Note: Descriptions are shown in the official language in which they were submitted.
3~3~8~
5810P/5518P
- 1 - 17323IB
TITLE Q~ THE INVENTION
TETRAH~DROCARBÆ~LE l-ALKANOIC ACIDS
1o BACKGROUND OF THE INVENTION
ThiS invention relates to prostas1andin
antagol~ists useful in treating a variety of
conditions, such as allergic asthma where excessive
contractile activity of prostaglandins and
prostaglandin biosynthetic intermediates occur.
These compo~nds antagonize the actions of
contractile prostaglandinsi such as PGF2a,
~ ~ PGG2, PGH2, PGD2 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
~; PGF2a, P~D~, PGG2, and PGH2, are potent
bronchospastic agents. Indeed human asthmatics have
been shown to be especially sensitive to the
~ : : bronchial constricting action of PGF2a.
: ~ '
'
:iL3~
5810P/5518P - 2 - 17323IB
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, atherosclerosis, myocardial ischemia,
premature labor, spontaneous abortion, dysmenorrhea,
glomerular nephritis, and systemic lupus erythem-
atosis. Consequently, the compounds of thisinvention will alleviate the above mentioned diseases.
In addition to the prostaglandin antagonist
actions, the compounds of this invention are
inhibitors of the biosynthesis of 5-lipoxygenase
metabolites of arachidonic acid, such as 5-HPETE,
5-HETE and the leukotrienes. Leukotrienes B4,
C4, D4 and E4 are known to contribute to
various disease conditions such as asthma, psoriasis,
pain, ulcers and systemic anaphylaxis. Thus
inhibition of the synthesis of such compounds will
alleviate these and other leukotriene-related disease
states.
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; noxious agent induced
:;
5810P/5518P - 3 - 17323IB
damage or necrosis of hepatic, pancreatic, renal, or
myocardial tissue; liver parenchymal damage caused by
hepatotoxic agents such as CCl~ and D-galactosamine;
ischemic renal failure; disease-induced hepatic
damage; bile salt induced pancreatic or gastric
damage; trauma- or stress-induced cell damage; and
glycerol-induced renal 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, analagesic 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-
lS carbazole carbo~ylic acids are known in the art asanti-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-benzyl-carbazole
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 British
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 leukotrine
biosynthesis.
5810P/5518P - 4 - 17323IB
DE SCR I PT I ON OF THE I NVENT I ON
The present invention relates to novel
compounds of Formula I:
R ~ ~ R7
~C) -R10
R~-CH R7 R9
5 ~ ~ ~ 6
R ~ ~ ~ R
wherein:
R , R , R3, R4, R5 and R6 a
each independently seIected 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 O to 3 and M is
a) oR13;
: b) halogen;
c) CF3;
d) SR
: 30 e) phenyl or substituted phenyl
: wherein substituted phenyl i5
as defined below in the
; ~ definition of R 3;
:
' ~ ' ' '' ' ,
5810P/5518P - 5 - 17323IB
f) COOR
g) -C-R
h) tetrazole;
O
i) -NH-C-R16 wherein R16 is
Cl to C6 alkyl, benzyl or
phenyl;
j) NR14R14;
k) -NHSO2R wherein R
is Cl to C6 alkyl,
4-methylphenyl, phenyl, or
co3;
1) -C-CH2OH;
m) -SoRl3;
n) coNR14R14;
o) -S2NR R
P) S2R
q) N02;
O ~C R 1 5
o
s) -o-C-NR14R14;
O
t) -O-C-OR16;
: v) N3;
: u) CN;
R7 is H or alkyl of 1 to 6 carbons;
R8 is H or alkyl of 1 to 6 carbon atoms;
:~ :
;
13Q~S
5810P/5518P - 6 - 17323I8
each R is independently H, OH, Cl to
C4-O-alkyl or alkyl of 1 to 4 carbons;
R is COOH; CH2OH; CHO; tetrazole;
NHSO2Rll wherein Rll 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; CONHSO2Rl ; hydroxy-
methylketone; C~; or CON(R )2;
r is 1 to 6;
each R13 independently is H; Cl to C6
alkyl; benzyl; phenyl or substituted phenyl wherein
the substituents are Cl to C3 alkyl, halogen, CN,
CF3, COORl , CH2COOR , Cl to C3 alkoxy,
lS or Cl to C4 perfluoroalkyl;
each R14 is independently H, phenyl, benzyl
or Cl to C6 alkyl; and,
each R independently is H,
(CH2)mCOORl wherein m is 0 to 4, Cl to C6
alkyl, CF3, phenyl, or substituted phenyl wherein
~ substituted phenyl is as defined above in the
; definition of R13;
~ or a pharmaceutically acceptable salt thereof.
: ~ As used herein, the~terms "each
: 25 independently" or the equivalents thereof are employed
: to describe a number of possible position isomers
andior structural variations. For example, as
: ~ described above~, the following unit is attached to
position l of the tetrahydrocarbazole ring:
: 30
I : R7
(C)r-R
~: : R9
~:
~:
'
~3~
5810P/5518P - 7 - 17323IB
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 -(CR R9)r~:
CH H H
~ 3 1
10(- C - C - C) ,(- CH2 -)
OH H H
H H H H H H H H
(--C -- C -- C--) ,(--C -- C -- C -- C -- C--)
OH CH3 OH H OH CH3 H H
H H H
(-C - C - C-) , and the like.
H CH3 H
If an R9 is OH and R10 is CO2H, such
comyounds may form a lactone, and such lactones are
to be regarded as part of the present invention.
The alkyl groups referred to above may be
straight chain or branched or may include cycloalkyl
groups. As used herein, the term "lower" as applied
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 iodo.
Pharmaceutically acceptable salts of ths
~ compounds described herein are included within the
: ~; :
... ...
5810P/5518P - 8 - 17323I~
scope of the present invention. Such salts may be
prepared from pharmaceutically acceptable non-toxic
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, sodium calcium and magnesium salts.
Salts derived from pharmaceutically acceptable organic
non-toxic bases include salts of primary, secondary,
and tertiary amines, substituted amines including
naturally occurring substituted amines, cyclic amines
and basic ion exchange 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, methylglucamine,
theobromine, purines piperazine, N,N-dibenzyl-
ethylenediamine, piperidine, N-ethyl-piperidine,
morpholine, N-ethylmorpholine, polyamine resins and
the like.
Preferred compounds of the present invention
comprise the compounds of formula I
wherein:
Rl, R2, R3, R4, R5 and R6 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
, ~ :
~3~
5810P/5518P - 9 - 17323IB
wherein n is 0 or 1 and M is as defined
previously for Formula I;
R10 is COOH; CH2OH; CHO; tetrazole;
CONHSO2Rll wherein Rll 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; hydroxymethylketone;
CN; or CON(R )2;
r is 1 to 6; and the remaining substituents
are as defined previously for Formula I.
More preferred compounds of the present
invention comprise the compounds of Formula I.
wherein:
R , R2, R3, R4, R5 and R6
each independently selected from:
(1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
(3) alkenyl having 2 to 6 carbon atoms;
(4) M wherein M is as defined initially for
Formula I;
R is COOH; CH2OH; CHO; tetrazole;
hydroxymethylketone;
r is 1 or 2; and the remaining substituents
are as defined initially for Formula I.
Most preferred compounds of the present
: invention comprise the compounds of Formula I.
: wherein:
Rl R2 R3 R4, R5 and R are
each independently selected from:
~1) hydrogen;
(2) alkyl having 1 to 6 carbon atoms;
::
;
: '
5810P/5518A - 10 - 17323IB
(3) M wherein M is
a) oR13;
b) halogen;
c) CF ;
d) SR~3;
e) CooR14;
f) -I-Rl5;
g) tetrazole;
h3 -SoR13;
i) _coNRl4Rl4;
j ) -S02NR1 4Rl ;
k) -So2Rl3;
1) ~o-C-R15;
m) CN;
n) N3;
each R9 is independently H, or alkyl of 1
to 4 carbons;
R10 is COOH; or tetrazole;
; ~ r is 1 and the remaining substituents are as
defined initially for Formula I.
: In the above most preferred embodiment,
those compounds are particularly preferred wherein at
25: least one of Rl to R4 is not hydrogen; one of
R9 or R6 is not hydrogen; R7 is hydrogen; R9
:~ : is hydrogen, and the remaining substituents are as
defined in the most pr0ferred embodiment.
A furthe~r embodiment of the present invention
are the following novel compounds (Table 1). Among
: the resolved isomers in Table 1, the (-) isomers,
compounds 3, 37, 39, 41 and 63 are preferred.
:::: :: : : : :
~:: ' ~ '
:
'
5810P/5518P ~ ?~ 17323I~
Table 1
Novel Tetrahydrocarbazole
Alkanoic Acid~
R2
8 /
R -CH R --C-CO2H
6' ~ 2~ ~R9
R5~_R6
4'
Compound Rl R2 R5 R6 R, ~ R R
201 ~Ex.l) 6-F H 4'-Cl H H, H H H
.. . .. .. . . . _ _ _ _ _ _
2 (Ex. 4) 6~Me H 4'-Cl H H, H H H
-~ :
3 (Ex. 7) 6-f H 4'-Cl H H, H H H
2 5 ~-) i somer
- . .
1 ~Ex. El) 6-F H 4'-Cl H H, H H H
~) isomer
305 ~Ex. 9) 6-F H ~ H H H, H H H
6 ~Ex. 10) 6-F H 4'-OMe H H, H H H
:: :
..., . ~ ..
.
- '
: :
.
5810P/5518P - 12 - 173231B
Compound Rl p2 R R6 R, R R R8
7 (Ex. 11) 6-F H 3'-C1 4'-Cl H, H H H
8 (Ex. 12) 6-F H H H H, H H Me
9 (Ex 13) H H 4'-Cl H H, H H H
1 0 10 (Ex. 14) 6-Cl H 4'-Cl H H, H H H
11 (Ex. 15) 8-Me H 4'-Cl H H, H H H
12 (Ex. 16) 6-8r H 4'-Cl H H, H H H
13 (Ex. 17) 6-Me H 4'-Cl H H, H H H
14 (Ex. 19) 8-F H 4'-Cl H H, H H H
2 0 15 (Ex. 20) 6-F H 4'-Cl H H, H 3-t-Cu H
16 (Ex. 21) 5-F H 4'-Cl H H, H H H
-
17 (Ex. 21) 7-F H 4'-Cl H H, H H H
2 5 _ _ _ .. ._ -
18 (Ex. 22) S-Cl 7-C1 4'-Cl H H, H H H
19 (Ex. 23) 6-C1 8-C1 4'-Cl H H, H H H
~; ~ 3 0 20 (Ex. 18) 6-F H~ 4'-Cl H Me, H H H
~ 21 6-F H 4'-Cl H Me, Me H H
,, ~,,,~j, ,. ,., ~
.
~3~S~5
5810P/5518P - 13 - 17323IB
Compound Rl R2RS R6 R, R R R8
22 6-F H4 ' -Cl H H, H1 -Me H
23 8-Br H4 ' -Cl H H, H H H
-
24 (Ex, 24) 6-CH(Me)2 H 4'-Cl H H,H H H
0 25 (Ex. 25) 6-C(Me3 H 4'-Cl H H,H H H
26 ( Ex . 26) 6-CF3 H 4 ' -Cl H H, H H H
27 (Ex. 27) 6-SMe H 4'-Cl H H,H H H
28 (Ex. 28) 6-S(O)Me H 4'-Cl H H,H H H
29 (Ex. 29) 6-5(0)2Me H 4'-Cl H H,H H H
30 (Ex. 30) 8-CH(Me~ H 4'-Cl H H,H H H
31 (Ex. 31) 8-SMe H 4'-Cl H H,H H H
-
32 (Ex. 32) 8-S(O)Me : H 4'-Cl H H,H H H
2 5 : __
33 (Ex. 33) 6-F H 4'-Cl H H,H 3-Me H
:
34 (Ex. 34) 6-F 8-F 4'-Cl H ~ H,H H H
3 0 35 ( Ex . 35)6-Me 8-Me 4 i -Cl H H, H H H
:
' " ' ~'
:'
'' '
,
:
~3~;9~35
5810P/5518P - 14 - 17323IB
Compound R R2 R R6 R, R R R8
36 (Ex. 36) 6-OMe8-Me 4'-C1 H H,H H H
37 (Ex. 37) 6-F(-)Isomer 8-F 4'-C1 H H,H H H
38 (Ex. 38) 6-F(+)lsomer 8-F 4'-C1 H H,H H H
39 (Ex. 39) 8-Me(-)Isomer H 4'-C1 H H,H H H
40 (Ex. 40) 8-Me(+)Isomer H 4'-Cl H H,H H H
4l (Ex. 4l ) 8-F(-)Isomer H 4'-C1 H H,H H H
42 (Ex. 42) 8-F(+)Isomer H 4'-Cl H H,H H H
43 6-F 8-F3'-C1 4'-C1 H,H H H
44 (Ex. 46) 6-F 8-F 2'-C1 4'-C1 H,H H H
6-F 8-F 4'-OMe H H,H H H
:
46 6-F 8-F 4'-OH H H,H H H
2 5
47 ( Ex . 47) 6-F 8-F 4 ' -Sl1e H H, H H H
.
48 6-F H4'-S(O)Me H H,H H H
3 0 49 ( Ex . 59) 6-F 8-F 4 ' -NHCOMe H H, H H H
5û 6-F H 4'-S(0)2Me H H,H H H
`: :
~L3~5~85
5810P/5518P - 15 - 17323IB
Compound R R2~5 R6 R9 R9 ' R7 F8
51 6-F H4~-F HH,H H H
. _
52 6-F H4'-8r HHIHH H
53 6-F 8-Me 4 ' -Cl H H, H H H
54 6-F H4 ~ -cn2 H H H, H H H
6-F H 4 ' -C02Me H H,HH H
56 6-F 8-F 4 ' -n-C3H7 HHIHH H
57 6-F 8-F 3 ' -I 4 ' -OH H, H H H
58 6-F 8-F 4'-I HH,HH H
59 6-~ H 4'-Cl H H,H H H
:
6-F H 4'-N HH,HH H
-
61 (Ex. 48) 6-F 8-F 4'-S(O)Me HH,HH H
62 (Ex. 49) 6-F 8-F 4'-S(0)2Me H H,H H H
63 (Ex. 5û) 6-F(-);somer 8-F 4'-S(O)zMe H H,H H H
_ __
64 (Ex. Sl) 6-F(+)isomer 8-F 4'-5(0~ Me HH,HH H
.__
65 ( Ex .45 ) 6-F 8-F 2 ' -Cl HH,HH H
~: :
~: : : :
.
`:
: :'
:
:~i3~ 5
58].0P/5518P - 16 - 17323IB
CompoundRl R2 R R6 R, R R R8
66 (Ex. 52)6-F 8-F 4~-CF3 H H,H H H
67 (Ex. 53)6-F 8-F 4~-F H H,H H H
68 (Ex. 54)6-F 8-F 3'-C~ H H,H H H
0 69 (Ex. 55)6-F 8-F 4'-Cn2 Me H H,H H H
70 (Ex. 56) 6-F 8-F 4'-CONMe2 H H,H H H
71 (Ex. 57) 6-F 8-F 4'-COMe H H,H H H
72 (Ex. 58) 6-F 8-F 2 2 H,H H H
73 (Ex. 60) 6-F 8-F 4'-NHS02Me H H,H H H
-
20 74 (Ex. 61)6-F 8-F 4'-NHCONHMe H H,H H H
(Ex. 62) 6-F 8-F 4'-OMe H H,H H H
:
76 6-F 8-F 4 ' -C02H H H, H H H
2 5 . ... __
77 6-F 8-F 4 ' -NH2 H H, H H H
. _ _
78 6 F8-F 4'-OH H H,H H H
30 79 6-F 8-F 4'-ocy C2 H H H,H H H
~ ~ .
,,~ ~ ., ,,, - -
.
?~1S
5810P/551RP ~ 17 - 17323IB
The following reaction schemes illustrate
the preparation of the compounds of the present
invention:
5 Scheme I Preparation of Formula I Compounds
Rl ~7
R2 ~ ~ lower
10R4 N-NH2 ~ reflux
¦ HCl
~R8 ~C) r-C02R
R5 R6 I1I
II
R2 ~ R7 R ~ R7
R ~ N ~ R ~ N ~
¦ ~ ~ hYdrolysis_~ ¦ R ~R
~ R8 R9r 2~ ~8 R9r 2
25R5 ~ R6 R5 ~ 0 ~ R~
IIIa
The reaction can be conveniently carried out
: 30 in an alcohol solvent such as t-butanol, i-butanol,
and the like. The hydrolysis of the ester inter-
mediates IIIa is conveniently carried out by using
~3(~
5810P/5518P - 18 - 17323IB
NaOH or KOH in aqueous ethanol or methanol followed
by acidification to obtain compounds of Formula I.
The following ketones (1,2,4) of structure
III are known in the art, and ketones 3 and 5 are
readily prepared by procedures analogous to those for
the known ketones.
TABLE 2
ketones of Formula III
No.Structure Reference
Ethyl 2-cyclohexan~ne
1. ~ acetate; commercially
O ~ available (Aldrich)
C2Et
Methyl 2-cyclohexanone
2. ~ , propionate; J.A.C.S. 85
~ 207 (1963)
O y G. Stork, A. Brizzolara,
~ H. Landesman,
: 25 ~ J. Scmuszkovicz and
C02ME R. Terrell
3. Methyl 4-t-butyl-2-
~ cyclohexanone acetate
: ~ 30 ~
O~y
C02ME
:
:: ::
~3~
5810P/5518P - 19 - 17323IB
TABLE 2 (Cont'd)
4- Methyl 2-~2-cyclohexanone)
~ propionate
¦ I J.A.C.S. 85 207 (1963)
~ G. Stork, Ao Brizzolara,
I H. Landesman,
C02ME J. Scmuszkovicz and
R. Terrell
5- Ethyl 4-methyl-2-cyclo-
~ hexanone acetate
O ~f
\C02Et
The sequence described above is an applic-
ation of the Fischer Indole Synthesis. Numerous-
: 20 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. Y., 1979. Appropriate manipulations
~: of functional groups using sequences described in such
: 25 rev:iews will lead to the compounds of the presentinvention.
:: ,:
3~0
:
.
5810P/5518P - 20 - 17323IB
Scheme II Preparation of Hydrazine Derivatives (II)
5Rl IHR8
R3 ~ ~ toluene
R4 N-NH2 ~ R5 R6 reflux
olHCl
(IV) ( )
Rl
R2 ~ 7 is a leaving group such as
~ O ~ Cl, Br, I, mesylate or tosylate
R4 ~ \N-NH2
~ HCl
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 for 60 minutes.
Then, 7.1 g of p-chlorobenzyl~chloride was added.
Aft~r stirring 16 hours at reflux, triethylamine
hydrochloride was filtered off and washed with ethyl
ether. The filtrate and washing were concentrated in
:~
::
:
5810P/5518P - 21 - 17323IB
vacuo and chromatographed on a silica gel column
(hexane-ethyl acetate, 9:1) to give 6.64 g of 1-(4-
chlorobenzyl)-1-(4-methoxyphenyl)hydrazine. Other
hydrazines, similarly prepared, are also shown in
Table 3, below.
Examples of benzyl halides V are shown in
Table 3b.
TA~LE 1
Hydra~i nes
4 A
X~~
\/ \
N 2
~o Y~11
Compound
No. X Y R Compound Name
2 5 - -
1. 4-F 4-Cl H 1~ chlorobenzyl j-1-(4-
fl uorophenyl ) hydrazi ne
hydrochl ori de
: 2. 3.5-C12 4-Cl H 1-(4-chlorobenzyl )-1-(3,5-
dichlorophenyl)hydrazine
hydrocblor;de
~: :
:: :
'
g~
5810P/5518P - 22 - 17323I9
TA~LE 3 (Cont'd)
3, 4-OMe 4-Cl H 1-(4-chlorobenzyl)-1-(4-
methoxyphenyl) hydrazine
hydrochloride
4. 2-Me 4-Cl H 1-(4-chlorobenzyl)-1-(2-
methylphenyl) hydrazine
hydrochloride
5, 4-Me 4-Cl H 1-(4-chlorobenzyl)-1-(4-
methylphenyl) hydrazine
hydrochloride
1 5
6. 4-C1 4-Cl H 1-(4-chlorobenzyl)-1-(4-
chlorophenyl) hydrazine
hydrochloride
7. H 4-Cl H 1-(4-chlorobenzyl)-1-(phenyl)
hydrazine hydrochloride
8. 4-9r 4-Cl H 1-(4-chlorobenzyl)-1-(4-
bromophenyl) hydrazine
2 5 hydrochloride
: ~ 9. 3-F 4-Cl H 1-(4-chlorobenzyl)-1-(3-
: fluorophenyl) hydrazine
hydrochloride
3 0 :
10. 2,4-C12 4-C1 H 1-(4-chlorobenzyl)-1-(2,4-
dichlorophenyl)hydrazine
hydrochloride
~: : : ~:
,
:: ,
: :
5810P/5518P - 23 - 17323I~
tABLE 3 (Cont'd)
11. 4-F H H l-(benzyl)-1-(4-f1uoropheny1)
hydrazine hydroch1oride
12. 4-F 4-OMe H 1-(4-inethoxybenzyl)-1-(4-
fluorophenyl) hydrazine
hydrochlor;de
13. 4-F 3,4-C12 H 1-(3,4-dichlorobenzyl)-1-
(4-fluoro-phenyl) hydrazine
hydrochloride.
1 5 14. 4-F 3 1-tl-(phenyl)ethyl]-1-~4-
fluorophenyl) hydrazine
hydrochloride
15. 2-F 4-Cl H 1-(4-chlorobenzyl)-1-(2-
2 0 fluoropheny1) hydraz;ne
hydrochloride.
16. 1-t2-(4-chlorophenyl)ethyl]-1-(4-fluorophenyl) hydrazine
hydrochloride.
2 5
17. 1-(2-propyl)-1-(4-fluorophenyl)hydrazine hydrochloride.
18. 4-CH(Me)z 4-Cl ~ H 1-(4-ch10robenzyl)-1-(4-iso-
propylpheny1)hydrazine
3 0 hydroch10r;de
19. 4-C(Me)3 4-Cl H 1-(4-chlorobenzyl)-1-(4-tert-
butylphenyl)hydrazine)hydro-
chloride
~: :
.
~ ~ ' ' . `
.
: . .
'
: '
~3V~
5810P/5518P - 24 - 17323IB
TABLE 3 ( Cont ' d )
20. 4-CF3 4-Cl H 1-(4-chlorobenzyl )-1-(4-
tri fl uoromethyl phenyl )-
hydrazi ne hydrochl ori de
21. 4-SMe 4-Cl H 1-(4-chlorobenzyl )-1-(4-
methylthiophenyl)hydrazine hydrochloride
22. 2-CH(Me)2 4-Cl H 1-(4-chlorobenzyl)-1-(2-iso-
propylphenyl )hydrazine
hydrochl ori de
2 0
2 5;
: :
: `
~ '
'
.
'
~35f~1~S
5810P/5518P - 25 - 17323IB
~h~m~ Alte~q~t;ve Prepartion of F~rmula I Com~Qund~
lower alkanol R2~R7
III ~ I~l rrflu~ R3~\~ R CO R16
l 9
Ester i ntermedi ate
Hyd rol ys i s
R2~ 2) Acidify R3--~)
J ( C ) r-CQ2H l g
A/ R~
R ~LR6
Acid intennediate
; 25 Scheme III illustrates an alternative
~: synthesis of the compounds of Formula I. In this
Schem~ a Fischer indole synthesis is carried out using
a phenylhydrazine IV and the ketone III,:followed by
hydrolysis. The acid intermediate is then
: 30 N-benzylat~d with the reagent V, pre~erably using a
~: ~ : strong base such as potassium t-butoxide, sodium
~ hydride (NaHj or potassium hexamethyldisilazide
:~ (KHMDS) to effect the reaction. Acidification of the
~ ~ ~ reactLon mi~ture then yields the free acid of I.
, ~
' " ' ' ~ ~ , ~ - '
'' . :
'
~3~548S
~810P/5518P - 26 - 17323IB
Scheme IV Pr;~aration of Sulfo~ides and Sulfones of Formula I ComDound~
R 5 TC 1~
R2_~S R is re;lac~ b~ SR, S~O)n 3 or
~3~~ 19 11 ~ s~o~ 5t13
R X~/ N/R~7 R ~sRl3 or s(g~l3
I (C);
~/\R~
10 R V R6
SRl 3
tC - C02~l6
VI
l .5 ~9. of
~CPCA
~ S(0)2-R13
S(O)R ;~ eg. ~tRBA TC - tO R
16 ;~ 2
TC - tO2R
VI Ill VI I !~
¦H~drolrtl~ lHydrol~rsis
S~O)~ 5~0) ~
Tt - COzll ~ TC - C02H
VTI : VIII
~: 30
:
`
L3~:~5~8~
5810P/5518P - 27 -- 17323IB
In Scheme IV is illustrated a method of
preparing derivatives of Formula I in which one of
the substituents among Rl-R4 is a sulfoxide or a
sulfone. It will be obvious to one skilled in the
art that a sulfoxide or sulfone derivative of R5 or
R6 could be prepared in the same way.
Ester VI (a representative of III a, Scheme
I) is prepared according to Scheme I or Scheme III
followed by esterification of acid I. Treatment of
VI with a limited amount of an oxidizing agent such
as m-chloro-perbenzoic acid yields the sulfoxide
ester VIIa, which upon hydrolysis yields sulfoxide
acid VII. Further treatment of VIIa with the
oxidizing agent, or treatment of VI with an excess
~>2 eq.) of the oxidizing agent yields the sulfone
ester VIIIa, hydrolysis of which yields the sulfone
acid VIII. Both VII and VIII are representatives of
Formula I compounds.
_Y Preparation of Further tompounds of Formula I
R ~ THC uel
(C)
: ' " ' - .
:.
. , ~ , . .
'; :'
, .
-
:~L,3~
5810P/5518P - 28 - 17323IB
L i Al H4 PCC
THC - C02R -~ THC - CH20H ~ THC - CHO
(IIIa, Scheme 1) IX x
Hyd rol ys i s ¦
R 52NH2
SDCl 2 Et3N l l
THC - C02H ~ THC - COCl ~ THC - CONHSO2R
10 I XI XIV
CH2~ NH
9 9
THC - COtHN2 THC - CONR R
XII XV
5¦ Hz504 ~ R =R =H
lH2o
THC - COCH20H THC - CH2NH2 THC - CN
XIII XVI XVIII
~¦~R S02Cl lNaN3
N-NH
THC - CH2NH52R THC~
2 5 N=N
XVII XIX
.
Other compounds of Formula I can be prepared as
indicated in Scheme V. Thus the ester derivative
:30 IIIa can be reduced to the alcohol IX by lithium
aluminum hydride or other suitable reducing agents.
:;: Alcohol IX can then be oxidized to aldehyde X by
pyridinium chlorochromate or other suitable oxidizing
, . . .. . .
3~3![~54~3$
5810P/5518P - 29 - 17323IB
agents. Carboxylic acids of Formula I can be
converted to the acid chloride XI (the acid bromide
or a mixed carbonate anhydride could also be used)
which when reacted with diazomethane yields the
diazoketone XII. Compound XII, upon reaction with
aqueous acid, preferably a nonnucleophilic acid such
as sulfuric acid or p-toluenesulfonic acid, is
converted to the hydroxymethyl ketone XIII.
Acid chloride XI, upon reaction with a
sulfonamide, RllS02NH2, in the presence of a
weak base yields the acyl-sulfonamide XIV. Reaction
of XI with an amine, R9R9NH, yields amide XV.
Amide XV can be sequentially reduced, to amine XVI,
with diborane or lithium aluminum hydride, and
sulfonylated with RllS02Cl to produce sulfon-
amide XVII. Amide XV (when both R9 substituents
are hydrogen) can be dehydrated by standard reagents
to nitrile XVIII, which is converted to tetrazole XIX
by reaction with sodium azide, tri-n-butyltin azide
or other suitable methods. Compounds IX, X, XIII,
XIV, XV, XVII, XVIII and XIX are representatives of
Formula I compounds.
Scheme VI Prep~ratio~ of HydraziDe De~i~atives IV
R~)~ 2) li~25204 R~
R NH2 HCl R NHNHz e HCl
IV
~31US~5
5810P/5518P - 30 - 17323IB
With regard to Scheme VI, the preparation of
hydrazine starting materials is illustrated by pre-
paration of 4-methylthiophenyl hydrazine hydrochlor-
ide. 4-Methylthioaniline (13.9 g) was added dropwise
to cold HCl (6N) (50 mL) and stirred for 5 min in an
ice bath. A solution of NaNO2 in water (7.25 g, 15
mL) was then added dropwise and stirred for 15 ~in.
The cold dia~onium salt was then cannulated into a
stirred cold solution of Na2S2O4 in water (50
g, 250 mL). After 20 min, ether (200 mL) was added
and the reaction mixture basified with NaOH(lON).
The ether layer was decanted, washed with brine,
dried over Na2SO4 and HCl gas was passed through
the ether solution to form the hydrochloride salt
which precipitated out. After filtration, there was
obtained 7.0 g of pure final product. Other
hydrazines, similarly prepared, are also shown in
Table 4, below.
TA~LE 3a
HYDRAZINES
R
~2 ~
R4 NHNH2-HCl
IV
No. Rl R2 ComPound Name
l 4-SMe H 4-methylthiophenyl hydrazine
hydrochloride
.,: . . . - :
13~54B5
5810P/5518P - 31 - 17323IB
TABLE 3a (Cont'd)
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-methoxy-2-methylphenyl
hydrazine hydrochloride
R3=R4=H
TABLE 3b
20 Benzyl Halides V
z
: ~ CHR
: ~ ~ where R8 is H
~ R6
: R5
Compound
: : : 30 No. Z R5 R6 Compound Name
1. Cl 4-Cl H 4-chlorobenzyl
chloride (ALDRICH)
:
::
:: :
54~5
5810P/5518P - 32 - 17323IB
Compound
No Z R R~ Compound Name
2. Cl 4-OMe H 4-methoxybenzyl chloride
(ALDRICH)
3. Cl 2-C1 4-C1 2,4 dichlorobenzyl
chloride (ALDRICH)
4. Br 2-Cl H 2-chlorobenzyl bromide
(ALDRICH)
5. Br 3-Cl H 3-chlorobenzyl bromide
(ALDRICH)
15 6. Br 4-F H 4-fluorobenzyl bromide
(ALDRICH)
7. Br 4-CF3 H 4-trifluoromethyl-
benzyl bromide (ALDRICH)
8. Cl 4-CO2Me H 4-carbomethoxybenzyl
chloride (J.A.C.S. 1950,
72 5152)
~: 25 9. Cl 4-SMe H 4-methylthiobenzyl
: chloride (C.A.: 56: 4774
(1962))
.
~ 3;0
;~: : : :
,, . . , :
,~ :
.
'
3l~ 35
5810P/5518P - 33 - 17323IB
Compound
No, z ~5 R6 ComPound-Name
10~ Cl 4-SOMe H 4-methylsulfinyl- benzyl
chloride (C.A.: 84:
104277h (1976))
11. Cl 4-SO2Me H 4-methylsulfonylbenzyl
chloride (C.A.: 78:
1113259 (1973))
12. Br 4-NO2 H 4-nitrobenzyl bromide
(ALDRICH)
13. Cl 4-CONMe2 H 4-dimethylcarbox-
amidobenzyl chloride
14. Cl 4-S02NMe2 H 4-dimethylaminosulfonyl-
benzyl chloride (C.A.:
84: 135484r (1976))
15. Cl 4-C02H H 4-carboxybenzyl chloride
(ALDRICH~
16. Cl 4-COMe H 4-acetylbenzyl chloride
: (C.A.: 93: ~3999~5
(1980))
In those instances when asymmetric centers
are present, more than one stereoisomer is possible,
:: and all possible isomeric forms are deemed to be
30 ~included within the planar structural representations
: shown. Optically active (R) and (S) isomers may be
resolved using conventional techniques known to the
skilled artisan.
`` ~L3~5~
5810P/SS18P - 34 - 17323IB
The prostaglandin antagonist properties o~
the compounds of the present invention can be
demonstrated by a number of biological assays, two o
which, inhibition o~ platelet aggregation and
measurement Of PA2 valves are described below.
Inhibition of Induced Threshold Aggregation o~ Human
Platelets
Human platelet rich plasma (PRP) is prepared
from venous blood o~ male volunteers who have taken
no medication for ten days prior to test. Blood is
transferred into plastic centrifuge tubes containing
3.8% Trisodium Citrate in 0.9% NaCl (in a ratio of
blood to anticoagulant of 9:1~, mixed by gentle
inversion, and centrifuged at room temperature for
ten minutes at 116 g. The supernatant (PRP~ is
transferred into plastic tubes. Platelet poor plasma
(PPP) is obtained by centri~uging the residual blood
cells at 4000 g ~or ten minutes. PRP is le~t to
stand at least one half hour prior to testing.
Platelet Aggregation is measured using a
Payton~ Aggregometer and Recorder. Following
calibration of the instrument, a cuvette containing
PRP ~225 microliters) is incubated for three minutes
at 37C. Drug vehicle (control), or a drug concentra~
tion is then added in a volume of 0.5 microliter.
After one minute, the aggregating ayent (U4~069,
9,11-dideoxy-9,11-epoxymethano PGF2) is
added to the cuvette in a volume of 25 microliters.
Recordin~ is continued until the maximal response is
obtainedO
~3U5~
5810P/5518P - 35 - 17323I~
The threshold (approximately 20 - 30% of
maximum) aggregation concentration Oe the agonist to
be used i5 first determined in the presence of the
drug vehicle (control). Test compounds are then
assayed at 10 or 30 micrograms/ml initially, and if
active, are further tested in order to determine the
concentration ran~e at which ~0-80% of the threshold
aggregatory response is inhibited. All drugs are
dissolved in dimethylsulfo~ide.
The heigh~ of the aggregation response
tmeasured in divisions of the recorder paper, 1
division ~ 2.5 mm) in the presence of the drug is
recorded, and calculated as percent inhibition of the
mean height of the control threshold responses. The
IC50 (drug concentration which inhibits 50% of the
aggregatory response) is obtained by regression
analysis.
Estimation of PA2 Values in Guinea Pig Tracheal
Chain
Male albino Hartley strain guinea pigs
(300-350 gm) were sacrificed by a blow to the head
and exsanguinated. The trachea was removed, ~reed of
extraneous tissue and sectioned into rings of 1-2 mm
~5 thickness. Five rings were tied together in series,
ensuring that the tracheal muscle lay in the same
vertical plane, and the cartilage of each ring then
separated at a point directly opposite the muscle.
The chains were suspended under 1 9~ resting tension
in modified Krebs~ solution (NaCl, 6.87; NaHCO3
2.1; dextrose~, 2.1; RCl, 0.32: CaC12, 0.28;
MgSO4, 7H2O, 0.11; KH2PO4, 0.16; gm/L:
~ equilibrated with 5% CO2 in 2 ~or 1 hour)
: ~ :
:
:
:
~ ~ :
.~,
13~54~
5810P/5518P - 36 - 17323I~
containing indomethacin (1.4 s 10-5M) to suppress
endogenous protaglandin synthesis, Organ bath
temperature was maintained at 37C and 5~ CO2 in
2 diffused continously. Isometric tension changes
were recorded from a Gould-Statham~ (UTC 2) force
displacement transducer connected to a Beckman~ Type R
Dynograph. For assay purposes initial ma~imal
contractions were elicited with a high concentration
of the contractile agonist [U-44069, 9.11-dideoxy-
9a,11a-epo~ymethano PGF2~] and the tissue sub-
sequently washed at intervals until tension returned
to baseline. Agonist dose response curves were
obtained using a cumulative-dose schedule (4-8 doses)
and the preparations then washed at regular intervals
until baseline tension was recorded. After an
appropriate interval (1-1.5 hrs) agonist dose
response curves were repeated in the presence of
antagonist drug concentrations. Drug doses were
delivered in 10 ~1 volumes 5 minutes prior to the
second agonist challenge, and cumulative agonist
volumes did not exceed 100 ~1 per bath. EC50
values were obtained by regression analysis and used
to calculate 'apparent' and Schild Plot PA2 values
by the method o~ Tallarida and Murray 1981.
Compounds of Formula I can be tested using
the following assay to deter~ine their mammalian
leukotriene biosynthesis inhibiting activity.
Rat Peritoneal Polymorphonuclear (PMN~
_ Leukocyte Assay
Rats under ether anesthesia are injected
(i.p.) with 8 ml of a suspension of sodium caseinate
(6 grams in ca. 50 ml water). After 15-24 hr. the
`~ ~ 7
: . :
. .~ ,
13~54~5
5810P/5518P - 37 - 17323IB
rats are sacrificed (CO2) and the cells from the
peritoneal cavity are recovered by lavage with 20 ml
of buffer (Eagles MEM containing 30 mM HEPES adjusted
to pH 7.4 with NaOH). The cells are pelleted (350 x
g, 5 min.), resuspended in buffer with vigorous
shaking, filtered, through lens paper, recentrifuged
and finally suspended in buffer at a concentration of
10 cells/ml. A 500 ~1 aliquot of PMN suspension
and test compound are preincubated for 2 minutes at
37C, followed by the addition of 10 ~M A-23187.
The suspension is stirred for an additional 4 ~inutes
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 submaximal
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 noxious effects of strong irritants, for
example, 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.
:::
:
- ~
,
,
5810P/5518P - 38 - l7323Ia
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.
In Table 4 below are presented data
indicating the prostanoid antagonist activities of
compounds of the present invention indicated in Table
1. It is to be noted that PA2 values are on a
logerithmic scale, so that, for instance, a difference
between two PA2 values of 1 represents a difference
in potency by a factor of 10.
Compounds A, B, C and D in Table 4 are known
in the art: U.S. Patent 3,896,145 describes compounds
A and C, U.S. Patent 3,868,387 describes compound B,
and compound D is described in U.S. Patent 3,905,998.
Compound A, which is a positional isomer of
the novel compound 2, is nevertheless almost 12 times
less potent as an inhibitor of platelet aggregation
and its P~2 is a factor of 14 (antilog of 1.6) less
than that of compound 2. The homolog B, with one
carbon less than A, shows no significant activity.
Also of interest is the fact that the fully aromatic
carbazole analog of the novel compound 2, compound C,
does not possess any significant activity. Compounds
D and E, isomeric with compound B further demostrate
that direct attachment of the carboxyl group to the
: tetrahydrocarbazole nucleus results in severe loss of
activity.
Compound 8 indicates an interesting
differentiation of prostaglandin antagonist activity,
: depending upon the tissue, with very weak action on
the guinea pig trachea (PA2 6), but with very good
potency as an inhibitor of human platelet aggregation
(IC50~0o911g/ml)-
'' ' '
.
.
~3~
5810P/5518P - 39 - 17323IB
Compound F demonstrates that a hydrogen atom
attached to the 9-position (the nitrogen atom) results
in severe loss of activity. Likewise, compound G,
with a 9-alkyl substituted, has almost completely lost
activity. Compound H, with a 2-phenylethyl sub-
stituent at the 9-position has also suffered a serious
loss of activity by the addition of a CH2 group
compared to Compound 1. The last three compounds (F,
G and H) demonstrate the requirement for a benzyl or
substituted benzyl group at position-9 in the
compounds of the present invention.
Table 4
Prostanoid Antagonist Activities
Compound Inhibition of PA2
platelet aggregation
(IC50 in ~g/ml)
--~
A ~ CO~H 3,5 6.8
Cl
.; ., ., .. ~. .,
31 3~
5810P/5518P - 40 - 17323IB
Table 4 (Cont ' d2
MeO
CO2H < 6 . 8
B
1J
10 Cl ~/
MeO
\~3 >30 6 . 58
C ~J ~C2 H
20 Cl
iNeO l 02H
25 ~
D ~ ~ 6
3~0
Cl
:
:~ :
' ;
'
`, ;'`, .
~L3~
5810P/5518P 41 - 17323IB
Tab1e 4 (COnt d)
MeO
~ 4.23 6.66
E ~ CO H
~o 1
10 /\/
C1
.
F
~--\ \~ 3.41 <6
E ~J
H CO2 H
F
13.6 C6
N ~
2~5 G ~ LCO2H
Me Me
:: ~
::: : ` :
3 0
.,,: :
., .,.. , ,.,,,.. ~.,.. ,.. ,", .. .. .
~ ~ .
,
.
- :
.
. .
.
~L3~ 5
5810P/5518P - 42 - 17323I~
Table 4 (Cont ' d)
5~ ?
H ll 02H
13.6 6.8
Cl
15 F
0.03 8.6
C2 H
Cl
~5
MeO
S) 0,3~ 8.4
3~ 2 .) ~ 2
: ~C
.
. . ~ ,
,
.
, ~
13i~?~5
5810P/5518P - 43 - 17323IB
Table 4 (Cont ' d~
\~ 0 . 05 8 . 0
L
3 ) CO2H
~ /
1 o
Cl \~/
\~ 3~) 0.15 8.7
I L
6 ) C02~1
/\ /
25 ~J
MeO
: : '
:: :
~3~S~
5810P/5518P 44 - 17323IB
Table 4 (Cont ' d)
./\
~ 0.09 8.3
7 ~ CO2H
C~
15 `~/~
~\N~J o os
<6
B ~ H
(~ o oS 8.9
9 J ~ H
~/
Cl
; :
:,
:
' ".
~3~ 35
5810P/551BP - 45 - 17323I~
Table 4 ~Cont ' d)
Cl
5 \~
N~ 0 .10 8 . 0
10 ) LCOZH
C1~/
`, 2 olo gs
11 Me ) CO2
; 20
:~ 1
C1
~ ,
~ 2 5
,
: : 3 0
.
\
~13~
5810P/5518P - 46 - 17323IB
Table 4 (Cont ' d)
~r
5 ~
N~ 0.09 7 9
J L~o H
12 / 2
10 J~/
Cl
M e ~
N ~y 0. 08 7.6
J C02R
13~
Cl
~ ~J 0.08 9.4
14 ~ ) co2~
~/
Cl ~
~3~ L85
5810P/5518P - 47 - 17323IB
Ob~d)
, ~F)
5 .-~
~F') N \,/ 0.17 8 9
16 I LCt)21
~ -
Cl
Cl~
19 Cl J CO R 0-07 7.2
: 1~
Cl
:: 2 5
; 3 0
: ~
~:::::: : :
:
:
; ~ :
~, ... .. .. .
. ~
5810P/5518P - 48 - 17323IB
Table 4 (Cont'd)
~ ~ ~ 0.31 6.8
I CO
~1~
10 ~
Cl
The magnitude of a prophylactic or thera-
peutic dose of a compound of Formula I will, of
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 exact amount of a compound of Formula I
to be used as a cytoprotective agent will depend on,
inter alia, whether it is being administered to heal
damaged cells or to avoid future damage, on the nature
of the damaged ~ells (e.g., gastro-intestinal
ulcerations vs. nephrotic necrosis), and on the nature
of the causative agent. An example of use of a
compound of Formula I to avoid future damage is co-
administration with a non-steroidal anti-inflammatory
; drug (for example, indomethacin).
~ , . .:,
~3~X~3S
5810P/5518P - 49 - 17323IB
The effective daily dosage level for
compounds 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 route of administration may be
employed for providing a mammal, especially a human
with an effective dosage of a compound of Formula I.
For example, oral, rectal, topical, parenteral,
ocular, nasal, buccal, intravenous and the like may
be employed. Dosage forms include tablets, troches,
dispersions, suspensions, solutions, capsules, creams,
ointments, aerosols and the like.
lS The pharmaceutical compositions of the
present invention comprise a compound of Formula I as
an active ingredient or a pharmaceutically acceptable
salt thereof, and may also contain a pharmaceutically
acceptable carrier and optionally other therapeutic
ingredients. The term "pharmaceutically acceptable
salts" refers to salts prepared from pharmaceutically
acceptable non-toxic bases including inorganic bases
and organic bases. 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 o~ the active ingredient. They may
be conveniently presented in unit dosage form and
prepared by any of the methods well-known in the art
of pharmacy.
:
.
~3~
5810P/5518P - 50 - 17323IB
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
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
25 ~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,
oi~ntments, lotions, dusLing powder, and the like.
~ .
'
-
1~5~5
5810P/5518P - 51 - 17323I~
In practical use, a compound of Formula I
can be combined as the active ingredient in intimate
admixture with a pharmaceutical carrier according to
conventional pharmaceutical compounding techniques.
The carrier may take a wide variety of forms depending
on the form o~ preparation desired for administration,
e.g., oral or parenteral (including intravenous). In
preparinq the compositions for oral dosage form, any
of the usual pharmaceutical media may be employed,
such as, for example, water glycols, oils, alcohols,
flavoring agents, preservatives, coloring agents and
the like in the case of oral liquid preparations,
such as, for example, suspensions, elixirs and
solutions; or carriers such as starches, sugars,
microcrystalline cellulose, diluents, gran~lating
agents, lubricants, binders, disintegrating agents
and the like in the case of oral solid preparations
such as, for example, powders, capsules and tablets.
Because of their ease of administration, tablets and
capsules represent the mos~ 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 compositions of the present
~ invention suitable for oral administration may be
:
.~
~3~3~
5810P/5518P - 52 - 17323IB
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 a suspension in an aqueous liquid, a
non-aqueous liquid, an oil-in-water emulsion or a
water-in-oil liquid emulsion. Such compositions may
be prepared by any of the methods of pharmacy but all
methods include the step of bringing into association
the active ingredient with the carrier which consti-
tutes one or more necessary ingredients. In general,the compositions are prepared by uniformly and
intimately admixing the active ingredient with liquid
carriers or finely divided solid carriers or both,
and then, if necessary, shaping the product into the
desired presentation. For example, a tablet may be
prepared by compression or molding, optionally with
one or more accessory ingredients. Compressed tablets
may be prepared by compressing in a suitable machine,
the active ingredient in a free-flowing form such as
powder or granules, optionally mixed with a binder,
lubricant, inert diluent, surface active or dispersing
agent. Molded tablets may be made by molding in a
suitable machine, a mixture of the powdered compound
moistened with an inert liquid diluent. Desirably,
each tablet contains from about 2.5 mg to about 500
mg of the active ingredient and each cachet or capsule
contains from about 2.5 to about 500 mg of the active
ingredient.
The following are examples of representative
pharmaceutical dosage forms for the compounds of
Formula I:
:. : , . . .
~3~:9~i~8~
5810P/5518P - 53 - 17323IB
In~ectab ~ (I.M.) mg/ml
Compound of Formula I 2.0
Methylcellulose 5 0
Tween 80~ 0.5
5 Benzyl alcchol 9-0
Benzalkonium chloride 1.0
Water for injection to a total volume of 1 ml
Tablet mq/tablet
10 Compound of Formula I 25.0
Microcrystalline Cellulose415.0
Providone 14.0
Pregelatinized Starch 43.5
Magnesium Stearate 2 5
50~
CaPsule mq/capsule
Compound of Formula I 25.0
Lactose Powder 573.5
20 Magnesium Stearate 1 S
600
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, cyclooxygenase
- inhibitors, leukotriene antagonists, leukotriene
biosynthesis inhibitors, H2-receptor antagonists,
antihistaminic agents, prostaglandin antagonists, ACE
inhibitors, and thromboxane synthetase inhibitors.
: ~
~L3L?~
5810P/5518P - 54 - 17323I~
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 o~ each ingredient.
Generally, an ef~ective dose o~ each will be used.
Thus, for example, when a compound of the Formula I
is combined with a second active ingredient the
weight ratio o~ the compound of the Formula I to the
second ingredient will generally range from about
100~:1 to about 1:1000, preferably from 200:1 to
1:200. Combinations of a co~pound of the Formula I
and other active ingredients will generally be within
the aforementioned range, but in each case, an
e~fe-tive dose of each active ingredient should be
used.
NSAIDs can be characterized into five groups:
(1~ the propionic acid derivatives;
(2) the acetic acid derivatives;
(3~ the fenamic acid derivatives;
(4) the biphenylcarboxylic acid derivatives;
and
(5) the oxicams or a 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
30 140,709 (May 8, 1985).
::
;:
~3
- , :
'~ , ' ~' ~' ' .............. '
' .
`
.
.
5810P/5518P - 55 - 17323IB
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 Application Nos.
56,172 (July 21, 1982) and 61,800 (October 6, 19~2); and
in U.K. Patent Specification No. 2,058,785.
Pharmaceutical compositions comprising the
Formula I compounds may also contain as the second
active ingredient, other prostaglandin antagonists
such as those disclosed in European Patent Application
11,067 (May 28, 1980) or other thromboxane antagonists
such as those disclosed in U.S. 4,237,160. They may
also contain histidine decarboxyase inhibitors such
as ~-fluoromethyl-histidine, described in U.S.
4,325,961. The co~pounds 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 Z, 1981) and like
compounds, such as those disclosed in U.S. Patent
Nos. 4,283,408; 9,362,7-~6; 4,394,508.
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. Compounds of I may also be usefully combined
with most cell stabilizing agents, such as 1,3-bis(2-
: carboxychromon-5-yloxy)-2-hydroxypropane and related
54~
5810P~5518P - 56 - 17323IB
compounds described in British Patent Speci~ications
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, 1945,
and the like.
When the second active ingredient in
compositions o~ this invention is a thromboxane
synthetase inhibitor, such inhibitor can be as
described in U~ 2-,038,821 (e.g., UK 37248 and
dazoxiben hydrochloride), U.S.P. 4,217,357 (e.g., UK
34787), U.S.P. 4,444,775 (e.g., CGS 13080), U.S.P.
4,226,878 (e.g., ONO 046), U.S.P. 4,495,357 (e.g.,
U63557A) U.S.P. 4,273,782 (e.g., UK-38485), or EP
98,690 (e.g., CV-4151).
An embodiment of the invention is a cardio-
vascular composition useful ~or trea~ing arterialthrombosis which comprises an antithrombotic compound
of the Formula I.
A ~urther embodiment of the invention is a
cardiovascular composition useful for treating
arterial thrombosis which comprises: (1) the
antithrombotic Formula I compound de~ined above; and,
(ii) an angiotensin converting enzyme (ACE) inhibitor
compound which is a member o~ the group: carboxyalkyl
dipeptide derivatives; captopril [1-(3-mercapto-2-
methyl-l-oxopropyl)-L-proline]; 2-[N-(S)-l-ethoxy-
carbonyl-3-phenylpropyl)-S-alanyl]-cis,endo-2-azabi-
cyclo[3,3,0]octane-3(S)-carboxylic acid; N-((S)-l-
.
:
.' '
. ': - . ' : ,
- ~ .
~3~
~ 57 ~ 17323IB
ethoxycarbonyl-3-phenylpropyl)-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-carbonyl-3-phenylpropyl]-
L-alanyl)-1,2,3,4-tetrahydro-iso-isoquinoline-3(S)-
carboxylic acid; and, l-carboxy-methyl-3(S)-(l(S)-
ethoxycarbonyl-3-phenylpropylamino)-2,3,4,5-tetrahydro-
lH[l]-benzazepine-2-one.
In par-ticular the class of ACE inhibitors
which have been found to have a potentiating effect
when used in combination wi-th -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 inven-
tion are N-[l(S)--ethoxycarbonyl-3-phenylpropyl]-L-
alanyl-L-proline, also known and referred to herein
as enalapril; N-[l(S)-carboxy-3-phenylpropyl]-L-
alanyl-L-proline~ also known and referred to herein
2Q as enalapril diacid; and, Na-[l(S)-carboxy-3-phenyl-
propyl]-L-lysyl-L-proline, also known and referred to
herein as lisinapril.
The combination composition of the inven-
tion 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 l; preferably
from about 10 to l. In addition to the active
ingredients of (i) alone or of (i) and (ii) in combi-
3Q nation, the compositions of the invention canalso contain other conventional pharmaceutically
: 35
i~
5810P/5518P - 58 - 17323IB
acceptable compounding ingredients, as necessary or
desired. Such ingredients are generally referred to
as carriers or diluents. Conventional procedures for
preparing such compositions in appropriate dosage
S forms can be utilized. Whatever the dosage form, it
will contain a pharmaceutically effective amount of
the present composition.
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
:
.
-
:' ~ '- ' .
-
18~
5810P/5518P - 59 - 17323IB
the total composition. Dosage 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 weight, general health, sex, diet, time of
administration, route of administration, rate of
excretion, drug combination and the severity of the
particular disease undergoing therapy.
The composition of this invention inhibits
platelet accumulation at the damaged endothelial
surface via the Formula I compound. This inhibitory
effect is potentiated by the presence of the
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 vivo testing of the composition of this
invention in test animals (rabbits~ can be used to
demonstrate that this composition is pharmaceutically
; 25 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 ~hen in combination. The effect of a
:
:
,
~ :~3~54~
5810P~5518P - 60 - 17323I3
different class o~ antih~pertensive agents singly and
in combination with the Formula I compound of the
invention can also be detecmined for comparative
purposes, The methods employed are described in U.S.
Patent 4,558,037.
The following examples illustrate the
preparation of the compounds o~ the present invention
without, however, limiting the same thereto.
All temperatures are in degrees Celsius.
Reference Compounds
6 _ oro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-fluorophenyl) hydrazine hydrochloride and
ethyl-2-cyclohexanone acetate as starting materials,
the title compound was prepared.
M.P. 124 -126C
Reference Compounds
9-~1-(2-p-chlorophenyl)ethyl]-6-fluoro-1,2,3,4 tetra-
hydrocarbazol~ acetic acid _ _
-~ Following the procedure of Example 2, but
using 1-[2-(~-chlorophenyl)ethyl]-1-(4-fluorophenyl)
25~ hydrazine hydrochloride and ethyl 2 cyclohexanone
acetate as starting materials, the titl~ compound was
prepared.
Empirical Formula: C22H21NFC1O2
C H N
30 Calculated 68.48 5.49 3.63
Found 68.15 5.70 3.65
- .
''
~3~S~
5810P/5518P - 61 - 17323IB
Reference ComPounds
6-fluoro-9-isopropyl-1,2,3,4-tetrahydrocar~azol-1-yl-
acetic acid
Following the procedure of Example 1, but
using 1-(2-propyl)-1- (4-fluorophenyl)hydrazine
hydrochloride and ethyl 2-cyclohexanone acetate as
starting materials, the title compound was prepared.
Empirical Formula: C17H20NFO2
M.P. 144-144.5 C
Example 1
9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-
1- l-acetic acid
y
Step I
To 3.50 g of 1-(4-chlorobenzyl)-1-(4-fluoro-
phenyl3hydrazine hydrochloride in 70 cc of iso_
propanol was added 2.23 g of ethyl 2-cyclohexanone
acetate. The reaction was refluxed under nitrogen
for 16 hours. The resulting reaction mixture was
then evaporated to dryness and the residue suspended
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%).
Ste~
To 1.59 g of ethyl ester from step I in 10
cc of methanol was added 10 cc of water and 420 mg of
potassium hydroxide. The resulting solution was
refluxed for 4 hours. Upon cooling the reaction
mixture was then acidified with HCl (lN). The
resulting precipitate was filtered and washed with
,
~3~4~
5810P/5518P - 62 - 17323IB
water. Analytically pure material was prepared by
trituration the solid with a mixture of hexane/ethyl
acetate (9:1) followed by filtration and drying on a
high vacuum pump to give 1.24 g of the title compound
(89%).
Analysis calculated for C21HlgNClFO2
C H N Cl F
Calculated 67.83 5.15 3.77 9.53 5.11
Found 67.885.47 3.63 9.52 5.12
Example 2
3-[9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-yl]-propanoic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-fluorophenyl)hydrazine
hydrochloride and methyl-2-cyclohexanone propionate
as starting materials, the title compound was
prepared.
Empirical formula C22H21ClFNO2
C H N
Calculated 68.48 5.49 3.63
Found 68.26 5.57 3.60
Example 3
25 3-[9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetrahydro-
carbazol-l-Yl]-propanoic acid
; ~ Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-methoxyphenyl)hydrazine
hydrochloride and methyl-2-cyclohexanone propionate
as starting materials, the title compound was
prepared.
~:
., .
~.
- '
. .
5810P/5518P - 63 - 173231B
Empirical formula: C22H22CINO3
C H N Cl
Calculated 69.43 6.08 3.52 8.91
Found 69.24 5.98 3.60 8.85
ExamPle 4
9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetrahydrocarbazol-
l-yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl~-1-(4-methoxyphenyl)hydrazine
hydrochloride and ethyl-2-cyclohexanone acetate as
starting materials, the title compound was prepared.
M.P. 152-153C.
Example 5
2-[9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-Yl]ethano1
,
1.10 g of 9-p-chlorobenzyl-6-fluoro-1,2,3,4-
tetrahydrocarbazo-l-yl-acetic acid ethyl ester was
dissolved in 500 ml dry tetrahydrofuran and the
reaction was cooled at 0C and one equivalent of
lithium aluminium hydride (LAH) was added portion
wise. The reaction was allowed to warm up to room
temperature and stirred for 16 hrs. The reaction
`~ 25 mixture was quenched with NH4Cl (aq.). Ethyl
acetate was added (100 ml) and the organic phase
separated, washed with water and brine, dried and
evaporated. The product was isolated by column
chromatography.
M.P. 98.0 - 98.5 C.
~: : : : :
~:
.
::
.
~3C~5~
5810P/5518P - 64 - 17323IB
Example 6
3-[9-p-chlorobenzyl-6-methoxy--1,2,3,4-tetrahydro-
carbazol-l-ylJ-propanol
Following the procedure of Example 5, but
using 3-[9-p-chlorobenzyl-6-methoxy-1,2,3,4-tetra-
hydrocarbazo-1-yl]-propanoic acid methyl ester from
Example 3 as starting material, the title compound
was prepared.
Empirical formula: C23H26ClNO2
C ~ N
Calculated 71.95 6.83 3.65
Found 71.36 6.65 3.81
Example 7
(-)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Step I
10.0 g of 9-p-chlorobenzyl-6-fluoro-1,2,3,4-
tetrahydrocarbazo-l-yl-acetic acid from Example 1 was
dissolved in a mixture of hot (refluxing) aceto-
nitrile (150 cc), and ethanol (25cc) and 4.4 g of
d(+) ephedrine was added. The reflux was continued
for 15 min. 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 from
acetonitrile 3.9 g of the pure salt was obtained.
Step II
3.9 g of pure salt rom step I was dissolved
in 200 cc of methanol and acidified using 1 N hydro-
~ chloric acid. Water was added and the crystals were
'~:
: '
.
.
-
'
-
31 3~ 35
5810P/5518P - 65 - 17323IB
separated by filtration and dryed under vacuum. Upon
trituration with hexane ethyl acetate mixture (9:1)
the title compound was prepared.
aD = -42.5 (methanol) M.P. 151 - 151.5C.
Example 8
(+)9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-Yl-acetic acid
.
Following the method of Example 7, but using
1(-) ephedrine and 9-p-chlorobenzyl-6-fluoro-1,2,3,4-
tetrahydrocarbazo-l-yl-acetic acid as starting
material, the title compound was prepared.
aD = +43.0 (methanol) M.P. 150 - 150.53C.
ExamPle 9
9-benzyl-6-fluoro-1,2,3,4-tetrahydrocarbazol-1-yl-
acetic acid
Following the procedure of Example 1, but
using l-(benzyl)-l- (4-fluorophenyl)hydrazine
hydrochloride and ethyl 2-cyclohexanone acetate as
starting materials, the title compound was prepared.
Analysis calculated for C21H20NFO2
C H N
Calculated 74.76 5.98 4.15
25 Found 74.95 6.07 3.90
Example 10
9-p-methoxybenzyl 6-fluoro-1,2,3,4-tetrahydrocarbazol-
l-Yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-methoxybenzyl)-1-(4-fluorophenyl)hydrazine
; hydrochloride and ethyl 2-cyclohexanone acetate as
stating materials, the title compound was prepared.
:
~ .
~. . .
~3~
5810P/5518P - 66 - 17323IB
Analysis calculated for C22H22NFO3
C H N
Calculated 71.92 6.04 3.91
Found 71.70 6.22 4.05
Example 11
9-(3,4-dichloro)benzyl-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-vl-acetic acid
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.
Analysis calculated for C21H18NC12FO2
C H N
~ Calculated 62.08 4.47 3.45
;~ Found 61.964.71 3.67
' ~:
Example 12
20 9-[1-(1-phenyl)ethyl]-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-Yl-acetic acid
Following the procedure of Example 1, but
using l-[l-(l-phenyl)ethyl]-1-(4-fluorophenyl)-
hydrazine hydrochloride and ethyl 2-cyclohexanone
acetate as starting materials, the title compound was
prepared.
C H N F
Calculated 75.19 6.31 3.99 5.41
;~ Found 75.18 6.05 4.11 5.51
~ 30
:.
,
~ ~ :
:
.; .~ . ..:: . ,,
. ' ' .
.
5810P/5518P - 67 - 17323IB
Exarnple 13
9-p-chlorobenzyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetic
acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(phenyl)hydrazine hydro-
chloride and ethyl 2-cyclohexanone acetate as starting
materials, the title compound was prepared.
Empirical Formula: C21H20Nclo2
C H N Cl
Calculated 71.28 5.70 3.96 10.02
Found 70.7n 5.90 3.82 10.23
Example 14
9-p-chlorobenzyl-6-chloro-1,2,3,4-tetrahydrocarbazol-
l-yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-chlorophenyl)hydrazine
hydrochloride and ethyl-2-cyclohexanone acetate as
starting materials, the title compound was prepared.
0 Empirical Formula: C21HlgNC12O2
C H N C1
Calculated 69.96 4.93 3.61 18.26
Found 65.20 5.16 3.38 18.04
Example 15
9-p-chlorobenzyl-8-methyl-1,2,3,4-tetrahydrocarbazol-
yl-acetic acid _ _
Following the procedure of E~ample 1, but
using 1-~4-chlorobenzyl)-1-(2-methylphenyl)hydrazine
hydrochloride and ethyl-2-cyclohexanone acetate as
starting materials, the title compound was prepared.
:~
:
:
:: : ~ :
~ ,
-
~3C~-S~L~S
5810P/5518P - 68 - 17323IB
Empirical Formula: C22H22NC1O2
C H N Cl
Calculated 71.83 6.03 3.81 9.64
Found 72.19 6.23 4.12 9.84
s
Example 16
6-bromo-9-p-chlorobenzyl-1,2,3,4-tetrahydrocarbazol-1-
yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-bromophenyl)hydrazine
hydrochloride and ethyl 2-cyclohexanone acetate as
starting materials, the title compound was prepared.
Empirical formula: C21HlgBrClNO2
C H N Br Cl
Calculated 58.29 4.43 3.24 18.46 8.19
Found 58.49 4.60 3.44 18.50 8.27
Example 17
9-p-chlorobenzyl-6-methyl-1,2,3,4-tetrahydrocarbazol-
l-yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-methylphenyl)hydrazine
; ; hydrochloride and ethyl 2-cyclohexanone acetate as
starting materials, the title compound was prepared.
Empirical formula: C22H22ClNO2
C H N Cl
Calculated 71.83 6.03 3.81 9.64
Found 71.72 6.14 3.779.88
~30
:
~' :
~ :
~ ' ' '
: ~ . ' ' . ' :
: '
', ', . '
'~ '
~3~4&~
5810P/5518P - 69 - 17323IB
Example 18
Z-[9-p-chlorobenzyl-6-fluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-]propanoic acid.
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-fluorophenyl) hydrazine
hydrochloride and methyl 2-(2-cyclohexanone) pro-
pionate as starting materials, the title compound was
prepared.
M.P. 203-205C
Example 19
9-p-chlorobenzyl-8 fluoro-1,2,3,4-tetrahydrocarbazol-
l-Yl-acetic acid.
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)~1-(2-fluorophenyl) hydrozine
hydrochloride and ethyl 2-cyclohexanone acetate as
starting materials, the title compound was prepared.
M.P. 228-229C.
Example 20
3-[(~ and .~)-t-butyl-6-fluoro-9-(p-chlorobenzyl)-
1,2,3,4-tetrahydrocarbazol-1-yl]acetic acid.
Following the procedure of Example 1 but
using 4-t-butyl-2-carbomethoxymethyl cyclohexanone
and 1-(4-chlorobenzyl)-4-fluorophenylhydrazine hydro-
chloride as the starting materials, the title compound
was prepared.
M.P. 210-211C.
:: :
~ 30
:: :
:
,~
.. .. ... .
-: ' '
. ' . .
:. :
` ` ~3~ 5
5810P/5518P - 70 - 17323I~
Example 21
9-p-chlorobenzyl-5-fluoro-1,2,3,4-tetrahydrocarbazol-
1-yl-acetic acld and 9-p-chlorobenzyl-7-fluoro-
1,2,3,4-tetrahydocarbazol-1-yl-acetic acid tmixture).
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(3-fluorophenyl)hydrazine
hydrocloride and ethyl 2-cyclohexanone acetate as
starting materials, the title compounds were prepared.
Empirical Formula: C21H1gNClFO2
M.P. 211-219C
Example 22
9-p-chlorobenzyl-5,7-dichloro-1,2,3,4-tetrahydro-
carbazol-l-Y1-acetic acid.
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(3-5 dichlorophenyl)-
hydrozine hydrochloride and ethyl 2-cyclohexanone
acetate as starting materials, the title compound was
prepared.
Empirical formula: C21H18NC13O2
M.P. 204-206C
` Example 23
9-p-chlorobenzyl-6,8-dichloro-1,2,3,4-tetrahydro-
carbazol-l-Yl-acetic acid.
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(2-4-dichlorophenyl)-
hydrozine hydrochloride and ethyl 2-cyclohexanone
acetate as starting materials, the title compound was
prepared.
Empirical formula: C21H18NCl3O2
M.P. 203-204C.
:
'. ' .' : - ' ' .
: ' .` , ' ' '
.
~3~
5810P/5518P - 71 - 17323IB
ExamPle 24
9-p-Chlorobenzyl-6-isopropyl-1,2,3,4-tetrahydrocar-
bazol-l-yl-acetic acid
Following the procedure of Example 1, but
using 1(4-chlorobenzyl)-1-(4-isopropylphenyl)-
hydrazine hydrochloride and ethyl 2-cyclohexanone
acetate as starting material, the title compound was
prepared.
Empirical Formula: C24H26ClNO2
C H N Cl
Calc: 72.81 6.62 3.54 8.95
Found: 72.83 7.09 3.61 9.21
Example 25
9-p-Chlorobenzyl-6-tert-butyl-1,2,3,4-tetrahydrocar-
bazol-l-Yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-tert-butylphenyl)
hydrazine hydrochloride and ethyl2-cyclohexanone
acetate as starting materials, the title compound was
prepared.
Empirical Formula: C25H28ClNO2
C H N Cl
Calc. 73.24 6.88 3.42 8.65
25 Found: 73.21 7.32 3.10 8.26
Example 26
9-p-Chlorobenzyl-6-trifluoromethyl-1,2,3,4-tetra-
hydrocarbazol-l-yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chlorobenzyl)-1-(4-trifluoromethylphenyl)
: hydrazine hydrochloride and ethyl 2-cyclohexanone
::;
~`''~` '` `' ' .
,
~3~
5810P/5518P - 72 - 17323IB
acetate as starting materials, the title compound was
prepared. m.p. 167-168C.
Example 27
9-p-Chlorobenzyl-6-methylthio-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
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.
Empirical Formula: C22H22ClNO2S
C H N S Cl
Calc: 66.07 5.54 3.50 8.02 8.86
15 Found: 66.27 5.83 3.38 8.00 8.70
Example 28
9-p-Chlorobenzyl-6-methylsulfinyl-1,2,3,4-tetrahydro-
arbazol-l-yl-acetic acid
Step I
To 498 mg of ethyl 9-p-chlorobenzyl-6-methyl-
thio-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from
Example 27, Step I, 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 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 chromato-
graphy eluting with 20~ hexane/ethyl acetate and
yielded 420 mg (~2%) of the pure sulfoxide derivative.
,
.
~ ~ .
~3C~
5810P~5518P - 73 - 17323IB
Step II
Following the procedure of Example 1, Step
II, but using the ethyl ester from Step I, there was
obtained the title compound. m.p. 1~5-107C.
Empirical Formula: C22H22ClNO3S
C H N S Cl
Calc: 63.53 5.33 3.37 7.71 3.52
Found: 63.31 5.03 2.94 7.69 8.43
Example 29
9-p-Chlorobenzyl-6-methylsulfonyl-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Step I
To 439 mg of ethyl 9-p-chlorobenzyl-6-methyl-
sulfinyl-1,2,3,4-tetrahydrocarbazol-1-yl-acetate from
Example 28, Step I, 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
temperature. The reaction mixture 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 chromato-
~;~ graphy eluting with 30% hexane/ethyl acetate and
yielded 200 mg (42%) of the pure sulfone derivative.
:: :
Step II
Following the procedure of Example 1, Step
II, but using the ethyl ester from Step I, there was30 obtained the title compound. m.p. 101-102C.
,
, :~
.
~L3~ 5
5810P/5518P - 74 - 17323IB
Example 30
9-p-Chlorobenzyl-8-isopropyl-1,2,3,4-tetrahydrocar-
bazol-l-yl-acetic acid
Following the procedure of Example 1, but
using 1-(4-chloroben~yl)-1-(2-isopropylphenyl)
hydrazine hydrochloride and ethyl 2-cyclohexanone
acetate as starting materials, the title compound was
prepared.
Empirical Formula: C24H26ClNO2
C H
Calc: 72.81 6.62
Found: 72.59 6.90
Example 31
9-p-Chlorobenzyl-8-methylthio-1,2,3,4-tetrahydrocar-
; bazol-l-yl-acetic acid
Following the procedure of Example 34, but
using 1-(2-methylthiophenyl~ hydrazine hydrochloride
and ethyl 2-cyclohexanone acetate as starting
materials, the title compound was prepared. m.p.
141-142C.
Example 32
9-p-Chlorobenzyl-8-methylsulfinyl-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the procedure of Example 28, but
using the ethyl ester from Example 31, Step II, there
was obtained the title compound. m.p. 119-120.5C.
.
: .
S4L~
5~10P/5518P - 75 - 17323IB
_am~Ple 33
9-p-Chlorobenzyl-6-fluoro-3-methyl-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
_
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. m.p. 205-206C.
Empirical Formula: C22H21FClNO2
C H N Cl
Calc: 68.48 5.49 3.63 9.19
Found: 68.80 5.50 3.30 9.47
ExamPle 34
9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Step 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-cyclohexanone 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 washed with
water, sodium bicarbonate solution and brine. The
organic layer was dried over sodium sulfate and
evaporated to dryness. The crude product was passed
through a silica gel bed eluting with 5% ethyl
acetate/hexane to yield 84 g of a 1:2 mixture of
ethyl and isopropyl esters.
: :
5810P/5518P - 76 - 17323IB
Step II
84 g of esters from Step I was dissolved in
250 cc of methanol and 400 cc of sodium hydroxide
(lN) was added and refluxed 4 hours. After cooling,
the reaction mixture was washed with a (1:1) mixture
of ether/hexane and the aqueous layer was acidified
with HCl (lN). The resulting precipate was filtered,
washed with water and air dried to afford 50 g of
6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic
acid.
Step III
A solution of 11:1 g of acid from Step II in
100 cc of THF was added portionwise 10.3 g of
potassium tert-butoxide. The resulting mixture was
stirred for 45 min. at room temperature and 10.3 g
p-chlorobenzyl bromide was added portionwise. The
reaction mixture was stirred 18 hours at room
temperature. The resulting mixture was diluted with
100 cc of water and washed with hexane. The aqueous
layer was acidified with HCl (lN) and the resulting
precipitate filtered washed with water and air-dried
to afford 9.4 g of the title compound. m.p.
168.5-170C.
Example 35
9-p-Chlorobenzyl-6,8-dimethyl-1,2,3,4-tetrahydro-
~ carbazol-l-yl-acetic acid
; Following the procedure of Example 34, but
using 1-(2,4-dimethylphenyl~ hydrazine hydrochloride
and ethyl 2-cyclohexanone acetate in St~p I as
starting materials, the title compound was prepared.
m.p. 187-188C.
.~,,, ~ .
:i~3~ 5
5810P/5518P - 77 - 17323IB
Example 36
9-p-Chlorobenzyl-6-methoxy-a-methyl-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the procedure of Exam~le 34, but
using 1-(4-methoxy-2-methylphenyl) hydrazine
hydrochloride and ethyl 2-cyclohexanone acetate as
starting materials, the little compound was
prepared. m.p. 188-188.5C.
Example 37
~-)-9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the method of Example 7, but using
d(~)ephedrine and 9-p-chlorobenzyl-6,8-difluoro-
15 1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from
Example 34 as starting materials, the title compound
was prepared. From Example 34 [a]D = -64.3
; (methanol) m.p. 130-131C.
Example 38
(+~-9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the method of Example 37, but
using l(-)ephedrine, the title compound was prepared.
25 [a]D = +61.5~ (methanol) m.p. 129.5-130C.
:
:
Example 39
(-)-9-p-Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-
carbazol-l-Yl-acetic acid
.
Following the method of Example 7, but using
d(+)ephedrine and 9-p-chlorobenzyl-8-methyl-1,2,3,4-
tetrahydrocarbazol-l-yl-acetic acid from Example 15
' ',
-
~3~
5810P/5518P - 78 - 17323IB
as starting materials, the title compound was
prepared. [~]D = -51.6 (methanol) m.p.
196-198C.
Example 40
t+)-9-p~Chlorobenzyl-8-methyl-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the method of Example 39, but
using l(-)ephedrine, the title compound was prepared.
[~]D = +45-9 (methanol) m.p. 195-197C.
Example 41
(-)-9-p-Chlorobenzyl-8-fluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the method of Example 7, but using
d(+)ephedrine and 9-p-chlorobenzyl-8-fluoro-1,2,3,4-
tetrahydrocarbazol-l-yl-acetic acid from Example 19
as starting materials, the title compound was
prepared. [~]D = -62.1 (methanol) m.p. 74-75C.
Example 42
(~)-9-p-Chlorobenzyl-8 fluoro-1,2,3,4-tetrahydro-
carbazol-l~yl-acetic acid
Following the method of Example 41, ~ut
using l(-)ephedrine, the title compound was prepared.
; [a]D = +65.2 ~methanol) m.p. 94-94.5C.
Example 43
2-(9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-
carbazol-1-Y:1 ) ethanol
_ _
Following the procedure of Example 5, but
using a mixture of 9-p-chlorobenzyl-6,8-difluoro-
- ' ~ ,
.
~3~59~85
5810P/5518P - 79 - 17323IB
1,2,3,4-carbazol-1-yl-acetic acid ethyl and isopropyl
esters from Example 34 as starting materials, the
title compound is obtained.
; 5 Example 44
(-) or ( t) 2-(9-p-Chlorobenzyl-6,8-difluoro-1,2,3,4-
tetrahydrocarbazol-l-yl)ethanol
Following the procedure of Example 5, but
using (-) or (+) 9-p chlorobenzyl-6,8-difluoro-
10 1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid from
Example 37 or 38 as starting material, the title
compounds are obtained.
Example 45
15 9-o-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocar-
bazol-l-yl-acetic acid
A solution of 200 mg of 6,8-difluoro-1,2,3,4-
tetrahydrocarbazol-l-yl-acetic acid from Example 34
step II in 8 cc of DMF was added portionwise 40 mg of
sodium hydride. The resulting mixture was stirred
for 30 minutes at room temperature and 185 mg of
o-chloro-benzyl bromide was then added. After
stirring overnight at room temperature, the resulting
mixture was diluted with water and washed with
ether. The aqueous layer was acidified with (lN) HCl
and extracted with ether. The ethereal layer was
washed with brine, dried over Na2SO4 and
evaporated to dryness. The crude product was
purified on preparative plates (silica gel) eluting
with CHC13:MeOH:NH4OH (8:4:1) to yield 98 mg of
pure title product. m.p. 197-198C.
~: ::: ~
,.. ~,.......... .
'
5810P/5518P - 80 ~ 17323I~
Example 46
9-(2,4-Dichlorobenzyl)-6,8-difluoro-1,2,3,4-tetra-
hYdrocarbazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting 2,4 dichlorobenzyl chloride or
o-chlorobenzyl bromide as starting material, the
title compound was obtained; m.p. 160-161C.
Example 47
10 9-p-Methylthiobenzyl-6,8-difluoro-1,2,3,4-tetrahydro-
carbazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting p-methylthiobenzyl chloride for
o-chlorobenzyl bromide as starting material, the
15 title compound was obtained. m.p. 145-146C.
Example 48
9-p-Methylsulfinylbenzyl-6,8-difluoro-1,2,3,4-tetra-
hydrocarbazol-1-yl-acetic acid
Following the procedure of Example 45, but
substituting p-methylsulfinylbenzyl chloride for
o-chlorobenzyl bromide as starting material, the
; title compound was obtained. m.p. 186-188C.
.
Example 49
9-p-Methylsulfonylbenzyl-6,8-difluoro-1,2,3,4-tetra-
hydrocarbazol-l-yl-acetic acid
To a cold solution of (0C) of 4.0 g of
6,8-difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic
acid in 75 cc of tetrahydrofuran was added dropwise
'~ ~ 46.3 cc of a solution of KHMDS in toluene ~0.684 M)
i ~ and stirred for 10 minutes. To the resulting cold
:
.
:' : .
,
'
~3~ 35
5810P/5518P - 81 - 173231B
(0C) solution was added dropwise 3.7 g of a solution
of p-methylsulfonylbenzyl chloride in 12 cc of
tetrahydrofuran. The reaction mixture was then
stirred at room temperature for 2 hours. The
reaction mixture was diluted with water and washed
with ether. The aqueous layer was acidified with
(lN) HCl and extracted with ethyl acetate. The
organic layer was washed ~ith brine, dried over
Na2SO4 and evaporated to dryness. The residue
was triturated with a mixture of ethyl acetate:hexane
(3:7) and filtered to yield 5.1 g of the title
product. m.p. 217-219C.
Example 50
(-)9-p-Methylsulfonylbenzyl-6,8-difluoro-1,2,3,4-
tetrahYdrocarbazol-l-yl acetic acid
Following the method of Example 7, but using
1(-) ephedrine and 9-p-methylsulfonylbenzyl-6,8-
difluoro-1,2,3,4-tetrahydrocarbazol-1-yl-acetic acid
from Example 49 as starting materials, the title
compound was prepared [a]D = -56.C (methanol).
Example 51
(+)9-p-Methylsulfonylbenzyl-6,8-difluoro 1,2,3,4-
tetrahYdrocarbazol-l-yl-acetic acid
Following the method of Example 50, but
using d(+) ephedrine, the title compound was prepared
[a]D = +56.0 (methanol).
:
s
5810P~5518P - 82 - 17323IB
Example 52
9-p-Trifluoromethylbenzyl-6,8-difluoro-1,2,3,4-tetra-
hydrocarbazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting p-trifluoromethylbenzyl bromide for
o-chlorobenzyl bromide as starting material, the
title compound was obtained. m.p. 176-177C.
ExamPle 53
10 9-p-Fluorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocar-
bazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting p-fluorobenzyl bromide for o-chlorobenzyl
bromide as starting material, the title compound was
15 obtained. m.p. 195-196C.
Example 54
9-m-Chlorobenzyl-6,8-difluoro-1,2,3,4-tetrahydrocar-
bazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting m-chlorobenzyl bromide for o-chloro-
benzyl bromide as starting material, the title
compound was obtained. m.p. 188-189C.
Example 55
9-p-Carbomethoxybenzyl-6,8-difluoro-1,2,3,4-tetra-
hydrocarbazol-l-~l-acetic acid
Following the procedure of Example 45, but
substituting p-carbomethoxybenzyl chloride for
o-chlorobenzyl bromide as starting material, the
title compound was obtained. m.p. 169-170C.
~'~
:~!
` ~':
~ , ~
- .
~:,, ~ ' , . .
. ~ ' ' .
.
'
~3~S'~5
5810P/5518P - 83 - 17323IB
Example _
9-p-Dimethylcarboxamidobenzyl-6,8-difluoro-1,2,3,4-
tetrahydrocarbazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting p-dimethylcarboxamidobenzyl chloride for
o-chlorobenzyl bromide as starting material, the
title compound was obtained. m.p. 208 210C.
Example 57
10 9-p-Acetylbenzyl-6,8-difluoro-1,2,3,4-tetrahydrocar-
bazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting p-acetylbenzyl chloride for o-chloro-
benzyl bromide as starting material, the title
15 compound was obtained. m.p. 163-164C.
Example 58
9-p-Dimethylaminosulfonylbenzyl-6,8-difluoro-1,2,3,4-
tetra-hydro carbazol-l-acetic acid
Following the procedure of Example 45, but
substituting p-dimethylaminosulfonylbenzyl chloride
for o-chloro benzyl bromide as starting material, the
title compound was obtained m.p. 200-202C.
:
Example 59
9-p-Acetamidobenzyl-6,8-difluoro-1,2,3,4-tetra-hydro
carbazol-l-yl-acetic acid
SteP I
Following the procedure of Example 45, but
~ 30 substituting p-nitrobenzyl bromide for o-chlorobenzyl
:
:~ :
~:
,, . . ~ ., . ~ . :
:
.
5810P/5518P - 84 - 17323I~
chloride as starting material, the crude 9-p-nitro-
benzyl-6,8-difluoro-1,2,3,4-tetcahydrocarbazol-1-yl-
acetic acid was obtained.
S Step II
The crude acld from step I was dissolved in
ether and esterified with diazome~hane. The reaction
was monitored by TLC. The resulting solution was
evaporated to dryness and the oily residue was
chromatographed on flash silica gel column eluting
with ethylacetate:hexane mixture (1:4) to afford 4.1
g (from 4.1 g of
6,8-di~luoro-1,2,3,4-tetra-hydro-carbazol-1-yl-acetic
acid used in step I) of pure methyl
9-p-nitrobenzyl-6,8-difluoro-1,2,3,4-tetra-
hydro-carbazol-l-yl-acetate.
Step III
To a solution of 4.0 9 of ester from step II in 40cc
of ethyl acetate and 70 cc of ethanol was added 400
mg of Pd/c (I0~) and the resulting misture was
hydrogenated on the parr for 90 minutes under 30 psi
of hydrogen. The reaction mixture was filtered on
celite~ and the filtrate was evaporated to dryness
leaving 3.5 g of the aminoester derivative as a foam.
Step IV
To a solution of 595 mg of the aminoester derivative
; from step III and 0.325 cc of triethylaminP in 10 cc
of tetrahydrofuran was added dropwise 0.132 cc of
acetyl chloride and the resulting mi~ture was stirred
,
`~:
~3~
5810P/5518P - 85 - 17323IB
for 30 minutes at room temperature. The reaction
mixture was diluted with water and ether. The ether
layer was decanted, washed with brine, dried over
Na~S04 and evaporated to dryness. The residue
was triturated with a mixture of ethylacetate:hexane
(3:7) and filtered to afford 600 mg of the
acetamidoester derivative.
Step V
A solution of 600 mg of the acetamidoester
derivative from step IV in a 20 cc mixture of (2.5N)
NaOH:ethanol (1:1) was stirred for 30 minutes at room
temperature. The reaction mixture was acidified with
(lN) HCl and the precipitate was filtered, washed
with water and air-dri~d to afford 500 mg of the
title product m.p. 237-239C.
Example 60
9-p-Methylsulfonamidobenzyl-6,8-difluoro-1,2,3,4-
tetrahydro carbazol-l-Yl-acetic acid
Following the procedure of Example 59, step
IV and step V, but substituting methanesulfonyl
chlaride for acetyl chloride as starting material,
the title produce was obtained m.p. 196-198C.
~- 25
Example 6l
9-p-Methylureidobenzyl-6,8-di~luoro-1,2,3,4-tetra-
hydrocarbazol-l-yl-acetic acid _ _
~; Step I
To a solution of 538 mg of the aminoester
~ ; derivative from Example 59 step III in 10 cc of
,~
.
:
~3(~ 5
5810P/5518P - 86 - 17323IB
tetrahydrofuran was added 0.3 cc of methylisocyanate
and the resulting solution was stirred overnight.
The reaction mixture was diluted with water and ether.
The ether layer was decanted, washed with brine, dried
over Na2SO4 and evaporated to dryness leaving the
methyl ureido ester derivative.
Step_II
Following the procedure of Example 59, Step V
but substituting the methyl ureido ester derivative
of Step I for the acetamidoester derivative as
starting material, the title product was obtained
m.p. 218C (dec).
Example 62
9-p-Methoxybenzyl~6,8-difluoro-1,2,3,4-tetra-hydro
carbazol-l-yl-acetic acid
Following the procedure of Example 45, but
substituting p-methoxybenzyl chloride for o-chloro
benzyl bromide as starting material, the title
compound was obtained m.p. 149-151C.
i
::
~::
;~ ~
' ~
