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

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

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Publication number
WO1997006169A1
WO1997006169A1 PCT/JP1996/002132 JP9602132W WO9706169A1 WO 1997006169 A1 WO1997006169 A1 WO 1997006169A1 JP 9602132 W JP9602132 W JP 9602132W WO 9706169 A1 WO9706169 A1 WO 9706169A1
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WIPO (PCT)
Prior art keywords
compound
amino
oxo
methyl
tetrahydro
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Application number
PCT/JP1996/002132
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English (en)
Japanese (ja)
Inventor
Tomohisa Nagamatsu
Shuichi Miyazaki
Masahiro Imaizumi
Original Assignee
Yamasa Corporation
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Yamasa Corporation filed Critical Yamasa Corporation
Publication of WO1997006169A1 publication Critical patent/WO1997006169A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems
    • C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
    • C07D473/18—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 one oxygen and one nitrogen atom, e.g. guanine

Definitions

  • 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.
  • 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.
  • 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.
  • 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.
  • R represents a hydrogen atom, a lower alkyl group or a phenyl group which may have a substituent.
  • 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.
  • SCO Scobolamine
  • PIRA Piracetam
  • BIFE Bihuemelan hydrochloride
  • VEHICLE Solvent
  • the compound of the present invention is represented by the above formula (I).
  • 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.
  • the compound of the present invention can be synthesized according to the following scheme ⁇
  • R represents a hydrogen atom, a lower alkyl group or a phenyl group which may have a substituent.
  • 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).
  • 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.
  • an electrophilic aminating agent e.g., HAO S (hydroxylamine-O-sulfonic acid), DNPA (2,4- (iinitroplienoxyamiiie)
  • HAO S hydroxylamine-O-sulfonic acid
  • DNPA 2,4- (iinitroplienoxyamiiie)
  • 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.
  • a suitable separation and purification method of a nucleic acid base for example, a recrystallization method, various chromatography methods and the like.
  • 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.
  • the compound of the present invention 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.
  • 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.
  • a solid carrier when used, tablets, powders, granules, capsules, suppositories, troches, etc.
  • examples include syrup, emulsion, soft gelatin capsule, cream, gel, paint, spray, aii and the like.
  • 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)
  • 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)
  • 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)
  • Test example Evaluation of learning memory by elevated plus maze
  • 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).
  • piracetam (Piucetam Sigma) and biiemelane hydrochloride (Eisai) were used as the drugs to be tested.
  • scopolamine Scopolamine: manufactured by Wako Pure Chemical Industries, Ltd.
  • 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.
  • scobolamine which is known to cause amnesia
  • 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.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne des 1-amino-2-imino-méthyl-6-oxo-1,2,3,6-tétrahydro-7H-purines représentées par la formule générale (I) et un améliorant des fonctions d'apprentissage et de mémoire contenant ce produit comme principe actif. Dans cette formule, R représente un hydrogène, alkyle inférieur ou un phényle éventuellement substitué.
PCT/JP1996/002132 1995-08-04 1996-07-29 1-amino-2-imino-methyl-6-oxo-1,2,3,6-tetrahydro-7h-purines WO1997006169A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP21950895 1995-08-04
JP7/219508 1995-08-04

Publications (1)

Publication Number Publication Date
WO1997006169A1 true WO1997006169A1 (fr) 1997-02-20

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PCT/JP1996/002132 WO1997006169A1 (fr) 1995-08-04 1996-07-29 1-amino-2-imino-methyl-6-oxo-1,2,3,6-tetrahydro-7h-purines

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WO (1) WO1997006169A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040004863A (ko) * 2002-07-05 2004-01-16 삼성중공업 주식회사 선박용 이중반전 프로펠러 동력전달장치

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07242667A (ja) * 1994-03-07 1995-09-19 Yamasa Shoyu Co Ltd １−アミノ−２−イミノ−３−メチル−６−オキソ−１，２，３，６−テトラヒドロ−７ｈ−プリン類

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH07242667A (ja) * 1994-03-07 1995-09-19 Yamasa Shoyu Co Ltd １−アミノ−２−イミノ−３−メチル−６−オキソ−１，２，３，６−テトラヒドロ−７ｈ−プリン類

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20040004863A (ko) * 2002-07-05 2004-01-16 삼성중공업 주식회사 선박용 이중반전 프로펠러 동력전달장치

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