PHARMACEUTICAL COMPOSITION FOR USE AGAINST HYPERTENSION AND CONGESTIVE HEART FAILURE

COMPOSITION PHARMACEUTIQUE POUR UTILISATION CONTRE L'HYPERTENSION ET L'INSUFFISANCE CARDIAQUE CONGESTIVE

English Abstract

ABSTRACT
A pharmaceutical composition for use against hypertension and
congestive heart failure containing
a) A calcium antagonist and
b) the ACE-inhibitor
7-(N-[1-(S)-Ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-1,4-dithia-
7-azaspiro-[4,4]nonane-8-(S)-carboxylic acid.

Claims

- 24 - Case 100-6972
CLAIMS:
1. A pharmaceutical composition comprising
a) A calcium antagonist and
b) 7-(N-[1(S)-Ethoxycarbonyl-3-Phenylpropyl]-(S)-Alanyl)-
1,4-Dithia-7-Azaspiro-[4,4]Nonane-8-(S)-Carboxylic Acid
and the pharmaceutically acceptable salts thereof.
2) A pharmaceutical composition according to claim 1 charac-
terized in that the calcium-antagonists are those of formula I
<IMG> I)
wherein A is a residue of formula (a), (b) or (c)
<IMG> <IMG> <IMG>
(a) (b) (c)

- 25 - Case 100-6972
R1 is hydrogen, (1-6)alkyl, hydroxy(C2-6)alkyl, (C3-6)alkoxy-
alkyl, (C3-6)alkenyl, (C3-6)alkinyl, (C3-7)cycloalkyl or
(C4-8)cycloalkylalkyl, or (C7-9)phenylalkyl or (C9-12)-
phenylalkenyl, wherein the phenyl ring is unsubstituted
or mono-, di- or tri-substituted by halogen, hydroxy,
(C1-4)alkoxy,
R2 and R5 are each independently hydrogen, (C1-6)alkyl, (C7-10)-
phenylalkyl, (C3-7)cycloalkyl or (C4-8)cycloalkylalkyl,
whereby, when A is a residue b, one of R2 and R5 may also
be (C1-4)hydroxyalkyl or cyano,
R3 and R4 are independently -CN, -COOR7, -COR8, -S(O)nR9 or
-COO-B-N R10 R11,
n is 0, 1 or 2,
R6 is hydrogen, halogen, (C1-4)alkyl, (C1-4alkoxy, (C1-4)alkyl-
thio, (C1-4)alkylsulfonyl, trifluoromethyl, nitro,
hydroxy, azido, amino, (C1-4)alkylamino, di[(C1-4)alkyl]-
amino, (C1-5)alkanoylamino, (C2-5)carbalkoxy, aminocar-
bonyl, trifluoromethoxy, cyano, sulfamoyl, (C1-4)alkyl-
sulfamoyl or di[(C1-4)alkyl]sulfamoyl,
X is oxygen or sulphur,
m is 0, 1 or 2,
R7, R8 and R9 are each independently (C1-6)alkyl, (C3-6)alkenyl,
(C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl,
hydroxy-(C2-6)alkyl, (C3-6)alkoxyalkyl, hydroxy(C4-8)-
alkoxyalkyl, amino-(C2-6)alkyl,(C1-4)alkylamino(C2-6)-

- 26 - Case 100-6972
alkyl,di[C1-4)alkyl]aminoalkyl, phenyl, (C7-10)-
phenylalkyl, a 5- or 6-membered heterocyclic ring,
containing a nitrogen or oxygen or sulphur atom and which
may also contain 1, 2 or 3 additional ring nitrogen
atoms, or (C1-4)alkyl optionally substituted by a 5- or
6-membered heterocyclic ring containing a nitrogen or
oxygen or sulphur atom as heteroatom and which may
additonally contain 1, 2 or 3 further ring nitrogen
atoms, whereby, when A is a residue b, R7 may also be
trifluoroethyl,
B is (C1-14)alkylene,
R10 and R11 are each independently (C1-6)alkyl, (C3-6)alkenyl,
(C3-6)alkinyl, (C3-7)cycloalkyl, (C4-8)cycloalkylalkyl,
hydroxy(C2-6)alkyl, (C3-6)alkoxyalkyl, hydroxy(C4-8)-
alkoxyalkyl, amino(C2-6)alkyl, (C1-4)alkylamino(C2-6)-
alkyl, di-[(C1-4)alkyl]amino-(C1-4)alkyl, phenyl, or
(C7-10)phenylalkyl, or
R10 and R11 form together with the nitrogenatom to which they are
attached a 5-, 6- or 7-membered heterocyclic ring
optinally containing a further heteroatom selected from
oxygen or sulphur or a group -N-R12, wherein R12 is
(C1-4)alkyl, benzyl or bis- phenylmethyl optionally mono-
or independently disubstituted in the phenyl ring(s) by
halogen of atomic number from 9 to 35 or (C1-4)alkoxy.
3. A pharmaceutical composition aecording to claim 2
characterized in that the calcium-antagonists are those of
Formula Ia

- 27 - Case 100-6972
<IMG>
Ia
wherein
R1' is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or
alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon
atoms, cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of
7 to 9 carbon atoms or phenylalkenyl of 9 to 12 carbon atoms,
the phenyl ring being unsubstituted or mono-, di- or tri-
substituted independently by halogen, hydroxy or alkyl or
alkoxy of 1 to 4 carbon atoms.
R2' and R5', independently, are hydrogen or alkyl of 1 to 6 carbon
atoms,
R3' and R4', independently, are alkyl of 1 to 6 carbon atoms,
alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to
7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy
of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms,
alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4
to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 carbon
atoms, cycloalkoyoxy of 3 to 7 carbon atoms or cycloalkyl-
alkoxy of 4 to 8 carbon atoms, or R3' has the significance
0-8'-R7', wherein B' is an alkylene chain of 9 to 14 carbon
atoms and R7 is piperidine or piperazine both substituted in

- 28 - Case 100-697Z
the 4 position by methyl, benzyl or bis-phenylmethyl
optionally mono- or independently disubstituted in the phenyl
ring(s) by halogen of atomic number from 9 to 53 or alkoxy of
1 to 4 carbon atoms and R4' has the significance cited above,
R6' is hydrogen, halogen, alkyl or alkoxy or alkylthio or alkyl-
sulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl, nitro
or hydroxy, and
X has the significance stated in claim 2.
4. A composition according to claim 2, wherein
component a) is selected from 4-(2,1,3-benzoxadiazol-4-yl)-
1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid
diethyl ester; 4-(2,1,3)-benzoxadiazol-4-yl-1,4-dihydro-2,6-
dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid iso-
propyl ester; 4-(2,1,3-benzoxathiadiazol-4-yl)-2,6-dimethyl-
-1,4-dihydropyridin-3,5-dicarboxylic acid dimethyl ester and
(+)-(5)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxy-
carbonyl-2,6-dimethyl-3-pyridine carboxylic acid-110[4-(di-
phenylmethyl)-piperazin-l-yl]decyl]ester.
5. A composition according to claim 1 for use in
the treatment of hypertension and congestive heart failure.
6. A composition according to claim 5 wherein the calcium
antagonist is the 4-(2,1,3-Benzoxadiazol)-4-yl-1,4-dihydro-
2,6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid
isopropylester.
7. A composition according to claim 5 wherein the calcium
antagonist antagonist is the 4-(2,1,3-Benzoxadiazol-4-yl)-1,4-

- 29 - Case 100-6972
dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid
diethylester.
8. A composition according to claim 5 wherein the calcium
antagonist is the 4-(2,1,3-Benzoxathiadiazol-4-yl)-2,6-
dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid
dimethylester.
9. A composition according to claim 5 wherein the calcium
antagonist is the (+)-(S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-
dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridine carboxylic
acid-[10-[diphenylmethyl)-piperazin-1-yl]decyl]ester.
10. A composition according to claim 5 wherein component b) is the
7-(N-[1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-1,4-
dithia-7-azaspiro-[4,4]nonane-8-(S)-carboxylic acid
monohydrochloride monohydrate.
11. A compositon according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
characterized in that the weight ratio of component a) to
component b) is from 5:1 to about 1:3.
12. A composition according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10
characterized in that the weight ratio of component a) to component b)
is from 5:1 to 1:1
13. A pack or dispenser device containing a pharmaceutical
composition according to claim 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
together with instructions for use in hypertension or
congestive heart failure.
14. Use of a combination of component a) and component b) as
defined in claim 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 in the
manufacture of a pharmaceutical composition for the treatment
of hypertension a congestive heart failure.

Description

~ 13~422~
PHAR~ACBUTICAL CO~POSITION POR US~ AGAINST ~YPERT~NSION
. .
AND CONGBSTIVe EeART F~ILURB
This invention relates to novel pharmaceutical compositions effec-
tive against hypertension and congestive heart failure and to
their production and use.
The present invention provides a pharmaceutical composition
containing as active agents
a~ a Calcium-Antagonist
and
b) 7-(N-Il(S)-Ethoxycarbonyl-3-Phenylpropyl~-(S)-Alanyl)-1,4-Di-
thia-7-Azaspiro-[4,4]Nonane-8-(S)-Carboxylic Acid and its
pharmaceutically acceptable salts.
The present invention also provides a method of treating
hypertension or congestive heart failure in a subject which
comprises co-administering a) a calcium antagonist and b)
7-(N-[-l(S~-Ethoxycarbonyl-3-Phenylpropyl]-(S)-Alanyl)-1,4-Dithia-
7-Azaspiro-14,4}Nonane-8-(S)-Carboxylic Acid and its
pharmaceutically acceptable salts.

1314222
- 2 - Case 100-6972
The calcium antagonists comprise a class of physiologically active
substances characterised by their calcium antagonistic or calcium
channel blocking activity. A wide range of such compounds are now
known and have found wide therapeutic application, in particular
in the treatment of cardiovascular disturbances or disease, for
example in the treatment of coronary insufficiency, disturbance in
cerebral circulation, hypertension and in the treatment of other
disturbances in peripheral circulation. Typically,the calcium
antagonists are employed as vasodilators, e.g. in the treatment of
hypertension.
Component b) is an angiotensin-converting enzyme (ACE-) inhibitor.
Little has been published on its pharmacological and
biopharmaceutical properties. ACE inhibitors are known compounds
that influence the transformation of angiotensin I in angiotensin
II and that are useful in the lowering of elevated blood pressure
when this is due to the action of angiotension II. ACE-blocking
compounds when administered alone have to be used in relatively
high amounts that may lead to unwanted side effects.
The pharmaceutical composition of the idvention and also
co-administration of component a) and component b) possess
surprisingly and unexpectedly advantageous pharmaceutical
properties with an especially favourable or improved
pharmacological/therapeutic profile. In particular it has been
found that co-administration of a component a) and a component b)
as aforesaid in conjunction results in unexpected enhancement of
antihypertensive activity and an surprisingly potent activity
against congestive heart failure.
The component a) induce~ increase in central venous pressure and
consequently the increase in cardiac output is blunted in
component b) pretreated animals. The increase of central venous

13142~2
- 3 - Case 100-6972
pressure in the absence of cardiac depression (cardiac
contractility ~as accurately assessed with a strain gauge sewn
onto the myocardium) indicates an increased venous return caused
by arteriolar dilatation. The blunted effect of component a) hence
indicates an increased venous compliance after ACE inhibition.
Praferred calcium antagonists for use in the compositions of the
invention are those of the dihydropyridine class, e.g. of the
formula I
R~ ~ ~ 3 (I)
Rs ~l 1 R~2
wherein A is a residue of formula (a), (b) or (c)

131~222
- 4 - Case 100-6972
~X --Ç3 ~R6
(a) (b~ (c)
R1 is hydrogen, (C1 6)alkyl, hydroxy(C2 6)alkyl,
(C3 6)alkoxyalkyl, (C3 6)alkenyl, (C3 6)alkinyl,
(C3 7)cycloalkyl or (C4 8)cycloalkylalkyl, or
(C7 9)phenylalkyl or (C9 12)phenylalkenyl, wherein the phenyl
ring is unsubstituted or mono-, di- or tri-substituted by
halogen, hydroxy, (Cl 4)alkyl or (Cl_4)alkoxy,
R2 and R5 are each independently hydrogen, (C1 6)alkyl,
(C7 1O)ph~nylalkyl, (C3 7)cycloalkyl or (C4 8)cycloalkylalkyl,
whereby, when A 1A a residue b, one of R2 and R5 may also be
(C1 4)hydroxyalkyl or cyano,
R3 and R4 are independently -GN, -COOR7, -COR8, -S(O)nX9 or
-C00-B-N R1o R11,
n is 0,1 or 2,
R6 is hydrogen, halogen, SC1 4)alkyl, (1 4)alkoxy, (C1 4)alkyl
thio, (C1 4)alkylsulfonyl, trifluoromethyl, nitro, hydroxy,
azido, amino, (C1 4)alkylamino, di[(C1 4alkyllamino, (C1 5)

1314222
- 5 - Case 100-6972
alkanoylamino, (C2 5)carbalkoxy, aminocarbonyl,
trifluoromethoxy,cyano, sulfamoyl, (C1 4)alkylsulfamoyl or
dil(Cl 4)alkyl]sulfamoyl,
X is oxygen or sulphur,
m is 0, 1 or 2,
R7, R8 and R9 are each independently (C1 6)alkyl, (C3 6)alkenyl,
(C3 6)alkinyl, (C3 7)cycloalkyl, ~C4 8)cycloalkylalkyl,
hydroxy-(C2 6)alkyl,(C3 6)alkoxyalkyl, hydroxy
(C4 B)alkoxyalkyl, amino-(C2_6)alkyl7
(C1 4)alkylamino(C2 6)alkyl, di[(C1 4)alkyl]aminoalkyl, phe-
nyl, (C7 1O)phenylalkyl, a 5- or 6-membered heterocyclic ring,
containing a nitrogen or oxygen or sulphur atom and which may
also contain 1, 2 or 3 additional ring nitrogen atoms, or
(C1 4)alkyl optionally substituted by a 5- or 6-membered hete-
rocyclic ring containing a ni~rogen or oxygen or sulphur atom
as heteroatom and which may additionally contain 1, 2 or 3
further ring ntrogen atoms, whereby, when A is a residue b, R7
may also be trifluoroethyl,
B is (C1 14)alkylene,
R1o and R11 are each independently (C1 6)alkyl, (C3 6)alkenyl,
(C3 6)alkinyl, (C3 7)cycloalkyl, (C4 8)cycloalkylalkyl, hy-
droxy(C2 6)alkyl, (C3 6)alkoxyalkyl, hydroxy(C4 8)alkoxyalkyl,
amino(C2_6)alkyl, (Cl 4)alkylamino(C2_6)alkyl, dilCl 4)alkyl]-
amino-(C1_4)alkyl, phenyl, or (C7 1O)phenylalkyl, or
R1o and R11 form together with the nitrogenatom to which they are
attached a S-, 6- or 7-membered heterocyclic ring optionally

" 131~2~
- 6 - Case 100-6972
containing a further heteroatom selected from oxygen or
sulphur or a group ~N-R12 wherein R1z is (Cl_4)alkyl, benzyl
or bis- phenylmethyl, optionally mono- or independently
disubstituted in the phenyl ring(s) by halogen of atomic
number from 9 to 35 or alkoxy of 1 to 4 carbon atoms.
In formula I, (C1 6)alkyl groups preferably contain 1 to 4 carbon
atoms, more preferably 1 or 2 carbon atoms, methyl groups being
most preferred. (Cl 4)-alkyl, -alkoxy, -alkylthio and -alkylsulfo-
nyl groups preferably contain 1 or 2 carbon atoms. Hydroxy,
alkoxy, hydroxyalkoxy, amino and al~ylamino moieties of hydroxy-
alkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylamino-
alkyl groups R7 in residues -COOR7 are preferably not ateached at
the ~-carbon atom. Suitably they are in the terminal position.
Preferred alkylene moities of hydroxyalkyl, alkoxyalkyl, hydroxy-
alkoxyalkyl, aminoalkyl and alkylaminoalkyl are ethylene and pro-
pylene. The alkylene moiety of cycloalkylalkyl groups is suitably
methylene. Cycloalkyl moieties of cycloalkylalkyl groups are sui-
tably cyclopropyl, cyclopentyl or cyclohexyl. By halogen is meant
fluorine, chlorine or bromine, in particular chlorine.
The ~ultiple bond in alkenyl, alkinyl and phenylalkenyl groups R
or -COOR7 is preferably not in the x,~-position. Alkenyl and
alkinyl groups preferably have 3 to 5 carbon atoms. Alkenyl is
suitably allyl or 2-methylallyl is suitably propionyl. Phenyl-
alkenyl groups preferably have the trans-configuration and in-
clude, e.g. cinnamyl. When R1 is phenyl this is preferably un-
substituted. WheD R1 is di- or tri-substituted phenyl, the
substituents are preferably the same and are halogene or alkyl.
Hetrocyclic rings as R7, R8 and R9 are, e.g. furyl, thienyl,
pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxa-
zolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl,
pyridyl, pyri~idinyl, pyrazinyl, pyridazinyl, piperidinyl, morpho-

131~222
- 7 - Case 100-6972
linyl and triazinyl. Hetrocyclic rings comprised by R1o and R
together with the nitrogen atom to which they are attached are
preferably saturated and include pyrrolidine, piperidine, pipe-
razine, N-alkylpiperazine and morpholine rings. Most preferred is
however, di-phenyl-methyl-piperazine that can be substituted in
the phenylring(s) as described above. R2 and R5 are preferably
identical. R6 is suitably halogen, alkyl, alkoxy, nitro or tri-
fluoromethyl and is preferably in the o- or m-position with
respect to the position of attachement of the dihydropyridine
residue. When A is a residue a), R6 is preferably hydrogen.
In -COOBNRlo Rll B stands for an alkylene chain of 1 to 14 carbon
atoms preferably of 5 to 14 carbon atoms especially of 10 carbon
atoms.

~ ~`3~ ~2;~
- 8 - Case 100-6972
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v
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1 31~222
Case 100-6972
x u~ o u~ c~ o o o o o
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~314222
- l O - Case 100-6972
X O O O O ~ ~q O tq ~ V~
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t~: ~ u ~ C~ tJ v v t~ ~ ~ u
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:~: X ~ r~ r~ X a: ~ _
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1 31~222
- l l - Case 100-6972
x ~Q o u~ o o u~ o o
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V ~ t, ~ U~, U ~ ~ U
.~ U
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r~
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2.-
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Q ~ ~ r~

131~222
- l 2 - Case 100-6972
x c~ ~n o ~ o o u~ u~ o o o o o o
Is: S t~ ~: 3 83 ~ s S ~ U
.~ _ _
~:" ~ ~ Co) ~ O ~ ~ ~ O ~ O ~ ~ O
O O O O O O O OO O O O O O
U ~ ~ U C~ J U
~ ~ 3~ 3 ~ x
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-- ~ ~ ~ ~
u~ s ~ ~ ~ ~ v ~ ~ ~l -~
~ ~ u u cJ\ ~ u
O o~ O Q ~i o c~ o o o O Q O o
o o o o o o o o o o O o o o
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X ~ t~ ~ ~ u c~ v C~
z a~ x x
',' . , .~
o ~ ~ u~ o
C~

1314222
- 13 - Case 100-6972
~ ~. .
X O O ~ o ~ x _ ' ' ' ~ .
01 C -- '-- C~l N C~J N C~l
X ~ I I O~ Z T ~ T
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U~ ~ O
S~ ~ ~)<11 T NN I I I
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O~ _ ~ ~
S ~ ~ T _~ N ~q
P: ~ ~ O O ~1 ~y~ I T ~ I -- I t--
4_3 O~O
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1: :S: I Q ~
t ~ ~ E 1 1 ~ T ~ 2 :~ ~ T
Z 1: 0
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E

1314222
r
- 14 -
Case 100-6972
E ~ _ _
>, I I I ~ , .
3 ~
X
~
_
N ~ t~
.0 O O o 1
, I I I C
E O E O
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c~ ~ I T T
r,~ _
c~l T ~ T
I ~ U- L ;~
el T I T ~J ,~ ~
O O O O rJ~ 11
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L
a~
O ~O
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T, ~ ~ t,,),a3
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O ~ o o E ,~
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1:1 T 2 T I Er_~
o ._
Z ~ 1'
~:1 ~ o
o CO ~ O _ ~.- C
o

2 2 2
- 15 - Case 100-6972
Especially prefered calcium-antagonists according to a) have the
formula
R6
~ ~X
~ N/
RlO ~ ~ C~3 Ia
R
wherein
R1' is hydrogen, alkyl of 1 to 6 carbon atoms, alkenyl or alkinyl
of 3 to 6 carbon atoms, cycloalkyl of 3 to 7 carbon atoms,
cycloalkylalkyl of 4 to 8 carbon atoms, phenylalkyl of 7 to 9
carbon atoms or phenylalkenyl of 9 to 12 carbon atoms, the
phenyl ring bein~ unsubstituted or mono-, di- or trisubsti-
tuted independently by halogen, hydrGxy or alkyl or alkoxy of
1 to 4 carbon atoms.
R2' and R5, independently, are hydrogen or alkyl of 1 to 6 carbon
atoms,
R3' and R4', independently, are alkyl of 1 to 6 carbon atoms,
alkenyl or alkinyl of 3 to 6 carbon atoms, cycloalkyl of 3 to
7 carbon atoms, cycloalkylalkyl of 4 to 8 carbon atoms, alkoxy
of 1 to 6 carbon atoms, hydroxyalkoxy of 2 to 6 carbon atoms,
alkoxyalkoxy of 3 to 6 carbon atoms, hydroxyalkoxyalkoxy of 4
to 8 carbon atoms, alkenyloxy or alkinyloxy of 3 to 6 carbon
atoms, cycloalkyloxy of 3 to 7 carbon atoms or cycloalkylal-
koxy of 4 to 8 carbon atoms, or R3' has the significance
0-B'-R7', wherin B' is an alkylene chain of 9 to 14 carbon

131~222
- 16 - Case 100-6972
atoms and R7' is piperidine or piperazine both substituted in
the 4 position by methyl, benzyl or bis-phenylmethyl optio-
nally mono- or independently disubstituted in the phenyl
ring~s by halogen of atomic number from 9 to 53 or alkoxy of 1
to 4 carbon atoms and R'4 has the significance cited above,
R6' is hydrogen, halogen, alkyl or alkoxy or alkylthio or
alkylsulfonyl, each of 1 to 4 carbon atoms, trifluoromethyl,
nitro or hydroxy, and
X has the above significance.
The calcium antagonists used according to the invention are
generally described together with their calcium antagonistic and
i.a. antihypertensive activity in earlier published patents. In
these Patents may also be mentioned that salt forms of the
calcium-antagonists of formula I may be used instead of the free
bases. Further it may be contemplated that when the substituents
in the 2 and 6 positions and/or 3 and 5 positions of the
1,4-dihydropyridinyl moiety are different the calcium antagonists
may exist in racemic form or in idividual enentiomer forms.
Particularly interesting calcium-antagonists of ~ormula I or of
formula Ia are 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-
dimethyl-pyridine-3,5-dicarboxylic acid diethyl ester, hereinafter
referred to as compount No 1;4-(2,1,3-benzoxadiazol-4-yl)-
1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5-
carboxylic acid isopropyl ester, hereinafter referred to as
compound No 2,4-(2,1,3-benzoxathiadiazol-4-yl)-2,6-dimethyl-
1,4-dihydropyridine-3,5-dicarboxylic acid dimethyl ester,
hereinafter referred to as compound No 3 and (+)-(S)-4-
(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxycarbonyl-
2,6-dimethyl-3-pyridine carboxylic acid-[1~-14-(diphenylmethyl)-

`` 13142~
- 17 - Case 100-6972
piperazin-1-yl]decyllester referred eo as compound No 4;
especially interesting are compounds No 2 and No 4.
7-(N-~l(S)-Ethoxycarbonyl-3-Phenylpropyl~-(S)Alanyl)-1,4-
Dithia-7-Azaspiro[4,41Nonane-8-(S)-Carboxylic Acid has the
alternative chemical name 18S-[71R*)~,8R*l]-7-[2-[ll-
(Ethoxycarbonyl)-3-phenylpropyllaminol-1-oxopropyll-1,4-dithia-7-a
zaspirol4.4lnonane-8-carboxylic acid. It is also identified by
SCHERING as SC~-33844 and has the generic name SPIRAPRIL. This
compound is described in Example 3 of the US-Patent No 4,470,972.
In this US-Patent it is also stated that the compound has
antihypertensive activity. Pharmaceutical acceptable salt forms
may be used. The hydrate may be used. In this US-Patent different
salt forms are described that can be used instead of the free base
e.g. the hydrochloride as described in Example 4 of this patent or
the hemimaleate as described in Example 5 of this patent. The
preferred form is the monohydrochloride monohydrate.
The co-administration of a calcium antagonist and component b)
exhibits potent anti-hypertensive activity and activity against
congestive heart failure as indicated in pharmacological
experiments.
For example when a calcium antagonist especially a compound of
formula I ancl a component b) are co-administered to animals, the
natriuretic and diuretic activity of the calcium antagonists
especially of the compounds of formula I may be surprisingly
retained. Co-administering a calcium antagonist especially a
compound of formula I with the above ACE-inhibitor thus reduces
the need for further diuretics and/or beta-blockers. This is shown
in the hydrated rat test (method of Flackiger et al., Schweiz.
Mecl. Uochenschrift 93, No 35 [1963] 1232-7) described in the
following:

2 ~
- 18 - Case 100-6972
Groups of 12 rats are used. Component a) at a diuresis inducing
doses e.g. at 0.3 mg/kg p.o. to 3 mg/kg p.o. is investigated alone
or in combination with component b) at a dosage of 3 mg/kg s.c.
The compounds are administered at the same time. Urine is
collected for 3 hours and its volume and sodium excretion
measured.
This effect is confirmed in sodium-depleted rats. Rats are given
furosemide (50 mg/kg/day) with drinking water for tuo days. Groups
of 6 animals are used. The calcium antagonist is administered at
diuresis dosages e.g. of 0.3 to 3 mg/kg p.o and component b) at
dosages of 3 mg/kg s.c. The compounds are administered at the same
time. Urine is collected for 3 hours and its volume and sodium
excretion measured. Similar values as in the hydrated rat test are
obtained.
It has thus been unexpectedly found that the diuretic and natri-
uretic activity is generally maintained .
This is surprising and makes the combinations of the invention
particularly well-suited in the treatment of hypertension and
congestive heart failure and reduces the need for diuretics.
The importance of this effect is highlighted by the increasing
concerns in informed circles about the metabolic consequences of
diuretics administration over extended periods. The antihyper-
tensive effect of the co-administering a calcium antagonist and
component b), is further supplemented by the renal effect.
Both components a) and b) may be - as discussed above - in the
free base or where appropriate in salt, e.g. in acid addition salt
form.

13~ ~222
- 19 - Case 100-6972
The new composition may be prepared by a process comprising
formulating a calcium antagonist and component b) in a state of
purity sufficient for pharmaceutical acceptability. Conventional
pharmaceutical excipient including carrier and diluents, may also
be formulated there~ith.
The compositions of the invention are therefore indicated for use
in the treatment of hypertension and congestive heart failure.
The calcium antagonist may be administered at e.g. one third to
100 percent of the normal dose for treating e.g. hypertension or
congestive heart failure. An indicated oral daily dosage of
compounds of formula I is from about 0.2 mg to about 350 mg,
particularly from about 1 to 70 mg, conveniently administered in
divided doses 2 to 4 tlmes a day in unit dosage form containing
from about 0.05 mg to about 175 mg e.g. to 20 mg of the compounds,
or in sustained release form. The prefered compound is compound
No. 2. An indicated dose is from about 2.0 to about 10 mg twice or
once a day p.o.
An indicated preferred weight ratio of a calcium antagonist to the
component b) calculated on the free base moiety thereof, may be
from about 50:1 to about 1:10, particularly from about 10:1
to about 1:5, preferably from about 5:1 to about 1:3. Component b)
may be administered at e.g. one third to 100 percent of the normal
dose for treating hypertension or congestive heart failure.
Contemplated dosage forms include 3 mg, 6 mg, 12 mg and 24 mg.
Thus for compound No 2 and the component b) preferred ratio is
from about 50:1 to about 1:5, especially about e.g. 5:1 to 1.1
such as 1:1, 4:1, 3:1 or 2:1.

1314222
\
- 20 - Case 100-6972
Conveniently, components a) and b) are administered in the form of
a pharmaceutical composition in association with a pharmaceutical
carrier or diluent. Such compositions may be formulated in
conventional manner so as to be, for example, a solution such as
an injectable solution or supension, or preferably a solid form
such as a tablet or capsule. If desired one or both of the
components may be in sustained release form, e.g. in the case of
compound No. 1 and 2 as described in GB 218 1 053 A or 216 0 100
A.
If desired the active agents may be arranged in a pack to facili-
tate administration of a particular dosage regimen, e.g. in a
particular order in a blister pack.
A suitable composition may also consist of a pack containing
separately a component a) and component b) until required for
concomitant administration, conveniently together with
instructions for the concomitant administration of a predetermined
amount of compodnent a) and a predetermined amount of one of the
component b).
The following Examples are illustrative of compositions for use in
the invention.

13142~,2
- 21 - Case 100-6972
BXA~PLB 1: Hard gelatine capsules for oral administration
Hard gelatine capsules containing the ingredients indicated below
may be prepared by conventional techniques, and be administered
once a day for the treatment of hypertension and congestive heart
failure.
i
Ingredient Ueight
Compound No 2 10.0 mg
Component b) 2.0 mg
Lactose . 167.0 mg
Sodium lauryl sulfate 5.5 mg
Corn starch 128.0 mg
Aerosil 200~ 1.5 mg
Polyethylenglycol 6000 8.0 mg
322.0 mg
BXAHPL~ 2: Tablets for oral administration
Sufficient a~ounts of the components are mixed in conventional
manner and filled into gelatine capQule~ or compressed to tablets,
which are adM~nistered once a day for the treatment of hyper-
tenJion and congest1~e heart fail~e .

1314222
- 22 - Case 100-6972
Ingredient Ueight
Compound No 2 10.0 mg
Component b) 2.0 mg
Lactose 224.0 mg
Sodium lauryl sulfate 2.0 mg
Polyvinylpyrrolidone 8.0 mg
Corn starch 13.0 mg
Magnesium stearate 2.6 mg
- 262.0 mg
EIU~fPLR ~: Separate Co-administration
Capsules of compound No. 2 may be made up with the ollouing
composition
Compound No 2 10 mg
Microcrystalline Cellulose(Avicelj~ 47 mg
Cetyl Palmitate 10 mg
Hydroxypropyl meehylcellulose
(Methocel E4M)~ 90 mg
Silica colloidal 1 mg
Magnesium stearate 2 mg
160 mg
and Capsule~ of component b) may be made up with the follo~ing
composition

~ 3:~422 ~
- 23 - Case 100-6972
Component b) 12 mg
Lactose 349 mg
Silica (colloidal) 8 mg
Maleic acid (ground) 5 mg
Stearic acid 16 mg
400 mg
These may be arranged in calendar packs. If desired combined
capsules containing both active agents may be produced.