JP2008120699A - Novel pyridinium derivative and medicine - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a novel pyridinium derivative and a novel medicine that have excellent anti-tumor activity. <P>SOLUTION: The novel medicine comprises a pyridinium derivative represented by formula (I). The novel pyridinium derivative is comprised of a pyridinium ring binding to the 2-position of a naphthalene ring. In the formula, Q represents an aryl or an aromatic heterocycle group; R<SP>A</SP>and R<SP>B</SP>each represents a hydrogen atom, an alkyl, an aryl or the like; m represents 0 to 4; n represents 0 to 7; and X<SP>-</SP>represents a pharmacologically acceptable anion. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to a novel pyridinium derivative having anticancer activity and a pharmaceutical comprising the compound and the like.

  Conventionally, it is known that a 1-alkylpyridinium derivative having a naphthyl group at the 4-position has dye or liquid crystal properties (see, for example, Non-Patent Document 1 and Non-Patent Document 2).

  A naphthalene derivative in which a pyridinium ring or the like is bonded to the 1-position of a naphthalene ring represented by the following formula is known as a compound having a high light absorption intensity (see, for example, Patent Document 1). Examples of the substituent at the 1-position of the pyridinium ring include a hydroxy group, a methyl group, and a phenyl group.

(In the formula, A ₁ and A ₂ represent a pyridine ring and a pyridinium ring, and R _{1 to} R ₆ represent a hydrogen atom and a substituent)

  However, none of these compounds are known as pharmaceuticals, particularly as anticancer agents.

JP-A-8-198850 Journal of Heterocyclic Chemistry, 2001, 38, 11-23 Chemical Physics Letters 1995, 238, 47-53

  An object of the present invention is to provide a novel pyridinium derivative useful as a medicament and a pharmaceutical, particularly an anticancer agent, containing the pyridinium derivative and the like.

  The present inventors have found that a pyridinium derivative formed by bonding a naphthalene ring to a pyridinium ring having an aryl group or the like bonded to the 1-position has anticancer activity, and has completed the present invention. It was.

That is, the present invention
(1) Formula (I)

{In the formula, Q represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R ^A and R ^B are the same or different and each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cyclo group. Alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic ring A group, a substituted or unsubstituted aromatic heterocyclic alkyl group, OR ¹ (wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, substituted or Unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted Unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 2 ^R 3 ^(wherein, R ² and R ³ are the same or different, wherein ^{R 1 synonymous), S (O) pR 4} ( wherein, p is 0, 1 or 2, ^{R 4,} the ^{R 1} as synonymous), COR ⁵ (wherein, R ⁵ is as defined above for R ¹ ), COOR ⁶ (wherein R ⁶ is as defined above for R ¹ ), OCOR ⁷ (wherein R ⁷ is as defined above for R ¹ ), CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meaning as R ¹ ), NR ¹⁰ COR ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different, and R ¹ is synonymous with R ¹ ), NR ¹² COOR ¹³ , wherein R ¹² and R ¹³ is the same or different and has the same meaning as R ¹ ), NR ¹⁴ SO ₂ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same or different and have the same meaning as R ¹ ), NR ¹⁶ C (= Z) NR ¹⁷ R ^{18 wherein} Z is an oxygen atom, a sulfur atom, NR ¹⁹ (wherein R ¹⁹ has the same meaning as R ¹ above), NCN, CHNO ₂ or C (CN) ₂ and R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different and have the same meaning as R ¹ ], NR ²⁰ SO ₂ NR ²¹ R ²² (wherein R ²⁰ , R ²¹ and R ²² are The same or different and the same as R ¹ ), SO ₂ NR ²³ R ²⁴ (wherein R ²³ and R ²⁴ are the same or different and have the same meaning as R ¹ ), a nitro group, a cyano group Or a halogen atom, and m is 0 or If is an integer of 1 to 4, m is 2 or more, ^{R A} may be the same or different, n represents an integer of 0 or 1-7, when n is 2 or more, ^{R B} May be the same or different, X ⁻ represents a pharmacologically acceptable anion} a pharmaceutical comprising a pyridinium derivative represented by
(2) The medicament according to (1), wherein the medicament comprising the pyridinium derivative represented by the formula (I) is an anticancer agent,
(3) The compound represented by the formula (I) is represented by the following formula (Ia)

(Wherein Q, R ^A , R ^B , m, n, and X ⁻ are as defined above), and the pharmaceutical according to (1) or (2),
(4) The pharmaceutical according to (1) to (3) above, wherein the pyridinium group is bonded to the naphthyl group at the 4-position;
(5) The pharmaceutical according to the above (1) to (4), wherein Q is a substituted aryl group,
(6) The medicament according to the above (5), wherein the substituted aryl group is a 2,4-dinitrophenyl group,
(7) The medicament according to (1) to (6), wherein n is 0, and
(8) The pharmaceutical according to any one of (1) to (7), wherein the pharmacologically acceptable anion is a chloride ion.

The present invention also provides:
(9) Formula (Ia)

{In the formula, Q represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R ^A and R ^B are the same or different and each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cyclo group. Alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic ring A group, a substituted or unsubstituted aromatic heterocyclic alkyl group, OR ¹ (wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, substituted or Unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted Unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 2 ^R 3 ^(wherein, R ² and R ³ are the same or different, wherein ^{R 1 synonymous), S (O) pR 4} ( wherein, p is 0, 1 or 2, ^{R 4,} the ^{R 1} as synonymous), COR ⁵ (wherein, R ⁵ is as defined above for R ¹ ), COOR ⁶ (wherein R ⁶ is as defined above for R ¹ ), OCOR ⁷ (wherein R ⁷ is as defined above for R ¹ ), CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meaning as R ¹ ), NR ¹⁰ COR ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different, and R ¹ is synonymous with R ¹ ), NR ¹² COOR ¹³ , wherein R ¹² and R ¹³ is the same or different and has the same meaning as R ¹ ), NR ¹⁴ SO ₂ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same or different and have the same meaning as R ¹ ), NR ¹⁶ C (= Z) NR ¹⁷ R ^{18 wherein} Z is an oxygen atom, a sulfur atom, NR ¹⁹ (wherein R ¹⁹ has the same meaning as R ¹ above), NCN, CHNO ₂ or C (CN) ₂ and R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different and have the same meaning as R ¹ ], NR ²⁰ SO ₂ NR ²¹ R ²² (wherein R ²⁰ , R ²¹ and R ²² are The same or different and the same as R ¹ ), SO ₂ NR ²³ R ²⁴ (wherein R ²³ and R ²⁴ are the same or different and have the same meaning as R ¹ ), a nitro group, a cyano group Or a halogen atom, and m is 0 or If is an integer of 1 to 4, m is 2 or more, ^{R A} may be the same or different, n represents an integer of 0 or 1-7, when n is 2 or more, ^{R B} May be the same or different, and X ⁻ represents a pharmacologically acceptable anion}.

Furthermore, the present invention provides:
(10) The pyridinium derivative according to (9), wherein the pyridinium group is bonded to the naphthyl group at the 4-position;
(11) The pyridinium derivative according to the above (9) or (10), wherein Q is a substituted aryl group,
(12) The pyridinium derivative according to the above (11), wherein the substituted aryl group is a 2,4-dinitrophenyl group,
(13) The pyridinium derivative according to (9) to (12), wherein n is 0, and
(14) The pyridinium derivative according to (9) to (13), wherein the pharmacologically acceptable anion is a chloride ion.

  The pyridinium derivative of the present invention has excellent anticancer activity and can be used as an anticancer agent against various cancers.

Although there is no restriction | limiting in particular as a pharmaceutical containing the compound (henceforth a compound (I)) represented by the formula (I) of this invention, It is preferable to use as an anticancer agent.
When compound (I) is used as a pharmaceutical, the bonding position of the naphthalene ring and the pyridinium ring may be 1-position or 2-position of the naphthalene ring, or any position of 2-position to 4-position of the pyridinium ring. A compound bonded to the 2-position and any position from the 2-position to the 4-position of the pyridinium ring is preferable, and a compound bonded to the 2-position of the naphthalene ring and the 4-position of the pyridinium ring is more preferable.

  The alkyl group is, for example, linear or branched alkyl having 1 to 10 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, neopentyl. Hexyl, heptyl, octyl, nonyl, decyl and the like.

  Examples of the cycloalkyl group include cycloalkyl having 3 to 8 carbon atoms, specifically, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclooctyl, 1-cyclohexenyl and the like.

  The alkenyl group is, for example, linear or branched alkenyl having 2 to 10 carbon atoms, specifically vinyl, 1-propenyl, allyl, isopropenyl, 1-butenyl, 2-butenyl, 1,3-butadienyl, 2-pentenyl, 2-hexenyl and the like can be mentioned.

  The alkynyl group is, for example, linear or branched alkynyl having 2 to 10 carbon atoms, specifically, ethynyl, 1-propynyl, 2-propynyl, isopropynyl, 2-butynyl, 2-pentynyl, 2-pentene- 4-inyl, 2-hexynyl and the like can be mentioned.

  Examples of the aryl group include aryl having 6 to 14 carbon atoms, specifically, phenyl, naphthyl, anthryl, phenanthryl and the like.

  The aralkyl group has the same aryl part as the aryl group, and the alkyl part has the same meaning as the alkyl group. For example, aralkyl having 7 to 15 carbon atoms, specifically benzyl, phenethyl, phenylpropyl, benzhydryl, Examples include trityl and naphthylmethyl.

  The aromatic heterocyclic group is the same or different and consists of a 5- or 6-membered aromatic heterocyclic group containing at least one or more hetero atoms such as nitrogen, oxygen, sulfur and the like, It may be a monocyclic or a polycyclic fused aromatic heterocyclic group in which a plurality of the monocyclic heterocyclic groups are condensed with an aryl group, for example, a bicyclic or tricyclic heterocyclic group. Specific examples of the monocyclic aromatic heterocyclic group include furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, thiadiazolyl, isothiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl and the like. And polycyclic condensed aromatic heterocyclic groups include benzofuryl, benzothienyl, indolyl, carbazolyl, quinolyl, isoquinolyl, acridinyl, naphthyridinyl, benzoimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, indazolyl, quinoxalinyl, quinazolinyl Cinnolinyl, phthalazinyl, purinyl, pteridinyl, thiantenyl, phenoxatinyl, phenoxazinyl, phenothiazinyl, phenazinyl, etc. It can gel.

  The aromatic heterocyclic alkyl group has the same aromatic heterocyclic moiety as the aromatic heterocyclic group, and the alkyl moiety has the same meaning as the alkyl group, for example, an aromatic group containing at least one hetero atom. Heterocyclic alkyl, specifically pyridylmethyl, pyridylethyl, furanylmethyl, thienylmethyl and the like can be mentioned.

  The alicyclic heterocyclic group is the same or different and contains at least one or more hetero atoms such as nitrogen, oxygen, sulfur and the like, and may have a saturated or partially unsaturated bond. An alicyclic heterocyclic group, which may be monocyclic or a polycyclic fused alicyclic heterocyclic group in which the monocyclic heterocyclic group is condensed with an aryl group or an aromatic heterocyclic group. Good. Specific examples of monocyclic alicyclic heterocyclic groups include aziridinyl, pyrrolidinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, dihydrothiazolyl, tetrahydrofuranyl, 1,3-dioxolanyl, thiolanyl, piperidino, piperidyl, piperazinyl , Morpholino, morpholinyl, thiomorpholinyl, pyranyl, oxathianyl, oxadiazinyl, thiadiazinyl, dithiazinyl, azepinyl, dihydroazosinyl and the like. Specific examples of the polycyclic fused alicyclic heterocyclic group include indolinyl, isoindolinyl, chromanyl , Isochromanyl, quinuclidinyl and the like.

  The halogen atom means each atom of fluorine, chlorine, bromine and iodine.

Examples of the substituent in the alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group and alicyclic heterocyclic group include an alkyl group and a cycloalkyl group. , Alkenyl group, alkynyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group, alicyclic heterocyclic group, OR ^a , NR ^b R ^c , S (O) qR ^d (wherein , Q represents 0, 1 or 2), COR ^e , COOR ^f , OCOR ^g , CONR ^h R ⁱ , NR ^j COR ^k , NR ¹ COOR ^m , NR ⁿ SO ₂ R ^o , NR ^p C (= Z ^a ) NR ^q R ^r (wherein, Z ^a represents an oxygen atom, a sulfur atom, NR ^s , NCN, CHNO ₂ or C (CN) ₂ ), NR ^t SO ₂ NR ^u R ^v , SO ₂ NR ^w R ^x , a nitro group, a cyano group, a halogen atom, and the like are appropriately selected. Here, R ^{a to} R ^x are the same or different and each represents a hydrogen atom, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an aromatic heterocyclic group, an aromatic heterocyclic alkyl group, or An alicyclic heterocyclic group or the like is represented.

  The alkyl group, cycloalkyl group, alkenyl group, alkynyl group, aryl group, aralkyl group, aromatic heterocyclic group, aromatic heterocyclic alkyl group and alicyclic heterocyclic group are as defined above.

  In addition, an alkyl group, a cycloalkyl group, an alkenyl group, an alkynyl group, an aryl group, an aralkyl group, an aromatic heterocyclic group, an aromatic heterocyclic alkyl group, an alicyclic heterocyclic group and the like as a substituent are further substituted. The substituent may be the same as those described above.

  The number of substitutions of these substituents may be the same or different, and may be up to the number of hydrogen atoms present in each group, but is preferably 1 to 10, more preferably 1 to 5.

  Pharmacologically acceptable anions include hydroxide ions, halide ions (fluoride ions, chloride ions, bromide ions, iodide ions), sulfate ions, sulfite ions, nitrate ions, phosphate ions. Inorganic ions such as hydrogen phosphate ion, dihydrogen phosphate ion, carbonate ion, bicarbonate ion, borate ion, chlorate ion, perchlorate ion, chlorite ion, hypochlorite ion or organic acid Examples of the organic acid include carboxylic acids such as formic acid, acetic acid, trifluoroacetic acid, propionic acid, fumaric acid, malonic acid, succinic acid, maleic acid, tartaric acid, and benzoic acid, Examples include sulfonic acids such as methanesulfonic acid and p-toluenesulfonic acid, and amino acids such as glutamic acid and aspartic acid. Gen halide ions, among halide ions, are preferably used from chloride ions.

Next, the manufacturing method of compound (I) is demonstrated.
In addition, among the compounds (I), the compound represented by the formula (Ia) is a novel compound, and can be produced by the following production method.

Manufacturing method 1
Compound (I) can be produced according to the following reaction steps.

(In the formula, X represents a leaving group, and Q, R ^A , R ^B , X ⁻ , m, and n are as defined above.)

Examples of the leaving group in the definition of X include a halogen atom, a substituted or unsubstituted alkylsulfonyloxy group, a substituted or unsubstituted arylsulfonyloxy group, and the like. The halogen atom has the same meaning as described above. The alkylsulfonyloxy group has the same alkyl moiety as the alkyl group, and examples thereof include alkylsulfonyloxy having 1 to 10 carbon atoms, specifically, methanesulfonyloxy, trifluoromethanesulfonyloxy and the like. The aryl moiety of the arylsulfonyloxy group has the same meaning as the aryl group, and examples thereof include arylsulfonyloxy having 6 to 12 carbon atoms, such as benzenesulfonyloxy and toluenesulfonyloxy. Examples of the substituent include a halogen atom, an alkyl group, and a nitro group. The halogen atom has the same meaning as the halogen atom, and the alkyl group has the same meaning as the alkyl group. X represents a leaving group, but may become an anion in the reaction system, and may be X ⁻ as it is.

  Compound (I) comprises compound (II) and compound (III) in a suitable inert solvent such as halogenated hydrocarbons such as chloroform and dichloromethane, aromatic hydrocarbons such as benzene and toluene, diethyl ether, tetrahydrofuran, 1 -78 in ether solvents such as 1,4-dioxane, lower alcohols such as methanol, ethanol and isopropanol, aprotic polar solvents such as N, N-dimethylformamide, N-methylpyrrolidone and dimethyl sulfoxide, or a mixed solvent thereof. It can be obtained by reacting at a temperature between C. and the boiling point of the solvent used for 5 minutes to 48 hours.

  Compound (II) can be obtained as a commercial product, or can be obtained by the method described in Jie Jack Li et al. “Palladium in Heterocyclic Chemistry”, Pergamon Publishing, June 2000, p6-18 and p183-232. Compound (III) can be obtained as a commercial product.

Manufacturing method 2
Compound (I) can be obtained by using various cross-coupling reactions according to the method described in Jie Jack Li et al., “Palladium in Heterocyclic Chemistry” Pergamon Publishing, June 2000, p6-18 and p183-232. An example is described below.

Or

(In the formula, L represents a leaving group, M represents a metal-containing leaving group suitable for the cross-coupling reaction, and Q, R ^A , R ^B , X ⁻ , m, and n are as defined above).

The leaving group in the definition of L has the same definition as the leaving group in X, and X ⁻ of the compound (I) may be formed from the leaving group of L.

Examples of the metal of the metal-containing leaving group suitable for the cross-coupling reaction in the definition of M include lithium, boron, magnesium, aluminum, silicon, zinc, tin, etc. Specific examples of the metal-containing leaving group include _{-B (OH) 2, -MgCl,} -MgBr, -ZnBr, -ZnI, -Sn (nBu) 3, include -SiCl ₂ (Et) or the like.

  Compound (I) comprises compound (IV) and compound (V) or compound (VI) and compound (VII) in the presence of a transition metal catalyst and a base, such as a suitable inert solvent such as chloroform and dichloromethane. Halogenated hydrocarbons, aromatic hydrocarbons such as benzene and toluene, ether solvents such as diethyl ether, tetrahydrofuran and 1,4-dioxane, lower alcohols such as methanol, ethanol and isopropanol, N, N-dimethylformamide, N- It can be obtained by reacting in an aprotic polar solvent such as methyl pyrrolidone or dimethyl sulfoxide, water or a mixed solvent thereof at a temperature between −78 ° C. and the boiling point of the solvent used for 5 minutes to 48 hours. Examples of the transition metal of the transition metal catalyst include palladium, nickel, copper, and iron. Specific examples of the transition metal catalyst include tetrakis (triphenylphosphine) palladium (0), tetrakis (triphenylphosphine) nickel (0 ) And the like. These transition metal catalysts may be prepared in situ from the corresponding transition metal salt in the presence of a ligand. Examples of the ligand include triphenylphosphine, tributylphosphine, 1,1′-bis (diphenylphosphino). ) Ferrocene, 2,2′-bis (diphenylphosphino) -1,1′-binaphthyl and the like, and transition metal salts include palladium chloride, palladium acetate, nickel chloride, copper chloride (I), copper oxide (I ), Iron (II) chloride, iron (III) chloride and the like. Examples of the base include organic bases such as triethylamine and pyridine, inorganic bases such as potassium carbonate, potassium hydrogen carbonate, tripotassium phosphate, sodium hydroxide and sodium hydride, metal alkoxides such as sodium methoxide and potassium tert-butoxide, etc. Is mentioned.

  In addition, compound (IV) and compound (VI) can be obtained as a commercial product, or can be obtained according to the method described in EP453197 or the like, and compound (V) and compound (VII) are It is available as a commercial product.

  In the above production method, when the defined group changes under the conditions of the method of implementation or is inappropriate for carrying out the method, methods for introducing and removing protecting groups commonly used in organic synthetic chemistry [for example, Protective Groups in Organic Synthesis, see TW Greene, John Wiley & Sons Inc. (1981)] Thus, the target compound can be obtained. Further, the functional group contained in each substituent may be converted by a known method [eg, Comprehensive Organic Transformations, R.A. C. Larock (1989), etc.], and some of the compounds (I) can be further converted into novel derivatives (I) as synthetic intermediates.

  The intermediates and target compounds in each of the above production methods are isolated and purified by purification methods commonly used in synthetic organic chemistry such as neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various chromatography. can do. Further, the intermediate can be subjected to the next reaction without any particular purification.

  Although some isomers may exist in Compound (I), the present invention includes all possible isomers and mixtures thereof including these.

  When it is desired to obtain a salt of compound (I), if compound (I) is obtained in the form of a salt, it may be purified as it is, and if it is obtained in a salt form different from the target salt. Then, it may be dissolved or suspended in a suitable organic solvent, and an acid or base may be added to form a salt by a conventional method.

  Compound (I) and pharmacologically acceptable salts thereof may exist in the form of adducts with water or various solvents, and these adducts can also be used as the anticancer agent of the present invention. .

  The compound (I) or a pharmacologically acceptable salt thereof can be administered alone as it is, but it is usually desirable to prepare various pharmaceutical preparations. It can be produced by a conventional method of pharmaceutics by mixing with one or two or more types of carriers that are acceptable.

  Examples of the administration route include oral administration, inhalation administration, and parenteral administration such as intravenous administration.

  Examples of the dosage form include tablets, injections, etc. The tablets are mixed with various additives such as lactose, starch, magnesium stearate, hydroxypropyl cellulose, polyvinyl alcohol, surfactant, glycerin, etc. The inhalant may be produced according to a conventional method by adding, for example, lactose. An injection may be produced according to a conventional method by adding water, physiological saline, vegetable oil, solubilizer, preservative and the like.

  The effective amount and frequency of administration of compound (I) or a pharmacologically acceptable salt thereof vary depending on the administration form, patient age, body weight, symptoms, etc., but usually 0.001 mg to 5 g per adult, preferably Is administered in an amount of 0.1 mg to 1 g, more preferably 1 to 500 mg, once a day or several times a day.

  EXAMPLES Hereinafter, although an Example demonstrates this invention more concretely, the technical scope of this invention is not limited to these illustrations.

A. Preparation of 4- (2-naphthyl) pyridine (4) 0.89 g of sodium carbonate was dissolved in a mixed solution of 8 mL of benzene and 4 mL of water, and 40 mg of tetrakis (triphenylphosphine) palladium (0), 4-bromo 0.65 g of pyridine hydrochloride (3) and 0.64 g of 2-naphthaleneboronic acid were added, and the mixture was heated to reflux for 5 hours. The reaction product was extracted three times with ethyl acetate, washed with saturated brine, dried over magnesium sulfate, and the solvent was removed to obtain 0.65 g (yield 94%) of the title compound (4).

B. Production of 4- (2-naphthyl) -1- (2,4-nitrophenyl) pyridinium chloride (1) 0.65 g of the compound (4) obtained by the above production method in 15 mL of toluene, commercially available 2,4-dinitro 1.3 g of chlorobenzene (5) was dissolved and stirred at 70 ° C. for 2 hours. The reaction product was filtered, and the resulting solid was washed with acetone to obtain 0.10 g (yield 7.8%) of the title compound (1).
¹ H-NMR (300MHz, DMSO-d ₆ ) δ: 9.50-9.55 (2H, m), 9.17 (1H, d), 9.00-9.07 (4H, m), 8.52 (1H, d), 8.35 (1H, dd), 8.25 (1H, d), 8.18 (1H, dd), 8.10 (1H, dd), 7.68-7.80 (2H, m).

Cell Proliferation Inhibition Test Human cervical cancer-derived HeLa cells were treated with Dulbecco's modified Eagle's medium (DMEM; Invitrogen-Gibco BRL) containing 10% fetal bovine serum (FBS; Hyclone). Was cultured in a 96-well plate at a density of 5000 cells / well (cells / well) in a thermostatic chamber at 37 ° C. filled with 5% CO ₂ for 8 hours. A 10% FBS-containing DMEM solution of a test sample (prepared from a DMSO solution) prepared to have various concentrations was added to each well, and the culture was continued. The number of viable cells after culturing for 2 days is measured using a cell proliferation test kit (Promega, CellTiter96 (R) AQ _ueous One Solution Cell Proliferation Assay) by the MTS method, and the cell proliferation score is calculated according to the following formula: did.

Cell proliferation score (%) = 100 × M _S / M _D

M _S : Absorbance due to MTS reagent when sample is added M _D : Absorbance due to MTS reagent when only solvent for sample dissolution is added

The test result was expressed as a cell growth inhibition rate at each concentration. The results are shown in Table 1.

  A tablet is prepared by a conventional method using a composition comprising 10 mg of compound (1), 70 mg of lactose, 15 mg of starch, 4 mg of polyvinyl alcohol and 1 mg of magnesium stearate (100 mg in total).

  Add distilled water for injection to a composition consisting of 70 mg of Compound (1), 50 mg of purified soybean oil, 10 mg of egg yolk lecithin and 25 mg of glycerin by a conventional method so that the total volume becomes 100 mL, and after filling into a vial, heat-sterilized and injected Prepare the agent.

Claims (14)

Formula (I)

{In the formula, Q represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R ^A and R ^B are the same or different and each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cyclo group. Alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic ring A group, a substituted or unsubstituted aromatic heterocyclic alkyl group, OR ¹ (wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, substituted or Unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted Unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 2 ^R 3 ^(wherein, R ² and R ³ are the same or different, wherein ^{R 1 synonymous), S (O) pR 4} ( wherein, p is 0, 1 or 2, ^{R 4,} the ^{R 1} as synonymous), COR ⁵ (wherein, R ⁵ is as defined above for R ¹ ), COOR ⁶ (wherein R ⁶ is as defined above for R ¹ ), OCOR ⁷ (wherein R ⁷ is as defined above for R ¹ ), CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meaning as R ¹ ), NR ¹⁰ COR ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different, and R ¹ is synonymous with R ¹ ), NR ¹² COOR ¹³ , wherein R ¹² and R ¹³ is the same or different and has the same meaning as R ¹ ), NR ¹⁴ SO ₂ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same or different and have the same meaning as R ¹ ), NR ¹⁶ C (= Z) NR ¹⁷ R ^{18 wherein} Z is an oxygen atom, a sulfur atom, NR ¹⁹ (wherein R ¹⁹ has the same meaning as R ¹ above), NCN, CHNO ₂ or C (CN) ₂ and R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different and have the same meaning as R ¹ ], NR ²⁰ SO ₂ NR ²¹ R ²² (wherein R ²⁰ , R ²¹ and R ²² are The same or different and the same as R ¹ ), SO ₂ NR ²³ R ²⁴ (wherein R ²³ and R ²⁴ are the same or different and have the same meaning as R ¹ ), a nitro group, a cyano group Or a halogen atom, and m is 0 or If is an integer of 1 to 4, m is 2 or more, ^{R A} may be the same or different, n represents an integer of 0 or 1-7, when n is 2 or more, ^{R B} May be the same or different, and X ⁻ represents a pharmacologically acceptable anion}
The pharmaceutical containing the pyridinium derivative represented by these. The medicament according to claim 1, wherein the medicament comprising the pyridinium derivative represented by the formula (I) is an anticancer agent. The compound represented by the formula (I) is represented by the following formula (Ia)

(Wherein, Q, R ^A , R ^B , m, n and X ⁻ are as defined above)
The pharmaceutical according to claim 1 or 2, which is a pyridinium derivative represented by the formula: The pharmaceutical according to claims 1 to 3, wherein the pyridinium group is bonded to the naphthyl group at the 4-position. The pharmaceutical according to claims 1 to 4, wherein Q is a substituted aryl group. The pharmaceutical according to claim 5, wherein the substituted aryl group is a 2,4-dinitrophenyl group. n is 0, The pharmaceutical of Claims 1-6. The medicament according to claims 1 to 7, wherein the pharmacologically acceptable anion is a chloride ion. Formula (Ia)

{In the formula, Q represents a substituted or unsubstituted aryl group or a substituted or unsubstituted aromatic heterocyclic group, and R ^A and R ^B are the same or different and each represents a substituted or unsubstituted alkyl group, a substituted or unsubstituted cyclo group. Alkyl group, substituted or unsubstituted alkenyl group, substituted or unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted or unsubstituted aralkyl group, substituted or unsubstituted aromatic heterocyclic ring A group, a substituted or unsubstituted aromatic heterocyclic alkyl group, OR ¹ (wherein R ¹ is a hydrogen atom, a substituted or unsubstituted alkyl group, a substituted or unsubstituted cycloalkyl group, a substituted or unsubstituted alkenyl group, substituted or Unsubstituted alkynyl group, substituted or unsubstituted alicyclic heterocyclic group, substituted or unsubstituted aryl group, substituted Unsubstituted aralkyl group, a substituted or unsubstituted aromatic heterocyclic group, or a substituted or unsubstituted aromatic heterocyclic alkyl group), NR 2 ^R 3 ^(wherein, R ² and R ³ are the same or different, wherein ^{R 1 synonymous), S (O) pR 4} ( wherein, p is 0, 1 or 2, ^{R 4,} the ^{R 1} as synonymous), COR ⁵ (wherein, R ⁵ is as defined above for R ¹ ), COOR ⁶ (wherein R ⁶ is as defined above for R ¹ ), OCOR ⁷ (wherein R ⁷ is as defined above for R ¹ ), CONR ⁸ R ⁹ (wherein R ⁸ and R ⁹ are the same or different and have the same meaning as R ¹ ), NR ¹⁰ COR ¹¹ (wherein R ¹⁰ and R ¹¹ are the same or different, and R ¹ is synonymous with R ¹ ), NR ¹² COOR ¹³ , wherein R ¹² and R ¹³ is the same or different and has the same meaning as R ¹ ), NR ¹⁴ SO ₂ R ¹⁵ (wherein R ¹⁴ and R ¹⁵ are the same or different and have the same meaning as R ¹ ), NR ¹⁶ C (= Z) NR ¹⁷ R ^{18 wherein} Z is an oxygen atom, a sulfur atom, NR ¹⁹ (wherein R ¹⁹ has the same meaning as R ¹ above), NCN, CHNO ₂ or C (CN) ₂ and R ¹⁶ , R ¹⁷ and R ¹⁸ are the same or different and have the same meaning as R ¹ ], NR ²⁰ SO ₂ NR ²¹ R ²² (wherein R ²⁰ , R ²¹ and R ²² are The same or different and the same as R ¹ ), SO ₂ NR ²³ R ²⁴ (wherein R ²³ and R ²⁴ are the same or different and have the same meaning as R ¹ ), a nitro group, a cyano group Or a halogen atom, and m is 0 or If is an integer of 1 to 4, m is 2 or more, ^{R A} may be the same or different, n represents an integer of 0 or 1-7, when n is 2 or more, ^{R B} May be the same or different, and X ⁻ represents a pharmacologically acceptable anion}
A novel pyridinium derivative represented by The pyridinium derivative according to claim 9, wherein the pyridinium group is bonded to the naphthyl group at the 4-position thereof. The pyridinium derivative according to claim 9 or 10, wherein Q is a substituted aryl group. The pyridinium derivative according to claim 11, wherein the substituted aryl group is a 2,4-dinitrophenyl group. The pyridinium derivative according to claim 9, wherein n is 0. The pyridinium derivative according to claim 9 to 13, wherein the pharmacologically acceptable anion is a chloride ion.