LU87034A1 - DRUG ASSOCIATION BASED ON A CALCIUM INHIBITOR - Google Patents

Description

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Invention Patent Application cs · “* ................................... ..... ........ ______________________ <Vi I. Request

The ... company djtR,: ... SâJiI) OZ S.-A ..., Licht.st'.raa3.e .35, CHr 40Q2 „Bä i e ,. Switzerland (2) represented by Mr Louis EMRINGER ........ lawyer, ...... residing in Luxembourga _.......

acting in his capacity as agent ........................................______________________________________________________________ deposit) this October 30. 19.00-four-v / inflt-sept ..................................... < 4} at ...... hours, at the Ministry of the Economy and the Middle Classes, in Luxembourg: 1. this request for obtaining a patent of invention concerning: ..... Association. ..... medicated ..... based on ...... based on a ...... calcium channel blocker__________ ________________ (sj 2. description in language, Ë.r ançai se ..... .......................; ............... of the invention in triplicate: 3.. ................................ // drawing boards, in three copies: 4. the receipt of the taxes paid to the Registration Office in Luxembourg, 30.10 - J 987____________________________; 5. the delegation of power, dated __________........................... .............................. on 2 8 -10.1987 _________________; 6. the document before c ause (authorization); claims! nt) for the above patent application the priority of one (s) application (s) of (7). ........................Patent. _................................................. ............................ filed! if in (8) Great Britain ............ ........

I (9) November 3, 1986 under N °. 8626217 and on June 8, 1987 under N ° (10) ........ 8713349 ..................... ....... ....................._............................ .................................................. .................................................. ............

in the name of (11). .the applicant e .............................................. ............................ ...................... .................; ................................ ............................

elect (elect) domicile for him / her and. if appointed, for its representative, in Luxembourg 191, rue Albert

A den 26 32 Lu xemb.our g ......................................... .................................................. .................................................. .... _ .................... î 12) requests! nt) the grant of a patent for the invention for the object described and represented in the above-mentioned annexes, with postponement of this issue to .................... six .................... .................................................. ....................... ....... months. "13d

The depositor / agent: * "........................................... ...................................... 114d

Mm Π. Deposit Minutes

The aforementioned patent application has been filed with the Ministry of Economy and Movennes Classes. Intellectual Property Service in Luxembourg, dated: Λ7 ^ fs ζ “Τ ï y ~ .Λ Pr. The Minister of Research and the Middle Classes, f at ____ Λ Tr, ......... hours ξ . i. U L t ‘If p. d.

î% \! .. i l ~. The head of the Intellectual Impropriety department.

AÔÜ0B7_1 F "'__ / j / / f, is EXPttCAUONSREMITVES A * FORMlXAtRE-DErffiPÖI. // l“ * fi bj K il' si) y i lie ;. "Dcmanàc and c ^ ruficai from Aààiîjcn to the brief? prin-p * έ. \ uepznde main patent Ne ... .β ..... from! ........... "- milling ..- 1 γ; .." τ. γ-λϊ®. γγγ : λ-Ι ι.

* 100-6972 CLAIM OF THE PRIORITY of the patent application

In Great Britain From November 3, 1986 June 8, 1987 BRIEF DESCRIPTION filed in support of a request for

PATENT

at

LUXEMBOURG

in the name of: SANDOZ S.A.

for: Drug combination based on a calcium channel blocker

The subject of the present invention is a new drug combination which is effective in the treatment of hypertension and of global heart failure.

In particular, the invention relates, as a medicament, to a medicinal combination comprising, as active substances, a) a calcium channel blocker and b) 7- (N- [l (S) -ethoxycarbonyl-3-phenylpropyl acid) ] - (S) -alanyl) -10 l, 4-dithia-7-azaspiro- [4,4] nonane-8- (S) -carboxylic or one of its pharmaceutically acceptable salts.

The invention also relates to a pharmaceutical composition comprising, as active substances, a) a calcium channel blocker and b) 7- (N-Cl- (S) -ethoxy-carbonyl-3-phenylpropyl] -15 (S) - acid. alanyl) -1,4-dithia-7-azaspiro- [4,4] -nonane-8- (S) -carboxylic or one of its pharmaceutically acceptable salts, in association with a pharmaceutically acceptable vehicle or diluent.

Calcium channel blockers include a class of physiologically active substances, characterized by their calcium ion antagonistic 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 cardiovascular disorders or diseases, for example in the treatment of coronary insufficiency, cerebral circulation disorders, hypertension and in the treatment of other peripheral circulation disorders. Calcium channel blockers are generally used as vasodilators, for example in the treatment of hypertension.

2

Component b) is an angiotensin converting enzyme (ACE) inhibitor. There are few publications concerning its pharmacological and biopharmaceutical properties.

ACE inhibitors are known compounds which influence the transformation of angiotensin I into angiotensin II and are useful for lowering elevated blood pressure when this is due to the action of angiotensin II. When administered alone, ACE-blocking compounds should be used in relatively high amounts, which can 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 specially favorable or improved pharmacological / therapeutic profile. It has been found, in particular, that co-administration of component a) and component b) causes an unexpected increase in antihypertensive activity and surprisingly strong activity against overall 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 the cardiac function (the cardiac contractility was precisely measured by means of a strain gauge fixed on the myocardium) indicates an increase in the venous return caused by arterial dilation. The drop effect caused by component a) also indicates an increase in venous distancibility after ACE inhibition.

The 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 on next page 3

AT

T T (t)

5 UL

Ri I

10 in which A represents a residue of formula (a), (b) or (c) "K> 9.15 (a) (b) (c)

Rl stands for hydrogen, C1-C6 alkyl "hydroxy-C2-C6 alkyl, alkoxy-C3-C6 alkyl" C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl or cycloalkyl- C4-C8 alkyl or a phenyl-C7-C9 alkyl or phenyl-alkenyl C9-C12 group, in which the phenyl ring optionally carries one, two or three substituents chosen from halogens and hydroxy groups, C1-C4 and C1-C4 alkoxy, R2 and R5 each mean, independently of each other, hydrogen, C1-C6 alkyl, phenyl-C1-C10 alkyl> C3-cycloalkyl C7 or C4-C8 cycloalkyl-alkyl, one of the symbols R2 and R5 can also signify a hydroxy-C1-C4 alkyl or cyano group when A represents a residue b, R3 and R4 mean, independently one of l other, -CN, -COOR7, -C0R8, -S (0) nR9 or -COO-BN-Rlo-Rll, 30 n means 0, 1 or 2, Rô signifies hydrogen, halogen or an alkyl group in C1-C4, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, t rifluoromethyl, nitro, hydroxy, azido, amino, C1-C4 alkylamino, di (C1-C4 alkyl) -amino, C1-C5 alkanoylamino, 4 C2-C5 alkoxycarbonyl, aminocarbonyl, tri fluoromethoxy, cyano, sulfamoyl, alkylsulfamoyl in C1-C4 or di (alkyl in (4-C4) -sulfamoyl, X signifies oxygen or sulfur, 5 m signifies 0, 1, or 2, R7 R8 and Rg each represent, independently of each other, a (4-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl) C2-C6 hydroxyalkyl, C3-C6 alkoxyalkyl, hydroxy, C4- alkoxyalkyl C8, C2-C6 amino-alkyl, (C1-C4 alkyl) amino-C2-C6 alkyl "di (C1-C4 alkyl) aminoalkyl, phenyl, phenyl C7-C10alkyl, a heterocyclic ring of 5 or 6 members containing a nitrogen, oxygen or sulfur atom and which may also contain 1, 2 or 3 additional cyclic nitrogen atoms, or a C1-C4 alkyl group optionally substituted by a heterocyclic ring with 5 or 6 links containing a nitrogen, oxygen or sulfur atom as a hetero atom and which may also contain 1, 2 or 3 other cyclic nitrogen atoms, R7 may also represent a trifluoroethyl group when A signifies a residue b, B represents a group C1-C14 alkylene, RIO and Ru each mean, independently of one another, a C4-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C4 cycloalkylalkyl -C8, hydroxy-25 C2-C6 alkyl, alkoxyalkyl C3-C6, hydroxy-alkoxyalkyl C4-C8, amino-alkyl C2-C6, (C1-C4 alkyl) amino-C2-C6 alkyl, di (C1-C4 alkyl-friend no)-C1-C4 alkyl, phenyl, or phenyl-alkyl C7-C10 e »0L1 well

R10 and Ru together with the nitrogen atom to which they are attached form a 5-, 6- or 7-membered heterocyclic optionally containing another heteroatom selected from oxygen and sulfur, or a group = N-Ri2 in which R12 signifies a C1-C4 alkyl, benzyl or bis-phenylmethyl group 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.

In formula I, the C1-C6 alkyl groups preferably contain 1 or 4 carbon atoms, more preferably 1 or 2 carbon atoms, the methyl group being particularly preferred. The C1-C4 alkyl, alkoxy, alkylthio and alkylsulfonyl groups preferably contain 1 or 2 carbon atoms. The hydroxy, alkoxy, hydroxyalkoxy, ami no and alkylamino radicals of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxy-alkyl, aminoalkyl and alkylaminoalkyl groups represented by R7 are preferably attached to a carbon atom other than the carbon atom a. They are preferably in the terminal position. The preferred alkylene radicals of the hydroxyalkyl, alkoxyalkyl, hydroxyalkoxyalkyl, aminoalkyl and alkylaminoalkyl groups are the ethylene and propylene radicals. The alkylene residue of the cycloalkyl-alkyl groups is preferably a methylene residue. The cycloalkyl radicals of the cycloalkylalkyl groups are preferably cyclo-propyl, cyclopentyl or cyclohexyl radicals. Halogen means fluorine, chlorine or bromine, in particular chlorine.

The multiple bond in the alkenyl, alkynyl and phenylalkenyl groups represented by Ri or -COOR7 is preferably located in a position other than the α, β position. The alkenyl and alkynyl groups preferably have 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 R 1 represents a phenyl group, the latter is preferably unsubstituted. When R 1 represents a di- or trisubstituted phenyl group, the substituents are preferably the same and are halogens or alkyl groups. The heterocycles represented by R7S Rg and Rg are, for example, furyl, thienyl, pyrrolyl, * 6 thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridyl pyridyl pyridyl pyridyl , morpholinyl and triazinyl. The heterocycles represented by Rio and 5 Ru together with the nitrogen atom to which they are attached, are preferably saturated and include the pyrrolidine, pi per di ne, piperazine, N-alkylpiperazine and morpholine, more preferably di-phenyl- methyl-piperazine optionally substituted in the phenyl ring (s) as described above. R2 and R5 are preferably identical. Rß preferably signifies a halogen or an alkyl, alkoxy, nitro or trifluoromethyl group, preferably situated in the ortho or meta position relative to the point of attachment to the dihydropyridine ring. When A represents a residue a), Rg preferably signifies hydrogen.

In the group -COOBNRioR11, B represents an alkylene chain of 1 to 14 carbon atoms, preferably of 5 to 14 carbon atoms, especially of 10 carbon atoms.

The compounds of formula I in which A signifies a residue (a) which are particularly suitable for use according to the invention, are those indicated in the following table (“y” represents the position for fixing of (a) on the dihydropyridine ring .

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The especially preferred calcium channel blockers are those of formula la 5 /

Ia

R.IX

R1 in which R'I signifies hydrogen, a C1-C6 alkyl, alkenyl or C3-C6 alkynyl, C3-C7 cycloalkyl or C4-C8 cycloalkylalkyl group or a C7-C9 phenylalkyl group or phenyl- C9-C12 alkenyl, in which the phenyl ring optionally carries one, two or three substituents selected from halogens and hydroxy groups, C1-C4 alkyl and C1-C4 alkoxy, R12 and R'5 independently signify hydrogen or C1-C6 alkyl, R'3 and R'4 independently represent C1-C6 alkyl> C3-C6 alkenyl or alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl, C1-alkoxy Ci-Cß, C2-C6 hydroxy-alkoxy, C3-C6 alkoxyalkoxy, C4-C8 hydroxyalkoxy-alkoxy, C3-C6 alkenyloxy or alkynyloxy, C3-C7 cycloalkyloxy or C4-C8 cycloalkyl-alkoxy, or well R'3 means 0-B1-R'7, or B 'represents an alkylene chain containing from 9 to 14 carbon atoms and R'7 represents a pi perine or piperazine group both substituted at p position 4 by a methyl, benzyl or bis-phenylmethyl group optionally mono- or independently disubstituted in the phenyl ring (s) by a halogen of atomic number from 9 to 53 or by a C1-C4 alkoxy group and R'4 to the meaning indicated above, R'6 means hydrogen, halogen, an alkyl, alkoxy, alkylthio or alkylsulfonyl group each of C1-C4 or a trifluoromethyl, nitro or hydroxy group, 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 their antihypertensive activity, in patents published previously. In these patents, it may also be mentioned that the salts of the calcium channel blockers of formula I can be used in place of the free bases. It can also be considered that when the substituents in positions 2 and 6 and / or 3 and 5 of the 1,4-dihydropyridinyl residue are different, the calcium channel blockers can exist in racemic form or in the form of individual enantiomers.

The calcium antagonists of formula I or of formula la which are particularly advantageous are the diethyl ester of 4- (2,1,3-benzoxadiazol-4-yl) -1,4-dihydro-2,6-dimethyl acid -pyridine-3,5-dicarboxylic, designated hereafter compound n ° 1; isopropyl ester of 4- (2,1,3-benzoxadiazo1-4-yl) -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid, designated below after compound ne2; dimethyl ester of 4- (2,1,3-benzoxathiadiazol-4-yl) -2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid, hereinafter designated compound no 3 and (+) - (S) -25 4- (2,1,3-Benzoxadi azol-4-yl) -1 ester 10-C4- (diphenylmethyl) -piperazine-1-yl] decylic ester 4-di hydro-5-methoxycarbonyl-2,6-di-methyl-3-pyridine-carboxylic acid, designated hereafter compound n6 4; compounds 2 and 4 are particularly interesting.

7- (N-Cl (S) -ethoxycarbonyl-3-phenylpropyl] - (S) -alanyl) -1,4-dithia-7-azaspiro [4,4] nonane-8- (S) -carboxylic acid may also be designated Γ8-S- [7 [R * (R *)], 8R *]] - 7- [2 - [[- 1- (ethoxycarbonyl) -3-phenylpropyl] -amino] -1 oxopropyl> 1,4-dithia-7-azaspiro [4.4] nonane-8-carboxylic.

16

It is also designated by the company SCHERING as compound SCH-33844 and bears the generic name of SPIRAPRIL. This compound is described in Example 3 of American Patent No. 4,470,972. In this American patent, it is also mentioned that the compound exerts an antihypertensive activity. Pharmaceutically acceptable salts can be used. Hydrate can be used. In this American patent, various salts are described and they can be used in place of the free base, for example 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.

Co-administration of a calcium channel blocker and component b) exerts potent antihypertensive activity and activity against overall heart failure as shown in pharmacological trials.

Thus, for example, when animals are administered a calcium channel blocker, especially a compound of formula I, and component b), the natriuretic and diuretic activity of calcium channel blockers, especially compounds of formula I, is, surprisingly, maintained. Co-administration of a calcium channel blocker, especially a compound of formula I, and the ACE inhibitor indicated above, thereby eliminates the need to administer other diuretics and / or beta blockers. This effect was demonstrated in the following test of the hydrated rat described by Flückiger et al., In Schweiz. Med. Wochenschrift 93, ne 35 (1963) p. 1232-7:

Groups of 12 rats are used. Component a) is tested alone 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 17 subcutaneously. The compounds are administered at the same time. The urine is taken for 3 hours and its volume and the excretion of sodium are measured.

This effect is confirmed in rats deprived of sodium.

5 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 of, for example, between 0.3 and 3 mg / kg and component b) is administered 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 the excretion of sodium are measured. Values similar to those obtained in the hydrated rat test are obtained.

The Applicant has surprisingly found that the 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 global heart failure and reduces the need for diuretics.

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 further increased by the renal effect.

Components a) and b) - as indicated above - can 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 can be prepared according to the usual methods by mixing a calcium channel blocker and component b), with pharmaceutically acceptable excipients.

18

The compositions of the invention can therefore be used for the treatment of hypertension and global heart failure.

The calcium channel blocker can be administered at a dose of between 33 and 100% of the normal dose to treat, for example, hypertension or overall heart failure. The appropriate daily dose of the compounds of formula I is between approximately 0.2 mg and approximately 350 mg, in particular between approximately 1 and 70 mg, advantageously administered in divided doses 2 to 4 times 10 per day in the form of unit doses containing d about 0.05 mg to about 175 mg, for example 20 mg of compound, or in a sustained release form. The preferred compound is compound no 2. The appropriate dose is between about 2.0 and about 10 mg administered orally 1 or 2 times a day.

Compound b) can be administered at a dose of between about 33 and 100% of the normal dose to treat hypertension 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 basis can be between about 50: 1 and about 1:10, in particular between about 10: 1 and about 1: 5, preferably between about 5: 1 and approximately 1: 3.

For compound 2 and component b) the preferred weight ratio is between about 50: 1 and 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 combination with a pharmaceutically acceptable carrier or diluent. Such compositions can be formulated according to the usual methods in the form, for example of a solution, for example a solution or suspension for injection, or preferably in a solid form, for example in the form of tablets or 19 capsules. If necessary, one or both of the compounds can be in a sustained-release form, for example in the case of compounds 1 and 2 as described in British patent application 218 1 053 A or 216 0 100 A.

5 If necessary, the active substances can be placed in a package to facilitate the administration of a particular dose; they can, for example, be placed in a particular order in a blister package.

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

The following compositions are given by way of illustration but not limitation.

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 global heart failure.

Weight ingredients

Compound # 2 10.0 mg

Component b) 2.0 mg 25 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 30 322.0 mg 20 EXAMPLE 2 Tablets for oral administration

According to the usual methods, sufficient quantities of the ingredients are mixed and capsules or tablets are prepared, which are administered once daily for the treatment of hypertension and overall heart failure. Weight ingredients

Compound # 2 10.0 mg

Component b) 2.0 mg

Lactose 224.0 mg 10 Sodium lauryl sulfate 2.0 mg

Polyvinylpyrrolidone 8.0 mg

Corn starch 13.0 mg

Magnesium stearate 2.6 mg 262.0 mg 15 EXAMPLE 3: Separate co-administration

Capsules are prepared based on compound No. 2 having the following composition:

Compound # 2 10.0 mg

Microcrystalline cellulose (Avacel) 47.0 mg 20 Cetyl palmitate 10.0 mg

Hydroxypropyl-methylcellulose (Methocel E4M) 90.0 mg

Colloidal silica 1 mg magnesium stearate 2 mg 25 160.0 mg and capsules based on component b) having the following composition:

See composition on next page s »21 *

Component b) 12.0 mg

Lactose 349.0 mg

Silica (colloidal) 8.0 mg

Maleic acid 5.0 mg 5 Stearic acid 16.0 mg 400.0 mg

These capsules can be presented in packaging with an administration calendar. If necessary, combined capsules containing the two active substances can be prepared.

Claims (9)

1. As a medicament, the medicament combination comprising, as active principles, a) a calcium channel blocker and b) 7- (N-Cl (S) -ethoxycarbonyl-3-phenylpropyl] - (S) - acid alanyl) - 1.4- dithia-7-azaspiro- [4,4} ionane-8- (S) -carboxylic or one of its pharmaceutically acceptable salts. 2. A pharmaceutical composition, characterized in that it comprises, as active principles, a) a calcium channel blocker and b) 7- (N-Ü (S) -ethoxycarbonyl-3-phenylpropyl3- (S) - acid - alanyl) - 1.4- dithia-7-azaspiro-C4,4] nonane-8- (S) -carboxylic or one of its pharmaceutically acceptable salts. 3. A pharmaceutical composition according to claim 15 2, characterized in that the calcium channel blocker corresponds to the formula I A R * 1 \ / * 3 i) 20 IX * 1 25 in which A represents a residue of formula (a), (b) or (c) "<k>" "9 ç, (a) (b) (c) 30 23 a •" Rl means l hydrogen, C1-C6 alkyl, hydroxy-C2-C6 alkyl, alkoxy-C3-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl or C4 cycloalkyl-alkyl -C8 "or a phenyl-C7-C9 alkyl or phenyl-alkenyl C9-C12 group, in which the phenyl ring optionally carries one, two or three substituents chosen from halogens and hydroxy groups, C1-C4 alkyl and C1-C4 alkoxy, R2 and R5 each mean, independently of one another, hydrogen, C1-C6 alkyl, phenyl-C7-C10 alkyl> C3-C7 cycloalkyl or cycloalkyl C4-C8 alkyl, one of the symbols R2 and R5 can also signify a hydroxy-C1-C4 alkyl group or cyano when A represents a residue b, R3 and R4 mean, independently of one another, -CN, -COOR7, -CORg, -S (0) nR9 or -COO-BN-Rio-Rll, 15. means 0, 1 or 2, Rß sig nifies hydrogen, halogen or C1-C4 alkyl, C1-C4 alkoxy, C1-C4 alkylthio, C1-C4 alkylsulfonyl, trifluoromethyl, nitro, hydroxy, azido, amino, C1-C4 alkylamino, di (C1-C4 alkyl) -amino, C1-C5 alkanoylamino, C2-C5 alkoxycarbonyl, aminocarbonyl, trifluoromethoxy, cyano, sulfamoyl, C1-C4 alkylsulfamoyl or di (C1-C4 alkyl) -sulfamoyl, X means oxygen or sulfur, m means 0, 1, or 2, R7 Rg and R9 each independently of one another are C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalkylalkyl- C2- hydroxyalkyl C6 »C3-Cß alkoxyalkyl, hydroxy, C4-C8 alkoxyalkyl, C2-Cß no-alkyl friend, (C1-C4 alkyl) C2-C6 amino-alkyl, *» 24 € di (C1- alkyl C4) aminoalkyl, phenyl, C7-C10 phenylalkyl, a 5 or 6-membered heterocyclic ring containing one nitrogen, oxygen or sulfur atom and which may also contain 1, 2 or 3 additional cyclic nitrogen atoms, or a (4-C4) alkyl group optionally substituted by a 5- or 6-membered heterocyclic ring containing a nitrogen, oxygen or sulfur atom as heteroatom and which may also contain 1, 2 or 3 other atoms of cyclic nitrogen, R7 can also represent a trifluoroethyl group when A signifies a residue 10 b, B represents an alkylene group at (4-C14, RIO and Ru each signify independently including one another, C1-C6 alkyl, C3-C6 alkenyl, C3-C6 alkynyl, C3-C7 cycloalkyl, C4-C8 cycloalk-ylalkyl, hydroxy-15 C2- alkyl C6, C3-C6 alkoxyalkyl, hydroxy-C4-C8 alkoxyalkyl, amino-C2-C6 alkyl, (C1-C4 alkyl) amino-C2-C6 alkyl, di (C1-C4 alkyl-friend no) - C1-C4 alkyl, phenyl, or phenyl-C7-C10 alkyl "or else R 10 and R11 together form, with the nitrogen atom to which they are attached, a 5, 6 or 7-membered heterocyclic optionally containing another heteroatom chosen from oxygen and sulfur, or a group = N-R12 in which R12 signifies a C1-C4 alkyl, benzyl or bis-phenylmethyl group 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-V alkoxy group * 25 <m> 4. A pharmaceutical composition according to claim 2 or 3, characterized in that the calcium channel blocker corresponds to the formula laK \ M la 'R1 in which R'i signifies hydrogen, a C1-C6 alkyl group, alkenyl or C3-C6 alkynyl, C3-C7 cycloalkyl or C4-C8 cycloalkylalkyl or a C7-C9 phenylalkyl or C9-C12 phenylalkenyl group, in which the phenyl ring optionally carries one, two or three selected substituents among halogens and hydroxy groups, C1-C4 alkyl and C1-C4 alkoxy, R'2 and R'5 independently represent hydrogen or a C1-C6 alkyl group, R'3 and R'4 independently represent a C1-C6 alkyl, alkenyl or C3-C6 alkynyl, C3-cycloalkyl group -C7, C4-C8 cycloalkyl, C1-C6 alkoxy, C2-C6 hydroxy-alkoxy> C3-C6 alkoxyalkoxy, C4-C8 alkoxy-alkoxy, C3-C6 alkenyloxy or alkynyloxy, C3-cycloalkyloxy -C7 or C4-C8 cycloalkyl-alkoxy, or else R'3 means 0-B'-R17, where B 'represents an alkylene chain containing from 9 to 14 carbon atoms and R'7 30 represents a pi peridine group or piperazine both substituted in position 4 by a methyl, benzyl or bis-phenylmethyl group optionally mono- or independently disubstituted in the phenyl ring (s) by a halogen of atomic number from 9 to 53 or by a C1-C4 alkoxy group and 35 R14 has the meaning indicated above, ft ft * Λ ► * 26 R'6 means hydrogen, halogen, alkyl, alkoxy, alkylthio or alkylsulfonyl cha no C1-C4 or a tri-fluoromethyl, nitro or hydroxy group, and X has the meaning indicated above. 5. A pharmaceutical composition according to any one of claims 2 to 4, characterized in that component a) is chosen from the diethyl ester of 4- (2, l, 3-benzoxadiazol-4-yl) acid. -1,4-dihydro-2,6-dimethyl-pyridine-3,5-dicarboxylic acid, dimethyl ester of 4- (2,1,10 3-benzoxathiadiazol-4-yl) -2,6- (+) - (S) -4- (2) dimethyl-1,4-dihydropyridine-3,5-dicarboxylic acid and the 10- [4- (diphenylmethyl) -piperazine-1-yl] dicylic ester , 1,3-benzoxadiazol - 4-yl) -1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-3-pyri di ne-carbo-xylic. 6. A pharmaceutical composition according to any one of claims 2 to 4, characterized in that the calcium channel blocker is the isopropyl ester of 4- (2, l, 3-benzoxa-diazol-4-yl) acid. -1,4-dihydro-2,6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic. .20 7. A pharmaceutical composition according to any one of claims 2 to 6, characterized in that the weight ratio of component a) to component b) is between 5: 1 and about 1: 3. 8. A pharmaceutical composition according to any of claims 2 to 7, for use in the treatment of hypertension and global heart failure. 9. The use of a combination comprising component a) and component b) as defined in any one of claims 1 to 6, for the preparation of a pharmaceutical composition for the treatment of hypertension and global heart failure.