MXPA98005083A - Method of treatment of disorders characterizopopor the over-expression of citidina deaminasa or deoxicitidina deamin - Google Patents

Abstract

A method for treating a disorder characterized by overexpression of deaminase or deoxycytidine deaminase in a subject in need of such treatment. The method comprises administering to the subject a compound of Formula (I), wherein X and X1 are each independently CoN; R1 is a lower alkyl, lower alkenyl, lower alkynyl, halogen or haloalkyl; R2 is H, -N3, - OH, amino or halogen, or a pharmaceutically acceptable salt thereof, in an amount effective to treat the disorder. Pharmaceutical formulations useful in the method of this invention are also disclosed

Description

METHOD OF TREATMENT OF DISORDERS CHARACTERIZED BY THE OVER-EXPRESSION OF CITIDIN DEAMINASE OR DEOXYZYTDIN DEAMINASE RELATED APPLICATION This application is a continuation in part of the application of United States Patent Serial No. 08 / 577,185, filed on December 22, 1995 .

BACKGROUND OF THE INVENTION FIELD OF THE INVENTION The present invention relates to an active agent of Formula I and to the treatment of a disorder associated, in part, with overexpression of cytidine deaminase or deoxycytidine deaminase, which comprises administering 5-methyl-2 ' , 3'-dideoxy-3'-azidocytidine (5mAZC), analogues thereof or a pharmaceutically effective salt thereof to a subject in need of such treatment, in an amount effective to treat the disorder and improve its symptoms. Overexpression of cytidine deaminase (CD) is associated with several human disorders. For example, some classes of leukemia are refractory to the widely used anticancer agents, cytosine arabinoside (araC). The lack of response to araC is found to be due mainly to the inactivity of the deoxicitidine kinase gene site (whose product is required for the activation of araC towards its form to kill the cancer) or to the overexpression of cytidine deaminase. or deoxycytidine deaminase (which inactivates araC by deamination to an inactive form araUracil). Currently there are no adequate methods of treatment to overcome this araC resistance due to overexpression of cytidine deaminase or deoxycytidine deaminase.

Overexpression of cytidine deaminase is also implicated in the ineffective cycle of the human immunodeficiency virus (HIV), the virus involved in AIDS. The initial stages of infection with HIV are characterized by the over-expression of cytidine deaminase by the CD4 + T lymphocytes that are the target of the viruses. The elimination of this set of infected cells could be important in a critical way to control the level of subsequent infection. Currently, a treatment of HIV infection and AIDS is the administration of 3'-azido-3'-deoxythymidine associated with this treatment. However, problems of toxicity are associated with this treatment. This toxicity arises, in part, due to the fact that AZT is administered in a systematic manner and damages the host cells in all compartments of the replication tissue. Currently there is a need for a treatment for HIV infection that has the same efficacy or improved efficacy with respect to AZT, with no side effects associated with toxicity. One solution to this problem would be the prodrug for AZT that exhibits reduced toxicity to the replicating cells, and that was preferentially activated to its virus-terminating form (AZT) in HIV-infected cells. In addition, inflammatory cells associated with arthritis symptoms are also known to produce overexpression of cytidine deaminase. Therefore, it is desired to provide a relatively non-toxic prodrug that would be preferentially activated to form a metabolite that is toxic to the inflammatory cells involved in arthritis.

SUMMARY OF THE INVENTION A method for treating a disorder associated with overexpression of cytidine deaminase or deoxycytidine deaminase which consists in administering to a subject in need of this treatment 5-methyl-2 ', 3'-dideoxy-3'-azidocytidine (5mAZC) or an analogous thereof or pharmaceutically acceptable salts thereof, hereinafter referred to as "active compound", in an amount effective to treat the disorder. A method for treating a disorder associated with overexpression of cytidine deaminase or deoxycytidine deaminase in a subject in need of such treatment, comprising administering to the subject an effective amount for treating the disorder, of a compound of Formula I: wherein X and X] _ are each independently C or N; R-L is a lower alkyl, lower alkenyl, lower alkynyl, halogen or haloalkyl; and P2 is H, -N3, -OH, amino or halogen; or a pharmaceutically acceptable salt thereof. A method for combating leukemia resistant to cytosine arabinoside (araC) which consists of administering to cytosine arabinoside (araC) which consists in administering to a subject in need of this treatment, a compound of the Formula I in an amount effective to fight araC-resistant leukemia. A method for combating HIV infection in a subject in need of this treatment by administering a compound of Formula I to the subject in an amount effective to treat HIV infection. A method for combating arthritis in a subject in need of this treatment, by administering a compound of Formula I, in an amount effective to treat arthritis. a method for combating cancer in a subject in need of this treatment, wherein the cancer is characterized by overexpression of cytidine deaminase, administering a compound of Formula I to the subject, in an amount effective to fight cancer. The agent of this invention is suitable for preparing a medicament that can be applied to the aforementioned treatments. The medicament is provided as an oral, parenteral, topical and transdermal formulation, as well as in the form of an implant in a kit.

BRIEF DESCRIPTION OF DRAWINGS Figure 1 is a graph of a dose-response curve comparing the efficacy of 5mAZC in HT-CD 29SF cells, which overexpress cytidine deaminase, and HT-29SF cells that do not. HT-29SF cells are plated on CD plate in the lower compartment and HT-29SF cells in the upper compartment of a culture box "Transwell" (1,000 cells each). A semipermeable membrane separates the two compartments of the Trans ell device, so that the drugs administered in the tissue culture medium bathe both compartments equally. The numbers on the x-axis indicate the concentrations (in μM) at which the 5mAZC is continuously administered for 72 hours; the numbers on the y-axis indicate the number of surviving cells. The data points indicated by a circle (•) represent the dose- CD response for HT-29SF cells. The data points indicated by a square (C) represent the dose-response for the HT-29SF cells.

DETAILED DESCRIPTION OF THE INVENTION The method of the present invention can be used to treat a disorder associated with overexpression of cytidine deaminase and / or deoxycytidine deaminase by administering to a subject in need of such treatment, an amount of the compound of this invention, which is effective to treat the disorder. That is, 5-methyl-2 ', 3'-dideoxy-3'-azidocytidine (5mAZC), or an analogue thereof or pharmaceutically acceptable salts thereof (ie "active compounds"). Examples of these disorders include, without limitation: cancer, leukemia that is resistant to cytosine arabinoside (araC), HIV infection, and arthritis. In a preferred embodiment, the method of the present invention is used to treat a subject suffering from cancer, which is characterized by overexpression of cytidine deaminase. Examples of these cancers include adenocarcinoma of the colon, adenocarcinoma of the lung, adenocarcinoma of the stomach, breast adenocarcinoma, Wilm's tumor, chondrosarcoma, chondrosarcoma, leukemia, prostate tumors, brain tumors (e.g. glioma, astrocytoma), liver tumors, pancreatic tumors, cervical tumors, hepatic tumors (for example hepatoblastoma, hepatocarcinoma), neuroblastoma, retinoblastoma, melanoma, basal cell carcinoma, sarcoma and metastatic cancers to the liver (for example colon cancer). While the applicants do not wish to be bound by any particular theory in the present invention, 5mAZC apparently is metabolized to 3'-azido-3'-deoxythymidine (AZT) by cytidine deaminase and deoxycytidine deaminase, as illustrated in the Scheme 1 next: -methyl-2 ', 3' -dideoxy-3 '2', 3 '-dideoxy-3' -azidothymidine azidocytidine (5mAZC) (also 3 '-azido-3'-deoxythymidine) (AZT) While they do not adversely affect cells that do not overexpress cytidine deaminase, 5mAZC is preferably deaminated in AZT, in tumor cells that overexpress cytidine deaminase. The present invention relates primarily to the treatment of human subjects, but can also used for the treatment of other mammalian subjects, for example dogs and cats, for veterinary purposes. In the sense used herein, the term "lower alkyl" refers to branched or linear alkyl, Cl to C4, as for example: methyl, ethyl, propyl, butyl, isopropyl, sec-butyl and tert-butyl. Methyl is the one that is currently preferred. In the sense used herein the term "lower alkenyl" refers to straight or branched alkenyl of C2 to C5, for example ethenyl, propenyl and butenyl. As used herein, the term "lower alkynyl" refers to straight or branched alkynyl of C2 to C5, for example propynyl and butynyl. As used herein, the term "haloalkyl" refers to a lower alkyl as defined above, wherein one or more hydrogens are substituted with a halo group (for example a chloro, fluoro, bromo or iodo group, with -CF3 being the currently preferred The active compounds useful in the practice of this invention include compounds of the chemical Formula I: where X and X ^ are, independently, C or N; R] is a lower alkyl, lower alkenyl, lower alkynyl, halogen or haloalkyl; and R2 is H, -N3, -OH, amino or halogen. In a preferred embodiment of the present invention, R] _ is methyl or -CF3, and R? is -N¡ or -OH. In a particular preferred embodiment of the invention R 1 is methyl and R 2 is 3-N. Also encompassed herein are pharmaceutically acceptable salts of this compound. The 5mAZC analogs useful in the practice of the invention include, without limitation, 5-methyl-2 ', 3'-dideoxycytidine, 5-ethyl-2', 3'-dideoxycytidine, 5-ethyl-2 ', 3' - dideoxy-3 '-azidocytidine, 5-propyl-2', 3'-dideoxy-cytidine, 5-propyl-2 ', 3'-dideoxy-3' -azidocytidine, 5-propene-2 ', 3'-dideoxycytidine, -propene-2 ', 3'-dideoxy-3' -azidocytidine, 5-propino-2 ', 3'-dideoxycytidine and 5-propino-2', 3'-dideoxy-3'-azidocytidine. The structure of 5mAZC is known. Refer, for example, to T.S. Lin et al., J. Med. Chem. 26, 1691-1696 (1983). 5mAZC is obtained from ChemSyn Laboratories (Lenexa, Kansas, USA). The compounds useful for carrying out the present invention can be synthesized according to known procedures that will be apparent to those of skill in the art. Refer, for example, to T.S. Lin et al., Supra; T. Kuliko ski et al., Acta Biochim. Polonica 16, 201-217 (1969); J.J. Fox et al., J. Amer. Chem. Soc. 81, 178-187 (1959). The active compounds disclosed herein can, as already mentioned, be prepared in the form of their pharmaceutically acceptable salts. "Pharmaceutically acceptable salts" are salts that retain the desired biological activity of the parent compound and do not impart undesired toxicological effects. Examples of these salts are: (a) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; and salts formed with organic acids such as for example acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid , polyglutamic acid, naphthalenesulfonic acid, methanesulfonic acid, p-toluenesulfonic acid, naphthalenedisulfonic acid, polygalacturonic acid and the like; (b) salts formed from elemental anions such as chlorine, bromine and iodine and (c) salts derived from bases, for example, ammonium salts, alkali metal salts such as sodium and potassium salts, salts of alkaline earth metals such as calcium and magnesium, and salts with organic bases such as dicyclohexylamine and N-methyl-D-glucamine. The dose of the active compounds for the treatment will vary depending on the condition being treated and the condition of the subject. In general, the dose may be as low as 0.1 μmol / kg, but more preferably it is at least 1.0 μmol / kg and more preferably it is at least 25 μmol / kg. The dose of the active compound in general can be as high as 1000 μmol / kg, but more preferably it is less than 500 μmol / kg and still more preferably less than 100 μmol / kg. Depending on the solubility of the particular formulation of the active compound administered, the daily dose may be divided among one or more unit dose administrations. The administration of the active compounds can be effected in a therapeutic manner, ie as a rescue treatment, or in a prophylactic form.

Pharmaceutical compositions which are used in the method herein to treat disorders associated with overexpression of cytidine deaminase and / or deoxycytidine deaminase include those suitable for administration by inhalation, oral, rectal, parenteral (including subcutaneous, intradermal, intramuscular, intravenous) and transdermal. The compositions may conveniently be present in a unit dosage form and may be prepared by any of the methods well known in the art. The most appropriate administration route in any case may depend on the anatomical location of the disorder in the subject, the nature and severity of the condition being treated and the particular formulation that is being used. The formulations may conveniently be present in a unit dosage form and may be prepared by any of the methods well known in the art. In the method of the present invention for treating leukemia or other disorders characterized by overexpression of cytidine deaminase or deoxycytidine deaminase, the active compound is administered in a range of doses as provided above. The dose of the active agent will vary according to the condition being treated and the dose at which the adverse pharmacological effects occur. An expert in this field will take these factors into account when determining the dose. In one embodiment of the present invention, the active compound is administered to the subject with araC-resistant leukemia in an amount sufficient to be metabolized with cytidine deaminase or deoxycytidine deaminase in AZT, in sufficient concentration to kill araC-resistant cancer cells.

In a further aspect of the present invention, the active compound can be used alone or in combination with one or more anti-leukemia agents for the prophylaxis or treatment of araC-resistant leukemia. In the manufacture of a pharmaceutical composition according to the invention (a "formulation"), the active agents or the physiologically acceptable salts thereof (the "active compounds") are typically mixed with, among others, an acceptable carrier. The carrier must, of course, be acceptable in the sense of being compatible with any other ingredient of the formulation and should not be detrimental to the patient. The carrier can be a solid or a liquid, or both, and is preferably formulated with the compound as a unit dose formulation, for example, a tablet that can contain from 0.5% to 99% by weight of the active compound. One or more active compounds may be incorporated into the formulations of the invention (for example, the formulation may contain one or more additional agents as mentioned above), these formulations may be prepared by any of the well-known pharmacy techniques, consisting essentially of mix the components together, optionally including one or more accessory therapeutic ingredients. Formulations suitable for administration may be present in discrete units, such as capsules, dragees, pills or tablets, each containing a predetermined amount of the active compound; like a powder or granule; as a solution or suspension in aqueous or non-aqueous liquid; or as an oil in water or water in oil emulsion. These formulations can be prepared by any suitable pharmacy method including the step of bringing into association the active compound and a suitable carrier (which may contain one or more accessory ingredients as noted above). In general, the formulations of the invention are prepared by uniformly and intimately admixing the active compound with a liquid or a finely divided solid carrier, or both, and then, if necessary, shaping the resulting mixture. For example, a tablet may be prepared by compressing or molding a powder or granules containing the active compound, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compression in a suitable machine; the compound in free flowing form, for example in the form of a powder or granules, is optionally mixed with a binder, lubricant, inert diluent and / or surfactant / dispersing agent. The molded tablets can be made by molding, in a suitable machine, the powdered compound is moistened with an inert liquid binder. Formulations for oral administration may optionally include enteric coatings known in the art, to avoid degradation of the formulation in the stomach and provide release of the drug in the small intestine. Formulations suitable for buccal (sub-lingual) administration include dragees comprising the active compound in a flavored base, typically sucrose and acacia or tragacanth; and tablets comprising the compound in an inert base, for example gelatin and glycerin or sucrose and acacia. Formulations of the present invention suitable for parenteral administration comprise sterile, aqueous and non-aqueous injectable solutions of the active compound, these preparations are preferably isotonic with the blood of the container in question. These preparations may contain antioxidants, regulators, bacteriostats and solutes which render the formulation isotonic with the blood of the recipient in question. Aqueous and non-aqueous sterile suspensions may include suspending agents and thickening agents. The formulations may be present in unit dose or multiple dose bases, for example sealed vials and vials, and may be stored in a lyophilized condition that requires only the addition of the sterile liquid carrier, eg, injection in saline or water , immediately before use. The extemporaneous injection solutions and suspensions of this same type can be prepared from sterile powders, granules and tablets of the kind described above. Suitable formulations for rectal administration are preferably presented as unit dose suppositories, which can be prepared by mixing the active compound with one or more conventional solid carriers, for example, cocoa butter and then shaping the resulting mixture. Suitable for transdermal administration can be presented as discrete patches adapted to remain in intimate contact with the epidermis of the recipient, for a prolonged period of time Formulations suitable for transdermal administration can also be administered by iontophoresis (refer to for example, Pharmaceutical Research 3, 318 (1986)) and typically take the form of an optionally regulated aqueous solution of the active compound The following examples are provided to fully illustrate the present invention and should not be construed as limiting thereof In the following examples, g means grams h means hours, kg means kilograms, ml means milliliters, M means molar, μg means micrograms and μmol means micromoles, nmol means nanomoles, pmol means picomoles, μCi means microCuries.

EXAMPLE 1 EFFECT OF 5MAZC ON OUE CELLS OVER-EXPRESS CITIDIN DEAMINASE Human HT-29SF adenocarcinoma cells naturally express a high level of CD cytidine deaminase (CD). The HT-29SF cells are a sub-line of the line HT-29SF expressing even higher levels of CD in relation to normal (approximately 5.4 times the level of expression of HT-29SF cells). In order to see if cells that overexpress cytidine deaminase are more sensitive to CD 5mAZC than other cells, HT-29SF cells are plated in the upper compartment of a culture box Transwell, while HT-29SF cells are placed in the lower compartment (1000 cells each). A semipermeable membrane separates the two compartments of the Transwell box, so that the drugs administered in the tissue culture medium bathe the two compartments equally. 5mAZC was continuously administered for 72 hours at concentrations ranging from 0 μM to 50 μM. The results of this experiment are shown in Figure 1. The results of this experiment confirm the idea that cells that overexpress CD to a high degree are sensitive to 5mAZC.

EXAMPLE 2 IN VITRQ ACTIVITY OF 5MA.ZC Based on the results obtained previously in Example 1, the dose of 50 μM 5mAZC was selected for a deeper analysis. Two experiments were performed by quintuplicate, in the same Trans ell boxes, which contained CD HT-29SF cells and the HT-29SF cells in separate compartments, only by the membrane permeable to 5mAZC. The results are given below in Table 1: Table 1, Effects of 5mAZC exposure of 50μM (72 hours) of human colonic adenocarcinoma cells HT-29SF CD and HF-29SF, in boxes of the Transwell culture system.

EXAMPLE 3 5MAZC IN VIVO ACTIVITY: HUMAN TUMOR GENQINJERTO MODEL To determine if 5mAZC exhibits in vivo activity, three female Balb / C nu / nu mice, sixteen weeks old, were inoculated subcutaneously with 2.0 x 10 HT- cells. 29SF in the left scapular region, and 2.0 x 10 cells CD HT-29SF in the right scapular region. One mouse received twice the daily intraperitoneal dose of 150 mg / kg of 5mAZC. The other mouse received only saline.

This treatment continued for 5 weeks, at which time the animals were euthanized and the solid tumors were dissected and weighed. The tumors examined had the following weight characteristics: HT-29SF ° + 5mAZC: 0.22g ± 0.31 g (N = 2) HT-29SF + 5mAZC: 1.02 ± 0.13 g (N = 2) CD HT-29SF + sol. saline: 0.96 g (N = l HT-29SF + saline: 1.13 g (N = l) In another experiment, thirty naked BALB / c 6 mice received subcutaneous injections of 5 x 10 HT-29SF cells. Twelve of the animals received 600 mg / kg / day of 5mAZC in the flank for 28 days. Eighteen animals received injections of saline in the same scheme. On day 29, the animals were sacrificed and the tumor volume was quantified by standard methods. The average tumor volume for the control group receiving 3 saline solution was 509 ± 292 mm. In contrast, animals treated with 5mAZC had an average tumor volume of 273 ± 97 mm, an average reduction of 46% in size. These results clearly show that 5mAZC is activated in vitro and in vivo in molecular species exclusively toxic to tumor cells that overexpress cytidine deaminase.

EXAMPLE 4 OVEREXPRESSION OF CD IN COLON TUMORS: DATA FROM EX-LIVING PATIENTS The hypothesis that cytidine deaminase (CD) is overexpressed in certain tumors compared to normal tissue was demonstrated in experiments conducted with surgical specimens obtained of patients who underwent a bowel resection for colon cancer. Tumor samples and adjacent normal tissues obtained from the pathological evaluation were analyzed for CD activity 3 using [H] -cytidine as a substrate, according to the method of R.L. Momparler and J. Laliberte, J. Leukemia Res., 14 (9), 751-54 (1990). In summary, tumors of the colon and the adjacent mucosa of the surgical samples were homogenized in 5mM Tris-Cl, pH 7.4, were sonified on ice in three pulses of 5 seconds and then adjusted to 50mM with Tris-HCl, pH 7.4. The homogenates were centrifuged at 12,000 x g for 15 minutes at 4 ° C and the homogenates were stored at -70 ° C until analysis. The protein concentration was determined using the BioRad protein assay and the bovine globulin range was used as standard. To determine the activity of cytidine deaminase, the reaction mixture (100μL) containing 25 mM Tris-Cl, pH 7.4, 0.5 μCi of [H] -cytidine and 0.02-0.05 mg of homogenate tissue. The reactions were carried out at 37 ° C for 30 minutes and then stopped with 3 mL of cold 0.001 N HCl.

The reaction mixture was placed in a Whatman P-81 phosphocellulose disc which was washed with 3 mL of H20, 1 mL of 0.1 N HCl and 3 mL of H2O, twice before use. The mixture was allowed to flow gently by gravity for 1 hour and then determined by radioactivity. The results were normalized for the protein content and expressed as nmol / min / mg protein. The results of this experiment are presented in Table 2.

EXAMPLE 5 PREMATERIAL DETERMINATION OF 5MA.ZC IN AZT IN CUTTING TUMORS: The hypothesis that 5mAZC is preferentially deaminated in AZT in human colonic tumors as opposed to in the normal adjacent mucosa, was demonstrated in the same ex vivo samples described above for 3 Example 4. Using [H] -5mAZC as a substrate, the 3 [H] -AZT product of the enzymatic reaction was isolated by HPLC and the radiolabelled product was quantified as described in J.W. Nyce et al., Proc. Nati Acad. Sci USA 90, 2960-2964 (1993). In summary, the procedures described in Example 4 were repeated with the following exceptions: Every 3 reaction mixture contained 0.26 μCi of [H] -5mAZC. The reactions were terminated with 50 μL of 2M perchloric acid and the mixture was separated by HPLC using an Ultrasphere ODS Beckman 4.6 x 25 cm column with a mobile phase of 12.5% acetonitrile in 40 mM sodium acetate, pH 7.0. The unlabeled 5mAZC and AZT were used to authenticate the resulting peaks. The fractions corresponding to radiolabeled 5mAZC and AZT were collected and analyzed for radioactivity by scintillation counting. The results were normalized by protein content and expressed as pmol / min / mg protein, and are provided in Table 3. To confirm that the AZT found in the colonic tumor tissue was being reduced by the activity of cytidine deaminase (see Scheme 1 above) cytidine deaminase inhibitor tetrahydrouridine (THU) was added to the reaction mixtures containing the homogenate of the tumor tissue and the radiolabeled 5mAZA. The amount of the radiolabelled AZT produced was assessed in the above manner, then compared with the amount of radiolabelled AZT produced in the reaction mixtures that did not contain THU. The results of this experiment are given in Table 3.

The above examples illustrate the present invention and should not be construed as limiting thereof. The invention is defined by the following claims, with the equivalents thereof included herein.

TABLE 2 DATA OF EX-LIVING PATIENTS: ACTIVITY OF CITIDINE DEAMINASA IN TUMORS IN CONTRAPOSITION TO THE ACTIVITY IN NORMAL ADJACENT MUCOSA TABLE 3 DATA OF EX VIVO PATIENTS: PREMATERIAL DEVELOPMENT OF 5MA.ZC IN AZT IN TUMORS, IN CONTRAPOSITION TO NORMAL ADJACENT MUCOSA

Claims (50)

CLAIMS:

1. An agent that has the chemical formula C7N3H802R1R2XX1, where x X and X are each, independently, C or N, but the two can not be C; R1 is selected from the group consisting of lower alkyl, alkenyl and alkynyl, halogen and haloalkyl; R2 is selected from the group consisting of H, -H3, -OH, amino and halogen; or pharmaceutically acceptable salts thereof.

2. The agent according to claim 1, wherein R-j_ is methyl and R2 is -N.

3. The agent according to claim 1 or 2, wherein R1 is CF3.

4. The agent according to claims 1 to 3, wherein it is selected from the group consisting of: 5-methyl-2 ', 3-dideoxycytidine, 5-ethyl-2', 3'-dideoxy-3'-azidocytidine, -propyl-2 ', 3-dideoxycytidine, 5-propyl-2', 3'-dideoxy-3-azidocytidine, 5-propene-2 ', 3'-dideoxy-3' O-azidocytidine, 5-propyne-2 ' , 3'-dideoxy-3 '-azidocytidine, 5-propino-2', 3'-dideoxycytidine and 5-propino-2 ', 3'-dideoxy-3'-azidocytidine.

5. The agent according to claims 1 to 4 or pharmaceutically acceptable salts thereof having the chemical formula: (I)

6. The agent according to claims 1 to 5, wherein x comprises N and XI comprises C.

The agent according to claims 1 to 5, wherein X comprises C and XI comprises N.

8. The agent according to claims 1 to 5. , wherein X comprises N and XI comprises N.

9. The agent according to claims 1 to 8, wherein it further comprises a radiolabel.

10. The agent according to claims 1 to 9, which is freeze-dried or lyophilized.

11. The agent according to claims 1 to 10, wherein R1 is haloalkyl which is selected from the group consisting of alkyl substituted with one or more of chloro, fluoro, bromo and iodo.

12. An agent according to claims 1 to 11, wherein R1 is fluoroalkyl comprising CF3 ion.

13. A composition comprising the agent of claims 1 to 12 and a pharmaceutically acceptable carrier.

The composition according to claim 13, comprising about 0.5 to about 99% of the agent.

15. The composition according to claims 13 to 14, in unit dosage form.

16. The composition according to claims 13 to 15, in the form of multiple doses.

17. The composition according to claims 13 to 16, in a form selected from the group consisting of capsule, lozenges, pills, pills, powders, granules, solutions, suspensions, emulsions and tablets.

18. The composition according to claims 13 to 17, wherein the carrier is selected from the group consisting of solid and liquid carriers.

The composition according to claims 13 to 18, further comprising an agent selected from the group consisting of other therapeutic agents, flavorings, lubricants, suspending agents and thickeners, binders, inert diluents, surfactants, dispersants, antioxidants, regulators, Bacteriostats and solutes to achieve isotonicity.

20. A composition according to claims 13 to 19, wherein the therapeutic agent comprises an anti-leukemia agent.

The composition according to claims 13 to 20, wherein the anti-leukemia agent comprises cytosine arabinoside.

22. An oral formulation comprising the composition of claims 13 to 21 and an enteric coating.

23. A sublingual formulation comprising the composition of claims 13 to 22, wherein the flavoring and inert diluent is selected from the group consisting of sucrose, acacia, tragacanth, gelatin and glycerin.

24. A parenteral formulation comprising the composition of claims 13 to 21, comprising a solution, suspension or emulsion.

25. A vial or vial comprising the formulation of claims 13 to 21 and 24.

26. A rectal formulation comprising the composition of claims 13 to 21, in unit dosage form.

27. A transdermal formulation comprising the composition of claims 13 to 21 and an iontophoretic medium.

28. A transdermal device comprising a patch consisting of the formulation of claims 13 to 21 and 27.

29. An iontophoretic device comprising the transdermal device of claim 28, and means for iontophoretic administration.

30. A therapeutic kit comprising, in a sealed container, the composition of claims 13 to 29 and instructions for its administration.

31. A method for preventing or treating a disorder associated with overexpression of cytidine deaminase or deoxycytidine deaminase, which comprises administering to a subject in need of such treatment, an anti-disorder effective amount of an agent selected from the group consisting of agent of the chemical formula: C7N3H802R: LR2XX: L, wherein X and X are independently C or N, R1 is selected from the group consisting of lower alkyl, alkenyl and lower alkynyl, halogen and haloalkyl, and R2 is selected from the group consists of H, -N3, -OH, amino and halogen; or pharmaceutically acceptable salts thereof.

32. The method according to claim 31, wherein R1 is methyl and R2 is -N3.

The method according to claims 31 or 32, wherein the agent is selected from the group consisting of 5-methyl-2 ', 3-dideoxycytidine, 5-ethyl-2', 3'-dideoxy-3'-azidocytidine, 5-propyl-2 ', 3-dideoxycytidine, 5-propyl-2', 3-dideoxycytidine, 5-propyl-2 ', 3'-dideoxy-3-azidocytidine, 5-propino-2', 3'-dideoxy- 3'-azidocytidine, 5-propino-2 ', 3'-dideoxy-3'-azidocytidine, 5-propino-2', 3'-dideoxycytidine and 5-propino-2 ', 3'-dideoxy-3'-azidocytine .

34. The method according to claims 31 to 33, wherein the disorder is cytosine-resistant leukemia arabinoside (araC).

35. The method according to claims 31 to 34, further comprising administering to the subject an anti-leukemia effective amount of an anti-leukemia agent.

36. The method according to claims 31 to 35, wherein the anti-leukemia agent is administered concurrently with the agent.

37. The method according to claims 31 to 36, wherein the anti-leukemia agent comprises cytosine arabinoside (araC).

38. The method according to claims 31 to 37, wherein the disorder comprises arthritis.

39. The method according to claims 31 to 38, which is a prophylactic method.

40. The method according to claims 31 to 38, which is a therapeutic method.

41. The method according to claims 31 to 40, wherein the agent is administered parenterally.

42. The method according to claims 31 to 40, wherein the agent is administered orally.

43. The method according to claims 31 to 40, wherein the agent is administered transdermally.

44. The method according to claims 31 to 43, wherein the agent is administered in an amount of about 0.1 to about 1000 umol / kg body weight.

45. The method according to claims 31 to 44, wherein the subject is a human.

46. The method according to claims 31 to 45, wherein the subject is a non-human animal.

47. The method according to claims 31 to 46, wherein the non-human animal is selected from the group consisting of animunder the care of a veterinarian.

48. The method according to claims 31 to 47, for treating a cancer associated with overexpression of cytidine deaminase or deoxycytidine deaminase, wherein the agent is administered in an anti-cancer effective amount.

49. The method according to claims 31 to 47, for preventing to treat an infection with HIV, wherein the agent comprises administering in an anti-HIV effective amount.

50. The method according to claims 51 to 49, for reducing the number or toxicity of proinflammatory cells that overexpress cytidine deaminase or deoxycytidine deaminase, wherein the agent is administered in an effective anti-inflammatory amount. SUMMARY OF THE INVENTION A method for treating a disorder characterized by overexpression of deaminase or deoxycytidine deaminase in a subject in need of such treatment. the method comprises administering to the subject a compound of the Formula (I), wherein X and X- | _ are each independently C or N; Rj_ is a lower alkyl, lower alkenyl, lower alkynyl, halogen or haloalkyl; and R2 is H, -N3, -OH, amino or halogen; or a pharmaceutically acceptable salt thereof, IN an amount effective to treat the disorder. Pharmaceutical formulations useful in the method of this invention are disclosed. CD Dosage-response curve for 5-mAZC in HT-29SF and HT-29SF cells 10 15 20 25 30 35 40 45 £ 0 5 > CD HT-29SF cells are a sub-line of HT-29SF human colonic adenocarcinoma cells that were chosen in this laboratory for overexpression of cytidine deaminase. The HT-29SF cells were plated in the lower compartment CD and the HT-29SF in the upper compartment of a "Transwell" culture box (1,000 cells in each). A semipermeable membrane separates the two compartments of the Transwell box, so that the drug administered to the tissue culture medium bathes the two compartments equally. 5-mAZC was administered continuously for 72 hours at the indicated concentrations.