JP2782823B2 - Nicotinamide compounds - Google Patents

Description

Description: TECHNICAL FIELD The present invention relates to a novel nicotinamide compound or a pharmaceutically acceptable acid addition salt thereof which is useful as a drug, especially as an anticancer agent.

[Conventional technology]

JP-A-55-81861 discloses a bisnicotinamide derivative having an anti-inflammatory action and an arachidonic acid-induced thromboprotective action, and JP-A-56-75474 discloses an antithrombotic action, an anti-atherosclerotic action, 1,2 with vasospasm inhibitory action
-Bis (nicotinamide) propane is disclosed.

[Problems to be solved by the invention]

In recent years, deaths from cancer, especially from lung cancer, have shown a significant increase. However, despite the remarkable increase in the number of lung cancer patients, few existing chemotherapeutic agents are effective for lung cancer, especially non-small cell lung cancer. Therefore, there is a need for the development of drugs that are effective for lung cancer, especially non-small cell lung cancer, and for the development of drugs that are specific for lung cancer in order to reduce side effects and toxicity.

[Means for solving the problem]

Therefore, the present inventors have conducted intensive studies from this viewpoint, and as a result, the novel nicotinamide compounds are not only lung cancer, especially non-small cell lung cancer in which existing anticancer drugs show no effect as well as small cell lung cancer. The present inventors have found that the present invention is specifically effective also for lung cancer such as large cell carcinoma and linear carcinoma, and completed the present invention.

That is, the present invention relates to the general formula Or a pharmaceutically acceptable acid addition salt thereof.

In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a formyl group, -COOR ⁶ (wherein R ⁶ represents a hydrogen atom, a lower alkyl group or an aralkyl group.)
A group represented by (Wherein, R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, a lower alkyl group or an aralkyl group, or R ⁷ and R ⁸ represent a group which forms a heterocyclic ring together with an adjacent nitrogen atom A), or (Wherein, R ⁹ and R ¹⁰ are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group, or R ⁹ and R ¹⁰ are a group which forms a heterocyclic ring together with an adjacent nitrogen atom. A represents at least one sulfur atom or NR ¹¹ (wherein R ¹¹ represents a hydrogen atom, a lower alkyl group or an acyl group) in the chain.
Having 2 to 2 carbon atoms which may have a lower alkyl group, a phenyl group, an aralkyl group, an oxo, an oxime (oxime includes an alkoxyme) or an amine as a substituent on the chain. 30 alkylene, alkenylene or alkynylene, and Het represents a fused heterocyclic ring.

In the present specification, a halogen atom is fluorine, chlorine,
Bromine and iodine, lower alkyl groups are methyl, ethyl,
Propyl, isopropyl, butyl, etc. isobutyl ,, tert-butyl, methoxy and lower alkoxy groups, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, and the like tertiary butoxy, in -COOR ^6, R ⁶
A lower alkoxycarbonyl group is a lower alkyl group such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, isopropoxycarbonyl, butoxycarbonyl, isobutoxycarbonyl, tert-butoxycarbonyl group and the like, and an aralkyl group is benzyl, phenylethyl, A phenylpropyl or benzyl ring in which a benzene ring is substituted with a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, etc., is meant. Further, the fused heterocycle means a fused heterocycle containing at least one nitrogen atom, oxygen atom or sulfur atom, such as indole, isoindole, indolizine, quinoline, isoquinoline, benzimidazole, imidazopyridine, imidazothiazole, benzo Thiophene, benzofuran, imidazobenzothiazole, thiazorobenzimidazole and the like. Examples of the group which forms a heterocyclic ring with an adjacent nitrogen atom include a cyclic amino compound which may have a hetero atom such as nitrogen, oxygen, sulfur atom and the like in addition to the nitrogen atom, for example, pyrrolidinyl, morpholino, thiomorpholino , A 5- to 7-membered saturated cyclic amino compound such as piperidino, piperazinyl, homopiperazinyl and the like and a 5- to 6-membered unsaturated cyclic compound such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazinyl and pyrimidinyl. It is. The cyclic compound may have a substituent. Examples of the substituent include a lower alkyl group (as defined above), a lower alkoxy group (as defined above), an acyl group (acetyl, propionyl, butyryl, etc.), a phenyl group (Which may be substituted by 1 to 3 halogen atoms, lower alkyl group, lower alkoxy group, trifluoromethyl group, hydroxyl group, etc.).

Alkylene having 2 to 30 carbon atoms includes, for example, ethylene, trimethylene, tetramethylene, pentamethylene,
Hexamethylene, heptamethylene, octamethylene, decamethylene, dodecamethylene, tetradecamethylene, hexadecamethylene, octadecamethylene, eicosamethylene, triacontamethylene and the like, alkenylene having 2 to 30 carbon atoms include vinylene, Propenylene,
Butenylene, butadienylene, pentenylene, hexenylene, hexadienylene, heptenylene, octenylene, decenylene, octadesenylene, eicosenylene,
Examples of triacontenylene and the like and alkynylene having 2 to 30 carbon atoms include, for example, ethynylene, propynylene, butynylene, pentynylene, hexynylene, heptynylene, octynylene, decinylene, octadecynylene, eicosynylene, and triacontinylene. These alkylene, alkenylene and alkynylene represent a sulfur atom or NR ¹¹ in the chain, wherein R ¹¹ represents a hydrogen atom, a lower alkyl group or an acyl group (acetyl, propionyl, butyryl, etc.). At least one, preferably 1 to 3
And a lower alkyl group, a phenyl group, an aralkyl group, an oxo group, or an oxime group as a substituent on the chain [oxime is an alkoxym having an alkyl portion having 1 to 4 carbon atoms (methoxym, ethoxym, propoxym , Butoxime, etc.) or an amine.

Examples of acceptable acid addition salts of the compound of the formula (I) include inorganic acid salts such as hydrochloride, hydrobromide, sulfate and phosphate, and maleate, fumarate, citrate and succinate. Organic acid salts such as acid salts, tartrate salts, methanesulfonate salts, and p-toluenesulfonate salts. Hydrates are also included in the present invention.

The cis and trans geometric isomers, optical isomers and stereoisomers based on asymmetric carbon, and mixtures thereof in the compound of the formula (I) of the present invention are all included in the present invention.

 The production method of the compound of the present invention is as follows.

Method 1) The compound represented by the general formula (I) (Wherein each symbol is as defined above) and a compound represented by the general formula (Wherein each symbol has the same meaning as described above.), Or a reactive derivative thereof.

When the compound of the general formula (III) is a free carboxylic acid, the reaction is carried out with dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halide (phosphorus trichloride, phosphorous pentachloride, phosphorous oxychloride), diethylchlorophosphite, o-phenylene In the presence of a condensing agent such as chlorophosphite or ethyldichlorophosphite, an inert solvent (any solvent may be used as long as the reaction is not hindered. For example, dimethylformamide, diethylformamide, dimethylacetamide, tetrahydrofuran, etc., or any mixture thereof) It is a solvent and can be appropriately selected and used)
It is carried out for several hours to several tens of hours under medium, cooling, room temperature or heating.

When an acid chloride (chlorine, bromine, iodine, etc.) is used as a reactive derivative of the compound of the general formula (III), the reaction may be carried out in a suitable solvent (any one that does not hinder the reaction,
For example, halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; esters such as ethyl acetate and butyl acetate; ethers such as tetrahydrofuran and dioxane; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; acetonitrile; In a nitrile such as pionitrile, an aromatic hydrocarbon such as benzene, toluene and xylene, an amide such as dimethylformamide, diethylformamide and dimethylacetamide, or an arbitrary mixed solvent thereof, a deoxidizing agent (for example, triethylamine, In the presence of an organic salt such as pyridine or N, N-diethylaniline or an inorganic base such as sodium carbonate, potassium carbonate or sodium bicarbonate), the reaction is carried out for several hours to several tens of hours under cooling or at room temperature or under heating.

When a symmetrical anhydride or a mixed acid anhydride such as an alkyl carbonate mixed acid anhydride, an alkyl phosphoric acid mixed acid anhydride or an alkyl phosphorous acid mixed acid anhydride is used as a reactive derivative of the compound of the general formula (III), The reaction is carried out in an inert solvent (tetrahydrofuran, dimethylformamide, diethylformamide, dimethylacetamide or a mixed solvent thereof) in the presence of a tertiary base such as triethylamine, pyridine, N-methylmorpholine or N, N-dimethylaniline. The reaction is carried out under cooling, at room temperature, or under heating for several hours to several tens of hours.

When an active amide such as acid imidazolide, acid pyrrolidide, or 2,4-dimethylpyrazolide is used as a reactive derivative of the compound of the general formula (III), the reaction is performed in an inert solvent (any reaction solvent may be used as long as it does not hinder the reaction. For example, alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, and isobutyl alcohol; hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate and butyl acetate; tetrahydrofuran and dioxane Ethers, such as acetone, methyl ethyl ketone, ketones such as methyl isobutyl ketone, acetonitrile, nitriles such as propionitrile, benzene, toluene,
In an aromatic hydrocarbon such as xylene, an amide such as dimethylformamide, diethylformamide, or dimethylacetamide, or any mixed solvent thereof) under cooling or at room temperature or under heating for several hours to several tens of hours. .

When the reactive derivative of the compound of the general formula (III) is an ester (e.g., methyl ester, ethyl ester, phenyl ester, p-nitrophenyl ester), the reaction may be carried out in an inert solvent (any solvent that does not hinder the reaction, For example, methyl alcohol, ethyl alcohol,
Alcohols such as propyl alcohol, isopropyl alcohol, butyl alcohol, and isobutyl alcohol;
Hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; esters such as ethyl acetate and butyl acetate; ethers such as tetrahydrofuran and dioxane; ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone; acetonitrile and propionitrile , Aromatic solvents such as benzene, toluene and xylene, amides such as dimethylformamide, diethylformamide and dimethylacetamide, or any mixed solvent thereof) at room temperature or under heating, preferably under reflux. It takes several hours to several tens of hours.

Method 2) The compound represented by the general formula (I) (Wherein each symbol is as defined above) and a compound represented by the general formula (Wherein each symbol has the same meaning as described above.), Or a reactive derivative thereof.

When the compound of the general formula (V) is a free carboxylic acid, the reaction is carried out with dicyclohexylcarbodiimide, titanium tetrachloride, phosphorus halide (phosphorus trichloride, phosphorous pentachloride, phosphorous oxychloride), diethylchlorophosphite, o-phenylene In the presence of a condensing agent such as chromatophosphite or ethyldichlorophosphite, an inert solvent (any solvent may be used as long as it does not hinder the reaction; for example, dimethylformamide, diethylformamide, dimethylacetamide,
In tetrahydrofuran or the like or an arbitrary mixed solvent thereof, which can be appropriately selected and used) under cooling or at room temperature or under heating for several hours to several tens of hours.

When an acid chloride (chlorine, bromine, iodine, etc.) is used as a reactive derivative of the compound of the general formula (V), the reaction may be carried out in any suitable solvent (any one which does not hinder the reaction, for example, methylene chloride, chloroform, tetrachloromethane, chloroform, etc.). Halogenated hydrocarbons such as carbon chloride, esters such as ethyl acetate and butyl acetate, ethers such as tetrahydrofuran and dioxane, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, A deacidifying agent (for example, triethylamine, pyridine, N, N-diethyl) in an aromatic hydrocarbon such as benzene, toluene and xylene, an amide such as dimethylformamide, diethylformamide and dimethylacetamide, or an arbitrary mixed solvent thereof. Organic salts such as aniline and sodium carbonate , Potassium carbonate, carried out in several tens of hours to several hours under cooling or at room temperature or heating in the presence of an inorganic base) such as sodium bicarbonate.

When a symmetrical acid anhydride or a mixed acid anhydride such as a mixed acid anhydride of an alkyl carbonic acid, a mixed acid anhydride of an alkyl phosphoric acid and a mixed acid anhydride of an alkyl phosphorous acid is used as a reactive derivative of the compound of the general formula (V). The reaction is carried out in an inert solvent (tetrahydrofuran, dimethylformamide, diethylformamide, dimethylacetamide or any mixed solvent thereof) in the presence of a tertiary base such as triethylamine, pyridine, N-methylmorpholine, N, N-dimethylaniline. The reaction is performed for several hours to several tens of hours under cooling, at room temperature, or under heating.

When an active amide such as acid imidazolide, acid pyrrolidide, or 2,4-dimethylpyrazolide is used as a reactive derivative of the compound of the general formula (V), the reaction may be carried out in an inert solvent (any solvent may be used as long as it does not hinder the reaction, For example, alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, and isobutyl alcohol; hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate and butyl acetate; tetrahydrofuran and dioxane Ethers, such as acetone, methyl ethyl ketone, ketones such as methyl isobutyl ketone, acetonitrile, nitriles such as propionitrile, benzene, toluene, aromatic hydrocarbons such as xylene, dimethylformamide,
Amides such as diethylformamide and dimethylacetamide, or any mixed solvent thereof) under cooling or at room temperature or under heating for several hours to several tens of hours.

The reactive derivative of the compound of the general formula (V) is an ester (methyl ester, ethyl ester, phenyl ester, p
-Nitrophenyl ester), the reaction may be carried out in an inert solvent (any solvent that does not interfere with the reaction,
For example, alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, and isobutyl alcohol; hydrocarbons such as methylene chloride, chloroform, and carbon tetrachloride; esters such as ethyl acetate and butyl acetate; tetrahydrofuran and dioxane Ethers such as acetone, methyl ethyl ketone, ketones such as methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, aromatic hydrocarbons such as benzene, toluene and xylene, dimethylformamide, diethylformamide and dimethylacetamide. (Amides or a mixed solvent thereof) at room temperature or under heating, preferably under reflux for several hours to several tens of hours.

Method 3) In the compound of the general formula (I), one of R ¹ and R ² and / or one of R ³ , R ⁴ and R ⁵ is The compound having a group represented by the general formula (In the formula, ^one of Z ¹ and Z ² and / or one of Z ³ , Z ⁴ and Z ⁵ represents a halogen atom. Z ¹ , Z ² and Z ³ , Z ⁴ and Z ⁵ do not show a halogen atom. Each represents a substituent defined on one of R ¹ and R ² and on one of R ³ , R ⁴ and R ⁴ .
Other symbols are as defined above. ) And the general formula (Wherein the symbols have the same meanings as described above).

The reaction may be carried out in an inert solvent (any solvent may be used as long as it does not hinder the reaction, for example, alcohols such as methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, isobutyl alcohol, tertiary butyl alcohol, methylene chloride, chloroform, Halogenated hydrocarbons such as carbon tetrachloride, ethyl acetate, esters such as butyl acetate, tetrahydrofuran,
Ethers such as dioxane, ketones such as acetone, methyl ethyl ketone and methyl isobutyl ketone, nitriles such as acetonitrile and pyropionitrile, benzene,
Aromatic hydrocarbons such as toluene and xylene, amides such as dimethylformamide and diethylformamide, dimethylsulfoxide and the like, and any mixed solvent thereof)
In a deoxidizing agent (eg, triethylamine, pyridine, N,
Organic bases such as N-dimethylaniline and sodium carbonate,
(Potassium carbonate, sodium bicarbonate, etc.). The reaction temperature and reaction time are not particularly limited, and the reaction is usually performed at 0 ° C. to the boiling point of the solvent for several hours to several tens of hours.

The compound of the general formula (I) thus obtained is recrystallized,
It can be isolated and purified by a conventional method such as a chromatographic method alone or in an appropriate combination. Although the compound of the present invention has an asymmetric carbon, all optical isomers and mixtures thereof are included in the scope of the present invention. The racemic compound can be separated, if desired, by the action of, for example, an optically active acid (tartaric acid, diacetyltartaric acid, tartranylic acid, dibenzoyltartaric acid, etc.). A compound having a desired configuration can also be stereoselectively obtained by using an optically active raw material compound. Separation and fractionation can also be performed by a chromatographic method (column chromatography, liquid chromatography).

The compound of the present invention can be prepared by a conventional method using an inorganic acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid or an organic acid such as maleic acid, fumaric acid, citric acid, succinic acid, tartaric acid, methanesulfonic acid, p-toluenesulfonic acid. To give the above-mentioned pharmaceutically acceptable acid addition salt.

[Action and effect of the invention]

The compound of the present invention exhibits an anticancer effect, especially an excellent effect on small cell lung cancer and non-small cell lung cancer in which existing cancer drugs show no effect, and is extremely useful as an anticancer agent.

Such an effect of the compound of the present invention is, for example, as shown below in 3- (4,5-dimethylaminothiazole-2-
Yl) -2,5-diphenyltetrazolium bromide (M
TT) [Carmichael et al .: Cancer Res 47 , 836
942 (1987), Mossman: J. Immunol Methods 65 , 55-63
(1983)] can be confirmed by cytotoxic effects on cultured human tumor cells.

That is, 10 ⁴ human cultured tumor cells (PC-13 large cell lung cancer, CCRF-CEM T cell leukemia, etc.) and
96 well micro test plate (FALCON 3072) suspended in RPMI1640 medium containing 10% fetal calf serum (FCS)
At 37 ° C. for 72 hours under 5% carbon dioxide gas. After the culture, 10 μM of MTT (5 mg / ml) was added to each well, and the cells were further cultured at 37 ° C. and 5% carbon dioxide for 4 hours. Then, 100 μl of a 10% sodium dodecyl sulfate-0.01 N hydrochloric acid solution was added to each well. Added. After standing overnight, the absorbance at 570 nm is measured using a microplate reader, and the inhibition rate (% cytotoxity) is calculated by the following equation.

After dissolving each sample in dimethyl sulfoxide, RP
It is used after being diluted with MI 1640 medium, and the final dimethyl sulfoxide concentration is adjusted to be 0.25% or less.

When the compound of the present invention is used as an anticancer agent, it is preferably mixed with pharmaceutically acceptable carriers, excipients, diluents and the like, and powders, granules, tablets, capsules, syrups, suppositories, external preparations, It can be safely administered to patients in the form of injections, infusions and the like. In the case of oral administration, the dose is usually about 1 to 100 mg per adult per day, and these are administered once or divided into several times. Further, the compound of the present invention can be used in combination with other anticancer agents, immunostimulants or other acceptable drugs.

〔Example〕

Hereinafter, the present invention will be described specifically with reference to examples, but the present invention is not limited thereto.

Example 1 300 ml of dimethylformamide of 9.5 g of 5-acetoxy 1-butyl-2-methyl-1H-indole-3-carboxylic acid, 6.5 g of N- (6-aminohexyl) nicotinamide and 4.4 g of 1-hydroxybenzotriazole Under ice-cooling, 7.3 g of dicyclohexylcarbodiimide was added to the solution with stirring under ice cooling, and reacted at room temperature for 3 hours. After filtering off the insoluble matter, water is added to the filtrate, and the mixture is extracted three times with ethyl acetate. After washing with water, the extract is dried over magnesium sulfate and concentrated under reduced pressure. The obtained residue was subjected to silica gel (150 g) column chromatography,
Crystals obtained from the fraction eluted from chloroform-methanol (100: 5) were recrystallized from isopropyl alcohol pisopropyl ether to give N- (6-nicotinoylaminohexyl) -5 as white crystals having a melting point of 136 to 138 ° C.
4.7 g of -acetoxy-1-butyl-2-methyl-1H-indole-3-carboxylic acid amide are obtained.

Example 2 3.4 g of 2-methyl-1-indole-3-carboxylic acid,
4.8 g of dicyclohexylcarbodiimide is added to a solution of 4.3 g of N- (6-aminohexyl) nicotinamide and 200 ml of dimethylformamide containing 2.9 g of 1-hydroxybenzotriazole with stirring under ice-cooling, and the mixture is reacted at room temperature for 3 hours. After filtering off the insoluble matter, the filtrate was concentrated under reduced pressure, the residue was subjected to silica gel (100 g) column chromatography, and the crystals obtained from the fraction eluted from chloroform-methanol (100: 5) were purified from isopropyl alcohol-isopropyl ether. Recrystallization gives 3.0 g of N- (6-nicotinoylaminohexyl) -2-methyl-1H-indole-3-carboxylic acid amide as white crystals with a melting point of 154-156 ° C.

Example 3 N- (6-aminohexyl) nicotinamide dihydrobromide (7.6 g) was added to chloroform (80 ml), then triethylamine (8.1 g) was added, and the mixture was stirred for 1 hour, and then cooled under ice-cooling. 4.6 g of imidazo [1,2-a] pyridine-3-carboxylic acid chloride / acid acid are added little by little. After reacting at room temperature for 1 hour, reflux for 7 hours. After cooling, the reaction solution is concentrated under reduced pressure, acetonitrile is added to the residue, and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized twice from acetonitrile to obtain N- (6) as white crystals having a melting point of 133 to 136 ° C.
1.1 g of (nicotinoylaminohexyl) -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid amide are obtained.

Example 4 8.5 g of N- (3-aminopropyl) nicotinamide dihydrobromide was added to 100 ml of chloroform, 10.1 g of triethylamine was added, and the mixture was stirred for 1 hour, and then cooled under ice-cooling. -6-phenylimidazo [2,1-b]
7.8 g of thiazole-3-carboxylic acid chloride hydrochloride are added in small portions. After reacting at room temperature for 1 hour, reflux for 4 hours.
After cooling, the reaction solution is concentrated under reduced pressure, ethanol and acetonitrile are added to the residue, and the precipitated crystals are collected by filtration. The obtained crystals were recrystallized from a mixed solvent of ethanol and isopropyl alcohol, and further recrystallized from ethanol to obtain N- (3-nicotinoylaminopropyl) -2-methyl-6-methyl-6 as white crystals having a melting point of 199 to 202 ° C. 2.0 g of phenylimidazo [2,1-b] thiazole-3-carboxylic acid amide are obtained.

Example 5 N- [3- (2-chloronicotinoylamino) propyl] -2-methylimidazo [1,2-a] pyridine-3-
A solution of 4.0 g of carboxylic acid amide and 10 ml of piperidine in 100 ml of dimethylformamide is stirred at 90-100 ° C. for 18.5 hours. After cooling, water is added to the reaction solution, and the mixture is extracted three times with ethyl acetate. After washing with water, the extract is dried over magnesium sulfate and concentrated under reduced pressure. Dissolve the residue in ethyl acetate and add 1.5 g of fumaric acid when warm
Add. After cooling, the precipitated crystals were collected by filtration and recrystallized from a mixed solvent of isopropyl alcohol and ethyl acetate to give N- [3- (2-
1.3 g of piperidinonicotinoylamino) propyl] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid amide fumarate monohydrate are obtained.

For example, the following compounds can be obtained in the same manner as in the above Examples.

(6) N- (3-nicotinoylaminopropyl) -2
-Methylimidazo [1,2-a] pyridine-3-carboxylic acid amide, melting point 146-150 ° C (7) N- [3- (2-chloronicotinoylamino)
Propyl] -2-methylimidazo [1,2-a] pyridine-3-carboxylic acid amide 1/2 fumarate, melting point 173-
176 ° C (8) N- {3- [2- (4-methyl-1-piperazinyl) nicotinoylamino] propyl} -2-methylimidazo [1,2-a] pyridine-3-carboxyamide
Trihydrochloride / 3/2 hydrate, melting point 237-242 ° C (decomposition) (9) N- [3- (2-diethylaminonicotinoyl) propyl] -2-methylimidazo [1,2-a] pyridine- 3-carboxylic acid amide fumarate, mp 146
-149 ° C (10) N- [3- (2-piperidinonicotinoylamino) propyl] -1-butyl-5-hydroxy-1H-indole-3-carboxylic acid amide, melting point 136-139 ° C (11) N- (3-nicotinoylaminopropyl) -6
-Methylimidazo [2,1-b] thiazole-5-carboxylic acid amide, melting point 158-161 ° C (12) N- (3-nicotinoylaminopropyl) -3
-Methylazolo [3,2-a] benzimidazole-2-
Carboxamide, melting point 194-197 ° C (13) N- (6-nicotinoylaminohexyl) -2
-Methylazolo [3,2-a] benzimidazole-3-
Carboxyamide, melting point 193-196 ° C (14) N- [3- (2-chloronicotinoylamino)
Propyl] -2-methylthiazolo [3,2-a] benzimidazole-3-carboxylic acid amide, melting point 218-222 ° C (15) N- (3-nicotinoylaminopropyl) -2
-Methylimidazo [2,1-b] benzothiazole-3-
Carboxamide, melting point 222-225 ° C (16) N- (6-nicotinoylaminohexyl) quinoline-3-carboxylic acid amide, melting point 174-177 ° C

────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification symbol FI C07D 513/04 331 C07D 513/04 331 338 338 521/00 521/00 (56) References British publication 1022935 (GB, A) United Kingdom Patent 1022936 (GB, B) (58) Fields investigated (Int. Cl. ⁶ , DB name) CA REGISTRY (STN)

Claims (1)

(57) [Claims] (1) General formula Or a pharmaceutically acceptable acid addition salt thereof. In the formula, R ¹ , R ² , R ³ , R ⁴ , and R ⁵ are the same or different and are each a hydrogen atom, a halogen atom, a hydroxyl group, a lower alkyl group, a lower alkoxy group, a formyl group, -COOR ⁶ (wherein R ⁶ represents a hydrogen atom, a lower alkyl group or an aralkyl group.) (Wherein, R ⁷ and R ⁸ are the same or different and represent a hydrogen atom, a lower alkyl group or an aralkyl group, or R ⁷ and R ⁸ represent a group which forms a heterocyclic ring together with an adjacent nitrogen atom Or a group represented by (Wherein, R ⁹ and R ¹⁰ are the same or different and each represent a hydrogen atom, a lower alkyl group or an aralkyl group, or R ⁹ and R ¹⁰ are a group which forms a heterocyclic ring together with an adjacent nitrogen atom. A represents at least one sulfur atom or NR ¹¹ (wherein R ¹¹ represents a hydrogen atom, a lower alkyl group or an acyl group) in the chain.
Having 2 to 2 carbon atoms which may have a lower alkyl group, a phenyl group, an aralkyl group, an oxo, an oxime (oxime includes an alkoxyme) or an amine as a substituent on the chain. 30 alkylene, alkenylene or alkynylene, and Het represents a fused heterocyclic ring.