Title of Invention

"COMPOUNDS WHICH INHIBIT THE RELEASE OF INFLAMMATORY CYTOKINES"

Abstract

The present invention relates to compound which are capable of. preventing the extracellular release of inflammatory cytokines, said compounds, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, have the formula (I): wherein R comprises ethers or amines; Rl is:a) substituted or unsubstituted aryl; orb) substituted or unsubstituted heteroaryl; R2a and R2b units are each independently hydrogen, ethers, amines, amides, carboxylates, or said units can form a double bond, a carbonyl, or R2a and R2b can be taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms, said ring selected from the group consisting of: i) carbocyclic; ii) heterocyclic; iii) aryl; iv) heteroaryl; v) bicyclic; and vi) heterobicyclic

Full Text

FIELD OF THE INVENTION The present invention relates to compounds which inhibit the release of extracellular inflammatory cytokines said cytokines responsible for one or more human or higher mammalian disease states. The present invention further relates to compositions comprising said compounds and method for preventing, abating, or otherwise controlling enzymes which are understood to be the active components responsible for the herein described disease states. BACKGROUND OF THE INVENTION Interleukin-1 (IL-1) and Tumor Necrosis Factor- a (TNF-a) are among the important biological substances known collectively as "cytokines". These molecules are understood to mediate the inflammatory response associated with the immunological recognition of infectious agents. These pro-inflammatory cytokines are suggested as an important mediators in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis, inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, cachexia, and therefore responsible for the progression and manifestation of human disease states. US 3222366 dislcoses l,l-Malonyl-l,2, dihyrdo cinnoline derivatives suggesting these to be therapeutics which can be used as anti-inflamatory, analgesics and antipyretics. Kakutani M, et al report JTE-607, an N-benzoyl-L-phenylalanine-derived compound, a multiple-cytokine inhibitor which they found that strongly suppress production of proinflammatory cytokines. (Kakutani M, Takeuchi K, Waga I, Iwamura H, Wakitani K. Inflamm Res. 1999 ;48(8):461-8.) However these compounds suggested report toxicity and causing edema some times. Further, the pharmacological effect of the compounds was clinically not well validated. Hence, their was need of a compound which can block, abate, control, mitigate, or prevent the release of cytokines from cells which produce them and which has been tested for efficacy as well. Therefore, the inventors of the application developed a new compound to inhibit the release of cytokines form cells which produce them and validated it for efficacy. SUMMARY OF THE INVENTION The present invention meets the aforementioned needs in that it has been surprisingly found that certain [5,6] and [5,6, 6] fused ring pyrazolones and derivatives thereof are effective for inhibiting release of inflammatory cytokines, inter alia, interleukin-1 (IL-1) and tumor necrosis factor (TNF) from cells and thereby preventing, abating, or otherwise controlling enzymes which are proposed to be the active components responsible for the herein described disease states. The first aspect of the present invention relates to compounds, including all enantiomeric and diasteriomeric forms and pharmaceutical acceptable salts thereof, said compounds having the formula: R is a substituent at the 2-position of the pyrimidin-4-yl portion of the general scaffold, said R unit is: a) an ether having the formula -O[CH2]kR3; or b) a primary or secondary amino unit having the formula wherein R3 is substituted or unsubstituted CrC4 alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituied heterocyclyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl; the index k is from 0 to 5. The following are the various aspects of R units according to the present invention wherein R is an ether having the formula -OfCHJuR3. However, the formulator is not limited to the herein exemplified iterations and examples. A) R units encompassing ethers having the formula -OR3 (the index k equal to 0) and R3 is substituted or unsubstituted aryl. i) One iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following nonlimiting example of R: phenoxy, 2-fluorophenoxy, 3-fluorophenoxy, 4- fluorophenoxy, 2,4-difluorophenoxy, 3-trifluoromethyl-phenoxy, 4- trifluoromethylphenoxy, 2,4-trifluorom ethyl phenoxy, and the like. ii) Another iteration of this aspect of R comprises ethers having the formula —OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: 2-methylphenoxy, 3-metnylphenoxy, 4-methy!pbenoxy, 2,4-dimethylphenoxy, 2-cyanophenoxy, 3-cyanophenoxy, 4-cyanophenoxy, 4- ethyl phenoxy, and the like. iii) A further iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is substituted or unsubstituted aryl. This iteration includes the following non-limiting examples: (2-methyoxy)phenoxy, (3-methoxy)phenoxy, (4- methoxy)phenoxy, 3-[(N-acetyl)amino]phenoxy, 3-benzo[1,3]dioxol-5-yl, and the like. B) R units encompassing ethers having the formula -OR3 (the index k equal to 0) and R3 is substituted or unsubstituted heteroaryl. i) A first iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like. ii) A second iteration of this aspect of R comprises ethers having the formula -OR3 and R3 is substituted heteroaryl. This iteration includes the following non-limiting examples: 2-aminopyrimidin-4-yl, and the like. C) R units encompassing ethers having the formula -OCH2R3 (the index k equal to 1) and R3 is substituted or unsubstituted aryl. i) A first iteration of this aspect of R comprises ethers having the formula -OCH2R3 and R3 is substituted or unsubstituted heteroaryl. This iteration includes the following non-limiting examples: pyrimidin-2-yl, pyrimidin-4-yl, 2-aminopyrimidin-4- yl, 4-aminopyrimidin-6-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, and the like. ii) A second iteration of this aspect of R wherein R is an ether having the formula -OCH2R3 and R3 is substituted or unsubstituted alkyleneheteroaryl. This iteration includes the following non-limiting examples: pyridin-3-ylethyl. (2-methyl-2-pyridin- 3-yl)ethyl, and the like. D) R units encompassing ethers having the formula -OR3 (the index k equal to 1) and R3 is substituted or unsubstituted CrC4 alkyl. i) A first iteration of this aspect of R is an ether having the formula -OR3 and R3 is unsubstituted C^-C* linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: methyl, ethyl, isopropyl, (S}-1-methypropyl, and the like. ii) A second iteration of this aspect of R is an ether having the formula -OR3 and R3 is a substituted C]-C4 linear, branched, or cyclic alkyl. This iteration includes the following non-limiting examples: 2-methoxyethyl, (S>-1-methy-3-methyoxypropyl, and the like. The following are the various aspects of R units according to the present invention wherein R is an amine having the formula -NR*aR4b, R4a and RAb are each independently: a) hydrogen; or b) each R^and R*are independently hydrogen, -OR7, -N(R7)2, -CO2Rr. -CONKR^Ct-C* linear, branched, or cyclic alkyl, and mixtures thereof, R6 is hydrogen, -OR7, -N(R7)z, -CO2R7, - CON(R7)2; substituted or unsubstituted C,-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C,-C4 alkyl, or substituted or unsubstituted aryl; the index x is from 0 to 5. However, the formulator is not limited to the herein exemplified iterations and examples. A) R units encompassing chira! amino groups wherein R43 is hydrogen, R53 is hydrogen and R* is methyl, said units having the formula: and the indicated stereochemistry. i) A first iteration of this aspect of R is an amine comprising an R8 which is substituted or unsubstituted phenyl. This iteration includes the following nonlimiting examples: (S)-1-methyl-1-phenylmethylamino, (S)-1-me*hyl-1-(4- fluorophenyl)methylamino, (S)-1 -methyl-1 -(4-methylphenyl)methyl-amino, (S)-1 - methyl-1 -(4-methoxyphenyl)methylamino, (S)-1 -methyl-1 -(2- aminophenyl)methylamino. (S)-1-methyl-1-(4-aminophenyl)methylamino, and the like. ii) A second iteration of this aspect of R is an amine comprising an Rfl which is substituted or unsubstituted heteroaryl. This iteration includes the following nonlimiting examples: (S)-1 -methyl-1 -{pyridin-2-yl)methylamino, (S)-1-methyl-1- (pyridin-3-yl)methylamino. (S)-1 -methyl-1 -(pyridin-4-yl)methylamino, (S)-l-methyl- 1 -(furan-2-yl)methylamino, (S)-1-methyI-1-(3-benzo[1,3]dioxol-5-yl)methylamino, and the like. iii) A third iteration of this aspect of R is an amine comprising an R6 which is C,-G* substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples: (S)-l-methylpropylamino, (S)-1-methyl-2-{methoxy)ethylamino. B) R units encompassing chiral amino groups wherein R4a is hydrogen, R53 and R56 are each CrC4 alkyl, said units having the formula: 5a and the indicated stereochemistry when R a, Rr-> 5band R are not the same. i) A first iteration of this aspect of R is an amine which does not have a chiral center, non-limiting examples of which includes 1,1-dimethylethylamine, 1,1- dimethylbenzylamine and the like. ii) A second iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted CrC4 alkyl. This iteration includes the following nonlimiting examples: (S)-1-methyl-2-hydroxy-2-methylpropylamine, (S)-1-methyl-2- hydroxy-2-methylbutyIamine, and the like. C) R units encompassing alkylenearyl amines wherein R4a is hydrogen, both R53 and R* of R4b are hydrogen, R6 is substituted or unsubstituted aryl, said unit having the formula: H wherein R11 is hydrogen or a "substituted unit" as defined herein above, i) A first iteration of this aspect comprises the following non-limiting examples of R units: benzylamino, (2-aminophenyl)methylamino; (4-fluorophenyl)methylamino, (4-methoxyphenyl)methylamino; (4-propanesulfonylphenyl)methvlamino; and the like. ii) A second iteration of this aspect comprises the following non-limiting examples of R units: (2-methylphenyl)methylamino; (3-methylphenyl)-methylamino; (4- methylphenyl)methylamino; and the like. D) R units encompassing amines wherein R4' is hydrogen, R4bcomprises R53 equal to hydrogen and R56 equal to -CO2R7 or -CON(R7)2; said unit having the formula: i) A first iteration of this aspect of R is an amine comprising an R6 which is • substituted or unsubstituted phenyl. This iteration includes the following nonlimiting examples: wherein R11 is hydrogen or a "substitute" as defined herein above. A second iteration of this aspect of R is an amine comprising an R6 which is substituted or unsubstituted alkyl. This iteration includes the following non-limiting examples: H H H N O — N O — N - H " OH HjC OCHj R1 units are selected from: a) substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl. The first aspect of R1 units encompasses halogen substituted phenyf units, non-limiting examples of which include 4-fluorophenyl, 2,4-difluorophenyl, 4-chlorophenyt, and the like. R23 and R2" units are each independently selected from the group consisting of: a) hydrogen; b) -OtCH^R8; c) -(CH2)jNR9aR9b; d) -{CHaJjCOzR10; e) - f) -{CKypOhKR10^ g) two R23 or two R26 units from the same carbon atom can be taken together to form a carbonyl unit; h) one R2a and one Ra are taken together to form a double bond; i) one R2a and one R25 are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms, said ring selected from the group consisting of: i) carbocyclic; ii) heterocyclic; iii) aryl; iv) heteroaryl; v) bicyclic; and vi) heterobicydic; j) and mixtures thereof; R8, R9a, R9", and R10 are each independently hydrogen, CrC4 alkyl, and mixtures thereof; R9a and R91" can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5. [5.61-Fused Rings Systems A first aspect of the present invention relates to ring scaffolds wherein the indices m and n are each equal to 2. thereby comprising a 2-(R1-substituled)-3-(2-R-substituted-pyrimidin-4-yl}- 5,6,7,8-tetrahydro-pyrazo!o[1,2-a]pyridazin-1-one scaffolds having the formula: wherein the R2" and Ra units are each independently hydrogen, (CH2))CON(R10)2, and mixtures thereof. Iterations of this scaffold include the core scaffold having the formula: the S.G.T.S-tetrahydro-pyrazotoII^-aJ-pyridazin-l-one 8-position esters and amides having the formula: R R as well as the 5,6,7,8-tetrahydro-pyrazolo[1.2-a]-pyridazin-1-one 5-position esters and amides having the formula: A second aspect of the present invention as it relates to R23 and R26 units, comprises 2- (R1-substituted)-3-{2-R-substituted-pyrimidin^-y!)-5l6,7,8-tetrahydro-pyrazolo[1,2-a]pyridazin-1- one scaffolds having the formula: o .R24 R wherein each of the R23 and R2" units is independently selected form the group consisting of: a) hydrogen; b) -0(CH2)jR8; and c) -(CH2)]NR9aRflb. Iterations of this aspect include 6-hydroxy-2-(R1-substituted)-3-(2-R-substituted-pyrirnidin- 4-yl)-5.6,7,8-tetrahydro-pyrazolo[1,2-a]-pyridazin-1 -ones, 7-hydroxy-2-(R1-substituted)-3-(2-Rsubstituted- pyrimidin-4-yl)-5,6t7,8-tetrahydro-pyrazolo[1,2-a]-pyridazin-1 -ones, 6-(dimethylamino)- 2-(R1-substituted)-3-(2-R-substituted-pyrimidin-4-yl)-5I6,7,8-tetrahydro-pyrazolo[1.2-a]-pyridazin-1- ones, 6-morpholino-2-(R1-substituted)-3-(2-R-substituted-pyrimidin-4-yl)-5.6,7.8-tetrahydropyrazolo[ 1,2-a]-pyridazin-1-ones A third aspect of the present invention as it relates to R23 and R2* units, comprises scaffolds wherein two adjacent R23 and R2b units are taken together to form a double bond, for example a 2-(R1-substituted)-3- pyridazin-1 -one scaffolds having the formula: [5.6.X1-Fused Rings Systems The present invention also relates to [5,6,X]-fused ring systems wherein X is a ring formed when one R2a and one R2b are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms. The rings formed are selected from the group consisting of: i) > carbocyclic; ii) heterocyclic; Hi) I") v) vi) aryl; heteroaryl; bicyclic; and heterobicyclic; A first embodiment of this aspect relates to ring systems wherein one R2" and one Ra are taken together to form a 6-membered aryl ring, inter alia, the [5,6,6]-fused rings system; 2-(R1- substituted)-3-(2-R-substituted-pyrimidin-4-yl)-5,10-dihydro-pyrazolo[1,2-b]phthalazin-1-one having the formula: o Iterations of this aspect include analogs which are substituted on the C-ring, for example compounds having the formula: wherein R12 is a substituent as described herein above. A non-limiting example of the [5,6,6] ring scaffolds of the present invention are the 2-(R1-substituted)-3-{2-R-substituted-pyrimidin-4-yl)- 5,10-dihydro-pyrazolo[1,2-o]phthalazin-1-one ring scaffolds, for example the compound having the formula: The first aspect of Category I analogs capable of inhibiting release of inflammatory cytokines according to the present invention relates to compounds comprising a 5,10-dihydropyrazolo[ 1,2-Jb]phtha!azine-1-one scaffold having the formula: wherein R units are amines having the formula -NHtCHR^R8. and R1. R4a, R5, and R8 are described herein below in Table I. The stereochemistry of R5b is the configuration shown when R5b is not hydrogen. (Table Removed) The following is a scheme for preparing compounds belonging to the first aspect of Category I according to the present invention. The first stage encompasses utilization of Type I intermediates, for example, intermediate 3 to introduce the selected R1 unit into the assembling scaffold. General Scheme for Intermediate Type I (Figure Removed) Reagents and conditions: (a) IDA, THF, -78 °C, 45 min. (Table Removed) Reagents and conditions: (b) CrOs. CHaCb. rt, 16 hr. EXAMPLE 1 2-(4-Fluorophenvl)-3-f2-methvlsulfanvl-pvrimidin-4-vl)-3-oxopropionic acid methyl ester (3) The following is a procedure for the preparation of 2-methy!sulfanyl-pyrimidine-4- carbaldehyde. 1, adapted from the procedure of H. Bredereck et al., Chem. Ber., 97, pp 3407- 3417 (1964) included herein by reference. To a 12 L 3-neck flask under inert atmosphere is charged N,N-dimethyl-formamide dimethyl acetyl (801 g) and pyruvic aldehyde dimethyl acetal (779 g). The mixture is heated to reflux for 18 hours during which time the temperature decreases from about 109 °C to about 80 °C. The solution is cooled and methanol (4 L) is added to dissolve the crude residue. The solution is then cooled to 20 °C and thiourea (892 g, 11.7 mol) is added. After allowing the mixture to stir about 15 minutes, sodium methoxide (741 g, 13.7 mol) is added in 4 equal portions over 1 hour while maintaining the solution temperature in the range of 18 - 28 °C. The mixture is stirred for 5 hours at room temperature, cooled to 20 °C, then methyl iodide (2 kg) is added over 1.25 hours while maintaining the reaction temperature in the range of 17 - 29 °C. Stirring is continued for 18 hours at room temperature. The methanol and unreacted methyl iodide is removed by heating the solution at 35 °C @ 40 torr to produce about 4.46 kg of a dark residue which is partitioned between 14 L of water and 5 L of ethyl acetate. The water fraction is extracted a . second time with ethyl acetate, the organic layers combined and concentrated in vacuo too afford 685 g of an oil which is purified over silica to 522 g of 4-dimethoxymethy!-2-methylsuIfanylpyrimidine. The dimethyl acetal obtained above is then hydrolyzed to the free aldehyde by heating to 60 °C for 3 hours in 1 M HCI. Workup for neutral using ethyl acetate to extract the product affords 347 g crude product which is purified over silica to afford 401 g of 2-methylsulfanyll-pyrimidine-4- carbaldehyde. 1. Reagents and conditions: (a) NaH, DMF, 90 °C, 3 hr. Reagents and conditions: (b) SOCI2, MeOH, rt, 72 hr. EXAMPLE 2 1,2.3.4-Tetrahydrophthatazlne (5) Preparation of 1,4-dihydrophthalazine-2,3-dicarboxylic acid di-tert-butyl ester (4): To a solution of di-tert-butylhydrazodiformate (3.0 g, 13.0 mmol) in DMF (20 mL) at room temp is added NaH (0.5 g, 13.0 mmol). After stirring 1 hour at room temp, 1,2-bis-bromomethylbenzene (3.4 g, 13.0 mmol) is added to the reaction mixture. After stirring 1 hour at room temperature, another portion of NaH (0.5 g, 13.0 mmol) is added to the reaction mixture. The mixture is then heated to 90 °C for 3 hours, allowed to cool to room temperature and stirring is continued at room temp for 15 hours. The reaction can then be quenched by pouring the reaction solution into aqueous saturated NH4CI. The aqueous phase is extracted with ether, the organic phase dried (MgSO4). filtered and concentrated in vacua. The crude residue is purified over silica (5% EtOAc/hexanes) to afford 1.0 g (23% yield) of the desired product as a clear oil. Preparation of 1,2,3,4-tetrahydrophthalazine (5): 1,4-dihydrophthalazine-2,3- dicarboxylic acid di-terf-butyl ester, 4, (1.0 g, 3 mmol) is dissolved in MeOH (20 mL) and SOCI2 (0.5 mL) added dropwise. After stirring at room temp for 72 hours, the solvent is removed in vacua to afford 0.6 g of the desired product as white solid. The following scheme illustrates the assembly of the 3-pyrimidin-4-yl-5,10-dihydropyrazolo[ 1.2-D]phthalazine-1-one scaffold by the convergent step which condenses intermediates 3 and 5. The resulting intermediate is then transformed into the final compound having the selected R unit. OCHj SCBj SCH3 Reagents and conditions: (c) pyridine, reflux 16 hr. SCH3 . SOjCH, Reagents and conditions: (d) OXONE®, THF/MeOH, rt 2 hr. SOjCHj Reagents and conditions: (e) toluene. 140 °C 12 hr. EXAMPLE 3 2-(4-Fluorophenvl^-3-r2-(S)-(1-phenvlethvlamino)pvrimidin-4-vll-5.10-dihvdropyrazolof1,2- tolphthalazin-1-one (8) Preparation of 1-{4-fIuorophenyl)-3-(2-methyIsuIfany!-pyrimidin-4-yl)-5,10- dihydropyrazolo[1,2-b]phthalazin-1-one (6): To a solution of 1,2,3,4-tetrahydro-phthalazine, 5, (0.3 g, 1.4 mmol) in pyridine (5 mL) is added 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimidin-4-yl)- 3-oxo-propionic acid methyl ester, 3, (0.4 g, 1.4 mmol). The reaction mixture is then heated to reflux for 16 hours. The solvent is removed in vacua and the resulting residue was purified by preparative HPLC to afford 0.2 g (45% yield) of the desired product as a tan solid. Preparation of 2-(4-fluorophenyl)-3-{2-methanesulfonyl-pyTimidin-4-yl)-5,10- dihydropyrazolo[1,2-b]phthalazm-1-one (7): To a solution of 1-(4-fluorophenyl)-3-(2- methylsulfanyl-pyrimidin-4-yl)-5,10-dihydropyrazoIo[1,2-/)]phthalazin-1-onel 6, (2.4 g, 6.8 mmol) in THF:MeOH (80 ml of 1:1 mixture) is added dropwise a solution of OXONE® (16.8 g, 27.2 mmoi) in H2O (80 ml). After stirring for 2 hours at room temperature the reaction mixture is diluted with aqueous saturated NaHCO3 and extracted three times with ethyl acetate. The combined organic phases are dried (NaaSO,!), filtered and concentrated in vacua to afford 1.5 g (58% yield) of the desired product as a yellow solid. Preparation of 2-(4-fluorophenyl)-3-[2-(S)-(1-phenylethylamino)pyrimidin-4-yl]-5,10- dihydropyrazolo[1,2-Jb]phthalazin-1 -one (8): 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin- 4-yl)-5l10-dihydropyrazolo[1,2-b]phthalazin-1-one, 7, (0.9 g, 2.3 mmol) is dissolved in toluene (18 mL) together with (S)-(-)-a-methylbenzylamine (10.5 mL, 81.6 mmol). The resulting mixture is heated to 140 °C for 12 hours, cooled to room temperature and the solvent removed in vacua. The resulting residue is purified over silica (1:1 EtOAc/hexanes) to afford 0.8 g (80% yield) of the desired product as a red sticky solid. The first aspect of Category II analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,8-dihydropyrazolo[ 1.2-a]-pyridazin-1-one scaffold wherein R2a and R2" are taken together to form a double bond, said scaffold having the formula: wherein R1. R5b, and R6 are described in Table II. The stereochemistry of R5b is the configuration shown when R56 or R6 is not hydrogen. (Table Removed) The compounds which comprise the analogs of the first aspect of Category II can be prepared by the synthesis outline herein below in the following scheme. Reagents and conditions: (a) NaH, DMF; 0 °C to 90 °C 4 hr. Reagents and conditions: (b) SOCI2, MeOH; 0 °C, 17 hr. Reagents and conditions: (c) pyridine, 90 °C, 16 hr. Reagents and conditions: (d) OXONE®, THF/MeOH/waten rt 2 hr. Reagents and conditions: (e) (S)-(-}-a-methylbenzylamine. toluene; 140 °C for 12 hr. EXAMPLE 4 2-(4-Fluorophenyl)-3-f2-(1-phenvlethvlamlno)pvrimidin-4-vn-5,8=dihvdropyrazolof1.2- alpvridazin-1-one (13) •Preparation of 3,6-dihydro-pyridazine-1,2-dicarboxyIic acid di-tert-butyl ester (9): To a solution of di-ferf-butylhydrazodiformate (18.6 g, 80.0 mmol) in DMF (220 mL) cooled to 0 °C is added NaH (8.0 g of a 60% suspension in mineral oil, 200.0 mmol) portionwise. After allowing the solution to warm and stir 45 minutes at room temp, c/s-1,4-dich!oro-2-butene (8.4 mL, 80.0 mmol) is added dropwise to the reaction mixture. The mixture is then heated at 90 °C for 4 hours, cooled to room temperature and stirred an additional 15 hours. The reaction is quenched by pouring the contents of the reaction vessel into ice water. The resulting aqueous phase is extracted with ether, the combined organic phases washed with aqueous saturated NaHCO3, dried, filtered and concentrated in vacua. The obtained crude product is taken up in hexane and the resulting solid recovered by filtration to afford 24 g of the desired product as white powder. Preparation of 1,2,3,4-tetrahydro-pyridazine (10): To a solution of 3,6-dihydropyridazine- 1,2-dicarboxylic acid di-terf-butyl ester, 9, (10.0 g. 35.2 mmol) in MeOH (140 mL) at 0 °C is added dropwise SOCI2 (22.0 ml). After gradually warming to room temp and stirring for 17 hours, the solvent is removed in vacuo yielding a tan solid. The isolated solid is then dissolved in MeOH (10 mL) and diluted with ether (250 ml). The resulting white solid is collected by filtration to afford 4.3 g (79% yield) of the desired product as the di-HCI salt. Preparation of 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrimIdin-4-yl)-2,315I8- tetrahydro-pyrazolo[1,2-a]pyridazin-1-one (11) To a solution of 1,2,3,4-tetrahydro-pyridazine, 5, (5.4 g, 34.2 mmol) in pyridine (100 mL) is added 2-(4-fluorophenyl)-3-(2-methylsulfanyl-pyrirnidin- 4-yl)-3-oxo-propionic acid methyl ester, 3. (7.3 g, 22.8 mmol). The reaction mixture is heated to 90 °C for 16 hours. The solvent is then removed in vacuo and the resulting residue purified over silica (100% EtOAc) to afford 3.5 g (43% yield) of the desired product as a yellow solid. Preparation of 2-(4-fluorophenyl)-3-(2-methanesulfonyl-pyrimidin-4-yl)-2,3,5,8- tetrahydro-pyrazolo[1,2-a]pyridazin-1-one (12): To a solution of 2-(4-fluorophenyl)-3-(2- melhylsulfanyl-pyrimidin-4-yl)-2,3,5,8-tetrahydro-pyrazolo[1^-a]pyridaan-1-one, 11, (2.4 g, 6.8 mmol) in THF:MeOH (80 mL of 1:1 mixture) is added dropwise a solution of OXONE® (16.8 g, 27.2 mmol) in H2O (80 mL). After stirring 2 hours at room temp, the reaction mixture is diluted with aqueous saturated NaHCO3 and extracted with EtOAc (3x). The combined organic phases are dried, filtered, and concentrated in vacuo to afford 1.5 g (58% yield) of the desired product as a yellow solid. Preparation of 2-{4-fluorophenyI)-3-[2-(1-(S)-phenylethylamino)pyrirnidin-4-yl]-5,8- dihydropyrazolo[1,2-a]pyridazin-1-one (13): 2-(4-Fluorophenyl)-3-(2-methanesulfonylpyrimidin- 4-yl)-2,3,5,8-tetrahydro-pyrazolo[1,2-a]pvridazin-1-one, 12, (0.9 g. 2.3 mmol) is dissolved in toluene (18 mL) and (S)-(-)-a-methylbenzylamine (10.5 mL, 81.6 mmol) added. The resulting mixture is heated to 140 °C for 12 hours, cooled, and the solvent removed in vacuo. The resulting crude product is purified over silica (1:1 EtOAc/hexanes) to afford 0.8 g (80% yield) of the desired product as a red sticky solid. The second aspect of Category II analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6,7.8-tetrahydropyrazolo[ 1,2-a]-pyridazin-1-one scaffold having the formula: wherein R, R1. R23, and R26 are described herein Table III (Table Removed) For the second aspect of Category II, intermediates such as compound 13, can be utilized to prepare the analogs listed in Table IV, for example, compound 14. 13 14 Reagents and conditions: (a) OsO*. KsFefCNJe; f-BuOH:H2O, rt 12 hr. EXAMPLES 2-(4-Fluorophenyl)-6.7-dihvdroxv-3-f2-(1-phenvlethvlamino)pvrimldin-4-vt1- 5.6.7..8=tetrahvdropvrazolori.2-alpvridazln-1-one(14) Preparation of 2-{4-Fluorophenyl)-6,7-dihydroxy-3-[2-(1 -phenylethylamino)- pyrimidin-4-yl]-5,6,7,,8-tetrahydropyrazolo[1,2-a]pyridazin-1-one (14): To a solution of 2-(4- fluoropheny))-3-I2-(1-phenylethylamino)pyrimidin-4-yr]-5,8-dihydro-pyrazolo[1,2-a]pyridazin-1-one, 13. (0.8 g, 1.88 mmol) in f-BuOH:H2O (24 mL of 1:1 mixture) is added K3Fe(CN)6 (1.9 g, 5.64 mmol), K2CO3 (0.8 g, 5.6 mmol) and NaHCO3 (0.5 g. 5.6 mmol), followed by osmium tetroxide (0.1 g, 0.3 mmol). The resulting mixture is stirred at room temperature for 12 hours. The reaction is quenched by the addition of aqueous saturated KHSO4 solution (10 mL). The aqueous phase is extracted with EtOAc (3x) and the combined organic phases are dried, filtered and concentrated in vacua. The resulting crude product is purified over silica (100% EtOAc) to afford 0.4 g (48% yield) of the desired product. In addition, a compound such as 14 can itself be utilized as an intermediate to other analogs, for example, compound 15. wherein R comprises an ether. R, R1 and R10 are described herein below in Table II and the analogs have the indicated stereochemistry. (Table Removed) The compounds which comprise .the analogs of the first aspect of Category lit can be prepared by the synthesis outline herein below in the following scheme. COjH COO Reagents and conditions: (a) C2O2CU, CHaCb; rt 18 hr. (Figure Removed) Reagents and conditions: (b) CHaCJz, rt 3 hr. (Figure Removed) Reagents and conditions: (c)TEA. CH2CI2.; rt 18 hr. (Figure Removed) Reagents and conditions: (d) NaOH. MeOH. rt 20 min. (Figure Removed) Reagents and conditions: (e) TMS-CHN-. CH2CI2/MeOH; 20 min rt. (Figure Removed) Reagents and conditions: (f) OXONE®. THF/MeOH. rt 4 hr (Figure Removed) Reagents and conditions: (g) phenol, NaH. THF; rt 1 hr. EXAMPLE? 2-(4-Fluorophenvt)-3-oxo-1-(3-phenoxvphenvO-S,6.7.8-tetrahvdro-3H-pvrazploriJ2- a]pvndazine-S-carboxvlic acid methyl ester (22) Preparation of 2-methylsulfanyl-pyrimidine-4-carbony! chloride (16): To a solution of 2-methylsulfanyl-pyrimidine-4-carboxylic acid (20 g, 117.7 mmol) in CH2CI2 (100 ml) is added oxalyl chloride (17.2 g, 197 mmol) and DMF (20 drops). The reaction solution is stirred at room temperature for 18 hours after which the solvent is removed in vacua to afford 21.2 g, (95% yield) of the desired product as a dark green solid. Preparation of 1 -(methylsulfanyl-pyrimidine-4-carbonyl)hexahydro-pyridazine-3- carboxylic acid methyl ester (17): To a solution of hexahydro-pyridazine-3-carboxylic acid methyl ester (1.5 g, 8.3 mmol) in CH2CI2 (80 ml) is added 2-methyIsuIfanyl-pyrimidine-4-carbonyl chloride, 16, (1 ..41 g, 7.5 mmol) and triethylamine (1.2 mL, 8.3 mmol). The mixture is stirred at room temperature for 3 hours. The reaction solution is then diluted withl N HCI (100 mL) and the organic phase is decanted. The aqueous phase is extracted with additional solvent and the organic layers are combined, dried, and concentrated in vacua. The crude product is purified over silica(ethyl acetate/hexane 1:1) to afford 0.9 g (36% yield) of the desired product as a yellow solid. Preparation of 2-(4-fluorobenzoyl)-1-(2-methylsulfanyl-pyrimldine-4-carbonyl)- hexahydro-pyridazine-3-carboxylic acid methyl ester (18): To a solution of 1-(methylsulfanylpyrimidine- 4-carbonyl)hexahydro-pyridazine-3-carboxylic acid methyl ester, 17, (0.9 g, 3 mmol) in CH2CI2 (80 mL) is added 4-fluorophenylacetyl chloride (0.63 mL. 4.6 mmol) and triethylamine (0.55 mL, 3.6 mmol). The reaction solution is stirred at room temperature for 18 hours then dilute with 1 N HCI (50 mL) and the organic layer decanted. The organic phase is extracted with additional solvent, the organic layers are combined, dried, and concentrated in vacuo to afford the crude product. The crude material is purified over silica (ethyl acetate/hexane 1:1) to afford 1.15 g (89% yield) of the desired product as a yellow solid. Preparation of 2-(4-fluorophenyl)-1-(3-methylsuIfanyl-pyrimidin-4-yl)-3-oxo-5,6,7,8- tetrahydro-3H-pyrazoIo[1,2-a]pyridazine-5-carboxylic acid (19): To a solution of 2-(4- fluorobenzoyl)-1-(2-methylsulfanyl-pyrimidine-4-carbonyl)-hexahydro-pyridazJne-3-carboxylicacid methyl ester, 18, (1.13 g, 2.62 mmol) in methanol (40 mL) is added NaOH (1.26 g, 31.4 mmol). The reaction is stirred at room temperature for 20 minutes then diluted wit 1 N HCI (50 mL). The solution is extracted with ethyl acetate (3 x 250 mL), the organic layers are combined, dried, and concentrated in vacuo to afford 0.83 g (79% yield) of an oil which is used without further purification. Preparation of 2-(4-fluorophenyl)-1 -(3-methyIsulfanyl-pyrimidln-4-yI)-3-oxo-5,6,7,8- tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxyHc acid methyl ester (20): To a solution of 2-(4fluorophenyI)-1-(3-methylsulfanylphenyl)-3-oxo-5,6.7,8-tetrahydro-3H-pyrazolo[1l2- a]pyridazine-5-carboxy!ic acid. 19. (0.83 g, 2.1 mmol) in methylene chloride (50 mL) is added trimethylsilyl-diazomethane (1.5 mL of a 2 M solution is hexane. 3 mmol). The reaction is stirred for 20 minutes at room temperature then concentrated in vacuo to afford the crude product as an oil which is purified over silica (hexane/ethyl acetate 1:4) to afford 0.51 g (59% yield) of the desired product as a yellow foam. Preparation of 2-(4fluorophenyl)-1 -{3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5,6,7,8- tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester (21): To a stirred solution of Preparation of 2-(4f1uorophenyl)-1-(3-methylsulfanylphenyl)-3-oxo-5,6, 7 ,8-tetrahydro- 3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 20, (0.51 mg, 1.23 mmol) in methanol (30 ml) is cooled to 0 °C. Oxone® (2.27 g, 3.7 mmol) is dissolved in water (30 ml) and added dropwise to the reaction solution over 1 hour. The solution is allowed to warm to room temperature and stir a total of 3 additional hours. NaHCO3 (sat.) is added until the pH is about 7. The reaction solution is then extracted several times with ethyl acetate, the organic phases combined, dried, and concentrated in vacuo to afford 0.5 g (91 % yield) of the desired product as a yellow foam. Preparation of 2-(4-fluorophenyl)-1 -(2-phenoxy-pyrimidin-4-yl)-3-oxo-5,6,7,8- tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester (22): To a solution of 2- (4fluorophenyl)-1-(3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5,6,7,8-tetrahydro-3/-/-pyrazolo[1,2- a]pyridazine-5-carboxyllc acid methyl ester, 21, (0.033 g, 0.074 mmol) in THF (3 ml) is added phenol and NaH (0.009 g, 0.22 mmol). The reaction mixture is stirred at room temperature for 1 hour. The reaction is quenched by the addition of 1 N HCI (20 ml_) and the solution is extracted with ethyl acetate (3 x 25 ml_). The organic phases are combined, washed with brine, dried, and concentrated in vacuo to afford the crude product which is purified over silica (hexanes/ethyl acetate 1:3) to afford 0.012 g (35% yield) of the desired product as a white solid. 1H NMR (300 MHz, CDCI3) 6 8.64 (d, J = 4.6 Hz 1 H), 7.59-7.63 (m, 2 H), 7.40-7.45 (m, 3 H), 7.28-7.30 (m, 1 H), 7.18 (d, J = 8.4 Hz, 2 H), 7.03-7.08 (m, 2 H), 4.50-4.56 (m, 1 H), 3.99-4.04 (m, 1 H), 3.86 (s, 1 H), 3.01-3.10 (m, 1 H), 2.33-2.41 (m, 1 H), 1.86 (br s, 2 H), 1.64 (br s, 3 H); ESI/MS: 461 (M+H). Other compounds according to this aspect of Category III can be formed by the following procedure. 22 23 Reagents and conditions: (a) UOH. MeOH/water, ret. 3 hr. EXAMPLES Preparation of 2-{4-fluorophenyl)-1-(2-phenoxy-pyrimidin-4.yl)-3-oxo-5,6,7,8- tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (23): To a solution of 2-(4- fluorophenylJ-l-tZ-phenoxy-pyrimidin^-yJJ-S-oxo-S.GJ.S-tetrahydro-SH-pyrazoloII^-alpyridazine- 5-carboxylic acid methyl ester, 22. (0.02 g, 0.0143 mmol) in methanol (1 mL) and water (1 ml_) is added LiOH (0.016 g, 0.65 mmol). The reaction solution is stirred at room temperature for 3 hours then quenched by the addition of 1 N HCI (20 mL). The reaction solution is extracted with ethyl acetate (3 x 50 mL), the organic layers are combined, washed with brine, dried, and concentrated in vacuo to afford 0.012 g (63% yield) of the desired product as a yellow solid. 1H NMR (300 MHz, CDCI3) 8 8.45 (dd, J = 4.6,2.1 Hz, 1 H). 7.14-7.44 (m, 7 H), 6.S4-6..95 (m. 3 H), 4.93 (dd. J = 11.7. 9.3 Hz. 1 H), 4.23 (brd. J= 12.9 Hz, 1 H). 3.04-3.11 (m. 1H), 2.46-2.52 (m. 2 H). 1.71-1.93 (m. 2 H), APCI/MS: 447 (M + H). 2-(4-Fluorophenyl)-1-[2-(4-fluorophenoxy)pyrimidin^-yl]-3-oxo-5l6,7,8-tetrahydro-3Hpyrazolo[ 1,2-a]pyridazine-5-carboxylic acid: 'H NMR (300 MHz, CDCI3) 6 8.50 (d. J = 5.1 Hz, 1 H), 7.36 (dd, J = 8.7. 5.4 Hz, 2 H), 7.20-7.31 (m, 4 H), 7.02 (t, J = 8.7 Hz, 2 H), 6.97 (d, J = 5.1 Hz, 1 H), 5.23-5.25 (m. 1 H), 4.24 (d, J = 11.4 Hz, 1 H). 3.74 (s. 3H). 2.94-2.99 (m. 1 H), 2.54-2.59 (m, 1 H), 1.82-2.00 (m. 3 H); ESI/MS: 479 (M+H). The second aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6,7,8-tetrahydropyrazolo[ 1,2-a]-pyridazin-1-one scaffold having the formula: wherein R units are amines having the formula -NHfCHR^R8, and R1, R*. R6, and R10 are 5b • described herein below in Table I. The stereochemistry of R is the configuration shown when ,5b R is not hydrogen. (Table Removed) The compounds which comprise the analogs of the second aspect of Category III can be prepared by the synthesis outline herein below in the following scheme. SOjCHj 21 HjC" Reagents and conditions: (a) (S)-(-)-a-fnethy1benzylamine, toluene; 100 °C 4 hr. Reagents and conditions: (b) LiOH. MeOH/water. rt 3 hr. EXAMPLE 9 2-(4-Fluorophenvl)-3-oxo-1-f2-(1-(S)-(phenvlethvlamlno)pyrimidin^-vn-5.6,7.8-tetrahvdro- 3H-pvrazoloI1,2-a1pvridazine-5-carboxylic acid methyl ester (24) Preparation of 2-(4-fluorophenyl)-3-oxo-1 -[2-(1-(S)-phenylethylamino)pyrirnidin-4- yl]-5,6J,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester (24): To a solution of 2-(4fluorophenyl)-1 -(3-methanesulfonyl-pyrimidin-4-yl)-3-oxo-5,6,7,8-tetrahydro-3/-/- pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 21, (0.10 g, 0.22 mmol) in toluene (1.4 mL) is added (S)-(-)-a-methylbenzylamine (1.4 mL, 1.12 mmol). The reaction solution is heated to 100 °C for 4 hours after which the reaction is cooled and diluted with 1 N HCI. The resulting solution is extracted with ethyl acetate (3 x 25 mL), the organic layers are combined, dried, and concentrated in vacuo to afford 0.071 g (66% yield) of the desired product as a yellow solid. *H NMR (300 MHz, CDCI3) 5 8.22 (ddd, J = 11.4, 5.1, 2.1 Hz, I H), 7.22-7.37 (m. 7 H), 6.97 (dt, J = 8.7, 2.1 Hz, 2 H), 6.41 (ddd, J = 15.6, 5.1, 2.1 Hz, 1H), 5.72-5.83 (m, 1 H), 5.2 (brs, 2 H). 5.52- 5.62 (m, 1 H), 3.77 (s, 3 H), 3.47 (d, J = 2.7 Hz, 1 H), 2.47-2.51 (m, 2 H), 2.00 (br s, 1 H), 1.41 (d, J = 6.6 Hz, 3 H); APCI/MS: 487 (M+H). EXAMPLE 10 2-(4-Fluorophenyl)-3-oxo-1-T2-{1-(S)-(phenvlethvlamino)pvrimidin-4-vn-5,6,7,8-tetrahvdror 3H-pyrazoloT1,2-alpvridazine-5-carboxylic acid (25) Preparation of 2-(4-fluorophenyl)-3-oxo-1 -[2-{1 -{S)-pheny!ethylamino)pyrimidin-4- yO-5,6,7,8-tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid (25): To a solution of Preparation of 2-(4-fluorophenyl)-3-oxo-1 -[2-(S)-(1 -phenylethylamino)pyrimidin-4-yf]-5.6,7,8- tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester, 24, (0.066 g, 0.14 mmol) in methanol (2 mL) and water (2 mL) is added LiOH (0.033 g, 1.36 mmol). The mixture is stirred at room temperature for 3 hours then diluted with 1 N HCI (25 ml) after which the solution is extracted with ethyl acetate (3 x 50 mL). The combined organic layers are washed with brine, dried, and concentrated in vacuo to afford 0.043 g (65% yield) of the desired product as a yellow solid. 'H NMR (300 MHz, CDCI3) 8 8.13-8.19 (m. 1 H), 722-7.34 (m, 7 H), 6.97 (t, J = 8.7 Hz, 2 H), 6.34 (dd, J = 15.3. 5.1 Hz, 1 H), 5.11-5.24 (m, 2 H). 3.56 (br s. 1 H), 2.96 (br s. 1 H), 2.52-2.64 (m, 2 H), 1.79-1.96 (m, 2 H), 1.57 (d, J = 6.9 Hz, 3 H): ESI/MS: 474 (M+H). 2-(4-Fluorophenyl)-3-oxo-1-[2-(1-(S)-methyl-methoxyethylamino)pyrimidin-4-yl]-5,6t7,8- tetrahydro-3H-pyrazolo[1,2-a]pyridazine-5-carboxylic acid methyl ester: 1H NMR (300 MHz, CDCI3) 6 8.25 (d. J = 5.1 Hz. 1 H). 7.43 (dd. J = 9.0. .7 Hz. 2 H), 6.99 (t. J = 9.0 Hz, 2 H), 6.44 (d. J = 5.1 Hz. 1 H). 5.50-5.54 (m, 1 H). 5..26 (d. J = 3.6 Hz, 1 H). 4.15-4.25 (m, 2 H). 3.76 (s. 3 H), 3.37-3.47 (m. 4 H). 2.95-3.06 (m, 1 H). 2.51-2.62 (m. 1 H). 1.92-2.02 (m, 3 H). 1.23-1.30 (m. 3 H); ESI/MS: 456 (M+H). The third aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6,7,8-tetrahydropyrazolo[ 1,2-a]-pyrkJazin-1-one scaffold having the formula: wherein R is an ether moiety of the formula: -OR3. Table VI describes the various values of R, R1, andRto (Table Removed) The compounds which comprise the third aspect of Category 111 analogs can be prepared by the procedure outlined in the following scheme. (Figure Removed) Reagents and conditions: (a) (Boc^O, TEA. CHaCk; rt, 12 hr. (Figure Removed) Reagents and conditions: (b) CH2CI2. TEA, rt ,10 hr. (Figure Removed) Reagents and conditions: (c) TFA, CH2Cl2/water; 0 °C 2 hr - rt 1 hr. (Figure Removed) Reagents and conditions: (d) TEA, CH-CI2; rt 12 hr. (Figure Removed) Reagents and conditions: (e) NaOH, MeOH; rt 15 hr. (Figure Removed) Reagents and conditions: (f) CH2N2. ET2O/EtOAc; rt 5 min. (Figure Removed) Reagents and conditions: (g) Oxone , THF/MeOH/waten rt 5 hr. (Figure Removed) Reagents and conditions: (h) phenol, NaOH, THF: rt 8 hr. EXAMPLE 11 2-(4-Flurophenvl)-1-oxo-3-(2-phenoxvpvrimidin-4-vl)-5.6.7.8-tetrahvdro-1H-pvrazolof1.2-alpvridazine- 5-(S)-carboxvlic acid methyl ester (33) Preparation of tetrahydro-pyridazine-1,3-dicarboxylicacid 1-tert-butyl ester 3-(S)- methylester (26): To piperazic acid methyl ester (3.44 g, 19 mmol) in methylene chloride (150 ml.) is added (Boc)2O (4.2 g, 19 mmol) and triethylamine (2.65 ml, 19 mmol). The reaction mixture is stirred 12 hours concentrated in vacua to provide a yellow oil which is purified over silica (ethyl acetate/hexane 1:1) to afford 4.5 g (98% yield) of the desired product as a light yellow oil. Preparation of 2-(2-methylsulfanylpyrimidine-4-carbonyl)-tetrahydropyridazine-1,3- dicarboxylic acid 1-terf-butyl3-(S)-methylester (27): Tp a solution of tetrahydro-pyridazine-1,3- dicarboxylic acid 1-tert-butyl ester 3-(S)-methylester, 26, (3.91 g, 15.9 mmol) in methylene chloride (200 mL) is added 2-methanesulfanylpyrimidine-4-carbonyl chloride, 16, (3.32 g,17.6 mmol) and triethylamine (3.5 mL, 25.3 mmol) such that the pH is approximately neutral. The resulting mixture is stirred for 10 hours at room temperature and the mixture washed with water (100 mL), brine (100 mL), dried and concentrated in vacuo to afford an oil which is purified over silica (ethyl acetate/hexane 1:1) to afford 5.22 g (83% yield) of the desired product as a yellow oil. Preparation of 2-(2-methylsulfanylpyrimidine-4-carbonyl)-tetrahydropyridazine-1,3- dicarboxylic acid 3-(S)-methylester (28): To a solution of 2-(2-methylsulfanylpyrimidine-4-carbonyl)- tetrahydropyridazine-1,3-dicarboxylic acid 1-tert-butyl 3-(S)-methylester, 27, (7 g,17.6 mmol) in methylene chloride (50 mL) is added trifluoroacetic acid (50 mL) at 0°C. The reaction is stirred for 2 hours in the cold, 1 hour at room temperature, then concentrated in vacuo to a residue which can be taken up in toluene and re-concentrated to afford 7.2 g (100% yield) of the desired yield as the trifluoroacetate salt as a yellow oil which is used without further purification. Preparation of 1 -[2-(4-fluorophenyl)-2-oxo-ethyl]-2-(2-methylsulfanylpyrimidin-4- carbonyl)-hexahydropyridazine-3-(S)-carboxylic acid (29): To a solution of 2-(2-methylsulfanylpyrimidine- 4-carbonyl)-tetrahydropyridazine-1,3-dicarboxylic acid 3-(S)-methylester, 28, (7.2 g, 17.6 mmol) in methylene chloride (150 mL) is added 4-fluorophenylacetyl chloride (3 g, 17.6 mmol) and triethylamine (3.65 mL, 26.4 mmol). The resulting mixture is stirred for 12 hours then concentrated in vacuo to afford a brown oil. The crude residue is purified by prep HPLC to afford 5.33 g (70% yield) of the desired product as a yellow oil. Preparation of 2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-1 -oxo-5,6,7,8- tetrahydro-1H-pyrazolo[1^-alpyridazine-5-(S)-carboxy!ic acid (30): To a solution of 1-[2-(4- fluorophenyl)-2H)xo-ethyn-2-(2-methylsulfanylpyrirnmidin-4-carbonyl)-hexahydropyrida2ine-3-(S)- carboxylic acid, 29, (1 g) in methanol (170 mL) is added NaOH (0.23 g, 5.8 mmol). The resulting mixture is stirred for 15 hours and the mixture is concentrated In vacua to provide a residue which is dissolved in water (150 ml). The solution is acidified to pH 1 with 3 N HCI and extracted with ethyl acetate (300 mL). The organic layer is concentrated in vacuo and the resulting crude material is purified by prep HPLC to afford 7.0 g (76% yield) of the desired product as a creamcolored solid. Preparation of 2-(4-fluorophenyl)-3-{2-methylsulfanylpyrimidin-4-yl)-1 -oxo-5,6,7,8- tetrahydro-1H-pyrazolo[1,2-a]pyrldazine-5-(S)-carboxyHc acid methyl ester (31): To a solution of 2-(4-fluorophenyl)-3-(2-methylsulfanylpyrimidin-4-yl)-1 -oxo-5.6,7,8-tetrahydro-1 Hpyrazolo[ 1,2-a]pyridazine-5-carboxyIic acid, 30, in diethyl ether/ethyl acetate (2.5:1. 7o mL) is added freshly generated diazomethane in diethyl ether (5 mL). The reaction is stirred for 5 minutes then quenched by the addition of HOAc (0.5 mL). The resulting solution is washed with NaHCO3, brine, dried, and concentrated in vacua to afford 1 g (98% yield) of the desired product as a light yellow solid. Preparation of 2-(4-fluorophenyl)-3-(2-methanesulfonylpyrlmidin-4-y1)-1 -oxo-5,6,7,8- tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-(S)-carboxyHc acid methyl ester (32): To a solution of 2-(4-fluorophenyi)-3-(2-methylsulfanylpyrimidin-4-yl)-1 -oxo-5.6,7,8-tetrahydro-1 Hpyrazolo[ 1,2-a]pyridazine-5-carboxylic acid methyl ester, 31, (0.48 g, 1.16 mmol) 1:1 THF/methanol (50 mL) is added Oxone® (2.14 g. 3.5 mmol) in water (50 mL). The reaction mixture is stirred for 5 hours at room temperature, reduced in volume in vacuo to about 25 mL and ethyl acetate (200 mL) is added. The organic phase is treated with NaHCO3, brine, dried, and concentrated in vacuo to afford 0.5 g of the desired product as a yellow solid. Preparation of 2-(4-fluorophenyl)-3-(2-phenoxypyrimidin-4-yl)-1 -oxo-5,6,7,8- tetrahydro-1H-pyrazolo[1,2-a]pyridazine-5-(S)-carboxyIic acid methyl ester (33): NaOH (0.112 g, 2.8 mmol) is added to a solution of phenol (0.316 g, 3.36 mmol) in THF (100 mL). 2-(4- Fluorophenyl)-3-(2-methanesulfonylpyrimidin-4-yl)-1 -oxo-5,6,7.8-tetrahydro-1 H-pyrazolo[1,2- alpyridazine-5-carboxylic acid methyl ester, 32, (0.5 g) is dissolved in THF (50 mL) and added dropwise to the solution over 5 minutes. The resulting mixture is stirred at room temperature for 8 hours after which water (20 mL) is added. The solution is extracted with ethyl acetate (100 mL the organic layer washed with brine (50 mL) and concentrated in vacuo to afford 0.278 g (54% yield) of the desired product as a yellow solid. 'H NMR (300 MHz, CDCl3) B 1.75 (m. 2 H), 1.97 (m 1 H), 2.42 (d, J = 12.8 Hz, 1 H), 3.27 (m, 1 H), 3.27 (m, 1 H), 3.6 (s, 3 H), 4.5 (br d, J = 12.8 Hz, 1 H), 5.25 (m, 1 H), 6.87 (d, J = 5.7 Hz, 1 H), 7.05 (m, 2H), 7.23 (m. 2 H), 7.35 (m, 3 H), 7.52 (m, 2 H), 8.42 (d, J = 5.7 Hz, 1 H): exact mass calc. for CaHaFNA 460.46, MS-ESI (M-H) 461. The fourth aspect of Category III analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5,6,7,8-tetrahydropyrazolo[ 1,2-a]-pyridazin-1-one scaffold having the formula: COjR10 wherein R units are amines having the formula -NH[CHR5l>lR6, and R1. R5b, R6, and R10 are described herein below in Table VII. The stereochemistry of R5b is the configuration shown when R-,5 b is not hydrogen (Table Removed) The compounds which comprise the analogs of the fourth aspect of Category III can be prepared by the synthesis outline herein below in the following scheme starting with intermediate The fifth aspect of Category ill analogs according to the present invention capable of inhibiting release of inflammatory cytokines relates to compounds comprising a 5.6,7.8-tetrahydropyrazolo[ 1,2-a]-pyridazin-1-one scaffold having the formula: 0 CON(R9sR9b) R R wherein R, R1. R9a. and R* are defined herein below in Table VIII. TABLE VIII (Table Removed) Another iteration of this aspect relates to compounds wherein R9a and R9*1 are taken together to form a carbocyclic or heterocydic ring comprising from 3 to 7 atoms. Table IX describes compounds encompassed by this iteration of the fifth aspect of Category III. (Table Removed) Other compounds according to the present invention include: 2-(4-Fluorophenyl)-5-(piperazine-1-carbonyl)-3-(2-phenoxypyrimidin-4-yl)-5.6,7,8- tetrahydro-3H-pyrazolo[1 ,2-a]pyridazin-1 -one: 2-(4-Fluorophenyl)-8-(piperazine-1-carbony!)-3-(2-phenoxypyrimidin-4-yl)-5l6,7l8- tetrahydropyrazolo[1,2-a]pyridazin-1-one 2-(4-Fluorophenyl)-8-(morpholine-4-carbonyl)-3-(2-phenoxypyrimidin-4-yI)-5,6,7,8- tetrahydropyrazolo[1,2-a]pyridazin-1 -one; 2-(4-Fluorophenyl)-5-(morpholine-4-carbonyI)-3-[2-(4-fluorophenoxy)pyrimidin-4-yl]- 5,6,7,8- tetrahydropyrazolo[1,2-a]pyridazin-1-one; 2-(4-Fluorophenyl)-8-(morpholine-4-carbonyi)-3-[2-(4-fluorophenoxy)pyrimidin-4-yI]- 5,6,7,8- tetrahydropyrazolo[1,2-a]pyridazin-1-one; 2-(4-Fluorophenyl)-5-(morpholine-4-carbonyl)-3-{2-{1-(S)-(aHmethyl)benzylamino]- pyrimidin-4-yl}-5,6,7,8- tetrahydropyrazolo[1,2-a]pyridazin-1-one; 2-(4-Fluorophenyl)-8-(morpholine-4-carbonyl)-3-{2-[1-(SHa)-(methyl)benzylaTnino]- pyrimidin-4-yl}-5,6,7,8- tetrahydropyrazolo[1,2-a]pyridazin-1 -one; The analogs (compounds) of the present invention are arranged in several categories to assist the formulator in applying a rational synthetic strategy for the preparation of analogs which are not expressly exampled herein. The arrangement into categories does not imply increased or decreased efficacy for any of the compositions of matter described herein. Compounds listed and described herein above have been found in many instances to exhibit activities (ICso in the cell based assay described herein below or ones which are referenced herein) at a level below 1 micromolar (jiM). The compounds of the present invention are capable of effectively blocking the production of inflammatory cytokine production from cells, which thereby allows for the mitigation, alleviation, control, abatement, retardation, or prevention of one or more disease states or syndromes which are related to the extracellular release of one or more cytokines. Inflammatory disease states include those which are related to the following non-limiting examples: i) lnterleukin-1 (IL-1): implicated as the molecule responsible for a large number of disease states, inter alia, rheumatoid arthritis, osteoarthritis, as well as other disease states which relate to connective tissue degradation, ii) Cydoxygenase-2 (COX-2): inhibitors of cytokine release are proposed as inhibitors of inducible COX-2 expression, which has been shown to be increased by cytokines. M. K. O'Banion et al., Proc. Natl. Acad. Sci. U.S.A., 89, 4888 (1998), iii) Tumor Necrosis Factor-a (TNF-ct): This pro-inflammatory cytokine is suggested as an important mediator in many disease states or syndromes, inter alia, rheumatoid arthritis, osteoarthritis. inflammatory bowel disease (IBS), septic shock, cardiopulmonary dysfunction, acute respiratory disease, and cachexia. Each of the disease states or conditions which the fomnulator desires to treat may require differing levels or amounts of the compounds described herein to obtain a therapeutic level. "Hie formulator can determine this amount by any of the known testing procedures known to the artisan. The present invention further relates to forms of the present compounds, which under normal human or higher mammalian physiological conditions, release the compounds described herein. One iteration of this aspect includes the pharmaceutically acceptable salts of the analogs described herein. The formulator, for the purposes of compatibility with delivery mode, excipients, and the like, can select one salt form of the present analogs over another since the compounds themselves are the active species which mitigate the disease processes described herein. Related to this aspect are the various precursor of "pro-drug" forms of the analogs of the present invention. It may be desirable to formulate the compounds of the present invention as a chemical species which itself is not active against the cytokine activity described herein, but instead are forms of the present analogs which when delivered to the body of a human or higher mammal will undergo a chemical reaction catalyzed by the normal function of the body, inter alia, enzymes present in the stomach, blood serum, said chemical reaction releasing the parent analog. The term "pro-drug" relates to these species which are converted in vivo to the active pharmaceutical. FORMULATIONS The present invention also relates to compositions or formulations which comprise the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, the compositions of the present invention comprise: a) an effective amount of one or more bicyclic pyrazolones and derivatives thereof according to the present invention which are effective for inhibiting release of inflammatory cytokines; and b) one or more pharmaceutically acceptable excipients. For the purposes of the present invention the term "excipient" and "carrier" are used interchangeably throughout the description of the present invention and said terms are defined herein as, "ingredients which are used in the practice of formulating a safe and effective pharmaceutical composition." The formulator will understand that excipients are used primarily to serve in delivering a safe, stable, and functional pharmaceutical, serving not only as part of the overall vehicle for delivery but also as a means for achieving effective absorption by the recipient of the active ingredient. An excipient may fill a role as simple and direct as being an inert filler, or an excipient as used herein may be part of a pH stabilizina svstRm nr r.nating to insure delivery of the ingredients safely to the stomach. ,ke advantage of the fact the compounds of the present invention have improved cellular potency, pharmacokinetic properties, as well as improved oral btoavailability. The present Invention also relates to compositions or formulations which comprise a precursor or "pro-drug" form of the inflammatory cytokine release-inhibiting compounds according to the present invention. In general, these precursor-comprising compositions of the present invention comprise: a) an effective amount of one or more derivatives of bicydic pyrazolones according to the present invention which act to release in vivo the corresponding analog which is effective for inhibiting release of inflammatory cytokines; and b) one or more pharmaceutically acceptable excipients. METHOD OF USE The present invention also relates to a method for controlling the level of one or more inflammation inducing cytokines, inter alia, interleukin-1 (IL-1), Tumor Necrosis Factor-a (TNF-a), interleukin-6 (IL-6), and interleukin-8 (IL-8) and thereby controlling, mediating, or abating disease states affected by the levels of extracellular inflammatory cytokines. The present method comprises the step of administering to a human or higher mammal an effective amount of a composition comprising one or more of the inflammatory cytokine inhibitors according to the present invention. Because the inflammatory cytokine inhibitors of the present invention can be delivered in a manner wherein more than one site of control can be achieved, more than one disease state can be modulated at the same time. Non-limiting examples of diseases which are affected by control or inhibition of inflammatory cytokine inhibitors, thereby modulating excessive cytokine activity, include osteoarthritis. rheumatoid arthritis, diabetes, human Immunodeficiency virus (HIV) infection. PROCEDURES The compounds of the present invention can be evaluated for efficacy, for example, measurements of cytokine inhibition constants, Kj, and ICso values can be obtained by any method chosen by the formulator. Non-limiting examples of suitable assays include: i) UV-visible substrate enzyme assay as described by L. Al Reiter, Int. J. Peptide Protein Res., 43, 87-96 (1994). ii) Fluorescent substrate enzyme assay as described by Thornberry et al., Nature, 356, 768-774 (1992). iii) PBMC Cell assay as described in U.S. 6,204,261 B1 Batchelor et al., issued March 20, 2001. Each of the above citations is included herein by reference. In addition, Tumor Necrosis Factor, TNF-a, inhibition can be measured by utilizing lipopolysaccharide (IPS) stimulated human monocytic cells (THP-1) as described in: i) K. M. Mohler et al., "Protection Against a Lethal Dose of Endotoxin by an Inhibitor of Tumour Necrosis Factor Processing", Nature, 370, pp 218-220 (1994). ii) U.S. 6,297,381 B1 Cirillo et al., issued October 2,2001, incorporated by reference and reproduced herein below in relevant portion thereof. The inhibition of cytokine production can be observed by measuring inhibition of TNF-a in lipopolysaccharide stimulated THP cells. All cells and reagents are diluted in RPM11640 with phenol red and L-glutamine, supplemented with additional L-glutamine (total: 4 mM), penicillin and streptomycin (50 units/ml each) and fetal bovine serum (FBS 3%) (GIBCO, all cone. Final). Assay is performed under sterile conditions, only test compound preparation is non-sterile. Initial stock solutions are made in DMSO followed by dilution Into RPM11640 2-fold higher than the desired final assay concentration. Confluent THP.1 cells (2 x 106 cells/mL, final cone.; American Type Culture Company, Rockville, Md.) are added to 96 well polypropylene round bottomed culture plates (Costar 3790; sterile) containing 125 ^L test compound (2-fold concentrated) or DMSO vehicle (controls, blanks). DMSO concentration should not exceed 0.2% final. Cell mixture is allowed to preincubate for 30 minutes at 37 °C, 5% CO2 prior to stimulation with lipopolysaccharide (LPS, 1 fig/mL final; Sigma L-2630, from E. co//serotype 0111.B4; stored as 1 mg/mL stock in endotoxin screened diluted H2O vehicle at -60 °C). Blanks (unstimulated) receive H2O vehicle; final incubation volume is 250 pL. Incubation (4 hours) proceeds as described above. Assay is to be terminated by centrifuging plates 5 minutes at room temperature, 1600 rpm (4033 g); supematants are then transferred to clean 96 well plates and stored at —80 °C until analyzed for human TNF-a by a commercially available ELISA kit (Biosource #KHC3015. Camarillo, Ca.). The calculated ICso value is the concentration of the test compound that caused a 50% decrease in the maximal TNF-a production. • While particular embodiments of the present invention have been illustrated and described, it would be obvious to those skilled in the art that various other changes and modifications can be made without departing from the spirit and scope of the invention. It is therefore intended to cover in the appended claims all such changes and modifications that are within the scope of this invention. 1. A compound, including all enantiomeric and diasteriomeric forms and pharmacei^tically acceptable salts thereof, said compound having the formula: wherein R is: a) hydrogen; b) -O[CH2lkR3; or c) -NR4aR4b; R3 is substituted or unsubstituted C,-C4 alkyl, substituted or unsubstituted cyclic hydrocarbyl, substituted or unsubstituted heterocyclyl, substituted or unsubstitutecjl aryl, substituted or unsubstituted heteroaryl; the index k is from 0 to 5; R4a and R4b are each independently: a) hydrogen; or b) ^(R^R0")]^6; each R^and R^are independently hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7]2, CrC4 linear, branched, or cyclic alkyl, and mixtures thereof; R6 is -OR7, -N(R7)2, -CO2R7, - CON(R7)2; substituted or unsubstituted CrC4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, Ci -C4 alkyl, or substituted or unsubstituted aryl; the index x is from 0 to 5; R1is: a) substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl; R2aand R^ units are each independently selected from the group consisting of: a) b) c) d) e) f) hydrogen; -{CH2)jNR93R9b; -(CH2)jCO2R10; -(CH,)jOC02R10 -(CH2)JCON(R10)2; h) g) two R23 or two R25 units from the same carbon atom can be taken together to form a carbonyl unit; one R23 and one R2b are taken together to form a double bond; one R2a and one R2" are taken together to form a substituted or unsubstituted ring comprising from 4 to 8 atoms, said ring selected from the group consis ng of: i) carbocyclic; ii) heterocyclic; iii) aryl; iv) heteroaryl; v) bicyclic; and vi) heterobicyclic; j) and mixtures thereof; R8, R9a. R9b, and R10 are each independently hydrogen, Ci-C4 alkyl, and mixture R9a and R9b can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or h ring comprising from 3 to 7 atoms; j is an index from 0 to 5; m is an index from an index from 1 to 5; m + n = from 2 to 6. s thereof; terocyclic to 5, n is ' We claim: 1. A fused ring pyrazolone compound, including all enantiomeric and diasteriomeric forms and pharmaceutically acceptable salts thereof, for use in controlling the extracellular release of inflammatory cytokines, said compound having (Formula Removed) the formula: wherein: R is -NR4a R4b; R4a and R4b are each independently: [C(R5aR5b])xR6; each R5aand R5bare independently hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7)2, ft 1 C1-C4 linear, branched, or cyclic alkyl, and mixtures thereof; R is -OR , -N(R7)2, -CO2R7, - CON(R7)2; substituted or unsubstituted C1C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C1-C4 alkyl, or substituted or unsubstituted aryl; the index x is from 0 to 5; R1is: a) substituted or unsubstituted aryl; or b) substituted or unsubstituted heteroaryl; R2aand R2b units are each independently selected from the group consisting of: a) hydrogen; b) -O(CH2)jR8;- C) (CH2)jNR9aR9b d) (CH2)jCO2R10 e) (CH2)jOCO2R11 f) CH2)jCON(R10)2 g) one R2a and one R2b are taken together to form a double bond; R8,R9a,R9b,andR10 are each independently hydrogen, C1-C4 alkyl, and mixtures thereof; R9a and R9 can be taken together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; two R10 units can be take together to form a carbocyclic or heterocyclic ring comprising from 3 to 7 atoms; j is an index from 0 to 5; m is an index from 1 to 5, n is an index from 1 to 5; m + n = from 2 to 6. 2. A compound as claimed in claim 1, wherein R1 is preferably 4- fluorophenyl; R is an ether unit selected from the group consisting of phenoxy, 2- fluorophenoxy,3-fluorophenoxy,4-fluorophenoxy,2,6-difluorophenoxy,2- cyanophenoxy,3-cyanophenoxy,2-trifluoromethylphenoxy,4- trifluoromethylphenoxy,2-methylphenoxy,4-methylphenoxy, 2,4-dimethylphenoxy, 3- N-acetylaminophenoxy, 2-methoxyphenoxy, 4-methoxyphenoxy, and 3- benzo[l,3]dioxol-5-yl; or R is an amino unit selected from the group consisting of 1- (S)-phenylethylamino, 1-(S)-(4-fluorophenyl)ethylamino, 1-(S)-(2- minophenyl)ethylamino, 1 -(S)-(2-methylphenyl)ethylamino, 1 -(S)-(4- methylphenyl)ethylamino, 1 -(S)-(4-methylphenyl)ethylamino, 1 -(S)-(4- propanesulfonylphenyl)ethylamino,l-(S)-(3-benzo[l,3]dioxol-5-yl)ethylamino,l-(S)- (pyridin-2-yl)ethylamino, 1 -(S)-(pyridin-3-yl)ethylamino, methylamino, ethylamino, propylamino, cyclopropylamine, cyclopropyl-methylamino, terf-butylamino, 1-(S)- (cyclopropyl)ethylamino, 1 -(S)-(cyclopropylmethyl)-ethylamino, 1 -(R)-(a)- (carboxy)benzylamino, andl -(S)-(a)-(methyl)benzylamino. 3. The compound as claimed in claim 1, wherein R is preferably methyl group. 4. The compound as claimed in claim 1, wherein R6 is selected from hydrogen, -OR7, -N(R7)2, -CO2R7, -CON(R7)2; substituted or unsubstituted C1-C4 alkyl, substituted or unsubstituted aryl, or substituted or unsubstituted heteroaryl; R7 is hydrogen, a water-soluble cation, C1-C4 alkyl, or substituted or unsubstituted aryl; the index x is 0;R1 is selected from the group consisting of 4-fluorophenyl, 2,4-difluorophenyl, and 4-chlorophenyl. 5. The compound as claimed in claim 1, wherein R6 is preferably phenyl group. 6. The compound as claimed in any of the preceding claims for preparing a composition for use in controlling the extracellular release of inflammatory cytokines.

Documents:

1586-DEL-2004-Abstract-(08-10-2008).pdf

1586-DEL-2004-Abstract-(15-04-2009).pdf

1586-del-2004-abstract.pdf

1586-del-2004-assignment.pdf

1586-DEL-2004-Claims-(05-06-2009).pdf

1586-DEL-2004-Claims-(08-10-2008).pdf

1586-DEL-2004-Claims-(10-06-2009).pdf

1586-DEL-2004-Claims-(15-04-2009).pdf

1586-del-2004-claims.pdf

1586-DEL-2004-Correspondence-Others-(03-10-2008).pdf

1586-DEL-2004-Correspondence-Others-(05-06-2009).pdf

1586-DEL-2004-Correspondence-Others-(08-10-2008).pdf

1586-DEL-2004-Correspondence-Others-(15-04-2009).pdf

1586-del-2004-correspondence-others.pdf

1586-DEL-2004-Description (Complete)-(15-04-2009).pdf

1586-del-2004-description (complete).pdf

1586-del-2004-form-1.pdf

1586-del-2004-form-18.pdf

1586-DEL-2004-Form-2-(15-04-2009).pdf

1586-del-2004-form-2.pdf

1586-del-2004-form-26.pdf

1586-DEL-2004-Form-3-(03-10-2008).pdf

1586-del-2004-form-3.pdf

1586-del-2004-form-5.pdf

1586-DEL-2004-Others-Document-(08-10-2008).pdf

1586-del-2004-pct-210.pdf

1586-del-2004-pct-304.pdf

1586-del-2004-pct-409.pdf

1586-del-2004-pct-416.pdf

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