JPH08134044A - New pyrimidine compound, intermediate and their production - Google Patents

Abstract

PURPOSE: To obtain the subject compound useful as an antiviral agent, a preventive or a therapeutic agent for influenza, showing antiviral effect, by reacting a specific compound in the presence of a condensation agent. CONSTITUTION: This compound is shown by formula I [R1 is H, a lower alkyl, a halogen, OH, a 1-4C alkoxy, a 1-6C hydroxyalkoxy or NH2 ; R2 is H, NH2 or NHCOCH3 ; R3 is a group of formula II (R5 is H, a lower alkyl; R6 and R7 are each a lower alkyl; (n) is 0-4), etc.; R4 is H, a halogen, NH2 , CN, CHO, CH2 OH, etc.] such as 2-amino-6-chloro-4-[(3-hydroxy-2,2-dimethylpropyl) amino]pyrimidine. The compound is obtained by reacting a pyrimidine compound of formula III with an amine compound of formula IV in a solvent (solventless state) in the presence of a condensation agent (e.g. calcium carbonate), for example, under cooling to the boiling point of the solvent for 1-7 hours.

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to a novel pyrimidine compound, more specifically, a novel pyrimidine compound which has an antiviral activity and is useful as a preventive or therapeutic agent for various viral diseases and a pharmacologically acceptable salt thereof. , An intermediate for producing these, and a method for producing them.

[0002]

2. Description of the Related Art Currently, there are no satisfactory drugs for many viral diseases from the viewpoint of efficacy and safety, and development of excellent antiviral agents is desired. Conventionally, the following are known as pyrimidine-related derivatives having a cycloalkyl ring. Japanese Patent Application Laid-Open No. 2-304088 discloses a cyclopentenecarbinol compound substituted with a pyrimidinylamino group as an intermediate for producing an antiviral agent known as Carbovir. JP-A-3-47169 discloses a pyrimidine derivative having a cyclobutylamino group as a synthetic intermediate for carbocyclic nucleoside analogs.
JP-A-60-130571 discloses a pyrimidine derivative having a cyclopropylmethylamino group, which is useful as a herbicide or a microbicide. However, there is no report that it has a structure like the pyrimidine compound according to the present invention and has an antiviral action.

[0003]

At present, there is no satisfactory therapeutic drug for viral diseases, the development of new antiviral agents is desired, and various researches have been made under the present circumstances. An object of the present invention is to provide a novel compound useful as an antiviral agent. Another object of the present invention is to provide an antiviral agent containing the novel compound. Another object of the present invention is to provide a method for producing the novel compound. A further object of the present invention is to provide an intermediate useful for producing the novel compound. A further object of the present invention is to provide a method for producing the intermediate.

[0004]

DISCLOSURE OF THE INVENTION As a result of intensive studies conducted by the present inventors in view of the above-mentioned circumstances, the novel pyrimidine compound according to the present invention has an excellent antiviral activity, and the synthesis of this compound is easy. The present invention has been completed and the present invention has been completed.
That is, the present invention provides the following general formula [I]

[0005]

[Chemical 21]

[In the formula I, R1 is H, a lower alkyl group having a carbon number of C1 to C4, a halogen atom, --OH, a carbon number of C1 to C4.
C4 alkoxy group, C1 to C6 hydroxyalkoxy group or --NH2; R2 is H, --NH2 or --N
HCOCH3; R3 is a group selected from the following (a) to (d)

[0007]

[Chemical formula 22]

(Wherein R5 is H or a lower alkyl group having 1 to 4 carbon atoms; R6 and R7 are the same or different and each is a lower alkyl group having 1 to 4 carbon atoms; R8 is H;
--OH, C1 -C4 hydroxy lower alkyl group or --CH2 OC (O) CH3; R9 is H, --OH, C1 -C4 lower alkyl group, C1 -C4 hydroxyalkyl group, carbon An alkoxy group having a number of C1 to C4, a vinyl group, -O (CH2) kR (R is an aromatic ring group, and the aromatic ring group has a lower alkyl group having a carbon number of C1 to C4, a halogen atom and It may have a substituent selected from an alkoxy group having 1 to 4 carbon atoms, and k is
An integer of 0 to 4), or-(CH2) jR '(R' is a benzoyloxy group or an aromatic ring group, and the aromatic ring group is a lower alkyl group having a carbon number of C1 to C4, a halogen atom. R10 may have a substituent selected from an atom and an alkoxy group having 1 to 4 carbon atoms; j is an integer of 0 to 4);
Is H, --OH or an alkoxy group having 1 to 4 carbon atoms; or R9 and R10 may form a methylene group (= CH2) or a carbonyl group (C = O) together with the carbon atom to which they are bonded; In (b) and (d), the cycloalkyl ring may have a double bond at any position in the ring; n is an integer of 0 to 4 and m is an integer of 0 to 4); R4 is H, halogen atom, --NH2, --CN,-
CHO, --CH2 OH, --COOH, --CH2 NH2,
-CONH2 or -CH = NA (A is -OH or a lower alkyl group having 1 to 4 carbon atoms); provided that n = 0 and R8
= Except for H]], or a pharmacologically acceptable salt thereof.

In the above general formula [I] of the present invention, the alkyl group having 1 to 4 carbon atoms represented by R1 may be linear or branched, for example, methyl, ethyl, n-propyl, iso. -Propyl, n-butyl or iso-butyl group,
Preferred is a methyl or ethyl group, most preferred is a methyl group; examples of the halogen atom include chlorine, bromine, fluorine and iodine atoms, and most preferred is chlorine or fluorine: C1 to C4 carbon atoms. The alkoxy group may be linear or branched and is, for example, methoxy, ethoxy, n-propoxy, iso-propoxy or n-.
Butoxy group, preferably methoxy or ethoxy group, most preferably methoxy group: carbon number C1
The alkoxy moiety of the -C6 hydroxyalkoxy group may be linear or branched, and may contain a cycloalkyl ring. Examples include 2-hydroxyethoxy, 3-hydroxypropoxy, 4-hydroxybutoxy or 1-hydroxymethylcyclobutyl-1-methoxy groups.

Examples of the halogen atom represented by R4 include chlorine, bromine, fluorine and iodine atoms.

The C1 -C4 lower alkyl group represented by R5 may be linear or branched and is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl. Groups.

The carbon number C1 to C4 represented by R6 or R7
The lower alkyl group of may be linear or branched, and examples thereof include a methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl group, preferably methyl, ethyl or propyl. A group, most preferably a methyl or ethyl group.

The C1-C4 hydroxy lower alkyl group represented by R8 may have a linear or branched alkyl moiety, for example hydroxymethyl, 1-
Hydroxyethyl, 1-methyl-2-hydroxyethyl, 1-hydroxypropyl, 2-hydroxyethyl,
3-hydroxypropyl or 4-hydroxybutyl group can be mentioned, preferably hydroxymethyl, 1-hydroxyethyl, 1-methyl-2-hydroxyethyl or 2-
It is a hydroxyethyl group, most preferably a hydroxymethyl, 1-hydroxyethyl or 2-hydroxyethyl group.

The lower alkyl group having 1 to 4 carbon atoms represented by R9 may be linear or branched and is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl. Group, preferably a methyl, ethyl, n-propyl or iso-propyl group, most preferably an n-propyl or iso-propyl group: carbon number C
The 1-C4 hydroxyalkyl group may have a linear or branched alkyl moiety, for example, a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl, 3-hydroxypropyl or 4-hydroxybutyl group. Of these, preferred is a hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl or 3-hydroxypropyl group, and most preferred is a hydroxymethyl group: an alkoxy group having 1 to 4 carbon atoms is linear or branched. It may be any chain, for example, methoxy, ethoxy, n-propoxy, iso-propoxy or n-butoxy group, preferably methoxy or ethoxy group,
Most preferably, it is a methoxy group.

R in -O (CH2) k-R represented by R9 is an aromatic ring group, and the aromatic ring group may have a substituent on the ring. Number of carbon atoms as said substituent C1 to C4
The lower alkyl group may be linear or branched, and examples thereof include a methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl group, preferably methyl, ethyl, n. -Propyl or iso-propyl group, most preferably methyl group: Examples of the halogen atom include chlorine, bromine, fluorine and iodine atoms, most preferably chlorine or fluorine: carbon number C1 to C4.
Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, iso-propoxy or n-butoxy group,
A methoxy or ethoxy group is preferred, and a methoxy group is most preferred.

When R'in-(CH2) j-R 'represented by R9 is an aromatic ring group, the aromatic ring group may have a substituent on the ring. The number of carbon atoms as the substituent C1
The C4 lower alkyl group may be linear or branched, and examples thereof include a methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl group, preferably methyl, ethyl, Propyl or iso-propyl group, most preferably methyl group: Examples of the halogen atom include chlorine, bromine, fluorine and iodine atoms, most preferably chlorine or fluorine: C1 to C4 carbon atoms.
Examples of the alkoxy group include methoxy, ethoxy, n-propoxy, iso-propoxy or n-butoxy group,
A methoxy or ethoxy group is preferred, and a methoxy group is most preferred. A phenyl group etc. are mentioned as an aromatic ring group shown by R or R '.

The C1-C4 alkoxy group represented by R10 may be linear or branched, and examples thereof include methoxy, ethoxy, n-propoxy, iso-propoxy and n-butoxy groups. , Preferably a methoxy or ethoxy group.

The lower alkyl group having 1 to 4 carbon atoms represented by A may be linear or branched and is, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl or iso-butyl. Groups.

The compound of the above-mentioned general formula [I] of the present invention can be converted into a pharmacologically acceptable salt, if desired, by reacting with a suitable acid, or from the formed salt. The base can also be liberated. Examples of the acid which forms a pharmacologically acceptable acid addition salt of the compound represented by the above general formula [I] of the present invention include hydrochloric acid, hydrobromic acid,
Mineral acids such as sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, trifluoromethanesulfonic acid, lower alkylsulfonic acids such as ethanesulfonic acid, arylsulfonic acids such as benzenesulfonic acid, acetic acid, maleic acid, fumaric acid, citric acid Examples thereof include organic acids such as malic acid, malic acid, oxalic acid, lactic acid, and tartaric acid, and the salt-forming reaction can be easily performed by a conventional method.

The following are preferable examples of each substituent in the general formula [I]. R3 is a group represented by the formula (a) or (b),
R4 is H, halogen atom, --NH2, --CN, --CH
O, CH2 OH or --CH = NOH, R8 is --OH, a C1 to C4 hydroxy (lower) alkyl group or-
CH2 OC (O) CH3, R9 is H, --OH, carbon number C
1 to C4 lower alkyl group, C1 to C4 alkoxy group, C1 to C4 hydroxyalkyl group, -O (C
H2) k-R (R is a phenyl group which may have a substituent, k is an integer of 0 to 4), or-(CH2) j-R '.
(R 'is a phenyl group which may have a substituent, j is 0
To an integer of 4), R10 is H or an alkoxy group having 1 to 4 carbon atoms, n is an integer of 1 to 4 (more preferably 1 or 2), and m is an integer of 0 to 3 (more preferably 1 or 2). .
Among the compounds represented by the general formula [I], R 5 is H, R 8 is a hydroxymethyl group, n is 1, m is 1 or 2
The compound (1) has an excellent antiviral effect and is a preferable compound.

The novel pyrimidine compound represented by the above general formula [I] of the present invention can be produced by various methods. For example, it can be manufactured according to the following method.

[0022]

[Chemical formula 23]

In the formula, R1, R2, R3 and R4 have the same meanings as described above, and the compound of the formula [III] has the following formulas [III- _I ] to [III
_-IV ]

[0024]

[Chemical formula 24]

(Wherein R5, R6, R7, R8, R9 and R10 have the same meanings as described above).

[0026]

[Chemical 25]

[0027]

[Chemical formula 26]

[0028]

[Chemical 27]

[0029]

[Chemical 28]

[0030]

[Chemical 29]

[0031]

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[0032]

[Chemical 31]

[0033]

Embedded image

[0034]

[Chemical 33]

[0035]

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[0036]

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[0037]

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In the above formulas, R1, R2, R3 and R4 have the same meanings as described above, X represents a halogen atom such as Br, Cl, I or F atom, and R13 represents a dialkyl acetal or a cyclic acetal. Represents a protective group for a carbonyl group.

Method A is a method for producing the compound [I] of the present invention. Method A is the method of preparing a pyrimidine compound having the general formula [II] by the general formula [III- _I ], [III- _II ] or [III _{- I} ].
_-III ] or an alcohol compound of the general formula [III- _IV ] is reacted in the presence of a condensing agent without solvent or in a solvent to produce [I].

The organic solvent used in the condensation reaction in the present production method may be any organic solvent as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol, ethanol, isopropanol and n-butanol, tetrahydrofuran, dioxane and acetone. , Polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide, and nonpolar solvents such as benzene, toluene, xylene and chloroform. The reaction is carried out in the range from cooling to the boiling point of the solvent. Reaction time is 1
7 hours.

As the condensing agent, a base which is a dehydrohalogenating agent (deoxidizing agent) can be used. For example, potassium carbonate,
Examples thereof include sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine, sodium hydride and the like.

Method B is a method for producing a compound [Ic] in which R4 is an amino group among the compounds represented by the above general formula [I]. In the first step, a mixture of a pyrimidine compound having the general formula [Ia], p-chloroaniline and sodium nitrite is subjected to a diazo coupling reaction at around 0 ° C. in an acidic aqueous solution of hydrochloric acid or the like to give the general formula [Ib].
] The compound which introduce | transduced the p-chlorophenyl azo group into the 5-position of the pyrimidine ring represented by these is manufactured, and as a 2nd process,
[Ic] can be produced from a diazo compound represented by the general formula [Ib] by a conventional method such as a reduction reaction using zinc-acetic acid.

In the method C, a compound [Id] or [If] having a halogen at the 5-position of the pyrimidine ring is produced by reacting a pyrimidine compound represented by the general formula [Ia] or [Ie] with a halogenating agent. Is the way to do it.

As a reaction method, a pyrimidine compound represented by the general formula [Ia] or [Ie] is reacted with a halogenating agent in a solvent. As the halogenating agent used in this production method, chlorine, bromine, iodine, N-chlorosuccinimide, N-bromosuccinimide, N-iodosuccinimide or the like can be used.

Any solvent may be used in the present production method as long as it does not inhibit the reaction, and examples thereof include polar solvents such as methanol, ethanol, isopropanol, acetic acid, N, N-dimethylformamide, benzene, toluene and xylene. And the like, aprotic apolar solvent such as chloroform, dichloromethane, carbon tetrachloride, ethyl ether, iso-propyl ether, tetrahydrofuran, and dioxane. The reaction is carried out in the range from cooling to the boiling point of the solvent.

Method D is a method for producing a compound represented by the above general formula [Ih], [Ii] or [Ij]. D
In the method, a dehalogenation reaction and a reduction reaction of a diazonium salt are carried out simultaneously or separately by reducing a pyrimidine compound having the general formula [Ib] or [Ig].
The pyrimidine compound represented by h], [Ii] or [Ij] can be produced. The reducing agent used in the present production method is preferably palladium hydroxide, and can be treated by a conventional method.

Method E is a method for producing the compound represented by the above general formula [Il]. 2,5,6-substituted-4- (1-hydroxymethyl-3, represented by the general formula [Ik],
A pyrimidine compound represented by the general formula [Il] can be produced by subjecting a 3-dialkylacetal (or cyclic alkylacetal) cycloalkylmethylamino) pyrimidine compound to an acid treatment by a conventional method. The acid used in the present production method is an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid or the like, or an organic acid such as formic acid, oxalic acid, acetic acid or the like alone or as a mixed acid.

Method F is a method for producing the compound represented by the above general formula [In]. The pyrimidine compound represented by the general formula [In] can be produced by reducing the pyrimidine compound represented by the general formula [Im]. The reducing agent used in the present production method may be any reducing agent capable of reducing a carbonyl group, and can be reduced and treated by a conventional method.

Method G is a method for producing the compound represented by the above general formula [Ip]. The pyrimidine compound represented by the general formula [Ip] can be produced by oxidizing the pyrimidine compound represented by the general formula [Io]. The oxidizing agent used in the present production method can be oxidized by osmium tetroxide or a combined use of osmium tetroxide and a co-oxidizing agent, but osmium tetroxide oxidization is preferable and the oxidant can be treated by a conventional method.

Method H is a method for producing the compound represented by the above general formula [Ir]. The pyrimidine compound represented by the general formula [Ir] can be produced by reducing the pyrimidine compound represented by the general formula [Iq]. The reducing agent used in the present production method may be any reducing agent capable of reducing the formyl group, and can be reduced and treated by a conventional method.

Method I is a method for producing the compound represented by the above general formula [Is]. The pyrimidine compound represented by the general formula [Is] can be produced by reacting the pyrimidine compound represented by the general formula [Iq] with hydroxylamine in a solvent or without a solvent.

The organic solvent used in the condensation reaction in the present production method may be any organic solvent as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol, ethanol, isopropanol and n-butanol, tetrahydrofuran, dioxane and acetone. , Polar solvents such as acetonitrile, N, N-dimethylformamide and dimethylsulfoxide, and nonpolar solvents such as benzene, toluene, xylene and chloroform. The reaction is carried out in the range of room temperature to the boiling point of the solvent.

Method J is a method for producing a compound represented by the general formula [It]. In the general formula [I], R4 is -CH = NO.
A compound having H group can be dehydrated in the presence of a dehydrating agent to produce a pyrimidine compound represented by the general formula [It].

Examples of the dehydrating agent used in the present production method include acetic anhydride, acetic anhydride-sodium acetate, thionyl chloride, phosphorus pentoxide, phosphorus pentachloride and benzoyl chloride.

Synthesis of Intermediates The above-mentioned general formulas [III- _I ], [III- _II ], [III- _III ] and [III- _IV ] used as intermediates in this production method
Some of the compounds represented by [III- _I ] are
No. 2,618,658, [III- _II ] is Bull, soc, Chim, F
rance, in 1965, 204, [III _-III] British Patent No. 1,169,027
In the specification, [III- _IV ] is Zhur, Obshchei, Khim, 23 ,
It is a known compound in 1994 (1953) and the like and can be produced by the method described in the literature.

Further, the above general formula [III- _II ] which is an intermediate is
Among the compounds represented by the general formula [III _-II ']

[0057]

Embedded image

[In the formula, m'represents an integer of 1 to 4;
, R8, R9, R10 and n are as defined above. The cycloalkyl ring in the formula may have a double bond at any position in the ring. Provided that R5, R9, and R10 are all hydrogen atoms, R8 is hydroxymethyl, m'is an integer of 1 to 4, n is 1, and the cycloalkyl ring is a saturated ring, and n8 is R8 = H. Except the case] is a novel compound and can be produced by the following method.

The amine compound represented by the formula [III- _II ], which is an intermediate, can be produced according to the following method.

[0060]

[Chemical 38]

[0061]

[Chemical Formula 39]

[0062]

[Chemical 40]

[0063]

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[0064]

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[0065]

[Chemical 43]

[0066]

[Chemical 44]

[0067]

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In each of the above formulas, R5, R8, R9, R10, X
And m are as defined above, R11 represents an alkyl group, preferably an alkyl group having a carbon number of C1 to C4 such as methyl group and ethyl group, and R12 represents an alkyl group, preferably methyl group and ethyl group. Represents a C1-C4 alkyl group or a benzyl group, R14 represents an acyl group such as a benzoyl group, and R15 represents H or a C1-C3 alkyl group. In the formula [III- _{I I} e], R5 is a carbon number C1
~ Represents a C4 alkyl group.

Method K is a method for producing the compound represented by the above general formula [III- _II a]. First step: β-substitution of dialkyl malonate-α, ω-
In the presence of an alkyl dihalide and an alcoholate, a ring-closing reaction is performed to give a 3-substituted-1,1-dicarboxylic acid dialkyl ester cycloalkane, and a second step: 3-substituted-1,1-dicarboxylic acid dialkyl ester cycloalkane Selective hydrolysis in the presence of alkali to give 3-substituted-1-carboxylic acid-1-cycloalkylcarboxylic acid alkyl ester, third step; 3-substituted-1-carboxylic acid-1-cycloalkylcarboxylic acid alkyl ester In a non-polar solvent in the presence of a base, with ethyl chlorocarbonate, and further with ammonia or amines to give 3-substituted-1-carboxamido-1-cycloalkylcarboxylic acid alkyl ester, the fourth step The obtained 3-substituted-1-carboxamide-
The 1-cycloalkylcarboxylic acid alkyl ester can be reduced by a conventional method to produce a 3-substituted-1-hydroxymethyl-1-cycloalkylmethylamine compound represented by the general formula [III- _IIa ].

As the reaction method, as the alcoholate used in the first step, sodium methylate, sodium ethylate, potassium tert-butyrate and the like can be mentioned, and the reaction temperature may be in the range from under cooling to the boiling point of the solvent, The reaction time is in the range of 1 hour to 5 hours. Examples of the alkali used in the second step include aqueous solutions of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and the like, or hydrous alcoholic solutions of sodium hydroxide and potassium hydroxide. The reaction temperature may be in the range from cold to the boiling point of the solvent, preferably room temperature, and the reaction time is in the range of 1 hour to 72 hours.
Examples of the nonpolar solvent used in the third step include nonpolar solvents such as benzene, toluene, xylene and chloroform, and examples of the base include triethylamine and dimethylaniline. The reaction temperature may range from -10 ° C to the boiling point of the solvent. LiAlH4 can be mentioned as the reducing agent used in the fourth step, which can be reduced and treated by a conventional method. For example, examples of the reaction solvent include tetrahydrofuran, ethyl ether, dioxane, pyridine and the like. The reaction temperature may range from 0 ° C. to the boiling point of the solvent, and the reaction time may range from 1 to 5 hours.

Method L is a method for producing the compound represented by the above general formula [III- _IIa ]. First step: 3-substituted-1-carboxylic acid-1-cycloalkylcarboxylic acid alkyl ester is reacted with a halogenoacylating agent in a nonpolar solvent or in the absence of a solvent, which is then reacted with ammonia or amines in the presence of a base. To give 3-substituted-1-carboxamide-1-cycloalkylcarboxylic acid alkyl ester, and the second step; the obtained 3-substituted-1-carboxamide-
The 3-substituted-1-hydroxymethyl-1-cycloalkylmethylamine compound represented by the general formula [III- _IIa ] can be produced by reducing 1-cycloalkylcarboxylic acid alkyl ester by a conventional method.

Examples of the solvent used in the first step include nonpolar solvents such as benzene, toluene, xylene and chloroform, and examples of the halogenoacylating agent include thionyl chloride, phosphorus oxychloride, phosphorus pentachloride and the like. Examples of the base include triethylamine and dimethylaniline. The reaction is carried out in the range of -10 ° C to the boiling point of the solvent. LiAlH as the reducing agent used in the second step
4, which can be reduced and treated by a conventional method. For the reaction solvent and the reaction conditions, refer to the fourth step of Method K.

Method M is a method for producing the compound represented by the above general formula [III- _II b]. First step; alkyl cyanoacetate is subjected to ring closure reaction in the presence of β-substituted-α, ω-dihalogenated alkyl and alcoholate to give 3-substituted-1-cyano-1-cycloalkylcarboxylic acid alkyl ester, Two steps; 3-substituted-1-cyano-1-cycloalkylcarboxylic acid alkyl ester obtained is reduced by a conventional method to give 3-substituted-1-hydroxymethyl-1 represented by the general formula [III- _II b]. -Methylamine cycloalkyl compounds can be prepared.

As the alcoholate used in the first step, sodium methylate, sodium ethylate, potassium tert-butyrate and the like can be mentioned. The reaction temperature may be in the range from under cooling to the boiling point of the solvent, and the reaction time is 1 hour. To 5 hours. Examples of the reducing agent used in the second step include LiAlH4, B2 H6, Na BH4 and the like. The catalyst is aluminum chloride as a Lewis acid or cobalt chloride as a transition metal salt. , Can be processed. For example, the catalyst can be used in the range of 0.1 to 1.5 equivalents. Examples of the reaction solvent include tetrahydrofuran, ethyl ether, dioxane and the like. The reaction temperature may be in the range from under cooling to the boiling point of the solvent, and the reaction time is in the range of 1 to 5 hours.

Method N is a method for producing the compound represented by the above general formula [III- _II c]. First step: 3-substituted-1-cyano-1-cycloalkylcarboxylic acid alkyl ester is reacted with an alkali metal hydride and dimethyl sulfoxide in an anhydrous solvent to give 3-substituted-1-cyano-1-cycloalkylmethylsulfinyl. As a methylcarbonyl compound, the second step; the obtained 3-substituted-1-cyano-1-cycloalkylmethylsulfinylmethylcarbonyl compound is reduced with a metal amalgam in a solvent to give 3-substituted-1-cyano-1-cyclo. The alkylacetyl compound is used, and the third step is carried out. The obtained 3-substituted-1-cyano-1-cycloalkylacetyl compound is reduced by a conventional method to give a 3-substituted-1- represented by the general formula [III- _IIc ]. (Α-Alkyl) hydroxymethyl-1-cycloalkylmethylamino compounds can be prepared.

Examples of the alkali metal hydride used in the first step include sodium hydride and potassium hydride, and examples of the anhydrous solvent include tetrahydrofuran, ethyl ether, dioxane, benzene, toluene and xylene. The reaction temperature may be in the range of 10 to 50 ° C, and the reaction time may be in the range of 0.5 to 3 hours. As the anhydrous solvent used in the second step, tetrahydrofuran, ethyl ether, dioxane, benzene, toluene, xylene,
Examples include chloroform, methylene chloride, dichloroethane and the like. Examples of the metal amalgam used include aluminum amalgam. Reaction temperature is from room temperature to 8
The temperature may be in the range of 0 ° C, and the reaction time is in the range of 1 to 5 hours. As the reducing agent used in the third step, LiAlH
4, etc., and can be processed by reduction by a conventional method. For the reaction solvent and the reaction conditions, refer to the fourth step of Method K.

Method P is a method for producing the compound represented by the above general formula [III- _II d]. First step; reacting 1-acyloxymethyl-3-methylenecycloalkyl with peroxide in anhydrous non-polar solvent,
1-acyloxymethyl-3-cycloalkylmethylene oxide, the second step; the obtained 1-acyloxymethyl-3-cycloalkylmethylene oxide is reacted with saturated alcoholic ammonia to give a compound represented by the general formula [III- _II d]. 1
-Hydroxymethyl-3-hydroxy-3-cycloalkylmethylamine compounds can be prepared.

The starting material of the first step, 1-acyloxymethyl-3-methylenecycloalkyl, can be produced as follows. 1-ethoxycarbonyl-
3-methylenecyclobutane is reduced to 1-hydroxymethyl-3-methylenecyclobutane, which is reacted with an acyl halide in the presence of a base to protect the hydroxyl group.
-Acyloxymethyl-3-methylenecycloalkyl is obtained.

As the anhydrous non-polar solvent used in the first step, acetonitrile, tetrahydrofuran, ethyl ether, dioxane, benzene, toluene, xylene, chloroform, methylene chloride, dichloroethane and the like can be mentioned. As the peroxide, perbenzoic acid, Examples include metachloroperbenzoic acid and the like. The reaction temperature may be in the range of room temperature to the boiling point of the solvent, and the reaction time is in the range of 0.5 to 12 hours. Examples of the saturated alcoholic ammonia used in the second step include a saturated ammonia-methanol solution and the like, and the reaction can be carried out in the solution. The reaction temperature may range from under cooling to the boiling point of the solvent, and the reaction time may be 0.5
~ 5 hours.

Method Q is a method for producing the compound represented by the above general formula [III- _II e]. 1,3-Substitution-1-
Cycloalkylmethylamine compound in a solvent, NaBH
The compound represented by the general formula [III- _II e] can be produced by the reductive alkylation reaction of amino with formaldehyde or an alkyl aldehyde in the presence of a reducing agent such as 3CN or Na BH 4. The organic solvent used in the condensation reaction in the present production method may be any organic solvent as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol, ethanol, isopropanol, and n-butanol. The reaction temperature may be in the range from under cooling to the boiling point of the solvent, and the reaction time is in the range of 1 to 20 hours.

Method R is a method for producing the compound represented by the above general formula [III- _II e]. 1,3-Substitution-1-
A cycloalkylmethylamine compound is reacted with an alkyl halide in a solvent in the presence of a base as a dehydrohalogenating agent to give a 3-substituted-cycloalkyl-1- (represented by the general formula [III- _IIe ]. N-alkyl) methylamine compounds can be prepared.

The organic solvent used in the condensation reaction in the present production method may be any organic solvent as long as it does not inhibit the reaction, and examples thereof include alcohol solvents such as methanol, ethanol, isopropanol and n-butanol, acetone, acetonitrile and N. Aprotic polar solvent such as N, N-dimethylformamide, dimethylsulfoxide,
Or benzene, toluene, xylene, chloroform, dichloromethane, carbon tetrachloride, ethyl ether, is
Examples thereof include aprotic apolar solvents such as o-propyl ether, tetrahydrofuran, and dioxane. Examples of the base used as the dehydrohalogenating agent include potassium carbonate, sodium carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, pyridine, triethylamine and the like. The reaction is carried out in the range from cooling to the boiling point of the solvent. The reaction time is in the range of 1 to 24 hours.

Method S is a method for producing the compound represented by the above general formula [III- _II f]. First step; 3-substituted-1-alkoxycarbonyl-1-
Cycloalkylcarboxylic acid is dissolved in a dry non-polar solvent,
In the presence of a base, it is heated to react with diphenylphosphoric azide (DPPA) (Curtius rearrangement) and then to an alcohol represented by the formula: R12OH (alkyl alcohol or benzyl alcohol) to give 3-substituted-1-alkoxycarbonyl- 1-cycloalkylalkoxy (or benzyloxy) carbamate, second step; 3-substituted-1-alkoxycarbonyl-1-
Reduction of the alkoxycarbonyl group of cycloalkylalkoxy (or benzyloxy) carbamate to give 3-substituted-1-hydroxymethyl-1-cycloalkylalkoxy (or benzyloxy) carbamate, third step; 3-substituted-1- Hydroxymethyl-1-cycloalkylalkoxy (or benzyloxy) carbamate is subjected to hydrogenolysis or acid decomposition to give a compound of the general formula [III- _II
f]]-substituted-1-hydroxymethyl-1-
Cycloalkylamine compounds can be prepared.

As the non-polar solvent used in the first step, benzene, toluene, xylene, ethyl ether, iso-
Examples include propyl ether, tetrahydrofuran, dioxane, and the like, and examples of the base include triethylamine, dimethylaniline, and the like. The heating reaction can be carried out up to the boiling point of the solvent, and the reaction time is in the range of 1 to 15 hours. LiAlH as the reducing agent used in the second step
4, LiBH4 and the like can be mentioned, which can be reduced and treated by a conventional method. For example, examples of the reaction solvent include tetrahydrofuran, ethyl ether, dioxane and the like. The reaction temperature may be in the range from under cooling to the boiling point of the solvent, and the reaction time is in the range of 0.5 to 5 hours. Examples of the hydrogenolysis method used in the third step include a method of hydrogenating at normal pressure using a palladium catalyst. Examples of the reaction solvent include methanol, ethanol and propanol, and the reaction temperature is in the range of room temperature to the boiling point of the solvent. Examples of the palladium catalyst include palladium hydroxide and palladium chloride, which can be used in an amount of 0.05 to 1 equivalent. The reaction time is in the range of 1 to 5 hours. Examples of the acid used in the acid decomposition method include phosphonium iodide, acetic acid, a mixed acid of hydrogen bromide or hydrogen chloride in acetic acid, and the like. Examples of the reaction solvent include water and alcohol, and the reaction temperature is from room temperature to the boiling point of the solvent. The reaction time is in the range of 1 to 5 hours.

[0085]

INDUSTRIAL APPLICABILITY The novel pyrimidine compound of the present invention exhibits an antiviral effect and is useful as a preventive and / or therapeutic agent for various viral diseases, particularly as an anti-influenza agent.

The novel pyrimidine compound represented by the above general formula [I] of the present invention and the pharmacologically acceptable salt thereof have antiviral activity and are expected as antiviral agents. Examples of viruses include influenza viruses A and B, rotavirus, HIV (Human Immunode
ficiency virus) including retrovirus, herpes simplex virus, cytomegalovirus, VZV (Varicella-Z)
oster virus), EBV (Epstein-barr Virus), hepatitis virus, etc.

The compound of the present invention is administered as an antiviral agent composition prepared by mixing with a suitable pharmaceutical carrier. The dosage form may be oral or parenteral. The dosage form of the oral administration agent includes, for example, tablets, capsules, powders, fine granules, granules, solutions and syrups, and the dosage form of the parenteral administration agent includes, for example,
Examples include injections and suppositories. In the preparation of these preparations, pharmacologically and pharmaceutically acceptable additives can be added, and excipients, disintegrants or disintegration aids, binders, lubricants, coating agents, dyes, etc. Used.

In the oral preparation, as excipients, glucose, lactose, D-mannitol, starch, crystalline cellulose, etc., and as disintegrants, disintegration aids, carboxymethyl cellulose, starch, carboxymethyl cellulose calcium, etc. As the agent, hydroxypropyl cellulose, hydroxymethyl cellulose, polyvinylpyrrolidone, gelatin and the like, as the lubricant, magnesium stearate, talc and the like, as the coating agent, hydroxypropyl methyl cellulose, sucrose, titanium oxide and the like, In the injection, as a solubilizer or solubilizing agent, distilled water for injection, physiological saline, propylene glycol or the like, and as an isotonicity agent, glucose, sodium chloride, D-mannitol, glycerin or the like, p
As the H-preparing agent, a conventional formulation component such as an inorganic acid, an organic acid or an inorganic base, or an organic base is used.

The dose of the compound of the present invention to a patient to be treated varies depending on the symptoms, age and administration method of the patient to be administered.
Usually, it is 0.1 mg to 500 mg / kg / day.

The content of the active ingredient of the present invention in the antiviral agent composition of the present invention varies greatly depending on the form of the preparation and is not particularly limited, but usually it is 0. 01-90% by weight, preferably 0.01
˜20% by weight, particularly preferably 0.1 to 10% by weight.

The present invention will be described in more detail below with reference to Reference Examples, Examples and Test Examples, but the present invention is not limited to the specific details of these examples.

[0092]

Examples Method A Example-1 Method A-1 2-amino-6-chloro-4-[(3-hydroxy-
2,2-Dimethylpropyl) amino] pyrimidine (Compound No.-20) 3-Hydroxy-2,2-dimethylpropylamine
2.5 g (0.0243 mol) and 2-amino-
4,6-dichloropyrimidine 4.0 g (0.0243)
(mol) was dissolved in 100 ml of ethanol, 5 ml of triethylamine was added, and the mixture was refluxed for 24 hours, then the solvent was distilled off under reduced pressure, the residue was washed with water, dried and recrystallized from chloroform-methanol to give 3.96 g (7) of colorless prism crystals.
0.7%). mp203-207 ° C (chloroform-methanol)

Example-2 Method A-2 2-Amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-35) 1-Hydroxymethyl-1 -Cyclobutylmethylamine 5.75 g (0.05 mol), 2-amino-4,6
-Dichloropyrimidine 8.20 g (0.05 mo
l), 200 ml of ethanol and triethylamine
After refluxing 20 ml of the mixture overnight, the solvent was distilled off under reduced pressure, the residue was washed with water, dried and recrystallized from acetone to obtain 11.2 g (92.3%) of colorless prism crystals.
mp192-194 ° C (acetone)

Example-3 Method A-3 2-amino-6-chloro-4-[[(3-hydroxymethyl-3-oxetanyl) methyl] amino] pyrimidine (Compound No.-26) 3-aminomethyl-3 -Hydroxymethyl oxetane
1.17 g (0.01 mol), 2-amino-4,6-
Dichloropyrimidine 1.64 g (0.01 mol),
After refluxing a mixture of 40 ml of ethanol and 4 ml of triethylamine for a whole day and night, the solvent was distilled off under reduced pressure, ethyl acetate was added to the residue, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column purification. (Chloroform: methanol = 20: 1, later 10:
1) Then, 0.8 g (32.8%) of colorless prism crystals were obtained. mp185-186 ° C (acetone)

Example-4 Method A-4 2-Amino-6-chloro-4-[(1-hydroxymethyl-1-cyclobutyl) methoxy] pyrimidine (Compound No.-95) 60% sodium hydride 0.4 g ( (0.01 mol)
Was suspended in 40 ml of dry dioxane, and 1.16 g (0.01 mol) of dihydroxymethylcyclobutane dissolved in 40 ml of dry dioxane was added dropwise thereto.
After stirring at 70 ° C. for 30 minutes, 1.64 g (0.01 mol) of 2-amino-4,6-dichloropyrimidine was added, and the mixture was refluxed for 3 hours and then filtered, the solvent of the filtrate was evaporated under reduced pressure, and the residue was silica gel. After column purification (chloroform: methanol = 50: 1), white crystals 1.24 g (50.8)
%) Was obtained. mp125-127 ° C (acetone)

Example-5 Method A-5 2-amino-6-chloro-4-[[(3- (2-phenylethyl) -1-hydroxymethyl-1-cyclobutyl) methyl] amino] -5-formyl Pyrimidine (Compound No.-71) 1-Hydroxymethyl-3- (2-phenylethyl)-
1-cyclobutylmethylamine 3.51 g (0.01
6 mol) was dissolved in 60 ml of ethanol to give 2-amino-4,6-dichloro-5-formylpyrimidine 3.07.
g (0.016 mol) and triethylamine 6 ml
Was added and refluxed for 2 hours, then the solvent was distilled off under reduced pressure, chloroform was added to the residue and the mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (chloroform, then chloroform: Methanol = 10
0: 1) gave 2.4 g (40.0%) of pale yellow crystals. mp130-137 ° C (ether)

Example-6 Method A-6 2-Amino-6-chloro-4-[[1-hydroxymethyl-1- (2-cyclopentenyl) methyl] amino] pyrimidine (Compound No.-50) diethyl malonate 121.5 ml (0.8 mol) and cis-1,4-dichloro-2-butene 44.3 ml (0.1 mol).
4 mol) to Janal. Org. Chem. , Vol. 27 , 2395 (1962)
The reaction was carried out in the same manner as described in 1. to obtain a mixture of diesters A-46.0 g (54.1%). To 25.5 g (0.12 mol) of the mixture of diesters A, 7.9 g (0.12 m) of potassium hydroxide dissolved in 90% ethanol.
ol) was added and hydrolyzed at room temperature for 2 days, the solvent was distilled off under reduced pressure, the residue was acidified with hydrochloric acid and extracted with ether to obtain 17.4 g (78.8%) of monoester product B-1. To 17.4 g (0.095 mol) of monoester compound B, 13.2 ml (0.095 mol) of triethylamine and 9.1 ml (0.095 mol) of ethyl chlorocarbonate were added under ice-cooling and reacted with ammonia gas for 15 minutes to form an amide ester compound. C-14.2 g (81.8%) was obtained. Amide ester compound C-3.66 g (0.02 mol) was dissolved in dry tetrahydrofuran to obtain LiAlH4 2.28 g.
By reducing with (0.06 mol), a mixture D-2.43 g (95.5%) of aminoalcohol compound was obtained.
Amino alcohol D-1.27 g (0.01 mol)
2-amino-4,6-dichloropyrimidine 1.64
g (0.01 mol), ethanol (40 ml) and triethylamine (2.1 ml) were added and the mixture was refluxed for a whole day and night.
The solvent of the filtrate was distilled off under reduced pressure and the residue was isolated by silica gel column purification (chloroform: methanol = 50: 1) to obtain 0.86 g of colorless prism crystals of the desired product (Compound No. -50).
(33.8%) was obtained. mp201-203 ° C (acetone)

Example-7 Method A-7 2-Amino-6-chloro-4-{[1-hydroxymethyl-1- [2- (1-hydroxyethyl) cyclopropyl] methyl] amino} pyrimidine (Compound No. -34)
And 2-amino-6-chloro-4-[[1-hydroxymethyl-1- (3-hydroxycyclopentyl) methyl] amino] pyrimidine (Compound No.-51) Mixture C of amide ester compounds obtained in Example-6 -3.6
6 g (0.02 mol) was dissolved in 15 ml of dichloromethane, 4.31 g (0.02 mol) of metachloroperbenzoic acid dissolved in 40 ml of dichloromethane was added, and the mixture was stirred at room temperature for 3 days and treated by a conventional method to obtain an epoxy compound E.
I got Without purification, dry tetrahydrofuran was used as a solvent and LiAlH4 2.28 g (0.0
6 mol) reduces the mixture of aminodiols F-
2.1 g (72.4%) were obtained. Aminodiol F-
2-Amino-4,6 was added to 2.03 g (0.014 mol).
-Dichloropyrimidine 2.3 g (0.014 mo)
l), 55 ml of ethanol and triethylamine
After adding 5.5 ml and refluxing for a whole day and night, the solvent was distilled off under reduced pressure, chloroform was added to the residue and the insoluble matter was filtered, and the filtrate was purified with a silica gel column (chloroform: methanol = 2).
0: 1). In the fractions 52 to 71, 0.82 g (21.5%) of the desired product (Compound No.-34) was obtained as colorless prismatic crystals of mp169-171 ° C. (acetone). In addition, the desired product (compound number-5
1), 0.26 g (6.8%) of colorless prism crystals with mp188-190 ° C (acetone) were obtained.

Example-8 Method A-8 2-Amino-6-chloro-4-[(3-benzoyloxymethyl-1-hydroxy-1-cyclobutyl) methoxy] pyrimidine (Compound No.-91) and 2-amino −
6-chloro-4-[(3-hydroxymethyl-1-hydroxy-1-cyclobutyl) methoxy] pyrimidine (Compound No.-92) First step; 60% sodium hydride 0.16 g (0.10 g)
(04 mol) was suspended in 20 ml of dry dioxane, 0.95 g (0.04 mol) of 3-benzoyloxymethyl-1-hydroxy-1-cyclobutylmethanol dissolved in 10 ml of dry dioxane was added dropwise, and the temperature was 60-70 ° C.
After stirring at room temperature for 30 minutes, 0.66 g (0.04 mol) of 2-amino-4,6-dichloropyrimidine was added, and the mixture was refluxed for 3 hours and then filtered, the solvent of the filtrate was distilled off under reduced pressure, and the residue was purified by a silica gel column (chloroform). : Methanol = 100:
1) Then, the desired product, compound number-91, 2-amino-6-chloro-4-[(3-benzoyloxymethyl-
There was obtained 0.46 g (31.5%) of white crystals of 1-hydroxy-1-cyclobutyl) methoxy] pyrimidine. Second step; 2-amino-obtained in the same manner as in the first step
6-chloro-4-[(3-benzoyloxymethyl-1
-Hydroxy-1-cyclobutyl) methoxy] pyrimidine was dissolved in 20 ml of saturated ammonia-methanol solution, sealed, reacted at room temperature for 4 days, and the solvent was distilled off under reduced pressure.
The residue was purified with a silica gel column (chloroform: methanol = 100: 3) to give the desired product, compound number -92: 2-amino-6-chloro-4-[(3-hydroxymethyl-1-hydroxy-1-cyclobutyl). 0.28 g (77.8%) of white crystals of methoxy] pyrimidine were obtained. mp128-130 ° C (acetone)

Method B Example-9 2,5-Diamino-6-chloro-4-[[(3-benzyloxy-1-hydroxymethyl-1-cyclobutyl)
Methyl] amino] pyrimidine (Compound No.-60) First step; 2-amino-6-chloro-4-[[(3-benzyloxy-1-hydroxymethyl-1-cyclobutyl) methyl] amino] -5- [ (P-chlorophenyl)
Azo] pyrimidine 2-amino-6-chloro-4-[[(3-benzyloxy-1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine 9.15 g (0.04mo)
Sodium acetate (48.3 g), acetic acid (200 ml) and water (200 ml) were added to and dissolved in 1), and p-chloroaniline (5.61 g, 0.044 mol) was dissolved in water (40 ml) and concentrated hydrochloric acid (12 ml) in a solution of 2-3. 40 ° C water
3.31 g (0.04 g) of sodium nitrite dissolved in ml
Cold p-chlorobenzenediazonium chloride solution prepared by adding 8 mol) was added dropwise at room temperature and stirred overnight. The precipitated crystals are collected by filtration and washed with water to give orange-yellow crystals 1.
Obtained 0.07 g (72.9%). mp267-269
C (methanol) second step; 6-chloro-2,5-diamino-4-
[[(3-Benzyloxy-1-hydroxymethyl-1
-Cyclobutyl) methyl] amino] pyrimidine 2-amino-6-chloro-5-[(p-chlorophenyl) azo]
170 g of ethanol in 7.3 g (0.02 mol) of 4-[[(3-benzyloxy-1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine.
1, 170 ml of water and 17 ml of acetic acid are added, the mixture is heated to 70 ° C., 16.5 g of zinc dust is gradually added in a nitrogen stream with stirring, and the mixture is stirred at the same temperature for 1.5 hours to form a solution. The reaction solution was filtered, the solvent of the filtrate was evaporated under reduced pressure, water was added to the residue, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (chloroform: methanol = 100: 3) to obtain 2.6 g (53.4%) of light brown crystals. mp147-
149 ° C (ethyl acetate)

Method C Example-10 Method C-1 2-Amino-5,6-dichloro-4-[[(1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-33) 2- Amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine 0.24 g (2.0 mmol) to N-chlorosuccinimide 0.27 g (2.0 mmol) and dimethylformamide 1 After adding 5 ml and stirring at room temperature for 2 days,
After adding ethyl acetate and washing with water and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (chloroform: methanol = 100: 1) to give 0.3 g (54.2%) of colorless prism crystals. Obtained. mp17
9-181 ° C (acetone)

Example-11 Method C-2 2-amino-5-bromo-4-[[(1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-6) 2-amino-4- [[(1-Hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine 0.21 g
(1.0 mmol) was added with 3 ml of acetic acid and heated to 110 °, 0.18 g of sodium acetate trihydrate was added, and 70 ° C.
Then, 60 μl of bromine dissolved in 0.5 ml of acetic acid was added dropwise.
After cooling, water was added to the reaction product, which was neutralized with ammonia water under ice cooling, extracted with ethyl acetate, dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone to give colorless prism crystals 0 .21 g (72.4%) was obtained. mp1
56-158 ° C (acetone)

Method D Example-12 Method D-1 2-amino-4-[[(1-hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-2) 2-amino-6-chloro- 4-[[(1-Hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine 1.46 g (6.0 mmol) were added with ethanol 40 ml, cyclohexene 15 ml, and palladium hydroxide 0.2 g under a nitrogen stream, and the mixture was refluxed for 2 hours. , The reaction is filtered,
When the solvent of the filtrate was distilled off under reduced pressure, white amorphous crystals 1.
34 g (quantitative) were obtained.

Example-13 Method D-2 2,5-diamino-4-{[[1-hydroxymethyl-
3- (2-Phenylethyl) -1-cyclobutyl] methyl] amino} pyrimidine (Compound No.-14) 2-amino-6-chloro-5- (p-chlorophenyl)
Azo-4-{[[1-hydroxymethyl-3- (2-phenylethyl) -1-cyclobutyl] methyl] amino}
Pyrimidine (1.21 g, 2.5 mmol) was added with ethanol (40 ml), cyclohexene (15 ml) and palladium hydroxide (0.2 g) under a nitrogen stream, and the mixture was refluxed for a whole day and night. The reaction product was filtered, and the solvent in the filtrate was evaporated under reduced pressure. Was purified by silica gel column (chloroform: methanol = 5: 1) to obtain 0.43 g (52.4%) of light brown crystals. Hydrochloride mp 214-217 ° C (methanol)

Example-14 Method D-3 6-chloro-2,5-diamino-4-{[[3- (2-
Phenylethyl) -1-hydroxymethyl-1-cyclobutyl] methyl] amino} pyrimidine (Compound No.-6
4) 2-amino-6-chloro-5- (p-chlorophenyl)
Azo-4-{[[3- (2-phenylethyl) -1-hydroxymethyl-1-cyclobutyl] methyl] amino}
To 1.21 g (0.0025 mol) of pyrimidine, 20 ml of ethanol, 20 ml of water and 2 ml of acetic acid were added, and 70
The mixture was heated to 0 ° C., 16.5 g of zinc dust was gradually added to the solution in a nitrogen stream with stirring, and the solution was stirred at the same temperature for 2 hours. The reaction solution was filtered, the solvent of the filtrate was evaporated under reduced pressure, water was added to the residue, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column ( Chloroform: methanol = 100: 1) gave 0.74 g (82.2%) of light brown crystals. mp14
9-151 ° C (ethyl acetate)

Method E Example 15 2-Amino-6-chloro-4-[[(1-hydroxymethyl-3-oxo-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-41) 2-Amino- 6-chloro-4-[[(1-hydroxymethyl-3,3-dimethoxy-1-cyclobutyl) methyl] amino] pyrimidine 0.61 g (2.0 mmol)
Acetone (50 ml) and 20% hydrochloric acid (0.5 ml) were added, and the mixture was refluxed for 30 minutes, neutralized with 10% ammonia-methanol under ice cooling, the solvent was distilled off under reduced pressure, and the residue was recrystallized from acetone to give colorless prisms. 0.36 g (7
0.1%) was obtained. mp171-173 ° C (acetone)

Method F Example-16 2-Amino-6-chloro-4-[[(1-hydroxymethyl-3-hydroxy-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-38) 2-amino- 6-chloro-4-[[(1-hydroxymethyl-3-oxo-1-cyclobutyl) methyl] amino] pyrimidine 2.21 g (8.26 mmol) was dissolved in 80 ml of ethanol, and sodium borohydride was cooled under ice cooling. After adding 31 g (8.26 mmol) little by little, the mixture was stirred at room temperature for 30 minutes, neutralized by adding hydrochloric acid-ethanol, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (chloroform: methanol = 100). : 7) to obtain 2.14 g (quantitative) of white crystals. mp136-
139 ° C (ethyl acetate)

Method G Example-17 2-Amino-6-chloro-4-[[(3-hydroxy-
3-Hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-27) 2-amino-6-chloro-4-[[(3-methylene-1
-Cyclobutyl) methyl] amino] pyrimidine 1.1
2 g (0.005 mol) was dissolved in acetone (15 ml) and water (10 ml), N-methylmorpholine N-oxide (0.64 g, 0.0055 mol) and osmium tetroxide (3 mg) were added, and the mixture was stirred under a nitrogen stream for 5 hours.
The solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (chloroform: methanol = 100: 7, then 10: 1) to obtain 0.96 g (74.4%) of colorless prism crystals. mp158-160 ° C (ethanol)

Method H Example-18 2-Amino-6-chloro-5-hydroxymethyl-4-
[[(1-Hydroxymethyl-1-cyclobutyl) methyl] amino] pyrimidine (Compound No.-72) 2-amino-6-chloro-4-[[(1-hydroxymethyl-1-cyclobutyl) methyl] amino]- 0.75 g (2.0 mmol) of 5-formylpyrimidine was dissolved in 20 ml of ethanol to obtain 40 m of sodium borohydride.
g (1.0 mmol) was added, the mixture was stirred at room temperature for 30 minutes, 0.1 ml of acetic acid was added, the solvent was distilled off under reduced pressure, and the residue was extracted with hot acetone to give 0.49 g of colorless prism crystals.
(65.3%) was obtained. mp167-170 ° C (acetone)

Method I Example 19 2-Amino-6-chloro-4-{[[1-hydroxymethyl-3- (2-phenylethyl) -1-cyclobutyl] methyl] amino} -5-carbaldehyde oxime Pyrimidine (Compound No.-79) 2-Amino-6-chloro-4-{[[1-hydroxymethyl-3- (2-phenylethyl) -1-cyclobutyl] methyl] amino} -5-formylpyrimidine 0.7
Hydroxylamine hydrochloride of 0.5 g was added to 5 g (2.0 mmol).
14 g (2.2 mmol) and 30 ml of ethanol were added and the mixture was refluxed for 2 hours. Ammonia-methanol solution was added under ice cooling to neutralize, the solvent was distilled off under reduced pressure, the residue was extracted with hot acetone, and the solvent was distilled off under reduced pressure to give pale yellow crystals.
Obtained 75 g (96.2%). mp154-156 ° C
(ether)

Method J Example-20 2-amino-4-{[[1-hydroxymethyl-3-
(2-Phenylethyl) -1-cyclobutyl] methyl]
Amino} -5-cyanopyrimidine (Compound No. -11) First step; 2-amino-4- [1-acetoxymethyl-
3- (2-phenylethyl) -1-cyclobutylmethylamino] -5-cyanopyrimidine (Compound No.-12) 2-amino-4- [1-hydroxymethyl-3- (2-
Phenylethyl) -1-cyclobutylmethylamino]-
5-Pyrimidinecarbaldehyde oxime hydrochloride 1.1
25 ml of acetic acid was added to 8 g (3.0 mmol), the mixture was refluxed for 16 hours, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel column (chloroform: methanol = 100: 1) to give 0.26 g (22) of pale yellow prismatic crystals. .8%). mp156-159 ° C (methanol) Second step; 2-amino-4- [1-hydroxymethyl-
3- (2-Phenylethyl) -1-cyclobutylmethylamino] -5-cyanopyrimidine (Compound No.-11) 2-amino-4- [1-acetoxymethyl-3- (2-
Phenylethyl) -1-cyclobutylmethylamino]-
After adding 50 ml of a saturated ammonia-methanol solution to 0.95 g (2.5 mmol) of 5-cyanopyrimidine and allowing it to stand at room temperature for a day and night, the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (chloroform: methanol = 50:
1) Then, pale yellow prismatic crystals 0.61 g (71.4
%) Was obtained. mp184-189 ° C (methanol)

Representative compounds of the present invention prepared by a method similar to that described in the above examples are shown in the following table.
It goes without saying that the present invention is not limited to these compounds. The abbreviations in the table have the following meanings. MeOH: methanol, EtOH: ethanol, Et2 O: ethyl ether, iso-PrOH: isopropanol AcOEt: ethyl acetate dec: decomposition

[0113]

[Table 1]

[0114]

[Table 2]

[0115]

[Table 3]

[0116]

[Table 4]

[0117]

[Table 5]

[0118]

[Table 6]

[0119]

[Table 7]

[0120]

[Table 8]

[0121]

[Table 9]

[0122]

[Table 10]

[0123]

[Table 11]

[0124]

[Table 12]

[0125]

[Table 13]

[0126]

[Table 14]

[0127]

[Table 15]

[0128]

[Table 16]

[0129]

[Table 17]

[0130]

[Table 18]

[0131]

[Table 19]

[0132]

[Table 20]

[0133]

[Table 21]

Synthesis of Intermediate Example K Method Example-21 K Method-1 3-Benzyloxy-1-hydroxymethyl-1-cyclobutylmethylamine (Compound No.-110) First Step; Diethyl 3-benzyloxy Sodium -1,1-cyclobutyldicarboxylate 10.1 g (0.44 mol) was dissolved in 220 ml of ethanol, 90 ml was transferred to a dropping funnel, and diethyl malonate 42.
After dropwise adding 3 g (0.26 mol), 90 ml of sodium ethylate and 2-benzyloxy-1,3-under reflux.
67.39 g (0.22 mol) of dibromopropane was added dropwise at the same time and the mixture was refluxed for 2 hours. The reaction product is filtered, the solvent of the filtrate is distilled off under reduced pressure, and the residue is distilled under reduced pressure to yield bp175-
Colorless oily matter at 182 ° C./3 mmHg 32.16 g (4
7.7%). Second step; 3-benzyloxy-1-ethoxycarbonyl-1-cyclobutylcarboxylic acid 90% potassium hydroxide 6.5 g (0.099 mol)
Dissolved in 500 ml of ethanol, diethyl 3-benzyloxy-1,1-cyclobutyldicarboxylic acid 30.3
g (0.099 mol) was added and the mixture was allowed to stand at room temperature for 3 days, and then the solvent was distilled off under reduced pressure. 100 ml of water was added to the residue and washed with ether. The aqueous layer was acidified with 10% hydrochloric acid, extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 24.47 g (88.8 g) of colorless oil. %)
I got Third step: Ethyl 3-benzyloxy-1-carboxamido-1-cyclobutylcarboxylate 3-Benzyloxy-1-ethoxycarbonylcyclobutylcarboxylic acid 24.2 g (0.087 mol) was dissolved in 400 ml of chloroform and iced. Under cooling, 8.8 g (0.087 mol) of triethylamine was added, 9.4 g (0.087 mol) of ethyl chlorocarbonate was added at 0 ° C., and the mixture was stirred for 15 minutes, then introduced with ammonia gas for 10 minutes and stirred at room temperature for 1 hour. I left it all day and night. The reaction product was filtered, the filtrate was concentrated, and hexane was added to give 25.0 g of colorless oil.
(90.1%) was obtained. Fourth step; 3-benzyloxy-1-hydroxymethyl-1-cyclobutylmethylamine LiAlH4 6.57 g (0.173 mol) was suspended in 200 ml of dry tetrahydrofuran, and ethyl 3-benzyloxy dissolved in 200 ml of dry tetrahydrofuran under ice cooling. 1-Carboxamido-1-cyclobutylcarboxylate 16.0 g (0.0577 mol) was added dropwise and the mixture was refluxed for 5 hours. Under ice cooling, 17 ml of water, 30 ml of 10% potassium hydroxide and 17 ml of water were sequentially added dropwise, then the reaction mixture was filtered, chloroform was added to the filtrate, washed with saturated saline, dried over anhydrous magnesium sulfate, and then the solvent. Was distilled off under reduced pressure to obtain 10.5 g (82.2%) of a pale yellow oily matter.

Example-22 Method K-2 3-Isopropyl-1-hydroxymethyl-1-cyclobutylmethylamine (Compound No.-108) First Step; Diethyl 3-isopropyl-1,1-cyclobutyldicarboxylate 2-isopropyl-1,3-propanediol di-p
-Toluene sulfonate 17.1 g (0.04 mo)
l), diethyl malonate 7.05 g (0.044 mo)
l) is dissolved in 100 ml of dry dioxane, 95-10
Sodium hydride (1.6 g, 0.04 mol) suspended in dry dioxane (10 ml) was added dropwise at 0 ° C., and the mixture was stirred at the same temperature for 1 hour. Then, sodium hydride (1.6 g, 0, 0) was further suspended in dry dioxane (10 ml). 0.04 mol) was added dropwise and the mixture was stirred at the same temperature for 20 hours. After cooling, filtration was carried out, the solvent of the filtrate was distilled off under reduced pressure, ether was added to the residue and the mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure, and the residue was purified by a silica gel column (hexane: ethyl acetate = 20: 1)
This gave 6.14 g (63.3%) of a colorless oil. Second step; 1-ethoxycarbonyl-3-isopropyl-1-cyclobutylcarboxylic acid 9-diethyl 3-isopropyl-1,1-cyclobutyldicarboxylate 6.06 g (0.025 mol)
1.65 g (0.025 mol) of sodium hydroxide dissolved in 125 ml of 0% ethanol was added and the mixture was allowed to stand at room temperature for 3 days, and then the solvent was distilled off under reduced pressure. Water was added to the residue, washed with ether, neutralized with 10% hydrochloric acid under ice cooling, extracted with ether, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 4.72 g (88.1%) of colorless oil. ) Got. Third step: 1-ethoxycarbonyl-3-isopropyl-1-cyclobutylcarboxamide 1-ethoxycarbonyl-3-isopropyl-1-cyclobutylcarboxylic acid 4.5 g (0.021 mol) was dissolved in 100 ml of chloroform and iced. Under cooling, triethylamine (2.12 g, 0.021 mol) and ethyl chlorocarbonate (2.27 g, 0.021 mol) were added, and the mixture was stirred for 10 minutes. Ammonia gas was introduced for 5 minutes, and the mixture was stirred overnight at room temperature. The reaction product was filtered, the solvent of the filtrate was distilled off under reduced pressure, and the residue was recrystallized from hexane to give 3.83 g of colorless crystals.
(85.5%) was obtained. Fourth step; 3-isopropyl-1-hydroxymethyl-
1-Cyclobutylmethylamine 1.94 g (0.051 mol) of LiAlH4 was suspended in 60 ml of dry tetrahydrofuran and 1-ethoxycarbonyl-dissolved in 60 ml of dry tetrahydrofuran.
3.63 g (0.017 mol) of 3-isopropyl-1-cyclobutylcarboxamide was added dropwise, and the mixture was refluxed for 4 hours. Under ice cooling, 5 ml of water, 9 ml of 10% potassium hydroxide
Was dropped and then filtered, and the residue was washed with chloroform. The filtrate was combined and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.67 g (quantitative) of a colorless oily substance.

L Method Example-23 3-Benzyloxy-1-hydroxymethyl-1-cyclobutylmethylamine (Compound No. 110) First Step; Ethyl 3-benzyloxy-1-carboxamido-1-cyclobutyl Carboxylate 3-benzyloxy-1-ethoxycarbonyl-1-cyclobutylcarboxylic acid (27.55 g (0.1 mol)) was dissolved in 100 ml of chloroform and cooled to 0 ° C. or lower, and thionyl chloride (15.5 g, 0.13 mol) was dissolved. ) Is added dropwise, and the mixture is heated under reflux for 1.5 hours. The reaction mixture was distilled under reduced pressure to obtain 23.7 g (0.079 mo) of the objective pale yellow oily substance.
l) was obtained. The obtained 3-benzyloxy-1-ethoxycarbonyl-1-cyclobutylcarboxylic acid chloride was dissolved in 100 ml of chloroform, cooled to −10 ° C. or lower, introduced with ammonia gas, and reacted at room temperature for 3 hours. The reaction mixture was washed with water and dried over anhydrous magnesium sulfate, then the solvent was distilled off to give 21.6 g (78%) of a colorless oil.
I got Second step; 3-benzyloxy-1-hydroxymethyl-1-cyclobutylmethylamine 9.9 g (0.26 mol) of LiAlH4 was suspended in 250 ml of dry tetrahydrofuran, and ethyl 3-benzyl dissolved in 200 ml of dry tetrahydrofuran under ice cooling. Oxy-1-carboxamido-1-cyclobutylcarboxylate (24.1 g, 0.087 mol) was added dropwise and the mixture was refluxed for 5 hours. Under ice-cooling, 17 ml of water, 45 ml of 10% potassium hydroxide and 26 ml of water were sequentially added dropwise, then the reaction mixture was filtered, chloroform was added to the filtrate, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent. Was distilled off under reduced pressure to obtain 17.0 g (88.3%) of a pale yellow oily matter.

M Method Example-24 3- (2-phenylethyl) -1-hydroxymethyl-
1-Cyclobutylmethylamine (Compound No.-106) First step; 1-Ethoxycarbonyl-3- (2-phenylethyl) -1-cyclobutylcarbonitrile 2- (2-phenylethyl) -1,3-dibromo To a mixture of 21.4 g (0.07 mol) of propane and 8.5 g (0.07 mol) of ethyl cyanoacetate was added 3.2 g (0.14 mol) of sodium at 70-75 ° C and ethanol 7.
A solution dissolved in 5 ml was added dropwise, the mixture was refluxed for 3 hours, and then filtered. The solvent of the filtrate was distilled off under reduced pressure, ether was added to the residue, the mixture was washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
Ethyl acetate = 100: 7) to give 9.3g of colorless oil.
(51.7%) was obtained. Second step: 3- (2-phenylethyl) -1-hydroxymethyl-1-cyclobutylmethylamine 3.98 g (0.105 mol) of LiAlH4 was suspended in 150 ml of anhydrous ether and 1-ethoxycarbonyl was dissolved in 40 ml of anhydrous ether. -3- (2-phenylethyl) -1-cyclobutylcarbonitrile 9.0 g
(0.035 mol) was added dropwise and the mixture was refluxed for 2 hours. 10 ml of water under ice cooling and 10 ml of 10% potassium hydroxide were added dropwise, the mixture was filtered, the residue was washed with chloroform, combined with the filtrate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to give 7.1 g of a colorless oil (92). .2%).

N Method Example-25 3- (2-phenylethyl) -1- (1-hydroxyethyl) -1-cyclobutylmethylamine (Compound No.-
114) First step; 1- (methylsulfinyl) methylcarbonyl-3- (2-phenylethyl) -1-cyclobutylcarbonitrile 60% sodium hydride 0.72 g (0.018mo)
8 ml of dimethyl sulfoxide was added to l) and the mixture was stirred at 70 ° C for 45
After stirring for 1 minute, 1-ethoxycarbonyl-3 under ice cooling
A solution of 3.86 g (0.015 mol) of-(2-phenylethyl) -1-cyclobutylcarbonitrile in 8 ml of tetrahydrofuran was added, and the mixture was stirred at room temperature for 30 minutes. The reaction product was poured into 25 ml of ice water, acidified with 10% hydrochloric acid, extracted with chloroform, washed with water, dried over anhydrous magnesium sulfate,
The solvent was distilled off under reduced pressure and the residue was purified by a silica gel column (chloroform) to give 3.0 g of white crystals with mp 77-83 ° C.
(69.1%) was obtained. Second step; 1-acetyl-3- (2-phenylethyl)
-1-Cyclobutylcarbonitrile 1- (methylsulfinyl) methylcarbonyl-3-
190 ml of tetrahydrofuran and 21 ml of water were added to and dissolved in 2.9 g (0.01 mol) of (2-phenylethyl) -1-cyclobutylcarbonitrile, and aluminum amalgam (an aluminum plate was immersed in 2% mercuric chloride for 15 seconds, It was washed with ethanol and ether, cut into 1 cm square pieces and used.) After adding 2.7 g and refluxing for 1 hour,
It was filtered through Celite. The solvent of the filtrate was concentrated under reduced pressure, the residue was extracted with ether, washed with water, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (hexane: chloroform = 2: 1, then chloroform).
This gave 1.8 g (79.3%) of a colorless oil. Third step; 3- (2-phenylethyl) -1- (1-hydroxyethyl) -1-cyclobutylmethylamine 0.58 g (15.2 mmol) of LiAlH4 was suspended in 20 ml of anhydrous ether and dissolved in 10 ml of anhydrous ether. 1-acetyl-3- (2-phenylethyl) -1
-Cyclobutylcarbonitrile 1.73 g (7.6 mm
ol) was added dropwise and the mixture was refluxed for 2 hours. Under ice cooling, 15 ml of water,
After 20 ml of 10% potassium hydroxide was added dropwise, the mixture was filtered, the residue was washed with chloroform, combined with the filtrate, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
1.78 g (quantitative) of white crystals at 81 ° C. were obtained.

P Method Example-26 3-Hydroxymethyl-1-hydroxy-1-cyclobutylmethylamine (Compound No. 117) First step; 3-benzoyloxymethyl-1-cyclobutylmethylene oxide 3-benzoyloxy Methyl-1
-Methylenecyclobutane 10.1 g (0.05 mol)
Was added dropwise to a solution of m-chloroperbenzoic acid in 100 ml of dry methylene chloride, and the mixture was reacted at room temperature for 24 hours with stirring. The reaction mixture was washed with 10% acidic sodium sulfite, saturated sodium bicarbonate, and saturated saline in this order, the organic layer was dried over anhydrous magnesium sulfate, the solvent was evaporated, and the residue was purified by silica gel column (hexane: ethyl acetate = 20). : 1) and then 3.85 g (3
5.3%) was obtained. Second step; 3-hydroxymethyl-1-hydroxy-1
-Cyclobutylmethylamine 3-benzoyloxymethyl-1-obtained in the first step
Cyclobutyl methylene oxide 1.83 g (0.008 g)
4 mol) to a saturated ammonia-methanol solution of 30 m
It was dissolved in 1 and reacted under stirring at room temperature for 4 days. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column (hexane: ethyl acetate = 20: 1) to give a colorless oily substance 0.9
3 g (85%) were obtained.

Q Method Example-27 Q Method 1-Hydroxymethyl-1- (N-methyl) cyclobutylmethylamine (Compound No.-119) 1.15 g (0 of 1-hydroxymethyl-1-cyclobutylmethylamine 0.01 mol) was dissolved in 1.9 ml of formic acid and 0.2 ml of water, to which 37% formalin of 0.01 was added.
89 ml (0.011 mol) was added and reacted at room temperature for 2 hours. After that, heat reaction for another 7 hours, and further at room temperature,
The reaction was performed for 8 hours. The reaction mixture was concentrated under reduced pressure to dryness, and the residue was purified by silica gel column (chloroform: methanol =
50: 1) gave 1.0 g (77.4%) of a colorless oil.

R Method Example-28 1-Hydroxymethyl-1- (N-isobutyl) cyclobutylmethylamine (Compound No.-120) 11.5 g (0.1 mol of 1-hydroxymethyl-1-cyclobutylmethylamine) ) Is dissolved in 50 ml of benzene, 1-bromoisobutane and an equimolar amount of triethylamine are added, and the mixture is heated under reflux for 5 hours. The reaction solution is cooled, washed with water, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. Silica gel column purification of the residue (chloroform:
Methanol = 50: 1), then colorless oily substance 14.3 g
(83.5%) was obtained.

S Method Example-29 1-Hydroxymethyl-1-cyclobutylamine (Compound No.-122) First Step; 1-Ethoxycarbonyl-1-cyclobutylbenzyloxycarbonylamine 1-Ethoxycarbonyl-1-cyclobutyl Dissolve 3.44 g (0.02 mol) of carboxylic acid in dry benzene and diphenylphosphoryl azide 5.5 g (0.02 m)
ol) and 2.02 g of triethylamine (0.02 m
was added and refluxed for 1 hour, and then 2.45 g (0.022 mol) of benzyl alcohol was added and refluxed for 13 hours. The solvent was distilled off under reduced pressure, the residue was dissolved in ethyl acetate,
The extract was washed with 5% hydrochloric acid, saturated aqueous sodium chloride solution and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column (chloroform: hexane = 1: 1).
This gave 4.67 g (84.1%) of a colorless oil. Second step: 1-hydroxymethyl-1-cyclobutylbenzyloxycarbonylamine 1-ethoxycarbonyl-1-cyclobutylbenzyloxycarbonylamine 2.77 g (0.01 mol) was dissolved in 5 ml of dry tetrahydrofuran and then dissolved in dry tetrahydrofuran. Lithium borohydride 0.33g
(0.015 mol) was added dropwise and the mixture was stirred at room temperature for 1 hour.
After adding 1 ml of 50% acetic acid under ice cooling, adding 15 ml of water and extracting with ether, washing with saturated sodium bicarbonate and saturated saline, and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 2.33 g of a colorless oily substance. (99.1%) was obtained. Third step: 1-hydroxymethyl-1-cyclobutylamine 1-hydroxymethyl-1-cyclobutylbenzyloxycarbonylamine 2.35 g (0.01 mol) was dissolved in 100 ml of ethanol and palladium hydroxide 0.5
g and 20 ml of cyclohexene were added, the mixture was refluxed for 1 hour and then filtered, and the solvent in the filtrate was evaporated under reduced pressure to give 1.
0 g (quantitative) was obtained.

The following intermediate was prepared by a method similar to that described in the above example. 1-hydroxy-1-cyclobutylmethylamine, 1-
(2-hydroxyethyl) -1-cyclobutylmethylamine, 1- (1-hydroxyethyl) -1-cyclobutylmethylamine, 1-hydroxymethyl-1- (2-aminoethyl) cyclobutyl, 3-hydroxy-1 -Hydroxymethyl-1-cyclobutylmethylamine, 3,3
-Dimethoxy-1-hydroxymethyl-1-cyclobutylmethylamine, 3-phenyl-1-hydroxymethyl-1-cyclobutylmethylamine, 3-benzyl-1-
Hydroxymethyl-1-cyclobutylmethylamine, 3
-(2-phenylethyl) -1-acetyloxymethyl-1-cyclobutylmethylamine, 3- (3-phenylpropyl) -1-hydroxymethyl-1-cyclobutylmethylamine, 3-hydroxy-3-hydroxymethyl -1-Cyclobutylmethylamine, 1- (1-hydroxyethyl) -1-cyclopentanemethylamine, 3-hydroxy-1-hydroxymethyl-1-cyclopentanemethylamine, 3-benzyloxy-1-hydroxymethyl- 1-cyclopentanemethylamine, 1-hydroxymethyl-1- (3-cyclopentene) methylamine,
1- (1-hydroxyethyl) -1-cyclohexanemethylamine.

Representative intermediates of the present invention produced by the same method as described in the above Examples are shown in the following table, but it goes without saying that the present invention is not limited to these intermediates. .

[0145]

[Table 22]

[0146]

[Table 23]

[0147]

[Table 24]

[0148]

[Table 25]

[0149]

[Test example]

Assay of Antiviral Activity The assay method of antiviral action, the toxicity test method and the results thereof for the compound of the present invention are shown. Ribavirin and Amantadine were used as control drugs.

Test Example-1: Assay test and evaluation of compounds against influenza virus type A and type B All test compounds were dissolved in dimethyl sulfoxide (DMSO) so as to be 10 mg / ml and stored at -20 ° C. Influenza virus A / PR / 8/34 /
Strains and B / Gifu / 2/73 strains were propagated by inoculation of the 11-day-old embryonated chicken egg chorioallantoic membrane and the virus titer (PlaqueFo
rming Units (PFU) and then stored at -80 ° C. Eagle's minimum essential medium (MEM) containing MDCK cells, which is a cell line of dog kidney cells, containing 10% fetal calf serum
Was used for culturing.

Antiviral activity assay: A 50% plaque reduction assay was used. Method is MDC on 24-well microplate
K cells were cultured in a monolayer and 50 PFU / 0.1 ml of influenza virus A / PR / 8/34 strain or B / Gi
Fu / 2/73 strain was inoculated. The virus was adsorbed to the cells at 37 ° C. for 1.5 hours, the cell layer surface was washed three times with MEM, and then the sodium bicarbonate agar medium (ME containing various concentrations of the compound was added thereto).
M was mixed with 10 μg / ml of trypsin, a 3-fold concentration of amino acids and vitamins, and a mixed medium in which 0.8% agar was added at 45 ° C. or lower) to overlay the cell layer. After culturing at 37 ° C for 48 hours, the cells were fixed with formalin, stained with a crystal purple solution, and the number of plaques was counted. Antiviral activity was measured by determining the number of plaques in control cell cultures containing no compound.
Compound concentration that reduces by 50% (50% plaque suppression amount,
50% Plaque inhibition dose: ID ₅₀ = μg / ml)
Indicated by.

The results are shown in Table 26. As shown in Table 26, all the compounds of the present invention exhibited excellent anti-influenza virus activity. In addition, ribavirin and amantadine used as control drugs showed the same activity as described in the literature.

[0153]

[Table 26]

Test Example-2: Cytomegalovirus (HC
MV) and herpes simplex type 1 (HSV-1), type 2 (H
Assay test and evaluation of compounds against SV-2) Antiviral activity measurement method: Human fibroblasts were inoculated and cultured in a 24-well microplate, and a simple culture was used for the measurement. The cells HSV-1 VR-3 strain and its thymidine kinase deficient mutant VRTK ^-, HSV-2,
UW-268 strain and its thymidine kinase-deficient mutant U
WTK ^- and human cytomegalovirus AD-1
69 strains of 20 PFU / 0.2 ml suspension were inoculated. 1
The virus was adsorbed to the cells at 37 ° C. for a period of time, the virus solution was removed, and a MEM medium containing 0.5% methylcellulose containing a drug at a predetermined concentration was overlaid. HSV-1, HS
V-2 for 3 days, cytomegalovirus for 2-3 weeks 37
After culturing at ℃, fixed with formalin, stained the cells with crystal purple solution, and counted the number of plaques. 50 on the graph
% The appearance of plaques determined suppressing drug concentration was 50% plaque inhibitory concentrations (ID _50).

Results for cytomegalovirus (HCMV) are shown in Table 27. As shown in Table 27, the compounds of the present invention showed excellent anti-cytomegalovirus activity.

[0156]

[Table 27]

Table 28 shows the results for herpes simplex type 1 (HSV-1) and type 2 (HSV-2). As shown in Table 28, the compounds of the present invention showed anti-herpes simplex virus activity.

[0158]

[Table 28]

Test Example-3: Toxicity test Male ICR mice (body weight 25-35) fasted overnight
The test compound was orally administered to g), and life or death by 24 hours was determined. The results are shown as the minimum lethal dose. The results are shown in Table 29. As shown in Table 29, all the compounds of the present invention showed low toxicity values.

[0160]

[Table 29]

 ─────────────────────────────────────────────────── ─── Continuation of the front page (72) Inventor Tatsuo Sitani 2-4, Midorigaoka, Asahikawa City Medical College Dormitory 502-23

Claims (12)

[Claims] 1. The following general formula [I]: [In the formula I, R1 is H, a lower alkyl group having 1 to 4 carbon atoms, a halogen atom, -OH, an alkoxy group having 1 to 4 carbon atoms, a hydroxyalkoxy group having 1 to 6 carbon atoms or -NH2; , -NH2 or -NHCOCH3
R3 is a group selected from the following (a) to (d): (In the formula, R5 is H or a lower alkyl group having 1 to 4 carbon atoms; R6
And R7 are the same or different and each have a carbon number of C1 to C.
4 lower alkyl group; R8 is H, --OH, carbon number C1
C4 hydroxy lower alkyl group or --CH2 OC
(O) CH3; R9 is H, --OH, a lower alkyl group having 1 to 4 carbon atoms, a hydroxyalkyl group having 1 to 4 carbon atoms, an alkoxy group having 1 to 4 carbon atoms, a vinyl group,
O (CH2) k-R (R is an aromatic ring group, and the aromatic ring group is a substituent selected from a lower alkyl group having 1 to 4 carbon atoms, a halogen atom and an alkoxy group having 1 to 4 carbon atoms on the ring. May have a group, k is an integer of 0 to 4),
Or-(CH2) j-R '(R' is a benzoyloxy group or an aromatic ring group, and the aromatic ring group has a carbon number C on the ring.
1 to C4 lower alkyl group, halogen atom and carbon number C
It may have a substituent selected from 1 to C4 alkoxy groups. j is an integer of 0 to 4); R10 is H, --OH or an alkoxy group having 1 to 4 carbon atoms; or R9 and R10.
And may form a carbonyl group (C = O) together with a methylene group (= CH2) or a carbon atom to which they are attached;
In formulas (b) and (d), the cycloalkyl ring may have a double bond at any position in the ring; n is 0 to
4 is an integer, m is an integer of 0 to 4); R4 is H, a halogen atom, --NH2, --CN, --CHO, --CH2 O.
H, --COOH, --CH2 NH2, --CONH2 or-
CH = NA (A is -OH or a lower alkyl group having 1 to 4 carbon atoms); provided that n = 0 and R8 = H is excluded.]
A pyrimidine compound represented by or a pharmaceutically acceptable salt thereof. 2. An antiviral agent containing as an active ingredient at least one of the pyrimidine compound or the pharmaceutically acceptable salt thereof according to claim 1. 3. An agent for preventing or treating influenza, which comprises at least one of the pyrimidine compound or the pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient. 4. The general formula [II]: The compound represented by the following general formula [III- _I ] ~ [III
_-IV ] [Chemical 4] A compound represented by the general formula [I]: A method for producing a pyrimidine compound represented by the formula [in the above formulas, R
1, R2, R3 and R4 have the same meaning as in claim 1. formula
In [III- _II ] and [III- _IV ], the cycloalkyl ring may have a double bond at any position in the ring. However, except when n = 0 and R8 = H]. 5. A compound represented by the general formula [III- _II ']: [In the formula, m'represents an integer of 1 to 4, and R5, R8, R9
, R10, and n have the same meaning as in claim 1. The cycloalkyl ring in the formula may have a double bond at any position in the ring. However, all of R5, R9, and R10 are hydrogen atoms, R8 is hydroxymethyl, m'is an integer of 1 to 4, and n is
Is 1, the cycloalkyl ring is a saturated ring, and n =
0 except for the case where R 8 = H]]. 6. The amine compound according to claim 5, which is selected from the group consisting of the following compounds. 1) 1-hydroxymethyl-1-cyclobutylamine, 2) 1-hydroxy-1-cyclobutylmethylamine, 3) 1-hydroxymethyl-1- (N-methyl) cyclobutylmethylamine, 4) 1-hydroxymethyl -1- (N-isobutyl)
Cyclobutylmethylamine, 5) 1- (2-hydroxyethyl) -1-cyclobutylmethylamine, 6) 1- (1-hydroxyethyl) -1-cyclobutylmethylamine, 7) 1-hydroxymethyl-1- (2-Aminoethyl) cyclobutyl, 8) 3-isopropyl-1-hydroxymethyl-1-
Cyclobutylmethylamine, 9) 3-hydroxy-1-hydroxymethyl-1-cyclobutylmethylamine, 10) 3,3-dimethoxy-1-hydroxymethyl-1
-Cyclobutylmethylamine, 11) 3-benzyloxy-1-hydroxymethyl-1
-Cyclobutylmethylamine, 12) 3-hydroxymethyl-1-hydroxy-1-cyclobutylmethylamine, 13) 3-phenyl-1-hydroxymethyl-1-cyclobutylmethylamine, 14) 3-benzyl-1- Hydroxymethyl-1-cyclobutylmethylamine, 15) 3- (2-phenylethyl) -1-hydroxymethyl-1-cyclobutylmethylamine, 16) 3- (2-phenylethyl) -1- (1-hydroxy Ethyl) -1-cyclobutylmethylamine, 17) 3- (2-phenylethyl) -1-acetyloxymethyl-1-cyclobutylmethylamine, 18) 3- (3-phenylpropyl) -1-hydroxymethyl- 1-cyclobutylmethylamine, 19) 3-hydroxy-3-hydroxymethyl-1-cyclobutylmethylamine, 20) 1- ( - hydroxyethyl) -1-cyclopentane methylamine, 21) 3-hydroxy-1-hydroxymethyl-1-cyclopentanemethylamine, 22) 3-benzyloxy-1- hydroxymethyl -1
-Cyclopentanemethylamine, 23) 1-hydroxymethyl-1- (3-cyclopentene) methylamine, and 24) 1- (1-hydroxyethyl) -1-cyclohexanemethylamine. 7. A general formula:Specially for reducing the carboxamide compound represented by
General formula [III _-IIa] [Chemical 8]A method for producing an amine compound represented by: [wherein R11 is
The alkyl group, R5, R9, R10, and m are the same as in claim 1.
Express significance. The cycloalkyl ring in the formula is at any position in the ring
It may have a double bond. However, R5, R9,
Each of R10 is a hydrogen atom, m is an integer of 0 to 4, cycloalkyl
Except when the Rukyl ring is a saturated ring]. 8. A general formula: Which comprises reducing the in-carbonitrile compound represented by the general formula [III _{-I I} b] embedded image [Wherein R11 is an alkyl group, R9, R10, and m are as defined in claim 1] The cycloalkyl ring in the formula may have a double bond at any position in the ring. However, the case where both R9 and R10 are hydrogen atoms, m is an integer of 0 to 4, and the cycloalkyl ring is a saturated ring]. 9. (a) General formula: A carbonitrile compound represented by the following formula is reacted with dimethyl sulfoxide and an alkali metal hydride to give a compound represented by the general formula: A methylsulfinyl compound represented by the formula (b) is reduced with a metal amalgam to give a compound represented by the general formula: The acetyl compound represented by the formula (c) is further reduced by a conventional method, which has the general formula [III- _II c] [Wherein R11 is an alkyl group, R9, R10, and m are as defined in claim 1] The cycloalkyl ring in the formula may have a double bond at any position in the ring]. 10. (a) 1-Ethoxycarbonyl-3-methylenecyclobutane is reduced to give 1-hydroxymethyl-
3-methylenecyclobutane, (b) reacting this with an acyl halide in the presence of a base to protect the hydroxyl group, (c)
The obtained 1-acyloxymethyl-3-methylenecyclobutane is reacted with a peroxide to give 1-acyloxymethyl-3-epoxycyclobutane, and (d) the reaction is performed with saturated alcoholic ammonia.
Formula [III- _II d] The manufacturing method of the amine compound shown by these. 11. A general formula: The compound represented by the general formula [III- _II e] [wherein is N-alkylated by reacting with an alkyl halide or with formaldehyde or an alkyl aldehyde in the presence of a reducing agent. 17 [In the above formulas, R5 represents an alkyl group having 1 to 4 carbon atoms, and R8, R9, R
10, n and m have the same meaning as in claim 1. The cycloalkyl ring in the formula may have a double bond at any position in the ring]. 12. (a) General formula: A carboxylic acid compound represented by the formula: is reacted with diphenylphosphoric acid azide in the presence of a base, and then with an alcohol represented by the formula: R12OH to obtain a compound represented by the general formula: A carbamate compound represented by the formula (b) which is reduced, [III- _II f] [Wherein R11 is an alkyl group, R12 is an alkyl group or a benzyl group, m is an integer of 1 to 4, and R9 and R10 are R1 and R10].
Expresses the same meaning as. The cycloalkyl ring in the formula may have a double bond at any position in the ring].