AU735319B2 - 2-halo-2'-deoxyadenosine treatment for inflammatory bowel disease - Google Patents

Description

AUSTRALIA

Patents Act 1990 COMPLETE SPECIFICATION STANDARD PATENT Applicant(s): THE SCRIPPS RESEARCH INSTITUTE Invention Title: 2-HALO-2'-DEOXYADENOSINE TREATMENT FOR INFLAMMATORY BOWEL

DISEASE

The following statement is a full description of this invention, including the best method of performing it known to me/us: 1A- 2-HALO-2'-DEOXYADENOSINE TREATMENT FOR INFLAMMATORY BOWEL DISEASE Description Technical Field This invention relates to the treatment of inflammatory bowel disease (IBD), and more particularly to a process for treating IBD that utilizes a 2-halo-2'deoxyadenosine.

Background of the Invention 2-Halo-2'-deoxyadenosines have been reported to be useful in treating autohemolytic anemia (U.S.

Patent No. 5,106,837) and rheumatoid arthritis (allowed 15 U.S. Patent Application Serial No. 07/838,546). In those disclosures, the 2-halo-2'-deoxyadenosine was described as acting primarily against monocytes.

•The 2-halo-2'-deoxyadenosine used in those studies was 2-chloro-2'-deoxyadenosine (CdA), which was used at a dosage of 0.1 mg/kg body weight/day administered by infusion over a five-day time period at about monthly intervals for a total of three courses of treatment. Patient monocyte levels dropped substantially to zero during treatment cycles and rose to about pretreatment levels about ten days after CdA infusion was stopped. Patients showed improvement in various assays for rheumatoid arthritis during the treatment. Follow-up letters from personal physicians to one of those inventors, Dr. Carson, indicated a white cell count at about 50 percent of pretreatment values that lasted for one to three years after treatment ceased. Those personal physicians also reported greater patient improvements that became evident several months after cessation of treatment.

1 1 2 The toxicity of CdA to monocytes and lymphocytes has also been reported by Carrera et al., J.

Clin. Invest., 86:1480-1488 (1990). That paper also disclosed the use of CdA in clinical trials in patients having chronic lymphoid malignancies. Toxicity in vitro of CdA and 2-fluorodeoxyadenosine (FdA) toward resting and proliferating lymphocytes had been reported by the same research group in Carson et al., Proc. Natl. Acad.

Sci., USA, 79:3848-3852 (1982). Priebe et al., Cancer Res., 48:4799-4800 (1988) reported that CdA elevated in vivo NK cell activity at concentrations (6-25 mg/kg/day) that inhibited T-dependent and T-independent antibody responses in mice.

Carson et al., Blood, 62(4):737-743 (1983) 15 reported on the in vitro effects of CdA on a variety of cells and cell lines including resting normal T lymphocytes, slowly dividing malignant T cells from a patient with mycosis fungoides and CCRF-CEM malignant T lymphoblasts. A time- and concentration-dependent 20 relation for CdA cytotoxicity was reported, with the malignant T lymphoblasts being more sensitive to CdA than were resting normal T lymphocytes.

Carson et al., Proc. Natl. Acad. Sci, USA, 81:2232-2236 (1984) and Piro et al., Blood, 72:1069-1073 25 (1988) also reported on the positive effect of CdA on various human lymphocytic neoplastic disorders, including chronic lymphocytic leukemia (CLL), and had previously reported that CdA was an effective agent for treating the murine B cell L1210 lymphoid leukemia in vivo. Carson et al., Blood, 62:737-743 (1983).

The Piro et al., Blood, 72:1069-1073 (1988) studies with CLL illustrated some partial responses (4/18) and other clinical improvements but no complete responses. Those workers also reported that in vitro studies of the sensitivity of patient CLL cells to 3- CdA did not correlate with in vivo findings. Other in vitro studies indicated that T cells were more vulnerable than B cells to CdA, but that difference was not clinically apparent. Saven et al., N. Enql. J.

Med., 330(10):691-697 (1994).

Avery et al., Cancer Res., 49:4972-4978 (1989) also reported the effects of CdA on T-lymphoblastic, B-lymphoblastic and non-T, non-B cell lines, as well as in vivo effects on mice inoculated with L1210 leukemia of 2-bromo-2'-deoxyadenosine (BrdA) at 11.25 mg/kg/injection alone and paired with other therapeutic agents. Saven and Piro, N. Enql. J. Med., 330(10):691- 697 (1994) reported on the use of CdA and 2'-deoxycofurmycin in treating hairy cell leukemia, a B cell neoplasm.

Parsons et al., Biochem. Pharmacol., 35:660- 665 (1986) reported results with two human melanoma cell lines that were sensitive to each of CdA, FdA and BrdA.

Saven et al., J. Clin. Oncol., 11(4):671-678 (1993) 20 noted that because of the interferon-sensitivity of hairy cells and the sensitivity of those cells to CdA, melanoma and renal cell carcinoma that are also sensitive to interferon might be similarly sensitive to CdA in vivo, as were the two melanoma cell lines reported by Parsons et al. sensitive in vitro. The results of the above Saven et al. CdA studies with human patients with melanoma (nine patients) and renal cell carcinomas (two patients) showed no responses to the treatment. Contrarily, two of seven patients with astrocytomas, a tumor not noted to be sensitive to interferon, showed marked improvement. Thus, the attempted parallel between tumor cell interferonsensitivity and successful treatment with CdA was not evident from those studies. In addition, the in vitro 4 sensitivity of the assayed melanoma cell lines to CdA was not observed in vivo, in a clinical setting.

Reiter et al., Purine and Pyrimidine Metabolism in Man VII, Part A, Harness et al., eds., Academic Press, New York (1991) pages 69-73 reported on the combined use of interferon-a (IFN-a) and CdA upon various tumor cell lines including a hairy cell leukemia-like cell line, (Eskol 17), a cervical carcinoma cell line, a chronic myelogenous leukemia cell line and an AIDS-related Kaposi's sarcoma. They reported an additive time- and dose-dependent effect on cell growth, but no synergy between the two treating agents. Those workers also reported that CdA did not affect NK cell-mediated cytotoxicity of Eskol 17 cells 15 in the presence or absence of IFN-a. Although CdA neither affected the activity of NK cells nor was involved in the priming of NK cells by IFN-a, CdA was reported to affect the target tumor cells.

Beutler et al., Leukemia and Lymphoma, 5:1-8 20 (1991) reported that CdA treatment provided mixed results in patients with T cell lymphomas that were resistant to conventional therapies. Here, of the evaluable patients, some had complete remissions (3/17), some had partial remissions (5/17) and more than half 25 had no response This paper also reported results with low grade as well as high and intermediate grades of non-Hodgkin's lymphomas. For the low grade disease, just under 40 percent of the evaluable patients (15/40) exhibited a complete or partial response, and the remainder exhibited no response (25/40). Somewhat poorer results were found for patients with intermediate or high grade diseases; 7/26 complete or partial response and 19/26 no response. Results with other hematologic disorders involving fewer patients were also reported.

5 Petzer et al., Blood, 78(10):2583-2587 (1991) reported the effects CdA on various progenitor cells from bone marrow, including so-called T lymphocyte colony forming cells (CFU-TL). Those authors reported a dose-dependent inhibition of the growth of CFU-TL in vitro, and also reported that the drug concentration needed for complete inhibition much higher than that required for erythroid and granulocyte/macrophage progenitors. Those authors commented that the more mature the treated colony forming cells were, the higher the CdA concentration that was needed to inhibit proliferation. They also noted that the assay they used probably does not detect the true T lymphocyte progenitor, and that their assay may not accurately 15 reflect regulatory mechanisms in vivo.

It is thus seen that the effects of a 2-halo- 2'-deoxyadenine upon tumor growth are not yet predictable as to which tumors are sensitive, although once activity for one compound is found, the other 20 2-halo-dA's also possess that activity; that in vitro studies may not correlate with in vivo, patient studies; and that the effects of a drug from this group such as CdA upon a tumor cell type can vary widely from patient to patient even where a positive inhibition of growth is 25 found.

Other studies, Montgomery et al., J. Am. Chem.

Soc., 82:463-468 (1959), indicated that 2-fluoroadenosine exhibits a relatively high degree of cytotoxicity. Those workers reported that C57 black mice implanted with Adenocarcinoma 755 (Ad755) could tolerate only about 1 milligram per kilogram of body weight. 2-Fluoroadenosine was found to be inactive at that level against Ad755 as well as leukemia L1210 and the Erlich ascites tumor.

I

6 The phrase inflammatory bowel disease (IBD) encompasses two distinct, but similar disease states; Crohn's disease (CD) and ulcerative colitis (UC).

Crohn's disease includes three conditions that were once separately named as regional enteritis, an inflammation involving the entire wall of a portion of the small gut; ileocolitis, a similar condition involving the ileum and/or colon, and (iii) granulomatous colitis that involves any portion of the colon with a granulomatous pathologic process.

Ulcerative colitis involves the mucosa of the colon and can include portions of or the entire colon.

Both manifestations of IBD have similar and also distinct clinical manifestations and pathologies.

15 Both diseases also affect patients in two similar age ranges; about age 15-25 (15-20 for CD and 20-25 for UC) and about age 50-60 (55-60 for CD and 50-60 for

UC).

Patients with both diseases also have lesions 20 that include large numbers of inflammatory cells such as macrophages and B and T lymphocytes that are usual characteristics of chronic inflammation. Both also have an acute component marked by a constant flux of neutrophils out of the circulation into the inflamed 25 mucosa, and then through the epithelium and into the intestinal lumen. Patients with long term disease that have been treated with steroids or sulfasalazine exhibit significant total lymphocytopenia and a decrease in T cells, that is not noted in newly diagnosed patients.

Patients with active Crohn's disease also have relatively high numbers of T cells bearing a positive phenotype for T9, and a further subset of cells that also bear the Fc a receptor.

Although mononuclear cells (MNC) such as macrophages and cytotoxic T lymphocytes (CTL) are 7 present in IBD lesions, such intestinal MNC have been found to be poor mediators of cellular cytotoxicity such as ADCC or spontaneous cell-mediated cytotoxicity when compared to MNC from peripheral blood. These facts, and others, have led some workers to conclude that lymphocytes in a solid organ compartment such as the intestine differ from peripheral blood lymphocytes and have their own, unique biological and functional capabilities. Peripheral blood MNC that were non-T, non-B Fc receptor-bearing K-cells were found to be implicated in UC, and antigen-sensitized T cells able to lyse intestinal epithelial cell targets have been found in patients with IBD. Thus, both cellular and humoral immune responses are present in IBD. See, MacDermott et 15 al., below, at page 294-297.

A discussion of CD and UC can be found in Cecil Textbook of Medicine, Beeson et al., eds., fifteenth ed., W.B. Saunders Co., Philadelphia (1979) pp. 1560-1578, that is incorporated by reference. A 20 more recent review of IBD can be found in MacDermott et al., Advances in Immunology, Vol. 42, Academic Press, Inc., New York, pages 285-328 (1988).

A picture of IBD that can be drawn from the above findings is that T cells and other lymphocytes in long term patients are depleted and that usual effector cells of the monocyte/macrophage lineage and T cells act differently in this disease from the way those cells act in other immunoinflammatory diseases. Overall cellmediated cytotoxic activity is decreased, but there appears simultaneously to be specifically sensitized T and/or Fc receptor bearing cells present in patients who have IBD. Activated T cells appear to play a central role in the disease.

There is no known specific therapy for IBD.

Adrenal corticosteroids such as prednisone and the 8 peptide corticotropin (ACTH) are widely used in treating both UC and CD. These drugs are said to improve a patient's sense of well-being and often stimulate the appetite. These drugs do not affect the histopathology of the disease and have not been shown to influence the long-term course of the disease. Prolonged treatments can be hazardous.

Immunosuppressive therapy using azathioprine (Imuran) has shown some positive effects if only in its steroid-sparing use. Other drugs such as sulfonamides (especially Azulfidine), 6-mercaptopurine (Purinethol), methtrexate and cyclosporin have also been used to break the inflammatory cycle.

Prednisone, alone, or with another drug, is the usually used medicament. Surgery to remove portions of the ileum or ileum and colon has often been followed by recurrence of disease.

A process for successfully treating IBD is disclosed hereinafter that utilizes a 2-halo-2'- 20 deoxyadenosine as the active agent. It has been surprisingly found that use of one of those adenosine derivatives provided relatively rapid relief to each of the patients to which the compound was administered.

S 25 Summary of the Invention The present invention contemplates a process for treating inflammatory bowel disease in a mammalian host such as a human. The compound utilized in the present process as active agent in that treatment is a 2-halo-2'-deoxyadenosine, which has a structure that corresponds to that of Formula I: 1 I 9

NH

2

N

y-N N

HOCH

2

O

OH

wherein Y is a halogen that is fluoro, chloro or bromo, preferably chloro.

A contemplated process comprises administering to a mammalian host in need thereof a composition that contains a pharmacologically acceptable carrier that itself contains dissolved or dispersed therein a therapeutically effective dose of a substituted adenine derivative having a structure that corresponds to that of Formula I or a pharmacologically acceptable acid addition salt thereof as an active ingredient or agent.

Exemplary therapeutic dosages range from about 0.04 to 20 about 1.0 mg/kg/day, with dosages of about 0.04 to about 0.2 mg/kg/day being more preferred. Typically, the amount is sufficient to provide a concentration in the animal host's .plasma of about 0.5 nanomolar (nM) to about 100 nM, more preferably of about 1 nM to about S 25 50 nM.

The substituted adenine derivative of Formula II, below, 2-chloro-2'-deoxyadenosine (CdA); where Y is chloro, is a particularly preferred adenine derivative of Formula I.

Y N

NH

HOCH2

OH

10 The present invention has several benefits and advantages.

One benefit is that use of one of its process can provide alleviation from the symptoms of IBD.

An advantage of the present invention is that use of its process can substantially reduce a patient's dependence on prednisone or other drugs whose prolonged use can itself be detrimental to the patient.

Still another advantage of the invention is that use of its process can improve the pathological condition of a recipient patient's bowel so that objective indicia of disease are greatly reduced.

Still further benefits and advantages of the invention will be apparent to those skilled in the art from the description that follows.

Detailed Description of the Invention The present invention contemplates a process for treating inflammatory bowel disease (IBD). A 20 contemplated process utilizes a 2-halo-2'-deoxyadenosine (an adenine derivative) as an active agent compound in a composition that is administered to a mammalian host in need of such a treatment; having IBD.

25 A. Compounds A compound utilized in the present invention is a 2-halo-substituted-2'deoxyadenosine derivative whose structure is represented by Formula I: 30

NH

2 0

HOCH

2

O

OH

11 wherein Y is a halogen that is fluoro, chloro or bromo. Y is preferably chloro in which case the compound has a structure represented by Formula II, below, and can be named 2-chloro-9,1'-beta-2'-deoxy-Dribofuranosyladenine, more simply as 2-chloro-2'deoxyadenosine or most simply as CdA.

NH

2

CI

HOCH

2

OH

In the above formulas, and in all other 15 formulas shown herein, hydrogen atoms on the purine and furanosidyl rings that are not needed to show conformation about a particular bond are not shown.

Thus, for example, the 7-position adenine hydrogen is not shown.

20 It is also to be understood that the D isomers of compounds of the formulas are the isomers contemplated. It is further to be noted that the designation "halo" used herein is meant to include fluorine, chlorine and bromine derivatives, and to exclude iodine derivatives, which are unstable and decompose, and astatine derivatives that are radioactive. Where specific halogen derivatives are intended, those compounds are named specifically.

The pharmacologically acceptable salts of a compound of Formula I or Formula II are also utilized.

The phrase "pharmacologically acceptable salts," as used herein, refers to non-toxic acid addition salts that are generally prepared by reacting a compound with a suitable organic or inorganic acid. Representative salts include the hydrochloride, hydrobromide, 12 sulfate, phosphate, citrate, acetate, maleate and the like.

B. Compositions A compound of Formula I and its pharmacologically acceptable dissolved or dispersed in or together with a pharmacologically acceptable carrier constitutes a composition useful in a process of this invention. A compound of Formula II and its pharmacologically acceptable salts is preferred for use in both short and long term treatment.

Although a compound of Formula I and its pharmacologically acceptable salts can be administered as the pure chemical, it is preferred that it be S. 15 administered as a pharmaceutical composition. In either event, a contemplated compound is administered in an amount sufficient to provide a therapeutically effective dose as is discussed hereinafter.

Accordingly, the present invention utilizes a 20 pharmaceutical composition comprising a therapeutically effective dose of a compound of Formula I or Formula II, or a pharmacologically acceptable salt thereof, a ea hereinafter referred to as the "active ingredient" or "agent," dissolved or dispersed in a pharmacologically acceptable carrier or diluent.

A pharmaceutical composition is prepared by any of the methods well known in the art of pharmacy all of which involve bringing into association the active compound and the carrier therefor. For therapeutic use, a compound utilized in the present invention can be administered in the form of conventional pharmaceutical compositions. Such compositions can be formulated so as to be suitable for oral or parenteral administration, or as suppositories. In these compositions, the agent is 13 typically dissolved or dispersed in a physiologically tolerable carrier or diluent.

A carrier or diluent is a material useful for administering the active compound and must be "pharmacologically acceptable" in the sense of being compatible with the other ingredients of the composition and not deleterious to the recipient thereof. Thus, as used herein, the phrases "physiologically tolerable" and "pharmacologically acceptable" are used interchangeably and refer to molecular entities and compositions that do not produce an allergic or similar untoward reaction, such as gastric upset, dizziness and the like, when administered to a mammal, particularly, a human. The pharmacologically tolerable carrier can take a wide S 15 variety of forms depending upon the preparation desired for administration and the intended route of administration.

As an example of a useful composition, a compound of Formula I can be utilized in liquid 20 compositions such as sterile suspensions or solutions, 0 a or as isotonic preparations containing suitable preservatives. Particularly well-suited for the present purposes are injectable media constituted by aqueous injectable isotonic and sterile saline or glucose solutions. Additional liquid forms in which these compounds can be incorporated for administration include

S

flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil, peanut oil, and the like, as well as elixirs and similar pharmaceutical vehicles.

An active agent can also be administered in the form of liposomes. As is known in the art, liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by monoor multilamellar hydrated liquid crystals that are dispersed in an aqueous medium. Any non-toxic, 14 physiologically acceptable and metabolizable lipid capable of forming liposomes can be used. The present compositions in liposome form can contain stabilizers, preservatives, excipients, and the like in addition to the agent. The preferred lipids are the phospholipids and the phosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, New York, N.Y.

(1976), p. 33 et seq.

An agent of Formula I can also be used in compositions such as tablets or pills, preferably containing a unit dose of the compound. To this end, see the agent (active ingredient) is mixed with conventional Stableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate, gums, or similar materials as non-toxic, physiologically tolerable 20 carriers. The tablets or pills can be laminated or otherwise compounded to provide unit dosage forms affording prolonged or delayed action.

*It should be understood that in addition to the aforementioned carrier ingredients the pharmaceutical formulation described herein can include, as appropriate, one or more additional carrier ingredients such as buffers, flavoring agents, binders, surface active agents, thickeners, lubricants, preservatives (including antioxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

The tablets or pills can also be provided with an enteric layer in the form of an envelope that serves to resist disintegration in the stomach and permits the 15 active ingredient to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, including polymeric acids or mixtures of such acids with such materials as shellac, shellac and cetyl alcohol, cellulose acetate phthalate, and the like. A particularly suitable enteric coating comprises a styrene-maleic acid copolymer together with known materials that contribute to the enteric properties of the coating. Methods for producing enteric coated tablets are described in U.S. Patent 4,079,125 to Sipos, which is herein incorporated by reference.

The term "unit dose", as used herein, refers to physically discrete units suitable as unitary dosages for administration to warm blooded animals, each such S"unit containing a predetermined quantity of the agent calculated to produce the desired therapeutic effect in association with the pharmaceutically acceptable diluent. Examples of suitable unit dosage forms in accord with this invention are tablets, capsules, pills,.

powder packets, granules, wafers, cachets, teaspoonfuls, dropperfuls, ampules, vials, segregated multiples of any of the foregoing, and the like.

C. Processes As noted earlier, a process of treating IBD is contemplated here. Inflammatory bowel disease is meant to include Crohn's disease and ulcerative colitis.

Broadly, in that process, a mammalian host having IBD is administered a composition containing a pharmacologically acceptable carrier having dissolved or dispersed therein, as an active ingredient, a 2-halo-2'deoxyadenosine whose structure corresponds to that of previously discussed Formula I, or a pharmacologically acceptable acid addition salt thereof. The substituted 16 adenine derivative, is present in the composition in an amount sufficient to provide a therapeutically effective dose over the period of administration.

The above treatment is typically repeated periodically such as daily, weekly or monthly over a time period of one to several months to about one year.

In another pattern of administration, the active ingredient is administered daily for about 5 to about 7 days, followed two to four weeks later by another similar administration for a total of three to about four cycles or courses of administration. That series of courses of administration is then repeated at six months to yearly intervals, as required.

The amount of a compound of Formula I present in a composition and used in a process as described herein is a function of several variables, as is well known in the medicinal arts. The amount administered is less than that which substantially impairs bone marrow functions as determined by usual procedures.

20 The above amount of a 2-halo-2'-deoxyadenine S. derivative of Formula I or its pharmacologically acceptable salt present in the composition is also an amount sufficient to provide about 0.04 to about mg/kg of body weight of the treated host mammal per day, more preferably about 0.04 to about 0.2 mg/kg/day, more preferably still at about 0.05 to about 0.15 mg/kg/day and most preferably about 0.1 to about 0.12 mg/kg/day, when given in vivo. This amount is another way of defining a therapeutically effective dose that is particularly useful when a compound of Formula I is administered by infusion.

The molar plasma concentration of the compound of Formula I or the pharmacologically acceptable salts thereof during treatment is preferably in the range of about 0.5 nanomolar (nM) to about 100 nM, particularly 17 about 1 nM to about 50 nM, and more preferably about nM to about 20 nM. Molarity of the 2-halo-2'deoxyadenine derivative in plasma of the treated (administered to) host animal thus provides still another measure of a therapeutically effective dose from which the amount in a composition can be calculated.

It is to be understood that the above therapeutically effective dosages need not be the result of a single administration, and are usually the result of the administration of a plurality of unit doses.

Those unit doses can in turn comprise portions of a daily or weekly dosage, and thus, the therapeutically effective dose is determined over the period of treatment.

15 Unit dosage forms of the adenine derivative can contain about 0.1 milligrams to about 10 milligrams thereof. A preferred unit dosage form contains about 0.1 to about 1 milligram of agent and can be administered 1 to 5 times per day. However, it should be noted that continuous infusion at a rate designed to maintain the above described plasma concentration is also contemplated.

As noted before, duration of a particular treatment can also vary, depending on severity of the disease. Typical administration lasts for a time period of about 5 to about 14 days, with a 5- to 7-day time course being usual. Courses (cycles) of administration can also be repeated at monthly intervals, or parenteral unit dosages can be delivered at weekly intervals.

Such an administration can be carried out on an out-patient basis for humans using an intravenous infusion lasting about 2 to about 4 hours in a doctor's office. As such, the treatment is far less invasive than is a continuous infusion over a period of several days that usually requires a hospital stay for the host 18 mammal; human patient. A less invasive continuous infusion method that employs a pump linked to a catheter that automatically infuses a predetermined dosage permits the patient to be ambulatory during the infusion. A more preferred and still less invasive route of administration is by subcutaneous injection.

The efficacy of a process of this invention can be assessed in one or more of several reported procedures. One assay procedure is the Crohn's Disease Activity Index (CDAI) developed by the National Cooperative Crohn's Disease Study Group and described in Best et al., Gastroenterolocvy, 70:439-444 (1976). The CDAI provides a numerical score based upon eight mainly clinical variables those noted by the patient over a S 15 time period of one week.

The so-called "simple" index based on one day's entry of the CDAI values was shown by Harvey et al., Lancet, 1:514 (1980) to correlate well with the CDAI values and to be more easily used. That "simple" 20 index is used here.

Another tool for measuring efficacy of a contemplated treatment process is whether the patient host mammal is able to lessen other medication taken to relieve the effects of his/her IBD. There are two broad types of medications usually taken to treat IBD: steroidal anti-inflammatory drugs such as prednisone, and other medications that can include additional antiinflammatory medicaments such as azathioprine (Imuran) and anti-diarrheal medicaments such as lomotil. These drugs, although prescribed by a treating physician, are typically administered by the patients in their homes, and the amount of one or the other types of medication taken before and after administration of a contemplated process is ascertained by the patients themselves.

Those amounts taken before and after a contemplated 19 process are then compared. Such a comparison is another means by which efficacy is demonstrated here.

Disease state can also be assessed endoscopically using the Crohn's Disease Endoscopic Index of Severity (CDEIS) in which endoscopic examinations are videotaped and then assessed by qualified gastroenterologists who are not aware of the treatment or lack thereof being given. Comparative radiologic studies of the small bowel before and after treatment are also useful in assessing efficacy.

Use of the "simple" CDAI and/or a lessening of anti-inflammatory or other IBD-treating drugs can be used as the primary endpoints to demonstrate efficacy.

Therapeutic outcomes are deemed successful if the 15 "simple" CDAI is reduced by 50 percent or the use of one or the other IBD-treating drugs is reduced by 50 percent at a time 12 weeks after beginning of a treatment process. The treatment regimen is typically stopped once one or more of the successful endpoints is reached.

20 A review of various methods for assessing severity and acetivity in IBD is provided in Kjeldsen et al., Scand. J. Gastroenterol., 28:1-9 (1993).

Results Three patients took part in a pilot study to assess the effect of a 2-halo-2'-deoxyadenosine on IBD.

The exemplary adenosine used was 2-chloro-2'deoxyadenosine (CdA), and Crohn's disease (CD) was the specific IBD manifestation.

CdA was administered to each patient subcutaneously at 0.12 mg/kg/day for each of five consecutive days. Administration was repeated at monthly intervals for a total of three cycles (courses) of administration.

20 Each patient had refractory Crohn's disease and was taking prednisone as well as another medication at the time the study began. The patients were permitted to continue their prior therapies as needed during this study, and they monitored the amounts of medication taken, particularly any lessening in those amounts. One patient had pre- and post-treatment endoscopies.

As can be seen from the data in Table 1, below, whose data represent results at three months (12 :weeks) after the start of therapy, all three patients exhibited significant improvement of all clinically relevant endpoints. No significant side effects were observed. The patient who had pre- and post-treatment endoscopies showed complete resolution of mucosal ulceration and inflammation. In addition, at six months after starting therapy, patient #3 no longer required prednisone and was no longer taking any medication to treat the disease.

21 Patient #1 Patient #2 Patient #3 Table 1 Prednisone (mgi) (mcr/day) Before After Percent Treatment Treatment Reduction 30 0 100 10 5.5 20 5 20 Patient #1 Patient #2 Patient #3 Before Treatmer 8 18 11 CDAI (Simiple Index) Af ter it Treatment R 3 16 6 Percent eduction 63- 11 Other Medications (mcQ/day) Before After Percent Treatment Treatment Reduction 15-20* 0 100 2400** 0 100 100*** 0 100 Patient #1 Patient #2 Patient #3 *Lomotil **Asacol SAzathioprine 22 The foregoing description is intended as illustrative and is not to be taken as limiting. Still other variations within the spirit and scope of this invention are possible and will readily present themselves to those skilled in the art.

In the claims which follow and in the preceding summary of the invention, except where the context requires otherwise due to express language or necessary implication, the word "comprising" is used in the sense of "including", i.e. the features specified may be associated with further features in various embodiments of the invention.

It is to be understood that a reference herein to a *...prior art publication does not constitute an admission that the publication forms a part of the common general k i t knowledge in the art in Australia, or any other country.

i:: ooo S S So S So ooSoo 5oo55 S

Claims (4)

1. A process for treating inflammatory bowel disease in a mammal comprising administering to said mammal a therapeltically effective dose of a substituted adenine derivative or a pharmacologically acceptable acid addition salt thereof as an active ingredient dissolved or dispersed in a pharmacologically acceptable carrier, said adenine derivative having a structure represented by the formula: NH 2 Nj HOCH 2 O OH 9 wherein Y is fluoro, chloro or bromo. .9°

9. 20 2. The process of claim 1 wherein said adenine derivative is administered in an amount of about 0.04 to about 1.0 milligrams per kilogram of body weight per day. o 25 3. The process of claim 1 wherein said adenine derivative is administered in an amount of about 0.04 to about 0.20 milligrams per kilogram of body weight per day. 30 4. The process of claim 1 wherein said mammal is a human. The process of claim 4 wherein said human has Crohn's disease. 24 6. The process of claim 4 wherein Y is chlorine. 7. The process of claim 1 wherein said administering is repeated a plurality of times. 8. A process for treating inflammatory bowel disease in a human patient comprising administering to said patient a substituted adenine derivative or a pharmacologically acceptable acid addition salt thereof in an amount of about 0.04 to about 1.0 milligrams per kilogram of body weight per day dissolved or dispersed in a pharmacologically acceptable carrier, said adenine derivative having a structure represented by the formula: NH 2 N N N N CI N N 20 0 HOCH 2 7 OH 9. The process of claim 8 wherein said adenine derivative is administered in an amount of about 0.04 to about 0.20 milligrams per kilogram of body weight per day.

10. The process of claim 9 wherein said patient has Crohn's disease.

11. The process of claim 10 wherein said administerinq is repeated a plurality of times. Dated this.23rd day of April 2001 STHE SCRIPPS RESEARCH INSTITUTE R AL By their Patent Attorneys uj GRIFFITH HACK