
2,3-dihydroxypropoxy


585
hexyl
H
H
H
2,3-dihydroxypropoxy


586
octyl
H
H
H
2,3-dihydroxypropoxy


587
decyl
H
H
H
2,3-dihydroxypropoxy


588
1-hexenyl
H
H
H
2,3-dihydroxypropoxy


589
3-methyl-2-butenyl
H
H
H
2,3-dihydroxypropoxy


590
methyl
H
H
H
3,4-dihydroxybutoxy


591
ethyl
H
H
H
3,4-dihydroxybutoxy


592
hexyl
H
H
H
3,4-dihydroxybutoxy


593
octyl
H
H
H
3,4-dihydroxybutoxy


594
1-propenyl
H
H
H
3,4-dihydroxybutoxy


595
1-octenyl
H
H
H
3,4-dihydroxybutoxy





















TABLE 18





Compound







No.
R1
R2
R3
R4
R5







596
geranyl
H
H
H
3,4-dihydroxybutoxy


597
methyl
H
H
H
carboxymethoxy


598
ethyl
H
H
H
carboxymethoxy


599
propyl
H
H
H
carboxymethoxy


600
isopropyl
H
H
H
carboxymethoxy


601
butyl
H
H
H
carboxymethoxy


602
s-butyl
H
H
H
carboxymethoxy


603
pentyl
H
H
H
carboxymethoxy


604
hexyl
H
H
H
carboxymethoxy


605
2-methylpentyl
H
H
H
carboxymethoxy


606
heptyl
H
H
H
carboxymethoxy


607
1-ethylpentyl
H
H
H
carboxymethoxy


608
4-methylpentyl
H
H
H
carboxymethoxy


609
1-ethylhexyl
H
H
H
carboxymethoxy


610
octyl
H
H
H
carboxymethoxy


611
1-ethylhexyl
H
H
H
carboxymethoxy


612
decyl
H
H
H
carboxymethoxy


613
vinyl
H
H
H
carboxymethoxy


614
1-propenyl
H
H
H
carboxymethoxy


615
2-butenyl
H
H
H
carboxymethoxy


616
1-hexenyl
H
H
H
carboxymethoxy


617
1-octenyl
H
H
H
carboxymethoxy


618
1-decenyl
H
H
H
carboxymethoxy


619
3-methyl-2-butenyl
H
H
H
carboxymethoxy


620
geranyl
H
H
H
carboxymethoxy


621
prenyl
H
H
H
carboxymethoxy


622
methyl
H
H
H
2-carboxyethoxy


623
ethyl
H
H
H
2-carboxyethoxy


624
butyl
H
H
H
2-carboxyethoxy


625
hexyl
H
H
H
2-carboxyethoxy


626
octyl
H
H
H
2-carboxyethoxy


627
1-propenyl
H
H
H
2-carboxyethoxy


628
1-octenyl
H
H
H
2-carboxyethoxy


629
geranyl
H
H
H
2-carboxyethoxy


630
ethyl
H
H
H
3-carboxypropoxy





















TABLE 19





Compound







No.
R1
R2
R3
R4
R5







631
butyl
H
H
H
3-carboxypropoxy


632
hexyl
H
H
H
3-carboxypropoxy


633
octyl
H
H
H
3-carboxypropoxy


634
2-butenyl
H
H
H
3-carboxypropoxy


635
prenyl
H
H
H
3-carboxypropoxy


636
ethyl
H
H
H
4-carboxybutoxy


637
butyl
H
H
H
4-carboxybutoxy


638
hexyl
H
H
H
4-carboxybutoxy


639
octyl
H
H
H
4-carboxybutoxy


640
1-octenyl
H
H
H
4-carboxybutoxy









The term “physiologically acceptable salts” as used herein means nontoxic alkali addition salts of, for example, the above-described compounds, which include sodium salts, potassium salts, magnesium salts, calcium salts, ammonium salts, and the like. These physiologically acceptable salts can be produced by known methods from the benzopyran derivatives represented by the aforementioned general formula (I).


The benzopyran derivatives represented by the general formula (I) have excellent stability and bioabsorption compared to the aforementioned comparative compounds A, B and C disclosed in Journal of Medicinal Chemistry, volume 31, p. 1437 to 1445, 1988 (Donald. T. Witiak, J. Med. Chem., Vol. 31, P. 1437-1445, 1988.) (Non-patent Publication No. 1) and U.S. Pat. No. 4,845,121 (Patent Publication No. 3), as described later in examples. Therefore, the benzopyran derivatives represented by the general formula (I) are excellent active ingredients having favorable characteristics, especially when used as pharmaceutical agents.


Additionally, the benzopyran derivatives represented by the general formula (I) have low toxicity and excellent therapeutic effects on circulatory insufficiency, as described later in examples.


The term “circulatory insufficiency” as used herein includes occlusive or functional arterial diseases, venous diseases and complex arteriovenous diseases. For example, acute arterial occlusion, chronic arterial obstruction, functional circulatory disorder, and secondary circulatory disorders due to diabetes mellitus and the like.


The aforementioned acute arterial occlusion includes the acute thrombosis due to the rupture of proximal atherosclerotic plaques (i.e. a yellow atheromatous substance formed on the endothelial surface due to the lipid deposition in the endarterium and such an atheromatous substance may decrease or disrupt blood flow) or latent atherosclosis (i.e. arteriosclerosis characterized by lipid deposition irregularly distributed in the intima of aorta or medium-sized artery). The acute occlusion also includes venous thrombosis, deep-venous thrombosis, pulmonary embolism or the like that can be developed in veins due to the similar mechanisms, and such a disease can be caused from thrombus that travels from the heart, aorta or other large-sized vessel. Additionally, the acute occlusion further includes thrombus, embolus and vascular stenosis that occur secondary to external injury, surgery, percutaneous transluminal coronary angioplasty (PTCA), coronary artery bypass graft surgery (CAGB) and the like.


The aforementioned chronic arterial occlusion, which presents chronic ischemia, is a disease developed and progressed due to gradual expansion of atheromatous plaques (i.e. a yellow limited area or swelling on the intimal surface of the artery due to the lipid deposition in the endomembrane). The chronic arterial occlusion also includes thromboangitis obliterans and Buerger's disease.


The aforementioned functional circulatory disorder includes vasospastic Raynaud's phenomenon, Raynaud's disease, acrocyanosis and the like. The aforementioned secondary circulatory disorder includes circulatory disorders that occur secondary to diseases such as diabetes mellitus, maintenance hemodialysis, collagen disease, hypertension, or hyperlipemia.


The benzopyran derivatives represented by the general formula (I) have soothing effects and therapeutic effects against numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, gangrene, among others, that accompany the above-mentioned diseases. Additionally, the benzopyran derivatives can be used for prophylactic purposes to prevent the onset and recurrence of cerebral infarction caused from thrombotic or embolic ischemic disorders.


The improving effect on circulatory insufficiency in the present invention is completely different from the anti-allergic effect or the therapeutic effect for heart diseases disclosed in Japanese Unexamined Patent Application, Publication No. 2003-81827 (Patent Publication No. 1) or Japanese Unexamined Patent Application, Publication No. Hei 09-315967 (Patent Publication No. 2). Namely, the anti-allergic effect described in Japanese Unexamined Patent Application, Publication No. 2003-81827 (Patent Publication No. 1) is a preventive or therapeutic effect against allergic diseases caused by the excessively activated immune system in a living body induced by external or internal antigens. Such allergic diseases include, for example, immediate asthma, delayed asthma, bronchial asthma, pediatric asthma, nasal congestion, atopic dermatitis, allergic dermatitis, hives, eczema, allergic conjunctivitis, allergic rhinitis, pollenosis, food allergy, allergic gastroenteritis, allergic colitis, drug allergy, contact dermatitis and autoimmune diseases, and thus are completely different from circulatory insufficiency described in the present invention.


The heart diseases described in Japanese Unexamined Patent Application, Publication No. Hei 09-315967 (Patent publication No. 2) include arrhythmia such as supraventricular extrasystole, paroxysmal supraventricular tachycardia, paroxysmal atrial fibrillation, chronic atrial fibrillation, atrial fibrillation, premature ventricular contraction, ventricular tachycardia, ventricular fibrillation and atrioventricular block, arrhythmia accompanied with ischemic cardiopathy (such as myocardial infarction and cardiac angina), acute myocardial infarction, chronic myocardial infarction, cardiac failure, cardiac angina and the like. Thus, these heart diseases are completely different from circulatory insufficiency described in the present invention.


The drug for treating circulatory insufficiency containing the benzopyran derivatives represented by the general formula (I) as active ingredients can be administered orally or parenterally (for example, intravenous administration, subcutaneous administration, percutaneous absorption, rectal administration or the like). Such a pharmaceutical agent can be made into various dosage forms according to the purpose, such as tablets, capsules, granules, fine subtilaes, powders, troches, sublingual tablets, suppositories, ointments, injections, emulsions, suspensions, medicated syrups, chewable tablets and the like.


These dosage forms can be prepared in accordance with known techniques using pharmaceutically-acceptable additives commonly used in these types of drugs, such as excipients, bonding agents, disintegrators, lubricants, preservatives, anti-oxidative agents, isotonic agents, buffering agents, coating agents, sweetening agents, solubilizing agents, bases, dispersing agents, stabilizing agents, coloring agents and the like. Illustrative examples of these pharmaceutically acceptable additives are listed in the following.


Firstly, as excipients, the following can be listed: starch and derivatives of starch (such as dextrin, or carboxymethyl starch), cellulose and derivatives of cellulose (such as methylcellulose, or hydroxypropylmethylcellulose), sugars (such as lactose, sucrose, or glucose), silicic acid and silicates (such as natural aluminum silicate, or magnesium silicate), carbonates (such as calcium carbonate, magnesium carbonate, sodium bicarbonate), aluminum magnesium hydroxide, synthetic hydrotalcite, polyoxyethylene derivatives, glyceryl monostearate, sorbitan monooleate and the like.


As bonding agents, the following can be listed: starch and starch derivatives (such as alpha starches, or dextrin), cellulose and derivatives of cellulose (such as ethyl cellulose, sodium carboxymethyl cellulose, or hydroxypropyl methylcellulose), gum arabic, traganth, gelatin, sugars (such as glucose, or sucrose), ethanol, polyvinyl alcohols and the like.


As disintegrators, the following can be listed: starch and starch derivatives (such as carboxymethyl starch, or hydroxypropyl starch), cellulose and cellulose derivatives (such as sodium carboxymethyl cellulose, crystalline cellulose, or hydroxypropyl methylcellulose), carbonates (such as calcium carbonate, or calcium bicarbonate), traganth, gelatin, agar and the like.


As lubricants, the following can be listed: stearic acid, calcium stearate, magnesium stearate, talc, silicic acid and its salts (such as light silicic anhydrides, or natural aluminum silicates), titanium oxide, calcium hydrogen phosphate, dry aluminum hydroxide gel, macrogol and the like.


As preservatives, the following can be listed: p-hydroxybenzoate esters, sulfites (such as sodium sulfites, or sodium pyrosulfite), phosphates (such as sodium phosphate, calcium polyphosphate, sodium polyphosphate, or sodium metaphosphate), alcohols (such as chlorobutanol, or benzyl alcohol), benzalkonium chloride, benzethonium chloride, phenol, cresol, chlorocresol, dihydroacetic acid, sodium dihydroacetate, glyceryl sorbate, sugars and the like.


As anti-oxidative agents, the following can be listed: sulfites (such as sodium sulfite, or sodium bisulfite), rongalite, erythorbic acid, L-ascorbic acid, cysteine, thioglycerol, butylhydroxyanisol, dibutylhydroxytoluene, propyl gallate, ascorbyl palmitate, dl-alpha-tocopherol and the like.


As isotonic agents, the following can be listed: sodium chloride, sodium nitrate, potassium nitrate, dextrin, glycerol, glucose and the like.


As buffering agents, the following can be listed: sodium carbonate, hydrochloric acid, boric acid, phosphates (such as sodium hydrogen phosphate) and the like.


As coating agents, the following can be listed: cellulose derivatives (such as hydroxypropyl cellulose, cellulose acetate phthalate, or hydroxypropyl methylcellulose phthalate), shellac, polyvinylpyrrolidone, polyvinylpyridines (such as poly-2-vinylpyridine, or poly-2-vinyl-5-ethylpyridine), polyvinylacetyl diethylaminoacetate, polyvinyl alcohol phthalate, methacrylate/methacrylate copolymers and the like.


As sweetening agents, the following can be listed: sugars (such as glucose, sucrose, or lactose), sodium saccharin, sugar alcohols and the like.


As solubilizing agents, the following can be listed: ethylenediamine, nicotinamide, sodium saccharin, citric acid, citrates, sodium benzoate, soaps, polyvinylpyrrolidone, polysorbate, sorbitan fatty acid esters, glycerol, propylene glycol, benzyl alcohols and the like.


As bases, the following can be listed: fats (such as lard), vegetable oils (such as olive oil, or sesame oil), animal oil, lanolin acid, petrolatums, paraffin, wax, resins, bentonite, glycerol, glycol oils, higher alcohols (such as stearyl alcohol, or cetanol) and the like.


As dispersing agents, the following can be listed: gum arabic, traganth, cellulose derivatives (such as methyl cellulose), stearic acid polyesters, sorbitan sesquioleate, aluminum monostearate, sodium alginate, polysorbate, sorbitan fatty acid esters and the like.


Lastly, as stabilizing agents, the following can be listed: sulfites (such as sodium bisulfite), nitrogen, carbon dioxide and the like.


Although the content of the benzopyran derivatives represented by the general formula (I) in these pharmaceutical preparations varies depending on the dosage forms, they may be contained preferably in a concentration of from 0.01% to 100% by weight.


The dose of the drug for treating circulatory insufficiency of the present invention can be varied over a broad range depending on each warm-blooded animal to be treated, including humans, severity of the symptoms, doctor's judgement, among others. In general, however, it may be administered preferably in a dose of from 0.01 to 100 mg, more preferably from 0.1 to 70 mg, as the active ingredient, per day per kg body weight in the case of oral administration. In the same way, it may be administered preferably in a dose of from 0.01 to 100 mg, more preferably from 0.1 to 70 mg, as the active ingredient, per day per kg body weight in the case of parenteral administration. The daily dose described above may be administered once a day or divided into several batches, and may be also changed optionally in accordance with the extent of diseases and doctor's judgement.


EXAMPLES

The present invention will be described in detail with reference to examples. However, the present invention is not limited to examples.


Example 1
Acute Toxicity Test in Rats

We performed this test using rats in order to confirm the safety of the benzopyran derivatives used in the present invention (to be referred to as “the compounds of the present invention” hereinafter).


<Method>

The compounds of the present invention Nos. 9, 67, 98, 118, 119, 120, 121, 123, 124, 125, 131, 141, 144, 174, 179, 196, 214, 237, 244, 261, 280, 295, 333, 347, 388, 429, 445, 449, 451, 468, 477, 485, 491, 506, 525, 547, 551, and 633 were added to 0.5 (w/v) % methyl cellulose solution and prepared. Each solution was administered with oral gavage at the doses of 500, 1000 and 2000 mg/kg to male SD rats (body weight is 120 to 200 g, 5 rats per one group), using a feeding tube for rats.


After the administration, the animals were kept in cages for 7 days, to observe general symptoms and to count dead animals. Lethal dose (LD50: mg/kg) was extrapolated from the mortality at the 7th day after administration.


<Result>

In the result, the LD50 of all compounds tested were over 2000 mg/kg, and therefore it was clearly shown that the compounds of the present invention, the benzopyran derivatives, have high safety.


Example 2
The Pharmacological Effect on a Circulatory Insufficiency Model Induced by Lauric-Acid in Rats

We performed this test in order to evaluate the pharmacological effect of the compounds of the present invention using a circulatory insufficiency model of rats induced by injection of lauric-acid into their femoral artery.


<Method>

13-week-old male Wistar rats (body weight is 280 to 316 g), 8 rats per one group, were used. The rats were held in a supine position under anesthesia due to administration of 40 mg/kg of sodium pentobarbital by intraperitoneal injection. Then, the right femoral area was incised, thereby injecting 0.15 mL of 10 mg/mL lauric-acid solution into the femoral artery in order to induce lower limb gangrene caused by the peripheral vascular disorder. A few drops of instant adhesive (Aron-alpha; registered trademark) were used to stop bleeding, followed by topical application of antibiotics (potassium penicillin G solution) to prevent infection, and the incision site was then sutured.


Each compound of the present invention was added to 0.5 (w/v) % methyl cellulose solution to prepare 0.5 (w/v) % methyl cellulose suspension containing the compound of the present invention. The suspension was administered, by means of multiple oral dosing, 1 hour prior to and 3 hours after injection of lauric-acid and twice daily (at 10:00 and 17:00) for the following 9 days, at the dose of 30 mg/kg for each compound. Ticlopidine hydrochloride was added to 0.5 (w/v) % methyl cellulose solution to prepare 0.5 (w/v) % methyl cellulose suspension containing ticlopidine hydrochloride to use as a positive control. The suspension was administered orally 3 hours prior to injection of lauric-acid at the dose of 300 mg/kg.


The extent of lesions was evaluated 3 days and 10 days after injection of lauric acid by the following criteria:















<Point>



















No change (Normal)
0



Black discoloration limited to tiptoes
1



Black discoloration of toes
2



Necrosis of toes
3



Loss of toes
4










The lesion of each toe was graded and the total points of 5 toes were use as a lesion index, wherein 5 points were further added when the lesion reached the heel (i.e. the maximum lesion index was 25 points).


<Results>

The pharmacological effects of the control (vehicle treatment) group and each compound are shown in Table 20. The shown number refers to the average value of the lesion index obtained from the evaluation.









TABLE 20







The pharmacological effect on a lauric-acid-induced model










Lesion Index










Compound
after



No.
3 days
after 10 days












 9
2.5
7.8


 67
2.8
7.5


 98
3.0
8.4


118
2.4
8.3


119
2.5
7.1


120
2.3
8.0


121
2.8
7.3


123
2.6
7.9


124
3.0
8.3


125
2.6
8.1


131
3.0
7.5


141
2.6
7.8


144
2.5
7.2


174
2.7
7.5


179
3.6
8.4


196
3.3
7.4


214
3.5
7.9


237
3.4
7.9


244
3.5
7.4


261
3.7
7.6


280
2.7
7.9


295
3.0
7.2


333
3.0
7.4


347
2.3
8.1


388
2.9
7.5


429
2.2
7.9


445
2.7
7.5


449
2.8
7.3


451
2.6
7.2


468
2.8
7.8


477
2.9
7.7


485
2.8
7.9


491
2.9
7.4


506
2.7
7.3


525
2.9
7.8


547
3.0
7.2


551
2.5
7.8


633
2.6
7.4


control
7.5
19.4


Ticlopidine
2.8
7.4


hydrochloride









The results clearly showed that the compounds of the present invention decreased the lesion index compared to the control (vehicle treatment) group. This revealed that their pharmacological effect was equal to or greater than that of the positive control of ticlopidine hydrochloride. Thus, it was evident that the compounds of the present invention were useful as a drug for treating circulatory insufficiency.


Example 3
Effect on Bleeding Time in Rats
<Method>

5-week-old male SD rats (body weight is 138 to 152 g), 6 rats per one group, were used. The comparative substances (aspirin, cilostazol, beraprost sodium and ticlopidine hydrochloride) or the compounds of the present invention (compound Nos. 125, 144, 445, 451 and 525) were added to 0.5 (w/v) % methyl cellulose solution to prepare 0.5 (w/v) % methyl cellulose suspensions containing the comparative substances or the compounds of the present invention. The suspension was administered orally at the doses of 100 mg/kg for aspirin, 300 mg/kg for cilostazol, 1 mg/kg for beraprost sodium and 30 mg/kg for each compound of the present invention (compound No. 125, 144, 445, 451 and 525). 50 minutes after the administration, 50 mg/kg of pentobarbital sodium was intraperitoneally injected into the rat.


Because the pharmacologically-active form of ticlopidine hydrochloride (comparative substance) is its in vivo metabolite, the time between the administration of the test compound and tail cutting was set longer. Namely, 2 hours and 50 minutes after the administration of ticlopidine hydrochloride, 50 mg/kg of pentobarbital sodium was injected intraperitoneally. 10 minutes later, the tail was cut off at a position of 2 mm from the tip using a surgical blade, and was immediately immersed into a glass container (Magnus bath) filled with physiological saline maintained at approximately 37° C. to observe until the rat stopped bleeding.


The bleeding time was taken as the time from the tail cutting to the cessation of bleeding. The tail was marked at a position of 5 cm from the tip in advance, and was immersed in the physiological saline in the glass container at the depth of 5 cm from the surface. The maximum observation time was defined as 60 minutes after the tail cutting.


<Results>

Table 21 shows the results of those having 60 minutes between oral dosing of vehicle (control) or test compounds and the tail cutting












TABLE 21






Dosage
Time (min) between oral
Bleeding time


Compounds
(mg/kg)
dosing and the tail cutting
(min.)


















vehicle

60
4.9


aspirin
100
60
40.2


cilostazol
300
60
50.1


beraprost sodium
1
60
42.2


125
30
60
8.0


144
30
60
8.9


445
30
60
9.1


451
30
60
7.8


525
30
60
8.5









Table 22 shows the results of those having 180 minutes between oral dosing of vehicle (control) or test compounds including ticlopidine hydrochloride and the tail cutting.












TABLE 22






Dosage
Time (min) between oral
Bleeding time


Compounds
(mg/kg)
dosing and the tail cutting
(min.)


















vehicle

180
6.3


ticlopidine
300
180
36.1


hydrochloride


125
30
180
8.4


144
30
180
8.2


445
30
180
8.3


451
30
180
7.5


525
30
180
8.1









The results clearly showed that the compounds of the present invention were drugs having little effect on bleeding time prolongation compared with the existing drugs.


Example 4
Stability

In order to demonstrate stability of the compounds of the present invention, a stability test was conducted in an acidic solution or basic solution with respect to the compounds No. 125, 451 and 525 of the present invention, and the comparative compounds A, B and C.


<Method>

The test compounds were dissolved in an acidic solution (phosphate buffer (pH3.4)) and in a basic solution (phosphate buffer (pH7.3)) at the concentration of 1 mmoL/L. Immediately after they were dissolved, each solution was analyzed with liquid chromatography using an acidic solution (phosphate buffer (pH3.4)) or basic solution (phosphate buffer (pH7.3)) as an eluent. The peak area of the test compounds was measured as the initial value. Furthermore, a time-course analysis with liquid chromatography was conducted to measure the peak area at each time point. The solution containing the test compound was kept in an incubator at 37° C. Based on the measured peak area of the test compounds, the percentage (%) of the peak area at each measurement time point was calculated, taking the peak area of the initial value as 100(%). The half-life (the time to show a 50% residual rate of the test compounds) of the test compounds was further calculated, and its stability was evaluated based on the half-life.


<Result>

The results of the present example are shown in Table 23.












TABLE 23









Half-life (hr)












Compounds
pH 3.4 solution
pH 7.3 solution















Comparative compound A
30
65



Comparative compound B
53
70



Comparative compound C
35
65



125
>>100
>>100



451
>>100
>>100



525
>>100
>>100










In this result, no decrease in peak area was observed even after 100 hours, and this revealed that no degradation occurred with regard to the compounds of the present invention. Thus, the results clearly demonstrated that the compounds of the present invention were superior in stability to the aforementioned comparative compound A, B or C disclosed in Journal of Medicinal Chemistry, volume 31, p. 1437 to 1445, 1988 (Donald. T. Witiak, J. Med. Chem., Vo L. 31, P. 1437-1445, 1988.) (Non-patent publication No. 1) and U.S. Pat. No. 4,845,121 (Patent Publication No. 3).


Example 5
Bioabsorption

We conducted a plasma concentration measurement in rats with oral administration to compare the absorption of the compound of the present invention (compound No. 451) with the comparative compound A and B.


<Method>
1. Administration and Blood Sampling

6-week-old male SD rats (body weight is 200 to 230 g) were used for this test (3 rats per one group). The required amount of test compound was weighed and pulverized in an agate mortar. Then, a 0.5 (w/v) % methyl cellulose solution was added to prepare the suspension at the concentration of 10 mg/5 mL. 5 mL per kg body weight of the suspension was orally administered to rats once using a feeding tube for rats. About 0.3 mL of blood was sampled from the caudal vein using a heparinized glass tube at 0.25, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after the administration, and was centrifuged to obtain plasma.


2. Sample Preparation

30 μL of methanol and 300 μL of acetonitrile were added to 120 μL of the obtained plasma, and mixed with a Vortex mixer for 15 seconds. The sample was centrifuged to obtain 300 μL of the supernatant. The supernatant was dried, and 120 μL of an eluent was added thereto, and then mixed with a Vortex mixer for 15 seconds. After the mixture was centrifuged, the amount of each test compound remaining in the plasma was determined with liquid chromatography.


3. Measurement Determination of the Test Compound with Liquid Chromatography


40 μL of the sample, as prepared above, was applied to liquid chromatography with the following conditions to conduct the measurement.


(1) Liquid Chromatographic Condition for the Compound No. 451

Column: InertsiL (registered trademark) ODS-3 4.6 mmI.D.×250 mm;


Column temperature: 40° C.;


Eluent: Solution A (10 mmoL/L ammonium acetate:methanol=50:50), and Solution B (10 mmoL/L ammonium acetate:methanol=10:90);


Gradient condition (eluent composition): solution A→20 min.→solution B (5 min. elution)→1 min.→solution A (12 min. elution);


Flow rate: 1.0 mL; and


Detection wavelength: 314 nm.


(2) Liquid Chromatographic Condition for the Comparative Compound A

Column: InertsiL (registered trademark) ODS-3 4.6 mmI.D.×150 mm;


Column temperature: 40° C.;


Eluent: Solution A (aqua:methanol:acetic acid=90:10:0.5), and Solution B (aqua:methanol:acetic acid=10:90:0.5);


Gradient condition (eluent composition): solution A→20 min.→solution B (5 min. elution)→1 min.→solution A (12 min. elution);


Flow rate: 1.0 mL; and


Detection wavelength: 323 nm.


(3) Liquid Chromatographic Condition for the Comparative Compound B

Column: InertsiL (registered trademark) ODS-3 4.6 mmI.D.×150 mm;


Column temperature: 40° C.;


Eluent: Solution A (pH=2.2 phosphate buffer:acetonitrile=90:10), and Solution B (pH=2.2 phosphate buffer:acetonitrile=10:90);


Gradient condition (eluent composition): Solution A→10 min.→Solution B (2.5 min. elution)→0.5 min.→Solution A (9 min. elution);


Flow rate: 2.0 mL; and


Detection wavelength: 315 nm.


(Result)

Based on the peak area obtained in the liquid chromatography analysis with respect to 1 μg/mL of each test compound in plasma, the plasma concentration (μg/mL) at each time point was calculated. The results are presented in Table 24.












TABLE 24








Compound
Comparative
Comparative


Time point
No. 451
Compound A
Compound B













(h)
Mean
S.D.
Mean
S.D.
Mean
S.D.
















0.25
23.6
13.6
0.6
0.1
7.4
0.0


0.5
23.6
11.2
0.3
0.0
4.1
1.0


1.0
17.9
10.3
0.3
0.0
2.0
0.4


2.0
11.8
9.9
0.3
0.0
1.4
0.9


4.0
9.2
4.9
0.3
0.0
0.3
0.2


6.0
6.8
3.7
0.3
0.0
0.1
0.1


8.0
3.0
2.5
0.2
0.0
0.1
0.0


12.0
1.2
1.2
Not

0.0
0.0





detected


24.0
0.5
0.4
Not

0.0
0.0





detected









Additionally, each pharmacokinetic parameter calculated from the results is presented in Table 25, where “Cmax” refers to the maximum plasma concentration, “Tmax” refers to the time required to reach to the maximum plasma concentration, and “AUC” refers to the area under the plasma concentration-time curve, which represents the sum of the plasma concentration observed from the time point of administration of each test compound to the time point of 24 hours after the administration.













TABLE 25







Compound
Comparative
Comparative



No. 451
Compound A
Compound B



















Cmax (μg/mL)
25.1 ± 13.3
0.6 ± 0.1
7.4 ± 0.2


Tmax (h)
0.3 ± 0.1
0.25 ± 0.0 
0.25 ± 0.0 


AUC (μg · h/mL)
99.5 ± 64.4
2.2 ± 0.1
8.3 ± 2.6









In the results, it was clearly shown that the plasma concentration of the compounds of the present invention was about 3 to 40 times higher than that of the comparative compound A or B at each time point, and that such a high concentration can be maintained for a long time in plasma. Thus, it was evident that the compounds of the present invention were compounds having excellent bioabsorption.


It was clearly shown from the results of Examples 4 and 5 that the compounds of the present invention were superior in stability and bioabsorption compared to the comparative compounds A, B or C disclosed in Journal of Medicinal Chemistry, volume 31, p. 1437 to 1445, 1988 (Donald. T. Witiak, J. Med. Chem., Vo L. 31, P. 1437-1445, 1988.) (Non-patent Publication No. 1) and U.S. Pat. No. 4,845,121 (Patent Publication No. 3). Accordingly, the compounds of the present invention have excellent characteristics to be used as pharmaceutical agents.


Example 6
100 mg Tablet

To produce a 100 mg tablet, 100 mg of compound No. 451, 50 mg of lactose, 20 mg of crystalline cellulose, 20 mg of crosscarmellose sodium, 9 mg of hydroxypropyl cellulose and 1 mg of magnesium stearate (i.e. total of 200 mg/tablet) were used (750-fold volume of each component was actually used to produce the 100 mg tablet, as described below).


First, compound No. 451 was pulverized with a jet mill to obtain its pulverized powder. Next, 37.5 g of lactose, 15 g of crystalline cellulose, 15 g of crosscarmellose sodium and 75 g of the pulverized power of compound No. 451 were mixed in the granulator. Then, the mixture was granulated while spraying 67.5 g of a 10% hydroxypropy cellulose solution. After drying, 0.75 g of magnesium stearate was added to the resulting mixture, and the mixture was pulverized in a cutter mill, and further mixed. Then, the mixture was loaded into a tableting machine to obtain objective tablets.


Example 7
10% Powders

100 mg of the compound 451 crystals was pulverized with a mortar, and 900 mg of lactose was added thereto. The mixture was thoroughly mixed by way of pulverizing with a pestle to obtain 10% powders.


Example 8
10% Granules

300 mg of the compound 525 was mixed with 300 mg of starch in a mortar, and the mixture was pulverized therein. This was further mixed with 2000 mg of lactose and 370 mg of starch. Separately from this, 30 mg of gelatin was mixed with 1 mL of purified water, solubilized by heating, and cooled. Then, 1 mL of ethanol was added thereto while stirring whereby a gelatin solution was prepared. Thereafter, the above-prepared mixture was mixed with the gelatin solution, and the resulting mixture was kneaded, granulated and then, dried to obtain granules.


INDUSTRIAL APPLICABILITY

The drug containing as an active ingredient the benzopyran derivatives of the present invention can be medically applicable as a therapeutic agent for circulatory insufficiency. Additionally, the use of the aforementioned drug of the present invention and the method for treating circulatory insufficiency using the aforementioned drug of the present invention can be medically applicable for circulatory insufficiency because of their remarkable effectiveness in treating circulatory insufficiency.

Claims
  • 1. A drug for treating circulatory insufficiency containing a benzopyran derivative represented by the following general formula (I):
  • 2. The drug for treating circulatory insufficiency according to claim 1, wherein R1 is an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms; and any one of R2, R3, R4 and R5 is a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, an alkenyloxy group having 2 to 10 carbon atoms, an alkoxy group having 1 to 4 carbon atoms substituted with an hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms substituted with an carboxy group, and the others are hydrogen atoms.
  • 3. The drug for treating circulatory insufficiency according to claim 2, wherein the alkoxy group substituted with a hydroxyl group is an alkoxy group substituted with 1 or 2 hydroxyl groups.
  • 4. (canceled)
  • 5. The method for treating a peripheral vascular disorder resulting from occlusive or functional arterial diseases, venous diseases and complex arteriovenous diseases, the method comprising: using the drug for treating circulatory insufficiency according to claim 1.
  • 6. The drug for treating circulatory insufficiency according to claim 3, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral vascular disorder.
  • 7. The drug for treating circulatory insufficiency according to claim 6, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 8. Use of a benzopyran derivative represented by the following general formula (I):
  • 9. The drug for treating circulatory insufficiency according to claim 3, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 10. The drug for treating circulatory insufficiency according to claim 1, wherein the alkoxy group substituted with a hydroxyl group is an alkoxy group substituted with 1 or 2 hydroxyl groups.
  • 11. The drug for treating circulatory insufficiency according to claim 10, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral vascular disorder.
  • 12. The drug for treating circulatory insufficiency according to claim 11, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 13. The drug for treating circulatory insufficiency according to claim 3, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 14. The drug for treating circulatory insufficiency according to claim 1, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral vascular disorder.
  • 15. The drug for treating circulatory insufficiency according to claim 14, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 16. The drug for treating circulatory insufficiency according to claim 2, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral vascular disorder.
  • 17. The drug for treating circulatory insufficiency according to claim 16, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 18. The drug for treating circulatory insufficiency according to claim 1, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 19. A drug for treating peripheral circulatory insufficiency containing a benzopyran derivative represented by the following general formula (I):
  • 20. The drug for treating peripheral circulatory insufficiency according to claim 9, wherein R1 is an alkyl group having 1 to 10 carbon atoms or an alkenyl group having 2 to 10 carbon atoms; and any one of R2, R3, R4 and R5 is a hydroxyl group, an alkoxy group having 1 to 10 carbon atoms, an alkenyloxy group having 2 to 10 carbon atoms, an alkoxy group having 1 to 4 carbon atoms substituted with a hydroxyl group, or an alkoxy group having 1 to 4 carbon atoms substituted with a carboxy group, and the others are hydrogen atoms.
  • 21. The drug for treating peripheral circulatory insufficiency according to claim 20, wherein the alkoxy group substituted with a hydroxyl group is an alkoxy group substituted with 1 or 2 hydroxyl groups.
  • 22. The drug for treating peripheral circulatory insufficiency according to claim 21, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral circulatory insufficiency.
  • 23. The drug for treating peripheral circulatory insufficiency according to claim 22, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 24. A method for treating peripheral circulatory insufficiency, the method comprising: using the drug for treating peripheral circulatory insufficiency according to claim 9.
  • 25. The drug for treating peripheral circulatory insufficiency according to claim 19, wherein the alkoxy group substituted with a hydroxyl group is an alkoxy group substituted with 1 or 2 hydroxyl groups.
  • 26. The drug for treating peripheral circulatory insufficiency according to claim 25, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral circulatory insufficiency.
  • 27. The drug for treating peripheral circulatory insufficiency according to claim 26, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 28. The drug for treating peripheral circulatory insufficiency according to claim 19, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral circulatory insufficiency.
  • 29. The drug for treating peripheral circulatory insufficiency according to claim 20, which is used for treating at least one symptom selected from the group consisting of numbness, coldness, intermittent claudication, pain at rest, ulcer, extremity ulcer, cutaneous ulcer, and gangrene which are accompanied with the peripheral circulatory insufficiency.
  • 30. The drug for treating peripheral circulatory insufficiency according to claim 19, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 31. The drug for treating peripheral circulatory insufficiency according to claim 20, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 32. The drug for treating peripheral circulatory insufficiency according to claim 21, which is administered in a dose of from 0.01 to 100 mg as the active ingredient, per day per kg body weight.
  • 33. Use of a benzopyran derivative represented by the following general formula (I):
Priority Claims (1)
Number Date Country Kind
2005-309771 Oct 2005 JP national
PCT Information
Filing Document Filing Date Country Kind 371c Date
PCT/JP2006/321052 10/23/2006 WO 00 4/24/2008