MXPA06009269A

MXPA06009269A - Novel compounds

Info

Publication number: MXPA06009269A
Application number: MXPA/A/2006/009269A
Authority: MX
Inventors: Ivan Leo Pinto; Shahzad Sharooq Rahman; Neville Hubert Nicholson
Original assignee: Neville Hubert Nicholson; Ivan Leo Pinto; Shahzad Sharooq Rahman; Smithkline Beecham Corporation
Priority date: 2004-02-14
Filing date: 2006-08-14
Publication date: 2007-04-10

Abstract

The present invention provides therapeutically active compounds which are xanthine derivatives, processes for the manufacture of said derivatives, pharmaceutical formulations containing the active compounds and the use of the compounds in therapy, particularly in the treatment of diseases where under-activation of the HM74A receptor contributes to the disease or where activation of the receptor will be beneficial, having the formula (II):wherein R1 is selected from:hydrogen and C1-4 alkyl which may be optionally substituted with one or more groups selected from CN and CF3, R2 is selected from:C2-10 unsubstituted alkyl, C1-10 alkyl substituted with one or more groups selected from fluorine and CN, C5 alkenyl, unbranched C4 alkenyl, and C1-4 alkyl substituted with cycloalkyl, and R3 is selected from halogen and CN.

Description

NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian patent (AM, Published: AZ. BY, KG, KZ, MD, UK, TJ, TM), Euwpe n patent (AT, - without international search report and to be republished BE, BG, CH, CY, CZ, DE, DK, EE, ES, Fl, FR, GB, GR., upon receipt of that report HU, IE, IS, IT, LT, LU, MC, NL, PL PT, RO, SE, SI, SK, TR). OAPl patent (BF, BJ, CF. CG, Cl, CM, GA, GN, GQ, For two-letter codes and other abbreviations.reference to the "GuidGW, ML, MR, NE, SN, TD, TG) ance Notes on Codes and Abbreviations "appearing at the beginnings of inventorship (Rule 4.17 (iv)) for US only, no regular issue of the PCT Gazette.

MEDICATIONS WITH HM74A RECEIVER ACTIVITY DESCRIPTIVE MEMORY The present invention relates to therapeutically active compounds which are xanthine derivatives, to processes for the manufacture of said derivatives, to pharmaceutical formulations containing the active compounds and to the use of the compounds in therapy, particularly in the treatment of diseases in which an under-activation of the HM74A receptor contributes to the disease or in which receptor activation will be beneficial. Dyslipidemia is a general term used to describe individuals with aberrant lipoprotein profiles. Clinically, the main classes of compounds used for the treatment of patients with dyslipidemia and, therefore, with risk of cardiovascular disease are statins, fibrates, bile acid binding resins and nicotinic acid. Nicotinic acid (Niacin, a vitamin B) has been used clinically for more than 40 years in patients with various forms of dyslipidemia. The main mode of action of nicotinic acid is through the inhibition of hormone-sensitive triglyceride lipase (HSL), which results in a reduction in the plasma levels of non-esterified fatty acids (NEFA) which, at its Once, it alters the hepatic fat metabolism reducing the production of LDL and VLDL (low and very low density lipoproteins). It is believed that reduced VLDL levels reduce the activity of cholesterol ester transfer protein (CETP), which results in an increase in HDL (high density lipoprotein) levels, which may be the cause of cardiovascular beneficial effects observed. In this way, nicotinic acid produces a very desirable alteration in lipoprotein profiles; reducing the levels of VLDL and LDL while increasing HDL levels. It has also been shown that nicotinic acid has beneficial effects modifying the disease, reducing the progression and increasing the regression of atherosclerotic lesions and reducing the number of cardiovascular events in several trials. The observed inhibition of HSL by nicotinic acid treatment is mediated by a reduction in cellular cyclic adenosine monophosphate (cAMP) caused by inhibition mediated by the G protein of adenylyl cyclase. Recently, the G-protein coupled receptors HM74 and MH74A have been identified as receptors for nicotinic acid (PCT patent application WO02 / 84298; Wise et al., J. Biol Chem., 2003, 278 (11), 9869-9874). ). The DNA sequence of human HM74A can be found in the Genbank; access number AY148884. Two additional documents confirm this discovery (Tunaru et al., Nature Medicine, 2003, 9 (3), 352-255 and Soga et al., Biochem Biophys Res Commun., 2003, 303 (1) 364-369), however, the Nomenclature differs slightly. In the Tunaru document, what is called human HM74 is actually HM74A and in the Soga document HM74b is identical to HM74A. Cells transfected to express MH74A and / or HM74 acquire the ability to induce responses mediated by the G G protein after exposure to nicotinic acid. In mice lacking the homologue of HM74A (m-PUMA-G), nicotinic acid can not reduce plasma levels of NEFA. Certain xanthine derivatives have been synthesized and are described in the prior art. For example, EP0389282 discloses xanthine derivatives as potential mediators of cerebrovascular disorders. Jacobson et al. in J. Med. Chem., 1993, 36, 2639-2644, identified a series of xanthine derivatives as adenosine receptor antagonists. Now we present a new group of xanthine derivatives that are selective agonists of the nicotinic acid receptor HM74A and that, in this way, are beneficial in the treatment, prophylaxis and suppression of diseases in which the under activation of this receptor contributes to the disease or in which receptor activation will be beneficial.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides therapeutically active xanthine derivatives and the use of these derivatives in therapy, particularly in the treatment of diseases in which an under-activation of the HM74A receptor contributes to the disease or in which receptor activation will be beneficial, in particular diseases of the lipid metabolism, including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia and mixed dyslipidemia, heart failure, hypercholesteremia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia. As such, the compounds may also find utility as therapeutic agents for coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, as well as cardiovascular indications associated with type II diabetes mellitus, type I, insulin resistance, hyperlipidemia, anorexia nervosa and obesity. The compounds may also be useful in the treatment of inflammatory diseases or conditions, as further indicated below. The intermediates, formulations, methods and procedures described in this document constitute additional aspects of the invention.

DETAILED DESCRIPTION OF THE INVENTION In accordance with one aspect of this invention, a compound of Formula (I) is provided and a physiologically functional derivative thereof, wherein R 1 is selected from hydrogen and C 1 alkyl which may be optionally substituted with one or more groups selected from CN and CF 3; R 2 is selected from: unsubstituted C 3-10 alkyl, C 1 -C 10 alkyl substituted with one or more groups selected from fluoro and CN, C 5 alkenyl, unbranched C 4 alkenyl, and C 4 alkyl substituted with cycloalkyl; and R3 is selected from halogen and CN; with the provisos that: (1) when R3 represents Cl, and R1 represents ethyl, R2 is other than propyl; (ii) when R3 represents Br, and R1 represents propyl, R2 is other than propyl; (iii) when R3 represents Cl or Br, and R1 represents butyl, R2 is other than butyl; and (iv) when R1 represents C, .4 alkyl, CH2CN or (CH2) 3CF3, R2 is other than branched alkyl. The compounds are useful in the treatment of diseases in which an under-activation of the HM74A receptor contributes to the disease or in which activation of the receptor will be beneficial, in particular diseases of lipid metabolism including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia and mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular diseases including atherosclerosis, arteriosclerosis and hypertriglyceridemia.

As such, the compounds may also be beneficial as therapeutic agents for coronary artery diseases, thrombosis, angina, chronic renal failure, peripheral vascular diseases and stroke, as well as cardiovascular indications associated with type II diabetes mellitus, diabetes of type I, insulin resistance, hyperlipidemia, anorexia nervosa and obesity. As such, the compounds of the present invention may find utility as agonists or partial agonists of HM74A (modulators of HM74A). In particular embodiments, R 1 is selected from: hydrogen, C 1 alkyl, CH 2 CN, and (CH 2) 3 CF 3; in more particular embodiments R1 is selected from: hydrogen and methyl. In certain embodiments, R2 is selected from: alkyl of C3-10 unsubstituted, C, _6 alkyl with one or more CN substitutions, C1-10 alkyl with one or more fluorine substitutions, C5 alkenyl, unbranched C4 alkenyl, and C1-4 alkyl substituted with cycloalkyl.

Particularly, R2 is selected from: unsubstituted C3-10 alkyl; (CH2) 1-gCN; C2.5 alkyl with one or more fluorine substitutions; alkenyl of C5; and C 1-4 alkyl substituted with cycloalkyl. More particularly, R 2 is selected from n-unsubstituted C 4 alkyl, for example pentyl; (CH2) ?. 3CN, for example, (CH2) CN or (CH2) 3CN; C3.4 alkyl with one or more fluorine substitutions; in particular when the terminal carbon is fully saturated with fluorine, for example (CH2) 2.3CF3; and C5 alkenyl, in particular when there is only one double bond, for example, when the double bond is located between the fourth and fifth carbons (terminal alkenyl). In particular embodiments, R3 represents halogen. More particularly, R3 is selected from chlorine and bromine. More particularly, R3 represents chlorine. It will be understood that the present invention includes any combination of the particular embodiments and includes all combinations of particular substituents described hereinbefore. Particular compounds of the present invention include (8-Chloro-2,6-d-oxo-1, 2,6-J-tetrahydro-3H-purin-3-yl) acetonitrile, 3-Butyl-8 -chloro-3-hydroxy-1 - / - purine-2,6-dione, 8-chloro-1-methyl-3-pentyl-3-hydroxy-1-purine 2,6-dione, 8-Chloro-3- (4,4,4-trifluorobutyl) -3J-dlhydro-1 y-purine-2,6-dione, 8-Bromo-1-methyl-3-pentyl-3J ~ Hydro-1 / - -purine-2,6-dione. 8-Chloro-3- (3,3,3-trifluoropropyl) -3J-dihydro-1r / -purin-2,6-dione, 8-Chloro-1-propyl-3- (2,2,2-trifluoroethyl) -3J-dihydro-1ry-purine-2,6-dione, 3-Butyl-8-chloro-1-methyl-3J-dihydro-1 - / - purine-2,6-dione, (3-Butyl-8- chloro-2,6-dioxo-2,3,6J-tetrahydro-1ry-purin-1-yl) acetonitrile, 8-chloro-3- (2-cyclopropylethyl) -3J-dihydro-1 / - / - purine-2,6-dlone, 8-chloro-1,3-bis (4,4,4-trifluorobutyl) -3J-dihydro-1 H-purine-2,6-dione, 4- (8-chloro-1) -methyl-2,6-dioxo-, 2,6J-tetrahydro-3-purin-3-yl) butanonitrile, 8-chloro-1-ethyl-3- (2,2,2-trifluoroethyl) -3J-dihydro-1 - / -purine-2,6-dione, 1-methyl-4-propyl-1-methyl -3J-dihydro-1 ry-purine-2,6-dione, 8-chloro-3- (3-methylbutyl) -3J-dihydro-1H-purine-2,6-dione, 8-chloro-3-pent l-3J-dihydro-1 H-purine-2,6-dione, 8-chloro-3-propyl-3J-d-hydroxy-1-purine-2,6-dione, 3-butyl-1-methyl- 2,6-dioxo-2,3,6J-tetrahydro-1H-purine-8-carbonitrile, 8-Chloro-3- (4-penten-1-yl) -3,7-dihydro-1 W-purine-2 , 6-d ione, 8-chloro-3-hexyl-3J-dihydro-1-purine-2,6-dione, 4- (8-chloro-2,6-dioxo-1, 2,6J etrahydro-3 - / - purin -3-yl) butanonitrile, 8-chloro-3-hexyl-1-methyl-3J-dihydro-1 W-purine-α-dione, 3-Butyl-8-chloro-1-ethyl-3J-dihydro-1 -purine-2,6-dione, [8-chloro-3- (2-cyclopropylethyl) -2,6-dioxo-2,3,6J-tetrahydro-1 H -purin-1-yl) acetonitrile, (d- Chloro ^.? - dioxo-S-propyl ^ .S.TJ-tetrahydro-l r -purin-l-yl) acetonitrile, 8-C [oro-1- (4,4,4-trifluorobuíl) -3 - (2,2,2-trifluoroetyl) -3J-d-hydroxy-1 / - / - purine-2,6-dione, 8-chloro-3- (2,2,2-trifluoroethyl) -3J-dihydro-1 - -purine-2,6-dione, 2,2 '- (8-chloro-2,6-dioxo-6J-dihydro-1 H-purine-1,3 (2H) -diyl) diacetonitrile, 8-chloro-1 -methyl-3- (4,4I4-trifluorobutyl) -3J-dihydro-1H-purine-2,6-dione, 8-chloro-3- (2-cyclohexylethyl) -3J-dihydro-1 - / - purine- 2,6-dione, 1,3-Dibutyl-2,6-dioxo-2,3,6J-tetrahydro-1 r / -purine-8-carbonitrile, 1,3-Dibutyl-8-iodo-3J-dihydro-1 H-purine -2,6-dione, 8-Chloro-3- (4-methylpentyl) -3J-dihydro-1 - / - purine-2,6-dione, 8-Chloro-3- (6-methylheptyl) -3 J-dihydro-1 ry-purine-2,6-dione, 8-chloro-3-octyl-3J-dihydro-1 / - / - purine-2,6-dione, 8-chloro-3-decyl-3J- dihydro-1 / - / - purine-2,6-dione, 8-chloro-3- (cyclohexylmethyl) -3J-dihydro-1 - / - purine-2,6-dione, (+/-) - 8-Chlorine -3- (3-methylpentyl) -3J-dihydro-1H-purine-2,6-dione, 8-chloro-3- (2-cyclopentylethyl) -3J-dihydro-1r / -purine-2,6-dione, 8-chloro-3- (cyclopropylmethyl) -3J-dihydro-1ry-purine-2,6-dione, (+/-) - 8-Chloro-3- (2-methylbutyl) -3J-dihydro-1ry-purine-2,6-dione, (+/-) - 8-Chloro-3- (2-methylpentyl) -3J-dihydro-1 - / - purine-2,6-dione, 8-Chloro-3- (cyclobutylmethyl) -3J-dihydro-1 ry-purine-2,6-dione, 8-Chloro-3- (cyclopentylmethyl) -3J-dihydro-1 / - / - purine-2,6- dione, 8-chloro-3- (3-cyclopropylpropy) -3J-dihydro-1-purine-2,6-dione, 8-chloro-3- (2-cyclobutylethyl) -3J-dihydro-1 / - / - purine -2, 6-dione, 8-chloro-3- (4-fluorobutyl) -3J-dihydro-1 f / -purine-2,6-dione, 8-chloro-3- (3-fluoropropyl) -3J-dihydro -1 / - / - purine-2,6-dione, 8-chloro-3- (5-fluoropentyl) -3J-dihydro-1 - / - purine-2,6-dione, 4- (8-chloro-1 -methyl-2,6-dioxo-1, 2,6J-tetrahydro-3H-purin-3-yl) butanonitrile, 3- (3-Buten-1 -yl) -8-chloro-3J-dihydro-1 - / -purine-2,6-dione, 6- (8-chloro-2,6-dioxo-1, 2,6J-tetrahydro-3H-purin-3-yl) -2.2- dimethylhexanonitrile, and 8-chloro-3 - (6-fluorohexyl) -3J-dihydro-1 / - -purine-2,6-dione. Throughout the present specification and the appended claims, the words "understand" and "include" and variations such as "comprises", "comprising", "includes" and "including" must be interpreted inclusively. That is, these words pretend to express the possible inclusion of other elements or whole numbers not specifically cited, when the context allows it. As used herein, the terms "halogen" or "halo" refer to fluorine, chlorine, bromine and iodine. As used herein, the term "alkyl" (when used as a group or as part of a group) refers to a straight or branched hydrocarbon chain unless otherwise indicated, which contains the number of atoms of carbon specified. For example, C3-C10 alkyl refers to a straight or branched hydrocarbon chain containing at least 3 and at most 10 carbon atoms. Examples of alkyl, as used herein, include, but are not limited to, methyl (Me), ethyl (Et), n-propyl and i-propyl. The term "n-alkyl" refers specifically to an unbranched hydrocarbon chain. As used herein, the term "cycloalkyl" refers to a hydrocarbon ring containing between 3 and 6 carbon atoms, comprising heteroatoms or conjugated double bonds. Examples of cycloalkyl as used herein include, but are not limited to, cyclopropyl and cyclohexyl. As used herein, the term "alkenyl" refers to a straight or branched hydrocarbon chain containing the specified number of carbon atoms and containing one or more double bonds. As used herein, when a group is cited as being "substituted" with another group or having "one or more substitutions", unless a particular position is specified for such substitution, it should be understood that a substitution may be made. in any position in the group. As used herein, the term "physiologically functional derivative" refers to any pharmaceutically acceptable derivative of a compound of the present inven, for example, an amide thereof, and includes any pharmaceutically acceptable salt of a compound of formula (I) ), and any pharmaceutically acceptable solvate of a compound of formula (I) which, upon administration to a mammal, such as a human, is capable of providing (directly or indirectly) a compound of formula (I) or a metabolite or active residue thereof. Those skilled in the art will appreciate that the compounds of formula (I) can be modified to provide physiologically functional derivatives thereof in any of the functional groups in the compounds, and that, therefore, the compounds of formula (I) can be modified in more than one position. As used herein, the term "pharmaceutically acceptable" used in relation to an ingredient (active ingredient or excipient) that can be included in a pharmaceutical formulation for administration to a patient, refers to that the ingredient is acceptable in the sense that it is compatible with any of the other ingredients present in the pharmaceutical formulation and that it is not harmful to the recipient thereof. As used herein, the term "solvate" refers to a complex of variable stereochemistry formed by a solute (in this inven, a compound of formula (I), a salt thereof or a physiologically functional derivative thereof) and a solvent Such solvents for the purposes of the present inven can not interfere with the biological activity of the solute. The solvent used can be a pharmaceutically acceptable solvent. Examples of suitable pharmaceutically acceptable solvents include water, ethanol and acetic acid. An example of a solvent that can be used is water, in which case the solvate can be cited as a hydrate of the solute in question. It will be appreciated that, for pharmaceutical use, the "salt or solvate" mentioned above will be a pharmaceutically suitable salt or solvate. However, other salts or solvates may be used, for example, in the preparation of a compound of formula (I) or in the preparation of a pharmaceutically acceptable salt or solvate thereof. Pharmaceutically acceptable salts include those described by Berge, Bighiey and Monkhouse, J. Pharm. Sci, 1977, 66, 1-19. Suitable pharmaceutically acceptable salts include alkali metal salts formed from the addition of alkali metal bases such as alkali metal hydroxides. Examples of suitable alkali metal salts are sodium salts and potassium salts. Other acceptable pharmaceutically acceptable salts include alkaline earth metal salts such as calcium salts or magnesium salts, ammonium salts; or salts with organic bases such as ethanolamine, triethanolamine, ethylenediamine, triethylamine, choline and meglumine; or salts with amino acids such as arginine, lysine and histidine. The compounds of formula (I) have a potential therapeutic beneficial effect in the treatment and improvement of the symptoms of many diseases of lipid metabolism, including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia and mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia, diabetes mellitus type II, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa and obesity. Likewise, the compounds may also be useful as therapeutic agents for coronary artery disease, thrombosis, angina, chronic renal insufficiency, peripheral vascular disease and apoplexy. In addition, it is also believed that the HM74 and HM74A receptors are involved in inflammation. Inflammation represents a group of vascular, cellular and neurological responses to trauma. Inflammation can be characterized as the movement of inflammatory cells such as monocytes, neutrophils and granulocytes into the tissues. This is usually associated with a reduction in endothelial barrier function and tissue edema. Inflammation considered a disease is typically called chronic inflammation and can last a lifetime. Such chronic inflammation can manifest itself through the symptoms of the disease. Therefore, the goal of anti-inflammatory therapy is to reduce this chronic inflammation and facilitate the progress of the physiological healing and tissue repair process. Examples of inflammatory diseases or conditions for which the compounds of the present invention can demonstrate utility include those of the joints, particularly arthritis (e.g., rheumatoid arthritis, osteoarthritis, joint prosthesis failure), of the gastrointestinal tract (e.g. ulcerative colitis, Crohn's disease and other inflammatory bowel and gastrointestinal diseases, gastritis and inflammation of the mucosa due to an infection, or the enteropathy caused by non-steroidal anti-inflammatory drugs), of the lung, (for example, respiratory failure in adults, asthma, cystic fibrosis or chronic obstructive pulmonary disease), the heart (for example, myocarditis), nervous tissue (for example, multiple sclerosis), the pancreas (for example, inflammation associated with diabetes mellitus and complications of the same), the kidney (for example, glomerulonephritis), the skin (for example, dermatitis, psoriasis, eczema, urticaria and burn injuries), of the eye (eg, glaucoma), as well as of transplanted organs (eg, rejection) and multiple organ diseases (eg, systemic lupus erythematosus or sepsis), and Inflammatory sequelae of viral or bacterial infections, inflammatory conditions associated with atherosclerosis, and inflammatory conditions that appear after hypoxia or ischemia (with or without reperfusion), for example in the brain or in ischemic heart disease. In particular, the compounds of this invention are useful in the treatment and prevention of inflammation, diabetes and cardiovascular diseases or conditions including atherosclerosis, arteriosclerosis, hypertriglyceridemia and mixed dyslipidemia. Nicotinic acid has a significant side effect profile, possibly because it is dosed at a high level (daily gram quantities). The most common side effect is an intense reddening of the skin. In certain embodiments of the present invention, the compounds may have fewer side effects than nicotinic acid. HM74A has been identified as a high affinity receptor for nicotinic acid, while HM74 is a receptor with lower affinity. The compounds of the present invention may find utility as selective agonists or partial agonists of HM74A; in which case they will show a greater affinity for HM74A than for HM74. The ability of the compounds of formula (I) to activate HM74A can be demonstrated, for example, by using the following enzymatic and whole cell assays in vitro: In-fro assays For transient transfections, HEK293T cells (HEK293 cells stably expressing SV40 large T antigen) were maintained in DMEM containing 10% fetal bovine serum and 2 mM glutamine. The cells were seeded in 90 ml culture dishes and cultured to 60-80% confluence (18-24 h) before transfection. Human HM74A (accession of GenBank ™ AY148884) was subcloned into a mammalian expression vector (pCDNA3: Invitrogen) and used for transfection using Lipofectamine reagent. For transfection, 9 μg of DNA was mixed with 30 μl of Lipofectamine in 0.6 ml of Opti-MEM (Life Technologies Inc.) and the mixture was incubated at room temperature for 30 minutes before the addition of 1.6 ml of Opti-MEM . The cells were exposed to the Lipofectamine / DNA mixture for 5 hours and then 6 ml of 20% (v / v) fetal bovine serum was added in DMEM. The cells were harvested 48 hours after transfection. The Pertussis toxin treatment was carried out by supplementation in medium at 50 ngml "1 for 16 hours.All transient transfection studies involved the co-transfection of the receptor together with the G / o > Goia protein.

For the generation of stable cell lines, the above method was used to transfect CHO-K1 cells seeded in six-well plates that developed to a 30% confluence. These cells were maintained in DMEM F-12 HAM medium containing 10% fetal bovine serum and 2 mM glutamine. Forty-eight hours after transfection, the medium is supplemented with 400 μg / ml Geneticin (G418, Gibco) for the selection of antibiotic-resistant cells. Clonal CHO-K1 cell lines stably expressing HM74A were confirmed by measurements of [35 S] -GTP? S binding, after the addition of nicotinic acid. P2 membrane preparation - Particulate P2 fractions containing plasma membrane were prepared from frozen cell pastes at -80 ° C after harvesting. All procedures were performed at 4 ° C. Cell pellets were resuspended in 1 ml of 10 mM Tris-HCl and 0.1 mM EDTA, pH 7.5 (buffer pH A) and by homogenization for 20 seconds with Ultra Turrax followed by passes (5 times) through a needle 25 gauge. The cell lysates were centrifuged at 1,000 g for 10 minutes in a microcentrifuge to pellet the nuclei and cells that had not ruptured, and fractions of P2 particles were recovered by microcentrifugation at 16,000 g for 30 minutes. The P2 particle fractions were resuspended in pH A buffer and stored at -80 ° C until required. Union of ^ SJ-GTP? S - The assays were performed at room temperature in a 384-cavity format based on previously described methods (Wieland, T. and Jakobs, KH (1994) Methods Enzymol., 273, 3- 13). Briefly, the dilution of conventional or test compounds was prepared and added to a 384 well plate in a volume of 10 μl. Membranes (HM74A or HM74) were diluted in assay pH buffer (20 mM HEPES, 100 mM NaCl, 10 mM MgCl 2, pH 7.4) supplemented with saponin (60 μg / ml), Leadseeker WGA beads (Amersham, 250 μg / cavity) and GDP 10 μM, so that the volume of 20 μl added to each cavity contained 5 μg of membranes. [35 S] -GTP? S (1170 Ci / mmole, Amersham) (1: 1500) was diluted in assay buffer and 20 .mu.l was added to each well. After addition of the radioligand, the plates were hermetically sealed, centrifuged by pulses and incubated for 4 hours at room temperature. At the end of the incubation period, the plates were read on a Leadseeker machine (VIEWLUX PLUS: Perkin-Eimer) to determine the specific binding levels.

In vivo assay HM74A agonists were tested on male Sprague-Dawley rats (200-250 g) that had been fasted for at least 12 hours before the study. The compounds were dosed intravenously (5 ml / kg) or by means of an oral probe (10 ml / kg). Blood samples (0.3 ml by the tail vein) were taken before administering the dose and at three times after dosing (varying the times from 15 minutes to 8 hours from dose administration). Each blood sample was transferred to a heparin tube (Becton Dickinson Microtainer, PST LH) and centrifuged (10,000 g for 5 minutes) to produce a plasma sample. Plasma samples were tested for non-esterified fatty acid (NEFA) levels using a commercially available kit (Randox). The inhibition of plasma levels of NEFA, with respect to the levels prior to dose administration, was used as an indicator of agonist activity of HM74A. To determine whether the HM74A compounds exhibited the redness response associated with nicotinic acid, they were administered to anesthetized guinea pigs. Male Dunkin Hartley guinea pigs (300-800 g) were fasted for 12 hours before being anesthetized with a mixture of ketamine hydrochloride (Vetalar, 40 mg / kg, im), Xylazine (Rompun, 8 mg / kg im) and pentobarbitone sodium (Sagatal, 30 mg / kg, ip). After anesthesia a tracheo-tomia was performed and the animals were ventilated mechanically with ambient air (10-12 ml / kg, 60 breaths / min). A jugular vein and a carotid artery were cannulated for intravenous administration of the test compound and for collecting blood respectively. An infrared temperature probe (Extech Instruments) was placed at a distance of 3-5 mm from the tip of the left ear. The temperature measurements were recorded every minute from 5 minutes before administering the test compound and up to 40 minutes after administration of the test compound. The data was automatically collected in a Psion computer before being transferred for the analysis of the data within an Excel spreadsheet. Before, and at frequent time points after administration of the compound, blood samples (0.3 ml) were taken through the cannula of the carotid artery and transferred to Microtainer tubes (BD) containing lithium heparin. The samples were thoroughly mixed in a blood mixer and then stored on ice before centrifugation at 1200 g for 5 minutes. Nicotinic acid (10 mg / kg, i.v.) produced an average increase (± s.e.m.) in the temperature of the ear equivalent to 10.42 ± 1.44 (area under the curve; arbitrary units; n = 6). For comparison, the compound of 2,6-dioxo 30 (10 mg / kg iv) produced an average increase (± sem) in the temperature of the ear equivalent to 1.52 + 0.39 (area under the curve, arbitrary units, n = 6 ), a reduction of 85%. The compounds according to Formula (1) have been synthesized (see the synthetic examples presented below) and tested in one or more of the assays described above. All exemplified compounds have a pEde C50 value of 4.9 (± 0.3 logarithmic units) or greater and an efficacy of 30% or greater. Some particular compounds are exemplified below.

General purification and analytical methods: Mass spectra (MS) were recorded on a Fisons VG Platform mass spectrometer using positive electrospray ionization mode [(ES + ve to give molecular ions MH + and M (NH4) +] or Negative electrospray ionization [(ES-ve to give molecular ions (MH)].] The 1 H NMR spectra were recorded using a Bruker DPX 400 MHz spectrometer using tetramethylsilane as an external standard Biotage ™ Chromatography refers to purification performed using the equipment sold by Dyax Corporation (the Flash 40i or the Flash 150i) and cartridges pre-filled with KPSil.Autoprep directed to masses refers to methods in which the material was purified by high performance liquid chromatography on a HPLCABZ + column of 5 μm (5 cm x 100 mm di) with 0.1% HCO2H in water and 95% MeCN, 5% water (0.5% HCO2H) using the following gradient elution conditions: 0-1.0 minutes 5% B, 1.0-8.0 minutes 5? 30% B, 8.0-8.9 minutes 30% B; 8.9-9.0 minutes 30? 95% B, 9.0-9.9 minutes 95% B, 9.9-10 minutes 95- 0% B at a flow rate of 8 ml minute "1 (System 2) The fraction collector Gilson 202 was activated by a VG Platform Mass Spectrometer after detection of the mass of interest.Preparative Hplc refers to methods in which the material was purified by high performance liquid chromatography on a 5 μm HPLCABZ + column (10 cm x 21.2 mm diameter). ) with 0.1% HCO2H in water (A) and MeCN (0.5% HCO2H) (B) using the generic gradient elution conditions expressed as "xay" gradient with the following gradient system: 0.1-1.45 minutes x% B, 1.45-20 minutes x? Y% B, 20-24 minutes and? 95% B, 24-30 minutes 95% B, 32-34 minutes 95- x% B at a flow rate of 8 ml minute "1. The Gilson 233 fraction collector was activated by UV (254 nm). SPE (solid phase extraction) refers to the use of cartridges sold by International Sorbent Technology Ltd. Strata Phenyl SPE refers to the use of cartridges sold by Phenomenex. The compound was introduced into a cartridge previously conditioned with MeCN and equilibrated with 5% MeCN in water. The compound was eluted with 0.1% HCO2H in water and MeCN (0.5% HCO2H) in a suitable gradient in a Combiflash Optix 10. As indicated above, the compounds of Formula (I) can find utility in human or veterinary medicine , in particular as activators of HM74A, in the treatment of dyslipidemia and hyperlipoproteinemia. Thus, as a further aspect of the present invention, there is provided a compound of formula (I) or a physiologically functional derivative thereof, for use in human or veterinary medicine, particularly in the treatment of disorders of lipid metabolism including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia and mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular diseases including atherosclerosis, arteriosclerosis and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa and obesity. As such, the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke. As another aspect of the present invention there is provided a compound of formula (I) or a physiologically functional derivative thereof for use in the manufacture of a medicament for the treatment of disorders of lipid metabolism including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia. and mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa and obesity. As such, the compounds are also provided for use in the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke. It will be appreciated that references in this document to treatment include prophylaxis, prevention of recurrence and suppression of symptoms, as well as treatment of established conditions.

According to another aspect of the invention, there is provided the use of a compound of formula (II) and physiologically functional derivatives thereof, wherein: R1 is selected from: hydrogen and C, .4 alkyl which may be optionally substituted with one or more groups selected from CN and CF3; R2 is selected from: unsubstituted C2-10 alkyl, C1-10 alkyl substituted with one or more groups selected from fluorine and CN, C5 alkenyl, unbranched C4 alkenyl, and C, "4 alkyl substituted with cycloalkyl; and R3 is selected from halogen and CN. In the manufacture of a medicament for the treatment of disorders of lipid metabolism, including dyslipidemia or hyperiipoproteinemia. In particular, e! Use of a compound of Formula (II) in the manufacture of a medicament for the treatment of diabetic dyslipidemia or mixed dyslipidemia, heart failure, hypercholesterolemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke, and cardiovascular diseases including atherosclerosis, arteriosclerosis, and hypertriglyceridemia. In one embodiment of the invention, there is provided a compound of formula (11) for use in the treatment of disorders of lipid metabolism including dyslipidemia or hyperlipoproteinemia. In particular, the use of a compound of Formula (II) in the manufacture of a medicament for the treatment of diabetic dyslipidemia or mixed dyslipidemia, heart failure, hypercholesterolemia, type II diabetes mellitus, type I diabetes, insulin resistance is provided. , hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, stroke and cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia. In particular embodiments, R1 is selected from: hydrogen, C1-4 alkyl, CH2CN and (CH2) 3CF3. In more particular embodiments, R1 is selected from: hydrogen and methyl. In certain embodiments, R2 is selected from: unsubstituted C3_alkyl, C1_4alkyl substituted with one or more groups selected from fluorine and CN, C5alkenyl, unbranched C4alkenyl, and substituted C1-4alkyl. with cycloalkyl. Particularly, R2 is selected from: unsubstituted C3.10 alkyl, C1 alkyl with one or more CN substitutions, C1-10 alkyl with one or more fluoro substitutions, C5 alkenyl, unbranched C4 alkenyl and alkyl of C 1-4 substituted with cycloalkyl. More particularly, R2 is selected from: C3 alkyl. 10 unsubstituted; (CH2)., .5CN; C2.5 alkyl with one or more fluorine substitutions; C5 alkenyl; and C, _4 alkyl substituted with cycloalkyl. More particularly, R 2 is selected from n-unsubstituted C 4 alkyl, for example, pentyl; (CH ^ CN, for example, (CH2) CN or (CH2) 3CN; C3.4 alkyl with one or more fluorine substitutions, in particular, when the terminal carbon is fully saturated with fluorine, for example (CH2) 2.3 CF3; and C5 alkenyl, in particular, when there is only one double bond, for example, when the double bond is located between the fourth and fifth carbons (terminal alkenyl.) In particular embodiments, R3 represents halogen. selects between chlorine and bromine More particularly, R3 represents chlorine Particular compounds for use in the treatment of or in the manufacture of a medicament for the treatment of lipid metabolism disorders, including dyslipidemia or hyperlipoproteinemia include: (8-chloro- 2,6-d.oxo-1,2,6J-tetrahydro-3ry-purin-3-yl) acetonitrile, 3-Butyl-8-chloro-3J-dihydro-1 - / - purine-2,6-dione, d-Chloro-l-methyl-S-pentyl-SJ-dihydro-I H-purine ^ -dione, 8-Chloro-3- (4,4> 4-trifluorobutyl) -3J-dihydro-1-purine- 2,6-dione , 8-Bromo-1-methyl-3-pentyl-3J-dihydro-1 - / - purine-2, 6-dione, 8-chloro-3- (3,3,3-trifluoropropyl) -3J-dihydro-1 rV-purine-2,6-dione, 8-chloro-1-propyl-3- (2,2 , 2-trifluoroethyl) -3J-dihydro-1 H-purine-2,6-dione, 3-Butyl-8-chloro-1-methyl-3J-dihydro-1 / V-purine-2,6-dione, ( 3-Butyl-8-chloro-2,6-dioxo-2,3,6J-tetrahydro-1 - / - purin-1-yl) acetonitrile, 8-Chloro-3- (2-cyclopropylethyl) -3J-dihydro- 1 H-purine-2,6-dione, 8-Chloro-1,3-bis (4,4,4-trifluorobutyl) -3J-dihydro-1 H-purine-2,6-dione, 4- (8- Chloro-1-methyl-2,6-dioxo-1, 2,6J-tetrahydro-3H-purin-3-yl) butanonitrile, 8-Chloro-1-ethyl-3- (2,2,2-trifluoroethyl) - 3J-dihydro-1 H-purine-2,6-dione, 1-Methoxy-2,6-dioxo-3-pentyl-2,3,6J-tetrahydro-1 H-purine-8-carbonitrile, 8- Chloro-3-propyl-1-methyl-3J-dihydro-1 H-purine-2,6-dione, 8-Chloro-3- (3-metpbut-T) -3J-dihydro-1W-purine-2,6 -done, 8-Chloro-3-pentyl-3-J-dihydro-l? V-purine-2,6-dione, 8-chloro-3-propyl-3-J-dihydro-1-yr-purine-2,6-dione , 3-Butyl-1-methyl-2,6-dioxo-2,3,6J-tetrahydro-1 / - / - purine-8-carbonitrile, 8-Chloro-3- (4-penten-1-yl) - 3J-dihydro-1 H-purin a-2,6-dione, 8-chloro-3-hexyl-3J-dihydro-1 / - / - purine-2,6-dione, 4- (8-chloro-2,6-dioxo-1, 2, 6J-tetrahydro-3 / - / - purin-3-yl) butanonitrile, 8-chloro-3-hexyl-1-methyl-3J-dihydro-1 / - / - purine-2,6-dione, 3-Butyl- 8-chloro-1-eti-3, J-dihydro-1 / - / - purine-2,6-dione, [8-chloro-3- (2-cyclopropylethyl) -2,6-dioxo-2, 3,6J-tetrahydro-1 H-purin-1-yl) acetonitrile, (d-Chloro-2,6-dioxo-3-propyl-2,3,6J-tetrahydro-1 H-purin-1-yl) acetonitrile , d-Chloro-1- (4,4,4-trifluorobutyl) -3- (2,2,2-trifluoroethyl) -3J-dihydro-1 / - / - purine-2,6-dione, d-Chloro- 3- (2,2,2-Trifluoroethyl) -3J-dihydro-1H-purine-2,6-dione, 2,2 '- (8-chloro-2,6-dioxo-6,7-dihydro- 1 H-purine-1, 3 (2H) -diyl) diacetonitrile, 8-Chloro-1-methyl-3- (4,4,4-trifluorobutyl) -3J-dihydro-1 H-purine-2,6-dione , 8-Chloro-3- (2-cyclohexylethyl) -3J-dihydro-1 / - / - purine-2,6-dione, 1,3-Dibutii-2,6-dioxo-2,3,6J-tetrahydro- 1 r -purine-8-carbonitrile, 1,3-dibutyl-8-iodo-3J-dihydro-1 / - / - purine-2,6-dione, d-Chloro-3- (4-methylpentyl) -3J- dihydro-1 H-purine-2,6-dione, d-Chlorine -S-Ie-methylheptyl-SJ-dihydro-l r -purine ^.? - dione, d-Chloro-3-octyl-3J-dihydro-1 H-purine-2,6-dione, d-Chloro-S -decyl-SJ-dihydro-I H-purine ^^ -dione, 8-Chloro-3- (cyclohexylmethyl) -3J-dihydro-1 r7-purine-2,6-dione, (+/-) - d-Chlorine -3- (3-methylpentyl) -3J-dihydro-1 r / -purine-2,6-dione, d-Chloro-3- (2-cyclopentylethyl) -3J-dihydro-1H-purine-2,6- dione, d-Chloro-3- (cyclopropylmethyl) -3J-dihydro-1 f -purine-2,6-dione, (+/-) - d-Chloro-3- (2-methylbutyl) -3J-dihydro-1H -purine-2,6-dione, (+/-) - 8-Chloro-3- (2-methylpentyl) -3J-dihydro-1 H-purine-2,6-dione, d-Chloro-3- (cyclobutylmethyl) ) -3J-dihydro-1 / - -purine-2,6-dione, d-Chloro-3- (cyclopentylmethyl) -3J-d -hydro-1 H-purine-2,6-dione, d-Chloro-3 - (3-cyclopropylpropyl) -3J-dihydro-1 / - / - purine-2,6-dione, d-Chloro-3- (2-cyclobutylethyl) -3J-dihydro-1 - / - purine-2,6- dione, d-Chloro-3- (4-fluorobutyl) -3J-dihydro-1 r / -purine-2,6-dione, d-Chloro-3- (3-fluoropropyl) -3J-dihydro-1r -purine- 2,6-dione, d-Chloro-3- (5-fluoropentyl) -3J-dihydro-1-purine-2,6-dione, 4- (d-Chloro-1-methyl- 2, 6-dioxo-1, 2,6J-tetrahydro-3 / - / - purin-3-yl) butanonitrile, 3- (3-Buten-1-yl) -d-chloro-3J-dihydro-1 H- purine-2,6-dione, 6- (d-Chloro-2,6-dioxo-1, 2,6J-tetrahydro-3H-purin-3-yl) -2,2-dimethylhexanonitrile, 8-Chloro-3 - (6-fluorohexyl) -3J-dihydro-1 r / -purine-2,6-dione, and d-chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6- diona It will be understood that this aspect of the present invention includes any combination of particular embodiments and encompasses all combinations of particular substituents described herein above for the compounds of Formula (II). In addition, the present invention provides the use of a compound of formula (I) or a physiologically functional derivative thereof, in the manufacture of a medicament for the treatment of inflammatory diseases or conditions of the joints, particularly arthritis (e.g., rheumatoid arthritis). , osteoarthritis, joint prosthesis failure), gastrointestinal tract (eg, ulcerative colitis, Crohn's disease and other inflammatory bowel and gastrointestinal diseases), gastritis or inflammation of the mucosa due to an infection, or the enteropathy caused by non-steroidal anti-inflammatory drugs), of the lung (for example, respiratory distress syndrome in adults, asthma, cystic fibrosis or chronic obstructive pulmonary disease), heart (e.g., myocarditis), nervous system (e.g., multiple sclerosis), pancreas (e.g., inflammation associated with diabetes mellitus and complications thereof), kidney (e.g., glomerulonephritis), skin ( for example, dermatitis, psoriasis, eczema, urticaria and burn injuries), eyes (eg, glaucoma), as well as transplanted organs (eg, rejection) and multiple organ diseases (eg, systemic lupus erythematosus or sepsis), inflammatory sequelae of viral or bacterial infections, inflammatory conditions associated with atherosclerosis and conditions that appear after situations of hypoxia or is Quemia (with or without reperfusion), for example in the brain or in ischemic heart disease. In a further or alternative aspect, a method is provided for the treatment of a human being or an animal with a condition in which the under-activation of the HM74A receptor contributes to the condition or in which activation of the receptor will be beneficial , the method comprising administering to said human or animal an effective amount of a compound of formula (I) or a physiologically acceptable solvate thereof. Again, it will be understood that this aspect of the present invention includes any combination of particular modalities and includes all combinations of particular substituents described above for the compounds of Formula (I). More particularly, the present invention provides a method for the treatment of disorders of lipid metabolism including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia and mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia, diabetes mellitus of type II, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa and obesity, said method comprising administering to said human or animal an effective amount of a compound of formula (I) or a physiologically acceptable salt or solvate thereof. As such, these compounds may also find utility in methods for the treatment of coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease and stroke, said methods comprising administering to said human or animal an effective amount of a compound of formula (I). The amount of HM74A modulator that is required to achieve the desired biological effect, of course, will depend on several factors, for example, the mode of administration and the precise clinical status of the recipient. In general, the daily dose will be in the range of 0.1 mg to 1 g / kg, typically 0.1 to 100 mg / kg. An intravenous dose may be, for example, in the range of 0.01 mg to 0.1 g / kg, typically 0.01 mg to 10 mg / kg, which may conveniently be administered as an infusion, or 0.1 μg to 1 mg per minute. Infusion fluids suitable for this purpose may contain, for example, 0.01 μg to 0.1 mg per milliliter. Unit doses may contain, for example, 0.01 μg to 1 g of an HM74A modulator. In this way, the ampoules for injection may contain, for example, from 0.01 μg to 0.1 g and orally administrable single dose formulations, such as tablets or capsules, may contain, for example, 0.1 mg to 1 g. No toxicological effects are indicated / expected when a compound of the invention is administered in the aforementioned dosage range. A compound of the present invention can be used as a compound per se in the treatment of a disease in which an under-activation of the HM74A receptor contributes to the disease or in which activation of the receptor will be beneficial, being an example of this when a compound of the present invention is presented with an acceptable vehicle in the form of a pharmaceutical formulation. The vehicle, of course, must be acceptable in the sense of being compatible with the other ingredients of the formulation and must not be detrimental to the recipient. The vehicle can be a solid or a liquid, or both, and can be formulated with the HM74A modulator as a single-dose formulation, eg, a tablet, which can contain from 0.05% to 95% by weight of the HM74A modulator.

Formulations include those suitable for oral, rectal, topical, buccal (e.g., sublingual) and parenteral (e.g., subcutaneous, intramuscular, intradermal or intravenous) administration. In accordance with the invention there is also provided a process for the preparation of such a pharmaceutical composition comprising mixing the ingredients. Formulations suitable for oral administration may be presented in discrete units such as capsules, stamps, dragees or tablets, each containing a predetermined amount of an HM74A modulator; in the form of powder or granules; as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil in water or water in oil emulsion. In general, the formulations are prepared by uniformly and intimately mixing the active modulator of HM74A with a liquid or finely divided solid carrier, or both, and then, if necessary, shaping the product. For example, a tablet may be prepared by compressing or molding a powder or granules of the HM74A modulator optionally with one or more auxiliary ingredients. Compression tablets can be prepared by compressing, in a suitable machine, the compound in a fluid form, such as a powder or granules, 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 powder compound moistened with an inert liquid diluent.

The tablets and capsules for oral administration may contain conventional excipients such as binding agents, for example syrup, gum arabic, gelatin, sorbitol, tragacanth, starch mucilage or polyvinyl pyrrolidone; fillers, for example, lactose, microcrystalline cellulose, sugar, corn starch, calcium phosphate or sorbitol; lubricants, for example, magnesium stearate, stearic acid, talc, polyethylene glycol or silica; disintegrants, for example, potato starch, croscarmellose sodium or sodium starch glycolate; or wetting agents such as sodium lauryl sulfate. The tablets can be coated according to methods well known in the art. Oral liquid preparations may be in the form of, for example, aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be presented as a dry product to be reconstituted with water or other suitable vehicle before use. Such liquid preparations may contain conventional additives such as suspending agents, for example, sorbitol syrup, methylcellulose, glucose / sugar syrup, gelatin, hydroxymethyl cellulose, carboxymethyl cellulose, aluminum stearate gel or hydrogenated edible fats; emulsifying agents, for example, lecithin, sorbitan monooleate or gum arabic; non-aqueous vehicles (which may include edible oils), for example almond oil, fractionated coconut oil, oily esters, propylene glycol or ethyl alcohol; or preservatives, for example, methyl or propyl p.-hydroxybenzoates or sorbic acid. The preparations may also contain pH regulating salts, flavoring agents, colorants and / or sweeteners (e.g., mannitol) as appropriate. Formulations suitable for buccal (sublingual) administration include dragees comprising a modulator of HM74A in a flavored base, usually sucrose and gum arabic or tragacanth, and lozenges comprising the modulator of HM74A in an inert base such as gelatin and glycerin or sucrose and gum arabic. Formulations of the present invention suitable for parenteral administration conveniently comprise sterile aqueous preparations of an HM74A modulator. The formulation can be isotonic with the blood of the recipient for which it is intended. These preparations could be administered intravenously, although administration can also be done by means of subcutaneous injection., intramuscular or intradermal. Such preparations can conveniently be prepared by mixing the HM74A modulator with water and making the resulting solution sterile and isotonic with the blood. Injectable compositions according to the invention will generally contain from 0.1 to 5% w / w of the HM74A modulator. Thus, formulations of the present invention suitable for parenteral administration comprising a compound according to the invention can be formulated for parenteral administration by bolus injection or continuous infusion and can be presented in unit dosage form, for example, as ampoules, vials, small-volume infusions or pre-filled syringes, or in multi-dose containers with an added preservative. The compositions may take such forms as solutions, suspensions or emulsions in aqueous or non-aqueous vehicles, and may contain formulatory agents such as antioxidants, pH regulators, antimicrobial agents and / or toxicity adjusting agents. Alternatively, the active ingredient may be in powder form to be reconstituted with a suitable vehicle, eg, sterile, pyrogen-free water, before use. The dry solid presentation can be prepared by introducing a sterile powder aseptically in individual sterile containers or by aseptically introducing a sterile solution into each container and lyophilizing. Formulations suitable for rectal administration may be presented as unit dose suppositories. These can be prepared by mixing an HM74A modulator with one or more conventional solid carriers, for example, cocoa butter or glycerides, and then molding the resulting mixture. Formulations suitable for topical application to the skin may take the form of an ointment, cream, lotion, paste, gel, spray, aerosol or oil. Vehicles that can be used include petrolatum, lanolin, polyethylene glycols, alcohols, and combinations of two or more thereof. The HM74A modulator is generally present at a concentration of 0.1 to 15% w / w of the composition, for example 0.5 to 2%. In the term "topical administration", as used herein, administration by insufflation and inhalation is included. Examples of various types of preparation for topical administration include ointments, creams, lotions, powders, vaginal suppositories, sprays, aerosols, capsules or cartridges for use in an inhaler or insufflator, or drops (e.g., eye or nasal drops). The ointments and creams can be formulated, for example, with an aqueous or oily base with the addition of suitable thickeners and / or gelling agents and / or solvents. Such bases may include, for example, water and / or an oil such as liquid paraffin or a vegetable oil such as arachis oil or castor oil, or a solvent such as polyethylene glycol. Thickening agents that can be used include soft paraffin, aluminum stearate, cetostearyl alcohol, polyethylene glycols, microcrystalline wax and beeswax. The lotions may be formulated with an aqueous or oily base and will generally also contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents or thickening agents. Powders can be formed for external application with the aid of any suitable powder base, for example, talc, lactose or starch. Drops may be formulated with an aqueous or non-aqueous base also comprising one or more dispersing agents, solubilizing agents or suspending agents. Spray compositions can be formulated, for example, as aqueous solutions or suspensions or as aerosols supplied from pressurized containers, with the use of a suitable propellant, for example dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, 1, 1, 2,3,3 , 3-heptafluoropropane, 1, 1, 1, 2-tetrafluoroethane, carbon dioxide or other suitable gas. Capsules and cartridges for use in an inhaler or insufflator of, for example, gelatin, can be formulated so as to contain a powder mixture of a compound of the invention and a suitable powder base such as lactose or starch. The pharmaceutical compositions according to the invention can also be used in combination with other therapeutic agents, for example in combination with other classes of dyslipidemic drugs (for example, statins, fibrates, bile acid binding resins or nicotinic acid). The compounds of the present invention can be used in combination with one or more other therapeutic agents, for example, in combination with other classes of dyslipidemic drugs, for example, inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (statins) , fibrates, bile acid binding resins or nicotinic acid. Thus, in a further aspect, the invention provides the use of such a combination in the treatment of diseases in which an under-activation of the HM74A receptor contributes to the disease or in which the activation of the receptor will be beneficial, and the use of a compound of formula (I) or (II) or a pharmaceutically acceptable salt, solvate or physiologically functional derivative thereof in the manufacture of a medicament for the combination therapy of disorders of lipid metabolism, including dyslipidemia or hyperlipoproteinemia, such as diabetic dyslipidemia and mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa or obesity. When the compounds of the present invention are used in combination with other therapeutic agents, the compounds may be administered sequentially or simultaneously by any convenient route. The combinations mentioned above can conveniently be presented for use in the form of a pharmaceutical formulation and, thus, constitute a further aspect of the invention pharmaceutical formulations comprising a combination as defined above optimally together with a pharmaceutically available carrier or excipient. acceptable. The individual components of such combinations can be administered sequentially or simultaneously in separate or combined pharmaceutical formulations. When combined in the same formulation, it will be appreciated that the two components should be stable and compatible with each other and with the other components of the formulation and can be formulated for administration. When formulated separately, they can be provided in any convenient formulation, conveniently in the manner known to such compounds in the art. When it is a combination with a second therapeutic agent active against the same disease, the dose of each component may differ from that used when the compound is used alone.

The appropriate doses will be readily appreciated by those skilled in the art. Thus, in another aspect, the invention provides a combination comprising a compound of formula (I) or (II) or a physiologically acceptable salt or solvate thereof together with another therapeutically active agent. The aforementioned combination can conveniently be presented for use in the form of a pharmaceutical formulation and, thus, pharmaceutical formulations comprising a combination as defined above together with a pharmaceutically acceptable carrier represent another aspect of the invention. The compounds of the present invention have a useful duration of action. The compounds of the present invention and their salts and solvates can be prepared by the methodology described below, constituting a further aspect of this invention.

Process A: A process according to the invention for preparing a compound of formula (I) or formula (11) in which R1 is H or is the same as R2 and R3 is Cl, comprises: i) Alkylation of guanine with allyl bromide ii) Diazotization with sodium nitrite followed by hydrolysis to form xanthine iii) Chlorination iv) Alkylation in N3 and / or dialkylation in N1 and N3 v) Removal of the palladium catalyst from the allyl group Method B: A process according to the invention for preparing a compound of formula (I) or of formula (II) in which R3 is CN comprises steps (i) and (ii) of Process A followed by: i ?? L *? CS kX ??? ^. - s-s!, _? X = * "- -r R YA; X iii) Alkylation in N3 iv) Alkylation in N1 v) Formation of aldehyde in C8 by lithiation with LiHMDS and inactivated DMF vi) Conversion of aldehyde in nitrile vii) Removal of palladium catalyst from the allyl group Process C: A process according to the invention for preparing a compound of formula (I) or of formula (II) in which R3 is Cl or Br comprises steps (i) to (v) of Process B followed by: f? 3 = C or Br i) Halogenation in C8 using NCS or NBS ii) Removal of the palladium catalyst from the allyl group Process D: A process according to the invention for preparing a compound of formula (I) or of formula (II) in which R3 is CN , comprises steps (i) to (iv) of Procedure B followed by: A "-" xX-i .o nA '' -ji * A fi ss. " to" v) Ester formation vi) Hydrolysis of the methyl ester vii) Conversion of the acid into the amide viii) Conversion of the amide into the nitrile ix) Removal of the palladium catalyst from the allyl group Process E: A process according to the invention for preparing a compound of formula (I) or of formula (II) in which R3 is Cl, comprises: J ftítoay i H.:J0 Psí "M. m * .: i) Alkylation in N3 ii) Alkylation in N1 iii) Debhenylation iv) Chlorination in C3 Process F: A process according to the invention for preparing a compound of formula (I) or of formula (II), in which R1 is different of R2 and R3 is Cl, comprises steps (i) to (iv) of Procedure A followed by: v) Alkylation in N1 vi) Removal of the palladium catalyst from the allyl group Process G: A process according to the invention for preparing a compound of formula (I) or of formula (II) in which R1 is different from R2 and R3 is Cl, comprises steps (i) to (v) of the Process F (where R2 of process F is specifically SEM or MEM) followed by: vi) Cleavage of the MEM or SEM protecting group vii) Alkylation at N3 followed by removal of the palladium catalyst from the allyl group Process H: A process according to the invention for preparing a compound of the formula (I) or of the formula (II) ), wherein R3 is Cl, Br, I or F, comprises steps (i) to (iv) of Process B followed by: v) Removal of the palladium catalyst from the allyl group vi) Halogenation at C8 using NCS, NBS or NIS Process I: A process according to the invention for preparing a compound of formula (I) or formula (II) in which R1 is H or alkyl, R2 is alkyl and R3 is C !, comprises: ) Formation of pyrimidinedione ii) Nitrosation ii) Reduction using Na2S2O4 or a similar reducing agent iv) Formation of xanthine v) Alkylation in N1 (optional) vi) Halogenation in Cd using NCS When desired or necessary, as a final phase in either of the above synthetic procedures, a resulting compound of formula (I) or (II) can be converted into a physiologically tolerable salt form or vice versa, or a salt form converted to another physiologically acceptable salt form. abbreviations THF Tetrahydrofuran Ac Acetyl DCM Dichloromethane DMEM Eagle Medium Modified Dulbecco HEPES 4- (2-Hydroxyethyl) piperazine-1-ethanesulfonic acid DMSO Dimethylsulfoxide NBS N-bromosuccinimide NCS N-chlorosuccinimide NIS N-iodosuccinimide DMF Dimethylformamide LiHMDS lithium hexamethyldisilamide DBAD dibenzyl azodicarboxylate DIPEAdiisopropylethylamine PyBOP benzotriazol-1- hexafluorophosphate yloxytripyrrolidinophosphonium MEM Metoxietiloximetilo SEM 2- (trimethylsilyl) etox¡metilo TFA Trifluoroacetic acid TA Ambient temperature? Heat The following non-limiting examples illustrate the invention: SYNTHETIC EXAMPLES EXAMPLE 1 8-Chloro-3- (4-penten-1-yl) -3,7-dihydro-1 H-purine-2,6-dione a) 2-Amino-7- (2-propen-1 -yl) -1 J-dihydro-1 / - / - purin-6-one A mixture of guanosine (20 g, 0.071 moles), allyl bromide (14 J ml, 0.169 mmoles) and anhydrous DMSO (100 ml) was stirred at room temperature under a nitrogen atmosphere for 1 d hours. Concentrated HCl (50 ml, 37%) was added in one portion, the mixture was stirred for 45 minutes and then poured into MeOH (600 ml). The methanolic solution was neutralized with a solution of 2 M NaOH (aq.) And the resulting white precipitate was collected by filtration. The white solid was dried under vacuum at 50 ° C for 18 hours to yield the title compound (16 g, crude, 19%). m / z 192.2 [MH b) 7- (2-Propen-1 -yl) -3J-dihydro-1 H-purine-2,6-dione A mixture of 2-amino-7- (2-propen-1-yl) -1,7-dihydro-6 / - / - purin-6-one (40 g, 0.209 mol) in AcOH (900 ml) and water (100 ml) was heated to 55 ° C. Sodium nitrite (57.74 g, 0.837 mmol) in water (100 ml) was added dropwise. Watch out; toxic fumes. After the addition was completed (approximately 25 minutes), the reaction mixture was allowed to cool to room temperature and then concentrated to about 1/3 of its original volume. Water (500 ml) was added and the resulting precipitate was collected by filtration. The residue was washed with water and then dried at 50 ° C over P2O5 and under vacuum for 2 hours to give the title compound (17.20 g). The aqueous fraction was concentrated and water (100 ml) was added. The resulting solid was filtered again and dried. This gave more compound of the title (2.31 g). Combined product (19.52 g, 49%). m / z 193.2 [MH +]. c) 8-Chloro-7- (2-propen-1-yl) -3J-dihydro-1 H-purine-2,6-dione To a solution of 7- (2-propen-1-yl) -3J-dihydro-1 - / - purine-2,6-dione) (10.562 g, 54J mmoles) in anhydrous DMF (60 ml) was added NCS (8.04 g, 60.2 mmol). The reaction mixture was allowed to stir under a nitrogen atmosphere at 20 ° C for 6 hours. The reaction mixture was concentrated in vacuo to give an amber oil. MeOH was added and left to stand for 18 hours. The resulting residue was filtered and dried under vacuum to give the title compound (7.69 g, 62%). m / z 22J.2 [MH +]. d) 8-Chloro-3- (4-penten-1-in-3J-dihydro-1 r - / - purine-2,6-dione D-chloro-7- (2-propen-1-yl) -3J-dihydro-1 r / -purine-2,6-dione (0.10 g, 0.44 mmol) was dissolved in DMF (1.5 ml) containing sodium carbonate (0.12 g, 0.49 mmole) and 5-bromopentene (0.07 g, 0.49 mmole) and the mixture was stirred for 13 hours. After the alkylation was completed, morpholine (0.5 ml) and tetrakis (triphenylphosphine) palladium (0) (0.08 g, 0.07 mmol) were added and stirring continued for 3.5 h. The reaction was diluted with ethyl acetate (10 ml), washed sequentially with 2N hydrochloric acid (2 x 5 ml) and brine (3 x 5 ml) and the organic extracts were isolated, dried (MgSO4) and concentrated . The crude product was suspended in methanol (2 ml) and purified on an aminopropyl SPE cartridge (5 g) eluting first with methanol and then with 5% acetic acid in methanol to elute the title compound, which was isolated in form of a white solid after concentration (0.039 g, 35%). NMR; (400 MHz, d6-DMSO) 1.75 (m, 2H), 2.05 (m, 2H), 3.85 (t, 2H, J = 7 Hz), 4.95 (m, 1 H), 5.05 (m, 1 H), 5.d (m, 1 H), 11.1 (sa, 1 H), no interchangeable proton was observed at dH 13; m / z 255 [MH +].

EXAMPLE 2 8-Chloro-3 ° hexyN3J ° dihydro ° 1 H ° purin3-2,6 ° dione Prepared in a similar manner to Example 1, using hexyl iodide to produce the title compound. NMR; dH (400 MHz, d6-DMSO) 0.65 (t, 3H, J = 7 Hz), 1.25 (ss, 6H), 1.6 (m, 2H), 3.65 (t, 2H, J = 8 Hz), 11.2 (s) , 1 H), no interchangeable proton was observed at dH 13; m / z 271 [MH +].

EXAMPLES 3 and 4 (8-Chloro-2,6-dioxo-1.2.6J-tetrahydro-3H-purin-3-yl) acetonitrile and 2.2 '- (8-chloro-2,6-dioxo-6,7-dihydro-1H-purine -1.3 (2H) -diyl) diacetonitrile a) [8-Chloro-2,6-dioxo-7- (2-propen-1-in-1,2,6,7-tetrahydro-3 H -purin-3-inacetonitrile v 2,2'-rd-chloro-2,6 -dioxo-7- (2-propen-1 -D-6J- dihydro-1 rV-purine-1,3 (2H) -diyl-1-diacetonitrile A solution of d-chloro-7- (2-propen-1-yl) -3J-dihydro-1r / -purine-2,6-dione (0.445 g, 2.0 mmol) in DMF (d ml) was treated with carbo sodium acetate (0.1dg, 1.7 mmoles) and bromoacetonitrile (0.1 ml, 1.4 mmoles). The stirred mixture was heated at 70 ° C for 3 hours, then cooled to 50 ° C and treated with more bromoacetonitrile (0.06 ml, O.d mmoles). The mixture was maintained at 50 ° C for a further 2 hours and then cooled to room temperature and evaporated to dryness. The residue was treated with 1 M aqueous hydrochloric acid (20 ml) and extracted with ethyl acetate (2 x 50 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and evaporated. The residue was dissolved in dichloromethane (2 ml) and after 20 minutes, the resulting precipitated solid (d-chloro-7- (2-propen-1-yl) -3J-dihydro-1 r7-purine-2,6- unreacted dione) was removed by filtration and washed with more dichloromethane. The filtrate was concentrated in vacuo and subjected to flash chromatography using ethyl acetate / cyclohexane as eluent in a gradient elution from 1: 3 to 4: 1 to yield the two title compounds: [d-Chloro-2, 6-dioxo-7- (2-propen-1-ii) -1, 2,6J-tetrahydro-3-purin-3-yl] acetonitrile White solid (0.064 g, 16%); m / z 266 [MH +]. 2,2 '- [8-chloro-2,6-dioxo-7- (2-propen-1-yl) -6J-dihydro-1 ry-purine-1,3 (2H) -diyl] diacetonitrile White solid ( 0.195 g, 32%); m / z 305 [MH + j. b) (8-Chloro-2,6-dioxo-1, 2,6J-tetrahydro-3H-purin-3-iPacetonitrile A solution of [8-chloro-2,6-dioxo-7- (2-propen-1-yl) -1, 2,6,7-tetrahydro-3H-purin-3-yl] acetonitrile (0.084 g, 0.32 mmoles) in THF (5 ml) was degassed by the successive application of vacuum and nitrogen pressure to the reaction mixture. Subsequently, the solution was treated with morpholine (0.3 ml, 3.4 mmoles) and tetrakis (triphenylphosphine) palladium (0) (0.03 g, 0.33 mmoles). After 2 hours, the mixture was treated with 2 M aqueous hydrochloric acid (3 ml) and chloroform (5 ml). The mixture was separated and the organic phase was evaporated. The product was purified from the residue using mass-directed HPLC to yield the title compound as a white solid (0.018 g, 25%). NMR dH (400 MHz, d6-DMSO) 4.95 (s, 2H), 11.49 (s, 1 H), 14.63 (br s, 1 H); m / z 226 [MH +]. c) 2,2 '- (8-Chloro-2,6-dioxo-6J-dihydro-1 H-purine-1,3 (2H) -diiPdiacetonitrile The title compound was prepared from 2,2 '- [8-chloro-2,6-dioxo-7- (2-propen-1-yl) -6J-dihydro-1 / -purin-1, 3 (2H) -diyl] acetonitrile using the conditions described for the synthesis of 8- (chloro-2,6-dioxo-1, 2,6J-tetrahydro-3/7-purin-3-yl) acetonitrile to produce the compound of the title in the form of a white solid, 0.06 g (4%); NMR dH (400 MHz, d6-DMSO) 4.88 (s, 2H), 5.06 (s, 2H), NH was not observed at dH 14; m / z 282 [MH +].

EXAMPLE 5 8-C! Gold-3- (3,3,3-trif! Uoropropyl) -3,7-dihydro-1 H-purine-2,6-dione It was prepared in a manner similar to that of 2,6-dioxo-3 using 3-bromo-1,1,1-trifluoropropane as the alkylating agent to produce the title compound.

NMR dH (400 MHz, d6-DMSO) 2.64-2.76 (m, 2H), 4.12 (t, 2H, J 7 Hz), 11.30 (s, 1 H), 14.46 (s a, 1 H); m / z 283 [MH +]. EXAMPLE 6 8-Chloro-3- (2,2,2-trifluoroethyl) -3,7-dihydro-1 H-purine-2,6-dione It was prepared in a similar manner to Example 3 using 2-bromo-1,1,1-trifluoroethane as the alkylating agent and sodium bicarbonate as a base to produce the title compound. NMR dH (400 MHz, d4-MeOD) 4.68 (c, 2H, J = 8.5 Hz); m / z 267.1 [M-H] ".

EXAMPLES 7 and 8 8-Chloro-3- (4,4,4-trifluorobutyl) -3 J-dihydro-1 H-purin3-2,6-dione and 8-chloro-1,3-bis (4,4,4-trifluorobutyl) -3J-dihydro-1H-purine-2,6-dione a) 8-Chloro-7- (2-propen-1-yl) -3- (4,4,4-trifluorobutyD-3J-dihydro-1 H-purine-2,6-dione and 8-chloro-7- (2 -propen-1-yl) -1, 3-bis (4,4,4-trifluorobutyl) -3J-dihydro-1 H-purine-2,6-dione 8-Chloro-7- (2-propen-1-yl) -3,7-dihydro-1R / -purine-2,6-dione (1.5 g, 6.64 mmol), sodium carbonate (644 mg, 7.9 mmoles) and 4-bromo-1,1,1-trifluorobutane (1.39 g, 7.3 mmoles) in dimethylformamide (25 ml., dry) for seven days. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with hydrochloric acid (2N) and brine, dried (MgSO4) and then evaporated to dryness. The crude product was triturated with ether and the solid was collected by filtration to yield d-chloro-7- (2-propen-1-yl) -3- (4,4,4-trifluorobutyl) - 3J- dihydro-1 / - / - purine-2,6-dione as a white solid (1.23 g, 57%). m / z 337 [MH +]. The reduced filtrate was chromatographed on silica, SPE column (20 g). Elution with cyclohexane: ethyl acetate (10: 1 to 2: 1) yielded 3-chloro-7- (2-propen-1-yl) -1, 3-bis (4,4,4-trifluorobutyl) -3J -dihydro-1 H-purine-2,6-dione in the form of a syrup (480 mg, 16%). m / z 447 [MH +]. b) 8-Chloro-3- (4,4,4-trifluorobutyl) -3, J-dihydro-1 H-purine- 8-Chloro-7- (2-propen-1-yl) -3- (4,4,4-trifluorobutyl) -3J-dihydro-1 - / - purine-2,6-dione (64 mg, 0.25 g) was degassed. mmoles) and morpholine (250 μl, 2.5 mmol) with nitrogen in tetrahydrofuran (3 ml), then tetrakis (triphenylphosphine) palladium (0) (29 mg, 0.025 or mmoles) was added and the reaction was stirred at room temperature overnight . The white precipitate was collected by filtration and washed with tetrahydrofuran and ether to yield the morpholine salt of the title compound (59 mg). This was treated with 2 N HCl and methanol and the solvents were evaporated to dryness to produce, before redissolution in DMSO / MeOH and purification by preparative HPLC using a gradient of 10 to 40%, the title compound (11 mg , 14.9%). NMR dH (400 MHz, d4-MeOD) 1.92-2.03 (m, 2H), 2.19-2.33 (m, 2H), 4.06 (t, 2H, J = 7 Hz); m / z 297 [MH +]. c) d-Chloro-1,3-bis (4,4,4-trifluorobutyD-3J-dihydro-1 H-purine-2,6-dione It was degassed d-chloro-7- (2-propen-1-yl) -1, 3-bis (4,4,4-trifluorobutyl) -3J-dihydro-1-purine-2,6-dione (476 mg , 1.1 mmol) and morpholine (397 μl, 11 mmol) with nitrogen in tetrahydrofuran (10 ml) and then tetrakis (triphenylphosphine) palladium (0) (123 mg, 0.11 mmol) was added and the reaction was stirred at room temperature for one night. The reaction mixture was partitioned between dichloromethane and 2 N hydrochloric acid. The organic phase was separated and reduced to give the crude product. This was purified by aminopropyl SPE (5 g) followed by re-crystallization from acetonitrile to yield the title compound (75.5 mg, 16.9%). NMR dH (400 MHz, CDCl 3) 1.96-2.13 (m, 4H), 2.15-2.29 (m, 4H), 4.15-4.23 (m, 4H), 12.94 (s a, 1 H); m / z 407 [MH +].

EXAMPLE 9 8-Chloro-3- (2-cyclopropylethyl) -3,7-dihydro-1 H-purine-2,6-dione a) 8-Chloro-3- (2-cyclopropylethyl) -7- (2-propen-1-yl) -3J- dihydro-1 H-purine-2,6-dione 8-Chloro-7- (2-propen-1-yl) -3J-dihydro-1 H-purine-, 6-dione (1.5 g, 6.64 mmol), sodium carbonate (844 mg, 7.9 mmol) were stirred and 2-cyclopropylethio methanesulfonate (1.19 g, 7.3 mmol) in dimethylformamide (25 ml, dry) for two days at 80 ° C. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was separated and washed with hydrochloric acid (2N) and brine, dried (MgSO4) and then evaporated to dryness. The crude product was triturated with ether and the solid was collected by filtration to yield the title compound as a white solid (0.96 g, 49%). m / z 295 [MH + 1. b) 8-Chloro-3- (2-cyclopropylethyl) -3J-dihydro-1 / - / - purine-2,6-dione 8-Chloro-3- (2-cyclopropylethyl) -7- (2-propen-1-yl) -3J-dihydro-1-purine-2,6-dione (74 mg, 0.25 mmol) and morpholine were degassed. 220 μl, 2.5 mmol) with nitrogen in tetrahydrofuran (3 ml) and then tetrakis (triphenylphosphine) palladium (0) (29 mg, 0.025 mmol) was added and the reaction was stirred at room temperature overnight. The white precipitate was collected by filtration and washed with tetrahydrofuran and ether to yield the morpholine salt of the title compound (52 mg). This was treated with 2N HCl and methanol and the solvents were evaporated to dryness before re-dissolution in DMSO / MeOH and purification by preparative HPLC using a gradient of 10 to 40% to give the title compound (22 mg , 34.6%).

NMR dH (400 MHz, d4-MeOD) 0.00-0.05 (m, 2H), 0.37-0.43 (m, 2H), 0.67-0.77 (m, 1 H), 1.61 (c, 2H, J = 7 Hz), 4.06-4.11 (m, 2H); m / z 255 [MH +].

EXAMPLE 10 3-Butyl-8-chloro-3,7-dihydro-1H-purine-2,6-dione a) 3-Butyl-8-chloro-7- (2-propen-1 -yl) -3,7-dihydro-1-purine-2,6-dione jj O AAcNr To a solution of 3-butyl-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (3.34 g, 13.4 mmol) in anhydrous DMF (19 ml) NCS (1.97 g, 14.d mmoles) was added and allowed to stir at room temperature under a nitrogen atmosphere for 22 hours. The mixture was concentrated in vacuo to give a yellow solid which was filtered and washed with methanol. The filtrate was concentrated and the process repeated. After the final wash, the filtrate was purified with an SPE cartridge (Si, 20 g) eluting with 1: 1 EtOAc: cyclohexane. The combined solids were dried in vacuo to yield the title compound (2.42 g, 64%); m / z 2d3.3 [MH +]. b) 3-Butyl-d-chloro-3J-dihydro-1 r7-purine-2,6-dione H 0XrfX tí A solution of 3-butyl-8-chloro-7- (2-propen-1-yl) - 3J-dihydro-1H-purine-2,6-dione (100 mg, 0.35 mmol) in anhydrous THF (4 mL) and anhydrous DMSO (0.4 mL) was treated with Pd (PPh3) 4 (61 mg, 0.053 mmol). The mixture was degassed under mild vacuum, morpholine (303 μl, 3.5 mmol) was added and allowed to stir at room temperature under a nitrogen atmosphere for 4 hours. The yellow solution was partitioned between 2 M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed through an aminopropyl SPE cartridge (5 g), eluting with MeOH followed by 5% AcOH / MeOH. The product fractions were combined and concentrated in vacuo to yield the title compound as an off-white solid. NMR dH (400 MHz, d6-DMSO) 0.89 (t, 3H, J = 7.5 Hz), 1.23-1.34 (m, 2H), 1.55-1.65 (m, 2H), 3.85 (t, 2H, J = 7 Hz ), 11.17 (s, 1 H), 14.37 (ss, 1 H); m / z 243.3 [MH +].

EXAMPLE 11 8-Chloro-3-propyl-3J-dihydro-1H-purine-2,6-dione 3-Propyl-3J-dihydro-1 / -purine-2,6-dione (J. Med. Chem., 1993, 36 (10), 1360-6) (0.3 g, 1.5 mmol) and N- were dissolved. Chlorosuccinimide (0.21 g, 1.5 mmol) in DMF (5 ml) and the solution was stirred for 5 h. The solution was concentrated and the solid residues were washed with methanol and filtered to provide the product as a white solid (0.146 g, 42%). NMR dH (400 MHz, d6-DMSO) 0.d5 (t, 3H, J = 7 Hz), 1.65 (m, 2H), 3.6 (t, 2H, j = 7 Hz), 11.2 (s, 1H), no interchangeability was observed at dH 13; m / z 229 [MH +].

EXAMPLE 12 8-Chloro-3-pentyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3-pentyl-7- (2-propen-1 -yl) -3J-dihydro-1 H-purine-2,6-dione To a solution of d-chloro-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (100 mg, 0.44 mmol) in anhydrous DMF (3 ml) Sodium carbonate (0.051 g, 0.484 mmol) was added. After 10 minutes of stirring at room temperature, pentyl iodide (0.063 ml, 0.484 mmol) was added and stirring was continued under a nitrogen atmosphere at room temperature for 18 hours. The reaction mixture was diluted with water (25 ml) and extracted with EtOAc (2 x 25 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. Purification by SPE (Si, 5 g) eluting with 4: 1 EtOAc / cyclohexane afforded the title compound as a white solid (96 mg, 74%); m / z 297.2 [MH +]. b) 8-Chloro-3-pentyl-3-J-dihydro-1 / - / - purine-2,6-dione A flask containing tetrakis (triphenylphosphine) -paradium (0) (56 mg, 0.049 mmol) was flushed with nitrogen, before the addition of a solution of d-chloro-3-pentyl-7- (2-propen-1) -yl) -3H ~ dihydro-1H-purine-2,6-dione (96 mg, 0.323 mmol) in anhydrous THF (1.5 ml) followed by DMSO (0.1 ml) and morpholine (0.28 ml, 0.049 mmol) . The resulting mixture was stirred at room temperature under a nitrogen atmosphere for 72 hours. The reaction mixture was dissolved in EtOAc (25 mL) and washed with aq. 2 M (25 ml). The organic extract was dried (MgSO4), filtered and evaporated under reduced pressure. The purification was carried out with an aminopropyl SPE cartridge (2 g) loading and washing with methanol and then eluting the product with 5% acetic acid in methanol. Evaporation of the fractions containing the product afforded the title compound as a white solid (27 mg, 33%). NMR; dH (400 MHz, d6-DMSO) 0.85 (t, 3H, J = 7Hz), 1.20-1.34 (m, 4H), 1.57-1.67 (m, 2H), 3.64 (t, 2H, J = 7Hz) , 11.19 (s, 1 H), 14.36 (ss, 1 H); m / z 257.2 [MH +].

EXAMPLE 13 8-Chloro-3- (3-methylbutyl) -3,7-dihydro-1H-purine-2,6-dione TO ANA a) 8-Chloro-3- (3-methylbutyl) -7- (2-propen-1-yl) -3J-dihydride / -purine-2,6-dione A solution of 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 H-purine-2,6-dione (1.5 g, 6.6 mmol) in DMF (40 ml) was treated with sodium carbonate (0.9 g, 8.5 mmoles) and 1-bromo-3-methyIbutane (1.04 g, 6.9 mmoles). The stirred mixture was heated at 50 ° C for 18 hours and then cooled and evaporated to dryness. The residue was treated with water (60 ml) and extracted with ethyl acetate (3 x 80 ml). The organic fractions were combined, dried over magnesium sulfate, filtered and evaporated. The residue was triturated with a mixture of diethyl ether and cyclohexane to give the product as a white solid which was filtered off and dried. This gave the title compound as a white solid m / z 297 [MH +]. b) 8-Chloro-3- (3-methylbutyl) -3J-dihydro-1H-purine-2,6-dione A solution of 8-chloro-3- (3-methylbutyl) -7- (2-propen-1-yi) -3,7-dihydro-1 ry-purine-2,6-dione (0.074 g, 0.25 mmol) ) in THF (2 ml) was treated with morpholine (0.035 ml, 4.0 mmol) and the mixture was degassed by alternately and repeatedly applying vacuum and nitrogen to the reaction vessel. The mixture was then treated with a solution of tetra-quis (triphenylphosphine) palladium (0) (0.03 g, 0.026 mmol) in degassed THF (0.5 ml). After 2 hours, the mixture was treated with 2 M aqueous hydrochloric acid (2 ml) and diethyl ether (3 ml). The precipitated product was removed by filtration, washed with diethyl ether and dried. This produced the title compound as a white solid (0.036 g, 56%). NMR dH (400 MHz, d6-DMSO); 0.91 (d, 6H, J = 6.3 Hz), 1 .47-1.62 (m, 3H), 3.67 (t, 2H, J = 7.5 Hz), 11.19 (sa, 1 H), 14.33 (sa, 1 H) , m / z 259 [MH +].

EXAMPLE 14 4- (8-Chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purine-3-yl) butanonitrile Prepared as in example 13 using 4-bromobutyronitrile as the alkylating agent. NMR dH (400 MHz, d6-DMSO); 1.69-2.00 (m, 2H), 2.55 (t, 2H, J = 7.0 Hz), 3.95 (t, 2H, J = 6.5 Hz), 11.25 (s a, 1 H), 14.40 (s a, 1 H); m / z 254 [MH4].

EXAMPLE 15 8-Chloro-3- (2-cyclohexylethyl) -3,7-dihydro-1 H-purine-2,6-dione 8-Chloro-7- (2-propen-1-yl) -3-J-dihydro-1 H-purine-2,6-dione (100 mg, 0.442 mmol) was stirred with sodium carbonate (52 mg, 0.486). mmoles) in dry DMF (3 ml) for 30 minutes. Cyclohexylethyl bromide (93 mg, 0.486 mmol) was added and the mixture was stirred at 37-40 ° C under a nitrogen atmosphere for 65 h, followed by heating at 90 ° C for 1 d h. After cooling, the solution was degassed by evacuation and introduction of nitrogen several times and tetrakis (triphenylphosphine) palladium (0) (76 mg, 0.066 mmol) and morpholine (0.385 ml, 4.42 mmol) were added and the mixture was stirred for 18 hours. h. Additional amounts of tetrakis (triphenylphosphine) palladium (0) (50 mg, 0.043 mmol) and morpholine (0.2 ml) were added and stirring was continued for 1 h more. Ethyl acetate and 2 M aqueous HCl (ca. 10 ml each) were added and the organic layer was separated, washed with brine and evaporated. The residue was dissolved in THF and loaded into a 5 g aminopropyl SPE cartridge. The cartridge was washed with THF followed by MeOH and the acid product was eluted with AcOH in MeOH (5% increasing to 10%). The product obtained in this way was further purified by autopreparative HPLC to provide the title compound, 5.5 mg, 3%. NMR dH (400 MHz, d6-DMSO) 0.80-0.95 (m, 2H), 1.05-1.35 (m, 4H), 1.45-1.55 (m, 2H), 1.55-1 JO (m, 3H), 1.70-1.80 (m, 2H), 3.86 (t, 2H, J = 8 Hz), 11.07 (s, 1 H), no interchangeability was observed, m / z 297 (MH +).

EXAMPLE 16 3-Butyl-1-methyl-2,6-dioxo-2.3.6J-tetrahydro-1H-purine-8-carbonitrile a) 3-Butyl-7- (2-propen-1 -yl) -3,7-dihydro-1 / - / - purine-2,6-dione A stirred solution of 7- (2-propen-1-yl) -3J ~ dihydro-1 H-purine-2,6-dione (10 g, 52 mmol) in anhydrous DMF (100 ml) was treated with K2CO3 (7.91). g, 57.2 mmoles) and, after 10 minutes, with Bul (6.51 ml, 57.2 mmoles). After reacting for 2 days, the reaction mixture was partitioned between 2 M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo to give an off white solid. This was washed with hot cyclohexane and dried under vacuum to give the title compound (8.87 g, 68%); m / z 249.3 [MH +]. b) 3-Butyl-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1r / -purine-2,6-dione A stirred solution of 3-butyl-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (1.0 g, 4.03 mmol) in anhydrous DMF (10 ml) was treated with Na2CO3 (470 mg, 4.43 mmol) followed by methyl iodide (275 μL, 4.43 mmol). The mixture was heated at 35 ° C for 17 hours. K2CO3 (500 mg, 3.6 mmol) and methyl iodide (275 μL, 4.43 mmol) were added and then stirred at 50 ° C for 18 hours. The reaction mixture was allowed to cool and then partitioned between 2M HCl (aq) and EtOAc. The organic layer was separated and the aqueous layer was extracted once more with EtOAc. The combined extracts were washed with brine, dried (MgSO4) and concentrated to give a yellow / brown oil (1.24 g). The product was purified by silica SPE (10 g) eluting with EtOAc / cyclohexane mixtures. The product fractions were combined and concentrated to yield the title compound as a pale yellow solid (1.11 g, quant.); m / z 263.3 [MH +]. c) 3-Butyl-1-methyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6,7-tetrahydro-1 rY-purine-8-carbaldehyde A or £ K A pre-dried flask was charged with 3-butyl-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1-r7-purine-2,6-dione (300 mg, 1.14 mmol) and anhydrous THF (6 ml), cooled to -75 ° C under a nitrogen atmosphere and then treated with LiHMDS (1.37 ml of a 1.0 M solution in THF). The resulting solution was allowed to warm to -60 ° C for 1.5 hours before the addition of anhydrous DMF (177 μl., 2.29 mmole). The solution was allowed to warm to -10 ° C for 3 hours and then quenched with a saturated solution of NH 4 Cl (aq). The mixture was partitioned between 1 M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give a brown oil (350 mg). The product was purified by SPE (Si, 10 g) eluting with EtOAc / cyclohexane mixtures to give the title compound as a white solid (131 mg, 39%).; NMR dH (400 MHz, d6-DMSO) 0.91 (t, 3H, J = 7.5 Hz), 1.28-1.39 (m, 2H), 1.63-1.73 (m, 2H), 3.25 (s, 3H), 4.02 (t , 2H, J = 7.5 Hz), 5.03 (dd, 1 H, J = 17 and 1 Hz), 5.17 (dd, 1 H, J = 10 and 1 Hz), 5.31 (d ap., 2H, J = 5.5 Hz), 5.98-6.09 (m, 1 H), 9.99 (s, 1 H). d) 3-Butyl-1-methyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1 H-purine-8-carbonitrile A solution of 3-butyl-1-methyl-2,6-dioxo-7- (2-propen-1 -yl) -2,3,6J-tetrahydro-1r / -purine-9-carbaldehyde in anhydrous pyridine (5) ml) was treated with hydroxylamine hydrochloride (63 mg, 0.91 mmol) and heated at 50 ° C for 1 hour. The mixture was allowed to cool, concentrated and treated with acetic anhydride (5 ml), and then heated at 100 ° C for 2.5 hours and at 125 ° C for 45 minutes. The mixture was allowed to cool again and then partitioned between water and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to yield the title compound as a yellow residue (230 mg, crude, 114%); m / z 288.3 [MH +]. e) 3-Butyl-1-methyl-2,6-dioxo-2,3,6J-tetrahydro-1 / - / - purine-8-carbonitrile A solution of 3-butyl-1-methyl-2,6-dioxo-7- (2-propen-1 -yl) -2,3,6J-tetrahydro-1 H-purine-8-carbonitrile (230 mg, 0.80 mmoles) in anhydrous THF (5 ml) and anhydrous DMSO (0.5 ml) was treated with Pd (PPh3) 4 (185 mg, 0.16 mmol). The mixture was degassed under gentle vacuum, morpholine (698 μl) was added and it was allowed to stir at room temperature under a nitrogen atmosphere for 2 hours. The yellow solution was partitioned between 2 M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed through an amino-propyl SPE cartridge (5 g), eluting with MeOH followed by 5% AcOH and then with mixtures of 10% AcOH, 20% and 5 30% / MeOH. The product fractions were combined and concentrated to yield a pale yellow solid (116 mg). This was washed with MeOH and the title compound, a white solid, was collected by filtration and dried in vacuo (55 mg, 28%). NMR dH (400 MHz, d6-DMSO) 0.90 (t, 3H, J = 7.5 Hz), 1.25-1.35 (m, 2H), 1.59-1.68 (m, 2H), 3.24 (s, 3H), 3.96 (t , 2H, J = 7 or Hz), NH was not observed at dH 15; m / z 248.2 [MH +].

EXAMPLE 17 1-Methyl-2,6-dioxo-3-pentyl-2,3,6J-tetrahydro-1 H-purine-8-carbonitrile a) 3-Pentyl-7- (2-propen-1 -yl) -3J-dihydro-1 H-purine-2,6-dione 7- (2-Propen-1-yl) -3J-dihydro-1-purine-2,6-dione (0.61 g, 3.2 mmol), sodium carbonate (0.60 g, 5.7 mmol) and pentium iodide ( 0.64 g, 3.2 mmol) in DMF (5 ml) at 50 ° C for 18 h. The solution was cooled, separated between ethyl acetate and brine and the organic extracts were isolated, dried (MgSO4) and concentrated. Chromatography on silica (gradient elution of dichloromethane to 5: 1 dichloromethane / ethyl acetate) gave the title compound as a pale yellow solid (0.47 g, 56%). m / z 263 [MH *]. b) 1-Methyl-3-pentyl-7- (2-propen-1-yl) -3J-d-hydroxy-1 / - / - purine-2,6-dione 3-Pentyl-7- (2-propen-1-yl) -3J-d, h -dro-1 r / -purine-2,6-dione (0.20 g, 0J6 mmoles), carbonate was stirred. potassium (0.4 g, 2.9 mmol) and methyl iodide (0.5 ml, 4.9 mmol) and heated at 50 ° C in DMF (5 ml) for 3 hours. The solution was allowed to cool and was separated between ethyl acetate and brine. The organic extracts were isolated, dried (MgSO4) and concentrated to give the title compound (0.21 g, 100%). m / z 277 [MH +]. c) 1-Methyl-2,6-dioxo-3-pentyl-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1 - / - purine-8-carbaldehyde To 1-methyl-3-pentyl-7- (2-propen-1-yl) -3J-dihydro-1 f / -purine-2,6-dione (1.05 g, 3.6 mmol) in THF (15 ml at -78 ° C LiHMDS (4 mL, 1 M in hexane, 4 mmol) was added over 10 minutes and the solution was stirred for 0.5 h. DMF (0.5 ml) was added and the solution was stirred at -78 ° C for 0.5 h and then allowed to warm to room temperature with the cooling bath for 2 h. The reaction was quenched with 2N hydrochloric acid (3 mL) and partitioned between ethyl acetate and brine. The organic extracts were isolated, dried and concentrated. The crude product was chromatographed on silica (gradient elution: dichloromethane to 5: 1 dichloromethane / ethyl acetate) to give the title compound as a white solid (0.35 g, 30%). m / z 305 [MH +]. d) 1-Methyl-2,6-dioxo-3-pentyl-7- (2-propen-1-yl) -2I3,6J-tetrahydro-1 / - purine-8-carbonitrile 1-methyl-2,6-dioxo-3-pentyl-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1H-purine-8-carbaldehyde (0.18 g, 0.6 mmol) was heated hydroxylamine hydrochloride (0.053 g, 0J6 mmol) at 50 ° C in pyridine (5 ml) for 1 hour and then cooled to room temperature. Acetic anhydride (0.08 g, 0.78 mmol) was added and the solution was stirred for 18 h. The solution was concentrated to provide the acetate and dissolved in acetic anhydride (3 ml) and heated at 130 ° C for 3 h, cooled and concentrated to yield the crude product. Chromatography on silica (eluting with dichloromethane) afforded the title compound as a clear oil (0.17 g, 95%). m / z 302 [MH +]. e) 1-methyl-2,6-dioxo-3-pentyl-2,3,6J-tetrahydro-1 H-purine-8-carbonitrile 1-Methyl-2,6-dioxo-3-pentyl-7- (2-propen-1-yl) -2,3! 6J-tetrahydro-1 7'-purine-8-carbonitriio (0.17 g) was dissolved. , 0.56 mmole) and morpholine (0.6 ml, 6J mmoles) in THF (5 ml) containing DMSO (0.5 ml). The flask containing the solution was placed under vacuum and the air was replaced by nitrogen (x3). Tetrakis (triphenylphosphine) palladium (0) (0.13 g, 0.11 mmol) was added and the solution was stirred for 2.5 h. The solution was separated between ethyl acetate (20 ml) and 2N hydrochloric acid (10 ml) and the organic extracts were isolated and washed with brine (3 x 10 ml). Then, the organic extracts were washed with a 2 N sodium hydroxide solution (2 x 10 ml) and the aqueous layer was acidified with 2 N hydrochloric acid and extracted with ethyl acetate (2 x 10 ml). The organic extracts were isolated, dried (MgSO4) and concentrated to yield the title compound (0.026 g, 18%). NMR; dH (400 MHz, CDCl 3) 0.92 (t, 3H, j = 7 Hz), 1.32-1.43 (m, 4H), 1.79 (m, 2H), 3.54 (s, 3H), 4.15 (t, 2H, J = 7.5 Hz), 14.35 (s at, 1 H); m / z 262 [MH +].

EXAMPLE 18 8-Chloro-3-hexyl-1-methyl-3,7-dihydro-1 H-purine-2,6-dione a) 8-Chloro-3- ( { [2- (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1 -yl) -3J-dihydro-1 - / - purine-2 , 6-dione To a solution of 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (6 g, 26.5 mmol) in anhydrous DMF (30 ml) Sodium carbonate (3.09 g, 29.15 mmol) was added. After 10 minutes of stirring at room temperature, methoxyethoxymethyl chloride (3.03 ml, 26.5 mmol) was added and stirring was continued under a nitrogen atmosphere at room temperature for 66 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 ml) and washed with brine (100 ml), the aqueous extract was extracted with DCM (100 ml) and the organic extracts were dried (MgSO4), they were combined and concentrated in vacuo. The residue was triturated with EtOAc and the solid was removed by filtration. Concentration of the filtrate afforded a light brown oil which was absorbed on silica and purified by SPE (Si, 50 g) eluting with a gradient of 1: 1 EtOAc / cyclohexane to EtOAc to yield the title compound as a solid white (2 g, 24%), m / z 315.2 [MH +]. b) 8-Chloro-1-methyl-3- ( { [2- (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1-yl) -3J-dihydro-1 - / -purine-2,6-dione To a solution of 8-chloro-3- ( { [2- (methoxy) ethyl] oxy} methyl) -7- (2-propen-1-yl) -3J-dihydro-1 / - / - Purine-2,6-dione (2 g, 6.37 mmol) in anhydrous DMF (15 ml) was added sodium carbonate (0.743 g, 7 mmol). After 10 minutes of stirring at room temperature, methyl iodide (0.44 ml, 7 mmol) was added and stirring was continued under a nitrogen atmosphere at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 ml) and washed with brine (100 ml). The organic extract was dried (MgSO4), filtered and concentrated to yield the title compound as a brown oil (purity 85%) (2.98 g, quant.), M / z 329.2 [MH +]. c) 8-Chloro-1-methyl-7- (2-propen-1 -yl) -3J-dihydro-1 / - / - purine- 2,6-dione To a solution of 8-chloro-1-methyl-3- ( { [2- (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1-yl) -3, J-dihydro -1 H-purine-2, 6-dione (2.9 g, 6.37 mmol) in dioxane (20 ml) and water (20 ml) was added 5 M HCl (20 ml). The resulting mixture was heated to 100 ° C under a nitrogen atmosphere for 18 hours. Then, the reaction mixture was concentrated in vacuo, the residue was dissolved in EtOAc (100 ml) and washed with water. The organic extract was dried (MgSO4), filtered and evaporated. Purification by SPE (Si, 20 g) eluting with 2: 3 EtOAc / cyclohexane afforded the title compound as a white solid (1.04 g, 68%). m / z 241.1 [MH +]. Alternatively, 8-chloro-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione can be prepared with SEM protection. a) 8-Chloro-7- (2-propen-1 -yl) -3- ( { [2- (trimethylsilyl) ethyl] oxy} methyl) -3J-d-hydroxy-1 / -purine -2,6-diona To a solution of 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (5 g, 22.1 mmol) in DMF (80 ml ) was added 2-2- (trimethylsilyl) ethoxymethyl chloride (4.3 ml, 24.2 mmol) and sodium carbonate (2.6 g, 24.2 mmol). After stirring overnight at room temperature, additional 2-2- (trimethylsilyl) ethoxymethyl chloride (4.3 ml, 24.2 mmol) and sodium carbonate (1.3 g, 12.1 mmol) were added and stirring was continued for 2 hours. The reaction mixture was then partitioned between 5% aq LiCl. and ethyl acetate. The organic extract was separated, washed with brine, dried (MgSO4) and concentrated. Purification by Biotage ™ chromatography using a silica cartridge and eluting with 1: 2-1: 2 ethyl acetate / cyclohexane afforded the title compound (3.14 g, 40%); m / z 374.2 [MNH]. b) 8-Chloro-1-methyl-7- (2-propen-1-yl) -3- ( { [2- (trimethylsilyl) ethyl] oxy} metii) -3J-dihydro-1 t ' -purine-2,6-dione To a solution of 8-chloro-7- (2-propen-1-yl) -3- ( { [2- (trimethylsilyl) eti!] Oxy} methyl) -3J-dihydro-1 H-purine -2,6-dione (3.14 g, 8.82 mmol) in DMF (50 mL) was added methyl iodide (0.659 mL, 10.58 mmol) and cesium carbonate (3.45 g, 10.58 mmol) and the reaction mixture was stirred for one night at room temperature. The reaction mixture was partitioned between water and ethyl acetate. The organic extract was separated, washed with brine, dried (MgSO4) and concentrated to yield the title compound, 2.99 g (92%); m / z 388 [MNH4 +]. c) 8-Chloro-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1 7-purine-2,6-dione To a solution of 8-chloro-1-methyl-7- (2-propen-1-yl) -3- ( { [2- (trimethylsilyl) oxy-methyl-J-dihydro-yl-purine ^ -dione ( 2.99 g, 8.08 mmol) in DCM (20 ml) was added TFA (10 ml) and the reaction was stirred for 2.5 hours at room temperature, then the reaction mixture was concentrated and the residue was treated with more DCM and evaporated once again Purification by SPE (Si) eluting with 1: 9-4: 1 ethyl acetate / cyclohexane yielded an impure product (1.31 g) which was dissolved in methanol (20 ml) and treated with aq. sat (20 ml) After stirring overnight, the mixture was partitioned between water containing 2 M HCl (1 ml) and ethyl acetate.The organic extract was separated, washed with brine, dried (MgSO 4). ) and concentrated to yield the title compound, 0.87% (45%); m / z 241.1 [MH4] d) 8-Chloro-3-hexyl-1-methyl-3J-dihydro-1 r / -purine- 2l6-dona To a solution of 8-chloro-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1H-purine-2,6-dione (100 mg, 0.42 mmol) in anhydrous DMF (3 ml. ) was added sodium carbonate (58 mg, 0.54 mmol) and, after 10 minutes of stirring, hexyl iodide (0.08 mL, 0.54 mmol) was added and the reaction mixture was stirred at room temperature under a nitrogen atmosphere. for 90 hours. Then Pd (PPh3) 4 (73 mg, 0.063 mmol) was added and the reaction vessel was evacuated and washed abundantly with nitrogen (x3), morpholine (0.37 ml, 4.3 mmol) was added and stirring was continued at room temperature. environment in a nitrogen atmosphere for 4 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with aq. 2 M (25 ml). The organic extract was dried (MgSO4), filtered and evaporated. Purification by SPE from aminopropyl (5 g) loading the title compound and washing with MeOH before elution of the product with 5% AcOH / MeOH afforded the title compound as a white solid (65 mg, 54%) . NMR; dH (400 MHz, d6-DMSO) 0.85 (t, 3H, J = 7 Hz), 1.23-1.33 (m, 6H), 1.58-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t, 2H, J = 7.5 Hz), 14.46 (br s, 1 H); m / z 285.3 [MH4].

EXAMPLE 19 8-Chloro-1-methyl-3-propyl-3,7-dihydro-1H-purine-2,6-dione It was prepared in a manner similar to Example 18 but using propyl iodide to be alkylated at N3. NMR; dH (400 MHz, d6-DMSO) 0.87 (t, 3H, J = 7.5 Hz), 1.61-1.73 (m, 2H), 3.22 (s, 3H), 3.89 (t, 2H, J = 7.5 Hz), 14.45 (sa, 1 H), m / z 243 [MH4].

EXAMPLE 20 1.-Dibutyl-2,6-dioxo-2,3,6,7-tetrahydro-1 H-purine-8-carbonitrile a) 1,3-Dibutyl-7- (2-propen-1 -yl) -3,7-dihydro-1 - / - purine-2,6-dione A solution of 1, -di-N-butyl xanthine 810 g, 38 mmol) in anhydrous DMF (80 ml) was treated with K2CO3 (5.2 g, 38 mmol) followed by allyl bromide (3.6 ml, 42 mmol). The mixture was heated to 55 ° C under a nitrogen atmosphere for 18 hours. After cooling to room temperature, the mixture was partitioned between water and EtOAc. A few milliliters of 2 M HCl (aq.) Was added to aid in separation. The organic layer was separated and the aqueous layer was extracted once more with EtOAc. The organic extracts were washed with brine, dried (MgSO4) and concentrated to yield the title compound as an off-white solid (12.23 g, 106%) m / z 305.3 [MH4]. b) 1,3-Dibutyl-2,6-dioxo-7- (2-propen-1 -yl) -2,3,6,7-tetrahydro-1 / - / - purine-8-carboxylate methyl A solution of 1,3-dibutyl-7- (2-propen-1-yl) -3,7-dihydro-1 / - / - purine-2,6-dione (3.0 g, 9.9 mmol) in anhydrous THF (30 ml ) was cooled to -50 ° C and treated with LiHMDS (18 ml of a 1.0 M solution in THF, 17.8 mmol). After 1 hour at -50 ° C methyl chloroformate (1.9 ml, 24.6 mmol) was added and the mixture was allowed to warm to -30 ° C for 2 hours and then quen with a sat. of NH4CI (ac). The mixture was partitioned between EtOAc and 1 M HCl (aa). The organic layer was separated, washed with brine, dried (MgSO4) and concentrated to give a dark orange oil (4.07 g). The oil was taken up in 15% EtOAc / cyclohexane and passed through a Si Biotage ™ chromatographic column. The product fractions were combined and concentrated to yield the title compound as a yellow solid (1.35 g, 38%). m / z 363.2 [MH]. c) 1,3-dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1 H-purine-8-carboxylic acid A stirred solution of 1, 3-dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1 H-purine-8-carboxylic acid methyl ester (1.30 g, 3.6 mmol) in MeOH (15 ml) was treated with LiOH (215 mg) and water (1.5 ml). After 3 hours at room temperature, the mixture was diluted with water and the pH adjusted to approx. pH 5 with HCl (aq.) 2 M. EtOAc was added and then separated, washed with brine, dried (MgSO4) and concentrated to yield the title compound as an 85% pure yellow solid (1.2 g, 88%). m / z 349.2 [MH4]. d) 1,3-Dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6, J- tetrahydro-I H-purine-8-carboxamide A stirred solution of 1,3-dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6,7-tetrahydro-1 / - / - purine ~ 8-carboxylic acid (1.09 g, 2.9 mmol) in anhydrous DMF (10 ml) was treated sequentially with DIPEA (1.1 ml), PyBOP and 2 M NH3 (3.6 ml). After 2 hours, the product mixture was partitioned between 2 M HCl (aq) and EtOAc. The organic layer was separated, washed with a saturated solution of NaHCO3 (aq) and brine, then dried (MgSO4) and concentrated to an orange oil (ca.2 g). The product was purified by Biotage ™ chromatography eluting with mixtures of 5% EtOAc - > 40% / cyclohexane. The appropriate fractions were combined and concentrated to give the pure 90% amide (790 mg, 78%). m / z 392.3 [M + formic acid-H] ". e) 1,3-Dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1H- purine-8-carbonitrile A solution of 1,3-dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1 / -purine-8-carboxamide (300 mg) in DMF Anhydrous (J ml) at 0 ° C was treated dropwise with POCI3 (237 μl). The ice bath was removed and after 2 hours, the mixture was partitioned between water and Et2O. The aqueous layer was extracted again with Et2O and the combined extracts were separated, washed with water (x2) and brine, then dried (MgSO4) and concentrated, giving a yellow oil (312 mg). The oil was taken up in cyclohexane and purified by SPE (Si, 10 g) eluting with EtOAc / cyclohexane mixtures. Concentration of the product fractions gave the title compound as a colorless oil (150 mg, 53%); m / z 330.3 [MH4]. f) 1,3-D-butyl-2,6-dioxo-2,3,6J-tetrahydro-1 W-purine-8-carbonitrile A solution of 1,3-dibutyl-2,6-dioxo-7- (2-propen-1-yl) -2,3,6J-tetrahydro-1 - / - purine-8-carbonitrile (140 mg, 0.43 mmole) in anhydrous THF (4 ml) and anhydrous DMSO (0.4 ml) was treated with Pd (PPh3) 4 (74 mg, 0.064 mmol). The mixture was degassed under gentle vacuum, morpholine (371 μl) was added and allowed to stir at room temperature under a nitrogen atmosphere for 4 hours. The yellow solution was partitioned between 2 M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed through an aminopropyl SPE cartridge (5 g), eluting with MeOH followed by 5% -50% AcOH / MeOH. The product was eluted with a small impurity which was removed by washing with cyclohexane, after concentration, to yield the title compound as an off-white solid (30 mg, 24%). NMR dH (400 MHz, d6-DMSO) 0.89 (td ap., 6H, J = 7 and 3 Hz), 1.25-1.35 (m, 4H), 12.48-1.55 (m, 2H), 1.58-1.69 (m, 2H), 3.87 (t, 2H, j = 7 Hz), 3.95 (t, 2H, J = 7 Hz), NH was not observed at dH 15; m / z 290.3 [MH4].

EXAMPLE 21 1, 3-Dibutyl-8-iodo-3 J-dihydro-1 H-purine-2,6-dione A stirred solution of 1,3-di-N-butyl xanthine 8100 mg, 3.39 mmol) in anhydrous DMF (3 mL) was treated with NIS (94 mg, 3.75 mmol) and allowed to stir at room temperature under an atmosphere of nitroge-no for 23 hours. The mixture was partitioned between a saturated solution of Na2SO3 (aq) and EtOAC. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated in vacuo. The product was purified by passing it through an SPE cartridge (Si, 5 g), eluting with EtOAc / cyclohexane mixtures. The product fraction was concentrated to yield the title compound as a white solid (75 mg, 51%); NMR dH (400 MHz, d6-DMSO) (td ap., 6H, J = 7.5 and 4 Hz), 1.21-1.34 (m, 4H), 1.45-1.54 (m, 2H), 1.56-1.66 (m, 2H ), 3.84 (t, 2H, J = 7.5 Hz), 3.93 (t, 2H, J = 7.5 Hz), 14.10 (s, 1 H); m / z 391.3 [MH4].

EXAMPLE 22 (3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1 H -purin-1-yl) acetonitrile To a mixture of 3-butyl-8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 - / - purine-2,6-dione (200 mg, 0J07 mmol) and Cs2CO3 (254) mg, 0.J78 mmoles) in anhydrous DMF (5 mL) was added chloroacetonitrile (0.054 mL, 0.85 mmol). The mixture was heated at 50 ° C for 18 hours and then allowed to cool to room temperature and degassed under mild vacuum and then nitrogen was introduced. This was repeated twice, Pd (PPh3) 4 (82 mg, 0.071 mmol) was added and the mixture degassed one more time before the addition of morpholine (0.617 ml, 7.07 mmol) and the mixture was allowed to stir for 3 hours. hours at room temperature. The mixture was partitioned between 2 M HCl (aq) and EtOAc. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed through an aminopropyl SPE cartridge (5 g), eluting with MeOH followed by 5-10% AcOH / MeOH. The product fraction was concentrated to give the title compound, 52 mg (26%). NMR dH (400 MHz, d6-DMSO) 0.90 (t, 3H), 1.26-1.37 (m, 2H), 1.60-1.69 (m, 2H), 3.94 (t, 2H, J = 7.5 Hz), 4.87 (s, 2H), 14J2 (s at, 1 H); m / z 299.2 [MNH44].

EXAMPLE 23 (8-Chloro-2,6-dioxo-3-propyl-2,3,6,7-tetrahydro-1 H -purin-1-yl) acetonitrile a) 8-Chloro-7- (2-propen-1-yl) -3-propyl-3J-dihydro-1-and-2,6-dione A mixture of 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (1.5 g, 6.6 mmol), 1-iodopropane (1.2 g, 6.9 mmoles) and sodium carbonate (0.9 g, 8.5 mmol) in DMF (40 ml) was heated at 50 ° C for 18 hours. The reaction mixture was concentrated in vacuo and the residue was treated with water (60 ml) and extracted with ethyl acetate (3 x 80 ml). The combined organic extracts were dried (MgSO4), filtered and evaporated. The residue was triturated with ether / cyclohexane, the solid was removed by filtration and dried to yield the title compound (0.82 g, 46%); m / z 269.1 [MH4]. b) 8-Chloro-2,6-dioxo-3-propyl-2,3,6J-tetrahydro-1 H-purin-1-yl) acetonitrile A solution of 6-chloro-7- (2-propen-1-yl) -3-propyl-3J-dihydro-I H-purine ^ .β-dione (0.067 g, 0.25 mmol) in DMF (2 ml) was treated with cesium carbonate (0.082 g, 0.25 mmole) and bromoacetonitrile (0.044 g, 0.37 mmole). The mixture was heated at 80 ° C for 4 hours and then cooled to room temperature. The DMF was removed in vacuo and the residue was treated with THF (2 ml). The solvent was degassed by the successive application of vacuum and nitrogen pressure to the reaction mixture. Then, the mixture was treated with morpholine (0.035 ml, 0.4 mmol) and tetrakis (triphenylphos-fine) palladium (0) (0.03 g, 0.026 mmol). After 2 hours the mixture was treated with 2 M aqueous hydrochloric acid (2 ml) and the product was extracted with chloroform (3 x 5 ml). The organic fractions were combined and evaporated. The residue was subjected to purification by mass-directed HPLC to yield the title compound as a white solid (0.22 g, 33%). NMR dH (400 MHz, d6-DMSO) 0.88 (t, 3H, J = 7.5 Hz), 1.63-1.74 (m, 2H), 3.91 (t, 2H, J = 7.5 Hz), 4.87 (s, 2H), no NH was observed at dH 14; m / z 268 [MH4].

EXAMPLE 24 [8-Chloro-3- (2-cyclopropylethyl) -2,6-dioxo-2,3,6,7-tetrahydro-1 H-purin-1- illacetonitrile Prepared as (8-chloro-2,6-dioxo-3-propyl-2, 3,6,7-tetrahydro-1 / - / - purin-1-yl) acetonitrile (example 23) using 8-chloro-3 - (2-cyclopropylethyl) -7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione. NMR dH (400 MHz, d6-DMSO) -0.06-0.00 (m, 2H), 0.31-0.39 (m, 2H), 0.64-0.74 (m, 1 H), 1.57 (c, 2H, J = 7 Hz) , 4.04 (t, 2H, J = 7 Hz), 4.87 (s, 2H), 14.68 (ss, 1 H); m / z 294 [MH4].

EXAMPLE 25 8-Chloro-1-ethyl-3- (2,2,2-trifluoroethyl) -3,7-dihydro-1 H-purine-2,6-dione a) 8-Chloro-7- (2-propen-1-yl) -3- (2,2,2-trifluoroethyl) -3J-dihydro-1 / - / - purine-2,6-dione A F F To a solution of 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 / t'-purine-2,6-dione (1.5 g, 6.62 mmol) in anhydrous DMF (50 ml) Sodium bicarbonate (0.98 g, 9.25 mmol) was added followed by 1, 1, 1-trifluoro-2-iodoethane (1.20 g, 5 J2 mmol) and the mixture was heated with stirring for 6 h at 50 ° C in an atmosphere of nitrogen. The solution was allowed to cool to room temperature for 10 h and then heated for 48 h at 120 ° C. More 1,1,1-trifluoro-2-iodoethane (0.43 g, 2.05 mmol) was added and the mixture was heated at 120 ° C for a further 3 h. The solvent was removed under reduced pressure and the residue was triturated with DCM and then filtered. The reaction was repeated using 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1H-purine-2,6-dione (3.80 g, 16.8 mmol), sodium bicarbonate (2.45 g, 23.1 mmol) and 1,1,1-trifluoro-2-iodoethane (4. 05 g, 19.3 mmol) in anhydrous DMF (125 mL). The mixture was heated for 16 h at 120 ° C, the solvent was removed under reduced pressure and the residue was triturated with DCM and then filtered. The DCM filtrates of the two modalities were combined, concentrated under reduced pressure and then purified using Biotage ™ chromatography (eluting with cyclohexane / ethyl acetate 1: 1 and then 7: 3) to give the title compound as a white solid (1.6 g, 23%). m / z 309 [MH4]. b) 8-Chloro-1-ethyl-3- (2,2,2-trifluoroethyl) -3J-dihydro-1H-purine-2,6-dione. or QXKXH F f To a solution of 8-chloro-7- (2-propen-1-yl) -3- (2,2,2-trifluoroethyl) -3J-dihydro-1-purine-2,6-dione (0.070 g, 0.23 mmoles) in anhydrous DMF (2 ml) was added cesium carbonate (0.085 g, 0.26 mmole) followed by 1-iodoethane (0.061 g, 0.39 mmole). The mixture was heated for 5 h at 80 ° C and then stirred for 16 h at room temperature under a nitrogen atmosphere. The solvent was removed under reduced pressure using a vacuum centrifuge and the residue was dissolved in anhydrous THF (2.5 ml). To the mixture was added tetrakis palladium (0.030 g, 0.026 mmoles) and morpholine (0.040 g, 0.45 mmoles) and the reaction mixture was degassed using nitrogen and then stirred at room temperature for 72 hours. The mixture was partitioned between chloroform and aq HCl. 2 N and the aqueous layer was extracted again. The organic extracts were combined and evaporated in a stream of nitrogen and then purified using aminopropyl SPE (eluting with acetic acid: methanol: DCM, 1: 2: 2) to give the title compound as a white solid with a purity of > 90% (0.041 g, 60%). NMR dH (400 MHz, d-MeOD) 1 .20 (t, 3H, J = 7 Hz), 4.03 (c, 2H, J = 7 Hz), 4.73 (c, 2H, j = 8.5 Hz), m / z 297 [MH4].

EXAMPLE 26 8-Chloro-1-propyl-3- (2,2,2-trifluoroethyl) -3,7'-dihydro-1 H-purine-2,6-dione It was prepared in a similar manner to Example 35 using propyl iodide to be alkylated at N1. NMR dH (400 MHz, CDCl 3) 0.99 (t, 3H, J = 7.5 Hz), 1.68-1.79 (m, 2H), 4.07 (t, 2H, J = 7.5 Hz), 4.77 (c, 2H, J = 8.5 Hz), NH was not observed at dH 13; m / z 311 [MH4].

EXAMPLE 27 8-Chloro-1- (4,4,4-trifluorobutyl) -3- (2.2.2-trifluoroethyl) -3J-dihydro-1H-purine-2,6-dione It was prepared in a similar manner to EXAMPLE 25 using 1,1,1-trifluorobutane for alkylation in N1. NMR dH (400 MHz, d4-MeOD) 1.83-1.95 (m, 2H), 2.14-2.32 (m, 2H), 4.06 (t, 2H, J = 7 Hz), 4.74 (c, 2H, J = 8.5 Hz ), m / z 377 [MH] ".

EXAMPLE 28 8-Bromo-1-methyl-3-pentyl-3,7-dihydro-1 H-purine-2,6-dione a) 1-Methyl-3-pentyl-3J-dihydro-1 - / - purine-2,6-dione 1-Methyl-3-pentyl-7- (2-propen-1-yl) -3J-dihydro-1-purine-α-dione (0.45 g, 1.63 mmol), phenylsilane (0.25 ml, 2.03 mmol) were dissolved. ) and tetrakis (triphenylphosphine) palladium (0) (0.35 g, 0.3 mmol) in DCM (10 ml) containing acetic acid (6 ml). The air in the flask was replaced by nitrogen by evacuating the flask and then charging with nitrogen (x3) and the reaction mixture was heated at 45 ° C for 4 h. The solution was allowed to cool and was diluted with DCM and then washed with water and then with a saturated solution of sodium bicarbonate. The organic extracts were isolated, dried and concentrated to yield the crude product. Purification by SPE (silica) eluting with ether gave the product, 0.06 g, 16%. m / z 237 [MH4]. b) 8-Bromo-1-methyl-3-pentyl-3J-dihydro-1r7-2,6-dione 1-Methyl-3-pentyl-3J-dihydro-1 - / - purine-2,6-dione was dissolved (0.06 g, 0.25 mmole) in DMF (2 ml) and N-bromosuccinamide (0.045 g, 0.25 mmole) was added. The mixture was stirred for 18 h, concentrated and the crude product was purified by eluting it through an aminopropyl SPE cartridge (5 g) first with methanol and then with 5% acetic acid / methanol to elute the product. The product was further purified by mass directed autoprep to produce the title compound as a white solid (0.01 g, 12%). NMR dH (400 MHz, d6-DMSO) 0.86 (t, 3H, J = 7 Hz), 1.21 -1.35 (m, 4H), 1.59-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t , 2H, J = 7 Hz), 14.39 (s at, 1 H); m / z 315, 317 [MH4].

EXAMPLE 29 8-Chloro-1-methyl-3-pentyl-3,7-dihydro-1 H-purine-2,6-dione X ^ cr a) 8-Chloro-1-methyl-3-pentyl-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione To a solution of 8-chloro-3-pentyl-7- (2-propen-1-yl) -3J-dydro-1r / -purine-2,6-dione (3.9 g, 13.3 mmol) in DMF (35 ml ) cesium carbonate was added and the mixture was stirred for 10 minutes, after which iodomethane (0.91 ml, 14.6 mmol) was added and the mixture was stirred for 18 h. The reaction was partitioned between ethyl acetate and a 2 N HCl solution and the organic extracts were isolated, dried (MgSO4) and concentrated. Chromatography on a silica SPE cartridge eluting with cyclohexane / ethyl acetate (5% -20%) provided the product as an oil, 2.78 g, 68%. m / z 311 [MH4]. b) 8-Chloro-1-methyl-3-pentyl-3-J-dihydro-1 / - / - purine-2,6-dione Tetrakis (triphenylphosphine) palladium (1.0, 0.90 mmol) was placed in a flask which was evacuated and then charged with nitrogen (x3). A solution of 8-chloro-1-methyl-3-pentyl-7- (2-propen-1-yl) -3J-dihydro-1rt, -purin-2,6-dione (2J8 g, 8.96 was added. rnmoles) in 50 ml of THF and the flask was evacuated one more time and nitrogen was introduced. DMSO (4.5 ml) and morpholine (7.8 ml, 89.6 mmol) were added and the solution was stirred for 5 h. The solution was partitioned between ethyl acetate and a 2 N HCl solution and the organic fraction was washed with brine, dried (MgSO4) and concentrated. The crude product was purified with an aminopropyl SPE cartridge eluting first with methanol and then with methanol containing 0-15% acetic acid to provide the title compound as a white solid, 1.12 g, 46%. NMR dH (400 MHz, d6-DMSO) 0.86 (t, 3H, J = 7 Hz), 1.21-1.35 (m, 4H), 1.59-1.68 (m, 2H), 3.22 (s, 3H), 3.91 (t , 2H, J = 7.5 Hz), NH was not observed; m / z 271 [MH4].

EXAMPLE 30 3-Butyl-8-clo? o-1-methyl-3, 7-dihydro-1H-purine-2,6-dione It was prepared in a manner similar to Example 29, using 3-butyl-8-chloro-7- (2-propen-1 -yl) -3,7-dihydro-1 H-purine-2,6-dione as the departure. NMR dH (400 MHz, d6-DMSO) 0.88 (t, 3H, J = 7 Hz), 1.25-1.35 (m, 2H), 1.6-1.66 (m, 2H9, 3.22 (s, 3H), 3.91 ( t, 2H, J = 7.5 Hz), 14.46 (sa, 1 H), m / z 257 [MH +].

EXAMPLE 31 4- (8-Chloro-1-methyl-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl) butantromethyl To a mixture of 8-chloro-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1 H-purine-2,6-dione (70 mg, 0.292 mmol) and Na2CO3 (37 mg , 0.35 mmole) in DMF (3 ml) was added 4-bromobutyronitrile (0.035 ml, 0.35 mmole). The mixture was stirred at room temperature overnight, before degassing under mild vacuum and introducing nitrogen. Pd (PPh3) 4 (50 mg, 0.044 mmol) and morpholine (0.254 ml, 2.92 mmol) were added sequentially. After two hours of stirring at room temperature, more fresh Pd (PPh3) 4 (50 mg, 0.044 mmol) was added and stirring was continued overnight. The reaction mixture was partitioned between ethyl acetate (20 ml) and water (20 ml) by adding a small amount of 2 M HCl to aid in separation. The organic layer was separated, washed with brine, dried (MgSO4) and concentrated. The residue was taken up in MeOH and passed through an aminopropyl SPE cartridge (5 g), eluting with MeOH followed by 3-5% AcOH / MeOH. The product fraction was concentrated to yield the title compound, 39.7 mg (51%); NMR dH (400 MHz, d6-DMSO) 1.91-2.00 (m, 2H), 2.55 (t, 2H, J = 7 Hz), 3.22 (s, 3H), 4.03 (t, 2H, j = 7 Hz) ), 14.49 (ss, 1 H); m / z 268.1 [MH4].

EXAMPLE 32 8-Chloro-1-methyl-3- (4,4,4-trifluorobutyl) -3,7-dihydro-1H-purine-2,6-dione A solution of 8-chloro-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1 H-purine-2,6-dione (0.048 g, 0.2 mmol) in THF (1 ml) it was treated with cesium carbonate (0J8 g, 0.24 mmole) and 4-bromo-1,1,1-trifluorobutane (0.044 g, 0.25 mmole). The mixture was stirred at room temperature for 1 hour and then heated at 50 ° C for 4 hours and then cooled. The mixture was degassed by alternately applying vacuum and nitrogen pressure to the mixture and then treated with morpholine (0.17 ml, 2 mmole) and tetrakis (triphenylphosphine) palladium (0) (0.023 g, 0.02 mmole). After 2 hours, the mixture was carefully treated with 2 M aqueous hydrochloric acid (2 ml) and the product was extracted with chloroform (2 x 4 ml). The combined organic extracts were evaporated and the product was purified by HPLC directed to reverse phase masses to yield the title compound, 6.2 mg (10%); NMR dH (400 MHz, d6-DMSO) 1.84-1.92 (m, 2H), 2.28-2.35 (m, 2H), 3.22 (s, 3H), 3.99-4.03 (m, 2H), 14.31 (sa, 1 H) ); m / z 311.2 [MH4].

EXAMPLE 33 3-Butyl-8-chloro-1-ethyl-3,7-dihydro-1Hpurine-2,6-dione a) 3-Butyl-7- (phenylmethyl) -3J-dihydro-1 / - / - purine-2,6-dione 7-Benzyl-3J-dihydro-1 / t'-purine-2,6-dione (17.14 g, 70.8 mmol) was suspended [Synthetic Communications, 20 (16), 2459-2467, 1990] and potassium carbonate (1.43). g, 82.8 mmol) in DMF (400 ml) at 40 ° C. After stirring for thirty minutes, butyl iodide (8.76 ml, 77.0 mmol) was added and the mixture was stirred at 40 ° C overnight. 50% aqueous acetic acid (6 ml) was added and the solution was concentrated under reduced pressure. The residue was suspended in water (500 ml) and the products were extracted into chloroform. The organic extracts were collected, concentrated and the product was isolated using flash chromatography eluting with 1% methanol in dichloromethane to provide the product (9.49 g, 45%); 1 H NMR (400 MHz, CDCl 3) d 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31- 7.40 (5H, m), 7.56 (1 H, s), 8.21 (1 H, sa); m / z 299 [MH4]. b) 3-Butyl-1-ethyl-7- (phenylmethyl) -3J-dihydro-1 r7-purine-2,6-dione 3-Butyl-7- (phenylmethyl) -3J-dihydro-1 / - / - purine- 2,6-dione (0.429 g, 1.24 mmol) and potassium carbonate (0.256 g, 1.85 mmol) were suspended in DMF ( 8 ml) and iodoethane (0.113 ml, 1.42 mmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness and the residue was partitioned between water and ethyl acetate. The organic layer was washed with water, followed by brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield the title compound; H NMR (400 MHz, CDCl 3) d 0.96 (3H, t), 1.25 (3H, t), 1.36-1.45 (2H, m), 1 J2-1 J6 (2H, m), 4.05-4.13 (4H, m ), 5.50 (2H, s), 7.32-7.40 (5H, m), 7.52 (1 H, s); m / z 327 [MH4]. c) 3-Butyl-1-etl-3J-dihydro-1-r7-purine-2,6-dione 3-Butyl-1-ethyl-7- (phenylmethyl) -3J-dihydro-1 / - / - purine-2,6-dione (0.353 g, 1.08 mmol) was dissolved in acetic acid (30 ml), hydroxide was added of palladium at 20% on carbon (0.238 g) and the mixture was stirred under a nitrogen atmosphere (at 3.515 kg / cm2 (344.73 kPa)) overnight. The catalyst was removed by filtration through Celite® and washed with acetic acid. The filtrate was concentrated under reduced pressure to yield the title compound (0.227 g, 89%); 1 H NMR (400 MHz, CDCl 3) d 0.97 (3H, t), 1.28 (3H, t), 1.38-1.47 (2H, m), 1.74-1.82 (2H, m), 4.12-4.17 (4H , m), 7.80 (1 H, s); m / z 237 [MH4]. d) 3-Butyl-8-chloro-1-ethyl-3,7-d-h-dro-1 H-purine-2,6-dione 3-Butyl-1-ethyl-3,7 ™ dihydro-1 H-purine-2,6-dione (100 mg, 0.42 mmol) and NCS (56 mg, 0.42 mmol) in MeCN (5 ml) were suspended. and heated to 120 ° C with microwave irradiation. The reaction mixture was concentrated under reduced pressure and the title compound was isolated using HPLC. [HPLC conditions used for purification: execution time 23 minutes. Solvents: 0.1% TFA in MeCN and 0.1% TFA in water. MeCN increased from 5% to 95% linearly for 15 minutes. Maintained at 95% for 2 minutes. Then reduced to 5% linearly for 1 minute and equilibrated at 5% for 5 minutes before the next injection]; 1 H NMR (400 MHz, CDCl 3) d 0.97 (3H, t), 1.31 (3H, t), 1.38-1.45 (2H, m), 1.72-1.80 (2H, m), 4.09-4.20 (4H , m), 13.40 (1 H, sa); m / z 271 [MH4].

EXAMPLE 34 8-Chloro-3- (4-methylpentyl) -3J-dihydro-H-purine-2,6-dione From 1-bromo-4-methylpentane (81 mg) Recrystallized from MeOH Yield 34.8 g (29%), NMR, (400 MHz, d6-DMSO) dH 0.83 (d, 6H, J = 8 Hz), 1.12- 1.22 (m, 2H), 1.55 (septuplet, 1 H, J = 8 Hz), 1.58-1.68 (m, 2H), 3.83 (t, 2H, J = 7.5 Hz), 11.20 (s, 1 H); m / z 271 [MH4].

EXAMPLE 35 6- (8-Chloro-2,6-dioxo-1,2,6,7-tetrahydro-3H-purin-3-yl) -2.2- dimethylhexanonitrile From 6-bromo-2,2-dimethylhexanonitrile (100 mg) recrystallized from MeOH. Yield 48.5 mg (35%); NMR, (400 MHz, d6-DMSO) dH 1.27 (s, 6H), 1.35-1.44 (m, 2H), 1.54-1.59 (m, 2H), 1.63-1.72 (m, 2H), 3.88 (t, 2H , J = 7 Hz), 11.24 (s, 1H); m / z 310 [MH4].

EXAMPLE 36 8-Chloro-3- (6-dimethylheptyl) -3,7-dihydro-1 H-purine-2,6-dione From 1-bromo-6-methyleneheptane (95 mg) Recrystallized from MeOH Yield 36 mg (27%), NMR, (400 MHz, d6-DMSO) dH 0.83 (d, 6H, J = 7.5 Hz), 1.10-1.17 (m, 2H), 1.20-1.34 (m, 4H), 1.48 (septuplet, 1 H, J = 7.5 Hz), 1.58-1.68 (m, 2H), 3.84 (t, 2H, J = 8 Hz ), 11.22 (s, 1 H); m / z 299 [MH4].

EXAMPLE 37 8-Cyoro-3-octii-3.7-dihydro-1 H-purine-2,6-dione 8-Chloro-3J-dihydro-1 r -purine-2,6-dione (100 mg, 0. 44 mmol) with sodium carbonate (52 mg, 0.49 mmol) in dry DMF (3 ml) for 20 min., Then 1-iodooctane (118 mg, 0.49 mmol) was added and the mixture was stirred under a nitrogen atmosphere at 40 ° C. ° C for 65 h. After cooling to room temperature, the mixture was degassed thoroughly by the evacuation of the vessel and charging again with nitrogen several times. Tetrakis (triphenylphosphine) palladium (0) (102 mg, 0.09 mmol) was added, the mixture degassed again and then morpholine (0.385 ml, 4.4 mmol) was added and stirring continued for 6.5 hours. 2M HCl and EtOAc were added and the two phase system was filtered. The product was present predominantly in the filtered solid, which was recrystallized from THF-acetonitrile, followed by MeOH, with filtration, to yield the title compound. Yield 48 mg (36%); NMR, (400 MHz, d6-DMSO) dH 0.84 (t, 3H, J = 7 Hz), 1.18-1.30 (m, 10H), 1.57-1.66 (m, 2H), 3.84 (t, 2H, J = 7.5 Hz), 11.22 (s, 1 H); m / z 299 [MH4] EXAMPLE 38 8-Chloro-3-decyl-3,7-dihydro-1H-purine-2,6-dione It was prepared by the 2,6-dioxo 37 method, starting with 1-bromodecane (108 mg). Further purification was performed by recrystallization in MeOH followed by autoprep. directed to masses. Yield 2 mg (1.4%); NMR, (400 MHz, d4-methanol) dH 0.89 (t, 3H, J = 7 Hz), 1.26-1.38 (m, 14H), 1.68-1.76 (m, 2H), 3.97 (t, 2H, J = 7.5 Hz); m / z 327 [MH4].

EXAMPLE 39 8-Chloro-3- (cyclohexylmethyl) -3J-dihydro-1H-purine-2,6-dione It was prepared in a manner similar to Example 37, from (bromomethyl) cyclohexane (87 mg) with the exception that it was further heated to 80 ° C over a period of 18 h. Recrystallized from MeOH. Yield 31 mg (25%); NMR, (400 MHz, d6-DMSO) dH 0.90-1.02 (m, 2H), 1.08-1.20 (m, 3H), 1.53-1.69 (m, 5H), 1.77-1.87 (m, 1 H), 3.70 (d, 2H, J = 7.5 Hz), 11.21 (s, 1 H); m / z 283 [MH4].

GENERAL METHOD FOR EXAMPLES 40-46 To 8-chloro-3J-dihydro-1r / -purine-2,6-dione (100 mg, 0.442 mmol) in dry THF (3 mL) was added alcohol (0.442 mmol). The mixture was stirred at 0 ° C as a solution of dibenzyl azodicarboxylate (280 mg of 94% purity, 0.88 mmol) in dry THF (2 ml) was added dropwise over 5 minutes. After 30 more minutes at 0 ° C, stirring was continued at room temperature for 18 h. The mixture was degassed thoroughly by the evacuation and filling of! container with nitrogen several times, then tetrakis (triphenylphosphine) palladium (0) (102 mg, 0.088 mmol) was added followed by morpholine (0.385 ml, 4.42 mmol) and stirring was continued for 4.5 h. EtOAc and 2 M HCl were added and the mixture was filtered to remove a yellow precipitated solid. The filtrate was separated and the organic phase was concentrated and redissolved in a mixture of THF and MeOH. This solution was passed through an aminopropyl SPE cartridge, eluting with THF-MeOH (1: 1) followed by MeOH and then 5% AcOH in DCM-MeOH (1: 1). The fractions of the product thus obtained were concentrated and recrystallized from MeOH to yield the pure title compound.

EXAMPLE 40: (+/-) - 8-Chloro-3- (3-methylpentyl) -3,7-dihydro-1H-purine-2,6-dione From (+/-) - 3-meti! -1-pentanol, 45 mg. Yield 20.2 mg (17%); NMR; (400 MHz, d6-DMSO) dH 0.83 (t, 3H, J = 7.5 Hz), 0.90 (d, 3H, J = 6.5 Hz), 1.12-1.21 (m, 1 H), 1.30-1.48 (m, 3H ), 1.58-1.68 (m, 1 H), 3.87 (t, 2H, J = 7.5 Hz), 11.21 (s, 1 H); m / z 271 [MH4].

EXAMPLE 41 8-Chloro-3- (2-cyclopentylethyl) -3,7-dihydro-1 H-purine-2,6-dione From 2-cyclopentylethanol, 50 mg. Yield 24.6 mg (20%); NMR; (400 MHz, d6-DMSO) dH 1.04-1.15 (m, 2H), 1.40-1.67 (m, 6H), 1.70-1.82 (m, 3H), 3.86 (t, 2H, J = 7.5 Hz), 11.22 (s, 1 H); m / z 283 [MH4].

EXAMPLE 42 8-Chloro-3- (cyclopropylmethyl) -3J-dihydro-1 H-purine-2,6-dione From cyclopropylmethanol, 32 mg. Yield 22.3 mg (21%); NMR; (400 MHz, d6-DMSO) dH 0.34-0.40 (m, 2H), 0.40-0.48 (m, 2H), 1.17-1.27 (m, 1H), 3.74 (d, 2H, J = 7.5 Hz), 11.23 ( s, 1 H); m / z 241 [MH4].

EXAMPLE 43 (+/-) - 8-Chloro-3- (2-methylbutyl) -3,7-dihydro-1H-purine-2,6-dione From (+/-) - 2-methyl-1-butanol, 39 mg. Yield 12 mg (9.5%); NMR; (400 MHz, d6-DMSO) dH 0.81 (d, 3H, J = 7 Hz), 0.86 (t, 3H, J = 7.5 Hz), 1.06-1.17 (m, 1 H), 1.30-1.41 (m, 1 H), 1.90-2.00 (m, 1 H), 3.68 (dd, 1 H, J - 13.5 and 8 Hz), 3.75 (dd, 1 H, J = 13.5 and 7.5 Hz), 11.22 (s, 1 H); m / z 257 [MH4].

EXAMPLE 44 (+/-) - 8-Chloro-3- (2-methylpentyl) -3J-dihydro-1H-purine-2,6-dione From (+/-) - 2-methyl-1-pentanol, 45 mg. Yield 22.4 mg (19%); NMR; (400 MHz, d6-DMSO) dH 0. 81 (d, 3H, J = 7 Hz), 0.84 (t, 3H, J = 7.5 Hz), 1 .05-1.16 (m, 1 H), 1 .98-2.09 (m, 1 H), 3.67 ( dd, 1 H, J = 13.5 and 8 Hz), 3.74 (dd, 1 H, J = 13.5 and 7 Hz), 11.22 (s, 1 H); m / z 271 [MH4].

EXAMPLE 45 8-Chloro-3- (cyclobutylmethyl) -3,7-dihydro-1H-purine-2,6-dione From cyclobutylmethanol, 38 mg. Yield 30.5 mg (27%); NMR; (400 MHz, d6-DMSO) dH 1.73-1.85 (m, 4H), 1.86-1.97 (m, 2H), 2.66-2.79 (m, 1 H), 3.90 (d, 2H, J = 7.5 Hz), 1 1.22 (s, 1 H); m / z 255 [MH4].

EXAMPLE 46 8-Chloro-3- (cyclopentylmethyl) -3,7-dihydro-1 H-purine-2,6-dione From cyclopentylmethanol, 44 mg. Yield 15 mg (13%); NMR; (400 MHz, d6-DMSO) dH 1.20-1.32 (m, 2H), 1.42-1.54 (m, 2H), 1.54-1.66 (m, 4H), 2.32-2.45 (m, 1 H), 3.79 (d, 2H, J = 8 Hz), 11.22 (s, 1 H), m / z 269 [MH4].

EXAMPLE 47 8-Chloro-3- (3-cyclopropylpropyl) -3J-dihydro-1 H-2,6-dione From 3-cic? Uμ? Uμ ?? -? -μ? Uμap? L (P.J. Wagner, J. Amer. Soc, 1981, 103, 3837-3841). (44 mg). Yield 277 mg (23%); NMR; (400 MHz, d6-DMSO) dH -0.03- + 0.03 (m, 2H), 0.34-0.40 (m, 2H), 0.65-0.75 (m, 1 H), 1.15-1.23 (m, 2H), 1.66-1.76 (m, 2H), 3.87 (t, 2H, J = 7 Hz), 11.15 (s, 1 H); m / z 269 [MH4].

EXAMPLE 48 8-Chloro-3- (2-cyclobutyl-ethyl) -3J-dihydro-1H-purine-2,6-dione From 2-cyclobutylethanol (P. Vergnon, Eur. J. Med. Chem., 1975, 10, 65-71) (44 mg). Yield 21.5 mg (18%); NMR; (400 MHz, d6-DMSO) dH 1.53-1.64 (m, 2H), 1.68-1.85 (m, 4H), 1.92-2.03 (m, 2H), 2.19-2.03 (m, 2H), 2.19-2.30 (m , 1 H), 3.78 (t, 2H, J = 7 Hz), 11.20 (s, 1 H); m / z 269 [MH4].

EXAMPLE 49 8-Chloro-3- (4-fluorobutyl) -3J-dihydro-1H-purine-2,6-dione a) 8-Chloro-3- (4-fluorobutyl) -7- (2-propen-1 -ii) -3J-dihydro-1 / - / - purine-2,6-dione To a solution of 8-chloro-7- (2-propen-1-yl) -3J-dihydro-1 / - -purine-2,6-dione (200 mg, 0.88 mmol, 1 equiv.) In anhydrous DMSO ( 1 ml) in a 1.5 ml microwave flask equipped with a stirrer was added sodium bicarbonate (113 mg, 1.07 mmol, 1.2 equiv.) Followed by 1-bromo-4-fluorobutane (114 μl, 165 mg, 1.06 ml. mmoles, 1.2 equiv.). The bottle was sealed and heated with agitation using a microwave, maintaining the temperature at 120 ° C for 25 minutes with a maximum output power of 300W. The resulting dark brown solution was diluted with methanol (1 ml) and purified by mass-directed autopreparative HPLC to give the title compound as a solid (159 mg, 60%). m / z 301.3 [MH4]. 8-Chloro-3- (4-fluorobutyl) -3J-dihydro-1 H-purine-2,6-dione To a suspension of 8-chloro-3- (4-fluorobutyl) -7- (2-propen-1) -Il) -3,7-dihydro-1 r -purine-2,6-dione (100 mg, 0.33 mmol, 1 equiv.) in anhydrous DCM (2 ml) was added tetrakis palladium (38 mg, 0.033). mmoles, 10% bw), followed by acetic acid (115 μl, 121 mg, 2.01 mmol, 6 equiv.) and phenyl silane (410 μl, 360 mg, 3.33 mmol, 10 equiv.). The resulting light yellow solution was stirred at room temperature for 16 h to give a dark purple solution. The solvent was removed in a stream of nitrogen and the residue was dissolved in a solution of DMSO / methanol (3 ml, 2: 1) with heating. The gelatinous mixture was allowed to cool to room temperature, filtered and then purified by mass directed autopreparative HPLC to give the title compound as a white solid (35 mg, 43%). m / z 261.2 [MH4]; NMR, (400 MHz, MeOD) dH 4.45 (2H, dt, J = 47 and 6 Hz), 4.03 (2H, t, J = 7 Hz), 1.90-1.65 (4H, m). The following compounds were prepared in a similar manner and purified by preparative or mass-directed autopreparative HPLC as appropriate: EXAMPLE 50 8-Chloro-3- (3-fluoropropyl) -3,7-dihydro-1 H-2,6-dione NMR (400 MHz, MeOD) dH 4.51 (2H, dt, J = 47 and 6 Hz), 4.11 (2H, t, J = 7 Hz), 2.18-2.03 (2H, m). m / z 247 [MH4].

EXAMPLE 51 8-Chloro-3- (5-fluoropentyl) -3,7-dihydro-1H-purine-2,6-dione NMR (400 MHz, MeOD) dH 4.41 (2H, dt, J = 48 and 6 Hz), 3.99 (2H, t, J = 8 Hz), 1.84-1.63 (4H, m), 1.52-1.40 (2H, m ). m / z 273.29 [MH "].

EXAMPLE 52 3- (3-Buten-1-yl) -8-chloro-3,7-dihydro-1H-purine-2,6-dione 8-Chloro-3,7-dihydro-1 / t'-purine-2,6-dione (100 mg, 0.44 mmol) was stirred with sodium carbonate (52 mg, 0.49 mmol) in dry DMF (3 mL) for 45 minutes, then 4-bromo-1-butene (66 mg, 0.49 mmol) was added and the mixture was stirred under a nitrogen atmosphere at 40 ° C for 65 h. After cooling to room temperature, the mixture was thoroughly degassed by evacuation and refilling of the vessel with nitrogen several times. Tetrakis (triphenylphosphine) palladium (0) (102 mg, 0.09 mmol) was added, the mixture degassed again and then morpholine (0.385 ml, 4.4 mmol) was added and stirring was continued for 6.5 h. 2M HCl and EtOAc were added and the two phase system was filtered to remove a yellow precipitated solid. The organic phase of the filtrate was separated and evaporated. The residue was dissolved with heating in THF-MeOH (1: 1) and loaded into an aminopropyl SPE cartridge (5 g) which was eluted with THF-MeOH (1: 1) followed by MeOH and then 5% AcOH. % in MeOH-DCM (1: 1). The product fraction was further purified by mass directed autoprep to produce the title compound. Yield 27.5 mg (26%), NMR; (400 MHz, d6-DMSO) dH 2.40 (dt, 2H, J = 7 and 6 Hz), 3.93 (t, 2H, J = 7 Hz), 4.97-5.07 (m, 2H), 5.74-5.85 (m, 1 H), 11.22 (s, 1 H); m / z 241 [MH4].

EXAMPLE 53: 8-Chloro-3- (6-fluorohexyl) -3-dihydro-1 H-purine-2,6-dione NMR; (400 MHz, MeOD) dH 4.40 (2H, dt, 48 and 6 Hz), 3.98 (2H, t, 8 Hz), 1.80-1.60 (4H, m), 1.52-1.35 (4H, m) ,. m / z 287 [MH j \ EXAMPLE 54 8-Chloro-3-ethyl-1-methyl-3,7-dihydro-1H-purine-2,6-dione a) 8-Chloro-3- ( { [2- (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine- 2,6-dione To a solution of 8-chloro-7- (2-propen-1-ii) -3J-dihydro-1 - / - purine-2,6-dione (6 g, 26.5 mmol) in anhydrous DMF (30 ml) was added sodium carbonate (3.09 g, 29.15 mmol). After 10 minutes of stirring at room temperature methoxyethoxymethyl chloride (3.03 ml, 26.5 mmol) was added and stirring was continued under a nitrogen atmosphere at room temperature for 66 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 ml) and washed with brine (100 ml), the aqueous extract was extracted with DCM (100 ml) and the organic extracts were dried (MgSO4), they were combined and concentrated in vacuo. The residue was triturated with EtOAc and the solid was removed by filtration. Concentration of the filtrate afforded a light brown oil which was absorbed on silica and purified by SPE (Si, 50 g) eluting with a gradient of 1: 1 EtOAc / cyclohexane to EtOAc to yield the title compound as a solid white (2 g, 24%), m / z 315.2 [MH4]. b) 8-Chloro-1-methyl-3- ( { [2- (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1-yl) -3J-dihydro-1 / - / -purine-2,6-dione To a solution of 8-chloro-3- ( { [2 ~ (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1-yl) -3J-dihydro-1 / - / - Purine-2,6-dione (2 g, 6.37 mmol) in anhydrous DMF (15 ml) was added sodium carbonate (0.743 g, 7 mmol). After 10 minutes of stirring at room temperature, methyl iodide (0.44 ml, 7 mmol) was added and stirring was continued under a nitrogen atmosphere at room temperature for 18 hours. The reaction mixture was concentrated in vacuo and the residue was dissolved in EtOAc (100 ml) and washed with brine (100 ml). The organic extract was dried (MgSO4), filtered and evaporated to yield the title compound as a brown oil (purity 85%) (2.98 g, quant.), M / z 329.2 [MH4]. c) 8-Chloro-1-methyl-7- (2-propen-1-yl) -3J-dihydro-1 / Apurine-2,6-dione To a solution of 8-chloro-1-methyl-3- ( { [2- (methyloxy) ethyl] oxy} methyl) -7- (2-propen-1-1) -3J-d hydro-1 t'-purine-2,6-dione (2.9 g, 6.37 mmol) in dioxane (20 ml) and water (20 ml) was added aq. 5 M (20 ml). The resulting mixture was heated to 100 ° C under a nitrogen atmosphere for 18 hours. The reaction mixture was then concentrated in vacuo, the residue was dissolved in EtOAc (100 ml) and washed with water. The organic extract was dried (MgSO4), filtered and evaporated. Purification by SPE (Si, 20 g) eluting with 2: 3 EtOAc / cyclohexane afforded the title compound as a white solid (1.04 g, 68%). m / z 241.1 [MH4]. d) 8-Chloro-3-ethyl-1-methyl-3J-dihydro-1H-purine-2,6-dione To a solution of 1-methyl-7- (2-propen-1-yl) -3J-dihydro-1 / - / - purine-2,6-dione (100 mg, 0.42 mmol) in anhydrous DMF (3 ml) Sodium carbonate (58 mg, 0.54 mmol) was added and after 10 minutes of stirring added ethyl iodide (0.043 ml, 0.54 mmol) and the reaction mixture was stirred at room temperature under a nitrogen atmosphere for 90 hours. Then Pd (PPh3) 4 (73 mg, 0.063 mmol) was added and the reaction vessel was evacuated and abundantly washed with nitrogen (x3), morpholine (0.37 ml, 4.3 mmol) was added and stirring was continued at room temperature in room temperature. a nitrogen atmosphere for 4 hours. The reaction mixture was diluted with EtOAc (25 mL) and washed with aq. 2 M (25 ml). The organic extract was dried (MgSO4), filtered and evaporated. Purification by SPE (5 g) loading the title compound and washing with MeOH before eluting the product with 5% AcOH / MeOH afforded the title compound as a white solid (67 mg, 70%). NMR; dH (400 MHz, d6-DMSO) 1.20 (t, 3H, J = 7 Hz), 3.22 (s, 3H), 3.97 (c, 2H, J = 7 Hz), 14.46 (1 H, s a); m / z 227.2 [MH]. "All publications including, but not limited to, the patents and patent applications cited in this specification, are incorporated herein by reference as if it were specifically and individually indicated that each individual publication is incorporated as a reference in this document as if it were presented in detail.

Claims

NOVELTY OF THE INVENTION CLAIMS

1 .- An entity selected from: a compound of Fórmu¬

(I) and a physiologically functional derivative thereof, wherein R is selected from: hydrogen and C alquilo alkyl which may be optionally substituted with one or more groups selected from CN and CF3; R 2 is selected from: unsubstituted C 3 -10 alkyl, C 1 0 -alkyl substituted with one or more groups selected from fluorine and CN, C 5 -alkenyl, unbranched C 4 -alkenyl, and C 1 -alkyl substituted with cycloalkyl; and R3 is selected from halogen and CN; with the provisos that: (1) when R3 represents Cl, and R1 represents ethyl, R2 is other than propyl; (ii) when R3 represents Br, and R1 represents propyl, R2 is other than propyl; (iii) when R3 represents Cl or Br, and R1 represents butyl, R2 is other than butyl; and (iv) when R1 represents alkyl of C, ^, CH2CN or (CH2) 3CF3, R2 is other than branched alkyl. 2. The compound according to claim 1, further characterized in that R is selected from: hydrogen, C1-4 alkyl, CH2CN and (CH2) 3CF3; R2 is selected from: unsubstituted C3.10alkyl, (CH2) 1.5CN, C2.5alkyl with one or more fluorine substitutions, C5alkenyl and C4-4alkyl substituted with cycloalkyl; and R3 is selected from halogen and CN; with the provisos that: (1) when R3 represents Cl, and R represents ethyl, R2 is other than propyl; (ii) when R3 represents Cl or Br, and R1 represents butyl, R2 is other than butyl; and (iii) when R1 represents alkyl of C, 4, CH2CN or (CH2) 3CF3, R2 is other than branched alkyl.

3. The compound according to claim 1 or 2, further characterized in that R1 is selected from: hydrogen and methyl.

4. The compound according to any of the preceding claims, further characterized in that R2 is selected from: n-unsubstituted C4-alkyl, (CH2) 1-3CN, C3.4 alkyl with one or more fluoro and alkenyl substitutions of C5.

5. The compound according to any of the preceding claims, further characterized in that R3 represents halogen.

6. The compound according to any of the preceding claims, further characterized in that R3 is selected from: chlorine and bromine.

7. The compound according to any of the preceding claims, further characterized in that R3 represents chlorine.

8. The compound according to any of the preceding claims for use in human or veterinary medicine.

9. The compound according to any one of claims 1 to 7 for use in the treatment of disorders of lipid metabolism including dyslipidemia and hyperlipoproteinemia and / or inflammatory diseases or conditions.

10. The compound according to any one of claims 1-7 for use in the treatment of diabetic dyslipidemia, mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia, type II diabetes mellitus, diabetes Type I, insulin resistance, hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure, peripheral vascular disease or stroke.

11.- An entity selected from: a compound of Fór¬ and a derivative physiologically works! thereof, wherein: R1 is selected from: hydrogen and C, _4 alkyl which may be optionally substituted with one or more groups selected from CN and CF3; R2 is selected from: unsubstituted C2.10alkyl, C1-10alkyl substituted with one or more groups selected from fluoro and CN, C5alkenyl, unbranched C4alkenyl, and C4.4alkyl substituted with cycloalkyl; and R3 is selected from halogen and CN; for use in the manufacture of a medicament for the treatment of diabetic dyslipidemia, mixed dyslipidemia, heart failure, hypercholesterolemia, cardiovascular disease including atherosclerosis, arteriosclerosis and hypertriglyceridemia, type II diabetes mellitus, type I diabetes, insulin resistance, hyperlipidemia, anorexia nervosa, obesity, coronary artery disease, thrombosis, angina, chronic renal failure or stroke.

12. The use of an entity selected from: a compound of Formula (II) and a physiologically functional derivative thereof, wherein: R1 is selected from: hydrogen and C, alkyl, which may be optionally substituted with one or more groups selected from CN and CF3; R2 is selected from: unsubstituted C2.10alkyl, C1-6alkyl substituted with one or more groups selected from fluorine and CN, C5alkenyl, unbranched C4alkenyl, and C4alkyl substituted with cycloalkyl; and R3 is selected from halogen and CN; for the preparation of a medicament for the treatment of a human or animal subject having a condition in which an under-activation of the HM74A receptor contributes to the condition or in which activation of the receptor will be beneficial.

13. The use claimed in claim 12, wherein the human or animal subject has a disorder of lipid metabolism including dyslipidemia or hyperlipoproteinemia or an inflammatory disease or condition.

14. A pharmaceutical formulation comprising a compound according to any one of claims 1-7 and one or more physiologically acceptable diluents, excipients or vehicles.

15. A combination for co-administration or separate, sequential or simultaneous in separate or combined pharmaceutical formulations, said combination comprising a compound according to any one of claims 1-7 together with another therapeutically active agent.

16. A pharmaceutical formulation comprising: (i) a compound according to any one of claims 1-7; (ii) one or more active ingredients selected from statins, fibrates, bile acid binding resins and nicotinic acid; and (iii) one or more physiologically acceptable diluents, excipients or vehicles.

17. A method for the preparation of a compound according to any one of claims 1-7, wherein R3 is halogen, the method comprising: (i) alkylation in N1 or N3, or dialkylation in N1 and N3 of a N7 protected xanthine; (ii) halogenation at C8; and (iii) deprotection in any order, with the proviso that deprotection is performed after alkylation.