SE427183B - MONO- (ALKEN-1-YL) -XANTINES FOR USE AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC VALUABLE HYDROXIAL COOLXANTIN COMPOUNDS - Google Patents
MONO- (ALKEN-1-YL) -XANTINES FOR USE AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC VALUABLE HYDROXIAL COOLXANTIN COMPOUNDSInfo
- Publication number
- SE427183B SE427183B SE7807853A SE7807853A SE427183B SE 427183 B SE427183 B SE 427183B SE 7807853 A SE7807853 A SE 7807853A SE 7807853 A SE7807853 A SE 7807853A SE 427183 B SE427183 B SE 427183B
- Authority
- SE
- Sweden
- Prior art keywords
- alken
- mono
- intermediates
- compounds
- preparation
- Prior art date
Links
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
- C07D473/10—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
-
- 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
- C07D473/08—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
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
- Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)
- Steroid Compounds (AREA)
Description
7807853-2 Uppfinningen avser således mellanprodukter med den allmänna Rï j? \N "l:-N-R3 (I) / ß N» i 12 i R formeln l vari en av grupperna R , R2 och R3 utgör en mono(alken-l-yl)-grupp med 4-8 kolatomer, varvid (wßl)-ställningen icke uppbär någon för- grening, och de båda andra grupperna är alkylgrupper med l-l2 kol- atomer, men varvid Rl eller R3 även kan vara väte. Dessa föreningar kan framställas genom att man på i och för sig känt sätt omsätter en halogenalken med en dubbelbindning i ändställning, vilken icke inne- håller någon tertiär kolatom och vari halogenatomen är bunden vid mättat kol, med ett alkalisalt av motsvarande xantinförening med de ovan angivna substituenterna. Man använder företrädesvis halogenalkener med ogrenad kolkedja, i vilka halogenatomen och dubbelbindningen är belägna på största möjliga avstånd från varandra. 7807853-2 The invention thus relates to intermediates with the general R Wherein N of the groups R, R2 and R3 is a mono (alken-1-yl) group having 4-8 carbon atoms, wherein The (wßl) position does not carry any branching, and the other two groups are alkyl groups having 1-2 carbon atoms, but wherein R 1 or R 3 may also be hydrogen, these compounds can be prepared by knowing per se In this way, a haloalkene with a double bond in the terminal position, which does not contain any tertiary carbon atom and in which the halogen atom is bonded to saturated carbon, reacts with an alkali salt of the corresponding xanthine compound with the above-mentioned substituents. and the double bond are located at the greatest possible distance from each other.
Lämpliga föreningar enligt uppfinningen är exempelvis l-(3'- buten-l'-yl)-, l-(4'-penten-1'-yl)-, l-(5'-hexen-l'-yl)-, l-(2'-metyl- -3'-buten-1'-yl)-3,7-teobromin, l-(5'-hexen-l'-yl)-3-metyl-7-etyl-, -7-propyl-, -7-butyl-, -7-isobutyl- och -7-decylxantin, vidare 7-(2'- metyl-3'-buten-l'-yl)-, 7-(3'-buten-l'-yl)-, 7-(4'-penten-1'-yl)-, 7-(5'-hexen-l'-yl)- och 7-(6'-hepten-l'-yl)-teofyllin såväl som 3-metyl-7-(5'-hexen-l'-yl)-xantin och derivat därav med i l-ställningen föreliggande propyl-, isobutyl-, pentyl- eller hexylgrupp.Suitable compounds according to the invention are, for example, 1- (3'-buten-1'-yl) -, 1- (4'-penten-1'-yl) -, 1- (5'-hexen-1'-yl) - , 1- (2'-methyl--3'-buten-1'-yl) -3,7-theobromine, 1- (5'-hexen-1'-yl) -3-methyl-7-ethyl-, -7-propyl-, -7-butyl-, -7-isobutyl- and -7-decylxanthine, further 7- (2'-methyl-3'-buten-1'-yl) -, 7- (3'- buten-1'-yl) -, 7- (4'-penten-1'-yl) -, 7- (5'-hexen-1'-yl) - and 7- (6'-hepten-1'- yl) -theophylline as well as 3-methyl-7- (5'-hexen-1'-yl) -xanthine and derivatives thereof having in the 1-position propyl, isobutyl, pentyl or hexyl group.
Uppfinningen avser såväl mono(alken-l-yl)-metylxantiner som deras homologer, vari åtminstone en metylgrupp är ersatt med en alkylgrupp med 2-l2 kolatomer. De sistnämnda föreningarna kan exempelvis vara sådana att åtminstone en av grupperna.Rl, R2 och R3 innehåller minst 5 kolatomer.The invention relates both to mono (alken-1-yl) -methylxanthines and to their homologues, in which at least one methyl group is replaced by an alkyl group having 2 to 12 carbon atoms. The latter compounds may, for example, be such that at least one of the groups R1, R2 and R3 contains at least 5 carbon atoms.
Omsättningen av halogenalkenen med alkalimetallsaltet av xantin- föreningen kan utföras på sedvanligt sätt, exempelvis med användning av dimetylformamid såsom aprotiskt lösningsmedel vid l20°C. Reaktions- förloppet såväl som tidpunkten för fullständig omsättning kan med lätt- het övervakas med tunnskiktskromatografiska metoder. Reaktionsproduktana kan isoleras genom avdunstning av lösningsmedlet, exempelvis under redu- cerat tryck. 7807853-2 Alkenylxantinerna enligt uppfinningen kan således användas såsom mellanprodukter vid framställning av terapeutiskt användbara hydroxi- alkylxantiner. Således befrämjar exempelvis l-(5'-hydroxihexyl)-teobro- min genomblödningen. _ Uppfinningen åskådliggöres närmare medelst följande exempel, vari de angivna temperaturerna avser Celsius-grader.The reaction of the haloalkene with the alkali metal salt of the xanthine compound can be carried out in the usual manner, for example using dimethylformamide as the aprotic solvent at 120 ° C. The course of the reaction as well as the time of complete reaction can be easily monitored by thin layer chromatographic methods. The reaction products can be isolated by evaporation of the solvent, for example under reduced pressure. Thus, the alkenyl xanthines of the invention can be used as intermediates in the preparation of therapeutically useful hydroxyalkyl xanthines. Thus, for example, 1- (5'-hydroxyhexyl) -theobromine promotes blood flow. The invention is further illustrated by the following examples, in which the temperatures indicated refer to degrees Celsius.
Exempel l. l-(5'-hexen-l'-yl)-teobromin 16,3 g l-brom-hexen~(5) omsättes under omröring med 20,2 g teobromin-natrium i 200 ml dimetylformamid vid 1200, tills omsätt- ningen avslutats efter ungefär 6-8 timmar, såsom fastställts medelst tunnskiktskromatogram, varefter lösningsmedlet avlägsnas under redu- cerat tryck. Återstoden löses i 100 ml metylenklorid vid 200, av- skiljes från olöslig natriumbromid och renas för eliminering av en mindre mängd mörkfärgade föroreningar på en pelare av neutral alumi- niumoxid. Ur n-hexan kristalliseras färglösa, i klasar förenade nålar med smältpunkten 76-770. Utbyte 24,1 g (92 %). Enligt tunnskiktskromato- grafering på Merck "DC-Fertigplatten Kieselgel 60 F254" med bensen/ aceton (volym 6:4) såsom vätskeflöde (se följande tabell) uppvisar produkten ett Rf-värde av 0,47 och med nitrometan/bensen/pyridin (volym 20:l0:3) såsom vätskeflöde ett Rf-värde av 0,60. Såsom indikator an- vändes UV-ljus, varvid emellertid pyridint i vätskeflödet på grund av sina fluorescenssläckande egenskaper måste avlägsnas vid 500 under reducerat tryck.Example 1. 1- (5'-hexen-1'-yl) -theobromine 16.3 g of 1-bromo-hexene-(5) are reacted with stirring with 20.2 g of theobromine sodium in 200 ml of dimethylformamide at 1200, until the reaction is completed after about 6-8 hours, as determined by thin layer chromatogram, after which the solvent is removed under reduced pressure. The residue is dissolved in 100 ml of methylene chloride at 200, separated from insoluble sodium bromide and purified to eliminate a small amount of dark-colored impurities on a column of neutral alumina. Colorless, clustered needles with melting point 76-770 crystallize from n-hexane. Yield 24.1 g (92%). According to thin layer chromatography on Merck "DC-Fertigplatten Kieselgel 60 F254" with benzene / acetone (volume 6: 4) as liquid flow (see following table) the product has an Rf value of 0.47 and with nitromethane / benzene / pyridine (volume 20: 10: 3) as liquid flow an Rf value of 0.60. UV light was used as the indicator, however, pyridine in the liquid stream due to its fluorescence quenching properties must be removed at 500 under reduced pressure.
Föreningen kan på följande sätt överföras till l-(5'-hexen-l'- yl)-teobromin: 2,6 g av nämnda l-(5'-hexen-l'-yl)-teobromin upphettas ungefär 24 timmar till kokpunkten tillsammans med 25 ml lN svavelsyra. Ett prov av den klara lösningen undersökes tunnskiktskromatografiskt på ovan angivet sätt med avseende på vattenanlagringsgraden, varvid den önskade förfarandeprodukten uppvisar fluorescenssläckning inom ett Rf- intervall av 0,30-0,37 [(nitrometan/bensen/pyridin)}. Efter avslutad omsättning neutraliseras reaktionsblandningen och extraheras med mety- lenklorid. Ur extraktionslösningarna erhåller man förfarandeprodukten i form av färglösa kristaller, som efter omkristallisation ur metanol uppvisar en smältpunkt av 1260. Utbyte 2,6 g (93 %). ' Försöket enligt exempel l upprepas, varvid man erhåller följande mono(alken-l-yl)-xantiner: 7807853-2 4 _. . Rf N Exempel Forenlng 1) 2) Smaltpunkt 2 l-(3'-buten-l'-yl)-teobromin 0,52 0,50 1150 små färglösa stavar ur acetçn " 3 1-(4'-penten-1'-yl)fteobromin 0,54 0,46 K 940 färglösa nålar ur hexan 4 7- (3 Hbuten-l '-y1) -teofyllin o,s4 o, es 11o° färglösa nålar ur aceton s 7- (4 Hpenten-r-yl) -teøfyllin 0,66 0,52 ' sz° små färglösa stavar ur hexan 6 7-<5'-hexan-1'-yl)-teofyllin o,s1 o,e7 42° färglösa stavar ur hexan 7 l-hexyl-3-metyl-7-(5'-hexen-l'- - - 1930 * yl)-xantin * kokpunkt (0,3 mm Hg)The compound can be converted to 1- (5'-hexen-1'-yl) -theobromine in the following manner: 2.6 g of the 1- (5'-hexen-1'-yl) -theobromine are heated for about 24 hours to the boiling point together with 25 ml of 1N sulfuric acid. A sample of the clear solution is examined by thin layer chromatography in the manner indicated above with respect to the degree of water storage, the desired process product exhibiting fluorescence quenching within an Rf range of 0,30-0,37 [(nitromethane / benzene / pyridine)}. After completion of the reaction, the reaction mixture is neutralized and extracted with methylene chloride. From the extraction solutions, the process product is obtained in the form of colorless crystals which, after recrystallization from methanol, have a melting point of 1260. Yield 2.6 g (93%). The experiment of Example 1 is repeated to give the following mono (alken-1-yl) -xanthines: 7807853-2 4 _. . Rf N Example Compound 1) 2) Melting point 2 1- (3'-buten-1'-yl) -theobromine 0.52 0.50 1150 small colorless rods from acetyl "1- 1- (4'-penten-1'- yl) phteobromine 0.54 0.46 K 940 colorless needles of hexane 4 7- (3 Hbuten-1'-y1) -theophylline o, s4 o, es 110 ° colorless needles of acetone s 7- (4 Hpenten-r yl) -theophylline 0.66 0.52 'sz ° small colorless rods of hexane 6 7- <5'-hexan-1'-yl) -theophylline o, s1 o, e7 42 ° colorless rods of hexane 7 l-hexyl -3-methyl-7- (5'-hexen-1'- - - 1930 * yl) -xanthine * boiling point (0.3 mm Hg)
Claims (1)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US48587074A | 1974-07-05 | 1974-07-05 | |
US05/485,869 US4108995A (en) | 1973-07-11 | 1974-07-05 | Hydroxyhexyl-alkylxanthines and pharmaceutical compositions containing hydroxyhexyl-alkylxanthines |
Publications (2)
Publication Number | Publication Date |
---|---|
SE7807853L SE7807853L (en) | 1978-07-14 |
SE427183B true SE427183B (en) | 1983-03-14 |
Family
ID=27048497
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SE7507726A SE420097B (en) | 1974-07-05 | 1975-07-04 | PROCEDURE FOR THE PREPARATION OF HYDROXIAL CHYLXANTINES |
SE7807853A SE427183B (en) | 1974-07-05 | 1978-07-14 | MONO- (ALKEN-1-YL) -XANTINES FOR USE AS INTERMEDIATES IN THE PREPARATION OF THERAPEUTIC VALUABLE HYDROXIAL COOLXANTIN COMPOUNDS |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
SE7507726A SE420097B (en) | 1974-07-05 | 1975-07-04 | PROCEDURE FOR THE PREPARATION OF HYDROXIAL CHYLXANTINES |
Country Status (14)
Country | Link |
---|---|
JP (1) | JPS5250800B2 (en) |
AR (1) | AR210330A1 (en) |
AT (1) | AT339917B (en) |
CA (1) | CA1062710A (en) |
CH (2) | CH622519A5 (en) |
DK (1) | DK140214B (en) |
ES (1) | ES439141A1 (en) |
FI (1) | FI59249C (en) |
FR (1) | FR2277089A1 (en) |
GB (1) | GB1500039A (en) |
LU (1) | LU72897A1 (en) |
NL (1) | NL166476C (en) |
NO (1) | NO143224C (en) |
SE (2) | SE420097B (en) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
HU197569B (en) * | 1984-01-12 | 1989-04-28 | Sandoz Ag | Process for producing 8alpha-acylaminoergoline derivatives and pharmaceuticals comprising such compounds |
DE3525801A1 (en) * | 1985-07-19 | 1987-01-22 | Hoechst Ag | TERTIA HYDROXYALKYLXANTHINE, METHOD FOR THE PRODUCTION THEREOF, THE MEDICINAL PRODUCT CONTAINING IT AND THEIR USE |
EP0570831A2 (en) * | 1992-05-20 | 1993-11-24 | Hoechst Aktiengesellschaft | Use of Xanthinderivatives for treatment of cerebral nerve dammages after disruption of the blood circulation |
-
1975
- 1975-07-02 CH CH859275A patent/CH622519A5/en not_active IP Right Cessation
- 1975-07-03 JP JP50081475A patent/JPS5250800B2/ja not_active Expired
- 1975-07-03 DK DK301775AA patent/DK140214B/en not_active IP Right Cessation
- 1975-07-03 LU LU72897A patent/LU72897A1/xx unknown
- 1975-07-04 FI FI751958A patent/FI59249C/en not_active IP Right Cessation
- 1975-07-04 ES ES439141A patent/ES439141A1/en not_active Expired
- 1975-07-04 AT AT517275A patent/AT339917B/en not_active IP Right Cessation
- 1975-07-04 GB GB28341/75A patent/GB1500039A/en not_active Expired
- 1975-07-04 CA CA230,790A patent/CA1062710A/en not_active Expired
- 1975-07-04 SE SE7507726A patent/SE420097B/en not_active IP Right Cessation
- 1975-07-04 FR FR7521043A patent/FR2277089A1/en active Granted
- 1975-07-04 AR AR258487A patent/AR210330A1/en active
- 1975-07-04 NO NO752423A patent/NO143224C/en unknown
- 1975-07-04 NL NL7507976.A patent/NL166476C/en not_active IP Right Cessation
-
1978
- 1978-07-14 SE SE7807853A patent/SE427183B/en not_active IP Right Cessation
-
1980
- 1980-04-29 CH CH331680A patent/CH622018A5/en not_active IP Right Cessation
Also Published As
Publication number | Publication date |
---|---|
CA1062710A (en) | 1979-09-18 |
GB1500039A (en) | 1978-02-08 |
NO752423L (en) | 1976-01-06 |
SE7507726L (en) | 1976-01-07 |
FI59249C (en) | 1981-07-10 |
FR2277089A1 (en) | 1976-01-30 |
JPS5134194A (en) | 1976-03-23 |
NO143224B (en) | 1980-09-22 |
ES439141A1 (en) | 1977-02-16 |
ATA517275A (en) | 1977-03-15 |
SE420097B (en) | 1981-09-14 |
LU72897A1 (en) | 1976-05-31 |
FR2277089B1 (en) | 1978-03-17 |
NL7507976A (en) | 1976-01-07 |
AU8275575A (en) | 1977-01-06 |
NL166476B (en) | 1981-03-16 |
JPS5250800B2 (en) | 1977-12-27 |
DK140214B (en) | 1979-07-09 |
DK301775A (en) | 1976-01-06 |
FI59249B (en) | 1981-03-31 |
AT339917B (en) | 1977-11-10 |
NL166476C (en) | 1981-08-17 |
AR210330A1 (en) | 1977-07-29 |
CH622519A5 (en) | 1981-04-15 |
DK140214C (en) | 1979-12-03 |
CH622018A5 (en) | 1981-03-13 |
SE7807853L (en) | 1978-07-14 |
FI751958A (en) | 1976-01-06 |
NO143224C (en) | 1981-01-02 |
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