JPH0584319B2 - - Google Patents

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides novel fused pyrimidine derivatives and pharmaceutically usable acid addition salts thereof, as well as hydrates of said derivatives and pharmaceutically usable acid addition salts thereof. The present invention relates to addition salts, methods for their production, and drugs comprising said derivatives and novel intermediates, methods for their production, and methods for using said drugs. (Prior Art) In British Patent No. 1072414, thiazole (3,2-a) pyrimidine derivatives are disclosed. According to it, these compounds act on the circulatory system and have analgesic stability, diuretic properties, cytostatic properties, bacteriostatic properties, anti-inflammatory properties,
It is also reported to have antipyretic effects. Japanese Patent Publication No. 55-64591 discloses dioxo derivatives of thiazolo(3,2-a)pyrimidine having immunomodulatory effects. As is well known, one of the important objectives of infectious disease prevention is to increase the efficiency of immunoprophylaxis and to create a uniform immune status in a large population. Compounds capable of stimulating the immune system provide useful aids in achieving the above objectives. (Objective of the Invention) The object of the present invention is to provide a novel fused pyrimidine derivative having an excellent immunostimulatory effect. (Summary of the _Invention ) According to the present invention, the general formula [Formula] (wherein A is _-CH2 - _CH2- , _-CH2-CH2 - _CH2- , _-CH2 - _CH2 -CH ₂ −CH ₂ −, and −CH=
represents an atomic group selected from the group consisting of CH-, R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group, and r is 0, 1 , 2, 3, or 4, and R ₁ represents a hydrogen atom or a C _1-5 alkanonyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanonyl group, and the general formula [Formula] (in the formula , R is a hydrogen atom, a C _1-4 alkyl group,
Represents a group selected from the group consisting of a _C2-4 alkenyl group, a phenyl group, and a phenyl- _C1-3 alkyl group. ) represents a group selected from the group consisting of the following groups, and R ₃ represents a hydrogen atom. ) Novel fused pyrimidine derivatives and pharmaceutically usable acid addition salts thereof, as well as hydrates and pharmaceutically usable acid addition salts thereof of the compounds represented by the general formula are provided. The compound represented by the general formula () (in the formula, R ₁ , R ₂ and R ₃ each represent a hydrogen atom) is
It is represented as two tautomers as shown in Figure A. In the formula A, R ₄ and r have the same meaning as before. It has been found that a novel compound of the general formula () considerably increases the cell-mediated immune response, has an immunostimulatory effect, and shows no incompatibility with the vaccines used. The term " _C1-4 alkyl group" refers to a straight-chain or branched saturated aliphatic hydrocarbon group (e.g., methyl, ethyl, n-propyl, isopropyl, n-butyl, etc.) ). When R ₄ is a phenyl group, it represents one or more of the same or different substituents (e.g. halogen, nitro, lower alkyl, or lower alkoxy)
can be selectively held. The term _C1-5 alkanonyl denotes an acid group derived from an aliphatic carboxylic acid having 1 to 5 carbon atoms (e.g. formyl, acetyl, propionyl, butyryl). base, etc.). The term _C2-4 alkenyl group refers to a straight-chain or branched aliphatic hydrocarbon group consisting of an olefin double bond (e.g. vinyl group, allyl group,
(methallyl group, etc.). The "phenyl-C _1-3 alkyl group" is, for example, a benzyl group or a β-phenylethyl group. "A" represents 1,2-ethylene, 1,3-propylene, 1,4-butylene, or vinyl. General formula () (wherein A represents _-CH2 - _CH2- or _-CH2 - _{CH2 -CH2-} , _R4 represents a hydrogen atom or a methyl group, r is 1, R ₁
and R ₃ represents a hydrogen atom, and R ₂ represents a hydrogen atom or a group represented by general formula (i) (wherein R represents an ethyl group). ),
and its pharmaceutically usable acid addition salts have particularly useful medicinal properties. Particularly preferred compounds of the general formula () are the following derivatives. 7-amino-5-imino-2,3-dihydro-
5H-thiazolo(3,2-a)pyrimidine; 8-amino-6-imino-3,4-dihydro-
2H,6H-pyrimido(2,1-b)(1,3)thiazine; 8-amino-6-imino-3-methyl-2H,
6H-pyrimido(2,1-b)(1,3)thiazine; N-ethyl-N'-(5-imino-2,3-dihydro-5H-thiazolo[3,2-a]pyrimidin-7-yl ) thioureas and their pharmaceutically usable acid addition salts. Pharmaceutically usable acid addition salts of compounds of general formula () are prepared with inorganic or organic acids (e.g., halogen salts such as hydrochloride or hydrobromide, carbonates, bicarbonates). salts, sulfates, acetates, fumarates, maleates, citrates, ascorbates, etc.). According to the present invention, there are provided compounds of general formula () and methods for making their pharmaceutically usable acid addition salts and hydrates. The method comprises: (a) a 2-mercapto-4,6-diaminopyrimidine derivative of the general formula [formula] (wherein R ₁ , R ₂ and R ₃ have the same meanings as before); with the general formula [Formula] in which Y represents halogen, preferably bromine, Z is halogen, preferably chlorine or bromine, and A, R ₄ and r have the same meanings as before. (b) 2-mercapto- represented by the general formula ()
4,6-diaminopyrimidine is reacted with _a dihalo compound represented by _the general formula ( ₎ , which is produced by _the general formula:
has the same meaning as before. ) is separated and then cyclized, or (c) the compound represented by the general formula () (in which R ₁ and/or R ₂
represents a hydrogen atom. ),
(d) by reacting with a carboxylic acid represented by the general formula R ₅ -COOH () (in the formula, R ₅ represents a hydrogen atom or a C _1-4 alkyl group) or a reactive derivative thereof; A compound represented by the general formula () (in the formula, R ₂ represents a hydrogen atom) is represented by the general formula RN=C=S () (in the formula, R has the same meaning as before.) (e) General formula [Formula] (wherein A' is -CH ₂ -CH ₂ -, or -CH
=CH- and R ₄ and r have the same meaning as before. ) is reacted with malondinitrile represented by the general formula NC-CH ₂ -CN (), and if necessary, the compound represented by the general formula () is reacted with its acid which can be used pharmaceutically. converting into an addition salt, removing the base represented by the general formula () from the acid addition salt thereof, or converting the compound represented by the general formula () or its pharmaceutically usable acid addition salt into a hydrate; It consists of stages. According to method (a), 2- represented by the general formula ()
Mercapto-4,6-diaminopyrimidine is reacted with a dihalo compound represented by the general formula (). The reaction is carried out in an inert organic solvent. Examples of reaction solvents include dialkylamides (e.g. dimethylformamide), dialkyl sulfoxides (preferably dimethyl sulfoxide),
aliphatic alcohols (e.g. ethanol or isopropanol), chlorinated aliphatic hydrocarbons (e.g. chloroform, carbon tetrachloride, methylene dichloride),
Aromatic hydrocarbons (e.g. benzene, toluene,
xylene), aliphatic ethers (e.g. diethyl ether, tetrahydrofuran, dioxane),
Aliphatic hydrocarbons (eg hexane or petrol), aliphatic ketones (eg acetone or methyl ethyl ketone), or mixtures of at least two of the above solvents are used. Particular preference is given to using dimethylformamide as solvent. The reaction is carried out in the presence of an acid binder. So, for example, alkali carbonates (e.g. sodium carbonate or potassium carbonate), alkali bicarbonates (e.g. sodium bicarbonate or potassium bicarbonate), alkali hydroxides (e.g. sodium hydroxide or potassium hydroxide), alkali Earth metal hydroxides (e.g.
Calcium hydroxide), or tertiary amines (eg, pyridine, triethylamine, or other trialkylamines) are used. Sodium carbonate and potassium carbonate are particularly useful as acid binders. The starting materials represented by the general formulas () and () are used in equimolar amounts, or the dihalo compound represented by the general formula () is used in about 0.1 to 0.5 mol.
A slight excess is added. The reaction temperature depends on the reactivity of the starting materials.
Generally, the reaction is carried out between room temperature and the boiling point of the reaction mixture. About 70°C is preferred. The compound represented by the general formula () is an acid addition salt,
Preferably it is mostly isolated in the hydrobromide form, but other pharmaceutically usable acid addition salts are also produced. According to method (b), 2- represented by the general formula ()
Mercapto-4,6-diaminopyridine is reacted with a dihalo compound represented by the general formula (), and the thus produced compound represented by the general formula () is separated and then cyclized. The reaction is carried out in an inert organic solvent in the presence of an acid binding agent. The inert organic solvent and acid binder are each
Those listed in method (a) are used. The intermediate of general formula () is produced at a lower temperature than in method (a). Reaction at 30-50℃
It is preferable to carry out the test within the range of . Particular preference is given to carrying out at about 40°C. In addition, the reaction time (formation of the compound represented by the general formula () and ring closure) of method (b) is longer than that of method (a). The reaction time depends on the activity of the starting materials used and the temperature, but is approximately 10
~20 hours. The cyclization of the compound of general formula () is accomplished at elevated temperatures, preferably between about 50° C. and the boiling point of the reaction mixture. The reaction mixture is prepared by known methods. According to method (c), the compound represented by the general formula () (in which R ₁ and/or R ₂ represent a hydrogen atom) is a carboxylic acid represented by the general formula () or a reaction thereof. acylated by the sexual derivative. As reactive acid derivatives, preferably the corresponding anhydrides, acid halides or esters are used. Acylation is carried out by known methods. When the acylation is carried out using an acid chloride, it is desirable to add an acid binder to the reaction mixture.
For this purpose, for example, alkali carbonates, alkali hydrogen carbonates, alkali hydroxides or triethylamine are used. If an acid anhydride is used as the acylating agent, the excess acid anhydride can serve as the reaction medium and can also be carried out in the presence of an inert organic solvent. When using a free carboxylic acid represented by the general formula (), the acylation is preferably carried out in the presence of a dehydrating agent (for example, dicyclohexylcarbodiimide). Acylation is generally carried out at a temperature between 10°C and the boiling point of the reaction mixture. It depends on the reactivity of the starting materials. In the course of method (c), one or two acyl groups are introduced into the molecule (ie, the amino or imino group attached to the pyrimidine ring is acylated). It depends on the amount of acylating agent used. According to method (d), the general formula ( ) (wherein R ₂ is
Represents a hydrogen atom. ) is reacted with an isothiocyanate represented by the general formula () to produce a compound represented by the general formula () (wherein R ₂ represents a group represented by the general formula (a)). to generate. The reaction is carried out in an inert organic solvent at a temperature between room temperature and the boiling point of the reaction mixture. Alkanol (e.g. ethanol) as reaction medium
It is desirable to use The isothiocyanate represented by the general formula () is used in an amount of 1 to 1.5 molar equivalents to the amino compound represented by the general formula (). According to method (e), the general formula ( ) (where R ₁ , R ₂
and R ₃ represent a hydrogen atom, and A is -CH ₂ -
Represents CH ₂ − or −CH=CH−. ) is a compound represented by the general formula (),
It is prepared by reacting with malondinitrile represented by the general formula (). Preferably, the solvents listed in process (a), excluding aliphatic ketones, are used as reaction medium. Particular preference is given to using aliphatic alcohols as reaction medium. Preferably, the reaction is carried out in the presence of a basic catalyst. For this purpose, it is preferred to use an alkali alcoholate (e.g. sodium methylate or sodium ethylate), but method (a)
Other bases listed in can also be used. The starting materials represented by the general formulas () and () are used in equimolar amounts, or the malondinitrile represented by the general formula () is used in excess of about 0.1 to 0.5 mol. The reaction is accomplished at a temperature between room temperature and the boiling point of the reaction mixture. It depends on the reactivity of the starting materials used. The reaction mixture is prepared in a known manner. The compound represented by the general formula () thus obtained is converted into its acid addition salt by a known method. Therefore, a compound represented by the general formula () is reacted with a corresponding inorganic or organic acid in an inert organic solvent. The compound represented by the general formula () is removed from the acid addition salt by treatment with a base in a known manner. The compound represented by the general formula () and its acid addition salt can produce a hydrate. The hydrate is obtained by adding water to the compound represented by the general formula () or an acid addition salt thereof, or
Alternatively, it is naturally produced by moisture absorption of the anhydrous compound represented by the general formula (). According to the invention, the general formula () (wherein A is _-CH2 - _CH2- , _-CH2 - _CH2 - _CH2 , _{-CH2- CH2 -CH2} - _CH2- , −CH＝
represents an atomic group selected from the group consisting of CH-, R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group, and r is 0, 1 , 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanonyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanonyl group, and general formula (a) (formula (wherein, R represents a group selected from the group consisting of a hydrogen atom, a _C1-4 alkyl group, a _C2-4 alkenyl group, a phenyl group, and a phenyl- _C1-3 alkyl group). represents a group selected from the group consisting of the groups shown, R ₃ represents a hydrogen atom, and Y represents a hydrogen atom. ) and acid addition salts thereof are provided. According to the present invention, a method for producing a compound represented by the general formula () and a salt thereof is provided. This method is based on the general formula () (where R ₁ , R ₂ and R ₃ are
has the same meaning as before. 2-Mercapto-4,6-diaminopyrimidine represented by the general formula () (wherein, Y represents a halogen, preferably bromine, Z represents a halogen, preferably chlorine or bromine, A, R ₄ and r have the same meanings as before), and if necessary, the thus obtained compound represented by the general formula () is converted into its acid addition salt. It's been a long time since I've been in the middle of a long time since I've been in the middle of a long time. Once the new intermediate of general formula () is prepared, it is converted into the compound of general formula () after separation as described in method (b). 2-mercapto used as starting material
4,6-diaminopyrimidine is a known compound and has been described by the improved Traube synthesis method (W. Traube, Ann.
331, p. 64 (1904)). General formulas (), (), (), () and ()
The compound represented by is a known compound and is a commercially available product that is easily available. The compound represented by the general formula () has excellent immunostimulatory properties. The problem of extrinsic modulation of the immune sensitization system, ie, the correction of hyperactivity or dysfunction of the system, has attracted attention over the past decade, and with it, the immunological processes have become more detailed. In a microbiological sense, immunity refers to the defense of an organism against pathogens (eg, bacteria, viruses, fungi, or parasites) and their toxic substances. In any case, the current state of immunity, and immune formation, in addition to genetic characteristics,
It is also influenced by the biological effects of the environment. Cells of the immune system work based on a strictly defined "division of labor." In other words, some have the ability to recognize substances in the outside world (antigens), while others produce antibodies or differentiate into reactive immune cells.
Others control and adjust the relationships between limited cell groups. In this way, immunity is characterized by the fact that the living body recognizes foreign substances and generates an immune response against the foreign substances through strictly determined intercellular interactions. From the perspective of preventing infectious diseases, the so-called "active immunity" that is artificially created through vaccination when various attenuated pathogens, killed pathogens, or their toxins are ingested into living organisms is extremely meaningful. be. The immunogenic effects of vaccines applied for immunoprophylaxis vary considerably. Some vaccines provide lifelong immunity; others
Provides two years of protection, and most
The immune state can only last for a few months before it ends. Over the past 10 years, as a result of the identification and practical application of substances that modulate or stimulate immunity, we have achieved the establishment and improvement of the correction of immunodeficiency in the body, and vaccines that have only a weak immunogenic effect. was able to improve the efficiency of The latter development shows that the creation of immunological homogeneity in large animal populations is one of the fundamental requirements for achieving the objective that domestic animals must be produced at production levels commensurate with their genetic potential. It has important significance in the rapidly growing field of veterinary science. In the process of conducting experiments to study the immunostimulatory effect of a certain compound, the inventor of the present application discovered that
The compound represented by the general formula () has an excellent effect on the cell infection defense of living organisms, and when used appropriately, some types of herpesvirus vaccines (for example, Aweski ( have been found to enhance the immunogenic effect of vaccines used against A. Aujeszky's disease. Tables 1 and 2 show the results regarding the immunostimulatory effect of the compound represented by the general formula () obtained through model tests conducted on mice and pigs. [Table] [Table] Gender

Claims (1)

[Claims] 1 General formula [Chemical formula] (wherein A is -CH ₂ -CH ₂ -, -CH ₂ -CH 2 -CH ₂ -, -CH _{2 -CH 2 -CH 2} -CH ₂ −, and −CH=CH
- represents an atomic group selected from the group consisting of; R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group; r represents 0, 1, 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanoyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanoyl group, and the general formula R is a hydrogen atom, a _C1-4 alkyl group, _C2-4
alkenyl group, phenyl group and phenyl-C _1-3
represents a group selected from the group consisting of alkyl groups), R ₃ represents a hydrogen atom) and pharmaceutically usable fused pyrimidine derivatives Acid addition salts thereof, as well as hydrates and pharmaceutically usable acid addition salts of the compound represented by the general formula (). 2 A is -CH ₂ -CH ₂ - or -CH ₂ -CH ₂ -
CH ₂ -, R ₄ represents a hydrogen atom or a methyl group, r is 1, R ₁ and R ₃ represent a hydrogen atom, and R ₂ represents a hydrogen atom or general formula (i) (formula 2. The compound according to claim 1, wherein R represents an ethyl group. 3 7-amino-5-imino-2,3-dihydro-5H-thiazolo(3,2-a)pyrimidine, 8-amino-6-imino-3,4-dihydro-
2H,6H-pyrimido(2,1-b)(1,3)thiazine, 8-amino-6-imino-3-methyl-2H,
6H-pyrimido(2,1-b)(1,3)thiazine, N-ethyl-N'-(5-imino-2,3-dihydro-5H-thiazolo(3,2-a)pyrimidin-7-yl ) thiourea _and one or more pharmaceutically usable acid _addition salts thereof with _{the general formula} , −CH ₂ −CH ₂ −CH ₂ −CH ₂ −, and −CH=CH
- represents an atomic group selected from the group consisting of; R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group; r represents 0, 1, 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanoyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanoyl group, and the general formula R is a hydrogen atom, a _C1-4 alkyl group, _C2-4
alkenyl group, phenyl group and phenyl-C _1-3
represents a group selected from the group consisting of alkyl groups), R ₃ represents a hydrogen atom) and pharmaceutically usable fused pyrimidine derivatives Acid addition salts thereof and compounds represented by the general formula (). _{4 General formula _ _ _ _ _ _} CH
- represents an atomic group selected from the group consisting of; R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group; r represents 0, 1, 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanoyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanoyl group, and the general formula R is a hydrogen atom, a _C1-4 alkyl group, _C2-4
alkenyl group, phenyl group and phenyl-C _1-3
represents a group selected from the group consisting of alkyl groups), R ₃ represents a hydrogen atom) and pharmaceutically usable fused pyrimidine derivatives In the method for producing acid addition salts thereof, as well as hydrates and pharmaceutically usable acid addition salts of compounds of general formula (), ( _a ) general _formula 2-mercapto-4,6-diaminopyrimidine derivatives represented by the general formula (wherein, Y represents halogen _, preferably bromine, and Z represents halogen, preferably chlorine or bromine, and A, R ₄ and r have the same definitions as above), or (b) 2 of the general formula () -Mercapto-
4,6-dianopyrimidine is _reacted with _a dihalo compound represented by _the general formula (), _which is produced by the general formula: ,
The compound represented by (same definition as above),
After separation, cyclization or (c) general formula () (wherein R ₁ and/or R ₂ are
(represents a hydrogen atom) is a carboxylic acid represented by the general formula R ₅ -COOR () (wherein R ₅ represents a hydrogen atom or a C _1-4 alkyl group) or a reactive derivative thereof. (d) A compound represented by the general formula () (in the formula, R ₂ represents a hydrogen atom) is reacted with the general formula R-N=C=S () (in the formula, R is as defined above). or (e) with the isothiocyanate _{represented by} the general formula
CH-, R ₄ and r are the same as defined above) is reacted with malondinitrile represented by the general formula NC-CH ₂ -CN (), and if necessary, , converting the compound represented by the general formula () into its pharmaceutically usable acid addition salt, or removing the base represented by the general formula () from the acid addition salt, or converting the compound represented by the general formula () into its acid addition salt; The above production method 5, which is characterized by converting the compound or a pharmaceutically usable acid addition salt thereof into a hydrate, involves the reaction of the compounds of general formulas () and (),
5. The manufacturing method according to claim 4, wherein the manufacturing method is carried out in the presence of an acid binder. 6. As an acid binder, an alkali carbonate, an alkali hydrogen carbonate, an alkali hydroxide, an alkaline earth metal hydroxide, or a tertiary amine is used, preferably potassium carbonate or sodium carbonate. A manufacturing method according to claim 5. 7. The manufacturing method according to any one of claims 4 to 6, characterized in that the reaction is carried out in an inert organic solvent. 8 As the solvent, dialkylamides, dialkyl sulfoxides, aliphatic alcohols, chlorinated aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic ethers,
8. Process according to claim 7, characterized in that an aliphatic hydrocarbon, an aliphatic ketone or a mixture of two or more of said solvents is used, preferably dimethylformamide. 9. Claims 4 to 8, characterized in that the reaction is carried out at a temperature between room temperature and the boiling point of the reactants.
The manufacturing method described in any of paragraphs. 10 While slightly heating, the compound of general formula () is heated preferably at 30 to 50°C, more preferably at 40 to 45°C.
5. The manufacturing method according to claim 4, wherein the production is performed at a temperature of .degree. 11. The manufacturing method according to claim 4, characterized in that an anhydride, a halide, or an ester is used as the reactive derivative of the carboxylic acid represented by the general formula (). 12. The production method according to claim 11, characterized in that the acylation is carried out with an acid halide of a carboxylic acid of general formula () in the presence of an acid binder. 13. The production method according to claim 11, characterized in that when carrying out the acylation with the acid halide of the carboxylic acid represented by the general formula (), an excess amount of acid anhydride is used as a reaction medium. 14 Claims 11 to 14, characterized in that the reaction is carried out at a temperature between 10°C and the boiling point of the reactant.
The manufacturing method according to any one of Item 13. 15. The production method according to claim 4, wherein the reaction is carried out at a temperature between room temperature and the boiling point of the reaction mixture. 16 _{As an} active ingredient _{, at least a compound of the} general formula −, and −CH=CH
- represents an atomic group selected from the group consisting of; R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group; r represents 0, 1, 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanoyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanoyl group, and the general formula R is a hydrogen atom, a _C1-4 alkyl group, _C2-4
alkenyl group, phenyl group and phenyl-C _1-3
represents a group selected from the group consisting of alkyl groups), R ₃ represents a hydrogen atom) and pharmaceutically usable fused pyrimidine derivatives An immunostimulating pharmaceutical composition comprising an acid addition salt thereof, as well as a hydrate of a compound represented by the general formula () and a pharmaceutically usable acid addition salt thereof. 17 _{As an} active ingredient _{, at least a compound of the} general formula −, and −CH=CH
- represents an atomic group selected from the group consisting of; R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group; r represents 0, 1, 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanoyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanoyl group, and the general formula R is a hydrogen atom, a _C1-4 alkyl group, _C2-4
alkenyl group, phenyl group and phenyl-C _1-3
represents a group selected from the group consisting of alkyl groups), R ₃ represents a hydrogen atom) and pharmaceutically usable fused pyrimidine derivatives An immunostimulatory pharmaceutical product characterized by mixing the acid addition salt thereof, as well as the hydrate of the compound represented by the general formula () and the pharmaceutically usable acid addition salt thereof, with a suitable solid or liquid carrier. Method for producing the composition. _{18 General formula _ _ _ _ _ _} CH
- represents an atomic group selected from the group consisting of; R ₄ represents a group selected from the group consisting of a hydrogen atom, a C _1-4 alkyl group, and a selectively substituted phenyl group; r represents 0, 1, 2, 3 or 4, R ₁ represents a hydrogen atom or a C _1-5 alkanoyl group, and R ₂ represents a hydrogen atom, a C _1-5 alkanoyl group, and the general formula [formula] (wherein, R is a hydrogen atom, a _C1-4 alkyl group, _C2-4
alkenyl group, phenyl group and phenyl-C _1-3
(represents a group selected from the group consisting of alkyl groups), R ₃ represents a hydrogen atom, and Y represents a halogen) and its acid addition salt. 19 2-mercapto-4 represented by the general formula () (R ₁ , R ₂ and R ₃ are the same as defined above),
6-diaminopyrimidine is represented by the general formula () (wherein,
Y represents a halogen, preferably bromine, Z is a halogen, preferably chlorine or bromine, A, R ₄ and r are as defined above), and the necessary A method for producing a compound of the general formula (), which comprises converting the thus obtained compound represented by the general formula () into an acid addition salt thereof. 20. A method for producing a compound of general formula () according to claim 19, characterized in that the reaction is carried out in the presence of an acid binder. 21 As the acid binder, an alkali carbonate, an alkali hydrogen carbonate, an alkali hydroxide, an alkaline earth metal hydroxide, or a tertiary amine is preferably used,
21. The manufacturing method according to claim 20, characterized in that potassium carbonate or sodium carbonate is used. 22. The manufacturing method according to any one of claims 19 to 21, characterized in that the reaction is carried out in an inert organic solvent. 23 As the solvent, dialkylamides, dialkyl sulfoxides, aliphatic alcohols, chlorinated aliphatic hydrocarbons, aromatic hydrocarbons, aliphatic ethers, aliphatic hydrocarbons, aliphatic ketones, or mixtures of two or more of the above solvents are used. 23. The method according to claim 22, characterized in that dimethylformamide is preferably used. 24 The reaction is carried out at 0-50°C, preferably 40-45°C.
24. The manufacturing method according to any one of claims 19 to 23, characterized in that the manufacturing method is carried out at a temperature of .