CA2070422A1 - Substituted indole-, indene-, pyranoindole and tetrahydrocarbazole- alkanoic acid derivatives as inhibitors of pla2 and lipoxygenase - Google Patents

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;
R3 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 halo, R5 is (r); R7 is lower alkyl; Y is -CH2- or -O-; R8 is lower alkyl or -(CH2)mCO2R3; R9 is (s) 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, 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-passageway conditions, such as allergic rhinitis, allergic bronchial asthma and the like; and as gastric cytoprotective agents.

Description

2~7~2~
`VO 9t/06~37 Pcr/uS90/06251 SUBSTITUTED INDOLE-, INDENE-, PYRANOINDOLE- AND
TETRAHYDROCARBAZOLE- ALKANOIC ACID DERIVATIVES
AS INHIBITORS OF PLA~ ~ND l IPOXYGENASE
s This invention relates to novel substituted indene-, indole-, pyrano-indole- and tetrahydrocarbazole alkanoic acid derivatives possessing lipoxygenase inhibitory, phospholipase A2 inhibitory and leukotriene antagonist activity, which are useful as anti-inflammatory, antiallergic and cytoprotective agents.
lt 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 amply elucidated in recent years. It is now known that prostaglandins arise from the endoperoxides PGG2 and15 PGH2 by the cyclooxygenase pathway of arachidonic acid metabolism. These endoperoxides are also the precursors of the thromboxanes (Tx) A2 and B2. TxA2 is a vasoconstrictor which stimulates platelet aggregation. ln the normal situation, the vasoconstrictive and platelet aggregating proper~ies of the thromboxanes are balanced by another product arising from the endoperoxides in the cyclooxygenase pathway,20 prostacyclin (PGI2), which is a vasodilator with platelet aggregation inhibitory activity.
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., 1 291 (1980) and J. B. Smith, Am. J. Pathol., 99, 743 (1980). Cyclooxygenase 25 metabolites are known to participate direcdy in the inflammatory 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 augmentation of peptide mediator vascular permeability and edema forming properties. Finally, various aspects of cell mediated immunity are influenced by cyclooxygenase products.
The other pathway of AA metabolism involves lipoxygenase enzymes and results in the production of a number of oxidative products called leukotrienes.
The latter are designated by the LT nomenclature system, and the most significant products of the lipoxygenase metabolic pathway are the leukotrienes B4, C4 and D4.
The substance denominated slow-reacting substance of anaphylaxis (SRS-A) has been 35 shown to consist of a mixture of leukotrienes, with l,TC4 and LTD4 as the primary products and having varying amounts of other leukotriene metabolites [see Bach et al., WO 91/06537 pcrlus9o/û6251 2 ~

J. Immun.,215, 115-118 (1980); Biochem. Biophvs. Res. Commun.,~, 1121-1126 (1980)].
The significance of these leukotrienes is that a great deal of evidence has been accumulated showing that leukotrienes participate in inflammatory reactions, 5 exhibit chemotactic activities, stimulate lysosomal enzyme release and act as importan factors in the immediate hypersensitivity reaction. It has been shown that LTC4 and LTD4 are pount bronchoconstrictors of the human bronchi [see Dahlen et al., Nature, 288, 484-486 (1980) and Piper, Int. Arch. Appl. Itnmunol., 76, suppl. 1, 43 (1985)]
which stimulate the release of mucus from airways in vitro [Marom et al., Am. Rev.
10 Resp. Dis.~ 126, 449 (1982)], are potent vasodilators in skin [see Bisgaard et al., Prosta~landins~ 23. 797 (1982)], and produce a wheal and flare response [Camp et al., Br. J. Pharrnacol., 80, 497 (1983)]. The nonpeptide leukotriene, LTB4, is a powerful chemotactic factor for leukocytes [see A. W. Ford-Hutchinson, J. Rov. Soc. Med., 74, 831-833 (1981), which stimulates cell accumulation and affects vascular smooth 15 muscle [see Bray, Br. Med. Bull., 39, 249 (1983)]. The activity of leukotrienes as mediators of inflammation and hypersensitivity is extensively reviewed in Bailey and Casey, Ann. Reports Med. Chem., 19, 87 (1986).
Phospholipase A2 (PLA2) is the critical rate limiting enzyme in the arachidonic acid (AA) cascade since it is responsible for the hydrolysis of esterifled AA
20 from the C-2 position of membrane phospholipids. This reaction generates two products (1) free AA which is then available for subsequent metabolism by either the cyclooxygenase or lipoxygenase enzymes and (2) Iysophospholipid. When alkyl-arachidonoyl-glycerophosphatidylcholine is acted upon by the PLA2 the generation of platelet activating factor (PAF) is initiated; PAF is pro-inflammatory in its own right 25 [see Wedmore et al., Br. J. Pharrnacol.,74, 916-917 (1g81)]. In this regard it may be noted that the anti-inflarnmatory steroids are thought to inhibit eicosanoid synthesis by inducing the synthesis of a PLA2 inhibitory protein denominated macrocortin or lipomodulin [see Flower et .-.. . Nature, London, 278, 456 (1979) and Hirata et al., Proc. Natn. Acad. Sci. U.S.A., 77, 2533 (1980)].
As the initial step leading to subsequent conversion of AA to the various eicosanoids by the cyclooxyger.ase and lipoxygenase pathways, the PLA2-mediated release of AA from membrane phospholipids is a critical event in attempting to deal with the various physiological manifestations which are based on the activity of the eicosanoids and/or PAF. Thus, while PLA2 has been shown to be required for platelet 35 aggregation [Pickett et al., Biochem. J., 160, 405 (1976)], cardiac contraction and excitation [Geisler et al., Pharrn. Res. Commun.,2, 117 (1977)], as well as W O 91/06537 2 ~ l 2 .~ PC~r/US90/06251 prostaglandin synthesis [Vog~, Adv. Prostagl. Thromb. Res., 3, 89 (1978)], the inhibition of PLA2 is indicated in the therapeutic treatment of both PAF induced or cyclooxygenase andlor lipoxygenase pathway product-mediated physiological conditions.
There is also evidence that products of the cyclooxygenase/lipoxygenase pathways play key roles in both the pathogenesis of gastric mucosal damage due to extracellular (gast~ic and intestinal contents, microorganisms, and the like) or intra-cellular (ischemia, viruses, etc.) agents, as well as in cytoprotection against such damage. Thus, on the one hand prostaglandins exert a cytoprotective effect on the gastric mucosa [see Robert, Gastroenterolo~v, 77, 761-767 (1979)] and this action of the prostaglandins, especially of the E series, is considered to be of importance in the treatment of gastro-intestinal ulceration [see Isselbacher, ~Y. 33 (suppl.), 38-46 (1987)]. On the other hand, ex vivo experiments have shown that gastfic mucosal tissue from ethanol-pretreated rats is capable of LTC4 generation and that this LTC4 production is quantitatively related to the severity of the ethanol damage [see Lange et al., Naunvn-Schmiedeber~'s Arch. Pharrnacol. Suppl., ~Q, R27, (1985)]. It has also been demonstrated that LTC4 can induce ~asocons~iction in both venous and arteriolar vessels in the rat submucosa [see Whittle, ~UPHAR Ninth Int. Cong. of Pharrn., S30-2. London, England (1984)]. This is significant since ethanol-induced lesion formation in gastric mucosa may be multifactorial with, for example, stasis of gastric blood flow contributing significandy to the development of the hemorrhagic necrotic aspects of the tissue injury [see Gudh et al., Gastroenterologv. 87~ 1083-90 (1984)]. Moreover, in the anesthetized cat, exogenous LTD4 evokes both increased pepsin secretion and decreased transgastric potential [Pendleton et al., Eur. J. Pharmacol., 125, 297-99 (1986)]. A particularly significant recent finding in this regard is dhat 5-lipoxygenase inhibitors and some leukotriene antagonists protect the gastlic mucosa against lesions induced by the oral or parenteral administration of most nonsteroidal anti-inflammatory drugs [see Rainsford, Agents and Actions, 21, 316-319 (1987)]. Platelet activating factor (PA~;) is also implicated as a mediator of gas!rointestinal damage, and it has been recently shown that 5-lipoxygenase inhibitors inhibit PAF-induced gastric mucosal damage (Gastroenterolo~.96, A55, A434, 1989). Accordingly, a significant body ofevidence implicates the involvement of lipoxygenase products in the development of pathological features associated with gastric mucosal lesions, such as for example, those induced by ethanol exposure and administration of non-steroidal anti-inflamma-tory drugs. Thus, compounds which inhibit the biological effects of leukotfienes and WO 91/06~37 2 ~ 2 2 PCI /US90/06251 PAF and/or which control the biosynthesis of these substances, as by inhibiting 5-lipoxygenase, are considered to be of value as cytoprotective agents.
Accordingly, the biological activity of the leukotrienes and SRS's, and of lipoxygenase as the enzyme leading to the metabolism of AA to leukotrienes, 5 indicates that a rational approach to drug therapy to prevent, remove or ameliorate the symptoms of allergies, anaphylaxis, asthma and inflammation and for gastric cyto-protection must focus on either blocking the release of mediators of these conditions or antagonizing their effects. Thus, compounds which inhibit the biological effects of the leukotrienes and SRS's and/or which control the biosynthesis of these substances, as lO by inhibiting the PLA2-mediated release of arachidonic acid from membrane phospho-lipids, or by inhibiting lipoxygenase, are considered to be of value in treating such conditions as allergic bronchial asthma, allergic rhinitis, as well as in other immediate hypersensitivity reactions and in providing gastric cytoprotection.
It has now been found that certain novel substituted indene-, indole-, lS pyranoindole- and tetrahydrocarbazole alkanoic acid derivatives inhibit PLA2 and lipoxygenase, and antagonize products of the lipoxygenase pathway, and so are useful as anti-inflamrnatory, anti-allergic and cytoprotective agents. The present invention provides novel compounds having the following formula:
A(CH2)naB
20 wherein A is C4-Cg alkyl, phenoxyethyl, phenoxyphenyl or a group having the forrnula R21~ R

wherein Rl3 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 t~;fluoromethyl;
R2 is hydrogen or lower alkyl; or Rl and R2 taken together forrn a benzene ring;
R3 is hydrogen or lower alkyl;
nis l -2;

W O 91/06537 ~PC~r/US90/062~1 B is Rb$2)mC02R3 ~CHCo2R3~(CH2)mR4 (1H2,nA R9 wherein O O O
R4 is -CO2R2, -N(OH)CNH2, -N(oH)CR7, -NHCNHOH, O O
-CN(OH)R7 or-CNHSO2RIl;
misO-3;
R5 is A(CH2)nO ~ ; 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 ,~y A(CH2)nO ' R7 is lower alkyl;
Y is -CH2- or -O-;
R8 is lower alkyl or ~(CH2)mCo2R3;
o R9is -CRI or -CH2R1;
R10 is lower alkyl, phenyl, phenyl substituted with carboxy, halo, loweralkylthio or loweralkylsulfinyl, pyridyl, furanyl or quinolinyl;
Rl 1 is lower alkyl or phenyl;
20 and the phamlacologically acceptable salts thereof.

WO 91/06537 2 ~) 7 ~ Pcr/us90/U625l -The terms "lower aLkyl" and "lower alkoxy" refer to moieties having 1-6 carbon atoms in the carbon chain. The term "halo" refers to fluoro, chloro or bromo.
The grouping A embraces, inter alia, 5- or 6- membered unsaturated nitrogen, sulfur or oxygen containing mono- or benzofused-heterocycles, optionally 5 substituted with lower alkyl or phenyl. The foregoing definition embraces the following heterocyclic moieties: furyl, pyrrolyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridyl, pyrazinyl, pyrimidinyl, benzofuranyl, benzothienyl, benzothia-zolyl, indolyl, benzoxazolyl, quinolinyl, quinazolinyl, benzimidazolyl, quinoxalinyl, quinazolinyl and the like. Especially preferred are quinolinyl, benzothiazolyl, 10 benzimidazolyl and 2-phenylthiazole.
The compounds of the invention can form pharmacologically acceptable salts from pharmacologically acceptable organic and inorganic acids such as hydrochloric, hydrobromic, sulfonic, sulfuric, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, pamoic, succinic, methanesulfonic, acetic, propionic, tartaric, citric, 15 lactic, malic, mandelic, cinnamic, palmitic, itaconic and benzenesulfonic. The compounds which are carboxylic acids are capable of forming aLkali metal and alkaline earth carboxylates and carboxylates of pharmacologically acceptable cations derived from ammonia or a basic amine. Examples of the latter include but are not limited to cations such as ammonium, mono-, di-, and trimethylarnmonium, mono-, di- and 20 triethylammonium, mono-, di- and ~ripropylammonium (iso and normal~, ethyldimethylammonium, benzyldimethylammonium, cyclohexylammonium, benzy-lammonium, dibenzylammonium, piperidinium, morpholinium, pyrrolidinium, piperazinium, 1-methylpiperidinium, 4-ethylmorpholinium, 1-isopropylpyrrolidinium, 1,4-dimethylpiperazinium, l-n-butyl-piperidinium, 2-methylpiperidinium, 1-ethyl-2-25 methylpiperidinium, mono-, di- and triethanolammonium, ethyl diethanolarnmonium, n-butylmonoethanolammonium, tris(hydroxymethyl)methylammonium, phenyl-monoethanolammonium, and the like.
The compounds of the invention can be prepared by the following reaction schemes. When it is desired to prepare compounds having the formula ~ ,(CH2)mCo2R3 A(CH2)nO ~3~

CHRs ~-methoxybenzaldehyde, for example, is reacted with propionic anhydride, followed by reduction and ring closure to yield the intermediate ~methoxy-2-methyl- l-indanone W O 91/06537 .? ~ 7 ~ P ~ /US90/0625]

(C2H5CO)20 ~ H2 sodium propionate ~y Pd/C
CHO CH=C-CO2H

polyphosphoric acid ~

The indanone intermediate is then subjected to demethylation and the resulting hydroxy-indanone is reacted with an appropriate haloaL~cyl-A compound where A is as defined S hereinbefore and hal is halo CH3~ AlBr3 ~
benzene CH3 A(CH2)n~ O
A(cH2,nha, r ¦1 l K2CO3 / 1 8-crown-6 ~CH3 The latter intermediate, where n=l, is reacted with triethylphosphonoacetate in sodium hydride to yield an interrnediate indene-3-acetic acid ethyl ester, which is then 10 hydrolyzed and concomitantly reacted with an appropriate reactant to introduce the desired RS-methylene group onto the indene-3-acetic acid moiety, exemplified below by the introduction of a E~chlorophenylmethylene grouping o A(CH2)nO~o(C2HsO)2PCH2CO2C2Hs / NaH
W\CH3 toluene W O 91/06~37 PC~r/US90/06251 7 ~

A(CH2)nO ~ ~COC2H5 NaO CH3/ C H30 H

Cl A(cH2)no~cHzcooH

~C H

Cl Compounds in which the R5 group is lower aL~ylthiophenyl can be prepared by using an appropriate loweralXylthiobenzaldehyde. The compounds in which R5 is a lower-S alkylsulfinylphenyl grouping can be prepared from the loweralkylthiophenyl-containing compounds by ~eaction with 30% H22 in chlorofom~lacetic acid.
~(cH2)no~cH2cooH

C H3 30% H22 ,~
~ C H C13/ C H3CCX~H

A(C H2)n ~ C HH3C O O H

~C H

W O 91/06537 PC~r/US90/06251 g In an alternative preparation scheme, the intermediate hydroxyindanone can be reacted with cyanoacetic acid to give the corresponding hydroxyindene-3-acetic acid, which is then esterified before introduction of the R5-methylene grouping in order to facilitate the purification of desired intermediates. Since introduction of the S RS-methylene grouping is accompanied by ester hydrolysis, the intermediate free acid is re-esterified to facilitate purification followed by reaction with an appropriate halo-alkyl-A group to yield the desired final product HO~ NCCH2COOH ~ ~CH2COOH
~ NH40Ac / HOAc --~CH3 HO~CH2COOCH3 ~ p-toluenesulfonic acid / H20 ~ ~CH3 CH30H

1. NaOCH3 / CH30H ~CH2COOCH3 ~CH3 A(CH2)nhal K2CO3 / 18-crown-6 Cl , ~
2. p-toluenesulfonic acid H20 bJ

Cl A(CH2)nO~rCH2COOCH3 ~\CH3 CH

WO 91/06~37 PCI/US90/06251 Compounds having the formula halo (CH2)mCooR3 HC ~o(cH2)nA

can be prepared by reacting a halo-indene-3-acetic acid with a A(CH2)n-containing benzaldehyde prepared from the corresponding individual components A(CH ) hal NaOC2Hs /EtOH A(CH2) o~CHO

OH
halo NaOCH3 / -/
f\~l--CH2COOH C~

~\CH3 ~/ ~CH2COOH
~3 O--(CH2)nA
In all of the above-outlined reac~ion schemes, the final product free acids can be esterified via conventional methods and in like fashion, final product esters can be hydrolyzed by known procedures to yield the corresponding free acids.
Compounds of the invention having the formula A(CH2)nO ~X

R3 H R7 Rs 2 ~ ,',J
W O 91/06537 P ~ /US90/06251 in which X is -CH2- can be prepared by initially reacting 4-methoxyphenylhydrazine with, for example, 2-carbomethoxymethyl-2-alkylcyclohexanone, followed by ring closure to yield an intermediate tetrahydro-methoxy-lH-carbazole-1-acetic acid o CH30~b<R7 1) toluene/~

~NHNH22) glacial acetic acid /

~r~
The latter intermediate is demethylated with hydrobromic acid to yield the corresponding hydroxy compound, which is then reacted with an appropriate halo-loweraLIcyl-A compound by one of several routes. In one such preparative sequence, two equivalents of the starting 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 derivative of the hydroxycarbazole-1-acetic acid may be prepared by treating the acid with an aLl~ali metal alkoxide, such as sodium methoxide.

A(CH2)nhal + ~Q NaOCH3 R3 H R7 CH2co2R3 A(CH2)n~ NaOH

R3 H R7 CH2CO(CH2)nA
1~

WO91/06537 23?~adf~ PCr/USsO/06251 A(CH2)nO ~1 In dhe above sequence, A, n, m and R7 are as defined hereinbefore and hal denotes chloro, bromo or iodo.
In an alternative sequence, it is possible to use only one equivalent of 5 starting material A(CH2)nhal with the metal derivative to obtain the desired final product direcdy, widlout proceeding dlrough the ethyl ester intermediate.
In yet another reaction sequence, the desired final products can be prepared by the aL~cylation of alkyl esters of the hydroxycarbazole-l-acetic acid:

HO ~'~1 K2CO3 / Acetone ~N ~J A-(CH2)nhal A~ ),O--~Q hydrolyns A~(CH2)n' ~Q

where A, n, m, R3, R7, R8 and hal are as defined hereinbefore. Hydrolysis is carried out using a dilute hydroxide, such as for example sodium hydroxide.
Compounds of the invention having the formula A-(CH2)nO ' ~X

lS R3 H R7 R8 WO91/06537 ' ~ PCr/US90/06251 in which X is -O- can be prepared by the above-outlined reaction sequences which dif-fer only in the preparation of the starting tetrahydro-6-hydroxypyrano[3,4-b~indole-1-lower aL~canoic acid esters. The latter can be prepared by the reaction of, for example, a 5-benzyloxytryptophol with a lowerallcyl-(R7-carbonyl)lower aLlcanoate in boron 5 trifluoride etherate to yield an interrnediate 1-R7-tetrahydro-6-(phenylmethoxy)pyrano-[3,4-b]indole-1-aL~canoic acid ester, which is then subjected to reduction to yield the corresponding 6-hydroxy ester ~LCH2O~CH2CH20H R7-C(CH2)mCooCH3 BF Et O

~LCH20~;~ Pd/c R3 H R7 (CH2)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 final compounds.
Another scheme by which the starhng tetrahydro-6-hydroxypyrano[3,4-b]indole l-aL~anoic acid ester can be prepared involves reducing 7-loweralkyltryptophol 15 to 7-loweraLlcyl-2,3~ihydrotryptophol, followed by reacting the latter with potassium nitrosodisulfonate to yield a 7-loweraL~cyl-5-hydroxytryptophol, which is then reacted with a suitable lower alkyl-3-methoxy-lower aL~canoate to yield the desired intermediate tetrahydro-6-hydroxypyrano[3,4-b]indole- l-loweralkanoic acid ester W O 91/06537 PC~r/US90/06251 h ~;~CH2CH20H acid ~.JCH2cH20~ (KS03)2NO

H~CH2CH20H OCH3 HO~

R3 H R7 (CH2)mCOOCH3 As with the previously described indene-l-acetic acid derivatives, the carbazole final product free acids can be esterified via conventional methods and in like fashion, final product esters can be hydrolyzed by known procedures to yield thecorresponding free acids.
Compounds of the invention having, for example, the fonnula ~ ~(CH2)mCOOR2 A(cH2)no ~J~R3 can be prepared by reacting 5-hydroxy-2-methyl-lH-indole-3-loweralkanoic acid with an appropriate A(CH2)nhal compound in the presence of sodium methoxide/methanol to yield the intermediate A(CH2)nO-containing indole alkanoic acid denvative, which is ~en esterified and reacted with a suitable substituted benzyl or benzoyl halide to yield Wo 91/06~37 ~ ~ 7 ~ Pcr/US90/06251 the desired final product in ester form, which can be converted to the fTee acid form by conventional methods.
Ho~ (cH2)mcooH A(CH2)nhal ~

l~ J~ NaOCH3 / CH30H /
H CH3 dimethylfolmamide A(CH2)n~r(CH2)mCHCH2N2 / Et20 ~ N J~CH3 tetrahydrofuran A(CH2)nO~ (CH2)mCOOCH3 NaH / dimethylformamide D
~/ N CH3 R9hal H

A(CH2)nO~ r(CH2)mcOOcH3 Compounds of the invention having the formula A(CH2)nO- ~ CHCo2R3 (CH2)nA

can be prepared via the following reaction sequence: ~benzyloxyaniline is reacted with 10 sodium nitrite in the presence of stannous chloride to yield 4-benzyloxyhydrazine, which is reacted with a-methyl-3-oxocyclohexanone acetic acid to yield an intermediate Wo 91/06537 2 ~3 r~ 2 ~ pcr/us9o/o62s1 o~-methyl-tetrahydrocarbazole acetic acid, which is esterified with ethanol to yield the interrnediate ethyl ester.

~CH20~ NaNO2 NH2 HCI SnCl2 2H2O
o ~CH20~ CH

EtOH / H2SO4 C3--CH20~ CHCOOCH2CH3 The a-methyl tetrahydrocarbazole acetic acid ester intermediate is reacted under reflux with chloranil in xylene under a nitrogen atmosphere to yield the corresponding -methylcarbazole acetic acid, which is reduced by hydrogenation to remove the benzyloxy group, yielding the 6-hydroxy-a-methyl carbazole acetic acid ester 10 intermediate.
o ~CH20 N CHCOOCH3~yl~ne / N~

~CH2O~ CH3 Pd/C
CHCOOCH3 EtOH
H

W O 91/06537 2 ~ 7 ~ ~ ~,s,~ PC~r/US90/0625]

HO~ CHCoocH2cH3 The latter interrnediate is then hydrolyzed to give the free carboxylic acid intennediate, which is then reacted with an appropriate haloalkyl-A compound, where A is as hereinbefore defined and hal is halo, to yield the desired final product.

HO~;~LCHCOOCH2CH CH O
H

- HO~ CH3 A(CH2)nhal ~N ~LCH2COOH DMSO / NaOH
H

A(CH2)n~ cHH3cOoH

(CH2)nA
The conventional starting materials used in the reaction sequences outlined above are available comrnercially or can be prepared by methods known in the art. Thus, for 10 exarnple, the intermediate compound 2-bromomethylquinoline can be prepared by the following reaction sequence:

HCI Xl`CH3 2 ~ 7 ~ '2 ~
WO 91/06~37 PCr/lJS90/06251 N-Br Y _ ~ ~
(C6HscO)2o2 ~ N CH2Br The benzo-fused heterocyclic compounds used in the above reaction sequences are also either commercially available or can be prepared by methods conventional in the art.
Thus, for example, such intermediates as 1-methyl-2-chloromethylbenzimidazole, 5 2-chloromethylbenzthiazole and 2-chloromethylbenzoxazole can be prepared by the following reaction scheme NH
Rl ~ ClCHzCOCH3 R~ CH3CI

wherein X is O, S or NCH3. The reaction is preferably carried out at a controlled low temperature in an organic solvent, such as methylene chloride.
Certain compounds within the scope of the invention exist in the fo~m of E and Z stereoisomers and the individual isomers can be differentiated by the prefixes E
and Z, as assigned by the accepted sequence rules procedures. Accordingly, the present invention embraces the E, Z and mixed isomer forms of those final product compounds exhibiting this form of stereoisomerism.
The compounds of the invention, by virtue of their ability to inhibit the activity of PLA2 enzyme, as well as that of lipoxygenase enzyme and to antagonize mediators arising from the enzymatic pathway, are useful in the treatment of conditions mediated by products of the oxidation of arachidonic acid. Accordingly, the com-pounds are indicated in the treatment of such diseases as rheumatoid arthritis, 20 inflammatory bowel disease, osteoarthritis, tendinitis, bursitis, psoriasis (and related skin inflammation) and similar conditions involving inflammation. Moreover, by virtue of their ability to antagonize the effect of LTC4, LT~4 and LTE4, which are the constituents of SRS-A, they are useful for the inhibition of symptoms induced by these leukotrienes. Accordingly, the compounds are indicated in the prevention and treatment 25 of those disease states in which LTC4, LTD4 and LTE4 are causative factors, for example allergic rhinitis, allergic bronchial asthrna and other leukotriene mediated naso-bronchial obstructive air-passageway conditions, as well as in other immediate hyper-WO 91/06~37 2 ~ pcr/usso/o62s1 sensitivity reactions, such as allergic conjunctivitis. The compounds aTe 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 conventional non-steroidal anti-5 inflammatory drugs, whose major side effect is gastrointestinal irritation. The cyto-protective effect of the compounds of the invention significantly reduces the gastro-irritant impact of conventional anti-inflammatory drugs. This effect is based not only on the ability of the compounds of the invention to inhibit the biological effects of leukotrienes and/or control ~he biosynthesis of these substances, as by inhibiting lO lipoxygenase, but also by a shunting effect, whereby the control of the lipoxygenase pathway "shunts" the oxidation of arachidonic acid into the cyclooxygenase pathway, giving rise to an increase in the formation of cytoprotective prostaglandins. These biological effects make the compounds of the invention especially useful in treating such conditions as erosive esophagitis, inflammatory bowel disease and induced lS hemorrhagic lesions such as those induced by alcohol or non-steroidal anti-inflamma-tory drugs (NSAID's), hepatic ischemia, noxious agent induced damage or necrosis of hepatic, pancreatic, renal or myocardial tissue; liver parenchymal damage caused by hepatotoxic agents such as carbon tetrachloride and D-galactosamine; ischemic renal failure; disease-induced hepatic darnage; bile salt-induced pancreatic or gastric damage;
20 trauma or stress-induced cell damage; and glycerol-induced renal failure.
When the compounds of the invention are employed in the treatment of allergic airway disorders, as anti-inflamrnatory agents and/or as cytoprotective agents, they can be formulated into oral dosage forms such as tablets, capsules and ~he like.
The compounds can be adrninistered alone or by combining them with conventional 25 carriers, such as magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethyl-cellulose, low melting wax, cocoa butter and the like. Diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, tablet-disintegrating agents and the like may be employed. The compounds may be encapsulated with or without other 30 carriers. In all cases, the proportion of active ingredients in said compositions both solid and liquid will be at least to impaTt the desired activity thereto on oral administra-tion. The compounds may also be injected parenterally, in which case they are used in the form 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.

WO 91/06537 ~ 2 ,~ Pcr/us9n/06251 The dosage requirements vary with the particular compositions employed, the route of administration, the severity of the symptoms presented and the particular subject being treated. Treatment will generally be initiated with small dosages less than the optimum dose of the compound. Thereafter the dosage is increased until 5 the optimum effect under the circumstances is reached. In general, the compounds of the invention are most desirably adminis~ered at a concentration that will generally afford effective results without causing any haImful or deleterious side effects, and can be administered either as a single unit dose, or if desired, the dosage may be divided into convenient subunits adrninistered at suitable times throughout the day.
The PLA2 and lipoxygenase inhibitory and leukotriene antagonist effects, as well as the anti-inflammatory and potential gastroirritant effects of the compounds of the invention, may be demonstrated by standard pharmacological procedures which are described more full in the examples given hereinafter.
These procedures, inter ~, determine the specificity of action of the 15 compounds of the invention as PLA2 inhibitors as measured by their ability to inhibit the synthesis of LTB4 and P~E2 by rat glycogen-elicited polymorphonuclear leukocytes, as well as measure their ability to inhibit arachidonic acid release mediated by human and non-human source PLA2. The procedures further measure the ability of the compounds of the invention to inhibit, in vivo, the activity of exogenously 20 administered PLA2. The pharmacological testing additionally demonstrates the ability of the compounds of the invention to inhibit, in vivo, the lipoxygenase and cyclooxy-genase pathways of arachidonic acid metabolism; the in vitro, leukotriene antagonist activity of the compounds of the invention; and also measures the in vivo activity of the compounds as anti-inflammatory agents in the rat carrageenan paw edema assay.
25 Finally, the potential of the compounds to induce acute gastroirritation in rats is measured in a test procedure.
The follo ving examples show the preparation and pharmacological testing of compounds within the invention.

WO 91/06537 2 ~ 7 ~ Ll ~ ~ Pcr/US90/06251 Example 1 3-[(4-Chlorophenyl)methylene]-~2-methyl-6-(2-quinolinyl-Tn~thoxv)l-3TT-indene-l-acetic acid A.p-Methoxv-a-methvl cvnnamic acid 5A mechanically stirred mixture of 4-methoxybenzaldehyde (47.6 g, 0.35 mole), propionic anhydride (78.3 g, 0.602 mole) and sodium propionate (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) under vigorous stirring a yellow solid isobtained. It is redissolved in 2N-KOH (pH 11) and the solution is extracted with ether.
10 The aqueous phase is acidified (ice bath) with concentrated HCI. The white solid is collected, washed with water and dried to provide 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, m/z): 192 (b.p., M)+.
Analvsis for: CllH1203.
Calculated: C, 68.74; H, 6.29.
Found: C, 68.80; H, 6.43.
20 B . ~Methoxv-ot-methv! hydrocvnnamic acid A rnixture of the acid (44 g, 0.229 mole) of Step A, and 10% Pd/C
(4.4 g) in dry methanol (500 mL) is hydrogenated overnight at 50 psi. The mixture is filtered (SoL~ca-Floc) and the filtrate evaporated to dryness to yield a pale yellow oil, which is used without further purification (44.5 g).
25 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. 6-Methoxv-2-methvl-1-indanone A mechanically stirred mixture 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, W). The warm mixture is poured into water (3 L) and stirred overnight at room temperature. It is then extracted with ether and ethyl acetate W O 91/06537 2 ~ 2 PC~r/US90/06251 and the combined extracts are washed with saturated NaHC03 to neutral. The organic phase is washed with brine and dried (MgSO4). Removal of the solvent provides the title compound as an arnber oil. It is purified by flash chromatography (on silica Merck-60, dichloromethane as eluent) to yield 25.58 g (64%) of a pale yellow oil.
NMR (CDC13, 400 MHz): ~ 1.31 (d, J 7.4 Hz, 3H, 2-CH3), 2.65 (dd, lH, ArCH) and 2.74 (m, lH, ArCH), 3.32 (dd, lH, CH), 3.83 (s, 3H, OCH3), 7.20 (m, 2H, ArH), 7.34 (d, lH, ArH).
MS (EI, m/z): 176 (M)+, 161 (b.p., M-CH3)+.
D . 6-Hvdroxv-2-methvl- 1-indanone To a stirred solution of anhydrous aluminum bromide (69.82 g, 0.261 mole) in anhydrous benzene (250 mL) kept 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 (TLC, dichloromethane-ethyl acetate 8:2, UV), cooled in an ice bath and treated dropwise with 6N-HCl (ca.
200 mL) to decompose the aluminum complex. The aqueous phase is extracted with ether (3 times), the extracts are concentrated at reduced pressure and extracted with 2.5N-NaOH (2x7S rnL and lx50 mL). The basic extracts are neutralized (ice bath) with concentrated HCI and the oil that separates is extracted with ether (3 times). The combined extracts are washed with brine, dried (MgSO4) and evaporated to yield an oil that readily solidifies. The crude material is flash chromatographed (on silica Merck-60, gradient CH2C12, CH2C12-ethyl acetate 85:15) to provide the pure title compound (13.60 g, nearly colorless solid, 82%).
NMR (CDC13, 400 MHz): ~ 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, m/z): 162 (M)+, 147 (b.p., M-CH3)+, 133 (M-C2Hs)+.
E. 6-(2-Ouinolinvlmethoxv)-2-methvl- 1 -indanone A mixture of the phenol (15.16 g, 93.58 mmole) of Step D, powdered anhydrous potassium carbonate (12.93 g, 93.6 mmole), 18-crown-6 (2.47 g, 9.36 mmcie) and dry acetonitrile (200 mL) is stirred at room temperature under anitrogen for 15 minutes. 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 mixture is placed in an oil bath heated at 65 C for 11 hours (ll,C, dichloromethane-methanol 9:1, UV). The solvent is removed in vacuo and the residue is partitioned between ethyl acetate and water. The organic phase is washed with brine, dried WO 91/06537 23 PCr/USso/0625l (MgSO4) and evaporated to yield an oil which solidifies upon trituration with hexane (ca. 31 g). The crude product is purified by flash chromatography (on silica Merck-60, absorbed in methylene chloride, eluted with CH2C12-ethyl acetate 90:10 and 8~:15) to provide 5.95 g of slightly impure material together with 24.55 g of the pure title 5 compound (pale yellow solid, 84.8%).
NMR (CDC13, 400 MHz): ~ 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,Jca7Hz, lH,ArH),7.83(d,J8Hz, lH,ArH),8.11 (d,J8.4 Hz, lH, ArH), 8.20 (d, J 8.4 Hz, IH, ArH).
MS (EI, m/z): 303 (M)+, 142 (b.p-, Cl0H8N)+. 115.
F. 2-Methvl-5-(2-quinolinvlmethoxv)-indene-3-acetic acid ethvlester Triethylphosphonoacetate (22.41 g, 100 mmole) is added dropwise under nitrogen to a stirred and cooled (O C) slurry of NaH (57% in oil, 4.27 g, 15 100 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 mmole) of Step E, in toluene (50 mL) is then added dropwise. The flask is placed in an oil bath heated at 95-C for 19 hours (TLC, traces of starting material present, dichloromethane-ethyl 20 acetate 9:1, UV, Vaughn's). The reddish solution is cooled, diluted with water and extracted with ethyl acetate (3 times). The combined ext~acts 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 provide the title compound as a rMxture of endo 25 and exo isomers (16.3 g, 87.4%, oil that 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-r(4-Chlorophenvl~methvlenel-r2-methvl-6-(2-quinolinvlmethoxv~1-3H-indene-1-acetic acid To a vigorously stirred mixture of the ester (mixture of isomers, 6.9 g, 18.5 mmole) prepared as described in Step F, and p-chlorobenzaldehyde (2.86 g, 20.3 mmole, 1.1 equiv.) in dry methanol (45 mL) is added dropwise under nitrogen25% methanolic sodium methoxide (8 mL, 2 equiv.). The mixture is warmed until itbecomes homogeneous (ca. 65 C, bath temp.) and then refluxed for a total of 13 hours.
35 After overnight at room temperature, the slurry (bright yellow precipitate) is treated WO91/06537 2~7~ ) 3 Pcr/usso/o62 dropwise with water (35 mL) and a little methanol and refluxing is continued foranother 4 hours (reaction followed by TLC). The dark orange solution is cooled, the 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 5 bright yellow solid. The latter is slurried in water and neutralized (to pH 6-6.5) with 10% acetic acid. The mixture is extracted with ethyl acetate (large volume), the extract is washed with brine and evaporated to dryness. The residue is azeotroped with benzene to provide an orange solid [7.52 g, mixture of Z (major) and E (minor) isomers]. This material is slulTied in ether, stilTed for 30 minutes, filtered and dried 10 (4.32 g). The solid is extracted portionwise with hot ethyl acetate (containing some methanol and dichloromethane) until almost completely dissolved. The filtrate isconcentrated in vacuo until precipitation occurs, diluted 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 [see: Shuman et al., J. Oro. Chem., 42, 1914, (1977)] with the Zisomer.
NMR (I)MSO-d6, 400 MHz): o 2.11 (s, 3H, CCH3), 3.54 (s, 2H, CH2COO), 5.326 (s, 2H, OCH2Ar), 6.60 (dd, lH ArH), 6.95 (d, J 2.35 Hz, lH), 7.14 (m, 2H, ArH), 7.52 (m, 4H, ArH), 7.60 (t, J 7.03 Hz, lH, ArH), 7.66 (d, J 8.39 Hz, lH, ArH), 7.77 (t, lH, ArH), 7.99 (m, 2H, ArH), 8.4 (d, J=8.9 Hz, lH, ArH).
UV (~ max, MeOH, nm): 232 ( 39,594), 285.2 (14,83~), 287.8 (14,g21), 288 (14,921), 338.2 (10,839).
MS (+FAB, m/z): 468 (lCI, M+H)+, 237,131,91 (b.p.).
25 Analvsis for: C2gH22ClNO3 Calculated: C, 74.43; H, 4.74; N, 2.99.
Found: C, 74.54; H, 4.67; N, 3.13.
Example 2 2-Methyl -3- [[4-(methylthio)phenyllmetbylene] -6- (2-guinolinvlmethoxv)-3H-indene-l-a~etic acid To a vigorously stirred mixture of the ester (mixture of isomers, 6.7 g, 17.96 mmole), prepared as described in Example 1, Step F, and (4-methylthio)benzaldehyde (3.05 g, 19.06 mmole, 1.1 equiv.) in dry methanol (75 mL) is added dropwise under nitrogen 25% methanolic sodium methoxide (7.7 mL, 2 35 equiv.). The mixture is warmed until it becomes homogeneous (ca. 65 C, bath temp.) W O 91/06537 2 ~ ; ' PC~r/US90/06251 and then refluxed for a total of 13 hours (TLC, CH2CI2-ethyl acetate 9:1). Afterovernight at room temperature, the slurry (bright yellow precipitate) is treated dropwise with water (65 mL) and a little methanol and refluxing is continued for another 5.~
hours (reaction followed by TLC). The brown solution is cooled, the methanol 5 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 yellow solid. The latter is slurried in water and neutralized (to pH 6-6.5) with 10% acetic acid. The mixture is extracted with ethyl acetate (l&rge volume), the extract is washed with brine and evaporated to dryness. The residue is azeotroped with benzene to provide a yellow 10 solid (4.47 g, 52%). This material is slurried in ether, stirred for 30 minutes, filtered and dried (4.13 g, m.p. 205-207-C, dec.). The solid is extracted portionwise 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 [see: Shuman et al., J. Or~. Chem., 42, 1914, (1977)] with the Z-isomer.
NMR a)MSO-d~, 400 MHz): ~ 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 (t, lH, J ca. 7 Hz, ArH), 7.99 (m, 2H, ArH), 8.4 (d, lH, J 8.49 Hz, ArH).
UV (~ max, MeOH, nm): 231.5 ( 37,382), 303 (9,739), 307.5 (9,342), 315 (10,525), 352.5 (13,407).
MS (+FAB), m/z): 480 (M+H)+.
25 Analvsis for: C30H2sNO3S
Calculated: C7 75.13; H, 5.25; N, 2.92.
Found: C, 7S.30; H, 5.25; N, 2.95.
Example 3 2-Methyl-3-[[(4-methylsulfinyl)phenyl]methylene]-6-(2-~uinolvlmethoxv)-3H-indene-1-acetic acid monohvdrate A slurry of the thioether (1.67 g, 3.48 mmole) of Example 2 in a cold mixture of chlorofoml ~nd glacial acetic acid (65:35, 40 mL) is treated dropwise (via sy~inge) with 30% H22 (0.403 mL). The rnixture is stirred 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 ~ ~ ~) t~ "`~

reaction to completion (reaction followed by TLC, aliquot treated with water andextracted with ethyl acetate). The chloroforrn is evaporated, the residue is diluted with water and neutralized in the cold with the calculated amount of NH4OH. The precipitate is filtered, slurried in water, collected, washed with water and dried in vacuo 5 (over P2Os) to yield the crude acid as a yellow ~solid. The solid is redissolved in a large volume of warm (30-35-C) ethyl acetate (containing some methanol and dichloromethane) and filtered. The filtrate is concentrated in vacuo until precipitation starts and diluted with ether. The precipitate is collected, washed with ether and dIied (fluffy solid, m.p. 136-137-C, sintenng and foaming).
10 NMR (DMSO-d6, 400 MHz): ~ 2.12 (s, 3H, 2-CH3), 2.80 (s, 3H, SOCH3), 3.55 (s, 2H, CH2COO), 5.32 (s, 2H, ArCH2O), 6.58 (dd, lH, ArH), 6.96 (d, J 2.3 Hz, lH), 7.14 (d, J 8.36 Hz, lH, ArH), 7.21 (s, lH, ArH), 7.58-7.80 (m 7H, ArH), 7.98 (m, 2H, ArH), 8.39 (d, J 8.5 Hz, lH, ArH), 12.36 (s, lH, COOH).
MS (+FAB, m/z): 518 (M+Na)+, 496 (M+H)+.
Analvsis for: C30H2sNO4S H2O
Calculated: C, 70.19; H, 5.30; H, 2.73.
Found: C, 69.15; H, 4.93; N, 2.65.
Example 4 5-Fluoro-2-methyl-1-[[4-(2-quinolinylmethoxy)-~henvllmethvlenel-l H-indene-3-acetic acid A. ~[Q~uinolinvl)-methoxvl-benzaldehvde To a solution of sodium metal (0.9 g, 39.13 g.a.) in absolute ethanol (50 mL) is added dropwise under nitrogen a solution of 4-hydroxybenzaldehyde (5 g, 25 40.94 mmole) in absolute ethanol (50 mL). The mixture is gently refluxed for 1 hour and then treated dropwise with a solution of 2-c}, ~romethylquinoline (free base, 7.24 g, 40.76 mmole), freshly prepared from the HCl salt) in ethanol (50 mL). The rnixture is refluxed for 24 hours, the solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic layer is washed with 5% NaOH (pH 8), 30 water, brine to neutral and dried (MgSO4). Rernoval of the solvent yields the tide com-pound as a yellow solid (9.81 g). The crude material is further purified by flash chromatography (on silica Merck-60, hexane-ethyl acetate 9:1 to remove less polar impurities and 8:2 to elutç the product). Yield: 7.37 g (71.5%), m.p. 82-83 C.
NMR (CDC13, 200 MHz): ~ 5.5 (s, 2H, ArCH2O), 7.2-8.6 (m, 9H, ArH), 9.80 (s, lH, CHO).

r~ V ~ V ~
wo 9t/06537 Pcr/Us90/06251 B. 5-Fluoro-2-methvl-1-~f4-(2-quinolinvlmethoxv)phenvllmethvlenel-lH-indene-3-acetic acid To a mixture of 5-fluoro-2-methyl-indene-3-acetic acid (prepared according to the procedure disclosed in U.S. 3,654,349) (2 g, 9.7 mmole) and thealdehyde (3.2g, 12.19mmole) of Step A, in d~y methanol (40mL) is added dropwise under nitrogen 25% methanolic sodium methoxide (6.48 mL). The mixture is warmed until homogeneous and then refluxed for a total of 16 hours. The solvent is evaporated and the residue is slurried in water. The gelatinous precipitate is collected, washed with water and dried. It is then slurried in ether, filtered and dried to provide 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 ~6.5) with 10% acetic acid. The acid isextracted with ethyl acetate (large volume), dried (MgSO4) and evaporated to dryness.
The crude acid is recrystallized from a hot mixture of methanol and ethanol (large volume needed to dissolve, concentrate to smaller volume after filtration). The analytical sample is dried overnight in vacuo at 35 C. The yellow solid (m.p. 218-221-C, dec) is a rnLxture of Z and E isomers in approximately 6:1 ratio (NMR).
NMR (DMSO-d6, 400 MHz): o 1.84 (s, 2-CH3, minor E isomer), 2.12 (s, 2-CH3, major Z isomer), 3.55 (s, 2H, CH2COO), 5.41 (s, ArCH2O, possibly E
isomer), 5.44 (s, ArCH20, possibly Z isomer), 6.70 (dt, lH, ArH), 6.85-7.3 (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, lH, ArH), 7.79 (t, J, 7 Hz, lH, ArH), 8.01 (nm, 2H, ArH), 8.44 (d, lH, 8.5 Hz, ArH), 12.4 (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-r(2-naphthvl~methoxvl-~H-indene-1-acetic acid A. ~r(2-Naphthvl)methoxvl-2-methvl-indanone A mixture of the indanone (14 g, 86.4 mmole) prepared as described in Example 1, Step D, anhydrous K2CO3 (11.24 g, 81.4 mmole), 18-crown-6 (2.29 g, 6.4mmole) and 2-bromomethylnaphthalene (11.6g, 95mmole) in acetonitrile W O 91/06537 ~ 2 ~ 28 - P Cl/US90/062S1 (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 water, extracted with ethyl acetate, dried (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 provide the title compound as a white solid (13.49 g, 52%).
NMR (CDCl3, 400 MHz): ~ 1.30 (d, J 3.2 Hz, 3H, 2-CH3), 2.70 (m, 2H, ArCH2C), 3.35 (m, IH, CHCO), 5.25 (s, 2H, ArCH2O), 7.32 (m, 3H, ArH), 7.50 (m, 3H, ArH), 7.85 (m, 4H, ArH).
MS (EI, m/z): 302 (M)+, 141.
10 B. I) 6-[(2-Naphthyl)methoxy]-2-methyl-indan-1-ylidene-acetic acid ethylester (Z isomer) II) 6-[(2-Naphthyl)methoxy]-2-methyl-indan-1-ylidene-acetic acid ethylester (E isomer) m) 5-r(2-Naphthvl)methoxvl-2-methvl-indene-3-acetic acid ethvl ester Triethylphosphonoacetate (19.8 g, 88.3 mmole) is added dropwise under nitrogen to a stirred and cooled suspension of NaH (60% in oil, 3.53 g, 88.2 mmole) in toluene (225 mL). The cooling bath is removed. A clear solution is obtained after 10 minutes at room temperature. A solution of the indanone (13.3 g, 44 mmole) of Step A, in toluene (40 mL) is added dropwise and the mixture is placed in an oil bath 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 reextracted with ethyl acetate (3 times). The extracts are dried (K2C03) and evaporated 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.
hexane-ethyl acetate 9:1) provides small amounts of each of the pure isomers (i.e. I, II
and m) together with mixed fractions and unreacted starting material (ca. 5.24 g). The structures of the isomers are confirmed by MS and NMR and assigned by NOE. The mixture of endo and exo esters is routinely used in the next step (combined yield 8.94 g or 54.7%; 90% based upon recovered starting material).
Isomer 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 and 2.5 Hz, ArH), 7.17 (d, J 8.4 Hz, WO 91/06537 2 ~ ~ 3 i~ Pcr/US90/06251 lH, ArH), 7.49 (m, 2H, ArH), 7.59 (d, J ~.4 Hz, lH, ArH), 7.82 (m, 3H, ArH), 7.95 (s, lH, ArH), 8.61 (s, lH, ArH).
MS (EI, m/z): 372 (M)+, 231, 141 (b.p.).
Isomer II
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 (dd, J 16.3 and 7.1 Hz, lH, ArCHC), 3.88 (m, lH, CCH), 4.22 (q, J ca. 7 Hz, 2H, ester CH2), 5.24 (s, 2H, ArCH2O), 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, m/z): 373 (M+H)+, 261 (b.p.), 233 Isomer III
NMR (CDC13, 400 MHz): ~ 1.20 (t, J 7 Hz, 3H, ester 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 ester CH2), 5.25 (s, 2H, ArCH2O), 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).
MS (CI, m/z): 373 (M+H)+, 285 C. 2-Methvl-3-rr~(methvlthio)~henvllmethvlenel-6-r(2-naphthvl)methoxyl-3H-indene-l-acetic acid To a mixture of the ester (mixture of isomers prepared as described above (2.5 g, 6.71 mmole) and 4-(methylthio)-benzaldehyde (1.124 g, 7.38 mmole) in anhydrous methanol (60 mL) is added dropwise under nitrogen 25% methanolic sodium methoxide (2.9 mL). The mixture is refluxed for 16 'hours, the solvent removed and the residue slurried in water and stilred overnight (the initial yellow oil turns into a solid). The water is evaporated in vacuo and the residue is triturated with ether (to remove unreacted aldehyde), filtered, washed with ether and dried(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. lt is again washed with ether and dried (1.02 g, 32%, m.p. 209-211-C, dec.). The NMR shows it to be a mixture of Z and E isorners in approximately 8:1 ratio.
NMR (DMSO-d6, 400 MHz): ~ 1.81 (s, 2-CH3, minor isomer E~, 2.11 (s, 2-CH3, major isomer Z), 2.51 (s, 3H, SCH3), 3.54 (s, 2H, CH2COO), 5.23 (s, ArCH2O, Z isomer) and 5.28 (s, ArCH2O, E isomer), 6.60 (dd, lH, ArH), WO 91/06S37 2 ~ 2 ~ PCI/US90/062S1 6.90 (d, J 2.2 Hz, lH, ArH), 7.12 (s, lH, ArH), 7.27-7.36 (m, 3H, ArH), 7.46-7.62 (m, SH, ArH), 7.88-8.00 (m, 4H, ArH), 12.33 (broad s, lH, COOH).
MS (CI, m/z): 479 (M+H)+, 435 (M+H-COO)+, 141 (CIlHg, naphthyl)+.

5 Analvsis for: C31H26O3S
Calculated: C, 77.80; H, 5.48.
Found: C, 77.44; H, 5.47.
Example 6 3-[(4-Chlorophenyl)methylene]-[2-methyl-6.(2-~ui~nlin~lmethoxv)l-3H-indene-l-acetic acid A. 5-Hvdroxv-2-methvl indene-3-acetic acid A mixture of the indanone (1.81 g, 11.17 mmole) of Example 1, Step D, cyanoacetic acid (1.05 g, 12.3 mmol) ammonium acetate (0.17 g), acetic acid (0.66 g) and toluene (5 mL) is heated at reflux with water removal (Dean-Stark) for 24 15 hours (TLC, CH2C12-ethyl acetate 8:2). The toluene is evaporated and the residual yellow solid is redissolved in ethand (6 mL) containing 2.2 N-KOH (1.4 mL). A
solution of KOH (2.2 g, 85) in water (15 mL) is added and the solution is refluxed under nitrogen for 18 hours. The ethanol is evaporated, the residue is diluted with water and extracted with ether (2 times~. The aqueous layer is acidified in the cold with 20 6N-HCl (to pH 3) and extracted wi~h ethyl acetate. The extracts are washed with b~ine, dried (MgSO4) and evaporated to provide the crude tide compound together with traces of unreacted indanone. It is used as such in the next step.
NMR (DMSO-d6, 200 MHz): o 2.02 (s, 3H, 2-CH3), 3.2 (s, 2H, ArCH2), 3.4 (s, 2H, CH2COO), 6.48 (d, IH, ArH), 6.6 (s, lH, ArH), 7.1 (d, IH. ArH), 9.08 (broad, lH, OH).
B. 5-Hvdrox~-2-methvl-indene-3-acetic acid methvlester To a solution of the crude acid as prepared in Step A, above, in dry methanol (120 mL) is added p-toluenesulfonic acid monohydrate (1.9 g) and the rnixture is gently refluxed for 1.5 hours. The methanol is evaporated, the residue 30 dissolved in ethyl acetate, washed with brine and dried (MgSO4). Removal of the solvent provides a brown oil that readily solidifies upon drying in vacuo. The residue is flash chromatographed (silica Merck-60, absorbed in dichloromethane, eluted with dichloromethane-ethylacetate 98:2 and 94:6) to yield the pure title compound as an off-white solid (9.4 g, 80%).

2 ~ 7 ~ 2 `~0 91t06~37 PC~r/US90/0625~

NMR (CDCI3, 400 MHz): 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 (EI, m/z): 218 (M)+, 158 (b.p.).
5 C. 3-r(4-Chlorophenvl)methvlenel-r2-methvl-6-hvdroxv!-3H-indene-1-acetic acid To a solution of sodium metal (0.170 g, 7.39 g.a.) in anhydrous methanol (2.5 mL) 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 10 heated at 65-70 C for 6 hours followed by standing overnight at room temperature (TLC, CH2C12-ethyl acetate 93:7). Water (10 mL) and methanol (2 mL) are added and the mixture is again refluxed under nitrogen for 3 hours (TLC, CH2C12-ethyl acetate 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-HCl 15 (to pH 3) and extracted with ethyl acetate. The extracts are washed (brine) and evapo-rated to yield a greenish-yellowish solid (0.8 g). The NMR spectrum shows that it is a mixture of the title compound and 5-hydr~xy-2-methyl-indene-3-a2~etic acid. They are best separated as their methylesters (see below).
D. 3-r(4-Chlorophenvl)methvlenel-~methvl-~hvdroxvr-3H-indene-l-acetic acid methvlester A solution of the crude acids (2.46 mmole, obtained as described in Step C, above) in methanol (10 mL) containing p-toluenesulfonic acid monohydrate(60 mg) is refluxed for 5 hours. The methanol is evaporated and the residue dissolved in ethyl acetate, washed with brine and dried (~gSO4). The solvent is evaporated and 25 the residue is flash chromatographed (on silica Merck-60, absorbed in 1:1 dichloromethane-hexane, eluted with toluene-isopropanol 95:5) to provide the title compound (less polar spot, 0.103 g, yellow solid) together with some impure material (0.390 g, oil that solidifies upon standing). The Z configuration is confirmed by NOE. The more polar spot is identical (NMR, TLC) with methyl-5-hydroxy-2-30 methylindene-3-acetate.
NMR (CDC13, 400 MHz): ~ 2.17 (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 Hz, 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 (1 Cl, M)+, 231 (b.p.) Wo 91/06537 Pcr/us9O/06251 7 ~

E. 3-1(4-Chlorophenvl~methvlenel-r2-methvl-~(2-quinolinvlmethoxv)1-3H-indene-l-acetic 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 stirred at room temperature for 15 minutes. 2-Chloromethylquinoline is added (free base, 0.149 g, 1.42 mmole, freshly prepared from the hydrochloride salt) and thedeep red mixture is s~rred under nitrogen for 15 hours in an oil bath heated at 65-C. A
10% excess of potassium carbonate, crown ether and the 2-chloromethylquinoline is then added and the reflux is continued for another 2 hours (TLC, hexane-isopropanol 10 93:7~. The solvent is evaporated and the residue is partitioned between water and ethyl acetate. The organic phase is washed (brine), dried (MgSO4) and evaporated to dry-ness. The crude product is identical (NMR, TLC) with the material described in Example 7, below.
F. 3-r(4-Chlorophenvl)methvlenel-r2-methvl-~(2-quinolinvlmethoxv~L-3H-indene-l-acetic 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 mixture is refluxed under nitrogen for 3 hours. After stirring overnight at room temperature (TLC, hexane-isopropanol 93:7), the methanol is evaporated and the residue washed with ether. The 20 solid is slurried in water, neutlalized in the cold with 10% acetic acid (tO pH ~6.5) and extracted with ethyl acetate (vigorous stirring is necessary to achieve solution). The ex~acts are washed with brine, dried (MgS04) and evaporated to yield the crude acid (0.250 g, 43%). It is reclystallized fr~m hot ethyl acetate/methylene chloride (dissolve in a large volume and concentrate the filtrate until precipitation occurs). The pure title 25 compound (m.p. 216-21 8-C) is identical (TLC, NMR) with the material described in Example 1, Step G. (Z isomer).
Example 7 3-[(4-Chlorophenyl)methylene]-[2-methyl-6-(2-quinolinyl-methoxY~1-3~-indene-1-a~et~cid ~ethvlester A suspension of the acid (1.88 mmole, crude material before purifica-tion, obtained as described in Example 1, Step G), in methanolic HCI (15 mL) is refluxed until the reaction is complete by TLC (dichloromethane-methanol 9:1, UV).
The methanol is evaporated and the residue is partitioned between ethyl acetate and Wo 9l/06537 2 ~ 7 ;3 i~ pcr/usso/o6251 dilute NH4OH. The extracts are washed with brine, dried (K2C03) and evaporated to dryness to provide a yellow oil that foams in vacl~o (0.900 g). The crude product is flash chromatographed (on silica Merck-60, toluene-hexane-isopropanol 50:50:1 aseluent) to yield the pure title compound (0.630 g, yellow foam that solidifies upon trituration with ethanol, 69.6% over 2 steps). Mixture of Z and E isomers in approxi-mately 4:1 ratio (based upon the position of the 2-CH3 signal in the NMR spectrum).
NMR (CDC13,4,00 MHz): ~ 1.81 (s, 2-CH3, minor isomer E), 2.17 (s, 2-CH3, major isomer Z), 3.56 (s, 2H, CH2COO), 3.62 (s, 3H, OCH3) 5.42 (s, 2H, ArOCH2), 6.52 (dd, IH, ArH), 6.89 (d, J 2.4 Hz, IH), 7-8.3 (m, 12H, ArH).
MS (+FAB, m/z): 482 (lCI, M+H)+, 360, 217, 143 (b.p.)+, 91.
Example 8 1,8-Diethyl-1,3,4,9-tetrahydro-6-(2-quinolinyl-methoxy)evranor3.4-blindo!e-l.acetic ari~
A. 7-Ethvl-2~3-dihvdrotrvptophol A mixture consisting of 7-ethyltryptophol (28.0 g, 0.148 mol) and 250 mL of trifluoroacetic acid is stirred at room temperature. Sodium borohydride pellets (5.4 g, 0.145 mol) are added over a 4 hour period. After addition is complete, the reaction is stirred for 1 hour. The reaction mixture is poured onto ice and neutral-ized with 50% NaOH to pH 10. The aqueous layer is extracted with ether (3 x 200 mL). The ether layers are combined and extracted with 5% HC1 solution (3 x 200 rnL). The combined acidic solution is then made aLkaline with 50% NaOH
and extracted with ether (3 x 200 rnL). The combined ether layers are washed with water (2 x 200 mL), once with l~rine (200 mL), dried (MgSO4), filtered and concen-trated to afford 17.3 g of oil. Flash chromatography using 60% ethyl acetate/hexane, and then 80% ethyl acetate/ hexane affords 13.5 g of solid title compound, m.p. 73-75 C.
NMR (CDC13): o 6.98 (d, J=8.3 Hz, lH, Ar), 6.93 (d, J=5.3 Hz, lH, Ar), 6.74 (t, - J=7.5 Hz, lH, Ar), 3.7 (m, 3H, OCH?OO, 3.68 (m, 2H, NH-C_2). 3.56 (m, lH), 3.33 (m, lH, NH-CH2), 2.49 (q, J-7.6 Hz, 2H, CH~CH3), 2.11 (m, lH, CH~CH2), 1.80 (m, lH, CH2CH2), 1.21 (t, J=7.6 Hz, CH2C_3).
MS: m/e 191 (M+), 130, 118.
B. 7-Ethvl-5-hvdroxvtrvptophol 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 stirring solution of 7-WO 91/06537 Pcr/us9O/06251 2~7~ 2~

ethyl-2,3-dihydrotryptophol (5.0 g, 0.026 mol) in 350 mL of acetone. Ten rninutes after the addition is comple~e, the reaction mixture is extracted with ethyl acetate (4 x 300 mL). The combined ethyl acetate layers are washed with distilled water (2 x 200 rnL), once with brine (200 mL), dried (MgSO4) and concentrated to afford 5.6 g of crude product. The crude product is loaded onto a flash chromatography column. The next day, it is flashed using 70% ethyl acetate/hexane tO afford 2.5 g of title compound.
NMR (DMSO-d6): o 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), 4.55 (t, J-5.3 Hz, lH, CH2O~), 3.57 (m, 2H), 3.32 (s, lH, Ar-OO, 2.7 (m, 4H), 1.20 (t, J=7.5 Hz, 3H).
MS: 205 (M)+, 174, 159.
Analvsis for: Cl2HlsNo2 Calculated: C, 7Q.22; H, 7.37; N, 6.82.
Found: C, 70.15; H, 7.52; N, 6.60.
C. 1.8-Diethvl-1.3.4.9-tetrahvdro-6-hydroxvpvranor3.4-blindole-1-acetic acid methvl ester A mixture consisting of 7-ethyl-5-hydroxytryptophol (15.5 g, 0.076 mol), 20% tetrahydrofuran/methylene chloride (1200 mL), methyl 3-methoxy-2-pentenoate (17.5 g, 0.0121 mol) and boron trifluoride etherate (23.0mL, 0.187 mol) is stirred at room temperature for 28 hours. The reaction mixture is diluted with 100 rnL of methylene chloride and washed with 5% NaHCO3 (3 x 500 mL), once with water, dried (MgSO4) and concentrated to give 30.3 g of crude. Flash chromatography using 25% ethyl acetatelhexane as an eluent afforded 16.0 g of title compound, m.p. 153-154-C.
NMR (CDC13): ~ 8.90 (bs, lH), 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 Calculated: C, 68.12; H, 7.30; N, 4.41.
Found: C, 67.73; H, 7.23; N, 4.24.
D . 1.8-Diethvl- 1.3.4.9-tetrahvdro-6-hvdroxvpvranor3.4-blindole- 1 -acetic acidA mixture consisting of the methyl ester (43.1 g, 0.136 mol) of Step C, potassium hydroxide (2.4g, 0.407mol), 1600mL of methanol and 160mL
water is refluxed for 5 hours under a nitrogen atmosphere. The excess methanol is ~7~ 12 '~
W O 91/06~37 PC~r/US90/06251 evaporated and water (1000 mL) is added to the residue. The mixture is extracted with ether (3 x 500 rnL). The aqueous layer is made acidic with 5% HCI (pH 2), then extracted with chloroform (4 x 300 mL). The combined chloroforrn layers are washed with water (2 x 500 mL), brine (500 mL), dried (MgSO4), and concentrated S under vacuo to yield 43.0 g of foam. Flash chromatography using 15%
acetone/toluene as eluent, affords 40.0 g of foam. This is crystallized from aceto-nitrile/toluene to afford 35.4 g of pure title compound, m.p. 172-173-C.
H NMR (DMSO-d6): ~ 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, 2H), 2.89 (q, 2H), 2.87 (d, J=13.5 Hz, lH, CH2COOH), 2.75 (d, J=15.8 Hz, lH, CH2COOH), 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 (KBr, cm~ 3590 (OH), 1720 (CO).
UV (MeOH, nm): 276 (9940), 295 (6400).
MS: rn/e 303 (M+), 244.
15 Analvsis for: Cl7H2lNO4 Calculated: C, 67.31; H, 6.98; N, 4.62.
Found: C, 66.99; H, 6.80; N, 4.96.
E. 1.8-Diethvl-1.3,4~_tetrahvdro-~2 uinolinylmethoxv)pvranor3,4-blindole-1-acetic acid A mixture consisting of 1,8-diethyl-1,3,4,9-tetrahydro-6-hydroxy-pyrano[3,4-b]indole acetic acid methyl ester (5.0 g, 0.0158 mol), dimethylsulfoxide (250 mL), and potassium iodide (150 mg) is stirred at room temperature. A solution of sodium hydroxide (3.9 g, in 20 rnL H20) is added and sti~red at room temperature followed by addition of 2-chloromethyl quinoline hydrochloride (8.4 g, 0.0392 mol).
25 The reaction mixture is heated at 70-80 C for 3.5 hours, cooled and diluted with water (100 mL). The rnixture is made acidic with lN HCI to pH 4, and extracted with ethyl acetate (3 x 400 mL). The combined organic layers are washed with water (3 x 200 rnL), once with brine (200 mL), dried over MgS04, filtered and concen-trated to give 10.0 g of crude product. The crude product is chromatographed on silica 30 gel using 7% methanoVmethylene chloride as eluent to afford 2.9 g pure product. The latter is dissolved in 200 cc ethyl acetate and precipitated by dropwise addition to petroleum ether (700 mL) to afford 2.7 g of the title compound, m.p. 179-lBl-C.
H NMR (400 MHz, DMSO-d6): ~ 8.38 (d, J=8.5 lH, 4Q), 8.0 (d, J=8.6 lH, 8-Q), 7.97 (d, J-7.2, lH-SQ), 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 6~372~} ~ Pcr/US90/0625 lH ar.), 5.32 (s, 2H-OCH~Q), 3.6 (m, 2H), 2.79 (m, 2H), 2.74 (D, J=15.2 lH), 2.64 (d, J=14.2, lH), 2.55 (m, 2H, 2.0 (q, J=7.2, 2H, CH~CH3), 1.22 tS, J=7.5 3H CH2CH3), 0.66 (t, J=7.2 3H, 8 CH2CH3).
IR: (KBr): 3400 (NH, OH), 1740 (C=O) cm-l.
Mass: (M+-H),445, 239, 217.
Analvsis for: C27H28N2o4 Calculated: C, 72.95; H, 6.35; N, 6.30.
Found:C, 71.04; H, 6.19; N, 6.21.
Example 9 10 1-Ethyl-1,3,4,9-tetrahydro-6-(quinolinylmethoxy)-Dvranor3.4-blindole-1-acetic acid A . L -Ethvl- 1.3.4.9-tetrahvdr~6-(phenvlmethoxv~pvranor3.4-blindole- 1 -acetic acid methvl ester A mixture consisting of 5-benzyloxytryptophol (24.0 g, 0.090 mol), 15 methylene chloride (600 mL), methyl 3-methoxy-2-pentenoate (16.8 g, 0.177 mol) and borontrifluonde etherate (2 mL) is stilred at room temperature for 3 hours. The reaction mixture is washed with 5% NaHC03 (2 x 200 mL), water (2 x 200 mL) and once with brine (200 mL), dried (MgSO4), filtered and concentrated to give 38.0 g crude product. The crude product is flash chromatographed on silica gel using 20 20% ethyl acetate~exane as an eluent to a~ford 29.0 g pure title compound, m.p. 98-100-C.
lH NMR, CDC13): ~ 8.87 (BS, lH NH), 7.47 (d, J=7.3, 2H Bz), 7.36 (t, J=7.6, 2H
Bz), 7.29 (m, lH), 7.24 (d, J=7.S, lH), 7.04 (d, J=2.4, lH3, 6.91 (dd, Jl=8-7, J2=2.4, lH), 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, lH), 2.89 (d, J=16.6 lH), 2.75 (m, 2H), 2.0 (m, 2H), 0.81 (t, ~=7.4 3H CH2CH3).
Mass: (M+) 379, 350, 288.
Analvsis for: C23H2sNO4 Calc~ated: C, 72.80; H, 6.64; N, 3.69.
30 Found: C, 72.61; H, 6.63; N, 3.69.
B. 1-Ethvl-1.3.4.9-tetrahvdro-~(Rhenvlmethoxv!pvranor3.4-blindole-1-acetic acid A mixture consisting of the ester (29.0 g, 0.0765 mol) of Step A, methanol (800 mL), water (50 mL) and potassis~m hydroxide (16.0 g, 0.29 mol) is 7 2 ~ 7 ~ ~t "' ~,~ PCr/US90/06251 refluxed for 4 hours. The reaction rnixture is cooled to room temperature, concentrated and diluted with water (500 mL). The aqueous layer is washed with ether (2 x 200 mL) and made acidic with a 1 :1 mixture of concentrated HCl and water to pH 2.71 is extracted with chloroforrn (4 x 300 mL) and the combined chloroform layers are washed once with water (2 x 300 mL), once with brine (300 mL), dried (MgSO4), filtered and concentrated to give 26.0 g of title compound, m.p. 163-165-C.
lH NMR (400 MHz, CDC13): o 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 lH), 6.90 (dd, Jl=8.8, J2=2.4 lH), 5.10 (s-OC_2 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 (KBr): 3380 (NH), 1710 (CO) cm~
Mass: (M+) 365, ions 336, 306.
Analvsis for: CæH23NO4 Calculated: C, 72.31; H, 6.34; N, 3.83.
Found: C, 72.17; H, 6.29; N, 3.65.
C. l-Ethvl-1.3.4,9-~etrahvdro-6-hvdroxv-~vranor3.4-blindole-1-acetic acid A mixture consisting of 10% Pdk on charcoal (3.5 g), ethanol (800 rnL), tetrahydrofuran (100 rnL) and the acid (21.0 g, 0.056 mol) of Step B, is hydrogenated at 30 psi for 18 hours. The reaction mixture is filtered and concentrated to give 21.0 g of crude product, which is used in the next reaction without further purification.
H NMR (DMSO-d6): ~ 10.36 (s, NH), 7.16 (d, J=7.4, lH Ar), 6.68 (d, J=2.2 lH
Ar), 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), 2.0-1.90 (m, 2H), 0.61 (t, J=7.3 3H
CH2CH3).
IR (KBr): Broad peak. 3700-3300 cm-l (NH, OH), 1710 cm-l (C=O).
Mass: M ion: 275, ion 246, 216, 202.
Analvsis for: ClsHI7NO4 Calculated: C, 65.44; H, 6.22; N, 5.09.
Found: C, 68.82; H, 6.72; N, 4.81.
D. 1-Ethvl-1.3.4.9-tetrahvdr~6-(quinolinvlmethoxv)pvranor3.4-blindole-1-acetic acid A rnixture consisting of the 6-hydroxy pyrano acid (21.0 g, 0.076 mol) of Step C, dimethyl sulfoxide (900mL), sodium hydroxide (180.0g in 100mL

WO 9l/06~37 2 ~ Pcr/us9O/06251 H2O) and 2-chloromethylquinoline hydrochloride (23.0 g, 0.0107 mol) is heated to70-80 C for 1 hour. The reaction mixture is cooled, poured into water (1500 mL) and made acidic with lN HCI to pH 4. It is extracted with ethyl acetate (4 x 500 mL) and the combined organic layers are washed once with water (2 x 300 mL), once with S brine (300 rnL), dried (MgSO4), filtered and concentrated to give 33.0 cmde product, which is chromatographed on silica gel using 7% methanoUmethylene chloride as eluent to afford 13.9 g pure product. The pure product is dissolved in 100 mL ethyl acetate, and precipitated by adding dropwise to petroleum ether (3000 mL), and filtered to give 13.8 g product, which is crystallized from benzene to give 12.0 g of pure product, m.p. 105-C (dec.).
H NMR DMSO-d6: o 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, lH, SQ), 7.78 (dt, Jl=6.9, J2=1.4, lH 7Q), 7.70 (d, J=8.5, lH, 3Q), 7.60 (dt, Jl=6.9, J2=1., lH, 6Q), 7.21 (d, J=8.7, lH ar.), 7.06 (d, J=22.3, lH Ar), 6.82 (dd, Jl=8.7, J2=2.5, lH Ar.), 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).
IR (Kl?.r): 3400 cm-l (NH,OH) 1705 cm-l (C=O).
Mass: FAB: M+H 417 ion M+357.
Analysis for: C2sH25N24 Calculated: C, 72.10; H, 5.81; N, 6.73.
Found: C, 72.55; H, 5.91, N, 6.48.
Example 10 l-Methyl-1,3,4,9-tetrahydro-6-(2-quinolinyl-methoxv)pyranor3.4-blindQIe-l-acetic acid A. l-Methyl-1.3.4~9-tetrahYdro-6-(phenvlmethoxv~pvranor3.4-blindole-l-acetic acid~ ethvl ester A mixture consisting of 5-benzyloxytryptophol (4.5 g, 0.017 mol), benzene (200 mL), 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 mixture is cooled to room temperature and washed with 5% sodium bicarbon-ate, (1 x 200 mL), water (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. 9~98-C.

WO9l/06537 2 ~ 7 ~ 2 PCT/US90/06251 H NMR 400 MHz CDC13: o 8.96(bs,lH,NH),7.47 (d, J=7.0, 2H ar., O-Bz), 7.36 (dt, Jl=7.1, J2=1.8, 2H Ar., O-CH2Bz), 7.3(m,lH,OCH2-Bz), 7.23 (d,J=8.7lH Ar.),7.04 (d, J=2.5,lH Ar.), 6.90 (dd, Jl=8.7,J2=2.3lH Ar), 5.10(s,2H,O-CH2-0), 4.22-4.14(m, 2H),4.01 (m, 2H), 2.98 (d, J=16.5, lH),2.85 (d, J=16.4,lH),2.79 (t, J= 2H),1.7(s,3H,CH2),1.3 (t, J= 3H
COOCH2CH3).
Mass: EI: ~Ve: 379,ions292,158.
B . I -Methvl- 1 .3~4.9-tetrahvdro-6-(phenvlmethoxv~pvranor3~4-blindole- 1 -ace~c A mixture consisting of the ester (5.5 g, 0.013 mol) of Step A., methanol (300 mL), water (20 rnL) and potassium hydroxide (4.0 g, 0.071 mol) is refluxed for 4 hours. The reaction mixture is cooled to room temperature, concen-trated, diluted with water (200 mL) and made acidic with a 1:1 solution of concentrated HCl:water to pH of 1. The mixture is extracted with chlorofo~n (3xlS0 mL), the combined chloroform extracts are washed once with water (2 x 100 mL), once with brine (100 rnL), dried (MgSO4), filtered and concentrated to give 4.6g of product, which is used in ~e next reaction, m.p.157-158-C (dec.).
H NMR (400 MHz, DMSO-d6): ~ 11.98(bs,1H,CCh~D,10.62(s,1H,NH~, 7.45 (d, J=7.1, 2H-Bz), 7.38 (dt, Jl=7.1j J2=1.8, 2H, Bz), 7.30 (m, lH, Bz), 7.18 (d, J=8.7,lH Ar.), 6.99 (d, J=2.3,lH Ar.), 6.76 (dd, Jl=8.7, J2=2.5, lH Ar.), 5.07(s,2H,OCH20),3.95-3.84 (m, 2H), 2.78(d,J=13.8, lH),2.68 (d, J=13.8,lH),2.60 (t, J=5.4,2H),1.56(s,3H).
Mass: ~ Ve: 351, ions 292,260,130.
C. 1-Methyl-1.3.4.9-tetrahvdro-6-hvdroxv-pvranor3.4-blindole-1-acetic acid A mixture consisting of the acid (4.5g,0.013 mol) of Step B, ethanol (150 mL), tetrahydrofuran (20 mL) and 10% Pd/c on charcoal (800mg) is hydro-genated at 30 psi for 18 hours. The mixture is filtered and concentrated to give 3.1 g of product, which is used into next reaction without further purification.
lH NMR (400 MHz, DMSO-d6): ~ 7.19(d,J=8.5,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),l.55(s,3H).
Mass: EI: Mte: 261, ions: 216,160,101.

WO 91/06537 ~ 3 L~ ~ ~ PCr/US90/06251 D. 1 -Methvl- 1 ~3.4.9-tetrahvdro-6-(2-quinolinvlmethoxv)pvranol3.4-blindole- 1 -acetic acid A mixture consisting of 1 -methyl- 1,3,4,9-tetrahydro-6-hydroxy-pyrano[3,4-b]indole-1-acetic acid (3.0 g, 0.011 mol) of Step C, dimethyl sulfoxide (300 rnL), potassium iodide (100 mg) and sodium hydroxide (2.5 g in 20 mL water)is stirred at room temperature. 2-Chloromethylquinoline hydrochloride (5.8 g, 0.022 mol) is added and the reaction mixture is heated for 3.5 hours, cooled anddiluted with water (700 mL). The rnixture is made acidic to pH 4 with IN HCI, extracted with ethyl acetate (4 x 300 mL) and the combined organic layers are washed once with water (2 x 200 mL), once with brine (200 mL), dried (MgSO4), filtered and concentrated to yield crude product, which is flash chromatographed on silica gel using 10% methanoVmethylene chloride as an eluent to give 1.0 g product. The latter is dissolved in ethyl acetate (20 mL) and precipitated by adding dropwise to petroleum ether (500 mL) to give 1.0 g pure compound, m.p. 175-177-C (dec.).
lH NMR (400 MHz DMSO-d6): o 11.2 (bs, lH, NH), 8.37 (d, J=8.5, lH 4Q), 8.0 (d, J=8.7 lH, 8Q), 7.97 (d, J=7.6, lH, SQ), 7.77 (dt, Jl=6.9, J2=1.4, lH, 7Q), 7.69 (d, J=8.5, lH, 3Q), 7.58 (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, J2=2.3 lH Ar), 5.34 (s, 2H, OCH?Q), 3.88-3.84 (m, 2H), 2.62 (bs, 2H), 2.48 (bs, 2H), 1.56 (s, 3H-~).
IR (KBr): 3400 cm ~1 (broad NH, OH, ), 1700 cm-l (C=O).
Mass: EI: M/e: M+ 402, ions 202, 157.
Analvsis for: C24HæN204 Calculated: C, 71.63; H, 5.57; N, 6.96.
Found: C, 69.20; H, 5.38; N, 6.60.
Example 11 1-Ethyl-2,3,4,9-tetrahydro-6-(2-quinolinyl-methoxv)-lH-carbazole-l-acetic acid A. l-Ethvl-23.4.9-tetrahvdro 6-methoxv-lH-carbazole-1-acetic acid methvl ester A mixture 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 hours under a nitrogen atmosphere and the water is removed using a Dean-Stark trap. The reaction mixture is cooled and concentra~ed to give crude hydrazone. (~ 56 g).

~ v ~ v ~
WO 91/06~37 PCI /US90/06251 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 lN NaOH (2 x 500 mL), water (2 x 500 mL), once with brine (500 mL), dried (MgSO4), filtered and concentra~edto give 47.0 g of crude product. The crude product is flash chromatographed using 10% ethyl acetate/hexane as an eluent to afford 18.0 g product; m.p. 72-74 C.
H NMR (400 MHz, CDCl3): o 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, OCH~), 2.68-2.62 (m, 4H), 1.95-1.61 (m, 6H), 0.8 (t, Jl=7.6, 3H, CH2CH3).
Mass: EI: M/e: 301, ions272,228(basepeak).
B . 1 -Ethvl-2~3.4~9-tetrahydro-~hvdroxv- l 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 (450 mL) is heated at 125 C for 6 hours. The reaction mixture is cooled, diluted with water (1500 mL) and extracted with ethyl acetate (3 x 500 mL). The organic layers are combined and washed once with water(2 x 500 mL), once with brine (500 mL), dried (MgSO4), filtered and concentratedtO give 15.8 g product as a foam.
IH NMR (400 MHz, DMSO-d6): ~ 10.21 (s, lH, COO~), 8.45 (bs, lH, N~), 7.03 (d, J=8.5, lH Ar.), 6.63 (d, J=l.9, lH Ar.), 6.48 (dd, Jl=7.3, l2=1.3, lH Ar.), 2.54-2.46 (m, 4H), 1.98-1.66 (m, 6H), 0.70 (t, J=7.3, CH~CH~).
Mass: EI: M/e: 273 (M~) ions244,214, 198.
C. l-Ethvl-2.3.4.9-tetrahvdro-6-(2~uinolinvlmethoxv~-lH-carbazole-l-acetic acid A mixture consisting of the hydroxy acid (8.0 g, 0.028 mol) of Step B, dimethyl sulfoxide (500 mL), potassium iodide (100 mg), and sodium hydroxide (7.0 g in 300 mL H2O 0.175 mol) is stirred at room temperature, 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 acetate (3 x 500 mL). The organic layers are combined, washed once with water (2 x 300 mL), once with brine (300 mL). The organic layers are combined, washed once with water (2 x 300 mL), once with brine (300 mL), dried (MgSO4), filtered and concentrated tO give 9.0 g of crude product which is flash chro-matographed using 10% methanoUmethylene chloride as an eluent to give 3.0 g pure W O 91/06~37 PC~rlUS90/06251 --product, which is dissolved in ethyl acetate (20 mL) and added dropwise to petroleum ether (500 mL). The precipitate is filtered off to give 2.5 g product, m.p. 120-125C.
H NMR (400 MHz, DMSO-d6): ~ 10.80 (bs, lH, NH), 8.37 (d, J=8.5, lH, 4Q), 8.0 (d, J=8.5, lH, 8Q), 7.98 (d, J=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).
Mass: M+ 415 Analvsis for: 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-1-propyl-6-(2-quinolinyl-methox~ ranor3.4-hlindole-1-a~etic açi~l A . Ethvl- 1 -propvl- 1 ~3.4.9-tetrahvdro-~(phenylmethoxv)pvranor3~4-blindole- ] -acetate A solution of 5-benzyloxytryptophol (4.72 g, 17 mmol) and ethyl butyrylacetate (3.16 g, 20 mmol) in methylene chloride (75 ml) is treated dropwise with boron trifluoride etherate (3 mL) and stirred under nitrogen at room temperature overnight. The reaction mixture is diluted with methylene chloride (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 7.0 g of a crude dark oil. Purification by flash column chromatography (ethyl acetate:hexane, 1:9 eluent) on silica gel (50:1 ratio, 230-400 mesh) affords the title compound (5.5 g, 79%) as a slightly amber oil homogeneous by TLC.
H NMR (200 MHz, CDC13): ~ 8.93 (bs, lH, NH), 7.25-7.80 (m, 5H, C6Hs), 7.22 (d, J=9.3 Hz, lH, 8-ArH), 7.04 (d, J=2.8 Hz, lH, 5-ArH), 6.91 (dd, J=9.3, 2.8 Hz, 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, CH2CO2C2Hs), 2.60-2.87 (m, 2H, 4-H's), 1.82-2.20 (m, 2H, l-CH2(a)), 1.25 (t, J=7.0Hz, 3H, CH3 ester), 1.00-1.50 (m, 2H, l-CH2(~)), 0.86 (t, J=7.0 Hz, 3H, l-CH3).

WO91/06537 2~3 ~ PCl/US90/06251 B . Ethvl- I -propvl- 1 ~3~4~9-te~ahvdro-6-hydroxv~yranor3~4-blindole- 1 -acetate A suspension of the 6-benzyloxypyranoindole (5.4 g, 13.25 mmol) of Step A, and 10% Pd/C catalyst (600 mg) in ethanol (150 mL) is hydrogenated for 6hours in a PalT shaker. Filtration of the catalyst and evaporation of the solvent affords 5 the title compound (3~75 g, 89%) as a crearn-colored foam homogeneous 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, 5-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, CH2CO2C2Hs), 2.57-2.88 (m, 2H, 4-H's), 1.82-2.20 (m, 2H, 1-CH2(a)), 1.25 (t, J=7.0Hz, 3H, CH3 ester), 1.00-1.60 (m, 2H, 1-CH2(~)), 0.87 (t, J=7.0 Hz, 3H, 1-CH3).
C . 1.3~4.9-Tetrahvdro- I -propyl-~(2-quinolinylmethoxv~pyranor3~4-~2Lindole- 1 -acetic acid A solution of the ~hydroxypyranoindole (3~5 g, 11 mmol) of Step B, 15 in dimethylsulfoxide (80 mL) is treated with 2~5N NaOH (20 mL, 50 mmol) and stirred at 40 C under nitrogen for 5 minutes. 2-Chloromethylquinoline hydrochloride (4~71 g, 22 mmol) is added as a solid in one aliguot and the reaction mixture heated to 80 C for 30 minutes. After cooling, the pH of the reaction is adjusted to 12.0 with 2.5N NaOH. After ex~action with ether (3 x 250 rnL), the aqueous layer is carefully 20 acidified to pH 3.0 with 2N HCI and 0.1N HCI (near end point) followed by rapid extraction with ether (4 x 300 mL). The cornbined ether extracts are washed withwater (2 x 200 mL), dried (MgSO4), and filtered. Evaporation of the solvent affords a crude yellow foam (4.16 g, 88%). Purification by flash column chromatography (methanol:methylene chloride, 5:95 eluent) on silica gel (10û:1 ratio, 230-40û mesh) 25 affords an amber foam (2.08 g, 61%) homogeneous by TLC. A concentrated methylene chloride solution of the foam is added dropwise to cooled, rapidly stirred, petroleum ether (200 mL). Fil~ration of the resulting precipitate yields the title com-pound as a cream colored arnorphous solid (3.2 g, 61%) homogeneous by TLC. Afterhigh vacuum drying (36 hours) the compound still retains solvent of crystallization as 30 indicated by NMR, m.p. 10û 110-C (dec.).
lR (KBr): 3400 (NH, OH), 1710 (C=O) cm~l.

WO 91/06~37 i3 s~ ;~ PCr/US90/06251 H NMR (400 MHz, CDC13): ~ 8.93 (s, lH, NH), 8.26 (d, J=8.5 Hz, IH, 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, IH, 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=2.4 Hz, lH, 5-ArH), 6.97 (d, J=8.8 Hz, lH, 8-ArH), 6.84 (d, J=8.8, 2.4Hz, lH, 7-ArH), 5.49 (s, 2H, OCH~Q), 4.03 (ddd, J=11.4, 4.7, 4.3Hz, lH, 3-Heq.), 3.92 (ddd, J=11.4, 7.2, 4.8Hz, lH, 3---Hax), 3.05 (d, J=16.8 Hz, lH, 4-Hax), 2.66 (ddd, J=15.4, 4.7, 4.7 Hz, lH, 4-Heq.), 1.91-2.14 (m, 2H, l-cH2(a))~ 1.08-1.48 (m, 2H, l-cH2(~
0.88 (t, J=7.0 Hz, 3H, l-CH3).
MS (EI); m/e 430 (1.4, M+), 160 (50, QCH20H2~E3), 143 (100, QCH3e3).
Analy$i f~r: C26H26N2o4 Calculated: C, 72.54; H, 6.09; N, 6.51.
Found:C, 72.64; H, 7.52; N, 5.41.
Example 13 1-Ethyl-1,3,4,9-tetrahydro-6-(2-quinolinylmethoxy)-~y~ngr3.4-blindole-1-acetic acid. methyl ester Trimethylsilyldiazomethane (40 mL, 10% by weight methylene chloride) is added dropwise to a mixture consisting of l-et'nyl-1,3,4,9-tetrahydro-(2-quinolinylmethoxy)pyrano[3,4-b]indole-l^acetic acid (1.0 g, 0.002 mol) as prepared in Example 9, methylene chloride (150 mL) and methanol (15 mL). The reaction mixture is stilTed at room temperature for 1/2 hour, and is concentrated to give 1.2 g of oily residue, which is very difficult to crystallize. The ester is converted to the hydrochloride salt by adding ether/HCI. The hydrochloride salt is recrystallized from methanoUether to afford 0.75 g pure compound, m.p. 185-187-C.
lH NMR (400MHz, DMSO-d6): o 8.71 (d, J=8.2Hz, lH, 4Q), 8.21 (d, J=8.2Hz, lH, 8Q), 8.13 (d, J=8.2Hz, lH, 5Q), 7.93-7.89 (m, 2H, 3Q, 7Q3, 7.76 (t, J=7.8Hz, 6Q), 7.23 (d, J=8.6Hz, lH Ar), -.10 (d, J=2.6Hz, lH Ar), 6.86 (dd, Jl=8.6, J2=2.3, lH Ar.), 5.5 (s, 2H, OCH2-q), 3.91 (m, 2H), 3.51 (s, 311, COOCH3), 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, J=7.2 Hz, 3H, CH2~
IR (KBr) 3400 cm-l, 3200 cm-l ~NH, OH), 1740 cm~l (C=O).
Mass: EI (m/e) M+ 430, ions 401, 357.

WO 91/06~37 ~ Pcr/US90/062~1 Analvsis for: C26H26N2O4 HCI
Calculated: C, 66.88; H, 5.83; N, 6.00.
Found: C, 66.58; H, 5.75; N, 5.96.
Example 14 1,3,~,9-Tetrahydro-l,l-dimethyl-6-(2-quinolinyl-metho~v)D vranor3.4-blindole A .1.3.4~9~rahvdro- 1. I -dimethvl-6-(~h~nvlmethoxv)pvranor3.4-blindole A mixture consisting of 5-benzyloxytryptophol (3.2 g, 0.012 mol), acetone t7 mL), benzene (300 mL) and ~-toluene sulfonic acid (500 mg) is refluxed 10 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 rnL). It is dried (MgSO4), filtered and concentrated to give 5.0 g product as thick oil. The crude product is flash chromatographed with 15%
ethyl acetate/hexane as an eluent to afford 2.5 g product, m.p. 128- 129 C.
15 B. 1.3.4.9-Tetrahvdro-l!l~imethvl-~hvdroxv-pvranor3.4-blindole A mixture consisting of 10% Pd/c on charcoal (0.7 g), ethanol (150 mL) and 1,3,4,9-tetrahydro-1,1-dimethyl-6-(phenylmethoxy)pyrano[3,4-b]indole (4.2 g, 0.014 mol) of Step A, is hydrogenated at 30 psi for 18 hours. The reaction rnixture is filtered and concentrated to give 3.5 g product which is used in the 20 next reaction without further purification.
C . 1.3.4.9-Tetrahvdro- 1.1 -dimethvl-6-(2-Quinolinvlmethoxv)pvranor3.4-blindoleA 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, 25 0.016 mol~ is heated at 60 C for 24 hours. The reaction mixture 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 30 gel using 40% ethyl acetate/hexane 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. l64-165 C.
H NMR (400MHz, DMSO-d6): ~ 10.68 (s, IH, NH), 8.38 (d, J=8.6Hz, lH, 4Q), 8.0 (d7 1=8.4Hz, lH, 8Q), 7.97 (d, J=8.1Hz, lH, 5Q), 7.77 (t, WO 91/06:~37C~ PCI`/US90/06251 J=7.1 Hz, lH, 7Q), 7.69 (d, J=8.6 Hz, lH, 3Q), 7.59 (t, J=7.1 Hz, lH, 6Q), 7.18 (d, J=8.7 Hz, lH Ar), 7.04 (d, J=2.4 Hz, lH Ar), 6.B2 (dd, Jl=8.6, J2=2.4 Hz, lH Ar), 5 34 (s, 2H, OCH~Q), 3.85 (t, J=5.3 Hz, 2H), 2.56 (t, J=5.3 Hz, 2H), 1.44 (s, 6H, (CH3)2).
S IR (KBr): 3410 cm- (broad NH).
Mass: EI: m/e: 358 (M+),343 143.
Analvsis for: C23H22N2o2 Calculated: 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~ diethyl-6-(2-quinolinyl-methoxv~Dvranor3.4-blindo!e A. 1.3.4.9-Tetrahvdro-l.1-diethvl-6-(phenvlmethoxv)pvranor3.4-blindole A mixture consisting of S-benzyloxytryptophol (7.0 g, 0.0262 mol), 15 diethyl ketone (10 mL), benzene (400 rnL) and p-toluene sulfonic acid is refluxed for 3.5 hours using a Dean-Stark tap to remove the water. The reaction mixture is cooled to room temperature, washed with 5% sodium bicarbonate, water (200 mL), brine (200 mL), dried ~MgSO4), filtered and concentrated to give 9.9 g of crude product.
The crude product is flash chromatographed on silica gel using 15% ethyl 20 acetate/hexane as an eluent to afford 6.5 g of pure title compound.
B. 1.3.4.9-Te~ahvdro-l.l-diethvl-6-(hvdroxv~pvranor3.4-blindole A mixture consisting of 10% Pd/c on charcoal (l.Og), ethanol (125 mL), and 1,3,4,9-tetrahydro-1,1-diethyl-~(phenylmethoxy)pyrano[3,4-b]indole(6.5 g, 0.0193 mol), of Step A, is hydrogenated at 30 psi for 18 hours. The reaction 25 rnixture is filtered and concentrated to give 5.2 g of product which is used in the next reaction without further purification.
C . 1.3.4.9-Tetrahvdro- 1.1 -diethvl-~f2-quinolinvlmethoxv)pvranor3.4-blindole A mixture consisting of the ~hydroxy compound (5.2 g, 0.0212 mol) of Step B, dimethyl sulfoxide (150 mL), sodium hydroxide (6.0 g, 0.15 mol in 30 20 mL water), and 2-chloromethylquinoline hydrochloride (6.0 g, 0.028 mol) isheated to 70-80 C for 6 hours. The reaction mixture is cooled to room temperature, diluted with water (800 mL), and extracted with ethyl acetate (3 x 150 mL). The combined organic layers are washed once with water (2 x 150 mL), once with brine W O 91/06537 2 ~ PC~r/VS90/06251 (100 mL), dried (MgS04), filtered and concentrated to give 9.9 crude product. The crude product is flash chromatographed on silica gel using 25% ethyl acetate/hexane as an eluent to afford 4.5 g pure product as a thick oil. The oil is dissolved in ether (150 mL) and ether/HCI is added dropwise. The precipitate is filtered off and the 5 product crystallized from methanoVether to give 2.6 g product as a yellow crystalline solid, m.p. 164-166-C.
H NMR (400 MHz, DMSO-d6): o 10.64 (s, lH, NH), 8.70 (d, 1=8.6 Hz, lH, 4Q), 8.21 (d, J=8.5 Hz, lH, 8Q), 8.13 (d, J=8.1 Hz, lH, SQ), 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), 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, J=5.4 Hz, 2H), 1.80 (m, 4H, CH~CH3 l,l-diethyl), 0.71 (t, J=7.3 Hz, 6H, CH2~3, l,l-diethyl).
IR: (KBr) 3410 cm-l (NH).
Mass: EI: M/e: 386 (M+) ions 357, 216, 142, 128.
15 Analvsis for: C2sH26N2O2-HCI
Calculated: C, 70.99; H, 6.43; N, 6.62 Found: C, 71.20; H, 6.43; N, 6.66.
Example 16 1-[(4-Chlorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-lH-_ indole-3-acetic acid hvdrochloride ~uarter hvdrate A. 2-Methvl-5-(2~uinolinvlmethoxv)-lH-indole-3-acetic acid. one tenth hvdrate To a previously degassed mixture of dimethylformamide (70 mL) and sodium methoxidelmethanol 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.
25 After 15 minutes 2-chloromethylquinoline (3.46 g, 19.5 mmol) is added and themixture stirred overnight. The dimethylformamide is evaporated and the mixture parti-tioned between pH 4 buffer solution and ethyl acetate. The organic phase is dried (MgSO4), filtered and partially concentrated. A solid is filtered off and crystallized using ethanol - water. This gives the title compound as a solid (2.96 g), 44% yield, 30 m.p. 208-210-C.
Analvsisfor: C21H18N2O3 0.1 H2O
Calculated: C, 72.44; H, 5.26; N, 8.04.
Found: C, 72.29; H, 5.38; N, 7.93.

WO 9l/06537 2 ~ 7 ~ d 2 2 PCr/US90/0625l B. 2-Methvl-5-(2-quinolinvknethoxv)-lH-indole-3-acetic acid methvl ester.
To a stirring mixture of the indole-acetic acid substrate (1.2 g, 3.4 mmol) in tetrahydrofuran (25 mL) is added slowly, a freshly prepared diazomethane/diethyl ether solution at ambient temperature. Upon consumption of 5 starting material, a few drops of acetic acid are added. The solvent is evaporated and methylene chloride is added. This organic phase is washed with water and dried (MgSO4). Solvent removal gives the product as an oil (1.2 g). Yield is quantitative.
C. I-r(4-Chlorophenvl)methvll-2-methvl-5-(2-quinolinylmethoxv)-lH-indole-3-acetic acid methvl ester To a stirring rnixture of the indole-ester substrate (0.8 g, 2.2 mmol) in dimethylformamide (15 mL) is added sodium hydride (0.058 g, 2.4 mmol). The reaction is stirred for 30 minutes at ambient temperature. 4-Chloro-benzylchloride (0.35 g, 2.2 mmol) is then added. After 2 hours the dimethylformamide is evaporated and the residue partitioned using pH 4 buffer solution and ethyl acetate. The organic 15 phase is separated, dried (MgSO4) and filtered. Solvent removal produces a solid that is flash chromatographed using chloroform as eluent, then crystallized with acetonitrile to yield the product as a crystalline solid (0.162 g 16?o yield) m.p. 132-134-C. Analvsis for: C2gH2sN2O3Cl Calculated: C, 71.82; H, 5.20; N, 5.78.
20 Found: C, 71.48; H, 5.17; N, S.88.
D. 1-r(4-Chlorophenvl)methvll-2-meth~1-5-(2-quinolinvlmethoxv~-lH-indole-3-acetic acid hvdr~chloride quarter hvdrate The above ester ~2.2 g, 4.5 mmol) is combined with tetrahydrofuran (50 mL), lN NaOH solution (50 rnL) and heated to reflux ~3.5 hours). The tetra-25 hydrofuran is removed in vacuo and the aqueous phase acidified with lN HCI. Acrude solid is filtered and recrystallized using ethanol to produce 1.16 g of product as the hydrochloride salt (50% yield), m.p. 249-251-C.
Analvsis for: C2gH23ClN2O3 - HCL 1/4 H2O
Calc~ated: C, 65.69; H, 4.82; N, 5.47.
30 Found: C, 65.64; H, 4.92; N, 5.41.

WO 91 /06S37 ~ ~ pcr/us9o/o6251 Example 17 1-(4-Chlorobenzoyl)-2-methyl-5-(2-quinolinylmethoxy)-lH.indole.3.acetic acid three uuarters hvdrate A.1-(4-Chlorobenzovl)-2-methvl-5-(2-quinolinvlmethoxv)-lH-indole-3-ace~c 5acid methv! ester one tenth hvdrate To a solulion of 2-methyl-5-(2-quinolinylmethoxy)-lH-indole-3-acetic acid methylester (O.g5 g, 2.6 mmol) (see Exarnple 16B) in dimethylformamide (10 mL) at O-C is added sodium hydride (0.12 g, 50% dispersion) and the mixture stilTed 20 minutes. 4-Chlorobenzoyl chloride (0.45 g, 2.6 mmol) is then added and 10 the mixture stirred overnight; 100 mL of 5% acetic acid is used to quench the reaction.
After extraction with a 1:1 mixture of ether:ethyl acetate, the organic phase is washed with water, saturated NaHCO3 solution, water and brine. It is then separated and dried (MgSO4). Solvent rernoval gives a crude solid which is flash chromatographed using methylene chloride-methanol (99-1) as eluen~ The product is isolated and crystallized 15 from acetonitrile (0.20 g, m.p. 117-118-C), yield is 15%.
Analvsis for: C2gH23ClN2O4 0.1 H2O
Calculated: C, 69.55; H, 4.66; N, 5.59.
Found: C, 69.35; H, 4.48; N, 5.56.
B. 1-(4-Chlorobenzovl)^2-methvl-5-(2-quinolinv!methoxv)-lH-indole-3-acetic acid three quarters hvdrate To a mixture of the above ester (0.5 g, 1.0 mmol) in acetonitrile (20 rnL) is added iodotrimethyl silane (0.46 g, 2.2 mmol). After refluxing for 24 hours the mixture is diluted with ethyl acetate then washed with 10% Na2S2O3 solu-tion, water and 15% NaHCO3 solution. A precipitate forms which is filtered off, 25 washed with lN HCl and dried in vacuo to give the title compound as a solid (0.05 g, 10% yield), m.p. 191-193-C.
Analvsis for: C2&H2l ClN2O4 . 0.75 H2O
Calculated: C, 67.47; H, 4.55; N, 5.62.
Found: C, 67.6X; H, 4.22; N, 5.94.

WO 91/06537 Pcr/US9O/06251 2 ~ r~
- so -Example 18 2-Methyl-5-(2-quinolinylmethoxy)~1,2-(quinolinyl-methvl)-l~-indQ~-3-aCeti:~ acid-_ To a stirred suspension of sodium hydride (1.4 g, 29.2 mmol) in 5 dimethylformamide (40 mL) at O-C is added 5-hydroxy-2-methyl-lH-indole-3-acetic acid t2.0 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 tempera-ture. After stirring overnight water is added and the pH was adjusted to 5 with 0.5N
HCI. The reaction mixture is extracted with methylene chlonde, the organic extract is 10 dried over MgSO4 and evaporated to a solid which upon sequential trituration with ethanol and hot ethanol affords 2.5 g (52% ) of a beige solid, m.p. 198-200-C.
Analvsis for: C31H2sN~O3 Calculated: C, 76.37; H, 5.17; N, 8.62.
Found:C, 76.72; H, 5.24; N, 8.74.
Example 19 1-[(4-Chlorophenyl)methyl~-5-(hexyloxy)-2-methyl - 1 H.indol~-3-acetic acid A. 5-(Hexv!oxv)-2-methvl-lH-indo!e-3-acetic 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 evaporated, dimethylformamide (40 mL) is added followed by hexyl iodide (35.0 mmol). After 2 days the solvent is removed and the residue is partitioned between ethyl acetate and pH-1 buffer. The organic layer is separated, dried over MgSO4 and evaporated to 8.6 g of a brown solid. Recrystallization from ethanoVwater - 25 affords 6.23 g (62%) of white crystals, m.p. 65-67-C.
Analysis for: C17H23NO3 Çalculated: C, 70.56; H, 8.01; N, 4.84.
Found: C, 70.52; H, 7.98; N, 4.83.
B. l-r(4-Ç~loropbenvl)methv!l-S~hexvloxv)-2-methvl-lH-indole~-acetic acid The acid f~m part A is converted to the methyl ester (m.p. 148-150-C) via diazomethane (see Exarnple 16B). To a solution of the ester (4.5 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 W O 91/06537 ~ ~ 7 ~ P ~ /US90/06251 overnight, the solvent is removed and the residue is partitioned between ethyl acetate and pH=4 buffer. The organic layer is separated, dried over MgSO4 and evaporated to a red solid. Sequential recrystallization from ether and isopropanol gives 2.2 g of crystals (36%), m.p. 148-150C.
5 Analvsis ~or: 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-5-(2-quinolinylmethoxy)-1-(2-quinolinyl-methvl~-lH-indole-3-carboxvlic acid ethvl ester Under an atmosphere of nitrogen, a mixture of ethyl-5-hydroxy-2-methyl-3-indolyl carboxylate (3.5 g, 16 mmol), finely powdered anhydrous potassium carbonate (2.2 g, 16 mmol) and 18-crown-6 (0.48 g, 1.8 mmol) in dry acetonitrile (50 rnL) is stirred at room temperature for 0.5 hours. In one portion 2-chloromethylquinoline (free base, 2.85 g, 16 mmol) is added and the mixture isstirred at 55 C overnight. The reaction (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. Recrystallization from ethyl acetate gives 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 a-Methy1-6-(2-quinolinylmethoxy3-9-(2~quinolinyl-methvl)-9H-carba~ole-2-acetic acid A. 4-Benzvloxvphenvlhvdrazine hvdrochloride A solution of sodium nitrite (3.8 g, 0.055 mol in 20 mL of H20), is added dropwise to an ice cold stirring suspension of 4-benzyloxyaniline (13.0 g,0.055 mol in 150 rnL of concentrated HCI). The reaction mixture is stirred for 90 minutes at -8- to lODC. A solution of SnC12 2H20 (32.0 g, 0142 mol in 50 rnL
concentrated HCI) is added and stirred for 1 hour at O-C. The reaction mixture is removed from the ice bath and is stirred at room temperature for 20 hours. The mixture WO 91/06537 2 ~ 7 ~ Pcr/usso/o6251 is then filtered and washed with water to give 13.0 g (95% yield) of product, m.p.
182- 185'C.
B. 6-Benzvloxv-^methvl-1~2.3~4-tetrahvdrocarbazole-2-acetic acid ethyl 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 room temperature under a nitrogen atmosphere for 2.5 hours. The mixture is then refluxed for 20 minutes, cooled and poured into 200 mL of ice/H20~ The precipitate is filtered ~o give 80 g of red colored crude product.
The crude product is dissolved in ether (600 mL) concentrated H2SO4 (5 mL) is added and the mixture refluxed for 24 hours~ The reaction mixture is cooled, concentrated and diluted with ether (lOOmL), then washed with lN NaOH
(2 x 200 mL), water (2 x 200 mL) and finally once with brine (200 mL), dried over anhydrous MgSO4, filtered and concentrated to give 40~0 g crude product as a thickoiL
C. ~Benzvloxv--methvl carbazole-2-acetic acid ethv! ester A mixture consisting of 6-benzyloxy-a-methyl-1,2,3,4-tetrahydro-carbazole-2-acetic acid ethyl ester (15.0 g, 0~0398 mol) xylene (500 mL), and chloranil (10.0 g, 0.0408 mol) is refluxed in the dark under a nitrogen atmosphere for 24 hours. The reaction mixture is concentrated to 200 mL and the precipitate is removed by filtration. The precipitate is triturated with benzene (3 x 100 mL), the solvent fractions are combined and washed with lN NaOH (3 x 150 mL), washed with water until neutral to pH paper, dried over MgS04, filtered and concentrated to give 15.8 crude product~ The crude product is flash chromatographed on silica gel using 15% ethyl acetate/hexane as an eluent to give 7.5 g product as a thick oiL
D. ~Hvdroxv-a-methvl carbazole-2-acetic acid ethv! ester A mixture consisting of ~benzyloxy-a-methyl carbazole-2-acetic acid ethyl ester (7.3 g, 0.0195 mol) and ethanol (130 mL) is subjected to hydrogenation over 10% Pd/c (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 ~hydroxy--methyl carbazole-2-acetic acid ethyl ester (5~0 g, 0.021 mol), potassium hydroxide (5.0 g, 0~089 mol), methanol 2 ~
W O 91~06537 PC~r/US90/06251 (300 mL), and water (20 mL) is refluxed for 15 hours. The reaction n~ixture is cooled concentrated and acidified with a 1: 1 solution of concentrated 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 concentrated to give 2.6 g 5 of product as a foam.
F. a-Methyl-~(2-quinolinvlmethoxv)-9-(2-quinolinv!methvl)-9H-carbazole-2-acetic acid A mixture consisting of ~hydroxy-a-methyl carbazole-2-acetic acid (2.6g, 0.010mol), dimethyl sulfoxide (200mL), sodium hydroxide (2.0g in 10 20 mL H2O, 0.05 mol) and 2-chloromethylquinoline HCI (4.0 g, 0.018 mol) is heated to 80-C for 3 hours. The reaction mixture is cooled, poured into water (1000 tnL), 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), once with brine (300 mL), dried over MgSO4, filtered and 15 concentrated to give 3.0 g of crude product. The latter is chromatographed on silica gel using 109~o methanoVmethylene chloride as an eluent to give 8 g of product, m.p.
197-199-C.
Analvsis for: C3SH27N3o3 Calculated: C, 78.19; H, 5.06; N, 7.82.
20 Found: C, 76.01; H, 5.02; N, 7.36.
Example 22 1-[(4-Chlorophenyl)methyl]-2-methyl-N-(methyl)-N-(hydroxy)-5-(2-~uinoliny! nethoxv)-!H-indole-3-acetamid~ three quarters hvdrate To a solution of the acid of Example 16 (0.2 g, 0.42mmol), N-methyl-25 hydroxylamine hydrochloride (0.035 g, 0.42mmol) and benzotriazole-1-yloxytris(di-methylamino)phosphonium hexafluorophosphate (0.188g, 0.42mmol) in methylene chloride (5 mL) is added triethylamine (0.12rnL, 2 equiv). The reaction mixture is s~red overnight and then is quenched by addition of brine. After sequential washes with water, 0.5N HCI and water, the organic layer is dried over MgSO4 and evaporated 30 to afford a crude solid, which upon chloroform recrystallization(twice) affords a crystalline solid, m.p. 192-194C. This material is washed sequentially with 0.5N
NaOH and water and dried to afford white crystals, m.p. 191-193C.

wo 91/06~37 Pcr/US90/06251 2 ~ ~ /l',?, '., Analvsis for: C2gH26ClN303 3/4 H20 Calculated: C, 67.83; H, 5.39; N, 8.18.
Found: C, 67.87; H, 5.10; N, 8.39.
Example 23 1-[(4 Chlorophenyl)methyl]-2-methyl-N-(phenylsulfonyl)-5-(2-auinolinylmethoxv)-lH-indole-3-acetamide To a soluhon of the acid of Example 16 (l.Og, 2.12mmol), benzene-sulfonamide (0.34g, 2.12mmol) and benzotriazole-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (0.94g, 2.12mmol) in methylene chlonde(25 mL) is added ~iethylamine (0.6mL, 2 ec,uiv). The reaction mixture is stirred overnight and then is quenched by addition of brine. After sequential washes with waler, 0.5N HCl and water, the organic layer is dried over MgSO4 and evaporated to afford a crude solid, which upon toluene recrystallization affords a crystalline solid, m.p. 194-197C.
Analysis for: C34H2gClN304S
Calçulated: C, 66.93; H, 4.63; N, 6.89.
Found: C, 67.01; H, 4.66; N, 7.33.
Example 24 1-[(4-Fluorophenyl)methyl]-2-methyl-5-(2-quinolinyl-methoxv~-lH-indo!e-3-acetic acid hemihvdrate The title compound is prepared according to the method of Exarnple 16 using 4-fluoro'oenzyl bromide. A crys~alline solid is obtained, m.p. 199-202C.
Analvsis for: C2gH23FN203 1/2 H20 Calculated: C, 72.55; H, 5.21; N, 6.04.
Found: C, 72.84; H, 5.31; N, 5.68.
Example 25 1-[(4-Bromophenyl)methyl]-2-methgl-5-(2-quinolinyl-methoxv)-1H-indole-3-acetic acid hemihvdrate The title compound is prepared according to the method of Example 16 using 4-bromobenzyl bromide. A crystalline solid is obtained, m.p. 215-217C.

~ " ~ ''. .1 ~) '1 `~0 91/06537 ~ J ~ "J Pcr/us90/06251 Analvsis for: C2gH23BrN2O3 1/2 H20 Calculated: C, 64.12; H, 4.61; N, 5.34.
Found: C, 64.40; H, 4.76; N, S.01.
Example 26 1-[(Phenyl)methyl-2-methyl]-5-(2-quinolinyl-m~thsxv)-lH-indole-3-a~i~ acid tenth hvdrate The title compound is prepared according to the method cf Example 16 using benzyl bromide. A crystalline solid is obtained, m.p. 199-202C.
Analvsisfor: C28H24N2O3 0.1 H2O
~alculated: 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-uinolin~lm~ho~v)-lH-indole-3-acetic a~i~
The title compound is prepared according to the method of Exarnple 16 using 4-(chloromedlyl)benzoic acid. A crystalline ~olid is obtained, m.p. 232-234C.
Analvsis for: C29H24N25 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)-nhenv!lmethvll-lH-indQle-3-acetic acid h~mibvd~ate The title compound is prepared according to the method of Example 16 using 4-(2-quinolinylmethoxy)benzyl chloride. A crystalline solid is obtained, m.p.
182-185C.
Analvsis for: C3gH3lN3O4 1/2 H20 Calculated: C, 75.73; H, 5.35; N, 6.97.
Found: C, 75.41; H, 5.33; N, 6.78.

W O 91/06537 ~ PC~r/~S90/06251 Example 29 2-Methyl-l-pentyl-5-(2-quinoliny1methoxy)-l~.indole-3-acetic acid hemihydrate The title compound is prepared according to the method of Example 16 5 using pentyl iodide. A crystalline solid is obtained, m.p. 90-93C.
Analysis for: C26H2gN2O3 - 1/2 H20 Calculatç~. C, 73.38; H, 6.86; N, 6.58.
Found: C, 73.37; H, 7.11; N, 6.41.
Example 30 1-Hexyl-2-methyl-5-(2-quinolinylmethoxy)-lH-indole-3-acetic acid three ~uarters hvqrate The title compound is prepaled according to the method of Example 16 using hexyi iodide. A crystalline solid is obtained, m.p. 122-124C.
Analvsis for: C27H30N2o3 - 3/4 H2O
15 Calculated: C, 73.03; H, 7.15; N, 6.30.
Found: C, 73.25; H, 7.10; N, 6.30.
Example 31 l-Heptyl-2-methyl-5-(2-quinolinyl-methol~y)-lH-indole-3-acetic acid The title compound is prepared according to the method of Example 16 using heptyl iodide. A crystalline solid is obtained, m.p. 127-131C.
Analvsis for: C28H32N2o3 Calculated: C, 75.65; H, 7.26; N, 6.30.
Found: C, 75.80; H, 7.19; N, 6.26.
Example 32 l-Methyl-2-methyl-5-(2-quinolinyl-nethoxv~-lH-indo!e-3-acetic acid The title compound is prepared according to the method of Example 16 using methyl iodide. A crystalline solid is obtained, m.p. 18~ 188C.

2~7~
WO 91/06~37 pcr/us9o/o6251 Analvsis for: C22H20N23 Calculated: 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-methoxv~-1 H-indole-3-acetic acid The title compound is prepared according to the method of Example 16 using 5-hydroxy-lH-indole-3-acetic acid. The desired product is obtained as white crystals, m.p. 158-159C.
10 Analvsis for: C27H2lclN2o3 Calculated: C, 70.97; H, 4.63; N, 6.13.
~: C, 71.13; H, 4.67; N, 6.03.
Example 34 1-[(4-Chlorophenyl)methyl]-2-methyl-5-(2-naphthalenyl-_ methQxY)-l ~-indo!e-3-acetic acid The dde compound is prepared according to the method of Exarnple 16 using 2-(bromomethyl)naphthalene. A clystalline solid is obtained, nLp.168-170C.
Analvsis fo~: C2gH24ClNO3 Calculated: C, 74.12; H, 5.15; N, 2.98.
20 Found: C, 74.43; H, 5.31; N, 2.74.
Example 35 . 1-1(4-Chlorophenyl)methyl]-2-methyl-5-(nhenvlmethoxv~-lH-indole-3-acetic acid The ide compound is prepared according to the method of Example 16 25 using benzyl chloride. A crystalline solid is obtained, m.p. 140-142C.
Analvsis for: C2sH22ClNO3 Calculated: C, 71.51; H, 5.28; N, 3.34.
Found: C, 71.54; H, 5.29; N, 3.47.

Wo 91/06537 PCr/US90/06251 Example 36 1-[(4-Chlorophenyl)methyl]-2-methyl-5-(2-nvridinvlmethoxv)-lH-indole-3-acetic acid The title compound is prepared according to the method of Example 16 S using 2-(chloromethyl)pyridine. A crystalline solid is obtained, m.p. 231-233C.
Analvsis for: C24H2lclN2o3 Calculated: C, 68.49; H, 5.03; N, 6.66.
Found: C, 68.61; H, 5.12; N, 6.39.
Example 37 1-[(4-Chlorophenyl)methyl]-2-methyl-5-(2-benzo-thiazolvlmethoxv)-lH-indole-3-acetic acid A. 2-Methvl-5-(2-benzothiazolvlmethoxv~-lH-indole-3-acetic acid ethvl ester To a mixture of 5-hydroxy-2-methyl- lH-indole-3-acetic acid ethyl ester (5.6 g, 17.15 mmol) and cesium carbonate (15.0 g, 46.04 mmol) in dimethylsulfoxide 15 (70 rnL) that has been previously stirred for 30 minutes is added 2-(chloromethyl)-benzothiazole (4.6 g, 25.08 mmol). After 1 hour the reaction is poured into ice water and extracted with ethyl acetate. The organic layer is washea sequentially with 0.1N
NaOH, water and brine, dried over MgSO4 and evaporated to a black oil which is purified by flash chromatography (eluant: ethyl acetate-hexane) to afford 5.4g (59%) of 20 the aL~cylated ester.
B. 1-r(4-ChlorophenYl)methvll-2-methvl-5-(2-benzothiazolvlmethoxv)-lH-indole-3-acetic acid The title compound is prepared according to the method of Example 16 using 2-methyl-5-(2-benzothiazolylmethoxy)-lH-indole-3-acetic acid ethyl ester and 4-25 chlorobenzyl chloride; however, the hydrolysis is carried out in aqueous methanol.Recrystallization from acetonitrile affords 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 ~ .r~
`~0 9t/06~37 PC~r/US90/06251 Example 38 1-[(4-Chlorophenyl)methyl]-2-methyl-5-[(2-phenyl-4-thiazolvl)methoxvl-1H-indole-3-acetic acid The title compound is prepared according to the method of Exarnple 37 5 using 4-(chloromethyl)-2-phenylthiazole. White crystals are obtained, m.p. 150-151C.
Analvsis for: C2gH23ClN2O3S
Calculated: C, 66.86; H, 4.61; N, 5.57.
Found: C, 66.46; H, 4.59; N, S.S9.
Example 39 1-[(4-Chlorophenyl)methyl]-2-methyl-5-[[2-(4-trifluoromethyl-~henvl)-4-thiazQIvllmethnxYl-lT~-indole-~-acetic acid The title compound is prepared according to the method of Example 37 using 4-chloromethyl-[(4-trifluoromethyl)-2-phenyl]thiazole. White crystals are 15 obtained, m.p. 19~197~C.
Analysis for: C2gH22ClF3N2O3S
Calculated: C, 61.00; H, 3.88; N, 4.91.
Found: C, 60.95; H, 3.97; N, 4.89.
Example 40 1-~(Phenyl)methyl]-2-methyl-5-[(2-phenyl-4-thiazolvl~methQxvl-1T~-indole-3-~cetic acid The title compound is prepared according to the method of Example 37 using 4-(chloromethyl)-2-phenylthiazole and benzyl chloride. White crystals are obtained from toluene, m.p. 150-151C.
25 Analvsis for: C2gH24N2O3S
Calculated: C, 71.77; H, S.16; N, 5.98.
Found: C, 71.53; H, 5.11; N, 5.90.

WO 91/06537 ~ ~.j 7 ~ ¢~ ~ ,.,, PCI /US90/06251 Example 41 2-Methyl-S-(2-quinolinylmethoxy)-1-[[4-(2-quinolinyl-~tlloxv)Dhenvllme~-lH~ind~e-3-acetic acid A. 2-Methvl-5-(2-quinolinvlmethoxv)-lH-indene-3-acetic acid methvl ester A mixture of 2-methyl-S-hydroxy-lH-indene-3-acetic acid methyl ester (1.8 g, 8.25 mmol), powdered anhydrous potassium carbonate (1.13 g, 8.25 mmol) and 18-crown-6 (0.219 g) in acetonitrile (21 mL) is stirred at room temperature for 15 minutes. 2-(Chloromethyl)quinoline (1.6 g, 9.08 mmol) is then added and the mixture is stirred for 15 hours at 65C. After the solvent is removed, the residue is partitioned 10 between water and ethyl acetate. The organic phase is dried over MgSO4 and evaporated. The crude product is purified by flash chromatography (eluant: methylene chloride-ethyl acetate) to afford 2.35 g (79%) of the desired product.
B. 2-Methyl-5-(2-quinolinvlmethoxv)-1-rr4-(2-quinolinvlmethoxv)phenvll methv!enel-1H-indene-3-acetic acid lS To a solution of the above ester (1.77 g, 4.93 rnmol) in anhydrous methanol (20 mL) is added 4-[(2-quinolinyl)methoxy]benzaldehyde (1.63 g., 6.19 mmol) followed by dropwise addition of 2S% methanolic sodium methoxide(3.46 ~).
After the reaction rnixture is refluxed for 13 hours, the solvent is removed and water is added. The pH is adjusted to 6.5 and the resulting precipitate is extracted sequentially 20 with methylene chloride and ethyl acetate. The combined extracts are dried over MgSO4 and evaporated to a crude solid which is triturated with diethyl ether and then redissolved in hot ethyl acetate. After the insolubles are filtered off, the solution is concenttated until precipitation occurs. The precipitate is filtered, washed diethyl ether and hexane and dried to afford 1.31 g(45%) of the desired product as a Z/E rnixture 25 (7.6/1), m.p. 191-193C(dec.).
Analvsis for: C3gH30N204 Calculated: C, 79.30; H, 5.12; N, 4.74.
Found: C, 79.11; H, 5.05; N, 4.59.

W O 91/06537 2 ~ 7 ~i d ~ PC~r/US90/06251 Example 42 N-[[1-[(4-Chlorophenyl)methyl]-2-methyl-5-(2-quinolinyl-metho~v~-1H-indol-3-vllmethvll-N'-hvdrnxvurea To a solution of the acid of Example 16 (0.72 g, 1.52 mmol), in S benzene (25 mL) is added triethylarnine (0.23 mL, 1.1 equiv) followed by diphenyl-phosphoryl azide (0.46 g,1.1 equiv). After the reaction mixture is heated at 90C for 1 hour, a solution of hydroxylamine hydrochloride (0.23 g, 2.2 equiv.) in a mixture of triethylamine (0.46 rnL) and water (0.25 mL) is added to it, and the reaction mixture is heated at 90C overnigh~ The reaction is quenched by addition of ammonium chloride solution, and the resulting precipitate is filtered off, washed with water and ethyl acetate and dried to afford 0.45 g (59%) of a white solid, m.p. 184-186C.
Analvsis for: C28H2sclN4o3 Calculated: C, 67.13; H, 5.03; N, 11.18.
Found: C, 66.85; H, 5.06; N, 10.85.
Examele 43 The compounds 5- and 12-hydroxyeicosatet~aenoic acid (5-HETE and 12-HETE) and LTB4 are early arachidonic acid oxidahon products in the lipoxygenase cascade, which have been shown to mediate several aspects of inflamrnatory and aller-gic response. This is especially true with respect to 5,12-diHETE, which is alsodenoted as LTB4 [see Ford-Hitchinson, J. Rov. Soc. Med., ~, 831 (1981)~. Com-pounds which inhibit the PLA2-mediated release of arachidonic acid thereby effeclively prevent the oxidation of arachidonic acid to the various leukotriene products via the lipoxygenase cascade. Accordingly, the specificity of action of PLA2 inhibitors can be determined by the activity of test compounds in this assay, which measures the ability of compounds to inhibit the synthesis of LTB4 by rat glycogen-elicited polymorpho-nuclear leukocytes (PMN) in the presence of exogenous substrate.
The assay is carried out as follows:
Rat polymolphonuclear leukocytes (PMNs) are obtained from female Wistar rats (150-200 g) which receive an injection of 6% glycogen (10 ml i.p.). Rats are sacrificed 18-24 hours post injection by CO2 asphyxiation and the elicited cells are harvested by peritoneal lavage using physiological saline (0.9% NaCI). The exudate is centrifuged at 400 xg for 10 minutes. The supernatant fluid is discarded and the cell WO 9l/06S37 2 ~ 7 ~ Pcr/usgo/n6251 -pellet is resuspended to a concentration of 2.0 x 107 cells/mL in HBSS containing Ca++ and Mg~ and 10 ~LM L-cysteine.
To 1 mL aliquots of cell suspension, test drugs or vehicle are added, then preincubated at 37 C for 10 minutes. A23187 (1 IlM), [3H]-AA (3.0 ~Ci/mL) and S unlabeled AA (1 IlM) are then added and the sarnples are further incubated for 10 minutes. The reaction is terminated by centrifugation and pelleting cells. Supernatants are then analyzed by HPLC analysis on a 15 cm x 4.6 mm ID supelcosil LC-18 (Supelco)(3M) column, using 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
Solvent B. CH3CN
Gradient: (system is equilibrated with Solvent A) Tirne Percent A Percent B
o 100 1515.0 100 0 20.0 65 35 40.0 65 35 42.0 10 90 50.0 10 90 20~0.1 100 0 Percent solvent changes are accomplished in a linear fashion.
Injections: 140 llL of each supernatant is injected directly onto column and 3H
arachidonic acid metabolites are monitored using an on-line radioactivity detector (Ramona, IN/US, Fairfield, NJ).
Standards: 104 - 2.0 x 104 dpm of eicosanoids of interest are injected in 90 IIL EtOH cocktail.
Co-chromatography with standard [3H] leukotriene B4 (LTBq) in medium of stimulated PMN exposed to drug is compared to that found in medium of stimulatedcells exposed to no drug, generating percent inhibition.
Results are expressed as percent inhibition at a given compound dose or as an ICso value.
Testing compounds of the invention in this assay gave the following results:

W O 91/06537 2 ~ 7 ~ d ~, ' P ~ /US90/06251 Table I
Compound of Example No. % Inhibition carprofen -10* (at lO~lM) S etodolac 21 (atO.S~
indomethacin 31 (at lOIlM) sulindac -10* (at IO~M) 96 (at lOIlM) 2 96 (at lOIlM) 4 92 (at O.S~
8 91 (at lOIlM) 9 96 (at lOIlM) 91 (at lOIlM) 11 95 (at lO~LM) IS 14 91 (at lOIlM) 16 96 (at lOIlM) 16C 88 (at 0.511M) 17 46 (at 0.511M) 17A 96 (at lO~
18 88 (atO.S~M) 92 ~at lO~
21 92 (at lO,uM) 24 97 (at lOIlM) 93 (at lO~lM) 26 85 (at lO~
29 88 (at lO~lM) 90(at lO~
31 85 (at lOIlM) 41 100 (at lO~lM) * negative number denotes potentiation E~amn~e 44 The procedure of Example 43 is also employed for the determination of the extent to which compounds of the invention inhibit the synthesis of the arachidonic acid cyclooxygenase oxidation product PGE2.

W O 91/06~37 P ~ /VS90/06251 ~
2 ~

In this assay, the procedure of Example 43 is carried out as described.
However, in order to determine cyclooxygenase activity, the samples are co-chromatographed with authentic reference [3H]-PGE2.
The results are calculated as in Example 43 and presented below:
Table II
Compound of Example No. % Inhibition carprofen 83 (at lOIlM) etodolac 100 (atO.51lM) 10 indomethacin 100 (at lO~M) sulindac 23 (at lO~M) 81 (at lO~
2 92 (at lO~lM) 4 7 (at 0.5',1M) 8 47 (at lO~
9 75 (at lO~lM) -41 * (at lO

11 80 (at lO
14 -48* (at lO~
16 * (at lO~M) 16C * (at lO~
17 60 (atO.511M) 17A 50 (at lO~M) 18 -31* (at 0.5~
* (at lO~LM) 21 -94* (at lOIlM) 24 -126* (at lO',lM) -67* (at lO~
26 -125* (at lOIlM) 29 -123* (at lOIlM) -130 *(at lOIlM) 31 -145 *(at lOIlM) 41 -21~ (at 0.5 * Denotes a potentiation of cyclooxygenase (PGE2 syn~esis).

3 !~
W O 91/06537 P ~ /US90/06251 E~am~l~ 45 The compounds of the invention are tested in an in vitro isolated phospholipase A2 assay to determine the ability of the test compounds to inhibit the release of arachidonic acid from an arachidonic acid-containing substrate by the action 5 of phospholipase A2 enzyme from human and non-hurnan sources.
This assay is carried out as follows:
Into a 15 rnL polypropylene tube are added the following:
Agent Volume! ~ILFinal Conc.
3H-AA E. coli substrate 1 25 5 nmoles PL
10 CaC12 (O.lM) 2 5 SrnM
Tris-HCI ~O.SM) pH 7.5 32Q 100 mM
Water 4 25 Drughehicle 5 1 50,uM
PLA2 25 Volume yielding 12%
hydrolysis in 10 min.

* pre-incubate at room temperature 30 min prior to substrate addition.
Prepared by adding 2 mL deionized and distilled water to 2 rnL
3H-arachidonate 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 S m substrate (containing 1000 nmoles phospholipid).
2 Stock 0.1 m CaC12, required for enzyrne activity.
3 Stock 0.5 m Trisma-Base.
Stock 0.5 M Trisma-HCI. Adjust pH to 7.5 (optimum for enzyme).
25 4 Deionized and distilled water.
S Stock 10 rnM prepared in dimethyl sulfoxide. Make 1:2 dilution with dimethyl sulfoxide and add 1 ~L to 100 ,uL assay tube.
6 Two human PLA2 enzymes are used:
a) Semi-purified human platelet acid extract PLA2 (in 10 mM
30sodium acetate buffer, pH 4.5). Remove protein precipitate by centrifugation at about 2200 rpm for 10 minu~es.
b) Purified human synovial fluid.
Incubate the lOO~lL reaction mixture for 10 minutes at 37-C in a shaking water bath. The reaction is terminated by the addition of 2 rs~L tetrahydrofuran, followed by WO 91/06~37 Pcr/uS90/06251 vortexing. NH2 columns (100 ~g/mL - Analytichem International) are conditioned with 0.5 mL tetrahydrofuran followed by 0.5 mL tetrahydrofuran/water (2 mL:0. I mL, v/v).
The sample is loaded onto the columns and slowly drawn through them. The 5 hydrolyzed arachidonic acid retained in the columns is eluted therefrom with 1 mL
tetrahydrofuran/glacial acetic acid (2%). The arachidonic acid is transferred toscintillation vials and quantitated by ,B-counting analysis. A "total counts" sample is prepared by pipetting 25 ~lL 3H-arachidonate E. coli directly into a scintillation vial to which is added l mL tetrahydrofuran. 10 mL aquasol (scintillation cocktail) is added lO to all samples.
Calculations:
[3HlAA dpm (sample) - ~3H]AA dpm (nonspecific hydrolysis) % hydrolysls = x 100 total counts dpm vehicle dpm - drug dpm % change = x 100 vehicle dpm ~ç~vitv of Sta, ndard Dru~s:
, I C ~ o t~,l M ), Hurnan Platelet Human Synovial PLA~ PLA
Arachidonic Acid 8.6 3.2 Monoalide 25.2 0.14 When tested in this assay, the compounds of the invention gave the following results:
Table m % Inhibition at 10 ~lM lCso (~IM) Compound of 25Ex~ple No. ~ HSF** ~ HSF
sulindac 33 34 30.2 indomethacin 38 (atSOIlM) 144.8 --- 9.7 2' 3.6 l6 46 4.1 l7 58 14.9 18 47 30 27.0' W O 91/06~37 2 0 7 ~ 2P ~ /US90/06251 Table III (cont'd.) %Inhibitionat IO~IMIC~o (~lM) Compound of Example No. HP* HSF** HP HSF

26 92 2.6 29 53 15.5 46 16.4 34 33.7 3S 28 52.9 41 90 3.8 * human platelet ** human synovial fh~id ~m~
The ability of the compounds of the invention to inhibit paw edema induced by the exogenous administration of PLA2 is measured in the in vivo PLA2 murine paw edema assay.
The assay is camed out as follows:
Non-fasted, male CD-1 mice (8 weeks old; 31-36 grams) are placed in plastic boxes in groups of six. The right hind paw volume is measured using mercury plethysmography (zero time). Compounds are dosed orally (0.5 mL of 0.5% Tween-80) 1 or 3 hours prior to PLA2 injection or intravenously (0.2mL in 0.3 %

W O 91/06537 ~ g' ~ PC~r~US90/06251 dimethylsulfoxide/saline) 3 minutes prior to PLA2 injection. A solution of purified PLA2, from the diamond back cotton mouth snake (A. piscivorus piscivorus) is prepared in saline at a concentration of 6 ~g/mL. Fifty (50) ~,lL (0.3 ~g) of this PLA2 solution is injected subcutaneously into the right hind paw with a plastic 1 mL plastic 5 sylinge (27 gauge, 1" need~e). Paw volume of the injected paw is measured again at 10 minutes, 30 minutes and 60 minutes after PLA2 injection. Animals are euthanized with C2 at the completion of the study.
The paw edema is calculated by subtracting the zero time volume from the volume recorded at each time period. Mean paw edema for each treatment group is then 10 calculated and expressed as (~lL + S.E.). Drug effects are expressed as a percent change from control (vehicle) values. Statistical significance is determined by a one-way analysis of variance with LSD comparison to control (p < 0.05). EDso's are determined using repression analysis.
The activity of standard drugs in this assay is as follows:
EDso mg/kg p.o.
Compolmd at +10 min.
Cyproheptadine 3. 1 Dexamethasone* 10 Naproxen 18 Aristolochic Acid ** Not Active Luffarrellolide ** Not Active * p.o.-3hr.
** Some activity (30% inhibition) only when co-injected with enzyme.
When tested in this assay, the compounds of the invention gave the following results:
Table IV
% Chan~e in Edema Compound of Dose 30Example No.m g/k ~ 10 min 30 min 60 min indomethacin10 (p.o.)** -32 -31 -42 10 (i.v.)* -6 -g -40 100 (p.o.) +4 -27 -6 2 10 (i.v.) -39 -43 -37 3~ 100 (p.o.) -6 -22 +18 -18 30 (i.p.)*** -19 ~VO 9t/06537 2 ~ 7 ~ L~ 2 ~ PC~r/US90/06251 19 30 (i.p.) -30 60 (i.p.) -34 * intravenous ** peroral 5 *** intraperitoneal The results show that the compounds of the invention are effective in vivo in inhibiting edema induced by the exogenous administration of snake venom PLA2.
Exam~le 47 The compounds of the invention are evaluated for their ability to inhibit the lipoxygenase and/or cyclooxygenase pathways of arachidonic acid metabolism in the in vivo murine zymosan peritonitis assay.
This assay is carried out as follows:
Male CD-1 mice (8 weeks old) are placed in plastic boxes in groups of six.
15 Animals are injected with 1 mL i.p. of either 1% zyrnosan in pyrogen free 0.9% saline or saline (unstirnulated control). Compounds are dosed orally 1 hour pnor to zymosan injection. Twenty minutes after zymosan injection, the rnice are asphyxiated by CO2 inhalation and the peritoneal cavity is lavaged with 2 mL ice cold Hanks Balanced Salt Solution (HBSS) without CaC12, MgSO4 7H20 and MgC12- 6H20. Peritoneal 20 lavage fluid from each mouse is removed by syringe and placed in 5 rnL plastic test tubes put on ice and volume is noted. Preparation of samples for evaluation by ELISA
is as follows: Samples are centrifuged at 800 xg for 15 minutes; 1 mL of the supernatant is added to 8 rnL ice cold methanol and kept at -70 C overnight to precipitate protein; and samples are then centrifuged at 800 xg for 1~ minutes, followed 25 by a drying procedure in a Savant speed vac concentrator. The samples are reconstituted with 1 mL ice cold ELISA buffer and stored at -70-C until assayed. The assay for eicosanoids (LTC4 and 6-keto-PGFla) is performed according to conventional ELISA procedures.
Compounds to be tested orally are suspended in 0.5% Tween 80.
30 Compounds to be tested intraperitoneally are suspended in 0.5% methylcellulose in 0.9% saline.
The total metabolite level in lavage fluid/mouse is calculated and the significance is determined by a one-way analysis of variance with LSD comparisons to control (p S 0.05). Drug effects are expressed as a percent change from control values.

W O 91/06537 ~ r~;~) PC~r/US90/06251 The activity of standard drugs in this assay is as follows:
Compound E D s o m /k ~ p . o .
LTC4 6-keto-PGFI,~/TxB7 B W 755C <10 22.0 S Phenidone 24.0 <30.0 Indornethacin Not Active 0.126 Ibuprofen Not Acive 7.0 When tested in this assay a compound of the invention and the anti-inflammatory compound etodolac gave the following results:
TableV
% Inhibition Compound of Dose Example No. m~/k~ LTÇ_ 6-keto-PGF
indomethacin lO (p.o.) * +25 ~5 10 50 (p.o.) 11 -5 **
11 50 (p.o.) -49 ~* 47 * perorally administered ** negadve values denote potentiadon The ~esults show that the compounds of the invendon exert an inhibitory 20 effect on both the lipoxygenase pathway and the cyclooxygenase pathway.

Exam~1~ 48 The LTD4 antagonist activity of the compounds of the invention is assessed in the in vitro isolated guinea pig trachea assay.
This assay is carried out as follows:
Male Hartley guinea pigs (350400 g) are euthanized by a blow to the head, the neck is opened and the trachea removed. The trachea is maintained in aerated physiological salt solution, cleared of connective tissue and fat and cut into rings approximately 2 mm in width (usually containing two cartilaginous segrnents per ring).
30 Two pieces of silk suture are then passed through the lumen of the tracheal ring and are tied around the cartilage, one on each side of the trachealis muscle. The tracheal ring is suspended between a glass hook and a force displacement transducer in a lO mL organ bath for measurement of isometric tension. Tissues are maintained at 37 C in aerated 2 ~ r,~

(95% C02/5% C02) physiological salt solution of the following composition: NaCI
(100 mM), KH2P04 (1.18 mM), KCI (4.74 mM), CaC12 (2.5 mM). MgS04 7 H20 (1.19 mM), NaHCL3(25 mM), dextrose (11.1 mM) and indomethacin (1 ~M). The tracheal rings are maintained at 2 g resting tension and equilibrated for 45 minutes (with 5 frequent washing and readjustment of resting tension).
The tracheal rings are first contracted by the addition of carbachol (3x10-6M), to deternune tissue responsiveness and establish a reference contraction. On attainment of a stable level of contraction (approximately 30 minutes), the tissues are washed several times until baseline tension has been restored and then re-equilibrated for 30 minutes.
10 The tissues are then incubated for 45 minutes with a test antagonist (either lxlo-fiM or lx1~5M) or 10 ~L of an appropriate solvent control (control, non-treated). One tissue in each group serves as the control. Twenty minutes prior to the construction of the LTD4 cumulative concentration-response curve, L-cysteine (lx10-2M final bath concentration) is added to inhibit bioconversion of LTD4 to LTE4. Only one LTD4 15 concentration-response curve is constructed in each tissue.
All responses to LTD4 in an individual tissue are measured as a percentage of the reference contraction of that tissue to carbachol. LTD4 antagonist activity is determined by comparison of the concentration response curves of LTD4 in the presence and absence of antagonist. Assessment of the relative rightward shift of the 20 antagonist treated curve relative to the solvent (control) treated tissue is calculated as a concentration ratio (Eq. A) and used in subsequent calculations to derive an antagonist pKg value (Eqs B and C). In the event that the maximum response to LTD4 is depressed, the ECso for that particular curve is deterrnined, an "apparent" pKg reported, and the compound reported as "non-competitive."
ECso treated tissue A) Concentration Ratio (CR) =
ECso control [Test Compound]
B) KB=
CR-l C) -log KB = PKB
If a compound is found to be active and/or depress the maximal response to LTD4, then a range of concentrations of the test compound should be used generating 30 multiple concentration ratios which would then be used to perform a Schild analysis, and deteImination of a pA2 value where appropriate.

WO 91/06537 ~ 3 ~ ~ ~ Pcr/US9O/06251 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 Whén tested in this assay, a compound of the invention gave the following results:
Table VI
Compound of Example No. ~Concentration Ratio (M~
9 6.26+0.28lx10-5 18 5.85 + 0.12 1 x 10-5 The above results demonstrate that the compounds tested have significant leukotriene antagonist activity as measured in the in vitro isolated guinea pig 15 trachea assay.
~am~2 The compounds of the invention are further tested in the rat carrageenan paw edèma assay to determine their ability to inhibit the acute inflammatory 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 of 1 % caTTageenan at zero time. Mercury plethysmographic readings (mL) of the paw are made at zero time and 3 hours later.
Test compounds are suspended or dissolved in 0.5% methylcellulose and given perorally 1 hour prior to carrageenan administration.
The increase in paw volume (edema in mL) produced by the carrageenan is measured. Paw edema is calculated (3 hour volume minus zero time volume), and percent inhibition 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:
Drug Oral ED~n (95% C.L.? mg/kg Indomethacin 3.7 ( 0.6, 23.8) Aspirin 145.4 (33.1, 645.6) Phenylbutazone 26.2( 2.3,291.0) `~0 91/06~37 ~ ~ 7 ~ S PC~r/US90/0625 When tested in this assay, a compound of the invention and the anti-inflarnmatory drug etodolac gave the following results:
Table VII
Compound of Dose * % Inhibition Oral EDso S ~Dm~ (m,e/k~50 mg/k~ (pero~al) m ~/k etodolac 23 11 50 +1 10 * administered perorally The results show that the compounds tested have activity in the rat carrageenan paw edema assay, evidencing an effect on the acute inflammatory response.
~mUI 50 The assay of this Example measures the ability of the compounds tested to inhibit 5-lipoxygenase in hurnan whole blood.
This assay is carried out as follows:
Blood is obtained in 50-100 ml quantities from male donors. White blood cell counts and differentials are made. Two ml of blood are placed in a 15 ml 20 polypropylene test~tube. Compounds are solubilized in dimethylsulfoxide and diluted 1:10 in 10% bovine serum albumin in phosphate buffered saline, pH 7.4 resulting in a final dimethylsulfoxide concentration of 0.1% in the blood. Then, compounds are added to the blood in a shaking water bath at 37-C for 10 minutes prior to the addition of 30 ,uM calcium ionophore (A23187; Sigma). After ionophore adrninistration, whole 25 blood samples are mixed and incubated for 20 rninutes at 37-C in a shaking water bath.
Incubation is terminated by placing samples in an ice bath and immediately adding ethylene glycol-bis-(,B-aminoethyl ether)-N,N,N',N'-tetraacetic acid (10 mM).
Samples are mixed and centrifuged at 1200 x g for 15 minutes at 4 C. Preparation of samples for evaluation by RIA or ELISA is carried out by the following protocol.30 Plasma is removed from sample tubes, placed in 15 ml polypropylene test tubescontaining 8 ml methanol, and then vortexed to precipitate protein. Samples are stored at -70-C ovemight. The next day, samples are centrifuged at 200 x g for 15 minutes at 4 C to pellet the precipitate. Sarnples are dried in a Savant speed vac concentrator, WO 91/06537 Pcr/us9o/o62sl ~3~ 12 h reconstituted to original volume with ice cold E~IA or ELISA buffer, and stored at -70 C
until assayed. The assay for eicosanoids (LTB4, TxB2, and PGE2) is performed as described by the manufacturer of the [3H]-RIA kit or ELISA kit (LTB4-Amersham, TxB2 and PGE2 - Caymen Chemical).
The total eicosanoid level in 2 ml of blood is calculated and reported as ng/lO6neutrophils. Significance is determined by a one-way analysis of variance with least significant difference (LSD) comparisons to control (p < 0.05) and lCso's (~lM) are determined by regression analysis (Finney, l978). Drug effects are expressed as percent change fTom control values.
Compounds tested in vitro are solubilized in dimethylsulfoxide and diluted l:lO in lO% bovine serum albumin in phosphate buffer saline resulting in a final dimethylsulfoxide concentration of 0. l % in the blood.
The results for compounds of the invention tested in this assay are presented in Table IX.
Table VIII
Compound of Dose Example No.(llM)% Inhibition of LTB4 L-663,536 3 96

Claims (47)

AMENDED CLAIMS
[received by the International Bureau on 28 October 1991 (28.10.91);
original claim 1 amended; remaining claims unchanged (2 pages)]

1. A compound having the formula A(CH2)nO-B
wherein A is C4-C8 alkyl, phenoxyethyl, phenoxyphenyl or a group having the formula or wherein X is -N- or ;
Z is = , , , , -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 benzene ring;
R3 is hydrogen or lower alkyl; with the proviso that when B is or A is other than phenyl;
n is 1 - 2;
B is , , or ;

wherein R4 is -CO2R2, , , , or ;
m is 0-3;
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. The compound of Claim 1, 3-[(4-chlorophenyl)methylene]-[2-methyl-6-(2-quinolinylmethoxy)]-3H-indene-1-acetic acid.

3. The compound of Claim 1, 2-methyl-3-[[4-(methylthio)phenyl]-methylene]-6-(2-quinolinylmethoxy)-3H-indene-1-acetic acid.

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

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

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

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

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

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

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

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

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

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

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

15. The compound of Claim 1, 1,3,4,9-tetrahydro-1,1-dimethyl-6-(2-quinolinylmethoxy)pyrano[3,4-b]indole.

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

17. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

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

19. The compound of Claim 1, 1-(4-chlorobenzoyl)-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

20. The compound of Claim 1, 1-(4-chlorobenzoyl)-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid methyl ester.

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

22. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-5-(hexyloxy)-2-methyl-1H-indole-3-acetic acid.

23. The compound of Claim 1, 2-methyl-5-(2-quinolinylmethoxy)-1-(2-quinolinylmethyl)-1H-indole-3-carboxylic acid ethyl ester.

24. The compound of Claim 1, .alpha.-methyl-6-(2-quinolinylmethoxy)-9-(2-quinolinylmethyl)-9H-carbazole-2-acetic acid.

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

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

27. The compound of Claim 1, 1-[(4-fluorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

28. The compound of Claim 1, 1-[(4-bromophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

29. The compound of Claim 1, 1-[(phenyl)methyl-2-methyl]-5-(2-quinolin-ylmethoxy)-1H-indole-3-acetic acid.

30. The compound of Claim 1, 1-[(4-carboxyphenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

31. The compound of Claim 1, 2-methyl-5-(2-quinolinylmethoxy)-1-[[4-(2-quinolinylmethoxy)phenyl]methyl]-1H-indole-3-acetic acid.

32. The compound of Claim 1, 2-methyl-1-pentyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

33. The compound of Claim 1, 1-hexyl-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

34. The compound of Claim 1, 1-heptyl-2-methyl-5-(2-quinolinylmethoxy)-1H-indole-3-acetic acid.

35. The compound of Claim 1, 1-methyl-2-methyl-5-(2-quinolinyl-methoxy)-1H-indole-3-acetic acid.

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

37. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-naphthalenylmethoxy)-1H-indole-3-acetic acid.

38. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-(phenylmethoxy)-1H-indole-3-acetic acid.

39. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-pyridinylmethoxy)-1H-indole-3-acetic acid.

40. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-benzothiazolylmethoxy)-1H-indole-3-acetic acid.

41. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-[(2-phenyl-4-thiazolyl)methoxy]-1H-indole-3-acetic acid.

42. The compound of Claim 1, 1-[(4-chlorophenyl)methyl]-2-methyl-5-[[2-(4-trifluoromethylphenyl)-4-thiazolyl]methoxy]-1H-indole-3-acetic acid.

43. The compound of Claim 1, 1-[(phenyl)methyl]-2-methyl-5-[(2-phenyl-4-thiazolyl)methoxy]-1H-indole-3-acetic acid.

44. The compound of Claim 1, 2-methyl-5-(2-quinolinylmethoxy)-1-[[4-(2-quinolinylmethoxy)phenyl]methylene]-1H-indene-3-acetic acid.

45. The compound of Claim 1, N-[[1-[(4-chlorophenyl)methyl]-2-methyl-5-(2-quinolinylmethoxy)-1H-indol-3-yl]methyl]-N'-hydroxyurea.

46. 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 intennediate 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 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 , or 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 halo 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.

47. A process as claimed in Claim 46 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.