CA1177080A - N"-cyano-n-1-oxido-4-pyridinio-n'-substituted guanidine compounds - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

Processes are provided herein for producing new compounds with the general formula I

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, 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 effects.

Description

~ ~t~ 3 The present invention relates to processes for preparing a series of new antihypertensive compounds, and to the compounds so formed.
In a previous patent specification published, e.g., as German Offenlegungsschrift 25 57 438 (1976) or ~.S. Patent No. 4,057,636, the antihypertensive effect of certain 2-, 3-, or 4-pyridyl 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 above-identified compounds generally have high potency, it is - desirable to provide compounds having additional advantages, e.g., superior pharmacokinetic properties.
Thus, an object of one aspect of this inveniton is the provision of novel antihypertensive copounds and processes for making them.
The new compounds of one aspect of this invention have the general formula I N-CN

O ~ H-C-NH-R 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, carbocyclic aryl or aralkyl, aryl meaning unsubstituted or substituted pherlyl or naphthyl, and the alkyl moiety of aralkyl having from l to 6 carbon atoms.
More particularly, R may represent a rnethyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl radical, or one of the isomeric pentyl radicals, e.g., the pentyl, isopentyl, tert-pentyl and neopentyl radical, or one of the isomeric hexyl radicals, e.g., the neohexyl, 1,2,2-trimethylpropyl and l-ethyl-l-methylpropyl radical, or one of the isomeric heptyl radicals, e.g., the l,l-diethylpropyl and 1,1,3-trimethylbutyl radicals, or corresponding alkenyl radicals, phenyl, ~7~

p-chlorophenyl, 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 R carbon atoms are valuable for the purpose specified below.
In the case where compounds of aspects of this invention contain one or more asymmetric carbon atoms, these compounds exist in several stereoisomeric forms. The present invention, in another of its aspects, comprises the production of all such stereoisomers and mixtures of the same.
The compounds of aspects of this invention are weak bases, but - form salts with strong organic or inorganic acids, among which the non-toxic, pharmaceutically acceptable acids are appropriate, e.g., the hydro-halides, sulphuric or nitric acids, or methanesulphonic acid .
Specific preferred compounds of aspects of this invention include the following:
(a) N"-cyano-N-l-oxido-4-pyridinio-N'-1,2,2-trimethylpropyl-guanidine;
(b) N"-cyano-N-l-oxido-4-pyridinio-N'-tert-pentylguanidine;
(c) N-benzyl-N"-cyano-N'-l-oxido-~l-pyridinioguanidine;
(d) N"-cyano-N-1-ethyl-1-methylpropyl-N'-1-oxido-~i-pyridinio-guanidine;
(e) a compound of the formula I

O ~ -N ~ -~H-C-~H-R

wherein R is 3 i-C3H7 .3~

n-CLsH9 1 C4Hg t-C~Hg i-C5Hll ne-C5Hll CHEt2 C(Me2) (CH2)2CH3 C ( 1`~1 e ~ ) C H~l e ~;, -- --CH(~e)CH2C~e2 CH(Et)CHMe2 CEt3 C(~e~)CH~CH~le~
C (?~e2 ) CH2C~[e3 CH(,~e)(CH2)3CHGMe2 p-Cl-C6H4-or 6 5 2 2 (f) N"-cyano-N-1--oxido-4-pyridinio-N'-1,2,2-tri.methylpropyl-guanidine;
(g) N"-cyano-N-I-ethyl-l.-methylpropyl /-N ~ -1-OX1dO-4 guanidine;
(h) N-benzyl-N"-cyano-N-l-oxido-4-pyridinioguanidine;
(i) N"-cyano-N-l-oxido-4-pyridinio-N'-tert-pentylguanidine.
By one aspect of this invention, therefore, a process is pro-vided for producing a compound of formula I

`I3~

O ~ -N ~ H--C-NH-R

or.the tautomeric forms thereof in which R stands for a straight or branched, saturated or unsaturated, aliphatic hydrocarbon radical havinp, from 1 to 8 carbon atoms, mono- or bicyclic, carbocyclic a}yl or aralkyl;
and salts thereof with non-toxic, pharmaceutically acceptable salts, which process comprises: oxidizing a compound of formula 1I to a com-pound of formula I according to the following reaction scheme:

N ~ H-C--NH-R ~ 0~'--~ H-C-NH-R
N-C~ N-C~
II I

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 thereaction; and thereafter recovering the compound so formed as such or in the form of a salt as defined above.
By a variant thereof, R represents a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl radical, one of the isomeric pentyl radicals, selected from the pentyl, isopentyl, telt-pentyl and neopentyl radical, one of the isomeric hexyl radicals, selec~ed from the neohexyl, 1,2,3-trimethylpropyl and l-ethyl-l-methylpropyl radi-cals, one of the isomeric heptyl radicals, selected from the l,l-diethyl-propyl and 1,1,3-trimethylbutyl radical, or corresponding alkenyl radicals, phenyl, p-chlorophenyl, naphthyl, benzyl, or phenethyl radicals.
By another variant, the non-toxic, pharmaceutically acceptable salts are from strong organic or inorganic non-toxic, pharmaceutically acceptable acids selected from hydrohalides, sulphuric acid, nitric acid, 7~

and methanesulphonic acid.
By a further variant, the oxidizing agent is an inorganic or organic peracid.
By a further variant, the oxidizing agent is selected from perboric, peracetic, perbenzoic, m-chloroperbenzoic, perchloric acid, peroxymonosulfuric acid and persulfates.
By a further variant, the oxidizing agent is molybdenum, tung-sten, vanadium, manganese, or chromium in a high or highest oxidation state in the form of an oxide or acid or salt of such acid.
By a further variant, the oxidizing agnet is also used as the reaction medium.
By a further variant, the oxidizing agent is perhydrol (hydrogen peroxide), with isopropanol as the reaction medium and sodium tungstate as the catalyst.
By yet another variant, the oxidation is perEormed by way of electrolytic oxygenation.
By specific preferred variants of this invention, processes are provided for the preparation of:
(a) N"-cyano-N-l-oxido-4-pyridinio-N'-1,2,2-trimethylpropyl-guanidine which comprises oxidizing N"-cyano-N-4-pyridyl-N'-1,2,2-tri-methylpropylguclnidine with m-chloroperbenzoic acid in an isopropanol solvent;
(b) N"-cyano-N-oxido-~i-pyridinio-N'-tert-pentylguanidine which comprises oxidizing N"-cyano--N-tert-pentyl-N'-4-pyridylguanidine with m-chloroperbenzoic acid in an ethanol solvent;
(c) N-benzyl-N"-cyano-N'-oxido-4-pyridinioguanidine which com-prises oxidizing N-benzyl-N"-cyano-N'-4-pyridylguanidine with m-chloro-perbenzoic acid in an ethanol solvent;

.~'7'7~
(d) N"-cyano-N-l-ethyl~ nethylpropyl-N'-l-oxido-4-pyridinio-guanidine which comprises oxidi~ing N"~cyano-N-l-ethyl-l-methylpropyl-N'-4-pyridylguanidine with m-chloroperben~oic acid in an isopropano solvent;
(e) a compound of the formula O ~---N ~ N-CN

wherein R is n~C3H7 n~C4H9 ' -C4H9 t -C4H9 n- C SHl 1 neo-C SH
CHEt 2 C(Me2) (C~2)2CH3 C (~e2 ) CH~e2 CH(Me)CH2CH~e2 CH(Et)CHMe2 CEt3 C(Me2)CH2CHMe2 C(~e2)CH2CMe3 CH(Me)(CH2) 3CHMe2 p-~,l-C6H4-or 6 5 2 2 S~

which comprises oxidizing a respective compound of the formula Il ~H-C-NH-R
N-C~
II

wherein R is as defined above with m-chloroperbenzoic acid in an ethanol - or isopropanol solvent.
(f) N"-cyano-N-l-oxido-4-pyridinio-N'~1,2,2-trimethylpropyl-guanidine which comprises oxidizing N"-cyano-N-4-pyridinio-N'-1,2,2-tri-methylpropylguanidine with m-chloroperbenzoic acid in a chloroform solvent;
(g) N"--cyano-N-l-ethyl-l-methylpropyl-N'-l-oxido-4~pyridinio-guanidine which comprises oxidizing N"-cyano-N-l-ethyl-l-methylpropyl-N'-4-pyridylguanidine with hydrogen peroxide in glacial acetic acid;
(h) N-benzyl-N"-cyano-N-l-oxido-4-pyridinioguanidine which com-prises oxidizing N-benzyl-N"-cyano-N'-~i-pyridylguanidine with hydrogen peroxide in hydrochloric acid containing a sodium tungstate catalyst;
and (i) N"-cyano-N-]-oxido-4-pyridinio-N'-tert-pentylguanidine which comprises oxidizing N"-cyano-N-tert-pentyl-N'-4-pyridylguatlidine with potassium persulfate in water.
The oxygenating process can be performed by well-known proce-dures. Thus, for instance, inorganic and organic peracids, e.g., perboric acid, peracetic acid, perbenzoic acid, m-chloro-perbenzoic acid, perchloric acid, peroxymonosulfuric acid, or persulfates, may be mentioned as illus-trating 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 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 may be performed in a suitable solvent or reaction medium, e.g., an inert medium as chloroform for a sufficient time and at an adequate ~emperature with a view to accomplishing the desired conver-sio~, usually at a temperature from 0-30C. In an appropriate embodirnent the peracids may be used as the solvent and thus may 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-perben~oic acid is appropriately used as the oxygenating 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 embodi-ment, the oxygenation can be performed by way of electrolytic oxygenation.
The starting materials of formula ~I 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 pre-paration of compounds of formula II as described in the above mentionedDOS 25 57 438 can be exposed to an oxygenation process as that described hereinbefore, and thereafter as the corresponding ~-oxides be converted into the desired compounds of formula I of aspects of the present inven-tion by the processes described in the said DOS 25 57 438. The compounds of formula I may by conventional procedures be transformed into their acid salts.
In the processes 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 startin~ material, whereafter the resulting mixture may be subjected to a racernate resolution, e.g., by crystallization of a suitable salt with an optically active, strong acid, in a known manner.
Although the above-identified known compounds generally have a remarkably high potency, the compounds of aspects of the present invention have been found to have certain advantages over them. The compounds of aspects of this invention are similarly strong antihypertensives, but they are superior in their 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 compound of aspects of this invention than is the case with the above mentioned compound, and the effect is of longer duration.
The reason for this may at least in some cases be that the com-pounds of aspects of this invention under the influence of oxidoreductases are partially converted to the corresponding more potent pyridyl compounds of formula II
~ TH-C-~I_R II

N-C~

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-l-oxido-4-pyridinio-N'-1,2,2-tri-methylpropylguanidine (P 1368) and N"-cyano-N-4-pyridyl-N'-1,2,2-tri-methylpropylguanidine (P 1134), respectively, after oral administration of 3 mg/kg of P 1368 to dogs.

_ 9 _ '7~

Table _~
l Dog No. l ¦ Dog ~o. 2 Hours a~ter administration P 1368 P 1134 P 1368 P 1134 , ng/mlng/ml ng/ml ng/ml . _ -- = _ 1 63 ~ ~2 33 `~ 29, ~38 3 2~4 l~ 4~/ lO/0 ~ ~4~ 8~1 ~12 101 6 288 c`16 460 748 . 7 279 747 357 630 8 ~71 6~9 ~81 ''3 24 126 ~6 10.4 _ A similar in vivo conversion of P 1368 to P 1134 has been observed in human volunteers.
The compounds of aspects of this invention are of low toxicity and have been shown to exert a strong and prolonged antihypertensivc effect in various animal species when administered enterally or paren-terally, 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 biocon-version to the corresponding pyridyl analogs of formula II.
Thus, it has surprisingly been found that compounds of aspects of this invention have a favourable therapeutic index by enteral as well as parenteral administration, relieving hypertensive conditions and being well-tolerated compounds which in preliminary experiments have not shown any adverse effects.

¢~8~

The compounds of aspects of this in~ention are int~nded for use in pharmaceutical cornpositions which are useful in the treatment of hypertension and similar conditions.
Tllese 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 sustained release preparations.
The cornpositions may ~urther contain other therapeutically active compounds applied in the treatment of hypertension and similar conditions, for instance diuretics~ reserpine, a-meth~
dopa, and in particular ~-adrenergic blockers.
The composi-tions can be worked up -to various pharma-ceutical forms o:E presentation, e.g., tablets, pills, dragees, capsules, sustained release tablets, suspensions, suppositories, injection medicine, containing the com-pounds of formula I or their atoxic salts.
In human therapy, the compounds and their salts can conveniently be admin-istered (to adults) in dosage units con-taining not less -than 0.5 mg and up -to 500 mg, preferably from 5 to ~50 mg.

By the terrn "dosage unit" is mean~ a unitary, i.e. a single dose which is capable of being administered to a patient, and which ma~ be readily handled and packed, re-maining as a physically stable unit dose comprising either '7~3~3q3 the active material as such or a mixture of it with solid or liquid pharmaceutical diluents or carriers.
In the form of dosage units, the cornpounds may be administered once or more times a day at appropriate inter-vals, always depending, however, on the condition of the patient, and in accordance with the prescription made by the medical practitioner.
The compounds of aspects of this invention shall be administered in such doses that the desired activity is achieved without simultaneous secondary effects.
In human therapy, the compounds and their salts of aspects of this invention can conveniently be administered (to adults) in a daily dose from 5 mg and 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 rng/kg body weight.
The in~ention will now be further-described in the following non-limiting Exarnples:

E.Yample l N"-Cvano-N-l~oxido-4-~yridinio-N'~1.2,~-trimethvl~ropvl-guanidine A suspension of anhydrous N"-cyano-N-4-pyridyl-N~--1,2,2_trimethylpropylguanidine (10.0 g ; 40 mmol) in iso-propanol (60 ml) was stirred at 0 C, while m-chloroperbenzoic acid (goo,b 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 ( 00 ml), and the mixture was filtered and washed with ether to leave a crude product. ~urther purification was accomplished by stirring with acetone (75 ml) and filtration.
The solid residue was subjected to selec~ive precipi-tation by sol~ation in excess 1 N aqueous hydrochloric acid and adjustment of the pH to 1.3 by addition of solid sodium acetate.
~ he pure crystalline product was collected b~ filtration washed with water and air-dried.
Mp.: 242_24~ C (dec.) IR(KBr): showed strong bands at 2180 cm 1 and at 1560~1620 cm 1.
The ~MR spectrum ((CD3)2SO) showed signals at ~ = 0.93 (s, 9H), 1.10 (d, J-7 Hz, 3H), 3.93 (q, J-7 Hz, lH), 7.28 (bd, 2H), 7.40 (bs, lH), 8.15 (bd, 2H), 9.50 (bs, lH) ppm. Tetra-methylsilane was used as internal reference.

4~

The compound has been administered orally to conscious dogs previously made hypertensive according to the method of Goldblatt et al. (J. Exp. ~ed. 59, 347, (1934)) at the doses of 3.0 and 10.0 mg/kg. A fall of the blood pressure o~ 42 + 12 mmHg and 79 ~ 16 mmHg (mean * SEM, 3 animals/each dose) respectively has been obser~ed. The peak effect was obtained 3-4 hrs after dosing and a hypotensive effect was still present 8 hrs after dosing.
In normotensive dogs 1.0 and 3.0 mg/kg of the above compound intravenously administered caused a fall of the blood pressure of 15 7 mmHg and 28 + 9 mmHg (mean + SEM, 3 animals/each dose) respectivelv. The peak fall of the blood pressure occurred about 10 mins after dosing. The hypotensive effect vanished 2 hrs later.

E~ample 2 N"-Cvano-N-l-oxido-4-pyridlnio-N'-tert-pentvlguanidine A suspension of N"-cyano-~ tert-pentvl-~-4-pyridyl-guanidine (2.31g; 10 mmol) in ethanol (13 ml) was stirred at 0C, while sodiu~ bicarbona~e (1.70 g; ~0 mmol) and then m-chloroperbenzoic 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 ths 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 1550-60 cm 1.

Example -Benzvl~ cvano N'-l-oxido-4-~vridinioguanidine N-Benzyl-N"-cyano-N'-4-pyridylguanidine ~1.04 g; 4 mmol) was suspended in ethanol (~ ml). While stirring at 0 C, sodium bicarbonate (67~ mg; 8 mmol) and m-chloroperbenzoic acid (90~0 pure) (1.~4 g; 8 mmol) ~-ere added. Stirring at VC was continued for 10 hours. After storage in the refrigerator for 3 days, ~he miYture was cooled to approx. -20 C and fiItered~ Washings with small amounts of cold ethanol and with ether left the crude product. The pure crystalline subs~ance ~-as obtained by dissolving in e.~cess lN hydro-chloric acid, charcoaling and adjusting the pH with sodium acetate to approx. 1.3, causing select~ve precipitation of the N-oxide.
IR (KBr): Strong absorption bands at 2180, 1640-30, and 1580 cm 1.
The NMR spectrum ((CD3)2S0) showed signals at ~ _ 4.46 (bd, ~H), 7.29 (bd, 2H), 7.32 (s, 5H), 8.10 (bd, 2H), 8.18 (bt, lH), 9.48 (bs, lH) ppm. Tetramethylsilane was used as internal reference.

~'7~ 3 Example 4 N"-Cvano-N-l-ethv}-l-methylDro~yl-N'-l-oxido-4-Pvridinio-guanidine N"-Cyano-N-l-ethyl-l-methylpropyl-N'-4 pyridylguanidine (2.45 g; lO mmol) was suspended in isopropanol (20 ml).
While stirring at 0 C, sodium bicarbonate (840 mg; 10 mmol) and m-chloroperbenzoic acid (900,h 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 bv filtration and washed with small quantities of cold isopropanol and with ether. ~urlher work-up of the residue was performed by consecutive stirrings with water (13 ml) and acetone (20 ml), with intermediate filtration, and final washing with acetone and ether.
The pure crystalline compound was obtained by dis-solution in eYcess l ~ hydrochloric acid (25 ml) and selective precipitation by adjustment of the pH to appro~.
1.5 with solid sodium acetate.
l~p: 229-30C (dec.).
IR (KBr): Strong absorption bands at 2165, 1610-16009 and 1565-1550 cm 1.

~1l7'7~ 3 E~Yamples 5 - 24 B~ following the procedure described in E~ample 1 or , but using compounds of formula II, in which R has the meanings defined in the table below instead of being the 1,2,2-tri-methylpropyl radical, the compounds of formula I, in which R has the meanings defined in the table below are prepared.
Table . ~ N-CN
0~ N . ~H-C-NH-R- I
- \=/ , EY. REx. R
- ._ . . _ , n--C3X7 lg C(M~2)CH~Ie2 6 i-C3H7 16 CH(Me)CH2C~Me2 7 n~C4H9 L7 CH(Et)CHMe2 8 i-C4Hg 18 CEt3 ~ t-C4Hg 19 C(~e2)CH~CHMe2 g 11 20 C~Me2)CH2CMe3 11 5 11 21 CH(~e)(CH2)3CHMe2 12 neo-C5Hll 22 C5H3 13 CHEt2 23 p-Cl-C6H4-14 C(Me2)(CH2)2CH3 2L~ 6 3 2 CH2 ~ . .. _ __ .__ . .. _ Exam~le ? ~
N"-C~vano-N-l-o~ido-4-Pyridinio-N'-1,2,2-trimethvl~ropvl-uanidine Anhydrous N"-cyano-N-4-pyridyl-N'-1,2,Z-trimethyl-propylguanidine (2.45 g; 10 mmol) was suspended in chloro-form (25 ml~. While stirring at 0 C 6 portions of m-chloro-perbenzoic acid '(90% pure) (a total of 2.50 g; 13 mmol) were added over 1 hour. The mixture was kept at 0C overnight and evaporated in vacuo at 0 C~ The residue was triturated with 3 portions of ether (25 ml) - wi~h intermittent decant-ings - and the crude product ~vas obtained by filtration and several washings with ether. It ~-as dlssolved 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.
.~Ip.: 242-243C (dec.) Example ~6 N"-Cvano-N-l-eth~rl-l-meth~ roDvl-N I -l-oxido-4-~vridlni.o~
uanidine A solution of N"-cyano-N-l-ethyl-l-methylpropyl-N'-4-20 -pyridylguanidine (2.45 g; 10 mmoL) in glacial acetic acid (50 ml) was stirred at 10 C, while 300,h aqueous hydrogen pero~ide (5 ml) was added. The mi~ture was heated at 60 C
for 5 hours and evaporated in vacuo at 25C. The pH of the residue was brought to neutral by addition of aqueous sodium carbonate, and the crude product was filtered o~f and washed ~ 7~

with water. Selective precipitation (cf. Example 1) at pH
1.3 and recrystallization ~rom aqueous acetic acid afforded the pure pro~uct.
Mp.: 229-230 C (dec.).

Exam~e 27 N-Benzyl-NI'-cvano-N-l-oxido-4-pyridinioguanidine N-Benzyl-N"-cyano~N'-4-pyridylguanidine (2.~1 g; 10 mmol) was dissolved in 1 N hydrochloric acid ~20 ml; 20 mmol), con-taining sodium tungstate, dihydrate (200 mg). With stirring at 0C, 30,~ aqueous hydrogen peroxide (2.0 ml; ~0 mmol) was gradually added, and the mixture was then allowed to assume room temperature. ~fter 6 hours, the pH was adjus~ed to l.S, 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.

Exam~le 28 ~"-Cvano-~-l oxido-4-~ridinio-N~-tert-pentvl~uanidine A suspension of N 1l -cyano-~-tert-pe~tyl-~-4-pyridyl-guanidine (2.31 g; 10 mmol) in water (40 ml) was stirred at 0 C, while potassium persulfate (3.60 g) was added portion-wise, resulting in a thin suspension. A~ter 5 hours at 0C
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 recrystalliza-tion from aqueous acetic acid yielded the pure compound, identical with that of Example 2.
~Ip.: 247C ~dec.)~

3~C3 E.Yamp1e 2 Capsule anufacture of 100,000 ca~sules ~P 1368 ........................... 1.000 kg Lactose .......... 0...................... 10.000 kg (Polyvinylpyrrolidone ......... .... 0.200 kg Water, deionized ................... .1.000 kg ~Silicone dioxide, colloidal ........ Ø050 kg III ( (~agnesium stearate ................. Ø100 kg .~ I ln a planetary mi~Yer. Wet-granulate I with II.
Pass the we~ mix through a screen with 1.~ mm apertures.
Dry the wet granulate 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 III.
Fill the-granulate in capsules size 4 with a target weight of 113.~ mg granulate per capsule, corresponding to 10 mg P 1368 per capsule..

7~ g3 Exam~le 30 Tablet Manufacture of 100.000 tablets ~P 1368 .............................. 1.000 kg I ~Corn starch ........................ 2.250 kg (Lactose ................... A ~ i0 ~ 825 kg Polyvinylpyrrolidone ................ 0.300 kg II
Water, deioniæed .................... 1.500 kg (Talc ......... ,.......................... 0.500 kg 10 III ~Magnesium stearate ................... 0.075 kg ~ilicone dioYide, colloidal ......... 0.0;0 kg Mix I in a planetary mi~er. Wet granulate I with II.
Pass the wet miY through a screen with 1.5 mm apertures.
Dry the screened granulate in a "fluld bed" at 60 C. Pass the dry granulate through a screen with o.8 mm apertures and lubricate the screened granulate with III.
Compress the granulate into table~s with target weight:
0.150 g.
Punch size: 7 mm, circular, flat tablets with bevelled edge.
Tablet hardness: 4-5 kp.

Claims (33)

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A process for producing a compound of formula I

I

or the tautomeric forms thereof in which R stands for a straight or branched, saturated o} 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, which process comprises: oxidizing a compound of formula II to a com-pound of formula I according to the following reaction scheme:

II I

in which R is as defined above, the oxidatian being performed in a suitable medium for a sufficient time and at an adequate temperature with a view to accomplishing thereaction; and thereafter recovering the compound so formed as such or in the form of a salt as defined above.

2. The process of claim 1 wherein R represents a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl radical, one of the isomeric pentyl radicals, selected from the pentyl, isopentyl, tert-pentyl and neopentyl radical, one of the isomeric hexyl radicals, selected from the neohexyl, 1,2,3-trimethylpropyl and 1-ethyl-1-methylpropyl radi-cals, one of the isomeric heptyl radicals, selected from the 1,1-diethyl-propyl and 1,1,3-trimethylbutyl radical, or corresponding alkenyl radicals, phenyl, p-chlorophenyl, naphthyl, benzyl, or phenethyl radicals.

3. The process of claim 1 wherein said non-toxic, pharmaceuti-cally acceptable salts are from strong organic or inorganic, non-toxic pharmaceutically acceptable acids selected from hydrohalides, sulphuric acid, nitric acid, and methanesulphonic acid.

4. A process according to claim 1, wherein said oxidizing agent is an inorganic or organic peracid.

5. A process according to claim 4, wherein said oxidizing agent is selected from perboric, peracetic, perbenzoic, m-chloro-perbenzoic, perchloric acid, peroxymonosulfuric acid and persulfates.

6. A process according to claim 4, wherein said oxidizing agent is molybdenum, tungsten, vanadium, manganese, or chromium in a high or highest oxidation state in form of an oxide or acid or salt of such acid.

7. A process according to claim 1, wherein said oxidizing agent is also used as the reaction medium.

8. A process according to claim l, wherein said oxidizing agent is perhydrol (hydrogen peroxide), with isopropanol as the reaction medium and sodium tungstate as the catalyst.

9. A process according to claim 1, wherein the oxidation is per--formed by way of electrolytic oxygenation.

10. A process for the preparation of N"-cyano-N-1-oxido-4-pyridinio-N'-1,2,2-trimethylpropylguanidine which comprises oxidizing N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine with m-chloroper-benzoic acid in an isopropanol solvent.

11. A process for the preparation of N"-cyano-N-oxido-4-pyridinio-N'-tert-pentylguanidine which comprises oxidizing N"-cyano-N-tert-pentyl-N'-4-pyridylguanidine with m-chloroperbenzoic acid in an ethanol solvent.

12. A process for the preparation of N-benzyl-N"-cyano-N'-oxido-4-pyridinioguanidine which comprises oxidizing N-benzyl-N"-cyano-N'-4-pyridylguanidine with m-chloroperbenzoic acid in an ethanol solvent.

13. A prcoess for the preparation of N"-cyano-N-1-ethyl-1-methylpropyl-N'-1-oxido-4-pyridinioguanidine which comprises oxidizing N"-cyano-N-1-ethyl-1-methylpropyl-N'-4-pyridylguanidine with m-chloroper-benzoic acid in an isopropanol solvent.

14. A process for preparing a compound of the formula I

I

wherein R is n-C3H7 i-C3H7 n-C4H9 i-C4H9 t-C4H9 n-C5H11 i-C5H11 neo-C5H11 CHEt2 C(Me2)(CH2)2CH3 C(Me2)CHMe2 CH(Me)CH2CHMe2 CH(Et)CHMe2 CEt3 C(Me2)CH2CHMe2 C(Me2)CH2CMe3 CH(Me)(CH2)3CHMe2 p-C1-C6H4-or . C6H5CH2-CH2-which comprises oxidizing a respective compound of the formula II

wherein R is as defined above with m-chloroperbenzoic acid in an ethanol or isopropanol solvent.

15. A process for the preparation of N"-cyano-N-1-oxido-4-pyridinio-N'-1,2,2-trimethylpropylguanidine which comprises oxidizing N"-cyano-N-4-pyridinio-N'-1,2,2-trimethylpropylguanidine with m-chloro-perbenzoic acid in a chloroform solvent.

16. A process for the preparation of N"-cyano-N-1-ethyl-1-methyl-propyl-N'-1-oxido-4-pyridinionguanidine which comprises oxidizing N"-cyano-N-1-ethyl-1-methylpropyl-N'-4-pyridylguanidine with hydrogen peroxide in glacial acetic acid.

17. A process for preparing N-benzyl-N"-cyano-N-1-oxido-4-pyridinioguanidine which comprises oxidizing N-benzyl-N"-cyano-N'-4-pyridylguanidine with hydrogen peroxide in hydrochloric acid containing a sodium tungstate catalyst.

18. A process for preparing N"-cyano-N-1-oxido-4-pyridinio-N'-tert-pentylguanidine which comprises oxidizing N"-cyano-N-tert-pentyl-N'-4-pyridylguanidine with potassium persulfate in water.

19. A compound of formula I

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 o carbon atoms, mono- or bicyclic, carbocyclic aryl or aralkyl;
and salts thereof with non-toxic, pharmaceutically acceptable acids, when-ever prepared by the process of claim 1 or by its obvious chemical equi-valent.

20. The compound of claim 19 wherein R represents a methyl, ethyl, propyl, butyl, isobutyl, sec-butyl, or tert-butyl radical, one of the isomeric pentyl radicals, selected from the pentyl, isopentyl, tert-pentyl and neopentyl radicals, one of the isomeric hexyl radicals, selected from the neohexyl, 1,2,2-trimethylpropyl and 1-ethyl-1-methylpropyl radi-cals, one of the isomeric heptyl radicals, selected from the 1,1-diethyl-propyl and 1,1,3-trimethylbutyl radical, or corresponding alkenyl radicals, phenyl, p-chlorophenyl, naphthyl, benzyl, or phenethyl radicals, whenever prepared by the process of claim 2 or by its obvious chemical equivalent.

21. The compound of claim 19 in the form of a non-toxic, pharma-ceutically acceptable salt of a strong organic or inorganic, non-toxic, pharmaceutically acceptable acid selected from hydrohalides, sulphuric acid, nitric acid and methanesulphonic acid, whenever prepared by the pro-cess of claim 3 or by its obvious chemical equivalent.

22. The compound of claim 19, whenever prepared by the process of claims 4 or 5 or by their obvious chemical equivalents.

23. The compound of claim 19, whenever prepared by the process of claims 6 or 7 or by their obvious chemical equivalents.

24. N"-cyano-N-1-oxido-4-pyridinio-N'-1,2,2-trimethylpropyl-guanidine, whenever prepared by the process of claim 10 or by its obvious chemical equivalent.

25. N"-cyano-N-1-oxido-4-pyridinlo-N'-tert-pentylguanidine, whenever prepared by the process of claim 11 or by its obvious chemical equivalent.

26. N-benzyl-N"-cyano-N'-1-oxido-4-pyridinioguanidine, whenever prepared by the process of claim 12 or by its obvious chemical equivalent.

27. N"-cyano-N-1-ethyl-1-methylpropyl-N'-1-oxido-4-pyridinio-guanidine, whenever prepared by the process of claim 13 or by its obvious chemical equivalent.

28. A compound of the formula I

wherein R is n-C3H7 i-C3H7 n-C4H9 i-C4H9 t-C4H9 n-C5H11 i-C5H11 neo-C5H11 CHEt2 C(Me2)(CH2)2CH3 C(Me2)CHMe2 CH(Me)CH2CHMe2 CH(Et)CHMe2 CEt3 C(Me2)CH2CHMe2 C(Me2)CH2CMe3 CH(Me)(CH2)3CHMe2 p-Cl-C6H4-or C6H5CH2-CH2-whenever prepared by the process of claim 14 or by its obvious chemical equivalent.

29. N"-cyano-N-1-oxido-4-pyridinio-N'-1,2,2-trimethylpropyl-guanidine, whenever prepared by the process of claim 15 or by its obvious chemical equivalent.

30. N"-cyano-N-1-ethyl-1-methylpropyl-N'-1-oxido-4-pyridinio-guanidine, whenever prepared by the process of claim 16 or by its obvious chemical equivalent.

31. N-benzyl-N"-cyano-N-1-oxido-4-pyridinioguanidine, whenever prepared by the process of claim 17 or by its obvious chemical equivalent.

32. N"-cyano-N-1-oxido-4-pyridinio-N'-tert-pentylguanidine, whenever prepared by the process of claim 18 or by its obvious chemical equivalent.

33. The compound of claim 19, whenever prepared by the process of claims 8 or 9 or by their obvious chemical equivalents.