CA2136241C - Fluorinated quinoline indoles as inhibitors of the biosynthesis of leukotrienes - Google Patents

Abstract

This invention relates to compouds having formula (I), wherein R1 is H, F or MeO, which 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

TITLE OF THE INVENTION
FLUORINATED QUINOLINE INDOLES AS INHIBITORS OF THE
BIOSYNTHESIS OF LEUKOTRIENES
CROSS REFERENCE
The compounds of Formula I' are described in U.S.
Patent 5,204,344.
to BACKGROUND OF. THE INVENTION
European Patent Applications 166,591 and 275,667 disclose a series of indole-based compounds with activity as prostaglandin antagonists and inhibitors of leukotriene biosynthesis respectively. In EP 181,568 and EP 200,101 are disclosed a series of compounds, i s containing two aromatic nuclei, which are described as possessing activity as lipoxygenase inhibitors. In EP 279,263 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 2o phosphodiesterase and tumor metastasis. The chemical preparation of quinoIylindoles is referred to by Sheink_man, 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.
2s 9g, 197936 (1983), by Pakula, et al., Chem. Ab., Vol. 10S, 190835 (1986), and in British Pat. Spec. 1,228,848.
EP 419,049 (March 27, 1991 ) teaches (quinolin-2-ylmethoxy)indoles as inhibitors of leukotriene biosynthesis. WO
92/03132 (March 5, 1992) teaches indole derivatives as inhibitors of 30 leukotriene biosynthesis.

r~-' l. ' .

_2_ SUMMARY OF THE INVENTION
The present invention relates to fluorinated quinoline indoles 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). ,:;y 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 l o 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 ~ndotoxin shock. The compounds of the present invention are useful in the treatment of inflammatory and allergic diseases of the 15 eye, including allergic conjunctivitis. The compounds are also useful as cytoprotective agents and far the treatment of migraine headache.
Thus, the compounds of the present invention may also be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis; erosive esophagitis; inflammatory bowel 2o 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 CCIq, and D-galactosamine; ischemic renal failure;
disease-induced hepatic damage; bile salt induced pancreatic or gastric 2s 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 Bq., C4, D4 and 3o 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 INVENTION
The compounds of this invention are within the scope of Formula I':
R\\ ~ Ra R
~~ ~i~ ~ ~ ~~ \ iy » Ri~R» -C~

2 N X ~ ~----(CR R )"-Ym-(C )P
(0)v R3 \ 8 R
wherein:
R l , R2, R3, R4 and R 1 ~ are independently hydrogen, halogen, lower is alkyl, lower alkenyl, lower alkynyl; -CFA; -CN, -N02> -N3;
-C(OH)R11R11, _C02R12~ -SRl'l, -S(O)R14, -S(O)ZR14, _S(O)2Ng15R15~ -OR15, -NR15R159 _C(O)R16 or _(CH2)tR2l;
2o RS is hydrogen, -CH3, CF3, -C(O)H, Xl-R6 or XZ-R~;
R6 and R9 are independently alkyl, alkenyl, -(CH~)uPh(R1~)2 or -(CH~)u'Th(R 1 ~)2;
2s R'1 is -CF3 or R6;
R$ is hydrogen or X3-R9;
each R 11 is independently hydrogen or lower alkyl, or two R 11's on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;
R 1 ~ is hydrogen, lower alkyl or -CH2R21;

WO 94/00446 ~ ~ J ~ ~,, ~ 1 R 13 is lower alkyl or -{CH2)rR2l ;
R14 is -CF3 or R13;
R 15 is hydrogen, -C(O)R 1 ~', R 13, or two R 15 '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; - .
to R16 is hydrogen, -CF3, Iower alkyl, lower alkenyl, lower alkynyl or -(CH2)rR21;
R1 ~ is -(CH2)s_C(R 18R 18)-(CH2)s-R 19 or -CHZC(O)NR 15R 15;
R 18 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 2 ° formed of 5 or 6 atoms, or b) the radical W-R20;
R2o is alkyl or -C(O)R23;
X21 is phenyl substituted with 1 or 2 R22 groups;

R22 is hydrogen, halogen, lower alkyl, lower alkoxy, lower allcylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -N02 or -N3;
R23 is alkyl, cycloallcyl, 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;
mi50to 1;

WO 94/00446 ~ ~ ~ ~ ~ ~ ~ PCr'/CA93/00256 nisOto3;
p is 1 to 3 when m is 1;
p is 0 to 3 when m is 0;
risOto2;
sis0to3;
tisOto2;
uisOto3;
vis0orl;
WisO,SorNRIS;
X1 is O, or IllRl~;
X2 is C(O), CR I 1 R 11, S, S (O) or S (0)2;
X3 is C(O), CR 11 R 11, S (0)2 or a bond;
X4 is CH=CH, CHZ-Y 1 or Y I -CH2;
is Y is Xl or X2;
Y l is O, S, S (0)2 or CH2;
NHS(O)2 14 - NHR15 Q is -CG~2R12, -C(O)NHS(O)2R14, _ R , S(~)2 -C(C)~g15R15~ _Cp2RI~, -C(O)NR18R24~ -CH20H, or IH- or ZH-2 o tetrazol-5-yl;
or the pharmaceutically acceptable salts thereof.
Specifically, the present invention provides compounds of 25 the formula I:
3o R. o 0 0~-~

wherein R1 is H, F or MeU.

w0 94/0044b ,~ ' ' PCT/CA93/0025b or the pharmaceutically acceptable salts thereof.
Definitions The following abbreviations have the indicated meanings:
lVle = methyl Bz = benzyl Ph = phenyl i o t-Bu = tart-butyl i-Pr = isopropyl c-C6H 11 = cyclohexyl c-Pr = cyclopropyl c- = cyclo 1 s Ac = acetyl Tz = 1H- or 2H- tetrazol-5-yl Th = 2- or 3- thienyl c-CSH9 = cyclopentyl 1-Ad = 1-adamantyl.
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, norbomyl, 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 3 o include methyl, ethyl, propyl, isopropyl, butyl, sec- and tart-butyl, penfiyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, 2-methylcyclopropyl, cyclopropylmethyl, and the like.

PC'I"/CA93100256 w0 94/00446 The term "cycloalkyl" refers to a hydrocarbon ring having from 3 to 7 carbon atoms. Examples of cycloalkyl groups are cyclopropyl, cyclopentyl, cycloheptyl and tk~e like.
"Lower alkenyl" groups include those alkenyl groups of 2 s to 7 carbon atoms. Examples of lower alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl; heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, 1-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like.
"Lower alkynyl" groups include those alkynyl groups of 2 to to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 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 straight, branched, or cyclic configuration. Examples of lower alkoxy groups include 1 s methox ethox , pro ox , iso ro ox c cIo ro Iox , c clohex lox , Y, Y P Y P P Y' Y P PY Y Y Y Y
and the like.
As used herein the term "lower alkylthio" includes those alkylthio groups of from 1 to 7 carbon atoms of a straight, branched or cyclic configuration. Examples of lower alkylthio groups include 2 o methylthio, propylthio, isopropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group signifies -SCH2CH2CH3.
The term "monocyclic monoheterocyclic ring" which defines R~3 includes those monocyclic groups of 5 to 7 members containing only 1 heteroatom selected from N, S or O in the ring.
2s 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-isoindoi-2-yl, 1,3-dihydro-2H-isoindol-z-yl; 2,4-imidazolinedion-1-yl, 2,6-piperidinedion-1-yl, 2-imidazolyl, 2-oxo-1,3-dioxolen-4-yl, piperidin-1-yl, morpholin-1-yl, piperazin-1-yl and the like.
The point of attachment of any heterocyclic ring may be at any free valence of the ring.

j,t,..w -g-It is understood in the art that when the variable v is 1, the nitrogen of the quinolinyl N-oxide so formed 1s positively charged, and the oxygen is negatively charged.
The term standard amino. ac'icI is employed to include the following amino acids: alanine, a~paragine, aspartic acid, arginine, cysteine, glutamic acid, glutaminew glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serene, threonine, tryptophan, tyrosine and valine. (See F.H.C. Crick, Symposium of the Society for Experimental Biology, 1958 (12) p. 140.) to 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.
The terms Ph(R~~)2 and Th(R10)2 indicate a phenyl or thienyl group substituted -with two Rlo substituents.
i s Halogen includes F, Cl, Br, and I.
It is intended that the definitions of any substituent (e.g., R l , R2, R 15, Ph(R 1 ~)2, etc.) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, -NR15R15 represents -NHH; -NHCH3; -NHC6H5, etc.
20 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 = C02R17) are intended to include the esters such as are described by Saari et al., J.
2s - -Med. Chem., 21, No. 8, 746-753 (1978), Sakamoto ~t al., Chem.
Pharm: BuIL, 32, No. 6, 2241-2248 (1984) and Bundgaard et al., J.
Med. Chem., 30, No. 3, 45I-454 (1987).
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a 3 o 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, .. ~1362~1 WO 94/00446 PCT1CA93/00~56 lithium, magnesium, manganic salts, rnanganous, potassium, sodium, zinc and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium andsodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts 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;N 1-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-1 o 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 acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, 20 lactic, malefic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid and the like. Particularly preferred are citric, hydrobromic, hydrochloric, malefic, phosphoric, sulfuric and tartaric acids.
It will be understood that in the discussion of methods of 2s treatment which follows, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
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 3 o 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) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic WO 94/00446 ~ PCT/CA93/0025b conjunctivitis, and the Iike, 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 chemica~l~(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 1 o 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.
Two assays can be used to measure cytoprotective ability:
These assays are; (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140,6$4.
The magnitude of prophylactic or therapeutic dose of a 2o 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 2s 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 outside 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 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 213~~~1 WO 94/00446 ' PCT/CA93/00256 Formula I per kg of body weight per day and for cytoprotective use from about O.I mg to about I00 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.
s 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.I mg to 1 o about 100 mg (preferably from about 1 mg to about I00 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-I % by weight 1 s 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 damage, on 20 me 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 2s otherwise cause such 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).
3 o 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.

,....
,.
WO 94/00446 PC.°T/CA93/00256 136' 41 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 azi active ingredient or a s 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 or acids including inorganic bases or acids and organic bases ~or.acids o 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 1 s 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 2o spray presentation from pressurized packs or nebulisers.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 2s Suspension or solution 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.
3 o 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., WO 94/00446 ~ ~ ~ ~ PCT/CA93/00256 _13_ 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, such 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 1 o the solid oral preparations being preferred over the liquid preparations.
Because of their ease of 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 is 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 such as tJnose described in U.S. Patent Nos. 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200 and 20 4,008,719.
Pharmace~aical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a 2s 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 3 0 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 presentation. 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 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.
to The following are examples of representative pharmaceutical dosage forms for the compounds of Formula I:
Iniectable Suspension ILM.) m ml Compound of Formula I 10 1 s Methylcellulose 5.0 Tween 80~ 0.5 Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection 2 o to a total volume of 1 ml Ta let m tablet Compound of Formula I 25 Microcrystalline Cellulose 415 2s providone 14.0 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 30 Capsule m ca sule Compound of Formula I 25 Lactose Powder 573.5 Magnesium Stearate 1.5 b00 ~l~fi~~l WO 94/00446 - ~ PCT/CA93/00256 - IS -Aerosol Per canister Compound of Formula I 24 mg Lecithin, NF Liquid Concentrate 1.2 mg s Trichlorofluoromethane, NF 4.025 gm Dichlorodifluoromethane, NF 12.15 gm In addition to the compounds of Formula I, the pharmaceutical compositions of the present invention can also contain i o other active ingredients, such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac diflur~isal 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.
i s 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 corr~pound of the Formula I to the NSAID will generally range from about 1000:1 to about 1:1000, preferably about 200:1 to about 1:200. Combinations of a compound of the Formula I
20 ~d 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.
NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;

z5 the acetic acad derivatives;
(2) (3) the fenamic acid derivatives;

(4) the biphenylcarboxylic acid derivatives;
and (5) the oxicams or a pharmaceutically acceptable salt thereof.
3 o The propionic acid derivatives which may be used comprise: alininoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, prano-profen, suprofen, tiaprofenic acid, and tioxaprofen. Structurally related J

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 having a free -CH(CH3)COOH or -CH2CH~CO~OH group (which optionally can be in the form of a pharmaceutically acceptable salt group, e.g., -CH(CH3)COO-Na+ or -CHZCH2C00-Na+), typically attached directly or via a carbonyl function to a ring system, preferably to an aromatic ring system.
io The acetic acid derivatives which may be used comprise:
indomethacin, which is a preferred NSAIIJ, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, isoxepac, oxpinac, sulindac, tiopinac, tolmetin, zidometacin ~ s 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. -CH2C00-Na+), typically attached directly to a ring system, preferably to an aromatic or heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise:
2 s ~~enarnic 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 3 o narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:
H

2I3~~4~.

which can bear a variety of substituents and in which the free -COOI-I
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:
v/ a is C02H
which can bear a variety of substituents and in which the free -COON
group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO-Na+.
20 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 2s analgesics/non-steroidal anti-inflammatory drugs which have the general formula:
OH
.1 ~ C(O)NHR
~N~
O/ \O CHs wherein R is an aryl or heteroaryl ring system.

f,.~,.

36'~ ~~
~1 The following NSAIDs may also be used: amfenac sodium, aminoprofen, anitrazafen, antrafenine, auvarlofin, bendazac lysinate, benzydanine, beprozin, broperamole, ~bufezolac, cinmetacin, ciproquazone, cloximate; dazidamine, 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, 1 o isofezolac, isonixim, isoprofen, isoxicam, lefetamine HCI, 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 i s 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:
20 4g0156S, A.A861, AD1590, AFP802, AFP860, AI77B, AP504;
AU8001, BPPC, BW540C, CHINOIN I27, CN100; EB382, EL508, F1044, GV3658, ITF182; KCNTEI6Q90; KME4, LA2851; MR714, MR897, MY309, ON03144; PR823, PV 102, PV 108; 8830, RS2131, SCR152; SH440, SIR133, SPAS51O; SQ27239, ST281, S~6001, TA60, zs T~_901 (4-benzoyl-1- indancarboxylic acid), TVX2706, U60257, UR2301, and WY41770. .
Finally,. NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acidand the phenylbutazones, and pharmaceutically acceptable salts thereof.
In addition to indomethacin, other preferred NSAIDS are acetyl salicylic acid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ketoprafen, 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
s 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).
1 s 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 U.S. Pat.
4,237,160. They may also contain histidine decarboxylase inhibitors 2 o such as a-fluoromethyl-histidine, described in U.S. Pat. 4,325,961. The compounds of the Formula I may also be advantageously combined with an H 1 or H2-receptor antagonist, such as for instance acetamazole, aminothiadiazoles disclosed in EP 40,696 (December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, 2s r~ridine, terfenadine and like compounds, such as those disclosed in U.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 3o most cell stabilizing agents, such as 1,3-bis(2-carboxy-chromon-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 serotonin antagonists described in Nature, 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, terbutaiine, fenoterol and the like, and the anti-asthmatic drugs theophylline, choline theophyllinate and enprofylline, the calcium antagonists nifedipine, diltiazem, nitrendipine, 1 o verapamil, nimodipine, felodipine, etc. and the corticosteroids, hydrocortisone, methylprednisolone, betamethasone, dexamethasone, beclomethasone, and the like.
Compounds of Formula I' can be prepared according to the following methods. Temperatures are in degree Celsius.
1 s The starting methoxy phenylhydrazines I_I are either commercially available or are described in the chemical literature as are the acetamidophenols XXVI. The benzyl phenylhydrazine starting materials III are prepared as described in EP 166,591 (17102 IA) and the ketones IV and XXXI are prepared as described in EP 166,591 and 2o 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 2s 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 a o literature: see for example, "Heterocyclic compounds" Volume 25, Parts I, II, III, W.J. Houlihan (Ed.), Interscience, 3. 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"

2.~ 36241 The -CO2H and -C02R 12 groups in the intermediates and final products in the various methods can be transformed to other representatives of Q such as ~COI~THS(O)2RI4, -NHS(O)2R14~
-CONR15R15~ _CH20H or tetrazol-5-yl by the methodology described in U.S. Patent 4,808,608. The preparation of the pro-drug forms (Q is -C02R 1 ~) from the acids may be effected by the methodology of EP
104,885.
It will be apparent to one skilled in the art that the various 1 o functional groups (R 1, R2, Y, Q, etc.) must be chosen so as to be compatible with the chemistry being carried out. Such compatibility can often be achieved by protecting groups, or by specific variations in the sequence of the reactions.
Wrhen RS is S-R7, the corresponding sulfoxides and 15 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 acid or ozone (Trost, J. Org. Chem., 1988, pg.532).
Many of the following methods involve a basic hydrolysis 20 of an ester function to obtain the corresponding carboxylic acid. In all cases, the free acid is obtained by acidification of the reaction mixture with a suitable acid such as hydrochloric, sulfuric, acetic, trifluoroacetic acid, etc.

WO 94/00446 , . . PCT/CA93/OOZSb ME'~HOD 1 R4 R~
(R 1°)2PhCH2-Hal Me0 l NEt3/Bu4NBr/CH2C12'' Me0 ~ NH
R3 ~ NHNH~ R3 / N' z II / ~1L
~R10)2 l0 I~ R5 1 ) FISCHER/1'~L
C~2812 2) LiOH
O

. ~ Rs Me0 l ~ CO2H
// N P
1 ) NaS-t-8u/HMPA R~

2 0 2) C H2N2 ~R 10)2 \ ~ .
I
R4 R5 R5=~-R7 ~' t HO l/~ ~ C02Me j ) ,~pCi3/EtSH/CH2C12 R3 [~ Rit~Rlp 1 2) CH2N2 ~R10)2 \ VI

\ H
3o HO ~/ ~ ~ C02Me R3 N / \!P

~Rio)2 ~ 1X

213~~4~.

METHOD 1 ~oont'd) Ra Rs R4 HO ~\\ ~\\ H
I C02Me HO ~ I C02Me R~ N P / '~ N
./\ ~ R11 R11 R3 ~ J R11 R11 (Rio)z ~ 1o m (R }z ~ ~ Ix R1 1 ) K2C03/DMF/Vil \ \ \ 1 } R COCI/AIC13 / ~ Hai 2) LiOH C2H4C12 / N

2} NaOMelMeOH

a W Rs / i O-~ I H
R ~ N 3/ / N ~~~o~ C 02 R R11 ~R/p11 Vili(I) 1o 20 (R )2 i_ ~/ R 4 \ C~R~
) K2C0~/DMF/Vil HOy , ( PCOzMe y 2) LiOH R ~, R11 R11 (Rio}z \ x R1 R~
\ \ \ r~ ~ CORD
o ; I Co H
/ N l / z R2 Rs/ N P

( )z \ xi(i)~

WO 94/00446 PCTlCA93/00256 1 ~1~6'~ ~~~.

Method 1 Intermediate V is prepared by a .Fischer reaction between benzylphenylhydrazine III and ketone IV,wfollowed by hydrolysis with an aqueous solution 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 hexamethylphosphorictriamide (HMPA) or N-methylpyrrolidone (NMP). The reaction mixture is acidified and the i o crude acid so obtained is converted to the methyl ester VI by treatment with diazomethane. The phenol VI is coupled to the 2-halomethyl-quinoline 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 is yield VIII, a compound of Formula I'.
When intermediate V contains a sulfide group attached to position 3, treatment with a Lewis acid, such as AICI~, and an aliphatic thiol; simultaneously effects demethylation and removes the sulfide group. Suitable solvents for this reaction are methylene chloride, 1,2-20 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, R~COCl; 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 treatment with 2s $adium methoxide in MeOH to yield acylphenol X. Phenol X is coupled with VII as described for the coupling of VI and VII above. In these coupling reactions, it is at times advantageous to add a catalyst such as potassium iodide or tetrabutylammonium bromide, especially when Hal is chlorine. A final hydrolysis yields compound XI.

WO 94/00446 ~ 13 6 ~ 41 PCT/CA93/OOZ56 FISCHER
II + IV Me0 ~~ s ~ Co2R12 R3 N ' 1 ) KHMDS/THF/-78°G XII
2) RBHaI
R4 . R5 RSeS-R7 R4 H
MeO ~/ / C~2812 HO ~~ /. ~ C~2812 N ' '~ N
R3 ( R 1 R 11 R3 R$ XVI R8 R11 R11 III
1 ) LiOH 1 ) R7COCI/NEt3rfHF
2) NaS-t-Bu/HMPA 2) R~COCI/AICI~
3) CH2N2 1 ) NaCNBH3IZnl~
R4 . C2H4C12 R4 ~ R5 2) NaOMe/MeOH ~ \ COR
HO ~ / ~ Co2Me R C~2 '~ / ~ Go2R12 R3 N~~_~P R3 N~~_~P

my xvlll ;~ ~:,::~

~~.~.~c~ ~~

METHOD 2 (cont'd) XIV
s ..' 1 ) K2C03/DMF/Vil ',,' ' XVIII
2) LiOH
1 ) NaOMe/MeOH

1o Re \ \ R R5 2) K2C03/DMF/VII
O ~ ~ 3) LiOH
R2 N s/ / N~C02H
R R8 Ri? R»
XV (!) R~ Ra '~ ~~ \ COR7 C, , R2 N 3/ / N~.l,(~C02H
~,P
2o R ~8 R1~ R1~
XiX (!) WO 94/00446 ~ ~ ~ PCT/CA93/002~6 Method 2 Intermediate XII is prepared by a Fischer reaction between methoxyphenyl hydrazine II and ketone IV. Alkylation of the indole nitrogen, after deprotonation using potassium hexamethyldisilazane in an ether solvent such as tetrahydrofuran (THF), with an alkyl or aralkyl halide affords XIII.
The methoxy group in XIII is removed using the conditions of Method 1. 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 Formula I'.
When intermediate XIII contains a sulfide at position 3, treatment with a Lewis acid such as AICI~ 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 1, the phenolic hydroxyl in XVI is first acylated with the reagent R7C~Cl (XVH~ 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 AIC13, to yield the intermediate XVIII. Acyl ester XVIII
may then be reduced to a 3-alkyl indole XIV using sodium cyanoborohydride in dichloroethane using zinc iodide as catalyst.
Acyl ester XVIII is cleaved to the indole phenol by ~ hydrolysis with sodium methoxide in methanol and is coupled to 2-halomethyl quinoline VII using a base such as an alkali hydride or carbonate in a solvent such as DMF or NMP. Hydrolysis of the resulting compound using base yields the compound XIX.

i.'~'y.'y WO 94/00446 ~ g , ' ~ PCT/CA93/0025b Ra Ra (CH3)3CCOC1 HO l/ / _ t_gUC02 L~ /

XX . XX I
Ra 1 ) HCI/NaNO2 to 2) Na2S20a t-BUC02 ~// ~R~~)2phCH2HaI

R Net3/BUaNBr/

Ra r~ ~
t-BUGO
2 boo N,NH~

~R1~)2 ~~ XXlll FISCHER/IV
a R R~
t-BUCO2 l ~ CO2R12 ~ N
R3 R1~ R11 (R'°)2 NaOMelMeOH
VI as per Method 1 Vlll I
_ ( ).

~13~~4~.
w0 94/00446 PCT/CA93100256 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 situ to the hydrazine XXII using sodium hydrosulfite in water. ~enzylation of the hydrazine is effected as described in Method I.
The O-pivaloyl-loT-benzylhydrazine XXIII is subjected to a l o Fischer indolization using the appropriate ketone IV to produce the indole XXIV. Cleavage of the O-pivaloyl group using sodium methoxide in methanol transforms the product into the phenolic illdole VI which is converted to the products of Formula I' as described in Method 1.

R~ s R
XXlI + IV FiSCHER
2o t-BuCO~ ~~ / ~ C02R~2 XXV H R» R»
1 ) KHMDSlI-HF
2) R8-Hai 3) NaOMe/MeOH
as per Method 2 xy y)~ x!v Method 4 The pivaloyloxyphenylhydrazine~ XXII is used directly in the Fischer indolization using ketone IV. . N.:~llkylation of the indole XXV, as described in Method 2, followed by removal of the pivaloyl s group as described, yields the phenolic indole XIV which is converted as described in Method 2 to the products of Formula I' io is 2s WO 94/00446 213 6 2 41 PCT/CA93/002~6 R4 KzC03/DMF/5Lll HO \ \ R' NHAc ~ I\ ~
R3 0 ~ Hal N

R' R4 \~
O ~\ ~ KOH/aq. EtOH/heat / / ~ ~-Rz N R3 ~ NHAc XXV I I
R~ R4 15 ~\ ~ \ ~~ a 1 ) HCI/NaNOz s O ; 2) NazSz04 RZ N ss / NHz xxvlll R
R~
\ \ \ ~Rla)2PhCHz-Hal / , ~~\
R2 N ~/ / NHNHz ~~-Pr)zNEt/Bu4NBr/CH2C12 R
XXIX
R~ Ra 1 ) Fischeril,~L
C , , Q--. - vlll 3 o 2 N ~/ / N' NHz 2) LiOH
R Rs ~R~o)z ~ XXX

wo 9~iooaas . ~~6,.~ ~.~ ~crica~3ioozs6 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 quinolinyhnethoxy aniline dea-ivative to the hydrazine analogue XXIX is effected through reduction of the intermediate diazonium salt using 1 o sodium hydrosulfite in an aqueous medium.
The hyrdrazine 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.
i s The hydrazine XXX is then processed using a Fischer indolization with ketone IV accoz~ding to Methods 1, 2, 3 and 4 to produce compounds of Formula I'.

~0 WO 94/00446 ~ ~ ~ ~ ~ ~ ~ PCT/CA93/00256 ME'I'H4D 6 R5 o C(~2R12 1) FISCHER/XXIX
'n 2) KHMDS/THF/RBHaI
R~~ R~~
XXXI \ \ \ R4 R5 C ~ o ~\ \
2 ~ N L/ / N ~ Cp2R~2 to R R3 ~ 8 R~ ~»
XXXI I R
R'~MgBr R~ R4 LiAIH4/THF \ \ \ R~ R~i ~ , ~ ~\ \
/ a N y- I
R2 R3 N n ~ ~~ Rat LiAIH4 R8 R
R 1 R4 XXXI l l 20 \ \ \
~ ~~ ~ R R»
C, , o ; ~
/ N
R2 R3 ~ n OH
R8 R~~ R~1 XXXIV
2~ R~~ 1) NaHITHF/XXXV
Hal'( )p C02Me 2) LiOH
XXXV
R~ R4 '\ \ '~. s 30 ~\ \ R R~1 R»
C, . o ;
N L~ ~ N n O~~p'Cp2H
R Rs ~ a R~ R»
XXXV I I ' R

w0 94100446 PCTlCA93100256 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 er through the use of lithium aluminum hydride in ether solvents like THF. The carbinols XXXIV so produced may be further 1 o 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 Formula I'.

WO 94/00446 2 ~ 3 ~ 2 41 PCTI CA93/002~6 AICI /EtSH
XII s ~ H
(R5=S-R~) HO ~ / I C02R12 R , ~11 H R R
XXXV I I
VII

R1 R4 .
~\ w. ~ .~ H
XXIX + IV / / O ~ 12 / N l~ / ~~~~ C 02 R
R~ R3 FiSCHER
XXXVIII
R1 R~ .

C , O ~' ' R5-CI
,2 R2 / N 3~ / ~( P 02R AiCl3 R ~ R11 R11 XXXiX
R$-Hal/base XV (I)' a,,:;, w0 94/00446 PC'T/CA93/00256 136 ~~.

Method 7 Phenol XXXVII is obtained~by treatment of XII (RS = S-R~) with a Lewis acid and a thiol, asvin Method 1 for the conversion of V to IX. Compound XXXVIII is then obtained by reaction of XXXVII
with VII in the presence of a base in a suitable solvent, as described for the conversion of VI to VIII in Method 1. The introduction of RS in XXXIX is conveniently effected by an electrophilic reaction between XXXVIII and RS-Cl (RS not = Xl-R6). Such reactions are frequently catalysed by Lewis acids or proton acids such as AlCl3, SnCl4, TiCl4, 1 o BBr3, HCI, HBr and the like. They may be carried out in a variety of solvents, with a preference for non-protonic solvents such as dichloromethane, 1,2-dichloroethane, nitromethane, chlorobenzene and the like. It will be obvious to one skilled in the art, that the chlorine in R~-Cl, in this and the other Methods, may often be replaced by another 15 halogen or by a hydroxyl group, or RS-CI may be replaced by an acid anhydride (R~CO)20. An alternative synthesis of XXXIX is to effect a Fischer reaction between compounds IV and XXIX. Introduction of Rg into XXXIX, is accomplished by alkylation with Rg-Hal and a base as described previously for Methods 2, 4 and 6. Finally, hydrolysis of the ester will yield XV. Alternatively, the ester group in XXXIX can be hydrolysed, and the corresponding free acid (R12 = H) alkylated on the indole nitrogen with Rg-Hal and an aqueous base, such as NaOH, and a phase-transfer catalyst, such as methyltrioctylammonium chloride.
Alkylation of the acid corresponding to XXXIX (R12 = H) can also be effected using a strong base such as sodium hydride in a solvent such as DMF. This latter procedure usually gives the ester of XV in which the carboxyl group has also been alkylated. The free acid XV can be obtained by standard hydrolysis procedures. If Rg in XV or the ester 3o Precursor of XV is alkenyl, it can be reduced to alkyl using hydrogen gas, and a Pt or Pd catalyst in a suitable solvent, at atmospheric pressure.

WO 94/00446 PCT/CA93/04zS6 1VIET~IC)D 8 {VI + VII) or I\ \ \ ~~'~ S°R7 o ~ 12 e, ~~~co2R
{R5=S-R7) R2 R3 N F

R1o AiCl3/GH2C12 { )2 ~ XL

~\~ \ r\~ H
O ~ I 12 R2 (~,j ~~ / ~~.1~~G02R

%«f {R1a)2 R7-C~CI/Lewis Acid/CH2Cl2 25.
~= . - ~ - '. ~ . . :~;e.- '. ;., _ , .; , . . , ; ; . , : . , . . ..

WO 94/00446 PCT/CA93/00~56 .,~~ ~, ~~, ~ 1 - 3~ -METHOD 8 (cont'd~
R~-COCI/Lev~ris Acid/CH2C12 R1 Ra I\ \ \ ~~ ~ COR7 ~ ~ ~ 12 R2 ~ 3/ / N~i~~~CO2R
to R P

XLII (R1°)2° ~ +
I

Hydrolysis R Ra '~ \ R~
I / o ~\ w I Co2R92 X! (I)' R Rs X

~R1°)2 ~ XLIII
Hydrolysis R1 Ra \ \ \ R~
N ~~ CO2H
R
1'~~ 11 .~ R R
(R1o)2 xLlv (!)' 3 0 -°-°

Method 8 Compound XL may be prepared either by the coupling of VI to VII (Method 1 ) or by a Fischer reaction between IV and XXX
(Method 5). Compound XL may be desulfurized by treatment with a Lewis acid such as A1CI3, or by reduction with Raney~ nickel, to give compound XLI. A Friedel-Crafts reaction on XLI with the reagent R~COCI and a Lewis acid catalyst such as AIC13 yields the 3-acyl derivative XLII, hydrolysis of which yields XI. In the Friedel-Crafts reaction, carbon monoxide may be lost and compound XLIII is formed;
to hydrolysis under standard conditions then yields XLIV. The formation of XLIII occurs when the cation R~+ is especially stable and when the reagents R~C:OCI and the Lewis acid are mixed before adding XLI. If the Lewis acid is added last, the main product is usually the acylated compound XLII. If a milder Lewis acid such as TiCI,I is used, the main product is also XLII.
It will be obvious to one skilled in the art that the reagent R~COCI can often be replaced by RICO-Hal (Hal = F, Br or I) or (R~CO)20.

36y ~.'1 METH~D 9 Ra R°
Tf20, PYr~ Tf0 r\
VI CH CI L/ o I CO~Me 2 2 R 3 I~1 ~~~ P
R~~ Rig (R'°)2 . / XLV
Ra Me0 Pd(OAc}2/CO
DMBO MeOH Et N ~/ ~ C02Me O ~ I~j~ ~~P
1,1-Bis(diphenyiphos- R~ R~~ Rj~
phino)ferrocene (R ~ 0)2 70-80°C ~' XLVI
Ra 1 } NaOH HO
~) DIBAL, THF ~ ( CO H MnO2 N~~r~IP 2 CH2C12 0°C to r.t. R R~ ~ Ro . (R~o)2 XLVI I

WO ~4/0044b PCT/C~193/00256 2i3~241 MET'~dOD 9 ~cont'd~

C / i PPh \ ~ N , 3 HCC? '/ / ( C~2H R XLlX
R3 N l~lP

(R 1 °)z ' ~ XLV! I I -70°C to r.t.

~ \ \ R5 C ~ ~\ \ H2, ~ 0% Pd/C
2 ~ N ~ ~' H ~ C02H Et~Ac R R3 ~~P

L (I), (R1o)2 ~

I\ \ \ R5 r\ ....
~ ~ N ~ l/ / ~ CO2H
RZ R3 I~) ~lP

(R1°)2 r LI I ' Method 9 Indole phenol VI which may be prepared according to Methods 1 or 2 is transformed to a phenol triflate XLV by treatment with trifluoromethyl sulfonic anhydride (T;f2t~) in a solvent like pyridine in dichloromethane. The phenol triflate may be carboxy-methylated to a compound like XLVI under palladium acetate catalysis in an atmosphere of carbon monoxide, a phosphine ligand like 1,1-bis(di-phenylphosphinoferrocene) enhances this reaction. Reduction of the carboxymethylated indole may be effected with a variety of hydride 1 o reducing agents. Conveniently diisobutylaluminumhydride is used in TI-iF on the hydrolysed ester. The reduced carbinol product XLVII is conveniently oxidized to a formylated derivative XLVIII with manganese dioxide in methylene chloride as a typical solvent. Aldehyde XLVIII can then be homologated under carbanion conditions, typically is using Wittig reagent XLIX (see U.~. pat. 4,851,409) as shown in the method, under anydrous conditions in an ethereal solvent like THF.
The temperature of this reaction is typically from -70°C to room temperature. Indole styryl quinoline analogues (trans) L are thus formed. Further transformation of the styryl system may be effected 20 by catalytic reduction using 1=I2 and Pd/C in an organic s~lvent like ethyl acetate to yield the saturated compound LI.

WO 94/00446 ~ ~ ~ ~ ~ ~ PCTJCA93/00256 V
s BBr3lCH2Cl2 ~4 R5 CICBNMe2 HO , ~/~ ~ R" NaH, DMF

R~~
O~ ~Rt~
i s P-~
L! i '' 5 Me2N ~ ~ ~ R
~/ / ! Rat Rig O R»
LIII

Me N S ~\ ~ R 1. MeONa, MeOH
2 ~ ~/ / I R~1 2. SOCi2 , MeOH
3o S R~ N
R~~
Or R»

~~.3~'~ ~1 METHOD 10 (cont'd) I~4 5 s ~ R
R11 R" Ph3P
l 102Me Dioxane, H20 R" P
LV

l0 r~ '~ R" R" V i i HS
i 5 ~/ .i R3 N ~ f' COzMe H R" P-1 LVI
1) (R,o)2PhCH2Cl '~ ~ ~ R5 NaH, DMF
i , ~' ~ ! R t ~ R"
R2 N 3/ ~ N CO Me z~ hydrolysis ~ 2 " F' LViI H R

WO 94/00446 _ ~ 3 6 ~ ~ ~ PCT/CA93/00256 ME'T'HOD 10 f cont'd) Rs QuCH S r \ ~ R~~ R» R5 ~ H
/ N C02H R~COCI/AIC13 R R~1 p-1 CH2C1~, -20°
Rio / I
( )2 ~ L VIII

r~ ~ COR7 Rj~ R~s QuCH2S ~/
3 N ~ ~' C02H
R R» P-1 (Rio)2 s I LIX (I)~
R~
I\ w Qu a C~ , ~
2o R2 ~N

1~~~ ~'1 _ _ Method 10 Indole thio analogues of I' such ~~as LIX are conveniently prepared by the sequence shown in Metl~o'd ~10. The treatment of compound V with BBr3 in a chlorinat~dw'solvent such as CH2Cl2 cleaves s both the methyl ether and the indole N-benzyl group and cyclizes the product to an indole lactam LII. Derivatization of this compound as an N,N-dimethylthiocarbamoyl indole LIII followed by thermal rearrangement at >200°C gives rise to an N,N-dimethyl-carbamoyl-thioindole derivative LIV. Depending on the duration of heating, i o dethiolation (R5=-S-t-Bu # RS=H) may also take place. The hydrolysis of LIV may be effected using strong base, typically sodium methoxide in methanol is used. Spontaneous formation of disulfide LV may occur in this reaction. The reduction of LV can be achieved using triphenylphosphine in aqueous dioxane to produce LVI. Coupling of Ws LVI to an appropriately substituted quinoline derivative VII takes place under organic base catalysis; typically triethylamine, in an organic solvent such as methylene chloride, is used. Transformation of indole LVII to an N-benzylated derivative LIX is achieved under standard conditions described in Method 2 or by benzylation with an appropriate ° benzyl halide using a base such as sodium hydride in a non-protic solvent such as dimethylformamide.

2.136~4~.

s LiAIH4 SOCI
-C02R~2 (12) 2 -FOCI R14S~~~2NH2 _C~NHS~~~2R14 R -H
R»Hal 1~
base R OH ~5 15 R R NH
R' 2=H
base _C02R»
-CONR15R»
is dehydrate/P205 R ~ S-R~ S~H
-CN
NaN3 25 N~N~ H
1 H- or 2H-tetrazol-5-yi WO 94/00446 ~~ ~~ _ PCT/CA93/00256 .
_ ~$ _ Method 11 The preparation of the various definitions of Q is outline in Method 1 l, starting from the readily :available carboxylic acid derivative -C02R 12s . .
s It will be obvious to one skilled in the art that many of the reactions indicated are reversible. Thus, by way of illustration, the -CN group can serve as the starting material to prepare the amide and carboxylic acid functional groups. The reactions depicted in Method 11 as well as methods for synthesis of the sulfonamide group (-S(O)2NHR15) are well-known in the art. See, for instance the following text books:
1. J. March, Advanced Organic Chemistrv, 3rd ed., J. Wiley and Sons, Toronto, 1985.

2. S.R. Sandier and W. Karo, Organic Functional Group Preparations. I & II, Academic Press, Toronto, 1983 and 1986.

_~13~241 WO 94100446 ~ PC'~'/CA93100256 uCH p r\ \ Cp2R12 Q

2 ~/ ~ ~ NH p 11 p11 LX
R R R
( R i ~)2 i _ ~~

Q~Chi2p ' / ~/ PC02R ~ ) p2~5~GH3Sp3H
/ N~ /~ 11 (solvent) (R1~)2 I LXI
R~
~~ ~ H R1 ~LiCH2p l I Cp R12 ~'\
3 / [rj p 2 C~u = C a R
(R10)2 ~ R11 R11 R2 XLI

-$Q-Method 12 3-Unsubstituted indole analog XLI, described in Method 8, may be more conveniently prepared by the process illustrated in Method 12 and described in greater detail in D. Zhao, et al., J. Org. Chem., 56, 3001, (1991). Thus, the suitably substituted hydrazine XXX is reacted with the suitably substituted methyl ketone LX to provide the hydrazone LXI. The hydrazone LXI is treated with a combination of phosphorous pentoxide and methane sulfonic acid, optionally in the presence of a suitable co-solvent, such as sulfolane, dichloromethane and to the like, to provide the 3-unsubstituted indole XLI.
Representative Compounds Table I illustrates the compounds of the present invention.
is TAB LE I
F
oo O
2o R N
\N/ ~C02H
CI
2s Ex. No. R 1 30 ~ ZA F
2B OMe Assays for Determining Biological Activity Compounds of Formula 1 can be tested using the following assays to determine their mammalian leukotriene biosynthesis inhibiting activity.
Rat Peritoneal Pol mporphonuclear (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 (C02) and the cells from the peritoneal i o cavity are recovered by lavage with 20 mL of buffer (Eagles MEM
containing 30 mM HEPES adjusted to pH 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 suspended in buffer at a concentration of 10 cells/mL. A 500 mL
aliquot of PMN suspension and test compound are preincubated for 2 minutes at 37°C, followed by the addition of 10 mM A-23187. The suspension is 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 37°C. The LTB4 produced in the first incubation causes 2o aggregation of the second 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 ch~ge in the compound-free control.
Human Polymorphonuclear (PMNI Leukoc~rte LTB~ Assay A . Preparation of Human PMN. Human blood was obtained by antecubital venepuncture from consenting volunteers who 3o 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 ILT/mL). PMNs were isolated from anticoagulated blood by dextran sedimentation of erythrocytes followed by centrifugation through Ficoll-HypaqueTM (specific gravity 1.077) as -,, .: ,.
WO 94/00446 PCTlCA93/OO256 .
-s2-described by Boyum (Scand. J. Clin. Lab. Invest., 21 Su . 97 ,~
77(1968)). Contaminating erythrocytes were removed by lysis following exposure to ammonium chloride (0.16 M) in Tris buffer (pH

7.6s), and the PMNs resuspended at s x~ 105 cells/mL in HEPES (1s mM)-buffered Hanks balanced salt solution containing Ca2+ ( 1.4 mM) and Mg2+ (0.7 mM), pH 7.4. Viability was assessed by Trypan blue exclusion and was typically greater than 98%.
B . Generation and Radioimmunoassay of LTB4.
1 o pMNs (0.s mL; 2.s x 1 OS cells) were placed in plastic tubes and incubated (37°C, 2 min) with test compounds at the desired concentration or vehicle (DMSO, final concentration 0.2%) as control.
The synthesis of LTB4 was initiated by the addition of calcium ionoplzore A23187 (final concentration IO mM) or vehicle in control i s samples and allowed to proceed for s minutes at 37°C. The reactions were then terminated by the addition of cold methanol (0.2s mL) and samples of the entire PMN reaction mixture were removed for radioimmunoassay of LTB4.
Samples (s0 mL) of authentic LTB4 of known 2o concentration in radioimmunoassay buffer (RBA) buffer (potassium phosphate 1 mM; disodium EDTA 0.1 mM; Thimerosal 0.02s 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 (I0 nCi in 100 mL RIA buffer) and LTB4-anriserum (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 4°C. To separate antibody-bound from free LTB4, aliquots (s0 mL) of activated charcoal (3% activated charcoal in RIA buffer containing 0.2s% Dextran T-70) o were added, the tubes vortexed, and allowed to stand at room temperature for 10 minutes prior to centrifugation (1s00 x g; 10 min;
4°C). 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 WO 94/00446 PCf/CA93/00256 radioimmunoassay did not 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 to 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 is 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 2o Place by four clamps and an airtight seat is maintained by a soft rubber gasket. Through the center of each end of the chamber a Devilbiss TM
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 (PTS-A) which is then connected to a Beckman 2s Type R Dynograph through appropriate couplers. While aerosolizing the antigen, the 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 3o 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%
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.
1 o They are either dissolved in saline or 1 % methocelTM or suspended in 1 methoceln'~. 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 1 s controls. Usually, a compound is evaluated at a series of doses and an ED50 is determined. This is defined as the dose (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 20 limiting. All temperatures are in degrees Celsius.

WO 94/00446 ~ ~ PCT/CA93/00256 REACTION SCI-IEME I
Preparation of Compound of Example 1 HO S~
I
1 N~ v ~C02Me F
~ Sr i o '..J N
-CI
CS2Og NBS
benzoyl peroxide 0 0~
~N CH3 F
20 0 0_ N
O S
N~~C02Me 25 . LiOH
F ~CI
"N
O S ""~
'N~ ~C02H
~CI
.,.,, , . , W~ 94/00446 PCT/GA93/00256 ~.~3by ~~.

Pre,~aration of com~,ound of Example 2A
Preparation of com~aund of Example 2B
HO S
to ~~~CO2Me F
Br CI
NBS
~ s benzoyl-peroxiae F
F
F ~ S
F N CH3 N C02Me F ~CI

-$7-REACTION SCHEME 2 (cont'd) Preparation of com"~ound of Example 2A
Preparation of compound of Example 2B
FOO x ,a ~N~
a LiOH/MeOH
THF 70°C, 6hr F
F N
O S
{Example 2A) N~
~ C02Na CI
F
Me0 'N 1.~
O S
3 0 Exam 1e 2S
{ P ) N~ CO H

CI
~$,',... , .;..,. ~--; ., , , "~,r ,' , . , - . .

WO 94/U0446 P~.'p'/CA93/002~6 ~.~36'~ ~~.

3-[N-(p-chlorobenzyl)-3-(t-butyltfiio)-5-(6-fluoro-quinolin-2-vlmethoxX)indoI-2-y112.2-dimethy_1=propanoic acid, sodium salt St_ ep A: 2=Bromometh~rl-6-fluoroc~uinoline To a solution of 6-fluoro-2-methylquinoline (see C.M.
Leir, J. Org. Chem., vol 42; pp 911-913, 1977) (21.67 g) in carbon tetrachloride (700 mL) were added N-bromosuccinimide (26.32 g) and 0 benzoyl peroxide ( 1.62 g). The mixture was brought to reflux with two spot lights of 150 Watts. The mixture was irradiated for 24 hours at reflux. The mixture was then cooled to room temperature, evaporated to dryness and chromatographed on flash silica gel using pure toluene as eluant to give, as the slower running compound, a beige solid (11.9 g);
1 s m,p. 90-92°C.
Step B: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6-fluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoate 20 To a solution of Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (See EP419,049, Example 1, Step C) (322 mg) in acetonitrile (7 mL) were added solid cesium carbonate (456 mg) and 2-bromomethyl-6-fluoroquinoline (190 mg) from Step A: The mixture was stirred at 2 s room temperature for 18 hr. The mixture was poured into 25 % aqueous NH40Ac (50 mL), extracted with ethyl acetate (2 x 50 mL), washed with brine (50 mL); dried (MgS04) and evaporated to dryness. The residue was chromatographed on flash silica gel using ethyl acetateaoluene (5:95) as eluant to give the title compound as a white 3 o solid; m.p. 165-167°C.

~1~fi241 w0 94/00446 PCT/CA93/002~6 Step C: 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6-fluoro-quinolin-2-yhnethoxy)indol-2-yl]-2,2-dimethyl-~r~anoic acid sodium salt .
The compound (302 mg) from Step B was hydrolyzed by dissolving it in THF (4 mL), MeOH (2 mL) and 2N LiOH ( I mL). The solution was heated at 70°C for 6 hr. The solution was cooled to room temperature, diluted with H20 (50 mL), acidified with glacial AcOH to pH5 and then diluted with 25°Jo NH40Ac (50 mL). The mixture was extracted with ethyl acetate (3 x 50 mL), washed with brine (50 :n~L) to and dried (MgS04). The solution was evaporated to dryness, coevaporated with toluene (50 mL) to provide the title acid as a white solid, m.p. 213-215°C. The title compound was prepared as follows:
the acid was suspended in ethanol (3 mL) and treated with I .0 N NaOH
{1 equiv.) diluted with H20 (5 mL) and lyophilized to give the title 1 s product.
Anal. Calc'd for C34H33N203SC1FNa~H20 Calcd: C, 63.29: H, 5.47; N, 4.34 Found: C, 63.42; H, 5.38; N; 4.07 20 Exam~~le 2A
3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6,7-difluoro-quinolin-2-ylmethoxy, indol-2-, 1Y 1=2 2-dimethvlnr_opanoicacid. sodium salt 2s Example 2B
3-[N-(p-chlorobenzyl-3(t-butylthio)-5-(6-fluoro-7-methoxyquinolin-2-,ylmethoxX indol-2-yll-2 2-dimethXl_propanoic acid sodium salt 3 o to A: 6,7-Difluoro-2-methXlquinoline Crotonaldehyde (226.34 g, 3.23 mol) in 100 mL of 2-butanol was added dropwise. to a refluxing solution of 3,4-difluoroaniline (417.27 g, 3.23 mol), .p-chloranil (794.65 g, 3.23 mol) and HCl conc. (808 mL) in 5.4 L of 2-butanol. After 2 hours of heating WO 94/00446 PCTlCA93/00256 2.7 L of solvent was removed under vacuum at ca. 60°C. Then 2 L of toluene was added to the reaction mixture followed by removal of 2.5-3 L of solvent or until a very pasty solid formed. THF (2L) was added and the mixture heated 30 min. after which it was cooled to 0°C. The solid was collected and washed with THF until pure by tlc. The solid was then dissolved in aq. K2C03JEtOAc and the organic phase separated. The aqueous phase was extracted with EtOAc (2X) and the organic phases combined, dried over MgS04 and the solvent removed.
The product was crystallized in the minimum amount of EtOAc to give l0 328.08 g (57%) of the title compound.
1 H NMR (CD3 COCD3): 8 8.19 ( 1 H, d), 7.75 (2H, m), 7.4 ( 1 H, d), 2.64 (3H, s).
Step B: 2-bromomethyl-6.7-difluoroquinoline Following the procedure of Example 1, Step A, but starting with'6,7-difluoro-2-methylquinoline from Step A, the title compound was obtained as a white solid; m.p. 113-115°C.
Step C: Methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-(6,7-difluoroquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-propanoate Following the procedure of Example 1, Step B but using 2-bromomethyl-6,7-difluoroquinoline from Step B, the title compound was obtained as a white solid; m.p. 171-173°C.
Step D: 3-[N-{p-chlorobenzyl)-3-(t-butylthio)-5-{6,7-difluoro-quinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethylpropanoic-acid, sodium salt and a o 3-[N-(p_chlorobenzyl-3(t-butylthio)-5-(6-fluoro-7-methoxyquinolin-2-ylmethoxy)indol-2-yl]-2,2-dimethyl-pronanoic acid, sodium salt The compound (423 mg) from Step C was hydrolyzed .by dissolving it in THF (6 mL), MeOH (6 ml) and 2N LiOH ( 1.3 mL).

WO 94/00446 ~ ~ ~ ~ ~ ~ ~ PCT/CA93/00256 The solution was heated at 70°C for 6 hr. The solution was diluted with H20 (50 mL), acidified with glacial AcOH to pHS, diluted with 25%
NH40Ac (50 mL) extracted with ethyl acetate (3 x 50 mL), washed with brine (50 mL), and dried (MgS04). The solution was evaporated to dryness, co-evaporated with toluene (50 mL) to give a mixture of both title acids. The mixture was dissolved in a ( 1:1 ) mixture of CH2Cl2: THE and chromatographed on flash silica gel using a mixture of ethyl acetate:hexane:acetic acid (30:70:2.5) as eluant to afford,the 6,7-difluoro acid in the fast fraction (white solid; m.p. 218-220°C), and o the 6-fluoro-7-methoxy acid in the slow fraction (white solid; m.p.
230°C (d)) in a (3:1) ratio.
Both sodium salts were prepared as described in Example 1, Step C to give the title products.
15 6;7-difluoro derivative: (Example 2A) dal. Calcd. for C34H32N2O3SC1F2Na~3H20 Calcd: C, 58:40; H, 5.48; N, 4.01 Found: C, 58.12; H; 5.21; N, 4.14.
20 6-fluoro-'7-methoxv derivative: (Example 2B) Anal. Calcd. for C35H35N20'4SCIFNa~2H20 Calcd: C, 60.64; H, 5:67; N, 4.04 Found: C, 60.93; H, 5:22; N, 4.12.

Claims (14)

WHAT IS CLAIMED IS:

1. A compound of the Formula I:

wherein: R1 is H, F or MeO;
or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1, wherein R1 is H.

3. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 or 2 and a pharmaceutically acceptable carrier.

4. A pharmaceutical composition of claim 3 addi-tionally 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; leuko-triene antagonists; leukotriene biosynthesis inhibi-tors; H1- or H2-receptor antagonists; antihistamic agents; prostaglandin an antagonists; thromboxane antago-nists; thromboxane synthetase inhibitors; and ACE
antagonists.

5. A pharmaceutical composition of Claim 4, wherein the second active ingredient is a non-steriodal anti-flammatory drug.

6. A pharmaceutical composition comprising a therapeutically effective amount of a compound of Claim 1 or 2, an effective amount of a second active ingredient which is a non-steriodal anti-inflammatory drug, and a pharmaceutically acceptable carrier, wherein the weight ratio of said compound of Claim 1 or 2 to said second active ingredient ranges from about 1000:1 to 1:1000.

7. The use of a compound of Claim 1 for the manufacture of a medicament for preventing the synthesis, the action, or the release of SRS-A
or leukotrienes in a mammal, said medicament comprising a therapeutically effective amount of said compound of Claim 1.

8. The use of Claim 7 wherein the mammal is man.

9. The use of a compound of Claim 1 for the manufacture of a medicament for the treatment of asthma in a mammal, said medicament comprising a therapeutically effective amount of said compound of Claim 1.

10. The use of a compound of Claim 1 for the manufacture of a medicament for the treatment of inflammatory diseases of the eye in a mammal, said medicament comprising a therapeutically effective amount of said compound of Claim 1.

11. The use of Claim 10 wherein the mammal is man.

12. Use of a compound of Formula I, as defined in Claim 1 or 2, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for treat-ment of asthma or inflammatory diseases of the eye.

13. A compound of claim 1 or 2 for use in inhibiting symptoms induced by leukotrienes.

14. A leukotriene biosynthesis inhibitor pharmaceu-tical composition comprising an acceptable inhibiting amount of a compound of Formula I, as defined in claim 1 or 2, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable carrier.