CA1337427C

CA1337427C - (quinolin-2-ylmethoxy)indoles as inhibitors of the biosynthesis of leukotrienes

Info

Publication number: CA1337427C
Application number: CA 609031
Authority: CA
Inventors: Peppi Prasit; Michel Belley; John Gillard; Richard Frenette; Rejean Fortin; Serge Leger; John Hutchinson
Original assignee: Individual
Current assignee: Merck Frosst Canada and Co
Priority date: 1989-08-22
Filing date: 1989-08-22
Publication date: 1995-10-24
Anticipated expiration: 2012-10-24

Abstract

Compounds having the formula I:

I

are inhibitors of leukotriene biosynthesis.
These compounds are useful as anti-asthmatic, anti-allergic, anti-inflammatory, and cytoprotective agents. They are also useful in treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea, and migraine.

Description

Fl TITLE OF THE INVENTION
(QUINOLIN-2-YLMETHOXY)INDOLES AS INHIBITORS OF THE
BIOSYNTHESIS OF LEUKOTRIENES.

BACKGROUND OF THE INVENTION
European PatentApplications 166,591 (published January 2, 1986) and 275,667 (published December 15, 1987) disclose a series of indole-based compounds with activity as prostaglandin antagonists and inhibitors of leukotriene biosynthesis respectively. In EP 181,568 (published October 30, 1985) and EP 200,101 (published April 16, 1986) are disclosed a series of compounds, containing two aromatic nuclei, which are described as possessing activity as lipoxygenase inhibitors. In EP
279,263 (published February 2, 1988) is disclosed a series of indoles, benzofurans and benzothiophenes which are described as possessing activity as lipoxygenase inhibitors. U.S. Patent 4,629,733 describes novel indolinones which are antithrombotic and inhibit both "~''''~

~ 337427 Fl phosphodiesterase and tumor metastasis. The chemical preparation of quinolylindoles is referred to by Sheinkman, et al., Chem. Ab., Vol. 67, 54017 (1967), without mentioning any utility for such compounds. A
number of N-acyl derivatives of indole-3-acetic acid are described as potential anti-inflammatory agents by Biniecki, et al., Chem. Ab., Vol. 98, 197936 (1983), by Pakula, et al., Chem. Ab., Vol. 105, 190835 (1986), and in British Pat. Spec. 1,228,848.

SUMMARY OF THE INV~;N110N
The present invention relates to compounds having activity as leukotriene biosynthesis inhibitors, to methods for their preparation, and to methods and pharmaceutical formulations for using these compounds in mammals (especially humans).
- Because of their activity as leukotriene biosynthesis inhibitors, the compounds of the present invention are useful as anti-asthmatic, anti-allergic, and anti-inflammatory agents and are useful in treating allergic rhinitis and chronic bronchitis and for amelioration of skin diseases like psoriasis and atopic eczema. These compounds are also useful to inhibit the pathologic actions of leukotrienes on the cardiovascular and vascular systems for example, actions such as result in angina or endotoxin shock. The compounds of the present invention are useful in the treatment of inflammatory and allergic diseases of the eye, including allergic conjunctivitis. The compounds are also useful as cytoprotective agents and for the treatment of migraine headache.

El 7 3 3 7 4 2 7 Thus, the compounds of the present invention may also be used to treat or prevent mammalian (especially, human) disease ~tateæ such as erosive gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions;
hepatic ischemia; noxious agent-induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CC14 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure.
The compounds of this invention are inhibitors of the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETE and the leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contribute to various disease conditions such as asthma, psoriasis, pain, ulcers and systemic anaphylaxis. Thus inhibition of the synthesis of such compounds will alleviate these and other leukotriene-related disease states.

DETAILED DESCRIPTION OF THE INv~NLlON
The present invention provides novel compounds of the formula I:

R~?~CH~O ~ ~cRllRll)n-ym-(cRllRll)p-Q

(o) v R3 R~
I

Fl wherein:

Rl, R2, R3, R4 and R10 are independently hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, -CF3, -CN, -N02, -N3, -C(OH)RllRll, -C02R12, -SR14 S(o)Rl4 S(0)2R14 -s(o)2NR15R15, _oR15, _NR15R15, -C(O)R16 or -(CH2)tR21;

R5 is hydrogen, -CH3, CF3, -C(O)H, Xl-R6 or X2-R7;

R6 and R9 are independently alkyl, -(CH2)UPh(Rl0)2 or -(CH~)UTh(Rl0)2;

R7 is -CF3 or R6;

R8 is hydrogen or X3-R9;

each Rll is independently hydrogen or lower alkyl, or two Rll's on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

R12 is hydrogen, lower alkyl or -CH2R21;

R13 is lower alkyl or -(CH2)rR21;

R14 is -CF3 or R13;

R15 is hydrogen, -C(O)R16, R13, or two R15 's on the same nitrogen may be joined to form a monocyclic heterocyclic ring of 4 to 6 atoms containing up to 2 heteroatoms chosen from 0, S or N;

R16 is hydrogen, -CF3, lower alkyl, lower alkenyl, Fl lower alkynyl or -(CH2)rR21;

R17 is -(CH2)S-C(Rl8Rl8)-(CH2)s-Rl9 or -CH2C(o)NR15R15;

R18 is hydrogen or lower alkyl;

R19 is a) a monocyclic or bicyclic heterocyclic ring containing from 3 to 9 nuclear carbon atoms and 1 or 2 nuclear hetero-atoms selected from N, S or 0 and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or b) the radical W-R20;

R20 is alkyl or -C(o)R23;

R21 is phenyl substituted with 1 or 2 R22 groups;

R22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -N02 or -N3;

R23 is alkyl, cycloalkyl, or monocyclic monoheterocyclic ring;

R24 is the residual structure of a standard amino acid, or R18 and R24 attached to the same N can cyclize to form a proline residue;

m is 0 to 1;
n is 0 to 3;
p is 1 to 3 when m is 1;

Fl p is 0 to 3 when m is 0;
r is 0 to 2;
s is 0 to 3;
t is 0 to 2;
u is 0 to 3;
v is 0 or 1;
W is O, S or NR15;
xl is 0, or NR15;
x2 is C(0), CRllRll, S, S(0) or S(0)2;
X3 is C(0), CRllRll, 5()2 or a bond;
Y is Xl or X2;

Q is -C02R12, -C(o)NES(0)2R14, -NHS(0)2R14, -S(0)2NHR15 -C(o)NR15R15, -C02R17, -C(o)NR18R24, -CH2OH, or lH- or 2H-tetrazol-5-yl;

and the pharmaceutically acceptable salts thereof.

A preferred embodiment of Formula I is that in which:

Rl, R2, R3 and R4 are hydrogen;
R5 is X2-R7 or -oR6;
R7 is R6;
R8 is R9;
Rl is hydrogen or halogen;
m is 0;
n is 1 to 3;
u is 0 in R6 and 1 in R9;
x2 is cRllRll or S;

Q is -C02R12; and the remaining substituents are as defined for Formula I;
and the pharmaceutically acceptable salts thereof.

Fl Definitions The following abbreviations have the indicated meanings:

Me = methyl Bz = benzyl Ph = phenyl t-Bu = tert-butyl i-Pr = isopropyl c-C6Hll = cyclohexyl c-Pr = cyclopropyl c- = cyclo Ac = acetyl Tz = 5-tetrazolyl Th = 2- or 3- thienyl Alkyl, alkenyl, and alkynyl are intended to include linear, branched, and cyclic structures and combinations thereof.
As used herein, the term "alkyl" includes "lower alkyl" and extends to cover carbon fragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, norbornyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3,7-diethyl-2,2-dimethyl-4-propylnonyl, cyclododecyl, adamantyl, and the like.
As used herein, the term "lower alkyl"
includes those alkyl groups of from 1 to 7 carbon atoms. Examples of lower alkyl groups include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, ~ 337427 Fl 2-methylcyclopropyl, cyclopropylmethyl, and the like.
The term 'Icycloalkyl" refers to a hydrocarbon ring having from 3 to 7 carbon atoms.
Examples of cycloalkyl groups are cyclopropyl, cyclopentyl, cycloheptyl and the like.
"Lower alkenyl" groups include those alkenyl groups of 2 to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, iæopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like.
"Lower alkynyl" groups include those alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include-ethynyl, propargyl, 3-methyl-1-pentynyls 2-heptynyl and the like.
As used herein, the term "lower alkoxy"
includes those alkoxy groups of from 1 to 7 carbon atoms of a ætraight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
The term "monocyclic monoheterocyclic ring"
which defines R23 includes those monocyclic groups of 5 to 7 members containing only 1 heteroatom selected from N, S or 0 in the ring. Examples include tetrahydrofuran, tetrahydrothiophene, pyrrolidine, piperidine, tetrahydropyran, and the like.
The term "monocyclic or bicyclic heterocyclic ring" which defines R19 may be 2,5-dioxo-1-pyrrolidinyl, (3-pyridinylcarbonyl) amino, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl, 1,3-dihydro-2H-isoindol-2-yl, 1 ~37427 Fl 2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl, 2-oxo-1,3-dioxolen-4-yl, piperidin-l-yl, morpholin-l-yl, piperazin-l-yl and the like.
The point of attachment of any heterocyclic ring may be at any free valence of the ring.
The term standard amino acid is employed to include the following amino acids: alanine, asparagine, aspartic acid, arginine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine and valine. (See F.H.C. Crick, Symposium of the Society for Experimental Biology, 1958 (12) p. 140.) It is understood that Rl and R2 may be located at any of positions 3,4,5,6,7 or 8 of the quinoline ring.
As used herein the term "lower alkylthio'l includes those alkylthio groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
The terms Ph(R10)2 and Th(R10)2 indicate a phenyl or thienyl group substituted with two R10 substituents.
Halogen includes F, Cl, Br, and I.
It is intended that the definitions of any substituent (e.g., Rl, R2, R15, Ph(R10)2, etc.) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, -NR15R15 represents Fl -NHH, -NHCH3, -NHC6H5, etc.
The monocyclic heterocyclic rings formed when two R15 groups join through N include pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine, and N-methylpiperazine.
The prodrug esters of Q (i.e., when Q =
Co2R17) are intended to include the esteræ such as are described by Saari et al., J. Med. Chem., 21, No.
8, 746-753 (1978), Sakamoto et al., Chem. Pharm.
Bull., 32, No. 6, 2241-2248 (1984) and Bundgaard et al., J. Med. Chem., 30, No. 3, 451-454 (1987).
Some of the compounds described herein contain one or more asymmetric centers and may thus give rise to diastereomers and optical isomers. The present invention is meant to comprehend such possible diastereomers as well as their racemic and resolved, enantiomerically pure forms and pharmaceutically acceptable salts thereof.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt, thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases.
Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium and ~ 337~27 Fl sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include æalts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as arginine, betaine, caffeine, choline, N,Nl-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acidæ. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, pho~phoric, sulfuric and tartaric acids.
It will be understood that in the discussion of methods of treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.

Fl The ability of the compounds of Formula I to inhibit biosynthesis of the leukotrienes makes them useful for inhibiting the symptoms induced by the leukotrienes in a human subject. This inhibition of the mammalian biosynthesis of leukotrienes indicates that the compounds and pharmaceutical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: 1) pulmonary conditions including diseases such as asthma, 2) lo allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunctivitis, and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skin conditions such as psoriasis and the like, 6) cardiovascular conditions such as angina, endotoxin shock, and the like and 7) renal insufficiency arising from ischaemia induced by immunological or chemical (cyclosporin) etiology, and that the compounds are cytoprotective agents.
The cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non-steroidal anti-inflammatory drugs on the gastrointestinal tract, animal studies show that cytoprotective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions and the like.

Fl 1 3 3 7 4 2 7 Two assays can be used to meaæure cytoprotective ability. These assays are; (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140,684.
The magnitude of prophylactic or therapeutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration. It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for anti-asthmatic, anti-allergic or anti-inflammatory use and generally, uses other than cytoprotection, lie within the range of from about 0.001 mg to about 100 mg per kg body weight of a mammal, preferably 0.01 mg to about 10 mg per kg, and most preferably 0.1 to 1 mg per kg, in single or divided doses. On the other hand, it may be necessary to use dosages outsi-de these limits in some cases.
For use where a composition for intravenous administration is employed, a suitable dosage range for anti-asthmatic, anti-inflammatory or 2s anti-allergic use is from about 0.001 mg to about 25 mg (preferably from 0.01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.

Fl In the case where an oral composition is employed, a suitable dosage range for anti-asthmatic, anti-inflammatory or anti-allergic use is, e.g. from about 0.01 mg to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 0.1 mg to about 10 mg per kg and for cytoprotective use from 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 10 mg to about 100 mg) of a compound of Formula I per kg of body weight per day.
For the treatment of diseases of the eye, ophthalmic preparations for ocular administration comprising 0.001-1% by weight solutions or suspensions of the compounds of Formula I in an acceptable ophthalmic formulation may be used.
The exact amount of a compound of the Formula I to be used as a cytoprotective agent will depend on, inter alia, whether it is being administered to heal damaged cells or to avoid future d~amage, on the nature of the damaged cells (e.g., gastrointestinal ulcerations vs. nephrotic necrosis), and on the nature of the causative agent. An example of the use of a compound of the Formula I in avoiding future damage would be co-administration of a compound of the Formula I with a non-steroidal anti-inflammatory drug (NSAID) that might otherwise cause æuch damage ~for example, indomethacin). For such use, the compound of Formula I is administered from 30 minutes prior up to 30 minutes after administration of the NSAID. Preferably it is administered prior to or simultaneously with the NSAID, (for example, in a combination dosage form).

Fl Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the like may be employed. Dosage forms include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term "pharmaceutically acceptable lS saltsll refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic bases or acids and organic bases or acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or nebulisers.

Fl The compounds may also be delivered as powders which may be formulated and the powder composition may be inhaled with the aid of an insufflation powder inhaler device. The preferred delivery system for inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or æolution of Compound I in suitable propellants, such as fluorocarbons or hydrocarbons.
Suitable topical formulations of Compound I
include transdermal devices, aerosols, creams, ointments, lotions, dusting powders, and the like.
In practical use, the compounds of Formula I
can be combined as the active ingredient in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, æuch as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral preparations being preferred over the liquid preparations. Because of their ease of I ~37427 Fl administration, tablets and capsules represent the most advantageous oral dosage unit form in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be coated by standard aqueous or nonaqueous techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices ~uch as those described in U.S.
Patent Nos. 3,845,770; 3,916,899; 3,536,809;
3,598,123; 3,630,200 and 4,008,719.

Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets - or tablets each cont-aining a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired pre~entation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable 1 ;~37427 Fl machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 2.5 mg to about 500 mg of the active ingredient and each cachet or capsule contains from about 2.5 to about 500 mg of the active ingredient.
The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:

lS

Fl 1 3 3 7 4 2 7 Injectable Suspension (I.M.) ~/ml Compound of Formula I 10 Methylcellulose 5.0 5 TweenT~80 0.5 Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection to a total volume of 1 ml lO Tablet mg/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 ! Providone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate Capsule ~/capsule Compound of Formula I 25 20 Lactose Powder 573 5 Magnesium Stearate 1.5 AeroRol Per canister 25 Compound of Formula I 24 mg Lecithin, NF Liquid Concentrate 1.2 mg Trichlorofluoromethane, NF 4.025 gm Dichlorodifluoromethane, NF 12.15 gm ~ ' Fl In addition to the compounds of Formula I, the pharmaceutical compositions of the present invention can also contain other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflunisal and the like. The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a compound of the Formula I is combined with an NSAID
the weight ratio of the compound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferab~y about 200:1 to about 1:200.
Combinations of a compound of the Formula I and other active ingredients will generally also be within the aforementioned range, but in each case, an effective dose of each active ingredient should be used.
20 ~ NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives;
and (5) the oxicams or a pharmaceutically acceptable salt thereof.
The propionic acid derivatives which may be used comprise: alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, Fl miroprofen, naproxen, oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, and tioxaprofen. Structurally related propionic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be included in this group.
Thus, ~'propionic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs lo having a free -CH(CH3)COOH or -CH2CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO~Na+ or -CH2CH2COO~Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
The acetic acid derivatives which may be used comprise: indomethacin, which is a preferred NSAID, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin and zomepirac. Structually related acetic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "acetic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CH2COOH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g.
-CH2COO~Na+), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.

1 3374~7 Fl The fenamic acid derivatives which may be used comprise: flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid.
Structurally related fenamic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "fenamic acid derivatives" as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:

~ H

which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO~Na+.
The biphenylcarboxylic acid derivatives which can be used comprise: diflunisal and flufenisal. Structurally related biphenylcarboxylic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, ~biphenylcarboxylic acid derivatives"
as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:

1 ~37427 Fl ~'i which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO-Na+.
The oxicams which can be used in the present invention comprise: isoxicam, piroxicam, sudoxicam and tenoxican. Structurally related oxicams having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, "oxicams" as defined herein are non_ narcotic analgesics/non-steroidal anti-inflammatory drugs which have the general formula:

OH
C( O) NHR

/j~\ 3 O O
wherein R is an aryl or heteroaryl ring system.
The following NSAIDs may also be used:
amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydanin~, beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate, dazidamine, Fl deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, etodolac, etofenamate, fanetizole mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, glucametacin, guaimesal, ibuproxam, isofezolac, isonixim, isoprofen, isoxicam, lefetamine HCl, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone, nabumetone, nictindole, nimesulide, orpanoxin, oxametacin, oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirazolac, pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, talmetacin, talniflumate, tenoxicam, thiazolinobutazone, thielavin B, tiaramide HCl, tiflamizole, timegadine, tolpadol, tryptamid and ufenamate.
The following NSAIDs, designated by company code number (see e.g., Pharmaprojects), may also be used:
480156S, M861, AD1590, AFP802, AFP860, AI77B, AP504, AU8001, BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714, MR897, MY309, ONO3144, PR823, PV102, PV108, R830, RS2131, SCR152, SH440, SIR133, SPAS510, SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX2706, U60257, UR2301, and WY41770.
Finally, NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid Fl ~ 3 3 7 ~ 2 1 and the phenylbutazones, and pharmaceutically acceptable salts thereof.
In addition to indomethacin, other preferred NSAIDS are acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ~etoprofen, naproxen, phenylbutazone, piroxicam, sulindac and tolmetin.
Pharmaceutical compositions comprising the Formula I compounds may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed in EP 138,481 (April 24,1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP
140,709 (May 8, 1985).

The compounds of the Formula I may also be used in combination with leukotriene antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP

104,885 (April 4, 1984), and others known in the art such as those disclosed in EP Application Nos. 56,172 (July 21, 1982) and 61,800 (June 10, 1982); and in U.K. Patent Specification No. 2,058,785 (April 15, 1981).

2s Pharmaceutical compositions comprising the Formula I compounds may also contain as the second active ingredient, prostaglandin antagonists such as those disclosed in EP 11,067 (May 28, 1980) or thromboxane antagonists such as those disclosed in ~.S. Pat. 4,237,160. They may al80 contain histidine decarboxylase inhibitors such as a-fluoromethylhistidine, described in U.S. Pat.
4,325,961. The compounds of the Formula I may also be advantageously combined with an Hl or H2-receptor Fl 1 337427 6/DAM2 - 26 - ~ 17940 antagoniæt, such as for instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine, terfenadine and like compounds, such as those disclosed in ~.S. Patent Nos. 4,283,408; 4,362,736; and 4,394,508. The pharmaceutical compositions may also contain a K+/H+
ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of Formula I may also be usefully combined with most cell stabilizing agents, such as 1,3-bis(2-carboxychromon-5-yloxy)-2-hydroxypropane and related compounds described in British Patent Specifications 1,144,905 and 1,144,906. Another useful pharmaceutical composition comprises the Formula I compounds in combination with serotonin antagonists such as methysergide, the serptonin antagonists described in ~ature, Vol. 316, pages 126-131, 1985, and the like.

-Other advantageous pharmaceutical compositions comprise the Formula I compounds in combination with anti-cholinergics such as ipratropium bromide, bronchodilators such as the beta agonist salbutamol, metaproterenol, terbutaline, fenoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllinate and enprofylline, the calcium antagonists nifedipine, diltiazem, nitrendipine, verapamil, nimodipine, felodipine, etc. and the corticosteroids, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, and the like.

~'.

Fl 1 3 3 7 4 2 7 Compounds of the present invention can be prepared according to the following methods.
Temperatures are in degree Celsius.
The starting methoxy phenylhydrazines II are either commercially available or are deæcribed in the chemical literature as are the acetamidophenols ggVI. The benzyl phenylhydrazine starting materials III are prepared as described in EP 166,591 (17102 IA) and the ketones IV are prepared as described in EP 275,667 (17496 IA). The 2-(halomethyl)quinolines VII are available from literature methods described in "Quinolines" Parts I and II, G. Jones (ED.), John Wiley & Sons, Toronto, 1977 and 1982. The preparation of VII by halogenation of the corresponding 2-methylquinolines is also described in the Jones' volumes. The benzyl halides, (R10)2 PhCH2-Hal, are readily prepared and many such compounds are described in the prior art, such as U.S. Patent 4,808,608 (17323 IB). Hal in VII and (R10)2 PhCH2-Hal represents Cl, Br or I.
Many syntheses of indoles are well-known in the chemical literature: see for example, "Heterocyclic compounds" Volume 25, Parts I, II, III, W.J. Houlihan (Ed.), Interscience, J. Wiley ~ Sons, N.Y., 1979, and "The Chemistry of Indoles" by R.J.
Sundberg, Academic Press, N.Y., 1970. One of the most common syntheses is known as the Fischer Indole Synthesis, and is abbreviated in the following methods as "Fischer".
The -CO2H and -CO2R12 groups in the intermediates and final products in the various methods can be transformed to other representatives of Q such as -CoNHS(0)2R14, -NHS(0)2R14, -CoNR15R15, Fl ~ s37427 -CH2OH or tetrazol-5-yl by the methodology described in U.S. Patent 4,808,608 (17323IV). The preparation of the pro-drug forms (Q is -Co2R17) from the acids may be effected by the methodology of EP 104,885 (published April 4, 1984) (16830 IA).
It will be apparent to one s~illed in the art that the various functional groups (Rl, R2, Y, Q, etc.) must be chosen 80 as to be compatible with the chemistry being carried out. Such compatibility can lo often be achieved by protecting groups, or by specific variations in the sequence of the reactions.
When R5 is S-R7, the corresponding sulfogides and sulfones can be prepared by oxidation of the sulfides with one or two equivalents of an oxidizing agent such as m-chloroperbenzoic acid or monoperoxyphthalic ~cid or oxone (Trost, J. Org.
Chem.,~1988, pg.532).
Many of the following methods involve a basic hydrolysis of an ester function to obtain the corresponding carboxylic acid. In all cases, the free acid i8 obtained by acidification of the reaction mixture with a suitable acid such as hydrochloric, sulfuric, acetic, trifluoroacetic acid, etc.
Compounds VIII, XI, ~, XIX, XXXVI and their precursor esters are all examples of the Formula I
compounds of the present invention.

,.. ~

Fl Method I
R4~ R4 M~O I ( Rlo)2pbcH2-H~l MeO ;~
~IHNH2 NE13/ Bu4N)3' / CH2C12 ~ 3~ - -3 H2 _5 .Il R ~/

~Rll Rll 1 ) F3scHER/~
p C02R~2 HO--~~'Rl~ R~l 1) N~s-l-E~ulHJ~3pA M~O ~ ~
R3 N ~ C02Mc 2 ) CH2N.2 ~ p C02H
3~10 ~ Vl R] R5 S-R7 ,~ 1 )K2C031DMFI VII I ~ ~3C13/EISH /CH,C12 ~ ~ ~HAL 2 ) LiOH 2 ) CH23'2 R ' ~^~-- R4 R5 R4 H
2 0 ~_~ ~ ~ ~/ , COzH HO _ ~ p CO2M

R10~R10{~ ~X

VIII ( I ) 1 ) R'COC3 / A~C33 / C2H~C12 2 5 2 ) N OM I McOH

R4 R33 R31 1) K2CO3/DMF/VII R4 Cl~IORRll "l~o ~N P C2H ) Li HO ~ 02~c R10~ X~ ( I ) Rlo ~ X

Fl Method 1 Intermediate y is prepared by a Fischer reaction between benzylphenylhydrazine III and ketone IV, followed by hydrolysis with an aqueous golution of an alkali hydroxide or other suitable hydroxide in mixture with a suitable water miscible organic solvent such as tetrahydrofuran (THF) or methanol (MeOH). The methoxy acid V is demethylated by heating with an alkali salt of an aliphatic thiol in a suitable solvent such as hexamethylphosphorictri-amide (HMPA) or N-methylpyrrolidone (NMP). The reaction mixture is acidified and the crude acid so obtained is converted to the methyl ester VI by treatment with diazomethane. The phenol VI is coupled to the 2-halomethylquinoline VII, by stirring with a base (preferably an alkali hydride or carbonate) in a suitable solvent such as dimethyl formamide (DMF), NMP, acetone or the like. The resulting ester is hydrolysed by base to yield VIII, a compound of the present invention.
When intermediate V contains a sulfide group attached to position 3, treatment with a Lewis acid, such as AlC13, and an aliphatic thiol, simultaneously effects demethylation and removes the sulfide group.
Suitable solvents for this reaction are methylene chloride, 1,2-dichloroethane, etc. The resulting acid is then converted to the methyl ester IX with diazomethane. A Friedel-Crafts reaction between IX
and an acid chloride, R7COCl, simultaneously introduces the acyl substituent into the 3-position of the indole ring and onto the phenolic hydroxyl group. The acyl group is removed from the phenol by Fl treatment with sodium methoxide in MeOH to yield acylphenol ~. Phenol X is coupled with VII as described for the coupling of VI and VII above. In these coupling reactionæ, it i8 at times advantageous to add a catalyst such as potassium iodide or tetraethylammonium bromide, especially when Hal is chlorine. A final hydrolysis yields compound XI.

Fl 1 337427 Method 2 FISCHER MeO ~/RIl R~
+ lV ~ , /~co2R~2 R- H
1 ) 1CHMDS /THF / 78~
2 ) R H~l/

R~ RR151 R~ cl3lE~sHlc2H4c~2 ~HR~I Rll McO ~ C02R~2 R5 ~ s-R7 ' ~ C02R~2 R xnl xvl 1 , ~ LiOH 1 ) R7COCI /NE13 /THF
2 ) Na S-t-Bu / H~PA ~ 2 ) R7CoC3 / AIC13 / C2H~C12 3 ) CH2~2 , ~ X~II

~/Rll Rl~ ~ ) NacNBH3lzsll2lc2H4cl2R7co2~ - Rll ~
>0 - ~N~ 2) NaOMe/MeOH R~ 18 p C02R12 R Xlv XVIII
I ) N~OMe / M~OH
1 ) K2CO3 / DMF / VII 2 ) K2C03 / DMF /
2 ) LiOH 3 ) LiOH

k ~CO~H ~ ~OIH

XV (}) XIX (1~

Fl 1 3 3 7 4 2 7 Method 2 Intermediate XII is prepared by a Fischer reaction between methoxyphenyl hydrazine II and ketone IV, followed by alkylation of the indole nitrogen, after deprotonation using potassium hexamethyldisilazane in an ether solvent such as tetrahydrofuran (THF), with an alkyl or aralkyl halide.
The methoxy group in XIII is removed using the conditions of Method l. The corresponding phenol XIV is now coupled with the 2-halomethylquinoline VII
by stirring with a base (preferably an alkali hydride or carbonate) in a suitable solvent such as DMF, NMP
or the like. The resulting ester is hydrolysed using base to yield XV a compound of the present invention.
When intermediate XIII contains a sulfide at position 3, treatment with a Lewis acid such as AlCl3 and an aliphatic thiol simultaneously effects demethylation and removes the sulfide group.
Suitable solvents for this reaction are dichloromethane or dichloroethane. In a variation of Method l, the phenolic hydroxyl in XVI is first acylated with the reagent R7COCl (XVII) in the presence of a weak base such as triethylamine. A
Friedel-Crafts reaction is then carried out on the O-acylated intermediate, with an additional mole of XVII and AlCl3, to yield the intermediate XVIII.
Acyl ester XVIII may then be reduced to a 3-alkyl indole XIV using sodium cyan-oborohydride in dichloroethane using a zinc iodidecatalyst.
Acyl ester XVIII is cleaved to the indole phenol by hydrolysis with sodium methoxide in methanol and is coupled to 2-halomethyl quinoline VII

Fl 1 3 3 7 4 2 7 using a base such aæ an alkali hydride or carbonate in a solvent such as DMF or NMP. Hydrolysis of the resulting compound using base yields the compound of the present invention XIX.

~ THOD 3 ~ (CH3~3C~oCI ~ I ) HCI/N~N02 ~\
t~ !J~ ~(CH3~3CC021 11 , (CH3)3CCO+ ll R3~ NH2 R3NH2 2 ) N~2S24 R~NHNH2 xx ~ x~a /(R10)2PnCH2H~
l NE13 / Bu4NBr / CH2C12 ~RIl Rll PISCHER / IV

(CU33CC02-- ~`C02RI~ (CU33CC02~$~ ,N3 N~OMe / MeOH

as ~er l`~l~t h~ 1 Vl ~ Vm(I) Fl Method 3 A suitably substituted aminophenol XX is protected on oxygen by the use of pivaloyl chloride dissolved in CH2C12 using triethyl amine as base.
The pivaloate ester XXI is then diazotized using hydrochloric acid and sodium nitrite in an aqueous solvent and the transient diazonium species reduced in æitu to the hydrazine XXII using sodium hydrosulfite in water. Benzylation of the hydrazine is effected as described in Method 1.
The 0-pivaloyl-N-benzylhydrazine XXIII is subjected to a Fischer indolization using the appropriate ketone IV to produce the indole XXIV.
Cleavage of the 0-pivaloyl group using sodium methoxide in methanol transforms the product into the phenolic indole VI which is converted to the products of this invention as described in Method 1.

~ THOD 4 X~ IV FISCHER ~ ~11 2 ) R8-H~ p Me~hDd 2 R3 N C02R12 3 ) ~OMelMeOH

XXV

Fl Method 4 The pivaloyloxyphenylhydrazine XXII is used directly in the Fischer indolization using ketone IV. N-Alkylation of the indole XXV, as described in Method 2, followed by removal of the pivaloyl group as described, yields the phenolic indole XIV which is converted as described in Method 2 to the products of this invention.

Fl Method 5 R4K2CO3 / DMF / VII R~ R4 ~NHAc R~ ~NHAc o R R3 XXVI XXVII

KOH t 4. ErOH / Heu R~ I)HCI/NNO2 Rl ~_ R2 R32) N~2524 R2 R3 NH2 XX~ XXVIII
( Rl )2PhCH2-H~I
2 0 ( i-Pr)2NEI / Bu4NBr / CH2CI2 Rl ~ ,~I)FISCHER/ IV

R3 N~--O ,~``N'2 2 ) UOH vm ( I ) 2 5 Rl~J

Fl 1 33 7 4 2 7 Method 5 A suitable N-acetylated aminophenol XXVI is reacted with VII using an alkali hydride or carbonate, such as potassium carbonate as a base in a polar solvent like DMF or NMP. The quinolinylmethoxy acetanilide XXVII is then de-acetylated using standard basic conditions, preferably using alcoholic potassium hydroxide under reflux to produce the quinolinylmethoxy aniline derivative XXVIII.
Conversion of the quinolinylmethoxy aniline derivative to the hydrazine analogue XXIX is effected through reduction of the intermediate diazonium salt using sodium hydrosulfite in an aqueous medium.
The hydrazine XXIX is then N-benzylated using a benzyl halide in an organic solvent such as methylene chloride containing an amine base such as diisopropylethylamine and preferably tetra-n-butylammonium bromide as catalyst.
The hydrazine XXX is then processed using a ~ischer indolization with ketone IV according to Methods 1, 2, 3 and 4 to produce compounds of the present invention.

Fl 1 33 7 4 2 7 Method 6 R5~J~ 2 ) IUMD5/THl~/R8H~1 ~ ~C02R12 X~

~H4 /THF /
/ RIlMgBr 15 ~ ~1 ,o~ ~u~

~WV XX~ ' Rll \ I ) N HtTHF/ XXXV
20S~ \ 2) LiOH
H CO2Me X~V

2 5 ~'\~ ~ P Co2H

~CXVI ( I ) Fl Method 6 Hydrazine XXIX may also be transformed directly to unsubstituted indoles by a Fischer reaction with various ketones like XXXI.
N-Alkylation of the indoles is effected using the conditions described in Method 2 to produce quinolinylmethoxyindole alkanoate esters XXXII. Such esters are transformed to ketones or carbinols via Grignard conditions using alkyl magnesium halides in ether solvents like diethyl ether or through the use of lithium aluminum hydride in ether solvents like THF. The carbinols XXXIV so produced may be further transformed into ester compounds of the present invention by reacting with a-halo esters XXXV using sodium hydride as base in a suitable solvent like THF. Subsequent hydrolysis of the esters using Method 1 leads to acid compounds of the present invention.

Fl 1 3 3 7 4 2 7 Representative Compounds Table I illustrates compounds ha~ing the formula Ia representative of the present invention. "Attach point" is the position on the indole nucleus where the quinolylmethoxy moiety is attached.

~ ~5 8 Ia R

Assays for Determining Biological Ac~ivity Compounds of Formula I can be tested using the following assays to determine their mammalian leukotriene biosynthesis inhibiting activity.

Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay Rats under ether anesthesia are injected (i.p.) with 8 mL of a suspension of sodium caseinate (6 grams in ca. 50 mL water). After 15-24 hr. the rats are sacrificed (CO2) and the cells from the peritoneal cavity are recovered by lavage with 20 mL
of buffer (Eagles MEM containing 30 m~ HEPES adjusted to p~ 7.4 with NaOH). The cells are pelleted (350 x g, 5 min.), resuspended in buffer with vigorous shaking, filtered through lens paper, recentrifuged and finally ~uspended in buffer at a concentration of 10 cells/mL. A 500 mL aliquot of PMN

Fl TABLE I

R~CH20 ~ CHz-Y-~CR~lR~1)p-COzH

R~ I~

Ex Rl R2 R3 ATTACH R8 R5 Y (cRllRll No. POINT

1 H,H H 5 -CH2Ph-1 Cl -S-t-Bu C(Me)2 2 H,H H 5 -CH2Ph 1 Cl Me C(Me)2 3 H,H H 5 -CH2Ph-4-S-t-Bu -S-t-Bu C(Me)2 4 H,H H 5 -CH2Ph ~ Cl -SPh C(Me)2 6 H,H H 5 -CH2Ph ~ Cl _S(0)2Ph C(Me)2 7 H,H H 5 -CH2Ph 1 Cl -S(O)Ph C(Me)2 2 0 8 H,H H 5 -CH2Ph ~ Cl H C(Me)2 9 H,H H 5 -CH2Ph-1 Cl -C(O)Ph C(Me)z lû H,H H 5 -CH2Ph ~ Cl -CH2Ph C(Me)2 11 H,H H 5 -CH2Ph 1 Cl -C(O)CH2-t-Bu C(Me)2 12 H,H H 5 -CH2Ph ~ Cl -S-t-Bu CH20CH
13 H,H H 5 -CH2Ph-4-Cl -CH2CH2-t-BU C(Me)2 14 H,H H 5 -CH2Ph 1-Cl -S-t-Bu CH(Me) Fl Ex Rl R2 R3 ATTACH R8 R5 Y-(cRl lpl 1 No. POINT

6-Cl, 7-Cl H 5 -CH2Ph~Cl Me C(Me)2 16 H, 7-Cl H 5 -CH2Ph 1 Cl Me C(Me)2 17 H,H 4-allyl 5 -CH2Ph l Cl -S-t-Bu C(Me)z 18 H,H 4-al lyl 5 -CH2Ph~Cl H C(Me)z 19 H,H H 6 -CH2Ph 1 Cl -S-t-Bu C(Me)2 2û H,H H 4 -CH2Ph 'I Cl -S-t-Bu C(Me)2 21 H,H H 7 -CH2Ph 'I Cl -S-t-Bu C(Me)2 22 H,H H 5 -CH2Ph 1 Cl -S-t-Bu CH20CH(Me) 23 H,H H 4 -CH2Ph 1 Cl H C(Me)2 24 H,H H 6 Me -C(O)Ph-4-Cl C(Me)2 25 H,H H 6 Me -CH2Ph 1 Cl C(Me)2 26 H,H H 5 -CH2Ph 1 Cl -O-i-Pr C(Me)2 Fl 1 337421 suspension and test compound are preincubated for 2 minutes at 37-C, followed by the addition of 10 mM
A-23187. The suspension iB stirred for an additional 4 minutes then bioassayed for LTB4 content by adding an aliquot to a second 500 mL portion of the PMN at 37C. The LTB4 produced in the first incubation causes aggregation of the ~econd PMN, which is measured as a change in light transmission. The size of the assay aliquot is chosen to give a submaximal transmission change (usually -70%) for the untreated control. The percentage inhibition of LTB4 formation is calcuated form the ratio of transmission change in the sample to the transmission change in the compound-free control.
~uman Polymorphonuclear (PMN) Leukocyte LTB/, Assay A. Preparation of Human PMN. ~uman blood was obtained by antecubital venepuncture from consenting volunteers who had not taken medication within the previous 7 days. The blood was immediately added to 10% (v/v) trisodium citrate (0.13 M) or 5% (v/v) sodium heparin (1000 IU/mL). PMNs were isolated from anticoagulated blood by dextran sedimentation of erythrocytes followed by centrifugation through Ficoll-Hypaque' (specific gravity 1.077), as described by Boyum (Scand. J. Clin. Lab. Invest., ~1 (Supp.
~1~. 77(1968)). Contaminating erythrocytes were removed by lysis following ezposure to ammonium chloride (0.16 M) in Tris buffer (pH 7.65), and the PMNs resuspended at 5 z 105 cell~/mL in EEPES (15 mM)-buffered Hanks balanced salt solution containing Ca2+ (1.4 mM) and Mg2+ (o 7 mM), pH 7.4. Viability was assessed by Trypan blue exclusion and was typically greater than 98Z.

A

Fl 1 3 3 7 4 2 7 B. Generation and Radioimmunoassay of LTB4.
PMNs (0.5 mL; 2.5 x 105 cells) were placed in plastic tubes and incubated (37C, 2 min) with test compounds at the desired concentration or vehicle (DMS0, final concentration 0.2%) as control. The synthesis of LTB4 was initiated by the addition of calcium ionophore A23187 (final concentration 10 mM) or vehicle in control samples and allowed to proceed for 5 minutes at 37C. The reactions were then terminated by the addition of cold methanol (0.25 mL) and samples of the entire PMN reaction mixture were removed for radioimmunoassay of LTB4.
Samples (50 mL) of authentic LTB4 of known concentration in radioimmunoassay buffer (RIA) buffer (potassium phosphate 1 mM; disodium EDTA 0.1 mM;
Thimerosal 0.025 mM; gelatin 0.1%, pH 7.3) or PMN
reaction mixture diluted 1:1 with RIA buffer were added to reaction tubes. Thereafter [3H]-LTB4 (10 nCi in 100 mL RIA buffer) and LTB4-antiserum (100 mL
Of a 1:3000 dilution in RIA buffer) were added and the tubes vortexed. Reactants were allowed to equilibrate by incubation overnight at 4C. To separate antibody-bound from free LTB4, aliquots (50 mL) of activated charcoal (3% activated charcoal in RIA buffer containing 0.25% Dextran T-70) were added, the tubes vortexed, and allowed to stand at room temperature for 10 minutes prior to centrifugation (1500 x g; 10 min; 4C). The supernatants containing antibody-bound LTB4 were decanted into vials and Aquasol 2 (4 mL) was added. Radioactivity was quantified by liquid scintillation spectrometry.
Preliminary studies established that the amount of methanol carried into the radioimmunoassay did not Fl influence the results. The specificity of the antiserum and the sensitivity of the procedure have been described by Rokach et al. (Prostaglandins Leukotrienes and Medicine 1984, 13, 21.) The amount of LTB4 produced in test and control (approx. 20 ng/106 cells) samples were calculated. Inhibitory dose-response curves were constructed using a four-parameter algorithm and from these the IC50 values were determined.

Asthmatic Rat Assay Rats are obtained from an inbred line of asthmatic rats. Both female (190-250 g) and male (260-400 g) rats are used.
Egg albumin (EA), grade V, crystallized and lyophilized, is obtained from Sigma Chemical Co., St.
Louis. Aluminum hydroxide is obtained from the Regis Chemical Company, Chicago. Methysergide bimaleate was supplied by Sandoz Ltd., Basel.
The challenge and subsequent respiratory recordings are carried out in a clear plastic box with internal dimensions 10 x 6 x 4 inches. The top of the box is removable; in use, it is held firmly in place by four clamps and an airtight seal is maintained by a soft rubber gasket. Through the center of each end of the chamber a Devilbiss nebulizer (No. 40) is inserted via an airtight seal and each end of the box also has an outlet. A
Fleisch No. 0000 pneumotachograph is inserted into one end of the box and coupled to a Grass volumetric pressure transducer (PT5-A) which is then connected to a Beckman Type R Dynograph through appropriate couplers. While aerosolizing the antigen, the Fl t 337427 outlets are open and the pneumotachograph is isolated from the chamber. The outlets are closed and the pneumotachograph and the chamber are connected during the recording of the respiratory patterns. For challenge, 2 mL of a 3% solution of antigen in saline is placed into each nebulizer and the aerosol is generated with air from a small Potter diaphragm pump operating at 10 psi and a flow of 8 liters/minute.
Rats are sensitized by injecting (subcutaneously) 1 mL of a suspension containing 1 mg EA and 200 mg aluminum hydroxide in saline. They are used between days 12 and 24 postsensitization. In order to eliminate the serotonin component of the response, rats are pretreated intravenously 5 minutes prior to aerosol challenge with 3.0 mgm/kg of methysergide. Rats are then exposed to an aerosol of 3~/O EA in saline for exactly 1 minute, then their respiratory profiles are recorded for a further 30 minutes. The duration of continuous dyspnea is measured from the respiratory recordings.
Compounds are generally administered either orally 1-4 hours prior to challenge or intravenously 2 minutes prior to challenge. They are either dissolved in saline or 1% methocel or suspended in 1%
2s methocel. The volume injected is 1 mL/kg (intravenously) or 10 mL/kg (orally). Prior to oral treatment rats are starved overnight. Their activity is determined in terms of their ability to decrease the duration of symptoms of dyspnea in comparison with a group of vehicle-treated controls. Usually, a compound is evaluated at a series of doses and an ED50 is determined. This is defined as the dose Fl 1 3 3 7 4 2 7 (mg/kg) which would inhibit the duration of symptoms by 50%.
The invention is further defined by reference to the following examples, which are intended to be illustrative and not limiting. All temperatures are in degrees Celsius.

Example 1 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2, 2-dimethylpropanoic acid Step A: 3-[N-p-Chlorobenzyl-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid methyl ester To a solution of 39 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in a mixture of 300 mL of toluene and 150 mL of glacial acetic acid was added 15 g of NaOAc and 50 g of 1-(4-methoxyphenyl)-1-(p-chlorobenzyl)hydrazine hydrochloride. The reaction was maintained with stirring at room temperature for 3 days under argon in the dark. The mixture was poured into 3 L of H2O
and extracted with 3 x 500 mL of EtOAc. The ethyl acetate was washed with 3 x 500 mL of water then solid NaHCO3 was added. The mixture was filtered and the filtrate washed twice with water . The organic phase was dried over MgSO4 and evaporated to dryness to provide the title compound. m.p. 102-103 C.

Fl Step B: 3-tN-(p-Chlorobenzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid The compound from Step A was hydrolysed using 325 mL of THF, 600 mL of MeOH and 325 mL of l.OM LiOH. The æolution was heated to 80 C for 3 h. The æolution was acidified with lN HCl and extracted with 3 x 200 mL of EtOAc. The organic phase was washed with water (2 x 150 mL) and dried over MgSO4. The solution was evaporated to dryness to provide the title compound. m.p. 190-191 C.

Anal C, H, N: Calc. C 65.27; H 6.57; N 3.04, Found C 65.28; H 6.58; N 3.04 Step C: Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoate 0 A solution of 61 mL of t-butylthiol in 650 mL of dry HMPA at 0 C was treated portionwise with 26 g of 50% NaH in mineral oil after removal of oil with hexane. The reaction was stirred at RT for 30 5 mins and 46 g of the compound from Step B was added.
The reaction was then heated under N2 at 175 C for 5 hours. The solution was cooled, and poured onto crushed ice, after which it was treated with 2 N HCl to pH 5 and extracted with EtOAc (3 x 500 mL). The organic phase was washed with H2O (3 x 200 mL) dried (MgSO4) and evaporated.

El 1 3 3 7 4 2 7 The residue was dissolved in 300 mL of ether and ethereal diazomethane was added until all acid was consumed. The excess solvent was removed and the oily residue triturated with hexane to leave a crystalline mass which was recrystallized from EtOAc/hexane to provide the title compound as a white crystalline solid, m.p. 170-171 C. From the mother liquors was isolated methyl 3-[N-(p-t-butylthio-benzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-di-lo methyl propanoate which was used as such in Example 3.

Step D: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoate.
Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate (33.6 g) from Step C was dissolved in 500 mL of dry DMF and the solution was charged with 2.4 g of KI, 30.3 g of K2C03, 4.77 g of Cs2C03 and 23.5 g of 2-(chloromethyl)quinoline hydrochloride. The reaction was stirred at RT, under N2, for 72 hours then it was poured into water (1.5 L), acidified with lN HCl and extracted (3 x 200 mL) with CH2C12. The organic phase was washed with H20 (3 x 150 mL), dried and evaporated. The residue was dissolved in hot EtOAc and upon cooling crystallized to deposit 22.0 g of the title compound, m.p. 166-167 C

Step E: 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2, 2-dimethylpropanoic acid Fl Using the hydrolytic procedure of Step B but substituting the ester of Step D for the ester of Step A provided the title compound, which was recrystallized from 1:1 EtOAc/hexane. m.p. 208C.

Anal C, H, N: Calc. C 69.55; H 6.01; N 4.77, Found C 69.77; H 6.05; N 4.70 Example lA
3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid Step A: N-Acetyl-4-(guinolin-2-ylmethoxy)aniline A mixture containing 2-(chloromethyl)-quinoline hydrochloride (100.0 g), 4-acetamido-phenol (70.69 g) and milled anhydrous potassium carbonate (194 gj was stirred in DMF (1.2 L) using a mechanical stirrer for 48 hours. The mixture was carefully poured onto ice/water (3 L) with vigourous ætirring. After the ice had melted, the solid was filtered and rinsed thoroughly with water. It was recrystallized from 95% ethanol and filtered to give the title compound in three crops.
Step B: 4-(Quinolin-2-ylmethoxy)aniline A suspension of N-acetyl-4-(quinolin -2-ylmethoxy)aniline (Step A, 108.9 g) in 1 L of 95%
ethanol containing 10 M KOH (120 mL) was heated at reflux under nitrogen in a heating mantle. When the hydrolysis was complete (approx. 36 h), the Fl reaction mixture was cooled and ethanol was partially removed under vacuum. The mixture was then diluted with water (200 mL) and the fine off-white crystals were collected and thoroughly rinsed with water. The material, after air-drying, yielded the title compound which was used as such in the next step.

Step C: 4-(Quinolin-2-ylmethoxy)phenylhydrazine A quantitiy of 84 g of 4-(quinolin-2-ylmethoxy)aniline from Step B was suspended in 300 mL
of deionized H2O and 84 mL of 12 M HCl. The suspension was stirred vigourously to obtain a fine particle suspension. Then a precooled solution (5C) of 23.88 g of sodium nitrite dissolved in 75 mL of deionized H2O was added dropwise to the suspension at 5C over 25 minutes. The solution was stirred at 5C
for 60 min to obtain the diazonium salt as a clear brown solution. The presence of excess HNO2 was confirmed by KI-starch paper, and the pH of the solution was about 3Ø If a white suspension persisted after 1 h, the mixture was filtered through a glass wool plug, to give the diazonium salt in the filtrate.
In the meantime a sodium hydrosulfite solution was prepared by dissolving 321 g of sodium hydrosulfite (approx. 85~/o purity) in 2 L of deionized water, and cooled at 0 to 5C. To this solution were added 15 mL of 2N NaOH and 2 L of ether. The biphasic solution was kept near 0C by additon of crushed ice and was stirred vigorously. To this solution was added dropwise the diazonium salt Fl 1 3 3 7 4 2 7 solution with stirring maintained throughout. At the end of the addition an orange solid was formed and 600 mL of NaOH (2N) was added over 30 minutes. The reaction was finally stirred for 60 minutes at 25C.
The solid was collected, æuspended in ether (1 L) and filtered. The process was repeated with 2 L of water to yield the title compound as a pale yellow solid after freeze-drying overnight. m.p. 73-85C (dec).
O Step D: l-(p-chlorobenzyl)-l-[4-(quinolin-2 methoxy)phenyl]hydrazine A quantity of 10 g of 4-(quinolin-2-ylmethoxy)phenylhydrazine from Step C was added to a solution of 10.5 mL of diisopropylethylamine and 150 mL of CH2C12. To the yellow suspension was added 9.11 g of p-chlorobenzyl chloride followed by 3.64 g of Bu4NBr and 50 mL of CH2C12. The reaction was stirred for approximately 24 hours. When no starting material remained, the reaction was diluted with H20 and extracted 3 times with CH2C12. The combined organic phase was washed once with water and dried (MgS04), filtered and evaporated to dryness. The solid residue was dried under vacuum overnight prior to being swished in ether/methanol 90/10 to give the title compound as a pale yellow solid. m.p. 130C.

Step E: 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid The methyl ester of the title compound was prepared according to the method described in Step A

Fl of Example 1 but using the phenylhydrazine from Step D of Example lA as starting material.
The title compound was prepared under the conditions described in Step B of Example 1.

Example 2 3-tN-(p-Chlorobenzyl)-3-methyl-5-(quinolin-2-yl-methoxy)indol-2-yll-2.2-dimethylpropanoic acid The title compound was prepared according to the method of Example 1, but using methyl 2,2-dimethyl-4-oxohexanoate as starting material in Step A in place of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate. m.p. 215-217 C.
Example 3 3-[N-(p-t-Butylthiobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid The methyl ester byproduct from Step C of Example 1 was reacted 2-(chloromethyl)quinoline according to the conditions of Steps D & E of Example 1 to provide the title compound. m.p. 172-173 C.
Example 4 3-[N-(p-Chlorobenzyl)-3-(phenylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid The title compound was prepared according to the method described for Example 1, but substituting methyl-5-phenylthio-2,2-dimethyl-4-oxopentanoate for Fl methyl 5-t-butylthio-2,2-dimethyl-4-oxopentonoate in Example 1 (Step A).

Anal. C, H, N for sodium salt- 2 H20:
Calc. C 64.91; H 5.30; N 4.20 Found C 64.94; H 5.04; N 4.15 Example 5 3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid. N-oxide Methyl 3-[N-(p-chlorobenzyl)-3-(phenylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoate (430 mg) from Step D of Example 4 was dissolved in 5 mL cold CH2C12 and treated with a solution of 448 mg of 80% m-chloroperbenzoic acid (MCPBA) in CH2C12. After 24 hours, the solution was poured onto 10 mL of sat. aqueous NaHC03 solution, extracted with 3 x 10 mL of CH2C12, washed with 2 x 10 mL of H20, dried with magnesium sulfate and evaporated to dryness. ~he residue was crystallised from 2:1 CH2C12/EtOAc to yield 280 mg of the title compound as its methyl ester. Hydrolysis using the conditions described in Example 1 (Step B) provided the title compound, m.p. 197 C (dec.) Anal. C, H, N: Calc. C 66.0; H 4.77; N 4.28 Found C 66.06; H 4.77; N 4.19.

Fl Examples 6 and 7 3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid and 3-[N-(p-Chlorobenzyl)-3-(phenylsulfinyl)-5-(quino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid Methyl 3-[N-p-chlorobenzyl-3-(phenyl lo thio)-5-(quinolin-2-methoxy)indol-2-yl]-2,2-dimethyl propanoate (430 mg) from Example 4 (Step D) was dissolved in 5 mL of cold methylene chloride and a solution of 150 mg of 80% (MCPBA) in methylene chloride was added. After 24 hours, the reaction solution was poured onto 10 mL of saturated aqueous sodium bicarbonate solution and this mixture was extracted 3 times with 10 mL of methylene chloride.
The combined organic phases were washed twice with 10 mL of water, dried with magnesium sulfate and evaporated under vacuum.
Chromatography over silica gel (2 hexane: 1 ethyl acetate) provided two compounds which were separately hydrolyzed using the procedure described in Example 1 (Step B).
3-[N-(p-Chlorobenzyl)-3-(phenylsulfonyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid:
Anal . C, H, N f or sodium salt H2O:
Calc. C 63.57; H 4.89; N 4.12 Found C 63.28; E 4.77; N 3.90 Fl t 3 3 7 4 2 7 3-[N-(p-Chlorobenzyl)-3-(phenylsulfinyl)-5-(quino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid:
Anal. C, H, N for sodium salt- H20:
Calc. C 63.38; H 5.17; N 4.11 Found C 63.28; H 4.89; N 3.97 Example 8 3-[N-(p-Chlorobenzyl)-5-(quinolin-2-ylmethoxy)-indol-2-yl~-2~2-dimethylpropanoic acid Step A: Methyl 3-[N-(p-chlorobenzyl)-5-hydroxyindol-2-yll-2,2-dimethylpropanoate A suspension of 1.0 g of 3-tN-(p-chloro-benzyl)-3-(t-butylthio)-5-methoxyindol-2-yl]-2,2-dimethylpropanoic acid (from Example 1 Step B) in 50 mL of CH2C12 was treated with 1.3 mL of ethanethiol and 3.47 g of AlC13 at 0C under argon. After 40 min the mixture was poured onto 50 mL lN HCl, extracted with 3 x 50 mL of CH2C12 washed with 2 x 50 mL of H20, dried with MgS04 and the solvent removed. The residue was dissolved in 10 mL ether and ethereal diazomethane added until all the acid was consumed.
The excess solvent was removed and the residue chromatographed on silica gel to afford the title compound.

Step B: 3-[N-(p-Chlorobenzyl)-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid The title compound was prepared by treating 1 ~37427 Fl the ester from Step A with 2-(choromethyl)quinoline hydrochloride under the conditions of Step D and effecting hydrolysis under the conditions of Example 1 (Step B), m.p. 193-194C.

Example 9 3-[N-(p-Chlorobenzyl)-3-benzoyl-5-(quinolin-2-yl-methoxy~indol-2-yll-2,2-dimethylpropanoic acid Step A: Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-benzoyloxyindol-2-yll-2~2-dimethylpropanoate Methyl 3-[N-(p-chlorobenzyl)-5-hydroxy indol-2-yl~-2,2-dimethylpropanoate (609 mg) from Example 8 (Step A) was dissolved in 10 mL of 1,2-dichloroethane and the solution charged with 0.5 mL of benzoyl chloride and 680 mg of AlC13. The reaction was heated to 80 C under argon for 1.5 h, then quenched with 20 mL of 0.5N Na, K tartrate solution, extracted with 3 x 20 mL of ether, washed with 10 mL of H2O and dried (MgSO4). Removal of solvent provided an oily residue which was chromatographed on silica gel to give the title compound.
5 Step B: Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-hydroxyindol-2-yll-2.2-dimethylpropanoate The compound from Step A (300 mg) was dissolved in 4 mL of MeOH and treated with 1 mL of a 1.4 M solution of NaOMe in MeOH under argon for 3 hrs. The mixture was poured onto 20 mL of NH40Ac (25Z solution), extracted with 3 x 15 mL of ether, Fl washed with 10 mL of H20, dried over MgS04 and the solvent removed under vacuum. The resulting oil was purified by chromatography on silica gel to afford the title compound.

Step C: 3-[N-(p-Chlorobenzyl)-3-benzoyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethyl-propanoic acid The title compound was prepared using the conditions described in Step D and Step E of Example 1, but substituting the ester from Step B for the ester of Example 1 , Step C; m.p. 165-166C.

Example 10 3-[N-(p-Chlorobenzyl)-3-benzyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid Step A: Methyl 3-[N-(p-Chlorobenzyl)-3-benzyl-5-(benzoyloxy)indol-2-yl]-2,2-dimethyl-propanoate Methyl 3-[N-(p-chlorobenzyl)-3-benzoyl-5-(benzoyloxy)indol-2-yl]-2,2-dimethyl-propanoate (360 mg) (prepared in Step A of Example 9), 800 mg of ZnI2, and 500 mg of sodium cyanoborohydride were stirred in 5 mL of dichloroethane at RT under argon for 30 min. The temperature was then raised to 65 C for 3 hr. After the solution had cooled, it was poured onto 10 mL of NH40Ac (25% solution), extracted with 3 x 15 mL of ether, washed with 10 mL of ~2 and dried (MgS04).

Fl The solution was evaporated to dryness and the residue was chromatographed on silica gel to yield the title compound as a white foam.
Step B: 3-[N-(p-Chlorobenzyl)-3-benzyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethyl-propanoic acid The title compound was prepared under the lo conditions described in Step B and Step C of Example 9 but substituting the ester from Example 10 (Step A) for the ester of Example 9 (Step A), m.p. 178C.

Example 11 3-[N-(p-Chlorobenzyl)-3-(3,3-dimethyl-1-oxo-1-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2, 2-dimethylpropanoic acid The title compound was prepared according to 2~ the method described in Example 9, but using t-butylacetylchloride in place of benzoyl chloride in Step A, m.p. 183-184C.

Example 12 2s 2-tN-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl~ethoxyethanoic acid Step A; Methyl 2- [n- ( p-Chorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]
ethanoate The title compound was prepared according to the method outlined in Steps A-D of Example 1, but Fl using methyl 4-t-butylthio-3-oxo-butanoate in Step A
instead of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate.

Step B: 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yllethanol The compound from Step A (192 mg) was dissolved in 3 mL of THF at RT under an argon lo atmosphere and treated with 30 mg of lithium aluminum hydride. After 1 hr, the reaction was poured onto 10 mL of 0.5 N Na,K tartrate solution and extracted with 3 x 10 mL of EtOAc. The organic layer was washed with 10 mL of H20, dried (MgS04) and evaporated to dryness to yield the title compound.

Step C: 2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethoxy-ethanoic acid To 91 mg of 2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethanol from Step B in 2 mL THF at 0 C under an argon atmosphere was added 40 mg of 80% sodium hydride over 30 min. Ethyl bromoacetate (0.3 ml) was added to the solution and the reaction stirred at RT
overnight. The reaction was poured onto 10 mL of NH40Ac (25~/o solution), extracted with 3 x 10 mL of EtOAc, washed with 20 mL of H20 and dried over 4 MgS04. Removal of the solvent followed by column chromatography on silica gel afforded the ethyl eæter of title compound. Hydrolysis of this ester under 1 ~37427 Fl the conditions described in Step B of Example 1 provided the title compound, m.p. 185C (dec.).

Example 13 3-[N-(p-Chlorobenzyl)-3-(3,3-dimethyl-1-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2.2-dimethylpropanoic acid The title compound was prepared according to the method described in Example 10 but using methyl 3-[N-(p-chlorobenzyl)-3-(3,3-dimethy-1-oxo-l-butyl)-5-(t-butylacetyloxy)-indol-2-yl]-2,2-dimethylpropanoate (obtained as an intermediate from Example 11) as starting material, m.p. 188C (dec.). 5 i Example 14 3-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl~-2-methylpropanoic acid - The title compound was prepared according to the method of Example 1 using methyl 5-t-butyl-thio-2-methyl-4-oxopentanoate as starting material in Step A in place of methyl 5-t-butylthio-2,2-dimethyl-4-oxopentanoate.
2s lH NMR (250 MHz, acetone-d6) ~ 1.05 (3H, d, J = 6Hz), 1.15 (9H, s), 2.7 (lH, m), 3.2 (2H, d, J = 7Hz), 5.4 (2H, s), 5.6 (2H, s), 6.9 (lH, dd), 7.0 (2H, d), 7.3 (4H, m), 7.6 (lH, td), 7.7 (lH, d), 7.8 (lH, td), 7.9 (lH, d), 8.1 (lH, d), 8.3 ppm (lH, d).

Fl 1 3 3 7 4 2 7 Example 15 3-[N-(p-Chlorobenzyl)-3-methyl-5-(6,7-dichloro-quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanolc acid The title compound was prepared according tothe method described in Example 1 but using methyl 2,2-dimethyl-4-oxohexanoate as starting material in Step A and 2-(bromomethyl)-6,7-dichloroquinoline in Step D.

Anal. C, H, N: Calc. C 63.21; H 4.74; N 4.91 Found C 63.47; H 4.94; N 4.67 - - Example 16 3-[N-(p-Chlorobenzyl)-3-methyl-5-(7-chloroquino-lin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid The title compound was prepared according to the method described in Example 15 but using 2-(bromomethyl)-7-chloroquinoline instead of 2-(bromomethyl)-6,7-dichloroquinoline. m.p.
105-107C.

Anal. C, H, N: Calc. C 67.41; H 5.24; N 5.24 Found C 67.82; H 5.12; N 4.32 Example 17 3-[N-(p-Chlorobenzyl)-4-allyl-5-(quinolin-2-yl-methoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoic acid Fl Step A: Methyl 3-cN-(p-chlorobenzyl)-5-allyloxy -3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoic acid 500 mg. of methyl 3-[N-(p-chlorobenzyl)-5-hydroxy-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoate from Step C of Example 1 was dissolved in 5 mL of DMF and 20 mg of K2C03 and 150 mg of allyl bromide were added. The reaction was stirred for 16 hrs. Water was added and the organic phase extracted with EtOAc (3 x 5mL). The organic phase was dried with MgSO4 and evaporated to yield, after chromatography on silica gel (EtOAc:hexane 1:5), the title compound.
Step B: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-4-allyl-5-hydroxyindol-2-yl]-2,2-dimethyl-propanoate 500 mg of the ester of Step A was converted to the title compound by heating to 180 in m-xylene for 4 hours.

Step C: 3-[N-(p-Chlorobenzyl)-4-allyl-5-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid The title compound was prepared from the compound of Step B using the methodology of Example 30 1, (Steps D and E), m.p. 103-105C.

Anal. C, H, N: Calc. C 69.09; H 6.11; N 4.35 Found C 70.55; H 6.31; N 4.29 Fl Example 18 3-~N-(p-Chlorobenzyl)-4-allyl-5-(quinolin-2-yl-methoxy)indol-2-yll-2.2-dimethylpropanoic acid The methyl ester of the title compound was prepared according to the method of Example 17 but substituting methyl 3-[N-(p-chlorobenzyl)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate as starting material (obtained in Step A Example 8) for the ester 0 in Example 17 (Step A). Hydrolysis was then effected according to the conditions of Step B of Example 1 to provide the title compound, m.p. 196-197C (dec.).

Example 19 3-[N-(p-Chlorobenzyl)-6-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid The title compound was prepared according to the conditions of Example 1, Steps A to E, but substituting 1-(3-methoxyphenyl)-1-(p-chloro-benzyl)hydrazine hydrochloride for the starting material in Example 1 (Step A). Chromatographic separation of the desired regioisomer was achieved at 2s Step A by iæolating the most polar product, methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-6-methoxy-indol-2-yl]-2,2-dimethylpropanoate. The properties of the title compound were as follows: m.p.
165-167C.
Anal C, H, N: Calc. C 69,54; H 6.01; N 4.77 Found C 69.46; H 6.18; N 4.96 Fl Example 20 3-[N-(p-Chlorobenzyl)-4-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid Methyl 3-tN-(p-chlorobenzyl)-3-(t-butylthio)-4-methoxyindol-2-yl]-2,2-dimethylpropanoate was obtained as a by-product from Step A of Example 19 and isolated by chromatography as the less polar product. The compound was used as starting material for the preparation of the title product using the methodology of Steps B to E of Example 1.

Anal C, H, N: Calc. C 69.54; H 6.01; N 4.77;
Found C 69.80; H 6.24; N 4.86 Example 21 3-~N-(p-Chlorobenzyl)-3-(t-butylthio)-7-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid The title product was prepared according to Steps A to E of Example 1 but substituting 1-(2-methoxyphenyl)-1-(p-chlorobenzyl)hydrazine hydrochloride for 1-(4-methoxyphenyl)-1-(p-chlorobenzyl hydrazine hydrochloride in Example 1 ~Step A), m.p. 206C.

Anal. C, H, N: Calc. C 69.54; H 6.01; N 4.77, Found C 69.40; H 5.88; N 4.65 Fl Example 22 2-[2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quino-lin-2-ylmethoxy)indol-2-yl]ethoxy]propanoic acid sodium salt dihydrate Step A: Methyl 2-[2-[N-(p-chlorobenzyl)-3-(t-butyl-thio)-5-quinolin-2-ylmethoxy)indol-2-yl]-ethoxylpropanoate The title compound was prepared from 251 mg of 2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethanol (Step B of Example 12) under the conditions described in Step C
of Example 12 using methyl P,L-2-bromopropanoate instead of ethyl bromoacetate.
Step B: 2-[2-[N-(p-Chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethoxy]-propanoic acid sodium salt dihydrate The acid corresponding to the title compound of Example 22 was prepared from the ester of Step A
of Example 22 under the conditions described in Step B of Example 1. A quantity of 204 mg of the acid was suspended in 1.5 mL of EtOH and treated with 1 equiv.
of lN aq. NaOH and freezed dried for 2 days to afford the title compound.

Anal. C, H, N: Calc. C 61.25; H 5.61; N 4.33, Found C 61.75; H 5.70; N 3.97 Fl Example 23 3-[N-(p-Chlorobenzyl)-4-(quinolin-2-ylmethoxy)-indol-2-yll-2.2-dimethylpropanoic acid Step A: Methyl 3-[N-(p-chlorobenzyl)-4-hydroxyindol-2-yll-2,2-dimethylpropanoate The title compound was prepared using methodology from Step A of Example 8 but substituting lo 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-4-methoxy indol-2-yl]-2,2-dimethylpropanoic acid (Step B of Example 20) for the propanoic acid in Example 8 (Step A).
5 Step B: 3-[N-(p-Chlorobenzyl)-4-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic - acid The title product was prepared according to conditions described in Steps D and E of Example 1 substituting methyl 3-[N-(p-chlorobenzyl)-4-hydroxy indol-2-yl]-2,2-dimethylpropanoate for the propanoate in Example 1 (Step D), m.p. 158-160C.

Anal. C, H, N: Calc. C 72.20; H 5.45; N 5.61 Found C 72.25; H 5.60; N 5.75 Example 24 3-[N-Methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-yl-methoxy)indol-2-yll-2.2-dimethylpropanoic acid Fl Step A: Methyl 3-[6-methoxy-3-(t-butylthio) indol-2-yll-2.2-dimethylpropanoate A mixture of 4.2 g of 3-methoxyphenyl-hydrazine hydrochloride and 4.9 g of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate in 100 mL of t-butanol was refluxed for 18 hours. The mixture was cooled to R.T., and evaporated to dryness. The residue was suspended in ether (150 ml) and stirred for 30 min. The salts were filtered and the filtrate evaporated to dryness to give a residue which was chromatographed on flash silica gel using as eluant ethyl acetate:toluene (1:99) to isolate the title compound as the most polar product; m.p. 133C.
Step B: Methyl 3-[N--methyl-3-(t-butylthio)-6-methoxyindol-2-yll-2.2-dimethylpropanoate A solution of 1.75 g of the indole from Step A in 30 mL of THF and 3 mL HMPA was cooled to -78C
and to this solution was slowly added a solution of O.54M KHMDS in toluene (10.2 mL). The mixture was stirred at this temperature for 15 min. and treated with 0.34 mL of iodomethane. The mixture was stirred at -78C for 5 h, quenched with lN HCl (100 mL), extracted with ethyl acetate, and the organic layer washed with H20, dried over Na2SO4 and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:hexane (20:80) as eluant to afford the title compound as a solid; m.p.
97-98C.

Fl Step C: Methyl 3-[N-methyl-6-hydroxyindol-2-yl]-2~2-dimethylpropanoate To a cold solution of 940 mg of the indole ester from Step B and 1.6 mL of ethanethiol in CH2C12 (50 mL) was added portion-wiæe 4.3 g of AlC13. After complete addition, the mixture was stirred at R.T.
for 2 h. The mixture was then cooled to 0C and carefully quenched with a solution of 0.5 M Na,K
tartrate (200 mL) and extracted with CH2C12. The organic layer was dried over Na2S04 and evaporated to dryness to give a solid which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to afford the title compound; m.p.
125-126C.

Step D: Methyl 3-[N-methyl-6-(p-chlorobenzoyloxy)-3-(p-chlorobenzoyl)indol-2-yl]-2,2-di-methylpropanoate To a cold solution of 393 mg of hydroxy indole from Step C in 5 mL of THF were added 0.31 mL
of Et3N followed by 0.21 mL of p-chlorobenzoyl chloride. The mixture was stirred at R.T for 15 min and quenched with H20. The mixture was extracted with ethyl acetate which was dried over Na2S04 and evaporated to dryneæs to give a solid which was dissolved in 10 mL of 1,2-dichloroethane. To this mixture were added successively at R.T. 0.38 mL of p-chlorobenzoyl chloride and 803 mg of AlC13. The mixture was heated at 80C for 3 h, cooled to R.T.
and quenched with 50 mL of 0.5 N HCl. The mixture was extracted with CH2C12, washed with H20, Fl dried over Na2S04 and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetate:hexane (20:80) as eluant to afford the title compound as a white solid. m.p. 138C.

Step E: Methyl 3-[N-methyl-3-(p-chlorobenzoyl)-6-hydroxyindol-2-yll-2~2-dimethylpropanoate To a suspension of 270 mg of the p-chlorobenzoate from Step D in 3 mL of MeOH was added 1.2 mL of a solution of 1.3M NaOMe in MeOH and the mixture was stirred at R.T. for 2 hr. The reaction mixture was poured onto 25% aq. NH40Ac and extracted with ethyl acetate. The organic extract was dried over Na2S04, evaporated to dryness and the residue chromatographed on flash silica gel using ethyl acetate:hexane (40:60) as eluant to afford the title compound as a yellow foam.
0 Step F: Methyl 3-[N-methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2~2-dimethylpropanoate To a solution of 180 mg of the phenol from Step E in 5 mL of DMF were added 124 mg of milled K2C03 followed by 150 mg of 2-(bromomethyl) quinoline. The mixture was 8tirred at R.T. for 18 h, poured onto 25% aq. NH40Ac and extracted with ethyl acetate. The extract was dried over Na2S04 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam.

Fl Step G: 3-~N-Methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid To a æolution of 230 mg of ester from Step F
in 1.5 mL of THF and 3 mL of MeOE was added lM aq.
LiOH and the mixture stirred at 80C for 4 h. The mixture was cooled to R.T. and evaporated to dryness in vacuo. The residue was dissolved in a mixture of 20 mL of 25% aq. NH40Ac and 20 mL of ethyl acetate using vigourous stirring. The organic layer was separated, dried over Na2SO4 and evaporated to dryness to give a yellow solid (216 mg). This solid was swished for 2 h in 5 mL of a mixture of Et2O:hexane (1:1). The solid was filtered and rinsed with a 1:2 mixture of Et2O:hexane to give the title product as a yellow solid, m.p. 203-205C:

Anal. C, H, N: Calc. C 70.65; H 5.16; N 5.32;
Found C 70.42; H 5.25; N 5.40 Example 25 3-[N-Methyl-3-(p-chlorobenzyl)-6-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid, sodium salt hemihydrate Step A: Methyl 3-~N-methyl-3-(p-chlorobenzyl)-6-(p-chlorobenzoyloxy)indol-2-yl]-2,2-dimethyl-propanoate 0 To a solution of 500 mg of the benzoyl derivative from Step D of Example 24 in 10 mL of Fl ~ ~3 742 7 1,2-dichloroethane were added 1.19 g of ZnI2 and 700 mg of NaBH3CN. The mixture was heated at 65C for 5 hours and cooled to R.T. The mixture was quenched with lN aq. ~Cl and extracted with CH2C12. The extracts were washed with brine, dried over Na2S04 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (15:85) as eluant to isolate the title compound as a white foam.

Step B: Methyl 3-[N-methyl-3-(p-chlorobenzyl)-6-hydroxyindol-2-yl~-2.2-dimethylpropanoate To a suspension of 425 mg of p-chlorobenzoate from Step A in 3 mL of MeOE was added 1.9 mL of a solution of 1.3M NaOMe in MeOH.
The mixture was stirred at R.T. for 1 h, poured into 20 mL of 25% aq. N~40Ac, and extracted with ethyl acetate. The organic extract was dried over Na2S04 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a white foam.
5 Step C: Methyl 3-tN-methyl-3-(p-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl3-2,2-dimethylpropanoate To a solution of 315 mg of the ester from Step B in 3 mL of DMF were added 225 mg of milled K2C03 and 272 mg of 2-(bromomethyl)quinoline. The mixture was stirred at R.T. for 18 h, poured into 25%
aq. NH40Ac, and extracted with ethyl ? 337427 Fl acetate. The organic extract was dried over Na2SO4 and evaporated to dryness to give an oil which was chromatographed on flash silica gel using ethyl acetate:hexane (30:70) as eluant to give the title compound as a foam.

Step D: 3-~N-Methyl-3-(p-chlorobenzyl)-6-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid, sodium salt hemihydrate To a solution of 367 mg of the ester from Step C in 3 mL of THF and 6 mL of MeOH was added 1 M
aq. LiOH and the mixture was heated at 80C for 2 h.
The mixture was cooled to R.T. and evaporated to dryness. The residue was dissolved in a mixture of 20 mL of 25% aq. NH40Ac and 20 mL of ethyl acetate (vigourous stirring required). The organic layer was separated, dried over Na2SO4 and evaporated to dryness to give a white solid (346 mg). The solid was swished at R.T. for 2 h with 10 mL of a mixture of Et2O:hexane (1:1), filtered, rinsed with a mixture of (1:2) Et2O:hexane and the solid collected to give the title compound as its free acid, a white solid:
m.p. 185C.
The title compound was prepared by dissolving the above acid in 1 mL of EtOH to which 0.63 mL of lN aq. NaOH was added. The mixture was freeze dried for 2 days to give the title product as a white solid.
Anal. C, H, N: Calc. C 67.32; H 5.29; N 5.07;
Found C 67.15; H 5.35; N 5.17

Claims

1. A compound of the formula I:

I

wherein:
R1, R2, R3, R4 and R10 are independently hydrogen, halogen, lower alkyl, lower alkenyl, lower alkynyl, -CF3, -CN, -NO2, -N3, -C(OH)R11R11, -CO2R12, -SR14, S(O)R14, -S(O)2R14, -S(O)2NR15R15, -OR15, -NR15R15, -C(O)R16 or -(CH2)tR21;

R5 is hydrogen, -CH3, -CF3, -C(O)H, X1-R6 or X2-R7;

R6 and R9 are independently: alkyl, -(CH2)uPh(R10)2 or -(CH2)uTh(R10)2;

R7 is -CF3 or R6;

R8 is hydrogen or X3-R9;

each R11 is independently hydrogen or lower alkyl, or two R11's on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

R12 is hydrogen, lower alkyl or -CH2R21;

R13 is lower alkyl or -(CH2)rR21;

R14 is -CF3 or R13;

R15 is hydrogen, -C(O)R16, R13, or two R15 's on the same nitrogen may be joined to form a monocyclic heterocyclic ring of 4 to 6 atoms containing up to 2 heteroatoms chosen from O, S or N;

R16 is hydrogen, -CF3, lower alkyl, lower alkenyl, lower alkynyl or -(CH2)rR21;

R17 is -(CH2)s-C(R18R18)-(CH2)s-R19 or -CH2C(O)NR15R15;

R18 is hydrogen or lower alkyl;

R19 is a) a monocyclic or bicyclic heterocyclic ring containing from 3 to 9 nuclear carbon atoms and 1 or

2 nuclear hetero-atoms selected from N, S or O and with each ring in the heterocyclic radical being formed of 5 or 6 atoms, or b) the radical W-R20;

R20 is alkyl or C(O)R23;

R21 is phenyl substituted with 1 or 2 R22 groups;

R22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -NO2 or -N3;

R23 is alkyl, cycloalkyl, monocyclic monoheterocyclic ring of 5 to 7 nuclear carbon atoms and containing only one hetero atom selected from N, S or O in the ring;

R24 is the residual structure of a standard amino acid, or R18 and R24 attached to the same N can cyclize to form a proline residue;

m is 0 to 1;
n is 0 to 3;
p is 1 to 3 when m is 1;
p is 0 to 3 when m is 0;
r is 0 to 2;
s is 0 to 3;
t is 0 to 2;
u is 0 to 3;
v is 0 or 1;
W is 0, S or NR15;
X1 is 0, or NR15;
X2 is C(O). CR11R11, S, S(O) or S(O)2;
X3 is C(O), CR11R11, S(O)2 or a bond;
Y is X1 or X2;

Q is -CO2R12, -C(O)NHS(O)2R14, -NHS(O)2R14, -S(O)2NHR15 -C(O)NR15R15, -CO2R17, -C(O)NR18R24, -CH2OH, or 1H- or 2H-tetrazol-5-yl;

and the pharmaceutically acceptable salts thereof.

2. A compound of Claim 1 wherein;

R1 R2, R3 and R4 are hydrogen;
R5 is X2-R6 or -OR6;

R7 is R6;
R8 is R9;
R10 is hydrogen or halogen;
m is 0;
n is 1 to 3;
u is 0 in R6 and 1 in R9;
X2 is CR11R11 or S;

Q is -CO2R12; and the remaining substituents are as defined for Formula I;
and the pharmaceutically acceptable salts thereof.

3. A compound of Claim 1 of the formula Ia:

Ia

4. A compound of Claim 1 of the formula 1b wherein the substituents are as follows:

Ib R1 R2 R3 R5 R8 Y-(CR11R11)p 6-C1 7-Cl H Me -CH2Ph-4-Cl C(Me)2;
H 7-Cl H Me -CH2Ph-4-Cl C(Me)2;
H H 4-allyl -S-t-Bu -CH2Ph-4-Cl C(Me)2;
H H 4-allyl ? -CH2Ph-4-Cl C(Me)2;
H H H -O-i-Pr -CH2Ph-4-Cl C(Me)2;
H H H -S-t-Bu -CH2Ph-4-Cl CH2OCH(Me);
H H H -S-t-Bu -CH2Ph-4-Cl CHMe;
H H H -S-t-Bu -CH2Ph-4-S-t-Bu C(Me)2 or H H H -S-t-Bu -CH2Ph-4-Cl CB2OCH2.

5. A compound of Claim 1 of the Formula Ic:

Ic

6. A compount of Claim 5 of the formula Ic wherein the substituent R5 is: hydrogen, -CH3, -S-t-Bu, -SPh, -S(O)2Ph, -S(O)Ph, C(O)Ph, -CH2Ph, -C(O)CH2-t-Bu or -CH2CH2-t-Bu.

7. The compound according to Claim 1 which is:

3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-methyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-t-butylthiobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-3-(phenylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-(phenylsulfonyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid, N-oxide;
3-tN-(p-chlorobenzyl)-3-(phenylsulfonyl)-5-(quin-olin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropan-oic acid;
3-[N-(p-chlorobenzyl)-3-(phenylsulfinyl)-5-(quin-olin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropan-oic acid;
3-[N-(p-chlorobenzyl)-5-(quinolin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-benzoyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-benzyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-(3,3-dimethyl-1-oxo-1-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethoxyethanoic acid;
3-[N-(p-chlorobenzyl)-3-(3,3-dimethyl-1-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-pxopanoic acid;
3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-Z-yl]-2-methylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-methyl-5-(6,7-dichloro-quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-3-methyl-5-(7-chloro-quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chloxobenzyl)-4-allyl-5-(quinolin-2-yl-methoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-4-allyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-6-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-4-(quinolin-2-ylmethoxy)-3-(t-buty}thio)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-7-(quinolin-2-ylmethoxy)-3 (t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid;
2-[2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quino-lin-2-ylmethoxy)indol-2-yl]ethoxy]propanoic acid;
3-[N-(p-chlorobenzyl)-4-(quinolin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-yl-methoxy)indol-2-yl]-2-2-dimethylpropanoic acid or 3-[N-methyl-3-(p-chlorobenzyl)-6-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid.

8. The 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid.

9. A pharmaceutical composition for inhibiting leukotriene biosynthesis comprising a therapeutically effective amount of a compound of Claim 1, 2, 3, 4, 5, 6 or 7, and a pharmaceutically acceptable carrier.

10. The pharmaceutical composition of Claim 9 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; H2-receptor antagonists; antihistaminic agents;
prostaglandin antagonists; thromboxane antagonists;
thromboxane synthetase inhibitors; and ACE antagonists.

11. A pharmaceutical composition according to Claim 10, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

12. A pharmaceutical composition of Claim 11, wherein the weight ratio of said compound to said second active ingredient ranges from about 1000:1 to 1:1000.

13. The use of a compound of claim 1, 2, 3, 4, 5, 6 or 7 for inhibiting leukotriene biosynthesis.

14. The use of a compound of claim 1, 2, 3, 4, 5, 6 or 7 as an anti-asthmatic, anti-allergic, anti-inflammatory or cytoprotective agent.

15. The use of a compound of claim 1, 2, 3, 4, 5, 6 or 7 for treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea or migraine.

16. A pharmaceutical composition for inhibiting leukotriene biosynthesis comprising a therapeutically effective amount of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid and a pharmaceutically acceptable carrier.

17. A composition according to claim 16 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; H2-receptor antagonists; antihistaminic agents;

prostaglandin antagonists; thromboxane antagonists;
thromboxane synthetase inhibitors; and ACE antagonists.

18. A pharmaceutical composition according to Claim 17, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

19. A composition according to claim 18, wherein the weight ratio of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid to the second active ingredient ranges from about 1000:1 to 1:1000.

20. The use of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid for inhibiting leukotriene biosynthesis.

21. The use of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid as an anti-asthmatic, anti-allergic, anti-inflammatory or cytoprotective agent.

22. The use of 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid for treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea or migraine.

23. A sodium salt of a compound of the Formula Ic:

Ic wherein the substituent R5 is: hydrogen, -CH3, -S-t-Bu, -SPh, -S(O)2Ph, -S(O)Ph, C(O)Ph, -CH2Ph, -C(O)CH2-t-Bu or -CH2CH2-t-Bu.

24. A sodium salt of a compound which is:

3-[N-(P-chlorobenzyl)-3-(t-butylthio)-5-(quinolin 2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-methyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-t-butylthiobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-3-(phenylthio)-5-(guinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-(phenylsulfonyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl propanoic acid, N-oxide;
3-[N-(p-chlorobenzyl)-3-(phenylsulfonyl)-5-(quin-olin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropan-oic acid;
3-[N-(p-chlorobenzyl)-3-(phenylsulfinyl)-5-(guin-olin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropan-oic acid;
3-[N-(P-chlorobenzyl)-5-(quinolin-2-ylmethoxy) indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-benzoyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-cblorobenzyl)-3-benzyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-(3,3-dimethyl-1-oxo-1-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
2-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]ethoxyethanoic acid;
3-[N-(p-chlorobenzyl)-3-(3,3-dimethyl-1-butyl)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(quinolin-2-ylmethoxy)indol-2-yl]-2-methylpropanoic acid;
3-[N-(p-chlorobenzyl)-3-methyl-5-(6. 7-dichloro-quinolin-2-ylmethoxy)indol-2yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-3-methyl-5-(7-chloro-quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-4-allyl-5-(quinolin-2-yl-methoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethyl-propanoic acid;
3-[N-(p-chlorobenzyl)-4-allyl-5-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-6-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-4-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-(p-chlorobenzyl)-7-(quinolin-2-ylmethoxy)-3-(t-butylthio)indol-2-yl]-2,2-dimethylpropanoic acid;
2-[2-[N-(p-chorobenzyl)-3-(t-butylthio)-5-(quino-lin-2-ylmethoxy)indol-2-yl]ethoxy]propanoic acid;
3-[N-(p-chlorobenzyl)-4-(quinolin-2-ylmethoxy)-indol-2-yl]-2,2-dimethylpropanoic acid;
3-[N-methyl-3-(p-chlorobenzoyl)-6-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid or 3-[N-methyl-3-(p-chlorobenzyl)-6-(quinolin-2-yl-methoxy)indol-2-yl]-2,2-dimethylpropanoic acid.

25. A pharmaceutical composition for inhibiting leukotriene biosynthesis comprising a therapeutically effective amount of a compound of claim 23 or 24, in association with a pharmaceutically acceptable carrier.

26. The use of a compound of claim 23 or 24 for inhibiting leukotriene synthesis.

27. The use of a compound of claim 23 or 24 as an anti-asthmatic, anti-allergic, anti-inflammatory or cytoprotective agent.

28. The use of a compound of claim 23 or 24 for treating diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion, dysmenorrhea or migraine.

29. The use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 for treating inflammatory bowel disease in a mammal.

30. A use according to claim 29, wherein the mammal is a man.

31. The use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 for treating arthritis in a mammal.

32. A use according to claim 31, wherein the mammal is a man.

33. The use of a compound of claim 1, 2, 3, 4, S, 6, 7, 8, 23 or 24 for treating allergic rhinitis in a mammal.

34. A use according to claim 33, wherein the mammal is a man.

35. The use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 for treating allergic conjunctivitis in a mammal.

36. A use according to claim 35, wherein the mammal is a man.

37. The use of a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 for treating renal insufficiency arising from ischaemia induced by immunological or chemical toxicology in a mammal.

38. A use according to claim 37, wherein the mammal is a man.

39. A composition for treating inflammatory bowel disease in a mammal, which comprises a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 in association with a pharmaceutically acceptable carrier.

40. A composition according to claim 39, wherein the mammal is a man.

41. A composition for treating arthritis in a mammal, which comprises a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 in association with a pharmaceutically acceptable carrier.

42. A composition according to claim 41, wherein the mammal is a man.

43. A composition for treating allergic rhinitis in a mammal, which comprises a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 in association with a pharmaceutically acceptable carrier.

44. A composition according to claim 43, wherein the mammal is a man.

45. A composition for treating allergic conjunctivitis in a mammal, which comprises a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 in association with a pharmaceutically acceptable carrier.

46. A composition according to claim 45, wherein the mammal is a man.

47. A composition for treating renal insufficiency arising from ischaemia induced by immunological or chemical toxicology in a mammal, which comprises a compound of claim 1, 2, 3, 4, 5, 6, 7, 8, 23 or 24 in association with a pharmaceutically acceptable carrier.

48. A composition according to claim 47, wherein the mammal ia a man.