KR960005145B1 - Pharmaceutical composition for use against hypertension and congestive heart failure - Google Patents

Abstract

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Description

Pharmaceutical composition for the treatment of hypertension and congestive heart failure

The present invention relates to a novel pharmaceutical composition effective for treating congestive heart failure and hypertension, a method for preparing the same, and a method of using the same.

The present invention relates to a pharmaceutical composition containing the following a) and b) as active ingredients.

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 its pharmaceutically acceptable salts.

The invention also relates to a) calcium antagonist and b) 7- (N- [1 (S) -ethoxycarbonyl-3-phenylpropyl]-(S) -alanyl) -1, 4-dithia-7- Provided are methods for treating congestive heart failure or hypertension by administering azaspiro- [4,4] nonane-8- (S) -carboxylic acid and pharmaceutically acceptable salts thereof to a subject together.

Calcium antagonists include a group of physiologically active substances having calcium antagonistic activity or channel channel blocking activity. A variety of such compounds are now known, and these compounds are used for the treatment of cardiovascular disorders or cardiovascular diseases such as coronary insufficiency, cerebral hematopoiesis, hypertension, and for the treatment of peripheral circulation. It has a wide range of therapeutic applications that have been shown to be useful for the treatment of other disorders, including. Calcium antagonists are generally used as vasodilators, such as in the treatment of hypertension.

Component b) is an angiotensin converting enzyme inhibitor (ACE-inhibitor). Little is known about their pharmacological and biopharmaceutical properties. ACE inhibitors are known compounds that affect the process of converting angiotensin I to angiotensin II, and are known to act to lower the blood pressure rise caused by angiotensin II. When administering the ACE-blocking compound alone, a relatively large amount must be used, which may cause undesirable side effects.

The pharmaceutical compositions of the present invention and the co-administration therapy of component a) and component b) have pharmaceutical properties that are significantly improved and exhibit good pharmacological / therapeutic aspects. In particular, co-administration of components a) and b) has been shown to have surprising efficacy on antihypertensive activity and congestive heart failure as described above.

Component a) increases central venous pressure, resulting in increased cardiac blood ejection, but in the case of animals pretreated with component (b) it is insensitive. Increasing central venous pressure without cardiac depression (as assessed by placing strain gauges in the myocardial layer) suggests increased venous retrograde caused by dilation of the arteries. Thus being insensitive to component a) means increased venous compliance after ACE inhibition.

Preferred calcium antagonists for use in the compositions of the present invention are dihydropyridines represented by the following formula (I):

Wherein A is a residue of formula (a), (b), or (c)

R ₁ is hydrogen, (C _1-6 ) alkyl, hydroxy (C _2-6 ) alkyl, (C _3-6 ) alkoxy alkyl, (C _3-6 ) alkenyl, (C _3-6 ) alkynyl, (C _3-7 ) cycloalkyl, or (C _4-8 ) cycloalkylalkyl or (C _7-9 ) phenylalkyl or (C _9-12 ) phenylalkenyl, wherein the phenyl ring is halogen, hydroxy, _Mono- , double- or triple-substituted or unsubstituted with (C _1-4 ) alkyl or (C _1-4 ) alkoxy, R ₂ and R ₅ are each independently hydrogen, (C _1-6 ) alkyl , (C _7-10 ) phenylalkyl, (C _3-7 ) cycloalkyl or (C _4-8 ) cycloalkylalkyl and when A is residue (b) one of R ₂ and R ₅ is (C _1-4 Hydroxyalkyl or cyano, R ₃ and R ₄ are each independently —CN, —COOR ₇ , —COR ₈ , —S (O) _n R ₉ or —COO—B—NR ₁₀ R ₁₁ , where n is 0, 1 or 2, R ₆ is hydrogen, halogen, (C _1-4 ) alkyl, (C _1-4 ) alkoxy, (C _1-4 ) alkylthio, (C _1-4 ) alkylsulfonyl, tri fluoromethyl, nitro, hydroxy, azido, amino, (C _1-4) Kill amino, di [(C _1-4) alkyl] amino, (C _1-5) alkanoylamino, (C _2-5) carbalkoxy alkoxycarbonyl, aminocarbonyl, trifluoromethoxy, cyano, sulfamoyl, (C _1-4 ) alkylsulfamoyl or di [(C _1-4 ) alkyl] sulfamoyl, X is oxygen or sulfur, m is 0, 1 or 2 and R ₇ , R ₈ and R ₉ are each Independently (C _1-6 ) alkyl, (C _3-6 ) alkenyl, (C _3-6 ) alkynyl, (C _3-7 ) cycloalkyl, (C _4-8 ) cycloalkylalkyl, hydroxy- (C _2-6 ) alkyl, (C _3-6 ) alkoxyalkyl, hydroxy- (C _4-8 ) alkoxyalkyl, amino- (C _2-6 ) alkyl, (C _1-4 ) alkylamino (C _{2 -6} ) alkyl, di [(C _1-4) alkyl] aminoalkyl, phenyl, (C _7-10 ) phenyl alkyl, containing nitrogen or oxygen or sulfur atoms and containing one, two or three additional ring nitrogen atoms A heterocyclic ring of 5- or 6-membered, or nitrogen or oxygen or sulfur, which may be a hetero atom and additionally 1, 2 or 3 (C _1-4 ) alkyl optionally substituted with a 5- or 6-membered heterocyclic ring which may contain additional ring nitrogen atoms, wherein R ₇ is trifluoroethyl when A is residue (b) B may be (C _1-14 ) alkylene, and R ₁₀ and R ₁₁ are each independently (C _1-6 ) alkyl, (C _3-6 ) alkenyl, (C _3-6 ) alkynyl , (C _3-7 ) cycloalkyl, (C _4-8 ) cycloalkylalkyl, hydroxy (C _2-6 ) alkyl, (C _3-6 ) alkoxyalkyl, hydroxy (C _4-8 ) alkoxyalkyl, Amino (C _2-6 ) alkyl, (C _1-4 ) alkyl, amino (C _2-6 ) alkyl, di [(C _1-4 ) alkyl] -amino- (C _1-4 ) alkyl, phenyl, or (C _7-10 ) phenyl alkyl, or R ₁₀ and R ₁₁ together with the nitrogen atom to which they are linked are 5-, 6-, or 7-element optionally containing an additional hetero atom selected from oxygen or sulfur or = NR ₁₂ group; A heterocyclic ring consisting of: wherein R ₁₂ is (C _1-4 ) alkyl or optionally element number 9 Halogens from up to 35 or alkoxy having 1 to 4 carbon atoms are optionally monosubstituted or double-substituted bis-phenylmethyl, or benzyl, respectively.

In formula (I), the (C _1-6 ) alkyl group preferably contains 1 to 4 carbon atoms, more preferably 1 or 2 carbon atoms, of which methyl group is most preferred. The (C _1-4 ) -alkyl, -alkoxy, -alkylthio and -alkylsulfonyl groups preferably comprise 1 or 2 carbon atoms. Residue R ₇ is hydroxyalkyl in -COOR _7, alkoxyalkyl, hydroxy-alkoxyalkyl, aminoalkyl and hydroxy-alkyl amino, alkoxy, hydroxy, alkoxy, amino and alkylamino group is part of that is not connected to the α- carbon atom It is preferable. They are suitably in terminal positions. The alkylene portion of hydroxy alkyl, alkoxy alkyl, hydroxy alkoxy alkyl, amino alkyl and alkyl aminoalkyl is preferably ethylene and propylene. The alkylene portion of the cycloalkylalkyl group is suitably methylene. The cycloalkyl moiety of the cycloalkylalkyl group is preferably cyclopropyl, cyclopentyl, or cyclohexyl. Halogen means fluorine, chlorine or bromine, especially chlorine.

Preferably, the multiple bonds in the alkenyl, alkynyl and phenylalkenyl groups which are R ₁ or -COOR ₇ are not present at the α, β-positions. Alkenyl and alkynyl groups preferably have 3 to 5 carbon atoms. Alyl is preferably allyl, or 2-methyl allyl is propionyl. Phenyl alkenyl groups preferably have a trans configuration, and include cinnamil groups and the like. When R ₁ is phenyl, it is preferably unsubstituted. When R ₁ is a bi- or tri-substituted phenyl, the substituents are preferably the same and are halogen or alkyl. Heterocyclic rings such as R ₇ , R ₈ and R ₉ are, for example, furyl, thienyl, pyrrolyl, thiazolyl, isothiazolyl, thiadiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, imidazolyl , Pyrazolyl, triazolyl, tetrazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridininyl, piperidinyl, morpholinyl and triazinyl. The heterocyclic ring, which R ₁₀ and R ₁₁ form together with the nitrogen atom to which they are linked, is preferably saturated and includes a pyrrolidine, piperidine, piperazine, N-alkylpiperazin and morpholine ring. However, most preferred is di-phenyl-methyl piperazine, as described above, wherein the phenyl ring (s) may be substituted. It is preferable that R <_2> and R <_5> are the same. R ₆ is suitably halogen, alkyl, alkoxy, nitro or trifluoromethyl and is preferably present in the ortho- or meta-position relative to the position of attachment of the dihydropyridine residue. When A is residues a), R ₆ is preferably hydrogen.

B in —COOBNR ₁₀ R ₁₁ means an alkylene chain consisting of 1 to 14 carbon atoms, preferably an alkylene chain consisting of 5 to 14 carbon atoms, in particular 10 carbon atoms.

The compounds shown in the following table are particularly suitable compounds of the formula (I) used according to the invention in which A is residue (a) (the numbers listed under "y" in the table below refer to the dihydropyridine nucleus ( a) represents the combined position).

Compounds of formula (I) in which A is residue (b) suitable for use according to the invention are illustrated in the table below:

The following are compounds of formula (I) wherein compound number (72) is suitable for use according to the invention and A is residue (c).

R ₁ = H, R ₂ = CH ₃ , R ₃ = COOC ₂ H ₅ , R ₄ = COOC ₂ H ₅ , R ₅ = CH ₃ , and R ₆ = o-SCH ₃

Particularly preferred calcium antagonists by component a) are represented by the following formula (Ia):

Wherein R ₁ ′ is hydrogen, alkyl having 1 to 6 carbon atoms, alkynyl or alkenyl having 3 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cyclo having 4 to 8 carbon atoms Alkylalkyl, phenylalkyl having 7 to 9 carbon atoms, or phenylalkenyl having 9 to 12 carbon atoms, said phenyl ring being halogen, hydroxy or alkoxy or alkyl having 1 to 4 carbon atoms, respectively, single, double Or triple substituted or unsubstituted, R ₂ ′ and R ₅ ′ are each hydrogen or alkyl of 1 to 6 carbon atoms, R ₃ ′ and R ₄ ′ are alkyl each having 1 to 6 carbon atoms, 3 Alkynyl or alkenyl having 3 to 6 carbon atoms, cycloalkyl having 3 to 7 carbon atoms, cycloalkylalkyl having 4 to 8 carbon atoms, alkoxy having 1 to 6 carbon atoms, 2 Hydroxyalkoxy having 3 to 6 carbon atoms, alkoxyalkoxy having 3 to 6 carbon atoms, hydroxyalkoxyalkoxy having 4 to 8 carbon atoms, alkynyloxy or alkenyloxy having 3 to 6 carbon atoms, 3 to 7 carbon atoms Cycloalkyloxy having 3 carbon atoms or cycloalkylalkoxy having 4 to 8 carbon atoms or R ₃ 'means O-B'-R ₇ ' wherein B 'is alkylene having 9 to 14 carbon atoms And R ₇ ′ is piperidine or piperazine, both of which are methyl, benzyl or bis-phenyl, optionally monosubstituted or separately disubstituted by a phenyl ring with a halogen having from 9 to 53 carbon atoms or with a halogen having 1 to 4 carbon atoms. will the 4-position is substituted by methyl, R ₄ 'has the above meaning, R _6' is alkyl or alkoxy or alkenyl having from hydrogen, halogen, each of 1 to 4 carbon atoms Or alkylthio or alkylsulfonyl, trifluoromethyl, and nitro or hydroxyl, X has the aforementioned meaning.

Calcium antagonists used in the present invention have generally been described together with sulfur hypertension activity and their calcium antagonism in already published patents. The patent mentions that the salt form of the calcium antagonist of formula (I) may be used in place of the free base. The patent also finds that when the substituents at positions 2 and 6 and / or 3 and 5 of the 1,4-dihydropyridinyl moiety are different, the calcium antagonist may exist in racemic or individual enantiomeric forms. Could be.

Of particular interest are calcium antagonists of formula (I) or formula (Ia), 4- (2, 1, 3-benzoxadiazol-4-yl) -1, 4-dihydro, represented by compound number (1) hereafter. -2, 6-dimethyl-pyridine-3, 5-dicarboxylic acid diethyl ester; 4- (2, 1, 3-benzoxadiazol-4-yl) -1, 4-dihydro-2, 6-dimethyl-3-methoxycarbonyl-pyridine-, hereafter referred to as compound number (2) 5-carboxylic acid isopropyl ester; 4- (2, 1, 3-benzoxathiadiazol-4-yl) -2, 6-dimethyl-1, 4-dihydropyridine-3, 5-dicarboxyl, hereinafter referred to as compound number (3) Acid dimethyl esters; And (+)-(S) -4- (2, 1, 3-benzoxadiazol-4-yl) -1, 4-dihydro-5-methoxycarbonyl, hereinafter referred to as compound number (4) -2,6-dimethyl-3-pyridinecarboxylic acid- [10- [4- (diphenylmethyl) -piperazin-1-yl] decyl] ester, of which numbers (2) and (4) Of particular note are the compounds.

7- (N- [1 (S) -ethoxycarbonyl-3-phenylpropyl]-(S) -alanyl) -1,4-dithia-7-azaspiro [4, 4] nonan-8- (S) -carboxylic acid is [8S- [7 [R ^* ], 8R ^* ]]-7- [2-[[1- (ethoxycarbonyl) -3-phenylpropyl] amino] -1-oxopropyl ] -1,4-dithia-7-azaspiro [4,4] nonane-8-carboxylic acid, and is also classified as SCH-33844 by SCHERING, and has the generic name SPIRAPRIL. This compound is shown in Example 3 of US Pat. No. 4, 470, 972. In this patent the compound is described as having antihypertensive activity. Pharmaceutically acceptable salt forms can also be used. Hydrates can also be used. The US patent states that instead of the free base form, other salt forms may be used as the hydrochloride salt shown in Example 4 of this patent or the hemimaleate salt shown in Example 5, and the like. Preferred form is monohydrochloride mono hydrate.

Co-administration of calcium chelating agent and component b) showed effective antihypertensive activity and activity against congestive heart failure.

For example, administration of a calcium antagonist of component a), in particular a compound of formula (I) and component b), together with the animal maintained the sodium diuretic and diuretic activity of the calcium antagonist of formula (I). Co-administration of a calcium antagonist, a compound of formula (I), together with the above ACE-inhibitor reduces the need for the use of separate diuretics and / or beta-blockers. This was confirmed in the hydrated rat test described below. (Method by Fluckiger et al., Schweiz. Med. Wochenschrift 93, No 35 [1963] 1232-7):

The group consisted of 12 rats. Dosages from 0.3 mg / kg (oral) to 3 mg / kg (oral) administered alone or in combination with a component b) of 3 mg / kg (subcutaneous) were investigated to induce diuretic effects. . Compounds are administered simultaneously. Urine was collected for 3 hours and its volume and sodium emissions measured.

This effect was confirmed in rats deficient in sodium. Rats were fed 50 mg / kg / day of furosemide in drinking water for 2 days. The group consisted of six animals. Calcium antagonists were administered at diuretic doses, i.e., 0.3 to 3 mg / kg (oral), and component b) was administered at 3 mg / kg (subcutaneous). The compound is administered simultaneously. Urine was collected for 3 hours and its volume and sodium emissions measured. Similar measurements were obtained as in the hydrated rat test.

It was an unexpected finding that diuretic and sodium diuretic activity was generally maintained. This has produced a combination of the invention which is particularly suitable for the treatment of hypertension and congestive heart failure and reduces the need for diuretics.

The importance of this effect is increasing, as it is known that metabolic problems occur during long-term diuretics. The antihypertensive effect by coadministration of calcium antagonist and component b) was further enhanced by the renal effect described above.

Both components a) and b) can be in the form of a suitable salt, such as free base form or acid addition salt form, as described above.

The new composition was prepared by combining component b) with calcium antagonist component a) in sufficient pharmaceutically acceptable purity. Conventional pharmaceutical excipients, including carriers and diluents, may be combined together.

Therefore, the composition of the present invention can be used for the treatment of hypertension and congestive heart failure.

Calcium antagonists can be administered in amounts of 1/3 to 100% of the usual dose for treating hypertension or congestive heart failure. The daily oral dosage of the compound of formula (I) is known to be about 0.2 mg to 350 mg, in particular about 1 to 70 mg, preferably in unit dosage form containing about 0.05 mg to about 175 mg, such as about 20 mg per day. To four divided doses or sustained release. Preferred compound is compound number (2). Known dosages are about 2.0 to about 10 mg orally once or twice daily.

The preferred weight ratio of the calcium antagonist of component a) to component b) (calculated for their free base) is from about 50: 1 to about 1:10, in particular from about 10: 1 to about 1: 5, preferably About 5: 1 to about 1: 3. Component b) may be administered in an amount of 1/3 to 100% of the usual dose for treating hypertension or congestive heart failure. Suitable dosage forms contain 3 mg, 6 mg, 12 mg and 24 mg.

The preferred ratio of compound number (2) and component b is about 5: 1 to 1: 1, such as about 50: 1 to about 1: 5, in particular about 1: 1, 4: 1,3: 1 or 2: 1. .

Conveniently, components a) and b) are administered in the form of a pharmaceutical composition mixed with a pharmaceutical carrier or diluent. Such compositions may be prepared by conventional methods in the form of a solvent such as an injectable or suspending agent, or preferably in the form of a solid form such as a tablet or capsule. If desired, both one or both components may be prepared in sustained release form, such as in the case of compounds Nos. (1) and (2) set forth in GB218 1 053A or 216 0 100A.

If desired, the actives may be packed into packs to facilitate administration by a particular dosing regimen, such as arranging the actives in a particular order in a blister pack.

A suitable composition also consists of a pack containing components a) and components b) separately, which are separated until co-administration is necessary and, if co-administration is required, in a predetermined amount of component a) and One may be administered together.

The following examples illustrate the compositions according to the invention.

Example 1

Hard gelatin capsules for oral administration

Hard gelatin capsules containing the following ingredients can be prepared by conventional methods and can be administered once daily to treat hypertension and congestive heart failure:

Example 2

Oral Tablets

The following ingredients are mixed in a conventional manner and filled into gelatin capsules or compressed into tablets and administered once daily to treat hypertension and congestive heart failure.

Example 3

Split simultaneous administration

Capsules of compound number (2) can be prepared by combining the following ingredients.

And capsules of component b) can be prepared by combining the following components.

Ingredient b) 12mg

Lactose 349mg

Colloidal Silica 8mg

Maleic Acid 5 mg

16 mg stearic acid

400 mg

They can also be made in calendar packs. If desired, complex capsules containing two active agents may also be prepared.

Claims (2)

a) 4- (2, 1, 3-benzoxadiazol) -4-yl-1, 4-dihydro-2, 6-dimethyl-3-methoxycarbonyl-pyridine-5-carboxylic acid isopropyl Ester and b) 7- (N- [1 (S) -ethoxycarbonyl-3-phenylpropyl]-(S) -alanyl) -1, 4-dithia-7-azaspiro- [4, 4 ] Pharmaceutical for treating hypertension and congestive heart failure, comprising nonane-8- (S) -carboxylic acid and pharmaceutically acceptable salts thereof, wherein a): b) has a weight ratio of 5: 1 to 1: 3. Composition. The pharmaceutical composition of claim 1, wherein the composition is in the form of a pack or dosage device.