MXPA99007508A

MXPA99007508A - Substituted (1,3-bis(cyclohexylmethyl)-1,2,3,6-tetrahydro-2,6-dioxo-9h-purin-8-yl)phenyl derivatives, their preparation and their use in the treatment of inflammatory conditions and immune disorders

Info

Publication number: MXPA99007508A
Application number: MXPA/A/1999/007508A
Authority: MX
Inventors: Mary Daluge Susan; Wolberg Gerald; Alan Livingston Douglas
Original assignee: Glaxo Group Limited
Priority date: 1997-02-14
Filing date: 1999-08-13
Publication date: 2000-04-24

Abstract

A compound of formula (I) or a solvate thereof wherein:X is -O- or -NH-;Q is (-CH2-)p, (-CH=CH-)p, (-C=C-)p where p is an integer of from 0 to 4;R1 is hydrogen or methyl;R2 and R3 independently represent O or S;n is an integer of 1 to 50;and R is hydrogen or methyl. This series of complex esters and amides of selected phenyl xanthine derivatives inhibit the expression of adhesion molecules on human umbilical vein endothelial cell (HUVEC) monolayers at very low concentrations and which are therefore indicated for treatment of inflammatory conditions and immune disorders.

Description

"DERIVATIVES OF (1, 3-BIS (CIC OHEXILMETIL) -1, 2, 3, 6 -TETRAHIDRO- 2,6-DIOXO-9H-PURIN-8-I) FENI OR SUBSTITUTED, ITS PREPARATION AND ITS USE IN THE TREATMENT OF IMMUNE INFLAMMATORY AND TRANSTOR CONDITIONS " FIELD OF THE INVENTION The present invention relates to complex amides and esters of phenyl xanthine derivatives, to processes for their preparation, to pharmaceutical formulations containing them, and their use in medicine, particularly in the prophylaxis and treatment of septic shock, inflammatory conditions, thus as well as immunological disorders.

BACKGROUND OF THE INVENTION Septic shock is induced by a complex series of events that involve many different and mediating forms of disease response (see, for example, The Lancet, Vol. 338 (1991), p 732-739, and Annals of Internal Medicine Vol. 115 (1991), p 457-469), which includes, inter alia, products of arachidonic acid metabolism and platelet aggregation. The adhesion of leukocytes circulating to the vascular endothelium is a crucial event in the pathogenesis of inflammatory responses. The mediators REF .: 30988 inflammatory and immune can stimulate the adhesion process by increasing the adhesiveness of the leukocyte or the endothelial cell through the activation, upregulation, or induction of several adhesion molecules on the cell surface. The commonly available anti-inflammatory drugs have limited efficacy, often with side effects. Monoclonal antibodies used experimentally for anti-adhesion therapies have theoretical disadvantages for the treatment of chronic diseases. Therefore, the discovery and development of small molecules which specifically block or inhibit the adhesive interactions of leukocytes and endothelium is an attractive area of therapeutic intervention. PCT Application No. GB 9501808 describes compounds of the formula: wherein m and n are independently integers from 0 to 10; X and Y are independently oxygen or sulfur; (-Q-) is (-CH2-) P or (-CH = CH-) P where p is an integer from 1 to 4; and A and B are independently methyl, alkyl of 3 to 6 carbon atoms branched, cycloalkyl of 3 to 8 carbon atoms or cycloalkenyl of 3 to 8 carbon atoms; and pharmaceutically acceptable salts, solvates and amides and esters thereof; and its use in the treatment of septic shock, allergic and inflammatory conditions. The compounds have been found to inhibit one or more of the enzymes 5-lipoxygenase, cyclooxygenase, and lyso-PAF; acetyl-CoA acetyltransferase. A series of complex amides and esters of selected phenyl xanthine derivatives have now been discovered which inhibit the expression of adhesion molecules in monolayers of human umbilical vein endothelial cells (HUVEC) at very low concentrations and which they are therefore indicated for the treatment of inflammatory conditions and immune disorders.

DESCRIPTION OF THE INVENTION Accordingly, the present invention provides a compound of the formula (I): or a solvate thereof wherein: X is -O- or -NH-; Q is (-CH2-) P, (-CH = CH-) P, (-CsC-) p wherein p is an integer from 0 to 4; R1 is hydrogen or methyl; R2 and R3 independently represent O or S. v n is an integer from 1 to 50; and R is hydrogen, q methyl. According to a further aspect, the present invention provides a compound of the formula (I) as defined above wherein X is -O- or -NH- and R1 is H; of these, the compounds are preferred wherein n is an integer from 8 to 20, and more preferred are those wherein n is an integer from 8 to 15. Conveniently, R3 represents 0 and R2 represents O or S but in a manner most preferred R3 and R2 both represent O. In accordance with a further aspect of the invention, P preferably represents 0 or 1. According to a further aspect, the present invention provides a compound of the formula (I) as defined previously where Q is. { -CH = CH-) P.

Preferably the substituent of fixes or joins the phenyl ring in the para position. The invention also includes mixtures of compounds of the formula (I) in any ratio, for example where n varies within the same sample. A particular subgroup of compounds is of the formula (la) or a solvate thereof where: X is -0- or -NH-; Q is (-CH2-) P, - (CH = CH-) P where p is an integer from 1 to 4; R1 is hydrogen or methyl; n is an integer from 1 to 50; and R is hydrogen or methyl. Particularly preferred compounds of the invention include Decaethylene Glycol Methyl Ether Ester of (E) -4- (l, 3- Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin -8-il) cinnamic; Nonaethylene Glycol Methyl Ether Ester of (E) -4- (l, 3- Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic acid ester; Nonaethylene Glycol Methyl Ether Ester of Acid (E) -3- [1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid; Nonaethylene Glycol Methyl Ether Ester (E) -4- [1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid amide; Nonaethylene Glycol Methyl Ether (E) -4- [l, 3- Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid ester; or a solvate thereof.

The compounds of the present invention are capable of existing as geometric and optical isomers. All isomers, individually and as mixtures, are included within the scope of the present invention. Where Q contains a double bond, the compounds are preferred in the form of E-geometric isomers. As mentioned above, the compounds of the formula (I) and solvates thereof, have utility in the prophylaxis and treatment of inflammatory conditions and immune disorders, as later demonstrated in the biological assays in which the compounds representative of the present invention have been shown to be active. Examples of inflammatory conditions or immune disorders are those of the lungs, joints, eyes, intestines, skin, and heart; particularly those associated with the infiltration of leukocytes into the inflamed tissue. Lung conditions include asthma, respiratory deficiency syndrome in adults, bronchitis and cystic fibrosis (which may additionally or alternatively involve the bowel or other tissue (s)). Joint conditions include rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritis conditions. Inflammatory eye conditions include uveitis (including iritis) and conjunctivitis. Inflammatory bowel conditions include Crohn's disease, ulcerative colitis and distal proctitis. Skin diseases include those associated with the proliferation of cells such as psoriasis, eczema and dermatitis (whether or not they are allergic in origin). Heart conditions include coronary infarct damage. Other inflammatory conditions and immune disorders include tissue necrosis in chronic inflammation, endotoxin shock, smooth muscle proliferation disorders (eg, restenosis after angioplasty), and tissue rejection after transplant surgery. Accordingly, the present invention provides a method for the prophylaxis or treatment of an inflammatory condition or immune disorder in a mammal, such as a human, which comprises administering a therapeutically effective amount of a compound of the formula (I), or a pharmaceutically acceptable solvate thereof; The present invention further provides a method for the prophylaxis or treatment of septic shock in a mammal, such as a human, which comprises administering a therapeutically effective amount of a compound of formula (I), or a solvate thereof pharmaceutically. acceptable. Alternatively, a compound of the formula (I), or a pharmaceutically acceptable solvate thereof for use in medical therapy is also provided.; particularly, for use in the prophylaxis or treatment of an inflammatory condition or immune disorder in a mammal, such as a human. The present invention further provides a compound of the formula (I), or a pharmaceutically acceptable solvate thereof for use in the prophylaxis or treatment of septic shock. The amount of a compound of the formula (I) or pharmaceutically acceptable solvate thereof, which is required to achieve the desired biological effect, will depend on a number of factors such as the use for which it is proposed, the means of administration, and the recipient. A typical daily dose for the treatment of septic shock, for example, can be expected to be in the range of 0.005 mg / kg - 100 mg / kg, preferably 0.5-100 mg / kg, and more preferably 0.5-20 mg / kg. This dose can be administered as a single unit dose or as several separate unit doses or as a continuous infusion. An intravenous dose can be expected to be in the range of 0.0025 mg / kg to 200 mg / kg and could typically be administered as an infusion. Similar dosages may be applicable for the treatment of other disease states. For administration to the lungs of a subject by aerosol, a sufficient amount of the compound should be used to achieve concentrations of the surface fluid of the subject's airway from about 2 to 1000 pmol. Therefore, in a further aspect of the present invention, there are provided pharmaceutical compositions comprising, as an active ingredient, a compound of the formula (I) or a pharmaceutically acceptable solvate or salt thereof, together with at least one pharmaceutical carrier or container. These pharmaceutical compositions can be used in the prophylaxis and treatment of conditions such as septic shock, inflammatory conditions, and immune disorders. The carrier must be pharmaceutically acceptable to the container and must be compatible with, that is, not have a detrimental effect on the other ingredients in the composition. The carrier can be a solid or liquid and is preferably formulated as a unit dose formulation, for example, a tablet that can contain from 0.05 to 95% by weight of the active ingredients. If desired, other physiologically active ingredients can also be incorporated into the pharmaceutical compositions of the invention. Possible formulations include those suitable for. oral, sublingual, buccal, parenteral (e.g., subcutaneous, intramuscular, or intravenous), rectal, topical administration that includes transdermal, intranasal, and inhalation administration. The most suitable means of administration for a particular patient will depend on the nature and severity of the condition to be treated and on the nature of the active compound, but where possible, for example, iv administration for the treatment is preferred. of septic shock. For the treatment of a condition such as asthma, however, oral or inhalation administration could be the preferred route of administration. Formulations suitable for oral administration can be provided as discrete units, such as tablets, capsules, wafers, lozenges, each containing a predetermined amount of the active compound; as powders or granules; as solutions or suspensions in aqueous or non-aqueous liquids; or as emulsions of oil in water or water in oil.

Formulations suitable for sublingual or buccal administration include lozenges comprising the active compound and, typically a flavored base, such as sugar and acacia or tragacanth and lozenges comprising the active compound in an inert base, such as gelatin and glycerin or Acacia Sucrose Formulations suitable for parenteral administration typically comprise sterile aqueous solutions containing a predetermined concentration of the active compound; the solution is preferably isotonic with the blood of the proposed container. Although the solutions are preferably administered intravenously, they can also be administered by subcutaneous or intramuscular injection. Formulations suitable for rectal administration are preferably provided as single dose suppositories comprising the active ingredient in one or more solid carriers forming the base, of the suppository, for example, cocoa butter. Formulations suitable for topical or intranasal application include ointments, creams, lotions, pastes, gels, powdered liquids, aerosols and oils. Suitable carriers for such formulations include petroleum jelly, lanolin, polyethylene glycols, alcohols, and combinations thereof. The active ingredient is typically present in such formulations at a concentration of 0.1 to 15% w / w. The formulations of the invention can be prepared by any suitable method, typically by uniformly and narrowly mixing the active compound with finely divided solid carriers or liquids or both, in the required proportions and then, if necessary, shaping the resulting mixture in the form desired. For example, a tablet can be prepared by compressing an intimate mixture comprising a powder or granules of the active ingredient and one or more optional ingredients, such as a binder, lubricant, inert diluent, or active dispersing agent on the surface, or by molding a intimate mixture of active ingredient in powder and inert liquid diluent. Aqueous solutions are typically prepared by dissolving the active ingredient in saline to which cyclodextrin has been added. Formulations suitable for administration by inhalation include powders of fine particles or vapors or mists that can be generated by means of various types of aerosols. pressurized nebulizers, or metered dose insufflators. For pulmonary administration via the mouth, the particle size of the powder or droplets is typically in the range of 0.5-10μm, preferably 1-5μm, to ensure delivery in the bronchial trunk. For nasal administration, a particle size in the range of 10-500μm is preferred to ensure retention in the nasal cavity. The metered dose inhalers are pressurized aerosol dispensing means, typically containing a suspension formulation or solution of the active ingredient in a liquefied propellant. During use, these devices discharge the formulation through a valve adapted to deliver a metered volume, typically 10 to 150μl, to produce a fine particle spray containing the active ingredient. Suitable propellants include certain chlorofluorocarbon compounds, for example, dichlorodifluoromethane, triclsrofluoromethane, dichlorotetrafluoroethane and mixtures thereof. The formulation may additionally contain one or more cosolvents, for example, surfactant-ethanol agents, such as oleic acid or sorbitan trioleate, antioxidants and flavoring or flavoring-suitable agents. Nebulizers are commercially available devices that transform solutions or suspensions of the active ingredient into a therapeutic spray mist already. either by means of accelerating a compressed gas, typically air or oxygen, through a narrow venturi orifice, or by means of ultrasonic agitation. Formulations suitable for use in nebulizers consist of the active ingredient in a liquid carrier and, which comprise up to 40% w / w of the formulation, preferably less than 20% w / w. The carrier is typically water or a dilute aqueous alcohol solution, preferably made isotonic with body fluids by the addition of, for example, sodium chloride. Optional additives include preservatives if the formulation is not sterile prepared, for example, methyl hydroxybenzoate, antioxidants, flavoring agents, volatile oils, buffering agents and surfactants. Formulations suitable for administration by insufflation include finely ground powders which can be delivered or delivered by means of an insufflator or taken into the nasal cavity in the form of a powdered tobacco. In the insufflator, the powder is contained in capsules or pellets, typically made of gelatin or plastic, which are either punctured or opened in situ and the dust released by air is entrained through the inhalation device or by means of .. a manually operated pump. The powder employed in the insufflator consists of only the active ingredient or a powder mixture comprising the active ingredient, a suitable powder diluent, such as lactose, and an optional surfactant. The active ingredient typically comprises from 0.1 to 100 w / w of the formulation. Therefore, in accordance with a further aspect of the present invention, there is provided the use of a compound of the formula (I) or a pharmaceutically acceptable solvate thereof in the preparation of a medicament for the prophylaxis or treatment of an inflammatory condition. or immune disorder. The compounds according to the invention can be made according to any suitable method of organic chemistry. Therefore, according to a further aspect of the invention, there is provided a process for preparing the compounds of the formula (I), or solvates thereof, which comprises reacting the compound of the formula (II) or an activated derivative thereof with a compound of the formula (III) wherein Q, X, R1, R, R2 and R3 and n are as defined above; and optionally converting the compound of the formula (I) thus formed to a different compound of the formula (I) or to a corresponding solvate. When X • is oxygen, the esterification can be carried out by standard methods, for example using an acid catalyst and, optionally, an inert solvent such as toluene, benzene, or a xylene. Suitable acid catalysts include mineral acids; for example, sulfuric acid, hydrochloric acid, and phosphoric acid; and organic acids; for example, methanesulfonic acid, or toluenesulfonic acid. The esterification is typically carried out at an elevated temperature, for example, 50-150cC, preferably with removal of the water formed by distillation. Where X is oxygen or -NH-, the reaction can be carried out first by preparing an activated derivative of the compound of the formula (II). Suitable activated derivatives include activated esters or acid halides and can be isolated prior to the reaction with the compound of the formula (III) or prepared in situ. Particularly useful activated esters of the compound of the formula (II) are acylimidazoles which are easily prepared by reaction of the compound of the formula (II) with N, N 1 -carbonyldiimidazole. The conversion of an activated derivative of the compound of the formula (II) to a compound of the formula (I) can be carried out in an inert solvent, optimally in the presence of a non-nucleophilic base, such as potassium t-butoxide, sodium hydride, or a non-nucleophilic organic base, such as 1,8-diazabicyclo [5.4.0] undec-7-ene. The compound of the formula (II) can be prepared as described in PCT Application No. GB 9501808.

The compounds of the formula (III) are commercially available or can be prepared by methods of the literature. For example, R.A. Bartsch et al, J. Org. Chem. 1989, 5_4: 857-860 and J. M. Harris, Macromol. J.Sci. Rev. Polymer Phys. Chem. 1985, C25 (3): 325-373, y.S. Zalopsky, Bioconjugate Chem. 1995, 6: 150-165. Alternatively, the compounds of the formula (I) can be prepared by condensation of a compound of the formula (IV) or an acetal derivative thereof, wherein Q, X ,, _ R1, n and R are as defined above, with 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil (which can be prepared as described in the Examples). The condensation is suitably carried out in a polar solvent at non-extreme temperature as described in the PCT Application No. ?? GB9501808. The compounds of the formula (IV) can be prepared by coupling or linking a compound of the formula (III) with the appropriate carboxylic acid. The methods for effecting this binding and for preparing the carboxylic acid are described in PCT Application No. GB9501808. The conversion of a compound of the formula (I) to a solvate thereof can be carried out by standard methods known to a person skilled in the art. Now the invention will be described only by way of illustration, by the following examples: REFERENCE EXAMPLE Example 1 (E) -4- [1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid (a) 1,3-Bis (cyclohexylmethyl) urea A mixture of cyclohexanmethylamine (Aldrich, 68.66 g) and 5 N of sodium hydroxide (Fisher, 200 ml) was stirred vigorously with cooling (-10 ° C) while a solution of phosgene (30.0 g) in toluene (600 ml) It was added quickly. After stirring for 20 minutes, the resulting mixture was filtered and the precipitated solid was washed with water (-1500 ml) and dried at 67 Pa (0.5 Torr) to provide 1,3-bis (cyclohexylmethyl) urea as white powder (72.72 g, 95%), mp 150-152 ° C; NMR-1H (DMSO-d6) 5: 5.74 (t ampl, J = 5.8 Hz, 2, 2 NH), 2.81 (t, J = 6.3 Hz, 4, 2 NCH2), 1.62, 1.25, and 0.85 (all, 22, 2 cyclohexyl). Anal. Cale. For C? SH2? N20: C, 71.38; H, 11.18; N, 11.10. Found: C, 71.22; H, 11.17; N, 11.15. (b) 6-Amino-l, 3-bis (cyclohexylmethyl) uracil The cyanoacetic acid (Aldrich, 21.0 g) was dissolved in acetic anhydride (260 ml). This solution was added to 1,3-bis (cyclohexylmethyl) urea (from step (a), 54.5 g) and the solution was maintained at 80 ° C for 2 h under nitrogen. The volatiles were removed in vacuo and the residual oil was dried by evaporation of portions of 10% water-ethanol (3x400 ml). The residual solids were dissolved in ethanol (600 ml) -water (300 ml) at 80 ° C with pH adjustment to 10 by the addition of 10% aqueous sodium carbonate. The hot solution was diluted with water (75 ml) and cooled to room temperature. The colorless crystals that formed were separated by filtration, washed with water (3x500 ml) and dried at 67 Pa (0.5 Torr) to provide 6-amino-l, 3-bis (cyclohexylmethyl) uracil (64.98 g, 94 %), pf 138-141 ° C; NMR-1H (DMSO-d6) d: 6.73 (broad s, .2, NH2), 4.63 (s, 1, H-5), 3.67 (d, J = 7.3 Hz, 2, NCH2), 3.57 (d, J - 7.3 Hz, 2, NCH2), 1.55 and 1.09 (both m, 22, 2 cyclohexyl) Analysis calculated for C18H29N3O2? 2O: C, 64.07; 9.26: N, 12.45. Found: C, 63.98; H, 9.27; N, 12.48. (c) 6-Amino-l, 3-bis (cyclohexylmethyl) -5-nitrosouracil The 6-amino-l, 3-bis (cyclohexylmethyl) uracil (from step (b), 25.0 g) was dissolved in glacial acetic acid (440 ml), water (440 ml) and ethanol (440 ml) at reflux. To this solution was added sodium nitrite (5.65 g).

The resulting mixture was stirred while cooling slowly to room temperature. The precipitate, lilac or lavender, was separated by filtration, washed with 1: 1 water-ethanol and dried to give 6-amino-l, 3-bis (cyclohexylmethyl) -5-nitrosouracil as light purple crystals (23.46 g, 86%), m.p. 240-243 ° C dec, with effervescence; NMR-1H (DMSO-d6) d: 13.23 (s ampl., 1, = NOH), 9.00 (s.ampl., 1, = NH), 3.73 (t ampl., J = 6.86, 4, 2 NCH2) , 2.0-1.6 and 1.7-1.1 (both m, total 22, 2 cyclohexyl). Analysis calculated for C, 62.05; H, 8.10; N, 16.08. Found: C, 62.13; H, 8.12; N, 16.03. (d) (E) -4- [1,3-Bis (cyclohexyl-ethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl3 cinnamic acid The title compound was prepared from 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil by the method of J. Perutmattam, Syn. Commun. 1989, 19: 3367-3370. 1,3-Bis (cyclohexylmethyl) -5,6-diaminouracil was recently prepared by stirring a mixture of 6-amino-1,3-bis (cyclohexylmethyl) -5-nitrosouracil (from step (c), 5.00 g) in methanol ( 250 ml) -water (25 ml) with 10% palladium on carbon (0.50 g) under hydrogen at 344.7 kPa (50 pounds / in2) on a Parr shaker for 2 h. The catalyst was removed by filtration (Celite MR) and the colorless filtrate was concentrated to 25 ml. 4-Formyl cinnamic acid (Aldrich, 2.53 g, 14.35 mmol) was added to this solution of 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil and the resulting yellow mixture was concentrated and the residual yellow solid was dried by evaporation. of several portions of absolute ethanol. The resulting yellow powder (Schiff base intermediate) was stirred in dimethoxyethane (115 ml) with iodine (4.0 g) at 60 ° C (oil bath) for 20 h. A saturated aqueous solution of sodium thiosulfate was added to the hot reaction mixture until the complete decolorization of the resulting iodine. The pale yellow precipitate was separated by filtration, washed with water, and dried at 67 Pa (0.5 Torr) to give the acid (E) -4- [1,3-bis (cyclohexylmethyl) -1,2,3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid as a pale yellow powder (6.73 g, 91%), mp > 300 ° C. Such samples were further purified by dissolving them in IN aqueous sodium hydroxide, filtering the resulting cloudy solution through Celite ™, and acidifying the clear filtrate with hydrochloric acid. The resulting precipitate was filtered and washed with water to give the title compound as a pale yellow powder, m.p. > 300 ° C; NMR-H (DMSO-d6) d: 13.80 and 12.40 (both m ampl., 1 each, C02H and NH), 8.12 (d, J = 8.3 Hz, 2, 2 phenyl CH), 7.84 (d, J = 8.4 Hz ", 2, 2 phenyl CH), 7.64 (d, J = 16.0 Hz, 1, CH =), 6.64 (d, J = 16.0 Hz, 1, CH =), 3.93 (d, J = 7.0 Hz, 2, CH2N), 3.79 (d, J = 6.8 Hz, 2, CH2N), 2.0-1.4 and 1.3-0.85 (both m ampl., 22 total, 2 cyclohexyl).

Analysis calculated for C28H34N404: C, 68.55; H, 6.99; N, 11.42. Found: C, 68.45; H, 6.98; N, 11.48.

SYNTHETIC EXAMPLES Example 2 Triethylene Glycol Ether Ester Methyl Ether (E) -4- (1,3-Bis (cyclohexylmethyl) -l, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl cinnamic The monomethyl ether of triethylene glycol (Aldrich, 80.0 g) was dried by evaporating portions of xylenes (3x50 ml) under a stream of N2 at 125 ° C. Then (E) -4- [1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid was added. (from step (d) Example 1, 4.00 g) to glycol, and the mixture was further dried by evaporation of xylenes (40 mi). Sulfuric acid (0.41 g) was added to the reaction mixture, which was then heated to 190 ° C. The xylenes were added in 50 ml portions to replace what was separated by distillation. After 2 h, the reaction mixture was treated with additional sulfuric acid (0.2 g). After an additional 3 h at 140 ° C, during this time the xylenes were continuously replaced, the reaction mixture was allowed to cool to room temperature, which caused a large amount of solid precipitated from the brown solution. The mixture was diluted with chloroform (200 ml), and washed with water (4x50 ml). The organic layer was dried (sodium sulfate) and concentrated to yield a yellow solid, which was subjected to chromatography on silica gel. The title compound was eluted with 1-4% methanol in ethyl acetate and recrystallized from ethyl acetate by the addition of hexanes to give the title compound as a white powder (3.2 g, 62%), m.p. 189-192 ° C; NMR-1H (DMSO-d6) d: 8.16 (d, J = 8.0 Hz, 2.2 phenyl CH), 7.88 (d, J = 8.3 Hz, 2.2 phenyl CH), 7.70 (d, J = 16.1 Hz , 1, CH =), 6.77 (d, J = 16.1 Hz, 1, CH =), 4.28 (m, 2, C02CH2), 3.92 (d, J = 6.8 Hz, 2, CH2N), 3.78 (d, J = 6.8 Hz, 2, CH2N), 3.68 (m, 2, CH20), 3.6-3.5 (m, 6, 3 CH20), 3.40 (2, CH20), 3.23 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C 35 H 8 N 4 O 7: C, 66.02; H, 7.60; N, 8.80. Found: C, 65.91; H, 7.58; N, 8.76.

Example 3 Methyl Ether Ester (n = 7.2) Polyethylene Glycol (E) -4- (l, 3-bis (cyclohexyl-ethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic acid A watery paste of (E) -4- [1,3 bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid (from step (d) Example 1, 0.50 g) in poly (ethylene glycol) monomethyl ether (Aldrich, average molecular weight • 350, 21 g, dried by evaporation of toluene prior to use) containing sulfuric acid (51 mg) was stirred at 1 Torr. for 15 min. The yellow reaction mixture was then stirred at 190 ° C (oil bath) and 1 Torr for 3 hours, during this time the solids dissolved, leading to a brown solution. After cooling to room temperature, the dark solution was poured into water (100 ml). The aqueous mixture was stirred for 1.75 hours before being extracted with dichloroethane (3x30 mL). The combined extracts were then dried (sodium sulfate), and concentrated to a waxy solid, which was subjected to chromatography on reverse phase silica gel of C-18 (EM Separations LiChroprep RP-18). The column was eluted with a gradient of water-10% methanol to pure methanol; crude product eluted in pure or unmixed methanol as a yellow waxy solid, which was converted to slurry in water (25 ml). The water was then evaporated under vacuum to provide the title compound as a yellow waxy solid (620 mg, 61%), m.p. 147-154 ° C; NMR-XH (DMSO-d6) d: 8.15 (d, J = 8.1 Hz, 2.2 phenyl CH), 7.88 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.70 (d, J = 16.0 Hz , 1, CH =), 6.77 (d, J = 16.0 Hz, 1, CH =), 4.28 (m, 2, C02CH2), 3.91 (d, J = 7.0 Hz, 2, CH2N), 3.78 (d, J = 7.1 Hz, 2, CH2N), 3.68 (m, 2, CH20), 3.6-3.38 (m, ca 25, ca 12.5 CH20), 3.22 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C29H36N04 (C2H40) 7.2'0.6 H20: C, 62.56 H, 8.00; N, 6.69. Found: C, 62.62; H, 8.01; N, 6.69.

Example 4 Tetraethylene Glycol Methyl Ether Ester of (E) -4- (1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl acid ester cinnamic The methyl ether ester (n = 7.2) of polyethylene glycol of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin -8-yl) cinnamic (from Example 3, 2.0 g) was separated into its components by repeated chromatography using a Chromatotron (Harrison Research). The portions of the ester mixture (250-350 mg) in ethyl acetate were applied to 1 mm thin silica plates which had been pre-equilibrated with hexanes. The plates were then eluted with a gradient of 5-20% ethyl acetate in hexanes. The fractions containing discrete oligomers. were isolated separately, and identical fractions from several plates were poured and concentrated. All the mixed fractions were combined and re-chromatographed. In this manner, tetraethylene glycol methyl ester of (E) -4- (l, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-il ) Cinnamic were obtained as a white powder (43 mg), mp 171-174 ° C; NMR-1H (DMSO-d6) d: 8.18 (d, J-8.4 Hz, 2.2 phenyl CH), 7.91 (d, J = 8. 4 Hz, 2, 2 phenyl CH), 7.72 (d, J = 16.1 Hz, 1, CH =), 6. 80 (d, J = 16.1 Hz, 1, CH =), 4.30 (m, 2, C02CH2), 3. 94 (d, J = 7.1 Hz, 2, CH2N), 3.80 (d, J = 7.1 Hz, 2, CH2N), 3.71 (,, 2, CH20), "3.58-3.42 (m, 12, 6 CH20), 3.24 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 cyclohexyl) Analysis Calculated for C29H36NO (C2H4O) 4"0.6 H20: C, 64.25; H, 7.75; N, 8.10. Found: C, 64.11; H, 7.56; N, 8.07.

Example 5 Pentaethylene Glycol Methyl Ether Ester of (E) -4- (l, 3-bis (cyclohexylmethyl) -1, 2, 3, 6, 6-tetra idro-2,6-dioxo-9H-purin-8- il) cinnamic Separation by methyl ether ester chromatography (n = 7.2) of poly (ethylene glycol) of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo) -9H-purin-8-yl) cinnamic (for example 3, 2.0 g) in its components as described in Example 4 provided the title compound as a yellow waxy solid (92 mg), mp. 166-167 ° C; NMR-1H (DMSO-d6) d: 8.18 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.72 (d, J = 16.0 Hz , 1, CH =), 6.79 (d, J = 16.1 Hz, 1, CH =), 4.30 (m, 2, C02CH2), 3.94 (d, J = 7.0 Hz, 2, CH2N), 3.80 (d, J = 7.0 Hz, 2, CH2N), 3.70 (m, 2, CH20), 3.60-3.40 (m, 16, 8 CH20), 3.24 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both ampl. , 22 total, 2 cyclohexyl). Analysis Calculated for C29H36N404 (C2H40) 5-0.15 H20: C, 64.38; H, 7.80; N, 7.70. Found: C, 64.44; H, 7.90; N, 7.57.

Example 6 Hexamethylene Glycol Methyl Ether Ester of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl acid ester cinnamic The chromatographic separation of methyl ether ester (n = 7.2) of polyethylene glycol of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo- 9H-purin-8-yl) cinnamic (from Example 3, 2.0 g) in its components as described in Example 4, provides the title compound as a yellow waxy solid (170 mg), mp. 160-162 ° C; NMR-1H (DMSO-d6) d: 8.18 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.74 (d, J = 16.0 Hz , 1, CH =), 6.79 (d, J = 16.1 Hz, 1, CH =), 4.30 (, 2, C02CH2), 3.93 (d, J = 6.8 Hz, 2, CH2N), 3.80 (d, J = 7.2 Hz, 2, CH2N), 3.70 (m, 2, CH20), 3.60-3.40 (m, 20, 10 CH20), 3.24 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ampl. , 22 total, 2 cyclohexyl). Analysis Calculated for C29H36N04 (C2H40) 6"0.20 H20: C, 63.74; H, 7.88; N, 7.25, Found: C, 63.69; H, 7.92; N, 7.34.

Example 7 Heptaethylene Glycol Methyl Ether Ester of (E) -4- (1, 3-bis (cyclohexylmethyl) -l, 2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic The chromatographic separation or by methyl ether ester chromatography (n = 7.2) of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-polyethylene glycol) -dioxo-9H-purin-8-yl) cinnamic acid (from Example 3, 2.0 g) in its components as described in Example 4, provides the title compound as a yellow waxy solid (105 mg), mp. 154-156 ° C; NMR-XH (DMSO-d6) d: 8.18 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.73 (d, J = 16.0 Hz , 1, CH =), 6.79 (d, J = 16.1 Hz, 1, CH =), 4.30 (m, 2, C02CH2), 3.94 (d, J = 7.0 Hz, 2, CH2N), 3.80 (d, J = 7.2 Hz, 2, CH2N), 3.70 (m, 2, CH20), 3.60-3.40 (m, 24, 12 CH20), 3.24 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ., 22 total, 2 cyclohexyl). Analysis Calculated for C 29 H 36 N 404 (C 2 H 40) 7'0.25 H20: C, 63.18; H, 7.95; N, 6.85. Found: C, 63.15; H, 7.97; N, 6.93.

EXAMPLE 8 Methyl Ether Ester of Qctaethylene Glycol of (E) -4- (1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl acid ester cinnamic The chromatographic separation of methyl ether ester (n = 7.2) of polyethylene glycol of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo- 9H-purin-8-yl) cinnamic (from Example 3, 2.0 g) in its components as described in Example 4, provides the title compound as a yellow waxy solid (120 mg). p.f. 150-151 ° C; NMR-XH (DMSO-d6) d: 8.18 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.6 Hz, 2.2 phenyl CH), 7.73 (d, J = 16.0 Hz , 1, CH =), 6.79 (d, J = 16.1 Hz, 1, CH =), 4.30 (m, 2, C02CH2), 3.94 (d, J = 7.0 Hz, 2, CH2N), 3.80 (d, J = 7.2 Hz, 2, CH2N), 3.70 (, 2, CH20), 3.60-3.40 (m, 28, 14 CH20), 3.24 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C29H36N04 (C2H0) 8"0.25H20: C, 62.73; H, 8.01; N, 6.50, Found: C, 62.65; H, 8.10; N, 6.56.

Example 9 Decaethylene Glycol Methyl Ether Ester of (E) -4- (l, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl acid ester cinnamic (a) Decaethylene Glycol Monomethyl Ether Potassium t-butoxide (Aldrich, 95%, 239.24 g) is added in portions over a period of 1.25 h to a solution of triethylene glycol monomethyl ether (Aldrich, 300 ml, 1.9 moles) and 1,2-bis (2-chloroethoxy). ) ethane (Aldrich, 500 g). The reaction temperature was maintained at 16-20 ° C during the addition (glacial or ice bath). During the removal of the cooling bath, the reaction temperature reached 30 ° C before cooling to room temperature. The reaction mixture was stirred at room temperature for 2 h, followed by 18 h at 110 ° C, before the volatiles were removed (19 Torr, - 110-125 ° C). The viscous residue was then diluted with toluene (1.7 L), and filtered through Celite. The toluene was distilled off so that the temperature of the crucible never exceeded 165 ° C, and then the methyl hexaethylene glycol chloride was isolated via fractional distillation of the light brown residue (0.6 Torr, 155-190 ° C, 95.78 g, 16 %).

Potassium t-butoxide (Aldrich, 95%, 39.0 g) was added to a solution of tetraethylene glycol (Aldrich, 412.7 g) and methyl hexaethylene glycol chloride (95.8 g) at 18 ° C over a period of 25 minutes. (ice bath / acetone). The reaction mixture was then-stirred at 120 ° C overnight. The pH was adjusted to 7 by the addition of hydrochloric acid (12 N, 11.7 ml), and the volatile substances were removed 64 Pa (0.48 Torr), up to 185 ° C). The residual dark oil was diluted with toluene (250 ml), and treated with calcium chloride (38.1 g). After stirring for 18 h, the mixture was filtered through Celite ™ and concentrated to a dark oil (102 g), which was distilled by fractionation to provide decaethylene glycol monomethyl ether as a. Amber oil (64.6- gr, 45%). An analytical sample was obtained via chromatography on silica gel, eluting with 4% methanol in chloroform to provide a colorless oil; NMR- ^? (DMS0-d) d: 4., 58 (t, J = 5.5 Hz, 1, OH), 3.58-3.38 (m, 40, 20 OCH2), 3.24 (s, 3, OCH3). Analysis Calculated for C 21 H 44 O 11: C, 53.37; H, 9.38. Found: C, 53.09; H, 9.47. (b) 4- (dimethoxymethyl) cinnamate of (E) -Methyl The dimethyl acetal of 4-formyl cinnamic acid (Cleeland, Jr., et al., US Pat. No. 3,969,373) (20.00 g) and anhydrous potassium carbonate (12.44 g) were stirred in anhydrous N, N-dimethylformamide (189 ml) for 5 minutes. Methyl iodide (12.8 g) is added and the resulting mixture is stirred vigorously with moderate heating (oil bath at 40 ° C) for 18 h. The volatiles were evaporated in vacuo and the residue was partitioned between hexanes (400 ml) and water (100 ml). The hexane layer was dried (magnesium sulfate) and evaporated to give (E) -methyl 4- (dimethoxymethyl) cinnamate as a pale yellow oil (18.98 g, 89%), NMR ^ H (DMSO-d6). with the structure. Analysis Calculated for C? 3H? 604: C, 66.09; H, 6.83. Found: C, 65.96; H, 6.86. (c) Decaethylene Glycol Methyl Ether Ester of 4-formyl cinnamic acid A solution of methyl 4- (dimethoxymethyl) cinnamate (from step (b), 4.96 g), monomethyl ether of decaethylene glycol (from step (a), 14.87 g), and titanium (IV) isopropoxide (Aldrich, 1.05 ml) ) was stirred at 110 ° C under high vacuum for 18 h. The resulting black oil was then cooled to 35 ° C, treated with hydrochloric acid (1 N, 24.5 ml), and extracted with toluene (3x100 ml). The combined extracts were concentrated to a dark or turbid oil, which was subjected to chromatography on silica gel. The title compound was eluted with 10% methanol in chloroform as a yellow oil (4.60 g, 34%), XH-NMR (DMSO-d6) d: 10.54 (s, 1, CHO), 7.98 (m, 4, 4 phenyl CH), 7.76 (d, J = 16 Hz, 1, CH =), 6.88 (d, J = 16 Hz, 1, CH =), 4.31 (m, 2, C02CH2), 3.70 (, 2, OCH2 ), 3.51 (m, 36, 18 OCH2), 3.25 (s, 3, OCH3). Analysis Calculated for C3? H50O13 - 0. 65 H20: C, 537. 96; H, 8 05 Found: C, 57. 95; H, 7 95 (d) Decaethylene Glycol Methyl Ether Ester (E) -4- (1, 3-bis (cyclohexyl ethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic acid The title compound was prepared from 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil by the method of J. Perutmattam, Syn. Commun. 1989, 19: 3367-3370. In the manner of step (d) of Example 1, 6-a ino-1,3-bis (cyclohexylmethyl) -5-nitrosouracil (from step (c), example 1, 2.00 g) was converted to 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil, which was then combined with decaethylene glycol methyl ester of 4-formyl cinnamic acid (from step (c), 3.62 g) in ethanol (50 ml). The resulting yellow mixture was concentrated, and the residual yellow semi-solid was dried by evaporation of several portions of absolute ethanol. The resulting yellow semi-solid (Schiff base intermediate) was then stirred in dimethoxyethane (60 ml) with iodine (1.60 g, 6.31 mmol) at 50 ° C (oil bath) for 18 hours. Sufficient saturated aqueous sodium thiosulfate solution was added to the hot reaction mixture to effect complete decolorization of iodine. The aqueous mixture was concentrated to a volume of 20 ml, diluted with water (50 ml), and extracted with chloroform (4x50 ml). The combined organic layers were then dried (magnesium sulfate) and concentrated to give an oily solid, which was subjected to chromatography on silica gel. The title compound eluted in 6% methanol, in chloroform as a yellow oil (3.6 g), which was partitioned between chloroform (150 ml) and water (50 ml). The organic layer was concentrated, and the resulting oil was precipitated from dichloromethane by the addition of hexanes to give the title compound as a yellow powder, which was then washed with hexanes and dried under vacuum at 56 ° C (2.57). g, 47%), pf 143-145 ° C; NMR-XH (DMSO-de) d: 8.16 (d, J = 8.4 Hz, 2.2 phenyl) CH), 7.88 (d, J = 8.5 Hz, 2, 2 phenyl CH), 7.70 (d, J = 16.0 Hz, 1, CH =), 6.78 (d, J = 16.0 Hz, 1, CH =), 4.29 (m, 2, C02CH2), 3.92 (d, J = 7.1 Hz, 2, CH2N), 3.78 (d, J = 7.1 Hz, 2, CH2N), 3.69 (t, J = 4.6 Hz, 2, CH20), 3. 60-3.35 (m, 36, 18 CH20), 3.23 (s, 3, CH3), 2.0-1.5 and 1. 3-0.9 (both m ampl, 22 total, 2 cyclohexyl). Analysis Calculated for C49H76N4O? 4: C, 62.28; H, 8. 10; N, 5.93. Found: C, 62.14; H, 8.06; N, 6.02.

EXAMPLE 10 Nonaethylene Glycol Methyl Ether Ester of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl. cinnamic (a) Nonaethylene Glycol Monomethyl Ether A mixture of hexaethylene glycol (Aldrich, 100 g) and benzyl bromide (Aldrich, 12 g) in aqueous sodium hydroxide (50% (w / w), 80 ml) was stirred at 100 ° C (oil bath) under nitrogen for 2 h. The reaction mixture was then cooled to room temperature, diluted with water to a total volume of 500 ml, and extracted with diethyl ether (200 ml) to remove the dibenzylated product. Sodium chloride (100 g) was added to the aqueous layer, which was further extracted with diethyl ether (6x100 ml). These ether extracts were combined, dried (sodium sulfate), and concentrated to provide hexaethylene glycol monobenzyl ether as an oil (25 g, 20% glycol-based), NMR ^ H (CDC13) d: 7.30 (m , 5, 5 phenyl CH), 4.53 (s, 2, benzyl CH2), 3.69-3.54 (m, 22, 11 OCH2), 3.06 (s ampl., 3, OH and CH20). A solution of toluene sulfonyl chloride (Aldrich, 38 g) and methylene glycol monomethyl ether (Aldrich, 16.4 g) in dry pyridine (150 ml) was stirred at 0 ° C (ice bath) for 4 hours, followed by 18 hours. room temperature. Then the solution was poured into ice water (500 ml) and extracted with diethyl ether (3 x 300 ml). The ether extracts were combined, washed with hydrochloric acid (3 N) and water, dried (sodium sulfate), and concentrated to give methylene glycol methyl tosyl ether as a colorless oil (20.0 g, 62% based on glycol), NMR-XH (CDC13) d: 7.75 (d, J = 8.0 Hz, 2.2 phenyl CH), 7.30 (d, J = 8.1 Hz, 2.2 phenyl CH), 4.11 (t, J = 4.8 Hz, 2, CH2OS), 3.65-3.41 (m, 10, 5 CH20), 3.32 (s, 3, CH3O) and 2.40 (s, 3, benzylic CH3).

A solution of hexaethylene glycol monobenzyl ether (22.3 g) in THF (100 ml) is added to a suspension of 50% NaH (3.5 g) in anhydrous THF (100 ml). The suspension was stirred at room temperature for 30 min and then a solution of the methylene glycol methyl tosyl ether of the aforesaid (22.0 g) in THF (100 ml) was added dropwise. The mixture was refluxed under nitrogen overnight, cooled to room temperature, quenched with water (500 ml), and extracted with diethyl ether (3x300 ml). The ether extracts were combined, dried (sodium sulfate), and concentrated in vacuo to give the nonaethylene glycol benzyl methyl ether as an oil (27 g, 88%), 1 H-NMR (CDC13) d: 7.31 (m , 5, 5 phenyl CH), 4.54 (s, 2, benzyl CH), 3.62-3.52 (m, 36, 18 CH20), 3.35 (s, 3, CH3) • One, nonaethylene glycol benzyl methyl ether solution of the aforementioned previously (38 g) in methanol (200 ml) was shaken or shaken with 10% palladium-on activated charcoal (Aldrich, 1.0 g) under hydrogen 344.7 kPa (50 lb / in2) on a Parr apparatus overnight . The catalyst was removed by filtration (Celite ™), and the filtrate was concentrated in vacuo to give nonaethylene glycol benzyl monomethyl ether as an oil (23 g, 74%), XH-NMR (CDC13) d: 3.67-3.47 (m, 36 , 18 OCH2), 3.32 (s, 3, CH3). Analysis Calculated for C? 9H40O? 0: C, 53.26; H, 9.41. Found: C, 53.25; H, 9.41. (b) Nonaethylene Glycol Monomethyl Ether Ester (E) -4- (1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic acid A mixture of 4-formyl cinnamic acid (Aldrich, 22.0 g), nonaethylene glycol monomethyl ether (from step (a), 60.0 g), and toluene sulfonic acid (Aldrich, 10 g) in dry xylenes (600 ml) were subjected to reflux for 4 hours (oil bath) until approximately 2.0 ml (110 mmol) of water was collected in a Dean Stark trap. The reaction mixture was then concentrated to about 100 ml, cooled to room temperature, and passed through a column of silica gel. The methyl ester of nonaethylene glycol of 4-formyl cinnamic acid eluted with chloroform: acetone (60:40) as an oil (72 g, 97%), XH-NMR (CDC13) d: 10.01 (s, 1, CHO) , 7.89 (d, J = 8.1 Hz, 2, 2 phenyl CH), 7.71 (d, J = 16.1 Hz, 1, CH =), 7.66 (d, J = 8.0 Hz, 2, 2 phenyl CH), 6.57 ( d, J = 16.1 Hz, 1, CH =), 4.37 (m, 2, C02CH2), 3.77 (m, 2, CH20), 3.67-3-52 (m, 32, 16 CH20), 3.35 (s, 3 , CH3). The title compound was prepared from 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil by the method of J. Perutmatta, Syn. Commun. 1989, 19: 3367-3370. In the manner of step (d) of Example 9, the 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil (from step (d) Example 1, 10.4 g) was condensed with nonamethylene glycol monomethyl ether 4-formyl cinnamic acid as described above (18.0 g) to afford the title compound as a light yellow solid (20.0 g, 74%), mp 143-145 ° C; NMR-XH (DMS0-d6) d: 8.28 (d, J = 8.3 Hz, 2.2 phenyl CH), 7.74 (d, J = 16.2 Hz, 1, CH =), 7.67 (d, J = 8.4 Hz, 2, 2 phenyl CH), 6.55 (d, J = 15.9 Hz, 1, CH =), 4.40 (m, 2, C02CH2), 4.08 (d, J = 6.9 Hz, 2-, CH2N), 4.00 (d, J = 7.3 Hz, 2, CH2N), 3.80 (m, 2, CH20), 3.72-3.52 (m, 32, 16 CH20), 3.35 (s, 3, CH3), 2.05-1.03 (m, 22, 2 cyclohexyl ). Analysis Calculated for C47H72N40? 3: C, 62.65; H, 8.05; N, 6.32. Found: C, 62.40; H, 7.92; N, 6.42.

EXAMPLE 11 Methyl Ether Ester (n = 11.7) of Polyethylene Glycol from (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H- acid purin-8-yl) cinnamic A suspension of (E) -4- [l, 3 bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic (from step (d) Example 1, 5.50 g) in poly (ethylene glycol) monomethyl ether (Aldrich, average molecular weight 550, 365 g, dried by evaporation of toluene prior to use) containing sulfuric acid (0.57 g) it was stirred at 133 Pa (1 Torr) for 15 minutes. The yellow reaction mixture was then stirred at 190 ° C (oil bath) and 133 Pa (1 Torr) for 3 h, during this time the solids dissolved, leaving a brown solution. After cooling to room temperature, the dark solution was poured into water (150 ml). The aqueous mixture was stirred for 1.5 h before being extracted with dichloroethane (3x120 ml). Then the combined extracts were washed with water (150 ml) and the pH of the aqueous layer was adjusted to a value of 6.5 by the addition of concentrated ammonium hydroxide. After drying (sodium sulfate), the extracts were concentrated and the resulting oil was chromatographed on reverse phase silica gel of C-18 (EM Separations LiChroprep RP-18). The column was eluted with a gradient of 30% ethanol-water to pure methanol; crude product eluted in pure methanol. This orange waxy solid was also subjected to chromatography on silica gel. The title compound was eluted in 1-5% methanol in chloroform as a yellow waxy solid, which was then dissolved in chloroform and precipitated through the addition of hexanes to give the title compound as a yellow waxy solid pale (6.34 g, 56%), mp 140-143 ° C; NMR-XH (DMSO-d6) d: 8.15 (d, J = 8.5 Hz, 2.2 phenyl CH), 7.88 (d, J = 8.5 Hz, 2.2 phenyl CH), 7.70 (d, J = 16.0 Hz , 1, CH =), 6.77 (d, J = 16.1 Hz, 1, CH =), 4.28 (m, 2, C02CH2), 3.92 (d, J = 7.0 Hz, 2, CH2N), 3.78 (d, J = 17.2 Hz, 2, CH2N), 3.70 (m, 2, CH20), 3.6-3.35 (, ca 42, ca 10.5 CH2CH20), 3.23 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C29H36 4O4 (C2H40) u.6 * 0.4 H20: C, 61.30; H, 8.20; N. 5.48. Found: C, 61.24; H, 8.26; N, 5.54.

Example 12 Hexaethylene Glycol Ester of (E) -4- (l, 3- Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic acid (a) Hexamethylene Glycol Ester of 4-Formyl-cinnamic Acid The (E) -methyl 4- (dimethoxymethyl) cinnamate (from step (b) Example 9, 16.1 g, 68.1 mmol), and titanium isopropoxide (Aldrich, 6.34 g) were stirred in an excess of crude mono (tetrahydropyranyl) ether hexaethylene glycol (JW Cornforth, ED Morgan, KT Potts, RJ Rees, Tetrahedron 1973, 29: 1659.1667, 52.76 g) at room temperature for 3 d. Then the solution was stirred under vacuum (2 Torr) at 120 ° C for 4 h. After the solution was cooled to 32 ° C, hydrochloric acid (1 N, 80 ml, 80 mmol) was added. The resulting aqueous solution was stirred for 1.5 h at 32-40 ° C before being diluted with water (10 ml). The solution was stirred for an additional 30 minutes before another 10 ml portion of water was added. After 2.5 h, the solution was cooled to room temperature and extracted with toluene (3x100 ml). The toluene extracts were combined, dried (sodium sulfate), and concentrated to an oil (33.81 g), which was chromatographed on silica gel. The title compound was eluted in 10% methanol in ethyl acetate, and dried by evaporation of ethanol to provide the title compound as a yellow waxy solid (8.80 g, 29%) H-NMR (DMSO-d6) d : 10.06 (s, 1, CHO), 7.98 (m, 4, 4 phenyl CH), 7.77 (d, J = 16.0 Hz, 1, CH =), 6.88 (d, J = 16.0 Hz, 1, CH =) , 4.60 (m, 1, OH), 4.31 (m, 2, C02CH2), 3.71 (m, 2, CH20), 3.51 (m, 20, 10 CH20). Analysis Calculated for C22H32O9'0.35 H2O-0.25 C2H60: C, 58.97; H, 7.52. Found: C, 58.43; H, 7.40. (b) Hexamethylene Glycol Ester of (E) -4- (1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic ester The title compound was prepared from 1,3-bis (cyclohexyl ethyl) -5,6-diaminouracil by the method of J. Perutmattam, Syn. Commun, 1989, 19: 3367-3370. In the manner of step (d) of Example 9, the 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil (from step (d) Example 1, 7.68 g) is condensed with hexaethylene glycol ester of 4-acid. formyl cinnamic (from step (a), 10.52 g) to afford the title compound as a light yellow solid (8.0 g, 45%), mp 165-168 ° C; NMR-XH (DMSO-de) d: 8.17 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.90 (d, J = 8.4 Hz, 2.2 phenyl (CH), 7.78 (d, J = 16.0 Hz, 1, CH =), 6.80 (d, J = 16.0 Hz, 1, CH =), 4.60 (m, 1, OH), 4.30 (m, 2, C02CH2), 3.93 (d, J = 6.9 Hz, 2, CH2N), 3.80 (d, J = 7.2 Hz, 2, CH2N), 3.71 (m, 2, CH20), 3.65-3.40 (m, 20, 10 CH20), 2.1-1.5 and 1.6-0.9 (both m ampl., 22 total, 2 cyclohexyl) Analysis Calculated for C4oH58N4O? o'0.9 H20: C, 62.30; H, 7.82; N, 7.27. Found: C, 62.33; H, 7.80; N, 7.26.

Example 13 Methyl ether ester (n = 23.9) of polyethylene glycol of (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H- acid purin-8-il) cinnamic (a) (E) -1,3-Bis (cyclohexylmethyl) -8- (4- (2- (lH-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H) -diona A watery slurry of (E) -4- [1,3 bis (cyclohexylmethyl) -l, 2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid (from step (d) Example 1, 2.97 g) in anhydrous N, N-dimethylformamide (50 ml) was briefly heated to near reflux under nitrogen. Then N, N '-carbonyldiimidazole (Lancaster Synthesis, 1.17 g) was added to the pale yellow waxy paste, which is diluted or thinned and becomes orange like a stripped gas. After a few minutes the watery paste turned bright yellow and thickened like a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow filter plug was washed with dichloromethane (30 ml), and partially dried with air. The wet solid was then dried at 0.1 Torr and 40 ° C to provide (E) -1,3-bis (cyclohexylmethyl) -8- (4- (2- (1H-imidazol-1-ylcabornyl) vinyl) phenyl) - 9H-purin-2, 6 (1H, 3H) dione. as a yellow powder (3.25 g, 96%), m.p. 310 ° C (dec): NMR-XH (DMSO-d6) d: 8.74 (s, 1, imidazole CH), 8.20 (d, J = 8.9 Hz, 2.2 phenyl CH), 8.06 (d, J = 7.7 Hz, 2, 2 phenyl CH), 8.03 (d, J = 14.8 Hz, 1, CH =), 7.93 (s, 1, imidazole CH), 7.72 (d, J = 15.7 Hz, 1, CH =), 7.14 (s, 1, imidazole CH), 3.92 (d, J = 7.0 Hz, 2, CH2N), 3.77 (d, J = 7.4 Hz, 2, CH2N), 2.00-1.50 and 1.25-0.90 (both ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C3? H36 6O3'0.35 C3H NO: C, 67.98; H, 6.84; N, 15.71. Found: C, 67.93; H, 6.67; N, 15.92. (b) Methyl ether ester (n = 23, .9) of Polyethylene glycol Acid (E) - 4- (1,, 3- Bis (cyclohexylmethyl) - i, 2, 3, 6-tetrahydro-2,, 6-dioxo-9H-purin-8-yl) Cinnamic A slurry of (E) -1,3-bis (cyclohexylmethyl) -8- (4- (2- (lH-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (1H, 3H) -dione (from step (a), 2.25 g) in anhydrous N, N-dimethyl formamide (50 ml) was heated at 60 ° C (oil bath) under nitrogen. Poly (ethylene glycol) monomethyl ether (Shearwater Polymers, average molecular weight 1100, 4.80 g, dried by evaporation of toluene prior to use) was added to the bright yellow gouache, followed by 1,8-diazabicyclo [5.4.0] ] undec-7-ene (Aldrich, 658 mi). The addition of the base produced an intense red reaction mixture and caused almost complete dissolution of the acyl imidazole. The red mixture was stirred at 60 ° C for 2.5 d, during this time all solids dissolved. The pH of the light red solution was then adjusted to a value of 5 by the addition of sulfuric acid. Volatile substances were removed from the resulting light yellow solution at 0.24 Torr and 47 ° C to give a yellow oil (11.37 g), which was subjected to chromatography on reverse phase silica gel of C-18 ( EM Separations LiChroprep RP-18). The column was eluted with a 40% methane-water gradient to pure methanol; the crude product eluted in pure methanol yielded a yellow solid (10.25 g), which was further subjected to chromatography on silica gel. The title compound was eluted with 4-10% methanol in dichloromethane as a pale yellow glass (5.73 g, 92%), which was triturated with hexanes to give a yellow waxy solid, m.p. 97-98 ° C; NMR-XH (DMSO-d6) d: 8.18 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.6 Hz, 2.2 phenyl CH), 7.72 (d, J = 15.8 Hz , 1, CH =), 6.79 (d, J = 15.9 Hz, 1, CH =), 4.30 (m, 2, C02CH2), 3.94 (d, J = 7.0 Hz, 2, CH2N), 3.80 (d, J = 7.8 Hz, 2, CH2N), 3.70 (m, 2, CH20), 3.57-3.41 (m, ca 88, ca 44 CH20), 3.25 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C29H36N404 (C2H40) 23.4'0.30 H20: C, 59.02; H, 8.53; N, 3.58. Found: C, 59.05; H, 8.57; N, 3.62.

Example 14 Methyl Ether Ester (n = 41.5) of Polyethylene Glycol of (E) -4- (1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dio? 9H-purin-8-yl) cinnamic In the form of example 13, (E) -l, 3-bis (cyclohexylmethyl) -8- (4- (2- (1H-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H) -dione (from step (a) Example 13, 2.16 g) was coupled or linked to the poly (ethylene glycol) monomethyl ether (Aldrich, average molecular weight 2000, 9.60 g) to provide the title compound as a yellow powder (6.80 g, 76%), p.f. 56-64 ° C; NMR-1H (DMSO-d6) d: 8.18 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.72 (d, J = 16.0 Hz , 1, CH =), 6.80 (d, J = 16. 1 Hz, 1, CH =), 4.30 (m, 2, C02CH2), 3.70-4.00 (m, 6, 2 CH2N, and CH20), 3.70-3.40 (m, ca 160, ca 80 CH20), 3.25 (s, 3, CH3), 2.0-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 ciciohexyl). Analysis Calculated for C29H36N404 (C2H40)? .5: C, 57.67; H, 8.73; N, 2.40. Observed: C, 57.51; H, 8.51; N, 2.31.

Example 15 Methyl Ether Ester (n = 15) of Polyethylene Glycol of (E) -4- (1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H- acid purin-8-il) cinnamic In the manner of example 13, (E) -l, 3-bis (cyclohexylmethyl) -8- (4- (2- (lH-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H) -dione (from step (a) Example 13, 2.16 g, 3.84 mmol) were attached or mixed with poly (ethylene glycol) monomethyl ether (Aldrich, average molecular weight 750, 3.30 g, 4.40 mmol) to provide the title compound as a yellow waxy solid (3.30 g, 74%), mp 124-125 ° C, XH-NMR (DMS0-d6) d: 8.18 (d, J = 8.2 Hz, 2.2 phenyl CH), 7.91 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.72 (d, J = 16.0 Hz, 1, CH =), 6.80 (d, J = 16.0 Hz, 1, CH =), 4.31 (m, 2, C02CH2), 3.94 (m, 2, CH2N), 3.80 (m, 2, CH2N), 3.70 (m, 2, CH20), 3.6-3.4 (m, ca 58, ca 29 CH20), 3.25 (s, 3, CH3), 1.8-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 ciciohexyl). Analysis Calculated for C29H36N404 (C2H40)? 5-0.5 H20: C, 57.67; H, 8.73; N, 2.40. Found: C, 57.51; H, 8.51; N, 2.31.

Example 16: Ester (n = 32.2) of Polyethylene Glycol of (E) -4- (1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8 acid -il) cinnamic (E) -1, 3-Bis (cyclohexylmethyl) -8- (4- (2- (1H-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H) -dione (from step (a) Example 13, 1.69 g) was added to molten poly (ethylene glycol) (Aldrich, average molecular weight 1500, 90.0 g, 60.0 mmol, dried by evaporation of toluene prior to use) under nitrogen.

The yellow wash was diluted with anhydrous N, N-dimethyl formamide (40 ml), and heated to 60 ° C (oil bath). Then 1,8-diazabicyclo [5.4.0] undec-7-ene (Aldrich, 494 ml) was added, producing a dark red reaction mixture and causing complete dissolution of the acyl imidazole. The mixture was stirred at 60 ° C for 16.5 h, during this time all the solids were dissolved. The pH of the orange solution was then adjusted to 5 through the addition of the sulfuric acid. Volatile substances were removed from the resulting yellow solution at 0.7 Torr and 50 ° C, and the residual orange oil was chromatographed on reverse phase silica gel of C-18 (EM Separations LiChroprep RP-18). The column was eluted with a gradient from 40% water-methanol to pure methanol; The crude product was eluted in pure methanol to give a yellow film (8.50 g), which was further subjected to chromatography on silica gel. The title compound was eluted with 6-15% methanol in dichloromethane as a pale yellow glass (5.83 g), which was triturated with hexanes to give a yellow waxy solid (4.773 g, 83%), m.p. 83-84 ° C; NMR-1H (DMSO-de) d: 13.92 (s, 1 NH), 8.14 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.87 (d, J = 8.5 Hz, 2.2 phenyl CH), 7.68 (d, J = 15.7 Hz, 1, CH =), 6.76 (d, J = 16.1 Hz, 1, CH =), 4.56 (t, J = 5.5 Hz, 1, OH), 4.26 (, 2 , C02CH2), 3.90 (d, J = 7.3 Hz, 2, CH2N), 3.76 (d, J = 6.9 Hz, 2, CH2N), 3.66 (m, 2, CH20), 3.6-3.2 (m, ca 120, ca 60 CH20), 2.0-1.5 and 1.3-0.8 (both m ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C28H34N404 (C2H40) 32.2"0.2 H20; C, 58.02; H, 8.60; N, 2.93, Observed: C, 58.01 H, 8.59; N, 2.92.

Example 17 Ester (n = 18.9) of Polyethylene Glycol of (E) -4- (1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8 acid -il) cinnamic In the form of example 16, (E) -l, 3-bis (cyclohexylmethyl) -8- (4- (2- (1H-imidazol-1-ylcabonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H) -dione (from step (a) Example 13, 1.69 g) was mixed with poly (ethylene glycol) (Aldrich, average molecular weight 1000, 60.0 g) to give the title compound as a yellow waxy solid (2.747). g, 85%), pf < 40 ° C; NMR-1H (DMSO-de) d: 13.88 (s, 1, NH), 8.11 (d, J = 8.0 Hz, 2.2 phenyl CH), 7.83 (d, J = 8.4 Hz, 2.2 phenyl CH) , 7.66 (d, J = 16.1 Hz, 1, CH =), 6.73 (d, J = 16.1 Hz, 1, CH =), 4.55 (t, J = 5.5 Hz, OH), 4.26 (m, 2, C02CH2 ), 3.87 (d, J = 6.9 Hz, 2, CH2N), 3.74 (d, J = 7.0 Hz, 2, CH2N), 3.66 (m, 2, CH20), 3.6-3.3 (m, ca 88, ca 40 CH20, superimposed H20), 2.1-1.5 and 1.3-0.9 (both m ampl., 22 total, 2 cyclohexyl). Analysis Calculated for C28H34N04 (C2H40)? 8.9-l .2 H20: C, 58.77; H, 8.39; N, 4.17. Found: C, 58.77; H, 8.28; N, 4.10.

Example 18 Ester (n = 13) of Polyethylene Glycol of (E) -4- (1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8 acid -il) cinnamic In the manner of example 16, (E) -l, 3-bis (cyclohexylmethyl) -8- (4- (2- (1H-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H) -dione (from step (a) Example 13, 5553 g) was mixed with poly (ethylene glycol) (Dow, average molecular weight 600, 121.0 g) to give the title compound as a yellow waxy solid (6.94). g, 64%), pf 142-143 ° C; NMR-2H (DMS0-d6) d: 8.18 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.90 (d, J = 8.4 Hz, 2.2 phenyl CH), 7.72 (d, J = 16.0 Hz , 1, CH =), 6.79 (d, J = 16.0 Hz, 1, CH =), 4.58 (t, J = 5.3 Hz, OH), 4.30 (m, 2, C02CH2), 3.94 (d, J = 7.2 Hz, 2, CH2N), 3.80 (d, J = 7.0 Hz, 2, CH2N), 3.70 (m, 2, CH20), 3.61-3.42 (m, ca 48, ca 24 CH20), 2.0-1.5 and 1.3- 0.9 (both m ampl., 22 total, 2 ciciohexyl). Analysis Calculated for C28H34N404 (C2H40) 13-1 H20: C, 59.98; H, 8.20; N, 5.18. Found: C, 59.96; H, 8.18; N, 5.13.

Example 19 Nonaethylene Glycol Monomethyl Ether Ester Acid 3-. { 4- [1, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] phenyl} propionic A solution of nonaethylene glycol monomethyl ether ester of (E) -4- (l, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- il) cinnamic (from step (b) Example 10, 200 mg) in isopropanol (50 ml) was stirred under H 2 (0.02 Bar) in the presence of 10% palladium on activated charcoal (Aldrich, 40 mg) in a Hydrogenator of Flow to Pressure Büchi for 23 h. The catalyst was removed by filtration (Celite), and the volatiles were evaporated under vacuum. The chloroform (5 x 10 mL) was evaporated from the oily residue, which, after being dried (0.2 mm Hg, 50 ° C) afforded the title compound as a waxy yellow solid (165 mg, 83%), m.p. 85-86 ° C, RM ^ H (DMS0-d6) consistent with the structure. Analysis Calculated for C4 H74N40? 3: C, 62.51; H, 8.26; N, 6.21. Found: C, 62.39; H, 8.27; N, 6.27.

Example 20 Nonaethylene Glycol Ether Ester of 3- Acid Glycol. { 4- [1, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] phenyl} propiolic (a) Ethyl ester of Acid 3-. { 4- [1, 3- Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] phenyl} -2, 3-di romopropionic A solution of 0.64 g (4.0 mmol) of bromine in 10 mL of chloroform was added to a stirred solution of 1.90 g (3.66 mmol) of ether ester of (E) -4- (1,3-bis (cyclohexylmethyl) ether. -1, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic in 25 ml of chloroform. The mixture was stirred at room temperature then the solvent was evaporated to yield the title compound as a white solid (2.5 g, 100%) 1H-NMR (CDC13) d: 8.31 (d, J = 8.4 Hz, phenyl CH, 2H ), 7.56 (d, J = 8.4 Hz, phenyl CH, 2H), 5.40 (d, J = 11.7 Hz, CHBr, 1H), 4.83 (d, J = 11.7 Hz, CHBr, 1H), 4.38 (q, J) = 7.3 Hz, C02CH2, 2H), 4.08 (d, J = 7.2 Hz, CH2N, 2H), 4.03 (d, J = 7.3 Hz, CH2N, 2H), 2.04 (m, c-hexyl CH, 1H), 1.89 (m, c-hexyl CH, 1H), 1.5-1.8 (m, c-hexyl) CH2, 10 H), 1.39 (t, J = 7.3 Hz, CH3-terminal, 3H), 1.0-1.3 (m, c-hexyl CH2, 10H). (b) Acid 3-. { 4- [1,3-Bis (cyclohexylmethyl) 1, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl] phenyl} propiolic 2.8 g (4.1 mmol) of ethyl ester of 3- [4- [1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8 are added. -il] phenyl} -2, 3-dibromo-propionic (part a of this example) to 56 ml of 1M potassium t-butoxide in t-butanol (Aldrich) at room temperature. The mixture was stirred at room temperature for 2.5 hours, then 0.10 ml of water was added. The solution was stirred for an additional hour then 1 g of charcoal was added in 250 ml of water. The mixture was stirred for 30 minutes then filtered. The filtrate was acidified with concentrated hydrochloric acid (pH = 1), then the resulting suspension was stirred for 15 minutes, filtered and then washed with 3 × 50 ml of water. The solid was dried under reduced pressure to give 1.63 g (81%) of the title compound; NMR-1H (DMS0-d6) d: 8.15 (d, J = 8.0 Hz, phenyl CH, 2H), 7.73 (d, J = 8.0 Hz, phenyl CH, 2H), 3.87 (d, J = 6.6 Hz, CH2N , 2H), 3.74 (d, J = 6.8 Hz, CH2N, 2H), 1.88 (s ampl., C-hexyl CH, 1H), 1.4-1.8 (m, c-hexyl CH, CH2, 11H), 0.8- 1.2 (m, c-hexyl CH2, 10 H); MS (ES "): 487 (M-1), 443 (M-1-C02). (c) Nonaethylene Glycol Methyl Ether Ester 3- [4- [1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) ] phenyl } propiolic A solution of 324 mg (2.0 mmol) of 1,1'-carbonyldimidazole in 10 mL of acetonitrile was added to a stirred solution of 650 mg (1.33 mmol) of 3- [4- [1,3-bis (cyclohexylmethyl)] -1, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl] phenyl J-propyol in 40 ml of anhydrous tetrahydrofuran. The mixture was stirred for 4 hours, then 40 ml of acetonitrile were added, and the suspension was stirred for an additional 30 minutes and filtered. The solid was washed with 2x10 ml of acetonitrile and dried overnight under reduced pressure., then mixed with 10 ml of anhydrous dimethyl formamide. The monomethyl ether of nonaethylene glycol (857 mg) was added to the suspension and the mixture was stirred under nitrogen. 1,8-Diazabicyclo [5. .0] undec-7-ene (300 μl) was added dropwise and the red solution was stirred at room temperature for one hour, then at 40 ° C for an additional hour. The solution was cooled to 20 ° C, 100 ml of methylene chloride was added, and the pH was adjusted to 5 with 1M potassium sulfate. The phases were separated and the aqueous phase was washed with 2x20 ml of methylene chloride. The combined organic phases were dried with anhydrous magnesium sulfate, then filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography using ethyl acetate / ethanol (9: 1) as eluent, to obtain 105 mg (9%) of the title compound; NMR-XH (CDC13) d: 8.27 (d, J = 8.3 Hz, phenyl CH, 2H), 7.71 (d, J = 8.3 Hz, phenyl CH, 2H), 4.41 (t, J = 4.6 Hz, C02CH2, 2H ), 4.06 (d, J = 7.3 Hz, CH2N, 2H), 3.97 (d, J = 7.2 Hz, CH2N, 2H), 3.78 (t, J = 4.8 Hz, CH20, 2H), 3.6-3.7 (m, CH2, 30 H), 3.52 (m, CH20, 2H), 3.34 (s, OCH3, 3H), 2.04 (m, c-hexyl CH, 1H), 1.85 (m, c-hexyl CH, 1H), 1.6 -1.8 (m, c-hexyl CH, CH2, 10H), 1.0-1.2 (m, c-hexyl CH2, 10 H). MS (FAB +): 899 (M + 1), 921 (M + Na).

Example 21 Nonaethylene Glycol Methyl Ether Ester of (E) -3- [1, 3-Bis (cyclohexylmethyl) -l, 2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) ] cinnamic (a) (E) -3- [(1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid As in part (d) of Example 1, the 6-amino-1,3-bis (cyclohexylmethyl) -5-nitrosouracil (from step (c) Example 1, 2.79 g, 8.00 mmol) was reduced to 1.3-bis (cyclohexylmethyl) -5,6-diaminouracil, and condensed with 3-formyl cinnamic acid (T. Higa, AJ Krubsack, J. Org, Chem. 1975, 40: 3037-3045, 1.424 g) to give the acid (E) -3- [1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid as a whitish solid (1947 g, 49%), pf > 350 ° C; NMR-XH (DMSO-dβ) consistent with the structure. Analysis Calculated for C28H34N404 '0.10 H20: C, 68.30; H, 7.00; N, 11.38. Found: C, 68.33; H, 6.93; N, 11.34. (b) Nonaethylene Glycol Methyl Ether Ester Acid (E) -3- [1, 3-Bis (cyclohexylmethyl) -l, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic A watery paste of acid (E) -3- [1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid (from step (a), 0.50 g) in N , Anhydrous N-dimethylformamide (10 mL) was briefly heated to near reflux under nitrogen. Then N, N'-carbonyldiimidazole (Aldrich, 0.202 g, 1.22 mmole) was added to the pale yellow waxy paste, which was diluted and turned orange as a detached gas. Within a few minutes the watery paste turned bright yellow and thickened or condensed as a yellow solid formed. The mixture was stirred for 18 h, diluted with dichloromethane (30 mL), and filtered. The bright yellow solid was washed with dichloromethane (30 ml), and dried at 40 ° C to provide (E) -l, 3-bis (cyclohexylmethyl) -8- (3- (2- (1H-imidazol-1) -i1carbonyl) vinyl) phenyl) -9H-purin-2,6,6 (1H, 3H) -dione as a yellow powder (0.403 g). To the mixture of this compound (0.40 g, 0.74 mmol) and nonaethylene glycol monomethyl ether, (part (a) of Example 10, 0.350 g) in N, N-dimethylformamide (10 mL) was added 1,8-diazabicyclo [ 5.4.0] undec-7-ene (Aldrich, 0.112 g). The resulting solution was stirred at 55 ° C for 20 h. The solution was cooled to room temperature and adjusted to pH 7 by the addition of IN HCl. Chloroform (50 ml) was added and the solution was washed with water (2x20 ml). The combined organic layers were washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. The residual waxy solid was subjected to chromatography on silica gel eluted with 10% methanol / chloroform to give the methyl ether ester of nonaethylene glycol of (E) -3- [1,3-bis (cyclohexylmethyl) -1 acid, 2, 3, 6-tetrahydro-2,6-dioxo-9H-? Urin-8-yl] cinnamic acid as a white waxy solid (0.421 g, 63%); NMR-XH (DMS0-d6) d: 8.53 (s, 1, aryl CH), 8.13 (d, J = 7.7, 1, aryl CH), and 7.80 (d, J = 8.5, 1, aryl CH), 7.71 (d, J = 16, 1, CH =), 7.58 (m, 1, aryl CH), 6.78, (d, J = 15.9, 1, CH =), 4.28 (, 2, CH20), 3.91, (d , J = 7.2, 2, CH2N), 3.77 (d, J = 7.2, CH2N), 3.68 (m, 2, CH20), 3.70-3.40 (m, 32, 16 CH2), 3.21 (s, 3, CH3) , 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH). Analysis Calculated for C H72N40? 3: C, 62.65; H, 8.05; N, 6.22. Found: C, 62.57; H, 7.83; N, 6.50.

Example 22 Amide of Nonaethylene Glycol Methyl Ether of (E) -4- (l, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-i1 cinnamic (a) 2,5,8,11,14,17,20,23,26-nonaoxo-octacosyl-28-amine Sodium hydride (8.6 g, 344 mmol as 95%) is added to a solution of hexaethylene glycol ( Aldrich, 100 g) in anhydrous tetrahydrofuran (1000 ml) at 15 ° C. The resulting mixture was stirred while reaching room temperature for 1 h. Benzyl bromide (Aldrich, 59.9 g) was added dropwise over 1 h and the resulting mixture was stirred at room temperature for 16 h. The cooled mixture was diluted with water (200 ml) and extracted with diethyl ether (3 × 350 ml). The combined diethyl ether extracts were washed with water (2x100 ml). The combined aqueous layers were saturated with sodium chloride and extracted with methylene chloride (4x400 ml). The combined methylene chloride layers were washed with saturated sodium chloride (200 ml) and dried (magnesium sulfate). Removal of volatile substances under reduced pressure left hexaethylene glycol monobenzyl ether glycol (80.5 g, 64%); X-NMR identical to that described in part (a) of Example 10. A solution of hexaethylene glycol monobenzyl ether (80.0 g) in anhydrous THF (750 ml) was added to a suspension of sodium hydride (95%, 5.4 g). ) in tetrahydrofuran. The resulting mixture was stirred at room temperature for 30 min, and then a solution of triethylene glycol methyl tosyl ether (prepared as described in part (a) of Example 1, 68.4 g) in THF (100 ml) was added dropwise. ). The mixture was refluxed under nitrogen overnight. The additional sodium hydride (2.5 g) was added and the reflux continued for an additional 24 h. The mixture was cooled (ice bath or cooling bath), quenched with water (2 L), and extracted with diethyl ether (2x200 ml). The aqueous layer was washed with methylene chloride (2x250 ml). The combined organic layers were dried (magnesium sulfate) and concentrated to a brown oil which was filtered through a pad of silica gel washed with methylene chloride. Methylene chloride was evaporated to nonaethylene glycol benzyl methyl ether as an oil (63.1 g, 57%), XH-NMR (DMSO-de) d: 7.23 (m, 5, 5 phenyl CH), 4.38 (s, 2 , benzyl CH2), 3.50-3.30 (m, 36, 18 CH20), 3.13 (s, 3, CH3). A solution of nonaethylene glycol benzyl methyl ether (10 g, 19.3 mmol) in ethanol (200 ml) was stirred with 10% palladium on activated charcoal (Aldrich, 1.0 g) under nitrogen at 344.7 kPa (50 pounds / in2) in a Parr appliance for 3 h. The catalyst was removed by filtration (Celite ™), and the filtrate was concentrated in vacuo and dried by evaporation of toluene to give nonaethylene glycol monomethyl ether as an oil (8.17 g, 99%), XH-NMR (DMSO-D6) d : 4.56 (t, 1 OH), 3.60-3.35 (m, 36, 18 OCH2), 3.22 (S, 3, CH3). To a solution of nonaethylene glycol monomethyl ether (2.0 g, .4.7 mmol) in pyridine (15 mL) at 0 ° C was added toluenesulfonyl chloride (1.35 g). After stirring at room temperature overnight, the mixture was cooled to 0 ° C and adjusted to pH 2 by the addition of 12N HCl. Water (200 ml) was added and the solution was washed with methylene chloride (3x50 ml). The combined organic layers were washed with brine, dried (magnesium sulfate) and evaporated to give nonaethylene glycol methyl tosyl ether as a colorless oil (2.7 g), XH-NMR (DMSO-d6) d: 7.85 and 7.55 (2d , 4, C6H4), 4.18 (m, 2, CH2OTos), 3.7-3.45 (m, 34, 17 CH2), 3.2 (s, 3, OCH3), 2.40 (s, 3, CH3). To a solution of nonaethylene glycol methyl tosyl ether (2.6 g, 4.42 mmol) in N, N-dimethylformamide (10 mL), was added a sodium azide (Aldrich, 0.35 g) and sodium iodide (Aldrich, 20 mg). . The solution was refluxed 18 h, cooled to room temperature, and diluted with chloroform (50 ml). This solution was washed with water (2x10 ml) and the organic layer was dried (magnesium sulfate) and concentrated to a colorless oil (2.25 g). The oil was dissolved in ethanol (100 ml), and stirred with 10% palladium on carbon (Aldrich, 200 mg) under hydrogen (15 psi) for 48 h on a Buchi hydrogenation apparatus. The catalyst was removed by filtration (Celite) and the solvent was evaporated to leave 2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxo-octacosyl-28-amine as a colorless oil (1.59 g, 77%). %); NMR-XH (DMSO-d6) d: 3.60-3.40 (m, 36, 18 CH2 and NH2), 3.20 (3, CH3); MS (Cl) 428 (100%, M + 1). (b) Amide of Nonaethylene Glycol Methyl Ether (E) -4- (1, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic acid To a mixture of (E) -1, 3-bis (cyclohexylmethyl) -8- (4- (2- (lH-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (1H, 3H ) -dione (part (a) of example 13), (0.5 g, 0.92 mmoles) and the. 2, 5, 8, 11, 14, 17, 20, 23, 26-nonaoxo-octacosyl-28-amine (part (a) of this example, 0.43 g, 1.0 mmol) in N, N-dimethyl formamide (10 ml) ) 1,8-diazabicyclo [5.4.0] undec-7-ene (Aldrich, 0.168 g) was added. The resulting red solution was stirred at 55 ° C for 18 h. Additional amine (0.43 g) was added and heating continued for an additional 20 h. The resulting solution was cooled to room temperature and adjusted to pH 7.0 by the addition of IN hydrochloric acid. Water (25 ml) was added and the solution was washed with ethyl acetate (50 ml). The organic layer was washed with brine, dried (magnesium sulfate) and concentrated under reduced pressure. Chromatography on silica gel eluted the title compound with 10% methanol-chloroform. Evaporation of the solvent left the title compound as a yellow solid (64 mg, 8%); NMR-XH (DMSO-d6) d: 8.24 (t, 1, NH), 8.15 (d, J = 8.4, 2, 2 aryl CH), 7.69 (d, J = 8.3, 2, 2 aryl CH), 7.47 (d, J = 15.5, 1, CH =), 6.75 (d, J = 15.8, 1, CH =), 3.92 (d, J = 7.1, 2, CH2N), 3.78 (d, J = 7.2, 2, CH2N), 3.6-3.3 (m, 36, 18 CH2), 3.23 (s, 3, CH3), 2.0-1.5 and 1.25-0.95 (both m, 22, cyclohexyl CH2 and CH). Analysis Calculated for C47H73 5O? 20.85 H20: C, 61.67; H, 8.22; N, 7.65. Found: C, 61.66; H, 8.07; N, 7.67.

EXAMPLE 23 Nonaethylene Methyl Ether Ester Glycol of (E) -3 - [(1,3-Bis (cyclohexylmethyl) -l, 2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- il] enzoic (a) Acid (E) -3- [(1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid 1,3-Bis (cyclohexylmethyl) -5,6-diaminouracil was prepared as in part (d) of Example 1 by reduction of 1,6-amino-3-bis (cyclohexylmethyl) -5-nitrosouracil. (2.00 g) and condensed immediately with 3-formylbenzoic acid (Aldrich, 1424 g) by the method of J. Perumattam (Synthetic Commun, 1989, 19: 3367-3370) to provide the title compound as an off-white solid ( 2.27 g, 85%), pf > 250 ° C; NMR-XH (DMSO-de) consistent with the structure. Analysis Calculated for C 26 H 32 N 404: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.10; H, 6.97; N, 12.04. (b) Nonaethylene Glycol Methyl Ether Ester Acid (E) -3- [(1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid A watery paste of (E) -3 - [(1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid (from the part (a) of this example, 0.500 g) in anhydrous N, N-dimethylformamide (10 mL) was heated briefly to about reflux under nitrogen N, N'-carbonyldiimidazole (Aldrich, 0.213 g) was added to the yellow paste After a few minutes, the watery paste became a bright yellow and precipitated yellow solid.The mixture was stirred for 18 h, diluted with dichloromethane (30 ml), which was diluted and turned orange like a detached gas. The solid was washed with dichloromethane (30 ml) and dried at 40 ° C to provide (E) -1,3-bis (cyclohexylmethyl) -8- [3- (2- (lH-imidazole). 1-ylcarbonyl) vinyl) phenyl] -9H-purin-2,6 (1H, 3H) -dione as a yellow powder (0.46 g) A mixture of this solid (0.45 g), nonaethylene glycol monomethyl ether, ( from part (a) of example 10, 0.393 g) and potassium carbonate or anhydrous (0.242 g) in acetonitrile (10 ml), stirred at reflux for 20 h. Chloroform (50 ml) was added and the solution was washed with IN HCl (20 ml). The organic layer was washed with brine, dried (magnesium sulfate), and chromatographed on silica gel. Elution by evaporation with methanol-chloroform to 10% of the solvents gave nonaethylene glycol methyl ether of (E) -3- [1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro- 2,6-dioxo-9H-purin-8-yl] benzoic acid as a white waxy solid (0.262 g, 38%): XH-NMR (DMS0-d6) d: 8.79 (s) and 8.43 (d, J = 7.9 ), 8.11 (d, J = 8.0), and 7.57 (m, every 1, C6H4), 4.50 (m, 2, CH20 >, 3.99 (d, J = 7.1, 2, CH2N), 3.83 (m, 4, CH2N and CH20), 3.70- 3.40 (m, 32, 16 CH2), 3.28 (s, 3, CH3), 2.1-1.6 and 1.4- 1.0 (both m, 22, cyclohexyl CH2 and CH). Analysis Calculated for C45H70N4O? 3-0.52 H20: C, 61.05; H, 8.10; N, 6.33. Found: C, 61.05; H, 8.09; N, 6.25.

Example 24 Nonaethylene Methyl Ether Ester Glycol of (E) -4 - [(1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- il] benzoic (a) (E) -4- [(1,3-Bis (cyclohexylmethyl) -1,2,3,6-tetra idro-2,6-dioxo-9H-purin-8-yl] benzoic acid 1,3-bis (cyclohexylmethyl) -5,6-diaminouration was prepared as in part (d) of Example 1 by reduction of 1,6-amino-3-bis (cyclohexylmethyl) -5-nitrosouracil (1.00 g) and was immediately condensed with 4-formylbenzoic acid (Aldrich, 1424 g) by the method of J. Perumattam (Synthetic Commun, 1989, 19: 3367-3370) to give the title compound as an off-white solid (720 mg, 54% ), pf > 300 ° C; NMR-XH (DMSO-dd) consistent with the structure.

Analysis Calculated for C 26 H 32 N 404: C, 67.23; H, 6.94; N, 12.06. Found: C, 67.29; H, 6.98; N, 12.02. (b) Nonaethylene Methyl Ether Ester Glycol of (E) -4- [(1,3-bis (cyclohexymethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purine 8-yl] benzoic A watery paste of (E) -4 - [(1,3-bis (cyclohexylmethyl) -1,3,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid (from the part (a) of this example, 0.50 g) in anhydrous N, N-dimethylformamide (10 ml), briefly heated to near reflux under nitrogen, then N, '-carbonyldiimidazole (Aldrich, 0.211 g) was added to the slurry. pale yellow, which was diluted and turned orange like a detached gas.After a few minutes the watery paste turned a bright yellow and thickened like a yellow solid formed.The mixture was stirred for 18 h, Dilute with dichloromethane (30 mL), and filter The bright yellow solid was washed with dichloromethane (30 mL), and dried at 40 ° C to provide (E) -l, 3-bis (cyclohexylmethyl) -8- [3- (2- (1H-imidazol-1-ylcarbonyl) vinyl) phenyl] -9H-purin-2,6 (1H, 3H) -dione as a yellow powder (0.32 g) A mixture of this sample (0.32 g) g), nonaethylene glycol monomethyl ether (from part (a) of example 10, 0.27) 7 g) and anhydrous potassium carbonate (0.170 g) in acetonitrile (10 ml) was refluxed for 20 h. Chloroform (50 ml) was added and the solution was washed with IN HCl (20 ml). The organic layer was washed with brine, dried (magnesium sulfate), and eluted from a column of silica gel with 10% methanol-chloroform. Evaporation of solvents left a yellow waxy solid which was re-precipitated from ethyl acetate-hexanes. The yellow waxy solid precipitate was filtered and dried to nonaethylene glycol methyl ether of (E) -4- [l, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2-6- dioxo-9H-purin-8-yl] benzoic acid (0.355 g, 65%); NMR-XH (DMS0-d6) d: 8.24 (d, J = 8.4, 2, 2 CH), 8.06 (d, I = 8.6, 2, 2 CH), 4.40 (m, 2, CH20), 3.90 (d , J = 7.3, 2, CH2N), 3.75 (m, 4, CH2N and CH20), 3.70-3.40 (m, 32, 16"CH2), 3.19 (s, 3, CH3), 2.1-1.6 and 1.4-1.0 (m, 22, cyclohexyl CH2 and CH) Analysis Calculated for C45H70N4O? 3: C, 61.77; H, 8.06; N, 6.40, Found: C, 61.55; H, 7.99; N, 6.52.

Example 25 Nonaethylene Methyl Ether Ester Glycol of (E) -2 - [(1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8- il] benzoic (a) Acid (E) -2- [(1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid The 1,3-bis (cyclohexylmethyl) -5,6-dia inouracil is prepared as in part (d) of Example 1 by reduction of 1,6-amino-3-bis (cyclohexylmethyl) -5-nitrosouracil (2.00 g) and condensed immediately with 2-formylbenzoic acid (Aldrich, 1424 g) by the method of J. Perumattam (Synthetic Commun, 1989, 19: 3367-3370) to give the title compound as an off-white solid (1.22 g, 46%). %), pf 271-274 ° C; RMN-XH (üMSO-dβ) consistent with the structure. Analysis Calculated for C26H32N04: C, 67.22; H, 6.94; N, 12.06. Found: C, 67.25; H, 6.99; N, 12.11. (b) Nonaethylene Glycol Methyl Ether Ester Acid (E) -2- [(1,3-Bis (cyclohexylmethyl) -l, 2, 3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid (E) was converted -2 - [(1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] benzoic acid (from part (a) of this example, 0.100 g) by the method of part (b) of Example 24 to nonaethylene glycol methyl ether of (E) -2 - [(1,3-bis (cyclohexylmethyl) -1, 2, 3, 6-methyl ester tetra idro-2, 6-dioxo-9H-purin-8-yl] benzoic acid (0.082 g, 43%), as an amber oil; XH-NMR (DMS0-d6) d: 7.80-7.50 (m, 4, 4 aromatic CH), 4.20 (m, 2, CH20), 3.80-3.60 (m, 4, 2CH2N), 3.50-3.20 (m, 34, 17 CH2), 3.20 (s, 3, CH3), 1.9-1.4 and 1.2 -0.8 (m, 22, cyclohexyl) Analysis Calculated for C 5 H 7 o N 4013'0.85 EtOAc'0.64 H20: C, 60.50; H, 8.18; N, 5.83, Found: C, 60.50; H, 18.19; N, 5.83.

Example 26 Nonaethylene Glycol Methyl Ether Ester of (E) -4- (l, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-6-oxo-2-thioxo-9H-purin-8 -il) cinnamic (E) -4- (1,3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-6-oxo-2-thioxo-9H-purin-8-yl) cinnamic acid (WO) 96/04280, 500 mg, 0.99 mmol) is esterified with nonaethylene glycol methyl ether by the method of part (b) of Example 24. The title compound was isolated as a yellow waxy solid (0.145 g, 20%): NMR-XH (DMSO-de) d: 8.17 (d, J = 8.4, 2, 2 aryl CH), 7.90 (d, J = 8.4, 2, 2 aryl CH), 7.69 (d, J = 15.9, 1, CH =), 6.77 (d, J = 16.1, 1, CH =), 4.53 (d, J = 7.0, 2, CH2N), 4.40 (d, J = 7.0, 2, CH2N), 4.25 (m, 2, CH20), 3.70 (m, 2, CH20), 3.6-3.3 (m, 32, 16 CH2), 3.23 (s, 3, CH3), 2.4-2.0 (2m, 2, 2CH of cyclohexyl), 1.80-1.60 and 1.20-1.0 (both m, 20, cyclohexyl CH2). Analysis Calculated for C47H73N4O12S "0.89 H20: C, 60.49; H, 7.97; N, 6.00; S, 3.44, Found: C, 60.49; H, 7.70; N, 6.31; S, 3.55.

Example 27 Nonaethylene Glycol Methyl Ether Ester of (E) -4- (l, 3-Bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl acid ester cinnamic To a mixture of (E) -1, 3-bis (cyclohexylmethyl) -8- (3- (2- (lH-imidazol-1-ylcarbonyl) vinyl) phenyl) -9H-purin-2,6 (lH, 3H ) -dione (60.75 g, 0.112 mmol) and potassium carbonate (31.0 g, 0.225 mol) in acetonitrile (650 ml) was added nonaethylene glycol monomethyl ether, (part (a) of Example 10, 57.8 g, 135 mmol). The mixture was refluxed 18 h, cooled to room temperature, and diluted with chloroform (1200 ml). The chloroform solution was washed with IN hydrochloric acid (800 ml), water (500 ml), and brine (2 × 200 ml) and dried (magnesium sulfate). The evaporation of chloroform left the crude title compound as a yellow waxy solid. This solid was chromatographed twice on silica gel, first using 10% methanol-chloroform and then using 10% methanol-ethyl acetate as eluent, to give the title compound as a yellow waxy solid. Reprecipitation from chloroform-hexanes and drying in vacuo gave the title compound as a yellow waxy solid (64.5 g, 65%); X-NMR identical to the sample described in Example 10, part (b). Analysis Calculated for C47H72 4O13: C, 62.65; H, 8.05; N, 6.22. Found: C, 62.33; H, 7.94; N, 6.25.

Examples of Pharmaceutical Formulations In the following examples, the "active ingredient" can be any compound of the formula (I) or a pharmaceutically acceptable salt or solvate thereof, preferably the compound of Examples 2 to 26. (1) Formulations of tablets (i) Oral mg / tablet A B C Active ingredient 25 25 25 AvicelMR 13 7 Lactose 78 47 Starch (corn) 9 Starch (pregelatinized, NF15) 32 Sodium Starch Glicoate 5 Povidone MR 3 3 Magnesium Stearate 1 1 125 85 65 (ii) Sublingual mg / tablet D E Active ingredient 25 25 AvicelMR 10 Lactose 36 Mannitol 51 57 Sucrose 3 Acacia 3 Povidone MR 3 Magnesium stearate 1 90 125 Formulations A to E can be prepared by wet granulation of the first six ingredients with the povidone ™, followed by the addition of magnesium stearate and compression. iii) Muccal mg / tablet Active ingredient 25 Hydroxypropylmethyl cellulose (HPMC) 25 PolycarbofilMR 39 Magnesium stearate 1 90 The formulations can be prepared by direct compression of the mixed ingredients.

() Capsule formulations (i) Powder mg / Capsule F G Active Ingredient 25 25 A, .vi.celiMR 45 Lactose 153 Starch (1500 NF) 117 Sodium starch glycoate 2 2 Magnesium stearate 225 150 The formulations F and G can be prepared by mixing the. ingredients and filling two-part hard gelatin capsules with the resulting mixture. (ii) Liquid filling mg / Capsule H I Active ingredient 25 25 MacrogolMR 4000 BP 200 - Lecithin - 100 Oil of 'Cacahuate - 100 225 225 Formulation H can be prepared by melting the MacrogolMR4000 BP, dispersing the active ingredient in the melt and filling the two-part hard gelatin capsules therewith. Formulation I can be prepared by dispersing the active ingredient in the lecithin and peanut oil and filling the elastic, soft gelatin capsules with the dispersion. (iii) Controlled release mg / tablet Active ingredient 25 Avicel ™ 123 Lactose 62 Triethylcitrate 3 Ethylcellulose 12 225 The formulation can be prepared by mixing and extruding. the first four ingredients and giving them spherical shape and drying the extruded product. The dried pills were coated with. ethylcellulose as a membrane that controls the release and filled into two-part hard gelatin capsules. (3) Intravenous injection formulation (i)% by weight Active ingredients 2% Sodium hydroxide q.s. at pH 7 Water for 100% injections The active ingredient is recovered in the citrate buffer and sufficient hydrochloric acid is added to affect the solution and adjust the pH to 7. The resulting solution is brought to a volume and filtered through a micropore filter in sterile glass jars which are sealed and resealed.

Example G: Powder capsules for inhalation Active ingredient (0.5-7.0 μm powder) 1.0 mg Lactose (30-90 μm powder) 49.0 mg The powders were mixed until they became homogeneous and filled into appropriately sized hard gelatine capsules (50 mg per capsule).

Example H: Aerosol for inhalation Active ingredient (0.5-7.0μm powder) 50.0 mg Sorbitan trioleate 100.00 mg Sodium Saccharin (powder 0.5-7.0μm) 5.0 mg Methanol 2.0 mg Trichlorofluoromethane 4.2 mg Dichlorodifluoromethane at 10.0 ml The trioleate of sorbitan and methanol were dissolved in the trichlorofluoromethane. The sodium saccharin and the active ingredient were dispersed in the mixture which was then transferred to a container or container suitable for aerosol and the dichlorofluoromethane was injected through the valve system. This composition provided 0.5 mg of the active ingredient in each 100μl dose.

"Biological activity I) Test in Carrageenan Pleurisy The anti-inflammatory activity of compounds of the invention were determined by the method of Vinegar, R, et al., Proc. Soc. Exp. Biol. Med., 1981, 168, 24-32, using 150 male Lewis rats. £ 20 grams. The carrageenan dose was 0.075 mg / rat. The pleural exudate was collected four hours after the injection of carrageenan. Acute anti-inflammatory activity was determined by inhibition of pleural edema and inflammatory cells (neutrophils) from a negative (vehicle) control group. 2) Colitis Assay with Acetic Acid The activity of the compounds of the invention was determined in the rat model with Acetic Acid Colitis using the procedure of Fretland, D., et al., 1990, 255: 572.-576 in Lewis rats. male of 275 + 25 grams. The compounds were administered either orally or rectally 24, 16 and 4 hours prior to installation in 40 seconds. 3% acetic acid solution in the proximal 6 cm of the colon under light anesthesia. The colon was immediately washed with 5 cc of saline. 24 hours later the rats were sacrificed and 6 cm of proximal colon were excised and weighed for edema. Neutrophil inflammation was determined by measuring the MPO levels in the scraped colonic mucosa of these rats. The antigenic activity was quantified by inhibition of edema formation and mucosal MPO levels were compared with the negative control group (vehicle).

Results NT = Not tested ic = Intracolonic administration po = Oral administration The main acid is, the compound of reference example 1 is inactive in both tests. 3) In Vivo Septic Shock Model: C Parvum / Shock LPS Male CD-1 mice, 25-30 g (Charles River: Raleigh, NC), are injected intravenously (i.v.) with 100 μg of dead or killed C. parvum (Coparvax, Burroughs Wellcome, RTP, NC). Ten days later the mice are injected i.v. with 20 μg E. Coli 026: B6 lipopolysaccharide (LPS; Difco Labs, Detroit, MI) in the presence of analgesic butorphenol (150 μg per mouse).

The test compounds are dissolved in dimethyl sulfoxide and diluted in 0.5% methyl cellulose and then orally dosed 2 hours before the LPS and at the same time as the LPS.

Results It is noted that in relation to this date, the best method known by the applicant to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property

Claims

1. A compound of the formula (I) or a solvate thereof characterized in that: X is -O- or -NH-; Q is (-CH2-) P, (-CH = CH-) P, (-C = C-) P wherein p is an integer from 0 to 4; R1 is hydrogen or methyl; R2 and R3 independently represent 0 or S n is an integer from 1 to 50; and R is hydrogen? methyl.

2. A compound according to claim 1, characterized in that X is -O- or -NH- and R1 is H.

3. A compound according to claim 1 6 2, characterized in that n is an integer from 8 to 20.

4. A compound according to claim 3, characterized in that n is an integer of 8-15.

5. A compound according to any of claims 1-4, characterized in that R3 represents O and R2 represents O O S.

6. A compound according to claim 5, characterized in that R2 and R3 represent O.

7. A compound according to any of claims 1-6, characterized in that p represents 0 or 1.

8. A compound according to any of claims 1-7, characterized in that Q represents (-CH = CH-) P.

9. A compound according to any of the preceding claims characterized in that the substituent binds to the phenyl ring in the position for

10. A compound of the formula (la) or a solvate thereof, characterized in that X is -O- or -NH-; Q is (-CH2-) P, (-CH = CH-) P, (-CsC-) p wherein P is an integer from 1 to 4; R1 is hydrogen or methyl; n is an integer from 1 to 50; and R is hydrogen or methyl.

11. A compound according to claim 1, characterized in that it is: Decaethylene Glycol Methyl Ether Ester of (E) -4- (1, 3-Bis (cyclohexylmethyl) -l, 2, 3, 6-tetrahydro-2, 6-dioxo-9H-purin-8-yl) cinnamic; and Nonaethylene Glycol Ether Ester Methyl Ether (E) -4- (1, 3-bis (cyclohexylmethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl) cinnamic; Nonaethylene Glycol Ether Ester of Acid (E) -3- [1, 3-bis (celohexyl eti1) -1, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic; Amide of Nonaethylene Glycol Ether Methyl Ether (E) -4- [l, 3-bis (cyclohexyl ethyl) -1,2,3,6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic; Nonaethylene Glycol Ether Ester of (E) -4- [1, 3-bis (cyclohexylmethyl) -1, 2, 3, 6-tetrahydro-2,6-dioxo-9H-purin-8-yl] cinnamic acid ester .

12. A compound according to any of claims 1 to 11 or a pharmaceutically acceptable solvate thereof for use in therapy.

13. A pharmaceutical composition characterized in that it comprises a pharmaceutically acceptable compound or solvate thereof according to any of claims 1 to 11 together with a pharmaceutically acceptable diluent or carrier.

14. The use of a compound according to any of claims 1 to 11 or a solvate thereof pharmaceutically acceptable for the manufacture of a medicament for the treatment of inflammatory conditions and immune disorders.

15. A method for the treatment of inflammatory conditions and immune disorders in a subject in need thereof, which is characterized in that it comprises administering to the subject a therapeutically effective amount of a compound according to any of claims 1 to 11 or a solvate thereof pharmaceutically acceptable.

16. A process for preparing a compound according to claims 1-11 or solvates thereof, characterized in that it comprises reacting a compound of the formula (II). O li H O N N '\ O N N (Q) _C_0 (II) or an activated derivative thereof with a compound of the formula (III). wherein Q, X, R1, R and n are as defined in claim 1, and optionally converting the compound of the formula (I) thus formed to a different compound of the formula (I) or to a corresponding solvate.

17. A process for preparing a compound of the formula (I), characterized in that it comprises the condensation of a compound of the formula (IV):. or an acetal derivative thereof, wherein Q, X, R1, n and R are as defined above, with 1,3-bis (cyclohexylmethyl) -5,6-diaminouracil.