Synthesis of 9-hydroxyalkyl-substituted purines from the corresponding 4-(C-cyanoformimidoyl)imidazole-5-amines

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1992 2119 Synthesis of 9-Hydroxyalkyl-substituted Purines from the Corresponding 4-(C-Cyanoformimidoyl)imidazole-5-amines Brian L. Booth,8 Alice M. Diasb and M. Fernanda ProenGa*rb a Department of Chemistry, University of Manchester Institute of Science and Technology, Manchester M60 IQD, UK I.N.I.C. Centre of Pure and Applied Chemistry, University of Minho, Braga, Portugal ~~ The amino alcohols HO(CH,),NH, (n = 2, 3 and 5) react readily with ethyl (Z)-N-(2-amino-1,2- dicyanoviny1)formimidate 5 to give the amidines 6a-c, which cyclize in the presence of DBU (1,8-diazabicyclo[5.4.0] undec-7-ene) to give the corresponding 4- (cyanoformimidoyl) imidazole-5-amines 7a-c, which can be isolated in the cases where n = 2 or 3. In the presence of aldehydes and ketones, the imidazoles 7a-d lead to the 6-carbamoyl-1,2-di- hydropurines9a-f which, in some cases, are oxidised to the corresponding 6-carbamoylpurines.The reaction of the imidate 5 with 2-methoxyethylamine leads to the amidine 6d and, on treatment with DBU, the reactive imidazole 7d which can be used directly for further reaction. Since the discovery of acyclovir great research effort has been devoted to the synthesis of new acyclic nucleoside analogues as potential anti-herpes (HSV) and anti-human cytomegalovirus (HCMV) agents.' Potent antiviral activities have been found for 'carbo-acyclic' nucleoside analogues such as I,'*, and purine derivatives with simple 9-hydroxyalkyl substituents, such as HO\ 1 2 X = NHiHCI; R = CH(CHMeOH)(CH2)5CH3 3 X = OH; R = CH(CHMeOH)(CH&CH3 4 X = OH; R = (CH2kOCONH(C02H)(CH2)3I NHC(=NH)I NH2 2 and 3, have biological activity.,v4 The hydroxyalkyl side chain is also useful for the introduction of further side chain func- tionality as, for example, with 6-chloro-9-(5-hydroxypentyl)-purine, which is an intermediate for the synthesis of the arginyl hypoxanthine derivative, PCF-39 4.This, in uitro, activates human neutrophil chemiluminescence and suppresses NK (natural killer) cell activity.' As part of a general study of the synthesis of (C-cyanoform- imidoyl)imidazole-5-amineswe now report the preparation and reactions of new 1-(hydroxyalky1)-4-( C-cyanoformimidoy1)- imidazole-5-amines and 1-(2-methoxyethyl)-4-(C-cyanoform-imidoyl)imidazole-5-amine.These have been found to be useful intermediates for the synthesis of 9-(2-hydroxyalkyl)- and 9-(2- methoxyethy1)- 1 ,Zdihydropurine and -purine derivatives.Results and Discussion The reaction of 2-aminoethanol, 2-methoxyethylamine and 5-aminopentanol with ethyl (Z)-N-(2-amino-l,2-dicyanovinyl)-formimidate 5, prepared according to a previously described procedure,* occurs readily at room temperature to give the corresponding amidines 6a-cin up to 90%yield (Scheme 1). The IR spectra of the compounds prepared showed typical N-H and 0-H stretching vibrations in the 3300-3400 cm-' region and two characteristic strong (CEN) absorptions around 2200 and 2220 cm-'. The C-0 stretching vibration is a medium intensity band in the 1056-1075 cm-' region.In the 'H NMR spectra, the proton directly attached to C-8 always showed up as a sharp singlet in the region 7.6-7.8 ppm. In the amidine 6a, the -NCH,-protons resonate at lower field than do those of the -OCH,-group, which can be easily identified by the observed coupling to the hydroxy proton. In amidines 6band 6c these two signals collapse to either a broad singlet or a distorted multiplet. When 3-aminopropanol was used the reaction with form- imidate 5 could not be stopped at the amidine stage, and was carried on through to the imidazole 7bdirectly. The cyclization of these amidines to the imidazoles 7occurs in the presence of base and both the choice of base and the solvent are critical if the pure product is to be isolated.The use of mild aqueous bases (Na,CO,, NaHCO,) leads to a mixture of imidazoles 7and 8, as elimination of HCN from compound 7 is accelerated under these conditions. The use of Ba(OH), in either methanol or ethanol, a method successfully used for the cyclization of similar amidines,* led in this case to a mixture of imidazoles 7 and 8 together with darkening of the solution due to decomposition. The use of Ba(OH), in propan-2-01, keeping the temperature around 0 "C, enabled imidazole 7a to be isolated in yields of approximately 50% after 7 d. The best procedure for the cyclization of N'-hydroxyalkylamidines requires the use of DBU (1,8-diazabicyclo[5.4.O]undec-7-ene) in ethyl acetate. Under these conditions the imidazoles 7a and b were formed within 1-2 h at room temperature and isolated in 70-80% yield.The IR spectra of both these imidazole derivatives showed a complex set of peaks in the 3100-3400 cm-' region, typical of the N-H and 0-H stretching vibrations. A characteristic spectroscopic feature of these compounds is that the C=N stretching vibration, is either absent or present as only a very weak band in the 2200 cm-' region of the IR spectrum. Three intense bands at ca. 1630,1658 and 1545 cm-' are also typical of these compounds. In the 'H NMR spectra the proton at C-8 is a sharp singlet in the region 7.1-7.3 ppm and the -NCH2- protons always resonate at lower field than do the -OCH2- protons. The cyclization of N'-methoxyalkylamidine 6d, isolated in 90% yield, is slow even with DBU in ethyl acetate.After 4 d at room temperature, all the amidine had been consumed, but attempts to isolate the imidazole 7d led to a viscous oil which rapidly turned deep green and further evolved to the J. CHEM.SOC. PERKIN TRANS. 1 1992 while two intense peaks at 1123 and 1014 cm-' were assigned to OEt i LH4NTH2N CN 5 H+hNHN3 CN 8a, n = 2, R = H (75Y0) 7a, n = 2, R = H (81%) b, n = 3, R = H (62%) b, n = 3, R = H (73%) C, n=5,R=H(80%) d, n = 2, R = Me (59%) c, n =5,R=H(*) d, n =2, R = Me (*)I [ * not isolatedbut H2NF=0 9a, n -2,R=H,R'=Ff=Me(82%) + b, n =2,R=H,R1=R2=Et(66%)~-c, n =3,R=HlR'=p=Me(77%) d, n =3,R=H,Ri=R2=Et(80%) e, n = 5, R = H.R' = R2= Me (43%) f, n =2,R=Ri=R2=Me(54%) 10a. n = 2, R = H, R' = Me (63V0) b, n = 2, R = H, R' = CF3 (85%) C, n = 2, R = H, R' = CH=CHCH3 (38Y0) d, n' = 2, R = H, R' = Ph (38%) 8, n = 3, R = H, R' = Me (70%) f, n = 3, R = H, R' = CF3 (43%) Scheme 1 Reagents and conditions: i, NH,(CH,),OH, EtOAc, room temp.; ii, DBU (2 drops), CH3CN or EtOAc, room temp.; iii, 1 mol dm-3 KOH, room temp.; iv, excess R'COR,, room temp.; v, R1COR2, room temp. corresponding 5-aminoimidazole-4-carbonitrile8d. Neverthe-less, imidazole 7d could be prepared in situ from the corre- sponding amidine either in ethyl acetate or acetonitrile in the presence of DBU, and the reaction was complete (by TLC) after 24 h at room temperature. Contamination with imidazole 8d could never be avoided and the resulting solution was used directly for further reaction.Addition of acetone led to the 1,2- dihydropurine 9f in 54% yield after 2 d at room temperature. The formation of 1 -hydroxyalkyl-5-aminoimidazole-4-carbo-nitriles 8a-d can be accelerated in the presence of a stronger base (1 mol dm-3 aqueous KOH at room temperature or 0 "C) either from the corresponding 4-(C-cyanoformimidoyl)imid-azol-5-amines7a and b or directly from the amidine structure 6c and d in 60-80% yield. In contrast to the compounds of type 7 these compounds show a strong CkN IR stretching vibration in the 2200 cm-' region and two intense bands at ca. 1660 and 1587 cm-'. The C-OH stretching vibration occurs at v 1062 cm-' the same vibration with the C-O-CH3 substituent. In the 'H NMR spectra the proton at C-8 is again a sharp signal in the region 6 7.1-7.3 and once again the -NCH2- protons resonate at lower field than do the -OCH2- protons, which in some cases couple with the OH proton.Imidazoles 7a-c were also allowed to react with carbonyl compounds. The use of acetone or pentan-3-one produces 9- substituted-6-carbamoyl-1,2-dihydropurines9a-c while in the presence of aldehydes (acetaldehyde and crotonaldehyde) or p-diketones (acetylacetone and trifluoroacetylacetone),oxidation of the intermediate dihydropurines occurs to give the corre- sponding 9-substituted-6-carbamoylpurines1Oa-f. It is a general observation that the imidazoles 7a-q which possess a free hydroxy group, appear to react with aldehydes and ketones at a faster rate than imidazole 7d.So, for example, reaction of the 1-(5'-hydroxypentyl)imidazole 7c with acetone at room temperature is complete after only 4 h, while the 3'- hydroxypropyl-and 2'- hydroxyethyl-imidazoles 7a and b, respectively, require 24 h for complete reaction under similar conditions. Reaction of the 2'-methoxyethyl derivative 7d is particularly slow and complete reaction is achieved only after more than 2 d at room temperature. The reason for these rate differences is not yet apparent, but it demonstrates that in these reactions it is not only unnecessary to protect the hydroxy k,N,C=O I H Scbeme 2 group but it is undesirable and offers the possibility that this methodology could be used to synthesise new N-nucleosides without the need for extensive protection-deprotection stra-tegies. It is interesting that the signal for the proton on C-8 (6 7.5 9a and 7.4 9b) appears as a broad signal with an integration 1.Similarly, the signal for the proton of the 9-NCH, group (6 3.8) is also broadened and integrates for 2 H in contrast to the signal for the OCH, protons which are sharp and have the expected integration value. Raising the temperature to 75 "C after addition of water results in the appearance of the C-8 proton as a sharp singlet, while those for the 9-NCH, group appear as a well-defined triplet (J 5 Hz) having the anticipated integration value. The 13C NMR spectra of compounds 9a-f also show evidence of an exchange process.The signals for the C atoms of the substituents on the 9-N and C-2 positions are sharp, as are the signals for C-2 and the C=O of the carb- oxamido substituent. In contrast, the signals for C-4, C-5, C-6 and C-8 are broadened considerably and reduced in intensity. In some cases these signals are lost in the noise and cannot be observed. The spectroscopic evidence suggests that in solution these dihydropurine derivatives exist as an equilibrium mixture of the two tautomers shown in Scheme 2. Support for this comes from the synthesis of the trifluoroacetyl derivative 11 byreaction of 9a with trifluoroacetic anhydride (Scheme 3). The acylation product is a single compound but the position of acylation (i.e.1-or 3-) has not yet been established unambiguously. The 'H NMR spectrum of this compound has sharp signals for all the protons and in the I3C NMR spectrum the signals for C-4 (6, 156.3), C-5 (6, 120.0), C-6 (6, 149.1) and C-8 (6,148.2 by DEPT 135) appear as sharp singlets. Compound 11 decomposes readily in water to give green- 2121J. CHEM. SOC. PERKIN TRANS. 1 1992 9a I H2NF=0 11 (76%) 12 (67Yo) Scheme 3 Reagents and conditions: i, (CF,C0)20, 0 oC-woom temp.; ii, excess H,O, room temp. ish-yellow crystals shown by microanalysis and spectroscopic data to be 1-(2’-hydroxyethyl)-4-oxamoylimidazole-5-amine12. Hydrolytic decomposition to compounds of type 12 appears to be a general property of the dihydropurines. So, for example, when 9a is stored at room temperature with water, compound 12 is obtained in 67% yield.The hydrolysis is accelerated by silica, and attempted purification of these and similar dihydro- purines by flash chromatography on silica often leads to partial decomposition to compounds of type 12. Although the compounds described above have only simple, achiral hydroxyalkyl substituents it is clear that similar reactions could, in theory, be camed out using more complex, chiral amino alcohols leading to valuable 44 C-cyanoformimidoyl)imidazole-5-amine and 5-aminoimidazole-4-carbonitrileintermediates. The IR spectra of purines 10 show a strong carbonyl ab- sorption in the 1683-1703 cm-I region and an intense C-0 stretching vibration at v 1052-1066 cm-‘.In the NMR spectra, the proton at C-6 is a sharp singlet in the region 6 8.5-9.0, and the -0CH2- protons, at higher field than the -NCH2- protons, usually couple with the OH protons.All the 6-carbamoyl- 1,2-dihydropurines prepared showed typical N-H stretching vibrations in the 3100-3340 cm-’region and strong carbonyl absorptions in the 1684-1700 cm-’region. The C-0 stretching vibration could always be identified as an intense band around 1080 cm-l. ExperimentalH NMR spectra were recorded on Hitachi-Perkin-Elmer R-24B (60MHz) or Bruker XL300 (300MHz) instruments, I3C NMR spectra either on a Bruker WP80 or XL300 instrument. All J values are given in Hz. IR spectra were recorded on a Shimadzu IR-435, mass spectra on a Kratos Concept instru- ment, and UV spectra on a Perkin-Elmer Lamda 15 UV-VIS spectrometer.M.p.s are uncorrected. Physical and spectroscopic data for compounds 6-12 are given in Tables 1-9. form (20 cm3), containing a catalytic amount (0.01 g) of anilinium hydrochloride and the mixture was stirred at room temperature. After 2 h, all the imidate had been consumed (evidence by TLC) and an off-white solid precipitated out of solution. The product was filtered off to give title compound 6c (1.92 g, 8.7 mmol; 90%). Preparation of (Z)-N-(2-Amino-1,2-dicyanouinyl)-N’-(2’-methoxyethyl yormamidine 6d.-Ethyl (Z)-N-(Zamino- 1,2-di- cyanoviny1)formimidate (Q.71 g, 4.3 mmol) was added to 2- methoxyethylamine (0.75 an3,8.7 mmol) and a catalytic amount (0.01 g) of anilinium hydrochloride was added.The viscous mixture was scratched with a spatula, at room temperature for 15 min, until the reaction was complete. Chloroform (8 cm3) was added to the resulting viscous suspension and the solid was filtered and washed with diethyl ether-chloroform (1 :1) leading to an off-white solid identified as titlecompound6d (0.74 g, 3.9 mmol; 90%). Preparation of 4-(CyanoformimidoyZ)-l-(2‘-hydroxyethyl)-imidazole-5-amine 7a.-Two drops of DBU were added to a suspension of 6a (0.27 g, 1.5 mmol) in ethyl acetate (10 cm3)and the mixture was stirred at room temperature. After 2 h all the amidine had been consumed, as evidenced by TLC. The off- white suspension was filtered and washed with a few drops of ethyl acetate followed by chloroform, to give title compound 7a (0.22 g, 1.23 mmoi; 81%) as an off-white solid.Preparation of 4-(Cyanoformimidoyr)- 1-(3’-hydroxypropyl)- imidazole-5-amine 7b.-3-Aminopropan- 1-01 (0.54 cm’, 7.05 mmol) was added to a solution of ethyl (Z)-N-(Zamino-1,2- dicyanoviny1)formimidate(1.0 g, 7.05 mmol) in ethyl acetate (10 cm3)and the mixture was stirred at room temperature. After 2 h, the imidate was no longer present, as evidenced by TLC, and 2 drops of DBU were added to the reaction mixture. After 1 h, an off-white solid started to precipitate out of solution and within a few minutes all the amidine had been converted into the title compound 7b which was filtered off and washed with ethyl acetate and chloroform (0.86 g, 4.5 mmol; 73%).Preparation of 4-(Cyanoformimidoyl)-l-(2‘-methoxyethyl)-imidazole-5-amine 7d.-Two drops of DBU were added to a suspension of 6d (0.15 g, 0.77 mmol) in ethyl acetate (10 cm3) and the mixture was stirred at room temperature for 4 d, when all the amidine had been consumed. The imidazole 8d was already present in solution, asevidenced by TLC. Compound 7d could not be isolated and the solution was used directly for further reaction. Preparation of 5- Amino- 1 -(hydroxyalkyl)imidazole-4-carbo-nitriles 8.-A mixture of 7 and aqueous 1 mol dm-’ KOH (1 equiv.) was stirred either at room temperature or in an ice bath for 20-45 min. The resulting suspension was filtered off and Preparation of (Z)-N-(2-Amino-l,2-dicyanovinyl)-N’-(2’-hy-washed with a few drops of iced water and diethyl ether to give droxyethyl vormamidine 6a.-2-Aminoethanol (0.47 g, 7.7 mmol) was added to a solution of ethyl (Z)-N-(2-amino-1,2- dicyanoviny1)formimidate (1.0 g, 6.4 mmol) in ethyl acetate (10 cm3) and the mixture was stirred at room temperature.After 2 h an off-white solid precipitated out of the red solution, and, shortly after, it was indicated by TLC that all the imidate had been consumed. The product was filtered off and washed with chloroform to give title compound 6a (0.65 g, 3.67 mmol; 57%) as an off-white solid. title compound 8 (8a, 75%; 8b, 62%). In the preparation of & (80%) and 8d (59%), compound 6 was used as starting material, instead of 7.Reaction of 4-( Cyanoformimidoy1)- 1 -(2’-hydroxyethy1)imid- azole-5-amine with Ketones.-(a) Acetone. A suspension of the imidazole (0.39 g, 2.2 mmol) in acetone (5 cm3) was stirred at room temperature overnight. The orange solid was filtered, washed with diethyl ether and dried to give 6-carbamoyl-2,2- dimethyl-9-(2’-hydroxyethyl)-1,2-dihydropurine 9a (0.43 g, 1.8 Preparation of (Z)-N-(2-Amino-1,2-dicyanouinyl)-N’-(5’-hy-mmol; 82%). An analytical sample was obtained after flash droxypentyl )formamidine &.--Ethyl (Z)-N-(2-amino- 1,2-di- chromatography (silica 60; dry acetone eluent) which gave cyanoviny1)formimidate (1.59 g, 9.7 mmol) was added to a orange crystals. solution of 5-aminopentan-1-01 (1.50 g, 14.6 mmol) in chloro- (b) Pentan-3-one.A suspension of the imidazole (1.0 g, 5.6 2122 J. CHEM. SOC. PERKIN TRANS. 1 1992 Table 1 Physical data for compounds 612 Found (%) Requires (%) Com- Molecular Found: Requires: pound M.p. (T/"C) Formula C H N C H N m/z M 6a 6c 6d 7a 7b 8a 8b 8c 8d !hl 9b 9c w 9e w 1Oa lob 1OC 1Od 1Oe 1Of 11 12 100 (decomp.) 113 (decomp.) 141 (decomp.) 143 (decomp.) 137.6-141.0 (decomp.) 1 92-1 95 (decomp.) 132.9-1 34.7 136.8-1 37.0 124.1-1 25.8 168.4-169.4 (decomp.) 150.4-1 5 1.9 (decomp.) 1 3 8.8-1 4 1.1 (decomp.) 139.3-1 39.7 (decomp.) 2 18-223 23S238 141 (decomp.) 149 (decomp.) 219.2-220.4 241 (decomp.) 185.4-186.6 189.9-191.0 146-152 (decomp.) 21 1-214 (decomp.) C7H9N5O C7H9N5O C6HBN4O C10H15N50 CBH11N50 C8Hl lN50 C7H 1ON40 C9H 14N40 C7H 1ON40 C10H15N502 cl ZH19N502 cl 1H17N502 C13H21N502 C13H21N502 cl lHl 7N502 C9H11N502 C9HBF3N5O* C11H13N502 C14H13N502 CIOHl 3N502 1OH 10F3N502 1ZH 14F3N503HZ0 C7H10N403 46.6 5.1 38.8 54.3 7.1 32.0 50.0 5.3 36.1 46.8 4.7 38.8 49.8 5.3 36.0 47.1 5.2 36.8 50.5 5.9 33.9 55.7 7.2 28.8 50.3 5.8 33.7 50.9 6.7 29.8 54.0 7.4 26.5 52.8 6.8 28.2 55.6 7.6 24.8 HRMSb 279.1696 52.3 6.9 27.7 48.6 4.9 31.6 39.1 2.8 25.6 53.8 5.4 28.6 59.0 4.4 24.7 HRMSb 235.1079 41.2 3.4 23.9 F, 19.5 41.2 4.6 19.9 F, 16.1 42.6 5.2 28.6 46.9 5.0 39.1 54.3 6.8 31.7 49.7 5.0 36.3 46.9 5.0 39.1 49.7 5.0 36.3 47.4 5.3 36.8 50.6 6.0 33.7 55.7 7.2 28.9 50.6 6.0 33.7 50.6 6.4 29.5 54.3 7.2 26.2 52.6 6.8 27.9 55.9 7.5 25.1 HRMS 279.1695 52.6 6.8 27.9 48.9 5.0 31.7 39.3 2.9 25.9 53.5 5.3 28.3 59.4 4.6 24.7 HRMS 235.1069 41.5 3.5 24.2 F, 19.7 41.0 4.6 19.9 F, 16.1 42.4 5.1 28.3 180(M + l)', 153 (base) 222 (M + l)', 195 (base) 194(M + 1)' 180 (M + 1+, 153 (base) (M + 1)'; 167 (base) 153(M + 1)' 167(M + I)+ 195(M + 1)' 167(M + 1)' 238 (M + l)', 204 (base) 266(M + 1)' 252 (M + 1)', 236 (base) 280(M + 1)' 280 (M + l)', 264 (base) 252 (M + l)+, 233 (base) 276(M + 1)+ 248(M + 1)' 236(M + 1)' 290(M + 1)+ 334 (M + 1)', 238 (base) 199 (M + 1)', 128 (base) 179 22 1 193 179 193 152 166 194 166 237 265 25 1 279 279 25 1 22 1 275 247 283 235 289 333 198 '(M + 1)' is absent in the spectrum.High-resolution mass spectrum. Table 2 UV Spectroscopic data for compounds 6-12 mmol) in acetylacetone (2 cm3) was stirred at room temmr- ature.' After 4 d, no imidazole was present in solution- (as ~m*x(EtOH)/nm Anax(EtOH)/nmCompound (&/dm3 mol-' cm-') Compound (&/dm3 mol-I cm-') evidenced by TLC) and a white solid had been formed.Ethanol (5 an3)was added to the mixture and the solid was filtered and 6a 330 (18 165) 9c 431 (3 190) washed with a few drops of ethanol and diethyl ether. White 228 (10 950) 219 (11 420) crystals were obtained, which were identified as 6-carbamovl-9- 6c 331 (24 720) w 429 (3 507) (f-hydroxyethyl)-2-methylpurine1Oa (0.33 g, 1.4 mmol; 63%). 230 (9 569) 219 (12 417) An analytical sample was obtained from hot ethanol, which 6d 330 (24 748) 1Oa 252 (10 080) 228 (11 751) 205 (19 060) gave white needle crystals. 7b 348 (7669) lob 282 (7278) (d) Trfluoroacetylucetone. Trifluoroacetylacetone (0.1 an3, 227 (10 335) 211 (22 387) 0.13 g, 0.84 mmol) was added dropwise to a suspension of 8a 244 (14 416) 1OC 316 (7990) imidazole (0.1 g, 0.6 mmol) in acetonitrile (5 cm3), kept in an ice 242 (31 821) bath, with efficient stirring.After the addition was complete, the 206 (17 890) temperature was allowed to rise to room temperature and the 8b 245 (12 627) 1Od 316 (7980) 251 (25 256) orange mixture was stirred for 2 h, when all the imidazole had 206 (30 751) been consumed. Attempts to isolate the dihydropurine by 8c 245 (13 932) 1Oe 291 (7527) concentrating the solvent in the rotary evaporator and adding 205 (22 490) chloroform were unsuccessful as the purine was already present, 8d 245 (1 2 295) 1Of 282 (7287) as evidenced by TLC.The mixture was then stirred at room 210 (22 378) temperature for 1 d, leading to a white suspension which was 9a 430 (3236) 11 407 (4723) 220 (1 1 576) 251 (3618) filtered. The solid was recrystallized from hot ethanol to give 220 (11 281) white needles identified as 6-carbamoyl-9-(2'-hydroxyethyl)-2-9b 443 (3 147) 12 344 (7 399) trifluoromethylpurine lob (0.14 g, 0.5 mmol; 85%). 219 (11 676) 220 (11 619) Reaction of 4-(Cyanoformimidoyl)-1-(2'-hydroxyethyZ)imid-azole-5-amine with Al&hydes.--(a) Acetaldehyde. Acetaldehyde (large excess) was added to a solution of the imidazole (0.10 g, mmol) in freshly distilled pentan-3-one (12 cm3) was stirred at 0.56 mmol) in dry acetonitrile (50 an3),kept in an ice bath.After room temperature. After 3 d, an orange solid started to 15 min at room temperature only dihydropurine and purine precipitate, and the reaction was complete 7 d later. Addition of were present in solution (evidenced by TLC). The reaction was the chloroform and partial removal of the solvent on the rotary complete after 1 week. Dry flash chromatography (silica 60; evaporator led to an orange solid, which was washed with acetone eluent) led to a white solid identified as 6-carbamoyl-9-chloroform and diethyl ether, and identified as 6-carbamoyl-2,2- (2'-hydroxyethyl)-2-methylpurine 1Oa (0.014 g, 0.063 mmol; diethyl-9-(2'-hydroxyethyl)-1,2-dihydropurine 9b (0.97 g, 3.7 12%).mmol; 65%). An analytical sample was obtained after flash (b)Crotonaldehyde.Crotonaldehyde (0.3 1 g, 4.48 mmol) was chromatography (silica 60; dry acetone eluent) which gave added to a suspension of the imidazole (0.40 g, 2.24 mmol) in bright orange crystals. absolute ethanol (10 cm3) and the mixture was stirred at room (c) Acetylacetone. A suspension of the imidazole (0.4 g, 2.2 temperature for 30 min, when all the starting material had been J. CHEM. SOC. PERKIN TRANS. 1 1992 Table 3 IR and 'H NMR spectroscopic data for compounds 6-3 ~~ Compound v,,, @(Nujol)/cm-' 6, b[2H6]-DMS0 6a 2210s, 2203s, 1647s, 1633s, 16OOs, 1552s, 1056m 6c 2222s, 2199s, 1636s, 1614s, 1594s, 1545s, 1075s 6d 2224s, 2200s, 1634s, 1609.9, 1595s, 1531s, 1114s, 1075m 7a 2221w, 1634s, 1584s, 15453, 1508s, 1065s 7b 2202m, 1659m, 1625s,1585s, 1546s, 1 515m, 1056s 8a 2193s, 1664s, 1633w, 1588s, 153Om, 1062s 8b 2205vs, 166Os, 1588s, 1559w, 1069m 8c 2208m, 1662m, 1592m, 1532m, 1074m 8d 2203s, 1659s, 1586s, 153 Is, 1123s, 1014s 3.4 (2 H, q, J 6, NCH,), 3.5 (2 H, t, J 6, OCH,), 4.7 (1 H, br s, OH), 6.1 (2 H, br s, NH,), 7.6 (1 H, d, J4,2-H) and 7.7 (1 H, br d, J4, NH) 1.3-1.6 (6 H, complex m, CH,(CH,),CH,), 3.3 [I2 H, dt, J (CH,NH) 6 and J (CH,CH,) 7, NCH,], 3.4 (2 H, m, OCH,), 4.4 (1 H, t, J 5, OH), 6.1 (2 H, br s, NH,), 7.7 (1 H, d, J 4, 2-H) and 7.8 (1 H, br d, J 4, NH) 3.4 (3 H, s, OMe), 3.5-3.6 (4 H, complex m, NCH,CH,O), 6.2 (2 H, br s, NH,), 7.7 (1 H, d, J4, 2-H) and 7.9 (1 H, d, J 4, NH) 3.7 (2 H, t, J 5,OCH,), 3.9 (2 H, t, J 5,NCH,), 6.7 (? H, br s, NH,), 7.3 (1 H, s, 2-H) and 10.9 (1 H, s, NH)1.9 (2 H, quint, J 6, CH,CH,CH,), 3.5 (2 H, t, J 6, OCH,), 3.9 (2 H, t, J 7, NCH,), 4.8 (1 H, br s, OH), 6.8 (2 H, br s, NHJ and 7.3 (1 H, s, 2-H) 3.7 (2 H, dt, J 5, OCH,), 3.9 (2 H, t, J 5, NCH,), 5.1 (1 H, t, J 5,OH), 6.2 (2 H, s, NH,) and 7.2 (1 H, S, 2-H) 1.9 (2 H, quint, J 6, CH,CH,CH,), 3.6 (2 H, m, OCH,), 4.0 (2 H, t, J 6, NCH,), 4.9 (1 H, t, OH), 6.4 (2 H, s, NH,) and 7.3 (1 H, s, 2-H) 1.2 (2 H, quint, J 7, CH,CH,CH,), 1.4 (2 H, quint, J 7, OCH,CH,), 1.6 (2 H, quint, J 7, NCH,CH,), 3.3 (2 H, m, OCH,), 3.7 (2 H, t, J7, NCH,), 4.3 (1 H, t, J4, OH), 6.2 (2 H, s, NH,)and 7.1 (1 H, s, 2-H) 3.3 (3 H, s, OMe), 3.6 (2 H, t, J 5,OCH,), 4.0 (2 H, t, J 5,NCH,), 6.2 (2 H, br s, NH,) and 7.7 (1 H, S, 2-H) a All spectra show strong bands in the range 3470-3100 for 0-H and N-H stretching vibrations.J Values are given in Hz. Table 4 IR and 'H NMR spectroscopic data for compounds 9 % 1648s, 1618s, 1542~~ 1529s, 152Om, 1507m, 1080s 9b 1697s, 1664s, 1625s, 1604s, 1553m, 1526s, 1084s k 1684m, 1654s, 1625m, 1593, 1527s, 1082s w 1688m, 166Os, 1626m, 1602s, 153Os, 1084m 9e 1686s, 1653s, 1624s, 1588m, 1576m, 1523s, 1041s 9f 1689s, 1658s, 1633m, 1593m, 1521m, llllm, 1006m 1.5 (6 H, s, 2-Me,), 3.7 (2 H, t, J5,OCH,), 3.8 (1-2 H, br s, NCH,), 5.2 (1 H, br s, OH), 6.3 (1 H, br s, 1-H), 7.5 (1 H, s, 8-H), 7.95 (1 H, br s, CONH) and 8.3 (1 H, s, CONH)0.9(6H,t,J7,CH2Me),1.6and1.75(each1H,dq,J7and14,CH,Me),3.7(2H,t,J5,OCH,),3.8 (2 H, br s, NCH,), 5.1-6.25 (1 H, vbr, s, OH), 7.4 (1 H, br s, 8-H), 7.95 (1 H,br s, CONH) and 8.3 (1 H, s, CONH) 1.4 (6 H, s, 2-Me,), 1.9 (2 H, quint, J 5,CH,), 3.5 (2 H, t, J 5,OCH,), 3.8 (2 H, br s, NCH,), 7.5 (1 H, br s, 8-H), 7.9 (1 H, br s, CONH) and 8.3 (1 H, br s, CONH) 1.1 (6 H, t, J 5,CH,Me), 1.8 and 1.9 (each 1 H, dq, J 7 and 14, CH,Me), 2.0 (2 H, quint, J 5,CH,), 3.6 (2 H, t, J 5,OCH,), 3.9 (2 H, br s, NCH,), 7.6 (vbr s, 8-H), 8.1 (vbr s, CONH), 8.4 (1 H, br s, CONH) and 8.9 (1 H, br s, NH) 1.5 (2 H, br s, CH,CH,H2), 1.6 (8 H, br s, 2-Me,, OCH,CH,), 1.9 (2 H, br s, NCH,CH,), 3.9 (2 H, br s, NCH,), 4.6 (1 H, br s, OH), 6.6 (vbr s, NH), 7.7 (vbr s, 8-H), 8.0 (1 H, br s, CONH) and 8.5 (1 H, br s, CONH)1.4(6H,s,2-Me2),3.8(3H,s,OCH,),3.5(2H,brs,OCH,),3.7(2H,brs,NCH,),7.5(1H, br s, 8-H), 8.0 (vbr s, CONH) and 8.2 (vbr s, CONH) All spectra show strong bands in the range 3470-3100 for 0-H and N-H stretching vibrations.['H,]-Acetone was used as solvent. J Values are given in Hz. Table 5 IR and 'H NMR spectroscopic data for compounds 1W2 Compound v,,"(Nujol)/cm-' 1Oa 1819w, 1688s, 1649w, 1639w, 1594m, 1580s, 1504m, 1066s 10b 18OOw, 1703s, 1591m, 1580w, 1559w, 1541w, 1503m, 1216m, 1187s, 114Os, 1067m 1oC 1685s, 1656m, 163Om, 1594m, 1576s, 1503s, 1067s 1Od 1684s, 1625w, 1604w, 1586m, 1568m, 1540w, 1503w, 1066m 1Oe 1695s, 1656w, 1625m, 1594s, 1588s, 1501m, 1088m 1Of 1668s, 1594s, 15 12m, 1226s, 1 192s, 1144s, 1072m 11 1710s, 1678s, 1659s, 1583m, 1523m, 151Om, 1213s, 1186s 1 120s, 1069s 12 1687m, 1656s, 1547s, 1511s, 1067s dHb[2H6]-DMS0 ~ ~~ ~-2.7 (3 H, s, 2-Me), 3.95 (4 H, s, OCH,CH,N) and 8.5 (1 H, s, 8-H) 3.85 (2 H, br s, OCH,),4.4(2 H, t, NCH,), 5.0(1 H, brs, OH), 8.3 (2 H, brs, NH,) and 8.8 (1 H, s, 8-H) 2.1(3H,dd,J7and2,Me),3.9(2H,dt,J5,OCH,),4.4(2H,t,J5,NCH2),5.2(1H,t,J5,OH),6.7(1 H, dq, J 16 and 2, XH,), 7.3 (1 H, dq, J7 and 15.5, XH,), 8.2 (1 H, s, CONH), 8.5 (1 H, s, CONH) and 8.7 (1 H, s, 8-H) 3.9(2H,t,J4,0CH,),4.5(2H,t,J5,NCH2),5.0(1H,brs,OH),8.0(1 H,brs,NH),8.6(1H,brs, NH) and 8.8 (1 H, s, 8-H) 2.0 (2 H,m, CH,), 2.7 (3 H, s, 2-Me), 3.4 (2 H,t, OCH,), 4.3 (2 H, t, NCH,), 4.4 (1 H, br s, OH), 7.8 (1 H, br s, CONH), 8.2 (1 H, br s, CONH) and 8.4 (1 H, s, 8-H) 2.0 (2 H, quint, J 7, CH,), 3.4 (2 H, dt, J 5 and 6.5, OCH,), 4.4 (2 H, t, J 7, NCH,), 4.6 (1 H, t, J 5, OH), 8.3 (1 H, br s, NH), 8.4 (1 H, br s, NH) and 9.0 (1 H, s, 8-H) 2.7 (6 H, s, 2-Me,), 3.7 (2 H, t, J 5, OCH,), 4.1 (2 H, t, J 5,NCH,), 7.9 (1 H, s, 8-H), 8.5 (1 H, s, CONH) and 8.9 (1 H, s, CONH) 3.7 (2 H, dt, J5,OCH,), 4.0 (2 H, t, J5, NCH,), 5.2 (1 H, t, J5, Off),7.2 (2 H, S, NH,), 7.3 (1 H, S, 2-H), 7.7 (1 H, s, CONH) and 8.4 (1 H, s, CONH) ~-a All spectra show strong bands in the range 3470-3100 for 0-H and N-H stretching vibrations.J Values are given in Hz, J. CHEM. SOC. PERKIN TRANS. 1 1992 Table 6 13C Chemicals shifts (&[2H6]-DMSO) for amidines 6 Compound C-2 c-4 c-5 CkN OCH, NCH, (CH,), OCH, 6a 154.9 119.2 110.6 120.3 63.2 47.2 120.8 6c 154.8 119.1 11 1.0 120.3 64.7 44.4 27.1 120.6 32.2 36.1 6d 154.7 119.2 110.3 120.3 62.0 44.2 74.0 121.0 Table 7 I3C Chemicals shifts (c~,[~H,]-DMSO) for imidazoles 7,8 and 12 Compound C-2 C-4 c-5 CZN C=NH OCH, NCH, (CH,), OCH, ~ ~~~ 7a 137.0 117.7 147.1 120.3 148.6 49.5 63.4 7b 136.4 117.7 147.2 120.3 148.4 43.7 61.4 35.7 8a 138.5 95.4 152.9 122.8 51.0 64.5 8b 136.7 94.2 151.6 121.6 44.0 61.2 35.9 ac 136.5 94.0 151.4 121.5 46.8 64.4 26.3 32.7 35.8 8d 137.2 94.2 151.6 121.5 46.9 73.7 62.1 12 " 137.6 122.3 153.7 49.5 63.2 " Additional signals are 170.6 (CONH,) and 183.5 (M).Table 8 I3C Chemicals shifts (&[2H6]-DMSO) for dihydropurines 9 and 11 Compound C-2 C-4 c-5 C-6 C-8 M== OCH, NCH, (CH,), R',R2 9a 9b 9c 9d 9e 76.0 63.8 76.0 82.0 75.9 130-165" 160.5 130-165" -b ? 121.0 (br) 120.2 (br) 121.1 (br) 120.0 (br) 121.0 (br) 130-165" 151.5 (vbr) 130-165" -b 153.1 130-165" 137 (vbr) 130-165" -136.7 (br) b 167.7 (br) 167.6 (br) 167.6 (br) 167.5 167.8 49.4 49.2 43.5 43.5 46.3 63.8 63.2 61.4 61.3 66.4 36.0 35.9 26.4 32.5(Me) 12.0 (Me) 32.4 (Me) 11.9 (Me) 32.3(Me) 36.3 (br) (C,Me) 36.4 (br) (C,Me) 32.5 35.8 11" 75.2 156.3 120.0 149.1 148.2 163.2 50.9 62.8 30.4 (Me) ~~~ " Very broad band likely to include broad signals for C-8, C-6 and C-4.Not visible in the spectrum. Additional signals for 11 are 121.2 (CF,, J 289) and 162.8 (C CF,, J 32).Table 9 Chemical shifts (&[ZH6]-DMSO) for purines 10 Compound C-2 c-4 c-5 C-6 C-8 M== OCH, NCH, CH, R' 1Ob 151.6 157.9 136.2 152.0 155.4 167.35 50.7 62.8 124.0 (CF,) (J36.6) (J275) 1Od 157.0 154.7 130.0 147.4 149.2 164.8 46.3 59.1 128.2 (0-C?) 128.7 (m-C?) 130.5 (p-C) 137.3 (C?) 1Oe 164.6 157.9 132.9 151.1 151.7 168.5 44.8 61.7 35.95 29.6 (2-Me) lof 151.6 157.7 136.2 151.9 155.2 167.3 45.6 61.7 35.6 124.0 (CF,) (J 36) (J275) converted into the orange dihydropurine. The solvent was to a suspension of the imidazole (0.30 g, 1.7 mmol) in aceto- removed in the rotary evaporator to give a brown oil, from nitrile (5 cm3) and the mixture was stirred for 5 weeks at room which no solid could be isolated.The oil was dissolved in temperature. The homogeneous yellow solution containing ethanol and stirred at room temperature for another 2 d leading imidazole, dihydropurine and purine (as evidenced by TLC), to an off-white suspension. After addition of diethyl ether and slowly turned pale yellow and a white solid precipitated out of cooling in an ice bath, the solid was filtered and washed with solution. Partial removal of acetonitrile by rotary evaporation, diethyl ether. A brownish solid was isolated and identified as 6-addition of absolute ethanol (5 cm3)and standing for a further carbamoyl-9-(2'-hydroxyethyl)-2-C(E)-prop-l-enyl]purine 1Oc week at room temperature led to 6-carbamoyl-9-(2'-hydroxy-(0.21 g, 0.85mmol; 38%). An analytical sample was obtained by ethyl)-2-phenylpurine 1Od (0.18 g, 6.4 mmol; 38%) as an off-recrystallization from hot ethanol leading to off-white shiny white solid.An analytical sample was obtained after flash crystals (38% yield). chromatography (silica 60 acetonitrile eluent) to give white (c) Benzaldehyde. Benzaldehyde (0.20 g, 1.9 mmol) was added needle crystals. J. CHEM.SOC. PERKIN TRANS. 1 1992 Reaction of 4-( Cyanoformimidoy1)- 1 -(3’-hydroxypropy1)imid-azole-5-amine with Ketones.--(a) Acetone. A solution of imid- azole (0.23 g, 1.2 mmol) in acetone (20 cm’) was stirred at room temperature for 24 h. The acetone was partially removed by rotary evaporation and the orange crystals were isolated, washed with chloroform, and identified as 6-carbamoyl-2,2- dimethyl-9-( 3’-hydroxypropy1)- 1,2-dihydropurine !k (0.23 g, 0.92 mmol; 77%).An analytical sample was obtained after flash chromatography (silica 60; acetone as eluent) to give orange needle crystals. (b) Pentan-3-one. A mixture of the imidazole (0.25 g, 1.3 mmol) and pentan-3-one (2 cm’) was stirred for 3 d at room temperature. The crystals were filtered and identified as 6- carbamoyl-2,2-diethyl-9-(3’-hydroxypropy1)- 1 ,Zdihydropurine W (0.29 g, 1.1 mmol; 80%). An analytical sample was obtained after flash chromatography (silica 60;dry acetone eluent) to give red crystals. (c) Acetylacetone. Acetylacetone (0.12 cm’,0.12 g, 1.2 mmol) was added to a suspension of the imidazole (0.1 1 g, 0.6 mmol) in dry acetonitrile (5 cm’) and the mixture was stirred at room temperature. After 8 d, all the imidazole had been converted into dihydropurine, which in turn had partially evolved to the purine (as evidenced by TLC).After 20 d, the purine was the only product present, and the suspension was filtered and washed with chloroform to give an off-white solid identified as 6-carbamoyl-9-(3’-hydroxypropyl)-2-methylpurine1Oe (0.10 g, 0.4 mmol; 70%). The product was treated with charcoal and recrystallized from hot ethanol to give white crystals. (d) Trifluoroacetylacetone. Trifluoroacetylacetone (0.26 g, 1.67 mmol) was added to a stirred suspension of the imidazole (0.29 g, 1.48 mmol) in dry acetonitrile (8 cm’), kept at 0 “C. After the addition was complete, the mixture was stirred at room temperature for 2 d when all the orange dihydropurine had been converted into the colourless purine.The resulting suspension was filtered and the solid washed with a few drops of acetone and chloroform. The grey solid isolated (0.24 g) was purified by flash chromatography (silica 60,acetonitrile eluent), leading to white crystals identified as 6-carbamoyl-9-(3’-hydroxypropyl)-2-trifluoromethylpurine 1Of (0.18 g, 0.6 mmol; 43%). Reaction of 4-(Cyanoformimidoy1)- 1 -(3’-hydroxypropy1)imid-azole-5-amine with Acetaldehyde.-(a). Acetaldehyde (large excess) was added to a suspension of the imidazole (0.12 g, 0.6 mmol) in dry acetonitrile (10 cm’) kept in an ice bath, with efficient stirring. After 15 min at room temperature a mixture of dihydropurine and a small amount of purine were present in solution (as evidenced by TLC).Only purine was present after 5 d and the solution was flash chromatographed (silica 60; chloroform, ethyl acetate and acetonitrile eluents). Partial removal of the solvent from the ethyl acetate fraction led to a white solid identified as 6-carbamoyl-9-(3’-hydroxypropyl)-2-methylpurine (0.015 g, 0.06 mmol; 10%) 1Oe by comparison of its IR spectrum with that of an authentic sample. (b).(3-Aminopropan-l-ol(O.15cm’, 1.98 mmol) was added to a solution of imidazole (0.22 g, 1.3 mmol) in acetonitrile (5 cm’) and the reaction mixture was stirred at room temperature for 2 h. The excess of 3-aminopropan-1-01 was removed by flash chromatography (silica 60; acetonitrile eluent) and the resulting solution containing 4-(cyanoformimidoyl)-l-(3’-hydroxy-propyl)imidazole-5-amine was concentrated in the rotary evaporator and treated with DBU (2 drops).Acetonitrile (large excess) was added to the previous solution, which was stirred at room temperature for 2 d, when the imidazole was no longer present by TLC. The solvent was removed by rotary evaporation leading to an oil which was solubilized in absolute ethanol and stirred at room temperature for 4 d. Dry flash chromatography (silica 60; acetone eluent) led to a white solid identified as 6-carbamoyl-9-(3’-hydroxypropyl)-2-methylpurine 2125 1Oe (0.12 g, 0.5mmol; 50%) by comparison of its IR spectrum with that of an authentic sample. Reaction of 4-( Cyanoformimidoy1)- 1 -(2‘-methoxyethyl)- imidazole-5-amine with A cetone.-4-(Cyanoformimidoyl)-1-(2’-methoxyethyl)imidazole-5-aminewas prepared from forma- midine 6d (0.15 g, 0.77 mmol) and DBU (2 drops) in ethyl acetate (10 cm’) and used in situ for further reaction.Acetone (5 cm’) was added to the above solution, and the reaction was complete after 2 d at room temperature with magnetic stirring. Removal of the solvent on the rotary evaporator led to orange crystals which were filtered and washed with chloroform and diethyl ether. The product was identified as 6-carbamoyl-2,2-dimethyl-9-(2’-methoxyethyl)-1,2-dihydropurine 9f (0.10 g, 0.40 mmol; 54%). Reaction of 4-( Cyano form im idoy 1 ) -1-( 5’-hydroxypen ty 1) im i- dazole-5-amine with Acetone.-4-(Cyanoformimidoyl)-1-(5’-hydroxypentyl)imidazole-5-aminewas prepared from the corre- sponding formamidine 6c (0.13 g, 0.59 mmol) and DBU (2 drops) in acetonitrile (5.0cm’).This compound was isolated as an oil after flash chromatography (silica 60; acetonitrile eluent) and removal of the solvent on the rotary evaporator. The oil was solubilized in acetone (7 an’) and the reaction was complete after 4 h at room temperature, under magnetic stirring. Re- moval of the solvent on the rotary evaporator and addition of chloroform, led to orange crystals which were filtered and washed with dry diethyl ether. The product was identified as 6-carbamoyl-2,2-dimethyl-9-(5’-hydroxypenty1)- 1,2-dihydro- purine 9e(0.07 g, 0.25 mmol; 43%).Reaction of 6-Carbamoyl-9-(2’-hydroxyethyl)-2,2-dimethyl-1,2-dihydropurine with Trijluoroacetic Anhydride.-Trifluoro- acetic anhydride (0.09 cm’, 0.14 g, 0.61 mmol) was added to a suspension of 6-carbamoyl-9-(2’-hydroxyethyl)-2,2-dimethyl-1,2-dihydropurine (0.14 g, 0.61 mmol) in acetone (40 cm’). The mixture was stirred at room temperature for 10 min until the starting material was no longer present in solution. Partial removal of the solvent on the rotary evaporator led to a greenish-yellow solid identified as 6-carbamoyl-9-(2’-hydroxy-ethyl)-2,2-dimethyl-3-trifluoroacetyl-1,2-dihydropurine 11(0.16 g, 0.46 mmol; 76%). Synthesis of l-(2’-Hydroxyethyl)-4-oxamoylimidazole-5-amine 12.-A solution of 6-carbamoyl-9-(2’-hydroxyethyl)-2,2-dimethyl-l,2-dihydropurine(0.37 g, 1.56 mmol) in water (3 cm’) was stirred at room temperature for 19 h, when all the di- hydropurine had been consumed. The resulting suspension was filtered and washed with ethanol and diethyl ether to give title compound 12 (0.24 g, 1.06 mmol; 67%).An analytical sample was obtained after dry flash chromatography (silica 60 acetone eluent), leading to greenish-yellow crystals. Acknowledgements Thanks are due to the Instituto Nacional de Investigaqiio Cientifica, and the Junta Nacional de Investigaqiio Cientifica e Tecnolbgica, Portugal, for financial support. References 1 C. K. Chu and S.J. Cutler, J.Heterocycl. Chem., 1986,23,289 and refs. therein. 2 M. R.Harnden, R.L. Jarvest, T. H. Bacon and M.R. Boyd, J. Med. Chem., 1987, 30, 1636; M. R. Harnden and R. L. Jarvest, J. Chem. Soc., Perkin Trans. I, 1989,2207 and refs. therein. 3 R. J. Suahadolnik, Nucleosides as Biological Probes, Wiley-Inter-science, New York, 1979, p. 217. 4 S. L. Norton and J. W. Hadden, Eur. Pat. Appl., 9154 (1980). J. CHEM. SOC. PERKIN TRANS. 1 1992 5 M. Giovarelli, R. Arione, C. Jemma, T. MUSSO,G. Benetton,G. Forni 8 M. J. Alves, B. L. Booth and M. F. J. R. P. ProenGa, J. Chem. Soc., and P. Carnaglia-Ferraris, Int. J. Immunopharmacol.,1987,9,659. Perkin Trans. 1, 1990, 1705. 6 P. Carnaglia-Ferraris, L. S. Perezzani, R. Stradi and C. Riccardi, Drugs of the Future, 1987,12, 134. Paper 2/0 1292H 7 P. Carnaglia-Ferraris, L. Carnara and A. Melodia, Int. J. Immuno-Received 10th March 1992 pharmacol., 1986,8,463. Accepted 28th April 1992