CA1334415C - 3-hetero-substituted-n-benzyl-indoles - Google Patents

Abstract

Compounds having the formula:

Description

~,195P/1193A

TITLE OF THE INVENTION
3--HETERO-~u~ .u~-u-N-BENZYL--INDOLES

BA~ OF Ti~E INVENTION
The leukotrienes and their biological 10 activities, especitlly their roles in various disease ~tates and conditions have been described. For example, ~ee EP 1~0,684 (May 8, 1985).
8everal classes of c, '- exhibit ability 15 to inhibit the biosynthesis of leukotriene~ in mammals, especially humans.
~ ee, for example, EP 166,591 (January 2, 1986). The _ ~- of the pre~ent invention are distinguished from those of EP 166,591 in the 20 important feature of p~ssessing a heteroatom at po6ition 3 in pl~ce of a hydrogen or carbon ~ub~tituent. The heteroatom introduces unigue F/l electronic and chemical properties into the indole nucleus. The '~ of the present invention are further distinguished in that they uniquely inhibit the biosynthesis of leukotrienes, whereas those of CA
1,241,660 are antagonists of prostaglandins which also possess leukotriene biosynthesis inhibitory properties CH-A 454,858 (June 23, 1968) and CH-A 455,777 (July 15, 1968) teach derivatives of indole-2-acetic 10 acid as useful for the treatment of inflammatory d;ee/~qPe.
The, _ e of these two Swiss patents are distinguished from those of the present invention by the same chemical differences as in CA 1,241,440, as well as by differences in the scope of their biological activities.
Walton et al., J. Med. Chem., 11, 1252 (1968) teach certain indole-3-acetic acid derivatives assayed for tumor chemotherapy activity. Walton et al. teach c, '- with an alkanoic acid in the 20 3-position, rather than in the 2-position, and they also lack a heteroatom substituent. The single c ' of Walton e~t al. with a 2-alkanoic acid also lacks a 3-hetero substituent. Walton et al. disclose - no useful biological activity for their indole 25 2-alkanoic acid.
JP 60/130567 (July 12, 1985) teaches 3-substituted-2-phenyl-indole derivatives as having lipoxygenase and cyclooxygenase inhibiting activity. In addition to F/l the important differences in biological activities, these -- _ u,.ds possess a phenyl group in the 2-position and are lacking the N-benzyl substituent of the ~ ~ul-ds of the present invent ion .

SUMr5ARY OF THE INVENTION
The present invention relates to c~ ~ rl~
having activity as leukotriene biosynthesis inhibitors, to methods for their preparation, and to 10 methods and pharmaceutical formulations for using these -, u--~:j in mammals (especially humans).
Because of their activity as leukotriene biosynthesis inhibitors, the compounds of the present invention are useful as anti-asthmatic, anti-allergic, 15 and anti-inf lammatory agents and are useful in treating allergic rhinitis and chronic bronchitis and for amelioration of skin diseases like psoriasis and atopic eczema. These compounds are also useful to inhibit the pathologic actions of leukotrienes on the 20 cardiovascular and vascular systems for example, actions such as result in angina or endotoxin shock.
The compounds of the present invention are useful in the treatment of inf lammatory and allergic diseases of the eye, including allergic conjunctivitis. The 25 - '- are also useful as cytoprotective agents and for the treatment of migraine hPA~l~h~.
Thus, the ~ _ u.-ds of the present invention may also be used to treat or prevent mammalian (espeoially, human) disease states such as erosive 30 gastritis; erosive esophagitis; inflammatory bowel disease; ethanol-induced hemorrhagic erosions;

F/l hepatic ischemic; noxious agent induced damage or necrosis of hepatic, pancreatic, renal, or myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CC14 and D-galactosamine; ischemic renal failure; disease-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal f ai lure .
The c, ~ ds of this invention are inhibitors of the biosynthesis of 5-lipoxygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETE and the leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contribute to various disease conditions such as asthma, psoriasis, pain, ulcers and systemic anaphylaxis. Thus inhibition of the synthesis of such compounds will alleviate these and other leukotriene-related disease states.
DETAILED DESCRIPTION
The compounds of this invention are best realized by Formula I:

~ \
R5tO 1 l R6>V ~ (CR2R ) n~E
R _Rl R7 ~R8 ` 1 3344 1 5 F/l wherein:
Rl is H or loweralkyl;
R2 is H or loweralkyl, or two R2's may be joined to form a ring of 3-6 atoms;
s R3 is alkyl, C2-C6 alkenyl, substituted or unsubstituted phenyl, -(CH2)m-Het, or M-substituted alkyl; 4, R5 and R6 is each independently H, lower-alkyl, C2-C6 alkenyl, or -(CR2R2) M; 0 R7 and RB are independently H, Cl-C3 alkyl, halogen, OH, CN, CF3, Cl-C3 alkoxy, Cl-C3 alkylthio, CO2H, Cl-C3 alkoxycarbonyl, Cl-C3 alkyl-carbonyl, or azide;
R9 is CF3, loweralkyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenyl;
R10 is H, loweralkyl, unsubstituted phenyl, unsub-stituted benzyl, or two R10 ' s attached to a nitrogen may form a ring of 5 to 7 members;
Rll is H or -(CH2) R9;
R12 is loweralkyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenyl;
R13 is H, loweralkyl, substituted or unsubstituted phenyl, or substituted or unsubstituted benzyl:
R14 is -CH2CH2N(R10)2, CH2CH(OH)CH2OH, -cH2o2CC ( CH3 ) 3, --CH ( CH3 ) o2CC ( CH3 ) 3, o 3 o -CH2N~
o F/l --CH-N~, --CH2CH2NHC ~) IC2 O
O O
Il 11 -(CH2)2N~,--(CH2)~, --(CH2)2NHAc, \\ N
2 ~7, --CH2~, --CH2--N /

~=( , -CH-N~ I , or -CH2-N~;
\ / 11 E is CH2OH, Co2R13, Co2R14, tetrazol-5-yl, CHO, 25 C(O)NR2R2, C(O)NHS(O) R9, or C(O)N(OR2)R2;
M is a) OR10; 2 b) halogen;
c) CF3;
d) SR9;

`` ~3344~5 F/l e) substituted or unsubstituted phenyl;
f ) COOR10;
o g ) C-Rl l;
h) tetrazole;
o i ) -NH-C-Rl l;
j ) NRl Rl 0;
k ) -NHSO2R

1 ) --C--CH2OH;
m) -S(O)R9;
n) -CONRlOR10;
o) -S(0)2NRlOR10;
p) --S(O)2R;
q) NO2;
o s) O-C-NRlOR10;
t ) O--C--OR 1 2;
u) CN;
v) N3; or w) H;
X is O, S, S(O), or S(O)2;
m is 0-2;
n is 0-5;
p is 0-3; and 30 q is 0-4;
and the rhArr~ceutically acceptable salts thereof.
Alkyl and alkenyl are intended to include linear, branched, cyclic, and linear/cyclic (e.g., alkylcycloalkyl) structures.

`` 1 3344 1 5 F/l As used herein, the term "alkyl" includes " loweralkyl " and extends to cover carbon f ragments having up to 20 carbon atoms. Examples of alkyl groups include octyl, nonyl, norbornyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, eicosyl, 3, 7-ethyl-2, 2-methyl-4-propylnonyl, cyclododecyl, A~19 ~yl and the like.
As used herein, the term " loweralkyl"
includes those alkyl groups of from 1 to 7 carbon atoms. Examples of loweralkyl fragments include methyl, ethyl, propyl, isopropyl, butyl, sec- and tert-butyl, pentyl, hexyl, heptyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and the 1 ike .
Alkenyl groups include vinyl, allyl, isopropenyl, pentenyl, hexenyl, heptenyl, cyclo-propenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, l-propenyl, 2-butenyl, 2-methyl-2-butenyl and the like .
As used herein, the term "alkoxy" includes those alkoxy groups of f rom 1 to 7 carbon atoms of either a straight, branched, or cyclic configuration.
Examples of alkoxy fragments include methoxy, ethoxy, propoxy, isopropoxy, cyclopropyloxy, pentyloxy, cycloheptyloxy, and the like.
Substituted phenyl and substituted benzyl include 1 or 2 substituents on the benzene ring selected from Cl-C3 alkyl, halogen, CN, CF3, Cl-C3 alkoxy, Cl-C3 alkylthio, C02H, Cl-C3 alkoxycarbonyl, Cl-C3 alkylcarbonyl and azide .

F/l By "Het" is meant 2-, 3-, or 4-pyridyl;
tetrazolyl; 2- or 3-thienyl; 2-, 4-, or 5-thiazolyl;
2-, 4-, or 5-thiazolinyl; 1-, 2-, 4-, or 5-imid-azolyl; 3-[1,2,5]-thiadiazolyl; benzothiazol-2-yl; or 5 2-, 3-, or 4-quinolinyl, each optionally substituted with 1 or 2 substituents selected from Cl-C3 alkyl, halogen, CN, CF3, Cl-C3 alkoxy, Cl-C3 alkylthio , CO2H , Cl-C3 alkoxycarbonyl , Cl-C3 alkylcarbonyl and azide.
By "halogen" is meant F, Cl, Br, and I.
It is intended that the definitions of any substituent (e.g., R2, R4, R5, etc. ) in a particular molecule be independent of its def initions elsewhere in the molecule. Thus, -NR2R2 represents 15 -NHH, -NHCH3, -NCH3CH3, etc.
Some of the , ~ ds described herein contain one or more centers of asymmetry and may thus give rise to diastereoisomers and optical isomers.
The present invention i6 meant to comprehend such 20 possible diastereoisomers as well as their racemic and resolved, optically active forms. Optically active (R) and (S) isomers may be resolved using conventional techniques.
Some of the compounds described herein 25 contain olef inic double bonds, and unless specif ied otherwise, are meant to include both E and Z
geometric isomers.

F/l Preferred compounds of Formula I are represented by Formula Ia:
R~ X-R3 ( CR2R2 ) nE I a 7~O~
\/
wherein:
15 R3 is loweralkyl (preferably branched loweralkyl), alkylcycloalkyl, alkyl-substituted phenyl, unsubstituted phenyl, or unsubstituted benzyl;
R4 is loweralkyl (preferably branched loweralkyl), halo, substituted or unsub-stituted phenyl, or alkoxy;
R7 is alkyl, alkoxy, azide, halogen, or hydroxy;
R13 is }~ or loweralkyl;
E is Co2R13, CO~3H2, or tetrazol-5-yl;
25 n is 1-3;
and the r~ ;n;ng substituents are as defined for Formula I.
It will be understood that in the discussion of methods of treatment which follows, references to the c, u~ds of Formula I are meant to also include the rh~rr~ceutically acceptable salts.

F/l 1 3344 1 5 The ability of the compounds of Formula I to inhibit biosynthesis of the leukotrienes makes them useful for inhibiting the symptoms induced by the leukotrienes in a human subject. This inhibition of the mammalian biosynthesis of leukotrienes indicates that the c~, u--ds and pharmacuetical compositions thereof are useful to treat, prevent, or ameliorate in mammals and especially in humans: 1) pl~lr slry conditions including diseases such as asthma, 2) allergies and allergic reactions such as allergic rhinitis, contact dermatitis, allergic conjunc-tivitis, and the like, 3) inflammation such as arthritis or inflammatory bowel disease, 4) pain, 5) skin conditions such as psoriasis and the like, and 6) cardiovascular conditions such as angina, endo-toxin shock, and the 1 ike, and that the compounds are cytoprotective agents.
The cytoprotective activity of a compound may be obse,v~d in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the noxious effects of strong irritants, for example, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non-steroidal anti-inf lammatory 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 cyto-protective ability. These assays are; (A) an ethanol-induced lesion assay and (B) an indomethacin-induced ulcer assay and are described in EP 140, 684 .

F/l Compounds of Formula I can be tested using the following assays to determine their mammalian leukotriene biosynthesis inhibiting activity.
Rat Peritoneal Polymorphonuclear (PMN) Leukocyte Assay Rats under ether anesthesia are injected (i.p. ) with 8 ml of a suspension of sodium caseinate (6 grams in ca. 50 ml water). After 15-24 hr. the rats are sacrificed (CO2) and the cells from the peritoneal cavity are recovered by lavage with 20 ml of buffer (Eagles MEM containing 30 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 1ll aliquot of PMN suspension and test ~- _ ' are preincubated f or 2 minutes at 37C, followed by the addition of 10 IIM A-23187, The suspension is stirred for an additional 4 minutes then bioassayed for LTB4 content by adding an aliquot to a second 500 1ll portion of the PMN at 37C . The LTB4 produced in the f irst incubation causes a~y-eyc--ion of the second PMN, which is measured as a change in light transmission. The size of the assay aliquot is chosen to give a slll 'r~l transmission change (usually -70%) for the untreated control. The percentage inhibition of LTB4 formation is calculated from the ratio of transmission change in the sample to the transmission change in the ~ d-f ree contro1.

l33q415 F/l Mouse Macrophaqe Assay Mouse peritoneal macrophages are treated sequentially with arachidonic acid (labelled with tritium); the compound being evaluated as an 5 inhibitor, and a stimulator (zymosan). Metabolites derived from arachidonic acid (PGE2, 6-keto PG-Fla and leukotriene C4 ) are separated f rom the incuba-tion medium by extraction and chromatography, and then quantitated by determining the amount of radio-10 activity (cpm) associated with each of them.Inhibitors cause a reduction in the amount of radio-activity (cpm) associated with a given metabolite.
(This protocol is identical to that described in the reference except that the radioactivity herein 15 associated with the LTC4 is deter~; n~d by counting an aliquot of the final aqueous solution directly rather than chromatographing it f irst .
Reference: Humes, J.L. et al., J. Biol.
Chem., 257, 1591-4, (1982).
Antiqen Challenqe 'in vitro' Assay Male guinea pigs weighing 300-350 g are sensitized by injecting (intraperitoneally) 0.5 ml of a suspension containing 0 . 4 mg of egg albumin 25 (Ovalbumin, Grade V, Sigma Chemical Co.) and 4.0 g aluminum hydroxide in 19.6 ml of saline. Two weeks are permitted for sensitization to occur.
Three sensitized guinea pigs are stunned and exanguinated . The tracheas are removed, f reed of 30 a&ering tissue and divided longitudinally by cutting through the cartilaginous tissue directly opposite the muscle insertion. Each opened trachea is then F/l transected between every second cartilage. Four of the cut sections are tied together, end to end, in a series with No . 7 silk thread ensuring that the tracheal muscles are all in the same vertical plane.
5 Thus, each chain consists of tissue from three dif f erent animals .
The chain so formed is then suspended under 1 g of tension (by silk ties at each end) in a 20 ml organ bath containing 10 ml of modif iedl Krebs-10 Henseleit buffer solution gassed with 95% 2 and 5%C2 at 37C. Two different methods are used to test experimental compounds Protocol A:
Mepyramine (0.55 llg/ml) and indomethacin (2.67 llg/ml) are added to the buffer lmodified Krebs solution in grams/liter and (mM):
NaCl - 6.87 (120); glucose - 2.1 (11); NaHCO3 -2.1 (25); KCl - 0.32 (4.72); CaC12 - 0.28 (2.5);
MgSO4.7H2O -- 0.11 (0.5); KH2PO4 -- 0.16 (1.2): pH at bathing solution = 7.35 + 0.05.

F/l to avoid the contribution of histamine receptor6 and cyclooxygenase products to the contraction. To record responses one end of the tracheal chain is attached to a Gould-Statham UC-2~ force displacement tr~nc~ r~r 5 which is connected to a Beckman~ Type R-dynograph.
The preparations are allowed to eguilibrate for one hour during which time the tissues are automatically washed (10 ml volume displacement) every 6 minutes.
After the equilibration period the tissues 10 are primed with methacholine (3 llg/ml: 1.5 x 10 5M), washed and allowed to recover to baseline.
The tissues are treated again with a second dose of methacholine, washed, allowed to return to baseline and washed for an additional hour.
Two chains are used as a control. These are incubated in a concentration of egg albumin sufficient to induce an average contraction of 50-80% of the methacholine response.
Each:, ' to be tested is added to a bath (at a final concentration of 10 ~g/ml) 15 minutes prior to challenging the fresh chains with egg albumin.
The response of the challenged tissue is expressed as a percentage of the methacholine maximum. The percentage inhibition for each ~ .d is then calculated. C _ '- which at 10 llg/ml (final concentration) inhibit the egg albumin response by 50% or more are retested at a lower cor.~ ation.

F/l Protocol B:
Tracheal chains are prepared as described above. Experiments are carried out on tonal (no 5 ~n~l( Ll~acin) or non-tonal (o . 5 mg/mL indomethacin) preparations in the presence of 1 x lo 7M atropine and/or 2.0 mg/mL mepyramine. The effects of various , '~ alone or in combination (30 minutes pretreatment) or drug vehicle (DMSO or H2O) are 10 det~rm;n~d against a standared single dose challenge to 0.1 mg/mL ovalbumin. The responses are expressed as a percent of the maximal contraction that could be produced by histamine (10 mg/mL) before addition of the various compounds. Peak percent maximal cont-15 ractile responses to antigen are recorded at varioustime intervals (0-60 min) after addition of antigen to control and compound-treated tissues.
For non-tonal experiments, indomethacin is added to the Krebs' buffer at the beginning of the 20 experiment so that the tissues are continuously bathed with this drug throughout the experiment. All tissues are primed 2-3 times with a maximal cc,~ ation of histamine (10 mg/mL) and responses to antigen are expressed at a percent of the maximum 25 contraction to histamine.
In the absence of indomethacin (tonal), the tissues spontanously develop intrinsic tone following the initial priming procedure with histamine ( lo - mg/mL) and isoproterenol (0.5 mg/mL) which are 30 administered to determine maximum contraction and relaxation, respectively. If the: 1 tested in the absence of indomethacin (tonal preparation) decreases intrinsic tracheal tone, this l 3344 1 5 F/l alteration in baseline tone is taken into account and responses to antigen challenge are expressed as a percent of the new histamine maximum (histamine response plus the decrease in baseline tone).
Asthmatic Rat Assay Rats are obtained from an inbred line of asthmatic rats. Both female and male rats from 200 to 300 g are used.
Egg albumin (EA), grade V, crystallized and lyophilized, is obtained from Sigma Chemical Co., St.
Louis. Bordetella pertussis vaccine, containing 30 x 109 killed bacteria per ml is obtained from the Institute Armand-Frappier, Laval des Rapides, Quebec. Aluminum hydroxide is obtained from the Regis Chemical Company, Chicago.
The challenge and subsequent respiratory recordings are carried out in a clear plastic box with internal dimensions 10 x 6 x 4 inches. The top of the box is removable: in use, it is held firmly in place by four clamps and an airtight seal is maintained by a soft rubber gasket. Through the center of each end of the chamber a Devilbiss nebulizer (No. 40) is inserted via an airtight seal and each end of the box also has an outlet. A
Fleisch No. 0000 pneumotachograph is inserted into one end of the box and coupled to a Grass volumetric pressure tr~n~lu~er (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 P/l the recording of the respiratory patterns. For challenge, 2 ml of a 3% solution of antigen in saline is placed into each ne~ulizer and the aerosol is generated with air from a small Potter diaphragm pump 5 operating at 10 psi and a flow of 8 liters/minute.
Rats are sens it i zed by inj ect ing ( sub-cutaneously) 1 ml of a suspension containing 1 mg EA
and 200 mg aluminum hydroxide in saline. Simul-taneously, they receive an injection ( intra-10 peritoneally) of 0.5 ml of B. pertussis vaccine.They are used between days 14 and 18 postsensi-tization. In order to eliminate the serotonin t of the response, rats are pretreated intravenously 5 minutes prior to aerosol challenge 15 with 30 gm/kg methylserzide. Rats are then exposed to an aerosol of 3% EA in saline for exactly 1 minute, then their respiratory prof iles are recorded for a further 25 to 30 minutes. The duration of continuous dyspnoea is measured from the respiratory 20 recordings.
C, u.,ds are generally administered either intraperitoneally 1 hour prior to challenge or orally 1 and 1/2 hours prior to challenge. They are either dissolved in dimethylsulfoxide or aua~.,ded in 0.1%
25 methocel and 0 . 5% Tween 80. The volume injected is 2 ml/kg (intraperitoneally) or 10 ml/kg (orally).
Prior to oral treatment rats are starved overnight.
Their activity is deter~;ned in terms of their ability to decrease the duration of symptoms of 30 d~ oea in comparison with a group of vehicle-treated controls. Usually, a -. __u..d is evaluated at a series of doses and an ED50 is determined.
=

_ 1 3344 1 5 F/l This is def ined as the dose (mg/kg) which would inhibit the duration of symptoms by 50%.
PAF-Induced Hyperalqesia Assay Female Sprague-Dawley rats, 35 to 40 g are fasted overnight. Platelet activating factor, PAF, (L-lecithin B-acetyl O-alkyl) 1 llg/O.1 ml is given by subplantar injection in the rat paw. The - ,_ tl~ to be evaluated are homogenized in Aqueous Vehicle ( 0 . 9% benzyl alcohol, 0 . 5% Tween 80 and 0 . 4%
methylcellulose) and administered orally in a volume of 0.1 ml, 30 minutes prior to PAF.
Animals are tested 1, 2, 3 and 4 hours after PAF administration. The vocalization threshold, def ined as the pressure (mmHg) needed to evoke a squeak response, was recorded for both the injected and contralateral paw. I~o animal is subjected to pressure greater than 60 mmHg. Hyperalgesia is defined as a decrease in vocalization threshold as compared to a normal paw. Percent inhibition of hyperalgesia is calculated as the proportion of animals with vocalization thresholds greater than 200% of controls.
Brewer ' s Yeast Hyperalqesia Assay The standard method [Winter, C.A. et al., J.
Pharm. Exp. Ther . 150, 165-171 (1965) ] for yeast hyperalgesia is used. Female Spraque-Dawley rateæ, 35-40 g are fasted overnight. A 5% solution (volume 0.1 ml) of Brewer's yeast is injected into the rat paw. The compound is ~- ,. ; zed in aqueous vehicle and given orally 2 hours after yeast. Vocalization F/l thresholds are recorded 1 hour after drug (3 hours after yeast). Percent inhibition of hyperalgesia is determinPd by the proportion of animals with vocalization thresholds greater than 25 mmHg.
The magnitude of a prophylactic or thera-peutic dose of a compound of Formula I will, of course, vary with the nature of the severity of the condition to be treated and with the particular compound of Formula I and its route of administration.
It will also vary according to the age, weight and response of the individual patient. In general, the daily dose range for anti-asthmatic, anti-allergic or anti-inf lammatory 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.
The exact amount of a c i 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 the nature of the damaged cells (e.g., gastrointestinal ulcerations vs. nephrotic necrosis), and on the nature of the causative agent. An example of the use of a ~, ' of the Formula I in avoiding future damage would be co-administration of a ~ d of the Formula I with a non-steroidal anti-inflammatory drug that might otherwise cause such damage (for example, indomethacin). For such F/l use, the compound of Formula I is administered from 30 minutes prior up to 30 minutes after administra-tion of the NSAID. Preferably it is administered prior to or simultaneously with the NSAID, (for 5 example, in a combination dosage form).
The effective daily dosage level for compounds of Formula I inducing cytoprotection in mammals, especially humans, will generally range from about 0.1 mg/kg to about 100 mg/kg, preferably from 10 about 1 mg/kg to about 100 mg/kg. The dosage may be administered in single or divided individual doses.
The rhAr~ eutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a rhArr~ceutically acceptable 15 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 20 inorganic bases or acids and organic bases or acids.
Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic, manganous, potassium, sodium, zinc salts and the like. Particularly 25 preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from phAr-n^~eutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally 30 occurring substituted amines, cyclic amines and basic ion PYrhAn~E resins, such as arginine, betaine, caffeine, choline, N,Nl-dibenzylethylenediamine, `- 1 3344 1 5 F/l diethylamine, 2-diethylaminoethanol, 2-dimethylamino-ethanol, ethanolamine, ethylenediamine, N-ethyl morpholine, N-ethylpiperidine, glucamine, glll~os ne, histidine, hydrabamine, isopropylamine, S lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine and the like.
When the compound of the present invention 10 is basic, salts may be prepared from rh~rr~eutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzene-sulfonic, benzoic, camphorsulfonic, citric, ethane-sulfonic, fumaric, gluconic, glutamic, hydrobromic, lS hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric acid, p-toluenesulfonic and the like. Particularly preferred are hydrobromic, hydrochloric, phosphoric, 20 and sulfuric acids.
The compositions include compositions suitable for oral, rectal, topical, parenteral ( including subcutaneous, intramuscular, and intravenous), ocular (ophthalmic), p -l- ~ry (nasal 25 or buccal inhalation), or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently 30 presented in unit dosage form and prepared by any of the methods well-known in the art of pharmacy.

`- 1334415 F/l Dosage formæ include tablets, troches, dispersions, suspensions, solutions, capsules, creams, ointments, aerosols, and the like.
For use where a composition for intravenous 5 administration is employed, a suitable dosage range for anti-asthmatic, anti-inflammatory or anti-allergic use is from about 0.001 mg to about 10 mg (preferably from about 0 . 01 mg to about 1 mg) of a compound of Formula I per kg of body weight per day 10 and for cytoprotective use from about 0.1 mg to about 100 mg (preferably from about 1 mg to about 100 mg and more preferably from about 1 mg to about 10 mg) of a compound of Formula I per kg o~ body weight per day .
In the case where an oral composition is employed, a suitable dosage range for anti-asthmatic, anti-inf lammatory 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 cyto-protective use from about 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 _, d of Formula I per kg of body weight per day.
For administration by inhalation, the c~ of the present invention are conveniently delivered in the form of an aerosol spray presenta-tion from pressurized packs or a nebuliser, or as a powder which may be formulated as a cartridge from which the powder composition may be inhaled with the aid of a suitable device. The preferred delivery system for inhalation is a metered dose inhalation `- 1334415 F/l (Ml~I) aerosol, which may be formulated as a suspension or solution in fluorocarbon propellants.
Suitable topical formulations of Compound I
include tran~APrr?1 devices, aerosols, creams, 5 ointments, lotions, dusting powders, and the like.
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 10 ophthalmic formulation may be used.
In practical use, the - ~ ~ of Formula I
can be combined as the active ingredient in intimate admixture with a rhArr~eutical carrier according to conventional rhArr~eutical compounding techniques.
15 The carrier may take a wide variety of forms depending on the form of preparation desired for administration, e . g ., oral or parenteral ( including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media 20 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 25 as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations such as, for example, powders, capsules and tablets, with the solid oral 30 preparations being preferred over the liquid preparations. 3ecause of their ease of administration, tablets and capsules represent the F/l 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.
s In addition to the common dosage forms set out above, the ~, 'R of Formula I may also be administered by controlled release means andtor -delivery devices such as those described in U.S.
Patent Nos. 3,845,770; 3,916,899; 3,536,809;
3, 598 ,123; 3, 630, 200 and 4, 008, 719 .
Pharmaceutical compositions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets 15 or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion Dr a water-in-oil liquid emulsion. Such compositions may 20 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 consti-tutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and 25 intimately ~ ;ng the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if n~cess~ry, shaping the product into the desired presentation. For example, a tablet may be prepared by ~ ,~ession or molding, optionally with 30 one or more accessory ingredients. C _ esed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as ;

F/l 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 5 E .. '~Led ~ d 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 f rom about 2 . 5 to about 500 mg of the active ingredient.
The following are examples of representative rh~rr--eutical dosage forms for the compounds of Formula I:
Injectable 6uspension (I .M. ) mq/ml 15 C _ ~ul-d of Formula I 10 Methylcellulose 5 . 0 Tween 80 5 Benzyl alcohol 9 . 0 Benzalkonium chloride 1. 0 20 Water for injection to a total volume of 1 ml Tablet mq/tablet C _ 1 of Formula I 25 Mi~;.o~:Ly:.~alline Cellulose 415 25 Providone 14 . 0 Pregelatinized Starch 43 . 5 Magnesium Stearate 2 . 5 30 Capsule mq/capsule C __ ~1 of Formula I 25 Lactose Powder 573 . 5 Magnesium Stearate 1. 5 P/l In addition to the c,, '- of Formula I, the pharmaceutical compositions of the present invention can also contain other active ingredients, 5 such as cyclooxygenase inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac, dif lunisal and the like. The weight ratio of the c ,- ~ of the Formula I to the second active ingredient may be 10 varied and will depend upon the effective dose of each ingredient. Generally, an effective dose of each will be used. Thus, for example, when a ~, ~ of the Formula I is combined with an NSAID
the weight ratio of the , ~ld of the Formula I to 15 the NSAID will generally range from about looO :1 to about 1:1000. 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 20 should be used.
NSAIDs can be characterized into five groups:
(1) the propionic acid derivatives;
(2) the acetic acid derivatives:
(3) the fenamic acid derivatives:

(4) the biphenylcarboxylic acid derivatives:
and ( 5 ) the oxicams or a rhsrr~eutically acceptable salt thereof.
NSAIDs which are within the scope of this invention are those disclosed in EP 140,684.
phArr7^eutical compositions comprising the Formula I c , .u-lds may also contain inhibitors of the biosynthesis of the leukotrienes such as are disclosed F/l in EP 138,481 (April 24, 1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP 140,709 (May 5, 1985).
The ~ 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 10 such as those disclosed in European Patent Application Nos. 56,172 (July 21, 1982) and 61,800 (October 6, 1982); and in U.K. Patent Specification No. 2,058,785.
Pharmaceutical compositions comprising the 15 Formula I ~ , Ju-.ds may also contain as the second active ingredient prostaglandin ( including thr~ ' 9) antagonists such as those disclosed in EP 11,067 (May 28, 1980), EP 166,591 (January 1, 1986), or in U.S. 4,237,160. They may also contain 20 histidine decarboxylase inhibitors such as -fluoromethylhistidine, described in U.S.
~.,325,961. The - '- of the Formula I may also be advantageously combined with an Hl or H2-receptor antagonist, such as for instance benadryl, dramamine, 25 histadyl, phenergan, terfenadine, acetamazole, cimetidine, ranitidine, famotidine, aminothiadiazoles disclosed in EP 40,696 (De~ '~r 2, 1981) and like ds, such as those disclosed in U.S. Patent Nos.
4,283,408; 4,362,736; and 4,394,508. The pharma-30 ceutical compositions may also contain a K+/H+ATPase inhibitor such as omeprazole, disclosed in U.S.
., F/l Pat. 4,255,431, and the like. Another useful rhArr?ceutical composition comprises the Formula I
, u..~s in combination with serotonin antagonists such as methysergide, the serotonin antagonists disclosed in Nature, vol. 316, pages 126-131, 1985, and the 1 ike .
When the second active ingredient in compositions of this invention is a thr~ ` e synthetase inhibitor, such inhibitor can be as described in UK 2,038,821 (e.g., UK 37248 and dazoxiben hydrochloride), U.S.P. 4,217,357 (e.g., UK
34787), U.S.P. 4,444,775 (e.g., CGS 13080), U.S.P.
4,226,878 (e.g., ONO 046), U.S.P. 4,495,357 (e.g., U63557A) U.S.P. 4,273,782 (e.g., UK-38485), or EP
98,690 (e.g., CV-4151).
The combination compositions can be administered orally or other than orally: e.g., parenterally, by insufflation, topically, rectally, etc.; using appropriate dosage forms; e.g., tablets, capsules, suspensions, solutions, and the like, for oral administration; suspension emulsions, and the like, for parenteral administration; solutions for intravenous administration; and ointments, trAnsderr~l patches, and the like, for topical administration.
These compositions are formulated similarly to the compositions discussed above.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific ~( ' employed, the age, 13344~5 F/l body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
C, ~c of the present invention can be prepared according to the following methods.
METHOD A - From Non-indole Precursors a) Fischer Cyclization o R5 ~ R~ (CR2R2)n-E solvent >

Bnz ~or H) HCl I I Bnz = -CRlRl~ R7 R5 ~(CR2R2)n-E
Bnz (or H) I (or VII-a) These ~ (E= CO2R13, CH2OH, 30 CONR2R2, CONHSO2R9) are prepared utilizing standard Fischer Indole conditions. (See, for example, the review in "Heterocyclic C, u.-ds", 25, Parts I, II, and III, W.J. Houlihan, ed., Interscience, John Wiley & Sons, New York, 1979 . ) F/l - Thu8, treatment of the hydrazine II with the -heteroketone Ill in an alcoholic solvent at a temperature between 20C and the ref lu~ing temperature Of the solvent yields 1. Illustrative of 5 such alcoholic solvents are: methanol, ethanol, iso-propanol, tert-butanol, tert-amylalcohol and the like.
Where the substituent on the hydrazine nitrogen is H, this method yields C: -unds of the formula VII-a. 0 b) Via N-chloroanilines R~_INBnHz t-BUQCl > R~LBnCzl IV V

X ll R4 SR3 1) R \/\(CR )n R5~
2) Et3N R6 N (CR2R2)n-E
2 5 Bnz ~ (E e C02R 3 ) The N-chloroaniline V is formed ln situ 30 using t-butyl hypochlorite or some other chlorinating source. (See, P.G. Gassman and T.J. van Bergen, J.
Amer. Chem, SoC~ 95 590 (1973)). Reaction 4195P/llg3A - 32 _ 1 3344 1 5 17496IA
of y with the thioketone III at low temperature (-78C - -23C) and subsequent treatment with a trialkylamine base (such as triethylamine, diiso-propylethylamine, etc. ) affords the 3-thioindole I .
THOD B - From Indole Precursors a~ Metalated En: n~
R~A SMe R5~(CR R )n E VI
VI-a ~\ ~
~\ 2 ) R3 -s-s-R3 R (CR2R )n~E or H R3--S-so2R3 Yl or R3-S-Cl R5~J( R6~. N (CR2R2) E
. YII

t~344t5 Ftl Using the procedure of Method A, _ .u-~ds VI-a (which are representatives of ~1=~) are prepared, which can then be desulfurized with Raney nickel to yield indoles VI.
Deprotonation of indoles of the type VI at the nitrogen atom usinq a strong base (EtMgBr, MeMgBr, butyllithium, lithium diisopropylamide, potassium hexamethyldisilamide, etc. ) and reaction of the resultant salt with the appropriate thiolating 10 reagent affords the 3-thioindole VII. Use of the reagent R3SCl often proceeds spontaneously and a weak base such as triethylamine is necessary only to neutralize the HCl formed.
b) Alkylation at Nitro~en ~ / 1) Base/THF
R5t ¦ l ~ HMPA
R6~/\N (CR2R2)n-E 2) Bnz-Hal H (Hal = Cl, Br, I) VI I -a Deprotonation of _ _u--d VII-a (from Method 25 A) with base (lithium diisopropylamide, potassium hexamethyldisilamide, ethyl magnesium bromide, potassium hydride, etc. ) and reaction of the resultant anion with a benzyl halide or substituted benzyl halide gives I-133~4t~

c) SulfenYlation of R-BenzYlindoles S R5 ~3~ R --S--Cl Rj~s_R3 R6 N (CR2R )n~E R6 N (CR2R2)n-E
Bnz Bnz ~ I
Altt~rnatively, sulf ide derivatives of I can be prepared by the action at 0C to ref lus temperatures of substituted sulfenyl halides in the presence of a weak base on N-benzylindole derivative 15 2~ in solvent (such as methylene chloride or chloroform, 1,2-dichloroethane).
METHOD C - Functional Group Manipulations a) PreDaration of Sulfosides and Sulfones \~/\~;~ osidizinq aqent R6~ N (CR2R2)n-E
Bnz I

.- t3344~5 o 5 R5tO ¦ ll osidizin nt R6~V\N (CR2R2)n-E q aae >
Bnz I

R5 $i~
R6>~ ( cR2R2 ) n-E
Bnz I

Sulfoxide and sulfone derivatives of I can be prepared by using known osidizing agents such as 20 meta-chloroperbenzoic acid (m-CPBA), hydrogen peroside, peracetic acid, o~one and the like, on a sulfoside or sulfide precursor as illustrated in Method C(a). In a similar way, sulfo~ide and sulfone derivatives of intermediates such as VII can be 25 prepared. Either limiting the amount of o~idizing agent or monitoring the course of the reaction allows isolation of the sulfo~ides.
.

:- 1334415 F/l b) Alkylation at Carbon 5R5~(C R )n_lC E 1) Base Bnz H 2 ) R2-LG
-78 C - ref lus 1 (E = Co2R13, C02NR R , C~}O) R ~ X-R
15 R5~(CR2R2 )_C-E
Bnz R2 I -b Deprotonation at the carbon to the E
group can be carried out utilizing a strong base such as lithium or potassium diisopropylamide (or potassium he~amethyldisilamide or XEI) in an inert 25 solvent (e.g., tetrahydrofuran, ether, toluene, or mistures thereof) at temperatures from -78C to 0C.
Reaction of the resultant enolate with an alkylating reagent (R2-LG; LG=Cl, Br, I, O-tosyl, O-mesyl;
R2 is loweralkyl) at from -78C to the reflu~
30 temperature of the solvent gives the corresponding alkylated ~ _ ~u,.ds I-b.

- ` 1334415 F/l c~ O~cidation and Reduction of E
I-c 1) E= CO2R (iso-Bu)2Al--H o or E= CH2OH or CH
LiAlH4 10 2 ) E= CO2H BH3 THF/B ( OCH3 ) 3 or E= CH2OH
BH3-SMe2~B(OCH3)3 or 3 ) E= CH2OH pyridinium O
chlorochromate> E= CH
or Swern o_idation Mof f at o_idation 4 ) E= CH2OH Jones Reaaent ~ E= CO2H
or or O pyridinium dichromate C-H
OY;I1;7~d or reduced derivatives (I-c) of I
30 may be prepared by the above sequences.

- t334415 F/l d) PreDaration of Amides & Tetrazoles (E= C02H) (CO(LG ) )2 R5~(CR2R2) -C_LG2 or Bnz EtO-C-Cl/Et3N VIII (LG2 ~ LGl or (LGl=Cl or Br) O
OC-OEt ) 3 R4` X-R3 01 NH40H RS--~1 (CR R2) -C-NR2R2 d >
H2NR or Bnz (NR2R2 = NH2) HNR R IX (I) R ~ n--Bu3SnN3, R6~/ N (CR R )n-C_N or Bnz 3 ' (CR2R2)~ X
Bnz N
XI ( ~) P/l Formation of the activated carboxylic acid derivative VIII and reaction with ammonia gives the amide IX. This material can be dehydrated to give 5 the nitrile X which in turn affords the tetrazole XI
on treatment with various sources of azide. Both IX
and XI are representatives of structure I.
Et3N
VIII + R9S(0)2NH2 >
XIII

R~\~(CR R ~n-C-NHS(0)2R
Bnz Reaction of VIII with sulfonamide derivative XI I I in the presence of a weak base such as triethylamine affords the acylsulfonamide compounds 25 of I, It is deemed to be within the skill of those in the art to protect certain functional groups when employing these methods, as by the use of suitable blocking groups. It is also deemed to be within the 30 skill of those inthe art to convert certain functionalities to others ~t various stages of these ~195P~1193A - 40 -- 17496IA
methods by standard transformations such as hydrolysis, esterification, oxidation, reduction, and the 1 ike .
Referring to Methods A and B above, useful 5 benzyl halides (Bnz-hal, where Rl = Rl = H) are shown in Table 2:

0 Compound No. Hal R7 R8 r, ' Name 1. Cl q-Cl H q-chlorobenzyl chlorid~
(Aldrich Chem. Co.) 2. Cl q-OHe H ~ 1 chloride (Aldrich) 3. Cl Z-Cl q-Cl 2,q-dichlorobenz~l chloride (Aldrich) .

4. Br 2-Cl H 2-chlorobenzyl bromide (Aldrich) 5. Br 3-Cl H 3-chlorobenz~l bromide (Aldrich~

6. q-F 3-Cl H~ q-fluorobenzyl bromide (Aldrich) 7. Br q_CF3 H q-trifluorometh~Sbenzyl bromide (Aldrich) 1~34415 TA~' F 2 (C~ 'd.
Compound 5 No. Hal R7 R8 r. ' ~' a. cl 4-C02Me H 4-.d.; ~ 1 chloride (Journ. Amer. Chem. Soc., 1950, 72, SlSZ) 9. Cl 4-SMe H 4-methylthioben2yl chloride (Chem. Abstr. 56:4773 (~962) lû. Cl 4-S(O)Me H 4-methylsulfinylbenzyl chloride (C.A.:84:105277h (1976)) 11. Cl 4-5(0)2Me H 4-methylsulfonylbenzyl chloride (C.A.:78~ 325 q (1973)) 20 12. 3r 4-No2 H 4-nitrobenzyl bromide (Aldrich) 13. Cl 4-CONMe2 H 4-dimethylcarbo~amidobenzyl chloride 14. Cl 4-5(0)2NMe2 H 4-dimthylsulfamoylbenzyl chloride (C.A. 84:1354a4, (1976)) lS. Cl 4--C02H H 4--ca~L ~' ~1 chloride (~ldrich) 30 16. Cl 4-COMe H 4-acetylbenzyl chloride (C.A. :93:230û04: ( 1980) ) Other l-benzyl phenylhydrazines of Formula II prepared by the methods of Preparations 1 and 2, are shown in Table 3.

1-Benzvl Phenylhydrazines Compound . R R R R R Rl Rl r .
1. Z-Me,H,H 4-Cl ,H H,H 1-(4-chlorobenzyl )-l-(Z-methyl phenyl ) hyd raz i ne hydrochl ori de z. 3-F,H,H 4-Cl,H H,H 1-(4-chlorobenzyl)-1-(3-fluorophenyl )hydrazine hydrochloride 3. Z,4-Clz,H 4-Cl ,H H,H 1-(4-chlorobenzylû-l_(Z,4-dichlorophenyl)hydrazine hydrochl ori de 4. 4-F,H,H H,H H,H l-(benzyl-1-(4-fluorophenyl )-hydrazine hydrochloride 5. 4-F,H,H 4-ûMe,H H,H 1_(~ - yl )-1-(4-2 5 f 1 uorophenyl ) hyd raz i ne hydrochl ori de 6. 4-F,H,H 3,4-Clz H,H 1-(3,4-dichlorobenzyl )-1-(4-fluoro-phenyl)hydrazine 3 0 hyd rochl ori de 7. 4-F,H,H H,H CH3,H l-[l-(phenyl)ethyl]-1-(4-fluorophenyl )hydrazine hydrochl ori de - `
13344t5 F/l TABLE 3 (Cont.d) l-Benzyl ph~nvl hYdr~~i nes Compound No. R R R R R Rl R1 r, ~ Name B. 2-F,H,H 4-Cl,H H,H 1-(4-chlorobenzyl~-1-)2-0 fluorophenyl)hydrazine hydrochl ori de 9. 4-CF3,H,H 4-Cl,H H,H 1(4-chlorobenzyl)-1-(4-trifluoromethylphenyl )_ hydrdzine hydrochloride lû. 4-SMe,H,H 4-Cl,H H,H 1-(4-chlorobenzyl)-1-(4-methylthiophenyl)hydrazine hydrochl ori de 11. 2-CH(Me)2, 4-Cl,H H,H 1-(4-chlorobenzyl)-1-(2-iso-propyl phenyl )hydrazi ne hydrochl ori de :- 1334415 The following abbreviations have the indicated meanings:
Me = methyl Bz = benzyl Ph = phenyl t-Bu = tert-butyl i-Pr = isopropyl c-C6Hll = cyclohexyl c-Pr = cyclopropyl c- = cyclo Ac = acetyl Tz = 5-tetrazolyl The following compounds (Table 1) are within the scope of the invention:

Novel 3-Hetero-substituted-N-benzyl-indoles R~X l~3 Bnz F/l 6IA

X ~
V = ~, N o~ O
~y ^~r~ ~ =~
-- ,0, 0 =~ 1 =N
~C~ = = = = = = = = =
U.ly = = = = = = = = =
~D: ~ C r ~

- ` 1334415 X Vl ~, O oN
IAI oN oN N N N N N N N
N~ --~" N N N
Ne = N N N ~, G
U~ = = = = = = = = =
G", I I ~ V , I
~Y G G 5 G G C C S G
m~, ~, _ I ~ m m m m 1~1 ~ O _ N ~ ~ D 1~ Q

:- 13344~5 XV> % % V~ ~ .~ V~ % %
O O O O O O O O O
~0~ = = = = = = = = =
U~ = = = , = = = = =
- L L L L ~ L
_.
C
I-- 1. _ ~1 ~I N ~ 1 N ~1 N

F/l X Vl o o o o .~ Vl V~
4- o o o o o =N Z =O
o C^ ~ ~ ~ N N ~N
N~ ^~, ,_, =N =N _~, _:~1 N
Y
1~7 = = . = = = = = =
. I ._ C Q 71 Q ~ Q Q Q ID ~
LJ Q _ _ _ _ -- -- -- --10 ~ Q C ~ _ N ~ er ~ ~D

V) ~" Vl C = =
,. ., ~ ~, Z o o N-- = _ _ _1 _N = =~ ~N _ _ ~
~Dc~ = = = = = = =
= = = = = = = = =
C C
C ~ C C C C C
._._ ._ ._ ._ ._ ._ , :~1 , N
C~ 0 0~ ~ ~
~L .. C IJ L~ I.J 1~ L
N N ~ ~ Q ~ ~ N
~ ~ ~ ~ ~ I I ~r c c ~
~o X o~ C ~ ~ ~

F/l X V- ~> O oN
. LIJ ON ~ N N oN oN oN N oN
N ~ ~ -- " V
~O = = = = = = = = =
= = = = = = = = =
N I N N N
L ~ L =~ N N ~N
N
~` ~ ~` c el~ c e:r er X ~ U~ N

4195P/1193A - Sl - 17496IA
X (~ N o O ", Vl 3 V~
h~ oN N N oN N N oN oN o~
N ~
~Dy _ = = = = = = = =
L C, C ~
._ , g~ ~, I _ ~ ' N N N , I E I C
G ~ ~ ~ 3 y7 ~D U~ 3 ' C~ _ N

t ~ ~ 4 4 t 5 X V~ o o o 1-1 oN oN oN oN oN N N N oN
N -- _ q _ ~ _ ~ ~ ." --," --Ny ~ ~, N _N
~Oy .y L L L L L L
,/~ C C
y y . , N N 3 3, Y ~ ~ ~ ~ V V ~ ~ ._ V o~ V V V V V V V V
-- N

t 3344l 5 F/l 4195P/1193A - ~3 - 17496IA
N C`J oN
X V) ," V~
hl oN N N oN oN N oN N oN
N _ ~ ~1 _" ^~, ~ ~ ~N N
Ncy ~ N
~IY = = = = = I = ~o r 1~'1~ = = = = = = = = =
~ L
C ~ ~ C C C
C ~I C C ~ I
m ~ 7 ~ _ ~ I m O m ~ c ~ m ~ m c m m _ 13344l5~
F/l XV~ G O V~ Vl V) Vl V~
1.1 oN N N oN N N N N oN
N~ N N =~
G G G
`C = C
U.y L ~ L L L L L
L ~ C, C~ G ~. 5 ~ ~
._ ._ 0~
C C e~
~ G =N I ~ =N
CC C I ~L I I Z Z
N
N ~ I ~o ~ " ~ m In Q
~ ¢ C~ O
3ID ~ G ¢I C_ C~ CD ~ CT~

t 3344 1 5 5~ ~ Vl " V~
N ='`J = =~, N
C ~ _ ~ _ _ _ _ ~
N : -- -- -- (J
~Oy ._ 0~ 0~ =
~ L
_ I _ ~ ,~ Z
", G Z
^. N :~1 c 3 ~ N ~ ~I ~I r~l n ,~ G C~

~33~41~

X Vl V~ O N
--N ~ N ~ ~ oN
_N ~ N N TN
l.J N N N N =N N =N
~ N N N N N ~I N N N
N G (J ~ ~N N N
~ = = = = = = = = = T
U~a = = = = = = T = = = =
._ ._ _ _ ._ ._ ._ c~ ~ m ~ , c ~
~ i o N o C Ir) o G o ~ O
~ 1,1 _ _ _ _ _ _ 133~4t5 -F/l N N
Vl VOl ~ V~ O O
=N = = = = =N =N N N
N _ _ q _ ~ ^", --~ _ N
_N _~ =N , N ~N ~ =N _`~ , N
`a: = = = = = = = = r- =
Ul = = = = = = = r~ ~ =
C C C C C ~ C C C C
c c ~n . ~ ~ LJ
C I I I oN N
N Iq ~ ~ `D 1` ~ ` N

t3-3~15 F/l 4195Ptll93A - 58 - 17496IA
X V~ ~7 QN ~ Q oN
, N
_N _N

8 --N _N oN 8N 8N 8N 8N 8N 8N 8N
=N
~I N ~ I N ~ N N
N _ ~ =Q ^ ." =N
/J _N =N _N =N _N , N _N =N _N =N _N
~D~ = = = = = = = = = = =
-- O
v~ 8 C ~ C
U~ "-, I I I I , , , , _ U~
_N
C ~ .~ ~. .~ ~ _. ~ N ~ ..
N I ~ ~ Q I Q m "
~ _ N N N N N N N

13344t5 -F/l 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.

PREPARATION OF STARTING MATERIALS
Preparation 1 l-(p-chlorobenzyl ) -1-[ 4-( i-propyl )phenyl ]hydrazine 10 hydrochloride Method A
A mixture of 17 . 9 g of 4-1so-propylphenyl hydrazine, 300 mL of dry toluene, 19.1 g 4-chloro-15 benzyl chloride and 1.16 g tetra-_-butylammonium bromide was heated at ref lux f or 4 h . The reaction mixture was then cooled to room temperature, diluted with ether and 0.1 N NaOH (100 mL) added. The organic layer was separated, washed with water and 20 brine and dried over MgSO4. Filtration and concentration in vacuo gave an orange oil. This material was dissolved in a 2 :1 mixture of hexane-ether and treated with dry HCl gas. Collection of the resultant solid by vacuum filtration gave the 25 title ~ d, which was used as such in subsequent reactions .
Method B
A dry 5 1 flask, equipped with mechanical 30 stirring and a nitrogen inlet, was charged with 4-isopropylphenylhydrazine hydrochloride ( 186 . 6 gm, mol ) and toluene ( 1. 2 1 ), then f lushed with nitrogen. Triethylamine (202 gm, 2 mol), t ~344 t 5 tetra-n-butylammonium bromide ~10 gm, 0.03 mol) and 4-chlorobenzyl chloride (160 gm, 1 mol) were then added and the mixture heated at ref lux for 4 h. The reaction was allowed to cool to room temperature, 5 f iltered, then concentrated to about 600 ml to remove residual triethylamine.
Toluene ( 2 . 5 1 ) and ether ( 1. 2 1 ) were added, the mixture cooled to 0C, then treated with a solution of HCl (1 mol) in toluene. The resultant 10 hydrochloride salt was allowed to crystalize overnight at 0C and suction filtered. Washing with ether and drying (25C/0.4 torr) yielded the title product .
Preparation 2 l-(p-chlorobenzyl )-1-[ 4-(t-butyl )phenyl ]hydrazine hydrochloride Step 1: A mixture of 51 g tert-butylaniline, 700 mL
20 toluene and 53 g 4-chlorobenzaldehyde was heated at reflux with removal of water. After 1 h the solvent was removed in vacuo and replaced with 800 mL of dry tetrahydrofuran. A solution containing 21. 5 g of sodium cyanoborohydride in 100 mL of methanol was 25 then added and the resultant mixture acidif ied by the slow addition of acetic acid (20 mL).
After stirring overnight the reaction mixture was cooled to 0 and excess 3 N hydrochloric acid added. The resultant precipitate was collected 30 by vacuum filtration, washed twice with ether and dried in vacuo to yield N-(p-chlorobenzyl)-4-t-butyl-aniline hydrochloride salt.

'- 1334415 F/l Step 2: A suspension of 50 g of the hydrochloride salt from Step 1, 500 mL water, 250 mL ether and 170 mL of 1 N hydrochloric acid was treated with a solution of 12.3 g sodium nitrite in 50 mL of water.
5 After stirring for 2 h at room temperature the reaction mixture was extracted twice with ether. The combined extracts were washed with water and dried over MgSO4. Filtration and concentration gave N-nitroso-N-(p-chlorobenzyl )-4-t-butylaniline .
Step 3: A cold (0), stirred mixture of 25 g of the nitroso derivative from Step 3 and 500 mL tetrahydro-furan, under nitrogen, was treated with 285 mL of a 1 M solution of diisobutylaluminum hydride in toluene.
15 Stirring was continued at room temperature for two days then at reflux for 4 h. The reaction mixture was cooled and carefully poured into dilute hydro-chloric acid. The resultant mixture was extracted with ethyl acetate (3x) and the combined extracts 20 were evaporated to dryness. The material thus obtained was dissolved in a mixture of hexane and ethyl acetate ( 1:1 ) and treated with dry HCl gas .
Collection of the resultant solid by vacuum filtra-tion gave the title ~- _ u~-d, which was used without 25 further purification.
Additional hydrazine starting materials are known; e.g., see Example 1 of EP 166,591.
Preparation 3 30 1-(p-chlorobenzyl)-1-(4-biphenyl)hydrazine hydro-chlor ide Following the procedure of Preparation 2, but using 4-aminobiphenyl as the starting material, the title cl _ 1 was obtained.

13344~5 F/l Prepar at ion 4 ~-Hetero-l~etone Startinq Materials A . Methyl 2, 2-Dimethyl-4-oxo-5-phenylthiopentanoate 5 ( C~
Step 1: A stirred solution containing 10 g of 2,2-dimethyl-4-oxo-pentanoic acid in 200 mL of dry methanol was treated with 3 . 75 mL of bromine dropwise 10 over a 15 min period. The mixture was then stirred at room temperature for 2 h and at reflux for 2 h.
After cooling to room temperature, water and solid sodium bicarbonate were added and the mixture diluted with ethyl acetate. The organic layer was separated 15 and washed with brine and dried over MgSO4.
Filtration and concentration gave an orange oil which was redried in ether over MgSO4. Isolation and distillation (87-95, 1.3 torr) gave methyl 5-bromo-2, 2-dimethyl-4-oxopentanoate .
I~ (film) 2958, 1772 and 1720 cm 1;
H NMR (250 MHz, CDC13) 6 1.26 (s, 6H), 2.93 (s, 2H), 3.67 (s, 3H), 3.86 (s, 2H).
Step 2: To a cold (0), stirred suspension of sodium hydride (365 mg) in 66 mL dry tetrahydrofuran, under nitrogen, was added 1.4 g thiophenol. Stirring was continued at 0 for 30 min. and at room tempera-ture for 30 min. The resultant white suspension of sodium thiophenoxide was cooled to -78 and a solution containing 3.0 g of methyl 5-bromo-2,2-dimethyl-4-oxopentanoate from Step 2 in 10 mL dry tetrahydrofuran was then added. The reaction mixture was stirred at -78 for 15 min. and at ambient F/l temperature for 6 h then quenched with saturated aqueous ammonium sulfate. Ether was added, the organic layer separated and washed with water (2x) and brine and dried over MgSO4. Filtration and 5 cuc~ ation gave a yellow oil which was purified by flash chromatography on silica gel. Elution of the column with a 4 to 1 mixture of hexane and ethyl acetate gave the title product.
IR (film) 3040, 2960, 1721 and 1145 cm 1;
lH IlMR (250 MHz, CDC13) ~ 1.18 (s, 6H), 2.91 (s, 2H), 3.60 (s, 3H), 3.63 (s, 2H), 7.13-7.35 (m, 5H) -B. Other a-Hetero-Ketones Using procedures analogous to those above, the hetero-ketones 2-10, 12, and 14-21 of Table 4-1 were prepared.
C. Methyl 5-methoxy-4-oxopentanoate (Compound 13) To a solution of 6 . 75 g ( 0 . 05 mole) of methyl (3-chloroformyl)propionate in 150 ml diethyl ether, was added O . 075 mole diazomethane in ether at OC. The reaction was stirred at room temperature for 3 hours, after which it was treated with 2 ml glacial acetic acid. 40 ml of a 1:1 solution of anhydrous methanol and ether were added dropwise.
The solvents were removed after 24 hours by vacuum distillation and the product was isolated by passage through a small silica gel column, followed by short-path vacuum distillation ( 1 mm Hg, 60-80C) .
C ~ -d 11 of Table 4-1 was prepared by an analogous procedure.

`` - 1 3344 1 5 F/l D . Methyl 5-t-Butylthio-2, 2-dimethyl-4-oxopentanoate u..d 6 ) SteP 1: A 5 L 3-necked flask equipped with an air driven stirrer, pressure equalizing addition funnel, and nitrogen inlet was charged with diisopropylamine (136 gm, 1.34 mol) and dry tetrahydrofuran (1.5 1). The mixture was cooled to 0C and a 1. 6M solution of butyl lithium in hexane (800 ml, 1.28 mol) was then added over a 30 min period and stirring was continued for an additional 15 min.
The resultant solution of lithium diisopropylamide (1.28 mol) was then treated with a solution of ethyl isobutyrate ( 134 gm, 1.16 mol) in 300 ml of dry tetrahydrofuran over a period of 1 h. The reaction mixture was then allowed to warm to room temperature and stirred for 18 h.
2,3-Dichloro-l-propene (142 gm, 1.28 mol) was then added at oC and the resultant solution stirred at room temperature for 6 h.
The reaction mixture was then cooled to 0C, quenched with saturated a~ueous ammonium chloride, and diluted with ethyl acetate (approx. 2 L). The organic layer was separated, washed with lN HCl (1 L), water (2 x 500 ml), brine (1 L) and dried over MgSO4. Filtration and concentration gave a brown oil which was purified by ` - 1 33441 5 F/l distillation (bp 69-78C, 20 Torr) to give 200 gm (90%) of pure (250 MHz NMR) ethyl 4-chloro-2, 2-dimethyl-4- pentenoate .
5 steP 2: A 3 L 3-necked f lask, equipped with a magnetic stirrer and thf Ler, was charged with 4-chloro-2, 2-dimethyl-4-pentenoate from step 1 (1.5 mole), methanol (1.13 L), and water (0.37 L) and cooled to 0C . Bromine ( 1. 55 mole) was then added dropwise over a 1 h period. The resultant yellow solution was then stirred at room temperature for 90 min. Ethyl acetate (4 L) and water were added. The organic layer was separated, washed with water, lN NaOH (3x), water and brine and dried over MgSO4.
Filtration and concentration gave a yellow liquid which was purified by distillation (bp 83-112, 1.2 Torr) to afford 284 gm of a colorless oil. This material was shown by lH I~MR to contain a mixture of methyl 5-bromo-2, 2-dimethyl-4-oxopentanoate ( 90%) and 5-chloro-2,2-dimethyl-4-oxopentanoate ( 10% ) and was used in the next step without further purif ication .
steP 3: To a cold (0C) stirred solution of the bromoketone from step 2 (1.17 mole), in 800 mL of dry tetrahydrofuran, were sequentially added 2-methyl-2-propylthiol ( 1. 23 mole) and triethylamine (1.41 mole). The reaction mixture was then allowed to warm to room temperature. After 18 h, ~thyl acetate - t 3344 ~ 5 F/l (2.5 L) was added and the mixture washed with water, lN HCl (2x), water and brine and dried over MgSO4. Filtration and concentration afforded a pale yellow oil which, after distillation (110-132C, 1.0 Torr ), gave the title product .

F/l a-Hetero-Ketones S O

R3-X~ ( CR R ) C-OR

Compound No. R3 -(CR R ) ~ X R13 Compound Name 15 2 M~ -(CH2)- 5 Et Ethyl 4-methylthio-3-oxo-butano2te 3 Ph -(CH2)- S Et Ethyl 3 1 1 ;' Jlthio butanoate 4 Me -CH2C(CH3)2- 5 Me Methyl 2,2-dimethyl-5-methyl thi o 1, 5 Ph -CH2C(CH3)2- 5 Me Methyl 2,2-dimethyl-4-oxo-5-phenyl th i opentanoate 6 t-Bu -CH2C(CH3)2- 5 Me Methyl 5-t-butylthio-2,2-dimethyl ~:, ' '~
30 7 Me ( 2)2 Me Methyl S-methylthio 1-oxo pentanoate 13344~5 F~2 4195P/llg3A -- 68 -- 17496IA
~ABLE 4-1 ( cont ' d ) Compound No. R3 -(CR R ) - X R Compound Name 8 Ph -(CHz)z- S Me Methyl 4-oxo-S-phenylthio pentanoate 9 Ph -(CHz)zC(CH3)z- 5 Me Methyl 2,2-dimethyl-5-oxo-6-phenylthiohexanoate 15 10 Ph -CH2C(CH3)2- 0 Me . Methyl 2,2-dimethyl-4-oxo-S-phenoxypentanoate ll Me -CH2C(CH3)2- 0 Me Methyl 2,2-dimethyl-S-methoxy-4-oxopentanoate 12 Ph 2 2 Me Methyl 4-oxo-S ;' ~r~ anoate 13 Me -(CHz)z- 0 Me Meth~l S ~ anoate 25 14 CHz-c-Pr -CH2C(CH3)z- 5 Me Methyl Z,Z-dimethyl ~-oxo-S-(l-cyclopropylmethylthio~pentanoate 15 CH2-c-C6H -CH2C(CH3)2- 5 Me Methyl 2,2-dimethyl ~-oxo-S-( 1 -cycl ohexyl methyl th i o ) pentanoate 16 S-Cl-benzo- -CH2C(CH3)2- 5 Me Methyl 2,2-dimethyl-4-oxo-S-thiazol-2-yl (S-chlorobenzothiazol-2-ylthio)-pentanoate `- 1334415 TABLE 4-1 (cont'd) 5 Compound tlo. R -(CR R2) ~ X R13 Compound Name 17 _CH2CH2CH=CH2 -~H2~( 3 2 Me Methyl 2,2-dimethyl-4-oxo-S-(1-buten-4-ylthio)pentanoate IB t-eu -CH2C-(CH2)3-CH2 S Me Methyl 1-[3-(t-butylthio)-2-oxo- prop-l -yl ] cycl opentane carboxyl ate 19 Bz -CH2C(CH3)z- 5 Me Methyl 2,Z-dimethyl-4-oxo-S-(benzyl-thio)pentanoate 2~ n-Bu -CH2C(CH3~2- 5 Me Methyl 2,2-dimethyl-4-oxo-5-(butyl-thio jpentanoate 21 2-(i-C3H7)c6H4 -~H2C( 3 2 Me Methyl 2,2-dimethyl-4-oxo-S-(2-i-propylphenylthio)pentdnoate _ ~334415 F/l Preparation 5 Ethyl 5-chloro-3-phenylthioindole-2-carboxylate To a cold (0), stirred solution of ethyl 5-chloroindole-2-carboxylate (223 mg) in 4 . 5 mL dry 5 tetrahydLoruran~ under argon, was added 0 . 55 mL of a solution of ethylmagnesium bromide in ether. The resultant mixture was stirred for 30 min then cooled to -78. Solid S-phenyl benzenethiosulfonate (300 mg) was added and the mixture stirred at -78 for 30 10 min and 0 for 1 h. The mixture was then diluted with ether and saturated aqueous ammonium chloride added. The organic layer was separated, washed with water and brine and dried over MgSO4. Filtration and concentration gave a yellow oil which was 15 purified by flash chromatography on silica gel.
Elution with hexane-ethyl acetate (85:15) gave the title product.
IR (KBr) 3340, 3060, 2994, 1680, 1508, 1263 and 738 cm 1;
lH NMR (250 MHz, CDC13) ~ 1.28 (t, 3H, J = 7 Hz), 4.39 (q, 2H, J = 7 Hz), 7.08 - 7.24 (m, 5H), 7.27 (dd, lH, J = 9 and 2 Hz), 7.39 (d, lH, J = 9 Hz), 7.60 (d, lH, J = 2 Hz).
Preparation 6 5-Chloro-3-phenylthioindole-2-carboxylic acid To 57 mg of ethyl 5-chloro-3-phenylthio-indole-2-carboxylate from Preparation 5 in 1. 7 mL of dry tetrahydrofuran, under argon, was added 48 mg of solid potassium trimethylsilanolate. The resultant 30 mixture was stirred at room temperature for 20 h.
Ethyl acetate and 1 N HCl were then added. The organic layer was washed with brine (2x) and dried F/l over MgSO4. Filtration and concentration gave a yellow gum which was triturated with ether-hexane to give the title compound.
lH NMR (250 MHz, CDC13) ~ 7 . 09 - 7 .18 (m, 3H), 5 7.20 - 7.25 (m, 2H), 7.30 (dd, lH, J = 8.6 and 2.0 Hz), 7.43 (d, lH, J = 2.0 Hz), 7.52 (d, lH, J = 8.6 Hz) .
Preparation 7 4-Methylthiophenyl hydrazine hydrochloride 4-Methylthioaniline ( 13 . 9 g) was added dropwise to cold HCl (6N, 50 mL) and stirred for 5 15 min in an ice bath. A solution of NaNO2 in water (7.25 g, 15 mL) was then added dropwise and stirred for 15 min. The cold diazonium salt was then cannulated into a stirred cold solution of Na2S2O4 in water (50 g, 250 mL). After 20 min, 20 ether (200 mL) was added and the reaction mixture basif ied with NaOH ( 10N) . The ether layer was decanted, washed with brine, dried over Na2SO4 and HCl gas was passed through the ether solution to form the hydrochloride salt which precipitated out.
25 After filtration, there was obtained pure title product .
The following phenyl hydrazines were similarly prepared:
2-i60propylphenylhydrazine hydrochloride 2-methylthiophenylhydrazine hydrochloride 2,4-dimethylphenylhydrazine hydrochloride 4-methoxy-2-methylphenylhydrazine hydrochlor ide F/l Other phenylhydrazines can also be prepared by the method described by Demers and Klaubert, Tetrahedron Letters, 28, 4933 (1987).
5 PKEPARATION OF FINAL ~KO~U~:LS

Ethyl l-(p-chlorobenzyl)-5-chloro-3-thiophenylindole-2-carboxylate To a cold (-78); stirred solution containing 664 mg of ethyl 5-chloro-3-thiophenylindole-2-carboxylate from Preparation 5 in 3.5 mL of dry tetrahydrofuran, under argon, was added 3 . 5 mL of a 0 . 62 M solution of potassium hexamethylsilamide in toluene. The reaction mixture was stirred at -78 for 1 h and at 0 for 1 h then recooled to -78.
0.75 mL of E~-chlorobenzyl chloride, 1.0 mL of hexamethylphosphoric triamide and 20 mg of tetra-_-butylammonium bromide were then added. The resultant mixture was allowed to warm to room temperature and stirred for 18 h. Saturated aqueous ammonium chloride and ether were added. The ether layer was separated, washed with water, 10% aqueous cupric sulfate, water and brine and dried over MgSO4.
Filtration and concentration gave a solid which was purified by flash chromatography on silica gel. Elution of the column with a mixture of hexane-ethylacetate (9:1) gave the title product, mp 95 . 5-96 .

F/l Analysis calculated for C24HlgC12NO2S:
C, 63.16; H, 4.20; N, 3.07.
Found: C, 63.35; H, 4.44; N, 3.01.

EX~MPLE 2 l-(p-Chlorobenzyl)-5-chloro-3-thiophenylindole-2-carboxyl ic ac id Following the procedure of Preparation 6, 10 but using ethyl 1-(p-chlorobenzyl)-5-chloro-3-thio-phenylindole-2-carboxylate from Example 1 as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 185-188 (dec. ) .

Ethyl l-(p-Chlorobenzyl ) -5-f luoro-3-methylthio-indole-2-acetate To 2 . 40 g of ethyl 4-methylthio-3-oxobutano-ate in 35 mL tert-butanol was added 4.30 g of 2 0 l-p-chl orobenzyl ) -1- ( 4-f luor ophenyl ) hydr az ine hydrochloride . The reaction mixture was ref luxed under nitrogen for 16 h. The reaction mixture was then evaporated to dryness and the residue suspended in ether. The ether layer was washed with 1 N HCl 25 (2x), water and brine and dried over MgSO4.
Filtration and concentration gave a pale yellow oil which was purified by flash chromatography on silica gel. Elution of the column with a mixture of hexane-ethyl acetate (85:15) gave the title compound as a solid, mp ~18-119.

F/l l-(p-Chlorobenzyl ) -5-f luoro-3-methylthioindole-2-acetic acid Following the procedure of Preparation 6, 5 but using ethyl 1-(p-chlorobenzyl)-5-fluoro-3-methylthioindole-2-acetate f rom Example 3 as the starting material and tetrahydrofuran as the solvent, the title compound was prepared, mp 154-155C (dec . ) .

l-(p-Chlorobenzyl)-5-fluoro-3-methylsulfonylindole-2-acetic acid To 200 mg of 1-(p-chlorobenzyl)-5-fluoro-3-methylthioindole-2-acetic acid from Example 4 in a 15 mixture of 3 mL water and 3 mL ethanol was added 1. 6 g of oxone. After stirring for 6 h the reaction mixture was diluted with brine and ether. The ether layer was washed with 1 N HCl, and brine and dried over MgSO4. Filtration and concentration gave the title compound, mp 202-202 . 5 .

l-(p-Chlorobenzyl ) -5-f luoro-~-methyl-3-methylthio-indole-2-acetic acid Ste~ To a cold (-78), stirred solution of 560 mg of ethyl l-(p-chlorobenzyl)-5-fluoro-3-methylthio-indole-2-acetate from Example 3 in 6 . 75 mL dry tetrahydrofuran, under argon, was added 2. 72 mL of a 0 . 63 M solution of potassium hexamethyldisilazide in toluene. After 2 h at -78, 123 IIL of methyl iodide was added and the mixture stirred at -78 for 30 min and 0 for 1 h. 10% aqueous sodium bisulfate ` - 1 3344 1 5 F/l and ether were then added. The organic layer was separated, washed with 10% aqueous sodium bisulfate, water and brine and dried over MgSO4. Filtration and concentration gave a pale yellow oil which was 5 purified by flash chromatography on silica gel.
Elution with a mixture of hexane-ethyl acetate (85:15) gave an indole derivative, mp 131-132.
steP 2: Following the procedure of Preparation 6, 10 but using ethyl l-(p-chlorobenzyl )-5-f luoro--methyl-3-methylthioindole-2-acetate from Step 1 as starting material and tetrahydrofuran as solvent, the title , ~ was prepared, mp 136-140.
15 Analysis calculated for ClgH17ClFNO2S:
C, 60.39; H, 4.53; N, 3.71 Found: C, 60.13; H, 4.57; N, 3.65 20 1-(p-Chlorobenzyl)-,a-dimethyl-5-fluoro-3-methylthioindole-2-acetic acid Following the procedure of Example 6, but us ing ethy 1 1- ( p-ch l o r obenzyl ) - 5 - f 1 uo r o--methy 1-3 -methylthioindole-2-acetate, from Example 6, Step 1, 25 as the starting material and tetrahydrofuran as solvent the title ~ d was prepared.
IR (KBr) 3430, 1708, 1482 and 1167 cm 1;
H NMR (250 MHz, CDC13) ~ 1.81 (s, 6H), 2.29 (s, 3H), 5.35 (s, 2H), 6.82 (d, 2H, J = 8.4 Hz), 6.85 (m, 2H), 7.22 (d, 2H, J = 8.4 Hz), 7.46 (d, lH, J =
9,5 Hz).

F/l l-(p-Chlorobenzyl )-5-f luoro-3-phenylthioindole-2-acetic acid Following the procedures of Examples 3 and 5 4, but using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)-hydrazine hydrochloride and ethyl 3-oxo-4-phenyl-thiobutanoate as the starting material, the title compound was prepared, mp 167 . 5-168 . 5 .
Analysis calculated for C23H17ClFN02S:
C, 64.86; H, 4.02; N, 3.29.
Found: C, 64.72; H, 4.21; N, 3.15.
EX~MPLE 9 15 l-(p-Chlorobenzyl ) -5-f luoro-a-methyl-3-phenylthio-indole-2-acetic acid Following the procedure of Example 6, but using ethyl l-(p-chlorobenzyl )-5-f luoro-3-phenylthio-indole-2-acetate (Example 8, Step 1) as the starting 20 material and tetrahydrofuran as the solvent, the title compound was prepared, mp 80-82.

l-(p-Chlorobenzyl ) -3-phenylthio-5-( i-propyl ) -indole-2-25 acetic acidstel~ 1: To 229 mg of ethyl 3-oxo-4-phenylthio-butanoate in 3 mL of t-butanol was added 300 mg of l-(p-chlorobenzyl ) -1-( 4-i-propylphenyl )hydrazine hydrochloride . The reaction was ref luxed under 30 nitrogen for 2 h. The reaction mixture was then evaporated to dryness and the residue suspended in ether , washed with water , 1 N HCl ( 2x), water and - ` 1 33441 5 F/l brine and dried over MgSO4. Filtration and Cu..Le.,L~ation gave a yellow oil which was purified by flash chromatography on silica gel. Elution with a mixture of hexane-ethyl acetate (85:15) gave ethyl 5 l-(p-chlorobenzyl ~-3-phenylthio-5-( i-propyl ) -indole-2-acetate as a solid.
Analysis calculated for C28H28O2ClNS:
C, 70.35; H, 5.90.
Found: C, 70.69; H, 6.20.
Step 2: To 100 mg of the ethyl ester from Step 1 in 1. 0 mL tetrahydrofuran and 0 . 5 mL methanol was added 0 . 5 mL of 2 . 0 N LioH at room temperature . After 45 15 min 1 N HCl and ethyl acetate were added. The organic layer was separated, washed with brine and dried over MgSO4. Filtration and concentration gave the title compound as a white solid which was triturated with hexane and filtered, mp 151-153.
Analysis calculated for C26H24ClNO2S:
C, 69.39; H, 5.38; N, 3.11 Found: C, 69.18; H, 5.42; N, 3.04 l-(p-Chlorobenzyl )-a-methyl-3-phenylthio-5-( i-propyl ) -indole-2-acetic acid Step 1: Following the procedure of Example 6, Step 1, but using ethyl 1-(p-chlorobenzyl)-3-phenylthio-5-(i-propyl)-indole-2-acetate (Example 10, Step 1) as the starting material, lithium diisopropylamide as base, and tetrahydrofuran as solvent, ethyl F/l l-(p-chlorobenzyl )-a-methyl-3-phenylthio-5-( i-propyl )-indole-2-acetate was prepared.
Analysis calculated for C29H30ClNO2S:
C, 70.78; H, 6.14 Found: C, 70.86; H, 6.21 Step 2: To 306 mg of the ethyl ester from Step 1 in 3 mL tetrahydrofuran and 1. 5 mL methanol was added 1.5 mL of 2 N LioH. After 1 h at reflux the mixture was cooled to room temperature, acidif ied with 1 N
HCl and diluted with ether. The ether layer was washed with brine (2x) and dried over MgSO4.
Filtration and concentration gave the title , u--d, mp 181-181. 5 .

l-(p-Chlorobenzyl )-5-(t-butyl )-3-phenylthio-indole-2-acetic acid Following the procedure of Example 10, but using l-(p-chlorobenzyl)-1-(4-t-butylphenyl)hydrazine hydrochloride and ethyl 3-oxo-4-phenylthiobutanoate as starting materials and t-butanol as the solvent, the title ~ , ~u--d was prepared, mp 148-150C.

l-(p--Chlorobenzyl)-5-(t-butyl)-3-phenylsulfinyl-indole-2-acetic acid To a cold (-10) solution of l-(p-chloro-benzyl)-5-(t-butyl)-3-phenylthioindole-2-acetic acid (67 mg) from Example 12 in 1.45 mL dry methylene chloride, under nitrogen, was added 3~ mg of F/l m-chloroperbenzoic acid. The reaction mixture was stirred at -10 for 1 h and room temperature for 30 min. The reaction mixture was then diluted with ether and washed with water (2x) and brine and dried 5 over MgSO4. Filtration and concentration gave a solid which was passed through a short column of silica gel. Elution with ethyl acetate gave the title c ~, mp 160-161 (dec. ) .

l-(p-Chlorobenzyl ) -5-( t-butyl )-3-phenylsulf onyl-indole-2-acetic acid Following the procedure of Example 5, but using l-(p-chlorobenzyl)-5-(t-butyl)-3-phenylthio-2-indole-2-acetic acid f rom Example 12 as the starting material and a mixture of ethanol and water as solvent, the title c~ _ u~ld was prepared, mp 177-179 (dec. ) .
2 0 EX~MPLE 15 l-(p-Chlorobenzyl )-5-f luoro-3-phenylthioindole-2-propanoic acid Following the procedure of Example 10, but us ing 1- ( p-chl orobenzyl ) -1- ( 4-f luor ophenyl ) hydr az ine hydrochloride and methyl 4-oxo-5-phenylthiopentanoate as starting materials and t-butanol as the solvent, the title compound was prepared, mp 138-139.

-`- 1334415 F/l l-(p-Chlorobenzyl )-3-phenylthio-5-( i-propyl )-indole-2-propanoic acid Following the procedure of Example 10, but 5 us ing 1- ( p-chlorobenzyl ) -1- ( 4- i-propylphenyl ) hydrazine hydrochloride and methyl 4-oxo-5-phenylthio-pentanoate as starting materials and t-butanol as the solvent, the title compound was prepared, mp 149-150.
Analysis calculated for C27H26ClNO2S:
C, 69.89; H, 5.64; N, 3.02 Found: C, 69.60; H, 5.73; N, 2.93 15 1-(p-Chlorobenzyl)-5-fluoro-3-methylthioindole-2-propanoic acid Following the procedure of Example 10, but using l-(p-chlorobenzyl ) -1-( 4-f luorophenyl )hydrazine hydrochloride and methyl 5-methylthio-4-oxopentanoate 20 as starting materials and t-butanol as the solvent, the title compound was prepared, lH NMR (250 MHz, CDC13) 6 2.29 (s, 3H), 2.58 (broad t, 2H, J - 7.8 Hz), 3.23 (broad t, 2H, J = 7.8 Hz), 5.37 (s, 2H), 6.87 (d, 2H, J = 8.5 Hz), 6.89 -25 6.95 (m, lH), 7.08 (dd, lH, J = 4.3 and 8.9 Hz), 7.25 (d, 2H, J = 8.5 Hz), 7.40 (d,d, lH, J = 2.6 and 9.4 Hz) .

.
F/l EX~MPLE 1 8 l-(p-Chlorobenzyl)-a,a-dimethyl-5-fluoro-3-phenylthio-indole-2-propanoic acid Following the procedure of Example 10, but 5 using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 2, 2-dimethyl-4-oxo-5-phenyl-thiopentanoate as starting materials and hydrolysis at ref lux, the title compound was prepared, mp 162-163 .
Analysis calculated for C26H23ClFN02S:
C, 66.72; H, 4.95; N, 3.00 Found: C, 66.83; H, 5.02; N, 2.94 l-(p-Chlorobenzyl )-a,a-dimethyl-3-phenylthio-5-( i-propyl ) -indole-2-propanoic acid Following the procedure of Example 10, but using l-(p-chlorobenzyl)-l-[4-(i-propyl)phenyl]
hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-phenylthiopentanoate as starting material and hydrolysis at ref lux, the title compound was prepared, mp 162-165.
EX~5PLE 20 l-(p-Chlorobenzyl ) -a ,a-dimethyl-3-phenylsulf inyl-s-(i-propyl)-indole-2-propanoic acid steP 1: To a cold (-10 ), stirred solution containing 255 mg of methyl l-(p-chlorobenzyl)-,a-dimethyl-3-phenylthio-5-( i-propyl ) -indole-2-propanoate f rom Example 19, Step 1, in 5 mL dry methylene chloride, under nitrogen, was added 118 mg of m-chloroper-.
F/l benzoic acid. The reaction mixture was warmed to 0 over a period of 1 h then quenched with 1 N NaOH and diluted with ether. The organic layer was washed with 1 N NaOH (2x), brine (2x) and dried over 5 MgSO4. Filtration and concentration gave a pale yellow foam which was crystallized from a hexane-toluene mixture to gave the sulfoxide of the starting ester, mp 114-115 (dec. ) .
10 steP 2: A solution containing 118 mg of the methyl ester from Step 1 in a mixture of 2 mL tetrahydrofuran and 1 mL of methanol was treated with 1 mL of 2 N
LiOH and refluxed for 4 h. The resultant yellow solution was cooled to room temperature, acidified 15 with 1 N HCl and diluted with ethyl acetate. The organic layer was dried over MgSO4. Filtration and cu~ .ation, followed by recrystallization from hexane-ethyl acetate gave the title product, mp 142-144 ( dec . ) .

l-(p-Chlorobenzyl )-a,a-dimethyl-3-phenylsulfonyl-5- ( i-propyl ) - indo 1 e-2-pr opano ic ac id Step 1: To a cold (0), stirred solution containing 25 376 mg of methyl l-(p-chlorobenzyl)-a,a-dimethyl-3-phenylthio-5-(i-propyl)-indole-2-propanoate, from Example 19, Step 1, in 7.4 mL dry methylene chloride, under nitrogen, was added 319 mg of m-chloroper-benzoic acid. After 20 min at 0 and 40 min at room 30 temperature the resultant slurry was diluted with ether and washed with saturated agueous sodium bicarbonate (2x) and brine and dried over MgSO4.

.
F/l Filtration and concentration gave a yellow solid which was recrystallized from a mixture of hexane-toluene to give the sulfone of the starting ester, mp 153-153 . 5 .

Step 2: A solution containing 139 mg of the methyl ester f rom Step 1 in a mixture of 1. 5 mL
tetrahydrofuran and mL methanol was added 1. 0 mL of 2 N LiOH and refluxed for 4 h. The resultant solution 10 was cooled to room temperature, acidified with 1 N
HCl and diluted with ethyl acetate. The organic layer was dried over MgSO4, f iltered and concentrated to give the title c _ ulld as a pale yellow solid which was recrystallized from 15 hexane-ethyl acetate to give the title compound, mp 169-172 .

l-(p-Chlorobenzyl)-a,a-dimethyl-5-phenyl-3-phenyl-20 thioindole-2-propanoic acid Following the procedure of Example 10, but us ing 1- ( p-ch 1 orobenzyl ) -1- ( 4-biphenyl ) hydr az ine hydrochloride and methyl 2, 2-dimethyl-4-oxo-5-phenylthiopentanoate as starting materials and 25 hydrolysis at ref lux, the title c _ .u--d was prepared, mp 182-183.
Analysis calculated for C32H28ClNO2S:
C, 73.06; H, 5.36: N, 2.66 30 Found: C, 72.58: H, 5.67: N, 2.66 - ` 1 3344 1 5 F/l EXA?5PLE 23 l-(p-Chlorobenzyl)-a,-dimethyl-5-fluoro-3-methyl-thioindole-2-propanoic acid Following the procedure of Example 10, but 5 using 1-(p-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-5-methylthio-4-oxopentanoate as starting materials and hydrolysis at reflux, the title compound was prepared, mp 161-163 .

l-(p-Chlorobenzyl ) -,-dimethyl-3-methylthio-5-(i-propyl)-indole-2-propanoic acid Following the procedure of Example 10, but 15 using 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]
hydrazine hydrochloride and methyl 2,2-dimethyl-5-methylthio-4-oxopentanoate as starting materials and hydrolysis at reflux, the title c~ _ ' was prepared, mp 143-144 .
Analysis calculated for C24H28C1O3NS:
C, 67.04; H, 6.65 Found: C, 66.72; H, 6.78 2 5 EX~MPLE 2 5 l-(p-Chlorobenzyl )-3-(t-butylthio)-,-dimethyl-5-( i-propyl ) -indo le-2-propano ic acid Following the procedure of Example 10, but using l-(p-chlorobenzyl)-1-[(4-(i-propyl)phenyl]
hydrazine hydrochloride and methyl 2,2-dimethyl-5-(t-butylthio)-4-oxopentanoate as starting materials and hydrolysis at reflux, the title u--d was prepared, mp 189-192.

-- ` 1334415 F/l Analysis calculated for C27H34ClNO2S:
C, 68.69; H, 7.25; N, 2.97 Found: C, 68.34; H, 7.35; N, 3.08 l-(p-Chlorobenzyl)-3-(t-butylsulf inyl)-,-dimethyl-5-( i-propyl ) -indo le-2-propano ic ac id Following the procedure of Example 20, but 10 using methyl 1-(p-chlorobenzyl)-3-(t-butylthio)-,-dimethyl-5-( i-propyl)-indole-2-propanoate (Example 25, Step 1) as the starting material, the title ~- , ul,d was prepared, mp 138-150 (dec. ) .
EX~MPLE 2 7 l-(p-Chlorobenzyl)-3-(t-butylsulfonyl)-,-dimethyl-5-( i-propyl ) - indo 1 e-2-propano ic ac id Following the procedure of Example 21, but using methyl l-(p-chlorobenzyl)-3-(t-butylthio)-20 ,-dimethyl-5-(i-propyl)-indole-2-propanoate (Example 25, Step 1) as the starting material, the title compound was prepared, mp 225-226 (dec. ) .

25 1-(p-Chlorobenzyl)-3-(t-butylthio)-,-dimethyl-5-phenylindole-2-propanoic acid Following the procedure of Example 10, but using l-(p-chlorobenzyl)-1-(4-biphenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-5-(t-butylthio)-30 4-oxopentonoate as starting materials and hydrolysis at reflux, the title ~ lld was prepared, mp 245-246 .

_ Analysis calculated for C30H32ClNO2S:
C, 71.20; H, 6.37; N, 2.76; S, 6.33 Found: C, 71.28; H, 6.35; N, 2.77; S, 6.71 l-(p-Chlorobenzyl)-a,-dimethyl-3-(phenylthio)-5-( i-propyl )-indole-2-butanoic acid Following the procedure of Example 10, but using l-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]
10 hydrazine hydrochloride and methyl 2,2-dimethyl-5-oxo-6-phenylthiohexanoate as the starting materials and hydrolysis at ref lux, the title compound was prepared, mp 164-166.

3-[ l-(p-Chlorobenzyl )-3-(t-butylthio)-5-( i-propyl )-indole-2-yl ] -2, 2-dimethylpropanol To a solution of 200 mg of methyl l-(p-20 chlorobenzyl)-3-(t-butylthio)- a,a-dimethyl-5-( i-propyl ) -indole-2-propanoate ( f rom Example 25 ) in 1.5 mL tetrahydrofuran (THF) was added 0.4 ml of a solution of lithium aluminum hydride ( 1. 0 M in THF) at 0C. After 2h at 0C, the reaction mixture was 25 ~nrh~d with saturated aqueous Na2SO4, diluted with ether and stirred at room temperature for lh.
The resultant slurry was filtered and the filtrate cu~ e..L~ated to dryness. The resultant oil was purified by flash chromatography (eluant: hexane-ethyl 30 acetate, 8:2) to give the title ~ -d as a viscous oil .

lH NMR (250 MHz, Acetone-D6) ~ : 0.94 (s, 9H), 1.26 (s, 6H), 1.27 (d, 2H J=7.0 Hz), 2.95 - 3.08 (m, 2H), 2.99 (septuplet, lH, J=7.0 Hz), 3.27 (d, 2H, J=7.0 Hz), 4.02 (t, lH, J=7.0 Hz, exchanges with D2O), 4.69 (broad s, 2H), 6.92 (d, 2H, J=8.5 Hz), 7.00 (dd, lH, J=7.5 and 2.0 Hz), 7.24 (d, lH, J=7.5 Hz); 7.29 (d, 2H, J=8.5 Hz), 7.58 (d, lH, J=2.0 Hz) IR (CDC13) 3420 cm 1, EX~SPLE 10 2 l-(p-Chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-(n-butylthio) indole-2-propanoic acid Following the procedure of Example 104, but using 1-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-n-butylthiopentanoate as starting materials followed by hydrolysis at reflux gave the title c~ d, m.p. 129 - 130.

l-(p-Chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-cyclohexylthioindole-2-propanoic acid To a mixture of 461 mg of l-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]hydrazine hydrochloride and 121 mg of anhydrous sodium acetate in 2 . 5 mL of anhydrous toluene was added 1. 24 mL of - glacial acetic acid. After 15 min, a solution containing 336 mg of methyl 2,2-dimethyl-4-oxo-5-cyclohexylthio-pentanoate in 0 . 5 mL of toluene was added and the reaction mixture stirred for 24h at room temperature. The reaction was then diluted with F/l ether, washed with lN NaOH(2x), H2O and brine and dried over MgSO4. Filtration and concentration gave a viscous oil which was purif ied by f lash chromatography on silica gel (eluant: hexane-ethyl 5 acetate, 85:15). Hydrolysis to the title compound was effected using 2N LiOH in methanol/THF (1:2) for 6h at reflux followed by qllPnrh;ng with lN HCl and filtration, m.p. 166 - 168.

N-tl-(p-chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-t-butylthioindole-2-propanoyl]qlycine sodium salt To 472 mg l-(p-chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-t- butylindole-2-propanoic acid ~ p~n~l~d in 5 ml methylene chloride, under nitrogen, was added 417 IIL Et3N. 150 IIL
isobutyl chloroformate was added dropwise. The reaction was cooled to 0 and kept for 1. 5h. Glycine ethyl ester hydrochloride ( 182 mg) dissolved in 1. 5 ml methylene chloride was added and the reaction allowed to come to room temperature for 2h. The product was separated by chromatography on silica gel using ethyl acetate-hexane as eluent (3:7).
Hydrolysis to the title c __. ' was effected using lN NaOH in methanol/THF (1:1) for 16h. followed by evaporation of the solvents, m.p. 280 ~e- _ -sition .

F/l l-(p-chlorobenzyl)-,a-dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propanoic acid Following the procedure of Example 104, but using l-(p-chlorobenzyl- 1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-cyclopropylmethylthiopentanoate as starting materials followed by hydrolysis at reflux, the title compound was isolated, m.p. 123 - 124.

l-(p-chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propionamide To a solution of 110 mg of methyl l-(p-chlorobenzyl)-a,a- dimethyl-5-isopropyl-3-cyc 1 opropylmethylthi o indo 1 e-2-propano ate ( f r om Example 108) in 1 ml CH2C12 was added 1 ml of no(~; ~hylalane (Me2AlNH2) in hexane/CH2C12 ( 1. OM) and the reaction heated at 65 for 16h. The reaction was quenched with 2N HC1 at 0C, O . 5M NaK tartrate was added and the solution extracted with ether. The product from ether was purified by chromatography on silica gel (Toluene/Acetone/Acetic acid) 85 :15 :1 to yield the title ~ d, m.p. 137 - 138.

F/l E~C~MPLE 11 5 l-(p- :n~b~n7yl)-,-dimethyl-5-isopropyl-3-phenylsulfonylindole-2-propanoic acid Ste~ 1: Methyl [1-(4-nitrobenzyl)-,-dimethyl-5-isopropyl-3-phenylsulfonylindole]-2-propanoate was prepared according to the method described in Example 22, but using l-(p-nitrobenzyl )-1-[ 4-( i-propyl )phenyl ] -hydrazine hydrochloride and methyl 2,2-dimethyl-4- oxo-5-phenylthiopentanoate as starting materials.
SteP 2: A solution of 480 mg methyl[l-(4-nitrophenyl)-,~1-dimethyl-5-isopropyl-3-phenylsulfonylindole-2-propanoate] in 45 ml ethyl acetate was heated with 100 mg Pd/C
( 5%) catalyst and the solution hydrogenated a '.5 psi for 16h. A further 50 mg catalyst was added and the ~-ydLoge.. ation continued for another 16h. The catalyst was removed by filtration through celite- and the product isolated (480 mg) after removal of solvent.
Hydrolysis was achieved by treatment of the ester with 2N NaOH in 3 ml MeOH/THF 1:1.
The solution was neutralized with 0 . 5N HCl and the product extracted with ethyl acetate 3x10 ml. The solution was dried (Na2SO4) and stripped to yield the title product, m.p. 290 dec sition.
~ .

`- 1334415 F/l EX~MPLE 11 6 l-(p-Chlorobenzyl)-,a-dimethyl-5-isopropyl-3-(5-chlorobenzothiazol-2-ylthio)indole-2-propanoic acid Following the procedure of Example 104, but using l-(p-chlorobenzyl)- 1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-(5-chlorobenzothiazol-2-ylthio)pentanoate as starting materials followed by hydrolysis at reflux gave the title u~ld, m.p. 154 - 156.

1-[ (p-Chlorobenzyl)-5-( isopropyl)-3-(t-butylthio)-indole-2-methyl]-1-cyclopentane carboxylic acid Following the procedure of Example 104, but using l-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 1-[3-(t-butylthio)-2-oxoprop-1-yl]cyclopentane carboxylate as 20 starting materials followed by hydrolysis at reflux gave the title c, ~ u--d, m.p. 203 - 204.

l-(P-Chlorobenzyl)-,a-dimethyl-5-isopropyl-3-(1-25 buten-4-ylthio)indole-2-propanoic acid, sodium salt Following the procedure of Example 104, but us ing 1- ( p-chlorobenzyl ) - 1- [ 4- ( i-propyl ) phenyl ] -hydrazine hydrochloride and methyl 2,2-dimethyl-4-30 oxo-5-(1-buten-4-ylthio)pentanoate as starting materials followed by hydrolysis at reflux and isolation as the sodium salt, the title compound was prepared, m.p. 206 - 207.

F/l l-(p-Chlorobenzyl ) -, a-dimethyl-5-isopropyl-3-(benzylthio) indole-2-propanoic acid Following the procedure of Example 104, but using l-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-benzylthiopentanoate as starting materials followed by hydrolysis at reflux gave the title _, ul-d, m.p. 135 - 137.
EX~MPLE 12 9 l-(p-Chlorobenzyl)-,-dimethyl-5-isopropyl-3-(2-isopropylphenylthio) indole-2-propanoic acid Following the procedure of Example 104, but using l-(p-chlorobenzyl)-1-[4-(i-propyl)phenyl]-hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-5-(2-isopropylphenylthio)pentanoate as starting 20 materials followed by hydrolysis at reflux gave the title ~ ~ d, m.p. 142 - 143.

l-(p-chlorobenzyl)-,-dimethyl-5-isopropyl-3-(2-2 5 isopropylphenyl-sul f onyl ) indo 1 e-2-pr opano i c ac id Following the procedure of Example 21, but using methyl l-(p-chlorobenzyl)-,~-dimethyl-5-isopropyl-3-(2-isopropylphenylthio) indole-2-30 propanoate as starting material (from Example 129)followed by hydrolysis at reflux gave the title _ul-d, m.p. 181 - 182.

-F/l l-(p-Chlorobenzyl )-3-(t-butylthio)-a,a-dimethyl-5-( i-propyl ) indole-2-propanoic acid, sodium salt 5 Step 1: A lL f lask equipped with a magnetic stirrer and a nitrogen inlet was charged with l-(p-chlorobenzyl )-1-[ 4-( i-propyl )phenyl ]
hydrazine hydrochloride (62 g, 0.2 mole), anhydrous sodium acetate (18g, 0.22 mol) and toluene (400 mL). Glacial acetic acid (200 mL) was added, the mixture stirred for 15 min and then treated with a solution of methyl 5-(t-butylthio)-2,2-dimethyl-4-oxopentanoate (54.1 g, 0.22 mol) in toluene (100 mL). The resultant mixture was stirred in the dark f or 4 days .
The reaction mixture was diluted (4x) with 200 mL of distilled water and the phases separated. The aqueous phase (pH ~ 2) was discarded and the organic phase neutralized by shaking with NaOH ( 5N) . The organic layer was separated and evaporated without drying to give a brown syrup which was hydrolyzed without further purif ication .
Step 2: The resulting syrup obtained in step 1 was dissolved in 300 mL of MeOH and 100 mL of THF and then 100 mL of 2N LiOH was added.
The resulting suspension was stirred at ref lux overnight . The clear mixture was allowed to cool to room temperature and neutralized with HCl (3N). The reaction was set aside in an ice bath and the product crystallized out. The crude acid was then isolated by f iltration and ret,u~ ded in 400 mL of cold methanol and swished for 3-4 hours. The product was then filtered from the swished liquors and was dried in vacuo to give 55 g of the title compound as the free acid. A second crop of 7 g was obtained from the mother liquors.
Step 3: To a solution of the acid isolated in step 3 (36.5 gm, 0.077 mol) in distilled tetrahydrofuran (234 ml), was added a 1. 00 M
solution of sodium hydroxide in deionized water (76 ml). The reaction mixture was stirred at room temperature for 30 min and then concentrated to a viscous oil from which was evaporated ethanol (2x) and ether (2x). Crystallization of the residue from hexane and wa6hing with ether gave after drying (50C, 0.5 Torr) the title compound, m.p. 289C (dec).

Claims (16)

1. A compound of the formula:
I
wherein:
R1 is H or loweralkyl;
R2 is H or loweralkyl, or two R2's may be joined to form a ring of 3-6 atoms;
R3 is C1-20 alkyl, C2-C6 alkenyl, phenyl unsubstituted or substituted with one or two substituents selected from C1-3 alkyl, halogen, CN, CF3, C1-3 alkoxy, C1-3 alkylthio, COOH, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyl or azide; -(CH2)m, -Het, or M-substituted C1-20 alkyl; wherein Het includes 2-, 3-, or 4-pyridyl; tetrazolyl; 2- or 3-thienyl; 2-, 4-, or 5-thiazolyl; 2-, 4-, or 5-thiazolinyl; 1-, 2-, 4- or 5-imid-azolyl; 3-[1,2,5]-thiadiazolyl; benzothiazol-2-yl; or 2-, 3-, or 4-quinolinyl, each optionally substituted with 1 or 2 substituents selected from C1-C3 alkyl, halogen, CN, - 95a -CF3, C1-C3 alkoxy, C1-C3 alkylthio, CO2H, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl and azide.
R4, R5 and R6 is each independently H, lower-alkyl, C2-C6 alkenyl, or -(CR2R2) pM;
R7 and R8 are independently H, C1-C3 alkyl, halogen, OH, CN, CF3, C1-C3 alkoxy, C1-C3 alkylthio, CO2H, C1-C3 alkoxycarbonyl, C1-C3 alkylcarbonyl, or azide;
R9 is CF3, loweralkyl, benzyl unsubstituted or substituted with one or two substituents selected from C1-3 alkyl, halogen, CN, CF3, C1-3 alkoxy, C1-3 alkylthio, COOH, C1-3 alkoxycarbonyl, C1-3 alkylcarbonyl or azide; or phenyl as defined above; R10 is H, loweralkyl, unsubstituted phenyl, unsubstituted benzyl, or two R10's attached to a nitrogen may form a ring of 5 to 7 members;

R11 is H or -(CH2)qR9;
R12 is loweralkyl, substituted or unsubstituted benzyl as defined above, or substituted or unsubstituted phenyl as defined above;
R13 is H, loweralkyl, substituted or unsubstituted phenyl as defined above, or substituted or unsubstituted benzyl as defined above;
R14 is -CH2CH2N(R10)2, CH2CH(OH)CH2OH, -CH2O2CC(CH3)3,-CH(CH3)O2CC(CH3)3, , , , , , -(CH2)2NHAc, , , , , , or ;

E is CH2OH, CO2R13, CO2R14, tetrazol-5-yl, CHO, C(O)NR2R2, C(O)NHS(O)2R9, or C(O)N(OR2)R2;
M is a) OR10;
b) halogen;
c) CF3;
d) SR9;
e) substituted or unsubstituted phenyl as defined above:
f) COOR10;
g) ;
h) tetrazole;
i) ;
j) NR10R10;
k) -NHSO2R9;
l) ;
m) -S(O)R9;
n) -CONR10R10;

o) -S(O)2NR10R10;
p) -S(O)2R9;
q) NO2;
r) ;
s) ;
t) ;
u) CN;
v) N3; or w) H;
X is O,S, S(O),or S(O)2;
m is 0-2;
n is 0-5;
p is 0-3; and q is 0-4;
and the pharmaceutically acceptable salts thereof.

2. A compound of Claim 1 wherein the substituents are as follows:

3. The compounds of Claim 1 which are:
ethyl 1-(p-chlorobenzyl)-5-chloro-3-thiophenylindole-2-carboxylate:
1-(p-chlorobenzyl)-5-chloro-3-thiophenylindole-2-carboxylic acid;
ethyl 1-(p-chlorobenzyl)-5-fluoro-3-methylthio-indole-2-acetate;
1-(p-chlorobenzyl)-5-fluoro-3-methylthioindole-2-acetic acid;
1-(p-chlorobenzyl)-5-fluoro-3-methylsulfonylindole-2-acetic acid;
1-(p-chlorobenzyl)-5-fluoro-a-methyl-3-methylthio-indole-2-acetic acid;
1-(p-chlorobenzyl)-a,a-dimethyl-5-fluoro-3-methylthioindole-2-acetic acid;
1-(p-chlorobenzyl)-5-fluoro-3-phenylthioindole-2-acetic acid;
1-(p-chlorobenzyl)-5-fluoro-a-methyl-3-phenylthio-indole-2-acetic acid;
1-(p-chlorobenzyl)-3-phenylthio-5-(i-propyl)-indole-2-acetic acid;
1-(p-chlorobenzyl)-a-methyl-3-phenylthio-5-(i-propyl)-indole-2-acetic acid;
1-(p-chlorobenzyl)-5-(t-butyl)-3-phenylthio-indole-2-acetic acid;
1-(p-chlorobenzyl)-5-(t-butyl)-3-phenylsulf inyl-indole-2-acetic acid;
1-(p-chlorobenzyl)-5-(t-butyl)-3-phenylsulfonyl-indole-2-acetic acid;
1-(p-chlorobenzyl)-5-fluoro-3-phenylthioindole-2-propanoic acid;
1-(p-chlorobenzyl)-3-phenylthio-5-(i-propyl)-indole-2-propanoic acid;

1-(p-chlorobenzyl)-5-fluoro-3-methylthioindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-fluoro-3-phenylthio-indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-3-phenylthio-5-(i-propyl )-indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-3-phenylsulfinyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-3-phenylsulfonyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-phenyl-3-phenyl-thioindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-fluoro-3-methyl-thioindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-3-methylthio-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-3-(t-butylthio)-.alpha.,.alpha.-dimethyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-3-(t-butylsulfinyl)-.alpha.,.alpha.-dimethyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-3-(t-butylsulfonyl)-.alpha.,.alpha.-dimethyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-3-(t-butylthio)-.alpha.,.alpha.-dimethyl-5-phenylindole-2-propanoic acid;
1-(p-chlorobenzyl)-a,a-dimethyl-3-(phenylthio)-5-(i-propyl)-indo1e-2-butanoic acid;
3-[1-(p-chlorobenzyl)-3-(t-butylthio)-5-(i-propyl)-indole-2-yl]-2,2-dimethylpropanol;
1-(p-chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-(n-butylthio)indole-2-propanoic acid;
1-(p-chlorobenzyl)-a,a-dimethyl-5-isopropyl-3-cyclohexylthioindole-2-propanoic acid;

N-[1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-t-butylthioindole-2-propanoyl]glycine sodium salt;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propionamide;
1-(p-aminobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-phenylsulfonylindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-(5-chlorobenzothiazol-2-ylthio)indole-2-propanoic acid;
1-[(p-chlorobenzyl)-5-(isopropyl)-3-(t-butylthio)-indole-2-methyl]-1-cyclopentane carboxylic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-(1-buten-4-ylthio)indole-2-propanoic acid, sodium salt;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-(benzylthio)indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-(2-isopropylphenylthio)indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-(2-isopropylphenylsulfonyl)indole-2-propanoic acid; and 1-(p-chlorobenzyl)-3-(t-butylthio)-.alpha.,.alpha.-dimethyl-5-(i-propyl)indole-2-propanoic acid, sodium salt.

4. The compounds of Claims 3 which are:
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-3-phenylthio-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-3-phenylsulfonyl-

5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-phenyl-3-phenyl-thioindole-2-propanoic acid;

1-(p-chlorobenzyl)-3-(t-butylthio)-.alpha.,.alpha.-dimethyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-3-(t-butylsulfonyl)-.alpha.,.alpha.-dimethyl-5-(i-propyl)-indole-2-propanoic acid;
1-(p-chlorobenzyl)-3-(t-butylthio)-.alpha.,.alpha.-dimethyl-5-phenylindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-cyclohexylthioindole-2-propanoic acid;
N-[1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-t-butylthioindole-2-propanoyl]glycine sodium salt:
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propanoic acid;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-cyclopropylmethylthioindole-2-propionamide;
1-(p-chlorobenzyl)-.alpha.,.alpha.-dimethyl-5-isopropyl-3-(2-isopropylphenylsulfonyl)indole-2-propanoic acid; and 1-(p-chlorobenzyl)-3-(t-butylthio)-.alpha.,.alpha.-dimethyl-5-(i-propyl)indole-2-propanoic acid, sodium salt.
5. A compound of Claim 1 of the formula:

Ia wherein:
R2 is loweralkyl, C1-C7 alkyl -C3-C7 cycloalkyl (an alkyl group with a cycloalkyl group at one end), C1-C7 alkyl-substituted phenyl, unsubstituted phenyl, or unsubstituted benzyl;
R4 is loweralkyl, halogen selected from the group consisting of F, C1, Br or I, C1-C7 alkyl-substituted or unsubstituted phenyl, or C1-C7 alkoxy;
R7 is C1-C3 alkyl, C1-C7 alkoxy, azide, halogen, or hydroxy;
R13 is H or loweralkyl;
E is CO2R13, CONH2, or tetrazol-5-yl; and n is 1-3.

6. A compound of Claim 5 where in the definition of R3, loweralkyl is a branched loweralkyl.

7. A compound of Claim 5 where in the definition of R4, loweralkyl is a branched loweralkyl.

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

9. The pharmaceutical composition of Claim 8 additionally comprising an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors; leukotriene antagonists; leukotriene biosynthesis inhibitors; H2-receptor antagonists; antihistaminic agents;
prostaglandin antagonists; thromboxane antagonists; and thromboxane synthetase inhibitors.

10. A pharmaceutical composition according to Claim 9, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

11. A pharmaceutical composition of Claim 10, wherein the weight ratio of said compound of Claim 1 to said second active ingredient ranges form about 1000:1 to 1:1000.

12. The use of a composition of Claim 1 for preventing the synthesis of leukotrienes in a mammal.

13. A use according to Claim 12 wherein the mammal is a man.

14. The use of a compound of Claim 1 for inducing cytoprotection in a mammal.

15. The use of a compound of Claim 1 for treating inflammatory diseases of the eye in a mammal.

16. A use according to Claim 15 wherein the mammal is a man.