CA1330090C - Tetrahydrocarbazole esters - Google Patents

Abstract

TITLE OF THE INVENTION

TETRAHYDROCARBAZOLE ESTERS

ABSTRACT OF THE DISCLOSURE

Tetrahydrocarbazole esters are disclosed.
The compounds act as prostaglandin and thromboxane antagonists and are useful in treating asthma, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, premature labor, spontaneous abortion and dysmenorrhea and as cytoprotective agents. The compounds of the present invention have the general formula:

I
wherein:
R1, R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 to 3 and M is a) OR11;
b) halogen;
c) CF3;

d) SR11;
e) phenyl or substituted phenyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy;
f) COOR12;
g) ;
h) ;
i) -NR12R12;
j) -NRSO2R15;
k) ;
l) SOR11;
m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;
q) ;
r) ;
s) ;
t) CN;
u) N3;
provided that when R1, R2, R3 or R4 is alkyl having 1 to 6 carbons, it is not located at position 6;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbons;

each R9 is independently H, OH, C1 to C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy;
substituted or unsubstituted benzyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy; or substituted or unsubstituted phenyl wherein the substituents are as defined above;
each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituents are as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl; and, each R13 is independently H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is C1 to C6 alkyl, benzyl or phenyl;
each R15 is C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;
r is 1 to 6 or a pharmaceutically acceptable salt thereof.

Description

5010P/1286A 1 3 3 o ~ q o TITLE OF TH~ INVENTION
TETRAHYDROCARBAZOLE ESTERS

BACKGROUND OF T~E INVENTION
This invention relates to prostaglandin antagonists useful in treating a variety of conditions, such as allergic asthma where excessive contractile activity of prostaglandins and prostaglandin biosynthetic intermediates occur.
These compounds antagonize the actions of contractile prostaglandins, such as PGF2a, PGG2, PGH2, PGD2 and TXA2. The use of agents which act as prostaglandin antagonists oEfers new approaches to therapy in a number of disease states.
For esample, certain prostaglandins, such as PGF2X, PGD2, PGG2, and PGH2, are potent bronchospastic agents. Indeed human asthmatics have been shown to be especially sensitive to the bronchial constricting action of PGF2a.

, 1 3300~0 The compounds of the present invention are also antithrombotic agents. Thus, they are useful in the treatment and/or prevention of thromboembolic diseases such as arterial thrombosis and those involving platelet deposition, e.g. prothesis.
In addition to the involvement of contractile prostaglandins in asthma, prostaglandins are known to play a role in other allergic conditions, as well as, diarrhea, hypertension, angina, platelet aggregation, cerebral spasm, cerebral ischemia, arrythmia, circulatory shock, sudden death, athero-sclerosis, myocardial ischemia, premature labor, spontaneous abortion, dysmenorrhea, glomerular nephritis, and systemic lupus erythematosis.
15 Consequently, the compounds 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 biosynthesi~ of 5-lipo-ygenase metabolites of arachidonic acid, such as 5-HPETE, 5-HETE and the leukotrienes. Leukotrienes B4, C4, D4 and E4 are known to contribute to variaus disease conditions such as asthma, psoriasis, pain, ulcers and systemic anaphyla~is. Thus inhibition of the synthesis of such compounds will alleviate these and other leukotriene-related disease states.
The compounds of the present invention may be used to treat or prevent mammalian (especially, human) disease states such as erosive gastritis;
erosive esophagitis; ethanol-induced hemorrhagic erosions; hepatic ischemia; no~ious agent induced . ~
~ damage or necrosis of hepatic, pancreatic, renal, or ".. ~,._.. ~ .

- : -.
.
~: ' ~ '` ` ' ' ' ' , . `

1 3300q3 myocardial tissue; liver parenchymal damage caused by hepatoxic agents such as CC14 and D-galactosamine;
ischemic renal failure; dissase-induced hepatic damage; bile salt induced pancreatic or gastric damage; trauma- or stress-induced cell damage; and glycerol-induced renal failure.
Certain 9-benzyl-1,2,3,4-tetrahydro-carbazole acetic acids or esters thereof are shown as chemical intermediates in the preparation of carbazoles that are known in the art as anti-inflammatory, analgesic and anti-rheumatic agents (see U.S. Patent 3,896,145 and British Patent 1,385,620). Certain 9-benzyl-1,2,3,4-tetrahydro-carbazole carboxylic acids are known in the art as anti-inflammatory, analgesic and anti-rheumatic agents (see U.S. Patents 3,868,387; 4,009,181;
3,905,998 and 3,758,496), and 9-benzylcarbazole carboxylic acids (U.S. Patents 3,956,295 and 4,057,640) and 9-benzylcarbazole acetic acids and esters thereof ~U.S. Patent 3,896,145 and ~ritish Patent 1,385,620) are known as anti-inflammatory, analgesic and anti-rheumatic agents. None of these compounds, however, are shown to be prostaglandin or thromboxane antagonists or inhibitors of leukotriene biosynthesis.

,, .

DESCRIPTION OF THE INVENTION
One embodiment of the present invention is a pharmaceutical composition containing a compound of Formula I:
s Rl R7 R2~\~

¦ / (C) r-C-O-R
R3-CH R7 ~9 ~ 6 R ~ R

I

wherein:
R , R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;

(2) alkyl having 1 to 6 carbons;

(3) alkenyl having 2 to 6 carbons;

(4) -(CH2~nM
wherein n is 0 to 3 and M is CJRll b) halogen;
c) CF3;

d) sRll;
e) phenyl or substituted phenyl;
f) COOR12;

1 3300qO

g) -C-R13;

h) -NH-C-R14 i) _NR12R12;
j) -NHSo2R15;

k) -C-CH2OH;

1) -SORll;
m) coNR12R12;
n) _so2NRl2Rl2;

p) N02;

q r) -O-C-NR12R12;
~ 14 s) -O-C-OR
t) CN;
u) N3;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbons;
each R9 is independently H, OH, Cl to C4-O-alkyl or alkyl of 1 to 4 carbons;

R10 is lower alkyl, substituted or unsubstituted 2-phenethyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenyl ~.~

1 3300qO

5010P~1286A - 6 - 17358IA

each R~ independently H; Cl to C6 alkyl; benzyl; phenyl or substituted phenyl;
each R12 i~ independently H, phenyl, benzyl or Cl to C6 alkyl;
each R i~ independently H, (CH2)mCOOR12 wherein m i~ 0 to 4, Cl to C6 alkyl, CF3, phenyl, or substituted phenyl;
each R14 is independently Cl to C6 alkyl, benzyl or phenyl;
each R15 i~ independently Cl to C6 alkyl, 4-methylphenyl, phenyl, or CF3;

r is 1 to 6 or a pharmaceutically acceptable salt thereof.
Preferred compositions of the present invention contain a compound of formula I
wherein:

~p - "
1 3300qO

R , R , R3, R4, R5 and R6 are each independently selected from:
(1~ hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 or 1 and M is as defined previously for Formula I;
and the remaining substituents are as defined previously for Formula I.
More preferred compositions of the present invention contain a compound of Formula I.
wherein:
R , R , R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) M, wherein M is as defined initially for Formula I;
r is 1 or 2; and the remaining substituents are as defined initially for Formula I.
Most preferred compositions of the present invention contain a compound of Formula I.
wherein:
R , R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen:
(2) alkyl having 1 to 6 carbons;
(3) M wherein M is a) ORll;
b) halogen;

1 3300~0 5010P~1286~ - 8 - 17358IA

C) C~;
A) sR~l;
~) COOR12;

f) -C-R13;

g) -SORll;
h) _coNRl2Rl2;
~ ) -so2NRl2Rl2;
j ) -S2R

k) -o-C-R13;
1) C~;
m) N3;
each R9 i8 ~ndependently H, or alkyl of to 4 carbon~;
R10 i~ lower alkyl;

r ~8 1 and the remaining substituents are as defined initially for Formula ~.
Another embodiment of the present invention relate~ to no~el compound~ of Formula I:

~,.",,~.~' ~70 R8-CH R7 ~)r-~-O-R10 5~R6 wherein:
R , R2, R3, R4, RS and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 to 3 and M is a) oRll;
b) halogen;
c) CF3;

d) sRll;
e) phenyl or substituted phenyl;
f) COOR

g) -C-R13;
h) ~NH~C~Rl4;

,A~

i) NR12R12;
j) -NHSo2Rl5;

k) -C-CH2OH;

1) -SORll;
m) _coNRl2Rl2;
n) _so2NRl2Rl2;
o) _so2Rll;
p) NO2;
q) -o-C-R13;

r) -O-C-NR12R12;
O
s) -o-C-oR14;
t) CN;
u) N3;
provided that when R1, R2, R3 or R4 is alkyl havlng 1 to 6 carbons, it is not located at position 6;
R7 i8 H or alkyl of 1 to 6 carbons;
R is H or alkyl of 1 to 6 carbons;
each R i5 independently H, OH, Cl to 5 C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl, substituted or unsubstituted benzyl,or substituted or unsubstituted phenyl:

. .

5010P/1286A ~ 17358IA

each Rll independently i5 H; Cl to C6 alkyl; benzyl; phenyl or ubstituted phenyl;
each R12 is independently H, phenyl, benzyl or Cl to C6 alkyl; and, each R13 is independently H, (CH2)mCOORl2 wherein m i3 0 to 4, Cl to C6 alkyl, CF3, phenyl, or sub~tituted phenyl;
each R14 is Cl to C6 alkyl, benzyl or phenyl;
each R15 is Cl to C6 alkyl, 4-methylphenyl, phenyl, or CF3;

r is 1 to 6 or a pharmaceutically acceptablP salt thereof.
As used herein, the terms ~each independently~ or the equivalents thereof are employed to describe a number of possible position isomers and/or structural variations. For e~ample, as described above, the following unit is attached to position 1 of the tetrahydrocarbazole ring:

1 3300qG

R7 q -(C)r-C-O-R

The letter r represents possible alkane chains of from 1 to 6 carbon atoms, each having the R7 and R9 substituent groups. On each carbon atom of the alkane chain, the R7 and/or R9 substituent may be different. The above description therefore contemplates structures such as the following for the segment -(CR7R9)r-:

CH H H

(- ~C - C - C) , (- CH2 -) OH H H

H H H HH H H H
I
(--C -- C -- C--) , (--C -- C -- C -- C -- C--) , H Hl Hl (-C - C - C-) , and the like.

Substituted phenyl, substituted benzyl, and substituted phenethyl signifies the presence of 1 or 2 substituents on the benzene ring selected from Cl to C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12, or Cl to C3 alkosy.
The alkyl groups referred to above may be straight chain or branched or may include cycloalkyl qroups. As used herein, the term ~lower~ as applied ~ 1 330093 to alkyl, acyl, alko~y and the like, unless stated otherwise refers to groups having 1 to 6 carbon atoms. Halogen or halo means fluoro, chloro, bromo and~or ~odo.

Pharmaceutically acceptable salts of the compounds described herein are included within the scope of the present in~ention. Su~h salts may be prepared from pharmaceutically acceptable non-to~ic bases including inorganic bases and organic bases.
Salts derived from inorganic bases include sodium, potassium, lithium, ammonium, calcium, magnesium, ferrous, zinc, copper, manganous, aluminum, ferric, manganic salts and the like. Particularly preferred are the potassium, æodium, calcium and magnesium salts. Salts derived from pharmaceutically acceptable organic non-to~ic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion e~change resins, such as isopropylamine,tri-methylamine, diethanolamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylamino -ethanol, tomethamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, imidazole, betaine, ethylenediamine, glucosamine, methyl-glucamine, theobromine, purines piperazine, 1 3300qO

5010P/1286A ~ 14 - 17358IA

N,N-dibenzyl- ethylenediamine, piperidine, N-ethyl-piperidine, morpholins, N-ethylmorpholine, polyamine resins and the like.
Preferred novel compounds of the present invention comprise the compound of Formula I
wherein:
R , R2, R3, R4, R5 and R6 ar each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
~ 3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 or 1 and M is as defined previously for the compounds of Formula I;
and the remaining substituents are as defined previously for the compounds of Formula I.
More preferred novel compounds of the present invention comprise a compound of Formula I
wherein:
Rl R2 R3 R4 R5 nd R6 are a each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl haYing 2 to 6 carbons;
(4) M, wherein M is as defined initially for the compounds of Formula I;
r is 1 or 2; and the remaining substituents are as defined initially for the compounds of Formula I.
Most preferred novel compounds of the present invention comprise the compound of Formula I
wherein:

. . .

. ~ ~

R , R , R , R , and R are each independently selected from:
~1) hydrogen;
~2) al~yl having 1 to 6 carbons;
(3) M wherein M is a) ORll;
b) halogen;
c) CF ;
d) SR~l;
e) COOR12;
o Il 13 f) -C-R

g) -SORll;
h) _coNRl2Rl2;
i) _so2NRl2Rl2;
; ) -S02R

k) - o-C-R13;
1) CN;
m) N3;
R6 is located at position 3' or 4' and is selected from:
(1) alkyl having 1 to 6 carbons;
(2) M wherein M is ' ' 1 1 b) halogen;
c) CF ;
d) sR~l;
e) COOR12;
~ ol 13 f) -C-R

~.~

5010P~1286A - 16 - 17358IA

g) -SORll;
h) ~CNRl2Rl2;

S ~ ) -S02R

k) -o-8-R13;
1) CN:
m) N3;
pro~ided that when Rl, R2, R3 or R4 is alkyl having 1 to 6 carbons, it is not located at position 6;
each R9 is independently H, or alkyl of 1 to 4 carbons;
~10 is lower alkyl;

r is 1 and the remaining substituents are as def$ned initially for the compounds of Formula I.

,,f - 1 3300')0 Table 1 Novel TetrahYdrocarbazole Alkanoi~ Esters Rl 5 4 R7 RS~R6 Compound Rl R2 R R6 R9 R9' R7 R8 R10 1 (Ex.l) 6-F H 4'-Cl H H, H H H Et 2 (Ex. 4) 6~Me H 4'~1 H H, H H H Et 3 (Ex. 18) 6-F H 4'-Cl H H, H H H Me (-) i somer 10 4 (Ex. 19) 6-F H 4'-Cl H H, H H H Me (~) i somer 5 (Ex. 5) 6-F H H H H, H H H Et 6 (Ex. 6) 6-F H 4'~0Mo H H, H H H Et 7 (Ex. 7) 6-F H 3'-C1 4'-Cl H, H H H Et 20 8 (Ex. 8) 6-F H H H H, H H Mo Et _ _ 9 (Ex 9) H H 4'-Cl H H, H H H Et 10 (Ex. 10) 6-Cl H 4'-Cl H H, H H H Et 11 (Ex. 11) 8-Me H 4'-Cl H H, H H H Et 12 (Ex. 12) 6-3r H 4'-Cl H H, H H H Et 30 13 (Ex. 13) 6-Me H 4'-Cl H H, H H H Et ., ~ 3300qO

Co~pound R R2 R5 R6 R , RR R R

14 (Ex. 15) 8-F H 4'-Cl H H, H H H Et 6-F H 4'-Cl H H, H3-t-5u H CH2C6H5 16 5-F H 4'-Cl H H, H H H CH2OAc 17 7-F H 4'-Cl H H, H H H ~
0~0 o 18 (Ex. 16) 5-C1 7-C1 4'-Cl H H, H H H Et 19 (Ex. 17) 6-C1 8-C1 4'-Cl H H, H H H Et o ~ N-Me 6-F H 4'-Cl H Me, H H H CH2-N

o 21 6-F H 4'-Cl, H Me, Me H H

~L, 22 6-F H 4'-Cl H H, H l-Me H CH2-N ~

_ _ _ 1 3300~3 23 (ex 20) 6-CH~Me)2 H 4'-Cl H H,H H H Et 24 (ex 21) 6-C(Me)3 H 4'-Cl H H,H H H Et 25 (ex 22) 6-CF3 H 4'-Cl H H,H H H Et 26 (ex 23) 6-SMe H 4'-C1 H H,H H H Et 27 (ex 24) 6-SOMe H 4'-Cl H H,H H H Et 28 (ex 25) 6-SO2Me H 4'-Cl H H,H H H Et 29 (ex 26~ 8-CH(Me)2 H 4'-Cl H H,H H H Et 30 (ex 27) 8-SMe H 4'-Cl H H,H H H Me 10 31 (ex 28) 8-SOMe H 4'-Cl H H,H H H Me 32 (ex 29) 6-F H 4'-Cl H H,H 3-Me H Et 33 (ex 30) 6-F 8-F 4'-Cl H H,H H H Me 34 (ex 31) 6-Me 8-M~ 4'-C1 H H,H H H Me 35 ( ex 32) 6-OMe 8-Me 4 ' -Cl H H, H H H Me 15 36 (ex 33) 6-F(-)Isomer 8-F 4'~1 H H,H H H Me 37 (ex 34) 6-F(~)Isom~r 8-F 4~-Cl H H,H H H Me 38 (ex 35) 8-Me(-)Isomer H 4'-Cl H H,H H H Me 39 tex 36) 8-MQ(~)Isomer H 4'-Cl H H,H H H Me 40 (ex 37) 8-F(-)Isomer H 4'-Cl H H,H H H Me 20 41 (ex 38) 8-F(~)Isomer H 4'-Cl H H,H H H Me 42 6-F 8-F 3'-C1 4'-Cl H,H H H Me 43 6-F 8-F 2'-C1 4'-Cl H,H H H Me 44 6-F 8-F 4'-OMe H H,H H H Me 6-F 8-F 4'-OH H H,H H H Me 25 46 6-F . 8-F 4 ' -SMe H H, H H H Me 47 6-F H 4'-S(O)Me H H,H H H Me 48 6-F 8-F 4 ' -NHCOMe H H, H H H Me 49 6-F H 4'-S(O)2Me H H,H H H Me 6-F H 4 ' -F H H, H H H Me 51 6-F H 4'-Br H H,H H H MQ
52 6-F 8-Me 4'-Cl H H,H H H Me 53 6-F H 4'-C02H H H,H H H Me 54 6-F H 4'~02Me H H,H H H Me 6-F 8-F 4'-n-C3H7 H H,H H H Me 56 6-F 8-F 3'-I 4'4H H,H H H Me S7 6-F 8-F 4'-I H H,H H H Me 58 6-N3 H 4'-Cl H H,H H H Me 59 6-F H 4'-N3 H H,H H H Me -` ~ 330~9 The following reaction schemes illustrate the preparation of the compounds of the present invention:

5 Scheme I PreParation of Formula I Compounds Rl R2 ~ R7 lower R ~ ~ alkanol R N - NH2 ~ ~ ~ >
¦ . HCl R7 ~ R7 reflux ~--\ R8 \(C) r-C02R14 II

RZ~/~;

~1~ \(C) r-Co2R14 R5 ~ 0 ~ R6 R8 ~/
2S ,,Ia The reaction can be conveniently carried out in an alcohol solvent such as t-butanol, i-butanol, i-propanol .
and the like.
The following ketones (1,2,4) of structure III are known in the art, and ketone 3 is readily prepared by procedures analogous to those for the known ketones.

1 3300~0 5010P/1286A - 2~ - 17358IA

Ketones of Formula III

No Structure Reference Ethyl 2-cyclohexanone 1. ~ acetate; commercially ~ ~ available (Aldrich) O~y C2Et Methyl 2-cyclohexanone 2. ~ propionate; J.A.C.S. 85 ~ ) 207 (1963) 0~' y G. Stork, A. Brizzolara, H. Landesman, J. Scmuszkovicz and CO2Me R. Terrell 3. Methyl 4-t-butyl-2-~ cyclohexanone acetate O
C2Me 4. Methyl 2-(2-cyclohexanone) ~ propionate ~ ) J.A.C.S. 85 207 ~1963) O y G. Stork, A. Brizzolara, H. Landesman, / CO2ME J. Scmuszkovicz and R. Terrell 1 330~ql~

TABLE 2 (continued) KETONES OF FORMULA III

5 No. Structure Reference 5. Ethyl 4-methyl-2-cyclo-~ / hexanone acetate The sequence described above is an application of the Fischer Indole Synthesis. Numerous indole syntheses are described in reviews, such as, for example "Heterocyclic Compounds~ Volume 25, Parts I, II, III, W. J. Houlihan (Ed.), Interscience, J. Wiley & Sons, N. ~., 1979. Appropriate manipulations of functional groups using sequences described in such reviews will lead to the compounds of the present invention.

.... . .
. .
~ - .

. . .
.' "

Scheme IIPreparation of Hydrazine Derivatives (II) Rl CHR8 R2 ¦` 1 ~ \ 5 ~ toluene >
R4 N-NH2 ~ R R6 reflux H .HCl (IV) (v) Rl R2 ~ Z is a leaving group such as 15 R3 ~ ~ Cl, ~r, I, mesylate or tosylate.
O I
R4~ ~ N-NH2 1 .HCl ~ R8 20 R5 ~ R6 II
With regard to Scheme II, the preparation of hydrazine starting materials is illustrated by the preparation of 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)-hydrazine. A mixture of 10 g of p-methoxyphenyl-hydrazine hydrochloride, 75 ml of toluene and 11.5 ml of triethylamine was heated at reflux ~or 60 minutes.
Then, 7.1 g of p-chlorobenzyl chloride was added.
After stirring 16 hours at reflus, triethylamine hydrochloride was filtered off and washed with ethyl 1 33009~

ether. The filtrate and washing were concentrated in vacuo and chromatographed on a silica gel column (hesane-ethyl acetate, 9:1) to give 6.64 9 of 1-(4-chlorobenzyl)-1-(4-methosyphenyl)hydrazine. Other hydrazines, similarly prepared, are also shown in Table 3, below.

1 33~0qO

H~draz ines 4 ~
X~

N - NH2 HCl 4 ~ R8 Compound No. X Y R Compound Name 1. 4-F 4-C1 H 1-(4-chlorobensyl)-1-(4-20 ~luorophenyl) hytrazlne hydro-chlorldo 2. 3,5-C12 4-Cl H 1-(4-chlorobenzyl)-1-~3,5-dichlorophenyl)hydrazine hydrochlorlde 3. 4-OMe 4-Cl H 1-(4-chlorobenzyl)-1-(4-metho~yphenyl) hydrazine - hydrochlorido 4~ 2-Mo 4-Cl H 1-(4-chlorobenzyl)-1-(2-methylphenyl) hydrazine hydrochlorido .. ,, . ., : , ~` 1 330~0 TABLB 3 (Cont'dl 5. 4-Me 4-Cl H 1-~4-chlorobenzyl)-1-(4-methylphenyl) hydrazine hydrochloride 6. 4-C1 4-Cl H 1-(4-chlorobenzyl)-1-(4-chloropher,yl) hydrazine hydrochloride 7. H 4-Cl H 1-(4-chlorobenzyl)-1-(phenyl) hydrazine hydrochloride 8. 4-Br 4-Cl H 1-(4-chlorobenzyl)-1-(4-bromophenyl) hydrazine hydrochloride 9. 3-F 4-Cl H 1-~4-chlorobenzyl)-1-(3-fluorophenyl) hydrazine hydrochlorlde 10. 2,4-C12 4-Cl H 1-(4-chlorobenzyl)-1-~2,4-dichlorophenyl)hydrazine hydrochloride 11. 4-F H H l-(benzyl)-1-~4-fluorophenyl) hydrazine hydrochloride 12. 4-F 4-OMe H 1-~4-metho~ybenzyl)-1-~4-fluorophenyl) hydrazine hydrochlorlde ,.. ,.. ~,. . . .
. ~ .
.: ~

-TABLE 3 ~Cont'd~

13. 4-F 3,4-C12 H 1-~3,4-dichlorobenzyl)-1-(4-fluoro-phenyl) hydrazine hydrochloride.

14. 4-F H CR3 1-tl-(phenyl)ethyl]-1-(4-fluorophenyl) hydrazine hydrochlorlde 15. 2-F 4-Cl H 1-(4-chlorobenzyl)-1-(2-fluorophenyl) hydrazine hydrochloride.

15 16. 4-CH(Me)2 4-Cl H 1-(4-chlorobenzyl)-1-(4-lso-propylphenyl)hydrazine hydro-chloride 17. 4-C(Me)3 4-Cl H 1-(4-chlorobenzyl)-1-(4-tert-butylphanyl)hydrazine)hydro-chloride 18. 4-CF3 4-Cl H 1-(4-chlorobenzyl)-1-(4-tri-fluoromethylphenyl)hydrazine , hydrochloride 19. 4-SMe 4-Cl H 1-(4-chlorobenzyl)-1-(4-methyl-thiophenyl)hydrazine hydro-chloride 20. 2-CH(Me)2 4-Cl H 1-(4-chlorobenzyl)-1-(2-i~o-propylphenyl)hydrazine hydro-chloride ~` 1 3300qn 5010P~12~6A - 30 - 17358IA

To prepare certain esters representative of the Formula I compounds, it may be advantageous to first prepare the lower alkyl esters as illustrated in Scheme I. Hydrolysis of these lower alkyl esters by conventional means, such as by using NaOH or XOH in agueous ethanol, followed by acidification, then produces the corresponding carbo~ylic acids VI, as illustrated in Scheme III. The carbo~ylic acid is then reacted with an alkylating agent, R10-Z, in the presence of a suitable base and solvent combination, such as for e~ample, Na2CO3 in acetone or triethylamine in dimethylformamide, to produce the esters Ib. Compounds 15, 16, 17, 20, 21 and 22 of Table I are conveniently prepared by this method.
Another method of preparing the esters of Formula I from the acid, VI consists of treating the latter with a diazoalkane (such as diazomethane) in a suitable non-reactive solvent such as ether or methanol to obtain an ester Ic. Other methods are shown in Ogliaruso and Wolfe in Patai, The Chemistry of Acid Derivatives, Supplement ~, Wiley, New York, 1979, pp. 411-436).

5010P~1286A 3~ - 17358IA 1 3 3 0 0 9 O

SChem~ III PneD~rat;On ~f FOnnU1a I COmDOUndS

R7 ~14 ~17 LR (C)n~O2 J R (C)n-CO2H
R5~6 R9 R ~R

Ia VI

2 2 / ¦ Rlû z solvent / basQ
~ sol~ont R2~R7 R~)~R7 ~N~ R ~N~)R
,~ (C),-C02M~ ~ (C~r-COzM10 IC . / Ib In tho~e instances whon asymmetric centers are pre~ent, mor- than on~ ~tereoisomer i~ pos~ible, and all po~siblo isomeric forms are deemea to be included within the planar structural representations shown. Optically active (R) and (S) isomer~ may bo resolqed using conqentional technigues known to the skilled artisan.

~, .

1 3300~0 5010P~1286A - 32 - 17358IA

Among the resolved isomers in Table 1, the esters of the minus ~-) acids, compounds 3,36,38 and 40 are preferred.

Schem- IV Alt~rnat~vo PreDarat1on of Fonnula I CornDound~

low-r ~lk~nol R R

~ IV r-flw~ ~R~ 14 H ~C)r-C02Q
Est~r 1ntermediatQ

1Hydrolys1 s ~7 ~as per Scheme III R
lb, lc H (C)r~C2H

Acld 1 nt~ d1at~

Scheme IV illustrate~ an alternative synthesis of the compound~ of Formula I. In this Scheme a Fischer indole synthesis i~ carried out using a phenylhydrazine IV and the ketone IIr, followed by hydrolysi~. The acid intermediata is then N-benzylated with ths reagent V, preferably using a strong basa such as potas~ium t-buto~ide to effect the reaction.

~., .. ... .

..

`~ `, .i, .:

1 3300qO

Acidification of the reac~ion misture then yield~ the acid VI which can be converted to compounds of Formula I as indicated in Schem~ III.

S ~chem~ V PreDarat~on of Sulfox1des and Sulfones of Fonnul~ I comDourlds 7 ~ TC b-low.
R2'~\ /~ R is replacod by SR 1, S(O)Rll or R3~ l 11 J S~)2Rll ~\N/~ R2-R6 ;~5Rll 0~ S(o)Rll ~L R ~C) ~--R5--~_R6 ~SRl 1 Id 1.5 ~9. o~
` ,~P~ .
- S(O)R 2 o9. mCPB~ ~ ~ )2 TC-C02R , TC-C02R

In Scheme V ig illustrated a method of preparing derivative~ of Formula I in which one of the substi-tuents among Rl-R4 is a sulfo~idc or a sulfone.
It will be obviou~ to one s~illed in the art that a ... .,, .~ .

1 3300qO
5010P~1286A - 34 17358IA

sulfoside or sulfone deri~ative of R5 or R6 could be prepared in the ~ame way.
E~ter I~ ~a representative of I) is prepared according to Scheme I or Scheme III. Treatment of I~
wit~ a limited amount of an osidizing agent such as m-chloro-perbenzoic acid yields the sulfoside ester Ie. Further treatment of Ie with the osidizing agent, or treatment of Id with an esress (>2 eg.) of the osidizing agent yields the sulfone ester lf.

Sch~ VI , Prec~r~t~on of Hvtra21n~ D~n~t~v~s IV

~ 1 ) N~N2 ~ lz-lCl NH2^HCl ) 2 2 4 SV

With regard to Scheme VI, th0 preparation of hydrazine ~tartlng mater~al~ is ~llustrate~ by prepara-tion of 4-methylthiophenyl hy~razine hydrochloride.
4-Methylthio~niline ~13.9 9) wa~ added dropwise to cold HCl (6N) (50 mL) and st~rred for 5 min in an ice ~ath.
A solution of NaN02 in water ~7.25 g, 15 mL) was then ad~ed dropwise and stirred for 15 min. The cold diazonium salt wa~ then cannulatea into a stirred cold solution of Na2S204 in water (50 9, 250 mL).
After 20 min, ether (200 mL) wa~ added an~ the reaction misture basified with NaOH(lON). The ether layer was decanted, washed with brine, dried over Na2S04 and HCl gas wa~ passed through the ether solution to form .. ,, , , ~ ~ , , _ 5010P~1286A 1 3 3 0 0 9 ~ l7358IA

the hydrochloride salt which precipitated out. After filtration, there was obtained 7.0 9 of pure final product. Other hydrazines, similarly prepared, are also shown in ~able 4, below.
s HYDRAZ INES

R2~\
R ~
R ~ ~NHNH2-HCl IV
R~ ~ Compound Name 1 4-SMe H 4-methylthiophenyl hydrazine hydrochloride 2 2-CH(Me)2 H 2-isopropylphenyl hydrazine hydrochloride 3 2-SMe H 2-methylthiophenyl hydrazine hydrochloride 4 2-Me 4-Me 2,4-dimethylphenyl hydrazine hydrochloride 2-Me 4-OMe 4-metho~y-2-methyl-phenyl hydrazine hydrochloride R3~R4~

1 33009~

The prostaglandin antagonist properties of the compositions and compounds of the present invention can be demonstrated by the biological assay described below.
s Agonist-induced Bronchonconstriction in Anesthetized Guinea Pias (Konzett-Rossler~
Male Hartley strain guinea-pigs (350-500 g) are anesthetized wtih urethane (1.5 g/kg i.p.), given succinylcholine chloride (5 mg/kg s.c.) to suppress spontaneous respiration and artificially ventilated at 60 breaths/minute. Changes in insufflation pressure (resistance to inflation) are measured using a Statham PM-5E differential pressure transducer and recorded on a Beckman Type R-Dynograph. Increases in insufflation pressure are induced at 20 minute intervals with bolus intravenous injections of arachidonic acid (0.5 mg/kg), or U-44069 (15(S)-hydrosy-9, lla-(eposymethano)-prosta-5-cis, 13-trans-dienoic acid) (a stable prostaglandin endoperoside analogue) (2 ~g/kg). After obtaining at least two reproducible control responses to the agonist under study, the antagonist activity of the test compound is determined. In order to assess antagonist activity, the test compound (in solution or suspension) or drug vehicle (1 ml/kg) is administered intravenously in cumulative doses 5 minutes prior to each subsequent agonist challenge.
Reductions of the agonist response are calculated as a percent of the control response which immediately preceded the initial antagonist or vehicle dose.

~. .

ED50 values (dose requir~d to inhibit the insufflation pressure increase by 50 percent) are calculated by regression analysis.
In a variation of the assay, the test compound is administered as a single dose intraduo-denally (injected into the duodenum which has been previously esposed through a ventral mid-line incision) 10 minutes before challenge with arachidonic acid ~0.5 mg/kg) or U-44069 ~2 ~g/kg). The agonist challenge is continued 10 minutes after adminis-tration of the antagonist and every 20 minutes thereafter for a period of up to 2 hours. Reduction of the post drug response is calculated as a percent of the pre-drug control response. This variation of the assay also permits the evaluation of antagonists with a delayed onset of action.
Compounds of Formula I can be tested using the following assay to determine their mammalian leukotriene biosynthesis inhibiting activity.
Rat Peritoneal Polymorphonuclear (PMN) LeukocYte Assay Rats under ether anesthesia are injected (i.p.) with 8 ml o a suspension of sodium caseinate (6 grams in ~. 50 ml water). After 15-24 hr. the rats are sacrificed (CO2) and ~he cells from the peritoneal cavity are recovered by lavage with 20 ml of buffer (Eagles MEM containing 30 m~ HEPES adjusted to pH 7.4 with NaOH). The cells are pelleted (350 x g, 5 min.), resuspended in buffer with vigorous shaking, filtered, through lens paper, recentrifuged and finally suspended in buffer at a concentration of , ... ., . " , ~ ... .. ..

- `
1 3300~0 10 cells/ml. A 500 ~1 aliquot of PMN suspension and test compound are preincubated for 2 minutes at 37C, followed by the addition of lO ~M A-23187.
The suspension is stirred for an additional 4 minutes then bioassayed for LTB4 content by adding an aliquot to a second 500 ~1 portion of the PMN at 37C . The LTB4 produced in the first incubation causes aggregation of the second PMN, which is measured as a change in light transmission. The size of the assay aliquot is chosen to give a subma~imal transmission change (usually -70%) for the untreated control. The percentage inhibition of LTB4 formation is calculated from the ratio of transmission change in the sample to the transmission change in the compound-free control.
The cytoprotective activity of a compound may be observed in both animals and man by noting the increased resistance of the gastrointestinal mucosa to the nosious effects of strong irritants, for e~ample, the ulcerogenic effects of aspirin or indomethacin. In addition to lessening the effect of non-steroidal anti-inflammatory drugs on the gastro-intestinal tract, animal studies show that cyto-protective compounds will prevent gastric lesions induced by oral administration of strong acids, strong bases, ethanol, hypertonic saline solutions and the like.
Two assays can be used to measure cyto-protective ability. These assays are; (A) an ethanol-induced lesion assay and ~B) an indomethacin-induced ulcer assay and are described in EP 140,684.

, ~;' . .

1 3300q The magnitude of a prophylactic or thera-peutic dose of a compound of Formula I will, o~
course, vary with the nature or the severity of the condition to be treated and with the particular compound of Formula I and its route of administration.
In general, the daily dose range for anti-asthmatic, anti-allergic, or anti-thrombotic use lies within the range of from about 0.01 mg to about 100 mg per kg body weight of a mammal.
The esact amount of a compound of Formula I
to be used as a cytoprotective agent will depend on, inter ~li~, whether it is being administered to heal damaged cells or to avoid future damage, on the nature of the damaged cells (e.g., gastro-intestinal lS ulcerations vs. nephrotic necrosis), and on the nature of the causative agent. An e~ample of use of a compound of Formula I to avoid future damage is co--administration with a non-steroidal anti-inflammatory drug (for esample, indomethacin).
The effective daily dosage level for compound8 of Formula I 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.
Any suitable rou~e of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of Formula I.
For e~ample, oral, rectal, topical, parenteral, ocular, nasal, buccal, intravenous and the like may be employed. Dosage forms include tablets, troches, ~ 330090 5010P/1286A - 4g - 17358IA

dispersions, suspensions, solutions, capsules, creams, ointments, aerosols and the like.
The pharmaceutical compositions of the present invention comprise a compound of Formula I as an active ingredient or a pharmaceutically acceptable salt thereof, and may also contain a pharmaceutically acceptable carrier and optionally other therapeutic ingredients. The term ~pharmaceutically acceptable salts~ refers to salts prepared from pharmaceutically acceptable non-to~ic bases including inorganic bases and organic bases. The compositions include compositions suitable for oral, rectal, ophthalmic, pulmonary, nasal, dermal, topical or parenteral (including subcutaneous, intramuscular and intravenous) administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. They may be conveniently presented in unit dosage form and prepared by any of the methods well-known in the art of pharmac~.
For use where a composition for intravenous administration is employed, a suitable dosage range for anti-asthmatic, or anti-allergic use is from about 0.01 mg to about 20 mg (preferably from about 0.1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day and for cytoprotective use from 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 10 mg) of a compound of Formula I per kg of body weight per day. In the case where an oral composition is employed, a suitable dosage SOlOP/1286A - 41 - 17358IA

range for anti-asthmatic, or anti-allergic use is, e.g. from about 1 to about 100 mg of a compound of Formula I per kg of body weight per day, preferably from about 5 mg to about 40 mg per kg and for cyto-protective use from about 0.01 mg to about 100 mg (preferably from about 0.1 mg to about 30mg and were preferably from about 0.1 mg to about 10 mg) of a compound of Formula I per kg of body weight per day.
For administration by inhalation, the compounds of the present invention are conveniently delivered in the form of an aerosol spray presenta-tion from pressurized packs or a nebuliser, or a powder which may be formulated as a cartridge from which the powder composition may be inhaled with the aid of a suitable device. The preferred delivery system for inhalation in a metered dose inhalation (MDI) aerosol, which may be formulated as a suspension or solution in fluorocarbon propellants.
Suitable topical formulations of compound I
include transdermal devices, aerosols, creams, ointments, lotions, dusting powder, and the like.
In practical use, a compound of Formula I
can be combined as the active ingredient in intimate admisture with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
The carrier may take a wi~de variety of forms depending on the form of preparation desired for administration, e.g., oral or parenteral (including intravenous). In preparing the compositions for oral dosage form, any of the usual pharmaceutical media may be employed, such as, for esample, water glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and . ", , :

1 3300q0 5010P~128~A - 42 - 17358IA

the like in the case of oral liquid preparation~, such aæ, for e~ample, suspensions, eli~irs and solutions; or carriers such as ætarches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binder~, disintegrating agents and the like in the case of oral solid preparations such aæ, for e~ample, powder~, capsules and tablets.
Because of their ease of administration, tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar coated or enteric coated by standard techniques.
In addition to the common dosage forms set out above, the compounds of Formula I may also be administered by controlled release means and/or delivery devices such as 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 composltions of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient, as a powder or granules or as a solution or 3 suspension in an aqueous liquid, a non-aqueous liquid, an oii-in-water emulsion or a water-in-oil liquid emulsion. Such compositions may be prepared by any of the methods of pharmacy but all methods include the step of bringing into association the acti~e ingredient with the carrier which consti-tutes one or more necessary ingredients. In general, the compoæitions are prepared by uniformly and ~,~

-`` 1 330090 SOlOP~1286A - 43 - 17358IA

intimately admi~ing the active ~n~redient with liquid carriers or finely d~vided solid carrier~ or both, and then, if necessary, shaping the product into the desired presentat~on. For e~ample, a tablet may be S prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine, the active ingredient in a free-flowing form such as powder or granules, optionally mi~ed with a binder, lubricant, inert diluent, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine, a mi~ture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 2.5 mg to about 500 lS mg of the active ingredient and each cachet or capsule contains from about 2.5 to about S00 mg of the active ingredient.
The following are e~amples of representative pharmaceutical dosage forms for the compounds of Formula I:

In;ectable Suspension (I.M.) mg/ml Compound of Formula I 2.0 Methylcellulose S.0 25 Tween-80 O.S
8enzyl alcohol - 9.0 ~enzalkonium chloride 1.0 Water for injection to a total volume of 1 ml Tablet ma/t2blet Compound of Formula I 25.0 Microcrystalline Cellulose 415.0 Providone 14.0 5 Pregelatinized Starch 43.5 Magnesium Stearate 2.5 Capsule ma/capsule 10 Compound of Formula I 25.0 Lactose Powder 573.5 Magnesium Stearate 1.5 In addition to the compounds of Formula I, the pharmaceutical compositions of the present invention can also contain other active ingredients, such as non-steroidal anti-inflammatory drugs (NSAIDs), peripheral analgesic agents such as zomepirac, diflunisal and the like, cycloosygenase inhibitors, leukotriene antagonists, leukotriene biosynthesis inhibitors, H2-receptor antagonists, antihistaminic agentæ, prostaglandin antagonists, ACE
inhibitors, and thrombo~ane synthetase inhibitors.
The weight ratio of the compound of the Formula I to the second active ingredient may be varied and will depend upon the effective dose of each ingredient.
Generally, an effective dose of each will be used.
Thus, for example, when a compound of the Formula I
is combined with a second active ingredient the weigh~ ratio of the compound of the Formula I to the second ingredient will generally range from about - 1 3300qO

looo:l to about l:looo, preferably from 200:1 to 1:200. Combinations of a compound of the Formula I
and other active ingredients will generally be within the aforementioned range, but in each case, an effec-tive dose of each active ingredient should be used.
NSAIDs can be characterized into five groups:
(l) the propionic acid derivatives;
(2) the acetic acid derivatives;
(3) the fenamic acid derivatives;
(4) the biphenylcarboxylic acid derivatives;
and (5) the oxicams or a pharmaceutically acceptable salt thereof.
NSAIDS which are within the scope of this invention are those disclosed in EP 140,684.
Pharmaceutical compositions comprising the Formula I compounds may also contain other inhibitors of the biosynthesis of the leukotrienes such as are disclosed in EP 138,481 (April 24, 1985), EP 115,394 (August 8, 1984), EP 136,893 (April 10, 1985), and EP
140,709 (May 8, lg85).
The compounds of the Formula I may also be used in combination with leukotriene antagonists such as those disclosed in EP 106,565 (April 25, 1984) and EP 104,885 (April 4, 1984), and others known in the art such as those disclosed in European Patent Appli-cation Nos. 56,172 and 61,800; and in U.K. Patent Specification No. 2,058,785.

.

' ':- .

5010P/1~86A - 46 - 17358IA

Pharmaceutical compositions comprising the Formula I compounds may also contain as the second active ingredient, other prostaglandin antagonists such as those disclosed in Eusopean Patent Application 11,067 (May 28, 1980) or other thrombosane antagonists such as those disclosed in U.S. 4,237,160. They may also contain histidine decarbosyase inhibitors such as a-fluoromethyl-histidine, described in U.S.
4,325,961. The compounds of the Formula I may also be advantageously combined with an Hl or H2-receptor antagonist, such as for instance benadryl, dramamine, histadyl, phenergan, terfenadine, acetamazole, cimetidine, ranitidine, famotidine, aminothiadiazoles disclosed in EP 40,696 ~December 2, 1981) and like compounds, such as those disclosed in U.S. Patent Nos. 4,283,408; 4,362,736; ~,39~,S08.

The pharmaceutical compositions may also contain a ~+~H+ ATPase inhibitor such as omeprazole, disclosed in U.S. Pat. 4,255,431, and the like. Compounds of I may also be usefully combined with most cell stabilizing agents, such as 1,3-bis(2-carbo~ychromon-5-ylosy)-2-hydrosypropane and related compounds described in ~ritish Patent Specifications 1,144,905 and 1,144,906. Another useful pharma-ceutical composition comprises the Formula I
compounds in combination with serotonin antagonists such as methysergide, the serotonin antagonists described in Nature, Vol. 316, pages 126-131, 1985, and the like.

1 33009~

When the second active ingredient in compositions of this invention is a thromboxane synthetase inhibitor, such inhibitor can be as described in UK 2,038,821 (e.g., UK 37248 and dazosiben hydrochloride), U.S.P. 4,217,357 (e.g., UK
34787), U.S.P. 4,444,775 (e.g., CGS 13080), U.S.P.
4,226,878 ~e.g., ONO 046), U.S.P. 4,495,357 te.g., U63557A) U.S.P. 4,273,782 (e.g., UK-38485), or EP
98,690 (e.g., CV-4151).
An embodiment of the invention is a cardio-vascular composition useful for treating arterial thrombosis which comprises an antithrombotic compound of the Formula I.
A further embodiment of the invention is a cardiovascular composition useful for treating arterial thrombosis which comprises: (1) the antithrombotic Formula I compound defined above; and, (ii) an angiotensin converting enzyme ~ACE) inhibitor compound which is a member of the group: carboxyalkyl dipeptide derivatives; captopril 11-(3-mercapto-2-methyl-l-osopropyl)-L-proline~; 2-tN-(S)-l-ethosy-carbonyl-3-phenylpropyl)-S-alanyl~ ,endo-2-azabi-cyclol3,3,0]octane-3(S)-carbosylic acid; N-((S)-l-ethosycarbonyl-3-phenylpropyl)-L-alanyl-N~(2-indanyl)-glycine; l-(N-t(S)-l-ethosy-carbonyl-3-phenylpropyl~-L-alanyl)-cis,~yn-octahyd~o-(H-indole-2-S)-carboxylic acid; 2-(N-t~S)-l-ethosy-carbonyl-3-phenylpropyl]-L-alanyl)-1,2,3,4-tetrahydro-iso-isoguinoline-3(S)-carbosylic acid; and, l-carbosy-methyl-3(S)-(l(S)-ethosycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-lH~l]-benzazepine-2-one.

5010P~1286A - 4~ - 17358I~

In particular the clas~ o~ ACE inhibitors which have been found to have a potentiating effect when used in combination with the Formula I compounds are those disclosed in U.S. Patent 4,374,829, which also discloses methods for their preparation.
Of the carboxyalkyl dipeptides disclosed in U.S. Patent 4,374,829, those of particular interest in this invention are N-[l~S)-ethosycarbonyl-3-phenyl-propyl]-L-alanyl-L-proline, also ~nown and referred to herein as enalapril; N-tl(S)-carbo~y-3-phenyl-propyl]-L-alanyl-L-proline, also know and referred to herein as enalapril diacid; and, N-tl(S)-carbo~y-3-phenylpropyl]-L-lysyl-L-proline, also known and referred to herein as lisinapril.
The combination composition of the invention can contain varying amounts of (i) the Formula I
antithrombotic compound and (ii) ACE inhibitor antihypertensive compounds. The weight ratio of (i):(ii) can range from about 25 to 1; preferably from about 10 to 1. In addition to the active ingredients of (i) alone or of (i) and (ii) in combination, the compositions of the invention can also contain other conventional pharmaceutically acceptable compounding ingredients, as necessary or desire~. Such ingredient~ are generally referred to as carriers or diluents. Conventional procedures for preparing such compositions in appropriate dosage forms can be utilized. Whatever the dosage form, it will contain a pharmaceutically effective amount of the present composition.

r~4i ~

The combination compositions can be administered orally or other than orally; e.g., parenterally, by insufflation, topically, rectally, etc.; using appropriate dosage forms; e.g., tablets, capsules, suspensions, solutions, and the like, for oral administration; suspension emulsions, and the like, for parenteral administration; solutions for intravenous administration; and ointments, transdermal patches, and the like, for topical administration.
These compositions are formulated similarly to the compositions discussed 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;
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 form for cardiovascular use will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for oral administration may contain from 5 mg to 5 gm of active agents compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. josage unit forms will generally contain between from about 20 mg to about 500 mg of active ingredients.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, .. . . .

body waight, general health, se~, diet, time of administration, route of administration, rate of e~cretion, drug combination and tho severity of the particular disease undergoing therapy.
S The composition of this invention inhibits platelet accumulation at the damaged endothelial surface via the Formula I compound. This inhib~tory effect i~ potentiated ~y the presence of th~
antihypertensive compound.
Thus, the compositions of the invention are useful in treating thrombosis and are also of value in the management of acute and chronic congestive heart failure, and limitation of myocardial infarct damage.
In ViVQ testing of the composition of this invention in test animals (rabbits) can be used to demonstrate that this composition is pharmaceutically effective in decreasing platelet-related arterial thrombic formation.
To demonstrate the potentiation of the antihypertensive compound on the anti-thrombotic Formula I compound comprising the combination composition of the invention, the effect of these compounds on test animals ~rabbits) can be determined separately and then in combination. The effect of a different class of antihypertensive agents singly and in combination with the Formula I compound of the invention can also be determined for comparative purposes. The methods employed are described in U.S.
Patent 4,558,037.

fA~

5010P~1286A - 51 - 1 3 3 0 9 l7358IA

The following esamples illustrate th~
preparation of the compounds of the present invention without, however, limiting the æame thereto.
All temperature are in degrees Celsius.

E~ample 1 Ethyl 9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-s ~ ~azo~ ~ acetate _ _ To 3.50 9 of 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hy~rochloride in 70 cc of -propan~ ~was added 2.23 g of ethyl-2-cyclo-he~anone acetate. The reaction was reflused under nitrogen for 16 hours. The resulting reaction misture was then evaporated to dryness and the residue 6uspended in ether. The solid material was then filtered. The ether filtrate was washed with water, dried and evaporated. The resulting syrup was chromatographed on silica gel to give 2.8 g (42%) of the title compound.
H NMR S :1.25 (t, 3H, C02CH2~
1.80-2.00 ~m, 4H); 2.35-2.85 (m, 4H); 3.38 (m, lH);
4.10 (q, 2H, C02~CH3); 5.28 (2d, 2H, Ar ~2); 6.80-7.30 (m, 7H, Ar).

EsamDle 2 Methyl 3-(9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetra-hYdrocarbazol-l-rl~-proDanoate Following the procedure o Esample 1, but u8ing 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hyarochlo~ide and methyl 2-cyclohesanone propionate as starting material~, the title compound is prepared.

~ ., : .
~ .. I

.

ExamPle 3 Methyl 3-(9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetra-hydrocarbazol-l-yl)-propanoate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine hydrochloride and methyl 2-cyclohexanone propionate as startinq materials, the title compound is prepared.

Example 4 Ethyl 9-p-chlorobenzyl-6-methosy-1,2,3,4-tetrahydro-carbazol-l-yl-acetate Following the procedure of E~ample 1, but using 1-(4-chlorobenzyl)-1-(4-metho~yphenyl)hydrazine hydrochloride and ethyl 2-cyclohe~anone acetate as starting materials, the title compound is prepared.

E~am~le 5 Ethyl 9-benzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-l-rl-acetate Following the procedure of E~ample 1, but using l-(benzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohe~anone acetate as starting materials, the title compound was prepared.
HNMR~ : 1.15 (t, 3H, CO2CH2~3);
1.80-2.00 (m, 4H); 2.38-2.85 (m, 4H); 3.45 (m, lH);
4-10 (q, 2H, CO2~CH3); 5.30 (2d, 2H, Ar Ç~2); 6.78-7.25 (m, 8H, Ar).

_.,-,. . .

.

Example 6 Ethyl 9-p-methosybenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-l-yl-acetate Following the procedure of Example 1, but using 1-(4-methosybenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohe~anone acetate as star~ing materials, the title compound was prepared.
H NMRS: 1.15 (t, 3H, CO2,CH2CH3);
1.80-1.95 (m, 4H); 2.40-2.85 (m, 4H); 3.63 (m, lH);
3.75 ~s, 3H, OCH3); 4.13 (q, 2H, CO2CH2CH3);
5.25 (2d, 2H, Ar Ç~2); 6.75-7.25 (m, 7H, Ar).

ExamDle 7 Ethyl 9-(3,4-dichloro)benzyl-6-fluoro-1,2,3,4-tetra-hYdrocarbazol-l-yl-acetate Following the procedure of Example 1, but using 1-(3,4-dichlorobenzyl)-1-(4-fluorophenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
H NMR~: 1.15 (t, 3H, CO2CH2~3~;
1.80-2.00 (m, 4H); 2.30-2.85 (m, 4H); 3.35 (m, lH):
4.1S (q, 2H, CO2CH2CH3); 5.25 ~2d, 2H, Ar CH2); 6.70-7.45 (m, 6H, Ar).
Esa~Dle 8 Ethyl 9-[1-(1-phenyl)ethyl]-6-fluoro-1,2,3,4-tetra-hydrocar~azol-l-yl-acetate _ Following the procedure of Esample 1, but using 1-tl-(1-phenyl)ethyl~-1-(4-fluorophenyl)-hydrazine hydrochloride and ethyl 2-cyclohesanone acetate as starting materials, the title compound was prepared.

., 1 3300~0 5010P~1286A - 54 - 17358IA

H NMR S : 1.15 (t, 3H, CO2CH2CH3);
1.80-2.00 (m, 4H); 2.05 (d, 3H, Ar - CH - Me); 2.50-2.85 (m, 4H); 4.55 (m, lH); 4.20 (Q, 2H, CO2CH~CH3); 5.65 (q, lH, Ar - CH-CH3); 6.60-7.40 (m, 8H, Ar).

Example 9 Ethyl 9-p-chlorobenzyl-1,2,3,4-tetra~ydrocar~azol-l-yl-acetate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(phenyl)hydrazine hydrochloride and ethyl 2-cyclohesanone acetate as starting materials, the title compound was prepared.
H NMR ~ : 1.25 (t, 3H, CO2CH2CH~);
1.80-2.00 (m, 4H); 2.38-2.88 (m, 4H); 3,40 (m, lH);
4.15 (q, 2H, CO2C_~ H3); 4.30 (2d, 2H, Ar CH2); 6.85-7.55 (m, 8H, Ar).

E~am~le lQ
Ethyl 9-p-chlorobenzyl-6-chloro-1,2,3,4-tetrahydro-carbazol-l-yl-acetate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-chlorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as stating materials, the title compound was prepared.
H NMR ~ : 1.25 ~t, 3H, CO2CH2Ç~
1.80-2.00 (m, 4H); 2.35-2.85 (m, 4H); 3.40 (m, lH);
4.15 (q, 2H, Ar CH2); 6.82-7.50 (m, 7H, Ar).

1 3300qO

E~amPle 11 Ethyl 9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-l-yl-acetate Following the procedure of E~ample 1, but S using 1-(4-chlorobenzyl)-1-t2-methylphenyl)hydrazine hydrochloride and ethyl 2-cyclohe~anone acetate as starting materials, the title compound was prepared.
lH NMR ~: }.30 (t, 3H, CO2CH2CH3);
2.00-2.25 (m, 4H); 2.60-3.15 (m, 4H); 3.58 (m, lH);
4.40 (q, 2H, CO2~2CH3); 5.78 (2d, 2H, Ar ~2); 6.95-7.65 (m, 7H, Ar).

E~ample 12 Ethyl 6-bromo-9-p-chlorobenzyl-1,2,3,4-tetrahydro-carbazol-l-Yl-acetate Following the procedure of E~ample 1, but using 1-(4-chlorobenzyl)-1-(4-bromophenyl)hydrazine hydrochloride and ethyl 2-cyclohesanone acetate as starting materials, the title compound is prepared.
E~am~le 13 Ethyl 9-p-chlorobenzyl-6-methyl-1,2,3,4-tetrahydro-carbazol-l-yl-acetate Following the procedure of E~ample 1, but using 1-(4-chlorobenzyl)-1-(4-methylphenyl)hydrazine hydrochloride and ethyl 2 cyclohexanone acetate as starting materials, the title compound is prepared.

1 3300qO

E~ample 14 Methyl 2-(9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetra-hydrocarbazol-l-yl~-Dropanoate Followinq the procedure of Esample 1, but using 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine hydrochloride and methyl 2-(2-cyclohexanone) propionate as starting materials, the title compound was prepared.
lH NMR S 0.98 ~d, 3H, CH3-CH-CO2 Me);
1.72-2.00 (m, 4H); 2.60-2.85 ~m, 3H); 3.35 ~m, lH~;
3.64 (s, 3H, CO2~); 5.27 (2d, 2H, Ar-~2);
6.75-7.25 ~m, 7H, Ar).

ExamDle 15 Ethyl 9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-l-Yl-acetate Following the procedure of Example 1, but using 1-~4-chlorobenzyl)-1-~2-fluorophenyl)hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared.
lH NMR~ : 1.25 ~t, 3H, CO2 CH2 Ç~
1.50-2.00 (m, 4H); 2.38-2.95 ~m, 4H); 3.38 ~m, lH);
4.15 ~q, 2H, CO2~2CH3); 5.45 (2d~ 2H~ Ar CH2); 6.78-7.40 ~m, 7H, Ar).
ExamDle 16 Ethyl 9-p-chlorobenzyl-5,7-dichloro-1,2,3,4-tetra-hydrocarbazol-l-yl-acetate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(3,5-dichlorophenyl)-hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.

~ . , 1 3300qo Example 17 Ethyl 9-p-chlorobenzyl-6,8-dichloro-1,2,3,4-tetra-hydrocarbazol-l-yl-acetate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(2,4-dichlorophenyl)-hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound is prepared.

Esample 18 (-)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-l-Y1-acetic acid. methyl ester Step I
To 1.59 g of ethyl ester from Esample 1, in 10 cc of methanol was added 10 cc of water and 420 mg of potassium hydro~ide. The resulting solution was refluxed for 4 hours. Upon cooling the reaction misture was then acidified with HCl (lN). The resulting precipitate was filtered and washed with water. Analytically pure material was prepared by triturating the solid with a misture of hesane/ethyl acetate (9:1) followed ~y filtration and drying on a high vacuum pump to give 1.24 g of the racemic acid.
(89%).
Analysis calculated for C21HlgNClFO2 C H N Cl F
Calculated 67.83 5.15 3.77 9.53 5.11 Found 67.88 5.47 3.63 9.52 5.12 : .

~ - "
1 3300'10 Step II
10.0 g of 9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro~arbazol-l-yl-acetic acid from Step I was dissolved in a mixture of hot (reflusing) acetonitrile (150 cc~ and ethanol (25cc), and 4.4 g of d(+) ephedrine was added. The reflux was continued for 15 minutes and the hot solution was filtered and allowed to cool to room temperature. Crystals separated from the solution and were separated by filtration. After three recrystallizations form acetonitrile 3.9 g of the pure salt was obtained.

Step III
3.9 g of pure salt from Step II was dissolved in 200 cc of methanol and acidified using lN hydrochloric acid. Water was added and the crystals were separated by filtration and dryed under vaccum. Upon trituration with he~ane-ethyl acetate ~9:1) the resolved acid was prepared.
~D = -42.5 (methanol) m.p. 151 - 151.5C.

Step IV
To a solution of 1.0 g of the acid from Step III in 50 ml of ether is added a solution of diazomethane in ether until a slight escess of diazomethane is present. The escess diazomethane is destroyed by addition of a few drops of acetic acid.
The reaction mixture is washed with 50 ml of 5 Na2C03 solution, water, and dried over MgS04.
Filtration and evaporation of the ,solvent leaves the title compound.

,.

.. .~., . , ;

1 330~qO
5010P~1286A - 59 - 17358IA

E~am~le 19 (+) 9-p-chlorobenzyl-6-fluoro~1,2,3,4-tetrahydro-carbazol-l-yl-acetic acid. methyl ester Following the method of Example 18, but using 1~-) ephedrine in Step II, there is obtained the title compound.

EsamPle 20 Ethyl 9-p-chlorobenzyl-6-isopropyl-1-2,3,4-tetra-hydrocarbazol-l-yl-acetate Following the procedure of Example 1, but using l-~4-chlorobenzyl)-1-(4-isopropylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a misture of ethyl and isopropyl esters.

Example 21 Ethyl 9-p-chlorobenzyl-6-tert-butyl-1-2,3,4-tetra-hydrocarbazol-l-yl-acetate Following the procedure of Esample 1, but using 1-(4-chlorobenzyl)-1-(4-tert-butylphenyl) hydrazine hydrochloride and ethyl 2-cyclohesanone acetate as starting materials, the title compound was prepared as a misture of ethyl and isopropyl esters.
Esa~ple 22 Ethyl 9-p-chlorobenzyl-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazol-l-vl-acetate Following the procedure of Esample 1, but using 1-~4-chlorobenzyl)-1-~4-trifluoromethylphenyl) hydrazine hydrochloride and ethyl 2-cyclohesanone acetate as starting materials, the title compound was prepared as a mixture of ethyl and isopropyl esters.

...

Example 23 Ethyl 9-p-chlorobenzyl-6-methylthio-1,2,3,4~tetra-hYdrocarbazol-l-y~-acetate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-methylthiophenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the title compound was prepared as a mi~ture of ethyl and isopropyl esters.
The pure title compound was obtained by purification on a flash chromatogram.

E~ample 24 Ethyl 9-p-chlorobenzyl-6-methylsulfinyl-1,2,3,4-tetra-hydrocarbazol-l-yl-acetate To 498 mg of ethyl 9-p-chlorobenzyl-6-methylthio-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Esample 23 in 10 cc of methylene chloride was added 300 mg of m-chloro perbenzoic acid. The resulting mixture was stirred for 1.5 hours at room temperature. The reaction mixture was diluted with ether and consecutively washed with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 20% hesane/ethyl acetate and yielded 420 mg (82%) df the pure title compound.

Esample 25 Ethyl 9-p-chlorobenzyl-6-methylsulfonyl-1,2,3,4-tetra-hYdroearbazol-l-yl-acetata ~ o 439 mg of ethyl 9-p-chlorobenzyl-6-methyl-sulfinyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from Esample 24, in 10 cc of methylene chloride was added 353 mg of m chloro perbenzoic acid. The resulting mixture was stirred for 18 hours at room temper-ature. The reaction misture was diluted with ether and washed consecutively with a solution of sodium bicarbonate, water and brine. The crude product obtained after evaporation of the organic layer was purified on silica gel by flash chromatography eluting with 30% hexane/ethyl acetate and yielded 200 mg (42~) of ths pure title compound.
Example 26 Ethyl 9-p-chlorobenzyl-8-isopropyl-1,2,3,4-tetra-hYdrocarbazol-l-yl-acetate Following the procedure of Esample 1, but using 1-(4-chlorobenzyl)-1-~2-isopropylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetàte as starting materials, the title compound was prepared as a misture of ethyl and isopropyl esters.

EsamPle 27 9-p-Chlorobenzyl-8-methylthio-1,2,3,4-tetrahydro-carbaæol-l-yl-acetic acid, methyl ester Following the procedure of Esample 30, but using 1-(2-methylthiophenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate as starting materials, the ti*le compound was prepared.

E~am~le 28 9-p-Chlorobenzyl-8-methylsulfinyl-1,2,3,4-tetrahydro-carba~ol-l-Yl-acetic acid, methYl_e~ter Following the procedure of Example 24, but using methyl ester from E~ample 27, there is obtained the title compound.

- ~ 3300q Example 29 Ethyl 9-p-chlorobenzyl-6-fluoro-3-methyl-1,2,3,4-tetrah~droca~bazol-l-yl-acetate Following the procedure of Example 1, but using 1-(4-chlorobenzyl)-1-(4-fluorophenyl) hydrazine hydrochloride and ethyl 4-methyl-2-cyclohexanone acetate as starting materials, the title compound was prepared as a misture of ethyl and isopropyl esters.

Esample 30 9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-l-yl-acetic acid. methyl ester SteD I
To 114 g of 1-(2,4-difluorophenyl) hydrazine hydrochloride in 350 cc of 2-propanol containing 40 cc of acetyl chloride was added 138 g of ethyl 2-cyclohesanone acetate. The reaction was refluxed under nitrogen for 2 days. After cooling, 200 cc of ether was added and the precipitate filtered. The filtrate was evaporated to dryness. The resulting residue was dissolved in a (1:1) mixture of ether~ethyl acetate and consecutively ashed with water, sodium bicarbonate solutin and brine. The organic iayer was dried over sodium sulfate and evaporated to dryness. The crude product was passed through a silica gel bed eluting with 5% ethyl acetate/hesane to yield 84 g of a 1:2 mi~ture of ethyl and isopropyl esters.

.

:

.. ,~ .

Step II
84 9 of esters from Step I was dissolved in 250 cc of methanol and 400 cc of sodium hydroside (lN) was added and reflused 4 hours. After cooling, the reaction misture was washed with a (1:1) misture of ether~hesane and the aqueous layer was acidified with HCl ~lN). The resulting precipate was filtered, washed with water and air dried to afford 50 9 of 6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid.

Ste~ III
A solution of 11.1 9 of acid from Step II in 100 cc of THF was added portionwise 10.3 9 of potasslum tert-butoside. The resulting misture was stlrred for 45 min at room temperature and 10.3 9 p-chlorobenzyl bromide was added portionwise. The reaction misture wa~ stirred 18 hour~ at room .20 temperature. The resultlng mlsture was diluted with ; 100 cc of water and washea with hesane. The agueous layer wa~ acidified with HC1 (lN) and the resulting precipitate filteredi, washed with water and air-dried to afford 9.4 g of 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid.

SteD IV
Following the method of Esample 18, Step IV
but using the acid of Step III, there was obtained the title compound.
~.i.. , J ~ ~

. ~ .

.:. ~ :: :

. . `
: -.,~` `` , , ~: . `

; - ' "`:` " :

5010P/1286A - fi4 - 17358IA

lH NMR (CDC13) ~ 1.75-2.00 (m, 4H, (CH2)2) 2.38-2.78 (m, 4H, CH2CO2Me, CH2-C=C), 3.35-3.45 (m, lH, CH-C=C), 3.70 (s, 3H, CO2Me), 5.40 (dd, lH, CH2-Ar), 6.60 (ddd, lH, H7), 6.92 (dd, lH, H5), 6.82 and 7.22 (2d, 4H, Ar).

Esample 31 9-p-Chlorobenzyl-6,8-dimethyl-1,2,3,4-tetrahydro-carbazol-l-Yl-acetic acid. methvl ester Following the procedure of Example 30, but using 1-(2,4-dimethylphenyl) hydrazine hydrochloride and ethyl 2-cyclohexanone acetate in Step I, as starting materisl, the title compound is prepared.

EsamDle 32 9-p-Chlorobenzyl-6-methosy-8-methyl-1,2,3,4-tetrahydro-carbazol-l-yl-acetic acid. methYl ester Following the procedure of Esample 30, but using 1-(4-methosy-2-methylphenyl) hydrazine hydrochloride and ethyl 2-cyclohesanone acetate in Step I, as starting material, the title compound is prepared.

Esample 33 ~-) 9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-- carbazol-l-yl-acetic acid. methyl ester Following the method of Example 18, Step II
to Step IV, but using 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Esample 30, Step III and using d(~)ephedrine in Step III, there was obtained the title compound.

~ 330090 H NMR (CDC13) ~ 1.75-2.00 (m, 4H, (CH2)2) 2.38-2.78 (m, 4H, C~2C02Me, CH2-C=C), 3.35-3.45 (m, lH, CH-C=C), 3.70 (s, 3H, C02Me), 5.40 (dd, lH, Ç~2Ar), 6.60 (ddd, lH, 47), 6.92 (dd, lH, H5), 6.82 and 7.22 (2d, 4H, ~r).

~sample 34 (~) 9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-l-yl-acetic a~id, methyl ester Following the method of Example 18, Step II
to Step IV, but using 9-p-chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from Example 30, Step III and using l(-~ephedrine in Step III, there is obtained the title compound.
Example 35 (-) 9-p-Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-l-Yl-acetic acid methyl ester Following the method of Esample 18, but using the ethyl ester from esample 11 in Step I and using d(~)ephedrine in Step I~, there i8 obtained the title compound.

Esample 36 ~) 9-p-Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-l-Yl-acetic acidJ methyl ester Following the method of Example 18, but using ethyl ester from Esample 11 in Step I and using l(-)ephedrine in Step II, there is obtained the title compound.

1 3300qo E~ample 37 (-) 9-p-Chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-l-yl-acetic acid. methyl ester Following the method of Esample 18, but using the ethyl ester from Esample 15 in Step I and using d(+)ephedrine in Step II, there is obtained the title compound.

E~ample 38 (~) 9-p-Chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-l-yl-acetic acid. methyl ester Following the method of Esample 18, but using the ethyl ester from Example 15 in Step I and using l(-)ephedrine in Step II, there is obtained the title compound.

Claims (34)

1. A pharmaceutical composition for inhibiting leukotriene synthesis and antagonizing prostaglandins in mammals comprising an effective amount of a compound of the formula:
I
wherein:
R1, R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 to 3 and M is a) OR11;
b) halogen;
c) CF3;
d) SR11;
e) unsubstituted or substituted phenyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy;

f) COOR12;
g) ;
h) ;
i) -NR12R12:
j) -NHSO2R15;
k) ;
l) -SOR11;
m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;
q) ;
r) ;
s) ;
t) CN;
u) N3;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl. of 1 to 6 carbons;
each R9 is independently H, OH, Cl to C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted

2-phenethyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy; substituted or unsubstituted benzyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy; or substituted or unsubstituted phenyl, wherein the substituents are as defined above;

each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituents are as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl;
each R13 is independently H, (CH2)mCOOR12 wherein m is O to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is independently C1 to C6 alkyl, benzyl or phenyl;
each R15 is independently C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;
r is 1 to 6 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier.

2. A pharmaceutical composition according to Claim 1, wherein:
R1, R2 R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons (3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 or 1 and M is a) OR11;
b) halogen;
c) CF3;
d) SR11;
e) unsubstituted or substituted phenyl wherein the substituents are as defined in claim 1;
f) COOR12;
g) ;
h) ;
i) -NR12R12;
j) -NHSO2R15 k) ;
l) -SOR11;
m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;

q) ;
r) ;
s) ;
t) CN;
u) N3;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbons;
each R9 is independently H, OH, C1 to C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl wherein the substituents are as defined in claim 1, substituted or unsubstituted benzyl wherein the substituents are as defined in claim 1, or substituted or unsubstituted phenyl wherein the substituents are as defined above;
each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituents are as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl;
each R13 is independently H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is independently C1 to C6 alkyl, benzyl or phenyl;
each R15 is independently C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;
r is 1 to 6.

3. A pharmaceutical composition according to Claim 2, wherein:
R1, R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) M, wherein M is a) OR11;
b) halogen;
c) CF ;
d) SR11;
e) phenyl or substituted phenyl wherein the substituents are as defined in claim 2;
f) COOR12 g) ;

h) ;
i) -NR12R12;
j) -NHSO2R15;
k) ;
l) -SOR11;
m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;
q) ;
r) ;
s) ;
t) CN;
u) N3;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbons;
each R9 is independently H, OH, C1 to C4-O alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl wherein the substitutents are as defined in claim 2, substituted or unsubstituted benzyl wherein the substitutents are as defined in claim 2; or substituted or unsubstituted phenyl wherein the substitutents are as defined above;

each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituent is as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl;
each R13 is independently H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituent is as defined above;
each R14 is independently C1 to C6 alkyl, benzyl or phenyl;
each R15 is independently C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;
r is 1 or 2.

4. A pharmaceutical composition according to Claim 3, wherein:
R1, R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;

3) M wherein M is a) OR11;
b) halogen;
c) CF3;
d) SR11;
e) COOR12;
f) ;
g) -SOR11;
h) -CONR12R12;
i) -SO2NR12R12;
j) -SO2R11;
k) ;
l) CN;
m) N3;
R7 is H or alkyl of 1 to 6 carbons;
R6 is H or alkyl of 1 to 6 carbons;
each R9 is independently H or alkyl of 1 to 4 carbons;
R10 is lower alkyl;
each R11 is independently H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substituent is as defined in claim 3;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl;

each R13 is independently H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above; and r is 1.

5. A compound of the formula:
I
wherein:
R1, R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 to 3 and M is a) OR11;
b) halogen;
c) CF3;

d) SR11;
e) phenyl or substituted phenyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy;
f) COOR12;
g) ;
h) ;
i) -NR12R12;
j) -NRSO2R15;
k) ;
l) SOR11;
m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;
q) ;
r) ;
s) ;
t) CN;
u) N3;
provided that when R1, R2, R3 or R4 is alkyl having 1 to 6 carbons, it is not located at position 6;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl or 1 to 6 carbons;

each R9 is independently H, OH, C1 to C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy;
substituted or unsubstituted benzyl wherein the substituents are selected from the group consisting of C1-C3 alkyl, halogen, CN, CF3, COOR12, CH2COOR12 and C1-C3 alkoxy; or substituted or unsubstituted phenyl wherein the substituents are as defined above;
each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituents are as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl; and, each R13 is independently H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is C1 to C6 alkyl, benzyl or phenyl;
each R15 is C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;

r is 1 to 6 or a pharmaceutically acceptable salt thereof.

6. A compound according to Claim 5, wherein:
R1, R2, R3, R4, R5 and R6 ar each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) -(CH2)nM
wherein n is 0 or 1 and M is a) OR11;
b) halogen;
c) CF3;
d) SR11;
e) phenyl or substituted phenyl wherein the substituents are as defined in claim 5;
f) COOR12;
g) ;
h) ;
i) -NR12R12;
j) -NRSO2R15;
k) ;

m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;
q) ;
r) ;
s) ;
t) CN;
u) N3;
provided that when R1, R2, R3 or R4 is alkyl having 1 to 6 carbons, it is not located at position 6;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbons;
each R9 is independently H, OH, Cl to C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl wherein the substituents are as defined in claim 5, substituted or unsubstituted benzyl wherein the substituents are as defined in claim 5, or substituted or unsubstituted phenyl wherein the substituents are as defined above;
each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituents are as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl; and, each R13 is independently H, (CH2)mCOORl2 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is C1 to C6 alkyl, benzyl or phenyl;
each R15 is C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;
r is 1 to 6.

7. A compound according to Claim 6, wherein:
R1, R2, R3, R4, R5 and R6 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) alkenyl having 2 to 6 carbons;
(4) M, where M is a) OR11;
b) halogen;

c) CF3:
d) SR11;
e) phenyl or substituted phenyl;
wherein the substituents are as defined in claim 6;
f) COOR12;
g) ;
h) ;
i) -NR12R12;
j) -NRSO2R15;
k) ;
l) SOR11;
m) -CONR12R12;
n) -SO2NR12R12;
o) -SO2R11;
p) NO2;
q) ;
r) ;
s) ;
t) CN;
u) N3;
provided that when R1, R2, R3 or R4 is alkyl having 1 to 6 carbons, it is not located at position 6;
R7 is H or alkyl of 1 to 6 carbons;

R8 is H or alkyl of 1 to 6 carbons;
each R9 is independently H, OH, C1 to C4-O-alkyl or alkyl of 1 to 4 carbons;
R10 is lower alkyl, substituted or unsubstituted 2-phenethyl, substituted or unsubstituted benzyl, or substituted or unsubstituted phenyl, wherein the substituents are as defined in claim 6;
each R11 is independently H; C1 to C6 alkyl;
benzyl; phenyl or substituted phenyl wherein the substituents are as defined above;
each R12 is independently H, phenyl, benzyl or C1 to C6 alkyl; and, each R13 is independently H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is C1 to C6 alkyl, benzyl or phenyl;
each R15 is C1 to C6 alkyl, 4-methylphenyl, phenyl, or CF3;
r is 1 or 2.

8. A compound according to Claim 7, wherein:
R1, R2, R3, R4, and R5 are each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbons;
(3) M, wherein M is a) OR11;
b) halogen;
c) CF3;
d) SR11;
e) COOR12;
f) ;
g) SOR11;
h) -CONR12R12;
i) -SO2NR12R12;
j) -SO2R11;
k) ;
l) CN;
m) N3;

R6 is located at position 3' or 4' and is selected from:
(1) alkyl having 1 to 6 carbons;
(2) M wherein m is a) OR11;
b) halogen;
c) CF3;
d) SR11;
e) COOR12;
f) ;
g) SOR11;
h) -CONR12R12;
i) -SO2NR12R12;
j) -SO2R11;
k) ;
l) CN;
m) N3;
provided that when R1, R2, R3 or R4 is alkyl having 1 to 6 carbons, it is not located at position 6;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbons atoms;
each R9 is independently H or alkyl of 1 to 4 carbons;

R10 is lower alkyl;
each R11 is independently H; C1 to C6 alkyl; benzyl; phenyl or substituted phenyl wherein the substitutents are as defined in claim7;
each R12 is independtly H, phenyl, benzyl or C1 to C6 alkyl;
each R13 is independtly H, (CH2)mCOOR12 wherein m is 0 to 4, C1 to C6 alkyl, CF3, phenyl, or substituted phenyl wherein the substituents are as defined above;
each R14 is C1 to C6 alkyl, benzyl or phenyl; and r is 1.

9. A compound according to Claim 5 which is: ethyl 9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbozol-1-yl-acetate;
methyl 3-(9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetra-hydrocarbazol-1-yl)-propanoate;
methyl 3-(9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetra-hydrocarbazol-1-yl)-propanoate;
ethyl 9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;
ethyl 9-benzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetate;
ethyl 9-methoxybenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;

ethyl 9-(3,4-dichloro)benzyl-6-fluoro-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-[1-(1-phenyl)ethyl]-6-fluoro-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-chloro-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;
ethyl 6-bromo-9-p-chlorobenzyl-1,2,3,4-tetrahydro-carbazol-1-yl acetate;
methyl 2-(9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetra-hydrocarbazol-1-yl)-propanoate;
ethyl 9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-5,7-dichloro-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate:
ethyl 9-p-chlorobenzyl-6,8-dichloro-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-isopropyl-1-2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-tert-butyl-1-2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-trifluoromethyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-methylthio-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-methylsulfinyl-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-6-methylsulfonyl-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;

ethyl 9-p-chlorobenzyl-8-isopropyl-1,2,3,4-tetra-hydrocarbazol-1-yl-acetate;
9-p-Chlorobenzyl-8-methylthio-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
9-p-Chlorobenzyl-8-methylsulfinyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
ethyl 9-p-chlorobenzyl-6-fluoro-3-methyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate;
9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
9-p-Chlorobenzyl-6,8-dimethyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
9-p-Chlorobenzyl-6-methosy-8-methyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester; or (-) 9-p-Chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester.

10. A compound according to Claim 5, which is:
ethyl 9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetate;
ethyl 9-p-chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetate; or 9-p-chlorohenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester.

11. A compound according to Claim 5, which is a pure optical isomer.

12. A compound according to Claim 11, which is the (+)-isomer.

13. A compound according to Claim 11, which is the (-)-isomer.

14. A compound according to Claim 11, which is (-)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester or (+) 9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester.

15. A compound according to Claim 11, which is:
(-)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;
(-) 9-p-Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester;or (-) 9-p-Chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-carbazol-1-yl-acetic acid, methyl ester.

16. A compound which is ethyl 9-p-chloro-benzyl-6- methyl-1,2,3,4,6-tetrahydrocarbazol-1-yl-acetate.

17. A compound of the formula:
wherein:

Compound R1 R2 R5 R6 R9,R9' R7 R8 R10 1 6-F H 4'-C1 H H,H H H Et 2 6-OMe H 4'-C1 H H,H H H Et 3 6-F H 4'-C1 H H,H H H Me (-) isomer 4 6-F H 4'-C1 H H,H H H Me (+) isomor 6-F H H H H,H H H Et 6 6-F H 4'-OMe H H,H H H Et 7 6-F H 3'-C1 4'-C1 H,H H H Et 8 6-F H H H H,H H Me Et 9 H H 4'-C1 H H,H H H Et 6-C1 H 4'-C1 H H,H H H Et 11 8-Me H 4'-C1 H H,H H H Et 12 6-Br H 4'-C1 H H,H H H Et 13 6-Me H 4'-C1 H H,H H H Et Compound R1 R2 R5 R6 R9,R9' R7 R8 R10 l4 8-F H 4'-C1 H H,H H H Et 5-Cl 7-Cl 4'-C1 H H,H H H Et 16 6-Cl 8-Cl 4'-C1 H H,H H H Et Compound R1 R2 R5 R6 R9,R9' R7 R8 R10 17 6-CH(Me)2 H 4'-Cl H H,H H H Et

18 6-C(Me)3 H 4'-Cl H H,H H H Et

19 6-CF3 H 4'-Cl H H,H H H Et 6-SMe H 4'-Cl H H,H H H Et 21 6-SOMe H 4'-Cl H H,H H H Et 22 6-SO2Me H 4'-Cl H H,H H H Et 23 8-CH(Me)2 H 4'-Cl H H,H H H Et 24 8-SMe H 4'-Cl H H,H H H Me 8-SOMe H 4'-Cl H H,H H H Me 26 6-F H 4'-Cl H H,H 3-Me H Et 27 6-F 8-F 4'-Cl H H,H H H Me 28 6-Me 8-Me 4'-Cl H H,H H H Me 29 6-OMe 8-Me 4'-Cl H H,H H H Me 6-F(-)Isomer 8-F 4'-Cl H H,H H H Me 31 6-F(+)Isomer 8-F 4'-Cl H H,H H H Me 32 8-Me(-)Isomer H 4'-Cl H H,H H H Me 33 8-Me(+)Isomer H 4'-Cl H H,H H H Me 34 8-F(-)Isomer H 4'-Cl H H,H H H Me or 8-F(+)Isomer H 4'-Cl H H,H H H Me 18. The use of a compound of Claim 5 for inhibiting leukotriene synthesis in a mammal.

19. The use of a compound of Claim 5 for antagonizing prostaglandins in mammals.

20. A use according to Claim 19, wherein the prostaglandins are thromboxanes.

21. A pharmaceutical composition which comprises a composition of Claim 1 and an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents;
cyclooxygenase inhibitors; leukotriene antagonists;
leukotriene biosynthesis inhibitors; H1-receptor antagonists; H2 receptor antagonists; prostaglandin antagonists; ACE inhibitors, thromboxane synthetase inhibitors, or serotonin antagonists.

22. A pharmaceutical composition according to Claim 21, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

23. A pharmaceutical composition according to Claim 22, wherein the non-steroidal anti-inflammatory drug is indomethacin.

24. A pharmaceutical composition according to Claim 21, wherein the second active ingredient is a thromboxane synthetase inhibitor.

25. A pharmaceutical composition of Claim 21, wherein the weight ratio of said compound of Claim 1 to said second active ingredient ranges from about 1000:1 to 1:1000.

26. A composition of Claim 25, wherein said ratio is 200:1 to 1:200.

27. A pharmaceutical composition according to Claim 25, wherein the second active ingredient is a non-steroidal anti-inflammatory drug.

28. A pharmaceutical composition according to Claim 27, wherein the non-steroidal anti-inflammatory drug is indomethacin.

29. A pharmaceutical composition which comprises an effective amount of a compound of Claim 5 and an effective amount of a second active ingredient selected from the group consisting of non-steroidal anti-inflammatory drugs; peripheral analgesic agents; cyclooxygenase inhibitors;
leukotriene antagonists; leukotriene biosynthesis inhibitors; H1-receptor antagonists; H2 receptor antagonists; prostaglandin antagonists; ACE
inhibitors, thromboxane synthetase inhibitors, or serotonin antagonists.

30. A pharmaceutical composition according to Claim 29, wherein the weight ratio of said compound of Claim 6 to said second active ingredient ranges from about 1000:1 to 1:1000.

31. A pharmaceutical composition according to Claim 30, wherein said ratio is 200:1 to 1:200.

32. A pharmaceutical composition according to Claim 29, wherein the second active ingredient is a non-sterodial anti-inflammatory drug.

33. A pharmaceutical composition according to Claim 32, wherein the non-steroidal anti-inflammatory drug is indomethacin.

34. A pharmaceutical composition according to Claim 29, wherein the second active ingredient is a thromboxane synthetase inhibitor.