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WO1996034871A1 - Derives de benzopyrane - Google Patents

Derives de benzopyrane Download PDF

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Publication number
WO1996034871A1
WO1996034871A1 PCT/JP1996/001180 JP9601180W WO9634871A1 WO 1996034871 A1 WO1996034871 A1 WO 1996034871A1 JP 9601180 W JP9601180 W JP 9601180W WO 9634871 A1 WO9634871 A1 WO 9634871A1
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compound
group
formula
atom
compounds
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Inventor
Keizo Tanikawa
Kazuhiko Ohrai
Masayuki Sato
Takashi Horiuchi
Toru Yamashita
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Nissan Chemical Corp
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Nissan Chemical Corp
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Priority to AU55153/96A priority Critical patent/AU5515396A/en
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/04—Ortho-condensed systems

Definitions

  • This invention relates to novel benzopyran derivatives having pharmacological activity and to the use of said derivatives as a medicine for cardiac insufficiency.
  • 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.
  • 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.
  • 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.
  • the present invention is directed to a benzopyran derivative of the following formula (I):
  • X 1 and X 2 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, -C 4 alkyl group), carbonyl or thiocarbonyl;
  • A represents a hydrogen atom, a hydroxyl group, or 0C(0)R 4 (in which R 4 represents a Ci -C 4 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 R 3 ;
  • R 1 and R 2 independently represent a hydrogen atom, a phenyl group or a C, -C 4 alkyl group, or they may together form 1,4-butylene group or 1, 5-pentylene group which is unsubstituted or substituted by C, -C 4 alkyl group;
  • R 3 represents a hydrogen atom, a halogen atom, a C, -C 6 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, -C 4 alkyl group or a C, -C 4 alkoxy group)), a C 3 -C 6 cycloalkyl group, a phenyl group (said phenyl group is unsubstituted or substituted by a halogen atom, a hydroxyl group, a C, -C 6 alkyl group or a C, -C 4 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.
  • X 2 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, -C 4 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
  • R 1 represents a hydrogen atom or a C, -C 4 alkyl 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.
  • 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.
  • R 1 and R 2 examples 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.
  • R' and R 2 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 R 3 .
  • R 3 examples include a hydrogen atom, a chlorine atom, a bromine atom, an iodine atom.
  • 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.
  • n is 0 or an integer of 1, 2, 3 or 4 as the number of the substituent R 3 ; when n is plural, R 3 may be the same or different each other.
  • R 3 ' and R 3 ' have the same meaning as defined in R 3 , but they may be different from R 3 respectively.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 .
  • 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.
  • 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.
  • it can use two- phase mixed solvent of one or more of these
  • 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 .
  • 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.
  • 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,
  • 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 .
  • 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 .
  • 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 .
  • 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.
  • 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.
  • an inorgnic base such as potassium carbonate, sodium hydroxide, potassium hydroxide, sodium hydride or organic base such as tetraalkyl-ammonium hydroxide.
  • 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.
  • 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 (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.
  • 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.
  • 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).
  • 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.
  • 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.
  • 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.
  • 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 (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.
  • 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).
  • 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.
  • dehydration may occur at the neutralization of the post-treatment.
  • 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.
  • 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 (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).
  • 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.
  • 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.
  • 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).
  • 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.
  • dehydration may be generated.
  • 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.
  • 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.
  • the reaction temperature in this reaction is, usually, from ice-cooled temperature to the reflux temperature for the reaction solvent used.
  • 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 .
  • 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.
  • 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.
  • 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.
  • 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)).
  • 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.
  • 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.
  • 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 (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.
  • 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 .
  • 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.
  • 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 (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.
  • 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 (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.
  • Lawesson reagent para-methoxyphenylthiophosphine sulfide dimer
  • the reaction temperature is from 5 °C to 160 °C , preferably from 20 °C to 130 °C .
  • 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.
  • 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 (44) in which A represents 0C(0)R 4 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 poificat or polyethylene glycol (PEG); lubricants such as talc, magnesium or calcium stearate, silica; and smoothers such as sodium laurate, glycerol, etc.
  • 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
  • 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.
  • a solvent for the active ingredient such as water, ethyl alcohol, isopropyl alcohol, propylene glycol, 1,3-butylene glycol or polyethylene glycol
  • surfactants such
  • 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.
  • the intended compound was synthesized in the same manner as in Reference Example 3, using the optically active
  • the formulation is prepared by dissolving the compound in distilled water whenever it is required.
  • 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%-0 2 /5%-C0 2 .
  • 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 .
  • 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:
  • 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.
  • 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.
  • 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%-C0 2 .
  • the specimen was overhung under tension of 1 g in an organ bath filled with a nutrient liquid, which was kept at 31 V .
  • 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.
  • 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.
  • 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
  • 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.

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Abstract

Dérivés de benzopyrane représentés par la formule (I), dans laquelle X1 et X2 sont absents ou représentent un atome d'oxygène; X représente un atome d'oxygène, un atome de soufre, un atome d'azote (ledit atome d'azote est non substitué ou substitué par un atome d'hydrogène ou par un groupe alkyle C¿1?-C4), carbonyle ou thiocarbonyle; A représente un groupe hydroxyle ou peut constituer une liaison unique avec B; B représente un atome d'hydrogène ou peut constituer une liaison unique avec A; Y représente un groupe 1-pyrrolyle, un groupe 1-pyrazolyle, un groupe 1-imidazolyle, un groupe 1-(1,2,3,-triazolyle) ou un groupe 1-(1,2,4-triazolyle) non substitué ou substitué par R?3; R1 et R2¿ représentent indépendamment un atome d'hydrogène, un groupe phényle ou un groupe alkyle C¿1?-C4; R?3¿ représente un atome d'hydrogène, un atome d'halogène, un groupe alkyle C¿1?-C6. L'invention concerne aussi des médicaments destinés à traiter l'insuffisance cardiaque et contenant ledit composé en tant qu'ingrédient actif. Ces composés présentent une activité puissante de renforcement de la contraction des muscles cardiaques et de diminution du rythme cardiaque. Etant donné que ces composés ne sont pas toxiques, ils constituent des médicaments utiles pour traiter l'insuffisance cardiaque.
PCT/JP1996/001180 1995-05-01 1996-04-30 Derives de benzopyrane Ceased WO1996034871A1 (fr)

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AU55153/96A AU5515396A (en) 1995-05-01 1996-04-30 Benzopyran derivatives

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JP7/107450 1995-05-01
JP10745095 1995-05-01

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WO1996034871A1 true WO1996034871A1 (fr) 1996-11-07

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7229986B2 (en) 2000-05-16 2007-06-12 Takeda Pharmaceutical Company Ltd. Melanin-concentrating hormone antagonist

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991014690A1 (fr) * 1990-03-29 1991-10-03 Basf Aktiengesellschaft Lactames de n-benzoxodiazolopyranyl insatures, leur fabrication et utilisation

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1991014690A1 (fr) * 1990-03-29 1991-10-03 Basf Aktiengesellschaft Lactames de n-benzoxodiazolopyranyl insatures, leur fabrication et utilisation

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7229986B2 (en) 2000-05-16 2007-06-12 Takeda Pharmaceutical Company Ltd. Melanin-concentrating hormone antagonist

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