MXPA99007236A - Certain dinucleotides and their use as modulators of mucociliary clearance and ciliary beat frequency - Google Patents

Abstract

The present invention relates to certain novel dinucleotides and formulations thereof which are highly selective agonists of the P2Y2 and/or P2Y4 purinergic receptor. They are useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, PCD, cystic fibrosis, as well as prevention of pneumonia due to immobility. Furthermore, because of their general ability to clear retained mucus secretions and stimulate ciliary beat frequency, the compounds of the present invention are also useful in the treatment of sinusitis, otitis media and nasolacrimal duct obstruction. They are also useful for treatment of dry eye disease and retinal detachment.

Description

CERTAIN DINUCLEOTIDES AND THEIR USE AS MODELERS OF MUCOCILIAR ELIMINATION AND FREQUENCY OF THE CILIARY RHYTHM I NTRODUCTION Technical Field This invention relates to certain dinucleotides that increase the hydration of secretions of retained mucosa, stimulate the production of mucins and increase the frequency of the ciliary rhythm to increase the elimination of retained secretions. BACKGROUND OF THE INVENTION Chronic obstructive pulmonary disease (COPD) affects 15 million patients in the US. and it is the sixth leading cause of death. It is characterized by the retention of secretions of the mucosa in the lungs. Many patients who have been diagnosed with COPD have a condition called chronic bronchitis (BC) and 600,000 patients are hospitalized every year due to a watery BC exacerbation. Cystic fibrosis and Primary Ciliary Dyskinesia (PCD) are other examples of lung disorders that assume a clinical profile similar to COPD. Ciliary dyskinesia, either primary or secondary, results in retained secretions that can only be removed by coughing. Another disease state characterized by the accumulation of secretions of retained mucosa is sinusitis. Sinusitis is an inflammation of the paranasal sinuses normally associated with an upper respiratory infection. In this country, it is a more common concern for health care, affecting an estimated 31 million people. (A. Moss and V. Parsons, National Center for Health Statistics, 1986: 66-7, DHHS Publication No. (PHS) 86-1588 (1985)). Otitis media (OM) is a viral or bacterial infection of the middle ear that primarily afflicts children under three years of age. Usually, it is precipitated by an upper respiratory infection that diffuses in the middle ear via nasopharyngeal and the eustachian tube. Approximately 25-50 million departmental visits are made every year for the diagnosis and treatment of OM. At age three, approximately 75% of the children had had at least one episode of acute OM (J. Klein, Clin. Infect. Dis. 19, 823-33) (1994)). After appropriate antibiotic treatment, fluid accumulated in the middle ear remained, causing hearing damage and potential delay in language and cognitive development. The improved ability to eliminate secretions in the middle ear could reduce or eliminate the significant sequelae of otitis media. An additional disorder that results from retained secretions is pneumonia. Patients who are immobilized for a variety of reasons are at high risk of developing pneumonia. Despite the extra surveillance and numerous interventions, pneumonia develops in more than 400,000 patients every year, with significant morbidity and mortality. There are also situations where it is therapeutically convenient to increase the lacrimal drainage system, when the lacrimal drainage system does not work properly the result can be excessive tearing (epiphora), mucopurulent discharge and recurrent dacryocystitis. Current treatments for nasolagrymal obstruction are commonly invasive surgical procedures and researchers have tried to discover non-invasive pharmaceutical treatments. The secretion of tears can be stimulated by the tissues of the lacrimal access via mechanisms mediated by the purinergic receptor of P2Y2 and / or P2Y4 similar to those in which the epithelium of the airways is hydrated. Eye dryness disease is the general term for indications produced by abnormalities of the precorneal lacrimal film characterized by a decrease in the production of tears or an increase in the evaporation of the tear film, together with the ocular surface disease that result. Currently, the pharmaceutical treatment of eye dryness disease is commonly limited to the administration of artificial tears (saline) to temporarily moisturize the eyes. However, the relief is short and frequent dosing is necessary. Normally, mucous secretions are removed via the mucociliary clearance system (MCE). EMC is within the integrated action within three components: a) secretion of the mucosa by balloon cells and submucosal glands; 2) the movement of the cilia on the epithelial cells that drives the mucosa through the luminal surface; and 3) the transport of ions in and out of luminal epithelial cells that concomitantly control the flow of water in the mucosa. It is now known that nucleotide phosphates such as uridine 5'-triphosphate (UTP) modulate all the components of the EMC system. First, it has been shown that UTP increases both the regimen and the total amount of mucin secretion by the balloon cells in vitro (M. Lethem, et al., Am. J. Respir., Cell Mol. Biol. 9, 315-22. (1993)). Second, UTP has been shown to increase the rate of cilia rhythm in human airway epithelial cells in vitro (D. Drutz, et al., Drug, Dev. Res. 37 (3), 185 (1996)) . And third, it has been shown that UTP increases the secretion of IC ", and therefore the secretion of water from airway epithelial cells in vitro (S. Mason, et al., Br. J. Pharmacol, 103, 1649- 56 (1991)) In addition, it was thought that the release of the surfactant from Type II alveolar cells in response to UTP (Gobran, Am. J. Physiol. 267, L625-L633 (1994)) contributes to the optimal functioning of the lungs and can help to increase MCE (M. Knowles, et al., N. Engl. J. Med. 325, 533-38 (1991).) UTP has been shown to increase intracellular Ca ++ due to stimulation of phospholipase C by the P2Y2 receptor (H. Brown, et al., Mol.Pharmacol, 40, 648-55 (1991).) Modulation of the UTPs of all components of the mucociliary augmentation system results in a 2.5-fold improvement in the mucociliary lung clearance in normal volunteers without any significant lateral effect (K. Olivier, et al., Am. J. Respir. Crit. Care Med. 154, 217-23 (1996)). In addition, UTP significantly increased cough elimination (removal of retained secretions from coughing) in patients with PCD (P. Noone, et al., Am. J. Respir. Crit. Care Med. 153, A530 (1996)). It should be noted that PCT Application WO 96/40059, published on December 19, 1996, disclosed nucleotide compounds useful in the treatment of respiratory airway diseases. Because UTP demonstrated the ability to increase the removal of retained mucosal secretions, the applicants were motivated to investigate whether other nucleoside phosphates could be equal, if not more, therapeutically effective. The present invention is based on this investigation. The dinucleotides previously described are listed in Table I, together with their references in the corresponding literature. TABLE I DINUCLEOTIDES IN LITERATURE (the numbers in parentheses correspond to the following references) Np5N Np5N 'Np6N Np6N' Np9N Ap5A (4) Ap5T (20) Ap6A (4) Ap5T (20) Ap9A (4) AppZppA DppZppD ApZppZpA ApSpZpSpA CH2 (8) CH2 (15) CH2 (8) CHF (8) CH2CH2 (8) CH2CH2 (15) CH2CH2 (8) CF2 (8) CHF (8) CHF (15) CHF (8) O (8) CF2 ( 8) CF2 (15) CF2 (8) CHCl (8) CHCl (15) CHCl (8) CCI2 (8) CCI2 (15) CCI2 (8) A = Adenosine eA = Ethanoadenosine U = Uridine m7G = 7-Methylguanosine G = Guanosine m2,7G = 2,7-Dimethylguanosine T = Thimidine m2'27G = 2,2,7-Trimethylguanosine X = Xanthosine NAD = Nicotinamide Riboside TAD = Thiazofurin C-NAD = C-nicotinamide riboside BAD = Benzamide riboside C-PAD = C-picolinamide riboside D = 2,6-Diaminopurine N = Nucleoside (1) M.A.G. Sillero et al., Eur. J. Biochem. 76, 331 (1977) 2) C.G. Vallejo and others, Biochim. Biophys. Acta, 483, 304 (1976) 3) H. Coste et al., J. Biol. Chem.262, 12096 (1987 4) K.E. Ng et al., Nucleic Acid Res., 15, 3573 (1987) 5) J. Stepinski et al., Nucleosides & Nucleotides, 14, 7171 (1995) 6) A. Zatorski et al., J. Med. Chem. 39, 2422 (1996) 7) P. Rotilan et al., FEBS, 280, 371 (1991) 8) P.C. Zamecnik and others, Proc. Natl. Acad. Sci., 89, 2370 (1992) 9) J. Walker et al., Biochemistry, 32, 14009 (1993) (10) R.H. Hiderman et al., J. Biol. Chem. 266, 6915 (1991) 11) J. Luthje et al., Eur. J. Biochem., 173, 241 (1988) 12) R.H. Silverman et al., Microbiological Rev., 43, 27 (1979) 13) C.D. Lobaton et al., Eur, J. Biochem., 40, 495 (1975) 14) G. Lowe et al., Nucleosides & Nucleotides, 10, 181 (1991) (15) G.M. Blackburn et al., Nucleosides & Nucleotides, 10, 549 (1991) 16) (JC Baker et al., Mutation Res., 208, 87 (1988) 17) G. Klein et al., Biochemistry, 27, 1897 (1988) 18) E. Castro et al. Br. J. Pharmacol., 100, 360 (1990) (19) DR Elmaleh et al., Proc. Natl. Acad. Sci.81, 918 (1984) ) R. Bone et al., J. Biol. Chem., 261, 16410 (1986) 21) Fed. Amer. Soc. Exper. Bio. Abstr. Part I, no. 1878 (1991) 22) M.T. Miras-Portugal and others, Ann. NY Acad. Sci. 603, 523 (1990) (23) A, Guranowski et al., Biochemistry, 27, 2959 (1988) (24) F. Grummt et al., Plant Mol. Bio., 2, 41 (1983) (25) A.G., McLenan et al., Nucleic Acid Res., 12, 1609 (1984) (26) P. Azmecnik et al., Analytical Biochem., 134, 1 (1983) (27) E. Rapaport et al., Proc. Natl. Acad. Sci., 78, 838 (1981) (28) T. Kimura and others Biol. Pharm. Bull., 18, 1556 (1995) (29) E. Schulze-Lohoff et al., Hypertension, 26, 899 (1995) (30) B.K. Kim and others., Proc. Natl. Acad. Sci., 89, 2370 (1992-) (31) P.C. Zamecnik and others, Proc. Natl. Acad. Sci.89, 2370 (1992) (32) H. Morii et al., Eur. J. Biochem., 205, 979 (1992) (33) E. Castro et al. Pflugers Arch., 426, 524 (1994) (34) H. Schluter et al., Nature, 367, 186 (1994) (35) E. Castro et al., Br. J. Pharmacol., 206, 833 (1992) ( 36) T. Casillas et al., Biochemistry, 32, 14203 (1993) (37) J. Pintor et al., J. Neurochem., 64, 670 (1995) (38) E. Castro et al., J. Biol. Chem., 270, 5098 (1995) (39) VA Panchenko et al., Neuroscience, 70, 353 (1996) (40) E. Castro et al., Br. J. Pharmacol., 100, 360 (1990) (41) J. Pintor et al., Gen. Pharmac, 26, 229 (1995) (42) J. Pintor et al. Br. J. Pharmacol., 115, 895 (1995) (43) A. Kanavarioti et al., Tett. Lett., 32, 6065 (1991) COMPENDIUM OF THE INVENTION The invention provides novel compounds of the Formula I and pharmaceutical compositions thereof. The invention also provides compounds useful in the removal of retained mucus secretion and the increase in ciliary rhythm frequency.

Accordingly, a broad embodiment of the invention is directed to compounds of the general Formula I or pharmaceutically acceptable esters or salts thereof: Formula I wherein X is oxygen, methylene, difluoromethylene, imido; n = 0, 1 or 2; m = 0, 1 or 2; n + m = 0, 1, 2, 3 or 4; and B and B 'are each independently a purine residue or a pyrimidine residue bound through the 9 or 1 position, respectively; Z = OH or N3; Z '= OH or N3; Y = H or OH; Y '= H or OH; as long as Z is N3, Y is H or when Z 'is N3, Y' is H; and as long as the others are excluded from the compounds in Table I. The compounds of the present invention are highly selective agonists of P2Y2 and / or P2Y4 purinergic receptor, therefore, they may be useful in the treatment of chronic obstructive pulmonary diseases such as chronic bronchitis, DCP and cystic fibrosis and may also be useful in the treatment of chronic obstructive pulmonary diseases. treatment of immobilized patients who are at risk of developing pneumonia. In addition, because of their general ability to eliminate secretions from retained mucosa and stimulate ciliary rhythm frequency, the compounds of the present invention may also be useful in the treatment of sinusitis, otitis media and obstruction of the nasolacrimal duct. They can also be useful for the treatment of eye dryness, retinal detachment and wound healing. In addition, due to the pharmacological actions of these compounds, they are useful in facilitating sputum induction procedures. Additionally, it was postulated that the compounds of the present invention could increase the performance of athletes by increasing the elimination of mucosal secretions from the lungs. DETAILED DESCRIPTION OF THE INVENTION This invention provides novel compounds of Formula I and pharmaceutical compositions thereof. The invention also provides compounds useful in the removal of retained mucosa and in the increase in ciliary rhythm frequency. Accordingly, a broad embodiment of the invention is directed to novel compounds of the general Formula I: Formula I wherein X is oxygen, methylene, difluoromethylene, imido; n = 0, 1 or 2; m = 0, 1 or 2; n + m = 0, 1, 2, 3 or 4; and B and B 'are each independently of a purine residue or a pyrimidine residue linked through the 9 or 1 position, respectively; Z = OH or N3; Z '= OH or N3; Y = H or OH; Y '= H or OH; as long as Z is N3, Y is H or when Z 'is N3, Y' is H; and as long as the others are excluded from the compounds of Table I; or pharmaceutically acceptable esters or salts thereof. The furanose sugar is preferably in the β-configuration. The furanose sugar is more preferably in the β-D configuration. The preferred compounds of Formula I are the compounds of Formula IA. Formula IA where X = O; n + m = 1 or 2; Z, Z ', Y and Y' = OH; B and B 'are uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas I I and l l l; or X = 0; n + m = 3 or 4; Z, Z ', Y and Y' = OH; B = uracil; B 'is uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; or X = O; n + m = 1 or 2; Z, Y and Y '= OH; Z '= H; B = uracil; B 'is uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; or X = O; n + m = 0, 1 or 2; Z and Y = OH; Z '= N3; Y '= H; B = uracil; B '= thymine; or X = 0; n + m = 0, 1 or 2; Z and Z '= N3; Y and Y '= H; B and B '= thymine; or X = CH2, CF2 or NH; n and m = 1; Z, Z \ Y and Y '= OH; B and B 'is uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; or as long as the compounds of Table I are excluded; or the pharmaceutically acceptable salts thereof. Another group of the compounds of Formula I are the compounds of Formula IB or the pharmaceutically acceptable salts thereof: Formula IB wherein x is oxygen, methylene, difluoromethylene, imido; n = 0 or 1; m = 0 or 1; n + m = 0, 1 or 2; and B and B 'are each independently a purine residue, as in Formula I I, or a pyrimidine residue, as in Formula III, linked through position 9 or 1, respectively. In the case where B and B 'are uracil, attached to the N-1 position to the ribosyl portion, then the total of m + n can be equal to 3 or 4 when X is oxygen (see example 5). The ribosyl portions are in the D configuration, as shown, but may be L, D and L. The D configuration is preferred. Formula I I wherein Ri is an alkyl or aryl moiety as defined below or? -A (alkyl of d-6) WITH H (C? -6 alkyl) wherein A is amino, mercapto, hydroxy or carboxyl; R 2 is O (1-adenine oxide derivatives) or is absent (adenine derivatives); or Ri and R2 taken together form a 5-membered fused imidazole ring (derivatives of 1, N6-ethenoadenine), optionally substituted at the 4 or 5 positions of the ethene portion with the alkyl, aryl or aralkyl portions as defined below; R3 is alkyl, aryl or aralkyl, alkylamino, arylamino or aralkylamino (NHR '); alkoxy, aryloxy or aralkyloxy (OR '); alkylthio, arylthio or aralkylthio (SR ') as defined below; or? -A (C? .6 alkyl) CONH (C?. β alkyl) B- wherein A and B are independently amino, mercapto, hydroxy, carboxyl, or esters, amides or pharmaceutically salts thereof acceptable Thus substituted adenine derivatives include 1-adenine oxide; 1, N6- (4 or 5 substituted ethene) adenine; 6-substituted adenine; or 8-substituted aminoadenine, wherein R 'of wherein the 6- or 8-HNR' groups are chosen from: arylalkyl groups (C? .6) with the aryl moiety optionally functionalized as described below; I rent; and alkyl groups with functional groups therein, such as: ([6-aminohexyl] carbamoylmethyl) and? -aminoacetylated (hydroxy, thiol and carboxy) (C2.10) alkyl wherein the acyl group is selected from, but is not limited to, acetyl, trifluoroacetyl, benzoyl, substituted benzoyl, etc., or the carboxylic portion is present as its ester or amide derivative, for example, the ethyl or methyl ester or its methyl, ethyl or benzamido derivative. The? -amino (hydroxy, thiol) moiety can be alkylated with a C? Alkyl group. . Likewise, B or B ', or both, can be a pyrimidine with the general formula of Figure III, linked through position 1: Formula III wherein: R 4 is hydrogen, hydroxy, mercapto, amino, cyano, aralkoxy, Cilt-alkylthio, Ci-β alkoxy, C?-6 alkylamino or dialkylamino, alkyl groups optionally linked to form a heterocycle; Rs is hydrogen, acyl (e.g., acetoyl or benzoyl), C? S alkyl), aroyl, optionally functionalized as defined below, C? -5 alkanoyl, benzoyl or sulfonate; R6 is hydroxy, mercapto, alkoxy, aralkoxy, C? .6 alkyl, amino, C? -5 disubstituted amino, triazolyl, alkylamino or dialkylamino, wherein the alkyl groups are optionally linked to form a heterocycle or a bond to N3 to form an optionally substituted ring; Rs and Rβ taken together form an imidazole ring fused with 5 members between positions 3 and 4 of the pyrimidine ring (3-N, -ethenocytosine derivatives) optionally substituted with the 4 or 5 positions of the ethene portion with the alkyl, aryl or aralkyl moieties as defined below. R7 is hydrogen, hydroxy, cyano, nitro, alkenyl with the alkenyl portion optionally linked through oxygen to form an optionally substituted ring on the carbon adjacent to the oxygen with the alkyl or aryl groups, substituted alkynyl, halogen, alkyl, substituted alkyl, perhalomethyl (e.g., CF3), C2.6 alkyl, C2.3 alkenyl or substituted ethenyl (e.g., allylamino, bromovinyl and ethyl propenoate or propenoic acid), C2-3 alkynyl or substituted alkynyl; or R6 and R7 can together form a saturated or unsaturated 5- or 6-membered ring linked through N or O in R6, so that the ring can contain substituents which themselves contain functionalities; as long as R8 is amino or substituted amino, R7 is hydrogen; and R8 is hydrogen, amino or substituted amino, alkoxy, arylalkoxy, alkylthio, arylalkylthio, carboxamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy or phenylthio, or pharmaceutically acceptable esters, amides or salts thereof. In the general structures of Formulas II and II above, the acyl groups advantageously comprise alkanoyl or aroyl groups. Alkyl groups that can be straight or branched advantageously contain from 1 to 8 carbon atoms, particularly from 1 to 4 carbon atoms optionally substituted by one or more appropriate substituents as described below. The aryl groups including the aryl portions of said groups as aryloxy are preferably phenyl groups optionally substituted by one or more appropriate substituents as described below. The aforementioned alkenyl and alkynyl groups advantageously contain from 2 to 8 carbon atoms, particularly from 2 to 6 carbon atoms, v. gr. , ethenyl or ethynyl, optionally substituted by one or more appropriate substituents as described below. Suitable substituents of the aforementioned alkyl, alkenyl, alkenyl and aryl groups are advantageously selected from halogen, hydroxy, C? - alkoxy, C? -4 alquilo alkyl, Cß- ar aryl, C ar. ar arylalkyl, C7-? 2 arylalkoxy. Arylalkoxy, carboxy, cyano, nitro, sulfonamido, sulphonate, phosphate, sulphonic acid, amino and substituted amino wherein the amino is substituted once or twice by a C? - alkyl and when substituted twice, the alkyl groups being attached optionally to form a heterocycle. The compounds of the present invention encompass their pharmaceutically acceptable esters, such as, but not limited to, acetyl and benzoyl esters. The esters can be formed by the reaction of the desired hydroxy compound with the appropriate acid, activated with carbonidiimidazole, dicyclohexylcarbodiimide or other suitable condensing agent, or with an acid anhydride or acid chloride with or without a basic catalyst such as a tertiary amine, salt of quaternary ammonium or an inorganic base. The compounds of the present invention also encompass their non-toxic pharmaceutically acceptable salts, such as, but not limited to, an alkali metal salt such as sodium or potassium.; an alkaline earth metal salt such as manganese, magnesium or calcium; or an ammonium or tetrakyl ammonium salt, that is, NX4 + (where x is C? -). The pharmaceutically acceptable salts are salts that retain the desired biological activity of the parent compound and do not impart undesirable toxicological effects. The present invention also encompasses the acylated prodrugs (eg, esters) of the compounds described herein. Those skilled in the art will recognize various synthetic methodologies that can be employed to prepare pharmaceutically acceptable non-toxic salts and acylated prodrugs of the compounds encompassed by Formulas I, IA and IB. The compounds of the present invention are highly selective agonists of the purinérgino receptor of P2Y2 and / or P2Y4; thus, they are useful in the treatment of mammals including humans suffering from chronic obstructive pulmonary diseases such as chronic bronchitis, FAD, cystic fibrosis, as well as the prevention of pneumonia due to immobility. In addition, because of the general ability to clear retained mucosal secretions and stimulate ciliary rhythm frequency, the compounds of the present invention are also useful in the treatment of sinusitis, otitis media and obstruction of nasolacrimal duct in mammals, including humans . Additionally, the compounds of the present invention are useful for treating mammals including humans with dry eye and retinal detachment. Although the compounds of the present invention are primarily concerned with the treatment of human subjects, they can also be used for the treatment of other mammalian subjects such as dogs and cats for veterinary purposes. The pharmaceutical utility of the compounds of this invention is indicated by the analysis of inositol phosphate for P2Y2 and other P2Y receptor activity. This analysis is widely used, as described in E. Lazarowski, et al., Brit, J. Pharm. 1 16, 1619-27 (1995), are based on the formation of inositol phosphate as a measure of activation receptor activity of bound compounds via G proteins to phospholipase C. Compounds of General Formulas I, IA or IB they may be administered orally, topically, parenterally by inhalation or spraying, intra-operatively, rectally or vaginally in dosage unit formulations containing conventional pharmaceutically acceptable non-toxic carriers, adjuvants and vehicles. The term "topically" as used herein includes patches, gels, creams, ointments, or drops for nose, ears or eyes. The term "parenteral" as used herein, includes subcutaneous injections, intravenous, intramuscular, instrasternal injection or infusion techniques. In addition, a pharmaceutical formulation comprising a compound of the general formulas I, IA or I B and a pharmaceutically acceptable carrier is provided. U or more compounds of the formulas I, IA or I B may be present in relation to one or more non-toxic pharmaceutically acceptable carriers, diluents or adjuvants and, if desired, other active ingredients. One such vehicle could be sugar, where the compounds can be incorporated intimately into the matrix through glasification or simply mixed with the vehicle (eg, lactose, sucrose, trehalose, mannitol) or other excipients acceptable for delivery to the lung or respiratory airways. One or more compounds of Formulas I, IA or I B can be administered separately or together, either separately or together with mucolytics such as DNAse or acetylcysteine. The pharmaceutical compositions containing the compounds of the general formulas I, IA or IB may have the form suitable for oral use, for example, as tablets, troches, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules. , or syrups or elixirs. The compositions intended for oral use can be prepared according to any method known in the art for the manufacture of pharmaceutical compositions and said compositions can contain one or more agents selected from the group consisting of wetting agents, flavoring agents, coloring agents and preservatives in order to provide pharmaceutically elegant and tasty preparations. The tablets contain the active ingredient in admixture with pharmaceutically acceptable non-toxic excipients which are suitable for the manufacture of tablets. These excipients may be, for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate.; granulating or disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example, starch, gelatin and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to retard disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a long period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate can be used. Formulations for oral use can also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient it is mixed with water or with oily substances, for example, peanut oil, liquid paraffin or olive oil. Aqueous suspensions containing the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Said excipients are suspending agents, for example, calcium carboxymethylcellulose, methylcellulose and sodium alginate. The dispersing agents or humectants can be products present in the nature of phosphatide or condensation of allylene with fatty acids, or condensation products with ethylene oxide with long-chain aliphatic alcohols, or condensation products with ethylene oxide with partial acid esters fatty acids and hexitol, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides. Those skilled in the art will recognize that many specific excipients and wetting agents are encompassed by the above general description. The aqueous suspensions may also contain one or more preservatives, for example, ethyl p-hydroxybenzoate or n-propyl one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin. Dispersible powders and granules suitable for the preparation of an aqueous suspension by the addition of water provide the active ingredient mixed with a dispersing agent or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those mentioned above. Additional excipients, for example, sweetening, flavoring and coloring agents, may also be present. The compounds of the general formulas I, IA or I B can be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and pH regulating agents can be dissolved in the vehicle. The sterile injectable preparation can be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent. Among the vehicles and acceptable solvents that may be employed are sterile water, saline or Ringer's solution. The compounds of the general Formulas I, IA, or I B can also be administered in the form of suppositories for administration in the ears, rectal or vaginal of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at body temperature and therefore melted to release the drug. These materials are cocoa butter and polyethylene glycols. The solutions and compounds of the general formulas I, IA or I B can be administered by intra-operative installation. The dose levels of the order of about 10'7 M to about 10"1 M, preferably in the range of 10" 5 to 10"1 M, are useful in the treatment of the conditions indicated above. it can be combined with the carrier materials to produce a single dosage form that will vary depending on the host treated and the particular mode of administration., it will be understood, that the specific dose level for any particular patient will depend on a variety of factors including the activity of the specific compound employed, age, body weight, general health, sex, diet, time of administration, route of and regimen of excretion, combination of the drug and the severity of the particular disease that undergoes therapy. The compounds encompassed by the present invention can be prepared by condensation of a mono, di- or nucleoside triphosphate, activated with a condensing agent such as, but not limited to, carbonyldiimidazole or dicyclohexylcarbodiimide, with a second molecule thereof a mono, di - or triphosphate or different to form the desired polynucleotide dinucleotide; or a nucleoside phosphate, activated as above, can be sequentially condensed with a portion of mono, di or polyphosphate without nucleoside, such as, but not limited to a monophosphate or pyrophosphate linkage to give the desired dinucleotide polyphosphate, the intermediate not isolated in such a case being a mononucleotide polyphosphate; or a portion of mono, di- or polyphosphate, activated as mentioned above, or in the form of an acid halide or other reagent derivative towards nucleophilic displacement, can be sequentially condensed with a dinucleotide or polyphosphate phosphate to give the polyphosphate The desired dinucleotide or desired dinucleotide polyphosphate can be formed by modification of a dinucleotide polyphosphate formed by substitution or derivatization of a portion or portions of the purine, pyrimidine or carbohydrate ring. The nucleoside phosphates used as starting materials may be commercially available or they may be made from the corresponding nucleosides by methods well known to those skilled in the art. Likewise, wherein the nucleosides are not commercially available, or they can be formed by modification of other readily available nucleosides or by the synthesis of heterocyclic and carbohydrate precursors by methods well known to those skilled in the art. The following is a list of Trademarks that appear in the following examples DEAE ™ Cellulose PEI ™ Column (Aldrich) AG-MP50 ™ Strong Cation Exchange (BioRad) DowexdO (H +) ™ DEAE Sephadex ™ Resin PRPX-100 ™ Column ( Hamilton) Sephadex DEAE A25 ™ Column Those skilled in the art will recognize that the starting materials may vary and the additional steps to produce compounds encompassed by the present invention, as demonstrated by the following examples. In some cases the protection of certain reactive functionalities may be necessary to achieve some of the above transformations. In general, the need for protecting groups will be apparent to those skilled in the art in organic synthesis as well as the conditions necessary to bind and remove such groups. The invention is further illustrated by the following examples which are not intended to limit the invention in scope or spirit to the processes described therein. Example 1 Preparation of P1, P4-Di (5'-P2, P3-uridine methylenetetraphosphate) Methylenediphosphonic acid (Aldrich, 0.0088 g, 0.05 mmol) was dissolved in anhydrous DMF (0.5 mL) with the addition of tributylamine (24 μL, 0.1 mmol). The solution was evaporated to dryness twice with anhydrous DMF (2 x 1 mL), the dried residue was dissolved in anhydrous DMF (0.5 mL) and a 4-morpholine-N, N'-dicyclohexylcarboxamidine salt solution was added. 5'-monofosfomorfolidato of similarly dried uridine (Sigma, 0.137 g, 0.2 mmol) in DMF anhydride (0.5 μL). The reaction mixture was heated at 80-90 ° C for 7 hours; then the solvent was removed by evaporation under reduced pressure. The residue dissolved in water (2 μL) was applied to a DEAE cellulose column (2.5 x 50 cm volume bed) in the bicarbonate form. The column was eluted with water, followed by a gradient of ammonium bicarbonate (0-0.33 M, in 900 mL). The progress of the elution was monitored by absorbance of the eluate at 254 nm; the fraction eluting between 0.23 and 0.26 M is recovered, evaporated to dryness and desalted by repeated evaporation with deionized water. The residue was dissolved in water (300 μL) and purified in aliquots of 50 μL by semipreparative HPLC (Alltech PEÍ 5μ, 10 x 250 mm, gradient 0 - 0.66-M ammonium bicarbonate, 5.0 mL / min, 20 minutes); the peaks eluting at 8.7 -9.0 minutes of each operation were combined and lyophilized to give the title compound (0.007 mmol, 14% yield, quantified by comparing its absorbance at? max 263 with that of a normal monophosphate solution of uridine). The chromatographic purity was 96.5% on an Alltech PEI column, gradient of 0-0.66-M ammonium bicarbonate, 1.0 mL / min, 20 min. , retention time 13.03 minutes. 1 H NMR in D20 (d ppm tetramethylsilane): 2.39 (t, J = 21.5 Hz, 2H); 4.12 (m, 6H); 4.243 (m, 4H); 5,841 (d, J = 7.9 Hz, 2H); 5,847 (d, J = 4.5 Hz, 2H); 7.77, d, J = 8.1 Hz, 2H). 31 P NMR in DzO (ppm of H3P04) -10.2 to -10.7 (m complex, 2P); 7.8 to 8.4 (complex m, 2P). Example 2 Preparation of P1, P-Di (5'-P2, P3-uridine difluoromethylenetetraphosphate) The tributyl ammonium salt of difluoromethylene diphosphonic acid (as described in C. McKenna, et al., J. Org. Chem. 46, 4574 -76 81981) and D. Burton, et al., J. Fluorine Chem. 15, 263-66 (1980)) (0.014 g, 0.025 mmol), was converted to the salt as described for the methylene phosphonic acid was dissolved in a solution of a salt of 4-morpholine-N, N'-dicyclohexylcarboxamidine of 5'-monophosphomorbolidat of uridine (Sigma, 0.034 g, 0.05 mmol) in dimethyl sulfoxide anhydride (0.7 mL) and heated for 9 days at 50 ° C . The cooled reaction mixture was diluted with water and applied to a DEAE cellulose column (2.5 x 50 cm volume bed) in the bicarbonate form. The column was eluted with water, followed by a gradient of ammonium bicarbonate (0-0.33 M, total volume of 900 mL). The elution process was followed by monitoring the absorbance of the eluate at 254 nm. The fraction eluting between 0.29 and 0.30 M was evaporated to dryness and desalted by repeated evaporations with deionized water to give the title compound (0.001 1 mmol, 4.4% yield, quantified by comparing its absorbance at? Max 263 nm with the of a normal solution of uridino monophosphate). The chromatographic purity was 88.5% in an Alltech PEI column, 0.66-M gradient of ammonium bicarbonate, 1.0 m L / min, 20 min. , retention time 12.03 min. RM N 1 H in D20 (d ppm tetramethylsilane): 4.05-4.085 (m, 6H); 4.18-4.20 (m, 4H), 5.80 (d, J = 8.0 Hz, 2H); 5.81 (d, J = 4.5 Hz, 2H); 7.77 (d, J = 7.9 Hz, 2H). 3 P NMR in D20 (d ppm H3PO4) -10.53 (dd, J P = 18.3, 1 1 .3 Hz, 2P); -5.83 (tdd, J = 75, 18.3, 1 1 .3 Hz, 2P). 19 F NMR in D 2 O 73.406 (t, J = 75.5 Hz). Example 3 Preparation of P1, P4-Di (5'-P2, P3-uridine imidotetraphosphate) Tetrasodium imidodiphosphate (Sigma, 0.05) was dissolved in water (0.5 mL) and applied to a strong cation exchange resin column. BioRad AG-MP50 (2 mL volume bed, 2 meq) in its tributylamine form. The column was eluted with water (~ 10 μL), the eluate was dried freeze-dried by evaporation of dry DMF. The treatment of salt of 4-morpholine-N, N'-dicyclohexylcarboxamide of 5'-monophosphomorbolidat of uridine (Sigma, 0.068 g, 0.1 mmol) with a solution of tetrabutylammonium imidodiphosphate (0.05 mmol) in anhydrous DMF (1.0. mL) for 20 days at room temperature and isolation essentially as described above gave the title compound as the ammonium salt (1.6%). 1 H NMR in D20 (d ppm tetramethylsilane): 4.07 -4.09 (m, 6H); 4.17-4.22 (m, 4H); 5.79 (d, J = 8.1 Hz, 2H); 5.80 (d, J = 4.8 Hz, 2H); 7.78 d, J = 8.2 Hz, 2H). 31 P NMR in D 2 O (d ppm H 3 PO), - 10.82 (m, 4 H); coupling pattern similar to the operation of P1, P4-di (adenosine 5'-tetraphosphate (Sigma) under the same conditions.) Example 4 Preparation of P1, P4-Di (5'-tetraphosphate of 4-thiouridine) The salt was dissolved of 4-thiouridine sodium monophosphate (Sigma, 25 mg, 0.057 mmol) in water (0.5 mL), applied to a strong cation exchange resin column BioRad AG-MP50 (2 mL volume bed 3 meq) in its tributylamine form, the column was eluted with water (~ 10 mL) and the eluate was lyophilized, the tributylammonium salt was dissolved in anhydrous DMF (0.5 mL) and carbonyldiimidazole (4.86 mg, 0.3 mmol) was added. The reaction was left aside under nitrogen at room temperature for twelve days.The reaction mixture was evaporated to dryness under vacuum at room temperature, the residue was dissolved in water (2 mL) and applied to a DEAE cellulose column ( 2.5 x 50 cm volume bed) in the bicarbonate form.The column was eluted with water (~ 2 50 mL), then with a gradient of ammonium bicarbonate (0-0.33 M, total volume 900 mL). This was followed by a gradient of 0.33 to 0.5 M ammonium bicarbonate over 400 mL. The progress of the elution was followed by monitoring the absorbance of the eluate at 280 nm. The fraction eluting between 0.336 and 0.339 M was evaporated to dryness and desalted by repeated evaporations with deionized water to give the title compound (0.0045 mmoles, 18% yield, quantified by comparison with its absorbance at max 332 with that of a normal solution of 4-thiouridine diphosphate). 1 H NMR in D 2 O (d ppm tetramethylsilane): 4.09-4. 1 1 (m, 6H); 4.18-4.24 (m, 4H); 5.76 (d, J = 4.5 Hz, 2H); 6.47 (d, J = 7.7 Hz, 2H); 7.67, d, J = 8.2 Hz, 2H). 31 P NMR in D 2 O (d ppm of H 3 PO 4) -22.57 to -22.73 (m, 2 =); -10.76 to -10.91 (m, 2 =); PP coupling pattern similar to P1, P4-di (adenosine 5'-tetraphosphate (Sigma) operated under the same conditions.) Example 5 Preparation of P1, P4-Di (uridine 5'-pentaphosphate) A round bottom flask of 100 ml was charged with a DMF solution of tributylammonium salt of uridine 5'-diphosphate (1.81 mmol, 10 ml) and carbonyldiimidazole (469 mg, 2.90 mmol) and the solution was stirred under N2 under 2 hours. he added a solution of tributylammonium salt of uridine 5'-triphosphate (1.81 mmol, 10 ml) and the solution was stirred at 60 ° C. for 24 hours.The solution was evaporated in vacuo and purified twice by column chromatography (DEAE Sephadex, H2O gradient> 0.5 MN H4HC03) The pure fractions were concentrated in vacuo at 35 ° C, and H2O was added and re-evaporated ten times to obtain a white solid (200 mg) 1 H NMR in D20 (d ppm tetramethylsilane): 4.0 (m, br, 6H), 4.1 (m, 4H), 5.7 (m, 4H), 7.7 (d, J = 8.1 Hz, 2 H); 31 P NMR in D20 (d ppm of H3P04) -22.3 (m, 3P, -10.6 (d, J = 42.9 Hz, 2P). Example 6 Preparation of P1, P4-Di (5'-tetraphosphate of 3, N4-ethenocytidine) To a solution of P1, P4'di (cytidine 5'-tetraphosphate) (reference 3, Table I, ammonium salt, 6 μmoles in 0.66 mL of water) was added sodium bicarbonate (0.005 g, 60 μmoles) and the solution was lyophilized in ammonia. The residue was dissolved in a mixture of water and (0.20 mL) and chloroacetaldehyde solution (50% water, 0.30 mL), and the reaction mixture was left at room temperature for six days. The reaction mixture was lyophilized and the oily residue was partitioned between deuterium oxide (0.7 mL) and methylene chloride (1.5 mL). The 1 H NMR spectrum of the aqueous solution indicated that the ethenylation progressed approximately 50%, while the 31 P spectrum confirmed that the tetraphosphate chain remained intact. The additional chloroacetaldehyde solution (0.25 μL) was added to the NMR solution and the mixture was separated for an additional ten days. The solution was lyophilized, and the residue was lyophilized again with deuterium oxide to remove interchangeable protons. The residue was partitioned between deuterium oxide and methylene chloride as above and complete conversion to the ethenyl derivative was confirmed by NMR spectroscopy. The deuterium oxide solution was applied to the DEAE cellulose column (2.5 x 30 cm volume bed) in the bicarbonate form. The column was eluted with water (-250 mL), followed by a gradient of 0 to 0.5 M of 100 mL of ammonium bicarbonate. The progress of the elution was followed by monitoring the absorbance of the eluate at 280 nm. The fraction eluting at 0.29 and 0.32 M was evaporated to dryness and desalted by repeated evaporations with deionized water to give the title compound (1.584 μmol, 26.4% yield, quantified by comparison with its absorbance at? Ma? 273 nm with that of the normal 5'-monophosphate solution of 3, N4-ethenocytidine). 1 H NMR in DzO (d ppm tetramethylsilane): 4.123 (m, 6H), 4.258 8m, 4H); 5,986 (s, 2H); 6.92 (d, J = 8.1 Hz, 2H); 7.461 (s, 2H), 7.772 (s, 2 H); 8.00 (d, J = 7.6 Hz, 2 H). 3 P NMR in D 2 O (d ppm of H 3 PO 4), -22,474 (m, 2P); -10,650 (m, 2 P); coupling pattern of P-P = almost similar to that of P1, P -di (5'-adenosine tetraphosphate [Sigma]) operated under the same conditions. Example 6 (a) Tretramonium salt of P1, P-Di (midazole [1, 2-c] pyrimidin-6 (6H) -one-2- (3-nitro) -phenyl-5-tetraphosphate] ß -d-ribofuranoside) The tretramonium salt of P1, P4-Di (cytidine 5'-tetraphosphate) (100 mg, 0.1 17 mmol) (reference 3, Table I) was dissolved in water (10 mL) and rinsed through a Dowex 50H + resin column (3 g, pre-washed with methanol and water) and washed with 50 mL of water.

Tributylamino (1 mL) and dimethylformamide (DMF) (5 mL) was added and the solution was evaporated to an oil. The oil was dissolved in dry DMF (10 μL) and the evaporation cycle was repeated twice. The final oil was dissolved in dry DMF (10 μL) and tributylamine (1.5 mL) to which α-bromo-3'-nitro-acetophenone (86 mg, 0.351 mmol) was added. The reaction mixture was heated under nitrogen gas at 70 ° C for 20 hours, when more of -bromo-3'-nitro-acetophenone (50 mg, 0.205 mmol) was added. After heating for 18 hours, the solvent was removed in vacuo and the residue was purified by flash chromatography (DEAE Sephadex, 0> 1.0M NH 4 HCO 3) to obtain a yellow solid (13.5 mg); 1 H NMR (D 2 O, TMS) d 4.0-4.2 (m, br, 10 H), 6.0 (d, J = 5.7 Hz, 2 H), 6.4 (d, J = 8.1 Hz, 2 H), 7.35 (t, J = 7.8 Hz, 2H), 7.5 (d, J = 8.1 Hz, 2H), 7.80 (m, 3H), 8.03 (s, 2H); 31 P NMR (D20, H3P0 norm.) D -10.67 (m, 2 P), -22.26 (m, 2 P). Example 7 P1- (Thymidine-5 '-) P4 (Uridine 5'-tetraphosphate) (UP4T) A Uridine 5'-triphosphate (UTP) salt solution (ProBioSint, 5.86g, 0.01 mole) in water ( 5 mL) was passed through a column of strong exchange resin BioRad Ag-MP 50 in its tributylamine form (50 ml volume bed) and eluted with distilled water (approximately 300 mL). To this solution was added tributylamine (5 mL), and the suspension was stirred until the pH of the aqueous fraction was raised to 8. The layers were separated and the aqueous solution was evaporated to a small volume, then lyophilized overnight. . The residue was dissolved in dry dimethylformamide (DMF, 20 mL) and the solvent was evaporated at 0.1 mmHg. The dry tributylamine salt was formed up to 100 mL with anhydrous acetone to give a stock solution (0.1 M in UTP). Dicyclohexylcarbodiimide (DCC) (Baker, 0.1 g, 0.5 mmol) was added to an aliquot of the above UTP solution (1.0 mL 0.1 mmol) and the solution was stirred at room temperature for 30 minutes. The deposited dicyclohexylurea was removed by filtration, the reaction mixture was extracted with ether (10 mL) and the residue was dissolved in dry deuterated dimethylsulfoxide (DMSO-d6, 0.3 mL). This solution of 5'-cyclic uridine metaphosphate (UcTP) was added to a solution of thymidine 5'-monophosphate (TMP, 0.064 g, 0.2 mmol) and triethylamine (0.2 mL) in DMSO-d6 (0.3 mL) and set aside at 50 ° C for 24 hours. The reaction mixture was evaporated under high vacuum overnight, the residue was dissolved in water (1.0 mL), filtered to remove residual residual dicyclohexylurea and separated by semipreparative ion exchange chromatography (Hamilton PRP X-100 column, eluting with 1.0 M isocratic ammonium bicarbonate, 5 mL / min., 30 min., 100 μL multiple injection). The dinucleotide tetraphosphate was eluted between 21 and 23 minutes; the product (11.1% yield based on UTP) was quantified by comparison with its ultraviolet absorption at? max 263 nm with the normal ones of UMP and TM0. 1 H NMR in D20, d ppm of tetramethylsilane: 1. 78 (2, 3H), 2.19-2.22 (m, 2H); 4.04-4.13 (m, 6H), 4.22-4.27 (m, 2H); 4.52 (m, partially obscured by D20); 4.74 (m, partially obscured by D2O); 5.83 (d, J = 8.1 Hz, 1H); 5.84 (d, J = 5.0 Hz, 1H), 6.195 (t, J = 6.9 Hz, 1H), 7.61 (s, 1H), 7.82 (d, J = 8.1 Hz, 1 H), 31 P NMR (D20, d ppm of H3P04 ), -22.71 (m, 2 =); -10.97 (m, 2P).

Example 8 P '- (Inosine 5' -) P4- (Uridine 5'-tetraphosphate) (UP4I) The condensation of 5'-cyclic uridine trimetaphosphate (UcTP) and inosine 5'-monophosphate was carried out essentially as it was described above, except that the reaction mixture was stored at 25 ° C for five weeks before the evaporation of the solvent. The residue was dissolved in water (1.0 ml), filtered and separated into 150 μl aliquots by ion exchange chromatography on a Hamilton PRP X-100 column., eluting with 1.0 M isocratic ammonium bicarbonate, 5 ml / min, 30 min. The fractions eluting between 6 and 9 minutes were evaporated and lyophilized overnight to remove the buffer solution. Dinucleotide tetraphosphate (8% yield, 96% purity by HPLC (AUC)) was quantified by comparing its ultraviolet absorption at 260 nm with those of UMP and IMP at the same wavelength. 1 H NMR (D 20, d ppm tetramethylsilane): 4.13 (m, 6H) 4.24-4.27 (m, 2H); 4.47 (m, partially obscured by D20); 5.78 (d, J = 7.9 Hz, 1 H); 5.83 (d, J = 4.7 Hz, 1 H); 6,003 (d, J = 5.7 Hz, 1 H); 7.79 (d, J = 7.9 Hz, 1 H); 8.10 (s, 1 H); 8.37 (s, 1 H). 31 P NMR (D 2 O, d ppm H 3 PO 4) -22.43 (8m, 2P); -10.72 (m, 2P). Example 9 P '- (4-thiouridine 5' -) P4- (uridine tetraphosphate) (UP4 (4-SH-U)) Sodium salt of 4-thiouridine monophosphate (25 mg, 0.057 mmol) was dissolved ) in water (0.5 ml), was applied to a strong cation exchange resin column of Biorad AG-MP50 (2 ml bed volume, 3 meq) in its tributylamine form, the column eluted with water (-10 ml ) and the eluate was lyophilized. The resulting tributylamine salt of 4-thio-UMP was condensed with 5-cyclic uridine trimetaphosphate (0.1 mmole) prepared by activation of UTP with cyclohexylcarbodiimide (206 mg) essentially as described in Example 7 (72 hr reaction time ). After evaporation of the DMSO from the reaction mixture, the residue was dissolved in water (~1 ml) and separated into 200 μl aliquots by ion exchange chromatography on a Hamilton PRP X-100 column, eluting with ammonium bicarbonate Socratic 1.0 M, 5 ml / min, monitoring the elution at 328 nm. The fractions eluting between 15 and 25 minutes were lyophilized to give the title compound (9.7% yield, 99.7% purity by HPLC (AUC)), which was quantified by comparing its ultraviolet absorption at 332 nm with that of 4- tio-UMP at the same wavelength. 1 H NMR (D 20 d ppm tetramethylsilane): 4.04 (m, partially overlapped by HOD); 4.14 (m, partially overlapped by HOD); 5.72 (m, 3H); 6.42 (d, J = 7.4 Hz); 7.55 (d, J = 7.6 Hz); 7.70 (d, J = 8.1 Hz). 31 P NMR (DzO, d ppm of H3P04); -20.88 (m, 2P), -9.27 (m, 2P). Examples 10-12 were prepared from uridine 5'-cyclic trimetaphosphate (0.1 mmole) and the relevant 5'-monophosphate nucleoside (0.2 mmole) essentially as described in Example 7, except that hexane was used instead. of ester to extract the excess of DCC from the reaction mixture. Example 10 P '- (cytosine ß-D-arabinofuranoside 5' -) P - (5'-tetraphosphate of uridine), (UP4araC) (20 mg); 1 H NMR (D 2 O) d 4.30: 3.95 (m, 10 H), 5.99 (d, J = 6.7 Hz, 1 H), 6.08 (d, J = 5.2 Hz, 1 H)), 7.82-7.77 (m, 2 H); 31 P NMR (D 2 O) d -10.79 (m, 2P), -22.52 (m, 2P). Example 11 P '- (Uridine 5' -) - P4- (5'-tetraphosphate of xanthosine), (UP4X) (27.7 mg); 1 H NMR (D 20) d 4.50-4.40 (m, 10H), 5.80-5.70 (m, 3H), 7.70 (d, J = 8 Hz, 1H), 7.88 (s, 1H); 31 P NMR (D 2 O) d -10.73 (m, 2P), -22.41 (m, 2P). Example 12 P '- (2'-deoxyuridine 5' -) - P - (5'-tetrahydrofuran of uridine), (UP4dU) (40.6 mg); 1H NMR (D2O) d 2.20-2.15 (m, 2H), 4.45-3.95 (m, 9H), 5.80-6.74 (m, 3H), 6.12 (t, J = 6.7 Hz, 1H), 7.80-7.74 (m 2H); 31 P NMR (D20) d 2.9 (m, 2P), -8.9 (m, 2P). Example 13 P '- (3'-azido-3'-deoxythymidine 5' -) - P - (uridine 5'-tetraphosphate) (UP4 (AZT)) and Example 14, P1, P -di (5 ') 3'-azido-3'-deoxythymidine-tetrastearate) (AZT) 2P4 The sodium salt of 5'-monophosphate of 3'-azido-3'-deoxythymidine (AZTMP) (50 mg, 0.135 mmol) was dissolved in water (1 ml) and applied to a column of strong cation exchange resin Biorad AG-MP50 in its tributylamine form. The column was eluted with water (-10 ml) and the eluate was lyophilized. The resulting tributylamine salt was condensed with U-cyclic S'-cyclic trimetaphostat (0.1 mmol) prepared by the activation of UTP with dicyclohexylcarbodiimide (206 mg) essentially as described in Example 7. The residue after evaporation of the mixture of The reaction was dissolved in water (1.0 ml = passed through a 0.45 μ syringe filter to remove a small solid and the filtrate was subjected to preparative HPLC on a Hamilton PRP X-100 column, eluting with a Socratic mixture of 1.0 M ammonium bicarbonate (75%) and methanol (25%) (4 ml / min) The fraction eluting between 5 and 8 minutes was lyophilized to give UP (AZT) (7.9%), it was quantified by comparing its ultraviolet absorption at 264 nm with those of UMP and TMP at the same wavelength 1H NMR D20 d ppm tetramethylsilane: 1.78 (s, 3H), 2.30-2.34 (m, 2H); 4.07-4.14 (m, 6H), 4.22-4.29 (m, 2H); 4.52 (m, 1H), 5.82 (d, J = 4.4 Hz, 1H); 5.84 (d, J = 8.1 Hz, 1H); 6.12 (t, J = 7Hz, 1H); 7.62 (s, 1H); 7.81 (d, J = 8.1 Hz, 1H). 31 P NMR (DzO, d ppm H3P04) -22.51 (m, 2P); -11.06 (m, 1P); -10.81 (m, 1P). The collection and lyophilization of the fractions eluting between 25 and 40 minutes of the same reaction mixture gives P1, P4-Di (3'-tetraphosphate 3'-azido-3'-deoxythymidine) (3%), quantified by comparison of its ultraviolet spectrum at 266 nm without that of TMP. 1 H NMR D20, d ppm tetramethylsilane: 1.80 (s, 6H); 2.31-2.35 (m, 4H); 4.09-4.11 (m, 6H) 4.46-4.47 (m, 2H); 6.12 (t, J = 7Hz, 2H); 7.63 (s, 2H). 31 P NMR (D20, d ppm H3P04) -22.47 (m, 2P); -11.35 (m, 2P).

Example 14 P1, P4-di (uridine 5'-hexaphosphate) (U2P6) Dinucleotide hexaphosphate (6.97%) was formed by the reaction of uridine cyclic trimetaphosphate with uridine 5'-triphosphate under similar conditions. 1 D2O NMR, d ppm tetramethylsilane: 4.06-4.19 (m, 6H); 4.21-4.4 (m, 4H); 5.78 (d, J = 8.2 Hz, 2H); 5.81 (d, J = 5.4 Hz, 2H); 7.78 (d, J = 8.1 Hz, 1H), 31 P NMR (D20 d ppm of H3P04) -22.47 (m, 2P); -11.35 (m, 2P). Example 15 2 '(3') - benzoyl-P1, P4- di (5'-tetraphosphate of uridine) (Example 15) and P1, P4-di (5'-tetraphosphate of 2 '(3') - benzoyl uridine) (Example 16). Benzoic acid (61.7 mg, 0.505 mmol) and 1,1-carbonyldiimidazole (81.8 mg, 0.505 mmol) were combined in anhydrous DMF (1 ml) and stirred at room temperature for 1 hour. P1, P4-di (uridine 5'-tetraphosphate) (97 mg, 0.102 mMole) in DMF anhydride (2 ml) was added and the mixture was stirred at room temperature for 4 hours. The temperature was increased to 35 ° C and the stirring continued for 6 days. The reaction mixture was evaporated to dryness, dissolved in water, applied to the Sephadex DEAE A25 column (2.5 x 20 cm) and eluted with a gradient of ammonium bicarbonate (from 0 to 0.3 M, 400 ml of total volume ) followed by isocratic ammonium bicarbonate (0.5 M, 500 ml). Two fractions were collected, dried to dryness, then repeatedly co-evaporated with water to remove the ammonium salts. The material that was eluted before was identified as the monobenzoyl ester. 1 H NMR (D 2 O) d 4.0-4.23 (m, 9H), 5.35-5.45 (m, 1H), 5.65-5.85 (m, 3H), 5.98-6.02 8m, 1H), 7.32-7.95 (m, 7H); 31 P NMR (D20) d -10.70 (m, 2P), -22.28 (m, 2P); the material eluted after was identified as the dibenzoyl ester: 1 H NMR (D20) d 4.05-4.40 (m, 8H); 5.30-6.05 (m, 6H); 7.2-7.95 (m, 12H); 31 P NMR (D 2 O) d -10.70 (m, 2P), -22.45 (m, 2P). Examples 17. 18, 19 and 20 P '- (5'-P4 of 2'-deoxyguanosine) - (5'-tetrahydfate of uridine) (UP4dG) (Example 17); P '- (5'-P4 of 2'-deoxyadenosine) - (5'-tetrahydfate of uridine) (UP4dA) (Example 18); P '- (5'-P4 of 2'-deoxy-inosine) - (Uridine 5'-tetraphosphate) (UP4dl) (Example 19); and P '- (5'-P4 of 2'-deoxycytidine) - (Uridine 5'-tetraphosphate) (UP4dC) (Example 20) Uridine 5'-triphosphate (5.0 g) in water (18 ml) was passed to through a Dowex 50 H + column, and tributylamine (3.0 g) was added to the eluent. The mixture was concentrated to an oil, dried by evaporation with dry DMF and redissolved in dry DMF (18 ml). Dicyclohexylcarbodiimide (DCC, 3.5 g) was added, the solution was stirred at room temperature for 30 minutes and the precipitate was removed by filtration. Hexane (70 ml) was added to the filtrate, the lower layer was separated and washed again with hexane (70 ml) to complete the removal of DCC. This solution of 5'-cyclic uridine metaphosphate (UcTP) was used in the following experiments: Example 17 P1- (5'-P4 of 2'-deoxyguanosine) - (5'-tetrahydfate of uridine) (UP4dG) It was dissolved. '- 2'-deoxyguanosine monophosphate (d-GMP, Sigma, 500 mg) in DMF (4.5 ml), tributylamine (1.0 ml) was added and the solution was concentrated to an oil under vacuum. One third of the 5'-cyclic uridine metaphosphate solution (UcTP, above) was added to the hot solution at 40 ° C for 24 hours. The solution was evaporated to an oil, dissolved in water (10 ml) and applied to a Sephadex DEAE column (350 ml on a 4.5 x 22 cm column) in its bicarbonate form, pre-equilibrated with 0.25 M of ammonium bicarbonate. The column was eluted successively with 0.25, 0. 30, 0.35, 0.40 and 0.50 M of ammonium bicarbonate. The elution was monitored by CLAR (SynchroPak AX-300, 75% 0.50 M KH2PO, 25% MeCN 1.0 mL / min, UV 254 nm) and the fraction containing UP dG was concentrated to a solid, then co-evaporated 6.7 times with water to give the ammonium salt of the dinucleotide as an orange-yellow solid (140 mg, purity calculated by HPLC (AUC) of 94%).

Example 18 P1- (5'-P4 of 2'-deoxyadenosine) - (Uridine 5'-tetraphosphate) (UP4dA) The reaction of 5'-monophosphate of 2'-deoxyadenosine (d-AMP, Sigma, 500 mg) with 5-cyclic metaphosphate of uridine essentially as described above gave UP dA as the solid white ammonium salt (140 mg, purity of HPLC as above, 99%). Example 19 P1- (5'-P4 of 2'-deoxy-inosine) - (5'-tetraphosphate of uridine) (UP dl) The 5'-monophosphate of 2'-deoxy-inosine (d-IMP, Sigma, sodium salt 1.0 g) was converted to the free acid form with Dowex 50 (H +) resin as described above for UTP . The eluent was neutralized with tributylamine (2.0 L) and the mixture was concentrated to an oil under vacuum. The resulting tributylamine salt was dried by evaporation with DMF, the residue was dissolved in DMF (4.5 ml) and treated with 5'-cyclic uridine trimetaphosphate essentially as described above to give P2- (5'-P4 2 '). -deoxy-inosine) - (5'-tetraphosphate of uridine). Example 20 p1. (5'.p4 of 2'-deoxycytidine) - (5'-tetraphosphate of uridine) (UP4dC) '-2'-deoxycytidine monophosphate (d-CMP, Sigma, 500 mg) treated essentially as before, gave P1- (5'-P4 of 2'-deoxycytidine) - (Uridine 5'-tetraphosphate) as a white solid (130 mg), purity calculated with HPLC 82%.

Example 21 Pharmacological activity measured by inositol phosphate analysis The compounds of Examples 1-20 were tested for their ability to give receptor activity P2Yi, P2Y2, P2Y4 and P2Y6 using the inositol phosphate assay as described by E. Lazarowski, et al., Brit. J. Pharm. 116, 1619-27 (1995). The results are summarized in the following Table II. TABLE II SUMMARY OF ACTIVITY OF DINUCLEOTIDES ECsn's smoke) IA Response < 2 times BASE WEAK EC5o > 100μmoles (XX%) Percentage response of the same study positive control nd not determined The invention and the way and process to make and use it, are now described in such complete, clear, concise and exact terms to allow any expert in the technique to which it belongs, to form and use it. It should be understood that the foregoing describes the preferred embodiments of the presumed intervention and that modifications may be made therein without departing from the spirit or scope of the present invention as set forth in the claims. To particularly point out and claim in a different manner the subject matter of the object with respect to the invention, the following claims conclude this specification.

Claims (21)

CLAIMS A compound of Formula I: Formula I wherein X is oxygen, methylene, difluoromethylene, imido; n = 0, 1 or 2; m = 0, 1 or 2; n + m = 0, 1, 2, 3 or 4; and B and B 'are each independently of a purine residue or a pyrimidine residue linked through the 9 or 1 position, respectively; Z = OH or N3; Z '= OH or N3; Y = H or OH; Y '= H or OH; as long as Z is N3, Y is H or when Z 'is N3, Y' is H; and as long as the others are excluded from the compounds of Table I; or TABLE I DI NUCLEOTIDES NpsN Np5N 'Np6N Np6N' Np9N Ap5A (4) Ap5T (20) Ap6A (4) ApsT (20) Ap9A (4) AppZppA D ppZppD ApZppZpA ApSpZpSpA CH2 (8) CH2 (15) CH2 (8) CHF (8) CH2CH2 (8) CH2CH2 (15) CH2CH2 (8) CF2 (8) CHF (8) CHF (15) CHF (8) O (8) CF2 ( 8) CF2 (15) CF2 (8) CHCl (8) CHCl (15) CHCl (8) CCI2 (8) CCI2 (15) CCI2 (8)
1. A = Adenosine eA = Ethanoadenosine U = Uridine m7G = 7-Methylguanosine G = Guanosine m 2'7G = 2,7-Dimethylguanosine T = Thimidine m 2,2,7 G = 2,2,7-Trimethylguanosine X = Xantosine NAD = nicotinamide riboside TAD = thiazofurine C-NAD = C-nicotinamide riboside BAD = Benzamide riboside C-PAD = C-picolinamide riboside D = 2,6-Diaminopurine N = Nucleoside or esters or pharmaceutically acceptable salts thereof.
2. 2. A compound of Formula IA, its esters and pharmaceutically acceptable salts as long as the compounds of Table I are excluded: Formula IA where X = O; n + m = 1 or 2 Z, Z \ Y and Y '= OH; B and B 'are uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; or X = 0; n + m = 3 or 4 Z, Z \ Y and Y '= OH; B = uracil; B 'is uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; or X = O; n + m = 1 or 2; Z, Y and Y '= OH; Z '= H; B = uration; B 'is uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; or X = O; n + m = 0, 1 or 2; Z and Y = OH; Z '= N3; Y '= H; B = uracil; B '= thymine; or X = O; n + m = 0, 1 or 2; Z and Z '= N3; Y and Y '= H; B and B '= thymine; or X = CH2, CF2 or NH; n and m = 1; Z, Z ', Y and Y' = OH; B and B 'is uracil, thymine, cytosine, guanine, adenine, xanthine, hypoxanthine or as defined in Formulas II and III; Formula II wherein Ri is an alkyl or aryl moiety, as in: C? -8 alkyl; phenyl or phenyloxy (which can be substituted with halogen); hydroxy; C? - alkoxy; C? - alkyl; aryl of C6-? o; carboxy; cyano; nitro; sulfonamido; sulfonate; phosphate; sulfonic acid; amino or substituted amino, wherein the amino is substituted once or twice by a C? - alkyl and when substituted twice, the alkyl groups may be linked to form a heterocycle); or? -A (C? s alkyl) CONH (C? .6 alkyl) wherein A is amino, mercapto, hydroxy or carboxyl; or R2 is O or is absent; or Ri and R2 taken together form a 5-membered fused imidazole ring (which may optionally be substituted at the 4 or 5 positions of the ethene portion with d, phenyl or phenyloxy alkyl, which may be substituted with halogen; hydroxy; C 1 - alkoxy, C 1 - phenyl or phenyloxy alkyl, which may be substituted by halogen, hydroxy, C 1 alkoxy, C 4 alkyl, d 6 alkyl, C 6 alkoxy; carboxy; cyano; nitro; sulfonamido; sulfonate; or phosphate; sulphonic acid; amino or substituted amino, wherein the amino is substituted once or twice by C1-alkyl and where when substituted twice, the alkyl groups may be ligated to form a heterocycle or arylalkyl of C? 2); R3 is C? -8 alkyl; phenyl or phenyloxy (which may be substituted by halogen, hydroxy, C? -4 alco alkoxy, C? -4 alquiloalkyl, C6- aralkyl or carboxy; cyano; nitro; sulfonamido; sulfonate; phosphate; sulfonic acid; or substituted amino, wherein the amino is substituted once or twice by a C? alkyl and when substituted twice, the alkyl groups may be linked to form a heterocycle); or arylalkyl of C -? 2; alkylamino of C? -4; phenylamino or arylalkylamino of C -? 2, C? -4 alkoxy, or arylalkyloxy of C? 2; C.sub.12-, phenylthio or aryl-alkylthio of C7-? 2; or? -A (A? cyl of C? .6) CONH (C? -6 alkyl) B- where A and B are independently amino, mercapto, hydroxy, carboxyl; Formula lll wherein: R 4 is hydrogen, hydroxy, mercapto, amino, cyano, aralkoxy, C 1 -6 alkylthio, C 1 -6 alkylamino or C 1 - alkylamino, wherein the alkyl groups may be linked to form a heterocycle; R5 is hydrogen, acetoyl or benzoyl, C6-6alkyl, phenyloxy, ds, alkanoyl, benzoyl or sulfonate; Rs is hydroxy, mercapto, C? -4 alkoxy, c7 a 2 aralkoxy, Ci-s alkylthio, amino, disubstituted amino in Ci, triazolyl, C?-6 alkylamino, or C? - dialkylamino, wherein the alkyl groups are optionally linked to form a heterocycle or a bond to N3 to form a substituted ring; or R5 and e taken together form an imidazole ring fused with 5 members between positions 3 and 4 of the pyrimidine ring (derivatives of 3, N4-ethenocytosine) optionally substituted at positions 4 or 5 of the ethene portion with C1 alkyl -; phenyl or phenyloxy, which can be substituted with halogen; hydroxy; C? alkoxy?; d- alkyl; C6-? o 'aryl, carboxy; cyano; nitro; sulfonamide; sulfonate or phosphate; sulfonic acid; amino or substituted amino; wherein the amino is substituted once or twice by a C? - alkyl and when substituted twice, the alkyl groups may be linked to form a heterocycle; or arylalkyl of C? 2; R7 is hydrogen, hydroxy, cyano, nitro, C2-8 alkenyl; wherein the alkenyl portion can be bonded through oxygen to form an optionally substituted ring on the carbon adjacent to the oxygen with C? - alkyl, C? - phenyl, substituted C2-8 alkynyl, halogen, C? -4, substituted C1-4 alkyl, CF3, C2-6 alkyl. C2-3 alkenyl, allylamino, bromovinyl, ethyl propenoate, propenoic acid, C2-3 alkynyl; or R6 and R7 can together form a saturated or unsaturated ring of 5 or 6 members linked through N or O in R6, so that the ring can contain substituents which themselves contain functionalities; as long as R8 is amino or substituted amino, R7 is hydrogen; and R8 is hydrogen, amino or dialkylamino of C? -, alkoxy of C? -4, arylalkoxy of C7-? , alkylthio of C? -, ary lalqu i Itio of C, carboxyamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy or phenylthio.
3. 3. A compound according to claim 1, of Formula IB: Formula IB wherein X is oxygen, methylene, difluoromethylene, imido; n = 0 or 1; m = 0 or 1; n + m = 0, 1 or 2; and B and B 'are each independently a purine residue, as in Formula II, or a pyrimidine residue, as in Formula III, linked through position 9 or 1, respectively; Formula II wherein Ri is an alkyl or aryl moiety, as in: C? -8 alkyl; phenyl or phenyloxy (which can be substituted with halogen); hydroxy; C1-4 alkoxy; C? -4 alkyl; aryl of C6-? o; carboxy; cyano; nitro; sulfonamido; sulfonate; phosphate; sulfonic acid; amino or substituted amino, wherein the amino is substituted once or twice by an alkyl of d-4 and when substituted twice, the alkyl groups may be linked to form a heterocycle); or? -A (C? .6 alkyl) CONH (C? -6 alkyl) wherein A is amino, mercapto, hydroxy or carboxyl; or R2 is O or is absent; or RT and R2 taken together form a 5-membered fused imidazole ring (which can optionally be substituted at the 4 or 5 positions of the ethene portion with C? -4 alquilo alquilo alkyl; phenyl or phenyloxy, which may be substituted with halogen; hydroxy, C, -4 alkoxy, d.4 alkyl, phenyl or phenyloxy, which may be substituted by halogen, hydroxy, C? - alkoxy, C? -4 alkyl, C? alkyl, C6 aryl, -? o; carboxy; cyano; nitro; sulfonamido; sulfonate; or phosphate; sulphonic acid; amino or substituted amino, where the amino is substituted once or twice by C? -4 alkyl and where when replaced twice , the alkyl groups may be linked to form a heterocycle or arylalkyl of C7.12); R3 is C? 8 alkyl; phenyl or phenyloxy (which may be substituted by halogen; hydroxy; C? -4 alco alkoxy; C?-alkyl; C3- [alpha] aryl; or carboxy; cyano; nitro; sulfonamido; sulfonate; phosphate; sulfonic acid; substituted amino, wherein the amino is substituted once or twice by a C? alkyl- and when substituted twice, the alkyl groups may be linked to form a heterocycle); or arylalkyl of C? 2; alkylamino of C? -4; phenylamino or arylalkylamino of C.? 2, C? alkoxy. , or C7-? 2 arylalkyloxy; C.sub.12-, phenylthio or aryl-C-3 alkylthio of C7-; or? -A (alkyl of C? -6) CONH (alkyl of d.6) B- wherein A and B are independently amino, mercapto, hydroxy, carboxyl; Formula lll wherein: R is hydrogen, hydroxy, mercapto, amino, cyano, aralkoxy, alkylthio of C? .6, C 1-6 alkoxy, C?. or dialkylamino alkylamino of C? -4, wherein the alkyl groups may be bound to form a heterocycle; Rs is hydrogen, acetoyl or benzoyl, C1-6 alkyl, phenyloxy, C1-5 alkanoyl, benzoyl or sulfonate; R6 is hydroxy, mercapto, C4-4 alkoxy, c7.12 aralkoxy, C? -6 alkylthio, amino, disubstituted amino in d, triazolyl, C1.6 alkylamino, or dialkylamino of d-. wherein the alkyl groups are optionally linked to form a heterocycle or a bond to N3 to form a substituted ring; or Rs and Rs taken together form an imidazole ring fused with 5 members between positions 3 and 4 of the pyrimidine ring (derivatives of 3, N4-ethenocytosine) optionally substituted at positions 4 or 5 of the ethene portion with alkyl of C? -4; phenyl or phenyloxy, which can be substituted with halogen; hydroxy; C4-4 alkoxy; C? .4 alkyl; aryl of C3-? o. carboxy; cyano; nitro; sulfonamide; sulfonate or phosphate; sulfonic acid; amino or substituted amino; wherein the amino is substituted once or twice by a C? -4 alkyl and when substituted twice, the alkyl groups may be linked to form a heterocycle; or arylalkyl of C? 2; R7 is hydrogen, hydroxy, cyano, nitro, C2.8 alkenyl; wherein the alkenyl portion may be bonded through oxygen to form an optionally substituted ring on the carbon adjacent to the oxygen with C? alkyl. , C phenyl. , substituted C2-8 alkynyl, halogen, C? -4 alkyl, substituted C? -4 alkyl, CF3, C2-s alkyl, C2.3 alkenyl, allylamino, bromovinyl, ethyl propenoate, propenoic acid, C2-3 alkynyl; or R6 and R7 can together form a saturated or unsaturated ring of 5 or 6 members linked through N or O in R6, so that the ring can contain substituents which themselves contain functionalities; as long as R8 is amino or substituted amino, R7 is hydrogen; and R8 is hydrogen, amino or dialkylamino of C? -, C? -4 alkoxy, C7.12 arylalkoxy, C1-4 alkylthio, C arylalkylthio, carboxyamidomethyl, carboxymethyl, methoxy, methylthio, phenoxy or phenylthio.
4. 4. A compound according to claim 2 or 3, wherein the asyl groups of Formulas II and III comprise alkyl or aryl groups, the alkyl groups having from 1 to 4 carbon atoms and the aryl groups including the aryl portions of said groups as aryloxy are phenyl groups, wherein the alkyl and aryl groups are substituted with the substituents selected from the group consisting of halogen, hydroxy, C? -4 alkoxy, C -? ar aryl, C7.2 arylalkoxy, carboxy , cyano, nitro, sulfonamido, sulphonate, phosphate, sulphonic acid, amino and substituted amino where the amino is substituted once or twice by a C? -4 alkyl, and when it is replaced twice, the alkyl groups are linked to form a heterocycle.
5. 5. A compound according to claims 1-3, wherein B and B 'are uracil attached in the N-1 position to the ribosyl portion and wherein the total of m + n is equal to 3 or 4, wherein X is oxygen.
6. 6. A compound according to claims 1-3, wherein the ribosyl portions have the D-configuration.
7. 7. A compound according to claim 1-3, wherein the ribosyl portions have the L-configuration.
8. 8. A compound according to claim 1-3, wherein the ribosyl portions have the D and L configuration.
9. 9. P1, P4-Di (5'-P2, P3-uridine methylenetetraphosphate).
10. 10. P1, P4-Di (5'-P2, P3-diffuoromethylenetetraphosphate of uridine).
11. 11. P \ P4-D¡ (5'-P2, P3-imidotetraphosphate of uridine).
12. 12. P1, P4-Di (5'-tetraphosphate of 4-thiouridine).
13. 13. P1, P4-Di (5'-tetraphosphate of 3, N4-ethenocytidine).
14. 14. A pharmaceutical composition comprising a compound of Formulas I, IA or IB as described in claims 1-3, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier therefor.
15. 15. A method for treating chronic obstructive pulmonary diseases in a mammal by administering an effective chronic obstructive pulmonary disease treatment amount of a compound of Formulas I, IA or IB as described in claims 1-3.
16. 16. A method for treating sinusitis, otitis media or obstruction of the nasolacrimal duct in a mammal by administering an effective amount to eliminate mucosal secretion of a compound of Formulas I, IA or IB as described in claims 1-3.
17. 17. A method for treating dryness of the eye in a mammal by administering an effective amount for the dry eye treatment of a compound of Formula I, IA, or IB as described in claims 1-3.
18. 18. A method for treating retinal detachment in a mammal by administering an effective amount for the retinal detachment treatment of a compound of Formula I as described in claim 1.
19. 19. A method for facilitating the induction of sputum in a mammal administering an amount of a compound of Formula I as described in claim 1, effective to facilitate the induction of sputum.
20. 20. A method for facilitating expectoration in a mammal by administering an amount of a compound of Formula I as described in claim 1, effective to facilitate expectoration.
21. 21. A compound selected from the group consisting of: P1- (5'-P4 of thymidine) - (uridine d-phosphate) (UP4T), P1- (5'- P4 of lnosine) - (5'-tetraphosphate of uridine) (UP4I), P1- (5'-P4 of 4-thiouridine) - (5'-tetraphosphate of uridine) (UP4 (4-SHU)), P1- (5'-P4 of β-D-arabinofuranoside of cytosine) - (Uridine 5'-tetraphosphate) (UP4araC), P1- (5'- P4 of uridine) - (xantosine 5'-tetraphosphate) (UP4X), P1- (5'-P4 of 2'-deoxyuridine) ) - (Xantosine 5'-tetraphosphate) (UP4dU), P1- (5'-P4 of 3'-azido-3'-deoxythymidine) - (5'-tetrahydrate of uridine) (UP4 (AZT)), P1, P4-di (3'-azido-3'-deoxythymidine 5'-tetraphosphate) (AZT) 2P4), 2, (3 ') - benzoyl-P1, P4-di (5'-tetraphosphate of uridine), P1, P4-di (5'-tetraphosphate of 2' (3 ') - benzoyluridine), P1- (5'-P4 of 2'-deoxyguanosine) - (5'-tetraphosphate of uridine) (UP4dG), P1- (5'-P4 of 2'-deoxyadenosine) - (5'-tetraphosphate of uridine) (U P4dA), P1-5'-P4 of (2'-deoxy-inosine) - (5 ' uridine-tetraphosphate) (UP4dl), and P1- (5'-P4 of 2'-deoxycytidine) - (5'-tetrahydfate of uridine) (U P4dC).