• 专利附录
  • 专利说明
  • 权利要求
  • 类似技术
  • 同族专利
  • 引用文献
  • 法律状态
  • 优先权
    • 专利摘要:
    The present invention relates to novel purine derivatives which selectively inhibit PDE IV and their pharmacologically acceptable salts.
    公开号:KR20030072251A
    申请号:KR1020030013401
    申请日:2003-03-04
    公开日:2003-09-13
    发明作者:켄이치미야모토；히로유키사와니시；히로카즈스즈끼；마나부야마모토；스스무시무라
    申请人:롯데제과주식회사；가부시끼가이샤 롯데；
    IPC主号:
    专利说明:

    New Purine Derivatives {NOVEL PURINE DERIVATIVE}
    [1] The present invention relates to novel purine derivatives which selectively inhibit PDE IV and their pharmacologically acceptable salts.
    [2] Phosphodiesterase (PDE) is a generic term for enzymes that hydrolyze phosphate diesters and convert them into phosphate monoesters. Type I PDEs (calcium-calmodulin dependent cyclic AMP PDEs), type III PDEs (cyclic GMP inhibitors) Cyclic AMP PDE) and type IV PDE (cyclic AMP specific PDE). Type IV PDE is a PDE that specifically acts on cyclic AMP, which is known to increase intracellular cyclic AMP by inhibition of type IV PDE and consequently to relax vascular and vascular smooth muscle [Shahid et al. , Br. J. Pharmacol ., 104: 471-477, 1991]. In addition, the present inventors have confirmed that an increase in intracellular cyclic AMP increases bone density in osteoporosis model animals or promotes bone formation in osteoblast culture systems [Miyamoto, K. et al., Biochem. Pharmacol ., 54 : 613-617, 1997; Waki, Y. et al., Jpn. J. Pharmacol ., 79 : 477-483, 1999].
    [3] On the other hand, if the physiological phenomenon that catecholamine acts on adipose tissue and promotes lipolysis is based on the theory that cyclic AMP is a secondary messenger, an increase in intracellular cyclic AMP due to inhibition of type IV PDE may result in lipolytic action. It is also effective in improving obesity.
    [4] PDE IV inhibitors known to date include xanthine derivatives [Nicholson, CD et al., Br. J. Pharmacol ., 97 : 889-897, 1989; Mtyamoto, K. et al. Eur. J. Pharmacol ., 267 : 317-322, 1994; Miyamoto, K. et al., Biochem. Pharmacol ., 48 : 1219-1223, 1994; Miyamoto, K. et al., Biol. Pharm. Bull. 18 : 431-434, 1995; Sanae, F. et al., Jpn. J. Pharmacol. , 69 : 75-82, 1995], Phenylpyrrolidone derivatives based on rolyphram [Wachtel, H., Psychopharmacology , 77 : 309-316, 1982; Reeves, ML et al., Biochem. J. , 241 : 535 to 541, 1987], pyridpyrimidinedione derivatives [Lowe, III. JA et al., J. Med. Chem. , 34 : 624-628, 1991] and naphthyridinone derivatives [Suzuki, F. et al., J. Med. Chem ., 35 : 4866-4874, 1992: Matsuura, A. et al., Biol. Pharm. Bull ., 17: 498-503, 1994].
    [5] The inventors of the present invention, while studying the structure-activity correlation of the alkyl xanthine derivative, confirmed that the PDE IV inhibitory effect and organ relaxation effect were significantly increased by extending the alkyl group at the N-1 position from the ethyl group to the propyl group [Sakai, R. et. al., J. Med. Chem ., 35 : 4039-4044, 1992; Miyamoto, K. et al., Biol. Pharm. Bull ., 18 : 431-434, 1995. This suggests that the interaction of the alkyl group at the 1-position and the oxo group at the 2-position or the 6-position is partly involved in the active expression.
    [6] On the other hand, in the structure-activity correlation study of the condensed cyclic purine derivative, the purine derivative substituted with the alkyl group at the 9 position has a stronger inhibitory effect on the PDE IV than the purine derivative substituted with the 7 position, and the size of the condensed hetero ring is It was confirmed that the larger the inhibitory effect. In addition, the inhibitory effect on the PDE IV of the condensed cyclic purine derivative is stronger in the order of the condensed hetero ring in the order of the tetrazole ring, the dihydroimidazole ring, and the imidazole ring, but in the case of the imidazole ring, It was also confirmed that the selectivity to PDE IV was lowered due to the inhibitory activity [Sawanishi, H. et al., J. Med. Chem. , 40 : 3248-353, 1997]. This suggests that purine derivatives substituted with alkyl groups at positions 3 and 7 or positions 3 and 9 and condensed with dihydroimidazole rings as hetero rings are involved in the active expression of selective PDE IV inhibition.
    [7] Accordingly, an object of the present invention is to provide a compound that selectively inhibits PDE IV by synthesizing a novel purine derivative represented by Chemical Formula 1.
    [8] The present invention is characterized by a compound represented by the following formula (1) or a pharmacologically acceptable salt thereof:
    [9]
    [10] In Formula 1, R 1 , R 2 and R 3 are each independently a hydrogen atom, or a C 1 to C 6 alkyl group which is unsubstituted or substituted with a substituent selected from a hydroxyl group, a lower alkyloxy group and an acyl group, or A phenyl group is represented, and R 4 and R 5 each independently represent a C 1 to C 6 alkyl group or a phenyl group which is optionally substituted with a hydroxyl group, a lower alkyloxy group and an acyl group.
    [11] In another aspect, the present invention is characterized by another compound or pharmacologically acceptable salt represented by the formula (2):
    [12]
    [13] In Formula 2, R 1 and R 2 each independently represent a hydrogen atom or a C 1 to C 6 alkyl group or a phenyl group which is unsubstituted or substituted with a substituent selected from a hydroxyl group, a lower alkyloxy group and an acyl group. ; n represents 2 or 3.
    [14] Referring to the present invention in more detail as follows.
    [15] In the compound represented by the formula (1) or (2) according to the present invention, as the lower alkyloxy group which can substitute the alkyl group of C 1 to C 6 represented by R 1 , R 2 , R 3 , R 4 and R 5 For example, a methoxy group, an ethoxy group, n-propoxy group, isopropoxy group, n-butoxy group, isobutoxy group, sec-butoxy group, Tert-butoxy group, etc. are mentioned, As an acyl group, For example, acetyl group , Propionyl group, butyryl group, pentanoyl group, hexanoyl group and the like. Further, as the alkyl group of C 1 ~C 6, for example, methyl group, ethyl group, n- propyl group, isopropyl group, n- butyl group, isobutyl group, sec- butyl group, tert- butyl group, n- pentyl group, iso A pentyl group, neopentyl group, n-hexyl group, etc. are mentioned, This invention is not limited to these.
    [16] The condensed purine derivatives represented by Formula 1 or 2 according to the present invention include, for example, alkali metals such as sodium and potassium, inorganic metals such as alkaline earth metals such as calcium and magnesium, basic amino acids such as lysine and arginine, and ammonium and the like. It can be used in the form of pharmacologically acceptable non-toxic salts with organic amines and the like. In addition, the condensed purine derivative represented by Formula 1 or 2 according to the present invention can be used in the form of a pharmacologically acceptable non-toxic acid addition salt. Examples of such acid addition salts include inorganic acid salts such as hydrochloride, sulfate, hydrobromide and phosphate; Organic acid salts such as formate, acetate, succinate, maleate, purinmarate, malate, citrate, mandelate, glutamine, aspartinate, methanesulfonate, and p-toluenesulfonate. The invention is not limited to these.
    [17] On the other hand, the condensed purine derivative represented by Formula 1 or 2 according to the present invention can be synthesized using a general synthesis method as shown in the following schemes 1-3.
    [18]
    [19]
    [20]
    [21] In addition, in the preparation method according to Scheme 1, 3-alkyl-4- (1,2,4-triazol-4-yl) purin-2-one used as a starting material may be prepared by the method shown in Scheme 4 below. It can synthesize | combine it , and it is shown to the Reference Examples 1-4 specifically [Miles, RW et al., J. 0rg. Chem. , 60 : 7066, 1995].
    [22]
    [23] In the above, R is an alkyl group (carbon number = n), and R 'is an alkyl group (carbon number = n + 1).
    [24] In addition, the manufacturing method of other starting raw materials is shown in the following reference example.
    [25] Although the specific example of the novel condensed purine derivative represented by the said Formula (1) or (2) according to this invention is listed below, the compound of this invention is not limited to these compounds.
    [26] Compound 1: 8-methyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [27] Compound 2: 8-methyl-3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo- [2,1-i] purin-5-one
    [28] Compound 3: 8-methyl-1,4-dipropyl-4,5,7,8-tetrahydro-1H-imidazo [2,1-i] purin-5-one
    [29] Compound 4: 7-methyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [30] Compound 5: 7-methyl-3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo- [2,1-i] purin-5-one
    [31] Compound 6: 7-methyl-1,4-dipropyl-4,5,7,8-tetrahydro-1H-imidazo [2,1-i] purin-5-one
    [32] Compound 7: 4-propyl-4,5,7,9-tetrahydro-1H-imidazo- [1,2-a] purin-9-one
    [33] Compound 8: 4-propyl-4,6,7,10-tetrahydro-1H-pyrimid- [1,2-a] purin-10-one
    [34] Compound 9: 1,4-dipropyl-4,6,7,9-tetrahydro-1H-imidazo- [1,2-a] purin-9-one
    [35] Compound 10: 1,4-Dipropyl-4,6,7,10-tetrahydro-1H-pyrimid- [1,2-a] purin-10-one.
    [36] Type I PDE (Calcium-Calmodulin Dependent Cyclic AMP PDE), Type III PDE (Cyclic GMP Inhibitory Cyclic AMP PDE) and Types Isolated from Mormot Cerebral and Mormot Hearts for Novel Condensed Purine Derivatives According to the Invention The inhibitory effect on the IV PDE (cyclic AMP specific PDE) activity was tested according to the method of Test Example 1 below.
    [37] In addition, the novel condensed purine derivatives according to the present invention induced pro-fat culture cells into mature adipocytes by the method of the following Test Example 2, and tested the lipolytic action with the change of the extracellular glycerol concentration as an indicator.
    [38] In addition, in the PDE inhibition test, XT-044 (Control 1), which is known as a Type IV PDE inhibitor, is described in Miyamoto, K. et al., Biochem. Pharmacol ., 48 : 1219-1223, 1994]. 3-isobutyl- also known as Denbufylline (Control 2), Rolipram (Control 3), Amrinone (Control 4) known as type III PDE inhibitors, and non-selective PDE inhibitors. 1-Methylxanthine (IBMX) (Control 5) was used as a control compound. In the lipolysis test, in addition to the control compound, isoprenin (active control 1), which is known to stimulate lipolysis, was added as an active control compound.
    [39] The structure of the control compound used in the test examples of the present invention is as follows:
    [40]
    [41] According to the test results of the present invention, all of the compounds of the present invention showed little inhibitory action against type III PDE, only compound 2 and compound 3 showed weak inhibitory action against type I PDE. On the other hand, compounds 2 and 3 showed comparable inhibitory activity to the control compounds 1, 2 and 3, which are type IV PDE inhibitors, and it became clear that they were relatively selective for type IV PDE activity. In addition, compounds 5, 6 and 9 also selectively inhibited type IV PDE activity.
    [42] In the lipolytic action, when the lipolysis rate of the active control 1 compound was 100%, the compounds 2 and 3 showed moderate lipolysis, and the compounds 5 and 6 showed weak lipolysis. In addition, the actions of Compounds 2 and 3 were less than those of Control 2, but on the same level as those of Controls 1 and 3. Accordingly, it has been found that the compounds of the present invention have an effect of promoting lipolysis in adipocytes, and have been found to be applicable to improving obesity by using these compounds alone or in combination.
    [43] In addition, these compounds are also expected to act to increase intracellular cyclic AMP by selectively inhibiting type IV PDE activity, and thus, applications as a bronchodilator or osteoporosis therapeutic agent are also expected.
    [44] When using the novel purine derivatives of the present invention or pharmacologically acceptable salts thereof as pharmaceutical compositions, oral preparations, such as powders, granules, granules, tablets, coated tablets, capsules, and syrups, may be used as a method of administration. And external preparations such as ointments and patchs, and injection preparations. Formulations can be prepared according to conventional methods using conventional formulation carriers.
    [45] To prepare oral preparations, the compounds of the present invention, excipients, binders, disintegrants, lubricants, coloring agents, copulation agents, and the like are added, and powders, fine granules, granules, tablets, coating powders and capsules are prepared in a conventional manner. , Syrup.
    [46] As the excipient, for example, lactose, corn starch, white sugar, glucose, mannitol, sorbitol, crystalline cellulose, silicon dioxide and the like can be used. As the binder, for example, polyvinyl alcohol, polyvinyl ether, methyl cellulose, ethyl cellulose, gum arabic, tragacanth, gelatin, shrak, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl pyrrolidone, polypropylene glycol, Polyoxyethylene block polymer, meglumine and the like can be used. As the disintegrant, for example, starch, agar, gelatin powder, crystalline cellulose, calcium carbonate, sodium bicarbonate, calcium citrate, dextrin, pectin, carboxymethyl cellulose calcium and the like can be used. As the lubricant, for example, magnesium stearate, talc, polyethylene glycol, silica, hardened vegetable oil and the like can be used. As a coloring agent, what can be added to a pharmaceutical, for example can be used. And as a copper | coating agent, a cocoa powder, peppermint brain, an aromatic acid, peppermint oil, a dragon's brain, cinnamon powder etc. can be used, for example. These formulations may be appropriately coated according to sugar and other needs.
    [47] In addition, in order to be formulated as an injection, a compound according to the present invention may be formulated according to a conventional method by adding a pH adjuster, a solubilizer, an isotonic agent, and the like as necessary, and a dissolution aid, a stabilizer, and the like.
    [48] The method for producing the external preparation is not particularly limited, and can be produced according to a conventional method. As the base raw material, raw materials used in various medicines, quasi-drugs, cosmetics, and the like can be used. Examples of the base material include animal and vegetable oils, mineral oils, ester oils, waxes, higher alcohols, fatty acids, silicone oils, surfactants, phospholipids, alcohols, water-soluble polymers, clay minerals and purified water. In addition, a pH adjuster, an antioxidant, a chelating agent, a preservative, an antiseptic agent, a coloring agent, a flavoring agent, etc. can be added as needed.
    [49] In addition, the dosage in the case of using the compound of the present invention as a pharmaceutical composition can be changed depending on symptoms, age, weight, administration method, and the like, and an appropriate dosage is determined by a doctor, but usually by oral administration to an adult. To about 100 mg / day, and about 1 to 50 mg / day by parenteral administration.
    [50] The present invention as described above will be described in more detail by the following Reference Examples, Examples and Test Examples, but the present invention is not limited thereto.
    [51] Reference Example 1 4 (5) -propylamino-1H-imidazole-5 (4) -carbonitrile
    [52] 1) A solution of 20 g of 4 (5) -amino-1H-imidazole-5 (4) -carbonitrile, 20 g of propionaldehyde, and 100 mL of EtOH was stirred for 2 h on an oil bath of external oil of 60 to 70 ° C. After the reaction, the mixture was concentrated under reduced pressure, and the precipitate precipitated by suction, washed with benzene.
    [53] 2) In 300 mL of EtOH, 4.5 g of NaBH 4 were slowly added under ice-cooled stirring conditions, and the imine solid obtained in 1) was slowly added at the same temperature. It was further refluxed for 4 hours. After the reaction, water was added, the precipitated solids were removed, the filtrate was concentrated under reduced pressure, and the residue was dried in a solution of AcOEt: CH 3 CN (1: 1), separated by silica gel column, and recrystallized with CH 2 Cl 2 . This gave 18.5 g (67%) of (5) -propylamino-1H-imidazole-5 (4) -carbonitrile (compound 4).
    [54] mp 101-102 ° C .; Elemental analysis (C 7 H 10 N 4 ) calc. C, 55.98: H, 6.71: N, 37.31; Found C, 56.02: H, 6.74: N, 37.35; 1 H-NMR (CD 3 OD) δ 1.00 (3H, t, J = 8), 1.60 (2H, sep, J = 8), 3.27 (2H, t, J = 8), 7.23 (1H, s); IR (KBr-TAB, cm −1 ) 3072, 2220, 1626.
    [55] Reference Example 2: 4 (5)- 3 N-benzoyl- One N-propylureido-1H-imidazole-5 (4) -carbonitrile
    [56] 0.50 g (0.0033 mol) of 4 (5) -propylamino-1H-imidazole-5 (4) -carbonitrile obtained in Reference Example 1 was dissolved in 10 mL of AcOEt, and 0.50 g (0.0034) of benzoyl isocyanate with stirring at room temperature. mol) was added and stirred for 20 hours. After the reaction, precipitate precipitate was aspirated, washed with isopropyl ether, and recrystallized with MeOH to give 4 (5) -3 N-benzoyl- 1 N-propylureido-1H-imidazole-5 (4) -carboni Yield 0.08 g (91%) of tril.
    [57] mp 177-178 ° C; Elemental Analysis (C 15 H 15 N 5 O 2 ) Calculated C, 60.06: H, 5.09: N, 23.56; Found C, 60.58: H, 4.99: N, 23.47; 1 H-NMR (DMSO-d 6 ) δ 0.89 (3H, t, J = 7.3), 1.56 (2H, sep, J = 7.3), 3.75 (2H, t, J = 7.3), 7.40 to 7.90 (5H, m), 8.30 (1 H, s); IR (KBr-TAB, cm -1 ) 3072, 2220, 1732.
    [58] Reference Example 3 6-Amino-3-propylpurin-2-one
    [59] 5.90 g (0.022 mol) of 4 (5) -3 N-benzoyl- 1 N-propylureido-1H-imidazole-5 (4) -carbonitrile obtained in Reference Example 2 was added to 60 mL of EtOH and 60 mL of concentrated ammonia water. In a solution of and stirred at room temperature for 2 days. After the reaction, the solvent was distilled off under reduced pressure, and the residue was recrystallized from MeOH to obtain 3.40 g (80%) of 6-amino-3-propylpurin-2-one.
    [60] mp> 300 ° C .; Elemental analysis (C 8 H 11 N 5 O) calc. C, 49.73: H, 5.74: N, 36.25; Found C, 49.65: H, 5.73: N, 36.27; 1 H-NMR (DMSO-d 6 ) δ 0.89 (3H, t, J = 7.3), 1.65 (2H, sep, J = 7.3), 3.90 (2H, t, J = 7.3), 7.85 (1H, s) , 7.50 (1H, broad singlet); IR (KBr-TAB, cm −1 ) 3328, 3128, 1662, 1606, 1498.
    [61] Reference Example 4: 3-propyl-4- (1,2,4-triazol-4-yl) purin-2-one
    [62] 1.02 g (0.0053 mol) of 6-amino-3-propylpurin-2-one obtained in Reference Example 3 was suspended in 20 mL of pyridine, 1.4 g (0.016 mol) of diformylhydrazine, 8.6 g of trimethylsilyl chloride ( 0.08 mol) and 3.7 g (0.037 mol) of triethylamine were added sequentially, and it stirred at 100-110 degreeC for 20 hours. After the reaction, the solvent was distilled off under reduced pressure, and 30 mL of water and 20 mL of CHC1 3 were added to the residue to suction off the insoluble matter. 0.60 g (46%) of 3-propyl-4- (1,2,4-triazol-4-yl) purin-2-one (colorless prism crystal) was obtained by recrystallization of the obtained crude product with MeOH-H 2 O. Obtained.
    [63] mp 263-264 ° C .; Elemental analysis (C 10 H 11 N 7 O) calc. C, 48.98: H, 4.52: N, 39.98; Found C, 48.87: H, 4.53: N, 39.83; 1 H-NMR (DMSO-d 6 ) δ 0.93 (3H, t, J = 7.3), 1.72 (2H, sext, J = 7.3), 4.05 (2H, t, J = 7.3), 8.30 (1H, s) , 9.44 (2H, s); IR (KBr-TAB, cm −1 ) 3500,1666.
    [64] Reference Example 5: 6-[(2-hydroxy-1-methyl) ethyl] amino-3-propylpurin-2-one
    [65] 1.50 g (0.0061 mol) of 3-propyl-4- (1,2,4-triazol-4-yl) purin-2-one obtained in Reference Example 4 was dissolved in 30 mL of pyridine, and 2-amino- 5 mL of 1-propanol was added to reflux overnight. After the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column (CHCl 3 : developing solvent of MeOH (3: 1)) to give 6-[(2-hydroxy-1-methyl) ethyl] amino-3- 1.15 g (75%) of propylpurin-2-one were obtained.
    [66] mp 296-297 ° C .; Elemental Analysis (C 11 H 17 N 5 O 2 ) Calculated C, 52.58: H, 6.82: N, 27.87; Found C, 57.92: H, 6.34: N, 22.56; 1 H-NMR (DMSO-d 6 ) δ 0.94 (3H, t, J = 7.3), 1.17 (3H, d, J = 6.8), 1.62 (2H, sext, J = 7.3), 3.88 (2H, t, J = 7.1), 4.23 (1 H, br s), 4.95 (1 H, br s), 7.23 (1 H, br s), 7.88 (1 H, s); IR (KBr-TAB, cm −1 ) 3325, 1635, 1612.
    [67] Reference Example 6: 6- (2-hydroxypropyl) amino-3-propylpurin-2-one
    [68] 1.50 g (0.0061 mol) of 3-propyl-4- (1,2,4-triazol-4-yl) purin-2-one obtained in Reference Example 4 was dissolved in 30 mL of pyridine, and 1-amino- 1 mL of 2-propanol was added to reflux overnight. After the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column (CHCl 3 : developing solvent of MeOH (3: 1)) to give 6-[(2-hydroxy-1-methyl) ethyl] amino-3- 1.25 g (81%) of propylpurin-2-one were obtained.
    [69] mp 289-290 ° C .; Elemental Analysis (C 11 H 17 N 5 O 2 ) Calculated C, 52.58: H, 6.82: N, 27.87; Found C, 57.92: H, 6.34: N, 22.56; 1 H-NMR (DMSO-d 6 ) δ 0.85 (3H, t, J = 7.3), 1.10 (3H, d, J = 6.2), 1.62 (2H, sext, J = 7.3), 3.87 (2H, t, J = 7.1), 5.10 (1 H, br s), 7.60 (1 H, br s), 7.88 (1 H, s); IR (KBr-TAB, cm −1 ) 3448, 3309, 3238, 1643, 1614.
    [70] Reference Example 7 6-Chloro-3,7-dipropylpurin-2-one
    [71] 13.6 g of 3,7-dipropylxanthine was added to 60 mL of POCl 3 and refluxed for 2 hours. After the reaction, POCl 3 was distilled off under reduced pressure, and the residue was poured into iced water and alkalinized with NaHCO 3 to extract the CH 2 Cl 2 soluble part, washed with water, dried over Na 2 SO 4, and then the solvent was distilled off. The residue was reextracted with CH 2 Cl 2 -IPE to give 13.5 g (92%) of 6-chloro-3,7-dipropylpurin-2-one (colorless acicular crystal).
    [72] mp 109-110 ° C .; Elemental analysis (C 11 H 15 N 4 OCl) calcd C, 51.87: H, 5.94: N, 22.00; Found C, 51.72: H, 6.07: N, 21.85; 1 H-NMR (CDCl 3 ) δ 1.0 (3H, t, J = 8), 1.05 (3H, t, J = 8), 2.0 (4H, sex, J = 8), 4.50 (4H, t, J = 8), 8.0 (1H, s); IR (KBr-TAB, cm −1 ) 1664, 1598.
    [73] Reference Example 8: 6-[(2-hydroxy-1-methyl) ethyl] amino-3,7-dipropylpurin-2-one
    [74] O.51 g (O.O020 mol) of 6-chloro-3,7-dipropylpurin-2-one obtained in Reference Example 7 was dissolved in 10 mL of pyridine, and 4 mL of 2-amino-1-propanol was dissolved. And refluxed overnight. After the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (3: 1)) to give 6-[(2-hydroxy-1-methyl) ethyl] amino-3, 0.35 g (60%) of 7-dipropylpurin-2-one was obtained.
    [75] Mass m / z (C 14 H 23 N 5 O 2 ) Theoretical 293.1852, found 293.1857; 1 H-NMR (CDCl 3 ) δ 0.95 (3H, t, J = 7.3), 0.98 (3H, t, J = 7.3), 1.27 (3H, d, J = 6.6), 1.64 to 2.03 (4H, m) , 2.45 (1H, broad singlet), 3.50-4.28 (7H, singlet), 4.49 (1H, broad singlet), 7.47 (1H, broadly); IR (KBr-TAB, cm −1 ) 3390, 1633.
    [76] Reference Example 9: 6- (2-hydroxypropyl) amino-3,7-dipropylpurin-2-one
    [77] O.76 g (O.O030 mol) of 6-chloro-3,7-dipropylpurin-2-one obtained in Reference Example 7 was dissolved in 10 mL of pyridine, and 6 mL of 1-amino-2-propanol was dissolved. And refluxed overnight. After the reaction, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (3: 1)) to give 6- (2-hydroxypropyl) amino-3,7-dipropylpurine-. 0.52 g (59%) of 2-one was obtained.
    [78] Mass m / z (C 14 H 23 N 5 O 2 ) Theorem 293.1852, found 293.1856; 1 H-NMR (CDCl 3 ) δ 0.95 (6H, t, J = 7.1), 1.18 (3H, d, J = 6.2), 1.64 to 2.03 (4H, m), 2.70 (1H, br s), 3.20 to 3.48 (2H, m), 3.73-3.31 (5H, m), 6.07 (1H, br s), 7.48 (1H, s); IR (KBr-TAB, cm −1 ) 3323, 1628, 1610, 1587.
    [79] Reference Example 1O: 5-propylaminoimidazole-4-carboxamide
    [80] 1.0 g (0.0062 mol) of 5-aminoimidazole-4-carboxamide hydrochloride was dissolved in 10 mL of methanol, 0.31 g (0.0049 mol) of NaBH 3 CN and 0.43 g (0.0074 mol) of propionaldehyde were added for 24 hours at room temperature. Stirred. After the reaction, the insolubles were suctioned off and the solvent was concentrated under reduced pressure. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (6: 1)), and the obtained crude product was recrystallized from CHCl 3 -MeOH to give 0.66 g of 5-propylaminoimidazole-4-carboxamide ( 63%) was obtained.
    [81] mp 155-156 ° C; Elemental analysis (C 7 H 12 N 4 O) calc. C, 49.99: H, 7.19: N, 33.31; Found C, 49.72: H, 7.01: N, 33.38; 1 H-NMR (DMSO-d 6 ) δ 0.88 (3H, t, J = 7.1), 1.49 (2H, sext, J = 7.1), 3.14 (2H, t, J = 7.1), 6.00 (1H, br s ), 6.64 (2H, broad singlet), 7.20 (1 H, broaden), 11.57 (1H, broaden); IR (KBr-TAB, cm −1 ) 3413, 3351, 3302, 1651, 1631.
    [82] Reference Example 11: 5- [N- (benzoylthiocarbamoyl) -N-propylamino] imidazole-4-carboxamide
    [83] 0.66 g (0.0039 mol) of 5-propylaminoimidazole-4-carboxamide obtained in Reference Example 10 was suspended in 15 mL of CH 2 Cl 2 , and 0.77 g (0.0047 mol) of benzoylisothiocyanate was added dropwise thereto. It was added and stirred at room temperature for 6 hours. Precipitation was filtered off and recrystallized with methanol to give 0.88 g (68%) of 5- (N'-benzoylthiocarbamoyl) propylaminoimidazole-4-carboxamide.
    [84] mp 185-186 ° C; Elemental analysis (C 16 H 17 N 5 O 2 S) calcd C, 54.36: H, 5.17: N, 21.13; Found C, 54.14; H, 5. 12: N, 20.78; 1 H-NMR (DMSO-d 6 ) δ 0.82 (3H, t, J = 7.2), 1.59 (2H, sext, J = 7.2), 3.16 (2H, t, J = 7.2), 6.00 (1H, br s ), 6.64 (2H, broad singlet), 7.52 to 8.00 (8H, broad-range), 11.13 (1H, broad singlet); IR (KBr-TAB, cm -1 ) 3344, 3284, 3234, 1658
    [85] Reference Example 12 3-propyl-2-thioxanthine
    [86] 2.7 g (0.0082 mol) of 5- (N'-benzoylthiocarbamoyl) propylaminoimidazole-4-carboxamide obtained in Reference Example 11 was dissolved in 30 mL of 1M NaOH and refluxed for 3 hours. After the reaction was neutralized with hydrochloric acid, and the precipitate was filtered off. The crude product was recrystallized from methanol to give 1.36 g (79%) of the title compound 3-propyl-2-thioxanthine.
    [87] mp 185-186 ° C; Elemental analysis (C 8 H 10 N 4 OS) calcd C, 45.70: H, 4.79: N, 26.65; Found C, 45.55: H, 4.83: N, 26.69; 1 H-NMR (DMSO-d 6 ) δ 0.91 (3H, t, J = 7.2), 1.78 (2H, sext, J = 7.2), 4.42 (3H, t, J = 7.2), 8.16 (1H, s) , 12.37 (1H, broad singlet); IR (KBr-TAB, cm -1 ) 3471, 1654, 1620
    [88] Reference Example 13: 3-propyl-2-thiomethylxanthine
    [89] 0.65 g (0.0031 mol) of 3-propyl-2-thioxanthine obtained in Reference Example 12 was dissolved in 3 mL of 2M NaOH, and 0.47 g (0.0037 mol) of dimethyl sulfuric acid was added thereto, followed by stirring at room temperature for 1 hour. After the reaction was neutralized with acetic acid, the precipitate was filtered off and recrystallized from AcOEt-MeOH to give 0.41 g (59%) of the title compound 3-propyl-2-thiomethylxanthine.
    [90] mp 257-258 ° C; Elemental analysis (C 9 H 12 N 4 OS) calcd C, 48.20: H, 5.39: N, 24.98; Found C, 48.31: H, 5.27: N, 24.89; 1 H-NMR (CDCl 3 ) δ 0.92 (3H, t, J = 7.2), 1.80 (2H, sext, J = 7.2), 2.56 (3H, s), 4.18 (3H, t, J = 7.2), 8.10 (1H, s), 13.50 (1H, broad singlet); IR (KBr-TAB, cm -1 ) 3467, 1630, 1618
    [91] Reference Example 14 2-hydroxyethylamino-3-propylpurin-6-one
    [92] 0.40 g (0.0018 mol) of 3-propyl-2-thiomethylxanthine obtained in Reference Example 13 and 2-aminoethanol were mixed in 10 mL of pyridine to reflux overnight. After the reaction was concentrated under reduced pressure, and the residue was recrystallized from AcOEt-MeOH to give 0.35 g (82%) of 2-hydroxyethylamino-3-propylpurin-6-one.
    [93] mp 253 to 254 ° C .; Elemental analysis (C 10 H 15 N 5 O 2 ) calc. C, 50.62: H, 6.37: N, 29.52; Found C, 50.33: H, 6.40: N, 29.67; 1 H-NMR (DMSO-d 6 ) δ 0.88 (3H, t, J = 7.2), 1.70 (2H, sext, J = 7.2), 3.38-3.62 (2H, m), 4.05 (2H, t, J = 7.2), 4.90 (1 H, br s), 7.84 (1 H, s), 12.98 (1 H, br s); IR (KBr-TAB, cm -1 ) 3448, 3228, 3164, 1630, 1606
    [94] Reference Example 15 2-hydroxypropylamino-3-propylpurin-6-one
    [95] 0.47 g (0.0021 mol) of 3-propyl-2-thiomethylxanthine obtained in Reference Example 13 and 3-aminopropanol were mixed and refluxed in 10 mL of pyridine overnight. After the reaction, the mixture was concentrated under reduced pressure and the residue was recrystallized from AcOEt-MeOH to give 0.32 g (61%) of 2-hydroxypropylamino-3-propylpurin-6-one.
    [96] mp 194-195 ° C .; Elemental Analysis (C 11 H 17 N 5 O 2 ) Calculated C, 52.58: H, 6.82: N, 27.87; Found C, 52.73: H, 6.70: N, 27.77; 1 H-NMR (DMSO-d 6 ) δ 0.88 (3H, t, J = 7.2), 1.45-1.83 (4H, m), 4.04 (2H, t, J = 7.3), 4.68 (1H, br s), 6.97 (1 H, br s), 7.84 (1 H, s), 12.69 (1 H, br s); IR (KBr-TAB, cm -1 ) 3421, 3282, 3337, 1681
    [97] Reference Example 16: 3-phenyl-6-thioxanthine
    [98] 2 g (0.0088 mol) of 3-phenylxanthine and 2.42 g (0.0109 mol) of phosphorus pentasulfide were mixed in 30 mL of pyridine and refluxed for 3 hours. After the reaction, the mixture was concentrated under reduced pressure and the residue was recrystallized to obtain 1.86 g (87%) of 3-phenyl-6-thioxanthine.
    [99] mp> 290 ° C .; Elemental analysis (C 11 H 8 N 4 OS) calcd C, 54.09: H, 3.30: N, 22.94; Found C, 53.88: H, 3.52: N, 22.71; 1 H-NMR (DMSO-d 6 ) δ 7.24-7.75 (6H, m), 8.77 (1H, br s), 12.50 (1H, br s); IR (KBr-TAB, cm -1 ) 3460, 3437, 1679, 1601
    [100] Reference Example 17 6-[(2-hydroxy-1-methyl) ethyl] amino-3-phenylpurin-2-one
    [101] Instead of 6-chloro-3,7-dipropylpurin-2-one in Reference Example 8, 2-amino-1- was obtained by using 3-phenyl-6-thioxanthine obtained in Reference Example 16 as a raw material. By reacting with propanol, the same procedure as in Reference Example 8 was carried out to obtain 6-[(2-hydroxy-1-methyl) ethyl] amino-3-phenylpurin-2-one.
    [102] Reference Example 18 6- (2-hydroxypropyl) amino-3-phenylpurin-2-one
    [103] Instead of 6-chloro-3,7-dipropylpurin-2-one in Reference Example 9, 1-amino-2 was obtained by using 3-phenyl-6-thioxanthine obtained in Reference Example 16 as a raw material. Reaction with -propanol was carried out in the same manner as in Reference Example 8 to obtain 6- (2-hydroxypropyl) amino-3-phenylpurin-2-one.
    [104] Reference Example 19 8-Methyl-4-phenyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [105] 0.57 g (0.0020 mol) of 6-[(2-hydroxy-1-methyl) ethyl] amino-3-phenylpurin-2-one obtained in Reference Example 17 was mixed with 0.30 g (0.0030 mol) of triethylamine. And methanesulfonyl chloride 0.34 g (0.0030 mol) was added under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column and the crude product was recrystallized to give 8-methyl-4-phenyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one 0.27 g (50%) was obtained.
    [106] Reference Example 2O: 7-Methyl-4-phenyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [107] 0.29 g (0.0010 mol) of 6- (2-hydroxypropyl) amino-3-phenylpurin-2-one obtained in Reference Example 18 and 0.15 g (0.0015 mol) of triethylamine were mixed, and methanesulfonyl chloride 0.18 g (0.0015 mol) was added under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column and the crude product was recrystallized to give 7-methyl-4-phenyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one 0.13 g (50%) was obtained.
    [108] Example 1 8-Methyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [109]
    [110] 0.63 g (0.0025 mol) of 6-[(2-hydroxy-1-methyl) ethyl] amino-3-propylpurin-2-one obtained in Reference Example 5 was mixed with 0.30 g (0.0030 mol) of triethylamine. And methanesulfonyl chloride 0.34 g (0.0030 mol) was added under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (6: 1)) and the crude product was recrystallized from ethanol to give 8-methyl-4-propyl-4,5,7,8-tetrahydro-1H. -32 g (55%) of -imidazo- [2,1-i] purin-5-one were obtained.
    [111] mp 248-249 ° C .; Elemental analysis (C 11 H 15 N 5 O) calc. C, 56.64: H, 6.48: N, 30.02; Found C, 56.57: H, 6.51: N, 29.97; 1 H-NMR (CDCl 3 ) δ0.87 (3H, t, J = 7.3), 1.30 (3H, d, J = 5.9), 1.68 (2H, sext, J = 7.3), 3.92 (2H, t, J = 7.3), 4.05-4.34 (1H, m), 7.60 (1H, s), 12.40 (1H, br s); IR (KBr-TAB, cm -1 ) 3423, 1708, 1664.
    [112] Example 2: 7-Methyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [113]
    [114] 3.20 g (0.013 mol) of 6- (2-hydroxypropyl) amino-3-propylpurin-2-one obtained in Reference Example 6 and 1.5 g (0.015 mol) of triethylamine were mixed and methanesulfonyl chloride 1.75 g (0.015 mol) was added under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (6: 1)), and the crude product was recrystallized from ethanol to give 7-methyl-4-propyl-4,5,7,8-tetrahydro-. 1.62 g (55%) of 1H-imidazo- [2,1-i] purin-5-one were obtained.
    [115] mp 272-273 ° C; Elemental analysis (C 11 H 15 N 5 O) calc. C, 56.64: H, 6.48: N, 30.02; Found C, 56.71: H, 6.66: N, 29.94; 1 H-NMR (CDCl 3 ) δ 0.87 (3H, t, J = 7.3), 1.38 (3H, d, J = 6.1), 1.68 (2H, sext, J = 7.3), 4.02 (2H, t, J = 7.3), 4.47 to 4.66 (1 H, m), 7.69 (1 H, s), 12.65 (1 H, br s); IR (KBr-TAB, cm −1 ) 1710, 1654.
    [116] Example 3: 8-methyl-1,4-dipropyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [117]
    [118] 0.38 g (0.0013 mol) of 6-[(2-hydroxy-1-methyl) ethyl] amino-3,7-dipropylpurin-2-one obtained in Reference Example 8 and 0.16 g (0.0016 mol) of triethylamine ) Were mixed and 0.18 g (0.0016 mol) of methanesulfonyl chloride were added under ice cooling. After stirring at room temperature for 6 hours, the reaction mixture was concentrated under reduced pressure. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (6: 1)) and the crude product was recrystallized from petroleum ether to give 8-methyl-1,4-dipropyl-4,5,7,8- 0.28 g (84%) of tetrahydro-1H-imidazo- [2,1-i] purin-5-one were obtained.
    [119] mp 128-129 ° C .; Elemental analysis (C 14 H 21 N 5 O) calc. C, 61.07: H, 7.69: N, 25.43; Found C, 61.33: H, 7.72: N, 25.38; 1 H-NMR (CDCl 3 ) δ 0.96 (3H, t, J = 7.2), 0.97 (3H, t, J = 7.2), 1.34 (3H, d, J = 6.4), 1.52 to 2.04 (4H, m) 3.45 (1H, doublet of doublets, J = 7.1, 9.1), 3.86 to 4.42 (6H, m), 7.43 (1H, s); IR (KBr-TAB, cm −1 ) 1693, 1651.
    [120] Example 4: 7-methyl-1,4-dipropyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one
    [121]
    [122] 0.38 g (0.0013 mol) of 6- (2-hydroxypropyl) amino-3,7-dipropylpurin-2-one obtained in Reference Example 9 was mixed with 0.16 g (0.0016 mol) of triethylamine, and 0.18 g (0.0016 mol) of sulfonyl chloride was added under ice cooling. It stirred at room temperature for 6 hours, and it dried under reduced pressure after reaction. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (12: 1)) to 7-methyl-1,4-dipropyl-4,5,7,8-tetrahydro-1H-imidazo- [ 0.26 g (74%) of 2,1-i] purin-5-one (viscous oil) was obtained.
    [123] Mass m / z (C 14 H 21 N 5 O) requires 275.1746, found 275.1744; 1 H-NMR (CDCl 3 ) δ 0.96 (3H, t, J = 7.4), 1.44 (3H, d, J = 5.9), 1.64 to 2.05 (4H, m), 3.64 (1H, dd, J = 4.6 , 13.7), 3.88-4.48 (6H, m), 7.45 (1H, s); IR (KBr-TAB, cm −1 ) 1691, 1658.
    [124] Example 5: 8-Methyl-3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo- [2,1-i] purin-5-one
    [125]
    [126] 0.18 g (0.00076 mol) of 8-methyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one obtained in Example 1; 0.13 g (0.00092 mol) of anhydrous K 2 CO 3 was mixed in 5 mL of DMF and 0.084 mL (0.00092 mol) of propyl bromide was added. It stirred at room temperature for 10 hours, and it concentrated under reduced pressure after reaction. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (12: 1)), and the obtained crude product was recrystallized from petroleum ether to give 8-methyl-3,4-dipropyl-4,5,7, 0.18 g (85%) of 8-tetrahydro-3H-imidazo- [2,1-i] purin-5-one was obtained.
    [127] mp 111-112 ° C .; Elemental analysis (C 14 H 21 N 5 O) calc. C, 61.07: H, 7.69: N, 25.43; Found C, 61.33: H, 7.84: N, 25.50; 1 H-NMR (CDCl 3 ) δ 0.94 (3H, t, J = 7.3), 0.97 (3H, t, J = 7.2), 1.34 (3H, d, J = 6.4), 1.60 to 2.04 (4H, m) , 3.45 (1H, doublet of doublets, J = 6.8, 10.4), 3.89-4.49 (6H, m), 7.52 (1H, s); IR (KBr-TAB, cm −1 ) 1685, 1653.
    [128] Example 6: 7-methyl-3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo- [2,1-i] purin-5-one
    [129]
    [130] 1.61 g (0.0069 mol) of 7-methyl-4-propyl-4,5,7,8-tetrahydro-1H-imidazo- [2,1-i] purin-5-one obtained in Example 2; 1.13 g (0.0082 mol) of anhydrous K 2 CO 3 were mixed in 3 mL of DMF and 0.74 mL (0.0082 mol) of propyl bromide was added. It stirred at room temperature for 10 hours, and concentrated under reduced pressure after reaction. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (12: 1)) to 7-methyl-3,4-dipropyl-4,5,7,8-tetrahydro-3H-imidazo- [ 1.61 g (85%) of 2,1-i] purin-5-one (viscous oil) were obtained.
    [131] Mass m / z (C 14 H 21 N 5 O) requires 275.1746, found 275.1744; 1 H-NMR (CDCl 3 ) δ 0.95 (3H, t, J = 7.3), 0.97 (3H, t, J = 7.2), 1.42 (3H, d, J = 6.1), 1.50-2.12 (4H, m) , 3.59 (1H, doublet of doublets, J = 4.4, 13.7), 3.82 to 4.56 (6H, m), 7.42 (1H, s); IR (KBr-TAB, cm −1 ) 1689, 1658.
    [132] Example 7: 4-propyl-4,6,7,9-tetrahydro-1H-imidazo- [1,2-a] purin-9-one
    [133]
    [134] 0.15 g (0.00063 mol) of 2-hydroxyethylamino-3-propylpurin-6-one obtained in Reference Example 14 and 0.23 g (0.0019 mol) of thionyl chloride were mixed in 30 mL of CH 2 Cl 2 at room temperature. Stir for 24 hours. After the reaction, the solvent was distilled off, the residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (3: 1)), and the obtained crude product was recrystallized from AcOEt-MeOH to obtain 4-propyl-4,5, 10 g (70%) of 6,7-tetrahydro-1H-imidazo- [1,2-a] purin-9-one was obtained.
    [135] mp 256-257 ° C .; Elemental analysis (C 10 H 13 N 5 O) calc. C, 54.78: H, 5.98: N, 31.94; Found C, 54.99: H, 6.05: N, 31.97; 1 H-NMR (DMSO-d 6 ) δ 0.95 (3H, t, J = 7.2), 1.77 (2H, sext, J = 7.2), 3.82-4.36 (6H, m), 8.24 (1H, s), 12.19 (1H, broad singlet); IR (KBr-TAB, cm −1 ) 3458, 1722, 1639.
    [136] Example 8: 4-propyl-4,6,7,10-tetrahydro-1H-pyrimid- [1,2-a] purin-10-one
    [137]
    [138] 0.50 g (0.0020 mol) of 2-hydroxypropylamino-3-propylpurin-6-one obtained in Reference Example 15 and 0.71 g (0.0060 mol) of thionyl chloride were mixed in 10 mL of CH 2 Cl 2 at room temperature. Stir for 24 hours. After the reaction, the solvent was distilled off, the residue was purified by a silica gel column (developing solvent of CHCl 3 : MeOH (3: 1)), and the obtained crude product was recrystallized from AcOEt-MeOH to give the title compound 4-propyl-4, 0.29 g (62%) of 5,6,7-tetrahydro-1H-pyrimid- [1,2-a] purin-10-one were obtained.
    [139] mp 280-281 ° C .; Elemental analysis (C 11 H 15 N 5 O) calc. C, 56.64: H, 6.48: N, 30.02; Found C, 56.33: H, 7.40: N, 29.67; 1 H-NMR (DMSO-d 6 ) δ 0.93 (3H, t, J = 7.2), 1.45 (2H, sext, J = 7.2), 1.96 (2H, quint, J = 5.6), 3.47 (2H, t, J = 5.6), 3.95 (2H, t, J = 5.6), 4.18 (2H, t, J = 7.2), 8.13 (1H, s), 12.03 (1H, br s); IR (KBr-TAB, cm −1 ) 3471, 1716, 1597.
    [140] Example 9: 1,4-dipropyl-4,6,7,9-tetrahydro-1H-imidazo- [1,2-a] purin-9-one
    [141]
    [142] 0.43 g (0.0020 mol) of 4-propyl-4,5,6,7-tetrahydro-1H-imidazo- [1,2-a] purin-9-one obtained in Example 7 and anhydrous K 2 CO 3 0.41 g (0.0029 mol) was mixed in 10 mL of DMF and 0.27 mL (0.0030 mol) of propyl bromide was added. It stirred at room temperature for 10 hours, and it concentrated under reduced pressure after reaction. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (20: 1)) and the crude product obtained was recrystallized from petroleum ether to give 1,4-dipropyl-4,5,6,7-tetrahydro 0.32 g (63%) of -1H-imidazo- [1,2-a] purin-9-one were obtained.
    [143] mp 108-109 ° C .; Elemental analysis (C 13 H 19 N 5 O) calc. C, 59.75: H, 7.33: N, 26.80; Found C, 59.90: H, 7.31: N, 26.89; 1 H-NMR (CDCl 3 ) δ 0.94 (3H, t, J = 7.3), 0.98 (3H, t, J = 7.3), 1.64-2.12 (4H, m), 3.86-4.25 (8H, m), 7.39 (1H, s); IR (KBr-TAB, cm −1 ) 1682, 1637.
    [144] Example 1O: 1,4-Dipropyl-4,6,7,10-tetrahydro-1H-pyrimid- [1,2-a] purin-10-one
    [145]
    [146] 0.30 g (0.0013 mol) of 4-propyl-4,5,6,7-tetrahydro-1H-pyrimid- [1,2-a] purin-10-one obtained in Example 8 and anhydrous K 2 CO 3 0.21 g (0.0016 mol) was mixed in 6 mL of DMF and 0.14 mL (0.0016 mol) of propyl bromide was added. It stirred at room temperature for 10 hours, and it concentrated under reduced pressure after reaction. The residue was purified by silica gel column (developing solvent of CHCl 3 : MeOH (10: 1)) and the crude product obtained was recrystallized from petroleum ether to give 1,4-dipropyl-4,5,6,7-tetrahydro 0.22 g (62%) of -1H-pyrimid- [1,2-a] purin-10-one were obtained.
    [147] mp 105 to 106 ° C .; Elemental analysis (C 14 H 21 N 5 O) calc. C, 61.07: H, 7.69: N, 25.43; Found C, 63.33: H, 6.24: N, 24.67; 1 H-NMR (CDCl 3 ) δ 0.94 (3H, t, J = 7.3), 0.96 (3H, t, J = 7.3), 1.49 to 2.01 (6H, m), 3.53 (2H, t, J = 5.8 ), 3.84-4.25 (6H, m), 7.39 (1H, s); IR (KBr-TAB, cm -1 ) 1676, 1633
    [148] Test Example 1 PDE Inhibitory Activity
    [149] Type I PDE (calcium-calmodulin dependent cyclic AMP PDE), Type III PDE (cyclic GMP inhibitory cyclic AMP PDE) and Type IV PDE ( Inhibitory effect on click AMP specific PDE) activity was tested.
    [150] Compounds 1 to 10 of the present invention, XT-044 (Control 1), which is a PDE IV inhibitor, Denbuphylline (Control 2), which is a PDE IV inhibitor, and Rolipram (Control 3), which is a PDE IV inhibitor, type Amrinone (Control 4), which is a III PDE inhibitor, and 3-isobutyl-1-methylxanthine (IBMX), (Control 5), which is a non-selective PDE inhibitor, were used as the test compound. Each of the compounds under test was dissolved in dimethylsulfoxide and diluted with buffer. In addition, the final concentration of dimethyl sulfoxide was made 2.5% or less.
    [151] Isolation of PDEs I and IV from Mormot's cerebrum and Isolation of PDE III from heart [Reeves, ML et al., Biochem. J. , 241 : 535-541, 1987; Nicholson, CD et al., Br. J. Pharmacol ., 97 : 889-897, 1989] and prepared by passing DEAE-Sepharose CL-6B through a packed column.
    [152] Cyclic AMP hydrolytic activity of each isoenzyme in the presence or absence of the test compound was determined according to Thompson and Appleman's method [ Biochemistry , 10 : 311-316, 1971] to determine the 50% activity inhibitory concentration of each test compound. Was obtained.
    [153] The results are shown in Table 1 below.
    [154] PDE isoenzyme inhibitory action Test compoundIC 50 (μM) PDE IPDE IIIPDE IV Compound 1> 100> 10088 Compound 235921.9 Compound 341944.7 Compound 4> 100> 100> 100 Compound 598> 10015 Compound 677> 10019 Compound 7> 100> 100> 100 Compound 8> 100> 100> 100 Compound 9> 100> 10024 Compound 10> 100> 10070 Control 1 (XT-044)> 100> 1005.7 Control 2 (Denbuphylline)77.6> 1001.5 Contrast 3 (rollifram)> 100> 1002.9 Contrast 4 (Amnonone)> 10018> 100 Control 5 (IBMX)154.616
    [155] All of the compounds of the present invention showed no noticeable inhibitory action against type III PDEs, while compounds 2 and 3 showed weak inhibitory actions against type I PDEs, while the other compounds showed significantly weaker inhibitory actions. On the other hand, Compounds 2 and 3 exhibited a Type IV PDE inhibitory activity comparable to Controls 1, 2 and 3, indicating that the compounds of the present invention are relatively selective for Type IV PDE activity. In addition, compounds 5, 6 and 9 also weakly inhibited Type IV PDE activity, suggesting that the compounds of the present invention are inhibitors specific for Type IV PDE.
    [156] Test Example 2: Lipolytic Action on Cultured Adipose Cells
    [157] In this test example, compounds 1 to 10 of the present invention, isoprenin (Active Control 1) having a lipolytic action, XT-O44 (Control 1), which is a PDE IV inhibitor, and Dennbufylline (Control, which is a PDE IV inhibitor) 2), Rolipram (Control 3), a PDE IV inhibitor, Amrinone (Control 4), a type III PDE inhibitor, and 3-Isobutyl-1-methylxanthine (IBMX), a non-selective PDE inhibitor. (Control 5) was used as the compound to be tested so that the final concentration was 10 mu M.
    [158] MC3T3-C2 / PA6 profat cells were seeded in a 24-well culture plate at a cell density of 10 5 / cm 3 , and cultured in a carbon dioxide gas incubator at 37 ° C. in α-MEM added with 10% fetal bovine serum and 100 μM kanamycin sulfate. It was. On days 8-12, incubation with α-MEM with 10% fetal bovine serum, 100 μM kanamycin, 4.5 g / L glucose, 500 μM 3-isobutyl-1-methylxanthine (IBMX) and 250 nM dexamethasone The medium was exchanged and after 4 more days, α-MEM was added with 10% fetal bovine serum, 100 μM kanamycin sulfate and 4.5 g / L glucose. Subsequently, at 2 days intervals, medium was exchanged with α-MEM added with 10% fetal bovine serum, 100 μM kanamycin and 4.5 g / L glucose, and the fat was accumulated in cells between 16 and 22 days from the start of culture. Mature adipocytes formed.
    [159] After maturation of adipocytes, α-MEM was incubated for 1 hour by exchange with a parallel salt solution containing 2% bovine serum albumin, 4.5 g / L glucose and the test compound. After completion of the culture, the culture was collected, and the glycerol concentration in the culture was measured using a triglyceride G-test wako. In addition, the cells from which the culture solution was removed were solubilized, and the protein concentration in the cells was also measured using a DC protein assay. The lipolytic activity of the test compound was expressed in terms of lipolysis rate when the lipolysis effect of isoprenin (activity control 1) was 100% based on the amount of lipolysis per unit protein amount.
    [160] The results are shown in Table 2 below.
    [161] Lipolytic Action on Mature Adipocytes Test compoundFat breakdown rate (%) Compound 14 Compound 244 Compound 335 Compound 4One Compound 512 Compound 611 Compound 79 Compound 85 Compound 90 Compound 100 Active Control 1 (Isoprenaline)100 Control 1 (XT-044)58 Control 2 (Denbuphylline)85 Contrast 3 (rollifram)36 Contrast 4 (Amnonone)3 Control 5 (IBMX)21
    [162] Compounds 2 and 3 were less than active Control 1 or Control 2 compounds, but showed comparable lipolysis rates to Control 1 and Control 3 compounds, type IV PDE inhibitors, or Control 5 compounds, which are non-selective PDE inhibitors. In contrast, Control 4, a control III PDE inhibitor, did not have this effect. This indicates that Type IV PDE inhibitors have a relatively strong lipolytic action.
    [163] From the above results, it can be seen that the type IV PDE selective inhibitor promotes lipolysis and is effective for improving obesity.
    [164] The condensed purine derivatives represented by Formula 1 or 2 according to the present invention are novel compounds, in particular, Compounds 2 and 3 selectively show high inhibitory activity against Type IV PDE, and compounds 5, 6, and 9 also inhibit activity. Indicated. As for the lipolytic action, Compounds 2 and 3 showed moderate and Compounds 5 and 6 exhibited weak lipolytic action.
    [165] In this regard, the condensed purine derivatives of the present invention are effective as agents for improving obesity, bronchodilators, and osteoporosis.
    权利要求:
    Claims (2)
    [1" claim-type="Currently amended] A compound represented by the following formula (1) or a pharmacologically acceptable salt:
    [Formula 1]
    In Formula 1, R 1 , R 2 and R 3 are each independently a hydrogen atom, or a C 1 to C 6 alkyl group which is unsubstituted or substituted with a substituent selected from a hydroxyl group, a lower alkyloxy group and an acyl group, or A phenyl group, R 4 and R 5 each independently represent a C 1 to C 6 alkyl group or a phenyl group which is unsubstituted or substituted with a substituent selected from a hydroxyl group, a lower alkyloxy group and an acyl group.
    [2" claim-type="Currently amended] A compound represented by the following formula (2) or a pharmacologically acceptable salt:
    [Formula 2]
    In Formula 2, R 1 and R 2 are each independently a hydrogen atom, or a C 1 to C 6 alkyl group, or a phenyl group which is unsubstituted or substituted with a substituent selected from a hydroxyl group, a lower alkyloxy group and an acyl group. Represent; n represents 2 or 3.
    类似技术:
    公开号 | 公开日 | 专利标题
    RU2650512C2|2018-04-16|Compounding, which inhibites activity of btk and/or jak3 kinases
    US9284329B2|2016-03-15|Thienopyridone derivatives useful as activators of AMPK
    CN100372849C|2008-03-05|Pyrrolo pyrimidines, process for their preparation, their use and pharmaceutical compositions containing them
    JP4790703B2|2011-10-12|Cyclic compounds
    US9078887B2|2015-07-14|Bicyclic heteroaryl inhibitors of PDE4
    ES2236360T3|2005-07-16|New derivatives of pirazolopidine substituted with carbamate.
    EP1720872B1|2011-04-20|Aryl and heteroaryl-piperidinecarboxylate derivatives, the preparation and the use thereof in the form of faah enzyme inhibitors
    RU2403252C2|2010-11-10|Azaindoles, useful as inhibitors of jak and other proteinkinases
    DE602004001397T2|2007-04-26|Spirosubstituted pyrrolopyrimidines
    AU2001261167B2|2006-10-05|Beta-carboline derivatives useful as inhibitors of phosphodiesterase
    DK169271B1|1994-09-26|8-Phenylxanthine derivatives, method of preparation thereof, pharmaceutical composition containing such compound, and such compound for use in therapy
    ES2336603T3|2010-04-14|Pirido compounds | pyrimidine-2,4-diamine as inhibitors of ptp1b.
    US5665721A|1997-09-09|Heterocyclic substituted cyclopentane compounds
    RU2235725C2|2004-09-10|Derivatives of imidazopyridine, method for their preparing and intermediate compounds, pharmaceutical preparation based on thereof |, method for inhibition of gastric acid secretion and method for treatment of states associated with helicobacter pylori infection
    US6583147B1|2003-06-24|Pyrazolopyrimidinone derivatives for the treatment of impotence
    JP4275733B2|2009-06-10|Pyrrolopyrimidine and process for producing the same
    DE60214198T2|2007-08-09|Isoxazolyl-pyrimidines as inhibitors of src and lck protein kinases
    RU2138500C1|1999-09-27|Xanthine derivatives and their pharmacologically tolerantable salts
    JP5297414B2|2013-09-25|Xanthine oxidase inhibitor
    US5965563A|1999-10-12|Aryl and heteroaryl purine compounds
    KR0162654B1|1998-11-16|N-[pyrrolo | pyrimidin-3yl acryl]-glutamic acid derivatives
    EP1339716B1|2004-11-03|lactam-substituted pyrazolopyridine derivatives
    US7700607B2|2010-04-20|Substituted pyridone compounds and methods of use
    AU716383B2|2000-02-24|Novel N-7-heterocyclyl pyrrolo|pyrimidines and the use thereof
    KR100539143B1|2005-12-26|Indole derivatives and their use as 5-ht2b and 5-ht2c receptor ligands
    同族专利:
    公开号 | 公开日
    JP2003252875A|2003-09-10|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    2002-03-04|Priority to JP2002058098A
    2002-03-04|Priority to JPJP-P-2002-00058098
    2003-03-04|Application filed by 롯데제과주식회사, 가부시끼가이샤 롯데
    2003-09-13|Publication of KR20030072251A
    优先权:
    申请号 | 申请日 | 专利标题
    JP2002058098A|JP2003252875A|2002-03-04|2002-03-04|Novel purine derivative|
    JPJP-P-2002-00058098|2002-03-04|
    [返回顶部]