FR2605885A1 - DRUG ASSOCIATION BASED ON A CALCIUM INHIBITOR - Google Patents

Abstract

THE SUBJECT OF THE PRESENT INVENTION IS A MEDICINAL ASSOCIATION COMPRISING A CALCIUM INHIBITOR AND 7- (N-1 (S) -ETHOXYCARBONYL-3-PHENYLPROPYL- (S) -ALANYL) -1,4-DITHIA-7-AZA- SPIRO-4,4NONANE-8- (S) -CARBOXYLIC. THIS ASSOCIATION CAN BE USED IN THE TREATMENT OF HYPERTENSION AND GLOBAL HEART FAILURE.

Description

The subject of the present invention is a new association

  drug therapy effective in the treatment of hypertension and

  of global heart failure.

  In particular, the invention relates, as a medicament, to a combination agent comprising, as active substances, a) a calcium channel blocker and

  b) 7- (N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] - (S) -alanyl) -

  1,4-dithia-7-azaspiro [4,4] nonane-8- (S) -carboxylic acid or one of

  pharmaceutically acceptable salts thereof.

  The invention also relates to a pharmaceutical composition

  comprising, as active substances, a) an inhibitor

  calcium and b) 7- (N- [1- (S) -ethoxy-carbonyl-3-phenylpropyl] -

  (S) -alanyl) -1,4-dithia-7-azaspiro [4,4] -nonan-8- (S) -carboxylic acid or a pharmaceutically acceptable salt thereof, in combination with

  a pharmaceutically acceptable carrier or diluent.

  Calcium inhibitors include a class of physiologically active substances characterized by their calcium ion antagonist or calcium channel blocking activity. A wide variety of these compounds are currently known which have wide therapeutic application, in particular in the treatment of disorders or cardiovascular diseases, for example in the treatment of coronary insufficiency, disorders of the cerebral circulation, hypertension and in the treatment of other circulatory disorders. The

  calcium channel blockers are usually used as vaso

  dilatates, for example in the treatment of hypertension.

  Component b) is an inhibitor of angiotensin converting enzyme (ACE). There are few publications

  concerning its pharmacological and biopharmaceutical properties.

  ACE inhibitors are known compounds that affect the transformation of angiotensin I to angiotensin II and are useful for lowering high blood pressure when it is due to the action of angiotensin II. . When administered alone, compounds that block ACE must be used in relatively large amounts, which may

  cause unwanted side effects.

  The Applicant has now found that the combination of component a) and component b) surprisingly and unexpectedly has advantageous pharmaceutical properties and a particularly favorable or improved pharmacological / therapeutic profile. It has been found, in particular, that the co-administration of the component

  component b) causes an unexpected increase in activity

  antihypertensive and surprisingly a strong activity

  against global heart failure.

  Component a) causes an increase in central venous pressure, so that the increase in cardiac output

  is weakened in animals pretreated with component b).

  The increase in central venous pressure in the absence of depression of cardiac function (cardiac contractility was measured accurately through a strain gauge attached to the myocardium) indicates an increase in venous return caused by arterial dilation. The downward effect of component a) also indicates an increase in

  venous distancibility after inhibition of ACE.

  Preferred calcium channel blockers for use according to the invention are those of the class of dihydropyridines, for example those of formula I See formula next page A R4 t

HAVE)

  Rs wherein A represents a radical of formula (a), (b) or (c)> N / X gR6) R6 (a) (b) (c) R1 is hydrogen, C1-C6 alkyl, hydroxy C 2 -C 6 alkyl, C 3 -C 6 alkoxyalkyl, C 3 -C 6 alkenyl, C 3 -C 6 alkynyl, C 3 -C 7 cycloalkyl or C 4 -C 8 cycloalkylalkyl, or C 7 -C 7 phenylalkyl group; -C9 or phenyl-C6-C12 alkenyl, wherein the phenyl ring optionally carries one, two or three substituents selected from halogens and hydroxy, C1-C4 alkyl and C1-C4 alkoxy, R2 and R5 each signify , independently of one another, hydrogen, C1-C6alkyl, phenyl-C7-C10alkyl, C3-C7cycloalkyl or cycloalkyl-C4-C8alkyl, one of the

  symbols R2 and R5 may also signify a hydroxyl group

  C1-C4alkyl or cyano when A represents a residue b, R3 and R4 mean, independently of one another, -CN, -COOR7, -COR8, -S (O) nRg or -COO-BN-Rlo -R1, n is 0, 1 or 2, R6 is hydrogen, halogen or C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, C1-C4alkylsulfonyl, trifluoromethyl, nitro, hydroxy, azido, amino, C1-C4alkylamino, di-C1-C4alkylamino, C1-C5alkanoylamino, C2-C5alkoxycarbonyl, aminocarbonyl, trifluoromethoxy, cyano, sulfamoyl, C1-C4alkylsulfamoyl or di-C1-C4alkyl -C4) -sulfamoyl, X is oxygen or sulfur, m is 0, 1, or 2, R7 R8 and Rg are each independently of one another C1-C6 alkyl, C3-C6 alkenyl C3-C6alkynyl, C3-C7cycloalkyl, C4-C8cycloalkylalkyl, C2-C6hydroxyalkyl, C3-C6alkoxyalkyl, hydroxy, C4-C8alkoxyalkyl, C6-C6aminoalkyl, C1-C4) amino-C2-C6 alkyl, di (C1-C4 alkyl) aminoalkyl, phenyl , C 7 -C 10 phenylalkyl, a 5- or 6-membered heterocyclic ring containing a nitrogen, oxygen or sulfur atom and which may also contain 1, 2 or 3 additional cyclic nitrogen atoms, or a group

  C1-C4 alkyl optionally substituted with a hetero ring.

  a 5- or 6-membered ring containing a nitrogen, oxygen or sulfur atom as a heteroatom and which may also contain 1, 2 or 3 other cyclic atoms, R 7 may also represent a trifluoroethyl group when A signifies a residue b, B represents a C1-C14 alkylene group, Rlo and R11 each signify, independently of one another, a C1-C6 alkyl, C3-C6 alkenyl or C3-C6 alkynyl group;

  C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, hydroxyl-

  C2-C6alkyl, C3-C6alkoxyalkyl, C4-C8hydroxyalkylalkyl, amino-C2-C6alkyl, -C1-C4alkylamino-C2-C6alkyl, di (C1-C6alkyl) C4-amino) -C1-C4alkyl, phenyl, or phenyl-C7-C10alkyl, or R101 and R11 together with the nitrogen atom to which they are attached form a 5-, 6-membered heterocyclic or 7-membered ring optionally containing another heteroatom selected from oxygen and sulfur, or a group = N-R12 in which R12 is C1-C4 alkyl, benzyl or bisphenylmethyl, optionally mono- or independently disubstituted in the ring (s) phenyl by a halogen having an atomic number of 9 to 35 or by

a C1-C4 alkoxy group.

  In formula I, C1-C6 alkyl groups

  preferably contain 1 to 4 carbon atoms, more preferably

  1 to 2 carbon atoms, the methyl group being particularly preferred. The C 1 -C 4 alkyl, alkoxy, alkylthio and alkylsulfonyl groups preferably contain 1 or 2 carbon atoms. The radicals hydroxy, alkoxy, hydroxyalkoxy, amino and

  alkylamino groups hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy

  alkyl, aminoalkyl and alkylaminoalkyl represented by R7 are preferably attached to a carbon atom other than the α-carbon atom. They are preferably in the terminal position. The preferred alkylene radicals of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl groups are the residues

  ethylene and propylene. The alkylene residue of the cycloalkyl groups

  alkyl is preferably methylene. Cycloalkyl residues

  cycloalkylalkyl groups are preferably cycloalkyl radicals

  propyl, cyclopentyl or cyclohexyl. Halogen means the

  fluorine, chlorine or bromine, especially chlorine.

  Multiple binding in alkenyl, alkynyl groups

  and phenylalkenyl represented by R1 or -COOR7 is preferably located

  position other than position a, B. The alkenyl and alkynyl groups preferably have from 3 to 5 carbon atoms. The alkenyl group is preferably an allyl or 2-methylallyl group, and the alkynyl group is preferably a propargyl group. The phenylalkenyl groups preferably have the trans configuration and include, for example, the cinnamyl group. When R1 represents

  a phenyl group, the latter is preferably unsubstituted.

  When R 1 is di or tri-substituted phenyl, the substituents are preferably the same and are halogens or alkyl groups. The heterocycles represented by R 7, R 8 and R 8 are for example furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, piperidinyl, morpholinyl and triazinyl. The heterocycles represented by R 10 and R 11 together with the nitrogen atom to which they are attached, are

  preferably saturated and include pyrrolidine, piperine and

  ridine, piperazine, N-alkylpiperazine and morpholine, more preferably

  optionally di-phenyl-methyl-piperazine optionally substituted in the phenyl ring (s) as described above. R2 and R5 are preferably the same. R6 preferably means a halogen or a

  alkyl, alkoxy, nitro or trifluoromethyl group, preferably located

  in ortho or meta position relative to the point of attachment to the dihydropyridine ring. When A represents a remainder a), R6

  preferably means hydrogen.

  In the group -COOBNRjoR11, B represents an alkylene chain of 1 to 14 carbon atoms, preferably 5 to 14 atoms

  carbon, especially 10 carbon atoms.

  The compounds of. formula I in which A represents a residue (a) particularly suitable for use according to the invention, are those indicated in the following table ("y").

  represents the binding position of (a) on the dihydropy-

  ridinique. Compound n R 1 R R R 3 R 4 R R 6 X y 1 H CH 3 CN COO-i-Bu CH 3 B O 4

2HCH3 COOC2H5 SO2 3 CH3 H 0 4

3 H CH3 CN COOC2H5 CH3 H O 4

4 H CII3 CN COOC2115 CHi3 H S 4

CH3 CN COOCH2CH (CH3) 2 C3 I S 4

3 COC2CC3) 2

6 H CH3 COOCH3 COC6115 C! I3 H O 4

CH3

  7 H CH3 COO (CH2) 2 COOC2H5 CH3 H O 4

CII3

  8 H CH3 COO (CH2) 2N COOC2H5 CH3 H S 4

CH2C6H5

/ C6 3

8 H CH3 COO (CH2) COO-C2H CH3 H S 4

CH2C6H5

  CH 3 COO (CH 2) 2 N (C) 13 COO (CH 2) 2 N (C 13) 2 4 * oe n ci co c> o. It is the same as the time of the day.

H9 DZHD

  the S. 9 Z S O HfRO SIIZDOD NZ (ZHD) OOO úHD H flI [Hi) / EO

S H ÜHD S DOOD (ND) OOD HÈ H

  IID sH9 r I {SHIZDOOD Z (H) NZ zH) oo D H

0 H D HDN <H: 6D) OHZ H OD

  SHH :) Z (C: H5) N (ZX :) (ú I :) NZ (ZH :)) OoD úHD H Ot AX 9U r tH ú lu asodwo3 SS ID-> ú1D SIlDOOD úHDOODlidH WHERE SSU Hú3 511Z30D sHZ300D úHD H 6Z S TO-L ú113 SHzDOD sHZDOOD HD the 8Z sr

H1DO-SH3 0HZDO3 HDOO3úH3 H LZ

  t SH CHD ú DOOD C OOD H t'S HtH3 ú113003 C113003ú113H 9 t O T3-L.H3 ú11300D úHDO3 úH3 H SZ b SH CHD (ú113) DD003 c (H3) 3003 CH HZSH ú1H SHZDOOD SHZDOOD úH3 HZ t OH úH3 SHZ3003 SHZD003 úH3 HZ t OH úH3 SH93ZHD03 úH3003 úH1 HI t OH úIlD ú13003 -SH93D-Z (ZHD) OODúHD H oZ t OH SH11ZO HZ DOOD v H 61 X 9U sC 0 úlZ of the osodwoj b OH C1 <IOOúD 11003 IHZ> b IOIRI 0 IIDOOZ ( H) 1D O1D3U1DH1 tl b1'SH tfl3H tZIDOO i3D út!) HIO b OH úH). úH ZOOD HDO3D C11DH 6C b úIl 3 úHO10) HOD ú1 H 0 c SSH úH13DO :)) IlZD03 úH3H 9 'bS-L úH3 SHZ DOD 3H0; 50 ú113H 5ú D {' 'SHti; DHDO-Hi gHDOD ú H DOD úHDH 0 {b 0 ú3HH HD 3OHDO3 H3OD ú113H> O TO-L tHÈúH303 úHD03 úH3 H Zú gS HH gid O 13-L Cfl3 úfClHZDD 'Cú1! 303úHD3H 9 0 TD-LRD HDOD CH {DO; DúHiH Zr b' SH úH11 ú H ( CHO) [CúH; DO> Dú1H1H lú p IxRD úD) úo HD 0u H sodwo I xu Id UE Húu psodwo3 0O H HD ZooD DO () HDOOl D) OODEHDH 9 SIOH CHD C JIOODSHZDOZ (Zj3) 3OODúDH vs IOH úI IîDOOD ZúH) DO (<HD) OODCHDH Cs IOH CHD CHDOOD CHDOe (eHD) OODtHDH Z5 OH CHl- CHDOOD (Ci) DOD HdH Tg SSH r iDOOD S 11ZDO {(rZHDO) OODUHDH OS SH 'IiD SIlDOOD úH DO' (ID) OODúD H ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR2 ## ## STR13 ## ## STR2 ## Z (CHD) HDZHDOODUHDH 5t> $ H HrD SHZOOO) (rHiD) HDIHDOODCHDH v {SOH úrd3 HZ DOOD SHZDOOD HrD HC b X 9u the E {C: Id 0 u asodwo3 Compound n R1 R2 R3 R4 R5 R6 X y

57 H CH3 COOCH3 COOC2H5 CH3 H O 4

  58 CH3 CH3 COOC2H5 COOC2H5 CH3 H 0 4

  59 n-C3H7 CH3 COOC2H5 COOC2H5 CH3 H 0 4

H CH3 COO (CH2) 10-COOCH3 CH3 H O 4

  The compounds of formula I in which A represents a residue (b) suitable for use according to the invention are those indicated in the following table: ## STR1 ##

3 2 3 3 3

  62 H CH3 COOCH3 COOC2H5. CH3 2,3-di-Cl - - 2 63 H CH3 COOCH COOCH CHOH mNO - - 1

COOC2H5 2 2

  64 H CH3 COOCH (CH3) 2 COOCH -CN m-NO2 -

3C 3-N231

CH HCH, 3COOCH 3 CH 3 m-NO 2 - - 1

H CH3 COO (CH2) 2NCH2-C CH

CH5-CH62

  66 H CH COOCH3 C COOCH3 CH o-NO - - o 67 H C3 (2) 2 3 7 (2) 2 37CH3 m 2 Co '67 H CH 3 C00 (Cil 2) 20C3H7COCl22o37C -O2 -C Compound n RR R3 R4 R5 R6 xy mni

  68 H CH3 COO (CH2) 20 CH3 COOCH (CH3) 2 CH m-NO - -

69 H CH3o-NO2 - -

  CH3 COOCH3 COOCH2CH (CH3) 2 CH3 o-NO2 1 CH3 COOC2H5 COOCH3 CH m-NO2 1

3 2 5 33 2

  Embedded image A compound of formula I wherein A signifies a residue (c) suitable for use according to the present invention is compound No. 72 in which: R.sub.2, R.sub.2 CH.sub.3, R.sub.3 COOC.sub.2 H.sub.5 The most preferred calcium channel blockers are those of the formula Ia R 1, R 2 CO 5 H 5, R 5 CH and R 6

\ X

  wherein R'l is hydrogen, C1-C6 alkyl, C3-C6 alkenyl or alkynyl, C3-C7 cycloalkyl or C4-C8 cycloalkylalkyl or C7-C9 phenylalkyl or phenyl-alkenyl; C9-C12, wherein the phenyl ring optionally carries one, two or three substituents selected from halogens and hydroxy, C1-C4 alkyl and C1-C4 alkoxy, R'2 and R'5 independently signify hydrogen or a C1-C6 alkyl group R'3 and R'4 independently represent a C1-C6 alkyl group,

  C3-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, cycloalkyl

  C 4 -C 8 alkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 hydroxyalkoxy, C 3 -C 6 alkoxyalkoxy, C 4 -C 8 hydroxyalkoxyalkoxy, C 3 -C 6alkenyloxy or C 3 -C 6alkynyloxy, C 3 -C 7cycloalkyloxy or cycloalkyl- C4-C8 alkoxy, or R'3 is O-B'-R'7, B 'is an alkylene chain containing 9 to 14 carbon atoms and R'7 is piperidine or piperazine both substituted in position 4 with a methyl, benzyl or bis-phenylmethyl group optionally mono- or independently disubstituted in the phenyl ring (s) by a halogen atom of atomic number 9 to 53 or by a C1-C4 alkoxy group and R'4 at the R'6 meaning hydrogen, halogen, alkyl, alkoxy, alkylthio or alkylsulfonyl each of C1-C4 or trifluoromethyl, nitro or hydroxy, and

  X has the meaning indicated above.

  The calcium channel blockers used according to the invention are generally described as well as their calcium ion antagonist activity and antihypertensive activity in previously published patents. In these patents, it may also be mentioned that the salts of calcium channel blockers of formula I may be used in place of free bases. It can further be considered that when the substituents in the 2 and 6 and / or 3 and 5 positions of the 1,4-dihydropyridinyl moiety are different, the calcium channel blockers may exist in racemic form or in the form of

of individual enantiomers.

  Calcium antagonists of formula I or of formula la which are of particular interest are the diethyl ester of the acid

  4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5

  dicarboxylic acid, hereinafter referred to as compound n 1; ester

  isopropyl acid of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-

  2,6-dimethyl-3-methoxycarbonylpyridine-5-carboxylic acid, hereinafter referred to as compound n 2; the dimethyl ester of 4- (2,1,

  3-benzoxathiadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-

  dicarboxylic acid, hereinafter referred to as compound No. 3 and the ester 10- [4-

  (diphenylmethyl) -piperazin-1-yl] decyl (+) - (S) -

  4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-di-

  methyl-3-pyridine-carboxylic acid, hereinafter referred to as compound No. 4; the

  Compounds No. 2 and No. 4 are particularly interesting.

  7- (N- [1 (S) -ethoxycarbonyl-3-phenylpropyl] - (S) - acid

  alanyl) -1,4-dithia-7-azaspiro [4,4] nonane-8- (S) -carboxylic can

  also be designated as rF8-S- [7 [R * (R *)], 8R *]] - 7- [2 - [[- 1-

  (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl-1,4-dithia

  7-azaspiro [4.4] nonane-8-carboxylic acid. It is also designated by SCHERING as compound SCH-33844 and bears the generic name of SPIRAPRIL. This compound is described in Example 3 of US Patent No. 4,470,972. In this US patent, it is also mentioned that the compound has antihypertensive activity. The pharmaceutically acceptable salts can be used. The hydrate can be used. In this US patent, various salts are described and can be used in place of the free base, for example the hydrochloride as described in Example 4 of this patent, or hemimaleate such as

  described in Example 5 of this patent. The preferred form is mono-

hydrochloride monohydrate.

  Co-administration of a calcium channel blocker and component b) has potent anti-hypertensive activity and activity against global heart failure as shown

pharmacological tests.

  Thus, for example, when animals are given a calcium channel blocker, especially a compound of formula I, and component b), the natriuretic and diuretic activity of calcium channel blockers, especially

  Formula I, is surprisingly maintained. The co-administrators

  The treatment of a calcium channel blocker, especially a compound of formula I, and the ACE inhibitor indicated above, thus eliminates the need to administer other diuretics and / or beta-blockers. This effect has been demonstrated in the following test of the hydrated rat described by FlUckiger et al. In Schweiz. Med. Wochenschrift 93, No. 35 (1963) p. 1232-7: Groups of 12 rats are used. Component a) alone is tested at doses causing diuresis, for example at a dose of 0.3 to 3 mg / kg administered orally, or in combination with component b) at a dose of 3 mg / kg administered. subcutaneously. The compounds are administered at the same time. The urine is taken for 3 hours and its volume is measured

and sodium excretion.

  This effect is confirmed in sodium-deprived rats.

  The rats receive furosemide (50 mg / kg / day) with water for two days. Groups of 6 animals are used. The calcium channel blocker is administered orally at doses of

  diuresis, for example, between 0.3 and 3 mg / kg and

  component b) at doses of 3 mg / kg subcutaneously. The compounds are administered at the same time. The urine is taken for 3 hours and its volume and sodium excretion are measured. Values similar to those obtained in

the rat test hydrated.

  The Applicant has surprisingly found that

  diuretic and natriuretic activity is generally maintained.

  This is surprising and makes the combinations of the invention particularly well suited for the treatment of hypertension and congestive heart failure and reduces

diuretic needs.

  The importance of this effect is evident from the constant concern of specialists regarding the consequences on the metabolism of the administration of diuretics for long periods. The antihypertensive effect resulting from the co-administration of a calcium channel blocker and component b) is still

increased by renal effect.

  Components a) and b) - as mentioned above-

  may be in the form of a free base or, if necessary, in the form of

  a salt, for example in the form of an acid addition salt.

  The pharmaceutical compositions of the invention may be prepared according to the usual methods by mixing an inhibitor

  calcium and component b), with pharmaceutical excipients

acceptable.

  The compositions of the invention can therefore be used for the treatment of hypertension and insufficiency

overall heart.

  The calcium channel blocker may be administered at a dose of between 33 and 100% of the normal dose to treat, for example, hypertension or congestive heart failure. The appropriate daily dose of the compounds of formula I is from about 0.2 mg to about 350 mg, particularly from about 1 to mg, advantageously administered in divided doses 2 to 4 times daily in unit doses containing about 0.05 mg to about 175 mg, for example 20 mg of compound, or in sustained release form. The preferred compound is compound No. 2. The appropriate dose is from about 2.0 to about 10 mg

  administered orally 1 or 2 times daily.

  Compound (b) may be administered at a dose

  approximately 33% to 100% of the normal dose to treat hyper-

  tension or overall heart failure. The appropriate doses

are 3 mg, 6 mg, 12 mg and 24 mg.

  The preferred weight ratio of the calcium channel blocker to compound b) calculated on the free base can be from about 50: 1 to about 1:10, in particular from about 10: 1 to about 10: 1.

  about 1: 5, preferably between about 5: 1 and about 1: 3.

  For compound no. 2 and component b) the preferred weight ratio is from about 50: 1 to about 1: 5,

  especially from about 5: 1 to 1: 1, for example 1: 1, 4: 1, 3: 1 or 2: 1.

  Components a) and b) are suitably administered in the form of a pharmaceutical composition in association with a pharmaceutically acceptable carrier or diluent. Such compositions may be formulated according to the usual methods in the form of, for example, a solution, for example an injectable solution or suspension, or preferably in a solid form, for example in the form of tablets or capsules. If necessary, one or both of the compounds may be in a sustained release form, for example in the case of compounds Nos. 1 and 2 as described in British Patent Application 218 1053 A or 216 0 100 A. necessary, the active substances may be placed in a package to facilitate the administration of a particular dose; they can, for example be placed in an order

  particularly in a blister pack.

  A suitable composition may also be presented in a package containing separately a component a) and a component b) until required for concomitant administration, advantageously together with the instructions for concomitant administration of a predetermined amount of

  component a) and a predetermined quantity of component b).

  The following compositions are given as

illustrative but not limiting.

  EXAMPLE 1 Capsules for Oral Administration The capsules containing the ingredients indicated below can be prepared according to the usual methods, and be administered once a day for the treatment of hypertension.

  and overall heart failure.

  Ingredients Weight 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 Polyethylene Glycol 6000 88.0 mg 322.0 EXAMPLE 2: Tablets for oral administration In the usual methods, sufficient amounts of the ingredients are mixed and filled with capsules or prepared into tablets, which are administered once a day for the treatment of the patient. hypertension and overall heart failure. Ingredients Weight Compound # 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 EXAMPLE 3: Separate Coadministration Compounds No. 2 having the following composition were prepared: Compound No. 2 10.0 mg Microcrystalline Cellulose (Avacel) 47.0 mg Cetyl Palmitate 10.0 mg

Hydroxypropyl methylcellulose -

  (Methocel E4M) 90.0 mg Colloidal Silica 1 mg magnesium stearate 2 mg 160.0 mg and capsules based on component b) having the following composition: See composition on the next page Component b) 12.0 mg Lactose 349.0 mg Silica (Colloidal) 8.0 mg Maleic Acid 5.0 mg Stearic Acid 16.0 mg 400.0 mg These capsules may be presented in calendar-dose packs. If necessary, combined capsules

  containing the two active substances can be prepared.

Claims (9)

  1. As a medicinal product, the medicinal combination comprising, as active ingredients, a) a calcium channel blocker and b) 7- (N-1 (S) ethoxycarbonyl-3-phenylpropyl] - (S) -alanyl acid) 1,4-dithia-7-azaspiro-4-butane-8- (S) -carboxylic acid or one of   pharmaceutically acceptable salts thereof.   2. A pharmaceutical composition, characterized in that it comprises, as active ingredients, a) a calcium channel blocker and   b) 7- (N- [1S) -ethoxycarbonyl-3-phenylpropyl] - (S) -alanyl) -   1,4-dithia-7-azaspiro [4,4] nonane-8- (S) -carboxylic acid or one of   pharmaceutically acceptable salts thereof.   3. A pharmaceutical composition according to claim 2, characterized in that the calcium channel inhibitor has formula IA IQ R 3 I) He.   Wherein A represents a radical of formula (a), (b) or (c) R6 I '"(a) (b) (c) R1 is hydrogen, C1-C6alkyl, hydroxyalkyl C2 -C6, -C3-C6alkoxyalkyl, -C3-C6alkenyl, -C3-C6alkynyl, -C3-C7cycloalkyl or -C4-C8cycloalkylalkyl, or a phenyl-C7-C9alkyl or phenyl-C4-C8alkyl group. C 1 -C 12 alkenyl, wherein the phenyl ring optionally carries one, two or three substituents selected from halogens and hydroxy, C 1 -C 4 alkyl and C 1 -C 4 alkoxy, R 2 and R 5 each independently on the other, hydrogen, C1-C6 alkyl, phenyl-C7-C10 alkyl, C3-C7 cycloalkyl or cycloalkyl-C4-C8 alkyl, one of the   symbols R2 and R5 may also signify a hydroxyl group   C1-C4 alkyl or cyano when A represents a b, R3 and R4 mean, independently of each other, -CN, -COOR7, -COR8, -S (O) nR9 or -COO-BN-R10 -R11, n is O, 1 or 2, R6 is hydrogen, halogen or C1-C4alkyl, C1-C4alkoxy, C1-C4alkylthio, C1-C4alkylsulfonyl, trifluoromethyl, nitro, hydroxy, azido, amino, C1-C4alkylamino, di-C1-C4alkylamino, C1-C5alkanoylamino, C2-C5alkoxycarbonyl, aminocarbonyl, trifluoromethoxy, cyano, sulfamoyl, C1-C4alkylsulfamoyl or di-C1alkylcarbonyl -C4) -sulfamoyl, X is oxygen or sulfur, m is O, 1, or 2, R7 R8 and Rg are each, independently of each other, C1-C6 alkyl, C3-C6 alkenyl , C 3 -C 6 alkynyl, C 3 -C 7 cycloalkyl, C 4 -C 8 cycloalkylalkyl, C 2 -C 6 hydroxyalkyl, C 3 -C 6 alkoxyalkyl, hydroxy, C 4 -C 8 alkoxyalkyl, C 2 -C 6 aminoalkyl, C1-C4) amino-C2-C6 alkyl, di (C1-C4 alkyl) aminoalkyl, phenyl e, phenylC7-C10oalkyl, a 5- or 6-membered heterocyclic ring containing a nitrogen, oxygen or sulfur atom and which may also contain 1, 2 or 3 additional nitrogen-cyclic atoms, or a group C1-C4alkyl optionally substituted with a 5- or 6-membered hetero-ring ring containing a nitrogen, oxygen or sulfur atom as a heteroatom and which may also contain 1, 2 or 3 other nitrogen atoms cyclic, wherein R 7 may also represent a trifluoroethyl group when A is a b, B is a C 1 -C 14 alkylene group, R 10 and R 11 are each independently of one another a C 1 -C 6 alkyl, alkenyl group; C3-C6, C3-C6 alkynyl,   C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, hydroxyl-   C2-C6alkyl, C3-C6alkoxyalkyl, C4-C8hydroxyalkylalkyl, amino-C2-C6alkyl, (C1-C4alkyl) amino-C2-C6alkyl, di (C1-C4alkyl) -amino) -C1-C4alkyl, phenyl, or phenyl-C7-C10alkyl-or R10o and R11 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocyclic linkages optionally containing another heteroatom selected from oxygen and sulfur, or a group = NR12-wherein R12 is C1-C4alkyl, benzyl or bisphenylmethyl optionally mono- or independently disubstituted in the phenyl ring (s) by a halogen having an atomic number of 9 to 35 or by a C1-C4 alkoxy group.   4. A pharmaceutical composition according to claim   cation 2 or 3, characterized in that the calcium channel inhibitor corresponds to formula Ia R ' 6 N At N / Ia R40C 3 I   Wherein R '1 is hydrogen, C 1 -C 6 alkyl, C 3 -C 6 alkenyl or alkynyl, C 3 -C 7 cycloalkyl or C 4 -C 8 cycloalkylalkyl or C 7 -C 9 phenylalkyl or phenylalkenyl; in which the phenyl ring optionally carries one, two or three substituents selected from halogens and hydroxy, C1-C4 alkyl and C1-C4 alkoxy, R'2 and R'5 independently signify hydrogen or a C1-C6 alkyl group, R'3 and R'4 independently represent a C1-C6 alkyl group,   C3-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, cycloalkyl   C 4 -C 8 alkylalkyl, C 1 -C 6 alkoxy, C 2 -C 6 hydroxyalkoxy, C 3 -C 6 alkoxyalkoxy, C 4 -C 8 hydroxyalkoxyalkoxy, C 3 -C 6alkenyloxy or C 3 -C 6alkynyloxy, C 3 -C 7cycloalkyloxy or cycloalkyl- C4-C8 alkoxy, or R'3 is O-B'-R'7, or B 'is an alkylene chain containing 9 to 14 carbon atoms and R'7 is piperidine or piperazine both substituted in position 4 with a methyl, benzyl or bis-phenylmethyl group optionally mono- or independently disubstituted in the phenyl ring (s) by a halogen atom of atomic number 9 to 53 or by a C1-C4 alkoxy group and R'4 at the meaning indicated above, R'6 is hydrogen, halogen, alkyl, alkoxy,   alkylthio or alkylsulfonyl each in C1-C4 or tri-group   fluoromethyl, nitro or hydroxy, and   X has the meaning indicated above.   5. A pharmaceutical composition according to any one   Claims 2 to 4, characterized in that the component a)   is selected from the diethyl ester of the acid   4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5   dicarboxylic acid, dimethyl ester of 4- (2,1-   3-benzoxathiadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-   dicarboxylic acid, and the ester 10- [4- (diphenylmethyl) -piperazine   1-yl] decyl acid of (+) - (S) -4- (2,1,3-benzoxadiazole-   -4-yl) -l, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyridine-carboxylic   xylique. 6. A pharmaceutical composition according to any one   Claims 2 to 4, characterized in that the inhibitor   Calcium is the isopropyl ester of 4- (2,1,3-benzoxacid   diazol-4-yl) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine   carboxylic acid. 7. A pharmaceutical composition according to any one   Claims 2 to 6, characterized in that the weight ratio   component a) to component b) is from 5: 1 to about 1: 3. 8. A pharmaceutical composition according to any one   Claims 2 to 7 for use in the treatment of   hypertension and overall heart failure.   9. The use of an association comprising component a) and component b) as defined in any one of   Claims 1 to 6 for the preparation of a composition   pharmaceutical for the. treatment of hypertension and overall heart failure.