WO1997023209A1 - Agent therapeutique contre l'insuffisance cardiaque - Google Patents

Agent therapeutique contre l'insuffisance cardiaque Download PDF

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Publication number
WO1997023209A1
WO1997023209A1 PCT/JP1996/003761 JP9603761W WO9723209A1 WO 1997023209 A1 WO1997023209 A1 WO 1997023209A1 JP 9603761 W JP9603761 W JP 9603761W WO 9723209 A1 WO9723209 A1 WO 9723209A1
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Prior art keywords
group
amino
hydrogen atom
atom
alkyl
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PCT/JP1996/003761
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English (en)
Japanese (ja)
Inventor
Keizo Tanikawa
Kazuhiko Ohrai
Masayuki Sato
Toru Yamashita
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Nissan Chemical Industries, Ltd.
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Publication of WO1997023209A1 publication Critical patent/WO1997023209A1/fr

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
    • A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/4025—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil not condensed and containing further heterocyclic rings, e.g. cromakalim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/453—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a six-membered ring with oxygen as a ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole

Definitions

  • the present invention relates to the use of pharmacologically active benzopyran shoes for treating heart failure in mammals, including humans.
  • JP-A-51-14777 UK Patent No. 1 495 526, U.S. Pat.No. 4,048,317, JP-A-56-57778 ⁇ g Leaked Patent 2 No. 864, U.S. Pat.No. 4,336,811), Japanese Patent Application Laid-Open No. 56-57776 86
  • Heart failure which is a function of the heart, is a disease based on a decrease in cardiac fiber strength, and a drug that increases myocardial TO strength is used clinically to treat it.
  • these ⁇ flJs are considered to have a problem with excessive consumption of myocardial energy based on the effect of increasing heart rate, and it is said that there is a problem with the postnatal improvement effect in long-term administration. Therefore, there is a demand for a drug that reduces the heart muscle energy consumption burden by reducing the heart rate. Disclosure of the invention
  • the present inventors have found that among the benzopyran derivatives, the antihypertensive effect is low and the heart rate is reduced. As a result of an exploratory search for the compound represented by the formula (I), it was found that the compound represented by the formula (I) has a strong bradycardia effect and was useful as a treatment for heart failure, and thus the present invention was made.
  • the present invention provides a compound of the formula (I)
  • R 1 and 03 ⁇ 42 are respectively: hydrogen atom, halogen atom, nitrocyanoformyl! ⁇ Amino d-alkyl amino di-C physician ⁇ alkylamino C physician ⁇ alkylcarbonyl ⁇ amino d -!, Alkylsulfonyl ⁇ amino 3 ⁇ 4 Ami Nokarubo sulfonyl 3 ⁇ 4 ⁇ alkyl ⁇ amino carboxymethyl sulfonyl ⁇ di ⁇ -, alkyl ⁇ Mino Cal Boniru alkyl Cal Poni group or C, -! a ⁇ alkoxycarbonyl two Le group S *, and
  • R 6 represents a ⁇ »3 ⁇ 4C, alkoxy group or a Ci- « alkylcarbonyloxy group, or forms a bond with ⁇ R e ,
  • R T and U ⁇ each represent a hydrogen atom or a C, alkyl group, or R T and R «together with the atom to which they are attached, pyrrolidinyl, imi Dazolidinyl, birazolidinyl, biberidyl, piperazinyl, perhydroazepinyl, 1,3-oxazolidinyl, morpholinyl, 1,3-belhydroxazebine, 1,4-perhydrooxazepinyl, 1,3-thiazolidinyl, 1,4-peridin Hydrothiazolinyl, 1,3-perhydride ⁇ -thiazolidinyl, 1,4 Or a pyrrolyl ring optionally substituted by R 9 together with the nitrogen atom to which they are attached such that R 7 and R 8 are "" ⁇ (R 8 has the same meaning as R 1. ) ]
  • the benzopyran derivative represented by the formula (I) or a salt thereof that is H-tolerant is an active ingredient.
  • the compound provided by the present invention has a strong heartbeat-lowering effect, is effective in improving the ability of the patient, and can be used as a therapeutic agent for heart failure.
  • nj is the normal
  • ij means iso
  • the r s j is secondary
  • RTJ is r c "tertiary means cyclo.
  • halogen atom examples include a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.
  • a fluorine atom, a chlorine atom and a bromine atom are mentioned.
  • methyl, ethyl, n-propyl, i-propyl, ⁇ -butyl and the like are mentioned.
  • methoxy, ethoxy, ⁇ -propoxy and i-propoxy are preferred You.
  • Examples of d- e alkylamino groups include methylamino, ethylamino, n-propylamino, i-propylamino, c-propylamino, ⁇ -butylamino, i-butylamino, s-butylamino, t-butylamino, c-butylamino, and 1-pentylamino.
  • methylamino, ethylamino, n-propylamino, i-propylamino and ⁇ -butylamino are used.
  • dialkylamino group examples include dimethylamino, getylamino, di-n-propylamino, di-i-butylamino, di-C- ⁇ -pyramino, di- ⁇ -butylamino, di-i-butylamino, and di-s-amino.
  • dimethylamino, getylamino, di-n-propylamino, di-i-propylamino, di-n-butylamino are used.
  • dealkylcarbonylamino group examples include methylcarbonylamino, ethylcarbonylamino, ⁇ -propylcarbonylamino, i-propylcarbonylamino, ⁇ -butylcarbonylamino, i-butylcarbonylamino, and s-butyl.
  • methylcarbonylamino, ethylcarbonylamino, ⁇ -propyl ⁇ carbonylcarbonylamino, i-propylcarbonylamino, and n-butylcarbonylamino are exemplified.
  • Examples of the ⁇ - alkylsulfonylamino group include methylsulfonylamino, ethylsulfonylamino, ⁇ -propylsulfonylamino, i-propylsulfonylamino, n-butylsulfonylamino, i-butylsulfonylamino, s -Butylsulfonylamino, t-butylsulfonylamino, 1-pentylsulfonylamino, 2-pentylsulfonylamino, 3-pentylsulfonylamino, i-pentylsulfonylamino, neopentylsulfonylamino, t-pentylsulfonylamino Mino, 1-hexylsulfonylamino, 2-hexylsulfonylamino
  • Preferred examples include methylsulfonylamino, ethylsulfonylamino, n-propylsulfonylamino, i-propylsulfonylamino, and n-butylsulfonylamino.
  • alkylaminocarbonyl group examples include methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl, n-butylaminocarbonyl, i-butylaminocarbonyl, and s-butylamino.
  • methylaminocarbonyl, ethylaminocarbonyl, n-propylaminocarbonyl, i-propylaminocarbonyl and n-butylaminocarbonyl are used.
  • dialkylaminocarbonyl groups include dimethylaminocarbonyl, diethylaminocarbonyl, di- ⁇ -propylaminocarbonyl, di-i-propylaminocarbonyl, di-C-propylaminocarbonyl, di-n- Butylaminocarbonyl, di-i-butylaminocarbonyl, di-s-butylaminocarbonyl, di-t-butylaminocarbonyl, di-C-butylaminocarbonyl, di-1-pentylaminocarbonyl, Di-2-bentylaminocarbonyl, di-3-pentylaminocarbonyl, di-i-pentylaminocarbonyl, di-neopen
  • dimethylaminocarbonyl, acetylaminocarbonyl, di- ⁇ -propylaminocarbonyl, di-i-propylaminocarbonyl, di-C-propylaminocarbonyl, di-n-butylaminocarbonyl Is reduced.
  • the C have e alkyl group, methylcarbonyl, E chill carbonyl, n- propyl carbonyl, i- propyl carbonyl, n- Puchirukaruponiru, i- butyl carbonyl, s- butylcarbonyl, t- butyl, 1- pentylcarbonyl , 2-pentylcarbonyl, 3-pentylcarbonyl, i-pentylcarbonyl, neopentylcarbonyl, t-pentylcarbonyl, 1-hexylcarbonyl, 2-hexyl carbonyl, and 3-hexylcarbonyl Can be
  • methyl carbonyl, ethyl carbonyl, n-propyl carbonyl, i-propyl carbonyl and II-butyl carbonyl are used.
  • Examples of the dealkoxycarbonyl group include methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i-butoxycarbonyl, s-butoxycarbonyl, t-butoxycarbonyl, and 1-butoxycarbonyl. Pentyloxycarbonyl, 2-pentyloxycarbonyl, 3-pentyloxyka Luponyl, i-pentyloxycarbonyl, neopentyloxycarbonyl, t_pentyloxycarbonyl, 1-hexyloxycarbonyl, 2-hexyloxycarbonyl, 3-hexyloxycarbonyl, etc.
  • methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, i-propoxycarbonyl, n-butoxycarbonyl, i_butoxycarbonyl, s-butoxycarbonyl and t-butoxycarbonyl are exemplified.
  • Preferred compounds used in the present invention include the following compounds.
  • Ri and o- 2 are each a hydrogen atom, a hydrogen atom, a logen atom, a nitro group, a cyanoformyl amino group, a C-alkylamino group, a di-dealkylamino group, and a Cl-6 alkylcarbonylamino group.
  • R 8 and R 4 are each independently a -alkyl group or a C 8 -e cycloalkyl group together with the atoms to which R s and R 4 are attached, and
  • R 6 is meant bonded in or R e and one cord means hydroxyl group or d-e alkyl carbonylation Ruokishi group,
  • R e represents a hydrogen atom or together with R 6 a bond
  • R 7 ⁇ 03 ⁇ 4 beta is, do you mean respectively elevational a hydrogen atom or a d-e alkyl group, a pyrrolidinyl together with the nitrogen atom to which they become R 7 and R 8 gar cord is attached, I Mi Dazorijiniru , Bisazolidinyl, piperidyl, piberazinyl, morpholinyl, 1,3-thiazolidinyl group, or R 7 may be optionally substituted with R 7 together with the nitrogen atom to which they are attached
  • R 7 and R 8 together form a pyrrolidinyl, imidazolidinyl, virazolidinyl, piperidyl, piperazinyl, morpholinyl group together with the nitrogen atom to which they are attached, or ⁇ and R 8 together nitrogen atom linked co a R e optionally substituted which may be pyrrole ring by (R 8 has the same meaning as R 1.) the to the (1) compound described.
  • R 8 ⁇ 03 ⁇ 4 4 are the same d-e alkyl group (2) compounds according.
  • R 2 is a hydrogen atom, Bruno, androgenic atom, Shiano Amino C, - an e alkylcarbonylamino ⁇ iminocarbonyl d-e-alkylaminocarbonyl group or gripping ⁇ ⁇ Le kills aminocarbonyl group (3) word S mounting the reduction ⁇ .
  • R 2 is a hydrogen atom, a halogen atom, an amino group or a C, - 6 alkyl carbonyl ⁇ amino group above (4) according spoon ⁇ .
  • R 1 is a hydrogen atom, hagen atom, nitro cyano formyl amino
  • C is beta alkylamino! ⁇ Di de alkylamino 3 ⁇ 4 ⁇ - beta alkylcarbonyl amino ⁇ amino carbonyl group, C -! A e alkylcarbonyl ⁇ amino group or a di CI- e Aruki Rua amino group (5) compounds according.
  • R 1 is a hydrogen atom, a nitro group, Shiano 3 ⁇ 4 ⁇ C physician ⁇ alkylcarbonyl ⁇ amino group, amino Nokarubo sulfonyl ⁇ - is a ⁇ alkyl ⁇ amino carbonyl or grip d-6 Arukiruamino force Ruponiru group (6>, wherein Compound. (8)
  • R 1 is a hydrogen atom
  • R 2 is methylcarbonyl ⁇ amino
  • R s ⁇ 03 ⁇ 4 4 is methyl
  • R 6 is water
  • R e is a hydrogen atom
  • R 7 ⁇ Arufa3 ⁇ 4 beta are attached they Te summer together
  • a benzopyran derivative represented by the formula (I) which is a pyrrolidinyl group together with an atom, or a freshly acceptable salt thereof.
  • R 2 is methylcarbonylamino
  • R 8 and R 4 are methyl
  • R 6 is a hydroxyl group
  • Re is a hydrogen atom
  • R 7 and R 8 are A benzopyran derivative represented by the formula (I), which is a pyrrolidinyl group together with a nitrogen atom, or a pharmaceutically acceptable salt thereof.
  • R 1 is Nitro
  • R 2 is Amino! ⁇
  • R 8 ⁇ 4 is a methyl group
  • R 6 is ⁇ ⁇
  • R e is hydrogen atom
  • taken R 7 and R 8 guard ⁇ is H.
  • Jiniru group together with the nitrogen atom to which they are attached formula Benzopyran-induced or pharmaceuticals represented by (I) ⁇ tolerable ⁇ ULO
  • R 1 is nitro
  • R 2 is a hydrogen atom
  • R 8 and R 4 is methyl
  • R 6 is hydroxyl
  • R e is hydrogen atom, together with the nitrogen atom to which R T ⁇ Y3 ⁇ 4 8 are attached they become H3 ⁇ 4
  • R ' is Nito.
  • R 2 is nowadays Elementary atom, R 3 and R 4 are methyl R 6 is hydroxyl! ⁇ R e is a hydrogen atom, together with the nitrogen atom to which they become R 7 ⁇ 03 ⁇ 4 8 guard cord is attached to the R »
  • Me represents a methyl group
  • Et represents an ethyl group
  • Pr represents a propyl group
  • Bu represents a butyl group
  • Ac represents an acetyl group (COCH 8 ).
  • the compound KKl used in the present invention has asymmetry at the 3- and 4-positions of the silane ring, and there is an optical isomer based on the asymmetric weave. Can be used for applications.
  • the relative configuration of the 3- and 4-positions of the pyran ring is trans.
  • Sulfoxides represented by dimethylsulfoxide, amides represented by dimethylformamide or dimethylacetamide, ethers, dimethoxyethane or ethers represented by tetrahydrofuran, dichloromethane, Halogen compounds represented by oral form and dichloroethane, and alcohol compounds represented by methanol, ethanol, or propanol are obtained. You can also perform ⁇ ; Preferably, an alcohol solvent is used.
  • the Sitv Sitl usually ranges from 20 to the difficulty of the machine used, preferably from 60 to 100.
  • the chemical formula (III) and the chemical formula (I) are in the range of 0.5 to 0, and preferably in the range of 1.0 to 2.0.
  • Hl3 ⁇ 43 ⁇ 4 (II) can be prepared by known methods (eg, J. Med. Chem. 1 9 8 3, 26, 15 8 2 and J. Med. Chem. 19) 8 4, 2 7, 1 1 2 7).
  • R 7 and R * are linked together to form a pyrrole ring together with the nitrogen atom to which they are attached ⁇ ( ⁇ ⁇ ( ⁇ ). ) Is obtained by centering the compound represented by (II) and the compound represented by " ⁇ (V) ⁇ under a base as shown by the following.
  • V ⁇ R 6 is a ⁇ ⁇ group
  • R e is a hydrogen atom c
  • Examples include alcoholic solvents typified by genous, methanol, ethanol, or propanol.
  • sis can be performed without solvent.
  • sulfoxide and amide solvents are used.
  • Examples of the base include sodium hydride, hydrogen hydride, and lithium t-butoxide, and preferably sodium hydride.
  • Sf SKiiii atmospheric - 2 is up to the reaction solvent used from 0, the preferred properly 0 'C ⁇ 6 is 0 e C.
  • the ratio of base / compound (V) is in the range of 0.5 to 2.0, and preferably in the range of 1.0 to 1.5.
  • the molar ratio of the raw materials is such that compound (V) / compound (II) is in the range of 0.5 to 2.0, preferably in the range of 1.0 to 2.0.
  • the compound represented by (VI II) can be obtained in the presence of Can be In the formula (V ⁇ ), R 6 is a group, and R e is a hydrogen atom.
  • the SJSW molar ratio is: ⁇ (VIII) / ⁇ ! (VU) is in the range of 0.5 to 4.0, preferably (gffl) of 1.0 to 2.0.
  • m-fiber and propionic acid are used.
  • the optical compound is synthesized by a method of optically resolving a racemate (Japanese Patent Application Laid-Open No. 8-141,286, US Pat. No. 5,097,037) issue Is done.
  • the synthesis of the photopolymer represented by the formula (10) is performed by asymmetric synthesis.
  • the compound represented by- ⁇ (I) has a strong heart rate effect. It has no heart rate-lowering effect because it is not used for production. Can be Therefore, the compound according to the present invention is also useful for the treatment of cardiac HUfiL tract disease taking into account metabolism, oxygen consumption or energy consumption related to heart movement, and treatment mainly considering heart rate decreasing action. Is expected.
  • tSX in mammals including humans, as a drug for deficiency, or in the reversal of cardiovascular disease that induces heart failure, such as ⁇ ⁇ jfii 3 ⁇ 43 ⁇ 4 3 ⁇ 43 ⁇ 4 mm, mm im, lung ⁇ ⁇ ⁇ ⁇ , ⁇ m m .
  • the present invention provides a medicament comprising an effective amount of a compound of formula (I) for these treatments.
  • Examples of the dosage form of the compound according to the present invention include parenteral administration by mm (subcutaneous, intravenous, intramuscular, intraperitoneal injection), ointment, suppository, aerosol, etc., or capsule, granule, Oral administration by syrup u, liquid preparation, mu suspension, etc. can be provided.
  • the above-mentioned pharmaceutical or non-pharmaceutical products containing the compound according to the present invention contain the compound of the present invention in an amount of about 0.01 to 99.5%, preferably about 0. 1-30
  • compositions according to the invention can include a plurality of compounds according to the present invention.
  • the clinical dosage of the compounds provided in the present invention may be increased or decreased depending on age, body weight, patient's condition, fiber of symptoms or administration method.
  • the effective dose is 0.001 mg / kg to 50 mg / k daily, preferably 0.01 mgZKg to 20 mg / kgSS.
  • amounts outside the above range can also be used depending on
  • the compounds provided by the present invention are formulated for administration by pharmaceutical means. That is, capsules, granules, and pills for oral administration are excipients, such as sucrose, lactose, glucose, starch, mannitol; binders, such as hydroxypropyl cellulose, syrup, gum arabic, and gelatin. Sorbitol, tragacanth, methylcellulose, polyvinylpyrrolidone; disintegration, for example, starch, carboxymethylcellulose or its calcium salt, microcrystalline cellulose, polyethylene glycol; lubricating, for example, talc, magnesium or calcium stearate, silicic acid Force; prepared using lubricants, such as sodium laurate, glycerol, etc.
  • excipients such as sucrose, lactose, glucose, starch, mannitol
  • binders such as hydroxypropyl cellulose, syrup, gum arabic, and gelatin.
  • Sorbitol, tragacanth methylcellulose
  • solutions, emulsions, suspensions, syrups and aerosols are solvents for pirates, such as water, ethyl alcohol, isopropyl alcohol , Propylene glycol, 1,3-butane Lenglycol, polyethylene glycol; surfactant, for example, sorbitan H fatty acid ester, polyoxoxylene sorbitan B fatty acid ester, boroxixylene fatty acid ester, hydrogenated castor oil boroxixylene Teru, lecithin; hanging drops such as carboxymethyl sodium salt, cellulose-induced tragacanth such as methylcellulose, natural gums such as gum arabic; preservatives such as esters of paraoxybenzoic acid, benzalkonium chloride, sorbic acid salt, etc. It is prepared by
  • ointment which is a pure adjuvant.
  • Suppositories are, for example, cocoa butter, polyethylene glycol, lanolin, fatty acid triglycerides. It is prepared using celite, coconut oil, borisorbate, etc.
  • the mixture After mixing the Xiao Xiao component in a conventional manner, the mixture is filled into gelatin capsules to produce 10,000 capsules containing 1 mg of active ingredient per capsule.
  • the mixture is filled into No. 3 soft gelatin capsules by a conventional method to produce 10 000 soft capsules containing 1 mg of the active ingredient in one capsule.
  • the upper portion is mixed in a conventional manner, poured into a suppository container, solidified, and 1,00 D 1 g of suppository containing 1 mg of active pirates are fibred.
  • the samples were cumulatively applied with isoproterenol to find the maximum. After washing with the drug, 5 W of 60 minutes was performed while exchanging nutrients, and then each compound was applied to act.
  • the compound according to the present invention exhibited a port rate-dependent heart rate decreasing effect.
  • the compound provided in the present invention is useful for enhancing cardiac muscle strength and improving cardiac function.
  • the present invention can be a useful therapeutic agent for heart failure.

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Abstract

L'invention porte sur un agent thérapeutique contre l'insuffisance cardiaque dont le principe actif est soit un dérivé du benzopyrane de formule générale (I), soit ou l'un de ses sels pharmacocompatibles. Dans la formule (I), ou R1 et R2 représentent chacun indépendamment H, halogéno, nitro, cyano, amino, alkylcarbonylamino C¿1-6?, etc.; R?3 et R4¿ représentent chacun indépendamment H, alkyle C¿1-6? ou phényle ou R?3 et R4¿ sont liés ensemble pour former cycloalkyle C¿3-6?, en association avec l'atome de C leur étant fixé; R?5¿ représente hydroxy, alcoxy C¿1-6? ou alkylcarbonyloxy C1-6, ou est lié à R?6¿ pour former une liaison; R6 représente H ou est lié à R5 pour former une liaison; et R7 et R8 représentent chacun indépendamment H ou alkyle C¿1-6?, ou R?7 et R8¿ sont liés ensemble pour former pyrrolidinyle, imidazolidinyle, pyrazolidinyle, pipéridyle, pipérazinyle, etc., en coopération avec l'atome d'azote leur étant fixé, ou R7 et R8 sont liés ensemble pour former, en association avec l'atome d'azzote leur étant lié, un cycle pyrrole facultativement substitué par R9 (R9 ayant ici la même signification que R1).
PCT/JP1996/003761 1995-12-25 1996-12-24 Agent therapeutique contre l'insuffisance cardiaque WO1997023209A1 (fr)

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JP33556295 1995-12-25
JP7/335562 1995-12-25

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004542A1 (fr) * 1996-07-26 1998-02-05 Nissan Chemical Industries, Ltd. Derives de chromane
WO2009017190A1 (fr) * 2007-08-01 2009-02-05 Mitsubishi Tanabe Pharma Corporation Composé bicyclique condensé
US7534801B2 (en) 2003-10-10 2009-05-19 Wyeth Piperidinylchromen-6-ylsulfonamide compounds as 5-hydroxytryptamine-6 ligands
CN100564377C (zh) * 2001-05-16 2009-12-02 西托维亚公司 用作半胱天冬酶激活剂和细胞凋亡诱导剂的取代的4h-色烯和类似物及其应用

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JPS5757786A (en) * 1980-09-26 1982-04-07 Nippon Kokan Kk <Nkk> Dry-process quenching apparatus for coke
WO1985001290A1 (fr) * 1983-09-14 1985-03-28 Beecham Group P.L.C. Pyrrylchromanes antihypertensifs

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998004542A1 (fr) * 1996-07-26 1998-02-05 Nissan Chemical Industries, Ltd. Derives de chromane
CN100564377C (zh) * 2001-05-16 2009-12-02 西托维亚公司 用作半胱天冬酶激活剂和细胞凋亡诱导剂的取代的4h-色烯和类似物及其应用
US7534801B2 (en) 2003-10-10 2009-05-19 Wyeth Piperidinylchromen-6-ylsulfonamide compounds as 5-hydroxytryptamine-6 ligands
WO2009017190A1 (fr) * 2007-08-01 2009-02-05 Mitsubishi Tanabe Pharma Corporation Composé bicyclique condensé
US8258131B2 (en) 2007-08-01 2012-09-04 Mitsubishi Tanabe Pharma Corporation Fused bicyclic compound
RU2468017C2 (ru) * 2007-08-01 2012-11-27 Мицубиси Танабе Фарма Корпорейшн Конденсированное бициклическое соединение
US8410166B2 (en) 2007-08-01 2013-04-02 Mitsubishi Tanabe Pharma Corporation Fused bicyclic compound
JP5357027B2 (ja) * 2007-08-01 2013-12-04 田辺三菱製薬株式会社 縮合二環式化合物

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