NO164353B - Analogifremgangsmaate til fremstilling av terapeutisk aktive pyridopyrimidiner. - Google Patents
Analogifremgangsmaate til fremstilling av terapeutisk aktive pyridopyrimidiner. Download PDFInfo
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- NO164353B NO164353B NO855342A NO855342A NO164353B NO 164353 B NO164353 B NO 164353B NO 855342 A NO855342 A NO 855342A NO 855342 A NO855342 A NO 855342A NO 164353 B NO164353 B NO 164353B
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- general formula
- pyridopyrimidines
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- therapeutic active
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- 238000000034 method Methods 0.000 title claims description 8
- 150000008518 pyridopyrimidines Chemical class 0.000 title claims description 6
- 238000002360 preparation method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title description 2
- 150000001299 aldehydes Chemical class 0.000 claims description 6
- OYRRZWATULMEPF-UHFFFAOYSA-N pyrimidin-4-amine Chemical compound NC1=CC=NC=N1 OYRRZWATULMEPF-UHFFFAOYSA-N 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 3
- 125000006273 (C1-C3) alkyl group Chemical group 0.000 claims description 2
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical group C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 2
- -1 dicarbonyl compound Chemical class 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 9
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- 238000006243 chemical reaction Methods 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 239000002904 solvent Substances 0.000 description 4
- JPXBZYGAWLXNHZ-UHFFFAOYSA-N 2,6-dimorpholin-4-ylpyrimidin-4-amine Chemical compound N=1C(N)=CC(N2CCOCC2)=NC=1N1CCOCC1 JPXBZYGAWLXNHZ-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- XYIBRDXRRQCHLP-UHFFFAOYSA-N ethyl acetoacetate Chemical compound CCOC(=O)CC(C)=O XYIBRDXRRQCHLP-UHFFFAOYSA-N 0.000 description 3
- 238000007710 freezing Methods 0.000 description 3
- 230000008014 freezing Effects 0.000 description 3
- JUJWROOIHBZHMG-UHFFFAOYSA-N pyridine Substances C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 3
- 239000007858 starting material Substances 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 208000004880 Polyuria Diseases 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 2
- 230000004087 circulation Effects 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000003792 electrolyte Substances 0.000 description 2
- DWRWSNAREGLUHZ-UHFFFAOYSA-N ethyl pyrimidine-4-carboxylate Chemical compound CCOC(=O)C1=CC=NC=N1 DWRWSNAREGLUHZ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- 210000002254 renal artery Anatomy 0.000 description 2
- 210000002700 urine Anatomy 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 1
- AIEVJAUPVXXFJH-UHFFFAOYSA-N 2-(4,5-dihydro-1h-imidazol-2-ylmethyl)-4,5-dihydro-1h-imidazole Chemical compound N=1CCNC=1CC1=NCCN1 AIEVJAUPVXXFJH-UHFFFAOYSA-N 0.000 description 1
- CSDSSGBPEUDDEE-UHFFFAOYSA-N 2-formylpyridine Chemical compound O=CC1=CC=CC=N1 CSDSSGBPEUDDEE-UHFFFAOYSA-N 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 238000005684 Liebig rearrangement reaction Methods 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 238000009835 boiling Methods 0.000 description 1
- 244000309464 bull Species 0.000 description 1
- 239000012876 carrier material Substances 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 125000004989 dicarbonyl group Chemical group 0.000 description 1
- WASQWSOJHCZDFK-UHFFFAOYSA-N diketene Chemical compound C=C1CC(=O)O1 WASQWSOJHCZDFK-UHFFFAOYSA-N 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 229940030606 diuretics Drugs 0.000 description 1
- 150000002170 ethers Chemical class 0.000 description 1
- NSNUINNJLWFMJH-UHFFFAOYSA-N ethyl 7-methyl-2,4-dimorpholin-4-yl-5-[3-(trifluoromethyl)phenyl]-5,8-dihydropyrido[2,3-d]pyrimidine-6-carboxylate Chemical compound C=12C(C=3C=C(C=CC=3)C(F)(F)F)C(C(=O)OCC)=C(C)NC2=NC(N2CCOCC2)=NC=1N1CCOCC1 NSNUINNJLWFMJH-UHFFFAOYSA-N 0.000 description 1
- LYCAIKOWRPUZTN-UHFFFAOYSA-N ethylene glycol Natural products OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 230000000004 hemodynamic effect Effects 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- YLGXILFCIXHCMC-JHGZEJCSSA-N methyl cellulose Chemical compound COC1C(OC)C(OC)C(COC)O[C@H]1O[C@H]1C(OC)C(OC)C(OC)OC1COC YLGXILFCIXHCMC-JHGZEJCSSA-N 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 238000009519 pharmacological trial Methods 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- QJZUKDFHGGYHMC-UHFFFAOYSA-N pyridine-3-carbaldehyde Chemical compound O=CC1=CC=CN=C1 QJZUKDFHGGYHMC-UHFFFAOYSA-N 0.000 description 1
- BGUWFUQJCDRPTL-UHFFFAOYSA-N pyridine-4-carbaldehyde Chemical compound O=CC1=CC=NC=C1 BGUWFUQJCDRPTL-UHFFFAOYSA-N 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 230000029058 respiratory gaseous exchange Effects 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 230000007306 turnover Effects 0.000 description 1
- 230000000304 vasodilatating effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/10—Antioedematous agents; Diuretics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D211/80—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D211/84—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two 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 directly attached to ring carbon atoms
- C07D211/90—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Heart & Thoracic Surgery (AREA)
- Cardiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Endocrinology (AREA)
- Reproductive Health (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Nitrogen Condensed Heterocyclic Rings (AREA)
- Plural Heterocyclic Compounds (AREA)
- Nitrogen And Oxygen Or Sulfur-Condensed Heterocyclic Ring Systems (AREA)
- Pyridine Compounds (AREA)
Description
Foreliggende oppfinnelse vedrører fremstilling av nye pyridopyrimidiner. Forbindelsene har terapeutisk aktivitet og påvirker spesielt kretsløpet.
Det er allerede kjent at man får derivater av 1,2,3,7-tetrahydro-8-(2-iroidazolin-2-yl)-imidazol\ l, 2-a],-pyridin, når man bringer ekvimolare mengder av et aldehyd og en p-dikarbonyl-forbindelse til reaksjon med hydrogenkloridet av 2,2'-metylendiimidazolin (H. Meyer, Liebigs Ann. Chem. 1981, 1523).
De nye pyridopyrimidiner som fremstilling har den generelle formel I
hvor
R<1> står for pyridyl,
R<2> står for en C1-C3-alkyl,
r<3> står for metyl, og
R<*>, og R<5>, og R** og R^ danner sammen med et oksygenatom en morfolinring.
Pyridopyrimidinene av generell formel I fremstilles ved at man bringer aldehyder av generell formel IV
hvor
R<1> har den ovenfor angitte betydning, til reaksjon med p-dikarbonylforbindelse av generell formel
V,
hvor
R<2> og R<3> har den ovenfor angitte betydning, og 6-aminopyrimidiner av generell formel III,
hvor
R<4>, R<5>, R^ og R<7> har den ovenfor angitte betydning, eventuelt i nærvær av organiske oppløsningsmidler.
Pyridopyrimidinene av formel I er nye og har verdifulle farmakologiske egenskaper. På grunn av den kretsløps-påvirkende, renalt vasodilaterende og diuretiske virkningen kan de anvendes som anti-hypertensivt middel, som vasodila-torer og som diuretlka ved forskjellige forstyrrelser i kretsløpet og elektrolytt-balansen, og utgjør således et viktig tilskudd til farmasien.
På grunn av de basiske funksjonene kan forbindelsene av formel I, avhengig av. fremstillingsfremgangsmåten, oppnås som salter.
Avhengig av typen av de anvendte utgangsstoffene kan syntesen av forbindelsene av formel I gjengis ved følgende for-melskjema, hvor fremstillingen av 2,4-dimorfolino-7-metyl-5-(3-trifluormetylfenyl)-5,8-dihydro-pyrido[2,3-d]-pyrimidin-6-karbonsyreetylester er valgt som eksempel:
Ifølge fremgangsmåten bringes et aldehyd av den generelle formelen IV til reaksjon med en e-dikarbonylforbindelse av generell formel V og et 6-aminopyrimidin av generell formel III
I formlene IV, V og III har restene R<1>, R<2>, R<3>, R<4>, R5, R6 og R<7> den ovenfor angitte betydning.
De aldehydene av formel IV som kan anvendes som utgangsstoffer er kjente fra litteraturen eller kan fremstilles ved fremgangsmåter som er kjente fra litteraturen (se f.eks. Mosettig, Org. Reactions VIII, 218 ff (1954)).
g<->dikarbonylforbindelsene av generell formel V som kan anvendes ifølge oppfinnelsen er kjente fra litteraturen eller kan fremstilles ved fremgangsmåter som er kjente fra litteraturen (f.eks. D. Borrmann, "Umsetzung von Diketen mit Alkoholen, Phenolen und Mercaptanen", i Houben-Weyl, Methoden der Organischen Chemie, bind VII/4, 230 (1968); Y,. Oikawa, K. Sugano og 0. Yonemitsu, J. Org. Chem. 43, 2087 (1978)).
De som utgangsstoffer anvendte 6-aminopyrimidinene av generell formel III er kjente fra litteraturen, eller kan fremstilles ved fremgangsmåter som er kjente fra litteraturen (se f.eks. Chem. Pharm. Bull 19, 1526 (1971)).
Som fortynningsmidler kommer fortrinnsvis organiske op-pløsningsmidler på tale, eksempelvis alkoholer som metanol, etanol eller isopropanol, eller etere som dioksan, tetrahyd-rofuran, glykolmonometylester eller glykoldimetyleter eller dimetylformamid, dimetylsulfoksyd, acetonitril, pyridin, heksametylfosforsyretriamid eller iseddik.
Reaksjonstemperaturene kan variere innen et vidt området. Generelt arbeider man mellom 20° C og 150°C, fortrinnsvis mellom 20°C og 120°C, spesielt ved koketemperaturen for det anvendte oppløsningsmiddelet.
Omsetningen kan gjennomføres ved normaltrykk, men også ved forhøyet trykk. Generelt arbeider man under normaltrykk.
Ved gjennomføringen av fremgangsmåten Ifølge oppfinnelsen bringes 1 mol aldehyd til reaksjon med 1 mol B-dikarbonylforbindelse og 1 mol 6-amInopyrimidin i et egnet oppløsningsmid-del. Isoleringen og rensingen av stoffene foregår fortrinnsvis, slik at man avdestiUerer oppløsningsmiddelet I vakuum og omkrystalliserer den oppnådde resten fra et egnet oppløsningsmiddel, eller ved en av de kjente rensefremgangs-måtene ifølge teknikkens stand, som eksempelvis søyle-kromatografi på egnede bærermaterialer.
Forbindelsene fremstilt Ifølge oppfinnelsen viser over-raskende en spesiell virkning i det renale området: På bedøvede hunder som gis kunstig åndedrett utøver de ovenfor omtalte forbindelsene en spesifikk renal kar-dilaterende virkning, den kommer til uttrykk i en økning av blodstrømmen i A.renalis. For å fastlegge denne effekten legges nyrearteriene fri og befris for det omgivende vevet. Deretter festes et elektromagnetisk "Flow"-målehode. Den selektive gjennomstrømningsøkningen i nyrearteriene obser-veres etter tilførsel av doser fra 0,03 mg/kg av forbindelsene av formel I. Først i høyere doser, fra ca. 1 mg/kg, kan effekter på den generelle hemodynamikken påvises.
I tillegg viser forbindelsene av formel I en dieuretisk virkning, som kan påvises på bevisste rotter etter oral tilførsel. For dette formålet belastes bevisste rotter med 10 til 30 ml vann, henholdsvis 0,9# koksaltoppløsning pr. kg kroppsvekt, behandles oralt med faststoff som er tatt opp i tylose-suspensjon og holdes deretter i et stoffskiftebur for oppsamling av. urinen over 6 timer. De angitte forbindelsene forhøyer i doser fra 3 mg/kg p.o. urinvolumene, samt de i disse tidsrommene totalt utskilte elektrolyttmengdene av natrium og klorid. Den renale kaliumutskillelsen er sammenlignet med ubehandlede kontrolldyr bare svakt forhøyet.
Fremstillingseksempler
Eksempel 1
Omsetning av pyridin-2-aldehyd, aceteddiksyreetylester og 6-amino-2,4-dimorfolino-pyrimidin i etanol gir 2,4-dimorfolino-7-metyl-5-(pyridyl-2 )-5 ,8-dihydropyrido [ 2 ,3-d}pyrlmidin-6-karbonsyreetylester, med frysepunkt: 226°C (etanol/dimetylformamid). Utbytte: 53#.
Eksempel 2
Analogt eksempel 1 fikk man ved omsetning av pyridin-3--aldehyd, aceteddiksyreetylester og 6-amino-2,4-dimorfolino-pyrimidin i etanol, 2,4-dimorfolino-7-metyl-5-(pyridyl-3)-5,8-dihydropyrido£2,3-dJ pyrimidin-6-karbonsyreetylester, med frysepunkt: 229°C (etanol). Utbytte: 56*.
Eksempel 3
Analogt eksempel 1 fikk man ved omsetning av pyridin-4— aldehyd, aceteddiksyreetylester og 6-amino-2,4-dimorfolino-pyrimidin i etanol, 2,4-dlmorfolino-7-metyl-5-(pyridyl-4)-5,8-dihydropyrido f2 ,3-dJ pyrimidin-6-karbonsyreetylester, med frysepunkt: 209°C (toluene). Utbytte: 53%.
Farmakologiske forsøk:
De etterfølgende tabellene angir virkningen av noen av forbindelser fremstilt ifølge oppfinnelsen.
Claims (1)
- Analogifremgangsmåte til fremstilling av terapeutisk aktive pyridopyrimidiner av generell formel (I) hvor R<1> står for pyridy1,R<2> står for en C1-C3-alkyl,R<3> står for metyl, ogR<4>, og R<5>, og r<6> og R<7> danner sammen med et oksygenatom en morfolinring, karakterisert ved at man omsetter aldehyder av generell formel (IV) med en g<->dikarbonylforbindelse av generell formel (V), og et 6-aminopyrimidin av generell formel (III), hvor R<*> til R<7> har den ovenfor angitte betydning, eventuelt i nærvær av inerte organiske oppløsningsmidler ved temperaturer mellom 20 og 150'C.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19853501696 DE3501696A1 (de) | 1985-01-19 | 1985-01-19 | Pyridopyrimidine, mehrere verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO855342L NO855342L (no) | 1986-07-21 |
| NO164353B true NO164353B (no) | 1990-06-18 |
| NO164353C NO164353C (no) | 1990-09-26 |
Family
ID=6260235
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO855342A NO164353C (no) | 1985-01-19 | 1985-12-30 | Analogifremgangsmaate til fremstilling av terapeutisk aktive pyridopyrimidiner. |
Country Status (18)
| Country | Link |
|---|---|
| US (1) | US4621082A (no) |
| EP (1) | EP0189045B1 (no) |
| JP (1) | JPS61167688A (no) |
| CN (1) | CN1010947B (no) |
| AT (1) | ATE50407T1 (no) |
| AU (1) | AU578783B2 (no) |
| CA (1) | CA1276636C (no) |
| DE (2) | DE3501696A1 (no) |
| DK (1) | DK23386A (no) |
| ES (1) | ES8704491A1 (no) |
| FI (1) | FI81574C (no) |
| GR (1) | GR860117B (no) |
| HU (1) | HU195812B (no) |
| NO (1) | NO164353C (no) |
| NZ (1) | NZ214842A (no) |
| PH (1) | PH22610A (no) |
| PT (1) | PT81860B (no) |
| ZA (1) | ZA86363B (no) |
Families Citing this family (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AU598093B2 (en) * | 1987-02-07 | 1990-06-14 | Wellcome Foundation Limited, The | Pyridopyrimidines, methods for their preparation and pharmaceutical formulations thereof |
| JP2829451B2 (ja) | 1990-11-30 | 1998-11-25 | 大塚製薬株式会社 | 活性酸素抑制剤 |
| JPH04260503A (ja) * | 1991-02-13 | 1992-09-16 | Sekisui Jushi Co Ltd | ピッキングシステム |
| JP3013905B2 (ja) * | 1991-06-28 | 2000-02-28 | 花王株式会社 | 自動倉庫の入出庫方法 |
| PT100905A (pt) * | 1991-09-30 | 1994-02-28 | Eisai Co Ltd | Compostos heterociclicos azotados biciclicos contendo aneis de benzeno, ciclo-hexano ou piridina e de pirimidina, piridina ou imidazol substituidos e composicoes farmaceuticas que os contem |
| US5405848A (en) * | 1993-12-22 | 1995-04-11 | Ortho Pharmaceutical Corporation | Substituted thiazolylaminotetrahydropyridopyrimidines derivatives useful as platelet aggregation inhibitors |
| US6756367B2 (en) | 1998-02-03 | 2004-06-29 | Novartis Ag | Benzo-oxadiazoles, -thiadiazoles and -1,4-diazines, pharmaceutical compositions containing them and a process for preparing them |
| US6184226B1 (en) | 1998-08-28 | 2001-02-06 | Scios Inc. | Quinazoline derivatives as inhibitors of P-38 α |
| JP2006515847A (ja) * | 2002-12-13 | 2006-06-08 | ニューロジェン・コーポレーション | カプサイシン受容体調節剤としてのカルボン酸、ホスフェート又はホスホネート置換キナゾリン−４−イルアミン類縁体 |
| US20070082920A1 (en) * | 2005-10-06 | 2007-04-12 | Yongsheng Song | NAD+-dependent DNA ligase inhibitors |
| DE102006026583A1 (de) * | 2006-06-07 | 2007-12-13 | Bayer Healthcare Aktiengesellschaft | Aryl-substituierte hetero-bicyclische Verbindungen und ihre Verwendung |
| DE102006026585A1 (de) * | 2006-06-07 | 2007-12-13 | Bayer Healthcare Aktiengesellschaft | Substituierte 4-Aryl-1,4-dihydro-1,6-naphthyridine und ihre Verwendung |
| CN107405350A (zh) * | 2016-02-04 | 2017-11-28 | 江苏恒瑞医药股份有限公司 | 一种含有吡啶并嘧啶类衍生物或其可药用盐的药物组合物 |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3021332A (en) * | 1954-01-04 | 1962-02-13 | Burroughs Wellcome Co | Pyrido (2, 3-d) pyrimidine compounds and method of making |
| GB1129084A (en) * | 1965-02-18 | 1968-10-02 | Wellcome Found | Novel pyrido[2,3-d]pyrimidines |
| DE3438350A1 (de) * | 1984-10-19 | 1986-04-24 | Gödecke AG, 1000 Berlin | 4-oxo-pyrido (2,3-d) pyrimidin-derivate, verfahren zu deren herstellung und deren verwendung |
| DE3438351A1 (de) * | 1984-10-19 | 1986-04-24 | Gödecke AG, 1000 Berlin | 4-alkoxy-pyrido(2,3-d)pyrimidin-derivate, verfahren zu deren herstellung und deren verwendung |
-
1985
- 1985-01-19 DE DE19853501696 patent/DE3501696A1/de not_active Withdrawn
- 1985-12-30 NO NO855342A patent/NO164353C/no unknown
-
1986
- 1986-01-07 DE DE8686100096T patent/DE3669041D1/de not_active Expired - Lifetime
- 1986-01-07 AT AT86100096T patent/ATE50407T1/de not_active IP Right Cessation
- 1986-01-07 US US06/816,594 patent/US4621082A/en not_active Expired - Fee Related
- 1986-01-07 EP EP86100096A patent/EP0189045B1/de not_active Expired - Lifetime
- 1986-01-10 AU AU52193/86A patent/AU578783B2/en not_active Ceased
- 1986-01-16 FI FI860197A patent/FI81574C/fi not_active IP Right Cessation
- 1986-01-16 NZ NZ214842A patent/NZ214842A/xx unknown
- 1986-01-17 PH PH33297A patent/PH22610A/en unknown
- 1986-01-17 ES ES551013A patent/ES8704491A1/es not_active Expired
- 1986-01-17 ZA ZA86363A patent/ZA86363B/xx unknown
- 1986-01-17 GR GR860117A patent/GR860117B/el unknown
- 1986-01-17 HU HU86250A patent/HU195812B/hu unknown
- 1986-01-17 CA CA000499768A patent/CA1276636C/en not_active Expired - Lifetime
- 1986-01-17 JP JP61006593A patent/JPS61167688A/ja active Pending
- 1986-01-17 PT PT81860A patent/PT81860B/pt not_active IP Right Cessation
- 1986-01-17 DK DK23386A patent/DK23386A/da not_active Application Discontinuation
- 1986-01-18 CN CN86100279A patent/CN1010947B/zh not_active Expired
Also Published As
| Publication number | Publication date |
|---|---|
| AU5219386A (en) | 1986-07-24 |
| EP0189045A3 (en) | 1988-10-05 |
| JPS61167688A (ja) | 1986-07-29 |
| ES8704491A1 (es) | 1987-04-01 |
| EP0189045B1 (de) | 1990-02-14 |
| FI860197A (fi) | 1986-07-20 |
| PT81860B (pt) | 1988-05-27 |
| PH22610A (en) | 1988-10-17 |
| US4621082A (en) | 1986-11-04 |
| HU195812B (en) | 1988-07-28 |
| FI81574C (fi) | 1990-11-12 |
| NZ214842A (en) | 1988-07-28 |
| CN1010947B (zh) | 1990-12-26 |
| CN86100279A (zh) | 1986-11-19 |
| DE3501696A1 (de) | 1986-07-24 |
| DK23386A (da) | 1986-07-20 |
| ES551013A0 (es) | 1987-04-01 |
| ZA86363B (en) | 1986-09-24 |
| DE3669041D1 (de) | 1990-03-22 |
| FI860197A0 (fi) | 1986-01-16 |
| NO164353C (no) | 1990-09-26 |
| GR860117B (en) | 1986-05-16 |
| EP0189045A2 (de) | 1986-07-30 |
| AU578783B2 (en) | 1988-11-03 |
| CA1276636C (en) | 1990-11-20 |
| DK23386D0 (da) | 1986-01-17 |
| FI81574B (fi) | 1990-07-31 |
| NO855342L (no) | 1986-07-21 |
| HUT40127A (en) | 1986-11-28 |
| PT81860A (en) | 1986-02-01 |
| ATE50407T1 (de) | 1990-02-15 |
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