WO2017150174A1 - Pharmaceutical composition containing 2,4-diaminoquinazoline derivative or salt thereof as active ingredient, and 2,4-diaminoquinazoline derivative having specific structure - Google Patents

Abstract

Provided is a pharmaceutical composition for the treatment or prevention of Plasmodium diseases, the pharmaceutical composition being characterized by containing at least one quinazoline derivative represented by general formula (I) or a salt thereof.

Description

Pharmaceutical composition containing 2,4-diaminoquinazoline derivative or a salt thereof as an active ingredient, and 2,4-diaminoquinazoline derivative having a specific structure

The present invention relates to a pharmaceutical composition for preventing or treating malarial protozoal diseases, which comprises a 2,4-diaminoquinazoline derivative or a salt thereof as an active ingredient, and further relates to a novel 2,4-diaminoquinazoline derivative having a specific structure.

Malaria caused by malarial parasite infection is the most serious parasitic infection in human history. The causative agent of malaria is a protozoan belonging to the genus Plasmodium, for example, P. falsiparum, which is widely distributed throughout the tropical areas of Africa, Asia and Latin America, tropical and wetland bodies around the world Distribution of P. vivax (P. vivax), which is distributed in parts of the world, P. ovale (P. ovale) distributed mainly in tropical West Africa, and P. malaria (P. malariae) distributed all over the world. Protozoa infect humans by transmitting Anopheles mosquitoes. According to the World Malaria Report 2015 by WHO, the number of patients in 2015 is reported as 214 million and the number of deaths is 640,000, and 90% of the deaths belong to Africa There is. The economic loss is estimated to be 1 trillion yen or more every year, and the habitats of Anopheles mosquitoes that mediate these are surely spreading with global warming. Development of a drug for preventing or treating malarial protozoal diseases is considered to be a problem to be noted from the viewpoint of future safety and security.

Quinazoline derivatives are considered as antimalarial drugs in medicine, and are used as antihypertensive drugs and other medicines.

Non-patent literature J. Med. Chem. , 24, 127-140 (1981) show that 2,4-diaminoquinazoline derivatives have antimalarial activity, and specifically show the activity against malarial parasites for 99 compounds. In particular, preclinical tests were conducted on compounds of the following structure, but the results are not good, and it is stated that further studies have been concluded (Non-patent Document 1)

Non-patent literature Antimicrob. Agents Chemother. , 54, 2603-2610 (2010) disclose that compound QN254 having the following structure showing dihydrofolate reductase inhibitory activity has antimalarial activity. However, it is described that these compounds have strong inherent side effects possessed by dihydrofolate reductase, and have abandoned the further development of QN254 due to the high risk of cardiotoxicity (Non-patent Document 2).

In addition, non-patent document Nature, 465, 305-310 (2010) discloses a 2,5-diaminoquinazoline-based compound. (Non-patent document 3)

Furthermore, non-patent literature ChemMedChem. , 9 (10), 2360-2373 (2014) disclose that diaminoquinazoline derivatives having a 6-membered ring amino group (piperidine, piperazine) at position 2 or a 7-membered ring amino group have antimalarial activity. (Non-Patent Document 4). In addition, non-patent literature J. Med. Chem. , 57, 682 2-683 (2014) disclose that a 2,4-diaminoquinazoline derivative is a lysine methyltransferase inhibitor (Non-patent Document 5).

U.S. Patent Nos. 3,511,836, 3,635,979, and 3,663,706 disclose that the following compounds are useful as antihypertensive agents (Patent Document 1, Patent Document) 2, Patent Document 3).

JP-T-2-502462 shows that the following compounds and salts thereof inhibit proton, potassium and ATPase and are therefore useful as antiulcer agents (Patent Document 4).

Furthermore, in Japanese Patent Publication No. 5-75729, the following compounds described in US Patent No. 4,188, 390 show that Doxazosin suppresses the fibrogenesis and lipid deposition of atherosclerotic lesions. It has been disclosed to reduce atherosclerotic lesions (US Pat. No. 5,677,859).

Furthermore, the following compounds are disclosed as representative examples of 2,4-diaminoquinazoline derivatives which enhance antitumor activity in Japanese Patent Application Laid-Open No. 6-500117 (Patent Document 6).

On the other hand, recently, in malarial parasites represented by chloroquine and artemisinin, the appearance of resistant bacteria has become apparent, and development of novel antimalarials is desired.

U.S. Pat. No. 3,511,836 U.S. Patent No. 3,635,979 U.S. Pat. No. 3,663,706 Japanese Patent Publication No. 2-502462 Tokuhei 5-75729 Japanese Patent Publication No. 6-500117

An object of the present invention is to provide a pharmaceutical composition for the prevention or treatment of a malaria parasite disease comprising a 2,4-diaminoquinazoline derivative or a salt thereof as an active ingredient, and it is a novel 2,4- having a specific structure. The present invention relates to diaminoquinazoline derivatives (including salts).

As a result of intensive studies to achieve the above object, the present inventors have found a 2,4-diaminoquinazoline derivative or a salt thereof having a specific structure that achieves the above object, and containing Malayla derivative as an active ingredient. A pharmaceutical composition for preventing or treating protozoal diseases has been found.

By using a pharmaceutical composition containing a 2,4-diaminoquinazoline derivative having a specific structure or a salt thereof, a pharmaceutical composition for preventing or treating a malaria parasite disease which has excellent effects and can be manufactured inexpensively is provided.

The present invention is achieved by the following method. That is,

<1> A pharmaceutical composition for preventing or treating a malarial protozoal disease, which comprises at least one quinazoline derivative represented by the following general formula (I) or a salt thereof.

In the formula, R ₁ represents a hydrogen atom or a monovalent substituent, and R ₂ represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a heterocyclic group, an acyl group, or an alkylaminocarbonyl group. n represents an integer of 1 to 4, and m represents an integer of 0 to 3. The sum of n and m represents four. When n is 1, the substitution position of R ₂ -O- is at the 6th or 7th position. R ₃ represents an alkyl group, an alkenyl group, an aryl group, or a heterocyclic group (except for piperidyl group), and R ₄ and R ₅ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or Represents a heterocyclic group. R ₄ and R ₅ may be bonded to each other to form a 5-membered ring.

<2> The pharmaceutical composition for preventing or treating a malarial parasite disease according to <1>, wherein the quinazoline derivative represented by the general formula (I) is represented by the following general formula (II).

In the formula, R ₃ , R ₄ and R ₅ have the same meaning as R ₃ , R ₄ and R ₅ represented by General Formula (I). R ₆ and R ₇ each independently represent a hydrogen atom or a substituent, and R ₈ and R ₉ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or a heterocyclic group. R ₈ and R ₉ may be bonded to each other to form a 5- to 7-membered ring.

<3> The malaria protozoal disease prevention according to <1> or <2>, wherein the quinazoline derivative represented by the general formula (I) or the general formula (II) is represented by the following general formula (III) Or a therapeutic pharmaceutical composition.

_Wherein, R 3, _{R 4,} and _{R 5,} formulas (I) and (II) in _R 3, _{R 4,} and _{R 5} to be synonymous.

The compound or its salt represented with <4> following General formula (IV).

In the formula, R ₄ represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or a heterocyclic group. R ₁₀ represents an alkyl group, an alkenyl group, a phenyl group not substituted with a heterocyclic group, or a heterocyclic group (with the exception of the piperidyl group), L represents a methylene group, and p is 0, 1 or Represents 2 Y represents a heterocyclic group composed of a nitrogen atom and a carbon atom.

<5> A pharmaceutical composition for preventing or treating malarial protozoal disease, comprising the compound according to <4> or a salt thereof.

The compound or its salt represented with <6> the following general formula (V).

In the formula, R ₁₁ represents an unsubstituted alkyl group, an aryl group, a heterocyclic group (excluding piperidyl group), or-(A) -XR ₁₂ , and A represents an alkylene group which is a divalent linking group, Represents a phenylene group or an aralkylene group, and X represents -O-, -S-, -SO _2- , -C (= O) O-, -O- (C = O)-, -NHSO _2- or It represents -SO ₂ NH-. R ₁₂ represents an alkyl group, an alkenyl group, an aryl group or a heterocyclic group.

<7> A pharmaceutical composition for preventing or treating malarial protozoal disease, comprising the compound according to <6> or a salt thereof.

The compound or its salt represented by <8> the following general formula (VI).

In the formula, R ₁₃ represents a C ₁ to C ₁₀ unsubstituted alkyl group, R ₁₄ represents a hydrogen atom or a C ₁ to C ₁₀ unsubstituted alkyl group, and R ₁₅ represents a C ₄ to C ₁₀ unsubstituted group It represents a substituted alkyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group.

<9> A pharmaceutical composition for preventing or treating malarial protozoal disease, which comprises the compound according to <8> or a salt thereof.

<10> The monovalent substituent of R _{1 in} the general formula (I) is a halogen atom, a nitro group, a hydroxy group, a cyano group, a carboxyl group, a sulfo group, a phosphonic acid group, an alkyl group having 1 to 8 carbon atoms, 5-membered, 6-membered or containing at least one member selected from a nitrogen atom and a sulfur atom other than a carbon atom as a carbon atom, as a carbon atom, and an aryl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms 7-membered heterocyclic group, silyl group having 3 to 12 carbon atoms, alkoxy group having 1 to 8 carbon atoms, aryloxy group having 6 to 12 carbon atoms, aromatic heterocyclic group, heterocyclic oxy acids having 1 to 12 carbon atoms Group, silyloxy group having 1 to 8 carbon atoms, acyloxy group having 2 to 12 carbon atoms, alkoxycarbonyloxy group having 2 to 8 carbon atoms, aryloxycarbonyloxy group having 7 to 11 carbon atoms, carbamoyl having 1 to 12 carbon atoms Xy group, sulfamoyloxy group having 1 to 12 carbon atoms, alkylsulfonyloxy group having 1 to 8 carbon atoms, arylsulfonyloxy group having 6 to 12 carbon atoms, acyl group having 1 to 12 carbon atoms, 2 to 12 carbon atoms 8 alkoxycarbonyl group, aryloxycarbonyl group having 7 to 12 carbon atoms, carbamoyl group having 1 to 12 carbon atoms, amino group, anilino group having 6 to 12 carbon atoms, heterocyclic amino group having 1 to 8 carbon atoms, carbon A carbonamido group of 2 to 10, a ureide group of 1 to 12 carbon atoms, an imide group of 8 or less carbon atoms, an alkoxycarbonylamino group of 2 to 8 carbon atoms, an aryloxycarbonyl carbon number of 12 to 7 carbon atoms Amino group, sulfonamide group having 1 to 8 carbon atoms, sulfamoylamino group having 1 to 12 carbon atoms, azo group having 1 to 12 carbon atoms, alkylthio group having 1 to 12 carbon atoms An arylthio group having 6 to 12 carbon atoms, a heterocyclic thio group having 1 to 12 carbon atoms, an alkylsulfinyl group having 1 to 12 carbon atoms, an arylsulfinyl group having 6 to 12 carbon atoms, an alkylsulfonyl group having 1 to 8 carbon atoms A arylsulfonyl group having 6 to 12 carbon atoms, a sulfamoyl group having 12 or less carbon atoms, a phosphonyl group having 1 to 12 carbon atoms, and a phosphinoylamino group having 1 to 12 carbon atoms, The pharmaceutical composition for preventing or treating malarial protozoal disease as described in>.

Next, each substituent of the general formulas (I) to (VI) will be described in detail.
In Formula (I), R ₁ represents a hydrogen atom or a monovalent substituent, and the monovalent substituent of R ₁ may be selected from Substituent Group A described below.
Substituent group A is a halogen atom (for example, fluorine, chlorine, bromine, iodine), a nitro group, a hydroxy group, a cyano group, a carboxyl group, a sulfo group, a phosphonic acid group, an alkyl group (linear, branched or cyclic Is preferably an alkyl group having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, still more preferably 1 to 4 carbon atoms, and examples thereof include methyl, ethyl, propyl, butyl, isopropyl, 2-ethylhexyl, t-butyl, cyclopropyl, And alkenyl groups (linear, branched or cyclic) preferably having 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms, still more preferably 2 to 4 carbon atoms, and examples thereof include vinyl and allyl. , 3-buten-1-yl), an aryl group (preferably having 6 to 12 carbon atoms, more preferably 6 aryl groups such as phenyl and naphthyl),

Aromatic heterocyclic group (In the present specification, “aromatic heterocyclic group” is a 5-membered member containing at least one member selected from nitrogen atom and sulfur atom in addition to carbon atom as atoms forming a ring, An aromatic heterocyclic group having 6 to 12 carbon atoms, preferably having 2 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and still more preferably 2 to 6 carbon atoms. Ring, imidazole ring, thiazole ring, triazole ring, thiadiazole ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, indole ring, benzothiophene ring, benzimidazole ring, benzothiazole ring, purine ring, quinoline ring, isoquinoline ring, Cinnoline ring, quinoxaline ring),

Heterocyclic group (In the present specification, “heterocyclic group” is a 5-, 6- or 7-membered member containing at least one member selected from nitrogen atoms and sulfur atoms in addition to carbon atoms as atoms constituting the ring The same applies to a group to which “heterocycle” is prefixed and suffixed, preferably a heterocyclic group having 1 to 12 carbon atoms, more preferably 2 to 8 carbon atoms, and still more preferably 2 to 6 carbon atoms. For example, morpholine ring, thiophene ring, furan ring, pyrroline ring, pyrrolidine ring, imidazole ring, pyrazole ring, thiazole ring, piperidine ring, piperazine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, benzothiazole ring, Benzotriazole ring, thiadiazole ring, quinoline ring, quinazoline ring), silyl group (preferably 3 to 12 carbon atoms, more preferably carbon atoms And silyl groups of 6 to 6 such as trimethylsilyl, triethylsilyl, tributylsilyl, t-butyldimethylsilyl, t-hexyldimethylsilyl, and alkoxy groups (with 1 to 8 carbon atoms, preferably 1 to 6 carbon atoms, more preferably 1-4 alkoxy groups, for example, methoxy, ethoxy, 1-butoxy, 2-butoxy, isopropoxy, t-butoxy, cycloalkyloxy groups, for example cyclopentyloxy, cyclohexyloxy, aryloxy groups (carbon number) 6 to 12, more preferably an aryloxy group having 6 carbon atoms, for example, phenoxy, 1-naphthoxy),

A heterocyclic oxy group (preferably a heterocyclic oxy group having a carbon number of 1 to 12, more preferably a carbon number of 1 to 8, for example, 1-phenyltetrazol-5-oxy, 2-tetrahydropyranyloxy), a silyloxy group Preferably, it is a silyloxy group having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and examples thereof include trimethylsilyloxy, t-butyldimethylsilyloxy, diphenylmethylsilyloxy), and acyloxy groups (preferably 2 to 12 carbon atoms). More preferably, it is an acyloxy group having 2 to 8 carbon atoms, more preferably 2 to 4 carbon atoms, and for example, acetoxy, pivaloyloxy, benzoyloxy), an alkoxycarbonyloxy group (preferably 2 to 8 carbon atoms, more preferably 2 to 6 carbon atoms). 6 alkoxycarbonyloxy group, for example, ethoxycarbonylo And t-butoxycarbonyloxy, cycloalkyloxycarbonyloxy group, for example, cyclohexyloxycarbonyloxy), aryloxycarbonyloxy group (preferably having 7 to 11 carbon atoms, more preferably 7 carbon atoms). For example, phenoxycarbonyloxy), a carbamoyloxy group (preferably a carbamoyloxy group having 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms), for example, N, N-dimethylcarbamoyloxy, N-butylcarbamoyl Oxy, N-phenylcarbamoyloxy, N-ethyl-N-phenylcarbamoyloxy), sulfamoyloxy group (preferably having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms); , N, N-Diechi Sulfamoyloxy, N-propylsulfamoyloxy), alkylsulfonyloxy groups (preferably having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms), such as methylsulfonyloxy, hexadecyl Sulfonyloxy, cyclohexylsulfonyloxy), arylsulfonyloxy group (preferably having 6 to 12 carbon atoms, more preferably having 6 carbon atoms, for example, phenylsulfonyloxy), an acyl group (preferably having 1 to 6 carbon atoms) 12, more preferably an acyl group having 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms, such as formyl, acetyl, pivaloyl, benzoyl, tetradecanoyl, cyclohexanoyl), an alkoxycarbonyl group (preferably having 2 carbon atoms). To 8, preferably carbon number 2 to 6 alkoxycarbonyl groups, for example, methoxycarbonyl, ethoxycarbonyl, octadecyloxycarbonyl, cyclohexyloxycarbonyl), aryloxycarbonyl groups (preferably having 7 to 12 carbon atoms, more preferably having 7 carbon atoms) For example, phenoxycarbonyl), carbamoyl group (preferably having a carbon number of 1 to 12, more preferably having a carbon number of 1 to 8, and still more preferably 1 to 6), such as carbamoyl, N, N-diethylcarbamoyl, N-ethyl-N-octylcarbamoyl, N, N-dibutylcarbamoyl, N-propylcarbamoyl, N-phenylcarbamoyl, N-methyl N-phenylcarbamoyl, N, N-dicyclohexylcarbamoyl), amino group (preferably carbon) An amino group having a number of 12 or less, more preferably 6 or less carbon atoms, such as amino, methylamino, N, N-dibutylamino, tetradecylamino, 2-ethylhexylamino, cyclohexylamino, anilino (preferably carbon) And the like. For example, anilino, N-methylanilino, N-ethylanilino, N-phenylanilino), heterocyclic amino group (preferably having a carbon number of 1 to 8, more preferably 1) -6 heterocyclic amino groups, for example, 4-pyridylamino, 2-pyridylamino, 3-pyridylamino, 2-imidazolylamino, 3-pyrazolylamino, 4-quinolylamino, 4-quinazolylamino, 2-triazolylamino),

A carbonamido group (preferably having a carbon number of 2 to 10, more preferably 2 to 8, still more preferably 2 to 4), such as acetamide, benzamide, tetradecaneamide, pivaloylamide, cyclohexaneamide, ureido group (preferably Is a ureido group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, and for example, ureide, N, N-dimethyl ureido, N-phenyl ureido, an imide group (preferably having 8 or less carbon atoms, more preferably) The imide group having 6 or less carbon atoms, for example, N-succinimide, N-phthalimido, alkoxycarbonylamino group (preferably having 2 to 8 carbon atoms, more preferably having 2 to 6 carbon atoms), for example, Methoxycarbonylamino, ethoxycarbonylamino, t-butoxyca Bonylamino, octadecyloxycarbonylamino, cyclohexyloxycarbonylamino), aryloxycarbonylamino group (preferably an aryloxycarbonylamino group having 7 to 16 carbon atoms, more preferably 7 carbon atoms, for example, phenoxycarbonylamino), sulfonamide A sulfonamide group preferably having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms, and more preferably 1 to 4 carbon atoms; for example, methane sulfonamide, butane sulfonamide, benzene sulfonamide, hexadecane sulfonamide, cyclohexane Sulfonamide), sulfamoylamino group (preferably sulfamoylamino group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms), and examples thereof include N, N-dipropylsulfamoylamino, N-ethyl- N- Decylsulfamoylamino), an azo group (preferably an azo group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, for example, phenylazo, 3-pyrazolylazo), an alkylthio group (preferably 1 to carbon atoms) 12, more preferably an alkylthio group having 1 to 8 carbon atoms, still more preferably 1 to 4 carbon atoms, for example, methylthio, ethylthio, octylthio, cyclohexylthio), an arylthio group (preferably having 6 to 12 carbon atoms, more preferably a carbon number 6 arylthio groups, for example, phenylthio), heterocyclic thio groups (preferably having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms), for example, 2-benzothiazolylthio, 2- Pyridylthio, 1-phenyltetrazolylthio), alkylsulfinyl group (preferably having a carbon number of 1 to 12, more preferably Is an alkylsulfinyl group having 1 to 6 carbon atoms, for example, dodecanesulfinyl), an arylsulfinyl group (preferably an arylsulfinyl group having 6 to 12 carbon atoms, more preferably 6 carbon atoms, for example, phenylsulfinyl), alkylsulfonyl Group (preferably an alkylsulfonyl group having 1 to 8 carbon atoms, more preferably 1 to 6 carbon atoms), for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, butylsulfonyl, isopropylsulfonyl, 2-ethylhexylsulfonyl, hexadecylsulfonyl, Octyl sulfonyl, cyclohexyl sulfonyl), aryl sulfonyl group (preferably having 6 to 12 carbon atoms, more preferably having 6 carbon atoms, for example, phenyl sulfonyl, 1-naphthyl sulfonyl), A phamoyl group (preferably a sulfamoyl group having 12 or less carbon atoms, more preferably 6 or less carbon atoms), for example, sulfamoyl, N, N-dipropylsulfamoyl, N-ethyl-N-dodecylsulfamoyl, N-ethyl- N-phenylsulfamoyl, N-cyclohexylsulfamoyl), phosphonyl group (preferably having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms), such as phenoxyphosphonyl, octyloxyphosphonyl, Phenyl phosphonyl),

A phosphinoylamino group (preferably a phosphinoylamino group having 1 to 12 carbon atoms, more preferably 1 to 6 carbon atoms, such as diethoxyphosphinoylamino, dioctyloxyphosphinoylamino).

The substituent of R ₁ may further have a substituent, and may be substituted by at least one group selected from the substituent group A described for the substituent of R ₁ . When substituted by two or more substituents, those substituents may be the same or different.
m represents an integer of 0 to 3, and when m is 2 or more, the substituents of R ₁ may be the same or different, and when m is 2 or more, positions are adjacent to each other at substituted positions When this is done, two R _{1 's} may be bonded to each other to form a 5- to 7-membered ring. Furthermore, when R ₁ is bonded to a substitution position adjacent to R ₂ , R ₁ and R ₂ may be bonded to each other to form a 5- to 7-membered ring.

R ₂ in the general formula (I) represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a heterocyclic group, an acyl group, or an alkylaminocarbonyl group. n represents an integer of 1 to 4, and preferred ranges of the alkyl group of R ₂ , an alkenyl group, an aryl group, a heterocyclic group, an acyl group, and an alkylamino carboninyl group are those described in Substituent Group A of R ₁ It is the same.
When the alkyl group, alkenyl group, aryl group, heterocyclic group, acyl group and alkylaminocarbamoyl group of R ₂ can be further substituted, they have at least one substituent selected from Substituent Group A When it has 2 or more substituents, those substituents may be same or different.

n represents an integer of 1 to 4, and when n is 2 or more and substituted at the adjacent substitution position, R ₂ is mutually bonded to form a 5-, 6-, or 7-membered ring May be When n is 2 or more, R ₂ may be the same or different. The sum of m and n represents four.
When n in the general formula (I) is 1, the substitution position of R ₂ —O— represents the 6- or 7-position.

R ₃ in the general formulas (I) to (III) represents an alkyl group, an alkenyl group, an aryl group, or a heterocyclic group (excluding piperidyl group), and an alkyl group, an alkenyl group or an aryl group of R ₃ And the preferable range of the heterocyclic group is the same as those described in Substituent Group A of R ₁ above.
The alkyl group, the alkenyl group, the aryl group, and the heterocyclic group of R ₃ may have at least one substituent selected from Substituent Group A described for R ₁ above, and two or more of them may be substituted When having a group, those substituents may be the same or different.

The _{R 5} of the general formula (I) ~ _{R 4} of formula (IV), and the general formula (I) ~ the general formula (III), each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or Represents a heterocyclic group. R ₄ and R ₅ may be bonded to each other to form a 5-membered ring.
The preferred range of the alkyl group, alkenyl group, aryl group and heterocyclic group of R ₄ and R _{5 is the same as} the alkyl group, alkenyl group, aryl group and heterocyclic group described in Substituent Group A of R ₁ above. . The alkyl group, alkenyl group, aryl group and heterocyclic group of R ₄ and R ₅ may be further substituted by at least one substituent selected from Substituent Group A described for R ₁ above. When substituted by two or more substituents, those substituents may be the same or different.

R ₄ and R ₅ may be bonded to each other to form a 5-membered ring with the nitrogen atom, and the ring formed may be a saturated ring or an unsaturated ring. When the ring formed is further substitutable, it may have at least one substituent selected from Substituent Group A described for R ₁ above, and may be substituted with two or more substituents. If any, their substituents may be the same or different.
Examples of the 5-membered ring formed together with the nitrogen atom include pyrrolidine ring, imidazolidine ring, pyrazoline ring, imidazole ring, pyrazole ring, triazole ring, indole ring, and purine ring.

Next, R ₆ , R ₇ , R ₈ and R _{9 in the} general formula (II) will be described.
R ₆ and R ₇ each independently represent a hydrogen atom or a monovalent substituent, and the monovalent substituent of R ₆ and R ₇ is the substituent group A described for the monovalent substituent of R ₁ above. And the preferred range is also the same.
R ₆ and R ₇ may be further substituted by at least one substituent selected from Substituent Group A described for R ₁ above, and when they are substituted by two or more substituents, they are The substituents of may be the same or different.

R ₈ and R ₉ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or a heterocyclic group. R ₈ and R ₉ may be bonded to each other to form a 5- to 7-membered ring.
The alkyl group, the alkenyl group, the aryl group and the heterocyclic group of R ₈ and R _{9 have} the same meanings as the alkyl group, the alkenyl group, the aryl group and the heterocyclic group described in Substituent Group A of R ₁ , Preferred ranges are also the same.
The alkyl group, alkenyl group, aryl group and heterocyclic group of R ₈ and R ₉ may be further substituted by at least one substituent selected from Substituent Group A described for R ₁ above; When substituted by one or more substituents, those substituents may be the same or different.
R ₈ and R ₉ may be bonded to each other to form a 5-, 6-, or 7-membered ring, and the ring formed is selected from Substituent Group A described for the substitution of R ₁ above. It may be substituted by at least one substituent. When substituted by two or more substituents, those substituents may be the same or different. The ring to be formed is preferably a 5-membered ring linked by a methylene group or a 6-membered ring linked by an ethylene group.

Next, R ₁₀ , L, p and Y in the general formula (IV) will be described in detail.
R ₁₀ in the general formula (IV) represents an alkyl group, an alkenyl group, an aryl group not substituted with a heterocycle, or a heterocyclic group (excluding a piperidine ring group), and an alkyl group of R ₁₀ and an alkenyl group Are the same as those described in Substituent Group A of R ₁ above.
The phenyl group which is not substituted by the heterocyclic group of R ₁₀ may be substituted by the substituent except the heterocyclic group among the groups described in the substituent group A of R ₁ . Moreover, it may be substituted by two or more substituents. When two or more groups are substituted, those substituents may be the same or different.

Preferred examples of the substituent to be substituted on the phenyl group of R ₁₀ include a halogen atom (eg, fluorine, chlorine, bromine), an alkyl group, an alkenyl group, an aryl group, an alkoxy group, an aryloxy group, a heterocyclic oxy group, hydroxy Group, carboxyl group, cyano group, nitro group, alkylthio group, arylthio group, heterocyclic thio group, acyl group, alkoxycarbonyl group, carbamoyl group, amino group, acylamino group, ureido group, alkoxycarbonylamino group, sulfonamide group, A sulfamoyl group, an imide group, an alkylsulfonyl group, an arylsulfonyl group etc. are mentioned.

The heterocyclic group (excluding piperidyl group) of R ₁₀ represents a 3- to 7-membered heterocyclic ring having at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and it is unsaturated even if it is a saturated ring May be a ring, aziridine ring, azetidine ring, pyrrolidine ring, piperazine ring, morpholine ring, furan ring, thiazol ring, oxazole ring, pyridine ring, pyrimidine ring, pyrazine ring, pyridazine ring, triazole ring, quinoline ring, quinazoline And rings, quinoxaline rings, cinnoline rings, purine rings and the like.
When the heterocyclic group of R ₁₀ (excluding the piperidine ring group) is a substitutable group, it may be substituted by the group described in Substituent Group A of R ₁ above, and two or more substituents When substituted, the substituents may be the same or different.

L in the general formula (IV) represents a methylene group, and p represents 0, 1 or 2. When the methylene group of L is substitutable, it may be substituted by at least one substituent selected from Substituent Group A of R ₁ , and when substituted by two or more substituents, , And their substituents may be the same or different.

Y in the general formula (IV) represents a heterocyclic group composed of a nitrogen atom and a carbon atom, and for example, as a 5-membered ring, pyrrolidine ring, pyrroline ring, pyrazoline ring, pyrazolidine ring, pyrrole ring, pyrazole Rings, imidazole rings, triazole rings, etc., and examples of 6-membered rings include piperidine ring, piperazine ring, pyrimidine ring, pyridine ring, pyridazine ring, pyrimidine ring, pyrazine ring, triazine ring, quinoline ring, quinoline ring, isoquinoline ring, cinnoline And rings, quinoxaline rings, quinazoline rings, purine rings and the like. When these heterocycles can be further substituted, they may be substituted by at least one substituent selected from Substituent Group A of R ₁ and may be substituted by two or more substituents. In those cases, the substituents may be the same or different.

Next, R ₁₁ in the general formula (V) will be described in detail.
R ₁₁ in the general formula (V) represents an unsubstituted alkyl group, an aryl group, a heterocyclic group (excluding piperidyl group), or-(A) -XR ₁₂ , and A is a divalent linking group Represents an alkylene group, a phenylene group or an aralkylene group, and X represents -O-, -S-, -SO _2- , -C (= O) O-, -O- (C = O)-, -NHSO _2- or -SO ₂ NH-. R ₁₂ represents an alkyl group, an alkenyl group, an aryl group or a heterocyclic group.

The unsubstituted alkyl group of R ₁₁ is a linear, branched or cyclic alkyl group, preferably having 1 to 12 carbon atoms, more preferably 1 to 8 carbon atoms, still more preferably 1 to 6 carbon atoms. Examples of the group include methyl, ethyl, propyl, butyl, pentyl, hexyl, isopropyl, sec-butyl, cyclopropyl, cyclopentyl, cyclohexyl and the like.

The aryl group of R _{11 has} the same meaning as the aryl group described in Substituent Group A of R ₁ above, and preferred ranges are also the same. Examples of the aryl group of R ₁₁ include a phenyl group and a naphthyl group. The phenyl group and the naphthyl group of R ₁₁ may be substituted by the group described in Substituent Group A of R ₁ above, and in the case where they are substituted by two or more substituents, those substituents are identical Or may be different. The phenyl group and the naphthyl group of R ₁₁ may be further fused with other 5- to 7-membered saturated ring, unsaturated ring and heterocycle.

The heterocyclic group (excluding piperidyl group) of R ₁₁ is a 5- to 6-membered heterocyclic group having at least one atom selected from nitrogen atom, oxygen atom and sulfur atom in addition to carbon atom, and Pyrrolidine ring, piperazine ring, furan ring, thiophene ring, pyrrole ring, imidazole ring, pyrazole ring, triazole ring, oxazole ring, thiazole ring, thiadiazole ring, pyridine ring, pyrazine ring, pyridazine ring, pyrimidine ring and the like can be mentioned.

The _{R 11 - (A) -X-} R 12 will be described.
-(A)-is a divalent linking group and represents an alkylene group, a phenylene group or an aralkylene group, and the alkylene group of A preferably has 1 to 6 carbon atoms, more preferably 1 to 4 carbon atoms And groups such as methylene, ethylene, propylene and butylene. As the phenylene group of A, 1,2-phenylene, 1,3-phenylene, 1,4-phenylene and the like can be mentioned. Examples of the aralkylene group of A include benzylene, phenethylene and the like.
When the alkylene group of A, the phenylene group, and the aralkylene group are substitutable groups, they may be substituted by the group described in Substituent Group A of R ₁ above, and may be substituted by two or more groups. When the groups are identical or different.

X represents —O—, —S—, —SO ₂ —, —C (= O) O—, —O— (C = O) —, —NHSO ₂ — or —SO ₂ NH—.
R ₁₂ represents an alkyl group, an alkenyl group, an aryl group or a heterocyclic group, and has the same meaning as the alkyl group, the alkenyl group, the aryl group and the heterocyclic group described in the description of Substituent Group A of R ₁ above. The preferred range is also the same.

Next, substituents of the general formula (VI), R ₁₃ , R ₁₄ and R ₁₅ will be described.
R ₁₃ in the general formula (VI) represents a C ₁ to C ₁₀ unsubstituted alkyl group, and the unsubstituted alkyl group of R ₁₃ is a linear, branched or cyclic unsubstituted alkyl group, For example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyl, hexyl, heptyl, octyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pentylene, 2-ethylhexyl and the like can be mentioned.

R ₁₄ in the general formula (VI) represents a hydrogen atom or a C ₁ to C ₁₀ unsubstituted alkyl group, and the unsubstituted alkyl group of R _{14 has} the same meaning as the unsubstituted alkyl group of R ₁₃ .
R ₁₅ in the general formula (VI) represents a C ₄ to C ₁₀ unsubstituted alkyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group, and the unsubstituted alkyl group of R ₁₅ is It is the same as the C ₄ to C ₁₀ alkyl group of the aforementioned R ₁₃ unsubstituted alkyl group.

R ₁₅ represents a substituted or unsubstituted benzyl group, and the substituted benzyl group may be substituted by the substituents described in Substituent Group A of R ₁ above, and when two or more substituents are substituted And their substituents may be the same or different.

R ₁₅ represents a substituted or unsubstituted aryl group, unsubstituted aryl group, a phenyl group, or a naphthyl group, a substituted aryl group, optionally substituted by a group described for R ₁ in the substituent group A Also when it is substituted by two or more substituents, those substituents may be the same or different.

Next, preferable ranges of the general formula (I) to the general formula (VI) will be described.
In general formula (I), R ₁ is preferably a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group, an alkoxy group, an aryloxy group, an amino group or an acylamino group, more preferably a hydrogen atom, a halogen atom, R ₂ is a hydroxy group, an alkoxy group, particularly preferably a hydrogen atom or an alkoxy group, and R ₂ is a hydrogen atom, an alkyl group, an alkenyl group or an aryl group, more preferably an alkyl group or an aryl group Is 0 or 1 and more preferably 0, n is 1, 2 or 3 and more preferably 2 and R ₃ is an alkyl group, an alkenyl group, an aryl group or hetero ring, more preferably an alkyl group, an alkenyl group, an aryl group, more preferably an alkyl group, an aryl group, R ₄ and R ₅ are each Standing a hydrogen atom, an alkyl group, an aryl group, an aromatic heterocyclic group, represented by R ₄ and R ₅ are combined to form a five-membered ring.

General formula (I) may be the following aspect.
R ₁ represents a hydrogen atom, a halogen atom, a hydroxy group, an alkyl group having 1 to 8 carbon atoms, an alkoxy group having 1 to 8 carbon atoms, an aryloxy group having 6 to 12 carbon atoms, an amino group having 12 or less carbon atoms, or In the acylamino group, R ₂ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, or an aryl group having 6 to 12 carbon atoms, m is 0 or 1 and n And R ₃ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a hetero atom having 1 to 12 carbon atoms. In the ring, R ₄ and R ₅ each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, an aromatic heterocyclic group having 6 to 12 carbon atoms, or R ₄ and R An embodiment in which ₅ is bonded to each other to form a 5-membered ring.

In addition, general formula (I) may have the following aspect.
R ₁ is a hydrogen atom, a halogen atom, a hydroxy group or an alkoxy group having 1 to 8 carbon atoms, R ₂ is an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 12 carbon atoms, m is 0 Or 1, n is 1, 2 or 3 and R ₃ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms or an aryl group having 6 to 12 carbon atoms, _The embodiment in which ₄ and R ₅ are bonded to each other to form a 5-membered ring.

Furthermore, the following formula may be sufficient as general formula (I).
m is 0, n is 2 and R ₂ is an alkyl group having 1 to 8 carbon atoms or an aryl group having 6 to 12 carbon atoms, R ₃ is an alkyl group having 1 to 8 carbon atoms or 6 carbon atoms A mode in which R ₄ and R ₅ are bonded to each other to form a 5-membered ring in an aryl group of ̃12.

Formula (I) is more preferably represented by formula (II).
In general formula (II), R ₃ is preferably an alkyl group, an alkenyl group, an aryl group or a heterocycle, more preferably an alkyl group, an alkenyl group or an aryl group, still more preferably an alkyl group or an aryl group R ₄ and R ₅ each independently represent a hydrogen atom, an alkyl group, an aryl group, an aromatic heterocyclic group, or a combination of R ₄ and R ₅ with each other to form a 5-membered ring R ₆ and R ₇ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group, an alkyl group, an amino group, or an acylamino group, more preferably a hydrogen atom or an alkoxy group, R ₈ and R ₉ are each independently a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or a 5-membered ring and R ₈ and R ₉ are bonded by a methylene group, 6-membered ring der bonded with an ethylene group Te, more preferably a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, particularly preferably represented by the alkyl group.

General formula (II) may be the following aspect.
R ₃ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heterocycle, and R ₄ and R ₅ are each independently a hydrogen atom or carbon an alkyl group having 1 to 8, an aryl group having 6 to 12 carbon atoms, an aromatic heterocyclic group, represented by R ₄ and R ₅ are combined to form a 5-membered ring together, R ₆ and R ₇ each independently represent a hydrogen atom, a halogen atom, hydroxy group, an alkoxy group having 1 to 8 carbon atoms, an alkyl group, having 12 or less of the amino group having a carbon number of 1 to 8 carbon atoms, or an acylamino group, R ₈ And R ₉ each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, or R ₈ and R ₉ are a methylene group Embodiment which is a 5-membered ring and a 6-membered ring linked by an ethylene group.

In addition, general formula (II) may have the following aspect.
R ₃ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, and an aryl group having 6 to 12 carbon atoms, and R ₄ and R ₅ are each independently a hydrogen atom or 1 carbon atom R ₆ and R ₇ are each represented by an alkyl group of to 8, an aryl group having 6 to 12 carbon atoms, an aromatic heterocyclic group, and R ₄ and R ₅ bonded to each other to form a 5-membered ring; R ₈ and R ₉ each independently represent a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, carbon The aspect which is an aryl group of several 6-12.

The general formula (I) and the general formula (II) are more preferably represented by the general formula (III) to the general formula (VI).
In general formula (III), R ₃ is preferably an alkyl group, an alkenyl group, an aryl group or a heterocycle, more preferably an alkyl group, an alkenyl group or an aryl group, still more preferably an alkyl group or an aryl group R ₄ is a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group, and R ₆ and R ₇ are each independently a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group or an alkyl group An amino group or an acylamino group, more preferably a hydrogen atom or an alkoxy group, wherein R ₈ and R ₉ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or R ₈ 5-membered ring and R ₉ are bonded by a methylene group, a 6-membered ring bonded with an ethylene group, more preferably a hydrogen atom, an alkyl group, an alkenyl group, an aryl group I, particularly preferably represented by the alkyl group. L is a methylene group, p is 0, 1 or 2 and X is a heterocyclic group.

General formula (III) may be the following aspect.
R ₃ is an alkyl group having 1 to 8 carbon atoms, an alkenyl group having 2 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, or a heterocyclic ring, and R ₄ is a hydrogen atom or an alkyl having 1 to 8 carbon atoms R ₆ and R ₇ each independently represent a hydrogen atom, a halogen atom, a hydroxy group, an alkoxy group having 1 to 8 carbon atoms, or 1 carbon atom. And R ₈ and R ₉ each independently represents a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, or an alkenyl having 2 to 8 carbon atoms. Group, an aryl group having 6 to 12 carbon atoms, or a 5-membered ring in which R ₈ and R ₉ are linked by a methylene group, or a 6-membered ring linked by an ethylene group, wherein L is a methylene group and p is 0 1 or 2, and X is a heterocyclic group.

In addition, general formula (III) may have the following aspect.
R ₃ is an alkyl group having 1 to 8 carbon atoms and an aryl group having 6 to 12 carbon atoms, R ₄ is a hydrogen atom, an alkyl group having 1 to 8 carbon atoms, an aryl group having 6 to 12 carbon atoms, R ₆ and R ₇ each independently represent a hydrogen atom or an alkoxy group having 1 to 8 carbon atoms, and R ₈ and R ₉ each independently represent a hydrogen atom or 1 to carbon atoms An alkyl group of 8; an alkenyl group of 2 to 8 carbon atoms; and an aryl group of 6 to 12 carbon atoms, wherein L is a methylene group, p is 0, 1 or 2 and X is a heterocyclic group The aspect represented by

Formula (III) is more preferably represented by Formula (IV), Formula (V), or Formula (VI).
In the general formula (IV), R ₄ is preferably a hydrogen atom, an alkyl group, an aryl group or an aromatic heterocyclic group, and R ₁₀ is a phenyl group which is not substituted with an alkyl group, an alkenyl group or a heterocyclic ring Or a heterocyclic group, L is a methylene group, p is 0, 1 or 2 and Y is an aromatic heterocyclic group composed of a nitrogen atom and a carbon atom.

In general formula (IV), more preferably, R ₄ is a hydrogen atom or an alkyl group, R ₁₀ is an alkyl group, a phenyl group not substituted with a heterocycle, L is a methylene group and p is 0 1 or 2 and Y is represented by an aromatic heterocyclic group composed of a nitrogen atom and a carbon atom.

Formula (IV) is most preferably R ₄ is a hydrogen atom, R ₁₀ is an alkyl group, a phenyl group not substituted with a heterocycle, L is a methylene group and p is 0 or 1 Y is represented by a 6-membered aromatic heterocyclic group composed of a nitrogen atom and a carbon atom.

In the general formula (V), preferably, R ₁₁ is a non-substituted alkyl group, an aryl group, a heterocyclic group, or -A-XR ₁₂ , and A is an alkylene group or a phenylene group; Is -O-, -COO-, or -OC (= O)-, and R ₁₂ is represented by an alkyl group, an aryl group or a heterocyclic group.
In general formula (V), R ₁₁ is preferably represented by a non-substituted alkyl group or an aryl group.

In formula (VI), R ₁₃ is preferably a C ₁ to C ₈ linear or branched unsubstituted alkyl group, and R ₁₄ is a hydrogen atom or a C ₁ to C ₈ linear group A branched or branched unsubstituted alkyl group, wherein R ₁₅ is a C ₄ to C ₈ linear or branched unsubstituted alkyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted Is represented by the aryl group of

More preferably, in the general formula (VI), R ₁₃ is a C ₁ to C ₆ linear or branched unsubstituted alkyl group, and R ₁₄ is a hydrogen atom or a C ₁ to C ₂ straight chain A linear unsubstituted alkyl group, wherein R ₁₅ is a C ₄ to C ₈ linear or branched unsubstituted alkyl group, or a substituted or unsubstituted benzyl group.

In general formula (VI), most preferably, R ₁₃ is a C ₁ to C ₆ linear or branched unsubstituted alkyl group, and R ₁₄ is a hydrogen atom, or a C ₁ to C ₂ straight chain A chained unsubstituted alkyl group, wherein R ₁₅ is a C ₄ to C ₈ linear or branched unsubstituted alkyl group, or an unsubstituted benzyl group.

Specific compound examples of quinazoline derivatives represented by the general formulas (I) to (VI) are shown below, but the present invention is not limited thereto.

　

The quinazoline derivative of the general formula (I) to the general formula (VI) can be used as various salts in the medicament for treating a malarial parasite disease of the present invention. For example, inorganic acid salts (eg, hydrochloride, bromate, sulfate, nitrate, phosphate) or organic acid salts (eg, methanesulfonate, p-toluenesulfonate, acetate, lactate, oxalate) Salts such as acid salts, tartrates, malonates, succinates, citrates, trifluoroacetates, fumarates, maleates, glucuronates, isethionates) can be used.

Examples of basic salts include alkali metal salts (sodium, potassium etc.), alkaline earth metals (calcium, magnesium etc.), ammonium salts, pharmaceutically acceptable organic amines (tetramethyl ammonium, triethylamine, methylamine, dimethyl) Amine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris (hydroxymethyl) amine, lysine, arginine, N-methyl-D-glucan and the like) can be used.

The malaria protozoal disease therapeutic agent containing a quinazoline derivative represented by the general formula (I) to the general formula (VI) of the present invention may contain one or more of the compounds of the present invention as an active ingredient, If necessary, it may be used in combination with any other therapeutic agent known to those skilled in the art, including conventionally used malaria parasite infection agents. Preferred examples of such malaria parasite infection agents include chloroquine, primaquine, mefloquine, artemisinin, atovacone, piperaquine, sulfadoxine, chloroguanyl, pyrimethamine and the like.

Sodium chloride as a suitable example of the pharmaceutical carrier or diluent which can be used in the pharmaceutical composition of the present invention in combination with the quinazoline derivative represented by the general formula (I) to the general formula (VI) of the present invention; Magnesium chloride, zinc chloride, glucose, sucrose, lactose, ethyl alcohol, glycerin, mannitol, sorbitol, sorbitol, pentaerythritol, diethylene glycol, propylene glycol, dipropylene glycol Mono-, di- and triglycerides of fatty acids such as glyceryl trilaurate, and glyceryl distearate; pectin; starch; arginic acid; xylose; talc; Olive oil, peanut oil, castor oil, corn oil, safflower oil, wheat germ oil, Oils and fats such as corn oil, sesame seed oil, sunflower oil and cod liver oil; gelatin; lecithin; silica; cellulose; cellulose; cellulose derivatives such as methyl hydroxypropyl cellulose, methyl cellulose, hydroxyethyl cellulose Salts of fatty acids having 12 to 22 carbon atoms such as calcium stearate, calcium laurate, magresium oleate, calcium palmitate, calcium behenate and magnesium stearate; cyclodextrins (eg, α-cyclodextrin, β-cyclo Dextrin, γ-cyclodextrin, hydroxyethyl-β-cyclodextrin, hydroxypropyl-β-cyclodextrin, dihydroxypropyl-β-cyclodextrin, carboxymethylethyl-β-cyclodextrin Cycloawadorin and dimethyl-β-cyclodextrin etc .; emulsifiers (for example, saturated and unsaturated fatty acids having 2 to 22 carbon atoms, in particular 10 to 18 carbon atoms, glycol, glycerin, diethylene glycol- Esters with monohydric aliphatic alcohols or polyhydric alcohols having 1 to 20 carbon atoms such as pentachloroerythritol, ethyl alcohol, butyl alcohol and octadecyl alcohol; and dimethyl Silicones such as polysiloxanes, etc. Additionally, any additional carrier known to those skilled in the art conventionally used in pharmaceutical compositions can be used in the pharmaceutical composition of the present invention.

The pharmaceutically effective amount of the compound of the present invention and the administration method or administration means are based on the weight of the medical condition, the course of treatment, the patient's age, weight, sex, general health condition, and (genetic) race of the patient. Those skilled in the art can appropriately select depending on the background. In general, the dosage of the compounds of this invention is 1 to 10,000 mg / day / 70 kg body weight, more usually 50 to 2000 mg / day / 70 kg body weight.

The pharmaceutical composition of the present invention can be in any form known to those skilled in the art depending on the administration method, administration route and the like. They can be administered in any suitable manner. For example, it is in the form of liquid, tablet or colloid. When it is in liquid form, it may be injected intravenously, intraperitoneally or subcutaneously in the form of a solution in 5% aqueous glucose solution or in the form accompanied by the above-mentioned carrier or diluent. In the case of the tablet form, oral administration may be mentioned, and in the case of the colloid form, a method such as application to the skin may be mentioned. The compounds represented by the above general formulas (I) to (VI) can be contained in appropriate amounts depending on the purpose, object, shape, etc. of the pharmaceutical composition of the present invention. Usually, it is contained in an amount of about 1 mg to 10,000 mg, preferably about 10 mg to 3,000 mg.

In order to explain the present invention in detail in the following, synthesis examples of the compound of the present invention, and in order to clarify the efficacy of the pharmaceutical composition containing the compound of the present invention, screening of malaria parasite, growth inhibitory activity in vitro Testing and in vivo therapeutic efficacy using malaria infected mice were tested and evaluated. The technical scope of the present invention is not limited to these examples.

Example 1
Next, the synthesis of the quinazoline derivative represented by the general formula (I) to the general formula (VI) of the present invention will be described in detail.
The quinazoline derivative of the present invention can be generally synthesized according to the methods described in US Pat. Nos. 3,635,979 and 2657760.

Synthesis Example 1 Synthesis of Exemplified Compound S-3 A compound was synthesized according to the following synthesis scheme A.

Synthesis scheme A

Synthesis of Exemplified Compound S-3 To 1.04 g (4 mmol) of 2,4-dichloro-6.7-dimethoxyquinazoline (manufactured by Wako Pure Chemical Industries, Ltd.) was added 10 ml of acetonitrile, and the mixture was stirred at room temperature. To this solution was added dropwise 0.43 g (9.6 mmol) of ethylamine. After completion of the dropwise addition, the reaction was completed by heating to 35 ° C.-40 ° C. and stirring for 3 hours. The solution was poured into 100 ml of water, and the precipitated crystals were filtered and dried. 0.88 g (yield: 82.2%) of compound A was obtained.

5 ml of dimethylacetamide was added to 535 mg (2 mmol) of Compound A and 470 mg (5 mmol) of 4-aminopyridine, and the mixture was heated to 140 ° C. to 145 ° C. and stirred for 12 hours to complete the reaction. After completion of the reaction, the reaction solution was poured into 100 ml of water and stirred. Sodium bicarbonate was added to this aqueous solution to neutralize. The precipitated crystals were filtered and dried. The crystals were washed by heating with ethyl acetate to give 397 mg (yield: 61.0%) of exemplary compound S-3.
¹ H-NMR (DMSO-d6)
δ 9.06 (d, 2 H), 7. 10 (brs, 4 H), 7.72 (S, 1 H), 7. 10 (s, 1 H), 3.93 (s, 3 H), 3.9 1 (S, 3 H), 3.68 (q, 2 H), 1.31 (t, 3H)

Synthesis Example 2
The exemplified compounds shown in Table 1 were synthesized by the same method as the method of synthesizing the exemplified compound S-3.
The results of ¹ H-NMR are shown in Table 1.

[Activity and selectivity against malarial parasites]
1. Culture of Plasmodium falciparum In this experiment, Plasmodium falciparum NF 54 strain protozoa was used. The culture medium used in the experiment was RPMI-1640 medium filter-sterilized, and human serum was added to a concentration of 5%. The culture of the malarial parasite was carried out at an O ₂ concentration of 3%, a CO ₂ concentration of 4%, an N ₂ concentration of 93%, and a temperature of 37 ° C.

2. Malaria parasite growth inhibition screening test The compound of the present invention and the comparative example compound used in the test were dissolved in dimethyl sulfoxide (DMSO) to prepare a test solution of a predetermined concentration. Cultured malaria parasite infected erythrocytes were collected by centrifugation and diluted with non-infected erythrocytes to make the initial infection rate 0.15%. The hematocrit value at this time was 2.5%. 200 μL of malaria infection culture solution was added to the wells of a 96-well culture plate, and a test solution containing a predetermined concentration of drug or DMSO without drug was added and adjusted. The test solution was taken in duplicate. After 48 hours of culture at 37 ° C., 0.5 μCi of radioactive sodium ( ³ H) -labeled hypoxanthine was added to each well. After further culturing for 24 hours under the same conditions, it was collected on a glass fiber filter and washed with distilled water. The radiation intensity was measured with a beta plate liquid scintillation counter (manufactured by Wallac), and the malaria parasite infection rate of the test solution added group and the controller was calculated.

From the malarial parasite infection rate determined above, the growth inhibition rate was calculated by the following equation to determine the 50% growth inhibition concentration (EC ₅₀ ).
Growth inhibition rate (%) = {1- (ba) / (ca)} × 100
a: Initial infection rate b: Infection rate when test solution is added c: Control infection rate

3. Rat L6 Cell Growth Inhibition Test Rat-derived L6 cells (rat skeleta myoblast cells) were used. The medium was added to RPMI 1640 medium so that L-glutamine (200 mM) was 1% and fetal bovine serum was 10%, and the medium was cultured at 37 ° C., 5% CO ₂ concentration.
The compound of the present invention used for the test or the reference drug was dissolved in DMSO to give a test solution of a predetermined concentration. The whole culture was carried out and the medium containing cells in the logarithmic growth phase was placed in the wells of a 96-well culture plate, and then a test solution containing a predetermined concentration of drug or DMSO without drug was added. The test solution was taken in duplicate. After culturing the culture plate for 72 hours in an incubator, the growth inhibitory activity was evaluated. Evaluation was performed as follows.
To each well, 10 μL of Alamar Blue aqueous solution was added, and the cells were further cultured for 2 hours. Next, the culture plate is attached to a fluorescent microplate reader (Spectaramax Gemeni XS; manufactured by Molecular Devices, Inc., USA) and irradiated at an excitation wavelength of 536 nm, and the fluorescence intensity of 588 nm is measured to test L6 cells containing test solution and control. The residual rate of was calculated.

From the cell survival rate determined above, the growth inhibition rate to L6 cells was calculated by the following equation to determine 50% growth inhibition concentration (EC ₅₀ ).
Growth inhibition rate (%) = {(CA) / (BA)} × 100
A: Initial cell number B: Number of control cells after 3 days C: Number of cells 3 days after addition of test solution

4. Determination of efficacy against malaria The antimalarial activity of the sample is evaluated from the EC ₅₀ value of the sample against malarial parasite and rat L6 cells. Chemotherapeutic coefficient, which is used as an indicator of selective toxicity to malarial parasites, was calculated according to the following equation to determine its efficacy.
The higher the value of selective toxicity, the lower the risk of side effects.
Chemotherapy index = (EC ₅₀ value of sample for rat L6 cells) ÷
(EC ₅₀ value of sample for malarial parasite)

The EC ₅₀ values of the samples against Plasmodium falciparum and rat L6 cells for the compounds of the present invention and the compounds of the comparative examples, and the selective toxicity coefficients are shown in Table 2. In this table, the "Plasmodium falciparum NF 54" column shows the EC ₅₀ value of the sample against malarial parasites and the "Cytotoxity L6" column shows the EC ₅₀ value of the sample against rat L6 cells.

Comparative example compound

H-5 compounds described in Nature. 465, 305-310 (2010)

[Corrosion test of oral administration of malaria-infected mice (in vivo)]
Rodent malaria parasite (Plasmodium berghei GFP ANKA) was used in this test.
Infected serum is used as infected by intraperitoneal or tail vein administration at 4 to 6 weeks (20 to 26 g) in NMRI female SPF mice. Blood was collected from the tail vein of malaria-infected mice, and the infection rate was determined to confirm appropriate infection (10% to 20%), and then malaria-infected blood was collected from the mouse heart with a syringe with heparin. Thereafter, the blood was diluted with physiological saline so as to be 5.0 × 10 ⁻⁶ malaria parasites per 1 ml of dose based on the number of red blood cells (cells / ml) and protozoal infection rate. This was infected from the tail vein by 0.2 ml per 20 g of body weight of uninfected mice (NMRI female female 5 weeks old) (Day 0). The compounds used for the test were dissolved in a 10 w% DMSO solution (a mixture of 1 ml of DMSO and 9 ml of glucose solution).

The mice were divided into groups of 3 mice and orally administered four times in total for 24 hours (Day-1), 48 hours (Day-2), 72 hours (Day-3) and 96 hours (Day-4) of malaria infection .
Blood is collected from the tail of mice at 138 hours for malaria infection (Day 6), thin layer smears are prepared, and the malaria parasite infection rate in the compound administration group and control (non-compound administration) group is measured under a microscope, The malarial parasite infection rate (Parasitemia) was calculated.

The cure rate (Suppresion) at the time of drug administration was calculated by the following formula from the malarial protozoal infection rate obtained above.
Cure rate: Suppression (%) = (B-A) / B x 100
A: Protozoan infection rate of mice administered with the compound of the present invention B: Protozoan infection rate of control (non-compound administered) mice Lifespan days: MSD (day) = (from the day of malaria infection of mice administered with the compound of the present invention Average number of days)-D
D: Average value of the number of days from the date of malaria infection in control (non-administered) mice to the day of death

The results obtained in the above experiments are shown in Table 3 below.

As can be seen from Table 2, the 2,4-diaminoquinazoline derivative of the present invention is a conventionally known quinazoline derivative, for example, the compound H-5 described in Nature, 465, 305-310 (2010) (comparison in this example) The compound H-5 has a higher ability to kill malarial parasites than the compound having the strongest antimalarial activity among the compounds having quinazoline skeleton in FIG. The compounds represented by V) and (VI) were found to be excellent. It was also found that the selective toxicity coefficient was about 7 to 1000 times better. Furthermore, as can be seen from Table 3, in the evaluation system (in vivo) for malarial parasite-infected mice, particularly, the compound S-2 achieves a cure rate of 99.7%, and the survival rate is as excellent as 14 days or more. was gotten. Furthermore, the compounds of the present invention are characterized in that synthetic raw materials are inexpensive and easily available, and can be manufactured inexpensively in simple operations. By including the 2,4-diaminoquinazoline derivative of the present invention in the active ingredient, it is possible to provide an inexpensive drug for preventing or treating malarial parasite disease.

Industrial application field

The present invention relates to a drug composition for preventing or treating a malarial parasite disease, which is a pharmaceutical composition, and relates to a pharmaceutical composition comprising a 2,4-diaminoquinazoline derivative having a specific structure and a salt thereof as an active ingredient. . Further, the present invention relates to a 2,4-diaminoquinazoline compound having a novel structure which is useful as a malaria disease preventive and therapeutic agent.

Claims (9)

1. A pharmaceutical composition for preventing or treating a malaria parasite disease, which comprises at least one quinazoline derivative represented by the following general formula (I) or a salt thereof.
   

   

   
   (Wherein, R ₁ represents a hydrogen atom or a monovalent substituent, and R ₂ represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a heterocyclic group, an acyl group, or an alkylaminocarbonyl group. N Represents an integer of 1 to 4, and m represents an integer of 0 to 3. The sum of n and m represents 4. When n is 1, the substitution position of R ₂ -O- is 6 or 7 R ₃ represents an alkyl group, an alkenyl group, an aryl group or a heterocyclic group (except for piperidyl group), and R ₄ and R ₅ each independently represent a hydrogen atom, an alkyl group, an alkenyl group or an aryl group R ₄ and R ₅ may be bonded to each other to form a 5-membered ring)
2. The pharmaceutical composition for preventing or treating malarial parasite disease according to claim 1, wherein the quinazoline derivative represented by the general formula (I) is represented by the following general formula (II).
   

   

   
   (Wherein, R ₃ , R ₄ and R ₅ have the same meaning as R ₃ , R ₄ and R ₅ represented by general formula (I). R ₆ and R ₇ each independently represent a hydrogen atom or a monovalent atom. R ₈ and R ₉ each independently represent a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, or a heterocyclic group, and R ₈ and R ₉ are combined to form a 5- to 7-membered member. May form a ring of
3. The quinazoline derivative represented by the general formula (I) or the general formula (II) is represented by the following general formula (III), for preventing or treating a malaria parasite disease according to claim 1 or 2 Pharmaceutical composition.
   

   

   
   _(Wherein, R 3, _{R 4,} and _{R 5,} formulas (I) and (II) _R 3, _{R 4} in, and _{R 5} to be synonymous.)
4. The compound or its salt represented by the following general formula (IV).
   

   

   
   (Wherein, R ₄ represents a hydrogen atom, an alkyl group, an alkenyl group, an aryl group or a heterocyclic group. R ₁₀ represents an alkyl group, an alkenyl group, a phenyl group not substituted with a heterocyclic group, or a heterocyclic group And L represents a methylene group and p represents 0, 1 or 2. Y represents a heterocyclic group composed of a nitrogen atom and a carbon atom.
5. A pharmaceutical composition for preventing or treating malarial protozoal disease, which comprises the compound according to claim 4 or a salt thereof.
6. The compound or its salt represented by the following general formula (V).
   

   

   
   (Wherein, R ₁₁ represents an unsubstituted alkyl group, an aryl group, a heterocyclic group (excluding piperidyl group), or-(A) -XR ₁₂ , and A represents an alkylene group which is a divalent linking group) X represents an -O-, -S-, -SO _2- , -C (= O) O-, -O- (C = O)-, -NHSO _2- , Or -SO ₂ NH-, wherein R ₁₂ represents an alkyl group, an alkenyl group, an aryl group or a heterocyclic group)
7. A pharmaceutical composition for preventing or treating malarial protozoal diseases, which comprises the compound according to claim 6 or a salt thereof.
8. The compound or its salt represented by the following general formula (VI).
   

   

   
   (Wherein, R ₁₃ represents a C ₁ to C ₁₀ unsubstituted alkyl group, R ₁₄ represents a hydrogen atom or a C ₁ to C ₁₀ unsubstituted alkyl group, and R ₁₅ represents a C ₄ to C ₁₀ unsubstituted group Represents a substituted alkyl group, a substituted or unsubstituted benzyl group, or a substituted or unsubstituted aryl group)
9. A pharmaceutical composition for preventing or treating malarial parasite disease, which comprises the compound according to claim 8 or a salt thereof.