NO145404B - ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PURINE COMPOUNDS AND SALTS THEREOF - Google Patents
ANALOGUE PROCEDURE FOR THE PREPARATION OF THERAPEUTICALLY EFFECTIVE PURINE COMPOUNDS AND SALTS THEREOF Download PDFInfo
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- NO145404B NO145404B NO760679A NO760679A NO145404B NO 145404 B NO145404 B NO 145404B NO 760679 A NO760679 A NO 760679A NO 760679 A NO760679 A NO 760679A NO 145404 B NO145404 B NO 145404B
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- Prior art keywords
- formula
- compound
- amino
- hydroxy
- salt
- Prior art date
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- 238000000034 method Methods 0.000 title claims description 8
- 238000002360 preparation method Methods 0.000 title description 4
- 150000003212 purines Chemical class 0.000 title description 3
- 150000001875 compounds Chemical class 0.000 claims description 31
- 150000003839 salts Chemical class 0.000 claims description 17
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 8
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 8
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 8
- -1 mercapto, hydroxy, amino Chemical group 0.000 claims description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- 230000007062 hydrolysis Effects 0.000 claims description 5
- 238000006460 hydrolysis reaction Methods 0.000 claims description 5
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 4
- 235000019253 formic acid Nutrition 0.000 claims description 4
- 238000007098 aminolysis reaction Methods 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- 125000005843 halogen group Chemical group 0.000 claims description 3
- 239000001257 hydrogen Substances 0.000 claims description 3
- 229910052739 hydrogen Inorganic materials 0.000 claims description 3
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 3
- 238000003797 solvolysis reaction Methods 0.000 claims description 3
- 125000000026 trimethylsilyl group Chemical group [H]C([H])([H])[Si]([*])(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 3
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004414 alkyl thio group Chemical group 0.000 claims description 2
- 125000003277 amino group Chemical group 0.000 claims description 2
- 150000001540 azides Chemical class 0.000 claims description 2
- 125000000717 hydrazino group Chemical group [H]N([*])N([H])[H] 0.000 claims description 2
- 125000004356 hydroxy functional group Chemical group O* 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 238000006722 reduction reaction Methods 0.000 claims description 2
- 125000004665 trialkylsilyl group Chemical group 0.000 claims description 2
- 125000000561 purinyl group Chemical class N1=C(N=C2N=CNC2=C1)* 0.000 claims 1
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 18
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 12
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 12
- 239000000243 solution Substances 0.000 description 9
- 239000000203 mixture Substances 0.000 description 7
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- KDCGOANMDULRCW-UHFFFAOYSA-N Purine Natural products N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 6
- OFDJYPIEYXKRHP-UHFFFAOYSA-N 2-[(2-amino-6-oxo-3h-purin-9-yl)methoxy]ethyl formate Chemical compound O=C1NC(N)=NC2=C1N=CN2COCCOC=O OFDJYPIEYXKRHP-UHFFFAOYSA-N 0.000 description 5
- UYTPUPDQBNUYGX-UHFFFAOYSA-N Guanine Natural products O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- TYHQCBMIGOIZEH-UHFFFAOYSA-N 2-[(2,6-diaminopurin-9-yl)methoxy]ethyl formate Chemical compound NC1=NC(N)=C2N=CN(COCCOC=O)C2=N1 TYHQCBMIGOIZEH-UHFFFAOYSA-N 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 4
- 230000000840 anti-viral effect Effects 0.000 description 4
- 239000002585 base Substances 0.000 description 4
- 239000006071 cream Substances 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 3
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 3
- 238000009833 condensation Methods 0.000 description 3
- 230000005494 condensation Effects 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 3
- PTXSLPXLYZHGEM-UHFFFAOYSA-N 2-(chloromethoxy)ethyl formate Chemical compound ClCOCCOC=O PTXSLPXLYZHGEM-UHFFFAOYSA-N 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000036142 Viral infection Diseases 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 239000007900 aqueous suspension Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 150000005690 diesters Chemical class 0.000 description 2
- 238000001704 evaporation Methods 0.000 description 2
- 230000008020 evaporation Effects 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 230000004927 fusion Effects 0.000 description 2
- 239000008187 granular material Substances 0.000 description 2
- 208000015181 infectious disease Diseases 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 150000007524 organic acids Chemical class 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 239000000375 suspending agent Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 230000009385 viral infection Effects 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- WNXJIVFYUVYPPR-UHFFFAOYSA-N 1,3-dioxolane Chemical compound C1COCO1 WNXJIVFYUVYPPR-UHFFFAOYSA-N 0.000 description 1
- CSMCRCLIPQDIKB-UHFFFAOYSA-N 2-[(2,6-diaminopurin-9-yl)methoxy]ethanol Chemical compound NC1=NC(N)=C2N=CN(COCCO)C2=N1 CSMCRCLIPQDIKB-UHFFFAOYSA-N 0.000 description 1
- XDWWJDAXPMJQLC-UHFFFAOYSA-N 2-[(6-amino-2-azidopurin-9-yl)methoxy]ethyl formate Chemical compound N(=[N+]=[N-])C1=NC(=C2N=CN(C2=N1)COCCOC=O)N XDWWJDAXPMJQLC-UHFFFAOYSA-N 0.000 description 1
- QFNIAQMULZQGOW-UHFFFAOYSA-N 2-[bis(trimethylsilyl)amino]-8-trimethylsilyl-3,7-dihydropurin-6-one Chemical compound O=C1NC(N([Si](C)(C)C)[Si](C)(C)C)=NC2=C1NC([Si](C)(C)C)=N2 QFNIAQMULZQGOW-UHFFFAOYSA-N 0.000 description 1
- QPSGXYRAHOXLLI-UHFFFAOYSA-N 2-formyloxyacetic acid Chemical compound OC(=O)COC=O QPSGXYRAHOXLLI-UHFFFAOYSA-N 0.000 description 1
- IAFAXGYXSQSJIX-UHFFFAOYSA-N 2-formyloxyethoxymethyl acetate Chemical compound CC(=O)OCOCCOC=O IAFAXGYXSQSJIX-UHFFFAOYSA-N 0.000 description 1
- UKQJDWBNQNAJHB-UHFFFAOYSA-N 2-hydroxyethyl formate Chemical compound OCCOC=O UKQJDWBNQNAJHB-UHFFFAOYSA-N 0.000 description 1
- 101710169336 5'-deoxyadenosine deaminase Proteins 0.000 description 1
- 102000055025 Adenosine deaminases Human genes 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 1
- 241000450599 DNA viruses Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 208000001860 Eye Infections Diseases 0.000 description 1
- 208000000903 Herpes simplex encephalitis Diseases 0.000 description 1
- 208000037018 Herpes simplex virus encephalitis Diseases 0.000 description 1
- 208000007514 Herpes zoster Diseases 0.000 description 1
- 208000005100 Herpetic Keratitis Diseases 0.000 description 1
- XQFRJNBWHJMXHO-RRKCRQDMSA-N IDUR Chemical compound C1[C@H](O)[C@@H](CO)O[C@H]1N1C(=O)NC(=O)C(I)=C1 XQFRJNBWHJMXHO-RRKCRQDMSA-N 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 206010073938 Ophthalmic herpes simplex Diseases 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229930040373 Paraformaldehyde Natural products 0.000 description 1
- 241000700618 Vaccinia virus Species 0.000 description 1
- 206010046865 Vaccinia virus infection Diseases 0.000 description 1
- 235000011054 acetic acid Nutrition 0.000 description 1
- ORWKVZNEPHTCQE-UHFFFAOYSA-N acetic formic anhydride Chemical compound CC(=O)OC=O ORWKVZNEPHTCQE-UHFFFAOYSA-N 0.000 description 1
- MKUXAQIIEYXACX-UHFFFAOYSA-N aciclovir Chemical compound N1C(N)=NC(=O)C2=C1N(COCCO)C=N2 MKUXAQIIEYXACX-UHFFFAOYSA-N 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 125000002252 acyl group Chemical group 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 238000006136 alcoholysis reaction Methods 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 125000004429 atom Chemical group 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000003197 catalytic effect Effects 0.000 description 1
- 239000003610 charcoal Substances 0.000 description 1
- RCTYPNKXASFOBE-UHFFFAOYSA-M chloromercury Chemical class [Hg]Cl RCTYPNKXASFOBE-UHFFFAOYSA-M 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 229940012356 eye drops Drugs 0.000 description 1
- 208000011323 eye infectious disease Diseases 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 150000004820 halides Chemical class 0.000 description 1
- 229910052736 halogen Inorganic materials 0.000 description 1
- 150000002367 halogens Chemical class 0.000 description 1
- 201000010884 herpes simplex virus keratitis Diseases 0.000 description 1
- 150000002391 heterocyclic compounds Chemical class 0.000 description 1
- GNOIPBMMFNIUFM-UHFFFAOYSA-N hexamethylphosphoric triamide Chemical compound CN(C)P(=O)(N(C)C)N(C)C GNOIPBMMFNIUFM-UHFFFAOYSA-N 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 206010022000 influenza Diseases 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 239000013067 intermediate product Substances 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 229940100662 nasal drops Drugs 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000003883 ointment base Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 229910052763 palladium Inorganic materials 0.000 description 1
- 229920002866 paraformaldehyde Polymers 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000002798 polar solvent Substances 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000002243 precursor Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 150000003230 pyrimidines Chemical class 0.000 description 1
- 239000000376 reactant Substances 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 238000001228 spectrum Methods 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- BDHFUVZGWQCTTF-UHFFFAOYSA-N sulfonic acid Chemical compound OS(=O)=O BDHFUVZGWQCTTF-UHFFFAOYSA-N 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- LMBFAGIMSUYTBN-MPZNNTNKSA-N teixobactin Chemical compound C([C@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H](CCC(N)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CO)C(=O)N[C@H]1C(N[C@@H](C)C(=O)N[C@@H](C[C@@H]2NC(=N)NC2)C(=O)N[C@H](C(=O)O[C@H]1C)[C@@H](C)CC)=O)NC)C1=CC=CC=C1 LMBFAGIMSUYTBN-MPZNNTNKSA-N 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 238000004809 thin layer chromatography Methods 0.000 description 1
- 229940100611 topical cream Drugs 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 229940100615 topical ointment Drugs 0.000 description 1
- 238000001665 trituration Methods 0.000 description 1
- 241001529453 unidentified herpesvirus Species 0.000 description 1
- 241000712461 unidentified influenza virus Species 0.000 description 1
- 208000007089 vaccinia Diseases 0.000 description 1
- 230000003612 virological effect Effects 0.000 description 1
- 238000005406 washing Methods 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Description
Foreliggende oppfinnelse som er en videreutvikling i henhold til norsk utlegningsskrift nr. 144.216, vedrører fremstilling av terapeutisk virksomme, substituerte purinforbindelser med formelen: The present invention, which is a further development in accordance with Norwegian explanatory document no. 144,216, relates to the production of therapeutically effective, substituted purine compounds with the formula:
hvor R er en hydroksy- eller aruinogruppe. Det er oppdaget at disse forbindelsene har antiviral aktivitet mot for- where R is a hydroxy or aruino group. It has been discovered that these compounds have antiviral activity against pro-
skjellige klasser av DNA-virus in vitro. Forbindelsene er spesielt aktive mot influensa, vaccinia og herpes virus, different classes of DNA viruses in vitro. The compounds are particularly active against influenza, vaccinia and herpes viruses,
inkludert simplex, zoster og varicella, hos pattedyr, hvilke forårsaker slike sykdommer som f.eks. herpetisk keratitis hos kaniner og herpetisk encephalitis hos mus. En forbind- including simplex, zoster and varicella, in mammals, which cause such diseases as e.g. herpetic keratitis in rabbits and herpetic encephalitis in mice. A connect-
else med formel I hvor R er hydroksy eller et salt derav, else with formula I where R is hydroxy or a salt thereof,
er foretrukket. is preferred.
Salter som er spesielt hensiktsmessige for terapeu- Salts which are particularly suitable for therapeutic
tisk anvendelse er salter av farmasøytisk akseptable organiske syrer slik som melkesyre, eddiksyre, eplesyre eller p-toluen-sulfonsyre, samt salter av farmasøytisk akseptable mineral- tical application are salts of pharmaceutically acceptable organic acids such as lactic acid, acetic acid, malic acid or p-toluenesulphonic acid, as well as salts of pharmaceutically acceptable mineral
syrer, slik som saltsyre eller sulfonsyre. Andre salter kan også fremstilles og deretter omdannes til salter som er direkte egnet for behandlingsformål. acids, such as hydrochloric or sulphonic acid. Other salts can also be prepared and then converted into salts that are directly suitable for treatment purposes.
Forbindelsene med formel I fremstilles ifølge oppfinnelsen ved at man The compounds of formula I are prepared according to the invention by
a) omdanner en forbindelse med formelen: a) converts a compound with the formula:
hvor enten både M og G er et halogenatom, en merkapto-, hydroksy-, amino-, alkyltio-, alkoksy-, azid- eller hydra-zinogruppe, forutsatt at både M og G ikke er amino unntagen når M skal omdannes til hydroksy, og forutsatt at M ikke er hydroksy når G er amino unntagen når M skal omdannes til amino, til en forbindelse med formel I ved hydrolyse, aminolyse eller reduksjon, eller where either both M and G are a halogen atom, a mercapto, hydroxy, amino, alkylthio, alkoxy, azide or hydra-zino group, provided that both M and G are not amino except when M is to be converted to hydroxy, and provided that M is not hydroxy when G is amino except when M is to be converted to amino, to a compound of formula I by hydrolysis, aminolysis or reduction, or
b), omsetter en forbindelse med formelen: b), reacts a compound with the formula:
hvor Q er hydrogen, med en forbindelse med formelen: where Q is hydrogen, with a compound of the formula:
hvor A er karboksylat, eller where A is carboxylate, or
c) forestrer en alkohol med formelen: c) esterifies an alcohol with the formula:
hvor R har den ovenfor angitte betydning, ved omsetning med where R has the meaning given above, when trading with
maursyre, eller formic acid, or
d) en forbindelse med formelen: d) a compound of the formula:
hvor RQ er -0X eller -NHX, og X er en lavere trialkylsilyl-gruppe, fortrinnsvis trimetylsilylgruppe, omdannes til en forbindelse med formel I ved hydrolyse eller solvolyse; where RQ is -OX or -NHX, and X is a lower trialkylsilyl group, preferably trimethylsilyl group, is converted to a compound of formula I by hydrolysis or solvolysis;
og, om ønsket, når produktet fra ovenstående reaksjon er en base, omdanner en forbindelse med formel I til et syre-addisjonssalt derav, eller, om ønsket, når produktet er et salt av en forbindelse med formel I, omdanner dette salt til dets base eller et annet salt derav. and, if desired, when the product of the above reaction is a base, converting a compound of formula I into an acid addition salt thereof, or, if desired, when the product is a salt of a compound of formula I, converting this salt into its base or another salt thereof.
Omdannelse av en forbindelse med formel II ved hjelp av metode a) kan oppnås på flere forskjellige måter. Gruppen M kan f .eks. omdannes til en hydroksygruppe ved hydrolyse, og Conversion of a compound of formula II by means of method a) can be achieved in several different ways. The group M can e.g. is converted to a hydroxy group by hydrolysis, and
G og/eller M. kan omdannes til amino ved aminolyse. Slike metoder er velkjente og beskrives i "Heterocyclic compounds - Fused Pyrimidines", del II Puriner av D.J. Brown (197i), Wiley-Interscience. G and/or M. can be converted to amino by aminolysis. Such methods are well known and are described in "Heterocyclic compounds - Fused Pyrimidines", part II Purines by D.J. Brown (197i), Wiley-Interscience.
Omdannelse kan alternativt bevirkes ved anvendelse av enzymer og adenosin-deaminase omdanner f.eks. på effektiv måte en 2,6-diaminoforbindelse til den nødvendige guaninforbindelse i en vandig suspensjon ved omkring 37°C og en innledende pH-verdi på omkring 7,0. Conversion can alternatively be effected by the use of enzymes and adenosine deaminase converts e.g. efficiently a 2,6-diamino compound to the required guanine compound in an aqueous suspension at about 37°C and an initial pH of about 7.0.
De forbindelser som inneholder forløpere for hydroksy-og aminogrupper og kan omdannes til forbindelser med formel I, kan betraktes som mellomprodukter i syntesen av slike forbindelser . The compounds which contain precursors for hydroxy and amino groups and can be converted into compounds of formula I can be regarded as intermediate products in the synthesis of such compounds.
I metode b) er atomet eller gruppen A som avspaltes en reaktiv rest av en organisk eller uorganisk syre og kan derfor være et halogenatom eller en karboksylatgruppe, og Q er hydrogen eller acyl. Den foretrukne metode omfatter kondensering av en purinforbindelse som har den ønskede 2- og 6-substituering med en formylblokkert 2-halogenalkbksy-etanol, f.eks. 2-formyloksyetoksymetylklorid, i et sterkt polart oppløsningsmiddel slik som dimetylformamid (DMF) eller heksametylfosforamid, og i nærvær av en protonakseptor slik som en base, f.eks. trietylamin eller kaliumkarbonat. Reaksjonen utføres fortrinnsvis ved romtemperatur over et lengre tidsrom, dvs. det kan være nødvendig med flere dager for opp-nåelse av rimelige utbytter. In method b), the atom or group A which is split off is a reactive residue of an organic or inorganic acid and can therefore be a halogen atom or a carboxylate group, and Q is hydrogen or acyl. The preferred method involves the condensation of a purine compound having the desired 2- and 6-substitution with a formyl-blocked 2-haloalkbxy-ethanol, e.g. 2-formyloxyethoxymethyl chloride, in a strongly polar solvent such as dimethylformamide (DMF) or hexamethylphosphoramide, and in the presence of a proton acceptor such as a base, e.g. triethylamine or potassium carbonate. The reaction is preferably carried out at room temperature over a longer period of time, i.e. several days may be necessary to achieve reasonable yields.
Man kan alternativt foreta en termisk kondensering, dvs. en sammensmeltningsreaksjon, for å oppnå produktet direkte. For denne reaksjon blir en hensiktsmessig substitu-ert purinforbindelse oppvarmet sammen med formyloksyalkoksy-metylkarboksylat i nærvær av en katalytisk mengde av en sterk syre slik som svovelsyre. Temperaturer i overkant av 100°C er i alminnelighet nødvendig, men temperaturen bør fortrinnsvis ikke overstige ca. 200°C for å gjøre dekomponer-ingen så liten som mulig. Temperaturen bør velges slik at blandingen av reaktanter smelter før de utsettes for de-komponering . One can alternatively carry out a thermal condensation, i.e. a fusion reaction, to obtain the product directly. For this reaction, an appropriately substituted purine compound is heated together with formyloxy-methylcarboxylate in the presence of a catalytic amount of a strong acid such as sulfuric acid. Temperatures in excess of 100°C are generally necessary, but the temperature should preferably not exceed approx. 200°C to minimize decomposition. The temperature should be chosen so that the mixture of reactants melts before they are subjected to de-composition.
Smeltereaksjonen kan også utføres under vesentlig de The melting reaction can also be carried out under substantially de
samme betingelser som angitt ovenfor, med muligens noe lavere temperaturer, mellom en 9-acylpurinforbindelse og et alkoksy-metylkarboksylat eller -halogenid. Sammensmeltningsreaksjonen kan alternativt utføres under anvendelse av diesteren f.eks. 2-formyloksyetoksymetylacetat. same conditions as stated above, with possibly somewhat lower temperatures, between a 9-acylpurine compound and an alkoxymethylcarboxylate or halide. Alternatively, the fusion reaction can be carried out using the diester, e.g. 2-Formyloxyethoxymethyl acetate.
I metode d) kan amino- og hydroksy-gruppene reversi-belt blokkeres f.eks. med trimetylsilylgrupper. En slik forbindelse vil være produktet av kondenseringen av en trimetyl-silylert purin og en ester eller diester. Slike blokkerende grupper er meget labile og kan fjernes ved solvolyse med alkoholisk eller vandig ammoniakk, eller ved alkoholyse. In method d), the amino and hydroxy groups can be reversibly blocked, e.g. with trimethylsilyl groups. Such a compound would be the product of the condensation of a trimethylsilylated purine and an ester or diester. Such blocking groups are very labile and can be removed by solvolysis with alcoholic or aqueous ammonia, or by alcoholysis.
Merkurikloridsaltet av en purinforbindelse kan alternativt fremstilles i nærvær av alkali og deretter kon-denseres med en halogeneter i et oppløsningsmiddel av aro-matisk organisk type. Før fremstilling av saltet må imidler-tid alle reaktive substituenter på purinforbindelsen være blokkert og det siste trinnet i denne metode består derfor i fjerning av de blokkerende grupper. Alternatively, the mercury chloride salt of a purine compound can be prepared in the presence of alkali and then condensed with a halogen ether in an aromatic organic type solvent. Before producing the salt, however, all reactive substituents on the purine compound must be blocked and the last step in this method therefore consists in removing the blocking groups.
Et farmasøytisk preparat omfatter spesielt en forbindelse med formel I i en effektiv enhetsdose-form. Den benyttede betegnelse "effektiv enhetsdose" betegner en bestemt antiviral mengde som er tilstrekkelig til å virke effektivt mot virale organismer in vivo. Farmasøytisk akseptable bærere er materialer som er nyttige for det for-mål å administrere legemidlet, og kan være faste, flytende eller gassformige materialer hvilke ellers er inerte og medisinsk akseptable bg er forenlige med de aktive bestand-deler . A pharmaceutical preparation comprises in particular a compound of formula I in an effective unit dose form. The term "effective unit dose" used denotes a specific antiviral amount which is sufficient to be effective against viral organisms in vivo. Pharmaceutically acceptable carriers are materials that are useful for the purpose of administering the drug, and can be solid, liquid or gaseous materials which are otherwise inert and medically acceptable bg are compatible with the active constituents.
Disse farmasøytiske preparater kan gis parenteralt, These pharmaceutical preparations can be given parenterally,
oralt, anvendes som suppositorium eller pessarium, anbringes topisk som en salve, krem, aerosol, pulver eller gis som øye-eller nese-dråper, osv., avhengig av preparatet anvendes for behandling av indre eller ytre virale infeksjoner. orally, used as a suppository or pessary, applied topically as an ointment, cream, aerosol, powder or given as eye or nose drops, etc., depending on whether the preparation is used for the treatment of internal or external viral infections.
For indre infeksjoner administreres preparatene oralt eller parenteralt ved doseringsnivåer beregnet som den frie base, på 0,1-250 mg/kg legemesvekt, og anvendes hos mennesker i en enhetsdoseringsform, administrert noen ganger i en mengde på 1-250 mg/enhetsdose. For internal infections, the preparations are administered orally or parenterally at dosage levels calculated as the free base, of 0.1-250 mg/kg body weight, and used in humans in a unit dosage form, sometimes administered in an amount of 1-250 mg/unit dose.
For oral administrasjon kan fine pulvere eller granulater inneholde fortynnings-, dispergerings- og/eller overflateaktive midler, og kan gis i en drikk, i vann eller i en sirup; i kapsler eller drageer, i tørr tilstand eller i en ikke-vandig oppløsning eller suspensjon, hvori suspen-sjonsmidler kan være inkludert; tabletter som kan omfatte bindemidler og smøremidler; eller i en suspensjon i vann eller en sirup. Der det er ønskelig eller nødvendig kan det anvendes smaksstoffer, preserveringsmidler, suspenderings-midler, fortykningsmidler eller emulgeringsmidler. Det foretrekkes tabletter og granulater, og disse kan være be-lagte . For oral administration, fine powders or granules may contain diluents, dispersants and/or surfactants, and may be given in a drink, in water or in a syrup; in capsules or dragees, in the dry state or in a non-aqueous solution or suspension, in which suspending agents may be included; tablets which may include binders and lubricants; or in a suspension in water or a syrup. Where it is desirable or necessary, flavourings, preservatives, suspending agents, thickeners or emulsifiers can be used. Tablets and granules are preferred, and these can be coated.
For parenteral administrasjon eller for administrasjon i form av dråper, slik som for øyeinfeksjoner, kan forbindelsene presenteres i vandig oppløsning i en konsentrasjon på 0,1-10%, fortrinnsvis 0,1-7%, og helst 0,2% vekt/ volum. Oppløsningen kan inneholde antioksydasjonsmidler, bufferstoffer, osv. For parenteral administration or for administration in the form of drops, such as for eye infections, the compounds can be presented in aqueous solution at a concentration of 0.1-10%, preferably 0.1-7%, and preferably 0.2% w/v . The solution may contain antioxidants, buffer substances, etc.
For infeksjoner på øyet eller andre ytre vev, f.eks. munn og hud, blir preparatene fortrinnsvis påført på den infiserte del av legemet hos pasienten i form av en topisk salve eller krem. Forbindelsene kan foreligge i en salve, f.eks. med en vannoppløselig salvebasis, eller i en krem, f.eks. med en olje i vann-krem-basis, i en konsentrasjon på 0,1-10%, fortrinnsvis 0,1-7% og helst 1% vekt/vol. For infections of the eye or other external tissues, e.g. mouth and skin, the preparations are preferably applied to the infected part of the patient's body in the form of a topical ointment or cream. The compounds can be present in an ointment, e.g. with a water-soluble ointment base, or in a cream, e.g. with an oil in a water-cream base, in a concentration of 0.1-10%, preferably 0.1-7% and preferably 1% w/v.
Av forbindelsene med formel I foretrekkes 9-(2-formyloksyetoksymetyl)guanin fordi denne forbindelse har meget høy antiviral aktivitet mot Herpes. Of the compounds of formula I, 9-(2-formyloxyethoxymethyl)guanine is preferred because this compound has very high antiviral activity against Herpes.
Ved behandling av virale infeksjoner hos pattedyr administreres en effektiv antiviral mengde av en forbindelse med formel I eller et farmasøytisk akseptabelt salt derav. Administreringen foretas fortrinnsvis ved topisk påføring eller ad oral eller parenteral vei. In the treatment of viral infections in mammals, an effective antiviral amount of a compound of formula I or a pharmaceutically acceptable salt thereof is administered. The administration is preferably carried out by topical application or ad oral or parenteral route.
Oppfinnelsen skal i det følgende illustreres under henvisning til nedenstående eksempler. In what follows, the invention will be illustrated with reference to the examples below.
Eksempel 1 Example 1
En oppløsning av 9-(2-hydroksyetoksymetyl)guanin (4,73 g) i 97% maursyre (24 ml) ble omrørt ved romtemperatur natten over. Den ravfargede oppløsning ble fortynnet med omkring 200 ml tørket eter og avkjølt. Det resulterende hvite bunnfall ble filtrert, tørket og omkrystallisert fra tørr dimetylformamid og dette ga 9- (2-foriuyloksyetoksymetyl) - guanin (3,6 g, smp. 225-275°C). A solution of 9-(2-hydroxyethoxymethyl)guanine (4.73 g) in 97% formic acid (24 mL) was stirred at room temperature overnight. The amber solution was diluted with about 200 ml of dried ether and cooled. The resulting white precipitate was filtered, dried and recrystallized from dry dimethylformamide to give 9-(2-phoriuyloxyethoxymethyl)-guanine (3.6 g, mp 225-275°C).
Eksempel 2 Example 2
En oppløsning av 2-amino-9-(2-hydroksyetoksymetyl)-adenin (0,5 g) i 97% maursyre (2,5 ml) ble omrørt i et is-bad i 3 timer, og deretter ved romtemperatur natten over. Tørr eter (80 ml) ble tilsatt og blandingen avkjølt. Det faste stoff ble fjernet ved filtrering og oppløst i varm acetonitril (125 ml); resterende faste stoffer ble fjernet ved filtrering. Filtratet ble anbragt på en kolonne innehold-ende silisiumdioksydgel (14 g) i acetonitril. Kolonnen ble eluert med tørr aceton. Elueringsmidlet ble fordampet og det resterende faste stoff omkrystallisert fra acetonitril hvilket ga 2-amino-9-(2-formyloksyetoksymetyl)adenin (93 mg), smp. 238-240°C. A solution of 2-amino-9-(2-hydroxyethoxymethyl)-adenine (0.5 g) in 97% formic acid (2.5 ml) was stirred in an ice bath for 3 hours, and then at room temperature overnight. Dry ether (80 mL) was added and the mixture cooled. The solid was removed by filtration and dissolved in hot acetonitrile (125 mL); residual solids were removed by filtration. The filtrate was placed on a column containing silica gel (14 g) in acetonitrile. The column was eluted with dry acetone. The eluent was evaporated and the remaining solid recrystallized from acetonitrile to give 2-amino-9-(2-formyloxyethoxymethyl)adenine (93 mg), m.p. 238-240°C.
Eksempel 3 Example 3
9-[ ( 2- formyloksyetoksy) metyl] 2, 6- diaminopurin 9-[(2-formyloxyethoxy)methyl]2,6-diaminopurine
En oppløsning av 9-[(2-formyloksyetoksy)metyl]-2-azidoadenin (610 mg) i tørr dimetylformamid (125 ml) inne-holdende 5% palladium (120 mg) på trekull, ble hydrogenert ved et innledende trykk på 3,5 kg/cm 2 i 24 timer ved romtemperatur. Tynnsjiktskromatografi (silisiumdioksydgel i aceton) viste bare en flekk tilsvarende autentisk 9-[(2-. formyloksyetoksy)metyl]- 2,6-diaminopurin og intet utgangs-materiale. A solution of 9-[(2-formyloxyethoxy)methyl]-2-azidoadenine (610 mg) in dry dimethylformamide (125 ml) containing 5% palladium (120 mg) on charcoal was hydrogenated at an initial pressure of 3, 5 kg/cm 2 for 24 hours at room temperature. Thin layer chromatography (silica gel in acetone) showed only one spot corresponding to authentic 9-[(2-formyloxyethoxy)methyl]-2,6-diaminopurine and no starting material.
Oppløsningen ble filtrert gjennom en pute av "Celite", puten ble vasket med etylacetat og de kombinerte vaskeoppløs-ninger og filtrat inndampet i vakuum ved en badtemperatur på 60°C. Det resulterende gule faste stoff ble renset ved kolonnekromatografi (silisiumdioksydgel), idet det ønskede produkt ble eluert med aceton. The solution was filtered through a pad of "Celite", the pad was washed with ethyl acetate and the combined washing solutions and filtrate evaporated in vacuo at a bath temperature of 60°C. The resulting yellow solid was purified by column chromatography (silica gel), eluting the desired product with acetone.
Triturering av de innndampede eluater med aceton ga 119 mg (22%) 9-[(2-formyloksyetoksy)metyl]-2,6-diaminopurin hvis U.V.- og N.M.R.-spektra var i overensstemmelse med den bestemte struktur, smp. 238-240°C. Trituration of the evaporated eluates with acetone gave 119 mg (22%) of 9-[(2-formyloxyethoxy)methyl]-2,6-diaminopurine whose U.V. and N.M.R. spectra were consistent with the determined structure, m.p. 238-240°C.
Eksempel 4 Example 4
9-( 2- formyloksyetoksymetyl) guanin 9-(2-formyloxyethoxymethyl)guanine
Hydrogenkloridgass ble boblet inn i en avkjølt (0°C) suspensjon av etylenglykolmonoformiat (3,6 g, Annalen der chemie, 641, 1 (1961)) og paraformaldehyd (1,2 g) i tørr diklormetan (100 ml) inntil blandingen var mettet. Den olje-aktige suspensjon ble tørket over molekylarsikter etanol og vannfritt kalsiumklorid, filtrert og oppløsningsmidlet ble fjernet ved inndampning under redusert trykk (badtemperatur Hydrogen chloride gas was bubbled into a cooled (0°C) suspension of ethylene glycol monoformate (3.6 g, Annalen der chemie, 641, 1 (1961)) and paraformaldehyde (1.2 g) in dry dichloromethane (100 mL) until the mixture was saturated. The oily suspension was dried over molecularly sieved ethanol and anhydrous calcium chloride, filtered and the solvent was removed by evaporation under reduced pressure (bath temperature
<3 0°C). Det resulterende urene 2-formyloksyetoksymetylklorid (2,5 g) ble tilsatt til en oppløsning av tris-(trimetylsilyl)-guanin (4,8 g) i tørr toluen (50 ml) og blandingen oppvarmet ved tilbakeløp under nitrogen i 24 timer. Oppløsningsmidlet ble fjernet under redusert trykk hvilket ga 9-(2-formyloksyetoksymetyl)bis-N 2 ,0 6-)-trimetylsilyl)guanin som en olje som ble benyttet uten rensing. Et overskudd metanol ble tilsatt til oljen og blandingen omrørt i 1 time. Metanolen ble fjernet ved inndampning og resten omkrystallisert fra dimetylformamid og acetonitril og dette ga 9-(2-formyloksyetoksymetyl)guanin, smp. 225-227°C. <3 0°C). The resulting crude 2-formyloxyethoxymethyl chloride (2.5 g) was added to a solution of tris-(trimethylsilyl)-guanine (4.8 g) in dry toluene (50 mL) and the mixture heated at reflux under nitrogen for 24 h. The solvent was removed under reduced pressure to give 9-(2-formyloxyethoxymethyl)bis-N 2 ,0 6-)-trimethylsilyl)guanine as an oil which was used without purification. An excess of methanol was added to the oil and the mixture stirred for 1 hour. The methanol was removed by evaporation and the residue recrystallized from dimethylformamide and acetonitrile to give 9-(2-formyloxyethoxymethyl)guanine, m.p. 225-227°C.
Eksempel 5 Example 5
9-( 2- formyloksyetoksymetyl) guanin 9-(2-formyloxyethoxymethyl)guanine
Til en blanding av eddiksyre-maursyreanhydrid (1,0 ml) og p_-toluensulfonsyre (0,1 g) ble det under omrøring til- To a mixture of acetic acid-formic anhydride (1.0 ml) and p_-toluenesulfonic acid (0.1 g) was added, while stirring, to
satt dioksolan (1,0 g), og siden reaksjonen er eksoterm, added dioxolane (1.0 g), and since the reaction is exothermic,
ble forsiktighet utvist. Oppløsningen fikk avkjøles i flere minutter. Tørr toluen (10 ml) og guanin (1,0 g) ble tilsatt og reaksjonsblandingen oppvarmet ved 50°C i 24 timer. Toluenet ble avdekantert og resten grundig vasket med tørr toluen (25 ml) og omkrystallisert to ganger fra tørr dimetylformamid hvilket ga 9-(2-formyloksyetoksymetyl)guanin, caution was exercised. The solution was allowed to cool for several minutes. Dry toluene (10 mL) and guanine (1.0 g) were added and the reaction heated at 50°C for 24 hours. The toluene was decanted and the residue thoroughly washed with dry toluene (25 mL) and recrystallized twice from dry dimethylformamide to give 9-(2-formyloxyethoxymethyl)guanine,
smp. 225-227°C. m.p. 225-227°C.
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