GB1597882A - Injectable pharmaceutical compositions comprising pteridine derivatives - Google Patents

Description

PATENT SPECIFICATION ( 11) 1 597 882

r ( 21) Application No 26630/80 ( 22) Filed 3 Jan 1978 ( 19) N :0 ( 62) Divided Out of No 1597881 ( 31) Convention Application No 2700073 ( 32) Filed 3 Jan 1977 in,, ( 33) Fed Rep of Germany (DE) Wi ( 44) Complete Specification Published 16 Sep 1981 v.4 ( 51) INTCL 3 A 61 K 31/495 \' ( 52) Index at Acceptance A 5 B 180 382 384 38 Y 482 48 Y 511 51 Y 552 55 Y 576 57 Y 586 58 Y 650 65 Y H ( 54) INJECTABLE PHARMACEUTICAL COMPOSITIONS COMPRISING PTERIDINE DERIVATIVES ( 71) We, ROHM PHARMA G m b H, a German Body Corporate, of Darmstadt, Germany do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by

the following statement:-

The invention relates to pharmaceutical preparations having diuretic and anti 5 hypertensive properties which are useful in heart and coronary therapy, and in particular to such compositions in injectable form containing pteridine derivatives as active ingredients.

A well-known use of diuretically active substances is the treatment of oedema Relatively good therapeutic results have been achieved for example, with saluretics (used herein in the strict sense to denote a substance which displays salt-separating activity directly by 10 inhibition of sodium reverse resorption in the renal tubes and secretes mainly chloride ions as the anion).

With the discovery of the hypotensive properties of saluretics, their area of use has been considerably enlarged In particular, in the treatment of essential hypertension which is not accessible to causal treatment and accounts for approximately 80 % of all hypertensive 15 cases, saluretics have a particularly important r 6 le Important representatives of this group of compounds are benzothiadiazine derivatives such as chlorothiazide and hydrochlorothiazide However, depending on the electrolytic regime of the patient, the use of benzothiadiazine derivatives is subject to serious limitations In patients with existing liver and kidney diseases, therapy with this group of compounds may present serious risks Also, 20 in prolonged treatment, dangerous disturbances of the electrolytic and fluid regime can occur (e g hypochloroaemia, hypocalcaemia, hypokalaemia, and alkalosis) Especially undesirable is the loss of potassium ions when using saluretics alone.

The development of "potassium-retaining" diuretics has, therefore, been undertaken.

One aim was the competitive inhibition of the adrenal cortical hormone aldosterone which 25 (in normal metabolism) promotes sodium reverse resorption and potassium secretion in the renal tubes This aim has been achieved to some extent with the steroid derivative spironolactone, although therapy generally requires high dosages ( 0 2 to 1 g per day).

Potassium-retaining diuretics which do not act via competitive inhibition of aldosterone include amiloride (N-amidino-3, 5-diamino-6-chloropyrazine carboxamide) and triam 30 terene ( 2,4,7-triamino-6-phenylpteridine).

Triamterene has proved to be an extremely valuable active therapeutic substance either alone or in combination e g with saluretics in oedema and high blood pressure therapy As a result, studies have been made of the active mechanism and metabolism of triamterene.

Model tests on the main excretory duct of the salivary gland of rats (whose epithelium is 35 similar in function to the distal renal tube) have resulted in triamterene completely blocking sodium ion reverse resorption and reducing potassium ion secretion by half The model tests on the excretory duct of the salivary gland is fully in accordance with findings in the kidney and can be considered as a reliable indication of the "potassiumretaining" diuretic activity of triamterene lH Knauf et al Europ J Clin Invest 6,43 ( 1976)l Furthermore, 40 triamterene has a cardio-protective effect An antiarrythmic effect for triamterene can be proved by electrophysiological measurements on the individual myocardial fibres of isolated papillary muscles of guinea pigs lB Luderitz et al Verh Dtsch Ges Kreislaufforschung 41, 305 ( 1975)l.

Although triamterene fulfills very well the therapeutic requirements of a diuretic, 45 2 1 597 882 2 including a low level of of side effects the search has continued for even better therapeutic materials A distinct disadvantage of triamterene is its low solubility in water which renders parenteral application difficult Thus, starting from the pteridine structure, studies have been carried out with a systematic variation of substituents to investigate the connection between structure and (diuretic)activity lL Weinstock et al J Med Chem 11, 573 5 579,( 1968)l.

The triamterene derivatives which showed noteworthy diuretic activity were generally those compounds which possess non-polar substituents such as the p-toluyl homologues of triamterene Derivatives with polar groups, e g amino or nitro groups, were diuretically inactive according to the findings of Weinstock (loc cit Table VIII) 10 It is an object of the present invention to provide new and advantageous pharmaceutical compositions possessing valuable diuretic properties.

Surprisingly it has been found that injectable solutions of previously known pteridine derivatives possess such properties.

According to one feature of the present invention we provide pharmaceutical 15 compositions in injectable form comprising as active ingredient at least one pteridine compound of formula I H O-R H 2 O 20 N N H N 8 Nv s N s NH 2 25 25 lin which R represents a hydrogen atom, a physiologically acceptable cation or a C 1 to C 6 alkyl group, preferably a methyl groupl together with at least on injectable pharmaceutical carrier or excipent 30 The preparation of the compounds of formula I can be carried out in conventional manner.

The compounds of formula I are, as a rule, crystalline, relatively highmelting compounds (partly with decomposition) They can be re-crystallised, for example, from aqueous solutions, if desired with the addition of formamide, acetonitrile, or from acids, 35 such as formic, acetic or phosphoric acids.

The compounds of formula I in which R is hydrogen and its physiologically acceptable salts, especially the sodium, potassium and lithium salts as well as physiologically acceptable salts with amines and guanidines (for example, N-alkylsubstituted ethanolamines and (basic) derivatives, as well as propan-2-olamines and (basic) derivatives), and the 40 corresponding compound of formula I in which R represents a methyl group are valuable therapeutic compounds which when administered by injection have a pronounced diuretic activity with simultaneous potassium retention as well as extra-renal, especially cardioprotective, activity The compounds of formula I in which R represents a hydrogen atom or a methyl group have particularly valuable therapeutic properties 45 In contrast to the findings of Weinstock above we have for example surprisingly found that 2,4,7-triamino-6-(p-hydroxyphenyl)-pteridine when administered by injection has even in small concentrations a pronounced diuretic and potassium-retaining effect The potassium-retaining activity is quantitatively more pronounced than that of triamterene.

The compound 2,4,7-triamino-6-(p-hydroxyphenyl)-pteridine also shows, compared with 50 the non-hydroxylated analogue (triamterene), an improved solubility in water, especially in the form of its physiologically compatible salts.

We have thus found that the injectable pharmaceutical compositions comprising compounds of formula I have advantageous properties, for example over triamterene, and accordingly represent an advance in the art For a direct comparison of diuretic and 55 potassium-retaining activity, tests on the epithelium of the main excretory duct of the submaxiliary gland of rats according to Knauf (loc cit) can be used As an indication of the cardio-protective effect the electro-physiological tests on isolated heart structures of guniea pigs and dogs according to Luderitz (loc cit) can be employed.

The compounds of formula I also tend to have a better solubility in water than 60 triamterene.

The compounds of formula I can be administered by injection in doses depending on the type of indication and the individual requirement of the patient.

Because of the improved diuretic activity over triamterene, the dosage of the compound of formula I used in practice will generally be below that of triamterene; in many cases, the 65 1 597 882 1 597 882 normal dosages of triamterene can therefore be considered as an upper limit of the dosage range of the active substances of formula I.

The injectable pharmaceutical compositions according to the invention can be formulated in conventional manner e g with conventional carriers and adjuvants.

The preparation of one such compound of formula I suitable for use in the compositions 5 of the present invention is illustrated in the following Example.

EXAMPLE 1:

Preparation of 2,4,7-triamino-6-p-methoxyphenyl-pteridine In a 1-litre 3-necked flask 1 85 g of sodium ( 0 08 mol) are dissolved with stirring in 480 ml 10 of ethyleneglycol monoethyl ether The solution is heated and mixed sucessively with stirring with 12 g of 2,4,6-triamino-5-nitrosopyrimidine ( 0 078 mol) and 11 85 ml ( 12 8 g) of p-methoxy-benzyl cyanide ( 0 087 mol) After approximately 15 minutes the initially violet-red reaction mixture becomes brown; after approximately 25 minutes reflux distillation is carried out and a brown and crystalline deposit is precipitated The mixture is 15 refluxed for a further 2 hours After cooling to room temperature the deposit is filtered on a G 4 frit,washed with 220 ml of water, 100 ml of acetone and 100 ml of diethyl ether, sucked dry and dried to constant weight in vacuo over P 4010.

Yield: 18 21 g ( 82 4 % of theory).

T l c (butanone-acetone-water 60:6:10): uniform 20 Elementary analysis: C 13 H 13 N 70 ( 283 30) Calculated: C 51 1 % H 4 6 % N 34 6 % Found: C 55 3 % H 5 5 % N 34 9 % The following Example illustrates the preparation of a pharmaceutical composition according to the invention: 25 EXAMPLE 2

Preparation of a pharmaceutical composition suitable for parenteral, particularly intravenous, administration 25 mg of 2,4,7-triamino-6-(p-hydroxyphenyl)-pteridine are treated at ambient tempera 30 ture with 10 ml of a 10 % aqueous solution of dimethylaminoethanol The pharmaceutically active substance is dissolved The mixture is then diluted to 100 ml with physiological saline.

A clear, yellowy solution is obtained with a p H value of 10 9.

Other compounds of formula I such as, for example, 2,4,7-triamino-6-(pmethoxyphenyl)-pteridine can also be made up into injectable pharmaceutical compositions 35 using a method analogous to that described above.

Claims (5)

WHAT WE CLAIM IS;-

1 Pharmaceutical compositions in injectable form comprising as active ingredient at least one pteridine compound of formula I NH O-R 40 NNN I (I) 45 H 2 N N N NH 2 2 lin which R represents a hydrogen atom, a physiologically acceptable cation or a C 1 to C 6 alkyl groupl together with at least one injectable pharmaceutical carrier or excipient.

2 A composition as claimed in claim 1 wherein the active ingredient comprises 50 2,4,7-triamino-6-(p-hydroxy-phenyl)-pteridine.

3 A composition as claimed in claim 1 wherein the active ingredient comprises 2,4,7-triamino-6-(p-methoxy-phenyl)-pteridine.

4 Pharmaceutical compositions as claimed in claim 1 substantially as herein described.

5 Pharmaceutical compositions in injectable form substantially as herein described in 55 Example 2.

For the Applicants, FRANK B DEHN & CO, Chartered Patent Agents, 60 Imperial House, 19 Kingsway, London WC 2.

Printed for Her Majesty's Stationery Office, by Croydon Printing Company Limited, Croydon Surrey 1981.

Published by The Patent Office, 25 Southampton Buildings, London, WC 2 A l AY, from which copies may be obtained.