Note: Descriptions are shown in the official language in which they were submitted.
~ 7~39~ 2302A FTE
ANTIHYPERTENSIVE AGENTS, PHARMACEUTICAL COMPOSITIONS
CONTAINING THEM AND PROCESSES FOR THE PREPARATION
OF THE AGENTS AND cor1posITIoNs
The present invention relates to (benzothia~
diazine, benzamido, and benzenesulfonyl)-phanyl-
substituted carboxyalkyl dipeptide compounds which have
antihypertensive activity. Compounds of this invention
are useful as antihypertensive agents, in the treatment
of congestive heart failure and glaucoma. In addition,
compounds of this invention are useful as diuretics.
More particularly, this invention relates to
compounds represented by the following formula:
~1 ' .,
C==O R3
z~ y (CH2)m--C--N~IH-~-W~CoR4
,~.
!,
ii39~ii
wherein W is
~5 --~ _ c Z q I I q (~Z~q
R5 R N 1--
II III IV V
n is O or 1; m is O to 2
p and q are each 0, 1 or 2, provided that the
sum of p and q is 1 or 2, and that in formula V, p is not
O;
Y is -CH2-, -CH20-, or -CH2S-, attached at the
2 or 4 position of the phenyl group;
z is
~o~R R HN02S ~ _
R6HN02S S 2 J Cl
VI VII
wherein A is Cl or CF3; o
is (CH2)u ~ -CH20-~ -CH2S-; -CH2cNH-;
G is -CoNR7(cH2)t-~ or -So2NR7(cH2)t-; t is O
or 1;
R1 and R4 are independently hydroxy, alkoxy
having from 1 to 8 carbon atoms, K-Xr-(CH~)s-O-, wherein
K is phenyl, substituted phenyl, 1- or 2-naphthyl, X is
oxygen or sulfur, r is O or 1 and s is O or 4, and
wherein the substitutents on the phenyl are chosen from
group M, wherein M is halogen, hydroxy, trifluoromethyl,
alkoxy having from 1 to 6 carbon atoms, alXyl from 1 to 6
carbon atoms, 2- and 3-furanyl, 2- and 3-thienyl and
phenyl (which phenyl group may be substituted with
`
,
.
-3~
halogen, hydroxy, trifluoromethyl, alkoxy having from 1
to 6 carbon atoms or alkyl having from 1 to 6 carbon
atoms), provided that when s is zero, r is zero, -OCH2-
OCO-alkyl wherein the alkyl has from 3 to 8 carbon atoms,
-OCH2CO- phenyl, wherein the phenyl may be substituted
with group M, 1-glyceryl,
~ -OCH2~H2
R2, R5, R6 and R9 are hydrogen or lower alkyl;
R3 is hydrogen, lower alkyl or amino lower
alkyl;
R7 is hydrogen, lower alkyl or
phenyl(lower)alkyl; --
R8 is hydrogen, lower alkyl, phenyl, or phenylsubstituted by group M;
u is 1 or 2;
and the pharmaceutically acceptable salts thereof.
Preferred compounds of the invention are those
wherein W is represented by formula III, IV or V. When W
is of formula III or IV, preferred values for p and q are
0 and 1, respectively; when W is of formula V, preferred
values of p, q and n are 1, 1 and 0 respectively.
Two additional ~roups of preferred compounds
are that wherein R2 and RS are hydrogen, and that wherein
R4 is hydroxy.
Particularly preferred compounds are those
wherein W is represented by formula III or V; n, pr q~ Y~
R2, and XS are as defined above for preferred compounds;
R3 is methyl or amino butyl; Z is of formula VI, wherein
A is chlorine, or Z is of formula VII and G is -CONH-CH2-
,
-4~ 7~
or -S02NH-CH2; R6 and R7 are hydrogen or methyl; and
is hydroxy, ethoxy, methoxy, phenoxyethoxy, or
pivaloyloxymethoxy.
As used herein, "lower alkyl" means straight or
branched chain hydrocarbon radicals of from 1 to 6
carbons, e.g. methyl, ethyl, propyl, ispropyl, butyl, t-
butyl, pentyl and hexyl. Similarly, "lower alkoxy" means
straight or branched alkoxy radicals having 1 to 6 carbon
atoms, e.g. methoxy, ethoxy, propoxy, butoxy, iso-butoxy,
pentoxy and hexyloxy. "Halogen" means fluorine, chlorine
and bromine.
Compounds of the instant invention include
various stereoisomers. Preferred stereoisomers are those
in which the absolute configuration at each of the three
carbon atoms adjacent to both a nitrogen and a carbonyl
group corresponds most closely to the absolute configura-
tion of L-amino acids~
The compounds of this invention form salts with
various inorganic and organic acids and bases which are
also within the scope of the invention. Such salts
inc~ude ammonium salts, alkali metal salts, e.g. sodium
and potassium salts, and alkaline earth metal salts, e.g.
calcium and magnesium salts. Salts with organic and
inorganic acids may be prepared, e.g., HCl, HBr, H2S04,
H3P04, methanesulfonic acid, toluenesulfonic acid, maleic
acid, fumaric acid and camphorsulfonic acid. The non-
toxic pharmaceutically acceptable salts are preferred,
although other salts are also useful, e.g., in isolating
or purifying the product. The acid salts (e.g. HCl and
maleate) are preferred, especially the hydrochloride.
The salts may be formed by conventional means,
as by reacting the free acid or base forms of the product
with one or more equivalents of the appropriate base or
acid in a solvent or medium in which the salt is
insoluble, or in a solvent such as water which is then
.:
,
: . ' '
~.s~ 3~
removed 1n vacuo or by exchanging the cations of an
existing salt for another cation on a suitable ion
exchange resin.
Compounds of formula I may be prepared by
several rou~es using methods known in the art.
For example, compounds of formula I may be
prepared by condensing an amino acid of formula VIII with
a keto compound of formula IX in the presence of a
reducing agent such as sodium cyanoborohydride in a
solvent such as ethanol:
~o~l '1
~} 2~m 1 ~H2 ~ R3J~ ~W-CoR4
VIII IX
wherein Z, Y, Rl, R2, R3, R4, m and W are as defined
above.
Starting materials of formula VIII may be
prepared by well known methods. An example of such a
preparation is shown below, wherein 5-(4-[6-chloro-7-
sulfamoyl-3,4-dihydro-1,1-dioxo-1,2,4-benzothiadiazinyl-
3 )methoxy]benzyl)cysteine (formula XVI) is prepared,
starting with 2-bromo~ diethoxyethane and p-cresol:
CH3C112o~ t-9U021: CH3CH2
CH CH ~ H2H~CH3 DMF ~Hz O~CH3
X Xl Xll
XXI N~3S CH3CH2 /--~
CC~ ~~ ~C~28r
XIII
C02HNaOH ~ o ~ CH2SCX2CH--NH
XISI ~ H5CH2CHN112 ~t20~TNF C~13t:H2
XIY
H2NO25 S2NH2 Cl H COOH
XTV C~XNH2 I~Cl H2N02S~FCH2~) ~}CH2-SCH2-CH-NH2
XV XVI
`
.
-6- ~ ~'7~3~
Starting materials of formula IX may be
prepared by reacting an amino acid derivative XVIII with
an ~-keto acid chloride XVII to give the substituted
amino acid:
H-W-C-R4 + o=c-coc~ R3J ~ ~ W-COR4
XVIII XVII o
IX
The reaction is carried out in an inert solvent such as
methylene chloride in the presence of a base such as
triethylamine or pyridine.
Compounds of formula I wherein Y is -CH2-, and
Z is a group of formula VII, are preferably prepared by
the reaction of an acid of formula XIX with an amine of
formula XX:
R6N02S ~O~ R3 DEC
Cl ~ H ~ CH2CH2CHNHCHCO2H ~ HW-CoR4 HYDROXYB~NZOTRIAZOLE
DMF
XIX XX
.
wherein ~1, R3, R4, R6 and W are as defined above, and
"DEC" refers to 1-~3-dimethylaminopropyl)-3-ethyl
carbodiimide HCl.
Compounds oE formula XIX may be prepared from
known starting materials by techniques well known in the
art. The following reaction scheme describes a method of
preparing a compound of formula XIX (designated formula
XIXa):
.-
-7~ '7~
so2~
02N ~Ctl2CH2C~NH2
XXI I ~O~Cl
.~ ~
COaEt 3~r-cHco2 But EtO2~ CH3
02N ~'CH2~2~ 2 ~-- ~32~C~?2cH25H~!~H
XXI I ! ~p.~-~
~ ,
H2N-~CH2CH~NCl~C021~ut H~TlClt Et2~ 1~H3
XXV 02 ii ~5 ~02N~H2CH2 11~ H CO2~U~
l~coc~ XXIV
02 o E~02~ ~/3
~C~C~2e~taGHl~HCH-C02
" XXV~
CF3C02jl
C~ C~ CH2cH2~plH~co2H
XIX~
.
.. . .
-8~ 3~
A preferred method for the conversion of
compounds of formula XXII to XXIV in the reaction scheme
above which eliminates the preparation of diastereomers
of formula XXIII and their subsequent separa~ion is to
use the specific diastereomer t-butyl 2R-(trifluoro-
methanesulfonyloxy)propionate (triflate reagent). In
this process, the single diastereomer of the
triflate reagent reacts by nucleophillic displacement
with the -aminoacid ester (e.g., a compound of formula
XXII) to give a high yield of the corresponding specific
single diastereomer of the resulting monoamino
dicarboxylic acid ester (e.g., a compound of formula
XXIV).
Since the preEerred compounds of formula I have
an S-configuration at the carbon to which R3 is attached
the triflate reagent used herein is the 2-R diastereomer
(see Preparation 4). However, the process is generally
applicable to converting a broad range of ~-aminoacid
esters to the desired specific single diastereomer by
using the appropriate triflate diastereomer. In place of
the t-butyl ester of the triflate, other lower alkyl
esters or the benzyl ester may be used.
The reaction proceeds at room temperature
(i.e., 20-50C, preferably about 25C) in an inert
solvent such as chloroform, dichloromethane, carbon-
tetrachloride, benzene, toluene, or ethyl acetate in the
presence of a base such as a tertiary amine ~e.g.,
triethylamine or N-methylmorpholine). The reaction is
complete in about 24 hours or less. The desired compound
is recovered from the reaction mixture and purified by
standard techniques. For example, the crude product is
extracted into an organic solvent such as ether and
concentrated to a crude oil, which is then purified by
column chromatography to yield the desired specific
diastereomer.
,
~ .
_9~ 3~ ~ ~
Carboxy-protected compounds of formula XX are
prepared by methods well known in the art. See, for
example, Neustadt et al. in European Patent Application
50,800, published May 5, 1982.
Alternativ~ly, compounds of formula I wherein Y
is ~CH2-, and Z is a group of formula VII may be prepared
by the reaction of an acid chloride of formula XXVII with
a dipeptide of formula XXVIII:
R6HN02S COCl COR I 3
C 1~ + H2~H2~CHN8-CH-C-W-CoR4 I
~ NEt3
XXVI I :CXVI I I
wherein R1, R3, R4, R6 and W are as defined above.
Compounds of formula XXVII may be prepared by
known methods.
Compounds of formula XXVIII may be prepared by
well Xnown methods, an example of which is shown in the
following reaction scheme:
EtO21~ CH3
XXIV CF3Co2H 02N ~ H2CH2~HNH~H-Co2H
XX~X
hyc ~oxybenzot~la~ole
C02CH2P
UIN ~CH2CH,~C02 CH2Pb
XXX l 02N ~Y2ECH~ tfH ~HC~
XXX
. .
--10--
3~3~
H2-PdJC EtO2~ ~3
XX3~1 - P H7N~(CHz~ C::-NHCH-C ~ C0
XXVIIIa
. . .
Alternatively, XXX may be hydrogenated directly
to give XXVIIIa using a catalyst such as palladium on
carbon.
Alternatively, XXXII may be reacted with a
compound of formula XIXa to give a compound of formula I
wherein R4 is benzyloxy. The benzyloxy group may be then
removed by hydrogenation ~ith an appropriate catalyst
such as palladium on carbon.
The known coupling methods above include amino
group protection during the coupling reaction, for
example by M-formyl, N-t-butoxycarbonyl and N-carbo-
henzyloxy groups, followed by their removal to yield
compounds of formula I. Furthermore, the CoR4 function
wherein R4 is OH may be protected by removable ester
groups such as benzyl, ethyl, t hutyl and the like.
If desired the so obtained compounds can be
subjected to salt formation and/or esterification and/or
trans-esterification and/or de-esterification accordin~ t~ :
known methods. If necessary tne i~ idual isomers can be
be isolated according to known methods.
The more complex esters at Rl (i.e., Rl is
other than- hydroxy or alkoxy) are most conveniently
prepared by esteriEying compounds of formula I wherein
is hydroxy and R4 is benzyloxy with the appropriate
.~ .
reagent, then removing the benzyl ester at R4~ For
example, compounds of formula I where Rl is hydroxy and
R4 is henzyloxy may be reacted with chloromethyl pivalate
to obtain the corresponding pivaloyloxymethyl ester.
The following examples Eurther illustrate the
preparation of compounds of this invention.
''
.,
.
:
.. . .
-12
PREPARATION 1
1-Pyruvoyl-cis,syn-Octahydro-1H-Indole-2(S)-Carboxylic
A
Ao Dissolve 27.0 g of ethyl indole-2-carboxylate in
250 ml of trifluoroacetic acid~ Add 2.05 g of platinium
oxide, hydrogenate the mixture at 50 lb/in2 at room
temperature. Filter the mixture and concentrate the
filtrate in vacuo to give a residue. Suspend the residue
in ether and treat with cold dilute sodium hydroxide
solution. Dry the organic layer over magnesium sulfate
and concentrate it to give ethyl octahydroindole-2-
carboxylate, a pale yellow oil.
B. Dissolve 116 g of 10-d-camphorsulfonic acid in 1
liter of warm ethyl acetate and add a solution of 86 g of
the product of part A in 1 liter of ethyl acetate. Allow
the mixture to crystallize, heat to reflux, cool to room
temperature, and filter. Recrystallize the filter cake
from a mixture of 500 ml of isopropanol and 1800 ml ethyl
acetate, filter and dry the crystals to obtain 2(S)-
carboethoxy-cis,syn-octahydro-lH-indole, d-10-
camphorsulfonate, m~p. 192-193C.
C. Slurry 10 g of the product of part B in 1 liter
of ether, adjust to pH 11 with aqueous sodium hydroxide,
and stir for 5 minutes. Wash the organic layer with
sodium chloride solution, dry over magnesium sulfate,
filter, and evaporate in vacuo at room temperature to
obtain 2(S)-carboethoxy-cis,syn-octahydro-1H-indole as a
colorless oil. Dissolve the resultant oil in 50 ml of
methanol containing 23 ml of 1N sodium hydroxide, stir at
25C for 30 minutes, adjust to pH 7 with 1N hydrochloric
acid, and evaporate ~he solvent to give cis,syn-
octahydro-1H-indole-2~S)-carboxylic acid.
_13- ~ ~'7~33~
D. Cool 23 ml of benzyl alcohol to 0C under
nitrogen and add 5.95 g of thionyl chloride dropwise over
IS minutes, maintaining the temperature at O~C. Add the
product of part C, stir for 1 hour at 0C, then stir for
24 hours at room temperature. Pour the resulting mixture
into 500 ml of ether, stir 1 hour under nitrogen, then
allow to stand under nitrogen until the solution is
clear. Decant the supernatant, wash the precipitate with
25 ml of ether, then slurry the precipitate in 200 ml of
ether and adjust to pH 8-9 with 1-N sodium hydroxide.
Stir 5 minutes, wash the organic layer with sodium
chloride solution, dry over magnesium sulfate, filter and
evaporate in vacuo at room temperature to obtain cis,syn-
octahydroindole-2(S)-carboxylic acid, benzyl ester as a
colorless oil (TLC in ether: one spot, Rf 0.3).
E. To 26 g of the product of part D in 100 ml of
dichloromethane and 7.8 ml of pyridine add 11.0 g of
pyruvoyl chloride and stir the resulting mixture at room
temperature. Extract the reaction mixture with water and
dry the organic layer over magnesium sulEate.
Concentrate the dichloromethane solution in vacuo and
distill the residue to give 1~pyruvoyl-cis,syn-octahydro-
1H-indole-2tS)-carboxylic acicl, benzyl ester.
F. To 20 g of the product from part E in 400 ml of
ethanol, add 2.0 g o~ 10% palladium-on-charcoal and
hydrogenate at 50 psi at room temperature. Filter the
resulting mixture and concentrate the filtrate in vacuo
to give the title compound.
.
' . ' :
,
3~36
PREPARATION 2
1-{N-[1(S)-Ethoxycarbonyl-2-~4-aminophenyl)ethxl]-(S)-
alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid
Method I
A. To a solution of 4-nitrophenylalanine, ethyl
ester, hydrochloride (54.0 g) in dry dimethylformamide
(400 ml), add t-butyl 2-bromopropionate (112.3 g) and
triethylamine (76 ml) and heat the resulting mixture at
70 for 18 hours under a nitrogen atmosphere. Pour the
reaction mixture into water and extract with methylene
chloride (6 x 300 ml). Combine the organic layers, dry
over magnesium sulfate and concentrate in vacuo to give a
liquid (contains DMF). Chromatograph this liquid on a
Prep 500 (3 silica gel cartridges) using hexane (8 l)
then hexane:ethylacetate 4:1 and isolate N-[1(S)-
ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(R)alanine,
t-butyl ester, [~]D26 - +24.7 (methanol), and N- 1(S)-
ethoxycarbonyl-2-(4-nitrophenyl)ethyl] (S)alanine,
t-butyl ester.
. Add cold trifluoroacetic acid (600 ml) (ice
bath) to N-[1(S)-ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-
(S)-alanine, t-butyl ester (25.5 g) and stir the
resulting mixture at room temperature under a nitrogen
atmosphere for 4 hours. Concentrate the solution in
vacuo to give a viscous oil. Triturate the viscous oil
with hexane (3 l) and then ether to yield N-~1(S)-
ethoxycarbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine.
C. To a solution of the product of Step B (17.84
g), cis,~ octahydro-1H-indole-2(S)-carboxylic acid,
benzyl ester (11.50 g), and triethylamine (4.46 g) in
dimethyl~ormamide (450 ml) at 0-5 under a nitrogen
atmosphere, add 1-hydroxybenzotriazole (6.76 g) and
_15~ 3~
1-~3-dimethylaminopropyl)-3-ethylcarbodiimide,
hydrochloride (16O13 g). Stir the reaction mixture at
0-5 for 25 minutes and then at room temperature for 90
minutes. Concentrate the reaction mixture in vacuo and
partition between dichloromethane and saturated sodium
bicarbonate solution. Dry the organic layer over
magnesium sulfate and concentrate in vacuo to give a
viscous oil which contains 1-{N-[1(S)-ethoxycarbonyl-2-
~4-nitrophenyl)ethyl]-(S)-alanyl}-cis r syn-octahydro-1H-
indole-2(S)-carboxylic acid, benzyl ester.
D. Hydrogenate the product from Step C above in
absolute ethanol (250 ml) in the presence of 10%
palladiu~ on carbon at 60 psi in a Parr Shaker Apparatus.
Remove the catalyst by fiitration through celite and
concentrate the filtrate in vacuo to give a foam.
Chromatograph the foam on the Prep 500 (3 cartriges)
using chloroform:methanol:ammonium hydroxide 200:30~5 as
eluant to give the title compound ~a]D26 = -44.0~ ~MeOH).
Method II
A. To a solution of 4-nitrophenylalanine,
ethylester, hydrochloride (2.3 g) in dichloromethane (10
ml), add triethylamine (2.55 ml) and then t-butyl 2(R)-
(trifluoromethanesulfonyloxy)propionate (2.80 g) (see
Preparation 4) in dichloromethane (10 ml). Stir the
resultinq solution at room temperature for 20 hours.
Concentrate the reaction mixture, add diethyl ether and
extract with salt solution. Dry over magnesium sulfate
and concentrate the ether solution ln vacuo to give an
oil. Place the oil on a column of silica gel t100 ml,
60-200 mesh) and elute with diethyl ether:hexane 60:40 to
~ive N-[l(s)-ethoxycarbonyl)-2-(4-nitrophenyl)ethyl]-(s)
alanine, t-butyl ester.
.
:
.
-16~ 3~6
B. to D. Proceed as described in Method I.
PREPARATION 3
1- {N [ 1 ( S ) - E thoxycarbonyl- 3 ( 4- aminophenyl)pro~yl]-(S)-
alanyl}-cis,syn-octahydro-1H-indole-2(S)-carboxylic acid
Method I
A. To a solution of 2-acetamido-4-(4-nitrophenyl)-
butyric acid (57.65 g) in hot 95% ethanol (1000 ml) add
d~ -methylbenzylamine (25.2 g) in hot 95~ ethanol
(125 ml), cool the solution slowly and keep at room
temperature 18 hours. Collect the solid and wash with
cold 95% ethanol, and dry to give an orange-yellow
solid. Recrystallize this solid from 95% ethanol treated
with charcoal to give 2(S)-acetamido-4-(4-nitrophenyl)-
butyric acid, d-(~ -methylben~yl amine salt [~]D26
= +45.6 (MeOH), m.p. 211-213C.
B. Suspend the product of part A (29.00 g) in ether
(500 ml) and add 1N Nao~ (150 ml). Separate the aqueous
solution and wash with ether. Cool the aqueous solution
in an ice-NaCl bath, add concentrated hydrochloric acid
to pH 1 and stir the resulting mixture for 1 hour.
Remove 2(S)-acetamido-4-(4-nitrophenyl)butyric acid, a
white solid, [~]D26 = + 83.9 (MeOH), m.p. 266C.
C. Treat the compound prepared in part B above
(18.65 g) with 6N hydrochloric acid (700 ml) and heat the
resulting mixture under reflux for 2.5 hours. Con-
centrate the solution ln vacuo to give 2(S)-amino-4-(4-
nitrophenyl)butyric acid, hydrochloride, a solid, m.p.
186-189C, [~]D26 = ~46.9 (MeOH).
D. Hsat the compound prepared in part C (19.30 9)
in absolute ethanol saturated with hydrogen chloride acid
(400 ml) under reflux for 1-1/2 hour. Remove the solvent
;
:
.
-17- ~ 3~
_ vacuo and triturate the residue with ether to give 2(S)-
amino-4-(4-nitrophenyl)butyric acid, ethyl ester,
hydrochloride, a white solid m.p. 288.5 [~]D26 ~ 40.6
(MeO~)~
E. Treat the compound prepared in part D (18.00 g)
in dry dimethylformamide (250 ml) with t-butyl 2-bromo-
propionate (35.20 g) and triethylamine (18.90 g) as
described in Preparation 2A. Use Prep 500 (2 cartridges)
and hexane (6 l) and then hexane/ethyl acetate 8:1 as
eluants and isolate N-~1(S3-ethoxycarbonyl-3-(4-
nitrophenyl)propyl~-(S)-alanine, t-butyl ester [~]D26 =
-8.0 (MeOH).
F. To the product of part E (6.90 g) at 0 5 ~ add
trifluoroacetic acid (500 9) and treat the resulting
mixture as described in Preparation 2B and isolate N-
[1(S)-ethoxycarbonyl-3-(4-nitrophenyl)propyl]-(S)-
alanine, trifluoroacetic acid salt, a viscous oil.
G. To a cold 50 5) solution of the product of part
F (6.68 g) and cis,syn-octahydro-1H-indole-2(S)-
carboxyli~ acid, benzyl ester (3.95 g) in anhydrous
dimethylformamide (250 ml) and triethylamine (3.38 g),
add 1-hydroxybenzotriazole (2.80 g) and 1-(3-dimethyl-
aminopropyl)-3-ethylcarbodiimide, hydrochloride (5.85 g)
and stir the resulting mixture at 0-5C for 30 minutes
and then at room temperature for 1.5 hour. Pour the
reaction mixture into saturated sodium bicarbonate and
extract with dichloromethane (2 x 1 l). Dry the organic
layer over magnesium sul~ate and concentrate in vacuo to
give a viscous oil. Chromatograph this oil on the~Prep
500 ~2 cartridges) using ethyl acetate:hexane 3:20 and
then 1:1 and isolate 1-~N[l(S)-ethoxycarbonyl-3-(4-
nitrophenyl)propyl]-(S)-alanyl},-cis,syn-octahydro-1H-
indole-2(S)-carboxylic acid, benzyl ester.
:
. . . :
~ . .
'7~ 6
H. Hydrogenate the product of part G (4.69 9) in
absolute ethanol (250 ml) in the presence of 5~
palladium-on-charcoal (0.50 g) at 60 psi in a Parr Shaker
Apparatus. Remove catalyst by filtration and concentrate
the filtrate to give the title compound, a foam 1~]D26 =
-29.7 (MeOH)~
Method II_
A. to ~. Proceed as described in Method I.
E. Treat the product of part D as described in
Preparation 2, Method II, part A to obtain N-[1(S)-
ethoxycarbonyl)-3-~4-nitrophenyl)propyl]-(S)-alanine,
t-butyl ester.
F. to H. Proceed as described in Method I.
PREPARATION 4
; t-Butyl 2R-(Trifluoromethanesulfonyloxy)Propionate
A. Add 2S-(~æ-toluenesulfonyloxy)propionic acid (4 4
g) to a cold solution of 10 ml isobutylene and 0.4 ml
concentrated sulfuric acid in 30 ml methylene chloride in
a pressure vessel, seal, and agitate at room temperaure
for 48 hours. Pour into 50 ml 15% sodium carbonate
solution, dry over magnesium sulfate and concentrate to
obtain t-butyl 2S-(p-toluenesulfonyloxy)propionate as an
oil (NMR 1.37). Distilled material (Kugelrohr, 120)
has [~]D26 = -45.9 (EtOH, c-1).
B. Combine the product of part A (100 g) with
acetic acid (40.0 g) and triethylamine (67.2 g) in 200 ml
dry DMF~ ~eat at 65 for 20 hours. Partition with 2 l
each ether and water, and wash the ether with citric
acid, then with sodium bicarbonate solution. Dry and
concentrate the ether solution to obtain t-butyl 2R-
acetoxypropionate as a colorless liquid, bp 50C/0.1 mm.
,: '
'
,
.
- l 9- ~
C. Combine the product of part B ~62.6 9) with
ethylenediamine (11.6 g) and heat at 70 for 24 hours.
Allow to cool, add 300 ml ether and filter. Wash the
ether with water, 10% citric acid, and then in sodium
bicarbonate solution. Dry and concentrate the ether
501ution to leave a colorless oil. Crystallize from
hexane at ~20 to ~ive t-butyl 2R-hydroxypropionate as
white needles, m.p. 41-2Co
D. Combine the product of part C (7.3 g) with
pyridine ~4.0 g) in 50 ml methylene chloride. Cool to
-5C, and add dropwise a solution of trifluoro
methanesulfonic anhydride (14.1 g) in 25 ml methylene
chloride. Allow the reaction to reach room temperature,
then wash successively with water, 1N sulfuric acid and
1N sodium bicarbonate solution. Dry and concentrate the
methylene chloride solution to leave the title compound
as a colorless oil.
NMR (in CDC13) = 5.10 q; 1.73 d; 1.50 s.
EXAMPLE 1
1-{N-[1(S)-Ethoxycarbonyl-2-[4-(3-sulfamoyl-4-
chlorobenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-
octahydro-lH-ind~le-2(S)-carboxylic acid
':
To a 0-5C solution of the product of
Preparation 2 (2.00 g) in anhydrous tetrahydrofuran (100
ml) and triethylamine (0.94 q), add a solution of 4- -
chloro-3-sulfamoylbenzoylchloride (1.61 g) in anhydrous
tetrahydrofuran ~10 ml) over a period of 30 minutes.
Stir the resulting mixture for 15 minutes at 0-5 and
then at room temperature for 18 hours. Filter the
reaction mixture and concentrate the filtrate ln vacuo to
~ive a residue. Chromatograph the residue on the Prep
; .
-20- ~ 7~
500 (1 cartridye) using chloroform:methanol: ammonium
hydroxide 200:30:5 as eluant to give the title compound,
a Eoam, [~]D26 -16.1 (MeOH).
In a similar mannerl using appropriate starting
materials, prepare the following:
1-{N-[1(S)-ethoxycarbonyl-2-[4-(4-chloro-3-N-methyl-
sulfamoylbenzamido)phenyl]ethyl]-(S)-alanyl}-cis,~L_-
octahydro-1H-indole-2(S)-carboxylic acid, [a]D26 =-18.7
(methanol).
1-{N-[1(S)-ethoxycarbonyl-3-[4-(2-hydroxy-4-chloro-5-
sulfamoylbenzamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-
octahydro-lH-indole-2(S)-carboxylic acid; ~a]D26 =-18.1
(methanol).
EXAMPLE 2
1-{N-[1(S)-Carboxy-2-[4~(4-chloro-3-sulfamoylbenzamido)-
phenyl~ethyl]-(S)-alany~}-cis,syn-octahydro-1H-indole-
2(S)-carbox~lic acid
To the product of Example 1 (0.35 9) add 0.5N
NaOH (5 ml) and stir at room temperature for 1 hour. Add
8io-Rad Resin (AG 50W-X3, 100-200 mesh, hydrogen form)
and then add to a column of the same resin. Elute with
water ~200 ml) and then water:pyridine 96:4. Concentrate
the desired fractions to give the title compound. ~3D26 =
-7.0 (MeOH).
In a similar manner, prepare l-{Nt1 (S)-carboxyl-
2-[4-(4-chloro-3-N-methylsulfamoylbenz-
amido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-
indole-2(S)-carboxylic acid, t~]D26 = 8.9 (~ethanol).
-
.
: ' :
. .
'
3~
EXAMPLE 3
1-{N-[I(S)-Ethoxycarbonyl-3-[4-(4-chloro-3-
sulfamoylbenzamido)phenyl]propyl]-tS)-alanyl}-cis, syn=
octahydro-1H-indole-2(S)-carboxylic acid
To a 0-5 solution of the compound of
Preparation 3 (1.50 g) in anhydrous tetrahydrofuran (100
ml) and triethylamine (0.68 9), add a solution of 4-
chloro-3-sulfamoylbenzoylchloride (1.11 g) and treat as
described in Example 1, except use chloroform (2 l) and
then chloroform:methanol:ammonium hydroxidelO0:30:5 as
eluants and isolate the title compound, a foam [~]D26 =
-9.1 (methanol).
In a similar manner using appropriate starting
materials, prepare 7-{N-[1(S)-Ethoxycarbonyl-3-[4-(4-
chloro-3-N-methylsulfamoylbenzamido)phenyl]propyl]-(S)-
alanyl}cis,s~n-octahydro-1 -indole-2(S)-carboxylic acid.
EXAMPLE 4
1-{N-[1(S)-Carboxy-2-([4-[(6-Chloro-3,4-Dihydro-7-
Sulfamy~2H-1,2,4-Benzothiadia2in-3-yl-l~l-Dioxide)-
Methyloxy]Phenyl]Methylthioethyl)-(S)-Alanyl}-cis,syn-
Octahydro-1H-Indole-2(S)-Carboxylic Acid
A. Combine bromoacetaldehyde diethylacetal (19.7 g)
and p-cresol (10.8 g) in dry dimethylformamide (DMF) (100
ml) and stir. Add potassium t-butoxide (9.6 g) and
continue stirring for 24 hours, then evaporate the DMF in
vacuoO Parti~ion the resultant residue between ethyl
acetate and water. Separate the organic layer, wash with
10~ aqueous sodium hydroxide followed by brine, then dry
the organic layer over sodium sulfate and filter.
Evaporate the solvent in vacuo and purify the crude
product on a silica gel column to obtain 4-~2,2-
diethoxy)ethoxy]toluene:
' . - ' ' ' - ,
~: '
-22- ~ ~t7~3~
NMR ~ = I.l2 (6H, t,CH3); 2.15 (s, 3H,-CH3);
3.55 ~q 4H, CH2-0); 3.90(d, 2H, CH2_phenyl); 4.77 (t,1H,
-CH2-); and 6.80 (m, 4H, Ar).
B. Combine N-bromosuccinamide (0.877 g) and the
product of Step A (1 g) in carbon tetrachloride (20 ml)
and stir at reflux for 18 hours. Filter the resultant
solid and evaporate the solvent in vacuo to obtain 4-
[(2,2-diethoxy)ethoxy]benzyl bromide:
NMR = 1.10 (t, 6H, CH); 3.59 (q, 4H, -OCH2);
3.86 (d, 2H, C-CH20); 4.31(s, 2H, CH2-Br); 4.70 (t, 1H,
-CH-); 7.00 (m, 4H, Ar).
C. Combine methyl alcohol (20 ml) and 19 M sodium
hydroxide (10 ml). Add L-cysteine (0.1 g), stir for 15
minutes, then add the product of Step B and stir at room
temperature overnight. Adjust the resultant solution to
approx. pH 7 and filter the resultant solid. Wash the
solid with ether and dry under vacuum to obtain (S)-~4-
[(2,2-diethoxy)ethoxybenzyl3cysteine.
D. Dissolve 4-amino-6-chloro-1,3-benzene-
disulfonamide (0.74 g) in dimethoxyethane (10 ml), add
the product of Step C (0.99 g), stir while heating to
reflux, and add 2 drops of concentrated hydrochloric
acid. Reflux 4 hours, then evaporate the solvent ln
vacuo. Wash tne resultant solid with ether and dry under
vacuum to obtain S-[4-~(6-chloro-3,4-dihydro-7-sulfamyl-
2H-1,2,4-benzothiadiazin-3-yl-1,1-dioxide)methoxylbenzyl-
L-cysteine.
E. React 0.02 moles of the product of part D in 20
ml of tetrahydrofuran with 0.02 moles of the product of
Preparation 1 and add 20 ml of molecular sieves 4A (Rohm
and Haas). Stir the resulting mixture for 4 hours, add
,. ' ' ' . ' ~ ~ '
.. ' ' ' , ~ .
-23~
12 g of sodium cyanoborohydride in 20 ml oE methanol and
stir the reaction mixture 20 hours. Filter, concentrate
to dryness, and partition the residue between water and
dichloromethane. Absorb the aqueous phase on strong
acidic ion-exchange resin and elute with 4% pyridine in
water. Separate the isomers on a column of silica gel
using CHCl3: isopropanol: 7% ammonium hydroxide 1:1:1
(organic phase) as eluant to give the title compound~
EXAMPLE 5
1-~N-[?(S)-Ethox~carbonyl-2-[4-(6-chloro-3,4-dihydro-
1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-
acetamido)phenyl]ethyl]-(S)-alanyl}-cis,syn-octahydro-1H-
_dole-2(S)-carboxylic acid
A. Hydrogenate a solution of N-[1(S)-ethoxy-
carbonyl-2-(4-nitrophenyl)ethyl]-(S)-alanine, t-butyl
ester (20.0 g) (see Preparation 2, IA) in absolute
ethanol (500 ml) in the presence of 10% palladium on
carbon (1.5 g~ at 50 psi in a Parr shaker apparatus.
Remove the catalyst by filtration and concentrate the
filtrate ln vacuo to give N-[1(S)-ethoxycarbonyl-2-(4-
aminophenyl)ethyl]-(S)-alanine, t-butyl ester.
B. To a solution of the produ`ct of part A in
dimethylformamide (150 ml), add 6-chloro-3,4-dihydro-1,1-
dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetic acid
(14.4 9), 1-hydroxybenzotriazole (6.8 9) and 1-(3-
dimethylaminopropyl)-3-ethylcarbodiimide, hydrochloride
(9.6 g) at 0-5. Warm the reaction mixture to room
temperature and stir for 18 hours. Concentrate ~he
reac~ion mixture in vacuo, add dichloromethane and
concentrate in vacuo. Dissolve the residue in ethyl
acetate and extract ~ith lN sodium bicarbonate. Dry
(MgSO4) and concentrate the ethyl acetate solution ln
-24- ~,~t~J~3,~
vacuo. Chromatograph the residue on silica gel using the
Waters Prep 500 using ethylacetate as eluant to give N-
~1(S)-ethoxycarhonyl-2-[4-(6-chloro-3,4-dihydro-1,1~
dioxo-7-sulfamoyl 1,2,4-benzothiadiazine-3~acetamido)-
phenyl]ethyl]-(S)-alanine, t butyl ester.
C. Treat the product (11.0 g) prepared in Example
5B with dioxane saturated with hydrogen chloride (100 ml)
for 20 hours at RT~ Concentrate the reaction mixture ln
vacuo and tritrate the residue with anhydrous ether to
isolate N-[1(S)-ethoxycarbonyl-2-[4-(6-chloro 3,4-
dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-
acetamido)phenyl]ethyl-~S)-alanine hydrochloride salt.
D. Treat the product of part C as described in
Preparation 2I, C to obtain {1- N-[1(S)-[ethoxycarbonyl-
2-~4-(6-chloro-3,4-dihydro-1,1-dioxo-7-sulfamoyl-1,2,4-
benzothiadiazine-3-acetamido)phenyl]ethyl]-(S)-alanyl}-
cls,syn-octahydro-1H-indole-2(S)-carboxylic acid, benzyl
ester.
E. Treat the product (7.3 g) of part D with 20% ~Br
in glacial acetic acid (30 ml) at 0-5 and then stir at
room temperature for 3 hr. Concentrate the reaction
mixture in vacuo and wash the residue with ether to give
the title compound, hydrobromide.
F. Treat the product (3.0 g) of part E with Bio~Rad
Resin (AG 50W-X2, 100-200 mesh) in water and then add to
a column of the same resin. Elute with water, then
water:pyridine 96:4 and then water:pyridine: absolute
ethanol 76:20:4. Concentrate the fractions (iodine
positive) in vacuo to give the title compound.
r
D~ m ~ Rl'\
-25~ 3~6
EXAMP_E 6
- 1-{N-[1(S)-Carboxy-2-[4-(6-chloro-3,4-dihydro-1,1-dioxo-
7 s~ noyl-1,2,_ benzothiadiazine 3-acetamido)phenyl]-
ethyl]-(S?-alanyl}cis,syn-octahydro-1H-indo e-2(S)-
carboxylic acld
To the product from Example 5 (3.0 g) add 1N
NaOH (20 ml) and treat as described in Example 2 to give
the title compound.
~ EXAMPLE 7
1-{N-[1($)-Ethoxycarbonyl-3-~4-(6-chloro-3,4-dihydro-
1,1-dioxo-7-sulfamo~l-1,2,4-benzothiadiazine~3-
acetamido)phenyl]p~opyl]~(S)-alanyl}~cis ! syn-octahydro-
1H-indole-2(S)-carboxylic acid
Treat the product of Preparation 3IE as
described in Example 5 to produce the title compound.
EXAMPLE 8
1-{N-[1(S)-Carboxy-3-~4-(6-chloro-3,4-dihydro-1,1-dioxo-
7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido!phenyl]-
pro~yl]-(S)-alanyl}cis,syn-octahydro-1H-indole-2(S~-
carboxylic acid
Treat the product of Example 7 as described in
Example 2 to produce the title compound.
, . . ' ' ' ' :
-
: '.- . ' . :
.~, , ~ ., .
.
-26~ 7~
~ y following the procedures described in the
above preparations and examples, and by using the
appropriate reagents, the following compounds may be
prepared:
1- {Na- [1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4~dihydro-
1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiaæine-3-
acetamido)phenyl]propyl]-(S)-lysyl }-Ci5, syn-octahydro lH-
indole-2(S)-carboxylic acid;
1-{N-[1(S)-methoxycarbonyl-4-[4-(6-chloro-3,4-dihydro-
1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine~3-
acetamido)phenyl]butyl]-(S)-alanyl}-cis,~ octahydro-1H-
indole-2(S)-carboxylic acid;
2-{N-~1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-
dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-acetamido)-
phenyl]propyl]-(S)-alanyl}-1,2,3,4-
tetrahydroisoquinoline-3(S)-carboxlic acid;
1-{N-[l(S)-(2-phenoxyethoxycarbonyl)-3-[4-(4-chloro-3-
sulfamoylbenzamido)phenyl]propyl]-(S)-alanyl}-cls,syn-
octahydro-1~-indole-2(S)-carboxylic acid;
1-{N-[1(S)-pivaloyloxymethoxycarbonyl)-3-[4~(4-chloro-3-
sulfamoylbenzenesulfonamido)phenyllpropyl]-(S)-
alanyl}-cis,syn-octahydro-lH-indole-2(S)-carboxylic acid;
1-{N-[l(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro-1,1-
dioxo-2-methyl-7-methylsulfamoyl-1,2,4-benzothiadiazine-
3 acetamido)phenyl]propyl]-(S)-alanyl}-cis,syn-octahydro-
1H-indole-2(S)-carboxylic acid;
1-{N-[1(S)-ethoxycarbonyl-3-[4-(4-chloro-3~sulfamoyl-
benzenesulfonamido)phenyl]propyl]-(S)-alanyl}-(S)-
proline;
-27- ~ 3~
l-{N-[l (S)-carboxy-3-[4-t6-chloro-3,4-dihydro-1,1-dioxo-
7-sulfamoyl-1,2,4-ben20thiadiazine-3-acetamido)phenyl]-
propyl]-(S)-alanyl}-(S)-proline;
7-{N-[l(S) carboxy-3-[4-(6-chloro-3,4-dihydro-1,1-dioxo~
7-sulfamoyl-t,2,4-benzothiadiazine-3-acetamido)phenyl]-
propyl]-(S)-alanyl}-1,4-dithia-7-azaspiro[4.4]nonane-
8(S)-carboxylic acid;
7-{N-[1(S)-carboxy-3-[4-(4-chloro-3-sulfamoylbenzamido)-
phenyl]propyl]-(S)-alanyl}-1,4~dithia-7-azaspira[4.4~-
nonane-8(S)-carboxylic acid;
2-{N-[1(S)-carboxy-3-[4-(4-chloro-3-sulfamoylbenzene-
sulfonamido)phenyl]propyl]-(S)-alanyl}-1,2,3,4-tetra-
hydroisoquinoline-3(S)-carboxylic acid;
l-{N-[l (S)-ethoxycarbonyl-4-[2-(6-trifluoromethyl-3,4-
dihydro 1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazinyl-3-
acetamido)phenyl]propyl]-glycyl}-cls,syn-octahydro-1H-
indole-2(S)-carboxylic acid;
l-{N-[1(S)-ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-2-
benzyl-1,1-dioxo-7-sulfamoyl-1,2,4-benzothiadiazine-3-
acetamido)phenylthio]ethyl]-(S)-alanyl}-cis,syn-
octahydro-1~-indole-2(S)-carboxylic acid;
l-{N-[1 (S)-ethoxycarbonyl-2-[4-(6-chloro-3,4-dihydro-1,1-
dioxo-7-sulfamoyl-1, ,4-benzothiadiazine-2-benzyl-3-
acetamido)phenyl]methoxyethyl]-(S)-alanyl}-cis,syn-
octahydro-lH-indole-2(S)-carboxylic acid;
1-{N-[1(S)-ethoxycarbonyl-3-[4-(6-chloro-3,4-dihydro~
dioxo-7-sulfamoyl 1,2,4-benzothiadiazin-3-yl)methyl-
' .
-
~' , '
. . . .
,
~d~39~
-28-
thiophenyl~propyl]-(S)-alanyl}-cls,syn~octahydro-lH-
indole-2(S)-carboxylic acid;
l-[N-ll(S)-carboxy-3-[4-(4-chloro-3-sulfamoyl benzamido)-
phenyl]propyl]-(S)-alanyl]~cis~syn~octahydroindole-2-(S)-
carboxylic acid; [a] D26, -1. 5 MeOH
l-[N-[l~S)-carboxy-3-[4-(4-chloro-3-N-methyl-sulfamoyl
ben~amido~phenyl]propyl]-(S)-alanyl]-cis,syn-
octahydroindole-2(S)-carboxylic acid; [a]D26 = -1.2 MeOH
The compounds of this invention are useful in
view of ~heir pharmacological properties. In particular,
they possess activity as antihypertensive agents, as
evidenced by their ability to reduce blood pressure in
mammals in which the blood pressure has become abnormally
elevated.
Since these compounds are believed to act as
angiotensin converting enzyme inhibitors, it is also
contemplated that they may be used in treating other
cardiovascular disorders, for example congestive heart
failure, and glaucoma in the same manner as other ACE
inhibitors such as captopril and enalapril may be used.
The compounds oE this invention can be combined
with pharmaceutical carriers and administered in a
variety of well-known pharmaceutical forms suitable for oral
transdermal or ~arenteral administration to provi.de compositions
use~ul in the treatment of cardiovascular disorders and
particularly mammalian hypertension.
The effactive daily antihypertensive dose
(ED50) of the compounds of this invention will typically
be in the range of about 0.1 to about 25 mg/kg, of
mammalian weight, administered in single or divided
doses. The exact dose to be administered is determined
-29- ~ ~t7~3~
by the attending clinician and is dependent upon where
the particular compound lies within the above quoted
range, as well as upon the age, weight and condition of
the individual.
Generally, in treating humans having
hypertension, the compounds of this invention may be
administered to patients in need of such treatment in a
dosage range o~ about 5 to about 500 mg per patient
generally given several times a day, thus giving a total
daily dose of from about 5 to about 2000 mg per day.
The antihypertensive compositions containing
the compounds of this invention will preferably contain
from about 5 to about 250 mg o~ the active compound per
dosage unit.
The compositions of the present invention are
most preferably administered orally. Typical
formulations for oral administration are those such as
tablets, capsules, syrups, elixirs or suspensions.
Typical injectable formulations include solutions and
suspensions. Also contemplated are mechanical delivery
systems, e.g. transdermal dosage forms.
The typical acceptable pharmaceutical carriers
for use in the formulations described above are
exemplified by: sugars such as lactose, sucrose,
mannitol and sorbitol; starches such as corn starch,
tapioca starch and potato starch; cellulose and
derivatives such as sodium carboxymethyl cellulose, ethyl
cellulose and methyl cellulose; calcium phosphates such
as dicalcium phosphate and tricalcium phosphate; sodium
sulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyl
alcohol; stearic acid; alkaline earth metal stearates
such as magnesium stearate and calcium stearate, stearic
acid, vegetable oils such as peanut oil, cottonseed oil,
sesame oil, olive oil and corn oil; non-ionic, cationic
.
.. . . .
' ~. ', ' ' '' . : ' ' - ' .'
.
6~
-30-
and anionic sufactants; ethylene gylcol polymers; beta-
cyclodextrin; fatty alcohols and hydrolyzed cereal
solids; as well as other non-toxic compatible fillers,
binders, disintegrants, buffers, preservatives, anti
oxidants, lubricants, flavoring agents, and the like
commonly used in pharmaceutical formulations.
., . ' ' ~
-31- ~
The active compound~ of the inven~lon (ACE
inhibitor~) are adm~nist~red in the form ,of oplhthalmic
pharmaceutical compositions Ddapte~ ~o~ topical
admin1~t~ation to th~ ey~ such a~ 501~1~9,
5 o inem~ and sol id in~rt~ ~ Formulations of the~
compound~ may contaln fro~ O . 00001 t~ and esPeci311v n . r)
to 1~ of mQdicament. Oth~r cons:~rtraeion~ m~y b~
employ~d provid~ th~ do~ 18 2;~i!0~tiY~II ln lowor~ng
in~r~ocular pre~ure. A~ a unlt do~ag~ form, be~cween
:10 0 . Q l~ug to 1. o mg., c.~.d
e3pecially 1. 0 to l~O,~la o~ th~ activ~ compound i8
applied 'co th~ hum~n ey~, g~nerally o~ ~ d~ily ba~i~O
Individual do~age requirement~ are var~abl~, how@ver, and
mus~ be administered on the ba~ o~ th~ severity of the
disease and the response o~ ~he patient~
To prepare ~uitabl~ dosage form~, the actLve
compound~ may b~ conveniently 2dmlxed with a non-toxic
pharmaceutically acceptabl~ carrier suitable for topical
oph~halmolg~c ad~ln~stra~ion. Typical of such
phar~aceutically ac~eptabl~ cflrrier~ are, for example,
water, mixtur~ of w~t2~ and watermisciblQ ~olvents such
as lower alkanol~ or vegetabl~i oil3 ~ petroleum ba3ed
~nlly~ and inclu~ing ~180 fro~ O.S to 5~ ty weight o~
hyroxyethyl collulo~ thyl oleat~, oarboxyrne~hyl
cellulos~, polyv~nylpy~rol~don2, and o~her wat~r ~oluble
ophthalmologically acc~pt`abl~ non-toxic polymer~, Eor
exampl~, c~llulo~ dQrivative~ ~uch a~ methyl c~llulo5e,
al~ali me~al carboxymethyl c~llulo~e, hydroxye~hy~
cellulo~ey hydroxypropyl c~llulose, hydroxypropyl~2thyl
C~llulo~et acryl~t~ sueh a~ polyac~ylic acids ~alt~,
~thyl~cryl~te~7 polyacrylamide~; naturat products such as
g~latln, a~glnate3, p~tln~, tr~gacanth, k~raya,
chondrus, agar9 aca~1a; th~ starch derlvative3 such a~
~ 33 ~ ~
star~h acetate, hydroxyethyl starch ethers, hydroxypropyl
starch, as well as other synthetic deriva~ives such as
polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl
methyl ether, polyethylene ~xide, neutralized carbopol
and xanthan gum and mixtures of these polymers. The
pharmaceutical preparation may also contain non-toxic
auxiliary substances sueh as emulsifying, preserving,
wetting, ~odying agents and the like, as for example,
~s~ ~ polyethylene glycols 200, 300, 400 and 600,
1,000, 1,500, 4,000, 6,000 and 10,000, antibacterial
components such as quaternary ammonium compounds;
phenylmercuric salts known to have cold sterilizing
properties and which are non-injurious in use;
thimerosal, methyl and propyl paraben, benzyl alcohol,
phenyl ethanol; bufferinq ingredients such as alkali
metal chloride, borate, acetate, gluconate buffers;
antioxidants such as sodium metabisulfite, bu~ylated
hydroxyanisole ~BHA), bu~ylated hydroxytoluene (BHT~ and
the like; and other conventional ingredients such as
sorbitan monolaurate, triethanolamine, oleate,
polyoxyethylene sorbitan monopalmitylate, dioctyl alkali
metal sulfosuccinate, monothioglycerol, ethylenediamine
tetracetic acid and the like.
AAditi~nally, suita~le ophthalmic vehicles can
be used as carrier media for the present purpose including
conventional phosphate buffer vehicle systems, isotonic
boric acid vehicles, isotonic alkali chloride vehicles,
tris and the like.
The pharmaceutical preparation may al50 be
in the form of a solid insert. For example, one may
use a solid water soluble polymer as the carrier for the
medicamentO Inserts that are known in the art tha~ are
suitable for this use include those described in aritish
... : . .
,, ~ '
~,~t;~
Patent 15611, and in United States Patents 3,99~,071;
3,9~6,510: 3,86~,445; and 3,867,510. Solid water insoluble
inserts, such as those prepared from ethy~ene vinyl
acetate copolymer, may also be utilized.
The compositions of the invention may include
additional therapeutic agents in addition to the ACE
inhibitor. For example antibiotics, anesthetics as well
as other IOP lowering agents may be present.
' -
' ~., '.. ' ' - ' ' ,
- .- . -:
.
.
-3~-
In the following examples, the "active
ingredient" is l-{N-[l(S)-ethoxycarbony1-3-[4-(6-chloro-
3,4-dihydro~ dioxo-7-sulfamoyl-2H-1,2,4-
benzothiadiazine)acetamido]phenyl]propyl]-(S)-alanyl}-
cis,syn-octahydro-lH-indole-2(S)-carboxylic acid It is
contemplated, however, that this compound may be replaced
by equally effective quantities of other compounds within
the scope of formula I.
'
- ' ~ ' ' '
~5 _
EXAMPLE 10
Capsule Amount (mg)
Active ingredient 250.0 125.0
Lactose 173.0 86.5
Corn Starch 75.0 37.5
Magnesium stearate 2.0 1.0
5~0 0 25000
Blend the active ingredient, lactose, and corn
starch until uniform; then blend the magnesium stearate
into the resulting powder. Encapsulate the mixture into
suitably sized two-piece hard gelatin capsules.
EXAMPLE 11
~ '
Tablet Amount (mcl)
Active Ingredient 250.0 125.0
Lactose 161.0 80.5
Corn Starch 12.0 6.0
Water (per thousand tablets) 120 ml 60 ml
(evaporates) (evaporates)
Corn Starch 75.0 37.5
Magnesium Stearate 2.0 l.0
500.0 250.0
Blend the active ingredient with the lactose
until uniform. Blend the smaller quantity of corn starch
with the water and add the resulting corn starch paste,
.
'
,
_3~
then mix until a uniEorm wet mass is formed. ~dd the
remaining corn starch to the remaining wet mass and mix
until uniform granules are obtained. Screen the granules
through a suitable milling machine, using a 3/4 inch
stainless steel screen. Dry the milled granules in a
suitable drying oven until the desired moisture content
is obtained. Mill the dried qranules through a suitable
milling machine using a 16 mesh stainless steel screen.
Blend in the magnesium stearate and compress the
resulting mixture into tablets of desired shape,
thickness, hardness and disintegration.
EXAMPLE 12
Injectable Solution mg/ml
Active ingredient 5.00
Methyl p-hydroxybenzoate 0.80
Propyl p-hydroxybenzoate 0.10
Disodium Edetate 0.10
Citric Acid Monohydrate 0.08
Dextrose 40.0
Water for injection qs. ad.1.0 ml
Dissolve the ~-hydroxybenzoates in a portion of
water for injection at 60-70C and cool the solution to
25-25C. Charge and dissolve all other excipients and
the active ingredient. Bring the solution to final
volumet filter it through a sterilizing membrane and fill
into sterile containers.
~ r`~7s~3~
2302A
Ophthalmic Compositions:
a) ~2~mlc Solution
aetive ingredlent,
Po1 yvi nyl Al cohol ~ ~
Sodium phosDhate Dmasic 1.2
Sodium phospha~e Monobas~c 0.64
Edetate Disodium 0.1
Sod~um Chlor~de` 6.0
Benzal kon~ um Cbl oride 0 . 1
Purifie4 Dist~lled W~ter QS, A.D. . l.Oml
b) O~t~almic SQlution
mg/ml
actlv~ i~gredie~t *
Hydroxypropyl Methylcellulosa 5.0
Borlc acid- 10.0 ~ :
Benzalkonium Chloride 0.1
: Sodium Bora~e O.7
Edetate Disodlum 0.1
Sodium Chlorlde 3.0
Purified Distllled Water QS.A.D. l.Oml
~cl OPhthalmic Oin~ment: ;
r~2L~
active ingredient * *
Purifled Distilled Water -O.lml
Methyl Paraben o,~
Propyl Paraben 0.1
.Hydrophilic Petrolatum QS. A.D. l.Og
d) O~hthalmLc Olntm~nt ;u.~
active ingredient * *
Chlorobut-a'nol S
Anhydou3 lanolin 10
Mlneral Oil 10
White Pe~rolatum QS. A.D. l.Og
.
'~ .
: - -
'7~ 6
-38
e) ~ el:
active ingredlent * *
Hydroxypropyl Methylcellulosa 40.0
~oric Acid 10.0
Ban2alkonium Chloride 0.1
Sodlum 30rate - O.7
Edetate Disodium 0.1
Purifled Dl~llled Water QS. A.D.l.Oml
* stands for the concentration of the active ingredient
which i5 0 . O 001-10 . O mg/ml,
* * stands for the concentration of the active ingredient
which i5 O. 0001 - 10. 0 mgjg.
Similarly, substitute other compounds of the
: present invention to prepare other compcsitions of the
present invention.
.' ' ' ' ' .
;3~
-39-
As mentioned before the compounds of this invention show
valuable antihypertensive activity. It can be concluded
from animal tests that these compounds have high angio-
tensin converting enzyme inhibitory activity (ACE inhi-
bltory activity).
The in-vivo ACE inhibitory activity of
Compound A:
1- [N-[l(S)-carboxy-3- [4-(4-chloro-3-sulfamoyl
benzamido) phenyl] propyl]~S)-alanyl]cis,syn-
octahydroindole-2-(S)-carboxylic acid
Compound B:
1-[N-[1 (S)-carboxy-3-[4-(4-chloro-3-N-methyl-
sulfamoyl benzamido)phenyl]propyl]-(S)-alanyl]cis,
syn-octahydroindole-2 S)-carboxylic acid
is as follows:
IDso (i.v.) ID50 (oral)
Compound A 36 ~g/kg 3 mg/kg
Compound B 33Jug/kg 3 mg/kg
ID50: Dose (intravenous or oral respectively) required to
inhibit the pressor response to i.v. antiotensin I by 50
in anesthethised rats.
.
