CA2090042A1 - Substituted indole-, indene-, pyranoindole- and tetrahydrocarbazole- alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase - Google Patents

Abstract

Abstract There are disclosed compounds of the formula:
A(CH2)nO-B, wherein A is C4-C8 alkyl, phenoxyethyl, phenoxyphenyl or a group having formula (a) or (b), wherein X is -N- or (c); Z is (d),(e),(f),(g),-S- or -O-;R1 is hydrogen, lower alkyl, phenyl or phenyl substituted with trifluoromethyl; R2 is hydrogen or lower alkyl; or R1 and R2 taken together form a benzen ring; R? is hydrogen or lower alkyl; n is 1-2; B is (h),(i),(j) or (k); wherein R4 is -CO2R2, (l), (m), (n), (o) or (p); m is 0-3; R5 is (q); or phenyl or phenyl substituted by halo, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl; R6 is A(CH2)nO- or halo; with the proviso that when R6 is ha-lo, R5 is (r); R7 is lower alkyl; Y is CH2- or -O-; R8 is lower alkyl or -(CH2)mCO2R3; R9 is (5) or -CH2R10; R10 is lower alkyl, phenyl, phenyl substituted with carboxy, halo, loweralkylthio or loweralkylsulfinyl, pyridyl, fura-nyl or quinolinyl; R11 is lower alkyl or phenyl; and the pharmacologically acceptable salts thereof, and their use in the treatment of inflammatory conditions, such as rheumatoid arthritis, ulcerative colitis, psoriasis and other immediate hypersensitivity reactions; in the treatment of leukotriene-mediated naso-bronchial obstructive air-pas-sageway conditions, such as allergic rhinitis, allergic bronchial asthma and the like; and as gastric cytoprotec-tive agents.

Description

20~00~2 SUBSTITUTED INDOLE~, INDENE-, PYRANOINDOLE- AND
TETRAHYDROCARBAZOLE- ALKANOIC ACID DERIVATI~ES
AS INH~RTTORS OF PLA~ A~D ~ ~POXY(-EN~SF

This invention relates to novel substituted indene-, indole-, pyrano-indole- and tetrahydrocarbazole alkanoic acid derivuives possessing lipoxygenaseinhiWtory, phospholipase A2 inhibi~ory and leukotriene antagonist activity, which are useful as anti-inflammatory, antiaUergic and cytoprotective agents.
It is now well-established that arachidonic acid (AA) is metabolized in mammals by two distinct pathways. The metabolism of arachidonic acid by cyclooxy-genase enzymes results in the production of prostaglandins and thromboxanes. Thephysiological activity of the prostaglandins has already been arnply elucidated in recent years. It is now known that prostaglandins arise from the endoperoxides PGG2 andPGH2 by the cyclooxygenase pathway of arachidonic acid metabolism. These endoperoxides are also the precursors of the thromboxanes tTX~ A2 and B2. TxA2 is a vasoconstrictor which stimulates platelet aggregation. In the normal situation, the vasoconstrictive and platelet aggregadng propenies of the thromboxanes are balanced by another product arising from the endoperoxides in the cyclooxygenase pathway,prostacyclin (PGI2), which is a vasodilator with platelet aggregation inhibitory acivity.
In the event prostacyclin synthesis is impaired and/or platelet activation is enhanced.
then thrombosis and vasoconstriction is favored. The role of prostanoids in haemo-stasis and thrombosis are reviewed by R.J. Gryglewski, CRC Crit. Rev. Biochem., 7.
291 (1980) and J. B. Smith, Am. J. Pathol., 99, 743 (1980). Cyclooxygenase metabolites are known to participate direcdy in dhe inflamrnatory response ~see Higgs et al., Annals of Clinical Research, 16, 287-299 (1984!]. This is through their vasode-pressor activities, participation in pain and fever augrnenution of peptide mediator vascular permeability and edema fomling properties. Finally, various aspects of cell mediated immunity are influenced by cyclooxygenase products.
The other pathway of AA metabolism involves lipoxygenase enzyrnes and results in ~he production of a number of oxidative products called leukotrienes.
The latter are designated by the LT nomenclature system, and the most significan~
products of the lipoxygenase rnetabolic pathway are the leukotrienes B4, C4 and D4.
The substance denominated slow-reacting substance of anaphylaxis tSRS-A) has been shown to consist of a mix~u~ of leukotrienes, with LTC~, and LTD4 as the primaryproducts and having varying amounts of other leukotriene metaboliles [see Bach et al., 2~G0~2 I. Imrnun.~15, 115-118 (1980); Biochem. Bio~hvs. Res. Comm~ , 1121-1126 (1980)]-The signifieance of these leukotrienes is that a great deal of evidence hasbeen accumulated showing that leukotrienes partieipate in inflarnmatory reactions, S exhibit chemotactic activities, s~mulate Iysosomal enzyme release and act as imporrant faetors in the immediate hypersensitivity reaction. It has been shown that LTC4 and LTD4 are potent bronch~onstrictors of the hurnan bronchi [see Dahlen et al., Nature.
288. 484486 ~1980~ and Piper, Int. Arch. A,DPI. Immunol.. 1~. suppl. 1, 43 (1985)]
whieh stimula~e the release of mueus from airways in y~Q ~Marom et al., Am. Rev.10 Rç5~Dis~. ~, 449 (1982)], are polent vasodilators in skin [see Bisgaard et al., Pro~taglandins. ~, 797 (1982)], and produce a wheal and flare ~esponse [Camp et al., Br. 3. Pha~rnacol.. ~Q, 497 ~1983)]. The nonpeptide leukotriene, LTB4, is a powerful ehemotactie faetor for leukocytes lsee A. W. Ford-Hutchinson, l. Rov. S~e. Med.. ~, 831-833 (1981), which stimulates cell accumulation and affects vascular smooth musele [see Bray, Br. ~vled. Bull,. ~, 249 (1983)]. The activiy of leukotrienes as media~ors of inflammation and hypersensitivity is e~tensively reviewed in Bailey and Casey, Ann. ReDorts Med. Chem.. 19. 87 (1986).
Phospholipase A2 (PLA2) is the eridcal rate limiting enzyme in the arachidonic acid (AA) caseade sinee it is responsible for the hyd~lysis of esterified AA
20 from the C-2 position of membrane phospholipids. This reaetion generates two produets (I) free AA which is then available for subsequent metabolism by either the eyelooxygenase or lipoxygenase enzymes and (2) Iysophospholipid. When alkyl-araehidonoyl-glyeerophosphatidylcholine is acted upon by the PLA2 the genera~ion of platelet ac~ivating factor (PAF) is il~itiated; PAF is pro-inflammatory in its own right 25 [see Wedmore et al., ~J. PharmaeQI.. ~, 91~917 (1981)]. In this regard it may be noted that the anti-inflarnmatory steloids are thought to inhibit eicosanoid synthesis by inducing the synthesis of a PLA2 inhibitory protein denominated macrocornn or lipomodulin lsee E:lowcr et al., ~aturG London, 27~. 456 (1979) and Hirata et al., P~c. Natn. Acad. Sci~U.S.A.. l:Z. 2533 (1980)].
As the initial step leading to subsequent conversion of AA to thc variosus eicosanoids by the cyclooxygenase and lipoxygenase pathways, the PLA2-mediated release of AA from membrane phospholipids is a critical event in attempting to deal with the various physiological mani~estations which are based on the activity of the eicosanoids andlor PAF. Thus, while PLA2 has becn shown to be required for platelet aggregauon [Pickett et al., Biochem. ~.. 16Q. 405 (1976)], cardiac contraction and excitation [Geisler et al., Pharm. Res. Commun.. 9, 117 (1977)~, as well as 2 0 Q ~ 2 proslaglandin synthesis [Vog~, Adv. Prostael. Thromb. d,~ , 89 (1978)], the inhibition of PLA2 is indieated in the therapeude treatrnent of both PAF indueed or cyelooxygenase and~or lipoxygenase pathway produet-mediated physiologieal conditions.
There is also evidence that produets of the eyelooxygenaseJlipoxygeDase pathways play key roles in oo~h the pathogenesis of gastrie mucosal damage due to extracellular (gastric and intestinal contents, mieroorgarJisms, and the like) or ~ntra-cellular ~isehemia, viruses, ete.) agents, as well as in eytoprotecdon against sueh damage. Thus, on the one hand prostaglandins exert a eytoprotective effeet on the gastrie mucosa lsee Robert, Gastroentçrolo~v. ZZ, 761-767 (1979)] and this aetion of the prostaglandins, espeeially of the E series, is eonsidered ~o be of imporranee in the treatment of gastr~intestinal uleeration lsee Isselbaeher, Prugs. 33 (suppl.), 38~6 (1987)~. On the other hand, ex vivo experiments have shown that gasrric mueosal tissue from ethanol-pretreated rats is capable of LT4 generation and that this LTC4 produetion is quantitatively related to the severity of the ethanol darnage [see Lange et a'L. Naunvn-Schmiedebere's Arch. Pharrnae$~l. Suppl., ~5L R27, (1985)]. It has also been demonstrated that LT4 ean induee vasoconstrietion in both venous and attcriolar - v~ssels in the rat submueosa [see Whittle, lUPHARNiritb Int, Con~. of PhannS3~~,London, England (1984)1. This is signitfieant sinee ethanol-induced lesion fonna~ton in gastrie mucosa may be multifaetorial with, for example, stasis of gastrie blood flow eontributing significandy to d e development of the hemorrhagie neerotie aspeets of the tissue injury lsee Guth et al., Gastroenterologx. 87. 1083-90 (1984)]. Moreover, in the anesthetized cat, exogenous LTD4 evokes both increased pepsin secretion and deereascd transgastrie po2ential [Pendleton et al:, Eur. J. Pharrnacol.. 125, 297-99 (1986)]. A particularly signifieant recent finding in dhis regard is that 5-lipoxygenase inhibitors and some leukotriene anugonists proteet the gastrie mucosa against lesions indueed by the oral or parenteral adrninistration of st nons~eroidal anti-inflammatory drugs [see Rainsford, A,eents and ActiQns. ;~L 316-319 (1987)]. Platelet activating faetor (PAF) is also implicated as a mediator of gastrointestinal damage, and it has been reeently shown that 5-lipoxygenase inhibitors inhibit PAF-induced gastrie mueosal damage (Gastroenlerolo~v. 2~, ASS, A434, 1989). Accordingly, a significant body of evidenee implieates the involvement of lipoxygenase products in the development of pathological features associated with gastric mucosal lesions, such as for exarnple, those induced by elhanol exposure and administration of non-steroidal anti-inflamma-tory drugs. Thus, compounds which inhibit the biological effects of leukotrienes and 2~ac~2 PAF and/or which control the biosyn~hesis of these substanees, as by inhibidng 5-lipoxygenase, are considered lo be of value as cytoprotective agents.
Aceordingly, the biologieal actiYity of the leukotrienes and SRS's, and of lipoxygenase as the enzyme leading to the metabolism of AA to leukotrienes, S indicates that a radonal approach to drug therapy to prevent, remove or ameliorate the symptoms of allergies, anaphylaxis, asthma and inflammadon and for gastrie eyto-protection must focus on either blocking the release of mediators of these eonditioDs or antagonizing their effeets. Thus, compounds whieh inhibit the biological effects of the Ieukotrienes and SRS's andlor which con~ol the biosynthesis of these substances, as 10 by inhibidng the Pl.A2~mediated release of araehidonie acid from membrane phospho-lipids, or by inhibidng lipoxygenase, are eonsidered to be of value in treating sueh condidons as allergic bronchial asthma, allergie rhinitis, as well as in other imrnediate hype~sensitivity reactions and in providing gastric cytoprotecdon.
It has now been found that certain novel substituted indene-, indole-, 15 pyranoindole- and tetrahydmcarbazole alkanoie aeid derivatives inhibit PLA2 and lipoxygenase, and antagonize products of the lipoxygenasc pathway, and so ate use~ul zs anti-inflamrnatory, and-allergie and cytoprotective agents. The present inventioD
p~ndes no~el cornpounds hqving the follovnng fommla:
A(CH2h,~B
20 wherein A is C4 CB alkyl. phenoxyethyl, phenoxyphenyl or a group having the fon~ula I~ or wherein - -X is -N- or -C- ;

Zis-C=C-, -C=N-, -N=C-, -N-, -S- or-O-;
Rl is hydrogen, lower alkyl, phenyl or phenyl substituted with ~ifluoromethyl;
R2 is hydrogen or lower aLlcyl; or R I and R2 taken together form a benzene ring;
R3 is hyd~gen or lower aL~cyl;
nis 1 -2;

2~0~2 B is RbC$;l2)=co2R3 ~y C~3\CHCO2R3 ~(C3~)=R~, (~H2)nA R9 whercin O O O
R4 is -CO2R2, -N(OH)CNH2, -N(o~)CR7, -NHCNHOH, O O
-CN(oH)R7 or-CNHSO2Rll;
misO-3;
R5 is A(CH2)nO--~ ; or phenyl or phenyl substituted by halo, lower aLI~ylthio, lower alkylsulfinyl or lower aLcylsulfonyl;
R6 is A(CH2)nO- or halo; with the pral~nso that when R6 is halo, R5 is A(C~2)n R7 is lowcr aLIcyl;
Y is -CH2- or -O-;
R8 is lower alkyl or ~(CH2)mCo2R3;

R9is -CRI or -CH2RI~;
R10 is lower alkyl, phenyl, phenyl substituted with carboxy. halo, loweralkylthio or loweralkylsul~lnyl, pyridyl. furanyl or quinolinyl;
Rl I is lower alkyl or phenyl;
23 and the pha~nacologically acceptable salts thereof.

2 ~

The terrns "lower alkyl" and "lower alkoxy" refer to moieties having 1-6 carbon atoms h the earbon ehain. The tam "halo" refers to fluoro, chloro or bromo.
The grouping A embraees, ter alia. 5- or ~ membered unsaturated nitrogen, sulfur or oxygen containing mono- or benzofused-heterocycles, optionally S substituted with lower alkyl or phenyl. The foregoing definition embraces the following heterocyclic moieties: furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, py~zinyl, pyrirnidhyl, benzofuranyl, benzothienyl, benzothia-zolyl, indolyl, benzoxazolyl, quholinyl, quhazolhyl, benzimidazolyl, quinoxalhyl, quinazolinyl ant the like. Espeeially preferred are quinolinyl, benzothiazolyl, 10 benzirnidazolyl and 2-phenylthiazole.
The eompounds of the inventiosl ean form pharrnaeologically acceptable salts from pharmacologically acceptable organie and inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitrie, rnaleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric.
15 laetie, malie, mandelic, einnamic, palmitie, itaeonie and benzenesulfonic. The cornpounds which are carboxylic acids are capable of forming aLkali metal and alkaline earth earboxylates and carboxylates of pharmaeologically acceptable cations derived from ammonia or a basic amine. Examples of the latTer inelude but are not limited to cadons such as ammonium, mono-, di-, and trirnethylammonium, mono-, di- and 20 triethylammonium, mono-, di- and tripropylammonium (iso and normal), ethyldimethylammonium, benzyldimethylammonium, cyelohexylammonium, benzy-lammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium.
piperazinium, l-methylpiperidinium, ~ethylmoIpholinium, l-isopropylpyrrolidinium.
1,4 dimethylpipcrazinium, l-n-buql-piperidinium, 2-methylpiperidinium, 1-ethyl-2-25 me~ylpiperidinium. mono-, di- and tnethanolammonium, ethyl diethanolammonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenyl-monoethandammonium, and the like.
The eompounds of the invention ean be prepared by the following reaetion schemes. When it is desi~d to prepare eompounds having the formula ~ ,(CH2)mCO2R3 A(CH2)nO--~ R3 ~-methoxybenzaldehyde, for example, is reacted with propionic anhydride. followed by reduction and ring closure to yield the intermè~iate 6-methoxy-2-methyl- l-indanone ~ - 2~00~

(C2H5CO)2o hl H2 sodium propionate ~ PdlC
CHO CH=C-CO2H

polyphosphoric acid ~f Thc indanone interrnediate is then subjected to demethylation and the resulting hydt~xy-indanone is reacted with an appropriate haloaLtcyl-A compound where A is as defined 5 h~einbefore and hal is halo CH3~f A1Br 1~ benzene A(CH2)"0 ~ ~
A(CH~)nh~
K.CO3 / 1 8-crown-6 ~CH3 The laner intermediate, where n=1, is reacted with triethylphosphonoacetate in sodium hydride to yield an intermediate indenc-3-acetic acid cthyl ester, which is thcn10 hydrolyzed and concomitanùy reacted with an appropriate reactant to introduce the desired R5-methylene gn~up onto the indene-3-acetic acid moiety, exemplified below by the introduc~ion of a ~ch~orophenylmethylene grouping O
A(CH2)nO~fO (C2HsO)2PCH2CO2C2H5 / NaH
CH3 tolueDe o ~ l~

1l A(CH2)nO ~ ~COC2Hs \~ ~ NaOCH3 / CH30H
~\CH3 CHO

A(al~2C00l3 C~
Compounds in which thc R5 group is lower aL~cylthiophenyl can be preparcd by UsiDg an appropriate loweraL~cylshiobenzaldehyde. The compounds in which R5 is a low~-5 aLlcylsulfinylphenyl grouping can be p~ parcd from thc lowcrallcylthiophcnyl-conra~mng compounds by rcacoon with 30% H2~2 in chlorofonDlacetic acid.
A(CH2)n~rCH2CH

~\CH3 30% H22 _~
~5 CHC13 I CH3COOH
s~3 A(CH2)"0~LII COOH

~CH
'~, ~
lC~3 20~042 In an al~ernaive prcparation scheme, the intcrrnediate hydtoxyindanone can be reacted with cyanoacetic acid to give thc corresponding hydroxyindene-3-acetic acid, which is then esterified before introduction of the R5-methylene grouping in order to facilitate Ihe purification of desired intermediates. Since introducdon of the S R5-methylene gn~uping is accompanied by ester hydrolysis, the intermediate free acid is re-esterified to facilitate purification followed by reaction with an appropriatc halo-alkyl-A group to yield thc desired final product HO~ NCCH2COOH ~ ~CH2COOH
NH40Ac / HOAc ~CH3 HO~ H2COOCH3 ~ p-toluenesulfonicacidIH20 1. NaOCH3 / CH30H ~CH2COOCH3 CH3A(CH2?nhal CH K2CO3 1 1 8-crown-6 Cl 2. p-toluenesulfonicacid H20 1~ J

Cl A(CH2)nO~CH2COOCH3 ~11 2~ ~042 Compounds hav~ng the folmula halo ~(CH2)mCooR3 HC ~O(CH2)nA

can be prepared by reaeting a hal~indene-3-ace~c acid with a A(CH2)n-containing balzaldehyde pn:p~d *om the con~onding indhndual eomponenss A(CH2) hal NaOC2H5/EtOH A(CH2) o{~CHO
CHO

OH
halo NaOCH3 / -/
~\~CH2COOH CH~
~CH3 ~ I~CH2COOH

O~ H2)nA
In all of the above~utlined ~eaction schemes, the final product ~e acids can be esterificd ma conventional methods and in like fashion, final p~duc~ este~s can be hydrolyzed by known p~ocedures to yield the eo~responding free acids.
Compounds of the invendon ha~ring the fonm~la A(CH2)l,0 ~IX

R3 H R7 Rs ~ ~ 203004~

in which X is -CH2- can be prepared by initially reacdng 4-methoxyphenylhydrazine with, for example, 2-carbomethoxymethyl-2-alkylcyclohexanone, followed by ring closure to yield an intermèdiate tet~hydro methoxy-lH-carbazole-l-acetic acid O

~ + b~R7 1) Io!uene/~
- ~ 2) glacialacesicacid1 ~ H ~ ~
The latter intermediate is demethylated with hydsobromic acid to yield the corrcsponding hydroxy compound, which is then reacted with arl appropriate halo-loweraLIcyl-A compound by one of several routes. In one such preparative sequence, two cquivalents of the staning material, A(CH2)nhal, are reacted with a metal derivative 10 of the hydroxycarbazole-l-acetic acid to form an intermediate ester ether which is hydrolyzed to yield the desired final products. The metal desivative of the hydroxycarbazole-l-acetic ac~d may be prepared by treating the acid with an aL~ali met31 allcoxide, such as sodium methoxide.

A(CH2)nhal + ~ NaOCH3 A(CH2)n ~Q NaOH

R3 H R7 ` CH2CO(CH2)nA

A(CH2)nO~,,l~l ~3 H R7 CH2COOH
In the above sequence, A, n, m and R7 are as defincd hereinbefore and hal denotes chlc)ro, bromo or iodo.
In an alternative sequencc, it is possible to use only one equivalent of 5 star~ng tnaterial A(CH2)nhal with the metal derivative to obtain thc desired final p~duct directly, without proceeding through the ethyl ester iMermediatc.
In yet another reacuon sequencc, the desired final products can be prcpared by the alkylation of alkyl est~s of the hydroxycarbazole-l-acetic acid:
H0 ~ K~C03 / Acetone N ~ A-(CH2)nhal A~(CH2)nO--~N~Q hydrolysis R3 H R~ R3 A-(~2~0 Q Q

whcrc A, n, m, R3, R7, R8 and hal are as defincd hereinbefore. Hydrolysis is camed out using a dilute hydroxide, such as for example sodium hydroxide.
Compounds of the invention having the fon~ula A-(CH2)"0--~X
R3~ H R7 R8 2~042 in which X is -O- can be preparcd by the above-outlincd rcaction sequences which dif-fer only in the preparadon of the starting tetrahydn~6-hydroxypyrano~3,4-b~indole- 1-lower aLtcanoic acid esters. The lattcr can be prepared by the reaction of, for exarnple, a 5-benzyloxytTyptophol with a loweralkyl-(R7-carbonyl)lower alkanoate in boron 5 trifluotide ethe~te to yield an interrnediate l-R7-tetrahydro-~(phenylmethoxy)pytano-[3,4-b]indole-1-alkanoic acid ester, which is then subjected to reduction to yield the corresponding ~hydtoxy ester ~LCH2O~CH2CH20HR7-C(CH2)mCooCH3 NBF3 Et20 ~LCH2O~ Pd/c R3 H R7 (~H2)mCOOCH3 HO

> \ CH2)mCOOCH3 The latter intermediate can then be reacted as outlined earlier with an appropriate A(CH2)nhal compound to yield the desired finai cornpounds.
Another scheme by which the starting tetrahydro ~hydroxypyranol3.
b]indole 1-alkanoic acid ester can be prepared involves reducing 7-loweraLlcyltryptophol 15 to 7-lowerallcyl-2,3~ihydrotryptophol, followed by reacting the lat~er with potassium nitrosodisulfonate to yield a 7-loweralkyl-5:hydroxyt~ptophol, which is then reacted vith a suitable lower allcyl-3-methoxy-lower aLIcanoate lo yield the desired intermediate tetrahydro-~hydroxypyrano[3,4-b~indole-1-loweraLlcanoic acid ester 2~0~2 ~CH2CH20H trifluoroacetic ~CH2CH20H (Kso3)2No H~ ~CH2CHiOH

HO~

R3 H R7 (CH2)mCOOC~3 S As with the previously described indenc-l-acetic acid derivatives. the carbazole f~nal product frce acids can be esterified via conventional mcthods and in like fashion, final product csters can be hydrolyzed by known procedures to yield theco~sponding frec acids.
Cornpounds of the invention having, for cxarnple, the formula ~ (CH2)mCOOR2 A(C}l2)nO--~N J~R3 can be prepared by reacting S-hydroxy-2-methyl-1H-indole-3-lowe~ canoic acid with an appropriate A(CH2)nhal compound in the presence of sodium methoxidelmethanol to yield Ihe in~ermedia~e A(CH2)nt) containing indole aL~anoic acid derivaive. which is then esterified and reacled with a sui~able subsituted benzyl or benzoyl halide to yield ~0~042 the desired flnal product in ester fos~n, which can be convertcd to the free acid foml by convendonal methods.
HO~(CH2)mCOOHA(CH2)~hal CHNaOCH3 I CH30H /
N 3dirncthylforlslamide A(CH2)nO~(CH2)mCOOH CH2N2 ! Et~0 ~, ~ N CH3 te~ahydrofu~an H

A(CH2)nO ~
1 --(cH2)mco~cH3 NaH/dimethylfonnan~dc N CH3 R9hal H

A(cH2)no ~
~, 1~ (CH2)mCOOCH3 Compounds of Ihe invention having ~he formula A(CH2)n ~ IRC'HCo2R3 (CH2)nA

can be prepared via the following reaction sequence: 4-benzyloxyaniline is reacsed vish 10 sodium nisri~e in the presence of ssannous chloride to yield 4-benzyloxyhydrazine.
which is reac~ed with -meshyl-3-oxocyclohexanone acesic acid to yield an intemlediate ` 2~0~2 .
.

-mcthyl-tetrahydrocarbazole acetic acid, which is cster;~ficd with ethanol to yield the intermediate ethyl ester.

C3~20~ NaNO2 NH2- HCI SnC12 2H2 . O

0~o~ CHCOOH

EtOH / H2SO4 NH2NH2 HCl 2~

The ~-methyl tctrahydroear~azole aceic acid ester intermediate is rcacted under reflux with chloranil in xylene under a nitrogen atmosphere ~o yicld ~hc corrcsponding a-methylcarbazole accic acid. which is rcduced by hydrogenation to remove the benzyloxy group, yielding the ~hydroxy-a-methyl carbazole acetic acid ester 10 in~mediate.

0~ ¦

~H20,~LCH3 Pd/C
CHCOOCH3 EtOH
H

20900~2 The lar~r inte~ncdiate is then hydrolyzed to givc the free carboxylic acid intennediale, which is then reacted with an appropsiate haloallcyl-A compound, where A is as heranbcfote defined and hal is hal4 to yield the desi~d final ~OdUCL
HO~ ;~ KOH
H

HO~ I 3 A(CEI2)nhal D
N ~LCH2COOH DMSO / NaOH
H

A~CH2)"0 (CH2)nA `
The conventional starong ma~enals used in the reacaon sequences outlined above sre available commercially or can be prepared by mc~ods known in the ar~ Thus, for 10 example, the interTnediate compound 2-bTomomethylquinoline can be prepared by the following Ieac~on sequcnce:
~ CH3CH--CHCHO

20$~0~2 I~N-Br (C6H5C0)202 ~CH2Br The benzo-fused hetet~cyclic compounds used in the abovc reaction sequences are also either commercially available or can be preparcd by methods convcntional in the an Thus, for example, such intermediates as l-methyl-2-chloromethylbenzimidazole, 5 2-chloromethylbcnzthiazole and 2-chloromethylbenzoxazole can bc prepared by thc following Ieaction schemc ~3~ CICH2COCH3 R1 ~CN/>--whcrein X is O, S or NCH3. The reaction is prcferably carried out a~ a con~rolled low tempcraturc in an organic solvent, such as mcthylcnc chloridc.
Certain compounds within thc scopc of thc invcntion cxist in the fonn of E and Z stereoisomers and the individual isomcrs can be diffcrcntiated by the prefixcs E
and Z, as assigned by thc accepted scquencc rules procedures. Accordingly, the prescnt invendon embraces the E, Z and mixed isomer forms of those final productcompounds cxhibiting this form of stereoisome~ism.
The compounds of the invention, by virtuc of their ability t~ inhibit thc activity of PLA2 enzyme, as well as that of lipoxygenase enzymc and to anugonizcmediators arising from the cnzymatic pathway, are uscful in the sreatment of conditions mediatcd by products of the oxidation of arachidonic acid. Accordingly, the com-pounds are indicatcd in the trcatment of such diseases as rheumatoid arthritis, 20 inflammatory bowel disease, osleoanhritis, tendinids, bursitis, psoriasis (and related skin inflammation) and similar condidons involving inflammation. Morcover, by virtue of their ability to antagonize the effect of LTC4, LTD4 and LTE4, which are the constituents of SRS-A, ~hey are useful for the inhibiion of sytnpsoms induced by thcse leuko~ienes. Accordingly, the compounds are indicated in thc prevention and trea~nent 25 of those disease states in which LTC4, L~4 and LTE4 are causative fac~ors, for example allergic rhinitis, allergic bronchial asthma and olher leulcotriene mediated naso bronchial obsrruclive air-passageway conditions, as well as in other immediate hyper-20~0~2 sensidvity reactions, such as allergic conjunctivids. The compounds are especiallyvaluable in the prevention and treatment of allergic bronchial asthma.
The compounds of the invention are cytoprotective agents and are considered especially useful when administered with convendonal non-steroidal anti-5 inflammatory drugs, whose major side effect is gastrointestinal irritalion. The cyto-protecdve effect of the compounds of the invention signif~cantly reduces the gastro irritant impact of convendonal anti-inflammatory dlugs. This effect is based not only on the abiliy of the compounds of the invendon to inhi~it the biological effects of leukotrienes andlor control the biosynthesis of these substances, as by inhibiting 10 lipoxygenase, but also by a shundng effect, whereby the eontrol of the lipoxygenase pathway "shunts" the oxidation of arachidonic acid into the cyclooxygenase pathway, giving rise to an increase in the forrnation of cytoprotective prostaglandins. These biolodcal effects make thc compounds of the invention especially useful in treating such conditions as erosive esophagitis, inflarnmatory bowel disease and induced 15 hemorrhagic lesions such as those induced by alcohol or non-steroidal anti-inflat~na-to~y drugs (NSA~:)'s), hepatic ischernia, noxious agent induced damage or necrosis of hepadc, pancreatic, rcnal or myocardial dssue; liYer parenchymal damage caused by hepatotoxic agents such as carbon tetrachlonde and D-galactosamine; ischemic renal failure; disease-induced hepa~ic damage; bile salt-induced pancreatic or gastrie damage;
20 trauma or stress-induccd cell damage; and glycerol-induced renal failure.
When thc compounds of the invention are employed in the treatment of allergic ai~way disorders, as anti-inflammatory agents and/or as cy~oprotective agents, they can be fo~mula~ed into oral dosage forms such as tablets, capsules and the like.
The compounds can be administered alone or by eornbining them with convendonal 25 carriers, such as magnesium carbonate, rnagnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, ttagacanth, methylcellulose, sodium carboxymethyl-cellulose, low melting wax, cocoa butter and the like. Diluents, aavoring agents, solubilizers, lubricants, suspending agents, binders, tablet-disintegrating agents and the like may be ernployed. The compounds may be encapsulated with or without other 30 carriers. In all cases, ~he proportion of active ingredients in said compositions both solid and liquid will be at least to impart the desired activity thereso on oral administra-tion. The compounds may also be injected parenterally, in which case they are used in the forrn of a sterile solution containing other solutes, for example, enough saline or glucose to make the solution isotonic. For administration by inhalation or insufflation, 35 the compounds may be formulated into an aqueous or partially aqueous solution, which can then be utilized in the form of an aerosol.

2a9~0~2 The dosage requiremen~s vary with the partieular compositions employed, the route of administradon, the severity of the symptoms presented and the pardcular subject being treated. Treatment will generally be initiated with small dosages less than the opdm: ~ dose of the compound. Thereafter the dosage is increased undl S the optimum effecs under the circusnstances is reached. In general. the compounds of the invention are most desirably administered at a coneentration that will genetally afford èffective results without causing any ha~nful or ddetelious side effects, and ean be a~inistd either as a single unit dose, or if desi~ed, the tosage may be divided into convenient subunits administc~d a~ suitable t~nes th~oughout the day.
The PLA2 and lipoxygenase inhibitory and leu~otriene antagonist effects, as well as the anti-inflamma~ory and potendal gastroimtant effeets of the compounds of the inven~on. may be demonstrated by standard phannacological pmcedures which are described more full in the examples given h~e inafter.
These proeedures, inter ~, determine the specificity of aetion of the 15 c~npounds of the invention as PLA2 inhibitors as measured by their ability to inhibit the synthesis of Ll1~4 and PGE2 by rat glycogen-elicited polymorphonuclear leulGocytes, as well as measure their ability to inhibit araehidonic acid release mediated by human and non-human source PLA2. The proccdures fmther measure the ability ofthe compounds of the invention to inhibit~ vivo. the activity of exogenously 20 administercd PLA2. The pham~acological testing additionally demonstrates the ability of the compounds of the invention to inhibit, in vivo. the lipoxygenase and cyclooxy-genase pa~hways of arachidonic acid metabolism the m vitro. Ieukotriene antagonist-activity of the compounds of the invention; and also measures the in vivo actiYity of the compounds as anti-inflammatory agents in the ~at carrageenan paw ederna assay.
25 Fmally, the po~ential of the compounds to induce acute gastro~rritation in rats is measu~d in a test procedure.
The following examples show the preparation and pharmacologieal testing of compounds within the invention.
. .

20~1~0~2 Example 1 3-[(4-Chlorophenyl)methylene] [2 methyl~6 (2 quinolinyl~
methoYv)1-3H-indene-l-aceti~ acid A. p-Methoxv-o~-methYl cvMamic acid S A mechanically stirrcd mixturc of 4-methoxybenzaldehyde (47.6 g, 0.35 mole), propionic anhydride (78.3 g, 0.602mole) and sodium propiona~e ~33.5 g, 0~35 mole) is placed under nitrogen in an oil bath heated at 150-C for 15 hours. Upon addition of water (130 mL) us~der vigorous stilTing a yellow solid is obtaincd. It is redissohed in 2N-KOH (pH 11) and the solution is extracted with cther.
The aqueous phase is acidified (ice bath) with concentrated HCI. The white solid is co11ected, washed with water and dried to pr~vide the title compound (47.69 g, 71%, m.p. 153-154-C).
NMR (DMSO-d6, 400 MHz): ~ 2.01 (d, J 1.34 Hz, 3H, 2-CH3), 3.77 (s, 3H, OCH3), 6.98 (d, J 8.81 Hz, 2H, ArH), 7.43 (d, J 8.7 Hz, ArH), 7.53 (s, lH, , ArCH=C).
MS (EI, mlz): 192 (b.p., M)+.
~nalvsis for: Cl lHl2o3.
Calculatcd: C, 68.74; H, 6.29.
Esa3n~: C, 68.80; H, 6.43.
B. p-Methoxv-a-mç~yl hvdrQc~nnamic acid A mixture of the acid (44 g, 0.229 mole) of Ssep A, and 10% Pd/C
(4.4 g) in dry methanol (500 mL) is hydrogcnated overnight at 50 psi. The mixture is filtered (Solka-Floc) and the filtrate evaporated to dryness to yield a pale yellow oil, which is used without further purification 144.5 g).
NMR (CDC13, 400 MHz). ~ 1.16 (d, J 6.9 Hz, 3H, 2-CH3), 2.62 (dd, lH, ArCH) and 2.70 (m, lH, ArCH), 3.00 (dd, lH, CH), 3.78 (s, 3H, OCH3), 6.82 (d, 2H, ArH), 7.09 (d, 2H, ArH).
MS (EI, m/z): 194 (M)+, 121 (b.p.).
C. ~Methoxv-~-methvl-l-indanone A mechanically stirred mixlure of the crude propionic acid (44 g, 0.227 mole) of Step B, is added to warm (50 C) polyphosphoric acid (420 g). The mixture is then placed in an oil bath heated at 95 C for 90 minutes (TLC. 9:1 dichloromethane-methanol, UV). The warm mixture is poured into water (3 L) and stirred overnight at room temperature. It is then extracted with ether and ethyl acetate 2~0~)42 and the combined extracts are washed with saturatcd NaHCO3 to neutral. Thc organic phase is washed with brine and dried (MgSO4). Removal of the solvent provides the title compound as an amber oil. It is purified by flash chromatography ton silica Merck-60, dichloromethane as eluent) to yield 25.58 g (64%) of a pale yellow oilNMR (CDC13, 400 MHz): o 1.31 (d, J 7.4 Hz, 3H, 2-CH3), 2.65 (dd, lH. .:rCH) . . . . .. .
and 2.74 (m, IH, Ar~H), 3.32 (dd, IH, CH), 3.83 (s, 3H, OCH3). ~ m.
2H, ArH), 7.34 (d, lH, ArH).
MS (El, rn/z) 176 (M)+, 161 (b.p., M-CH3)+.
D. ~Hvdroxv-2-methvl- I-indanone To a stirred solution of anhydrous aluminum bromide (69.82 g, 0.261 mole) in anhydrous oenzene (250 mL) ~ept under nitrogen is added dropwise over 30 minutes a solution of the methoxy indanone (18 g, 0.102 mole) of Step C, in benzene (60 mL~. The mixture is gently refluxed for 3 hours ( ll.C, dichlorometharle-ethyl acetate 8:2, UV), cooled in an ice bath and treated dropwise with 6N-HCI (ca.
15 200 mL) to decompose the aluminucomplex. The aqueous phase is extracted with etfier (3 timcs), the extrac~s arc concentratcd at reduccd pressure and extracted with 2.5N-NaOH (2x75 mL and lx50 m_ The basic extracts are neutralized (ice bath) with concentrated HCI and the oil thal separates is extracted with ether (3 times). lhe combined ext~acts are washed with brine, dried (MgS04) and e~aporated to yield an oil that readily solidifies. The crude material is flash chromatographed (on silica Merck-60, gradient CH2C12, CH2Cl2-ethyl acetate 85:15) to provide the pure title compound (13.60 g, nearly colorless solid, 82%).
NMR (CDC13, 400 MHz): o 1.31 (d, J 7.44 Hz, 3H, 2-CH3), 2.65 (dd, lH, ArCH) and 2.76 (m, lH, ArCH), 3.32 (dd, lH, CH), 6.68 (s, lH, OH), 7.18 (dd, lH, ArH), 7.30 (m, 2H, ArH).
MS (EI, mJz): 162 (M)+, 147 (b.p., M-CH3)+, 133 (M-c2Hs)+.
E. 6-(2-Ouinolinvlmethoxv~2-rnethv!-1-indanone A rnixture of the phenol (15.16 g, 93.58 mmole) of Step D, powdered anhydrous potassium carbonate (12.93g, 93.6mmole), 18-crown-6 (2.47g, 9.36 mmole) and dry acetonitnle (200 tnL) is stirred u room temperature undcr a nitrogen for 15 minu~es. 2-Chloromethylquinoline (free base, freshly prepared from 18.29 g or 102.96 mmole of the hydrochloride salt) is added in one portion and the rnixture is placed in an oil bath heated at 65-C for 11 hours (~C, dichloromethane-mcthanol 9:1, W). The solvent is removed in vacuo and the residue is partitioncdbetween ethyl acetate and water. The organic phase is washed with brine, dried 2~1~0~

(MgSO4) and evaporated to yield an oil whieh solidifies upon trituration with hexan~
(ca. 31 g). The crude produc~ is purified by flash ehroma~ography (on siliea Merek-60, absorbed in thylene chloride, eluted with CH2C12-ethyl aeetate 90: 10 and 85: 15) to provide S.95 g of slighdy impure material together with 24.55 g of the pure title 5 compound (pale yellow solid, 84.8%).
NMR (CDC13, 400 MHz): o 1.29 (d, J 7.36 Hz 3H, 2-CH3), 2.65 (dd, lH, ArCH) and 2.73 (m, lH, ArCH), 3.32 (dd, lH, CH), 5.41 (s, 2H, ArCH2O), 7.3-7.38 (m, 3H, ArH), 7.55 (t, J ca. 7 Hz, lH, ArH), 7.64 (d~ J 8.5 Hz, lH, ArH), 7.74 (t, 1 ca 7 Hz, lH, ArH), 7.83 (d, J 8 Hz IH, Ar}I), 8.11 (d, J 8.4 Hz, lH, ArH), 8.20 (d, J 8.4 Hz ~H, ArH).
MS (El, m/z): 303 (M)~, 142 (b.p., CloHgN)+, 115.
F. 2-Methvl-~-L2~uinolinvlmethoxlr)-indene-3-acetic acid ethyl~ter Triethylphosphonoacetate (22.41 g, 100 mmole) is added dropwise under nitrogen to a stirrcd and cooled (O C) slurry of NaH (57% in oil, 4.27 g, 100 mmole) in dry toluene (250 mL). The cooling bath is removed and stirring continued at room temperature for 60 minutes whereby an almost homogeneous solution is obtained. A solution of the indanone (15.15 g, 50 mrnole) of Step E, in toluene (50 snl,) is then added dropwise. The flas~ is placed in an oil bath heated at 95 C for 19 hours (~LC, traces of starting material present, dichloromethane-ethyl acetate 9:1, UV, Vaughn's). The reddish solution is cooled, diluted with water and extracted with ethyl acela~e (3 umes). The combined extracts are washed with brine, dried (anhydrous K2C03) and evaporated to dryness. The residue (heavy brown oil) is flash chromatographed (on silica Merck-60, eluted using a gradient dichloromethane ~
dichloromethane:ethyl acetate 84: 16) to p~vide the title compound as a mixture of endo and exo isomers (16.3 g, 87.4%, oil ~at solidifies upon standing) together with unreacted, more polar starting material (1.84 g, 12% recovery~.
MS (EI, m/z): 373 (M)+, 344 (M-C2Hs)+, 300 (M-COOC2Hs)+, 143 (b.p.), 115.
G. 3-~(~Chloro~henvl)met~_ e~hoxv)1-3H-indene-1-a~çe~iç acid To a vigorously stirred mixture of the es~er (mixture of isomers, 6.9 g, 18.5 mmole) prepared as described in Step F, and p-ehlorobenzaldehyde (2.85 g, 20.3 mmole, 1.1 equi~v.) in dry methanol (45 mL) is added dropwise under nitrogen 25% methanolic sodium methoxide (8 mL, 2 equiv.). The rnixmre is warmed until itbecomes homogeneous (ca 65 C, bath temp.) and then refluxed for a total of 13 hours.
After overnight at room temperature, the slurry (bright yellow precipitate) is treated :
2~0~2 ., dropwise with water (35 rnL) and a littlc mcthanol and refluxing is continucd for another 4 hours (reaction followed by TLC). The dark orange solution is coolcd, thc methanol evaporated, more water added and the gelatinous precipitate is collected, washed with water and dried to provide the sodium salt of the title compound as a S briaht ydlow solid. The latter is slurned in water and neutralized (to pH ~6.5) with 10 ,~o acetic aci~ The mixture is extracted with ethyl acetate (large volume), the extract is washed with brine and evaporated to dryness. ` The residuc is azeotroped withbenzene to prt~vide an orangc solid 17.52 g, mixmrc of Z (major) and E (rninor) isomers]. -This rnatcrial is slurried in ether, stirrcd for 30 rninutes. filtcred and dried 10 (4.32 g). The solid is extracted portionwise with hot ethyl ace~e (containing some methanol and dichloromcthane) un~il almost completely dissolvcd. Thc filtrate isconcentrated jn vacuo unil preapilalion occurs, dilutcd with ether and the yellow solid collected and dried (3.1 g, m.p. 218-220'C). Concentration of the mother liquorsprovides additional product (1.1 g, m.p. 200-203-C). Combined yield is 4.4 g 15 (51%). The NMR spectrum is consistent [sec: Shuman et al., J. Or~. Chem.. ~, 1914, (1977)~ with the Z-isomer.
NMR (DMSO~, 400 MHz): o 2.11 (s, 3H, CCH3), 3.54 (s, 2H, CH2COQ), 5.326 (s, 2H, OCH2Ar), 6.60 (dd, IH ArH), 6.95 (d, J 2.35 Hz, IH), 7.14 (m, 2H, ArH), 7.52 (m, 4H, ArH), 7.60 (t, J 7.03 Hz, IH, ArH), 7.66 (d, J 8.39 Hz, IH, ArH), 7.77 (t, IH, ArH), 7.99 (m, 2H, ArH), 8.4 (d, J=8.9 Hz, lH, ArH).
UV (~ ma~, MeOH, nm): 232 (E 39,594), 285.2 (14,830), 287.B (14,921), 288 (14,9213, 338.2 (10,839).
MS (+FAB,2nlz): 468 (ICl, M+~I)', 237,131,91 (b.p.).
25 Anal~ s for: C2oH22ClN03 Calc~atcd: C. 74.43; H, 4.74; N, 2.99.
E~: C, 74.54; H, 4.67; N, 3.13.
Example 2 2 Methyl-3-1[4-(methylthio)phenyllmethylene]-6.(2 :30 oy;nolinylmethoY~ H.indene-l-acet~c acid To a vigorously s~d mixture of thc cstcr (mixturc of isomers, 6.7 g, 17.96 mmole), prcpared as dcscribed in Examplc 1, Stcp F, and (4-methylthio)bcnzaJdehyde (3.05 g, 19.06 mrnole, 1.1 equiv.) in dry methanol (75 mL) is added dropwisc under ni~ogcn 25% methanolic sodium mcthoxide (7.7 mL, 2 3S equiv.). Thc mixturc is warmcd until it becomes homogcneous (ca. 65'C, bath temp.) 2 ~ 2 and therl refluxed for a total of 13 hours (TLC, CH2C12-ethyl accute 9:1). Afterovernight at room tcmpcrature, the slurry (bright yellow prccipitatc) is trcatcd dropwisc with water (65 mL) and a little methanol and refluxing is continued for another 5.5 hours (reaction followed by TLC). Tho brown soludon is cooled, the methanol S evaporated, more watcr added and the gelatinous precipiute is coUccted, washcd with watcr and dried to provide the sodium salt of the tide compound as a yellow solid. The lattcr is slurried in water and neulrali~cd (to pH 6-6.5) with 10% acetic acid. The r~xture is cxtracted with cthyl acetate (large volume), the cxtract is washcd with brine and evaporated to dryness. The residue is azeotroped with benzene oo pro~ride a yeUow 10 solid (4.47 g, 52%). 'rhis material is slturied in ether, stirred for 30 minutes, filtered and dried (4.13 g, m.p. 205-207 C, dec.). The solid is extracted portionwisc with hot ethyl acetate (containing some methanol and dichloromethane) until almost completely dissolved. The filtrate is concentrated in vacuo until precipitation occurs and diluted with ether. The yellow solid is collected and dried (3.5 g, 35.4%, m.p. 207-209-C, 15 dec.). The NMR spectrum is consistent lsee: Shuman et al., J. Org. Chem.
1914, (1977)] with the Z-isomer.
NMR (DMSO-d6, 400 MHz): o 2.11 (s, 3H, CCH3), 2.51 (s, 3H, SCH3), 3.53 (s, 2H, CH2COO), 5.32 (s, 2H, OCH2Ar), 6.60 (dd, lH, ArH), 6.95 (d, lH, J 2.35 Hz), 7.13 (s, lH, ArH), 7.30 (m, 3H, ArH), 7.47 (d, 2H, J 8.4 Hz, ArH), 7.60 (t, J 7.0 Hz, lH, ArH), 7.66 (d, lH, J 8.49 Hz, ArH), 7.77 (~, lH, J ca. 7 Hz, ArH), 7.99 (m, 2H, ArH3, ~.4 (d, lH, J 8.49 Hz, ArH).
UV (~ max, MeOH, nm): 231.5 t 37,382), 303 (9,739), 307.5 (9,342), 315 (10,525), 352.5 (13,407).
MS (+FAB), m/z): 4~0 (M+H)+.
25 Analvsis for: C30H2sNo3s Calculated: C, 75.13; H, 5.25; N, 2.92.
Found: C, 75.30; H, 5.25, N, 2.95.
Example 3 2-Methyl-3-[[(4-methylsulfinyl)phenyl]methylene]-6-(2-~LuinolvlmethQxv)-3~7-indene-l-acetic acid monohvdrate A slurry of the thioether (1.67 g, 3.48 mmole) of Example 2 in a cold mixture of chloroform and glacial acetic acid (65:35, 40 tnL) is treated dropwisc (via sy~inge) with 30% H22 (0.403 mL). The mixture is stir~ed for 30 minutes in the cold and then at room temperature for 24 hours. A clear solution is obtained after 2 hours 35 and a small amount of H22 is added after 4 and 7 hours, respectively, tO drive the 2~0~

reaction tO complction (reaaion followcd by TLC, aliquot trcated with water and cxtracted with ethyl acctatc). Thc chlorof~rrn is cvaporatcd, thc rcsidue is diluted with water and ncutralizcd in the cold with the calcu!atcd amount of NH40H. The precipitate is filtercd, slurricd in watcr, collectcd, washed with water and dried in vacuo S (over P20s) to yield the crude acid as a yellow solid. Thc solid is redissolved in a largc volume of warrn (30-35-C) ethyl acetate (containing some methanol and dichlo~>methanc) and filter~ The filtrate is concentrated in vacuo until precipitation starts and diluted with ether. Thc precipitate is collected, washed with ether and d~ied (fluffy solid, m.p. 136-137-C, sintesing and foaImng).
NMR (DMSO-d6, 400 MHz): o 2.12 (s, 3H, 2-CH3), 2.80 (s, 3H, SOCH3), 3.5~ (s, 2H, CH2COO), 5.32 (s, 2H, ArCH20), 6.58 (dd, lH, ArH), 6.96 (d, J 2.3 Hz, lH), 7.14 (d, J 8.36 Hz, IH, ArH), 7.21 (s, lH, ArH~, 7.5~-7.80 (m 7H, ArH), 7.98 (m, 2H, ArH), 8.39 (d, J 8.5 Hz, lH, ArH), 12.36 (s, lH, COOH).
MS (+FAB, mlz): 518 (M+Na)+, 496 (M+H)+.
~y~j~ C30H25NO4S H20 Calculated: C, 70.19; H, 5.30, H, 2.73.
E~: C, 69.15; H, 4.93; N, 2.65.
E~ample 4 5-Flooro-2-methyl-1-[[4.(2.quinolinylmethoxy)-~henvll~ne~h~lenel-l H.indene.3.acetic acid A. 4-r(2~uinolinvl)-methoxYl-ben7~ldehYdc To a solution of sodium mct I (0.9 g, 39.13 g.a.) in absolute ethanol (50 mL) is added dropwise undcr nitrogen a so!ution of ~hydroxybcn7~ldehydc (5 g, 25 40.94 rnmolc) in absolulc ethanol (50 mL). Thc mixturc is gendy rcfluxed for 1 ~our and thcn treated dropwisc with a solution of 2-chloromethyl~uinoline ~free base,7.24 g, 40.76 mmolc), frcshly prcpared from dhc HCI salt) in cthanol (50 mL). The mLxture is refluxcd for 24 hou~, the solvent is evaporated and the rcsidue is panisioncd bctween water and ethyl acetatc. Thc organic laycr is washed with 5% NaOH (pH 8), 30 watcr, brine to neutral and dricd (MgS04). Rcmoval of thc solvcnt yiclds thc title com-pound as a yellow solid (9.81 g). Thc crude material is further purificd by flash chromatography (on silica Mcrck-60, hexane-ethyl acctate 9:1 to rcmovc less polar impurities and ~:2 to clute the product). Yield: 7.37 g (71.5%), m.p. 82-83 C.
NMR (CDC13, 200 MHz): ~ 5.5 (s, 2H, ArCH~O), 7.2-8.6 (m, 9H, ArH), 9.80 (s, lH, CHO).

209~0~

B. 5-FluoT~2-methvl-1-rr4-(2~uinolinvlme~hoxv~phenvllmethv!enel-1~1.-~-3-acetic acid To a mixture of 5-fluoro-2-methyl-indcne-3-aceoc acid (prepared according to the procedure disclosed in U.S. 3,654,349) (2 g, 9.7 mmole) and ;healdehyde (3.2g, 12.19mmole) of Step A, in dry methanol (40mL) is added dropwise under nitrogen 25% methanolic sodium methoxide (6.48 mL). The rnLlctureis warmed until homogeneous and ~hèn lefluxed for a total of 16 hours. The solvent is e~raporated and thc res.due is slurried in water. The gelatinous precipitatc is collected, washed with water and dried. It is ~hen slur~icd in ether, filtered and dried to pro~ride the sodium salt of the title compound as a yellow solid ~2.03 g, 46.3%). The salt is slurried in water and neutralized (to pH 6-6.5) with 10% acetic acid. The acid is extracted with ethyl acctate (large volume3, dried ~MgSO4) and evaporated to dryness.
T~he crude acid is recrystallized from a hot mixmre of methanol and ethanol (large volumc needcd to dissolve, concentrate to smaller volume after filtrauon). The analytical samplc is dried overnight in vacuo at 35-C. Thc ycllow solid (ttLp. 218-221-C, dec) is a mixtu~ of Z and E isomers in approximatcly 6: 1 ratio (NMR).
NMR (DMSO-d6, 400 MHz): ~ 1.84 (s, 2-CH3, minor E isomer), 2.12 (s, 2-CH3, major Z isomcr), 3.55 (s, 2H, CH2COO), 5.41 (s, ArCH20, possibly E
isomcr), 5.44 (s, ArCH20, possibly Z isomer), 6.70 (dt, lH, ArH), 6.8S-7.3 (m, lH, ArH), 7.18 (d, 2H, J 8.7 Hz, ArH), 7.28 (s, lH, ArH), 7.32-7.40 (m, lH, ArH), 7.51 (d, 2H, J 8.6 Hz, ArH), 7.62 (t, lH, J ca. 7 Hz, ArH), 7.68-7.76 (m, IH, ArH), 7.79 (t, J, 7 Hz, lH, ArH), 8.01 (nm, 2H, ArH), 8.44 (d, lH, 8.5 Hz, ArH), 12A (broad s,.lH, COOH).
MS (Cl, m/z): 452 (M+H)+, 408 (M-COOH)~.
Analvsis for: C2gH22FNO3 Calculated: C, 77.15; H. 4.91; N, 3.10.
Found:C, 77.08; H, 4.93; N, 3.12.
Example 5 2-Methyl-3-[[4-(methylthio)phenyl]methylene]-6-1!2-naDhthvl)methox~1-3H-indene-l-acetic acid A. 6-r(2-Naphthvl)methoxvl-2-methvl-indanone A mixturc of the indanone (14 g, 86.4 mmole) prepaled as described in Example 1, S~ep D, anhydrous K2CO3 (11.24 g, 81.4 mmole), 18-crown-6 (2.29 g, 6.4mmole) and 2-bromomethylnaphthalene (11.6g, 95mmole) in acetoni~rile 2~0~

(275 mL) is heated under nitrogen for 24 hours (in an oil bath set at 70 C). Theacetonitrile is evaporated and the residue is dissolved in waler, extracted with ethyl acetate, dned (MgSO4) and evaporated to dryness. The crude product (tan solid) is flash chromatographed (on silica Merck-60, preabsorbed in CH2C12, eluted with 8:2 hexane-ethyl acetate) to providc the dtle compound as a white solid {13.49 g,52%).
NMR (CDC13, 400 MHz): o 1.30 (d, J 3.2 Hz, 3H, 2-CH3), 2.70 (m, 2H, ArCH2C), 3.35 (m, lH, CHCO), 5.25 (s, 2H, ArCH20), 7.32 (m, 3H, ArH), 7.50 (m, 3H, ArH), 7.85 (m, 4H, ArH).
MS (EI, mlz): 302 (M)~, 141.
10 B. I) ~[(2-Naphthyl)methoxy3-2-tr~ethyl-indan-1-ylidene-acetic acid ethyles~er (Z isomer) ~) ~[(2-Naphthyl)methoxy3-2-methyl-indan- 1 -ylidene-acctic acid ethylester (E isomer) III) S-r(2-Na~hthvl~me~hoxvl-2-methvl-indene-3-acetic acid ethvl ester ~ Triethylphosphonoacetate (19.8 g, 88.3 mmole) is added dropwise under nitrogcn to a stirrcd and cooled suspension of NaH (60% in oil, 3.53 g, 88.2 mmole) in toluene (225 mL). Thc cooling bath is removed. A clear solution is obtained after 10 minutes at room temperature. A soludon of the indanone (133 g,44 nffnole) of Step A, in toluene (40 rnL) is added dropwise and the rnixture is placed 2û in an oil ba~h heated at 100-C for 54 hours (follow by TLC, hexane-ethyl acetate 7:3).
Water is added, the layers are separated and the aqueous phase is rcextracted with ethyl acetate (3 times). Thc extracts are dried (~C2C03) and evaporaled to dryness to yield the crude product as an amber oil (21.5 g), mixture~of endo and exo isomers. Flash chromatography of this crude material (on silica Merck-60, preabsorbed in CH2C12, 25 hexanc-ethyl acctate 9:1~ provides small amounts of each of the pure isomers (i.e. I, II
and m) togethcr with mixed fractions and uns~ed starting material (ca 5.24 g). The structmes of ~he isomers are confinned by MS and NMR and assigned by NOE. The mixturc of endo and cxo esters is routincly used in the next step (combined yield 8.94 g or 54.7%; 90% based upon recovered starnng material).
30 Isomcr I
NMR (CDC13, 400 MHz): o 1.26 (d, J 6.8 Hz, 3H, 2-CH3), 1.32 (t, J 7 Hz, 3H, ester CH3), 2.54 (d, J 15.1 Hz, lH, ArCHC), 3.1 (m, 2H, ArCHC + CCH~, 4.22 (q, J 7.2 Hz, 2H, ester CH2~, 5.28 (s, 2H, ArCH2O), 5.85 (s, lH, C=CH-COO), 7.04 (dd, lH, J 8.4 Hz arld 2.5 Hz, ArH), 7.17 (d, J 8.4 Hz, 20900~2 lH, ArH), 7.49 ~m, 2H, ArH), 7.59 (d, l 8.4 Hz, lH, ArH), 7.82 (m, 3H, ArH), 7.95 (s, lH, ArH), B.61 (s, lH, ArH).
MS (EI, rn/z): 37Z (M)~, 231, 141 (b.p.).

S NMR (CDC13, 400 MHz): o 1.21 (d, 3H, J 7 Hz, 2-CH3), 1.33 (t, 3H, J 7.1 Hz, ester CH3), 2.56 (d, J 16.3 Hz, lH, ArCHC), 3.18 (dL ~ 16.3 and 7.1 Hz, lH, ArCHC), 3.88 (m, lH, CCH), 4.22 (q, J ca 7 Hz, 2H, cster CH2), 5.24 (s, 2H, ArCH20), 6.19 (s, lH, C=C-COOEt), 7.06 (dd, J 8.4 and 2.4 Hz, lH, ArH), 7.17 (d, J 2.3 Hz, lH, ArH), 7.23 (d, J 8.4 Hz, lH, ArH), 7.49 (m, 2H, ArH), 7.54 (dd, J 8.4 and 1.6 Hz, lH, ArH), 7.88 (m, 4H, ArH).
MS (CI, mJz): 373 (M+H)~, 261 (b.p.~, 233 Isomer m NMR (CDC13, 400 MHz): o 1.20 (t, J 7 Hz, 3H, cster CH3), 2.11 (s, 3H, 2-CH3), 3.28 (s, 2H, ArCH2), 3.48 (s, 2H, CH2COO), 4.09 (q, J 7.1 Hz, 2H cstcr CH2), 5.25 (s, 2H, ArCH20), 6.79 (dd, J 8.1 and 2.3 Hz, lH, ArH), 6.98 (s, lH, ArH), 7.24 (d, 8.8 Hz. lH, ArH), 7.48 (m, 2H, ArH), 7.56 (dd, J 8.4 and 1.7 Hz. lH, ArH), 7.87 (m, 4H, ArH).
I~LS(C~,m/z): 373(M+H)~,285 C. 2-Methvl-3-rr4-(methvlthio~phenvllmethvlenel-6-r(2-nal~hthvllmethoxyl-3H-indene-l-acçtlc acid To a mixture of thc estcr (mixture of isomers prepared as descri~ed above (2.5 g, 6.71 mmole) and 4-(methylthio)-benzaldehyde (1.124 g, 7.38 rnmole)in anhydrous methanol (60 mL) is addcd dropwisc under nitrogcn 2~% methanolic sodium methoxide (2.9 mL). The mixture is renuxed for 16 hours, the sol~ent removet and the residue slurried in water and stirred ovcmigh~ (the initial yellow oil turDs into a solid). The water is evaporated in vacuo and the residue is triturated with ethcr (to remove unreacted aldehyde), filtered, washed with ether and dricd(yellow solid, 2.65 g). The crude sodium salt is slurried in water and acidified (to pH 6.5) with 10% acetic acid. The acid is collected, washed and dried in vacuo. It is again washed with ether and ~ried (1.02 g, 32%, m.p. 209-211 C, dec.~. The NMR shows it to be a rnixture of Z and E isomcrs in appsoxirnatcly 8:1 ratio.
NMR (DMSO-d6,400MHz): ~ 1.81 (s,2-CH3,minorisomerE),2.11 (s,2-CH3, major isomer Z), 2.51 (s, 3H, SCH3), 3.54 (s, 2H, CH2COO), 5.23 (s, ArCH2. Z isomer) and 5.28 ts, ArCH2O, E isomer), 6.60 (dd, lH, ArH), ~ 20~9~4~

6.90 (d,J 2.2 H~,lH, ArH),7.12 (s, lH, ArH),7.27-7.36 (m,3H, ArH), 7.46-7.62 (m, 5H, ArH), 7.88-8.00 (m, 4H, ArH), 12.33 (broad s, lH, COOH). . , MS (C~, mlz): 479~+H)~,435(M+H-CO0)+,141 (CllHg, naphthyl)~.
S Analvsis for: C31H26O3S
Cal~: C, 77.80; H, 5.48.
Fount: C, 77.44; H, 5.47.
E~ample 6 3-1(4-Chlorophenyl)methylene~.t2-methyl.6.(2-A. ~-Hvdroxv-2-methvl inden~-3-acetic~cid A mixture of the indanone (1.81 g, 11.17 mmole) of Example 1, Step D cyanoace~c acid (1.05 g, 12.3 mmol) ammonium acetatc (0.17 g), acetic acid (Q66 g) and toluenc (5 mL) is hcated at rcflux with ~atcr remo~ral ~Dean-Starlc) for 24 15 hours (ll,C, CH2C12-ethyl acclate 8:2). Thc toluene is c~aporated and the residual ycl!ow solid is rcdissolved in cthanol (6 mL) containing 2.2 N-KOH (1.4 mL). A
solution of KOH (2.2 g, 85) in water (15 mL) is addcd and the solution is refluxed urlder nitrogen for 18 hours. Thc ethanol is e~raporated, the rcsidue is diluted with watcr and extracted with ether (2 times). The aqucous laycr is acidified in the cold ~nth 20 6N-HCI (to pH 3) and extracted with ethyl acetate. The extracts are washed with brine, dried (MgSO4) and evaporated to providc ~hc crudc titlc cornpound togethcr with t~aces of unreacted indanone. It is used as such in the next step.
NMR (DMSO-d6, 200 MHz): S 2.02 (s, 3H, 2-C~3), 3.2 (s, 2H, ArcH2)~ 3-4 ~s, 2H, CH2COO), 6.48 (d, lH, ArH), 6.6 (s, lH, ArH~, 7.1 (d, lH. ArH3,9.08 (broad, IH, OH).
.
B. 5-Hvdr~xv-2-me*v!-indene-3-aceic acid metbvlester To a solution of thc crude acid as preparcd in Step A, above, in dry methanol ~120 mL) is added p-lolucncsulfonic acid monohydrate (1.9 g) and the mixtgre is gendy refluxed forl.S hours. The methanol is evaporated, the residuledissohcd in ethyl acetatc, washed with b~ine and dricd (MgS04). Removal of the solvent provides a brown oil ~at rcadily solidifies upon drying in vacuo. The residue is flash ch~matographed (silica Merck-60, absorbed in dichloromethane, eluted with dichlo~nethane~thylacctate 98:2 and 94:6) to yield the pure title compound as an off-white solid (9.4 g, 80%).

2 0 ~

NMR (CDC13, 400 I~z): o 2.1 (s, 3H, 2-CH3), 3.26 (s, 2H, ArCH2), 3.49 (s, 2H, CH2COO), 3.67 (s, 3H, COOCH3), 4.89 (broad s, OH), 6.59 (dd, lH, ArH), 6.75 (d, lH, J 2.4 Hz. ArH), 7.18 (d, lH, 7.9 Hz, ArH).
MS (E~, m/z): 218 (M)~, 158 (b.p.).
C. 3-rr4 Chloro~henvl)m~hyle~ç~2-methyl-~hvdroxvl-3~-indene-1-aceie acL
To a solution of sodium metal (0.170 g, 7.39 g.a.) in anhydrous methanol (2.5 tnL) under nitrogen is added dropwise with cooling a solution of the ester (0.537 g, 2.46 mmole) of step B, in methanol (5 mL) followed by p-chloro-benzaldehyde (0.381 g, 2.71 mmole, 1.1 equiv.). The mixture is stirred in an oil bath heated at 6~-70 C for 6 hours followed by standing overnight at room temperature(lLC, CH2C12-ethyl acetate 93:7). Wuer (10 mL) and methanol (2 mL) are added and the mixture is again refluxed under nitrogen for 3 hours (TLC, CH2CI2-ethyl aceute 90:10). The methanol is evaporated. the residue is dissolved in water, and washed with ether (2 times). The aqueous phase is acidified in the cold with 6N-HCI
(to pH 3) and extracted with ethyl acetate. The ext~acts are washed (brine) and evapo-rated to yield a greenish-yellowish solid (0.8 g). The ~IMR speclrum shows that it is a mDm~ of the title eompound and 5-hydroxy-2-methyl-indene--3-acetie acid. They are best separated as their methylesters (see below).
D. 3-r(4-Chlorophenyl2me~hvlenel-r2-methvl-~hv~roxyL-3H-indene- I -acetic melhvlesrer A soluuon of the crude acids (2.46 mmole, obtained as described in Step C, abo~e) in methanol (10 mL) conuining p-toluenesulfonic acid monohydrate (60 mg) is refluxed for 5 hours. The methanol is evaporated and the residue dissolved in ethyl aceta~e, washed with brine and dried (MgSO4). The solvent is evaporalted and the residue is flash chromatographed (on silica Merck-60, absorbed in 1:1 dichloromethane-hexane, elu~ed with toluene-isopropanol 95:5) to provide the ti~le compound (less polar spot, 0.103 g, yellow solid) together with some impure rnalerial (0.39û g, oil that solidifies upon standing). The Z configuration is confirtned by NOE. The more polar spot is jdentical (NMR, TLC) with methyl-5-hydroxy-2-methylindene-3-acetate.
NMR (CDC13,-400 MHz): ~ Z.17 (s, 3H, 2-CH3), 3.55 (s, 2H, CH2COO), 3.69 (s, 3H, COOCH3), 6.33 (dd, lH, ArH), 6.67 (d, J 2.3 H~, lH, ArH), 7.01 (s, lH), 7.14 (d, J 8.3 Hz, lH, ArH), 7.40 (dd, 4H, ArH).
MS (EI, m/z): 342/340 ( I Cl, M)+, 231 (b.p.~

2~3~

E. 3-r(4-Chlorophenvl)methvlenel-r2-methYI-~(2-quinolinY!methoxv~1-3H-indene-l-a~ene acid methvlester A mixture of the ester (0.410 g~ 1.2 mmole) of Step D, anhydrous potassium carbonate (0.17 g), and 18-crown-6 (0.050 g) in acetonitrile (7 mL) is5 snrred at room temperature for 15 minutes. 2-Chloromethylquinoline is added (frce base, 0.149 g, 1.42 mmole, freshly prepared from the hydrochloride sal~) and theteep red mixture is stirred under nitmgen for 15 hours in an oil bath heated at 6S'C. A
10% excess of potassium carbonate, crown ether and the 2-chloromethylquinoline is then added and the reflux is continued for anothe~ 2 hours (ll,C, hexane-isopropanol 10 93:7). The solvent is evapo~a~d and the ~esidue is par~tioned between water and ethyl aeetate. The organie phase is washed (brine), dried (MgS04) and evaporated to dry-ness. The erude product is identical (NMR, TLC) with the material described in Example 7, below.
F.- 3-rPI ChloTophenvl~methvlenel-r2-methvl-~(2-quino!invlmethoxv)1-3H-indene-l-acetie acid lN-KOH (3.72 rnL) is added dropwise to a warm solution of the ester (0.600 g, 1.24 mmole) of Step E, in methanol (7 mL). The rnixture is refluxed under nitrogen for 3 hours. After stirring overnight at room temperature ('Il.C, hexane-isopmpanol 93:7), ~he methanol is evaporated and the residue washed with ether. The solid is slurried in water, neutrali~ed in the cold with 10% acetic acid (to pH 6-6.5) and extracted with ethyl acetate (vigorous stirring is necessary to achieve solution). The extracts are washed with brine, dried (MgS04) and evapo~ated to yield the crude acid - (0.250 g, 43%). lt is rec,rystallized fTom hot ethyl acetateJmethylene chloride (dissolve in a large volume and concentrate ~he filtrate until precipitation occurs). The pure dde compound (m.p. 21~218-C) is identical (l~C, NMR) with the material described in Example 1, Step G. (Z isomer).
E~cample 7 . 3-1(4-Chlorophenyl)methylene3.12.methyl.6.(2.quinolinyl-- metho~v)l-3H-indelle-l.aeetie aeid meth~vleste~
A suspension of the acid (1.88 mmole, crude material before purifica-tion, obtained as dcscribed in Example 1; Step G), in methanolic HCl (15 mL~ is refluxed until the reaction is comple~e by TLC (dichloromethane-methanol 9:1~ UY).
The methanol is evaporated and ~he residue is partitioned between ethyl acetate and 20~00~

dilute NH4OH. The extracts are wasbed with brine, dried (K2co3) and evaporated to dryness to provide a yellow oil that foams in vacuo (0.900 g). The crude product is flash chromatographed (on silica Merck-60, toluene-hexane-isopropanol 50:50:1 aseluent) ~o yield the pure title compound (0.630 g, yellow foam that solidifies upon S trituration Witil ethanol, 69.6% over 2 steps)~ Mixture of Z and E isomers in appsoxi-rnately 4:1 ratio (based upon the position of the 2-CH3 signal in the NMR spec~um).
NMR (CDC13, 400 MHz): ~ 1.81 (s, 2-CH3, minor isomer E), 2.17 (s, 2-CH3, tnajor isomer Z), 3.56 (s, 2H, CH2COO), 3.62 (s, 3H, OCH3) 5.42 (s, 2H, ArOCH2), 6.52 (dd, lH, ArH), 6.89 (d, J 2.4 Hz, lH), 7-8.3 (m, 12H, ArH).
MS (+FAB, mlz): 482 (1CI, M+H)+, 360, 217, 143 (b.p.)+, 91.
Exampie 8 1,8-Diethyl-1,3,4,9-tetrahydro-6-(2-quinolinyl-~=~
A. 7-Ethvi-2.3-dihvdrotr~tophol A mixture consisting of 7-ethyltryptophol (28.0 g, 0.148 mol) and 250 mL of trifluoroacetic acid is stirrcd at room temperaturc. Sodium borohydridc pcllcts (5.4 g, 0.145 mol) are addcd over a 4 hour period. After addition is completc, thc reaction is stirrcd for I hour. Thc reaction mixn~ is pourcd onto icc and ncutral-ized with 50% NaOH ~o pH 10. The aqueous laycr is cxtracted with ether (3 x 200mL). The e~her layers are combined and extracted with 5% HCI solution (3 x 200 mL). The combined acidic solution is then made aLI~aline with 50% NaOH
and extracted with ether (3 x 200 mL). The combined ether layers are washed withwater (2 x 200 mL), once with brine (200 mL), dried (MgS04), filtered and concen-~atcd to afford 17.3 g of oil. Flash ch~omatog~aphy using 60% ethyl aceutelhexane, and then 80% ethyl acetate/ hexane affords 13.5 g of solid title compound, m.p. 73-75-C.
NMR (CI)C13): o 6.98 (d, J=8.3 Hz, IH, Ar), 6.93 (d, J=5.3 Hz, lH, Ar), 6.74 (t,J=7.5 ~z, IH, Ar), 3.7 (m, 3H, 5~2O. 3.68 (m, 2H, NH-CH ), 3.56 (m, lH), 3.33 (m, IH, NH-CH ), 2.49 (q, J-7.6 Hz. 2H, CH CH3), 2.11 (m, lH, CH CH2), 1.80 (m, lH, CH~CH2), 1.21 (t, J=7.6 Hz, CH2CH3).
MS: m/e 191 (M+), 130, 118.
B. 7-Ethv1-5-hvdroxv~ptophol A solution of potassium nitrosodisulfonate (17.0 g, 0.063 mol) in pH 7 buffer ~760 mL) is added over a 20 minute period to a stimng solution of 7-203~0'~

ethyl-2,3-dihydrotIyptophol (5.0 g, 0.026 mol) in 350 mL of acetone. Ten minu~esaf~er the addidon is complete, the reacuon mLlcturc is extracted with ethyl aceta~e (4 x 300 mL). The combincd e~hyl acetate layers are washed ~th distilled wa~er (2 x 200 mL), once with b~ine (200 mL), dried (MgSO~) md concentratcd to afford 5 5.6 g of crude producL Thc crude product is loaded omo a flash chroma~ography column. The next day, i~ is flashed using 70% ethyl aceta~e~hexane ~o afford 2.5 g of tide compound.
NMR (DMS~d~ 8.43 (s, lH, 6.97 (d, J=2.3 Hz, 2H, arom), 6.60 (d, J=2.1 Hz, lH, arom), 6.40 (d, J-2,1 Hz, lH, arom), 4.5S (t, J-5.3 Hz, lH, CH2 3.57 ~m, 2H), 3.32 (s, IH, Ar-O_), 2.7 (m, 4H), 1.20 (t, J~7.5 Hz, 3H).
MS: 20S (M)~, 174, 159.
Analvsjs,,~r: Cl2HlsNo2 C~alculated: C, 70.22; H, 7.37; N, 6.82.
~51: C, 70.15; H, 7.52; N, 6.60.
C. 1~8-Diethvl-1._~4,~tetrahvdro-f.-l~vdroxvpvranor3.4-blindo]e-l-ace~ic acjd methvl cster A mixture consisting of 7-ethyl-5-hydroxytryptophol (15.5 g, 0.076 mol), 20% tetrahydrofuran/methylenc chloride (1200 mL), methyl 3-metho~cy-2-pentcnoa~e (17.5 g, 0.0121 mol) and boron trifluoridc e~herate (23.0mL, 20 0.187 mol) is sdrred at room ~cmperaturc for 28 hours. The reacdon mixnlre is dilutcd with 100 mL of me~hylene chloride and washcd with 5% NaHC03 (3 x 500 mL), once with wa~cr, dried (MgS04) and conccntra~ed to give 30.3 g of crude. Flash chromatography using 25% ethyl aceta~e/hexane as an eluen~ afforded 16.0 g of title compound, m.p. 153-154-C.
25 NMR (CDC13): o 8.90 ~bs, IH), 6.74 ~ d, J=23 Hz, H, arom), 6.49 (d, J=2.4 Hz, lH, arom), 4.50 (s, lH, Ar-OO, 4.00 (m, 2H), 3.7 (s, 3H), 3.0-2.70 (m, 6H), 2.20 (m, 2H), 1.33 (t, J~7.6 Hz, 3H), 0.82 (t, J=7.6 Hz, 3H).
MS: 317 (M)~, 288, 244.
Analvsis for: ClgH23NO4 30 Calculated: C, 68.12; H, 7.30; N, 4.41.
Found: C, 67.73; H, 7.23; N, 4.24.
D. 1.8-l)iethvl-1.3.4.9-tetrahvdro ~hvdroxvpvranQ~4-b~s~lç-1-acetic acid A mix~ure consisting of the me~hyl es~cr (43.1 g, 0.136 mol) of S~ep C, po~assium hydroxide (2.4g, 0.407mol), 1600mL of methanol and 160mL
35 water is refluxed for 5 hours under a nitrogen atmosphere. The excess methanol is 20~042 evaporated and watcr (1000 mL) is added to the rosidue. The mixture is extractcd with ether (3 x 500 mL). The aqueous layer is made acidic with 5% HCI (pH 2), then extracted with chloroform (4 x 300 mL). The combincd chloroforrn laycrs arc washed with water (2 x 500 mL), brine (S00 rnL), dried (MgSO4), and concentratedS under vacuo to yield 43.0g of foam. Flash chroma~ogTaphy using 15æ
acetoneltoluene as eluent, affords 40.0 g of foam. This is crystallized from aceto-nitrileltoluene to afford 35.4 g of pure title compound, m.p. 172-173 C
H NMR (DMSO-d6): o 8.44 (s, lH, -NH), 6.51 (d, J=2.1 Hz, lH, Ar), 6.39 (d, J=1.96 Hz, lH, Ar), 3.89 (m. ~H), 2.89 (q, 2H), 2.87 (d, J=13.5 Hz, lH, CH~COOH), 2.75 (d, J=15.8 Hz, lH. CH2~00H), 2.71-2.57 (m, 2H), 1.99 (q, J=7.2 Hz, 2H), 1.20 (t, J=7.6 Hz 3H), 0.60 (t, J=8.5 Hz, 3H).
IR (lCBr, cm l): 3590 (OH), 1720 (CO).
W (MeOH, nm): 276 (9940), 295 (6400).
MS: rn/e 303 (M~), 244.
Analvsis for: Cl7H21NO4 C~ulatcd: C, 67.31; H, 6.98; N, 4.62.
E~d: C, 66.99; H, 6.80; N, 4.96.
E. 1.8-Diethvl-1.3.4.9-tetrahvdro-6-(2~uinolinvlTne~_oxv~pvranor3.4-blindolc-1-acedc ~ad A mixture consisting of 1,8-diethyl-1,3,4,9-tetrahydro-6-hydroxy-pyranol3,4-blindole aceic acid mcthyl ester (5.0 g, 0.0158 mol), dimethylsulfoxide (250 rnL), and potassium iodide (150 mg) is sirred a~ room temperaturc. A solution of sodium hydroxide (3.9 g, in 20 mL H20) is added and sti~ed at room temperature followed by addition of 2-chloromethyl quinoline hydrochloride (8.4 g, 0.0392 rnol).
The reaction mixture is heated at 7~80-C for 3.5 hours, cooled and dilu~ed with water (100 rnL). Thc rnixture is made acidic with lN HCI to pH 4, and ex~racted with ethyl acetate (3 x400mL). The cornbined organic layers are washed with water (3 x 200 mL), once with brine (200 tnL), dried over MgS04, fillered and concen-~ated to give 10.0 g cf crude product. The crudc product is chromatographed on silica gel using 7% melhanoUme~hylene chloride as eluent to afford 2.9 g pure product. The latter is dissolved in 200 cc elhyl acetate and precipitated by dropwise addition to petroleum ether (700 mL) to afford 2.7 g of the title compound, m.p. 179-181-C.
IH NM~ (400 MHz, DMSO-d6): o 8.38 (d, J=8.5 lH, 4Q), 8.0 (d, J=8.6 lH, 8-Q), 7.97 (d, J-7.2, lH-5Q), 7.76 (dt, Jl=6.8, J2=1-5 lH, 7Q), 7.70 (d, J=8.5 lH
3Q), 7-58 (dt, Jl=6.9, J2=1.1 lH 6Q), 6.86 (d, J=2.2 lH ar.), 6.67 (d, J-2.2 20~00~.2 lH ar.), 5.32 (s, 2H-OCH2Q), 3.6 (m, 2H), 2.79 (m, 2H), 2.74 (D, J=15.2 lH), 2.64 (d, l=14.2, lH), 2.55 (m, 2H, 2.0 (q, J=7.2, 2H, C~CH3), 1.22 (5, J=7.5 3H CH2CH3), 0.66 (t, J=7.2 3H, 8 CH2CH3).
IR: (KBr): 3400 (NH, OH), 1740 (C=O) cm-l. -S Mass: (M+ H), 445, 239, 217.
Anaivsis for: C27H28N2o4 Calculatcd: C, 72.95; H, 6.35; N, 6.30.
~: C, 71.04: H, 6.19;~N, 6.21.
Example 9 1-Ethyl-1,3,4,9-tetrahydro-6-(quinoli nylmethoxy)-r~r anor3.4.hlindole.1 -a~etic a~
A. I -Ethvl- L3.4.9-tetrahvdro-6-(~henyimct~ c.xv)~yntno~3~4~QIe- I -acetic acidm~thvl ester A mixlurc consisting of 5-bcnzyloxytryptophol (24.0 g, 0.090 mol), methylenc chloridc (600 mL), methyl 3-methoxy-2-pcntenoate (16.8 g, 0.177 mol) and bo~ontTifluoride etherate (2 mL) is stirret at room temperaturc for 3 hours. The rcaction mixturc is washed with 5% NaHC03 (2 x 200 mL), water (2 x 200 mL) ant once with brine (200 mL), dried (MgSO4), fi1tercd and concentrated to gi~,re38.0 g crude product. The crude product is flash chrornatographed on silica gel using 20% ethyl aceEalelhexane as an cluent to afford 29.0 g pure title compound, m.p. 98-100-~. .
H NMR, CDC13): ~ 8.87 (BS, lH NH), 7.47 (d, J=7.3, ZH Bz), 7.36 (t, J=7.6, 2H
Bz), 7.29 (m, IH), 7.24 (d, J=7.5, lH), 7.04 (d, J=2.4, lH), o.91 (dd, Jl=8.7, J2=2.4, IH), 5.10 (s, 2H O-CH~-Bz) 4.06-3.90 (m, 2H), 3.71 (s, 3H
CH2COOC~3), 2-99 (d, J=16.6, IH), 2.89 (d, J=16.6 lH), 2.75 (m, 2H), 2.0 (m, 2H), 0.81 (t, J=7.4 3H CH2CH3).
Mass: (M+) 3?9, 350. 288.
~nalvsis for: C23H2sNO4 Cal~ated:. C, 72.80; H, 6.64; N, 3.69.
Found: C, 72.61; H. 6.63; N, 3.69.
B . 1 Ethvl- 1.3.4.9-tetrahvdro-~(phenvlmethoxv)~y~nor3.4-blindole- 1 -acetic acid A mixturc consisting of thè ester (29.0 g, 0.0765 mol) of Step A, methanol (800 mL), water (50 mL) and potassium hydroxide (16.0 g, 0.29 mol) is 209~0~2 refluxcd for 4 hours. The reacdon rnixtur~ is cooled to room temperature, conccntrated and diluted wi~h water (S00 mL). The aqueous layer is washed with ether (2 x 200 mL) and rnade acidic with a 1:1 mixture of concentrated HCI and water to pH 2.71 is extracted with chloroform (4 x 300 mL) and the combined chloroform S layers arc washed once with water (2 x 300 mL), oncc with brine (300 mL), dried (MgSO4), filtered and concentrated ~o give 26.0 g of dtle compound, m.p. 163-165-C.
H NMR (400 MHz, CDC13): ~ 8.39 (BS, NH), 7.47 (d. J=7.4, 2H), 7.38 (dt, Jl=7.1, J2=1.8, 2H), 7.30 (m, lH), 7.22 (d, J=8.7, lH), 7.04 (d, J=2.4 IH), 6.90 (dd, Jl=8.8, J2=2.4 lH), ~.10 (s-OCH~ BZ? 4.08 (m, 2H), 3.02 (d, J=16.4 lH), 2.95 (d, J=16;3, lH), 2.80 (q, J=5.0 2H), 2.06 (m, 2H), 0.86 ~t, J=7.3 3H CH2CH3).
IR (RBr): 3380 (NH), 1710 (CO) cm-l-Mass: (M+) 365, ions 336, 306.
Analvsis for C22H23NO4 Calcul~te~: C, 72.31; H, 6.34; N, 3.83.
EQ~ : C, 72.17; H, 6.29; N, 3.65.
C. I-Ethvl-1.3.4.9-tetrahYdro-~hvdroxv-~vranor~3~4-~1indole-l-acetic acid A mixture consisdng of 10% Pd/c on charcoal (3.5 g), ethanol (800 mL), tetrahydrofuran (100 mL) and the acid (21.0 g, 0.056 mol) of Stcp B, is hydrogenated at 30 psi for 18 hours. The reaction tnixture is filtercd and concentratcd to givc 21.0 g of crude product, which is used in the next reaction without further purification.
IH NMR (DMS~d6): ~ lQ36 (s, NH), 7.16 (d, J=7.4, lH Ar), 6.68 (d, J=2.2 lH
A~), 6.53 (dd, Jl=8.5, J2=2.2 lH Ar), 3.89 (m, 2H), 2.82 (d, J=13.6, lH), 2.62 (d, J=13.6, lH), 2.58 (m, 2H), 2.0-1.9û (m, 2H), 0.61 (t, J=7.3 3H
CH2CH3).
IR (KBr): Broad peak. 370~3300 cm~l (NH, OH), 1710 cm-l (C=O).
Mass: M ion: 275, ion 246, 216, 202.
Analysis for: ClsH17NO4 Calculated: C, 65.44; H, 6.22; N, 5.09.
Found: C, 68.82; H, 6.72; N, 4.81.
D. I -Ethyl- 1.3.4~9-tç~hvdr~uinolinvlmethoxy~pyranol3,4-blindole- I -acetic A tnixturc consisting of the 6-hydroxy pyrano acid (21.0 g, 0.076 mol) of Step C, dime~hyl sulfoxide (900mL), sodium hydroxide (180.0g in 100mL

2~3~0~2 H2O) and 2-chloromethylquinoline hydrochloridc (23.0 g, 0.0107 mol) is heated to70-80-C for 1 hour. The reaction rruxture is cooled, poured into water (1500 mL) and madc acidic with lN HCI to pH 4. It is extracud with ethyl aceute (4 x 500 mL) and the combined organic layers are washed once with water (2 x 300 mL), once with brine (300 mL), dried t~MgSO4), filtered and concentrated to give 33.0 crude product, which is chromatographed on silica gel using 7% methanoVmethylene chloride as elueM
to afford 13.9 g pure product. The pure produc~ is dissolved in 100 mL ethyl acetate, and precipiuted by adding dropwise to pctroleum ether (3000 mL), and filured to give 13.8 g product, which is crysullized from benzene to give 12.0 g of pure product, m p. 105'C (dec.).
H NMR DMSO-d6: ~ 10.59 (s, lH, NH), 8.39 (d, J=8.5, lH, 4Q), 8.01 (d, J=8.5, lH, 8Q), 7.97 (d, J=8.2, 1H, SQ), 7.78 (dt, J~=6.9, J2=1.4, lH 7Q), 7.70 (d, J=8.5, lH, 3Q), 7.60 (dt, J~=6.9, J2=1Ø lH, oQ), 7.21 (d, J=8.7, lH ar.), 7.06 (d, J=22.3, lH A~), 6.82 (dd, Jl=8.7, J2=2.S, lH Ar.3, 5.34 (s, 2H, O-CH~-Q), 3.92-3.86 (m, 2H), 2.82 (d, J=13.6, lH), 2.62 (d, J=18.6, lH), 2.60 (m, 2H), 2.01-1.91 (m, 2H), 0.61 (t, J=7.3, CH2CH3).
~(KBr): 3400cm~1(NH,OH) 1705cm-1(C=O).
Mass: FAB: M+H 417 ionM~357.
Anal~sis for: C2sH2sN2o4 Calculated: C, 72.10; H, 5.81; N, 6.73.
EQ~: C, 72.55; H, 5.91, N, 6.48.
Example 10 l-Methyl-1,3,4,9-tetrahydro-6-(2.quinolinyl-methoxv)n~vranor3.4-hlindole-1-acetic acid A. 1 -Metbvl- I .3.4.9-tetrahvdro-~tphenvlmethox~p vranor3.4-blindole- 1 -aceic acid. ethvl ester A mixture ~onsisting of 5-benzyloxytryptophol (4.5 g, 0.017 mol), benzene (200 rnL), ethyl acetoacetate (3.4 g, 0.026 mol) and p-toluenesulfonic acid (0.5 g) is refluxed for 2.5 hours using a Dean-stock trap to remove the water. The 30 reaction ~ ~ixture is cooled ~o room temperature and washed with 5% sodium bicarbon-ate, (1 x 200 mL), wa~er (200 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated to give 8.0 g of crude product as a thick oil, which is flash chro-matographed on silica gel using 20% ethyl acetate/hexane as an eluent to afford 5.5 g oil which solidifies upon standing, m.p. 96-98 C.

. _ 20~ao42 .

H NMR 400 MHz CDC13: ~ 8.96 (bs, lH, NH), 7.47 (d, 1=7.0, 2H ar., O-Bz), 7.36 (dt, Jl--7.1, J2=1.8, 2H Ar., O-CH213z), 7.3 (m, lH, OCH2-Bz), 7.23 (d, J=8.7 lH Ar.), 7.04 (d, J=2.5, lH Ar.), 6.90 (dd, Jl=8.7, J2=2.3 lH Ar), 5.10 (s, 2H, O-CH2-0), 4.22-4.14 (m, 2H), 4.0t (m, 2H), 2.98 (d, J=16.5, lH), 2.85 (d, J=16.4, IH), 2.79 (t, J= 2H), 1.7 (s, 3H, CH2), 1.3 (t, J= 3H
COOCH2CH3~
Mass: EI: M/e: 379, ions 292, 158. -B . 1 -Methvl- I .3.4.9-tetrahvdr~(phenylm~hoxv)pvranor~blindole- I -acetic A mixture consisdng of the cster (55 g, 0.013 mol~ of Step A., methanol (300 mL), water (20 mL) and potassium hydroxide (4.0 g, 0.071 mol) is refluxed for 4 hours. The reaction mixture is coolcd to room tcmperature, concen-trated, diluted with water (200 mL) and rnadc acidic with a 1:1 solution of conccntrated HCl:water to pH of 1. The mixture is cxtractcd with chloroform (3 x lS0 rnL), the combined chloroform cxtracts are washcd once with water (2 x 100 m~), oncc with brine (100 mL), dricd (MgSO4), filtered and concentratcd to give 4.6 g of product, which is used in thc ncxt reaction, m p. 157-158-C (dcc.).
IH NMR (400 MHz, OMSO-d6): o 11.98 (bs, lH, COOO, 10.62 (s, lH, N~), 7.45 (d, J=7.1, 2H-Bz), 7.38 (dt, Jl=7.1, J2=1.8, 2H, Bz), 7.30 (m, lH, Bz), 7.18 (d. J=8.7. IH Ar.), 6.99 (d, J=2.3, lH Ar.), 6.76 (dd, Jl=8.7, J2=2.5. IH Ar.), 5.07 (s, 2H, OCH?0), 3.95-3.84 (m, 2H), 2.78 (d, J=13.8, lH), 2.68 (d, J=13.8, IH), 2.60 (t, J=5.4, 2H), 1.56 (s, 3H).
Mass: EI: l~Ve: 3Sl, ions 292, 260, 130.
C. l-Methvl-1.3.4.9-tetrahvdr~6-hvdroxv-pvrano~3.4-blindo1c-1-acetic acid A mixture consisting of the acid (4.5 g, 0.013 mol) of Step B, ethanol (150 mL), Ietrahydrofuran (20 mL) and 10% Pdlc on charcoal (800 mg) is hydro genated at 30 psi for 18 hours. l he mixturc is filtered and concentrated to give 3.1 g of product, wh~ch is used into next reactiosl without further purification.
IH NMR (400 MHz, DMSO-d6): ~ 7.19 ~d, J=B.S, lH Ar.), 6.70 (d, J=2.5, lH
Ar.), 6.55 (dd, Jl=8.5, J2=2.5. lH Ar.), 3.90 ~m, 2H), 2.77 (d, Jl=16.0, lH), 2.66 (d, J=16.0, lH), 2.55 (m, 2H), 1.55 (s, 3H).
Mass: EI: M/e: 261, ions: 216, 160, 101.

20~0~

D. I-Methvl-1~3.4.9-tet~hvdro-~(~ll~nQli~~
aceic acid A mixture consisting of l-methyl-1,3,4,9-tetrahydro-6-hydroxy-pyrano[3,4-yindolc-l-acctic acid (3.0 g, 0.011 mol) of Step C, dimethyl sulfoxide (300 mL), potassium iodide (100 mg) and sodium hydroxide ~2.5 g in 20 mL water) is stirred a~ room temperature. 2-Chloromethylquinoline hydrochloride (5.8 g, 0.022 mol) is added and the reaction mixture is heatcd for 3.5 hours, cooled anddiluted with water (700 mL). The mixture is made acidic to pH 4 with lN HCI, - extracted with ethyl acctate (4 x 300 mL) and the combincd orga~uc layers are washed 10 once with water ~2 x 200 rnL), once with orine (200 mL), dried (MgS04), filtered and conceDtrated to yield crudc product, which is flash chromatographed on silica gel using 10% methanoVmethylene chloride as an eluent to give 1.0 g product. Thc latter is dissolved m ethyl acetate (20 mL) and precipitated by adding dropwise to pelrokum ether (500 mL) to give 1.0 g pure compound, m.p. 175-177'C (dec.).
15 IH NMR (400 MHz DMSO-d6): o 11.2 (bs, lH, NH), 8.37 (d, J=8.5, IH 4Q), 8.0 (d, J=8.7 lH, 8Q), 7.97 (d, J=7.6, lH, 5Q~, 7.77 (dt, Jl=6.9, J2=1.4, lH, 7Q), 7.69 (d, J=8.5, lH, 3Q), ?.58 (dt, Jl=7.0, J2=1.0, lH, 6Q), 7.18 (d, J=8.7, lH Ar.), 7.03 (d, J=2.3 lH Ar.), 6.80 (dd, Jl=8.7, ~2=2.3 lH Ar), - 5.34 (s, 2H, OC~2Q), 3.88-3.84 ~m, 2H), 2.62 (bs, 2H), 2.48 (bs, 2H), 1.56 (s, 3H-S~)-IR (KBr): 3400 cm -I (broad NH, OH, ), 1700 cm-l (C=O).
Mass: EI: Mle: M+ 402, ions 202, 157.
Analvsis for: C24H22N2o4 Calculated: C, 71.63; H, 5.57; N, 6.96.
25 ~: C, 69.20; H, 5.38; N, 6.~0.
Example 11 l-Ethyl-2,3,4,9-tetrahydro-6 (2-quinolinyl-methoxy)-l~l-carhazole-l~acetLc acid A. I-Ethvl-2,3,4~9-tetrahvdro ~methoxv~lH-carbazole-l-acetic acid methvl ester A rnixture consisting of 4-methoxyphenylhydrazine (25.0 g, 0.162 mol), 2-carbomethoxymethyl-2-ethylcyclohexanone (42.0 g, 0.212 mol), and toluene (1000 mL) is refluxed for 24 ho~rs under a nilrogen a~nosphere and the water is removed using a Dean-StaTlc t~ap. The reaction mixturc is cooled and concentIated to give crude hydrazone. (_ 56 g).

20~00~2 The crude hydrazone (56 g) is dissolved in glacial acetic acid (500 mL) and refluxed for 25 minutes. The reaction mixture is cooled to room temperature.poured into water (2000 mL) and extracted with ethyl acetate (4 x 500 mL~. The organic layers are combined, washed with IN NaOH (2 x 500mL), water (2 x 500 mL), once with brine (500 mL), dried (MgSO4), filtered and concentratedto give 47.0 g of crude product. Thc crude product is flash chromatographed using 10% ethyl acetaseJhexane as an eluent to afford 18.0 g product; m p. 72-74'C
H NMR ~400 MHz, CDC13): ~ 8.94 (bs, lH, NH), 7.19 (d, J=8.0, lH Ar.), 6.90 (d, J=2.3 lH Ar.), 6.76 (dd, Jl=8.6, J2=2.3, lH Ar.), 3.81 (s, 3H.
COOC}~3), 3.64 (s, 3H, OS~3). 2.68-2.62 (m, 4H), 1.95-1.61 (m, 6H), 0.8 (t, 11=7.6, 3H, CH2CH33.
Mass: EI: I~/Ve: 301, ions272,228(basepeak).
B . 1 -Ethvl-2.3.4.9-tetrahvdro-6-hvdroxv- ! H-carbazole- 1 -acetic acid A mixture consisting of the methoxy compound (18.0 g, 0.060 mol) of Step A, and 48% hydrobromic acid (4S0 mL) is heated at 125-C for 6 hours. The reaction mixture is coolcd, diluted with water (1500 mL) and extracted with ethyl aceute (3 x 500 mL). The organic laycrs are combined ant washed once with water (2 x 500 rnL), once with brine (500 snL), dried (MgS04), filtered and concentrated to gi~re 15.8 g product as a foatn.
IH NMR (400 MHz, DMSO~ 10.21 (s, lH, COO~), 8.45 (bs, lH, N~), 7.03 (d, J=8.5, lH Ar.), 6.63 (d, J=1.9, lH Ar.), 6.48 (dd, Jl=7.3, J2=1.3, lH Ar.), 2.54-2.46 (m, 4H), 1.98-1.66 (m, 6H), 0.70 (t, J=7.3, CH2~3)-Mass: EI: I~Ve: 273 (M~) ions244,214,198. .
C .I -Elhvl -2.3.4.9-tetrahys~(2~uinolinvlmethoxy~- 1 H-carbazole- 1 -acc ic acid A mix~ure consisting of the hydroxy acid (8.0 g, 0.028 mol) of Step B, dimethyl sulfoxide (500 mL), potassium lodide (100 mg), and sodium hydroxide (7.0 g in 300 mL H20 0.175 mol) is stirred at room tempcrature, for 15 minutes.
2-Chloromethylquinoline hydrochloride (11.8 g, 0.055 mol) is added and the reaction mixture is heated to 70-80 C for 3 hours. The mixture is cooled to room temperature and poured into water (1500 mL), made acidic to pH 4 with lN HCl, and extracted with ethyl acetase (3 x 500 mL). The organic layers are combined, washed once with water (2 x 300 rnL), once wish brine (300 mL). The organic layers are combined, washel once with water (2 x 300 mL), once with brine (300 mL), dried (MgSO4), filtered and concensrated to give 9.0 g of crude product which is flash chro-matographed using 10% meshanoVmeshylene chloride as an eluens so give 3.0 g pure 2 0 ~, ~ O ~ 2 product, which is dissolvcd in ethyl aceta~e (20 mL) and added dropwise to petmleum ether (500 mL). The precipitate is fil~ered off to give 2.5 g product, m.p. 120-125-C.
H NMR (400 MHz, DMSO-d6): 8 10.80 (bs, lH, NH), 8.37 (d, J=8.5, lH, 4Q), 8.0 (d, J=8.5, lH, 8Q), 7.98 (d, 3=7.2, lH 5Q), 7.77 (dt, Jl=6.9, J2=1.5, lH, 7Q), 7.69 (d, J=8.5, lH, 3Q), 7.61 (dt, Jl=6.9, J2=1.1, lH, 6Q), 7.14 , - (d, J=8.7, lH Ar.), 6.96 (d, J=2.4, lH Ar.), 6.76 (dd, Jl=8.6, J2=2.4, lH
Ar.~, 5.32 (s, 2H -CH2Q), 2.52 (bs, 2H), 1.82-1.72 (m, 8H), 0.71 (t, J=7.3, 3H, CH~CH3).
IR (KBr): 3410 cm-l (NH, OH, broad), 1710 cm-l (C=O).
10 Mass: M' 415 Analvsis f~: C26H26N2o3 Calculated: C, 75.34; H, 6.32; N, 6.76.
Found: C, 73.49; H, 6.27; N, 6.48.
Example 12 1,3,4,9-Tetrahydro-l-propyl-6-(2-quinolinyl-methoxv~D~ranor3.4-l-lindole-1-aceti~ acid A. Ethvl- I -Dro~vl- I .3.4.9-tetrahvdlo-6-(phenvlmethoxv~Tanor3.4-blindole- 1 -acet~te A solution of 5-benzyloxytryptophol (4.72 g, 17 mmoi) and cthyl 20 butyrylacetate (3.16 g, 20 mmol) in methylenc chloride (75 ml) is treated dropwise with boron t~ifluoride e~herate (3 mL) and stirrcd under nitrogen at room temperature overnight. The reaction mixture is diluted with methylene chloTide (250 mL) and sequentially washed with 5% aqueous sodium bicarbonate (2 x 100 mL) and water (2 x 50 mL). The organic phase is dried (MgSO4), filtered, and evaporated to afford 25 7.0 g of a crude dark oil. Purification by flash coluinn chromatography (ethyl acctate:hexanc, 1 :9 eluent) on silica gel (50:1 ratio, 230400 mesh) affords the tide compound (5.5 g, 79%) as a slighdy amber oil homogeneous by l~C.
H NMR (200 MHz, CDC13): o 8.93 (bs, lH, NH), 7.25-7.80 (m, SH, C6Hs), 7.22 (d. J=9.3 Hz, IH, 8-ArH), 7.04 (d, J=2.8 Hz, lH, 5-ArH), 6.91 (dd, J=9.3, 2 rIz, lH, 7-ArH), 5.12 (s, 2H, OCH~Ar), 3.83-4.40 (m, 4H, CH2 ester, 3-H's), 3.03, 2.86 (d, J=17.2 Hz, 2H, CH7CO2C2Hs), 2.60-2.87 (m, 2H.
4-H's), 1.82-2.20 (m, 2H, 1-CH2(a)), 1.25 (t, J=7.0 Hz, 3H, CH3 ester), 1.00-1.50 (m, 2H, I-CH2(~)), 0.86 (t, J=7.0 Hz, 3H, 1-CH3).

2 0 ~

B . E~h~vl- I -propvl- I .3.4.9-~etrahvd~h~rdroxvpvrano~3~4-~lindole- 1 -acet~t~A suspension of the 6-benzyloxypyranoindole (5.4 g, 13.25 mmol) of Stcp A, and 10% PdlC catalyst (600 mg) in ethanol (150 mL) is hydrogenated for 6hours in a Parr shaker. Filtration of the catalys~ and evaporation of the solvent affords S the itle compound (3.75 g,89%) as a cream-colored foam homogencous by TLC
H NMR (200 MHz, CDC13): o 8.90 (bs, lH, NH), 7.20 (d, J=9.3 Hz, lH, 8-ArH), 6.92 (d, J=2.8 Hz, lH, S-ArH), 6.75 (dd, J=9.3, 2.8 Hz, lH, 7-ArH), 4.90 (bs, lH, OH), 3.85-4.40 (m, 4H, CH2 ester, 3-H's), 3.02, 2.88 (d, J=17.2Hz, 2H, CH~CO2C2Hs), 2.57-2.88 (m, 2H, 4-H's), 1.82-2.20 (m, 2H, l-CH2(0~)), 1.25 (t, J=7.0 Hz, 3H, CH3 ester), 1.00-1.60 (m, 2H, l-CH2(~)). 0.87 ~t,3=7.0 Hz. 3H, l-CH3).
C. 1.3.4.9-Tetrahvdro l-propvl-6-f2-quinolinvlmethoxv)pvranor3.4-blindole-1-acetic acid A solution of the ~hydroxypyranoindde (3.5 g, 11 mmol) of Stcp L, 15 in dimethylsulfoxide (80 mL) is treated with 2.5N NaOH (20 mL, 50 mmol) ant sti~ed at 40-C under nitrogen for 5 minutes. 2-Chloromethylquinoline hydrochloride (4.71 g,22 mmol) is added as a solid in one aliquo~ and the reaction m~xture hcated to 80-C for 30 minutes. After cooling, the pH of the reacdon is adjusted to 12.0 with 2.5N NaOH. After extracion with ether (3 x 250 mL), the aqueous layer is carefully acidified to pH 3.0 with 2N HCI and 0.1N HCI (near end point) followed by rapid extracdon with ether (4 x 300 mL). The combinecl ether ex~acts are washed with water (2 x 200 mL), dried (MgSO4), and filtered. Evaporaion of ;he solvent affords a crude yellow foam (4.16 g, 88%). Purification by flash column chromatography (methanol:methylene chloride, 5:95 eluent) on silica gel (100:1 ratio, 230-400 mesh) affords an amber foam (2.08 g, 61%3 homogeneous by TLC. A concentrated methylene chloride solution of the foam is added dropwise to cooled, rapidly stirred, petroleum ether (200 mL). Filtraion of the resulting precipitate yields the title com-pound as a crcam colored amorphous solid (3.2 g, 61%) homogeneous by TLC. After high vacuum dTying (36 hours) the compound still retains solvent of crystallizaion as indicated by NMR, m.p. 100-110'C (dec.).
IR (KBr~: 3400 ~N~, C)H3, 1710 (C=03 cm-l.

2~0042 H NMR ~400 MHz, CDC13): ~ 8.93 (s, lH, NH), 8.26 (d, J=8.5 Hz, lH, 4-Q), 8.19 (d, J=8.6 Hz, lH, 8-Q), 7.85 (d, J=8.2 Hz, lH, 5-Q), 7.81 (d, J=8.5 Hz, lH, 3-Q), 7.76 (dt, J=7.0, 1.2 Hz, lH, 7-Q), 7.58 (t, J=7.0 Hz, lH, 6-Q), 7.07 (d, J=2.4Hz, lH, 5-ArH), 6.97 (d, J=8.8 Hz, lH, 8-ArH), 6.84 (d, J=8.8, 2.4 Hz, lH, 7-ArH), 5.49 (s, 2H, OS~2Q). 4.03 (ddd, J=11.4, 4.7, 4.3Hz, lH, 3-Hcq.), 3.92 (ddd, J=11.4, 7.2, 4.8Hz, lH, 3--Hax), 3.05 (d, J=16.8 Hz, lH, 4-Hax~, 2.156 (ddd, J=15.4, 4.7, 4.7 Hz, lH, 4-Heq.~, 1.91-2.14 (m, 2H, l-CH2(~)), 1.08-1.48 (m, 2H, l-cH2(~
0.88 (t, J=7.0 Hz, 3H, l-CH3).
10 MS (EI); rn/c 430 (1.4, M+), 160 (50, QCH~OH2~), 143 (100, QCH393).
Analvsis for: C26H26N2o4 Calc!llàted: C, 72.54: H, 6.09; N, 6.51.
FoQnd: C, 72.64; H, 7.52; N, 5.41.
Example 13 1-Ethyl-1,3,4,9-tetrahydro-6-(2-quinolinylmethoxy)-~vranor3.4-hlindo!e-1-aSetic acid. ~hyl ester Trimc~hylsilyldiazomethane (40mL, 10% by weight methylcne chloride) is addcd dropwise ~o a mixturc consisting of l-ethyl-1,3,4,9-~etrahydm-(2-quinolinylmcrhoxy)pyrano[3,4-b]indole-1-acetic acid (1.0 g, Q002 mol) as prcparcd 20 in Example 9, methylene chloride (150 mL) and methanol (15 mL). The reaction rnmure is stirrcd a~ room temperaturc for 1/2 hour, at~d is concent~ated to gi~e 1.2 g of oily residue, which is very difficul~ ~o crystallize. The ester is converted to the hydrochloride salt by adding ctherlHCI. Thc hydr~chloride salt is recrystallized f~m rnc~noUed~cr ~o afford 0.75 g pure compound. m.p. 185-187-C
IH NMR (400MHz, DMSO-d6): ~ 8.71 (d, J=8.2Hz, lH, 4Q), 8.21 (d, J=8.2Hz, IH, 8Q), 8.13 (d, J=8.2Hz lH, 5Q), 7.93-7.89 (m, 2H, 3Q, 7Q), 7.76 (t, J=7.8 Hz, oQ), 7.23 (d, J=8.6 Hz, lH Ar), 7.10 (d, J=2.6 Hz, lH Ar), 6.86 (dd, J~=8.6, J2=2.3, lH Ar.), 5.5 (s, 2H, OcH2-q)~ 3-91 (m~
2H), 3.51 (s, 311, COO~3), 2.91 (d, J=13.7 Hz, lH), 2.74 ~d, J-13.5 Hz, lH), 2.56 (m, 2H), 1.93 (q, J--7.4 Hz, 2H), 0.60 (t, - .2 Hz, 3H, CH~CH3).
IR (KBr) 3400 cm-l, 3200 cm-l (NH, OH), 1740 cm-l (C~).
Mass: EI (rn/e) Mf 430, ions 401, 357.

20~00~2 Analvsis for: C26H26N204-HCI
Calculated: C, 66.88; H, 5.83; N, 6.00.
Found: C, 66.58; H, 5.7S; N, 5.96.
Example 14 1,3,4,9-Tetrahydro-l,l.dimethyl-6-(2-quinolinyl-~ methoxr)~vr~nQ[3,4-blindole A. 1~3~4~9-Tetrahyd~l~l-dimethv~ henvlmcthoxv~vranof3~4-blindole A mixture consisting of 5-benzyloxytryptophol (3.2 g, 0.012 mol), acetone (7 mL), benzene (300 mL) and E-toluene sulfonic acid (500 mg) is refluxed for 3.5 hours using a Dean-Stark trap to remove the water. The reaction mixture is cooled to room temperature and washed with 5% sodium bicarbonate (1 x 200 mL), water (200 mL) and brine (200 mL). It is dried (MgS04~, filtered and concentra~ed to giv~ 5.0 g product as thiclc oil. The erude product is flash ehromatographed with 15%
ethyl acetatelhexane as an eluen~ to afford 2.5 g product, m p. 128-129-C.
lS B. 1.3.49-Tetrahvdro 1.!~imethvl-~hvdroxv-pvranor3.4-blindole A mixture eonsisting of 10% Pd/e on chareoal (0.7 g), çthanol (150 mL) and 1,3,4,9-tetrahydro-1,1-dimethyl-6-(phenylmethoxy)pyranol3.4-b~indole (4.2 g, 0.014 mol) of Step A, is hydrogenated at 30 psi for 18 hours. The reaction rnLxture is filtered and concentrated to give 3.5 g product which is used in the next reaction without further purification.
C. 1.3.4.9-Tet~hvdro l.i-dimethvl-6-(2~uinolinvlmethoxv~pvranor3.4-blindole A mixture consisting of the 6-hydroxy compound (3.5 g, 0.016 mol) of Step B, dimethylformamide (100 mL), potassium carbonate, anhydrous (6.0 g, 0.043 mol), potassium iodide (100 mg) and 2-chloromethylquinoline (2.9 g, 2S 0.016 mol) is heated at 60 C for 24 hours. The reaction mixturc is cooled to room temperature, diluted with water (600 mL), and extracted with ethyl acetate (3 x 150 mL). The combined organic layers are washed with 2.5N NaOH, water ~2 x 100 mL), once with brine (100 mL), dried (MgS04), filtered and concentratedto give 3.8 g of crude product. The crude product is flash chromatographed on silica gel using 40% ethyl acetatelhexane as an eluent to afford 2.3 g of product which is recrystallized from methanol to afford 1.69 g pure title compound, m.p. 1~165-C.lH NMR (400 MHz, DMSO-d6): o 10.68 (s, lH, NH), 8.38 (d, J=8.6 Hz. lH, 4Q), 8.0 (d, J=8.4Hz, lH, 8Q); 7.97 (d, J=8.1 Hz, lH, 5Q), 7.77 (t.

20~00~2 J=7.1 Hz, lH, 7Q), 7.69 (d, J=8.6Hz, lH, 3Q), 7.59 (t, J=7.1 Hz, lH, 6Q), 7.18 (d, J=8.7Hz, lH Ar), 7.04 (d, J=2.4Hz, lH Ar), 6.82 (dd, Jl=8.6, J2=2.4 Hz, lH Ar), 5.34 (s, 2H, OCH~Q), 3.85 (~, J=5.3 Hz, 2H), 2.56 (t, J=5.3 Hz, 2H), 1.44 (s, 6H, (~3)2)-S IR (KBr): 3410 cm- (broad NH).
Mass: EI: mJe: 358 (M+), 343 143.
Analvsi~ for: C23~l22N2o2 Calet~ated: C, 77.07; H, 6.19; N, 7.81.
Found: C, 76.76; H, 6.25; N, 7.70.
Example 15 1,3,4,9-Tetrahydro-l,l.diethyi-6-(2-quinolinyl-, m e ~ h ox v ~ r v ra n n r 3 . 4 - h l i n d o l ~ , A. I.3.4.9-Tetrahvdro I.1~iethvl-~(phenvlmethoxv)pvranor3.4-blindole A mixture consisting of 5-benzyloxytryptopho~ (7.0 g, 0.0262 mol), diethyl ketone (10 mL), benzene (400 mL) and p-toluene sulfonic acid is refluxed for 3.5 hours using a Dean-Stark tap to remove the water. The reaedon mixture is eoolcd to room temperature, washed with 5% sodium biearbonate, water (200 mL), b~ine (200 mL), dried (MgSO4), filtered and eoncentrated to give 9.9 g of erude produeL
The erude produe~ is flash chromatographed on silica gel using 15% ethyl aeetate/hexane as an eluent to afford 6.5 g of pure itle compound.
B. I.3.4.9-Tetrahvdro l~l-diethvl-~(hvdroxv)~or3.4-blindo]e A mixture consisting of 10% PdJe on chareoal (1.0 g), ethanol (125 mL), and 1,3,4,9-tetrahydro 1,1-diethyl-~(phenylmethoxy)pyrano[3,4-b]indole(65 g, 0.0193 mol), of Step A, is hydrogenated at 30 psi for 18 hours. The reaction tr~L~tture is filtered and coneentrated to give 5.2 g of product which is used in the next reaction ;withoutfurtherpurification.
' C. ' 1.3.4.9-TetrahvdT~I.I-diethvl-6-(2~uinolinvlmethoxv)t~yranor3.4-blln~ole A mixture eonsisting of the 6-hydroxy eompound (5.2 g, 0.0212 mol) of Step B, dimethyl sulfoxide (150TTIL), sodium hydroxide (6.0 g, 0.15 mol in 20mL water), and 2-chloromethylquinoline hydrochloride (6.0 g, 0.028 mol) is heated to 70-80 C for 6 hours. The reaetion rnixn~re is cooled to room temperature, diluted with water (800 mL), and extraeted with ethyl aeetate (3 x 150 mL). The eombined organic layers are washed once with water (2 x 150 rnL), once with brine 20~0~2 (100 mL~, dried (MgSO4), fillered and concentrated to give 9.9 crude product. The crude product is flash chromatographed on silica gel using 25% ethyl acetate/hexane as an eiuent to afford 4.5 g pure product as a thicl~ oil. The oil is dissolved in ether (lS0 mL) and etherJHCI is added dropwise. The precipiute is filtered off and the5 product crystallized from methanoVether to give 2.6 g product as a yellow crystalline solid, m.p. 164-166'C.
IH NMR (400 MHz, DMSO-d6): o 10.64 f~s, lH, NH), 8.70 (d, J=8.6 Hz, lH, 4Q), 8.21 (d, J=8.5 Hz, lH, 8Q), 8.13 (d, J=8.1 Hz, lH, 5Q), 7.95-7.88 (m, 2H, 3 and 7 Q), 7.74 (t, J--7.3 Hz, lH, 6Q), 7.21 (d, J=8.6 Hz, lH Ar), _ 10 7.08 (d, J=2.4 Hz, lH Ar?~ 6.84 (dd. Jl=8.7, J2=2.4 Hz, lH Ar.), 5.50 (s, 2H, OCH?Q), 3.85 ~t, J=5.3 Hz, 2H), 2.57 (t, 3=5.4 Hz, 2H), 1.80 (m, 4H, CH~CH3 l,1-dicthyl), 0.71 (t, J=7.3 Hz, 6H, CH~CH~, 1,1-diethyl).
IR: fKBr) 3410 cm~~ (NH).
Mass: El: l~/e: 386 (M+) ions 357, 216, 142, 128.
15 Analvsis for: C2sH2~N2O2-HCI
Càlcula~d: C, 70.99; H, 6.43; N, 6.62 - EQIlng: C, 71.20; H, 6.43; N, 6.66.
.: . .
Example 16 l-t(4-Chlorophen~l)methyl]-2-methyl-5 (2-quinolinylmethoxy)-lH-indole-3-acetic acid _ h~rdroehlQride ~t~arter hvdrate A. 2-Me~hvl-5-f2-quinolinvlmethoxv~-lH-indole-3-acetic acid. one lenth hvdrate To a previously degassed mixture of dimethylfoImarnide (70 rnL) and sodium methoxidelmcthanol solution (25 wt %, 2 equivalents, 8.8 mL) is added 5-hydroxy-2-methyl-lH-indole-3-acetic acid (4.0 g, 19.5 mmol) at room temperature.
After 15 minutes 2-chloromethylquinoline (3.46 g, 19.5 mmol~ is added and the mixturc stirred overnigh~. The dimethylfolmamide is evaporated and the mixture parti-tioned between pH 4 buffer solution and ethyl acetate. The organic phase is dried (MgSO4), filtered and par~ially concentrated. A solid is filtered off and crystallized , ~ using ethanol - water. This gives the tit~e compound as a solid (2.96 g), 44% yield, 3n m.p. 208-210-C.
Analvsis f~r: C2lHl8N2o3 0.1 H2O
Calculated: C, 72.44; H. 5.26; N, 8.04.
Found: C, 72.29; H, 5.38; N, 7.93.

20~0~

.
B. 2-Melhvl-S-(~quinolinvlmethQxv!-l~-indole-3-acetic acid methvl ester.
To a sdrring mixture of the indole-acctic acid substrate (1.2 g, : - 3.4 mmol) in tetrahydrofuran (25 mL) is added slowly, a freshly prepared- diazomethane/dicthyl ether solution at ambicnt temperature. Upon consumpion of S starting matcrial, a few drops of acetic acid are added. Thc solvent is evaporated and mcthylene chloride is added. This organic phase is washed with water and dried (MgSO4). SolveM removal giYes the p~duct as an oil (1.2 g). Yield is quantitadve.
c. . I-r(4 Chlor~2hs~y!~methvll-2-methv!-s-!2~uinolinvlmçthoxv)-lH-indole-3 aceic acid methvl ester To a sirring rnixture of thc indole-ester substrate (0.8 g, 2.2 mmol) in dimethylformamide (15 mL) is added sodium hydride (0.058 g, 2.4 mrnol). The reactdon is stirred for 30 minutes at ambient temperature. 4-Chloro-benzylchloridc (0.35 g, 2.2 mrnol) is then addcd. Aftçr 2 hours the dimethylformamide is evaporated a~d the residue partitioned using pH 4 buffer solution and cthyl acetate. The orgas~ic 15 phase is separated, dried (MgSO4) and filtercd. Soivent removal produces a solid that is flash chromatogr~phed using chloroform as eluent, then c~ystallized with acetonitrile ~o yield the product as a crystalline solid (0.162 g 16% yield) m.p. 132-134 C.
Ana!vsis fQr: C2gH2sN2O3CI
Calculated: C, 71.82: H, 5.20; N, 5.78.
20 Found: C, 71.48; H, 5.17; N, 5.88.
.. ; . - .. . .
D. l-r(4-ChloroDhenvl)methvll~-methv!-5-(2~uinolinvlmethoxy~-lH-indole-~:
aceic acid hvdrochlondeQuarter hy~ate The above ester (2.2 g, 4.5 rnmol) is combined with tetrahydrofuran (50rnL), 1N NaOH solution (50 mL) and heated to reflux (3.5 hours). The tetra-25 hydrofuran is removed in vacuo and thc aqueous phase acidified with lN HCI. Acrude solid is filtered and recrystallized using ethanol to~producè 1.16 g of product as the hydrochloride salt (50% yield), m.p. 249-251-C.
- Anaivsis for: C2gH23ClN2O3 HCL 1l4 H20 Calculated: C, 65.69; H, 4.82; N, 5.47.
~: C, 65.64; H, 4.92; N, 5 2 ~

Example 17 1-(4-Chlorobenzoyl)-2-methyl-5-( -quinolinylmethoxy)~
indo!e-3-acetic acid three ~uarter,~ ~aL~
A. I-*Chlo~benzovl~-2-methvl-5-(2~uinolinvlmethoxv~-lH-indole-~-acetic acid methvl cster one tenth hvdrate To a solution of 2-methyl-5-(2-quinolinylmethoxy)-lH-indole-3-acetic acid methylester (0.95 g, 2.6 mmol) (sec Example 16B~ in dimethylfozmamide (10 rnL) at O-C is added sodium hydride (0.12 g, 50% dispersion) and the mix~e sirred 20 rninutes. ~Chlorooenzoyl chloride (0.45 g, 2.6 mmol) is then added andthe mixture stirred overnight; 100 rnL of 5% acetic acid is used to quench the reac~ion.
After extraclion with a 1:1 rnixture of ether ethyl aceute, the organic phase is washed with water, saturatcd NaHCO3 solution, water and brine. It is then separated and dricd (MgSO4). Solvent removal gives a crude solid which is flash chromatographed using methylene chloride methanol (99-1) as eluenL The product is isolated and crystallized from acctonitrile (0.20 g, m.p. 117-118-C), yicld is 15%.
Analvsi~ for: C2gH23ClN2O4 0.1 H20 Calculaîed: C, 69.55; H, 4.66; N, 5.59.
Found: C, 69.35; H, 4.48; N, 5.56.
B. 1-(4-Chl0~bcnzovl2-2-methvl-5-!2~uinolinv!methoxv)-lH-indole-3-acelic acid threc auarters hvdrate To a mixmre of the above cstcr (0.5 g, 1.0 mmol) in acctonitrilc (20 mL) is added iodotrimethyl silane (0.46 g, 2 2 mmol). A~ter refluxing for 24hours the rnixture is diluted with ethyl acctate then washed with 10% Na2S203 solu-don, water and 15% NaHCO3 solution. A prccipitate forms which is filtered off, washed with IN HCI and dried in vacuo to give the dtle compound as a solid (0.05 g, 10% yield), m.p. 191-193-C.
Analvsis for: C2gH21ClN2O4 . 0.7S H2O
Calculated: C, 67.47; H, 4.55; N, 5.62.
Found: C, 67.68; H, 4.22; N, 5.94.

2~9~0~2 so -Example 18 2.Methyl 5-(2-quinolinylmethoxy)-1,2-(quinolinyl-lnet~ic ~i~L
To a stirred suspension of sodium hydride (1.4 g, 29.2 mmol) in 5 dimethylformamide (40 mL~ at O C is added S-hydrmy-2-methyl-lH-irldole-3-acetic acid (2.0 g,~ 9.76 mmol). After 1 hour 2-chloromethylquinoline (3.44 g, 19.48 mmol) is added and the reaction mixture is allowed to warm to room tempesa-ture. After stming over~ight water is added and the pH was adjusted to 5 with O.SN
HCl. The reaction mixture is extracted with methylene chlo~ide, the organic ex~act is 10 dned over MgS04 and cYaporated to a solid which upon sequential ~ituration with ethanol and hot cthanol affords 2.5 g (52% ) of a beige solid, m.p. 198-200-C.
Analvsis for: C31H2sN3O3 Calculated: C, 76.37; H, 5.17; N, 8.62.
FoundC, 76.72; H, 5.24; N, 8.74.
Example 19 1 -[(4-Chlorophenyl)methyl]-5-(he~yloxy). ,, 2-methY!-lH-indole-3-acetic acid A. 5-(Hexvloxv)-2-methvl-lH-indole-3-ace~ic acid To a solution of 5-hydroxy-2-methyl-lH-indole-3-acetic acid (7.17 g, 35.0 mmol) in methanol (40 mL) is added sodium methoxide (70 mmol). The solu-tion is cvapora~ed, dimethylformamide (40 mL) is added followed by hexyl iodide (35.0 mmol). After 2 days the solvent is rem~vcd and the residue is partitioncd between ethyl acetate and pH=4 buffer. Thc organic layer is separated, dried over MgSO4 and evaporated to 8.6 g of a brown solid. Recrystallization from ethanoVwater affords 6.23 g (62%) of white crystals, m.p. 65-67 C.
Analvsis for C17H23NO3 Calculated: C, 70.S6; H, 8.01; N, 4.84.
~: C, 70.52; H, 7.98; N, 4.83.
B. I-~(~-Chlon~ethvll-S-(hexvloxv)-2-methvl-1H-indole-3-acçtic acid The acid from part A is converted lo the methyl ester (mp. 148-150-C) via diazomethane (see Example 16B). To a solution of the ester (4.S g, 14.83 mmol) in dimethylformamide (40 mL) is added sodium hydride (1.42 g, 29.6 mmol). After 30 minutes 4-chlorobenzylchloride (2.38 g, 14.83 mmol) is added. After stirring 209~0~

ovemight, the solvent is removed and the residue is panitioned between ethyl acetate and pH~ buffer. The organic layer is separated, dried over MgSO4 and evaporated to a red solid. Sequendal recrystallization from ether and isopropanol gives 2.2 g of crystals (36%), m.p. 148-lSO-C.
5 Analvsis for: C24H2gClNO3 Calculated: C, 69.64; H, 6.82; N, 3.38.
Found:C, 70.00; H, 6.71; N, 3.46.
Example 20 2-Methyl-~-(2-quinolinylmethoxy).1-(2-quinolinyl-methxl)-lH-indQI~ ~-carhoxxlic acid ~thYl ester Under an atmospherc of nitrogcn, a mixture of elhyl-5-hydroxy-2-methyl-3-indolyl carboxylate (3.5 g, 16 rnmol), finely powdered anhydrous potassium carbonate (2.2 g, 16 mmol) and 18-crown-6 (0.48 g, 1.8 mmol) in dry acetonirrile (S0 mL) is sirred at room temperature for 0.5 hours. In one portion2-chloromethylquinoline (free base, 2.85 g, 16 mmol) is added and the mixture isstirred a~ 55-C overnight. The reac~ion (found to be complete by TLC analysis) is filtered hot.
The filtrate affords the desired product (0.75 g, 9%) as a tan solid, m.p. 162-163-C. RecTystallization from ethyl acetate ~ives pure product (0.42 g, m p.
20 162-163-C).
Analvsis for: C32H27N3O3 Calculated: C, 76.63; H, 5.43; N, 8.3.
Found:C, 76.20; H, 5.59; N, 8.11.
Example 21 c~-Methyl-6-(2-quinolinylmethoxy).9.(2.quinolinyl-meth~ ~H-carbaz~le-2-acetic acid A. 4-Benzvloxvphenvlhvdrazine hvdrochloride A solution of sodium nitrite ~3.8 g, 0.055 mol in 20 mL of H2O), is added dropwise lo an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g,30 O.OSS mol in 150 mL of concentrated HCI). The reaction mixture is stirred for 90 minutes at -8- to lO C. A solution of SnC12 2H2O (32.0 g, 0142 mol in 50 mL
concentrated HCl) is added and stirred for 1 hour at O~C. The reaction mixture is removed from the ice bath and is stirred at room temperatur~ for 20 hours. The mixture 2~9~2 is thcn filtered and washed wi~h water to give 13.0 g (95% yield) of product, m.p.
182-185'C.
B. 6-Benzvloxv-a-m~hY1~1.2.3.4-tetrahvdrocarbazole-2-acetic acid ethvl ester A mixture containing 4-benzyloxyphenylhydrazine hydrochloride (37.0 g, 0.148 mol), a-methyl-3-oxocyclohexane acetic acid (40.0 g, 0.235 mol), glacial acetic acid (650 mL) and H20 (100 mL) is stirred at rwm temperature under a nitt~gen atrnosphere for 2.5 hours. The mixture is then refluxed for 20 minutes,cooled and poured into 200 rnL of ice/H20. The precipitate is filtered to give 80 g of r~d colored crude product.
The crude product is dissolved in ether (600 rnL) conccntrated H2S04 (5 mL) is added and the tnixture refluxed for 24 homs. I he Teac~on rnixture is cooled, concentrated and dilutcd with ether (100mL), then washed with lN NaOH
(2x 200mL), water (2 x 200 ml.) and finally once with brine (200 rnL), dried over anhyd~ous MgSO4, filtered and concentrated to give 40.0 g crude product as a thiclc oil.
C. ~BenzvloxY-a-methvl carbazole-2-acetic acid ethvl e~
- A mixture consisting of 6-benzyloxy-a-methyl-1,2,3,4-tetrahydro-carbazole-2-acetic acid elhyl ester (15.0 g, 0.0398 mol) xylene (500rnL), and chloranil (10.0 g. 0.0408 mol) is refluxed in the dark under a nitrogen atmosphere for 24 hours. Thc reaction mixture is concentrated to 200 rnL and the precipi~ate isremoved by filtrauon. 17 c precipitate is triturated with benzene (3 x 100 rnL), the solvent fractions are combined and washed with lN NaOH (3 x 150 rnL), washed with water until neutral ~o pH paper, dried over ~gSO4, filtered and concentrated to give 15.8 crude product. The crude product is flash chrornatographed on silica gel using 15% ethyl acetate/hexanc as an eluent to give 7.5 g product as a thick oil.
D. ~Hvdroxv-a-methvl ca~azole-2-acetic acid elhvl estcr - A mixture consisting of ~benyloxy-ac-methyl carbazole-2-acetic acid ethyl ester (7.3 g, 0.0195 mol) and ethanol (130 mL) is subjected to hydrogenation over 10% PdJc (0.9 g) for 18 hours at 35 psi. The reaction mixture is filtered and concentrated to give 5.0 g product as a foam.
E. ~Hvdroxv-~-methvl carbazole-2-acetic acid A rnixture consisting of o-hydroxy-cL-methyl carbazole-2-acetic acid ethyl ester (5.0 g. 0.021 mol), potassium hydroxide (5.0 g, 0.089 mol), methanol -20~0n42 (300 mL), and water (20 mL) is refluxed for 15 hours. Thc reacdon mixture is cooled concentrated and acidified with a 1: 1 solution of conccntrated HCI and water to pH 1.
The aqueous layer is extracted with ether (4 x 300 mL), washed with water (200 mL), brine (200 mL), dried over MgSO4, filtered and conccntrated to give 2.6 g 5 of product as a foar~
F. a-Me~hvl-~(2-qlainolinvlmethQxv~9-(2-quinolinvlmethvl)-9H-carbazole-2-acetic acid - A mixture consisting of 6-hydroxy-a-methyl carbazole-2-acctic acid (2.6g, 0.010mol), dimethyl sulfoxide (200mL), sodium hydroxide (2.0g in 10 20 mL H20, 0.05 mol) and 2-chloromethylquinoline-HCI (4.0 g, 0.018 mol) is heated to 80-C for 3 hours. The reacsion mixture is cooled, poured into watcr (1000 mL), and the pH is adjusted to 4 with lN HCI. The aqueous solution is extracted with ethyl acetate (4 x 300 mL) and the organic layers are combined, washed with water ~2 x 300 mL), oncc with brinc (300 rnL~, dried over MgSO4, filtered and 15 concentrated to givc 3.0 g of crude product. The latter is chrornatographed on silica gel using 10% methanoVmethylene chloride as an eluent to give 8 g of product, m p.
197-l99-C.
~iL~: C35H27N303 Calculated: C, 78.19; H, 5.06; N, 7.82.
~: C, 76.01; H, 5.02; N, 7.36.
Example 22 1.[(4.Chlorophenyl)methyll-2.methyl-N.(me~hyl).N.(hydroxy)-5-(2-inolinvimethn~v~-UI-irldol~-acetanude three g~larter~ h~drate To a soludon of the acid of Example 16 (0.2 g, 0.42mmol), N-methyl-25 hydroxylatnine hydrochloride (0.035 g, 0.42mrnol) and benwtriazolc-l-yloxy~is(di-methylamino)phosphonium hexafluorophosphate (0.188g, 0.42mmol) in methylenc chloride (5 mL) is added triethylarnine (0.12mL, 2 equiv). The reaction mixture is sdrrcd overnight and then is quenched by addition of brine. After sequendal washcs with water,0.5N HCI and water, the organic layer is dried over MgS04 and evaporated 30 to afford a crude solid, which upon chloroforrn recrystallization(twice) affords a crystalline solid, m.p. 192-194C. This rnaterial is washed sequentially with 0.5N
NaOH and water and dried to afford white crystals, m.p. 191-193C.

29~0~

Analvsis for: C2gH26ClN3O3 3/4 H20 Calculated: C, 67.83; H, 5.39; N, 8.18.
~: C, 67.87; H, 5.10; N, 8.39.
Example 23 S1-[(4-Chlorophenyl)methyl]-2-rnethyl-N-(phenylsulfonyl)-~-12-quinolinqlmethoxv~-1~-indo!e-~-acetamide To a solution of the acid of Example 16 (1.0g, 2.12mmol), benzenc-sulfonamidc (0.34g, 2.12mmol) and benzotriazole-1-yloxytris(dimcthylamino)-phosphonium hexafluorophosphate (0.94g, 2.12mrnol) in methylene chloride(2S mL) 10 is added triethylamine (0.6mL. 2 equiv). The DtiOn mL~cture is stu~ed overnight and then is quc~ched by addition of brine. After sequen~ial washes with water, 0.5N HCI
and water, the organic layer is dried ovcr MgS04 and evaporated to afford a crude solid, which upon tolucne recrystallization affords a crystalline solid, m.p. 194-197C.
15 Ana!vsis fa: C34H2gClN3O4S
- Calculated: C, 66.93; H. 4.63; N. 6.89.
EQ~: C, 67.01; H, 4.66; N, 7.33.
Example 24 1-1(4-Fluorophenyl)methyl].2.methyl i.(2.quinolinyl-methox~-lH-indoJe-3-acetic acid hemihYdrate The title compound is prepared accc~rding to the me~hod of Example 16 using 4-fluorobenzyl bromide. A crystalline solid is obtained. m.p. 199-202C.
Analvsis for: C28H231;N2O3 ln H20 Calculated: C, 72.55; H, 5.21; N, 6.04.
25 ~: C, 72 84: H, 5.31; N, 5.68.
Example 25 1-[~4-Bromophenyl)methyll-2-methyl.5.(2.quinolinyl-methoxY)-1~1-indole-3-acetic acid hemihYdra~
The title compound is prepared according lo the method of Example 16 30using 4-bromobenzyl bromide. A crystallinè solid is obtained. m.p. 215-217C.

2~0~2 Analvsis for: C28H23BrN2O3 1/2 H20 Çalçulated: C, 64.12; H, 4.61; N, 5.34.
Found: C, 64.40; H, 4.76; N, 5.01.
Example 26 S l-~(Phenyl)methyl 2 methjl]-5-(2-quinolinyl-J~SthQ~Y~ -indo!~-3-aceti~ acid ten~h h~vdrate The tide compound is prepared according to the method of Example 16 using benzyl brotnide. A crystalline solid is obtained, m.p. 199-202C.
Analvsisfor: C28H24N2O3 0.1 H2O
Calcula~ed: C, 76.72; H, 5.56; N, 6.39.
Found: C, 76.30; H, 5.37; N, 6.34.
Example 27 1-[(4-Carboxyphenyl)methyl]-2-methyl-5-(2-al~inolinYlrnethox-v)-l~-indQle-~-acetic aci~l lS The titlc compound is prepared according to the method of Example 16 using ~(chloromelhyl)benzoic acid. A crystalline solid is obtained, m.p. 232-234C.
Analvsis for C2sH24N2os Calculated: C, 72.49; H, 5.03; N, 5.83.
Found: C, 72.44: H, 5.18; N, 5.98.
Example 28 2-Methyl-5-(2-quinolinylmethoxy)-1-~[4.(2-quinolinylmethoxy)-DhenvllmethYIl-lH-indole-3-acetic acid hemihv~ra~
The itle compound is prepared according to the method of Example 16 using 4-(2-quinolinylmethoxy)benzyl chloride. A crystalline solid is oblained. rn p.
25 182-185C.
Analvsis for: C3gH3lN3O4 1/2 H20 Ca~culated: C, 75.73; H, 5.35; N, 6.97.
Found: C, 75.41; H, 5~33; N, 6.78.

20~q~ :

I' Example 29 2-Methyl-l-pentyl-5-(2-quinolinylmethoxy)-Tlse tide compound is prepa~ed acco~iing to thc method of ~xample 16 S using pentyl iodide. A crystalline solid is obtained, m.p. ~93C.
Analvsis for: ,_C26H2gN203 ln H20 C~alculated: C; 73.38, H, 6.86;'N, 6.58.
Found: , C, 73.37; H, 7.11; N, 6.41.
Example 30 l-Hexyl-2-methyl-5-(2-quinoli , Imethoxy)-lH-rterc, Il~drate The ti~lc compound is prepared according to the method of Example 16 using hexyl iodide. A crystallinc solid is obtained, m.p. 122-124C.
~. , C27E~30N203 314 H20 Ça~ C, 73.03; H, 7.15; N, 6.30.
~21m~: C, 73.25; H, 7.10; N, 6.30.
Example 31 , '' l.Heptyl-2.methyl 5-(2 quinoliDyl The title compound is prcpared accorcling to the method of Ex~nple 16 usi~g hepyl iodide. A crystalline solid is obtained, m.p. 127-131C.
Analvs~s for: C28H32N2o3 Calculat,ed: C, 75.65; H, 7.26; N, 6.30.
Found: C, 75.80; H, 7.19; N, 6.26.
~5 Example 32 l-Methyl-2-methyl-S~(2-quinolinyl-methoxy)- ! Il~
Thc title compound is prepared according to the method of Exarnple 16 using methyl iodide. A crystalline solid is obtained, m.p. 18~188C.

203~04~

Analvsis for: C22H2oN2o3 Calcul~C, 73.32; H, 5.59; N, 7.77.
Found:C, 73.03; H, 5.69; N, 7.57.
Example 33 1-[(4-Chlorophenyl)methyl]~5-(2-quinolinyl-methoYv).lH.indole.3.acetic acid Thc sitle compound is prcpaF~d according to the method of E~tamplc 16 using 5-hydroxy-lH-indolc-3-ace~c acid. The desired product is obuincd as white crystals, m.p. 158-159C.
10 Analvsis for: C27H2lclN2o3 Calculatcd: C, 70.97; H, 4.63; N, 6.13.
5i:C, 71.13, H, 4.67; N, 6.03.
Example 34 1 [(4 Chlorophenyl)methyll 2-methyl-5-t2-naphthalenyl methoxY~-lH-;ndo!e-3.aceti~ acid Thc title compound is p~epa~d according to the method of Examplc 16 using 2-(b~momcthyl)n~phthalene. A crystalline solid is obtained, mLp. 168-170C.
Anal~vsis for: C2gH24ClNO3 Calculate~: C, 74.12; H, 5.15; N, 2.98.
Found:C, 74.43; H, 5.31; N, 2.74.
Example 35 1 -[(4-Chlorophenyl)methyl]-2-methyl-5-lnhenl~lmethoxv)-!~-indole-3-acetic acid The titlc compound is prcparcd according to thc method of Example 16 25 using bcnzyl chloride. A crystalline solid is obtained, m.p. 140-142C.
Anal~sis for: C2sH22ClNO3 Calculated: C, 71.51; H, 5.28; N, 3.34.
Found:C, 71.54; H, 5.29; N, 3.47.

2~9~0~

Example 36 1-{(4 Chlorophenyl)methyl].2.methyl.S~(2-n~ridinvlmethQl~yL.la.indole~3-acetic ~cid The ~le compound is prepared according to the method of Example 16 S using 2-(chloromethyl)pyridine. A aystalline solid is obtained, m.p. 231-233C.
Analvsis for: C24H21ClN203 Ca~ lated: C, 68.49; H, 5.03; N, 6.66.
C, 68.61; H, 5.12; N, 6.39.
Example 37 1-[14-Chlorophenyl)methyl]-2-methyl-5-(2-benzo-thia7olYlmetboxv\-l~indole-3-aceti~ ae~
A.= 2-Methyl-5-(2-benzothiazolvlmethoxy)-1H-indole-3-aceic acid ethyl ester To a mixture of S-hydro%y-2-methyl-lH-indole-3-aceie acid ethyl ester (5.6 g, 17.15 mrnol) and cesium carbonate (lS.O g, 46.04 mrmol) in dimethylsulfoxide 15 (7~ mL) that has ~een preYiously stilred for 30 rninutes is added 2-(chloromeshyl)-benzothiazo!e (4.6 g, 25.08 mrnol). After 1 hour the reaction is poured into iee water and extracted with ethyl acetate. Ihe organic layer is washed sequentially with O.lN
NaOH, water and brine, dried over MgS04 and evaporated to a black oil which is purified by flash chromatography (eluant: ethyl acetate-hexane) to afford 5.4g (59%) of 20 the aLtcylated ester.
B . ! -r(4-Chlorophenvl~methvll-2-rnethv!-5-(2-benzothiazolvlmethoxY)- I H-indole-3-aceie,acid The itle compound is prepa~d according ~ the method of Exarnple 16 using 2-methyl-5 (2-benzothiazolylmethoxy)-lH-indole-3-acetic acid ethyl ester and 4-25 chlorobcnzyl chloride; however, the hydrolysis is carried out in aqueous methanol.Recrystallization fTom acetonitrile aff~s white crystals, m.p. 175-176C.
Analvsis for: C26H21CIN203S
Calculated: C, 65.47; H, 4.44; N, 5.87.
Found: C, 65.17; H, 4.61; N, 5.81.

2~90~2 Example 38 1.1(4..Chlorophenyl)methyl].2.methyl-5-[(2-phenyl.
4.thiazol~ thoxv1.1H.indole.3.acetic acid ......
- The tide compound is prepared according to the method of Example 375 using 4-(chloromeshyl)-2-phenyl~hiazole. White clysuls are obtained, m.p. 150- lS1C.
Analysis fo;: C2gH23ClN2O3S
C~cula~ C, 66.86; H, 4.61; N, 5.57.
Found: C. 66.46; H, 4.59; N, 5.59.
Example 39 1-[(4 Chlorophenyl)methyl~-2-methyl-5-[t2-(4-trifluoromethyl-nhen~l)-4-tltia~ lltnethnx~ iole-?s-aceti~ acid The title compound is prepared according to thc method of Examplc 37 using 4-chloromcthyl-1(4-trifluor~mcthyl)-2-phcnyl]thiazole. Whi~e crystals arc 15 obuincd, m.p. 196-197C.
Analvsis for: C29H22CIE:3N2O3S
~alculated: C, 61.00; H, 3.88; N, 4.91.
~: C, 60.95; H, 3.97; N, 4.89.
Example 40 1-[(Phenyl)methyll-2-methyl.~i-[(2-phenyl-4-thiazol~l)methnx~ ndQi~?s-acetic a~id The title compound is prepared according to the me~od of Exarnple 37 using 4-(chloromcthyl)-2-phenylthiazole and benzyl chloride. White crystals are obtained from toluene, m p. 15~151C.
Analvsis for: C2gH24N2O3S
Calcula~ed: C, 71.77; H, 5.16; N, 5.98.
Found: C, 71.53; H, S.ll; N, S.90.

20~00~

oO-Ex~mple 41 2.Methyl-5.(2.quinolinylmethoxy)-1.[14-(2-quinolinyl-methox l~)ohenY!lmethvlenel~ indene-~-acetic asi~l A. ~ 2-Me~hvl-~-f2-auinolinv!me~hoxvilH-indçne-3-acetic acid mcthvl ester 5 . , . ~ , A mixture of 2-methyl-5-hydroxy-lH-indene-3-acetic acid methyl ester (1.8 g, 8.25 mmol), pow~dered anhydrous potassium carQonate (1.13 g, 8.25 mmol) and 18-crown-6 (0.219 g) in acetonitrile (21 mL) is stirred at room semperature for 15 tninutes. 2-(Chlorcmethyl)quinolinc (1.6 g, 9.08 mmol) is then added and the r~uxture is stirred for 15 hours at 65C. Aft~ the solvent is removed, the residue is partitioned betwccn water and ethyl acetatc. Thç organic phasc is dricd ovcr MgS04 and evaporatcd. The crude product is purificd by flash chromatography ~eluant: methylene chlande-ethyl acetate) to afford 2.35 g (79%) of the desired product.
. .
B. 2-Methvl-5-(2-quinolinvlmethox~v~ rr4-(2~uinolinvlmethox~r)phenyll Tnethylenel-lH~ ene-3-acetic acid - To a soludon of the above ester (1.77 g, 4.93 mmol) in anhydrous methanol (20 mL) i5 added 4-1(2-quinolinyl)methoxy]benzaldehyde (1.63 g., 6.19 mntol) followcd by dropwisc addition of 25% methanolic sodium methoxide(3.46 mL).
- Aftcr the reaction mixturc is refluxed for 13 hours, the solvcnt is rcmoved and water is addcd. The pH is adjusted to 6.5 and the resulting prccipitate is cxtracted sequentially with methylene chloride and ethyl acetate. The combined extracts are dried over MgS04 and cvaporaled to a crude solid which is triturated with diethyl ether and then redissolvcd in ho~ ethyl acetate. After the insolubles are filtered off, the solution is concemrated until precipttation occurs. The prccipi~ate is fil~ered, washed dielhyl e~ter and hexanc and driëd to afford 1.31 g(45%) of the desired product as a Z/E mtxture (7.6/1), m.p. 191-193C(dec.).
~nabvsis for: C3gH30N204 Calcula~: C, 79.30; H, 5.12; N, 4.74.
Found: C, 79.11; H, 5.05; N, 4.59.

- 20~0~3~

Example 42 N-[[1-[(4-Chlorophenyl)methyl]-2-methyl-5-~2-quinolinyl-rnethoxy~-lH-indok3-v!lmethvll-N'-h~lro~yurea To a soludon of the aeid of Example 16 (0.72 g, 1.52 mmol), in 5 bènzene (25 mL) is added triethylamine (0.23 mL, 1.1 equiv) followed by diphenyl-phosphoryl azide (0.46 g, 1.1 equiv). After the reaetion mixture is heated at 90~C for 1 hour, a solution of hydroxylarnine hydroehloride (0.23 g, 2.2 equiv.) in a mLxture of triethylamine (0.46 mL) and water (0.25 mL) is added to it, and the reae~ion mixture is heated at 90C overnight. The reaetion is quenehed by addition of ammonium chloride 10 solution, and the resulting precipitate is filtered off, washed with water and ethyl acetate and dried IC afford 0.45 g (59%) of a white solid, rap. 184^186C.
Ana!ysi$ for: C2gH2sClN4O3 Caleulate~ C, 67.13; H, 5.03; N, 11.18.
~: C, 66.85; H, 5.06; N, 10.85.
~X~mDIe 4?5 The eompounds 5- and 12-hydroxyeieosate~raenoie acid (5-HEIE and 12-~E) and LlB4 are early ataehidonie acid oxidation products in the lipoxygenase easeade, which have been shown to mediate several aspeets of inflan~natory and aller-gic response. This is espeeially true wi~h respect to 5,12-diHETE, which is also20 denoted as LTB4 lsee Ford-Hitchinson, J. Rov. Soc. Med.~ 74, 831 (1981)1. Com-pounds which inhibit the PLA2-mediated release o araehidonie acid thereby effectively prevent the oxidation of araehidonie aeid to the vatious leukotriene produets via the lipoxygenase caseade. Aeeordingly, the specifieity of aetis)n of PLA2 inhibitors ean be det~nnined by the aetiviy of test eompounds. in this assay, which measures the abiliy 25 of eompounds to inhibit the synthesis of LTB4 by rat glyeogen-elieited polymorpho-nuelear leukocytes (PMN) in the presenee of exogenous substrate.
The assay is carried out as follows:
Rat polymorphonuclear leulcocytes (PMNs) are obtained from fernale Wistar rats (150-200 g) which receive an injection of 6% glycogen (10 ml i.p.). Rats are 30 sae,rifieed 18-24 hours post injection by CO2 asphyxiation and the elieited cells are halves~ed by peritoneal lavage using physiological saline (O.9% NaCl). The exudate is centrifuged at 400 xg for 10 rninutes. The supematant fluid is discarded and the cell 2~0~

pellet is resuspended to a concentration of 2.0 x 107 cells/mL in HBSS conta~ning Ca++ and Mg~ and 10 ~lM L-cysteine.
To 1 mL aliquots of eell suspension, test drugs or vehicle are added, then preineubated at 37-C for 10 minutes. A23187 (1 IlM), [3H]-AA (3.0 ~CUmL) and 5 unlabeled AA (1 IlM) are then added and the samples are further incubated for 10 ` trunutes. The ~eaction is te~minated by eentrifugation and pelleting eells. Sup~natants are then analyzed by HPLC analysis on a 15 em x 4.6 mm ID supeleosil LC-18 (Supeleo)(3M) column, usi~g a two solvent system at a flow rate of 1.4 mL total flow as follows:
.
Solvent A: 70:30 17.4 mM H3PO4:CH3CN
Sohrcrlt B. CH3CN
GradieM: (system is ~uilibrated with SolveM A) r~ Pereent A PercemB

15.0 100 0 20.0 65 35 40.0 65 . 35 42.0 10 90 50.0 . 10 90 50. 1 100 0 Pexen~ solvent changes are aceomplished in a linear fashion.
~jec~ons: 14û llL of each supanatant is injected direetly onto column and 3H
atachidonie aeid metabolitcs are monitored using an on-line radioactivity deteetor (Ramona, IN/US, Fairfield, Nn.
Ssandards: 104 - 2.0 x 104 dpm of eieosanoids of interest are injeeted in 90 IlL EtOH eoektail.
Co-chromatography with standard [3H~ leukotriene B4 (LTB4) in medium of stimulated PMN exposed to drug is compared to that found in medium of stimulatedcells exposed to no drug, gencrating percent inhibidon.
Results are expressed as pereent inhibition at a given compound dose or as an ICso value.
Testing compounds of the invention in this assay gave the following results:

2~9~42 Compound of Example No. % Inhibition ca~profen -10~ (at lO~
etodolac 21 (atO.5,uM) indomethacin 31 (at lO~
sulindac -10~ (at IO~M) - 1 96 (at lO~
2 96 (~t lO
4 92 (at O.5 8 91 (at lO

9 96 ~at lO~
91 (atlO~
11 95 (at lO
14 91(atlO
16 96 (at lO
16C 88(atO.S~
17 46 (at O.5 17A 96 (at lO~
18 88 (atO.511M) 92 (at lO~
21 92 (at lO~lM) 24 97 (at lO
93 (at lO~
26 85 (at lO~LM) 29 88 (at lO
90 (at lO~
31 85 (at lO~M) 41 100 (at lO~M) ~ negative number denotes polentiation The pT~cedure of Example 43 is also employed for the detemnnation of the cxtent to which compounds of the invention inhibit the synthesis of the arachidonic acid cyclooxygenase oxidation product PGE2.

2 ~ 9 ~ 0 !1 2 In this assay, the pt~cedurc of Exarnple 43 is carried out as described.
However, in order to deterrnine cyclooxygenase activity, the samplcs are co-chromatog~aphed with authentic refercncc ~3Hl-PGE2.
The results are calculatect as in Examplc 43 and pxsented below:
Tablc II
Compound of Examt~le ?~o. % Inhibition ca~fen 83 (at IO
ctodolac 100 (atQS~
i~acin 100 (at lO~t) sulin~ac 23 (at lO~
81 (at IO~
2 92 (atlO,uM) 4 7 (atO.5 8 47 (at lO~
9 7~ (a~ lO~M) -41~ ~a~ tO~lM) 11 80 (atlO~
14 -48* ~at lO~M) 16 * (at IO~LM) 16C * (at IOlM) 17 60 (atO~511M) 17A ~50 (at lQ~
18 -31~ (atO.S~I) ~ (at lO~
21 -94~ (at lO~LM) 24 -126* (at lO~
-67~ (a~ lO~LM) 26 -125* (at lO
29 -123~ (at lO

-130 *(at lO
31 -145 ~(at lO
4t ` -21* (atO.5 Denotes a potensauon of cyclooxygenase (PGE2 synthesis).

2 ~ 4 ~

FxamDIe 45 The compounds of the invention are tessed in an in vi~ro isolated phospholipase A2 assay to determine the ability of the test compounds to inhibit thc release of arachidonic acid from an arachidonic acid-containing substrate by the action 5 of phospholipase A2 enzyme f~om human and non-human sources.
This assay is ca~~Tied out as follows:
~to a 15 rnL polypropylcne tubc are added the following:
~ Volmnç,~L final Conc.
3H-AA E. coli substrate 1 25 5 nmoles PL
CaCI2(0.1M~ 2 5 5mM
Tris-HCi(05M)pH7.5 3 20 lOOmM
W~r 4 25 l~ughchicle 5 1 5011M
P~A2 25 Volusneyielding 12%
hydrolysis in 10 min.

pre-incubate at room temperature 30 min prior to substrate addition.
Prepared by adding 2 mL deionized and distilled wa~er to 2 mL
3H-arachidonatc labeled E. coli (lower count), to which is added 1 mL of 20 3H-arachidonate labeled E. coli (higher count) to yield a total of 5 m subst.~te (containing 1000 nles phospholipid).
2 Stock 0.1 m CaC:12, r~quired for enzyme activity.
3 Stock 0.5 m Trisma-Base.
Stock 0.5 M T~isma-HCI. Adjust pH to 7.5 (optimum for enyme).
4 Deionized and distilled water.
Stock 10 mM p epared in dimethyl sulfoxide. Make 1:2 dilution with dimethyl sulfoxidc and add 1 11L to 100 ~lL assay tubc.
6 Two human Pl A2 enzymes arc uscd:
a) Semi-purified human platelet acid extract PLA2 (in 10 mM
30sodium acetate buffer, pH 4.5). Remove protein precipitate by cent;ifu~a~ion at abous 2200 rpm for 10 minu~es.
b) Purifled human synovial nuid.
Incubate thc lOO~L reacsiorl mixtu~ for 10 minutes at 37-C in a shalcing water bath. The reaction is te~minated by the addition of 2 mL tetrahydrofuran. followed by 2 ~

vortexing. NH2 columns (100 llglmL - Analytichem International) are cDnditioned with 0.5 mL tetrahyd~fu~n followed by 0.5 mL tetrahydrofuran/watcr (2 mL:0. 1 mL.
vlv).
The sample is loaded onto the columns and slowly drawn through them. The S hydtolyzed arachidonic acid retained in the columns is eluted therefrom with 1 mL
tetrahydrofuranlglacial acetic acid (2%). The, arachidonic acid is transfe~Ted ~o 'scintillation vials and quantiuted by ,B-counting analysis. A "total counts" samplc is prepared by pipetting 25 ~lL 3H-arachidonate E. coli directly into a scintillation vial to which is added 1 mL teaahydrofuran. 10 mL aquasol (scintillation cocktail) is added 10 to all samples.
Calculations: ' [3HlAA dpm (sample) - ~3H~AA dpm (nonspecific hydrolysis) % hydrolysls = -- x 100 total counts dpm vehicle dpm - dmg dpm ~o change = x 100 vehicle dpm Ac, tivitv of Standard Dm~s:
, ICso, (u M) Human Platelet Human Synovial ~2~, ' P T A z P L A
A~chidonic Acid 8.6 3.2 Monoalide 25.2 0.14 When tested in this assay, the compounds of the invention gave the following rcsults:

%,lnhibition at 10 uM ICso (uM) Compound of ~m~ ,HP~~F** ~ ~E
suLindac 33 34 30.2 indomethacin 38 (at50,uM) 144.8 --- 9.7 2' 3.6 16 46 4.1 17 58 14.9 18 47 30 ~7.0 2U90~42 Table In (cont'd.) % InhiWtion at 10 ~M ~Cso (~1 M) Compound of Exam~le No. HP~ HSF~

26 92 2.6 29 53 1~.5 46 16.4 34 33.7 28 52.9 41 9~3 3.8 25 * human platelet ~J~ hurnan synovial fluid Thc ability of thc compounds of the invention to inhibit paw cdcma intuccd by thc exogcnous administration of PL.A2 is measured in thc i~Q PLA2 3b murinc paw ~dcma assay.
Thc assay is carried out as follows:
Non-fasted, male CD-I rnice (8 weeks old; 31-36 grams) are placcd in plastic bo~es in groups of six. The right hind paw volume is measured using mercury plcthysmog~aphy (zero time). Compounds are dosed orally (0.5 rnL of 0.5% Tween-80) 1 or 3 hours prior to PLA2 injcction or intravenously (0.2 mL in 0.3%

2a~o~

dimethylsulfoxide/saline) 3 minutes prior to PLA2 injection. A solution of purified PLA2, from ~he diamond back cotton mouth snake (A. ~iscivorus piscivorus~ is prepared in saline at a concentration of 6 ,ug/mL. Fifty (50) ,uL (0.3 ~lg) of this PLA2 soludon is injeeted subeutaneously into the right hind paw with a plastic I mL plastie 5 syringe (27 ~auge, 1" needle). Paw volume of the injeeted paw is measured again at 10 minutes, 30 minutes and 60 minutes after PLA2 injecdon. Animals are euthanized with C2 at the completion of the study.
The paw edema is calculated by subtraedng the ~ero time volume from the vdume reeorded at eaeh time petiod. Mean paw edana for ~aeh treatment group is then 10 caieulated and expressed as (llL + S.E.). Dn2g effects are expressed as a percent change from control (vehicle) values. Statistieal significance is detennined by a one-way analysis of variance with LSD comparison to control (p < 0.05). EDso's are delennined using repression analysis.
The acivity of standard drugs in this assay is as follows:
EDso mglkg p.o.
ComPound at +10 min.
Cyp~heptadine 3. 1 Datame~hasone* 10 20Naproxen 18 Aristolochic Acid ** Not Active Luffarrellolide ** NotActive *p.o. - 3 hr.
*~ Some activily (30~o inhibition) only when co-in3ected with enzyrne.
When tested in this assay, the compounds of the invention gave the following results:
Table IV
% Change in Edema Compound of Dose 30ExampleNo. m~/kg lOmin ~ 60min indometha~in 10 (p.o.)*}-32 -31 -42 10 (i-Y-)* -6 -9 -40 1OO ~P-o-) +4 -27 -6 2 1 0 (i.v.)-39 -43 -37 100 (p.o.) -6 -22 +18 18 30 (i.p.)*** -19 2~ 04~

19 30 (i.p.) -30 60 (i.p.) 34 ~ intravenous *~ poral S *J'~ intrspitoneal The rcsults show that the compounds of thc invention are effec~ive in ~ivo in inhibiting edema induced by the exogenous administration of snake venom PLA2. - ' '' Thc annpounds of thcmYention arc.evaluated for their ability to inbibit Ihc lipoxygcnæe and/or cyclooxygenase pathways of arachidonic acid meubolism in the in vivo munne zymosan peritonitis assay.
This assay is caTsied out as follows:
Male CD-I mice (8 weeks old) are placcd in plastic boxes in groups of SLS.
15 ~nimals are injected with 1 mL ip. of d~er l~o ~ymosan in py~ogcn frec 0.9% saline or salinc (uns~m~a~d con~ol). Compounds a~ dosed orally 1 hourp~iar to zymosan iniection. Tweny minutes af~ zyrnosan injection, thc mice are asphyxiated by ~02inhalador. and the p~itoneal ca~ity is ~vaged witll 2 mL ice cold ~Ianl~s Balanced Salt Solution (EIBSS) without CaC!2, MgS04 7H20 and MgC12- 6H20. Peritoneal 20 lavage fluid f~m each mouse is removed by syringe and placed in 5 rnL plasdc test tubcs put on ice and ~olume is notcd. P~ ation of samples for cvaluation by ELISA
is as follows: Samples are ccntrifugcd at 800 xg for 15 minutcs; 1 ml~ of the supernaunt is added to 8 mL ice cold methanol and kept at -7û''C overnigh~ to precipi~e plotein; and samples are then centIifugcd at 800 xg for 15 minmes, followed 25 by a drying procedur~ in a Savant speed ~rac coneentrator. The samples are rcconstituted with 1 mL ice cold El,ISA buffcr and sto~d at -70-C until assayed. The assay for cicosanoids (LTC4 and 6-kcto-PGFl~) is performed according so con~entional ELISA procedures. --Compounds tO be usted orally are suspended in 0.5% Tween 80.
30 Compounds to be tested inh~peritoneally are suspended in 0.5% mcthylcellulose in0.9% saline.
The total metabolite level in lavage fluid~mouse is calculated and the significance is deCed by a one-way analysis of variance with LSD comparisons to control (p S 0.05). Drug effec~s are exp=ssed as a pe~ent change f~m control ~alues.

2 0 9 ~ ~ ~ 2 , The activity of standard drugs in this assay is as follows:
Compound ED~gme/k~ p o.
~4 6-keto-PGFI~/TxB2 BW755C ~10 22.0 Phenidone 24.0 ~30.0 Indomethacin Not Active 0.126 Ibuprofen Not Active 7 .0 When tested in this assay a compound of the invention and thc anti-inflammatory cornpound etodolac gavc the following results:
TableV
% Inhibition Compound of Dosc ExamDle No. ~ LTC_ 6-keto-PGF
indomctha~in 10 (p.o.) * +25 50 (p.o.) 11 -5 11 50 (p.o.) -49 ** 47 pcr~ally administered ** negative values denote potentiation ... .
The results show that the compounds of the invention exert an inhibitory 20 effect on both the lipoxygenase pathway and the cyclooxygenasc pathway.

F.xamnle 43 The LTD4 antagonist activity of the compounds of the invention is assessed in the in vitro isoiated gl~inea pig trachca assay.
This assay is carried out as follows:
Male Hartley guiriëa pigs (~ 50~00 g) are euthanized by a blow to the head, the ncck is opened and the trachea .e--.oved. The trachea is maintzuned in aerated physiological salt solution, cleared Gi connective tissue and fat and cut into rings approximately 2 mrn in width (usually ccntaining two cartilaginous segments per ring).
30 Two pieces of siL~c suture are then passec t.irough the lumen of the tRcheal ring and are ~ed around the cartilage, one on each side of the trachealis muscle. The tracheal ring is suspended between a glass hoolc and a force displacement transducer in a 10 mL organ bath for measurement of isometric tension. Tissues are maintained at 37 C in aerated 2 ~

(95% C021~% C02) physiological salt solution of the following composidon: NaCI
(100 mM), KH2PO4 (1.18 mM), KCI (4.74 mM), CaC12 (2.5 mM), MgS04 7 H20 (1.19 rnM), NaHCL3(25 mM), dexttose (11.1 mM) and indomethacin (1 ,uM). The tracheal rings are maintained u 2 g resting ~ension and equilibsated for 45 minutes (with 5 frcquent washing and readjustment of resdng tension).
The tracheal nngs are first cont~d by the addition of carbachol (3xlO~M), to detenmne tissue responsiveness and cstablish a reference contraction. On attainn~nt of a stable level of contraction (approximately 30 minut~s), the tissues are washed several times unsil baseline teDsion has beeD Testored and thcn re~quilibrated for 30 minutes.
10 The tiss~les are then incubated for 45 sninutes with a test antagonist (either 1x lO~M or lxl~5M~ or 10 IlL of an appropriate solvent cont~l (control, non-treated). One tissue in each group serves as thc control. Twenty minutes prior to the construction of thc LTD4 cumulative conccntration-response curve, L-cysteine (lx10-2M final bath concenir~tdon) is added to inhibit bioconvmion of LTD4 to Ll~4. Only one LTD4 i5 concent~tion-response curve is constructed in each dssue.
All responses to LTD4 in an individual tissue are measurcd as a perccnsage of the reference contraction of that dssuc to carbachol. LTD4 antagonist acivity isdetesmined by comparison of the concentration response curvcs of LTD4 in the presenee and at~sence of antagonist. Assessmen~ of the relasive rightward shift of the 20 antagonist treated curve relative to the solvent (control~ treated tissuc is calculated as a concen~ation ratio (Eq. A) and used in subscquent calculations to derive an antagonist pKg value (E~s B and C). In the cvent thas the m~ximum response to LTD4 is depressed, the ECso for that particular curve is detcrmined, an "apparent pKg rcponed, and the compound rcpo~ted as "non-competitive."
E~o trca~ed tissue A) Concentration Ratio (CR) =
EC50 control 2~
[~est Compound]
B) KB=

C) - -lOg KB = PKB
Lf.a compound is found to be active andlor depress the maximal response to LTD4, then a range of concentrations of the test cotnpound should be used generating 30 multiple concen~ation ratios which would then be used to perfonn a Schild analysis.
and detem~inadon of a pA2 value where app~opnate.

~ 20~0~2 The activity of reference leukotriene antagonists in this assay is as follows:
Compound ~
Ly-171,883 7.44 + 0.12 Wy 48,252 6.90 + 0.23 When tested in this assay, a compound of the invention gave the following results:
Table Vl Compound of Example ~1O. ~Concent~tion Ratio fM) 9 6.26 + 0.28 I x 10-5 18 5.85+0.12lx10-5 The above results demonstrate that the compounds tested have significant leukotriene antagonist activity as measured in the ~ isolated guinea pig ttachea assay.
E~amnle 49 The compounds of the invention are further tested in the rat carrageenan paw edema assay to detern~ne their ability to inhibit lhe acute inflamrnatory response.
This assay is carried out as follows:
140-180 g Male Sprague-Dawley rats, in groups of 6 animals are injected subcutaneously in the right paw with 0.1 mL o. 1% ca~rageenan at zero time. Mercury plethysmographic readings (mL) of the paw are made at zero time and 3 hours later.
Test compounds are suspended or oissolved in 0.5% methylcellulose and given pcrorally 1 hour prior to carrageenan administ~ation.
The increase in paw ~olume (edema in rnL) produced by the calTageenan is measurcd. Paw edema is calculated (3 hour volume minus zero time volume), and percent inhibidon of edema is determined. Unpaired Student's t-test is used to determine statistical significance.
The activity of standard drugs in this assay is as follows:
u~ Oral ED~n (95% C.L.) m~
Indomethacin 3.7 ( 0.6, 23.8) Aspirin 145.4 (33.1, 645.6) Phenylbutazone26.2( 2.3,2gl.0) 20~ ~B4 ~

When tcsted in this assay, a compound of the invention and the ami-inflamma~oly drug ctodolac gave the ~ollowing rcsults:
Table VII
Compound of Dose ~ % ~hibition O~al EDso 5ExamDle NO! ~m~ ~m~
etodolac 23 11 50 +1 10 ~- ~ministeredpcr~rally The rcsults show that the compounds-tested havc activity in thc ra~
carragecnan paw cdcma assay, cvidencing an cffcct on the acute inflarnmatory response.
]3;1~a~~lple 50 Thc assay of this Examplc measurcs thc ability of thc compounds tes~-d to inhibit 5-lipoxygenasc in human wholc blood.
This assay is carried out as follows:
Blood is obtained in 50-100 ml quantitics from rnale donoss. White blood cell counts and differentials arc made. Two ml of blood are placed in a 15 rnl 20 polypropylene tes~ tube. Compounds arc solubilized in dimethylsulfoxidc and dilutcd 1:10 in 10% bovine serum albumin in phosphate buffered saline, pH 7.4 resulting in a final dimcthylsulfoxide concentration of 0.1% in thc blood. Then, compounds arc added to thc blood in a shaking water bath at 37-C for 10 minutcs prior to thc addition of 30 ~lM calcium ionophore (A23187; Sigma). Aftcr ionophorc administtation, wholc 25 blood samplcs arc tmxed and incubated for 20 minutes at 37-C in a shaking water bath.
Incubation is tesminated by placing sunples in an ice bath and immcdiately addin~
cthylene glycol-bis-(~-aminoethyl ethcr)-N,N,N',N'-tetraacetic acid (10 mM).
Samples are rnixed and centrifuged a~ 1200 x g for lS minotes at 4-C Preparadon of samples for e~valuadon by RIA or ELISA is ca~ried out by the following protocol.30 Plasma is rcmoved from sample tubes, placed in IS rnl polypropylcne test tubes containing 8 ml rnethanol, and then vortexed to precipitate protdn. Samplcs are storcd at -70-C overn1ght. The next day, samples are centrifuged at 200 x g for 15 minutes at 4-C to pellet the precipitatç. Sasnples are dried in a Savant spced vac concentrator, 20~0~

reconstituted to original volume with ice cold RIA or I~LISA buffer, and stored at -70 C
until assayed. The assay for eicosanoids (LTB4, TxB2, and PGE2) is perfonned as described by the manufacturer of the t3Hl-RIA kit or ELISA kit (LTB4-Amersham, TxB2 and PGE2 - Cayrnen Chemical).
The total dcosanoid level in 2 ml of blood is calculated and rcported as ng/106 neutrophils. Signif~cance is detamined by a onc-way analysis of variance with h:ast significant diffcrence (LSD) compa~sons to control (p < 0.05) and ICso's (~M) are - dcte~mincd by rcgrcssion analysis (Finncy, 1978). Drug cffccts are exp~essed as per~n~ change ~m control values.
Compounds tested in o a c solubilized in dimethylsulfoxide and diluted 1:10 in 109o bovine semm alb~nin in phospha~e buffer saline resulting in a final dimethylsulfoxide concentra~on of 0.1% in the blood.
The results for compounds of the invendon testcd in this assay are prcsented in Table IX.
Table vm Compound ofDose ~, (uM)% Inhibition of Ll~
A-64a77 5 72 L-663,536 3 96

Claims (43)

1. A compound having the formula A(CH2)nO-B
wherein A is C4-C8alkyl,phenoxyethyl,phenoxyphenyl or a group having the formula or wherein R1 is hydrogen, lower alkyl, phenyl or phenyl substituted with trifluoromethyl;
R2 is hydrogen or lower alkyl; or R1 and R2 taken together form a benzene ring;
R3 is hydrogen or lower alkyl; with the proviso that when B is A is other than phenyl;
n is 1-2;
B is , , or ;

wherein R4 is -CO2R2, , , , or ;

m is O-3;
R5 is ; or phenyl or phenyl substituted by halo, lower alkylthio, lower alkylsulfinyl or lower alkylsulfonyl;
R6 is A(CH2)nO- or halo; with the proviso that when R6 is halo, R5 is ;

R7 is lower alkyl;
Y is -CH2- or-O-;
R8 is lower alkyl or -(CH2)mCo2R3;
R9 is or-CH2R10;
R10 is lower alkyl, phenyl, phenyl substituted with carboxy, halo, loweralkylthio or loweralkylsulfinyl, pyridyl, furanyl or quinolinyl;
R11 is lower alkyl or phenyl;
and the pharmacologically acceptable salts thereof.

2. 3-[(4-chlorophenyl)methylene]-[2-methyl-6-(2-quinolinylmethoxy)]-3H-indene-1-acetic acid.

3. 2-methyl-3-[[4-(methylthio)phenyl]-methylene]-6-(2-quinolinylrnethoxy)-3H-indene-1-acetic acid.

4. 2-methyl-3-[[4-methylsulfinyl)phenyl]-methylene]-6-(2-quinolylmethoxy)-3H-indene-1-acetic acid.

5. 5-fluoro-2-methyl-1-[[4-(2-quinolinyl-methoxy)phenyl]methylene]-1H-indene-3-acetic acid.

6. 2-methyl-3-[[4-methylthio)phenyl]-methylene]-6-[(2-naphthyl)methoxy]-3H-indene-1-acetic acid.

7. 3-[(4-chlorophenyl)methylene]-[2-methyl-6-(2-quinolinylmethoxy)]-3H-indene-1-acetic acid.

8. 3-1[(4-chlorophenyl)methylene]-[2-methyl-6-(2-quinolinylmethoxy)]-3H-indene-1-acetic acid methylester.

9. 1,8-diethyl-1,3,4,9-tetrahydro-6-(2-quinolinylmethoxy)pyrano[3,4-b]indole-1-acetic acid.

10. 1 -ethyl- 1 ,3,4,9-tetrahydro-6-(quinolinyl-methoxy)pyrano[3,4-b]indole-1-acetic acid.

11. 1 -methyl-1,3,4,9-tetrahydro-6-(2-quinolinylmethoxy)pyrano[3,4b]indole-1-acetic acid.

12. 1-ethyl-2,3,4,9-tetrahydro-6-(2-quinolinyl-methoxy)-1H-carbazole-1-acetic acid.

13. 1,3,4,9-tetrahydro-1-propyl-6-(2-quinolinylmethoxy)pyrano[3,4-b]indole-1-acetic acid.

14. 1-ethyl-1,3,4,9-tetrahydro-6- (2-quinolinyl-methoxy)pyrano[3,4-b]indole-1-acetic acid, methyl ester.

15. 1,3,4,9-tctrahydro-1,1-dimethyl-6-(2-quinolinylmethoxy)pyrano[3,4-b]indole.

16. 1,3,4,9-tetrahydro-1,1-diethyl-6-(2-quinolinylmethoxy)pyrano[3,4-b]indole.

17. 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

18. 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid methyl ester.

19. 1-(4-chlorobenzoyl)-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

20. 1-(4-chlorobenzoyl)-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid methyl ester.

21. 2-methyl-5-(2-quinolinylmethoxy)- 1,2-(quinolinylmethyl)-1H-indole-3-acetic acid.

22. 1-[(4chlorophenyl)methyl]-5-(hexyloxy)-2-methyl-1H-indole-3-acetic acid.

23. 2-methyl-5-(2-quinolinylmethoxy)-1-(2-quinolinylmethyl)-1H-indole-3-carboxylic acid ethyl ester.

24. .alpha.-methyl-6-(2-quinolinylmethoxy)-9-(2-quinolinylmethyl)-9H-carbazole-2-acetic acid.

25. 1-[(4-chlorophenyl)methyl]-2-methyl-N-(methyl)-N-(hydroxy)-5-(2-quinolinylmethoxy)-1H-indole-3-acetamide.

26. 1-[(4-chlorophenyl)methyl]-2-methyl-N-(phenylsulfonyl)-5-(2-quinolinylmethoxy)-1H-indole-3-acetamide.

27. 1-[(4-fluorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

28. 1-[(4-bromophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

29. 1-[(phenyl)methyl-2-methyl]-5-(2-quinolin-ylmethoxy)-1H-indole-3-aceic acid.

30. 1-[(4-carboxyphenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1-H-indole-3-acetic acid.

31. 2-methyl-5-(2-quinolinylmethoxy)-1-[[4-(2-quinolinylmethoxy)phenyl]methyl]-1H-indole-3-acetic acid.

32. 2-methyl-1-pentyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

33. 1-hexyl-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

34. 1-heptyl-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3acetic acid.

35. 1-methyl-2-methyl-5-(2-quinolinyl-methoxy)-1H-indole-3-aceic acid.

36. 1-[(4-chlorophenyl)methyl]-5-(2-quinolinyl-methoxy)-1H-indole-3-acetic acid.

37. 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-naphthalenylmethoxy)-1H-indole-3-aceic acid.

38. 1-[(4-chlorophenyl)methyl]-2-methyl-5-(phenylmethoxy)-1H-indole-3-acetic acid.

39. 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-pyridinylmethoxy)-1H-indole-3-acetic acid

40. 2-methyl-5-(2-quinolinylmethoxy)-1-[[4-(2-quinolinylmethoxy)phenyl]methylene]-1H-indene-3-acetic acid.

41. N-[[1-[(4-chlorophenyl)methyl]-2-methyl-5 (2-quinolinylmethoxy)-1H-indol-3-yl]methyl]-N'-hydroxyurea.

42. A process for preparing a compound of Claim 1 comprising one of the following:

a) where the final product has the formula wherein R6 is A(CH2)nO
i) etherifying a compound of formula wherein R3 is as defined above, with a compound of formula A(CH2)n-X
where A and n are as defined above and X is a leaving group, followed by reaction with triethylphosphonoacetate, hydrolysis of the resulting acetic acid ester intermediate and then reaction with an appropriately substituted benzaldehyde to introduce the desired R5CH= moiety into the intermediate to yield the desired final product; or ii) reacting an intermediate having the formula wherein R3 in the -COOR3 moiety is lower alkyl, with an appropriately substituted benzaldehyde to introduce the desired R5CH= moiety into said intermediate and then etherifying said intermediate with a compound of formula A(CH2)n-X
where A and n are as defined above, and X is a leaving group and, if necessary, hydrolyzing the intermediate to yield a final product in which R3 is hydrogen; or b) where the final product has the formula wherein R6 is halo, R5 represents A(CH2)nO and R3 and n are as defined above, reacting a compound of formula with a compound having the formula where A and n are as defined above; and, if desired, esterifying the final product free acid;
c) where the final products have the formula wherein Y, R2, R3, R4, R7, R8, R9, A and n are as defined above.
i) etherifying a compound of formula or with a compound of formula A(CH2)n-X
where A and n are as defined above and X is a leaving group, and, if necessary, wherein the intermediate bears the ester function -CO2R3 or -CO2R2, hydrolyzing the intermediate, to yield a compound in which R2 or R3 in the moiety -CO2R2 or -CO2R3 is hydrogen; and further ii) reacting the intermediate compound with a compound having the formula R9hal wherein R9 is as defined above and hal represents a halo atom, to yield the final product ; or d) hydrolyzing a compound of formula I,II,III or IV, wherein the moiety -CO2R2 or -CO2R3 is an ester function, to yield a compound in which R2 or R3 in said moiety is hydrogen or a pharmacologically acceptable salt thereof; or e) converting a compound of formula I, II,III or IV to a pharmacologically acceptable salt.

43. A process as claimed in Claim 42 substantially or as hereinbefore described and illustrated in any one of Examples 1E, 1F, 1G, 2, 3, 4, 5B, 5C, 6C, 6E, 6F, 7, 8E, 9D, 10D, 11C, 12C, 13, 14C, 15C, 16A, 16C, 16D, 17, 18, 19, 20, 21F
and 22 through 42.