MXPA96004551A - Use of fosfonilmetoxialquil nucleosidos for the treatment of intraocular pressure elev - Google Patents

Abstract

The present invention relates to the use of a compound of formula (I) or its pharmaceutically acceptable salts for formulation as a medicament for reducing intraocular pressure, wherein formula (I) is: wherein: R1 and R2 are (i) or (ii) as follows: (i) R1 is CH2 (CH2) n, CH2CH (OH) (CH2) N, CH2CH (CH2) N (OH), CH2OCH (R7), CH2OCH (R7) ( CH2) p, CH2OCH (R7) (CH2) P or OO (CH2) pCH (R7) O; R2 is OH or O (CH2) rH; R7 is H, OH or (CH2) rOH, preferably (CH2) OH n is 0-6, preferably 0-3, r is 1-6, preferably 1-3, most preferably 1, p is 0-3, and m is from 0 to 3, or (ii) R1, R2 , n, m, r and p are defined as in (i), and R1 and R2 are linked to form a cyclic group, B is a pyrimidine or purine of the formula (II): and is selected from pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl; R3, R4, R5 and R6 are independently selected from NH2, alkylamino, aminoalkyl, hydroxyalkyl, hydrazino, H, OH, SH , alkylthio, alkyl, alkoxy, alkoxyalkyl, hal uro, hydroxylamino CH3-q (hal) q, in which q is 1-3 and hal is a halu

Description

USE OF PHOSPHONYLMETOXIALOUILNUCLEOSIDES FOR THE TREATMENT OF ELEVATED INTRAOCULAR PRESSURE DESCRIPTION This application is a continuation in part of the application of the United States Serial No. 08 / 360,995 of William Freeman, filed on December 20, 1994, entitled TREATMENT OF CONDITIONS OF ABNORMALLY INCREASED INTRAOCULAR PRESSURE BY ADMINISTRATION OF PHOSPHONYLMETHOXY-ALKYL NUCLEOSIDE ANALOGS AND RELATED NUCLEOSIDE ANALOGS, and is also a continuation in part of the United States Application Serial No. 08 / 222,128 of William Freeman, filed on April 4, 1994, entitled TREATMENT OF CONDITIONS OF ABNORMALLY INCRESED INTRAOCULAR PRESSURE BY ADMINISTRATION OF HPMPC AND RELATED PHOSPHONYL METHOXY-ALKYLCYTOSINES. The subject matter of each of the applications of the United States Serial Nos. 08 / 360,995 and 08 / 222,128 are incorporated herein by reference. The invention herein relates to compositions for and treatment of glaucoma and other abnormally increased intraocular pressure conditions. More particularly, it relates to the treatment by application of therapeutic compounds and compositions containing such compounds.

Glaucoma Glaucoma, which is the leading cause of blindness in the United States, is a group of diseases characterized by progressive atrophy of the optic nerve head leading to loss of visual field and finally blindness. Glaucoma is generally associated with elevated intraocular pressure, which is an important risk factor for visual field loss, because it also causes damage to the optic nerve fibers. There are several types of glaucoma, including open angle and closed angle glaucoma, all involve the abnormal increase in intraocular pressure mainly by obstruction of the flow of aqueous humor of the eye or less frequently, by the overproduction of aqueous humor within the eye. The most widespread time is primary open angle glaucoma in which the aqueous humor has free access to the iridocorneal angle, but the aqueous humor drainage is damaged. In contrast, in closed-angle glaucoma, the iridocorneal angle is closed by the peripheral iris. The blockage of the angle can usually be corrected by surgery. The less generalized types of glaucoma include secondary glaucomas related to inflammation, trauma and hemorrhage. Glaucoma in its various forms is widely described in the literature: see, for example, Leibrandt, ed. (1982) Professional Guide to Diseases, pp. 1203-1206 and Andreoli et al., (1986) Cecil: Essentials of Medicine, pp. 690-691. The therapeutic treatment of glaucoma is aimed at reducing intraocular pressure. Because the intraocular pressure is controlled by the dynamics of the aqueous humor, an understanding of the production and removal of the aqueous humor of the eyeball provides insight into the causes of the increased eye pressure associated with glaucoma. The aqueous humor is similar in the composition of electrolytes to plasma, but has a lower protein content. The aqueous humor keeps the eyeball inflated, supplies the nutritional needs of the vascular lens and the cornea and washes away the metabolites and the optical substances within the eye. The volume of aqueous humor formation is the product of active cellular secretion by non-pigmented epithelial cells of the ciliary process of active solute transport, probably sodium, followed by the osmotic flow of water from the plasma. The non-pigmented epithelial cells of the ciliary process are joined in their apical cell membranes by hermetic junctions. These cells and the vessels of the unfenestrated iris form the blood / aqueous barrier through which large molecules carried by the blood, including proteins, do not pass.

Intraocular pressure is a function of the difference between the speed at which aqueous humor enters and leaves the eye. Aqueous humor enters the posterior chamber by three means: 1) active secretion by non-pigmented epithelial cells of the ciliary process; 2) ultrafiltration of blood plasma; and 3) dissemination. The newly formed aqueous humor flows from the posterior chamber around the lens and through the pupil into the anterior chamber; the aqueous humor leaves the eye by flow in passive volume in the iridocorneal angle and uveoscleral flow. Any change in 1), 2) or 3) will interrupt the dynamics of the aqueous humor and probably alter the intraocular pressure. Treatments for Glaucoma Most treatments for glaucoma focus on reducing intraocular pressure. The treatment has involved the administration of beta-blockers such as timolol, to decrease the production of aqueous humor, epinephrine to decrease intraocular pressure or diuretics such as acetazolamine to reduce aqueous production, or administration of drops for miotic eyes such as pilocarpine for facilitate the outflow of aqueous humor. Acute forms of glaucoma may receive peripheral iridectomy surgery to relieve pressure, where drug therapy is ineffective and the patient's vision is at immediate risk. Other forms of treatment have included the physical or thermal destruction ("cycle-destruction") of the ciliary body of the eye, commonly by surgery or application of a laser beam, cryogenic fluid or high frequency ultrasound. Each of these methods of destruction is costly and unduly invasive. However there are many problems in effectively treating glaucoma and with long-term medicinal therapy or surgical therapies. One problem is the difficulty in devising means to generate pharmacologically effective intraocular concentrations to avoid the extraocular side effects produced by systemic administration. Many drugs are administered topically or locally. The amount of a drug that is in the eye, however, is only a small percentage of the dose applied topically, because the tissues of the eye are protected from such substances by numerous mechanisms, including tears, blinking, conjunctiva absorption in the systemic circulation and a highly selective corneal barrier. Also, there is a risk to develop an intolerance to medical therapy or laser therapy, in such a way that the filtering operation to control the intraocular pressure may become necessary. Current surgical techniques to decrease intraocular pressure, when drugs fail to decrease fluid flow within the eye or to increase fluid flow outflow, include procedures that allow fluid to drain from within the eye to the extraocular sites , creating a fluid conduit between the anterior chamber of the eye and the supra-scleral / sub-Tenon potential space, or alternatively, in or through the Schlemm Canal [see, for example, U.S. Patent No. 4,846,172] . The most common operations for glaucoma are operations to filter glaucoma, particularly trabeculectomy. These operations involve the creation of a fistula between the subconjunctival space and the anterior chamber. This fistula can be made by creating a hole in the limbus either by cutting a portion of the limbal tissues with either a scalpel blade or by burning with a cautery through the subconjunctival space within the anterior chamber. Then the fluid is filtered through the fistula and is gradually absorbed by vessels within the conjunctiva or is gradually filtered through the conjunctival tissues to be externally extruded with tears. For the surgery to be effective, the fistula must remain substantially unobstructed. These drainage or filtration procedures, however, often fail by closing the passage resulting from the healing of the wound created to gain access to the surgical site. The most frequent faults result from scarring at the site of the incisions in the conjunctiva and the tenon capsule. The surgery fails immediately in at least 15% of the patients and in the long term in a much higher percentage. Currently, the consequence of trabeculectomy, the closure of the canal, is treated with 5-fluorouracil and mitomycin C, which apparently prevent the closure by inhibiting cell proliferation. These drugs, however, are highly toxic and have undesirable side effects, including scleral fusion. In view of the limited number of treatment options, therefore, there is a need to develop more effective treatments for glaucoma. Therefore, it is an object of the present invention to provide compositions and methods for the treatment of glaucoma. Methods for lowering intraocular pressure are provided by the administration of compositions containing effective amounts of phosphonylmethoxyalkylnucleoside analogues. One aspect of this method of therapy is the apparent ability of a single dose or a series of lower doses of intraocular injections of the administered compound to provide substantial and long-lasting reduction in intraocular pressure. Relatively small reductions in pressure can be obtained to reduce up to as much as 20 mm Hg or more. The nucleoside analogs have the formula (I): "•" -.- "H O I II 8- (R 1) -0-C - (CH.) - P-OH H wherein: (i) R1 is CH2 (CH2) n, CH2CH (OH) (CH2) n, CH2CH (CH2) n (OH), CH2OCH (R7), CH2OCH (R7) (CH2), CH 2 OCH (R 7) (CH 2) O O 0 (CH 2) CH (R 7) 0; R2 is OH; R7 is H or 5 CH2OH; n is 0-6, generally 1-6, preferably 1-3, most preferably 1 or 2 and most preferably 1; p is 0-3, preferably 0 or 1; and m is 0 to about 3, preferably 0 or 1; or (ii) R1, R2, n, m and p are defined as in (i), and R1 and R2 are joined to form a cyclic ester group; B is a pyrimidine or purine represented by the formula (II): and is selected from pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl or their pharmaceutically acceptable salts or esters. In particular B is selected from pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl or their pharmaceutically acceptable salts or esters, particularly, the salts with ammonia or alkali metal amines or prodrug derivatives or other derivatives thereof, particularly derivatives that penetrate the cornea when administered topically as eye drops. R3, R4, R5 and R6 are independently selected from NH2, alkylamino, aminoalkyl, hydroxyalkyl, hydrazino, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, CH3_s (hal) s, wherein q is 1- 3 and hal is a halide, preferably fluoro, hydroxylated or another group selected from that resulting nucleoside analog that retains the capacity of the lower intraocular pressure. The alkyl and alkoxy groups are preferably lower alkyl, preferably contain 1-3 carbons, more preferably 1-2 and most preferably are methyl groups. R3, R4, R5 are preferably H, NH2, CH3, CH3CH2, dimethylamino, halide or OH. R6 is preferably H or halide. Preferred compounds are the phosphonylmethoxyalkyl compounds in which: (i) R1 is (CH2) n, CH (OH) (CH2) n or CH (CH2) n (OH), R2 is OH; n is 0-6, generally 1-6, preferably 1-3, more preferably 0 or 1 and most preferably m is 0; or (ii) R1 is defined as in (i), R2 is -O- and R1 and R2 are joined to form a cyclic ester group.

A The method produces significant and long-term decrease in intraocular pressure, preferably at a level that does not result in damage to the optic nerve, associated with increased eye pressure, more preferably at a pressure that is within the normal range of intraocular pressure or within a range of pressure that damages the fiber of the optic nerve or causes loss of the visual field. In particular, methods are provided for the treatment of glaucoma by administering an effective amount of the compound of the formula I to decrease the intraocular pressure to a level at which damage to the fibers of the optic nerve does not occur and the resulting visual loss. The compound of the formula I was formulated, preferably as a free drug or, alternatively, encapsulated in liposomes or other delivery systems A long-acting drug, for administration to the aqueous humor, such as intraocular injection, at a concentration that is effective to lower the intraocular pressure. The compounds can also be formulated for the application topical to the cornea, such as in the form of eye drops, if derivatives of the compounds are selected or designed to penetrate the aqueous humor, whereby contact is made with the ciliary body. The compounds are preferably formulated for the Administration of a single dose, such that the amounts in the range of about 1-1,000 μg, 10-200 μg, more preferably 10-50 μg and typically around 10-40 μg, or 10-20 μg they are supplied in a volume of approximately 0.05-0150 ml, preferably 0.1 ml inside of the eye. In this way, glaucoma treatment compositions formulated for the administration of a single dose containing an effective amount, typically 10-100 μg, preferably approximately 10-? ^ 40 μg, more preferably approximately 20-40 μg of a compound of the formula I in a pharmaceutically acceptable carrier. The above doses are 'specified with reference to (s) -1- (3-hydroxy-2-phosphonylmethoxypropyl) -cytosine [HPMPC]. The amount of the compound will be adjusted for differences in the molecular weight of the HPMPC, in such a way that comparable amounts are used on a molar basis. The quantity is also adjusted for any difference in power as described herein. For example, HPMPA presents approximately 10-50% of the power of the HPMPC. Compounds of lower potency than HPMPC, paularly those with a relatively high therapeutic index, are desirable because they allow the best titration in increments of the total dose. As described herein, the compounds are intended for be administered in increments to achieve intraocular pressure that does not adversely impact the field of vision. The compounds can also be formulated for implantation in the anterior or posterior chamber, preferably the vitreous cavity, in sustained release formulations, such as adsorbed to biodegradable supports, including collagen sponges, or in liposomes. Sustained-release formulations may be formulated for the administration of multiple doses, such that for a selected period of time, such as one month or up to about one year, several doses are administered. In this way, for example, liposomes can be prepared, such that a total amount of about two to about five or more times the individual dose is administered in one injection. In preferred embodiments, the composition is provided in a sterile, sealed vial containing an amount of a compound of formula I, which by intraocular administration will deliver 10-100 μg, preferably 10-40 μg, most preferably 10- 20 μg of a compound of the formula I in a volume of 0.100 ml. Typically, the bottles will contain, in this form, approximately 0.150 ml of the composition. Equipment is also provided for the practice of the methods herein. The equipment contains one or more 33 containers, such as sealed bottles with sufficient composition for the administration of a single dose and one or more needles such as 25-33 self-sealing gauge needles, preferably of size 33 or smaller needles, precision calibrated syringes or other devices supply calibrated with precision, suitable for intravitreal injection. The administration of the composition is preferably by intraocular injection, although other modes of administration may be effective, if the sufficient amount of the compound achieves contact with the vitreous cavity. Intraocular injection can be effected by intravitreal injection, aqueous humor injection or injection into the outer layers of the eye, such as subconjunctival injection or subtenon injection, or by topical application to the cornea, if a derivative of compound penetration is used. . It is believed that a single injection or series of injections of lower doses will be sufficient to produce a prolonged and perhaps permanent decrease in intraocular pressure. Typically, a relatively low dose of 10 μg to about 40 μg, preferably more than about 20 μg to about 40 μg, is initially administered and the intraocular pressure is controlled for a period of at least several days, typically about two or more days. more weeks until it does not change. If the pressure is still high, an additional dose may be administered and the pressure checked as above until a sufficiently low pressure is achieved that it will not cause any damage to the optic nerve fibers or result in loss of vision. In some cases, the initial series of treatments may be sufficient to achieve a permanent decrease in pressure. In other cases, additional injections may be required at infrequent intervals to achieve decreased pressure. The amount of the compound administered may be varied by the physician to obtain the desired degree of pressure decrease. Care must be taken to avoid achieving a pressure that is less than desired. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as is commonly understood by one skilled in the art to which this invention pertains. All patents and publications mentioned herein are incorporated by reference. As used herein, an effective amount of a compound to treat glaucoma is an amount that is sufficient to alleviate or in some way reduce a symptom or stop the progression of a condition, preferably by reducing the intraocular pressure, associated with Glaucoma Such quantity can be administered as a single dose or it can be administered according to a regimen, by which it is effective. The amount can cure glaucoma by permanently lowering the intraocular pressure to a level that does not cause damage to the optic nerve, but typically, it is administered to reduce intraocular pressure, thereby relieving any associated pathology or symptoms of the disease. Typically, repeated administration is required to achieve the desired reduction in pressure to or to arrest the progression of the associated pathology. As used herein, the adverse symptoms associated with elevated intraocular pressure is damage to the optic nerve seen as suction cup and / or loss of visual field. The suction cup refers to an observable depression in the central area or paracentral area of the optic nerve. As used herein, salts, esters or other derivatives of the pharmaceutically acceptable compounds include any of the salts, esters or derivatives that can be readily prepared by those skilled in the art, using known methods for such derivatization and that produce compounds which can be animal or human without substantial toxic effects and which are pharmaceutically active or are prodrugs. For example, hydroxy groups can be esterified or etherified. As used herein, IC50 refers to an amount, concentration or dose of a particular compound, which achieves 50% inhibition of a maximal response, in this case reduction of intraocular pressure. As used herein, CE5Q refers to a dose, concentration or amount of a particular test compound, which produces a dose-dependent response to 50% of the maximum expression of a particular response that is induced, elicited or potentiated by the particular test compound. As used herein, "treatment" means any form in which the symptoms or pathology of a condition, disorder or disease are alleviated or in any other way altered beneficially. The treatment also encompasses any pharmaceutical use of the compositions herein and particularly relates to decreases in intraocular pressure. As used herein, alleviation of the symptoms of a particular disorder, in this case alleviation of the progression of physiological changes associated with glaucoma and / or reduction in intraocular pressure, by administration of a particular pharmaceutical composition, refers to any decrease, permanent or temporary, lasting or transient that may be attributed to or associated with the administration of the composition. In particular, any decrease in intraocular pressure that is sufficient to prevent, inhibit, slow or stop damage to the optic nerve, as evidenced by visible changes in nerve structure by ophthalmoscopy or instruments that show the suction cup form in the nerve optical or by loss in the visual field, particularly in the periphery. As used herein, substantially pure means sufficiently homogeneous to appear free of easily detectable impurities, as determined by standard analytical methods, such as thin layer chromatography [TLC], gel electrophoresis and high pressure liquid chromatography [ CLAP], used by those skilled in the art to evaluate such purity or sufficiently pure in such a way that other purification could not detectably alter the physical and chemical properties such as enzymatic and biological activities of the substance. Methods for purifying the compounds to produce substantially chemically pure compounds are known to those skilled in the art. A substantially chemically pure form compound can, however, be a mixture of stereoisomers. In such cases, another purification must increase the specific activity of the compound.

As used herein, "biological activity" refers to the in vivo activities of a compound or physiological responses that result in the in vivo administration of a compound, composition or other mixtures. The biological activity, in this way, encompasses therapeutic effects and pharmaceutical activity of such compounds, compositions and mixtures. As used herein, "pharmaceutical activity" refers to the activity of the compounds herein to reduce intraocular pressure. For purposes of the present, the activity of the compounds in decreasing intraocular pressure can be measured in relation to the HPMPC activity in the guinea pig model described in the following. As used in. herein, a prodrug is a compound that by in vivo administration is metabolized or converted in any other way to the biologically, pharmaceutically or therapeutically active form of the compound. To produce a prodrug, the pharmaceutically active compound is modified such that the active compound will be regenerated by metabolic processes. The prodrug may be designed to alter the metabolic stability or transport characteristics of a drug, to mask side effects or toxicity, to improve the taste of a drug or to alter other characteristics or properties of a drug. Prodrugs or derivatives of the compounds that allow penetration into the aqueous human, when administered by topical application to the eye are of particular interest herein. By virtue of knowledge of pharmacodynamic processes and drug metabolism in vivo, once a pharmaceutically active compound is identified, those skilled in the pharmaceutical art can generally design prodrugs of the compound, [see, for example, Nogrady (1985) Medicinal Chemistry A Biochemical Approach, Oxford University Press, New York, pages 388-392]. As used herein, the doses of the compounds will normally be set forth herein in microgram (μg) per milliliter (ml) administered or μg / per milliliter (μg / ml) in the vitreous base. The human eye has a vitreous volume of approximately 4 ml; the vitreous volume of the guinea pig is approximately 0.25 ml. Unless noted otherwise, typically the volume administered to a human individual is 0.1 ml and the guinea pig is 0.05 ml. As used herein, lower alkyl, lower alkenyl and lower alkynyl refer to carbon chains having six or fewer carbon atoms in a chain, preferably three or less. In the preferred embodiments of the compounds provided herein, which include alkyl, alkenyl or alkynyl portions, the compounds include lower alkyl, lower alkenyl and lower alkynyl portions, which have three or fewer carbon atoms in a chain. As used herein, abbreviations for any of the substituent groups, protecting groups, amino acids and other compounds, are unless otherwise indicated, in accordance with their common use, recognized abbreviations or the Commission in the IUPAC-IUB Biochemical Nomenclature [see (1972) Biochem, 11: 17261. 10 A. Compounds Compositions formulated for the local administration of single doses for eyes containing the compounds of the formula (I) and derivatives of the formula (I ): H 0 I II B- (R 1) -0-C- (CH.) - P OH / - 'H in which: (i) R1 is CH2 (CH2) n, CH2CH (OH) (CH2) n, CH2CH (CH2) n (OH), CH2OCH (R7), CH2OCH (R7) (CH2), CH 2 OCH (R 7) (CH 2) 0 or O (CH 2) CH (R 7) O; R2 is OH or 0 (CH2) rH, preferably OH; R7 is H or CH2OH; n is 0-6, usually 1-6, preferably 1-3, most preferably 1 or 2 and most preferably 1; p is 0-3, preferably 0 or 1; r is 1-6, most preferably 1-3, most preferably 1 or 2; and m is from 0 to about 3, preferably 0 or 1; or (ii) R1, R2, n, m and p are defined as in (i), and R1 and R2 are linked to form a cyclic ester group; B is represented by the formula: R3 such that B is selected from pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl or their pharmaceutically acceptable salts or esters, particularly the salts with Ammonium or alkali metal amines or prodrug derivatives or other derivatives thereof, particularly derivatives that penetrate the cornea to deliberately provide the aqueous cavity of the eyes are provided. R3, R4, R5 and R5 are independently selected from NH2, alkylamino, aminoaikyl, hydroxyalkyl, hydrazino, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, CH3 -j_- £ (hal) s * »- , wherein q is 1-3 and hal is a halide, preferably fluoro, hydroxylamino or another group selected from that resulting nucleoside analog which retains the capacity of the lower intraocular pressure. The alkyl and alkoxy groups are preferably lower alkyl, preferably contain 1-3 carbons, more preferably 1-2 and most preferably are methyl groups. R3, R4, R5 and R6 are independently selected from NH, alkylamino, aminoalkyl, hydroxyalkyl, hydrazino, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, CH3 (halA, in which q is 1-3 and hal is a halide, preferably fluoro, hydroxylamino or another group selected from that resulting nucleoside analogue that retains the capacity of the lower intraocular pressure.The alkyl and alkoxy groups are preferably lower alkyl, preferably contain 1-3 carbons, of higher preference 1-2 and more preferably are methyl groups R3, R4 and R5 are preferably independently selected from NH2, H, OH, lower alkylamino, CH3, C (hal) 3, in which hal is halide, particularly CF3 or equivalent variations thereof R3, R4, R5 are more preferably H, NH2, dimethylamino, halide or OH R4 is preferably H, CH3 or halide and more preferably H or halide, particularly bromine R3, R4, R5 and R6 can be selected in such a way that B is uridinyl, thymidinyl, cytosinyl or adeninyl or their derivatives. In the most preferred embodiments the compounds are those in which R1 and R2 are only (i), wherein R1 is CH2CH (OH) (CH2) n, CH2CH (CH2) n (OH), CH2OCH (R7.). , CH2OCH (R7) (CH2) p, CH2OCH (R7) (CH2) O or O (CH2) CH (R7) O; R2 is OH or 0 (CH2) rH; R7 is OH or (CH2) rOH, preferably (CH2) OH, n is 0-6, preferably 0-3, r is 1-6, preferably 1-3, most preferably 1, p is 0-3, and m is from 0 to 3. Many of the compounds will have an asymmetric carbon atom, such as when n is 1 and R1 is different from methylene and exist in more than one enantiomeric form In such cases, the preferred compounds are racemic mixtures (RS) or, preferably they are in a form (S) and are in the form of a free acid or its salt The compounds of the formula (I) which contain a chiral center are preferred and it is preferred that they be in the s configuration.The racemic mixtures are, however, acceptable. Of the compounds of the formula (I), those with the following formula n particular interest: H H H H O H H H O I I I I II I I I II B-C-O-C-C-C-P-OH B -C-C -O-C-P-OH I l i l i J I I H R 'H H OH H Rt H OH H H H O H H H O I I! II! i I II B- C-0 -C -O-C - P-OH and B -O-C -O-C-P -OH l i l i (l l l ' H R 'H OH H R7 OH wherein B, R7 and the preferred embodiments of B, are as defined in the foregoing.

Among other preferred compounds of the formula (I) are those of the formula (II): H H O in which: 0H (i) R'esfCH,) ,,. - C- (CH.) - or CH. { CHa), (OH); R * is OH; i H n is 0-6, generally 1-6, preferably 1-3, most preferably 1 or 2 and most preferably 1; or (ii) RJ- and R2, which are as defined in (i), are joined to form a cyclic ester group; in which B and the preferred modalities of B are as defined in the above. The compounds of formula (I) and (II) for use in the present methods include, but are not limited to, compounds in which B is selected from uracil-1-yl, cytosin-1-yl, 5-methylcytosin-1-yl, timin-1-yl, 5-fluorouracil-1-yl, racil-3-yl, cytosine -3-yl, 5-methylcytosin-3-yl, timin-3-yl, 5-fluorouracil-3-yl, guanin-9-yl, guanin-7-yl, guanin-3-yl, adenin-9-yl , adenin-7-yl, adenin-3-yl, hypoxanthin-9-yl, hypoxanthin-7-yl, hypoxanthin-3-yl, 2-methyladenin-9-yl, 2-methyladenin-7-yl, 2-methyladenine -3-yl, 2-methylthioadenin-9-yl, 2-methyl-thioadenin-7-yl, 2-methylthioadenin-3-yl, 2-aminoadenin-9-yl, 2-aminoadenin-7-yl, 2-aminoadenin -3-yl, 2-aminopurin-9-yl, 2-aminopurin-7-yl, 2-aminopurin-3-yl, N-dimethyia? Enin-9-yl, N6-dimethyladenin-7-yl, N6- dimethiadenin-3-yl, 8-bromo-adenin-9-yl, 8-bromoadenin-7-yl, 8-bromoadenin-3-yl, 8-hydroxyadenin-9-yl, 8-hydroxyadenin-7-yl, 8- hydroxyadenin-3-yl, 6-hydroxyaminopurin-9-yl, 6-hydroxyaminopurin-7-yl, 6-hydroxyaminopurin-3-yl, 6-hydrazinopurin-9-yl, 6-hydrazinopurin-7-yl, 6-hydrazinopurin- 3-yl, 6-thiopurin-9-yl, 6-thio purin-7-yl, 6-thiopurin-3-yl, purin-9-yl, purin-7-yl, purin-3-yl, xanthin-9-yl, xanthin-7-yl and xanthin-3-yl. Among those preferred compounds are those in which B is uracil-1-yl, cytosin-1-ylc, 5-methyl-cytosin-1-yl, timin-1-yl, • 5-fluorouracil-1-yl, guanin- 9-yl, guanin-7-yl, adenin-3-yl, hypoxanthin-9-yl, 2-methyl-adenin-9-yl, 2-methylthioadenin-9-yl, 2-aminoadenin-9-yl, 2- aminopurin-9-yl, N ^ -dimethyladenin-9-yl, 8-bromoadenin-9-yl, 8-hydroxyadenin-9-yl, 6-hydroxylaminopurin-9-yl, 6-hydrazinopurin-9-yl, 6-thiopurin -9-yl, purin-9-yl and xanthin-9-yl. Compounds in which B is cytosin-1-yl, uracil-1-yl, 5-methylcytosin-1-yl, timin-1-yl and 5-fluorouracil-1-yl may be more preferred. Other preferred compounds include, but are not limited to, nucleoside analogs of N- (2-phosphonylmethoxy-ethyl) [PME] and N- (3-hydroxy-2-phosphonylmethoxypropyl) [HPMP] -pyrimidine and purine, particularly the pyrimidine analogues. HPMP analogs are currently generally preferred and sHPMP analogs are currently more preferred. In the preferred compounds R1 is a chiral center and is preferably in the s configuration. Some particularly preferred compounds include, but are not limited to: 9- (s) - (2-phosphonylmethoxy-3-hydroxypropyl) adenine - [HPMPA], 9- (2-phosphonylmethoxyethyl) adenine [PMEA], (s) -l - (3- 10 hydroxy-2-phosphonylmethoxypropyl) cytosine [HPMPC], (2-phosphonyl-methioxyethyl) cytosine [PMEC], (2-phosphonylmethoxyethyl) guanine [PMEGJ, 1- (s) -3-hydroxy-2-phosphonylmethoxypropyluracil [(S) - HPMPU], 9- (s) -3-hydroxy-2-phosphonylmethoxypropylguanine [(S) -HPMPG], (2-phosphonylmethoxyethyl) -2, 6-diaminopurine [PMEDAP] and 9- (s) -2-phosphonylmethoxypropyladenine [(S) -PMPA]. The cyclic compounds of (s) -3-hydroxy-2-phosphonylmethoxypropylcytosine [cHPMPC] and 9- (cyclic (s) -3-hydroxy-2-phosphonylmethoxypropyl) adenine [cHPMPA], are also among the preferred compounds. The compounds 9- (r) -20 3-hydroxy-2-phosphonylmethoxypropyladenine [(R) -HPMPA], 9- (r) -2- phosphonylmethoxypropyladenine [(R) -PMPA] and 9- (2-phosphonyl- methoxyethyl) adenine [PMEA] are also intended for use in the present. Among the preferred compounds of the present are: 9- (s) - (2-phosphonylmethoxy-3-hydroxypropyl) adenine [HMPA] and (s) -1- (3-hydroxy-2-phosphonylmethoxypropyl) cytosine [HPMPC]. B. Preparation and Selection of Compounds 1. Preparation Some of the compounds provided herein are compounds that are available for use as antiviral agents [see, e.g., U.S. Patent Nos. 5,142,051 and 4,724,233; see also U.S. Patent Nos. 4,605,658 and 4,230,708 and De Clercq et al., (1991) Biochemical Pharmacolosy 42: 963-972] and thus, can be obtained from commercial sources or synthesized by known methods [see, for example, example, U.S. Patent Nos. 5,142,051 and 4,724,233]. The novel compounds of the formulas (I) and (II) can be prepared by modifying the processes for the preparation of the known compounds. Such modification is within the skill level of the synthetic organic chemistry technique. The use of and formulation of the compounds to lower intraocular pressure has not been described so far. Antivirally effective doses, if administered to the eye, must necessarily be less than the doses to decrease intraocular pressure to avoid permanently reducing intraocular pressure in individuals who do not have high intraocular pressure or glaucoma. 2. Selection of Compounds The compounds of formulas (I) and (II) can be selected based on their activity in the guinea pig model. For example, injection of HPMPC, cHPMPC or HPMPA into the vitreous cavity of the guinea pig's eye results in a decrease in intraocular pressure, which decreases in parallel in human eyes. The results seem to be directly extrapolated to the effective doses in humans. The normal intraocular pressure in the guinea pig, which is very similar to humans, is an average of 14.7 mm Hg and the normal range is between approximately 10 mm to approximately 22 mm. Among these compounds HPMPC causes the greatest drop in the IOP / μg administered; and cHPMPC causes the least fall. All compounds showing activity in this model, however, should be useful, since it is advantageous for the treatment, to be effected by administering a series of administrations of the compound to avoid eliminating the IOP too much. The histological studies of the guinea pig show changes in the structure of the ciliary body, which could be expected to decrease the aqueous secretion. The optical properties of the compound, when injected into the vitreous cavity, are evaluated by indirect ophthalmoscopy and background photography, as well as observing the behavioral characteristics of the animals who endured the intravitreal injection. In all cases, the optical routes were normal, as was the visual behavior of the animal, indicating that the compound does not obstruct or affect the visual routes in any way. This indicates that the intravitreal injection of the compound, as described, should result without adverse effects and will have a major therapeutic effect. In the guinea pig model, injections are made with anesthetized animals and baseline intraocular pressures are taken for comparison with post-injection pressures. The manometric measurements of the intraocular pressure are made by placing a 33 gauge cannula inside the eye of the guinea pig and determining the pressure by manometry, using a pressure transducer and a recording device. The injection, by means of the limbus of compositions of 0.05 ml containing 2 μg, 10 μg, 50 μg, 80 μg, 100 μg and 250 μg of HPMPC (per 0.25 ml of vitreous humor) resulted in decreases in pressure, indicating a dose-response relationship in the range of approximately 10-200 μg / 0.25 ml of vitreous humor in this model. The results were parallel, although higher in concentrations, for the results observed in humans, in which the response-dose curve is linear in the range of approximately 10 μg to approximately 80-100 μg injected by 4 ml of vitreous humor in the human eye.

Multiple doses of HPMPC in this model also showed a clear dose response. The injection of 250 μg of HPMPC (approximately 1 mg / ml vitreous humor) in this model results in a substantial drop in intraocular pressure that eventually reaches zero to several days. The effect appears to be approximately equivalent to the administration of approximately 100 μg (25 μg / ml vitreous humor) to a human eye. An injection of 50 μg (200 μg / cc) to the guinea pig reduces the pressure by approximately 30-60% (less than 10 mm Hg) without adverse effects. This is equivalent to approximately 20-40 μg injected into the human eye. A dose of HPMPC of 6.25 μg caused a minimal fall or did not cause a fall in the IOP; and a dose of 156 μg causes a similar, slightly increased drop in IOP. The administration of 500 μg resulted in an IOP of zero. In humans, the administration of 10-20 μg of HPMPC causes a fall of approximately 2-4 mm of Hg and repeated injections every six weeks, cause another decrease in IOP. At a dose of 40 μg, there is a larger drop and at 100 μg the IOP drops to zero. Injection of cHPMPC at equivalent doses for HPMPC of 500 μg decreased the IOP gradually from the normal range to between 2 and 6 mm of Kg over the course of 4 weeks. The doses of 156 μg (equivalent to HPMPC) had no effect.

This indicates that cHPMPC is an agent that lowers the pressure very softly and thus, will allow the gradual decrease of the IOP to the normal range in a range of useful doses (doses in the range of 100 μg to 400 μg). HPMPA, which has been tested in this model, appears to be approximately 10 to 50% less potent than HPMPC, and appears to have a higher therapeutic index dose (therapeutic index = required dose that reduces the pressure to zero / dose to decrease to 10%) than HPMPC. HPMPA, in this way, will also be suitable for therapeutic use for the treatment of glaucoma, since it will allow precise titration of the appropriate total dose to achieve the desired decrease in pressure. Other compounds of formulas (I) and (II) are evaluated for the activity of decreasing intraocular pressure in this model. Compounds exhibiting intraocular pressure decrease activity, substantially similar to HPMPC or with higher specific activity than HPMPC in this model are preferred to be used herein. Compounds that are less potent but exhibit specific activity that is at least about 30-50% HPMPC are also suitable for use. As long as the activity is sufficient for a therapeutically effective dose (equivalent in activity to about 10 μg of HPMPC) they are supplied to the human eye in about 0.100 ml, a selected composition is suitable for use herein. In this way, any compound that exhibits activity that decreases the detectable IOP in this model must be suitable for use in the present. C. Formulation Compositions containing therapeutically effective amounts for lowering the intraocular pressure of the compounds of the formula (I) are provided herein. The compounds are formulated in suitable concentrations for the administration of a single dose by intraocular administration in an amount that decreases in increments the intraocular pressure from a high level to a level that is sufficiently low to avoid the damaging effects of elevated intraocular pressure. Typically, the concentrations of the compounds are between about 10% and 50%, preferably greater than about 20% and up to about 40% by weight / volume. The compositions are preferably formulated for intraocular, preferably intravitreal, administration such that injection of about 0.100 ml delivers about 10 μg to less than about 100 μg, preferably about 10 μg to about 40 μg or 50 μg. Currently, compositions formulated for the administration of a single dose of about 40 μg by volume of 0.1 ml are preferred. To prepare . The compositions, one or more compounds of the formula (I) or (II) are mixed with a suitable ophthalmologically acceptable carrier. By mixing or adding the compound or compounds, the resulting mixture can be a solution, suspension, emulsion or the like. In addition, the compounds can be formulated as the sole pharmaceutically active ingredient in the composition or can be combined with other active ingredients, particularly anti-glaucoma agents, or pharmaceutically inactive ingredients. Of the compounds of formulas (I) and (II), those which are polar and highly soluble in water are very suitable for ocular use, especially where intraocular injection is the preferred method of administration. If necessary, however, salts or other pharmaceutically acceptable derivatives can be prepared. If the resulting mixture is subjected to filtration, it can be sterilized by the filter using filter systems and sterile 0.22 μm syringe of a nylon 66 matrix, which does not cause ocular toxicity. The active compound is included in the fara-pharmaceutically acceptable carrier in an amount sufficient to exert a therapeutically useful effect in the absence of undesirable side effects on the treated patient. The therapeutically effective concentration can be determined empirically, by testing the compounds in ir systems. In vitro and in vivo known, particularly the guinea pig model is described herein. Based on a comparison of the activity of a particular compound in this model with the compounds, such as HPMPC, which are exemplified herein, compositions containing effective amounts of the selected compounds are prepared. Typically, a therapeutically effective dose by the administration of a single dose, should reduce the intraocular pressure by an amount of less than 20 mm Hg, preferably less than 10 mm Hg and in the order of. a decrease of 10% -30%, depending on the initial pressure. This may be repeated, usually after an interval of at least 14 days or more, until the intraocular pressure is sufficiently reduced to a level at which damage to the optic nerve and loss of visual field is consistent with the velocity of the eye. damage or reduced loss, preferably it is reduced substantially. The compositions are formulated in an ophthalmologically acceptable carrier for intraocular administration, preferably intravitreous in a volume between about 0.05 ml and 0.150 ml, preferably about 0.05 and 0.100 ml, containing between about 1-1,000 μg, preferably 10 μg at least about 100 μg, more preferably about 10-50 μg and more preferably about 20-40 μg of a compound of the formula (I) or (II). In this way, the compositions contain between about 10% and 50% (weight / volume), with about 25% or 30% to 40-50% preferred, of a compound of the formula (I) or (II). For administration by intraocular injection or-by me? -eye drops, carriers include, but are not limited to, physiological saline, phosphate buffered saline (PBS) ), balanced salt solution (BSS), lactate Ringers solution and solutions containing thickeners and solubilizers, such as glucose, polyethylene glycol and polypropylene glycol and mixtures thereof. Liposomal suspensions can also be as pharmaceutically acceptable carriers. These can be prepared according to methods known to those skilled in the art. The ophthalmologically acceptable holders, a? Ecu? Os, are known. The solutions or mixtures? Estina? As for ophthalmological use can be formulated as isotonic solutions? E 0.01% - 10%, Approximately pH 5-7, with appropriate salts [see, for example, the Patent "Uni? os Uni? os No. 5,116,868, which writes typical compositions? e solutions? and ophthalmic irrigation and solutions for the local application]. Such solutions, which have a pH adjusted to about 7.4, contain for example, 90-100 mM sodium chloride, 4-6 mM ibasic potassium phosphate, 4-6 mM ibasic phosphate, and sodium phosphate. citrate, 8-12 mM sodium chloride, magnesium chloride, 0.5-1.5 M, 1.5-2.5 mM calcium chloride, 15-25 mM sodium acetate, DL-β-hi? roxibutirato? e so? io 10-20 mM and glucose 5-5.5 mM. A- The compounds? And formulas (I) and (II) can prepare with carriers that protect against rapid elimination? The body, such as formulations? E release over time or coatings. Such carriers include formulations of controlled release, such as but not limited to, microencapsulated delivery systems. and bio-compatible, biocompatible polymers, such as vinylacetate and ethylene, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and other types and implants that can be placed? Directly? Did I enter the interior or rear chamber or sink? vitrea? the eye. The compositions can also be used in granules, such as Elvax granules (resin? E copolymer? Ethylene acetate? Vinyl). Liposomal suspensions, include? Or liposomes with target tissue, can also be a? Ecua? as pharmaceutically acceptable carriers. For example, lae liposome formulations can be prepared by methods known to those skilled in the art.

[See, for example, Kimm et al. (1983) Eicch. Eico Acts 728: 339-398; Assii et al. (1987) Arch Ophthalmol. 105: 400; Y U.S. Patent No. 4,522,811]. The nucleoside analogs provided herein may be encapsulated in the aqueous phase of the liposome system. He HPMPC has been encapsulated in liposomes used? Or a ^ r ~ - mo? ification? the method? e Kimm et al and it is written in the E EMPLO 4. The active materials can also be mixed with other active materials, which do not damage the desired action or with materials that supplement the desired action or have other action, include? Or viscoelastic materials, such as hyaluronic acid, which is under the trademark HEALON, which is a solution? A fraction? High molecular weight (MW)? And approximately 3 million? Hyaluronate? ? io [factory? o by Pharmacia, Inc; see, for example, the Patents? and the Uni? os Uni? os Nos. 5,292,362, 5,282,851, 5,273,056, 5,229,127, 4,517,295 and 4, 328,803]; VISCOAT [methacrylates containing fluorine, such as methacrylate and 1H, 1H, 2H, 2H-hepta-? Ecafluoro? see, for example, Patents? and Uni? os Units Nos. 5,278,126, 5,273,751 and 5,214,080; ? commercially available? e Alcon Surgical, Inc.], ORCOLON [see, e.g., U.S. Patent No. 5,273,056; commercially available from Optical Radiation Corporation], methyl cellulose, methyl hyaluronate, pol aculfide and p-methymethacrylamide [see, for example, United States Patent No. 5,273,751]. The viscoelastic materials are generally present in a quantity in the range of approximately 0.5 to 5.0%, preferably 1 to 3% by weight, the material conjugated and used to coat and protect the tissues. I treat you. The compositions may also include a colorant, such as blue, methylene, or other inert dye, such that the composition can be observed as it is injected into the eye. Agents that decrease intravitreal or anti-glaucoma pressure, including beta-blockers, such as epinephrine and urocheptics such as actazolamin, or pilocarpine, may also be included. The compositions may be contained in ampoules, disposable syringes or flasks, multiple eosis or a single made-up version, plastic, or other similar material. Such contained compositions can be provided in teams. In particular, the equipment containing flasks, ampoules or other container, and preferably jars with large quantities? The composition, to provide approximately 0.100 ml thereof, and disposable needles, preferably self-sealing 25-30 gauge needles are provided herein.

Pre-packaged vials of the compositions containing concentrations are provided: the composition of approximately 10 μg / 0.100 ml, 20 μg / 0.100 ml, 25 μg / 0.100 ml, 30 μg / 0.100 ml, 35 μg / 0.100 ml to approximately 100 μg / 0.100 ml in 5 or 10 μg / 0.100 ml in increments, with sufficient volume, typically 0.125-0.150 ml to deliver 0.100 ml. For the treatment of elevated intraocular pressure in the greater range, approximately 20 μg / 0.100 ml and less is approximately 80 μg / 0.100 ml, and preferably approximately 40 μg / 0.100 ml are preferred. Finally, the compounds can be packaged as articles, or packaging material, or containing manufacture, typically a bottle, an ophthalmologically acceptable composition containing a compound of formula (I) or (II) provides? it, which is effective for lowering intraocular pressure and a label that makes it necessary for the compound or salt to be used to lower intraocular pressure. D. Administration The compositions containing the compounds are administered intraocularly or by other means, such as topically in the form of penetrating eye drops, whereby the contact of the compounds with the aqueous humor is effect Intraocular administration can be effected by intravitreal injection, injection, "aqueous humor, injection," or "externally" into the eye, such as subjunctival injection or subtenon injection, and preference in free form, but alternatively, in liposomes or another "device" the supply of sustained drug. The administration of the compound is preference for intravitreal injection, and preference through self-sealing 25-30 gauge needles or other "positive" calibratable or even-equi-valent supply. The injection in the eye can be through pars plana by means of self-healing needles. Without being able to join any theory, with regard to the mechanism - this extended or possibly permanent period of effectiveness for glaucoma treatment by contact - does the compounds provide in it with the ciliary body that decreases the capacity? ? the ciliary body? the eye to secrete watery humor. Since preference is given to the ciliary body by vitreous injection or injection, the aqueous humor, such modes, and administration are currently preferred. Administration by other methods that ultimately result in intraocular pressure is reduced, such as injection into the outer layers of the eye, such as subjunctival injection or subtenon injection, or topical application to the eye. Cornea in a way that penetrates the eye, can be used. Such methods or administration should be designed to result in the introduction of a compound into the aqueous or vitreous fluids, thereby providing access to the ciliary body. The routes of administration, especially by the injection, were specialized and unique in the properties, the compound that make it highly suitable for use, include its lack of toxicity (in addition to the reduction). the watery secretion), therapeutic intraocular elevation, clari? a? optics, which prevents it from affecting the vision of the eye which is administered and its greater solubility in water, which allows extremely small volumes to be injected under topical or local anesthetics into the cavity? vitrea me? ia? the human eye. Typically, in order to avoid excessive decrease in intraocular pressure, the compounds are increased in doses in increments, generally more than approximately 20 μg to approximately 40 or 50 μg / injection,? Epen? In the initial pressure and fiber, the optic nerve observes and changes the visual field. The osmosis should be selected on the basis of the pressure and start, initial and observed symptoms and carefully selected to achieve a resulting pressure that is within the normal range of 8- 22 mm Hg. It seems that there are many cases, a single intravitreal injection may be enough to obtain permanent re-uction. However, care must be taken to avoid achieving a great recession in the prediction. Therefore, the doses may be preferred in increments. After administration of one injection, the intraocular pressure is controlled for one to three weeks and, if necessary, a second dose is administered to the composition, followed for one to three weeks. control. This is repeated until the intraocular pressure is reached, usually, although not necessarily, between the 8-22 mm range and Hg. It is understood that there are variations in the range of normal pressure. Therefore, for patients with glaucoma, the elevated pressure is determined by the pressure and evidence of the year in the optic nerve as visually gumly, by a decrease in the visual field or another. test in? ica? ora? e such? year. In patients with glaucoma, intraocular pressures are typically above 18-20 mm Hg, but in some patients, the visual field and changes in the optic nerve are observed at pressures in the eye. the range? e 15-22 mm? e Hg. Such glaucoma is mentioned as giauco at low tension. Also, in some patients, changes in the visual field and optic nerve do not occur until the pressure is as high as? E 30-33 mm? And Hg. In any case, the treatment is "isena" or to effect an "decrease" in intraocular pressure, so that the atrophic symptoms are? Eteni? Os or their progression? Is diminished. r. The effectiveness of the treatment can be evaluated by observing a decrease in pressure, whatever pressure or pressure has been applied before, and a concomitant stop or decrease in the year to the optic nerve and the 5 pér? i? a? the visual field. In this way, the amount? Absolute? The pressure changes and finally, the number? e? osis and? ossification? of the compounds? and the present, are? etermina? ons with reference to falling patient. In form? Eseable, the total ossification ? The effects of treatment, as they are stated in the present, should be minimized. Therefore, in small increments, typically about 20-60 μg, preferably 20-40 μg or about 50 μg per injection (0.100 ml injected), epen? The pressure Intraocular and changes observed in the optic nerve and peri? A? The visual field are a? Ministra? Os. Minor osmosis as low as 10 μg, 20 μg or 30 μg, can be administered, when the initial pressure is in or near the normal range. Currently, the oysters in the or? In Approximately 40 μg (35-45 μg) per injection seems to be preferred. After the patient is checked periodically and if the intraocular pressure is increased, a? Qsis is administered. Don? E re olution in the pressure is permanent, it is expected that Other injections will only be required on a non-frequent basis, since the effects of decreasing the intraocu- lar preemption of composite elements are long-term and possibly permanent. Furthermore, it is understood that for any particular individual, the specific regimes must be adjusted over time, according to the needs of the individual and professional judgment. person who a? Inistra or supervises the administration of the compositions, and that the concentration ranges established In the present, they are only exemplary and are not intended to limit the scope or practice of the referential methods or concentrations of the active compounds in the reivinic compositions. Also, it should be understood that the concentrations of the compounds are specific to weight / volume with reference to HPMPC and that the compounds of formula (I) or (II) vary in molecular weight and power compared with HPMPC. The adjustments in quantity are for differences in molecular weight and differences in potency, and HPMPC are expected to be encompassed in the present.

In this way, if a compound presents 50%? S activi? A? The HPMPC in the molar and the guinea pig established in the present, it is understood that the range of concentrations, expressed as μg, will be approximately the times established for HPMPC. Also, if the molecular weight is approximately 2% or more, concentrate them accordingly. The following examples are included for illustrative purposes only, and are not intended to limit the scope of the invention. EXAMPLE 1 Intravitreal injection of 10 μg-100 μg of HPMPC Twenty patients having relatively normal or intraocular pressure reduced, but suffering from cytomegalovirus (CMV) retinitis associated with HIV injection, injected into the cavi? to? vitrea with HPMPC in a quantity? ? e 10-100 μg? e total volume? e 0.1 ml. It is observed that injecting HIV-positive patients who have AIDS present with reocular intraocular pressure. In this way, the absolute values of the pressures observed in these patients should be considered in this context. The effect of decreasing the pressure started at 3-14 days and it was observed that it was long. The low blood pressure was a function of the osseous, with the lowest osmosis (~ 10 μg / ml) pro? Ucien? Cant? Is relatively small reduction of pressure, the largest output (~ 100 μg / ml) in the maximum refinement (in some cases? decrease to essentially 0 mm? and Hg) and the intermediate os? os pro? uce gra? Intermediate? e re? uccion? e the pressure.

EXAMPLE 2 Intravitreal injection of 20 μg of HPMPC The effects of injection of 0.1CC sterile saline ion) containing 20 μg of HPMPC in a consecutive series of 38 eyes of AIDS patients infected with CMV were evaluated. Intraocular pressure is measured by flattening the tonometry at the baseline, weeks 2 and weeks 4-6 after the injection. The analyzes are serialized in a series of 95 injections and pairs of means are compared using the Tukey-Kramer technique [JMP software, SAS Institute, Carey, NC], which corrects multiple comparisons. Twenty-six patients (52 eyes) were studied in the baseline, 38 eyes received 1 injection, 16 eyes received 2 injections and 7 eyes received 3 injections. The intraocular pressure me at the baseline was? 9.82; Weeks after the first injection was 7.31 and at 4-6 weeks it was 8.29. Two weeks after the second injection, the intraocular pressure was 6 and then 4-6 weeks was 7.25. Two weeks after the third injection, the intraocular pressure me was 7.14 and? Sputtered? 4-6 weeks was 8. The HSD? E Tukey-Kramer analysis [Software JMP, SAS Institute, Carey, NC], revealed that the difference between baseline pressure and pressure two weeks after the first injection, the difference between the baseline and the pressure? weeks? of the second injection and the difference between the baseline and the pressure at 4-6 weeks after the second injection were statistically significant. EXAMPLE 3 Effect of 40 μg by vitreous injection of HPMPC on intraocular pressure The HPMPC (40 μg in 0.100 ml) was injected into the patients' test, who were AIDS patients infected with CMV. Three eyes and three patients had been injected with 40 μg and HPMPC. All eyes had initial pressures in the typical low normal range of patients and AIDS. In one eye, the initial pressure was? E 14; was 12 on day 7 and 9 on days 35 and 31. In the second eye on the second patient, - the initial pressure was 10 and was 3 on day 11 and 2 on day 46. The pressure on The treated eye? the third patient was initially 10. After the injection, it was? 4 in the? 11 and 5 in the? 24? the vision remained good. These results, as well as those of the Examples 1 and 2 indicate that the drop in intraocular pressure is long in duration and may be permanent. Furthermore, comparisons of the results achieved with injections of 40 μg compared with injections of 20 μg, 10 μg and 100 μg indicate that there is an effect related to dosing on intraocular pressure. EXAMPLE 4 Preparation of HPMPC encapsulated in liposomes A mixture of lipids was prepared with chloroform, isolviene, imyristoylglycerol (1.5 mg), trioline (1.68 mg) and cholesterol (5.81 mg), dissolved in 1 ml of chloroform in a jar. The HPMPC (1 mg / ml? E solution? E sucrose) is dissolved in 200 mmoles of sucrose, pH? 6.8. One ml? E this solution is added in drops to a bottle containing the mixture? Lípi? O / chloroform. The bottle is hermetically sealed and vortexed for 6 minutes to produce spherules, droplets, and HPMPC coated with a monolayer, and the fluid floats in a "liquid" and chloroform and excess. lípi? os. One ml of this mixture is quickly added to one of the flasks containing 2.5 ml of glucose (240 mmoles / liter) and the suspension is vortexed for four seconds. The resulting liposomes are then dried while passing nitrogen over them (6 liters per minute) in a flask containing 250 mmol per liter of sucrose until no detectable chloroform remains. The mixture is centrifuged at 400 X G for 10 minutes, the supernatant is removed and the pellet? The liposome is resuspended in 0.9% sodium chloride solution and recentrifuged. This lava stage will be repeated 5 times to eliminate any HPMPC without encapsulating. The drug release eeudios were performed in triplicate at 37 ° C as follows. The liposomes are resuspended in phosphate buffered saline in a 30 ml syringe mounted on a rotating rotor. At intervals and time, the aliquots are removed and 3 ml are centrifuged. The resulting supernatants are extracted, the liposomes are broken by freezing and resuscitated in 1 ml of water, and the concentration and HPMPC were determined by CLAP and / or ultraviolet absorption at 254 nm. Spectrophotometric analyzes were performed on the samples with chloroform-methanol (2: 3 v / v) and the concentration was determined by comparison with a curve are? Ar. The liposomes are injected in the same way that the free drug is injected? Or, except that a slightly larger gauge needle (25-27 gauge) may be necessary and the HPMPC is slowly released? liposomes? weeks to months, why does it provide a gradual decrease in pressure and possibly, if larger doses are given, avoiding the need? and alternative injections. The period and effectiveness of the HPMPC encapsulate seems to be between approximately 170 and 240 Ω.

Since the oddings will be apparent for those with skill? In this technique, it is intended that this invention be limited only by the scope of the appended claims.

Claims (53)

1. CLAIMS 1. The use of a compound or formula (I) or pharmaceutically acceptable salts thereof for the formulation as a medicament for reducing intraocular pressure, wherein formula (I) is: H 0 II B- (R 1) -0-C- (CH.) - P-OH H Rs where: R1 and r2 are (i) or (ii) as follows: (i) R1 is CH2 (CH2) n, (CH2) n #CHOH (CH2) n, CH2CH (0H) (CH2) n, CH2CH (CH2) n (OH), CH2OCH CH 2 OCH (R 7) (CH 2) p, CH 2 OCH (R 7). (CH 2) 0 O O (CH 2) p CH (R 7) 0; R2 is OH or 0 (CH2) rH; R7 is H, OH or (CH2) rOH, and preference (CH2) 0H; n is 0-6,? e preference 0-3; r is 1-6,? preference 1-3,? e greater preference p is 0-3; and m is 0 to 3; or (ii) R1, R2, n, m, r and p are as defined in (i), and R1 and R2 are joined to form a cyclic ester group; B is a pyrimidine or purine formula (II) and is selected from pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl; R3, R4, R5 and R6 are selected independently from NH2'alkylamino, aminoalkyl, hydroxyalkyl, hydrolyzed, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, hydroxylamino CH3_a (halo) ) _, in which q is 1-3 and nal is a halide.
2. 2. The use? E conform? with claim 1, wherein the compound is selected? H H H H O H H H O I I I I II I I I 11 B-C-O-C-C-C-P-OH B-C-C-O-C-P-OH I H R 'H H OH H R' H OH H H H O H H H I! l B-C-0-C-O-C-P-OH B-O-C-C-O-C- P-OH - I I I I H H OH H R7 OH
3. 3. The use? E conform? with claim 1, wherein R1 is CH2CK (OH) (CH2) r, CH2CH (CH2) p (OH), CK2C H (R7), CH2OCH (R7) (CH2) p, CH2OCH (R7) (CH2) OOO (CH2) pCH (R7) O; R2 is OH or 0 (CH2) rH; R7 is OH or (CH2) rOH, preferably (CH2) OH; n is 0-6, preferably 0-3; r is 1-6,? e preference 1-3,? e greater preference i; p is 0-3; and is 0 to 3.
4. 4. The use of compliance? with claim 1, wherein the compound has the formula (III): H H O where R and R2 are selected from (i) or (ii): OH, i I (i) Rt is (CH,) _. CH3 (CH »> - - C -ÍCH,) ^ or CH (CH2) ñ (OH); R2 is OH; and H (ii) R1 and r2, which are as defined in (i), are joined to form a cyclic ester group.
5. 5. The use of conformity? with any one of claims 1-4, wherein n is 1-3,? e preference 1, p is 0 or 1, r is 1 and m is 0 or 1.
6. 6. The use of conformity? with any of claims 1-5, wherein R3, R4, R5 are each independently selected from H, NH2, CH3, CH3CH2, CF3, dimethylamino, halide and OH, and preferably NH2, H, OH , CH3 and halide and R6 is H or halide, and preference H.
7. 7. The use? E conform? with any one of claims 1-6, wherein B is selected from uracil-1-yl, cytosin-1-yl, 5-methylcytosin-1-yl, timin-1-yl, 5-fluorouracil- 1-yl, uracil-3-yl, cytosin-3-yl, 5-methylcytosin-3-yl, timin-3-yl, 5-fluorouracil-3-yl, guanin-9-yl, guanin-7-yl, guanin-3-yl, adenin-9-yl, a? enin-7-yl, a? enin-3-yl, hypoxanthin-9-yl, hypoxanthin-7-yl, hypoxanthin-3-yl, 2-methyla? enin-9-yl, 2-methyla enin-7-yl, 2-methyla enin-3-yl, 2-methylthioa-enin-9-yl, 2-methyl-thioa-enin-7-yl, 2- methylthioa? enin-3-yl, 2-aminoa? enin-9-yl, 2-aminoa? enin-7-yl, 2-aminoa? enin-3-yl, 2-aminopurin-9-yl, 2-aminopurin- 7-yl, 2-aminopurin-3-yl, N ^ -? Imethyla enin-9-yl, N6-? Imethyla enin-7-yl, N6-? Imethyla enin-3-yl, 8-bromo- a? enin-9-yl, 8-bromoa? enin-7-yl, 8-bromoa? enin-3-yl, 8-hydroxy? enin-9-yl, 8-hydroxy? enin-7- ilo, 8-hi? roxia? enin-3-yl, 6-hi? roxyaminopurin-9-yl, 6-hi? roxyaminopurin-7-yl, 6-hi? roxyaminopurin-3-yl, 6-hi? razinopurin- 9-yl, 6-hydrazinopurin-7-yl, 6-hi? Razinopurin- 3-yl, 6-thiopurin-9-yl, 6-thiopurin-7-yl, 6-thiopurin-3-yl, purin-9-yl, purin - '/ 7-yl, purin-3-yl, xanthin- 9-yl, xanthin-7-yl and xanth-3-yl.
8. 8. The use of conformity? with claim 7, wherein B is selected from the group consisting of uracil-1-5-yl, cytosin-1-yl, 5-methylcytosin-1-yl, timin-1-yl, 5-fluorouracil-1-yl , guanin-9-yl, guanin-7-yl, adenin-3-yl, hypoxanthin-9-yl, 2-methyla enin-9-yl, 2-methylthioa-enin-9-yl, 2-aminoa-enin -9-yl, 2-aminopurin-9-yl, N * > - dimethyladenin-9-yl, 8-bromoa? enin-9-yl, 8-hydroxy? enin-9-10 yl, 6-hy? roxylaminopurin-9-yl, 6-hi? razinopurin-9-yl, 6- thiopurin-9-yl, purin-9-yl and xanthin-9-yl.
9. 9. The use? E conform? with claim 7, wherein B is selected from the group consisting of adenin-9-yl, cytosin-1-yl, uracil-1-yl, 5-methylcydoin-1-yl, 15 timin-1-yl and 5-fluoroura-Al-yl.
10. 10. The use? E conform? with any one of claims 1-9, wherein the compound is selected from 9- (s) - (2-phosphonylmethoxy-3-hydroxypropyl) a? enine (HPMPA), 9- (2-phosphonylmethoxyethyl) a? Enine (PMEA), (s) -3- 20 cyclic hi-roxy-2-phosphonylmethoxypropylcytosine (cHPMPC), (2-phosphonylmethoxyethyl) cytosine (PMEC), (2-) phosphonylmethoxyethyl) -guanine (PMEG), 1- (s) -3-hi-roxy-2-phosphonylmethoxypropyluracil ((S) -HPMPU), 9- (s) -3-hi? Roxy-2-phosphonylmethoxypropylguanine . { (S) -HPMPG), (2-phosphonylmethoxyethyl) -2,6-iaminopurine 25 (PMEDAP) and 9- (s) -2-phosphonylmethoxypropyladenine ((S) -PMPA).
11. 11. The use according to any of claims 1-9, in which the compound ee (s) -l- (3- hi-roxy-2-phosphonylmethoxypropyl) cytosine (HPMPC) and the amount? ? elibera? by a simple? osis? the me? icamento 5 higher? Approximately 20 μg to approximately 50 μg.
12. 12. The use according to any of claims 1-9, wherein the compound is 9- (s) - (2-r-phosphonylmethoxy-3-hi-roxypropyl) (α-enin (HPMPA)). and the amount? elibera? by a simple? os? the largest me? icamento? e 10 approximamente 40 μg up to approximately 500 μg.
13. 13. The use? e conform?? to? e? claims 1-12, in which the compound is formulated for intravitreal administration 14.
14. The use "conformed" with any of the 15 claims 1-12, in the that the compound is formulated by? injection? and aqueous humor, by injection into the outer layers? the eye, or topically, by which contact is made with the? glass? cavity.
15. It conforms to any of the claims 1-12, in which the compound is formulated for intraocular administration
16. 16. A composition, characterized because it comprises a quantity. to? effective? a compound? e the formula I in a holder? phthalmologically acceptable: 25 '/. H O I 11 B- (R1) -0-C - (CH.) - P-OH H R2 wherein: R1 and r2 are (i) or (ii) as follows: (i) R1 is CH2 (CH2) n, (CH2) n, CHOH (CH2) n, CH2CH (OH) (CH2) n, CH2CH (CH2) n (OH), CH2OCH (R7), CH2OCH (R7) (CH2), CH2OCH (R7) (CH2) O or 0 (CH2) CH (R7) O; R2 is OH O 0 (CH2) rH; R7 is H, OH or (CH2) rOH, and preference (CH2) OH; n is 0-6,? e preference 0-3; r is 1-6,? e preference 1-3,? e greater preference 10 1; p is 0-3; and m is 0 to 3; or (ii) R1, R2, n,, r and p are as defined in (i), and R - * - and R2 are joined to form a cyclic ester group; B is a pyrimidine or purine formula (II): -A and eected from the group consisting of pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl; R3, R4, R5 and R6 are selected independently from NH2, alkylamino, aminoalkyl, hydroxyalkyl, hydrazin, 5H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, hydroxy ino CH3 (hal), in which q is 1-3 and hal is a halide; and the composition is formulated for intraocular r administration, and a single dose is the amount? effective and the 10th? It is effective in reducing intraocular pressure in a human, so that the progression of the associated symptoms with elevated intraocular pressure, se? et? n or? decrease, with con? ición? that the compound is not (s) -1- (3-hydroxy-2-phosphonylmethoxypropyl) cytosine (sHPMPC). 15
17. 17. The composition? E conform? with claim 16, characterized because the compound is selected from H H H H O H H H O I I I I II I I I II B-C-O-C-C-C-P-OH B-C-C-O-C-P-OH I S I I I I I I I H R 'H H OH H R7 OH H H H O H H H O I I I II I I I II B- C - 0-C-O-C- P-OH and B - O -C - C - O - C - P - OH l i l i l i l H 'H Rt H OH H R7 H OH
18. 18. The composition according to claim 16, characterized in that: R1 and R2 are selected only (i), and R1 is CH2CH (OH) (CH2) n, CH2CH (CH2) n (OH), CH2OCH (R7), CH2OCH (R7) (CH2), CH2OCH (R7) (CH2) OO (CH2) CH (R7) O; R2 is OH O 0 (CH2) rH; R7 is OH or (CH2) rOH,? E preference (CH2) OH; n is 0-6,? e preference 0-3; r is 1-6,? preference 1-3, most preferably 1; p is 0-3; and m is from 0 to 3.
19. 19. The composition of conformity? with claim 17, characterized because the compound has the formula (III): H H O I I II B - C - (R) - O - C - P - OH I I I H H Rl where: i I R is - c - (CHj) - or CH (CH2) n (OH), H and RJesOH. - »•.
20. 20. The composition according to any of claims 16-19, characterized because n ee 1-3,? E preference 1, p ee O or l, r is l and m is O or l.
21. 21. The composition? E conform? with any of the claims 16-20, characterized in that R, R4, R5 are selected to fall independently of H, NH2, CH3, CH3CH2, CF3, dimethylamino, halide and OH, Preference is given to NH2, H, OH, CH3 and halide and R6 is H or halide, and preference H.
22. 22. The composition? e conformed? with any of the claims 16-21, characterized in that R3, R4 and R5 are selected independently from NH2, H, OH, CH3, halide and R6 is H.
23. 23. The composition ? e conform? with any of the claims 16-21, characterized because B is 15 selects between uracil-1-yl, cytosin-1-yl, 5-methyl-cytosin-1-yl, timin-1-yl, 5-fluorouracil-1-yl, uracil-3-yl, cytosin-3 -yl, 5-methylcytosin-3-yl, timin-3-yl, 5-fluorouracil-3-yl, guanin-9-yl, guanin-7-yl, guanin-3-yl, a? enin-9-yl , a? enin-7-yl, a? enin-3-yl, hypoxanthin-9-yl, 20 hypoxanthin-7-yl, hypoxanthin-3-yl, 2-methyla enin-9-yl, 2-methyla enin-7-yl, 2-methyla enin-3-yl, 2-methylthioa y enin-9 - ilo, 2-methyl-thioa? enin-7-yl, 2-methylthioa? enin-3-yl, 2-aminoa? enin-9-yl, 2-aminoa? enin-7-yl, 2-aminoa? enin -3-yl, 2-aminopurin-9-yl, 2-aminopurin-7-yl, 2-aminopurin-3-yl, N6-? Ineethyl? Enin-9-yl, N6-? Imethyla enin-7-yl, N6-? Imethyl-a? Enin-3-yl, 8-bromo-a? Enin-9-yl, 8- bromoa? enin-7-yl, 8-bromoa? enin-3-yl, 8-hydroxyadenin-9-yl, 8-hydroxy? enin-7-yl, 8-hydroxyadenin-3-yl, 6-hydroxyaminopurin- 9-yl, 6-hydroxyminopurin-7-yl, 6-hydroxyaminopurin-3-yl, 6-hydrazinopurin-9-yl, 6-hi? Razinopurin-7-yl, 6-hi? Razino-purin-3- ilo, 6-thiopurin-9-yl, 6-thiopurin-7-yl, 6-thiopurin-3-yl, purin-9-yl, purin-7-yl, purin-3-yl, xanthin-9-yl, xanthin-7-yl and xanthin-3-yl.
24. 24. The composition? E conform? with any of the claims 16-23, characterized in that B is selected from the group consisting of uracil-1-yl, cytosin-1-yl, 5-methylcytosin-1-yl, timin-1-yl, 5-fluorouracil-1-yl, guanin-9-yl, guanin-7-yl, adenin-3-yl, hypoxanthin-9-yl, 2-methyla enin-9-yl, 2-methylthioa-enin-9- ilo, 2-aminoa? enin-9-yl, 2-aminopurin-9-yl, N6-? imethyla enin-9-yl, 8-bromo-a? enin-9-yl, 8-hi? roxia? enin -9-yl, 6-hydroxylaminopurin-9-yl, 6-hi-razinopurin-9-yl, 6-thiopurin-9-yl, purin-9-yl and xanthin-9-yl.
25. 25. The composition according to any of claims 16-23, characterized in that B is selected from the group consisting of cytosin-1-yl, urac 1-l-A-yl, 5-methyl-cytosyl-l-yl, thymine 1-yl and 5-f luorouracil -1-yl.
26. 26. The composition according to any of claims 16-21, characterized in that B is a purine.
27. 27. The composition? E conform? with claim 16, characterized in that the compound is selected from the group consisting of 9- (s) - (2-phosphonylmethoxy-3-hi-roxy-propyl) a? enine (HPMPA).
28. 28. The composition? E conform? with claim 16, characterized because the compound is 1- (s) -3-hi-roxy-2-phosphonylmethoxypropyluracil ((S) -HPMPU) or 9- (s) -3-hi-roxy-2 -phosphonylmethoxypropylguanine ((S) -HPMPG).
29. 29. The composition is in accordance with claim 16, characterized in that the compound is selected from 9- (s) - (2-phosphonylmethoxy-3-hy? Roxypropyl) a? Enine (HPMPA), 9- (2- phosphonylmethoxyethyl) a? enina (PMEA), (s) -3-hi? roxi-2-phosphonylmethoxypropylcytosine cyclic (cHPMPC), (2-phosphonylmethoxyethyl) cytosine (PMEC), (2-phosphonylmethoxyethyl) -guanine (PMEG), 9- (cyclo (s) -3-hi-roxy-2-phosphonylmeboxy-propyl) -a? enine (cHPMPA), (2-phosphonylmethoxyethyl) -2,6-amino-purine (PMEDAP) and 9- (s) - 2-phosphonylmethoxypropylanyl ((S) -PMPA).
30. 30. The composition? E conform? with any of the claims 16-29, characterized in that the concentration of the compound is about 10 μg to about 50 μg per 0.100 ml of the composition.
31. 31. The composition is in accordance with claim 28, characterized in that the concentration of the compound is about 20 μg to about 500 μg per 0.100 ml of the composition.
32. 32. The composition according to any one of claims 16-29, characterized in that the concentration? The compound is greater? About 20 μg to about 40 μg per 0.100 ml? E composition.
33. 33. A composition, characterized because you buy a song? effective of one (s) -1- (3-hydroxy-2-phosphonyl-methioxypropyl) cytosine (HPMPC), in which: the amount? is greater than about 20 μg to about 40 μg per 0.100 ml of the composition, is the composition formulated for intraocular administration of a single dose of the amount? effective and the amount? It is effective in reducing intraocular pressure in a human, so that the progression of the atrophic symptoms associated with intraocular pressure will increase or decrease.
34. 34. The use of a compliant composition? with any of the claims 16-33 as a remedy to reduce intraocular pressure.
35. 35. A team, characterized by the fact that they buy a container that contains a quantity of a compliant composition? with any one of claims 16-33, sufficient to supply a volume of approximately 0.100 ml; a syringe to supply the volume; and optionally, a needle for use with the syringe for intraocular injection of the volume.
36. 36. A team, characterized in that it purchases a container that contains approximately 0.100 ml? E a compliant composition? with any of claims 16-33, for intravitreal administration; and a needle for use with the syringe for intravitreal injection.
37. 37. An article? E manufacture, characterized? Or because they buy a material? E container and a composition? E conform? with any of the claims 16-33, contained within the packaging material, wherein the composition is formulated for application to the eye; and the packaging material includes a label that indicates that the compound is used to reduce the intraocular pressure.
38. 38. A procedure to reduce intraocular pressure, characterized by the fact that they buy the administration for the eyes a quantity? effective? e a composition? e conform? with any of the claims 16-33.
39. 39. The method is conformed? with claim 38, characterized because the compound is (s) -1- (3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC) and the amount? it is greater than about 20 μg up to about 50 μg.
40. 40. The method of compliance? with claim 38, characterized in that the compound is 9- (s) - (2-phenethylmethoxy-3-hy? roxy-propyl) a? enine (HPMPA).
41. 41. The method? E conform? with claim 38, characterized in that the compound is cyclic (s) -3-hi-roxy-2-phosphonylmethoxypropylcytosine (cHPMPC) or 9- (cyclo (s) -3-hi-roxy-2-phosphonylmethoxypropyl) a? enina (cHPMPA).
42. 42. The method? E conform? with any of claims 38-41, characterized because it is about 20 μg up to about 100 μg.
43. 43. The method? E conform? with any of the claims 38-41, characterized because the compound is administered intravitreally.
44. 44. The method? E conform? with any of claims 38-41, characterizes because the compound is "administered" or by injection "the aqueous humor, by injection in the outer layers" the eye, or topically so the contact is effected with the cavi? vitrea.
45. 45. The method according to any of claims 38-43, wherein the initial intraocular pressure a damages the optic nerve or re? Uci? O the visual field; And the method is characterized? or more? Because I buy, check the intraocular pressure? Then the injection and then, when the pressure stabilizes, inject another amount? effective? the compound; and repeat the check and the stage? and injection a plural? ? e times until the intraocular pressure is at a level, so that additional damage to the optic nerve or loss? the visual field do not occur.
46. 46. The use according to any of claims 1-9, wherein the compound is 9- (s) - (2-phosphonylmethoxy-3-hydroxy-propyl) a? Enine (HPMA).
47. 47. The use? E conform? with any one of claims 1-9, wherein the compound is (1) -l- (3-hydroxy-2-phosphonylmethoxypropyl) cytosine (HPMPC).
48. 48. The use? E conform? with any one of claims 1-9, wherein the compound is (2-phosphonylmethoxyethyl) guanine (PMEG).
49. 49. The use? E conform? with any one of claims 1-9, wherein the compound is 9- (2-phosphonylmethoxyethyl) a? enine (PMEA).
50. 50. The composition? E conform? with claim 16, characterized because the compound is 9- (s) - (2-phosphonylmethoxy-3-hydroxypropyl) a? enine (HPMPA).
51. 51. The composition? E conform? with claim 16, characterized because the compound is (2-phosphonylmethoxyethyl) guanine (PMEG).
52. 52. The composition? E conform? with claim 16, characterized because the compound is 9- (2-phosphonylmethoxyethyl) adenine (PMEA).
53. 53. A method for reducing intraocular pressure, characterized in that it comprises administering to the eye an effective amount of a composition containing a compound of formula (I) or its pharmaceutically acceptable salts for formulation as a drug to repair the intraocular pressure, in which the formula (I) is: H 0 I II B - (R1) - O - C - (CH2) - P-OH H R2 where: pl and r2 are (i) 0 (ü) as follows: (i) R1 is CH2 (CH2) n, (CH2) n, CH0H (CH2) n, CH2CH (0H) (CH2) n, CH2CH (CH2) n (OH), CH2OCH (R7), CH 2 OCH (R 7) (CH 2), CH 2 OCH (R 7) (CH 2) O or O (CH 2) CH (R 7) O; R2 is OH or 0 (CH2) rH; R7 is H, OH or (CH2) rOH, and preference (CH2) OH; n is 0-6,? e preference 0-3; r is 1-6, preferably 1-3, most preferably i; p is 0-3; and m is from 0 to 3; or (ii) R1, R2, n, m, r and p are as defined in (i), and R1 and R2 are joined to form a cyclic ester group; B is a pyrimidine or purine formula (II): and is selected from pyrimidin-1-yl, pyrimidinyl-3-yl, purin-3-yl, purin-7-yl and purin-9-yl; R3, R4, R5 and Rs are selected independently from NH2, alkylamino, aminoalkyl, hydroxyalkyl, hydroquinone, H, OH, SH, alkylthio, alkyl, alkoxy, alkoxyalkyl, halide, hydroxylamino CH3_ (hal), in which q is 1-3 and hal is a halide.