LU84375A1 - NOVEL DERIVATIVES OF N "-CYANO N-OXYDO-1 PYRIDINIO-4 GUANIDINE N'-SUBSTITUEE USEFUL AS ANTIHYPERTENSIVE DRUGS AND PROCESS FOR THEIR PREPARATION - Google Patents

Description

"1.

The present invention relates to novel derivatives of N "-cyano N-oxydo-1 pyridinio-4 guanidine N'-substituted useful as antihypertensive drugs and a process for their preparation.

The new compounds correspond to the general formula I

! -v N-CN

5 0 "-1 / V-NH-C-NH-R I

in which corresponding tautomeric forms are constituted, in which R represents a saturated or unsaturated, straight or branched aliphatic hydrocarbon radical having 1 to 8 carbon atoms, aryl or aralkyl carbocyclic mono- or bi-cyclic, the term aryl denoting a phenyl radical or unsubstituted or substituted naphthyl and the alkyl moiety of the aralkyl radical having 1 to 6 carbon atoms.

More particularly, R can represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl radical or one of the isomeric pentyles radicals, for example pentyl, isopentyl, tert-pentyl and neopentyl or one of the radicals isomeric hexyls, for example neohexyl, 1,2,2,2-trimethyl propyl and 1-ethyl-1-methylpropyl, or one of the isomeric radicuax isomers, for example 1,1,1-diethyl propyl and 1,1,3-trimethyl butyl, or the corresponding alkenyl radicals, a phenyl, p-chlorophenyl, naphthyl, benzyl or phenethyl radical, and their salts formed with strong, pharmaceutically acceptable acids, minerals and organic. cie and non-toxic.

In particular, the compounds of formula I in which R represents a straight or branched alkyl radical having 4 to 8 carbon atoms are useful in the use specified below.

In the case where the present compounds contain one or more asymmetric carbon atoms, these compounds exist in several stereoisomeric forms. The invention encompasses all these stereoisomers and their mixtures.

The compounds of the invention are weak bases η but they form salts with strong organic or inorganic / mineral acids, of which non-toxic acids suitable in pharmacy are suitable, for example halogenated hydracids, acid! sulfuric or nitric acid or methanesulfonic acid. .

I The DOS patent application n ° 25 57 438 filed in]! 5 Federal Republic of Germany and US Patent No. 4,057,635 describe the antihypertensive effect of certain pyridyl-2, -3 or -4 cyanoguanidines. Complementary studies of the compounds according to | these patents were published in J. Med. Chem, 21, -773 (1978).

Although said known compounds generally have very high activity, the compounds of the invention have been found to have certain advantages over them. They are similarly powerful antihypertensives but they are superior by their pharmacokinetic properties. For example, the antihypertensive activity is easier to adjust since the drop in blood pressure appears more gradually with the present compounds than in the case of the aforementioned compounds and the effect is more prolonged. The reason for this perhaps in some cases at least the compounds of the invention under the effect of oxidoreductases! [; 20 are partially transformed into the corresponding pyridyl compounds

I more powerful layers of formula II

N VkH-C-NH-R II

N-CN

î j; and therefore can be considered as prodrugs of

Ji these,! 25 This conversion appears from the examination of the following table <· i which shows the serum concentrations of N "-cyano N-oxydo-1 pyri-! Dinio-4 N'-trimethyl-1,2,2 propyl guanidine (P 1368 ) and in N "~ cyano p N-pyridyl-4 N'-trimethyl-1,2,2 propyl guanidine (P 1134), respectively, after administration of 3 mg / kg of p 1368 to dogs./ ! / ji

V V

3

Board

Dog n ° I Dog n ° 2

Hours after administration 1 „tion P 1368 P 113¾ P 1368 P 1134 ng / ml ng / ml ng / ml ng / ml 5 .1 6p 45 32 <5 2 330 297 238 3. 224 15 437 1070 U 201 ' '343 579 1000 5 245 851 512 1013 10 6 288 816 460 748 7 279 747 357 630 8 271 659 281 438 24 126? 6 10.4 <5

A similar in vivo conversion of P 1368 to P 1134 has been observed in human volunteers.

The novel compounds of the invention have low toxicity and have been shown to exert a potent and prolonged antihypertensive effect in various animal species when administered enterally or parenterally, without causing other pharmacodynamic effects. It seems that these compounds exert their antihypertensive action by an effect on the peripheral blood vessels, either as they are, or after bioconversion in the corresponding pyridylic analogs of formula II.

It has therefore been surprisingly found that the present compounds have a favorable therapeutic index, by enteral administration as by parenteral administration, that they relieve the states of hypertension and are well tolerated compounds which, in / i 4 .- L the invention also relates to a process for the preparation of the compounds described above which comprises an oxidation of a compound of formula II to a compound of formula I according to the reaction scheme;

5 N7 \ nH-C-NH-R - »Of-N / 'VnH-C-KH-R

N-CN N-CN

II I

in which R has the same definition as above.

Oxygenation can be carried out according to well known methods. For example, there may be mentioned as examples of oxygenating agents, mineral and organic peracids such as perboric acid, peracetic acid, perbenzoic acid, m-chloro perbenzoic acid, perchloric acid , peroxymono-sulfuric acid or persulfates. Also, as the oxidizing agents, molybdenum, tungsten, vanadium and manganese, chromium and the like of these groups of the Periodic Table can be used under high or maximum oxidation state or catalytic agents in the form of their corresponding oxides or acids or salts of such acids.

The reaction is carried out in a suitable solvent or reaction medium, for example an inert medium such as chloroform, for a sufficient time and at a temperature suitable for carrying out the desired conversion, generally at a temperature of 0 to 30 ° C. In a suitable embodiment, the peracids can be used as solvents and therefore used in excess. In other circumstances, the oxygenating agent is used in equimolecular or almost equi-molecular amounts which can be added successively during the operation.

In a suitable embodiment, oxygenation is carried out with perhydrol (30% hydrogen peroxide) in isopropanol as the reaction medium using sodium tungstate as catalytic agent. In another embodiment, m-chloroperbenzotic acid J is appropriately used

f '5 as oxygenating agent with for example chloroform, ethanol or isopropanol as reaction medium. In addition, a mixture of perhydrol and glacial acetic acid can be used as the oxygenating agent, and also as the reaction medium. In another embodiment, oxygenation can be accomplished by electrolytic oxygenation.

The starting materials of formula II are known from the above-mentioned DOS application and / or J. Med. Chem. 21, 773 (1978).

In another embodiment, the intermediates used in the preparation of the compounds of formula II, as described in the abovementioned DOS application, can be exposed to an oxygenation treatment as described above, then, in the form of the corresponding N-oxides, transform them into the desired compounds of formula I of the invention according to the methods described in said DOS application.

The compounds of formula I can be transformed into their acid salts according to conventional methods.

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

Alternatively, a racemate can be used as the starting material and then the mixture obtained can be subjected to resolution of the racemate, for example by crystallization of a suitable salt formed with an optically active strong acid, in known manner.

The invention also relates to pharmaceutical compositions which are useful in the treatment of hypertension and the like. These compositions can contain 0.1 to 99% of the compounds of formula I in admixture with solid or liquid, organic or inorganic vehicles and / or auxiliary agents, suitable for the preparation of various pharmaceutical forms suitable for oral administration. or enteral including slow release preparations.

The compositions may further contain other therapeutically active compounds used for the treatment of hypertension and similar conditions, for example diureas, reserpine, α-methyldopa and in particular / / β-adrenergic blockers.

6

The compositions of the invention can be presented. j in various pharmaceutical forms, such as tablets,! -pills, dragees, capsules, release tablets! Slows, suspensions, suppositories and injectable forms containing the compounds of formula I or their non-toxic salts, In human therapy, the compounds and their salts can be appropriately administered as unit doses containing not less than 0.5 mg and not more than 1500 mg, preferably 5 to 250 mg, of active product.

| ’10“ Unit dose ”is understood to mean a unit dose, that is to say a single dose, which can be administered to a patient and which can easily be handled and conditioned by keeping it under J. as a physically stable unit dose comprising either the active product or a mixture of this active product with solid or liquid diluents or pharmaceutical carriers.

In the form of unit doses, the can be administered. compound one or more times a day at appropriate intervals, however always depending on the patient's condition and as prescribed by the medical practitioner.

It is also advisable to choose the daily dosage of the compounds of the invention which can be administered in order to obtain the desired activity without simultaneous side effect.

In human therapy, the compounds and their salts may suitably be administered (to adults) in daily doses of from 5 mg to 1000 mg and preferably from 20 to 500 mg, i; calculated in the form of the base of formula I and in veterinary practice correspondingly doses can be used; daily from 0.07 to 14 mg / kg body weight.

I t · ’’ j. ’The invention is illustrated by the nonlimiting examples ΐ. * 30 following.

It laughed! Example 1 4 -.I I · * I * N "-cyano N-oxydo-1 pyridinio-4 K'-trimethyl-1,2,2 propyl guanidine

A suspension of 10.0 g (40 mmol) of / is stirred at 0 ° C.

N "-cyano N-pyridyl-4 N'-trimethyl-1,2,2 propyl guanidine in 50 ml A

(i / / / 7 of Isopropanol by introducing 31 g (160 mmol) of m-chloroper-benzoic acid (90% pure) to obtain a clear solution in 5 min.

After three days of storage at 0 ° C., the precipitate formed is filtered off. The filtrate is evaporated gently under vacuum at 0 ° C.

The residue is stirred with 200 ml of ether and the mixture is filtered and then washed with ether to leave a crude product. The additional purification is carried out by stirring with 75 ml of acetone and filtration.

The solid residue is subjected to selective precipitation by solvation in excess of 1N aqueous hydrochloric acid and adjustment of the pH to 1.3 by addition of solid sodium acetate 1.

The pure crystalline product is collected by filtration, washed with water and dried in air.

M.p .: 242-243 ° C (decomposition). IR (KBr): has strong bands at 2,180 cm ^ and 1,560-1,620 cm

The NMR spectrum ((CD ^^ SO) presents signals at: '& = 0.93 (s, 9H), 1.10 (d, J = 7 Hz, 3H), 3.93' (q, J = 7 Hz, 1H), 7.28 (dl, 2H), 7.40 (ol, 1H), 8.15 (dl, 2ll), 9.50 (si, 1H) ppm.

Tetramethylsilane is used as an internal reference.

The compound was administered orally to non-anesthetized dogs previously rendered hypertensive according to the method of Goldblatt et al. (J. Exp. Med. 59, 347, (1934)) at doses of 3.0 and 10.0 mg / kg. A drop in blood pressure of 42 + 12 mmHg and 79 + 16 mm Hg respectively (mean + standard error of the mean, 3 animals / each dose) was observed. A maximum effect was obtained 3 to 4 h after administration and a hypotensive effect remained 8 h after administration.

In normotensive dogs, intravenous doses of 1.0 and 3.0 mg / kg of the above compound caused a drop in blood pressure of 15 + 7 mm Hg and 28 + 9 mm Hg, respectively. (mean + standard error of mean, 3 animals / each dose), The maximum drop in blood pressure occurred about 10% after administration. The hypotensive effect ^ / 35 disappeared 2 h after, / // É. '8

Example 2 N "-cyano N-oxydo-1 pyridinio-4 N'-tert-pentyl guanidine, A suspension of 2.31 g (10 mmol) of; N" -cyano N-tert-pentyl is stirred at 0 ° C. N'-pyridyl-4 guanidine in 13 ml of ethanol 5 by introducing 1.70 g (20 mmol) of sodium bicarbonate then j

! 3.85 g (20 mmol) m-chloroperbenzoic acid. We maintain at 0 ° C

with stirring the suspension which thickens gradually and is left overnight in the refrigerator. We collect · by filtra-! tion the precipitate formed and washed with 10 ml of cold ethanol! } * 10 and ether. Finally, it is stirred with 10 ml of water, filtered, i s washed with water and dried in air to obtain the crude product.

j 'By selective precipitation by solvation in a · (1 excess of 1N aqueous hydrochloric acid and adjustment of the pH to 1.3 "with sodium acetate, the pure crystalline compound I 15 F. is obtained: 247 ° C (decomposition). IR (KBr): absorption bands at 2 170, l 1 620-1 600, and 1550-60 cm “1.

Example 3 [: R-benzyl N "-cyano N'-oxydo-1 pyridinio-4 guanidine 20 1.04 g (4 mmol) of N-benzyl is suspended. N" -cyano ti | . N'-pyridyl-4 guanidine in 5 ml of ethanol. By stirring at 0 ° C, we! add 675 mg (8 mmol) of sodium bicarbonate and 1.54 g (8 mmol). j 'of m-chloroperbenzoic acid (90% pure), stirring is continued at 0 ° C for 10 h. After 3 days of storage in the refrigerator, | 25 cools the mixture to about -20 ° C and filtered. The ri: j crude product is obtained by washing with small quantities of cold ethanol and j ether. The pure crystalline substance is obtained by dissolving in an excess of IN hydrochloric acid, treatment; with carbon ij and adjustment of the pH to about 1.3 with sodium acetate, which caused the selective precipitation of the N-oxide.

| IR (KBr): strong absorption band at 2,180, 1,640-30 I and 1,580 cm \ / j λ 1 r *

H

9

The NMR spectrum ((CD ^^ SO) presents signals at £ = 4.46 (dl, 2H), 7.29 (dl, 2H), 7.32 (s, 5H), 8.10 (dl, 2H), 8.18 (tl, 1H), 9.48 (si, 1H) ppm Tetramethylsilane is used as an internal reference.

Example 4 N "-cyano N-ethyl-1 methyl-1 propyl N'-oxydo-1 pyridinio-4 guanidine 2.45 g (10 mmol) of N" -cyano N-ethyl-1 methyl- are suspended. 1 propyl N'-pyridyl-4 guanidine in 20 ml of isppropanol. While stirring at 0 ° C., 840 rog (10 mmol) of 10 sodium bicarbonate and 3.85 g (20 mmol) of m-chloro-per-benzoic acid (90% pure) are added. The suspension, which thickens gradually, is stirred at 0 ° C. for a total of 14 hours and is left in the refrigerator for 2 nights. The crude product is collected by filtration and washed with small amounts of cold isopropanol and with ether. The residue is then treated by successive stirring with 15 ml of water and 20 ml of acetone with intermediate filtration and finally washing with acetone and ether.

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

Mp: 229-30 ° C (decomposition) IR (KBr): strong absorption bands at 2 165, 1 610-1 600 and 25 1 565-1 550 cm \ <„Examples. 5 to 24,

According to the procedure described in Example 1 or in Example 2, and using the compounds of formula II where R has the meaning indicated in the table below instead of representing the 1,2-trimethyl radical, 2 propyl, -the compounds of formula I are prepared where R has the meanings indicated / \ j in the table. I jiï T '10.

. Board . ‘„ · / "Λ! 'Cs

o <—ν 'xV-NH-C-NH-R _ · I

Example R Example · R

5 n-C ^ H-, 15 C (Me ,,.) CHMe9 6 · ‘l6 CK (Me) CH2CHMe., 7 · n-C ^ Hp 17 CH (Et) CHMe2 5 8 i-C ^ l8 CEt3 9 t-C, ^. 19 C (Me0) ÇH ,, CH> ie2 10 η-Ο-Ηχι 20 c (Mep) CH ;;) CMe3 11 21 CH (Me) (CH9) 3CHMe2 12 neo-C-H ,. 22 C ^ -K ^ P 11 O;> 10 13 CHEt2 23 p-C1-C6H4- lb C (Me2) (CH2) 2CH3 Zb CgK .CH ^ CH ^ j Example 25 • N "-cyano K-oxydo-1 pyridinio-4 N'-trimethyl-1,2,2 propyl guanidine ί 2.45 g | 15 (10 mmol) of N "-cyano N-pyridyl-4 N1trimethy1-1 are suspended in 25 ml of chloroform, 2, * 2 propyl guanidine | ‘In 25 ml of chloroform. While stirring at 0 ° C., in 1 hour and six hours, there are added dj portions of m-chloroperbenzol'que acid (90% pure) (total 2.50 g; ί 13 mmol). The mixture is kept at 0 ° C overnight and evaporated in vacuo at 0 ° C. The residue is triturated with three 20 'portions of ether (25 ml) with intermittent decantations, and f! the crude product by filtration and several washes with ether. Ony, / i f,> ·, 11 dissolves it in 8 parts of glacial acetic acid while heating gently and precipitates by addition of 32 parts of water.

The pure compound is collected by filtration, washed with water and dried in air, 5 ° C.: 242-243 ° C (decomposition).

Example 26 K "-cyano N-ethyl-1 methyl-1 propyl N'-oxydo-1 pyridinio-4 guanidine 'A solution of 2.45 g (10 mmol) of N" -cyano N-ethyl- is stirred at 10 ° C. 1 methyl-1 propyl N'-pyridyl-4 guanidine in 10 50 ml of glacial acetic acid by adding 5 ml of 30% aqueous hydrogen peroxide. The mixture is heated at 60 ° C for 5 h and evaporated in vacuo at 25 ° C. The residue is brought to neutral by the addition of aqueous sodium carbonate, the crude product is separated by filtration and washed with water. By selective precipitation (see Example 1) at pH 1.3 and recrystallization from aqueous acetic acid, the pure product is obtained.

M.p .: 229-230 ° C (decomposition).

Example .27 N-benzyl N "-cyano N-oxydo-1 pyridinio-4 guanidine 20 2.51 g (10 ramol) of N-benzyl N" -cyano N'-pyridyl-4 guanidine are dissolved in 20 ml (20 mmol) of 1N hydrochloric acid containing 200 mg of sodium tungstate dihydrate. While stirring at 0 ° C, 2.0 ml (20 mmol) of aqueous hydrogen peroxide is gradually added to 30, then the mixture is allowed to return to room temperature. After 6 h, the pH is adjusted to 1.5, the crude product is collected by filtration and washed with water. Recrystallized from aqueous acetic acid to obtain the pure compound identical to that of Example 3.

Example 28 N "-cyano N-oxydo-1 pyridinio-4 N1-tert-pentyl guanidine

A suspension of 2.31 g (10 mmol) of, N "-cyano N-tert-pentyl N'-pyridyl-4 guanidine in 40 ml of water is stirred at 0 ° C /? / # '·' ·· 12 by adding 3.60 g of potassium persulfate in portions to.

| r obtain a fluid suspension. After 5 h at 0 ° C., the mixture is left | warm to room temperature and continue stirring \. · 'J overnight. The mixture is cooled to 0 ° C, the crude product is separated by filtration and washed with water. By precipitation, · selective at pH 1.3 and recrystallization from acetic acid | aqueous, the pure compound is obtained identical to that of Example 2.

! Mp: 247 ° C (decomposition).

I - Example 29 S, Λ. , 10 Capsules; - Manufacturing of 100,000 capsules

Fl. Ί “™" “Mi -rr- I (P 1 368 ................................. 1,000 kg F 'i (îi (Lactose ................................. 10,000 kg- t] j_5 (Polyvinylpyrrolidone. .. ....... 0.200 kg | (Deionized water .......................... 1,000 kg n. (Silica, colloidal .. .................... 0.050 kg \ III. (I 20 (Magnesium stearate .................. 0.100 kg.; I mix in a planetary mixer. I. the granules of I are moistened with II. The wet mixture is passed through a sieve having 1.5 mm mesh openings. wet granules in a "fluid bed" at 60 ° C. The dry granules are passed through a sieve with 0.8 mm mesh opening and the sieved granules are lubricated with III.

We fill, capsules of size n ° 4 with a load l of 113.5 mg of granules per capsule which corresponds to 10 mg of / j Pl 368 per capsule, / j / f! 'ijjj *' -i 13 tf "

Example 30 Tablets

Manufacture of 100,000 tablets (P 1,368 ................................... 1,000 kg 5 I (Starch corn ............................ 2,250 kg (Lactose ................ .................... 10.825 kg v (Polyvinylpyrrolidone ...................... 0.300 kg II ((Deionized water ............................ 1,500 kg 10 (Talc ............. ......................... 0.500 kg (III (Magnesium stearate ................. .... 0.075 kg (Colloidal silica ........................ 0.050 kg

I is mixed in a planetary mixer. The granules of I are moistened with II. The wet mixture is passed through a screen having 1.5 mm mesh openings. The sieved granules are dried in a "fluid bed" at 60 ° C. The dry granules are passed through a sieve with 0.8 mm mesh opening. and the sieved granules are lubricated with III.

The granules are compressed into tablets weighing 0.105 g.

Punch size: 7 mm, flat circular tablets with a beveled edge.

Hardness of the tablets: 4-5 kp.

Of course, various modifications can be made by those skilled in the art to the devices or methods which have just been / have been described only by way of nonlimiting examples without / departing from the scope of the invention.

Claims (12)

4, N "-cyano N-oxydo-1 pyridinio-4 N'-trimethyl-1,2,2 ii" I propyl guanidine; and its salts as defined in claim 1. | 5. N "-cyano N-Oxydo-1 pyridinio-4 N'-tert-pentyl <ii guanidine, and its salts as defined in claim 1. 6. N-benzyl N" -cyano N'-oxydo-1 4-pyridinio guanidine; "And its eels as defined in claim 1, 7. N "-cyano N- (1-ethyl-1-methylpropy) N'-oxydo-1 1 pyridinio-4 guanidine; and its salts as defined in claim 1. 8, Process for producing a compound of formula I according to claim 1, characterized in that a compound / of formula II is oxidized to a compound of formula 1 according to the reaction / following scheme: //. If; %. '15. · · «N J \ -NH-C-NH-R-> 0 <- {^ —NH-C-NH-R W X-CN ^ I-CN II I 5 where R has the same definition as above, the oxidation being carried out in an appropriate medium for a sufficient time and at a temperature suitable for carrying out the reaction, then the compound thus obtained is recovered as is or in the form of a salt as defined in claim 1 . 9. Method according to claim 8, characterized in that a mineral or organic acid is used as an oxidizing agent. 10. Process according to claim 9, characterized in that the perboric, peracetic, perbenzoic, m-chloroperbenzoic, perchloric, peroxymonosulfuric acid or persulfates are used as oxidizing agent. 11. Method according to claim 9, characterized in that molybdenum, tungsten, vanadium, manganese or chromium are used in a high or maximum oxidation state in the form of an oxide, an acid or of a salt of such an oxide, as an oxidizing agent. 12. Method according to claim 8, characterized in. that the oxidizing agent is also used as the reaction medium. 13. The method of claim 8, characterized in that perhydrol is used as an oxidizing agent with Isopropanol as the reaction medium and sodium tungstate as catalyst. 14. Method according to claim 8, characterized in that the oxidation is carried out by electrolytic oxygenation. 15. New drugs useful in particular as antihypertensives characterized in that they contain as active product at least one of the compounds according to any one of the preceding claims or their pharmaceutically acceptable salts. • 16. New drugs according to claim 15, characterized in that they additionally contain, as active product, a β-adrenergic blocker, a diuretic, reserpine or Ι'α-me- / thyldopa. /) / Λ '·>' 16 17. Medicines according to claim 15, characterized in that they are packaged for the administration of • amounts corresponding to approximately 0.5 mg b 500 mg of the active product by enteral or parenteral route, Drawings: ...... plates Λ & pages of which ........ Λ ...... cover sheet ..... description pages .......... 3— pages of claim τ _______ descriptive abstract V Luxembourg, je Charles München i · t! · · I! w. t * * I ·! , · I. , I: l 4