Novel pyridazinylhydrazones and method of administering same

Abstract

Pyridazinylhydrazones capable of lowering blood pressure have the formula ##STR1## wherein R.sup.1 is hydrogen, chlorine, alkyl having from 1 to 4 carbon atoms, methoxy, hydroxyl, carbamoyl or cyano;R.sup.2 is chloro; andK is a group having the formula ##STR2## wherein one of R.sup.3, R.sup.4, R.sup.5 or R.sup.6 is carboxyl or alkoxycarbonyl.

Description

This invention relates to new pyridazinylhydrazones and pharmaceutically acceptable salts thereof.

More particularly, this invention relates to new pyridazinylhydrazones having the formula I ##STR3## wherein R.sup.1 is hydrogen, chlorine, alkyl having from 1 to 4 carbon atoms, methoxy, hydroxyl, carbamoyl or cyano;

R.sup.2 is hydrogen, chlorine or NR.sup.7 R.sup.8, wherein R.sup.7 and R.sup.8 each can be hydrogen, alkyl having from 1 to 5 carbon atoms, or hydroxyalkyl having from 2 to 4 carbon atoms, or R.sup.7 and R.sup.8 together with the nitrogen atom to which they are attached form a morpholine, piperidine, piperazine or N-methylpiperazine ring; K is a group having the formula II or a group having the formula III ##STR4## wherein R.sup.3 is hydrogen, alkyl having from 1 to 10 carbon atoms, cycloalkyl having from 3 to 7 carbon atoms, trifluoromethyl, phenyl, phenyl substituted with chlorine atom, nitro or one or more methoxy groups, pyridyl or alkoxycarbonyl having from 1 to 4 carbon atoms in the alkoxy moiety; R.sup.4 and R.sup.5 each can be hydrogen, alkyl having from 1 to 4 carbon atoms or alkoxycarbonyl having from 1 to 4 carbon atoms in the alkoxy moiety; R.sup.6 is hydrogen, carboxyl or the group --CO.sub.2 R.sup.9, wherein R.sup.9 is alkyl having from 1 to 9 carbon atoms, hydroxyalkyl having from 2 to 4 carbon atoms, or cycloalkyl having from 3 to 7 carbon atoms, or R.sup.6 is --CONHNH.sub.2 or --CONH.sub.2, n is 0, 1, 2, 3, 4 or 5; Q is a mono- or bicyclic alkyl having from 3 to 10 carbon atoms; and R.sup.10 is H or an alkyl having from 1 to 6 carbon atoms, with the proviso that when R.sup.3 is hydrogen or an alkyl having from 1 to 6 carbon atoms, R.sup.4 and R.sup.6 both represent hydrogen, and n is 0 then R.sup.5 may not represent an alkyl having from 1 to 4 carbon atoms.

Preferred representatives of the compounds having the formula I are those pyridazinylhydrazones, in which

R.sup.2 is chlorine, bis(2-hydroxyethyl)amino, dibenzylamino or morpholino; R.sup.3 is methyl, phenyl or pyridyl; R.sup.4 and R.sup.5 are hydrogen or methyl; R.sup.6 is carboxyl, carboxylic acid ester group or carboxamide group; Q is a cyclohexane or bornane ring; R.sup.10 is methyl and n is 0, 1 or 2.

It is well known that in human and higher animal organisms noradrenaline is the most important blood pressure regulating agent (see S. M. Rapoport: Med. Biochemie, VEB Verlag Volk und Gesundheit, Berlin, 720 (1965)). Pathologically high blood pressure can therefore be decreased by inhibition of the biosynthesis of noradrenaline (O. Schier and A. Marxer: Arzneimittelforschung, Vol. 13., Birkhauser Verlag, Basel, p. 107 (1969)). The first step of this biosynthesis consists in the hydroxylation of tyrosine, wherein thyrosine-hydroxylase enzyme acts as a bio-catalyst, while in the third step dopamine is .beta.-hydroxylated in the presence of the dopamine-.beta.-hydroxylase enzyme as a bio-catalyst.

Now it has been surprisingly found that new pyridazinylhydrazone derivatives having the formula I unexpectedly show a considerable tyrosine-hydroxylase and dopamine-.beta.-hydroxylase inhibiting effect, thereby inhibiting the biosynthesis of noradrenaline and exerting a significant and long-lasting blood pressure lowering activity.

Compounds having the formula I and pharmaceutically acceptable salts thereof are prepared according to the invention by

(a) reacting a compound having the formula IV ##STR5## wherein R.sup.1 and R.sup.2 are as defined above with a ketone of the formula V or VI ##STR6## wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.10, Q and n are as defined above, to give compounds of the formula I, in which K stands for a group of the formula II or III, wherein R.sup.3, R.sup.4, R.sup.5, R.sup.6, R.sup.10, Q and n are as defined above; or

(b) reacting a compound having the formula IV, wherein R.sup.1 and R.sup.2 are as defined above, with an acid having the formula VII or VIII ##STR7## wherein R.sup.3, R.sup.4, R.sup.5, R.sup.10, Q and n are as defined above, and treating the thus-obtained acid having the formula IX or X ##STR8## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, R.sup.5, R.sup.10, Q and n are as defined above, or a reactive derivative thereof with an alcohol having the formula R.sup.9 OH, wherein R.sup.9 is as defined above--in case of preparing tertiary butyl esters with isobutylene or tertiary-butanol--or with hydrazine or ammonia to prepare compounds of the formula I, wherein K represents the group having the formula II or III wherein R.sup.3, R.sup.4, R.sup.5, R.sup.10, Q and n are as defined above and R.sup.6 is a CO.sub.2 R.sup.9, --CONHNH.sub.2 or --CONH.sub.2 group, wherein R.sup.9 is as defined above; or

(c) reacting a compound of the formula IV, wherein R.sup.1 and R.sup.2 are as defined above, with an ester having the formula XI

R.sup.3 --C.tbd.C--CO.sub.2 R.sup.9 (XI) wherein R.sup.3 and R.sup.9 are as defined above, to prepare a compound of the formula I, wherein K represents a group of the formula II, wherein R.sup.3 is as defined above, R.sup.4 and R.sup.5 each are hydrogen, n is 0 and R.sup.6 is a group having the formula --CO.sub.2 R.sup.9, wherein R.sup.9 is as defined above, and, if desired, converting a compound of the formula I obtained into an acid addition salt thereof formed with a pharmaceutically acceptable acid.

According to a preferred embodiment of the invention compounds of the formula IV and V or VI are transformed into compounds of the formula I by reacting the two reactants in water or an organic solvent, preferably in an ether, such as diethyl ether or tetrahydrofurane, lower aliphatic alcohols, or aromatic hydrocarbons, such as benzene, toluene, or xylene, at a temperature of 10.degree. C. to 140.degree. C. In some instances it is advantageous to add an acid catalyst, e.g. 4-toluenesulphonic acid or hydrochloric acid, to the reaction mixture.

Out of the starting materials having the formula IV the following compounds have been described in the literature:

3-chloro-6-pyridazinylhydrazine [Yakugaku Zasshi, 75, 778 (1955); C.A. 50, 4970b (1956)];

3,6-dichloro-4-pyridazinylhydrazine [Pharm. Bull., 5, 376 (1957)]; 3-pyridazinylhydrazine [Bull. soc. chim. France, 1793 (1959)]; 3-methyl-6-pyridazinylhydrazine [J. Pharm. Soc. Jap., 75, 776 (1955)]; 3-cyano-6-pyridazinylhydrazine [Hungarian Patent Specification No. 165,304]; and amino-substituted pyridazinylhydrazines [see for example J. Med. Chem., 18, 741 (1975)].

Other pyridazinylhydrazines encompassed by the formula IV, which are new according to the state of art are described hereinbelow with presentation of experimental results.

Compounds of the formula V are known in the art. The carboxylic acid esters may be prepared for instance by Grignard reaction of the corresponding cyano compound, or by alkoxycarbonylating the corresponding methyl ketone derivative [see J. Am. Chem. Soc., 63, 2252 (1941) and 67, 2197 (1945)]. Another known method for preparing compounds of the formula V consists in subjecting the corresponding mixed anhydrides to Grignard reaction [Tetrahedron, 33, 595 (1977)].

Acid amides and acid hydrazides can be obtained by reacting the corresponding carboxylic acid esters with suitable amines or hydrazine, respectively [see for example Chem. Ber., 35, 583 (1902); Beilsteins Handbuch der Organischen Chemie, 3, 676].

From compounds of the formula VI cycloalkanone derivatives substituted by an alkoxycarbonyl group in the 2-position are prepared by reacting a corresponding cycloalkanone with an alkyl oxalate in the presence of sodium alcoholate [see e.g. Org. Synth., II, 531].

Cycloalkanone-2-carboxamides are prepared by condensing a corresponding cycloalkanone with urea and subsequently hydrolysing the spiro-compound obtained with an acid [J. fur Prakt. Chemie, 318, 773 (1976)].

Those compounds of the formula VI in which R.sup.6 stands for hydrogen are commercially readily available cyclic ketones, such as camphor, carvone or 2-methylcyclohexanone.

Reaction of the compounds having the formula IV with acids having the formula VII or VIII to give acids of the formula IX or X is preferably carried out on the analogy of the preparation of compounds of the formula I when starting from compounds of the formula IV and V.

Starting compounds of the formulae VII and VIII are usually prepared by a mild alkaline hydrolysis of the corresponding carboxylic acid esters [see for instance J. Am. Chem. Soc., 81, 2598 (1959); Liebigs Ann., 699, 33 (1966) and 317, 98 (1901); Chem. Ber., 72, 919 (1939)].

Compounds having the formula IX or X are preferably transformed into compounds having the formula I as described hereinbelow.

When carboxylic acid esters are to be prepared, i.e. in the formula I K stands for a group of the formula II or III and R.sup.6 represents a CO.sub.2 R.sup.9 group, wherein R.sup.9 is as defined above, in the first step compounds of the formula IX or X are transformed into their acid chlorides by means of thionyl chloride. As a solvent an excess amount of thionyl chloride can be used, or the reaction can be conducted in a chlorinated hydrocarbon, such as chloroform or dichloroethane; or in a hydrocarbon, such as benzene. The acid chloride obtained is then reacted with an alcohol having the formula R.sup.9 OH or with an alkali metal alcoholate of same, preferably in an excess amount of the alcohol, at a temperature between 0.degree. C. and the boiling point of the alcohol.

When methyl or ethyl esters are to be prepared, one can proceed also by reacting an acid having the formula IX or X with methanol or ethanol containing gaseous hydrochloric acid.

When the preparation of an acid hydrazide is intended, i.e. in the formula I K represents a group having the formula II or III and R.sup.6 is a --CONHNH.sub.2 group, it is advisable to react a methyl or ethyl ester, prepared from a corresponding compound of the formula IX or X as described above, with hydrazine in a methanolic or ethanolic solution.

When an acid amide is to be prepared, i.e. in the formula I K stands for a group having the formula II or III and R.sup.6 is a CONH.sub.2 group, a methyl or ethyl ester, prepared from a corresponding acid having the formula IX or X as described above, is reacted with ammonia in a methanolic or ethanolic solution.

Esters of the formula XI usually are prepared by reacting suitable alkyl triphenylphosphoranilidene acetates with an acid chloride and subjecting the acylylide obtained to pyrolytic decomposition [Liebigs Annalen, 282 (1977)].

Compounds of the formula I are preferably converted into their acid addition salts by dissolving a base of the formula I for example in ether, methanol, ethanol or isopropenol and adding to the solution obtained a solution of the corresponding inorganic acid in methanol, ethanol or ether or of the suitable organic acid in methanol, ethanol, isopropanol, ether or ketone, dropwise, while cooling. The precipitate is filtered off and recrystallized when necessary.

Preferred representatives of the suitable inorganic acids are: hydrochloric acid, hydrogen bromide, sulphuric acid and phosphoric acid. Tartaric acid, maleic acid, fumaric acid, methanesulphonic acid, ethanesulphonic acid and 4-toluenesulphonic acid are advantageously used as organic acids.

In vitro tyrosine-hydroxylase inhibiting activity (TH inhibiting activity) of the new compounds according to the invention was tested by the method of Nagatsu [Anal. Biochem., 9, 122 (1964)] on rat adrenal homogenate. Radioactive tyrosine was purified by the method elaborated by Ikeda [J. Biol. Chem., 241, 4452 (1966)]. TH activity of the rat adrenal homogenate amounted to 0.64 .+-.8 nmoles/mg protein/60 min.

Dopamine-.beta.-hydroxylase inhibiting activity (DBH inhibiting activity) of the compounds according to the invention was tested on bovine adrenal (gland) preparations by a modified version of Nagatsu's method [B.B. Acta, 139 319 (1967)]. Specific activity of the bovine adrenal preparation was found to be 780 .+-.50 nmoles/mg protein/60 min.

Inhibiting effect of several compounds encompassed by the formula I in comparison with some known compounds is listed in the following Table I.

TABLE I______________________________________ Concentration of the Enzyme inhibitingExample test compound activity, %No. [mole/liter] TH DBH______________________________________ 3 10.sup.-4 100 80 10.sup.-5 75 012 10.sup.-4 100 84 10.sup.-5 85 1013 10.sup.-4 95 90 10.sup.-5 40 1015 10.sup.-5 100 88 50 3217 10.sup.-4 85 70 10.sup.-5 33 1018 10.sup.-4 100 88 10.sup.-5 50 3219 10.sup.-4 82 75 10.sup.-5 30 1020 10.sup.-4 100 100 10.sup.-5 50 8741 10.sup.-4 92 0 10.sup.-5 50 022 10.sup.-4 100 100 10.sup.-5 50 5623 10.sup.-4 -- 70 10.sup.-5 -- 5024 10.sup.-4 -- 100 10.sup.-5 -- 5028 10.sup.-4 0 90 10.sup.-5 0 7129 10.sup.-4 50 70 10.sup.-5 0 4730 10.sup.-4 50 70 10.sup.-5 0 2234 10.sup.-4 -- 100 10.sup.-5 -- 4037 10.sup.-4 -- 100 10.sup.-5 -- 4149 10.sup.-4 -- 66 10.sup.-5 -- 5050 10.sup.-4 -- 73 10.sup.-5 -- 052 10.sup.-4 65 30 10.sup.-5 40 055 10.sup.-4 -- 50 10.sup.-5 -- 062 10.sup.-4 -- 60 10.sup.-5 -- --64 10.sup.-4 36 50 10.sup.-5 10 065 10.sup.-4 -- 73 10.sup.-5 -- 44Fusaric acid 10.sup.-4 0 100 10.sup.-5 0 100D,L-.alpha.-methyl-4-hydroxy-phenyl- 10.sup.-4 100 0alanine 10.sup.-5 60 0______________________________________

Blood pressure lowering activity of the new compounds according to the invention was tested on spontaneous hypertensive rats (Wistar-Okamoto rats) following the method described in Arzn. Forsch., 6, 222 (1956). Systolic blood pressure of waking animals was measured in arteria caudalis 4, 24, 48 and 72 hours after the oral administration of the test compounds. The results obtained are set forth in the following Table II.

TABLE II______________________________________ Reduction in blood pressure, % Acute toxicityExample 50 mg/kg dose [LD.sub.50 ] on miceNo. 4 hours 24 hours mg/kg p.o.______________________________________10 -41* -26* <20017 -23 -13 30019 -8 -9 >20020 -25 -25 53023 -21 -8 20025 -33 -17 20026 -38 -29 20028 -29 -25 >20029 -30 -15 25030 -31 -14 25038 -34 -27 20043 -32 -18 20048 -33* -8* 20049 -22.sup.+ -13.sup.+ <20050 -28.sup.+ -30.sup.+ 20052 -21.sup..times. -9.sup..times. 40053 -32 -27 20055 -39.sup.+ -14.sup.+ >20056 -20.sup.+ 0.sup.+ >20057 -28* -16* 20062 -29 -26 20064 -25 -11 >20065 -18 -23 >200Fumaric -33 0 80 (i.p.)acid______________________________________ .sup..times. = 1.25 mg/kg * = 2.5 mg/kg .sup.+ = 20 mg/kg.

Out of the compounds tested the compounds prepared in Examples 10, 17, 20, 23, 25, 26, 28, 29, 30, 38, 43, 48, 49, 50, 52, 53, 55, 56, 57, 62, 64 and 65 showed a significant blood pressure lowering activity (.gtoreq.-15%). Effect of the compounds 29 and 30 lasted 72 hours when they were used in a dose of 50 mg/kg. This period lasted 48 hours when the dose employed was 20 mg/kg. Acute oral toxicity and consequently therapeutic index of these compounds tested on rats are also favorable.

Biochemical and pharmacological experiments show that a lasting and strong blood pressure lowering effect appears together with the strong enzyme inhibiting effect. Compounds of the formula I can be used in the therapy in a daily dose of 50 to 3000 mg.

Further details of the invention are given in the following non-limiting Examples.

EXAMPLE 1

1,7,7-Trimethyl-2-bicyclo[2,2,1]heptylidene-(3-chloro-6-pyridazinyl)-hydrazone

Method (a)

A mixture of 30.4 g. (0.2 moles) of camphor, 29 g. (0.2 moles) of 3-chloro-6-pyridazinylhydrazine, 500 ml. of ethanol and 50 ml. of glacial acetic acid is kept at boiling temperature for three hours. The solvent is then distilled off in vacuo, the evaporation residue admixed with 200 ml. of water and adjusted to neutral under cooling with a 10% sodium carbonate solution. The precipitate obtained is filtered off, washed to neutral with water and dried. Recrystallization from ethanol affords 37.8 g. (67.5%) of the named compound, melting at 103.degree. C. to 105.degree. C.

The hydrochloric acid salt of the product obtained is prepared by suspending the base in ether and saturating the suspension with gaseous dry hydrochloric acid. The precipitate formed is filtered off, washed with ether and dried. M.p. of the acid addition salt obtained: 178.degree. C. (decomposition).

Method (b)

A mixture of 3.04 g. (20 mmoles) of camphor, 2.9 g. (20 mmoles) of 3-chloro-6-pyridazinylhydrazine, 50 ml. of ethanol and 2 drops of a concentrated hydrochloric acid solution is boiled for one and a half hours. Thereafter following the procedure described in Method (a) 3.2 g. (57%) of the named compound melting at 102.degree. C. to 105.degree. C. are obtained.

Method (c)

In a flask equipped with a Dean-Stark water separator a mixture of 3.04 g. (20 mmoles) of camphor, 2.9 g. (20 mmoles) of 3-chloro-6-pyridazinylhydrazine, 70 ml. of benzene and 0.1 g. of 4-toluenesulphonic acid is boiled until the calculated amount of water is separated. Thereafter proceeding as described in Method (a) 3.3 g. (58.5%) of the named compound melting at 103.degree. C. to 105.degree. C. are obtained.

Compounds of the formula I and acid addition salts thereof which may be prepared by the above procedure are listed in the following Table III.

TABLE III______________________________________ MeltingExample point Yield*No. Compound (.degree.C.) (%)______________________________________2 2,2-Dimethyl-3-bicyclo- [2,2,1]heptylidene-B 168 (b)** 78.53 1,7,7-Trimethyl-2-bicyclo- [2,2,1]heptylidene-B 133 to 135 604 1-(2,6,6-Trimethyl-1-cyclo- hexenyl)-1-ethylidene-A 180 to 182 58.55 1-Methyl-4-isopropenyl-2- cyclohex-6-enylidene-A 137 to 138 576 1,7,7-Trimethyl-2-bicyclo- [2,2,1]heptylidene-[3-(4- methyl-1-piperazinyl)-6- pyridazinyl]hydrazine 201 to 204 40.57 1-(2-Bicyclo[2,2,1]hept- 5-enyl)-1-ethylidene-A 91 to 93 30.58 1-Methyl-4-isopropyl-3- cyclohexylidene-A 130 to 132 38.59 1-Methyl-4-isopropylidene- 3-cyclohexylidene-A 132 to 135 3210 Cyclohexylidene-D 159 to 161 42.511 2-(Ethoxy-carbonyl)-1- cyclohexylidene-D 58 to 60** 7912 Cyclohexylidene-B 134 to 136 1713 1-Phenyl-1-ethylidene-B 153 to 156 44.514 Cyclohexylidene-C 104 to 105 5815 2-Methyl-1-cyclohexylidene- A 115 to 118 6316 2,6-Dimethyl-1-cyclohexyli- dene-A 92 to 93 58.517 2-(Ethoxycarbonyl)-1-cyclo- hexylidene-A 115 to 117 55.518 2-Carboxy-1-cyclohexyli- dene-A 238 to 241 22.519 2-Carboxy-1-cyclohexyl- dene-B 208 to 209 18.5______________________________________ Remarks: A = 3chloro-6-pyridazinylhydrazone B = 3pyridazinylhydrazine C = 3,6dichloro-4-pyridazinylhydrazone D = 3morpholino-6-pyridazinylhydrazone * = yield values after recrystallization ** = HCl salt b = decomposition compounds 10, 12 and 14 are products in which Q is cyclohexane and R.sup.10 and R.sup.6 are H.

EXAMPLE 20

3-(Ethoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)hydrazone

Method (a)

A mixture of 4.35 g. (30 mmoles) of 3-chloro-6-pyridazinylhydrazine, 3.93 g. (30 mmoles) of ethyl acetacetate and 36 ml. of ethanol is stirred at room temperature for 8 hours and then allowed to stand overnight. Thereafter ethanol is evaporated in vacuo, the residue is triturated with ether, filtered and dried. 5.6 g. (72.5%) of the named compound are obtained, melting at 124.degree. C. to 127.degree. C.

The corresponding hydrochloric acid salt is prepared as described in Example 1, Method (a). Melting point: 143.degree. to 145.degree. C.

The compounds having the formula I listed in the following Table IV are prepared by the procedure described above.

TABLE IV______________________________________ MeltingExample point Yield*No. Compound (.degree.C.) %______________________________________21 1-(Methoxycarbonyl)-1-ethyli- dene-A 203 to 205 4122 3-(Ethoxycarbonyl)-2-pro- pylidene-(3-pyridazinyl) hydrazone 170 to 173 28.523 4-(Methoxycarbonyl)2-butyli- dene-A 121 to 123 62.524 3-(Methoxycarbonyl)-2-pro- pylidene-A 124 to 125 7025 3-(Ethoxycarbonyl)-2-buty- lidene-A 79 to 81 4926 5-(Ethoxycarbonyl-2-penty- lidene-A 55 to 56 69.527 1-(Ethoxycarbonyl)-2-butyli- dene-A 107 to 108 32.528 3-(Propoxycarbonyl)-2-pro- pylidene-A 101 to 103 67.529 3-(Isopropoxycarbonyl)- 2-propylidene-A 128 to 129 59.530 3-(tert.-Butoxycarbonyl)- 2-propylidene-A 136 to 137 6631 3-(Octyloxycarbonyl)-2- propylidene-A 69 to 72 5732 3-(Cyclohexyloxycarbonyl)- 2-propylidene-A 106 to 108 7033 1-(Ethoxycarbonyl)-3,3,3- trifluoro-2-propylidene-A 158 to 160 64.534 1-(Ethoxycarbonyl)-2-phenyl- 2-ethylidene-A 131 to 132 6635 1-Ethoxycarbonyl)-2-(4-nitro- phenyl)-2-ethylidene-A 183 to 185 74.536 1-(Ethoxycarbonyl)-2-(3,4,5- trimethoxyphenyl)-2-ethyli- dene-A 139 to 141 47.537 1-(Ethoxycarbonyl)-2-(3- pyridyl)-2-ethylidene-A 145 to 146 6038 4-Carboxy-2-butylidene-A 194 to 196 6839 6-Carboxy-2-hexylidene-A 184 to 187 6740 1-(Ethoxycarbonyl)-1-ethyli- dene-B 175 to 176 5041 3-(Ethoxycarbonyl)-2-propy- lidene-(3,6-dichloro-4- pyridazinyl) hydrazone 82 to 83 60.542 3-(Ethoxycarbonyl)-2-propy- lidene-(3-chloro-5-ethylemino- 6-pyridazinyl) hydrazone 88 to 90 4043 4-(tert.-Butoxycarbonyl)- 2-butylidene-A 96 to 99 73.544 (Ethoxycarbonyl)-methylidene- A 224 to 226 7945 Carboxymethylidene-A 235 to 236 8046 4-(Methoxycarbonyl)-2- butylidene-B 124 to 127 3447 4-(tert.-Butoxycarbonyl)- 2-butylidene-B 107 to 110 4348 4-Carboxy-2-butylidene-B 192 to 193 59.549 6-(Ethoxycarbonyl)-2- hexylidene-A 33 to 35 3350 5-Carboxy-2-pentylidene-A 170 to 173 6851 3-(Isopropoxycarbonyl)-2- propylidene-B 120 to 122 35.552 3-(tert.-Butoxycarbonyl)-2- propylidene-B 143 to 145 73 187 to 189**53 3-(tert.-Butoxycarbonyl)-2- propylidene-(3-methyl-6- pyridazinyl) hydrazone 98 to 99 3854 3-(Ethoxycarbonyl)-2-pro- pylidene-(3-hydroxy-6- pyridazinyl) hydrazone 175 to 178 3155 4-Carboxy-2-butylidene- (3-methyl-6-pyridazinyl) hydrazone 164 to 167 4256 3-(tert.-Butoxycarbonyl)- 2-propylidene-(3-carbamoyl- 6-pyridazinyl) hydrazone 204 to 207 9257 5-Carboxy-2-pentylidene-B 183 to 186 34.558 5-(tert.-Butoxycarbonyl)- 2-pentylidene-B oil 2959 3-(tert.-Butoxycarbonyl)- 2-propylidene-(3-cyano-6- pyridazinyl) hydrazone60 3-(tert.-Butoxycarbonyl)- 2-propylidene-[3-bis(hydroxy- ethylamino)-6-pyridazinyl]- hydrazone oil 37.561 3-(tert.-Butoxycarbonyl)- 2-propylidene-[3-(2-hydroxy- propyl-methylamino)-6- pyridazinyl] hydrazone oil 36______________________________________ Remarks: A = 3chloro-6-pyridazinylhydrazone B = 3morpholino-6-pyridazinylhydrazone * = yield values after recrystallization ** = HCl salt

Method (b)

A mixture of 0.72 g. (5 mmoles) of 3-chloro-6-pyridazinylhydrazine, 100 ml. of an aqueous solution containing 1.02 g. (5 mmoles) of potassium hydrogenphthalate and 0.65 g. (5 mmoles) of ethyl acetacetate is stirred at room temperature for 40 minutes. The precipitate formed is filtered off, washed with water and dried. 1.0 g. (77.5%) of the named compound is obtained.

EXAMPLE 62

4-(Ethoxycarbonyl)-2-butylidene-(3-chloro-6-pyridazinl) hydrazone

A mixture of 1.21 g. (5 mmoles) of 4-carboxy-2-butylidene-(3-chloro-6-pyridazinyl) hydrazine and 10 ml. of a 10% aqueous hydrochloric acid solution is stirred at room temperature for 5 hours. The reaction mixture is poured into 25 ml. of water, its pH-value is adjusted to neutral with ammonia and the precipitate formed is filtered off, washed with water and recrystallized from ethanol. 0.8 g. (59%) of the named compound are obtained, melting at 98.degree. C. to 99.degree. C.

EXAMPLE 63

1-(Ethoxycarbonyl)-1-ethylidene-(3-chloro-6-pyridazinyl) hydrazone

Method (a)

Following the procedure described in Example 20, method (a) but starting from 1.45 g. (10 mmoles) of 3-chloro-6-pyridazinylhydrazine and 1.16 g. (10 mmoles) of ethyl pyruvate, 1.17 g. (52%) of the named compound melting at 174.degree. to 177.degree. C. are obtained.

Method (b)

A mixture of 2.15 g. (10 mmoles) of 1-carboxy-1-ethylidene-(3-chloro-6-pyridazinyl) hydrazone, 1.19 g. (11 mmoles) of ethyl bromide, 1.1 g. (11 mmoles) of triethylamine and 20 ml. of ethanol is boiled for 10 hours with stirring. The reaction mixture is allowed to cool to room temperature and the precipitate formed is filtered off, the filtrate is evaporated in vacuo and the residue is triturated with 6 ml. of water. The precipitated crystals are filtered off, washed with water and recrystallized from ethanol to give 0.85 g. (35% of) the named compound.

EXAMPLE 64

1,2-di-(Methoxycarbonyl)-ethylidene-(3-chloro-6-pyridazinyl) hydrazone

To a stirred mixture of 14.45 g. (0.1 moles) of 3-chloro-6-pyridazinylhydrazine and 100 ml. of dioxane a mixture of 14.21 g. (0.1 moles) of dimethyl acetylenedicarboxylate and 75 ml. of dioxane is added dropwise at room temperature in 30 minutes. The reaction mixture is stirred for further 5 minutes. The dioxane is then evaporated in vacuo and the residue recrystallized from ethanol to afford 19.5 g. (68.5%) of the named compound, melting at 138.degree. C. to 141.degree. C.

3-(Ethoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl) hydrazone (Example 20) was prepared by the same procedure, yield 38.5%.

EXAMPLE 65

2-(Ethoxycarbonyl)-1-ethylidene-(3-chloro-6-Pyridazinyl) hydrazone

One proceeds as described in Example 64, with the difference that ethyl propiolate is used as starting material; yield: 65%; m.p. 115.degree. C. to 117.degree. C.

EXAMPLE 66

2-(Ethoxycarbonyl)-1-ethylidene-(3-morpholino-6-pyridazinyl) hydrazone

One proceeds as described in Example 64, with the difference that ethyl propiolate and the corresponding 3-morpholino-6-pyridazinyllydrazine are used as starting materials; yield 43%; m.p. 180.degree. C. to 184.degree. C.

EXAMPLE 67

3-Carbamoyl-2-propylidene-(3-chloro-6-pyridazinyl) hydrazone

A mixture of 0.725 g. (5 mmoles) of 3-chloro-6-pyridazinylhydrazine, 0.5 g. (5 mmoles) of acetacetamide and 40 ml. of tetrahydrofurane is stirred at room temperature for 6 hours and subsequently allowed to stand overnight. The precipitate formed is filtered off, washed with tetrahydrofurane and dried. 0.48 g. (42%) of the named compound melting at 178.degree. C. to 180.degree. C. are obtained.

EXAMPLE 68

Oral tablets, containing 200 mg. of active ingredient and having the following composition are prepared:

______________________________________3-(tert.-butoxycarbonyl)-2-propylidene-(3-morpholino-6-pyridazinyl) hydrazone 200 mg.microcrystalline cellulose 146.4 mg.colloidal silica 1.8 mg.magnesium stearate 1.8 mg.______________________________________

The tablets are covered by a film coat.

Average weight: 350 mg.

Injection preparate:

Ampoules for parenteral application contain 25 mg. of active ingredient (expressed in base). The active ingredient is present in a sterile, frozen-dried form.

Claims

1. A compound of the formula ##STR9## wherein K is a group having the formula ##STR10## wherein R.sup.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.7 cycloalkyl, trifluoromethyl, phenyl, phenyl substituted by chloro, nitro, or at least one methoxy, pyridyl or C.sub.1 to C.sub.4 alkoxycarbonyl;

R.sup.4 and R.sup.5 are each hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.4 alkoxycarbonyl;

R.sup.6 is carboxyl, --CONH--NH.sub.2, --CONH.sub.2 or --CO.sub.2 R.sup.9

wherein

R.sup.9 is C.sub.1 to C.sub.9 alkyl, C.sub.2 to C.sub.4 hydroxyalkyl or C.sub.3 to C.sub.7 cycloalkyl; and

n is 0, 1, 2, 3, 4 or 5; or

K is selected from the group which consists of:

1. 7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-2,2-dimethyl-3-bicyclo(2,2,1)heptylideno,

1-(2,6,6-trimethyl-1-cyclohexenyl)-1-ethylideno

1-methyl-4-isopropenyl-2-cyclohex-6-enylideno,

1-(2-bicyclo[2,2,1]hept-5-enyl)-1-ethylideno,

1-methyl-4-isopropyl-3-cyclohexylideno,

1-methyl-4-isopropylideno-3-cyclohexylideno,

2-methyl-1-cyclohexylideno,

2,6-dimethyl-1-cyclohexylideno,

2-(ethoxycarbonyl)-1-cyclohexylideno,

2-carboxy-1-cyclohexylideno,

ethoxycarbonyl-methylideno, and

carboxymethylideno;

or a pharmaceutically acceptable salt thereof.

2. A compound of the formula ##STR11## wherein K is a group having the formula ##STR12## wherein R.sup.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, C.sub.3 to C.sub.7 cycloalkyl, trifluoromethyl, phenyl, phenyl substituted by chloro, nitro, at least one methoxy, pyridyl or C.sub.1 to C.sub.4 alkoxycarbonyl;

R.sup.4 and R.sup.5 are each hydrogen, C.sub.1 to C.sub.4 alkyl, or C.sub.1 to C.sub.4 alkoxycarbonyl;

R.sup.6 is carboxyl, --CONHNH.sub.2, --CONH.sub.2 or --CO.sub.2 R.sup.9 wherein

R.sup.9 is C.sub.1 to C.sub.9 alkyl, C.sub.2 to C.sub.4 hydroxyalkyl or C.sub.3 to C.sub.7 cycloalkyl; and

n is 0, 1, 2, 3, 4 or 5; or

K is selected from the group which consists of:

1. 7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-2,2-dimethyl-3-bicyclo(2,2,1)heptylideno,

1-(2,6,6-trimethyl-1-cyclohexenyl)-1-ethylideno,

1-methyl-4-isopropenyl-2-cyclohex-6-enylideno,

1-(2-bicyclo[2,2,1]hept-5-enyl)-1-ethylideno,

1-methyl-4-isopropyl-3-cyclohexylideno,

1-methyl-4-isopropylideno-3-cyclohexylideno,

2-methyl-1-cyclohexylideno,

2,6-dimethyl-1-cyclohexylideno,

2-(ethoxycarbonyl)-1-cyclohexylideno,

2-carboxy-1-cyclohexylideno,

ethoxycarbonyl-methylideno, and

carboxymethylideno;

or a pharmaceutically acceptable salt thereof.

3. A compound of the formula ##STR13## wherein K is a group having the formula ##STR14## wherein R.sup.3 is hydrogen, C.sub.1 to C.sub.10 alkyl, trifluoromethyl, phenyl, phenyl substituted by chloro, nitro, at least one methoxy, pyridyl or C.sub.1 to C.sub.4 alkoxycarbonyl;

R.sup.4 and R.sup.5 are each hydrogen or C.sub.1 to C.sub.4 alkyl;

R.sup.6 is carboxyl, --CONHNH.sub.2, --CONH.sub.2 or --CO.sub.2 R.sup.9

wherein

R.sup.9 is C.sub.1 to C.sub.9 alkyl, or C.sub.3 to C.sub.7 cycloalkyl; and

n is 0, 1, 2, 3, 4 or 5; or

K is selected from the group which consists of:

1. 7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-2,2-dimethyl-3-bicyclo(2,2,1)heptylideno,

1-(2,6,6-trimethyl-1-cyclohexenyl)-1-ethylideno,

1-methyl-4-isopropenyl-2-cyclohex-6-enylideno,

1-(2-bicyclo[2,2,1]hept-5-enyl)-1-ethylideno,

1-methyl-4-isopropyl-3-cyclohexylideno,

1-methyl-4-isoropylideno-3-cyclohexylideno,

2-methyl-1-cyclohexylideno,

2,6-dimethyl-1-cyclohexylideno,

2-(ethoxycarbonyl)-1-cyclohexylideno, and

2-carboxy-1-cyclohexylideno;

or a pharmaceutically acceptable salt thereof.

4. A compound of the formula ##STR15## wherein K is a group having the formula ##STR16## wherein R.sup.3 is alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group;

R.sup.4 and R.sup.5 are each hydrogen, alkyl having 1 to 4 carbon atoms, or alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group;

R.sup.6 is hydrogen, carboxyl, or the group --CO.sub.2 R.sup.9

wherein

R.sup.9 is alkyl having 1 to 9 carbon atoms; and

n is 0, 1, 2, 3, 4 or 5;

or a pharmaceutically acceptable salt thereof.

5. A compound of the formula ##STR17## wherein K is a group having the formula ##STR18## wherein R.sup.3 is alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group;

R.sup.4 and R.sup.5 are each hydrogen, alkyl having 1 to 4 carbon atoms, or alkoxy carbonyl having 1 to 4 carbon atoms in the alkoxy group;

R.sup.6 is hydrogen, carboxy, or the group --CO.sub.2 R.sup.9

wherein

R.sup.9 is alkyl having 1 to 9 carbon atoms; and

n is 0, 1, 2, 3, 4, or 5;

or a pharmaceutically acceptable salt thereof.

6. A compound of the formula ##STR19## wherein K is a group having the formula ##STR20## wherein R.sup.3 is alkoxycarbonyl having 1 to 4 carbon atoms in the alkoxy group;

R.sup.4 and R.sup.5 are each hydrogen or alkyl having 1 to 4 carbon atoms,

R.sup.6 is carboxy, or the group --CO.sub.2 R.sup.9

wherein

R.sup.9 is alkyl having 1 to 9 carbon atoms; and

n is 0, 1, 2, 3, 4 or 5;

or a pharmaceutically acceptable salt thereof.

7. 3-(isopropoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone or a pharmaceutically acceptable salt thereof.

8. 3-(tert-butoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone or a pharmaceutically acceptable salt thereof.

9. A compound selected from the group consisting of

3-(ethoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(methoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(ethoxycarbonyl)-2-butylidene-(3-chloro-6-pyridazinyl)-hydrazone;

5-(ethoxycarbonyl)-2-pentylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(propoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(isopropoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(tert-butoxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(octyloxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-(cyclohexyloxycarbonyl)-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-(ethoxycarbonyl)-3,3,3-trifluoro-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-(ethoxycarbonyl)-2-phenyl-2-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone

1-(ethoxycarbonyl)-2-(4-nitro-phenyl)-2-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-(ethoxycarbonyl)-2-(3,4,5-trimethoxyphenyl)-2-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-(ethoxycarbonyl)-2-(3-pyridyl)-2-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone;

4-carboxy-2-butylidene-(3-chloro-6-pyridazinyl)-hydrazone;

6-carboxy-2-hexylidene-(3-chloro-6-pyridazinyl)-hydrazone;

4-(methoxycarbonyl)-2-butylidene-(3-chloro-6-pyridazinyl)-hydrazone;

4-(tert-butoxycarbonyl)-2-butylidene-(3-chloro-6-pyridazinyl)-hydrazone;

6-(ethoxycarbonyl)-2-hexylidene-(3-chloro-6-pyridazinyl)-hydrazone;

5-carboxy-2-pentylidene-(3-chloro-6-pyridazinyl)-hydrazone;

4-(ethoxycarbonyl)-2-butylidene-(3-chloro-6-pyridazinyl)-hydrazone;

2-(ethoxycarbonyl)-1-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone;

3-carbamoyl-2-propylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1,7,7-trimethyl-2-bicyclo(2,2,1)heptylidene-(3-chloro-6-pyridazinyl)-hydrazone;

2,2-dimethyl-3-bicyclo(2,2,1)heptylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-(2,6,6-trimethyl-1-cyclohexenyl)-1-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-(2-bicyclo[2,2,1]hept-5-enyl)-1-ethylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-methyl-4-isopropyl-3-cyclohexylidene-(3-chloro-6-pyridazinyl)-hydrazone;

1-methyl-4-isopropylidene-3-cyclohexylidene-(3-chloro-6-pyridazinyl)-hydrazone;

2-methyl-1-cyclohexylidene-(3-chloro-6-pyridazinyl)-hydrazone;

2,6-dimethyl-1-cyclohexylidene-(3-chloro-6-pyridazinyl)-hydrazone;

2-(ethoxycarbonyl)-1-cyclohexylidene-(3-chloro-6-pyridazinyl)-hydrazone; and

2-carboxy-1-cyclohexylidene-(3-chloro-6-pyridazinyl)-hydrazone.