DE2760327C2 - - Google Patents

Description

The invention relates to pharmaceutical preparations with diuretic and antihypertensive agent, also for cardiac and coronary therapy are suitable.

The classic indication area of diuretically active substances is the edema treatment. Relatively good therapeutic success has been achieved e.g. B. with Saluretica (in the narrower sense: substances that exude salt Effect directly by inhibiting sodium reabsorption in the kidney tubules unfold and predominantly excrete chloride ion).

With the discovery of the hypotensive properties of Saluretica the indication area was expanded considerably. Especially at the treatment of essential hypertension, which is a causal treatment is accessible and accounts for about 80% of all hypertensions Saluretica a permanent place. Important representatives of this group are Benzothiazine derivatives such as chlorothiazide and hydrochlorothiazide. Because of the influence of the electrolyte balance of the patient is subject to the use of the benzothiadiazine derivatives is severely restricted. If you have liver or kidney disease Therapy with this group of active substances is a serious risk. In addition, dangerous malfunctions can arise with continued use of the electrolyte and fluid balance (hypochloremia, hypocalcaemia, Hypokalaemia and alkalosis). This is particularly undesirable Loss of potassium ions with monotherapeutic use of the Saluretics.  

It has therefore been attempted to develop "potassium-saving" diuretics. One goal was to inhibit adrenal cortex hormone competitively Aldosterone, which (physiologically in normal metabolism reasonable) the sodium reabsorption and the potassium secretion in the Promotes renal tubules. This goal was achieved with the steroid derivative Spironolactone roughly reached, however, the therapy demands high Dosages (0.2-1 g per day). As another "potassium-sparing" diuretic, which, however, do not have a competitive aldosterone inhibition, the amiloride (N-amidino-3,5-diamino-6-chloro-pyrazine-carboxamide) and found the triamterene (2,4,7-triamino-6-phenylpteridine).

The triamterene has proven to be an extremely valuable active ingredient, both monotherapy and in combination z. B. with Saluretica in edema and hypertension therapy. As a result, the Mechanism of action and the metabolism of triamterens in-depth studies dedicated. Model tests on the main salivary duct from rats (whose epithelium is functional to the distal renal tubule have shown that triamterene resorbs sodium ions completely blocked and the potassium ion secretion to half belittles. The model test on the salivary gland duct is ongoing in complete agreement with the findings on the kidney and can be a safe indicator of "potassium-sparing" diuretic effects of the type of the triamterene effect are considered [cf. H. Knauf et al. Europ. J. Clin. Invest. 6, 43 (1976)]. It also points Triamteren have a cardioprotective effect. An antiarrhythmic Effect for triamteren can be determined by electrophysiological measurements on the myocardial single fiber of isolated papillary muscles of Detect guinea pigs [B. Luderitz et al. Ratio German Ges. Kreislaufforschung 41, 305 (1975)].  

Although the triamterene meets the therapeutic requirements Diuretic also quite well in terms of side effects, the search for even better active ingredients continued. A not too The overlooked disadvantage of triamtering is e.g. B. its low water solubility, that effectively makes parenteral administration impossible. Thus, starting from the pteridine scaffold, in a systematic variation of the substituent studies on the relationship between structure and diuretic effects performed [J. Weinstock et al. J. Med. Chem. 11, 573-579 (1968)].

2,4,7-Triamino-6- (p-hydroxy phenyl) pteridine, one of the known metabolites of triamterene, involved. The findings lacked any diuretic effects (Weinstock et al. Loc. Cit., P. 578 ff.).

As far as the examined triamterene descendants worth mentioning diuretic Showed effect, these are compounds that are non-polar Have substituents, such as. B. the p-tolyl homologue of Triamterens. Derivatives with polar groups e.g. B. with an amino or a nitro group, however, according to the findings of Weinstock (loc. cit. Table VIII) diuretically ineffective.

Surprisingly, it was found that 2,4,7-triamino-6- (p-hydroxy phenyl) pteridine (compound of general formula IA) already in small concentrations a pronounced diuretic and potassium-retaining Has effect. The potassium-saving effect is there in the quantitative test more pronounced than that of the triamterene. The connection 2,4,7-triamino-6- (p-hydroxyphenyl) pteridine also shows compared to the non-hydroxylated body (triamterene), one improved water solubility, especially in the form of their physiological acceptable salts.  

Preparations also have the active ingredients of the general formula I. of claim 1, wherein R for a predominantly hydrophilic group - except for: the -SO₃H residue and the salts derived therefrom - is (compounds of the general formula IB), pharmaceutical usable properties in the general direction of action of the connection IA. Preparations are particularly preferred those due to their content of the active ingredients of the general formula IB, one versus both the Triamteren compound and opposite the compounds of general formula IA improved water solubility entail.

The preparation of the active compounds of the general formula I is known. It is described in the parent application P 27 00 073. In the publication H. Knauf et al. in "Therapy Week" 30, 6831-6847 (1980) u. a. Results of compounds of formula I with carboxyl groups reported in the side chain: With equally strong effectiveness such as triamteren in terms of diuresis, natriuresis and potassium retention the intravenous toxicity of these substances is only ¼ to ½ of the Triamterens. There is also data for hydroxy substituted alkyl ethers (Q = O, R₂ = OH) specified. Results with derivatives of Formula I in which Q stands for nitrogen are in the dissertation E. Wolf, University of Frankfurt / Main 1981 (especially pages 18, 50-55, 98-103, 126-127). An in-depth Investigation of the effectiveness of the 4-carboxy-alkoxy-substituted Representatives of the formula I and the esters thereof Class was part of the dissertation H. Priewer, University Frankfurt / Main 1985 (see pages 6-13, 20-23, 42-75, 86-89, 108-110). It is u. a. noted that the Potassium-saving effect with basic compounds already in low doses are reached (see p. 104). In the publication "30 Years of Triamteren", Ed. E. Mutschler u. H. Knauf, science publisher, Cologne 1984, the findings become one more summarized evaluation (pp. 86-89; 109-110).  

The active compounds of the general formula I are generally crystalline, relatively high-melting compounds (partly with decomposition).  

The active ingredients of the formula IA (2,4,7-triamino-6- (p-hydroxyphenyl) - pteridine ("p-hydroxy-triamterene") and its physiologically acceptable Salts, especially the sodium, potassium, lithium salt, and the Salts with the physiologically harmless, pharmacologically same-minded and the non-contraindicated amines and Guanidines, for example N-alkyl-substituted ethanolamines and (basic) derivatives, as well as the propanol-2-amines and (basic) Derivatives and the compounds of general formula IB are the Active ingredients of the pharmaceutical preparations according to the invention. they have an excellent diuretic effect at the same time Potassium retention, as well as extrarenal, especially cardioprotective Effect.

The pharmaceutical preparations according to the invention are state of the art Technology, for example the one containing triamter, consider and provide thus a real enrichment of the technology. For a direct comparison the diuretic and potassium retention effects for example the examinations on the epithelium of the main execution duct the submaxillary gland of rats according to Knauf (loc. cit.). As an indicator of the cardioprotective effect, e.g. B. the electrophysiological Examination of isolated heart structures of guinea pigs and dogs are brought to Lüderitz (loc. cit.).

There is also superiority over triamterene due to the better water solubility of the active ingredients of the general formula I according to Claim 1. With greatly improved water solubility generally to be expected for the compounds of the general formula I, the groups with pronounced salt-forming (strongly basic or acidic) Have properties.  

In this regard, those active ingredients are the general ones To name formula IB according to claim 5, in which in the β-position is an amine or an ammonium group to the phenolic oxygen. Particular mention should be made of the compounds of the general formula IB where q is such that there is a β-position to the phenolic oxygen there is a nitrogen atom.

The pharmaceutical preparations, which are the active ingredients of the general Formula I contained in suitable therapeutic preparations are suitable Therefore, in addition to oral, parenteral administration, especially if they are in salt form.

The active compounds of the general formula I can, depending on the Type of indication and the individual needs of the patient be dosed.

As a result of the improved diuretic effect compared to the triamterene the dosage used in practice is usually below that of the Triamterens lie; the normal doses of the triamterene can thus as the upper limit of the dosage range of the active ingredients of the general Formula I are considered.

The new pharmaceutical preparations can be manufactured in the usual way and they can use the usual carriers and auxiliaries contain. One embodiment of the invention provides fixed oral administration are suitable preparations, such as. B. tablets, Capsules, coated tablets, etc. For oral application, they can be used as carrier materials pharmaceutically inert solids, such as Mannitol, milk sugar, organic or inorganic calcium salts etc., be used. Suitable binders include a. Polyvinyl pyrrolidone, Gelatin or cellulose derivatives. Tablet disintegrants, such as starch or alginic acid, lubricants,  such as B. stearic acid or its salts and inorganic flow agents, such as B. talc or colloidal silica, as well as flavoring agents etc. can be used.

The active substances can be mixed with the auxiliary substances in the usual way and granulated wet and dry. Depending on the type of used Additives can also be added by simply mixing them directly tablettable powder can be obtained. The granules or powder can be filled directly into capsules or into tablet cores in the usual way be pressed.

When administered parenterally, the therapeutic agents can also be prepared and administered in the usual manner.

The following examples serve to explain the preparation of the therapeutic preparations according to the invention.

a) Manufacture of gastro-resistant tablets

The following composition can be used to manufacture the tablet cores be applied:

15 mg of 2,4,7-triamino-6- (p-acetoxyphenyl) pteridine as an active ingredient
10 mg magnesium stearate
12 mg talc
8 mg Aerosil
95 mg lactose granules
55 mg lactose, fine crystalline
25 mg corn starch
80 mg cellulose granules

The ingredients are mixed in an intensive mixer (type lödige) and compressed into tablets of 300 mg weight. Tablets are obtained of a breaking strength level 6.5-8.5 (determined on a ERWEKA breaking strength tester. Disintegration in water at 37 ° C: 2.5 min).

To produce the enteric coating is on the Tablet cores applied a lacquer suspension. A lacquer suspension is applied to 4 kg of the cores preheated to 40 ° C applied containing

100 g of a polyacrylic resin coating dispersion with 30% dry substance,
Containing 300 g of a pigment suspension
120 g of solid and
600 g water

The polyacrylic resin paint contains a copolymer of ethyl acrylate and methacrylic acid (1: 1).

The pigment suspension has the following composition:

50 g talc
63 g titanium dioxide
42 g color varnish
90 g polyethylene wax 600 °, 30% in water
30 g emulsifier (Tween 80®) 33% in water
200 g Tylose C 30®, 3% in water (water-soluble cellulose ether)
15 g cellulose, fine crystalline
183 g milk sugar
5 g anti-foam emulsion
326 g of water

After a spraying time of approx. 40 min. you get tablets with a gastric juice resistance of <3 h.

Analogously - for 2,4,7-triamino-6- (p-acetoxyphenyl) - pteridine described - can also the other active substances of general formula I can be formulated.  

b) Preparation of a suitable for parenteral administration Drug form

The preparation of the pharmaceutical form suitable for parenteral, in particular intravenous, administration can be carried out as follows:
10 ml of a 10% aqueous solution of dimethylaminoethanol are added to 25 mg of 2,4,7-triamino-6- (p-hydroxyphenyl) pteridine at room temperature. The active ingredient goes into solution or is dissolved. It is then diluted to 100 ml with physiological saline. A clear, yellowish colored solution of pH 10.9 is obtained.

Analogously - as for 2,4,7-triamino-6- (p-hydroxyphenyl) - pteridine described - can also the other active substances of general formula I can be formulated.

c) Preparation of an injection solution of the active ingredient of the formula I.

0.5% (w / v) active ingredient of the formula I is used together with one for the Isotonicize sufficient amount of sodium chloride in water "for Injection purposes "(Europ. Pharmacopoeia, Vol. 2) solved, the solution is filtered free of suspended matter, filled into ampoules and sealed. The sealed ampoules are sterilized.

Claims (1)

1. Pharmaceutical, in particular diuretic, antihypertensive and cardiac-active preparations, characterized in that they contain pteridine compounds of the general formula I. wherein R is hydrogen or a pharmacologically acceptable salt (compounds of general formula IA), or a hydrophilic group such as R ', where R' is a radical wherein R₁ is hydrogen, methyl or ethyl, R₂ is an OH group, hydrogen or an alkyl group having 1 to 4 carbon atoms, Q is oxygen, sulfur or a radical -NR₃, where R₃ has the same meaning as R₁ or Q together with the radical R₁ is an ammonium ion Z forms, where Z stands for a pharmacologically acceptable anion, and m stands for 0, 1, 2 or 3 or for a radical wherein n is 0, 1, 2, 3 or 4, and Y for an -OH group or a pharmacologically acceptable salt thereof or for a group -NR₄R₅, wherein R₄ and R₅ independently of one another for hydrogen or an optionally branched alkyl radical with 1 to 4 carbon atoms or for a radical - (O) _r -R₆, in which R₆ represents an alkyl radical having 1 to 6 carbon atoms or for a radical - (CH₂) _q -R₇, in which q represents 0, 1 or 2 and R₇ is one Morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl radical, which can be bonded via a carbon atom or via a nitrogen atom, provided q in the latter case does not simultaneously mean 0, and formally by addition of a compound R'₁Z ', wherein R'₁ and Z 'have the same meaning as R₁ and Z, ammonium compounds formed, and r represents 0 or 1, or a radical for a rest wherein R ″ ₁ has the same meanings as R₁ or for a radical wherein Y 'has the same meaning as Y, R₈ is hydrogen or an OH group, v, w and z are 0, 1 or 2, or a radical wherein q is 0, 1, 2 or 3, and R′₈ and Y ″ have the same meaning as R₈ or Y, or is a radical where M is hydrogen or physiologically acceptable cation, or a group R ″, wherein
R ″ for a residue -CH₂OAr
in which Ar represents a phenyl radical optionally substituted with chlorine or represents a radical R₉ in which R₉ represents an alkyl radical having 1 to 3 carbon atoms substituted with chlorine (compounds of the general formula IB) contain as active ingredient.