MXPA00002976A - Tetrazole-containing rapamycin analogs with shortened half-lives - Google Patents

Abstract

A compound having formula (I) or a pharmaceutically acceptable salt or prodrug thereof, is an immunomodulatory agent and is useful in the treatment of restenosis and immune and autoimmune diseases. Also disclosed are cancer-, fungal growth-, restenosis-, post- transplant tissue rejection- and immune- and autoimmune disease-inhibiting compositions and a method of inhibiting cancer, fungal growth, restenosis, post- transplant tissue rejection, and immune and autoimmune disease in a mammal, with minimized side-effects due to shortened half-lives.

Description

ANALOGS OF RAPAMYCIN CONTAINING TETRAZOL WITH STOCKINGS VI DAS ACORTADAS TECHNICAL FIELD The present invention relates to novel chemical compounds having immunomodulatory activity and synthetic intermediates useful for the preparation of novel compounds, and in particular to macrolide immuno-modulators. More particularly, the invention relates to semi-synthetic analogues of rapamycin, means for their preparation, pharmaceutical compositions containing such compounds, and methods of treatment employing them.

BACKGROUND OF THE INVENTION The cyclosporin compound (cyclosporin A) has found wide use since its introduction in the fields of organ transplantation and immunomodulation, and has brought a significant increase in the success rate for transplant procedures. Recently, several cyases of macrolide compounds having potent immunomodulatory activity have been discovered. Okuhara et al., In European Patent Application No. 184, 162, published June 1, 1986, discloses a number of isolated macrolide compounds of the genus Streptomyces, including the immunosuppressant FK-506, a 23-member macrocyclic lactone, which was isolated from a strain of S. tsukubaensis. Other relative natural products, such as FR-900520 and FR-900523, which differ from FK-506 in their alkyl substituent at C-21, have been isolated from S. hygroscopicus yakushimnaensis. Another analogue, FR-900525, produced by S. tsukubaensis, differs from FK-506 in replacing a portion of pipecolic acid with a proline group. The unsatisfactory side effects associated with cyclosporin and FK-506 such as nephrotoxicity, have led to a continuing investigation for immunosuppressive compounds having improved efficacy and safety, including an immunosuppressive agent which is topically effective, but ineffective systemically (US Pat. No. 5,457, 1 1 1). Rapamycin is a macrocyclic triene antibiotic produced by Streptomyces hygroscopicus, which has been found to have antifungal activity, particularly against Candida albicans, both in vitro and in vivo (C. Vezina et al., J. Antibiot, 1975, 28, 721; SN Sehgal et al, J. Antibiot 1975, 28, 727; H, A. Baker et al, J. Antibiot, 1978, 31, 539; U.S. Patent No. 3,929,992; and U.S. Pat. No. 3,993,749).

Rapamycin Rapamycin alone (Patent of U. U., No. 4,885, 171) or in combination with picibanil (U.S. Patent No. 4,401, 653) has been shown to have antitumor activity. In 1977, rapamycin was also shown to be effective as an immunosuppressant in the experimental model of allergic encephalomyelitis, a model for multiple sclerosis; in the adjuvant model of arthritis, a model for rheumatoid arthritis; and showed that it effectively inhibits the formation of antibodies such as IgE (R. Martell et al., Can. J. Physiol. Pharmacol., 1977, 55, 48). The immunosuppressive effects of rapamycin have also been described in FASEB, 1989, 3, 341 since it has its ability to prolong the survival time of organ grafts in histo-incompatible rodents (R. Morris, Med. Sci. Res. , 1989, 17, 877). The ability of rapamycin to inhibit T cell activation was described by M. Strauch (FASEB, 1989, 3, 341 1). These and other biological effects of rapamycin are reviewed in Transplantation Reviews, 1992, 6, 39-87. The mono ester and diester derivatives of rapamycin (esterification at positions 31 and 42) have been shown to be useful as antifungal agents (U.S. Patent No. 4,316,885) and as water soluble rapamycin prodrugs (U.S. Patent No. 4,650,803). The fermentation and purification of rapamycin and rapamycin 30-demethoxy have been described in the literature (C. Vezjna et al., J. Antibiot. (Tokyo), 1975, 28 (10), 721; SN Sehgal et al., J. Antibiot. (Tokyo), 1975, 28 (10), 727; 1983, 36 (4), 351; N. L. Pavia et al., J. Natural Products, 1991, 54 (1), 167-177). Numerous chemical modifications of rapamycin have been tried. These include the preparation of mono- and di-ester derivatives of rapamycin (WO 92/05179), oximes-27 of rapamycin (EPO 467606); rapamycin oxo-42 analog (Patent of E. U., No. 5, 120,727); silyl ethers of rapamycin (U.S. Patent No. 5, 120,842); and arylsulfonates and sulphamates (Patent of E. U., No. 5, 177,203). Rapamycin was recently synthesized in its naturally occurring enantiomeric form (KC Nicolaou et al., J. Am. Chem. Soc, 1993, 1 15, 4419-4420, SL Schreiber, J. Am, Chem, Soc, 1993, 1 15 , 7906-7907; SJ Danishefsky J. Am. Chem. Soc, 1993, 1 15, 9345- Rapamycin, such as FK-506, has been known to agglutinate to FKBP-12 (Siekierka, JJ; Hung, SHY; Poe; , M., Lin, CS, Sigal, NH Nature, 1989, 341, 755-757, Harding, MW, Galat, A., Uehling, DE, Schreiber, SL Nature 1989, 341, 758-760, Dumont, FJ; Melino, MR; Staruch, MJ; Koprak, SL; Fisher, PA; Sigal, NH; J. Immunol., 1990, 144, 1418-1424; Bierer, BE; Schreiber, SL; Burakoff, SJ Eur. J. Immunol., 1991; , 21, 439-445, Fretz, H., Albers, MW, Galat, A., Standaert, RF, Lane, WS, Burakoff, SJ, Bierer, BE, Schreiber, SLJ Am. Chem. Soc. 1991, 113, 1409-1411) It has recently been discovered that the rapamycin / FKBP-12 complex binds to yet other p Rotein, which is distinct from calcineurin, the protein that inhibits the FK-506 / FKBP-12 complex (Brown, E. J .; Albers, M. W .; Shin, T. B .; Ichikawa, K .; Keith, C. T .; Lane, W. S .; Schreiber, S. L. Nature 1994, 369, 756-758; Sabatini, D. M .; Erdjument-Bromage, H .; Lui, M .; Tempest, P .; Snyder, S. H. Cell. 1994, 78, 35-43). Although some of these modified compounds exhibit immunosuppressive activity, the need remains for macrocyclic immunosuppressants that do not have the serious side effects frequently associated with immunosuppressive therapy due, in part, to the extended half-lives of the immunosuppressants. Accordingly, an objective of this invention is to provide novel semisynthetic macrolides having the desired immuno-modulatory activity, but which can be found to minimize unwanted side effects due to their shortened half-life.

BRIEF DESCRIPTION OF THE FIGURE Figure 1 shows blood concentrations ± SEM (n = 3) of tetrapazole-containing rapamycin analogs dosed in monkeys.

BRIEF DESCRIPTION OF THE INVENTION In one aspect of the present invention, compounds represented by the structural formula are described: or a pharmaceutically acceptable salt or prodrug thereof. Another objective of the present invention is to provide synthesis processes for the preparation of such compounds from starting materials obtained by fermentation, as well as chemical intermediates useful in such synthesis processes. A further objective of the invention is to provide pharmaceutical compositions containing, as an active ingredient, at least one of the above compounds. Still another object of the invention is to provide a method for treating a variety of disease states, including restenosis, post-transplant tissue rejection, immune and autoimmune dysfunction, fungal growth, and cancer.

DETAILED DESCRIPTION OF THE INVENTION Definition of terms The term "prodrug", as used herein, refers to compounds that are rapidly transformed in vivo to the parent compound of the above formula, for example, by hydrolysis in blood. A full discussion is provided in "Prodrugs as Novel Delivery Systems," by T. Higuchi and V. Stella, Vol. 14 of the ACS Symposium Series, and in "Bioreversible Carriers in Drug Design," by Edward B. Roche, Ed. , American Pharmaceutical Association and Pergamon Press, 1987, both of which are incorporated herein by reference. The term "pharmaceutically acceptable prodrugs", as used herein, refers to those prodrugs of the compounds of the present invention which are, within the scope of medical judgment, suitable for use in contact with the tissues of humans and mammals. inferiors without toxicity, undue irritation and allergic response, commensurate with a reasonable benefit / risk ratio, and be effective for their intended use, as well as the zoning forms, where possible, of the compounds of the invention. Particularly preferred pharmaceutically acceptable pro-drugs of this invention are prodrug esters of the C-31 hydroxyl group of compounds of this invention. The term "prodrug esters," as used herein, refers to any of several ester-forming groups that are hydrolyzed under physiological conditions. Examples of prodrug ester groups include acetyl, ethanoyl, pivaloyl, pivaloyloxymethyl, acetoxymethyl, phthalidyl, methoxymethyl, indanyl, and the like, as well as ester groups derived from the coupling of amino acids occurring naturally or not for the hydroxyl group C-31 of compounds of this invention.

Modalities In one embodiment of the invention is a compound of formula: In another embodiment of the invention is a compound of formula: Preparation of Compounds of this Invention The compounds and processes of the present invention will be better understood in connection with the following synthesis schemes which illustrate the methods by which the compounds of the invention can be prepared. The compounds of this invention can be prepared by a variety of synthetic routes. A representative procedure is shown in Scheme 1.

Scheme I X-F, CF3 10 epimeric mixture (B / C) As shown in Scheme 1, the conversion of the C-42 hydroxyl of rapamycin to a provided group A leaving trifluoromethanesulfonate or trifluorosulfonate. Displacement of the left group with tetrazole in the presence of a non-nucleophilic, clogged base, such as 2,6-lutidine, or preferably diisopropylethyl amine provided B and C epimers, which were separated and purified by flash column chromatography. .

Synthesis Methods The foregoing can be better understood by reference to the following Examples which illustrate the methods by which the compounds of the invention can be prepared and are not intended to limit the scope of the invention as defined in the appended claims.

Example 1 42-Epi- (tetrazo! I!) - rapamycin (less polar isomer) Example 1A A solution of rapamycin (100 mg, 0.1 1 mmol in dichloromethane (0.6 mL) was treated sequentially at -78 ° C under a nitrogen atmosphere with 2,6-lutidine (53 μL, 0.46 mmol, 4.3 eq.) And trifluoromethanesulfonic anhydride (37 uL, 0.22 mmol), and then stirred for 15 minutes, warmed to room temperature and eluted through a pad of silica gel (6 mL) with diethyl ether.The fractions containing the triflate were grouped and concentrated to provide the compound designated as an amber foam.

Example 1 B 42-Epi- (tetrazoli!) -rapamycin (less polar isomer) A solution of Example A in isopropyl acetate (0.3 mL) was treated sequentially with diisopropylethylamine (87 μL, 0.5 mmol) and 1 H-tetrazole ( 35 mg, 0.5 mmol), and then stirred for 18 hours. This mixture was partitioned between water (10 mL) and ether (10 mL). The organic portions were washed with brine (10 mL) and dried (Na2SO4). Concentration of the organic portions gave a sticky yellow solid which was purified by chromatography on silica gel (3.5 g, 70-230 mesh) eluted with hexane (10 mL), hexane: ether (4: 1 (10 mL), 3: 1 (10 mL), 2: 1 (10 mL), 1: 1 (10 mL)), ether (30 mL), hexane: acetone (1: 1 (30 mL)). One of the isomers was collected in the ether fractions. MS (ESI) m / e 966 (M) "; Example 2 42-Epi- (tetrazolyl) -rapamycin (more polar isomer) Example 2A 42-Epi- (tetrazolyl) -rapamicin (more polar isomer) The collection of the slower moving band from the chromatography column using the mobile phase hexane: acetone (1: 1) in the Example 1 B provided the designated compound. MS (ESI) m / e 966 (M) ".

In Vitro Assay of Biological Activity The immunosuppressive activity of the compounds of the present invention was determined using the human mixed lymphocyte reaction (MLR) test described by Kino, T. et al in Transplantation Proceedings, XIX (5): 36-39 , Suppl. 6 (1987). The results of the test demonstrate that the compounds of the invention are effective immunomodulators at nanomolar concentrations, as shown in Table 1.

Table 1 The pharmacokinetic behaviors of Example 1 and Example 2 were characterized following a single intravenous dose of 2.5 mg / kg in cynomolgus monkey (n = 3 per group). Each compound was prepared as a 2.5 mg / mL solution in a vehicle of 20% ethanol: 30% propylene glycol: 2% cremophor EL: 48% dextrose 5% in water. The intravenous dose of 1 mL / kg was administered as a slow bolus (~ 1-2 minutes) in a saphenous vein of the monkeys. Blood samples were obtained from a femoral artery or vein of each animal before dosing and 0.1 (IV only), 0.25, 0.5, 1, 1.5, 2, 4, 6, 9, 12, 24, and 30 hours after each dose The samples preserved with EDTA were perfectly mixed and extracted for subsequent analysis. An aliquot of blood (1.0 μm L) was hemolyzed with 20% methanol in water (0.5 mL) containing an internal standard. The hemolysed samples were extracted with a mixture of ethyl acetate and hexane (1: 1 (v / v), 6.0 mL). The organic layer was evaporated to dry with a stream of nitrogen at room temperature. The samples were reconstituted in methanol: water (1: 1, 150 μL). The titled compounds (50 μL injection) were separated from contaminants using reverse phase HPLC with UV detection. The samples were kept cold (4o C) during the whole run. All samples from each study were analyzed as a single batch in the H PLC: The measurements of the area under the curve (AUC) of Example 1, Example 2 and the internal standard were determined using the Sciex MacQuan ™ software. The calibration curves were derived from the peak area ratio (parent drug / internal standard) of the peak blood standards using linear least squares regression of the ratio versus theoretical concentration. The methods were linear for both compounds over the range of the standard curve (correlation >; 0.99) with an estimated quantification limit of 0.1 ng / mL. The maximum blood concentration (CMAX) and the time to reach the maximum blood concentration (TMAX) were read directly from the blood-time concentration data observed. The blood concentration data were subjected to multi-exponential curve fitting using CSTR1 P to obtain estimates of pharmacokinetic parameters. The estimated parameters were then defined using NONL1 N84. The area under the blood-time concentration curve from 0 to t hours (point of time of measurable blood concentration at the end) after dosing (ABC0-t) was calculated using the linear trapezoidal rule for the blood-time profiles. The residual area extrapolated to infinity, determined as the measured final blood concentration (Ct) divided by the terminal elimination rate constant (ß), and added to ABC0-t to produce the total area under the curve (ABC0-). As shown in Figure 1 and Table 2, both Example 1 and Example 2 had a shorter terminal half life (t1 2) substantially surprisingly when compared to rapamycin.

Table 2 Methods of Treatment The compounds of the invention, including but not limited to those specified in the Examples, have immunomodulatory activity in mammals (especially humans). As immunosuppressants, the compounds of the present invention are useful for the treatment and prevention of immuno-mediated diseases such as resistance by transplantation of organs or tissues such as heart, kidney, liver, bone marrow, skin, cornea, lung, pancreas, small intestine, limb, muscle, nerves, duodenum, small intestine, pancreatic islet cell, and the like; graft-versus-host diseases caused by bone marrow transplantation; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, Hashimoto's thyroiditis, multiple sclerosis, myasthenia gravis, type I diabetes, uveitis, allergic encephalomyelitis, glomerulonephritis, and the like. Additional uses include the treatment and prophylaxis of inflammatory and hyperproliferative diseases of the skin and cutaneous manifestations of immunologically-mediated diseases, such as psoriasis, atopic dermatitis, contact dermatitis and additional eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, pemphigoid bullosa, epidermolysis bullosa, urticaria, angioedema, vasculitides, erythema, cutaneous eosinophilia, lupus erythematosus, acne and alopecia areata; various diseases of the eyes (autoimmune and others) such as keratoconjunctivitis, vernal conjunctivitis, uveitis associated with Behcet's disease, keratitis, herpetic keratitis, conical cornea, corneal epithelial dystrophy, corneal leucoma, and ocular pemphigus. In addition, reversible obstructed airways disease, which includes conditions such as asthma (eg, brochial asthma, allergic asthma, intrinsic asthma, extrinsic asthma, and powder asthma), particularly chronic or inveterate asthma (eg, late and hyper asthma). - airway sensitivity), bronchitis, allergic rhinitis, and the like are targets of the compounds of this invention. Inflammation of mucosa and blood vessels such as gastric ulcers, vascular damage caused by ischemic diseases and thrombosis. In addition, hyperproliferative vascular diseases such as intimal smooth muscle cell hyperplasia, restenosis and vascular occlusion, particularly following mechanical or biologically mediated vascular damage, could be treated or prevented by the compounds of the invention. Other treatable conditions include, but are not limited to intestinal ischemic diseases, necrotizing enterocolitis, intestinal inflammations / allergies such as Coeliac diseases, proctitis, eosinophilic gastroenteritis, mastocytosis, Crohn's disease and ulcerative colitis; nerve diseases such as multiple myositis, Guillain-Barre syndrome, Meniere's disease, polyneuritis, multiple neuritis, mononeuritis and radiculopathy; endocrine diseases such as hyperthyroidism, and Basedow's disease; blood diseases such as pure red blood cell aplasia, aplastic anemia, hypoplastic anemia, ideopathic thrombocytopenic purpura, autoimmune hemolytic anemia, agranulocytosis, pernicious anemia, megaloblastic anemia, and aneneritroplasia; bone diseases such as osteoporosis; respiratory diseases such as sacoidosis, lung fibrosis and idiopathic interstitial pneumonia; skin diseases such as dermatomyositis, leucoderma vulgaris, ichthyosis vulgaris, photoallergic sensitivity and cutaneous T-cell lymphoma; circulatory diseases such as arteriosclerosis, atherosclerosis, aortitis syndrome, polyarteritis nodosa and myocardosis; Collagen diseases such as scleroderma, Wegener's granuloma and Sjogren's syndrome; adiposis; eosinophilic fasciitis; periodontal disease such as lesions of gigiva, periodontium, alveolar bone, and bone dentis substance; Nephrotic syndrome such as glomerulonephritis; male pattern alopecia or alopecia senilis by preventing epilation or by providing hair germination and / or promoting the generation of hair and hair growth; muscular dystrophy; Pyoderma and Sezary syndrome; Addison's disease; active oxygen mediated diseases, such as, for example, organ damage such as ischemia-reperfusion injury of organs (such as heart, liver, kidney and digestive tract) that occur by preservation, transplantation or ischemic disease (e.g., thrombosis and infarction) cardiac); intestinal diseases such as endotoxin shock, pseudomembranous colitis and colitis caused by drug or radiation; kidney diseases such as acute ischemic renal failure and chronic renal failure; lung diseases such as toxinsis caused by lung or drug oxygen (eg, paracort and bleomycins), lung cancer and pulmonary emphysema; eye diseases such as cataract, siderosis, retinitis, pigmentosa, senile macular degeneration, vitreous scarring and burned corneal by alkali; dermatitis such as erythema multiforme, linear IgA balloon dermatitis and cement dermatitis; and others such as gingivitis, periodontitis, sepsis, pancreatitis, diseases caused by environmental contamination (for example air pollution), aging, carcinogenesis, carcinoma metastasis and hypobaropathy; diseases caused by release of histamine or leukotriene C; Behcet's disease such as intestinal disease-, vasculo-, or neuro-Behcet, and also of Behcet that affects the oral cavity, skin, eye, vulva, joint, epididymis, lung, kidney and so on. In addition, the compounds of the invention are useful for the treatment and prevention of liver diseases such as immunogenic diseases (e.g., chronic autoimmune liver diseases such as autoimmune hepatitis, primary biliary cirrhosis and sclerosing cholangitis), partial liver resection, acute necrosis of liver (eg, necrosis caused by toxin, viral hepatitis, shock or anoxia), hepatitis B virus, non-A / non-B hepatitis, cirrhosis (such as alcoholic cirrhosis) and liver failure such as fulminant hepatic failure, late-onset liver failure and acute-on-chronic liver failure (acute liver failure in chronic liver diseases), and are also useful for various diseases due to their useful activity such as increased chemotherapeutic effect, cytomegalovirus infection, HCMV infection particularly, anti-inflammatory activity, sclerosing and fibrotic diseases such as nephrosis, scleroder ma, pulmonary fibrosis, arteriosclerosis, congestive heart failure, ventricular hypertrophy, adhesions and post-surgical scarring, infarction, myocardial infarction and damage associated with ischemia and reperfusion, and the like. Additionally, the compounds of the invention possess antagonistic properties of FK-506. The compounds of the present invention can thus be used in the treatment of immunosuppression or a disorder involving immunosuppression. Examples of disorders involving immunosuppression include AIDS, cancer, fungal infections, senile dementia, trauma (including wound healing, surgery and shock), chronic bacterial infection, and certain disorders of the central nervous system. The immunosuppression to be treated can be caused by an overdose of a macrocyclic immunosuppressant compound, for example derivatives of 12- (2-cyclohexyl-1-methylvinyl) -13, 19,21,27-tetramethyl-11,28-dioxa-4- azatriciclo [22.3.1 .04-9] octacos-18-ene such as FK-506 or rapamycin. Overdose of such medications by patients is very common when they realize that they have forgotten to take their medication at the prescribed time and can lead to serious side effects. The ability of the compounds of the invention to treat proliferative diseases can be demonstrated according to the methods described in Transplantation Proceed, by Bunchman ET and Brookshire CA, 23 967-968 (1991); Biochem. Biophys. Res. Comm. de Yamagishi et al., 191 840-846 (1993); and J. Clin. Invest. from Shichiri et al., 87 1867-1871 (1991). Proliferating diseases include smooth muscle proliferation, systemic sclerosis, cirrhosis of the liver, adult respiratory distress syndrome, idiopathic cardiomyopathy, lupus erythematosus, diabetic retinopathy or other retinopathies, psoriasis, scleroderma, prosthetic hyperplasia, cardiac hyperplasia, restenosis that follows the damage of arteries or other pathological stenosis of blood vessels. In addition, these compounds antagonize cellular responses to various growth factors, and therefore possess anti-angiogenic properties, making them useful agents to control or reverse the growth of certain tumors, as well as fibrotic diseases of the lung, liver and kidney. The aqueous liquid compositions of the present invention are useful particularly for the treatment and prevention of various diseases of the eye such as autoimmune diseases (including, for example, conical cornea, keratitis, cornea, hepithelial dystrophy, leukoma, Mooren's ulcer, sclevitis and ophthalmopathy of Graves) and rejection of cornea transplant. When used in the above or other treatments, a therapeutically effective amount of one of the compounds of the present invention may be employed in pure form or, where such forms exist, in pharmaceutically acceptable salt, ester or prodrug form. Alternatively, the compound can be administered as a pharmaceutical composition containing the compound of interest in combination with one or more pharmaceutically acceptable excipients. The phrase "therapeutically effective amount" of the compound of the invention means a sufficient amount of the compound to treat disorders, with an acceptable benefit / risk ratio applicable to any medical treatment. It will be understood, however, that the total daily use of the compounds and compositions of the present invention will be decided by the attending physician within the scope of the medical judgment. The specific dose level therapeutically effective for any particular patient will depend on a variety of factors including the disorder to be treated and the severity of the disorder; the activity of the specific compound employed; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the administration time, route of administration, and excretion regime of the specific compound employed; the duration of the treatment; drugs used in combination or coincident with the specific compound used; and similar factors well known in the medical arts. For example, it is a fact within the skill of the art to start dose of the compound at levels lower than those required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved. The total daily dose of the compounds of this invention administered to a human or lower animal can range from about 0.01 to about 10 mg / kg / day. For purposes of oral administration, the most preferable doses may be in the range from about 0.001 to about 3 mg / kg / day. If desired, the effective daily dose can be divided into multiple doses for administration purposes; consequently, single dose compositions may contain such amounts or submultiples thereof to make the daily dose. Topical administration may involve doses that range from 0.001 to 3% mg / kg / day, depending on the application site.

Pharmaceutical Compositions The pharmaceutical compositions of the present invention comprise a compound of the invention and a pharmaceutically acceptable carrier or excipient, which can be administered orally, rectally, parenterally, intracisternally, intravaginally, intraperitoneally, topically (as in powders, ointments, drops or transdermal patch), buccally, or as an oral or nasal spray. The phrase "pharmaceutically acceptable carrier" means a diluent filler, encapsulating material or solid, semi-solid, or non-toxic auxiliary formulation of any type. The term "parenteral" as used herein, refers to modes of administration which include intravenous, intramuscular, intraperitoneal, intrasternal, subcutaneous and intraarticular injection and infusion. The pharmaceutical compositions of this invention for parenteral injection comprise pharmaceutically acceptable sterile aqueous or non-aqueous solutions or dispersions, suspensions or emulsions as well as sterile powders for reconstitution into sterile injectable solutions or dispersions just before use. Examples of suitable carriers, diluents, solvents or aqueous and non-aqueous vehicles include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and injectable organic esters such as ethyl oleate. The proper fluidity can be maintained, for example, by the use of coating materials such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants. These compositions may also contain auxiliaries such as preservatives, wetting agents, emulsifying agents, and dispersing agents. Prevention of the action of microorganisms can be ensured by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenolic sorbic acid, and the like. It may also be desirable to include isotonic agents such as sugars, sodium chloride, and the like. Prolonged absorption of the injectable pharmaceutical form can be brought about by the inclusion of agents delaying absorption such as aluminum monostearate and gelatin. In some cases, in order to prolong the effect of the drug, it is desirable to slow the absorption of the drug by subcutaneous or intramuscular injection. This can be done by using a liquid suspension of crystalline or amorphous material with poor water solubility. The absorption rate of the drug then depends on its rate of dissolution which, in turn, may depend on the size of the crystal and the crystalline form. Alternatively, the delayed absorption of a drug administered parenterally is accomplished by dissolving or suspending the drug in an oil vehicle. Injectable depot forms are made by forming microencapsulated matrices of the drug in biodegradable polymers such as polyglycolide polylactide. Depending on the drug to polymer ratio and the nature of the polymer employed in particular, the drug release rate can be controlled. Examples of other biodegradable polymers include poly (orthoesters) and poly (anhydrides). Injectable depot formulations are also prepared by trapping the drug in liposomes or microemulsions that are compatible with body tissues. The injectable formulations can be sterilized, for example, by filtration through a bacteria retention filter, or by the incorporation of sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium. before use. Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active compound is mixed with at least one excipient or inert carrier, pharmaceutically acceptable such as sodium citrate or dicalcium phosphate and / or) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate, e) solution retarding agents such as paraffin , f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol, and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, stearate of calcium, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents. Solid compositions of a similar type can also be employed as fillers in soft, semi-solid and hard filled gelatin capsules or liquid filled capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. Can? optionally containing opacifying agents and may also be of a composition that they release the active ingredient (s) only, or preferably, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedded compositions that can be used include polymeric substances and waxes. The active compounds may also be in microencapsulated form, if appropriate, with one or more of the aforementioned excipients. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and ices. In addition, of the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3-butylene glycol, dimethyl formamide, oils (in particular, cottonseed, peanut, corn, germ, olive, castor bean and sesame oils), glycerol, tetrahydrofurfuryl alcohol , polyethylene glycols and esters of sorbitan fatty acids, and their mixtures. In addition, of inert diluents, the oral compositions may also include auxiliaries such as wetting agents, emulsifying and suspending agents, sweetening, flavoring and perfume agents. The suspensions may contain, in addition to the active compounds, suspending agents such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters, microcrystalline cellulose, aluminum metahydroxide, bentonite, agar-agar, and tragacanth, and mixtures thereof.

Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye. Compositions for topical administration, including those for inhalation, can be prepared as a dry powder which may be pressurized or non-pressurized. In non-pressurized powder compositions, the active ingredient in finely divided form can be used in admixture with an inert carrier of larger pharmaceutically acceptable size comprising particles having a size of, for example, up to 100 microns in diameter. Suitable inert carriers include sugars such as lactose. Desirably, at least 95% by weight of the particles of the active ingredient have an effective particle size in the range of 0.01 to 10 microns. The compositions for topical use in the skin also include ointments, creams, lotions and gels. Alternatively, the composition can be pressurized and contain a compressed gas, such as nitrogen or a liquefied propellant gas. The liquefied propellant medium and indeed the total composition is preferably such that the active ingredient does not dissolve to any substantial degree. The pressurized composition may also contain a surface active agent. The surface active agent can be a liquid or solid nonionic surface active agent or can be a solid anionic surface active agent. It is preferred to use the solid anionic surface active agent in the form of a sodium salt. One more form of topical administration is for the eye, such as for the treatment of immuno-mediated eye conditions such as autoimmune diseases, allergic or inflammatory conditions, and corneal transplants. The compound of the invention is delivered in a pharmaceutically acceptable ophthalmic vehicle, such that the compound is kept in contact with the ocular surface for a sufficient period of time to allow the compound to penetrate the cornea and inner regions of the eye, such as, for example, the anterior chamber, posterior chamber, vitreous body, aqueous humor, vitreous humor, cornea, iris / ciliary, lenses, choroid / retina and sclera. The pharmaceutically acceptable ophthalmic vehicle can be, for example, an ointment, vegetable oil or an encapsulating material. Compositions for rectal or vaginal administration are preferably suppositories or retention enemas which can be prepared by mixing the compounds of this invention with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid. room temperature, but liquid at body temperature and therefore melt in the rectum or vaginal cavity and release the active compound. The compounds of the present invention 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. The liposomes are formed by mono- or multi-lamellar crystals of hydrated liquid that are dispersed in an aqueous medium. Any physiologically acceptable, metabolizable, non-toxic lipid capable of forming liposomes can be used. The compositions present in the form of a liposome may contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients and the like. The preferred lipids are phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic. Methods for forming liposomes are known in the art. See, for example, Prescott, Ed., Methods in Cell Biology, Vol. XIV, Academic Press, New York, N. Y., (1976), p. 33 et seq. The compounds of the present invention can also be co-administered with one or more immunosuppressive agents. Immunosuppressive agents within the scope of this invention include, but are not limited to, sodium azathioprine IMU RAN®, brequinar de sodio, gusperimus trihydrochloride SPANIDIN® (also known as deoxispergualin), mizoribine (also known as bredinin), mycophenolate mofityl CELLCEPT®, Ciclosporin A NEORAL® (also marketed as a different formulation of Cyclosporin A under the trademark SANDIMMU NE®), tacrolimus PROGRAF® (also known as FK-506), sirolimus and RAPAMUNE®, leflunomide (also known as HWA-486), glucocorticoids, such as prednisolone and its derivatives, antibody therapies such as orthoclone (OKT3) and Zenapax®, and anti-cytotoxic globulins, such as thymoglobulins. It is understood that the foregoing detailed description and the appended examples are merely illustrative and should not be construed as limitations on the scope of the invention, which is defined solely by the appended claims and their equivalents. Various changes and modifications to the described modalities will be apparent to those skilled in the art. Such changes and modifications, including without limitation those relating to chemical structures, substituents, derivatives, intermediates, syntheses, formulations and / or methods for use of the invention, may be made without departing from the scope and spirit thereof.

Claims (8)

1. CLAIMS 1. A compound that has the formula: or a pharmaceutically acceptable salt or prodrug thereof.
2. 2. A compound according to claim 1 of formula:
3. 3. A compound according to claim 1 of formula:
4. 4. A method for inhibiting restenosis in mammals in need of such treatment, which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1.
5. A method for inhibiting immune or autoimmune diseases in a mammal in need of such treatment, which comprises administering to the mammal a therapeutically effective amount of a compound of claim 1.
6. 6. A method for inhibiting rejection of post-transplant tissue transplantation in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
7. 7. A method for inhibiting fungal growth in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.
8. 8. A method for inhibiting cancer in a mammal in need of such treatment, comprising administering to the mammal a therapeutically effective amount of a compound of claim 1.