JPH0438757B2 - - Google Patents

Description

[Detailed description of the invention]

The present invention relates to 7-deazapurine derivatives and methods for producing the same. Natural 6 having the same skeleton as the compound of the present invention
-Oxo-modified bases (e.g. Q base, PreQ ₁ base)
is a specific tRNA (tRNA ^Tyr , tRNA ^His , tRNA ^Asp
It is widely distributed in the living world as a component of tRNA and tRNA ^Asn ), and is located at the first position of the anticodon of the above tRNA, and has important biological significance as it directly recognizes genetic information from mRNA and is involved in protein synthesis. have. In particular, with recent advances in basic biochemical research, the structure of tRNA and its role in biological phenomena have been rapidly elucidated, and the differences in tRNA between cancer cells and normal cells have also become clear. One of these is that Q bases are not completely incorporated into tRNA precursors in cancer cells, and Q-defective tRNAs are always present. Furthermore, by externally supplying a Q base, Q-deficient tRNA incorporates the Q base into a predetermined position (the first letter of the anticodon) and returns to normal tRNA, and furthermore, Q base incorporation is generally not observed in normal cells. It has been observed that it is specific to cancer cells (Nishimura et al., Metabolism, Vol. 17 , special issue "Cancer 80", p. 127-136 (1980)). Therefore, the present inventors conducted various searches on derivatives of these 6-oxo-modified bases, and found that compounds in which the 6-position of these bases is a thio form are novel compounds, and also have excellent antitumor and antibacterial effects. As a result of further research based on this finding, the present invention was completed. The present invention provides: (1) General formula [In the formula, R ₁ is a hydrogen atom or an acyl group, R ₄
and R ₅ each represent a hydrogen atom or an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aralkyl group, or an aryl group, each of which may have a substituent, and R ₄
and R ₅ may form a cyclic amino group together with the adjacent nitrogen atom. ] 7
- deazapurine derivative or salt thereof, and (2) general formula [In the formula, R ₁ is a hydrogen atom or an acyl group, R ₂
and R ₃ each represents an alkyl group, an alkenyl group, or an aralkyl group in which the α-position is a methylene group, and R ₂ and R ₃ may form a cyclic amino group together with the adjacent nitrogen atom. ] or its salt represented by the general formula [In the formula, R ₄ and R ₅ each represent a hydrogen atom or an alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, aralkyl group or aryl group that may have a substituent,
R ₄ and R ₅ may form a cyclic amino group together with adjacent nitrogen atoms. however,

【formula】 The base is

[Formula] Not the same as the group. This is a method for producing a compound () or a salt thereof, which is characterized by subjecting the compound () to a substitution reaction with an amine represented by () or a salt thereof. In the above formula, the acyl group represented by R ₁ is
Preferably, the molecular weight as a base is about 400 or less,
Specific examples include an alkanoyl group and an aroyl group. The above alkanoyl group preferably has 1 to 18 carbon atoms,
Examples include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, heptanoyl, octanoyl, 2-ethylhexanoyl,
Examples include nonanoyl, decanoyl, undecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, heptadecanoyl, octadecanoyl, and among them, those having 1 to 10 carbon atoms are advantageously used. The above aroyl group preferably has 7 to 12 carbon atoms, examples of which include benzoyl, toluoyl,
Examples include naphthoyl, among which benzoyl group is advantageously used. The groups represented by R ₂ and R ₃ may be the same or different, and examples of the alkyl group having a methylene group at the α-position include those having about 1 to 10 carbon atoms, such as methyl, ethyl, n-propyl, n -Butyl, isobutyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, etc., among which 1 carbon number
From about 6 to about 6 alkyl groups are advantageously used. Examples of alkenyl groups having a methylene group at the α-position include those having about 3 to 13 carbon atoms, such as allyl (2-propenyl), 2-butenyl, 2-pentenyl, 2-hexenyl, 4-propyl-2-pentynyl, cinnamyl, Examples include 2-nonyl-2-butenyl group, among which alkenyl groups having about 3 to 9 carbon atoms are conveniently used. These alkyl groups and alkenyl groups may have 1 to 3 substituents at any position other than the α-position, and such substituents include alkyl groups having about 1 to 4 carbon atoms (for example, methyl , ethyl, propyl, isopropyl, butyl, isobutyl, sec-
butyl, tert-butyl), alkoxy groups having about 1 to 4 carbon atoms (e.g., methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-
butoxy, sec-butoxy, tert-butoxy group),
Alkanoyl group having 1 to 4 carbon atoms (e.g., formyl, acetyl, propionyl, n-butyryl, iso-butyryl group), hydroxyl group, nitro group, halogen atom, (e.g., fluorine, chlorine, bromine, iodine), carboxy group, cyano group, trifluoromethyl group,
Examples include dialkylamino groups (eg, dimethylamino, diethylamino, dipropylamino, diisopropylamino, dibutylamino groups), alkanoylamide groups (eg, formamide, acetamide, propionylamide, butyrylamide, isobutyrylamide groups), and the like. Examples of the aralkyl group having a methylene group at the α position represented by R ₂ and R ₃ include benzyl, phenethyl, 3-phenylpropyl, naphthylmethyl, and naphthylethyl groups having about 7 to 12 carbon atoms. However, the benzyl group is advantageously used. These aralkyl groups may also have a substituent on the alkylene chain portion and/or the aryl (phenyl) ring portion other than the α-position, and such substituents include the groups exemplified for the alkyl group and alkenyl group above. can give. Examples of the cyclic amino group formed by R ₂ and R ₃ together with the adjacent nitrogen atom include a 5- to 6-membered cyclic amino group, in which a second ring heteroatom (e.g., N , O). Such cyclic amino groups include, for example, 1-pyrrolidinyl, 1-pyrrolinyl, 1-
imidazolidinyl, 1-imidazolinyl, 1-pyrazolidinyl, 1-pyrazolinyl, morpholino,
Examples include piperidino and 1-piperidinyl groups, and these cyclic amino groups may have substituents except for the position adjacent to the nitrogen atom (α-position). Such substituents include the alkyl group and Each group illustrated as an alkenyl group is mentioned. In the above formula, each of the optionally substituted alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, aralkyl group, or aryl group represented by R ₄ and R ₅ has a molecular weight of about 400 or less is preferred. In the above formula, the alkyl group represented by R ₄ and R ₅ is, for example, an alkyl group having 1 to 18 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-
Butyl, pentyl, isopentyl, hexyl, isohexyl, heptyl, octyl, nonyl, decyl, undenyl, dodecyl, tetradecyl, hexadecyl, octadecyl, 1,2-dimethylpropyl, 1-ethylpropyl, 1,2,2-trimethylpropyl, 1 -propylbutyl, 2-ethylhexyl group). Examples of the alkenyl group represented by R ₄ and R ₅ include alkenyl groups having 1 to 12 carbon atoms [e.g., vinyl, allyl, 1-methylvinyl, 2-methylvinyl,
1-octenyl, 1-decenyl group]. Examples of the cycloalkyl group include cycloalkyl groups having 3 to 12 carbon atoms (eg, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl group). Examples of the cycloalkenyl group represented by R ₄ and R ₅ include cycloalkenyl groups having 3 to 8 carbon atoms (e.g., cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, cyclopentadienyl,
cyclohexadienyl, cycloheptadienyl,
cyclooctadienyl group). Examples of the aralkyl group represented by R ₄ and R ₅ include aralkyl groups having 7 to 13 carbon atoms (eg, benzyl, α-methylbenzyl, phenethyl, diphenylmethyl groups). Examples of the aryl group represented by R ₄ and R ₅ include aryl groups having about 6 to 10 carbon atoms (eg, phenyl, α-naphthyl, β-naphthyl groups). R ₄ and R ₅ may form a ring together with adjacent nitrogen atoms. Such a ring is preferably a 4- to 10-membered ring, such as azetidinyl, pyrrolidinyl, pyrrolinyl, pyrrolyl, imidazolyl, pyrazolyl, imidazolinyl, piperidino, morpholinodihydropyridyl, tetrahydropyridyl, N-methylpiperazinyl, N-ethylpiperazinyl. Lyle, azacycloheptyl, azacyclooctyl, isoindolyl, indolyl, indolinyl, 2-isoindolinyl, azacyclononyl,
Examples include azacyclodecyl. The alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, aralkyl group or aryl group represented by these R ₄ and R ₅ or
The ring formed by R ₄ and R ₅ together with adjacent nitrogen atoms may have 1 to 3 substituents.
Such substituents include, for example, alkyl groups having about 1 to 4 carbon atoms (eg, methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl,
tert-butyl), alkoxy groups having 1 to 4 carbon atoms which may have a hydroxyl group as a substituent (e.g., methoxy, ethoxy, propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-
butoxy, tert-butoxy group), alkanoyl group having 1 to 4 carbon atoms (e.g. formyl, acetyl, propionyl, n-butyryl, iso-butyryl group), alkanoyloxy group having 1 to 4 carbon atoms (e.g. formyl Oxy, acetyloxy,
propionyloxy, n-butyryloxy, iso
-butyryloxy group), carboxy group, carbon number 2
to about 4 alkoxycarbonyl groups (e.g., methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, iso-propoxycarbonyl group, n-butoxycarbonyl, isobutoxycarbonyl, t-butoxycarbonyl), halogen atoms (e.g., fluorine, chlorine, bromine, iodine), hydroxyl group,
Nitro group, cyano group, trifluoromethyl group, amino group, monosubstituted amino group (e.g., methylamino,
ethylamino, propylamino, isopropylamino, butylamino, carboxymethylamino groups), dialkylamino groups (e.g. dimethylamino,
Examples include diethylamino, dipropylamino, diisopropylamino, dibutylamino, dicarboxymethylamino groups), alkanoylamide groups (eg, formamide, acetamide, propionylamide, butyrylamide, isobutyrylamide groups), and the like. In addition, in the compound represented by the general formula () and the compound represented by (),

[Formula] group in the compound represented by the general formula ()

[Formula] shall not be the same as the group. The molecular weight of the amine represented by the general formula () is
About 500 or less is preferred. The substitution reaction with the amine of the present invention can be carried out using, for example, the compound () or its salt and the compound () or its salt at a molar ratio of about ()/() = 1 to 20 (mole ratio) by themselves or by using an appropriate reaction solvent. The reaction can be carried out by carrying out the reaction at a reaction temperature ranging from about 0°C to the boiling point of the reaction solvent, preferably about 20 to 100°C, for about 1 hour to 5 days. Also,
Compound () can be converted into a quaternary salt, such as methyl bromide, methyl iodide, methanesulfonic acid methyl ester,
When converted into salts such as benzenesulfonic acid methyl ester and p-toluenesulfonic acid methyl ester,
It is also possible to proceed under milder reaction conditions. At this time, the quaternary salt of the compound () produced is:
It may be isolated or may be directly subjected to a substitution reaction with compound () without isolation. In addition, if R ₁ is an acyl group, if necessary, the reaction solution may be
Deacylation is carried out by continuing to heat at 100°C and carrying out the deacylation reaction of _R1 , or by hydrolysis (e.g., acid hydrolysis, alkaline hydrolysis, ammonialysis) by a method known per se. I can do it. As a reaction solvent in the substitution reaction between compound () and compound (), for example, water, methanol, ethanol, propanol, butanol, pentanol, tetrahydrofuran, dioxane, acetonitrile, pyridine, dimethylformamide, dimethylsulfoxide, sulfolane, or appropriate ones thereof. A mixed solvent of When compound () or compound () is used in the form of a salt, a base (e.g. sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide,
By adjusting the pH to an optimal level (usually about 5 to 13) with salts (e.g., sodium chloride, potassium chloride, calcium chloride, sodium carbonate, potassium carbonate, sodium hydrogen carbonate) (triethylamine, N-methylmorpholine), The object () can be advantageously produced. Among these substituents of the hydrocarbon residues represented by R ₄ and R ₅ , for example, in the case of a carboxy group, hydroxyl group, amino group, or alkylamino group, if necessary, a method known per se [JFW
McOmie, Protective Groups in Organic
Chemistry Plenum Press, London and New
York (1973). ] using a starting compound () having a substituent protected or already protected (e.g., an alkanoyloxy group, an alkoxycarbonyl group, an alkanoylamide group) with another starting compound () After the reaction is carried out to form the compound (), the protecting group may be removed. The protecting group elimination reaction is carried out by subjecting the protective group to a commonly used protecting group elimination reaction. For example, acids (e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid,
trifluoroacetic acid, boron trifluoride, boron tribromide, hydrogen bromide-acetic acid) or bases (e.g. lithium hydroxide, sodium hydroxide, potassium hydroxide, barium hydroxide, potassium carbonate, sodium carbonate,
Ammonia water, methylamine, dimethylamine,
ethylamine, diethylamine, trimethylamine, triethylamine) and a suitable solvent (e.g., water, methanol, ethanol, propanol, butanol, dioxane, tetrahydrofuran, methyl ether, ethyl ether, dichloromethane, chloroform, carbon tetrachloride, benzene,
toluene, xylene or a suitable mixed solvent thereof) at a temperature of about -50 to 100°C, preferably -10 to 50°C, for about 30 minutes to 100 hours, preferably about 1 to 20 hours, or A suitable catalytic reduction catalyst (e.g. palladium, platinum,
By adding rhodium, ruthenium, nickel),
A suitable solvent (e.g. water, methanol, ethanol,
(propanol, butanol, dioxane, tetrahydrofuran, methyl ether, ethyl ether, benzene, toluene, xylene, ethyl acetate, methyl acetate, acetic acid, or an appropriate mixed solvent thereof) at a temperature of about 10 to 50°C.
This is done by catalytic reduction for 100 hours. The 7-deazapurine derivative () produced by the method of the present invention can be isolated from the reaction mixture by conventional separation and purification means, such as concentration, solvent extraction, chromatography, recrystallization, etc. Furthermore, when compound () is obtained in free form, it may be converted into a pharmaceutically acceptable salt form by a conventional method. Examples of salts of compound () include mineral acid salts such as hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, and boric acid, oxalic acid, tartaric acid, acetic acid, trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, and p-toluenesulfonic acid. , organic acid salts with camphor sulfonic acid, etc., and quaternary salts with methyl bromide, methyl iodide, methanesulfonic acid methyl ester, benzenesulfonic acid methyl ester, p-toluenesulfonic acid ester, etc. When the compound () is obtained in the form of a salt other than a quaternary salt, it can also be made into a free form if desired. In this case, it can be easily carried out by subjecting the salt of the compound () to a commonly used method such as neutralization reaction or anion exchange chromatography. The thus obtained compound () or its salt can be used for the growth of L5178Y cultured cells in vitro and for Meth.A and Sarcoma180 in vivo.
It has an antitumor effect because it suppresses the proliferation of each of these. In addition, the compound () or its salt is
Even if a dose of 200 mg/Kg was administered intraperitoneally to mice,
No fatal cases were observed. Therefore, the compound () or a salt thereof may be used in warm-blooded animals, especially mammals, e.g.
It can be used as an antitumor agent for the purpose of treating tumors in mice, rats, cats, dogs, rabbits, etc.). When used as an anti-tumor agent, it can be prepared as such or in the form of powders, granules, tablets, capsules, suppositories, etc. using pharmacologically acceptable carriers, excipients, diluents, etc. using commonly used methods. ,
It can be administered orally or parenterally in the form of an injection. The dosage varies depending on the target animal, disease, symptoms, type of compound, administration route, etc., but in the case of oral administration it is about 10 to 200 mg/Kg body weight of the compound () per day, and in the case of parenteral administration it is about 10 to 200 mg/Kg body weight per day.
Approximately 10 to 100 mg/Kg body weight per day. Furthermore, the compound () or its salt has antiviral and antibacterial effects against various viruses and microorganisms, and has low toxicity as mentioned above, so it is effective against warm-blooded animals, especially mammals (e.g., mice, rats, cats, etc.). It can be used as an antiviral agent, antibacterial agent, and disinfectant for the prevention and treatment of viral and bacterial infections in dogs, rabbits, and humans. When using the compound () or its salt as a bactericidal agent or disinfectant, for example, the compound () or its salt may be mixed with water at a concentration of about 0.5 to 500 mg/ml.
Isotonic glucose solutions, aqueous solutions such as Ringer's solution, or vegetable (e.g., cotton seeds, peanuts, corn,
It can be used to disinfect the administration site by making it into a liquid preparation containing it in a non-aqueous solution such as sesame (sesame) fatty oil and applying it to the hands, feet, ears, etc. of mammals. In addition, about 0.5 to 500 mg of the compound () or its salt can be used orally in the form of tablets containing excipients such as lactose, starch, and talc for the prevention and treatment of viral infections and bacterial infections in mammals. can. The dose in this case is about 10 to 200 mg/Kg body weight of the compound () per day. The compound () used as a raw material in the method of the present invention can be produced, for example, by the reaction steps shown below. In step A, the compound () and the chlorinating agent (e.g., thionyl chloride, phosphorus oxychloride, phosphorus pentachloride, oxalyl chloride, phthaloyl chloride) are mixed in a ratio of compound ()/chlorinating agent=1 to 1/
100 (molar ratio) using themselves or an appropriate reaction solvent at about 50 to 150°C for about 30 minutes to
By reacting for 10 hours, the reaction product () can be obtained. Examples of the solvent used in the above reaction include benzene, toluene, xylene, methylene chloride, chloroform, carbon tetrachloride, 1,2-dichloroethane, 1,1,2-trichloroethane, 1,1,2,2-tetrachloroethane, Examples include acetonitrile. During the above reaction, dimethylaniline, diethylaniline,
Addition of triethylamine, dimethylformamide, etc. allows the reaction to proceed under mild conditions. The sulfurization reaction in step B involves reacting the compound () with a sulfurizing agent (e.g., hydrogen sulfide, sodium sulfide, thiourea) at a molar ratio of compound ()/sulfurizing agent = 1 to 1/20. Usually at about 20 to 150℃ for about 30 minutes to 1 hour using a solvent that does not involve
This can be done by reacting for several days. Reaction solvents include water, alcohols (e.g. methanol, ethanol, propanol, butanol,
sec-butanol, t-butanol, ethylene glycol, methoxyethanol, ethoxyethanol), ethers (dimethyl ether, diethyl ether, tetrahydrofuran, dioxane,
monoglyme, diglyme), halogenated hydrocarbons (e.g. dichloromethane, chloroform, carbon tetrachloride), acetonitrile, dimethylformamide,
Or an appropriate mixed solvent thereof may be used. compound() is compound() and compound()
(Step C). Compound () and Compound () may be used in the form of a salt, and examples of such salts include those similar to the mineral acid salts or organic acid salts of Compound () described above. Formaldehydes include reagents that have an equivalent effect to formaldehyde during the Mannich reaction, such as formaldehyde,
Examples include paraformaldehyde, formalin, methylal, ethylal, piperidinomethylphthalimide, and hexamethylenetetramine. In the reaction of this step C, compound () and compound () are mixed by themselves or in a suitable reaction solvent at a ratio of ()/() = 1 to 50 (molar ratio) from about 0°C to the temperature of the reaction solvent. boiling point, preferably about
From about 10 minutes at reaction temperatures ranging from 20 to 100°C
Compound () can be obtained by reacting for about 48 hours and then treating with acid. In addition, as a reaction solvent, water, methanol, ethanol,
Propanol, butanol, pentanol, tetrahydrofuran, dioxane, acetonitrile,
Pyridine, dimethylformamide, dimethylsulfoxide, sulfolane or suitable mixtures thereof are used. Adjust the pH of the reaction solution to an acid (e.g., hydrochloric acid, sulfuric acid, phosphoric acid, boric acid, acetic acid, oxalic acid, tartaric acid,
trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid), bases (e.g., sodium hydroxide,
potassium hydroxide, lithium hydroxide, barium hydroxide, ammonia, triethylamine) or salts (e.g., sodium chloride, calcium chloride, sodium carbonate, potassium carbonate, sodium bicarbonate,
The reaction rate and yield can be improved by adjusting the pH to an optimum level (usually about 2 to 10) using ammonium chloride (ammonium chloride). The acids used in the final acid treatment include, for example, hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, acetic acid, oxalic acid, tartaric acid,
Examples include trifluoroacetic acid, methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like. The compound () produced by the above method can be obtained by separating and purifying the reaction mixture by conventional separation and purification means.
For example, it can be isolated using appropriate methods such as concentration, solvent extraction, recrystallization, and chromatography. When the compound () is obtained in free form in this manner, it may be converted into a salt form by a conventional method and used as a raw material compound in the method of the present invention. Examples of the salt of compound () include the same salts as the salts of compound () described above. The compound () used in the method of the present invention may be in the form of a salt. As the salt of compound (), the above-mentioned compound () and compound () can be used.
Salt and similar products can be mentioned. The present invention will be explained in more detail below by giving Examples, Reference Examples, and Examples. Experimental example 1 Incorporation experiment of the compound of Example 1 into tRNA: [ ^3H ]guanine-labeled tRNA (*)
(8000cpm), 70mM Tris hydrochloride, 60mM magnesium chloride, 0.5 units of rat liver tRNA-guanine transglycosylase, and 0.02OD ₂₆₀ of the compound obtained in Example 1 described below were adjusted to 100μ. , and reacted at 37°C for 17 hours. Pour the reaction solution onto Watzmann 3MM paper (Wattmann, USA).
Washed 3 times with 5% trichloroacetic acid aqueous solution, washed once each with ethanol/ether (1:1) and ether alone, dried, and measured with toluene-based scintillation solution to reveal 81% tRNA.
The compound of Example 1 was incorporated into the sample. (*) First character of tRNA anticodon [ ^3H ]
Guanine-labeled tRNA. Experimental Example 2 In the same manner as Experimental Example 1, the compound of Example 2 was prepared.
When the incorporation rate into tRNA was measured, it was 57%. Experimental Example 3 1 x 10 ⁴ L5178Y mouse tumor cells were placed in 2 ml culture medium RPMI-1640 (manufactured by Nissui Pharmaceutical Co., Ltd.) containing 10% fetal bovine serum, 20 μm 2-mercaptoethanol, and 100 μg/ml kanamycin. The cells were suspended and incubated at 37°C for 24 hours before drug administration. Next, using the above culture solution as a dilution solution, Example 1 described below
Add the compound obtained in 1/4 dilution in 5 steps to the culture medium so that the maximum concentration of the compound is 200 μg/ml.
After further culturing for 72 hours, the number of cells was measured using a counter, and the IC ₅₀ (50% growth inhibitory concentration) was calculated, setting the untreated control group as 100%, and found it to be 22 μg/ml. Experimental example 4 5×10 ⁴ subcutaneously into BALB/c mice weighing 20 g.
MethA tumor cells were transplanted, and on the 4th day after transplantation, the compound obtained in Example 1 described below was distilled once a day for 14 consecutive days so that the dose to the above mice was 100 mg/Kg. A solution dissolved in 0.1 ml of water was intraperitoneally injected into mice. Tumor nodules were removed 35 days after transplantation, and their weights were measured. Tumor growth was suppressed compared to that in the non-administered control group. The tumor inhibition rate was 71%. Reference example 1 2-amino-4-chloropyrrolo[2,3-d]
Production of pyrimidine: 2-aminopyrrolo[2,3-d]pyrimidine-
4-one (45 g) was suspended in phosphorus oxychloride (150 ml) and reacted with stirring at 110°C for 3 hours. Excess phosphorus oxychloride was distilled off under reduced pressure, and the residue was diluted with ice water (600
ml) and completely dissolved, the pH was adjusted to 9 with concentrated ammonia water while cooling and stirring. Remove the resulting precipitate,
After washing with water, the product was recrystallized from hot methanol (4) to obtain the desired product (34.6 g). NMR (DMSO-d ₆ , 60MHz): δ6.23 (d, 1H),
6.40 (bs, 3H), 7.05 (d, 1H) IR (KBr): ν3420, 3330, 3170, 2970, 2820,
1680, 1640, 1620, 1570 cm ^-1 UV λ ^MeOH _nax : 232, 258, 319 nm Reference Example 2 Production of 4-chloro-2-n-octanoylaminoprolo[2,3-d]pyrimidine: Obtained in Reference Example 1 The resulting 2-amino-4-chloropyrrolo[2,3-d]pyrimidine (16.9 g) was suspended and dissolved in dry pyridine (200 ml), and n-octanoyl chloride (21.2 g) was added while stirring under ice cooling. After that, the mixture was returned to room temperature and reacted for 1 hour. 9.9% ethanolic ammonia (w/v) was added to the reaction mixture, and the mixture was further stirred at room temperature for 2 hours, and then the solvent was distilled off under reduced pressure. Water (500 ml) was added to the residue, stirred at room temperature for 1 hour, and the resulting insoluble matter was removed, washed with aqueous sodium bicarbonate, then water, and dried to give yellow powder crystals (23.3 g). This product was recrystallized from 1,2-dimethoxyethane to obtain the desired product (20.9 g). NMR ( _CDCl3 /DMSO- _d6 , 60MHz): δ0.87(t,
3H), 1.30 (bs, 10H), 2.50 (t, 2H), 6.43
(d, 1H), 7.30 (d, 1H), 10.37 (s, 1H),
12.10 (bs, 1H) IR (KBr): ν3430, 3220, 2920, 1645, 1610,
1585, 1375cm ^-1 Reference example 3 2-n-octanoylaminopyrrolo [2,3-
d] Production of pyrimidine-4-thione: 4-chloro-2-n-octanoylaminopyrrolo[2,3-n]pyrimidine (19.9 g) obtained in Reference Example and thiourea (38 g) were combined with 2- Suspend and dissolve in methoxyethanol (240ml) and heat at 100℃.
The reaction was stirred for 2.5 hours. After distilling off the solvent under reduced pressure,
1.8% aqueous sodium bicarbonate (300 ml) was added to the residue, and the mixture was stirred well at room temperature. The resulting precipitate was collected and recrystallized from ethanol to obtain the desired product (15.7 g). NMR ( _CDCl3 /DMSO- _d6 , 60MHz): δ0.87(t,
3H), 1.33 (bs, 10H), 1.47 (t, 2H), 6.63
(q, 1H), 6.90 (q, 1H), 11.27 (bs, 2H),
13.20 (bs, 1H) IR (KBr): ν3220, 1680, 1635, 1600, 1310cm ^-1 Reference example 4 5-N,N-dibenzylaminomethyl-2-octanoylaminoprolo[2,3-d]pyrimidine -Production of 4-thione: 1-octanoylaminopyrrolo[2,3-d]pyrimidine-4-thione (3.5 g) obtained in Reference Example 3 and dibenzylamine (9.5 g),
It was dissolved in water/acetic acid (1:4, 120 ml), 35% formalin (4.2 g) was added, and the mixture was reacted at 60°C for 14 hours. The solvent was distilled off under reduced pressure, water (30 ml) was added, and the mixture was distilled off again. 2N-HCl (64 ml) and methanol (100 ml) were added to the residue, and the mixture was stirred at 60°C for 1.5 hours. Most of the methanol was distilled off under reduced pressure, and the aqueous layer was made into an ammoniacal alkali. After adding acidic sodium sulfite (5.7 g), the mixture was extracted with chloroform. The chloroform layer was concentrated to dryness to obtain the crude target product (3.95 g). This product can be used directly in the next reaction without further purification. NMR (CDCl ₃ , 60MHz): δ0.83 (t, 3H), 1.20
(bs, 10H), 2.70 (t, 2H), 4.07 (bs, 4H),
4.40 (bs, 2H), 7.20 (m, 11H) Reference example 5 5-N,N-diisobutylaminomethyl-2-
Production of octanoylaminopyrrolo[2,3-d]pyrimidine-4-thione: In the same manner as in Reference Example 4, 2-octanoylaminopyrrolo[2,3-d]pyrimidine-4-thione (3.5 g) and Reaction with diisobutylamine (4.5 g) gave the crude target compound (2.3 g). NMR (CDCl ₃ , 60MHz): δ0.85 (t, 3H), 0.90
(d, 12H), 1.20-2.00 (m, 12H), 2.40-2.70
(m, 6H), 4.40 (bs, 2H), 7.20 (bs, 1H) Example 1 2-amino-5-{(3S,4R,5S)-4,5-dihydroxycyclopent-1-ene-3 -ylaminomethyl}pyrrolo[2,3-d]pyrimidine-4-thione (6-thioQ base): Crude 5-N,N-dibenzylaminomethyl 2-octanoyl obtained in Reference Example 4 Aminopyrrolo[2,3-d]pyrimidine-4-thione (3.3g)
and (3S,4R,5S)-4,5-O-isopropylidene-4,5-dihydroxycyclopent-1-en-3-ylamine (1.55 g) were dissolved in ethanol (150 ml) and placed in a sealed tube. The reaction was carried out at 75°C for 20 hours. After cooling, add tetrahydrofuran (75ml) to the reaction solution.
and 40% potassium hydroxide aqueous solution (11ml),
It was left at 5°C for 3 days. A 30% ammonium chloride aqueous solution (11 ml) was added to this, concentrated to dryness, and the residue was purified by silica gel column chromatography.
% _NH3 containing ethanol/chloroform (1:4)
When separated and purified using effluent solvent, 2-amino-5
-{(3S,4R,5S)-4,5-O-isopropylidene-4,5-dihydroxycyclopent-1-en-3-ylaminomethyl}pyrrolo[2,3-
d] Pyrimidine-4-thione was obtained. The entire amount of this was mixed with methanol (100 ml) and 2N-HCl (16
ml) and left overnight at room temperature, the solvent was concentrated to dryness to obtain the desired dihydrochloride (1.07 g). NMR (D ₂ O, 60MHz): δ4.20-4.60 (m, 2H),
4.47 (bs, 2H), 6.13 (m, 2H), 7.03 (s, 1H) IR (KBr): ν2930, 2780, 1690, 1590, 1200cm ^-1 Example 2 2-Amino-5-aminomethylpyrrolo[2 ,3
-d]pyrimidine-4-thione (6-thio
Production of PreQ ₁ base): Crude 5-N,N-dibenzylaminomethyl-2-octanoylaminopyrrolo[2,3-d]pyrimidine-4-thione (1.0 g) obtained in Reference Example 4
ethanol (50ml), tetrahydrofuran (30ml)
and concentrated aqueous ammonia (20 ml), and reacted in a sealed tube at 80°C for 1.5 hours. After distilling off the solvent under reduced pressure, the residue was washed with ethanol, and the insoluble matter was separated and purified using cellulose powder (Avicel, manufactured by Asahi Kasei Corporation) using n-butanol saturated with concentrated ammonia as the eluent solvent to obtain the desired product (215mg). )
was gotten. Physical and chemical data were measured after converting to hydrochloride with methanolic hydrochloric acid. NMR (D ₂ O/CD _30D , 60MHz): δ4.13 (bs, 2H),
6.90 (bs, 1H) IR (KBr): ν2920, 1690, 1595, 1195 cm ^-1 Example 3 Production of 2-amino-5-isoamylaminomethylpyrrolo[2,3-d]pyrimidine-4-thione: Reference example Crude 5-N,N-dibenzylaminomethyl-2-n-octanoylaminopyrrolo[2,3-d]pyrimidine-4-thione (2.01
g; 4 mmol) isoamylamine (1.75 g; 20
mmol) in methanol (200 ml),
The reaction was stirred at 55°C for 17 hours. The reaction solution was concentrated under reduced pressure, the precipitated crystals were collected, washed with a small amount of methanol and ether, and dried to obtain the desired product (0.89
g) was obtained. NMR (DMSO-d ₆ , 90MHz): δ0.83 (d, 6H),
1.03-1.60 (m, 3H), 2.28 (t, 2H), 3.70 (s,
2H), 6.63 (s, 1H), IR (KBr): ν3350, 3200, 3100, 2960, 1600,
1540, 1460, 1320, 1240, 1200, 1025, 945cm
^-1 Example 4 In the same manner as in Example 3, crude 5-N,N-dibenzylaminomethyl-2-n-octanoylaminopyrrolo[2,3-d]pyrimidine-4-thione (4
7-deazapurine derivatives (20 mmol) were reacted with various amines (20 mmol) to obtain the corresponding 7-deazapurine derivatives (20 mmol) as shown in the table below. In the following, among the physical and chemical data, NMR is
at 90MHz using DMSO- _d6 as solvent and also by IR
was measured using KBr as a solvent. (1) Target product: 2-amino-5-(2-hydroxybenzyl aminomethyl)pyrrolo[2,3-
d] Pyrimidine-4-thione Yield: 1.07 (g) Physical properties: NMR: δ3.80 (s, 2H), 3.83 (s, 2H),
6.70 (s, 1H), 6.60~6.75 (m, 2H), 6.95~
7.17 (m, 2H), IR: ν3200, 1620, 1595, 1565, 1460, 1380,
1250, 1020cm ^-1 compound ():

[Formula] (2) Target product: 2-amino-5-cyclopentylaminomethylpyrrolo[2,3-d]pyrimidine-
4-thione Yield: 0.99 (g) Physical properties: NMR: δ1.20-1.83 (m, 8H), 2.84~
3.13 (m, 1H), 3.73 (s, 2H), 6.67 (s,
1H) IR: ν3180, 1640, 1590, 1560, 1535, 1490,
1360cm ^-1 compound ():

[Formula] (3) Target product: 2-amino-5-[2-(2-hydroxyethoxy)ethyl}aminomethyl]pyrrolo[2,3-d]pyrimidine-4-thione Yield: 0.47 (g) Physical properties: NMR: δ2.57 (t, 2H), 3.30-3.56 (m,
6H), 3.77 (s, 2H), 6.67 (s, 1H) IR: ν3200, 2950, 1640, 1590, 1540, 1480,
1390cm ^-1 compound ():

[Formula] (4) Target product: 2-amino-5-piperidinomethylpyrrolo[2,3-d]pyrimidine-4-thione Yield: 0.58 (g) Physical properties: NMR: δ1.43 (s, 6H) , 2.33~2.50 (s,
4H), 3.87 (s, 2H), 6.63 (s, 1H) IR: ν3150, 2950, 1620, 1590, 1535, 1460,
1240, 1020cm ^-1 compound ():

[Formula] (5) Target product: 2-amino-5-arylaminomethylpyrrolo[2,3-d]pyrimidine-4-thione Yield: 0.57 (g) Physical properties: NMR: δ3.10 (d, 2H) , 3.76 (s, 2H),
4.93~5.27 (m, 2H), 5.63~6.07 (m, 1H),
6.68 (s, 1H) IR: ν3200, 1630, 1590, 1540, 1465, 1240,
1020cm ^-1 Compound (): CH ₂ = CHCH ₂ NH ₂ (6) Target: 2-amino-5-[2-(2-aminoethylamino)ethyl}aminomethyl]pyrrolo[2,3-d]pyrimidine -4-thione Yield: 0.40 (g) Physical properties: NMR: δ2.57 (s, 8H), 3.80 (s, 2H),
6.70 (s, 1H) IR: ν3300, 2920, 1590, 1535, 1465, 1235,
1020cm ^-1 compound ():

[Formula] (7) Target product: 2-amino-5-phenylaminomethylpyrrolo[2,3-d]pyrimidine-4-thione Yield: 0.67 (g) Physical properties: NMR: δ4.40 (s, 2H) , 6.73 (s, 1H),
6.47~6.63 (m, 3H), 6.93~7.10 (m, 2H) IR: ν3300, 1625, 1600, 1565, 1440, 1385,
1200cm ^-1 compound ()

[Formula] (8) Target product: 2-amino-5-(2-hydroxyphenylaminomethyl)pyrrolo[2,3-d]
Pyrimidine-4-thione Yield: 0.31 (g) Physical properties: NMR: δ4.42 (s, 2H), 6.27-6.70 (m,
4H), 6.75 (d, 1H) IR: ν3340, 1625, 1595, 1565, 1440, 1200,
965cm ^-1 compound ()

[Formula] (9) Target product: 2-amino-5-tert-butoxycarbonylmethylaminomethylpyrrolo[2,3-
d] Pyrimidine-4-thione Yield: 0.54 (g) Physical properties: NMR: δ1.37 (s, 9H), 3.13 (s, 2H),
3.82 (s, 2H), 6.68 (s, 1H) IR: ν3350, 3150, 1730, 1650, 1560, 1365,
1235cm ^-1 compound ():

【formula】

Claims (1)

[Claims] 1. General formula [In the formula, R ₁ is a hydrogen atom or an acyl group, and R ₄ and R ₅ are hydrogen atoms or an alkyl group, alkenyl group, cycloalkyl group, cycloalkenyl group, aralkyl group, each of which may have a substituent. Each represents an aryl group, and R ₄ and R ₅ may form a cyclic amino group together with the adjacent nitrogen atom. ] A 7-deazapurine derivative or a salt thereof. 2 General formula [In the formula, R ₁ is a hydrogen atom or an acyl group, R ₂ and R ₃ are an alkyl group whose α position is a methylene group,
Each represents an alkenyl group or an aralkyl group, and R ₂ and R ₃ may form a cyclic amino group together with adjacent nitrogen atoms. ] or its salt represented by the general formula [In the formula, R ₄ and R ₅ represent a hydrogen atom or an alkyl group, an alkenyl group, a cycloalkyl group, a cycloalkenyl group, an aralkyl group, or an aryl group, each of which may have a substituent, and R ₄ and R ₅ may form a cyclic amino group together with adjacent nitrogen atoms. However, the [formula] group is not the same as the [formula] group. ] A general formula characterized by being subjected to a substitution reaction with an amine represented by or a salt thereof [In the formula, R ₁ , R ₄ and R ₅ have the same meanings as above. ] A method for producing a 7-deazapurine derivative or a salt thereof.