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AU2006331355B2 - Compositions and methods for the inhibition of phospholipase A2 - Google Patents

Compositions and methods for the inhibition of phospholipase A2 Download PDF

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AU2006331355B2
AU2006331355B2 AU2006331355A AU2006331355A AU2006331355B2 AU 2006331355 B2 AU2006331355 B2 AU 2006331355B2 AU 2006331355 A AU2006331355 A AU 2006331355A AU 2006331355 A AU2006331355 A AU 2006331355A AU 2006331355 B2 AU2006331355 B2 AU 2006331355B2
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acid
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Eric Boilard
Gilles Guichard
Gerard Lambeau
Gersande Lena
Pascal Muller
Didier Rognan
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ImmuPharma France SA
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Abstract

The present invention relates to various novel substituted dipeptide derived nitrogen-containing heterocyclic compounds, their pharmaceutically acceptable salt derivatives, and their methods of use.

Description

COMPOSITIONS AND METHODS FOR THE INHIBITION OF PHOSPHOLIPASE A2 Field of the Invention 5 The present invention relates to 7 and 8-membered ring dipeptide-derived nitrogen-containing heterocyclic compounds, and pharmaceutically acceptable salts thereof that are useful for the inhibition of phospholipase A2 (PLA2). In addition, the invention relates to compositions useful for the inhibition of a PLA2 enzyme, treatment or prevention of inflammation or both in a mammal in need 10 thereof. Background of the Invention Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms 15 part of common general knowledge in the field. Phospholipase A2 enzymes (PLA2s) are enzymes that catalyze the hydrolysis of phospholipids to release free fatty acids and lysophospholipids. This catalytic reaction is essential in the production of lipids involved in various physiological and pathophysio logical processes like prostaglandins, leukotrienes, 20 thromboxanes, platelet activation factor, lipoxins or lysophosphatidic acid. PLA2s can be divided into two groups, intracellular enzymes, including the calcium-dependent group IV PLA2s, and the calcium-independent group VI PLA2s; and secreted PLA2s (sPLA2s), which are low molecular weight proteins with a Ca -dependent catalytic activity. To date, 12 mammalian sPLA2s have 25 been identified and classified into 3 main structural collections: group I/II/V/X, III, and XII. Although a significant increase in sPLA2 activity is detected in serum in septic shock, rheumatoid arthritis, acute pancreatitis, multiple injuries, acute chest syndrome in patients with sickle cell disease, and in bronchoalveolar lavage 30 (BAL) of patients with acute respiratory distress syndrome (ARDS), the exact function of sPLA2s in physio-pathological processes is uncertain. It seems that the GIIA is very potent in hydrolyzing Gram positive bacteria membranes and could be involved in the host defense against micro-organisms. Importantly, elevated concentrations of hGIIA are found in the eyes, a privileged immune organ. The GIB is found at high level in pancreas, has an enhanced activity 5 toward its substrate in presence of deoxycholate, a detergent found in bile, and is activated in the intestine by trypsin. A function for GIB in phospholipid digestion was thus suggested. Knocking-out the gene coding for this enzyme could not show its essential role in lipid absorption at first glance, but feeding mice with a high-fat diet demonstrated GIB-knock-out mice were less likely to develop 10 obesity and obesity-related insulin resistance. Exogenous addition of GV and GX to various mammalian cell types leads to the release of arachidonate and eicosanoid generation, even without activation of the cPLA2. In addition, zymosan-treated peritoneal macrophages from GV knock-out mice have reduced prostaglandin E2 (PGE2) and leukotriene C4 15 (LTC4) production. Therefore, GV and GX are likely involved in the generation of eicosanoids under certain conditions. The physiological roles of GIIC, GIIE, GIIF, GIII, GXIIA and GXIIB have not yet been clarified, but some evidence suggests that GXII, even when devoid of any catalytic activity, may be involved in vertebrate neuronal development. 20 Recent evidence suggests that PLA2 proteins not only hydrolyze phospholipids but may also serve as ligands for different binding proteins. The best known sPLA2 binding protein is the M-type receptor (MtR). This receptor was initially cloned as a transmembrane glycoprotein having common characteristics with the macrophage mannose receptor, and the more recently 25 cloned receptors Endo-180 and Dec-205. This receptor has a large extracellular domain containing a N-terminal cysteine-rich domain, a fibronectin-like type I domain, eight C-type lectin like domains (CTLD), a single transmembrane domain and a short cytoplasmic tail. The M-type receptor can also quickly internalize sPLA2s suggesting a role in sPLA2 clearance. The identification of a soluble form 30 of the receptor that can inhibit enzymatic activity upon sPLA2 binding also agrees with this view. Furthermore, results obtained from gene targeting of the receptor and other studies using the pancreatic sPLA2 suggest the M-type receptor acts as a 2 a intracellular signaling molecule through sPLA2 binding, for example, by activating the MAPK cascade, inducing a proinflammatory phenotype, and upregulating the cell surface expression of Fas ligand. Structure-based strategies to discover group IIA specific sPLA2 inhibitors 5 led to the identification of indole analogues that inhibit this sPLA2 with nanomolar affinities. One analogue, LY311727, was able to inhibit the release of thromboxane A2 triggered by exogenously added hGIIA on guinea pig BAL fluids containing macrophages, eosinophils and epithelial cells. LY311727 could also inhibit the sPLA2 activity induced by lipopolysaccharides in a guinea pig 10 model of ARDS. Moreover, intravenous administration of LY311727 in transgenic mice overexpressing hGIIA led to a loss of PLA2 catalytic activity in blood, demonstrating that this inhibitor can be active in vivo, at least in blood circulation, in these animals. In a murine toxoplasmosis experimental model, LY3 11727 injection led to an earlier mortality, suggesting a protective role of at 15 least one sPLA2 sensitive to this inhibitor in these mice. In addition, lumbar intrathecal administration of LY311727 in 3 different experimental rat models of hyperalgesia attenuated all the inflammation-related symptoms observed. An indole-derived inhibitor of second generation, called S 5920/LY315920Na, significantly attenuated lung compliance, pulmonary edema, 20 vascular permeability and lung surfactant degradation in a rabbit acute lung injury model induced by oleic acid. Two other inhibitors of sPLA2, the LY333013 (S 3013) and 5-( 4 -benzyloxyphenyl)-4s-(7-phenylheptanoylamino)-pentanoic acid protected rats from dextran sulfate- and trinitrobenzene sulfonic acid-induced colitis. Oral administration of 5-(4-benzyloxyphenyl)-4s-(7 25 phenylheptanoylamino)-pentanoic acid also preserved rats intestine from injury following ischemia and reperfusion. Ear edema induced by tetracenoylphorbol-13-acetate in mice was reduced by YM-26734, a molecule known to be a potent inhibitor of mGIIA, mGIID, mGIIE, mGV and mGX. This same drug also significantly decreased the 30 accumulation of exudate fluid and leukocytes in a carageenin-induced pleurisy rat model. Despite the promising effects of sPLA2 inhibitors, no significant differences between the PLA2 inhibitor-treated and the placebo groups were 2a found when the S-5920/LY31592ONa was used in a clinical study involving humans with sepsis and organ failure. However, because the GIIA sPLA2 has antibacterial properties, and septic shock is provoked by a microbial invasion, it is arguable whether it makes sense to use a sPLA2 inhibitor as a septic shock 5 therapeutic drug. Recently, a clinical trial using another sPLA2 inhibitor, the orally distributed LY333013, on patients with rheumatoid arthritis led to significant reduction of the pathology during the first week of trial, but the benefits were lost thereafter. In this last report, the authors reported positive impacts on the 10 pathology when administering the inhibitor intravenously. This same inhibitor failed to show any benefit on inhaled allergen challenge in subjects with asthma. It is important to note that the LY333013 was well tolerated in these patients. Thus it appears that the path of administration (e.g., oral, parenteral, enteral, subcutaneous, intravenous, anal, etc...) and the biological system chosen 15 for an inhibitor can affect its efficacy. For example, BMS-1881162, an inhibitor of both GIIA and cPLA2, has a very potent anti-inflammatory activity when used as a topical agent in a mouse model with chronic skin inflammation induced with repeated exposures to phorbol ester. This same inhibitor was without effect in psoriatic patients. The use of labeled BMS-1881162 in volunteers showed almost 20 no discernible penetration of the drug, probably due to the thicker stratum corneum in human compared to mouse. An indole inhibitor called indoxam (IDX) inhibited PGE2 production induced by TGF-a and IL-1 in rat gastric epithelial cells. Me-indoxam (Me-IDX), a derivative of indoxam, is about 20 fold more potent than LY311727 to inhibit 25 hGIIA. This indole analogue is suitable for studies on mammalian cells, and not only it inhibits the enzymatic activity of hGIIA, but also that of other group I/II/V/X sPLA2s. The fact that IDX and its related indole compounds affect various inflammatory signals on mammalian cells and in animal models suggests that at least one sPLA2 from the group I/II/V/X is involved in these processes. 30 Because Me-IDX is known to bind to and to protrude from the catalytic groove of the sPLA2, it could interfere with sPLA2 interaction to molecules other than phospholipids. In fact, it was shown that IDX can block the binding of 2b porcine pancreatic group 113 and group X sPLA2 to the mouse cells expressing the M-type receptor with good efficiency (IC 5 0 = 130nM and 900nM respectively). However, it is not known if this observation can be extrapolated to other sPLA2s in an endogenous context, for example, using sPLA2 and M-type 5 receptor from the mouse. This research is of high importance as some pathophysiological disorders may involve sPLA2 binding to this receptor. Indeed, mice deficient for the M-type receptor are resistant to endotoxic shock and have lower concentrations of circulating IL-1 and TNF-ax after LPS treatment when compared to M-type receptor expressing mice. Nevertheless, the septic shock 10 induced by injection of lipopolysaccharides in wild-type mice can be attenuated by indoxam treatment. Recently we found that not only group IB and group IIA sPLA2s, but also several other mouse sPLA2s from the group I/II/V/X can bind to the M-type receptor initially identified with the snake venom sPLA2 OS2, leading to the hypothesis that one or several sPLA2s may be involved in these processes, 15 and that the effect of indoxam may be due to either inhibition of enzymatic activity or of binding to the M-type receptor. Results obtained with analysis of the direct binding properties of radiolabeled mammalian sPLA2s on cellular membranes in the presence of Me IDX, and evaluation of the inhibitory effects of various other molecules known as 20 inhibitors of sPLA2 strongly indicate that the effects observed with sPLA2 inhibitors in different studies may be not only due to the inhibition of the sPLA2 catalytic activity but also to the modulation of the sPLA2 binding properties to their receptors. As indicated, the ever growing body of research implicates PLA2 function 25 in many important physiological and pathological conditions. As such, the development of PLA2 inhibitors will be critical to both the study and further elucidation of PLA2's functional and pathophysiological roles but also for the development of pharmaceuticals for the treatment of conditions in which PLA2 function is implicated, for example, inflammatory diseases. These data also 30 suggest the importance of the design and development of therapeutics that are capable of discriminating between one of PLA2's functional modes (i.e., inhibition of enzyme activity, and induction of allosteric changes to the ligand of 2c the M-type receptor), and alternatively, developing therapeutics that affect both modes to inhibit all sPLA2s functions. It is an object of the present invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative. 5 Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of "including, but not limited to". Although the invention will be described with reference to specific 10 examples it will be appreciated by those skilled in the art that the invention may be embodied in many other forms. Summary of the Invention According to a first aspect of the present invention there is provided a 15 method for inhibiting the activity of a phospholipase A2 (PLA2) enzyme, said method comprising contacting a PLA2 enzyme with a composition comprising an effective amount of a compound having the general formula B: 0 R5.N kN, RI R4 R2 0R 3 0 (B) wherein R', R 2 , R 3 , R 4 , and R 5 represent, each independent from 20 the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (Cl-C10) alkyl; (Cl-C10) alkenyl; (Cl CIO) alkynyl; (C5-Cl2) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-Cl4) heteroaralkyl; and (Cl-C1O) monocyclic or bicyclic heteroaryl group having up to 5 25 heteroatoms selected from N, 0, S, and P said groups being able to be non substituted or substituted by I to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (Cl-C4)alkyl, amino, piperazine, 2d piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof, or a pharmaceutically acceptable salt thereof, 5 wherein the composition is effective for inhibiting PLA2. According to a second aspect of the present invention there is provided a kit when used for inhibiting the activity of a phospholipase A2 (PLA2) enzyme, said kit comprising a plurality of containers, wherein at least one of said containers contains a composition comprising an effective amount of a compound 10 having the general formula B: 0 R5..N ' N, R1 R4k R2 N
R
3 0 (B) wherein R', R 2 , R 3 , R 4 , and R' represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (Cl-C10) alkyl; (Cl-C10) alkenyl; (Cl 15 CIO) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (Cl-C0) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, 0, S, and P said groups being able to be non substituted or substituted by 1 to 6 substituents further selected from the 20 group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (CI-C4)alkyl, amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any 25 combination thereof, or a pharmaceutically acceptable salt thereof. According to a third aspect of the present invention there is provided use of a compound having the general formula B: 2e 0 R5 N N, R' R4 N R2(B
R
3 0 (BI) wherein R', R 2 , R 3 , R 4 , and R' represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (Cl-C1O) alkyl; (Cl-ClO) alkenyl; (Cl 5 C10) alkynyl; (C5-C 12) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (Cl-CIO) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, 0, S, and P said groups being able to be non substituted or substituted by I to 6 substituents further selected from the 10 group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (Cl-C4)alkyl, amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any 15 combination thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a composition for inhibiting the activity of a phospholipase A2 (PLA2) enzyme. The present invention relates to compounds and methods for synthesizing 20 compounds that are efficacious for the treatment and/or prevention of disease in a mammal, for example a human. In one aspect, the invention relates to novel dipeptide derived heterocyclic compounds synthesized using the methods of the invention. The invention also relates to pharmaceutical compositions comprising effective amounts of said compounds, and to therapeutic methods comprising their 25 administration to a mammal in need thereof. In one of the embodiments of the present invention is a method for synthesizing novel dipeptide derived heterocyclics of the formula I. 2f WO 2007/074169 PCT/EP2006/070256 Z (I) [0010] wherein, W is a member selected from the group consisting of -C(Rs)(Rsa)_ _ C 6) 6a_ 107a_ C(R )(R a)CR(R 7 a)-; -C(R 8
)=C(R
9 )-; -N(R 4), and combinations thereof; [0011] X is a member selected from the group consisting of -N(Ria)C(=Y)N(R 4
)-;
OC(=Y)N(R
4 )-; -N(Ria)C(=Y)O-; -N(Ria)S(=O)N(R 4 )-; -N(Rla)S(=0) 2
N(R
4 )-; C(R a)(R a)C(=Y)N(R 4 )-, and combinations thereof; [0012] Y and Z represent, each independent from the other, a member selected from the group consisting of oxygen ("0") and sulfur ("S"); and 1 la 2 3 3a 4 5 5a 6 6a 7 7a 8 91 [0013] R', Ri, R, R, Ra, R, R, Rs, R, Ra, R, Ra, R', R', and R14 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (Cl-C1O) alkyl; (Cl-C1O) alkenyl; (Cl-C1O) alkynyl; (C5-Cl2) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (Cl-C1O) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, 0, S, and P said groups being able to be non-substituted or substituted by 1 to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (Cl-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof. [0014] In any of the preferred embodiments, the present invention includes the free base or acid forms, as well as salts thereof, of the dipeptide derivatived heterocyclics compounds described by the above formula. The invention also includes the optical isomers, analogs, and derivatives of the compounds described by the above formula. In a further embodiment of the invention, mixtures of enantiomers and/or diastereoisomers, resulting from a single preparative step, combination, or interconversion are encompassed. In yet a further embodiment of the invention, the compounds described by the formula I are included in a pharmaceutically 3 WO 2007/074169 PCT/EP2006/070256 acceptable form, and optionally include at least one other ingredient, for example a suitable carrier, excipient, another pharmaceutically active ingredient or a combination thereof [0015] The invention also provides prodrug forms of the above described analogs and derivatives, wherein the prodrug is metabolized in vivo to produce an analog or derivative as set forth above. Indeed, some of the above described analogs or derivatives may be a prodrug for another analog or derivative. [0016] The term "prodrug" is well understood in the art and includes compounds that are converted to pharmaceutically active compounds of the invention in a mammalian system. For example, see Remington 's Pharmaceutical Sciences, 1980, vol. 16, Mack Publishing Company, Easton, Pa., 61 and 424. [0017] In another aspect of the invention, compositions containing the above described compounds are provided. Preferably, the compositions are formulated to be suitable for pharmaceutical or agricultural use by the inclusion of appropriate carriers or excipients. [0018] In still another aspect of the invention, methods are provided for the administration of a suitable amount of a pharmaceutically acceptable form of the compounds described herein, to a mammal in need thereof, for example a human, for the treatment and/or prevention of a disease. In one of the embodiments, the invention comprises methods for inhibiting a PLA2 enzyme. [0019] In another of the embodiments, the invention comprises methods for the administration of a suitable amount of a pharmaceutically acceptable form of the compounds described herein, to a mammal in need thereof, for the treatment and/or prevention of inflammatory diseases. [0020] Additional advantageous features and functionalities associated with the systems, methods and processes of the present invention will be apparent from the detailed description which follows. Brief Description of the Drawings [0021] Figure 1. Comparison of the 1,3,5-triazepan-2,6-dione scaffold, B, and 2,5 diketopiperazines, A. [0022] Figure 2. a) EtOCOCl, NMM, THF, -20'C, then NaN 3 in H 2 0; b) Toluene, 65'C, then HOSu and pyridine; c) TFA, 30 min; d) DIEA, MeCN; e) PS-DIEA, CH 2 Cl 2 . g = gem, refers to the 2-alkyl gem-diamino-derivative of the corresponding amino-acid according to the 4 nomenclature proposed by Chorev and Goodman. Figure 3. X-ray crystal structures of representative 1,3,5-triazepan-2,6 diones 4, 7 and 9. Figure 4. a) NaH (4 equiv), RX (4 equiv); b) KF/Al 2 0 3 (10 equiv) or NaH (2 equiv), RX (1.5 equiv). Figure 5. Half Maximum Inhibition Curves (IC50) for inhibitor molecules compared to Me-IDX. PLA2 enzymes hGX and hGV compared (Y-axis is percent activity of PLA2; X-axis is concentration of inhibitor); inhibitor molecule number (e.g., "mol 33#") identifies the particular compound used from Table 1. Figure 6. Half Maximum Inhibition Curves (IC50) for inhibitor molecules compared to Me-IDX. PLA2 enzymes hGX and hGV compared (Y-axis is percent activity of PLA2; X-axis is concentration of inhibitor); inhibitor molecule number (e.g., "mol 33#") identifies the particular compound used from Table I. Throughout the specification and claims, including Table I, the following compound numbers are taken to correspond to the following structures: 0 0 N NH N 0 (Mol 4) 0 N NH N / (Mol 5) 4a 0 0 0 0NN 0 (Mol 9) 0 HN NH H N N NH NN 0 0N Nr NH N NH 0 (Mol 34) 4b O OH 0 HO 0 o (Mol 35) 0 0 N N H 0 N 0 (Mol 36) 0 0 (Mol 40) 00 0 4c 0 N NH 0 0N (Mol 45) 0 0 0 (Mol 48) 0 H O HON NH 0 /N (Mol 49) 0 H O HON NH 0 / (Mol 52) 4d 0
H
2 N 0 (Mol 53) 5 TABLE I Structure Mol Formula MoWei ExactMass ClogP IogP 1 C12H15N302 233,2694 233.1164 1.13 0.47 N2 C12H15N302 233,2694 233.1164 1.13 0.47 3 C19H21N302 323,3938 323.1634 3.36 2.44 4 C18H25N304 347,4132 347.1845 3.24 1.11 5 C19H21N302 323,3938 323.1634 3.07 2.48 6 C14H17N302 259,3072 259.1321 1.31 0.78 7 C14H17N302 259,3072 259.1321 1.31 0.78 8 C26H27N302 413,5182 413.2103 5.80 4.41 5a Structure Mol Formula MoiWel ExactMass CogP IogP 9 C24H35N306 461,557 461.2526 10 C40H39N304 625,7658 625.2941 9.17 7.62 11 C14H19N302 261,323 261.1477 1.13 0.03 12 C10H17N302 211,2632 211.1321 1.25 0.08 13 C13H15N302 245,2804 245.1164 1.07 0.50 OA 14 C21H23N303 365,431 365.1739 2.94 2.23 15 C9H17N302 199,2522 199.1321 1.13 0.03 16 C33H33N302 503,6426 503.2573 7.74 6.41 5b Structure Mol Formula MoiWel ExactMass ClogP IogP 17 C21H22N404 394,4292 394.1641 18 C11H19N302 225,29 225.1477 1.36 0.34 H 19 C8H15N302 185,2254 85.1164 0.47 -0.32 NH 20 C15H17N302 271,3182 271.1321 1.46 0.72 21 C14H17N303 275,3066 275.1270 0.34 0.13 22 C20H34N604 422,5264 422.2642 3.37 0.16 23 C6H12N402 172,1864 172.0960 -1.24 -2.44 24 C14H17N304 291,306 291.1219 1.70 -0.03 5c Structure Mol Formula MolWei ExactMass ClogP logP 25 C7H14N402 186,2132 186.1117 -1.65 -2.33 26 C19H25CIN40 408,8839 408.1564 2.58 1.66 4 27 C18H19N302 309,367 309.1477 2.49 1.78 28 C21H21N304 379,4146 379.1532 2.69 1.72 29 C16H17N302 283,3292 283.1321 2.30 1.47 30 C17H20N406 376,3682 376.1383 -0.6 -1.79 31 C13H15N302 245,2804 245.1164 1.28 0.41 32 C11H13N302 219,2426 219.1008 0.85 0.19 5d Structure Mol Formula MolWei ExactMass ClogP logP H 33 C14H25N304 299,3692 299.1845 2.58 0.32 34 C15H21N302 275,3498 275.1634 2.69 1.65 35 C16H19N306 349,3426 349.1274 2.63 -0.52 36 C20H27N304 373,451 373.2002 3.42 1.42 37 C26H37N306 487,5948 487.2682 5.88 2.06 38 C21H23N302 349,4316 349.1790 3.54 2.75 09 39 C28H29N302 439,556 439.2260 5.98 4.72 40 C22H27N304 397,473 397.2002 4.41 2.11 5e Structure Mol Formula MoiWel ExactMass ClogP IogP 41 C19H25N304 359,4242 359.1845 3.60 1.05 42 C17H23N304 333,3864 333.1689 3.11 0.83 43 C24H29N304 423,5108 423.2158 4.71 2.42 44 C18H26N403 346,4284 346.2005 2.38 0.43 45 C15H19N304 305,3328 305.1376 1.95 0.24 46 C14H19N303 277,3224 277.1426 1.247 0.19 47 C14H17N303 275,3066 275.1270 1.4848 -0.29 48 C20H27N304 373,451 373.2002 3.5758 1.80 5f Structure Mol Formula MolWei ExactMass ClogP logP 49 C16H19N304 317,3438317.1376 1.8463 0.66 50 C14H18N404 306,3206 306.1328 0.5532 -0.51 51 C20H29N304 375,4668 375.2158 3.7939 1.68 52 C16H21N304 319,3596 319.3556 1.9053 0.55 53 C16H22N403 318,3748 318.1692 1.1233 -0.1 54 C14H18N403 290,3212 290.1379 0.8796 -0.68 5g Detailed Description of the Invention When describing the compounds, compositions and methods of the invention, the following terms have the following meanings, unless otherwise indicated. 5 "Pharmaceutically acceptable salt" means those salts which retain the biological effectiveness and properties of the parent compounds and which are not biologically or otherwise harmful as the dosage administered. The compounds of this invention are capable of forming both acid and base salts by virtue of the presence of amino and carboxy groups respectively. Pharmaceutically acceptable 10 base addition salts may be prepared from inorganic and organic bases. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, substituted amines including naturally-occurring substituted 15 amines, and cyclic amines, including isopropylamine, trimethyl amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2 dimethylaminoethanol, tromethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, N alkylglucamines, theobromine, purines, piperazine, piperidine, and N 20 ethylpiperidine. It should also be understood that other carboxylic acid derivatives would be useful in the practice of this invention, for example carboxylic acid amides, including 5h carboxamides, lower alkyl carboxamides, di(lower alkyl) carboxamides, and the like. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived 5 from organic acids include acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like. The term "treatment" as used herein includes any treatment of a condition or 10 disease in an animal, particularly a mammal, more particularly a human, and includes: (i) preventing the disease or condition fror occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (ii) inhibiting the disease or condition, i.e. arresting its development; relieving the disease or condition, i.e. causing regression of the condition; or relieving the conditions caused 15 by the disease, i.e. symptoms of the disease. The term "therapeutically effective amount" refers to that amount which is sufficient to effect treatment, as defined herein, when administered to a mammal in need of such treatment. The therapeutically effective amount will vary depending on the subject and disease state being treated, the severity of the affliction and the manner of 20 administration, and may be determined routinely by one of ordinary skill in the art. "Heterocycle" refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, 0 or S. "Alkyl" refers to a branched or unbranched alkyl group having 1-6 carbon atoms, a branched or unbranched alkenyl group having 1-6 carbon atoms, a branched or 25 unbranched alkynyl group having 1-6 carbon atoms. "Hydroxyl" refers the functional group -OH when it is a substituent in an organic compound. "Heterocyclic groups" can be optionally substituted with I to 5, and preferably I to 3 substituents, selected from the group consisting of alkoxy, substituted 30 alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxy, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, 6 aryloxy, heteroaryl, heteroaryloxy, heterocyclic, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, S02-alkyl, -S02-substituted alkyl, -S02-aryl, oxo (=O), and -S02-heteroaryl. Such heterocyclic groups can have a single ring or multiple condensed rings. Preferred 5 heterocyclics include morpholino, piperidinyl, and the like. Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, 10 carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles. The term "thiol" refers to the group -SH. 15 The term "thioalkoxy" refers to the group -S-alkyl. "Amino acid" refers to any molecule that contains both amino and carboxylic acid functional groups, and includes any of the naturally occurring amino acids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gin, Gly, His, Hyl, Hyp, lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D, L, or DL form. The side chains of naturally occurring amino 20 acids are well known in the art and include, for example, hydrogen (e.g., as in glycine), alkyl (e.g., as in alanine, valine, leucine, isoleucine, proline), substituted alkyl (e.g., as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine), alkaryl (e.g., as in phenylalanine and tryptophan), substituted arylalkyl (e.g., as in tyrosine), and heteroarylalkyl (e.g., as in histidine). 25 "Amidine" refers to a functional group that has two amine groups attached to the same carbon atom with one carbon-nitrogen double bond: HN=CR'-NH"2. "Alkoxyl" refers to an alkyl group linked to oxygen thus: R-O-, where R is an alkyl. "Substituted alkyl" refers to a branched or unbranched alkyl, alkenyl or 30 alkynyl group having 1-10 carbon atoms and having substituted by one or more substituents selected from the group consisting of hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl. These substituent generic groups having the meanings being 7 WO 2007/074169 PCT/EP2006/070256 identical with the definitions of the corresponding groups as defined herein. [0043] "Halogen" refers to fluorine, bromine, chlorine, and iodine atoms. [0044] "Acyl" denotes the group --C(O)Re, where Re is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, substituted arylalkyl, cycloalkyl, substituted cycloalkyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend. [0045] "Acloxy" denotes the group --OAc, where Ac is an acyl, substituted acyl, heteroacyl or substituted heteroacyl whereas these generic groups have meanings which are identical with definitions of the corresponding groups as defined in this legend. [0046] "Alkylamino" denotes the group --NRf Rg, where Rf and Rg, that are independent of one another, represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl, whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein. [0047] "Aryl" refers to an aromatic carbocyclic group having from 1 to 18 carbon atoms and being composed of at least one aromatic or multiple condensed rings in which at least one of which being aromatic. [0048] "Substituted aryl" refers to an aromatic carbocyclic group having from 1 to 18 carbon atoms and being composed of at least one aromatic ring or of multiple condensed rings at least one of which being aromatic. The ring(s) are optionally substituted with one or more substituents selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend. [0049] "Heteroaryl" refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, 0 or S with at least one ring of this group being aromatic. [0050] "Substituted heteroaryl" refers to a heterocyclic group having from 4 to 9 carbon atoms and at least one heteroatom selected from the group consisting of N, 0 or S with at least one ring of this group being aromatic and this group being substituted with one or more substituents selected from the group consisting of halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, hydroxyl, nitro, mercapto or sulfo, whereas these generic 8 WO 2007/074169 PCT/EP2006/070256 substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend. [0051] "Carboxyl" denotes the group --C(O)ORj, where R is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl , whereas these generic substituents have meanings which are identical with definitions of the corresponding groups defined herein. [0052] "Cycloalkyl" refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms. [0053] "Substituted cycloalkyl" refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms and being substituted by one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent groups have meanings which are identical with definitions of the corresponding groups as defined in this legend. [0054] "Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, 0, S or P. [0055] "Substituted heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group containing 3 to 15 carbon atoms which at least one ring carbon atom of its cyclic structure being replaced with a heteroatom selected from the group consisting of N, 0, S or P and the group is containing one or more substituents selected from the group consisting of halogen, alkyl, substituted alkyl, carbyloxy, carbylmercapto, aryl, nitro, mercapto or sulfo, whereas these generic substituent group have meanings which are identical with definitions of the corresponding groups as defined in this legend. [0056] The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferred aryls include phenyl, naphthyl and the like. [0057] The term "alkenyl" refers to a monoradical of a branched or unbranched unsaturated hydrocarbon group preferably having from 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms and even more preferably 2 to 6 carbon atoms. Preferred alkenyl groups include ethenyl (-CH=CH2), n-propenyl (-CH2CH=CH2), iso-propenyl (-C(CH3)=CH2), and the like. 9 WO 2007/074169 PCT/EP2006/070256 [0058] "Imidazole" refers to a heterocyclic base of the general formula: C 3
H
4
N
2 . [0059] "Aralkyl group" refers to, for example, a Cl -C6 alkyl group which is attached to 1 or 2 aromatic hydrocarbon rings having from 6 to 10 carbon atoms and which has a total of 7 to 14 carbon atoms, such as the benzyl, alpha-naphthylmethyl, indenylmethyl, diphenylmethyl, 2 phenethyl, 2-alpha-naphthylethyl, 3-phenylpropyl, 3-alpha-naphthylpropyl, phenylbutyl, 4-alpha naphthylbutyl or 5-phenylpentyl groups. [0060] "Guanidine" refers generally to the amidine of amidocarbonic acid and has the general formula of: C(NH 2
)
3 . [0061] The terms "aralkyl" and "heteroarylalkyl" refer to groups that comprise both aryl or, respectively, heteroaryl as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems according to the above definitions. [0062] The present invention relates to nitrogen-containing heterocyclic compounds represented by the general formula I as follows: [00631 (I)wherein, W is a member selected from the group consisting of -C(Rs)(Rsa); -C(R )(R 6 a)-C(R 7
)(R
7 a); -C(R 8
)=C(R
9 )-; -N(R 1 4), and combinations thereof; [0064] X is a member selected from the group consisting of -N(Ria)C(=Y)N(R 4
)-;
OC(=Y)N(R
4 )-; -N(Ria)C(=Y)O-; -N(R a)S(=O)N(R4)-; -N(R a)S(=0) 2
N(R
4 )-; C(R ia)(R 3a)C(=Y)N(R 4 )-, and combinations thereof; [0065] Y and Z represent, each independent from the other, a member selected from the group consisting of oxygen ("0") and sulfur ("S"); and 1 la 2 3 3a 4 5 5a 6 6a 7 7a 8 9 [0066] R', Ri, R, R, Ra, R, R, Rs, R, Ra, R, Ra, R', R9, and R 1 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (Cl-C1O) alkyl; (Cl-C1O) alkenyl; (Cl-C1O) alkynyl; (C5-Cl2) monocyclic or bicyclic aryl; (C5-C14) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-C14) heteroaralkyl; and (Cl-C1O) monocyclic or bicyclic heteroaryl group having up to 5 10 heteroatoms selected from N, 0, S, and P said groups being able to be non-substituted or substituted by I to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (Cl-C4), amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated 5 guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof. The intermediates and the desired compounds in the processes described can be isolated and purified by purification methods conventionally used in organic synthetic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, 10 recrystallization, and various kinds of chromatography. The intermediates may be subjected to the subsequent reaction without purification. The present invention covers all possible isomers including tautomers and mixtures thereof. Where chiral carbons lend themselves to two different enantiomers, both enantiomers are contemplated as well as procedures for separating the two enantiomers. 15 In the case where a salt of a compound is desired and the compound is produced in the form of the desired salt, it can be subjected to purification as such. In the case where a compound is produced in the free state and its salt is desired, the compound is dissolved or suspended in a suitable organic solvent, followed by addition of an acid or a base to form a salt. 20 The present invention also relates to pharmaceutically acceptable salts, racemates, and optical isomers thereof of formula 1. The compounds of this invention typically contain one or more chiral centers. Accordingly, this invention is intended to include racernic mixtures, diastereomers, enantiomers and mixture enriched in one or more stereoisomer. The scope of the invention as described and claimed encompasses the racemic forms of the 25 compounds as well as the individual enantiomers and non-racemic mixtures thereof. In a further aspect of the invention, methods for the use of the above described analogs and derivatives, as well as compositions, are provided. These methods include uses of the invention's compounds to inhibit a PLA2 enzyme, treat or prevent human and agricultural diseases and conditions or both. Examples of human diseases and conditions 30 include, but are not limited to, inflammation, septic shock, rheumatoid arthritis, acute pancreatitis, acute chest syndrome in patients with sickle cell disease, acute respiratory distress syndrome (ARDS), obesity, obesity-related insulin resistance, hyperalgesia, pulmonary edema, colitis, ischemia I I WO 2007/074169 PCT/EP2006/070256 reperfusion, pleurisy, microbial infection, rheumatoid arthritis, skin inflammation, psoriasis, cancer, osteoporosis, asthma, autoimmune diseases, HIV, AIDS, rheumatoid arthritis, systemic lupus erythematosus, Type I insulin-dependent diabetes, tissue transplantation, malaria, African sleeping sickness, Chagas disease, toxoplasmosis, psoriasis, restenosis, inhibition of unwanted hair growth as cosmetic suppression, hyperparathyroidism, inflammation, treatment of peptic ulcer, glaucoma, Alzheimer's disease, suppression of atrial tachycardias, stimulation or inhibition of intestinal motility, Crohn's disease and other inflammatory bowel diseases, high blood pressure (vasodilation), stroke, epilepsy, anxiety, neurodegenerative diseases, hyperalgesic states, protection against hearing loss (especially cancer chemotherapy induced hearing loss), and pharmacological manipulation of cocaine reinforcement and craving in treating cocaine addiction and overdose and other fungal bacterial, viral, and parasitic diseases. [0072] In another aspect of the invention, compositions containing the above described compounds are provided. Preferably, the compositions are formulated to be suitable for pharmaceutical or agricultural use by the inclusion of appropriate carriers or excipients. [0073] In still another aspect of the invention, methods are provided for the administration of a suitable amount of a pharmaceutically acceptable form of the compounds described herein, to a mammal in need thereof, for example a human, for the treatment and/or prevention of a disease. In one of the embodiments, the invention comprises methods for inhibiting a PLA2 enzyme. In another embodiment, the invention comprises molecules listed in Table I, which are useful for the inhibition of PLA2. In particular, molecules 49, 33, 40, 9, 5, 4, and 3 are useful for the inhibition of group V and group X sPLA2. The molecules demonstrated the following hierarchy in sPLA2 inhibition: mol 40 > mol 33 > mol 40; and mol 9 > mol 5 ~ mol 4 ~ mol 3, respectively. [0074] In another of the embodiments, the invention comprises methods for the administration of a suitable amount of a pharmaceutically acceptable form of the compounds described herein, to a mammal in need thereof, for the treatment and/or prevention of inflammatory diseases. [0075] The design and synthesis by combinatorial chemistry techniques of cyclic/polycyclic molecular frameworks that can efficiently distribute selected pharmacophores in the 3D space is an important method to identify small-molecules capable of modulating biological processes and for dissecting biological pathways. Molecules incorporating small or medium rings derived from 12 WO 2007/074169 PCT/EP2006/070256 peptides (e.g. 2, 5-diketopiperazines) are of particular interest owing to the facile access, the chemical and stereochemical diversity of peptide derivatives, as well as enhanced diversity resulting from appending operations. To expand further the skeletal diversity attainable with peptide substrates, we investigated the synthesis of the densely functionalized (five points of diversity) dipeptide-derived 1,3,5-triazepan-2,6-dione scaffold and demonstrated its utility by screening a small "prospecting" library against the PLA2. [0076] The description of the embodiments contained herein is given by way of example and is not limiting on the scope of the present invention. Additional advantageous features and functionalities associated with the systems, methods and processes of the present invention will be apparent from the following examples. Examples [0077] To date, 12 mammalian sPLA2s have been identified and classified into 3 main structural collections: group I/II/V/X, III, and XII. [0078] Although a significant increase in sPLA2 activity is detected in serum in septic shock, rheumatoid arthritis, acute pancreatitis, multiple injuries, acute chest syndrome in patients with sickle cell disease, and in bronchoalveolar lavage (BAL) of patients with acute respiratory distress syndrome (ARDS), the exact function of sPLA2s in physio-pathological processes is uncertain. It seems that the GIIA is very potent in hydrolyzing Gram positive bacteria membranes and could be involved in the host defense against micro-organisms. Importantly, elevated concentrations of hGIIA are found in the eyes, a privileged immune organ. [0079] The GIB is found at high level in pancreas, has an enhanced activity toward its substrate in presence of deoxycholate, a detergent found in bile, and is activated in the intestine by trypsin. A function for GIB in phospholipid digestion was thus suggested. Knocking-out the gene coding for this enzyme could not show its essential role in lipid absorption at first glance, but feeding mice with a high-fat diet demonstrated GIB-knock-out mice were less likely to develop obesity and obesity-related insulin resistance. [0080] Exogenous addition of GV and GX to various mammalian cell types leads to the release of arachidonate and eicosanoid generation, even without activation of the cPLA2. In addition, zymosan-treated peritoneal macrophages from GV knock-out mice have reduced prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) production. Therefore, GV and GX are 13 WO 2007/074169 PCT/EP2006/070256 likely involved in the generation of eicosanoids under certain conditions. The physiological roles of GIIC, GIIE, GIIF, GIII, GXIIA and GXIIB have not yet been clarified, but some evidence suggests that GXII, even when devoid of any catalytic activity, may be involved in vertebrate neuronal development. [0081] Recent evidence suggests that PLA2 proteins not only hydrolyze phospholipids but may also serve as ligands for different binding proteins. The best known sPLA2 binding protein is the M-type receptor (MtR). This receptor was initially cloned as a transmembrane glycoprotein having common characteristics with the macrophage mannose receptor, and the more recently cloned receptors Endo-180 and Dec-205. This receptor has a large extracellular domain containing a N-terminal cysteine-rich domain, a fibronectin-like type II domain, eight C-type lectin like domains (CTLD), a single transmembrane domain and a short cytoplasmic tail. The M-type receptor can also quickly internalize sPLA2s suggesting a role in sPLA2 clearance. The identification of a soluble form of the receptor that can inhibit enzymatic activity upon sPLA2 binding also agrees with this view. Furthermore, results obtained from gene targeting of the receptor and other studies using the pancreatic sPLA2 suggest the M-type receptor acts as a intracellular signaling molecule through sPLA2 binding, for example, by activating the MAPK cascade, inducing a proinflammatory phenotype, and upregulating the cell surface expression of Fas ligand. [0082] Structure-based strategies to discover group IIA specific sPLA2 inhibitors led to the identification of indole analogues that inhibit this sPLA2 with nanomolar affinities. One analogue, LY311727, was able to inhibit the release of thromboxane A2 triggered by exogenously added hGIIA on guinea pig BAL fluids containing macrophages, eosinophils and epithelial cells. LY311727 could also inhibit the sPLA2 activity induced by lipopolysaccharides in a guinea pig model of ARDS. Moreover, intravenous. administration of LY311727 in transgenic mice overexpressing hGIIA led to a loss of PLA2 catalytic activity in blood, demonstrating that this inhibitor can be active in vivo, at least in blood circulation, in these animals. In a murine toxoplasmosis experimental model, LY311727 injection led to an earlier mortality, suggesting a protective role of at least one sPLA2 sensitive to this inhibitor in these mice. In addition, lumbar intrathecal administration of LY311727 in 3 different experimental rat models of hyperalgesia attenuated all the inflammation-related symptoms observed. [0083] An indole-derived inhibitor of second generation, called S-5920/LY31592ONa, 14 WO 2007/074169 PCT/EP2006/070256 significantly attenuated lung compliance, pulmonary edema, vascular permeability and lung surfactant degradation in a rabbit acute lung injury model induced by oleic acid. Two other inhibitors of sPLA2, the LY333013 (S-3013) and 5-(4-benzyloxyphenyl)-4s-(7 phenylheptanoylamino)-pentanoic acid protected rats from dextran sulfate- and trinitrobenzene sulfonic acid-induced colitis. Oral administration of 5-(4-benzyloxyphenyl)-4s-(7 phenylheptanoylamino)-pentanoic acid also preserved rats intestine from injury following ischemia and reperfusion. [0084] Ear edema induced by tetracenoylphorbol-13-acetate in mice was reduced by YM 26734, a molecule known to be a potent inhibitor of mGIIA, mGIID, mGIIE, mGV and mGX. This same drug also significantly decreased the accumulation of exudate fluid and leukocytes in a carageenin-induced pleurisy rat model. Despite the promising effects of sPLA2 inhibitors, no significant differences between the PLA2 inhibitor-treated and the placebo groups were found when the S-5920/LY31592ONa was used in a clinical study involving humans with sepsis and organ failure. However, because the GIIA sPLA2 has antibacterial properties, and septic shock is provoked by a microbial invasion, it is arguable whether it makes sense to use a sPLA2 inhibitor as a septic shock therapeutic drug. [0085] Recently, a clinical trial using another sPLA2 inhibitor, the orally distributed LY333013, on patients with rheumatoid arthritis led to significant reduction of the pathology during the first week of trial, but the benefits were lost thereafter. In this last report, the authors reported positive impacts on the pathology when administering the inhibitor intravenously. This same inhibitor failed to show any benefit on inhaled allergen challenge in subjects with asthma. It is important to note that the LY333013 was well tolerated in these patients. [0086] Thus it appears that the path of administration (e.g., oral, parenteral, enteral, subcutaneous, intravenous, anal, etc...) and the biological system chosen for an inhibitor can affect its efficacy. For example, BMS-1881162, an inhibitor of both GIIA and cPLA2, has a very potent anti-inflammatory activity when used as a topical agent in a mouse model with chronic skin inflammation induced with repeated exposures to phorbol ester. This same inhibitor was without effect in psoriatic patients. The use of labeled BMS-1881162 in volunteers showed almost no discernible penetration of the drug, probably due to the thicker stratum corneum in human compared to mouse. [0087] An indole inhibitor called indoxam (IDX) inhibited PGE2 production induced by 15 WO 2007/074169 PCT/EP2006/070256 TGF-a and IL-I in rat gastric epithelial cells. Me-indoxam (Me-IDX), a derivative of indoxam, is about 20 fold more potent than LY311727 to inhibit hGIIA. This indole analogue is suitable for studies on mammalian cells, and not only it inhibits the enzymatic activity of hGIIA, but also that of other group I/II/V/X sPLA2s. The fact that IDX and its related indole compounds affect various inflammatory signals on mammalian cells and in animal models suggests that at least one sPLA2 from the group I/II/V/X is involved in these processes. [0088] Because Me-IDX is known to bind to and to protrude from the catalytic groove of the sPLA2, it could interfere with sPLA2 interaction to molecules other than phospholipids. In fact, it was shown that IDX can block the binding of porcine pancreatic group TB and group X sPLA2 to the mouse cells expressing the M-type receptor with good efficiency (IC 50 = 130nM and 900nM respectively). However, it is not known if this observation can be extrapolated to other sPLA2s in an endogenous context, for example, using sPLA2 and M-type receptor from the mouse. This research is of high importance as some pathophysiological disorders may involve sPLA2 binding to this receptor. Indeed, mice deficient for the M-type receptor are resistant to endotoxic shock and have lower concentrations of circulating IL-I and TNF-a after LPS treatment when compared to M-type receptor expressing mice. Nevertheless, the septic shock induced by injection of lipopolysaccharides in wild-type mice can be attenuated by indoxam treatment. Recently we found that not only group TB and group IIA sPLA2s, but also several other mouse sPLA2s from the group III/V/X can bind to the M-type receptor initially identified with the snake venom sPLA2 OS2, leading to the hypothesis that one or several sPLA2s may be involved in these processes, and that the effect of indoxam may be due to either inhibition of enzymatic activity or of binding to the M-type receptor. [0089] Results obtained with analysis of the direct binding properties of radiolabeled mammalian sPLA2s on cellular membranes in the presence of Me-IDX, and evaluation of the inhibitory effects of various other molecules known as inhibitors of sPLA2 strongly indicate that the effects observed with sPLA2 inhibitors in different studies may be not only due to the inhibition of the sPLA2 catalytic activity but also to the modulation of the sPLA2 binding properties to their receptors. [0090] Interest in designing and evaluating the dipeptide-derived 1,3,5-triazepan-2,6-dione scaffold stems from the remarkable biological activities exhibited by molecules with diazepine and triazepine skeletons. In particular seven-membered cyclic ureas have attracted much 16 WO 2007/074169 PCT/EP2006/070256 attention in recent years with application in the development of HIV-protease and reverse transcriptase inhibitors, Factor Xa inhibitors, beta-lactamases inhibitors, phospholipase C inhibitors, and chemokine receptor antagonists. [0091] The following studies establish that novel 7 and 8-membered ring nitrogen containing heterocyclic compounds of the invention are useful for the inhibition of PLA2, and can be effective for the treatment and prevention of inflammatory diseases. [0092] . Labeling of E.coli membranes with [ 3 H]-oleic acid: [0093] 1) Prepare a 10 ml overnight preculture from a single colony of an Ecoli strain in Luria Broth (LB) w/ or w/o ampicillin. DHOB and XL-1 strains seem better than JM101 strain, ie they give membranes with less background and are easier to pellet after the PLA2 assay). OD600nm of the saturated overnight preculture is about 2 UDO. Make a 1/5 dilution and measure OD600nm. [0094] 2) Dilute the preculture in 100 ml of fresh LB to 0.05 UOD600nm and add 250 pl of
[
3 H]-oleic acid (NET289, NEN, 5 mCi/ml, alcohol solution). Open the vial containing the radioactive stock solution under the hood and flush the vial with N2 before closure. Save a 1 0pl aliquot of the culture for the later quantification of incorporated oleic acid. [0095] 3) Grow cells for about 5 hours at 37 0 C with vigorous shaking (200-230 rpm) up tol UOD600nm. [0096] 4) Spin down the culture for 15 minutes/4,000 rpm/ 50 ml falcon tube/RT. Save 50 pl of supernatant for quantification of incorporated oleic acid. Discard the supernatant and resuspend the pellet in 50 ml of LB and grow the cells for an additional 30 minutes at 37 0 C under shaking (this step allows the remaining unincorporated labeled oleic acid to get incorporated into phospholipids). [0097] 5) Spin down again as above. Save 50 pl of supernatant for later quantification. Discard the supernatant and resuspend the pellet in 50 ml of washing buffer. [0098] 6) Spin down as above. Save 50 pl of supernatant for later quantification. Discard the supernatant and resuspend the pellet in 2 ml of washing buffer but WITHOUT BSA. Save a 2 pl aliquot for counting and transfer the remaining solution in a Corex glass tube. Put an aluminium foil as a cap and autoclave (20 minutes, 120 'C, 1.5 bar). This step can be done overnight. [0099] 7) The next day, save another 2 pl aliquot for counting and transfer the remaining 17 WO 2007/074169 PCT/EP2006/070256 solution into 2 eppendorf tubes. Rinse the Corex tube with 1 ml of washing buffer and combine with the 2 ml solution. [00100] 8) Spin down for 1 minute at 14,000 rpm (RT). Save 10 pl of supernatant for later quantification. Discard the supernatant and resuspend each pellet in 1.5 ml of washing buffer. repeat this step four more times. [00101] 9) Resuspend the pellet in 5 ml of washing buffer and count 5 pl for quantification of incorporated oleic acid. Dilute the solution to 100,000 dpm/pl and make aliquotes of 30 pl. [00102] 10) Count the different supernatants and calculate the percentage of radioactivity in step 9 versus the input amount. Typically, the incorporated radioactivity is more than 30-40% of the input radioactivity added in step 2. II. PLA2 assay: 1) Preparation of substrate: [00103] Pipet the required amount of radioactivity (100,000 dpm of labeled membranes per reaction x number of reactions) and dilute into 1 ml of PLA2 activity buffer in an eppendorf tube. [00104] Spin down for 1 minute at 14,000 rpm (RT). Discard the supernatant. Carefully resuspend the pellet into 150 pl of PLA2 activity buffer and add PLA2 activity buffer for the total number of reactions. Store the pool at room temperature (do not prepare the pool too much in advance). 2) PLA2 assay reaction: [00105] A typical reaction is made in an eppendorf tube and consists of a total volume of 150 pl made with 50 pl PLA2 activity buffer, a negligible volume of enzyme solution and 1 00pl of the above substrate pool (addition of a quite large volume of substrate with a multipipette results in enough mixing so that it is not necessary to vortex after substrate addition). [00106] Reaction mixtures are incubated for various periods of times up to 1 hour at 25'C or 37'C (Incubations are routinely performed at RT) and with different amounts of enzyme. Incubation times and sample volumes are adjusted to ensure hydrolysis rates within the linear range of enzymatic assays (typically 10-20% of total substrate hydrolysis). Control incubations in the absence of added sPLA2 were carried out in parallel and used to calculate specific 18 hydrolysis. 3) Stop the reaction by adding 300 l of stop buffer. Spin down the tubes for 3 minutes at 14,000 rpm at room temperature. Collect and count the supernatant containing released labeled oleic acid. 5 Count also 3 or 4 aliquotes of 100 pl of the substrate pool to determine the total amount of injected radioactivity/reaction. Note that we routinely considered that the counts in the above supematants correspond to free 3 H-oleate released from membrane phospholipids. One may verify that these counts are real free oleic acid by performing a thin layer chromatography on silica gel 10 60 in conditions where free oleic and phospholipid can be separated. Note also that this protocol does not specifically detect sPLA2 activity, but can also detect the activity of cytosolic PLA2s. Materials: DHI0B or XL-l E.coli strain (could be a strain carrying or not a plasmid); [ 3 H]-oleic acid (NET289, NEN, 5 mCi/mI in ethanol); Fraction V Fatty acid free 15 BSA (Sigma #A6003 or A751 1); Fraction V BSA (sigma #A7906); Corex glass tube or equivalent. Buffers: washing buffer : 0.1 M Tris/HCI pH 8.0, 1 mM EDTA containing 0.5% Fatty acid free BSA; PLA2 activity buffer : 0.1 M Tris/HCI pH 8.0, 10 mM CaCI2, 0.1% BSA; Stop buffer: 0.1 M EDTA containing 0.2% fatty acid free BSA. 20 Therapeutic Administration One of the embodiments of the present invention includes a method for inhibiting a PLA2 enzyme. Another of the embodiments of the present invention includes therapeutic compositions comprising the compounds of the invention in a pharmaceutically acceptable 25 form. In still another embodiment, the present invention includes methods for the treatment and/or prevention of disease, for example, an inflammatory disease, in a mammal, for example, a human, comprising administering of an effective amount of a compound of the invention in a pharmaceutically acceptable form. The compound of the invention may optionally be administered together with at least one of a carrier, an excipient, another 30 biologically active agent or any combination thereof. Suitable routes for administration include oral, rectal, vasal, topical (including 19 WO 2007/074169 PCT/EP2006/070256 ocular, buccal and sublingual), vaginal and parental (including subcutaneous, intramuscular, intravitreous, intravenous, intradermal, intrathecal and epidural). The preferred route of administration will depend upon the condition of the patient, the toxicity of the compound and the site of infection, among other considerations known to the clinician. [00115] The therapeutic composition of the invention comprises about 1% to about 95% of the active ingredient, single-dose forms of administration preferably comprising about 20% to about 90% of the active ingredient and administration forms which are not single-dose preferably comprising about 5% to about 20% of the active ingredient. Unit dose forms are, for example, coated tablets, tablets, ampoules, vials, suppositories or capsules. Other forms of administration are, for example, ointments, creams, pastes, foams, tinctures, lipsticks, drops, sprays, dispersions and the like. Examples are capsules containing from about 0.05 g to about 1.0 g of the active ingredient. [00116] The pharmaceutical compositions of the present invention are prepared in a manner known per se, for example by means of conventional mixing, granulating, coating, dissolving or lyophilizing processes. [00117] Preferably, solutions of the active ingredient, and in addition also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, are used, it being possible for these to be prepared before use, for example in the case of lyophilized compositions which comprise the active substance by itself or together with a carrier, for example mannitol. The pharmaceutical compositions can be sterilized and/or comprise excipients, for example preservatives, stabilizers, wetting agents and/or emulsifiers, solubilizing agents, salts for regulating the osmotic pressure and/or buffers, and they are prepared in a manner known per se, for example by means of conventional dissolving or lyophilizing processes. The solutions or suspensions mentioned can comprise viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin. [00118] Pharmaceutically acceptable forms include, for example, a gel, lotion, spray, powder, pill, tablet, controlled release tablet, sustained release tablet, rate controlling release tablet, enteric coating, emulsion, liquid, salts, pastes, jellies, aerosols, ointments, capsules, gel caps, or any other suitable form that will be obvious to one of ordinary skill in the art. [00119] Suspensions in oil comprise, as the oily component, the vegetable, synthetic or semi synthetic oils customary for injection purposes. Oils which may be mentioned are, in particular, 20 liquid fatty acid esters which contain, as the acid component, a long-chain fatty acid having 8-22, in particular 12-22, carbon atoms, for example lauric acid, tridecylic acid, myristic acid, pentadecylic acid, palmitic acid, margaric acid, stearic acid, arachidonic acid, behenic acid or corresponding unsaturated acids, for example oleic acid, elaidic acid, erucic acid, 5 brasidic acid or linoleic acid, if appropriate with the addition of antioxidants, for example vitamin E, .beta.-carotene or 3,5-di-tert-butyl-4-hydroxytoluene. The alcohol component of these fatty acid esters has not more than 6 carbon atoms and is mono- or polyhydric, for example mono-, di- or trihydric alcohol, for example methanol, ethanol, propanol, butanol, or pentanol, or isomers thereof, but in particular glycol and glycerol. Fatty acid esters are 10 therefore, for example: ethyl oleate, isopropyl myristate, isopropyl palmitate, "Labrafil M 2375" (polyoxyethylene glycerol trioleate from Gattefosee, Paris), "Labrafil M 1944 CS" (unsaturated polyglycolated glycerides prepared by an alcoholysis of apricot kernel oil and made up of glycerides and polyethylene glycol esters; from Gattefosee, Paris), "Labrasol" (saturated polyglycolated glycerides prepared by an alcoholysis of TCM and made up of 15 glycerides and polyethylene glycol esters; from Gattefosee, Paris) and/or "Miglyol 812" (triglyceride of saturated fatty acids of chain length C.sub.8 to C.sub.12 from Huls AG, Germany), and in particular vegetable oils, such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and, in particular, groundnut oil. The preparation of the injection compositions is carried out in the customary 20 manner under sterile conditions, as are bottling, for example in ampoules or vials, and closing of the containers. For example, pharmaceutical compositions for oral use can be obtained by combining the active ingredient with one or more solid carriers, if appropriate granulating the resulting mixture, and, if desired, processing the mixture or granules to tablets or coated 25 tablet cores, if appropriate by addition of additional excipients. Suitable carriers are, in particular, fillers, such as sugars, for example lactose, sucrose, mannitol or sorbitol cellulose preparations and/or calcium phosphates, for example tricalcium phosphate, or calcium hydrogen phosphate, and furthermore binders, such as starches, for example maize, wheat, rice or potato starch, methylcellulose, 30 hydroxypropylmethylcellulose, sodium carboxymethylcellulose and/or polyvinyl pyrrolidine, and/or, if desired, desintegrators, such as the above mentioned starches, and furthermore carboxymethyl-starch, cross-linked 21 WO 2007/074169 PCT/EP2006/070256 polyvinylpyrrolidone, alginic acid or a salt thereof, such as sodium alginate. Additional excipients are, in particular, flow regulators and lubricants, for example salicylic acid, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, and/or polyethylene glycol, or derivatives thereof. [00123] Coated tablet cores can be provided with suitable coatings which, if appropriate, are resistant to gastric juice, the coatings used being, inter alia, concentrated sugar solutions, which, if appropriate, comprise gum arabic, talc, polyvinylpyrrolidine, polyethylene glycol and/or titanium dioxide, coating solutions in suitable organic solvents or solvent mixtures or, for the preparation of coatings which are resistant to gastric juice, solutions of suitable cellulose preparations, such as acetylcellulose phthalate or hydroxypropylmethylcellulose phthalate. [00124] By "controlled release" it is meant for purposes of the present invention that therapeutically active compound is released from the preparation at a controlled rate or at a specific site, for example, the intestine, or both such that therapeutically beneficial blood levels (but below toxic levels) are maintained over an extended period of time, e.g., providing a 12 hour or a 24 hour dosage form. [00125] The term "rate controlling polymer" as used herein includes hydrophilic polymers, hydrophobic polymers or mixtures of hydrophilic and/or hydrophobic polymers that are capable of retarding the release of the compounds in vivo. In addition, many of the same polymers can be utilized to create an enteric coating of a drug, drug suspension, or drug matrix. It is within the skill of those in the art to modify the coating thickness, permeability, and dissolution characteristics to provide the desired controlled release profile (e.g., drug release rate and locus) without undue experimentation. [00126] Examples of suitable controlled release polymers to be used in this invention include hydroxyalkylcellulose, such as hydroxypropylcellulose and hydroxypropylmethylcellulose; poly(ethylene)oxide; alkylcellulose such as ethycellulose and methylcellulose; carboxymethylcellulose; hydrophilic cellulose derivatives; polyethylene glycol; polyvinylpyrrolidone; cellulose acetate; cellulose acetate butyrate; cellulose acetate phthalate; cellulose acetate trimellitate; polyvinylacetate phthalate; hydroxypropylmethylcellulose phthalate; hydroxypropylmethylcellulose acetate succinate; poly(alkyl methacrylate); and poly (vinyl acetate). Other suitable hydrophobic polymers include polymers or copolymers derived from acrylic or methacrylic acid esters, copolymers of acrylic and methacrylic acid esters, zein, 22 waxes, shellac and hydrogenated vegetable oils. To ensure correct release kinetics, the controlled release preparation of this invention contains about 5 and 75% by weight, preferably about 20 and 50% by weight, more preferably about 30 to 45% by weight controlled release polymer(s) and about I to 5 40% by weight, preferably about 3 to 25% by weight active compounds. The controlled release preparation according to the invention can preferably include auxiliary agents, such as diluents, lubricants and/or melting binders. Preferably, the excipients are selected to minimize the water content of the preparation. Preferably, the preparation includes an antioxidant. Suitable diluents include pharmaceutically acceptable inert fillers such as 10 microcrystalline cellulose, lactose, dibasic calcium phosphate, saccharides, and/or mixtures of any of the foregoing. The diluent is suitably a water soluble diluent. Examples of diluents include microcrystalline cellulose such as Avicel phl 12, Avicel pH 101 and Avicel pH 102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose DCL 21; dibasic calcium phosphate such as Emcompress; mannitol; starch; sorbitol; sucrose; and glucose. 15 Diluents are carefully selected to match the specific formulation with attention paid to the compression properties. Suitable lubricants, including agents that act on the flowability of the powder to be compressed are, for example, colloidal silicon dioxide such as Aerosil 200; talc; stearic acid, magnesium stearate, and calcium stearate. Suitable low temperature melting binders include polyethylene glycols such as PEG 6000; cetostearyl alcohol; cetyl 20 alcohol; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derivatives; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates; poloxamers; and waxes. To improve the stability in the controlled release preparation, an antioxidant compound can be included. Suitable antioxidants include sodium metabisulfite; tocopherols 25 such as alpha, beta, or delta-tocopherol esters and alpha-tocopherol acetate; ascorbic acid or a pharmaceutically acceptable salt thereof; ascorbyl palmitate; alkyl gallates such as propyl gallate, Tenox PG, Tenox s-1; sulphites or a pharmaceutically acceptable salt thereof; BHA; BHT; and monothioglycerol. The controlled release preparation according to the invention preferably can be 30 manufactured by blending the compounds with the controlled release polymer(s) and auxiliary excipients followed by direct compression. Other methods for manufacturing the preparation include melt granulation. Preferred melt granulation techniques include melt granulation together 23 WO 2007/074169 PCT/EP2006/070256 with the rate controlling polymer(s) and diluent(s) followed by compression of the granules and melt granulation with subsequent blending with the rate controlling polymer(s) and diluents followed by compression of the blend. As desired prior to compression, the blend and/or granulate can be screened and/or mixed with auxiliary agents until an easily flowable homogeneous mixture is obtained. [00130] Oral dosage forms of the controlled release preparation according to the invention can be in the form of tablets, coated tablets, enterically coated tablets or can be multiparticulate, such as in the form of pellets or mini-tablets. If desired, capsules such as hard or soft gelatin capsules, can contain the multiparticulates. If desired, the multiparticulate oral dosage forms can comprise a blend of at least two populations of pellets or mini-tablets having different controlled-release in vitro and/or in vivo release profiles. If desired, one of the pellet or mini-tablet populations can comprise immediate release multiparticulate, such as multiparticulates formed by conventional means. [00131] If desired, the controlled release matrix tablets or multiparticulates of this invention can be coated with a controlled release polymer layer so as to provide additional controlled release properties. Suitable polymers that can be used to form this controlled release layer include the rate controlling polymers listed above. [00132] As desired, the tablets, pellets or mini-tablets according to the invention can be provided with a light-protective and/or cosmetic film coating, for example, film-formers, pigments, anti-adhesive agents and plasticizers. Such a film former may consist of fast dissolving constituents, such as low-viscosity hydroxypropylmethylcelluose, for example Methocel E5 or D14 or Pharmacoat 606 (Shin-Etsu). The film coating may also contain excipients customary in film-coating procedures, such as light-protective pigments, for example iron oxide, or titanium dioxide, anti-adhesive agents, for example talc, and also suitable plasticizers such as PEG 400, PEG 6000, and diethyl phthalate or triethyl citrate. [00133] The controlled release polymer of this invention may consist of a hydrogel matrix. For instance, the compounds can be compressed into a dosage form containing a rate controlling polymer, such as HPMC, or mixture of polymers which when wet will swell to form a hydrogel. The rate of release from this dosage form is controlled both by diffusion from the swollen tablet mass and by erosion of the tablet surface over time. The rate of release may be controlled both by the amount of polymer per tablet and by the inherent viscosities of the polymers used. 24 WO 2007/074169 PCT/EP2006/070256 [00134] Dyes or pigments can be admixed to the tablets or coated tablet coatings, for example for identification or characterization of different doses of active ingredient. [00135] Pharmaceutical compositions, which can be used orally, are also hard capsules of gelatin and soft, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. The hard capsules can contain the active ingredient in the form of granules, mixed for example with fillers, such as maize starch, binders and/or lubricants, such as talc or magnesium stearate, and stabilizers if appropriate. In soft capsules, the active ingredient is preferably dissolved or suspended in suitable liquid excipients, such as greasy oils, paraffin oil or liquid polyethylene glycols or fatty acid esters of ethylene glycol or propylene glycol, it being likewise possible to add stabilizers and detergents, for example of the polyethylene sorbitan fatty acid ester type. [00136] Other oral forms of administration are, for example, syrups prepared in the customary manner, which comprise the active ingredient, for example, in suspended form and in a concentration of about 5% to 20%, preferably about 10% or in a similar concentration which results in a suitable individual dose, for example, when 5 or 10 ml are measured out. Other forms are, for example, also pulverulent or liquid concentrates for preparing of shakes, for example in milk. Such concentrates can also be packed in unit dose quantities. [00137] Pharmaceutical compositions, which can be used rectally, are, for example, suppositories that comprise a combination of the active ingredient with a suppository base. Suitable suppository bases are, for example, naturally occurring or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkanols. [00138] Compositions which are suitable for parenteral administration are aqueous solutions of an active ingredient in water-soluble form, for example of water-soluble salt, or aqueous injection suspensions, which comprise viscosity-increasing substances, for example sodium carboxymethylcellulose, sorbitol and/or dextran, and if appropriate stabilizers. The active ingredient can also be present here in the form of a lyophilisate, if appropriate together with excipients, and be dissolved before parenteral administration by addition of suitable solvents. Solutions such as are used, for example, for parental administration can also be used as infusion solutions. Preferred preservatives are, for example. Antioxidants, such as ascorbic acid, or microbicides, such as sorbic or benzoic acid. [00139] Ointments are oil-in-water emulsions, which comprise not more than 70%, but preferably 20-50% of water or aqueous phase. The fatty phase consists, in particular, 25 WO 2007/074169 PCT/EP2006/070256 hydrocarbons, for example vaseline, paraffin oil or hard paraffin's, which preferably comprise suitable hydroxy compounds, such as fatty alcohol's or esters thereof, for example cetyl alcohol or wool wax alcohols, such as wool wax, to improve the water-binding capacity. Emulsifiers are corresponding lipophilic substances, such as sorbitan fatty acid esters (Spans), for example sorbitan oleate and/or sorbitan isostearate. Additives to the aqueous phase are, for example, humectants, such as polyalcohols, for example glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and odoriferous substances. [00140] Fatty ointments are anhydrous and comprise, as the base, in particular, hydrocarbons, for example paraffin, vaseline or paraffin oil, and furthermore naturally occurring or semi synthetic fats, for example hydrogenated coconut-fatty acid triglycerides, or, preferably, hydrogenated oils, for example hydrogenated groundnut or castor oil, and furthermore fatty acid partial esters of glycerol, for example glycerol mono- and/or distearate, and for example, the fatty alcohols. They also contain emulsifiers and/or additives mentioned in connection with the ointments which increase uptake of water. [00141] Creams are oil-in-water emulsions, which comprise more than 50% of water. Oily bases used are, in particular, fatty alcohols, for example lauryl, cetyl or stearyl alcohols, fatty acids, for example palmitic or stearic acid, liquid to solid waxes, for example isopropyl myristate, wool wax or beeswax, and/or hydrocarbons, for example vaseline (petrolatum) or paraffin oil. Emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, for example fatty acid esters of polyalcohols or ethyleneoxy adducts thereof, such as polyglyceric acid fatty acid esters or polyethylene sorbitan fatty esters (Tweens), and furthermore polyoxyethylene fatty alcohol ethers or polyoxyethylene fatty acid esters, or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, for example sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate, which are usually used in the presence of fatty alcohols, for example cetyl stearyl alcohol or stearyl alcohol. Additives to the aqueous phase are, inter alia, agents which prevent the creams from drying out, for example polyalcohols, such as glycerol, sorbitol, propylene glycol and/or polyethylene glycols, and furthermore preservatives and odoriferous substances. [00142] Pastes are creams and ointments having secretion-absorbing powder constituents, such as metal oxides, for example titanium oxide or zinc oxide, and furthermore talc and/or aluminum silicates, which have the task of binding the moisture or secretions present. 26 Foams are administered from pressurized containers and they are liquid oil-in water emulsions present in aerosol form. As the propellant gases, halogenated hydrocarbons, such as chlorofluoro-lower alkanes, for example dichIorofluoromethane and dichlorotetrafluoroethane, or, preferably, non-halogenated gaseous hydrocarbons, air, 5 N.sub.2 0, or carbon dioxide are used. The oily phases used are, inter alia, those mentioned above for ointments and creams, and the additives mentioned there are likewise used. Tinctures and solutions usually comprise an aqueous-ethanolic base to which, humectants for reducing evaporation, such as polyalcohols, for example glycerol, glycols and/or polyethylene glycol, and re-oiling substances, such as fatty acid esters with lower 10 polyethylene glycols, i.e. lipophilic substances soluble in the aqueous mixture to substitute the fatty substances removed from the skin with the ethanol, and, if necessary, other excipients and additives, are admixed. The invention also relates to a process or method for treatment of the disease states mentioned above. The compounds can be administered prophylactically or 15 therapeutically as such or in the form of pharmaceutical compositions, preferably in an amount, which is effective against the diseases mentioned. With a warm-blooded animal, for example a human, requiring such treatment, the compounds are used, in particular, in the form of pharmaceutical composition. A daily dose of about 0.1 to about 5 g, preferably 0.5 g to about 2 g, of a compound of the present invention is administered here for a body weight 20 of about 70 kg. It is understood that the examples and embodiments described herein are for illustrative purposes only and that various substitutions, modifications or changes in light thereof will be suggested to persons skilled in the art and are included within the spirit and purview of this application and are considered within the scope of the appended claims. The 25 following examples are given by way of example of the preferred embodiments, and are in no way considered to be limiting to the invention. For example, the relative quantities of the ingredients may be varied to achieve different desired effects, additional ingredients may be added, and/or similar ingredients may be substituted for one or more of the ingredients described. All publications, patents, and patent applications cited herein are hereby 30 incorporated by reference in their entirety for all purposes. Examples of General Synthetic Schemes and Procedures: Example 1: Synthesis of [1,3,5]Oxadiazepane-2,6-diones (Formula la) 27 R N R N S(Ia) General Scheme synthetic scheme for Ia.
R
1
R
2 o R1 R 2 Bn, N NH2 a,b Bn'O BOC 0 R 5 0 R 5 0 01c, d R5NkO HN e 0 R' R R R RN N NH 3 * R2 R2 ONR R 20 00 O0R 5 a) lodobenzene bistrifluoroacetate (IBTFA), THF/H 2 0; b) Boc 2 0; c) p 5 nitrophenylchloroformate, CH 2
CI
2 , Diisopropylethylamine; d) trifluoroacetic acid; e) DIEA, HOBt; f) NaH, R 3 Br. Example 2: Synthesis of 2-Thioxo-[1,3,5]triazepan-6-ones (Formula Ib) R3 N N R4 R N N R I 10 General synthetic scheme for lb. RI R 2 0 R 1
R
2 N N Boc.a. Nab I H BocN N NH 2 ab Boc, N N N N R 0 R 5 R 0 R 5 S S c NH R R 2 NZN HN 1 d iy H R5 CF3COO H 2 N N N NF0 0 R' 0 R 5 S R20 Step a) Dipeptide amide lb-pl was dissolved in THF/water (3 :1) and treated 28 with iodobenzene bistrifluoroacetate (1.2 equiv.) for 3h, time after which starting material was consumed. Solvents were removed in vacuo and Et 2 0 was added. The solid which formed was collected and washed with Et 2 O to yield the corresponding gem-diamino derivative which was used in the next step without further purification. Quantitative Yield. 5 Step b) bis(benzotriazol-l-yl)methanethione (I equiv) was dissolved in CH2Cl2 at rt. The previously synthesized gem-diamino derivative was added dropwise and the reaction mixture was stirred for 18h. Solvent was removed under vacuum and the residue was redissolved in EtOAc and washed with 5% aqueous sodium carbonate, water and brine before drying over anhydrous sodium sulphate. Solvent was removed under vacuum and I b 10 p 2 was recrystallized from ethyl acetate. Step c) The l-thiocarbamoylbenzotriazole was treated with TFA at 0 0 C. After 30 min, TFA was removed by co-evaporation with hexane and the TFA salt precipitated by addition of diethylether. The resulting salt Ib-p3 was collected by filtration and dried under high vacuum. It was used in the next step without further purification. 15 Step d) The TFA salt Ib-p3 was dissolved in MeCN and diisopropylethylamine (2.5 equiv) was then added and the reaction mixture was stirred for 24h. Solvent was removed in vacuum and the residue was redissolved in EtOAc, washed with 5% aqueous sodium carbonate, I M HCI, water, and brine before drying over anhydrous sodium sulphate. Solvent was removed in vacuum and cyclic lb-I was purified by recrystallization from 20 CH2Cl 2 /diisopropyl ether. Example 3: Synthesis of 4-Benzyl-6-methyl-[ I,3,6]oxadiazepane-2,5-dione (Formula lb-I) S NH NH
H
3 C (b-1) 25 General synthetic scheme for lb-I. 29 WO 2007/074169 PCT/EP2006/070256 O I H N N Boc.. N NH2 a, b Boc -. N N N H H R 5 lb-p1 lb-p2 S ~,IC H N H - dI H N=N 9 H 3 N N /_ N
CF
3 COO / 0 1-b1 [00158] Step a) Dipeptide amide Ib-pl was dissolved in THF/water (3 :1) and treated with iodobenzene bistrifluoroacetate (1.2 equiv.) for 3h, time after which starting material was consumed. Solvents were removed in vacuo and Et 2 0 was added. The solid which formed was collected and washed with Et 2 0 to yield the corresponding gem-diamino derivative which was used in the next step without further purification. Quantitative Yield. [00159] Step b) bis(benzotriazol-1-yl)methanethione (1 equiv) was dissolved in CH2Cl2 at rt. The previously synthesized gem-diamino derivative was added dropwise and the reaction mixture was stirred for 18h. Solvent was removed under vacuum and the residue was redissolved in EtOAc and washed with 5% aqueous sodium carbonate, water and brine before drying over anhydrous sodium sulphate. Solvent was removed under vacuum and lb-p2 was recrystallized from ethyl acetate. [00160] Step c) The 1-thiocarbamoylbenzotriazole was treated with TFA at 0 0 C. After 30 min, TFA was removed by co-evaporation with hexane and the TFA salt precipitated by addition of diethylether. The resulting salt Ib-p3 was collected by filtration and dried under high vacuum. It was used in the next step without further purification. [00161] Step d) The TFA salt Ib-p3 was dissolved in MeCN and diisopropylethylamine (2.5 equiv) was then added and the reaction mixture was stirred for 24h. Solvent was removed in vacuum and the residue was redissolved in EtOAc, washed with 5% aqueous sodium carbonate, IM HCl, water, and brine before drying over anhydrous sodium sulphate. Solvent was removed in vacuum and cyclic lb-I was purified by recrystallization from CH 2 Cl 2 /diisopropyl ether. [00162] Example 4: Synthesis of 2-Thioxo-[1,3,5]oxadiazepan-6-ones (Formula Ic) 30 WO 2007/074169 PCT/EP2006/070256 K (Ic) [00163] General synthetic scheme for Ic. R' R 2 0 R 1
R
2 N N TBDMS' N a,b TBDMS N N N 0 L Nr NH 2 ~ yy 0 R 5 0 R 5 S S c
R
1
R
2 NN H N 1 d I H N 0 R 5 S R 0 [00164] a) lobenzene bistrifluoroacetate (IBTFA), THF/H 2 0; b) bis(benzotriazolyl)methanethione, CH 2 Cl 2 ; c) trifluoroacetic acid; d) diisopropylethylamine, MeCN, NaH. [00165] Example 5: Synthesis of [1,3,6]Oxadiaxocane-2,5-diones (Formula Id) (Id) [00166] General synthetic scheme for Id. Ha- a HO CH 0 NQ~ O0 b H 3 N N O C 0 R
N
2 -N 31 a) para-nitrophenyl chloroformate (2 eq), pyridine (1,1 eq), CH2CI2, TA overnight; b) TFA, TA 30 minutes; c) DIEA (2,6 eq), HOBt, (I eq), MeCN, TA 3 hours. Example 6: Synthesis of 4-Benzyl-6-methyl-[1,3,6]oxadiazocane-2,5-dione (Formula Id-I) _N 5 CH (Id-1) General synthetic scheme for Id-I. 0 0 Boc N OH,0 a Boc'N N O / Id-p1 Id-p2 NO 2 b,c N b~ , OId-1 a) para-nitrophenyl chloroformate (2 eq), pyridine (1,1 eq), CH 2 C1 2 , TA overnight; b) TFA, TA 30 minutes; c)DIEA (2,6 eq), HOBt (1 eq), MeCN, TA 3 hours. 10 I) Synthesis ofp-nitrophenyl carbonate precursor Id-p2 Boc' O 0 O NO2 C r (Id-p2) The starting dipeptide alcohol Id-p1 (300 mg, 0.93 mmol, I eq) is dissolved in 5 mL 15 CH 2
CI
2 and 82 pL pyridine (1.02 mmol, 1.1 eq). A solution of 4-nitrophenyl chloroformate (0.37 g, I .86 mmol, 2 eq) in 2mL. After stirring for 24h, the reaction mixture is diluted with 15 mL CH 2
CI
2 , and washed with IN NaHCO 3 The organic phase is dried on Na 2
SO
4 , concentrated and purified by flash chromatography (eluant 1:2 AE/cyclohexane) to yield pure carbonate Id-p2 with 59% yield. HPLC 20 tR 14.1 (gradient 30-100%B, 20 min.) 'H NMR (300 MHz, CDCl3) 8 8.3 (m, 2H, arom-H a-N02), 7.39 (m, 2H, arom-H p N02), 7.24 (m, 5H, arom-H), 5.34 (m, J= 10.55 Hz, I H NH), 4.85 (q, J= 14.9, 7.9 Hz, I H a-NH), 32 4.31 4.14 (dd, J= 9.97, 5.1 Hz, 2 H a-0), 3.77 3.54 (dd, J= 14.5, 5.2 Hz, 2H a-NMe), 2.98 (m, 2H a-Phe), 2.79 (s, 3H NMe), 1.43 (s, 9H Boc). "C NMR (100 MHz, CDCI3) 8 171.8 (CO amide), 154.8 (CO carbamate), 154.5 (CO carbonate), 151.6 (C arom a-NO2), 144.8 (C arom 5-N02), 135.5 (C arorn Phe), 128.8 (2CH Phe), 5 128.7 (2CH Phe), 127.8 (CH-Phe), 124.7 (CH arom), 121.1 (CH-arom), 79.3 (C Boc), 66.0 (CH2 a-0), 50.9 (CH a-NH), 46.4 47.0 (CH2 a-N), 39.4 (CH2 Phe), 35.8 33.6 (CH3 NMe), 27.7 (3 CH3 Boc). 2) Cyclization to Id-pl p-Nitrophenyl carbonate Id-p2 is treated with trifluoroacetic acid for 30'. Addition of 10 ether gave the corresponding TFA salt which precipitated as a white solid. It was filtered and used in the next step without further purification. The TFA salt (220 mg, 0.44 mmol, I eq) dissolved in MeCN (10 mL) was added slowly to a solution of Diisopropylethylamine (194 tL, 1.14 mmol, 2.6 eq) and hydroxybenzotriazole (HOBt) (60 mg, 0.44 mmol, I eq) in 25 mL MeCN. The reaction mixture was stirred for 3 days and concentrated in vacuo. CH 2 Cl 2 is then added and the organic 15 phase was washed with IN NaHCO3, brine, dried over Na2SO4 and concentrated in vacuo. The residue (110 mg) was then purified by silica gel chromatography. [CHCl3/MeOH/AcOH (20:0.5:0.1) then plus CHCl 3 /MeOH [20:1]) to afford 42 mg of Id-1. 2H 6 o H 4 H 0 H H H HZ >:-H H_ 3H' HPLC tR (Id-1) 5.88 (gradient 30-100%B, 20 min) 25 HRMS (ESI) calculated for C1 3 1H i 6
N
2 0 3 249.1234, found 249.1230. 'H NMR Id-i (300 MHz, CDCl 3 ) 8 7.25 (m, 5H, arom-H), 6.10 (d, H 4 ), 4.75 (dd, J= 8.9, 7.4 Hz, H), 4.20 (m, 2H 3 ), 4.15 (m, H 2 ), 3.28 (dd, J= 14.0, 7.6 Hz, I H 6 ), 3.17 (m, H 2 ), 3.02 (dd, I H 6 ), 3.0 (s, 3 H'). "C NMR Id-1 (100 MHz, CDCl 3 ) 8 172.3 (CO amide), 157.7 (CO carbonate), 136.9 30 (C-arom), 129.3 (2CH arom), 128.6 (2CH arom), 126.8 (CH arom), 69.6 (CH 2 a-0), 54.0 (CH a N), 52.9 (CH 2 a-N), 36.6 (CH 3 Me), 35.7 (CH 2 Phe). Example 7: Synthesis of 1,1-Dioxo-l 1X 6 -[,2,5,8]thiatriazocan-4-ones (Formula If) 33 WO 2007/074169 PCT/EP2006/070256 R~ R2 (If) [00184] General synthetic scheme for If.
R
4 0 R 6 O R 4 Boc'N N OH MeO2C'NS
R
1 R2 R 7 R7 N O R 6 R 2 NEt 3 N OMe o e Burgess reagent [00185] i) (a) TFA; (b) NaHCO 3 satured, DCM; ii) Burgess reagent (2,5 eq), THF, 70'C for two hours. [00186] Example 8: Synthesis of 10-methyl-6,6,1 1-trioxo-8,9,10,11,11 a,12-hexahydro-5H 6X 6 -thia-5 a,7, 1 0-triaza-cycloocta[b]naphthalene-7-carboxylic acid methyl ester (Formula If-1) (If-1) [001871 General synthetic scheme for If-1. R 0 N OH0 NN N~ ~~ O ,1 z MeO2C-N' R = Boc If-pl R = H If-p2 I NEt3 N OMe (i) (a) TFA, O 0 C, 30min ; (b) NaHC0 3 sature, o e DCM ; (ii) Burgess reagent (2,5 eq), THF, 70'C Burgess reagent 2h. [00188] i) The N-Boc protected dipeptide alcohol was treated with TFA for 30 minutes at 34 WO 2007/074169 PCT/EP2006/070256 0 0 C. The TFA was removed under vacuum and the residue was dissolved in AcOEt. Saturated NaHCO3 was added under stirring and after 10 minutes the organic phase was dried with Na2S04 and concentrated under vacuum to give If-pl. [00189] ii) Compound 1f-p1 (175 mg, 0.75 mmol, 1 eq), is dissolved in 10 mL anhydrous THF and Burgess reagent (534 mg, 2.24 mmol, 2.5 eq) is added. The solution is then heated under reflux at from about 70'C to about 90'C for 2 days. The reaction mixture is then poured into a solution of saturated NH 4 Cl (40 mL). The mixture is extracted with CH2Cl2 and the organic phase is washed with H 2 0, dried over Na 2
SO
4 and concentrated under vacuum. The crude mixture is then purified by silica gel chromatography (CHCl 3 /MeOH/AcOH (18:1:0.2) to yield If-1. 35

Claims (15)

  1. 3. A method according to claim 2, wherein the biologically active agent is a member selected from the group consisting of a steroid, non-steroidal anti inflammatory, acetylsiacylic acid, a cyclooxygenase inhibitor and a 5 combination thereof
  2. 4. A method according to any one of claims I to 3, wherein the compound is Mol 3: 0 NH 0 (3) 10
  3. 5. A method according to any one of claims I to 3, wherein the compound is Mol 4: 0 N NH 0 N / o (4) 15 6. A method according to any one of claifis I to 3, wherein the compound is Mol 5: 0 HN NH N 0 (5) 37
  4. 7. A method according to any one of claims 1 to 3, wherein the compound is Mol 9: 0 o 0 00 N N 0 N / (9) 5 8. A method according to any one of claims I to 3, wherein the compound is Mol 17: 0 HN NH H- NN NN / 0 K (17)
  5. 9. A method according to any one of claims I to 3, wherein the compound is Mol 33: 0 0 N NH 10 0 (33) 38
  6. 10. A method according to any one of claims 1 to 3, wherein the compound is Mol 34: 0 N NH N O (34) 5 11. A method according to any one of claims 1 to 3, wherein the compound is Mol 35: O OH HO N O (35)
  7. 12. A method according to any one of claims I to 3, wherein the compound is 10 Mol 40: 0 0 N NH N (40) 39
  8. 13. A method according to any one of claims I to 3, wherein the compound is Mol 45: 0 N NH N 0 (45) 5
  9. 14. A method according to any one of claims I to 3, wherein the compound is Mol 48: 0 o NJ NH 0 N / (48) 10 15. A method according to any one of claims I to 3, wherein the compound is Mol 49: 0 HO HO N NH 00 N 0(49) 40
  10. 16. A method according to any one of claims 1 to 3, wherein the compound is Mol 52: 0 HO N NH 0 N N (52) 5
  11. 17. A method according to any one of claims I to 3, wherein the compound is Mol 53: 0 H 2 N N NH 0 N 0 (53) 10 18. A kit when used for inhibiting the activity of a phospholipase A2 (PLA2) enzyme, said kit comprising a plurality of containers, wherein at least one of said containers contains a composition comprising an effective amount of a compound having the general formula B: 0 R5 NNRi R4- N I R2 (B R 3 0 (B) 4' wherein R', R 2 , R 3 , R4, and R 5 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an amino acid side chain; a (Cl-C0) alkyl; (Cl-C1O) alkenyl; (Cl-CO) alkynyl; (C5-C12) monocyclic or bicyclic aryl; (C5-Cl4) monocyclic or 5 bicyclic aralkyl; monocyclic or bicyclic (C5-Cl4) heteroaralkyl; and (Cl CIO) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, 0, S, and P said groups being able to be non-substituted or substituted by I to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3 10 triazole, alkoxy, (Cl-C4)alkyl, amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof, or a pharmaceutically acceptable salt thereof 15
  12. 19. Use of a compound having the general formula B: 0 R5 NR R4 N* R2 R 3 0 (B) wherein R', R2, R 3 , R 4 , and R 5 represent, each independent from the other, a member selected from the group consisting of: a hydrogen atom; an 20 amino acid side chain; a (C1-CIO) alkyl; (Cl-C1O) alkenyl; (Cl-CO) alkynyl; (C5-Cl2) monocyclic or bicyclic aryl; (C5-Cl4) monocyclic or bicyclic aralkyl; monocyclic or bicyclic (C5-Cl4) heteroaralkyl; and (Cl CIO) monocyclic or bicyclic heteroaryl group having up to 5 heteroatoms selected from N, 0, S, and P said groups being able to be non-substituted or 25 substituted by I to 6 substituents further selected from the group consisting of: a halogen atom, an NO 2 , OH, amidine, benzamidine, imidazole, 1,2,3 triazole, alkoxy, (Cl-C4)alkyl, amino, piperazine, piperidine, dialkylamino, guanidine group, bis alkylated or bis acylated guanido group, carboxylic 42 acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate, phosphonamidate, sulfhydryl and any combination thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a composition for inhibiting the activity of a phospholipase A2 (PLA2) 5 enzyme.
  13. 20. A method for inhibiting the activity of a phospholipase A2 (PLA2) enzyme, said method substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying drawings 10 and/or examples.
  14. 21. A kit when used for inhibiting the activity of a phospholipase A2 (PLA2) enzyme, said kit substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying 15 drawings and/or examples.
  15. 22. Use of a compound according to claim 19, said use substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying drawings and/or examples. 20 Dated this 16 th day of August 2011 Shelston IP Attorneys for: Immupharma France SA 43
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