GB2105331A - N-(1-oxido-4-pyridyl)-guanidines - Google Patents

Abstract

The present invention relates to new compounds with the general formula I <IMAGE> or the tautomeric forms thereof in which R stands for a straight or branched, saturated or unsaturated, aliphatic hydrocarbon radical having from 1 to 8 carbon atoms, mono- or bicyclic, carbocyclic aryl or aralkyl, aryl meaning unsubstituted or substituted phenyl or naphthyl, and the alkyl moiety of aralkyl having from 1 to 6 carbon atoms. The new compounds are of low toxicity and have been shown to exert a strong and prolonged antihypertensive effect in various animal species when administered enterally or parenterally, without giving rise to other pharmacodynamic effect.

Description

SPECIFICATION Chemical compounds The present invention relates to a series of new anti-hypertensive compounds, to methods of preparing them, to compositions containing them, to dosage units of the compositions which are useful in the human and vetinary medical practice, and to methods for treating patients with said compounds and compositions.

The new compounds have the general formula I

or the tautomeric forms thereof in which R stands for a straight or branched, saturated or unsaturated, aliphatic hydrocarbon radical having from 1 to 8 carbon atoms, mono- or bicyclic, carbocylic aryl or aralkyl, aryl meaning unsubstituted or substituted phenyl or naphthyl, and the alkyl moeity of aralkyl having from 1 to 6 carbon atoms.

More particularly, R may represent a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, secbutyl, or tert-butyl radical, or one of the isomeric pentyl radicals, e.g. the pentyl, isopentyl, tertpentyl and neopentyl radical, or one of the isomeric hexyl radicals e.g. the neohexyl, 1,2,2trimethylpropyl and 1-ethyl-i -methylpropyl radical or one of the isomeric heptyl radicals e.g. the 1,1-diethylpropyl and 1,1,3-trimethylbutyl radical, or corresponding alkenyl radicals, phenyl, pchlorophenyl, naphthyl, benzyl, or phenethyl, and salts thereof with non-toxic, pharmaceutically acceptable strong inorganic and organic acids.

In particular, compounds of formula I in which R stands for a straight or branched alkyl radical having from 4 to 7 carbon atoms are valuble for the purpose specified below.

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

The compounds of the invention are weak bases, but form salts with strong organic or inorganic acids among which the nontoxic, pharmaceutically acceptable acids are appropriate, e.g. the hydrohalides, sulphuric or nitric acids, or methane-sulphonic acids.

In a previous patent specification published e.g. as German Offenlegungsschrift 25 57 438 (1976) or U.S. Patent No. 4 057 636 the antihypertensive effect of certain 2-, 3-, or 4-pyndyl cyanoguanidines has been described. Further studies of compounds within the scope of that specification have been published in J. med. chem 21, 773 (1978).

Although the said known compounds generally have a remarkable high potency the compounds of the present invention have been found to have certain advantages over them.

They are similarly strong antihypertensives, but they are superior in the pharmacokinetic properties. For instance, the antihypertensive activity is easier to control because the fall of the blood pressure has a more gradual onset with the present compounds than is the case with the above mentioned compounds, and the effect is of longer duration.

The reason for this may at least in some cases be that the compounds of the invention under the inflence of oxidoreductases are partically converted to the corresponding more potent pyridyl compounds of formula II

and accordingly can be regarded as pro-drugs of the latter.

This conversion will appear from the following table which shows the serum concentrations of N"-cyano-N-1 -oxido-4-pyridinio-N '-1, 2,2-trimethylpropylguanidine (P 1 368) and N"-cyano-N-4- pyridyl-N'-1 ,2,2-trimethylpropylguanidine (P1134), respectively, after oral administration of 3 mg/kg of P1368 to dogs.

TABLE Hours after Dog No. 1 Dog No. 2 administration P1368 P1134 P1368 P1134 ng/ml ng/ml ng/ml ng/ml 1 65 < 5 52 < 5 2 330 s5 297 238 3 224 15 457 1070 4 201 348 579 1000 5 245 851 512 1015 6 288 816 460 748 7 279 747 357 630 8 271 659 281 438 24 126 96 10.4 A similar in-vivo conversion of P 1 368 to P 11 34 has been observed in human volunteers.

The new compounds of the invention are of low toxicity and have been shown to extert a strong and prolonged antihypertensive effect in various animal species when administered enternally or partenterally, without giving rise to other pharmacodynamic effects. It is believed that these compounds exert their antihypertensive action through an effect on the peripheral blood vessels, either as such or after bioconversion to the corresponding pyridyl analogs of formula II.

Thus, it has suprisingly been found that the present compounds have a favourable therapeutic index, by enteral as well as parental administration, relieving hypertensive conditions and being will-tolerated compounds which in preliminary experiments have not shown any adverse effects.

The invention also relates to a method for the preparation of the above described compounds comprising an oxidation of a compound of formula Il to a compound of formula I according to the reaction scheme:

in which R is as definded above.

The oxygenating process can be performed by well-known methods. Thus, for instance inorganic and organic peracids such as perboric acid, peracetic acid, perbenzoic acid, m-chloto- perbenzoic acid, perchloric acid, peroxymonosulphuric acid, or a persulphate, may be mentioned as illustrating oxygenating agents. Also molybdenum, tungsten, vanadium and manganese, chromium, and similar elements from these groups of the periodic system in a high or the highest state of oxidation are usable as oxygenating agents or catalytic agents in the form of their corresponding oxides or acids, or salts of such acids.

The reaction is performed in a suitable soivent or reaction medium, e.g. an inert medium auch as chloroform for a suffieienct time and at an adequate temperature with a view to accomplishing the desired conversion, usually at a temperature from 0-30"C. In an appropriate embodi ment the peracids may be used as the solvent and thus be used in excess. In other circumstances the oxygenating agent is used in equimolar amounts or substantially equimolar amounts which may be added successively during the operation.

In an appropriate embodiment the oxygenation is performed with perhydrol (hydrogen peroxide 30%) in isopropanol as the reaction medium using sodium tungstate as the catalytic agent. In another embodiment m-chloro-perbenzoic acid is appropriately used as the oxygenate ing agent with e.g. chloroform, ethanol or isopropanol as the reaction medium. Further, a mixture of perhydrol and glacial acetic acid can be used as oxygenating agent and as reaction medium as well. In a further embodiment the oxygenation can be performed by way of electrolytic oxygenation.

The starting materials of formula Il are known from the above mentioned DOS 25 57 438 and/or the J. Med.Chem. 21, 773 (1978).

In still another embodiment the intermediates used in the preparation of compounds of formula II as described in the above mentioned DOS 25 57 438 can be exposed to an oxygenation process as that described hereinbefore, and thereafter as the corresponding N oxides be converted into the desired compounds of formula I of the present invention by the methods described in the DOS 25 57 438. The compounds of formula I may by conventional methods be transformed into their acid salts.

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

Alternatively, a racemate may be used as starting material, whereafter the resulting mixture may be subjected tp a racemate resolution, e.g. by crystallization of a suitable salt with an optically active, strong acid, in known manner.

It is a further object of the present invention to provide pharmaceutical compositions which are useful in the treatment of hypertension and similar conditions.

Said compositions can contain from 0.1 and up to 99% of the compounds of formula I mixed with organic or inorganic, solid or liquid carriers and/or auxiliary agents suitable for preparation of various pharmaceutical forms of presentation for oral or enteral administration, including subtained release preparations.

The compositions may further contain other therapeutically active compounds applied in the treatment of hypertension and similar conditions, for instance diurectics, reserpine, < X-methyl- dopa, and in particular ssadrenergic blockers.

The composition of the present invention can be worked up to various pharamaceutical forms of presentation, such a tablets, pills, dragees, capsules, sustained release tablets, suspensions, suppositories, injection medicine, containing the compounds of formula I or their atoxic salts.

In the human therapy, the compounds and their salts can conveniently be administered (tq adults) in dosage units containing not less than 0.5 mg and up to 500 mg, preferably from 5'to 250 mg.

By the term "dosage unit" is meant a unitary, i.e. a single dose which is capable of being administered to a patient, and which may be readily handled and packed, remaining as a physically stable unit dose comprising either the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.

In the form of the dosage units, the compounds may be administered once or more times a day at appropriate intervals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner.

Another object of the invention resides in the selection of a daily dose of the compounds of the invention, which dose can be administered so that the desired activity is achieved without simultaneous secondary effects.

In the human therapy, the compounds and their salts can conveniently be administered (to adults) in a daily dose from 5mg up to 1000 mg, preferably from 20-500 mg, calculated as the base of formula I, and in the veterinary practice correspondingly in daily doses from 0. 07 to 14 mg/kg body weight.

The invention will now be further described in the following non-limiting Examples: Example 1 N"-Cyano-N- 1-oxido-4-pyridinio-N'- 1,2, 2-trimethylpropylguanidine A suspension of anhydrous N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine (10.0 g 40 mmol) in isopropanol (60 ml) was stirred at O"C, while m-chloroperbenzoic acid (90% pure) (31 g : 160 mmol) was introduced, resulting in a clear solution within 5 min. After storage at 0 C for 3 days the precipitate formed was removed by filtration. The filtrate was gently evaporated in vacuo at 0 C. The residue was stirred with ether (200 ml), and the mixtures wad filtered and washed with ether to leave a crude product.Further purification was accomplished bywstirring with acetone (75 ml) and filtration.

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

The pure crystalline product was collected by filtration washed with water and air-dried.

Mp.: 242-243'C (dec.) IR(KBr): showed strong bands at 2180 cm-1 and at 1560-1620 cm - The NMR sprectrum ((CD3)2SO) showed signals at 6 = 0.93 (s,9H), 1.10 (d, J = 7 Hz, 3H), 3.93 (q, J = 7 Hz, 1H), 7.28 (bd,2H), 7.40 (bs, 1H), 8.15 (bd, 2H), 9.50 (bs,lH) ppm.

Tetramethylsilane was used as internal reference.

The compound has been administered orally to conscious dogs previously made hypertensive according to the method of Goldblatt et al. (J. Exp. Med. 59, 347, (1934)) at the doses of 3.0 and 10.0 mg/kg. A fall of the blood pressure of 42 + 12 mmHg and 79 + 16 mmHg (mean i SEM, 3 Animals/each dose) respectively has been observed.The peak effect was obtained 3-4hrs after dosing and a hypotensive effect was still present 8 hrs after dosing.

In normotensive dogs 1.0 amd 3.0 mg/kg of the above compound intravenously administered caused a fall of the blood pressure of 1 5 i 7 mmHg and 28 j 9 mmHg (mean i SEM, 3 animals/each dose) respectively. The peak fall of the blood pressure occurred about 10 mins after dosing. The hypotensive effect vanished 2 hrs later.

Example 2 N "-Cyan o-N- I -oxido-4-pyridin io-N '-tert-pen tylguanidine A suspension of N"-cyano-N-tert-pentyl-N'-4-pyridyl-guanidine (2.31g; 10 mmol) in ethanol (13 ml) was stirred at 0 C, while sodium bicarbonate (1.70 g; 20 mmol) and then mchloroperbenzoic acid (90% pure) (3.85 g; 20 mmol) were introduced. The gradually thinning suspension was kept at 0 C with stirring and left overnight in the refrigerator. The formed precipitate was collected by filtration and washed with cold ethanol (10 ml) and ether. Finally, it was stirred with water (10 ml), filtered off, washed with water and air-dried to leave the crude product.

Selective precipitation by solvation in excess 1 N aqueous hydrochloric acid and adjustment of the pH to 1.3 with sodium acetate gave the pure, crystalline compound. Mp.: 247"C (dec.).

IR (KBr): absorption bands at 2170, 1620-1600, and 1550-60cm-1.

Example 3 N-benzyi-N "-cyano-N'- 1 -oxido-4-piridin iog uanidine N-Butyl-N"-cyano-N'-4-pyridylguanidine (1.40 g; 4 mmol) was suspended in ethanol (5 ml).

While stirring at 0 C, sodium bicarbonate (675 mg; 8 mmol) and m-chloroperbenzoic acid (90% pure) (1.54 g; 8 mmol) were added. Stirring at 0 C was continued for 10 hours. After storage in the refrigerator for 3 days, the mixture was cooled to approx. - 20 C and filtered. Washings with small amounts of cold ethanol and with ether left the crude product. The pure crystalline substance was obtained by dissolving in excess 1 N hydrochloric acid, treatment with charcoal and adjustment of the pH with sodium acetate to approx. 1.3, causing selective precipitation of the N-oxide.

IR (KBr): Strong absorption bands at 2180, 1640-30, and 1580 cm-'.

The NMR spectrum ((CD3)2SO) showed signals at S = 4.46 (bd, 2H), 7.29 (bd,2H), 7.32 (s,5H), 8.10 (b,2H), 8.18 (bt, 1 H), 9.48 (bs,1H) ppm. Tetramethylsilane was used as internal reference.

Example 4 N "-Cyano-N- 1-ethyl-i -meth ylpropyl-N'- 1 -oxido-4-pyridinioguanidine N '-Cyano-N-l-ethyl-l -methylpropyl-N '-4-pyridylguanidine (2.45 g; 10 mmol) was suspended in isopropanol (20 ml). while stirring at 0 C, sodium bicarbonate (840 mg; 10 mmol) and mchloroperbenzoic acid (90% pure) (3.85 g; 20 mmol) were added. The gradually thickening suspension was stirred at 0 C for a total of 14 hours and left in the refrigerator for 2 nights. The crude product was collected by filtration and washed with small quantities of cold isopropanol and with ether. Further work-up of the residue was performed by consecutive stirrings with water (15 ml) and acetone (20 ml), with intermediate filration, and final washing with acetone and ether.

The pure crystalline compound was obtained by dissolution in excess 1 N hydrochloric acid (25 ml) and selective precipitation by adjustment of the pH to approx. 1.5 with solid sodium acetate.

Mp: 229-30"C (dec.).

lR(KBr): Strong absorption bands at 2165, 1610-1600, and 1565-1550 cm-'.

Examples 5-24 By the following the procedure described in Example 1 or 2, but using compounds of formula II, in which R has the meanings defined inthe table below instead of being the 1,2,2trimethylpropyl radical, the compounds of formula I, in which R has the meaning defined in the table below are prepared.

Table

I Ex. R Ex. R 5 n-C3H, 15 C(Me2)CHme2 6 i-C3H7 16 CH(Me)CH2CHMe2 7 n-C4Hg 1 7 CH(Et)CHMe2 8 i-C4Hg 18 CEt3 a t-C4Hg 19 C(Me)CH2CHMe2 10 n-C5H" 20 C(Me2)CH2CMe3 11 i-CsH" 21 CH(Me) (CH2)3CHMe2 12 neo-C5H" 22 C6H5 :13 CHEt2 23 p-CI-C6H4- 14 C(Me2) (CH2)2CH3 24 C6H5CH2-CH2 Example 25 N"-Cyano-N- 1 -oxido-4-pyridinio-N'- 1,2, 24rimethylpropylguanidine Anhydrous N"-cyano-N-4-pyridiyl-N'-1,2,2-trimethylpropylguanidine (2.45 g; 10 mmol) was suspended in chloroform (25 ml).While stirring at O"C 6 portions of M-chloroperbenzoic acid (90% pure) (a total of 2.50 g; 1 3 mmol) were added over 1 hour. The mixture was kept at 0 C overnight and evaporated in vacuo at O"C. The residue was triturated with 3 portions of ether 825 miHvith intermediate decantings and the crude product was obtained by filtration and several washings with ether. It was dissolved in 8 parts of glacial acetic acid by gentle heating and precipitated by addition of 32 parts of water.

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

Mp.: 242-243"C (dec.).

Example 26 N"-Cyano-N- 1-ethyl- 1 -methylprnpyl-N'- 1 -oxido-4-pyridinioguanidine A solution of N"-cyano-N-1-ethyl-1-methylpropyl-N'-4-pyridylguanidine (2.45 g; 10 mmol) in glacial acetic acid (50 ml) was stirred at 10"C, while 30% aqueous hydrogen peroxide (5 ml) was added. The mixture was heated at 60"C for 5 hours and evaporated in vacuo at 25"C. The pH of the residue was brought to neutral by addition of aqueous sodium coarbonate, and the crude product was filtered off and washed with water. Selective precipitation (cf. Example 1) at pH 1.3 and recrystallization from aqueous acetic acid afforded the pure product.

Mp.: 229-230"C (dec.).

Example 27 N-Benzyl-N"-cyano-N- 1-oxido-4-pyridinioguanidine N-Benzyl-N"-cyano-N'-4-pyridylguanidine (2.51 g; 10 mmol) was dissolved in 1 N hydrochloric acid (20 ml; 20 mmol), containing sodium tungstate, dihydrate (200 mg). With stirring at O"C, 30% aqueous hydrogen peroxide (2.0 ml; 20 mmol) was gradually added, and the mixture was then allowed to assume room temperature. After 6 hours, the 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, identical with that of Example 3.

Example 28 N't-Cyano-N- 1-oxido-4-pyridino-N'-tert-pentylguanidine A suspension of N"-cyano-N-tert-pentyl-N'-4-pyridylguanidine (2.31 g; 10 mmol) in water (40 ml) was stirred at 0 C, while potassium persulphate (3.60 g) was added portion-wise, resulting in a thin suspension. After 5 hours at 0 C the mixture was allowed to heat 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. Selective precipitation at pH 1.3 and recrystallization from aqueous acetic acid yielded the pure compound, identical with that of Example 2.

Mp.: 247"C (dec.).

Example 29 Capsule Manufacture of 100,00 capsules (P 1 368 1.00 kg (Lactose 10.000 kg (Polyvinylpyrrolidone 0.200 kg II (Water, deionized 1.000 kg (Silicon dioxide, colloidal 0.050 kg Ill (Magnesium stearate 0.100 kg Mix I in a planetary mixer. Wet-granulated I with II. Pass the wet mix through a screen with 1.5 mm apertures. Dry the wet granulated in a "fluid bed" at 60"C. Pass the dry granulate through a screen with 0.8 mm apertures and lubricate the screened granulate with Ill.

Fill the granulate in capsules size 4 with a target weight of 11 3.5 mg granulate per capsule, corresponding to 10 mg P 1 368 per capsule.

Example 30 Tablet Manufacture of 100,000 tablets (P 1368 1.000 kg (Corn Starch 2.250 kg (Lactose 10.825 kg (Polyvinylpyrrolidone 0.300 kg II (Water, Deionized 1.500 kg (Talc 0.500 Ill (Magnesium Stearate 0.075 (Silicon dioxide, colloidal 0.050 kg Mix I in a planetary mixer. Wet granulate I with II. Pass the wet mix through a screen with 1.5 mm aperture. Dry the screened granulate in a "fluid bed" at 60do. Pass the dry granulate through a screen with 0.8 mm apertures and lubricate the screened granulate with III.

Compress the granulate into tablets with target weight: 0.1 50 g.

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

Tablet hardness: 4-5 Kp.

Claims (23)

1. A compound of formula I

or the tautomeric forms thereof in which R stands for a straight or branched, staturated, or unsaturated, aliphatic hydrocarbon radical having from 1 to 8 carbon atoms, mono- or bicyclic, carbocyclic aryl or aralkyl; and salts thereof with non-toxic, pharmaceutically acceptable salts.

2. A compound of formula I according to Claim 1, in which R is selected from the group consisting of straight and branched alkyl radicals having from 4 to 8 carbon atoms; and salts thereof as defined in Claim 1.

3. A compound of formula I according to Claim 1, in which R is selected from the group consisting of isobutyl, sec-butly, and tert-butyl radicals, the isomeric branched pentyl, hexyl, hepty!b,and octyl radicals; and salts thereof as defined in Claim 1.

4. N"-Cyano-N-1-oxido-4-pryidinio-N'-1,2,3-trimethylpropylguanidine; and salts thereof as defined in Claim 1.

5. N"-Cyana-N-1-oxido-4-pryidinio-N'-tert-pentylguanidine; and salts thereof as defined in Claim 1.

6. N-Benzyl-N"-cyano-N'-1-oxido-4-pryidinioguanidine; and salts thereof as defined in Claim 1.

7. N"-Cyano-N-(l -ethyl-l -methylpropyl)-N'-l -oxido-4-pyridinioguanidine; and salts thereof as defined in Claim 1.

8. A method for producing a compound of formula I of Claim 1, in which a compound of formula II is oxidized to a compound of formula I according to the following reaction scheme:

in which R is as defined above, the oxidation being performed in a suitable medium for a sufficient time and at an adequate temperature with a view to accomplishing the reaction; whereafter the compound thus obtained is recovered as such or in the form of a salt as defined in Claim 1.

9. A method according to Claim 8, in which an inorganic or organic acid is used as oxidizing agent.

10. A method according to Claim 9, in which perboric, peracetic, perbenzoic, m-chloroperbenzoic, perchloro acid, peroxymonosulphuric acid or a persulphate is used as oxidizing agent.

11. A method according to Claim 9, in which molybdenum, tungsten, vanadium, manganese, or chromium is used, in a high or highest oxidation state in form of an oxide or acid or salt of such acid, as oxidizing agent.

12. A method according to Claim 8, in which the oxidizing agent is used also as reaction medium.

1 3. A method according to Claim 8, in which perhydrol is used as oxidizing agent with isopropanol as reaction medium and sodium tungstate as catalyst.

14. A method according to Claim 8, in which the oxidation is performed by way of electrolytic oxygenation.

1 5. A composition containing as an active component at least one member selected from the group consisting of compounds of the formula I and salts thereof with non-toxic, pharmaceutically acceptable acids, together with solid or liquid pharmaceutical carriers and/or auxiliary agents.

16. A composition according to Claim 15, which contins at least 0.1% of the therapeutically active compound.

1 7. A composition containing as an active component at least one member selected from the group consisting of compounds of the formula I of claim 1 and salts thereof with non-toxic, pharmaceutically acceptable acids, in combination with other therapeutic compounds applied in the treatment of hypertension, besides the solid or liquid pharmaceutical carriers and/or auxiliary agents.

1 8. A composition according to claim 17, which as further therapeutic compound contains a ssadrenergic blocker, a diuretic, reserpine, or a-methyldopa.

1 9. A composition as claimed in anyone of claims 1 5 to 1 8 in whcih the composition is in the form of a dosage unit containing not less than 0.5 mg and up to 500 mg of a compound of formula I.

20. A composition as claimed in claim 19, wherein the dosage unit contains from 5 to 250 mg of compound of formula I.

21. A compound of formula I defined in claim 1 substantially as hereinbefore described in any one of Examples 1 to 28 of the foregoing Examples.

22. A method for producing a compound of formula I defined in claim 1 substantially as hereinbefore described in any one of Examples 1 to 28 of the foregoing Examples.

23. A pharmaceutical composition substantially as hereinbefore described in Example 29 or 30-of the foregoing Examples.