CA1089866A - Benzofuran derivatives, preparation thereof and pharmaceutical compositions thereof - Google Patents
Benzofuran derivatives, preparation thereof and pharmaceutical compositions thereofInfo
- Publication number
- CA1089866A CA1089866A CA257,342A CA257342A CA1089866A CA 1089866 A CA1089866 A CA 1089866A CA 257342 A CA257342 A CA 257342A CA 1089866 A CA1089866 A CA 1089866A
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- Prior art keywords
- benzofuran
- group
- alkyl group
- derivative
- lower alkyl
- Prior art date
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-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/86—Benzo [b] furans; Hydrogenated benzo [b] furans with an oxygen atom directly attached in position 7
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
- C07D307/79—Benzo [b] furans; Hydrogenated benzo [b] furans with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to carbon atoms of the hetero ring
- C07D307/80—Radicals substituted by oxygen atoms
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE
A benzofuran derivative of the formula:
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6, or 7 position of the benzofuran ring; and its pharmaceutically acceptable acid addition salt, a process for the preparation of the same and a pharmaceutical composition containing the same.
The benzofuran derivative and its pharmaceutically accepta-ble acid addition salt possess a superior .beta.-adrenergic blocking activity and local anesthetic activity, and are useful for the prevention and treatment of heart disease, hypertension and hyperthyroidism.
A benzofuran derivative of the formula:
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6, or 7 position of the benzofuran ring; and its pharmaceutically acceptable acid addition salt, a process for the preparation of the same and a pharmaceutical composition containing the same.
The benzofuran derivative and its pharmaceutically accepta-ble acid addition salt possess a superior .beta.-adrenergic blocking activity and local anesthetic activity, and are useful for the prevention and treatment of heart disease, hypertension and hyperthyroidism.
Description
lU89866 SUMMARY OF THE INVENTION
The present invention relates to a novel benzofuran derivative and its pharmaceutically acceptable acid addi-tion salt, a process for the preparation of the same and a pharmaceutical composition containing the same.
There hitherto have been known many kinds of medi-caments for treating diseases in circulatory system of Z5 peripheral nervous system but has still been desired the development of a further superior medicament.
It has been researched to find out other compounds useful for preventing and treating diseases in circulatory system or peripheral nervous system. As a result, it has _ q _ now been found out that some novel benzofuran derivatives and their pharmaceutically acceptable acid addition salts possess superior pharmacological activities.
An object of the present invention is to provide a novel benzofuran derivative and its pharmaceutically acceptable acid addition salt useful for preventing and treating diseases in circulatory system or peripheral ner-vous system, particularly, heart disease, hypertension and hyperthyroidism.
Another object of the invention is to provide a pro-cess for preparing the novel benzofuran derivative and its pharmaceutically acceptable acid addition salt.
Further object of the invention is to provide a pharmaceutical composition containing as an essential ac-tive ingredient the novel benzofuran derivative or itspharmaceutically acceptable acid addition salt.
These and other objects will become apparent more clearly in the descriptions hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are the ben-zofuran derivatives having the following formula (I):
R Cl~ ~ OCH2fHCH2N~R (I) H OH
wherein R is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position of the ben-zofuran rlng; and their pharmaceutically acceptable acid addition salts.
~-` 108986ti Suitable examples o~ the lower alkyl group included in the group R o~ the formula-(I) include straight or branched al~yl grou~s ~vi~g 1 t3 4 Garb9 atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec,-butyl and tert.-butyl. Suitable example~ o~ the lower aIkyl group defined as R include straight or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert,-butyl. Among them, branched alkyl groups having 3 to 4 carbon atoms, such as -isopropyl, isobutyl, sec,-butyl and tert-j-butyl are more suitable.
Suitable examples o~ the pharmaceutically acceptable acid addition salts oi the benzofuran derivatives (I) include inorganic acid additlon salt8 such as ~ydro-~ chloride, hydrobromide, sul~ate and nitrate, and organic :$ acid addition salts su¢h as acetate, oxalate, succinate, `~ malate, maleate, tartarate and tannate, The compounds o~ the present invention possess ~up~rior ~-adrenergic blocking acti~ities and looal a~e~thetiQ a~tiVitie~ but ~how lsw~ ~o~isit~ t~a~
known compounds possessing the same pharmacological aotivities, and are use~ul as medicaments ~or preventing and treating diseases in circulatory system or peripheral 25~ nervous system, particularly, heart diseases such as cardiac ~rrhythmias and angina pectoris, hypertension, and hyp~erthyroidi~m, rom the pharmacological activity, more suitable compound~ o~ the present invention are tho~e wherein - 30~ i8 methyl group and R is a branched alkyl group having 1 .
10~9t~6~i 3 to 4 carbon atoms, for instance, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-sec.-butylaminopropoxy)benzofuran, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-tert.-butylaminopropoxy)-benzofuran, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropyl-aminopropoxy)benzofuran, 2-(1-hydroxyethyl)-6-(2-hydroxy-3-tert.-butylaminopropoxy)benzofuran, 2-(1-hydroxyethyl)-5-(2-hydroxy-3-sec.-butylaminopropoxy)benzofuran and 2-(l-hydroxyethyl)-4-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran. Among them, the most suitable compounds are
The present invention relates to a novel benzofuran derivative and its pharmaceutically acceptable acid addi-tion salt, a process for the preparation of the same and a pharmaceutical composition containing the same.
There hitherto have been known many kinds of medi-caments for treating diseases in circulatory system of Z5 peripheral nervous system but has still been desired the development of a further superior medicament.
It has been researched to find out other compounds useful for preventing and treating diseases in circulatory system or peripheral nervous system. As a result, it has _ q _ now been found out that some novel benzofuran derivatives and their pharmaceutically acceptable acid addition salts possess superior pharmacological activities.
An object of the present invention is to provide a novel benzofuran derivative and its pharmaceutically acceptable acid addition salt useful for preventing and treating diseases in circulatory system or peripheral ner-vous system, particularly, heart disease, hypertension and hyperthyroidism.
Another object of the invention is to provide a pro-cess for preparing the novel benzofuran derivative and its pharmaceutically acceptable acid addition salt.
Further object of the invention is to provide a pharmaceutical composition containing as an essential ac-tive ingredient the novel benzofuran derivative or itspharmaceutically acceptable acid addition salt.
These and other objects will become apparent more clearly in the descriptions hereinafter.
DETAILED DESCRIPTION OF THE INVENTION
The compounds of the present invention are the ben-zofuran derivatives having the following formula (I):
R Cl~ ~ OCH2fHCH2N~R (I) H OH
wherein R is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position of the ben-zofuran rlng; and their pharmaceutically acceptable acid addition salts.
~-` 108986ti Suitable examples o~ the lower alkyl group included in the group R o~ the formula-(I) include straight or branched al~yl grou~s ~vi~g 1 t3 4 Garb9 atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec,-butyl and tert.-butyl. Suitable example~ o~ the lower aIkyl group defined as R include straight or branched alkyl groups having 1 to 4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec.-butyl and tert,-butyl. Among them, branched alkyl groups having 3 to 4 carbon atoms, such as -isopropyl, isobutyl, sec,-butyl and tert-j-butyl are more suitable.
Suitable examples o~ the pharmaceutically acceptable acid addition salts oi the benzofuran derivatives (I) include inorganic acid additlon salt8 such as ~ydro-~ chloride, hydrobromide, sul~ate and nitrate, and organic :$ acid addition salts su¢h as acetate, oxalate, succinate, `~ malate, maleate, tartarate and tannate, The compounds o~ the present invention possess ~up~rior ~-adrenergic blocking acti~ities and looal a~e~thetiQ a~tiVitie~ but ~how lsw~ ~o~isit~ t~a~
known compounds possessing the same pharmacological aotivities, and are use~ul as medicaments ~or preventing and treating diseases in circulatory system or peripheral 25~ nervous system, particularly, heart diseases such as cardiac ~rrhythmias and angina pectoris, hypertension, and hyp~erthyroidi~m, rom the pharmacological activity, more suitable compound~ o~ the present invention are tho~e wherein - 30~ i8 methyl group and R is a branched alkyl group having 1 .
10~9t~6~i 3 to 4 carbon atoms, for instance, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-sec.-butylaminopropoxy)benzofuran, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-tert.-butylaminopropoxy)-benzofuran, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropyl-aminopropoxy)benzofuran, 2-(1-hydroxyethyl)-6-(2-hydroxy-3-tert.-butylaminopropoxy)benzofuran, 2-(1-hydroxyethyl)-5-(2-hydroxy-3-sec.-butylaminopropoxy)benzofuran and 2-(l-hydroxyethyl)-4-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran. Among them, the most suitable compounds are
2-(1-hydroxyethyl)-7-(2-hydroxy-3-sec.-butylaminopropoxy)-benzofuran, 2-(1-hydroxyethyl)-7-(2-hydroxy-3-tert.-butyl-aminopropoxy)benzofuran and 2-(1-hydroxyethyl)-7-(2-hy-droxy-3-isopropylaminopropoxy)benzofuran.
The benzofuran derivatives (I) can be prepared by reacting a benzofuran derivative having the following formula (II):
,~:, RlfH ~ o ~ OH 5II) OH
wherein R is the same as defined above, and the hydroxy group is at the 3, 4, 5, 6 or 7 position of the benzo-furan ring, with a propanol derivative having the follow-ing formula (III):
I (III) OH
wherein X is a halogen atom, and R is the same as defined above; or its acid addition salt.
The benzofuran derivatives (II) are novel compounds.
Examples thereof are, for instance, 2-hydroxy-` 10~986~
methyl-hydroxybenzofuran, 2-~l-hydroxyethyl)-hydroxybenzofuran, 2-(l-hydroxypropyl)-hydroxybenzofuran, 2-(l-hydroxybutyl)-hydroxybenzofuran, 2-(l-hydroxy-2-methylpropyl)-hydroxy-benzofuran, 2-(l-hydroxypentyl)-hydroxybenzofuran, 2-(l-hydroxy-3-methylbutyl)-hydroxybenzofuran, 2-(l-hydroxy-2-methylbutyl)-hydroxybenzofuran and 2-(a-hydroxybenzyl)-hydroxybenzofuran In these compounds, the hydroxy group substituted to the benzofuran ring is at the 3, 4, 5, 6 or 7 po~ition o~ the benzofuran ring. Among them, 2-(l-hydroxyethyl)-hydroxybenzofuran is more suitable The benzofuran derivatives (II) can be readily prepared by reducing a benzoiuran derivative having the iollowing ~ormula (IV):
~2~ V) wherein R2 i8 a lower alkyl group, a lower alkoxy group or phenyl group, and the hydroxy group is at-the 3, 4, 5, 6 or 7 position oi the benzoiuran rlng.
In the benzoiuran derivative (I~), suitable .
~ examples oi the lower alkyl group included in the group ;`~ R2 include straight or branched alkyl groups having l to . . . . .
4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, i80butyl, sec.-butyl and tert.-butyl. Suitable examples of the lower alkoxy group included in the group R2 inolude ~traight or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec -butoxy and tert -butoxy, The reduction of the benzo~uran dertvatives (IV) .~;
, ~ , . , ~ 6 6~
is carried out according to a conventional reduction method employing a conventional reducing agent and a conventional reduction condition. A suitable reduction method is one employing a reducing agent such as lithium aluminum hyd- -S ride, sodium borohydride, lithium borohydride or diborane.
As the reaction solvent, there are usually employed metha-nol, ethanol, dioxane, tetrahydrofuran and a mixture there-of.
In the propanol derivatives (III), suitable examples of the halogen atom referred to as X are chlorine, bromine and iodine. Among them, chlorine atom is more suitable.
Examples of the propanol derivatives (III) are, for in-stance, l-methylamino-3-chloro-2-propanol, l-ethylamino-
The benzofuran derivatives (I) can be prepared by reacting a benzofuran derivative having the following formula (II):
,~:, RlfH ~ o ~ OH 5II) OH
wherein R is the same as defined above, and the hydroxy group is at the 3, 4, 5, 6 or 7 position of the benzo-furan ring, with a propanol derivative having the follow-ing formula (III):
I (III) OH
wherein X is a halogen atom, and R is the same as defined above; or its acid addition salt.
The benzofuran derivatives (II) are novel compounds.
Examples thereof are, for instance, 2-hydroxy-` 10~986~
methyl-hydroxybenzofuran, 2-~l-hydroxyethyl)-hydroxybenzofuran, 2-(l-hydroxypropyl)-hydroxybenzofuran, 2-(l-hydroxybutyl)-hydroxybenzofuran, 2-(l-hydroxy-2-methylpropyl)-hydroxy-benzofuran, 2-(l-hydroxypentyl)-hydroxybenzofuran, 2-(l-hydroxy-3-methylbutyl)-hydroxybenzofuran, 2-(l-hydroxy-2-methylbutyl)-hydroxybenzofuran and 2-(a-hydroxybenzyl)-hydroxybenzofuran In these compounds, the hydroxy group substituted to the benzofuran ring is at the 3, 4, 5, 6 or 7 po~ition o~ the benzofuran ring. Among them, 2-(l-hydroxyethyl)-hydroxybenzofuran is more suitable The benzofuran derivatives (II) can be readily prepared by reducing a benzoiuran derivative having the iollowing ~ormula (IV):
~2~ V) wherein R2 i8 a lower alkyl group, a lower alkoxy group or phenyl group, and the hydroxy group is at-the 3, 4, 5, 6 or 7 position oi the benzoiuran rlng.
In the benzoiuran derivative (I~), suitable .
~ examples oi the lower alkyl group included in the group ;`~ R2 include straight or branched alkyl groups having l to . . . . .
4 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, i80butyl, sec.-butyl and tert.-butyl. Suitable examples of the lower alkoxy group included in the group R2 inolude ~traight or branched alkoxy groups having 1 to 4 carbon atoms, such as methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, isobutoxy, sec -butoxy and tert -butoxy, The reduction of the benzo~uran dertvatives (IV) .~;
, ~ , . , ~ 6 6~
is carried out according to a conventional reduction method employing a conventional reducing agent and a conventional reduction condition. A suitable reduction method is one employing a reducing agent such as lithium aluminum hyd- -S ride, sodium borohydride, lithium borohydride or diborane.
As the reaction solvent, there are usually employed metha-nol, ethanol, dioxane, tetrahydrofuran and a mixture there-of.
In the propanol derivatives (III), suitable examples of the halogen atom referred to as X are chlorine, bromine and iodine. Among them, chlorine atom is more suitable.
Examples of the propanol derivatives (III) are, for in-stance, l-methylamino-3-chloro-2-propanol, l-ethylamino-
3-chloro-2-propanol, 1-n-propylamino-3-chloro-2-propanol, 1-isopropylamino-3-chloro-2-propanol, 1-n-butylamino-3-chloro-2-propanol, 1-isobutylamino-3-chloro-2-propanol, l-sec.-butylamino-3-chloro-2-propanol, l-tert.-butylamino-3-chloro-2-propanol, 1-methylamino-3-bromo-2-propanol, l-ethylamino-3-bromo-2-propanol, 1-n-propylamino-3-bromo-2-propanol, 1-isopropylamino-3-bromo-2-propanol, l-n-butylamino-3-bromo-2-propanol, 1-isobutylamino-3-bromo-2-propanol, 1-sec.-butylamino-3-bromo-2-propanol, 1-tert.-butylamino-3-bromo-2-propanol, 1-methylamino-3-iodo-2-propanol, 1-ethylamino-3-iodo-2-propanol, 1-n-propylamino-3-iodo-2-propanol, 1-isopropylamino-3-iodo-2-propanol, 1-n-butylamino-3-iodo-2-propanol, l-isobutyl-amino-3-iodo-2-propanol, 1-sec.-butylamino-3-iodo-2-pro-panol and l-tert.-butylamino-3-iodo-2-propanol. Among them, the propanol derivatives (III) having a branched alkyl group having 3 to 4 carbon atoms are more preferable.
8 9 8 6 ~
~ xample~ of the acid addition salts of the propanol derivatives (III) include inorganic acid addition salt8 such as hydrochloride, hydrobromide, sulfate and nitrate, and organic acid addition 3alt~ such as acetate, oxalate, succinate, malate, maleate, tartarate and tannate.
These acid addition ~alts can be readily obtained according to a conventi~nal method, for instance, by reacting a propanol derivative (III) with a corre~ponding acid in an appropriate organic solvent.
The reaction oi a benzoiuran dèrivative (II) with a propanol derivative (III) or it~ acid addition salt can be e~iected by heating about equimolecular amounts of them in a solvent at a temperature of 60 to 120C , pre~erably 80 to 100C. In order to capture 1~ an acid ~ormed duri~g the reaction and to accelerate the reaction, there may be added to the reaction medium an alkali such as pota8~ium hydroxide, 80dium hydroxide, anhydrous potas8ium carbonate, ~odium hydride or sodium amide, The reaction is usually completed within a period oi 5 to 24 hours. As the reaction solvent, there are preferably employed methanol, ethanol, dimethyliormamide, acetone, diglyme, ~ethyl ethyl ketone, hexamethylphosphoric triamide and a mixture thereof.
The benzofuran derivative~ (I) can be also prepared by reacting a benzoiuran derivative having the iollowing ~ormula (V):
RlC~ ~R3 (V~
~' :
~ - 8 .
~0~9~6~
wherein Rl is the same as defined above, and R3 iQ 2,3-epoxypropoxy group or 3-chloro-2-hydroxypropoxy group and is at the 3, 4, 5, 6 or 7 pc~tion oi the benzoiuran ring, with a primary amine having the followlng iormula (VI):
RNH2 (VI) wher~in R i8 the same as defined above.
The benzofuran derivatives (~) are novel compounds.
Examples thereof are, for instance, 2-hydroxymethyl-(2,3-epoxypropoxy)benzo~uran, 2-hydroxymethyl-(3-chloro-2-hydroxypropoxy)benzofuran, 2-(1-hydroxyethyl)-(2,3-epoxy-propoxy)benzofuran, 2-(1-hydroxyethyl)-(3-chloro-2-hydroxY-propoxy)benzofuran, 2-(1-hydroxypropyl)-(2,3-epoxypropoxy)-benzofuran, 2-(1-hydroxypropyl3-(3-chloro-2-hydroxypropoxy)-benzoiuran, 2-(1-hydroxybutyl)-(2,3-epoxypropoxy)benzofuran, 2-(1-hydroxybutyl)-(3-chioro-2-hydroxypropoxy)benzofuran, 2-(1-hydroxy-2-methylpropyl)-(2,3-epoxypropoxy)benzofur~n, 2-(1-hydroxy-2-methylpropyl)-(3-chloro-2-hydroxypropoxy)-benzoiuran, 2-(1-hydroxypentyl)-(2,3-epoxypropoxy)benzo-furan, 2-(1-hydroxypentyl)-(3-chloro-2-hydroxypropoxy)-benzoiuran, 2-(1-hydroxy-3-methylbutyl)-(2,3-epoxypropoxy)-benzoiuran, 2-(1-hydroxy-3-methylbutyl)-(3-chloro-2-hydroxy-` propoxy)benzofuran, 2-(1-hydroxy-2-methylbutyl)-(2,3-epoxy-propoxy)benzoiuran, 2-(1-hydroxy-2-methylbutyl)-(3-chloro-2-hydroxypropoxy)benæofuran, 2-(-hydroxybenzyl)-(2,3-epoxypropo~y)benzoiuran and 2-(a-hydroxybenzyl)-(3-Chloro-2 hydroxypropoxy)benzofuran, In these compounds, the substituted propoxy group is at the 3, 4, 5, 6 or 7 position '~ ; of the benzoiuran ring. Among them, 2-(1-hydroxyethyl)-(2,3-epoxypropoxy)benzoiuran and 2-(1-hydroxyethyl)-(3-3Q chloro-2-hydroxypropoxy)benzoiuran ~re more preferable.
g .
lQ~98~
The benzofuran derivatives (V) can be readily prepared by reacting a benzofuran derivative (II) with epichlorohydrin, The reaction can be effected by heating the reactant~ at the boiling point of epichlorohydrin in ; 5 the presence of a catalyst such as piperidine hydrochloride, piperidine or boron trifluoride.
Alternatively, the benzofuran derivatives (V) can be readily prepared by reducing a benzoiuran derivative having the following iormula (VII):
R20 ~ R3 (VII~
wherein R2 and R3 are the same as deiined above.
The method ~or reduoing the benzo~u~n derivati~es (VII) is not limited to a particular one, and any convention-al method can be adopted, The representative reduction method is one employing a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride i or diborane, As the reaction solvent, there are usually employed methanol, ethanol, dioxane, tetrahydro~uran and a mixture thereoi, Examples oi the primary amines (VI) include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine~ isobutylamine, sec.-butylamine and tert.-3, ~ 25 butylamine. Among them, there are preferably employed the primary amines having a branched al~yl group having 3 to 4 carbon atoms.
The method for reacting a benzo~uran derivative (Y) with a primary amine (VI) is not limited to a particu-i, .
~ 30 lar one and there can be adopted any conventional method : -- 10 such as a method of heating the reactants in a sealed tube, or a method of heating the reactant~ under reflux in an appropriate Qolvent, for instance, methanol, ethanol, isopropanol, n-butanol, sec.-butanol. Preferably, the benzofuran derivative (~) is heated with an excess amount of the primary amine, and, after the reaction, the excess .
amine is removed, The reaction temperature is usually selected from the range of a room temperature to 130C,, preferably the range of 50 to 110C. The reaotion proceeds smoothly witho.ut employing a catalyst, and is ; u~ally completed within a period of 30 minutes to 7 hours.
. After the completion oi the reaction, the reaction mixture is sub~ected to conventional separating and pruifying procedures to give a highly pure benzofuran derivative (I) in a yield of about 45 to about 70 %, The benzofuran derivatives (I) can be al~o obtained by reducing a benzofuran derivative having the following formula (VIII):
R2C ~ CH21OHC~2NHR (VIII) O OH
3~ wherein R2 i8 a lower alkyl group, a lower alkoxy group or phenyl group, R is the same as defined abo~e, and the substituted propoxy group i8 at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or an ac~d addition salt thereof, . ~
In the benzofursn derivatives (VIII), suitable .
examples of the lower alkyl group included in the group R2 ~: include straight or branched alkyl groups having 1 to 4 carbon atom~, such as methyl, ethyl, n-propyl, isopropyl, ' 1 ~ ' ' - 11 -lQ ~ 9 ~ 6~j _ _ n-butyl, isobutyl, sec.-butyl and tert,-butyl. Suitable ; examples of the lower alkoxy group include straight or branched alkoxy groups ha~ing 1 to 4 carbon atoms, such a~ methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec,-butoxy and tert.-butoxy.
Examples of the benzofuran derivatives (VIII) are, for in~tance, 2-acetyl-7-(2-hydroxy-3-sec,-butylamino`
propoxy)benzofuran, 2-acetyl-7-(2-hydroxy-3-tert.-butylamino-propoxy)benzofuran, 2-acetyl-7-(2-hydroxy-3-isopropylamino-propoxy)benzofuran, 2-acetyl-6-(2-hydroxy-3-tert.-butyl-aminopropoxy)benzofuran, 2-acetyl-5-(2-hydroxy-3-aec.-butylaminopropoxy)benzofuran, 2-acetyl-4-(2-hydroxy-3-isopropylaminopropoxy)benzofuran, 2-acetyl-3 (2-hydroxy- -3-sec,-butylaminopropoxy)benzofuran, 2-propionyl-7-(2-hydroxy-~-tert.-butylaminopropoxy)benzofuran, 2-n-butyryl-7-(2-hydroxy-3-tert.-butylaminopropoxy)benzofuran, 2-I i~obutyryl-4-(2-hydroxy-3-sec,-butylaminopropoxy)benzofuran, 1 2-n-valeryl-7-( 2-hydroxy-~-tert,-butylaminopropoxy) benzo-~ furan, 2-isovaleryl-7-(2-hydroxy-3-~ec.-butylaminopropoxy)-j 20 benzofuran, 2-pivaloyl-4-(2-hydroxy-3-~ec.-butylamino-propoxy)benzofuran, 2-methoxycarbonyl-7-(?-hydroxy-3-tert.-, ` butylaminopropoxy)benzoiuran, 2-methoxycarbonyl-7-(~-hydroxy-j- ~ 3-i~opropylaminopropoxy)benzofuran, 2-n-butoxycarbonyl-4-j . . . . .
i~ (2-hydroxy-3-tert.-butylaminopropoxy)benzofuran;~ 2 benzoyl-7-l~ ~ 25 (2-hydroxy-3-isopropylaminopropoxy)benzo~uran, 2-benzoyl-7"~ 4-(2-hydroxy-3-~ec.-butylaminopropoxy)benzofuran, Among them, benzofuran derivatives (VIII) where~n ~2 i8.
methyl ~roup are more preferable.
Examples of the acid addition salts of the 3 benzofuran derivatives (VIII) include inorg~nic acid 7. ~ ~
~ -~ - 12 io~9~
addition salt~ such as hydrochloride, hydrobromide, sulfate and nitrate, and organic acid addition salts such as acetats, oxalate, succinate, malate, maleate, tartarate and tannate. These acid addition salts can be readily obtained according to a conventional method, fo~ instance, by reacting a benzoiuran derivative (III) with the corresponding acid in an approprlate organic solvent.
The reduction of a benzofuran derivative (VIII) can be carried out according to a conventional reduction method. The following reduction methods are preferably adopted, The first reduction method i8 one employing a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride or diborane, As the ~eaction solvent, there are usually employed methanol, ethanol, dioxane, tetrahydrofuran and mi~ture~ thereo~.
; The reduction 18 usually oarried out at a temperatureof 5 to 50C. for a period of 10 to 180 minutes.
~ 20 The second reduction method is one employing - as a reducing agent a metal:such as sodium ethoxide, ; ~ or an alumlnum alkoxide. Suitable examples Q~ the alu-'~`'5.'`~,' ', minum alkoxide are aluminum ethoxide, aluminum isopropoxide and aluminum tert,-butoxide, A~ the reaction solvent, there are u~ually empIoyed -an alcohol such a~ ethanol isopropanol, tert.-butanol, a hydrocarbon such as benzene, ,~ toluene, xylene. The reduction i8 u~ually carried out at a temperature of 25 to 130C, ~or a period oi 30 minutes to 5 hours. -~
30 ~ The third reduction method is a catalystic ~ 13 -.., 10~9~
reduction. As the catalyst, there can be employed any conventional catalyst such as Raney nickel or palladium on carbon As the reaction ~olvent, there are usually employed methanol, ethanol, digxane, tetrahydrofuran, cyclohexane, water and a mixture thereof. The re-duction i~ usually carried out under a normal pressure or an elevated pressure at a temperature of 15 to 30C
for a period of 30 minutes to 20 hours.
The fourth reduction method is one employing an aromatic aldehyde ketone reductase which is widely distributed, e,g. in microorganism and orgsns such as liver, kidney, blood and intestinal canal of animals such as rabbit, hamster, mouse and rat. The reduction can be carried out by incubating a benzo~uran derivative (VIII) with the aromatic aldehyde ketone reductase and, if necessary, the coenzyma thereo~ according to a conventional method. The incubation is ususlly carried out in an aqueous medium oi pH 5 to 9, pre~erably 6,5 to 7,5 at a temperature of 5 to 50C.
In addition to the above conventional reduction methods, the reduction of a benzofursn derivative (VIII) ;~ can be effected by allowing an alkaline solution of it to stand. Suitable examples of the alkaline reagent are sodium hydroxide and potassium hydroxide.
In the reduction mentioned above, a benzofursn derivative (VIII) wherein R2 is a lower alkyl group or phenyl group gives a ben~ofuran derivative ~I) wherein l is the corresponding lower alkyl group or phenyl group, and a benzofuran derivative (VIII) wherein R2 is a lower alkoxy group gives a benzofuran derivative (I) wherein 10 ~ 9 Rl is hydrogen atom.
The benzofuran derivative (VIII) employed as the ~tarting material can be readily prepared according to a variety oi methods, ior instance, those described in United States Patent No. 3,85~,923. That is to ~ay, the benzofuran derivative (VIII) is prepared by reacting a benzo~uran derivative (VII) with a primary amine (VI), or by reacting a bens.o~ran derivative (IV) with a propanol derivative (III).
When the benzoiuran derivatives (I) prepared by the above-mentioned methods are iree bases, they can be readily converted into their pharmaceutically acceptable acid addition salts according to a conventional method, ior instance, by treating the free base with an acid, and in case o~ need, in the presence oi a suitable organic solvent such as methanol or ethanol. ~xamples oi the acid employed include inorganic acids such as hydrochloric acid, hydrobromic acid, suliuric acid and nitric acid, and or~anic acids 8uch a8 acetic acid, oxalic acid, 8uccinic acid, maleic acid, malic acid, tartaric acid and tannic acid, . . ~
The benzoiuran derivatives (I) o~ the present `.~ invention have l to 4 asymmetric carbon atoms, and a variety of stereoisomers may exist, Accordingly, the present invention relates to each oi the stereoi#omers and -; a-mixture thereof.
~ .
; The benzoiuran derivatives (I) of the present.
: invention and their pharmaceutically acceptable acid .~
addition salts are novel compounds and posse~s superior ~- 30 pharmacological activities. For instance, the benzofuran _ 15 1()~986~;
derivatives (I) improve an electrocardiogram under hypoxia or isoproterenol charge, and suppress isoproterenol-induced increases in myocardial contractile force and heart rate, and decrease in blood pressure, which show that they possess superior ~-adrenergic blocking activitie~. Furthermore, the benzofuran derivatives (I) show lower toxicities than a conventional ~-adrenergic blocking agent. Accordingly, the benzofuran derivatives ~I) are u8eful ~or the prevention and treatment of diseases such as heart di~esses, for in~tance, cardiac arrythmias and angina pectoris, hyper-tension and hyperthyroidism.
The superior pharmacological activities of the compounds of the present invention are effected by adminis-tration in a dosage o~ about 10 to about 200 mg./day.
As the method f~r administration, any conventional method such as oral administration, hypodermic in~ection or intravenous in~ection can be adopted The compounds of the present invention may be employed in a variety of preparation forms such as tablets, cap8ule~j powder~, granule~ or in~ections, ~he preparations can be prepared according to a conventional method employing a conventi~nal~carrier. ~xamples of such carriers include binders, solid diluents, liquid diluents, fillers and the ;like, such as starch, lactose, microcrystalline cellulose, suger, magnesium stearate, silicon dioxide, talc, water for in~ection and normal ~aline solution.
The present invention is more particularly described , in the following ~zamples which are intended a9 illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art, ~: S
1~ 9~
Reference Example 1 Into 10 ml. of epichlorohydrin was dissolved 0.5 g.
of 2-(1-hydroxyethyl)-5-hydroxybenzofuran, and a small amount of piperidine hydrochloride was added thereto. The resulting mixture was heated under reflux for 5 hours and then the excess epichlorohydrin was distilled off under a reduced pressure to give a residue. The residue was fractionated by a silica gel column to give 0.4 g. of an oily material.
With respect to the obtained oily material, the ele-mentary analysis, IR spectrum and NMR spectrum were de-termined. As a result, the oily material was identified as 2-(1-hydroxyethyl)-5-(2,3-epoxypropoxy)benzofuran to be employed as a starting material in the present inven-tion.
The NMR spectrum was measured in deutero chloroform at 100 MHz. The signal positions were expressed in values.
The elementary analysis, characteristic IR bands and ~ values of the oily material are as follows: The sym-bols in parentheses after each ~ values mean the number of proton and the multiplicity in that order.
Elementary analysis for C13H14O4:
Calcd. (%) C 66.84 H 5.99 Found (%) C 67.08 H 5.71 Characteristic IR bands (cm. l):vOH 3,400;
vcH 3,100, 3,060 values (p.p.m.): 1.58 (3H, d), 2.63 (lH, s), 2.71 tlH, dd), 2.86 (lH, dd), 3.32 (lH, m), 3.88 (lH, dd), 4.18 (lH, dd), 4.91 (lH, q), 6.44 (lH, s), 6.81 (lH, dd), 6.92 (lH, d), 10~986~
7.25 (lH, d) Reference E~amPle 2 The same procedure a~ in Reference E~ample 1 was repeated except that 0.5 g, of 2-(1-hydroxyethyl)-7-hydroxy-benzofuran was employed instead of 2-(1-hydroxyethyl)-5-hydro~ybenzo~uran employed in Reference Example 1, to give 0.45 g. of 2-(1-hydroxyethyl)-7-(2,3-epo~ypropoxy)benzo-furan to be employed as a starting material in the present invention, The elementary analysis, characteristic IR
bands and ~ values thereof are as follows:
~lementary analysis for C13H1404:
Calcd, (%) C 66.84 H 5.99 Found (%) C 66.59 H 6,14 Characteristic IR bands (cm.l): v0H 3,400;
~CH 3,125, 3,070 values (p,p.m.): 1.61 (3E, d), 2.76 (lH, dd), 2.90 (lH, 8), 3.42 (lH, m), 4,12 (lH, dd),
8 9 8 6 ~
~ xample~ of the acid addition salts of the propanol derivatives (III) include inorganic acid addition salt8 such as hydrochloride, hydrobromide, sulfate and nitrate, and organic acid addition 3alt~ such as acetate, oxalate, succinate, malate, maleate, tartarate and tannate.
These acid addition ~alts can be readily obtained according to a conventi~nal method, for instance, by reacting a propanol derivative (III) with a corre~ponding acid in an appropriate organic solvent.
The reaction oi a benzoiuran dèrivative (II) with a propanol derivative (III) or it~ acid addition salt can be e~iected by heating about equimolecular amounts of them in a solvent at a temperature of 60 to 120C , pre~erably 80 to 100C. In order to capture 1~ an acid ~ormed duri~g the reaction and to accelerate the reaction, there may be added to the reaction medium an alkali such as pota8~ium hydroxide, 80dium hydroxide, anhydrous potas8ium carbonate, ~odium hydride or sodium amide, The reaction is usually completed within a period oi 5 to 24 hours. As the reaction solvent, there are preferably employed methanol, ethanol, dimethyliormamide, acetone, diglyme, ~ethyl ethyl ketone, hexamethylphosphoric triamide and a mixture thereof.
The benzofuran derivative~ (I) can be also prepared by reacting a benzoiuran derivative having the iollowing ~ormula (V):
RlC~ ~R3 (V~
~' :
~ - 8 .
~0~9~6~
wherein Rl is the same as defined above, and R3 iQ 2,3-epoxypropoxy group or 3-chloro-2-hydroxypropoxy group and is at the 3, 4, 5, 6 or 7 pc~tion oi the benzoiuran ring, with a primary amine having the followlng iormula (VI):
RNH2 (VI) wher~in R i8 the same as defined above.
The benzofuran derivatives (~) are novel compounds.
Examples thereof are, for instance, 2-hydroxymethyl-(2,3-epoxypropoxy)benzo~uran, 2-hydroxymethyl-(3-chloro-2-hydroxypropoxy)benzofuran, 2-(1-hydroxyethyl)-(2,3-epoxy-propoxy)benzofuran, 2-(1-hydroxyethyl)-(3-chloro-2-hydroxY-propoxy)benzofuran, 2-(1-hydroxypropyl)-(2,3-epoxypropoxy)-benzofuran, 2-(1-hydroxypropyl3-(3-chloro-2-hydroxypropoxy)-benzoiuran, 2-(1-hydroxybutyl)-(2,3-epoxypropoxy)benzofuran, 2-(1-hydroxybutyl)-(3-chioro-2-hydroxypropoxy)benzofuran, 2-(1-hydroxy-2-methylpropyl)-(2,3-epoxypropoxy)benzofur~n, 2-(1-hydroxy-2-methylpropyl)-(3-chloro-2-hydroxypropoxy)-benzoiuran, 2-(1-hydroxypentyl)-(2,3-epoxypropoxy)benzo-furan, 2-(1-hydroxypentyl)-(3-chloro-2-hydroxypropoxy)-benzoiuran, 2-(1-hydroxy-3-methylbutyl)-(2,3-epoxypropoxy)-benzoiuran, 2-(1-hydroxy-3-methylbutyl)-(3-chloro-2-hydroxy-` propoxy)benzofuran, 2-(1-hydroxy-2-methylbutyl)-(2,3-epoxy-propoxy)benzoiuran, 2-(1-hydroxy-2-methylbutyl)-(3-chloro-2-hydroxypropoxy)benæofuran, 2-(-hydroxybenzyl)-(2,3-epoxypropo~y)benzoiuran and 2-(a-hydroxybenzyl)-(3-Chloro-2 hydroxypropoxy)benzofuran, In these compounds, the substituted propoxy group is at the 3, 4, 5, 6 or 7 position '~ ; of the benzoiuran ring. Among them, 2-(1-hydroxyethyl)-(2,3-epoxypropoxy)benzoiuran and 2-(1-hydroxyethyl)-(3-3Q chloro-2-hydroxypropoxy)benzoiuran ~re more preferable.
g .
lQ~98~
The benzofuran derivatives (V) can be readily prepared by reacting a benzofuran derivative (II) with epichlorohydrin, The reaction can be effected by heating the reactant~ at the boiling point of epichlorohydrin in ; 5 the presence of a catalyst such as piperidine hydrochloride, piperidine or boron trifluoride.
Alternatively, the benzofuran derivatives (V) can be readily prepared by reducing a benzoiuran derivative having the following iormula (VII):
R20 ~ R3 (VII~
wherein R2 and R3 are the same as deiined above.
The method ~or reduoing the benzo~u~n derivati~es (VII) is not limited to a particular one, and any convention-al method can be adopted, The representative reduction method is one employing a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride i or diborane, As the reaction solvent, there are usually employed methanol, ethanol, dioxane, tetrahydro~uran and a mixture thereoi, Examples oi the primary amines (VI) include methylamine, ethylamine, n-propylamine, isopropylamine, n-butylamine~ isobutylamine, sec.-butylamine and tert.-3, ~ 25 butylamine. Among them, there are preferably employed the primary amines having a branched al~yl group having 3 to 4 carbon atoms.
The method for reacting a benzo~uran derivative (Y) with a primary amine (VI) is not limited to a particu-i, .
~ 30 lar one and there can be adopted any conventional method : -- 10 such as a method of heating the reactants in a sealed tube, or a method of heating the reactant~ under reflux in an appropriate Qolvent, for instance, methanol, ethanol, isopropanol, n-butanol, sec.-butanol. Preferably, the benzofuran derivative (~) is heated with an excess amount of the primary amine, and, after the reaction, the excess .
amine is removed, The reaction temperature is usually selected from the range of a room temperature to 130C,, preferably the range of 50 to 110C. The reaotion proceeds smoothly witho.ut employing a catalyst, and is ; u~ally completed within a period of 30 minutes to 7 hours.
. After the completion oi the reaction, the reaction mixture is sub~ected to conventional separating and pruifying procedures to give a highly pure benzofuran derivative (I) in a yield of about 45 to about 70 %, The benzofuran derivatives (I) can be al~o obtained by reducing a benzofuran derivative having the following formula (VIII):
R2C ~ CH21OHC~2NHR (VIII) O OH
3~ wherein R2 i8 a lower alkyl group, a lower alkoxy group or phenyl group, R is the same as defined abo~e, and the substituted propoxy group i8 at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or an ac~d addition salt thereof, . ~
In the benzofursn derivatives (VIII), suitable .
examples of the lower alkyl group included in the group R2 ~: include straight or branched alkyl groups having 1 to 4 carbon atom~, such as methyl, ethyl, n-propyl, isopropyl, ' 1 ~ ' ' - 11 -lQ ~ 9 ~ 6~j _ _ n-butyl, isobutyl, sec.-butyl and tert,-butyl. Suitable ; examples of the lower alkoxy group include straight or branched alkoxy groups ha~ing 1 to 4 carbon atoms, such a~ methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec,-butoxy and tert.-butoxy.
Examples of the benzofuran derivatives (VIII) are, for in~tance, 2-acetyl-7-(2-hydroxy-3-sec,-butylamino`
propoxy)benzofuran, 2-acetyl-7-(2-hydroxy-3-tert.-butylamino-propoxy)benzofuran, 2-acetyl-7-(2-hydroxy-3-isopropylamino-propoxy)benzofuran, 2-acetyl-6-(2-hydroxy-3-tert.-butyl-aminopropoxy)benzofuran, 2-acetyl-5-(2-hydroxy-3-aec.-butylaminopropoxy)benzofuran, 2-acetyl-4-(2-hydroxy-3-isopropylaminopropoxy)benzofuran, 2-acetyl-3 (2-hydroxy- -3-sec,-butylaminopropoxy)benzofuran, 2-propionyl-7-(2-hydroxy-~-tert.-butylaminopropoxy)benzofuran, 2-n-butyryl-7-(2-hydroxy-3-tert.-butylaminopropoxy)benzofuran, 2-I i~obutyryl-4-(2-hydroxy-3-sec,-butylaminopropoxy)benzofuran, 1 2-n-valeryl-7-( 2-hydroxy-~-tert,-butylaminopropoxy) benzo-~ furan, 2-isovaleryl-7-(2-hydroxy-3-~ec.-butylaminopropoxy)-j 20 benzofuran, 2-pivaloyl-4-(2-hydroxy-3-~ec.-butylamino-propoxy)benzofuran, 2-methoxycarbonyl-7-(?-hydroxy-3-tert.-, ` butylaminopropoxy)benzoiuran, 2-methoxycarbonyl-7-(~-hydroxy-j- ~ 3-i~opropylaminopropoxy)benzofuran, 2-n-butoxycarbonyl-4-j . . . . .
i~ (2-hydroxy-3-tert.-butylaminopropoxy)benzofuran;~ 2 benzoyl-7-l~ ~ 25 (2-hydroxy-3-isopropylaminopropoxy)benzo~uran, 2-benzoyl-7"~ 4-(2-hydroxy-3-~ec.-butylaminopropoxy)benzofuran, Among them, benzofuran derivatives (VIII) where~n ~2 i8.
methyl ~roup are more preferable.
Examples of the acid addition salts of the 3 benzofuran derivatives (VIII) include inorg~nic acid 7. ~ ~
~ -~ - 12 io~9~
addition salt~ such as hydrochloride, hydrobromide, sulfate and nitrate, and organic acid addition salts such as acetats, oxalate, succinate, malate, maleate, tartarate and tannate. These acid addition salts can be readily obtained according to a conventional method, fo~ instance, by reacting a benzoiuran derivative (III) with the corresponding acid in an approprlate organic solvent.
The reduction of a benzofuran derivative (VIII) can be carried out according to a conventional reduction method. The following reduction methods are preferably adopted, The first reduction method i8 one employing a reducing agent such as lithium aluminum hydride, sodium borohydride, lithium borohydride or diborane, As the ~eaction solvent, there are usually employed methanol, ethanol, dioxane, tetrahydrofuran and mi~ture~ thereo~.
; The reduction 18 usually oarried out at a temperatureof 5 to 50C. for a period of 10 to 180 minutes.
~ 20 The second reduction method is one employing - as a reducing agent a metal:such as sodium ethoxide, ; ~ or an alumlnum alkoxide. Suitable examples Q~ the alu-'~`'5.'`~,' ', minum alkoxide are aluminum ethoxide, aluminum isopropoxide and aluminum tert,-butoxide, A~ the reaction solvent, there are u~ually empIoyed -an alcohol such a~ ethanol isopropanol, tert.-butanol, a hydrocarbon such as benzene, ,~ toluene, xylene. The reduction i8 u~ually carried out at a temperature of 25 to 130C, ~or a period oi 30 minutes to 5 hours. -~
30 ~ The third reduction method is a catalystic ~ 13 -.., 10~9~
reduction. As the catalyst, there can be employed any conventional catalyst such as Raney nickel or palladium on carbon As the reaction ~olvent, there are usually employed methanol, ethanol, digxane, tetrahydrofuran, cyclohexane, water and a mixture thereof. The re-duction i~ usually carried out under a normal pressure or an elevated pressure at a temperature of 15 to 30C
for a period of 30 minutes to 20 hours.
The fourth reduction method is one employing an aromatic aldehyde ketone reductase which is widely distributed, e,g. in microorganism and orgsns such as liver, kidney, blood and intestinal canal of animals such as rabbit, hamster, mouse and rat. The reduction can be carried out by incubating a benzo~uran derivative (VIII) with the aromatic aldehyde ketone reductase and, if necessary, the coenzyma thereo~ according to a conventional method. The incubation is ususlly carried out in an aqueous medium oi pH 5 to 9, pre~erably 6,5 to 7,5 at a temperature of 5 to 50C.
In addition to the above conventional reduction methods, the reduction of a benzofursn derivative (VIII) ;~ can be effected by allowing an alkaline solution of it to stand. Suitable examples of the alkaline reagent are sodium hydroxide and potassium hydroxide.
In the reduction mentioned above, a benzofursn derivative (VIII) wherein R2 is a lower alkyl group or phenyl group gives a ben~ofuran derivative ~I) wherein l is the corresponding lower alkyl group or phenyl group, and a benzofuran derivative (VIII) wherein R2 is a lower alkoxy group gives a benzofuran derivative (I) wherein 10 ~ 9 Rl is hydrogen atom.
The benzofuran derivative (VIII) employed as the ~tarting material can be readily prepared according to a variety oi methods, ior instance, those described in United States Patent No. 3,85~,923. That is to ~ay, the benzofuran derivative (VIII) is prepared by reacting a benzo~uran derivative (VII) with a primary amine (VI), or by reacting a bens.o~ran derivative (IV) with a propanol derivative (III).
When the benzoiuran derivatives (I) prepared by the above-mentioned methods are iree bases, they can be readily converted into their pharmaceutically acceptable acid addition salts according to a conventional method, ior instance, by treating the free base with an acid, and in case o~ need, in the presence oi a suitable organic solvent such as methanol or ethanol. ~xamples oi the acid employed include inorganic acids such as hydrochloric acid, hydrobromic acid, suliuric acid and nitric acid, and or~anic acids 8uch a8 acetic acid, oxalic acid, 8uccinic acid, maleic acid, malic acid, tartaric acid and tannic acid, . . ~
The benzoiuran derivatives (I) o~ the present `.~ invention have l to 4 asymmetric carbon atoms, and a variety of stereoisomers may exist, Accordingly, the present invention relates to each oi the stereoi#omers and -; a-mixture thereof.
~ .
; The benzoiuran derivatives (I) of the present.
: invention and their pharmaceutically acceptable acid .~
addition salts are novel compounds and posse~s superior ~- 30 pharmacological activities. For instance, the benzofuran _ 15 1()~986~;
derivatives (I) improve an electrocardiogram under hypoxia or isoproterenol charge, and suppress isoproterenol-induced increases in myocardial contractile force and heart rate, and decrease in blood pressure, which show that they possess superior ~-adrenergic blocking activitie~. Furthermore, the benzofuran derivatives (I) show lower toxicities than a conventional ~-adrenergic blocking agent. Accordingly, the benzofuran derivatives ~I) are u8eful ~or the prevention and treatment of diseases such as heart di~esses, for in~tance, cardiac arrythmias and angina pectoris, hyper-tension and hyperthyroidism.
The superior pharmacological activities of the compounds of the present invention are effected by adminis-tration in a dosage o~ about 10 to about 200 mg./day.
As the method f~r administration, any conventional method such as oral administration, hypodermic in~ection or intravenous in~ection can be adopted The compounds of the present invention may be employed in a variety of preparation forms such as tablets, cap8ule~j powder~, granule~ or in~ections, ~he preparations can be prepared according to a conventional method employing a conventi~nal~carrier. ~xamples of such carriers include binders, solid diluents, liquid diluents, fillers and the ;like, such as starch, lactose, microcrystalline cellulose, suger, magnesium stearate, silicon dioxide, talc, water for in~ection and normal ~aline solution.
The present invention is more particularly described , in the following ~zamples which are intended a9 illustrative only since numerous modifications and variations therein will be apparent to those skilled in the art, ~: S
1~ 9~
Reference Example 1 Into 10 ml. of epichlorohydrin was dissolved 0.5 g.
of 2-(1-hydroxyethyl)-5-hydroxybenzofuran, and a small amount of piperidine hydrochloride was added thereto. The resulting mixture was heated under reflux for 5 hours and then the excess epichlorohydrin was distilled off under a reduced pressure to give a residue. The residue was fractionated by a silica gel column to give 0.4 g. of an oily material.
With respect to the obtained oily material, the ele-mentary analysis, IR spectrum and NMR spectrum were de-termined. As a result, the oily material was identified as 2-(1-hydroxyethyl)-5-(2,3-epoxypropoxy)benzofuran to be employed as a starting material in the present inven-tion.
The NMR spectrum was measured in deutero chloroform at 100 MHz. The signal positions were expressed in values.
The elementary analysis, characteristic IR bands and ~ values of the oily material are as follows: The sym-bols in parentheses after each ~ values mean the number of proton and the multiplicity in that order.
Elementary analysis for C13H14O4:
Calcd. (%) C 66.84 H 5.99 Found (%) C 67.08 H 5.71 Characteristic IR bands (cm. l):vOH 3,400;
vcH 3,100, 3,060 values (p.p.m.): 1.58 (3H, d), 2.63 (lH, s), 2.71 tlH, dd), 2.86 (lH, dd), 3.32 (lH, m), 3.88 (lH, dd), 4.18 (lH, dd), 4.91 (lH, q), 6.44 (lH, s), 6.81 (lH, dd), 6.92 (lH, d), 10~986~
7.25 (lH, d) Reference E~amPle 2 The same procedure a~ in Reference E~ample 1 was repeated except that 0.5 g, of 2-(1-hydroxyethyl)-7-hydroxy-benzofuran was employed instead of 2-(1-hydroxyethyl)-5-hydro~ybenzo~uran employed in Reference Example 1, to give 0.45 g. of 2-(1-hydroxyethyl)-7-(2,3-epo~ypropoxy)benzo-furan to be employed as a starting material in the present invention, The elementary analysis, characteristic IR
bands and ~ values thereof are as follows:
~lementary analysis for C13H1404:
Calcd, (%) C 66.84 H 5.99 Found (%) C 66.59 H 6,14 Characteristic IR bands (cm.l): v0H 3,400;
~CH 3,125, 3,070 values (p,p.m.): 1.61 (3E, d), 2.76 (lH, dd), 2.90 (lH, 8), 3.42 (lH, m), 4,12 (lH, dd),
4,42 (lH, dd), 5.00 ~lE, q), 6.56 (lH, 8), 6.62 to 7.16 (3H, m) . . .
Referance ExamPle 3 Into 10 ml. of epichlorohydrin were added 900 mg, ~ ~ of 2-(1-hydroxyethyl)-4-hydroxybenzofuran and a small amount $ - 25 of piperidine hydrochloride. The resulting mixture was f heated under reflux for 3 hours and then the excess epichlorohydrin was distilled off to give a residue.
; The residue was shaken with 100 ml. of chloroform and , ~ .
Referance ExamPle 3 Into 10 ml. of epichlorohydrin were added 900 mg, ~ ~ of 2-(1-hydroxyethyl)-4-hydroxybenzofuran and a small amount $ - 25 of piperidine hydrochloride. The resulting mixture was f heated under reflux for 3 hours and then the excess epichlorohydrin was distilled off to give a residue.
; The residue was shaken with 100 ml. of chloroform and , ~ .
5 ml of conc. hydrochloric acid, and the ~eparated ; ~ 30 chloroform layer was washed with water, A~ter drying, s _ 18 ' `
10~9~6~
chloroform was distilled off and the obtained residue was purified by a silica gel column to give 300 mg. of 2-(1-hydroxyethyl)-4-(2-hydroxy-3-chloropropoxy)benzofuran (oily material) to be employed as a starting material in the present invention The elementary analysis, charac-teristic IR bands and ~ value~ thereoi are a~ follows:
Elementary analy3is for C13H1504Cl:
Calcd. (%) C 57.88 H 5.56 Cl 13.03 Found (%) C 57.93 H 5.32 Cl 12.88 Characteristic IR bands (cm.l): v0H 3,350 values (p.p.m.): 1.61 (3H, d), 2.26 (2H, 8), 3.76 (2H, t), 4.19 (3H, m), 4.99 (lH, q),
10~9~6~
chloroform was distilled off and the obtained residue was purified by a silica gel column to give 300 mg. of 2-(1-hydroxyethyl)-4-(2-hydroxy-3-chloropropoxy)benzofuran (oily material) to be employed as a starting material in the present invention The elementary analysis, charac-teristic IR bands and ~ value~ thereoi are a~ follows:
Elementary analy3is for C13H1504Cl:
Calcd. (%) C 57.88 H 5.56 Cl 13.03 Found (%) C 57.93 H 5.32 Cl 12.88 Characteristic IR bands (cm.l): v0H 3,350 values (p.p.m.): 1.61 (3H, d), 2.26 (2H, 8), 3.76 (2H, t), 4.19 (3H, m), 4.99 (lH, q),
6.67 (2H, m), 7.09 (2H, m) Referance ExamPle 4 ; The same procedure as in Reference Example 3 was repeated except that 0,9 g, of 2-(1-hydroxyethyl)-7-hydroxybenzofuran was employed in~tead of 2-(1-hydroxy-ethyl)-4-hydroxybenzofuran employed in Referance Fxample 3, to give 0.4 g. of 2~ hydroxyethyl)-7-(2-hydroxy-3-chloropropoxy)benzofuran (oily material) to be employed as a starting material in the present invention. The elementary analysis, characteristlc IR bands and ~ values thereof are as fol~ow~:
Elementary analysis for C13H1504Cl:
Calcd. (%) C 57.88 H 5.56 Cl 13.03 Found (%) C 58.13 H 5.69 Cl 12,75 . . . .
Characteristic IR bands (cm.l): v0H 3,350 value ~,p.~ 1.62 (3H, d), 2.49 (2H, s), .. . .
~ 30 3.79 (2H, t), 4,28 (3H, m), 5.02 (lH, q), . .
~. - 19 -~ .
-108g86~, 6.58 (IH, s), 6.70 to 7.20 (3H, m) Reference ~xamPle 5 Into 10 ml, of ethanol were added 0.2 g. of 2-acetyl-7-(2,3-epoxypropoxy)benzofuran and 50 mg. of sodium borohydride. The re~ulting mixture was reacted at a room temperature for 20 minutes. After the con-clusion of the reaction, ethanol was distilled off and ~ the obtained residue was extracted with 30 ml. of ether.
The extract was concentrated to give 0.22 g, of 2-(1-hydro~yethyl)-7-(2,3-epoxypropoxy)benzofuran (oily material) to be employed as a starting material in the prei3ent invention. It was found that the elementary analysis, characteristic IR bands and ~ value~ thereof were similar ~ 15 to those found in Refersnce ~xample 2.
i': ..
j Reference Exam~le 6 Into 20 ml, of ethanol were added 0,7 g. of i 2-acetyl-7-(2-hydro~y-3-chloropropoxy)benzofuran and 0.1 g. o~ sodium borohydride. The re~ulting mixture was reacted at a room temperature ior 20 minutes and then ethanol wa~ distilled of~, The obtained residue was e~tracted with 50 ml, of ether and then ether was di~tilled oif to give 0,75 g, oi 2-(1-hydroxyethyl)-7-(2-hydroxy-3-, . , - 25 chloropropoxy)benzo~uran (oily material) to be employed as a starting material in the present invention. It was found that the elementary analysis, characteri~tic IR
bands and ~ values thereof were similsr to those found in Reference Example 4.
.~
-" ~
,~
10~986~
Reference Example 7 The same procedure as in Reference E~ample 6 was repeated except that 0,2 g. of 2-acetyl-6-(2-hydroxy-3-chloropropoxy)benzofuran was employed instead of 2-acetyl-
Elementary analysis for C13H1504Cl:
Calcd. (%) C 57.88 H 5.56 Cl 13.03 Found (%) C 58.13 H 5.69 Cl 12,75 . . . .
Characteristic IR bands (cm.l): v0H 3,350 value ~,p.~ 1.62 (3H, d), 2.49 (2H, s), .. . .
~ 30 3.79 (2H, t), 4,28 (3H, m), 5.02 (lH, q), . .
~. - 19 -~ .
-108g86~, 6.58 (IH, s), 6.70 to 7.20 (3H, m) Reference ~xamPle 5 Into 10 ml, of ethanol were added 0.2 g. of 2-acetyl-7-(2,3-epoxypropoxy)benzofuran and 50 mg. of sodium borohydride. The re~ulting mixture was reacted at a room temperature for 20 minutes. After the con-clusion of the reaction, ethanol was distilled off and ~ the obtained residue was extracted with 30 ml. of ether.
The extract was concentrated to give 0.22 g, of 2-(1-hydro~yethyl)-7-(2,3-epoxypropoxy)benzofuran (oily material) to be employed as a starting material in the prei3ent invention. It was found that the elementary analysis, characteristic IR bands and ~ value~ thereof were similar ~ 15 to those found in Refersnce ~xample 2.
i': ..
j Reference Exam~le 6 Into 20 ml, of ethanol were added 0,7 g. of i 2-acetyl-7-(2-hydro~y-3-chloropropoxy)benzofuran and 0.1 g. o~ sodium borohydride. The re~ulting mixture was reacted at a room temperature ior 20 minutes and then ethanol wa~ distilled of~, The obtained residue was e~tracted with 50 ml, of ether and then ether was di~tilled oif to give 0,75 g, oi 2-(1-hydroxyethyl)-7-(2-hydroxy-3-, . , - 25 chloropropoxy)benzo~uran (oily material) to be employed as a starting material in the present invention. It was found that the elementary analysis, characteri~tic IR
bands and ~ values thereof were similsr to those found in Reference Example 4.
.~
-" ~
,~
10~986~
Reference Example 7 The same procedure as in Reference E~ample 6 was repeated except that 0,2 g. of 2-acetyl-6-(2-hydroxy-3-chloropropoxy)benzofuran was employed instead of 2-acetyl-
7-(2-hydroxy-3-chloropropo~y)benzofuran employed in Referance ~xample 6, to give 0.12 g. of 2-(1-hydroxyethyl)-6-(2-hydroxy-3-chloropropo~y)benzo~uran (crystalline material having a melting point of 78 to 82C.) to be employed as a starting material in the present invention.
The elementary analysis, characteristic IR bands and values thereo~ are as follows:
Elementary analysis for C13H1504Cl:
Calcd. (%) C 57,88 H 5,56 Cl 13.03 ~ound (%) C 57,83 H 5,41 Cl 13,19 Characteristic IR band~ (cm,~ OH 3,325 values (p,p,m,): 1,60 (3H,d), 2,49 (2H, 8), 3,74 (2H,t), 4,10 (3H, m), 4,96 (lH, 9), 6,82 (lH, dd), 6,96 (lH, d), 7,36 (IH,~d) Reference ExamPle 8 Into 20 ml, of methanol was dissolved 1,76 g, of 2-acetyl-4-hydroxybenzofuran, and 0,42 g, oi sodium boro-hydride was slowly added thereto with cooling with ice, The resulting mixture was reacted at a room temperature for 5 minutes. After the conclusion of the reaction, methanol was distilled off to give a re~idu~, To the residue were added 10 ml. of water and 1 ml. of glacial acetic acid and the re~ulting mixture was extracted five ` time~ with 10 ml. of ethyl acetate, The ethyl acetate layer was satisfactorily washed with a saturated aqueous solution 10~986~i of sodium bicarbonate and was dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off at a temperature of not more than 40C, under a reduced pressure to give a residue, The residue wa~ recry~tallized from benzene-acetone (9 : 1 by volume) to give 2-(1-hydroxy-ethyl)-4-hydroxybenzofuran (colorless, needle cry~tal having a melting point of 1~8 to 140C,) to be employed as a starting material in the pre~ent invention, The elementary analysis thereof is as follows:
Elementary analy~is for ~1oHloO3:
Calcd, (%) C 67,41 H 5,66 Eound (%) C 67,64 H 5,51 Reference ExamPles 9 to 11 The ~imilar procedure to that in Reference Example 8 was repeated except that 1,76 g, of 2-acetyl-5-'~ hydro y benzofuran (Reference Example 9), 1,76 g, of 2-aoetyl-6-hydroxybenzo~uran (Re~erenoe Example 10) and 1,76 g, of 2-acetyl-7-hydroxybenzofuran (Reference Example 11) ~, ç~ 20 are employed inctead of 2-a¢etyl-4-hydroxybenzofuran employed l in Reference Example 8, to give 1.16 g, of 2-(1-hydroxy-;~' ethyl)-5-hydroxybenzofuran having a melting point of 120,5 , to 122,5G, (Reference Example 9), 0,98 g, of 2-(1-hydroxy-ethyl)-6-hydroxybenzofuran having a melting point of 82 to 84C, (Referance Example 10) and 1,50 g, o~ 2-(1-hydroxy-ethyl)-7-hydroxybenzofuran having a meltlng point oi 159 to 161C. (Reference Example 11), respectively~ It wa~
found that the elementary analy~i~ of the obtained each compound i~ ~imilar to that found in Reference Example 8, `'~ ~ , , . ' - .
1089~6~i Example 1 [2-(1-hydroxyethyl)-7-(2-hydroxy-3-sec.-butylaminopropoxyi-benzofuran]
(A) Into a mixture of 20 ml. of dioxane and 2 ml.
of water was dissolved 0.61 g. of 2-acetyl-7-(2-hydroxy-3-sec.-butylaminopropoxy)benzofuran, and 0.05 g. of sodium borohydride was added thereto with cooling with ice.
The resulting mixture wa~ agitated at a room temperature for an hour and then poured into 100 ml. of ice water.
After addition of sodium chloride for salting-out, the mixture was extracted with ethyl acetate.
The organic phase was dried over anhydrous ~odium sulfate and the solvent therein was distilled oii under a reduced pressure. The obtained residue was recrystallized from benzene-petroleum ether (3 : 2 by volume) to give 0.54 g.
oi a white~ powdery compound having a melting point oi 88 to 90C.
With respect to the obtained compound, the elementary analysis, IR spectrum, thin-layer chromatogram and NMR spectrum were determined As a result, the compound was identified as 2-(1-hydroxyethyl)-7-(2-hydroxy--3-sec -butylaminopropoxy)benzoiuran.
a The thin-layer chromatogram was measured by r. employing Eieselgel (resistered trade mark) HF254 (made ~i 25 by Merck & Co., Inc.) as the ad~orbent and benzene-ethanol-. _ .
28 ~ ammonia water (6 : 4 : 0,3 by volume) a3 the developer.
From the thin-layer chromatogram, the Rf value of the oompound was calculated The NMR spectrum was measured . - ..
according to the same manner as in Reference Example 1.
3 The elementary analysis, characteristic IR bands, ~ . .
~ 23 S~
Rf value and ~ values of the compound are as followæ:
Elementary analy~is for C17H2504N: -Calcd. (~) C 66,42 H 8.20 N 4.56 ~ound (%) C 66.71 H 8.30 N 4.32 Characteristic IR band~ (cm.~ OH 3~375~ 3,325;
~NH 3,250; vc=C 1,627, 1,602, 1,589 Rf value in TLC: 0.41 values (p.p.m.): 0.92 (3H, t), 1.11 (3H,-d), 1,50 (2H, q), 1,65 (3H, d), 2.50 to 3.20 (6H, m), 4.20 (3H, m), 5.06 (IH, q), 6.64 (IH, 8), 6.80 to 7,40 (3H, m) (~) Into 70 ml. o~ ethanol were added 4 g. o~ 2-(1-hydroxyethyl)-7-(2,3-epoxypropoxy)benzofuran obtained in Reference ~xample 2 and 15 ml. o~ sec,-butylamine. The resulting mixture was heated under re~lux ~or 30 minutes i and then ethanol was di~tilled oi~ under a reduced presRure, The obtained residue wa~ recrystallized ~rom benzene-petroleum ether (3 : 2 by volume) to give 3 g. of a white powdery compound having a melting point o~ 88 to 90C.
It wa8 found that the elementary analysis, characteristic ~; IR band8, R~ value and ~ values oi the compound were similar to those o~ the compound obtained in Example 1, (A), '' ': '~ ` ..
xample ?
~2-(1-hydroxyethylj-7-(2-hydroxy-3-tert.-butylaminopropoxy)-benzo~uran~
(A) Into a mixture of 20 ml. o~ dioxane and 2 ml. of water was dissolved 0,61 g, of 2-acetyl-7-(2-hydroxy-3-tert.-butylaminopropoxy)benzofuran, and then 0,05 g. of sodium borohydride wa~ added thereto with cooling with ice, : -~- :
~ ~ - 24 10~9~
The resulting mixture was agitated at a room temperature for an hour. The reaction mixture was treated according to the same manner as in E~ample l,-(A) to give a residue.
The residue was recrystallized from benzene to give 0,49 g bf a white powdery compound having a melting point of 126 to 127C. The elementary analysis, characteristic IR bands, Rf value and ~ values o~ the compound are as follows:
Elementary analysis for Cl ~ 2504N:
Calcd. (%) C 66.42 H 8.20 N 4.56 ~ound (~) C 66.28 H 8.37 N 4,61 Characteristic IR band~ (cm.l): v0H 3,375;
~NH 3,200; vc=c 1,635, 1,605, 1,595 Rf value in T~C: 0.33 3 values (p,p.m.): 1.14 (9H, 8), 1.63 (3H, d), ; 2.60 to 3.20 (5H, m), 4,19 (3~, m), 5.04 (lH, q), 6,62 (lH, 8), 6.80 to 7,50 (3H, m) (B) Into 100 ~1, of ethanol were added 3,6 g of 2~ hydroxyethyl)-7-hydroxybenzofuran, 4.1 g. of l-tert.-, . .
; 20 butylamino-3-chloro-2-propanol hydrochloride obtained in Reference Example 11 and 2.4 g. of eodium hydroxide. --The resulting mixture was heated in a ~ealed tube at 100C for 10 hour3, After the conclusion of the reaction, the reaction mixture was filtered and the ~iltrate was evaporated under a reduced pressure to give ~; a residue. 500 ml, of an ethereal e~tract of the residue was concentrated and pas3ed through a silica gel column -to give a crude product. The product was recrystallized from benzene to give 0,95 g, of a white powdery compound having a melting point of 126 to 127C. It was found that the elementary analysis, characteristic IR bands, . , . : .
~ ~ - 25 Rf value and ~ values of the compound were similar to those of the compound obtained in Example 2, (A).
(C) A mixture of 3 g. of 2-(1-hydroxyethyl)-7-(2-hydroxy-3-chloropropoxy)benzofuran and 80 ml. of tert.-butylamine was heated in a sealed tube at 100 to 105C. for 7 hours, and then the excess tert.-butylamine was distilled off to give a residue. After addition of a 10% aqueous solution of sodium hydroxide, the residue was extracted with ether.
The ethereal layer was dried over anhydrous sodium sul-fate and then ether was distilled off. The obtained resi-due was recrystallized from benzene to give 2.1 g. of a white powdery compound having a melting point of 126 to 127C. It was found that the elementary analysis, char-acteristic IR bands, Rf value and ~ values of the com-pound were similar to those of the compound obtained in Example 2, (A).
Example 3 [2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran]
(A) Into a mixture of 20 ml. of dioxane and 2 ml. of water was dissolved 0.58 g. of 2-acetyl-7-(2-hydroxy-3- ;~
isopropylaminopropoxy)benzofuran, and 0.05 g. of sodium borohydride was added thereto with cooling with ice. The resulting mixture was agitated at a room temperature for an hour and then was treated according to the same manner as in Example 1, (A) to give a residue. The thus ob-tained residue was recrystallized from benzene-petroleum ether (1 : 1 by volume) to give 0.53 g. of a white pow-dery compound having a melting point of 77 to 81C. The lU~66 elementary analysis, characteristic IR bands, R~ value and ~ values of the compound are as follows:
Elementary analysis for C16H2304N:
Calcd (%) C 65 51 H 7,90 N 4.78 Eound (~) C 65.43 H 7,94 ~ 4,83 Characteristic IR bands (cm.l): v0H 3,375;
VNH 3,35G; vc=c 1,627, 1,600, 1,589 Rf value in T~C: 0.25
The elementary analysis, characteristic IR bands and values thereo~ are as follows:
Elementary analysis for C13H1504Cl:
Calcd. (%) C 57,88 H 5,56 Cl 13.03 ~ound (%) C 57,83 H 5,41 Cl 13,19 Characteristic IR band~ (cm,~ OH 3,325 values (p,p,m,): 1,60 (3H,d), 2,49 (2H, 8), 3,74 (2H,t), 4,10 (3H, m), 4,96 (lH, 9), 6,82 (lH, dd), 6,96 (lH, d), 7,36 (IH,~d) Reference ExamPle 8 Into 20 ml, of methanol was dissolved 1,76 g, of 2-acetyl-4-hydroxybenzofuran, and 0,42 g, oi sodium boro-hydride was slowly added thereto with cooling with ice, The resulting mixture was reacted at a room temperature for 5 minutes. After the conclusion of the reaction, methanol was distilled off to give a re~idu~, To the residue were added 10 ml. of water and 1 ml. of glacial acetic acid and the re~ulting mixture was extracted five ` time~ with 10 ml. of ethyl acetate, The ethyl acetate layer was satisfactorily washed with a saturated aqueous solution 10~986~i of sodium bicarbonate and was dried over anhydrous sodium sulfate, and then ethyl acetate was distilled off at a temperature of not more than 40C, under a reduced pressure to give a residue, The residue wa~ recry~tallized from benzene-acetone (9 : 1 by volume) to give 2-(1-hydroxy-ethyl)-4-hydroxybenzofuran (colorless, needle cry~tal having a melting point of 1~8 to 140C,) to be employed as a starting material in the pre~ent invention, The elementary analysis thereof is as follows:
Elementary analy~is for ~1oHloO3:
Calcd, (%) C 67,41 H 5,66 Eound (%) C 67,64 H 5,51 Reference ExamPles 9 to 11 The ~imilar procedure to that in Reference Example 8 was repeated except that 1,76 g, of 2-acetyl-5-'~ hydro y benzofuran (Reference Example 9), 1,76 g, of 2-aoetyl-6-hydroxybenzo~uran (Re~erenoe Example 10) and 1,76 g, of 2-acetyl-7-hydroxybenzofuran (Reference Example 11) ~, ç~ 20 are employed inctead of 2-a¢etyl-4-hydroxybenzofuran employed l in Reference Example 8, to give 1.16 g, of 2-(1-hydroxy-;~' ethyl)-5-hydroxybenzofuran having a melting point of 120,5 , to 122,5G, (Reference Example 9), 0,98 g, of 2-(1-hydroxy-ethyl)-6-hydroxybenzofuran having a melting point of 82 to 84C, (Referance Example 10) and 1,50 g, o~ 2-(1-hydroxy-ethyl)-7-hydroxybenzofuran having a meltlng point oi 159 to 161C. (Reference Example 11), respectively~ It wa~
found that the elementary analy~i~ of the obtained each compound i~ ~imilar to that found in Reference Example 8, `'~ ~ , , . ' - .
1089~6~i Example 1 [2-(1-hydroxyethyl)-7-(2-hydroxy-3-sec.-butylaminopropoxyi-benzofuran]
(A) Into a mixture of 20 ml. of dioxane and 2 ml.
of water was dissolved 0.61 g. of 2-acetyl-7-(2-hydroxy-3-sec.-butylaminopropoxy)benzofuran, and 0.05 g. of sodium borohydride was added thereto with cooling with ice.
The resulting mixture wa~ agitated at a room temperature for an hour and then poured into 100 ml. of ice water.
After addition of sodium chloride for salting-out, the mixture was extracted with ethyl acetate.
The organic phase was dried over anhydrous ~odium sulfate and the solvent therein was distilled oii under a reduced pressure. The obtained residue was recrystallized from benzene-petroleum ether (3 : 2 by volume) to give 0.54 g.
oi a white~ powdery compound having a melting point oi 88 to 90C.
With respect to the obtained compound, the elementary analysis, IR spectrum, thin-layer chromatogram and NMR spectrum were determined As a result, the compound was identified as 2-(1-hydroxyethyl)-7-(2-hydroxy--3-sec -butylaminopropoxy)benzoiuran.
a The thin-layer chromatogram was measured by r. employing Eieselgel (resistered trade mark) HF254 (made ~i 25 by Merck & Co., Inc.) as the ad~orbent and benzene-ethanol-. _ .
28 ~ ammonia water (6 : 4 : 0,3 by volume) a3 the developer.
From the thin-layer chromatogram, the Rf value of the oompound was calculated The NMR spectrum was measured . - ..
according to the same manner as in Reference Example 1.
3 The elementary analysis, characteristic IR bands, ~ . .
~ 23 S~
Rf value and ~ values of the compound are as followæ:
Elementary analy~is for C17H2504N: -Calcd. (~) C 66,42 H 8.20 N 4.56 ~ound (%) C 66.71 H 8.30 N 4.32 Characteristic IR band~ (cm.~ OH 3~375~ 3,325;
~NH 3,250; vc=C 1,627, 1,602, 1,589 Rf value in TLC: 0.41 values (p.p.m.): 0.92 (3H, t), 1.11 (3H,-d), 1,50 (2H, q), 1,65 (3H, d), 2.50 to 3.20 (6H, m), 4.20 (3H, m), 5.06 (IH, q), 6.64 (IH, 8), 6.80 to 7,40 (3H, m) (~) Into 70 ml. o~ ethanol were added 4 g. o~ 2-(1-hydroxyethyl)-7-(2,3-epoxypropoxy)benzofuran obtained in Reference ~xample 2 and 15 ml. o~ sec,-butylamine. The resulting mixture was heated under re~lux ~or 30 minutes i and then ethanol was di~tilled oi~ under a reduced presRure, The obtained residue wa~ recrystallized ~rom benzene-petroleum ether (3 : 2 by volume) to give 3 g. of a white powdery compound having a melting point o~ 88 to 90C.
It wa8 found that the elementary analysis, characteristic ~; IR band8, R~ value and ~ values oi the compound were similar to those o~ the compound obtained in Example 1, (A), '' ': '~ ` ..
xample ?
~2-(1-hydroxyethylj-7-(2-hydroxy-3-tert.-butylaminopropoxy)-benzo~uran~
(A) Into a mixture of 20 ml. o~ dioxane and 2 ml. of water was dissolved 0,61 g, of 2-acetyl-7-(2-hydroxy-3-tert.-butylaminopropoxy)benzofuran, and then 0,05 g. of sodium borohydride wa~ added thereto with cooling with ice, : -~- :
~ ~ - 24 10~9~
The resulting mixture was agitated at a room temperature for an hour. The reaction mixture was treated according to the same manner as in E~ample l,-(A) to give a residue.
The residue was recrystallized from benzene to give 0,49 g bf a white powdery compound having a melting point of 126 to 127C. The elementary analysis, characteristic IR bands, Rf value and ~ values o~ the compound are as follows:
Elementary analysis for Cl ~ 2504N:
Calcd. (%) C 66.42 H 8.20 N 4.56 ~ound (~) C 66.28 H 8.37 N 4,61 Characteristic IR band~ (cm.l): v0H 3,375;
~NH 3,200; vc=c 1,635, 1,605, 1,595 Rf value in T~C: 0.33 3 values (p,p.m.): 1.14 (9H, 8), 1.63 (3H, d), ; 2.60 to 3.20 (5H, m), 4,19 (3~, m), 5.04 (lH, q), 6,62 (lH, 8), 6.80 to 7,50 (3H, m) (B) Into 100 ~1, of ethanol were added 3,6 g of 2~ hydroxyethyl)-7-hydroxybenzofuran, 4.1 g. of l-tert.-, . .
; 20 butylamino-3-chloro-2-propanol hydrochloride obtained in Reference Example 11 and 2.4 g. of eodium hydroxide. --The resulting mixture was heated in a ~ealed tube at 100C for 10 hour3, After the conclusion of the reaction, the reaction mixture was filtered and the ~iltrate was evaporated under a reduced pressure to give ~; a residue. 500 ml, of an ethereal e~tract of the residue was concentrated and pas3ed through a silica gel column -to give a crude product. The product was recrystallized from benzene to give 0,95 g, of a white powdery compound having a melting point of 126 to 127C. It was found that the elementary analysis, characteristic IR bands, . , . : .
~ ~ - 25 Rf value and ~ values of the compound were similar to those of the compound obtained in Example 2, (A).
(C) A mixture of 3 g. of 2-(1-hydroxyethyl)-7-(2-hydroxy-3-chloropropoxy)benzofuran and 80 ml. of tert.-butylamine was heated in a sealed tube at 100 to 105C. for 7 hours, and then the excess tert.-butylamine was distilled off to give a residue. After addition of a 10% aqueous solution of sodium hydroxide, the residue was extracted with ether.
The ethereal layer was dried over anhydrous sodium sul-fate and then ether was distilled off. The obtained resi-due was recrystallized from benzene to give 2.1 g. of a white powdery compound having a melting point of 126 to 127C. It was found that the elementary analysis, char-acteristic IR bands, Rf value and ~ values of the com-pound were similar to those of the compound obtained in Example 2, (A).
Example 3 [2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran]
(A) Into a mixture of 20 ml. of dioxane and 2 ml. of water was dissolved 0.58 g. of 2-acetyl-7-(2-hydroxy-3- ;~
isopropylaminopropoxy)benzofuran, and 0.05 g. of sodium borohydride was added thereto with cooling with ice. The resulting mixture was agitated at a room temperature for an hour and then was treated according to the same manner as in Example 1, (A) to give a residue. The thus ob-tained residue was recrystallized from benzene-petroleum ether (1 : 1 by volume) to give 0.53 g. of a white pow-dery compound having a melting point of 77 to 81C. The lU~66 elementary analysis, characteristic IR bands, R~ value and ~ values of the compound are as follows:
Elementary analysis for C16H2304N:
Calcd (%) C 65 51 H 7,90 N 4.78 Eound (~) C 65.43 H 7,94 ~ 4,83 Characteristic IR bands (cm.l): v0H 3,375;
VNH 3,35G; vc=c 1,627, 1,600, 1,589 Rf value in T~C: 0.25
8 values (p.p,m,): 1.06 (6H, d), 1 5~ (3H, d), 2.60 to 3.00 (3H, m), 3,43 (3H, s), 3.90 to 4,30 (3H, m), 4.98 (IH, q), 6.67 (lH, 8), ; 6.75 to 7,15 (~H, m) (B) 0,61 g, of 2-acetyl-7-(2-hydroxy-3-isopropylamino-propoxy)benzofuran was incubated at pH 7.0, at a temperature of 37C., for 30 minutes, together with an enzyme fraction which is obtained by centrifuging 80 g, of liver homogenate of rabits under a centri~ugal force of 105 g and coenzyme (NADPH-generating system), Thereto was added 2N-aqueous solution of sodium hydroxide to stop the reaction. This reaction mixture was extracted with ether and then the solvent was di~tllled off, The thus obtained residue was recrystallized from benzene-petroleum ether (1 : 1 by volume) to give 0.4 g. of a white powdery compound having a melting point of 77 to 81C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ alues of the compound were similar to those of the compound obtained in Example 3, (A), (C) A solution of 0.61 g, of 2-acetyl-7-(2-hydroxy-3-i~opropylam~nopropoxy)benzo~uran in 100 ml. of ethanol :, -~ 30 was ~upplied together with 0.05 g. of Raney nickel catalyst ~ . ~
~ - - 27 ~089~
into a reaction ves3el and was shaken in a stream of hydrogen gas under a normal pressure for about 10 hours, The reaction mixture was filtered to remove the catalyst therefrom and then the solvent~was`distilled off under a reduced pressure. The thus obtained residue was re-cry~tallized from benzene-petroleum ether (1 : 1 by volume) to give 0,41 g, of a white. powdery compound having a melting point of 77 to 81C, It was found that the elementary analysis, characteristic IR bands, R~ value and S values of the compound were similar to those of the compound obtained in Example 3, (A).
(D) Into 30 ml, of isopropanol were dissolved 0,61 g.
o~ 2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran and 0,21 g. of aluminum isopropoxide. The resulting mixture was:heated with agitation under r.eflux, during which acetone produced was distilled off and isopropanol was dropped thereinto, When acetone came not to be distilled o~f, the reaction mixture was poured into ice water and was extracted with ethyl acetate, The solvent therein was then distilled o~f under a reduced pressure and the thus obtained residue was recrystallized from benzene-petroleum ether (3 : 2 by volume) to give 0,51 g, of a white powdery compound having a melting point o~ `
.77 to 81C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values o~ the compound were similar to those of the compound obtained in Example 3, (A), (E) Into 100 ml, o~ ethanol were added 4,35 g, of potassium salt of 2-(1-hydroxyethyl)-7-hydroxybenzofuran obtained in Reference Exampl~ 11 and 7,6 g, of l-isopropyl-10~66 amino-2-hydroxy-3-chloropropane, The resulting mixture wa~ reacted under reflux for 24 hours, After the conclu-sion of the reaction, the reaction mixture was filtered and the filtrate was evaporated under a reduced pressure, 400 ml, of an ethereal extract of the residue was con-centrated and passed through a silica gel column to give a crude product, ~he product was recrystallized from benzene-petroleum ether (1 : l by volume) to give 0,45 g, o~ a white powdery compound having a melting point of 77 to 81C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values of the compound were ~imilar to those of the compound obtained in Example 3, (A), (F) Into 50 ml, of ethanol were added 4,5 g, of 2-(1-hydroxyethyl)-7-~2,3-epoxypropoxy)benzofuran obtained in Reference Example 2 and 30 ml, of isopropylamine, The resulting mixture was heated under re~lu~ ~or an hour and then ethanol was distilled off under a reduced pressure, The thus obtained residue was recrystallized ~rom benzene-petroleum ether (1 : 1 by volume) to give 3,6 g, of a white .powdery compound having a melting point o~ 77 to 81C, It wa~ ~ound that the elementary analysis, charac-teristic IR bands, R~ value and ~ value~ o~ the compound were similar to those of the compound obtained in ~xample 3' (At.
.
; ExamPle 4 [2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzo~uran hydro~hloride]
Into 10 ml, of ethyl ether wa8 dis~olved 0,1 g,;of 108g86~
2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran obtained in Example 3, (A) and then hydrochloric acid gas was blown thereinto to give a white precipitate, The precipitate was separated by means of filtration and wa~ recrystallized from ethyl acetate to give 0,08 g, of a cQlorless needle hydrochloride having a melting point of 83 to 88C, ~xample 5 ~2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran acetate salt]
Into 20 ml, of ethyl acetate was diæsolved 0,75 g, of 2-(1-hydroxyethyl)-7-(2-hydroxy-3-i~opropylaminopropoxy)-benzofuran obtained in ~xample 3, (A) and then 200 mg, of acetic acid and 10 ml, of ether were added thereinto, The resulting mixture was left as it was over night at a cool place to gi~e 0,8 g, o~ a colorless needle acetate salt having a melting point of 104 to 107C, ExamPle 6 ~2-(1-hydroxyethyl)-4-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran]
: (A) Into a mixture of 20 ml, of dioxane and 2 ml, of water was dissol~ed 0,58 g, of 2-acetyl-4-(2-hydroxy-3-isopropylaminopropoxy)benzofuran, and 0,05 g, of sodium borohydride was added thereto with cooling with ice, ,~:
~:~ The resulting mixture was agitated at a room temperature ior one hour and then was treated according to the same manner as in Example 1, (A), The thus obtained residue ~0 was recrystallized from ether-petroleum ether (1 : 1 by 10~9~
volume) to give 0.31 g. of a white powdery compound having a melting point of 64 to 66C. The elem~nt.ary-analysi~, characteristic IR band~, R e value and o` values of the compound are a~ follows:
Elementary analysis for C16H2303N:
Calcd. (%) C 65,51 H 7.90 N 4.78 ~ound (%) C 65.73 H 7.91 N 4.59 Charscteristic IR bands (cm.~ 0~3 3,350;
V~H 3,280; vc=c 1,609, 1,595 Rf value in T~C: 0.27 values (p.p.m.): 1.26 (6H, d), 1.73 (3H, d), 2.50 to 3.20 (6H, m), 4.00 to 4.20 (3H, m), 5,04 (lH, q), 6.64 (l~I, dd), 6.68 (l~I, 8), 7.1 to 7.4 (~H, m) (B) Into 100 ml. OI ethanol were added 3.6 g. of 2-(1-hydroxyethyl)-4-hydroxybenzofuran obtained in Reference Example 8, 3.8 g. of 1-isopropylamino-3-chloro-2-propanol hydrochloride and 3.4 g. of potassium hydroxide. The resulting mixture was heated in a sealed tube at 100C.
20 for 10 hours. After the conclusion of the reaction, the reaction mixture was filtered and the filtrate was evaporated under a reduced pres~ure. The thus obtained residue was extracted with 300 ml. of ether. The extract was passed through a silica gel column and then was re~
25 crystallized from ether-petroleum ether (1: 1 by volume) to give 0.8 g. of a white, powdery compound having a melting point of 64 to 66C. It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values of the compound were similar to those of ~0 the compound obtained in Example 6, (A).
~J89~6~;
(C) 2 g. of 2-(1-hydroxyethyl)-4-(2-hydroxy-3-chloropropo~y)benzofuran obtained in Reference Example 3 and 50 ml, of i~opropylamine were reacted in a sealed tube at a temperature of 100 to 105C. for 7 hours.
The excess isopropylamine wa~ distilled off and the residue was divided into two liquid layers by adding thereto 10 % aqueous solution of ~odium hydroxide and ether, The ethereal layer was dried over anhydrou~
sodium sulfate and the ether was distilled off under a reduced pressure. The thus obtained re~idue was re-cry~tallized from ether-petroleum ether (1 : 1 by volume) to give 1,2 g. of a white powdery compound having a melting point of 64 to 66C, It was found that the elementary analysi3, characteristic IR bands, Rf vaiue and c~ values were similar to those o~ the compound ~' obtained in Example 6, (A).
ExamPle 7 [2-(1-hydroxyethyl)-5-(2-hydroxy-3-sec,-butylaminopropoxy)-benzo~uran~ ~
1., i''i' (A) Into a mixture of 20 ml, of dioxane and 2 ml. of water were dissolved 0,61 g. of 2-acetyl-5-(2-hydroxy-3-, , ~ sec,-butylaminopr,opoxy)benzo~uran, and 0,05 g, of sodium borohydride was added thereto with cooling with ice.
The resulting mixture was agitated at a room temperature or an hour, The reaction mixture was treated according i :. . -to the same manner a~ in ~xample 1, (A), and the obtained residue was recrystallized fr,om acetone-petroleum ether ~ 1 by volume) to gi~e 0.45 g, of a white, powdery -~ ~ 30 compound ha~ing a melting point of 94 to 96C. The - ~ 1 ~' ' ' , :~0~86~
elementary analysis, characteristic IR bands, Rf value and ~ values of~the compound are as follows:
Elementary analysis for C17H2504N:
Calcd. (%) C 66.42 H 8.20 N 4.56 Found (~) C 66.78 H 7.98 N 4.49 Characteristic IR bands (cm.l): ~OH 3,360;
~NH 3,280; vc=c 1,612, 1,608 Rf value in TIC: 0 38 ~ valùes (p p.m.): 0,99 (3H, t), 1 09 (3H, d), 1,47 (2H, d), 1,61 (3H, d), 2,50 to 3.20 (6H, m), 3.90 to 4.20 13H, m), 5.01 (lH, q), 6.57 (lH, s), 6.86 (lH, d), 6.99 (IH, dd), 7.39 (lH, d) (~) Into 100 ml. of ethanol were added 4.35 g. o~
15 potassium salt of 2-(1-hydroxyethyl)-5-hydroxybenzofuran obtained in Reference Example 9 and 8.25 g, of l-sec.-i butylamino-2-hydroxy-3-chloropropane, The resulting mixture wa~ heated in a sealed tube at a temperature of 100C, for 7 hours. After the conclusion of the reaction, the reaction mixture wa~ filtered and the filtrate was evaporated under a reduced pressure to give a re3idue.
500 ml. of an ethereal extract of the residue was con-c~ tea ~d ~a~sçd th~ou~h a silica ~el column to ~ive a crude product. The product was recrystallized from acetone-petroleum ether (1 : 1 by volume) to give 1.2 g.
~; of a white powdery compound having a melting point of 94 to 96C. It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values of the compound were similar to those of the compound obtained : .
~ 30 in Example 7, (A).
~ ' ~
: .
10~98~;~
(C) Into 50 ml, of ethanol were added 3 g, of 2-(l-hydroxyethyl)-5-(2,3-epoxypropoxy)benzofuran obtained in Reference Example 1 and 30 ml, of sec,-butylamine, The resulting mixture wa~ treated according to the same manner as in Example 1, (B) to give a residue, The residue was recrystallized from acetone-petroleum ether (1 : 1 by volume) to give 1,8 g, o~ a white powdery compound having a melting point of 94 to 96C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values o~ the compound were similar to those o~ the compound obtained in Example 7, (A), ~amPle 8 [2-(1-hydro~yethyl)-6-(2-hydroxy-3-tert,-butylamino-propoxy)benzofuran]
(A) Into a mixture o~ 20 ml, o~ dioxane and 2 ml, oi water was dissolved 0,61 g, of 2-acetyl-6-(2-hydroxy-3-tert,-butylaminopropoxy)benzofuran, The resulting mixture was treated according to the same manner a~ in ~xample 1, (~) to give a crude residue, The obtained residue was recrystallized from benzene to give 0,54 g, of a white powdery compound having a melting point of 129 to 131C, The elementary analysis, characteristic IR bands, R~ ~alue and ~ value~ o~ the compound are as 25 follow~:
Elementary analysis ~or C17H2504N:
; Calcd, (%) C 66,42 H 8,20 N 4,56 Found (%) C 66,54 H 8,13 N 4,80 Characteristic IR bands (cm,l): vOH 3,325;
3 ~NH 3,275; vc=c 1,628, 1,588 10~9~6~
Rf value in TLC; 0,27 value~ (p,p,m,): 1,16 (9H, s), 1,62 t3H, d), 2,60 to 3,00 (5H, m), 3,90 to 4,10 (3X, m), 5,03 (IH, q), 6,58 (IH, s), 6,93 (IH, dd), 7,07 (IH, d), 7,47 (IH, d) (~) Into 50 ml, of dimethylformamide was dissolved 3,6 g, of 2-(1-hydroxyethyl)-6-hydroxybenzofuran obtained in Reference Example 10, and 8,1 g, of anhydrous potassium carbonate was added thereto, The resulting mixture was heated with agitation to a temperature of 80 to 100C,, and then 4 g, of 1-tert,-butylamino-2-hydroxy-3-chloro-propane hydrochloride was i310wly dropped thereto and reacted for 8 hour~, After the conclusion of the reaction, the reaction mixture was filtered and the ~iltrate was ~-~ 15 evaporated under a reduced pressure to give a residue, i - The residue was extracted with 800 ml, of ether and the extract was passed through a silica gel column to give ~ a crude product, The product was recrystallized from '` benzene to give 0,6 g, of a white powdery compound ~
'' 20 having a melting point of 129 to 131C, It was found that the elementary analysi~, characteristic IR bands, ~' Rf value and ~ values of the compound were ~imilar to those of the compound obtained in Example 8, (A), (C) 1 g, of 2-(1-hydroxyethyl)-6-(2-hydroxy-3-chloropropoxy)benzofuran obtained in Reference Example 7 and 30 ml, o~ tert,-butylamine were heated in a sealed tube at a temperature of 100 to 105C, for 7 hours, and then the excess tert,-butylamine was distilled off to give a residue, The redidue was divided into two liquid 3Q layer~ by adding t~oreto 10 % aqueou8 801ution of 80dium . .
`.~ - 35 -hydroxide and ether, The etherezl layer was dried over anhydrous sodium sulfate and the ether was distilled off under a reduced pressure to ~ive a residue. The residue was recry~tallized from benzene to give 0,6 g, of a white powdery compound having a melting point of 129 to 131C, It was found that the elementary analy~i~, characteri~tic IR bands, Rf value and ~ values of the compound were similar to those of the compound obtained in Example 8, (A).
:ExamPle 9 [2-(1-hydroxybutyl)-7-(2-hydro~y-3-tert,-butylaminopropo~y)-benzofuran]
Into a mixture of 20 ml, of dioxane and 2 ml, of water was dissolved 0,66 g. f 2-butyryl-7-(2-hydroxy-3-tert,-butylaminopropoxy)benzofuran, and 0,05 g, of sodium borohydride was added thereto with cooling with ice, The resulting mixture was treated according to the same manner as in Example 1, (A) to give 0,43 g, of a yellow oily compound, The elementary analysis, characteristic IR bands, Rf value and ~ values of the compound are as follows: -Elementary analysis for Cl ~2904N:
Calcd, (%) C 68,03 H 8,71 N 4,18 Found (%) C 68,57 H ~,63 N 4,24 Characteristic IR band~ (cm,lj: vOH 3,375;
vNH 3,300; vc=c 1,622, 1,602, 1,590 Rf value in TIC: 0,35 values (p,p,m,): 0,93 (3H, t), 1,11 (9R, 8), 1,46 (2H, m), 1,91 (2R, q), 2,75 (2R, d), 3,70 (3H, 8), 4,23 (3H, m), 4,81 (IH, t), 1 ~ ~ 9 ~
6,60 (IH, s), 6.75 to 7.40 (3H, m) Example 10 [2-(a-hydroxybenzyl)-7-(2-hydroxy-3-isopropylaminopropo~y)-benzofuran]
Into 20 ml, of dioxane was dissolved 0.2 g. of 2-benzoyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran, and 0.02 g, of sodium borohydride was added thereto with cooling with ice, The resulting mixture was treated according to the ~ame manner as in Example 1, (A) to give a residue. The residue was recrystallized from acetone-petroleum ether (1 : 1 by volume) to give 0,1 g, of a white powdery compound having a melting point of 135 to 139C. The elementary analysis, characteristic IR
bands, Rf value and ~ value8 of the compound are as follows:
Elementary analysis for C21H2504N:
Calcd, (tO ) C 70.96 E 7.09 N 3.94 Found (%) C 70,88 H 7.16 N 3.79 Characteristic IR bands (cm.~ OH 3~33;
V~H 3,280; ~C=C 1,630, 1,600, 1,590 Rf value in TLC: 0.39 ; ~ val~es (p,p.m.)- 1,12 (6H, d), 2.70 to 3.20 (3H, m), 3.40 (3H, 8), 4.41 (3H, m), 5.96 (lH, 8), 6.40 (~I, ~), 6,60 to 7.60 (8H, m) ~ ' ~
ExamPle 11 [2-hydroxymethyl-7-(2-hydro~y-3-isopropylaminopropoxy)-benzofuran and acetate salt thereof]
3 Into 30 ml. of tetrahydrofuran was dissolved _ 37 ~ 9 ~ ~ ~
0,61 g, of 2-ethoxycarbonyl-7-(2-hydroxy-3-isopropylamino-propoxy)benzofuran,`and 0,05 g, of llthium aluminum hydridè
was added thereto with cooling with ice, The resulting mixture was agitated at a room temperature for 3 hours, and then was poured into 150 ml, of ice water, After addition of sodium chloride for ~alting-out, the reaction mixture was extracted with ethyl acetate, The organic layer was dried over anhydrous sodium sulfate and the solvent therein was distilled off under a reduced pressure to give 0,48 g, of a slightly-yellow. oily compound, The compound wa# treated according to the same manner as in Example 5 to give 0,4 g~ o~ a white powdery acetate salt having a melting point of 144 to 147C, The elementary analysis of the acetate salt is as follows:
Elementary analysis for C17H2506~:
Calcd, (~0) C 60,16 H 7,43 N 4,13 ~ound (%) C 59,87 H 7,21 N 4,38 ExamPle 12 Each o~ the compound~ obtained in Examples 1 to 11 was thoroughly blended with carriers in the ~ollowing ; proportion, .
Ingredient % by weight Essential active ingredient 12,5 Lactose 74.4 Avicel (Note) 8,8 Talc 2,9 Magnesium stearate 1,5 108986~i Note: The resistered trademark of a microcrystalline cellulose made by Asahi Chemical Co,, ~td.
The re~ulting powder was filled into capsule~
made of gelatin to give capsules containing 12,5 mg, o~
the essential active ingredient per one capsule, ExamPle 13 Each o~ the compounds obtained in Examples 1 to 11 wa~ dissolved into a normal saline æolution to give an in~ection containing 0,25 ~0 by weight of the e~ential active ingredient, ~xample 14 Ex~erimental 1:
~mploying anesthetized rats, inhibitions by the compound8 obtained in Exa~ples 1 to 3 a~d 6 t~ 9 agai~t i~oproterenol-induced decrease in blood pressure ~ere determined, Isoproterenol was administered in a dose of 1 ~g,/kg, The compounds to be tested and isoproterenol were administered by intravenous in~ection, ~ or re~erence, the same test a~ in the above was carried out with respect to propranolol which has been usually employed as a ~-adrenergic blocking agent, The result~ thereo~ are ~hown in Table 1, In ~able 1, the inhibition is expressed as 50 % inhibition ~ (ED5~).
I ExPerimental 2:
Employing mice, acute toxicitie8 (ID50) of the compounds obtained in ~xamples 1 to 3 and 6 to 9 were ::
determined, The compounds to be tested were administered ~ ~ .
~V8~8~
intravenously as a normal saline solution thereof.
For reference, the same test as in the above was carried out with respect to propranolol.
The results thereof are shown in Table 1, Erom ED50 and ID50 values obtained in E2perimentals 1 and 2, ~afety margin (~D50/~D50) and relative strengths (relative safety margin when the safety margin of propranolol is 1) were determined. These values are shown in Table 1.
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Example 15 Surface anesthetic property was tested by the method described by Murmann et al (Murmann W,, Saceani-Guelfi M. and Gamba A.; ~oll. Chim. Farm. 105 292 (1966)).
Eive male white guinea-pigs weighting about 400 g. were used, The compound obtained in Example 3 and propranolol were dissolved in normal ~aline solution. Each 0.1 ml.
of the solution was instilled in conjunctival sac of one ,eye and normal saline solution was applied to the other eye, The cornea was touched with a stimulating hair to elicit the blink reflex. The results thereo~ are shown in Table 2.
~ Table 2 Compound Concentration of Blink reflex time the compound (min. + S,E.) (% by weight) Example 3 0.5 8.0 + 2.00 Example 3 2.5 29.8 + 7.80 Propranolol 0.5 56.0 + 2.35
~ - - 27 ~089~
into a reaction ves3el and was shaken in a stream of hydrogen gas under a normal pressure for about 10 hours, The reaction mixture was filtered to remove the catalyst therefrom and then the solvent~was`distilled off under a reduced pressure. The thus obtained residue was re-cry~tallized from benzene-petroleum ether (1 : 1 by volume) to give 0,41 g, of a white. powdery compound having a melting point of 77 to 81C, It was found that the elementary analysis, characteristic IR bands, R~ value and S values of the compound were similar to those of the compound obtained in Example 3, (A).
(D) Into 30 ml, of isopropanol were dissolved 0,61 g.
o~ 2-acetyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran and 0,21 g. of aluminum isopropoxide. The resulting mixture was:heated with agitation under r.eflux, during which acetone produced was distilled off and isopropanol was dropped thereinto, When acetone came not to be distilled o~f, the reaction mixture was poured into ice water and was extracted with ethyl acetate, The solvent therein was then distilled o~f under a reduced pressure and the thus obtained residue was recrystallized from benzene-petroleum ether (3 : 2 by volume) to give 0,51 g, of a white powdery compound having a melting point o~ `
.77 to 81C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values o~ the compound were similar to those of the compound obtained in Example 3, (A), (E) Into 100 ml, o~ ethanol were added 4,35 g, of potassium salt of 2-(1-hydroxyethyl)-7-hydroxybenzofuran obtained in Reference Exampl~ 11 and 7,6 g, of l-isopropyl-10~66 amino-2-hydroxy-3-chloropropane, The resulting mixture wa~ reacted under reflux for 24 hours, After the conclu-sion of the reaction, the reaction mixture was filtered and the filtrate was evaporated under a reduced pressure, 400 ml, of an ethereal extract of the residue was con-centrated and passed through a silica gel column to give a crude product, ~he product was recrystallized from benzene-petroleum ether (1 : l by volume) to give 0,45 g, o~ a white powdery compound having a melting point of 77 to 81C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values of the compound were ~imilar to those of the compound obtained in Example 3, (A), (F) Into 50 ml, of ethanol were added 4,5 g, of 2-(1-hydroxyethyl)-7-~2,3-epoxypropoxy)benzofuran obtained in Reference Example 2 and 30 ml, of isopropylamine, The resulting mixture was heated under re~lu~ ~or an hour and then ethanol was distilled off under a reduced pressure, The thus obtained residue was recrystallized ~rom benzene-petroleum ether (1 : 1 by volume) to give 3,6 g, of a white .powdery compound having a melting point o~ 77 to 81C, It wa~ ~ound that the elementary analysis, charac-teristic IR bands, R~ value and ~ value~ o~ the compound were similar to those of the compound obtained in ~xample 3' (At.
.
; ExamPle 4 [2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzo~uran hydro~hloride]
Into 10 ml, of ethyl ether wa8 dis~olved 0,1 g,;of 108g86~
2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran obtained in Example 3, (A) and then hydrochloric acid gas was blown thereinto to give a white precipitate, The precipitate was separated by means of filtration and wa~ recrystallized from ethyl acetate to give 0,08 g, of a cQlorless needle hydrochloride having a melting point of 83 to 88C, ~xample 5 ~2-(1-hydroxyethyl)-7-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran acetate salt]
Into 20 ml, of ethyl acetate was diæsolved 0,75 g, of 2-(1-hydroxyethyl)-7-(2-hydroxy-3-i~opropylaminopropoxy)-benzofuran obtained in ~xample 3, (A) and then 200 mg, of acetic acid and 10 ml, of ether were added thereinto, The resulting mixture was left as it was over night at a cool place to gi~e 0,8 g, o~ a colorless needle acetate salt having a melting point of 104 to 107C, ExamPle 6 ~2-(1-hydroxyethyl)-4-(2-hydroxy-3-isopropylaminopropoxy)-benzofuran]
: (A) Into a mixture of 20 ml, of dioxane and 2 ml, of water was dissol~ed 0,58 g, of 2-acetyl-4-(2-hydroxy-3-isopropylaminopropoxy)benzofuran, and 0,05 g, of sodium borohydride was added thereto with cooling with ice, ,~:
~:~ The resulting mixture was agitated at a room temperature ior one hour and then was treated according to the same manner as in Example 1, (A), The thus obtained residue ~0 was recrystallized from ether-petroleum ether (1 : 1 by 10~9~
volume) to give 0.31 g. of a white powdery compound having a melting point of 64 to 66C. The elem~nt.ary-analysi~, characteristic IR band~, R e value and o` values of the compound are a~ follows:
Elementary analysis for C16H2303N:
Calcd. (%) C 65,51 H 7.90 N 4.78 ~ound (%) C 65.73 H 7.91 N 4.59 Charscteristic IR bands (cm.~ 0~3 3,350;
V~H 3,280; vc=c 1,609, 1,595 Rf value in T~C: 0.27 values (p.p.m.): 1.26 (6H, d), 1.73 (3H, d), 2.50 to 3.20 (6H, m), 4.00 to 4.20 (3H, m), 5,04 (lH, q), 6.64 (l~I, dd), 6.68 (l~I, 8), 7.1 to 7.4 (~H, m) (B) Into 100 ml. OI ethanol were added 3.6 g. of 2-(1-hydroxyethyl)-4-hydroxybenzofuran obtained in Reference Example 8, 3.8 g. of 1-isopropylamino-3-chloro-2-propanol hydrochloride and 3.4 g. of potassium hydroxide. The resulting mixture was heated in a sealed tube at 100C.
20 for 10 hours. After the conclusion of the reaction, the reaction mixture was filtered and the filtrate was evaporated under a reduced pres~ure. The thus obtained residue was extracted with 300 ml. of ether. The extract was passed through a silica gel column and then was re~
25 crystallized from ether-petroleum ether (1: 1 by volume) to give 0.8 g. of a white, powdery compound having a melting point of 64 to 66C. It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values of the compound were similar to those of ~0 the compound obtained in Example 6, (A).
~J89~6~;
(C) 2 g. of 2-(1-hydroxyethyl)-4-(2-hydroxy-3-chloropropo~y)benzofuran obtained in Reference Example 3 and 50 ml, of i~opropylamine were reacted in a sealed tube at a temperature of 100 to 105C. for 7 hours.
The excess isopropylamine wa~ distilled off and the residue was divided into two liquid layers by adding thereto 10 % aqueous solution of ~odium hydroxide and ether, The ethereal layer was dried over anhydrou~
sodium sulfate and the ether was distilled off under a reduced pressure. The thus obtained re~idue was re-cry~tallized from ether-petroleum ether (1 : 1 by volume) to give 1,2 g. of a white powdery compound having a melting point of 64 to 66C, It was found that the elementary analysi3, characteristic IR bands, Rf vaiue and c~ values were similar to those o~ the compound ~' obtained in Example 6, (A).
ExamPle 7 [2-(1-hydroxyethyl)-5-(2-hydroxy-3-sec,-butylaminopropoxy)-benzo~uran~ ~
1., i''i' (A) Into a mixture of 20 ml, of dioxane and 2 ml. of water were dissolved 0,61 g. of 2-acetyl-5-(2-hydroxy-3-, , ~ sec,-butylaminopr,opoxy)benzo~uran, and 0,05 g, of sodium borohydride was added thereto with cooling with ice.
The resulting mixture was agitated at a room temperature or an hour, The reaction mixture was treated according i :. . -to the same manner a~ in ~xample 1, (A), and the obtained residue was recrystallized fr,om acetone-petroleum ether ~ 1 by volume) to gi~e 0.45 g, of a white, powdery -~ ~ 30 compound ha~ing a melting point of 94 to 96C. The - ~ 1 ~' ' ' , :~0~86~
elementary analysis, characteristic IR bands, Rf value and ~ values of~the compound are as follows:
Elementary analysis for C17H2504N:
Calcd. (%) C 66.42 H 8.20 N 4.56 Found (~) C 66.78 H 7.98 N 4.49 Characteristic IR bands (cm.l): ~OH 3,360;
~NH 3,280; vc=c 1,612, 1,608 Rf value in TIC: 0 38 ~ valùes (p p.m.): 0,99 (3H, t), 1 09 (3H, d), 1,47 (2H, d), 1,61 (3H, d), 2,50 to 3.20 (6H, m), 3.90 to 4.20 13H, m), 5.01 (lH, q), 6.57 (lH, s), 6.86 (lH, d), 6.99 (IH, dd), 7.39 (lH, d) (~) Into 100 ml. of ethanol were added 4.35 g. o~
15 potassium salt of 2-(1-hydroxyethyl)-5-hydroxybenzofuran obtained in Reference Example 9 and 8.25 g, of l-sec.-i butylamino-2-hydroxy-3-chloropropane, The resulting mixture wa~ heated in a sealed tube at a temperature of 100C, for 7 hours. After the conclusion of the reaction, the reaction mixture wa~ filtered and the filtrate was evaporated under a reduced pressure to give a re3idue.
500 ml. of an ethereal extract of the residue was con-c~ tea ~d ~a~sçd th~ou~h a silica ~el column to ~ive a crude product. The product was recrystallized from acetone-petroleum ether (1 : 1 by volume) to give 1.2 g.
~; of a white powdery compound having a melting point of 94 to 96C. It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values of the compound were similar to those of the compound obtained : .
~ 30 in Example 7, (A).
~ ' ~
: .
10~98~;~
(C) Into 50 ml, of ethanol were added 3 g, of 2-(l-hydroxyethyl)-5-(2,3-epoxypropoxy)benzofuran obtained in Reference Example 1 and 30 ml, of sec,-butylamine, The resulting mixture wa~ treated according to the same manner as in Example 1, (B) to give a residue, The residue was recrystallized from acetone-petroleum ether (1 : 1 by volume) to give 1,8 g, o~ a white powdery compound having a melting point of 94 to 96C, It was found that the elementary analysis, characteristic IR bands, Rf value and ~ values o~ the compound were similar to those o~ the compound obtained in Example 7, (A), ~amPle 8 [2-(1-hydro~yethyl)-6-(2-hydroxy-3-tert,-butylamino-propoxy)benzofuran]
(A) Into a mixture o~ 20 ml, o~ dioxane and 2 ml, oi water was dissolved 0,61 g, of 2-acetyl-6-(2-hydroxy-3-tert,-butylaminopropoxy)benzofuran, The resulting mixture was treated according to the same manner a~ in ~xample 1, (~) to give a crude residue, The obtained residue was recrystallized from benzene to give 0,54 g, of a white powdery compound having a melting point of 129 to 131C, The elementary analysis, characteristic IR bands, R~ ~alue and ~ value~ o~ the compound are as 25 follow~:
Elementary analysis ~or C17H2504N:
; Calcd, (%) C 66,42 H 8,20 N 4,56 Found (%) C 66,54 H 8,13 N 4,80 Characteristic IR bands (cm,l): vOH 3,325;
3 ~NH 3,275; vc=c 1,628, 1,588 10~9~6~
Rf value in TLC; 0,27 value~ (p,p,m,): 1,16 (9H, s), 1,62 t3H, d), 2,60 to 3,00 (5H, m), 3,90 to 4,10 (3X, m), 5,03 (IH, q), 6,58 (IH, s), 6,93 (IH, dd), 7,07 (IH, d), 7,47 (IH, d) (~) Into 50 ml, of dimethylformamide was dissolved 3,6 g, of 2-(1-hydroxyethyl)-6-hydroxybenzofuran obtained in Reference Example 10, and 8,1 g, of anhydrous potassium carbonate was added thereto, The resulting mixture was heated with agitation to a temperature of 80 to 100C,, and then 4 g, of 1-tert,-butylamino-2-hydroxy-3-chloro-propane hydrochloride was i310wly dropped thereto and reacted for 8 hour~, After the conclusion of the reaction, the reaction mixture was filtered and the ~iltrate was ~-~ 15 evaporated under a reduced pressure to give a residue, i - The residue was extracted with 800 ml, of ether and the extract was passed through a silica gel column to give ~ a crude product, The product was recrystallized from '` benzene to give 0,6 g, of a white powdery compound ~
'' 20 having a melting point of 129 to 131C, It was found that the elementary analysi~, characteristic IR bands, ~' Rf value and ~ values of the compound were ~imilar to those of the compound obtained in Example 8, (A), (C) 1 g, of 2-(1-hydroxyethyl)-6-(2-hydroxy-3-chloropropoxy)benzofuran obtained in Reference Example 7 and 30 ml, o~ tert,-butylamine were heated in a sealed tube at a temperature of 100 to 105C, for 7 hours, and then the excess tert,-butylamine was distilled off to give a residue, The redidue was divided into two liquid 3Q layer~ by adding t~oreto 10 % aqueou8 801ution of 80dium . .
`.~ - 35 -hydroxide and ether, The etherezl layer was dried over anhydrous sodium sulfate and the ether was distilled off under a reduced pressure to ~ive a residue. The residue was recry~tallized from benzene to give 0,6 g, of a white powdery compound having a melting point of 129 to 131C, It was found that the elementary analy~i~, characteri~tic IR bands, Rf value and ~ values of the compound were similar to those of the compound obtained in Example 8, (A).
:ExamPle 9 [2-(1-hydroxybutyl)-7-(2-hydro~y-3-tert,-butylaminopropo~y)-benzofuran]
Into a mixture of 20 ml, of dioxane and 2 ml, of water was dissolved 0,66 g. f 2-butyryl-7-(2-hydroxy-3-tert,-butylaminopropoxy)benzofuran, and 0,05 g, of sodium borohydride was added thereto with cooling with ice, The resulting mixture was treated according to the same manner as in Example 1, (A) to give 0,43 g, of a yellow oily compound, The elementary analysis, characteristic IR bands, Rf value and ~ values of the compound are as follows: -Elementary analysis for Cl ~2904N:
Calcd, (%) C 68,03 H 8,71 N 4,18 Found (%) C 68,57 H ~,63 N 4,24 Characteristic IR band~ (cm,lj: vOH 3,375;
vNH 3,300; vc=c 1,622, 1,602, 1,590 Rf value in TIC: 0,35 values (p,p,m,): 0,93 (3H, t), 1,11 (9R, 8), 1,46 (2H, m), 1,91 (2R, q), 2,75 (2R, d), 3,70 (3H, 8), 4,23 (3H, m), 4,81 (IH, t), 1 ~ ~ 9 ~
6,60 (IH, s), 6.75 to 7.40 (3H, m) Example 10 [2-(a-hydroxybenzyl)-7-(2-hydroxy-3-isopropylaminopropo~y)-benzofuran]
Into 20 ml, of dioxane was dissolved 0.2 g. of 2-benzoyl-7-(2-hydroxy-3-isopropylaminopropoxy)benzofuran, and 0.02 g, of sodium borohydride was added thereto with cooling with ice, The resulting mixture was treated according to the ~ame manner as in Example 1, (A) to give a residue. The residue was recrystallized from acetone-petroleum ether (1 : 1 by volume) to give 0,1 g, of a white powdery compound having a melting point of 135 to 139C. The elementary analysis, characteristic IR
bands, Rf value and ~ value8 of the compound are as follows:
Elementary analysis for C21H2504N:
Calcd, (tO ) C 70.96 E 7.09 N 3.94 Found (%) C 70,88 H 7.16 N 3.79 Characteristic IR bands (cm.~ OH 3~33;
V~H 3,280; ~C=C 1,630, 1,600, 1,590 Rf value in TLC: 0.39 ; ~ val~es (p,p.m.)- 1,12 (6H, d), 2.70 to 3.20 (3H, m), 3.40 (3H, 8), 4.41 (3H, m), 5.96 (lH, 8), 6.40 (~I, ~), 6,60 to 7.60 (8H, m) ~ ' ~
ExamPle 11 [2-hydroxymethyl-7-(2-hydro~y-3-isopropylaminopropoxy)-benzofuran and acetate salt thereof]
3 Into 30 ml. of tetrahydrofuran was dissolved _ 37 ~ 9 ~ ~ ~
0,61 g, of 2-ethoxycarbonyl-7-(2-hydroxy-3-isopropylamino-propoxy)benzofuran,`and 0,05 g, of llthium aluminum hydridè
was added thereto with cooling with ice, The resulting mixture was agitated at a room temperature for 3 hours, and then was poured into 150 ml, of ice water, After addition of sodium chloride for ~alting-out, the reaction mixture was extracted with ethyl acetate, The organic layer was dried over anhydrous sodium sulfate and the solvent therein was distilled off under a reduced pressure to give 0,48 g, of a slightly-yellow. oily compound, The compound wa# treated according to the same manner as in Example 5 to give 0,4 g~ o~ a white powdery acetate salt having a melting point of 144 to 147C, The elementary analysis of the acetate salt is as follows:
Elementary analysis for C17H2506~:
Calcd, (~0) C 60,16 H 7,43 N 4,13 ~ound (%) C 59,87 H 7,21 N 4,38 ExamPle 12 Each o~ the compound~ obtained in Examples 1 to 11 was thoroughly blended with carriers in the ~ollowing ; proportion, .
Ingredient % by weight Essential active ingredient 12,5 Lactose 74.4 Avicel (Note) 8,8 Talc 2,9 Magnesium stearate 1,5 108986~i Note: The resistered trademark of a microcrystalline cellulose made by Asahi Chemical Co,, ~td.
The re~ulting powder was filled into capsule~
made of gelatin to give capsules containing 12,5 mg, o~
the essential active ingredient per one capsule, ExamPle 13 Each o~ the compounds obtained in Examples 1 to 11 wa~ dissolved into a normal saline æolution to give an in~ection containing 0,25 ~0 by weight of the e~ential active ingredient, ~xample 14 Ex~erimental 1:
~mploying anesthetized rats, inhibitions by the compound8 obtained in Exa~ples 1 to 3 a~d 6 t~ 9 agai~t i~oproterenol-induced decrease in blood pressure ~ere determined, Isoproterenol was administered in a dose of 1 ~g,/kg, The compounds to be tested and isoproterenol were administered by intravenous in~ection, ~ or re~erence, the same test a~ in the above was carried out with respect to propranolol which has been usually employed as a ~-adrenergic blocking agent, The result~ thereo~ are ~hown in Table 1, In ~able 1, the inhibition is expressed as 50 % inhibition ~ (ED5~).
I ExPerimental 2:
Employing mice, acute toxicitie8 (ID50) of the compounds obtained in ~xamples 1 to 3 and 6 to 9 were ::
determined, The compounds to be tested were administered ~ ~ .
~V8~8~
intravenously as a normal saline solution thereof.
For reference, the same test as in the above was carried out with respect to propranolol.
The results thereof are shown in Table 1, Erom ED50 and ID50 values obtained in E2perimentals 1 and 2, ~afety margin (~D50/~D50) and relative strengths (relative safety margin when the safety margin of propranolol is 1) were determined. These values are shown in Table 1.
.
.,,;
,~ .
... .
.,1 .
~ ~ 1 ,~ ~
- 40.;_ :, ,. . .
1089~6~
~ ....
h ~ ~ O
~ C~J O ~D ~ O
? r-- co ~ O ~i ., ~ ~
~0 0 .:
~ ~ ~ d r~ 1 u~
~ ~ J O 1 :~. O ~ C~ 0 ~ ~ I
c~
~ t~
~ ,_ ~ 0 . ~ o~ ~ ~ ~ ~ CO
~ ~ N ~ ~ ~ . ~O
~i 1~ ~ 0`! r-~ C~ O~
~1 I ~ ~ I
,Q ., , .
.~ , bD~
~ d ~1 oo ~ O
.~ ~ ~ 0 r~ , t~
~ tq h ~ ~ r--rl ~ ~Q o ,D h ~0 H
:~ ,' '~ ~0 . . . r-l N ~ ~1~ 0 ) o ,. ~ ~ ~
~ , ~ ' ~ ~ ~ ~1 ~1~1 c~
~ ~ o ~ .
.. . .
: .
:
1089~
Example 15 Surface anesthetic property was tested by the method described by Murmann et al (Murmann W,, Saceani-Guelfi M. and Gamba A.; ~oll. Chim. Farm. 105 292 (1966)).
Eive male white guinea-pigs weighting about 400 g. were used, The compound obtained in Example 3 and propranolol were dissolved in normal ~aline solution. Each 0.1 ml.
of the solution was instilled in conjunctival sac of one ,eye and normal saline solution was applied to the other eye, The cornea was touched with a stimulating hair to elicit the blink reflex. The results thereo~ are shown in Table 2.
~ Table 2 Compound Concentration of Blink reflex time the compound (min. + S,E.) (% by weight) Example 3 0.5 8.0 + 2.00 Example 3 2.5 29.8 + 7.80 Propranolol 0.5 56.0 + 2.35
Claims (28)
1. A process for preparing a benzofuran derivative having the following formula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises either (a) reacting a benzofuran derivative having the fol-lowing formula (II):
(II) wherein R1 is the same as defined above, and the hydroxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a propanol derivative having the following for-mula (III):
(III) wherein X is a halogen atom, and R is the same as defined above; or an acid addition salt thereof; or (b) reacting a benzofuran derivative having the following formula (V):
(V) wherein R1 is the same as defined above, and R3 is 2,3-epoxy-propoxy group or 3-chloro-2-hydroxypropoxy group and is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a primary amine having the following formula (VI):
RNH2 (VI) wherein R is the same as defined above; or (c) reducing a benzofuran derivative having the fol-lowing formula (VIII):
(VIII) wherein R2 is a lower alkyl group, a lower alkoxy group or phenyl group, R is the same as defined above, and the sub-stituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or an acid addition salt thereof.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises either (a) reacting a benzofuran derivative having the fol-lowing formula (II):
(II) wherein R1 is the same as defined above, and the hydroxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a propanol derivative having the following for-mula (III):
(III) wherein X is a halogen atom, and R is the same as defined above; or an acid addition salt thereof; or (b) reacting a benzofuran derivative having the following formula (V):
(V) wherein R1 is the same as defined above, and R3 is 2,3-epoxy-propoxy group or 3-chloro-2-hydroxypropoxy group and is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a primary amine having the following formula (VI):
RNH2 (VI) wherein R is the same as defined above; or (c) reducing a benzofuran derivative having the fol-lowing formula (VIII):
(VIII) wherein R2 is a lower alkyl group, a lower alkoxy group or phenyl group, R is the same as defined above, and the sub-stituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or an acid addition salt thereof.
2. A process for preparing a benzofuran derivative having the following formula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position of the benzo-furan ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a benzofuran deriva-tive having the following formula (II):
(II) wherein R1 is the same as defined above, and the hydroxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a propanol derivative having the following for-mula (III):
(III) wherein X is a halogen atom, and R is the same as defined above; or an acid addition salt thereof.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position of the benzo-furan ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a benzofuran deriva-tive having the following formula (II):
(II) wherein R1 is the same as defined above, and the hydroxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a propanol derivative having the following for-mula (III):
(III) wherein X is a halogen atom, and R is the same as defined above; or an acid addition salt thereof.
3. The process of claim 2, wherein the benzofuran derivative having the formula (II) is 2-(1-hydroxyethyl)-hydroxybenzofuran in which the hydroxy group substituted to the benzofuran ring is at the 3, 4, 5, 6 or 7 position of the benzofuran ring.
4. The process of claim 2, wherein X is a chlorine atom.
5. A process for preparing a benzofuran derivative having the following formula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a benzofuran derivative having the following formula (V):
(V) wherein R1 is the same as defined above, and R3 is a 2,3-epoxypropoxy group or a 3-chloro-2-hydroxypropoxy group and is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a primary amine having the following formula (VI):
RNH2 (VI) wherein R is the same as defined above.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises reacting a benzofuran derivative having the following formula (V):
(V) wherein R1 is the same as defined above, and R3 is a 2,3-epoxypropoxy group or a 3-chloro-2-hydroxypropoxy group and is at the 3, 4, 5, 6 or 7 position of the benzofuran ring, with a primary amine having the following formula (VI):
RNH2 (VI) wherein R is the same as defined above.
6. The process of claim 5, wherein the benzofuran derivative having the formula (V) is 2-(1-hydroxyethyl)-(2-hydroxy-3-chloropropoxy)benzofuran in which the substi-tuted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring.
7. The process of claim 5, wherein the benzofuran derivative having the formula (V) is 2-(1-hydroxyethyl)-(2,3-epoxypropoxy)benzofuran in which the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position of the benzo-furan ring.
8. A process for preparing a benzofuran derivative having the following formula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position at the benzo-furan ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a benzofuran deriva-tive having the following formula (VIII):
(VIII) wherein R2 is a lower alkyl group, a lower alkoxy group or phenyl group, R is the same as defined above, and the sub-stituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or an acid addition salt thereof.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted pro-poxy group is at the 3, 4, 5, 6 or 7 position at the benzo-furan ring; or a pharmaceutically acceptable acid addition salt thereof, which comprises reducing a benzofuran deriva-tive having the following formula (VIII):
(VIII) wherein R2 is a lower alkyl group, a lower alkoxy group or phenyl group, R is the same as defined above, and the sub-stituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or an acid addition salt thereof.
9. The process of claim 8, wherein R2 is a straight or branched alkyl group having 1 to 4 carbon atoms.
10. The process of claim 8, wherein R2 is a methyl group.
11. The process of claim 8, wherein R2 is a straight or branched alkoxy group having 1 to 4 carbon atoms.
12. The process of claim 1, wherein R1 is a straight or branched alkyl group having 1 to 4 carbon atoms.
13. The process of claim 1, wherein R is a straight or branched alkyl group having 1 to 4 carbon atoms.
14. The process of claim 1, wherein R1 is methyl group, and R is a branched alkyl group having 3 to 4 carbon atoms.
15. The process of claim 1, wherein there is prepared a benzofuran derivative which is 2-(1-hydroxyethyl)-7-(2-hy-droxy-3-tert.-butylaminopropoxy)benzofuran.
16. The process of claim 1, wherein there is prepared a benzofuran derivative which is 2-(1-hydroxyethyl)-7-(2-hy-droxy-3-sec.-butylaminopropoxy)benzofuran.
17. The process of claim 1, wherein there is prepared a benzofuran derivative which is 2-(1-hydroxyethyl)-7-(2-hy-droxy-3-isopropylaminopropoxy)benzofuran.
18. A benzofuran derivative having the following for-mula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 1.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 1.
19. A benzofuran derivative having the following for-mula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 2, 3 or 4.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 2, 3 or 4.
20. A benzofuran derivative having the following formula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 5, 6 or 7.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 5, 6 or 7.
21. A benzofuran derivative, as defined in claim 18, whenever prepared according to the process of claim 8.
22. A benzofuran derivative having the following for-mula (I):
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 9, 10 or 11.
(I) wherein R1 is hydrogen atom, a lower alkyl group or phenyl group, R is a lower alkyl group, and the substituted propoxy group is at the 3, 4, 5, 6 or 7 position of the benzofuran ring; or a pharmaceutically acceptable acid addition salt thereof, whenever prepared according to the process of claim 9, 10 or 11.
23. A benzofuran derivative as defined in claim 18, wherein R1 is a straight or branched alkyl group having 1 to 2 carbon atoms, whenever prepared according to the process of claim 12.
24. A benzofuran derivative as defined in claim 18, wherein R is a straight or branched alkyl group having 1 to 4 carbon atoms, whenever prepared according to the process of claim 13.
25. A benzofuran derivative as defined in claim 18, wherein R1 is methyl group, and R is a branched alkyl group having 3 to 4 carbon atoms, whenever prepared according to the process of claim 14.
26. 2-(1-Hydroxyethyl)-7-(2-hydroxy-3-tert.-butylamino-propoxy)benzofuran, whenever prepared according to the process of claim 15.
27. 2-(1-Hydroxyethyl)-7-(2-hydroxy-3-sec.-butylamino-propoxy)benzofuran, whenever prepared according to the process of claim 16.
28. 2-(1-Hydroxyethyl)-7-(2-hydroxy-3-isopropylamino-propoxy)benzofuran, whenever prepared according to the process of claim 17.
Applications Claiming Priority (8)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP126534/1975 | 1975-10-20 | ||
| JP50126534A JPS5919106B2 (en) | 1975-10-20 | 1975-10-20 | Method for producing benzofuran derivatives |
| JP51000351A JPS5951547B2 (en) | 1976-01-01 | 1976-01-01 | benzofuran derivatives |
| JP351/1976 | 1976-01-01 | ||
| JP6074/1976 | 1976-01-21 | ||
| JP51006075A JPS5951549B2 (en) | 1976-01-21 | 1976-01-21 | Method for producing benzofuran derivatives |
| JP6075/1976 | 1976-01-21 | ||
| JP51006074A JPS5951548B2 (en) | 1976-01-21 | 1976-01-21 | Method for producing benzofuran derivatives |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1089866A true CA1089866A (en) | 1980-11-18 |
Family
ID=27453151
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA257,342A Expired CA1089866A (en) | 1975-10-20 | 1976-07-20 | Benzofuran derivatives, preparation thereof and pharmaceutical compositions thereof |
Country Status (7)
| Country | Link |
|---|---|
| BE (1) | BE845156A (en) |
| CA (1) | CA1089866A (en) |
| CH (1) | CH628338A5 (en) |
| DE (1) | DE2635064C2 (en) |
| FR (1) | FR2328463A1 (en) |
| GB (1) | GB1502248A (en) |
| NL (1) | NL7610426A (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60202872A (en) * | 1984-03-27 | 1985-10-14 | Kaken Pharmaceut Co Ltd | Benzofuran derivative, its preparation, and hypotensive agent containing said derivative as active component |
| JPS61158976A (en) * | 1984-12-28 | 1986-07-18 | Shionogi & Co Ltd | Benzofuran and benzothiophene derivative |
| TR200101779T2 (en) | 1998-12-18 | 2001-12-21 | Basilea Pharmaceutica Ag | New bicyclic components |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB1058822A (en) * | 1963-07-30 | 1967-02-15 | Ici Ltd | 3-amino-2-hydroxypropoxy heterocyclic derivatives |
-
1976
- 1976-07-20 CA CA257,342A patent/CA1089866A/en not_active Expired
- 1976-07-29 GB GB3161576A patent/GB1502248A/en not_active Expired
- 1976-08-04 DE DE19762635064 patent/DE2635064C2/en not_active Expired
- 1976-08-05 CH CH997876A patent/CH628338A5/en not_active IP Right Cessation
- 1976-08-12 FR FR7624676A patent/FR2328463A1/en active Granted
- 1976-08-13 BE BE169780A patent/BE845156A/en not_active IP Right Cessation
- 1976-09-20 NL NL7610426A patent/NL7610426A/en not_active Application Discontinuation
Also Published As
| Publication number | Publication date |
|---|---|
| BE845156A (en) | 1976-12-01 |
| FR2328463B1 (en) | 1978-12-22 |
| DE2635064C2 (en) | 1986-07-24 |
| DE2635064A1 (en) | 1977-04-21 |
| CH628338A5 (en) | 1982-02-26 |
| NL7610426A (en) | 1977-04-22 |
| FR2328463A1 (en) | 1977-05-20 |
| GB1502248A (en) | 1978-02-22 |
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