DK159453B - METHOD FOR PREPARING 5'-DEOXY-5'-METHYLTHIOADENOSINE - Google Patents
METHOD FOR PREPARING 5'-DEOXY-5'-METHYLTHIOADENOSINE Download PDFInfo
- Publication number
- DK159453B DK159453B DK176481A DK176481A DK159453B DK 159453 B DK159453 B DK 159453B DK 176481 A DK176481 A DK 176481A DK 176481 A DK176481 A DK 176481A DK 159453 B DK159453 B DK 159453B
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- DK
- Denmark
- Prior art keywords
- deoxy
- sam
- methylthioadenosine
- concentrated
- preparing
- Prior art date
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/16—Purine radicals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Pharmacology & Pharmacy (AREA)
- General Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pain & Pain Management (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Rheumatology (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Biochemistry (AREA)
- Biotechnology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Saccharide Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Description
DK 159453 BDK 159453 B
Opfindelsen angår en fremgangsmåde til fremstilling af 5'-deoxy-5'-methylthioadenosin (MTA) med formlen NH,The invention relates to a process for the preparation of 5'-deoxy-5'-methylthioadenosine (MTA) of the formula NH,
JLJL
CH2-S-CH3 bCH2-S-CH3 b
OH OHOH OH
der er en fysiologisk forbindelse, der allerede findes i den levende organisme, og som er terapeutisk aktiv.there is a physiological compound that already exists in the living organism and which is therapeutically active.
5 Man har nu fundet en fremgangsmåde til fremstilling af denne forbindelse, der er særlig simpel og økonomisk set udfra et industrielt synspunkt, fremgangsmåden ifølge opfindelsen er ejendommelig ved at en vandig opløsning af S-adenosylmethionin (SAM) med formlen: nh2There is now found a process for preparing this compound which is particularly simple and economically from an industrial point of view, the process of the invention being characterized by an aqueous solution of S-adenosylmethionine (SAM) having the formula: nh2
Li/··' Γ2 ch„-s-ch9-ch9-ch-cooh 2,22 <rf “>.Li / ·· 'Γ2 ch „-s-ch9-ch9-ch-cooh 2.22 <rf“>.
OH OHOH OH
10 koncentreres ved opvarmning under vakuum ved 35-40 °C, den koncentrerede vandige opløsning hydrolyseres ved opvarmning med'tilbagesvaling, og det dannede 5'-deoxy-10 is concentrated by heating under vacuum at 35-40 ° C, the concentrated aqueous solution is hydrolyzed by reflux heating, and the 5'-deoxygen formed
DK 159453 BDK 159453 B
2 51 -methylthioadenosin fraskilles ved afkøling til 0-5 °C.2 51 -Methylthioadenosine is separated by cooling to 0-5 ° C.
' Som omtalt ovenfor omfatter den omhandlede fremgangsmåde specielt at udføre hydrolysen af S-adenosylmethio-nin (SAM) under strengt regulerede kritiske betingel-5 ser, der fører til praktisk taget total hydrolyse og fuldstændig udkrystallisation af MTA.In particular, as discussed above, the present process comprises performing the hydrolysis of S-adenosylmethionine (SAM) under strictly controlled critical conditions leading to virtually total hydrolysis and complete crystallization of the MTA.
nh2 Αλnh2 Αλ
kl/' NHat / NH
xmAn/ ' + f 1 h9o I CH2-S-CH2-CH2-CH-C00H --^xmAn / '+ f 1 h9o I CH2-S-CH2-CH2-CH-C00H - ^
OH OHOH OH
m2 LT> ch -s-ch, o - yH2m2 LT> ch -s-ch, o - yH2
Sp + H0-CH2-CH2-CH-C00H + H+ OH ohSp + H0-CH2-CH2-CH-C00H + H + OH oh
Den kontrollerede hydrolysemetode kan anvendes på SAM fremstillet på en hvilken som helst måde.The controlled hydrolysis method can be applied to SAM prepared in any way.
Imidlertid har fremstillingsmetoden af SAM-opløsnin-10 gen også betydning ved udførelsen af den omhandlede fremgangsmåde på en økonomisk og bekvem måde.However, the preparation method of the SAM solution is also important in carrying out the process in question in an economical and convenient manner.
DK 159453BDK 159453B
3 Følgende arbejdstrin udgør den mest økonomiske udførelsesform for fremgangsmåden ifølge opfindelsen: a) almindelig brødgær beriges med SAM ved behandling med methionin i overensstemmelse med Schlenk-metoden 5 (Schlenk F. (1965) Enzymologie 29, 283).3 The following working steps constitute the most economical embodiment of the process of the invention: a) common bread yeast is enriched with SAM by treatment with methionine in accordance with Schlenk Method 5 (Schlenk F. (1965) Enzymologie 29, 283).
b) Gærcellerne opslæmmes i vand og lyseres ved behandling med ethyl- eller methylacetat ved stuetemperatur (DT-offentliggørelsesskrift nr. 23 36401).b) The yeast cells are suspended in water and lysed by treatment with ethyl or methyl acetate at room temperature (DT Publication No. 23 36401).
Ved at indstille pH til mellem 4 og 6 og filtrere 10 fås en vandig opløsning, der indeholder praktisk talt alt tilstedeværende SAM i den oprindelige gær.By adjusting the pH to between 4 and 6 and filtering 10, an aqueous solution containing virtually all SAM present in the original yeast is obtained.
c) Opløsningen koncentreres i vakuum ved 35 - 40 °C til ca. 1/10 af det oprindelige rumfang.c) The solution is concentrated in vacuo at 35-40 ° C to approx. 1/10 of the original volume.
15 d) Koncentratet koges med tilbagesvaling ca. 30 minut ter, og pH indstilles til 7 med soda.D) The concentrate is boiled at reflux for approx. 30 minutes and the pH is adjusted to 7 with soda.
e) Opløsningen henstår ved 0-5 °C, og det udfældede^ MTA opsamles næsten fuldstændig og med god renhed.e) The solution is left at 0-5 ° C and the precipitated ^ MTA is collected almost completely and with good purity.
Trinene c, d og e, der som angivet er kritisk nødvendi-20 ge for at få fuldstændig selektiv hydrolyse af SAM til MTA uden dannelse af biprodukter, er hidtil ukendte.Steps c, d and e, as indicated, are critically necessary to obtain complete selective hydrolysis of SAM to MTA without the formation of by-products are novel.
Opfindelsen er nærmere illustreret nedenfor.The invention is further illustrated below.
EK5EMPELEK5EMPEL
Fremstilling af 51-deoxy-51-methylthioadenosin (MTA) 25 11 Liter et.hylacetat og 11 liter vand sættes ved stuetem-Preparation of 51-deoxy-51-methylthioadenosine (MTA) 25 liters of ethyl acetate and 11 liters of water is added at room temperature.
DK 159453 BDK 159453 B
4 peratur til 90 kg brødgær, der er beriget med SAM ved at tilsætte methionin, indtil SAM-indholdet er 6,88 g/kg.4 perature to 90 kg of bread yeast enriched with SAM by adding methionine until the SAM content is 6.88 g / kg.
Efter kraftig omrøring i 30 minutter indstilles pH til 5 4,5 med fortyndet H2S0^, blandingen filtreres, remanen sen vaskes med vand, hvorved der opnås 140 liter opløsning med et SAM-indhold på 4,40 g/1, svarende til 99,5¾ af SAM-indholdet i det oprindelige materiale.After vigorously stirring for 30 minutes, adjust the pH to 4.5 with dilute H 2 SO 4, filter the mixture, wash the residue with water to give 140 liters of solution with a SAM content of 4.40 g / l, corresponding to 99, 5¾ of the SAM content of the original material.
Det fremstillede lysat koncentreres i vakuum (30 mm 10 Hg; 35 - 40 °C) til rumfang på ca. 14 liter. Den koncen trerede opløsning koges med tilbagesvaling ved normalt tryk i 30 minutter. Der afkøles til 20 °C, pH indstilles til 7 med 40¾ soda, og opløsningen henstår natten over i køleskab (+3 °C).The lysate prepared is concentrated in vacuo (30 mm 10 Hg; 35 - 40 ° C) to volume of approx. 14 liters. The concentrated solution is refluxed at normal pressure for 30 minutes. Cool to 20 ° C, adjust the pH to 7 with 40¾ soda, and leave the solution overnight in the refrigerator (+3 ° C).
15 Det hvide bundfald, der er dannet, filtreres fra, der opløses i 10 liter kogende destilleret vand og udkrystalliseres ved at afkøle opløsningen.The white precipitate formed is filtered off, dissolved in 10 liters of boiling distilled water and crystallized by cooling the solution.
Der opnås 410 g krystallinsk MTA med stor renhed, hvilket svarer til 90¾ udbytte i forhold til det SAM, der. blev 20 hydrolyseret. Egenskaberne ved den fremstillede forbindelse svarer helt til egenskaberne for rent MTA, der er fremstillet ved andre metoder.410 g of crystalline MTA is obtained with high purity, which corresponds to 90¾ yield compared to the SAM present. was hydrolyzed. The properties of the compound obtained are completely similar to those of pure MTA prepared by other methods.
Den terapeutiske virkning af den fremstillede forbindelse er beskrevet i dansk patentansøgning nr. 251/84.The therapeutic effect of the compound prepared is described in Danish Patent Application No. 251/84.
Claims (2)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DK25184A DK163518C (en) | 1980-04-22 | 1984-01-20 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE ADENOSIN DERIVATIVES |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IT2155080 | 1980-04-22 | ||
| IT21550/80A IT1193529B (en) | 1980-04-22 | 1980-04-22 | ADENOSINIC DERIVATIVES FOR ANTI-INFLAMMATORY AND ANALGESIC ACTIVITIES AND THERAPEUTIC COMPOSITIONS THAT CONTAIN THEM AS AN ACTIVE PRINCIPLE |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| DK176481A DK176481A (en) | 1981-10-23 |
| DK159453B true DK159453B (en) | 1990-10-15 |
| DK159453C DK159453C (en) | 1991-03-18 |
Family
ID=11183457
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| DK176481A DK159453C (en) | 1980-04-22 | 1981-04-21 | METHOD FOR PREPARING 5'-DEOXY-5'-METHYLTHIOADENOSINE |
Country Status (17)
| Country | Link |
|---|---|
| JP (2) | JPS56166117A (en) |
| AR (1) | AR231144A1 (en) |
| BE (1) | BE888472A (en) |
| CA (1) | CA1198105A (en) |
| CH (2) | CH650514A5 (en) |
| DE (1) | DE3116067A1 (en) |
| DK (1) | DK159453C (en) |
| ES (2) | ES8206551A1 (en) |
| FI (1) | FI70227C (en) |
| FR (1) | FR2491761A1 (en) |
| GB (3) | GB2074446B (en) |
| IT (1) | IT1193529B (en) |
| LU (1) | LU83307A1 (en) |
| MX (1) | MX9203630A (en) |
| NL (1) | NL192111C (en) |
| NO (1) | NO150515C (en) |
| SE (3) | SE460198B (en) |
Families Citing this family (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT1177373B (en) * | 1984-12-06 | 1987-08-26 | Bioresearch Spa | SALTS OF 5'-METHYLLIUM-5'-DEOXYDENOSINE WITH LONG ALCHYLIC CHAIN SULPHONIC ACIDS |
| IT1227049B (en) * | 1988-07-29 | 1991-03-14 | Bioresearch Spa | USE OF ADENOSINIC DERIVATIVES FOR THE PREPARATION OF PHARMACEUTICAL COMPOSITIONS HAVING IMMUNOSTIMULATING ACTIVITIES. |
| JPH0497287A (en) * | 1990-08-10 | 1992-03-30 | Nec Ic Microcomput Syst Ltd | Picture display integrated circuit |
| DK1891961T3 (en) * | 2005-03-17 | 2009-12-21 | Proyecto Biomedicina Cima Sl | Use of 5'-methylthioadenosine (MTA) in the prevention and / or treatment of autoimmune diseases and / or graft rejection |
| ES2259552B1 (en) * | 2005-03-17 | 2007-06-16 | Proyecto De Biomedicina Cima, S.L. | EMPLOYMENT OF 5'-METHYLTIOENENINE (MTA) IN THE PREVENTION AND / OR TREATMENT OF AUTOIMMUNE DISEASES AND / OR REPLACEMENT OF TRANSPLANTS. |
| DE102010027595A1 (en) * | 2010-07-23 | 2012-01-26 | Helmut Vorbrüggen | Clinical application of adenosine derivative, preferably (dihydroxyphenyl)ethyl-amino-purin-9-yl-(hydroxymethyl)oxolane-diol, for reducing body temperature during impending ischemia of brain vessels, which occur during heart attacks |
| DE102011005232A1 (en) * | 2011-03-08 | 2012-09-13 | AristoCon GmbH & Co. KG | Adenosine and its derivatives for use in pain therapy |
| JP6214628B2 (en) * | 2013-04-05 | 2017-10-18 | ライオン株式会社 | Oral composition |
| WO2014163152A1 (en) * | 2013-04-05 | 2014-10-09 | ライオン株式会社 | Non-rem sleep-promoting agent, deep sleep-promoting agent and natural sleep-inducing agent |
| KR20150139508A (en) * | 2013-04-05 | 2015-12-11 | 라이온 가부시키가이샤 | Yeast culture, and composition for internal application |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE1259341B (en) * | 1962-12-22 | 1968-01-25 | Boehringer & Soehne Gmbh | Process for the preparation of new 5'-sulfoxides of nucleosides |
| DE1545645A1 (en) * | 1965-12-06 | 1969-08-21 | Boehringer Mannheim Gmbh | Process for the preparation of disubstituted adenosine derivatives |
| FR2252405B1 (en) * | 1973-11-27 | 1978-04-28 | Ajinomoto Kk | |
| FR2313937A1 (en) * | 1975-06-09 | 1977-01-07 | Anvar | DRUG BASED ON 5 'THIOETHERS OF ADENOSINE |
| FR2424027A1 (en) * | 1978-04-28 | 1979-11-23 | Merieux Inst | NEW MEDICINAL PRODUCT, IN PARTICULAR SEDATIVE AND SLEEP INDUCER AND PHARMACEUTICAL COMPOSITIONS CONTAINING IT |
-
1980
- 1980-04-22 IT IT21550/80A patent/IT1193529B/en active
-
1981
- 1981-04-17 BE BE0/204529A patent/BE888472A/en not_active IP Right Cessation
- 1981-04-21 ES ES501539A patent/ES8206551A1/en not_active Expired
- 1981-04-21 DK DK176481A patent/DK159453C/en not_active IP Right Cessation
- 1981-04-21 JP JP5930181A patent/JPS56166117A/en active Granted
- 1981-04-21 SE SE8102489A patent/SE460198B/en not_active IP Right Cessation
- 1981-04-21 AR AR285020A patent/AR231144A1/en active
- 1981-04-21 NO NO811346A patent/NO150515C/en unknown
- 1981-04-21 CA CA000375784A patent/CA1198105A/en not_active Expired
- 1981-04-21 LU LU83307A patent/LU83307A1/en unknown
- 1981-04-22 CH CH4716/84A patent/CH650514A5/en not_active IP Right Cessation
- 1981-04-22 DE DE19813116067 patent/DE3116067A1/en active Granted
- 1981-04-22 FR FR8107992A patent/FR2491761A1/en active Granted
- 1981-04-22 GB GB8112428A patent/GB2074446B/en not_active Expired
- 1981-04-22 FI FI811249A patent/FI70227C/en not_active IP Right Cessation
- 1981-04-22 CH CH263281A patent/CH645544A5/en not_active IP Right Cessation
- 1981-04-22 NL NL8101984A patent/NL192111C/en not_active IP Right Cessation
-
1982
- 1982-04-01 ES ES511039A patent/ES511039A0/en active Granted
-
1983
- 1983-08-15 GB GB08321947A patent/GB2144409B/en not_active Expired
-
1984
- 1984-05-25 GB GB08413454A patent/GB2144038B/en not_active Expired
-
1987
- 1987-03-04 SE SE8700914A patent/SE464635B/en not_active IP Right Cessation
- 1987-03-04 SE SE8700913A patent/SE466238B/en not_active IP Right Cessation
-
1989
- 1989-02-02 JP JP1022771A patent/JPH01301692A/en active Granted
-
1992
- 1992-06-26 MX MX9203630A patent/MX9203630A/en unknown
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PBP | Patent lapsed |