NO143064B - Analogifremgangsmaate for fremstilling av terapeutisk aktive hydroksyalkylxantiner - Google Patents
Analogifremgangsmaate for fremstilling av terapeutisk aktive hydroksyalkylxantiner Download PDFInfo
- Publication number
- NO143064B NO143064B NO790627A NO790627A NO143064B NO 143064 B NO143064 B NO 143064B NO 790627 A NO790627 A NO 790627A NO 790627 A NO790627 A NO 790627A NO 143064 B NO143064 B NO 143064B
- Authority
- NO
- Norway
- Prior art keywords
- methyl
- hydroxyhexyl
- residues
- xanthine
- compounds
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 5
- 230000001225 therapeutic effect Effects 0.000 title 1
- 125000004432 carbon atom Chemical group C* 0.000 claims description 18
- -1 5-hydroxyhexyl Chemical group 0.000 claims description 14
- 150000001875 compounds Chemical class 0.000 claims description 11
- 125000000217 alkyl group Chemical group 0.000 claims description 10
- LRFVTYWOQMYALW-UHFFFAOYSA-N 9H-xanthine Chemical class O=C1NC(=O)NC2=C1NC=N2 LRFVTYWOQMYALW-UHFFFAOYSA-N 0.000 claims description 9
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 9
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 5
- 229940083747 low-ceiling diuretics xanthine derivative Drugs 0.000 claims description 5
- 229910052783 alkali metal Inorganic materials 0.000 claims description 3
- 229940100198 alkylating agent Drugs 0.000 claims description 3
- 239000002168 alkylating agent Substances 0.000 claims description 3
- 239000002152 aqueous-organic solution Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 16
- 229940075420 xanthine Drugs 0.000 description 13
- 229960000278 theophylline Drugs 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 6
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical compound IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 description 5
- 235000011121 sodium hydroxide Nutrition 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- YAPQBXQYLJRXSA-UHFFFAOYSA-N theobromine Chemical class CN1C(=O)NC(=O)C2=C1N=CN2C YAPQBXQYLJRXSA-UHFFFAOYSA-N 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- 239000013543 active substance Substances 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 3
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 238000001704 evaporation Methods 0.000 description 3
- 230000008020 evaporation Effects 0.000 description 3
- 229940065721 systemic for obstructive airway disease xanthines Drugs 0.000 description 3
- 229960004559 theobromine Drugs 0.000 description 3
- QIAYXEJPDSASPC-UHFFFAOYSA-N 1-(5-hydroxyhexyl)-3-methyl-7-(2-methylpropyl)purine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)O)C(=O)C2=C1N=CN2CC(C)C QIAYXEJPDSASPC-UHFFFAOYSA-N 0.000 description 2
- FQMLNCMGNMEXAL-UHFFFAOYSA-N 1-(6-hydroxyhexyl)-3,7-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCCCO)C(=O)C2=C1N=CN2C FQMLNCMGNMEXAL-UHFFFAOYSA-N 0.000 description 2
- NUNLMISVGDRQTL-UHFFFAOYSA-N 7-(6-hydroxyhexyl)-3-methylpurine-2,6-dione Chemical compound O=C1NC(=O)N(C)C2=C1N(CCCCCCO)C=N2 NUNLMISVGDRQTL-UHFFFAOYSA-N 0.000 description 2
- NBXBTNZUOPMZAB-UHFFFAOYSA-N 7-butyl-1-(5-hydroxyhexyl)-3-methylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)O)C(=O)C2=C1N=CN2CCCC NBXBTNZUOPMZAB-UHFFFAOYSA-N 0.000 description 2
- RMGVVFDJVCGEPN-UHFFFAOYSA-N 7-decyl-1-(5-hydroxyhexyl)-3-methylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)O)C(=O)C2=C1N=CN2CCCCCCCCCC RMGVVFDJVCGEPN-UHFFFAOYSA-N 0.000 description 2
- RUNBVKCZPOHXJI-UHFFFAOYSA-N 7-ethyl-1-(5-hydroxyhexyl)-3-methylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)O)C(=O)C2=C1N=CN2CC RUNBVKCZPOHXJI-UHFFFAOYSA-N 0.000 description 2
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 2
- ZHNUHDYFZUAESO-UHFFFAOYSA-N Formamide Chemical compound NC=O ZHNUHDYFZUAESO-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 150000001447 alkali salts Chemical class 0.000 description 2
- 239000000010 aprotic solvent Substances 0.000 description 2
- 239000007795 chemical reaction product Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 125000004433 nitrogen atom Chemical group N* 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- GIHUMBWJDVZRRG-UHFFFAOYSA-N 1-(3-hydroxy-2-methylbutyl)-3,7-dimethylpurine-2,6-dione Chemical compound O=C1N(CC(C)C(O)C)C(=O)N(C)C2=C1N(C)C=N2 GIHUMBWJDVZRRG-UHFFFAOYSA-N 0.000 description 1
- NHTADXOAONFEIE-UHFFFAOYSA-N 1-(3-hydroxy-2-methylbutyl)-3-methyl-7-propylpurine-2,6-dione Chemical compound CN1C(=O)N(CC(C)C(C)O)C(=O)C2=C1N=CN2CCC NHTADXOAONFEIE-UHFFFAOYSA-N 0.000 description 1
- CYCCBWAHGKLLTR-UHFFFAOYSA-N 1-(4-hydroxypentyl)-3,7-dimethylpurine-2,6-dione Chemical compound O=C1N(CCCC(O)C)C(=O)N(C)C2=C1N(C)C=N2 CYCCBWAHGKLLTR-UHFFFAOYSA-N 0.000 description 1
- NDNNJYYEMVEBMY-UHFFFAOYSA-N 1-(4-hydroxypentyl)-3-methyl-7h-purine-2,6-dione Chemical compound O=C1N(CCCC(O)C)C(=O)N(C)C2=C1NC=N2 NDNNJYYEMVEBMY-UHFFFAOYSA-N 0.000 description 1
- CERFGCPAKWKZEK-UHFFFAOYSA-N 1-(5-hydroxyhexyl)-3-methyl-7-propylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)O)C(=O)C2=C1N=CN2CCC CERFGCPAKWKZEK-UHFFFAOYSA-N 0.000 description 1
- XHSVMDOOUYTASR-UHFFFAOYSA-N 1-(6-hydroxyheptyl)-3,7-dimethylpurine-2,6-dione Chemical compound O=C1N(CCCCCC(O)C)C(=O)N(C)C2=C1N(C)C=N2 XHSVMDOOUYTASR-UHFFFAOYSA-N 0.000 description 1
- KRRWXRJBMAJEMW-UHFFFAOYSA-N 1-(6-hydroxyhexyl)-3-methyl-7h-purine-2,6-dione Chemical compound O=C1N(CCCCCCO)C(=O)N(C)C2=C1NC=N2 KRRWXRJBMAJEMW-UHFFFAOYSA-N 0.000 description 1
- SYDUIYDGOZLHBZ-UHFFFAOYSA-N 1-(7-hydroxyoctyl)-3,7-dimethylpurine-2,6-dione Chemical compound O=C1N(CCCCCCC(O)C)C(=O)N(C)C2=C1N(C)C=N2 SYDUIYDGOZLHBZ-UHFFFAOYSA-N 0.000 description 1
- CYNYIHKIEHGYOZ-UHFFFAOYSA-N 1-bromopropane Chemical compound CCCBr CYNYIHKIEHGYOZ-UHFFFAOYSA-N 0.000 description 1
- YVJPMXPSIMGRCD-UHFFFAOYSA-N 1-hexyl-7-(5-hydroxyhexyl)-3-methylpurine-2,6-dione Chemical compound O=C1N(CCCCCC)C(=O)N(C)C2=C1N(CCCCC(C)O)C=N2 YVJPMXPSIMGRCD-UHFFFAOYSA-N 0.000 description 1
- MBCJUZGDAUDAIV-UHFFFAOYSA-N 3-butyl-1-(5-hydroxyhexyl)-7-propylpurine-2,6-dione Chemical compound O=C1N(CCCCC(C)O)C(=O)N(CCCC)C2=C1N(CCC)C=N2 MBCJUZGDAUDAIV-UHFFFAOYSA-N 0.000 description 1
- SVHJWYLTQYXDTO-UHFFFAOYSA-N 7-(3-hydroxypentyl)-1,3-dimethylpurine-2,6-dione Chemical compound CN1C(=O)N(C)C(=O)C2=C1N=CN2CCC(O)CC SVHJWYLTQYXDTO-UHFFFAOYSA-N 0.000 description 1
- WPHMRMYOYROJQY-UHFFFAOYSA-N 7-(6-hydroxyhexyl)-1,3-dimethylpurine-2,6-dione Chemical compound O=C1N(C)C(=O)N(C)C2=C1N(CCCCCCO)C=N2 WPHMRMYOYROJQY-UHFFFAOYSA-N 0.000 description 1
- KXIIMNWOLMKCKH-UHFFFAOYSA-N 7-hexyl-1-(5-hydroxyhexyl)-3-methylpurine-2,6-dione Chemical compound CN1C(=O)N(CCCCC(C)O)C(=O)C2=C1N=CN2CCCCCC KXIIMNWOLMKCKH-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
- 150000001298 alcohols Chemical class 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 150000001347 alkyl bromides Chemical class 0.000 description 1
- 150000001348 alkyl chlorides Chemical class 0.000 description 1
- 150000001350 alkyl halides Chemical class 0.000 description 1
- 150000001351 alkyl iodides Chemical class 0.000 description 1
- 230000008321 arterial blood flow Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 150000008050 dialkyl sulfates Chemical class 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 229960004592 isopropanol Drugs 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 150000003112 potassium compounds Chemical class 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 159000000000 sodium salts Chemical class 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000002594 sorbent Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/08—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 1 and 3, e.g. theophylline
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D473/00—Heterocyclic compounds containing purine ring systems
- C07D473/02—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6
- C07D473/04—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms
- C07D473/06—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3
- C07D473/10—Heterocyclic compounds containing purine ring systems with oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6 two oxygen atoms with radicals containing only hydrogen and carbon atoms, attached in position 1 or 3 with methyl radicals in positions 3 and 7, e.g. theobromine
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
Description
Legemidler som inneholder xantinderivater som i 1-, 3-
og 7-stilling inneholder like eller forskjellige alkylrester med 1-6 karbonatomer, av hvilke minst én oppviser en hydrofiliserende gruppe, f.eks. OH, som aktive stoffer, er kjent. Antall hydrofiliserende grupper pr. alkylrest skal da ligge mellom 1 og antallet av karbonatomer i alkylresten (hvorved forbindelser med en hydroksylgruppe ved nabo-C-atomet til ringnitrogenatomet er ustabile), og hydroksyalkylresten skal fortrinnsvis inneholde 1-4 karbonatomer. Særlig er imidlertid bare slike forbindelser åpenbart hvor hydroksyalkylresten eller -restene inneholder 2
eller 3 karbonatomer, hvorved en hydroksylgruppe står i I--
stilling til det tilhørende ringnitrogenatom, mens disse rester dog kan inneholde en ytterligere hydroksylgruppe og hvor alle ikke-hydroksylerte alkylrester er metylrester. Som monohydroksy-alkylforbindelser er spesielt også bare monohydroksyalkylderivater av teobromin og teofyllin åpenbart.
Det er videre kjent legemidler som som aktivt stoff inneholder substituerte xantiner som er substituert med tre alkylrester i 1-, 3- og 7-stilling, hvorved en, to eller tre av substituentene utgjør en monohydroksyalkylrest med 3-4 karbonatomer og de andre er alkylrester. En slik forbindelse er f.eks. 7- ((3-hydroksypropyl) -1, 3-dietylxantin.
Det er videre kjent legemiddelblandinger som som aktivt stoff inneholder f.eks. xantiner som i 1- eller 7-stilling inneholder en hydroksyalkylrest med 6-2 0 karbonatomer og i den annen, såvel som i 3-stilling en alkylrest med ett eller to C-atomer.
Men det er der verken åpenbart spesielle hydroksyalkylforbindelser eller posisjonene for hydroksygruppene.
Det er nå funnet en analogifremgangsmåte for fremstilling
av terapeutisk aktive xantinderivater av formel I:
hvor én av restene R-^, R2 og R, er en ou- eller (o>-l)-hydroksyalkylrest med 4-8 C-atomer og begge de andre rester er rettkjedede eller forgrenede alkylrester med 1-12 C-atomer, men hvor R^ eller R^ også kan være hydrogen, hvorved dog minst én av restene R-L, R2 og R^ har minst 5 C-atomer og hvorved dog R^ har en annen betydning enn 5-hydroksyheksyl når R2 og R^ er metyl,
og fremgangsmåten er karakterisert ved at alkalimetallsalter av forbindelser av formel I, hvor minst én av restene R^, R^ og R^ er et hydrogenatom, men hvor én av restene R^ og R^ er en hydroksyalkyirest, omsettes i - fortrinnsvis vandig-organisk - løsning med alkyleringsmidler. Fortrinnsvis fremstilles slike forbindelser i hvilke en alkylrest inneholder mer enn 2 C-atomer. Fortrinnsvis står hydroksyalkylresten i 1- eller 7-stilling og
er uforgrenet. Forbindelsene som fremstilles i henhold til oppfinnelsen, er nye.
De forbindelser som fremstilles i henhold til oppfinnelsen, viser sterk og langvarig virkning på blodomløpet i hjernen. Med hensyn til denne effekt adskiller de seg på overraskende måte fullstendig fra de kjente, kortkjedede hydroksyalkylderivater av teofyllin og teobromin. Det farmakologiske effektivitetsspektrum for substansene som fremstilles i henhold til oppfinnelsen, stemmer forøvrig overens med spektret for de kjente, kortkjedede hydroksyalkylderivater.av teofyllin og teobromin. Deres toksisi-tet er lav.
Overføringen til alkalisaltene kan f.eks. utføres i en alkohol med 1-3 karbonatomer, spesielt metanol, etanol eller iso-propanol, eller i et aprotisk løsningsmiddel, spesielt formamid, dimetylformamid eller dimetylsulfoksyd. Alkaliet kan særlig an-vendes i form av vandig natronlut, fast natriumhydroksyd eller natriumalkoholat eller de tilsvarende kaliumforbindelser. Alkalisaltene tilsettes U>-hydroksyalkylhalogenidene, og løsningen bringes under oppvarmning til omsetning.
Ved fremgangsmåten i henhold til oppfinnelsen omsettes alkalimetallsaltene av hydroksyalkylxantiner som fremdeles inneholder hydrogen, f.eks. i 1- og/eller 7-stilling, med vanlige alkyleringsmidler såsom rettkjedede eller forgrenede alkyl-halogenider, særlig alkylklorid, alkylbromid og alkyljodid, respektive dialkylsulfater. Den vandig-organiske løsning består av en blanding av vann med organiske løsningemidler som er bland-bare med vann, så som de ovenfor angitte alkoholer og aprotiske løsningsmidler. Som spesielle stoffer kan f.eks. nevnes 1-etyl-resp. l-propyl-3-metyl-7-(5-hydroksyheksyl)-xantin, l-butyl-3-metyl-7-(5-hydroksyheksyl)-xantin, l-isobutyl-3-metyl-7-(5-hydroksyheksyl )-xantin, l-pentyl-3-metyl-7-(5-hydroksyheksyl)-xantin, 1-heksyl-3-metyl-7-(5-hydroksyheksyl)-xantin, l-decyl-3-metyl-7- (5-hydroksyheksyl)-xantin, 1-(5-hydroksyheksyl)-3-metyl-7-etylxantin, 1-(5-hydroksyheksyl-3-metyl-7-propylxantin, 1-(5-hydroksyheksyl)-3-metyl-7-butylxantin, 1-(5-hydroksyheksyl)-3-metyl-7-isobutyl-xantin, 1- (5-hydroksyheksyl)-3-metyl-7-heksylxantin, 1-(5-hydroksyheksyl) -3-metyl-7-decylxantin, 1-(5-hydroksyheksyl)-3-butyl-7-propylxantin, såvel som de tilsvarende 2-metyl-3-hydroksybutyl-, hydroksyheptyl-, resp. hydroksybutylforbindelsene (sistnevnte så-fremst de også oppviser en annen rest med minst 5 karbonatomer). Nevnes kan f.eks. 1-(2-metyl-3-hydroksybutyl)-3-metyl-7-propylxantin respektive dens homologer og de analoge 7-(2-metyl-3-hydroksybutyl)forbindelser. Man kan også nevne l-alkyl-3-metyl-7-(6-hydroksyheksyl)-, resp. 1-(6-hydroksyheksyl)-3-metyl-7-alkyl-xantinene så som 1,3-dimetyl-7-(6-hydroksyheksyl)-xantin, l-(6-hydroksyheksyl)-3,7-dimetylxantin, 1-(6-hydroksyheksyl)-3-metyl-7-etyl-, resp. -propylxantin, videre 1-(6-hydroksyheksyl)-3-metyl-xantin, 3-metyl-7-(6-hydroksyheksyl)-xantin og de tilsvarende hydroksyheptyl-, hydroksypentyl- resp. hydroksybutylforbindelser (sistnevnte såfremt de også oppviser minst én annen rest med minst 5 karbonatomer), f.eks. 1,3-dimetyl-7-(3-hydroksypentyl)-xantin, 1-(2-metyl-3-hydroksybutyl)-3,7-dimetylxantin og 1,3-dimetyl-7-(2-metyl-3-hydroksybutyl)-xantin.
Xantinderivatene som fremstilles i henhold til oppfinnelsen, kan i legemidlet kombineres med ytterligere farmakodynamisk aktive forbindelser, inklusive vitaminer. Xantinderivatene som fremstilles i henhold til oppfinnelsen, har dessuten den effekt at de forbedrer blodets flyteegenskap og således utgjør virksomme substanser til behandling av arterielle blodomløpsforstyrrelser.
De i de følgende eksempler angitte R^-verdier ble bestemt ved hjelp av kromatografi på kiselgel ^ 254 (ferdige plater fra Merck) som sorpsjonsmiddel og med en blanding av benzen og aceton 'i volumforholdet 60:40 som løpemiddel.
Eksempel 1
250 mg 3-n-butyl-7-(5<1->hydroksyheksyl)-xantin løses i 10 ml av en blanding av metanol/etanol (1:1) og tilsettes 40 mg natriumhydroksyd. Etter tilsetning av 0,1 ml 1 n brompropan tilbakeløps-behandles dette i 28 timer. Etter fordampning av løsningsmidlet i vakuum digereres inndampningsresten tre ganger med kloroform. Løsningen inndampes, og reaksjonsproduktet kromatograferes over
en kiselgels kolonne. l-propyl-3-n-butyl-7-(5')-hydroksyheksyl)-xantinet fås i 64,5 % utbytte og med et smp. på 80-82°C.
Analogt fikk man: 1-etyl-resp. l-propyl-3-metyl-7-(51 - hydroksyheksyl)-xantin (smp. 84-85°C resp. smp. 53°C), 1-isobutyl-3-metyl-7-(5<1->hydroksyheksyl)-xantin (smp. 62-63°C), l-pentyl-3-metyl-7-(5<1->hydroksyheksyl)-xantin (smp. 65-67°C), l-heksyl-3-metyl-7-(5'-hydroksyheksyl)-xantin (smp. 68-69°C), 1-(5'-hydroksyheksyl)-3-metyl-7-etylxantin (smp. 87°C), 1-(5'-hydroksyheksyl)-3-metyl-7-propyl-xantin (smp. 76-77°C), 1-(5'-hydroksyheksyl)-3-metyl-7-butyl-xantin (smp. 56-57°C), 1-(5'-hydroksyheksyl)-3-metyl-7-isobutylxantin (smp. 54-55°C), 1-(5'-hydroksyheksyl)-3-metyl-7-decylxantin (smp. 37-38°C), 1-(6'-hydroksyheksyl)-3-metyl-7-etyl- resp. -propylxantin (smp. 93 resp. 68-70°C), 3-metyl-7-(6'-hydroksyheksyl)-xantin (smp. 219-220°C).
Eksempel 2
26,6 g 3-metyl-7-(5<1->hydroksyheksyl)xantin oppløses under tilsetning av en ekvimolar mengde av natriumhydroksyd i en blanding av 125 ml vann og 300 ml n-propanol i varme og tilsettes 20 g metyljodid. Løsningen kokes 3 timer under tilbakeløp, og man får 7-(5'-hydroksyheksyl)-teofyllin, smp. 95-96°C, i ca. 85 % utbytte.
Eksempel 3
6,3 g 3-mety1-7-(41-hydroksypentyl)-xantin oppløses under tilsetning av 1 g natriumhydroksyd i en blanding av 25 ml vann og 100 ml n-propanol i varme og tilsettes langsomt 5 g metyljodid.
Løsningen kokes 3 timer under tilbakeløp. Etter inndampning av løsningen på rotasjonsfordamper i vakuum fås 7-(4'-hydroksypentyl)-teofyllin i 80 % utbytte, smp. 83-84°C; Rf-verdi 0,13.
Eksempel 4
Som i eksempel 3 omsettes 2,8 g 3-metyl-7-(6'-hydroksyheptyl) -xantin med 5 g metyljodid, og dette opparbeides. I knapt 80 % utbytte får man 7-(6<1->hydroksyheptyl)-teofyllin, smp. 109°C; Rf-verdi 0,12.
Eksempel 5
Som i eksempel 3'overføres 0,1 g 3-metyl-7-(7<1->hydroksy-oktyl)-xantin med en ekvimolar mengde av natriumhydroksyd (15 mg) til natriumsaltet og metyleres med 0,1 ml metyljodid. Reaksjonsproduktet tas opp i kloroform og identiteten påvises kromato-grafisk. 7-(7'-hydroksyoktyl)-teofyllinet viser en R^-verdi på 0,23.
Analogt fikk man:
7-(6<1->hydroksyheksyl)-teofyllin (smp. 80°C), 7-(2<1->metyl-3'-hydroksybutyl)-teofyllin (ikke-krystallinsk) og
7-(5'-hydroksyheksyl)-teofyllin (smp. 93-94°C).
Eksempel 6
Som i eksempel 3 omsettes 2,52 g 1-(4'-hydroksypentyl)-3-metyl-xantin med 5 g metyljodid og opparbeides. I 75 % utbytte får man 1-(4'-hydroksypentyl)-teobromin, smp. 100°C; Rf-verdi 0,15.
Analogt fikk man:
1-(6'-hydroksyheksyl)-teobromin (smp. 98-100°C), 1-(2<1->metyl-3'-hydroksybutyl)-teobromin (olje), 1-(6'-hydroksyheptyl)-teobromin (R^-verdi 0,23) og 1-(7 '-hydroksyoktyl)-teobromin (R-^-verdi 0,27).
Strukturene til forbindelsene står i overensstemmelse
med UV-, IR-, kjerneresonans- og masse-spektrene.
Claims (1)
- Analogifremgangsmåte for fremstilling av terapeutisk aktive xantinderivater av formel I:hvor én av restene R^, R., og R^ er en uo- eller (o> -1) -hydroksyalkylrest med 4-8 C-atomer og begge de andre rester er rettkjedede eller forgrenede alkylrester med 1-12 C-atomer, men hvor R^ eller R^ også kan være hydrogen, hvorved dog minst én av restene R^, R2 og R^ har minst 5 C-atomer og hvorved dog R^ har en annen betydning enn 5-hydroksyheksyl når R2 og R^ er metyl, karakterisert ved at alkalimetallsalter av forbindelser av formel I, hvor minst én av restene R^, R2 og R^ betyr et hydrogenatom, men hvor én av restene R-^ og R^ er en hydroksyalkylrest, omsettes i - fortrinnsvis vandig-organisk - løsning med alkyleringsmidler.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE2335170A DE2335170C2 (de) | 1973-07-11 | 1973-07-11 | 1,3-Dialkyl-7-(hydroxyalkyl)-xanthine, Verfahren zu ihrer Herstellung und diese enthaltende Arzneimittel |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO790627L NO790627L (no) | 1975-01-14 |
| NO143064B true NO143064B (no) | 1980-09-01 |
| NO143064C NO143064C (no) | 1980-12-10 |
Family
ID=5886518
Family Applications (2)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO742464A NO140596C (no) | 1973-07-11 | 1974-07-05 | Analogifremgangsmaate for fremstilling av en terapeutisk aktive hydroksyalkylxantiner |
| NO790627A NO143064C (no) | 1973-07-11 | 1979-02-23 | Analogifremgangsmaate for fremstilling av terapeutisk aktive hydroksyalkylxantiner |
Family Applications Before (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO742464A NO140596C (no) | 1973-07-11 | 1974-07-05 | Analogifremgangsmaate for fremstilling av en terapeutisk aktive hydroksyalkylxantiner |
Country Status (17)
| Country | Link |
|---|---|
| US (1) | US4108995A (no) |
| AR (4) | AR199915A1 (no) |
| AT (1) | AT333300B (no) |
| BE (1) | BE816869R (no) |
| CA (1) | CA1062709A (no) |
| CH (4) | CH587852A5 (no) |
| DE (1) | DE2335170C2 (no) |
| DK (1) | DK147004C (no) |
| ES (3) | ES417828A1 (no) |
| FI (1) | FI61703C (no) |
| FR (1) | FR2236501B2 (no) |
| GB (1) | GB1480836A (no) |
| IE (1) | IE41822B1 (no) |
| NL (1) | NL168703C (no) |
| NO (2) | NO140596C (no) |
| SE (1) | SE415354B (no) |
| ZA (1) | ZA744373B (no) |
Families Citing this family (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4207321A (en) * | 1977-04-02 | 1980-06-10 | Hoechst Aktiengesellschaft | Pharmaceutical compositions containing xanthines |
| DE3138397A1 (de) * | 1981-09-26 | 1983-04-07 | Hoechst Ag, 6230 Frankfurt | "arzneimittel, darin enthaltene vicinale dihydroxyalkylxanthine und herstellungsverfahren fuer diese xanthinverbindungen" |
| US4636507A (en) * | 1984-04-30 | 1987-01-13 | Hoechst-Roussel Pharmaceuticals Inc. | Host defense mechanism enhancement |
| DE3525801A1 (de) * | 1985-07-19 | 1987-01-22 | Hoechst Ag | Tertiaere hydroxyalkylxanthine, verfahren zu ihrer herstellung, die sie enthaltenden arzneimittel und ihre verwendung |
| US5338741A (en) * | 1986-10-27 | 1994-08-16 | Nestec S.A. | 1-hydroxyalkylxanthines and medicaments containing them |
| DE3725554A1 (de) * | 1987-08-01 | 1989-02-09 | Hoechst Ag | Pharmazeutisches kombinationspraeparat sowie dessen herstellung und verwendung |
| DE3942871A1 (de) * | 1989-12-23 | 1991-06-27 | Hoechst Ag | R-(-)-1-(5-hydroxyhexyl)-3-methyl-7-propylxanthin, verfahren zu dessen herstellung und diese verbindung enthaltende arzneimittel |
| EP0570831A2 (de) * | 1992-05-20 | 1993-11-24 | Hoechst Aktiengesellschaft | Verwendung von Xanthinderivaten zur Behandlung von Nervenschädigungen nach Unterbrechung der Blutzirkulation |
| US5856330A (en) * | 1996-07-31 | 1999-01-05 | Hoechst Aktiengesellschaft | Use of xanthine derivatives for the inhibition of dephosphorylation of cofilin |
| US5981536A (en) * | 1996-07-31 | 1999-11-09 | Hoechst Aktiengesellschaft | Use of xanthine derivatives for the modulation of apoptosis |
| WO1999031101A1 (en) * | 1997-12-17 | 1999-06-24 | University Of South Florida | Adenosine receptor antagonists with improved bioactivity |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US2756229A (en) * | 1956-07-24 | Xanthine derivatives | ||
| US2517410A (en) * | 1947-08-15 | 1950-08-01 | Searle & Co | Hydroxy alkyl xanthines and the production thereof |
| DE926788C (de) * | 1952-11-07 | 1955-04-25 | Geigy Ag J R | Verfahren zur Herstellung von 1, 3-dialkylierten 7-Oxyalkyl-xanthinabkoemmlingen |
| FR1211333A (fr) * | 1955-10-19 | 1960-03-15 | Boehringer Sohn Ingelheim | Perfectionnements apportés aux procédés pour fabriquer des oxyalcoylxanthines |
| DE1810705C3 (de) * | 1968-11-25 | 1980-11-27 | Hoechst Ag, 6000 Frankfurt | Stabilisierung von Vitaminen |
| DE1911279A1 (de) * | 1969-03-05 | 1970-11-12 | Eckert Dr Theodor | Verfahren zur Erhoehung der Resorptionsfaehigkeit von Arzneistoffen |
-
1973
- 1973-07-11 DE DE2335170A patent/DE2335170C2/de not_active Expired
- 1973-08-02 CH CH1602376A patent/CH587852A5/xx not_active IP Right Cessation
- 1973-08-02 CH CH1124073A patent/CH587850A5/xx not_active IP Right Cessation
- 1973-08-02 CH CH1602476A patent/CH587851A5/xx not_active IP Right Cessation
- 1973-08-02 CH CH1602576A patent/CH587853A5/xx not_active IP Right Cessation
- 1973-08-03 AT AT684573A patent/AT333300B/de not_active IP Right Cessation
- 1973-08-09 DK DK438373A patent/DK147004C/da not_active IP Right Cessation
- 1973-08-10 AR AR249530A patent/AR199915A1/es active
- 1973-08-10 NL NLAANVRAGE7311123,A patent/NL168703C/xx not_active IP Right Cessation
- 1973-08-10 CA CA178,591A patent/CA1062709A/en not_active Expired
- 1973-08-10 SE SE7310986A patent/SE415354B/xx unknown
- 1973-08-11 ES ES417828A patent/ES417828A1/es not_active Expired
-
1974
- 1974-06-26 BE BE145889A patent/BE816869R/xx not_active IP Right Cessation
- 1974-06-28 GB GB28866/74A patent/GB1480836A/en not_active Expired
- 1974-07-05 NO NO742464A patent/NO140596C/no unknown
- 1974-07-05 FI FI2065/74A patent/FI61703C/fi active
- 1974-07-05 US US05/485,869 patent/US4108995A/en not_active Expired - Lifetime
- 1974-07-08 FR FR7423606A patent/FR2236501B2/fr not_active Expired
- 1974-07-08 ZA ZA00744373A patent/ZA744373B/xx unknown
- 1974-07-09 IE IE1456/74A patent/IE41822B1/en unknown
- 1974-10-01 AR AR255872A patent/AR202662A1/es active
- 1974-10-01 AR AR255873A patent/AR202663A1/es active
- 1974-10-01 AR AR255874A patent/AR200626A1/es active
-
1975
- 1975-04-29 ES ES437150A patent/ES437150A1/es not_active Expired
- 1975-04-29 ES ES437151A patent/ES437151A1/es not_active Expired
-
1979
- 1979-02-23 NO NO790627A patent/NO143064C/no unknown
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