WO1997006169A1

WO1997006169A1 - 1-amino-2-imino-3-methyl-6-oxo-1,2,3,6-tetrahydro-7h-purines

Info

Publication number: WO1997006169A1
Application number: PCT/JP1996/002132
Authority: WO
Inventors: Tomohisa Nagamatsu; Shuichi Miyazaki; Masahiro Imaizumi
Original assignee: Yamasa Corporation
Priority date: 1995-08-04
Filing date: 1996-07-29
Publication date: 1997-02-20

Abstract

Novel 1-amino-2-imino-3-methyl-6-oxo-1,2,3,6-tetrahydro-7H-purines represented by general formula (I) and an ameliorant for learning/memory functions containing the same as the active ingredient, wherein R represents hydrogen, lower alkyl or optionally substituted phenyl.

Description

Specification

1-Amino 2-imino 3-Methyl-6-oxo

1,2,3,6-tetrahydro-1 7-purine technology

The present invention relates to novel 1-amino-2-imino 3-methyl-6-oxo-1,2,3,6-tetrahydro-7-purines (l-amino-2-iniino-3-ie thy 1-6-0X0 -1, 2, 3, 6-tetrah7dro-7H-purines) and their uses.

Background technology

Conventionally, guanine derivatives having an amino group at position 1 include: 1-aminoguanine (Chem. Pharm. Bull., 22 (2), 342-348 (1974)), 1-amino-9-methylguanine, and 1,7-diamino-9 -Methyldanine, 1,8-diamino-9-methylguanine, 1-amino-18-hydroxy-9-methylguanine (±, Tetrahedron, 46 (5), 1531-1540 (1990)) and the like are known. However, these compounds were not synthesized for the purpose of drug discovery, and no report was made on the biological activity of the compounds.

Therefore, an object of the present invention is to find a guanine derivative having an amino group at the 1-position and having biological activity, and to apply this to a pharmaceutical.

Disclosure of invention

The present inventors have conducted intensive studies to achieve the above object, and as a result, a newly synthesized novel amino-1,2-imino 3-methyl-6-oxo-1,1,2,3,6- The present inventors have found that tetrahydrofurans have a powerful effect of improving learning and memory, and have completed the present invention. That is, the present invention provides 1-amino-12-iminor-3-methyl-16-oxo-1,2,3,6-tetrahydro-17-purines represented by the following formula (I). The present invention also provides a pharmaceutical product such as a learning and memory improving drug comprising the compound and a carrier that is acceptable.

0

(In the formula, R represents a hydrogen atom, a lower alkyl group or a phenyl group which may have a substituent.)

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a graph showing the results of Transfer Latency (TL) when piracetam was administered in the test examples described below.

FIG. 2 is a graph showing the results of lowering when bifemelane hydrochloride was administered in the test examples described later.

FIG. 3 is a graph showing the TL results when Compound 1 of Example 1 was administered in the test examples described below.

FIG. 4 is a graph showing the TL results when the compound 3 of Example 3 was administered in the test examples described below.

The abbreviations and symbols in each figure mean the following.

SCO: Scobolamine, PIRA: Piracetam, BIFE: Bihuemelan hydrochloride, VEHICLE: Solvent

#: P <0.05 (vs. VEHICLE), ##: p <0.01 (vs. VEHICLE)

*: P <0.05 (vs. SCO 0.5mg) **: p <0.01 (vs. SCO 0.5mg) BEST MODE FOR CARRYING OUT THE INVENTION

(1) Compound of the present invention

The compound of the present invention is represented by the above formula (I). In the formula, examples of the lower alkyl group represented by R include an alkyl group having 1 to 5 carbon atoms such as methyl, ethyl, propyl, and butyl.

The phenyl group which may have a substituent means both a phenyl group having no substituent and a phenyl group having various substituents. Specific examples of the phenyl group having a substituent Examples include halogenophenyl (2-chlorophenyl, 4-chlorophenyl, 4-bromophenyl, 2-fluorophenyl, 3-fluorophenyl, 4-fluorophenyl, etc.), nitrophenyl (412-trophenyl, etc.), and alkylphenyl (4-methylphenyl, 4 Phenyl), alkoxyphenyl (eg, 4-methoxyphenyl), alkylaminophenyl (eg, 4-dimethylaminophenyl), and the like.

The compound of the present invention may be in the form of a salt, hydrate or solvate, and examples of the salt include acid addition salts such as hydrochloride, sulfate, acetate and citrate.

Examples of the hydrate or solvate include those having 0.1 to 3. water or a solvent attached to the compound of the present invention or a salt thereof. Further, various isomers such as tautomers may be included in the compounds of the present invention. Specific examples of the compound of the present invention include the hydrogen atom represented by R in the above formula (I), methyl, ethyl, i-propyl, phenyl, 2-chlorophenyl, 3-chlorophenyl, 4-chlorophenyl, and 2-chlorophenyl. Bromophenyl 3-bromophenyl, 4-bromophenyl, 2-nitrophenyl 3-nitrophenyl, 4-nitrophenyl, 2-methoxyphenyl, 3-methoxyphenyl, and 4-methoxyphenyl No. (2) Method for synthesizing the compound of the present invention

The compound of the present invention can be synthesized according to the following scheme <

Raw material compound Intermediate compound

Transformation ^!

The compound used as a starting material, that is, the starting compound is a compound known in the literature! (Heterocycles, 33 (2), 775-790 (1992)), and can be prepared according to the method described in the literature.

The intermediate compound (intermediate) can be prepared from the starting compound by reacting the starting compound with liquid ammonia in an alcoholic solvent such as ethanol.

The reaction conditions at this time are pressurized conditions of 10 to 100 kg / cm ² (preferably about 50 kgZcm ² ) and heating conditions of 50 to 200 ° C (preferably 130 ° C). Before and after) and reaction time of 1 to 4 days (preferably about 2 days).

Next, the compound of the present invention is prepared from the intermediate compound by an intermediate compound and an electrophilic aminating agent (e.g., HAO S (hydroxylamine-O-sulfonic acid), DNPA (2,4- (iinitroplienoxyamiiie)), etc. For example, when HAOS is used as the electrophilic aminating agent, the intermediate compound and HAOS are dissolved in an aqueous solution of sodium hydroxide, hydroxylated lime, or the like. Is reacted at 10 to 50 ° C (preferably 20 to 30 ° C) for about 1 to 5 days to obtain the compound of the present invention.

The thus-obtained compound of the present invention can be isolated by performing a suitable separation and purification method of a nucleic acid base (for example, a recrystallization method, various chromatography methods and the like) as necessary. Can be.

(3) Uses of the compound of the present invention

The compound of the present invention has a learning and memory improving effect as apparent from the results of the test examples described below, and has a possibility that it can be used for the prevention or treatment of dementia. When the compound of the present invention is administered to mammals including humans, it can be administered by any of oral, enteral, parenteral and topical routes. Dosage, patient age, disease state, the force is properly determined in One Yo such as weight ^ usually 1 day 0. 01 ~ 1000 mg / kg body weight, preferably from within the range of 0. 1~10 OmgZk _g body weight It is selected and administered once or in divided doses.

In the preparation of the compound of the present invention, it is powerful to produce a composition containing carriers, excipients, and other additives that are commonly used. Carriers include solid carriers such as lactose, kaolin, sucrose, crystalline cellulose, corn starch, talc, agar, pectin, stearic acid, magnesium stearate, lecithin, sodium chloride, etc .; Olive oil, etano And liquid carriers such as benzyl alcohol, propylene glycol, and water.

The dosage form can take any form.For example, when a solid carrier is used, tablets, powders, granules, capsules, suppositories, troches, etc. Examples include syrup, emulsion, soft gelatin capsule, cream, gel, paint, spray, aii and the like.

Example

Hereinafter, the present invention will be described more specifically with reference to Examples and Test Examples.

Example 1: 1-amino-12-imino-3-methyl-6-oxo-1,2,3,6-tetrahydro-7H-purine (l-Amino-2-imino-3-metliy! -6-oxo-l , 2, 3, 6-tetrahydro-TH-purine: Compound 1)

(1) 3-Methyl-1-methylthio-6-oxo-1,3,6-dihydro-17-purine (3-methyth-2-methylthio-6-OXX-3,6-dihydro-7-purine) (0.98 g, 5 mmo 1) in ethanol (5 ml) to suspend

(30 ml), and reacted under heating (130 ° C) under pressure (50 kg / crn ² ) for 2 days.

After the reaction, the ammonia-ethanol solution was distilled off, and the residue was recrystallized from water to give 2-amino-13-methyl-6-oxo-1,3,6-dihydro-17 and monopurine (2-Amino-3-methyi). There was obtained 0.68 g (82% yield) of colorless needle crystals of the compound 6-ΟΣΟ-3, 6-di dro-7H-purine).

Melting point (mp): 338. C (decomposition)

Elemental analysis (as Cg H _{7 5} 0):

Calculated value (%): C, 43. 63; H, 4.27; N, 42. 41

Obtained value (%): C, 43.41; H, 4.22; N, 42.39

IR (KB r): 3315 ( S NH 2), 3125 (ΝΗπ), 3030 NH), 1626 O CO and 6NE 2) cm "1 1 H-NMR (60MH z, TFA-d 1) 6: 4. 02 (3H, s, NMe), 8. 56 (1 H, s, 8- H)

(2) 2-amino-3-methyl-6-oxo-3,6-dihydro-7-and-purine

(0.5 g, 3 mmo 1) was added to IN-NaOH (15 ml) and stirred. To this solution was added an aqueous solution (10 ml) of HAOS (1.02 g, 9 mmo 1) little by little, and the mixture was stirred at room temperature for 4 days. After the reaction, the precipitated crystals are recrystallized with water to give 1-amino-2-imino-13-methyl-16-oxo-1,2,3,6-tetrahydro-

0.18 g (33% yield) of colorless powdery crystals of 7-purine were obtained.

Melting point (mp): 304-306 ° C

Elemental analysis (as Cg H ₈ N ₆ ◦):

Calculated value (%): C, 40.0; H, 4.48; N, 46.65

Obtained value (%): C, 39.98; H, 4.43; N, 46.71

IR (KB r): 3400 O _as NH ₂ ), 3300 (s NH „), 3160

O NH), 3100 (00), 1712 OCO), 1 635 (δΝΗ ₂ ) -1

cm

¹ H-NMR (60 MHz, TFA-d ₁ ) 5: 4.05 (3H, s, NMe), 8.55 (1 H, s, 8-H).

Example 2 1-Amino-2-imino 3,8-dimethyl-1-oxo-1,2,3,6-tetrahydro-7H-purine Amino-2-imino-3,8-dimethyl 6-0X0 -1, 2, 3, 6-tetra ydro-7H-purine: Compound 2)

(1) 3,8-Dimethyl-2-methylthio-1-oxo-3,6-dihydro-7-purine (3,8-dimethyi-2-methylthio-6-oxo-3, 6-dihydro-7H-purine)

(1.05 g, 5 mmo 1) was suspended in ethanol (5 ml), and then liquid ammonia (30 ml) was added. The mixture was heated under pressure (50 kgZcm ² ) for 2 days. (130 ° C). After the reaction, the ammonia-ethanol solution was distilled off, and the residue was recrystallized from water to give 2-amino-3,8-dimethyl-6-oxo-1,3,6-dihydro 7-purine (2-Amino-3, 8- 0.72 g (80% yield) of colorless needle crystals of dimethytri 6-oxo-3,6-dihydro-7H-purine) were obtained.

Melting point (mp):> 330. C

Elemental analysis (as C _? H ₀ N ₅ ◦):

Calculated value (%): C, 46.92; H, 5.06; N, 39.08

Found (%): C, 46.99; H, 5.04; N, 39.13

IR (KB r): 3280 ( S NH 9), 3125 (s NH 2), 3025 ( re-NH), 1675 OCO), 1625 (5NH) cm one ¹

¹ H-NMR (60 MHz, TFA-d ₁ ) δ: 2.87 (3H, s, CMe),

4.02 (3H, s, NMe).

(2) 2-Amino-3,8-dimethyl-6-oxo-1,3,6-dihydro-7and-purine (0.54 g, 3 mmo 1) was added to IN-NaOH (15 ml) and stirred. To this solution was added an aqueous solution (10 ml) of HAOS (1.02 g, 9 mmo 1) little by little, and the mixture was stirred at room temperature for 4 days. After the reaction, the precipitated crystals were recrystallized from water to obtain 0.18 g of colorless powdery crystals of 1-amino-2-imimino 3,8-dimethyl-16-oxo-1,2,3,6-tetrahydro-7-purine. (31%).

Melting point (mp): 270-272 ° C

Elemental analysis (as C ₇ H ₁₀ N, 0):

Calculated value (%): C, 43.29; H, 5.19; N, 43.27

Actual value (%): C, 43.30; H, 5.18; N, 43.31

IR (KB r): 3390 ( S NH 2), 3310 Os 2), 3275 (NH), 3160 (NH), 1703 ( Li _{C_〇), 1615 (<5NH 2)} cm * ¹ H-NMR (60 MHz, TF Ad ₁ ) <5: 2.87 (3H, s, CMe), 4.07 (3H, s, NMe).

m 3: 1-Amino-2-imino 3-methyl-6-oxo-8-phenyl 1,2,3,6-tetrahydro-17-purine (i-Amino-2-imin.-3-methytri 6 -oxo- 8-phenytri 1, 2, 3, 6-tetrahydro-7 and -purine: compound 3)

(1) 3-Methyl-1-methylthio-1-oxo-8-phenyl 3,6-dihydro 7-purine (3-methylthio-6- 0∑0-8-plieny tri 3, 6-dihydro-7H-purine) (1.36 g, 5 mm o 1) was suspended in ethanol (5 ml), and liquid ammonia (30 ml) was added. ² ) The reaction was performed under heating (1 30 ° C) for 2 days. After the reaction, the ammonia-ethanol solution was distilled off, and the residue was recrystallized from DMF to obtain 2-amino-13-methyl-16-oxo-8-phenyl-3,6-dihydro-17-purine (2-Amino-3). 0.88 g (yield 73%) of colorless needle crystals of -methyl-6-oxo-8-phenyl-3,6-dihydro-7H-piirine) was obtained. Melting point (mp):> 300 ° C

IR (KB r): 341 0 (NH ₂ ), 3250 ( _s ΝΗ,), 3060 ΟΝΗ), 1 678 O CO), 1 626 (<5ΝΗ ₀ ) cm '' ¹

1 H-NMR (60 MHz, TFA-d ₁ ) 6: 4.12 (3Η, s, NMe), 7.72 (3H, m, PhH), 8.12 (2H, m, Phh)

(2) 2-Amino-3-methyl-6-oxo-18-phenyl-1,3,6-dihydro-7,7-purine (0.72 g, 3 mmo 1) was added to IN-NaOH (15 ml). And stirred. To this solution was added HAOS (1, 02 g, 9 mmo O aqueous solution (1 Om 1) little by little and stirred at room temperature for 4 days. After the reaction, the precipitated crystals were recrystallized with water to give 1-amino-1- 0.26 g (34% yield) of colorless powdery crystals of imino 3-methyl-6-oxo-18-phenyl-1,2,3,6-tetrahydro-7-purine were obtained. Melting point (mp): 277-279 ° C

IR (KB r): 3400 O _as NH ₂ ), 3310 ( _s NH ₂ ), 3200 ONH), 3080 ONH), 1695 OCO), 1630 (5NHo) cm 1

¹ H-NMR (60 MHz, TFA-d ₁ ) δ: 4.15 (3H, s, NMe), 7.69 (3H, m, Ph-H), 8.11 (2H, m, Ph-h) .

Test example: Evaluation of learning memory by elevated plus maze

Method

Animals:

ICR male mice (6 weeks old) were used. The maze consisted of two open arms (5 x 30 cm) and two closed arms (5 x 30 x 20 cm) extending from the platform (5 x 5 cm).

Drug:

Compounds 1 and 3 of the present invention, piracetam (Piucetam Sigma) and biiemelane hydrochloride (Eisai) were used as the drugs to be tested.

In the test, scopolamine (Scopolamine: manufactured by Wako Pure Chemical Industries, Ltd.) and piracetam were dissolved in physiological water. Other drugs were suspended in physiological water containing 0.5% carboxymethyl cellulose. Each drug was administered intraperitoneally. The method was performed based on the method of Ito et al. (Psychopharmacology 101, 27-33, 1990). That is, the test drug or the vehicle was administered to the mouse, and 15 minutes later, scopolamine (0.5 mgZkg) or the vehicle was administered. Acquisition trial (DAY1) The test was performed 15 minutes after bolamine administration. In other words, the mouse was placed at the tip of one open arm in the direction opposite to the platform, and the time required to enter the closed arm (Transfer Latency, TL) was measured. On the second day (playback trial; DAY2), the mouse was placed in the maze as in DAY1, and the TL was measured. In this experimental system, scobolamine, which is known to cause amnesia

(mACh antagonist) significantly prolonged DAY2 compared to the group administered with TL strong solvent (physiology: ^ water and / or 0.5% carboxymethylcell-containing physiological solution: ^ water) (Fig. 1 and (See Fig. 2). Piracetam (15 Omg / kg), a cognitive enhancer, and biphemeran hydrochloride (25 mgZkg), a cerebral metabolism improver, showed an antagonistic effect on TL prolongation by scopolamine (see FIGS. 1 and 2). In addition, Compounds 1 and 3 of the present invention antagonized the action of scopolamine at a dose of 3 mgZkg (see FIGS. 3 and 4).

Industrial use ^

The compound of the present invention antagonizes the action of scopolamine and has an effect of improving learning and memory as is clear from the results of the above test examples. Development can be expected.

Claims

2 Claims Formula (I)

(In the formula, R represents a hydrogen atom, a lower alkyl group or a phenyl group which may have a substituent.) 1-amino-2-imimino 3-methyl-6-oxo 1,2, 3,6-Tetrahydro-1-purines and freshly acceptable ones thereof.

2. The compound according to claim 1, wherein R is a hydrogen atom.

3. The compound of claim 1, wherein R is phenyl.

4. The compound according to claim 1, wherein the compound is R-progenophenyl.

5. The compound of claim 1, wherein R is ditrophenyl.

6. The compound according to claim 1, wherein R is alkoxyphenyl.

7. The compound of claim 1, wherein R is alkylphenyl.

8. The compound of claim 1, wherein R is alkylaminophenyl.

9. A pharmaceutical composition comprising at least one compound according to claim 1 and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition according to claim 9, which is a learning and memory improving agent.