DE2700073A1 - PTERIDINE COMPOUNDS WITH PHARMACEUTICAL EFFECTIVENESS - Google Patents

Description

The invention relates to pharmaceutical preparations with diuretic and antihypertensive effects, which are also used for heart and Coronary therapy are suitable, as well as new pharmaceutically active compounds.

The classic indication area for diuretic substances is the treatment of edema. Relatively good therapeutic success were e.g. with Saluretica (in the narrower sense: substances that excrete the salt directly by inhibiting the reabsorption of sodium unfold in the renal tubules and excrete mainly chloride ion as an anion).

With the discovery of the antihypertensive properties of saluretics, the range of indications was expanded considerably. Saluretics have a firm place in the treatment of essential hypertension, which is not accessible to any causal treatment and accounts for around 80% of all hypertension. Important representatives of this group are benzothiadiazine derivatives such as chlorothiazide and hydrochlorothiazide. Because of the influence on the electrolyte balance of the patient, the use of benzothiadiazine derivatives is subject to serious restrictions. If you have liver or kidney disease, therapy with this group of active ingredients means a serious risk. In addition, dangerous disorders of the electrolyte and fluid balance (hypochloremia, hypocalcemia, hypokalaemia and alkalosis) can develop with continued use. The loss of potassium ions is particularly undesirable in the case of monotherapeutic use of saluretics.

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It has therefore been undertaken to develop "potassium-sparing" diuretics. One of the aims was to be competitive Inhibition of the adrenal cortex hormone aldosterone, which (physiologically useful in normal metabolism) is the reabsorption of sodium and promotes potassium secretion in the renal tubules. This goal was achieved with the steroid derivative spironolactone Roughly achieved, but the therapy requires high dosages (0.2-1 g per day). As another "potassium-sparing" diuretic, which, however, do not act via competitive aldosterone inhibition, the amiloride (N-amidino-3,5-diamino-6-chloropyrazine-carboxamide) and the triamterene (2,4,7-triamino-6-phenylpteridine) found.

The triamterene has proven to be an extremely valuable active ingredient, Both monotherapy and in combination e.g. with saliuretics in edema and high blood pressure therapy. Subsequently, detailed investigations were devoted to the mechanism of action and the metabolism of triamterene. Model tests in the main duct of the rat salivary gland (the epithelium of which is functionally similar to the distal renal tubule) have shown that triamterene completely blocks the reabsorption of sodium ions and inhibits the secretion of potassium ions Half lower. The model experiment on the salivary gland duct is in complete agreement with the findings on the kidneys and can be used as a reliable indicator of a "potassium-sparing" diuretic effect of the triamterene effect type be considered Cvgl. H. Knauf et al. Europ.J.Clin.Invest. 6, 43 (1976) J. In addition, Triamteren has a cardioprotective effect Effect on. An anti-arrhythmic effect for Triamteren can be determined by electrophysiological measurements on the myocardial single fiber of isolated papillary muscles of guinea pigs Lb. Luederitz et al. Ratio German total Circulatory Research 41, 305 (1975)]].

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Although the Triamteren meets the therapeutic requirements of a diuretic quite well, also with regard to side effects, the search for even better active ingredients continued. A disadvantage of triamtering that cannot be overlooked is e.g. its low water solubility, which effectively makes parenteral application impossible. So, starting from Pteridine skeleton, in systematic variation of the substituents Investigations into the relationship between structure and (diuretic) Effect carried out LJ.Weinstock et al. J. Med. Chem. H, 573-579 (1968).].

The 2,4,7-triamino-6- (p-hydroxyphenyl) -pteridine, one of the known metabolites of triamterene. The findings left everyone there lack of diuretic effect (Weinstock et al. loc.cit., p. 578 ff.).

As far as the examined descendants of Triamteren are worth mentioning showed diuretic activity, the compounds were those which have non-polar substituents, e.g. the p-toluyl homologue of triamterene. Derivatives with polar Groups, e.g. with an amino or a nitro group, are, however, according to the findings of Weinstock (loc.cit.Table VIII) diuretically ineffective.

It has been found that, surprisingly, 2,4,7-triamino-6- (p-hydroxyphenyl) pteridine (compound of the general formula IA) has a pronounced diuretic and potassium-retaining effect even in small concentrations. The potassium-saving effect is more pronounced in the quantitative test than that of triamterene. The compound 2,4,7-triamino-6- (p-hydroxyphenyl) -pteridine also shows, compared with the non-hydroxylated body (triamterene), an improved solubility in water, especially in the form of its physiologically acceptable salts.

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The compounds of general formula I of claim 1, in which R is predominantly hydrophilic, also have Group - except: the -SO ^ H-Rect and those of it derived salts - stands (compounds of the general Formula I B), pharmaceutically utilizable properties, which in the general direction of action of the compound I A lie. Particularly preferred are the compounds of the general formula I B, which are both opposite to the compound Triamterene as well as compared to the compounds of the general formula I A with improved water solubility bring yourself.

The preparation of the compound of the general formula I A is known or can be carried out by known processes will. The compounds of the general formula I B can be prepared in a manner known per se, for example

a) by reacting the compound 2,4,6-triamino-5-nitrosopyrimidine (Compound of the formula II) with a substituted phenylacetonitrile compound of the general formula III

N == C - CH ₂ - ^ ';> - OR III

wherein R has the meaning given in claim 1, or as a less generally applicable process

b) by reacting the compound of the general formula IV

XR IV

in which R has the meaning given in claim 1 and in which X represents a radical acting as a leaving group in the acylation / alkylation , preferably chlorine, bromine or

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'! Il

if R is a radical -CR ^ - also stands for a radical -0-CR ₇ , where R _{7 has} the same, usually identical meaning as the radical R ^,

with the compound of the general formula IA, in which R is an alkaline cation such as sodium or potassium (compounds of the general formula IA ¹ ) or in which R is hydrogen, in the presence of an acid acceptor.

The choice of the process to be used for the preparation of the compounds of the general formula I B and of the reaction conditions depends, inter alia, on considerations relating to the relative Accessibility of the respective starting products of the formulas I A, II, III and IV, as well as the probability of the formation of By-products (e.g. by reaction of the amino functions), the ease with which the separation and purification are carried out can be, depend. For example, it must be ensured that under the conditions of the synthesis according to process variant a) the substituents R are sufficiently stable.

The preparation of the compounds of the general formula I B according to process a) can be carried out as follows: The compound of the formula II is dissolved in a suitable reaction medium which is inert under the reaction conditions, such as, for example, dimethylformamide or Ν, Ν-dimethyl acetamide, preferably in the presence of an alkali metal hydroxide or amide or an alkali metal alcoholate a lower alcohol, for example in an alkoxyalkanol such as 2-ethoxyethanol, or in methanol and at an elevated temperature, optionally reacted in suspension with the compound of the general formula III.

The reaction time is usually kept as short as possible, for example when working at reflux temperature. Working up can be carried out in the customary manner.

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A decomposition of the educt and / or the end product can for example by working at the lower limit of the possible reaction temperature, by using alkali metal alcoholates with low nucleophilicity, such as potassium tert-butoxide, can be prevented.

The compounds of general formula IB according to process b) can be prepared as follows: To the compound of general formula IA ¹ in a suitable inert solvent, such as a nitrile such as acetonitrile, an amide such as Ν, Ν-dimethylformamide , Hexamethylphosphorsäuretriamid, an alcohol such as tert-butanol, an amine such as pyridine, N, N-dimethylaniline, optionally in a mixture of solvents or in suspension are preferably added with stirring between room temperature and 120 ⁰ C or the boiling point of the Solvent the compound of the general formula IV, if appropriate in a suitable solvent, such as one of those mentioned, if appropriate with the addition of an acid acceptor, such as a tert. Amines, such as triethylamine, N, N-dimethylaniline, N-methylmorpholine.

One stirs to complete the reaction certain period of time, for example 2-24 hours, after which the batch can be worked up in the usual way.

The starting compounds of the general formulas IA ¹ , II, III and IV are known, or they can be prepared by known processes or in analogy to processes known per se.

The compounds of the general formula I are generally crystalline, relatively high-melting compounds (some with decomposition). They can be recrystallized, for example, from aqueous solution, if appropriate with the addition of formamide, acetonitrile, if appropriate also from acid, such as formic, acetic or phosphoric acid.

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The compound of the formula I A (2,4,7-triamino-6- (p-hydroxyphenyl) pteridine = "p-hydroxy-triamterene") and their physiological acceptable salts, in particular the sodium, potassium, lithium salt, as well as the salts with the physiologically harmless, pharmacologically similar, and not contraindicator effective 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 the general formula I B according to claim 4 are valuable pharmaceuticals. You own one excellent diuretic effect with simultaneous potassium retention, as well as extrarenal, especially cardioprotective Effect. The p-hydroxy-triamterene and the methyl ether (compounds of the general formula I A des Claim 1, wherein R is methyl).

The connections are superior to the state of the art, for example the Triamteren, and are therefore a real asset of the technology. For a direct comparison of the diuretic and the potassium retention effect, for example the investigations on the epithelium of the main duct of the submaxillary gland of rats according to Knauf (loc.cit.) to serve. The electrophysiological examination of isolated cardiac structures can be used as an indicator of the cardioprotective effect be used by guinea pigs and dogs according to Lüderitz (loc.cit.).

Moreover, the compounds of general formula I are superior to triamteres due to their better solubility in water. Greatly improved water solubility is generally to be expected in the case of compounds of general formula I which have groups with pronounced salt-forming (strongly basic or acidic) properties.

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In this regard, those compounds of the general formula I B according to claim 5 should be mentioned in particular which in ß-position to the phenolic oxygen an amine resp. an amraonium group stands. The compounds may be mentioned in particular of the general formula I B, in which q is dimensioned such that there is a nitrogen atom in the ß-position to the phenolic oxygen is located.

The compounds of the general formula I of the present invention in the suitable therapeutic preparations are therefore suitable not only for oral administration but also for parenteral administration, especially when they are in salt form.

The compounds of general formula I can as a function dosed on the type of indication and the individual needs of the patient.

As a result of the improved diuretic effect compared to the Triamteren, the dosage used in practice is as a rule lie below that of Triamterens; the normal dosages of triamterene can thus be used as the upper limit of the dosage range of the active ingredients of general formula I are considered.

The new pharmaceutical preparations can be based on the usual ones Manner are prepared, and they can contain the usual carriers and auxiliaries. One embodiment of the invention represent solid preparations suitable for oral administration, such as tablets, capsules, coated tablets, etc. For oral When applied, they can be used as carrier materials for pharmaceutically inert solids, such as mannitol, lactose, organic or inorganic calcium salts, etc. Suitable binders include polyvinylpyrrolidone, gelatine or cellulose derivatives. Other additives that can be used are tablet disintegrants, such as starch

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or alginic acid, lubricants such as stearic acid or their Salts and inorganic superplasticizers such as talc or colloidal silicic acid, as well as flavoring agents, etc. can be used.

The active ingredients can be mixed with the auxiliaries in a customary manner mixed and granulated wet or dry. Depending on the type of additives used, it may also be possible through a directly tablettable powder can be obtained by simple mixing. The granules or powder can be filled directly into capsules or pressed into tablet cores in the usual way.

In the case of parenteral administration, the therapeutic agents can also be prepared and administered in the usual manner will.

The following example is used to explain how the Compounds of the general formula I B, however, are not intended to restrict the invention in any way.

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example

Preparation of 2,4,7-triamino-6- (p-acetoxy-phenyl) -pteridine

410 mg of metal. Sodium is dissolved in 100 ml of 2-ethoxyethanol with stirring. 1100 mg of triaminonitrosopyrimidine and 1140 mg of p-acetoxybenzyl cyanide are added one after the other with stirring and the mixture is heated to the boil with stirring. The color of the mixture changes from purple to brown. After refluxing for two hours, the heating is switched off and the reaction mixture is allowed to cool. Then 70 to 80 % of the 2-ethoxyethanol in the V / ass he jet vacuum is drawn off, the remainder is taken up with 500 ml of water. After etherifying four times, the pH is adjusted to 5 with 2N hydrochloric acid. The deposited precipitate is filtered off with suction, washed with a little ice-cold acetone and recrystallized from 10% acetic acid. Further purification can be carried out using a silica gel column. The title compound is obtained at 319 - 321 ⁰ C decomposes (carbonization).

The reaction can advantageously also be carried out using alkali alcohol in methanol.

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Claims (1)

Claims H ₂ N where R is hydrogen or a pharmacologically acceptable salt or methyl (compounds of the general formula I A) or a hydrophilic group such as the radical R ¹ , v / obei R ^{1 represents} a radical - (CH) -CH ₀ - (Q) -R ,, in which R ₁ ■ m c. ρ ι ι R ₂ Hydrogen, methyl or ethyl, Rp is an OH group, hydrogen or an alkyl group with 1 to 4 carbon atoms, Q is oxygen, sulfur or a radical -NR ,, where R, has the same meanings as R ₁ or Q together with the Radical R _{1 is} an ammonium ion Z forms, where Z is a pharmacological is a harmless anion, and m is O, 1, 2 or 3 » ρ stands for O or 1 or for a radical - (CH ₂ ) CY, in which η is O, 1, 2, 3 or 4, and Y for an -OH group or a pharmacologically acceptable salt thereof or for a group -NR ^ Ri, in which R, and R_ independently of each other B09828 / 0U0 " ¹² " QRIGINAL INSPECTED for hydrogen or an optionally branched alkyl radical with 1 to h carbon atoms or for a radical - (0) -Rg, in which Rg is an alkyl radical with 1 to 6 carbon atoms or for a radical - (CH ₂ ) _q -Ry, in which q is 0, 1 or 2 and R ^ is a morpholinyl, pyrrolidinyl, piperidinyl, or piperazinyl radical, which can be bonded via a carbon atom or via a nitrogen atom, provided that in the latter case q is not simultaneously 0, and formally through Addition of a compound R ^ Z ', wherein R ¹ * and Z ^{1 have} the same meanings as R ₁ and Z, ammonium compounds formed, and r is 0 or 1, or
for a rest _y NH -NH-NH-C "or ^ NH ₂ for a rest ^Rff i wherein R ¹¹ -. has the same meanings as R ^ or for a residue CO Y « (CHR ₈ ) _V.
- (CH ₂ ) _Z -CH (CHR ₈ ) _W
CO Y ' wherein Y ^{1 has} the same meaning as Y, R _{Q is} hydrogen or an OH group, v, w and ζ is 0, 1 or 2, or 809828/0140 ο ο H ii
represents a radical -C- (CHTl ¹ Q) -CY ", in which q represents O, 1, 2 or Z , and R'g and Y ^{1! have} the same meanings as R and Y, respectively, or represents a radical O OM il - P ' OK wherein ¥ denotes hydrogen or a physiologically acceptable cation, or a group R ¹¹ , where R ^{11 is} a radical -CH ₂ -OAr v: orin Ar is optionally substituted by chlorine Phenyl radical means or represents a radical R _g , in which Rq represents a chlorine-substituted alkyl radical having 1 to 3 carbon atoms (compounds of the general formula IB) contained as an active ingredient. 2. Pharmaceutical, especially diuretic, antihypertensive and co.rdially effective preparations, characterized in that that they Z, 4,7-triomino-6- (p-hydroxyphenyl) -pteridine as Contain active ingredient. 3. Pharmaceutical, especially diuretic, anti-hypertensive and cardiac preparations, characterized in that they are Zj ^ .T-triamino-e-ip-methoxyphenylJ-pteridine as Contain active ingredient. 4. Pharmaceutical, especially diuretic, antihypertensive and cardially active preparations, characterized in that they are 2,4,7-triamino-6- (p-acetoxyphenyl) pteridine as Contain active ingredient. - 14 - η π ρ,? π / η 1 1 * ~ .i Pteridine compounds of the general formula IB -OR ' IB H ₀ N where R ^{1 is} a radical - (CH) ^ - CH ₂ - (G) -R ₁ , where R _{1 is} hydrogen, methyl or ethyl, R _{0 is} a CH group, hydrogen or an alkyl group with 1 to U carbon atoms, Q is oxygen, sulfur or a radical -NR- ,, where R, has the same meanings as R ₁ or Q together with the radical R "is an ammonium ion forms, where Z stands for a pharmacologically unrelated possible anion and m for O, 1, 2 or 3, ρ for 0 or 1 or 0 for a radical ~ (CH _o ) _n CY, in which η is 0, 1, 2, 3 or 4 and Y for an OH group or a pharmacologically acceptable salt thereof or for a group -NR ^ R ₁ -, in which R. and R- are each independently V / on Hydrogen or an optionally branched alkyl radical having 1 to 4 carbon atoms or a radical - (O) _r -Rg, wherein Rg is an alkyl radical having 1 to 6 carbon atoms, or represents a radical - (CHp) -Ry, where q is 0, 1 or 2 and Ry is a morpholinyl, pyrrolidinyl, piperidinyl or piperazinyl radical, which can be bonded via a carbon atom or via a nitrogen atom, provided that in the last Case q is not equal to 0, and its formally formed by the addition of a compound R ¹ ^ Z ¹ , in which R ¹ .. and Z ^{1 have} the same meanings as R ^ and Z, formed ammonium - 15 -809828 / OUO compounds, and r is O or 1, or NH for a radical -NH-NH-C ₁ , or ^V NH ₂ for a remainder R- wherein R ¹ J have the same meanings as R ,. owns or for a remainder CO Y ¹ (CHR ₈ ) _V - (CH ₂ ) _Z -CH CO Y ¹ wherein Y ¹ has the same meaning as Y, R _Q is hydrogen or an OH group, '/ w, and ζ O, 1 or 2, or represents a radical q _q -C- (CHR ' ₈ ) _q -CY ", where q is O, 1, 2 or 3 and R'g and Y ¹ 'have the same meanings as R _Q or Y, or is a radical 0 OM Il / -P where M is hydrogen or a ^X 0M is a physiologically harmless cation, or a group R ¹ ·, where R ¹ 'is a radical -CH ₂ -OAr in which Ar is a phenyl radical optionally substituted by chlorine or - 16 -809828 / OUO for a radical Rg, in which Rg is substituted by chlorine Denotes an alkyl radical with 1 to 3 carbon atoms (compounds of the general formula I B) means. 6. 2,4, γ-triamino-S- (p-acetoxyphenyl) -pteridine. 809828 / OUÖ