NO120683B - - Google Patents
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- NO120683B NO120683B NO30368A NO30368A NO120683B NO 120683 B NO120683 B NO 120683B NO 30368 A NO30368 A NO 30368A NO 30368 A NO30368 A NO 30368A NO 120683 B NO120683 B NO 120683B
- Authority
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- Norway
- Prior art keywords
- pyridazine
- hydrazino
- morpholino
- lower alkyl
- preparation
- Prior art date
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- 125000000217 alkyl group Chemical group 0.000 claims description 12
- 238000002360 preparation method Methods 0.000 claims description 12
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 10
- -1 carboxy, phenyl Chemical group 0.000 claims description 10
- 150000001875 compounds Chemical class 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 claims description 6
- PHBNMZNMGUQCFK-UHFFFAOYSA-N (6-morpholin-4-ylpyridazin-3-yl)hydrazine Chemical compound N1=NC(NN)=CC=C1N1CCOCC1 PHBNMZNMGUQCFK-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- GLUUGHFHXGJENI-UHFFFAOYSA-N Piperazine Chemical compound C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 claims description 4
- 229910052739 hydrogen Inorganic materials 0.000 claims description 4
- 239000001257 hydrogen Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- 150000001728 carbonyl compounds Chemical class 0.000 claims description 2
- 239000012442 inert solvent Substances 0.000 claims description 2
- 125000003386 piperidinyl group Chemical group 0.000 claims description 2
- 150000004892 pyridazines Chemical class 0.000 claims description 2
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 2
- PHGLUIAXQDYMBW-UHFFFAOYSA-N 6-morpholin-4-yl-N-(propan-2-ylideneamino)pyridazin-3-amine Chemical compound C(C)(C)=NNC=1N=NC(=CC1)N1CCOCC1 PHGLUIAXQDYMBW-UHFFFAOYSA-N 0.000 claims 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 12
- 238000002844 melting Methods 0.000 description 9
- 230000008018 melting Effects 0.000 description 9
- 239000000243 solution Substances 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- 239000002244 precipitate Substances 0.000 description 7
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 5
- ZUTZIMYUEFESGE-UHFFFAOYSA-N (6-piperidin-1-ylpyridazin-3-yl)hydrazine Chemical compound N1=NC(NN)=CC=C1N1CCCCC1 ZUTZIMYUEFESGE-UHFFFAOYSA-N 0.000 description 4
- RPTUSVTUFVMDQK-UHFFFAOYSA-N Hidralazin Chemical compound C1=CC=C2C(NN)=NN=CC2=C1 RPTUSVTUFVMDQK-UHFFFAOYSA-N 0.000 description 4
- LCTONWCANYUPML-UHFFFAOYSA-N Pyruvic acid Chemical compound CC(=O)C(O)=O LCTONWCANYUPML-UHFFFAOYSA-N 0.000 description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 4
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- CUGVKCJTONTOPS-UHFFFAOYSA-N (6-morpholin-4-ylpyridazin-3-yl)hydrazine;dihydrochloride Chemical compound Cl.Cl.N1=NC(NN)=CC=C1N1CCOCC1 CUGVKCJTONTOPS-UHFFFAOYSA-N 0.000 description 2
- GOCQGHHDQKPGGC-UHFFFAOYSA-N 3-piperidin-1-ylpyridazine Chemical compound C1CCCCN1C1=CC=CN=N1 GOCQGHHDQKPGGC-UHFFFAOYSA-N 0.000 description 2
- CHTSWZNXEKOLPM-UHFFFAOYSA-N 5-nitrothiophene-2-carbaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)S1 CHTSWZNXEKOLPM-UHFFFAOYSA-N 0.000 description 2
- 241000282472 Canis lupus familiaris Species 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960002474 hydralazine Drugs 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229940107700 pyruvic acid Drugs 0.000 description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- WLDKNDQFNZDHEA-UHFFFAOYSA-N 4-pyridazin-3-ylmorpholine Chemical compound C1COCCN1C1=CC=CN=N1 WLDKNDQFNZDHEA-UHFFFAOYSA-N 0.000 description 1
- SXINBFXPADXIEY-UHFFFAOYSA-N 5-Nitrofurfural Chemical compound [O-][N+](=O)C1=CC=C(C=O)O1 SXINBFXPADXIEY-UHFFFAOYSA-N 0.000 description 1
- ZAFNJMIOTHYJRJ-UHFFFAOYSA-N Diisopropyl ether Chemical compound CC(C)OC(C)C ZAFNJMIOTHYJRJ-UHFFFAOYSA-N 0.000 description 1
- JOYRKODLDBILNP-UHFFFAOYSA-N Ethyl urethane Chemical compound CCOC(N)=O JOYRKODLDBILNP-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 238000010171 animal model Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000004872 arterial blood pressure Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- OJYGBLRPYBAHRT-IPQSZEQASA-N chloralose Chemical compound O1[C@H](C(Cl)(Cl)Cl)O[C@@H]2[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]21 OJYGBLRPYBAHRT-IPQSZEQASA-N 0.000 description 1
- 229950009941 chloralose Drugs 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- YWEUIGNSBFLMFL-UHFFFAOYSA-N diphosphonate Chemical compound O=P(=O)OP(=O)=O YWEUIGNSBFLMFL-UHFFFAOYSA-N 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000005187 foaming Methods 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 150000002431 hydrogen Chemical class 0.000 description 1
- 239000003326 hypnotic agent Substances 0.000 description 1
- 230000001077 hypotensive effect Effects 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 1
- DLYUQMMRRRQYAE-UHFFFAOYSA-N phosphorus pentoxide Inorganic materials O1P(O2)(=O)OP3(=O)OP1(=O)OP2(=O)O3 DLYUQMMRRRQYAE-UHFFFAOYSA-N 0.000 description 1
- 206010038464 renal hypertension Diseases 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
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
Landscapes
- 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
Fremgangsmåte til fremstilling av nye farmako- Process for the production of new pharmaco-
logisk aktive 3,6-disubstituerte pyridazinfor- logically active 3,6-disubstituted pyridazine for-
bindelser. bonds.
Foreliggende oppfinnelse vedrorer en fremgangsmåte til fremstilling av nye farmakologisk aktive 3 >6-disubstituerte pyridazin-forbindelser. Forbindelsene har folgende formel: The present invention relates to a process for the production of new pharmacologically active 3>6-disubstituted pyridazine compounds. The compounds have the following formula:
hvor R» er hydrogen, lavere alkyl eller hydroksy-lavere alkyl, R" er lavere alkyl eller hydroksy-lavere alkyl, RT og R" kan sammen danne en piperazin-, morfolin- eller piperidinring, R"'f er hydrogen eller lavere alkyl, R<nn> er lavere alkyl, karboksy, fenyl, nitrofuryl eller nitrotienyl. where R» is hydrogen, lower alkyl or hydroxy-lower alkyl, R" is lower alkyl or hydroxy-lower alkyl, RT and R" can together form a piperazine, morpholine or piperidine ring, R"'f is hydrogen or lower alkyl , R<nn> is lower alkyl, carboxy, phenyl, nitrofuryl or nitrothienyl.
Forbindelsene fremstilles ved å Omsette en forbindelse med formelen: hvor R' og R" har den ovenfor angitte betydning, med minst en ekvimolekylar mengde av en karbonylforbindelse med formelen: The compounds are prepared by reacting a compound of the formula: where R' and R" have the above meaning, with at least an equimolecular amount of a carbonyl compound of the formula:
hvor R"' og R"" har den ovenfor angitte betydning, i et inert opplos-ningsmiddel. where R"' and R"" have the above meaning, in an inert solvent.
De fremstilte forbindelsene har vist seg å ha en sterk hypo-tensiv aktivitet som forekommer hos praktisk talt alle "'forbindelsene i klassen. The compounds prepared have been shown to have a strong hypotensive activity which occurs with practically all the compounds in the class.
'3-(2-isopropyliden-hydrazino)-6-morfolino-pyridazin og 3-/~2-(1-metylpropyliden)-hydrazino/-6-morfolino-pyridazin, forårsaket f.eks. ved intravenos administrasjon til hunder, som var bedovet med kloralose og uretan, en betydelig senkning av blodtrykket. Resultat-ene er gitt i tabell 1. '3-(2-isopropylidene-hydrazino)-6-morpholino-pyridazine and 3-/~2-(1-methylpropylidene)-hydrazino/-6-morpholino-pyridazine, caused e.g. by intravenous administration to dogs, which were anesthetized with chloralose and urethane, a significant lowering of blood pressure. The results are given in table 1.
Videre forsok ble foretatt på rotter med renal hypertensjon fremkalt ifolge den metode som er beskrevet av Grollman i Proe. Soc. Focptl. Biol. Med., 57, 102 (1944)• Det ble benyttet dyr som var preparert Further experiments were carried out on rats with renal hypertension induced according to the method described by Grollman in Proe. Soc. Focptl. Biol. Med., 57, 102 (1944)• Animals that had been prepared were used
minst 30 dager i forveien og som hadde et arterietrykk på ikke lavere enn l60 mm Hg. Forbindelsene ble administrert per os en gang om dagen i 5 dager, til grupper på 3-4 rotter i folgende doser: 5, 1, 0.5, 0.25, 0.1 mm/kg. Kt velkjent hypnotisk middel, hydralazin, som ble inngitt i de samme forhold, ble benyttet for sammenligning. Den minste dose ved hvilken forbindelsene enda ble funnet å være effektive, er angitt at least 30 days in advance and who had an arterial pressure of no lower than l60 mm Hg. The compounds were administered per os once a day for 5 days, to groups of 3-4 rats in the following doses: 5, 1, 0.5, 0.25, 0.1 mm/kg. The well-known hypnotic agent, hydralazine, administered in the same conditions, was used for comparison. The lowest dose at which the compounds were still found to be effective is indicated
i tabell 1 sammen med den tilsvarende LDcri for mus. Den effektive dose hos bedSvede hunder er også gitt. in Table 1 together with the corresponding LDcri for mice. The effective dose in bed-sweating dogs is also given.
Det fremgår fra denne tabell at mens toksisiteten er praktisk talt den samme i alle tilfellene, viser de ifolge oppfinnelsen fremstilte forbindelser en betydelig hSyere aktivitet i- forhold til hydralazin i begge typer forsoksdyr. It appears from this table that, while the toxicity is practically the same in all cases, the compounds produced according to the invention show a significantly higher activity compared to hydralazine in both types of experimental animals.
FSlgende eksempler illustrerer oppfinnelsen. The following examples illustrate the invention.
Eksempel 1. Fremstilling av 3-(2-isopropyliden-hydrazino)-6-mor-f olino- pyridazin. 20 g 3-hydrazino-6-morfolino-pyridazin opploses i 450 ml aceton. Opplosningen konsentreres til 7O-8O ml og avkjoles i is. Example 1. Preparation of 3-(2-isopropylidene-hydrazino)-6-mor-folino-pyridazine. Dissolve 20 g of 3-hydrazino-6-morpholino-pyridazine in 450 ml of acetone. The solution is concentrated to 70-80 ml and cooled in ice.
Det utfelte faste stoff separeres ved filtrering og væsken konsentreres til 50 roi* Etter å ha stått en stund kan et annet bunnfall oppsamles. De kombinerte utfellinger opploses i kokende etanol og omkrystalliseres ved'avkjSling. Utbytte 19*3 g (80%), smeltepunkt 187° - 190°C. The precipitated solid is separated by filtration and the liquid is concentrated to 50 roi* After standing for a while another precipitate can be collected. The combined precipitates are dissolved in boiling ethanol and recrystallized by cooling. Yield 19*3 g (80%), melting point 187° - 190°C.
Eksempel 2. Fremstilling av 3-/"2- (l-metylpropyliden)-hydrazino_7-6-morfolino- pyridazin. Example 2. Preparation of 3-[2-(1-methylpropylidene)-hydrazino-7-6-morpholino-pyridazine.
3*9 g 3-hydrazino-6-morfolino-pyridazin og 1.74 g metyletylketon kokes under tilbakelop sammen med vannfri etanol inntil oppløs-ning er fullstendig. Etter å ha stått natten over fordampes opplos-ningsmidlet ved 40°C under forminsket trykk. Resten omkrystalliseres fra isopropyleter. Utbytte 4.23 g (85$), smeltepunkt 125°- 127°C. Eksempel 3* Fremstilling av ~}-/_~ 2- (1-karboksyetyliden) -hydrazino_7-6-morf olino- pyridazin. - 3*90 g 3-hyd.razino-6-morfolino-pyrisazin tilsettes til en vandig opplosning av 1.68 g natriumbikarbonat og I.76 g pyrodruesyre. Blandingen omrores inntil opplosning er fullstendig. Opplosningen filtreres og deretter tilsettes 7*65 ml 10% saltsyre. Et gult bunnfall dannes som oppsamles ved filtrering, vaskes med isvann og torkes 3*9 g of 3-hydrazino-6-morpholino-pyridazine and 1.74 g of methyl ethyl ketone are refluxed together with anhydrous ethanol until dissolution is complete. After standing overnight, the solvent is evaporated at 40°C under reduced pressure. The residue is recrystallized from isopropyl ether. Yield 4.23 g ($85), melting point 125°- 127°C. Example 3* Preparation of ~}-/_~ 2-(1-carboxyethylidene)-hydrazino_7-6-morpholino-pyridazine. - 3*90 g of 3-hydr.razino-6-morpholino-pyrizazine are added to an aqueous solution of 1.68 g of sodium bicarbonate and 1.76 g of pyruvic acid. The mixture is stirred until dissolution is complete. The solution is filtered and then 7*65 ml of 10% hydrochloric acid is added. A yellow precipitate forms which is collected by filtration, washed with ice water and dried
under forminsket trykk over Pg1"^' Utbytte 4>40 g (83$), smeltepunkt 204°- 208°C. under reduced pressure above Pg1"^' Yield 4>40 g (83$), mp 204°- 208°C.
Eksempel 4« Fremstilling av 3-(2-isopropyliden-hydrazino)-6-(4-metyl-- 1- piperazino)- pyridazin. Example 4« Preparation of 3-(2-isopropylidene-hydrazino)-6-(4-methyl-1-piperazino)-pyridazine.
4.17 g 3-hydrazino-6-(4-metyl-l-piperazino)-pyridazin opploses i 20 ml varm aceton. Etter å ha stått en stund oppsamles det utfelte faste stoff og omkrystalliseres fra aceton. Utbytte 4» 27 g ( 86%), smeltepunkt I58<0-> l6l°C. 4.17 g of 3-hydrazino-6-(4-methyl-1-piperazino)-pyridazine are dissolved in 20 ml of hot acetone. After standing for a while, the precipitated solid is collected and recrystallized from acetone. Yield 4" 27 g (86%), melting point 158<0-> 161°C.
Eksempel 5« Fremstilling av 3-(2-benzyliden-hydrazino)-6-piperidino-pyridazin. Example 5« Preparation of 3-(2-benzylidene-hydrazino)-6-piperidino-pyridazine.
To etanolopplosninger inneholdende henholdsvis 3«86 g 3-hydrazino-6-piperidino-pyridazin og 2.12 g benzaldehyd, blandes sammen. Det tilveiebragte bunnfall omkrystalliseres fra isopropylalko-hol. Utbytte 4.5 g (80$), smeltepunkt 235°- 237°C. Two ethanol solutions containing respectively 3.86 g of 3-hydrazino-6-piperidino-pyridazine and 2.12 g of benzaldehyde are mixed together. The resulting precipitate is recrystallized from isopropyl alcohol. Yield 4.5 g ($80), melting point 235°- 237°C.
Eksempel 6. Fremstilling av J- £~ 2-(5-nitro-2-tenyliden)-hydrazino/- Example 6. Preparation of J-£~ 2-(5-nitro-2-thenylidene)-hydrazino/-
6- piperidino- pyridazin. 6-piperidino-pyridazine.
3•86 g 3-hydrazino-6-piperidino-pyridazin og 3-14 g 5-nitro-tiofenaldehyd opploses hver for seg i minst mulig mengde etanol. De to oppløsningene blandes og det utfelte faste stoff oppsamles. Utbytte 5.2 g (78$), smeltepunkt 238<0-> 240°C. 3•86 g of 3-hydrazino-6-piperidino-pyridazine and 3-14 g of 5-nitro-thiophenaldehyde are dissolved separately in the smallest possible amount of ethanol. The two solutions are mixed and the precipitated solid is collected. Yield 5.2 g ($78), melting point 238<0-> 240°C.
Eksempel 7- Fremstilling av 3-/~2-(5-nitro-2-tenyliden)-hydrazino/- Example 7- Preparation of 3-/~2-(5-nitro-2-thenylidene)-hydrazino/-
6- morfolino- pyridazin. 6-morpholino-pyridazine.
En alkoholoppl<y>sning inneholdende 3«14 g 5-nitro-2-tiofen-aldehyd tilsettes til en opplosning av 5«36 g 3-hydrazino-6-morfolino-pyridazin-dihydroklorid, opplost i metanol. Etter ca. 10 minutter dannes et bunnfall, som oppsamles og omkrystalliseres fra metanol. Dette produkt er 3-/~2-(5-nitro-2-tenyliden)-hydrazino_7-6-morfolino-pyridazin hydroklorid. Utbytte. 6.15 g, smeltepunkt 244°- 246°C, Eksempel 8. Fremstilling av 3-/~2-(5-nitro-2-furfuryliden)-hydrazinc^-6- morfolino- pyridazin. An alcohol solution containing 3.14 g of 5-nitro-2-thiophenealdehyde is added to a solution of 5.36 g of 3-hydrazino-6-morpholino-pyridazine dihydrochloride, dissolved in methanol. After approx. After 10 minutes, a precipitate forms, which is collected and recrystallized from methanol. This product is 3-[2-(5-nitro-2-thenylidene)-hydrazino_7-6-morpholino-pyridazine hydrochloride. Dividend. 6.15 g, melting point 244°-246°C, Example 8. Preparation of 3-[2-(5-nitro-2-furfurylidene)-hydrazinc^-6-morpholino-pyridazine.
To separate metanolopplosninger inneholdende henholdsvis 5.36 g 3-hydrazino-6-morfolino-pyridazin-dihydroklorid og 2.82 g 5~ nitro-2-furaldehyd blandes. Etter å ha stått noen timer oppsamles det dannede bunnfall, vaskes med metanol og torkes. Dette produkt er 3-/~2-(5_nitro-2-furfuryliden)-hydrazino/-6-morfolino-pyridazin hydroklorid. Utbytte 5•32 g (75$)• Intet smeltepunkt ble observert under 280°C. Two separate methanol solutions containing respectively 5.36 g of 3-hydrazino-6-morpholino-pyridazine dihydrochloride and 2.82 g of 5-nitro-2-furaldehyde are mixed. After standing for a few hours, the precipitate formed is collected, washed with methanol and dried. This product is 3-/~2-(5_nitro-2-furfurylidene)-hydrazino/-6-morpholino-pyridazine hydrochloride. Yield 5•32 g ($75)• No melting point was observed below 280°C.
Eksempel 9* Fremstilling av 3-Z~2-isopropyliden-hydrazino/-6-piperi-dino- pyridazin.. Example 9* Preparation of 3-Z~2-isopropylidene-hydrazino/-6-piperidino-pyridazine..
15 g 3-hydrazino-6-piperidino-pyridazin opploses i minst mulig aceton ved ca. 0°C. Gule krystaller dannes raskt og disse oppsamles ved filtrering. Den dannede frie base er ustabil og morkner hurtig. Krystallene omdannes derfor med en gang til tilsvarende hydroklorid ved hjelp av en opplosning av hydrogenklorid i dietyl-eter. Utbytte 10 g (42$), smeltepunkt 192° - 195°C. Dissolve 15 g of 3-hydrazino-6-piperidino-pyridazine in as little acetone as possible at approx. 0°C. Yellow crystals form quickly and these are collected by filtration. The free base formed is unstable and darkens rapidly. The crystals are therefore immediately converted to the corresponding hydrochloride by means of a solution of hydrogen chloride in diethyl ether. Yield 10 g ($42), melting point 192° - 195°C.
Eksempel 10. Fremstilling av 3-/~2-(1-karboksyetyliden)-hydrazino/- Example 10. Preparation of 3-[2-(1-carboxyethylidene)-hydrazino/-
6- piperidino- pyridazin. 6-piperidino-pyridazine.
88O mg pyrodruesyre opploses i 6 ml vann og 840 mg natriumbikarbonat tilsettes. Når skumdannelsen som skyldes utvikling av karbondioksyd har stoppet, tilsettes 1.94 g.3-hydrazino-6-piperidino-pyridazin sammen med 3 ml vann. Opplosningen avkjoles, surgjores med 2 N HC1 til en pH på ca. 4- Et gult bunnfall dannes, som oppsamles og torkes under forminsket trykk ved romtemperatur over fos-forpentoksyd. Utbytte 1.8l g (67.0$), smeltepunkt 152°- 155°C. Dissolve 880 mg of pyruvic acid in 6 ml of water and add 840 mg of sodium bicarbonate. When the foaming caused by the evolution of carbon dioxide has stopped, 1.94 g of 3-hydrazino-6-piperidino-pyridazine are added together with 3 ml of water. The solution is cooled, acidified with 2 N HCl to a pH of approx. 4- A yellow precipitate forms, which is collected and dried under reduced pressure at room temperature over phosphorus pentoxide. Yield 1.8l g (67.0$), melting point 152°- 155°C.
Eksempel 11 til 15 Examples 11 to 15
Folgende forbindelser ble fremstilt ved bruk av i alt vesentlig samme fremgangsmåte som er beskrevet i de foregående eksempler. The following compounds were prepared using substantially the same method as described in the preceding examples.
Claims (3)
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 (1)
| Publication Number | Publication Date |
|---|---|
| NO120683B true NO120683B (en) | 1970-11-23 |
Family
ID=9765208
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO30368A NO120683B (en) | 1967-01-25 | 1968-01-24 |
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)
| 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 |
-
1967
- 1967-01-25 GB GB3804/67A patent/GB1168334A/en not_active Expired
- 1967-12-29 IL IL2924867A patent/IL29248A/en unknown
-
1968
- 1968-01-11 NL NL6800466A patent/NL6800466A/xx unknown
- 1968-01-12 DE DE19681695380 patent/DE1695380C3/en not_active Expired
- 1968-01-16 SE SE54168A patent/SE337382B/xx unknown
- 1968-01-22 FI FI16668A patent/FI47663C/en active
- 1968-01-22 FR FR1568058D patent/FR1568058A/fr not_active Expired
- 1968-01-23 CH CH101668A patent/CH471132A/en not_active IP Right Cessation
- 1968-01-24 NO NO30368A patent/NO120683B/no unknown
- 1968-01-24 BR BR19648568A patent/BR6896485D0/en unknown
- 1968-01-24 AT AT70768A patent/AT271491B/en active
- 1968-01-24 DK DK26468A patent/DK117301B/en not_active IP Right Cessation
- 1968-01-25 ES ES349741A patent/ES349741A1/en not_active Expired
- 1968-01-25 BE BE709868D patent/BE709868A/xx not_active IP Right Cessation
- 1968-01-25 YU YU18468A patent/YU32078B/en unknown
- 1968-03-29 FR FR146475A patent/FR7580M/fr not_active Expired
Also Published As
| 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 |
| DE1695380C3 (en) | 1974-07-04 |
| 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 |
| IL29248A (en) | 1971-10-20 |
| BE709868A (en) | 1968-05-30 |
| FR7580M (en) | 1970-01-05 |
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