Indole carbamates as leukotriene antagonists

Compounds of the formula ##STR1## wherein R.sup.1 AND R.sup.2 are as defined, useful in the treatment of asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive airways diseases, psoriasis, allergic rhinitis, atopic dermatitis, shock, and other inflammatory diseases and for blocking the leucotriene D4 receptor, pharmaceutical compositions containing such compounds and methods of blocking leucotriene D4 receptors using such compositions.

BACKGROUND OF THE INVENTION 
The present invention relates to N-o-tolylsulfonylbenzamide compounds, 
pharmaceutical compositions comprising such compounds and the use of such 
compounds as antagonists of leukotriene D4. The compounds of this 
invention are useful in the treatment of inflammatory diseases. 
It is known that arachidonic acid (AA) is metabolized in mammals by two 
distinct pathways. The metabolism of arachidonic acid by cyclooxygenase 
enzymes results in the production of prostaglandins and thromboxanes. The 
other pathway of AA metabolism involves lipoxygenase enzymes and results 
in the production of a number of oxidative products called leukotrienes. 
The latter are designated by the LT nomenclature system, and one of the 
most significant products of the lipoxygenase metabolic pathway is the 
leukotriene D4. Leukotrienes participate in inflammatory reactions, 
exhibit chemotactic activities, stimulate lysosomal enzyme release and act 
as important factors in the immediate hypersensitivity reaction. For 
example, LTD4 is a potent bronchoconstrictor of the human bronchi. 
The biological activity of the leukotrienes indicates that a rational 
approach to drug therapy to prevent, remove or ameliorate the symptoms of 
asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic 
obstructive airways disease, psoriasis, allergic rhinitis, atopic 
dermatitis, shock and other inflammatory diseases must focus on either 
blocking the release of mediators of these conditions or antagonizing 
their effects. Thus, compounds which inhibit the biological effects of the 
leukotrienes are considered to be of value in treating such conditions 
defined above. 
SUMMARY OF THE INVENTION 
The present invention relates to a compound of the formula 
##STR2## 
or a pharmaceutically acceptable salt thereof, wherein 
R.sup.1 is CHO, CH.sub.2 F, CHF.sub.2 or CONR.sup.3 R.sup.4 wherein R.sup.3 
and R.sup.4 are each independently selected from the group consisting of 
hydrogen, (C.sub.1 -C.sub.6)alkyl, (C.sub.2 -C.sub.5)alkenyl, (C.sub.2 
-C.sub.6)alkynyl, (C.sub.6 -C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 
-C.sub.6)alkyl, ((C.sub.1 -C.sub.6)alkyl).sub.2 amino(C.sub.1 
-C.sub.5)alkyl, pyridinyl and CHR.sup.5 R.sup.6 wherein R.sup.5 and 
R.sup.6 are each independently (C.sub.1 -C.sub.6)alkyl or (C.sub.8 
-C.sub.10)aryl; 
or R.sup.3 or R.sup.4 may be taken together with the nitrogen to which they 
are attached to form morpholinyl, pyrrolidinyl or a group of the formula 
##STR3## 
wherein the broken lines represent optional double bonds; 
n is 0, 1 or 2; 
X, Y and Z are each independently CH, O, S or N; and 
R.sup.7 R.sup.8, R.sup.9, R.sup.10 and R.sup.11 are each independently 
selected from the group consisting or hydrogen, (C.sub.1 -C.sub.6)alkyl, 
(C.sub.2 -C.sub.6)alkenyl, (C.sub.2 -C.sub.6)alkynyl, (C.sub.8 
-C.sub.10)aryl, (C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl, ((C.sub.1 
-C.sub.6)alkyl).sub.2 amino(C.sub.1 -C.sub.6)alkyl, pyridinyl, CHR.sup.5 
R.sup.6 wherein R.sup.5 and R.sup.6 are each independently (C.sub.1 
-C.sub.6)alkyl or (C.sub.6 -C.sub.10)aryl; or benzhydryl optionally 
substituted by one to five halo; 
R.sup.2 is a group of the formula 
##STR4## 
or a group of the formula 
##STR5## 
wherein X is O, NH or CH.sub.2 ; and 
R.sup.12 is (C.sub.3 -C.sub.7)cycloalkyl or a group of the formula 
##STR6## 
wherein the broken line represents an optional double bond; n is 0 or 1; m 
is 0, 1 or 2; p is 0, 1 or 2; Q and R.sup.3 are both CH or both CH.sub.2 ; 
with the proviso that when Q and R.sup.3 are both CH, the broken line 
represents a double bond; and 
with the proviso that when n is 1 or 2, only two of the three variables X, 
Y and Z can be O, S or N. 
The term "alkyl", as used herein, unless otherwise indicated, includes 
saturated monovalent hydrocarbon radicals having straight, branched or 
cyclic moieties or combinations thereof, optionally substituted by 1 to 3 
halo. 
The term "aryl", as used herein, unless otherwise indicated, includes an 
organic radical derived from an aromatic hydrocarbon by removal of one 
hydrogen, such as phenyl or naphthyl, optionally substituted by 1 to 3 
substituents selected from the group consisting of fluoro, chloro, 
trifluoromethyl, (C.sub.1 -C.sub.6)alkoxy, (C.sub.6 -C.sub.10)aryloxy, 
trifluoromethoxy, difluoromethoxy and (C.sub.1 -C.sub.6)alkyl. 
Preferred compounds of formula I include those wherein R.sup.1 is 
CONR.sup.3 R.sup.4 wherein R.sup.3 and R.sup.4 are each independently 
selected from (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl and 
(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl. 
Other preferred compounds of formula I include those wherein X is O and 
R.sup.12 is cyclopentyl. 
Other preferred compounds of formula I include those wherein R.sup.1 is 
CONR.sup.3 R.sup.4 wherein R.sup.3 and R.sup.4 are each independently 
selected from (C.sub.1 -C.sub.6)alkyl, (C.sub.6 -C.sub.10)aryl and 
(C.sub.6 -C.sub.10)aryl(C.sub.1 -C.sub.6)alkyl; X is CH.sub.2 and R.sup.12 
is cyclopentyl. 
Specific preferred compounds of formula I include the following: 
4-[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy- 
N-o-tolylsulfonylbenzamide; 
4-[1-(hydroxycarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl 
]-3-methoxy-N-o-tolylsulfonylbenzamide; 
4-[1-((2-carboxyethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3 
-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide; 
4-[1-((2-tetrazolylethyl)carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indo 
l-3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide; 
4-[1-(methylphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylm 
ethyl]-3-methoxy-N-o-tolylsulfonylbenzamide; 
4-[1-(diphenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethy 
l]-3-methoxy-N-o-tolylsulfonylbenzamide; 
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-metho 
xy-N-o-tolylsulfonylbenzamide; and 
4-[1-(pyrrolidine-carbonyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylme 
thyl]-3-methoxy-N-o-tolylsulfonylbenzamide. 
The present invention also relates to a pharmaceutical composition for (a) 
treating a condition selected from the group consisting of asthma, 
rheumatoid arthritis, osteoarthritis, bronchitis, chronic obstructive 
airways disease, psoriasis, allergic rhinitis, atopic dermatitis, shock, 
and other inflammatory diseases or (b) blocking the leukotriene D4 
receptor in a mammal, including a human, comprising a leukotriene D4 
receptor blocking amount of a compound according to formula I and a 
pharmaceutically acceptable carrier. 
The present invention also relates to a method of treating a condition 
selected from the group consisting of asthma, rheumatoid arthritis, 
osteoarthritis, bronchitis, chronic obstructive airways disease, 
psoriasis, allergic rhinitis, atopic dermatitis, shock, and other 
inflammatory diseases in a mammal, including a human, comprising 
administering to said mammal an amount of a compound according to formula 
I effective in treating such a condition. 
The present invention also relates to a method of blocking the leukotriene 
D4 receptor in a mammal, including a human, comprising administering to 
said mammal a leukotriene D4 receptor blocking amount of a compound 
according to formula I. 
DETAILED DESCRIPTION OF THE INVENTION 
The following reaction scheme illustrates the preparation of the compounds 
of the present invention. Unless otherwise indicated R.sup.3, R.sup.4 and 
R.sup.12 in the reaction Schemes and the discussion that follow are 
defined as above. 
##STR7## 
In reaction 1 of Scheme 1, the compound of formula XI is converted to the 
corresponding 4-[1-(R.sup.3 R.sup.4 
carbamoyl)-1H-indol-3-ylmethyl]-benzoic acid methylester compound of 
formula X, wherein R.sup.3 and R.sup.4 are as defined above, by reacting a 
solution of XI and triethylamine in a polar aprotic solvent, such as 
methylene chloride, at a temperature between about -10.degree. C. to about 
0.degree. C., preferably about 0.degree. C., with a solution of phosgene 
in an aprotic solvent, such as toluene. The reaction mixture is warmed to 
room temperature and allowed to stir for a time period between about 30 
minutes to about 1.5 hours, preferably about 1 hour. To the reaction 
mixture so formed is added a compound of the formula NHR.sup.3 R.sup.4, 
wherein R.sup.3 and R.sup.4 are as defined above, and the resulting 
reaction mixture is stirred for an additional time period between about 10 
hours to about 14 hours, preferably about 12 hours. 
The compound of formula XI is converted to the corresponding 4-[1-(R.sup.3 
R.sup.4 carbamoyl)-1H-indol-3-ylmethyl]-benzoic acid methylester compound 
of formula X, wherein R.sup.3 is as defined above and R.sup.4 is hydrogen, 
by reacting a solution of XI and 4-dimethylaminopyridine in a polar 
aprotic solvent, such as methylene chloride, with a compound of the 
formula R.sup.3 NCO, wherein R.sup.3 is as defined above. The resulting 
reaction mixture is stirred at room temperature for a time period between 
about 16 hours to about 20 hours, preferably about 18 hours. 
The compound of formula XI is converted to the corresponding 4-[(1-R.sup.3 
R.sup.4 carbamoyl)-1H-indol-3-ylmethyl]-benzoic acid compound of formula 
X, wherein R.sup.3 and R.sup.4 are both hydrogen, by reacting XI with 
chlorosulfonylisocyanate in a polar aprotic solvent, such as methylene 
chloride. The reaction mixture is stirred at room temperature for a time 
period between about 4 days to about 6 days, preferably about 5 days. 
In reaction 2 of Scheme 1, the 4-[5-nitro-1H-indol-3-ylmethyl] benzoic acid 
methylester compound of formula X is converted to the corresponding 
4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-benzoic acid 
methylester compound of formula IX by hydrogenating X in the presence of a 
catalyst, such as 10% palladium on carbon, and a 1:1 ratio mixture of 
tetrahydrofuran and methanol. To a solution of the corresponding amine so 
formed and N-methylmorpholine in a polar aprotic solvent, such as 
methylene chloride, is added cyclopentylchloroformate. The resulting 
reaction mixture is stirred at room temperature for a time period between 
about 10 minutes to about 20 minutes, preferably about 15 minutes, and 
treated with an acid, preferably hydrochloric acid. 
In reaction 3 of Scheme 1, the benzoic acid methylester compound of formula 
IX is converted to the corresponding benzoic acid compound of formula VIII 
by (a) heating IX with lithium iodide in the presence of pyridine to 
reflux for a time period between about 10 hours to about 14 hours, 
preferably about 12 hours, or (b) treating IX with lithium hydroxide 
monohydrate in the presence of a 2:2:1 ratio mixture of tetrahydrofuran, 
methanol and water. 
The benzoic acid methylester of formula IX is converted to the 
corresponding benzoic acid compound of formula VIII, wherein R.sup.3 is as 
defined above and R.sup.4 is hydrogen or R.sup.3 and R.sup.4 are both 
hydrogen, by treating IX with lithium hydroxide monohydrate in the 
presence of a 2:2:1 ratio mixture of tetrahydrofuran, methanol and water. 
The reaction mixture is stirred at room temperature for a time period 
between about 10 hours to about 14 hours, preferably about 12 hours. 
In reaction 4 of Scheme 1, the benzoic acid compound of formula VIII is 
converted to the corresponding N-o-tolylsulfonylbenzamide compound of 
formula II by reacting a solution of VIII, 4-dimethylaminopyridine and 
1-[3-dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride in a polar 
aprotic solvent, such methylene chloride, with o-tolylsulfonamide. The 
resulting reaction mixture is stirred for a time period between about 10 
hours to about 14 hours, preferably about 12 hours, at room temperature. 
In reaction 1 of Scheme 2, the compound of formula XI is converted to the 
corresponding 4-[5-(R.sup.12 
oxycarbonyl)amino]-1H-indol-3-ylmethyl]-benzoic acid methylester of 
formula XIV by reacting XI with tin (II) chloride dihydrate in a polar 
protic solvent, such as ethanol. The reaction mixture is heated to reflux 
for a time period between about 20 hours to about 28 hours, preferably 
about 24 hours. To a solution of the corresponding amine so formed and 
N-methylmorpholine in a polar aprotic solvent, such as methylene chloride, 
is added a compound of the formula R.sup.12 OCOCl, wherein R.sup.12 is as 
defined above. The resulting reaction mixture is stirred for a time period 
between about 30 minutes to about 1.5 hours, preferably about 1 hour, at 
room temperature. 
In reaction 2 of Scheme 2, the benzoic acid methylester of formula XIV is 
converted to the corresponding benzoic acid compound of formula XIII by 
treating XIV with lithium hydroxide monohydrate in the presence of a 2:2:1 
ratio mixture of tetrahydrofuran, methanol and water. The reaction mixture 
is stirred at room temperature for a time period between about 10 hours to 
about 14 hours, preferably about 12 hours. 
In reaction 3 of Scheme 2, the benzoic acid compound of formula XIII is 
converted to the corresponding 4-[1-(R.sup.3 R.sup.4 
carbamoyl)-1H-indol-3-ylmethyl]-benzoic acid compound of formula XII by 
reacting a solution of XIII in a polar aprotic solvent, such as 
dimethylformamide, with a solution of sodium hydride in a polar aprotic 
solvent, such as dimethylformamide, at a temperature between about 
-10.degree. C. to about 10.degree. C., preferably about 0.degree. C. After 
stirring the reaction mixture for a time period between about 10 minutes 
to about 30 minutes, preferably about 20 minutes, a compound of the 
formula R.sup.3 R.sup.4 NCOCl, wherein R.sup.3 and R.sup.4 are as defined, 
is added and the resulting reaction mixture is allowed to stir for an 
additional time period between about 30 minutes to about 1.5 hours, 
preferably about 1 hour. 
In reaction 4 of Scheme 2, the benzoic acid compound of formula XII is 
converted to the corresponding N-o-tolylsulfonylbenzamide compound of 
formula III according to the procedure described above in reaction 4 of 
Scheme 1. 
In reaction 1 of Scheme 3, the compound of formula XI is converted to the 
corresponding 4-(1-difluoromethyl-1H-indol-3-ylmethyl)-benzoic acid 
methylester compound of formula XVII by treating XI with sodium hydride in 
a polar aprotic solvent, such as dimethylformamide. The reaction mixture 
is stirred at room temperature for a time period between about 10 minutes 
to about 30 minutes, preferably about 20 minutes. Freon is then bubbled 
into the reaction mixture for a time period between about 3 minutes to 
about 7 minutes, preferably about 5 minutes, and the resulting reaction 
mixture is quenched with water. 
In reaction 2 of Scheme 3, the 4-[5-nitro-1H-indol-3-ylmethyl]-benzoic acid 
methylester compound of formula XVIII is converted to the corresponding 
4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-benzoic acid 
methylester compound of formula XVII according to the procedure described 
above in reaction 2 of Scheme 1. 
In reaction 3 of Scheme 3, the benzoic acid methylester compound of formula 
XVII is converted to the corresponding benzoic acid compound of formula 
XVI according to the procedure described above in reaction 2 of Scheme 2. 
In reaction 4 of Scheme 3, the benzoic acid compound of formula XVI is 
converted to the corresponding N-o-tolylsulfonylbenzamide compound of 
formula XV according to the procedure described above in reaction 4 of 
Scheme 1. 
In reaction 5 of Scheme 3, the 
4-(1-difluoromethyl-1H-indol-3-ylmethyl)-N-o-tolylsulfonylbenzamide 
compound of formula XV is converted to the corresponding 
4-(1-formyl-1H-indol-3-ylmethyl)-N-o-tolylsulfonylbenzamide compound of 
formula IV by treating a solution of VI in a polar aprotic solvent, such 
as chloroform, with a solution of hydrochloric acid in ether. The 
resulting reaction mixture is stirred at room temperature for a time 
period between about 3 hours to about 5 hours, preferably about 4 hours. 
In reaction 1 of Scheme 4, the compound of formula XXV is converted to the 
corresponding carboxylic acid compound of formula XXIV by hydrogenating 
XXV in the presence of a catalyst, such as 10% palladium on carbon, formic 
acid and a polar aprotic solvent, such as dimethylformamide. 
In reaction 2 of Scheme 4, the carboxylic acid compound of formula XXIV is 
converted to the corresponding 
4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl]-benzoi 
c acid methylester compound of formula XXIII by reacting XXIV with 
4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide 
hydrochloride, triethylamine and 4,4,4-trifluoro-2-methylbutylamine 
hydrochloride in a polar aprotic solvent, such as methylene chloride. The 
reaction mixture was stirred at room temperature for a time period between 
about 10 hours to about 14 hours, preferably about 12 hours. 
In reaction 3 of Scheme 4, the benzoic acid methylester compound of formula 
XXIII is converted to the corresponding benzoic acid compound of formula 
XXII according to the procedure described above in reaction 2 of Scheme 2. 
In reaction 4 of Scheme 4, the benzoic acid compound of formula XXII is 
converted to the corresponding benzoic acid benzylester compound of 
formula XXI by reacting a solution of XXII, triphenylphospine and benzyl 
alcohol in an aprotic solvent, such as tetrahydrofuran, with diethyl 
azodicarboxylate at a temperature between about -10.degree. C. to about 
10.degree. C., preferably about 0.degree. C. The reaction mixture is 
warmed to room temperature and stirred for a time period between about 10 
hours to about 14 hours, preferably about 12 hours. 
In reaction 5 of Scheme 4, the benzoic acid benzylester compound of formula 
XXI is converted to the corresponding 4-[1-(R.sup.3 R.sup.4 
carbamoyl)-1H-indol-3-ylmethyl]-benzoic acid benzylester compound of 
formula XX according to the procedure described above in reaction 3 of 
Scheme 2. 
In reaction 6 of Scheme 4, the benzoic acid benzylester compound of formula 
XX is converted to the corresponding benzoic acid compound of formula XIX 
by hydrogenating XX in the presence of a catalyst, such as 10% palladium 
on carbon and a mixture of tetrahydrofuran ethyl acetate. 
In reaction 7 of Scheme 4, the benzoic acid compound of formula XIX is 
converted to the corresponding N-o-tolylsulfonylbenzamide compound of 
formula V according to the procedure described above in reaction 4 of 
Scheme 1. 
The compounds of the formula I and their pharmaceutically acceptable salts 
(the compounds of the present invention) are useful as selective 
antagonists of leukotriene D4, i.e., they possess the ability to block the 
leukotriene D4 receptor in mammals, and therefore they are able to 
function as therapeutic agents in the treatment of the aforementioned 
disorders and diseases in an afflicted mammal. 
The compounds of the present invention are believed to be antagonists of 
leukotriene D4 and therefore are of value in the treatment of a wide 
variety of clinical conditions the treatment of which are effected or 
facilitated by blocking the leukotriene D4 receptor. Such conditions 
include asthma, rheumatoid arthritis, osteoarthritis, bronchitis, chronic 
obstructive airways disease, psoriasis, allergic rhinitis, atopic 
dermatitis, shock, and other inflammatory diseases. Hence, these compounds 
are readily adapted to therapeutic use as selective antagonists of 
leukotriene D4 for the control and/or treatment of any of the aforesaid 
clinical conditions in mammals, including humans. 
The compounds of the present invention are readily adapted to clinical use 
as selective antagonists of leukotriene D4. The ability of the compounds 
or the pharmaceutically acceptable salts thereof to block the leukotriene 
D4 receptor may be shown by the following in vitro calcium mobilization 
assay. U-937 cells are grown in 50% RPMI 1640, 50% ethylene glycol 
dimethyl ether plus 5% heat inactivated FBS, 2 mM 1-glutamine, 100 
units/100 .mu.g Pen/Strop and 20 mM 
4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid (pH=7.4). Two to four 
days prior to the experiment, U-937 cells are incubated with 1.3% methyl 
sulfoxide, a treatment which is reported to cause chemotaxis and lysosomal 
enzyme release in response to chemical mediators (see: Kay et al., Infect. 
Immun., 41, 1166, (1983)). It appears that U-937 cells are induced to 
differentiate functionally to a human monocyte-like cell line by the 
methyl sulfoxide treatment. The cells are seeded at densities of 
3-8.times.10.sup.5 cells/ml in 50% RPMI 1640, 50% ethylene glycol dimethyl 
ether plus 10% heat inactivated FBS, 2 ml glutamine, 100 units/100 .mu.g 
Pen/Strep, 20 mM 4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid 
(pH=7.4) and 1.35 methyl sulfoxide in spinner culture at 37.degree. C. and 
grown in a closed system. 
Differentiated U-937 cells are harvested on days 2, 3 or 4 by 
centrifugation at 1000 rpm for 5 minutes. After washing 3 times with a 
Krebs-Ringer-Hensleit buffer solution, cells (6-12.times.10.sup.7) are 
resuspended in 15 ml of the buffer (118 mM sodium chloride, 4.6 mM 
potassium chloride, 1.1 mM magnesium chloride, 1 mM calcium chloride, 5 mM 
4-(2-hydroxyethyl)-1-piperazine-ethanesulfonic acid, 24.9 mM sodium 
hydrogen carbonate, 1 mM potassium hydrogen phosphate, 11.1 mM D-glucose 
and 0.1% bis(trimethylsilyl)acetamide, pH=7.4). To this cell suspension is 
added 10 ml of Krebs-Ringer-Hensleit buffer containing 50 .mu.l of 
fura-2/AM [Molecular Probes Catalog #F-1221, 50 .mu.g/vial, dissolved in 
50 .mu.l of silylation grade methyl sulfoxide (Pierce)] prior to an 
addition to the buffer. The cell mixture is then incubated at 37.degree. 
C. for 30 minutes. At the end of incubation, 25 ml of warmed 
Krebs-Ringer-Hensleit buffer (37.degree. C.) is added and the cell 
suspension is centrifuged at 1000 rpm for 5 minutes. The supernatant is 
discarded and the cells are resuspended in fresh warm 
Krebs-ringer-Hensleit buffer. The cell suspension is incubated for an 
additional 15 minutes at 37.degree. C. to allow for complete hydrolysis of 
the intracellular fura-2 ester. Twenty-five mls of cold 
Krebs-Ringer-Hensleit buffer is then added for and the sample is 
centrifuged at 1000 rpm for 5 minutes. The cells are resuspended at a 
final concentration of 1.times.10.sup.7 cells/ml in cold 
Krebs-Ringer-Hensleit buffer and kept at 4.degree. C. until use for 
fluorescence determination. 
The [Ca.sup.2+ ]i response is measured by an SLM DMX-100TM 
spectrofluorometer using an SLM-AMINCO Ion Quantitation Software (Version 
3.5). To set up the instrument, 1.8 ml of warmed Krebs-Ringer-Hensleit 
buffer plus 0.1 ml of fura-2 loaded U-937 cell suspension is placed in a 
curvette chamber containing a magnetic stir bar. Within the calcium 
software, the integration is set at 0.9 seconds and the gain on Channel A 
equal to 100, and adjusted the frequency such that Channel A read 
approximately 4.5-5.0.times.10.sup.4 (Channel B automatically changes 
itself). At the beginning of each experiment, an R.sub.max is determined 
(by addition of 10 .mu.l of 10% Triton X-100 to the curvette which 
contained 1.8 ml warm Krebs-Ringer-Hensleit buffer plus 0.1 ml fura-2 
loaded cells) followed by R.sub.min (by addition of 100 mM of 
ethylenebis(oxyethylenenitrilo)tetraacetic acid to the R.sub.max 
curvette). These values are used by the software to determine [Ca.sup.2+ 
]i concentration from the ratio of fura-2 emission intensities at two 
excitation wavelengths (a ratio of 340 nm to 380 nm). After setting the 
frequency for channel A and then determining R.sub.max and R.sub.min, the 
machine is ready for acquiring [Ca.sup.2+ ]i values. A curvette containing 
1.8 ml of warmed Krebs-Ringer-Hensleit buffer and 0.1 ml of cell 
suspension (2.times.10.sup.6 cells) is placed in the warmed curvette 
holder. The chamber is then closed and the shutters opened. The software 
began to acquire a [Ca.sup.2+ ]i signal from 0 to 20 seconds. After 
injection of either drug or methyl sulfoxide vehicle (2 .mu.l) via a 
special port, the incubation is continued for 180 seconds as the signal is 
still being recorded. At exact 200 seconds an agonist (dissolved in 
methylsulfoxide, 2-6 .mu.l) is injected into the curvette through the same 
port and the signal is recorded for an additional 100 seconds (Total run 
time=5 minutes). [Ca.sup.2+ ]i values are determined by the software (3.5 
version). 
The ability of the compounds of formula I to compete with radiolabelled 
LTD4 for specific receptor cites on guinea pig lung membranes may be 
tested as described by Cheng et al, Biochemical and Biophysical Research 
Communication, 118, 1, 20-26 (1984). 
To evaluate the compounds of the formula I in vivo, they are tested by the 
aerosolized antigen induced airway obstruction assay procedure. 
Male Hartley guinea pigs (300-250 grams) are passively immunized by 
subcutaneous injection of 0.375 mg/kg of purified guinea pig 
anti-ovalbumin IgG1, 48-72 hours prior to antigen challenge. Pyrilamino (5 
mg/kg) and propranolol (2 mg/kg) are administered subcutaneously 30 
minutes prior to challenge. Test compounds are administered into the 
stomach, either one or two hours prior to challenge, as a suspension in 
water and 2% Tween-80 using an Argyl feeding tube. 
Guinea pigs (5/test dose+5 controls) are then placed in a Tri-R Airborne 
infection apparatus (model A42). Ovalbumin (OA, 0.01-0.03% yield) is 
dissolved in 0.9% saline, placed in the glass nobulizer-venturi unit and 
aerosol generated for 5 minutes (main air flowmeter set at 10). This is 
followed by a 8 minute cloud decay (vacuum flow set at 7.0). 
After removal, animals are killed by injection of approximately 2 ml sodium 
pentobarbital. Animals die within 1 to 2 minutes of injection. As soon as 
they die, the animals' pleural spaces are opened by cutting into the 
xyphoid process allowing the lungs to collapse. Lungs are then removed, 
the heart cut away, and the trachea tied. The volume of air trapped air in 
the lugs is determined by measuring the upward force exerted on a 20 gram 
anchor, when the lungs and anchor are submerged in saline. The volume of 
trapped gas is normalised to the animals body weight and expressed as 
excised lung volume (ELGV) in ml/kg. 
A test compounds's performance is judged by its ability to reduce the drug 
treated group mean ELGV below that of the control group mean ELGV. A 
loglinear regression 
EQU ELGV=slope.multidot.log(dose)+intercept 
is performed on the grouped mean data and an ED.sub.50 is calculated as the 
dose necessary to produce a 50% reduction below the control group ELGV. 
EQU ELGV50%=((control ELGV-2)/2)+2) 
Data is reported either as the ED.sub.50 or as the % reduction in control 
ELGV 
EQU % reduction=(control ELGV-test drug ELGV)/control ELGV-2) 
at a given test drug dose. 
For treatment of the various conditions described above, the compounds of 
the present invention can be administered to the patient either alone or, 
preferably, in combination with pharmaceutically acceptable carriers or 
diluents in a pharmaceutical composition according to standard 
pharmaceutical practice. Such administration may be carried out in single 
or multiple doses. A compound can be administered via a variety of 
conventional routes of administration including orally, the dose range 
inhalation, and topically. When the compounds are administered orally, the 
dose range will generally be from about 0.5 to about 50 mg/kg/day for an 
average adult patient, preferably from about 2 to about 20 mg/kg/day in 
single or divided doses. If parenteral administration is desired, then an 
effective dose will generally be from about 0.5 to about 50 mg/kg/day. For 
intranasal or inhaler administration, the dosage will generally be 
formulated as a 0.1 to 1% (w/v) solution given in an amount of about 100 
to about 1,000 .mu.g/dose given 1 to 4 times daily. The compounds of 
formula I can also be administered topically in an ointment or cream in 
concentrations of about 0.5 to about 1%, generally applied 2 or 3 times 
per day to the affected area. In some instances it may be necessary to use 
dosages outside these limits, since the dosage will necessarily vary 
according to the species, age, weight, and response of the individual 
patient, severity of the patient's symptoms, potency of the particular 
compound being administered, type of pharmaceutical formulation chosen, 
and time period and interval at which administration is carried out. 
The compounds of the present invention can be administered in a wide 
variety of different dosage forms, such as in the form of tablets, 
powders, lozenges, troches, hard candies, sprays, creams, slaves, 
suppositories, jellies, gels, pastes, lotions, ointments, syrups or 
capsules, aqueous solutions or suspensions, injectable solutions, elixirs, 
and the like. Such carriers include solid diluents or fillers, sterile 
aqueous media and various non-toxic organic solvents, etc. In general, the 
therapeutically effective compounds of this invention are present in such 
dosage forms at concentration levels ranging from about 5.0% to about 70% 
by weight. 
For oral administration, tablets containing various excipients such as 
microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium 
phosphate and glycine may be employed along with various disintegrants 
such as starch (and preferably corn, potato or tapioca starch), alginic 
acid and certain complex silicates, together with granulation binders like 
polyvinylpyrrolidone, sucrose, gelation and acacia. Additionally, 
lubricating agents such as magnesium stearate, sodium lauryl sulfate and 
talc are often very useful for tabletting purposes. Solid compositions of 
a similar type may also be employed as fillers in gelatin capsules; 
preferred materials in this connection also include lactose or milk sugar 
as well as high molecular weight polyethylene glycols. When aqueous 
suspensions and/or elixirs are desired for oral administration, the active 
ingredient may be combined with various sweetening or flavoring agents, 
coloring matter or dyes, and, if so desired, emulsifying an/or suspending 
agents as well, together with such diluents as water, ethanol, propylene 
glycol, glycerin and various like combinations thereof. 
For parenteral administration (intramuscular, intraperitoneal, subcutaneous 
and intravenous use) a sterile injectable solution of the active 
ingredient is usually prepared. Solutions of a therapeutic compound of the 
present invention in either sesame or peanut oil or in aqueous propylene 
glycol may be employed. The aqueous solutions should be suitably adjusted 
and buffered (preferably pH greater than 8) if necessary and the liquid 
diluent first rendered isotonic. These aqueous solutions are suitable 
intravenous injection purposes. The oily solutions are suitable for 
intraarticular, intramuscular and subcutaneous injection purposes. The 
preparation of all these solutions under sterile conditions is readily 
accomplished by standard pharmaceutical techniques well known to those 
skilled in the art. 
Additionally, it is also possible to administer the compounds of the 
present invention topically and this may preferably be done by way of 
creams, jellies, gels, pastes, ointments and the like, in accordance with 
standard pharmaceutical practice.

The present invention is illustrated by but is not limited to the specific 
details of the following Examples and Preparations. 
EXAMPLE 1 
4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylme 
thyl]-3-methoxy-N-o-tolylsulfonylbenzamide (Formula II: R.sup.3 .dbd.H; 
R.sup.4 .dbd.CH(C.sub.8 H.sub.5).sub.2) 
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (0.50 grams, 1.47 mmol) and triethylamine (0.62 mL, 4.41 mmol) 
in methylene chloride (30 mL), at 0.degree. C., was added a solution of 
phosgene in toluene (1.9 M in toluene, 1.5 mL, 2.9 mmol). The solution was 
warmed to room temperature and stirred for 1 hour. To this was added 
aminodiphenylmethane hydrochloride (0.65 grams, 2.94 mmol) and the 
resulting solution was stirred for 12 hours at room temperature. The 
solution was concentrated in vacuo and the crude triturated with methanol. 
The resulting pale yellow solid was collected via filtration to give 
4-[1-(benzhydryl-carbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid methylester (0.672 grams, 83% yield). 
To a solution of 
4-[1-(benzhydryl-carbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid methylester (0.63 grams, 1.15 mmol) in 1:1 tetrahydrofuran:methanol 
(30 mL) was added 10% palladium on carbon (0.40 grams). The resulting 
mixture was hydrogenated at 30 psi for 2.5 hours. The solution was 
filtered through celite and the filtrate concentrated to give the crude 
product. Chromatography on silica gel (70% ethyl acetate/hexanes) gave the 
corresponding amine (0.556 grams, 93% yield). 
To a solution of the amine so formed (0.53 grams, 1.02 mmol) and 
N-methylmorpholine (0.11 mL, 1.02 mmol) in methylene chloride (30 mL) was 
added cyclopentylchloroformate (0.15 grams, 1.02 mmol). The resulting 
solution was stirred at room temperature for 15 minutes and then treated 
with 1 M hydrochloric acid (aq). The mixture was extracted with methylene 
chloride and the combined organics were dried over magnesium sulfate. 
Concentration in vacuo gave 
4-[1-(benzhydrylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylme 
thyl]-3-methoxy-benzoic acid methylester (0.616 grams, 96% yield). 
To a solution of 
4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylm 
ethyl]-3-methoxy-benzoic acid methylester (0.58 grams, 0.92 mmol) in 2:2:1 
ratio of tetrahydrofuran:methanol:water (30 mL) was added lithium 
hydroxide monohydrate (0.19 grams, 4.50 mmol). The resulting solution was 
stirred at room temperature for 12 hours and then concentrated in vacuo. 
The crude product was treated with 1 M hydrochloric acid (aq), and the 
resulting precipitate collected via filtration to give 
4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylm 
ethyl]-3-methoxy-benzoic acid (0.514 grams, 91% yield). 
To a solution of 
4-[1-(benzhydryl-carbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylm 
ethyl]-3-methoxy-benzoic acid (0.50 grams, 0.81 mmol), 
4-dimethylaminopyridine (0.015 grams, 1.21 mmol) and 
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (0.23 
g, 1.21 mmol) in methylene chloride (30 mL) was added o-tolylsulfonamide 
(0.14 g, 0.81 mmol). The resulting solution was stirred for 12 hours at 
room temperature. The solution was diluted with methylene chloride and 
washed with 1 M hydrochloric acid (aq). The organics were dried over 
magnesium sulfate and concentrated. Chromatography on silica gel (2% 
methanol/methylene chloride), followed by recrystallization from wet ether 
gave the titled compound (0.455 grams, 73% yield). m.p.=253-254.degree. C. 
Anal. calcd. for C.sub.44 H.sub.42 N.sub.4 O.sub.7 S: C, 68.55; H, 5.49; 
N, 7.27. Found: C, 69.21; H, 5.54; N, 7.14. HRMS calcd. for C.sub.44 
H.sub.42 N.sub.4 O.sub.7 S: 770.2774. Found 770.2736. 
EXAMPLE 2-10 
Reaction of the appropriate compound of the formula NHR.sup.3 R.sup.4 with 
the requisite 
4-[1-(chlorocarbonyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester intermediate, analogous to the procedure of Example 1, affords 
the following compounds of formula II. 
______________________________________ 
R.sup.3 and R.sup.4 
M.p..degree. 
Ex. # R.sup.3 R.sup.4 taken together C. M.W. 
______________________________________ 
2 hydrogen benzyl -- 175 694.8 
3 hydrogen 2-methoxybenzyl -- 202 724.8 
4 -- -- 4-chloro-phenyl- 160 910.9 
phenyl-methyl 
piperazine 
5 hydrogen 1-phenylethyl -- 172 708.8 
6 hydrogen phenethyl -- 130 708.8 
7 hydrogen 3-phenylpropyl -- 125 722.9 
8 hydrogen 2-dimethyl- -- 182 675.8 
aminoethyl 
9 hydrogen 3-pyridyl -- 277 681.8 
10 methyl 4-fluorophenyl -- 140 712.8 
______________________________________ 
EXAMPLE 11 
4-[1-(dimethylcarbamoyl)-5-(cyclopentyloxycarbonylamino-1H-inol-3-ylmethyl] 
-3-methoxy-N-o-tolylsulfonylbenzamide (Formula III: R.sup.3 .dbd.CH.sub.3 ; 
R.sup.4 .dbd.CH.sub.3 ; R.sup.12 .dbd.cyclopentyl) 
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (0.82 grams, 2.41 mmol) in ethanol (50 mL) was added tin (II) 
chloride dihydrate (2.70 grams, 12.05 mmol), and the resulting mixture was 
heated at reflux for 24 hours. The solution was cooled, then concentrated 
in vacuo. The crude product was treated with 2M sodium hydroxide and 
extracted with methylene chloride. The combined organics were dried over 
magnesium sulfate and concentrated. Chromatography on silica gel (40% 
ethyl acetate/hexanes.fwdarw.2% methanol/methylene chloride) gave the 
corresponding amine (0.618 grams, 83% yield). 
To a solution of the amine so formed (0.618 grams, 2.00 mmol) and 
N-methylmorpholine (0.22 mL, 2.00 mmol) in methylene chloride (30 mL) was 
added cyclopentylchloroformate (0.30 grams, 2.0 mmol). The resulting 
solution was stirred at room temperature for 1 hour. The solution was then 
diluted with methylene chloride and washed with 1 M hydrochloric acid 
(aq). The organics were dried over magnesium sulfate and concentrated in 
vacuo. Chromatography on silica gel (1:1 ethyl acetate:hexanes) gave 
4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid methylester (0.822 grams, 97% yield). 
To a solution of 
4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid methylester (0.82 grams, 1.95 mmol) in a 2:2:1 ratio of 
methanol:tetrahydrofuran:water (30 mL) was added lithium hydroxide 
monohydrate (0.41 grams, 0.73 mmol). The resulting solution was stirred 
for 12 hours at room temperature. The solution was concentrated, and the 
crude product treated with 1 hydrochloric acid (aq). The product was 
collected via filtration. Chromatography on silica gel (1:1 hexanes:ethyl 
acetate.fwdarw.5% methanol:methylene chloride) gave 
4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid (0.735 grams, 92 yield). 
To a slurry of sodium hydride (60% by wt in mineral oil, 0.037 grams, 0.77 
mmol) in dimethylformamide (5 mL), at 0.degree. C., was added a solution 
of 4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy-benzo 
ic acid (0.15 grams, 0.37 mmol) in dimethylformamide (5 mL). The resulting 
solution was stirred at 0.degree. C. for 20 minutes, then 
dimethylcarbamoyl chloride (0.071 mL, 0.77 mmol) was added. The solution 
was warmed to room temperature and stirred for 1 hour. The reaction was 
quenched by addition of 1 M sodium hydroxide (aq), and the mixture was 
extracted with ethyl acetate. The combined organics were washed with 1 M 
hydrochloric acid (aq) and set aside. The aqueous phase was made acidic 
with 1 M hydrochloric acid (aq) and extracted with ethyl acetate. All the 
organics were combined and dried over magnesium sulfate and concentrated. 
Chromatography on silica gel (2% methanol/methylene chloride) gave 
4-[1-(dimethylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmeth 
yl]-3-methoxy-benzoic acid (0.16 grams, 89% yield). 
To a solution of 
4-[1-(dimethylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmeth 
yl]-3-methoxy-benzoic acid (0.16 grams, 0.33 mmol), 4-dimethylaminopyridine 
(0.060 grams, 0.50 mmol) and 
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride 
(1,2-dichloroethane) (0.096 grams, 0.50 mmol) in methylene chloride (15 
mL) was added o-tolylsulfonamide (0.059 grams, 0.34 mmol). The resulting 
solution was stirred for 12 hours at room temperature. The solution was 
diluted with methylene chloride and washed with 1 M hydrochloric acid 
(aq). The organics were dried over magnesium sulfate and concentrated. 
Chromatography on silica gel (methylene chloride.fwdarw.2% 
methanol/methylene chloride), followed by recrystallization from wet ether 
gave the titled compound (0.094 grams, 455 yield). m.p.=152-153.degree. C. 
HRMS calcd. for C.sub.33 H.sub.36 N.sub.4 O.sub.7 S: 632.2348. 
EXAMPLES 12-20 
Reaction of the appropriate compound of the formula R.sup.12 OCOCl with the 
requisite 4-[5-amino-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
ethylester intermediate and the reaction of the appropriate compound of 
the formula R.sup.3 R.sup.4 NCOCl with the requisite 
4-[5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxybenzoic 
acid intermediate, analogous to the procedure of Example 11, affords the 
compounds of formula III. 
______________________________________ 
R.sup.3 and R.sup.4 
taken 
Ex. # R.sup.3 R.sup.4 together R.sup.12 M.P. .degree. C. M.W. 
______________________________________ 
12 ethyl ethyl -- cyclopentyl 
138 660.8 
13 -- -- morpholinyl cyclopentyl 146 674.8 
14 methyl phenyl -- cyclopentyl 138 694.8 
15 phenyl phenyl -- cyclopentyl 150 756.9 
16 -- -- pyrrolidinyl cyclopentyl 190 658.8 
17 ethyl ethyl -- endo- 195 686.8 
bicyclo- 
[2.2.1]- 
heptanyl 
18 phenyl phenyl -- endo- 206 782.9 
bicyclo- 
[2.2.1]- 
heptanyl 
19 phenyl phenyl -- exo-bicyclo- 239 782.9 
[2.2.1]- 
heptanyl 
20 ethyl ethyl -- exo-bicyclo- 223 686.8 
[2.2.1]- 
heptanyl 
______________________________________ 
EXAMPLE 21 
4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3- 
ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide (Formula II: R.sup.3 
.dbd.4-fluorophenyl; R.sup.4 .dbd.hydrogen) 
To a stirred solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid methylester (1.30 grams, 3.82 mmol) and 4-dimethylaminopyridine (0.58 
mL, 4.77 mmol) in methylene chloride (60 mL) was added 
4-fluorophenylisocyanate (0.70 mL, 5.73 mmol). The resulting solution was 
stirred for 18 hours, at room temperature, and then diluted with methylene 
chloride. The solution was washed with 1 M hydrochloric acid, water and 
brine, then dried over magnesium sulfate. Concentration in vacuo followed 
by trituration in diethylether gave 
4-[1-(4-fluoro-phenylcarbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-ben 
zoic acid methylester (1.60 grams, 88% yield). 
To a solution of 
4-[1-(4-fluoro-phenylcarbamoyl)-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-ben 
zoic acid methylester (1.50 grams, 3.14 mmol) in a 1:1 ratio of 
tetrahydrofuran:ethyl acetate (200 mL) was added 10% palladium on carbon 
(1.50 grams) and the resulting mixture was hydrogenated at 30 psi at room 
temperature for 1 hour. The mixture was filtered through celite and the 
filtrate concentrated in vacuo to give the crude product. Trituration in 
ethyl acetate/hexanes gave the corresponding amine (1.20 grams, 86% 
yield). 
To a solution of the amine so formed (1.17 grams, 2.61 mmol) and 
N-methylmorpholine (0.60 mL, 5.23 mmol) in methylene chloride (10 mL) was 
added cyclopentylchloroformate (0.39 grams, 2.61 mmol). The solution was 
stirred at room temperature for 18 hours, then diluted with ethyl acetate. 
The resulting solution was washed with 1 M hydrochloric acid (aq), 5% 
sodium hydrogen carbonate (aq), water, and brine, then dried over 
magnesium sulfate. Concentration in vacuo, followed by recrystallization 
from ethyl acetate/hexanes gave 
4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3 
-ylmethyl]-3-methoxy-benzoic acid methylester (1.35 grams, 92% yield). 
To a solution of 
4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3 
-ylmethyl]-3-methoxy-benzoic acid methylester (1.30 grams, 2.32 mmol) in a 
1:1:1 ratio of tetrahydrofuran:methanol:water (30 mL) was added lithium 
hydroxide monohydrate (0.20, 4.64 mmol) and the resulting solution was 
stirred, at room temperature, for 22 hours. The reaction mixture was made 
acidic with 1 M hydrochloric acid (aq) and extracted with chloroform. The 
combined organics were washed with water and brine then dried over 
magnesium sulfate. Concentration in vacuo gave 
4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)-amino-1H-indol- 
3-ylmethyl]-3-methoxy-benzoic acid (1.20 grams, 95% yield). 
To a stirred suspension of 
4-[1-(4-fluoro-phenylcarbamoyl)-5-(cyclopentyloxycarbonyl)-amino-1H-indol- 
3-ylmethyl]-3-methoxy-benzoic acid (1.28 grams, 2.35 mmol), 
o-tolylsulfonamide (0.44 grams, 2.58 mmol), and 4-dimethylaminopyridine 
(0.34 grams, 2.82 mmol) in methylene chloride (40 mL) was added 
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.54 grams, 
2.82 mmol). The mixture was stirred at room temperature for 18 hours, then 
diluted with methylene chloride. The solution was washed with 1 M 
hydrochloric acid (aq), water and brine then dried over magnesium sulfate. 
Concentration in vacuo, followed by chromatography on silica gel (1:19 
methanol:methylene chloride) gave 1.3 grams of the titled compound as a 
foam. Further purification by triturating in methylene chloride gave the 
titled compound (0.810 grams, 49% yield). m.p.=230.degree. C. (decomp.). 
Anal. calcd. for C.sub.37 H.sub.35 N.sub.4 SO.sub.7 F.multidot.2 water: C, 
60.48, H, 5.35; N, 7.62. Found: C, 59.75; H, 5.22; N, 7.57. 
EXAMPLES 22-26 
Reaction of the appropriate compound of the formula R.sup.3 NCO with the 
requisite 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester intermediate, analogous to the procedure of Example 21, 
affords the following compounds of formula II, wherein R.sup.4 is 
hydrogen. 
______________________________________ 
Example # 
R.sup.3 M.P..degree. C. 
M.W. 
______________________________________ 
22 methyl 182 618.7 
23 tert-butyl 160 660.9 
24 2,4-difluorophenyl 190 716.8 
25 2-chlorophenyl -- 715.1 
26 phenyl -- 680.8 
______________________________________ 
EXAMPLE 27 
4-[1-(carbomoyl)-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-met 
hoxy-N-o-tolylsulfonylbenzamide 
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (5.04 grams, 14.80 mmol) in methylene chloride (150 mL) was 
added chlorosulfonylisocyanate (1.3 mL, 14.80 mmol) and the resulting 
solution was stirred for 5 days at room temperature. The solution was then 
concentrated in vacuo, and the crude product dissolved in a 6:1 ratio of 
acetone:water (180 mL). The pH of this solution was adjusted to approx. 8 
by the addition of 2 M sodium hydroxide (aq). The resulting mixture was 
stirred, at room temperature, for 45 minutes. The reaction was diluted 
with water (300 mL) and the resulting suspension was stirred for 30 
minutes. Filtration, followed by trituration of the solid in methanol gave 
4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (1.75 grams). The filtrate was concentrated, and the crude 
chromatographed on silica gel (2.5% methanol/methylene chloride) to give 
additional 4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic 
acid methylester (0.36 grams, 37% yield overall). 
To a solution of 
4-[1-carbamoyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (1.99 grams, 5.19 mmol) in a 4:1 ratio of 
tetrahydrofuran:ethyl acetate (250 mL) was added 10% palladium on carbon 
(1.5 grams) and the resulting mixture was hydrogenated at 35 psi, at room 
temperature, for 3.5 hours. The mixture was filtered through celite, and 
the filtrate concentrated in vacuo. Recrystallization form a 4:1 ratio of 
methylene chloride:methanol gave the corresponding amine (0.727 grams). 
The mother liquor was concentrated and the crude chromatographed on silica 
gel (5% methanol/methylene chloride) to give additional amine (0.446 
grams, 64% overall). 
To a solution of the amine so formed (1.16 grams, 3.28 mmol) and 
N-methylmorpholine (0.072 mL, 6.56 mmol) in methylene chloride (40 mL) was 
added cyclopentylchloroformate (0.68 grams, 4.59 mmol). The resulting 
solution was stirred, at room temperature, for 3 days, then diluted with 
methylene chloride. The resulting solution was washed with 1 M 
hydrochloric acid (aq), water, and brine, then dried over sodium sulfate. 
The combined aqueous washings contained a suspension, which upon 
filtration gave 
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-meth 
oxy-benzoic acid methylester (1.05 grams). The organic phase was 
concentrated in vacuo, followed by chromatography on silica gel (25% ethyl 
acetate/methylene chloride) to give additional 
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-meth 
oxy-benzoic acid methylester (0.118 grams, 76% yield overall). 
To a solution of 
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-meth 
oxy-benzoic acid methylester (1.15 grams, 2.47 mmol) in a 6:1 ratio 
tetrahydrofuran:water (70 mL) was added lithium hydroxide monohydrate 
(0.21 grams, 4.94 mmol) and the resulting solution was stirred, at room 
temperature, for 46 hours. The reaction mixture was concentrated in vacuo 
to a volume of 15 mL, then diluted with water (300 mL). The aqueous 
solution was acidified by addition of 1 M hydrochloric acid (aq), and the 
resulting precipitate was collected via filtration to give 
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-meth 
oxy-benzoic acid (1.04 grams, 93% yield). 
To a suspension of 
4-[1-carbamoyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-meth 
oxy-benzoic acid (1.03 grams, 2.28 mmol), o-tolylsulfonamide (0.39 grams, 
2.28 mmol) and 4-dimethylaminopyridine (0.42 grams, 3.42 mmol) in 
methylene chloride (50 mL) was added 
1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (0.66 grams, 
3.42 mmol). The reaction was stirred for 4 days at room temperature, then 
diluted with methylene chloride (700 mL). This solution was washed with 1 
M hydrochloric acid (aq), water, and brine, then dried over sodium 
sulfate. Concentration in vacuo, followed by chromatography on silica gel 
(10% methanol/methylene chloride) gave the titled compound (0.90 grams, 
65% yield). HRMS calcd. for C.sub.31 H.sub.32 N.sub.4 O.sub.7 Na: 
627.1904. Found: 611.1924. 
EXAMPLE 28 
4-(1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl-3-m 
ethoxy-N-o-tolylsulfonylbenzamide 
To a solution of 4-[5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (0.15 grams, 0.44 mmol) in dimethylformamide (5 mL) was added 
sodium hydride (60% by wt. in mineral oil, 0.019 grams, 0.48 mmol). After 
stirring 20 minutes, at room temperature, freon was bubbled into the 
reaction mixture for approximately 5 minutes. The reaction was accompanied 
by a color change from deep-red/brown to a light green/yellow. The 
reaction was quenched by addition of water, and the solution was extracted 
with ethyl acetate. The combined organics were washed with water and 
brine, then dried over sodium sulfate. Concentration in vacuo, followed by 
chromatography on silica gel (methylene chloride) gave 
4-[1-difluoromethyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (0.128 grams, 75% yield). 
To a solution of 
4-[1-difluoromethyl-5-nitro-1H-indol-3-ylmethyl]-3-methoxybenzoic acid 
methylester (0.39 grams, 1.00 mmol) in tetrahydrofuran (50 mL) was added 
10% palladium on carbon (0.20 grams). The resulting solution was 
hydrogenated at 40 psi at room temperature for 4 hours. The mixture was 
filtered through celite and washed with tetrahydrofuran. The filtrate was 
concentrated in vacuo to give the crude product as a foam. Chromatography 
on silica gel (5% methanol/methylene chloride) gave the corresponding 
amine (0.15 grams, 42% yield). 
To a solution of the amine so formed (0.15 grams, 0.42 mmol) and 
N-methylmorpholine (0.14 mL, 1.26 mmol) in methylene chloride (8 mL), at 
0.degree. C., was added cyclopentylchloroformate (0.058 mL, 0.47 mmol). 
The resulting solution was warmed to room temperature and stirred for 12 
hours. The reaction mixture was treated with water and extracted with 
methylene chloride. The combined organics were washed with 1 M 
hydrochloric acid (aq) and brine then dried over sodium sulfate. 
Concentration in vacuo, followed by chromatography (10% ethyl 
acetate/methylene chloride) gave 
4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3 
-methoxy-benzoic acid methylester (0.185 grams, 95% yield). 
To a solution of 
4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3 
-methoxy-benzoic acid methylester (0.40 grams, 0.84 mmol) in a 5:5:2 ratio 
of methanol tetrahydrofuran:water (24 mL) was added lithium hydroxide 
monohydrate (0.18 grams, 4.18 mmol). The resulting solution was stirred 
for 24 hours at room temperature. The reaction mixture was then acidified 
with 1 M hydrochloric acid (aq) and extracted with ethyl acetate. The 
combined organics were washed with water and brine, then dried over sodium 
sulfate. Concentration in vacuo gave 
4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3 
-methoxy-benzoic acid as a white solid (0.40 grams, 1005 yield). An 
analytical sample was attained by recrystallization from ethyl 
acetate/hexanes. 
To a solution of 
4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3 
-methoxy-benzoic acid (1.10 grams, 2.37 mmol), 4-dimethylaminopyridine 
(0.44 grams, 3.63 mmol) and 1-[3-dimethylamino)propyl]-3-ethylcarbodiimide 
hydrochloride (1,2-dichloroethane) (0.70 grams, 3.64 mmol) in methylene 
chloride (100 mL) was added o-tolylsulfonamide (0.41 grams, 2.42 mmol). 
The resulting solution was stirred for 16 hours at room temperature. The 
solution was diluted with methylene chloride and washed with 1 M 
hydrochloric acid (ag) and brine. The organics were dried over sodium 
sulfate and concentrated. Chromatography on silica gel (5% 
methanol/methylene chloride gave 
4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3 
-methoxy-N-o-tolylsulfonylbenzamide (1.10 grams, 76% yield). HRMS calcd. 
for C.sub.31 H.sub.31 N.sub.3 O.sub.6 F.sub.2 S: 611.1902. Found: 
611.1924. 
EXAMPLE 29 
4-[1-formyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3-methoxy- 
N-o-tolylsulfonylbenzamide 
To a solution of 
4-[1-difluoromethyl-5-(cyclopentyloxycarbonyl)amino-1H-indol-3-ylmethyl]-3 
-methoxy-N-o-tolylsulfonylbenzamide (0.10 grams, 0.16 mmol) in chloroform 
(5 mL) was added a solution of hydrochloric acid (1 M in ether, 0.16 mL, 
0.16 mmol). The resulting solution was stirred for 4 hours, at room 
temperature, then concentrated in vacuo. Chromatography on silica gel (5% 
methanol, methylene chloride) gave the titled compound (0.92 grams, 96% 
yield). m.p.=145.degree. C. (decomp.) HRMS calcd. for C.sub.31 H.sub.31 
N.sub.3 O.sub.7 : 590.1961. Found: 590.1914. 
EXAMPLE 30 
4-[1-diethylcarbamoyl-5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol- 
3-ylmethyl]-3-methoxy-N-o-tolylsulfonylbenzamide (Formula V: R.sup.3 
.dbd.C.sub.2 H.sub.5 ; R.sup.4 .dbd.C.sub.2 H.sub.5) 
To a solution of 
4-[5-benzoxycarbonyl-1H-indol-3-ylmethyl]-3-methoxy-benzoic acid 
methylester (3.46 grams, 8.06 mmol) in dimethylformamide (40 mL) and 
formic acid (2 mL) was added 10% palladium on carbon (1.5 grams). The 
resulting mixture was hydrogenated at 30 psi for 1.5 hours. The mixture 
was filtered through celite and the filtrate diluted with ethyl acetate. 
This solution was washed several times with 1 M hydrochloric acid (aq). 
The organics were then dried over magnesium sulfate and concentrated. 
Recrystallization from methylene chloride gave 
3-(2-methoxy-4-methoxycarbonyl-benzyl)-1H-indole-5-carboxylic acid (1.97 
grams, 73% yield). 
To a solution of 
3-(2-methoxy-4-methoxycarbonyl-benzyl)-1H-indole-5-carboxylic acid (1.7 
grams, 5.00 mmol) in methylene chloride (50 mL), was added 
4-dimethylaminopyridine (0.67 grams, 5.50 mmol), 1,2-dichloroethane (1.06 
grams, 5.50 mmol), triethylamine (0.73 mL, 5.25 mmol) and 
4,4,4-trifluoro-2-methylbutylamine hydrochloride (0.93 grams, 5.25 mmol). 
The resulting solution was stirred 12 hours, at room temperature, then 
diluted with methylene chloride. The solution was washed with 1 M 
hydrochloric acid (aq), then the organics were dried over magnesium 
sulfate. Concentration in vacuo followed by trituration of the crude 
product in a 2:1 ratio of ether:hexanes gave 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid methylester (1.88 grams, 82% yield). 
To a solution of 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid methylester (1.80 grams, 3.90 mmol) in 2:2:1 
methanol:tetrahydrofuran:water (30 mL) was added lithium hydroxide 
monohydrate (0.82 grams, 19.50 mmol). The resulting solution was stirred, 
at room temperature, for 48 hours then concentrated in vacuo. The 
resulting crude product was treated with 1 M hydrochloric acid (aq), and 
the resulting precipitate was collected via filtration to vie 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid (1.74 grams, 99% yield). 
To a solution of 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid (1.54 grams, 3.43 mmol), triphenylphosphine (1.26 grams, 
4.8 mmol) and benzyl alcohol (0.50 mL, 4.8 mmol) in tetrahydrofuran (50 
mL), at 0.degree. C., was added diethyl azodicarboxylate (0.65 mL, 4.1 
mmol). The reaction is then warmed to room temperature and stirred 12 
hours. Concentration in vacuo followed by chromatography on silica gel 
(1:1 hexanes:ethyl acetate) gave 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid benzylester with impurities present. The product was 
dissolved in cold ether, and filtered. The filtrate was concentrated, and 
the remaining yellow foam was chromatographed on silica gel (1:1 
cyclohexane:ethyl acetate) to give 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid benzylester (1.56 grams, 87% yield). 
To a slurry of sodium hydride (60% by wt. in mineral oil, 0.035 grams, 0.72 
mmol) in dimethylformamide (3 mL), at 0.degree. C., was added 
3-methoxy-4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmeth 
yl]-benzoic acid benzylester (0.35 grams, 0.65 mmol). The resulting 
solution was stirred for 15 minutes, at 0.degree. C., then 
diethylcarbamoyl chloride (0.082 mL, 0.65 mmol) was added. The solution 
was warmed to room temperature and stirred for 12 hours. The solution was 
diluted with ethyl acetate and washed with 1 M hydrochloric acid (aq). The 
organics were dried over magnesium sulfate and concentrated in vacuo. 
Chromatography on silica gel (30% ethyl acetate/hexanes) gave the 
1-indole-diethylamide analog (0.316 grams, 76% yield). 
To a solution of the ureido compound (0.30 grams, 0.47 mmol) in ethyl 
acetate (30 mL) was added 10% palladium on carbon (0.20 grams). The 
mixture was hydrogenated at 30 psi for 2 hours, then filtered through 
celite and concentrated in vacuo. Chromatography on silica gel 
(ether.fwdarw.5% methanol/methylene chloride) gave 
4-[1-diethylcarbamoyl-5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol 
-3ylmethyl]-3-methoxy-benzoic acid (0.197 grams, 76% yield). 
To a solution of 
4-[1-diethylcarbamoyl-5-(4,4,4-trifluoro-2-methylbutylcarbamoyl)-1H-indol- 
3-ylmethyl]-3-methoxy-benzoic acid (0.12 grams, 0.22 mmol), 
4-dimethylaminopyridine (0.040 grams, 0.33 mmol) and 1,2-dichloroethane 
(0.063 grams, 0.33 mmol) in methylene chloride (15 mL) was added 
o-tolylsulfonamide (0.038 grams, 0.22 mmol). The resulting solution was 
stirred, at room temperature, for 12 hours. The reaction mixture was then 
diluted with methylene chloride and washed with 1 M hydrochloric acid 
(aq). The organics were dried over magnesium sulfate and concentrated in 
vacuo. Recrystallization from wet ether gave the titled compound (0.115 
grams, 75% yield), m.p.=153-154.degree. C. Anal calcd. for C.sub.35 
H.sub.39 H.sub.4 O.sub.6 SF.sub.3 : C, 59.92; H, 5.60; N, 7.99. Found: C, 
60.18; H, 5.68; N, 8.41. 
EXAMPLES 31-32 
Reaction of the appropriate compound of formula R.sup.3 R.sup.4 NCOCl with 
the requisite 
4-[5-(4,4,4-trifluoro-2-methyl-butylcarbamoyl)-1H-indol-3-ylmethyl benzoic 
acid intermediate, analogous to the procedure of Example 29, affords the 
compound of formula V. 
______________________________________ 
Example # R.sup.3 R.sup.4 M.P..degree. C. 
M.W. 
______________________________________ 
31 methyl phenyl 157 734.8 
32 phenyl phenyl 168 796.9 
______________________________________