DE1695380A1 - 3,6-Disubstituted pyridazines and processes for their preparation - Google Patents

Description

Dr, Walter Beil

. -pener 1895 380

Rech '«a ¹ WaItB u.iwlar«

Dr. Ik nr Joe ± un Wolff Er. Ears Cbr. ax

Frankfurt a. M.-Höchst

58 - TeL 3010 24

Our fffr. "14 448

lepetit S.p.A.

Gruppo per la Riceraa Scientifica e la Produsione Chimica

JParmaceutica Malland / Italy

3,6-Pisubstituted Pyridazines and Processes for Their Manufacturing

The invention relates to 3,6-disubstituted pyridazines of the general formula

in which R ^{1 is} hydrogen, a lower alkyl group or a lower hydroxyalkyl group, R "denotes a lower alkyl group, a lower hydroxalkyl group or a phenyl group and R ¹ and R ^N together also represent a heterocyclic ring m optionally substituted by lower alkyl groups, Lt 1 to 2 Can represent heteroatoms, R "· hydrogen or a medere alkyl group and R ^Mtl a lower alkyl group, Ji«. Garboxy group, an aryl group or optionally substituted furyl or ihienyl group.

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_ 2 -

The connections according to the invention are implemented tion of a compound of the general formula

in which R * and R ^{ir have} the meaning given above, with at least an equimolecular amount of a carbonyl compound of the general formula

H-

O - C

in which Ä ^MI and R " ^{m have} the meaning given above, obtained in an inert solvent.

The compounds of the invention have potent antihypertensive effects.

For example, if one uses 3 ~ (2-Ieopropyliden-hydrazino) -6-morphölin.opyridazin and 3- £ 2- (1-methylpropylidene) hydrazinoJ-6-morpholino-pyridazia administered intrarenoic to dogs that were anaathetized with Ohloraloee and urethane you get a significant decrease in blood pressure. The results obtained are shown in Table 1.

Table 1

Verb. Number of round Dosi3, a?. #: / Kg reduction of

IV, - ialutdrucics, mm Hg

1 '2 5 -yo

2 1 -75

1 "ü _t 5 -faO

i.v. . Blood pressure 5 -115 1 -105 0.1 - 60 10 -110 1 - 75 0.1 - 55 5 -102 1 . - 95 0.1 . -40

- 3 -

Verb. Number of dogs dose, mg / kg reduction in

iV blood pressure mn N

2 1
1
3

4- 2
2
3

14 1
3
2

Further experiments were carried out on rats with positive pressure caused by the kidney. The overpressure was according to your von Grollman in Proc. Soc. Exptl. Biol. Hed. _t 57 t 102 (1944), animals were used which had been treated at least 30 layers beforehand and which had an arterial blood pressure of not less than 160 me Hg. The compounds were orally administered to groups of 3 to 4 rats once a day for 5 days in the following doses: 5, 1, 0.5, 0.25 »0.1 mg / kg. A well-known hypnotic,. namely, hydralazine, was used as a comparative substance under the same conditions. The smallest doses at which the compounds were found to be more effective are listed in Table 2, together with the corresponding UDc ₀ bei hausen. The effective dose observed in anesthetized dogs is also given.

209033/1170

LD Table 2 link
of the Ver
suchs, no. 100 effective dose
mg / kg, orally at
_ΚΛ rats with
⁵⁰ overpressure 1 80 0.25 2 120 0.25 3 116 0.50 4th 150 0.25 13th 105
101 0.50 14th
Hydralazine 0.25
1

effective dose mg / kg, i «v. at anesthetized Dogs

0.1

0.1

0.25

0.1

0.25

0.1

From the table it follows that the toxicity in all Cases in practice are the same that the connections according to However, the invention is much more effective than hydralazine in both animal species.

The following examples illustrate the invention Procedure.

example 1

3- (2-IBOpropylidene-hydragino) -6-morpholino-pyridazine

20 g of 3-hydrasino-6- * orpholinopyridazine are dissolved in 450 ml of acetone. The solution is concentrated to 70 to 60 ml and cooled on ice. The precipitated solid substance is filtered off and the liquid is concentrated to 50 ml. After standing for a while, a second batch can be obtained. The combined batches are dissolved in boiling ethanol and recrystallized by cooling. Yield 19.3 g (80 Ji); 1 = 187-190 ° C.

Example 2

3-p2- (t-MethyIpropyliden) -hydrazinoI-6-morpholino-pyridazine 3.9 g of 3-hydrazino-6-morpholino-pyridazine and 1.74 g of methyl ethyl ketone are refluxed in anhydrous ethanol

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heated until complete solution has occurred - the compartment standing overnight is the solvent in a vacuum evaporated at 40 ° C. The residue is recrystallized from isopropyl ether. Yield 4.23 g (85 3 *) *? * 125 up to 127 ° C

Example 5

3-12- (1-CarboxyäthyIiaen) - h _r vdrazinoj -6-morpholino-pyridazine

3.90 g of 3-hydrazino-6-morphqlinopyridazine are added to an aqueous solution of 1.68 g of sodium bicarbonate and 1.76 g of pyruvic acid. The mixture is stirred until complete dissolution has occurred. The solution is filtered, then 7.65 ml of 10 # hydrochloric acid are added. A yellow precipitate forms, which is filtered off, washed with bis-water and dried in vacuo over Pp ^ 5. Yield 4.40 g (83 #) ; Ϊ ■ 204-208 ° C.

Example 4

3- (2-1sopropylidene-hydrazino) -6- (4-methyl-1-piperazino) - pyrldazine

4 ·, 17 g of 3-hydrazino-6 (4-aethyl-1-plerazino) -pyridazine become dissolved in 20 al of hot acetone. After standing, the precipitated solid is collected and recrystallized from acetone. Yield · 4.27 g (86 ji) f? - 158-161 ° C.

Example 5 3- (2-Benz.7lidene-hydrazino) -6-piperidino-pyridagine

An ethanol solution of 3.86 g of 3-hydrazino-6-piperidinoi-yridazine and an ethanol solution of 2.12 g of benzaldehyde are mixed together. The precipitate obtained is recrystallized from isopropyl alcohol. Yield 4.5 g (80 jiss); I ¹ = 235-237 ° C.

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Example 6

3-k2- | Hfitro-2-then.yliden) -hydrazine ^ -6-piperldino-pyridazine

3.86 g of 3-hydrazino-6-piptidino-pyridaain and 3.14 g of 5-urothiophene aldehyde are dissolved separately in the smallest possible amount of ethanol. The two solutions will be with each other mixed and the precipitated solid collected. Yield 5.2 g (78 ji) | P = 238-240 ° C.

Example 7

3-D? - (i? -I * itro-2-then.yliden) -hydrazinoj -6-morpholino-pyridazine

An alcoholic solution of 3.14 g of 5-nitso-2-thiophenaldehyde becomes a methanolic solution of 5.36 g 3-iIydrazino-6-morpholinopyridazine dihydrochloride. After about 10 minutes a precipitate separates out, which is collected and recrystallized from methanol. The product obtained is 3-12- (5-Hitro-2-thenylidene) -hydrazinoj -ö-morpholino-pyridazine hydrochloride. yield 6.15 gf P - 244-246 ° C.

Example 8

3- .2- (5-Nitro-2-j-cururylidene) -hydrasincu -6-aorpholino pyrldazine

A methanol-flat solution of 5.36 g of 3-hydrazino-6-morpholino-pyridaein dihydrochloride is made with a methanolic surface Mixed solution of 2.82 g of 5-nitro-2-furaldehyde. After the mixture has stood for a few hours, will the precipitate formed collected, washed with methanol and dried. The product consists of 3-Jl2- (5-nitro-2-ftirfuryliden) -hydrazinoj -6-morpholino-pyridazine hydrochloride. Yield 5.32 g (75 ^). Below 280 ° C no melting was observed.

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Example 9

3-1 , 2-l-propyldene-hydrazinqj-6-piperidino-p; yridazine

15 g of 3-hydrazino-6-piperidino-pyridazine are dissolved at about ⁰ ° C. in the small amount of acetone that is suitable. Yellow crystals soon form, which are filtered off. The resulting free base is unstable and quickly turns dark on standing. The crystals are therefore immediately converted into the corresponding hydrochloride with a solution of hydrogen chloride in diethyl ether. Yield 10 g (42 i) \ P = 192-195 ° C.

Example 10

3.-i 2- (1-carboxyethylidene) -hydrazinoI -6-piperidlno-pyridazine

880 mg of pyruvic acid are dissolved in 6 ml of water. 840 mg of sodium bicarbonate are then added. If that Foaming caused by the development of carbon dioxide has ceased, 1.94 g of 3-hydrazino-6-piperidinopyridasine and 3 ml of water are added. The solution is cooled and acidified to a pH of about 4 with 2N HCl. A yellow precipitate forms, which is collected and dried over phosphorus pentoxide in vacuo at room temperature. Yield 1.81 g (67.0 jt) | P »152. up to 155 ° C.

Example 11 to 15

The following compounds were prepared essentially according to the procedures described in the preceding examples:

Example connection F, ° C

R ¹ R "R" ¹ R ""

11 * -C ₂ H ₅

₃ -OH ₉ OH -CHpCHpOH -CH, -CH, 196-199

, ^? ° (MonohydrochloAd)

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169538Q

example

13th

-CH ₂ -CH ₂ OH

link

R "R" '-CH "CH" 0H -CH-

CH,

CH,

^k CH - CH

CH - CH - CH,

R " ^B

-C ₂ H ₅ 200-202 (monohydrochloride)

-UH, 173-175

15th

CH,

CH,

CH -

CH - CH ₁

241-245

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Claims (5)

Claim « 1. 3,6-disubstituted pyridazines of the general formula -HH - H R "" in which R ^{1 is} hydrogen, a lower alkyl group or a lower hydroxyalkyl group, R ^{11 is} a lower alkyl group, a lower hydroxyalkyl group or a phenyl group and E ¹ and R ^tt together also represent a heterocyclic ring optionally substituted by lower alkyl groups and having 1 to 2 heteroatoms R ¹ * ¹ denotes hydrogen or a lower alkyl group and R * ″ denotes a lower alkyl group, the carboxyl group, an aryl group or an optionally substituted juryl or dhienyl group. 2. 3- (2-Isopropylidene-hydrazino) -i6-raorpholino-pyridaseine. 3. 3- Iß " (* -Methylpropyliden) -hydraeinaQ -6-Biorpholin-pyridaxine. 4 · 3- (2-Iiopropylidtn-hydraiino) -6- (4-m * thyl-1-piperasino> pyridajtine. 5. Terfahren for the preparation of the Terbindungen according to claim 1, characterized in that one is a compound of the general formula 209939/1170 - to - in which R * is hydrogen, a lower alkyl group or a lower hydroxyalkyl group, R "denotes a lower alkyl group, a lower hydroxyalkyl group or a phenyl group and R ¹ and R" together also represent a heterocyclic ring with 1-2 heteroatoms which is optionally substituted by lower alkyl groups can, with at least the equimolecular amount of a carbonyl compound of the general formula R «» 0 «C in which R "'is hydrogen or a lower alkyl group and R ^{NN is} a lower alkyl group which is the carboxy group, an aryl group or an optionally substituted uryl or xhienyl group, in an inert solvent. Pure ! • petit S.P.A. Gruppo per la Ricerca Scientifica • la Produiione Chimica Parmaceutica. Milan / Italy Lawyer 209133/1170