INDENE sPLA2 INHIBITORS

Abstract: A class of novel indene-1-functional compounds is disclosed together with the use of such indene compounds for inhibiting sPLA2 mediated release of fatty acids for treatment of conditions such as septic shock. The compounds are indene-1-acetamides, indene-1-acetic acid hydrazides, and indene-1-glyoxylamides.

Description: Title INDENE SPLA2 INHIBITORS Cross Reference to Related Applications This application is a continuation-in-part of United States Patent Application SN 08/278,441 filed July 21, 1994. Field of the Invention This invention relates to novel indene compounds useful for inhibiting sPLA2 mediated release of fatty acids for conditions such as septic shock. Background of the Invention The structure and physical properties of human non- pancreatic secretory phospholipase A2 (hereinafter called, "sPLA2") has been thoroughly described in two articles, namely, "Cloning and Recombinant Expression of Phospholipase A2 Present in Rheumatoid Arthritic Synovial Fluid" by Seilhamer, Jeffrey J.; Pruzanski, Walde ar; Vadas Peter; Plant, Shelley; Miller, Judy A.; Kloss, Jean; and Johnson, Lorin K. ; The Journal of Biological Chemistry. Vol. 264, No. 10, Issue of April 5, pp. 5335-5338, 1989; and "Structure and Properties of a Human Non-pancreatic Phospholipase A2" by Kramer, Ruth M. ; Hession, Catherine; Johansen, Berit; Hayes, Gretchen; McGray, Paula; Chow, E. Pingchang; Tizard, Richard; and Pepinsky, R. Blake; The Journal of Biological Chemistry. Vol. 264, No. 10, Issue of April 5, pp. 5768-5775, 1989; the disclosures of which are incorporated herein by reference. It is believed that sPLA2 is a rate limiting enzyme in the arachidonic acid cascade which hydrolyzes membrane phospholipids . Thus, it is important to develop compounds which inhibit SP A2 mediated release of fatty acids (e.g., arachidonic acid) . Such compounds would be of value in general treatment of conditions induced and/or maintained by overproduction of sP A2 ; such as septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and etc. U.S. Patent No. 2,825,734 describes the preparation of 3- (2-amino-l-hydroxyethyl) indoles using 3-indole glyoxylamide intermediates such as l-phenethyl-2-ethyl-6- carboxy-N-propyl-3-indoleglyoxylamide (see, Example 30) . U.S. Patent No. 2,890,233 describes several amide derivatives of 3-indoleacetic acids. U.S. Patents No. 3,196,162; 3,242,162; 3,242,163; and 3,242,193 (see, Col. 3, lines 55-60, Example 56) describe indolyl aliphatic acids together with their related esters and amides. U.S. Patent No. 3,449,363 describes trifluoromethylindoles having glyoxylamide groups at the 3 position of the indole nucleus. These compounds are stated to be analgesics. U.S. Patent No. 5,132,319 describes certain 1- (hydroxyla inoalkyl) indoles derivatives as inhibitors of leukotriene biosynthesis. The article, "Structure-activity relationships leading to WAY-121,520, a tris aryl-type, indomethacin-based, phospholipase A2 (PLA2) /leukotriene biosynthesis inhibitor", by A Kreft, et. al. , Agents and Actions. Special Conference Issue Vol. 39 (1993) .PP. C33-C35. ISSN 0065-4299. published by Birkhauser Verlag, Basel Switzerland; (Proceedings of the Sixth International Conference of the Inflammation Research Association, September 20-24, 1992, at White Haven, PA/USA, Guest Editors, D.W. Morgan and A.K. Welton) describes the inhibition of phospholipase A2 by indomethacin analogs. Indole compounds having benzyl and acidic substituents are described. -3- The article, (Short communication) entitled, "Indolizine derivatives with biological activity VI 1- (2-aminoethyl) -3-benzyl-7-methoxy-2-methylindolizine, benanserin structural analogue" by GM Cingolani, F. Claudi, M. Massi, and F. Venturi, Eur. J. Med. Chem. (1990) 25, PP. 709-712 published by Elsevier, Paris describes selected indolizines and their activity on smooth muscle. European Patent Application No. 0 519 353 (Application No. 92109968.5) describes indolizin derivatives which have pharmacological activities such as inhibitory activity on testosteron reductase. European Patent Application No. 0 620 215 describes 1H- indole-3-acetamides having utility as sPLA2 inhibitors. It is desirable to develop new compounds and treatments for sPLA2 induced diseases. Summary of the Invention This invention is a novel use of indene compounds having the nucleus and substituent numbering shown below: Moreover, the indene compounds of the invention have the general configurations shown in structural formulae "G" below: -4 - In formula "G" an acetamide, acetic acid hydrazide, or glyoxylamide moiety is present at the 1 position; a large (C7-C30) organic (e.g., carbocyclic) group is present at the 3 position and is attached to the indene nucleus with a single, or optionally, a double bond; an acidic group is substituted at the 6 or 7 position, and a small organic group is substituted at the 2 position. This invention is also a pharmaceutical composition containing indene-1-functional compounds represented by the general formulae "G" and mixtures thereof. This invention is also a method of preventing and treating septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, rheumatoid arthritis, and related diseases by contact with a therapeutically effective amount of indene-1-functional compounds selected from the group consisting of the novel indene compounds represented by the general formulae "G" . Detailed Description of the Invention Definitions: The indene acetamides, acetic acid hydrazides (hereinafter called, "hydrazides) , and glyoxylamides of the invention employ certain defining terms as follows: The term, "alkyl" by itself or as part of another substituent means, unless otherwise defined, a straight or branched chain monovalent hydrocarbon radical such as ethyl, ethyl, n-propyl, isopropyl, n-butyl, ter .lary butyl, isobutyl, sec-butyl, n-pentyl, and n-hexyl . The term, "alkenyl" employed alone or in combination with other terms means a straight chain or branched monovalent hydrocarbon group having the stated number range of carbon atoms, and typified by groups such as vinyl, propenyl, crotonyl, isopentenyl, and various butenyl isomers. The term, "hydrocarbyl" means an organic group containing only carbon and hydrogen. The term, "halo" means fluoro, chloro, bromo, or iodo. The term, "heterocyclic radical", refers to radicals derived from monocyclic or polycyclic, saturated or unsaturated, substituted or unsubstituted heterocyclic nuclei having 5 to 14 ring atoms and containing from 1 to 3 hetero atoms selected from the group consisting of nitrogen, oxygen or sulfur. Typical heterocyclic radicals are pyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, phenylimidazolyl, triazolyl, isoxazolyl, oxazolyl, thiazolyl, thiadiazolyl, indolyl, carbazolyl, norharmanyl, azaindolyl, benzofuranyl, dibenzofuranyl, thianaphtheneyl, dibenzothiophenyl, indazolyl, imidazo(1.2-A)pyridinyl, benzotriazolyl, anthranilyl, 1,2-benzisoxazolyl, benzoxazolyl, benzothiazolyl, purinyl, pyridinyl, dipyridinyl, phenylpyridinyl, benzylpyridinyl, pyri idinyl, phenylpyri idinyl, pyrazinyl, 1,3 , 5-triazinyl, quinolinyl, phthalazinyl, quinazolinyl, and guinoxalinyl. The term, "carbocyclic radical" refers to radicals derived from a saturated or unsaturated, substituted or unsubstituted 5 to 14 membered organic nucleus whose ring forming atoms (other than hydrogen) are solely carbon atoms. Typical carbocyclic radicals are benzylidene, cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-eyelohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb) , where n is a number from 1 to 8. The term, "non-interfering substituent", refers to radicals which do not prevent or significantly reduce the inhibition of sPLA2 mediated release of fatty acids . Non- interfering substituents are suitable for substitution at positions 4, 5, 6, and/or 7 on the indene nucleus (as hereinafter depicted in Formula I) and radical (s) suitable for substitution on the heterocyclic radical and carbocyclic radical as defined above which do not have a significant adverse effect in reducing the inhibiting effect of sPLA2 mediated release of fatty acids. Illustrative non- interfering radicals are C1-C6 alkyl, C2-C6 alkenyl, C2-C6 al ynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2- C12 alkylcarbonyla ino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2- C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, C1-C6 haloalkoxy, C1-C6 haloalkylsulfonyl, Cι~ C6 haloalkyl, C1-C6 hydroxyalkyl, -C(0)0(Cι-C6 alkyl), - (CH2)n _ 0- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, -(CONHSO2R), -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, - (CH2)n _c θ2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Ci-Cβ carbonyl; where n is from 1 to 8. The term, "acidic group" means an organic group which when attached to an indene nucleus, through suitable linking atoms (hereinafter defined as the "acid linker"), acts as a proton donor capable of hydrogen bonding. Illustrative of an acidic group are the following: •5-tetrazolyl -SO3H, 0 ■ P- OH OR 89 0 OH OH 0 R99 0 P O (CH 2 )H N R 9 OR 89 R99 OH where n is 1 to 8, R89 is a metal or Cι-Cχo alkyl, and R99 is hydrogen or C1-C10 alkyl. The words, "acid linker" refer to a divalent linking group symbolized as, -(L a )-/ which has the function of joining the indene nucleus to an acidic group in the general relationship: Indene Nucleus '( a)" Acidic Group The words, "acid linker length", refer to the number of atoms (excluding hydrogen) in the shortest chain of the linking group - (L a A that connects the indene nucleus with the acidic group. The presence of a carbocyclic ring in -(L a )- counts as the number of atoms approximately equivalent to the calculated diameter of the carbocyclic ring. Thus, a benzene or cyclohexane ring in the acid linker counts as 2 atoms in calculating the length of -(L a )-. Illustrative acid linker groups are; 6/03120 -9- wherein, groups (a) , (b) , and (c) have acid linker lengths of 5, 7, and 2, respectively. The term, "amine", includes primary, secondary and tertiary amines. The Indene Compounds of the Invention: There are three types of Indene compounds of the invention as represented by structural formulae (I) , (II) , and (III) below: 1) The indene-1-acetamides are represented by the formula (I) , below: ■ 10 - where X is oxygen or sulfur and each Ri is independently hydrogen, C1-C3 alkyl, or halo and all other groups are as hereinafter defined. 2) The indene-1-hydrazides are represented by the formula (II) , as set out below: where X is oxygen or sulfur and each Ri is independently hydrogen, C1-C3 alkyl, or halo and all other groups are as hereinafter defined. 3) The indene-1-glyoxylamides are represented by the formula (III), as set out below: /03120 - 11 - where X is independently oxygen or sulfur and all other groups are as hereinafter defined. For formulae (I) , (II) , and (III) above the remaining groups are defined as follows: R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-Rso; where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rso is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(Cι-C2 alkyl), -S-(Cι~C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; (that is, the R12 radical may contain hydrogen atoms, but the remaining atoms comprising the total of 1 to 3 are non-hydrogen) ; R6 and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) -(acidic group); wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of R6 and R7 must be the combined group, - (L a ) - (acidic group); and ■ 12 - R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents. Preferred Subgroups of Indene Compounds of the Invention: A preferred subclass of compounds of formulae (I) , (II), and (III) are those wherein all X are oxygen. Another preferred subclass of compounds of formulae (I) , (II), and (III) are those wherein R2 is selected from the group; halo, cyclopropyl, methyl, ethyl, -O-methyl, and -S-methyl. Another preferred subclass of compounds of formulae (I) , (II) and (III) are those wherein for R3, -(L)- is selected from the group consisting of: ■ CH CH CH 2 (CH- (CH 2 )" (CH 2 ) ■ 0- 0 and (CH 2 )' 0 where s is 0 or 1. Another preferred subclass of compounds of formulae (I,' (II) , and (III) are those wherein tor R3 , group R80 s carbocyclic, attached to the indene ring with a double or single bond, and is selected from the group consisting of benzylidene, cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl , bicycloheptadienyl , toluyl , xylenyl , indenyl , stilbenyl, terphenylyl , diphenylethylenyl , phenyl- cyclohexenyl , acenaphthylenyl , and anthracenyl , biphenyl , bibenzylyl and related bibenzylyl homologues represented by the formula (bb) , where n is a number from 1 to 8. Particularly preferred are compounds wherein R3 is selected from the group consisting of ■ 14- and where Rio is a radical independently selected from halo, C_ Cio alkyl, Cχ-Cιo alkoxy, -S-(Cχ-Cιo alkyl) , and Ci-Cio haloalkyl, q is a number from 0 to 4, and t is a number from 0 to 5. Another preferred subclass of compounds of formulae (I), (II), and (III) are those wherein R7 comprises an acidic group and the acid linker for the R7 acidic group has an acid linker length of 2 or 3 and the acid linker group, -(La)-/ for R7 is selected from the group represented by the formula; where Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84 and R85 are each independently selected from hydrogen, C1-C10 alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Most preferred are compounds where the acid linker, -(L a )-, for R7 is selected from the specific groups; where R is H or C 1 -C 4 alkyl. Another preferred subclass of compounds of formulae ( I ) , ( II ) , and ( III ) are those wherein R6 comprises an acidic group and the acid linker of the R6 acidic group has - 16 - an acid linker with an acid linker length of 3 to 1C acorns and the acid linker group, -(L a )-, for Rς, is selected from; phenylene) where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84 and R85 are each independently selected from hydrogen, Cl-Cio alkyl, aryl, C1-C10 alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Most preferred are compounds where the acid linker, -(L a )-, for Rβ is selected from the specific groups; - 18 - and wherein; R is hydrogen or C1-C4 alkyl, R84 and R85 are each independently selected from hydrogen, C1-C1 0 alkyl, aryl, Cl-Cio alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. Another preferred subclass of compounds of formulae (I), (II), (III) are those wherein the acidic group (or salt, and prodrug derivatives thereof) on Rδ and/or R7 is selected from the following: -5-tetrazolyl, -SO3H, -20- 0 99 ■ 0- • 0- ( CH 2 ) - ■ N- 99 0R 8! R99 where n is 1 to 8, R89 is a metal or C1-C10 alkyl, and R99 is hydrogen or C1-C10 alkyl. Particularly preferred are compounds wherein the acidic group of Rζ and R7 is selected from; C0 2 H SO 3 H P ( O ) (OH ) 2 or salt, and prodrug (e.g., ester) derivatives thereof. The carboxyl group is the most preferred acidic group. It is highly preferred that only one of RQ or R7 contain an acidic group. Another preferred subclass of compounds of formula (I) , (II), and (III) are those wherein R4 and R5 are each independently selected from hydrogen and non-interfering substituents, with the non-interfering substituents being selected from the group consisting of C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl , Ci-Cβ alkoxy, C1-C6 alkenyloxy, C -C a " ,kyπy " .oxy, C2-C12 alkoxyalkyl, C2-C12 lkoxyalkyloxy, C2-C12 alkylcarbonyl , C2-C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl , C1-C12 alkylamino, Cχ-C6 alkylthio, C2-C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl , C - Cg alkylsulfonyl, Ci-Cβ haloalkoxy, C -Cs haloalkylsulfonyl, C1-C6 haloalkyl, C1-C6 hydroxyalkyl , -C(0)0(Cι-C6 alkyl) , - (CH2)n _ 0 _ (C1-C6 alkyl) , benzyloxy, phenoxy, phenylthio, -(CONHSO2R) ; -CHO, amino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, - (CH2 ) n-C02H, chloro, cyano, cyanoguanidinyl , fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and Ci-Cg carbonyl; where n is from 1 to 8. Specific preferred indene-1-acetamide type compounds of the invention (per formula I, supra) are represented by formulae 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14i, 14j , 17a, 17b; and acceptable salts, solvates and prodrug derivatives thereof: (14a) (14b) (14c) (14f) (14h) (14j) (17a) -27- (17b) The salts of the above indene-1-functional compounds represented by formulae (I) , (II) , (III) are an additional aspect of the invention. In those instances where the compounds of the invention possess acidic or basic functional groups various salts may be formed which are more water soluble and physiologically suitable than the parent compound. Representative pharmaceutically acceptable salts, include but are not limited to, the alkali and alkaline earth salts such as lithium, sodium, potassium, calcium, magnesium, aluminum and the like. Salts are conveniently prepared from the free acid by treating the acid in solution with a base or by exposing the acid to an ion exchange resin. Included within the definition of pharmaceutically acceptable salts are the relatively non-toxic, inorganic and organic base addition salts of compounds of the present invention, for example, ammonium, quaternary ammonium, and amine cations, derived from nitrogenous bases of sufficient basicity to form salts with the compounds of this invention (see, for example, S. M. Berge, et al . , "Pharmaceutical Salts," J. Phar. Sci .. 66: pp. 1-19 (1977)) . Moreover, the basic group(s) of the compound of the invention may be reacted with suitable organic or inorganic acids to form salts such as acetate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, camsylate, carbonate, chloride, clavulanate, citrate, chloride, edetate, edisylate, estolate, esylate, fluoride, fumarate, gluceptate, gluconate, glutamate, glycolylarsanilate, hexylresorcinate, bromide, chloride, hydroxynaphthoate, iodide, isothionate, lactate, lactobionate, laurate, malate, malseate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, oleate, oxalate, palmitate, pantothenate, phosphate, polygalacturonate, salicylate, stearate, subacetate, succinate, tannate, tartrate, tosylate, trifluoroacetate, trifluoromethane sulfonate, and valerate. Certain compounds of the invention may possess one or more chiral centers and may thus exist in optically active forms. Likewise, when the compounds contain an alkenyl or alkenylene group there exists the possibility of cis- and trans- isomeric forms of the compounds. The R- and S- isomers and mixtures thereof, including racemic mixtures as well as mixtures of cis- and trans- isomers, are contemplated by this invention. Additional asymmetric carbon atoms can be present in a substituent group such as an alkyl group. All such isomers as well as the mixtures thereof are intended to be included in the invention. If a particular stereoisomer is desired, it can be prepared by methods well known in the art by using stereospecific reactions with starting materials which contain the asymmetric centers and are already resolved or, alternatively by methods which lead to mixtures of the stereoisomers and subsequent resolution by known methods. Prodrugs are derivatives of the compounds of the invention which have chemically or metabolically cleavable groups and become by solvolysis or under physiological conditions the compounds of the invention which are pharmaceutically active in vivo. The prodrug derivative form often offers advantages of solubility, tissue compatibility, or delayed release in a mammalian organism (see, Bundgard, H., Design of Prodrugs. pp. 7-9, 21-24, Elsevier, Amsterdam 1985) . Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suitable alcohol, or amides prepared by reaction of the parent acid compound with a suitable amine. Simple aliphatic or aromatic esters derived from acidic groups pendent on the compounds of this invention are preferred prodrugs. In some cases it is desirable to prepare double ester type prodrugs such as (acyloxy) alkyl esters or ( (alkoxycarbonyl)oxy)alkyl esters. -30- Synthesis Methods Scheme- 1 PPA l Pd-C/H 2 (EtO) 2 PCH 2 COOEt NaOAc NaH AcOH toluene 6a:6-O e, R a =Me 6b:7-OMe, R a =Me 7a 8b,c 8b:7-OMe, R*=Me 8c:7-OMe, R a =Et OMe /r ~- COOE 8b,c 9b,c 7b,c CHCIa A mixture of an anisaldehyde 1, propionic anhydride, and sodium propionate is heated to produce 2 which is reduced by hydrogen in the presence of Pd/C to give 3. Acid cyclization of 3 yields 6. Alternatively, the aromatic position para to the methoxy group of 3 is blocked by bromination to give 4 which is cyclized to 5 by acid and then debrominated using hydrogen and Pd/C to give 6. Reaction of 6 with the anion of triethyl phosphonoacetate produces 7 and/or 8. Radical bromination of 8 gives 9, which on reduction with hydrogen in the presence of Ptθ2 yields 7. Alternatively, treatment of 8 with acid gives 7. Scheme-2 -32- Compound 7 is condensed with benzaldehyde and its derivatives in the presence of base to give 10. Indenes 10 are converted to an active ester using benzotriazo-1- yloxytris (dimethyla ino) hexafluorophosphonate and then reacted with ammonium hydroxide to form 11. Demethylation of 11 with BBr3 forms 12 which is O-alkylated using sodium hydride and an omega-bromoalkanoic acid ester to produce 13. Aqueous base hydrolysis of 13 yields 14. Scheme- 3 12c 15 16b 17b Compound 12c is O-alkylated using sodium hydride and methylbromoacetate to product 15 which is reduced by hydrogen in the presence of Pd/C to give a mixture of isomers 16a and 16b. Aqueous base hydrolysis of 16a and 16b gives 17a and 17b respectively. - 34 - 10d 18 19 20 Compound lOd is treated with lithium diisopropylamine, then air is bubbled into the solution to give 18. The indene 18 is converted to an active ester using benzotriazo-1- yloxytris(dimethylamino)hexafluorophosphonate and then reacted with ammonium hydroxide to form the hydroxy acetamide 19. Compound 19 is oxidized to 20 using N-methylmorpholine N-oxide in the presence of tetrapropylammonium perruthenate. EXAMPLES Reference numbers in the following Examples refer to compounds shown in the preceding Schemes. Ex^ p-,e 1 This Example illustrates preparation of compounds 14a thru 14j (see, structural formulae, supra.) which are indene- 3-acetamide type compounds of the invention. Part A: Preparation of 3- (4-Methoxyphenyl) -2-methyl- acrylic acid 2a A mixture of p-anisaldehyde (26.6 g, 0.195 mol) , propionic anhydride (43.0 ml, 0.347 mol) and sodium propionate (18.8 g, 0.195 mol) was heated at 150 °C overnight. After cooling, the reaction mixture was basified with 4N NaOH and washed with ether. The aqueous phase was acidified with concentrated HC1 and the precipitate was filtered to yield 28.5 g (76%) of the titled compound, mp, 152-155 °C. ~H NMR (CDCI3) δ 2.16 (3H, d, J=1.2 Hz), 3.85 (3H, s) , 6.95 (2H, d, J=8.7 Hz), 7.44 (2H, d, J=8.7 Hz), 7.78 (1H, br.s) . IR V max (KBr) 1662, 1605, 1570, 1510 cm "1 . Analyses: Calc'd for CHHX203 : C, 68.74; H, 6.29. Found: C, 68.49; H, 6.38. EIMS m/z=192 (M + , base peak) . Other Preparations: 3- (3-Methoxyphenyl) -2-methyl-acrylic acid 2b Mp, 78-79 °C. 93% yield. 2-Ethyl-3- (3-methoxyphenyl) -acrylic acid 2c Mp, 89-90 °C. 24% yield. Part B: Preparation of 3- (4-Methoxyphenyl) -2-methyl- propionic acid 3a A mixture of the acrylic acid (2a, 28.3 g, 0.147 mol) and 10% palladium-coal (2.49 g) in methanol (350 ml) was hydrogenated under 3 atm (3.0 x 10 5 Pa.) overnight. The catalyst was filtered off and the solvent was evaporated to give the desired product (21.2 g, 74%) . mp, 43 - 44 °C . Preparation of 3- (3-Methoxyphenyl) -2-methyl-propionic acid 3b Using the procedure described in the synthesis of compound 3a from 2a, the acrylic acid (7, 38.2 g, 0.199 mol), was hydrogenated under atmosphere to give the desired product (29.0 g, 75%) . Preparation of 2- (3-Methoxybenzyl) -butyric acid 3c. Quantitative yield. Part C: Preparation of 2- (2-Bromo-5-methoxy-benzyl) -butyric acid 4c To a solution of the butyric acid (3a, 33.9 g, 0.163 m mol) in acetic acid (50 ml) was added a solution of bromine (10.5 ml, 0.204 m mol) in acetic acid (20 ml) at 0 °C. The resulting orange solution was stirred at room temperature for 2.5 hours and then the mixture was partitioned between water and AcOEt. The aqueous layer was extracted with AcOEt and the combined organic layers were washed with saturated sodium thiosulfate solution, water and brine, dried over MgS04, filtered and evaporated in vacuo. The residue (14, 51.8 g) was used to the next preparation without further purification, mp, 39-42 °C. Part D: Preparation of 4-Bromo-2-ethyl-7-methoxy-l-indanone 5c A mixture of the butyric acid (4c, 51.6 g) and polyphosphoric acid (511 g) was heated at 100 °C for 2.5 hours. The mixture was poured into water (1 L) and extracted with AcOEt. The combined extracts were washed with water, 5% sodium bicarbonate solution and brine, dried over MgS04 and filtered. After removing the solvent under reduced pressure, the residue was chromatographed on silica gel elutir.g with hexane:AcOEt (4:1 to 1:2) to give the titled compound O.O g ) • Part E-l: Preparation of 6-Methoxy-2-methyl-1-indanone 6a To the propionic acid (3a, 21.0 g, 0.108 mol) was added polyphosphoric acid (about 200 g) at 50 °C, the reaction was maintained at 90 °C for 2 hours. The mixture was poured into water (1 L) , stirred at room temperature overnight and extracted with ether twice. The combined extracts were washed with saturated sodium bicarbonate solution and brine, dried over MgS0 and filtered. After removing the solvent under reduced pressure, the residue was chromatographed on silica gel eluting with CH 2 Cl :MeOH (10:0 to 9:1) and hexane:AcOEt (9:1 to 4:1) to give the titled compound (7.45 g, 39%) . 1 H NMR (CDC1 3 ) δ 1.31 (3H, d J=7.2 Hz), 2.58-2.84 (2H, m) , 3.33 (1H, dd, J=16.1, 7.1 Hz), 3.84 (3H, s), 7.15-7.23 (2H, m) , 7.30-7.40 (1H, m) . Part E-2 : Preparation of 7-Methoxy-2-methyl-1-indanone 6b To a solution of the propionic acid (3b, 17.4 g, 0.0897 mol) in trifluoroacetic acid (300 ml) was slowly added trifluoroacetic anhydride (70 ml) at 0 °C and the reaction was maintained at this temperature for 40 min. After removing the solvent, the residue was dissolved with ether and poured into 10% NaOH. The organic layer was separated and washed with 10% NaOH, water and brine. The aqueous layer was extracted with ether and the combined extracts were dried over MgSθ4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with hexane:AcOEt (9:1 to 1:1) to give the titled compound (2.66 g, 17%) . Part E-3 : Preparation of 2-Ethyl-7-methoxy-l-indanone 6c A mixture of the indanone (5c, 29.7 g, 0.110 mol), sodium acetate (15.0 g, 0.183 mol), 10% palladium-coal (3.01 g) in acetic acid (300 ml) was hydrogenated at ordinary pressure. The catalyst was filtered off and the solvent was evaporated. The residue was partitioned between water and AcOEt and the aqueous layer was extracted with AcOEt. The combined organic layers were washed with water, 5% NaHCθ3 and brine, dried, filtered and evaporated. The crude product was purified by recrystallization from hexane:AcOEt to give the pure titled compound (15.7 g, 3 steps yield 51%) , mp, 67-69 °C. Part F-l: Preparation of Ethyl (6-methoxy-2-methyl-3H- indene-1-yl) -acetate 7a To a solution of triethyl phosphonoacetate (17.2 g, 76.7 m mol) in toluene (100 ml) was added sodium hydride (60% oil suspension, 3.06 g, 76.5 m mol) at 0 °C. After the reaction mixture was stirred for 1 hour at this temperature, a solution of the indanone (6a, 1.35 g, 7.63 m mol) in toluene (25 ml) was slowly added. The mixture was refluxed for 4 hours, then was poured into IN HC1 and extracted with AcOEt. The extract was washed with water and brine, dried over MgSθ4, filtered and concentrated to produce a crude residue, which was chromatographed on silica gel eluting with hexane:AcOEt (19:1) to give the mixture of the compound 7a and its positional isomer (1.65 g, 88%). The mixture was used to the next preparation without further purification. ■ " ■ H NMR (CDCI3) δ 1.24 (3H, t, J=7.2 Hz), 2.12 (3H, s) , 3.27 (2H, s), 3.49 (2H, s) , 3.83 (3H, s) , 4.14 (2H, q, J=7.2 Hz), 6.68 (1H, dd, J=2.5, 8.1 Hz), 6.86 (1H, d, J=2.5 Hz), 7.24 (1H, d, J=8.1 Hz) . Part G: Preparation of Ethyl (7-methoxy-2-methyl-inden-l- ylidene) -acetate 8b To a solution of triethyl phosphonoacetate (12.7 g, 56.7 m mol) in toluene (100 ml) was added sodium hydride (60% oil suspension, 2.29 g, 57.3 m mol) at 0 °C. After the reaction mixture was stirred for 70 min at this temperature, a solution of the indanone (6b, 2.00 g, 11.4 m cl ) in toluene (28 ml) was added. The mixture was refluxed for overnight, then was poured into 2N HC1 and extracted with AcOEt. The extract was washed with water and brine, dried over MgS04, filtered and concentrated to produce a crude residue, which was chromatographed on silica gel eluting with hexane:AcOEt (9:1) to give the titled compound (1.36 g, 49%) . 1 H NMR (CDCI3) δ 1.24 (3H, d, J=6.6 Hz), 1.27 (3H, t, J=7.0 Hz), 2.50-2.71 (IH, m) , 2.93-3.19 (2H, m) , 3.81 (3H, s), 4.21 (2H, q, J=7.0 Hz), 5.81 (IH, d, J=2.0 Hz), 6.70 (IH, d, J=8.4 Hz), 6.86 (IH, d, J=7.6 Hz) , 7.25 (IH, t, J=7.8 Hz) . Preparation of Ethyl (2-ethyl-7-methoxyindan-l-yliden) -acetate 8c 36% yield. Part H-l: Preparation of Ethyl (2-bromo-7-methoxy-2-methyl- indan-1-ylidene) -acetate 9b To a solution of the ester compound (8a, 1.39 g, 5.65 m mol) in carbon tetrachloride (15 ml) were added N- bromosuccinimide (1.11 g, 6.22 m mol) and benzoyl peroxide (68.5 mg, 0.283 m mol) . The mixture was stirred at 50 °C for 6 hours, filtered, washed with saturated sodium thiosulfate solution and dried. After removing the solvent, the residue was chromatographed on silica gel eluting with hexane:AcOEt (19:1) to afford the titled compound (0.424 g, 23%), mp, 85- 91 °C. 1 H NMR (CDCI3) δ 1.23 (3H, t, J=7.2 Hz), 2.12 (3H, s) , 3.42 (2H, s), 3.84 (3H, s) , 4.22 (2H, qd, J=7.2, 1.0 Hz), 6.02 (IH, s), 6.79 (IH, d, J=8.0 Hz), 7.01 (IH, dd, J=7.2, 0.8 Hz), 7.13 (IH, t, J=7.7 Hz) . IR V maχ (KBr) 3435, 3063, 2956, 2939, 2908, 2837, 1750, 1611, 1580 cm "1 . EIMS m/z=199 (base peak), 324 (M + ) . HR-EIMS Calc'd for Cι 5 H 17 Br0 3 : 324.0361 Found: 324.0377. Part H-2 : Preparation of Ethyl (2-bromo-2-et-hyl-7-rp.etho--.y- indan-1-ylidene) -acetate 9c Using the procedure described in the preparation of compound 9b from 8b, the ester compound (17, 2.46 g, 9.44 m mol) in carbon tetrachloride (30 ml) was reacted with N- bromosuccinimide (2.03 g, 11.4 m mol) and benzoyl peroxide (0.116 g, 0.48 m mol) to give the crude product (1.67 g) . This compound was used to the next step without purification. Part F-2: Preparation of Ethyl (7-methoxy-2-methyl-3H- inden-1-yl) -acetate 7b The mixture of the ester compound (9b, 388 mg, 1.19 m mol) and platinum dioxide (38.4 mg) in acetic acid (4.0 ml) was hydrogenated under ordinary atmosphere overnight . The catalyst was filtered off and the solvent was evaporated. The residue was chromatographed on silica gel eluting with hexane:AcOEt (97:3 to 9:1) and crystallized from hexane:AcOEt to give 170 mg (59%) of the titled compound, mp, 76-79 °C. Part F-3 : Preparation of Ethyl (2-ethyl-7-methoxy-3H-inden- 1-yl) -acetate 7c (Method A) : Using the procedure described in the preparation of compound 7b from 9b, the ester compound (9c, 1.60 g) and platinum dioxide (0.160 g) in acetic acid (16.0 ml) was hydrogenated to give the titled compound (0.747 g, 2 Steps yield 32%. ) . (Method B) : To a solution of the ester compound (8c, 4.15 g, 0.0160 mol) in chloroform (40 ml) were added three drops of concentrated sulfuric acid. The resulting solution was refluxed for 40 min, dried over K2CO3 and filtered. After removing the solvent under reduced pressure, the residue was chromatographed on silica gel eluting with hexane:AcOEt (98:2 to 95:5) to give the titled compound (3.55 g, 85%). Part 1-1: Preparation of [ (3Z) -Benzylidene-δ-methoxy-2- methyl-3H-inden-l-yl] -acetic acid 10a To a solution of the crude indene (7a, 1.64 g, 6.66 m mol) in methanol (20 ml) were added benzaldehyde (1.35 ml, 13.3 m mol) and IN NaOMe (20.0 ml, 20 m mol) at room temperature. The resulting solution was refluxed for 160 min, evaporated, poured into IN HCl and extracted with AcOEt. The organic layer was washed with water and brine, dried over gSθ4, filtered and concentrated in vacuo. The residue was subjected successively to chromatography on silica gel eluting with hexane:AcOEt (9:1) and then CHCl3:MeOH (9:1) and to recrystallization (hexane:AcOEt) to afford 0.841 g (41% yield) of the desired product 10a, mp, 146-160 °C. 1 H NMR (CDC1 3 ) δ 2.19 (3H, s) , 3.59 (2H, s) , 3.78 (3H, s) , 6.40 (IH, dd, J=8.2, 2.4 Hz), 6.75 (IH, d, J=2.4 Hz), 7.12 (IH, s), 7.24 (IH, d, J=8.2 Hz), 7.30-7.56 (5H, m) . IR max < KBr > 3428, 3007, 2935, 2834, 1701, 1611, 1582 cm "1 . Analyses: Calc'd for C20H18O3 0.2H 2 O: C, 77.50; H, 5.98. Found: C, 77.35; H, 5.97. EIMS m/z=306 (M + , base peak). Other Preparations: [3 (Z) -Benziliden-7-methoxy-2-methyl-3H-inden-l-yl_ -acetic acid 10b. Mp, 165-175 °C. 59% yield. [ (3Z) -Benzylidene-2-ethyl-7-methoxy-3H-inden-l-yl]-acetic acid 10c. Deco p, 166-188 °C. 47% yield. (Z) -2- [3- (Biphenyl-2-ylmethylene) -2-ethyl-7-methoxy-3H-inden- 1-yl]-acetic acid lOd. Mp. , 230-232 °C. 39% yield (E/Z) -[3- (2-Benzyl-benzylidene) -2-ethyl-7-methoxy-3H-inden-l- yl] -acetic acid lOe. Mp, 119.5-136 °C. 62% yield. (Z) -[3- (3-Chloro-benzylidene) -2-ethyl-7-methoxy-3H-inden-l- yl] -acetic acid lOf. Mp, 173-178 °C. 79% yield. (Z) - [3- (2, 3-Dichloro-benzylidene) -2-ethyl-7-r:.et oxy- K-inden- 1-yl] -acetic acid lOg. Mp, 214.5-222 °C. 63% yield. (Z) - (2-Ethyl-7-methoxy-3-naphthalen-l-ylmethylene-3H-inden-l- yl) -acetic acid lOi. Mp, 188-191 °C. 46% yield. (Z) - (2-Ethyl-7-methoxy-3-naphthalen-2-ylmethylene-3H-inden-1- yl) -acetic acid 10 . Mp, 188-192.5 °C. 56% yield. Part J: Preparation of 2- [3 (Z) -Benzylidene-6-methoxy-2- methyl-3H-inden-l-yl] -acetamide 11a To a solution of the acetic acid derivative (10a, 200 mg, 0.645 m mol) in acetonitrile (10.0 ml) were added triethylamine (0.140 ml, 1.00 m mol) and benzotriazol-1- yloxytris (dimethylamino)phosphonium hexafuluorophoshate (434 mg, 0.981 m mol) at 0 °C. The resulting solution was stirred at room temperature for 45 min, and then 28% aqueous ammonia (0.440 ml) was added. After 30 min, the mixture was poured into 2N HCl and extracted with AcOEt. The organic layer was washed with water and brine, dried over MgS04 and filtered. After removing the solvent at reduced pressure, the residue was chromatographed twice on silica gel eluting with CH 2 Cl 2 :MeOH (99:1 to 98.5:1.5) and hexane:AcOEt (1:1 to 1:9) to give 183 mg (92%) of the titled compound, mp, 174-178 °C. 1 H NMR (CDC1 3 ) δ 2.22 (3H, s), 3.55 (2H, s), 3.79 (3H, s), 5.44 (IH, br.s), 5.64 (IH, br.s), 6.44 (IH, dd, J=8.4, 2.4 Hz), 6.73 (IH, d, J=2.4 Hz), 7.16 (IH, s) , 7.29 (IH, d, J=8.4 Hz), 7.32-7.60 (5H, m) . IR V mx (KBr) 3389, 3196, 2913, 1653, 1614 cm -1 . Analyses: Calc'd for C20H19NO2 O.3H2O: C, 77.30; H, 6.36; N, 4.51. Found: C, 77.18; H, 6.35; N, 4.40. EIMΞ m/z=305 (M + , base peak) . Other Preparations: 2- [3 (Z) -Benzilidene-7-methoxy-2-methyl-3H-inden-l-yl] - acetamide lib. Mp, 175-177 °C. 96% yield. 2- [ (3Z) -Benzylidene-2-ethyl-7-methoxy-3H-inder.- 1-yl] - acetamide lie. Mp, 153-156 °C. 99% yield. (Z) -2- [3- (Biphenyl-2-ylmethylene) -2-ethyl-7-methoxy-3H-inden- 1-yl] -acetamide lid. Mp., 190-200 °C. 91% yield. (E/Z) -2- [3- (2-Benzyl-benzylidene) -2-ethyl-7-methoxy-3H-inden- 1-yl] -acetamide lie. Mp, 133-147 °C. 74% yield. (Z) -2- [3- (3-Chloro-benzylidene) -2-ethyl-7-methoxy-3H-inden-l- yl] -acetamide llf. Mp, 204-208 °C. 85% yield. (Z) -2- [3- (2,3-Dichloro-benzylidene) -2-ethyl-7-methoxy-3H- inden-1-yl]-acetamide llg. Mp, 170-176.5 °C. 81% yield. (Z) -2- [2-Ethyl-7-methoxy-3- (3-trifluoromethyl-benzylidene) - 3H-inden-l-yl] -acetamide llh. Mp, 205.5-208 °C. 32% yield (2 steps) . (Z) -2- (2-Ethyl-7-methoxy-3-naphthalen-l-ylmethylene-3H-inden- 1-yl) -acetamide Hi. Mp, 172-175.5 °C. 91% yield. (Z) -2- (2-Ethyl-7-methoxy-3-naphthalen-2-ylmethylene-3H-inden- 1-yl) -acetamide 11j . Mp, 221-223 °C. 80% yield. Part K: Preparation of 2- [3 (Z) -Benzylidene-6-hydroxy-2- methyl-3H-inden-l-yl] -acetamide 12a To a solution of the acetamide (11a, 50.9 mg, 0.167 m mol) in dichloromethane (2.0 ml) was added dropwise borontribro ids- (1M in CH2CI2 solution, 0.860 ml, 0.860 m mol) at 0°C and the resulting mixture was stirred at room temperature for 80 min. After evaporation, methanol (2.0 ml) was added. The solution was stirred and evaporated .The residue was partitioned between 2N HCl and AcOEt, the extract was washed with water and brine, dried over MgS04 and concentrated in vacuo. The crude product was purified by preparative TLC on silica gel (200x200x0.25mm, elution with AcOEt) and recrystallization from hexane:AcOEt gave the titled compound (23.7 mg, 49%), mp, 178-180 °C. 1 H NMR (CDC1 3 ) δ 2.20 (3H, s), 3.56 (2H, s), 5.55 (IH, br.s), 5.77 (IH, br.s) , 6.41 (IH, d, J=8.4, 2.4 Hz), 6.69 (IH, d, J=2.4 Hz) , 7.14 (IH, s) , 7.25 (IH, d, J=8.4 Hz) , 7.30-7.56 (6H, m) . IR V maχ (KBr) 3416, 3212, 1657, 1602 cm -1 . Analyses: Calc'd for C 19 H 17 N0 2 0.4H 2 O: C, 76.44; H, 6.01; N, 4.69. Found: C, 76.66; H, 5.91; N, 4.63. EIMS m/z=232 (base peak) , 291 (M + ) . Other Preparations: 2- [3 (Z) -Benzilidene-7-hydroxy-2-methyi-3H-inden-l-yl] - acetamide 12b Mp, 200-203 °C. Quantitative yield. (Z) -2- (3-Benzylidene-2-ethyl-7-hydroxy-3H-inden-l-yl) - acetamide 12c. Deep., 176-180 °C. 87% yield. (Z) -2- [3- (Biphenyl-2-ylmethylene) -2-ethyl-7-hydroxy-3H-inden- 1-yl] -acetamide 12d. Mp., 168-172 °C. 49% yield. (Z) -2- [3- (2-Benzyl-benzylidene) -2-ethyl-7-hydroxy-3H-inden-l- yl] -acetamide 12e. Mp, 137.5-153.5 °C. 72% yield. (Z) -2- [3- (3-Chloro-benzylidene) -2-ethyl-7-hydroxy-3H-inden-l- yl] -acetamide 12f. Mp, 185-185.5 °C. 79% yield. (Z) -2- [3- (2,3-Dichloro-benzylidene) -2-ethyl-7-hydroxy-3H- inden-1-yl] -acetamide 12g. Mp, 193-194.5 °C. 90% yield. (Z) -2- [2-Ethyl-7-hydroxy-3- (3-trifluoromethyl-benzylidene) - 3H-inden-1-yl] -acetamide 12h. Mp, 184.5-186 °C. 96% yield. (Z) -2- (2-Ethyl-7-hydroxy-3-naphthalen-1-yImethylene-3H-inden- 1-yl) -acetamide 12i. Mp, 189-189.5 °C. 92% yield. (Z) -2- (2-Ethyl-7-hydroxy-3-naphthalen-2-ylmethylene-3H-inden- 1-yl) -acetamide 12j . Mp, 200-201.5 °C. 65% yield. Part L-l: Preparation of Ethyl 4- [1 (Z) -Benzylidene-3- carbamoylmethyl-2-methyl-lH-inden-5-yloxy] -butanate 13a To a solution of the hydroxy compound (12a, 43.7 mg, 0.150 m mol) in dimethylformamide (1.0 ml) was added sodium hydride (60% oil suspension, 21.3 mg, 0.533 m mol) . After addition, the mixture was stirred at room temperature for 60 min, and then ethyl 4-bromobutyrate (75 μl, 0.524 m mol) was added. The mixture was stirred at 0 °C for 45 min and then at room temperature for 75 min, and partitioned between IN HCl and AcOEt. The organic layer was separated, washed with water and brine, dried over MgSθ4, filtered and concentrated in vacuo. The residue was purified by preparative TLC (200x200x0.25 mm, elution with AcOEt) to give the product (38.0 mg, 63%), mp, 124-128 °C. 1 H NMR (CDCI3) δ 1.25 (3H, t, J=7.0 Hz), 1.99-2.17 (2H, m) , 2.21 (3H, s) , 2.50 (2H, t, J=7.2 Hz), 3.54 (2H, s) , 3.98 (2H, t, J=6.3 Hz), 4.14 (2H, q, J=7.0 Hz), 5.50 (IH, br.s) , 5.67 (IH, br.s), 6.42 (IH, dd, J=8.2, 2.4 Hz), 6.73 (IH, d, J=2.4 Hz), 7.16 (IH, s), 7.27 (IH, d, J=8.2 Hz), 7.32-7.58 (5H, m) . IR V max (KBr) 3445, 2972, 2919, 1739, 1687,1655, 1614 cm "1 . Analyses: Calc'd for C25H27 O4 O.9H2O: C, 71.20; H, 6.88; N, 3.32 Found: C, 71.13; H, 6.76; N, 3.52. EIMS m/z=115 (base peak) , 405 (M + ) . Part L-2: Preparation of Ethyl [1 (Z) -benzylidene-3- carbamoylmethyl-2-methyl-lH-inden-4-yloxy] -acetate 13b Using the procedure described in the synthesis of compound 13a from 12a, the hydroxy compound (12b, 53.1 mg, 0.182 m mol) in dimethylformamide (1.0 ml) was reacted with sodium hydride (60% oil suspension, 26.1 mg, 0.653 m mol) and ethyl bromoacetate (72 μl, 0.649 m mol) . Purification by preparative TLC (200x200x0.25 mm, elution with CHCI3 :MeOH=19 : 1) gave the produ -. (53.1 mg, 77%), mp, 162-165 °C. Other Preparations: (Z) -Ethyl (3-benzylidene-l-carbamoylmethyl-2-ethyl-3H-inden- 7-yloxy) -acetate 13c. Mp., 139-142 °C. 61% yield. (Z) -Ethyl [3- (biphenyl-2-yImethylene) -1-carbamoylmethy1-2- ethyl-3H-inden-7-yloxy] -acetate 13d. Mp. , 161-163 °C. 76% yield. Ethyl (Z) - [1- (2-benzyl-benzylidene) -3-carbamoylmethyl-2- ethyl-lH-inden-4-yloxy] -acetate 13e. Mp, 157.5-158.5 °C. 83% yield. Ethyl (Z) - [3-carbamoylmethyl-l- (3-chloro-benzylidene) -2- ethyl-lH-inden-4-yloxy] -acetate 13f. Mp, 182.5-184 °C. 57% yield. Ethyl (Z) - [3-carbamoylmethyl-l- (2, 3-dichloro-benzylidene) -2- ethyl-lH-inden-4-yloxy] -acetate 13g. Mp, 185.5-187.5 °C. 83% yield. Ethyl (Z) - [3-carbamoylmethyl-2-ethyl-l- (3-trifluoromethyl- benzylidene) -lH-inden-4-yloxy] -acetate 13h. Mp, 175.5-182.5 °C. 76% yield. Ethyl (Z) - (3-carbamoylmethyl-2-ethyl-l-naphthalen-l- ylmethylene-lH-inden-4-yloxy) -acetate 13i. Mp, 153.5-160 °C. 64% yield. Ethyl (Z) - (3-carbamoylmethyl-2-ethyl-l-naphthalen-2- ylmethylene-lH-inden-4-yloxy) -acetate 13j . Mp, 201-204 °C. 77% yield. Part M-l: Preparation of 4- [1 (Z) -Benzylidene-3- carbamoylmethyl-2-methyl-lH-inden-5-yloxy] -butanoic acid 14a IN Sodium hydroxide (0.200 ml, 0.200 m mol) was added to a solution of the ester (13a, 39.4 mg, 0.0972 m mol) in dimethylsulfoxide (1.0 ml) at room temperature. The solution was stirred at room temperature for 75 min, partitioned between IN HCl and AcOEt. The organic layer was separated, washed with water and brine, dried over MgS04, filtered and evaporated in vacuo. Recrystallization from AcOEt afforded the titled compound (19.5 mg, 53%), mp, 187-188 °C. : H NMR (d 6 -DMSO) δ 1.82-2.02 (2H, m) , 2.14 (3H, s) , 2.36 (2H, t, J=7.0 Hz), 3.94 (IH, t, J=6.3 Hz) , 6.42 (IH, dd, J=8.4, 2.0 Hz), 6.85 (IH, d, J=2.0 Hz), 6.96 (IH, br.s), 7.13 (IH, d, J=8.4 Hz), 7.16 (IH, s), 7.32-7.57 (6H, m) . IR V max (KBr) 3462, 3342, 3190, 2936, 1715, 1697, 1647, 1613, 1582 cm "1 . Analyses: Calc'd for C23H23NO4 O.5H2O: C, 71.49; H, 6.26; N, 3.62. Found: C, 71.47; H, 6.25; N, 3.47. EIMS m/z=232 (base peak), 377 (M + ) . Other Preparations: [1 (Z) -Benzylidene-3-carbamoylmethyl-2-methyl-lH-inden-4- yloxy] -acetic acid 14b. Mp, 224-226 °C. 55% yield. 1 H NMR (d 6 -DMSO) δ 2.12 (3H, s) , 3.64 (2H, s) , 4.69 (2H, s) , 6.70- 6.95 (4H, m) , 7.19 (IH, br.s), 7.31 (IH, s) , 7.35-7.57 (5H, m) , 13.2 (IH, br.s) . EIMS m/z=349 (base peak, M + ) . HR-EIMS Calc'd for C 2 ιH 19 N0 4 : 349.1312, Found: 349.1311. (Z) - (3-Benzylidene-l-carbamoylmethyl-2-ethyl-3H-inden-7- yloxy) -acetic acid 14c. Mp., 119-205 °C. 91% yield. 1 H NMR (300 MHz, d 6 -DMSO) δ 1.15 (3H, t, J=7.5 Hz), 2.60 (2H, q, J=7.5 Hz), 3.63 (2H, s), 4.65 (2H, s), 6.72-6.94 (IH, br m) , 6.76 (IH, t, J=7.5 Hz), 6.82 (IH, d, J=8.4 Hz), 6.90 (IH, d, J=7.2 Hz), 7.32 (IH, s) , 7.30-7.58 (6H, m) . IR V max (KBr) 3387, 3081, 3055, 3024, 2966, 2935, 2873, 1706, 1655, 1592, 1573, 1478, 1438, 1257, 1103, cm -1 . EIMS m/z=304 (base peak) , 363 (M + ) . HR-EIMS Calc'd for C22H21NO4: 363.1469, Found: 363.1485 (Z) - [1- (Biphenyl-2-ylmethylene) -3-carbamoyImethyl-2-ethyl-1H- inden-4-yloxy] -acetic acid 14d. Mp. , 205-209 °C. 93% yield. 1 H NMR (300 MHz, d 6 -DMSO) δ 0.91 (3H, t, J=7.5 Hz) , 2.41 (2H, q, J=7.5 Hz) , 3.59 (2H, s) , 4.68 (2H, s) , 6.72-6.90 (4H, m) , 7.00 (IH, s), 7.26 (IH, br.s), 7.30-7.62 (9H, m) . IR V max (KBr) 3403, 2959, 2931, 2869, 1719, 1689, 1660, 1600, 1577, 1478, 1437, 1258, 1231, 1096, 735, 700 cm -1 . Analyses: Calc'd for C28H25NO4 0.3H 2 O: C, 76.18; H, 6.31; N, 2.96. Found: C, 76.14; H; 6.35; N, 2.99. EIMS m/z=165 (base peak) , 439 (M + ) . (Z) - [1- (2-Benzyl-benzylidene) -3-carbamoyImethyl-2-ethyl-1H- inden-4-yloxy] -acetic acid 14e. Mp, 194-200 °C. Quantitative yield. """H NMR (d 6 -DMSO) δ 1.07 (3H, t, J=7. Hz), 2.36 (2H, q, J=7.4 Hz), 3.61 (2H, s), 3.97 (2H, s), 4.68 (2H, s) , 6.48 (IH, dd, J=6.4, 2.0 Hz), 6.67-6.80 (2H, m) , 6.80-6.91 (IH, br) , 7.04-7.43 (11H, m) . IR V max (KBr) 3414, 1725, 1647, 1597, 1479, 1438 cm -1 . EIMS m/z=179 (base peak) , 453 (M + ) . HR-EIMS Calc'd for C29H27 N0 : 453.1938, Found: 453.1944. (Z) - [3-CarbamoyImethyl-1- (3-chloro-benzylidene) -2-ethyl-lH- inden-4-yloxy] -acetic acid 14f. Mp, 213.5-214 °C. 82% yield. 1 H NMR (d 6 -DMSO) δ 1.14 (3H, t, J=7.4 Hz) , 2.58 (2H, q, J=7.4 Hz), 3.62 (2H, s), 4.69 (2H, s), 6.73-6.94 (4H, m) , 7.23-7.28 (IH, br), 7.28 (IH, s), 7.43-7.62 (4H, m) . IR V max (KBr) 3458, 3334, 2966, 1734, 1634, 1592, 1478, 1435 cm -1 . Analyses: Calc'd for C22H2O NO4CI 0.3H 2 O: C, 65.53; H, 5.15; N, 3.47; Cl, 8.79. Found: C, 65.57; H, 5.19; N, 3.58; Cl, 8.83. EIMS m/z=338 (base peak) , 397 (M + ) . (Z) - [3-Carbamoylmethyl-1- (2, 3-dichloro-benzylidene) -2-ethyl- lH-inden-4-yloxy] -acetic acid 14g. Mp, 226-228.5 °C. 89% yield. 1 H NMR (d 6 -DMSO) δ 1.17 (3H, t, J=7.4 Hz), 2.60 (2H, q, J=7.4 Hz), 3.63 (2H, s) , 4.68 (2H, s), 6.48 (IH, dd, J=6.4, 1.6 Hz) , 6.73-6.94 (3H, m) , 7.17 (IH, s), 7.12-7.33 (IH, br) , 7.38-7.61 (2H, m) , 7.73 (IH, dd, J=7.3, 1.6 Hz) . IR max ( KBr ) 3415, 2966, 1726, 1650, 1600, 1479, 1435, 1409 cm " ~ . EIMS m/z=378 (base peak), 431 (M + ) . HR-EIMS Calc'd for 22H19 N0 4 C1 2 : 431.0689, Found: 431.0685. (Z) - [3-Carbamoylmethyl-2-ethyl-l- (3-trifluoromethyl- benzylidene) -lH-inden-4-yloxy] -acetic acid 14h. Mp, 207- 211.5 °C. 70% yield. 1 H NMR (d 6 -DMSO) δ 1.16 (3H, t, J=7.4 Hz), 2.60 (2H, q, J=7.4 Hz) , 3.63 (2H, s), 4.69 (2H, s), 6.70-6.93 (4H, m) , 7.12-7.30 (IH, br) , 7.36 (IH, s) , 7.64- 7.91 (4H, m) . IR V maχ (KBr) 3428, 1730, 1646, 1587, 1438, 1328 cm "1 . Analyses: Calc'd for C23H20 NO4F3 : C, 64.04; H, 4.67; N, 3.25; F, 13.21. Found: C, 63.76; H, 4.71; N, 3.29; F, 13.02. EIMS m/z=372 (base peak) , 431 (M + ) . (Z) - (3-Carbamoylmethyl-2-ethyl-l-naphth-l-ylmethylene-lH- inden-4-yloxy) -acetic acid 14i. Mp, 210.5-213 °C. 90% yield. ^ ■ H NMR (dg-DMSO) δ 1.26 (3H, t, J=7.4 Hz) , 2.72 (2H, q, J=7.4 Hz), 3.66 (2H, s) , 4.66 (2H, s), 6.29 (IH, d, J=6.6 Hz) , 6.56-6.74 (2H, m) , 6.80-6.94 (IH, br) , 7.17-7.35 (IH, br) , 7.46-7.74 (5H, m) , 7.86-8.10 (3H, m) . IR V max (KBr) 3415, 2961, 1662, 1599, 1478, 1430, 1340 cm "1 . EIMS m/z=354 (base peak), 413 (M + ) . HR-EIMS Calc'd for C26H23NO4: 413.1624, Found: 413.1621. (Z) - (3-Carbamoylmethyl-2-ethyl-l-naphth-2-ylmethylene-lH- inden-4-yloxy) -acetic acid 14j . Mp, 210.5-215.5 °C. 70% yield. -" " H NMR (CDCI3) δ 1.27 (3H, t, J=7.6 Hz), 2.75 (2H, q, J=7.6 Hz), 3.80 (2H, s) , 4.68 (2H, s), 6.65 (IH, d, J=8.0 Hz), 6.80 (IH, t, J=8.0 Hz), 7.09 (IH, d, J=8.0 Hz), 7.39- 7.67 (6H, m) , 7.77-8.04 (4H, m) . IR V max (KBr) 3434, 2965, 1716, 1662, 1478, 1430 cm "1 . EIMS m/z=354 (base peak) , 413 (M + ) . HR-EIMS Calc'd for C26H23 O4: 413.1626, Found: 413.1629. Part N: Preparation of (Z) -Methyl (3-benzylider.e-1- carbamoylmethyl-2-ethyl-3H-inden-7-yloxy) -acetate 15 Using the procedure described in the prepartion of compound 13a from 12a. M . , 129-141 °C. 86% yield. 1 H NMR (300 MHz, CDC1 3 ) δ 1.24 (3H, t, J=7.5 Hz), 2.72 (2H, q, J=7.5 Hz), 3.81 (2H, s), 3.83 (3H, s) , 4.70 (2H, s) , 5.24 (IH, br.s), 6.60 (IH, d, J=8.1 Hz), 6.74 (IH, br.s) , 6.82 (IH, t J=7.8 Hz) , 7.04 (IH, d, J=7.2 Hz) , 7.30 (IH, s) , 7.31-7.53 (5H, m) . IR V max (KBr) 3398, 3174, 2958, 1751, 1684, 1620, 1591, 1573, 1479, 1435, 1390, 1223, 1101, 746, 703 cm -1 . Analyses: Calc'd for C23H23NO4 0.6H 2 O: C, 71.15; H, 6.28; N, 3.61. Found: C, 71.30; H; 6.09; N, 3.69. EIMS m/z=318 (base peak) , 377 (M + ) . Part 0: Preparation of (Z) -Methyl (3-benzyl-l- carbamoylmethyl-2-ethyl-3H-inden-7-yloxy) -acetate 16a and (Z) -methyl (3-benzyl-1-carbamoyImethyl-2-ethyl-IH-inden-7- yloxy) -acetate 16b A mixture of the acetic acid ester (15, 113 mg, 0.300 m mol) and 5% palladium-coal (11.9 mg) in methanol (5.0 ml) was hydrogenated under atmosphere for 18 min. The catalyst was filtered off and the solvent was evaporated. The residue was purified by preparative TLC on silica gel (200x200x0.25 mm, eluting with AcOEt) to give the crude product (16a, 55.3 mg, 49%) and the isomer (16b, 11.1 mg, 10%) . The crude product was recrystallized from CHC13-hexane to afford the pure product (16a, 48.8 mg, 43%) . 16a: Mp., 118-121 °C. Part P: Preparation of (Z) - (3-Benzyl-l-carbamoylmethyl-2- ethyl-3H-inden-7-yloxy) -acetic acid 17a To a solution of the ester (16a, 33.7 mg, 0.0888 m mol) in methanol (1.5 ml) was added IN sodium hydroxide (0.270 ml, 0.270 m mol) at room temperature. The solution was stirred at this temperature fo 50 min, evaporated, partitioned between IN HCl and AcOEt. The organic layer was separated, washed with water and brine, dried over MgS04, filtered and evaporated in vacuo. Recrystallization from CHCl;,-hexane afforded the titled compound (16.7 mg, 50%) , mp., 193-197 °C. 1 H NMR (300 MHz, d 6 -DMS0) δ 1.05 (3H, t, J=7.5 Hz), 2.16 (IH, dd, J=9.0, 14.7 Hz) , 2.23-2.39 (IH, m) , 2.53-2.70 (IH, m) , 3.06 (IH, dd, J=3.6, 14.7 Hz), 3.82 (2H, s) , 3.99 (IH, dd, J=3.2, 8.9 Hz) , 4.71 (IH, ABq, Apart J=16.8 Hz), 4.75 (IH, ABq, Bpart J=16.8 Hz), 6.60 (IH, d, J=8.1 Hz), 6.69 (IH, d, J=7.5 Hz), 6.84 (IH, br.s), 7.07 (IH, t, J=7.8 Hz) , 7.10- 7.30 (6H, m) . IR v max (KBr) 3422, 3225, 2966, 2932, 1718, 1647 1604, 1583, 1475, 1249, 1224, 1097 cm "1 . Analyses: Calc'd for C22H23 O4 0.4H 2 O: C, 70.91; H, 6.44; N, 3.76. Found: C, 70.79; H; 6.35; N, 3.75. EIMS m/z=231 (base peak), 365 (M + ) . Preparation of (Z) - (3-Benzyl-l-carbamoylmethyl-2-ethyl-lH- inden-7-yloxy) -acetic acid 17b 90% Yield. -""H NMR (300 MHz, d 6 -DMSO) δ 1.05 (3H, t, J=7.5 Hz), 2.12-2.37 (2H, m) , 2.55-2.70 (IH, m) , 3.05 (IH, dd, J=3.3, 14.7 Hz), 3.82 (2H, s) , 3.94-4.20 (IH, br m) , 4.69 (IH, ABq, Apart J=15.9 Hz), 4.73 (IH, ABq, Bpart J=15.9 Hz), 6.59 (IH, d, J=8.1 Hz), 6.69 (IH, d, J=7.5 Hz), 6.82 (IH, br.s), 7.06 (IH, t, J=7.8 Hz) , 7.10-7.33 (6H, m) . EIMS m/z=231 (base peak), 365 (M + ) . HR-EIMS Calc'd for C22H23NO4 : 365.1626, Found:365.1630 Part O: Preparation of (Z) -2- [3- (Biphenyl-2-ylmethylene) -2- ethyl-7-methoxy-3H-inden-l-yl] -2-hydroxy-acetic acid 18 To a solution of diisopropylamine (0.860 ml, 6.14 m mol) in THF (25.0 ml) was added n-butyllithium (1.6 M in hexane solution, 4.40 ml) at -20°C. After the reaction mixture was stirred for 20 min at -20°C and for 20 min at 0°C, a solution of acetic acid derivative (lOd, 0.501 g, 1.26 m mol) in THF (35 ml) was slowly added at -78°C. The mixture was gradually warmed to 0°C, was bubbled with air for 10 min at this temperature and then was poured into IN HCl and extracted with AcOEt. The extracts was washed with saturated Na2≤2θ3 solution, water and brine, dried over MgS04, filtered and concentrated in vacuo. The residue was roughly purified by preparative TLC on silica gel (200x200x2 mm, elution with CHCI3 :MeOH=95:5) to give the crude product (0.333 g) . The crude product was used the next preparation without furter purification. Part R: Preparation of (Z) -2- [3- (Biphenyl-2-ylmethylene) - 2-ethyl-7-methoxy-3H-inden-l-yl] -2-hydroxy-acetamide 19 Using the procedure described in the prepartion of compound 11a from 10, the hydroxy acetic acid (18, 0.286 g, 0.694 m mol) in acetonitrile (10 ml) was reacted with benzotriazol-1-yloxytris (dimethylamino) phosphonium hexafuluorophoshate (0.371 g, 0.839 m mol) , triethylamine (0.120 ml, 0.861 m mol) and 28% aqueous ammonia (0.470 ml, 6.95 mol) to give 100 mg (2 steps yield=22%) of the titled compound, mp., 204-209 °C. Part S: Preparation of (Z) -2- [3- (Biphenyl-2-ylmethylene) -2- ethyl-7-methoxy-3H-inden-l-yl] -2-oxo-acetamide 20 To a solution of the hydroxy acetamide (19, 49.3 mg, 0.120 m mol) in dichloromethane (1.5 ml) were added molecular sieves (4A powder, 61.3 mg) , N-methylmorpholine N-oxide (57.3 mg, 0.489 m mol) and tetrapropylammonium perruthenate (4.3 mg, 0.0112 m mol) at room temperature and then the reaction mixture was subjected successively to chromatography on silica gel eluting with CHCI3 and then CHCI3 :MeOH=9 :1, to prepreparative TLC on silica gel (200x200x2 mm) , eluting with CHCI3 :MeOH=97.5:2.5) and recrystallization from hexane-CHCl3 to afford 27.2 mg (55%) of the desired product, mp. , 172-179 °C. ■ " ■ H NMR (200 MHz, CDCI3) δ 1.02 (3H, t, J=7.6 Hz), 2.47 (2H, q, J=7.6 Hz), 3.80 (3H, s), 5.60 (IH, br.s), 6.73 (IH, br.s), 6.76 (IH, d, J=8.2 Hz), 6.96 (IH, t, J=7.8 Hz), 7.18 (IH, s), 7.24 (IH, d, J=7.6 Hz), 7.30-7.66 (8H, m) , 7.91 (IH, d, J=7.4 Hz) . IR \ maχ (KBr) 3437, 3211, 2968, 2934, 1665, 6/03120 - 53 - 1624, 1600, 1568, 1482, 1341, 1274, 1267, 1152, 1066, 748, 701 cm "1 . Analyses: Calc'd for C27H23NO3 0.5H O: C, 77.49 H, 5.78; N, 3.35. Found: C, 77.35; H; 5.86; N, 3.41. EIMS m/z=165 (base peak) , 409 (M+) . Therapeutic Use of indene-1-functional compounds The indene-1-functional compounds of the invention are believed to achieve their beneficial therapeutic action principally by direct inhibition of human SPLA2, and not by acting as antagonists for arachidonic acid, nor other active agents below arachidonic acid in the arachidonic acid cascade, such as 5-lipoxygenases, cyclooxygenases, and etc. The method of the invention for inhibiting sPLA2 mediated release of fatty acids comprises contacting a mammal, including a human, suffering from or susceptible to a disease in which SPLA2 mediated release of fatty acids is a cause with a therapeutically effective amount of compound corresponding to formulae (I), (II), (III) or a salt or a prodrug derivative thereof. The compounds of the invention may be used in a method of treating a mammal (e.g., a human) to alleviate the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis; wherein the method comprises administrating to the mammal at least compound represented by formulae (I), (II), (III) or any combination thereof in a therapeutically effective amount. A therapeutically effective amount is an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. The therapeutic amount of compound of the invention needed to inhibit SPLA2 may be readily determined by taking a sample of body fluid and assaying it for sPLA2 content by conventional methods. Pharmaceutical Formulations of the love-tier. As previously noted the compounds of this invention are useful for inhibiting sPLA2 mediated release of fatty acids such as arachidonic acid. By the term, "inhibiting" is meant the prevention or therapeutically significant reduction in release of sPLA2 initiated fatty acids by the compounds of the invention. By "pharmaceutically acceptable" it is meant the carrier, diluent or excipient must be compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. The specific dose of a compound administered according to this invention to obtain therapeutic or prophylactic effects will, of course, be determined by the particular circumstances surrounding the case, including, for example, the compound administered, the route of administration and the condition being treated. Typical daily doses will contain a non-toxic dosage level of from about 0.01 mg/kg to about 50 mg/kg of body weight of an active compound of this invention. Preferably the pharmaceutical formulation is in unit dosage form. The unit dosage form can be a capsule or tablet itself, or the appropriate number of any of these. The quantity of active ingredient in a unit dose of composition may be varied or adjusted from about 0.1 to about 1000 milligrams or more according to the particular treatment involved. It may be appreciated that it may be necessary to make routine variations to the dosage depending on the age and condition of the patient. The dosage will also depend on the route of administration. The compound can be administered by a variety of routes including oral, aerosol, rectal, transdermal, subcutaneous, intravenous, intramuscular, and intranasal. Pharmaceutical formulations of the invention are prepared by combining (e.g., mixing) a therapeutically effective amount of the indene-1-functional compounds of the invention (represented by formulae (I) , (II), (III)) together with a pharmaceutically acceptable cdrrι:.r or diluent therefor. The present pharmaceutical formulations are prepared by known procedures using well known and readily available ingredients. In making the compositions of the present invention, the active ingredient will usually be admixed with a carrier, or diluted by a carrier, or enclosed within a carrier which may be in the form of a capsule, sachet, paper or other container. When the carrier serves as a diluent, it may be a solid, semi-solid or liquid material which acts as a vehicle, or can be in the form of tablets, pills, powders, lozenges, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), or ointment, containing, for example, up to 10% by weight of the active compound. The compounds of the present invention are preferably formulated prior to administration. For the pharmaceutical formulations any suitable carrier known in the art can be used. In such a formulation, the carrier may be a solid, liquid, or mixture of a solid and a liquid. Solid form formulations include powders, tablets and capsules. A solid carrier can be one or more substances which may also act as flavoring agents, lubricants, solubilisers, suspending agents, binders, tablet disintegrating agents and encapsulating material. Tablets for oral administration may contain suitable excipients such as calcium carbonate, sodium carbonate, lactose, calcium phosphate, together with disintegrating agents, such as maize, starch, or alginic acid, and/or binding agents, for example, gelatin or acacia, and lubricating agents such as magnesium stearate, stearic acid, or talc. In powders the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets the active ingredient is mixed with a carrier having the necessary binding properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain from about 1 to about 99 weight percent of the active ingredient which is the novel compound of this invention. Suitable solid carriers are magnesium carbonate, magnesium stearate, talc, sugar lactose, pectin, dextrin, starch, gelatin, tragacanth, methyl cellulose, sodium carboxymethyl cellulose, low melting waxes, and cocoa butter. Sterile liquid form formulations include suspensions, emulsions, syrups and elixirs. The active ingredient can be dissolved or suspended in a pharmaceutically acceptable carrier, such as sterile water, sterile organic solvent or a mixture of both. The active ingredient can often be dissolved in a suitable organic solvent, for instance aqueous propylene glycol. Other compositions can be made by dispersing the finely divided active ingredient in aqueous starch or sodium carboxymethyl cellulose solution or in a suitable oil. The following pharmaceutical formulations 1 thru 8 are illustrative only and are not intended to limit the scope of the invention in any way. "Active ingredient", refers to a compound according to formulae (I) , (II) , (III) or a pharmaceutically acceptable salt, solvate, or prodrug derivative thereof. 6/03120 - 57 - Formyl-ζipn 1 Hard gelatin capsules are prepared using the following ingredients : Quantity (rog/ςapsule) Active ingredient 250 Starch, dried 200 Magnesium stearate 10. Total 460 mg ormul t on 2 A tablet is prepared using the ingredients below: Quantity (ma/tablet) Active ingredient 250 Cellulose, microcrystalline 400 Silicon dioxide, fumed 10 Stearic acid J5_ Total 665 mg The components are blended and compressed to form tablets each weighing 665 mg Foππwlation 3 An aerosol solution is prepared containing the following components: Weight Active ingredient 0.25 Ethanol 25.75 Propellant 22 (Chlorodifluoromethane) 74.00 Total 100.00 The active compound is mixed with ethanol and the mixture added to a portion of the propellant 22, cooled to -30°C and transferred to a filling device. The required - 58 - amount is then fed to a stainless steel container and diluted with the remainder of the propellant. The valve units are then fitted to the container. Formulation 4 Tablets, each containing 60 mg of active ingredient, are made as follows: Active ingredient Starch Microcrystalline cellulose Polyvinylpyrrolidone (as 10% solution in water) Sodium carboxymethyl starch Magnesium stearate Talc Total 150 mg The active ingredient, starch and cellulose are passed through a No. 45 mesh U.S. sieve and mixed thoroughly. The aqueous solution containing polyvinylpyrrolidone is mixed with the resultant powder, and the mixture then is passed through a No. 14 mesh U.S. sieve. The granules so produced are dried at 50°C and passed through a No. 18 mesh U.S. sieve. The sodium carboxymethyl starch, magnesium stearate and talc, previously passed through a No. 60 mesh U.S. sieve, are then added to the granules which, after mixing, are compressed on a tablet machine to yield tablets each weighing 150 mg. Formulation 5 Capsules, each containing 80 mg of active ingredient, are made as follows: Active ingredient 80 mg Starch 59 mg Microcrystalline cellulose 59 mg Magnesium stearate 2 mσ Total 200 mg The active ingredient, cellulose, starch, and magnesium stearate are blended, passed through a No. 45 mesh U.S. sieve, and filled into hard gelatin capsules in 200 mg quantities. Formulation 6 Suppositories, each containing 225 mg of active ingredient, are made as follows: Active ingredient 225 mg Saturated fatty acid glycerides 2.000 mσ Total 2,225 mg The active ingredient is passed through a No. 60 mesh U.S. sieve and suspended in the saturated fatty acid glycerides previously melted using the minimum heat necessary. The mixture is then poured into a suppository mold of nominal 2 g capacity and allowed to cool. Formulation 7 Suspensions, each containing 50 mg of active ingredient per 5 ml dose, are made as follows: Active ingredient 50 mg Sodium carboxymethyl cellulose 50 mg Syrup 1.25 ml Benzoic acid solution 0.10 ml Flavor q.v. Color q.v. Purified water to total 5 ml The active ingredient is passed through a No. 45 mesh U.S. sieve and mixed with the sodium carboxymethyl cellulose and syrup to form a smooth paste. The benzoic acid solution, flavor and color are diluted with a portion of the water and added, with stirring. Sufficient water is then added to produce the required volume. Formulation 8 An intravenous formulation may be prepared as follows: Active ingredient 100 mg Isotonic saline 1,000 ml The solution of the above ingredients generally is administered intravenously to a subject at a rate of 1 ml per minute. Assay Experiments The following chromogenic assay procedure was used to identify and evaluate inhibitors of recombinant human secreted phospholipase A2. The assay described herein has been adapted for high volume screening using 96 well microtiter plates. A general description of this assay method is found in the article, "Analysis of Human Synovial Fluid Phospholipase A2 on Short Chain Phosphatidylcholine- Mixed Micelles: Development of a Spectrophotometric Assay Suitable for a Microtiterplate Reader", by Laure J. Reynolds, Lori L. Hughes, and Edward A Dennis, Analytical Biochemistry. 204, pp. 190-197, 1992 (the disclosure of which is incorporated herein by reference) : 6/03120 - 61 - Reagents : REACTION BUFFER - CaCl2-2H20 (1.47 g/L) KC1 (7.455 g/L) Bovine Serum Albumin (fatty acid free) (1 g/L) (Sigma A-7030, product of Sigma Chemical Co. St. Louis MO, USA) TRIS HCl (3.94 g/L) pH 7.5 (adjust with NaOH) ENZYME BUFFER - 0.05 NaOAc.3H2θ, pH 4.5 0.2 NaCl Adjust pH to 4.5 with acetic acid DTNB - 5, 5 ' -dithiobis-2-nitrobenzoic acid RACEMIC DIHEPTANOYL THIO - PC racemic 1,2-bis(heptanoylthio) -1,2-dideoxy-sn- glycero-3-phosphorylcholine TRITON X-100™ prepare at 6.249 mg/ml in reaction buffer to equal lOuM. REACTION MIXTURE - A measured volume of racemic dipheptanoyl thio PC supplied in chloroform at a concentration of 100 mg/ml is taken to dryness and redissolved in 10 millimolar TRITON X- 100™ nonionic detergent aqueous solution. Reaction Buffer is added to the solution, then DTNB to give the Reaction Mixture. The reaction mixture thus obtained contains lmM diheptanoly thio-PC substrate, 0.29 mm Triton X-100™ detergent, and 0.12 mm DTMB in a buffered aqueous solution at pH 7.5. Assay Procedure: 1. Add 0.2 ml reaction mixture to all wells; 2. Add 10 ul test compound (or solvent blank) to appropriate wells, mix 20 seconds; - 62 - 3. Add 50 nanograms of sPLA2 (10 microlir.ers) to appropriate wells; 4. Incubate plate at 40 C for 30 minutes; 5. Read absorbance of wells at 405 nanometers with an automatic plate reader. All compounds were tested in triplicate. Typically, compounds were tested at a final concentration of 5 ug/ml . Compounds were considered active when they exhibited 40% inhibition or greater compared to uninhibited control reactions when measured at 405 nanometers. Lack of color development at 405 nanometers evidenced inhibition. Compounds initially found to be active were reassayed to confirm their activity and, if sufficiently active, IC50 values were determined. Typically, the IC50 values (see, Table I, below) were determined by diluting test compound serially two-fold such that the final concentration in the reaction ranged from 45 ug/mL to 0.35 ug/ml. More potent inhibitors required significantly greater dilution. In all cases, % inhibition measured at 405 nanometers generated by enzyme reactions containing inhibitors relative to the uninhibited control reactions was determined. Each sample was titrated in triplicate and result values were averaged for plotting and calculation of IC50 values. IC50 were determined by plotting log concentration versus inhibition values in the range from 10-90% inhibition. The results of Human Secreted Phospholipase A2 Inhibition tests are displayed in the Table below: TABLE SPLA2 Chromogenic Assay Data • 63 - While the present invention has been illustrated above by certain specific embodiments, it is not intended that these specific examples should limit the scope of the invention as described in the appended claims.

Claims: ■ 64 - We claim: 1. An indene-1-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (I) ; wherein; X is oxygen or sulfur; each Ri is independently hydrogen, C1-C3 alkyl, or halo; R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-R80; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(Cι-C2 alkyl), -SAC1-C2 alkyl), or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; R6 and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, -(L ) - (acidic group); wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least, ene of Re and R7 must be the group, - (L a ) - (acidic group); and R4 and 5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents. 2. The compound of Claim 1 wherein; (i) X is oxygen; (ii) R2 is selected from the group; halo, cyclopropyl, methyl, and ethyl; (iii) R3 has as a linking group -(L)- an alkylene chain of 1 or 2 carbon atoms and R80 s selected from the group consisting of benzylidene, cycloalkyl, cycloalkenyl, phenyl, naphthyl, norbornanyl, bicycloheptadienyl, toluyl, xylenyl, indenyl, stilbenyl, terphenylyl, diphenylethylenyl, phenyl-cyclohexenyl, acenaphthylenyl, and anthracenyl, biphenyl, bibenzylyl and related bibenzylyl homologues represented by the formula (bb) , where n is a number from 1 to 8; (iv) R6 or R7 have an (acidic group) on the group - (L a ) - (acidic group) selected from: -5-tetrazolyl, -SO3H, 0 P t OH 0R 89 0 O P t OH OR 89 0 P t OH OH O 0 P t OH OH where n is 1 to 8, R89 is a metal or Cι~Cιo alkyl, and R99 is hydrogen or C1-C10 alkyl; and (v) R4 and R5 are each independently selected from hydrogen and non-interfering substituents, with the non- interfering substituents being selected from the group consisting of the following: C±-Cζ alkyl, C2-C6 alkenyl, C2~ Cs alkynyl, C7-C12 aralkyl, C7-C12 alkaryl, C3-C8 cycloalkyl, C3-C8 cycloalkenyl, phenyl, toluyl, xylenyl, biphenyl, C1-C6 alkoxy, C1-C6 alkenyloxy, C1-C6 alkynyloxy, C2-C12 alkoxyalkyl, C2-C12 alkoxyalkyloxy, C2-C12 alkylcarbonyl, C2- C12 alkylcarbonylamino, C2-C12 alkoxyamino, C2-C12 alkoxyaminocarbonyl, C1-C12 alkylamino, C1-C6 alkylthio, C2~ C12 alkylthiocarbonyl, C1-C6 alkylsulfinyl, C1-C6 alkylsulfonyl, Ci-Cg haloalkoxy, C1-C6 haloalkylsulfonyl, Ci- C6 haloalkyl, C1-C6 hydroxyalkyl, -C(0)0(Cι~C6 alkyl), - (CH2)n _ 0- (C1-C6 alkyl), benzyloxy, phenoxy, phenylthio, -(CONHSO2R), -CHO, a ino, amidino, bromo, carbamyl, carboxyl, carbalkoxy, - (CH2)n~Cθ2H, chloro, cyano, cyanoguanidinyl, fluoro, guanidino, hydrazide, hydrazino, hydrazido, hydroxy, hydroxyamino, iodo, nitro, phosphono, -SO3H, thioacetal, thiocarbonyl, and C1-C6 carbonyl; where n is from 1 to 8. 3. The compound of Claim 2, wherein, (A) for (iii) , the group R3 is selected from the group consisting of • 68 - and where Rio is a radical independently selected from halo, Ci- Cχo alkyl, Cι-Cχo alkoxy, -S- (Cχ-Cιo alkyl) , and Cχ-Cιo haloalkyl, q is a number from 0 to 4, and t is a number from 0 to 5; and (B) for (iii) the linking group -(L)- of R3 is selected from the group consisting of: 03120 -69- CH CH CH 2 (CH 2 ) r (CH 2 ; ■ s- ( CH 2 ) s where s = 0 or 1; (C) for (iv) the (acidic group) of R6 or R7 is selected from: C0 2 H S0 3 H P(O) (OH) 2 4. The compound of claim 3 wherein R7 comprises an acidic group and has an acid linker with an acid linker length of 2 or 3 and the acid linker group, -(L a )-, for R7 is represented by the formula; where Q is selected from the group -(CH2)-, -0-, -NH- , and -S- , and R84 and R85 are each independently selected from hydrogen, Cι-Cχo alkyl, aryl, Cχ-Cιo alkaryl, Cι~Cιo aralkyl, carboxy, carbalkoxy, and halo. 5. The compound of Claim 4 wherein R7 comprises an acidic group and the acid linker group, -(L a )-, for R7 is selected from the group consisting of; R N CH 2 - 71 - where R is H or C 1 -C 4 alkyl 6. The compound of Claim 1 wherein R6 comprises an acidic group and has an acid linker with an acid linker length of 3 to 10 atoms and the acid linker group, -(L a )-, for Rβ is selected from; (phenylene) where r is a number from 1 to 7, s is 0 or 1, and Q is selected from the group -(CH2)-, -0-, -NH-, and -S-, and R84 and R85 are each independently selected from hydrogen, Cl-Cio alkyl, aryl, Ci-Cio alkaryl, Ci-Cio aralkyl, carboxy, carbalkoxy, and halo. 7. The compound of Claim 6 wherein the acid linker , !L ) -, for Rς is selected from group consisting of ; / J 7 _ and wherein ; R is hydrogen or C1-C4 alkyl, R84 and R85 are each indepen d ently selected from hydrogen, C1-C10 alkyl, aryl , Cl- C io alkaryl, C1-C10 aralkyl, carboxy, carbalkoxy, and halo. 8. An indene-1-acetic acid hydrazide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (II); wherein: X is oxygen or sulfur; each Ri is independently hydrogen, C1-C3 alkyl, or halo; R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-R80; where, -(L)- is a divalent linking group of 1 to 12 atoms and where R80 is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -OAC1-C2 alkyl) , -S-(Ci~C2 alkyl) , or a non-interfering substituent having a total of 1 to 3 atoms other than hydrogen; Rg and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group); wherein -(L a )-, is an acid linker having an acid /03120 -75 - linker length of 1 to 10; provided, that at least one of Rζ and R7 must be the group, - (L a ) - (acidic group); and R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents. 9. An indene-1-glyoxylamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is represented by the formula (III); X is oxygen or sulfur; R3 is selected from groups (a) , (b) and (c) where; (a) is C7-C20 alkyl, C7-C20 alkenyl, C7-C20 alkynyl, carbocyclic radical, or heterocyclic radical, or (b) is a member of (a) substituted with one or more independently selected non-interfering substituents; or (c) is the group -(L)-R80; where, -(L)- is a divalent linking group of 1 to 12 atoms and where Rso is a group selected from (a) or (b) ; R2 is hydrogen, halo, C1-C3 alkyl, C3-C4 cycloalkyl, C3-C4 cycloalkenyl, -0-(Cι-C2 alkyl), -s- (C1-C2 alkyl), or a non-interfering substituent having a total cf 1 no 2 atoms other than hydrogen; Rβ and R7 are independently selected from hydrogen, a non-interfering substituent, or the group, - (L a ) - (acidic group) ; wherein -(L a )-, is an acid linker having an acid linker length of 1 to 10; provided, that at least one of Rς and R7 must be the group, - (L a ) - (acidic group); R4 and R5 are each independently selected from hydrogen, non-interfering substituent, carbocyclic radical, carbocyclic radical substituted with non-interfering substituents, heterocyclic radical, and heterocyclic radical substituted with non-interfering substituents. 10. An indene-1-acetamide compound or a pharmaceutically acceptable salt, solvate or prodrug derivative thereof; wherein said compound is selected from the group represented by formulae 14a, 14b, 14c, 14d, 14e, 14f, 14g, 14h, 14i, 14j , 17a, and 17b as follows: (14b) (14c) (140 (14h) (14j) (17a) (17b) and mixtures thereof. 11. A pharmaceutical formulation comprising the indene- 1-acetamide as claimed in Claim 1 together with a pharmaceutically acceptable carrier or diluent therefor. 12. A pharmaceutical formulation comprising the indene- 1-hydrazide as claimed in Claim 8 together with a pharmaceutically acceptable carrier or diluent therefor. 13. A pharmaceutical formulation comprising the indene- 1-glyoxylamide as claimed in Claim 9 together with a pharmaceutically acceptable carrier or diluent therefor. 14. A method of treating a mammal to alleviate the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis; wherein the method comprises administration to said mammal of at least one indene-1-acetamide as claimed in Claim 1 in an amount sufficient to inhibit SPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. 15. A method of treating a mammal to alleviate the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis; wherein the method comprises administration to said mammal of at least one indene-1-hydrazide as claimed in Claim 8 in an amount sufficient to inhibit SPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. 16. A method of treating a mammal to alleviate the pathological effects of septic shock, adult respiratory distress syndrome, pancreatitis, trauma, bronchial asthma, allergic rhinitis, and rheumatoid arthritis; wherein the method comprises administration to said mammal of at least one indene-1-glyoxylamide as claimed in Claim 9 in an amount sufficient to inhibit sPLA2 mediated release of fatty acid and to thereby inhibit or prevent the arachidonic acid cascade and its deleterious products. 17. A method of treating a mammal, including a human, suffering from or susceptible to a disease in which sPLA2 mediated release of fatty acids is a cause which comprises administering an effective amount of a compound according to Claim 1. 18. A method of treating a mammal, including a human, suffering from or susceptible to a disease in which SPLA2 mediated release of fatty acids is a cause which comprises administering an effective amount of a compound according to Claim 8. 19. A method of treating a mammal, including a human, suffering from or susceptible to a disease in which sPLA2 mediated release of fatty acids is a cause which comprises administering an effective amount of a compound according to Claim 9.

Inventors: DILLARD ROBERT D, HAGISHITA SANJI, OHTANI MITSUAKI, DILLARD, ROBERT, D., HAGISHITA, SANJI, OHTANI, MITSUAKI
Applicants: DILLARD ROBERT D, HAGISHITA SANJI, LILLY CO ELI, OHTANI MITSUAKI, SHIONOGI & CO, DILLARD, ROBERT, D., ELI LILLY AND COMPANY, HAGISHITA, SANJI, OHTANI, MITSUAKI, SHIONOGI & CO., LTD.
Application year: 1995
Main classification: A61K31
IPC codes: A61K31, A61P9, A61P11, A61P27, A61P29, A61P31, A61P37, A61P43, C07C45, C07C49, C07C59, C07C69, C07C235, C07C243, C07C309, C07C323, C07C327, C07F9