NL192040C - Carbostyril compounds and a composition containing such a compound. - Google Patents

Description

1 192040

Carbostyril compounds and composition containing such a compound

The invention relates to carbostyril compounds.

Carbostyril compounds are well known, and several carbostyril compounds are known with hypotensive, platelet coagulation inhibiting or antiallergic activity as described in Japanese patent applications (OPI) nos. 130589/79, 135785/79, 135785/79, 138585/79, 141785/79, 76872/80, 49319/80, 53283/80, 53284/80 and 83781/80 (the designation “OPI” refers to a ter Japanese Unexamined Patent Application).

Furthermore, EP-A1-7525 and EP-A1-8014 describe isoquinoline compounds with cardiac and circulatory properties.

The invention now relates to new carbostyril compounds with cardiotonic action.

These new carbostyril compounds have the formula 1, wherein R 1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group, R 2 represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom or a 15 represents hydroxyl group,

Rg represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group, which may be substituted with a lower alkyl group, a lower alkanoylamino group, an N, N-dilagere alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group or a carboxymethyl group, R4 and R5, which may be the same or different, each represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or a nitro group, the bond between the 3- and 4-position of the carbostyril core a single bond or is a double bond and the place where the imidazopyridyl group of formula 24 is bonded to the carbostyril core is the 5 or 6 position, provided that when the imidazopyridyl group is bonded to the 5 position of the carbostyril core, R2 may not be a hydrogen atom, a lower alkyl group or a halogen atom.

The invention also relates to the pharmaceutically acceptable salts of such a compound. Preferred are the test compounds 4, 5, 6, 11, 15, 19, 20, 21, 24 and 27 to be discussed later in this description.

The invention also relates to a composition with cardiotonic activity, which contains as active substance a compound of formula I or a pharmaceutically acceptable salt thereof.

GB-A-2.031.404, which relates to carbostyril compounds, in which a pyridazinone derivative is substituted on the carbostyril core, can be mentioned as the prior art. These compounds therefore radically differ from the subject compounds in chemical structure. These known compounds have an antiplatelet action and an anti-hypertensive action, which makes it difficult to expect the cardiotonic activity of the present compounds.

Best Mode for Carrying Out the Invention 40

The compounds of the formula I and pharmaceutically acceptable salts thereof have cardiac muscle contractile stimulating effect or positive inotropic effect and coronary blood flow enhancing activity and are useful as a cardiotonic agent for the treatment of heart diseases, such as congestive heart defects and the like. They are advantageous because they only slightly or not raise the heart rate at all.

45 The term "lower alkyl" as used herein refers to a straight or branched chain alkyl group of 1-6 carbon atoms, such as a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, a t-butyl group, a pentyl group, a hexyl group , etc.

The term "" phenyl-lower alkyl "as used herein refers to a phenyl-lower alkyl group having a straight or branched alkyl group having 1-6 carbon atoms in the alkyl radical, such as a benzyl group, a 50-phenylethyl group, a 1-phenylethyl group, a 3-phenylpropyl group, a 4-phenylbutyl group, a 1,1-dimethyl-2-phenylethyl group, a 5-phenylpentyl group, a 6-phenylhexyl group, a 2-methyl-3-phenylpropyl group, etc.

The term "lower alkenyl" as used herein refers to a straight or branched chain alkenyl group containing 2-6 carbon atoms, such as a vinyl group, an allyl group, a crotyl group, a 1-methylallyl group, a 3-butenyl group, a 2-pentenyl group, a 3 -pentenyl group, a 4-pentenyl group, a 2-methyl-3-55 butenyl group, a 1-methyl-3-butenyl group, a 2-hexenyl group, a 3-hexenyl group, a 4-hexenyl group, a 2- methyl 4-pentenyl group, a 1-methyl-4-pentenyl group, a 2-methyl-3-pentenyl group, a 1-methyl-3-pentenyl group, etc.

192040 2

The term "lower alkynyl" as used herein refers to a straight or branched chain alkynyl group having 2-6 carbon atoms, such as an ethynyl group, a 2-propynyl group, a 1-propynyl group, a 2-butynyl group, a 3-butynyl group, a 2- pentynyl group, a 3-pentynyl group, a 4-pentynyl group, a 2-methyl-3-butynyl group, a 1-methyl-3-butynyl group, a 2-hexynyl group, a 3-hexynyl group, a 4-hexynyl group , a 2-methyl-4-pentynyl group, a 1-methyl-4-pentynyl group, a 2-methyl-3-pentynyl group, a 1-methyl-3-pentynyl group, etc.

The term "halogen" as used herein refers to a halogen atom, such as chlorine, bromine, iodine and fluorine.

The term "amino group which may be substituted with a lower alkyl group" as used herein refers to an amino group and an amino group which is substituted with 1 or 2 straight or branched chain lower alkyl groups of 1-6 carbon atoms, such as a methylamino group, a ethylamino group, a propylamino group, an isopropylamino group, a butylamino group, a t-butylamino group, a pentylami group, a hexylamino group, a Ν, Ν-dimethylamino group, a Ν, Ν-diethylamino group, an N-methyl-N-ethylamino group, methyl-N-propylamino group, an N-ethyl-N-isopropylamino group, an N, N-15 dipropylamino group, an N-methyl-N-butylamino group, an N-ethyl-Nt-butylamino group, an N, N-dibutyl amino group, an N -methyl-N-pentylamino group, an N-propyl-N-pentylamino group, an N, N-dipentylamino group, an N-methyl-N-hexylamino group, an N-butyl-N-hexylamino group, an N, N-dihexylamino group, etc.

The term "N, N-di-lower alkyl-aminomethyl" as used herein refers to an N, N-di-lower alkylaminomethyl group having straight or branched chain alkyl groups each containing 1 -6 carbon atoms, such as an N, N-dimethylaminomethyl group, a N-methyl-N-ethylaminomethyl group, an NN-diethylaminomethyl group, an N-methyl-N-propylaminomethyl group, an N-ethyl-N-isopropylaminomethyl group, an N, N-dipropylaminomethyl group, an N-methyl-N-butylamiriomethyl group, an N- ethyl-Nt-butylaminomethyl group, a Ν, Ν-dibutylaminomethyl group, an N-methyl-N-pentylaminomethyl group, an N-propyl-N-25 pentylaminomethyl group, a Ν, Ν-dipentylaminomethyl group, an N-methyl-N-hexylaminomethyl group, an N -butyl-N-hexylaminomethyl group, a Ν, Ν-dihexylaminomethyl group, etc.

The term "lower alkanoylamino" as used herein refers to a straight or branched chain lower alkanoylamino group of 1-6 carbon atoms, such as a formamido group, an acetamido group, a propionylamino group, a butyrylamino group, an isobutyrylamino group, a valerylamino group, a isovalerylamino group, etc.

The term "lower alkoxy" as used herein refers to a straight or branched chain alkoxy group having 1 to 6 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, a t-butoxy group, a pentyloxy group, a hexyloxy group, etc.

The compounds of the invention of the formula I can be prepared in various ways. A preferred example thereof is a method according to enclosed reaction scheme A.

In reaction scheme A, X1 represents a halogen atom and R6 represents a hydrogen atom or a lower alkyl group and R1, R2, R4, R5 and the bond between the 3- and 4-position of the carbostyril core have the same meaning as above.

Examples of halogen atoms represented by X in formula 2 are chlorine, fluorine, bromine and 40 iodine.

The reaction between the compound of the formula 2 and the compound of the formula 3, which is a known compound, can be carried out in the absence of solvents or in the presence of a suitable solvent, preferably in the presence of a solvent. There is no particular limitation on the solvents, and any solvent that does not adversely affect the reaction can be used.

Examples of suitable inert solvents to be used are water, lower alcohols, such as methanol, ethanol, isopropanol, butanol, etc., aromatic hydrocarbons, such as benzene, toluene, xylene, etc., ethers, such as dioxane, tetrahydrofuran, etc., nitriles, such as vinegar vacuole, propionzuumitrile, etc., dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric acid triamide, etc.

In the above reaction, the ratio of the compound of formula 3 to the compound of formula 2 is not limited and may vary widely. Usually the reaction is carried out with at least an equimolar amount and preferably 1.5-3 moles of the compound of the formula 3 per mole per bond of the formula 2.

Furthermore, the reaction can be carried out in the presence of a basic compound, which can be conveniently used as a dehydrohalogenating agent.

Examples of suitable basic compounds are inorganic basic compounds, for example, metal carbonates or hydrogen carbonates, such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, etc 1920, organic basic compounds, such as triethylamine, pyridine, N, N-dimethylaniline, etc.

The reaction can usually be carried out at a temperature of about room temperature 150 ° C and generally completed in about 1-10 hours.

Of the compounds of the formula 1, those in which the bond between the 3 and the 4-position 5 of the carbostyril core is a single bond (i.e. compounds of the formula 1a) and those in which this bond is a double bond (i.e. compounds of formula 1 b) are converted into each other by a reduction reaction or dehydrogenation reaction, as shown in reaction scheme B.

In reaction scheme B, R 1, R 2, R 3, R 4 and R 5 have the above meanings.

The dehydrogenation reaction of the compound of formula Ia can be carried out using a dehydrogenating agent in a suitable solvent. Examples of suitable dehydrogenating agents are benzoquinones, such as 2,3-dichloro-5,6-dicyanobenzoquinone, chloranil (2,3,5,6-tetrachlorobenzochino), etc., halogenating agents, such as N-bromobromic acid imide, N-chlorobromic acid imide, bromine, etc., dehydrogenating agents, such as sulfur, selenium dioxide, etc., metal catalysts for dehydrogenation, such as palladium carbon, palladium black, platinum black, palladium oxide, Raney nickel, etc.

When benzoquinones and halogenating agents are used as the dehydrogenating agent, the amount of dehydrogenating agent used is not limited and may vary widely. Usually 1-5 moles, preferably 1-2 moles of dehydrogenating agent per mole of compound of formula 1a are used. When metal catalysts are used for dehydrogenation, they are used in ordinary catalytic amounts. For example, the catalysts are used in the same amount by weight as the compound of formula 1a.

Examples of suitable solvents are water, ketones, such as acetone, etc., ethers, such as dioxane, tetrahydrofuran, methoxethanol, dimethoxyethane, etc., aromatic hydrocarbons, such as benzene, toluene, xylene, phenetol, tetralin, cumene, chlorobenzene, etc., halohydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., alcohols, such as methanol, ethanol, isopropanol, butanol, t-butanol, amyl alcohol, hexanol, etc., protic polar solvents, such as acetic acid, etc., aprotic polar solvents, such as DMF, DMSO, hexamethylphosphoric acid triamide, etc., and the like.

The reaction can usually be carried out at room temperature up to 300 ° C, preferably at room temperature up to 200 ° C and generally completed in about 1-40 hours. The reduction reaction of the compounds of the formula Ib can be carried out under conditions customary for catalytic reductions. Examples of the catalyst to be used are metals such as palladium, palladium black, palladium carbon, platinum, piatina oxide, platinum black, Raney nickel, etc., in the usual catalytic amounts used.

As a solvent, one can use, for example, water, methanol, ethanol, isopropanol, dioxane, THF, hexane, cyclohexane, ethyl acetate, acetic acid, etc.

The reduction reaction can be carried out either at atmospheric pressure or under pressure. Usually, the reaction is conducted at about 0-100 ° C, preferably room temperature to 70 ° C and atmospheric up to 10 kg / cm2, preferably atmospheric up to 5 kg / cm2 pressure.

In the accompanying reaction scheme C, R 1 represents a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group, X 2 represents a halogen atom and R 2, R 3, R 4 and R 5 have the above meaning.

According to reaction scheme C, in the case where the groups represented by R2, R3, R4 and R5 each are an inert group, a compound of the formula 1, wherein R1 represents a hydrogen atom, or a compound of the formula 1c can be converted into a corresponding compound of the formula 1, wherein 45 represents R, a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a phenyl-lower alkyl group, or a compound of the formula 1d.

More specifically, a compound of formula 1c can be reacted with a basic compound, for example sodium hydride, potassium hydride, sodium amide, potassium amide, alkali metals, such as metallic sodium, metallic potassium, etc., to convert the compound of formula 1c in its 50 alkali salt, in which the nitrogen atom in the 1-position of the carbostyril core participates in the salt formation. This reaction can be carried out in a suitable solvent, e.g. aromatic hydrocarbons, such as benzene, toluene, xylene, etc., saturated hydrocarbons, such as n-hexane, cyclohexane, etc., ethers, such as diethyl ether, diethylene glycol dimethyl ether, 1,2-dimethoxyethane, dioxane , etc., aprotic polar solvents, such as dimethylformamide, hexamethylphosphoric triamide, dimethyl-55 sulfoxide, etc., with aprotic polar solvents being preferred,

The reaction can be carried out at a temperature of 0-200 ° C, preferably room temperature up to 50 ° C.

192040 4

The alkali salt of the fat bond of the formula Ic thus obtained can be reacted in the usual manner with a halide of the formula 4. This reaction can proceed advantageously in a suitable solvent, which can be used for the reaction of a compound with the formula 1c in its alkali salt, usually at a temperature of about 0-70 ° C, preferably 0 ° C to room temperature.

The ratio of the basic compound to be used to the compound of the formula 1c is usually 1 to 5 moles, preferably 1 to 3 moles, basic compound per mole of the compound of the formula 1c.

On the other hand, the ratio of the halide to be used of the compound of the formula IV to the compound of the formula 1c is usually 1-5 moles, preferably 1-3 moles of halide of the formula 4 per mole of fat bond of the formula 1c. The reaction can be completed in about 0.5-15 hours.

The carbostyril compounds of the formula II which can be used as starting material in reaction scheme A can be easily prepared in various ways. For example, they can be prepared according to the methods shown in the accompanying reaction schemes D, E, F and G.

Of the compounds of the formula II, those in which R 2 represents a hydroxyl group or a lower alkoxy group can be prepared according to the attached reaction scheme D.

In reaction scheme D, R 1, R 6, and X 1 and the bond between the 3 and 4 position of the carbostyril core have the same meaning as above, X 3 represents a halogen atom and R 7 represents a hydrogen atom or a lower alkyl group.

The reaction between the carbostyril derivative of formula IV and the haloalkanoyl halide derivative of formula IV according to reaction scheme D can usually be carried out in the presence of a Lewis acid as catalyst.

Any conventional Lewis acid can be used to advantage in this reaction, for example, aluminum chloride, ferric chloride, zinc chloride, tin chloride, etc.

The reaction can be carried out either in the absence of solvents or in the presence of an appropriate inert solvent, for example, sulfur carbon, methylene chloride, 1,2-dichloroethane, chlorobenzene, nitrobenzene, diethyl ether, dioxane, etc.

The reaction can usually be carried out at about room temperature to 150 ° C, preferably room temperature to 100 ° C.

The ratio of the compound of formula 5 to the compound of formula 4 is usually an equimolar amount to a large excess, preferably 2-6.5 moles of compound of formula 5 per 30 moles of compound of formula 4.

Optionally, one can also prepare a compound of formula 2a by reacting a compound of formula 4 with a compound of formula 6 instead of a compound of formula 5 to form a compound of formula 7, followed by halogenation of this connection.

In the reaction between the compound of the formula 4 and the compound of the formula 6, the same reaction conditions as those in which the compound of the formula 4 and the compound of the formula 5 react may be used.

Halogenation of the compound of the formula 7 can be carried out in the presence of a conventional halogenating agent. Various known halogenating agents can be used in the reaction. Examples of these are bromine, chlorine, etc., N-halobromic acid imides, such as 40 N-bromobromic acid imide, N-chlorobromic acid imide, etc.

The ratio of the halo to the compound of formula 7 is usually about 1-10 moles, preferably 1-5 moles of halogenating agent per mole of formula 7 compound.

Examples of solvents to be used in the halogenation reaction of the compound of formula 7 are halohydrocarbons, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc., organic acids, such as acetic acid, pentionic acid, etc.

The reaction can usually proceed easily under ice cooling or at a temperature up to the boiling point of the solvent used, preferably at room temperature up to 40 ° C, and can generally be completed in about 1-10 hours. In the reaction, one can use a radical reaction initiator, such as benzoyl peroxide, hydrogen peroxide, etc.

In the accompanying reaction scheme E, Ra represents a lower alkanoyl group, R9 represents a lower alkyl group, and R1t Rg, R7, X., and the bond between the 3- and 4-position of the carbostyril core have the same meaning as above.

Acylation of a compound of formula 8 can be carried out by reacting the compound of formula 8 with a lower alkanoic anhydride or its acid halide, without a solvent, or in a solvent such as pyridine, benzene, nitrobenzene, ether, acetone, dioxane , etc. in the presence of a basic compound, for example, alkali carbonates, such as sodium carbonate, potassium carbonate, etc., organic bases, such as triethylamine, N, N-dimethylaniline, 1,5-diazabicyclo [5,4,0] undecene-5 (DBU) , etc.

5 192040 or an acidic compound, such as sulfuric acid, p-toluenesulfonic acid, etc.

The ratio of the lower alkanoic anhydride or its halide to be used to the compound of the formula 8 is usually at least 1 mole to a large excess, preferably 1-10 parts of anhydride or halide per mole of the formula 8.

The acetylation reaction can usually proceed at a temperature from about -10 ° C to 150 ° C, preferably from 0-100 ° C and generally complete in about 10 minutes to 10 hours.

Nitration of a compound of formula 9 can be carried out without a solvent or in a solvent, such as acetic acid, acetic anhydride, sulfuric acid, etc., in the presence of a nitrating agent, such as fuming nitric acid, concentrated nitric acid, a mixed acid (a mixture of sulfuric acid, 10 fuming sulfuric acid, phosphoric acid or acetic anhydride and nitric acid), a combination of aikalin nitrate and sulfuric acid, a mixed acid anhydride of an organic acid with nitric acid, such as acetyl nitrate, benzoyl nitrate, etc., a combination of nitric oxide or nitric acid and silver nitrate alkyl combination of acetone cyanide and sulfuric or polyphosphoric acid, etc. The amount of the nitrating agent to be used is usually 1-1.5 moles per mole of the compound of formula 9.

The reaction can usually proceed at about -10-50 ° C and generally can be completed in about 1-10 hours.

Hydrolysis of a compound of the formula 10 can be carried out in the absence of a solvent or in a suitable solvent, such as water, methanol, ethanol, isopropanol, acetic acid, using an acid or an alkali. Examples of suitable acids are hydrochloric acid, sulfuric acid, etc., and examples of alkali are potassium hydroxide, sodium hydroxide, potassium carbonate, sodium carbonate, sodium hydrogen carbonate, etc. The amounts of acid and alkali are at least 1 mole per mole of the compound of formula 10, respectively. it is used in a large excess relative to the compound of formula 10. The reaction can usually be carried out at a temperature from about room temperature to 100 ° C and generally completed in about 0.5-5 hours.

Alkylation of a compound of formula 9 can be carried out in the presence of a basic compound using a common alkylating agent. Examples of suitable basic compounds are alkali metals, such as metallic sodium, metallic potassium, etc. and hydroxides, carbonates, bicarbonates and alcoholates thereof, and amines, such as pyridine, piperidene, etc. Examples of alkylating agents are alkyl halides, such as alkyl iodide (e.g. methyl iodide, etc.) alkyl chloride, alkyl bromide (eg, methyl bromide, etc.), etc., dialkyl sulfates, such as dimethyl sulfate, diethyl sulfate, etc., and the like.

The reaction can proceed advantageously in a suitable solvent. Examples of suitable solvents are water, lower alcohols, such as methanol, ethanol, isopropanol, n-butanol, etc., ketones, such as acetone, methyl ethyl ketone, etc., and the like.

The alkylating agent is usually used in an at least equimolar amount to a large excess, preferably in 1 to 2 moles per mole of the formula 11 compound.

The reaction proceeds easily at a temperature from about room temperature to the boiling point of the solvent to be used. In general, it can be performed without heating.

Reduction of a compound of formula 12 or 11 can easily be accomplished by subjecting compound 40 of formula 12 or 11 to catalytic reduction in a solvent such as water, acetic acid, methanol, ethanol, diethyl ether, dioxane, etc., in the presence of a catalyst, such as palladium black, palladium carbon, palladium oxide, platinum black, Raney nickel, etc., usually at room temperature under atmospheric pressure, or using a combination of iron, zinc, tin or stannous chloride and an acid (e.g. formic acid, acetic acid, hydrochloric acid, phosphoric acid, sulfuric acid, etc.), a combination of iron, 45 ferrous sulfate, zinc or tin, and an alkali (e.g., alkali hydroxides, alkali carbonates, ammonia, etc.), sulfates, sodium dithionite, sulfites, etc.

Diazotization of a compound of the formula 13 or the reduction product of a compound of the formula 11 can be done in an aqueous solution using sodium nitrite or hydrochloric or sulfuric acid at a temperature of about -30 ° C to room temperature for about 1-3 hours .

The diazonium salt of a compound of the formula 11 or 13 can be further reacted with a compound of the formula 14 to form a compound of the formula 15. The amount of the compound of the formula 14 to be used is 1 to 5 moles, at preferably 1-2 moles per mole of diazonium salt.

The reaction can be advantageously conducted in the presence of a buffering agent, such as sodium acetate, sodium carbonate, calcium carbonate, etc., and sodium sulfite and copper sulfate as catalyst, usually about 1-5 hours at 0-40 ° C.

Halogenation of a compound of formula 15 can be done with a halogenating agent, such as 192040, 6 halogens, for example, bromine, chlorine, etc., or N-halobromic acid imides, for example N-bromobromic acid imide, N-chlorobromic acid imide, etc.

The ratio of the halogenating agent to the compound of formula 15 is usually 1 to 10 moles, preferably 1 to 5 moles of halogenating agent per mole of compound of formula 15.

Examples of suitable solvents to be used in the reaction are haloalkanes, such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride, etc.

The reaction can proceed easily under ice cooling or at a temperature to the boiling point of the solvent used, preferably at room temperature up to 40 ° C, and can usually be continued for about 1-10 hours. Radical reaction initiators, such as peroxides, for example, benzoyl peroxide, hydrogen peroxide, etc., may be used in the reaction.

Optionally, after the diazotization of the compound of formula 11 or 13, a compound of formula 25, wherein R3 and X have the above meaning, can be used instead of a compound of formula 14, whereby a compound of formula 2b can be directly be prepared from a compound of the formula 13. In this case, the same conditions as those under which the reaction is carried out using the compound of the formula 13 can be used.

Of the compounds of formula 15 or 2b, those in which R7 represents a hydrogen atom can be prepared by heating the compound of formula 15 or 2b in which R7 represents a lower alkyl group in a solvent such as water or dioxane in the presence of an acidic catalyst such as hydrobromic acid at 80-130 ° C for 30 minutes to 6 hours.

Furthermore, the compounds of formula 2, wherein R 2 represents a hydrogen atom, a lower alkyl group or a halogen atom, can be prepared according to the attached reaction scheme F.

In reaction scheme F, R10 represents a hydrogen atom, a lower alkyl group or a halogen atom, X4 represents a halogen atom, a hydroxyl group or a group of the formula 26 -0 (CO) -X., CH-R3, X5 represents a halogen atom, a hydroxyl group, or a group of the formula -O (CO) CH 2 R 3 for and R 1, R 3, X, 25 and the bond between the 3 and 4 position of the carbostyril core have the above meaning.

The reaction between the compound of the formula 16 and the compound of the formula 17 and that between the compound of the formula 16 and the compound of the formula 18 are so-called Friedel Crafts reactions, which can be carried out in a solvent in the presence of a Lewis acid.

Examples of suitable solvents are carbon sulfur, nitrobenzene, chlorobenzene, dichloromethane, dichloroethane, trichloroethane, tetrachloroethane, etc. As Lewis acid, any commonly used Lewis acid can be used, for example, aluminum chloride, zinc chloride, iron chloride, tin chloride, boron tribromide, boron trifluoride, concentrated sulfuric acid, etc.

The amount of Lewis acid to be used is not limited to certain limits and can vary widely. Usually, about 2-6 moles, preferably 3-4 moles, of Lewis acid per mole of the compound of formula 16 can be used.

The compound of the formula 17 and the compound of the formula 18 can each be used in an amount of usually at least 1 mole, preferably 1-2 moles, per mole of the compound of the formula 16.

The reaction temperature can be selected appropriately depending on other conditions.

Usually the reaction is carried out at about 0-120 ° C, preferably 20-70 ° C. The reaction time is widely variable depending on starting materials, catalysts, reaction temperatures and the like. Usually the reaction is completed in about 0.5-6 hours.

Halogenation of a compound of formula 19 can be carried out under the same conditions as in halogenation of a compound of formula 15.

45 Furthermore, the compounds of formula I, wherein R 3 may contain a halogen atom, a nitroso group, an amino group, a lower alkylamino group, a Ν, dil-dilagent alkylamino group, a lower alkanoylamino group, an N, N-di-lower alkylaminomethyl group, a carbomoylmethyl group, a cyanomethyl group or a carboxymethyl group are prepared from a compound of the formula 1A, wherein R6 represents a hydrogen atom (i.e. a compound of the formula 1e) according to the accompanying reaction schemes GK. In reaction scheme G, R 1, R 2, R 4, R 5 and the bond between the 3rd and 4 positions of the carbostyril core have the above meaning and Xe represents a halogen atom.

According to reaction scheme G, a compound of the formula 1f can be prepared by halogenating a compound of the formula 1e in a conventional solvent in the presence of a halogenating agent.

Any conventional halogenating agent can be used in the reaction. For example, one can use halogens such as chlorine, bromine, iodine, fluorine, etc., phosphorus oxychloride, phosphorus oxybromide, phosphorus pentachloride, phosphorus pentabromide, phosphorus trichloride, trionyl chloride, etc., and similar halogenating agents.

7 192040

The ratio of the halogenating agent to the compound of the formula Ia is not limited and can be widely used. Usually 1-10 moles, preferably 1-1.5 moles of halogenating agent per mole of compound of formula 1e can be used.

Examples of suitable inert solvents are halohydrocarbons, such as chloroform, dichloromethane, 1,2-dichloroethane, etc., ethers, such as diethyl ether, dioxane, etc., organic acids, such as acetic acid, propionic acid, etc., and the like.

Reaction can be performed under ice cooling or at a temperature of about 0-100 ° C, preferably at room temperature to 50 ° C, for 1-12 hours.

In reaction scheme A, R 1, R 2, R 4, R 5 and the bond between the 3 and 4 position of the carbostyril core 10 have the above meaning.

According to reaction scheme A, the compounds of the formula 1, wherein R 3 represents a nitroso group (i.e. a compound of the formula 1g) can be obtained by nitrocylation of a compound of the formula 1e.

The reaction can be carried out in the absence of solvents or in a suitable inert solvent using a nitrosylating agent and an acid. A variety of conventional nitrosylating agents can be used. Of these, nitrites such as sodium nitrite, potassium nitrite, etc. are preferred. The ratio of the nitrosylating agent to the compound of the formula 1e is usually 1-2 moles, preferably 1-1.2 moles of nitrosylating agent per mole of the compound of the formula 1e.

Examples of suitable acids are hydrochloric, sulfuric, phosphoric, acetic, propionic, butyric, isobutyric, and the like conventional acids, with inorganic acids being preferred. The acid can usually be used in excess of the compound of formula 1e when the reaction is conducted in the absence of solvents. On the other hand, the amount of acid can vary widely and is usually at least 1 mole per mole of the compound of the formula 1e when the reaction proceeds in a solvent.

As a solvent, it is preferable to use conventional inert solvents, such as water, lower fatty acids, for example acetic acid, propionic acid, butyric acid, isobutyric acid, etc., lower fatty anhydrides, for example acetic anhydride, propionic anhydride, butyric anhydride, isobutyric anhydride, etc., ethers, for example dioxane, tetrahydrofuran, etc., dimethylformamide, dimethyl sulfoxide, etc.

The reaction can usually be carried out at about -30-100 ° C, preferably 0-50 ° C and completed in about 30 minutes to 3 hours.

Reduction of the compound of the formula I g thus formed gives rise to the compounds of the formula 1, in which R 3 represents an amino group (i.e. a compound of the formula 1i).

This reduction reaction can be carried out using an ordinary reducing agent, for example a mixture of iron and hydrochloric acid, zinc and acetic acid and tin or stannous chloride and hydrochloric acid in an amount of 1 mole to a large excess, preferably 3-5 moles per mole of compound with the formula 1g.

Optionally, the above reaction can also be carried out using a suitable hydrogenation catalyst, such as palladium black, palladium carbon, Raney nickel, platinum dioxide, etc. The reaction can proceed advantageously in a solvent, for example, water, lower alcohols, such as methanol, ethanol, 40 isopropanol, etc., acetic acid, and the like. The reaction conditions are not particularly limited and can vary widely depending on the type and amount of reducing agent or hydrogenation catalyst. Usually the reaction is carried out at about 0-150 ° C, preferably 50-100 ° C, when a reducing agent is run and at about 0-100 ° C, preferably room temperature, at atmospheric pressure of hydrogen gas, when using a hydrogenation catalyst .

45 In reaction scheme I, R 1, R 2, R 4, R 5 and the bond between the 3- and 4-position of the carbostyril core have the same meaning as above, R 1 represents a hydrogen atom or a lower alkyl group and R 12 represents a hydrogen atom or a methyl group in front of.

According to reaction scheme I, the compounds of the formula 1, where R 3 represents a lower alkanoyl group (i.e. compounds of the formula 1j), can be prepared by acylation of a compound 50 of the formula 1i. In this reaction, various reaction conditions, including conventional acylation reactions, can be used. For example, the intended compound of formula II can easily be obtained by reacting a compound of formula II with a lower alkanoic acid or its anhydride or halide.

The reaction can usually be carried out in the presence of a basic compound or an acidic compound. Examples of suitable basic compounds are organic bases such as triethylamine, trimethylamine, pyridine, dimethylaniline, N-methylmorpholine, 1,5-diazabicyclo / 4,3,0 / nonene-5 (DBN), 1,5-diazabicyclo / 5.4 .0 / undecene-5 (DBU), 1,4-diazabicyclo / 2,2,2 / -octane (DABCO), etc., inorganic 192040 8 bases, such as potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, etc. Other examples of suitable acidic compounds inorganic acids, such as sulfuric acid, hydrochloric acid, etc.

The above reaction can generally proceed in a solvent. Examples of suitable solvents are halohydrocarbons, such as methylene chloride, chloroform, dichloroethane, etc., aromatic hydrocarbons, such as benzene, toluene, xylene, etc., ethers, such as diethyl ether, tetrahydrofuran, dimethoxyethane, etc., esters, such as methyl acetate, ethyl acetate, etc., and aprotic polar solvents, such as Ν, Ν-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, etc.

In the above reaction, the amount of lower alkanoic acid or its anhydride or halide is not particularly limited and can vary widely. Usually 1-10 moles, preferably 1-2 moles of lower alkanoic acid or its anhydride or halide can be used per mole of the compound of the formula II. Furthermore, there is no particular limitation on the reaction temperature and the reaction time. Usually, the reaction can be carried out at a temperature of about -30-150 ° C, preferably 0-100 ° C, for about 30 minutes to 12 hours.

The compounds of the formula 1k, in which R 12 represents a hydrogen atom, can be prepared by reduction of a compound of the formula 1j. The reduction can be carried out under the usual conditions, whereby the carbonyl group in an amido bond is reduced to a methylene group. For example, the reaction can be conducted in the presence of lithium aluminum hydride, sodium borohydride, or a similar catalyst.

The compounds of the formula 1k, in which Rn represents a hydrogen atom and R12 represents a methyl group, can be prepared by reduction of a compound of the formula II. In this reduction, the Eschweiler-Clarke reaction can be used, which can usually be easily carried out by heating the compound of formula II in the presence of formic acid and formalin and the absence of solvents.

The ratio of formic acid and formalin to the compound of formula II are not particularly limited and can vary widely. Usually formalin is used in an amount of about 1-5 moles, preferably 1-1.5 moles per mole of the compound of formula Ii, while the amount of formic acid is used in about 1-10 moles, preferably 3-5 moles per mole of compound with the formula is 1i. There is no particular limitation on the reaction temperature and time and these can be widely varied. Usually the reaction is carried out at about room temperature to 150 ° C, preferably 80-100 ° C, for about 3-30 hours.

In reaction scheme J, R 1, R 2, R 4, R 5, X 2 and the bond between the 3 and 4 position of the carbostyril core have the above meaning and R 13 represents a lower alkyl group.

The compounds of formula 1, wherein R 3 represents an N, N-di-lower alkylamino group (ie a compound of the formula 11) can be prepared by reacting a compound of the formula II with a compound of the formula 20. The reaction is carried out in the presence of a dehalogenation agent.

Various conventional basic compounds can be used as the dehalogenating agent. Good examples of such a basic compound are organic bases, such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium hydrogen carbonate, etc., alkali metals, such as metallic sodium, metallic potassium, etc., organic bases, such as triethylamine, pyridine, Ν, Ν-dimethylaniline, etc.

The reaction can proceed either in the absence of solvents or in the presence of a solvent. All kinds of solvents that do not participate in the reaction can be used. For example, alcohols such as methanol, ethanol, propanol, etc., ethers such as diethyl ether, tetrahydnofuran, 45 dioxane, ethylene glycol monomethyl ether, etc., aromatic hydrocarbons such as benzene, toluene, xylene, chlorobenzene, etc., ketones such as acetone , methyl ethyl ketone, etc., aprotic polar solvents such as Ν, Ν-dimethylformamide, dimethyl sulfoxide, hexamethylphosphoric acid triamide, etc. and similar solvents are used advantageously. The ratio of the compound of formula 20 to the compound of formula 1i is usually at least 2 moles, preferably 2-4 moles of fiber bond of formula 20 50 per mole of compound of formula 1i.

Using about 1 mole of fiber bond of Formula 20 per mole of compound of Formula III, a compound of Formula 1 wherein R3 represents a monollower alkylamino group can be prepared. This compound can be further reacted with a compound of the formula R13, X2, wherein R13 represents a lower alkyl group and X2 has the above meaning, to form a compound of the formula (I) wherein R3 is a Ν, Ν, -dialkylamino group the alkyl groups of which differ from one another.

The reaction can usually be carried out at about -30-100 ° C, preferably 0-50 ° C and generally completed in about 30 minutes to 12 hours.

In reaction scheme K, R 1, R 2, R 4, R 5, X 2 and the bond between the 3 and 4 position of the carbostyril core have the above meaning, R14, R15 and R16, which may be the same or different, each have a lower alkyl group and M represents an alkali metal.

According to reaction scheme K, the compounds of the formula 1, wherein R 3 represents an NN-di-lower alkylaminomethyl group (ie a compound of the formula 1 m) can be prepared by reacting a compound of the formula 1e with a di- low-alkyl amine of formula 21 and foimaline.

The reaction can be carried out either in the absence of solvents or in the presence of a solvent. As the solvent, all kinds of solvents can be used, which will participate in the reaction. For example, one can use water, lower alcohols, such as methanol, ethanol, isopropanol, etc., lower fatty acids, such as acetic acid, propionic acid, etc., and similar solvents.

The ratio of both the compound of formula 21 and of formalin to the compound of formula 1e is usually about 1-3 moles, preferably 1 mole of compound of formula 21 or formalin per mole of compound of formula 1e.

The reaction can usually be conducted at 0-150 ° C, preferably room temperature to 100 ° C, and generally completed in about 3-6 hours.

Furthermore, a tertiary ammonium salt of the formula 1n can be prepared by reacting a compound of the formula 1m thus obtained with a compound of the formula 22. The reaction can be carried out either in the absence of solvents or in the presence of a solvent.

All kinds of solvents which do not participate in the reaction can be used. For example, one can use water, lower alcohols, such as methanol, ethanol, isopropanol, etc., halohydrocarbons, such as dichloromethane, chloroform, carbon tetrachloride, etc., acetic nitrile, propionic acid nitrile, N, N-dimethylformamide and similar solvents.

The ratio of the compound of formula 22 to the compound of formula 1m is usually 1 mole to a large excess, preferably 1-2 moles of compound of formula 22 per mole of compound of formula 1m.

The reaction can usually be carried out at about 0-150 ° C, preferably 30-80 ° C and generally completed in about 30 minutes to 4 hours.

Also, the compounds of formula 1, wherein R 3 represents a carbamoylmethyl group (ie, a compound of formula 10) or represents a cyano group (ie, a compound of formula 1p), may be prepared by reacting a compound with the formula 1n with a compound of the formula 23.

Any reaction can be performed in an inert solvent, for example, water, lower alcohols, such as methanol, ethanol, isopropanol, etc., nitriles, such as acetic nitrile, propionic acid nitrile, etc., and the like.

Preferred examples of compounds of formula 23 are potassium cyanide, sodium cyanide, etc.

In the preparation of the compound of Formula 10, the compound of Formula 23 is usually used in an equimolar amount to large excess relative to the compound of Formula 1n. Hair is preferably used in an amount of 3-4 moles per mole of the compound of the formula 1n.

The reaction can usually be carried out at room temperature up to 150 ° C, preferably at 60-100 ° C, for about 3-12 hours, preferably 5-6 hours.

On the other hand, in the preparation of the compound of formula Ip, usually about 1-2 moles, preferably 1 mole of compound of formula 23 are reacted with 1 mole of compound of formula 1n at about room temperature to 150 ° C, preferably 60- 100 ° C, for about 30 minutes to 1 45 hours.

In addition, the compounds of formula 1 wherein R 3 represents a carbomoylmethyl group (i.e. a compound of the formula 1u) can be prepared by hydrolysis of a compound of the formula 10 or 1p. The hydrolysis reaction can be carried out in the absence of solvents or in a suitable solvent, for example water, lower alcohols, such as methanol, ethanol, isopropanol, etc., 50 acetic acid and the like in the presence of an acid or an alkali. As the acid, for example, inorganic acids, such as hydrochloric acid, sulfuric acid, etc. can be used. Examples of an alkali are sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, etc.

The acid or alkali can usually be used in at least 1 mole per mole of compound of formula 10 or 1p. Usually, a large excess of acid or alkali relative to the compound of formula I0 or 1p is used.

The reaction can usually be carried out at about room temperature to 150 ° C, preferably 50-100 ° C and generally completed in about 30 minutes to 10 hours.

192040 10

Furthermore, the compounds of formula 1 wherein R2 represents a hydroxyl group may be prepared by hydrolysis of a compound of formula 1 wherein R2 represents a lower alkoxy group under the same conditions as under which the compound of formula 15 or 2b is hydrolyzed.

The compounds of the invention of the above formula 1 can form pharmaceutically acceptable salts with acids and such pharmaceutically acceptable salts are also within the scope of the invention. The pharmaceutically acceptable acids which can be used for salt formation can be various inorganic acids, for example hydrochloric, sulfuric, phosphoric, bromohydroic, or organic acids such as oxalic, maleic, fumaric, malic, tartaric, citric, benzoic, etc. ..

The compounds of formula 1, when they have an acidic group, can be converted into a corresponding salt by reacting the acidic group with a pharmaceutically acceptable basic compound. Examples of basic compounds are inorganic basic compounds, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium hydrogen carbonate, etc.

As noted above, salts of a compound of the formula I acid addition salts thereof are meant by pharmaceutically acceptable acids and basic compounds, as well as quaternary ammonium salts thereof with halides, such as lower alkyl halides.

The compounds of formula 1 and their salts as described above can be recovered from the respective reaction mixtures upon completion and purified in the usual ways, for example, by solvent extraction, dilution, precipitation, recrystallization, column chromatography, preparative thin layer chromatography, etc. ..

The compounds of the formula I can of course exist in optically active forms and such optically active isomers are within the scope of the invention.

When the compounds of the invention of the formula I are used and their salts as therapeutic agents, these compounds can be processed into fatty compositions together with common pharmaceutically acceptable carriers. Suitable carriers to be used are, for example, solvents or excipients, such as fillers, fillers, binders, wetting agents, disintegrants, surfactants and lubricants, which are usually used, depending on the type of dosage form, to prepare such drugs.

According to the purpose of the therapy, different dosage forms of the therapeutic agents can be selected as the cardiotonic agent. Dosage forms which can be used are in particular tablets, pills, powders, liquid preparations, suspension, emulsions, granules, capsules, suppositories and injectable preparations (solutions, suspensions, etc.).

A large number of known carriers can be used in the compression molding of a pharmaceutical composition containing the compounds of the formula 1 or a pharmaceutically acceptable salt thereof as the active ingredient into a tablet form. Examples of suitable carriers are excipients such as lactose, white sugar, sodium chloride, glucose solution, urea, starch, calcium carbonate, kaolin, crystalline cellulose and silicic acid, binders such as water, ethanol, propanol, simple syrup, glucose, starch solution, gelatin solution , carboxymethyl cellulose, shellac, methyl cellulose, potassium phosphate and polyvinylpyrrolidone, disintegrants, such as dried starch, sodium alginate, agar powder, laminaria powder, 40 sodium hydrogen carbonate, calcium carbonate, Tween, sodium laurite sulfate, desintegrate, white starch, and sugarose inhibitors, lactose inhibitors stearic acid glyceryl ester, cocoa butter and hydrogenated oils, absorption promoters, such as quaternary ammonium bases and sodium lauryl sulfate, wetting agents, such as glycerol and starch, adsorbents, such as starch, lactose, kaolin, bentonite and colloidal silicic acid, talcic acids, such as purine acid ear acid powder, 45 Macrogol (trade name for a polyethylene glycol produced by Shinetsu Chemical Industry Co., Ltd.) and solid polyethylene glycol.

The tablets may, if desired, be coated and processed into sugar-coated tablets, gelatin-coated tablets, intestinal-coated tablets, film-coated tablets or tablets comprising two or more layers.

A wide variety of conventional carriers can be used in molding the pharmaceutical composition into pills. Examples of suitable carriers are excipients such as glucose, lactose, starch, cocoa butter, hardened vegetable oils, kaolin and talc, binder such as gum arabic powder, tragacanth powder, gelatin and ethanol and disintegrants such as laminaria and agar.

A large number of 55 different known carriers can be used in the compression molding of the pharmaceutical preparation into a suppository. Examples of suitable carriers are polyethylene glycol, cocoa butter, higher alcohols, esters of higher alcohols, gelatin and semi-synthetic glycerides.

When the pharmaceutical preparation is an injectable preparation, the resulting solution and 11 192040 suspension are preferably sterilized and are isotonic to the blood. When preparing the pharmaceutical composition to a solution or suspension, any diluents customary in the art can be used. Examples of suitable diluents are water, ethyl alcohol, propylene glycol, ethoxylated isosteayl alcohol, polyoxyethylene sorbitol and sibitan esters. Sodium chloride, glucose or glycerol can be included in a therapeutic agent, for example, a nephritis agent, in an amount sufficient to prepare isotonic solutions. The therapeutic agent may further contain ordinary solubilizers, buffers, pain relievers and preservatives and optionally dyes, perfumes, flavors, sweeteners and other drugs.

The amount of the compound of the formula I and pharmaceutically acceptable salts thereof of the invention to be incorporated into a pharmaceutical composition as a valuable cardiotonic agent is not particularly limited and can vary widely. A suitable therapeutically effective amount of a compound of the general formula 1 and pharmaceutically acceptable salts thereof of the invention is usually about 1 to about 70% by weight, preferably 5-50% by weight, based on the entire composition.

There is no particular restriction on that use of the cardiotonic agent and it can be administered by routes suitable for its particular forms. For example, the tablets, pills, liquid preparations, suspensions, emulsions, granules and capsules are administered orally. The injectable preparations are administered intravenously either alone or in conjunction with common auxiliary agents such as glucose and amino acids. Furthermore, as required, the cardiotonic agent can simply be administered intramuscularly, intracutaneously, subcutaneously or intraperitoneally. The suppository is administered intrarectally and the ointment is applied to the skin.

The dosage of the cardiotonic agent is suitably selected according to the intended purpose, symptoms, etc. Usually a preferred dose of the compounds of the invention is about 1-10 mg / kg body weight per day. It is advantageous that the active ingredient is present in a single dosage unit form in an amount of 50-250 mg.

The invention will now be described in further detail by reference examples, examples and preparation examples, but is not limited thereto.

Reference Example 1 8-Hydroxy-3,4-dihydroxycarbostyril (20 g) was suspended in acetic anhydride (100 ml). Sulfuric acid (5 drops) was added to the resulting suspension and the mixture was stirred at 80 ° G for 1.5 hours. Acetic acid (100ml) was added to the reaction mixture and the mixture was quenched with ice and a solution of 10.1mg concentrated nitric acid (d = 1.38) in 30ml acetic anhydride was added with stirring. Stirring was continued overnight at room temperature. The reaction mixture was poured into ice water, precipitating crystals, which were filtered to obtain 21.74 g of 6-nitro-8-acetoxy-3,4-dihydroxycarbostyril.

Melting point above 300 ° C, light yellow powder.

40 NMR (DMSO-d6) 8 (ppm) = 8.03 (d, J = 2.5 Hz, 1H), 7.96 (d, J = 2.5 Hz, 1H), 3.20 - 2, 98 (m, 2H), 2.68 - 2.45 (m, 2H), 45 2.33 (s, 3H)

Reference example 2

Hydrochloric acid (200 ml) was added to 6-nitro-8-acetoxy-3,4-dihydrocarbostyril (20 g) and the mixture was refluxed for 4 hours. After ice cooling, crystals precipitated, which were filtered off 50 and recrystallized from methanol to obtain 13.76 g of 6-nitro-8-hydroxy-3,4-dihydrocarbostyril. Melting point 270 ° C, light yellow flakes.

Reference Example 3 6-Nitro-8-hydroxy-3,4-dihydrocarbostyril (10 g) and potassium carbonate (13.3 g) were mixed with acetone 55 (70 ml) and water (70 ml) and refluxed dropwise addition of 12.1 g of dimethyl sulfate. After the refluxing was continued for 4 hours, the reagent was cooled and the precipitated crystals were filtered off and washed with water. 192040 12 to give 8.22 g of 6-nitro-8-methoxy-3,4-dihydrocarbostyrile.

Melting point 230 ° C, yellow needles.

Reference Example 4 5 6-Nitro-8-methoxy-3,4-dihydrocaibostyril (2 g) and 5% palladium carbon (0.2 g) were placed in ethanol (50 ml) and catalytic reduction was performed at a hydrogen gas pressure of 3 kg / cm2 for 1 hour. Then the reaction mixture was filtered and the filtrate was concentrated. The residue was recrystallized from benzene to obtain 1.7 g of 6-amino-8-methoxy-3,4-dihydrocarbostyril.

Melting point 157-158 ° C, colorless needles.

10

Reference example 5

In a mixture of 6-amino-8-methoxy-3,4-dihydrocarbostyril (12 g) concentrated hydrochloric acid (16 ml) and water (50 ml), ice (30 g) and sodium nitrite (5 g) and water (20 ml) were added. ) slowly added to the resulting mixture under ice cooling. When all was added, the resulting mixture was allowed to react at 0-5 ° C for 1 hour. On the other hand, a heated solution of acetaldehyde hemicicbazide (10 g) in water (50 ml) and then sodium sulfite (0.2 g) and copper sulfate (3.2 g) was added to a solution of sodium acetate (34 g) in water (40 ml) and the internal bath temperature was adjusted to 10-20 ° C. The solution was stirred and a solution prepared by adding a solution of sodium acetate (26 g) in water (46 ml) to the above diazonium salt solution was gradually added under the surface of the solution. After stirring was continued for 2 hours, the reaction was left overnight. The voided precipitate was filtered off and washed with water. It was placed in 200 ml of 2 N hydrochloric acid and the mixture was heated at reflux for 2 hours. After cooling, the reaction mixture was extracted twice with chloroform (150 ml) and the chloroform layer was washed with water. The solution was filtered through a short column filled with silica gel activated carbon. This column was washed with 500 ml of chloroform. The two chloroform layers were combined and the chloroform was evaporated. The residue was recrystallized from benzene to obtain 5.1 g of 6-acetyl-8-methoxy-3,4-dihydrocarbostyril.

Melting point 150 ° C, light yellow needles.

30 Reference example 6

To a solution of 6-acetyl-8-methoxy-3,4-dihydrocarbostyril (3.1 g) in chloroform (30 ml) was added a solution of bromine (2.26 g) in chloroform (20) with stirring at room temperature ml). When all was added, the mixture was stirred at room temperature for 30 minutes, then the reaction mixture was concentrated and the residue was recrystallized from methanol to give 3.2 g of 6- (α-bromoacetyl) -8-methoxy-3,4-dihydrocarbostyril .

Melting point 206-207 ° C, colorless needles.

Reference example 7

To a solution of aluminum chloride (44 g) and α-bromopropionyl chloride (43 g) in carbon sulfur (150 40 ml) was added portionwise under reflux with stirring while stirring 3,4-dihydrocarbostyril (8 g). When everything was added, the mixture was refluxed with stirring for 2 hours. After cooling, the mixture was poured into ice water and the precipitated crystals were filtered off and washed with water. Recrystallization from ethanol gave 14.2 g of 6- (α-bromopropionyl) -3,4-dihydrocarbostyril.

45 Melting point 192-193 ° C, light yellow flakes.

Reference example 8

To a solution of aluminum chloride (80 g) and chloroacetyl chloride (72 g) in carbon sulfur (220 ml) was added a slurry 50 of 3,4-dihydrocarbostyril (14.7 g) in carbon sulfur in 20 minutes under reflux with stirring. (100 ml). When all was added, the mixture was refluxed with stirring for 2 hours. After cooling, the reaction mixture was poured into ice water and the precipitated crystals were filtered off, washed with water and recrystallized from ethanol to give 20 g of 6-chloroacetyl-3,4-dihydrocarbostyril.

Melting point 230-231 ° C, colorless needles.

13 192040

Reference example 9

In the same manner as in Reference Example 8, except that carbostyril was used instead of 3,4-dihydrocarbostyril, 6-chloroacetylcarbostyril was obtained.

Melting point 275-277 ° C, light green needles.

5

Reference Example 10 8-Methyl-3,4-dihydrocarbostyril (16.1 g) was suspended in carbon sulfur (100 ml) and α-bromopropionyl bromide (35 g) was added to the suspension with stirring and cooling with ice water. Thereafter, anhydrous aluminum chloride (30 g) was added portionwise to the mixture followed by refluxing for 3 hours. Carbon sulfur was evaporated under reduced pressure and the residue was decomposed by adding ice water (500 ml).

Tar-like product, which precipitated, was separated and washed with water. A small amount of methanol was added to the product to form crystals. The crystals were filtered and recrystallized from methanol to obtain 14.3 g of 8-methyl-6-α-bromopropionyl-3,4-dihydrocarbostyril.

Melting point 232.5-233.5 ° C, colorless needles.

Reference example 11

To a solution of α-bromopropionyl bromide (60 g) and aluminum chloride (40 g) in carbon sulfur (100 20 ml) was added 8-chloro-3,4-dihydrocarbostyril (10 g). After the mixture was refluxed for 5 hours, carbon sulfur was evaporated and heated to 70-80 ° C for 5 hours. The reaction mixture was poured into ice water and left overnight. The mixture was extracted with chloroform and the chloroform layer was washed with water, dried and treated with activated charcoal, followed by evaporation of chloroform. The residue was washed with diethyl ether and filtered. The residue gave uniform crude crystals on thin layer chromatography. The crystals thus obtained were recrystallized from methanol to obtain 12 g of 8-chloro-6-α-bromopropionyl-3,4-dihydrocarbostyril.

Melting point 180-182 ° C, light yellow needles.

Reference Example 12 To a solution of 8-hydroxycarbostyril (27 g) and chloroacetyl chloride (37 ml) and nitrobenzene (250 ml) was added portionwise aluminum chloride (85 g) and the mixture was stirred at 70 ° C for 20 hours. After addition of 10% hydrochloric acid (500 ml), nitrobenzene was removed by steam distillation. After cooling, the crystals formed were filtered, washed with 300 ml of hot water and recrystallized from methanol to obtain 4.0 g of 5-chloroacetyl-8-hydroxycarbostyril.

Melting point 285-287 ° C (under decomposition), light yellow crystals.

Example I

6- (α-Bromopropionyl) -1-methyl-3,4-dihydrocarbostyril (5 g), 2 aminopyridine (4.77 g) and acetic acid nitrile (20 ml) were refluxed for 1.5 hours. The reaction mixture was cooled with ice water and the 40 precipitated crystals were filtered off. The crystals were dissolved in acetone and the solution adjusted to a pH of about 1 by adding 48% hydrobromic acid. The crystals formed were filtered off and recrystallized from water to obtain 5.68 g of 6- (3-methylimidazo [1,2-pyridin-2-yl) -1-methyl-3,4-dihydrocarbostyril monohydrobromide.

Melting point above 300 ° C, colorless powder.

45 NMR (DMSO-d6) § (ppm) = 8.85 (d, J = 7 Hz, 1H) 8.13-7.20 (m, 6H) 3.33 (s, 3H) 3.15-2 .87 (m, 2H) 50 2.73 (s, 3H) 2.68-2.37 (m, 2H)

Example II

8-Chloro-6- (α-bromopropionyl) -3,4-dihydrocarbostyril (4 g), 2-aminopyridine (3.57 g) and acetic acid nitrile (20 55 ml) were heated under reflux for 3 hours. The reaction mixture was concentrated to dryness and the residue (oily product) was washed with water. Then, the residue was dissolved in acetone and 48% hydrobromic acid was added to the solution to adjust the pH to about 1 and the 192040 crystals formed were filtered off. The crude crystals thus obtained were recrystallized from water to obtain 2.74 g of 8-chloro-6- (3-methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril mono hydrobromide hemihydrate.

Melting point above 300 ° C, light yellow powder.

5 (ppm) = 9.78 (s, 1H) 8.83 (d, J = 7Hz, 1H) 8.03 - 7.43 (m, 5H) 3.23 - 2.97 (m, 2H) 2.74 (s, 3H) 10 2.70-2.43 (m, 2H)

Example III

In an analogous manner as in Example II, the following compounds were prepared using appropriate starting materials.

8-Methyl-6- (3-methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrochloride monohydrate. Melting point 273-276 ° C (decomposition), light yellow powder.

6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide hydrate.

Melting point above 300 ° C, light yellow needles.

NMR (DMS0-d6-D20) 20 6 (ppm) = 8.65 (d, J = 7Hz, 1H) 8.06-7.73 (m, 2H) 7.67-7.40 (1m, 3H) 7.23 - 7.03 (m, 1H) 3.20-2.50 (m, 4H) 25 2.72 (s, 3H) 8-Methyl-6- (imidazo [1,2-a] pyridin-2-yl) - 3,4-dihydrocarbostyril monohydrochloride 3/2 hydrate.

Melting point above 300 ° C, light brown powder.

NMR (DMSO-de) 8 (ppm) = 9.64 (s, 1H) 30 8.86 (d, J = 7Hz, 1H) 8.70 (s, 1H) 8.03-7.30 (m, 5H) 3.10-2.83 (m, 2H) 2.67-2.40 (m, 2H) 35 2.32 (s, 3H) 8-Chloro-6- (imidazo [1,2-a] pyridine-2- yl) -3,4-dihydrocarbostyril monohydrochloride hemihydrate.

Melting point above 300 ° C, light brown cottony crystals.

MR (DMSO-d6) 5 (ppm) = 9.70 (s, 1H) 40 8.82 (d, J = 7Hz, 1H) 8.75 (s, 1H) 8.05-7.23 (m, 5H) 3.20-2.90 (m, 2H) 2.73-2.40 (m, 2H) 45 8-Methoxy-6- (imidazo [1,2-a] pyridin-2-yl) -3,4-dihydnocarbostyril monohydrobromide .

Melting point 294.5-296.0eC (decomposition) pale yellow cottony crystals.

6- (lmidazo [1,2-a] pyridin-2-yl) carbostyril monohydrochloride.

Melting point above 300 ° C, light yellow canteen-like crystals.

MR (DMSO-d6) 50 8 (ppm) = 8.74 (d, J = 7Hz, 1H) 8.61 (s, 1H) 8.31 (d, J = 2.5Hz) 8.17-7.10 (m, 6H) 6.58 (d, J = 9Hz, 1H) 55 6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) carbostyril monohydrobromide monohydrate.

Melting point above 300 ° C, colorless cotton-like crystals.

MR (DMS0-d6-D20) 15 192040 5 (ppm) = 8.81 (d, J = 7Hz, 1H) 8.14 (d, J = 10Hz, 1H) 8.05-7.45 (m, 6H) 6.69 (d, J = 10Hz, 1H) 5 3.45-3.00 (m, 2H) 1.38 (t, J = 7.5Hz, 3H) 6- (lmidazo [1,2-a] pyridin-2-yl) 3,4-dihydrocarbostyril.

Melting point 230-232 ° C (decomposition), colorless powder.

Example IV

In a suspension of 6- (imidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocart ostyrile (5 g) in dioxane (50 ml), DDQ (6, 47 g) added. The reaction mixture was heated under stirring for 5 hours. When the reaction was completed, the solvent was evaporated. The residue was extracted by addition of chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with 0.5 N sodium hydroxide, washed with water and dried. After evaporation of chloroform, the obtained residue was collected and purified using silica gel column chromatography. Obtained oily product was dissolved in acetone and the solution was adjusted to a pH of about 1 with concentrated hydrochloric acid. The crystals formed were filtered off. The crude crystals thus obtained were recrystallized from water to obtain 2.4 g of 6- (imidazo [1,2-a] pyridin-2-yl) carbostyril monohydrochloride.

20 Melting point above 300 ° C, pale yellow cotton-like crystals.

MR (DMSO-d6) 5 (ppm) = 8.74 (d, 'J = 7Hz, 1H) 8.61 (s, 1H) 8.31 (d, J = 2.5 Hz) 25 8.17- 7.10 (m, 6H) 6.58 (d, J = 9Hz, 1H)

Example V

In an analogous manner as in Example IV, 6- (3-ethylimidazo [1,2-a] pyridin-2-yl) -30 carbostyril monohydrobromide monohydrate was prepared using appropriate starting materials.

Melting point above 300 ° C, colorless cotton-like crystals.

MR (DMS0-d6-D20) 5 (ppm) = 8.81 (d, J = 7Hz, 1H) 35 8.14 (d, J = 10Hz, 1H) 8.05-7.45 (m, 6H) 6.69 ( d, J = 10Hz, 1H) 3.45-3.00 (m, 2H) 1.38 (t, J = 7.5Hz, 3H) 40

Example VI

To a solution of 8-methyl-6- (3-methylimidazo [1,2-a] pyridin-2-yl) carbostyril (2 g) in 40 ml of methanol was added 10% palladium carbon (0.2 g) and the mixture was subjected to catalytic reduction at 60 ° C for 8 hours at a hydrogen gas pressure of 2-3 kg / cm2. After the completion of the reaction, the catalyst was filtered off and the filtrate was concentrated to dryness. The residue was dissolved in acetone and the solution adjusted to a pH of about 1 with concentrated hydrochloric acid. The precipitated crystals were filtered off. The crude crystals thus formed were recrystallized from ethanol to obtain 1.2 g of 8-methyl-6- (3-methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrochloride monohydrate.

50 Melting point 273-276 ° C (decomposition), light yellow needles.

Example VII

In an analogous manner as in Example VI, the following compounds were prepared using the appropriate starting materials.

55 6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide hemihydrate.

Melting point above 300 ° C, light yellow needles.

NMR (DMS0-d6-D20) 192040 16 S (ppm) = 8.65 (d, J = 7Hz, 1H) 8.06-7.73 (m, 2H) 7.67-7.40 (m, 3H) 7 .23-7.03 (m, 1H) 5 3.20-2.50 (m, 4H) 2.72 (s, 3H) 8-Methyl * 6- (imidazo [1,2-a] pyridin-2-yl ) -3,4-dihydrocarbostyril monohydrochloride 3/2 hydrate.

Melting point above 300 ° C, light brown powder.

NMR (DMSO-d6) 10 S (ppm) = 9.64 (s, 1H) 8.86 (d, J = 7Hz, 1H) 8.70 (s, 1H) 8.03-7.30 (m, 5H) 3.10-2.83 (m, 2H) 15 2.67-2.40 (m, 2H) 2.32 (s, 3H) 8-Chloro-6- (imidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocartoostyril monohydrochloride hemihydrate.

Melting point above 300 ° C, light brown cottony crystals.

NMR (DMSO-d6) 20 6 (ppm) = 9.70 (s, 1H) 8.82 (d, J = 7Hz, 1H) 8.75 (s, 1H) 8.05-7.23 (m, 5H) 3.20-2.90 (m, 2H) 25 2.73-2.40 (m, 2H) 6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -1-methyl -3,4-dihydrocarbostyril monohydrobromide.

Melting point above 300 ° C, colorless powder.

NMR (DMSO-d6) 5 (ppm) = 8.85 (d, J = 7Hz, 1H) 30 8.14-7.20 (m, 6H) 3.33 (s, 3H) 3.15-2.87 ( m, 2H) 2.73 (s, 3H) 2.68-2.37 (m, 2H) 8-Methoxy-6- (imidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide.

Melting point 294.5-296.0 ° C (decomposition), pale yellow cottony crystals.

Example VIII

In a solution of 6- (3-methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril (3g) in dimethylfoima-40mide (50ml), 50% sodium hydride in oil (590 mg) and the mixture was allowed to react at room temperature for 2 hours. The mixture was then allowed to react for a further 3 hours after addition of methyl iodide (1.85 g) at room temperature. When the reaction was completed, dimethylformamide was evaporated. Chloroform and 0.5 N sodium hydroxide were added to the residue for extraction. The chloroform layer was washed thoroughly with water and dried, followed by evaporation of chforofim.

45 The residue was purified by silica gel column chromatography and the oily product thus obtained was dissolved in acetone. The solution was adjusted to a pH of about 1 by addition of 48% hydrobromic acid and crystals formed were filtered off. The crude crystals thus obtained were recrystallized from water to obtain 2.9 g of 6- (3-methylimidazo [1,2-a] pyridin-2-yl) -1-methyl-3,4-dihydrocarbostyril monohydrobromide.

50 Melting point above 300 ° C, colorless powder.

NMR (DMSO-d6) 6 (ppm) = 8.85 (d, J = 7Hz, 1H), 8.13-7.20 (m, 6H) 3.33 (s, 3H), 3.15-2.87 (m, 2H) 55 2.73 (s, 3H), 2.68-2.37 (m, 2H) 17 192040

Example IX

5- (α-Bromobutyryl) -8-methoxy-3,4-dihydrocarbostyril (5 g), 2-aminopyridine (4.33 g) and acetic acid nitrile (20 ml) were reacted under reflux for 6 hours. The reaction mixture was concentrated to dryness and the residue was brought to crystallization by addition of water. The crystals were filtered off and washed with water. The crystals were dissolved in acetone and the solution was adjusted to a pH of about 1-2 by addition of 48% hydrobromic acid. The crystals formed were filtered off. The crude crystals thus obtained were recrystallized from methanol-ether to obtain 3.73 g of 5- (3-ethylimidazot-1,2-a-pyridin-2-yl) -1-methoxy-3,4-dihydrocarbostyril monohydrobromide.

Melting point 254-256.5 ° C, colorless powder.

10

Example X.

5-Chloroacetyl-8-methoxycarbostyril (5 g), 2-amino-4-pikoline (6.45 g) and acetic acid nitrile (40 ml) were reacted under reflux and the reaction mixture was cooled with ice water. Crystals formed were filtered off. The crystals were suspended in acetone-methanol and the suspension was adjusted to a pH of about 1 by adding concentrated hydrochloric acid. Formed crystals were filtered and recrystallized from methanol to obtain 4.0 g of 5- (7-methylimidazo [1, 2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride 3/2 hydrate.

Melting point 269.5-271.5 ° C (decomposition), colorless powder.

Example XI

In an analogous manner as in Example II, the compounds below were prepared using appropriate starting materials.

5- (1midazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride monohydrate.

Melting point 256-257.5 ° C (decomposition), colorless cotton-like crystals (water).

5- (1midazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate.

Melting point 260-261 ° C (decomposition), colorless needles (methanol).

5- (3-Methylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide 3/2 hydrate.

Melting point 207.5-210.0 ° C, light yellow flakes (methanol-ether).

5- (3-methylimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrobromide.

Melting point 263-264.5 ° C, light yellow needles (methanol-ether).

5- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide 1/4 hydrate.

Melting point 299-231.5 ° C, colorless powder (methanol-ether).

1-Methy1 -5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride monohydrate. Melting point 259-260.5 ° C (decomposition), colorless needles (methanol-ether).

5- (6-Chloroimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride dihydrate.

Melting point 270-272.5 ° C (decomposition), colorless powder (methanol-ether).

5- (8-Methylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride monohydrate.

Melting point 255-258.0 ° C (decomposition), pale yellow cottony crystals (water).

5- (3,7-Dimethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide monohydrate.

40 Melting point 249-251 ° C, colorless prisms (methanol-ether).

5- (3-Methylimidazo [1,2-a] pyridin-2-yl) -8-hydroxycarbostyril monohydrochloride 1/4 hydrate.

Melting point above 300 ° C, pale yellow cottony crystals (water).

Elemental analysis for C 1 H 1 OgNa.HCI.IMHgO

45 -

C Η N

Ber. (%): 60.38 3.96 13.21

Gev. (%): 60.55 3.80 13.23 50 - NMR (DMSO-D20) 8 (ppm) = 8.82 (d, J = 7.0, 1H) 8.43 (s, 1H) 55 8.18 (d, J = 10.0.1H) 8.06-7.90 (m, 2H) 7.63-7.43 (m, 1H) 192040 18 7.44 (d, J = 8 , 0.1H) 7.23 (d, J = 8.0, 1H) 6.73 (d, J = 10.0, 1H) 5 5- (1midazo [1,2-a] pyridin-2-yl) - 8-hydroxy-3,4-dihydrocart) OStyril monohydrochloride 3/2 hydrate.

Melting point above 300 ° C, colorless cotton-like crystals (water).

Elemental analysis for C16 H1302N3.HCI.3 / 2H20 10 -: -

C Η N

Ber. (%) 56.06 5.00 12.26

Gev. (%): 55.82 4.91 12.34 Ί5 - NMR (DMSO) 5 (ppm = 9.02 (s, 1H) 8.93 (d, J = 7.0, 1H) 20 8.47 ( s, 1H) 8.10-7.80 (m, 2H) 7.60-7.40 (m, 1H) 7.23 (d, J = 8.0, 1H) 7.01 (d, J = 8, 0.1H) 25 3.26-2.97 (m, 2H) 2.63-2.36 (m, 2H) 5- (3-Methyl-6-nitroimidazo [1,2-a] pyridine-2- yl) -8-methoxycarbostyril monohydrobromide.

Melting point 247.5-250 ° C (decompn.), Yellow needles (methanol-ether).

5- (3-Methyl-8-hydroxyimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride.

Melting point 266-268 ° C (decomposition), colorless powder (methanol-ether).

5- (8-Methoxyimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride 5/2 hydrate.

Melting point 215.0-216.5 ° C (decomposition), colorless cotton-like crystals (water).

5- (3-Methyl-6,8-dibromimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide.

Melting point 246-247 ° C (decomposition), light yellow needles (methanol).

1-Allyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbosty rill monohydrochloride.

Melting point 250-252 ° C (decomposition), colorless needles (methanol-ether).

1-Benzyl-4- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride monohydrate. Melting point 243.5-245.5 ° C (decomposition), colorless needles (ethanol).

40 1 -Propagyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate. Melting point 241-242.5 ° C (decomposition), colorless needles (ethanol).

Example XII

To a solution of 5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxycaibostyril (4 g) in acetic acid (80 ml), a solution of bromine (2.22 g) was added dropwise at room temperature. ) in acetic acid (5 ml). When everything was added, the mixture was stirred for 3 hours. Precipitated crystals were filtered and washed with diethyl ether. The crystals thus obtained were dissolved in acetone and the solution was adjusted to a pH of about 1 by adding 48% hydrobromic acid. Precipitated crystals were filtered and recrystallized from methanol-ether to give 5 g of 5- (3-50 bromimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide monohydrate.

Melting point 245-247.5 ° C (decomposition) light yellow needles.

Example XIII

To a suspension of 5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydroxycarbostyril (2.5 g) in 300 ml 55 water was added 1.71 ml concentrated hydrochloric acid . The mixture was heated and the solution was cooled to 50 ° C and 10 ml of an aqueous solution of 0.65 g of sodium nitrite was added dropwise with stirring at 50 ° C. When all was added, the reaction was continued for an additional 2 hours and the 1920s reaction mixture was left overnight at room temperature. Precipitated crystals were filtered and recrystallized from methanol to obtain 1.9 g of 5- (3-nitrosoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyrile.

Melting point 236.5-238 ° C (decomposition), green cottony crystals.

5

Example XIV

To a suspension of 5- (3-nitrosoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril (20.85 g in methanol 500 ml) was added 20 ml of concentrated hydrochloric acid to make the suspension acidic. 10% Palladium carbon (2 g) was added to the slurry and catalytic reduction was performed at room temperature under atmospheric pressure. After the completion of the reaction, solution of water was added to the reaction mixture and the resulting mixture was heated. After the catalyst was filtered off, the filtrate was concentrated to dryness. Acetone was added to the residue and the precipitated crystals were filtered off and recrystallized from water to obtain 21.20 g of 5- (3-aminoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4 dihydrocarbostyril monohydrochloride hemihydrate.

Melting point 254.5-257.0 ° C (decomposition), light yellow needles.

Example XV

A solution of 5- (3-aminoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril (5 g) in 90% formic acid (10 ml) was left at 100 ° for 2 hours. C heated. When the reaction was completed, water was added to the reaction mixture, followed by neutralization with 1 N sodium hydroxide. Precipitated crystals were filtered off, washed with methanol and recrystallized from chloroform-methanol to give 3.05 g of 5- (3-formylaminoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4- dihydrocarbostyril. Melting point 303.5-305 ° C (decomposition), yellow prisms.

Example XVI

A mixture of 5- (3-aminoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril (5 g), 90% formic acid (15 ml) and 35% formalin (5 ml) was refluxed for 26 hours and the reaction mixture was concentrated to dryness. The residue was extracted by addition of 1 N sodium hydroxide and chloroform. The chloroform layer was washed with water and dried, followed by evaporation of the solvent. The residue was passed through a silica gel column and the resulting crystals were converted into hydrochloric acid salt in methanol. Recrystallization from methanol ether gave 500 mg of 5- (3-dimethylaminoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride.

Melting point 242-244.5 ° C (decomposition), colorless prisms.

Example XVII

In a solution of 5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril (5 g) in acetic acid (50 ml), 50% aqueous dimethylamine solution (1.7 g) and 35% formalin solution in water (1.62 g). The mixture was stirred at 60 ° C for 6 hours. After evaporation of the solvent, the residue was extracted by adding chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with water and dried, followed by evaporation of the solvent. The residue was dissolved in methanol and the solution was adjusted to a pH of about 1 by addition of concentrated hydrochloric acid and concentrated to dryness. Acetone was added to the residue to precipitate crystals which were filtered off. The crude crystals thus obtained were recrystallized from methanol-acetone to obtain 5- (3-dimethylaminomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril dihydrochloride chloride trihydrate.

Melting point 213.5-216 ° C (decomposition), colorless cotton-like crystals.

Example XVIII

To a suspension of 5- (3-dimethylaminomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril (1.5 g) in 50 vinegar vacuum nitrile (20 ml) was added methyl iodide (1.5 ml) and the mixture was stirred at 40 ° C for 1 hour.

Crystals so formed were filtered off and recrystallized from water to obtain 1.7 g of 5- (3-trimethylammoniomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyriododriod trihydrate.

Melting point 136-138 ° C (decomposition), light yellow granules.

55 Example XIX

5- (3-Trimethylammoniomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyrileodide (8 g) and sodium cyanide (3.2 g) were added to water (100 ml) and the mixture was stirred for 5 hours reflux heated.

192040 20

Precipitated crystals were filtered off. After washing with methanol, the compound in methanol with concentrated hydrochloric acid was converted into hydrochloric acid salt and recrystallized from methanol ether to give 3.6 g of 5- (3-carbamoylmethylimidazo [1,2-a] pyridin-2-yl) -8- methoxycarbostyril mono hydrochloride 5A hydrate.

5 Melting point 250.5-251.5 ° C (decomposition), colorless needles.

Example XX

A solution of 5- (3-trimethylammoniomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyriljodide (4.3 g) in water (40 ml) was heated under reflux with dropwise addition of 10 ml of solution in water of 440 mg of sodium cyanide. When all was added, the reaction mixture was allowed to react for 30 minutes and then cooled. Precipitated crystals were filtered off and recovered by passing over a silica gel column. The crude crystals thus formed were recrystallized from methanol to obtain 0.85 g of 5- (3-cyanomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyrile.

Melting point 261-263 ° C (decomposition), colorless prisms.

15

Example XXI

A mixture of 5- (3-carbamoylmethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril (1.6 g), potassium hydroxide (2.6 g), water (3 ml) and ethanol (9 ml) was heated under reflux for 1 hour. After the completion of the reaction, water was added to the reaction mixture, which was then treated with activated charcoal and adjusted to a pH of about 1 by addition of concentrated hydrochloric acid, followed by standing overnight. Precipitated crystals were filtered and recrystallized from dilute hydrochloric acid to give 0.9 g of 5- (3-carboxymethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril hemihydrate. Melting point 259-260.5 ° C (decomposition), colorless needles.

Example XXII

5- (1midazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril (1.4g) and DDQ (3.5g) were added to dioxane (30ml) and the mixture was heated at reflux for 5 hours. The reaction mixture was concentrated under reduced pressure and the residue was extracted by adding chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with 0.5 N sodium hydroxide and then twice with water. After drying, the chloroform was evaporated. The residue was collected and purified through a silica gel column. The crude crystals thus obtained were dissolved in acetone and hydrochloric acid was added to the resulting solution. Precipitated crystals were filtered and recrystallized from water to give 410 mg of 5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride monohydrate.

Melting point 256-257.5 ° C (decomposition), colorless cotton-like crystals.

Example XXIII

To a solution of 5- (3-ethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril (2 g) in methanol (50 ml) was added 10% palladium carbon (0.2 g) and catalytic reduction was performed for 6 hours at 50-60 ° C under hydrogen pressure of 2-3 kg / cm 2. The catalyst was filtered off and the filtrate was concentrated to bromine. The residue was dissolved in acetone and hydrobromic acid was added to the solution. Precipitated crystals were filtered off and the crude crystals thus obtained were recrystallized from methanol-ether to obtain 1.5 g of 5- (3-ethylimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4 dihydrocarbostyril monohydrobromide.

45 Melting point 254-256.5 ° C, colorless powder.

Example XXIV

In a solution of 5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril (3g) in dimethylformamide (100ml), 50% sodium hydride in oil ( 600 mg) and the mixture was stirred at room temperature for 2 hours. After addition of allyl bromide (1.48 g), the mixture was allowed to react at room temperature for 3 hours. The reaction mixture was concentrated to dryness and the residue was extracted by addition of chloroform and 0.5 N sodium hydroxide. The chloroform layer was washed with water and dried after evaporation. The residue was purified using silica gel column chromatography, and the oily product was dissolved in acetone and converted into hydrochloric acid salt by addition of hydrochloric acid. 55 Precipitated crystals were filtered and recrystallized from methanol-ether to obtain 1.76 g of 1 -Allyl-5 (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride.

Melting point 250-252 ° C (decomposition), colorless needles.

21 192040

Example XXV

In an analogous manner as in Example XXIV, the following compounds were prepared using appropriate starting materials.

1-Benzyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride monohydrate.

5 Melting point 243.5-245.5 ° C (decomposition), colorless needles (ethanol).

1-Propargyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate. Melting point 241.5-242.5 ° C (decomposition), colorless needles (ethanol).

1-Methyl-5-imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride monohydrate. Melting point 259-260.5 ° C (decomposition), colorless needles (methanol-ether).

10

Example XXVI

In an analogous manner as in Examples II and VI, the following compounds were prepared using appropriate starting materials.

6- (3,7-Dimethylimidazo [1,2-a] pyridin-2-yl) carbostyril monohydrochloride hemihydrate.

15 Melting point above 300 ° C, colorless needles (methanol).

NMR (DMSO-d6) 5 (ppm): 2.56 (s, 3H,), 2.67 (3.3H) 6.58 (d, J = 9Hz, 1H) 20 7.34 (bd, J = 7Hz, 1H), 7.49 (d, J = 8Hz, 1H) 7.64-8.11 (m, 4H), 8.59 (d, J = 7Hz, 1H) 6- (5-Methylimidazo [1,2-a ] pyridin-2-yl) carbostyliil monohydrochloride.

25 Melting point above 300 ° C, light yellow powder (methanol) NMR (CF3COOH) 5 (ppm): 2.94 (s, 3H), 7.30-7.55 (m, 2H), 7.83-8.17 (m .3H) .30 8.23-8.47 (m, 2H), 8.53 (bs, 1H), 8.70 (d, J = 9Hz, 1H) 6- (3-Dimethylaminomethylimidazo [1,2- a] pyridin-2-yl) carbostyril monohydrochloride trihydrate. Melting point 204.5-207 ° C (decomposition), colorless needles (water).

6- (3-Trimethylammoniomethylimidazo [1,2-a] pyridin-2-yl) carbostyrillodide 3/4 hydrate.

Melting point 185-188.5 ° C (decomposition), colorless powder (methanol-acetone).

6- (3-Nitrosoimidazo [1,2-a] pyridin-2-yl) carbostyril hemihydrate.

Melting point above 300 ° C, yellowish brown powder.

NMR (CF3COOH) -d ^ 40 5 (ppm): 7.24 (d, J = 9Hz, 1H), 7.83-8.07 (m, 2H), 8.25 (d, J = 9H, 1 H) , 8.43-8.77 (m, 2H), 8.87 (dd, J = 9Hz, 2Hz, 1H), 45 9.12 (d, J = 2Hz, 1H), 9.88 (bd, J = 7Hz, 1H ) 6- (3-Aminoimidazo [1,2-a] pyridin-2-yl) ca rbosty ril.

6- (1midazo [1,2-a] pyridin-2-yl) -1-propargylcarbostyril monohydrochloride 3/4 hydrate.

Melting point 252-253 ° C (decomposition), colorless needles (water).

50 6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide hemihydrate.

Melting point 314.5-318 ° C (decomposition), colorless cotton-like crystals (water). 6 * (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-allyl-3,4-dihydrocarbostyril monohydrochloride.

Melting point 279-282.5 ° C (decomposition), colorless needles (ethanol).

6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-propargyl-3,4-dihydrocarbostyril monohydrochloride monohydrate.

55 Melting point 264-265 ° C (decomposition), colorless cotton-like crystals (water).

6> (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-propargylcarbostyril monochloride 1/4 hydrate.

Melting point 265-266 ° C (decomposition), colorless needles (water).

192040 22 5- (8-Hydroxyimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride.

Melting point 266.5-268.5 ° C (decomposition), colorless powder (methanol-ether).

Example XXVII

In an analogous manner as in Example IV, the following compounds were prepared using appropriate starting materials.

6- (3,7-Dimethylimidazo [1,2-a] pyridin-2-yl) -carbostyrile monohydrochloride hemihydrate.

Melting point above 300 ° C, colorless needles (methanol).

NMR (DMSO-d6) 10 5 (ppm): 2.56 (s, 3H), 2.67 (s, 3H), 6.58 (d, J = 9Hz, 1H), 7.34 (db, J = 7Hz, 1H), 7.49 (d, J = 8Hz, 1H), 7.64-8.11 (m, 4H), 8.58 (d, J = 7Hz, 1H) 6- (5- methyl imidazo [1,2-a] pyridin-2-yl) caitoxystyril monohydrochloride.

Melting point above 300 ° C, light yellow powder (methanol) NMR (CFgCOOH-d 3) S (PPm): 2.94 (s, 3H), 7.30-7.55 (m, 2H), 7.83-8, 17 (m, 3H), 8.23-8.47 (m, 2H), 8.53 (bs, 1H), 8.70 (d, J = 9Hz, 1H) 25 6- (3-Dimethylaminomethylimidazo [1 , 2-a] pyridin-2-yl) carbostyril dihydrochloride trihydrate.

Melting point 204.5-207 ° C (decomposition), colorless needles (water).

6- (3-Trimethylammoniomethylimidazo [1,2-a] pyridin-2-yl) carbostyrillodide 3/4 hydrate.

Melting point 185-188.5 ° C (decomposition), colorless powder (methanol-acetone).

6- (3-Nitrosoimidazo [1,2-a] pyridin-2-yl) carbostyril hemihydrate.

30 Melting point above 300 ° C, yellowish brown powder.

NMR (CF3COOH-d.,) 8 (ppm): 7.24 (d, J = 9Hz, 1H), 7.83-8.07 (m, 2H), 8.25 (d, J = 9Hz, 1H), 35 8.34-8.77 (m, 2H), 8.77 (dd, J = 9Hz, 2Hz, 1H), 9.12 (d, J = 2Hz, 1H), 9.88 (bd, J = 7Hz, 1H) 6- (3-Aminoimidazo [1,2-a] pyridin-2-yl) carbostyrile.

40 6- (1midazo [1,2-a] pyridin-2-yl) -1-propargylcarbostyrile monochloride 3/4 hydrate.

Melting point 252-253 ° C (decomposition), colorless needles (water).

6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide hemihydrate.

Melting point 314.5-318 ° C (decomposition), colorless cotton-like crystals (water).

6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-propargylcarbostyril monohydrochloride 1/4 hydrate.

45 Melting point 265-266 ° C (decomposition), colorless needles (water).

5- (8-Hydroxyimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride.

Melting point 266.5-268.5 ° C (decomposition), colorless powder (methanol-ether).

Example XXVIII

In an analogous manner as in Example VIII, the following compounds were prepared using appropriate starting materials.

6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-allyl-3,4-dihydrocarbostyril monohydrochloride.

Melting point 279-282.5 ° C (decomposition), colorless needles (ethanol).

6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-propargyl-3,4-dihydrocarbostyril monohydrochloride monohydrate.

55 Melting point 264-265 ° C (decomposition), colorless cotton-like crystals (water).

6- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -1-propargylcarbostyril monohydrochloride 1/4 hydrate.

Melting point 265-266 ° C (decomposition, colorless needles (water).

23 192040 6- (1midazo [1,2-a] pyridin-2-yl) -1-propargylcarbostyril monohydrochloride 3/4 hydrate.

Melting point 252-253 ° C (decomposition), colorless needles (water).

Example XXIX

The pharmacological activity of the compounds of the invention have been determined as described below. Isolated blood perfused sinoatrial node preparations.

The experiments were performed on adult bastard dogs of both sexes. The sinoatrial node preparations were obtained from dogs, weighed 8-14 kg, anesthetized with pentobarbit al sodium (30 ml / kg i.v.), received heparin sodium (1000 unit / mg i.v.) and had been ejected. The preparation essentially consisted of the right atrium and was put on cold Tyrode's solution. The preparation was placed in a glass water jacket, which was kept at about 38 ° C and flowed through donated dog blood through the cannulated right coronary artery at a constant pressure of 100 mm Hg. Dogs used as donors had 18-27 kg body weight and were anesthetized with pentobarbital sodium (30 mg / kg IV). Heparin sodium was given at a dose of 1000 15 unit / kg i.v. The pressure developed by the right atrium was measured with a strain gauge translator. The right atrium was loaded with a weight of about 1.5 g. The sinus rate was measured by a cardiotachometer, driven by the developed right atrium tension. Blood flow through the right coronary artery was measured with an electromagnetic flow meter. Recording of developed tension, sinus rate and blood flow was done on cards with an ink-writing rectifier. Details of the formulation are described by Chiba et al. (Japan. J. Pharmacol., 25, 433-439, 1975; Naunym-Schmiedberg's Arch. Pharmacol., 289, 315-325, 1975).

The 10-30 µl compounds were injected intraarterially over 4 seconds. The inotropic effects of the compounds are expressed as a percentage of the developed suspension for the injection of the compounds. The effects of the compounds on sinus rate (beats / minute) or blood flow (ml / minute) are expressed as a difference between the values before and after the injection of the compounds.

The results obtained are shown in Table A below.

Test compounds.

1. 6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -1-methyl-3,4-dihydrocarbostyril monohydrobromide.

2. 8-Methoxy-4- (3-methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide.

3. 5- (3-Methyl-6,8-dibromimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide.

4. 1 -Propargyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate.

5. 5- (3,7-Dimethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide monohydrate.

6. 5- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide 1/4 hydrate.

7. 1- (Methyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride.

8. 5- (6-Chloroimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride dihydrate.

9. 5- (7-Methylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride 3/2 hydrate.

10. 5- (3-Dimethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril dihydrochloride trihydrate.

11.1 -Allyl-5- (1midazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride.

12.- (1-midazo [1,2-a] pyridin-2-yl) -8-hydroxycarbostyril monohydrochloride.

13. 6- (1midazole [1,2-a] pyridin-2-yl) carbostyril monohydrochloride.

14. 6- (3-Ethylimidazo [1,2-pyridin-2-yl) carbostyril monohydrobromide monohydrate.

15. 5- (3-Methyl-6-nitroimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril.

16. 5- (3-Bromoimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide monohydrate.

45 17. 5- (8-Hydroxyimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril.

18. 5- (8-Methoxyimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride 5/2 hydrate.

19. 5- (1midazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride.

20. 6- (1midazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrochloride.

21. 6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -8-methyl-3,4-dihydrocarbostyril monohydrochloride monohydrate.

50 22. 5- (3-Ethylimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrobromide.

23. 5- (3-Methylimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrobromide.

24. 5- (3-Methylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide hemihydrate.

25. 5- (1midazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride 3/2 hydrate.

26. 6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide hemihydrate.

55 27. 6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -8-chloro-3,4-dihydrocaibostyril monohydrobromide hemihydrate.

28. 5- (3-Nitrosoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril.

29. 5- (3-Aminoimidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-dihydrocarbostyril monohydrochloride hemihydrate.

192040 24 30. 5- (3-Trimethylammoniomethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyriljodide trihydrate.

31. 5- (3-Carbamoylmethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride 5/4 hydrate.

32. 5- (3-Cyanomethylimidazo [1,2-a] pyridin-2 * yl) -8-methoxycarbostyril.

33. 5- (3-Cafboxymethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril hemihydrate.

5 a. Isoprenaline (comparison) b. Amrinon (comparison)

TABLE A

10 Test binding Dose (pmol / l)% change in change in coronary contraction

Atrial muscle blood flow (ml / min) 15 1 1 77.7 3.6 2 1 129.4 1.6 3 0.3 41.2 1.8 4 1 63.2 2.4 5 1 109.1 4, 0 20 6 1 61.5 2 7 1 45.8 1.5 8 0.3 18.2 1.2 9 0.3 14.5 10 1 53.2 2.0 25 11 1 50.0 2.6 12 1 18.8 2.4 13 0.1 40.6 1.6 14 0.03 71.4 1.8 15 0.3 35.7 1.4 30 16 0.3 10.0 17 0.3 38.5 0.8 18 0.3 14.5 19 1 89.7 2.8 20 1 105 3.5 35 21 0.1 81.2 2.0 22 0.3 25 0.8 23 1 104, 2 1.0 24 1 84.6 0.4 25 1 95 1.2 40 26 0.3 123.3 2.4 27 1 194.7 2.0 28 0.1 18.8 29 1 37 1.6 30 0.3 40 0.6 45 31 0.3 13 0.8 32 0.3 73 1.2 33 0.1 20 a 1 x 10 s 84.8 3 b 1 86.4 4.8 SO -; -

Preparation Example I

8-Methoxy- (3-methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide 5 mg 55 Starch 132 mg

Magnesium stearate 18 mg

Lactose 45 mg

Total: 200 mg 25 192040

Tablets of the above composition were prepared in the usual manner.

Preparation Example II

6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -1-methyl-3,4-dihydrocarbostyril monohydrobromide 10 mg 5 Starch 127 mg

Magnesium stearate 18 mg

Lactose 45 mg

Total: 200 mg 10 Tablets of the above composition were prepared in the usual manner.

Preparation Example III

8-Chloro-6- (3-Methylimidazo [1,2-a] pyridin-2-yl) -3,4-dihydrocarbostyril monohydrobromide hemihydrate 500 mg

Polyethylene glycol (molecular weight: 4000) 0.3 g 15 Sodium chloride 0.9 g

Polyoxyethylene sorbitan monooleate 0.4 g

Sodium metabisulfite 0.1 g

Methyl paraben 0.18 g

Propyl paraben 0.02 g 20 Distilled water for injection 100 ml

The above parabens, sodium metabisulfite and sodium chloride were dissolved in the distilled water at 80 ° C with stirring. Resulting solution was cooled to 40 ° C and polyethylene glycol and polyoxyethylene sorbitan monooleate were dissolved in it. Distilled water for injection was then added to adjust the volume to the final volume. The mixture was filtered using a filter paper suitable for sterilization and then filled into a 1 ml ampoule, thus obtaining a preparation for injection.

Preparation Example IV

1 -Methyl-5- (imidazo [1,2-a] pyridin-2-yl) -8-methoxy-3,4-30 dihydrocarbostyril monohydrochloride monohydrate 5 mg

Starch 132 mg

Magnesium stearate 18 mg

Lactose 45 mg

Total: 200 mg 35

Tablets of the above composition were prepared in the usual manner.

Preparation Example V 5- (6-Chloroimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrochloride dihydrate 10 mg 40 Starch 127 mg

Magnesium stearate 18 mg

Lactose 45 mg

Total: 200 mg 45 Tablets of the above composition were prepared in the usual manner.

Preparation Example VI

5- (3,7-Dimethylimidazo [1,2-a] pyridin-2-yl) -8-methoxycarbostyril monohydrobromide monohydrate 500 mg

Polyethylene glycol (molecular weight: 4000) 0.3 g 50 Sodium chloride 0.9 g

Polyoxyethylene sorbitan monooleate 0.4 g

Sodium metabisulfite 0.1 g

Methyl paraben 0.18 g

Propylparabene 0.02 g 55 Distilled water for injection 100 ml

Claims (3)

192040 26 The above parabens, sodium metabisulfite and sodium chloride were dissolved in the distilled water at 80 ° C with stirring. Resulting solution was cooled to 46 ° C and polyethylene glycol and polyoxyethylene sorbitan monooleate dissolved therein. Distilled water for injection was then added to adjust the volume to the final volume. The mixture was filtered using a sterilization-suitable filter paper and then filled into a 1 ml ampoule, thus obtaining a preparation for injection. Industrial Applicability As described above, the carbostyril compounds and their pharmaceutically acceptable salts thereof are useful as a cardiotonic agent for treating heart diseases such as congestive heart defects, etc. Carbostyril compounds, characterized in that they have the formula 1, wherein R 1 represents a hydrogen atom, a lower alkyl group, a lower alkenyl group, a lower alkynyl group, or a phenyl-lower alkyl group, R 2 represents a hydrogen atom, a lower alkyl group, represents a lower alkoxy group, a halogen atom, or a hydroxyl group, Ra represents a hydrogen atom, a lower alkyl group, a halogen atom, a nitroso group, an amino group, which may be substituted with a lower alkyl group, a lower alkanoylamino group, an N, N-di-lower alkylaminomethyl group, a carbamoylmethyl group, a cyanomethyl group or a carboxymethyl group , R4 and Rs, which may be the same or different, each represent a hydrogen atom, a halogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group or a nitro bar, the bond between the 3- and 4-position of the carbostyril core a is a single bond or a double bond and the site where the imidazopyridyl group of formula 24 is bonded to the carbostyril core is 5- or 6-position, provided that when the imidazopyridyl group is at the 5-position of the carbostyril core Bonded, R 2 may not be a hydrogen atom, a lower alkyl group or a halogen atom, or a pharmaceutically acceptable salt thereof. A compound according to claim 1, characterized in that it is test compound 4, 5, 6, 11, 15, 19, 20, 21, 24 or 27 as referred to in the preceding description. 3. Pharmaceutical composition with cardiotonic action, characterized in that it contains as active substance a compound of the formula 1 according to claim 1 or a pharmaceutically acceptable salt thereof. Hereby 7 sheets drawing