CA1060442A - Pyridazinium compounds and a process for their production - Google Patents

Abstract

ABSTRACT OF THE DISCLOSURE

The present invention relates to new pyridazinium compounds of the general formula (I):

(I) where R1 is hydrogen, R2 denotes -NH2, R3 is hydrogen, R4 denotes the radical -SR6, R6 being an alkyl of 1 to 12 carbon atoms or the radical

Description

` ` 106044Z o . z . 31,560 ~, , Thi9 iS a diYisional application of Canadian application N. 181,003, filed September lZ, 1973. ~he present invention relates to new pyridazinium compounds and their production. These COmpOlXnd 9 are of pharmacological interest.
In DOS 1,912,941 6-alkoxypyridazinium compounds are said to have valuable pharmacological properties. Furthermore~ pyri-dazinium compounds are known for example as starting materials for pesticides and dyes from DOS 2,003,461 o~ U.S Patent 3,510,488.
The quaternization of pyridazines into pyridazinium compounds is de~cribed in an article in Acta Chem. Scand., 21 (1967~, 1067 to 1080, and the reaction of 6-chloropyridazinium compounds with amines i8 described in Volume 23 (1969), 2534 to 25~6.
he present invention provide~ a process for the produc-tion of ~ovel pyridazinium compound~ o~ the general formula (I):
Rl l R3 ~ R4 Y (I) where Rl is hydrogen, R2 denotes -NH2, R3 i~ hydrogen, R4 denotes the radical -SR6, R6 being an alkyl of 1 to 12 carbon ato~s, or the r~dical -N Rll , the individual radicals Rll being identical or different and denoting hydrogen, alkyl of 1 to 6 carbon atoms, or both radicals-Rll, together with the nitrogen atom, denoting a pyrrolidine, piperidine or morpholine ring, R5 iE
phenyl or a lower alkyl, particularly methyl or trifluoromethyl;
and ye is an a~ion o~ a pharmaceutically acceptable strong in~rganic or organic acid, wherein in a starting compound of the ormula tII):

~C
~ffl ....

~ 106~44Z o.z. ~1,560 Rl ~ R~ ye (II) Hal where ~1, R2, R3, R5 and ye have the above meanings and Hal is chlorlne or bromine, the chlorlne or bromine is replaced by reacting the compound with a thioalcohol of 1 to 12 carbon atoms in the presence of an agent which binds hydrogen chloride, or by reacting the compound with an approprlate sodium or potassium mercaptide, or by reactlng the compound with an amine of the formula:
Rll ~Rll , .
where the radicals Rll have the above meanings, in the presence or absenae Or a solvent at elevated temperature.
R4 prererably denotes the radical -SR6, R6 being an alkyl Or l to 6 aarbon atoms, or the radical -N~Rll , the individual radlcals R being ldentlaal or dir~erent and denoting hydrpgen, alkyl of 1 to 6, partlaularly 1 to 4, aarbon atomsJ or the two radlcals Rll together denoting tetramethylene, pentamethylene or ~-oxapentametby~ne.
In the compounds whlch can be obtalned by the process Or the i~entlon,the meaning particularly preferred ~or R5 is phenyl and the meaning partiaularly pre~erred for R4 are alkylthio, the alkyl being a lower alkyl, particularly methyl or ethyl, pyrrolldino and dialkylamino, the alkyl being a lower alkyl.
The starting aompound of rormula (II) may be obtained by ahlo-rination o~ a pyrldazone by the method descrlbed in DOS 2,016,691.
~The starting ¢ompounds may also be obtained as described by H.Lundt and P.Lunde ln Acta Chem. Scand~, 21 (1967), 1067 to 1080 by qua-ternlzatlon o~ appropriately substltuted pyrldazlnes.
For the rea¢tion ~or exchanging the halogen in the 6-positlon Or the pyridazlnium compound with a mercaptan or amine, the startlng ¢ompound ls dlssolved or suspended in an inert solvent, ror example aaetonitrlle, or ln an excess of reactant or solution of the same, base whl¢h binds hydrogen hallde, such as pyrldlne, trlethylamine,

-2-106~442 o.zO ~1,560 calls~lc soda solution, calcium hydroxide and sodium carbonate solu-tion, is added if necessary and the whole ls heated to a temperature of from 40 to 170C and preferably from 70 to 120C.
The production of 6-alkylthio-pyridazinium salts by reaction of the 6-halo compound wlth a mercaptan ls carried out as a rule by dlssolving or suspending the 6-halopyrldazlnium salt in an inert solvent, for examp'e acetonitrile, adding the equivalent amount of mercaptan and then the agent for blndlng hydrogen chlorlde, for example triethylamine, and stirring for half an hour to five hours at about 80C. The reaction product can be either obtained direct by suctlon flltratlon or recovered by concentra~tion of the reactlon mixture and adding water to the resldue, if deslred wlth perchloric acid. Water may itself also be used as solvent for the reactlon.
The compounds of the lnvention can be converted by conventional methods into the bases correspondlng thereto.
The new pyrldazlnium aompounds have valuable pharmacologlcal propertles. On test animals they have the effects, when administered perorally and lntravenously, of a prolonged increase in blood pres-sure, of showlng a reserpln antagonlsm and an antldepresslve or antl-Parkinson effect and are capable of increaslng excretion of urlne inrats. The antldepressive effect can be shown experimentally by suppresslon Or lld paralysls ln rats or mlce lnduced by tetrabena-zine and serpasll, an ln¢rease in the noradrenalln a¢tion in de¢apl-tated anlmals, a lowerlng of the body temperature and so on. Some members of the above class of compounds have also been found experl-mentally to be analgesic and antilnflammatory and to lnhlblt tremor lndu¢ed by tremorlne and phy ostlgmlne.
The new pyrldazinlum compounds, when adminlstered lntravenously to narcotlzed rats and cats, cause a powerful and prolonged lncrease ~0 in blood pressure ln doses of from 0.1 to 1 mg/kg. The noradrenalln pressor ef~ect ln pithed rats is conslderably increased by thls dosage. The clrculatory effects can be detected particularly clear-ly ln the oase o~ l-phenyl-4-amlno-~-methyl(and ethyl)mercaptopyrl-106~)44Z
o.z. 31,560 dazinium methosul~ate (or hydrogen sul~ate)O In the case of thesecompounds lncreased diuresis occurs a~ter 50 mg/kg p.o.
An antireserpin or antitetrabenazine e~ect can be demonstrated at a dosage of up to 10 mg/kg p.o. in mice in the case o~ the new pyridazlnium compounds because both ptosis and motlllty lnhlbltion are æuppressed. In the case of some o~ the pyridazlnium compounds there are also analgesic and antlinflammatory effects.
The ef~ects on the circulation in cats (Table 1), the e~fects on reserpin-induced ptosis in mice (Table 2) and neuropharmacolo-glcal e~fects ln mlce (Tables ~ to 5) are collected in the follow-ing Tables ~or some of the pyridaæinlum compounds.
Comparatlve investigations of some pyridazinium derivatives on the clr¢ulatlon o~ cats (Table 1) Method:
, Cat~ o~ both sexes in the welght range ~rom 1.3 to 3.7 kg are narcotlzed wlth hexabarbital sodlum (EVIPAN-SODIUM - reglstered Trade Mark) at 200 mg/kg s.c., ~urther narcotlc being given i~ ne-aessary. The anlmals breathe spontaneously. Pressure measurement ls carrled out by way of a Statham P2~Db-recorder in the A. remoralis.
The pulse frequency ls determined by means o~ a ratemeter (Eka-Puls., Messrs. HSE, Hugstetten, Germany) as a peak-to-peak lnte~ra-tlon ~rom the R-R distan¢e o~ the ECG. Perlpheral ~low ls determined electromagneti¢ally (Statham, Multlflow, m 4000) externally on the femoralls ln the vlcinity o~ the inguinal llgament.
The in~ection of the substances takes place ln increaslng dosage (three dose~; per anlmal)into a V. saphena.
Solvent: physiologlcal co~mon salt solutlon.
Concentratlon: 10 ~.

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1~6044Z
o . z . ~1, 560 Explanatlon o~ Tables 3 to 5:
Materlal:
The investlgations are carried out on female NMRI mice in the body weight range from 17 to 25 g. The test substances are adminis-tered orally; the volume administered ls 10 ml/kg body weight. The substanoe o~ Table 3 ls dissolved ln water in each case J those in Tables 4 and 5 are suspensions in 5% aqueous carboxymethylcellulose.
Methods:
(a) Coordlnatlon test on the rotatlng rod:
At 30, 60, 120 and 240 mlnutes post appllcatlonem (p.a.) the animals are reglstered whlch cannot keep thelr hold on the rod ro-tatlng at 10 rpm ~or two mlnutes (anlmals whlch fall).
(b) Maxlmum electrlc shock:
The anlmals are shocked by way of aural electrodes at 30 and 120 minu~e~ p.a.
Duration Or shoak: 0.2 ~eoond.
Frequenay: 50 pulses/second.
Strength o~ ~hock: 20 mllllamperes, sinus pulse.
The number of anlmals whioh do not react wlth a tonlc stretch-lng spasm, and ~atallty ln shoak are determlned.(a) Pentetrazole spasm:
Thlrty mlnutes a~ter admlnlstratlon o~ the test substance the anlmals reaelve 82.5 mg/kg o~ pentetrazole s.c. The number o~ anl-mals whl¢h do not rea¢t wlth spasms wlthln slxty mlnutes (spasm .
protectlon) and ~atallty ln shock are determlned durlng thls perlod.
(d) Barblturate slee~ perlod:
Thlrtg mlnutes a~ter the test substance has been admlnlstered the animals recelve an lntravenous lnJection o~ hexobarbital (82.5 .
mg/kg). The sleep perlod determlned ls the tlme whloh elapses untll ~0 reoocurrenoe Or the reflex to rlse, and under sleep prolongatlon there ls glven the number o~ anlmals havlng twloe the sleep period o~ the oontrols.

1 0 60 44Z o.z. 31,560 (e) Toxlc~
The number of animals which die within up to twenty-four hours p.a. is determined when groups of ten animals are kept in cages and in one case when kept separate.
Evaluatlon:
.. _........................................................... ~
In Tables 1 to 5 the number of reagents and the size of the group o~ anlmals or, where posslble, the mean value and the mean error (x + sx) are glven.
The new compounds are also important intermedlates for dyesJ
photosensltlzers, for growth regulators, for pestlcides and for pharmaceutical products.
The followlng pyridazlnium compounds of the general formula (I) are glven by way of example:
l-phenyl-4-amlno-6-methylmercaptopyridazinlum methosulfate, l-phenyl-4-amlno-6-ethylmercaptopyridazlnlum hydrogen sulfate, l-phenyl-4-amino-6-dimethylaminopyridazlnium perchlorate, l-phenyl-4-amino-6-pyrrolldlnopyrldazlnlum perchlorate, l-phenyl-4-amlno-6-morpholinopyrldazlnlum perchlorate, l-phenyl-4-amlno-6-plperldlnopyrldazlnlum perchlorate, and 1-phenyl-4-amlno-6-n-butylaminopyridazlnlum perchlorate.
The parts glven ln the following Examples are by welght.

24.4 parts of 1-methyl-4-amlno-6-chloropyrldazinium perchlorate ln 250 parts of acetonltrile ls stlrred wlth 10 parts of ethylmer-; ¢aptan and 10 parts of trlethylamlne for four hours at 50 to 60C.
A~ter the solvent has been dlstilled off, the resldue is washed with 100 parts of water. 18.3 parts (67.9% of theory) of l-methyl-

4 amlno-6-ethylmercaptopyridazinium perchlorate is obtained;
C7H1204N3SClJ m~lting point 136 to 137C after having been recrys-tallized from al¢ohol.

~0 37.1 parts of 1-phenyl-4-ammonium-6-chloropyridazinlum diper-chlorate in 200 parts of acetonitrile is stirred with 20.2 parts of la~rylmercaptan. 10 parts of triethylamine is added in the course of `"- 10~iO442 O.Z. 31,560 thirty minutes and the whole is stirred for two hours at 80C. A~ter the solvent has been distilled of~ and the residue has been treated with 100 parts of water, 32 parts (74.5~ o~ theory) of 1-phenyl-4-amlno-6-dodecylmercaptopyrldazinium perchlorate is obtained;
C22H~404N~SCl, meltlng point 95 to 9~C after having been recrys-tallized ~rom cyclohexane.

15.3 parts o~ 1-phenyl-4-amlno-6-chloropyrldazlnium perchlorate ls dlssolved ln 250 parts o~ water at 80 to 90C. 9.3 parts of anlllne ls added and the whole ls stlrred for one hour at 95 to 100C. After coollng, 12 parts (66.4% of theory) o~ 1-phenyl-4-amino-6-anlllnopyrldazinlum perchlorate is obtalned, C16H1504N4Cl, melt-ing polnt 164 to 166C after havlng been recrystalllzed from water.

12.5 parts (73.5% o~ theory) o~ 1-phenyl-4-amino-6-pyrrolldino-pyrldazlnSum perahlorate, C14H1704N4Cl, melting point 209 to 211C
2~ter having been re¢rystalllzed ~rom water, ls obtained~emethod des¢rlbed ln Example 3 using 7.1 parts Or pyrrolldine.

10 parts (56.3% o~ theory) Or l-phenyl-4-amino-6-morpholino-pyrldazinlum perahlorate, C14H1705N4Cl, meltlng point 150 to 152C
arter ha~lng been re¢rystallized rrom water, is obtained by the method described in Example 3 uslng 8.7 parts o~ morpholine.

12 parts (67.8% o~ theory) o~ 1-pheny1-4-amlno-6-piperidino-pyrldazinlum perchlorate, C15H1904N4Cl, meltlng point 137 to 139C
a~ter havi~g been re¢rystallized ~rom water, ls obtalned by the meth~d de~cribed in Example 3 using 8.5 parts of piperldlne.

9 parts (52.7% of theory~ o~ 1-phenyl-4-amlno-6-n-butylamlno-pyridazinlum perchlorate, C14H1904N4Cl, meltlng polnt 150 to 152C
after havlng been recrystallized ~rom a 1:1 mixture o~ water and methanol, is obtalned by the method desoribed ln Example 3 using 5.5 par~s of n-butylamine. -13-,........... . - - ~ . ... . .

Claims (4)

1. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:
   
   l. A process for the production of a pyridazinium compound of the general formula (I):
   
   (I) where R1 is hydrogen, R2 denotes -NH2, R3 is hydrogen, R4 denotes the radical -SR6, R6 being an alkyl of 1 to 12 carbon atoms, or the radical the individual radicals R11 being identical or different and denoting hydrogen, alkyl of 1 to 6 carbon atoms, or both radicals R11, together with the nitrogen atom, denoting a pyrrolidine, piperidine or morpholine ring, R5 is phenyl or a lower alkyl and y.THETA. is an anion of a pharmaceutically acceptable strong inorganic or organic acid, wherein in a starting compound of the formula (II):
   
   (II) where R1, R2, R3, R5 and y.THETA. have the above meanings and Hal is chlorine or bromine, the chlorine or bromine is replaced by react-ing the compound with a thioalcohol or 1 to 12 carbon atoms in the presence of an agent which binds hydrogen chloride, or by reacting the compound with an appropriate sodium or potassium mercaptide, or by reacting the compound with an amine of the formula:
   
   where the radicals R11 have the above meanings, in the presence or absence of a solvent at elevated temperature.
2. 2. A process as claimed in claim 1 for the production of 1-phenyl-4-amino-6-dimethylaminopyridazinium perchlorate, wherein 1-phenyl-4-amino-6-chloropyridazinium perchlorate is reacted with dimethylamine.
3. 3. A process as claimed in claim 1 for the production of 1-phenyl-4-amino-6-pyrrolidinopyridazinium perchlorate, wherein 1-phenyl-4-amino-6-chloropyridazinium perchlorate is reacted with pyrrolidine.
4. 4. A process as claimed in claim 1, wherein the lower alkyl represented by the radical R in the general formula (I) is selected from the group consisting of methyl and trifluoromethyl.