CA1288352C - Indole-2-alkanoic acids - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE
Indole-2-alkanoic acids are disclosed. The compounds have the following general formula:

Description

INDOL~-2-ALKA~OIC ACIDS
This is a divisional of application S.N. 484,174 filed June 17, 1985.
This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as aller~ic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur.
These compounds antagonize the actions of contractile prostaglandins, such as PGF2~, PGG2, PGH2, PG~2 and TXA2. The use of agents which act as prostaglandin antagonists offers new approaches to therapy in a number of disease states. For example, certain prostaglandins, such as PGF2~, PGD2, PGG2, and PGH2, are potent contractants of bronchial muscle. Indeed human asthmatics have been sho~n to be especially sensitive to the bronchial constricting action of PGF2~.

~ ~813~.

2B94PJ1039~ - 2 - 17102IA

The compounds of the present invention also peoduce antithrombotic effects. Thus, they are useful in the treatment and~or prevention of thromboembolic diseases such as aeterial thrombo6is.
In addition to the involvement o~
contractile prostaglandins in chronic obstructive lung disease (or asthma), erostaglandins are known to play a role in other allergic conditions, as well as inflammation, diarrhea, hypertension, angina, L0 platelet aggregation, cerebral spasm, cerebral ischemia, myocardial ischemia, prematuLe labor, spontaneous abortion, dismenorrhea, glomerular nephritis, and systemic lupus erythematosis.
Consequently, the com~ounds of this invention will alleviate the above mentioned diseases.
In addition to the prostaglandin antagonist actions, the compounds of this invention are inhibitors of the synthesis of leukotrianes.
Leukotrienes B4, C4, D4 and E4 are known to contribute to various disease conditions such as asthma, esoriasis, in~lammation, pain, ulcers and systemic anaehylaxis. Thus inhibition o~ the syn~hesis of such compounds will alleviate these disease states.
The compounds o~ the present inventi~n may be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis;
erosive esophagitis; inflammatory bowel disease:
ethanol-induced hemorrhagic erosions; hepatic ischemia; noxious agent induced damage or necrosis of hepatic, panc~eatic, renal, or myocardial tissue;
liver parenchymal damage caused by hepatoxic agents 3Si~
2893P/1046~
2894P~1039~ - 3 - 17102IA

6uch a~ CC14 and D-galacto~amine; ischemic renal failure; disea6e-induced hepatic damage; bile salt induced pancreatic or ga~tric damage; trauma- or stres6-induced cell damage; and glycerol-induced renal failure.
The pre~ent invent~on relat2~ to a pharmaceutical composition comprlsing a compound o~
the Formula I:

5 ~ 2 ? ~H-R

wherein:
R is H or alkyl of I to 6 carbons or Rl and R8 taken together form a group (CH2)~
wherein u is 1 to 7;

R2 i5 ~b~r EX~lp~(~)q~R9 wherein:
each R i~ lndependently H, OH, Cl to C4-0-al~yl or alkyl o~ 1 to 4 carbons: or an R
and an R taken together form a g~ou~ (CH2)V
wherein v i6 1 to 7.

2893PJ1046~

R i~ COOR : CH20H; CHO: tetrazole NHS02R10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or ehenyl substituted by alkyl or alkoxy g~oup6 of 1 to 3 carbons, halogen, hyd~oxy, COOH, CN, formyl or acyl to 1 to 6 carbons; CONHS02R
hydroxymethylketone; CN; or CON(R8)2:
X is O; S; SO; S02; NRLl wherein Rll is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, LO CN; CR R :
R,l R8 or the unit -C~ wherein the dotted line ~e~esents an oetional tri~le bond and in which the R and R substituents are absent when a t~iele lS bond is p~esent;
r and q are each inde~endently O to S and p i8 0 0~ 1 pcovided that the total of p, q and r is 2 to 6;
R is H, alkyl o~ 1 to 6 carbons: ehenyl or phenyl substituted by R ; or Cl to C4 alkyl-~henyl o~ CL to C4 alkylehenyl in which the ~henyl is substituted by R4:
R , R , R and R are each independently selected ~rom:
(~) hyd~ogen:
t2) alkyl having 1 to 6 carbon atoms;
(3) alkenyl having 2 to 6 carbon atoms;
(4) -(CH2~nM
wherein n is O to 3 and M is a) oR12 b) halogen;
c) CF3:

~ - - ~

2893PtlO4hA
2894P~1039~ - S - 17L02IA

d) SR
e) ehenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12;
f) COOR

g) ~-R
h) tetrazole;

i~ -NH-C-R15 wheeein R is Cl to C6 alkyl. benzyl OL
ehenyl j~ ~R13R13;
k) -NHS02Rl wheeein R16 i5 Cl to C6 alkyl, ehenyl, oe CF3;

1 ) -C-CH20H;

~) -SOR
n) CoNRL3RL3;
o~ -S02NR ~ ;
p) -SO2RlZ;
q) NO2;

r) o-C-R14:

s) 0-C-NR R
O
t) o-lC-oRl5;
u) CN;

5~
2~93P/1046~
2894P/1039~ - 6 - 17102IA

each Rl inde~endently ifi H; Cl to C6 alkyl; berlzyl; phenyl or substituted ~henyl ~hecein the 6ub~tituents are Cl to C3 alkyl, halogen. CN, CF3, CooR13, CH2COOR , Cl to C3 alkoxy, or Cl to C4 perfluoroal~yl;
each R13 ic independently H, phenyl or Cl to C6 alkyl; and, each R14 independently is H. (CH23nCOOR 3 wherein n i6 0 to 4, CL ~o C~ alkyl. CF3, phenyl, or substituted ehenyl whecein sub6tituted phenyl iz a6 deflned above in the deinitio~ o~ R
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

A6 used herein, the term~ "aach independently" or the equivalents thereo are emeloyed to describe a number of po~ible pos~tion isomers and/or structural variations. For examele, as described above, R i8:
R ¦-- 1 R
~(~)r~ ~X~~p~(C)q~R

~he letters r and q, represent possible al~ane chains of from O to 5 carbon atoms, each having the R and R substituent groups. On each ca~bon atom o~ the alkane chain. the Rl and~or Ra substituent may be diffeLent. The above de6cription therefore contemplates structures 6uch as the following for the segment~ -~CR R )r~ and ~~CRlR~)q~:

~l Z~s~335~

2~94P/L039~ - 7 - 171~2IA

3 ~ 3 C - C ~ C - C - ) bH ~ H3 ~ ~H2-CH3 H
C -- C--) ~ -- C -- C -- C -- C--) bH CH3 OH ~ OH ~H3 ~ ~
H H r (-C C - C-) , and the like.

The al~yl group~ referred to above ~ay be st~aight chain or b~anched or may include cycloalkyl lS groues. As used herein, the term "lo~er" a~ applied to alkyl, acyl. alkoxy and the like, unles6 stated otherwise refers to grou~s havinq 1 to 6 carbon atoms. Halogen or halo means fluoro, chloro, b~omo and~or iodo.
Pharmaceu~ically acceptable salts of the compound6 descrlbed herein are included within the ~cope of the present invention. Such salts may be prepared from pharmaceutically aCceetablQ non-toxic bas~s including inorganic ba~es and organic ba~es.
Salt~ derived ~rom inorganic bases include sodium, potassium, lithium, ammonium, calcium, magne6ium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic salts and the like. Particularly ereferred are the pota~sium, sodium calcium and magnesium ~alts. Salts derived from ~harmaceutically acceetable organic non-toxic bases include salts o~
p~imary, seconda~y, and tertiary amines, sub~tituted 335~

2~94P/1039A - 8 - 17102IA

amines including naturally occurring ~ubstituted amines, cyclic amines and basic ion exchange resin~, such as isoeropylamlne. tri-methylamine, diethanol-amine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylamino-ethanol, tomethamine, lysine, arginine, his~idine, ca~feine, procaine, hydrabamine, choline~ imidazole, betaine, ethylenediamine, glucosamine, methyl-glucamine, theob~omine, ~urines piperazine, N,N-dibenzylethylenediamine, piperidine, N-ethyl-piperidine, morpholine, N-ethylmorpholine, polyamine resins and the like.
Preferred compositions of the present invention comprise compounds of the Formula I wherein:
lS each R i~ H or alkyl of 1 to 6 carbons or R and R taken together form a group (CH2)V
whe~ein v i8 1 eO 7;
R2 is ~(~)r~ EX-~P ~ ~ q wherein:
each R i~ independently H, OH, Cl to C4-0 alkyl or alkyl of 1 to 4 carbon~; or an and an R taken together form a ~roup (CH~?~
wherein v i5 1 to 7;
R is COOR ; CH20H; CHO; tetrazole;
CONHS02Rlg wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, eerhaloalkyl of 1 to 6 carbon~, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbon~; hydroxymethyl-ketone; CN; or CON(R )2;

~2~3SX
2893P~1046~
2n94p~lo39A - 9 17102IA

X is O; S; SO; S02; NR whe~ein R
is Ho alkyl of 1 to 6 carbons, acyl of 1 to 6 ca~bons, CN; CR R
Rl R8 o~ ~he unit -C-~C- wherein the dotted line ~ep~esen~s an oetional triple bond and in which the R and R substituents are absent when a triple bond is p~esent;
r and q are each inde~endently 0 to 5 and e L0 is 0 o~ L eLovided that the total of P~ q and r is 2 to 4;
R is H, alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R ; or Cl to Cg alkyl-phenyl oc Cl to C4 alkylphenyl in which the ehenyl is substituted by R4;
R4, R5. R and R are each independently selected ~om:
(1) hydrogen;
(2) alkyl having L to 6 ca~bon atoms;
t3) alkenyl having 2 to 6 carbon atoms;
(4) -(CH2)nM
whe~ein n is 0 or 1 and M is a) OR
b) halogen;
c) CF3;

d) SR
e) phenyl o~ substituted ~henyl wherein substituted phenyl is as defined below in the de~inition o~ R

lZ~38352 2894P~1039~ - 10 - 171021A

~) cooP~l3;

g~ C-R14;
h) tetcazole;

i) -NH-L-R15 wherein R is Cl to C6 alkyl, benzyl oe phenyl;
j) -NR13R13 16 k) -NHS02R wheeein R
is Cl to C6 alkyl, phenyl, or CF3;

1 ) -C-CH20H;
~5 ~) -SOR
n) co~R13R13;
2 ~2 I? ) -S2R
q) 2;

e) ~-C-R14;

s) O-C-NR R

t) O-C-OR
u) C~;
each R is independently H; Cl to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C~ to C3 alkyl, halogen, CN, CF3, CooR13, Cl to C~ per~luoroalkyl: or CH2CooR~3;

12~3~35~
2893P/1046~
2894P/1039A ~ 17102IA

each R i~ independently H, ~henyl or Cl to C6 alkyl; and, each R14 is independently H, (CH2)nCooR13 wherein n is O to 4, Cl to C6 al~yl, CF3, phenyl, or substituted phenyl wherein ~ubstituted phenyl i5 a~ defined above in the definition of R
or a eharmaceutically acceptable salt thereof, and a phar~a~euti~ally acce~table carrier.
More ere~erred co~ositions of the present invention comerise comeounds of the Fo~mula I ~herein:
~ is H or alkyl of 1 to 6 carbons or R and a taken together foem a group (CH2)V
wherein v is 1 to 7:
R l ~
R~ i5 ~(~)r tx~ p~(C)q~R

wherein:
each R is independently H, OH, Cl to C~-O-alkyl or alkyl o~ 1 to 4 carbons; or an and an R8 taken together form a group (CH~)V
wherein v is 1 to 7;
R is COOR ; CH20H; CHO; tstrazole;
hydroxymethylketo~e;
~ i8 0; S; SO; S02; NR ~erein Rl Z5 i~ ~, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR R :
R~ R8 or the unit -C _~- wherein the dotted line re~resents an optional triple bond and in which the R and ~ subs~ituents are absent when a tri~le bond is presen~;

, .

~l2~33S~
2Q93P/1046~

r and q are each independently 0 to 5 and e is 0 or 1 provided that the total of P, q and r is 2 to 4:
R is H. alkyl of 1 to 6 carbons; ~henyl or phenyl substituted by R ; or Cl to C4 alkyl-~henyl or Cl to C4 alkyl~henyl in which the ehenyl is substituted by R4;
R , R , R and R are each indeeenden~ly selected from:
(1) hydrogen;
(2~ alkyl having 1 to 6 ca~bon atoms;
(3) alkenyl having 2 to 6 cacbon atoms;
(4) M wherein M is a) OR
b) halogen;
c) ~F3;

d) SR
e) phenyl or substituted ~henyl whe~ein substituted phenyl is as defined below in the definition oE R
f) COOR
C~ 1~
2s g) -R

h) te~Lazole;

i) -NH-C-R15 whecein R is Cl to C6 alkyl. benzyl or ehenyl;
13R13;

.. ; . .,.. i~

-- ~Z~352 2~93P/10~6~
2394P~1039A -- 13 - 17102IA

k) -NHS02R wherein R
is Cl to C6 alkyl, ~henyl, or CF3;

S 1 ) -C-CH20H;

m) -SOR12 wherein R~ is as defined above;
n) _coNRl3R~3;
) -S2NR R
p) -S02R~2;
q) N02;

~) o-~-R'4;
lS Q
s) 0-C-NR R

t) o-~C-oRl5;
u) CN:
each R is inde~endently H; Cl to C6 alkyl; benzyl; ehenyl or subs~ituted phenyl wherein the substituents are Cl to C3 alkyl, halogen, CN, CF3, CooRl3~ CH2COOR , or Cl to C4 eerfluoroalkyl;

2S each R is independently H, phenyl or Cl to C6 alkyl; and each al4 is independently H, ~CH2)nCooRL3 whecein n is 0 to 4, Cl to C6 alkyl, CF3, phenyl, or substituted phenyl wherein substituted ~0 phenyl is as defined above in the definition of Rl :
or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable cacrier.

.
, 2~93P/1046~

Most pre~er~ed compo~ition~ of the present invention comprise comeound~ of the Formula I wherein:
R is H or alk~l of 1 to 3 carbons or R and R taken ~ogether form a grou~ (CH2)~
wherein v is 1 to 7, with the provi60 that Rl on the benzylic carbon attached to the indole nitrogen i~ H;
R2 is ( )r E ~ P ' f ~q wherein:
each R is indeeendently H, o~ alkyl of 1 to 4 carbons: or an R and an R taken togethe ~orm a group (CH2)V wherein v is 1 to 7.
R is COOR ; CH20H; CHO; or tetrazole;
~ i5 0; S; ~;0; S02; NRll whQreiil RlL
is H, alkyl of 1 to 6 ca~bons, acyl o~ 1 to 6 carbon6, CN; CR R ;
Rl R8 or the unit ~ wherein the dotted line represents an optional tri~le bond and in which the R and R sub~tituent~ are ab~en~ when a triple bond is pre6ent;
r and q are aach independently O to 5 and p ic O or 1 provided that the total of e. q and r is 2 to 3;
R is alkyl of 1 to 6 carbons, but is not cycloalkyl;
R, R . R and R are each inde~Qndent~y selected from:
(1) hydrogen;
~2) alkyl having 1 to 6 ca~bon atoms;

~ 2~335~
2893P/1046~
2894PtlO39A - 15 - . 17102IA

(3) M wherein M is a) OR
b) halogen;
c) CF3;

d) SR
e) -SOR
o g) O-~-R wherein R is H, ~CH2)ncooR wherein n is O to 4, Cl to C6 alkyl, CF3, phenyl. or substituted ~henyl wherein substituted phenyl is as defined above in the definition of Rl ; H. C
to C6 alkyl. C~3. phenyl or substituted ~henyl wherein substituted ehenyl is as de~ined be10w in the definition of R
h) CN:
each R is independen~ly H; Cl to C6 alkyl; benzyl; ehenyl or substituted ~henyl wherein the substituents are Cl to C3 alkyl, halogen, CN, CF3, CooR13, CH2CooR13, wherein R13 is H, phenyl, Cl to C6 alkyl. or Cl to C4 per~luocoalkyl:
or a ~harmaceutically acce~table salt the~eof, and a phacmaceutically acceptable carrier.

~ 2~.35~
2893P/1046~
2~94P/1039A - 16 - 17102IA

The present in~ention also relates to no~el compounds of Formula I represented by Formula Ia:

\ N ~ R~
7 ~H-R
J!~
~/ I Ia ~ ~ 7 wherein: 1 R1 is H or alkyl of 1 to 6 carbons or R and RB taken together form a group (CH2)U
wherein v is 1 to 7;

R is ~(C)r~ EX-]p-(~)q wherein:
each R i8 indeeendent1y H, OH, Cl to C4-O-alkyl, or alkyl of 1 to 4 carbons or R and R taken together form a group (C~2)v wherein v is 1 to 7;
R i8 COOR ; CH20H; CHO: tet~azole;
NHSO2R1O wherein R is OH. alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or ~henyl substituted by alkyl or alkoxy 2893P~L046~
2894P/1039~ - 17 - 17102IA

groups o~ L to 3 carbons, halogen, hydroxy, COOH, CN, ~o~myl o~ acyl to 1 to 6 carbons; CONHS02R
hydroxymethylketone; CN; or CON(R8)2;
X is 0: S; SO; S02; NRl~ wherein RlL
is H, alkyl of L to 6 carbons, acyl of 1 to 6 carbons, CN; CR R ;
Rl` l8 oe the unit -C- ~- wherein the dotted line re~resents an optional t~iple bond and in which the LO R and R substituents are absent when a triple bond is eresent;
r and q are each independently O to 5 and e is O or 1 ~rovided that the total of p, q and r is 2 to 6, with the ~oviso that when R and R are H, L5 X is CH2, R is 5-methoxy and R is halogen, then the sums o~ e. q and r is 3 to 6;
R is H, alkyl o~ L to 6 ca~bons; ehenyl or ehenyl substituted by R ; o~ Cl to C4 alkyl-~henyl or C~ to C4 alkyl~henyl in which the phenyl is substituted by R ;
R~, R , R and R a~e each indeeendently selected fcom:
(1) hydrogen;
(2) alkyl having L to 6 carbon atoms;
(3) alkenyl having 2 to 6 ca~bon atams;
(4) -(CH2)nM
wherein n is O to 3 and M is a) OR
b) halogen;
c) CF3;

d) SR

~Z~33~
2893P/1046~
2894P/1039~ -- 18 - 171021A

e) phenyl or substituted phenyl whecein substituted ~henyl is as def ined below in the def inition of RL2:
~ ) COOR

g) ~_R14;
h~ tetcazole;

i) -NH-~-R whecein R is Cl to C6 alkyl. benzyl oe phenyl;
j~ NR13R13;
k) -NHSO2R wherein R
L5 - is Cl to C~ alkyl, phe nyl, o r CF ~;

1 ) -j~-SH20H;

m) -SOR12;
n) CoNal3~13;
) -S02~R R
~) -S02RL2;
q) ~2;
~ ?
r) 0-~ ~_aL4 s) 0-C-NR R
. ~?
t) 0-1C-OR
u) CN:

3L2~383~?, 2893P/10~6A
2894P/10~9A - 19 - 17102IA

each R is inde~endently H; Cl to C6 alkyl; benzyl; phenyl or substituted phenyl ~herein the substituents are Cl to C3 alkyl, halogen, CN, CF3, CooRl3~ CH2CoOR~3 Cl to C3 alkoxy, or Cl to C4 eerfluoroalkyl:
each R i~ independently H, phenyl or Cl to C6 alkyl; 13 each R is i~dependently H, (CH2)nCOOR
wherein n i8 0 to 4, Cl to C~ alkyl, CF3, phenyl, or substituted phenyl wherein substituted ehenyl i8 a6 defined above in the definition o~ R
or a pharmaceutically acceptable salt thereo~.

Preferred novel compounds of the present 5 invention a~e compounds of the Formula Ia wherain:
R is H or alkyl of 1 to 6 carbons or R
and R taken together form a group (CH2)y wherein v i~ 1 to 7;
R2 is (~r Ex Ip ( I)q whecein:
each R is independently H, OH, Cl to C4-O-alkyl, or alkyl o~ 1 to 4 carbons or R and R taken together form a group ~CH2)~ wherein v i~ 1 to 7:
R is COOR ; CH2OH; CHO; tetrazole;
CONHSOzRl0 wherein Rl0 is OH, al~yl or alkoxy of 1 to 6 carbons, perhaloalkyl o~ 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groues of l to 3 carbons, halogen, hydroxy, COOH, CN, ~2~83S~
2~93P/1046A
2894P/1039~ - 20 - L7102IA

-Eormyl or acyl to 1 to 6 carbons; hydroxymethyl-ketone; CN; or CON(R )2;
X is O; S; SO; SO2; NR~ wherein R
is H, al~yl of l to 6 carbons, acyl of l to 6 caebons, CN; CR R ;
Rl R8 oe the unit -C ~_Ç- wherein the dotted line eepresents an optional triple bond and in which the R and R substituents are absent when a triple bond is æresent;
r and q aee each independently O to 5 and p is O or l provided that the total o~ p. q and r is 2 to 4, with the proviso that when R and R are H, X is CH2, R is 5-methoxy and R is halogen, lS then the sums of p, q and r is 3 to 4;
R is H, alkyl of 1 ~o 6 carbons; phenyl or phenyl substituted by R , or Cl to C4 alkyl-ehenyl or Cl to C4 alkylphenyl in which the phenyl is substituted by R4;
R , R , R and R are each independently selected ~rom:
(l) hydrogen;
(2) alkyl having l to 6 carbon atoms;
(3) alkenyl having 2 to 6 carbon ato~s;
2S (4) -(CH2)nM
wherein n is 0 or l and ~ i6 a) OR
b) halogen;
c) C~3;
d) SR

~ 2~3~335 2a93P/1046~
2894P/L03gA - 2L - 171021A

e) ~henyl or substituted ~henyl whe~ein substituted phenyl is as defined below in the definition of RL2;
f) COOR

g) ~-R wherein R is H, (C~23nCOOR wherein n is 0 to ~, Cl to C6 ~o alkyl, CF3, phenyl, or substituted phenyl whe~ein substituted ehenyl is as defined below in the definition of R12;
h) tetrazole:

i) -N~-C-R15 wherein R15 is Cl to C~ alkyl, benzyl or ~henyl;
i) NR13R13;
k) -NHSO2R wherein R
is Cl to C6 alkyl, phenyl, or CF3;

1) -C-CH20H;

m) -SOR
n) coNR13R13;
o) -S2NR R
P) -SO2R12;
q) N02;

:. ~
.~
, .

8~33~

O C~ R14 s) O-~-NR R
O
t) O-~ oR15;
u) CN;
each R is indeeendently H; Cl to C6 alkyl; benzyl; ehenyl or substituted phenyl wheeein the substituents aEe Cl to C3 alkyl, halogen, CN, C~3, CooR13, CH2CoOR13 Cl to C3 alkoxy Cl to C4 eeefluoroalkyl;
each R is independently H, phenyl or Cl to C6 alkyl:
LS each R14 is independently H, (CHz)ncooR wherein n is 0 to 4, Cl to C6 alkyl, CF3, ehenyl, or substituted ehenyl wherein substituted phenyl is as defined above in the definition of a oe a ~harmaceutically acce~table salt theceof.
More ~referred novel compounds of the eresent invention are com~ounds o~ the focmula la wherein:
R is H or alkyl o~ L to 6 carbons o~ R
and R taken together form a groue (CH2)V
wheeein v is 1 to 7;
RL al R2 is R8 [ ~ R6 wheeein:
each R is independently H, OH, C1 to C4-0-alkyl, or alkyl of 1 to 4 carbons or Rl and 3~'9 2893P/L046~
2894P/1039~ - 23 - 171021A

R taken together form a groue (CH2)V wherein v is 1 to 7:

R is. COOR ; CH20H; CHO; teteazole:
hydroxymethylketone;
X is O; S; SO; SO2; NR wherein R
is H, alkyl o~ L to 6 carbons, acyl of 1 to 6 carbons, CN; CR R ;
RL R~
o~ the unit -C--C- wherein tha dotted line re~resents an optional triple bond and in which the R and R substituents a~e absent when a triele bond is present;
r and q are each indeeendently O to S and is O oe L provided that the total of p, q and r is 2 to 4, with the pcoviso that when R and R a~e H, X is CH2, R is 5-methoxy and R is haloqen, then the sums o~ p, q and r is 3 to 4;
R is H, alkyl of 1 to 6 carbons; phenyl or ehenyl substituted by R ; o~ CL to C4 alkyl-~henyl or Cl to C4 alkylphenyl in which the phenyl is substituted by R ;
R , R , R and R are each independentLy selected ~om:
(1) hydrogen;
~2) alkyl having 1 to 6 caLbon atoms;
S3) alkenyl having 2 to 6 carbon atoms;
(4) M wherein M is a) OR
b) halogen;
c) CF3;

83~
28g3P/104~
2394P/1039~ - 24 - 17L02IA

d) SR
e) ~henyl or substituted ehenyl wherein substituted phenyl is as de~ined below in the de~inition o~ R12;
~) COOR

g) ~C-R14;
h) tetcazole;

i) -NH-C-RL5 whecein R is C1 to C6 alkyl. benzyl or ~henyl;
j) ~R13R13;
k) -NHS02R wherein R
is CL to C6 al~yl, ehenYl~ oc CF3;
1l 1 ) -C-CH20H;

m) -SOR
n) co~R13R13;
o) -S2NR R
p) S02R
q) ~0~;

o s) 0-C-NR R

t) o-~-OR15;
u) C~;

2B93PrlO46A

each Rl~ is indeeendently H; Cl to C6 alkyl; benzyl; phenyl or sub6tituted phenyl whe~ein the ~ubstituents are Cl to C3 alkyl, halogen, CN, CF3, CooR13, CH2COOR . Cl to C3 alkoxy or ~1 t9 C4 ee~f luoroalkyl;
each R13 i6 independently H, phenyl or Cl eo C6 alkyl: and each R14 is a, (CH2)nCooR13 ~herein n i8 0 to 4, Cl to C6 alkyl, CF3, phenyl, or ~ub6titu~ed ehenyl wherein substituted phenyl is as defined above in the definition of R
or a pharmaceutically acceptable salt thereof.

Most preferred novel compound6 of the pcesent invention are compounds of the formula Ia wherein:
Rl is H or alkyl o~ 1 to 3 carbons or and R8 ta~en togeeher form a group ~CHz)v wherein v i5 1 to 7, with the provi~o that R on the benzylic carbon attached to the indole nitrogen is ~; ~ ' R2 is (C~r EX-lp-(C~q-R9 wheeein:
eaeh R i6 independently H, OH. C~ to C4-0-alkyl or alkyl vf 1 to 4 carbons or R and R ta~en ~ogether ~orm a group (CH2)V wherein v is 1 to 7;
R is COOR ; CH20H; CHO; or tetra~ole;

~3 i3~5~
2~93P/10~6~
2894P~1039~ - 26 - 17102IA

X is O; S: SO; S02; NR wheeein R
is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR R :
Rl ~8 5 OE the unit ~- C- wherein the dotted line reeresents an optional triple bond and in which the R and R substituents are absent when a triple bond is present;
r and q are each independently O ~o 5 and e lo is O or 1 provided that the total of p, q and r is 2 to 3, with the proviso that when R and R aee H, X is CH2, R is 5-methoxy and R is halogen, then the sum of r, p and q is 3 to 4;
R is alkyl of 1 to 6 carbons, but not cycloalkyl;
R , R , R and R are each independently selected f~om:
~1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) M wherein M i8 ORl 2 b) halogen:
c) CF3;

d) SR
e) -SOR
f) -S02R

g) O-~-R , wherein R is H, Cl to C6 alkyl, CF3, ~henyl or substituted phenyl wherein substituted phenyl is s'~

2893P/L046~
2894P/1039~ - 27 - 17102IA

as defined below in the definition of R12;
h) CN;
each R i5 independently H; C~ to C
5 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are Cl to C3 alkyl, halogen, C~, CF3, CooR~3, CH2CooRL3, Cl to C3 alkoxy;
or C1 to C4 perf 1UEa1kY1: ;
each R is independently H, phenyl or Cl to C6 alkyl;
or a ~harmaceutically acceptable salt thereof.

Most-earticularly preferred novel compounds of the p~esent invention are compounds of the fo~mula Ia whecein:
R is H or alkyl of 1 to 3 carbons, with the ~oviso tha~ R on the benzylic carbon attached to the indole nitrogen is H:
Rl Rl R is ~(C)r~ [-X-]~ (~)q wherein:
each R is independently H or alkyl of 1 to 4 cacbons, with the proviso that at least one of the R or R substituents in R is not hydrogen;
R is COOH; CH2OH; CHO; or tetrazole;
X is CR R ;
r and q are each inde~endently 0 to 3 and p :~
is 0 or 1 ~rovided that the total o~ p, q and r is 2 to 3;
R is alkyl of L to 6 carbons, bu~ not cycloalkyl:

~Z~3~335~.
2893P/1046~
2894P~1039~ - 28 - 17102IA

R4. R . R and R are ea~h independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) M wherein M is a) OR
b) halogen;
c) CF3;

LO d) SR
e) -SOR~2;

g) O-C-R , wherein R is H, Cl to C6 alkyl, CF3, phenyl or substituted phenyl wherein substituted ~henyl is as defined below in the definition of R
h) CN;
each R is inde~endently H; Cl to C6 alkyl: or benzyl;
or a pharmaceutically acceptable salt the~eof.

Other most-particularly preferred novel com~ound6 of the present invention are com~ounds of the formula Ia wherein:
R is H or alkyl of ~ to 3 carbons, with the pcoviso that R on the benzylic carbon attached to the indole nitrogen is H;
Rl Rl R is -~C)r-L-X-~ p~~C)q~R

~l2~3~3SX
28~3~/L046A
2B94P/1039~ 29 - 17102IA

wherein:
each R i6 independently H or alkyl of 1 to 4 ca~bons;
R is COOH; CH2OH; C~O; or tetrazole;
X is O; S; SO; o~ S02;
r and q are each independently 0 to 3 and e is 1 erovided that the total of p, q and r is 2 to 3;
R is alkyl o~ 1 to 6 ca~bons, but not cycloalkyl R , R5, R6 and R7 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) M wherein M is ) oR12;
b) halogen c) CF3;

d) SR
e) -soal2;
f) -SO2R

~) o-~-Rl4~ wherein R is H.
Cl to C6 alkyl. CF3.
ehenyl or substituted ehenyl wherein substituted phenyl is as defined below in the definition of R
h) CN:
each R is independently H; Cl to C6 alkyl; or benzyl;
or a ~harmaceutically acce~table salt thereo~.

5~
2893Pf 1046A
2894PflO39A - 30 - 1710ZIA

The following reaction scheme~ illu6trate the 2reparation of the compounds of the present invention:

Scheme I Pre~aration of Formula I Com~ound~

~ ~ lower ~ R3 R5 ~ N-NH2 0~ ~ 2 ref;u~ R ~ N ~ R
R~ . HC1 ~ ) R

II I

~

R~l/~R 1 ~R7 Ib 12~38352 2~93P/1046~
2894P/103gA - 31 - 17102IA

Scheme II Preparation of Hvdrazine Derivatives (II2 ~HRl 5~ t o l u ~ n ~
R NH-NH2 R6~1R7 reflux R -NH2 . HCl ¦ . HCl I~J ~J 6 ~/ R
R--_ ll ~R7 With regard to Scheme I. the alkanol solvent can have an important e~fect on the course of the reaction. With some of ehe ketones III, the ~inal product may contain a mixture of the isomers I and Ib. Formation of the undesired Ib i8 minimized by using is~ropanol or tert-butanol in place of methanol or ethanol.
The sequence de~cribed abo~e is an application of the Fische~ Indole Synthesis.
Numerous indole syntheses are described in reYiews, such as, ~or example "Heterocyclic Co~pound~l` Volume 25, Part~ I, II. III. W. J. Houlihan ~Ed.), Inter&cience, J. Wiley ~ Sons, N. Y., 1979.
Appropriate manipulations of functional groups using sequences described in such reviews will lead to the compounds of the present invention. ~nother useful sequence is shown in Scheme III.

~l2&~83~j~
2893P/1046~
2894P~1039A - 32 - 17102IA

Scheme III PceParation o~ Indole-2-~lkanoic acids ~2 ~ ~ X

VI VII ViII

L0 Lewis Acid R \ A
VIII ~o~R

ZnC12 or ~lC13 R5 ~ NH/ \ ~2 IX

R6 ~ CH2X IX _____~ R ~

R R6--~p)7 X - Cl; Br; o-S02 - ~ 3 The Bischler Indole Synthesis usad in the sequence descLibad foc the synthesis of com~ounds o~
the ~cesent invention envisages the alkylation of an 3Z33~

2894P~L039~ - 33 - 17102IA

appropriately substituted halo or tosyloxy ketone (VII) by an applopriately substituted aniline derivative (VI~, in an alcoholic solvent. The condensation step is effected through the use of a Lewis ~cid or mineral acid. The indole derivative so produced (IX) may then be alkylated by an aralkylhalide to product I.

The following ketones ~1-7) of structure III
10 are known in the art: :

35~
2893P/10~6~

TA~LE 1 ~etones of Formula III

No. Structure Reference ~ethyl 4-oxohexanoate:
1. / B. L. Feringa and ¦ W. Dannenber~, Synth.
0 ~ C0 Me Commun., 13, 509-514 2 (1983)-Ethyl 4-oxohexanoate:
2 / D. A. ~ehrli and V. Chu, ¦ Org. Synth., 58, 79-82 0 ~ C2Et (1978).

3-Methyl-~-oxohexanoa~e:
3 / ~. P. Cowling and l J. Mann, J. Chem. Soc., 0~ ~ C2Me Chem. Commun., 1006-1007 ~197~)-Methyl 2,2-dimethyl-4-4 / oxohexanoate:
l V R. Scar~ati, G. Scherillo, O ~ C02Me F. Imperato and R. ~.
~icolaus, Gazz. Chim.
ltal., 97, 654-664 (1967).

~ethyl 5-oxoheptanoate:
5. ~ M. K. Eberle and G. G.

I C02Me Kahle, Tetrahedron Lett., o~ ~ 21, 2303-2304 (19~0).

.~

i2 2893P/1046~
2894~/1039~ - 35 - L7~02IA

3-Methyl-5-oxoheptanoic 6. ~ acid: C. Conti, 1 1 C02H A. Niccoli and R. Rossi, 0~ ~ ~ Chim. Ind. (Milan~ 5~; 877 ~1976).

Methyl 6-oxooctanoate:
7 / T. Terasawa and T. Okada.
¦ Tetrahedron 33, 595-598 0 ~ ~ C02Me (~977) Ethyl 2,3-dimethyl-4-oxo-8 / hexanoate I I
~ ~ \C00Et Exameles of ~ocmula I comeounds useful in the eharmaceutical comeositions of the present invention are tabulated below. The numbe~s preceding the R , R R , and R definitions indicate the substituent position in the structu~e. Standa~d abb~eviations such a~ Me fo~ methyl, Et for ethyl, Pr for propyl, Bu for butyl, ~c for acetyl, and Ph for phenyl a~e used. Com2ounds 3 to 72 are no~el compounds.

, 3~5~
2893P/lOk6A

T~LE 2 Co~nds of the Formula 0 ~ 2 eH_Rl 6' ~ I

R~R7 4' Compound No. R _ R _ _ R R _ R R R
20 1 H ( 2)2 2 ~Se 5-OMe H 4'-Cl H
2 H ( 2) 2 2 He 5-OMe H 4 ' -Cl H
3 H ~CH2)2C02H He 5-F H 4`-Cl H
4 H 2 2 2 He 4-Cl 6-Cl 4 ~ -Cl H
H 2 2 2 ~le 4-OHe H 4 ' -Cl H
25 6 H 2 2 2 tle 6-ONe H 4 ` -Cl H
7 H (CH2)2C02~1 He 4-~e H 4'-Cl H
8 H ( 2 2 2 ~le 6-?le H 4 ' -Cl H
H ~ 2 4 2 ~le 5-OHe H 4 ' -Cl H
. 2 2 2 ~e 5-21e H 4 ' -Cl H
3011 H ~CH2)3C02H He 5-OHe H 4'-Cl H
12 H (C~12)2C02H Ne 5-OH H 4'-Cl H
13 H (CH2)2C02H He 5-C1 H 4~-Cl H

!.' ' . : ~

:' "..... ' ', :

~2~33~

Compound Na. Rl RH~ R3 R4 ~5 R6 R7_ 14 H 2 2 2 Me H H4'-Cl H
15 H 2 2 2 Ne 5-Br H 4'-Cl H

16 H t 2)2 2 Me 5-OMe H 4'-S-Me H
17 H 2 2 2 Me 5-OMe H 4'-SNe H
18 H (CH2)3C02H Me 5-OHe H 4'-SMe H
19 H (CH2)3C02H He 5-F H 4'-Cl H
20 H 2 2 2 He 5-F H 4'SMe 21 H t 2)~ 2 Me 5-F H 4'-~-Ue H
22 H CH(Ue)CH2C02H Me 5-OMe H 4'-Cl H
23 H CH20CH2C02H Ue 5-OHe H 4'-Cl H
24 H 2 2 2 Me 5-OAc H 4'-Cl H
25 H CH2CH~He)CH2C02H Ue 5-OHe H 4'-Cl H
2fi H (CH2~Clt(Me)CH2C02H H 5-F H 4'-Cl H
27 H CH2C~Ue~2C02H H 5-O~e H 4'-Cl H
28 H (CH2)3C02H He 5-F H 4'-SMe H
29 H 2 2 2 Me 5-OMe H H H
30 H 2 2 2 Me H H H H
31 H 2 2 2 Me 5-OMe H 4'-CF3 32 H ( 2)2 2 Ne 5-ONe H 4-SUe H
33 H ( 2)2 2 Me 5-O~e H 4-~ e H

34 H 2 2 2 Me 5-OMe H 4'-SMe H

35 H ( 2)2 2 He 5-F H 4'-Cl H
36 H (CH ) CO H He 5-Cl H 4'-Cl H
37 H ( 2 2 2 He 5-ar H 4'-Cl H
38 Me 2 2 2 Me 5-OMe H 4'-Cl H
39 H 2 2 2 Et 5-OMe H 4'-Cl H

3~

40 H 2 2 2 Ue 5-OH H 4'-Cl H
41 H 2 2 2 Ue 5-OAc H 4'-Cl H
42 H 2 2 2 He 4-OUe H 4'-Cl H
43 H 2 2 2 Me 4-Cl H 4'-Cl H
44 H 2 2 2 Ue 4-Cl 6-Cl 4~-CF3 H
45 H ~CH2~3C02H He 5-ONe 4-Cl H H
46 same as 2 to 16 with R being (CH2)3COOH
47 H CH(Ue)CH2C02H Me 5-OMe 4-Cl H H
48 same as 2 to 16 with R being CH(Ue)CH2COOH
10 b9 H CH2-CH(Me)-COOH Me 5-OUe H 4'-Cl H
same as 2 to 16 with R being CH2-CH(Me)COOH
51 H CH(Ue)(CH2)2-cOoH He 5-OMe H 4'-Cl 52 same as 2 to 16 with R being CH(Ue)(CH2)2-COOH
53 H CH2-CH(Me)CH2COOH Me S-OMe H 4'-CL H
54 same as 2 to 16 with R being CH2-CIH-CH2-COOH
~e 55 H CH2CH2CH(Ue)-COOH Me 5-OMe H 4'-Cl H
56 same as 2 to 16 with R bein~ (CH2)2-CH(Ue)COOH
57 H CH2-C(Me)2-COOH Ne 5-O~e H 4'-CI H
58 same as 2 to 16 with R being CH2-C(He)2-COOH
59 H CH2-C(Ue)2CH2COOH Me 5-OHe H 4'Cl H

same as 2 to 16 with R being CH~-C~Ue~2-CH2-COOH
61 H (CH2)2-ClMe)2-COOH Me S-OH~ H 4'Cl H
62 same as 2 to 16 with R being (CH2)2-C(Ne)2-COOH
63 H CH2-OCH2COOH Me S-OHe H 4'Cl H
64 same as 2 to 16 with R being CH2-OCH2COOH
65 H CH2-S-CH2C02H Me 5-OMe H 4'Cl H
66 H CH2-~-CH2C02H Me S-OMe H 4'Cl H

335~

6 7 H CH S-CH CO H He S -OMe H 4 ' C 1 H

68 same as 2 to 16 with R bein~ CH2-S-CH2C02H
69 sameas 2 to 16 with Rbein~, CH2-~-CH2C02H

7 0 Ht 3 ) 2 2 2 Me 5 -OMe H 4 ' C 1 H
71 HCH2U-CHCH2C02HMe 5-OHe H 4 ' Cl H
CN
10 72 same as 2 to 16 with R bein~, CH2-,-CH2C02H

73 same as 2 to 16 with ~ bein~, CH~CH3)2COOH
74 same as 2 to L6 with R bein~, CH(CH3)C(CH3)2CH2COOH

~5 ;~5 3r Seacific Examples of the Fo~mula I comounds are the following, all but the Eirst being novel:

3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]
S eeopionic acid;
.

3-[1-(4-chlo~obenzyl)-3-methyl-5-~luoLoindol-2-yl]
~ropionic acid;

L0 3-~1-(4-chlorobenzyl)-3,4-dimethylindol-2-yl]
eroPionic acid, 4-[1-~4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]
butanoic acid 3-~1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]
propionic acid:

3-~1-(4-chlorobenzyl)-3-methylindol-2-yl~propionic asid;

3-[1-(4-methylthiobenzyl)-3-methyl-5-methoxyindol-2-yl]p~opionic acid;

3-[1-~4-methylthiobenzyl)-3-meShyl-S-~luoroindol-2-yl3 propionic acid 3-~1-(4-methylsulfinylbenzyl)-3-methyl-S-methoxyindol-2-yl]eLopionic acid;
4 [1-t4-methylthiobenzyl)-3-methyl-5-methoxyindol-2-yl]butanoic acid : : .
'. .. . . . . .. . ..
'' ' ' "

2893P/1046~
2894P/1039A ~ 41 - 171021A

4-~1-t4-ehlocobenzyl)-3-methyl-5-fluorolndol-2-yl]
butano~c acid;

1-[1-(4-chlocobenzyl)-3-methYl-5-methoxyindol-2-yl]
~ethoxy acetic ac~d;

3-[1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl~-2,2-dimethylpropanoic acid;

3-~1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl]-3-methylpropanoic acid;

3-methyl-4-[1-(4-chlorobenzyl)-5-methoxy-3-methyl-indol-2-yl]butanoic acid;
3-methyl~ 1-(4-chlorobenzyl)-5-~luoro-3-methyl-indol-2-yl]butanoic acid;

3-[1-(4-chlorobenzyl~3-methyl-5-fluoro-2-indolyl)-2,2-~o dimethyl propanoic acid.

Fu~ther examples include:

~ -(4-chlorobenzyl~s-fiuoro-3-methyl-lH-indol-2 2,4,3,3-tetramethyl b~tanoic acid;

4-1l-(4-chlorobenzyl~S~fluoro-3-methyl-lH-indol-2-yl]-4,3,3-trimeth-yl butanoic acid 4-tl-(4-chlorobenzyl~5-fluoro-3-methyl-lH-indol-2-yl]-2,2,3-trimethyl butanoic acid;

3~i~
2893P/104~

4~ (4-chlo~obenzyl~5-fluoco-3-~et~rl-lH-indol-2-yl]-203,3-tci~etbyl butanoi~ acid:

4-~1-(4-chlorobenzyl~5-methoxy 3-met~yl-lH-indol-2-yl]-2,2,3-trimethyl butanoic acid;

4-tl-(4-chlo~obenzyl~5-ethoxy-3-meth~rl-lH-indol-2-yl~-2,2,3-trimethyl butanoic acid:

4-C1-~4-chlorobenzyl~5-chloro-3-mQt~l-lH-indol-2-yl~-2,2,3-t~imethyl butanoic acid:

4-[1-(4-chlorobenzyl~3-methyl-S-tcifluo~omethyl-lH-indol-2-yl]-2,4,3,3-tetramethyl butanoi~ acid;

4-tl-(4-chlorobenzyl~3-methyl-5-trifluoromethylth~o-lH-indol-2-yl]-2,4,3,3-tet~amethyl butanoic acid;

3-cl-(4-chlo~obenzyl)-5-ethoxy-3-methyl-lH-indol-2 2,2,3-trimethyl proeanoic acid:

3-tl-(4-chlorobenzyl)-5-ethoxy-3-m2thyl-lH-indol-2-~l]-2,3,3-trimethyl propanoic acid:

3-~1-(4-chlorobenzyl)-5-ethoxy-3-methyl-lH-indol-2-yl~-2,2,3,3-tet~amethyl pro~anoic a~id;

3-~1-(4-c~lorobenzyl)-5-methoxy-3-methyl-lH-indol--2-yl]-2,2,3-trimethyl propanoic acid 3-[1-(4-c~lorobenzyl)-5-~luoro-3-methyl-1~1-indol-2-yl]-2~2,3-trimethyl propanoic acid:

~3~3352 2894P/1039A - 43 - 1710ZlA

3-tl-(4~c~10robenzyl)-5-chloLo-3-methyl-lH-indol-2-yl~-2,2,3-trimethyl pLopanoic acid:

3-~1-p-chloroben~yl-3-methyl-S-~ethoryindol-2-yl)-2,2-dle~yl propanoic acid;

3-~1-(4-chlorobenzyl)-3 methyl-5-fluoroindol-2-yl]-2,2-diethyl propanoic acid;

3-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl3-2-ethyl propanoic acid;

3-[1-(4-chlorobenzyl)-3-ethyl-5-fluoroindol-2-yl]-3-methyl propanoic acid; and 3-[1-(4-chlorobenzyl~3-met~yl-5-metboxy-2-indolyl~
eentanoic acid, In those instances when asy~metric center6 are eresent. more than one stereoi~o~er is pos6ible, and all possible isomeric forms are deemed to be included within the planar structural representations shown. Optically active (R) and (S) isomers may be resolved u~iny conventional techniques known to the skilled artisan.
The pro~taglandin antagon1 5t properties of the compounds of the present invention can be demon~trated by a number of biologi~al a~says, one of which, inhibition of platelet aggregation, i6 ':
desccibed below.

83~

lnhibition of Induced Th~e~old Aggregation o Human Platelet~ _ Human platelet ci~h plasma (P~P~ i8 ~repared from venou~ blood o male ~olunteer6 vho have taken S no medication ~OE ten day6 prior to test. Blood i8 tran6fe~red into pla6tic centrifuge t~bes containing 3.8% T~isodium Citrate in 0.9~ NaCl (in a ratio of blood to anticoagulane of g:l), mixed by qentle inversion, and centrifuqed at room te~pacature ~oc tan minute6 at 116 g. The 6upernatant (PRP) i~
trans~erred into pla6tic tubs6. Platelet poor plasma (PPP) i6 obtained by centri~uging the ~esidual blood cells at 4000 y for ten minutes. PRP is le~t to stand at least one half hour pr~o~ to eesting.
Plateiet ~ggregation is measured u~ing a Payton Aggregometer and Recorder. Following calibration o~ the instrument, a cuvette containing PRP (225 microliters) i6 incubated ~or th~ee minute6 at ~7~C. D~ug vehicle ~control), or a drug concentra-tion i6 then added in a volume of 0.5 microliter.
~fter one minute, the a~gregating agent (U44069, 9,11-dideoxy-9a,11a-epoxymethano PG~22) ifi added to the cuvette in a volume of 25 microlitec6. Recoeding is continued until the maximal re6ponse i8 obtained.
The threshold (approximately 20 - 30~ of maximum) aggregation concentration of the agonis~ to be used i~ ~ir6t determined in the presence o~ the drug vehicle ~control). Test compound~ are then assayed at 10 or 30 microgra~s/ml initially, and if active, are ~urther tested in order to determine the eoncentration ~ange at which 20-80~ of the thre6hold aggregatory re~ponse is inhibited. All drug6 are dis601ved in dimethylsul~oxide.

~l.2883S~

2894P/1039~ - 45 - 17102IA

The heigh~ of the aggregation res~onse tmeasured in divisions of the recorder ~aper, 1 division = 2.5 mm) in the ~resence o~ the drug i6 recorded, and calculated as percent inhibition of the mean height of the control threshold responses. The IC50 (drug concen~ration which inhibits 50% of the aggregatory ~esponse) is obtained by regression analysis.
Compounds of Formula I or Ia can be tested using the following assay to determine their mammalian leukotriene biosyn~hesis inhibiting activity.

Rat Peritoneal Polymorphonuclear (P~N) 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 wa~er). Aftec L5-24 hc. the rats are sacrificed (C02) and the cells from the peritoneal cavity ace recovered by lavage with 20 ml o~ buf~er (Eagles MEM containing 30 mM HEPES adjusted to pH 7.4 with NaOH). The cells are ~elleted (350 x g, 5 min.), resuspended in bu~er with vigorous shaking, filtered, through lens ~a~ee, recentri~uged and ~inally suspended in buf~er at a concentration o~
10 cells~ml. A 500 ~1 aliquot of PMN suspension and test com~ound are ~reincubated ~or 2 minutes at 37C, ~ollowed by the addi~ion o~ 10 ~M ~-231~7.
The suspension is stirred for an additional 4 minutes then bioassayed for LTB4 content by adding an ali~uot to a second 500 ~1 portion of the PMN at 37OC. The LTB4 pcoduced in the ~irst incubation ~l2~ 35~
2893P/104fi~

causes aggregation of the second PMN, which is measueed as a change in light transmission. The size o~ the assay aliquot is chosen to give a submaximal transmission change (usually -70%) for the unteeated control. The percentage inhbition of LTB4 formation is calculated from the eatio of transmission change in the sample to the transmission change in the compound-free conteol.
The cytoprotective activity of a compound may be observed in both animals and man by no~ing the increased resistance of the gastrointestinal mucosa to the noxious effects of steong ireitants, for example, the ulcerogenic effects of aspirin or indomethacin. In addi~ion to lessening the e~ect o~
non-steroidal anti-inflammatory drugs on the gasteointestinal tract, animal s~udies show that cytopeotective com~ounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, e~hanol, hypeetonic 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.
. E_h nol-Induced Gastric Ulcer AssaY
Twenty-four hour fasted Sprague-Dawley (S.D.) rats are peeocally (p.o.) dosed with 1.0 ml absolute ethanol. Fifteen to thirty minutes erior to ethanol administration, groups of eats each receive eithee an aqueous vehicle (aqueous methylcellulose 5~ wt.) or ~ 3~3~

2894P/~039~ - 47 - 17102IA

the test comeound at various doses peeoeally. One houe latee, the animals ace sacrificed and stomach mucosae are examined for resulting lesions.

B. Indomethacin-Induced Ulcee ~ssaY
Indomethacin, 10 mgtk.g p.o., is used to induce ulcers in 24 hour fasted S.D. rats. Fifteen minutes prior to indomethacin a~ministration, groups of cats each receive either an aqueous vehicle (5% by weight methylcellulose) or the test compound at vaeiou~ doses perorally. Four hours later the animals are sacrificed and stomach mucosae are examined for eesulting ulcers.
The magnitude of a ærophylactic oe thera-peutic dose o~ a compound of Formula I oe Ia will, ofcouese, vary with the nature of the severity of the condition to be treated and with the particulae compound of Formula I or Ia and its route o~
administration. In general, the daily dose ranqe ~o~
anti-asthmatic, anti-allergic, anti-inflammatory, o~
anti-thrombotic use lies within the eange of feom about 0.01 mg to about 100 mg per kg body weight of a mammal.
The exact amount of a compound of Formula I
Z5 or Ia to be used as a cytoecotective agent will depend on, inter alia, whether it is being administered to heal damaged cells oc to avoid future damage, on the nature of the damaged cells (e.g., gasteo-intestinal ulcerations V6. nephrotic neceosis), and on the natuee of the causative agent. An example of use of a compound of Foemula I or la to avoid ... ~ .~

3~13'-3~
~893P/104~
2894P/103~A - 48 - 17102IA

future damage is co-administration with a non-steroidal anti-inflammatory drug tfor example, indomethacin).
The effectiYe daily dosage level foc compounds of Formulae I or Ia inducing cytoprotection in mammals, especially humans, will generally range from about 0.002 mg/kg to about 100 mg/kg, preferably from about 0.02 mg/kg to about 30 mg/kg. The dosage may be administered in single or divided individual doses.
~ ny suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of Focmula I
or Ia. For example, ocal, rectal, transdecmal, ~5 parenteral, intramuscular, intravenous and the like ma~ be employed. Dosage ~orms include tablets, troches, dispe~sions, suspensions, solutions, capsules and the like.
The pharmaceutical comeositions of the eresent invention comprise a com~ound of Formula I or Ia as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pha~maceutically acceptable carrier and optiona~ly other theraeeutic ingredients. The term "ehar~a-ceutically acceptable salts" eefe~s to salts ~reearedf rom pharmaceutically acceptable non-toxic bases including inorganic bases and organic bases. Salts derived from inocganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ~erric, manganic salts and the like. Particularly preferred are the ammonium, eotassium, sodium, calcium and 335~
2893P/1046~

magnesium salts. Salts derived from eharmaceuticallY
acceptable organic non-toxic bases include salts o~
pcimary, secondary, and tectiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, teipropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, tromethamine, lysine, arginine, histidine, caf~eine, procaine, hydrabamine, choline, betaine, ethylene-diamine, glucosamine, methylglucamine, theobromine, puLines, piperazine, piperidine, ~-ethylpiperidine, polyamine resins and the like. The compositions include compositions suitable for oral, rectal, o~hthalmic, pulmonary, nasal, dermal, topical or parenteral (including subcutaneous, inteamuscular and intcavenous) 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 convenien~ly presented in unit dosage form and prepared by any of the methods well-known in the art of eharmacy.
For use where a composition ~or intravenous administration is employed, a suitable dosage range for anti-asthmatic, anti-inflammato~y or anti-allergic use is from about 0.01 mg to about 20 mg (ereferably from about 0.1 mg to about 10 mg) of a compound of Formula I or Ia per kg of body weight per day and ~or cytoprotective use ~rom about 0.002 mg to about 100 mg (preferably from about 0.02 mg to about 30 mg and more preferably from about 0.1 mg to about ~l ~~3835~
2893P~10~6~
2a94P/1039h - 50 - 171021A

10 mg) of a compound o~ Formula I or la per kg of body weight par day. Tn the ~ase where an oral composition i8 employed, a ~uitable dosage range for anti-asthmatic, anti-inflammatoey or anti-allergic S use i~, e.g. from about 1 to about 100 ~g of a compound of Formula I or la eer kg of body weight pe~
day, preferably from about S mg to about 40 mg per kg and for cytoprotecti~e use from about 0.01 mg to about 100 mg (preferably fro~ about 0.1 mg to about 30mg and more preferably from about 0.1 mg to about 10 mg~ o~ a compound of Fo~mula I or Ia per kg of body weight per day.
For administration by inhalation, the compounds of the pre~ent invention are conveniently delivered in the form of an aero601 sp~ay pcesen~a-tion f~om precsurized pack~ o~ a nebuli~er. The prefecred composition for inhalation is a powder which may be formulated a~ a ca~tridge f~om which the powder compo6ition may be inhaled with the aid of a ~uitable device. In the ca6e of a pre~surized aero601, the do6age unit may be determined by providing a valve to deliver a metered amount.
In practical use, a compound o~ Focmula I or Ia can be combined as the acti~e ingredient in intimate admixture with a phacmaceutical carrier according to conventional pharmaceutical cnmpounding technique6. The carrier may take a wide variety of fo{ms depending on the for~ of p~eparation desired for administration, e.g., oral or in~ravenous. In preparing the compo~itions for oral dosage form, any of the usual pharmaceutical media may be em~loyed, such a6, for example, water glycol~, oil6, alcohols, s~
~" ~

flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs and solutions;
or carriers such as starches, sugars, diluents, granu-lating agents, lubricants, binders, disintegratingagents and the like in the case of oral solid prepa-rations such as, for example, powders, capsules and tablets. Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharma-ceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coa-ted by standard techniques.
In addition to the common dosage forms set out above, the compounds of Formula I or Ia may also be administered by controlled release means and/or 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 and by inhalation in the case of asthma therapy may be pre-sented as discrete units such as capsules, cachets or tablets each containing a predetermined amoun-t of the active ingredient, as a powder or granules or as a solution or a suspension in an aqueous liquid, a non-aqueous liquid, an oil-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association ';`~`~;

:

383~;~

2893P~L046A

the active ingredient with the careier which consti-tutes one or more necessar~ ingredients. In general, the comeositions are prepared by unifocmly and intimately admixing the active ingredient with liquid S carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired pcesentation. For example, a tablet may be prepared by compression or molding, optionally with one or more accessory ingredients. Compcessed tablets may be prepared by compeessing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mixed with a binder, lubeicant, inert diluent, lubricating, surace active or dispersing agent. Molded tablets may be made by L5 molding in a suitable machine, a mixture of the eowdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 25 mg to about 500 mg o~ the active ingredient and each cachet or capsule contains from about 25 to about 500 mg of the active ingredient.
The following are exameles of representative pharmaceutical dosage forms for ~he compounds of Formula I or Ia:

~383~i~
2893P/10~6~
2894P/1039~ - 53 - 17102IA

Iniectable susPension mq/ml Compound of Fo~mula I oe Ia 2.0 Methylcellulose 5.0 Tween 80~ 0.5 Benzyl alcohol 9.0 Methyl paraben 1.8 Propyl paraben 0.2 Watee for injection to a total volume o~ 1 ml L0 Tablet mq/tablet Compound of Formula I or Ia 25.0 Microcrystalline Cellulose 325.0 Providone 14.0 Microcrystalline Cellulose 90.0 L5 Pregelatinized Starch 43.5 ~agnesium stearate 2-2.5 Ca~sule m~/caPsule 20 Compound of ~ormula I or Ia 25.0 Lactose Powder 573.5 Magnesium Stearate 1-1.5 In addition to the compounds of Formula I or la, the phacmaceutical compositions o~ the peesent invention can also contain other active ingredients, such as non-steroidal anti-in~lammatory drugs (NS~IDs)i peripheeal analgesic agents such as zomepirac, diFlunisal and the like, cyclooxygenase inhibitors, leukotriene antagonists, leukotriene biosynthesis inhibitors, H2-receptor antagonists, 33S~

2~94P~1039A - 54 - 17102IA

antihistiminic agents, prostaglandin anta~oni~t~, ~CE
inhibitor6, and thromboxane synthetase inhibitor~.
The wei~ht rat~o of the compound of the ~ormula I oc la to t~e second active ingredient ~ay be varied and will depend upon the effective dose of each ingrediant~ Generally, an ekfecti~e dose of each will be u~ed. Thu~, for example, when a compound of the Formula I or Ia i~ ~ombined with a second active ingcediene the weight ratio o~ the compound of the Formula I or la ~o the second ingcedient will geneeally range from abou~ 1000:1 to about 1:1000, preferably from 200:1 to 1:200. Co~binations of a compound of the Formula I or Ia and other act~ve ingredients will generally be within t~e afore-mentioned range, but in each case, an effective dose of each active ingredient should be used.
NSAID6 can be characterized into five groups:
(1) the pcopionic acid derivatives;
(2) the acetic acid decivatives:
(3~ the fenamic acid deriYat~ve~
(4) the biphenylcarboxylic acid derivatives;
and (5) t~e ox~cam6 o~ a pharmaceutically ac~e~table salt thereo~.
~5 The pcopioniG a~id derivatives w~ich ~ay be used comprise: lbup~ofen, ibuprofe~ aluminum, indopcofen, ketoprofen, naproxen, benoxapcofen, flucbiprofen, fenoprofen, fenbufen, ketoprof en, indopro~en, pirproen, carprofen, o~aprozin, prano-peofen, micoprofen, tioxapsofen, supro~en, almino-profen, tiaerofenic acid, fluprofen and bucloxic 3~

2893P/~046~

acid. Steuctucally related propionic acid deriva-tives having similac analgesic and anti-in~lammatory propecties are also intended to be included in this group.
Thus, "proeionic acid derivatives" as de~ined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drugs having a free -CHtCH3)COOH
or -CH2CH2COOH group (which o~tionally can be in the form of a phaemaceutically acceetable salt group, e.g., -CH~CH3)C00 Na or -CH2CH2C00 Na ), typically attached directly or via a ca~bonyl function to a ring system, preferably to an aromatic ring system.
The acetic acid deeivatives which may be used comprise: indomethacin, which is a ~re~erred NSAID, sulindac, tolmetin, zomepirac, diclofenac, ~enclofenac, alclofenac, ibufenac, isoxepac, furofenac, tiopinac, zidometacin, acemetacin, ~entiazac, clidanac, oxpinac, and fenclozic acid.
Structually related acetic acid derivatives having similar analgesic and antiinflammatory proeerties are also intended to be encom~assed by ~his group.
Thus, "acetic acid derivatives" as defined heLein aee non-narcotic analgesics~non-steroidal anti-in~lammatory drugs having a free -CH2COOH group (which optionally can be in the focm of a phacma-ceutically acceptable salt group, e.g. -CH2C00 Na ), typically attached dieectly to a ring system, pre~ee-ably to an aromatic or heteroaromatic ring system.
The fenamic acid derivatives which may be used comprise: me~enamic acid, meclofenamic acid, ~lufenamic acid, ni~lumic acid and tol~enamic acid.

135~

2893P~1046A
2894P/1039A - 56 - 171021~

Structurally related fenamic acid derivatives having similar analqesic and anti-inflammatory proeerties are al50 intended to be enco~pa~sed by this group.
Thus, "fenamic acid derivative~" as defined herein are non-narcotic analge~ics/non-steroidal anti-inflammatory drugs ~hich contain the basic structure:

~ NH_ COOH

which can bear a va~iety of substituents and in which the free -COOH gcoup can be in the form of a ~5 pharmaceutically acceptable salt qroup, e.g., -Coo Na .
The biphenylcarboxylic acid derivatives which can be used comerise: diflunisal and flufenisal. Structucally relatecl biphenylcarboxyli~
acid derivatives ha~ing similar analgesic and anti-inflammatory properties are also intended to be encom~assed by this gLoup.
Thus, '`biphenylcarboxylic acid derivatives~
a~ defined herein are non-narcotic analgesics/non-steroidal anti-inflammatory drug~ which contain the basic structure:

~
COOH

. .

2B93P~1046A
2894P~1039A - 57 ~ 17102IA

which can bear a variety of substituents and in which the free -COOH group can be in the form of a pharmaceutically acceptable salt group, e.g., -COO Na .
s Th~ oxicams which can be used in the present invention comprise: ~iroxicam, sudoxicam, isoxicam and 4-hydroxyl-1,2-ben20thiazine l,l-dioxide 4-(N-phenyl)-carboxamide. Structurally eelated oxicams haviny similar analgesic and anti-inflammatory proper~ies are also intended to be encompassed by this group.
Thus, "oxicams" as de~ined herein are non-narcotic analgesics~non-steroidal anti-inflammatory drugs which have the geneLal formula:
OH

~1-N H - R

S \ CH3 (~2 wherein R i~ an aryl or heteroaryl ring ~ys~em.
The following NSAIDs may al60 be used:
acemetacin, alminopro$en, amfenac sodium, aminoprofen, anitrazafen, antrafenine, auranofin, bendazac lysinate, benzydamine, bepro2in, broperamole, bufezolac, carprofen, cinmetacin, ciproquazone, clidanac, cloximate, dazidamine, deboxamet, delmetacin, detomidine, dexindopro~en, diacerein, di-fisalamine, difenpyramide, emorfazone, enfenamic acid, enolicam, epirizole, etersalate, e~odolac, . .

~.2~33S~

2894P~1039A - 58 - 171021A

eto~enamate, ~anetizole mesyla~e, ~enclo~enac, fenclorac, fendosal, ~en~lumizole, ~entiazac, feerazone, ~loctafenine, flunixin, flunoxap~ofen, flu~roquazone, fo~i~toline, fosfosal, furclopcofen, fu~ofenac, glucametacin, guaimesal, ibuproxam, iso~ezolac, i~nixim, iso~rofen, isoxepac, isoxicam, lefetamine HCl, l~flunomide, lofemizole, lonazolac calcium, lotifazole~ loxoprofen, lysin clonixinate, meclofenamate sodium, meseclazone, miropro~en, nabumetone, nictindole. nimesulide, orpanoxin, oxametacin, oxapadol, oxa~rozin, p~risoxal citrate, ~imeprofen, eimetacin, ~i~roxen, pi~zolac, ~irfenidone, pirprofen, pranoero~en, peoglumetacin maleate, yroquazone, ~yridoxipro~en, sudoxica~, supro~en. talmetacin, talnifluma~e, tenoxicam, thi~zolinobutazone, thielavin a. tiapro~enic acid, tia~amide HCl, ti~lamizole, timegadine, tioxap~ofen, tolf~namic acid, toleadol, tryptamid, ufenamate, and zidometacin.
The following NSAIDs, designated by com~any code numbec. may also be used:
480156S, ~861, ~D1491, AD1590, ~FP802, AFP860, AHR6293, AI77B, AP504, AU8001, B~Yo8276, BPPC, BW540C, BW755C, CHINOIN 127, CN100, C0893XX, CPP, 2~ ~102q2, ~KA9, DV17, Ea382, EGYT2829, EL508, F1044, FZ, GP53633, GP650, GV3658, HG~3, ITCl, ITF, ITF182, KB1043, KC8973. KCNTEI6090, KME4, LA2851, LT696.
LU20884, M7074, MED15, MG18311, MR714, MR897, MX309, N0164, 0~03144, PR823, PV102, PV108, QZ16, R830, RS2131, RU16029, RU2&559, RUB265, SCR152, SH440, SIR133, SIR136, SIR92~ SPAS510, SQ27239, ST281, 5X1032, SY6001, SaH46798, TA60, TAI901, TEI615, 2893P~1046A

TVX2706, TVX960, TZI615, U60257, UR2310, WY23205, WY41770, YM09561, YM13162, YS1033, and Z~31945.
Finally, NSAIDs which may also be u~ed include the salicylates, spscifically aspirin, and the phenylbutazone~, and pharmaceutically acceptable salts thereof.
Pharmaceutical compositions comprising the Formula I or Ia compounds may also contain other inhibitors of the biosynthesis of the leukotrienes 10 such as are disclosed in EP 138~481 t~pril 2~, 1985), EP 115,394 (~ugust ~, 1984), EP 136,893 (~eril lO, 1985), and EP 140,709 (~ay 8, 1985)-The compounds of the Focmula I or Ia may also be used in combination with leukotriene antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984), and others known in the art such as those disclosed in European Patent Application Nos. 56,172 and 20 61,800; and in U.K. Patent Specification No. 2,058,785.

Pharmaceutical compositions comprising the Focmula I or Ia compounds ~ay also contain as the second active ingredient, antihistaminic agent6 such as benadryl, dramamine, histadyl, phenergan and the like. Alternatively, they may include othee erostaglandin antagonists such as those disclosed in European Patent ~pplication 11,067 ~May 28, 1930) or other thLomboxane antagonists such as those disclosed in U.S. 4,237,160. They may also contain hi~tidine s~
2B93P/1046~
2~9~P~1039~ - 60 - 17102~A

de~arboxylase inhibitoc~ ~uch a~ ~-fluoromet~yl-~istidine, ~e~r~b~d in U.S. 4,325,961. ~he ~ompounds o~ the Formula I ~ay also be advantageou~ly combined with an Hl or H2-~eceptor a~tagonifit, ~uch as for instance ci~e~ldine, rani~ldine, terfenadine, famotidine, aminot~iadiazoles dis~losed in ~P 40,696 (Decembe~ 2, 1981) and like ~ompound~, such a~ tho~e dis~losed in V.s. Pate~t ~08 .
4,283,40~; 4,362,736; 4,394.508; and a pending ~0 application, Can. S.N. 385,612, filed August 11, 1981.
The pharmaceutical compositions may also contain a K+/H+ ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like.

When t~e second a~tive ing~edient in compositions of thi6 inveneion ~.~ a ~comboxane synthetase inhibitor, su~h inhibitor can be as de~c ibed in UK 2,038,821 (e.g., ~K 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.~95,357 (e.q., U63557A) U.s.P. 4,273,782 (e.q~, uK-384a5)~ o~ EP
~,690 (e.g.. C~ 51).
An embodiment of the invention i~ a cardio-Ya~cula~ co~position useful ~or t~ea:ing arterial thrombo~i~ which compri6e6 an antlthromboti~ compound o~ the Formula I or la.
A further embodiment of the invention i6 a cardiovascular composition usè~ul fo~ treating 28g3P/1046P~

arte~ial thrombo6is which compri6e~: (1) the antithromboti~ Formula I o~ Ia compound deined above; and, (ii) an angiotensin ~onvecting enzyme ~ACE) inhibitor com~ound which is a member o~ the 5 groue: cacboxyalkyl dipeptide derivati~es: captopril [1-~3-mercapto-2-methyl-1-oxoecoeyl)-L-pcoline]:
2-tN-(5~-1-ethoxycarbonyl-3-~henylpropyl)-S-alanyl]-cis,endo-2-a~abicyclo[3,3,0]octane-3(S)-carboxylic acid: N-((S)-l-ethoxycarbonyl-3-ehenylp~opyl)-L-alanyl-N-~2-indanyl)-glycine; l-(N-[(S)-l-ethoxy-carbonyl-3-phenylpropyl]-L-alanyl)-cis,syn-octahydro-(H-indole-2-S~ carboxylic acid; 2-(N-~ (S)-l-ethoxy-ca~bonyl-3-phenylpropyl]-L-alanyl)-1,2,3,4-tetrahydro-iso-i60quinoline-3(S)-carboxylic acid; and, l-carboxy-methyl-3(S)-(l(S)-ethoxycarbonyl-3-phenylp~opylamino)~
2,3,4,5-tetcahyd~o-lH[l]-benzazepine-2-one.
In particular the class of ACE inhibitors whi~h have been found to have a eotentiating effect when used in combination with the Formula I or Ia compounds are those disclosed in U.S. Patent 4,374,829, which also discloses methods for their ereeacation and which compounds are generally represented by the Formula XI

~5 ~ Rl R3 R R o R-C-C -NH-lH - C - N - C - C - R
R2 0 ~7 XI
whe~ein 835~
~893P/104~
2894P/1039~ - 62 - 17L021A

R and R are the same or different and are hydroxy, lower Cl-C8 alkoxy;
lower Cl-C8 alkenoxy;
dilower Cl-C8 alkylamino lower Cl-CB
alkoxy (dimethylaminoethoxy);
acylamino lower Cl-C8 alkoxy (acetyl-aminoethoxy);
acyloxy lower Cl-C8 alkoxy (pivaloyloxy-me~hoxy3:
. aryloxy, wherein the aryl is C6 or C10 such as phenoxy;
arlower Cl-C8 alkoxy, such as benzyloxy:
substitu~ed aryloxy or substituted arlower-Cl-C8 alkoxy wherein the aryl is C6 or C10 and the substituent is methyl, halo oc methoxy:
amino:
lower Cl-C8 alkylamino:
dilower Cl-C8 alkylamino:
hydroxyamino:
arlower Cl-C8 alkylamino wherein the aryl g~oup is C6-C10 such as benzylamin~;
R is hydrogen;
hydrocarbon of from 1 to 20 carbon atoms which include branched and unsaturated (such as allyl) grou~s:
C3-C10 cycloalkyl;
substituted lower Cl-C8 alkyl wherein the substituent can be halo, hydroxy, lower Cl-C8 alkoxy, aryloxy wherein the aryl is C6-C10 such as phenoxy, amino, dilowee Cl-C~ alkylamino, acylamino such as acetamido and benzamido, arylamino wherein the aryl is C6 oc C10, guanidino.
S imidazolyl, indolyl, mercapto, l~wer Cl 8 alkylthio, arylthio wherein the aryl is C~ or C10 such as ehenylthio, carboxy or carboxamido, carbolower Cl 8 alkoxy;
aryl of C6-C10 such as phenyl or naphthyl;
substituted aryl of C6-C10 such as ~henyl wherein the substituent is lower Cl-C8 alkyl, lower Cl-C8 alkoxy lS or halo, unsub6tituted or substituted arloweralkyl, arlowecalkenyl, heteroarlower alkyl, or hetecoarlower alkenyl, wherein aeyl groues ace C6 or C10, the alkyl groups are C2-C8, and the heteroatoms ace one of 0, N oc S and the the ~ubstituent(s) is halo, dihalo, lower Cl-C8 alkyl, hydroxy, lower Cl-C8 al~oxy, amino, aminomethyl, acylamino (acetylamino or benzoylamino) dilower Cl-C8 alkylamino, lower Cl-C8 alkylamino, carboxyl, halolower Cl-C8 alkyl, cyano or sulfonamido;
arlower Cl-C8 alkyl or heteroarlower Cl-C8 alkyl whe~ein the aryl groue is C6 or C10 and the heteroatom is .. , , :
. , .
. .

s~
2~93P~1046~
2894P/L039~ - 64 - 17102IA

one o 0, N or S, substituted on the alkyl portion by amino or acylamino 2 7 ~acetylamino or benzoylamino) R and R are the same oe different and ace S hydrogen oc lower Cl-C8 alkyl;
R is hydrogen, lower Cl-C8 alkyl, phenyl lower Cl-C8 alkyl, aminomethyl ~henyl lower Cl-C8 alkyl, hydroxy phenyl lower Cl-C~ alkyl, hydroxy lower Cl-C8 alkyl, acylamino lower Cl-C8 alkyl ~such as benzoylamino lower Cl-C8 alkyl, acetylamino lowe~ Cl-C8 alkyl)~ amino lower Cl-C8 alkyl, dimethylamino lower Cl-C8 alkyl, halo lower C~-C8 alkyl, guanidino lower Cl-C8 alkyl, imidazolyl lower CL-C8 alkyl, indolyl lower Cl-C8 alkyl, mercap~o lower Cl-C8 alkyl, lower Cl-C8 alkyl thio lower Cl-C8 alkyl:
20 R is hydrogen or lower Cl-C8 alkyl;
R5 is hydrogen, lower Cl-C8 alkyl, phenyl, phenyl lower CL-C8 alkyl, hydroxy ~henyl lower Cl-C8 alkyl, hydroxy lower Cl-C8 alkyl, amino lower Cl-C8 alkyl~ guanidino lower Cl-C8 alkyl, imidazolyl lower Cl-C8 alkyl, indolyl lower Cl-C8 alkyl, mercapto lower Cl-C8 alkyl or lower Cl-C8 alkyl thio lower Cl-C8 alkyl; or, 0 R4 and R5 may be connected together to ~orm an alkylene bcidge o~ from 2 to 4 carbon atoms, an alkylene bridge of from 2 to 3 carbon 2893P~1046~
2894PtlO39A - 6S - 17102IA

atoms and one sulfur atom, an alkylene bridge o~ from 3 to 4 carbon atom~
containing a double bond or an alkylene bridge as above substituted with hydroxy, lower Cl-C8 alkoxy, lower Cl-~8 alkyl or dilower Cl 8 alkyl;
and, the pha~maceutically acceptable salts the~eo~.

Preferred ACE inhibitor compounds of Formula VI are those wherein: .
R and R can each independently be hydroxy, lower alkoxy, lower alkenoxy, arloweralkyloxy.
amino, diloweralkylamino lower alkoxy, acylamino lower alkoxy or acyloxy lower alkoxy;
R is hydrogen, alkyl of ~rom 1 to 20 carbon atoms, including branched, cyclic and unsaturated alkyl grou~s;
substituted lower alkyl wherein the substituent is halo, hydroxy, lower alkoxy, aryloxy, amino, loweralkylamino, diloweralkylamino, acylamino, arylamino, guanidino, imida20yl, indolyl, merca~to, loweralkylthio, aryl~hio, carboxy, carboxamido or carbolower alkoxy;
ehenyl;
substituted phenyl wherein the substituent is lower alkyl, lower alkoxy oc halo:
arloweralkyl or heteroaryloweralkyl arloweralkenyl or heteroarloweralkenyl, substituted arloweralkyl, substituted 33~ jh~

heteroarylloweralkyl, substituted arloweralkenyl or substituted heteroarloweralkenyl;
whecein the substituent is halo or dihalo lower alkyl, hydeoxy, lower alkoxy, amino, aminomethyl, acylamino, diloweralkylamino, loweralkylamino, carboxyl, halo alkyl, cyano or sulfonamido:
arloweralkyl or heteroarloweralkyl substituted on the alkyl eortion by amino or acylamino;
R and R are hydrogen;
R is lower alkyl, amino lower alkyl, imidazolyl, lower alkyl, halo lower alkyl:
R and R are joined to ~orm an alkylene bridge o~ from 2 to 4 carbon atoms or an alkylene bridge of ~rom 2 or 3 carbon atoms and one sulfur atom or an alkylene bridge o~ ~eom 2 to 3 carbon atoms and one sul~ur atom or an 2Q alkylene bridge of from 3 to 4 carbon atoms containing a double bond or an alkylene bridge of ~eom 3 to 4 cacbon atoms contain-ing a double bond or an alkylene bridge as abo~e substituted with hydroxy, lower alkoxy or lower alkyl:
or the eharmaceutically acceptable salts thereof wherein said aryl is a member selected from the group consisting o~ phenyl or naphthyl and said heteroaryl is a member selected ~rom the groue consisting of pyridyl, thienyl, ~ueyl, indolyl, benzthienyl, imidazoyl, or thiazolyl.

"` ~.2B835~

2894P/1039~ - 67 - 17102I~

Moce peefeeeed are those antihypertensive com~ounds of Formula VI wherein:
R and R can each independently be hydroxy, lower alkoxy, lower alkenoxy, arloweralkyloxy, amino, diloweralkylamino lower alkoxy, acylamino lowae alkoxy or acyloxy lower alkoxy;
R is alkyl having from 1-8 cacbon atoms, substituted lower alkyl wherein the alkyl group has 1-5 carbon atoms and the substituent is amino, arylthio, aryloxy oc aeylamino, aealkyl or heteeoaralkyl wherein the alkyl portion has ~-3 carbon atoms, substitu~ed aralkyl or heteroaralkyl wherein lS the alkyl geoues have 1-3 caebon atoms and the substituen~(s) is halo, dihalo, amino, am~noalkyl, hydroxy, lowe~ alkoxy or loweL
alkyl;
R and R are hydeogen;
R is lower alkyl or amino lower alkyl:
R and R can be joined togethee theough the carbon and nitrogen atoms to which they ace attached to form a eing of the formula:

~-y \l I ooR6 wherein Y is CH2, S, oe CH-OCH3 or the ehaemaceutically acceet~ble salts theeeof whecein said aryl is a member selected from 33~

2894P~1039~ - 68 - 17102IA

the groue consisting of phenyl or na~hthyl and said heteroaryl is a member selected ~com the group consisting of pyridyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl oe thiazolyl.

Still more pre~erred antihy~ertensive ~ompounds of Formula VI are those wherein:
R and R can each independently be hydroxy, lower alkoxy, aralkyloxy:
R and R are hydrogen;
R is methyl, aminoloweralkyl;
R and R are joined through the carbon and nitrogen atoms to form pcoline, 4-thiaproline or 4-methoxyproline and;
R is alkyl having ~com 1-8 cacbon atoms, substituted lower alkyl wherein the alkyl groue has 1-5 carbon atoms and the -substituent is amino, arylthio or aryloxy, aralkyl or heteroaralkyl wherein the alkyl poction has 1-3 cacbon atoms, substitutad aralkyl or heteroaralkyl wheeein the alkyl groups have ~-3 carbon atom~ and the substituent(s) is halo, dihalo. amino, aminoalkyl, hydroxy, lower alkoxy or lower alkyl;
and the eharmaceutically acceetable salts thereo~
wherein said aryl is a member selected from the group consisting of phenyl or naphthyl and said heteroaryl is a member selected ~rom the group consisting o~
pycidyl, thienyl, furyl, indolyl, benzthienyl, imidazoyl oc thiazolyl.

31!3;3X~

2894P~1039A - 69 - 171021A

Examples o~ Formula I or Ia compounds are set forth a~ove on pages 38-41.
Examples of Formula VI compound6 are:
(i) N-(L-carboxy-3-ehenylpropyl)-L-alanyl-1-proline;
(ii) N-(l-e~hoxycarbonyl-3-phenylpropyl~-L-alanyl-L- prol ine ;
(iii) N-(l-ethoxycarbonyl-4-methylpentyl)-L-alanyl-L-eroline: 10 (iv) N-(l-carboxy-S-aminopentyl)-L-alanyl-L-pcoline;
(v) N-a-(l-carboxy-3-phenylpropyl)-L-lysyl-L-eroline;
~vi) N-a-(l-ethoxycarbonyl-3-phenylproeyl)-L-ly~yl-L-proline;
(vii) N-a-[l-carboxy-3-(3-indolyl)-propyl]-L-lysyl-L-~roline;
(viii) N--~l-carboxy-3-(4-chlorophenyl)-propyl]-L-lysyl-L-proline;
20 (ix) N-a-~l-carboxy-2-phenylthioethyl]-L-lysyl-L-proline;
(x) N-a-[l-carboxy-3-(4-chlorophenyl)-propyl3-L-lysyl-trans-4-methoxy-L-proline;
(xi) N-a-tl-ca~boxy-5-amino~entyl~-L-lysyl-~-proline:
(xii) N-a-(l-carboxy-3-~henylpco~yl)-L-ocnithyl-L-proline;
(xiii) ethyl N~ ethoxycarbonyl-3-ehenylpco~yl)-L-alanyl-L-prolinate hydrochloride;
(xiv) N-[l-(ethoxycarbonyl)-3-(4-imidazolyl)propyl]-L-alanyl-L-proline.

~ 2~3~

(xv) N-[l-carboxy-3-(4-imidazolyl)propyl]-L-lysyl-L-proline;
(xvi) N-(l(S)-carboxy-3-phenylpropyl)-L-alanyl-L-proline;
(xvii) N-(l(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-proline maleate salt;
(xviii) N-~-(l(S)-carboxy-3-phenylpropyl)-L-lysyl-L-prol1ne;
(xix) ethyl N- (l(S)-ethoxycarbonyl-3-phenylpropyl)-L-alanyl-L-prolinate hydrochloride;
( XX ) N-G- (l(S)-ethoxycarbonyl-3-phenylpropyl)-L-lysyl-L-proline.
The above-described Formula VI compounds, their use and the method of preparation thereof are 15 disclosed in U.S. Patent 4,374,829.
The resolution of certain Formula I and Ia compounds into their optically pure enantiomers is as disclosed in U.S. Patents 4,424,355 and 4,435,579.

The combination composition of the inven-tion can contain varying amounts of the Formula I
or Ia (i) antithrombotic compound and Formula VI
(ii) antihypertensive compounds. The weight ratio of (i):(ii) can ran~e from about 25 to 1; prefera-bly from about 10 to 1. In addition to the active ingredients of (i) alone or of (i) and (ii) in combi-nation, the compositions of the invention can also contain other conventional pharmaceutically accept-able compounding ingredients, as necessary or de-sired. Such ingredients are generally referred to ascarriers or diluents. Conventional procedures for .~

. ~ , . . ~

~2~ Z

2893P/1046~
2894P/1039A _ 71 _ 171021A

preparing such compositions in appropriate dosage forms can be utilized. Whatever the dosage fo~m, it will contain a pharmaceutically effective amount of the present composition.
The combination compositions can be administered orally oe other than orally; e.g., parenterally, by insufflation, toeically, rectally, etc.; using ap~ro2riate dosage forms; e.g., tablets, capsules, sus~ensions, solutions, and the like, for oral administration; suspension emulsions, and the like, for parenteral administration; solutions for intravenous administration; and ointments, transdefmal eatches, and the like, for topical administration.
These compositions are formulated similarly to the L5 compositions discussed on pages 46 ~o 51, above.
Treatment dosage for human beings for cardiovascular use can be varied as necessary.
Generally, daily dosages of the composition of the invention can range from about 6000 to about 10 mg;
20 preferably, from about 3000 to about 20 mg.
The amount of active ingredient that may be combined with the carrier materials to produce a single dosage fo~m for cardiovascular use will vary depending upon the host treated and the particular mode of administcation. For example, a formulation intended for oral administration may contain from S
mg to 5 gm of active agents compounded with an approp~iate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 20 mg to about 500 mg of active ingredients.

~L~~83~

2893P/L046~
2~94P/1039~ - 72 - 171021A

It will be undeestood, however, that the specific dose level for any eacticular patient will depend upon a variety of factors including the activi~y of the s~ecific com~ound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the ~articular disease undergoing theraey.
The comeosi~ion of this invention inhibits ~latelet accumulation at the damaged endothelial surface via the Formula I or Ia compound. This inhibitory effect is potentiated by the eresence of the antihypertensive compound.
Thus, the comeositions of the invention are useful in treating thrombosis and are also of value in the management of acute and chronic congestive heart failure.
In vivo testing of the composition of this inven~ion in test animals (rabbits) can be used to demonstrate that this comeosition is eharmaceutically e~fective in decreasing platelet-related arterial thrombic formation.
To demonstrate t~e potentiation of the antihyeertensive comeound on the anti-thrombotic Formu~a I or Ia compound comprising the combination composition of the invention, the effect of these compounds on test animals ~rabbits) can be determined seearately and then in combination. The effect of a different class of antihypertensive agents singly and in combination with the Formula I or Ia comeound of the invention can also be determined for comearati~e eurposes. The methods employed are desccibed in a 33S~

copending application. attorneY docket no 17062. Can.
Serial No. 482,597, filed May 28, 1985.

The ~ollowing exameles illustrate the pee~aration of the compounds of the pre~ent invention without, however. limiting the ~ame thereto.
All temperatures are in degrees Celsiu6.

EX~MPLE 1 A. Preparation of Hydrazine Starting Materials l-[(~-Chlorophenyl)methyl]-1-~4-methylphenyl) hydrazine __ _ A mixture of 10 g of p-tolylhydrazine hydrochloride, 75 ml of toluene and 11.5 ml of triethylamine was heated at reflux for 60 minutes.
Then, 7.1 g of p-chlocobenzyl chloride was added.
A~ter sticring 16 hours at reflux, triethylamine hydrochloride was ~iltered of~ and washed with ethyl ether. The filtrate and washiny were concentrated in vacuo and chromatographed on a silica gel column (hexane-ethylacetate, 9:1) to glve 6.64 g of the title compound, (Compound No. 5 in Table 3).

B. Other hydrazines, similarly preeared, are also ~hown in Table 3.

3 8 ~
2893P/1046~

E~

~/
y/

Comeound No. X Y Compound Name 1. 4-F Cl 1-[(4-chlorophenyl3-methyl]-l-(4~fluoro-~henyl)hyd~azine hydro-chloride 2. 3,5-C12 Cl 1-[(4-chlo~ophenyl)-methyl]-l-(3,5-dichloco-phenyl)hydrazine hydco-chloride 3. 3-OMe Cl 1-~(4-chlorophenyl)-methyl]-l-t3-methoxy-phenyl)hydrazine hydro-chlocide 4- 3-Me Cl 1-[(4-chlorophenyl)-methyl~-1-(3-~ethyl-phenyl)hydrazine hydro-chlocide ~ 3~J

2893P/~046~
2894P/1039A - 7~ - 171021A

5. 4-Me Cl L-[~4-chlorophenyl)-methyl]-1-(4-methyl-phenyl)hydrazine hydco-chlo~ide 6. 4-Cl Cl l-tt4-chlorophenyl)-methyl]-1-(4-chloro-phenyl) hyd~azine hydro-chloride 7. H Cl l-t(4-chlorophenyl)-methyl3-1-(phenyl) hydrazine hydrochloride 8. 4-Br Cl l-~t4-chlorophenyl)-methyl]-l-(4-bromo-phenyl)hydrazine hydro-chloride 9. 4-OMe SMe 1-~(4-methylthiophenyl~-methyl]-l-(4-methoxy-phenyl) hydra2ine hydro-chloride 25 lQ. 4-OMe Cl 1-~4-chlorophenyl)-methyl]-l-t4-methoxy-phenyl) hydrazine hydro-chloride 11. 4-OMe No2 1--~(4-nitro~henyl~-methyl]-l-t4-methoxy-phenyl)hydrazine hydrochloride 1~3~33~

2894~/1039~ - 76 - ~71021~

12. 4-F SMe 1-~(4-methylthio~henyl)-methyl~-l-(4-fluo~o phenyl) hydrazine hyd~o-chloride EX~MPLE 2 3 (oc Beta)-[l-(p-Chlorobenzyl)-5-chlo~o-3-methyl-2-indolYl~ oPionic acid _ _ 10 steP, 1:
To 1.84 g of 1,1-[(4-chlo~ophenyl)methyl]-1-(~-chlo~ophenyl) hyd~azide hydrochloride in 60 cc o~
te~t-butanol was added 868 mg of methyl 4-oxo-hexanoate. The ~eaction mixtu~e was reflux~d undec nitcogen for 16 hours. The ~e~ulting ~eaction mixtu~e wa6 then evapoeated to dryne66 and the resulting residue su~pended in C~2C12. The 601id material was then filtered. The filtcate was washed with water, dried and evaporated. The re6ulting fiycup was then ch~omatog~aphed on silica gel to give 1.47 g o~ indole de~ivative (65~).
~MR: H N~R ~CDC13): 2.25 eem ~e, 3H, sin~let); 2.43 (CH2, 2H, triplet); 3.01 (CH2, 2H, t~ielet); 3.64 ~_~
(OMe, 3H, singlet); 5.29 (CH2 ~ \~ Cl, 2H, 6inglet); 6.83 (H-2' and H-6', 2H. d); 7.1 (H-6, and H-7, 2H, multi~let); 7.25 (H-3' and H-5'. 2H); 7.49 (H-4. lH, singlet).

, a3s~
28g3P~10~6~
2894P/1039~ - 77 - 171021A

Step 2:
To 1.06 g of methyl ester in 350 ml o~ EtOH
was added 169 mg of sodium hydroxide dissolved in 3 ml of H20. The cesulting solution was stireed at room temeerature ~or 16 houcs. The eeaction mixtuce was then acidified with HCl (lN) and concentrated.
The cesulting solution was then extracted with CH2C12 t3 times). The combined organic layer was washed with brine, dried over MqSO4, and evaeoeated to give 1 q of solid material (100% yield). An analytical sample of this material was be prepaeed by triturating the resulting solid material with hexane followed by a filtration (800 mg).
~nalysis calculated for ClgH17C12NO2:
C, 62.99; H. 4.74; N, 19.58 Found: C, 63.19: H, 4.78: N, 19.35.

EX~MPLE 3 3 toe Beta)~ (p-chlorobenzyl)-3-methyl-5-fluoeo-2 indol~ P~oPionic acid Following the proceduee of ExamPle 2, but using L-~4-chlocophenyl)methyl]-1-~4-fluorophenyl)-hydcazina hydcochlocide and methyl 4-oxohexanoate as the starting materials and ethanol as the solvent, the title comeound was eLePared.
~nalysis calculated for ClgH17ClFN02:
- C, 65.98; H, 4.95; Cl, 10.25 Found: C, 65.56; H, 5.17: Cl, 10.52.

383S;~:

2893P/1046~
2894P~1039A - 7~ - 17102IA

3 ~or Beta)-[l-p-Chlorobenzyl-3-methyl-4,6-dichloro-2-indolYllprolæ-onic acid Following the procedure o~ ~xam~le 2, but S using 1-[(4-chlorophenyl)methyl~-1-(3,5-dichloro-phenyl)hydcazine hydrochloride and methyl 4-oxohexanoate as the starting materials and ethanol as the solvent, the title compound was prepared.
~nalysis calculated for ClgH1602C13N:
C, 57.52; ~, 4.06 Pound: C, 57.40; H, 4.20.
., EX~MPLE 5 3 (oe Beta)-[l~(p-Chlorobenzyl)-3-methyl-4-methoxy-2-indolYllPeoPionic acid Following the procedure of Examele 2~ but using l-~(4-chlorophenyl)methyl]-1-(3-methoxyphenyl)-hydrazine hydrochlocide and ethyl 4-oxohexanoate as the starting materials and ethanol as the solvent, the title compound was prepared.
~nalysis calculated for C20H2003NCl:
C, 67.L2; H, 5.63 Found: C, 67.40; H, 5.43.

3 (or Beta)-~ e-chlorobenzyl)-3-methyl-6-methoxy-2-indolyllpeoPionic acid _ _ Following the procedure of Example 2, but using 1-~4-chlorophenyl)methyl~-1-(5-methoxyphenyl)-hydrazine hydrochloride and methyl 4-oxohexanoate as the starting materials and teet-butanol as the solvent, the title compound was preeaeed.

' . .

~ ~3835~
2893P/~046~
2894P/1039~ - 7g - 171021A

~nalysis calculated for C20H2003NCl:
C, 67.12; H, 5.63; N, 3.91: Cl, 9.90 Found: C, 67.08, H, 5.64: N, 4.09.

EX~MPLE 7 3 (or Beta)~ p-Chloeobenzyl)-3,4-dimethyl-2-indolyleroeionic acid and 3 (or Beta)-~l-tp-chloro-benzyl)-3,6-dimethyl-2-indolyl]propionic acid tas a _xture) _ _ __ Following the procedure o~ Example Z, but using 1-~(4-chlorophenyl)methyll-1-(3-methylphenyl)-hydrazine hydrochloride and methyl 4-oxohexanoate as the stacting materials and t-butanol as the solvent, the title compounds were pre~ared.
15 ~nalysis calcula~ed ~or C20H20NC102:
C, 70.26; H, 5.89; N, 4.09; Cl, 10.37 Found: C, 70.52: H, 5.57: N, 4.56: Cl, 10.03.

EX~MPLE 8 20 1-(4-Chlorobenzyl)-3-methyl 5-methoxy-2-t4`-carboxy-butYllindole __ __ __ Followiny the procedure o~ Examele 2, but using 1-~4-chloro~henyl)methyll-1-(4-methoxyphenyl)-hydrazine hydrochloride and methyl 6-oxooctanoate as the starting mate~ials and methanol as the solvent, the title compound was peepared.
Analysis calculated for C22H24N03Cl:
C, 68.57: H, 6.23; N, 3.63 Found: C, 68.~5; H. 6.41; ~, 3.35.

.. ,. ~

s35~
2893~/1046~
2894P/1039~ - 80 - 17102IA

EX~MPLE 9 3 (or Beta)-~l-(p-Chlorobenzyl)-3,5-dimethyl-2-indo 1Y1 leeopionic acid Following the procedure of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methylphenyl)-hydrazine hydcochloride and methyl 4-oxohexanoate as the ceactants and ethanol as the solvent, the title comeound was pcepared.
~nalysis calculated for C20H2002NCl~
C, 70.31; H, 5.90; N, 4.1: Cl, 10.37 Yound: CJ 70.37; H, 5.85; N, 4.10; Cl, 10.15.

1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-(3-carboxy-pco~yll~ndole Following the procedure of Examele 2, but using l-~(4-chlorophenyl)methyl~ 4-methoxyphenyl)-hydrazine hydrochloride and methyl 5-oxoheptanoate as the starting materials and ethanol as the solvent, the title compound was prepared.
~nalysis calculated ~or C21H22N03Cl:
C, 67.83: H, 5.92: N, 3.76 Found: C, 67.92; H, 5.97; N, 3.84.

EX~MPLE_ll 3 (or Beta)-[l-(p-Chlorobenzyl)-3-methyl-2-indolyl]-Propionic acid A
Following the procedure o~ Example 2, but using 1-[(4-chlorophenyl)methyl~-L-(phenyl)hydrazine hydrochloride and methyl ~-oxohexanoate as the starting matecials and tert-butanol as the solvent, the title compound was prepared.

s~

~nalysis calculatad ~or ClgH1~02ClN:
C, 67.15; H, 5.33; N, 4.12; Cl, 10.43 Found: C, 67.77: H, 5.42; N, 4.48; Cl, 10.48.

3 (or Beta)-[l-(p-Chlorobenzyl)-5-bromo-3-methyl-2-indolyllpropionic acid Following the procedure o~ Example 2, but using 1-~(4-chlorophenyl)methyl]-1-(4-beomophenyl)-hydrazine hydrochloride and methyl 4-oxohexanoate as the starting materials and t-butanol as the solvent.
the title compound was prepared.
Analysis calculated for ClgH17C102BrN:
C, 56,10; H, 4.21;
L5 Found: C, 56.07: H, 4.27.

EX~MPLE 13 1-(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(2-carboxYethyl)indole Following the ~rocedu~e of Example Z, but using L-[(4-methylthiophenyl)methyl~-1-(4-methoxy-phenyl)hydrazine hydrochlocide and methyl 4-oxo-hexanoate as the starting materials and tert-butanol as the solvent. the title compound was prapaeed.
Analysis calculated for C21H23N03S:
C, 68.29; H, 6.23; N, 3.79 Found: C, 68.03 H, 6.12; N, 3.76.

3l~ 3~;~

EX~MPLE_L4 1-(4-Thiomethylben~yl)-5-methoxy-3-methyl-2-(2-carboxyethyl)indole S-oxide Using the methyl ester of the title comeound o~ Example 13 as the starting material, 250 mg were dissolved in 20 ml o~ dichloro methane and cooled to 0C. Metachloroeeroxybenzoic acid, L38 mg, was added and the reaction stirred at 0C foe 1 hour. 200 mg anhydrous Ca(OH)2 was added and ~he reaction ~iltered and eva~orated to dryness. The methyl ester so obtained was hydrolyzed according to the conditions described in Example 2.
~nalysis calculated for C21H23N04S:
C, 63.45; H, 5.70; N, 3.47 Found: C, 63.55; H, 5.67; N, 3.32.
.

1--(4-Thiomethylbenzyl)-5-methoxy-3-methyl-2-(3-carboxypropYl)indole Following the method of Exam~le 2, but using 1-~(4-methylthiophenyl)methyl]-1-(4-methoxyphenyl~-hydrazine hydrochlocide and methyl 4-oxohe2tanoate as the starting materials and tert-butanol as the solvent, the title comeound was eceeared.
~nalysis calculated for C22H25N03S 1~2 H20:
C, 67.86; H, 6.64; N, 3.50 Found: C, 66.85; H, ~63; N, 3.31 :' 35~

2~94~/1039A - 83 - 171021 E~P~SPLE 1 6 4-[l~(p-Chlorobenzyl)-3-~ethyl-5-fluoro-2-in~olyl~-~_ .
Follo~ing the method of ~xa~ple ~, but u~ing l-t(4-c~locophenyl)methyl]-l-(4-fluocophenyl)hydcazlne hydcoehlocide and methyl 5-oxohep~anoate as the ~taeting material~ and te~t-butanol as the solvent, the ti~le compound wa~ pcepa ed.
Analy6i6 calculated foc C20HlgClFN0~:
C, 66.76: H, 5.32; Cl, 9.85 Found: C, 66.89; H, 5.24; Cl, 10.26.

~MPLE 17 3 (oe Beta)-tl-(p-Thiomethylbenzyl)-3-methyl-5-~luoro-2-indolvll~roPanoic acid ~ Following the pcocedu~e of Example 2, but using l-[(4-methylthiophenyl~meehyl~-1-(q-fluoco-phenyl)hyd~azine hydrochlocide and ~ethyl 4-oxo-hexanoate as the ~tarting material~ and tert-butanol a~ the ~olvent, the title compound ua6 pcepared.
Analysis calculated foc C20H2002FSN:
C, 67.20; H, 5.64; N, 3.91 Found: C, 67.21: H, 5.91: N, 3.88.

EXAMPLE 1~
3 (or Beta)-~l~p-Methyl~ul~oxylbenzyl~-3-methyl-5-fluoro-2-indolYll-proPanoic acid U~ng the title compound o~ Example 17, treated acco~ding to the procedura described in Example 14, the title compound wa~ obtained.
Analysis calculated ~oc C20H20FNO~S:
C, 64.32; H. 5.39: N, 3.75 Found: C, 64.18; H. 5.65; N, 3. 4a .

35~

2893P/1046~
2894P/1039~ - 84 - 17102IA

EX~MPLE 19 3-~1-(4-Chlorobenzyl)-3-methyl-5-methoxy-2-indolyl]-butanoic acid Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphe~yl)-hydrazine hydrochloride and methyl 3-methyl-4-oxohexanoate as the starting materials and methanol as the solvent, the title compound was prepared.
Analysis calculated for C21H22NO3Cl H2O:
C, 64.78; H, 6.13; N, 3.59 Found: C, 65.86; H, 6.12; N, 3.37.

3-Methyl-4-~1-p-chlorobenzyl-5-methoxy-3-methylindol-2-Yllbutanoic acid _ _ Following the method of Example 2, but using 1-~(4-chlorophenyl)methyl]-1-~4-methoxyphanyl~hydrazine hydrochloride and 3-methyl-5-oxoheptanoic acid as the starting materials and isopropanol as the solvent, the title compound was peepared.
Analy~is calculated ~or C22H2403NCl:
C, 68.48; H, 6.27; N, 3.63; Cl, 9.19 Found: C, 68.49; H, 6.50; N, 3.55; Cl, 8.93.

E:XI~!PLE~ al 3-Methyl-4-~1-p-chlorobenzyl-5-fluoco-3-methylindol-2-yllbutanoic acid Following the method o~ Example 2, but using 1-~(4-chlorophenyl)methyl]-1-(4-fluorophenyl)hydrazine hydrochloride and 3-methyl-4-oxoheptanoic acid as the starting materials and isopropanol as the solvent, the title compound was prepared.

: :.

33~;2 2893P/1046~
2894P/1039A - ~5 - 17102IA

~nalysis calculated for C21Hzl02NClF:
Calc.: C, 67.47; H, 5.66; N, 3.75; Cl, 9.48: F, 5.08 Found: C, 67.57; H. 5.90; ~. 3.60; Cl, 9.44: F, 4.50 EX~MPLE 22 3~(1-p-Chlorobenzyl-3-methyl-5-methoxyindol-2-yl)-2,2-dimethyl~roPanoic acid Following the method of Example 2, but using 1-[(4-chlorophenyl)methyl]-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxohexanoate as the s~arting materials and tert-butanol as the solvent, the title compound was prepared.
~nalysis calculated ~or C22H24NO3Cl:
Calc.: C, 64.48: H, 6.40; N, 3.63 Found: C, 68.32, H, 6.37; N, 3.53.

3-~1-e-Chlorobenzyl-5-hydroxy-3-meth~lindol-2-yl]-proPionic acid Beginning with 3-~1-p-chlorobenzyl-5-methoxy-3-methylindol-2-yl]~roeionic acid which is described in J. Med. Chem., 1252 (1968), (2.7 g) was dissolved in 20 ml CH2C12 at 0C. 7.6 ml BBr3 ~lM in CH2Cl2) was added dropwise and the reaction stirred for 60 minutes. After 180 minutes at 23C, anothe~ 4 ml BB~3 solution was added. The reaction was stirred for a ~urther 180 minutes. The reaction was cooled to -20C and 15 ml MeOH add~d. The organic phase was washed with NaHC03 ~aqueous), d~ied with Na2SO4 and chromatographed on silica gel. Hydrolysis o~ the methyl ester was carried out as described in Example 2 to yield 2.2 g of the title compound.

, :: .,: :;

s~
2893P~1046~
28~4P/1039A - 86 - L7102IA

~nalysis calculated ~or ClgH1803ClN:
C, 66.37; H, 5.27; N, 4.07; Cl, 10.31 Found: C, 66.54: H, 5.16: N, 3.85: Cl, 10.65.

X~MPLE ? 4 3-~1-p-Chlorobenzyl-5-acetoxy-3-methylindol-2-yl~-~ropionic acid ~ _ _ Using the title compound of Example 23 as sta~ting material, ~1 g) was dissolved in CH2C12 (20 ml) at 0C and 1 ml ~yridine added. 1.8 g acetic anhydride was added and the reaction let stir at 23 for 16 hours. The organic phase was washed with H20 (5 X 5 ml~, evaporated and chromatographed.
Analysis calculated ~oc C21H2003NCl:
Calc.: C, 65.37; H, 5.22; N, 3.63; Cl, 9.L9 Found: C, 65.35; H, 5.09; N~ 3.54; Cl, 9.25.

EX~MPLE ?5 3- r 4,6-dichloro-1-(4-chlorobenzyl)-3-methyl-lH-indol-2-Yll P~opanoic acid _ Following the method o~ Example 2, but using l-~l-(chloroehenyl)methyl-1-(3,5-dichloro~henyl) hydrazine hydrochloride and methyl 4-oxohexanoate as the starting matecials, in t-b~tanol as sol~ent, the title compound was prepared.
Analysis calculated ~oc ClgH16NC1302 C H
57.52 4.06Calc.
57,40 4.~0Found ,, ~ '' :

835~

2894P/1039A - ~7 - 17102IA

EX~MPLE 26 3-rl-(4-chlorobenzyl)-4-methoxy-3-methyl-lH indol-2-Yll P~o~_noic acid Following the method of Examele 2. but using 1-t4-(chlocobenzyl)-1-(3-methoxy ehenyl) hydrazine hydeochloride and methyl-4-oxohexanoate as the starting mateeials in t-bueanol as solvent, the title compound was peeeared, m.~. 145C.
~nalysis calculated Eor C20H2003NCl:
Calc.: C, 67.12; H, 5.63 Found: C, 67.40; H. 5.43.

1-[1-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-methoxv acetic acid _ _ Step 1. Methyl 1-(4-chlorobenzyl)-5-fluoro-3-methyl-indol-2-carboxvl te ~ _ _ Following the erocedure of Example 42 Ste~
1. but using 1-(4-chlorobenzyl)-1-(4-fluorophenyl)-hydrazine in place of 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine, there was obtained the title compound of 5tep 1.

SteD 2. l-rl-(4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yllmethanol _ _ 1.50 g 1-(4-chlorobenzyl)-3-methyl-5-fluoro-lH-indole-2-carboxylate Me ester was dissolved in 50 ml dry THF. Diisobutyl aluminum hydride tl.5 M) in tetrahydrofuran (THF) (2 equivalents) was added at -7a~C. The reaction was stirred for 16 hrs., allowed to reach room temperature and quenched with NH4Cl (aq.). The or~anic ehase was seearated. dried ~ 8~5?d 2893P/1046~
2~94P~1039A . - 8~ - 17102IA

(Na2S04) and evapocated to p~oduce 1.32 g of product which wa6 purifi~d on column c~romatogcaehy eO yield the title compound o Step 2.

Step 3. The title compound from Step 2 (1.0 g) wa~
di~solved ~n dry dimethylfoemamide (D~) (10 ml) at -20C. Pota~sium hexamet~yl disilazane bas~ in toluene ~0.69 M) was added (1.1 molar e~uivalents) and the reaction 6tored ~or 1 ~r. Et~yl 2-bromo ~0 acetate (580 mg) ~1.2 equivalent6) was added and the reaction ~t~rred for 16 ~ at 21C. Water was added (3 ml). The produc~ ~a~ i 80 lated a~te~ extraction ~rom the aqueou~ DMF with ether. Followinq purif icat~on on column chromatography, the title ethyl e6te~ was hydcoly6ed in ~N NaOH acco~ding to the pro~edure in Example 2.
.P. ~ 154 EXA~PLE 28 ~0 3-~1-(4-b~omobenzyl)-3-methyl-5-metho~yindol-2-yl]-2~2-dimethYlp~opanoic acid Followin~ the method of Example 2, but u~ing 1-~4-bcomobenzyl]-1-(4-methoxy phenyl~ hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxohexanoate as the ~tarting mate~ials, using t-butanol a6 the ~olvent, the title compound was prepa:ed.
~.P. = 170 2~93P/1046h E~MPLE 29 3-~1-(4-chlorobenzyl)-3-methyl-5-me~hoxyindol-2-ylJ
2-meth~l e~oDanoic acid Following the method o~ Example 2, but u6ing l-t4-chlorobenzyl]-1-~4-chlorophe~yl) hydrazine hydrochloride and methyl-3-methyl-4-o~ohexanoate a~
starting materials, u~ing t-butanol as ~olvent, the title compound wa~ prepaeed.
M.P. - 128 EXA~PLE 30 3-tl-(4-iodobenzyl)-3-methyl-5-metho~cyir~dol-2-yl]-2,2-dimethYl Dro~o~c acid ~ollowing the method of Exauple 2, but using 1-~4-iodobenzyl]-1-(4-methoxyphenyl)~ydra~ine hydrochlocide and methyl 2,2-dimethyl-4-oxo-hexanoate a6 starting mate~ial~, using t-butanol as 601vent, the title compound wa6 prepared.
~.P. = 152 EX~MPLE 31 3-[1-(4-chlorobenzyl~-3-methyl-5-methoxyindol-2-yl]-2,2-dimethyl p~oDanol _ _ .
700 mg of 3-~1-(4-chlorobenzyl)-3-methyl-5-methoxyindol-2-yl~-2,2-dimethyl proeanoic acid methy e~ter was di6601ved in 20 ml d~y tetrahydro~
~uran. The ~eaction was cooled to -78C and 2 equivalent6 di-i60butyl aluminium hydride (DIBAL) in THF wa~ added. The ~eaction wa~ allowed to watm to room temperatute and quenched with N~Cl (aq~).
E~hyl acetate was added (75 ml) and the organic phase 335~
2893P/1046~
2894P~L039~ - 90 - 17102lA

seearated, dried and eva~orated. The ecoduct was iolated by column chromatograehy.
M.P. = 100.1 E~AMPLE 32 3-[1-(4-chlorobenzyl)-3-methoxy-5-hydroxyindol-2-yl]-2,2-dimethYl ProPanOiC acid ~
Following the method of Examele 23, but using the ~roduct of Example 22 as starting material, the title com~ound was pceeared.
M.P. = 137 E_~MPLE 33 3-[1-(4-chloLobenzyl)-3-methyl-5-methoxyindol-2-ylJ-Propanol Following the method of Example 31, but using the starting material of Exam~le 23, the title compound wa~ e~e~ared.
M.P. = 118 EX~MPLE 34 3-[1-(4-chlorobenzyl~-3-methyl-S-fluoroindol-2-yl~-2,2-dimethyl ProPanoic acid _ _ Yollowing the method o~ Example 2, but using 1-[4-chlorobenzyll-1-(4-fluoroehenyl)hydrazine hydrochloride 1.9 g and 2,2-dimethyl-4-oxohexanoic acid (950 mg) as stacting materials, in t-butanol as solvent, after 16 hrs. at reflux, the solvent was removed in vacuo, and the title com~ound was isolated by crystallization and filtration, followed by ccystallization from hot ethyl acetate hexane 9:1.

335%
2893P/L046~
2894P~1039A - 9l - 17lO2IA

~nalysis for C21H21N02ClF
C H
67.47 5.62 Calc.
67.53 5.70 Found M.P. = ~24 E~MPLE 35 3~ (4-chlorobenzyl)-3-methyl-5-fluoroindol-2-yl]-3-methYl peoQanoic acid _ _ ~0 Following the method of æxamele 2, but using L-~4-chlorobenzyl]-1-(4-fluoroQhenyl) hydrazine hydeochloride and methyl 3-methyl-4-oxohexanoate as starting materials, the title comeound was pLepa~ed.
M.P. = 143 EX~MPLE 36 3~1-t4-chlorobenzyl)-3-methyl-5-hyd~oxyindol-2-yl~
butanoic acid _ _ _ Following the method of Exa~ele 23. but using the product of Example 19 as star~ing material, the title comeound was erepared.
M.P. = 162 EX~MP~E 37 Methyl 4-[1-(4-chloroben~yl)-3-methyl-5-fluoroindol-2~ butanoate Following the method o~ Example 44, but using the eroduct of Example 16 as starting materials. the title com~ound was ere~ared.
~nalysis for C2lH21N02FCl C H
67.475.62 Calc.
67.535.70 Found : ` '-: , 3835~ .
2893P~046A
2894P/1039~ - 92 - L71021A

3-[1-(4-chlorobenzyl)-3-methyl-4-propyl-5-hydroxyindol-2-yll-peoPanoic acid 210 mg of the methyl estec of Exam~le 39 was S heated in a Kugelhrohr vacuum distillation apparatus at 200C without ~acuum for 90 min. The Product was then distilled in vacuo at 0.1 mm Hg, 200C. The liquid obtained was chromatograehed on a ~repa~ative plate (hexane 8, ethyl acetate 2)o 125 mg. of 3-~ 4-chlorobenzyl)-3-methyl-4-(3-proeyl)-5-hydroxy-indol-2-yl]propanoic acid methyl ester was isolated, which was then hyd~ogenated with 10% ealladium on chaccoal in 10 ml of MeOH with 40 psi H2 foc 3 min. The methyl estec title com~ound was isolated lS from a preparative plate (SiO2) (hexane 8, ethyl acetate 2) (82 mg) and the corresponding acid was obtained from hydrolysis as shown in Example 2.
~nalysis calculated for C22H24O3NCl +

C H
62.43 6.06 Calc.
62.62 5.73 Found EX~MPLE 39 25 3~ (4-chlorobenzyl)-3-methyl-S-ero~-2-enoxyindol-2-Yll-ProPanoic acid Using 845 mg of the ecoduct o~ Example 23 as star~ing material, diluted in 23 ml of dimethyl ketone, ~76 mg of ~otassium carbonate and 225 ~1 o~
allyl bromine was added. The reaction was re~luxed overnight. The reaction was then diluted with water and the acetone removed in vacuo. Then the reaction . -.

835~
2893P~1046A

wa~ ext~acted with CH3C02Et and the organic pha~e wa~ dried and concentrated to yield atec fla~h chro~atogcaphy (hexane 8, ~thyl ace~aee 2) 790 mg of the compound. which wa~ then hydrolyzed following the proceduce of Example 2.
Analy6i6 calculated for C2~H2203NC1 68.63 5.77 Calc.
68.88 ~.09 Found ~.P. = 131.2 E~AMPLE gO
Methyl 3-[1-~4-chlo~obenzyl-3-methyl-5-methoxyindol-2-rl 1 2,2-dimethYl-~ro~anoate Following the method of Exa~ple 45. but using the peoduct of Example 22 as startins mate~ial, the title compound wa~ pcepa~ed.
M.P. - 110 EX~MPLE 41 3 [1-~4-chloroben2yl)-3-methyl 5-fluocoindol-2-ylJ-2-meth~l-butano~c acid S~ee_l. EthYl 2.3-dimethvl-4-oxo-he~anoate To 4.23 g ethyl 2-bromopropionate in 50 ml acetonitrile wa6 added 2.5 g N-~3-(pent-2-enyl)J-pyrrolidine. The reaction was re~lu~ed for 16 ~z.
The ~olvent wa6 ~emoved in vacuo and the produc~ wa~
isolated by chromatography on silica gel to yield 1.5 g of the title compound which was used a6 6uch in the 6econd ~tep.

2893P/1046~

Ste~ 2. Following the method o Examele 2, but using 1-[4-chlorobenzyl]-1-(4-fluorophenyl)hydrazine hydcochlocide and ethyl 2,3-dimethyl-4-oxo-hexanoate as stacting materials, the title com~ound was ere~ared.
M.P. = L77 EX~MPLE 42 1-(4-chloroben~yl)-3-methyl-5-methoxy-lH-indole-2-methoxY acetic_acid.
Step 1. Methyl 1-(4-chlorobenzyl)-5-methoxy-3-methyl-indol-2-carboxYlate To a solution of 1 g 2-keto butyric acid in 35 ml MeOH (to which had ~reviously been added 1 ml L5 CH3COCl at 0C) was added 12.82 g N-benzyl-4-methoxyphenyl hydrazine hydrochlo~ide. The solution was refluxed f OL 1 hr., the methanol distilled off and a crystalline ~asty residue triturated with methanol to give 2.6 g crys~alline material. The crystals were swished with 9:1 hexane:EtOAc overnight to yield 2.0 g pure product, which was used as such in the next ste~.

SteP 2. 1-(4-chlorobenzyl)-3-methyl-5-methoxy-lH-indole-2-methanol.
1.50 g 1-(4-chlorobenzyl)-3-methyl-5-methoxy-lH-indole-2-carboxylate methyl ester was dissolved in 50 ml dcy ~HF. Diisobutyl aluminum hydride (1.5 M) in THF (2 equivalents) was added at -78C. The reaction was stirred for 16 hrs., allowed to reach room tem~e~ature and quenched with ~H4C1 (aq.).
The organic ~hase was se~arated, d~ied (Na2S04) .

33S~

2a94P/1039~ - 95 - 1710~1A

and evaporated to pcoduce 1.32 g of product which was pu~ified on column ch~omatography to yield the title compound o~ Step 2.

Step 3. The p~oduct from Ste~ 2 above (1.0 g) was di6~01ved in dLy DMF tlO ml) at -20C. Pota~sium hexamethyl disilazane ba6e in toluene (0.69 M~ wa~
added (1.1 molar equivalents~ and the reaction stirred for 1 hr. Ethyl 2-bromo acetate (5BO mq) ~ 1.2 equivalent6 wa~ added and the reaction 6tir~ed for 16 h at 21C. Water wa6 added (3 ml). The p~oduct wa6 isolated aftec extzaction fcom the aqueou~ DMF with ether. Following puri~ication on column chro~ato-g~aphy, the title ethyl e~te~ was hydrolysed in 3N
NaOH according to the pcocedu~e in E~ample 2.
M.P. = l28 E~MPLE ~3 3-[1-(4-chlorobenzyl)-3-methyl-5-chloroindol-2-yl]-2,2-dimethYl-P~opanoic acid Followinq the method of Exa~ple 2, but u~ing 1-[4-chlorobenzyl]-1-~4-ct.lo~ophenyl~hyd~azine hydrochlo~ide and methyl 2,2-dimethyl-4-oxohexanoate ~n t-bu~anol a6 ~olvent, tbe title compound wa~
pr~pared.
.P. , 142.5 E~MPLE 44 Methyl 3-[ 1-(4-chlorobenzyl)-S-~ethoxy-3-methyl-1~-indol-2-yll proPanoate _ _ 3-[1-(4-chlorobenzyl)-5-metho~y-3-methyl-lH-indol-2-yl~ propanoic acid (50 g) was dis601ved in ~ ~38350.~

2894P/1039~ - 96 - 171021A

400 ml absolute methanol and cooled to 0C. Boron tri~luoeide etherate (50 ml) was added slowly over 25 min. The reaction was quenched after 16 hr. by the addition of water/NaHC03. Upon evaporation, the water was removed by extraction with CH2C12. The organic phase was dried and concentrated to yield 47 g of the title methyl ester.
Analysis calculated for C20H21N03Cl:
C H ~ Cl Calc.: 67.B3 5.96 3.77 9.53 Found: 67.67 5.21 3.68 9.68 3-~1-(4-aminobenzyl)-5-methoxy-3-methyl-~H-indol-2-vl~L~2-dimethYI Pro~anoic acid _eJ~ 3-[1-(4-nitrobenzyl)-5-methoxy-3-me~hyl-lH-~ 2-Yl~2~2-dimethyl Propanoic acid Following the me~hod of Example 2, but using 1-~(4-nitrophenyl)methyl-1-t4-methoxyphenyl) hydrazine hydrochloride and methyl 2,2-dimethyl-4-oxo-hexanoate as the starting materials and tert-butanol as the solvent, the title compound was ~repared.
~nalysis calculated ~o~ C22H2~05 C H N
Calc.: 66.67 6.06 7.07 Found: 67.00 6.12 7.10 2. 500 mg of the product of Step 1 was dissolved in 35 ml of absolute ethanol and 50 mg of 10% ~alladium on carbon catalyst added. The suspension was hydrogenated at 50 psi until consum~-tion of 2 mole equivalents of hydrogen occurred. The ~ ~3835f~
2893P~1046~
2894P/1039~ - 97 - 171021A

cataly~t wa6 cemoYed by ~ilt~ation and the title compound was ~aolated by vacuum di~tillation o~ the solvent (489 ~g).
M.P. = 173 EX~MPLE 46 4~ (4-~hloLobenzyl)-5-methoxy-3-methyl-lH indol-2-yl1-2 2-dimethYl butanoic a~id _ __ _ Following the method of Example 2. but u~ing 1-[(4-chlorobenzyl)-1-~-methoxyphenyl~ hydrazine hydrochlo~ide and methyl 2,2-dimethyl-5-oxoheptanoate aa ~tarting matecials, the title compound wa~
prepared.
~naly~ia calculated for C23H25N03Cl C - H N
Calc.: 69. 2e 6.52 3.51 Found: 69.21 6.93 3~22 E ~MPLE 47 4- r 1- ( 4-chlorobenzyl)-5-fluo~o-3-methyl-lH-indol-2-yll-2,2-dimethy~_butanoic acid Following the method of Example 2, but u~ing -~4-ct~lo~obenzyl]-1-14-~luorophenyll hydrazlne hydco~hloride and methyl 2,2-dimethyl-5-oxoheptanoate as starting materiala, in t-butanol a~ aolvent, the title compound wa~ ptepared.
~nalyaia calculated for C22H23N02ClF
C H N
Calc.: 68.13 5.60 3.61 Found: 68.34 5.69 3.41 83S~

~894P/1039A - 98 - 1710ZIA

EX~MPLE 48 4-[1-(4-chlocobenzyl)-5--hydroxy-3-methyl-lH-indol-2-YlL-3-methyl butanoic acid_ Following the method of Examele 23, but using 4~~1-t4-chlorobenzyl)-5-methoxy-3-methyl-lH-indol-2-yl]-3-methyl butanoic acid as starting material, the title compound was prepared.
~nalysis calculated ~or C21H22N03Cl C H N
67.13 5.92 3.76 Calc.
68.36 5.69 3.51 Found EX~MPLE 49 4-[1-t4-methylthiobenzyl)-5-methoxy-3-methyl-lH-indol-~ c~ ~____ noic acid Following the method o~ Examele Z, but using 1-~4-methylthiobenzyl]-1-~4-methoxyphenyl] hydrazine hydrochloride and methyl-3-methyl-5-oxohe~tanoate as starting materials, in t-butanol as solvent, the title compound was prepared ~nalysis calculated for C21H27N03S
C H N
69.56 6.92 3.52 Calc.
69,B5 7.20 3.50 Found EX~MPLE 50 3-~1-t4-chlorobenzyl)-5-hydroxy-3-methyl-lH-indol-2-Yl 1-2,2-dimethvl ProPanoic acid Following the method o~ Example 23, but using 3 ~1-(4-chlorobenzyl~-5-methoxy-3-methyl-lH-indol-2-yl]-2,2-dimethyl propanoic acid as starting material, the title compound was prepared.
M.P. = 110~ (decomPosition) 383S?~
2893P/104h~
2894P~L039A - 99 17102IA

EX~MPLE 5L
3~ 4-chlorobenzyl)-5-hydroxy-3-methyl-lH-indol-2-yll-3-methYl Propanoic acid Following the method of Example 23, but using 3-tl-~4-chlorobenzyl)-5-methoxy-3-methyl-lH-indol-2-yl~-3-methyl er~eanoic aci.d as starting material, the title comeound was prepared.

C H N
67.13 5.59 3.9 Calc.
67.22 5.74 3.97 Found EX~MPLE 52 3-~1-(4-chlorobenzyl)-5-ethoxy-3-methyl-lH-indol-2-yl]-2~2-dimethY-l Propanoic acid _ _ The title comeound of Example 50 was treated according to the method described in Example 39 using ethyl bromide as the alkylating agent. The product was isolated by chromatograehy on silica gel (CH2C12).
M.P. = 148

Claims

WHAT IS CLAIMED IS:

1. A pharmaceutical composition useful as a prostaglandin antagonist in mammals comprising a prostaglandin antagonizing amount of compound of the Formula I:
I
wherein:
R1 is H or alkyl of 1 to 6 carbons or R1 and R8 taken together form a group (CH2)V
wherein v is 1 to 7;

R2 is wherein:
each R8 is independently H, OH, C1 to C4-O-alkyl or alkyl of 1 to 4 carbons; or an R
and an R8 taken together form a group (CH2) wherein v is 1 to 7.

R9 is COOR1; CH2OH; CHO; tetrazole;
NHSO2R10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbons; CONHSO2R1 ;
hydroxymethylketone; CN; or CON(R8)2;
X is O; S; SO; SO2; NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR1R8;
or the unit wherein the dotted line represents an optional triple bond and in which the R1 and R8 substituents are absent when a triple bond is present;
r and q are each independently 0 to 5 and p is 0 or 1 provided that the total o, p, q and r is 2 to 6;
R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R4; or C1 to C4 alkyl-phenyl or C1 to C4 alkylphenyl in which the phenyl is substituted by R4;
R4, R5, R6 and R7 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) alkenyl having 2 to 6 carbon atoms;
(4) -(CH2)nM
wherein n is 0 to 3 and M is a) OR12;
b) halogen;
c) CF3;

d) SR12;
e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12;
f) COOR13;
g) ?-R14;
h) tetrazole;
i) - NH -?-R15 wherein R15 is C1 to C6 alkyl, benzyl or phenyl;
j) NR13R13;
k) -NHSO2R15 wherein R16 is C1 to C6 alkyl, phenyl, or CF3;
l) -?-CH2OH;
m) -SOR12;
n) -CONR13R13;
o) -SO2NR13R13;
p) -SO2R12;
q) NO2;
r) O-?-R14;
s) O-?-NR13R13;
t) O-?-OR15;
u) CN;

each R12 independently is H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR13, CH2COOR13, C1 to C3 alkoxy, or C1 to C4 perfluoroalkyl;
each R13 is independently H, phenyl or C1 to C6 alkyl; and, each R14 independently is H, (CH2)nCOOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R12;
and 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;
ACE inhibitors, and thromboxane synthetase inhibi-tors, wherein the weight ratio of said compound of Formula I to said second active ingredient ranges from about 1000:1 to 1:1000;
and a pharmaceutically acceptable carrier.

2. A composition according to Claim 1, wherein:
R1 is H or alkyl of 1 to 3 carbons or R1 and R8 taken together form a group (CH2)v wherein v is 1 to 7, with the proviso that R1 on the benzylic carbon attached to the indole nitrogen is H;
R2 is wherein:
each R8 is independently H, or alkyl of 1 to 4 carbons; or an R1 and an R8 taken together form a group (CH2)v wherein v is 1 to 7;
R9 is COOR1; CH2OH; CHO; or tetrazole;
X is O; S; SO; SO2, NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR1R8;

or the unit wherein the dotted line represents an optional triple bond and in which the R1 and R8 substituents are absent when a triple bond is present;
r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 3;
R3 is alkyl of 1 to 6 carbons, but is not cycloalkyl;
R4, R5, R6 and R7 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) M wherein M is a) OR12;
b) halogen;
c) CF3;
d) SR12;
e) SOR12;
g) O-?-R14 wherein R14 is H, (CH2)nCOOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12; H, C1 to C6 alkyl, CF3, phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12;
h) CN;
each R12 is independently H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR13, CH2COOR13, wherein R13 is H, phenyl; C1 to C6 alkyl or C1 to C4 perfluoroalkyl;
or a pharmaceutically acceptable salt thereof.

3. A pharmaceutical composition comprising an effective amount of a compound of the Formula Ia:
Ia wherein:
R1 is H or alkyl of 1 to 6 carbons or R1 and R8 taken together form a group (CH2)v wherein v is 1 to 7;

R2 is wherein:
each R8 is independently H, OH, C1 to C4-O-alkyl, or alkyl of 1 to 4 carbons or R1 and R8 taken together form a group (CH2)v wherein v is 1 to 7;
R9 is COOR1; CH2OH; CHO; tetrazole;
NHSO2R10 wherein R10 is OH, alkyl or alkoxy of 1 to 6 carbons, perhaloalkyl of 1 to 6 carbons, phenyl or phenyl substituted by alkyl or alkoxy groups of 1 to 3 carbons, halogen, hydroxy, COOH, CN, formyl or acyl to 1 to 6 carbons; CONHSO2R10;
hydroxymethylketone; CN; or CON(R8)2;
X is O; S; SO, SO2; NR11 wherein R11 is H, alkyl of 1 to 6 carbons, acyl of 1 to 6 carbons, CN; CR1R8;
or the unit wherein the dotted line represents an optional triple bond and in which the R1 and R8 substituents are absent when a triple bond is present;
r and q are each independently 0 to 5 and p is 0 or 1 provided that the total of p, q and r is 2 to 6, with the proviso that when R1 and R8 are H, X is CH2, R4 is 5-methoxy and R6 is halogen, then the sums of p, q and r is 3 to 6;
R3 is H, alkyl of 1 to 6 carbons; phenyl or phenyl substituted by R4; or C1 to C4 alkyl-phenyl or C1 to C4 alkylphenyl in which the phenyl is substituted by R4;
R4, R5, R6 and R7 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) alkenyl having 2 to 6 carbon atoms;
(4) -(CH2)nM
wherein n is 0 to 3 and M is a) OR12;
b) halogen;
c) CF3;
d) SR12;
e) phenyl or substituted phenyl wherein substituted phenyl is as defined below in the definition of R12;
f) COOR13;
g) ?-R14;
h) tetrazole;
i) -NH-?-R15 wherein R15 is C1 to C6 alkyl, benzyl or phenyl;
j) -NR13R13;
k) -NHSO2R16 wherein R16 is C1 to C6 alkyl, phenyl, or CF3;
l) -?-CH2OH;

m) -SOR12;
n) -CONR13R13;
o) -SO2NR13R13;
p) -SO2R12;
q) NO2;
r) O-?-Rl4;
s) O-?-NR13R13;
t) O-?-OR15;
u) CN;
each R12 is independently H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituents are C1 to C3 alkyl, halogen, CN, CF3, COOR13, CH2COOR13 C1 to C3 alkoxy, or C1 to C4 perfluoroalkyl;
each R13 is independently H, phenyl or C1 to C6 alkyl;
each R14 is independently H, (CH2)nCOOR13 wherein n is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein substituted phenyl is as defined above in the definition of R12;
or a pharmaceutically acceptable salt thereof;
and 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; ACE
inhibitors, and thromboxane synthetase inhibitors;
and a pharmaceutically acceptable carrier.