WO1981002421A1 - Carbostyryl derivatives - Google Patents

Carbostyryl derivatives Download PDF

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Publication number
WO1981002421A1
WO1981002421A1 PCT/JP1980/000122 JP8000122W WO8102421A1 WO 1981002421 A1 WO1981002421 A1 WO 1981002421A1 JP 8000122 W JP8000122 W JP 8000122W WO 8102421 A1 WO8102421 A1 WO 8102421A1
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WO
WIPO (PCT)
Prior art keywords
group
mouth
lower alkyl
positions
dehydrogenated
Prior art date
Application number
PCT/JP1980/000122
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English (en)
French (fr)
Japanese (ja)
Inventor
T Nishi
T Tanaka
K Nakagawa
Original Assignee
Otsuka Pharma Co Ltd
T Nishi
T Tanaka
K Nakagawa
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Otsuka Pharma Co Ltd, T Nishi, T Tanaka, K Nakagawa filed Critical Otsuka Pharma Co Ltd
Priority to AT0909480A priority Critical patent/AT381493B/de
Priority to DE803049959T priority patent/DE3049959T1/de
Priority to AU59859/80A priority patent/AU532319B2/en
Priority to NLAANVRAGE8020199,A priority patent/NL185146C/xx
Priority to DK250381A priority patent/DK151956C/da
Publication of WO1981002421A1 publication Critical patent/WO1981002421A1/ja
Priority to NO81813477A priority patent/NO160512C/no

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C07D215/227—Oxygen atoms attached in position 2 or 4 only one oxygen atom which is attached in position 2
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/36—Radicals substituted by singly-bound nitrogen atoms
    • C07D213/38—Radicals substituted by singly-bound nitrogen atoms having only hydrogen or hydrocarbon radicals attached to the substituent nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/20—Oxygen atoms
    • C07D215/22—Oxygen atoms attached in position 2 or 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D309/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings
    • C07D309/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D309/04—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms

Definitions

  • the present invention is a novel calbostilyl derivative.
  • the novel 5-parent rubostyryl derivative of the present invention is excellent in inhibiting platelet aggregation, inhibiting hosodiesterase, cardiac contractility-like, and exerting a strong effect (positive inotrope). effect), antiulcer activity, anti-inflammatory action, step-down operation, cerebral blood flow increasing action, platelet clumps dissociation action, scan port emission port key sub emission Alpha 2 etc. antagonism have a stroke. cerebral infarction.
  • myocardium 0 It is useful as a prophylactic and therapeutic agent for cerebral circulation such as infarction, a cerebral circulation improving agent, an anti-inflammatory agent, an anti-asthmatic agent, a cardiotonic agent, an antihypertensive agent, and a phos-hogesterase inhibitor.
  • the novel potent rubostyryl derivatives of the present invention are low toxic and have toxic effects on the heart, e.g., increase heart rate, heart, 5 effects of vascular thickening, Heart, muscle disorder. ! Weak action : good absorption into the blood of the stomach, and quick, there is a high blood pressure. The feature is that the duration of useful drug action is long. _.. 0
  • H 1 is a hydrogen atom, a lower propyl group, a lower alkyl group or a phenyl lower alkyl group
  • R 2 is
  • R 4 is at least one on the cycloalkyl ring
  • shea click port A Le key Le group c 3 _ 10 having as a substituent a ⁇ group, shea click port A Le key Le of c 3 _ 10 - lower A Le thousand Honoré group N nr J '"-1-, which may have at least one lower' alkoxy group as a substituent on the phenyl group or phenyl ring; :
  • Phenyl-lower alkyl group at least 1 p
  • Lower 'alkyl' group that may have a xy group as a substituent V to lower 'alkyl' group or at least one lower alkyl substituted with at least one aromatic ring residue
  • Each represents a group, and '-R 3 and are combined with an adjacent nitrogen atom with or without another nitrogen atom to form a group represented by the general formula -N or' B-R.
  • I also form a group of (here in R G 'full We two group, C 3 - 1 0 of shea click b a Le key group, full et two Le lower a Le kill groups;
  • B is main switch
  • the bond between the carbons at the 3- and 4-positions on the carbostyryl skeleton represents a single bond or a double bond;
  • substitution position of the group represented by r3 is Substitution positions mosquito group represented by -0 -A -C 0N 4 in However formulas; 5 on Li Le skeleton -, ⁇ -, 7 - - or 8 thickness may be Izu Re location position In the 5-, ⁇ -, 7- or 8-position on the rubostyryl skeleton, R 2 represents a hydrogen atom or a lower alkyl group, and R 2 represents
  • examples of the lower alkylene group include, but are not limited to, methylene, ethylene, methylenolemethylene, trimethylene, 2-methylene Remethylene, 2,2,2-dimethyltrimethylene, tetramethylene, pentamethylene, hexamethylene, 2-methylethylene
  • Examples of lower alkyl groups include methylol, ethyl, propyl,
  • lower alkyl group for hydroxy means a group in which the lower alkyl group is substituted with a hydroxyl group, for example, hydroxymethyl, 2-hydroxyl group.
  • heterocyclic residue means a 5- or 5-membered heterocyclic group having a nitrogen atom, an oxygen atom or a sulfur atom as a heteroatom.
  • a lower alkyl group substituted by a heterocyclic residue means a lower alkyl group in which the above-mentioned heterocyclic residue is bonded as a substituent;
  • Examples thereof include a heterocyclic ring residue in which a linear or branched alkyl group having an elemental atom is substituted with the aforementioned heterocyclic ring.
  • Lower alkyl groups include pinyl, aryl, 2-butenyl, 3-butyl, 1-methylaryl, 2-pentyl, and 2-pentyl. Examples include straight-chain or branched alkenyl groups having 2- ⁇ carbon atoms, such as -hexenyl groups.
  • the lower alkyl groups of phenyl include pennole, 2-phenylene, 1-phenylene, and 3-phenylene.
  • 6-Feninore Phosphoryl groups having 1 to ⁇ carbon atoms such as xinole and 2-methyl-5-phenyl propyl groups, or linear alkyl groups having 1 to ⁇ carbon atoms Phenyl groups substituted by a phenyl group.
  • Lower Alkoxy The lower alkyl groups include methoxymethyl, 2-methoxy, and 5-methoxypropyl.
  • Mouth pill 4-Acetone, 5-Acetone, Pencil 1-Methyl-2-Completed, 1-Methyl, 2-Acetyl.
  • Mouth pill 1, 1-Dimethyl -2 -Acetyl, 2-Pip porion, ⁇ -Propioni Shift.
  • Mouth pill 4-propio-loxy, 5-zl-pi-one -Huh. Mouth Pioni Roxif.
  • Penyl-lower alkyl groups include penyloxymethyl, 2-penyloxyethyl, 5-benzo, and innole Kisif.
  • Roll 0 4-Pennixole, 5—Pennyloxy, Penn-Venso, Innox, 1 -Memories-2-Penso, Inoreoxy, 2-Penis.
  • a C-IO-cyclyl alkyl group which may have a hydroxyl group as a substituent on a cycloalkyl ring is cycloalkyl.
  • Chino, 2 Hydroxy mouth.
  • Cycle mouth Alkyl lower alkyl groups having 3-10 groups are cycloalkyl. ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ Multi-level, 2-level, 2-level. Mouth pinhole, 3-cyclone nozzle: 7 ° Mouth pinhole, neck mouth Penetration hole, 2 — Mouth hole nozzle, 2-Mouth hole Kiss Noreff. Mouth Vinole, 2-cycloh.
  • a phenyl lower alkyl group which may have a lower alkoxy group as a substituent on the phenyl ring is, for example, 'benzyl, 2- full et two Le e Chi le, 1 - off d d Honoré et Ji Honoré, 3 - full et two Honoré full 0 necked le, 4 -.
  • a phenyl group which may have an alkyloxy group such as an oxy group as a substituent is substituted by an alkyl group having 1 to 0 carbon atoms. I can list things.
  • Cyclone is a non-reactive product. Mouth lip ⁇
  • Minocal Ponyl Mouth pox ⁇ -3,4-Carbostyryl and its dehydrogenation at the 3,4 position
  • the compound of the present invention can be prepared by the method shown in Reaction Scheme-1 if known.
  • R 2 represents a hydrogen atom, a lower alkyl group or a group -0-A-C00H (7t, where A is the same as above), and a group -0-A -The substitution position of C0OH may be at any of the 5-, ⁇ -, 7- or 8-positions on the lipostyrene skeleton; the group -0-A-C00H is a carbohydrate.
  • ⁇ ⁇ is water
  • 5-, ⁇ -, 7-and 8-positions are all hydrogen atoms
  • reaction process equation-1 is represented by the general formula (2).
  • a method of reacting an alkyl halide with carboxylic acid to form a mixed acid anhydride and reacting it with an amine (3) is a method of reacting an alkyl halide with carboxylic acid to form a mixed acid anhydride and reacting it with an amine (3).
  • telomer method ie, the carboxylic acid (2), is:
  • Active essences such as trophy pen and pen
  • carboxylic acid (2) is treated with a dehydrating agent such as acetic anhydride.
  • Examples of the method include a method of reacting a halogenated compound, that is, a carboxylic acid halide amine (3).
  • the mixed acid anhydride method is preferred.
  • Alkyl alcoholic acids used in the mixed acid anhydride method include methyl mouth formate, methyl bromate, formate ethyl bromate, and bromoyl. Ethyl formate, isobutyl formate and the like.
  • Mixed acid anhydrides are subject to the usual Schotten-Paumann reaction!
  • the compound of the present invention is produced by reacting the compound with amine (3) without isolation. The Schotten-Paumann reaction is performed in the presence of a basic compound.
  • a compound used for resentment in the Schotten-Paumann reaction is used.
  • Organic bases such as azabicyclo [5,4,0] ⁇ decen-5 (DBU :),, 4-zazacyclo [2,2,2] octane (DABC0 :), and carbonic acid carbonate.
  • inorganic bases such as sodium bicarbonate, sodium bicarbonate, sodium bicarbonate and sodium bicarbonate.
  • the reaction is carried out at a temperature of from 120 to 100 ° C, preferably from 0 to 50 ° C, and a reaction time is from 5 minutes to 10 hours, preferably from 5 minutes to 2 hours.
  • the reaction between the obtained mixed acid anhydride and amine (3) is 120-
  • the reaction is carried out at 150 ° C, preferably 10 to 50 ° G, and the reaction time is 5 minutes to 10 hours, preferably 5 minutes to 5 hours. It is performed under the matter.
  • the mixed anhydride method is generally performed in a solvent.
  • the solvent used may be any of the solvents commonly used in the mixed acid anhydride method.] 9 Specifically, such as methylene chloride, chloroform, and lactone Halogenated hydrocarbons, aromatic hydrocarbons such as benzene, toluene, xylene, etc., styrene ethers, tetrahydrofuran Ethers such as dimethoxethane, methyl acetate, esters such as ethyl acetate, N-dimethylaminoformamide, dimethyl Nonprotonic polar solvents such as sulfoxide and hexamethylene triphosphate amide.
  • the proportions of potassium sulfonate (2), alkylhalocarboxylic acid and amine (3) used are usually the same as those used in this method.
  • Alkyl'no, oral carboxylic acid and amine (3) may be used in an amount of 1 to 1.5 times that of 2).
  • carboxylic acid (2) is a known compound D and amine (3) is a known compound or a novel compound.
  • Amines are produced, for example, by the method shown in the following reaction formula -2 or 5.
  • the amine represented by the general formula (3) is converted into the known amine represented by the general formula (4) and the known halogen compound represented by the general formula (5). And are reacted in the presence of a basic compound. Further, according to the reaction process equation-3, the amine represented by the general formula (3) is converted into a known amine represented by the general formula (6) and a known halogen represented by the general formula (7). By reacting the compound with a basic compound in the presence of a basic compound].
  • This reaction is performed using a basic compound as a deoxidizing agent.
  • a basic compound can be widely used, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, and the like.
  • Inorganic bases such as sodium bicarbonate, potassium bicarbonate, silver carbonate, alcohols such as sodium methylate, sodium methylate, etc. , Triethylamine, pyrigne, N, N-dimethylanilinine and the like.
  • the reaction is carried out without a solvent or in the presence of a solvent, and all solvents which are inert and do not adversely affect the reaction are used.
  • ⁇ Used, for example, methanol, ethanol, fu.
  • Alcohols such as propanol, butanol, ethylene, and alcohol, dimethyl ether, tetrahydrofuran, Zeoxane, Monoglyme, Jiglyme-Ketones such as Ethers, Acetone, Methylethylketone, Benzene, etc.
  • Aromatic hydrocarbons such as toluene and xylene, methyl acetate, and ethyl acetate; esters such as N, N-methylmethyl amide; Non-metals such as methyl sulfoxide and hexyl methyl phosphate triamide.
  • Oral polar polar solvents and the like Alcohols such as propanol, butanol, ethylene, and alcohol, dimethyl ether, tetrahydrofuran, Zeoxane, Monoglyme, Jiglyme-Ketones such as Ethers, Acetone, Methyle
  • reaction is advantageously performed in the presence of a metal iodide such as sodium iodide or potassium iodide.
  • a metal iodide such as sodium iodide or potassium iodide.
  • the use ratio of compound (5) or compound (7) to compound (4) or compound (6) in the above method is not particularly limited, and may be appropriately selected from a wide range. When performing below, the latter is usually a large excess with respect to the former, and when performing in a solvent, the latter is usually equimolar to 5 times higher than the former, preferably equal, etc. It is desirable to use it in an amount of 2 to 2 times.
  • the reaction temperature is not particularly limited, it is usually carried out at room temperature to 200 ° C, preferably at 50 to 100 ° C.
  • the reaction time is usually 1 to 50 hours, preferably 5 to 15 hours.
  • Compound (1) of the present invention can also be produced by the method shown in Reaction Scheme-4.
  • OMFI 05 The ⁇ -, 7- and 8-positions are all hydrogen atoms.]) It is not substituted.] That is, the hydroxycarbo and styrene represented by the general formula (8)
  • the compound of the present invention (1) is obtained by reacting a haloalkane amide derivative represented by the general formula (9) with a haloalkane amide derivative in the presence of a basic compound.
  • aryl radicals represented by x ' include, for example, phenyl radicals, ⁇ -tonol radicals. ⁇ 0 0 0 0 0 0 0 0 0- ⁇ ⁇ 0-4-4-------- Tokishifu-No-Res-No-Re-Ho-Ki-No-Ki-Ki-Shi, 3-Kro-No-Re? ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇ ⁇
  • the compound of the formula (8) is a known compound!
  • the compound of the general formula (9), which is the other raw material, includes known or novel compounds.
  • the compound of the general formula (9) can be easily produced, for example, by the method shown in Reaction Scheme-5.
  • the compound of the general formula (9) can be obtained by reacting the compound of the general formula (CIO) with the compound of the general formula (3) according to a usual amide bond formation reaction.
  • the conditions for the amide bond formation reaction of the above-described reaction process equation-1 can be applied.
  • the substitution position is the same as above.
  • the compound of the present invention has a 3
  • R 2 is a hydrogen atom, a lower alkyl group or a group
  • R 2 is Ri a hydrogen atom or a lower A Le key Le group Der; and R 2 is a group - 0 If -M-C0N Ru 4 Dare, 5 on the force Le Pos Chile Le skeleton -, O -, 7 - and 8 - position is Ah Ri unsubstituted with all hydrogen atoms. ] That is, the general formula
  • the compound of the present invention in (1) is produced by reducing a carbostyryl derivative represented by the general formula ⁇ .
  • Conditions can be widely used to reduce a compound to a saturated aluminum compound, especially the method using catalytic reduction.
  • the catalytic reduction is carried out by hydrogenation using a catalyst in a suitable solvent according to a conventional method.
  • Platinum catalysts such as platinum black, platinum oxide, and colloidal platinum are used as catalysts.
  • Conventional catalysts are used for the nuclear hydrogenation reaction, such as nickel catalysts, nickel catalysts such as nickel oxide, nickel oxide, and nickel oxide.
  • Solvents used include lower alcohols (e.g., methanol, ethanol, isopropanol), water, drunk acid, steric acid ester, and ethanol.
  • the compound of the general formula (11), which is a starting compound in the reaction, is a novel compound.
  • the compound is produced, for example, by the method shown in the following reaction formula-9.
  • substitution position of the group -0-M-C0N 1 is the same as described above; and R 2 in the formula (13) is a hydrogen atom, a lower alkyl group or a group -0 -M-C00H (wherein M represents the same as above); the substitution position of the group -0-M-C00H may be any of the 5-, 6-, 7-or 8-position on the skeleton of carbostyril; Group-0 -M-C00H R 2 is hydrogen atom or lower alkyl when substituted at 5-, ⁇ -, 7- or 8-position on the carbostyryl skeleton Group, and in the case of IT group -0-M-C00H, on the carbostyrene skeleton The 5-, ⁇ -, 7- ⁇ and 8-positions of are all hydrogen atoms and are unsubstituted.)
  • R 5 is a lower alkyl group having a hydroxyl group as a substituent
  • R 6 is a lower alkyl group or a lower alkyl group or a penyl group.
  • X represents a halogen atom.
  • R 1 R 24 A A bond between the 3rd and 4th carbon atoms on the lipostyril skeleton.
  • the ester formation reaction from the lip derivative (1d) to the ester derivative (1e) can be widely used as the normal ester formation reaction. That is, the ester derivative (1e :) is a compound obtained by activating a hydroxy derivative (1d) and a carboxylic acid H 6 C00H or a compound that activates a hydroxyl group. Acid anhydride (R 6 CO) O, acid halides H 6 C0X, etc.]. ⁇ Shi Le agent and to Sanha b gain down product (R 6 C0X) also rather acid anhydride When using (R 6 C0) 2 0, reaction conditions tio Tsu Te emissions - Pa c Ma The reaction conditions can be easily adapted.
  • the reaction is carried out without a solvent or in the presence of a solvent.
  • the solvent used is a solvent commonly used in the Schotten-Pauman reaction, for example, halogenated hydrocarbons such as methylene chloride, chloroform, and the like. Acetones such as acetate and methyl ethyl ketone; -Ethyl ethers; ethers such as tetrahydrofuran; Fatty acids such as oral pionic acid, aromatic hydrocarbons such as benzene and toluene, dimethylformamide, hexamethylphosphine
  • Non-protonic polar solvents such as amide and acetonitril are used.
  • an inorganic base such as sodium acetate, potassium carbonate, sodium hydrogen carbonate, triethylamine, pyridin, N-methylmol Fluorine, 4-dimethylaminopyrimidine, diazapicicyclodecene-7 (DBU) 3 ⁇ 4
  • organic base P-toluenesulfonic acid, sulfuric acid, etc.
  • bronic acid, aluminum chloride, boron trifluoride, Lewis acid such as zinc chloride may be present.
  • the ratio of the hydroxy derivative (1d) to the carboxylic anhydride or acid halide was equimolar to that of the former for the former. It is better to use double moles or to use equimolar to double moles.
  • the reaction temperature and temperature in the present invention may be selected as appropriate, and are not particularly limited. In particular, the temperature is preferably about ⁇ 10 ° to 100 °, more preferably 0 to 50 °.
  • the reaction time depends on the type of raw materials and reaction conditions, but generally the reaction is completed in about 10 minutes to 10 hours.
  • carboxylic acid is used as the acylating agent
  • the dehydration reaction conditions of hydroxy compounds and carboxylic acids can be used widely.
  • This reaction is usually performed in the presence of a catalyst.
  • a catalyst used at this time, those used in ordinary esterification reactions can be widely used.
  • Typical examples are inorganic acids such as gaseous hydrochloride, concentrated sulfuric acid, phosphoric acid, polyphosphoric acid, boron trifluoride, perchloric acid, trifluoro acid, and the like.
  • Organic acids, acid anhydrides such as trifluoromethansulphonic anhydride, thiocyanyl chloride, acetondimethyl acetate, and the like.
  • an acidic ion exchange resin can also be used as a catalyst for this reaction.
  • the amount of the equal medium used may be a normal amount, and is not particularly limited. This reaction proceeds either without solvent or in a solvent.
  • a solvent used in a normal esterification reaction can be effectively used.
  • aromatic solvents such as benzene, toluene, and xylene can be used.
  • the ratio of the hydroxy derivative (1d :) to carboxylic acid is widely used.9 It can be selected as appropriate, but usually the latter is used in contrast to the former. This is done using an equimolar to 5xmolar.
  • the produced water must be removed from the antifouling system using a drying agent such as anhydrous calcium chloride, anhydrous copper sulfate, anhydrous calcium sulfate, and phosphorus pentoxide. It is possible to further increase the production rate.
  • the anti-IS temperature in this reaction may be appropriately selected and is not particularly limited, but is usually within the range of about 120 to 200 ° C. In particular, it is preferable to carry out at about 0 to 150 ° C.
  • the reaction time depends on the type of raw materials and the conditions, but generally the reaction is completed in about 10 minutes to 20 hours.
  • compounds having an acidic group form salts with pharmacologically acceptable basic compounds.
  • a basic compound include metal hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, aluminum hydroxide, and the like. Examples include alkaline metal alcoholates such as sodium methylate and potassium methylate.
  • a compound having a basic group can form a salt with a pharmacologically acceptable acid.
  • the acid include inorganic acids such as sulfuric acid, nitric acid, hydrochloric acid, and hydrobromic acid.
  • the compound of the present invention thus obtained can be easily isolated and purified by a commonly used separation means.
  • separation means include precipitation, extraction, recrystallization, column chromatography, pre-native thin-layer chromatography, and the like. Can be illustrated.
  • the compounds of the present invention can be administered to animals and humans as they are or together with conventional pharmaceutical carriers.
  • the dosage unit form is not particularly limited and may be appropriately selected and used as needed. Examples of such dosage unit forms include tablets, capsules, oral preparations such as granules and oral solutions, and parenteral preparations such as injections.
  • the amount of the active ingredient to be administered is not particularly limited and may be appropriately selected from a wide range. However, in order to achieve the intended effect, it is necessary to take one day! ) Weight 1)]) 0.0 ⁇ 10 ⁇ It is good. Further, it is preferable that the active ingredient is contained in a dosage unit form of 150.sup.500 ⁇ .
  • Oral preparations are manufactured according to a conventional method. That is, tablets are formed by mixing the compound of the present invention with pharmaceutical excipients such as gelatin, starch, lactose, magnesium stearate, talc, and arabia. Is done.
  • the cascellulose is prepared by mixing the compound of the present invention with an inert filler or diluent, and filling the mixture into hard gelatin capsules, soft capsules and the like.
  • a syrup or an elixir may be used to convert the compound of the present invention into a sweetener such as sucrose, a preservative such as methyl- and propyl-no-rabene, a coloring agent, a seasoning, and the like.
  • a drug for parenteral administration is produced by dissolving the compound of the present invention in a sterilized liquid carrier.
  • Preferred carriers are water or saline. Solutions which provide the desired degree of clarity, stability and suitability for parenteral use have a solubility in water of about 1-500 active ingredients in water and organic solvents, and a molecular weight of about 200-500. Manufactured by dissolving in ethyl alcohol. Such liquids include sodium carbohydrate, xylene methylcell mouths, methylcell mouths, polypinylpyrrolidon, and polyvinyl alcohol. It is preferable to contain a lubricant such as polyester.
  • fungicides and fungicides such as phenol alcohol, phenol and thimerosal, and sucrose and chloride as required. It may contain isotonic agents such as sodium, local anesthetics, stabilizers, buffering agents and the like.
  • isotonic agents such as sodium, local anesthetics, stabilizers, buffering agents and the like.
  • the parenteral dosage form is sterilized after filling, and water can be removed by lyophilization techniques known in the art.
  • the lyophilized powder can be reconstituted just before use.
  • locarbostyril 4 1000 tablets for oral use containing locarbostyril were prepared according to the following formula.
  • Methyl cellulose (Japanese Pharmacopoeia) 1.5 Magnesium stearate (Japanese Pharmacopoeia) 1
  • encapsulating agent 10 ⁇ ⁇ ⁇ ⁇ ⁇ - ⁇ 4-C-(2-hydroxyethyl)--(2-tetrahydrovinylmethyl) Aminocapor] butoxy ⁇ -5.0,4-dihydrophenol 100-piece two-piece rigid gelatin for oral use
  • the capsule was prepared according to the following formula.
  • Japanese Pharmacopoeia product 8 0 5 Japanese talc (Japanese Pharmacopoeia) 5 Magnesium stearate (Japanese Pharmacopoeia) 1 Finely pulverize the above ingredients and mix well to obtain a uniform mixture.
  • OMPI I P Filled into gelatin capsule.
  • Preparation of agent 3 ⁇ 4_ ⁇ A sterilized aqueous solution suitable for parenteral administration was prepared according to the following formulation. Total weight ( ⁇ ) ⁇ - ⁇ 5-[ ⁇ -(2-hydroxyshethyl)
  • the blood sample collected from rabbits is a mixture of sodium citrate and whole blood, and the mixing ratio is 1: 9 (volume ratio). The sample at 1000 rpm
  • PRP C platelet rich plasma
  • the number of platelets contained in the PRP is determined by the Brettcher-Clonkite method, and PRP is diluted with PPP to obtain adenosine.
  • Diphosphate (ADP)-for use in induced aggregation tests is determined by the Brettcher-Clonkite method, and PRP is diluted with PPP to obtain adenosine.
  • OMPI Measured using the aggregometer at a rotational speed 1 1 0 0 r P m of the ADP or Te This test odor co la chromatography gain down solutions au Moltrasio emissions' base B Na over to prepare the Use a buffer solution (pH 7.35).
  • the above ADP solution was prepared to have a concentration of 7.5 X 1 CT 5 M, and the collagen solution was prepared by adding the above buffer solution 5 to 100 ⁇ collagen.]) Crush and use supernatant as collagen inducer.
  • the platelet aggregation inhibitory effect is measured as the inhibition ratio ⁇ with respect to the aggregation ratio of the control (the aggregation ratio is calculated according to the following equation.
  • Table 1 shows the inhibitory effect of PPP on the platelet aggregation of rabbits induced by permeability collagen
  • Table 2 shows the inhibitory effect of ADP on the platelet aggregation of rabbits.
  • the test compounds are as follows! ).
  • C-AMP-PDE cyclic adenosine monophosphophosphoesterase
  • the test was performed using Biocliimica et Biophysica Acta, Vol. 429, pp. 485-497 (1970), and Biochemical Medicine, Vol. 10: pp. 31-31 (1974). )). That First, the rabbit PRP to 3 0 0 0 rpm in 1 0 min centrifugation to give precipitate platelets, pH 7. 4 5 0 millimeter molar - Application Benefits scan 1 gC 2 HCl buffer The platelets were suspended by adding a solution containing 10 ml of Millimol, and the platelets were ground using a homogenizer with a Tefpotter-type homogenizer. Apply 100 ⁇ of ultrasonic waves for 300 seconds, and after centrifugation, centrifuge at 100 000 ° C for & 0 minutes, and use the supernatant as crude enzyme solution.
  • the crude enzyme solution prepared above was added to a 1.5 ⁇ 20 cm DEAE-cellulose column previously buffered with 50 millimol-tris acetate buffer ( ⁇ 6.0 :). After passing through 10 and eluting with 0 ⁇ 50 milliliter-tris-acetate buffer, elute with 0-"! Mol sodium acetate-tris-acetic acid in this buffer. Elute by applying linear gradient with buffer (total eluate volume is about 500.) Set the flow rate to 0.5 ⁇ min, and take 5 fractions for each fraction. Depending on the procedure, a low activity of less than 2 n mol / m Z can be obtained at a high C-AMP substrate concentration of 100 A mol and a minimum activity of 10 OP mol / min or less. Collect active fractions. This is C-AMP-PDE.
  • Triton-toluene-type scintillator 10 was produced in a liquid scintillation counter with a triton-toluene-type scintillator 10 in the entire amount of this eluate. PDE activity is measured by measuring tritium adenosine.
  • test compound was determined according to the method PDE activity value (V. :) and co emissions collected by filtration Lumpur value (V c) (test compound
  • O.VIPI WIFO Calculate the PDE inhibition rate () from the following formula.
  • the concentration ( ic5C) value of the test compound that inhibits was determined, and the results are shown in Table 3 below.
  • Table 5 also shows the results of similar tests performed using 1-methyl-3-isobutyricane stan- tane as a control compound.
  • the blood is killed, the heart is excised in the lock solution, and the arterial papillary muscle is excised along with the intercardiac septum. Separate the septum artery, insert a polystyrene wrench, and ligate with a thread. The septal artery other than the papillary artery is ligated with a thread. Next, anesthesia was previously performed with sodium salt of pentopalpitar (50 ⁇ / 9 intravenous administration).
  • Blood was collected from the carotid artery of adult dogs weighing 18-27 treated with phosphorus (1000 ⁇ 1, intravenously) via peristaltic pump; 7 ° It is led to a polystyrene manure inserted in the septal artery to perfuse the papillary muscles.
  • the perfusion pressure is a constant pressure of 100 mm Hg.
  • the papillary muscle movement is sewn to the septum interevoculum using an electron tube stimulator under a static tension of 2 mm, 2 X (minimum effective) 2 Hz, 2 ms duration through a bipolar electrode Electrical stimulation is performed under the conditions, and the generated tension is measured via a force displacement transducer.
  • Coronary artery blood flow measures the blood flow guided to the septal artery via an electromagnetic flowmeter. Record all data on the Ink Recorder.
  • the test compound enters the septal artery
  • the antihypertensive effect of the compound of the present invention was examined by measuring the non-invasive systolic blood pressure under the anesthesia by the tail force method (Tail Cuff).
  • D0CA Dental and hypertension rats
  • DHR salt hypertension rat
  • ⁇ was administered subcutaneously, and 1 saline was given as drinking water. After surgery, was used in the experiment is systolic blood pressure by 5 weeks 1 5 0 thigh H G or more of even the fasted overnight.
  • Drugs are administered orally and blood pressure is measured before and after drug administration
  • the heart rate was measured 0 minutes after administration, and the increase in heart rate was calculated. The results are shown in Table 8 below.
  • the heart rate of a normal male Wistar rat is about 320. ⁇
  • Boiling point 1 1 7-19 ° C / 1 72Mi Hg Reference example 5
  • Boiling point 150-155 C / 1 1 H G

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PCT/JP1980/000122 1980-02-29 1980-06-04 Carbostyryl derivatives WO1981002421A1 (en)

Priority Applications (6)

Application Number Priority Date Filing Date Title
AT0909480A AT381493B (de) 1980-02-29 1980-06-04 Verfahren zum herstellen von neuen carbostyrilderivaten und ihren salzen
DE803049959T DE3049959T1 (de) 1980-02-29 1980-06-04 Carbostyryl derivatives
AU59859/80A AU532319B2 (en) 1980-02-29 1980-06-04 Carbostyryl derivatives
NLAANVRAGE8020199,A NL185146C (nl) 1980-02-29 1980-06-04 Farmaceutisch preparaat met een remmende werking op een aggregatie van bloedplaatjes, alsmede carbostyrilderivaat, dat met een aminocarbonylalkoxygroep is gesubstitueerd.
DK250381A DK151956C (da) 1980-02-29 1981-06-09 Analogifremgangsmaade til fremstilling af carbostyrilderivater
NO81813477A NO160512C (no) 1980-02-29 1981-10-15 Analogifremgangsmaate for fremstilling av terapeutisk aktive karbostyrilderivater.

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP80/25658 1980-02-29
JP2565880A JPS56122356A (en) 1980-02-29 1980-02-29 Carbostyril derivative

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KR (2) KR860002099B1 (en, 2012)
AT (1) AT381493B (en, 2012)
AU (1) AU532319B2 (en, 2012)
BE (1) BE883713A (en, 2012)
CA (1) CA1159068A (en, 2012)
CH (1) CH647765A5 (en, 2012)
DE (1) DE3049959T1 (en, 2012)
DK (1) DK151956C (en, 2012)
ES (1) ES492230A0 (en, 2012)
FI (1) FI76321C (en, 2012)
FR (1) FR2477149A1 (en, 2012)
GB (1) GB2070588B (en, 2012)
IT (1) IT1129812B (en, 2012)
MX (1) MX6752E (en, 2012)
NL (1) NL185146C (en, 2012)
NO (1) NO160512C (en, 2012)
PH (1) PH18532A (en, 2012)
PT (1) PT71359B (en, 2012)
SE (1) SE461147B (en, 2012)
SU (2) SU1169535A3 (en, 2012)
WO (1) WO1981002421A1 (en, 2012)
ZA (1) ZA803322B (en, 2012)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7208497B2 (en) 2001-07-02 2007-04-24 Novo Nordisk A/S Substituted piperazines and diazepanes

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4578381A (en) * 1982-07-05 1986-03-25 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivatives
DE3434271A1 (de) * 1984-09-19 1986-03-20 Beiersdorf Ag, 2000 Hamburg Substituierte 3,4-dihydro-chinolin-2(1h)-one verfahren zu ihrer herstellung und ihre verwendung sowie diese verbindungen enthaltende zubereitungen
US5227381A (en) * 1988-05-02 1993-07-13 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative
JP2753622B2 (ja) * 1988-05-02 1998-05-20 大塚製薬株式会社 カルボスチリル誘導体
US5506239A (en) * 1991-08-23 1996-04-09 Otsuka Pharmaceutical Co., Ltd. Carbostyril derivative and platelets aggregation inhibitory agent
JP2686887B2 (ja) * 1992-08-11 1997-12-08 キッセイ薬品工業株式会社 ピペリジノ−３，４−ジヒドロカルボスチリル誘導体
DE10316081A1 (de) * 2003-04-08 2004-10-21 Morphochem AG Aktiengesellschaft für kombinatorische Chemie Neue Verbindungen mit antibakterieller Aktivität
CN102639512B (zh) 2009-08-21 2015-12-09 大塚制药株式会社 苯并[b][1,4]二氮杂*-2,4-二酮化合物的制备方法
TWI481601B (zh) * 2009-08-21 2015-04-21 Otsuka Pharma Co Ltd 含氮化合物及藥學組成物

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BE647697A (en, 2012) * 1963-05-10 1964-11-09
FR2179715A1 (en, 2012) * 1972-04-13 1973-11-23 Otsuka Pharma Co Ltd
DE2453113A1 (de) * 1973-11-10 1975-05-15 Otsuka Pharma Co Ltd 5-(hydroxy-3-tert.-butylamino)-propoxy-3,4-dihydro-2-hydroxychinolin enthaltende arzneipraeparate
JPS50151881A (en, 2012) * 1974-05-20 1975-12-06
DE2527937A1 (de) * 1974-06-24 1976-01-08 Otsuka Pharma Co Ltd Benzcycloamidderivate und verfahren zu ihrer herstellung sowie pharmazeutische mittel, worin sie enthalten sind
DE2615406A1 (de) * 1975-04-09 1976-10-14 Abbott Lab Beta-adrenergische rezeptoren-blocker
JPS5273879A (en) * 1975-12-18 1977-06-21 Otsuka Pharmaceut Co Ltd Synthesis of ester derivatives
JPS5310988B2 (en, 2012) * 1974-04-25 1978-04-18
DE2825048A1 (de) * 1977-06-10 1978-12-14 Otsuka Pharma Co Ltd Neue carbostyrilderivate und verfahren zu deren herstellung

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DE1527937A1 (de) * 1966-12-10 1969-11-13 Blanc & Co Verfahren zur Herstellung eines sich konisch verjuengenden,einen nach aussen abgewinkelten flachen Rand aufweisenden Hohlteils sowie Einrichtung zur Durchfuehrung des Verfahrens
US4313947A (en) 1974-06-24 1982-02-02 Otsuka Pharmaceutical Co., Ltd. Platelet aggregation inhibiting 2-oxyindoles, their compositions and method of use
JPS545981A (en) * 1977-06-10 1979-01-17 Otsuka Pharmaceut Co Ltd Carbostyryl derivatives

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Publication number Priority date Publication date Assignee Title
BE647697A (en, 2012) * 1963-05-10 1964-11-09
FR2179715A1 (en, 2012) * 1972-04-13 1973-11-23 Otsuka Pharma Co Ltd
DE2453113A1 (de) * 1973-11-10 1975-05-15 Otsuka Pharma Co Ltd 5-(hydroxy-3-tert.-butylamino)-propoxy-3,4-dihydro-2-hydroxychinolin enthaltende arzneipraeparate
JPS5310988B2 (en, 2012) * 1974-04-25 1978-04-18
JPS50151881A (en, 2012) * 1974-05-20 1975-12-06
DE2527937A1 (de) * 1974-06-24 1976-01-08 Otsuka Pharma Co Ltd Benzcycloamidderivate und verfahren zu ihrer herstellung sowie pharmazeutische mittel, worin sie enthalten sind
DE2615406A1 (de) * 1975-04-09 1976-10-14 Abbott Lab Beta-adrenergische rezeptoren-blocker
JPS5273879A (en) * 1975-12-18 1977-06-21 Otsuka Pharmaceut Co Ltd Synthesis of ester derivatives
DE2825048A1 (de) * 1977-06-10 1978-12-14 Otsuka Pharma Co Ltd Neue carbostyrilderivate und verfahren zu deren herstellung

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7208497B2 (en) 2001-07-02 2007-04-24 Novo Nordisk A/S Substituted piperazines and diazepanes

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KR830002713A (ko) 1983-05-30
IT1129812B (it) 1986-06-11
NL185146C (nl) 1990-02-01
SE8102690L (sv) 1981-08-30
SU1395140A3 (ru) 1988-05-07
MX6752E (es) 1986-06-25
ZA803322B (en) 1982-01-27
FI801843A7 (fi) 1981-08-30
US4435404A (en) 1984-03-06
ES8105290A1 (es) 1981-05-16
AT381493B (de) 1986-10-27
AU532319B2 (en) 1983-09-22
NL8020199A (nl) 1981-12-01
FR2477149A1 (fr) 1981-09-04
GB2070588B (en) 1983-10-19
DK151956B (da) 1988-01-18
PT71359B (en) 1981-10-21
FI76321B (fi) 1988-06-30
DK250381A (da) 1981-09-03
AU5985980A (en) 1981-09-11
SE461147B (sv) 1990-01-15
JPS56122356A (en) 1981-09-25
ES492230A0 (es) 1981-05-16
CA1159068A (en) 1983-12-20
DE3049959T1 (de) 1982-07-29
ATA909480A (de) 1986-03-15
FI76321C (fi) 1988-10-10
FR2477149B1 (en, 2012) 1983-06-24
NO160512B (no) 1989-01-16
NO813477L (no) 1981-10-15
DE3049959C2 (en, 2012) 1993-07-08
KR860002100B1 (ko) 1986-11-25
SU1169535A3 (ru) 1985-07-23
IT8067888A0 (it) 1980-06-06
NO160512C (no) 1989-04-26
NL185146B (nl) 1989-09-01
JPS6334845B2 (en, 2012) 1988-07-12
GB2070588A (en) 1981-09-09
PT71359A (en) 1980-07-01
CH647765A5 (de) 1985-02-15
KR860002099B1 (ko) 1986-11-25
DK151956C (da) 1988-08-15
KR840004681A (ko) 1984-10-22
BE883713A (fr) 1980-12-09
PH18532A (en) 1985-08-09

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