NO157863B - ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. Download PDFInfo
- Publication number
- NO157863B NO157863B NO84840343A NO840343A NO157863B NO 157863 B NO157863 B NO 157863B NO 84840343 A NO84840343 A NO 84840343A NO 840343 A NO840343 A NO 840343A NO 157863 B NO157863 B NO 157863B
- Authority
- NO
- Norway
- Prior art keywords
- preparation
- atoms
- chain
- therapeutic active
- deoxyadenosine
- Prior art date
Links
- OIRDTQYFTABQOQ-KQYNXXCUSA-N adenosine Chemical class C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O OIRDTQYFTABQOQ-KQYNXXCUSA-N 0.000 title claims description 5
- 238000000034 method Methods 0.000 title claims description 5
- 238000002360 preparation method Methods 0.000 title claims description 3
- 230000001225 therapeutic effect Effects 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 13
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 8
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 6
- 125000004432 carbon atom Chemical group C* 0.000 claims description 6
- IYSNPOMTKFZDHZ-KQYNXXCUSA-N 5'-chloro-5'-deoxyadenosine Chemical compound C1=NC=2C(N)=NC=NC=2N1[C@@H]1O[C@H](CCl)[C@@H](O)[C@H]1O IYSNPOMTKFZDHZ-KQYNXXCUSA-N 0.000 claims description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 4
- 238000006243 chemical reaction Methods 0.000 claims description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 4
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002126 C01EB10 - Adenosine Substances 0.000 claims description 2
- LSDPWZHWYPCBBB-UHFFFAOYSA-N Methanethiol Chemical compound SC LSDPWZHWYPCBBB-UHFFFAOYSA-N 0.000 claims description 2
- 150000001263 acyl chlorides Chemical class 0.000 claims description 2
- 229960005305 adenosine Drugs 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 claims description 2
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 claims description 2
- 125000004805 propylene group Chemical group [H]C([H])([H])C([H])([*:1])C([H])([H])[*:2] 0.000 claims description 2
- 150000007970 thio esters Chemical class 0.000 claims description 2
- 125000005147 toluenesulfonyl group Chemical group C=1(C(=CC=CC1)S(=O)(=O)*)C 0.000 claims description 2
- 125000000654 isopropylidene group Chemical group C(C)(C)=* 0.000 claims 1
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- 239000000203 mixture Substances 0.000 description 5
- CGIGDMFJXJATDK-UHFFFAOYSA-N indomethacin Chemical compound CC1=C(CC(O)=O)C2=CC(OC)=CC=C2N1C(=O)C1=CC=C(Cl)C=C1 CGIGDMFJXJATDK-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 241000700159 Rattus Species 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- WUUGFSXJNOTRMR-IOSLPCCCSA-N 5'-S-methyl-5'-thioadenosine Chemical compound O[C@@H]1[C@H](O)[C@@H](CSC)O[C@H]1N1C2=NC=NC(N)=C2N=C1 WUUGFSXJNOTRMR-IOSLPCCCSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229960000905 indomethacin Drugs 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-M Formate Chemical compound [O-]C=O BDAGIHXWWSANSR-UHFFFAOYSA-M 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 206010030113 Oedema Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 241000906446 Theraps Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 229940113118 carrageenan Drugs 0.000 description 1
- 235000010418 carrageenan Nutrition 0.000 description 1
- 229920001525 carrageenan Polymers 0.000 description 1
- 239000000679 carrageenan Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 238000000921 elemental analysis Methods 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 1
Landscapes
- Saccharide Compounds (AREA)
Description
Foreliggende oppfinnelse angår en analogifremgangsmåte for fremstilling av terapeutisk aktive forbindelser av generell formel: The present invention relates to an analogue method for the production of therapeutically active compounds of the general formula:
hvori R er et rettkjedet eller forgrenet alkylradikal med 1-6 C-atomer eller fenylalkylen hvor alkylenkjeden har 1-6 C-atomer, in which R is a straight-chain or branched alkyl radical with 1-6 C atoms or phenylalkylene where the alkylene chain has 1-6 C atoms,
Rl og R2 er et alifati-sk acylradikal med 1-6 C-atomer, benzoyl eller toluensulfonyl, eller radikalene R1 og R2 kan sammen danne en isopropylenkjede. R1 and R2 are an aliphatic acyl radical with 1-6 C atoms, benzoyl or toluenesulfonyl, or the radicals R1 and R2 can together form an isopropylene chain.
Når enn videre er H, omfatter oppfinnelsen også fremstilling av syreaddisjonssalter av forbindelsene av formel (I) . When H is furthermore, the invention also encompasses the production of acid addition salts of the compounds of formula (I).
De foretrukne syreaddisjonssalter av forbindelsene av formel I er: klorid, sulfat, fosfat, formiat, acetat, citrat, tartrat, methansulfonat eller p-toluensulfonat. The preferred acid addition salts of the compounds of formula I are: chloride, sulfate, phosphate, formate, acetate, citrate, tartrate, methanesulfonate or p-toluenesulfonate.
Analogifremgangsmåten ifølge oppfinnelsen er kjenne-tegnet ved at a) når # 2 er acylradikal, The analog method according to the invention is characterized by the fact that a) when # 2 is an acyl radical,
omdannes adenosin til 5'-klor-5'-deoxyadenosin ved omsetning med thionylklorid i hexamethylfosforamid, 5'-klor-5'-deoxyadenosin omdannes til den krevede thioester ved omsetning med det tilsvarende mercaptan i 2N natrium-hydroxydløsning ved 80°C, hvoretter de erholdte forbindelser omsettes med det krevede acylklorid i vannfri pyridin, adenosine is converted to 5'-chloro-5'-deoxyadenosine by reaction with thionyl chloride in hexamethylphosphoramide, 5'-chloro-5'-deoxyadenosine is converted to the required thioester by reaction with the corresponding mercaptan in 2N sodium hydroxide solution at 80°C, after which the compounds obtained are reacted with the required acyl chloride in anhydrous pyridine,
b) når b) when
R2_R2 = :'-soProPy^-;'-c'en' R2_R2 = :'-soProPy^-;'-c'en'
omsettes forbindelsene erholdt ifølge (a) med aceton i nærvær av ZnC^. the compounds obtained according to (a) are reacted with acetone in the presence of ZnC^.
De erholdte produkter renses fortrinnsvis ved krystallisasjon fra en 1:1 kloroform/petroleumetherblanding. The products obtained are preferably purified by crystallization from a 1:1 chloroform/petroleum ether mixture.
Det etterfølgende eksempel illustrerer oppfinnelsen. The following example illustrates the invention.
Eksempel Example
Fremstilling av , 2',3'-triacetyl-51-deoxy-51-thioadenosin Preparation of , 2',3'-triacetyl-51-deoxy-51-thioadenosine
1 kg MTA (5'-deoxy-5<1->methylthioadenosin) ble sus- 1 kg of MTA (5'-deoxy-5<1->methylthioadenosine) was sus-
pendert i 10 liter vannfri pyridin, og 3 liter eddiksyre- suspended in 10 liters of anhydrous pyridine, and 3 liters of acetic acid
anhydrid ble tilsatt. Blandingen fikk reagere i 4 timer. anhydride was added. The mixture was allowed to react for 4 hours.
20 liter vann ble tilsatt, og blandingen ble konsentrert under vakuum under dannelse av en oljeaktig masse fri for pyridin. Denne ble løst i en varm 1:1 blanding av petroleum-ether/kloroform (10 liter) og fikk krystallisere. Produktet ble omkrystallisert fra en 1:1 petroleumether/kloroform-blanding. 1,140 kg produkt ble erholdt (utbytte 80%). 20 liters of water were added and the mixture was concentrated under vacuum to give an oily mass free of pyridine. This was dissolved in a warm 1:1 mixture of petroleum ether/chloroform (10 liters) and allowed to crystallize. The product was recrystallized from a 1:1 petroleum ether/chloroform mixture. 1,140 kg of product was obtained (yield 80%).
Den empiriske formel for forbindelsen ci7<H>21<N>5°6S ble bekreftet ved elementæranalyse som ga følgende resul-tater: C = 48,18% (beregnet 48,22) The empirical formula for the compound ci7<H>21<N>5°6S was confirmed by elemental analysis which gave the following results: C = 48.18% (calculated 48.22)
H = 5,05% (beregnet 5,00) H = 5.05% (calculated 5.00)
N = 16,59% (beregnet 16,54) N = 16.59% (calculated 16.54)
Det ultrafiolette spektrum av en 1% methanolisk løsning av forbindelsen utviser et absorpsjonsmaksimum ved 272 nanometer. The ultraviolet spectrum of a 1% methanolic solution of the compound exhibits an absorption maximum at 272 nanometers.
Som tidligere angitt er det funnet at forbindelsene av formel I utviser sterk anti-inflammatorisk aktivitet, ledsaget av analgesisk og antipyretisk virkning. Den anti-inflammatoriske aktivitet ble demonstrert først for enkelte representanter for klassen ved den eksperimentelle ødem-testen ved rotter med carragen, ved bestemmelse av den prosentvise beskyttelse etter Winter-metoden (J. Pharm. exper. Therap. 141, 369,1963). De erholdte verdier er vist i tabell 1. As previously indicated, the compounds of formula I have been found to exhibit strong anti-inflammatory activity, accompanied by analgesic and antipyretic action. The anti-inflammatory activity was demonstrated first for some representatives of the class by the experimental edema test in rats with carrageenan, by determining the percentage protection according to the Winter method (J. Pharm. exper. Therap. 141, 369, 1963). The obtained values are shown in table 1.
Som det fremgår av denne tabell, er ED^Q for indomethacin 9 mg/kg. Ved denne dose er det tilsynekomst av alvorlige mavelesjoner, mens dosene av de nye forbindelser ikke gir noen sekundær effekt på det gastro-intestinale system. Det skal også bemerkes at LD5Q for indomethacin hos rotter er 12 mg/kg (Martelli A. in Aspetti di farmacologia dell'infiammazione, s. 73, publisert ved Tamburini - Milano 1973), mens LD^Q for de nye forbindelser hos rotter er større enn 200 mg/kg/oa. As shown in this table, the ED^Q for indomethacin is 9 mg/kg. At this dose, there is the appearance of serious stomach lesions, while the doses of the new compounds do not produce any secondary effect on the gastro-intestinal system. It should also be noted that the LD5Q for indomethacin in rats is 12 mg/kg (Martelli A. in Aspetti di farmacologia dell'infiammazione, p. 73, published by Tamburini - Milano 1973), while the LD5Q for the new compounds in rats is greater than 200 mg/kg/oa.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO840343A NO157863C (en) | 1980-04-22 | 1984-01-30 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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 |
| NO811346A NO150515C (en) | 1980-04-22 | 1981-04-21 | PROCEDURE FOR PREPARING 5`-DEOXY-5`-METHYLTHIOADENOSINE |
| NO840343A NO157863C (en) | 1980-04-22 | 1984-01-30 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. |
Publications (3)
| Publication Number | Publication Date |
|---|---|
| NO840343L NO840343L (en) | 1981-10-23 |
| NO157863B true NO157863B (en) | 1988-02-22 |
| NO157863C NO157863C (en) | 1988-06-01 |
Family
ID=27273194
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO840343A NO157863C (en) | 1980-04-22 | 1984-01-30 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO157863C (en) |
-
1984
- 1984-01-30 NO NO840343A patent/NO157863C/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| NO840343L (en) | 1981-10-23 |
| NO157863C (en) | 1988-06-01 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US3450693A (en) | Method of synthesizing adenosine,2',3'-o-isopropylidene-adenosine and intermediates thereof | |
| US2183589A (en) | Derivatives of compounds of the | |
| DE68923387T2 (en) | 2 ', 3'-dideoxy-2', 2'-difluoronucleosides. | |
| US3635945A (en) | Trialkylphosphinegold complexes of 1-beta-d-glucopyranosides | |
| JPH0469634B2 (en) | ||
| GB2048268A (en) | Amides of acyl-carnitines process for preparing same and pharmaceutical compositions containing such amides | |
| EP0080229B1 (en) | Salicylic derivatives of n-acetylcysteine | |
| US4454122A (en) | Adenosine derivatives of anti-inflammatory and analgesic activity, and therapeutic compositions which contain them as their active principle | |
| US4373097A (en) | Process for preparing adenosine derivatives of anti-inflammatory and analgesic activity | |
| NL192111C (en) | Drug preparation with anti-inflammatory effect. | |
| US4552875A (en) | Novel carbacyclinamides, their preparation and use as medicinal agents | |
| NO157863B (en) | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE ADENOSIN DERIVATIVES. | |
| JPS62185093A (en) | Saccharide derivative and drug containing the same | |
| US3992531A (en) | 2-Substituted adenosine-5'-carboxylates in the treatment of anginal pain | |
| EP0124379B1 (en) | Hydroquinone derivatives and production thereof | |
| EP0081305A1 (en) | Erythromycin A derivatives | |
| US4374831A (en) | Modulators of the complement system comprising bis-glucopyranosyl arylene sulfate derivatives | |
| JPH0314030B2 (en) | ||
| DK163518B (en) | Analogy process for preparing therapeutically effective adenosine derivatives | |
| US3169968A (en) | Esters of ajmaline and related compounds | |
| US2653955A (en) | Cortisone esters and process | |
| EP0189427A1 (en) | Orally active heparin multiplets. | |
| HU179949B (en) | Process for preparing nitroso-carbamide derivatives | |
| PL143289B1 (en) | Process for preparing 5-/e/-/2-bromovinyl/-2'-desoxyuridine and its novel derivatives | |
| EP0741740A1 (en) | Method of preparing unsymmetrical phosphoric acid diesters and salts |