Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof

Definitions

• 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.
• 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 tel strictlyen (Effects of Medicines),tician 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).
• 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.
• amines such as aliphatic amines, for example lower alkylamines, such as trimethylamine or triethylamine
• 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.
• 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.
• 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.
• 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.
• a-methyldopa its laevo-rotatory antipode can preferably be used.
• Active substances with basic groups 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.
• 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; halogeno
• 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.
• compositions 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-
• 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.
• 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.
• 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.
• 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.
• compositions 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.
• 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 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).
• 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 an effective amount of a B-hydroxylase inhibitor selected from the group consisting of fusaric
• 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.
• 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 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.
• Process for the treatment of hypertonia characterized in that a pharmaceutical preparation of claim 1 is administered to a warm-blooded organism.

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• Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Chemical & Material Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Applications Claiming Priority (2)

Publications (1)

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Family Applications (1)

Country Status (9)

Cited By (3)

• 1972
  • 1972-10-17 IL IL40597A patent/IL40597A/en unknown
  • 1972-10-17 IE IE1403/72A patent/IE36780B1/xx unknown
  • 1972-10-27 NL NL7214607A patent/NL7214607A/xx unknown
  • 1972-10-30 US US302156A patent/US3883656A/en not_active Expired - Lifetime
  • 1972-11-04 DE DE2254018A patent/DE2254018A1/de active Pending
  • 1972-11-08 GB GB5151672A patent/GB1405949A/en not_active Expired
  • 1972-11-09 AU AU48642/72A patent/AU4864272A/en not_active Expired
  • 1972-11-09 FR FR7239713A patent/FR2159413B1/fr not_active Expired
  • 1972-11-10 BE BE791253D patent/BE791253A/fr unknown

Non-Patent Citations (2)

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