CH544763A - Spiro addn prods of n-heterocyclics and maleimides - useful as cholesterol lowering cpds - Google Patents
Spiro addn prods of n-heterocyclics and maleimides - useful as cholesterol lowering cpdsInfo
- Publication number
- CH544763A CH544763A CH1650771A CH1650771A CH544763A CH 544763 A CH544763 A CH 544763A CH 1650771 A CH1650771 A CH 1650771A CH 1650771 A CH1650771 A CH 1650771A CH 544763 A CH544763 A CH 544763A
- Authority
- CH
- Switzerland
- Prior art keywords
- spiro
- maleimides
- addn
- prods
- heterocyclics
- Prior art date
Links
- 125000003003 spiro group Chemical group 0.000 title claims abstract description 8
- 150000003923 2,5-pyrrolediones Chemical class 0.000 title claims description 3
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title 2
- 235000012000 cholesterol Nutrition 0.000 title 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims abstract description 10
- 125000000623 heterocyclic group Chemical group 0.000 claims abstract description 6
- PEEHTFAAVSWFBL-UHFFFAOYSA-N Maleimide Chemical compound O=C1NC(=O)C=C1 PEEHTFAAVSWFBL-UHFFFAOYSA-N 0.000 claims abstract description 5
- PBMFSQRYOILNGV-UHFFFAOYSA-N pyridazine Chemical compound C1=CC=NN=C1 PBMFSQRYOILNGV-UHFFFAOYSA-N 0.000 claims abstract description 5
- 239000002904 solvent Substances 0.000 claims abstract description 5
- XSCHRSMBECNVNS-UHFFFAOYSA-N benzopyrazine Natural products N1=CC=NC2=CC=CC=C21 XSCHRSMBECNVNS-UHFFFAOYSA-N 0.000 claims abstract description 4
- LFSXCDWNBUNEEM-UHFFFAOYSA-N phthalazine Chemical compound C1=NN=CC2=CC=CC=C21 LFSXCDWNBUNEEM-UHFFFAOYSA-N 0.000 claims abstract description 4
- 239000003112 inhibitor Substances 0.000 claims abstract description 3
- 238000005984 hydrogenation reaction Methods 0.000 claims abstract 2
- 238000000034 method Methods 0.000 claims description 11
- 229910052799 carbon Inorganic materials 0.000 claims description 6
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 229960000583 acetic acid Drugs 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- 239000012362 glacial acetic acid Substances 0.000 claims description 4
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 4
- 238000002360 preparation method Methods 0.000 claims description 4
- 239000007858 starting material Substances 0.000 claims description 3
- 150000002391 heterocyclic compounds Chemical class 0.000 claims description 2
- 238000006116 polymerization reaction Methods 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims 1
- 230000001419 dependent effect Effects 0.000 claims 1
- 125000005842 heteroatom Chemical group 0.000 description 5
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 4
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 3
- 238000002844 melting Methods 0.000 description 3
- 230000008018 melting Effects 0.000 description 3
- HIDBROSJWZYGSZ-UHFFFAOYSA-N 1-phenylpyrrole-2,5-dione Chemical compound O=C1C=CC(=O)N1C1=CC=CC=C1 HIDBROSJWZYGSZ-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- KYQCOXFCLRTKLS-UHFFFAOYSA-N Pyrazine Chemical compound C1=CN=CC=N1 KYQCOXFCLRTKLS-UHFFFAOYSA-N 0.000 description 2
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 2
- KAESVJOAVNADME-UHFFFAOYSA-N Pyrrole Chemical compound C=1C=CNC=1 KAESVJOAVNADME-UHFFFAOYSA-N 0.000 description 2
- SMWDFEZZVXVKRB-UHFFFAOYSA-N Quinoline Chemical compound N1=CC=CC2=CC=CC=C21 SMWDFEZZVXVKRB-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 2
- 125000003118 aryl group Chemical group 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 150000001721 carbon Chemical group 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- AWJUIBRHMBBTKR-UHFFFAOYSA-N isoquinoline Chemical compound C1=NC=CC2=CC=CC=C21 AWJUIBRHMBBTKR-UHFFFAOYSA-N 0.000 description 2
- 238000001819 mass spectrum Methods 0.000 description 2
- 239000000203 mixture Substances 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 125000001424 substituent group Chemical group 0.000 description 2
- JYEUMXHLPRZUAT-UHFFFAOYSA-N 1,2,3-triazine Chemical compound C1=CN=NN=C1 JYEUMXHLPRZUAT-UHFFFAOYSA-N 0.000 description 1
- BJEMXPVDXFSROA-UHFFFAOYSA-N 3-butylbenzene-1,2-diol Chemical compound CCCCC1=CC=CC(O)=C1O BJEMXPVDXFSROA-UHFFFAOYSA-N 0.000 description 1
- WSNMPAVSZJSIMT-UHFFFAOYSA-N COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 Chemical compound COc1c(C)c2COC(=O)c2c(O)c1CC(O)C1(C)CCC(=O)O1 WSNMPAVSZJSIMT-UHFFFAOYSA-N 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- ZCQWOFVYLHDMMC-UHFFFAOYSA-N Oxazole Chemical compound C1=COC=N1 ZCQWOFVYLHDMMC-UHFFFAOYSA-N 0.000 description 1
- PCNDJXKNXGMECE-UHFFFAOYSA-N Phenazine Natural products C1=CC=CC2=NC3=CC=CC=C3N=C21 PCNDJXKNXGMECE-UHFFFAOYSA-N 0.000 description 1
- WTKZEGDFNFYCGP-UHFFFAOYSA-N Pyrazole Chemical compound C=1C=NNC=1 WTKZEGDFNFYCGP-UHFFFAOYSA-N 0.000 description 1
- CZPWVGJYEJSRLH-UHFFFAOYSA-N Pyrimidine Chemical compound C1=CN=CN=C1 CZPWVGJYEJSRLH-UHFFFAOYSA-N 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 1
- GKIRPKYJQBWNGO-OCEACIFDSA-N clomifene Chemical compound C1=CC(OCCN(CC)CC)=CC=C1C(\C=1C=CC=CC=1)=C(\Cl)C1=CC=CC=C1 GKIRPKYJQBWNGO-OCEACIFDSA-N 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 230000008878 coupling Effects 0.000 description 1
- 238000010168 coupling process Methods 0.000 description 1
- 238000005859 coupling reaction Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 125000005843 halogen group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 125000001841 imino group Chemical group [H]N=* 0.000 description 1
- FPYJFEHAWHCUMM-UHFFFAOYSA-N maleic anhydride Chemical compound O=C1OC(=O)C=C1 FPYJFEHAWHCUMM-UHFFFAOYSA-N 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 150000005054 naphthyridines Chemical class 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 125000000962 organic group Chemical group 0.000 description 1
- 150000004893 oxazines Chemical class 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 230000003285 pharmacodynamic effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- 125000000719 pyrrolidinyl group Chemical group 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000001953 recrystallisation Methods 0.000 description 1
- 150000003413 spiro compounds Chemical class 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 238000010626 work up procedure Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
- C07D487/22—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains four or more hetero rings
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Title spiro 1:2 - adducts are prepd. by reacting a mono- or polynuclear heterocyclic cpd. >=1 > C=N- gp. in ring structure, e.g., phthalazine or pyridazine, with excess maleimide, in presence of a solvent, esp. glacial AcOH, and of a polymsn. inhibitor, and of their hydrogenation products.
Description
Das Hauptpatent betrifft ein Verfahren zur Herstellung von neuen Spiro-Verbindungen der Formel
EMI1.1
in welcher Ar einen gegebenenfalls Heteroatome aufweisenden aromatischen Rest und R' und R2 Wasserstoff oder organische Reste bedeuten, bei dem man eine Schiff'sche Base der Formel AR-CH=N-R' in Gegenwart eines Lösungsmittels bei erhöhter Temperatur mit einem am Stickstoffatom die Gruppe R2 aufweisenden Maleinimid reagieren lässt.
In Weiterentwicklung dieses Verfahrens ergab sich, dass entsprechende Verbindungen mit grösserer Ringzahl erhalten werden, wenn man anstelle von Schiff'schen Basen der genannten Formel einen Ausgangsstoff verwendet, bei dem die Gruppierung
EMI1.2
Bestandteil einer heterocyclischen Ringstruktur ist. Dass Stickstoff als Heteroatom enthaltende Strukturen aromatischen Charakters sich in dieser Reaktion generell wie Schiff'sche Basen verhalten, darf als unerwartet bezeichnet werden.
Die vorliegende Erfindung betrifft demgemäss ein Verfahren zur Herstellung von Spiro- 1 :2-Additionsprodukten aus Nhaltigen Heterocyclen und (gegebenenfalls N-substituierten) Maleinimiden, welche dadurch gekennzeichnet ist, dass man eine ein- oder mehrkernige heteroxyclische Verbindung, in deren Ringstruktur mindestens einmal zwischen einem Kohlenstoffatom und einem benachbarten Stickstoffatom eine ungesättigte Bindung vorliegt, mit einem Überschuss (mit Vorteil natürlich in einem Molverhältnis von 1:2) eines entsprechenden Maleinimids reagieren lässt.
Die Reaktion kann bei Raumtemperatur oder je nachdem mit Vorteil auch bei erhöhten Temperaturen, zweckmässig etwa zwischen 20 und 150es, erfolgen. Vielfach ist die Verwendung eines Lösungsmittels wie beispielsweise Eisessig angezeigt. In der Regel wird namentlich auch die Anwesenheit eines Polymerisations-Inhibitors vorteilhaft sein.
Beispiele von heterocyclischen Verbindungen, die beim Verfahren der Erfindung als Reaktionsteilnehmer verwendet werden können, sind etwa Pyrrol, Pyrazol, Oxazol, Pyridin, Pyridazin, Pyrimidin, Pyrazin, Triazin, Oxazine, Chinolin, Isochinolin, Pyrido-pyridine, Phthalazin und Benzisoxazin.
Darüber hinaus kommen ganz allgemein organische Verbindungen ungesättigten oder teilhydrierten Charakters in Betracht, bei denen eine Ringstruktur die Gruppierung -CH = N- enthält. Diese Ringstruktur kann auch aus weniger als fünf oder mehr als sechs Ringgliedern bestehen, die im übrigen durch Kohlenstoff und/oder weitere Heteroatome, also beliebige zum Eingehen kovalenter Bindungen mit Kohlenstoff befähigte Atome wie N,O,S und dgl., gebildet werden und in freien Positionen durch Halogen, Hydroxy-, Nitro- und andere Radikale oder organische Gruppen wie beispielsweise Alkyl-, Phenyl-, Naphthylreste substituiert sein können. Die Ringstruktur kann auch mit weiteren Ringen, insbesondere Benzolringen oder weiteren heterocyclischen Ringen kondensiert, also Teil eines mehrkernigen Systems sein.
Das als zweiter Reaktionsteilnehmer verwendete Maleinimid kann definitionsgemäss unsubstituiert sein oder am Stickstoffatom Substituenten wie beispielsweise eine aliphatische oder aromatische Gruppe aufweisen, die ihrerseits wieder substituiert sein können.
Die nach dem Verfahren der Erfindung erhaltenen Produkte lassen sich veranschaulichen durch eine Strukturformel, die sich von der eingangs wiedergegebenen dadurch unterscheidet, dass anstelle jedes der beiden dort benützten Symbole Ar und Rl ein Kohlenstoff- oder ein Heteroatom eingefügt ist und diese beiden Atome (sei es durch direkte Bindung oder über weitere Kohlenstoff- und/oder Heteroatome) ringförmig zusammengeschlossen sind, wodurch ein dem mittleren der drei Pyrrolidinringe der oben wiedergegebenen Formel zusätzlich ankondensierter Ring gebildet wird, der je nach Ausgangsstoff auch Substituenten und/oder weitere ankondensierte Ringe aufweisen kann.
Dass nach Ausweis der NMR-Spektren solche Spiro-Strukturen entstehen, widerspricht der Erwartung, nachdem von Cookson und Isaacs in Tetrahedron 19, 1237 (1963) für ein auf ähnliche Weise durch Reaktion von Pyridazin und Maleinsäureanhydrid erhaltenes 1:2-Addukt eine Struktur nachgewiesen worden ist, die unter Neubildung eines Sechserringes zustande kam.
Für nach dem erfindungsgemässen Verfahren erhaltene Produkte sowie auch für durch Reduktion ihrer Carbonyl- und gegebenenfalls verbleibenden Iminogruppen daraus erhaltene Folgeprodukte wurden interessante pharmakodynamische, namentlich cholesterinsenkende Eigenschaften nachgewiesen, die sie zur Verwendung als Arzneimittel geeignet erscheinen lassen.
Beispiel I
In einem Glasautoklaven wurde eine Mischung von 6,5 g (50 mM) Phthalazin, 17,3 g (100 mM) N-Phenylmaleinimid, 0,5 g p-tert.Butyl-benzcatechin und 100 ml Eisessig während 5 Stunden auf 100C erhitzt.
Nach dem Erkalten erhielt man durch Absaugen 19,4 g farbloses Pulver vom Smp. 206-2110C, Isomeres A, welches nach Umkristallisieren aus Butanol bei 210-2120C schmolz: Analyse für C28H20N404 (476,5):
C H N O Berechnet 70,58 4,23 11,76 13,44 Gefunden 70,34 4,17 11,60 13,88
Durch Aufarbeiten der Mutterlauge erhielt man insgesamt 88% d. Th. dieses Adduktes; weitere 4% d. Th. wurden als Isomeres B, Smp. 249-2500C/Butanol, gefasst:
C H N O Gefunden 70,25 4,28 11,67 13,79
Die Molekulargewichte der beiden Produkte wurden durch die Massenspektren bestätigt.
Die Struktur II
EMI2.1
geht aus den NMR-Daten der folgenden Tabelle hervor, in welcher die chemischen Verschiebungen (o[ppm]) und Kopplungskonstanten ([Hzj) der Protonen in den beiden Isomeren A (gemessen in CDCI3) und B (gemessen in Dimethylsulf oxyd-ds) aufgezeigt sind:
A B Hl 7,1-7,5 7,93
H2 5,54 5,07
H3 3,97 4,25
H4 3,82 4,45 Hs 3,51 3,40
H6 3,97 3,80
J23 6,5 7 J34 8 10 J56 19 19
Beispiel 2
Eine Mischung von 10,75 g (134 mM) Pyridazin, 46,06 g (266 mM) N-Phenylmaleinimid, 1,33 g p-tert. Butylbrenzcatechin und 250 ml Eisessig wurde während 24 Stunden bei 25 30OC stehengelassen.
Durch Absaugen des durchkristallisierten Reaktionsgemisches erhielt man 41,7 g Produkt vom Smp. 208 210oC, welches für die Analyse aus Alkohol umkristallisiert wurde: Smp. 209-210oC. Die Aufarbeitung der Mutterlaugen ergab eine Gesamtausbeute von 85% d.Th.
Analyse für C24H1sN404 (426,4)
C H N O Berechnet 67,59 4,26 13,13 15,01 Gefunden 67,40 4,36 12,82 15,42
Das Molekulargewicht wurde durch das Massenspektrum und die Spiro-Struktur III
EMI2.2
durch die NMR-Daten bestätigt (CDCI3): Hl=7,09; H2=6,55; H3=5,91; H4=4,68; Hs und Hs=je ca.
3,7; H7=3,96; Hs=3,04. J12=2; J13=2,5; J23= 10; J24=2; J34=2,5; J78 = 18.
The main patent relates to a process for the preparation of new spiro compounds of the formula
EMI1.1
in which Ar is an aromatic radical optionally containing heteroatoms and R 'and R2 are hydrogen or organic radicals, in which a Schiff's base of the formula AR-CH = NR' in the presence of a solvent at elevated temperature with a nitrogen atom is the group R2 having maleimide can react.
In a further development of this process, it was found that corresponding compounds with a larger number of rings are obtained if, instead of Schiff's bases of the formula mentioned, a starting material is used in which the grouping
EMI1.2
Is part of a heterocyclic ring structure. The fact that nitrogen as a heteroatom-containing structures of aromatic character generally behave like Schiff's bases in this reaction can be described as unexpected.
The present invention accordingly relates to a process for the preparation of spiro 1: 2 addition products from N-containing heterocycles and (optionally N-substituted) maleimides, which is characterized in that a mononuclear or polynuclear heteroxyclic compound in its ring structure at least once between an unsaturated bond is present on a carbon atom and an adjacent nitrogen atom, can react with an excess (advantageously of course in a molar ratio of 1: 2) of a corresponding maleimide.
The reaction can take place at room temperature or, depending on the case, advantageously also at elevated temperatures, expediently between about 20 and 150 °. The use of a solvent such as glacial acetic acid is often indicated. As a rule, the presence of a polymerization inhibitor will also be advantageous.
Examples of heterocyclic compounds which can be used as reactants in the process of the invention include pyrrole, pyrazole, oxazole, pyridine, pyridazine, pyrimidine, pyrazine, triazine, oxazines, quinoline, isoquinoline, pyridopyridines, phthalazine and benzisoxazine.
In addition, organic compounds of unsaturated or partially hydrogenated character in which a ring structure contains the grouping -CH = N- come into consideration. This ring structure can also consist of fewer than five or more than six ring members, which are otherwise formed by carbon and / or other heteroatoms, i.e. any atoms capable of entering into covalent bonds with carbon such as N, O, S and the like free positions can be substituted by halogen, hydroxy, nitro and other radicals or organic groups such as alkyl, phenyl, naphthyl radicals. The ring structure can also be condensed with further rings, in particular benzene rings or further heterocyclic rings, that is to say part of a polynuclear system.
The maleimide used as the second reactant can, by definition, be unsubstituted or have substituents on the nitrogen atom, such as an aliphatic or aromatic group, which in turn can be substituted again.
The products obtained by the process of the invention can be illustrated by a structural formula which differs from that given at the beginning in that instead of each of the two symbols Ar and Rl used there, a carbon atom or a hetero atom is inserted and these two atoms (be it by direct bond or via further carbon and / or heteroatoms) are joined together in a ring, whereby a ring condensed additionally to the middle of the three pyrrolidine rings of the formula given above is formed which, depending on the starting material, may also have substituents and / or further condensed rings.
The fact that such spiro structures are formed according to the NMR spectra contradicts expectations, after Cookson and Isaacs in Tetrahedron 19, 1237 (1963) demonstrated a structure for a 1: 2 adduct obtained in a similar manner by the reaction of pyridazine and maleic anhydride which came about with the formation of a six-ring.
For products obtained by the process according to the invention and also for secondary products obtained therefrom by reducing their carbonyl groups and any remaining imino groups, interesting pharmacodynamic, namely cholesterol-lowering properties have been demonstrated which make them appear suitable for use as medicaments.
Example I.
In a glass autoclave, a mixture of 6.5 g (50 mM) phthalazine, 17.3 g (100 mM) N-phenylmaleimide, 0.5 g p-tert-butyl-benzcatechol and 100 ml glacial acetic acid was heated to 100 ° C. for 5 hours .
After cooling, 19.4 g of colorless powder with a melting point of 206-2110C, isomer A, which melted at 210-2120C after recrystallization from butanol: Analysis for C28H20N404 (476.5):
C H N O Calculated 70.58 4.23 11.76 13.44 Found 70.34 4.17 11.60 13.88
Working up the mother liquor gave a total of 88% of theory. Th. Of this adduct; another 4% d. Th. Were as isomer B, m.p. 249-2500C / butanol:
C H N O Found 70.25 4.28 11.67 13.79
The molecular weights of the two products were confirmed by the mass spectra.
The structure II
EMI2.1
emerges from the NMR data of the following table, in which the chemical shifts (o [ppm]) and coupling constants ([Hzj) of the protons in the two isomers A (measured in CDCI3) and B (measured in dimethylsulfoxide-ds) shown are:
A B Hl 7.1-7.5 7.93
H2 5.54 5.07
H3 3.97 4.25
H4 3.82 4.45 Hs 3.51 3.40
H6 3.97 3.80
J23 6.5 7 J34 8 10 J56 19 19
Example 2
A mixture of 10.75 g (134 mM) pyridazine, 46.06 g (266 mM) N-phenylmaleimide, 1.33 g p-tert. Butyl catechol and 250 ml of glacial acetic acid were left to stand at 25 ° C. for 24 hours.
The reaction mixture which had crystallized through with suction gave 41.7 g of product with a melting point of 208 210 ° C., which was recrystallized from alcohol for analysis: melting point 209 ° -210 ° C. The work-up of the mother liquors gave a total yield of 85% of theory.
Analysis for C24H1sN404 (426.4)
C H N O Calculated 67.59 4.26 13.13 15.01 Found 67.40 4.36 12.82 15.42
The molecular weight was determined by the mass spectrum and the spiro structure III
EMI2.2
confirmed by the NMR data (CDCl3): HI = 7.09; H2 = 6.55; H3 = 5.91; H4 = 4.68; Hs and Hs = approx.
3.7; H7 = 3.96; Hs = 3.04. J12 = 2; J13 = 2.5; J23 = 10; J24 = 2; J34 = 2.5; J78 = 18.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH1650771A CH544763A (en) | 1970-03-26 | 1971-11-12 | Spiro addn prods of n-heterocyclics and maleimides - useful as cholesterol lowering cpds |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH460570A CH529152A (en) | 1970-03-26 | 1970-03-26 | Adducts of maleimides and schiff's base - with spiro ring structure |
| CH1650771A CH544763A (en) | 1970-03-26 | 1971-11-12 | Spiro addn prods of n-heterocyclics and maleimides - useful as cholesterol lowering cpds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CH544763A true CH544763A (en) | 1974-01-15 |
Family
ID=25695875
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CH1650771A CH544763A (en) | 1970-03-26 | 1971-11-12 | Spiro addn prods of n-heterocyclics and maleimides - useful as cholesterol lowering cpds |
Country Status (1)
| Country | Link |
|---|---|
| CH (1) | CH544763A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0319330A3 (en) * | 1987-12-03 | 1991-01-16 | May & Baker Limited | Pyrrolophthalazines |
| EP0728758A1 (en) * | 1995-02-27 | 1996-08-28 | F. Hoffmann-La Roche Ag | Dioxopyrrolo-pyrrole derivatives |
-
1971
- 1971-11-12 CH CH1650771A patent/CH544763A/en unknown
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0319330A3 (en) * | 1987-12-03 | 1991-01-16 | May & Baker Limited | Pyrrolophthalazines |
| EP0728758A1 (en) * | 1995-02-27 | 1996-08-28 | F. Hoffmann-La Roche Ag | Dioxopyrrolo-pyrrole derivatives |
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