DE1695380C3 - 3-hydrazinopyridazine derivatives and processes for their preparation - Google Patents

3-hydrazinopyridazine derivatives and processes for their preparation

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Publication number
DE1695380C3
DE1695380C3 DE19681695380 DE1695380A DE1695380C3 DE 1695380 C3 DE1695380 C3 DE 1695380C3 DE 19681695380 DE19681695380 DE 19681695380 DE 1695380 A DE1695380 A DE 1695380A DE 1695380 C3 DE1695380 C3 DE 1695380C3
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Germany
Prior art keywords
hydrazino
processes
preparation
morpholinopyridazine
blood pressure
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
DE19681695380
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German (de)
Other versions
DE1695380B2 (en
DE1695380A1 (en
Inventor
Elvio Albate Como Bellasio
Giulio Mailand Maffii
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
GRUPPO LEPETIT SpA MAILAND (ITALIEN)
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GRUPPO LEPETIT SpA MAILAND (ITALIEN)
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Publication of DE1695380A1 publication Critical patent/DE1695380A1/en
Publication of DE1695380B2 publication Critical patent/DE1695380B2/en
Application granted granted Critical
Publication of DE1695380C3 publication Critical patent/DE1695380C3/en
Expired legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/50—Pyridazines; Hydrogenated pyridazines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D237/00—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings
    • C07D237/02—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings
    • C07D237/06—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D237/10—Heterocyclic compounds containing 1,2-diazine or hydrogenated 1,2-diazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D237/20—Nitrogen atoms

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Nitrogen Condensed Heterocyclic Rings (AREA)

Description

in der R'" und R"" vorstehende Bedeutung haben, in einem Lösungsmittel umsetzt.in which R '"and R" "have the preceding meaning, is reacted in a solvent.

4545

Die Erfindung betrifft 3-Hydrazinopyridazinderivate der allgemeinen FormelThe invention relates to 3-hydrazinopyridazine derivatives of the general formula

R' RR 'R

R"R "

N = NN = N

in der R' und R" niedere Hydroxyalkylgruppen bedeuten oder R' und R" zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen gegebenenfalls durch niedere Alkylgruppen substituierten Morpholino- oder 4-Mcthylpiperazinorest bilden. R'" eine niedere Alkylgruppe und R"" eine niedere Alkyl- oder 6s die Carboxygruppe bedeutet.in which R 'and R "mean lower hydroxyalkyl groups or R' and R" together with the nitrogen atom, to which they are bound, a morpholino optionally substituted by lower alkyl groups or form 4-methylpiperazino radical. R '"is a lower alkyl group and R" "is a lower alkyl or 6s means the carboxy group.

Die Verbindungen gemäß der Erfindung lassen sich in an sich bekannter Weise durch Umsetzung einer Verbindung der allgemeinen Formel R'The compounds according to the invention can be in a manner known per se by reacting a Compound of the general formula R '

\-NH —NH,\ -NH -NH,

in der R' und R" niedere Hydroxyalkylgruppen bedeuten oder R' und R" zusammen mit dem Stickstoffatom, an das sie gebunden sind, einen gegebenenfalls durch niedere Alkylgruppen substituierten Morpholino- oder 4-Methylpiperazinorest bilden, R'" eine niedere Alkylgruppe und R"" eine niedere Alkyl- oder die Carboxygruppe bedeutet. in which R 'and R "mean lower hydroxyalkyl groups or R' and R" together with the Nitrogen atom to which they are attached, one optionally substituted by lower alkyl groups Morpholino or 4-methylpiperazino form, R '"a lower alkyl group and R" " means a lower alkyl or the carboxy group.

2. 3 - (2 - Isopropyliden - hydrazino) - 6 - morpholino-pyridazin. 2. 3 - (2 - isopropylidene - hydrazino) - 6 - morpholinopyridazine.

3. 3 - [2 - (1 - Methylpropyliden) - hydrazino]-6-morpholino-pyridazin. 3. 3 - [2 - (1 - Methylpropylidene) - hydrazino] -6-morpholinopyridazine.

4. 3-(2-Isopropyliden-hydrazino)-6-(4-methylpiperazino)-pyridazin. 4. 3- (2-Isopropylidene hydrazino) -6- (4-methylpiperazino) pyridazine.

5. Verfahren zur Herstellung eier Verbindungen nach Anspruch 1. dadurch gekennzeichnet, daß man in an sich bekannter Weise eine Verbindung der allgemeinen Formel5. A method for producing egg compounds according to claim 1, characterized in that a compound of the general formula is used in a manner known per se

NH-NH,NH-NH,

in der R' und R" vorstehende Bedeutung haben, mit mindestens der äquimolaren Menge einer Carbonylverbindung der allgemeinen Formelin which R 'and R "have the preceding meaning, with at least the equimolar amount of one Carbonyl compound of the general formula

R-N = N R- N = N

in der R' und R" die vorstehende Bedeutung haben, mit mindestens der äquimolaren Menge einer Carbonylverbindung der allgemeinen Formelin which R 'and R "have the preceding meaning, with at least the equimolar amount of a carbonyl compound the general formula

R'"R '"

O = CO = C

R""R ""

in der R'" und R"" die vorstehende Bedeutung haben, in einem Lösungsmittel erhalten.in which R '"and R" "have the above meaning, obtained in a solvent.

Die Verbindungen der Erfindung besitzen starke blutdrucksenkende Wirkung.The compounds of the invention have potent antihypertensive effects.

Wenn man z. B. 3-(2-Isopropyliden-hydrazino)-6-morpholinopyridazin und 3-[2-(l-Methylpropyliden)-hydrazino]-6-morpholino-pyridazin intravenös an Hunde verabreichte, die mit Chloralose und Urethan anästhesiert waren, beobachtete man eine deutliche Verringerung des Blutdrucks. Die erhaltener! Ergebnisse sind in der Tabelle ! zusammengestellt. Die in den Tabellen angegebenen Verbindungs-Nummern entsprechen den Nummern der nachfolgenden Beispiele.If you z. B. 3- (2-Isopropylidene-hydrazino) -6-morpholinopyridazine and 3- [2- (1-methylpropylidene) hydrazino] -6-morpholinopyridazine When administered intravenously to dogs anesthetized with chloralose and urethane, a marked increase was observed Decrease in blood pressure. The received ones! Results are in the table! compiled. The connection numbers given in the tables correspond to the numbers in the following Examples.

Tabelle 1Table 1

"T"T

Verringe-Decrease

An/ahl Dosis, Anfangs- rang des Verb. der mg kg blutdruck. Blut- An / ahl dose, initial rank of the conn. Of mg kg blood pressure. Blood-

Hunde i.v. mm Hg drucks. Dogs iv mm Hg press.

mmHgmmHg

■> s isn -90 ■> s isn -90

■> 1 17D -75■> 1 17D -75

-80 -40 -115 -105-80 -40 -115 -105

3 0.1 168 -603 0.1 168 -60

-> in IQ? -no-> in IQ? -no

"> ι ns —75"> ι ns -75

3 0.1 172 -553 0.1 172 -55

-102-102

3 I 181 -953 I 181 -95

2 0,1 160 -402 0.1 160 -40

Hydralazin 2 1 153 -50Hydralazine 2 1 153-50

(1-Hydrazino- 2 0.5 177 -48(1-hydrazino-2 0.5 177-48

phthalazin) η n] J59 _ 32phthalazin) η n] J _ 59 32

Die angegebenen Daten stellen die Durchschnittswerte des systolischen und diastolischen Blutdrucks der in den Versuchen behandelten Tiere dar. Der Druck wurde mit Hilfe eines »Pressor-Transduktors«. worunter man ein Manometer zum Messen des Blutdrucks versteht, das direkt an die Arterie angeschlossen wird, gemessen.The data presented represent the mean values of systolic and diastolic blood pressure of the animals treated in the experiments. The pressure was measured with the aid of a "pressor transducer". which is a pressure gauge that is connected directly to the artery to measure blood pressure is being measured.

Weitere Versuche wurden an Ratten mit durch die Niere verursachtem überdruck durchgeführt. Der tiberdruck war nach dem von Grollman in Proc. Soc. Exptl. Biol. Med., 57. 102 (1944), beschric-Further experiments were carried out on rats with overpressure caused by the kidney. the After that of Grollman, overpressure was in Proc. Soc. Exptl. Biol. Med., 57.102 (1944), described

Dosis,
mg kg
i.v.Dose,
mg kg
iv Ajifangs-Ajifangs-
blutdruck.blood pressure.
mmHgmmHg 55 180180 11 170170 0,50.5 174174 0.10.1 175175 55 199199 11 192192 0.10.1 168168 K)
1K)
1 192192 I
0.1 I.
0.1 172172 55 182182 II. 181181 0,10.1 160160 11 153153 0.50.5 177177 0.10.1 159159

benen Verfahren hervorgerufen worden, Es wurden Tiere verwendet, die mindestens 30 Tage zuvor behandelt worden waren und einen arteriellen Blutdruck von nicht unter 160mm Hg aufwiesen. Die Verbindungen wurden 5 Tage lang einmal täglich an Gruppen s von 3 bis 4 Ratten in den folgenden Dosen oral verabreicht: 5, 1, 0,5, 0,25, 0,1 mg,kg. Ein bekanntes Blutdruck senkendes Mittel, nämlich Hydralazin (1-HydrazinophthalazrA wurde unter den Radien Bedingungen als Vergleichssubstanz verwendet. Die kleinsten Dosen, bei denen sich die Verbindungen noch als wirksam erwiesen, sind in Tabelle 2 zusammengestellt, zusammen mit der entsprechenden LD50 bei Mäusen. Die bei anästhesierten Hunden beobachtete wirksame Dosis ist ebenfalls angegeben. Zur Bestimmung der LD5Q wurden die Medikamente intraperitoneal verabreicht. TabeHe 2 been caused surrounded methods Animals were used at least 30 days were previously treated and not having an arterial blood pressure of below 160 mm 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 known antihypertensive agent, namely hydralazine (1-hydrazinophthalazrA, was used as a comparison substance under the Radien conditions. The smallest doses at which the compounds were still found to be effective are listed in Table 2, together with the corresponding LD 50 in mice. The effective dose observed in anesthetized dogs is also given. The drugs were administered intraperitoneally to determine the LD 5 Q. TabeHe 2

Verbindung des
Versuchs Nr.Connection of the
Trial no. LD5,,
(mg kg)LD 5 ,,
(mg kg) Wirksame
Dosis mj! kg,
oral bei
Rauen mit
überdruckEffective
Dose mj! kg,
orally at
Rough with
overpressure Wirksame
Dosis mg kg,
i.v. bei
anästhe
sierten
HundenEffective
Dose mg kg,
iv at
anesthetize
sated
Dogs 11 !00! 00 0,250.25 0.10.1 22 8080 0,250.25 0,10.1 33 120120 0.500.50 0.250.25 44th 116116 0,250.25 0.10.1 55 150150 0.500.50 0,250.25 66th 105105 0,250.25 0.10.1 Hydralazin
(1-Hydrazino-
phthalazin)Hydralazine
(1-hydrazino
phthalazine) 101101 11 0.50.5

Als kleinste noch wirksame Dosis wird diejenige Dosis angesehen, die den Blutdruck um mindestens 40 mm Hg senkt. Die Werte hängen von mehreren Bedingungen ab und sind öfter untereinander unterschiedlich auf Grund der unterschiedlichen Empfindlichkeit der Individuen der gleichen Tiergruppe gegenüber den Medikamenten. Jedoch die Methode der Bestimmung des Blutdrucks ist sehr genau, und die Fehlergrenze ist mit Sicherheit nicht größer als ± 5%.The smallest effective dose is considered to be that dose which increases the blood pressure by at least 40 mm Hg lowers. The values depend on several conditions and are often different from one another due to the different sensitivity of the individuals to the same group of animals the medication. However the method of determining blood pressure is very accurate and that Error limit is definitely not greater than ± 5%.

Aus der Tabelle geht hervor, daß die Toxizität in allen Fällen praktisch gleich ist, daß die Verbindungen gemäß der Erfindung jedoch bei beiden Tierarten wesentlich stärker wirksam sind als Hydralazin.The table shows that the toxicity in all cases is practically the same as that of the compounds according to the invention, however, are much more effective than hydralazine in both animal species.

Die folgenden Beispiele dienen der weiteren Erläuterung der Erfindung.The following examples serve to further illustrate the invention.

Beispiel 1
3-( 2-1 sopropyliden-hydrazino)-example 1
3- (2-1 sopropylidene hydrazino) -

6-morpnolino-pyridazin6-morpnolinopyridazine

20 g 3-Hydrazino-6-morpholino-pyridazin werclen in 450 ml Aceton gelöst. Die Lösung wird auf 70 bis 80 ml eingeengt und auf Eis gekühlt. Die ausgeschiedene feste Substanz wird abfiltriert und die Flüssigkeit auf 50 rol eingeengt. Nach einigero Stehen kann eine zweite Charge gewonnen werden. Die vereinigten Chargen werden in siedendem Äthanol gelöst und durch Kühlen auskristallisiert Ausbeute 19,1 g (80%); F. = 187 bis 190° C.20 g of 3-hydrazino-6-morpholinopyridazine work dissolved in 450 ml of acetone. The solution is concentrated to 70 to 80 ml and cooled on ice. The eliminated solid substance is filtered off and the liquid is concentrated to 50 rol. After standing for a while, one can second batch can be obtained. The combined batches are dissolved in boiling ethanol and crystallized out by cooling, yield 19.1 g (80%); F. = 187 to 190 ° C.

Beispiel 2
3-[2-( 1 -Methy\propyliden)-hydrazino]-Example 2
3- [2- (1-methylene propylidene) hydrazino] -

6-morpholino-pyridazin6-morpholinopyridazine

3,9 g 3-Hydrazino-6-morpholino-pyridazin und 1,74 g*Methyläthylketon werden in wasserfreiem Älthanol unter Rückfluß erhitzt, bis vollständige Lösung eingetreten ist. Nach dem Stehen über Nacht wird das Lösungsmittel im Vakuum bei 400C abgedampft. Der Rückstand wird aus Isopropyläther umkristallisiert. Ausbeute 4,23 g (85%); F. = 125 bis 1270C.3.9 g of 3-hydrazino-6-morpholinopyridazine and 1.74 g of methyl ethyl ketone are refluxed in anhydrous ethanol until complete dissolution has occurred. After standing overnight, the solvent is evaporated in vacuo at 40 0 C. The residue is recrystallized from isopropyl ether. Yield 4.23 g (85%); F. = 125 to 127 0 C.

Beispiel 3
3-[2-( 1 -Carboxyäthyliden)-hydrazino]-Example 3
3- [2- (1 -carboxyethylidene) hydrazino] -

6-morpholino-pyridazin6-morpholinopyridazine

3,90 g 3-Hydraz:no-6-morpholinG-pyridazin werclen zu einer wäßrigen Lösung von 1,68 g Natriumbicarbonat und 1,76 g Brenztraubensäure gegeben Das Gemisch wird gerührt, bis vollständige Lösung eingetreter, ist. Die Lösung wird filtriert, dann werden 7,65 ml 10%iger Salzsäure zugegeben. Es bildet sich ein gelber Niederschlag, der abfiltriert, mit Eiswasser gewaschen und im Vakuum über P2O5 getrocknet wird. Ausbeute 4,40 g (83%); F. = 204 bis 208°C.3.90 g of 3-hydrazine: no-6-morpholineG-pyridazine works The mixture was added to an aqueous solution of 1.68 g of sodium bicarbonate and 1.76 g of pyruvic acid is stirred until complete solution has occurred. The solution is filtered, then be 7.65 ml of 10% hydrochloric acid were added. A yellow precipitate forms, which is filtered off with ice water washed and dried in vacuo over P2O5 will. Yield 4.40 g (83%); F. = 204 to 208 ° C.

Beispiel 4Example 4

3-(2-Isopropyliden-hydrazino)-6-(4-methylpiperazi0u)-pyridazin
4,17 g 3-Hydrazino-6-(4-methylpiperazino)-pyridazin werden in 20 ml heißem Aceton gelöst. Nach dem Stehen wird der ausgefallene Feststoff gesammelt und aus Aceton umkristallisiert. Ausbeute 4,27 g (86%); F. =-- 158 bis 161°C.3- (2-Isopropylidene hydrazino) -6- (4-methylpiperazio) pyridazine
4.17 g of 3-hydrazino-6- (4-methylpiperazino) pyridazine are dissolved in 20 ml of hot acetone. After standing, the precipitated solid is collected and recrystallized from acetone. Yield 4.27 g (86%); F. = - 158 to 161 ° C.

Beispiele 5, 6 und 7Examples 5, 6 and 7

Die folgenden Verbindungen wurden im wesentlichen nach den in den vorstehenden Beispielen beschriebenen Verfahren hergestellt:The following compounds were made essentially according to those described in the preceding examples Process made:

2525th

4040

4545

Beispiel
5example
5

CH2 CH2 OH
H3C.CH2 CH2 OH
H 3 C.

CH — CH2 CH - CH 2

CH CH2CH CH2

H3CH 3 C

CH2 — CH2 — OHCH 2 - CH 2 - OH

Verbindung RConnection R

CH2 — CH2 — OHCH 2 - CH 2 - OH

CH2-CH2-OHCH 2 -CH 2 -OH

R-R- R-"R- " CH3 CH 3 C2HC 2 H CH3 CH 3 CH3 CH 3 CH3 CH 3 CH3 CH 3

F.. CF .. C

200-202
(Monohydrochlorid)200-202
(Monohydrochloride)

173—175173-175

196—199
(Monohydrochlorid)196-199
(Monohydrochloride)

Claims (1)

Patentansprüche:Patent claims: 1. 3-Hydrazinopyridazinderivate der allgemeinen Formel1. 3-hydrazinopyridazine derivatives of the general formula R""R "" O = CO = C R""R ""
DE19681695380 1967-01-25 1968-01-12 3-hydrazinopyridazine derivatives and processes for their preparation Expired DE1695380C3 (en)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
GB3804/67A GB1168334A (en) 1967-01-25 1967-01-25 New Pharmacologically Active Pyridazines

Publications (3)

Publication Number Publication Date
DE1695380A1 DE1695380A1 (en) 1972-08-10
DE1695380B2 DE1695380B2 (en) 1973-11-08
DE1695380C3 true DE1695380C3 (en) 1974-07-04

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Country Status (15)

Country Link
AT (1) AT271491B (en)
BE (1) BE709868A (en)
BR (1) BR6896485D0 (en)
CH (1) CH471132A (en)
DE (1) DE1695380C3 (en)
DK (1) DK117301B (en)
ES (1) ES349741A1 (en)
FI (1) FI47663C (en)
FR (2) FR1568058A (en)
GB (1) GB1168334A (en)
IL (1) IL29248A (en)
NL (1) NL6800466A (en)
NO (1) NO120683B (en)
SE (1) SE337382B (en)
YU (1) YU32078B (en)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB1298210A (en) * 1968-12-30 1972-11-29 Sandoz Ltd Improvements in or relating to dihalo-pyridazine derivatives
IT1054107B (en) * 1970-12-15 1981-11-10 Isf Spa NEW 3, HYDRAZINOPYRIDAZINE 6, SUBSTITUTED FOR ANTI-HYPERTEN SIVA ACTIVITIES AND THEIR PREPARATION
EP0009655B1 (en) * 1978-10-02 1983-05-11 Gruppo Lepetit S.P.A. 6-amino substituted n-pyrrolyl-3-pyridazine amines, their preparation, and pharmaceutically antihypertensive compositions containing them

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Publication number Publication date
DK117301B (en) 1970-04-13
GB1168334A (en) 1969-10-22
AT271491B (en) 1969-06-10
ES349741A1 (en) 1969-04-01
YU18468A (en) 1973-10-31
YU32078B (en) 1974-04-30
DE1695380B2 (en) 1973-11-08
NL6800466A (en) 1968-07-26
DE1695380A1 (en) 1972-08-10
BR6896485D0 (en) 1973-05-10
CH471132A (en) 1969-04-15
SE337382B (en) 1971-08-09
FI47663B (en) 1973-10-31
FR1568058A (en) 1969-05-23
FI47663C (en) 1974-02-11
NO120683B (en) 1970-11-23
IL29248A (en) 1971-10-20
BE709868A (en) 1968-05-30
FR7580M (en) 1970-01-05

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Date Code Title Description
C3 Grant after two publication steps (3rd publication)
E77 Valid patent as to the heymanns-index 1977