NO165026B - ANALOGY PROCEDURE FOR THE PREPARATION OF THE SODIUM SALT 9- (1,2-DIHYDROXY-2-PROPOXYMETHYL) GUANINE. - Google Patents
ANALOGY PROCEDURE FOR THE PREPARATION OF THE SODIUM SALT 9- (1,2-DIHYDROXY-2-PROPOXYMETHYL) GUANINE. Download PDFInfo
- Publication number
- NO165026B NO165026B NO890477A NO890477A NO165026B NO 165026 B NO165026 B NO 165026B NO 890477 A NO890477 A NO 890477A NO 890477 A NO890477 A NO 890477A NO 165026 B NO165026 B NO 165026B
- Authority
- NO
- Norway
- Prior art keywords
- propoxymethyl
- guanine
- dihydroxy
- sodium salt
- compound
- Prior art date
Links
- 238000000034 method Methods 0.000 title claims description 3
- QFONVUCDRMRHIM-UHFFFAOYSA-N 2-amino-9-(1,2-dihydroxypropan-2-yloxymethyl)-3h-purin-6-one Chemical compound N1=C(N)NC(=O)C2=C1N(COC(O)(CO)C)C=N2 QFONVUCDRMRHIM-UHFFFAOYSA-N 0.000 title 1
- NOJNFULGOQGBKB-UHFFFAOYSA-M sodium;3-[3-tert-butylsulfanyl-1-[[4-(6-ethoxypyridin-3-yl)phenyl]methyl]-5-[(5-methylpyridin-2-yl)methoxy]indol-2-yl]-2,2-dimethylpropanoate Chemical compound [Na+].C1=NC(OCC)=CC=C1C(C=C1)=CC=C1CN1C2=CC=C(OCC=3N=CC(C)=CC=3)C=C2C(SC(C)(C)C)=C1CC(C)(C)C([O-])=O NOJNFULGOQGBKB-UHFFFAOYSA-M 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims description 21
- IRSCQMHQWWYFCW-UHFFFAOYSA-N ganciclovir Chemical compound O=C1NC(N)=NC2=C1N=CN2COC(CO)CO IRSCQMHQWWYFCW-UHFFFAOYSA-N 0.000 claims description 7
- 159000000000 sodium salts Chemical class 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 8
- 239000001257 hydrogen Substances 0.000 description 8
- 208000015181 infectious disease Diseases 0.000 description 8
- 241000699670 Mus sp. Species 0.000 description 5
- 150000002431 hydrogen Chemical class 0.000 description 5
- 241000700605 Viruses Species 0.000 description 4
- 125000000217 alkyl group Chemical group 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- -1 hydroxy, amino Chemical group 0.000 description 4
- 239000003443 antiviral agent Substances 0.000 description 3
- 229910052736 halogen Inorganic materials 0.000 description 3
- 150000002367 halogens Chemical class 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 230000009385 viral infection Effects 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- 125000004414 alkyl thio group Chemical group 0.000 description 2
- 230000000840 anti-viral effect Effects 0.000 description 2
- 230000002155 anti-virotic effect Effects 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 150000001540 azides Chemical class 0.000 description 2
- 238000004113 cell culture Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 229910052760 oxygen Chemical group 0.000 description 2
- 239000001301 oxygen Chemical group 0.000 description 2
- 239000011780 sodium chloride Substances 0.000 description 2
- 239000006228 supernatant Substances 0.000 description 2
- 231100000331 toxic Toxicity 0.000 description 2
- 230000002588 toxic effect Effects 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 1
- 239000006145 Eagle's minimal essential medium Substances 0.000 description 1
- 241000701074 Human alphaherpesvirus 2 Species 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 241000699666 Mus <mouse, genus> Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical group [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 125000004442 acylamino group Chemical group 0.000 description 1
- 125000003545 alkoxy group Chemical group 0.000 description 1
- 125000003282 alkyl amino group Chemical group 0.000 description 1
- 125000003710 aryl alkyl group Chemical group 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000006515 benzyloxy alkyl group Chemical group 0.000 description 1
- 125000003917 carbamoyl group Chemical group [H]N([H])C(*)=O 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 239000006285 cell suspension Substances 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
- 125000004663 dialkyl amino group Chemical group 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000012737 fresh medium Substances 0.000 description 1
- DKAGJZJALZXOOV-UHFFFAOYSA-N hydrate;hydrochloride Chemical compound O.Cl DKAGJZJALZXOOV-UHFFFAOYSA-N 0.000 description 1
- 125000004435 hydrogen atom Chemical group [H]* 0.000 description 1
- 230000002458 infectious effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000000250 methylamino group Chemical group [H]N(*)C([H])([H])[H] 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 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
- 239000000243 solution Substances 0.000 description 1
- 125000000446 sulfanediyl group Chemical group *S* 0.000 description 1
- 125000000472 sulfonyl group Chemical group *S(*)(=O)=O 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Denne oppfinnelse angår fremstilling av 9-(1,3-dihydroksy-2-propoksymetyl)guanin som er nyttige som anti-virusmidler. This invention relates to the preparation of 9-(1,3-dihydroxy-2-propoxymethyl)guanine which are useful as anti-viral agents.
Virus-infeksjoner er utbredt og medfører en rekke for-skjellige symptomer. Noen virus-infeksjoner bekjempes lett ved hjelp av kroppens forsvarsmekanisme, mens andre er av en Virus infections are widespread and cause a number of different symptoms. Some virus infections are easily fought off using the body's defense mechanism, while others are by a
mer alvorlig natur og fører til permanent skade, for eksempel blindhet eller til og med til død. En slik virus-familie som kan forårsake alvorlige infeksjoner, er Herpes virus-gruppen. more serious in nature and lead to permanent damage, such as blindness or even death. One such virus family that can cause serious infections is the Herpes virus group.
De midler som for tiden anvendes til bekjempelse av virus-infeksjoner, er i mange tilfeller inneffektive eller, hvis de er effektive, må de anvendes i store og/eller kontinuerlige doser som medfører alvorlige bivirkninger og/eller giftvirkninger. Det er derfor et behov for et effektivt anti-virusmiddel som er effektivt ved lavere doser enn de midler som for tiden er tilgjengelige, slik at man reduserer sjansen for mulige bivirkninger og giftvirkninger. The agents that are currently used to combat virus infections are in many cases ineffective or, if they are effective, they must be used in large and/or continuous doses that cause serious side effects and/or toxic effects. There is therefore a need for an effective anti-viral agent which is effective at lower doses than the agents currently available, so that the chance of possible side effects and toxic effects is reduced.
US-patent 4 199 574 beskriver forbindelser med den gene-relle formel: US patent 4,199,574 describes compounds with the general formula:
hvor X er svovel eller oksygen, R1 er hydrogen, halogen, hydroksy, alkoksy, azid, tio, alkyltio, amino, alkylamino eller dialkylamino; R2 er hydrogen, halogen, alkyltio, acylamino, amino eller azid; R<3> er hydrogen, lineær eller forgrenet eller cyklisk alkyl, hydroksyalkyl, benzyloksyalkyl eller fenyl; R where X is sulfur or oxygen, R 1 is hydrogen, halogen, hydroxy, alkoxy, azide, thio, alkylthio, amino, alkylamino or dialkylamino; R 2 is hydrogen, halogen, alkylthio, acylamino, amino or azide; R<3> is hydrogen, linear or branched or cyclic alkyl, hydroxyalkyl, benzyloxyalkyl or phenyl; R
er hydrogen, hydroksy eller alkyl; R<5> er hydrogen, hydroksy, amino, alkyl, hydroksyalkyl, benzyloksy, benzoyloksy, benzoyl-oksymetyl, sulfamoyloksy, fosfat, karboksypropiamyloksy, lineær eller cyklisk acyloksy med fra 1 til 8 karbonatomer, for eksempel acetoksy eller en substituert karbamoylgruppe med formelen is hydrogen, hydroxy or alkyl; R<5> is hydrogen, hydroxy, amino, alkyl, hydroxyalkyl, benzyloxy, benzoyloxy, benzoyloxymethyl, sulfamoyloxy, phosphate, carboxypropiamyloxy, linear or cyclic acyloxy with from 1 to 8 carbon atoms, for example acetoxy or a substituted carbamoyl group of the formula
NHCO-Z hvor Z er alkyl, aryl eller aralkyl eventuelt substituert med en eller flere av sulfonyl, amino, karbamoyl eller halogen; R er hydrogen eller alkyl, forutsatt at når X er oksygen og R2, R"^, r'* og R^ er hydrogen, er R^ ikke amino eller metylamino når R^ er hydrogen eller hydroksy, eller et salt derav. NHCO-Z where Z is alkyl, aryl or aralkyl optionally substituted with one or more of sulfonyl, amino, carbamoyl or halogen; R is hydrogen or alkyl, provided that when X is oxygen and R2, R"^, r'* and R^ are hydrogen, R^ is not amino or methylamino when R^ is hydrogen or hydroxy, or a salt thereof.
Den klasse forbindelser som representeres av den ovenstående formel og de farmasøytisk godtagbare syreaddisjons-salter derav er angitt og ha anti-virus-aktivitet. Se også Tetrahedron Letters, 21, 327-30 (1980). The class of compounds represented by the above formula and the pharmaceutically acceptable acid addition salts thereof are said to have anti-viral activity. See also Tetrahedron Letters, 21, 327-30 (1980).
Det er nu overraskende funnet at forbindelsen 9-(1,3-dihydroksy-2-propoksymetyl)guanin er et særlig aktivt anti-virusmiddel. Den selektive aktivitet av denne forbindelse illustreres særlig klart for forbindelsen sammenlignet med de strukturelt mest likeartede forbindelser beskrevet i US-patent 4 199 574 ved en anti-virus-undersøkelse som ef vist i detalj nedenfor. It has now surprisingly been found that the compound 9-(1,3-dihydroxy-2-propoxymethyl)guanine is a particularly active anti-viral agent. The selective activity of this compound is particularly clearly illustrated for the compound compared to the structurally most similar compounds described in US patent 4,199,574 by an anti-virus study as shown in detail below.
Ifølge oppfinnelsen fremstilles forbindelsen 9-(1,3-dihydroksy-2-propoksymetyl)guanin som kan representeres ved formelen According to the invention, the compound 9-(1,3-dihydroxy-2-propoxymethyl)guanine is produced which can be represented by the formula
ved at natriumsaltet omdannes til den tilsvarende frie forbindelse. in that the sodium salt is converted into the corresponding free compound.
Flere fremgangsmåter for fremstilling av forbindelsen med formel I og salter derav er beskrevet i stamsøknaden 82.1676, patent 161.740. Several methods for preparing the compound of formula I and salts thereof are described in parent application 82.1676, patent 161.740.
I det følgende er oppfinnelsen beskrevet ytterligere som illustrasjon. In the following, the invention is further described by way of illustration.
Eksempel Example
Natriumsaltet av 9-(1,3-dihydroksy-2-propaoksymetyl)guanin ble oppløst i en minimumsmengde vann, og fortynnet saltsyre ble tilsatt for å regulere pH-verdien til 7. 9-(l,3-dihydroksy-2-propoksymetyl)guanin, smp. 250°C (dekomp.) krystalliserte fra oppløsningen. The sodium salt of 9-(1,3-dihydroxy-2-propoxymethyl)guanine was dissolved in a minimum amount of water, and dilute hydrochloric acid was added to adjust the pH to 7. 9-(1,3-dihydroxy-2-propoxymethyl) guanine, m.p. 250°C (decomp.) crystallized from the solution.
Den meget gode antivirus-aktivitet hos forbindelsen med formel I illustreres ved de følgende undersøkelser: The very good antiviral activity of the compound of formula I is illustrated by the following investigations:
Herpes simplex-virus 2 stamme G for infeksjon ble fremstilt Herpes simplex virus 2 strain G for infection was prepared
i HEp-2 celle-kulturer. Virus ble adsorbert i 1 time, friske medier ble anbrakt på cellene, og de ble inkubert ved 35°C inntil alle celler var infisert. Celle-suspensjonen ble frosset ved -70°C, tinet og sentrifugert for å fjerne celle-avfall. in HEp-2 cell cultures. Virus was adsorbed for 1 hour, fresh media was placed on the cells, and they were incubated at 35°C until all cells were infected. The cell suspension was frozen at -70°C, thawed and centrifuged to remove cell debris.
Den supernatante . væske ble inndelt i passende porsjoner og lagret i frossen tilstand ved -70°C inntil den skulle brukes. The supernatant. liquid was divided into appropriate portions and stored frozen at -70°C until use.
En IO<6>'<7> fortynning av supernatant-væsken... ga en 50 % celle-kultur-infiserende dose (CCID^q) i HEp-2 celler, og en 10 3 '7 fortynning medførte en 50 % dødelig smitte (LC^g) hos mus. A 10<6>'<7> dilution of the supernatant fluid... gave a 50% cell culture infectious dose (CCID^q) in HEp-2 cells, and a 10 3 '7 dilution resulted in a 50% lethal infection (LC^g) in mice.
Grupper på 20 hunnmus (15-17 g) ble smittet intraperitonealt under anvendelse av 0,2 ml EMEM inneholdende 10 LC^0/mus av virus. Mus smittet med IO<0>'<5> mer eller mindre virus enn 10 LD5Q smitten, tjente som en kontroll på graden av smitte for å sikre at modellen virket viktig. Groups of 20 female mice (15-17 g) were infected intraperitoneally using 0.2 ml of EMEM containing 10 LC 0 /mouse of virus. Mice infected with IO<0>'<5> more or less virus than the 10 LD5Q infection served as a control on the degree of infection to ensure that the model appeared important.
Behandling med prøveforbindelsen begynte 6 timer efter smitte. Musene, oppdelt i grupper på 20, fikk administrert forbindelsen Treatment with the test compound began 6 hours after infection. The mice, divided into groups of 20, were administered the compound
i saltvann subkutant i en mengde på 5 mg/kg, 10 mg/kg og 20 mg/kg. En gruppe på 20 mus ble anvendt som kontrollgruppe og fikk administrert saltoppløsning subkutant. Behandlingen ble gjentatt 24, 48, 72 og 96 timer efter smitte. in saline subcutaneously in an amount of 5 mg/kg, 10 mg/kg and 20 mg/kg. A group of 20 mice was used as a control group and was administered saline subcutaneously. The treatment was repeated 24, 48, 72 and 96 hours after infection.
Prøveforbindelsene var forbindelsen med formel I og de tre forbindelser beskrevet i US-patent 4 199 574 som er strukturelt nærmest forbindelsen med formel I. The test compounds were the compound of formula I and the three compounds described in US patent 4,199,574 which are structurally closest to the compound of formula I.
Av de ovenstående resultater fremgår det at en sammenligning mellom antall overlevende dyr som har fått forbindelsen med formel I og antall overlevende dyr som har fått de tre tidligere kjente forbindelser, klart viser at forbindelsen med formel I har den beste anti-virus-aktivitet. From the above results, it appears that a comparison between the number of surviving animals that have received the compound of formula I and the number of surviving animals that have received the three previously known compounds clearly shows that the compound of formula I has the best anti-virus activity.
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| NO890477A NO165026C (en) | 1981-05-21 | 1989-02-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF THE SODIUM SALT 9- (1,2-DIHYDROXY-2-PROPOXYMETHYL) GUANINE. |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06267210 US4355032B2 (en) | 1981-05-21 | 1981-05-21 | 9-(1,3-dihydroxy-2-propoxymethyl)guanine as antiviral agent |
| NO821676A NO161740C (en) | 1981-05-21 | 1982-05-19 | ANALOGY PROCEDURE FOR THE PREPARATION OF THERAPEUTIC ACTIVE 9- (1,3-DIHYDROXY-2-PROPOXYMETHYL) GUANINE. |
| NO890477A NO165026C (en) | 1981-05-21 | 1989-02-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF THE SODIUM SALT 9- (1,2-DIHYDROXY-2-PROPOXYMETHYL) GUANINE. |
Publications (4)
| Publication Number | Publication Date |
|---|---|
| NO890477L NO890477L (en) | 1982-11-22 |
| NO890477D0 NO890477D0 (en) | 1989-02-06 |
| NO165026B true NO165026B (en) | 1990-09-03 |
| NO165026C NO165026C (en) | 1990-12-12 |
Family
ID=27352831
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| NO890477A NO165026C (en) | 1981-05-21 | 1989-02-06 | ANALOGY PROCEDURE FOR THE PREPARATION OF THE SODIUM SALT 9- (1,2-DIHYDROXY-2-PROPOXYMETHYL) GUANINE. |
Country Status (1)
| Country | Link |
|---|---|
| NO (1) | NO165026C (en) |
-
1989
- 1989-02-06 NO NO890477A patent/NO165026C/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| NO165026C (en) | 1990-12-12 |
| NO890477L (en) | 1982-11-22 |
| NO890477D0 (en) | 1989-02-06 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| MK1K | Patent expired |
Free format text: EXPIRED IN MAY 2002 |