US3535317A - 3-hydrazinopyridazines having hypotensive activity - Google Patents

3-hydrazinopyridazines having hypotensive activity Download PDF

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US3535317A
US3535317A US581753A US3535317DA US3535317A US 3535317 A US3535317 A US 3535317A US 581753 A US581753 A US 581753A US 3535317D A US3535317D A US 3535317DA US 3535317 A US3535317 A US 3535317A
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pyridazine
hydrazino
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Elvio Bellasio
Carlo Carpi
Giulio Maffii
Emilio Testa
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Gruppo Lepetit SpA
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom 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
    • 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
    • C07D237/22—Nitrogen and oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • 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
    • 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
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings

Definitions

  • Compound A was tested in doses of 5, 2, 1, 0.5, 0.25 mg./kg.; compound B in doses of 1, 0.25, 0.1 mg./kg.; compound C in doses of 1, 0.5, 0.25, 0.1 mg./kg.
  • Compound A showed a strong and lasting antihypertensive effect at every dose.
  • Compound B showed remarkable and lasting efiect at the tensive activity.
  • Compound C was effective at all doses higher than 0.1 mg./kg.
  • a comparison was also carried out between compound A and the well-known hypotensive agent hydralazine. Both compounds were tested on rabbits anesthesized This invention is concerned with new pharmacologically active compounds, and with a method for preparing them. with sodium pentobarbital.
  • the preparation of the compounds of the invention runs through two reaction steps.
  • the starting 3,6-dichloro-pyridazine I by reaction with about two equimolecular amounts of a primary or secondary amine, in an anhydrous organic solvent, gives a monoamino derivative, which is hereinbelow represented with formula II.
  • a monoamino derivative which is hereinbelow represented with formula II.
  • R' is a member selected from the class consisting of hydrogen, lower alkyl and hydroxy-lower alkyl groups
  • R" is a member selected from the class consisting of lower alkyl, hydroXy-lower alkyl and phenyl groups
  • R 0 NH and R" taken together form an optionally lower-alkyl substituted heterocyclic ring with 1-2 heteroatoms.
  • the heterocyclic ring is morpholine
  • I compound is 3-hydrazino-6-morpholino-pyridazine.
  • the compounds of the invention have proved useful 0 as hypotensive agents.
  • 3-hydrazino-6-morpholino-pyridazine (A), 3-hydrazino-6-piperidino-pyrida- II zine (B) and 3-hydrazino-6-bis-(Z-hydroxyethyl)-amino pyridazine (C) were administered by intravenous route NZN to dogs anesthesized with 35 rng./kg. of sodium pentobar- HI r. J
  • the following examples illustrate the invention.
  • EXAMPLE 1 Preparation of 3-hydrazino-6-morpholino-pyridazine An amount of 149 g. (1 mole) of 3,6-dichloropyridazine and 174 g. of morpholinc (2 moles) are mixed in 750 ml. of anhydrous ethanol. The mixture is refluxed for 2 hours: the two compounds completely dissolve. The solution is cooled and the precipitated solid is separated by filtration. The precipitate is taken up with water and again filtered. The collected solid is crystallized from water, thus obtaining 174 g. of pure product (yield 75%), M.P.; l38140 C. This product is 3-chloro-6-morpholinopyridazine.
  • the dihydrochloride prepared by bubbling HCl in a diethyl ether solution of the free base and collecting the precipitate, melts at 236 C.
  • the product is 3-hydrazino-6-bis- (Z-hydroxethyl)-amino-pyridazine dihydrochloride. (the free base, when isolated by usual procedure, is not stable). Yield 9.8 g. (66% M.P. 187.5-188.5 C.
  • the free base can be isolated by usual procedures, f.i. by adding an alkali hydroxide or carbonate to the aqueous solution of the dihydrochloride and extracting with diethyl ether.
  • the free base is scarcely stable at ordinary temperature and decomposes promptly on heating.
  • R is a member selected from the class consisting of hydrogen, lower alkyl and hydroxy-lower alkyl groups
  • R is a member selected from the class consisting of lower alkyl, hydroxy-lower alkyl and phenyl groups
  • R and R" taken together with the N-atom form a member of the group consisting of morpholino, piperidino and 4-methyl-piperazino, and its non-toxic mineral acid addition salts.
  • a compound as in claim 1, wherein the 3,6-disubstituted pyridazine is 3-hydrazino-6-bis-(2-hydroxyethyl)- amino-pyridazine hydrochloride.

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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)

Description

Patented Oct. 20, 1970 bital. The results obtained for the hypotensive effect are given in Table 1.
3,535,317 S-HYDRAZINOPYRIDAZINES HAVING HYPOTENSIVE ACTIVITY TABLE 1 Elvio Bellasio, Albate, Como, Carlo Carpi, Bresso, Milan, Decrease f and Giulio Maflii, Milan, Italy, and Emilio Testa, 5 Dose, blood pressure, Vacallo, Tessin, Switzerland, assignors to Lepetit S.p.A., (impound of Hg Milan, Italy 3 10 ...10s No Drawing. Filed Sept. 26, 1966, Ser. No. 581,753 2 5 Claims priority, application Great Britain, Oct. 8, 1965, A f :3? 42,818/ 65 1 011 40 Int. Cl. com 87/28, 57/00,- A61k 27/00 10 B 1 1 1 Us. (:1. 260-2475 5 Claims 3;? :2; 1 -80 O i a a ABSTRACT OF THE DISCLOSURE 1 0.01
New 3-hydrazino-6-substituted amino-pyridazines of the formula: It may be seen that said compounds have a strong,
gradual and lasting hypotensive effect; no alteration of breath was noted. The same compounds were tested also on rats with renal hypertension induced by Grollmans procedure described in Proc. Soc. Exptl. Biol. Med., 57, 102 (1944). The compound was administered once a day wherein R' is hydrogen, lower alkyl or hydroxy-lower alkyl, while R is lower alkyl, hydroXy-lower alkyl or phenyl, R and R" together forming an optionally lower alkyl substituted heterocyclic ring with one or two heteroatoms, such as morpholino, piperidino and 4-methyliperazino. The compounds have a high degree of hypofor 5 days, per os, in aqueous solution. Compound A was tested in doses of 5, 2, 1, 0.5, 0.25 mg./kg.; compound B in doses of 1, 0.25, 0.1 mg./kg.; compound C in doses of 1, 0.5, 0.25, 0.1 mg./kg. Compound A showed a strong and lasting antihypertensive effect at every dose. Compound B showed remarkable and lasting efiect at the tensive activity. dose of 1 and 0.25 mg./kg., a minor action at 0.1 mg./k.g. Compound C was effective at all doses higher than 0.1 mg./kg. A comparison was also carried out between compound A and the well-known hypotensive agent hydralazine. Both compounds were tested on rabbits anesthesized This invention is concerned with new pharmacologically active compounds, and with a method for preparing them. with sodium pentobarbital.
TAB LE 2 Starting Modifications in blood pressure, Dose, blood mm. Hg after minutes- No of mgJkg. pressure Compound rabbits i.v. mm. Hg 10 30 60 2 0.2 97 34 -41 43 Hydralazine 2 0. 2 104 --14 -27 -31 4 0. 1 116 49 47 IIydralazme 2 0. 1 123 9 19 20 8 0. 05 104 -15 27 -28 Hydralazine 7 0. 05 106 11 17 18 More particularly, the compounds hereinbelow disclosed are 3,6-disubstituted pyridazines of the general formula:
It may be seen that the remarkable hypotensive effect is prolonged, also with very low doses, beyond two hours. Compound A always shows a greater activity than hydralazine at equal doses.
The preparation of the compounds of the invention runs through two reaction steps. In the first step, the starting 3,6-dichloro-pyridazine I, by reaction with about two equimolecular amounts of a primary or secondary amine, in an anhydrous organic solvent, gives a monoamino derivative, which is hereinbelow represented with formula II. By refluxing componud II with hydrazine hydrate the corresponding hydrazino derivative III is obtained as follows:
wherein R' is a member selected from the class consisting of hydrogen, lower alkyl and hydroxy-lower alkyl groups, R" is a member selected from the class consisting of lower alkyl, hydroXy-lower alkyl and phenyl groups, R 0 NH and R" taken together form an optionally lower-alkyl substituted heterocyclic ring with 1-2 heteroatoms. When, for instance, the heterocyclic ring is morpholine, the
I compound is 3-hydrazino-6-morpholino-pyridazine.
The compounds of the invention have proved useful 0 as hypotensive agents. For instance, 3-hydrazino-6-morpholino-pyridazine (A), 3-hydrazino-6-piperidino-pyrida- II zine (B) and 3-hydrazino-6-bis-(Z-hydroxyethyl)-amino pyridazine (C) were administered by intravenous route NZN to dogs anesthesized with 35 rng./kg. of sodium pentobar- HI r. J The following examples illustrate the invention.
EXAMPLE 1 Preparation of 3-hydrazino-6-morpholino-pyridazine An amount of 149 g. (1 mole) of 3,6-dichloropyridazine and 174 g. of morpholinc (2 moles) are mixed in 750 ml. of anhydrous ethanol. The mixture is refluxed for 2 hours: the two compounds completely dissolve. The solution is cooled and the precipitated solid is separated by filtration. The precipitate is taken up with water and again filtered. The collected solid is crystallized from water, thus obtaining 174 g. of pure product (yield 75%), M.P.; l38140 C. This product is 3-chloro-6-morpholinopyridazine.
Fourty grams of the above product are suspended in 370 ml. of 98% hydrazine hydrate. The mixture is refluxed for two hours, then it is cooled, and the formed precipitate is collected, washed with about 50 ml. of hydrazine hydrate and recrystallized from toluene; yield 28 g. (75% M.P. 145-150 C.
The dihydrochloride, prepared by bubbling HCl in a diethyl ether solution of the free base and collecting the precipitate, melts at 236 C.
EXAMPLE 2 Preparation of 3-hydrazino-6-bis-(2-hydroxyethyl)- amino-pyridazine A solution of 61 g. of 3,6-dichloro-pyridazine and 87 g. of bis-(2-hydroxyethyl)-amine in 750 ml. of cyclohexanol is refluxed for 3 hours. The solvent is then removed in vacuo, and the residue is taken up in 150 ml. of water; this solution is extracted twice with petroleum ether in order to remove the still present small quantity of cyclohexanol. The solution is then salted with sodium chloride and extracted with ethyl acetate. The obtained solution, after drying over sodium sulfate, is concentrated to dryness, and the residue is crystallized from isopropyl alcohol. Sixty grams of 3-chloro-6-bis(Z-hydroxyethyl)-aminopyridazine are thus obtained (yield 70% M.P. 96- 98 C.
Eleven grams of this product are mixed with 300 ml. of 98% hydrazine hydrate and refluxed for two hours. The mixture is allowed to stand for 12 hours at room temperature, then it is concentrated in vacuo and the residue is taken up with hot ethanol. When this solution is cold, the precipitate is separated by filtration, and from the filtrate the solvent is removed in vacuo. The residue is dissolved in 60 ml. of hot isopropyl alcohol and then filtered on Fullers earth; the product precipitates from the filtrate by adding a diethyl ether solution of hydrogen chloride. The product is dissolved in anhydrous ethanol, from which is then recrystallized. The product is 3-hydrazino-6-bis- (Z-hydroxethyl)-amino-pyridazine dihydrochloride. (the free base, when isolated by usual procedure, is not stable). Yield 9.8 g. (66% M.P. 187.5-188.5 C.
EXAMPLE 3 Preparation of 3-hydrazino-6-(N-phenyl-N-methyl)- amino-pyridazine Three grams of 3,6-dichloropyridazine and 4.28 g. of N-methyl-aniline are dissolved in 15 ml. of boiling butanol and refluxed for three hours. The solvent is then removed in vacuo to dryness, and the residue is taken up with water; this solution is extracted several times with diethyl ether. The obtained solution yields, by removing the organic solvent in vacuo, the crude product, which is crystallized from diisopropyl ether. It is 3-chloro-6-(N- phenyl-N-methyl)-amino-pyridazine, yield 3.9 g. (75 M.P. 89-91 C.
An amount of 1.5 g. of this product is dissolved in 26 ml. of 98% hydrazine hydrate. The mixture is refluxed for 10 hours, then the solvent is distilled in vacuo to dryness. The residue is taken up with CI-lCl and washed twice with a. saturated aqueous solution of sodium chloride. The organic layer is then dried and chloroform is distilled off. The oily residue is dissolved in methanol and treated with a. diethyl ether solution of hydrogen chloride. On cooling, the solution yields a precipitate which is recrystallized from ethanol: it is 3-hydrazino-6-(N-phenyl-N-methyl)- amino-pyridazine dihydrochloride. Its weight is 1.3 g. M.P. 206208 C. The free base can be isolated by usual procedures, f.i. by adding an alkali hydroxide or carbonate to the aqueous solution of the dihydrochloride and extracting with diethyl ether. However, the free base is scarcely stable at ordinary temperature and decomposes promptly on heating.
EXAMPLES 4-5 The following compounds were prepared as shown in Example 1:
(4) 3-Hydrazino-6-piperidino-pyridazine, yield M.P. l40l45 C. (5) 3-Hydrazino-6-(4-methyl piperazino) pyridazine,
yield 70%, M.P. -167 C.
We claim: 1. A compound selected from a 3,6-disubstituted pyridazine of the formula:
wherein R is a member selected from the class consisting of hydrogen, lower alkyl and hydroxy-lower alkyl groups, R is a member selected from the class consisting of lower alkyl, hydroxy-lower alkyl and phenyl groups, and wherein R and R" taken together with the N-atom form a member of the group consisting of morpholino, piperidino and 4-methyl-piperazino, and its non-toxic mineral acid addition salts.
2. A compound as in claim 1, wherein the 3,6-disubstituted pyridazine is 3-hydrazino-6-bis-(2-hydroxyethyl)- amino-pyridazine.
3. A compound as in claim 1, wherein the 3,6-disubstituted pyridazine is 3-hydrazino-6-bis-(2-hydroxyethyl)- amino-pyridazine hydrochloride.
4. A compound as in claim 1, wherein the 3,6-disubstituted pyridazine is 3-hydrazino-6-morpholino-pyridazine.
5. A compound as in claim 1, wherein the 3,6-disubstituted pyridazine is 3-hydrazino-6-morpholino-pyridazine hydrochloride.
OTHER REFERENCES Morrison et al., Organic Chemistry, 1959, Allyn & Bacon, p. 847.
ALEX MAZEL, Primary Examiner R. V. RUSH, Assistant Examiner
US581753A 1965-10-08 1966-09-26 3-hydrazinopyridazines having hypotensive activity Expired - Lifetime US3535317A (en)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925381A (en) * 1973-03-07 1975-12-09 Isf Spa 6-Substituted 3-carbethoxyhydrazinopyridazine
US4086343A (en) * 1976-06-11 1978-04-25 I.S.F. Spa Acylated hydrazinopyridazine antihypertensives
US4259328A (en) * 1977-06-13 1981-03-31 Richter Gedeon Vegyeszeti Gyar Rt Morpholino pyridazinylhydrazones

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IT1054107B (en) * 1970-12-15 1981-11-10 Isf Spa NEW 3, HYDRAZINOPYRIDAZINE 6, SUBSTITUTED FOR ANTI-HYPERTEN SIVA ACTIVITIES AND THEIR PREPARATION
US4247551A (en) 1979-09-17 1981-01-27 Gruppo Lepetit S.P.A. N-Pyrrolyl-pyridazineamines and their use as antihypertensive agents

Citations (1)

* Cited by examiner, † Cited by third party
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US2484029A (en) * 1945-12-21 1949-10-11 Ciba Pharm Prod Inc Hydrazine derivatives of pyridazine compounds

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2484029A (en) * 1945-12-21 1949-10-11 Ciba Pharm Prod Inc Hydrazine derivatives of pyridazine compounds

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3925381A (en) * 1973-03-07 1975-12-09 Isf Spa 6-Substituted 3-carbethoxyhydrazinopyridazine
US4086343A (en) * 1976-06-11 1978-04-25 I.S.F. Spa Acylated hydrazinopyridazine antihypertensives
US4259328A (en) * 1977-06-13 1981-03-31 Richter Gedeon Vegyeszeti Gyar Rt Morpholino pyridazinylhydrazones

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