CN101405276A - Compositions and methods for the inhibition of phospholipase A2 - Google Patents

Abstract

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

Description

Compositions and methods for inhibiting phospholipase A2

This application is filed under 35 U.S.C. §119(e) in U.S. Provisional Patent Serial No. 60/755,631, filed December 29, 2005, entitled "Compositions and Methods for the Synthesis of Novel Heterocyclic Therapeutics ( Compositions and Methods for Synthesizing Novel Heterocyclic Therapeutics)” and U.S. Provisional Patent Serial No. 60/755,632, filed December 29, 2005, entitled “Compositions and Methods for Treatment and Prevention of Disease), and U.S. Provisional Patent Serial No. 60/755,626, filed December 29, 2005, entitled "Compositions and Methods for the Inhibition of Phospholipase A2 A2)" priority. Their entire contents are hereby incorporated by reference.

The present invention relates to U.S. non-provisional patent application "Compositions and Methods for the Treatment and Prevention of Disease" (ExpressMail No.) filed on December 22, 2006 : EV 902583365US) and the U.S. non-provisional patent application filed on December 22, 2006 "Compositions and Methods for Synthesizing Heterocyclic Therapeutic Compounds (Compositions and Methods for Synthesizing Heterocyclic Therapeutic Compounds)" (Express Mail Number: EV 902583374US) , the entire contents of which are hereby incorporated by reference.

technical field

The present invention relates to nitrogen-containing heterocyclic compounds derived from dipeptides of 7-membered ring and 8-membered ring, and their pharmaceutically acceptable salts useful for inhibiting phospholipase A2 (PLA2). In addition, the present invention also relates to compositions for inhibiting PLA2 enzymes, for the treatment or prevention, or the treatment and prevention of inflammation in an individual.

Background technique

Phospholipase A2 enzymes (PLA2) are a class of enzymes that catalyze the hydrolysis of phospholipids to release free fatty acids and lysophospholipids. This catalytic reaction is essential for the production of lipids such as prostaglandins, leukotrienes, thromboxanes, platelet activating factors, lipoxins or lysophosphatidic acid that are involved in various physiological and pathophysiological processes . PLA2 can be divided into two groups: intracellular enzymes, including the calcium-dependent group IV PLA2 group and the calcium-independent group VI PLA2; and secreted PLA2 (sPLA2), which is a low-lying enzyme with Ca ²⁺ -dependent catalytic activity. molecular weight protein. To date, 12 mammalian sPLA2s have been identified and grouped into three major morphological collections: Group I/II/V/X, Group III, and Group XII.

Although it has been reported in patients with septic shock, rheumatoid arthritis, acute pancreatitis, multiple injuries, acute chest syndrome in patients with sickle cell anemia, bronchoalveolar lavage (BAL), and patients with Significant increases in serum sPLA2 have been detected in patients with acute respiratory distress syndrome (ARDS), but the exact function of sPLA2 in physio-pathological processes remains uncertain. GIIA appears to be very efficient in the membrane hydrolysis of Gram-positive bacteria and may be involved in host defense against the microbe. Importantly, elevated concentrations of hGIIA were found in the eye, an immune-privileged organ.

Studies of the growing body implicate PLA2 function in many important physiological and pathological conditions. Because of this, the development of PLA2 inhibitors is important not only for the study and further elucidation of the functionalization of PLA2 and its pathophysiological role, but also for the development of drugs for the treatment of disorders involving PLA2 function, such as inflammatory diseases.

There is also a need to design and develop a therapy that recognizes one of the modes of PLA2 function (i.e. inhibition of enzymatic activity, and induction of isomeric changes in ligands for M-type receptors) and, alternatively, development of a response to inhibition of all PLA2 Both modes of function are effective therapies.

Contents of the invention

The present invention relates to a compound for effective treatment and/or prevention of a disease in an individual and a method of synthesizing the compound. In one aspect, the invention relates to novel dipeptide-derived heterocyclic compounds synthesized by the methods of the invention. The invention also relates to pharmaceutical compositions comprising an effective amount of said compounds, and methods of treatment by administering such compositions to an individual in need thereof.

One aspect of the present invention relates to a method for synthesizing novel dipeptide-derived heterocyclic compounds represented by chemical formula I.

Wherein, W is a member selected from the following group: -C(R ⁵ )(R ^5a )-, -C(R ⁶ )(R ^6a )-C(R ⁷ )(R ^7a )-, -C(R ⁸ )=C(R ⁹ )-, -N(R ¹⁰ ) and combinations thereof;

X is a member selected from the group consisting of -N(R ^1a )C(=Y)N(R ⁴ )-, -OC(=Y)N(R ⁴ )-, -N(R ^1a )C( =Y)O-, -N(R ^1a )S(=O)N(R ⁴ )-, -N(R ^1a )S(=O) ₂ N(R ⁴ )-, -C(R ^1a )( R ^3a )C(=Y)N(R ⁴ )- and combinations thereof;

Y and Z independently of each other represent a member selected from the group consisting of oxygen ("O") and sulfur ("S"); and

R ¹ , R ^1a , R ² , R ³ , R ^3a , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ^6a , R ⁷ , R ^7a , R ⁸ , R ⁹ , and R ¹⁰ independently represent the selected A member of the group consisting of: hydrogen atom, amino acid side chain, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5-C12) monocyclic Or bicyclic aryl, (C5-C14) monocyclic or bicyclic aralkyl, monocyclic or bicyclic (C5-C14) heteroaralkyl, and having up to 5 heteroatoms selected from N, O, S and P (C1-C10) monocyclic or bicyclic heteroaryl, said group may be unsubstituted or further substituted by 1-6 substituents selected from the group consisting of: halogen atom, NO ₂ , OH, Amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamine, guanidino, dialkylated or diacylated Guanidine group, carboxylic acid, carbamide, ester, hydroxamic acid, phosphinic acid, phosphonate (salt), phosphonamidate (phosphonamidate, phosphonamidate), mercapto and any combination thereof.

In any preferred embodiment, the present invention includes the free base or acid form of the dipeptide-derived heterocyclic compound represented by the above formula, and the salt form thereof. The present invention also includes optical isomers, analogs, and derivatives of the compounds represented by the above formulas. In other embodiments of the invention, mixtures of enantiomers and/or diastereomers obtained from a single preparative step, combination, or interchange are included. In other embodiments of the invention, the pharmaceutically acceptable form comprises a compound described by formula I, and optionally at least one other ingredient, such as a suitable carrier, excipient, other pharmaceutically active ingredient or their combination.

The present invention also provides prodrug forms of the above analogs and derivatives, wherein the prodrugs are metabolized in vivo to produce the analogs or derivatives as described above. In fact, some of the aforementioned analogs or derivatives may be prodrugs of another analog or derivative.

The term "prodrug" is art-recognized and includes compounds that are converted into pharmaceutically active compounds of the invention in mammalian systems. See, eg, Remington's Pharmaceutical Sciences , 1980, vol. 16, Mack Publishing Company, Easton, Pa., 61 and 424.

In another aspect of the present invention there is provided a composition comprising the compound described above. Preferably, the composition can be formulated for pharmaceutical or agricultural use by including suitable carriers or excipients.

In another aspect of the present invention, there is provided a method of administering a pharmaceutically acceptable form of a compound described herein in an appropriate amount to a mammal (eg, a human) in need thereof for the treatment and/or prevention of disease. In one embodiment, the invention encompasses methods for inhibiting the PLA2 enzyme.

In another embodiment, the invention comprises a method of administering a pharmaceutically acceptable form of a compound described herein in an appropriate amount to a mammal in need thereof for the treatment and/or prevention of an inflammatory disease.

Other advantageous features of the present invention and system-related functions, methods and processes will be apparent from the following detailed description.

Description of drawings

Figure 1: Comparison of 1,3,5-triazole-2,6-dione skeleton B with 2,5-diketopiperazine A.

Figure 2: a) EtOCOCl, NMM, THF, -20 °C, then _NaN3 in _H2O ; b) toluene, 65 °C, then HOSu and pyridine; c) TFA, 30 min; d) DIEA, MeCN; e )PS-DIEA, _{CH2Cl2 .} g = bis(gem), refers to the 2-alkyl bis-diamino derivative corresponding to the corresponding amino acid according to the nomenclature proposed by Chorev and Goodman.

Figure 3: Respective X-ray crystal structures of 1,3,5-triazole-2,6dione 4, 7 and 9.

Figure 4: a) NaH (4 equiv), RX (4 equiv); b) KF/Al ₂ O ₃ (10 equiv) or NaH (2 equiv), RX (1.5 equiv).

Figure 5: Half Maximum Inhibition Curves (Half Maximum Inhibition Curves) (IC50) for inhibitor molecules compared to Me-IDX. The PLA2 enzymes hGX and hGV were compared (Y-axis represents current activity of PLA2; X-axis is inhibitor concentration); the number of inhibitor molecules (eg "mol 33#") determines the specific compound used in Table 1.

Figure 6: Half-maximal inhibition curves (IC50) for inhibitor molecules compared to Me-IDX. Compare the PLA2 enzymes hGX and hGV (Y-axis represents current activity of PLA2; X-axis is inhibitor concentration); the number of inhibitor molecules (e.g. "mol 33#") determines the specific compound used in Table 1.

Detailed ways

When describing the compounds, compositions and methods of the present invention, unless otherwise indicated, the following terms have the following meanings.

"Pharmaceutically acceptable salt" means a biologically or otherwise innocuous salt that retains the biological effectiveness and properties of the parent compound and is administered as a dosage. Due to the presence of amino and carboxyl groups, the compounds of the present invention are capable of forming acid and base salts, respectively. Pharmaceutically acceptable base addition salts can be prepared from inorganic or organic bases. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts prepared from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines; substituted amines, including naturally occurring substituted amines; cyclic amines, including isopropylamine, trimethylamine, diethylamine, Triethylamine, Tripropylamine, Ethanolamine, 2-Dimethylaminoethanol, Tromethamine, Lysine, Arginine, Histidine, Caffeine, Procaine, Hydrabamine (Halamine, Hydrabamine) , choline, betaine, aminophylline, glucosamine, N-alkylglucamine, theobromine, purine, piperazine, piperidine, and salts of N-ethylpiperidine. Other carboxylic acid derivatives are also believed to be useful in the practice of this invention, such as carboxylic acid amines, including carboxamides, lower alkylcarbamides, di(lower alkyl)carbamides, and the like.

Pharmaceutically acceptable acid addition salts may be prepared with inorganic or organic acids. Salts are derived from inorganic acids including hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, and the like. Salts derived from 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, formic acid Organic acids such as sulfonic acid, ethanesulfonic acid, p-benzenemethanesulfonic acid, salicylic acid, etc.

The term "treatment" as used herein includes the treatment of conditions or diseases in animals, especially mammals, and more particularly humans, including:

(i) preventing a disease or condition occurring in a subject who may have a disease but has not been diagnosed;

(ii) inhibiting the disease or condition, ie, observing its development; relieving the disease or condition, ie, causing regression of the condition; or relieving the condition caused by the disease, ie, the symptoms of the disease.

As defined herein, the term "therapeutically effective amount" means an amount sufficient to effect treatment when administered to a mammal in need of such treatment. A therapeutically effective amount will vary with the subject and the state of the disease being treated, the severity of the affliction, and the mode of administration, and can be routinely determined by one of ordinary skill in the art.

"Heterocycle" refers to a heterocyclic group having 4 to 9 carbon atoms and at least one heteroatom selected from N, O or S.

"Alkyl" means a branched or unbranched alkyl group having 1 to 6 carbon atoms, a branched or unbranched alkenyl group having 1 to 6 carbon atoms, a branched or unbranched group having 1 to 6 carbon atoms Alkynyl group (alkinyl group).

"Hydroxy" refers to the functional group -OH when used as a substituent in an organic compound.

"Heterocyclic group" may be optionally substituted with 1 to 5, preferably 1 to 3 substituents selected from the group consisting of: alkoxy, substituted alkoxy, Cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, amide, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl ), azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxyalkyl, thioaryloxy, thioheteroaryloxy, thioheterocycle Oxy, sulfhydryl, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocycle, heterocycloxy, hydroxylamino , alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO ₂ -alkyl, -SO ₂ -substituted alkyl , -SO ₂ -aryl, oxo (=O), and -SO ₂ -heteroaryl. Such a heterocyclic group may have a single ring or multiple condensed rings. Preferred heterocyclic compounds 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, indazine, isoindole, indole, indazole, purine, quinozine, Isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthrene, isothiazole, hydrochloric acid Promethazine (phenazine), isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuryl, etc. Cyclic N-alkoxy-nitrogen.

The term "sulfhydryl" refers to a -SH group.

The term "thioalkoxy" refers to an -S-alkyl group.

"Amino acid" means any molecule comprising amino and carboxylic acid functional groups and includes any naturally occurring amino acid of the D, L or DL form (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl , Hyp, Ile, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val). The side chains of naturally occurring amino acids are well known in the art and include, for example, hydrogen (such as in glycine), alkyl (such as in alanine, valine, leucine, isoleucine, proline, acids), substituted alkyl groups (such as in threonine, serine, methionine, cysteine, aspartic acid, asparagine, glutamic acid, glutamine, arginine, and lysine) , alkaryl (such as in phenylalanine and tryptophan), substituted arylalkyl (such as in tyrosine), and substituted heteroarylalkyl (such as in histidine ).

"Amididine" refers to a functional group having two amino groups attached to the same carbon atom with a carbon-nitrogen double bond (HN=CR'-NH" ₂ ).

"Alkoxy" means an alkyl group attached to oxygen: R-O-, where R is an alkyl group.

"Substituted alkyl" means a branched or unbranched alkyl, alkenyl or alkynyl group having from 1 to 10 carbon atoms and substituted with one or more substituents selected from the group consisting of, Said group includes: hydroxyl, mercapto, carbylmercapto, halogen, carbyloxy, amino, amido, carboxyl, cycloalkyl, sulfo or acyl. These substituents generally have the same defined meanings as the corresponding groups defined herein.

"Halogen" refers to fluorine, bromine, chlorine and iodine atoms.

"Aryl" represents a _group -C(O)Re where _Re is halogen, alkyl, substituted alkyl, aryl, substituted aryl, aralkyl, substituted aralkyl, cycloalkyl , substituted cycloalkyl groups, and these general groups have the same definition as the corresponding groups defined in the description of the drawings.

"acloxy" refers to the -OAc group, where Ac is acyl, substituted acyl, heteroacyl, substituted heteroacyl, and these general groups have the same defined meanings as the corresponding groups defined in the description of the figures.

"Alkylamino" means a group _-NRfRg , where _Rf and _{Rg ,} independently of each other, represent hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted hetero Aryl, and these general groups have the same defined meanings as the corresponding groups defined herein.

"Aryl" means an aromatic carbocyclic group having from 1 to 18 carbon atoms and consisting of at least one aromatic or multiple condensed rings of which at least one is an aromatic ring.

"Substituted aryl" means an aromatic carbocyclic group having 1 to 18 carbon atoms and consisting of at least one aromatic or multiple condensed rings of which at least one is an aromatic ring. The ring is selected from the group consisting of halogen, alkyl, hydroxyl, carbylmercapto, alkylamino, carbyloxy, amino, amido, carboxyl, nitro, mercapto or sulfo One or more substituents in the group of are optionally substituted, and these general groups have the same defined meanings as the corresponding groups defined in the description of the figures.

"Heteroaryl" means a heterocyclic group having 4 to 9 carbon atoms and at least one heteroatom selected from N, O or S, at least one ring being aromatic.

"Substituted heteroaryl" means a heterocyclic group having 4 to 9 carbon atoms and at least one heteroatom selected from N, O or S, at least one ring of which is aromatic, and the group is selected from Substituted by a group in the group consisting of: halogen, alkyl, carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, nitro, mercapto or sulfo groups, and these general groups have the same defined meanings as the corresponding groups defined in the description of the figures.

"Carboxy" means a -C(O)OR _j group where R _j is hydrogen, alkyl, substituted alkyl, aryl, substituted aryl, heteroaryl, or substituted heteroaryl, and these typically The groups of have the same defined meanings as the corresponding groups defined herein.

"Cycloalkyl" means a monocyclic or polycyclic alkyl group having 3 to 15 carbon atoms.

"Substituted cycloalkyl" refers to a monocyclic or polycyclic alkyl group substituted by a group having 3 to 15 carbon atoms and selected from the group consisting of: halogen, alkyl, divalent carbon oxygen Carbyloxy, carbylmercapto, alkylamino, amido, carboxyl, nitro, mercapto or sulfo, and these general groups have the same definitions as the corresponding groups defined in the description of the accompanying drawings meaning.

"Heterocycloalkyl" refers to a monocyclic or polycyclic alkyl group having 3 to 15 carbon atoms in which at least one ring carbon atom in the ring structure is replaced by a heteroatom selected from N, O, S or P.

"Substituted heterocycloalkyl" means a monocyclic ring or ring having 3 to 15 carbon atoms in which at least one ring carbon atom in the ring structure is replaced by a heteroatom selected from the group consisting of N, O, S or P Polycycloalkyl, and the group contains one or more substituents selected from the group consisting of: halogen, alkyl, substituted alkyl, divalent carbonoxy, divalent carbon mercapto, aryl , nitro, mercapto or sulfo, and these general groups have the same definition as the corresponding groups defined in the description of the drawings.

The term "aryl" refers to an unsaturated aromatic carbocyclic group having 6 to 20 carbon atoms having a single ring (e.g. benzene) or multiple condensed rings (fused), wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, anthracenyl). Preferred are phenyl, naphthyl and the like.

The term "alkenyl" refers to a monovalent group of branched or unbranched unsaturated hydrocarbon groups, preferably having 2 to 40 carbon atoms, more preferably 2 to 10 carbon atoms, and more preferably 2 to 6 carbon atoms. Preferred alkenyl groups include ethenyl (-CH= _CH2 ), n-propenyl ( _-CH2CH = _CH2 ), isopropenyl (-C( _CH3 )= _CH2 ) and the like.

"Imidazole" means a heterocyclic group represented by the general formula C ₃ H ₄ N ₂ .

"Aralkyl" means, for example, a C1-C6 alkyl group bonded to 1 or 2 aromatic hydrocarbon rings having 6 to 10 carbon atoms and a total of 7 to 14 carbon atoms, such as phenyl, α-naphthalene Methylene, indenylmethyl, benzhydryl, 2-ethyl, 2-α-naphthylethyl, 3-phenylpropyl, 3-α-naphthylpropyl, phenylbutyl, 4-α-naphthylbutene base or 5-phenylpentyl.

"Guidine" generally refers to the amidine of carbamic acid and has the general formula: C(NH ₂ ) ₃ .

The terms "aralkyl" and "heteroaralkyl" are meant according to the above definitions to include aryl or heteroaryl as well as alkyl and/or heteroalkyl and/or carbocyclic and/or heterocycloalkyl ring systems, respectively.

The present invention relates to nitrogen-containing heterocyclic compounds represented by the following general formula I:

Wherein, W is selected from the group consisting of: -C(R ⁵ )(R ^5a )-, -C(R ⁶ )(R ^6a )-C(R ⁷ )(R ^7a )-, -C(R ⁸ )=C(R ⁹ )-, -N(R ¹⁰ ) and combinations thereof;

X is selected from -N(R ^1a )C(=Y)N(R ⁴ )-, -OC(=Y)N(R ⁴ )-, -N(R ^1a )C(=Y)O-, -N (R ^1a )S(=O)N(R ⁴ )-, -N(R ^1a )S(=O) ₂ N(R ⁴ )-,-C(R ^1a )(R ^3a )C(=Y) N(R ⁴ )-groups and combinations thereof;

Y and Z each independently represent a member selected from the group consisting of oxygen ("O") and sulfur ("S"); and

R ¹ , R ^1a , R ² , R ³ , R ^3a , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ^6a , R ⁷ , R ^7a , R ⁸ , R ⁹ and R ¹⁰ each independently represent Members of the following group groups: hydrogen atom, amino acid side chain, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5-C12) monocyclic or bicyclic aryl , (C5-C14) monocyclic or bicyclic alkenyl, monocyclic or bicyclic (C5-C14) heteroarylalkyl, and (C1-C10) having up to 5 heteroatoms selected from N, O, S and P ) monocyclic or bicyclic heteroaryl, which may be unsubstituted or further substituted by 1-6 substituents selected from the group consisting of: halogen atom, NO ₂ , OH, amidine, benzamidine, Imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamine, guanidino, dialkylated or diacylated guanidino, carboxy Acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate (salt), phosphonamidate (phosphonamidate), thiol, and combinations thereof.

Intermediates in the process and desired compounds can be isolated and purified by purification methods routinely used in synthetic organic chemistry, for example, neutralization, filtration, extraction, washing, drying, concentration, recrystallization, and various layers Analysis method. Intermediates can be subjected to subsequent reactions without purification.

The present invention covers all possible isomers (including tautomers) and mixtures thereof. Chiral carbons lend themselves to two different enantiomers, which are expected and have been separated into two enantiomers.

Such purification procedures may be subjected where a salt of a compound is desired and prepared in salt form. In the case where the compound is prepared in the nature of the free state and a salt thereof is desired, the compound is dissolved or suspended in a suitable organic solvent, and then the salt is formed by adding an acid or base.

The present invention also relates to pharmaceutically acceptable salts, racemic compounds, and optical isomers of formula I thereof. Compounds of the invention generally contain one or more chiral carbons. Accordingly, the present invention is intended to include racemic mixtures, diasteromers, enantiomers and mixtures enriched in one or more stereoisomers. The scope of the invention described and claimed includes the compounds as well as the racemic forms of the individual isomers and non-racemic mixtures thereof.

In another aspect of the invention, methods of using the above-described analogs and derivatives and compositions are provided. These methods include the use of compounds of the invention to inhibit the PLA2 enzyme, to treat or prevent human and crop diseases and disorders, or both. Examples of human diseases or conditions include, but are not limited to, inflammation, septic shock, rheumatoid arthritis, acute pancreatitis, acute chest syndrome in patients with sickle cell anemia, acute respiratory distress syndrome (ARDS), Obesity, obesity-related insulin resistance, hyperalgesia, pulmonary edema, colitis, ischemia, pleurisy, microbial infection, rheumatoid arthritis, skin infection, psoriasis, cancer, osteoporosis, asthma, autologous Immune disease, HIV, AIDS, rheumatoid arthritis, systemic lupus erythematosus, type I insulin-dependent diabetes, tissue transplantation, malaria, African sleeping sickness, Chagas disease, toxoplasmosis, psoriasis, restenosis, as a cosmetic Inhibition to inhibit unwanted hair growth, hyperparathyroidism, inflammation, treatment of peptic ulcer, glaucoma, Alzheimer's disease, inhibition of atrial tachycardia, stimulation or inhibition of intestinal motility, Crohn's disease and other inflammatory bowel diseases, hypertension (vasodilation), stroke, epilepsy, anxiety, neurodegenerative disorders, hyperalgesic states, protection against hearing loss (especially cancer chemotherapy-induced hearing loss), and cocaine reinforcement Pharmacological management and therapy in cocaine addiction and overdose addiction as well as other fungal, viral and parasitic diseases.

In another aspect of the present invention, there is provided a composition comprising the compound described above. Preferably, the composition can be formulated for pharmaceutical or agricultural use by adding suitable carriers or excipients.

In another aspect of the present invention there is provided a method of administering a compound described herein in a pharmaceutically acceptable form and in an appropriate amount to a mammal (eg a human) in need thereof for the treatment and/or prevention of disease. In one embodiment, the invention encompasses a method of inhibiting a PLA2 enzyme. In another embodiment, the invention comprises the molecules listed in Table 1, which are useful for inhibiting PLA2. Specifically, molecules 49, 33, 40, 9, 5, 4 and 3 are useful for inhibiting Group V and Group X sPLA2. These molecules indicate the following hierarchy in sPLA2 inhibition: Molecule 40 > Molecule 33 > Molecule 40; and Molecule 9 > Molecule 5 ≈ Molecule 4 ≈ Molecule 3, respectively.

In another embodiment, the present invention encompasses a method of administering a compound described herein in a pharmaceutically acceptable form and in a suitable amount to a mammal (eg, a human) in need thereof for the treatment and/or prevention of inflammation.

Combinatorial chemistry techniques for designing and synthesizing cyclic/polycyclic molecular scaffolds by efficiently arranging selected pharmacophores in 3D space is an important approach to identify small molecules that can modulate biological processes and analyze biological pathways. Due to the ease of access, the chemical and stereochemical diversity of derivatives of peptides, and the increased diversity due to increased manipulation, small or mesocyclic molecules derived from peptides (e.g., 2,5-diketopiperazines) especially interested. To further increase the diversity of scaffolds accessible to peptide substrates, we investigated the possibility of synthesizing densely functionalized (five-point differences) dipeptide-derived 1,3,5-triazepane-2,6-dione scaffolds And show that it counteracts the application of PLA2 by screening a small "prospecting" library.

The descriptions of the embodiments contained herein are given by way of example, and do not limit the scope of the invention. Other advantageous features and functionality associated with the systems, methods and processes of the present invention will be apparent from the following examples.

Example

To date, 12 mammalian sPLA2 species have been identified and grouped into three main collections: Group I/II/V/X, Group III, and Group XII.

Although it has been reported in septic shock, rheumatoid arthritis, acute pancreatitis, multiple injuries, acute chest syndrome in patients with sickle cell anemia, and in patients with acute respiratory distress syndrome (ARDS), sPLA2 activity is markedly increased in serum of bronchoalveolar lavage (BAL), but the exact function of sPLA2 in physio-pathological processes is uncertain. GIIA appears to be very efficient in the membrane hydrolysis of Gram-positive bacteria and may be involved in host defense against the microbe. Importantly, hGIIA concentrations were elevated in the eye, an immune-privileged organ.

It is found at high levels in GIB pancreas, has enhanced activity on substrates in the presence of deoxycholate in bile, detergents, and is activated by insulin in the intestine. A role for GIB in phospholipid digestion can thus be proposed. Knockout of the gene encoding the enzyme failed to show an initial important role in lipid absorption, but mice fed a high-fat diet showed that GIB-knockout mice were less obese and associated with Obesity-related insulin resistance.

Exogenous addition of GV and GX to various mammalian cells resulted in the release of arachidonate and eicosanoid generation, even without activation of cPLA2. Furthermore, prostaglandin E2 (PGE2) and leukotriene C4 (LTC4) production was reduced in zymosan-treated peritoneal macrophages from GV knockout mice. Therefore, GV and GX may be involved in the production of eicosanoids in some cases. The physiological roles of GIIC, GIIE, GIIF, GUI, GXIIA, and GXIIB are unclear, but some evidence suggests that GXII may be involved in vertebrate neuronal development, even in the absence of any catalytic activity.

Recent evidence has shown that PLA2 proteins not only hydrolyze proteins but also act as ligands for different binding proteins. The best known sPLA2-binding protein is the M-type receptor (MtR). This receptor was originally cloned as a transmembrane glycoprotein with the same general properties as the macrophage mannose receptor, and more recently cloned receptors Endo-180 and Dec-205. This receptor has a large extracellular domain comprising a cysteine-rich domain, a type II fibronectin-like protein domain, eight lectin-like domains (CTLDs), a single transmembrane region, and the N-terminus of a short cytoplasmic tail . The M-type receptor can quickly internalize sPLA2, thereby clearing sPLA2. A soluble form of the receptor that recognizes the enzymatic activity that inhibits sPLA2 binding is also consistent with this view. In addition, results obtained from receptor gene targeting and other studies using pancreatic sPLA2 suggest that M-type receptors function as intracellular signaling molecules through sPLA2 binding, for example by activating the MAPK cascade, inducing Pro-inflammatory response phenotype, and upregulation of Fas receptor expression on the cell surface.

A structure-based strategy for the discovery of group HA-specific sPLA2 inhibitors led to inhibition of this recognition by sPLA2 indole analogues with nanomolar affinity. An analogue, LY311727, was able to inhibit the release of thromboxane A2 triggered by exogenously added hGIIA in guinea pig BAL fluid containing macrophages, eosinophils and epithelial cells. LY311727 is also able to inhibit sPLA2 activity induced by lipopolysaccharides in the ARDA guinea pig model. Furthermore, intravenous administration of LY311727 to hGIIA-overexpressing transgenic mice resulted in a loss of sPLA2 catalytic activity in the blood, suggesting that this inhibitor could be activated in these animals, at least in the bloodstream. In an experimental model of toxoplasmosis in mice, where injection of LY311727 resulted in early death, at least one of the sPLA2s sensitive to this inhibitor was protective in these mice. Furthermore, lumbar intrathecal administration of LY311727 was observed to attenuate all symptoms associated with inflammation in three different experimental rat models of hyperalgesia.

The second-generation indole-induced inhibitor, called S-5920/LY315920Na, reduced lung compliance, pulmonary edema, vascular permeability, and pulmonary surfactant in a rabbit model of oleic acid-induced lung injury. Decomposition was significantly reduced. Two other inhibitors of sPLA2, LY333013 (S-3013) and 5-(4-benzyloxyphenyl)-4s-(7-phenylheptanamide)-valeric acid, protected rats from dextran sulfate and Nitrobenzenesulfonic acid-induced colitis. Oral administration of 5-(4-benzyloxyphenyl)-4s-(7-phenylheptanamide)-pentanoic acid also protects the intestine from ischemia and reperfusion injury in rats.

Ear edema induced by tetracenoyl phorbol-13-acetate in mice was reduced by YM-26734, an inhibitor of proteins known as mGIIA, mGIID, mGIIE, mGV, and mGX molecules. The same drug also significantly reduced the accumulation of exudate and granulocytes in a rat model of carageenin-induced pleurisy. Despite the predicted effect of sPLA2, no significant differences between treatment with PLA2 inhibitors and controls were found in clinical studies using S-5920/LY315920Na in relation to human sepsis and organ failure. However, since GIIA and PLA2 have antimicrobial properties, and septic shock is caused by microbial invasion, it can be argued whether sPLA2 inhibitors make sense in the treatment of septic shock.

A recent clinical trial utilizing orally distributed LY333013, another sPLA2 inhibitor, in patients with rheumatoid arthritis resulted in a significant reduction in symptoms during the first week of the trial, but this benefit disappeared thereafter. In a subsequent report, the authors reported a positive effect on pathology when this inhibitor was administered intravenously. In patients with asthma, the same inhibitors failed to show any benefit on inhaled allergen challenge. It is important to note the strong resistance to LY333013 in these patients.

Thus, the route of administration (eg, oral, parenteral, enteral, subcutaneous, intravenous, rectal, etc.) and the biological system used for the inhibitor can affect its efficacy. For example, BMS-1881162, an inhibitor of GIIA and cPLA2, was very potent when used in topical formulations in a mouse model of chronic skin infection induced by repeated irradiation. Anti-inflammatory activity. This inhibitor has no effect on people with psoriasis. Labeled BMS-1881162 used in volunteers exhibited barely discernible drug penetration, most likely due to the thicker stratum corneum in humans compared to mice.

An indole inhibitor called indoxam (IDX) inhibits the production of PGE2 induced by TGF-α and IL-I in rat gastric epithelial cells. Me-indoxam (Me-IDX) is a derivative of indoxam, which is about 20 times more potent than LY311727 in inhibiting hGIIA. This indole analog is suitable for use in studies on mammalian cells, and it not only inhibits the enzymatic activity of hGIIA, but also inhibits other group I/II/V/X sPLA2. The fact that IDX and its related indole compounds affect various inflammatory signals in mammalian cells and animal models points to the involvement of at least one sPLA2 from group I/II/V/X in these processes.

Since Me-IDX is known to bind to and protrude from sPLA2, it can interfere with interactions between molecules but not between phospholipids. In fact, it has been shown that IDX is able to block the binding of porcine pancreatic group IB and group X sPLA2 to murine cells expressing M-type receptors with good potency ( _IC50 = 130nM and 900nM, respectively). However, it is not known whether this observation can be extrapolated to other sPLA2 in an endogenous setting, for example, using sPLA2 and M-type receptors from murine. Such studies are important for pathophysiological disorders that may be related to sPLA2 binding to receptors. Indeed, mice lacking the M-type receptor were resistant to endotoxic shock and had lower circulating IL-I and TNF-α after LPS treatment compared with M-type receptor expressing mice concentration. Nevertheless, LPS-induced septic shock in wild-type mice was alleviated by indoxam treatment. Recently, we found that not only group IB and group IIAsPLA2, but also several mouse sPLA2 from groups I/II/V/X can initially bind to the M-type receptor recognized by the snake venom sPLA2 OS2, which led to the inference that : One or more sPLA2s are involved in these processes, and the effect of indoxam may be due to inhibition of enzymatic activity or binding to M-type receptors.

The results obtained by analyzing the direct binding properties of radiolabeled mammalian sPLA2 performed on cell membranes in the presence of Me-IDX, and the known as sPLA2 clearly demonstrate the effects observed with sPLA2 inhibitors in different studies The evaluation of the inhibitory effect of various other molecules of inhibitors may not only be due to the inhibition of sPLA2 catalytic activity, but also due to the modulation of the binding properties of sPLA2 to its receptor.

The interest in the design and evaluation of dipeptide-derived 1,3,5-triazepane-2,6-dione scaffolds stems from a study of diazepine and triazepine The backbone of the molecule is labeled for biological activity. In recent years, more attention has been paid in particular to the development of HIV proteases, as well as the conversion of transcriptase inhibitors, factor Xa inhibitors, β-lactamase inhibitors, phospholipase C inhibitors, and chemokine receptor antagonists. Ureas.

The following studies established that the novel 7-membered ring and 8-membered ring nitrogen-containing heterocyclic compounds of the present invention are useful in PLA2 and are effective for the treatment and prevention of inflammatory diseases.

I. Labeling of E.coli membranes with [ ³ H]-oleic acid:

1) Make a 10 ml overnight preculture in Luria Broth (LB) w/or w/o ampicillin with a single clone of E. coli strain. The DH 10B and XL-1 strains appeared to be superior to the JM101 strain, ie they were able to give films with less background and pelleted more easily in the PLA2 test. The _OD600nm of the saturated overnight preculture was approximately 2UDO. Dilute 1/5 and measure _OD600nm .

2) Dilute the preculture in 100 ml of fresh LB until 0.05 UOD _{600 nm} and add 25 μl of [ ³ H]-oleic acid (NET289, NEN, 5 mCi/ml, alcohol solution). Open the vial containing the stock solution in the hood and flush the vial with _N before closing. 10 [mu]l of the culture was kept for later quantification mixed with oleic acid.

3) Cells were grown at 37° C. for 5 hours with vigorous shaking (200-300 rpm) to 1 UOD _600nm .

4) Spin the culture for 15 min/4,000 rpm/50ml falcon tube/RT. 50 [mu]l of the supernatant was retained for later quantification mixed with oleic acid. The supernatant was removed and the pellet was resuspended in 50 ml of LB, and the cells were grown with shaking for an additional 30 minutes at 37°C (this step allowed the remaining unmixed labeled oleic acid to mix into the phospholipids).

5) Rotate as above. 50 μl of the supernatant was reserved for subsequent quantification. The supernatant was removed and the pellet was resuspended in 50 ml of wash buffer.

6) Rotate as above. 50 μl of the supernatant was reserved for subsequent quantification. The supernatant was removed and the pellet was resuspended in 2 ml of wash buffer (without BSA). A 2 μl portion was reserved for counting and the remainder of the solution was transferred to Corex glass tubes. Aluminum foil was used as a lid and autoclaved (20 min, 120° C., 1.5 bar). This step can be performed overnight.

7) The next day, keep 2 μl of the portion for counting and transfer the remaining solution to 2 centrifuge tubes (Eppendorf tubes). Wash the Corex tubes with 1 ml of wash buffer mixed with 2 ml of the solution.

8) Spin at 14,000 rpm (RT) for 1 minute. 10 μl of supernatant was reserved for subsequent quantification. The supernatant was removed and each pellet was pelleted with 1.5 ml of wash buffer. Repeat this step four or more times.

9) Resuspend pellet in 5ml wash buffer and count 5[mu]l for quantification of mixing with oleic acid. This solution was diluted to 10,000 dpm/μl and 30 μl was taken.

10) Count the different supernatants and calculate the percentage of radioactivity compared to the input amount in step 9. Typically, the mixed radioactivity is 30-40% greater than the input radioactivity added in step 2.

II. PLA2 test:

1) Prepare the substrate:

Pipette the desired amount of radioactivity (100,000 dpm labeled membrane per reaction x numbered reaction) and dilute to 1 ml of PLA2 activity buffer in a centrifuge tube.

Spin at 14,000 rpm (RT) for 1 min. Remove the supernatant. The pellet was carefully resuspended in 150 [mu]l of PLA2 activation buffer and PLA2 activation buffer was added for the total number of reactions. Store the pool at room temperature (do not prepare too many pools in advance).

2) PLA2 test response:

A typical reaction was performed in a centrifuge tube and a total volume of 150 μl included PLA2 activity buffer made up of 50 μl, a negligible volume of enzyme solution, and 100 μl of the above-mentioned substrate pool (adding a considerable amount of multiple pipettes (multipipette) The substrate results in sufficient mixing so that vortex mixing (vortex) is not necessary after substrate addition).

The reaction mixture was incubated with different amounts of enzyme for different periods of time up to 1 hour at 25°C or 37°C (incubation was routinely performed at room temperature (RT)). Incubation times and sample volumes are adjusted to ensure hydrolysis rates are within the range of the enzyme assay (typically 10-20% total substrate hydrolysis). Control incubations without sPLA2 addition were performed in parallel and used to calculate specific hydrolysis.

3) Stop the reaction by adding 300 μl of stop buffer. Spin the tube at 14,000 rpm for 3 minutes at room temperature. Supernatants containing released labeled oleic acid were collected and counted.

Three or four 100 μl aliquots of the substrate pool were counted to determine the total amount of e.g. radioactivity/reaction.

Note that we generally consider the counts in the supernatant to be the total number of free ³ H-oleate released from the membrane phospholipids above. One can confirm that these counts are true free oleic acid by performing thin layer chromatography on silica gel 60 under conditions that separate free oleic acid from phospholipids.

It should also be noted that this experimental design is not specific for sPLA2 detection, which can also be used to detect cytoplasmic PLA2 activity.

Material:

DH 10B or XL-1E.coli strain (can be a strain with or without plasmid); [ ³ H]-oleic acid (NET289 in ethanol, NEN, 5 mCi/ml); Component V fatty acid free BSA (Sigma #A6003 or A7511); Component V BSA (sigma #A7906); Corex glass tubes or equivalent. Buffer: Wash buffer: 0.1M Tris/HCl pH 8.0, 1mM EDTA containing 0.5% fatty acid free BSA; PLA2 activity buffer: 0.1M Tris/HCl pH 8.0, 10mM CaCl2, 0.1% BSA; Stop buffer: 0.1M EDTA with 0.2% fatty acid free BSA.

therapeutic administration

One embodiment of the invention includes a method of inhibiting the PLA2 enzyme. Another embodiment of the invention includes therapeutic compositions comprising a pharmaceutically acceptable form of the invention. In another embodiment, the present invention includes a method for treating and/or preventing a disease, such as an inflammatory disease, in a mammal, such as a human, comprising administering an effective amount of a compound of the present invention in a pharmaceutically acceptable form. Compounds of the invention may optionally be administered with at least one carrier, excipient, another biologically active agent, and any combination thereof.

Suitable routes of administration include oral, rectal, vascular, topical (including ocular, buccal and sublingual), vaginal and maternal (including subcutaneous, intramuscular, intravitreal, intravenous, intradermal, intrathecal and epidural). The preferred route of administration will depend on the patient's condition, the toxicity of the compound, and the site of infection, among other things known to the clinician.

Therapeutic compositions of the present invention comprise from about 1% to about 95% active ingredient, with administration in single dosage form preferably comprising from about 20% to about 90% active ingredient and administration in form of single dosage form preferably comprising about 5% of the active ingredient. About 20% active ingredients. The unit dosage forms are, for example, coated tablets, tablets, injections, vials (vials), suppositories or capsules. Other forms of administration are, for example, ointments, creams, pastes, creams, tinctures, lipsticks, drops, sprays, powders, and the like. An example of a capsule contains from about 0.05 g to about 1.0 g of active ingredient.

The pharmaceutical compositions according to the invention are prepared in a manner known per se, for example by conventional mixing, granulating, coating, dissolving or lyophilization processes.

Preferably, solutions of the active ingredient are used, and also suspensions or dispersions, especially isotonic aqueous solutions, dispersions or suspensions, e.g. containing the active ingredient itself or together with a carrier such as mannitol In the case of a lyophilized composition. The pharmaceutical composition may be sterilized and/or may contain excipients such as preservatives, stabilizers, wetting agents, and/or emulsifiers, solubilizers, salts for adjusting osmotic pressure and/or buffers , and it is prepared in a manner known per se, for example by conventional dissolution or lyophilization processes. The solutions or suspensions may include viscosity-increasing substances, such as sodium carboxymethylcellulose, carboxymethylcellulose, dextran, polyvinylpyrrolidone or gelatin.

Pharmaceutically acceptable forms include, for example, gels, lotions, sprays, powders, pills, tablets, controlled release tablets, sustained release tablets, rate controlling release tablets, enteric coated Coatings, emulsions, liquids, salts, pastes, gels, aerosols, ointments, capsules, gel caps, or any other suitable form well known to those of ordinary skill in the art.

Suspensions in oils contain, as the oily component, vegetable, synthetic or semi-synthetic oils which are customarily used for injection purposes. Specifically, the oil is a liquid fatty acid ester comprising as the acid component long-chain fatty acids with 8-22, especially 12-22 carbon atoms, for example, lauric acid, tridecanoic acid, Myristic acid, pentadecanoic acid, palmitic acid, margaric acid, stearic acid, arachidonic acid, behenic acid or corresponding unsaturated acids, e.g. oleic acid, elaidic acid, erucic acid (euric acid), brasidic acid and linoleic acid, if appropriate with the addition of antioxidants such as vitamin E, beta-carotene or 3,5-di-tert-butyl-4-benzyl alcohol. The alcohol component of these fatty acid esters has not more than 6 carbon atoms and is monohydric or polyhydric, such as monohydric, dihydric or trihydric alcohols, such as methanol, ethanol, propanol, butanol or pentanol, or its isomers, but especially ethylene glycol and glycerol. Thus, fatty acid esters are, for example: ethyl oleate, isopropyl myristate, "Labrafil M2375"" (polyoxyethylene glyceryl trioleate from Gattefosee, Paris), "Labrafil M 1944CS" (through unsaturated PEGylated glycerides prepared by hydrolysis and consisting of glycerides and polyethylene glycol esters; from Gattefosee, Paris), "Labrasol" (unsaturated PEGylated glycerol prepared by TCM alcoholysis and consists of glycerides and polyethylene glycol esters; from Gattefosee, Paris) and/or "Miglyol 812" (triglycerides from unsaturated fatty acids with a chain length of _C8 to _C12 , from HuIs AG, Germany), And in particular vegetable oils such as cottonseed oil, almond oil, olive oil, castor oil, sesame oil, soybean oil and especially peanut oil.

The preparation of injection compositions is carried out in the usual manner under sterile conditions, as by filling bottles (for example ampoules or vials), and closing the containers.

For example, pharmaceutical compositions for oral administration are obtained by combining the active ingredient with one or more solid carriers, and if the resulting mixture is suitable for granulation, and if desired, the mixture or granules can be made into coated tablets. Nuclei, if appropriate to add additional excipients.

Suitable carriers are, in particular, fillers such as sugars (for example lactose, sucrose, mannose or sorbitol cellulose) and/or calcium phosphates (for example tricalcium phosphate or dibasic calcium phosphate), and additionally viscous substances such as starch. Binder (such as corn, wheat, rice or potato starch,), methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and/or polyvinyl-pyrrolidine, and/or pulverizer ( desintegrator) (if desired), such as the above-mentioned starch, and carboxymethyl starch, cross-linked polyvinyl-pyrrolidone, alginic acid or their salts, such as sodium alginate. In particular, additional excipients are flow regulators, lubricants, such as salicylic acid, talc, stearic acid or their salts (such as magnesium stearate or calcium stearate), and/or polyethylene glycol, or their derivatives.

The core of the tablet can be provided with a suitable coating, if appropriate, a coating that is resistant to gastric juices, and the coating can additionally be made from a solution of concentrated sugar solution containing, if appropriate, gum arabic, Talc, polyvinylpyrrolidine, polyethylene glycol, and/or titanium dioxide; a coating solution in a suitable organic solvent or solvent mixture for the preparation of a coating resistant to gastric juices; or preparation of a suitable cellulose (e.g. A solution of acetylcellulose diacid or hydroxypropylmethylcellulose phthalate).

By "controlled release" it is meant that, for the purposes of the present invention, the therapeutically active compound, or both, is released from the formulation at a controlled rate or at a specific site (e.g., in the gut) such that therapeutically favorable blood levels (but below toxic concentrations) are maintained over extended periods of time, eg, 12-hour or 24-hour dosage forms are provided.

The term "rate controlling polymer" as used herein includes hydrophilic polymers, hydrophobic polymers or mixtures of hydrophilic and/or hydrophobic polymers capable of delaying the release of the composition in vivo. In addition, many of the same polymers can also be used to make enteric coatings for drugs, drug suspensions, or drug matrices. It is within the skill of the artisan to vary the thickness, permeability, and dissolution characteristics of the coating to provide the desired controlled release profile (eg, rate and site of drug release) without undue experimentation.

Examples of suitable release-controlling polymers for use in the present invention include hydroxyalkylcelluloses such as hydroxypropylcellulose and hydroxypropylmethylcellulose; poly(ethylene) oxides; alkylcelluloses such as ethylcellulose Carboxymethylcellulose; Hydrophilic cellulose derivatives; Polyethylene glycol; Polyvinylpyrrolidone; Cellulose acetate; Cellulose acetate propionate, Cellulose phthalate; Trimellitic acid Cellulose; Polyvinyl acetate phthalate; Hydroxypropyl methylcellulose phthalate; Hydroxypropyl methylcellulose acetate succinate; Poly(alkyl methacrylate) and poly( vinyl acetate). Other hydrophobic polymers include polymers or copolymers derived from acrylates or methacrylates, copolymers of acrylates or methacrylates, zein, waxes, shellac, and hydrogenated vegetable oils.

In order to ensure correct release kinetics, the controlled-release formulations of the present invention contain between about 5% and 75% by weight, preferably between about 20% and 50% by weight, more preferably between about 30% and 45% by weight of controlled-release polymers and about 1% to 40% by weight, preferably about 3% to 25% by weight, of active compounds. The controlled release formulations of the present invention may preferably include adjuvants such as diluents, lubricants and/or melting binders. Preferably, excipients are chosen to minimize the water content of the formulation. Preferably, the formulation includes an antioxidant. Suitable diluents include pharmaceutically acceptable inert fillers such as microcrystalline cellulose, lactose, dibasic calcium phosphate, sugars, 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 ph112, Avicel pH101 and Avicel pH102; lactose such as lactose monohydrate, anhydrous lactose and Pharmatose DCL 21; dibasic calcium phosphate such as Emcompress; mannitol; starch; Sucrose and Glucose. Diluents are carefully selected to match the compression characteristics of a particular formulation. Suitable lubricants include agents which contribute to the flow of the powder to be extruded, for example, colloidal silicon dioxide such as Aerosil 200, talc, stearic acid, magnesium stearate and calcium stearate. Suitable low temperature fusing agents include polyethylene glycols such as PEG 6000; cetostearyl alcohol; cetyl alcohol; polyoxyethylene alkyl ethers; polyoxyethylene castor oil derived substances; polyoxyethylene sorbitan fatty acid esters; polyoxyethylene stearates, polyols and waxes.

Antioxidants can be included to improve the stability of the controlled release formulation. Suitable antioxidants include sodium metabisulfite; tocopherols such as alpha, beta or delta tocopheryl esters and alpha-tocopheryl acetate; ascorbic acid and pharmaceutically acceptable salts thereof; ascorbyl palmitate; Alkyl gallates of Tenox PG, Tenox s-1; sulfites or their pharmaceutically acceptable salts; BHA; BHT and dihydroxypropyl mercaptan.

The controlled-release formulation of the present invention can preferably be directly compressed after blending the compound containing the controlled-release polymer and the auxiliary drug. Other methods for the manufacture of this formulation include melt granulation. A preferred melt granulation technique involves melt granulation with a rate controlling polymer and diluent followed by compression into granules, and subsequent melt granulation with the rate controlling polymer and diluent followed by compression of the blend. Prior to compression, the blend and/or granules need to be sieved and/or mixed with adjuvants until a homogeneous mixture which is readily drainable is obtained.

The oral dosage form of the controlled-release formulation of the present invention may be in the form of tablet, coated tablet, enteric-coated tablet or multiparticulate (for example in the form of pellets or small tablets). Capsules (eg hard or soft capsules) may contain the multiparticulates if desired. If desired, multiparticulate oral dosage forms may comprise a blend of at least two populations of pellets or minitablets with different controlled release profiles in vitro and/or in vivo. At least one of the pellets or population of minitablets may, if desired, comprise immediate release multiparticulates, eg produced by conventional means.

If desired, the controlled release matrix tablets and multiparticulates of the present invention can be coated with a layer of a controlled release polymer to provide additional controlled release properties. Polymers that can be used to form the controlled release layer include the rate controlling polymers listed above.

If desired, the tablets, pellets or minitablets of the present invention may be provided with a light-tight and/or cosmetic film coating, e.g., film formers, pigments, detackifiers and plasticizers, such film formers The formulation may consist of instant ingredients such as low viscosity hydroxypropyl methylcellulose such as methylcellulose Methocel E5 or D14 or Pharmacoat 606 (Shin-Etsu). The film coating may also include excipients commonly used in film-coating processes, such as opacifying pigments, such as iron oxides, titanium dioxide, anti-blocking agents such as talc, and suitable plasticizers such as PEG 400 , PEG 6000, diethyl phthalate and triethyl citrate).

The controlled release polymers of the present invention may consist of a hydrogel matrix. For example, the compound can be compressed into a dosage form containing a rate controlling polymer (such as HPMC), or a mixture of polymers when moisture swells it to form a hydrogel. The rate of release from this dosage form can be controlled by diffusion of the mass of the swollen tablet and erosion of the tablet surface over time. The rate of release can be controlled by the amount of polymer contained per tablet and the inherent viscosity of the polymer employed.

Dyestuffs or pigments may be incorporated into the tablets or the coatings of the tablets, eg for confirmation or identification of different doses of active ingredient.

The pharmaceutical composition for oral administration can also be hard or soft capsules, closed capsules of gelatin and a plasticizer, such as glycerol or sorbitol. Hard capsules may contain the active substances in the form of granules, for example mixed with fillers such as corn starch, binders and/or lubricants such as talc or magnesium stearate and, if appropriate, stabilizers. In soft capsules, the active ingredients are preferably dissolved or suspended in suitable liquid excipients, such as greasy oil, liquid paraffin, or liquid fatty acid esters of polyethylene glycol or ethylene glycol or propylene glycol, also Stabilizers and soil release agents may be added, for example of the polyethylene sorbitan fatty acid ester type.

For example, other oral forms of administration are syrup bases prepared in customary manner, containing the active ingredient, for example, in suspension or in a concentration of about 5% to 20%, preferably about 10%, or to bring about a suitable Forms of similar concentrations for individual dosages, for example when 5ml or 10ml are dosed. Other forms are, for example, powdered or liquid concentrates, for example in milk, also prepared by shaking. Such concentrates may also be presented in unit dosage portions.

Pharmaceutical compositions for rectal administration, such as suppositories, may consist of a combination of active ingredients with a suppository base. Suitable suppository bases are, for example, naturally occurring or synthetic triglycerides, paraffin hydrocarbons, polyethylene glycols or higher alkenols.

Compositions suitable for parenteral administration are aqueous solutions or aqueous injection suspensions of the active ingredients in water-soluble form (for example, water-soluble salts), which contain viscosity-increasing substances, such as sodium carboxymethylcellulose, sorbitol and/or or dextran. and stabilizers (if applicable). The active ingredient can also be present in lyophilized form (if suitable lyophilized with excipients) and dissolved by the addition of a suitable solvent prior to parenteral administration. For example, solutions used for parenteral administration can also be used as injection solutions. Preferred preservatives are, for example, antioxidants such as ascorbic acid and microbicides such as sorbic acid and benzoic acid.

Ointments are oil-in-water emulsions containing not more than 70%, but preferably 20-50%, water or an aqueous phase. The fatty phase comprises hydrocarbons to improve the ability to bind water, in particular petrolatum, liquid paraffin or hard paraffin's, preferably suitable hydroxyl compounds such as those of fatty alcohols or their esters, e.g. Cetyl alcohol or wool wax alcohol such as wool wax. Emulsifiers are corresponding lipophilic substances, for example sorbitan fatty acid esters (Spans), for example sorbitan monooleate and/or sorbitan. Additives in the aqueous phase are, for example, polyhydric alcohols such as wetting agents, eg glycerol, propylene glycol, sorbitol and/or polyethylene glycol, or preservatives and fragrance substances.

Fatty ointments are anhydrous or contain as a base hydrocarbons, in particular, such as paraffin, petrolatum or paraffin oil, and other naturally occurring or synthetic fats, such as hydrogenated coconut fatty acid triglycerides, or preferably hydrogenated oils , such as hydrogenated peanut oil or hydrogenated castor oil, and other partial esters of fatty acid glycerol, such as glycerol monostearate or distearate, and, for example, fatty alcohols. It may also contain emulsifiers and/or additives as described in connection with creams to enhance water absorption.

Creams are water-in-oil emulsions that contain more than 50% water. Specifically, the oil base used is fatty alcohol such as lauryl alcohol, cetyl alcohol or stearyl alcohol; fatty acid such as palmitic acid or stearic acid; liquid-solid wax such as isopropyl myristate, wool wax or beeswax (liquid tosolid waxe) and/or hydrocarbons such as petrolatum (mineral oil) or paraffin oil. Emulsifiers are surface-active substances with predominantly hydrophilic properties, such as corresponding nonionic emulsifiers, such as fatty acid esters of polyols or their vinyl oxygen adducts, such as polyglyceric fatty acid esters or polyethylene sorbitol fatty acids Esters (Tweens), and other polyoxyethylene fatty alcohol esters or polyoxyethylene fatty acid esters; or corresponding ionic emulsifiers, such as alkali metal salts of fatty alcohol sulfates, such as sodium lauryl sulfate, sodium cetyl sulfate or sodium stearyl sulfate which is commonly used in the presence of fatty alcohols such as cetyl stearyl or stearyl alcohol. Furthermore, additives added to the aqueous phase are agents that prevent the drying of the cream, for example polyalcohols such as glycerin, sorbitol, propylene glycol and/or polyethylene glycol, and other preservatives and fragrance substances.

Pastes are creams and ointments with secretion-absorbing powdery ingredients, such as metal oxides such as titanium oxide or zinc oxide, and talc and/or aluminum silicates with binding action to moisture or exudates present.

The foam is administered from a spray container and is a liquid oil-in-water emulsion in aerosol form. The sparging gas used is a halogenated hydrocarbon of the input lower chlorofluorocarbons, such as dichlorofluoromethane and dichlorotetrafluoroethane, or preferably, a non-halogenated gaseous hydrocarbon, air, _N2O or carbon dioxide. In addition, the oily phase used is the above-mentioned ointments and creams, and the said additives may be used.

Tinctures and solutions usually contain an aqueous-ethanolic base to reduce evaporation, such as polyalcohols such as glycerin, sorbitol, propylene glycol and/or polyethylene glycol, and fats such as with lower polyethylene glycols Re-oiling substances of acid esters, ie soluble in aqueous mixtures to replace lipophilic substances removed from the skin with ethanol, and if desired, other excipients and additives can also be mixed.

The present invention also relates to processes and methods for treating the aforementioned disease states. The compound may be administered in this way or in the form of a pharmaceutical composition for prophylactic or therapeutic purposes, preferably in an amount effective against the disease in question. For warm-blooded animals (eg humans) in need of such treatment, in particular, the compounds are used in the form of pharmaceutical compositions. For a body weight of about 70 kg, the daily dose of the compound of the present invention is about 0.1 to about 5 g, preferably 0.5 g to about 2 g.

It can be considered that the examples and implementations described herein are for illustrative purposes only, and that various slight (in light) substitutions, modifications or changes will be suggested to those skilled in the art and included in the scope of this application. spirit and scope and are considered to be within the purview of the appended claims. The following examples are given by way of preferred embodiments without limiting the invention in any way. For example, the relative amounts of ingredients may be varied to achieve different desired effects, additional ingredients may be added, and/or one or more desired ingredients may be substituted for like ingredients. All publications, patents, and patent applications cited herein are hereby incorporated by reference in their entirety.

Examples of general synthetic schemes and procedures:

Example 1: Synthesis of [1,3,5]oxadiazepane-2,6-dione (Formula Ia)

General Scheme Synthetic Scheme for Ia:

a) iodobenzene bistrifluoroacetate (lBTFA), THF/H ₂ O; b) BoC ₂ O; c) p-nitrophenyl chloroformate, CH ₂ Cl ₂ , diisopropylethylamine; d ) trifluoroacetic acid; e) DIEA, HOBt; f) NaH, R ³ Br.

Embodiment 2: the synthesis of 2-thio-[1,3,5]triazide-6-one (chemical formula Ib)

General synthetic scheme for Ib:

Step a) After consumption of the starting material, the dipeptide amide Ib-pl was dissolved in THF/water (3:1)) and treated with iodobenzene bistrifluoroacetate (1.2 equiv) for 3 hours. The solvent was removed in vacuo and Et2Θ was added. The solid formed was collected and washed with Et2Θ to yield the corresponding bis-diamino derivative which was used in the next step without further purification. Quantitative yield.

Step b) bis(benzotriazol-l-yl)methanethione (1 equiv) was dissolved in _CH2Cl2 at room temperature (rt ₎ . The previously synthesized bis-diamino derivative was added dropwise and the reaction mixture was stirred for 18 hours. The solvent was removed in vacuo and the residue was redissolved in EtOAc and washed with 5% aqueous sodium carbonate, water and brine before drying over anhydrous sodium sulfate. The solvent was removed under vacuum and Ib-p2 was recrystallized from ethyl acetate.

Step c) Treatment of 1-thiocarbamoylbenzotriazole with TFA at 0°C. After 30 minutes, TFA was removed by co-evaporation with hexanes and diethyl ether was added to precipitate the TFA salt. The resulting salt Ib-p3 was collected by filtration and dried under high vacuum. It was used in the next step without purification.

Step d) TFA salt Ib-p3 was dissolved in MeCN then diisopropylethylamine (2.5 equiv) was added and the reaction mixture was stirred for 24 hours. The solvent was removed in vacuo and the residue was redissolved in EtOAc, washed with aqueous sodium carbonate, 1M HCl, water and brine before drying over anhydrous sodium sulfate. The solvent was removed in vacuo and cyclic Ib-1 was purified by recrystallization from ether.

Example 3: Synthesis of 4-benzyl-6-methyl-[1,3,6]oxadiazole-2,5-dione (chemical formula Ib-1)

General synthetic scheme for Ib-1:

Step a) After consumption of the starting material, the dipeptide amide Ib-pl was dissolved in THF/water (3:1)) and treated with iodobenzene bistrifluoroacetate (1.2 equiv) for 3 hours. The solvent was removed in vacuo and Et2Θ was added. The solid formed was collected and washed with Et2Θ to yield the corresponding bis-diamino derivative which was used in the next step without further purification. Quantitative yield.

Step b) bis(benzotriazol-l-yl)methanethione ₍ 1 equiv) was dissolved in _CH2Cl2 at room temperature. The previously synthesized bis-diamino derivative was added dropwise and the reaction mixture was stirred for 18 hours. The solvent was removed in vacuo and the residue was redissolved in EtOAc and washed with 5% aqueous sodium carbonate, water and brine before drying over anhydrous sodium sulfate. The solvent was removed under vacuum and Ib-p2 was recrystallized from ethyl acetate.

Step c) Treatment of 1-thiocarbamoylbenzotriazole with TFA at 0°C. After 30 minutes, TFA was removed by co-evaporation with hexanes and diethyl ether was added to precipitate the TFA salt. The resulting salt Ib-p3 was collected by filtration and dried under high vacuum. It was used in the next step without purification.

Step d) TFA salt Ib-p3 was dissolved in MeCN, then diisopropylethylamine (2.5 equiv) was added and the reaction mixture was stirred for 24 hours. The solvent was removed in vacuo and the residue was redissolved in EtOAc, washed with aqueous sodium carbonate, 1M HCl, water and brine before drying over anhydrous sodium sulfate. The solvent was removed in vacuo and cyclic Ib-1 was purified by recrystallization from _CH2Cl2 / _diisopropyl ether.

Example 4: Synthesis of 2-thio-[1,3,5]oxydiazide-6-one (chemical formula Ic)

General synthetic scheme for Ic:

a) iodobenzene bistrifluoroacetate (lBTFA), THF/H ₂ O; b) BoC ₂ O; c) bis(phenyltrisazo)methanethione, CH ₂ Cl ₂ ; d) trifluoro Acetic acid; e) Diisopropylethylamine, MeCN, NaH.

Example 5: Synthesis of [1,3,6]oxadioxane-2,5-dione (chemical formula Id)

General synthetic scheme of Id:

a) p-nitrophenyl chloroformate ( ₂ equiv), pyridine (1.1 equiv), _CH2Cl2 , TA overnight; b) TFA, TA for 30 minutes; c) DIEA (2.6 equiv), HOBt, ( 1 equiv), MeCN, TA for 3 days.

Embodiment 6: the synthesis of 4-benzyl-6-methyl-[1,3,6]oxydiazide-2,5-dione (chemical formula Id-I)

General synthetic scheme of Id-1:

a) o-nitrophenyl chloroformate (2 equiv), pyridine (1.1 equiv), CH2Cl2, TA overnight; b) TFA, TA for 30 minutes; c) DIEA (2.6 equiv), HOBt (1 equiv), MeCN, TA 3 jours.

1) Synthesis of p-nitrophenyl carbonate Id-p2

The starting dipeptidol _Id -pl (300 mg, 0.93 mmol, 1 eq) was dissolved in 5 mL of _CH2Cl2 and 82 μL of pyridine (1.02 mmol, 1.1 eq). 2 mL of 4-nitrophenyl chloroformate solution (0.37 g, 1.86 mmol, 2 eq).

After stirring for 24 h, the reaction mixture was diluted with 15 mL of CH ₂ Cl ₂ and washed with 1 N NaHCO ₃ . The organic phase was dried over _Na2SO4 , concentrated and purified by flash chromatography (eluent 1 :2 AE/cyclohexane) to yield pure carbonate Id-p2 ( ₅₉ % yield). HPLC tR 14.1 (gradient 30-100% B over 20 minutes).

¹ H NMR (300MHz, CDC13) δ8.3 (m, 2H, atom-Hα-NO ₂ ), 7.39 (m, 2H, atom-H β-NO2), 7.24 (m, 5H, atom-H), 5.34 (m, J=10.55Hz, IH NH), 4.85 (q, J=14.9, 7.9Hz, IH α-NH), 4.314.14 (dd, J=9.97, 5.1Hz, 2H α-O), 3.77 3.54 (dd, J=14.5, 5.2 Hz, 2H α-NMe), 2.98 (m, 2H α-Phe), 2.79 (s, 3H NMe), 1.43 (s, 9H Boc).

¹³ C NMR (100MHz, CDC13) δ171.8 (CO amide), 154.8 (CO carbamate), 154.5 (CO carbonate), 151.6 (C atom α-NO2), 144.8 (C atom δ-NO2), 135.5 (C atom Phe), 128.8 (2CHPhe), 128.7 (2CH Phe), 127.8 (CH-Phe), 124.7 (CH atom), 121.1 (CH-atom), 79.3 (C Boc), 66.0 (CH2α-O) , 50.9 (CHα-NH), 46.447.0 (CH2α-N), 39.4 (CH2Phe), 35.833.6 (CH3 NMe), 27.7 (3 CH3 Boc).

2) Cyclization into Id-p1

p-Nitrophenylcarbonate was treated with trifluoroacetic acid for 30 minutes. Addition of ether precipitated the corresponding TFA as a white solid. It was filtered and used in the next step without purification. TFA salt (220 mg, 0.44 mmol, 1 eq) dissolved in MeCN (10 mL) was slowly added to a solution of diisopropylethylamine (194 μL, 1.14 mmol, 2.6 eq) and hydroxybenzotriazole ( HOBt) (60 mg, 0.44 mmol, 1 eq). The reaction mixture was stirred for 3 days and concentrated in vacuo. Then _CH2Cl2 was added and the organic phase was washed with 1N _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) followed by _CHCl3 /MeOH [20:1]) to provide 42 mg of Id-I.

HPLC _tR (Id-I) 5.88 (gradient 30-100% B over 20 minutes).

Calcd for _{Ci3Hi6N2O3 249.1234} by HRMS ( _ESI ) to give 249.1230 _.

¹ H NMR Id-I (300 MHz, CDCl ₃ ) δ 7.25 (m, 5H, aroma-H), 6.10 (d, H ⁴ ), 4.75 (dd, J=8.9, 7.4 Hz, H ⁵ ), 4.20 ( m, 2H ³ ), 4.15(m, H ² ), 3.28(dd, J=14.0, 7.6Hz, IH ⁶ ), 3.17(m, H ² '), 3.02(dd, IH ⁶ ), 3.0(8, 3H ¹ ).

¹³ C NMR Id-I (100MHz, CDCl ₃ ) δ172.3 (CO amide), 157.7 (CO carbonate), 136.9 (C-atom), 129.3 (2CH atom), 128.6 (2CH atom), 126.8 (CH atom ), 69.6 (CH ₂ α-O), 54.0 (CH α-N), 52.9 (CH ₂ α-N), 36.6 (CH ₃ Me), 35.7 (CH ₂ Phe).

Example 7: Synthesis of 1,1-dioxo-1λ-[1,2,5,8]thiatriazide-4-one (chemical formula If)

The general synthetic scheme of If:

i) (a) TFA; (b) saturated NaHCO ₃ , DCM; ii) Burgess reagent (2.5 eq), THF, 70° C. for two hours.

Example 8: 10-methyl-6,6,11-trioxo-8,9,10,11,11a,12-hexahydro-5H-6λ-thia-5a,7,10-triaza- Synthesis of Methyl Cyclooctyl[b]naphthalene-7-carboxylate (Chemical Formula If-1)

General synthetic scheme of If-1:

(i)(a)TFA，0℃，30分钟；(b)饱和的NaHCO₃，DCM；ii)Burgess试剂(2.5eq)，THF，70℃2小时。

(i) (a) TFA, 0 °C, 30 minutes; (b) saturated _NaHCO3 , DCM; ii) Burgess reagent (2.5 eq), THF, 70 °C, 2 hours.

i) Treat the N-Boc protected dipeptide alcohol with TFA at 0°C for 30 minutes. TFA was removed under vacuum and the residue was dissolved in AcOEt. Sat. NaHCO ₃ was added with stirring and after 10 min the organic phase was dried over Na ₂ SO ₄ and concentrated in vacuo to give If-pl.

ii) Compound If-pl (175 mg, 0.75 mmol, 1 eq) was dissolved in 10 mL of anhydrous THF and Burgess reagent (534 mg, 2.24 mmol, 2.5 eq) was added. The solution was then heated at reflux at about 70°C to about 90°C for 2 days. The reaction mixture was then poured into saturated _NH4Cl (40 mL) solution. The mixture was _extracted with _CH2Cl2 and the organic phase was washed with _H2O , dried over _Na2SO4 and concentrated in vacuo _. The crude mixture was then purified by silica gel chromatography ( _CHCl3 /MeOH/AcOH (18:1:0.2) to yield If-1.

Claims (14)

1. A compound for inhibiting PLA2 enzyme, comprising chemical formula I:

or a pharmaceutically acceptable salt thereof, Wherein, W is a member selected from the group consisting of: -C(R ⁵ )(R ^5a )-, -C(R ⁶ )(R ^6a )-C(R ⁷ )(R ^7a )-, -C(R ⁸ )=C(R ⁹ )-, -N (R ¹⁰ ) and combinations thereof; X is a member selected from the group consisting of: -N(R ^1a )C(=Y)N(R ⁴ )-, -OC(=Y)N(R ⁴ )-, -N(R ^1a )C(=Y)O-, -N(R ^1a )S(=O)N(R ⁴ )-,-N(R ^1a )S(=O) ₂ N(R ⁴ )-,-C(R ^1a )(R ^3a )C(=Y)N(R ⁴ ) - and combinations thereof; Y and Z independently of each other represent a member selected from the group consisting of oxygen ("O") and sulfur ("S"); and R ¹ , R ^1a , R ² , R ³ , R ^3a , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ^6a , R ⁷ , R ^7a , R ⁸ , R ⁹ , and R ¹⁰ independently represent the selected A member of the group consisting of: hydrogen atom, amino acid side chain, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5-C12) monocyclic Or bicyclic aryl, (C5-C14) monocyclic or bicyclic aralkyl, monocyclic or bicyclic (C5-C14) heteroaralkyl, and having up to 5 heteroatoms selected from N, O, S and P (C1-C10) monocyclic or bicyclic heteroaryl, said group may be unsubstituted or further substituted by 1-6 substituents selected from the group consisting of: halogen atom, NO ₂ , OH , amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamine, guanidino, dialkylated or diacyl guanidino, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate (salt), phosphonamido, mercapto, and any combination thereof. 2. A therapeutic composition for treating or preventing inflammation in an individual comprising an effective amount of a compound of formula I:

or a pharmaceutically acceptable salt thereof, Wherein, W is a member selected from the group consisting of: -C(R ⁵ )(R ^5a )-, -C(R ⁶ )(R ^6a )-C(R ⁷ )(R ^7a )-, -C (R ⁸ )=C(R ⁹ )-, -N(R ¹⁰ ) and combinations thereof; X is a member selected from the group consisting of: -N(R ^1a )C(=Y)N(R ⁴ )-, -OC(=Y)N(R ⁴ )-, -N(R ^1a )C(=Y)O-, -N(R ^1a )S(=O)N(R ⁴ )-,-N(R ^1a )S(=O) ₂ N(R ⁴ )-,C(R ^1a )(R ^3a )C(=Y)N(R ⁴ )- and combinations thereof; Y and Z independently of each other represent a member selected from the group consisting of oxygen ("O") and sulfur ("S"); and R ¹ , R ^1a , R ² , R ³ , R ^3a , R ⁴ , R ⁵ , R ^5a , R ⁶ , R ^6a , R ⁷ , R ^7a , R ⁸ , R ⁹ , and R ¹⁰ independently represent the selected A member of the group consisting of: hydrogen atom, amino acid side chain, (C1-C10) alkyl, (C1-C10) alkenyl, (C1-C10) alkynyl, (C5-C12) monocyclic Or bicyclic aryl, (C5-C14) monocyclic or bicyclic aralkyl, monocyclic or bicyclic (C5-C14) heteroaralkyl, and having up to 5 heteroatoms selected from N, O, S and P (C1-C10) monocyclic or bicyclic heteroaryl, said group may be unsubstituted or further substituted by 1-6 substituents selected from the group consisting of: halogen atom, NO ₂ , OH , amidine, benzamidine, imidazole, 1,2,3-triazole, alkoxy, (C1-C4), amino, piperazine, piperidine, dialkylamine, guanidino, dialkylated or diacyl guanidino, carboxylic acid, carboxamide, ester, hydroxamic acid, phosphinic acid, phosphonate (salt), phosphonamido, mercapto, and any combination thereof. 3. The therapeutic composition of claim 2, further comprising at least one of a pharmaceutically acceptable carrier, excipient, adjuvant, another biologically active agent, or a combination thereof. 4. The therapeutic composition of claim 3, wherein the biologically active agent comprises at least one of a steroid, a non-steroidal anti-inflammatory agent, acetylsalicylic acid, a cyclooxygenase inhibitor, or a combination thereof . 5. The therapeutic composition of claim 3, wherein the therapeutic composition is in a pharmaceutically acceptable form. 6. The therapeutic composition of claim 5, wherein the pharmaceutically acceptable form comprises a tablet or capsule with an enteric coating. 7. A method for treating or preventing an inflammatory disease or condition comprising An effective amount of the therapeutic composition of claim 2 is administered to an individual in need thereof. 8. The method of claim 7, wherein the therapeutic composition further comprises at least one other ingredient selected from the group consisting of a pharmaceutically acceptable carrier, an excipient, an adjuvant, another Bioactive agents or combinations thereof. 9. The method of claim 8, wherein the bioactive agent comprises a steroid, a non-steroidal anti-inflammatory agent, acetylsalicylic acid, a cyclooxygenase inhibitor, or a combination thereof. 10. The method of claim 7, wherein the therapeutic composition is administered in a pharmaceutically acceptable form. 11. The method of claim 10, wherein the pharmaceutically acceptable form comprises a tablet for oral administration or an enteric-coated capsule. 12. The method of claim 7, wherein the therapeutic composition is administered parenterally. 13. The method of claim 7, wherein the inflammatory disease or condition is selected from the group consisting of tissue damage, rheumatoid arthritis, osteoarthritis, eczema, lupus, IBD, Crohn's disease , ARDS, colitis, psoriasis, asthma, cystic fibrosis, AIDS, stenosis, restenosis, Alzheimer's disease, Parkinson's disease, cancer, atherosclerosis, arteriosclerosis, and cardiopulmonary-related diseases. 14. A kit for treating or preventing a physiological disease associated with inflammation, said kit comprising a plurality of containers, wherein at least one of said containers contains the therapeutic composition of claim 2 or a pharmaceutically acceptable Accepted salt.

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