DE4138584A1 - New carbocyclic phosphonate-nucleotide analogues - are effective antiviral agents against retroviral infections, e.g. HIV - Google Patents
New carbocyclic phosphonate-nucleotide analogues - are effective antiviral agents against retroviral infections, e.g. HIVInfo
- Publication number
- DE4138584A1 DE4138584A1 DE4138584A DE4138584A DE4138584A1 DE 4138584 A1 DE4138584 A1 DE 4138584A1 DE 4138584 A DE4138584 A DE 4138584A DE 4138584 A DE4138584 A DE 4138584A DE 4138584 A1 DE4138584 A1 DE 4138584A1
- Authority
- DE
- Germany
- Prior art keywords
- formula
- compound
- compounds
- hiv
- hydrogen
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- 239000003443 antiviral agent Substances 0.000 title abstract 2
- 125000002837 carbocyclic group Chemical group 0.000 title description 3
- 206010038997 Retroviral infections Diseases 0.000 title 1
- 239000003814 drug Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 150000001875 compounds Chemical class 0.000 claims description 104
- 239000001257 hydrogen Substances 0.000 claims description 14
- 229910052739 hydrogen Inorganic materials 0.000 claims description 14
- 239000000126 substance Substances 0.000 claims description 12
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 9
- LPXPTNMVRIOKMN-UHFFFAOYSA-M sodium nitrite Chemical compound [Na+].[O-]N=O LPXPTNMVRIOKMN-UHFFFAOYSA-M 0.000 claims description 8
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 7
- 239000003054 catalyst Substances 0.000 claims description 6
- 150000002431 hydrogen Chemical class 0.000 claims description 5
- 150000007529 inorganic bases Chemical class 0.000 claims description 5
- 150000007530 organic bases Chemical class 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- UEWDJCZJEIBPKX-UHFFFAOYSA-N 2,2-diethoxy-1-methylpyrrolidine Chemical compound CCOC1(OCC)CCCN1C UEWDJCZJEIBPKX-UHFFFAOYSA-N 0.000 claims description 4
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000012312 sodium hydride Substances 0.000 claims description 4
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 4
- 235000010288 sodium nitrite Nutrition 0.000 claims description 4
- 241001430294 unidentified retrovirus Species 0.000 claims description 4
- 239000002253 acid Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 230000003612 virological effect Effects 0.000 claims description 3
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 2
- 125000001511 cyclopentyl group Chemical class [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims 1
- 229940126601 medicinal product Drugs 0.000 claims 1
- RWQNBRDOKXIBIV-UHFFFAOYSA-N Thymine Natural products CC1=CNC(=O)NC1=O RWQNBRDOKXIBIV-UHFFFAOYSA-N 0.000 abstract description 20
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 abstract description 13
- 229940113082 thymine Drugs 0.000 abstract description 11
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 3
- 125000000217 alkyl group Chemical group 0.000 abstract description 3
- 208000015181 infectious disease Diseases 0.000 abstract 1
- 230000001177 retroviral effect Effects 0.000 abstract 1
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 27
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 21
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- 238000002844 melting Methods 0.000 description 14
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- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 10
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 10
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- 238000006243 chemical reaction Methods 0.000 description 7
- HKOGUJPOFIMXDS-UHFFFAOYSA-N 5-methyl-6-(1,2,4-triazol-1-yl)-1h-pyrimidin-2-one Chemical compound CC1=CNC(=O)N=C1N1N=CN=C1 HKOGUJPOFIMXDS-UHFFFAOYSA-N 0.000 description 6
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 6
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- 241000725303 Human immunodeficiency virus Species 0.000 description 6
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- -1 carbocyclic phosphonate Nucleotide Chemical class 0.000 description 6
- DJQGARJHMZLWPJ-UHFFFAOYSA-N 6-oxabicyclo[3.1.0]hex-1(5)-ene Chemical compound C1CCC2=C1O2 DJQGARJHMZLWPJ-UHFFFAOYSA-N 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 5
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 5
- LRSASMSXMSNRBT-UHFFFAOYSA-N 5-methylcytosine Chemical compound CC1=CNC(=O)N=C1N LRSASMSXMSNRBT-UHFFFAOYSA-N 0.000 description 4
- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical compound N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 description 4
- 108091003079 Bovine Serum Albumin Proteins 0.000 description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 4
- 241000700605 Viruses Species 0.000 description 4
- 239000006227 byproduct Substances 0.000 description 4
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- UYTPUPDQBNUYGX-UHFFFAOYSA-N guanine Chemical compound O=C1NC(N)=NC2=C1N=CN2 UYTPUPDQBNUYGX-UHFFFAOYSA-N 0.000 description 4
- 238000000338 in vitro Methods 0.000 description 4
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- 229910052763 palladium Inorganic materials 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 4
- 108010027044 HIV Core Protein p24 Proteins 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N ammonia Natural products N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
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- 239000006228 supernatant Substances 0.000 description 3
- BGSWIZAZSMVAGI-UHFFFAOYSA-N 4-amino-1-(4-hydroxycyclopent-2-en-1-yl)-5-methylpyrimidin-2-one Chemical compound O=C1N=C(N)C(C)=CN1C1C=CC(O)C1 BGSWIZAZSMVAGI-UHFFFAOYSA-N 0.000 description 2
- NSPMIYGKQJPBQR-UHFFFAOYSA-N 4H-1,2,4-triazole Chemical compound C=1N=CNN=1 NSPMIYGKQJPBQR-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- XKRFYHLGVUSROY-UHFFFAOYSA-N Argon Chemical compound [Ar] XKRFYHLGVUSROY-UHFFFAOYSA-N 0.000 description 2
- QXNVGIXVLWOKEQ-UHFFFAOYSA-N Disodium Chemical class [Na][Na] QXNVGIXVLWOKEQ-UHFFFAOYSA-N 0.000 description 2
- 241000713772 Human immunodeficiency virus 1 Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 2
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- ABLZXFCXXLZCGV-UHFFFAOYSA-N Phosphorous acid Chemical class OP(O)=O ABLZXFCXXLZCGV-UHFFFAOYSA-N 0.000 description 2
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- MGNZXYYWBUKAII-UHFFFAOYSA-N cyclohexa-1,3-diene Chemical compound C1CC=CC=C1 MGNZXYYWBUKAII-UHFFFAOYSA-N 0.000 description 2
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- FDGQSTZJBFJUBT-UHFFFAOYSA-N hypoxanthine Chemical compound O=C1NC=NC2=C1NC=N2 FDGQSTZJBFJUBT-UHFFFAOYSA-N 0.000 description 2
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- 229940047124 interferons Drugs 0.000 description 1
- 125000000959 isobutyl group Chemical group [H]C([H])([H])C([H])(C([H])([H])[H])C([H])([H])* 0.000 description 1
- 238000002955 isolation Methods 0.000 description 1
- 208000032839 leukemia Diseases 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 231100000682 maximum tolerated dose Toxicity 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 239000002480 mineral oil Substances 0.000 description 1
- 235000010446 mineral oil Nutrition 0.000 description 1
- 239000012452 mother liquor Substances 0.000 description 1
- 239000002773 nucleotide Substances 0.000 description 1
- 125000003729 nucleotide group Chemical group 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- XHXFXVLFKHQFAL-UHFFFAOYSA-N phosphoryl trichloride Chemical compound ClP(Cl)(Cl)=O XHXFXVLFKHQFAL-UHFFFAOYSA-N 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 1
- VTGOHKSTWXHQJK-UHFFFAOYSA-N pyrimidin-2-ol Chemical compound OC1=NC=CC=N1 VTGOHKSTWXHQJK-UHFFFAOYSA-N 0.000 description 1
- 238000010992 reflux Methods 0.000 description 1
- 230000007017 scission Effects 0.000 description 1
- 238000004062 sedimentation Methods 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 150000003852 triazoles Chemical class 0.000 description 1
- SJHCUXCOGGKFAI-UHFFFAOYSA-N tripropan-2-yl phosphite Chemical compound CC(C)OP(OC(C)C)OC(C)C SJHCUXCOGGKFAI-UHFFFAOYSA-N 0.000 description 1
- 229940035893 uracil Drugs 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
- C07F9/6509—Six-membered rings
- C07F9/6512—Six-membered rings having the nitrogen atoms in positions 1 and 3
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Biochemistry (AREA)
- General Health & Medical Sciences (AREA)
- Molecular Biology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
Description
Gegenstand der vorliegenden Erfindung sind carbocyclische Phosphonat- Nucleotidanaloge, deren Herstellung und Verwendung.The present invention relates to carbocyclic phosphonate Nucleotide analogs, their preparation and use.
Carbocyclische ungesättigte Nucleosidanaloga wie der Naturstoff Neplanocin A (Formel A)Carbocyclic unsaturated nucleoside analogues such as the natural product neplanocin A (Formula A)
oder das synthetische Derivat 9-[cis4-(Hydoxymethyl)-2-cyclopentenyl] guanin (Carbovir) (Formel B)or the synthetic derivative 9- [cis4- (hydoxymethyl) -2-cyclopentenyl] guanine (Carbovir) (Formula B)
sind als wirksam gegen DNS- bzw. Retroviren beschrieben (siehe z. B. E. DeClercq, Antimicrob. Agents Chemother. 1985, 28, 84 bzw. R. Vince und M. Hua, J. Med. Chem. 1990, 33,17).are described as being effective against DNA and retroviruses (see e.g. E. DeClercq, Antimicrob. Agents chemother. 1985, 28, 84 or R. Vince and M. Hua, J. Med. Chem. 1990, 33.17).
Besonders die Verbindung der Formel B, das carbocyclische Analogon der antiretroviral unwirksamen Substanz 2′,3′-Dideoxy-2′,3′-didehydroguanosin (siehe z. B. M. Baba et al., Biochem. Biophys. Res. Commun. 1987,145,1080), bei welcher der Sauerstoff des Dihydrofuranringes durch eine CH2-Gruppierung ersetzt wurde, weist eine gute in vitro-Wirkung gegen das humane Immundefizienzvirus Typ 1 (HIV-1) auf.In particular, the compound of formula B, the carbocyclic analog of the antiretrovirally inactive substance 2 ′, 3′-dideoxy-2 ′, 3′-didehydroguanosine (see, for example, BM Baba et al., Biochem. Biophys. Res. Commun. 1987, 145 , 1080), in which the oxygen of the dihydrofuran ring has been replaced by a CH 2 group , has a good in vitro activity against the human immunodeficiency virus type 1 (HIV-1).
Ferner sind acyclische Nucleosidanaloga bekannt, die anstelle der Sauerstoff-Phosphor-Bindung natürlicher Nucleotide eine Sauerstoff-Kohlenstoff-Phosphor-Gruppierung (Phosphonat-Nucleotidanaloga) tragen. Ein Beispiel dafür ist die Verbindung der Formel CFurthermore, acyclic nucleoside analogues are known which are used instead of Oxygen-phosphorus binding of natural nucleotides Oxygen-carbon-phosphorus grouping (phosphonate nucleotide analogs) wear. An example of this is the compound of formula C.
(siehe z. B. A. Holy et al., Antiviral Res. 1990, 13, 295). Eine literaturbekannte Synthese des Naturstoffes Aristeromycin (Formel D)(See, e.g., A. Holy et al., Antiviral Res. 1990, 13, 295). A literature synthesis of the natural product aristeromycin (formula D)
benutzt als Schlüsselschritt eine Palladium (O)-katalysierte Addition von Epoxycyclopenten an ein Purinsystem unter Bildung einer Verbindung der Formel Euses a palladium (O) -catalyzed addition of Epoxycyclopentene to a purine system to form a compound of formula E.
(siehe z. B. B. M. Trost et al., J. Am. Chem. Soc. 1988, 110, 621). Diese Reaktion wird in der Europäischen Patentanmeldung 03 69 409 beschrieben, um nach einer Folge von weiteren bekannten Reaktionsschritten, carbocyclische Phosphonate vom Typ der Formel E, wobei P z. B. ein über N9 gebundenes Purinsystem darstellt, herzustellen. Für solche Verbindungen wurde in der oben genannten Europäischen Patentanmeldung eine in Vitro-Wirkung gegen ein Mäuseretrovirus (murines Leukämievirus (beschrieben). Die Verbindung der Formel 11,(See, e.g., M. Trost et al., J. Am. Chem. Soc. 1988, 110, 621). This response is described in the European patent application 03 69 409 described to follow a series of other known Reaction steps, carbocyclic phosphonates of the type of the formula E, where P z. B. represents a purine system bound via N9. For such connections was in the above European Patent application for an in vitro activity against a mouse retrovirus (murines Leukemia virus (described). The compound of formula 11
deren Verwendung ein Gegenstand der vorliegenden Erfindung ist, erscheint bei D. M. Coe et al., J. Chem. Soc. Chem. Commun. 1991, 312, jedoch ohne daß eine antivirale Wirkung beschrieben wäre.whose use is an object of the present invention appears in D. M. Coe et al., J. Chem. Soc. Chem. Commun. 1991, 312, but without one antiviral effect would be described.
Wir haben nun überraschenderweise gefunden, daß speziell die Verbindungen der Formel 1 deren Herstellung und/oder antiretrovirale Wirkung in den oben erwähnten Publikationen nicht beschrieben ist, innerhalb der Reihe der Derivate der natürlichen Nucleobasen Adenin, Hypoxanthin, Guanin, Uracil, Cytosin und Thymin diejenigen sind, die eine besonders starke in vitro-Wirkung gegen das humane Immundefizienzvirus aufweisen.We have now surprisingly found that especially the compounds of Formula 1 their manufacture and / or antiretroviral activity in the above publications mentioned is not described within the series of derivatives of natural nucleobases adenine, hypoxanthine, guanine, uracil, cytosine and thymine are those that have a particularly strong in vitro action against the human Have immunodeficiency virus.
Gegenstand der vorliegenden Erfindung sind daher Verbindungen der Formel 1,The present invention therefore relates to compounds of the formula 1
wobei R1 und R2 unabhängig voneinander C1-C6-Alkyl oder Wasserstoff sind, sowie deren physiologisch verträgliche Salze anorganischer und organischer Basen und offensichtliche chemische Äquivalente, mit Ausnahme der Verbindung, in der R1 und R2 Wasserstoff bedeuten. Besonders bevorzugte Substituenten R1 und R2 sind C1-C4-Alkylgruppen.where R 1 and R 2 are independently C1-C6-alkyl or hydrogen, and their physiologically tolerable salts of inorganic and organic bases and obvious chemical equivalents, with the exception of the compound in which R 1 and R 2 are hydrogen. Particularly preferred substituents R 1 and R 2 are C1-C4-alkyl groups.
Die als Substituenten R1 und/oder R2 genannten Alkylgruppen können verzweigt oder unverzweigt sein. Beispielhafte Alkylgruppen sind die Methyl-, Ethyl-, Propyl-, Isopropyl-, Butyl-, Isobutyl- oder tert. Butylgruppe.The alkyl groups mentioned as substituents R 1 and / or R 2 can be branched or unbranched. Exemplary alkyl groups are the methyl, ethyl, propyl, isopropyl, butyl, isobutyl or tert. Butyl group.
Die erfindungsgemäßen Verbindungen der allgemeinen Formel 1 weisen zwei chirale Zentren auf. Die Verbindungen liegen in der Regel als Racemate vor; eine Herstellung bzw. Isolierung der reinen Enantiomere ist möglich. Gegenstand der Erfindung sind deshalb sowohl die reinen Enantiomeren als auch Mischungen derselben, wie z. B. das zugehörige Racemat.The compounds of general formula 1 according to the invention have two chiral centers. The compounds are usually present as racemates; a Production or isolation of the pure enantiomers is possible. Subject of The invention is therefore both the pure enantiomers and mixtures the same as e.g. B. the associated racemate.
Geeignete physiologisch verträgliche Salze der genannten Verbindungen sind z. B. die Alkali-, Erdalkali oder Ammoniumsalze. Offensichtliche chemische Äquivalente sind insbesondere Prodrugs, wie z. B. N-acylierte Verbindungen der Formel I.Suitable physiologically acceptable salts of the compounds mentioned are e.g. B. the alkali, alkaline earth or ammonium salts. Obvious chemical equivalents are in particular prodrugs, such as. B. N-acylated compounds of formula I.
Weiterhin gehören zum Gegenstand der vorliegenden Erfindung die vorgenannten Verbindungen der Formel 1, mit den genannten Bedeutungen für R1 und R2 als Arzneimittel, wobei die Verbindungen, in denen R1 und R2 Wasserstoff bedeuten nicht ausgenommen sind.The subject of the present invention furthermore includes the abovementioned compounds of the formula 1 with the meanings given for R 1 and R 2 as medicaments, the compounds in which R 1 and R 2 are hydrogen being not excluded.
Darüber hinaus betrifft die vorliegende Erfindung die Verwendung der genannten Verbindungen zur Herstellung von Arzneimitteln zur Behandlung von Viruserkrankungen, bevorzugt von Retroviruserkrankungen, insbesondere von Erkrankungen, hervorgerufen durch das HIV.In addition, the present invention relates to the use of the above Compounds for the manufacture of medicaments for the treatment of Viral diseases, preferably of retrovirus diseases, in particular of Diseases caused by HIV.
Des weiteren betrifft die vorliegende Erfindung Arzneimittel mit einem Gehalt an mindestens einer erfindungsgemäßen Verbindung. The present invention further relates to medicaments containing at least one compound according to the invention.
Die erfindungsgemäßen Arzneimittel können enteral (oral), parenteral (intravenös), rektal oder lokal (topisch) angewendet werden. Sie können in Form von Lösungen, Pulvern (Tabletten, Kapseln einschließlich Mikrokapseln), Salben (Cremes oder Gel) oder Suppositorien verabreicht werden. Als Hilfsstoffe für derartige Formulierungen kommen die pharmazeutisch üblichen flüssigen oder festen Füllstoffe und Streckmittel, Lösemittel, Emulgatoren, Gleitstoffe, Geschmackskorrigentien, Farbstoffe und/oder Puffersubstanzen in Frage. Als zweckmäßige Dosierung werden 0.1-10, vorzugsweise 0.2-8 mg/kg Körpergewicht verabreicht. Sie werden zweckmäßig in Dosierungseinheiten verabreicht, die mindestens die wirksame Tagesmenge der erfindungsgemäßen Verbindungen, z. B. 30-300, vorzugsweise 50-250 mg enthalten.The medicaments according to the invention can be administered enterally (orally), parenterally (intravenously), rectally or locally (topically). They can be in the form of solutions, Powders (tablets, capsules including microcapsules), ointments (creams or gel) or suppositories. As auxiliaries for such formulations come the pharmaceutically customary liquid or solid fillers and Extenders, solvents, emulsifiers, lubricants, flavor correctors, Dyes and / or buffer substances in question. As a convenient dosage 0.1-10, preferably 0.2-8 mg / kg body weight are administered. they are appropriately administered in dosage units that are at least the effective daily amount of the compounds of the invention, e.g. B. 30-300, preferably contain 50-250 mg.
Die erfindungsgemäßen Verbindungen können auch in Kombination mit anderen antiviralen oder antiparasitären Mitteln und Immunstimulantien, wie Interferonen, verabreicht werden.The compounds according to the invention can also be used in combination with other antiviral or antiparasitic agents and Immunostimulants such as interferons can be administered.
Im folgenden wird die Prüfung auf antiretrovirale Eigenschaften und die Herstellung der erfindungsgemäßen Verbindungen der Formel 1 beschrieben:The following is testing for antiretroviral properties and manufacture of the compounds of formula 1 according to the invention:
Periphere Lymphozyten (PBL) aus Citrat-behandeltem Blut von gesunden HIV- negativen Freiwilligen wurden durch Sedimentation auf ein Ficoll-Kissen isoliert. Die Zellen wurden mit Phytohaem-agglutinin (PHA) stimuliert, und in RPMI 1640 Medium (Biochrom), das mit 10% foetalem Kälberserum (FCS) supplementiert war, kultiviert. Nach 2-3 Tagen Wachstum unter PHA wurden die Zellen dreimal gewaschen und anschließend in flüssigem Stickstoff gelagert.Peripheral lymphocytes (PBL) from citrate-treated blood from healthy HIV negative volunteers were isolated by sedimentation on a Ficoll cushion. The Cells were stimulated with phytohaem agglutinin (PHA) and in RPMI 1640 Medium (biochrome) supplemented with 10% fetal calf serum (FCS), cultured. After 2-3 days of growth under PHA, the cells were three times washed and then stored in liquid nitrogen.
Aufgetaute PBL wurden in RPMI mit 10% FCS, das zusätzlich rekombinantes Interleukin - 2 (40 IU/ml; Roussel Uclaf; Frankreich) enthielt, 4 Tage lang kultiviert, bevor sie mit HIV für 30 Minuten infiziert wurden (2-4×105 TCIU/1×106 Zellen). (TCIU = tissue culture infecting units).Thawed PBL were cultured in RPMI with 10% FCS, which also contained recombinant interleukin-2 (40 IU / ml; Roussel Uclaf; France), for 4 days before they were infected with HIV for 30 minutes (2-4 × 10 5 TCIU / 1 × 10 6 cells). (TCIU = tissue culture infecting units).
Der Virusüberstand wurde durch Abzentrifugieren der Zellen entfernt und die infizierten PBL wurden in 24-Loch Zellkultur-Platten verteilt, in denen Testsubstanzen in den Konzentrationen 0,8, 4, 20 und 100 µg/ml bereits vorlagen. Nach 3 Tagen Inkubation in einem CO2 Brutschrank wurde die Virusvermehrung anhand der Syncytienbildung im Lichtmikroskop bestimmt. Zusätzlich wurde der Zellüberstand auf die Anwesenheit von HIV p24 Antigen untersucht.The virus supernatant was removed by centrifuging the cells and the infected PBL were distributed in 24-well cell culture plates in which test substances were already present in concentrations of 0.8, 4, 20 and 100 µg / ml. After 3 days of incubation in a CO 2 incubator, the virus multiplication was determined on the basis of syncytia formation in the light microscope. In addition, the cell supernatant was examined for the presence of HIV p24 antigen.
Die Zellüberstände wurden in Zellkulturmedium 1:10 verdünnt und mit einem käuflichen Antigen Test (Vironostika® HIV, Organon Teknika, Eppelheim, Deutschland) auf die Anwesenheit von HIV-Partikeln untersucht. In diesem Test wird hauptsächlich aber nicht exklusiv das HIV p24 Antigen erkannt. Die Testdurchführung erfolgte gemäß den Empfehlungen des Herstellers. The cell supernatants were diluted 1:10 in cell culture medium and with a commercially available antigen test (Vironostika® HIV, Organon Teknika, Eppelheim, Germany) for the presence of HIV particles. In this test the HIV p24 antigen is mainly but not exclusively recognized. The The test was carried out according to the manufacturer's recommendations.
Aufgetaute PBL wurden in RPMI mit 10% FCS und rekombinantem Interleukin-2 (40 IU/ml) 7 Tage lang kultiviert, bevor sie in 24-Loch Zellkultur-Platten ausgesät (2.5×105 Zellen/ml/Loch) und in Gegenwart verschiedener Konzentrationen der Testsubstanz kultiviert wurden. Nach 24, 48, 72 und 96 Stunden wurden die Zellen aus je zwei Löchern abgenommen und die Zellzahl in einem Zählgerät nach dem Coulter Prinzip bestimmt. Die Konzentration der Testsubstanz betrug 12,5, 25, 50 und 100 µg/ml. Alle Testsubstanzen wurden in Dimethylsulfoxid (DMSO) gelöst und in Zellkultur-Medium weiter verdünnt. Unter den verwendeten Konzentrationen kann der Einfluß von DMSO auf das Zellwachstum vernachlässigt werden.Thawed PBL were cultured in RPMI with 10% FCS and recombinant interleukin-2 (40 IU / ml) for 7 days before being seeded in 24-well cell culture plates (2.5 × 10 5 cells / ml / well) and in the presence of various Concentrations of the test substance were cultivated. After 24, 48, 72 and 96 hours, the cells were removed from two holes and the number of cells was determined in a counter according to the Coulter principle. The concentration of the test substance was 12.5, 25, 50 and 100 µg / ml. All test substances were dissolved in dimethyl sulfoxide (DMSO) and further diluted in cell culture medium. Under the concentrations used, the influence of DMSO on cell growth can be neglected.
Für Verbindung 11 lag die minimale Hemmkonzentration (MHK) gegen HIV bei 20 µg/ml, die maximal tolerierte Dosis bei <100 µg/ml. Die Wirksamkeit bis 20 µg/ml konnte im Antigen-Test bestätigt werden. Eine toxische Wirkung der Substanz wurde im Proliferationstest nicht festgestellt (Fig. 1).For compound 11, the minimum inhibitory concentration (MIC) against HIV was 20 µg / ml, the maximum tolerated dose at <100 µg / ml. The effectiveness up to 20 µg / ml could be confirmed in the antigen test. A toxic effect of the substance was not found in the proliferation test (Fig. 1).
Die Herstellung der erfindungsgemäßen Verbindungen der Formel 1 läßt sich z. B. mittels folgendem Reaktionsschema darstellen:The preparation of the compounds of formula 1 according to the invention can, for. B. using the following reaction scheme:
Thymin (Verbindung der Formel 2) wird in 5-Methyl-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-on (Verbindung der Formel 3) überführt, welches entweder in 4-Amino-5-methyl-pyrimidin-2(1H)-on (Verbindung der Formel 4) umgewandelt oder in einer Palladium(O)-katalysierten Reaktion mit Epoxycyclopenten zu 1-[(1RS, 4SR)-4-Hydroxy-cyclopent-2-en-1-yl]-5-methyl-4-(1,2,4-triazol-1 -yl)-pyrimidin-2(1H) on (Verbindung der Formel 5) umgesetzt wird. Aus dem Triazolderivat der Formel 5 wird durch Ammonolyse 4-Amino-5-methyl-1-[(1RS, 4SR)-4-hydroxy-cyclopent-2-en-1-yl]-pyrimidin-2(1H)-on (Verbindung der Formel 6) gewonnen. Die Verbindung der Formel 6 kann auch aus der Verbindung der Formel 4 durch Palladium(O)-katalysierte Addition von Epoxycycolpenten hergestellt werden. Durch Umsatz z. B. mit N-Methyl-2,2-diethoxypyrrolidin wird die Aminofunktion in der Verbindung der Formel 6 geschützt und man erhält die Verbindung der Formel 7. Reaktion dieser Verbindung mit Natriumhydrid und Diisopropyl[(p-toluolsulfonyl)oxy]methan-phosphonat oder Diisopropyl[(trifluormethansulfonyl)oxy]methan-phosphonat (Isopropyl steht hier beispielhaft für C1-C6-Alkyl) liefert den Phosphonsäureester der Formel 8. Der Umsatz der Verbindung der Formel 8 mit Natriumnitrit/Säure ergibt das Thyminderivat der Formel 9, woraus durch Hydrierung der Doppelbindung die Verbindung der Formel 10 (= Verbindung der Formel 1, worin R1 = R2 = Isopropyl) gewonnen wird. Die Spaltung des Phosphonsäureesters der Verbindung der Formel 10 liefert die Verbindung der Formel 11 (= Verbindung der Formel 1, worin R1 = R2 = Wasserstoff). Das Dinatriumsalz der Formel 12 (= Verbindung der Formel 1, worin R1 = R2 = Na) wird aus der Verbindung der Formel 11 durch Zugabe von 2 Äquivalenten Natronlauge gewonnen.Thymine (compound of formula 2) is converted into 5-methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) -one (compound of formula 3), which is either in 4-amino -5-methyl-pyrimidin-2 (1H) -one (compound of formula 4) converted or in a palladium (O) -catalyzed reaction with epoxycyclopentene to 1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2- en-1-yl] -5-methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) one (compound of the formula 5) is reacted. The triazole derivative of the formula 5 is converted into 4-amino-5-methyl-1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2-en-1-yl] pyrimidin-2 (1H) -one ( Compound of formula 6) obtained. The compound of formula 6 can also be prepared from the compound of formula 4 by palladium (O) catalyzed addition of epoxycyclopentene. Through sales z. B. with N-methyl-2,2-diethoxypyrrolidine, the amino function in the compound of formula 6 is protected and the compound of formula 7 is obtained. Reaction of this compound with sodium hydride and diisopropyl [(p-toluenesulfonyl) oxy] methane phosphonate or Diisopropyl [(trifluoromethanesulfonyl) oxy] methane phosphonate (isopropyl here stands for C 1 -C 6 alkyl for example) provides the phosphonic acid ester of the formula 8. The conversion of the compound of the formula 8 with sodium nitrite / acid gives the thymine derivative of the formula 9, from which by hydrogenation of the double bond the compound of formula 10 (= compound of formula 1, wherein R 1 = R 2 = isopropyl) is obtained. Cleavage of the phosphonic acid ester of the compound of formula 10 gives the compound of formula 11 (= compound of formula 1, wherein R 1 = R 2 = hydrogen). The disodium salt of formula 12 (= compound of formula 1, wherein R 1 = R 2 = Na) is obtained from the compound of formula 11 by adding 2 equivalents of sodium hydroxide solution.
Zum Gegenstand der vorliegenden Erfindung gehört weiterhin das Verfahren zur Herstellung von Verbindungen der Formel 1, das dadurch gekennzeichnet ist, daß eine Verbindung der Formel 6The subject of the present invention further includes the method for Preparation of compounds of formula 1, which is characterized in that a compound of formula 6
mit N-Methyl-2,2-diethoxy-pyrrolidin in eine Verbindung der Formel 7with N-methyl-2,2-diethoxy-pyrrolidine in a compound of formula 7
überführt wird, welche anschließend mit Natriumhydrid und einem Phosphonylmethylierungsreagenz in das Hemitosylat der Verbindung der Formel 8,is transferred, which then with sodium hydride and Phosphonyl methylation reagent into the hemitosylate of the compound of formula 8,
mit R1 und R2 = C1-C6-Alkyl umgewandelt wird, welches seinerseits mit Natriumnitrit und Säure in eine Verbindung der Formel 9with R 1 and R 2 = C 1 -C 6 alkyl is converted, which in turn with sodium nitrite and acid into a compound of formula 9
überführt wird und mit Wasserstoff und einem geeigneten Katalysator in das Cyclopentanderivat der Formel 1is transferred and with hydrogen and a suitable catalyst in the Cyclopentane derivative of formula 1
umgewandelt wird, wobei R1 und R2 die genannten Bedeutungen haben. Die Verbindung der Formel 1 kann ihrerseits durch Spaltung der Phosphonatesterfunktion in eine Phosphonsäure der Formel 11is converted, wherein R 1 and R 2 have the meanings mentioned. The compound of formula 1 can in turn by cleaving the phosphonate ester function into a phosphonic acid of formula 11
und daraus durch Reaktion mit einer Base in ein physiologisch verträgliches Mono- oder Di-Salz anorganischer oder organischer Basen, wie das Dinatriumsalz der Verbindung der Formel 11, überführt werden.and from it by reaction with a base in a physiologically acceptable mono- or Di-salt of inorganic or organic bases, such as the disodium salt of Compound of formula 11 are transferred.
Besonders geeignete Phosphonylmethylierungsreagenzien sind z. B. (C1-C6)- Alkyl[(p-toluolsulfonyl)oxy]methanphosphonat oder (C1-C6)- Alkyl[(trifluormethansulfonyl)oxy]methanphosphonat.Particularly suitable phosphonyl methylation reagents are e.g. B. (C 1 -C 6 ) alkyl [(p-toluenesulfonyl) oxy] methane phosphonate or (C 1 -C 6 ) alkyl [(trifluoromethanesulfonyl) oxy] methane phosphonate.
Geeignete Katalysatoren für die Hydrierung der Verbindung der Formel 9 sind z. B. Pd auf Kohle (vorzugsweise 10% Pd), oder Pd(OH)2 mit Cyclohexadien in Alkoholen.Suitable catalysts for the hydrogenation of the compound of formula 9 are e.g. B. Pd on carbon (preferably 10% Pd), or Pd (OH) 2 with cyclohexadiene in alcohols.
Die bevorzugten Bedingungen, unter denen das Herstellungsverfahren abläuft, können aus den folgenden Beispielen entnommen werden.The preferred conditions under which the manufacturing process takes place can be seen from the following examples.
Die Erfindung wird durch die Beispiele sowie durch den Inhalt der Patentansprüche näher erläutert.The invention is illustrated by the examples and by the content of the claims explained in more detail.
Unter Schutzgas (Stickstoff) werden zu einer Suspension von 69 g (1 Mol) 1,2,4-Triazol in 800 ml trockenem Acetonitril bei einer Innentemperatur von 0-50°C 50.6 g (0.33 Mol) Phosphorsäuretrichlorid gegeben. Sodann werden über einen Zeitraum von 1 Stunde 101.2 g (1 Mol) Triethylamin zugetropft. Nach weiterem 40 minütigem Rühren bei Raumtemperatur werden 18.9 g (0.15 Mol) Thymin (Verbindung der Formel 2) zugegeben. Die Suspension wird 24 Stunden bei Raumtemperatur gerührt, mit 25 ml Wasser versetzt, weitere 10 Minuten gerührt und danach filtriert. Der gelbe Rückstand wird in 400 ml Wasser suspendiert, gerührt und nach 1 Stunde abgesaugt. Man erhält 1.72 g 5-Methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-on (Verbindung der Formel 3) als gelbliches Pulver mit dem Schmelzpunkt 258-264°C. Die Acetonitrillösung wird eingeengt, der Rückstand in 400 ml Wasser suspendiert, gerührt und abgesaugt. Auf diese Weise werden weitere 7.21 g der Verbindung erhalten.Under protective gas (nitrogen) to a suspension of 69 g (1 mol) 1,2,4-triazole in 800 ml dry acetonitrile at an internal temperature of 0-50 ° C 50.6 g (0.33 mol) of phosphoric acid trichloride added. Then over a 101.2 g (1 mol) of triethylamine were added dropwise over a period of 1 hour. After another 40 minutes of stirring at room temperature, 18.9 g (0.15 mol) of thymine (Compound of formula 2) added. The suspension is at 24 hours Stirred at room temperature, mixed with 25 ml of water, stirred for a further 10 minutes and then filtered. The yellow residue is suspended in 400 ml of water stirred and suction filtered after 1 hour. 1.72 g are obtained 5-Methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) -one (compound of formula 3) as yellowish powder with a melting point of 258-264 ° C. The acetonitrile solution is concentrated, the residue is suspended in 400 ml of water, stirred and suctioned off. In this way, another 7.21 g of compound receive.
Die Verbindung der Formel 3 kann aus Dimethylformamid umkristallisiert werden und schmilzt dann bei 275-280°C. 1H NMR (60 MHz, d6-DMSO) δ[ppm]: ca. 12.0 (s, breit, 1H), 9.33 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 2.3 (s, 3H).The compound of formula 3 can be recrystallized from dimethylformamide and then melts at 275-280 ° C. 1H NMR (60 MHz, d6-DMSO) δ [ppm]: approx. 12.0 (s, broad, 1H), 9.33 (s, 1H), 8.40 (s, 1H), 8.13 (s, 1H), 2.3 (s, 3H).
Aus den Mutterlaugen lassen sich nach chromatographischer Auftrennung an
Kieselgel mit Dichlormethan/Methanol 9/1 als mobile Phase zwei Nebenprodukte
isolieren:
Nebenprodukt I: 2,4-Bis(1,2,4-triazol-1-yl)-5-methyl-pyrimidin, farbloses Pulver, Fp.:
193-196°C, 1H NMR (270 MHz, d6-DMSO), δ[ppm]: 9.76 (s, 1H), 9.74 (s, 1H),
9.01 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 2.64 (s, 3H).
Nebenprodukt II: 5-Methyl-2-(1,2,4-triazol-4-yl)-4-(1,2,4-triazol-1-yl)-pyrimidin,
farblose Kristalle, Fp.: 256-261°C, 1H NMR (270 MHz, d6-DMSO), δ[ppm]: 9.92
(s, 1H), 9.52 (s, 2H), 8.99 (s, 1H), 8.46 (s, 1H), 2.63 (s, 3H).
Beide Nebenprodukte lassen sich durch Behandlung mit 1N Natronlauge (6
Stunden, 30-50°C) in das 5-Methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-on
(Verbindung der Formel 3) überführen.After chromatographic separation on silica gel with dichloromethane / methanol 9/1 as mobile phase, two by-products can be isolated from the mother liquors:
By-product I: 2,4-bis (1,2,4-triazol-1-yl) -5-methyl-pyrimidine, colorless powder, mp: 193-196 ° C, 1H NMR (270 MHz, d6-DMSO) , δ [ppm]: 9.76 (s, 1H), 9.74 (s, 1H), 9.01 (s, 1H), 8.46 (s, 1H), 8.36 (s, 1H), 2.64 (s, 3H).
By-product II: 5-methyl-2- (1,2,4-triazol-4-yl) -4- (1,2,4-triazol-1-yl) pyrimidine, colorless crystals, m.p .: 256-261 ° C, 1H NMR (270 MHz, d6-DMSO), δ [ppm]: 9.92 (s, 1H), 9.52 (s, 2H), 8.99 (s, 1H), 8.46 (s, 1H), 2.63 (s , 3H).
Both by-products can be converted into 5-methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) -one (treatment with 1N sodium hydroxide solution (6 hours, 30-50 ° C) Transfer compound of formula 3).
In einem alternativen Verfahren kann die Verbindung der Formel 3 folgendermaßen
hergestellt werden:
Unter Schutzgas (Argon) werden 69 g (1 Mol) 1,2,4-Triazol in 800 ml trockenem
Acetonitril suspendiert. Bei 0-10°C werden dieser Suspension unter Rühren 251 g
(0.95 Mol) Phosphorsäurediphenylester-chlorid zugefügt. Anschließend werden
während einer Stunde 151.79 g (1.5 Mol) Triethylamin zugetropft bevor 63 g (0.5
Mol) Thymin (Verbindung der Formel 2) zugegeben werden. Die resultierende
Suspension wird 12 Stunden bei Raumtemperatur gerührt. Schließlich wird die
Mischung 5 Stunden auf 60-80°C erwärmt. Die abgekühlte Suspension wird mit
40 ml Methanol versetzt und 2 Stunden bei Raumtemperatur gerührt. Die
Suspension wird filtriert; der Rückstand wird mit einem Liter Diisopropylether
verrührt, erneut abgesaugt und mit 800 ml Wasser verrührt. Die wäßrige
Suspension wird filtriert und der feste Rückstand wird aus 1300 ml
Dimethylformamid umkristallisiert. Man erhält 28.6 g
5-Methyl-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-on (Verbindung der Formel 3) vom
Schmelzpunkt 275-280°C.In an alternative process, the compound of formula 3 can be prepared as follows:
69 g (1 mol) of 1,2,4-triazole are suspended in 800 ml of dry acetonitrile under protective gas (argon). At 0-10 ° C 251 g (0.95 mol) of phosphoric acid diphenyl chloride are added to this suspension with stirring. 151.79 g (1.5 mol) of triethylamine are then added dropwise over an hour before 63 g (0.5 mol) of thymine (compound of the formula 2) are added. The resulting suspension is stirred for 12 hours at room temperature. Finally, the mixture is heated to 60-80 ° C for 5 hours. The cooled suspension is mixed with 40 ml of methanol and stirred at room temperature for 2 hours. The suspension is filtered; the residue is stirred with one liter of diisopropyl ether, suction filtered again and stirred with 800 ml of water. The aqueous suspension is filtered and the solid residue is recrystallized from 1300 ml of dimethylformamide. 28.6 g of 5-methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) -one (compound of the formula 3) of melting point 275-280 ° C. are obtained.
1.06 g (6 mMol) 5-Methyl-4-(1,2,4-triazol-1-yl)-pyrimidin-2(1H)-on (Verbindung der Formel 3) werden in 30 ml konzentriertem wäßrigem Ammoniak gelöst und 3 Stunden bei Rückflußtemperatur gerührt. Die abgekühlte Lösung wird vollständig eingeengt, heiß in Wasser gelöst, abgekühlt und mit der dreifachen Menge Aceton versetzt. Der Niederschlag wird abgesaugt und im Vakuum getrocknet. Man erhält 0.73 g (97.3% d. Th.) 4-Amino-5-methyl-pyrimidin-2(1H)-on (Verbindung der Formel 4) als farbloses Pulver vom Schmelzpunkt 271-274°C.1.06 g (6 mmol) of 5-methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) -one (compound of Formula 3) are dissolved in 30 ml of concentrated aqueous ammonia and 3 Stirred for hours at reflux temperature. The cooled solution becomes complete concentrated, dissolved in hot water, cooled and with three times the amount of acetone transferred. The precipitate is filtered off and dried in vacuo. You get 0.73 g (97.3% of theory) of 4-amino-5-methyl-pyrimidin-2 (1H) -one (compound of the formula 4) as a colorless powder with a melting point of 271-274 ° C.
3.54 g (0.020 Mol) 5-Methyl-4-(1,2,4-triazol-1-yl)pyrimidin-2(1H)-on (Verbindung der Formel 3) werden in einer Mischung aus 40 ml trockenem Tetrahydrofuran und 20 ml trockenem Dimethylsulfoxid mit 5 Mol-% des in situ dargestellten Palladium-O-Katalysators (unter Stickstoff-Schutzgas wurden in 40 ml trockenem Tetrahydrofuran bei 0°C 224 mg (1 mMol) Palladium-II-acetat, 2.5 ml (10 mMol) Triisopropylphosphit und 1.5 ml 1.6 molare n-Butyllithium-Lösung in n-Hexan (2 mMol) zusammengegeben und gerührt) bei 0°C langsam mit der äquivalenten Menge Epoxycyclopenten versetzt, und die Reaktionsmischung wird 12 Stunden bei Raumtemperatur gerührt. Die erhaltene Suspension wird filtriert, das Filtrat wird eingeengt und der Rückstand wird an Kieselgel mit Dichlormethan/Methanol 9/1 chromatographiert. Man erhält 1.34 g (25.8% d. Th.) 1-[(1RS, 4SR)-4-Hydroxy-cyclopent-2-en-1-yl]-5-methyl-4-(1,2,4-triazol-1 -yl)-pyrimidin-2(1H) on (Verbindung der Formel 5) mit dem Schmelzpunkt 198-204°C. 1H NMR (270 MHz, d6-DMSO), δ[ppm]: 9.31 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 6.25 (m, 1H), 5.92 (m, 1H), 5.52 (m, 1H), 5.28 (d,1H), 4.71 (m, 1H), 2.87 (m, 1H), 2.30 (s, 3H), 1.47 (m, 1H). Als weiteres Produkt werden 0.59 g (13.2% d. Th.) 1-[(1RS, 4SR)-4-Hydroxy-cyclopent-2-en-1-yl]-5-methyl-4-methoxy-pyrimidin-2(1-H)-on mit dem Schmelzpunkt 143-146°C isoliert. 1H NMR (270 MHz, d6-DMSO); δ[ppm]: 7.58 (s, 1H), 6.16 (m, 1H), 5.81 (m, 1H), 5.48 (m, 1H), 5.21 (s, 1H), 4.56 (m, 1H), 3.86 (s, 3H), 2.79 (m, 1H), 1.89 (s, 3H), 1.33 (m, 1H).3.54 g (0.020 mol) of 5-methyl-4- (1,2,4-triazol-1-yl) pyrimidin-2 (1H) -one (compound of Formula 3) are in a mixture of 40 ml of dry tetrahydrofuran and 20 ml of dry dimethyl sulfoxide with 5 mol% of that shown in situ Palladium-O-catalyst (under nitrogen protective gas were in 40 ml dry Tetrahydrofuran at 0 ° C 224 mg (1 mmol) palladium-II-acetate, 2.5 ml (10 mmol) Triisopropyl phosphite and 1.5 ml 1.6 molar n-butyllithium solution in n-hexane (2nd mmol) added together and stirred) at 0 ° C slowly with the equivalent Amount of epoxycyclopentene added, and the reaction mixture is 12 hours stirred at room temperature. The suspension obtained is filtered, the filtrate is concentrated and the residue is on silica gel with dichloromethane / methanol 9/1 chromatographed. 1.34 g (25.8% of theory) 1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2-en-1-yl] -5-methyl-4- (1,2,4-triazol-1-yl) pyrimidine-2 (1H) on (compound of formula 5) with a melting point of 198-204 ° C. 1H NMR (270 MHz, d6-DMSO), δ [ppm]: 9.31 (s, 1H), 8.38 (s, 1H), 8.07 (s, 1H), 6.25 (m, 1H), 5.92 (m, 1H), 5.52 (m, 1H), 5.28 (d, 1H), 4.71 (m, 1H), 2.87 (m, 1H), 2.30 (s, 3H), 1.47 (m, 1H). 0.59 g (13.2% of theory) 1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2-en-1-yl] -5-methyl-4-methoxy-pyrimidin-2 (1-H) -one with the melting point 143-146 ° C isolated. 1H NMR (270 MHz, d6-DMSO); δ [ppm]: 7.58 (s, 1H), 6.16 (m, 1H), 5.81 (m, 1H), 5.48 (m, 1H), 5.21 (s, 1H), 4.56 (m, 1H), 3.86 (s, 3H), 2.79 (m, 1H), 1.89 (s, 3H), 1.33 (m, 1H).
0.4 g (1.54 mMol) der Verbindung der Formel 5 werden in konzentriertem wäßrigen Ammoniak suspendiert und 12 Stunden bei Raumtemperatur gerührt. Die Reaktionslösung wird vollständig eingeengt und über Kieselgel mit Dichlormethan/Methanol 5/1 chromatographiert. Man erhält 73 mg (22.9% d. Th.) 1-[(1RS, 4SR)-4-Hydroxy-cyclopent-2-en-1-yl]-thymin mit einem Schmelzpunkt von 190-192°C. Als zweite Fraktion werden 242 mg (75.9% d. Th.) 4-Amino-5-methyl-1-[(1RS, 4SR)-4-hydroxy-cyclopent-2-en-1-yl]-pyrimidin-2(1H)-on (Verbindung der Formel 6) mit dem Schmelzpunkt 242-245°C isoliert. 1H NMR (270 MHz, d6-DMSO), δ[ppm]: 7.23 (s, 1H), 7.12 (s, breit, 1H), 6.70 (s, breit, 1H), 6.09 (m, 1H), 5.74 (m, 1H), 5.45 (m, 1H), 5.17 (s, 1H), 4.61 (m, 1H), 2.71 (m, 1H), 1.81 (s, 3H), 1.27 (m, 1H).0.4 g (1.54 mmol) of the compound of formula 5 are in concentrated aqueous Suspended ammonia and stirred for 12 hours at room temperature. The The reaction solution is completely evaporated down and over silica gel Chromatographed dichloromethane / methanol 5/1. 73 mg (22.9% of theory) are obtained 1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2-en-1-yl] thymine with a melting point of 190-192 ° C. The second fraction is 242 mg (75.9% of theory) 4-Amino-5-methyl-1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2-en-1-yl] pyrimidin-2 (1H) -one (Compound of formula 6) isolated with the melting point 242-245 ° C. 1H NMR (270 MHz, d6-DMSO), δ [ppm]: 7.23 (s, 1H), 7.12 (s, broad, 1H), 6.70 (s, broad, 1H), 6.09 (m, 1H), 5.74 (m, 1H), 5.45 (m, 1H), 5.17 (s, 1H), 4.61 (m, 1H), 2.71 (m, 1H), 1.81 (s, 3H), 1.27 (m, 1H).
Alternativ kann die Verbindung der Formel 6 aus der Verbindung der Formel 4
hergestellte werden:
Zu einer Lösung des wie oben beschriebenen in situ hergestellten
Palladium-O-katalysators (1.6 Mol%) in 200 ml trockenem Tetrahydrofuran/200 ml
trockenem Dimethylsulfoxid werden bei 5°C 50 g (0.4 Mol) 5-Methylcytosin
(Verbindung der Formel 4) zugegeben. In diese Suspension werden unter Rühren
49.2 g (0.6 Mol) Epoxycyclopenten, gelöst in 100 ml Tetrahydrofuran, zugetropft
(1.5 Stunden). Die Mischung wird 3 Tage bei Raumtemperatur gerührt,
anschließend eingeengt, mit 2N Natriumcarbonat-Lösung verrührt, filtriert und der
Rückstand mit Wasser und Aceton gewaschen. Man erhält 20.2 g (24.4% d. Th.)
4-Amino-5-Methyl-1-[(1RS,4SR)-4-hydroxy-cyclopent-2-en-1-yl]pyrimidi-n-2(1H)-on
(Verbindung der Formel 6) vom Schmelzpunkt 241-245°C. Die Chromatographie
(Kieselgel, Dichlormethan/Methanol 3/1) der neutralisierten Mutterlauge liefert
neben 5-Methylcytosin (14.95 g, Schmelzpunkt 264-269°C) weitere 9.87 g (11.9%
d. Th.) der Verbindung der Formel 6; Gesamtausbeute: 36.3% d. Th.Alternatively, the compound of formula 6 can be prepared from the compound of formula 4:
50 g (0.4 mol) of 5-methylcytosine (compound of the formula 4) are added at 5 ° C. to a solution of the palladium-O-catalyst (1.6 mol%) prepared in situ (1.6 mol%) in 200 ml of dry tetrahydrofuran / 200 ml of dry dimethyl sulfoxide. admitted. 49.2 g (0.6 mol) of epoxycyclopentene, dissolved in 100 ml of tetrahydrofuran, are added dropwise to this suspension with stirring (1.5 hours). The mixture is stirred for 3 days at room temperature, then concentrated, stirred with 2N sodium carbonate solution, filtered and the residue washed with water and acetone. 20.2 g (24.4% of theory) of 4-amino-5-methyl-1 - [(1RS, 4SR) -4-hydroxy-cyclopent-2-en-1-yl] pyrimidi-n-2 (1H ) -on (compound of formula 6) melting point 241-245 ° C. Chromatography (silica gel, dichloromethane / methanol 3/1) of the neutralized mother liquor provides, in addition to 5-methylcytosine (14.95 g, melting point 264-269 ° C.), a further 9.87 g (11.9% of theory) of the compound of the formula 6; Overall yield: 36.3% of theory Th.
20.7 g (0.1 Mol) der Verbindung der Formel 6 werden in 350 ml trockenem Pyridin suspendiert, mit 77 ml N-Methyl-2,2-diethoxy-pyrrolidin versetzt und 4 Stunden bei Raumtemperatur gerührt. Danach werden 77 ml Wasser zugesetzt, und die entstandene Mischung wird 30 Minuten gerührt, danach im Vakuum eingeengt, 3mal mit 100 ml Toluol versetzt und erneut eingeengt. Der Rückstand wird über Kieselgel mit einer Mischung aus 9 Teilen Dichlormethan und einem Teil Methanol chromatographiert. Man erhält 23.3 g (83% d. Th.) 5-Methyl-4-[amino-(N-methyl-2-pyrrolidin-methyliden)]-1-[(1RS,4SR)-4--hydroxy-cyclo pent-2-en-1-yl]-pyrimidin-2(1H)-on (Verbindung der Formel 7) mit dem Schmelzpunkt 143-152°C. 1H NMR (270 MHz, d6-DMSO) δ[ppm]: 7.36 (d,1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.49 (m, 1H), 5.18 (d,1H), 4.63 (m, 1H), 3.46 (t, 2H), 3.00 (s, 3H), 2.94 (t, 2H), 2.81-2.72 (m, 1H), 1.98 (m, 2H), 1.89 (s, 3H), 1.30 (m, 1H).20.7 g (0.1 mol) of the compound of formula 6 are in 350 ml of dry pyridine suspended, mixed with 77 ml of N-methyl-2,2-diethoxy-pyrrolidine and at 4 hours Room temperature stirred. Then 77 ml of water are added, and the the resulting mixture is stirred for 30 minutes, then concentrated in vacuo, 3 times mixed with 100 ml of toluene and concentrated again. The backlog is over Silica gel with a mixture of 9 parts dichloromethane and one part methanol chromatographed. 23.3 g (83% of theory) are obtained 5-Methyl-4- [amino- (N-methyl-2-pyrrolidin-methylidene)] - 1 - [(1RS, 4SR) -4-hydroxy-cyclo pent-2-en-1-yl] pyrimidin-2 (1H) -one (compound of formula 7) with the Melting point 143-152 ° C. 1H NMR (270 MHz, d6-DMSO) δ [ppm]: 7.36 (d, 1H), 6.11 (m, 1H), 5.78 (m, 1H), 5.49 (m, 1H), 5.18 (d, 1H), 4.63 (m, 1H), 3.46 (t, 2H), 3.00 (s, 3H), 2.94 (t, 2H), 2.81-2.72 (m, 1H), 1.98 (m, 2H), 1.89 (s, 3H), 1.30 (m, 1H).
23.9 g (82.9 mMol) der Verbindung der Formel 7 werden in 400 ml trockenem Dimethylformamid gelöst und bei 5°C unter Rühren mit 5.23 g (124.4 mMol) einer 55%igen Suspension von Natriumhydrid in Mineralöl versetzt. Nachdem die Mischung 30 Minuten bei 5°C gerührt wurde, werden 43.5 g (124.4 mMol) Diisopropyl[(p-toluolsulfonyl)oxy]methanphosphonat, gelöst in 160 ml trockenem Dimethylformamid, in 60 Minuten bei 5°C zugetropft. Danach wird die Reaktionsmischung noch 3 Stunden bei Raumtemperatur gerührt. Schließlich wird die Lösung durch Zugabe von 200 ml 2N Essigsäure neutralisiert, im Vakuum eingeengt und der Rückstand über Kieselgel mit einem Gemisch von 9 Teilen Dichlormethan und einem Teil Methanol chromatographiert. Man erhält 17.31 g (54.2% d. Th.) eines braunen Öls, welches das Hemitosylat von 4-Amino-5-methyl-1-[(1RS,4SR)-4-diisopropylphosphonylmethoxy-cycopen-t-2-en-1- yl]pyrimidin-2(1H)-on darstellt. 1H NMR (270 MHz, d6-DMSO) δ[ppm]: 7.84 (s, breit, 2H), 7.31 (s, 1H), 6.37 (m, 1H), 5.98 (m, 1H), 5.47 (m, 1H), 4.68-4.51 (m, 3H), 3.83 (m, 2H), 2.73 (m, 1H), 1.90 (s, 3H), 1.54 (m, 1H), 1.25 (m, 12H). Die Signale des halben Äquivalentes p-Toluolsulfonsäure erscheinen bei 7.49, 7.11 und 2.30 ppm.23.9 g (82.9 mmol) of the compound of formula 7 are dried in 400 ml Dissolved dimethylformamide and at 5 ° C with stirring with 5.23 g (124.4 mmol) one 55% suspension of sodium hydride in mineral oil added. after the Mixture was stirred at 5 ° C for 30 minutes, 43.5 g (124.4 mmol) Diisopropyl [(p-toluenesulfonyl) oxy] methanephosphonate, dissolved in 160 ml of dry Dimethylformamide, added dropwise at 5 ° C. in 60 minutes. After that the Reaction mixture stirred for 3 hours at room temperature. Eventually neutralized the solution by adding 200 ml of 2N acetic acid in vacuo concentrated and the residue on silica gel with a mixture of 9 parts Chromatographed dichloromethane and a part of methanol. 17.31 g are obtained (54.2% of theory) of a brown oil which contains the hemitosylate of 4-amino-5-methyl-1 - [(1RS, 4SR) -4-diisopropylphosphonylmethoxy-cycopen-t-2-en-1- yl] pyrimidin-2 (1H) -one. 1H NMR (270 MHz, d6-DMSO) δ [ppm]: 7.84 (s, wide, 2H), 7.31 (s, 1H), 6.37 (m, 1H), 5.98 (m, 1H), 5.47 (m, 1H), 4.68-4.51 (m, 3H), 3.83 (m, 2H), 2.73 (m, 1H), 1.90 (s, 3H), 1.54 (m, 1H), 1.25 (m, 12H). The Signals of half the equivalent of p-toluenesulfonic acid appear at 7.49, 7.11 and 2.30 ppm.
19.25 g (40.9 mMol) des Hemitosylats der Verbindung der Formel 8 und 20.7 g (300 mMol) Natriumnitrit werden in 250 ml Wasser gelöst und mit 25 ml Eisessig und 50 ml 1 N Salzsäure versetzt. Die Reaktionsmischung wird 4 Stunden bei Raumtemperatur gerührt, anschließend mit Natriumcarbonat vorsichtig neutralisiert und im Vakuum eingeengt. Der Rückstand wird mehrmals mit Aceton ausgekocht; die Acetonextrakte werden im Vakuum eingeengt, und der resultierende Rückstand wird über Kieselgel mit Dichlormethan/Methanol 9/1 chromatographiert. Man erhält 10.84 g (68.7% d. Th.) 1-[(1RS,4SR)-4-Diisopropyl phosphonylmethoxy-cyclopent-2-en-1-yl]thymin (Verbindung der Formel 9) mit dem Schmelzpunkt 117-118°C. 1H NMR (270 MHz, d6-DMSO) δ[ppm]: 11.26 (s, 1H), 7.15 (d, 1H), 6.35 (m, 1H), 5.99 (m, 1H), 5.41 (m, 1H), 4.69-4.51 (m, 3H), 3.83 (d, 2H), 2.71 (m, 1H), 1.76 (d, 3H), 1.55 (m, 1H), 1.25 (m, 12H).19.25 g (40.9 mmol) of the hemitosylate of the compound of formula 8 and 20.7 g (300 mmol) sodium nitrite are dissolved in 250 ml of water and with 25 ml of glacial acetic acid and 50 ml of 1N hydrochloric acid were added. The reaction mixture is at 4 hours Stirred at room temperature, then carefully neutralized with sodium carbonate and concentrated in vacuo. The residue is boiled out several times with acetone; the acetone extracts are concentrated in vacuo, and the resulting residue is chromatographed on silica gel with dichloromethane / methanol 9/1. You get 10.84 g (68.7% of theory) 1 - [(1RS, 4SR) -4-diisopropyl phosphonylmethoxy-cyclopent-2-en-1-yl] thymine (compound of formula 9) with the Melting point 117-118 ° C. 1H NMR (270 MHz, d6-DMSO) δ [ppm]: 11.26 (s, 1H), 7.15 (d, 1H), 6.35 (m, 1H), 5.99 (m, 1H), 5.41 (m, 1H), 4.69-4.51 (m, 3H), 3.83 (d, 2H), 2.71 (m, 1H), 1.76 (d, 3H), 1.55 (m, 1H), 1.25 (m, 12H).
4.63 g (12 mMol) der Verbindung der Formel 9 werden in 100 ml Isopropanol gelöst, mit 500 mg Palladium auf Kohle (10%ig) versetzt und bei Raumtemperatur hydriert. Nach beendeter Wasserstoffaufnahme wird vom Katalysator abfiltriert, das Filtrat eingeengt und der Rückstand über Kieselgel mit Dichlormethan/Methanol 9/1 chromatographiert. Man erhält 4.64 g (99.7% d. Th.) 1-[(1RS,4SR)-4-Diisopropylphosphonylmethoxy-cyclopent-1-yl]thymin (Verbindung der Formel 10 = Verbindung der Formel 1, worin R1 = R2 = Isopropyl ist) mit dem Schmelzpunkt 82°C. 1H NMR (270 MHz, d6-DMSO) δ[ppm]: 11.18 (s, 1H), 7.56 (d, 1H), 4.98 (m, 1H), 4.63 (m, 2H), 4.02 (m, 1H), 3.74 (m, 2H), 2.27 (m, 1H), 1.99 (m, 2H), 1.82 (s, 3H), 1.64 (m, 3H), 1.26 (m, 12H).4.63 g (12 mmol) of the compound of formula 9 are dissolved in 100 ml of isopropanol, 500 mg of palladium on carbon (10%) are added and the mixture is hydrogenated at room temperature. When the uptake of hydrogen has ended, the catalyst is filtered off, the filtrate is concentrated and the residue is chromatographed on silica gel with dichloromethane / methanol 9/1. 4.64 g (99.7% of theory) of 1 - [(1RS, 4SR) -4-diisopropylphosphonylmethoxycyclopent-1-yl] thymine (compound of the formula 10 = compound of the formula 1 in which R 1 = R 2 = Isopropyl) with a melting point of 82 ° C. 1H NMR (270 MHz, d6-DMSO) δ [ppm]: 11.18 (s, 1H), 7.56 (d, 1H), 4.98 (m, 1H), 4.63 (m, 2H), 4.02 (m, 1H), 3.74 (m, 2H), 2.27 (m, 1H), 1.99 (m, 2H), 1.82 (s, 3H), 1.64 (m, 3H), 1.26 (m, 12H).
3.49 g (9 mMol) der Verbindung der Formel 10 werden in 40 ml trockenem Dimethylformamid gelöst und bei Raumtemperatur mit 13.1 ml Bromtrimethylsilan versetzt und 4 Stunden bei Raumtemperatur gerührt. Die erhaltene Reaktionslösung wird eingeengt, in 6.4 ml Wasser gelöst, mit 175 ml Aceton versetzt und über Nacht im Tiefkühlschrank aufbewahrt. Der gebildete Niederschlag wird abgesaugt, mit Aceton gewaschen, in Ethanol heiß gelöst, abgekühlt, abgesaugt, erneut mit Aceton gewaschen und im Vakuum getrocknet. Man erhält 1.84 g (67.2%) d. Th.) 1-[(1RS,4SR)-4-Phosphonylmethoxy-cyclopent-1-yl]thymin (Verbindung der Formel 11 = Verbindung der Formel 1, worin R1 = R2 = Wasserstoff ist) mit dem Schmelzpunkt 123-125°C. 1H NMR (270 MHz, D2O) δ[ppm]: 7.71 (d, 1H), 4.99 (m, 1H), 4.15 (m, 1H), 3.73 (m, 2H), 2.40 (m, 1H), 2.10 (m, 2H), 1.90 (s, 3H), 1.78 (m, 3H).3.49 g (9 mmol) of the compound of formula 10 are dissolved in 40 ml of dry dimethylformamide and 13.1 ml of bromotrimethylsilane are added at room temperature and the mixture is stirred at room temperature for 4 hours. The reaction solution obtained is concentrated, dissolved in 6.4 ml of water, mixed with 175 ml of acetone and stored in the freezer overnight. The precipitate formed is suction filtered, washed with acetone, dissolved in hot ethanol, cooled, suction filtered, washed again with acetone and dried in vacuo. 1.84 g (67.2%) d. Th.) 1 - [(1RS, 4SR) -4-phosphonylmethoxy-cyclopent-1-yl] thymine (compound of formula 11 = compound of formula 1, wherein R 1 = R 2 = hydrogen) with melting point 123-125 ° C. 1H NMR (270 MHz, D2O) δ [ppm]: 7.71 (d, 1H), 4.99 (m, 1H), 4.15 (m, 1H), 3.73 (m, 2H), 2.40 (m, 1H), 2.10 ( m, 2H), 1.90 (s, 3H), 1.78 (m, 3H).
0.669 g (2.2 mMol) der Verbindung der Formel 11 werden in 44 ml 0.1 N Natronlauge gelöst und 30 Minuten bei Raumtemperatur gerührt. Die Lösung wird im Vakuum eingeengt, der kristalline Rückstand mit Ethanol verrührt, abgesaugt und im Vakuum getrocknet. Man erhält 0.76 g (99.9% d. Th.) 1-[(1RS,4SR)-4-Phosphonylmethoxy-cyclopent-1-yl]thymin-dinatriumsalz- (Verbindung der Formel 12 = Verbindung der Formel 1, worin R1 = R2 = Natrium ist) mit dem Schmelzpunkt 274°C. 1H NMR (270 MHz, D2O) δ[ppm]: 7.73 (d,1H), 4.88 (m, 1H), 4.14 (m, 1H), 3.46 (d, 2H), 2.44 (m, 1H), 2.03 (m, 2H), 1.91 (s, 3H), 1.84 (m, 3H).0.669 g (2.2 mmol) of the compound of formula 11 are dissolved in 44 ml of 0.1 N sodium hydroxide solution and stirred for 30 minutes at room temperature. The solution is concentrated in vacuo, the crystalline residue is stirred with ethanol, suction filtered and dried in vacuo. 0.76 g (99.9% of theory) of 1 - [(1RS, 4SR) -4-phosphonylmethoxycyclopent-1-yl] thymine disodium salt (compound of the formula 12 = compound of the formula 1 in which R 1 = R 2 = sodium) with a melting point of 274 ° C. 1H NMR (270 MHz, D2O) δ [ppm]: 7.73 (d, 1H), 4.88 (m, 1H), 4.14 (m, 1H), 3.46 (d, 2H), 2.44 (m, 1H), 2.03 ( m, 2H), 1.91 (s, 3H), 1.84 (m, 3H).
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DE4138584A DE4138584A1 (en) | 1991-11-23 | 1991-11-23 | New carbocyclic phosphonate-nucleotide analogues - are effective antiviral agents against retroviral infections, e.g. HIV |
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