WO1996034871A1

WO1996034871A1 - Benzopyran derivatives

Info

Publication number: WO1996034871A1
Application number: PCT/JP1996/001180
Authority: WO
Inventors: Keizo Tanikawa; Kazuhiko Ohrai; Masayuki Sato; Takashi Horiuchi; Toru Yamashita
Original assignee: Nissan Chemical Corp
Current assignee: Nissan Chemical Corp
Priority date: 1995-05-01
Filing date: 1996-04-30
Publication date: 1996-11-07
Anticipated expiration: 1997-11-01
Also published as: IL118090A0; ZA963421B; AU5515396A

Abstract

Benzopyran derivatives of formula (I), wherein X?1 and X2¿ are absent or represent an oxygen atom; X represents an oxygen atom, a sulfur atom, a nitrogen atom (said nitrogen atom is unsubstituted or substituted by a hydrogen atom or C¿1?-C4 alkyl group), carbonyl or thiocarbonyl; A represents a hydroxyl group or may form a single bond together with B; B represents a hydrogen atom or may form a single bond together with A; Y represents 1-pyrrolyl group, 1-pyrazolyl group, 1-imidazolyl group, 1-(1,2,3-triazolyl) group or 1-(1,2,4-triazolyl) group which is unsubstituted or substituted by R?3; R1 and R2¿ independently represent a hydrogen atom, a phenyl group or a C¿1?-C4 alkyl group; R?3¿ represents a hydrogen atom, a halogen atom, a C¿1?-C6 alkyl group and medicines for treating cardiac insufficiency containing said compound as an active ingredient. The compounds have a strong activity of reinforcing the contraction of cardiac muscles and a strong activity of reducing the heart rate. As the compounds are not toxic, they are useful medicines for treating cardiac insufficiency.

Description

BENZOPYRAN DERIVATIVES

Technical Field

This invention relates to novel benzopyran derivatives having pharmacological activity and to the use of said derivatives as a medicine for cardiac insufficiency. Background Art

PCT International Patent Application Laid-open No. WO 94/22442 discloses that compounds which are prepared by substituting the 8-position of a benzopyran derivative by a diethylamino group, a pyrrolidinyl group, a piperidinyl group, etc. are useful as a composition for treating cardiac insufficiency.

The cardiac insufficiency which is a state of insufficient function of heart is a disease which is based on the depression of contraction of heart muscles. As a treatment therefor, it has been clinically used medicines for reinforcing the contraction of cardiac muscles. However, these medicines have such a problem that heart muscles energy is excessively consumed on the basis of the increase of the heart rate and thus, they have had problems to be solved with respect to effects to improve life recuperation after the administration of these medicines in a long period of time. It has been, thereofore, desired to develop medicines which reduce load in consumption of heart muscle energy by reducing heart rate or medicines which have an activity of increasing a contraction of heart muscles without increasing the heart rate.

Disclosure of Invention

The present inventors have found out that, in the benzopyran derivatives, the compounds of the present invention in which amino groups as substituent are unsaturated five- membered heterocyclic ring such as a pyrrolyl group, a pyrazolyl group, an imidazolyl group or a triazolyl group surprisingly has had a strong activity for reducing heart rate and have a stronger activity of reinforcing the constraction of heart muscles without increasing heart rate, in comparison with the know compounds and that the compounds of the present invention are useful as medicines for treating cardiac insufficiency. By these findings, the present invention was completed.

Specifically, the present invention is directed to a benzopyran derivative of the following formula (I):

( I )

wherein X¹ and X² are absent or represent an oxygen atom;

X represents an oxygen atom, a sulfur atom, a nitrogen atom (said nitrogen atom is unsubstituted or substituted by a hydrogen atom or C, -C₄ alkyl group), carbonyl or thiocarbonyl;

A represents a hydrogen atom, a hydroxyl group, or 0C(0)R⁴ (in which R⁴ represents a Ci -C₄ alkyl group), or may form a single bond together with B;

B represents a hydrogen atom, or may form a single bond together with A;

Y represents 1-pyrrolyl group, 1-pyrazolyl group, 1-imidazolyl group, l-( 1, 2, 3-triazolyl ) group or l-(1,2,4- triazolyl) group which is unsubstituted or substituted by R³ ;

R¹ and R² independently represent a hydrogen atom, a phenyl group or a C, -C₄ alkyl group, or they may together form 1,4-butylene group or 1, 5-pentylene group which is unsubstituted or substituted by C, -C₄ alkyl group; and

R³ represents a hydrogen atom, a halogen atom, a C, -C₆ alkyl group (said alkyl group is unsubstituted or substituted by a hydroxyl group or a phenyl group (said phenyl group is unsubstituted or substituted by a halogen atom, a hydroxyl group, a C, -C₄ alkyl group or a C, -C₄ alkoxy group)), a C₃ -C₆ cycloalkyl group, a phenyl group (said phenyl group is unsubstituted or substituted by a halogen atom, a hydroxyl group, a C, -C₆ alkyl group or a C, -C₄ alkoxy group), or salts thereof, and medicines for treating cardiac insufficiency containing as active ingredient said derivatives.

The present invention also relates to below mentioned compounds or salts thereof and medicines for treating cardiac insufficiency containing as active ingredient said derivatives.

(1) Benzopyran derivatives or salts thereof of the formula (I) in which X' is absent;

X² is absent or represents an oxygen atom;

X represents an oxygen atom, a sulfur atom or a nitrogen atom (said nitrogen atom is unsubstituted or substituted by a hydrogen atom or a C, -C₄ alkyl group);

A represents a hydroxyl group, or may form a single bond together with B;

B represents a hydrogen atom, or may form a single bond together with A; and

R¹ represents a hydrogen atom or a C, -C₄ alkyl group.

(2) The benzopyran derivatives or salts thereof described in the above item (1), wherein R' and R² independently represent a C, -C₄ alkyl group.

(3) The benzopyran derivatives or salts thereof described in the above item (2), wherein R³ represents a hydrogen atom.

(4) The benzopyran derivatives or salts thereof described in the above item (3), wherein Y represents a l-(1,2,4-triazolyl) group. (5) The benzopyran derivatives or salts thereof described in the above item (3), wherein Y represents a l-(1,2, 3-triazolyl ) group.

(6) The benzopyran derivatives or salts thereof described in the above item (3), wherein Y represents a 1-imidazolyl group.

(7) The benzopyran derivatives or salts thereof described in the above item (3), wherein Y represents a 1-ρyrazolyl group.

(8) The benzopyran derivatives or salts thereof described in the above item (3), wherein Y represents a 1-pyrrolyl group.

The compounds of the present invention have strong activity of reducing the heart rate and are useful for improving cardiac functions and therefore, they are usable as medicines for treating cardiac insufficiency. Moreover, the compounds of the present invention not only exert a strong activity of reducing the heart rate, but also exert a strong cardiotonic activity.

The substituents in the compounds of the formula (I) will be explained in more detail hereunder.

In this specification, "n-" means normal; "i-" means iso; "sec-" means secondary; "t-" means tertiary-; "c-" means cyclo-; "Me" means methyl; "Et" means ethyl; ^»p_r ^» means propyl; "Bu" means butyl; "Pen" means pentyl; "Hex" means hexyl; and "Ph" means phenyl.

Examples of R¹ and R² include a hydrogen atom, Ph, Me, Et, n-Pr, i-Pr, n-Bu, i-Bu, sec-Bu and t-Bu, preferably, Me, Et, n-Pr, i-Pr and n-Bu. Moreover, there are examples that R' and R² , together with the linkage carbon atoms, form (CH_Z )₄ or (CH_Z )₅ to give spiro-rings.

Examples of A include a hydrogen atom, a hydroxyl group, OC(0)Me, OC(0)Et, OC(0)-n-Pr, 0C(0)-i-Pr, OC(0)-n-Bu, OC(0)-i-Bu, OC(0)-sec-Bu and OC(0)-t-Bu, preferably, a hydroxyl group, OC(0)Me, OC(0)Et and OC(0)-n-Pr. A and B together may form a single bond.

Examples of X include an oxygen atom, a sulfur atom, carbonyl, thiocarbonyl, NH, NMe, NEt, N-n-Pr, N-i-Pr, N-c-Pr, N-n-Bu, N-i-Bu, N-sec-Bu and N-t-Bu, preferably, an oxygen atom, a sulfur atom, a carbonyl group, a thiocarbonyl group, NH, NMe, NEt and N-n-Pr.

Examples of Y include 1-pyrrolyl group, 1-pyrazolyl group, 1-imidazolyl group, l-( 1, 2, 3-triazolyl ) group or l-( 1, 2, 4-triazolyl ) group all of which are unsubstituted or substituted by R³.

Examples of R³ include a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom. Me, Et, n-Pr, i-Pr, c-Pr, n-Bu, i-Bu, sec-Bu, t-Bu, n-Pen, c-Pen, n-Hex, c-Hex, Ph, benzyl, para-chlorophenylmethyl, para-fluorophenylmethyl, para-bromophenylmethyl, para-methoxyphenylmethyl, meta- methoxyphenylmethyl, phenylethyl, para-chlorophenylethyl, para-fluorophenylethyl, para-bromophenylethyl, para- methoxyphenylethyl or meta-methoxyphenylethyl, preferably a hydrogen atom. Me, Et, n-Pr, Ph and benzyl.

Examples of the compounds of the present invention are mentioned below. However, the present invention is not to be restricted thereto. In these examples, "-" indicates the absence of X¹ and X² , "-" between A and B indicates a bond, "n" means 0 or an integer of 1, 2, 3 or 4 which is the number of substituent R³ , and when n is plural, R³ may be the same or different each other.

T a b l e 1

R³ X X¹ X² B R¹ R²

4- 5-

O - O OH H Me Me H H H H

O OH H Me Me H H H H

O Me Me H H H H

O - O OH H Et Et H H H H

O OH H Et Et H H H H

O Et Et H H H H

O OC(O)Me H Me Me H H H H

O OC(O)Et H Me Me H H H H

O - OC(O)-n-Pr H Me Me H H H H

O OH H Me Me H Me Me H

O OH H Me Me H Et Me H

O ^" Me Me H Me Me H

O OH H Me Me H Ph Ph H

O ^" Me Me H Ph Ph H s OH H Me Me H H H H

S O - OH H Me Me H H H H s Me Me H H H H s OC(O)Me H Me Me H H H H s OH H Et Et H Me Me H R³

Nc >. X X¹ X² A B R¹ R²

2- 3- 4- 5-

0 S OH H Me Me H CH₂Ph CH₂P1 l H 1 O OH H Me Me Me H H Me 2 NH - OH H Me Me H H H H 3 NH - Me Me H H H H 4 NMe - OH H Me Me Me H H Me 5 NMe - OH H Me Me H H H H 6 NEt - OH H Me Me Me H H Me 7 NEt - OH H Me Me H H H H 8 N-n-Pr - OH H Me Me H H H H 9 C(O) - - OH H Me Me H H H H 0 C(O) - - Me Me H H H H 1 C(S) - - OH H Me Me H H H H 2 C(S) - - Me Me H H H H 3 O OH H n-Pr n-Pr H H H H 4 O OH H n-Bu N-Bu H Me Me H 5 O OC(O)Me H Et Et H H H H 6 O OC(O)Et H Et Et H H H H 7 s OH H Et Et H H H H

O Me Me Me H H Me

O OH H -(CH₂)₂- H H H H

O OH H H H H H H H 1 O OH H Me Me H CH₂Ph CH₂Ph H

O OH H i-Pr i-Pr H H H H

O OH H Me Me H a Et H

] R³ . X X¹ X² A B R¹ R²

5- 4- 3- S - - OH H Me Me CH₂Ph H CH₂Ph O OH H Me Me H Me H NH - OH H Me Me H H H NH - Me Me H H H NMe - OH H Me Me H Me H NMe - OH H Me Me H H H NEt - OH H Me Me H Me H NEt - OH H Me Me H H H N-n-Pr - - OH H Me Me H H H C(O) - OH H Me Me H H H C(O) - Me Me H H H C(S ) - - OH H Me Me H H H C(S ) - Me Me H H H O OH H n-Pr n-Pr H H H O OH H n-Bu N-Bu Me H Me O OH H Me Me H Me Et O OC(O)Et H Et Et H H H S OH H Et Et H H H O Me Me H Me H O OH H -(CH₂)₂- H H H O OH H H H H H H O OH H Me Me CH₂Ph H CH₂Ph O OH H i-Pr i-Pr H H H O OH H Me Me Et H Et

T a b l e 4

R³

X X¹ X² A B R¹ R²

5- 3-

O - O OH H Me Me H H

O OH H Me Me H H O Me Me H H

O - O OH H Et Et H H

O OH H Et Et H H O ^" Et Et H H

O OC(O)Me H Me Me H H

O OC(O)Et H Me Me H H

O - OC(O)-n-Pr H Me Me H H

O OH H Me Me H Me

O OH H Me Me H Et

O Me Me H Me

O OH H Me Me H Ph

O ^" Me Me H Ph s OH H Me Me H H s c ) - OH H Me Me H H s _ Me Me H H s OC(O)Me H Me Me H H s OH H Et Et H Me R³ o. X X¹ X² A B R¹ R²

5- 3-

S - OH H Me Me H CH₂Ph O - OH H Me Me Me H NH - - OH H Me Me H H NH - - Me Me H H NMe - - OH H Me Me Me H NMe - - OH H Me Me H H NEt - - OH H Me Me Me H NEt - - OH H Me Me H H N-n-Pr - - OH H Me Me H H C(O) - - OH H Me Me H H C(O) - Me Me H H C(S) - - OH H Me Me H H C(S ) - Me Me H H O - OH H n-Pr n-Pr H H O - OH H n-Bu n-Bu H Me O - OH H Me Me H Me O - OC(O)Et H Et Et H H S - OH H Et Et H H O - Me Me H Me

O - OH H H H H H O - OH H Me Me CH₂Ph H O - OH H i-Pr i-Pr H H O - OH H Me Me Et H T a b l e 5

R³

X X¹ X² A B R¹ R²

5- 4-

O - O OH H Me Me H H

O - OH H Me Me H H

O - Me Me H H

O - O OH H Et Et H H

O - OH H Et Et H H O Et Et H H

O - OC(O)Me H Me Me H H

O - OC(O)Et H Me Me H H

O - OC(O)-n-Pr H Me Me H H

O - OH H Me Me H Me

O - OH H Me Me H Et

O - Me Me H Me

O - OH H Me Me H Ph

O - Me Me H Ph s - OH H Me Me H H s O - OH H Me Me H H s - Me Me H H s - OC(O)Me H Me Me H H s - OH H Et Et H Me R³ . X X ¹ X² A B R¹ R²

5- 4-

S - OH H Me Me H CH₂Ph O - OH H Me Me Me H NH - - OH H Me Me H H NH - - Me Me H H NMe - - OH H Me Me Me H NMe - - OH H Me Me H H NEt - - OH H Me Me Me H NEt - - OH H Me Me H H N-n-Pr - - OH H Me Me H H C(O) - - OH H Me Me H H C(O) - - Me Me H H C(S ) - - OH H Me Me H H C(S) - - Me Me H H O - OH H n-Pr n-Pr H H O - OH H n-Bu n-Bu H Me O - OH H Me Me H Me O - OC(O)Et H Et Et H H S - OH H Et Et H H O ^" Me Me H Me

O - OH H H H H H O - OH H Me Me CH₂Ph H O - OH H i-Pr i-Pr H H O - OH H Me Me Et H The compounds of the present invention have asymmetric carbon atoms at the 3-position and 4-position in the pyran ring and therefore, include optically active compounds based on the asymmetric carbon atoms. Such optically active compounds may be used in the present invention, like the racemic modifications. It is preferable to use optically active compounds. In addition, stereoisomers based on the 3-position and 4-position in the pyran ring may also be used. It is preferable to use compounds in which the relative configuration are trans. If the compounds may form salts, their pharmacologically acceptable salts may be used as the active ingredients of the present invention.

Methods for producing the compounds of the present invention will be explained below, in which n is 0 or an integer of 1, 2, 3 or 4 as the number of the substituent R³ ; when n is plural, R³ may be the same or different each other. R^{3 '} and R^{3 '} have the same meaning as defined in R³ , but they may be different from R³ respectively.

Of the compounds of the formula (I), as shown in the following reaction scheme, a compound of the formula (7) and a compound of the formula (8) in which X represents an oxygen atom and Y represents 1-pyrrolyl group are synthesized via two steps or three steps starting from a compound of the formula (3). A compound in which A represents a hydroxyl group is shown by a compound of the formula (7) and a compound in which A and B together may form a single bond is indicated by a compound of the formula (8).

(3) (4)

(8)

A compound of the formula (4) can be obtained by reacting a compound of the formula (3) with ammonia in an inert solvent .

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, alcohol solvents such as methanol and ethanol . Of these, preferred are alcohol solvents.

The reaction temperature in this reaction is, usually from ice-cooled temperature to the reflux temperature for the reaction solvent used, preferably from 40 °C to 80 °C .

The reaction is preferably conducted in a pressure glass tube or an autoclave.

A compound of the formula (7) is obtained by reacting a compound of the formula (4) with a compound of the formula (5) or a compound of the formula (6) in an inert solvent in the presence of an acid catalyst.

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane. The reaction may be conducted in the absence of the solvent. The acid catalyst may be used as it is, as a solvent.

The reaction temperature is, usually, from ice-cooled temperature to the reflux temperature for the reaction solvent used. The reflux temperature is preferable.

Regarding molar ratio of the starting compounds, the ratio of compound (5) or compound (6)/compound (4) is within the range of from 0.5 to 4.0, preferably from 1.0 to 2.0.

As the acid catalyst used, it is raised a hydrochloric acid, a sulfuric acid, a formic acid, an acetic acid and propionic acid.

A compound of the formula (8) is obtained at the time of a post-treatment of formation-reaction of a compound of the formula (7). At the neutralization in the post-treatment, when the heating and concentration are conducted at a state that an acid remains or alkali is excessively added, dehydration may occur.

However, this dehydration is apt to be influenced by the kind of the compounds formed, the conditions for the post-treatment and the heating-concentration temperatures.

A compound of the formula (8) is obtained by reacting, preferably, a compound of the formula (7) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or organic base such as tetraalkyl-ammonium hydroxide.

A compound of the formula (8) is also obtained by reacting a compound of the formula (3) and a compound of the formula (9) in an inert solvent in the presence of sodium hydride.

•⁽R³⁾„

V

& 1 (9)

N H

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as an ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane. It is preferable to use the amide solvents.

The reaction temperature is, usually, from ice-cooled temperature to the reflux temperature for the reaction solvent used. Preferable reaction temperature is from ice-cooled temperature to 40 °C .

Regarding molar ratio of the starting compounds, the ratio of compound (9)/compound (3) is within the range of from 0.5 to 4.0, preferably from 1.0 to 2.0.

Cis-form of a compound of the formula (7) is synthesized by the inversion of a hydroxyl group of a compound of the formula (4) . Namely, an oxazol ring formed by amidating a compound of the formula (4) and then treating the amidated compound with thionyl chloride is hydrolyzed in the presence of an acid to synthesize a cis-form of a compound of the formula (4).

The solvents usable for the amidation include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, nitrile solvents such as acetonitrile and propionitrile. Moreover, it can use two- phase mixed solvent of one or more of these organic solvents and water. It is preferable to use the two-phase solvent of one or more of the organic solvents and water.

The base to be used for the reaction includes, for example, triethylamine, pyridine, diisopropylethylamine and DBU (diazabicycloundecene) , sodium hydroxide, potassium hydroxide. It is preferable to use soduim hydroxide or potassium hydroxide.

The amidating agent includes acid halides such as an acid chloride and an acid bromide, and acid anhydrides.

The reaction temperature is, usually, from -20 °C to the reflux temperature for the reaction solvent used. Preferable reaction temperature is from 0 °C to 30 .

Regarding molar ratio of the starting compounds, the ratio of amidating agent/compound (4) is within the range of from 0.5 to 4.0, preferably from 1.0 to 2.0.

The solvent usable for the treatment with thionyl chloride includes, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, nitrile solvents such as acetonitrile and propionitrile, preferably halogenated solvents.

The reaction temperature is, usualy, from ice-cooled temperature to the reflux temperature for the reaction solvent used. Preferable reaction temperature is from 0 °C to 40 °C .

Regarding molar ratio of the starting compounds, the ratio of thionyl chloride/compound (4) is within the range of from 1.0 to 10.0, preferably from 1.0 to 5.0.

The solvent used for the hydrolysis includes, for example, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, nitrile solvents such as acetonitrile and propionitrile. It is preferable to use ether solvents or water.

Acids used for the hydrolysis include, for example, sulfuric acid and hydrochloric acid. The reaction temperature is, usually, from ice-cooled temperature to the reflux temperature for the reflux temperature for the reaction solvent used. Preferable temperature is from 60 °C to 100 °C .

Of the compounds of the formula (I), as shown in the following reaction scheme, a compound of the formula (12), a compound of the formula (13), a compound of the formula (14) and a compound of the formula (15) in which X represents an oxygen atom and Y represents 1-pyrazolyl group may be synthesized via two steps or three steps starting from the compound of the formula (3). A compound that A represents a hydroxyl group is shown by a compound of the formula (12) and a compound of the formula (13), and a compound in which A and B together may form a single bond is shown by a compound of the formula (14) and a compound of the formula (15).

A compound of the formula ^' (10) is obtained by reacting a compound of the formula (3) with hydrazine hydrate in an inert solvent.

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, alcohol solvents such as methanol and ethanol . Of these, preferred are alcohol solvents .

The reaction temperature in this reaction is, usually, from ice-cooled temperature to the reflux temperature for the reaction solvent used, preferably from 40 °C to 80 °C .

Regarding molar ratio of the starting compounds, the ratio of hydrazine hydrate/compound (3) is within the range of from 0.5 to 10.0, preferably from 1.0 to 2.0.

A compound of the formula (12) and a compound of the formula (13) are obtained by reacting a compound of the compound (10) with a compound of the formula (11) in an inert solvent.

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, alcohol solvents such as methanol and ethanol . The reaction may be conducted in the absence of the solvent.

The reaction temperature is, usually, form ice-cooled temperature to the reflux temperature for the reaction solvent used.

Regarding molar ratio of the starting compounds, the ratio of compound (11)/compound (10) is within the range of from 0.5 to 5.0, preferably from 1.0 to 2.0. A compound of the formula (12) and a compound of the formula (13) are isolated by the known isolation method in the organic chemistry such as recrystalization or column chromatography.

A compound of the formula (14) and a compound the formula (15) are obtained by reacting a compound of the formula (12) or a compound of the formula (13) in an inert solvent in the presence of an inorgnic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or organic base such as tetraalkyl-ammonium hydroxide.

After a compound of the formula (14) and a compound of the formula (15) are obtained by reacting a mixture of the compound of the formula (12) and the compound of the formula (13) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide, they may be isolated by the known isolation method in the organic chemistry such as recrystalization or column chromatography.

Of the compounds of the formula (I), as shown in the following reaction scheme, a compound of the formula (17) and a compound of the formula (18) in which X represents an oxygen atom and Y represents 1-imidazolyl group are obtained by reacting a compound of the formula (3) and a compound of the formula (16) in an inert solvent in the presence of sodium hydride. Coexistence with a phase transfer catalyst such as 18-crown-6 is preferable. A compound in which A represents a hydroxyl group is shown by a compound of the formula (17), and a compound in which A and B together may form a single bond is shown by a compound of the formula (18).

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, aromatic solvents such as benzene and toluene. It is preferable to use the aromatic solvents.

The reaction temperature is, usually, from ice-cooled temperature to the reflux temperature for the reaction solvent used.

Regarding molar ratio of the starting compounds, the ratio of compound (16)/compound (3) is within the range of from 0.5 to 5.0, preferably from 1.0 to 2.0.

A compound of the formula (18) is obtained at the time of a post-treatment of formation-reaction of a compound of the formula (17). However, this formation of a compound of the formula (18) is apt to be influenced by the kind of the compounds formed, the reaction solvents and the reaction temperatures.

A compound of the formula (18) may be obtained at the time of a post-treatment of the reaction. At the neutralization in the post-treatment, when the heating and concentration are conducted at a state that an alkali remains or an acid is excessively added, dehydration may occur.

However, this dehydration reaction is apt to be influenced by the kind of the compounds formed and the heating-concentration temperatures.

A compound of the formula (18) is obtained by reacting a compound of the formula (17) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

Of the compounds of the formula (I), as shown in the following reaction scheme, a compound of the formula (20) and a compound of the formula (21) in which X represents an oxygen atom and Y represents l-( 1, 2, 4-triazolyl ) group are obtained by reacting a compound of the formula (3) and a compound of the formula (19) in an inert solvent in the presence of sodium hydride. Coexistence with a phase transfer catalyst such as 18-crown-6 is preferable. A compound in which A is a hydroxyl group is shown by a compound of the formula (20), and a compound in which A and B together may form a single bond is shown by a compound of the formula (21).

The solvents usable for the reaction include, for example, sulfoxide solvent such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, aromatic solvents such as benzene and toluene. Of these, preferred are aromatic solvents.

The reaction temperature in this reaction is, usually, from ice-cooled temperature to the reflux temperature for the reaction solvent used.

Regarding molar ratio of the starting compounds, the ratio of compound (19)/compound (3) is within the range of from 0.5 to 5.0, preferably from 1.0 to 2.0.

A compound of the formula (21) is obtained at the time of a post-treatment in formation-reaction of a compound of the formula (20). However, this formation of a compound of the formula (21) is apt to be influenced by the kind of the compounds formed, reaction solvents and reaction temperatures.

A compound of the formula (21) may be obtained at the time of a post-treatment in the reaction. At the neutralization of the post-treatment, when the heating and concentration are conducted at a state that an alkali remains or an acid is excessively added, dehydration may occur.

However, this dehydration is apt to be influenced by the kind of the compounds formed and the heating-concentration temperatures.

A compound of the formula (21) is obtained by reacting a compound of the formula (20) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

Of the compounds of the formula (I), as shown in the following reaction scheme, a compound of the formula (23) and a compound of the formula (24) in which X represents an oxygen atom and Y represents l-(1, 2, 3-triazolyl) group are obtained by reacting a compound of the formula (3) with a compound of the formula (22) in an inert solvent in the presence of sodium hydride. Coexistence with a phase transfer catalyst such as 18-crown-6 is preferable. A compound in which A represents a hydroxyl group is shown by a compound of the formula (23), and a compound in which A and B together may form a single bond is shown by a compound of the formula (24).

Regarding molar ratio of the starting compounds, the ratio of compound (22)/compound (3) is within the range of from 0.5 to 5.0, preferably from 1.0 to 2.0.

A compound of the formula (24) is obtained at the time of a post-treatment of the formation-reaction of a compound of the formula (23). However, this formation of a compound of the formula (24) is apt to be influenced by the kind of the compounds formed, reaction solvents and reaction temperatures.

A compound of the formula (24) may be obtained at the time of a post-treatment of the reaction. At the neutralization of the post-treatment, when the heating and concentration are conducted at a state that an alkali remains or an acid is excessively added, dehydration may be generated.

However, this dehydration is apt to be influenced by the kind of the compounds formed, the heating-concentration temperatures.

A compound of the formula (23) and a compound of the formula (24) may also be synthesized via two steps or three steps starting from a compound of the formula (3), as shown in the following reaction scheme. azido compound

A compound of the formula (25) is obtained by reacting a compound of the formula (3) with azido compounds such as sodium azide, lithium azide and trimethylsilyl azide in an inert solvent. The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, aromatic solvents such as benzene and toluene. Of these, preferred are aromatic solvents.

Regarding molar ratio of the starting compounds, the ratio of azido compound/compound (3) is within the range of from 0.5 to 5.0, preferably from 1.0 to 2.0.

The compound of the formula (23) is obtained by reacting the compound of the formula (25) and the compound of the formula (26) in an inert solvent.

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane, aromatic solvents such as benzene and toluene. Of these, preferred are aromatic solvents. The reaction temperature is, nomally, from 5 °C to 140 °C , preferably, from 80 °C to 120 °C .

Regarding molar ratio of the starting compounds, the ratio of compound (26)/compound (25) is within the range of from 0.5 to 5.0, preferably from 1.0 to 2.0.

It is preferable to conduct this reaction in a pressure glass tube or an autoclave.

A compound of the formula (24) is obtained by reacting, preferably, a compound of the formula (23) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

A compound of the formula (3) which is the starting material of the compounds of the present invention is a known compound and the method for producing said compound is described in PCT International Patent Application Laid-open No. WO 94/22442. The whole flow for obtaining them are shown below.

Of the compounds of the formula (I), a compound of the formula (33), a compound of the formula (34), a compound of the formula (35), a compound of the formula (36), a compound of the formula (37) and a compound of the formula (38) in which X represents a sulfur atom or a nitrogen atom (which is unsubstituted or substituted by C_t -C alkyl group) are synthesized via four to six steps.

A compound of the formula (30) is synthesized from a compound of the formula (29) by the similar method for obtaining the compounds of the formula (7) or the compounds of the formula (12) or the compounds of the formula (17), the compounds of the formula (20) or the compounds of the formula (23). A compound of the formula (29) is a known compound and it is obtained by a known method (J. Med. Chem. 27. 1127(1987)).

(29) (30)

A compound of the formula (32) is obtained by the catalytic hydrogenation of a compound of the formula (31) which is obtained from a compound of the formula (30) by normal cleavege method using acid catalyst, in the presence of water and metallic catalyst such as palladium carbon, Raney nickel and platinum oxide.

(30) (31)

H₂/catalyst

(32)

Of the compounds of the formula (I), a compound of the formula (33) in which X represents a nitrogen atom is obtained by conducting the normal diazo reaction such as a method in which sodium sulfite is acted on a compound of the formula (32), in an aqueous solution in the presence of an inorganic acid such as a hydrochloric acid and a sulfuric acid or an organic acid such as acetic acid and then, subjecting the product to heating and ring-closing at from 5 °C to 100 °C , preferably from 50 °C to 100 °C .

A compound of the formula (34) is obtained by reacting, preferably, a compound of the formula (33) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

Of the compounds of the formula (I), a compound of the formula (35) and a compound of the formula (36) in which X represents an alkylamino group are obtained by reacting a compound of the formula (33) or a dehydrate (34) thereof with diazomethane or reacting a compound of the formula (33) or the dehydrate (34) thereof with alkyl-halide in the presence of potassium carbonate.

Of the compounds of the formula (I), a compound of the formula (37) in which X represents a sulfur atom is synthesized by acting a compound of the formula (32) with thionylaniline in an inert solvent such as benzene, toluene, xylene and dichlorobenzene.

The reaction temperature is from 5 °C to 120 °C , preferably from 50 °C to 100 °C . PhNSO

(32) (37)

(38)

Of the compounds of the formula (I), a compound of the formula (38) is obtained by reacting a compound of the formula (37) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

Of the compounds of the formula ( I ) , a compound of the formula (39) in which X represents a carbonyl group is obtained by acting a compound of the formula (32) with phosgene, diphenyl carbonate, N,N' -carbonyldiimidazole or paranitrophenyl chloroformate, in an inert solvent such as benzene, toluene, xylene, dichlorobenzene, dichloromethane. chloroform, ethyl ether, tetrahydrofuran and 1,4-dioxane.

The reaction temperature is from 5 °C to 160 °C , preferably from 20 °C to 130 °C .

A compound of the formula (40) is obtained by reacting a compound of the formula (39) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

Of the compounds of the formula (I), a compound of the formula (41) in which X represents a thiocarbonyl group is obtained by acting a compound of the formula (39) with Lawesson reagent (para-methoxyphenylthiophosphine sulfide dimer) in an inert solvent such as benzene, toluene, xylene, dichlorobenzene, dichloromethane, chloroform, ethyl ether, tetrahydrofuran, 1,4-dioxane.

A compound of the formula (42) is obtained by reacting a compound of the formula (41) in an inert solvent in the presence of an inorganic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or an organic base such as tetraalkyl-ammonium hydroxide.

Of the compounds of the formula (I), a compound of the formula (44) in which A represents 0C(0)R⁴ is synthesized by reacting a compound of the formula (43) with an acylating agent in an inert solvent in the presence of suitable base, as shown in the following reaction scheme.

(43) (44)

The solvents usable for the reaction include, for example, sulfoxide solvents such as dimethylsulfoxide, amide solvents such as dimethylformamide and dimethylacetamide, ether solvents such as ethyl ether, dimethoxyethane and tetrahydrofuran, halogenated solvents such as dichloromethane, chloroform and dichloroethane. The reaction may be conducted in the absence of the solvent.

The base to be used for the reaction includes, for example, triethylamine, pyridine, diisopropylethylamine and DBU (diazabicycloundecene) .

The acylating agent includes acid chloride and acid bromides, and acid anhydrides.

The reaction temperature is, usually, from an ice-cooled temperature to the reflux temperature for the reaction solvent used. Regarding the molar ratio of the starting compounds, the ratio of the acylating agent to the compound of the formula (43) is within the range of from 0.5 to 4.0, preferably from 1.0 to 2.0.

Of the compounds of the formula (I) of the present invention, optically active isomers may be produced, for example, by methods of optical resolution of racemic modification (see Japanese Patent Application Laid-open No. Hei 3-141286, U.S. Patent No. 5,097,037, European Patent No. 409,165) and methods of asymmetric synthesis (see Japanese Patent Application Laid-open No. Hei 5-301878, U.S. Patent No. 5,352,814 and European Patent No. 535,377.

As mentioned above, the present invention have found that the compounds of the formula (I) have a strong activity of reducing the heart rate and also have a strong activity of reinforcing the contraction of cardiac muscles. Since the compounds of the present invention have no activity of retarding cardiac functions but rather have an activity of reducing the heart rate, they may exert the activity of enhancing the contraction of cardiac muscles even when they are administered in the same amount as that necessary for expressing the cardiotonic activity. Because of their activities, it is considered that the compounds according to the present invention may reduce the amount of oxygen to be consumed by cardiac muscles to therefore reduce the motility load of cardiac muscles and exert the anti-stenocardiac activity. In addition, it is also considered that they have an activity of prolonging the effective refractory period to thereby exert an anti-arrhythmic activity. Therefore, it is expected that the compounds of the present invention are useful for curing cardiovascular disorders in consideration of the oxygen consumption, the energy consumption or the metabolism caused by the cardiac motility and also for curing other cardiac disorders essentially in consideration of the activity of the compounds of reducing the heart rate. For example, the compounds of the present invention are useful as medicines for cardiac insufficiency of mammals including human beings and also as medicines for curing cardiovascular disorders causing cardiac insufficiency of them such as, for example, as medicines for curing ischemic cardiopathy, medicines for curing hypertension, medicines for curing cardiac fluid retention, medicines for curing pulmonary hypertension, medicines for curing valvulitis, medicines for curing congenital cardiac disorders, medicines for curing cardiomuscular disorders, medicines for curing pulmonary edema, medicines for curing angina of effort, medicines for curing myocardial infarction, medicines for curing arrhythmia, and medicines for curing atrial fibrillation.

The present invention provides pharmaceutical compositions containing an effective amount of the compounds of the formula (I) for curing these diseases.

As the manner of administration of the compounds of the present invention, there may be mentioned parenterally administration by injections (subsutaneous, intraveneous, intramuscular or intraperitoneal injection), ointments, suppositories or aerosols, or an oral administration in the form of tablets, capsules, granules, pills, syrups, liquids, emulsions or suspensions.

The above pharmacological or veterinary compositions of the present invention contain the above-mentioned compounds of the present invention in an amount of from about 0.01 to 99.5 % by weight, preferably from about 0.1 to 30 % by weight, based on the total weight of the composition.

To the compounds of the present invention or to the compositions containing the present compounds, other pharmacologically or veterinarily active compounds may be incorporated. Further, the compositions of the present invention may contain a plurality of the compounds of the present invention.

The clinical dose of the compounds of the present invention varies depending upon the age, the body weight, the sensitivity or the symptom, etc. of the patient. In general, however, the effective daily dose is usually from about 0.003 to 1.5 g, preferably from about 0.01 to 0.6 g for an adult. If necessary, however, an amount outside the above range may be employed .

The compounds of the present invention may be prepared into various suitable formulations depending upon the manner of administration, in accordance with conventional methods commonly employed for the preparations of pharmaceutical formulations.

Namely, tablets, capsules, granules or pills for oral administration, may be prepared by using excipients such as white sugar, lactose, glucose, starch or mannitol; binders such as hydroxypropyl cellulose, syrups, arabic gum, gelatin, sorbitol, tragacanth gum, methyl cellulose or polyvinyl- pyrrolidone; disintegrants such as starch, carboxymethyl cellulose (CMC) or its calcium salt, crystal cellulose poweder or polyethylene glycol (PEG); lubricants such as talc, magnesium or calcium stearate, silica; and smoothers such as sodium laurate, glycerol, etc.

The injections, solutions (liquids), emulsions, suspensions, syrups or aerosol may be prepared using a solvent for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol or polyethylene glycol; surfactants such as sorbitan fatty acid esters, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene ether of hydrogenated castor oil, lecithin; suspending agents such as cellulose derivatives such as sodium salt of carboxymethyl cellulose derivatives such as methyl cellulose or natural rubbers such as tragacanth or arabic gum; or preservatives such as para-hydroxybenzoic acid, benzalkonium chloride, salts of sorbic acid, etc.

Ointments which are an endermic preparation may be prepared by using, e.g., white vaseline, liquid paraffin, higher alcohols, Macrogol ointoment, hydrophilic ointment base or hydrogel base, etc.

The suppositories may be prepared by using, e.g., cacao butter, polyethylene glycol, lanolin, fatty acid triglycerides, coconut oil, polysorbate, etc.

Best Mode for Carrying Out the Invention

Now the present invention is explained referring to examples, but it is not to be limited to these examples.

Synthesis Example

REFERENCE EXAMPLE 1:

Synthesis of Optically Active 7,8-dihydro-6,6- dimet_hyl-7,8-epoxy-6H-pyrano[2.3-f]benzo-2, 1-3- oxadiazole

To 300 m_l of a dichloromethane solution containing 40 g

(198 mmol) of 6,6-dimethyl-6H-pyrano[2,3-f]benzo-2,1,3- oxadiazole were added 2.44 g (3.7 mmol) of (R,R)-[1,2- bis(3,5-di-t-butyl-salicylidamino)cyclohexane]-manganeses(III) acetate. (The production of the acetate is described in Japanese Patent Application Laid-open No. Hei 5-507645 and European Patent No. 521,099.) The mixture was added with 1.2 liters of an aqueous solution of sodium hypochlorite (active chlorine content: 5 %). While adjusting the pH of the reaction system at 11.3 with a pH-stat, aqueous solution of 0.5 N-sodium hydroxide was added thereto. The resulting solution was stirred at room temperature for 10 hours. After stopping the stirring, the solution was allowed to stand at room temperature overnight. The reaction solution was extracted with chloroform (300 ml x 1; 200 ml x 1; 50 ml x 1) and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (benzene : ethyl acetate = 5 : 1) and again to silica gel column chromatography (benzene -→ benzene : ethyl acetate = 5 : 1), and the crystals obtained were recrystallized from ethanol (60 ml) to obtain 15.7 g of the intended compound, (yield: 36 %) Optical purity > 99 % ee.

Column: Chiralcell OJ (of Daisel Chemical Industries, Ltd.) Mobile Phase: hexane : isopropanol = 4 : 1 Detection: UV 254 nm Flow Rate: One ml/min Column Temperature: 40 °C Retention Time: 9.2 min. REFERENCE EXAMPLE 2

Synthesis of Enantiomer of Compound of Reference Example 1

An enaniomer of the compound of Reference Example 1 was synthesized in the same manner as in Reference Example 1, using (S,S-[1, 2-bis(3, 5-di-t-butylsalicylidamino)cyclohexane]- manganese( III ) acetate. The yield of the product was 20.8 g

(yield: 48 %).

Optical purity > 99 % ee

Retention time: 12.5 min

REFERENCE EXAMPLE 3

Synthesis of (± )-7,8-dihydro-6,6-dimethyl-7- hydroxy-8-amino-6H-pyrano[2, 3-f]benzo-2, 1, 3- oxadiazole

0.82 g (3.8 mmols) of (± )-7,8-dihydro-6, 6-dimethyl-7, 8- epoxy-6H-pyrano[2, 3-f]benzo-2, 1, 3-oxadiazole was dissolved in 25 ml of 16.7% NH₃ -EtOH and the mixture was reacted in a pressure glass tube at 60 °C for 48 hours. The reaction solution was distilled off and the residue was subjected to silica gel column chromatography (eluent: ethyl acetate : methanol = 5 : 1 ) to obtain 0.77 g of the intented compound as a brown solid. (yield: 87 %) A part of the compound was recrystallized from ethanol to obtain pure intended compound as coloreless crystals. m.p. 223 - 225 °C

NMR(CDC1₃ + DMS0-d₆ )δ (ppm) : 1.26 (3H), 1.49 (3H),

2.80-3.30(5H), 3.33(1H), 3.78(1H), 6.82(1H), 7.98(1H)

MS: 133(50%), 163(100%), 235(M⁺ , 3%)

REFERENCE EXAMPLE 4

Synthesis of (-)-7, 8-dihydro-6, 6-dimethyl-7- hydroxy-8-amino-6H-pyrano[2,3-f]benzo-2, 1,3- oxadiazole

The intended compound was synthesized in the same manner as in Reference Example 3, using the optically active

7, 8-dihydro-6, 6-dimethyl-7, 8-epoxy-6H-pyrano[2, 3-f]benzo-2, 1,3- oxadiazole. m.p. 145 to 146 °C

SYNTHESIS EXAMPLE 1:

Synthesis of Optically Active 7, 8-dihydro-6, 6- dimethyl-7-hydroxy-8-(N-pyrrolyl )-6H-pyrano- [2.3-f]benzo-2, 1-3-oxadiazole

5.00 g (25 mmol) of (-)-7, 8-dihydro-6, 6-dimethyl- 7-hydroxy-8-amino-6H-pyrano[2, -f]benzo-2, 1, 3-oxadiazole, 3.3 ml (25 mmols) of 2, 5-dimethoxytetrahydrofuran and 50 ml of acetic acid were heated under reflux for one hour. After the mixture was cooled to the room temperature, the mixture was added with a saturated aqueous sodium hydrogencarbonate solution and extraced thrice over chloroform. The chloroform layer was combined and washed with water, and then, dried over sodium sulfate. After the solvent was distilled off, the residue was subjected to silica gel column chromatography (eluent: ethyl acetate : hexane = 1 : 3) to obtain 3.68 g of the intended compound as white crystals, (yield: 52 %) m.p. 192 to 193 °C

FORMULATION EXAMPLE 1 Formulation of Tablets:

Compound 10 g

Lactose 260 g

Crystal cellulose powder 600 g

Corn starch 350 g

Hydroxypropyl cellulose 100 g

CMC-Ca 150 g

Magnesium stearate 30 g

Total 1500 g

The above-mentioned components were mixed by a usual method and then tabletted to produce 10000 sugar-coated tablets, each containing 1 mg of the active ingredient.

FORMULATION EXAMPLE 2

Formulation of Capsules: Compound 10 g

Lactose 440 g

Crystal cellulose powder 1000 g

Magnesium stearate 50 g

Total 1500 g

The above-mentioned components were mixed by a usual method and then packed in gelatin capsules to obtain 10000 capsules, each containing 1 mg of the active ingredient.

FORMULATION EXAMPLE 3

Formulation of Soft Capsules: Compound 10 g

PEG 400 479 g

Saturated fatty acid triglyceride 1500 g

Peppermint oil 1 g

Polysorbate 80 10 g

Total 2000 g

The above-mentioned components were mixed and packed in o. 3 soft gelatin capsules by a usual method to obtain 10000 soft capsules, each containing 1 mg of the active ingredient.

FORMULATION EXAMPLE 4

Formulation of Ointment:

Compound 1.0 g

Liquid paraffin 10.0 g

Cetanol 20.0 g

White vaseline 68.4 g

Ethylparaben 0.1 g

L-methol 0.5 g

Total 100.0 g

The above-mentioned components were mixed by a usual method to obtain 1 % ointment.

FORMULATION EXAMPLE 5

Formulation of Suppositories:

Compound 1 g

Witepsol H15* 478 g

Witepsol W35* 520 g

Polysorbate 80 1

Total 1000 g (* Trade name for triglyceride compound)

The above-mentioned components were melt-mixed by a usual method and poured into suppository containers, followed by cooling for solidification to obtain 1,000 suppositories of 1 g, each containing 1 mg of the active ingredient.

FORMULATION EXAMPLE 6

Formulation of Injection: Compound 1 mg

Distilled water for injection 5 ml

The formulation is prepared by dissolving the compound in distilled water whenever it is required.

PHARMACEUTICAL TEST EXAMPLES

Effect on the contraction force of cardiac muscles

Test Method:

The heart was taken out from a male Hartley guinea pig, and the left atrium cordis was separated from it in a Krebs Henseleit liquid aerated with 95%-0₂ /5%-C0₂. The specimen was overhung under tension of 0.5 g in an organ bath filled with a nutrient liquid, which was kept at 31°C . To determine the force of cardiac muscles of papillary muscle of right ventricle, electric stimulation was trasmularly imparted to the specimen via platinum bipolar electrodes and the tension generated by the contraction of force of cardiac muscles of the specimen was recorded. The conditions for the electric stimulation were as follows:

Voltage: two times the threshold potential to attain the contraction (V)

Time: 3 (m sec. )

Frequency: 1 (Hz)

After the specimen was equilibrated while exchanging the nutrient liquid, isoproterenol was accumulatively applied to the specimen to obtain the maximum contraction reaction of the specimen. After, the isoproterenol added was washed out, the specimen was again equilibrated for 60 minutes while exchanging the nutrient liquid. Afterwards, the test compounds mentioned below were applied to the specimen, while its action was observed.

As a control compound, (± )-7,8-dihydro-6,6-dimethyl- 7-hydroxy-8-(1-pyrrolidinyl)-6H-pyrano[2,3-f]benzo-2, 1,3- oxadiazole was used.

The actions caused by applying each compound are expressed by the rate of change (%), on the basis of the maximum contraction (100 %) previously obtained when isoproterenol had been applied. Results :

The test results are shown in the following table, which verifies that the compounds of the present invention have a strong activity of enhancing the contraction of cardiac muscles and that the activity is dependent on the concentration of the compounds applied.

Table 6

Test compound Rate of change (%)

Synthesis Example No. 10 M 100 μ M

10.7 82.0

Control compound nd 55.7

(nd: not detected)

Effect on the heart rate

Test Method:

The heart was taken out from a male Hartley guinea pig, and the right atrium cordis was separated from it in a Krebs Henseleit liquid aerated with 95%-0_ /5%-C0₂. The specimen was overhung under tension of 1 g in an organ bath filled with a nutrient liquid, which was kept at 31 V .

After the specimen was equlibrated while exchanging the nutrient liquid, isoproterenol was accumulatively applied with the specimen to obtain the maximum reaction of the specimen. After, the isoproterenol applied was washed out, the specimen was again equilibrated for 60 minutes while exchanging the nutrient liquid. Afterwards, the test compounds mentioned below were applied to the specimen, while its reaction was observed.

As a control compound, (± )-7,8-dihydro-6, 6-dimethyl- 7-hydroxy-8-(l-pyrrolidinyl )-6H-pyrano[2, 3-f]benzo-2, 1, 3- oxadiazole was used.

The actions caused by applying each compound are expressed by the rate of change (%), on the basis of the the maximum reaction (100 %) previously obtained when isoproterenol had been applied.

Results:

The test results are shown in the following table, which verifies that the compounds of the present invention have an activity of reducing the heart rate and that the activity is dependent on the concentration of the compounds applied. Table 7

Test compound Rate of change (%)

Synthesis Example No. 1 μ M 3 μ M 10 μ M

-5.7 -9.7 -14.3

Control compound nd ^■1.5 -4.6

(nd: not detected)

The compounds of the present invention have a strong activity of reinforcing the contraction of cardiac muscles and a strong activity of reducing the heart rate. As they are not toxic, they are useful as medicines for treating cardiac insufficiency.

Claims

C ΛIH5

A benzopyran derivative of the following formula (I)

wherein X¹ and X² are absent or represent an oxygen atom;

X represents an oxygen atom, a sulfur atom, a nitrogen atom (said nitrogen atom is unsubstituted or substituted by a hydrogen atom or C, -C₄ alkyl group), calbonyl or thiocarbonyl;

A represents a hydrogen atom, a hydroxyl group, or 0C(0)R⁴ (in which R⁴ represents a C, -C₄ alkyl group), or may form a single bond together with B;

B represents a hydrogen atom, or may form a single bond together with A;

Y represents 1-pyrrolyl group, 1-pyrazolyl group, 1-imidazolyl group, l-(1, 2, 3-triazolyl ) group or 1-(1,2,4- triazolyl) group which is unsubstituted or substituted by R³ ;

R¹ and R² independently represent a hydrogen atom, a phenyl group or a C, -C_< alkyl group, or they may together form 1,4-butylene group or 1, 5-pentylene group which is unsubstituted or substituted by a C_λ -C₄ alkyl group; and

R³ represents a hydrogen atom, a halogen atom, a C, -C₆ alkyl group (said alkyl group is unsubstituted or substituted by a hydroxyl group or a phenyl group (said phenyl group is unsubstituted or substituted by a halogen atom, a hydroxyl group, a C, -C₄ alkyl group or a d -C₄ alkoxy group)), a C₃ -C₆ cycloalkyl group, a phenyl group (said phenyl group is unsubstituted or substituted by a halogen atom, a hydroxyl group, a C, -C₆ alkyl group or a Cι -C_A alkoxy group), or salts thereof.

2. The benzopyran derivatives or salts thereof as claimed in claim 1 wherein X¹ is absent;

X² is absent or represents an oxygen atom;

A represents a hydroxyl group, or may form a single bond together with B;

B represents a hydrogen atom, or may form a single bond together with A; and

R¹ represents a hydrogen atom or a d -C₄ alkyl group.

3. The benzopyran derivatives or salts thereof as claimed in claim 2, wherein R¹ and R² independently represent a Cj -C₄ alkyl group.

4. The benzopyran derivatives or salts thereof as claimed in claim 3, wherein R³ represents a hydrogen atom.

5. The benzopyran derivatives or salts thereof as claimed in claim 4, wherein Y represents a l-(1,2,4-triazolyl) group.

6. The benzopyran derivatives or salts thereof as claimed in claim 4, wherein Y represents a l-(1,2,3-triazolyl) group.

7. The benzopyran derivatives or salts thereof as claimed in claim 4, wherein Y represents a 1-imidazolyl group.

8. The benzopyran derivatives or salts thereof as claimed in claim 4, wherein Y represents a 1-pyrazolyl group.

9. The benzopyran derivatives or salts thereof as claimed in claim 4, wherein Y represents a 1-pyrrolyl group.