AU615883B2

AU615883B2 - Pharmaceutical composition for use against hypertension and congestive heart failure

Info

Publication number: AU615883B2
Application number: AU80576/87A
Authority: AU
Inventors: Robert Paul Hof; Helene Siegl
Original assignee: Sandoz AG
Current assignee: Novartis AG
Priority date: 1986-11-03
Filing date: 1987-11-02
Publication date: 1991-10-17
Anticipated expiration: 2007-11-02
Also published as: PT86062A; DK574087D0; PH23249A; BE1002063A4; NZ222401A; SE8704272D0; DK574087A; LU87034A1; CA1314222C; MY102124A; FI874823A0; FI874823L; PT86062B; FR2605885A1; IL84343A; KR880006197A; IL84343A0; AU8057687A; IE60496B1; NO874539L

Description

CONKORWEALT~i. OP AUSTRALIA PATENT ACT 1952 COMPLETE SPECIFICATION 6158

F

(ORIGINAL)

FOR OFFICE USE CLASS INT. CLASS Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art-: 04 66 44*4 do of NAME OF APPLICANT: SANDOZ LTD.

ADDRESS OF APPLICANT: CH-4002 Basle, SWITZERLAND.

NAME(S) OF INVENTOR(S) Helene SIEGL, Robert Paul K-OF ADDRESS FOR SERVICE: DAVIES COLLISON, Patent Attorneys 1 Little Collins Street, Melbourne, 3000.

COMPLETE SPECIFICATION FOR THE INVENTION ENTITLED: PHARMACEUTICAL PREPARATION FOR 11SF AGAINST HYPEFRTFNSION AND CONGESTIVE HEART FAILUlRE The following statement is a full description of this invention, including the best method of performing it known to us -1- 1A PHARMACEUTICAl COMPOSITION OR UISE AGAINST HYPFRTFNSTON AND CONGESTIVF HEART FAIllRE This invention relates to novel pharmaceutical compositions effective against hypertension and congestive heart failure and to their production and use.

S The present invention provides a pharmaceutical composition 4 I C containing as active agents a Calcium Antagonist and 7-(N-[1(S)-Ethoxycarbonyl-3-Phenylpropyll-(S)-Alanyl)-1,4- Dithia-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 coadministering a) a calcium antagonist and b) Ethoxycarbonyl-3-Phenylpropyl]-(S)-Alanyl)-1,4-Dithia-7-Azaspiro- [4,4]Nonane-8-(S)-Carboxylic Acid and its pharmaceutically acceptable salts.

-g CJ 910716,tgcO32.let db8576.spe, 1

C.N

UT .i -2- 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 15 and that are useful in the lowering of elevated blood pressure when this is due to the action of angiotensin II. ACE-blocking compounds when administered alone have to be used in relatively high amounts that may lea to unwanted side effects.

The pharmaceuticalApr{ aa+ren of the invention and also coadministration 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 Sin unexpected enhancement of antihypertensive activity and an surprisingly potent activity against congestive heart failure.

The component a) induces increase in central venous pressure and consequently the increase in cardiac output is blunted in component I b) pretreated animals. The increase of central venous T o 901128,tgc032.1et,db80576.spe,2 3 pressure in the absence of cardiac depression (cardiac contractility was 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.

Preferred calcium antagonists for use in thecoposroh of the invention are those of the dihydropyridine class, e.g. of the formula

I

99r 9, 9 9 9 .499 r~ '9 999 4r .4* *r 9 9a *9 e9%( 9 4, wherein A is a residue of formula or (c) 901 128.gcO32Ietdb8076.spe 4 -Case 100-6972 R 6

(R

N 6 4(a) (c) c"Itt C.-r R is hydrogen, (C 1 )alkyl, hydroxy(C 2 )alkyl, (C 3 )alkoxyalkyl, (C 3 6 )alkenyl, (C 3 6 )alkinyl, (0 3- )cycloalkyl or (C 4 8 )cycloalkylalkyl, or zt (0 7- )phenylalkyl or (0 9- 12 )phenylalkenyl, wherein the phenyl ring is unsubstituted or mono-, di- or tni-substituted by 4 S halogen, hydroxy, (C 1 )alkyl or (C 1 4 )alkoxy, R2and R 5 are each independently hydrogen, (C 1 )alkyl, (C 7 10 )phenylalkyl, (C 3 )cycloalkyl or (04- 8 )cycloalkylalkyl, whereby, when A is a residue b, one of R2and R 5 may also be (01 )hydroxyalkyl or cyano, Rand R4are independently -ON, -COOR 7 -CORS, -S(0)n R 9 or -COO-B-N R 1 l n is 0,1or 2, R6is hydrogen, halogen, (C 1 )alkyl, 1 4 )alkoxy, (01- 4 )alkyl thio, 1 4 )alkylsulfonyl, tnifluoromethyl, nitro, hydroxy, azido, amino, (0 1- )alkylamino, di[((C 1 4 alkyllamino, (01-5) 5 Case 100-6972 4* t 4 4 tea.

a Ca.

4C a t .ae.

Ct C a 9.

a a 4S1 a at

C#

*aat Ga 9 4 a 4*9*;a a a, a C a a *a alkanoylamino, (0 2- 5 carbalkoxy, aminocarbonyl, trifluoromethoxy,cyano, sulfamoyl, (C 1 Qalkylsulfamoyl or dii (C 1 Qalkylisulfamoyl, X is oxygen or sulphur, m is 0, 1 or 2,

R

7 R. and R9are each independently (Cl6 6 )alkyl, (C 3 6 )alkenyl, (C 3 )alkinyl, (C 3 )cycloalkyl, (C 4 )cycloalkylalkyl, hydroxy-(C 2 6 )alkyl, (C 3 )alkoxyalkyl, hydroxy (0 4- )alkoxyalkyl, amino-( C 2 6 )alkyl, (C 1 )alkylamino (C 2 6 )alkyl, di[ (C 1 4 )alkyl]aminoalkyl, phenyl, (C 7 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 (C 1 4 )alkyl optionally substituted by a 5- or 6-nembered heterocyclic ring containing a nitrogen or oxygen or sulphur atom as heteroatom and which nay additionally contain 1, 2 or 3 further ring ntrogen atoms, whereby, when A is a residue b, R 7 nay also be trifluoroethyl, B is (Ci 1 4 )alkylene, R 10 and R 1are each independently (C 1 6 )alkyl, (03- 6 )alkenyl, (C 3- )alkinyl, (03- 7 )cycloalkyl, (C 4 8 cycloalkylalkyl, hydroxy(C 2 6 )alkyl, (C3- 6 )alkoxyalkyl, hydroxy (C 4 8 )alkoxyalkyl, amino(0 2 6 )alkyl, (Cl4 4 )alkylamino( C 2 6 )alkyl, di [C- 4 )alkyl]amino-(C 1 4 )alkyl, phenyl, or (07- 10 phenylalkyl, or R 10and R 1form together with the nitrogenatom to which they are attached a 6- or 7-menibered heterocyclic ring optionally 6 Case 100-6972 containing a further heteroatom selected from oxygen or sulphur or a group =N-R 12 wherein R12 is (C _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. (C 14)-alkyl, -alkoxy, -alkylthio and -alkylsulfo- S.nyl groups preferably contain 1 or 2 carbon atoms. Hydroxy, alkoxy, hydroxyalkoxy, amino and alkylamino moieties of hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl groups R 7 in residues -COOR 7 are preferably not attached at t the a-carbon atom. Suitably they are in the terminal position.

S= Preferred alkylene moities of hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl are ethylene and propylene. The alkylene moiety of cycloalkylalkyl groups is suitably methylene. Cycloalkyl moieties of cycloalkylalkyl groups are sui- 1 tably cyclopropyl, cyclopentyl or cyclohexyl. By halogen is meant fluorine, chlorine or bromine, in particular chlorine.

g The multiple bond in alkenyl, alkinyl and phenylalkenyl groups R 1 or -COOR 7 is preferably not in the a,O-position. Alkenyl and alkinyl groups preferably have 3 to 5 carbon atoms. Alkenyl is suitably allyl or 2-methylallyl is suitably propionyl. Phenylalkenyl groups preferably have the trans-configuration and in- Selude, e.g. cinnamyl. When R1 is phenyl this is preferably unsubstituted. When R 1 is di- or tri-substituted phenyl, the substituents are preferably the same and are halogene or alkyl.

Hetrocyclic rings as R 7 Rg and R 9 are, e.g. furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, morpho- 7 Case 100-6972 linyl and triazinyl. Hetrocyclic rings comprised by R 10 and R11 together with the nitrogen atom to which they are attached are preferably saturated and include pyrrolidine, piperidine, piperazine, N-alkylpiperazine and morpholine rings. Most preferred is however, di-phenyl-methyl-piperazine that can be substituted in the phenylring(s) as described above. R 2 and R 5 are preferably identical. R 6 is suitably halogen, alkyl, alkoxy, nitro or trifluoromethyl and is preferably in the o- or m-position with respect to the position of attachement of the dihydropyridine S• residue. When A is a residue R 6 is preferably hydrogen.

0 to In -COOBNR10 R B stands for an alkylene chain of 1 to 14 carbon it atoms preferably of-5 to 14 carbon atoms especially of 10 carbon atoms.

r c c r 4 I r yt 4 4 4 i/ i r 4* a 4' 4* *4* 4 *44 -4 a a 4

S

a 4 a 4 a -8- Particularly suitable compounds of formula 1, wherein A is a residue for use in accordance with the present invention are those shown in the following table (the figure indicated under represents the position of attachment of to the dihydropyridine nucleus). Compound Nos. 1 to 59 and 61 to 71 are described in GB 2138678A. Compound No. 60 is described in GB 2168052A.

Compound No. R 1

R

2

R

5 R6 x y 3 4 6 7 H CH 3 H CH 3 H CH 3 H CI1 3 H CH 3 H CH 3 H CH 3 COO-i-Bu

CH

3

H

CH

3

H

COOC

2

H

5 SO2CH 3 0 4

COOC

2

H

5 COOC 2 5

COOC

2

CH(CH(C

3 2

CH

3

CH

3

CH

3 CIT 3 0 4 H 0 4 H S 4 1 S 4 H 0 4 H 0 4 COOCH 3

COC

6 115

COOC

2

H

CH

COO(CH

2 2

N

NCH2C6HS

CH

3

CH

3 H CH 3

COO(CH

2 2

N\

COOC

2

H

5

CH

3 H S 4

CH

2

C

6

H

9 H CH 3 COO(CH 2 2

N(CH

3 2 COO (CH 2 2

N(CH

3 2 CH 3 H O 4 Ara a a.

a at a. a 0 a a a aa 0a a 9 a a-r *6 a a Compound No.

11 12 R 2

CH

3 CH 3 CH 3 COO

(CH

2 2 N (C 3 2 COO(CH) 2

N(CH

3 2

COO(CH

2 )N

(CU

3 2 O(CH )N(CH~ CH3 -C2H5 CH 3 x y S 4 0 4 S 4 13 H

CH

3 H

CH

3 H

CHU

3

/CH

3 C00

(CU

2 2 N

CH

2

C

6

H

CiU COO (CU 2

N

CHCH

Cu~

COO(CU

2 )2 N

C

H

COOC

H

2H5 CH 3 H-

S

COXC

2

H

5

CH

3 H 0 H 0 4

A

IL

cooc 2

H

5 COOCH 3

COOCH

3

COOCH

3

COOCH

3 COOCI-1 3

CH

3

CH

3

A

1 0 0 0 0 000 0 00 0 0 0 0 0 0 0 0 000 0 0 000 *00 000 000 .o :0 00 a 0 0 0 0 0 Compound.No. R 1 R 2 R5 R 6 x Cu 3 CH 3

CH

3 CH 3 CH 3

CH

3 CH 3 CH 3 CH 3

CH

3 CH 3 COO (CH 2 2 -C 6 H 5 COOCH 3 COOC2 H5 COOC2 H5 COOC (CH 3 )3~ COOCH 3 COOCH 3 COOC 2

H

5 COOC 2

H

5 COOCH 3 COOCH 2

C

6 H 5 COOC 2

H

COOC (CH 3 )3~

COOCH

COOC2 cc2 H5 COOC 2 1

A

Cu 3 CH 3

CH

3 CH 3 CH 3 CH 3 CH 3

CH

3 r'1l3 CH 3 CH13

H

7-Cl

H

S-0CH 3 7-Cl

H

4-Cl

T

ii C C 4 *9 9* 9* 10 ea a a a a a r *9 Lb *e a a. a. t LO10a S

S

a a a. a 90 a a a ao a; S a a ha La 4

C

Compound No. R 1

R

2

R

3 R4 H CH 3 H

CH

3 H

CH

3 H

CH

3 H

CH

3 H

CH

3 H CU1 3 H

CH

3 H

CH

3 H

CH

3 H

CU

3 H

CH

3 COC (CH 3 )3

COCH

3

COCH

3 OC2 H5

COC

2

H

COC

2

H

5 COC H

COCH

3

COOCH

3 coc 2 H 5CH r coocil2C(C COC

(CH

3 )3

COCH

3 COCH 3 Ccc 2

HU

5 COd 2

H

5

COC

2

H

COC

2

H

coc2H 3

COOCH

COOC

2

H

5 COOC11 3

COOCHJ.

R

5

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3 CUi 3

CH

3

CH

3 x y

H

7-Cl

H

5-OCH 3 7-Cl

H

4-Cl

H

4 t f ft ft f 4 0 2' *1 ft f .4 2n ft 2' 2' ft= 2' t .f .n ft 'I 1. ft r. ,4eX ft ft f t' Compound No. 1 43 H 44 H

H

46 H 47 H 48

H

49 H

H

51-

H

52.

H

53 H 54 H

CH

3 CH 3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

COOC

2 u 5

COOCH

2 CH(CH 3 )2

COOCH

2 CH

(CH

3 )2 COOC (CH 3 )3 COOCII 2 CH (CH 3 2 coo

(CU!

2 2

C

2

H

5 coo (Ciu 2 2 2

H

COO (CH 2 c2I5 COOCH(Cl 3 2 COO

(C

2 )2 OCH3

COO(CH

2 2

OCH(CH

3 COO(Cl 2 )2 2H5 COOC2

H

COOC

H

COOC 2 If COOC

(CH

3 )3

COOCH

2 CH(Cl 3 )2 CO0C 2 11 5

COOCH

25'

COOCH

3 2 COOCH 3 COOC 13

R

5

CH

3

CH

3

CH

3 C"3

CH

3 CH 3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3

CH

3 x Y H

CH

3

COO<]

coo (CUi 2 )2 2 CH 3

COOCH

3 COOd

(CU

3 )2 H 0 H 0 56 H

CH

3 rl .i *i 4 e t 2. 2. 42. 4 4 2.

4 2.

an 2. #6b Ir S 6 4 2. I 2.44 a, a 4 464 I1 44f.4 2.44w 1 43 a 2. 2 4 :i: Compound No. R 1

R

2 R5 R6 i

H

CH

3 n-C 3

H

7

CH

3

CH

3

CH

3

COOCH

3 COOC

H

COOC

2

H

5

COOC

2

H

5

COOC

C00 2H

CH

3

CH

3

CH

3 H CH 3 COO(CH 2 10 COOCH 3 3 10 U ro Suitable compounds of formula I, wherein A is a residue for use invention are those shown in the following table: H 0 in accordance with the present R1 R2 K 3 K 4 R5 R 6 x y m 61 H CH 3 62 H 63

H

G4 H

CH

3 CH 3 CH 3

COUCH

2 3

CF

COOCH

3 COOC2

H

COOCH(CH

3 2

CH

)(CH 2)2 N

C

CH 2

COOCH

3

COO(CH

2 2 0C 3

H

7

COOCH

3

COOC

2 H3

COOCH

3 CH 3 CH 3 CH2 OH

-CN

O-L I 2,3-di-Cl r-NO 2 rn-NO 2 1 1

I

H CH] COC CH3 m-NO2 66 H CH 3 67 H CH 3 GOOC 3 COO(C 11 2 2 0C 3 H 7 o-NO 2 m-NO 2 1 1 1 r A 4444 #4 44 14 14 44 14 1414 14 #4' -'1414 441414 14 14 14 *144 4444 fl14~. 4 14 'I 14 14 4414 14 14 14 14 14 14 14 n 1444 1414 1414 Compound No.RI x y H CH 3 H CH 3 H CH 3 H C H 3 COO(CH 2 2 0C'H 3 COOCH 3 COOC 2H5 COOC 2H5 COOCH(CH 3 2 COOCH CH(CH 3 COOCH 3 COOC 2H5 CH 3 CH 3 CH 3 CH 3 rn-NO 2 o-N0 2 rn-NO 2 o-CF 3 *1 1 .1 1 I A suitable compound of formula I, wherein invent-ion is compound No. 72 wherein: R1=H, R2= CH-i 3 1, 3 C0C 2 H 5 2 A is a residue for use in accordance with the present R 4= COOC 2 H 5 R 5= CH 3 and R 6= o-SCH3* f 00 0 0 0 a 0 e 9 o oe e 0 e0 a 4 6o 00 o o o 0 i0 ?a 1 Be; 15 Case 100-6972 Especially prefered calcium-antagonists according to a) have the formula

X

I I

R

"1 SN N wherein R 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 trisubstituted independently by halogen, hydroxy or alkyl or alkoxy of 1 to 4 carbon atoms.

R

2 and R 5 independently, are hydrogen or alkyl of 1 to 6 carbon atoms,

R

3 and R 4 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 cycloalkylalkoxy of 4 to 8 carbon atoms, or R 3 has the significance

O-B'-R

7 wherin B' is an alkylene chain of 9 to 14 carbon 4 I- 28 the 4 position by methyl, benzyl or bis-phenylmethyl optionally mono- or independently disubstituted in the ohenvl rina(s) by 16 Case 100-6972 atoms and R 7 is piperidine or piperazine both substituted in 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 R' 4 has the significance cited above, R 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 formula I or of formula la are 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6acid diethyl ester, hereinafter referred to as compound No 1;4-(2,l,3-benzoxadiazol-4-yl)- 1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5carboxylic 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 (2,1,3-benzoxadiazol-4-yl)-l,4-dihydro-5-methoxycarbonyl- 2,6-dimethyl-3-pyridine carboxylic acid-[10-[4-(diphenylmethyl)- 17 Case 100-6972 piperazin-l-yl]decyl]ester referred to as compound No 4; especially interesting are compounds No 2 and No 4.

7-(N-(1(S)-Ethoxycarbonyl-3-Phenylpropyl]-(S)Alanyl)-1,4- Dithia-7-Azaspiro[4,4]Nonane-8-(S)-Carboxylic Acid has the alternative chemical name (Ethoxycarbonyl)-3-phenylpropyl]amino]-l-oxopropyl]-1,4-dithia-7-a zaspiro[4.4]nonane-8-carboxylic acid. It is also identified by SCHERING as SCH-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.

0 *o 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.

i 4 o For example when a calcium antagonist especially a compound of formula I and 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 FlUckiger et al., Schweiz.

Med. Wochenschrift 93, No 35 [1963] 1232-7) described in the following: 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.

I* This effect is confirmed in sodium-depleted rats. Rats are given furosemide (50 mg/kg/day) with drinking water for two days. Groups t 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 Sitt 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 S it excretion measured. Similar values as in the hydrated rat test are obtained.

Ii r It has thus been unexpectedly found that the diuretic and natriuretic activity is generally maintained t 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 antihypertensive effect of the co-administering a calcium antagonist and component 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.

-I-111^13~li 19 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 ,nd diluents, may also be formulated therewith.

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 15 divided doses 2 to 4 times a day in unit dosage form containing from J about 0.05 mg to about 175 mg e.g. to 20 mg of the compounds, or in sustained release form. The preferred 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 preferably from about 5:1 to about 1:3. Component b) may be l25 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 1:5, especially about e.g. 5:1 to 1.1 such as 1:1, 4:1, 3:1 or 2:1.

910716,tgcO32.e0db80576.spe,19 n N 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 suspension, 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 o facilitate administration of a particular dosage regimen, 15 e.g. in a particular order in a blister pack.

The active agents may also be arranged 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 component a) and a predetermined amount of one of the component b).

The following Examples are illustrative of compositions for use in the invention.

910801,dbdat072,80576.res,20 21 Case 100-6972 EXAMPLE 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.

Ingredient Weight Compound No 2 10.0 mg Component b) 2.0 ag 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 4 EXAMPLE 2: Tablets for oral administration Sufficient amounts of the components are mixed in conventional manner and filled into gelatine capsules or compressed to tablets, which are administered once a day for the treatment of hypertension and congestive heart failure.

22 Case 100-6972 Ingredient Compound No 2 Component b) Lactose Sodium lauryl sulfate Polyvinylpyrrolidone Corn starch Magnesium stearate Weight 10.0 mg 2.0 mg 224.0 mg 2.0 mg 8.0 mg 13.0 ng 2.6 ing 262.0 mg *6 0 0 *000 p 0S 6606 9 06 6 4~*6 00 6 6 6 06 6 6 9 060 60 6 *6 0 0 0 EXAMPLE 3: Separate Co-administration Capsules of compound No. 2 may be made up with the following composi tion Compound No 2 10 mg Microcrystalline Cellulose (Avacel) 47 ng Cetyl Palmitate 10 mg Hydroxyprbpyl methylcellulose (Methocel E4M) 90 mg Silica colloidal 1 mg Magnesium stearate 2 mg 160 mg and Capsules of component b) may be made up composition with the following

I

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

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V

4 4*£ 4 4 444 V Is .~t

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4 V V C 4 VC*

V

I Vt 4 V V V V 4 V Vt *44% Vt

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Claims

7-if 24 THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 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 characterized in that the calcium-antagonists are those of formula I i itt C a a a it I- 4a *4t C. *440 wherein A is a residue of formula or (c) (R 6 )m (b) R 6 (c) 910716,tgcO32,1et 080576.spe,24 25 Case 100-6972 Ris hydrogen, 1 6 )a lkyl, hydroxy(C2-6)alkyl, (0 3- )alkoxy- alkyl, (C 3 )alkenyl, (C 3 )alkinyl, (C 3 7 )cycloalkyl or (C 4 )cycloalkylalkyl, or (C 7 )phenylalkyl or (C 9 12 phenylalkenyl, wherein the phenyl ring is unsubstituted or mono-) di- or tri-substituted by alogen, hydroxy, (C 1 -4 al1koxy, Rand R 5 are each independently hydrogen, (C 1 )alkyl, (C 7 10 phenylalkyl, (C 3 )cycloalkyl or (C 4 8 )cycloalkylalkyl, whereby, when A is a residue b, one of R2and R 5 may also be (C 1 4 )hydroxyalkyl or cyano, R3and R 4 are independently -CN, -COOR 7 0 COR 8 0 n R 9 or -COO-B-N R 10 R ill 12 (12 1212 12 12 12 12 12 12; I -t 112$ 12 (4 4 (It I 1461 1 12 I It 12 4 I- 1212 n is 0, 1 or 2, 12 t 12 12 Ris hydrogen, halogen, (C1-4)alkyl, (C 1- alkoxy, (C 1 )alkyl- thio, (C 1 4 )alkylsulfonyl, trifluoromethyl, nitro, hydroxy, azido, amino, (C 1 )alkylamino, dif(C 1 4 )alkylJ- amino, (C 1 5 )alkanoylamino, (C 2 5 )carbalkoxy, aminocar- bonyl, trifluoromethoxy, cyano, sulfamoyl, (c 1 4 )alkyl- sulfamoyl or di((C 1 4 )alkyllsulfamoyl, 124 12 12 t 12(1 lIlt 412 12 X is oxygen or sulphur, M i's 0, 1 or 2, R P R 8 and R 9 are each independently 1 6 )alkyl, (C 3 )alkenyl, (C 3 )alkinyl, (C 3 7 )cycloalkyl, (C4_ 8 )cycloalkylalkyl, hydroxy-(C 2 6 )alkyl, (C 3 6 )alkoxyalkyl, hydroxy(C 4 8 alkoxcyalkyl. amino-(C 2 6 alkyl, (C 1 Q4a~kylamino(C 2 6 21 SI fl 26 -Case 100-6972 alkyl,difC 14 )alkyllaminoalkyl, phenyl, (C 7 1 phenylalkyl, a 5- or 6-membered heterocyclic ring, contaiining a nitrogen or oxygen or sulphur atom and which ma al-sc, contain 1, 2 or 3 additional ring nitrogen atoms, or (C 1 4 )alkyl optionally substituted by a 5- or 6-membered heterocyclic ring containinhg 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, R 7 may also be trifluoroethyl, t "vB is (C 1 )alkylene, t t 9 Rio and .11are each independently (C 1 6 )alkyl, (C 3 6 )alkenyl, (C 3 )alkinyl, (C 3 7 )cycloalkyl, (C 4 8 )cycloalkylalkyl, hydroxy(C 2 6 )alkyl, (C 3 )alkoxyalkyl, hydroxy (C 4 8 alkoxyalkyl, amino(C 2 6 )alkyl, (C 1 4 )alkylamino (C 2 alkyl, di-KC 1 )aylmio( 1 )al!kyl, phenyl, or c t(C 7 )phenylalkyl, or 7-1 R i and R 1 form together with the nitrogenatom to which they are attached a 6- or 7-membered heterocyclic ring optinal2ly containing a further heteroatom selected from 'Ioxygen or sulphur or a group uN-Rl 2 wherein R Is (C1-4)alkyl, benzyl or bis- phenylimethyl optionally mono- or independently disubstituted in the phenyl ring(s) by halogen of atomic number from 9 to 35 or (C 1 )alkoxy. 3. A pharmnaceuticaY~pet u according to claim 1 or claim 2 characterized in that the calcium-antagonists are those of Formula Ia. 27 Case 100-6972 'NI R6 N Ia R 4 0C COR3 4 3 I I R N Sto ::,wherein R 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 alko.y of I to 4 carbon atoms. R and R independently, are hydrogen or alkyl of 1 to 6 carbon 2 5 atoms, and R 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 R has the significance wherein B' is an alkylene chain of 9 to 14 carbon atoms and R is piperidine or piperazine both substituted in -4 28 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 R 4 has the significance cited above, R 6 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 any of the claims 1 to 3, 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- acid isopropyl ester; 4- (2,1,3)-benzoxadiazol-4-yl-1,4-dihydro-2,6-dimethyl-1,4- acid dimethyl ester and (S)-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-5-methoxy- carbonyl-2,6-dimethyl-3-pyridine carboxylic acid-[10[4-(di- phenylmethyl)-piperazin-1-yl]decyl ]ester. A composition according to any of the claims 1 to 4 characterized in that the weight ratio of component a) to component b) is from 5:1 to about 1:3. 6. A composition according to claim 5 wherein the weight ratio is from 5:1 to 1:1. 7. A method of treating hypertension or congestive heart failure which comprises co-administering component a) and component b) as defined in anyone of the claims 1 to 6 to a subject in need of such treatment.
8. A method according to claim 7 wherein the calcium antagonist is the 4-(2,1,3-Benzoxadiazol)-4-yl-1,4-dihydro-2,6-dimethyl-3- TRA, methoxycarbonyl-pyridine-5-carboxylic acid isopropylester. I: 910716,tgcO32.etdb80576.spe,28 -29-
9. A methoi according to claim 7 wherein the calcium antagonist antagonist is the 4-(2,1,3-Benzoxadiazol-4-y1)-1,4-dihydro-2,6- acid diet.hylester.
10. A method according to claim 7 wherein the calcium antagonist is the 4-(2,1,3-Benizoxathiadiazol-4-yl)-2,6-di-ethyl-1,4- acid dimet~ylester.
11. A method according to claim 7 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-[lO- [diphenylmethyl)-piperazin-1-yl~decyllester.
12. A method according to claim 7 wherein component b) is the 7-(N- 4L15 [1(S)-ethoxycarbonyl-3-phenylpropyl]-(S)-alanyl)-1,4-dithia-7- azaspiro-[4,4]nonane-8-(S)-carboxylic acid monohydrochloride monohydrate. concomitant administration o7f a com ra component b) jl as defined in a e claims 1 to 6, said components a) bpi- id pack or dinPcsr-dA c Dated this 28th day of November, 1990 SANDOZ LTD By its Patent Attorneys DAVIES COLLISON 901 128,tgcO32.Ietdb80576.spe,29 AINT 0'