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Publication numberUS3883656 A
Publication typeGrant
Publication dateMay 13, 1975
Filing dateOct 30, 1972
Priority dateNov 11, 1971
Also published asDE2254018A1
Publication numberUS 3883656 A, US 3883656A, US-A-3883656, US3883656 A, US3883656A
InventorsPhyllis Roberta Hedwall
Original AssigneeCiba Geigy Corp
Export CitationBiBTeX, EndNote, RefMan
External Links: USPTO, USPTO Assignment, Espacenet
Pharmaceutical preparations for the treatment of hypertonia
US 3883656 A
Abstract
Pharmaceutical preparations containing a combination of the antihypertensively active amino acid and of a beta -hydroxylase inhibitor for the treatment of hypertonia. Said preparations prolong the antihypertensive action substantially greater than that would be achieved by administration of individual compounds.
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United States Patent [191 Hedwall [451 May 13, 1975 PHARMACEUTICAL PREPARATIONS FOR THE TREATMENT OF HYPERTONIA [75] Inventor: Phyllis Roberta Hedwall, Basel,

Switzerland [73] Assignee: Ciba-Geigy Corporation, Ardsley,

{22] Filed: Oct. 30, 1972 [2!] Appl. No.: 302,156

[30] Foreign Application Priority Data Nov, 11, 1971 Switzerland l6377/7l Sept, l5, I972 Switzerland 13545/72 [52] US. Cl 424/263; 424/319 [51] Int. Cl A6lk 27/00 [58] Field oi Search 424/263, 319

[5 6] References Cited OTHER PUBLICATIONS lkuko et al.-Chem. Abst. Vol. 75, (l97l), page Branislav et al.-Chem. Abst Vol. 74, (1971), page 97833n.

Primary Examiner-Sam Rosen Attorney, Agent, or Firm-Joseph G. Kolodny; John J. Maitner [57] ABSTRACT 10 Claims, No Drawings 1 PHARMACEUTICAL PREPARATIONS FOR THE TREATMENT OF HYPERTONIA The invention relates to new pharmaceutical preparations for the treatment of hypertonia. These new pharmaceutical preparations contain a combination of an anti-hypertensively active aminoacid and a B-hydroxylase inhibitor.

Anti-hypertensively active aminoacids are above all compounds of the type of a-methyldopa.

Anti-hypertensively active aminoacids, above all compounds of the type of a-methyldopa, especially a-methyldopa itself, have proved successful in the therapy of hypertonia. Thus, a-methyldopa is used successfully in practically all forms of hypertonia, at a dosage of about 0.5 g to about 2 g, and at times even up to about 4 g, per day, compare E. Mutschler, Arzneimib telwirkungen (Effects of Medicines), Wissenschaft liche Verlagsgesellschaft, mbH, Stuttgart l970, page 134.

B Hydroxylase inhibitors, for example bis- (diethylthiocarbamoyl )-disulphide, bis-{(3-aza-3- methyl-hexylene-l ,6)-thiocarbamoyl ]-disulphide and above all compounds of the type of fusaric acid, especially fusaric acid and its salts, such as its calcium salt, have also proved very successful in the therapy of hypertonia, compare .lap. Circ. J. 35, 339 (l97l).

It has now been found, surprisingly that by treatment of hypertonia with a combination of an antihypertensively active aminoacid and a B-hydroxylase inhibitor the antihypertensive action can be prolonged and be rendered more even and the dosage of the components, that is to say of the antihypertensively active aminoacid and of the ,B-hydroxylase inhibitor, can be reduced, as can be shown by Goldblatts method on male, renal hypertonic rats on administration of customary doses of the components orally or subcutaneously. The prolongation of the anti-hypertensive action here proves to be substantially greater than would correspond to the sum of the anti-hypertensive action of the active substance components.

This prolongation of the anti-hypertensive action makes it possible to manage with a single daily administration of the combination preparation according to the invention. The substantially more even action in lower ing the blood pressure considerably reduces the disad vantages of a fluctuation in blood pressure in the course of the day, such as occurs in the known treatment of hypertonia by means of the individual active substance components, and makes the therapy more balanced and more easily tolerated from the point of view of the patients. The reduction in the component dosages reduces the dangers of an overdosage and is of advantage especially because of the known high doses of the anti-hypertensively active aminoacids, especially of the compounds of the type of wmethyldopa, so that a general reduction in the strain on the organism of the patient is achievable.

Possible compounds of the type of a-methyldopa are above all or-amino-a-methyl-B-hydroxyphenylpropionic acids, their salts and esters.

Salts are especially salts with bases, such as alkali metal carbonates, for example sodium carbonate or potassium carbonate, alkali metal bicarbonates, alkali metal hydroxides, such as sodium hydroxide or potassium hydroxide, or corresponding alkaline earth metal compounds, such as those of calcium or magnesium, or

ammonia, as well as amines, such as aliphatic amines, for example lower alkylamines, such as trimethylamine or triethylamine, and also aluminium compounds, such as aluminium hydroxide, for example salts of two mols of acid and one mol of aluminium hydroxide which are suitable especially because of their slower resorption, lack of odour and low gastro-intestinal disturbances.

Esters are above all lower alkyl esters, such as methyl esters and ethyl esters. Lower radicals are, in the preceding and following texts, above all those with up to 7, preferably with up to 4, C atoms.

Compounds to be singled out particularly are a-amin0-a-methyl-B-(4-hydroxyphenyl)-propionic acid and very particularly a-amino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid, which is known by the name of a-methyldopa, as well as their salts, such as, in particular, their alkali metal salts or alkaline earth metal salts, and secondly their esters, such as lower alkyl esters.

B-Hydroxylase inhibitors are, for example, bis- (diethylthiocarbamoyl )-disulphide, bis-[ 3-aza-3- methyl-hexylene-l,6)-thiocarbamoyl]-disulphide and especially compounds of the type of fusaric acid.

Possible compounds of the type of fusaric acid are above all those of the formula I wherein R is an esterified or amidised carboxyl group but above all a free carboxyl group and R is an alkyl group, and their salts.

An esterified carboxyl group is, for example, a carboxyl group which is esterified with a lower alkanol, with the lower alkanol in particular having up to 8, preferably up to 4, C atoms and being branched, or preferably, straight-chain in the alkyl part. As examples of an esterified carboxyl group there may be mentioned: n-butoxycarbonyl, n-propoxycarbonyl, ipropoxycarbonyl and in particulalr ethoxycarbonyl and very especially methoxycarbonyl.

An amidised carboxyl group is, for example, a N- monosubstituted or N-disubstituted carbamoyl group and very particularly the N-unsubstituted carbamoyl group. As substituents there may be mentioned: lower alkyl, especially with up to 8 C atoms, such as branched or, in particular, straightchain lower alkyl with, in particular, up to 4 C atoms, for example n-butyl, n-propyl, i-propyl and especially ethyl and very particularly methyl.

An alkyl group R is, in particular, a branched or above all a straight-chain alkyl group with up to 9 C atoms, preferably n-pentyl and very particularly nbutyl.

Salts are especially salts with bases, such as those mentioned above, above all alkali metal salts and alkaline earth metal salts, and very particularly the calcium salt.

Depending on the number of their asymmetric carbon atoms the active substances mentioned can be present in the form of isomer mixtures, pure isomers (racemates) or optical antipodes. Preferably they are in each case used in the form of the more active or less toxic isomer or antipode. For example, as a-methyldopa its laevo-rotatory antipode can preferably be used.

Active substances with basic groups, especially esters of the type of a-methyldopa, can be present in the free form or in the form of their non-toxic salts. Possible salts of this nature are especially salts with organic or inorganic acids. such as hydrogen halide acids, sulphuric acid, phosphoric acid, nitric acid, perchloric acid, aliphatic, alicyclic, aromatic or heterocyclic carboxylic acids or sulphonic acids, such as formic, acetic, propionic, succinic, glycollic, lactic, malic, tartaric, citric, ascorbic, maleic, hydroxymaleic or pyruvic acid; phenylacetic, benzoic, p-aminobenzoic, anthranilic, phydroxybenzoic, salicylic or p-aminosalicylic acid, embonic acid, methanesulphonic, ethanesulphonic, hydroxyethanesulphonic and ethylenesulphonic acid; halogenobenzenesulphonic, toluenesulphonic and naphthalenesulphonic acid or sulphanilic acid; cyclohexyl-sulphamic acid, methionine, tryptophane, lysine or arginine.

The invention relates both to pharmaceutical prepa rations containing a combination of an antihypertensively active aminoacid, especially one mentioned above as being preferred, and a B-hydroxylase inhibitor, especially one mentioned above as being preferred, and to the manufacture of such preparations as well as the use of the active compounds in the form of the said preparations, or by combined but separate administration, for the treatment of hypertonia.

Pharmaceutical preparations to be particularly singled out contain, as the anti-hypertensively active aminoacid, a-aminoa-methyl-B-(4-hydroxyphenyl)- propionic acid or or-amino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid or a salt or a lower alkyl ester thereof, and as the B-hydroxylase inhibitor, a compound of the formula I] wherein R, is lower alkoxycarbonyl, carbamoyl or carboxyl and R is alkyl with 3-6 C atoms, or a salt thereof.

Suitable preparations are, in particular, also those which contain, as the anti-hypertensively active aminoacid, oz-methyl-p-tyrosine or a salt thereof, and, as the B-hydroxylase inhibitor, a compound of the for mulall 4 Very particularly preferred pharmaceutical preparations are those which contain, as the anti hypertensively active aminoacid, a-amino-a-methyhfi- 3,4-dihydroxyphenyl)-propionic acid (a-methyldopa), or the methyl ester, ethyl ester or a salt thereof, or a-methyl-p-tyrosine, and, as the B-hydroxylase inhibitor, 5-n-pentylpicolinic acid or preferably 5-nbutylpicolinic acid (fusaric acid), or the methyl ester, ethyl ester or a sait thereof, or bis-(diethylthiocarbamoyl)-disulphide or bis-l(3-aza-3-methyl-hexylene- 1,6 )-thiocarbamoyl l-disulphide.

The invention above all, however, relates to pharmaceutical preparations containing a-aminoa-methyl-/3- (3,4-dihydroxyphenyl)propionic acid or a nontoxic salt thereof and S-n-butyl-picolinic acid or a nontoxic salt thereof.

Accordingly, the use of these preferred preparations or the use of the individual components in a combination therapy is also a particular subject of the invention.

In the new preparations, the ratio of the antihypertensively active aminoacid to the B-hydroxylase inhibitor can vary within considerable limits.

The dosage of the new preparations depends on the effectiveness of the active substance components concerned and on the individual requirements of the patient. Using the preparations according to the invention the daily dosage of the active substance components can generally be reduced to between about half and one-third of the customary separate daily dosage.

Thus, for example, the abovernentioned preparations which have particularly been singled out can contain about -200 mg, especially -200 mg, of 0ramino-a-methyl-fi-( 3,4-dihdyroxyphenyl)-propionic acid and about 50-200 mg, especially 100-200 mg, of the calcium salt of 5-n-butylpicolinic acid.

The preferred preparations can, however, also contain about 100-200 mg, especially 150-200 mg, of mamino-a-methyl-B-(3,4-dihydroxyphenyl)-propionic acid and about 40-150 mg, especiaily 60-l00 mg, of bis-( diethylthiocarbamoyl)-disulphide or bis-[( 3-aza-3- methyl-hexylenel ,6 )-thiocarbamoyl l-disulphide.

The daily dosage is about 1-6 such individual dosages, which are preferably administered all at once.

The pharmaceutical preparations according to the invention are principally suited to oral or parenteral administration and are preferably in the form ofa mixture with a pharmaceutical, organic or inorganic, solid or liquid excipient which is suitable, for example, for enteral or parenteral administraton. Possible substances for forming the excipient are those which do not react with the active substances such for example, water, gclatine, lactose, starch. stearyl alcohol, magnesium stearate, talc, vegetable oils, benzyi alcohols, gum, propylene glycols, white petroleum jelly or other known medicinal excipients, The pharmaceutical preparations can, for example. be in the form of tablets, dragees, capsules or suppositories or in a liquid form as solutions (for example as an elixir or syrup), suspensions or emulsions. They are optionally sterilised andfor contain auxiliaries such as preservatives, stabilisers, wetting agents or emulsifiers, solubilising agents or salts for regulating the osmotic pressure or buffers. They can also contain other therapeutically valuable substances. The pharmaceutical preparations are forrnuiated in accordance with customary methods.

The anti-hypertensively active aminoacids employed, and the B-hydroxylase inhibitors, are known.

The invention is explained with the aid of the exam ples which follow without thereby in any way intending to restrict the scope of the invention.

EXAMPLE 1 Tablets containing 200 mg of oz-methyldopa and 300 mg of the calcium salt of fusaric acid:

Composition aMcthyldopa 200 mg Calcium salt of fusaric acid 300 mg Lactose 4] mg Wheat starch 75 mg Colloidal silica 16 mg Talc l6 mg Magnesium stearate 2 mg Manufacture The a-methyldopa and the calcium salt of fusaric acid are mixed with the lactose, a part of the wheat starch and with colloidal silica and the mixture is forced through a sieve. A further part of the wheat starch is worked into a paste with a 5-fold amount of water on a water bath and the powder mixture is kneaded with this paste until a slightly plastic mass has been produced.

The plastic mass is forced through a sieve of approx. 3 mm mesh width and dried and the dry granules are again forced through a sieve. Thereafter the residual wheat starch, talc and magnesium stearate are mixed in and the resulting mixture is pressed to give tablets weighing 650 mg (having a breaking groove).

EXAMPLE 2 Tablets containing the following active substances are manufactured analogously to Example l:

mMcthyldopu Bis-l dicthylthiocarbamoyl )-disulphidc EXAMPLE 3 Tablets containing the following active substances are manufactured analogously to Example I:

mMethyldopa 200 mg Bis-H 3-azz|-3-mcthyl-hcxylenc l .6)-thioeurhamoyl l-disulphinlc 80 mg I R1 wherein R is an esterified, amidised or free carboxyl group and R is an alkyl group, a non-toxic salt thereof, bis-(diethylthiocarbamoyl)-clisulphide and bis-[(3-aza- 3-methylhexylene-l ,6)-thiocarbamoyl ]-disulphide.

2. The pharmaceutical preparation of claim 1, containing an effective amount of a compound selected from the group consisting of a-aminoa-methylB-M- hydroxyphenyl)propionic acid, a-amino-a-methyl-B- (3,4-dihydroxyphenyl)-propionic acid and nontoxic salts thereof and an effective amount of a B-hydroxylase inhibitor selected from the group consisting of fusaric acid, bis-(diethylthiocarbamoyD-disulphide and bis-[(3-aza-3-methyl-hexylene-l,6)-thiocarbamoyl]-disulphide.

3. The pharmaceutical preparation of claim 1, which contains an effective amount of a compound selected from the group consisting of a-amino-a-methyl-B-(4- hydroxyphenyl)-propionic acid, a-amino-a-methyl-B- (3,4-dihydroxyphenyl)-propionic acid, the alkali metal salts and alkaline earth metal salt thereof and an effective amount of a compound selected from the group consisting of S-n-pentyl-picolinic acid, 5-nbutyl-picolinic acid, methyl and ethyl esters thereof and nontoxic salt thereof.

4. The pharmaceutical preparation of claim 1, which contains an effective amount of a compound selected from the group consisting of a-amino-a-methyl-B-(3,4- dihydroxyphenyll-propionic acid, non-toxic alkali metal salts thereof and non-toxic alkaline earth metal salts thereof and an effective amount of a compound selected from the group consisting of S-n-butylpicolinic acid, its methyl or ethyl ester, and a non toxic salt thereof.

5. The pharmaceutical preparation of claim 1, which contains a-amino-a-methyl-B-(3,4-dihydroxyphenyl)- propionic acid or a non-toxic salt thereof and 5-nbutyl-picolinic acid or a nontoxic salt thereof.

6. The pharmaceutical preparation of claim 1, which contains effective amounts of a-amino-a-methyl-B- (3,4-dihydroxyphenyl)-propionic acid or a non-toxic salt thereof, and bis-(diethylthiocarbamoyl)- disulphide.

7. The pharmaceutical preparation of claim I, which contains effective amounts of a-amino-oz-methyl-B- (3,4'dihydroxyphenyl)-propionic acid or a non-toxic salt thereof, and bis-[(3-aza-3-methyl-hexylene-l,6)- thiocarbamoyl]-disulphide.

8. The pharmaceutical preparation of claim 1, containing l00200 mg of a-amino-a-methyLB-(BA- dihydroxyphenyl)-propionic acid and 50-200 mg of the calcium salt of S-n-butylpicolinic acid.

9. The pharmaceutical preparation of claim 1, containing -200 mg of a-amino-amethyl-B-UA- dihydroxyphenyl)-propionic acid and l00-200 mg of the calcium salt of S-n-butylpicolinic acid.

10. Process for the treatment of hypertonia, characterized in that a pharmaceutical preparation of claim 1 is administered to a warm-blooded organism.

Non-Patent Citations
Reference
1 *Branislav et al., Chem. Abst. Vol. 74, (1971), page 97833n.
2 *Ikuko et al., Chem. Abst. Vol. 75, (1971), page 3746g.
Referenced by
Citing PatentFiling datePublication dateApplicantTitle
US4389415 *Jul 20, 1981Jun 21, 1983Merck & Co., Inc.Method of treating hypertension
US5414816 *Sep 3, 1993May 9, 1995Nec CorporationData transfer apparatus having means for controlling the difference in speed between data input/output ports and memory access
EP0038060A1 *Apr 13, 1981Oct 21, 1981Merck & Co., Inc.A pharmaceutical composition for treating hypertension containing L-alpha-methyl-3,4-dihydroxyphenylalanine and salicylamide
Classifications
U.S. Classification514/354, 514/479
International ClassificationA61K31/44
Cooperative ClassificationA61K31/44
European ClassificationA61K31/44