SE441357B - 4-PYRIDINO - CYANOGUANIDE INGREDIENTS, PROCEDURES FOR PREPARING THIS AND A COMPOSITION WITH ANTI-PRESSURING EFFECT - Google Patents

Description

U.S. Pat. No. 4,057,636 discloses the antihypertensive effect of certain 2-, 3- or 4-pyridylcyanoguanidines. Further investigations of associations within the framework of the mentioned publications have been reported in J. Med. Chem. 21, 773 (1978).

Although the said known compounds generally have a remarkably strong effect, the compounds intended according to the present invention have certain advantages over the known compounds. The new compounds have a similarly strong effect as the known ones in terms of blood pressure lowering effect but have better pharmacokinetic properties. For example, the antihypertensive effect can be more easily adjusted, since the antihypertensive is slower in the initial phase, as compared with the use of the above-mentioned known compounds; in addition, the effect becomes more long-lasting.

The reason for this seems to be, at least in some cases, that the compounds according to the invention are partially converted under the action of oxidoreductases to corresponding, more potent pyridyl compounds of formula II f \ N NH-3-NH-R II _-N-CN and consequently can are considered to be prodrugs of these compounds.

The conversion in question is shown in the table below, which shows the serum concentrations of N "-cyano-N-1-oxido-4-pyridinio-N'-1,2,2-trimethylpropylguanidine (P 1368) and N" -cyano-N -4-pyridyl-N'-1,2,2-trimethylpropylguanidine (P 1134) after P 1368 was administered orally to dogs in an amount of 3 mg / kg. 8205107-'9 3 Table Hours after Dog no. l Dog no. 2 i aaministre 'à “Pdi368 P ii3u P 1368 P 113: ring, ng / ml ng / ml ng / ml ng / ml í L 55 45 32 <5 i 2 330 = 5 217: je i 1 I 22% 15 4 : * ~~ I Ä ”Gl 348 573 iooo E 5 245 351 512 1315 i 6 288 Bio ueo 743 ä 7 270 7h7 357 530 I 3 271 659 281 L33 ¿zh 126 76 10,4 ¿5 É e 1 Vid tester med voluntary subjects, a similar in vivo conversion of P 1368 to P llšü has been observed.

The novel compounds of the invention have low toxicity and, when tested on various species of experimental animals (enteral or parenteral administration), have been found to exert a strong and long-lasting antihypertensive effect without giving rise to any other pharmacodynamic effects. These compounds are believed to exert their antihypertensive effect by affecting the peripheral blood vessels either as such: or after biological conversion to the corresponding pyridyl compounds of formula II.

Thus, it has unexpectedly been found that the present compounds have a favorable therapeutic index, in terms of both enteral and parenteral administration, in that they counteract hypertension and are well tolerated compounds which in preliminary experiments have not shown any adverse effects.

The invention also relates to a process for the preparation of the compounds described above. According to this process, a compound of formula II is oxidized to a compound of formula I according to the reaction scheme 825107-'9 f "\ /“ J.

NV \ vH-c-NH-R -> 0 & N / WH-C-NH-R J H \ ___ H - N_CN - / N-cN II wherein R has the meanings given above.

The oxygenation can be carried out according to generally known methods. Examples of oxygenating agents are inorganic and organic peracids, such as perboric acid, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perchloric acid, peroximonosulfuric acid or persulfates. Also molybdenum, tungsten, vanadium and manganese, chromium and similar elements from these groups of the periodic table in a high or highest oxidation stage are useful as oxygenating or catalytic agents in the form of their corresponding oxides or acids, or salts of such acids.

The reaction is carried out in any suitable solvent or reaction medium, e.g. an inert medium such as chloroform, for a sufficiently long time and at a suitable temperature to effect the desired conversion, usually at a temperature of O-BOOC. According to a suitable embodiment, the peracids can be used as solvents and thus used in excess. In other cases, the oxygenating agent is used in equimolar or substantially equimolar amounts, which can be added successively during the ongoing reaction.

According to a suitable embodiment, the oxygenation is carried out with perhydrol (30% hydrogen peroxide) in isopropanol as reaction medium, using sodium tungstate as catalytic agent. According to another embodiment, m-chloroperbenzoic acid is suitably used as the oxygenating agent, with e.g. chloroform, ethanol or isopropanol as reaction medium. It is also possible to use a mixture of perhydrol and glacial acetic acid both as oxygenating agent and as reaction medium. According to yet another embodiment, the oxygenation can be carried out electrolytically.

The starting materials of formula II are known from the above-mentioned DOS? 438 and / or J. Med. Chem. gg, 773 (1978).

Yet another embodiment of the process means that the intermediates used in the preparation of compounds II as described in DOS 25 H38 can be subjected to an oxygenation process of the kind described above, after which they can be converted in the form of the corresponding N The desired compounds of formula I according to the present invention, in accordance with the methods described in said DOS 25 57 438. The compounds I can be converted to their acid salts in a conventional manner.

In the above methods, a desired stereoisomer can be obtained by using the corresponding isomer of the starting material in the manufacturing process.

Alternatively, a racemate can be used as starting material, after which the resulting mixture can be subjected to racemate solution, for example by crystallizing a suitable salt with an optically active strong acid in a known manner.

The invention also relates to pharmaceutical compositions which are suitable for the treatment of hypertension and similar morbid conditions.

These compositions may contain 0.1 to 99% of the compounds of formula I in admixture with organic or organic solid or liquid carriers and / or excipients which are suitable for the preparation of various pharmaceutical dosage forms for oral or enteral administration. , including preparations from which the active substance is released only slowly and consequently for a longer period of time.

The compositions according to the invention may be formulated into various kinds of pharmaceutical dosage forms, for example tablets, pills, dragees, capsules, tablets for slow (prolonged) release of the active substance, suspensions, suppositories, injection preparations, containing the compounds I or their non-toxic salts.

In human therapy, the compounds and their salts may conveniently be administered in dosage units (for adults) containing at least 0.5 mg and up to 500 mg, preferably 5 to 250 mg.

By "dosage unit" is meant a dose in the form of a unit or portion, i.e. a single dose which can be given as such to a patient and which can be easily handled and packaged, leaving it a physically stable unit, comprising the active material either as such or in admixture with solid or liquid pharmaceutical diluents or carriers. .

When the compounds are in the form of dosage units, they can be administered once or several times daily at appropriate intervals - though, of course, always in accordance with the patient's condition and in accordance with the physician's prescriptions.

A further object of the invention is the selection of a daily dose of the compounds according to the invention, which can be administered so that the desired effect is obtained without the simultaneous occurrence of side effects.

In the case of human therapy, the compounds and their salts may conveniently be administered (in adults) in daily doses from 5 mg and up to 1,000 mg, preferably from 20 mg up to 500 mg, calculated as the base of formula I, and in the case of veterinary medicine. therapy, they may conveniently be administered in daily doses of 0.07 - 14 mg per kg of body weight.

The invention is further described in the following examples, which, however, are not limiting of the scope of the invention.

Example 1. N "-cyano-N-1-oxido-4-pyridinio-N'-1,2,2-trimethylpropylguanidine.

A suspension of 10.0 g (40 mmol) of anhydrous N "-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine in 60 ml of isopropanol was stirred at 0 ° C while introducing 31 g (160 mmol) 90% pure m-chloroperbenzoic acid A clear solution was obtained within 5 minutes After 3 days storage at 0 ° C the precipitate formed was filtered off and the filtrate was carefully evaporated in vacuo at 0 ° C. The residue was stirred with 200 ml of ether, and the mixture was filtered and washed with ether to give a crude product as a residue, which was further purified by stirring with 75 ml of acetone and filtration.

The solid residue was subjected to selective precipitation by preparing it into a solution in excess of 1 N hydrochloric acid in water, and the pH was adjusted to 1.3 by adding solid sodium acetate.

The pure crystalline product was collected by filtration, washed with water and air dried. melting point 242-243 ° C (decomposition).

IR (KBr): strong bands at 2180 cm_1 and at 1560-1620 cm_1.

The NMR spectrum ((CD 3) 2 SO) showed signals at δ = 0.93 δ 8205107-9 (s, 9H), 1.10 (d, J = 7 Hz, 3H), 3.93 (kv, J = 7Hz, 1H), 7.28 (bd, ZH), 7.40 (bs, 1H), 8.15 (bd, 2H), 9.50 (bs, 1H) ppm.

Tetramethylsilane was used as an internal reference.

The compound was administered orally to dogs who were conscious and who had previously been given elevated blood pressure according to the method of Goldbatt et al. (J. Exp. Med. Âg, 347 (1934)), the dosages being 3.0 and 10.0 mg / kg. Blood pressure drops of 42 É 12 mm fl g and 79 É 16 mmHg (mean É SEM, 3 animals / dose) were observed. The greatest effect was achieved 3-4 hours after administration, and a blood pressure lowering effect was still present 8 hours after administration.

In dogs with normal blood pressure, intravenous administration of 1.0 and 3.0 mg / kg of the above compound results in a reduction in blood pressure of 15 in 7 mmHg and 28 in 9 mmHg (mean value in SBM, 3 animals / dose). The largest drop in blood pressure occurred about 10 minutes after administration. The antihypertensive effect disappeared 2 hours later.

Example 2. N "-cyano-N-1-oxido-4-pyridinio-N'-tert-pentylguanidine A suspension of 2.31 g (10 mmol) of N" -cyano-N-tert-pentyl-N'- 4-Pyridylguanidine in 13 ml of ethanol was stirred at 0 ° C while first introducing 1.70 g (20 mmol) of sodium bicarbonate and then 3.85 g (20 mmol) of 90% pure m-chloroperbenzoic acid. The suspension, which was slowly diluted, was kept at 0 ° C with stirring and allowed to stand overnight in the refrigerator. The precipitate formed was collected by filtration and washed with 10 ml of cold ethanol and ether. Finally, it was stirred with 10 ml of water, filtered off, washed with water and air-dried to give the product in crude form.

Upon selective precipitation by preparing a solution in excess of 1 N aqueous hydrochloric acid and adjusting the pH to 1.3 with sodium acetate, the pure crystalline compound was obtained. melting point 247 ° c (sunburn> IR (KBr): absorption band at 2170, 1620-1600, and 1550-60 cm «1. .. _, f me» Meta * - .. ~ »- Example 3. N-Benzyl-N "-cyano-N'-1-oxido-4-pyridinioguanidine. 1.04 g (4 mmol) N-benzyl-N "-cyano-N'-4-pyridylguanidine was suspended in 5 ml of ethanol. While stirring at 0 ° C, 675 mg (8 mmol) of sodium bicarbonate and 1.54 g (8 mmol) of 90 Stirring pure m-chloroperbenzoic acid Stirring was continued at 0 DEG C. for 10 hours. After 3 days in a refrigerator, the mixture was cooled to about -20 DEG C. and filtered. The crude product was obtained by washing with small amounts of ethanol and ether. , the crystalline product was obtained by dissolving in excess of 1 N hydrochloric acid, treating with charcoal and adjusting the pH with sodium acetate to about 1.3, the N-oxide being selectively precipitated.

IR (KBr): strong absorption bands at 2180, 1640-30 and 1580 cm -1. The NMR spectrum ((CD 3) 2 SO) showed signals at δ = 4.46 (bd, ZH), 7.29 (bd, 2H) 7.32 (s, 5H), 8.10 (bd, 2H), 8.18 (bt, 1H), 9.48 (bs, 1H) ppm Tetramethylsilane was used as internal reference.

Example 4. N "-cyano-N-1-ethyl-1-methylpropyl-N'-1-oxido-4-pyridinioguanidine. 2.45 g (10 mmol) of N" -cyano-N-1-ethyl-1- methylpropyl-N'-4-pyridylguanidine was suspended in 20 ml of isopropanol. While stirring at 0 ° C, 840 mg (10 mmol) of sodium bicarbonate and 3.85 g (20 mmol) of 90% pure m-chloroperbenzoic acid were added.

The suspension, which slowly thickened, was stirred at 0 ° C for a total of 14 hours and allowed to stand in the refrigerator for 2 nights. The crude product was collected by filtration and washed with small amounts of cold isopropanol and with ether. Further work-up of the residue was carried out by stirring with first 15 ml of water and then 20 ml of acetone, with a filtration in between, and final washing with acetone and ether.

The pure crystalline compound was obtained by dissolving in excess of 1 N hydrochloric acid (25 ml) and selectively precipitating by adjusting the pH to about 1.5 with solid sodium acetate.

Melting point 229-30 ° C (decomposition). 8205107-9 IR (KBr): Strong absorption bands at 2165, 161o ~ 16oo and 1565-1550 cm -1.

Examples are prepared in the same manner as in Example 1 or 2, but using compounds of formula II in which R had the meanings given in the table below instead of the meanings 1,2,2-trimethylpropyl or tert-pentyl. In these cases, the compounds in which R has the meanings given below in the table were obtained.

The compounds in the table below have the formula _ N-cN o <- N // \\ NH-g-NH-R _ I ___... dääšime9 10 Ex. R Ex. R 5 n-c3H7 15 c (Me,) cHMeq 6 i_c3H7 16 cH (Me) cH2cHMe2 7 n-CAHQ 17 cH (Er) cHMe, 8 1-can? 18 cE: 3 Q n-cïnq 19 c (ne @) cHqcHMeq 10 n-cš fi ll 20 c (Me2) cH3cne3 11 1-csnll 21 cH (Me) (cH2) 3cHMe2 12 neo = C5Hll 22 C6H5 13 cHEr2 23 p-c1 -c6Ha- LA c (Me2) (cH2) 2cH3 24 c6H5cH2-oH2- Example 25. N "-cyano-N1-oxido-pyvidinio-N'-1,2,2-trimethylz. propylguanidine. 2.5 g (10 mmol) anhydrous N "-cyano-NU-pyridyl-N'-1,2,2-trimethyl-propylguanidine was suspended in 25 ml of chloroform. While stirring at 0 DEG C., 6 portions of 90% pure m-chloroperbenzoic acid (total 2.50 g; 13 mmol) were added within 1 hour. The mixture was kept overnight at 000 and then evaporated in vacuo at 000. The residue was triturated with 3 25 ml portions of ether, with decantations between these operations, and the crude product was obtained by filtration and washing repeatedly with ether. It was dissolved in 8 parts of glacial acetic acid under gentle heating and precipitated by adding 32 parts of water.

The pure compound was collected by filtration, washed with water and air dried.

Melting point: 2H2-QHBOC (decomposition).

Example 26. N "-cyano-N-1-ethyl-1-methylpropyl-N'-1-oxido-fl-pyridinioguanidine.

A solution of 2.5 H5 g (10 mmol) of N "-cyano-N1-ethyl-1-methylpropyl-N'-4-pyridylguanidine in 50 ml of glacial acetic acid was stirred at 1000 DEG C. while 5 ml of 30% hydrogen peroxide in water The mixture was heated for 5 hours at 6000 and evaporated in vacuo at 2500. The residue was adjusted to neutral pH by adding an aqueous solution of sodium carbonate, and the crude product was filtered off and washed with water.The pure product was obtained by selective precipitation (cf. Example 1) at pH 1.3 and recrystallization from acetic acid in water, melting point = 229-230 ° C.

Example 27. N-Benzyl-N "-cyano-N'-1-oxido-4-pyridinioguanidine. 2.51 g (10 mmol) of N-benzyl-N" -cyano-N'-4-pyridylguanidine were dissolved in 20 ml (20 mmol) of 1 N hydrochloric acid, containing 200 mg of sodium tungstate dihydrate. While stirring at 0 ° C, 2.0 ml (20 mmol) of 30% hydrogen peroxide in water was slowly added, and the temperature of the mixture was then allowed to rise to room temperature. After 6 hours, its pH was adjusted to 1.5, and the crude product was collected by filtration and washed with water. Recrystallization from aqueous acetic acid gave the pure compound, which was identical with the compound of Example 3.

Example 28. N "-cyano-N1-oxido-M-pyridinio-N'-tert-pentylguanidine A suspension of 2 μg (10 mmol) N" -cyano-N-tert-pentyl-N'-h- pyridylguanidine in 40 ml of water was stirred at 000 while 3.60 g of potassium persulfate were added portionwise. In this way, a thin suspension was obtained. After 5 hours at 0 ° C, the temperature of the mixture was allowed to rise to room temperature, and stirring was continued overnight. The mixture was cooled to 0 ° C, and the crude product was filtered off and washed with water. When selective precipitation was carried out at pH 1.5, with subsequent remistaling from aqueous acetic acid, the pure product was obtained, which was identical with the product of Example 2.

Melting point: 20700 (decomposition).

Example 29. Capsules Preparation of 100,000 capsules (P 1368 1,000 kg I Lactose l0,000 kg $ Polyvinylpyrrolidone 0.200 kg II deionized water 1,000 kg irisiaxia, koiioidai o, o5o kg III Magnesium stearate 0.100 kg Materials I are mixed in a planetary mixer. Materials I and II is then wet-granulated.The wet mixture thus obtained is sieved through a sieve with 1.5 mm openings.The wet granulate is dried in a fluidized bed at 6000. The dry granulate is sieved through a sieve with 0.8 mm openings, and the sieved granulate thus obtained is lubricated with the lubricants III. 825107 ~ 9 102.

The granulate is filled into capsules of size no. H with a bp weight 113.5 mg granules per capsule; corresponding to 10 mg P Example 30.

Tablets Preparation of 100,000 tablets (P 1368 I E starch I Lactose p Polyvinylpyrrolidone II šAvionised water Talc III Magnesium stearate Silica, colloidal 1368 per capsule. Kn Ka 10.825 kg kg ka ka Ks kv J The materials I are mixed in a planetary mixer. The wet mixture is sieved openings, the sieved granules are dried in 6000. The dry granules are sieved through one and the sieved granules thus lubricated. The granules are pressed into tablets with a fluidized bed through a sieve with a 1.5 mm sieve with a sieve with 0.3 mm openings. with the lubricating material III.

Punch size: 7 mm; round flat tablets with bevelled edge.

Degree of hardness of the tablets: H-5 kp.

Claims (10)

82951Û7 * 9 ”'13 P a t e n t k r a v 1. A compound characterized by the formula I 0 <'_' N H_ÃII: J: KI: _R (I) or its tautomeric forms, wherein R represents a straight or branched, saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms, a phenyl group, a p-chlorophenyl group, a benzyl group or a phenethyl group and non-toxic, pharmaceutically acceptable salts thereof. Compound I or its salt according to claim 1, characterized in that R represents straight or branched alkyl having 4-8 carbon atoms, preferably isobutyl, sec-butyl, tert-butyl, or any of the isomerically branched pentyl radicals. . the hexyl, heptyl or octyl groups. Compound I or its salt according to claim 1, characterized in that it consists of any of the following compounds resp. a corresponding salt: N "-cyano-N-1-oxido-4-pyridinio-N11,2,2-trimethylpropylguanidine; N" -cyano-N-1-oxido-4-pyridinio-N-tert-pentylguanidine; N-benzyl-N "-cyano-N11-oxido-4-pyridinioguanidine; N" -cyano-N- (1-ethyl-1-methylpropyl) -N: 1-oxido-4-pyridinoguanidine. 4. A process for the preparation of a compound of formula I or its non-toxic, pharmaceutically acceptable salt, characterized in that a compound of formula II is oxidized to compound I according to the following reaction scheme N R '' * ~ å Oé-íš :: ï> NH-C-NH-R __ I __ H N-CN N ~ CN (II) (I) in which formulas R represents a straight or branched, saturated or unsaturated, an aliphatic hydrocarbon group having 1 to 8 carbon atoms, a phenyl group, a p-chlorophenyl group, a benzyl group or a phenethyl group, the compound I being recovered as such or in the form of said salt. Process according to Claim 4, characterized in that either a) an inorganic or organic acid, preferably perboric acid, peracetic acid, perbenzoic acid, m-chloroperbenzoic acid, perchloric acid, peroximonosulfuric acid or persulphates, or b) molybdenum, tungsten, vanadium is used as oxidizing agent. , manganese or chromium in a high or highest oxidation stage in the form of oxide, acid or salt of the acid. 6. A process according to claim 4, characterized in that the oxidation is carried out with an oxidizing agent, which at the same time also uses solar reaction medium. Process according to Claim 4, characterized in that perhydrol is used as oxidizing agent, isopropanol as reaction medium and sodium tungstate as catalyst. Process according to Claim 4, characterized in that the oxidation is carried out as an electrolytic oxygenation. Composition having an antihypertensive effect, characterized in that it contains, together with solid or liquid pharmaceutical carriers and / or excipients, an active ingredient which consists of at least one compound of the formula I N-cN ° <* N / \ Hg- N 2 -R (I) optionally in the form of its salt with a non-toxic, pharmaceutically acceptable acid, wherein in said formula R represents a straight or branched, saturated or unsaturated aliphatic hydrocarbon group having 1 to 8 carbon atoms, a phenyl group, a p-chlorophenyl group, a benzyl group or a phenethyl group. 10. A composition according to claim 9, characterized in that it contains at least 0.1% of the active component.