CA2129429A1 - (azaaromaticalkoxy) indoles as inhibitors of leukotriene biosynthesis - Google Patents

Abstract

Compounds having formula (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

Wo93/1~69 PCT/CA93/~W~9 212~42~ --TITLE OF T~E INVENTION
(AZAAROMATICALKOXY~INDOLES AS INHIBITORS OF
LEUKOTRIENE BIOS~NT~SIS

BACKGRQUND OE_T~E INE~NTIQ~
European Patent Applications 166,591 and 275,667 disclose a series of indole-based compounds wi~h activity aæ prostaglandin antagonists and -inhibitors of leu~otriene biosynthesis respectively.
In EP 181,568 and EP 200,101 are disclosed a series of compounds, containing two aromatic nuclei, which are described as possessing activity as lipoxygenase inhibitors. In EP 279,263 is di~closed a series of indoles, benzofurans and benzothiophenes which are described as possessing activity as lipoxygenase : 30 W~#TJTUTE SHEEr .

W093/l~K9 PCT/CA93/~59 inhibitors. U.S. Patent 4,62~,733 describes novel indolinones which are antithrombotic and inhibit both phosphodiesterase and tumor metastasis. The chemical preparation of quinolylindoles is referred to by Shein~man, et ~1.. 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 Biniec~ al~, Chem. Ab., Vol. 98, 197936 (1983), by Pakula, ç~ al., Chem. Ab., Vol. 105, -190835 (1986>, and in British Pat. Spec. 1,228,848.
EP 419,049 (March 27, 1991) teaches (quinolin-2-ylmetho y )indoles as inhibitors of leu~otriene biosynthesis.
SUMMARY OF THE INVENTION
The present invention relates to compounds having activity as leu~otriene 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 leu~otriene 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 s~in diseases li~e psoriasis and atopic eczema. These compounds are also useful -to inhibit the pathologic actions of leukotrienes on the cardiovascular and ~ascular systems for example, ~JE~STITUTE Sh~T

W093/1~K9 2129 !~ PCT/CA93/~W~g actions such as reæult in angina or endotoxin shock.
The compounds of the preæent invention are useful in the treatment of inflammatory and allergic diseases of the eye, including allergic conjuncti~itis. The compounds are also useful as cytoprotecti~e agents and for the treatment of migraine headache.
Thu~, the compounds of the pre6ent invention may al~o be uæed to treat or prevent ma....~alian (especially, human) disease states such as erosi~e gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions;
hepatic ischemia; noxious agent-induced damage or necrosiæ of hepatic, pancreatic, renal, or myocardial tissue; li~er parenchymal damage caused by hepatoxic agents such as CC14 and D-galactosamine; i~chemic renal failure; disease-induced hepatic tamage; 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 S-~PETE, :
5-HETE and the leukotrienes. Leukotrienes B4, C~, D4 and E4 are ~nown to contribute to various disease conditions such as asthma, psoriasis, pain, ulcers and sy8temic anaphylaxis. Thus inhibition of the synthesis of such compounds will alleviate these and other leu~otriene-related disease states.

a;U~TITUTE SHEET

WO93/l~K9 PCT/CA93/~W~9, 4~
- 4 - ~
DETAILED DESC~IPTION OF l~ NTION ~;
The present invention provides novel compounds of the f ormula I: -Het--X4~CR12Rl2)n-y _(CR~2:Rl2) Q

\
R n R' wherein:
~et is ArRlR2R3;

Ar is a monocyclic aromatic 5- or 6-membered ring containing 1 to 3 N atoms, and the N-oxides --thereof; ~-Rl, R2, R3, R4, RS, and Rll are independently hydrogen, halogen, perhalo lower alkenyl, lower alkyl, lower al~enyl, lower alkynyl, 3 , N02, -N3, -C(OH)R12R12 C0 R13 -SR15, -S(O)R15, -s(0~2R15. -s(0)2NR16R16, _oR16 _NR16~16 -NR1350NR16R16 -CoR17 ~:
CONR16R16, or -(CH2)tR22;

R6 is hydrogen, -CH3, CF3, -C(0)~, Xl-R7 or X2-R8;
R7 and R10 are independently al~yl, al~enyl, -(CH2)UPh(Rll)2 or -(CH2)UTh(Rll)2;

~JE~ST~TUT~ ~ff~l~T

W~93/1~K9 2 1 2 9 ~1 2 PCT/CA93/~59 R~ is -CF3 or R7;

R9 is hydroge~ or X3-R10;

each R12 is independently hydrogen or lower alkyl, or two R12~s on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

R13 is hydrogen, lower al~yl or -CH2R22;
.~, R14 is lower alkyl or -(CH2)rR22;

Rl5 is -CF3 or R14;
R16 is hydrogen, -CoR17, R14, or two R16's on the same nitrogen may be joined to form a ;~
monocyclic heterocyclic ring of 4 to 6 atoms containing up to 2 het~roatoms chosen from 0, S, or N;

R17 is hydrogen, -CF3, lower al~yl, lower alkenyl, -lower al~ynyl or -(C~2)rR22;

l8 is -(CH2)S-C(Rl9Rl9)-(C~2)8-R20 or ~--cH2coNRl6Rl6;

R19 is hydrogen or lower alkyl;

- :~
';

~U~STITUTE SHEET

WO 93/16069 PCl`lCA93/00059 .

R20 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-R

R21 is alkyl or -CoR24;
R22 is phenyl substituted with 1 or 2 R23 groups;

R23 is hydrogen, halogen, lower ~lkyl, lower alkoxy, lower alkylthio, lower ~:
alkylsulfonyl, lower al~ylcarbonyl~ -CF3, -CN, -N02 or -N3;

R24 i~ alkyl, cycloalkyl, or monocyclic monoheterocyclic ring;
R25 is the residual structure of a standard amino acid, or Rl~ and R25 attached to the same N
can cyclize to form a proline residue;

R26 i~ hydroge~ or lower al~yl; ;~
:~
R27 is lower alkyl or R26 and R27 on the same carbon are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;
, .~-30 m is 0 or 1; ~.
n is 0 to 3;
~' ~W~STITUTE SHEET

~093t1~K9 2 1 2 ~ 4 ~ ~ PCT/CA93/~W~9 p is l to 3 when m is l;
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;
w i~ 0, S or NR16 xl is or NR16;
~2 is C0, CRl2Rl2, S, S(0), or S(0~2;
X3 is C0, CRl2Rl2, S(0)z, or a bond;
~4 is CR26=CR27, CR27=R26, ~R26R27~l or ylcR27R26;
is Xl or X2;
yl is ' S, S(0)2, or CR26R26;

Q is -Co2Rl3, -CoNHS(0)2Rl5, -NaS(0)2R15, S(O)2NHRl6 -CONRl6Rl6, _c02Rl8~
_coNRl9R25~ _CR12Rl2OH, or lH- or 2H~tetrazol-5-yl;

or a pharmaceutically acceptable salt thereof.

A preferred embodiment of Formula I is that -in which X4 is CHMe-0, and the remaining substituents are as defined for Formula I. ;~
Another preferred embodiment of Formula I is *
that in which Rl R2 R3, R4, and R5 are hydro~en;
R6 i8 ~2_R8 R8 is R7;
R9 is RlO;
Rll is hydrogen or halogen;

~U~STITUT S~-:ET

WO 93/16069 PC~/CA93/00059 ~
~,9 ~ at m is o;
n is 1 to 3;
u is 0 in R7 and 1 in R10;
x2 is cR12R12 or S;
X4 is CR26R27_yl;
yl is 0;

Q i~ -Co2R13 or l-H or 2H-tetrazol-5-yl; and the remaining substituents are as defined for Formula I;
or a pharmaceutically acceptable salt thereof.
,~
Def initions -The following abbre~iations have the -~
indicated meanings:

Me = methyl Bn = benzyl Ph = phenyl ~-DIBAL-N = diisobutyl alumnium hydride HMPA = hexamethylphosphorictriamide XHMDS = potassium hexamethyldisilazide t-Bu = tert-butyl i-Pr = isopropyl -C6H11 5 cyclohexyl c-Pr - cyclopropyl c- = cyclo Ac = acetyl Tz = lH- or 2H- tetrazol-5-yl Th = 2- or 3- thienyl c-C5Hg = cyclopentyl ~W~TITUTE SHEET

~VO 93/16069 PCI~/CA93/00059 _ 9_ l-Ad = l-adamantyl NBS = N-bromosuccinimide NCS = N-chlorosuccinimide Alkyl, alkenyl, and al~ynyl are intended to include linear, branched, and cyclic structures and combinations thereof.
"Al~yl" includes ~lower alkyl~' and extends ~
to co~er carbon fragments ha~ing up to 20 carbon ~:
atoms. E~amples 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. .~.
"Lower alkyl" means 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, 2-methylcyclopropyl, cyclopropylmethyl, and the like.
"Cycloalkyl" 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" meanæ alkenyl groups of 2 to 25 7 ca~bon atom~. E~amples of lower al~enyl groups ~.
include ~inyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, cycl.ohexsnyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl, and the like.

~ sHE~

WO 93/16069 PCr/CA93/00059 .

4~
- 10 - ~:
"Ls~wer alkynyl" means alkynyl groups of 2 to 7 carbon atoms. Examples of lower alkynyl groups include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl, and the like.
~ 'Lower alkoxy" meanæ alkoxy groups of from 1 to 7 carbon atoms of a straight, branched, or cyclic configuration. Examples of lower alkoxy groups include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, cyclohexyloxy, and the like.
~ Lower al~ylthio~ means al~ylthio groups of from 1 to 7 carbon atoms of a straight, ~ranched or cyclic configuration. Examples of lower alkylthio groups include methylthio, propylthio, i~opropylthio, cycloheptylthio, etc. By way of illustration, the propylthio group æignifies -SC~2CH2CH3.
The term "monocyclic monoheterocyclic ring~
which defines R24 means monocyclic groups of 5 to 7 members containing only 1 heteroatom selected from N, S or O in the ring; Examples include tetrahydro-furan, tetrahydrothiophene, pyrrolidine, piperidine, tetrahydropyran, and the like.
The term ~'monocyclic or bicyclic heterocyclic ring" which defines R20 may be 2,5-dioxo-1-pyrrolidinyl, (3-pyridinylcarbonyl) amino, 1,3-dihydro-1,3-dioxo-2~-isoindol-2-yl, 1,3-dihydro-2~-isoindol-2-yl, 2,4-imidazolinedion-l-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.

~STITUTE S~T

WO 93~16069 PCI~/CA93/00059 2~L2~42~j ~ Monocyclic aromatic 5- or 6-membered ring containing 1 to 3 N atoms, and the N-oxides thereof"
which defines ~Ar~ may include pyrrole, imidazole, 1,2,3-triazole, 1,2,4-triazole, pyridine, pyridazine, ;~
pyrimidine, pyrazine, 1,2,3-, 1,2,4-, or 1,3,5-triaæine, 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, lQ asparagine, aspartic acid, arginine, cysteine, glutamic acid, glutamine, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyro~ine and ~aline. (See F.H.C. Crick, Symposium of the Society for Experimental Biology, 1958 (12) p. 14~.) It i8 understood that Rl and R2 may be located at an~ free positions of Ar.
The terms Ph(Rll)2 and Th(Rll)2 indicate a phenyl or thienyl group substituted with two R
su~stituents.
~alogen includes F, Cl, Br, and I.
It is intended that the def initions of any substituent ~e.g., Rl, R2, R16, Ph(Rll)2, etc.) in a particular molecule be independent of its definitions elsewhere in the molecule. Thus, -NR16R16 represents -NHH, -NHCH3, -NHC6H5, etc.
! The~monocyclic heterocyclic rings formed when two R16 groups join through N include pyrrolidine, piperidine, morpholine, thiamorpholine, piperazine, and N-methylpiperazine.

~JeSTITUTE SHEET

,: '~
WO93/16069 PCr/CA93/00059................................................. :`~
~9 4.~

The prodrug esters of Q ( i . e ., when Q -C02R~8) are intended to include the esters such as are described by Saari et al., J. Med. Chem., 21, No.
8, 746-753 (1978), Sakamoto ~ al., Chem. Pharm.
Bull., 32, No. 6, 2241-~248 (1984) and Bundgaard et al., J. Med. Chem., 30, No. 3, 4~1-454 (1987).
Some of the compounds described herein contain one or more asymmetric centers and may thus gi~e rise to diastereomers and optical isomers. The present invention i8 meant to comprehend ~uch possible dia~tereomers aæ well as their racemic and resol~ed, 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 ba6es include aluminum, ;~
ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, 2S sodium, zinc and the li~e. Particularly preferred are the ammonium, calcium, magnesium, potassium andsodium salts. Salts derived from pharmaceutically acceptable or`ganic non-to~ic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion e~change resins, TITUTE S~EET

~W093/1~69 21~ 9~ ~ PCTlCA93/ ~ 59 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 li~e.
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, 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, phosphoric, sulfuric and tartaric acids.
It will be understood that in the discussion of methods of treatment which followæ, 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 leu~otrienes ma~es them useful $or inhibiting the symptoms induced by the leukotrienes in a human subject. This inhibition of the mammalian biosynthesis of leukotrienes indicates SU~TltUTE SHEET

W093/1~K9 PCT/CA93/~N~s 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 conjunctivitis, and the like, 3) inflammation such as arthritis or inflamma~ory 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 inæufficiency 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 s~rong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of 20 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 asæay and are described in EP 140.684-~U~STITUTE SHEES

WO 93/16069 PCI'~CA93/00059 2 ~ 2 ~ f~

The magnitude of prophylactic or therapeutic dose of a compou~d 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 ra~ge for anti-agthmatic, anti-allergic or anti-inflammatory u~e and generally, uses other than :~
cytoprotection~ lie within the range of from about ~-O.OOl mg to about 100 mg per kg body weight of a :.
mammal, preferably O.Ol mg to about 10 mg per kg, and .
most preferably O.l to 1 mg per kg, in gingle or di~ided doses. On the other hand, it may be .~.;
necessary to use dosages outæide these limits in æome 15 caseæ. :
For use where a composition for i~tra~enous admini~tration i8 employed, a suitable dosage range .~:.
for anti-asthmatic, anti-inflammatory or anti-allergic u~e is from about 0.001 mg to about 25 mg (preferably from O.Ol mg to about 1 mg) of a compound of Formula I per kg of body weight per day .
and for cytoprotective use from about O.l 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). .--25 of a compound of Formula I per kg of body weight per ~:-day. -In the case where an oral composition is employed, a ~uitable dosage range for anti-asthmatic, ~.
anti-infIammatory 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 O.l mg to about 10 mg per kg and for ~UE~TITUTE S~IEET

WO93/1~K9 PCT/CA93/~59 ~9~ - 16 - ~
CytoprQteCtiVe 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, ~ater ~lia, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e.g., gastrointestinal ulcerations vs. nephrotic necrosis), S 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 such damage (for example, indomethacin). For such use, the compound of Formula I iæ 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 e~ample. in a combination dosage form).
Any suitable route of administration may be employed for providin~ a mammal, especially a human with; an effective dosage of a compound of the present invention. For e~ample, oral, rectal, topical, parenteral, ocular, pulmonary, nasal, and the li~e may be employed. Dosage forms include tablets, ~U~SrltUTE StlF,T

~093Jl~K9 PCT/CA93~W~9 ~ ~ 2 ~

- 17 _ troches, dispersions, suspensions, solutions, capsules, creamst ointments, aerosols, and the like.
The pharmaceutical compositions of the present in~ention compri 8 e 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 or acids including inorganic bases or acids and organic bases or acids. ~;~
The compositions include compositions suitable for oral, rectal, topical, parenteral (including subcutaneouæ, intramuscular, and intravenous), ocular (ophthalmic), pulmonary (nasal or buccal inhalation), or nasal administratio~, 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 con~eniently delivered in the form of an aerosol spray presenta-S tion from pressurized packs or nebulisers. Thecompounds 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 3 inhalation is a metered dose inhalation (MDI) aerosol, which may be formulated as a ~uspenæion or ~J~STITUTE SHEET `

W093il~K9 PCTfCA93/~9 solution of Compound I in suitable propellants, such as fluorocarbons or hydrocarbons.
Suitable topical formulations of Compound I
include transdermal de~ices, a~rosols, creams, ointments, lstions, dusting powders, and the like.
In practical use, the compounds of Formula I
can be combined as the active ingredient in intimate admigture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
The carrier may ta~e a wide ~ariety 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 formt any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, fla~oring agents, presesvati~es, coloring agents and the like in the case of oral liquid preparationss ~uch as, for example, suspensions, elixirs and solutions; or carriers such as starches, sugars, microcrystalline cellulose, diluents, granulating agent~, 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. Becauæe 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 techniques.

~IJIS~STITUTE SHEET

WO 93/16069 PCJ~/CA93/00059 fa In addition to the common dosage forms set out abo~e, the compounds of Formula I may al~o be administered by controlled release means and/or delivery devices such as th~se described in ~.S.
Patent Nos. 3,84~,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 adminiætration may be presented as discrete units ~uch as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granuleæ 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 di~ided 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 tabletæ 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, æurface acti~e or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mixture of the - powdered compound ~oistened with an inert liquid SWEISTITUTE SHEET

WO93/1~K9 PCT/CA93/~ss diluent. Desirably, each table~ contains from about 2.5 mg to about 500 mg of the acti~e ingredient and each cachet or capsule contains from about 2.5 to about 500 mg of the act ve ingredient.
The follo~ing are examples of representative pharmaceutical dosage forms for the compounds of Formula I:

Iniectable Suspenæion (I.M.~ mg/ml Compound of Formula I 10 Methylcellulose 5.0 Tween 80 0.5 Benzyl alcohol 9.0 Benzalkonium chloride 1.0 Water for injection to a total ~olume of 1 ml Tablet m~/tablet Compound of Formula I 25 Microcrystalline Cellulose 415 Providone 14.0 - -Pregelatinized Starch 43.5 ~-Magnesium Stearate 2.5 , .
Cagsule m~tca~sule Compound of For~ula I 25 -:
Lactose Powder 573.5 Màgnesium Stearate 1.5 ~J~#TITUTE SHEET -~93/16069 PCT/CA93/ ~ 59 2I2~42~;

Aer~sol Per canister Compound of Formula I 24 mg Lecithin, NF Liquid Concentrate 1.2 mg 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 other acti~e ingredients, such as cycloo y genase 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. Generaliy, an effecti~e 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 FormNla 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 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.
NSAIDs can be characterized into five groups:
(1) the propionic acid deri~atives;
(2) the acetic acid derivatives;
(3~ the fenamic acid derivati~es;

(4) the oxicams; and (5) the biphenylcarboxylic acid deri~atives;
- or a pharmaceutically acceptable salt thereof.

~U~TITUTE SHEET

~ ~ .... ~

WO 93/16069 PCI'/CA93/00059~.
9 4.~h~

-- 22 _ The propionic acid derivatives which may be used comprise: alminoprofen, benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, napro~en, o%aprozin, 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 having a free -CH(C~3)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 aro:natic 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, soxepac, o~pinac, 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 analgesicslnon-steroidal ~-anti-inflammatory drugs having a free -C~2COOH group SU~ST~ S~l~EET

wos3/1~K9 21 29 ~1 2~ pcT/cAs3/~s (which optionally can be in the form of a pharmaceutically acceptable ~alt group, e.g.
-CH2COO~Na+), typica}ly attached directly to a ring system, preferably to an aromatic or heteroaromatic - ring system.
The fenamic acid deri~atives which may be used comprise: flufenamic acid~ meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid.
Structurally related fenamic acid derivatives having similar analge~ic and anti-inflammatory properties are also intended to be encompassed by this group.
Thus, ~'fenamic acid derivati~es~ as defined ~;
herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs which contain the basic structure:

which can bear a variety of substituents and in which the free -C00~ group can be in the form of a pharmaceutically acceptable salt group, e.g., 2s -Coo-Na~.
The biphenylcarboxylic acid derivatives which can be used compri~e: diflunisal and flufenisal. Structurally related biphenylcarboxylic acid derivatives having similar analgesic and anti-inflammatory properties are also intended to be encompassed by this group.

~U~TITUTE SHEET

W093/l~K9 PCT/C~93~H~9 Thus, "biphenylcarboxylic acid deri~ati~es~
as defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs ~-which eontain the basic strueture:

/=~/=~
~ ~y lo C2 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 o~icams which can be used in the present in~ention comprise: isoxicam, piro~icam, sudoxicam and tenoxican. Structurally related o~icams ha~ing 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 ha~e the general formula:
~:;
OH
~C( O) NHR
Il I I
/~\\ CH~
O O
wherein R is an aryl or heteroaryl ring system.

~I~ST~TUTE SHEET

WO 93/16069 PCr/CA93/00059 ~12~

The f ollowing NSAIDs may also be used:
amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofi~, bendazac lysinate, benzyda~ine, beprozin, broperamole, bufezolac, cinmetacin, ciproquazone, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindoprofen, diacerein, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, eter~alate, etodolac, etofenamate, fanetizole mesylate, fenclorac, fendosal, fenflumizole, feprazone, floctafenine, flunixin, flunoxaprofen, fluproquazone, fopirtoline, fosfosal, furcloprofen, glucametacin, guaimesal, ibuproxam, isofezolac, isoniæim, isoprofe~, isoxicam, lefetamine ~Cl, leflunomide, lofemizole, lonazolac calcium, lotifazole, loxoprofen, lysin clonixinate, meclofena~ate sodium, meseclazone, nabumetone, nictindole, nime~ulide, orpanoxin, o~ametacin, oxapadol, perisoxal citrate, pimeprofen, pimetacin, piproxen, pirlzolac, pirfenidone, proglumetacin maleate, proquazone, pyridoxiprofen, sudoxicam, talmetacin, talniflumate, ten~xicam, thiazolinobutazone, thiela~in B, tiaramide ~Cl, tiflamizole, timegadine, tolpadol, tryptamid and ufe~amate.
L The f~llowing NSAI~s, designated by company code number (see e.g., Pharma~rojects), may also be used- -480156S, M 861, AD1590, AFP802, AFP860, AI77B, AP504, A~8001, BPPC, BW540C, CHINOIN 127, CN100, EB382, EL508, F1044, GV3658, ITF182, KCNTEI6090, KME4, LA2851, MR714~ MR897, M~309, ONO3144, PR823, PV102, - PV108, R830, RS2131, SCR152, S~440, S~R133, SPAS510, SU~STITUTE SHEET

WO 93/16069 PCr/CA93/00059 ~.
9 ~

SQ27239, ST281, SY6001, TA60, TAI-901 (4-benzoyl-1-indancarboxylic acid), TVX2706, U60257, ~R2301, and WY4177~.
Finally, NSAIDs which may also be used include the salicylates, specifically acetyl salicylic acid and the phenylbutazones, and pharmaceutically acceptable salts thereof. .:
In addition to indomethacin, other preferred NSAIDS are acetyl salicylic açid, diclofenac, fenbufen, fenoprofen, flurbiprofen, ibuprofen, ~etoprofen, napro2en, phenylbutazone, piro~icam, sulindac and tolmetin.
Pharmaceutical compositions comprising the Formula I compounds may also contain inhibitors of the biosynthesis of the leu~otrienes 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), which are hereby incorporated herein by reference.
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) which are hereby incorporated herein by reference and otbers ~nown in the art such as thoæe 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), which are hereby incorporated here.in by reference.
Pharmaceutical compositions comprising the Formula I compounds may also contain as the second active ingredient, prostaglandin antagonists such as WI~STITUTE SHEET

W093~1~K9 PCT/CA93/ ~ 59 2 1 2 ~ 2 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 inhibitor~ æuch as a-f luoromethyl-histidine, 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 antagonist, such ~
as for instance acetamazole, aminothiadiazoles :-.
disclosed in ~P 40,696 ~December 2, 1981), benadryl, cimetidine, famotidine, framamine, histadyl, phenergan, ranitidine, 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 ~.S. Pat. 4,255,431, and the li~e. Compounds of Formula I may also be usefully combined with most cell stabilizing agentæ, such as 1,3-biæ(2-carboxy-chromon-5-yloxy)-2-hydro y propane and related compounds described in British Patent Specifications 1,144,905 and 1,144,906. Another useful pharmaceutical composition compriæeæ the ~ormula I
compounds in combination with serotonin antagonists such aæ methysergide, the serotonin antagonists described in Nature, Vol. 316, pages 126-131, 1985, and the li~e. Each of the references referred to in this paragraph is hereby incorporated herein by -reference.
Other advantageous pharmaceutical compositions comprise the Formula I compounds in combination with anti-cholinergics such as ipratropium bromide, bronchodilators such as the beta ~UeSTlT lTE SHEET

WO 93/16069 PCI/CA93/00059 ..

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.

Compounds of the present invention can be prepared according to the following methods.
Temperatures are in degrees Celsius.
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, h.Y., 1979~ and "The Chemistry of Indoles" by R.J. -;
Sundberg, Academic Press, N.Y., 1970. One of the most co,,~on syntheses is ~nown as the Fischer Indole Synthesis, and is abbreviated in the following `
methods as "Fischer~.
The -CO2H and -Co2R13 groups in the intermediates and final products in the various methods can be tranæformed to other representatives of Q such as -CONHS(0)2R15, -MHs(0)2R15, -CONR16R16, -CH2O~ or tetrazol-5-yl by the methodology described in ~.S. Patent 4,808,608 (17323IB). The preparation of the pro-drug forms (Q is -CO2R18) from the acids may be effected by the methodology of ~P 104,885 (16830 IA).

~USST~TIITE SHEET

W093f16069 PCT/CA93~W~9 21~g~ c.) It will be apparent to one skilled in the art that the ~arious functional groups (Rl, R2, Y, Q.
etc.) must be chosen so as to be çompatible 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.
When R6 is S-R8, the corresponding sulfoxides and ~ulfones can be prepared by oxidation of the sulfides with one or two equi~alents of an oxidizing agen~ such as m-chloroperbenzoic acid or monoperoxyphthalic acid or oxone (Trost, J. Org.
Chem., 1988, pg.532). :
Many of the following methods involve a basic h~drolysis of an ester function to obtain the corresponding carboxylic acid. In all cases, the free acid is obtained by acidification of the reaction mi~ture with a suitable acid such as hydrochloric, sulfuric, acetic, trifluoroacetic acid, etc.
Compounds 6, 10, 11, 16, 17, 19, 23, 24, 27, 28, and their precursor esters are all e~amples of the Formula I compounds of the present in~ention.
Compounds identified by Roman nu~erals (IV, V, XIV, ~Vl, ~gl, and ~ ) are known and correspond to those compounds in EP 419,049, which is incorporated herein by reference.

5U~TITIJ 1~ SH~ET

~WO 93/16069 PCI'/CAg3/00059.

~THOD 1 1 ) R2 7 _ Li 2) hydride reducing ::
Het - C02Rl 3 ~- Het - CR26R27OH
agent -:
or R26_Li 2 ~
. ~

_CR26R LG

NCS or Het-CR26R27H Het-CR26R27Hal ::
NBS
3 a +) .~
3 ~ PPh3 ~ Het - CHR27PPh3 ~-- ) :

bas e 27 ~ Het - CR = PPh~ ~-SUBSTITUTE SllEET

WO 93~16069 PCI'lCA93~00059 2 ~ 2 ~

M~;T~QP~ '' HO~I (CR R )p XIV

o ¦ bas e Het CR26R270~ ~C02M~
`~ (CR1~R12)p ~J~ST~TUTE SHEET

WO 93/16069 PCr/CA93/00059 ~
3 ~ ~
~ , Method l The carboxy derivative 1 may be reacted with an alkyl lithium reagent (R27Li) followed by a suitable hydride reducing agent such as lithium aluminum hydride, sodium borohydride, DIBAL-H, or the like, or by a second alkyl lithium reagent (R26Li) in appropriate solvents ~uch as ether, lk~, hexane, toluene, or mixtures thereof, to obtain alcohol 2.
The alcohol function of 2 can be con~erted to a suitable leaving group (LG) such as a halide, or a sulfonate ester (mesylate, tosylate, triflate, etc.) -~
by methods well known in the art to produce intermediate 3. A useful sub~roup of 3 can be prepared by halogenation of the alkyl compound Het-al~yl by heating with halogenating agents such as NCS or NBS in appropriate solvent~ such as carbon ~`
tetrachloride, benzene, and the li~e.
Reaction of 3 with triphenylphosphine in ether, acetonitrile, TEF, or similar solvents produces the phosphonium salt g. Compound 4 is converted into the ylid 5 by treating with a base `
such aæ Et3N, sodium hydride, butyl lithium, or an al~oxide, depending upon the reactivity of the -`-phosphonium salt 4.
Method 2 Compound 3 is reacted with phenol IV, in the presence of a suitable base such as potassium or cesium carbonate in a suitable solvent such as acetone, acetonitrile, or ~MF to yield compound 6 which can be converted to its corresponding carboxylic acid by standard procedures.

~U~TITUTE SHEET

W(~ 93/16069 2 ~ 2 ~ 3 pcr/cA93/ooos9 .. :

MEl~IOD ~ ;

HO~ KzC03 ~et - CRZ6RZ70~`~c KOH
H20/Et OH
heat R4 ~ ' R4 Het cR26R270~ 1. HCl/NaNO2 Het-CR26R27~ 2 s H2 R5 R 2. Na2S20~. _ ;

R6 CH2co(cRl2Rl2)pco2R = IV
Fis cher react ion , R ~ R6 ~ 3 KH~S

Het -CRZ6RZ~O~l/z l Z
R R

Het-CRZ6RZ7~11 ~ Rl2 ~UE~STITUTE SHEET

~093/l~K9 PCT/CA93/~59 ~ ~ - 34 - :~
Method 3 A suitable N-acetylated aminophenol X~YI is reacted with 3 using an al~ali hydride or carbonate, such as potassium carbonate as a base in a polar solvent like DMF or MMP. The re~ulting acetanilide 7 is then de-acetylated using standard basic conditions, preferably using alcoholic potassium :~
hydroxide under reflux to produce the aniline derivati~e ~. Conversion of the aniline derivati~e to the hydrazine analogue 9 is effected through reduction of the intermediate diazonium salt using ~-sodium hydrosulfite in an aqueous medium.
The hydrazine 9 is then processed using a Fischer indolization with ketone IV to produce compound 10, which is then al~ylated on the indole nitrogen using R9-Hal and a suitable base such as R~MDS in THF or NaH in DMF to give compound 11.

: 30 .
.
SUEI~TITUTE SHEET

WO 93/16069 212 ~3 4 2 J' P(~/CA93/000s9 ~;THQP 4 R4 6 Pd( OAc) 2 / Co ffz~ pyr~ ~R DM30, M~O~ Et3N
XIV ~ TfO~ l ll CO2~
CH2cl2 ~j~ Bl~ ( dlphenylphos -RS I R 2 Rl2 phino)fQrrocene R4 ~, 2 DI~3AL, lllF ~R
o~$ ) ~O~ CO~H

1~ 14 ;:

MnOz HCO~ CO2H --CH2Cl2 R~ R9 R Rl2 -70C to r. t.

1 5 ~

:.
R R H2. 10% Pd/C R4 R
Het~H E~tOI~ Het ~ - PJ~H

: ' SUE~STITUTE SHEEt WO 93/16069 PCl`/CA93~00059 J~

Method 4 Indole phenol ~IV is transformed to a phenol triflate 12 by treatment with trifluoromethyl sulfonic anhydride (Tf~0) in a sol~ent like pyridine -in dichloromethane. The phenol triflate may be carboxymethylated to a compound like 13 under palladium acetate catalysis in an atmosphere of carbon monoxide, a phosphine ligand like l,l-bis(di-phenylphosphinoferrocene) enhances this reaction.
Reduction of the carboxymethylated indole may be effected with a variety of hydride reducing agents.
Conveniently, DIBAL-H is used in THE on the hydrolysed ester. The reduced carbinol product 14 is conveniently oxidized to a formylated deri~ative 15 with manganese dioxide in methylene chloride as a typical sol~ent. Aldehyde 15 can then be homologated under carbanion conditions, typically using Wittig reagent ~ as shown in the method, under anydrous conditions in an etherial sol~ent like T~F. The temperature of this reaction is typically from -70~C
to room temperature. Indole styryl analogues 16 are thus formed. Further transformation of the styryl system may be effected by catalytic reduction using H2 and Pd/C in an organic sol~ent like ethyl acetate to yield the ~aturated compound 1~.

SUBST~TUTE SHEET

.93/16069 PCI`/CA93/00059 2~ 2g~

~IETH :)D 5 - ¦ E3Br 3/CH2Cl2 HO~l2 _ ~2Nb'~ 2 ~tR12 ) 0~12 )p-t ¦ 21 5~C

¦ R4 ~Rl~ Rl2~ 1. M3ONa, M~O}I R4 ¦ 2- soC12~ M3ON ~ ~2 2 0 Ph3P :
Dioxane, H20 E~4 R~ 3 R~

R~02 ~ --R2~7 ~7~0 1 ) R9~
NaE~ DMF
2) hydrolysis W0 93/16069 PCl`/CA93/00059 Method 5 Indole thio analogues of I such as 23 and 24 are conveniently prepared by the sequence shown in `~
Method 5. The treatment of compound V with BBr3 in a --chlorinated solvent æuch as CH2C12 cleaves both the methyl ether and the indole N-benzyl group and `~
cyclizes the product to an indole lactam 18.
Derivatization of this compound as an N,N-dimethyl-thiocarbamoyl indole 12 followed by thermal rearrangement at >200C gives ri~e to an N,N-dimethyl-carbamoylthioindole derivative 20. Depending on the duration of heating, dethiolation (R6=-S-t-Bu , R6=H) may also take place. The hydrolysis of 20 may be effected using strong base, typically sodium metho~ide in methanol is used. Spontaneous formation -15 of disulfide ~1 may occur in this reaction. The ~--reduction of 21 can be achieved using triphenyl-phosphine iD aqueous dio~ane to produce 2~- Coupling of 2~ to an appropriately substituted derivative 3 takes place under organic base catalysis. Typically -~
triethylamine, in an organic solvent such as methylene chloride, is used. Transformation of ~.
indole 2~ to an N-substituted derivative 24 is achieved under standard conditions described in Method 3.

~JBs rlT~lT

wn~s3/16o69 21~ 9 4 ~ ` PCI`/CA93/00059 MethQd 6 1 t 1 ) FIscHER/~ R4 6 ~-~Z) KHMDE;~I~F/R9Hal H~zt ~ )Co~R'3 X~ ~5 LiAlH~ Rl 2~Br / R4 R~

~ Het ~c ~0 R4 R6 R27 R5 Ig R~Rl2 Het ~ Z6 R

27 \ 1 ) NaH~IF/X~V
Rl 2 \ 2 ) LiOH

Hal p`CO 1 X~V

!~zt ~ RRt Rl2 R

~UeSTl~UTE SHEET

W093/1~K9 PCT/CA93/~
9 4$~r1~ ~
- 40 ~
Method 6 ~:
Hydrazine 2 may also be transformed directly :
to unsubstituted indoles by a Fischer reaction with various ~etones li~e g$gI. N-Alkylation of the ~-indoles is effected using the conditions deæcribed in Method 3 to produce hetmethoxyindole alkanoate esters --25. Such ester~ are transformed to ketones or ~:
carbinols via Grignard conditions using alkyl -;
magnesium halides in ether æolvents like diethyl ether or through the use of lithium aluminum hydride -in ether solvents like THF. The carbinols 27 80 produced may be further transformed into ester compounds of the present invention by reacting with ~
halo esters XXXV using sodium hydride as base in a :
suitable solvent li~e THF. Subsequent hydrolysis of the esters leads to acid compounds 28 of the present invention.

sT~TuTF SHEET

w~ 93/16~69 pcr/cAs3/o~oss _ 41 --Ml ;T~OD 7 -CHzOH
t ~
o Li~lH4 S( 0~ Cl2 R1 5S( ) 2N~2 CO R1 3 ~ - COCl - CONHS( ) 2R~ 5 l / . ,.
bas e R1 80H/ Rl 6Rl 6NH

R13=H ~ , / ~ , bas e - CO2Rl 8 - CONR1 6Rl 5 ~-¦ dehydrat e/P205 1R16=R16=H ;

-CN `:-NaN3 ~ , ,.
, 3 o N(--~H
.:
1 H- or 2H-tetrazol-5-yl SUII~TITUTE SHEET

W093/1~K9 .~ PCT/CA93/~59-. -Method 7 The preparation of the various definitions of Q is outlined in Method 7, starting from the readily available carboxylic acid derivative -Co2R13.
It will be ob~ious 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 carbo~ylic acid functional groups. The reactions depicted in Method 7, as well as methods for synthesis of the sulfonamide group (-S(0)2N~R16), are well-known in the art. See, for instance, the following textbooks:

1. J. March, Ad~an~ed Or~anic Chemistrv, 3rd ed., J.
Wiley and Sons, Toronto, 1985;

2. S.R. Sandler and W. ~aro, Or~anic Functional Group Preparations. I & II, Academic Press, Toronto, 1983 and 1986.
Representative Compounds Table I illustrates compounds representative of the present invention.

SuBsTlTlJTE SHEE~

WO93/16069 PCr/CA93/00059 2 g ~

_ 43 --TABLE I

RlR2R3_}~,r_X4~CH!-y-(cR~2Rl2)p-Q

R9 Ia 10 Ex Rl/R2/R3 Ar X4 R6 R9 Y-(CP12R 12) - No.

H/H/H pyrid-2-yl CHI~O S-t-Bu CH2Ph 4 Cl C~Me)2CO2H
2 H/H/H pyrid-2-yl (~)CHMeO S-t-Bu CH2Ph 1 Cl C(M~)2C02H
15 3 H~H/H p~rid-Z-~l (S)CHMeO S-t~u CH2Ph 1 Cl C(Me)2C02H
4 5-OMe/H/H pyrid-2-yl CHMeO S-t-Bu CH2Ph ~1 Cl C(Me)2C02H ~ -6-Cl/H/H pyrid-2-~1 CHMeO S-t-Bu CH2Ph~ClC(He)2CO2H
6 H~H/H pyra~in-2-yl CHMeO S-t~u CH2Ph~ClC(Me)2CO2H

7 H/H/H pyrim~din-2-yl CHMeO COCH2-t-BuCH2Ph~Cl C(Me)2CO2H

: 3 0 :::
` ' ' SUBSTITUTE SHEET `

.

WO 93/16069 PCI`/CA93/00059 Assays for Det~rminin& Biolo~ical Activitv Compounds of Formula I can be tested using the following assays to determine their m~mmalian leukotriene biosynthesis inhibiting activity.

Rat Peritoneal Polvmor~bQn~clear CE~) Leu~ocy~e Assav Rats under ether anesthesia are injected (i.p.~ with 8 mL of a suspension of sodium caseinate (6 grams in ca. 50 mL water). A~ter 15-24 hr. the lo rats are sacrificed (C02) and the cells from the peritoneal ca~i~y are reco~ered by la~age with 20 mL
of buffer (Eagles MEM containing 30 m~ ~EPES adjusted to pH 7.4 with NaOH). The eells are pelleted (350 x g, ~ min.), resuspended in buffer with vigorous 15 sha~ing, f iltered through lens paper, recentrifuged and finally suspended in buffer at a concentration of 10 cel~s/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 ætirred 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 tra~smission. The size of the assay aliquot is chosen to give a submaximal transmission change (u~ually -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.

SU~SSTIT~TE 5HEET

W093/16069 PCT/CA93/~59 212 ~ ,J ~

Human Polymor~honuclear (PMN) Leukocyte LT~4 Assav A. Preparation of Human PMN. Human blood is obtained by antecubital venepuncture from consentin~
volunteers who ha~e no~ taken medication within the previous 7 days. The blood is immediately added to lOX (v/v) trisodium citrate (0.13 M) or 5Z (v/v) sodium heparin (1000 IU/mL). PMNs are isolated from anticoagulated blood by dextran sedimentation of erythrocytes followed by centrifugation through Ficoll-~ypaque (specific gravity 1.077), as described by Boyum (Scand. J. Clin. Lab. Invest., ~1 (Supp.
97), 77(1968)). Contaminating erythrocytes are removed by lysis following exposure to ammonium chloride ~0.16 M) in Tris buffer (p~ 7.65), and the PMNs resuspended at 5 x 105 cells/mL in HEPES (15 -mM)-buffered Han~s balanced salt solutio~ containing Ca2+ (1.4 mM) and Mg2+ (0.7 mM), pH 7.4. Viability is assessed by Trypan blue exclusion.

B. Generation and Radioi unoassay of LTB4.
PMNs (0.5 mL; 2.5 x 105 cells) are 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 ~ynthesis of LTB4 is initiated by the addition of calcium ionophore A23187 (final concentration 10 mM) or vehicle in control ~amples and allowed to proceed for 5 minutes at 37~C. The reactions are then terminated by the addition of cold methanol (0.25 mL) and samples of the entire PMN reaction mi~ture removed -~
for radioimmunoassay of LTB4.

SUE~STITUTE SHEET

WO93/1~K9 PCT/CA93/~sg qr~ 46 -Samples (50 mL) of authentic LTB4 of known concentration in radioimmunoas6ay 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 are 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) are added and the tubes ~ortexed. Reactants are allowed to equilibrate by incubation overnight at 4C. To separate antibody-bound from free LTB4, aliquots (~0 mL) of acti~ated charcoal (3Z acti~ated charcoal in RIA
buffer containing 0.25% Dextran T-70) are added, the tubes vortexed, and allowed to stand at room temperature for 10 minutes prior to centrif~gation (1500 x g; 10 min; 4~C). The supernatants containing antibody-bound LTB4 are decanted into ~ials and Aquasol 2 (4 mL) added. Radioactivity is quantified by liquid scintillation spectrometry. The specificity of the antiserum and the sensitivity of the procedure have been described by Ro~ach et ~1-(ProstaElandins Leukotrienes and Medicine, 1984, 13, 21.) The amount of LTB4 produced in test and control (approx. 20 ng/106 cells) sampleæ is calculated.
Inhibitory dose-response curves are constructed using a four-parameter algorithm and from these the lC50 ~alues are determined.

Asthmatic Rat_Assav Rats are obtained from an inbred line of asthmatic rats. Both female (190-250 g) and male (260-400 g) rats are used.

SUI~STITUTE ~HEET

WO 93/16069 PCr/CA93/OOOS9 2 ~i 2 ~ c~

Egg albumin (~A), 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 is supplied by Sandoz Ltd., Basel.
The challenge and subsequent respiratory recordings are carried out in a clear plastic box with internal dimensions lOx6x4 inches. The top of the box is removable; in use, it is held firmly in place ~y four clamps and an airtight seal is maintained by a soft rubber gasket. Through the center of each end of the chamber a DeVilbi~s 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 ~olumetric pressure transducer (PT5-A) which is then connected to a Beckman 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 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 æmall Potter diaphragm pump operating at 10 psi and a flow of 8 literslminute.
~ats are sensitized by injecting (subcutaneously) 1 mL sf a suspension containing 1 mg EA and 200 mg aluminum hydroxide in saline. They are ., ':

SUE#TITUTE SHEET

~W093/1~69 PCT/CA93/~N~9 JS~
- 4~ -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 théir 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 intra~enously 2 minutes prior to challenge. They are either dissolved in saline or 1% methocel or suspended in 1%
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. ~sually, 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 5 0% .
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.

~VBSTITUTE SHEET

W0 93/16069 PCl'/CA93/0005~
212~4~

_ 49 --'',.

INTl~;R~DIATES
. .
Preparation 1~ Methyl 3-[1-(4-chlorobenzyl)-3-methyl- ~
.
5-hydroxy-indol-2-yl]-2,2-dimethyl-~ropanoate -To a solution of 1.05 g (2.7 mmol) of 3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]- ~-2,2-dimethylpropanoic acid (E~ 166,591, Example 22) and 800 ~L of ethanethiol (10 mmol) in 20 mL of CH2~12 at -20C was added in portions 2.17 g (16 ol) of AlC13. The reaction turned light orange and was stirred at room temperature overnight. In the morning, the reaction was completed (tlc) and it was ~-~
poured into a solution of lN HCl and extracted 3x with CH2C12. The combined organic layers were washed with brine, dried (MgS04), and filtered. The ~
filtrate was evaporated and to the residual syrup ~;:
(680 mg) was added 20 mL of Et20 followed by an ethereal solution of diazomethane. E~aporation of the solvent left the crude title compound which was used without further purification. -H NMR (Z50 MHz, CDC13): ~ 7.3-7.15 ~m, 3H, aromatic);
6.96 (m, 1~, aromatic): 6.70 (m, 3H, aromatic); 5.34 :
(s, ZH, N-CE2); 4.8-4.5 (M, lH, -OH); 3.76 (s, 3H, -~
-C02Me); 3.12 (s, 2H, 2-C~2); 2.40 (S, 3~, 3-Me);
1.44 (s, 6H, C(Me)2).

Pre~aration 2: Methyl 3-tl-(4-chlorobenzyl)-3-(t butylthio)~5-hydroy indol-2-yl]-:`~ 2.2-dimethylpro~anoate ` The t~tle compound was prepared as described in EP 419,049, Example 1, Step C.

SU~STITUTE SHEET

.:

WO ~3/16069 P~/CA93/00059 J ~i ?~

Prep~ration 3: 3-tl-(4-Chlorobenzyl>-3-(t-butylthio)-5-hydroxyindol-2-ylJ-2,2-dimethyl-- pr~panoic acid To a mixture of LiH (12.6 g) and HMPA (10 mL) in DMF (1050 mL) at 0C was added 2-methyl-2-propanethiol (178 mL). The mixture was stirred at room ~emperature for 30 min, then 3-~1-(4-chloro-benzyl)-3-(t-butylthio>-5-methoxyindol-~-yl]-2,2-lo dimethylpropanoic acid methyl ester (150 g) (EP
419,049, Example 1, Step A> in DMF (450 mL) was added slowly. The mixture was sl~wly heated to 150C and kept at that temperature for 18 hours. After cooling ~o room temperature, the supernatant layer was decanted and the residue diæsol~ed in H2Q and acidifed with lN HCl, extracted twice with Et20, washed twice with brine, dried o~er MgS04, filtered and evaporated to dryness to provide the title compound.

Preparation 4: 3-[1-(4-Chlorobenzyl)-3-(t-butylthio)-5-hydroxyindol-2-yl]-2,2-dimethyl-~ro~anoic acid all~l ester The compound from Preparation 3 (150 g> was dissolved in DME (1.2 L) then the solution was cooled in an ice-water bath. To this solution was added K2C03 (138 g) portionwise and the mixture was left to stir for 30 min. Then allyl bromide (162 g) was added, the ice bath removed, and the mixture stirred for 18 hours. To the mi~ture was added aqueous NH4Cl and it was extracted with Et20. The organic layer wa~ washed with H2O and brine, dried over MgS04, filtered, and evaporated to dryness. Purification by silica get chromatography afforded the title compound; m.p. 150-151~C.

SUE~TITUTE SHEET

WO 93/16069 PCI~/CA93/00059 ~ 1 2 ~

~;XAMPLE ~

3-~N-(p-chlorobenzyl)-3-(t-butylthio)-5-~1-(pyridin-S 2-yl)ethoxy)indol-2-yl]-2,2-dimethylpropanoic acid, sodium salt Step A: a-Methyl~ridine-2-methanol To a cold (0C) solution of 2-acetylpyridine (3.63 g) in absolute ethanol was added portionwise sodium borohydride (1.7 g). The mixture was ætirred at O~C for 1 hr. The reaction mixture was then poured into an aqueous solution saturated with NH4Cl (200 mL), extracted with ethyl acetate (3x 100 mL), washed with 100 mL of brine, and dried (MgS04). The solution was evaporated to dryness to yield the title compound as a liquid, which was used without further purification.
, 20 Step B: Methyl 3-[N-(p-chlorobenzyI)-3-(t-butylthio- :5-~1-(pyridin-2-yl]ethoxy)indol-2-yl]-2,2- -dimethyl~ropanoate :' To a cold (0C) solution of alcohol (246 mg) from Step A in DMF (5 mL) were added triethylamine (418 ~L) and methanesulfonylchloride (170 ~L). The ~;-mixture was stirred at 0C for 45 min. Then acetonitrile (5 mL) wag added to the mi~ture followed by cesium carbonate ~(2.44 g). To this mixture was added methyl 3-[N-(p-chlorobenzyl)-3-(t-butylthio)_5_ -hydro~y~indol-2-yl]-2,2-dimethylpropanoate (EP
419,049, Example 1, Step C> ~689 mg) and stirred at 70C for 2 hr. After the æolution had cooled, it was poured onto 100 mL of N~40AC (2~ solution), STITUTE SHEEl`

Wo 93/16069 pcr/cAs3/ooos9 extracted with 3x ~0 mL of ethyl acetate, washed ~ith 50 mL of brine, and dried over MgS04. The solution was evaporated to dryness and the residue was chromatographed on flash silica gel using ethyl acetate:toluene (1:9~ as eluant to yield the title compound as a white solid; m.g. 123-125~C.

~t~p C:
The compound (594 mg) from Step B was hydrolyzed by dissolving it in 16 mL of Tn~, 8 mL of -~
MeOH, and 4 mL of l.OM LiOH. The solution waæ heated at 70~C for 2 hr. The solution was diluted with 50 mL f ~2~ acidified with glacial AcOH to p~ 5 and !
then diluted with 50 ml of NH40Ac (25% solution).
The mixture was extracted with 3x 50 mL of EtOAc.
The organic layer was washed with (lx 50 mL of brine, and dried over MgS04. The solution was evaporated to ~-dryness and coevaporated with 50 mL of toluene to provide the title acid as a foam. The title product wa6 prepared as follows: the acid wa~ suspended in -ethanol (3 mL) and treated with l.ON NaOH (1 equivalentj, diluted with H20 (5 mL), and lyophilized to give the title compound.
Anal. Calc~d for C31H34N203SCl Na~2~20 Calc'd: C, 61.12; H, 5.63; N, 4.60 Eound: C, 61.34; H, 5.42; N, 4.65.
: .

SU~STITUTE SHEET

WO93/1~K9 PCT/CA93/~ S9 ~
2129~

~':
~ 3-~N-(p-chlorobenzyl)-3-(t-butylthio)-5-~
(pyridin-2-yl)ethoxy)indol-2-yl]-2,2-dimethylpropanoic ~:
acid~ sodium salt -~ollowing the procedure of Example 1, Steps ~.
B and C, but using ~ a-methylpyridine-2-methanol, :~
the title compound is obtained.
..

~ 3-[N-(p-chlorobenzyl)-3-(t-butylthio)-5-[1-(pyridin-2-yl)ethoxy)indol-2-yl~-2,2-dimethylpropanoic acid. sodium:sal~__ _ _ _ Following the proeedure of Egample 1, Steps B and C, but usi~g (~-a-methylpyridine-2-methanol, the title compound is obtained. -. .

ST~UTE SHEET

Claims (18)

WHAT IS CLAIMED IS:

1. A compound of the formula I:

I

wherein:
Het is ArR1R2R3;

Ar is a monocyclic aromatic 5- or 6-membered ring containing 1 to 3 N atoms, and the N-oxides thereof;

R1, R2, R3, R4, R5, and R11 are independently hydrogen, halogen, perhalo lower alkenyl, lower alkyl, lower alkenyl, lower alkynyl, -CF3, -CN, -NO2, -N3, -C(OH)R12R12, -CO2R13, -SR15, -S(O)R15, -S(O)2R15, -S(O)2NR16R16, -OR16, -NR16R16, -NR13CONR16R16, -COR17, CONR16R16, or -(CH2)tR22;

R6 is hydrogen, -CH3, CF3, -C(O)H, X1-R7 or X2-R8;

R7 and R10 are independently alkyl, alkenyl, -(CH2)uPh(R11)2 or -(CH2)uTh(R11)2;

R8 is -CF3 or R7;

R9 is hydrogen or X3-R10;

each R12 is independently hydrogen or lower alkyl, or two R12's on same carbon atom are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

R13 is hydrogen, lower alkyl or -CH2R22;

R14 is lower alkyl or -(CH2)rR22;

R15 is -CF3 or R14;

R16 is hydrogen, -COR17, R14, or two R16'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;

R17 is hydrogen, -CF3, lower alkyl, lower alkenyl, lower alkynyl or -(CH2)rR22;

R18 is -(CH2)s-C(R19R19)-(CH2)s-R20 or -CH2CONR16R16;

R19 is hydrogen or lower alkyl;

R20 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-R21;
R21 is alkyl or -COR24;
R22 is phenyl substituted with 1 or 2 R23 groups;

R23 is hydrogen, halogen, lower alkyl, lower alkoxy, lower alkylthio, lower alkylsulfonyl, lower alkylcarbonyl, -CF3, -CN, -NO2 or -N3;

R24 is alkyl, cycloalkyl, or monocyclic monoheterocyclic ring;

R25 is the residual structure of a standard amino acid, or R19 and R25 attached to the same N
can cyclize to form a proline residue;

R26 is hydrogen or lower alkyl;

R27 is lower alkyl or R26 and R27 on the same carbon are joined to form a cycloalkyl ring of 3 to 6 carbon atoms;

m is 0 or 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;
W is O, S or NR16 X1 is O or NR16;
X2 is CO, CR12R12, S, S(O), or S(O)2;
X3 is CO, CR12R12, S(O)2, or a bond;
X4 is CR26=CR27, CR27=R26, CR26R27y1, or Y1CR27R26;
Y is X1 or X2;
Y1 is O, S, S(O)2, or CR26R26;

Q i s -CO2R13, -CONHS(O)2R15, -NHS(O)2R15, -S(O)2NHR16, -CONR16R16, -CO2R18, -CONR19R25, -CR12R12OH, or 1H- or 2H-tetrazol-5-yl;

or a pharmaceutically acceptable salt thereof.

2. A compound of Claim 1 wherein X4 is CHMe-O;

or a pharmaceutically acceptable salt thereof.

3. A compound of Claim 1 wherein:

R1, R2, R3, R4, R5 are hydrogen;
R6 is X2-R8;
R8 is R7;
R9 is R10;

R11 is hydrogen or halogen;
m is 0;
n is 1 to 3;
u is 0 in R7 and 1 in R10;
X2 is CR12R12 or S;
X4 is CR26R27-Y1;
Y1 is 0; and Q is -CO2R13;
or a pharmaceutically acceptable salt thereof.

4. A compound of Claim 1 wherein:

R1, R2, R3, R4, and R5 are hydrogen;
R6 is X2-R8;
R8 is R7;
R9 is R10;
R11 is hydrogen or halogen;
m is 0;
n is 1 to 3;
u is 0 in R7 and 1 in R10;
X2 is CR12R12 or S;
X4 is CR26R27-Y1;
Y1 is 0; and Q is 1-H- or 2H-tetrazol-5-yl;
or a pharmaceutically acceptable salt thereof.

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

Ia wherein the substituents are as follows:

Ex R1/R2/R3 Ar X4 R6 R9 Y-(CR12R12)p-Q
No.

1 H/H/H pyrid-2-yl CHMeO S-t-Bu CH2Ph-4-Cl C(Me)2CO2H
2 H/H/H pyrid-2-yl (?) CHMeO S-t-Bu CH2Ph-4-Cl C(Me)2CO2H
3 H/H/H pyrid-2-yl (?) CHMeO S-t-Bu CH2Ph 4 Cl C(Me)2CO2H
4 5-OMe/H/H pyrid-2-yl CHMeO S-t-Bu CH2Ph-4-Cl C(Me)2CO2H
6-Cl/H/H pyrid-2-yl CHMeO S-t-Bu CH2Ph-4-Cl C(Me)2CO2H
6 H/H/H pyrazin-2-yl CHMeO S-t-Bu CH2Ph-4-Cl C(Me)2CO2H
7 H/H/H pyrimidin-2-yl CHMeO COCH2-t-Bu CH2Ph-4-Cl C(Me)2CO2H

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

7. A pharmaceutical composition of Claim 6 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; H1- or H2-receptor antagonists; antihistaminic agents; prostaglandin antagonists; thromboxane antagonists; thromboxane synthetase inhibitors; and ACE antagonists.

8. A pharmaceutical composition of Claim 6, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

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

10. A method of preventing the synthesis, the action, or the release of SRS-A or leukotrienes in a mammal which comprises administering to said mammal an effective amount of a compound of Claim 1.

11. A method of Claim 10 wherein the mammal is man.

12. A method of treating asthma in a mammal comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

13. A method of treating inflammatory diseases of the eye in a mammal which comprises administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Claim 1.

14. The method of Claim 13 wherein the mammal is man.

15. A leukotriene biosynthesis inhibitor pharmaceutical composition comprising:
an acceptable leukotriene biosynthesis inhibiting amount of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, 2, 3, 4 or 5, in association with a pharmaceutically acceptable carrier.

16. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, 2, 3, 4 or 5, as a leukotriene biosynthesis inhibitor.

17. A compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, 2, 3, 4 or 5, for use in the treatment of asthma, allergies, inflammatory diseases, allergic rhinitis or chronic bronchitis, or amelioration of skin diseases, or treatment of cardiovascular disorders, angina or endotoxin shock, or migraine headache.

18. Use of a compound of formula (I), or a pharmaceutically acceptable salt thereof, as defined in claim 1, 2, 3, 4 or 5, in the manufacture of a medicament for the treatment of asthma, allergies, inflammatory diseases, allergic rhinitis or chronic bronchitis, or amelioration of skin diseases, or treatment of cardiovascular disorders, angina or endotoxin shock, or migraine headache.