Synthesis and Cyclic AMP Phosphodiesterase 4 Isoenzyme Inhibitory Activity of Heterocycle Condensed Purines.

Abstract

cAMP-phosphodiesterase 4 (PDE4) inhibitors have relaxation effects on bronchochial smooth muscle and anti-inflammatory activities, and have attracted attention as a remedy for asthmatic patients.1,2) Our investigations on the structure-activity relationships of alkylxanthines as PDE4 inhibitors have shown that 1-, 3-and 7-substituents on the xanthine nucleus are important for PDE4 inhibitory activity.3-5) Although denbufylline (DBF) and XT-44, among compounds prepared by us, were effective against osteoporosis animal models, 6,7) two compounds caused emesis as an undesirable side effect, comparable to several prototype PDE4 inhibitors such as rolipram and its analogs. 8)Previous work in this series has shown that heterocycle condensed purines, namely tetrahydro-imidazo[2,1-i]purine (1) 9) and (2), 10) were effective for reducing the side effects of xanthines, and it became desirable to determine the effect of other condensed purines on PDE4 inhibitory activity.As a continuation of studies on [g,h]-condensed purines (3), 11) we have designed and synthesized a series of heterocy- (6), and [i]-condensed purines (7, 8) fixing the propyl group 12) as a substituent on the imidazole N atom, and examined their in vitro effects on PDE isoenzymes. Chemistry[a]-Condensed purines (4) were prepared according to the method of Nagamatsu et al.13) Treatment of 9 with propanal and sodium cyanoborohydride gave 5-(propylamino)imidazole (10), which was treated with benzoylisothiocyanate to give 11. Cyclization of 11 in aq. NaOH yielded 12. Successive S-methylation of 12, treatment of 13 with aminoalcohol, and ring closure of 14 with thionyl chloride gave the [a]-condensed purines (4a, b). N-Propylation of 4a, b afforded 4c and 4d, respectivery (Chart 3).[b]-Condensed purines (5) were prepared according to the method of Ahn et al. 14) 7-Benzyl-1-propylxanthine (17), which was obtained from regioselective benzylation 15) of 5,6-diamino-3-propyluracil (15) 16) and ring closure of 16 with diethoxymethyl acetate, was treated with excess phosphorus oxychloride to give 7-benzyl-2-chloropurine (18). By treat- Substituted [i]-condensed purines (7, 8) were prepared according to our reported method. 9) 6-(Hydroxyethylamino)-purines (dl-24, dl-25, dl-27 and dl-28) were obtained respec- September 2002Chem. Pharm. Bull. 50(9) 1163-1168 (2002) 1163 * To whom correspondence should be addressed. Ho-3 Kanagawa-machi, Kanazawa 920-1181, Japan: c Department of Hospital Pharmacy, School of Medicine; Kanazawa University; 13-1 Takara-machi, Kanazawa 920-8641, Japan: and d Central Laboratory, Lotte Co., Ltd.; 3-1-1 Numakage, Saitama 336-8601, Japan. Received January 31, 2002; accepted April 18, 2002 To

Diversity oriented syntheses of fused pyrimidines designed as potential antifolates

“…In N-alkyl 2-or 4-oxopurines that lack an NH of phenolic acidity, good yields of alkylamino derivatives have been obtained by direct substitution. 36 Similarly, 4-aminopurines are reactive 37 and pyrazino [3,4-d]pyrimidines undergo hydrolysis of a methylthio group at C4, a carbon atom activated by N6 in the pyrazine ring. 38 However in pyrrolo [2,3-d]pyrimidines, electron withdrawing groups are absent and the pyrrole ring can be regarded as relatively electron rich.…”

Microwave-assisted ring closure reactions: Synthesis of 8-substituted xanthine derivatives and related pyrimido- and diazepinopurinediones

“…2-Unsubstituted derivatives have previously been described by reaction of 10-amino-2,3,4,5-tetrahydropyrimido [1,6- a ][1,3]diazepine-7,9-dione with triethyl orthoformate, but the reported synthetic procedure does not allow the preparation of 2-substituted derivatives [27]. …”

Cyclic AMP Phosphodiesterase 4 Isoenzyme Inhibitory Activity of (R)- and (S)-Isomer of 7-Methyl- or 8-Alkyl-4,5,7,8-tetrahydroimidazo[2,1-i]-purin-5-one

“…Nuclear magnetic response spectrometer ( 1 H-NMR) was recorded with a JEOL EX 90A. Chemical shifts are quoted in parts per million 4) The amino alcohol used for synthesis of 6-hydroxyalkyl compounds was prepared with the method of Mckennin and Meyers. 7) IBMX and amrinone for PDE activity assay were purchased from Sigma Chemicals Co., and rolipram synthesized according to method of Crossland.…”

“…4,5) Treatment of 3-propyl-6-(1,2,4-triazol-4-yl)purine (4) or 6-chloro-3-propylpurine (7) with each of the (R)-and (S)-isomers of 2-amino-1-propanol, 2-amino-1-butanol, 2-amino-3-methyl-1-butanol, and 1-amino-2-propanol yielded the corresponding 6-(hydroxyethylamino)purines (5a-d, 8a-d …”