Classifications

• • 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
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• • 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
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof
• • 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
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof
  • C07D215/28—Alcohols; Ethers thereof with halogen atoms or nitro radicals in positions 5, 6 or 7
• • 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
  • C07D215/24—Oxygen atoms attached in position 8
  • C07D215/26—Alcohols; Ethers thereof
  • C07D215/32—Esters
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
  • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
  • C07D471/04—Ortho-condensed systems

Definitions

• the present invention relates to a carbostyril compound to be used as a cardiotonic agent and a salt which can be used as a cardiotonic agent, and a veterinary medicine containing the carbostyril compound or a type a thereof. Is what you do.
• EP-A1 -7525 and EP-A1 -8014 describe an isoquinoline compound that exerts a ⁇ cardiac action and a circulatory action ⁇ .
• carbosty-lilui-dani compound of the present invention is a new compound having a different structure from the conventional force-based compounds.
• One aim of the present invention is to introduce carbostyril compounds which exert a cardiotonic effect.
• Another purpose of the present invention is to carry out anti-theft with a cardiotonically effective amount of a carbostyril compound.
• the present invention provides a calbostyryl compound represented by the following formula (I) or a pharmaceutically acceptable:
• R 1 represents a hydrogen atom, a low alkyl group, a phenyl low alkyl group, a low alkenyl S or i-alkyl group, and a hydrogen atom or a dialkyl group, a low alkyl group, a halogen atom.
• H 3 is a hydrogen atom, a hydrogen atom, a halogen atom, a nitroso group, * a hydrogen atom which may form a lower alkyl S as a substituent, A low-alkylamino group, an N, iN'-dialkylalkylamino group, a carpamoylmeter, a sinomethyl group, or a carboxymethyl group are respectively shown.
• R and R 5 each represent a hydrogen atom, a halogen atom, a ⁇ alkyl group, a hydroxyl group, a low alkoxy S or a nitro group.
• the interposition between the third and fourth carbon atoms in the carbosteryl bone indicates a single or double bond.
• R 2 is a hydrogen atom, ⁇ ⁇ alkyl Le S The C b Gen atoms and a and La no 3]
• the present invention provides a compound containing a compound J of the formula (I) or a salt acceptable in the production thereof as a cardiotonically effective amount.
• the compound 3 of the present invention exerts an effect of increasing the yield of the heart muscle (positive inotropic action) and is useful as a cardiotonic agent, and is a recommended compound for treating congestive heart failure and the like as a recommendation. It is in the point that the action of the heartbeat is very weak, and that the coronary blood flow * is too low.
• the various bases are as follows.
• Examples of the low-effect alkyl include alkyl groups of carbon 1 to carbon such as methyl, ethyl, propyl. Isopropyl, butyl, ⁇ -butyl, pentyl, and hexyl. Benzyl, 2-phenylethyl, 1-phenyl-tyl, 3-phenylethyl, 4-phenylphenyl, 1,1-dimethyl-2 as low-alkyl Number of carbon atoms in the alkyl moiety of 1-phenylnityl, 5-phenylpentyl, -phenylhexyl, 2-methylphenylpropyl, etc. and a phenylalkyl group of (1).
• Low alkyl groups include vinyl, aryl, crotyl, 1-methylaryl, 3-butenyl, 2-5-pentyl, 3-pentenyl, and 4-pentenyl.
• Low alkyl - E is the Le Ji - le, 2 - pro peak - le, 1 - pro arsenide 0 sulfonyl, 2 - Buchini le, 3 - butenyl, 2 _ Pen Ji two Le, 3 - Pen Chi sulfonyl , 4 — MINCHUL-2-METHYL-3-BUTINYL, 1-METHEL-3-BUTIN-
• alkynyl having 2 to ⁇ carbon atoms such as a pentyl group.
• Amino, methylamino, ethylamino, probilumina, isoprovirino, isobutylamino may be an amino which may have an alkyl group as a lightning group.
• amino S that may be issued one or two times.
• ⁇ -di, alkylaminomethyl groups include ⁇ , ⁇ -dimethylaminomethyl, ⁇ ,-- ⁇ -dimethylaminomethyl, ⁇ , ⁇ -dimethylaminomethyl, No methyl, ⁇ -
• ⁇ , ⁇ -dialkylaminomethyl groups can be exemplified.
• the low alkanoyl groups include formamide, thioacetamide *, probiolamino, butyrilamino.
• alkanoylamino groups having 1 to ⁇ carbon atoms such as Rminomino, isonorelylamino, and hexanoylminino.
• Low-alkoxy groups include methoxy, ethoxy, proxy, isopro; carbons such as itoxy, butoxy, ieri-butoxy, penteloxy, and hexyloxy. ⁇ ⁇ 1- ⁇ ⁇ Alkoxy can be shown.
• the compound of the present invention is produced by various methods S, and a preferred example thereof is produced according to the following reaction formula-1.
• R 1 R 2 , R .R 5 and the carbon-carbon bond at the 3- and 4-positions of the rubostyryl skeleton are the same as those described in 10 above.
• X 1 represents a halogen atom.
• R 6 represents a hydrogen atom or a lower alkyl group. :!
• the reaction between the compound represented by the formula (H) and the compound represented by the known formula (OB) is carried out in a solvent or in a suitable solvent, preferably in a solution.
• a solvent or in a suitable solvent preferably in a solution.
• Any type of solution that can be used can be used as long as it does not have an effect on the anti-reflection method.
• k low alcohols such as methanol, ethanol, isopropanol and butanol
• aromatic hydrogen peroxides such as benzene, toluene and xylene
• Ethers such as oxane, tetrahydrofuran, etc., tritonitrile, and tritriles such as sigma-nitrile, dimethyl sulfoxide, etc.
• Examples include dimethyl formamide, hexamethyllin g triamide, and the like.
• the ratio of the compound of formula ( ⁇ ) to the compound of formula 033 is uncertain. However, the latter is usually at least about equimolar to the former, preferably! > 3 times better to 5
• the anti- ⁇ can be carried out by adding a usual basic compound as a dehydrogenating agent.
• the new basic compound # 1 is, for example, a carbon-metal compound such as charcoal S-Na-Vamu, charcoal-rich lithium, carbon S-hydrogen-Na'-Vamu, or a heavy carbon-metal compound.
• reaction is usually carried out at about room temperature to about 150, preferably at about 50 to 100, and the reaction is completed in about 1 to about 100 hours.
• the compound ⁇ (la) and the compound ⁇ ⁇ (la), in which the carbon-carbon bond at the 3-position and the 4-carbon of the carbostyril skeleton show a single polymerization can be converted into each other by the reduction reaction and the ⁇ 3 ⁇ 4hydrogen reaction.
• OMPI IPO [Wherein II 1 , R 2 , R 3 , R 4 and are the same as above.
• the dehydrogenation of the compound of formula 'U a) is carried out by using a suitable hydrogenating agent.
• a suitable hydrogenating agent for example, 2.3-dichloro-5,5-dicyanobenzoquinone, chloranil (2,3,5, ⁇ -tetrachlorodiethyl)
• Benzoquinone such as benzoquinone, bromoxacin, -chlorosuccinimide, halogenating agents such as bromine, thiocyanine, dihysterene, etc.
• I cormorant Rusetsu water iodinating agent e which may be mentioned parametric di U beam one-carbon, parametric di U beam black, platinum black, said chemical para Ji arm, hydrogen metal ⁇ such la conservation over nickel
• the amount of the agent used is not limited to ⁇ , but may be adjusted from the range that is not appropriate. However, it is usually better to use 1 to 5 times, preferably 1 to 2 times, the molar amount of the compound of formula (ia).
• the amount of the catalyst should be about the usual amount of the S medium, for example, the same weight as the compound of formula Cla). Is good.
• the solvent examples include ketones such as acetone, ethers such as dixane, tetrahydrofuran G franc, methoxyethanol, and dimethoxyxetane.
• ketones such as acetone
• ethers such as dixane, tetrahydrofuran G franc, methoxyethanol, and dimethoxyxetane.
• Aromatic hydrocarbons such as benzene, toluene, xylene, phenetole, tetralin, cumene, chlorbenzene, dikolome Tan, dichloroethane, black mouth, tetrahedral carbon, etc., hydrogen, hydrogen, methanol, ethanol, isopropa
• Alcohol veg, water, and polar proton solvents such as ethanol, nicotine, iitri-butanol, iitri-butanol, hexanol, etc.
• Polar non-peptone solvent such as dimethylformamide, dimethylsulfoxide, hexamethyllin triamide, etc. can be indicated.
• the reaction is usually carried out at room temperature to s 00, preferably at room temperature to 200
• the reaction is completed in about 1 to 40 ⁇ .
• the reduction reaction of the compound of the formula (I &) can be widely applied to the ordinary connection.
• Examples of the t element 3 ⁇ 4 ⁇ include palladium, palladium monoki, palladium monocarbon, platinum oxide, platinum, platinum black, and rac-nickel. 'You can use these as usual.
• the reaction is carried out under normal pressure, and its S pressure is preferably S ⁇ 10 s? Z ai, preferably normal pressure ⁇ 53 ⁇ 4 ⁇ .
• the reaction is usually 0 ⁇ 1 G 0 ° C, ⁇ Ma properly is preferably set to at coloration temperature ⁇ 7 0 c
• R represents a low alkyl g, a low water kill ⁇ , a low alcohol S or an alkynyl.
• X 2 represents a hagen atom; H 2 , R 3 , R 4 , and R; The carbon bond between position 3 and 40: of the rubostyryl skeleton is the same as described above. ] '
• R 1 represents a hydrogen atom
• the corresponding R 1 can be derived into a compound having a low alkyl, a low alkyl, a low alkyl S or a compound showing a low alkynyl group.
• a compound represented by the formula (ic) is converted to, for example, sodium hydride, lithium hydride, sodium lime, calcium oxide, metal sodium, metal
• a basic compound such as an alkali metal such as a lithium metal
• the m-position of the 1st atom of the calbostyril skeleton is led to the aluminum metal.
• a suitable solvent for the reaction for example, omme such as benzene, toluene, xylene, etc.
• Non-peptic contact solvents such as ether-based solvents such as hexane and dimethyl ether, hexane methyl lintriamide, dimethyl sulfonamide, and dimethyl sulfoxide It is preferably carried out in a non- ⁇ -based solvent such as S. Anti; ⁇ temperature is
• the reaction is carried out at 0 to 200, preferably at presentation to 50.
• the thus obtained alkali metal salt of the compound (7 CIc) is usually reacted with a halogen compound represented by the formula (W) for about 25 to 1 hour.
• W halogen compound represented by the formula (W)
• W halogen compound represented by the formula (W)
• W halogen compound represented by the formula (W)
• W halogen compound represented by the formula (W) for about 25 to 1 hour.
• W halogen compound represented by the formula (W) for about 25 to 1 hour.
• the stool dose is usually "! To 5 times mol, preferably about 1 to 5 times mol, and the halogenated compound is about 1 to 5 times mol, preferably about 1 to 5 times mol. Is completed in about 0.5 to 15 hours.
• the compound (III) used as a starting compound in the formula (11) can be easily produced according to various methods.
• the compound J can be prepared by the following reaction It can be manufactured according to the processes shown in process formulas 1, 4, 5, -0 and 17.
• RR 6 , X 1 and the carbon-carbon bond at the 3- and 4-positions of the carbostyril skeleton are the same as described above.
• X 3 represents a halogen atom.
• R 7 represents a hydrogen atom or low-alkyl S.
• the reaction between the complete calbostyryl derivative in Reaction Formula 14 and the haegeno alkanoyl halide derivative ⁇ in Formula (V) is , Which is usually located below ⁇ s of Louis V. ⁇ Known Louis V is used, such as aluminum chloride, iron chloride, iron ⁇ , Cheating
• the reaction is ⁇ even soluble, or two ⁇ carbon, salt Ihime Ji les emissions, 1, 2 - di-click B 13 E motor down, click throat base down peptidase down, two collected by filtration base down peptidase down, et ether, ⁇ ⁇ Can be performed in any suitable inert solvent.
• the reaction is usually carried out in a room of about 7 :! to about 150 u, preferably at room temperature to about 100 u.
• Use of compound 3 ⁇ 4 / ( ⁇ for compound 3 ⁇ 4nv) ⁇ 3 ⁇ 4 ⁇ Compound is usually equimolar to large excess, preferably 2 to 0.5 times molar amount.
• the reaction temperature is usually under ice-cooling to the reaction solvent at a point, preferably 3 ⁇ 4 ⁇ ! The reaction proceeds easily at this temperature.
• the anti-time is usually about 1 to 10 hours S.
• a radical reaction initiator such as benzoyl oxide, hydrogen peroxide, etc. for the reaction.
• Rogens [Wherein R s is a lower target Al Ka Bruno I le, denotes a low Al kill group. : ⁇ 1 , ⁇ 3 , ⁇ 7 , ⁇ : 1 and the carbon-carbon bond at positions 312 and 4 of the carbostiryl skeleton are the same as in the above-mentioned Co] formula (0). Leaching or pyridin—in a solvent such as benzene, nitrobenzen, gel, toluene, dioxane, sodium carbonate, or carbon power! J-rooms and more! J Metal charcoal salt, triethyl
• the reaction can be carried out by deoxidizing the low-alkali carboxylic acid s water or its acid halide.
• the amount of low-end carbonyl carbonate or water or its acid halide is preferably about equimolar to excess molar, preferably about equimolar to the compound of formula (). It is preferable to use a molar amount of 10 to 10 times.
• the silylation reaction can be carried out under cooling, at room temperature, or under heating, but is usually about 10 to 15 O, preferably! ] ⁇ 100 ⁇ , and the reaction is completed in about 10 minutes ⁇ 10 hours.
• the reaction may be carried out with a nitrifying agent such as an acid.
• the amount of the nitrating agent to be used is based on the formula (1); i It is preferable to use a molar amount of from 1 to 15 times (the reaction is usually about 10 to 50 S It is performed in 1 to "! 0 hours.
• the water content of the compound of the killing formula 00 can be obtained by adding an acid or alkali under a suitable solvent such as water or methanol, ethanol, ethanol, isopronoyl, or acid.
• a suitable solvent such as water or methanol, ethanol, ethanol, isopronoyl, or acid.
• Salts, sulfuric acid, etc., and alkalis such as sodium hydroxide, sodium oxide, calcium carbonate, sodium charcoal, sodium hydrogen carbonate, etc. Examples include um.
• the new 3 ⁇ 4 or alkali is preferably used in an amount of at least equimolar, usually a large excess, based on the compound of the formula (1).
• the reaction temperature is usually from room temperature to about 10 CTC.
• the reaction is completed in about 5 to 5 hours for one is:
• the alkylation reaction of the compound (7) of the formula (7); 5 is usually carried out by reacting with a known alkylating agent in the presence of a basic compound.
• the basic compound J used at this time includes, for example, alkaline metals such as gold and sodium, metal hydroxides, hydroxides of these alkaline metals, carbonates, and the like. Examples thereof include heavy coal or aromatic carbonyl compounds such as pyrrolidine and pyridine.
• alkylating agents examples include halogenated alkyls such as alkyl iodide, alkyl chlorides, and alcohols such as dithiol, and dialkyls such as dimethyl alcohol and getyl ⁇ .
• the reaction was aggressive in a short time, and the solvents used were methanol, ethanol, isopropanol, -butanol, and the like.
• ketones such as methyl and ketone ketones.
• the amount of the alkylating agent to be used is usually from equimolar to excess, but is preferably from equimolar to 2 times the molar amount of the compound of a single system. It is easy to follow with the temperature of 3 ⁇ 4g, which is ⁇ dotted ⁇ of ⁇ ⁇ , but at first, it can be ripe at 00.
• ⁇ ⁇ ⁇ ⁇ 'reaction is water, In the presence of palladium, para-radiocarbon, platinum oxide, platinum black, Raney nickel, etc., such as methanol, ethanol, ether, dioxane, etc. Through! Always; under pressure or normal, youthful, youthful ⁇ , ⁇ ⁇ ⁇ ⁇ ⁇ and others (eg, ringing, ⁇ , ⁇ , lin, 3 ⁇ 4, etc.), ⁇ , m-.
• Alkali forces include, for example, Alkali metal hydride, Alkali ⁇ .? 3 ⁇ 4MONMONI, etc.) Sulfide ⁇ , Nthionite g sodium, To Due to sulfuric acid etc.]?
• This reaction is usually carried out using 3 ⁇ 4 ⁇ 3 ⁇ 4 soda and ⁇ 5 copper in the presence of a buffer such as vinegar soda, charcoal soda, charcoal calcium, etc. It is better to perform at 0 to 40 degrees at a time, but contrary to the setting; S is completed in about 1 to 5 hours.
• a buffer such as vinegar soda, charcoal soda, charcoal calcium, etc.
• Completion of the formula (XV) ⁇ 7 can be performed by, for example, halogen molecules such as bromine and chlorine, or N-bromosuccinimide, and N-bromine such as M-chloramine. -It can be used for halogenation such as chromium ⁇ imide. Compound of formula (XV) 3 ⁇ 4J and C. It is desirable that the ratio of the gen molecule or the halogenating agent is usually 1 to 10 times, preferably 1 to 5 times the amount of the former.
• the solvent used in the reaction is a halogenated alkyl solution such as dichloromethane, dichloroethane, and cycloform-carbon tetrachloride.
• the reaction of the reaction S is usually under ice-cooling to the reaction solvent at a temperature of, preferably, about 40 ° C. The reaction proceeds easily at this g degree. Reaction time Words 1 to 10 hours.
• the reaction time Words 1 to 10 hours.
• the compound of formula UD which represents R 2 or a hydrogen atom, a low alkyl S or halogen atom, can be prepared according to the following reaction formula.
• R 10 a hydrogen atom, exhibit low ⁇ alkyl or C 13 Gen atoms.
• X 4 is a ⁇ -gen atom, a hydroxyl group or a group
• a halogen atom in the compound of the formula (1), a halogen atom, a nitroso group, an amino group, a low-alkyl group, an amino group, a low-alkyl group, a low-alkyl group
• the compound represented by the above reaction formula represents a lucanoyl-amino, N, N-di (g-alkylaminomethyl, carbamoylmethyl, sinomethyl, or carboxymethyl group).
• -1 can be set Among the compounds of the formula (IA), the compound represented by the formula J (Ie) in which H S represents a hydrogen atom can be produced by the method S shown in the following reaction schemes 17 to 11 below.
• the compound of formula (I) can be converted into a compound of formula (Is) in the presence of a ⁇ -genating agent in an ordinary inactive medium. It is manufactured by this.
• a ⁇ -genating agent used in such a reaction, known ones can be widely used, and examples thereof include halogen molecules such as nitrogen, element, iodine, and iodine, oxythirine, Examples of these compounds include phosphorus quinine, phosphorus pentachloride, phosphorus pentabromide, phosphorus trisulphate, titanium chloride, and the like. In the case of convenience, it is not defined as ⁇ and is widely changed from S.
• the halogenation reaction is usually carried out under ice cooling or about 0 to 100: preferably in a room ⁇ to 50, and the reaction time is usually about 1 to 12 hours.
• the compound (J CIg) in which R 3 represents - ⁇ - ⁇ -sodium can be obtained by converting the compound of formula (Ie) of the killing formula (Ie) into a two-port type.
• the reaction is carried out with a ⁇ solvent or ::! It can be performed in the appropriate inert solution.
• Any conventionally known tocosolic agent can be used, including sodium,
• 3 ⁇ 43 ⁇ 4S such as M glass.
• the proportion of the nitrating agent used is preferably from 1 g to 2 moles per mole of the compound (ie), preferably from 1 mole to 12 moles per mole of the compound (ie). It is performed in the presence of the anti- ⁇ and 3 ⁇ 4.
• known materials such as salt 3 ⁇ 4, ⁇ , ⁇ , acid, propylamine, butylin bag, isobutylin 3 ⁇ 4 etc. can be widely used. Mines are preferred.
• the excess amount of the compound of (Ie) is usually in excess, and the reaction in the solvent should be carried out in a solvent.
• the solvent used may be a normal inert solvent, such as water, if it is water, a low fat such as propion, butyrine, isobutylin, etc. Water vinegar m,,. Ethers such as on-drum, ⁇ water petitin, ⁇ water isobutyline ⁇ etc.-defatting _ protection ⁇ water 3 ⁇ 4, jixin xan, tetrahydrofuran etc. And dimethylformamide, dimethylsulfoxide and the like.
• the reaction is usually carried out at a temperature of 50 to 1 G0, preferably at a temperature of 0 to 50'C, and is usually carried out at S for about 30 minutes to 3 hours.
• the compound (Is) deduced from the formula (Is) can induce a compound (Ii) in which one of the compounds of the formula (I) shows aminos.
• the reaction may be carried out using a known reducing agent S.
• the reducing agent may be, for example, a mixture of iron and sulfuric acid, lead and ⁇ ⁇ , or a mixture of primary chloride and salt ⁇ . Is preferred.
• the amount of the reducing agent is preferably equimolar to a large excess with respect to the compound (Is), but preferably 5 to 5 times the molar amount.
• the reaction can be carried out by using a reaction-strength hydrogenation, for example, palladium black, palladium carbon, Raney-nickel, or platinum nitrate.
• the reaction proceeds in a solvent.
• the solvent include water, low alcohols such as methanol, ethanol, and isopropanol, and 1- ⁇ .
• the reaction condition is not limited at all. The distance may be set as appropriate depending on the type and amount of the S base or the hydrogenating agent.
• a reducing agent At 0 to 15 CTC (preferably 50 to 10 CTC), and when hydrogenation is used, the reaction is performed under hydrogen pressure and normal pressure at 0 to 100 S (preferably at 7) . Okay ⁇
• R 2 is hydrogen Kaeko or Represents a methyl group.
• the compound ⁇ in the kill formula (I) is changed to a compound ⁇ (I j) indicating a low alkanoylamino. ! You can do it.
• the usual conditions for acylation anti- ⁇ can be widely applied. For example, low-alkane carbon or its ⁇ ⁇ water ⁇ j or its 3 ⁇ 4Haguchi Genich 3 ⁇ 4J
• the anti- ⁇ is usually carried out in the presence of an S column compound or an acid S compound.
• an S column compound or an acid S compound for example, triethylamine, trimethylamine, pyridine, etc. Dimeter Rinrin, methyl morpholine, 1,5-Di-Zabicyclo [4.3,0] Nonene-5 (D ⁇ ⁇ ), 1.5-Di-Zabicyclo [5, 4, ND-5 (DBU) 1, 4-Zybicyclo [ ⁇ 2] octane (DA BG 0) which is suitable for charcoal, charcoal, charcoal, sodium, charcoal Bases such as acid-water cumulative calcium and hydrocarbon-hydrogen sodium can be mentioned. Also, as the compound, for example, Ryutsu, salt, etc. can be discussed.
• the reaction is carried out in a solvent or a solvent, for example, a solvent such as Shii-Dori-Methylene, K-form, or Cyclo-
• solvents include tonogenic solvents.
• the amount of the low-alkane carboxylic acid or its water or its halogenated compound used in the reaction is particularly suitably selected, but is usually equimolar to that of the compound (7 CM). A 10-fold molar amount (preferably equimolar to 2-fold molar amount) may be used. Also react
• OWM OWM
• the time is not particularly limited, it is usually carried out in about 30 to 150 hours (preferably 0 to 100 minutes) in about 30 minutes to 12 hours.
• a compound in which R 1 "represents a hydrogen atom, and-are produced by converting the compound of the formula () into S a compound in which R 1 "represents a hydrogen atom, and-are produced by converting the compound of the formula () into S.
• the conditions for reducing the carbonyl of a metal bond to methylene can be applied, for example, lithium aluminum hydride, sodium hydrogen hydride, or the like.
• R u is compound showing a and R 12 turtles chill 3 ⁇ 4 represents a hydrogen atom ⁇
• one killing formula (Ik) is produced by the combination of a compound 3 ⁇ 4 reducing child of over ⁇ (Ii). This reduction can be used for Etspiler's Clark reaction; This reaction is easily carried out by adding formic acid and formalin to the compound of the formula (Ii) usually in a solvent and heating.
• the proportion of girth and formalin used is not determined by the spine, but is appropriate: usually, it is usually about 5 to 5 times, more preferably about 5 times, for example, about formalin relative to compound (Ii).
• reaction temperature and the reaction time are not fixed to a coil and can be returned from a wide range, but are usually from room temperature to 150 ° C, preferably from 80 ° to 12 ° t: 3 hours to 30 ° C. It takes about ⁇ hours.
• the compound () in which R 3 is N, N-dialkylamino is the compound (J) which can be referred to as ID.
• the anti- ⁇ , halogen The reaction is carried out in the presence of a hydrogenating agent.3 ⁇ 4 ⁇
• -It can remove salt such as dimethyl chloride.
• the reaction can be carried out either in the presence of the anti- ⁇ solvent or in the presence of a solution.
• Any solvent that can be used as a solvent in the reaction can be conveniently used, for example, methanol, ethanol, phenol, alcohol, and getyl.
• Ethers such as ethers, tetrahydrofuran, dioxane, ethyl glycol monomethyl ether, etc., and benzyl alcohol
• Aromatic hydrocarbons such as len and chlorbenzen ⁇ , ketones such as acetone and methylethylketone, ⁇ , ⁇ -dimethylformamide, dimethylsulfoxide, and hexane
• Non-proton-based solvents such as methyl triamine are used for convenience.
• the stool ratio of the compound (e) to the compound (XX) is usually at least about 2 moles, preferably 2 to 4 moles per mole of the former.
• the compound (XX) is used in an equimolar amount with respect to this working ratio compound (li), whereby the amino having one low alkyl group as one of the compounds of the formula (I) is obtained. And the compound thus obtained is represented by the formula: H 1 X 2 (where R represents 3 ⁇ 4alkyl S and X 2 is the same as defined above).
• R represents 3 ⁇ 4alkyl S and X 2 is the same as defined above.
• R 3 represents a hydrogen atom among the compounds of the formula ⁇ U), and the compound Ue) has a dialkyl group and a formalin.
• R 3 can be a compound (im) in which R 3 represents a ⁇ , ⁇ -di-low alkylaminomethyl group.
• the reaction is carried out in a solvent or solvent, and the solvent which is not involved in the reaction can be widely used, for example, water, methanol, ethanol, or iso- Examples thereof include low alcohols such as propanol, and low fats such as acid and Provion II.
• the compound (CXII) and the formalin are usually used in an amount of about 1 to 3 moles per mole of the compound (le), preferably ⁇ . : Equimolar amount is recommended.
• the reaction is usually carried out at a temperature of about 0 to 150, preferably at a temperature of about 100 ° C to about 100 ° C, and the reaction is terminated at the time of the reaction.
• O PI WIPO Examples include halogenated hydrocarbons such as ⁇ -form and 23-carbon, acetonitril, propiotolyl, dimethylformamide and the like.
• Compound ⁇ ( ⁇ ) is harmful to compound 11 (convenient to compound ⁇ : ⁇ ⁇ ), but the latter 3 ⁇ 4: equimolar to very tight, preferably, equimolar to about 2 times Good to be.
• 3 ⁇ 4Reaction usually 0 ⁇ 150 ⁇ 0, preferably ⁇ , about 30 ⁇ 803 ⁇ 4, completes in about 30 minutes ⁇ 4 hours.
• the compound (XXffi) is converted to ⁇ by the compound ( ⁇ )
• the compound ( ⁇ ) is replaced by the compound ( ⁇ ffi)
• the compound of formula (I) '' J is a compound in which Calpamoyle methyl is 3 ⁇ 4CIo
• the compound ( ⁇ ⁇ UP) can be obtained.
• the anti-5 is carried out in an inactive manner to the anti- ⁇ .
• the solvent is water, for example. Low-end alcohols such as methanol, ethanol, and isopropanol, and two-triles such as o-set-triles and -7 ⁇ -bi-nitrile are listed.
• the compound represented by the formula ( ⁇ ) preferably includes, for example, preferably cyanyanium and sodium cyanide, etc.
• compound (XXI) is usually used in an equimolar amount to a large excess amount, preferably 3 to 4 times with respect to compound (la).
• the reaction is usually carried out at a temperature of about 150 to about 150, preferably at about 0 to 100, and is usually performed for about 3 to 12 hours, preferably about 5 to about 1 hour.
• the compound (ca) is usually used in an equimolar amount to 2 times, preferably about an equimolar amount to the compound ⁇ ( ⁇ ), and the room temperature is from 150 to 150, preferably from 0 to 1 oo: At 30 minutes
• R 3 represents carboxymethyl g ⁇ (Iq) is a compound ⁇ ( ⁇ ) or a compound (I?) Obtained by the above reaction; ? JD moisture can be ferocious. All of the reactions involve the use of a solvent or water, methanol, ethanol, impronominol, acid, or the like: The reaction is carried out in the solvent or by the action of an alcohol. Acids such as drums and acids, and alkalis such as sodium hydroxide, calcium hydroxide, gum, calcium carbonate, and sodium carbonate. Lime etc. can be illustrated.
• the temperature should be about 50 to 150, usually about 50 to "! 0 0 ⁇ , and the setting should be about 5 to 10 hours. I do.
• the carbostyril derivative ⁇ ⁇ represented by the formula (I) can be easily converted into an addition salt by applying a medically acceptable drum.
• OMPI For example, ⁇ 3 ⁇ 4 such as salt, phosphorus, beautified hydrogen, etc.
• Examples include oxalic acid, maleine, fumaric, lingo, limestone, corn, benzoic acid, and the like.
• sodium hydroxide, hydrated calcium hydroxide, and calcium hydroxide can be given.
• the compound exists as a compound optically active substance of the formula (I), and includes the present optically active substance.
• the agents are commonly referred to as base agents, dispersing agents, mixing agents, humectants, disintegrants, surfactants, lubricants, and any diluent or excipient.
• Various forms can be selected as the medical agent according to the purpose of treatment, and typical examples are suspicious agents, pills, powders, solutions, suspensions, emulsions, granules, and the like. Capsules, suppositories, injections (solutions, suspensions, etc.).
• those conventionally known in the art can be widely used as a carrier, such as milk, whitening, sodium fumigated sodium, buoy, and urea.
• Starch charcoal, calcium, kaolin, crystal cell, water, potassium, water, ethanol, propanol, syrup,, sugar Liquid, starch liquid, gelatin solution, carboxymethylcellulose, .cellac, methylcellulose, linker calcium, polyvinyl chloride binder, dry starch, etc.
• Alginate sodium, powdered can, powdered lamina, powdered sodium carbon, calcium carbonate, o: lioxyethylen rubitan fatty acid esters, rawry Sodium sulfate, stearin monoglyceride, starch, milk Disintegrants, whitening, stearin, dexterity, hydrogenated oils, etc., disintegration inhibitors, ⁇ -monium base, rauryl sulfate sodium, etc. Glycerin, starch, and other deepening agents, starch, milk, kaolin, bentonite, colloid ⁇ g g. Phosphoric acid, honey powder, ethylene glycol recall
• the suspect agent may be a normal agent as required, such as garments, gelatin capsules, liquor, film coating, double suspicion, or multi-layer suspicion. be able to.
• 3 ⁇ 4 ⁇ can be widely used in the field known in the art, such as bu, 3 ⁇ 4 ⁇ , starch, cacao, hardening, kaolin, talc
• any of the well-known 3 ⁇ 4 ⁇ can be used widely, for example, ⁇ ⁇ Lynch Ling Recall, cacao lunar, high alcohol, high alcohol
• the liquid and ⁇ agents can be used for blood injection and hemorrhage. It is preferable that these solutions, emulsions, and abrasives be used in the form of a powder when used in this field.
• water, ethyl alcohol, propylene glycol, ethanol alcohol, alcohol alcohol, alcohol alcohol, vitamin alcohol examples thereof include fatty acid esters.
• butto's ⁇ 1 or glycerin is included in the anti- 3 ⁇ 4 3 ⁇ 4 ⁇ ! You can do it,
• the amount of the compound of the present invention to be contained in the cardiotonic agent of the present invention is not limited to a specific amount, but is generally in the range of S, but is usually 1 to 70% by weight of the total composition, preferably 5%. ⁇ 50% by weight
• the method of administering the cardiotonic agent of the present invention is particularly limited, and is given by various preparation methods, the age of the patient, the method of enrollment of the patient, the degree of disease, etc.
• preparations pills, solutions, preparations, emulsions, granules and capsules
• injectables they are administered alone or mixed with normal replacement fluids such as boiled and mint, and given as a static solution. Supposedly or inwardly.
• suppositories they are administered directly.
• the administration of the cardiotonic agent of the present invention is appropriately selected according to the age, gender and other conditions of the patient, the degree of the disease, etc., but the amount of the present invention is usually 1 equivalent per day. ] 71 to 10 is good. In addition, the active ingredient in “Yufu” 51 condition is 5 C! ⁇ 250 is recommended.
• ⁇ -Acetyl-8.-Methoxy-3,4-Dihydroxy bostyril 3.1 ⁇ is dissolved in cromal form S 0, and bromine 6 and cromal ⁇ -form 20 are produced at a temperature of room temperature. Gradually lower the solution. 30 minutes at g for 30 minutes. The reaction solution was reduced, and the remaining S was recrystallized from methanol to give ⁇ -(-: / mouth cetyl)-8-methoxy-3,4-dihydrocarbostyril 5 ⁇ 2.
• 3,4-Diethyl cetylcarbostyl is used in the same manner as in Reference 8 except that carbostyril is used instead of dihydrocarbostyril.
• Color powder ⁇ crystal (metanol-ether)
• the starting compound is obtained in the same manner as in Example 2 and Example 6 to obtain the following compound.
• OMPI pigeon Anesthetize Heparin sodium salt at a dose of 10000 uZ is administered ⁇ and blood is lethal to prepare a sinus node artery sample.
• the specimen is mainly set from the right atrium into a cold mouth solution.
• the glass was then kept at 38: ⁇ ⁇ Placed in a water jacket and pre-infused with sodium salt of pentoparbital (30 ss / 3 ⁇ 4, intravenous).
• heparin-treated ni 100,000 UZK, given in the static area
• Weight 18 ⁇ : 27 ⁇ ⁇
• the perfusion pressure is set to a constant pressure of 10 OtrsH.
• the test compound is injected into the locomotor at a volume of 10 to 30 via a rubber tube that is in close proximity to the force-urea inserted into the right coronary vein.
• the positive inotropic effect of Kyo-Tai-Kai is expressed as a percentage change with respect to the kishi-tension before administration of the compound, and the change in coronary blood flow is expressed as the value of ⁇ vs. the value before administration. . ⁇ 1 is shown below. ⁇ ⁇
• the above agent was manufactured in a total of 200 ⁇ ⁇ conventional methods.
• Hydrogen hydride salt 10 Damp starch 2 1 Magnesium stearate end rate 1 8
• composition of the above composition was prepared in 1 ml, formulation example
• Pill-z-miraben 0.025 Injection ⁇ distilled water 100 0 Above paraben ⁇ , sodium metabolite and chloride
• CMPI WIPO The sodium is agitated and dissolved in about half of the above distilled water at 80 ° C. Discard the solution to 40, and add the compound of the present invention, and then add the ethylene glycol and lioxyethylenesolbitan monolate to the solution. Dissolved. Next, add the injection ⁇ distilled water to the final volume to make the final volume, put the appropriate filter paper on it and make it to SiP ⁇ ⁇ S. Dispense into 1. sample Then give the injection.
• VrTPO ⁇ ⁇ ⁇ is a heart agent that is acceptable in the product and its manufacturing process, and is a compound for the treatment of congestive heart failure.

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