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WO1995002589A1 - Nouveau compose du chromane, ses intermediaires et ses applications medicinales - Google Patents

Nouveau compose du chromane, ses intermediaires et ses applications medicinales Download PDF

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Publication number
WO1995002589A1
WO1995002589A1 PCT/JP1993/000992 JP9300992W WO9502589A1 WO 1995002589 A1 WO1995002589 A1 WO 1995002589A1 JP 9300992 W JP9300992 W JP 9300992W WO 9502589 A1 WO9502589 A1 WO 9502589A1
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Prior art keywords
group
dihydro
benzopyran
cyano
methoxymethyl
Prior art date
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PCT/JP1993/000992
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English (en)
Japanese (ja)
Inventor
Susumu Kato
Hidetsura Cho
Shinsuke Sayama
Yasuyuki KAJIMOTO
Saizo Shibata
Atsushi Mizushima
Tukuo YAMAKI
Itsuo Uchida
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Japan Tobacco Inc
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Japan Tobacco Inc
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Priority to PCT/JP1993/000992 priority Critical patent/WO1995002589A1/fr
Publication of WO1995002589A1 publication Critical patent/WO1995002589A1/fr
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/68—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with nitrogen atoms directly attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages

Definitions

  • the present invention relates to a novel Kuguchiman compound, an intermediate thereof and a medicinal use thereof, and more specifically, has a selective and excellent vasodilatory effect on the coronary artery system,
  • the present invention relates to a novel chroman compound useful as an agent for treating or preventing heart failure and an intermediate for producing the compound.
  • Potassium channels are involved in resting membrane potential. When this potassium channel is activated, the resting membrane potential changes more negatively (hyperpolarization) and approaches the equilibrium potential of potassium ion. In addition, activation of potassium channels inhibits activation of voltage-gated calcium channels, suppresses the influx of calcium in the cells, and reduces intracellular calcium due to sodium calcium exchange reaction. Pumping is promoted. As a result of the hyperpolarization of these membranes and the subsequent decrease in intracellular free calcium concentration, smooth muscle is relaxed, and the blood vessels are dilated, resulting in a hypotensive effect and a coronary vasodilatory effect.
  • Potassium channels are also widely distributed in other smooth muscles (trachea, intestinal tract, uterus, etc.) and are known to have an action of relaxing these. Therefore, these compounds having a potassium channel activating action are useful as therapeutic or preventive agents for hypertension, angina pectoris, heart failure, asthma and the like. There have already been reported some compounds that activate the potassium channel. For example, JP-A-2-300182 and JP-A-3-2797377 disclose 6 compounds.
  • the present inventors have conducted intensive studies to find a compound having a safer and superior coronary vasodilatory effect. As a result, the present inventors have found that the compound is effective in preventing or treating cardiovascular disorders such as the aforementioned diseases, angina pectoris, and heart failure.
  • a novel chroman compound and a pharmaceutically acceptable salt thereof which do not cause a high blood pressure drop which should cause tachycardia, that is, have a selective and excellent coronary vasodilator action, are to be found.
  • the invention has been completed.
  • R 1 is a cyano group, a nitro group or a halogen atom
  • R 2 is a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group, an aryloxyalkyl group or a tert-butyldimethylsilyloxyalkyl group,
  • R 3 is a hydrogen atom, a lower alkyl group, lower alkoxy Ryo alkyl group, a lower alkoxycarbonyl group, hydroxyalkyl group or tert one heptyl dimethylsilyl Okishiarukiru group, or that the R 3 together, one (CH 2 ), — 0— (CH 2 ) ffl — 0— (CH 2 ) n — ( where 1, and n are each independently 0 or an integer of 1-2, and m is an integer of 1-2) Form a group that is
  • R is a hydrogen atom, a hydroxyl group, a formyloxy group or a lower alkanoyloxy group
  • R 5 is a hydrogen atom, or R 4 and R 5 together represent a bond
  • R fi is an aryl group optionally substituted with a lower alkyl group or a halogen atom, a heteroaryl group optionally substituted with a lower alkyl group or a halogen atom, a substituent substituted with a lower alkyl group or a halogen atom.
  • X is N—CN, an oxygen atom or a zeo atom
  • R 7 is a hydrogen atom or a lower alkyl group.
  • the present invention also provides an intermediate useful for producing the above chroman compound [I].
  • These intermediates are represented by the following general formulas [3 '], [4'], [5 '], [8'] or [9].
  • R 2 ′ is a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group, an aryloxyalkyl group or a tert-butyldimethylsilyloxyalkyl group,
  • R 3 ′ is a hydrogen atom, a lower alkyl group, a lower alkoxyalkyl group, a lower alkoxycarbonyl group, a hydroxyalkyl group, or a tert-butyldimethylsilyloxyalkyl group, or R 3 ′ and R 3 ′ together , — (CH2), — 0— (CH 2 ) m — 0— (CH 2 ) n — (wherein, 1 and n are each independently 0 or an integer of 1 to 2, and m is 1 to 2 Where R 2 ′ is a lower alkoxyalkyl group, then R 3 ′ is a lower alkoxyalkyl group or a lower alkoxyalkyl group. A carbonyloxy group, a hydroxyalkyl group or a tert-butyldimethylsilyloxyalkyl group.)
  • the present invention provides a coronary vasodilator comprising the above chroman compound [I] or a pharmaceutically acceptable salt thereof as an active ingredient.
  • FIG. 1 shows the compound of the present invention (Example 39), remacalim (control compound a), and 2-methoxymethyl-2-methyl-4_ (1,2-dihydro-12-oxo-1-1-pyridyl) -16-cyano.
  • 3 is a graph showing the relationship between the change in mean blood pressure (%) (horizontal axis) and the change in coronary blood flow () (vertical axis) for each of 3-chromanol (control compound b).
  • “Lower alkyl group” means a straight-chain or branched alkyl having 1 to 5 carbon atoms, preferably 1 to 4 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group. Tert-butyl group, isobutyl group, sec-butyl group, tert-butyl group, and benzyl group.
  • lower alkoxyalkyl group means an alkoxyalkyl group having a total of 2 to 6, preferably 2 to 5, carbon atoms in the alkoxy moiety and the alkyl moiety, wherein the alkoxy moiety and the alkyl moiety are linear or branched. It may be either of the face.
  • methoxymethyl group 1-methoxyethyl group, 2-methoxyethyl group, 3-methoxypropyl group, 2-methoxypropyl group, 1-methoxy-1-methylethyl group, ethoxymethyl group, propoxymethyl group, It means a propoxymethyl group, a butoxymethyl group, an isobutoxymethyl group, a sec-butoxymethyl group, a tert-butoxymethyl group, a pentoxymethyl group and the like.
  • lower alkanoyloxy group means an alkanoyloxy group having 2 to 6, preferably 2 to 4 carbon atoms, and specifically includes an acetyloxy group, a propionyloxy group, a petyryloxy group and the like. means.
  • alkoxycarbonyl group J means an alkoxycarbonyl group having 2 to 6, preferably 2 to 5 carbon atoms, specifically, methoxycarbonyl group, ethoxy group It means a cicarbonyl group, a propoxycarbonyl group, an isopropoxycarbonyl group, a butoxycarbonyl group, an isobutoxycarbonyl group, a sec-butoxydicarbonyl group, a tert-butoxycarbonyl group, a pentoxycarbonyl group or the like.
  • ⁇ Halogen atom j specifically means a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.
  • aryl group specifically means a phenyl group, a 1-naphthyl group, a 2-naphthyl group, a 0-biphenyl group, an m_biphenyl group, a P-biphenyl group, or the like, preferably a phenyl group. It is.
  • the lower alkyl group J which may be substituted with a lower alkyl group or a halogen atom is the same as the above-mentioned "lower alkyl group J and 1 or 3 substituents selected from a halogen atom j.
  • Aryl group j specifically, 2-methylphenyl group, 3-methylphenyl group, 4-methylphenyl group, 2-ethylphenyl group, 3-ethylphenyl group, 4-ethylphenyl group, 2-bromopyrphenyl Phenyl, 3-propylphenyl, 4-propylphenyl, 2-fluorophenyl, 3-fluoro ⁇ -phenyl, 4-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl , 4-monophenyl, 2-bromophenyl, 3-bromophenyl, 4-morphophenyl, 2-methyl-1-naphthyl, 3-methyl-1-naphthyl, 4 Methyl-1-naphthyl, 5-methyl-1-naphthyl, 6-methyl-1-naphthyl, 7-methyl-1-naphthyl, 8-methyl-1-naphthyl, 2-ethyl
  • Heteroaryl group j is 2-pyridinyl, 3-pyridinyl, 4-pyridinyl, birazinyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-pyrimidinyl, 3-pyridazinyl, 4-pyridazinyl Group, 2-furanyl group, 3-furanyl group, 2-thenyl group, 3-thenyl group, 2-pyrrolyl group, 3-pyrrolyl group, pyridine-N-oxydoxy-2-yl group, pyridine-N-oxydol 3 —Yl group, pyridine-N-oxydoxy 4-yl group, 2-quinolyl group, 3-quinolyl group, 4-quinolyl group, 5-quinolyl 3 ⁇ 4, 6-quinolyl group, 7-quinolyl group, 8-quinolyl group , 2-Imidazolyl group, 4-Imidabrile group, 5-Imidabril group, 1-Vilabryl group, 3-Pyrazolyl group, 3-Isothiazolyl
  • 2-Indolyl tomb, 3-Indolyl, 4-Indolyl, 5-Indolyl, 1,8-Naphthyridine-1-yl, 1,8-Naphthyridine-1-yl, 1,8-Naphthyridine-1 Represents a 4-yl group, a 2-quinoxalinyl group, a 3-cinnolinyl group, a 4-cinnolinyl group, a 5-cinnolinyl group, a 6-cinnolinyl group, a 7-cinnolinyl group, an 8-cinnolinyl group, and the like; Pyridinyl group, 3-pyridinyl group, 4-pyridinyl group, birazinyl group, 2-phenyl group, 3-phenyl group, pyridine-1-N-oxyd-2-yl group, pyridine-N-oxyd-3-yl group ,
  • ⁇ heteroaryl group J optionally substituted with a lower alkyl group or a halogen atom is a group substituted with 1 to 3 substituents selected from the above-mentioned ⁇ lower alkyl group '' and ⁇ halogen atom.
  • hydroxydialkyl group means an alkyl group having 1 to 5 carbon atoms having a hydroxy group, specifically, a hydroxymethyl group, a hydroxyethyl group, a hydroxypropyl group, a hydroxyisopropyl group, and the like. Represents a hydroxymethyl group, a hydroxyethyl group or the like.
  • aryloxyalkyl group means an alkyl group having 1 to 5 carbon atoms having an aryloxy group, and specifically includes a phenyloxymethyl group, a phenyloxyethyl group, a nailoxypropyl group, and a phenyloxyalkyl group.
  • Phenyloxyisopropyl group 1-naphthyloxymethyl group, 1-naphthyloxyshethyl group, 1-naphthyloxypropyl group, 1-naphthyloxyisopropyl group, 2-naphthyloxymethyl group, 2-naphthyl Oxyshetyl group, 2-naphthyloxyquinpropyl group, 2-naphthyloxyisopropyl group, 0-biphenyloxymethyl group, 0-biphenyloxyxetyl group, 0-biphenyloxypropyl group, 0-biphenyl M-biphenyloxymethyl group, m-biphenyloxyshethyl group, m-biphenyloxypropyl group, m- A biphenyloxyisopropyl group, a p-biphenyloxymethyl group, a p-bi
  • aryl amino group examples include phenyl amino group, 1-naphthylamino group, 2-naphthylamino group, 0-biphenylamino group, m-biphenylamino group, p-biphenylamino group, and the like, and are preferable. Is a phenylamino group.
  • the “lower alkyl group or an arylamino group optionally substituted with a halogen atom” is the “lower alkyl group” and the “arylamino group which may be substituted with one to three substituents selected from“ halogen atoms ”as described above.
  • the substituted aryl group refer to those described above as the substituted aryl group.
  • aryloxy group refers specifically to phenyloxy, 1-naphthyloxy, 2-naphthyloxy, 0-biphenyloxy, m-biphenyloxy. And a p-biphenyloxy group and the like, and preferably a phenyloxy group.
  • '' Means an ⁇ aryloxy group '' which may be substituted with 1 to 3 substituents selected from the above-mentioned ⁇ lower alkyl group '' and ⁇ halogen atom '', and specific examples of the substituted aryl group are substitution.
  • substituents selected from the above-mentioned ⁇ lower alkyl group '' and ⁇ halogen atom '', and specific examples of the substituted aryl group are substitution.
  • aryl group reference is made to those exemplified above.
  • the group J represented by ⁇ one (CHz), one 0— CCH 2 ) B- 1 0— (CH 2 ) ⁇ — is specifically — CH 2 -0-CH 2 -0—, one CH 2 -0-CH 2 1 0— CH 2 —, — (CH 2 ) 2 — 0— CH 2 — 0— CH 2 —, 1 CH 2 — 0— (CH 2 ) 2 — 0— CH 2 (CH 2 ) 2 -0-CH, one 0— (CH 2 ) 2 —, one (CH 2 ) 2 — 0— (CH 2 ) 2 -0- (CH 2 ) 2 — and the like, preferably — CH 2 -0-CH 2 1 0 1 CH 2 —.
  • “Pharmaceutically acceptable salt” means, for example, various inorganic acid addition salts such as hydrochloride, hydrobromide, sulfate, phosphate, and nitrate; acetate, propionate, succinate, and glycol.
  • Various organic acid addition salts such as acid, lactate, malate, tartrate, citrate, maleate, fumarate, methanesulfonate, p-toluenesulfonate, and ascorbate; aspartic acid Salts and salts with various amino acids such as glutamate are included, but are not limited thereto.
  • the general formula [I] is included, but are not limited thereto.
  • the compound represented by [3 '], [4'], [5 '], [8'] or [9 '] may have one or more asymmetric carbons, In the case of one, a pure optically active substance, a mixture thereof in an arbitrary ratio or a racemic form is present, and in the case of two or more asymmetric carbons, an optically pure diastereomer, its racemic form, Alternatively, mixtures thereof may be present in any combination and ratio. Further, compound [I] has E-isomer and Z-isomer depending on the arrangement of the double bond in the amidine moiety. Further, a resonance structure may exist in the amidine moiety of the compound [I]. The present invention includes all these isomeric forms.
  • compound [I] When compound [I] is used as a pharmaceutical preparation, it is usually a pharmacologically acceptable carrier, excipient, diluent, bulking agent, disintegrant, stabilizer, preservative, buffer, emulsifier known per se. , Fragrance, colorant, sweetener, thickener, flavoring agent, solubilizer, other additives Agents, specifically water, vegetable oils, alcohols such as ethanol, benzyl alcohol or hydroxypropyl alcohol, carbohydrates such as polyethylene glycol, glycerol triacetate, gelatin, lactose, starch, etc., magnesium stearate, talc, Lanolin, Vaseline, lactose, lactose, sucrose, glucose, mannitol, sorbitol, crystalline cellulose, gum arabic, dextrin, pullulan, aluminum gayate, calcium phosphate, waxes, boric acid, DL-isocyanate, sodium fatty acid, magnesium lauryl sul
  • the dose may vary depending on the type and degree of the disease, the compound to be administered, the route of administration, the age, sex, weight, etc. of the patient.
  • the compound [I] is usually used in an adult at a dose of 0.001 per day. It is preferred to administer from 1 to 100 mg, especially from 0.1 to 100 mg.
  • [3] can also be manufactured.
  • the compound [1] used is commercially available in many cases, but if it is not commercially available, it can be prepared by acetylating the ortho-position from p-substituted phenol by Friedel 'Kraft reaction or Fries rearrangement. .
  • the compound [3] is reduced with a reducing agent such as sodium borohydride in an alcoholic solvent such as methanol, ethanol, tetrahydrofuran, preferably methanol or ethanol, under cooling or at room temperature, to give 4-chromanol (compound
  • Compound [4] is removed using a Dean-stark apparatus in a solvent such as benzene, toluene, or xylene in the presence of an acidic catalyst such as ⁇ -toluenesulfonic acid or camphorsulfonic acid to remove free water.
  • a solvent such as benzene, toluene, or xylene
  • an acidic catalyst such as ⁇ -toluenesulfonic acid or camphorsulfonic acid to remove free water.
  • acetic anhydride trifluoroacetic acid, methanesulfonyl chloride, trifluoromethanesulfonyl chloride, P-toluenesulfonyl chloride, etc.
  • the hydroxyl group of compound [4] is changed to an acetyl group, a trifluoromethyl group.
  • the chromene (compound [5]) (R) can be obtained by activating and releasing with a base such as triethylamine, N-methylmorpholine, or diazabicycloundecene, and particularly preferably with diazabicycloundecene. 1 , R 2 and R 3 are as described above).
  • Compound [5] can also be produced as follows. (Process 4-Process 5)
  • the hydroxyl group of compound [6] may be substituted with an acetyloxy group, a trifluoroacetyloxy group, a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or an activity such as a chlorine atom or a bromine atom.
  • a nonprotonic solvent such as benzene, toluene, methylene chloride, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethylsulfoxide, etc.
  • Process 5 Compound [7] is heated in a solvent that does not inhibit the reaction itself, such as benzene, toluene, acetonitrile, N, N-dimethylaniline, dimethylformamide, dimethylsulfoxide, etc., particularly preferably in dimethylaniline or dimethylsulfoxide.
  • the compound [5] can be produced preferably by heating to 100 to 18 (TC.
  • the compound [5] is described in JP-A-3-66681. As described above, there are known ones, and in that case, they can be produced according to the method described therein.
  • Compound [5] can be obtained by cooling m-chloroperbenzoic acid, peracetic acid, etc., in a solvent such as chloroform, methylene chloride or ether, under cooling or heating, particularly preferably under ice-cooling or room temperature. 3 by oxidizing the oxidation agent, 4-epoxychroman (compound [8]) (R 1, R 2 and R 3 are as defined above) as possible out to produce. Further, the conversion of compound [5] to compound [8] can also be performed in a plurality of steps.
  • compound [5] is treated with N-butyl moss imide in a mixed solvent of water and a solvent such as methylene chloride, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, dimethyl sulfoxide, methanol, ethanol, or the like.
  • the compound [8] can be obtained by converting the compound into a bromohydrin compound by removing the hydrogen bromide with a base such as caustic soda.
  • a base such as caustic soda.
  • optically active compounds [8] is described in Journal of American Chemical Society (J. Am. Chenj. Soc.) 1991, 113, 7063. It can be produced by stereoselectively oxidizing compound [5] with a (Salen) complex or the like.
  • Compound [8] is ring-opened with aqueous ammonia or lower alkylamine in an organic solvent such as methanol, ethanol, tetrahydrofuran or dioxane, particularly preferably in an alcoholic solvent such as methanol or ethanol under cooling or heating.
  • an organic solvent such as methanol, ethanol, tetrahydrofuran or dioxane, particularly preferably in an alcoholic solvent such as methanol or ethanol under cooling or heating.
  • Amino-3-chromanol (compound [9]) (R], R 2 , R 3 and R 7 can be obtained as described above.
  • aprotic solvents such as benzene, toluene, methylene chloride, triethylamine, chloroform, ether, dioxane, tetrahydrofuran, acetonitrile, dimethylformamide, and dimethyl sulfoxide; and alcohols such as methanol and ethanol.
  • an alcoholic solvent such as methanol or ethanol
  • the compound [Ia] is a amide (compound [10-2]) (R 6 is as described above, X ′′ is an oxygen atom or a zeo atom, and R is as described above). Ester, acid halide or acid anhydride and compound [9] with or without a solvent such as chloroform or methylene chloride in the presence or absence of a base such as gin, lutidine, and triethylamine, and the compound [9] under ice-cooling Alternatively, it can be obtained by reacting under heating.
  • Compound [Ia] is prepared by combining thiourea compound [10-3] (R e 'is a lower alkyl group or an aryl group which may be substituted with a halogen atom) and compound [9] with dimethylformamide and tetrahydrofuran.
  • Carbodiimide preferably in an organic solvent such as acetonitrile or dichloromethane, preferably 1- (3-dimethylaminopropyl) It can be obtained by reacting in the presence of 1-3-ethylcarbodimid.
  • Compound [la] is an isocyanate (compound [10-4]) (R 6 'and X "are as described above) and compound [9] are converted to an alcohol such as methanol and ethanol, or an organic compound such as tetrahydrofuran or dioxane. It can be obtained by reacting in a solvent, particularly preferably in an alcohol such as methanol or ethanol, at room temperature or under heating.
  • Compound [I c] (R 8 is an alkanoyloxy group or a formyloxy group) can be produced by alkanoylation or formylation of a hydroxyl group of the compound [I a] by a conventional method. That is, the alkanoylation of the compound [Ia] can be carried out in the presence of a base such as pyridine, lutidine or triethylamine in a solvent such as chloroform or methylene chloride, or without using a solvent. By reacting the compound with the compound [Ia] at ice-cooling to room temperature. The formylation of the compound [la] can be achieved by treating with refluxing formic acid and acetic anhydride in a solvent such as methylene chloride or chloroform which does not inhibit the reaction itself.
  • a base such as pyridine
  • lutidine or triethylamine in a solvent such as chloroform or methylene chloride
  • the hydroxyl group of the compound [4] is converted to an active leaving group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a chlorine atom or a bromine atom, and is converted to an azide It is manufactured by reacting sodium and further reducing it with zinc dust, iron powder, and the like.
  • an active leaving group such as a methanesulfonyloxy group, a trifluoromethanesulfonyloxy group, a p-toluenesulfonyloxy group, or a chlorine atom or a bromine atom
  • R 7 is a lower alkyl group (R 1 , R 2 and R 3 are as described above) corresponds to the compound [11] in which R 7 is a hydrogen atom and a lower alkyl group
  • a solvent such as benzene, toluene, methanol, and ethanol that does not hinder the reaction itself, and producing the imine by reducing it.
  • the reduction is carried out in the presence of a palladium catalyst, a nickel catalyst, a platinum catalyst or the like, preferably at a pressure of 1 to 10 atm, preferably 1 to 3 atm using palladium carbon as a catalyst, in the presence or absence of an acid such as acetic acid or hydrochloric acid.
  • the reaction can be carried out in a solvent that does not hinder the reaction itself, preferably in an alcoholic solvent such as methanol or ethanol.
  • the imine can be reduced using a hydride reducing agent, preferably sodium borohydride or sodium cyanoborohydride, in an alcoholic solvent such as methanol or ethanol, in a non-protonic solvent such as tetrahydrofuran, acetic acid,
  • a hydride reducing agent preferably sodium borohydride or sodium cyanoborohydride
  • an alcoholic solvent such as methanol or ethanol
  • a non-protonic solvent such as tetrahydrofuran
  • acetic acid acetic acid
  • Example 1-i 508 mg of methyl N-cyano 3-pyridine carboxymidate and t-14-amino-6-shiryono-1,4-dihydro-r-13-hydroxy-2-methoxymethyl- obtained in Example 1-i) 804 mg of an isomer mixture of 2-methyl-1H-1-benzopyran was added to 1 ml of methanol, and the mixture was stirred at room temperature for 3 days.
  • the precipitated precipitate is collected and purified by silica gel column chromatography (form: methanol-99: 1 to 9: 1) to form a low-polarity N'-cyano N- (6 —Cyanol 3,4-dihydro-c-1-3-hydroxy-r-1 2—Methoxymethyl-2-methyl-2H—1-benzopyran—t1—41-yl) 1-3—Pyridinecarboxamidine (A isomer) Methanol addition 64 mg, and highly polar N'-cyano N- (6-cyano 3,4-dihydro-t-3-hydroxy-r-1-2-methoxymethyl-2-methyl-2H-1-benzo-pyran-1 c-1 4- (Yl) 1-3-pyridinecarboxamidine (B isomer) 72 mg of a methanol adduct was obtained.
  • 6-cyanoh 3,4-dihydro-2,2-di (methoxymethyl) -12H-1-benzopyran-14one 12.1 g was dissolved in methanol 150 ml and hydrogenated under ice-cooled stirring. 1.96 g of sodium borohydride was added in small portions. After stirring for 1.5 hours, the mixture was concentrated, and the residue was added with ice and ethyl acetate, and washed with water, diluted hydrochloric acid, aqueous sodium bicarbonate, and brine in that order.
  • Example 4 from 4-amino-6-cyano 3,4-dihydro-1,2,2-di (methoxymethyl) -12H-1 monobenzopyran 246 mg and methyl N-cyano 3-pyridine power lipoximidate 253 mg N'-Cyanone-N- [6-cyano-3,4-dihydro-2,2-di (methoxymethyl) -12H-1-1-benzopyran-14-yl] -13-pyridine 259 mg of carboxamidine were obtained.
  • 6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2H-1-benzopyran isomer mixture 4 prepared according to the method described in JP-A-3-66681. From 3 g, 4-amino- in the same manner as in Example 10 2.7 g of a mixture of isomers of 6-cyano 3,4-dihydro-2-methoxymethyl-2-methyl-2H-11-benzopyran was obtained. Dissolve 2.4 g of this isomer mixture in a mixed solvent of dioxane 2 Om 1-water 1 ml, add 2.3 g of dibutyl dicarbonate under ice-cooling and stir, and stir at room temperature for 1 hour. did.
  • This O isomer (62 Omg) was dissolved in dioxane (4 ml), and thereto was added 4N hydrochloric acid (dioxane solution) (5 ml), and the mixture was stirred at room temperature for 15 hours. The residue obtained by evaporating the solvent was dissolved in a 1 N aqueous hydrochloric acid solution, and washed with ethyl acetate.
  • 6-Promo 3,4-dihydro-2,2-di (methoxymethyl) -1-2H-1-1-benzopyran-4-one 5.05 g was dissolved in 50 ml of methanol, and 0.67 g under ice-cooling and stirring. Of sodium borohydride was added little by little and stirred for 1.5 hours. Ethyl acetate was added to the residue obtained by evaporating the solvent, and the mixture was washed successively with 1 N hydrochloric acid, aqueous sodium bicarbonate, and brine, dried, and evaporated under reduced pressure to give an oily 6-promo 3,4-dihydro-2,2.
  • Ethyl N-Cyanol 3-Fluorobenzimidate 41 Omg and (3S, 4R) — 4-Amino-6-Cyanor 3,4 dihydro-2,2-di (methoxymethyl) -13-Hydroxy-2
  • 40 mg of H-1 benzopyran to the same reaction procedure as in Example 16
  • N′-cyano-N — [(3S, 4R) —6-cyano 3,4 dihydro-2,2 —Di (methoxymethyl) -13-hydroxy-2H-1-1-benzopyran-14yl] -13-fluorobenzamidine is obtained in an amount of 428 mg.
  • 2H—1 benzopyran 35 Omg to the same reaction procedure as in Example 16
  • N-cyano N'-phenylthiourea After 3 hours, add 34 mg of N-cyano N'-phenylthiourea and 34 mg of WSC / HC.After 3 hours, add ethyl acetate, wash with hydrochloric acid, aqueous sodium bicarbonate and brine, dry over magnesium sulfate, and evaporate the solvent. The residue was purified by silica gel chromatography, and N "—cyano N — [(3S, 4R) —6-cyano 3,4-dihydro-2,2-di (methoxymethyl) -1,3-hydroxy-2H—11 Benzopyran-1 4 '] 1 N'-Fenirguanidin 20 Om was obtained.
  • methyl l-cyano 3-pyridinecarboxymidate 64 lmg and t-14-amino-6-cyano-1,3,4-dihydro-1r-13-hydroxy-12-methyl-2-phenoxy From 660 mg of a mixture of isomers of cimethyl-2H- 1-benzopyran N'-cyano N- (6-cyano 3,4-dihydro-r-3-hydroxy-12-methyl-2-phenoxymethyl-12H-1-benzopyran-t 341 mg)
  • Low-polar A isomer of 346 mg of 1,3-pyridinecarboxamidine and 253 mg of high-polar B isomer were obtained.
  • 6-Cyan-1,2-di (hydroxymethyl) -1H-2 Benzopyran lg is dissolved in dimethylformamide, imidabul 793 mg is added, and the mixture is cooled under ice cooling. Add 1.52 g of t-butyldimethylsilyl chloride, stir at room temperature for 6 hours, and add the reaction solution to water. Extract with ethyl acetate, wash with water and brine, dry with magnesium sulfate, and evaporate the solvent to obtain 1.99 g of a solid.
  • 6-cyanore 3,4-epoxy-1,2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-2H-1-benzopyran 1.76 g of 4-amino-amino acid was prepared in the same manner as in Example 8. 1.18 g of 6-cyano-2,2-di (tert-butyldimethylsilyloxymethyl) -1,3,4-dihydro-3-hydroxy-2H-11-benzopyran was obtained.
  • N′-Cyanone N [(3S, 4R) —6-Cyanoh-3,4-dihydro-2,2-di (methoxymethyl) -13-hydroxy-2H—1-benzopyran obtained in Example 16 1.41]
  • 1-3-pyridinecarboxamidine (2.1 g) is dissolved in pyridine (4.7 ml), and formic acid-acetic anhydride (2; 1) is stirred at 50 ° C for 15 minutes.
  • reaction solution is added to ice water, extracted with ethyl acetate, and washed with aqueous sodium hydrogen carbonate and brine. After drying and concentration with sodium sulfate, recrystallization from ethyl acetate gave N'-cyano N-[(3S, 4R) -6-cyano-1,3,4-dihydro-2,2-di (methoxymethyl) 13- Formyloxy-2H-1-1-benzopyran-14-yl] -13-pyridinecarboxamidine 73 lmg is obtained.
  • the present invention is not limited only to the compounds shown in the examples, but includes the following compounds, for example.
  • the coronary blood flow is measured using an electromagnetic blood flow probe (Nihon Kohden, FJ-020T and FJ-025T) installed in the extracorporeal circuit leading from the femoral artery to the origin of the coronary artery when administering the drug into the artery.
  • an electromagnetic blood flow probe Nahon Kohden, FJ-020T and FJ-025T
  • FJ-020T and FJ-025T an electromagnetic blood flow probe attached to the left circumflex branch of the left coronary artery. Connected and measured. Each of these parameters was recorded on a hot pen reticule coder (Nihon Kohden, RJG-4128).
  • the test drug solution was prepared by dissolving the sample in a mixture of N, N-dimethylformamide (30%) and physiological saline (70) and appropriately diluting with physiological saline.
  • the test drug solution was prepared in the extracorporeal circulation circuit.
  • the control compounds were remacarim (control compound a) and 2-methoxymethyl-2-methyl--(1,2-) disclosed in JP-A-3-66681. Dihydro-l-oxo-l-l-pyridyl) -l-6-cyano 3-chromanol (low-polar isomer) (control compound b) was used, and the dose was 10 for the compound of the present invention (Example 39). , 30, 100 zgZkg, remacarim (control compound a) at 0.3, 1, 3 g / kg, and control compound b at 10, 30, 100 ⁇ gZkg.
  • the compound of the present invention shows only about a 3% decrease in blood pressure, whereas the control compound a has twice the blood pressure. Above about 8% decrease in blood pressure was observed. In addition, when trying to increase coronary blood flow by 50%, this compound causes only about 2% decrease in blood pressure. On the other hand, control compound a showed a drop in blood pressure of more than twice that of 5%, and control compound b showed a drop of blood pressure of more than three times that of about 7%.
  • the compound of the present invention and a pharmaceutically acceptable salt thereof have a selective and excellent effect of increasing coronary blood flow, but have a very weak effect of lowering blood pressure. Therefore, it is possible to selectively increase coronary blood flow without causing a rapid drop in blood pressure that causes tachycardia that adversely affects the heart, and this compound is a prophylactic or therapeutic agent for angina pectoris, heart failure, etc.
  • a pharmaceutically acceptable salt thereof have a selective and excellent effect of increasing coronary blood flow, but have a very weak effect of lowering blood pressure. Therefore, it is possible to selectively increase coronary blood flow without causing a rapid drop in blood pressure that causes tachycardia that adversely affects the heart, and this compound is a prophylactic or therapeutic agent for angina pectoris, heart failure, etc.
  • alopecia such as alopecia areata.

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Abstract

Composé de chromane représenté par la formule générale (I), ses applications médicinales en tant que vasodilatateur coronaire et ses intermédiaires, comprenant: 4-oxochromane, 4-hydroxychromane, chromène et 3,4-époxychromane. Dans la formule R1 représente cyano, nitro ou halogène; R2 représente alcoxyalkyle inférieur, alcoxycarbonyle inférieur, hydroxyalkyle, aryloxyalkyle ou t-butyldiméthylsilyloxyalkyle; R3 représente H, alkyle inférieur, etc.; R4 représente H, OH, etc.; R5 représente H, etc.; A représente (a); R6 représente hétéroaryle, arylamino, aryloxy, alkyle inférieur ou aryle substitué; X représente N-CN, O ou S; et R7 représente H ou alkyle inférieur.
PCT/JP1993/000992 1993-07-16 1993-07-16 Nouveau compose du chromane, ses intermediaires et ses applications medicinales Ceased WO1995002589A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6054477A (en) * 1997-08-26 2000-04-25 Bioavailability Systems, Llc Anti-first-pass effect compounds
WO2000069813A1 (fr) * 1999-05-12 2000-11-23 Bayer Aktiengesellschaft N-cyano-amidines substituees
US6248776B1 (en) 1997-08-26 2001-06-19 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US7230027B2 (en) 1997-08-26 2007-06-12 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61277678A (ja) * 1985-05-28 1986-12-08 ビーチャム・グループ・ピーエルシー 医薬組成物

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS61277678A (ja) * 1985-05-28 1986-12-08 ビーチャム・グループ・ピーエルシー 医薬組成物

Cited By (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6054477A (en) * 1997-08-26 2000-04-25 Bioavailability Systems, Llc Anti-first-pass effect compounds
US6248776B1 (en) 1997-08-26 2001-06-19 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US6476066B1 (en) 1997-08-26 2002-11-05 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US7230027B2 (en) 1997-08-26 2007-06-12 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US7378534B2 (en) 1997-08-26 2008-05-27 Bioavailability Systems, Llc. Anti-first-pass effect compounds
US7514572B2 (en) 1997-08-26 2009-04-07 Bioavailability Systems, Llc Anti-first-pass effect compounds
US7576123B2 (en) 1997-08-26 2009-08-18 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
US7576124B2 (en) 1997-08-26 2009-08-18 Bioavailability Systems, L.L.C. Anti-first-pass effect compounds
WO2000069813A1 (fr) * 1999-05-12 2000-11-23 Bayer Aktiengesellschaft N-cyano-amidines substituees

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