NL8702502A - PHARMACEUTICAL PREPARATION FOR APPLICATION AGAINST HYPERTENSION AND CONGESTIVE CARDIAL INSUFFICIENCY. - Google Patents

Description

s * 4 - Pharmaceutical formulation for use against hypertension and congestive cardiac insufficiency -

This invention relates to novel pharmaceutical compositions effective against hypertension and congestive cardiac insufficiency and to methods of preparing or manufacturing and using these compositions T

The present invention provides a pharmaceutical composition which as active ingredients: a) a calcium channel blocker, and b) 7- (Ν- / ί (S) -ethoxycarbonyl-3-phenylpropyl / ~ 10 (S) -alanyl) -1,4- di-thia-7-azaspiro- [k, 47nonane-8- (S) -carboxylic acid and its pharmaceutically acceptable salts.

The present invention also provides a method of treating hypertension and congestive cardiac insufficiency in a patient, comprising co-administering a) a calcium channel blocker and b) 7- (N- / H (S) -ethoxycarbonyl-3-phenyl) -propyl7- (S) -alanyl) -1,4-dithia-7-azaspiro- / 4, kj nonane-8- (S) -carboxylic acid and its pharmaceutically acceptable salts.

Calcium channel blockers comprise a class of physiologically active materials characterized by their calcium channel blocking or channel blocking action. A wide variety of such compounds are now known and these compounds have widespread therapeutic use, particularly for the treatment of cardiovascular disorders or diseases, for example, for the treatment of coronary insufficiency, disturbance of cerebral circulation, hypertension and he the treatment of other peripheral circulatory disorders. Typically, the calcium channel blockers are used as vasodilators, for example, in the treatment of hypertension.

Component b) is an angiotensin converting enzyme (ACE) inhibitor. Little has been published about its pharmacological and biopharmaceutical properties.

ACE inhibitors are known compounds that affect the conversion of angiotensin I to angiotensin II and are useful for lowering elevated blood pressure when due to the action of angiotensin II. When administered alone, ACE-10 blocking compounds must be used in relatively large amounts, which can lead to undesirable side effects.

The pharmaceutical preparations according to the invention and also the co-administration of component a) and component b) have respectively. leads to unexpected and surprisingly favorable pharmaceutical properties, with a particularly favorable or improved pharmacological-therapeutic profile. In particular, it has been found that the co-administration of a component a) and a component b), as defined above, in conjunction leads to a surprising increase in antihypertensive activity and a surprisingly potent activity against congestive cardiac insufficiency.

Component a) induces an increase in central venous pressure and consequently the increase in cardiac output is reduced in animals pretreated with component b). The increase in central venous pressure in the absence of impaired cardiac function (cardiac contractile ability was accurately determined with a strain gauge sewn to the myocardium) indicates increased venous backflow caused by arteriolar dilation. Thus, the attenuating action of component a) indicates increased venous elasticity or compliance after ACE inhibition.

Recommended calcium channel blockers for use in the compositions according to the invention are those of the dihydropyridine class, for example of the formula I, in which 870 2 50 2 - 3 - α »A is a radical of the formula Ia, Ib or Ic, Rj is a hydrogen atom, an alkyl group of 1-6 carbon atoms, a hydroxyalkyl group of 2-6 carbon atoms, a (C8-g) alkoxyalkyl group, an alkenyl group of 3-6 carbon atoms, an alkinyl group of 3-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms or a (C. O) cycloalkylalkyl group or a (C7-9) phenylalkyl group or (C9_12) phenylalkenyl group, wherein the phenyl group is unsubstituted or by halogen, hydroxyl alkyl, 1-4 carbon atoms or alkoxy with 1-4 carbon atoms. , di- or tri-substituted, represents R 2 and R 1 - independently, a hydrogen atom, an alkyl group of 1-6 carbon atoms, (C 7 ^ Q) phenylalkyl group, cycloalkyl group of 3-7 carbon atoms, or (C ^ g) represent cycloalkylalkyl group, where if A is a radical of formula Ib, one of the substituents R2 and R1 can also be a hydroxyalkyl group having 1-4 carbon atoms or cyano group,

Rg and R ^, independently, represent a -CN, -COORy, -CORg, -S (0) nRg or -COO-B-N R ^ gR ^ group, n = 0, 1 or 2,

Rg a hydrogen or halogen atom, an alkyl group of 1-4 carbon atoms, an alkoxy group of 1-4 carbon atoms, an alkylthio group of 1-4 carbon atoms, an alkyl sulfonyl group of 1-4 carbon atoms, the trifluoromethyl group, nitro group, hydroxyl group, azido group, amino group , alkylamino group of 1-4 carbon atoms, a di / T (C 1 -6) a Ikyl] amino group, alkanoylamino group of 1 to 5 carbon atoms, (C 2-^) carbaloxy group, aminocarbonyl group, trifluoromethoxy group, cyano group, sulfamoyl-3Q group (C 1 -6) alkylsulfamoyl group or di / C 1 -6-alkylsulfamoyl group, X represents an oxygen or sulfur atom, m = 0, 1 or 2, R 7, R and R, independently, an alkyl group just 1-6 carbon atoms, alkenyl group with 3-6 carbon atoms, alkinyl group with 3-6 carbon atoms, cycloalkyl group 8 7 0 2; 0 2 - 4 - with 3-7 carbon atoms, (C ^ _g) cycloalkylalkyl group, hydroxyalkyl group with 2-6 carbon atoms, (Cg ^ jalkoxyalkyl group, hydroxy (C ^ _g) alkoxyalkyl group, aminoalkyl group with 2-6 2 carbon atoms, (C ^ alkyl alkyl (C 2-8) alkyl group, di C 1-6 alkyl alkyl group, phenyl group, C 1-6 phenyl alkyl group, a 5- or 6-membered heterocyclic ring containing a nitrogen; oxygen or sulfur atom, which may also contain 1,2 or 3 additional nitrogen atoms in the ring, or an alkyl group of 1 to 4 carbon atoms, Q optionally substituted by a 5- or 6-membered heterocyclic ring having a nitrogen, oxygen or sulfur atom as, - heteroatom and which may additionally contain 1,2 or 3 further nitrogen atoms in the ring, where, if A is a radical of formula Ib, may also be the trifluoroethyl group,, | 2 B is an alkylene group with 1-14 carbon atoms, R10 and, independently, an alkyl group with 1-6 carbon atoms, an alkenyl group with 3-6 carbon atoms, an alkinyl group with 3-6 carbon atoms, 2Q a cycloalkyl group with 3-7 carbon atoms , a (C 1 -g) cycloalkylalkyl group, a hydroxyalkyl group of 2-6 carbon atoms, a (Cg -g) alkoxyalkyl group, a hydroxy (C 1 -g) alkoxyalkyl group, an aminoalkyl group of 2-6 carbon atoms, a (C.) alkylamino ( C 1-6 alkyl group, a di ^ (C 1-6) alkyl / amino- (C 1-6) alkyl group, f enyl group 2 ^ or a (C1-4 ^ g) phenylalkyl group, or wherein R10 and R1 together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocyclic ring, optionally another heteroatom selected from oxygen or sulfur or a -NR 4 group, wherein a 2Q alkyl group of 1-4 carbon atoms is a benzyl group or a bis-phenylmethyl group, the phenyl ring (s) of which is optionally mono or independently substituted by halogen with a sequence number of 9-35 or alkoxy with 1-4 carbon atoms.

In formula I, the alkyl groups having 22 1-6 carbon atoms preferably contain 1-4 carbon atoms, especially 1 or 2 carbon atoms, the methyl groups being most recommended. (C-alkyl, alkoxy, -alkylthio and -alkylsulfonyl groups preferably contain 1 or 2 carbon atoms.

670 2 50 2 κ - 5 -

Hydroxy, alkoxy, hydroxyalkoxy, amino and alkylamino moieties of hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl groups Ry in residues -COORy are preferably not attached to the O (carbon atom. They are conveniently located in a terminal position Recommended alkylene moieties of hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl moieties are ethylene and propylene.

The alkylene portion of cycloalkylalkyl groups is suitably methylene. Cycloalkyl portions of cycloalkylalkyl groups are suitably cyclopropyl, cyclopentyl or cyclohexyl. By halogen is meant fluorine, chlorine or bromine, in particular chlorine.

The multiple bond in alkenyl, alkinyl and phenylalkenyl groups or COORy is preferably not in the β-position. Alkenyl and alkinyl groups 1 ^ preferably have 3-5 carbon atoms. Alkenyl is suitable allyl or 2-methylallyl is suitable propionyl It is recommended that phenylalkenyl groups have the trans configuration and include, for example, cinnamyl. If R 1 represents a phenyl group, it is preferably unsubstituted R 1 represents a di-2Q or tri-substituted phenyl group, then the substituents are preferably the same and represent halogen or alkyl Heterocyclic rings such as Ry, Rg and Rg are, for example, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, pyrazolyl, pyridolinyl pyridazinyl, piperidinyl, morpholinyl and triazinyl Heterocyclic rings present in R 1 q and R 2 together with the nitrogen atom to which they are attached are preferably saturated and includes pyrrolidine, piperidine, piperazine, N-alkylpiperazine and morpholine rings. Most preferred, however, is diphenylmethylpiperazine, the phenyl ring (s) of which can be substituted in a manner described above. It is recommended that R2 and Straight are. Rg is suitably a halogen atom, alkyl group, alkoxy group, nitro group or trifluoromethyl group and is preferably in the o or m position relative to the position of the attachment of the dihydropyridine residue. If A represents a radical of formula I70, 2, 20, 6, mule Ia, R 1 is preferably a hydrogen atom.

In a -COOBNR ^ R ^ group, B is an alkylene chain with 1-14 carbon atoms, preferably 5-14 carbon atoms, especially 10 carbon atoms.

Particularly suitable compounds of formula I, wherein A represents a radical of formula Ia, for use in the present invention are those listed in the following table (the number indicated under "y" indicates the attachment site of the group of formula Ia to the dihydropyridine nucleus pat ^.

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8702502 * · »- 14 -

Particularly recommended calcium channel blockers according to a) have formula IHa, wherein R. | a hydrogen atom, an alkyl group of 1-6 carbon atoms, an alkenyl or alkinyl group of 3-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a cycloalkylalkyl group of 4-8 carbon atoms, a phenylalkyl group of 7-9 carbon atoms or represents a phenylalkenyl group of 9-12 carbon atoms, the phenyl ring being unsubstituted or mono-, di- or tri- (independently) substituted by halogen, hydroxyl or alkyl or alkoxy of 1-4 carbon atoms, R 4 'and R 4' , independently, represent a hydrogen atom or an alkyl group with 1-6 carbon atoms, R ^ and R ^ 1, independently, ^ an alkyl group with 1-6 carbon atoms, alkenyl or alkinyl group with 3-6 carbon atoms, cycloalkyl group with 3-7 carbon atoms, cycloalkylalkyl group with 4-8 carbon atoms, alkoxy group with 1-6 carbon atoms, hydroxyalkoxy group with 2-6 carbon atoms, alkoxy alkoxy group with 3-6 carbon atoms, hydroxyalkoxyalkoxy group with 4-2Q 8 carbon atoms, alkenyloxy group or alk inyloxy group of 3-6 carbon atoms, cycloalkyloxy group of 3-7 carbon atoms or cycloalkylalkoxy group of 4-8 carbon atoms, or wherein R ^ 'has the meaning O-B'-R ^', wherein B 'is an alkylene chain of 9-14 is carbon atoms and R 1 'is piperidine or piperazine, the 2-position of which is substituted in both cases by methyl, benzyl or bis-phenylmethyl, the phenyl ring (s) of which is optionally mono or, independently, disubstituted by halogen with a sequence number of 9-53 or alkoxy of 1-4 carbon atoms and R ^ 'has a predefined meaning, R ^' a hydrogen or halogen atom, an alkyl, alkoxy, alkylthio or alkylsulfonyl group, each having 1- 4 represents carbon atoms, a trifluoromethyl, nitro or hydroxyl group, and X has a previously defined meaning. The calcium antagonists according to the invention used have generally been described in 87 0 2 2 together with their calcium antagonistic and, inter alia, antihypertensive activity.

V

- 15 - previously disclosed patents. It also mentions that salt forms of the calcium channel blockers of formula I can be used instead of the free bases. Furthermore, it should be considered that if the substituents in the 2-5 and 6 position and / or 3 and 5 position of the 1,4-dihydropyridinyl moiety differ, the calcium channel blockers may be in racemic form or in separate, enantiomeric forms appearance.

Particularly interesting calcium channel blockers of formula I or formifelila are the diethyl ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid, hereinafter referred to as compound No. 1, the isopropyl ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid, hereinafter designated as compound no. 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 Z.10- / 4- (diphenylmethyl) piperazin-1-yl / decyl / ester of (+) - (S) -4- (2,1,3-benzoxadiazol-4-yl) -1, 4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3 "pyridine carboxylic acid, designated compound no. 4, particularly interesting are the compounds of numbers 2 and 4.

7- (Ν- £ ί (S) -ethoxycarbonyl-3 ~ phenylpropyl7 "(S) alanyl) - !, 4-dithia-7-azaspiro / 4,47nonane-8- (S) -carboxylic acid has the alternative chemical name / 8S- / 7. / R *) 7 ", 8R * ^ / - 7- (ethoxycarbony1) -3-phenylpropyl? Amino7 ~ 1-oxopropyl / -1,4-dithia-7-a-25 zaspiro / 4,4 / nonane-8-carboxylic acid The compound has also been identified by SCHERING as SCH-33844 and has the generic name SPIRAPRIL This compound is described in Example 3 of U.S. Patent 4,470,972 This U.S. patent also teaches that the compound has antihypertensive activity 50. They can use pharmaceutically acceptable salt forms Also the hydrate can be used In this US patent various salt forms which can be used instead of the free bases are described, for example the hydrochloride described in example 4 of this 35.

patent or the hemimalate described in Example 5 of this patent. The recommended form is the monohydrochloride monohydrate.

870 2 50 2 - 16 -

The co-administration of a calcium channel blocker and component b) provides a potent anti-hypertensive activity and an action against congestive cardiac insufficiency, as shown by pharmacological tests.

For example, if a calcium channel blocker, in particular a compound of formula I and a component b) are co-administered to animals, the natriuretic and diuretic activity of the calcium channel blockers, in particular of the compounds of formula I, may surprisingly be retained. Thus, co-administering a calcium channel blocker, especially a compound of formula I, with the aforementioned ACE inhibitor reduces the need for further diuretics and / or beta blockers. This is demonstrated in the test on a hydrated rat (method of Flückiger et al., Schweiz. Med. Wochenschrift 93, No. 35 (1963) 1232-7), which is described as follows:

Groups of 12 rats were used.

Component a) in a diuresis-inducing dose, for example from 0.3 mg / kg p.o. to 3 mg / kg p.o. was used alone or in combination with ·) component b) at a dose of 3 mg / kg s.c. investigated. The compounds were administered simultaneously. Urine was collected for 3 hours and its volume and sodium excretion were determined.

This effect was confirmed in rats 25 with sodium depletion. Rats were administered furosemide (50 mg / kg / day) with drinking water for 2 days. Groups of 6 animals were used. The calcium channel blocker was administered in diuresis doses, e.g., from 0.3 to 3 mg / kg p.o. and component b) in doses of 3 mg / kg s.c. The compounds were administered 50 simultaneously. Urine was collected for 3 hours and its volume and sodium excretion were determined. Corresponding values as in the previous test on a hydrated rat were obtained.

Surprisingly, it was thus found that in general the diuretic and natriuretic activity were retained. This is surprising and makes the combinations according to the 870 2 50 2 - 17 invention particularly suitable for the treatment of hypertension and congestive cardiac insufficiency and reduces the need for diuretics.-.-

The importance of this effect is emphasized by the increasing concern among those skilled in the art regarding the metabolic consequences of administering diuretics over prolonged periods of time. The antihypertensive effect of co-administering a calcium channel blocker and component b) is further supplemented by the effect on the kidneys.

Both components a) and b) can, as already discussed above, be in the form of a free base or, if appropriate, in salt form, for example an acid addition salt.

The new compositions may be prepared or prepared by methods comprising formulating a calcium channel blocker and component b) in sufficient purity for pharmaceutical acceptability.

Common pharmaceutical excipients include carriers and diluents, which can also be included.

Thus, the compositions of the invention are indicated for use in the treatment of hypertension and congestive cardiac insufficiency.

For example, the calcium channel blocker can be administered in a third to 100% of the normal dose to treat, for example, hypertension or congestive cardiac insufficiency. An indicated oral daily dose of compounds of formula I is between about 0.2 mg to about 350 mg, especially between about 1 and 30 mg, suitably in divided doses 2 to 4 times daily in a unit dosage form of about 0.05 mg to about 175 mg, for example contains up to 20 mg of the compounds, or in a slowly released form. The recommended compound is compound 2. An indicated dose is between about 2.0 and about 10 mg administered 2 or 1 times daily p.o.

An indicated recommended weight ratio of a calcium channel blocker to component b) calculated at 870 2: 0 2 - 18 -.- * based on its free base portion may be between about 50: 1 and about 1:10, especially between about 10: 1 and about 1: 5, especially between about 5: 1 and about 1: 3. For example, component b) can be administered in a 5 third to 100% of the normal dose to treat hypertension or congestive cardiac insufficiency. The intended dosage forms contain 3 mg, 6 mg, 12 mg and 24 mg.

Thus, for compound No. 2 and component b), the recommended ratios are between about 50: 1 to about 1: 5, especially about, for example, 5: 1 to 1.1, such as 1: 1, 4: 1, 3: 1 or 2: 1.

Suitably components a) and b) are administered in the form of a pharmaceutical preparation, optionally together with a pharmaceutical carrier or diluent.

Such preparations may be prepared or prepared in a conventional manner, such as, for example, a solution, for example an injectable solution or suspension, or preferably in a solid form, such as a tablet or capsule.

If desired, one or both components may be present in a slowly released form, for example in case of compound no. 1 and 2 as described in GB 218 1 053 or 216 0 100 A.

If desired, the active ingredients may be contained in a pack, in order to facilitate administration via a special dosage prescription, for example in a special order in a blister pack.

A suitable preparation may also consist of a pack containing separately components a) and b) until necessary for co-administration, suitably accompanied by prescriptions for co-administration of a predetermined amount of component a) and a predetermined amount of a component b).

The following examples illustrate the invention.

Example 1: hard gelatin capsules for oral administration.

Hard gelatin capsules containing the ingredients listed below 8702 50 2 f: 19 can be prepared by conventional methods and administered once daily for treating hypertension and congestive cardiac insufficiency.

5

Ingredient; : 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 8.0 mg 15 322.0 mg

Example 2: tablets for oral administration

Sufficient amounts of the ingredients are mixed in a conventional manner and placed in gelatin capsules or compressed into tablets administered 1 time daily to treat hypertension and congestive cardiac insufficiency.

Ingredient Weight 25 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 30 Corn Starch 13.0 mg

Magnesium stearate 2.6 mg 262.0 mg

Example 3: Separate Administration of

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Capsules of the compound no. 2 can be manufactured with the following composition: 87 0 2 50 2 s - 20 -

Compound No. 2 10 mg

Microcrystalline Cellulose (Avacel) 47 mg

Cetyl palmitate 10 mg

Hydroxypropylmethylcellulose (Methocel E4M) 90 mg • 5 Colloidal silicon dioxide 1 mg

Magnesium stearate 2 mg 160 mg and capsules of component b) can be composed of the following composition 10 component b) 12 mg

Lactose 349 mg

Silica (colloidal) 8 mg--

Maleic acid (ground) 5 mg

Stearic Acid 16mg 15-400mg are manufactured. They can be brought in calendar packages. If desired, combined capsules containing both active ingredients can be prepared.

20 87 0 2-10 2

Claims (17)

A pharmaceutical composition containing a) a calcium channel blocker, and b) 7- (N-ƒ.1 (S) -ethoxycarbonyl-3-phenyl-propyl / - (S) -alany1) -1,4-dithia- 7-azaspiro- / 4.47nonane-8- (S) -carboxylic acid and its pharmaceutically acceptable salts. A pharmaceutical preparation according to claim 1, characterized in that the calcium antagonist used is compounds of the formula I, wherein 10. a radical of the formula Ia, Ib or Ic, R 1 is a hydrogen atom, an alkyl group with 1-6 carbon atoms, a hydroxyalkyl group with 2 to 6 carbon atoms, a (C 6 -g) alkoxyalkyl group, a 15-alkenyl group with 3-6 carbon atoms, an alkinyl group with 3-6 carbon atoms, a cycloalkyl group with 3-7 carbon atoms, a (C 4 -g) cycloalkylalkyl group, a (C 1 -6) phenylalkyl group or a (C 8 -6) -phenylalkenyl group, in which the phenyl ring is unsubstituted or is mono-, di- or tri-substituted by halogen, hydroxyl, alkoxy with 20 1-4 carbon atoms, and R ^, independently, a hydrogen atom, an alkyl group of 1-6 carbon atoms, a (C 1 -G J-phenylalkyl group, a cycloalkyl group of 3-7 carbon atoms, or a (C) cycloalkylalkyl group, 4 ~ 8 where where A is a radical of the formula Ib is one of the substituents R1 and R. ,. also may be a hydroxyalkyl group having 1-4 carbon atoms or cyano, Rg and, independently, a -GN, -COOR ^, -CORg, -S (O) ^ Rg or -COO-BN R ^ qR ^ group 30, n = 0, 1 or 2, Rg a hydrogen or halogen atom, an alkyl group with 1-4 carbon atoms, an alkoxy group with 1-4 carbon 8702: 02-22 substance atoms, an alkylthio group with 1-4 carbon atoms, an alkylsulfonyl group with 1-4 carbon atoms, the trifluoromethyl group, nitro group, hydroxyl group, azido group, amino group, an alkylamino group with 1-4 carbon atoms, a di /. (C 1) alkyl / amino group, a 1-4 alkanoylamino group with 1-5 carbon atoms, a carbaloxy group, an aminocarbonyl group, a trifluoromethoxy, cyano or sulfamoyl group, an alkyl sulfamoyl group with 1-4 carbon atoms, or a di / XC1 alkyl / sulfamoyl group, X represents an oxygen or sulfur atom, 10 m = 0, 1 or 2,, Rg and R ^, independently, an alkyl group with 1-6 carbon atoms, an alkenyl group with 3-6 carbon of atoms, an alkinyl group of 3-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a (C 1 -g) cycloalkylalkyl group, a hydroxyalkyl group of 2 to 6 carbon atoms, a (C 8 -g) alkoxyalkyl group, a hydroxy (C ^ _g) -alkoxyalkyl group, an aminoalkyl group with 2-6 carbon atoms, a (C ^ _ ^) alkylamino (C2_g) alkyl group, a di / (C ^ _ ^) alkyl / aminoalkyl group, phenyl group, a (C ^ ^) phenylalkyl group , a 5- or 6-membered heterocyclic ring containing a nitrogen, oxygen or sulfur atom and may also contain 1,2 or 3 ring nitrogen atoms or an alkyl group of 1-4 carbon atoms which may be optionally substituted by a heterocyclic 5- or 6-ring which contains a nitrogen, oxygen or sulfur atom as a hetero atom and may additionally contain 1,2 or 3 nitrogen atoms in the ring, where, if A is a radical of the formula Ib, Ry also the trifluoroethyl group can be, B represents an alkylene group with 1-14 carbon atoms, R10 and R4, independently of each other r, a 30-alkyl group with 1-6 carbon atoms, an alkenyl group with 3-6 carbon atoms, an alkinyl group with 3-6 carbon atoms, a cycloalkyl group with 3-7 carbon atoms, a (C 1-8) cycloalkylalkyl group, a hydroxyalkyl group with 2- 6 carbon atoms, a (C8_g) alkoxyalkyl group, a hydroxy (C ^ _g) -alkoxyalkyl group, a 35 aminoalkyl group with 2-6 carbon atoms, a (C ^ _ ^) alkylamino (C2_g) - 8702 502 * -23-alkyl group, a - /. (C ^ _ ^) alkyl / amino- (C1-8 alkyl group, phenyl group or (C ^ _ ^ Q) phenylalkyl group, or wherein R10 and together with the nitrogen atom to which they are attached represent a heterocyclic 5-, 6 - or 7-ring 5, optionally containing a heteroatom selected from oxygen, sulfur or a "NR" group, wherein R 1 is an alkyl group of 1-4 carbon atoms, a benzyl group or a bis-phenyl-methyl group of which the phenyl ring ( and) optionally is mono- or, independently, disubstituted by halogen having a sequence number 10 of 9-35 or alkoxy of 1-4 carbon atoms. A pharmaceutical preparation according to any one of claims 1 and 2, characterized in that the calcium antagonist of formula III used is wherein R 1 'is a hydrogen atom, an alkyl group with 15 to 6 carbon atoms, an alkenyl or alkinyl group with 3- 6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a cycloalkylalkyl group of 4-8 carbon atoms, a phenylalkyl group of 7-9 carbon atoms or a phenylalkenyl group of 9-12 carbon atoms, the phenyl ring being unsubstituted or mono-, di- or tri is (independently) substituted by halogen, hydroxyl or alkyl or alkoxy of 1 to 4 carbon atoms, R 2 * and R 2, independently, represent a hydrogen atom or an alkyl group of 1 to 6 carbon atoms, Rg 'and R' ', independently of each other, an alkyl group of 1-6 carbon atoms, an alkenyl or alkinyl group of 3-6 carbon atoms, a cycloalkyl group of 3-7 carbon atoms, a cycloalkylalkyl group of 4-8 carbon atoms, an alkoxy group of 1-6 carbon atoms, a hydroxyalkoxy group of 2-6 carbon atoms, an alkoxyalkoxy group of 3-6 carbon atoms, a hydroxyalkoxyalkoxy group of 4-8 carbon atoms, an alkenyloxy or alkinyloxy group of 3-6 carbon atoms, a cycloalkoxyoxy group of 3- Represent 7 carbon atoms or a cycloalkyl-alkoxy group of 4-8 carbon atoms, or wherein R ^ 1 35 represents an O-B'-R ^ 'group, wherein B' is an alkylene chain of 9-14 carbon atoms and R ^ V represents a piperidine or piperazine group, where the 4 position of both is substituted 870202 - \ - 24 - by methyl, benzyl or bis-phenylmethyl, the phenyl ring (s) of which is optionally mono- or, independently, disubstituted by halogen with a sequence number from 9 - 53 or al koxy of 1-4 carbon atoms in which R1 'has a previously defined meaning, R2' is a hydrogen or halogen atom, an alkyl, alkoxy, alkylthio or alkyl sulfonyl group, each having 1-4 carbon atoms, the trifluoromethyl group, nitro group or hydroxyl group and has the meaning defined in claim 2. A composition according to any one of claims 1-3, wherein component a) is selected from the diethyl ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl- pyridine-15 3,5-dicarboxylic acid, the isopropyl ester of 4- (2,1,3-benzoxadiazol-4-yl-1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid, the dimethyl ester of 4- (2,1,3-benzoxathiadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridin-3,5-dicarboxylic acid and the / 4 / 4- (diphenylmethyl) -piperazin-1-yldecyl ester of (+) - (S) -4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridine carboxylic acid. A composition according to any one of claims 1-4 for use in the treatment of hypertension and congestive cardiac insufficiency. Preparation according to claim 5, characterized in that the calcium channel blocker is the isopropyl ester of 4- (2, 1,3-benzoxadiazole) -4-yl-1,4-dihydro-2,6-dimethyl-3-methoxy-carbonyl -pyridine-5-carboxylic acid. 7. A composition according to claim 5, characterized in that the calcium channel blocker contains the diethyl ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl-pyridine-3.5- dicarboxylic acid. Preparation according to claim 5, characterized in that the calcium channel blocker is the dimethyl ester of 4- (2,3,3-benzoxathiadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid . 67 0 2 50 2 - 25 - t Preparation according to claim 5, characterized in that the calcium channel blocker contains the 10-10 diphenylmethyl) -piperazin-1-yl / decyl ester of (+) - (S) -4- (2,1,4-benzoxadiazole) - 4-yl) -1,4-dihydro-5-methoxy-carbonyl-2,6-dimethyl-3-pyridine-3 carboxylic acid. Preparation according to claim 5, characterized in that component b) 7- (N ~ ZJ (S) -ethoxycarbony1-3-phenylpropyl / - (S) -alanyl) -1,4-dithia-7-azaspiro- / 4,4_ / nonane-8- (S) -carboxylic acid monohydrochloride monohydrate. ^ 0 11. A composition according to any one of claims 1 to 10, characterized in that the weight ratio of component a) to component b) is between 5: 1 to about 1: 3. Preparation according to claim 11, characterized in that the weight ratio is between 5: 1 and 1: 1. ^ 13. A pack or administering device containing a pharmaceutical composition according to any one of claims 1-12 together with instructions for use in hypertension or congestive cardiac insufficiency. 14. A method of treating hypertension or congestive cardiac insufficiency, characterized in that component a) and component b), as defined according to any one of claims 1-12, are administered to a patient in need of such treatment. 15. A method of preparing or manufacturing a pharmaceutical composition for treating hypertension or congestive cardiac insufficiency, characterized in that it comprises a combination of component a) and component b) as defined in any one of the claims 1-12. 16. Compositions as described in the description and / or examples. Molded pharmaceutical preparations according to any of the preceding claims. 35 -ooooo- 2: c 2 t 'Λ ί Rt r ^ Vv-r' Λ X CXxx V Rj n \ y I 10 lb i ^ N ¢ 3 XX coo (CH4 - {3 ~ <XZ 1! \ X / Ic IT Rfc J-. ^ N \ ΊΧ \ COR3 (»II Rs n ^ r! Jr Ri SANDOZ AG Basel, Switzerland 87 0 2 00 2