DE3852531T2 - NUCLEOSIDES AND NUCLEOSIDE ANALOGS, PHARMACEUTICAL COMPOSITION AND METHOD FOR PRODUCING THE INGREDIENTS. - Google Patents
NUCLEOSIDES AND NUCLEOSIDE ANALOGS, PHARMACEUTICAL COMPOSITION AND METHOD FOR PRODUCING THE INGREDIENTS.Info
- Publication number
- DE3852531T2 DE3852531T2 DE3852531T DE3852531T DE3852531T2 DE 3852531 T2 DE3852531 T2 DE 3852531T2 DE 3852531 T DE3852531 T DE 3852531T DE 3852531 T DE3852531 T DE 3852531T DE 3852531 T2 DE3852531 T2 DE 3852531T2
- Authority
- DE
- Germany
- Prior art keywords
- formula
- compound
- anomer
- therapeutically acceptable
- acceptable salts
- 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.)
- Expired - Fee Related
Links
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- 239000004615 ingredient Substances 0.000 title 1
- 150000001875 compounds Chemical class 0.000 claims abstract description 43
- 150000003839 salts Chemical class 0.000 claims abstract description 13
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- 238000002560 therapeutic procedure Methods 0.000 claims abstract description 5
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims abstract description 4
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- 125000006239 protecting group Chemical group 0.000 claims description 12
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- KDCGOANMDULRCW-UHFFFAOYSA-N 7H-purine Chemical group N1=CNC2=NC=NC2=C1 KDCGOANMDULRCW-UHFFFAOYSA-N 0.000 claims description 4
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- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract 2
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- 125000000217 alkyl group Chemical group 0.000 abstract 1
- 125000004432 carbon atom Chemical group C* 0.000 abstract 1
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- RJWBTWIBUIGANW-UHFFFAOYSA-N 4-chlorobenzenesulfonic acid Chemical compound OS(=O)(=O)C1=CC=C(Cl)C=C1 RJWBTWIBUIGANW-UHFFFAOYSA-N 0.000 description 1
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- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
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- LNOPIUAQISRISI-UHFFFAOYSA-N n'-hydroxy-2-propan-2-ylsulfonylethanimidamide Chemical compound CC(C)S(=O)(=O)CC(N)=NO LNOPIUAQISRISI-UHFFFAOYSA-N 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000005440 p-toluyl group Chemical group [H]C1=C([H])C(=C([H])C([H])=C1C(*)=O)C([H])([H])[H] 0.000 description 1
- 239000011713 pantothenic acid Substances 0.000 description 1
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- 235000019161 pantothenic acid Nutrition 0.000 description 1
- HTYIXCKSEQQCJO-UHFFFAOYSA-N phenaglycodol Chemical compound CC(C)(O)C(C)(O)C1=CC=C(Cl)C=C1 HTYIXCKSEQQCJO-UHFFFAOYSA-N 0.000 description 1
- ZJAOAACCNHFJAH-UHFFFAOYSA-N phosphonoformic acid Chemical compound OC(=O)P(O)(O)=O ZJAOAACCNHFJAH-UHFFFAOYSA-N 0.000 description 1
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- IGFXRKMLLMBKSA-UHFFFAOYSA-N purine Chemical compound N1=C[N]C2=NC=NC2=C1 IGFXRKMLLMBKSA-UHFFFAOYSA-N 0.000 description 1
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- 239000006188 syrup Substances 0.000 description 1
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- LCJVIYPJPCBWKS-NXPQJCNCSA-N thymosin Chemical compound SC[C@@H](N)C(=O)N[C@H](CO)C(=O)N[C@H](CC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CO)C(=O)N[C@H](CO)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H]([C@@H](C)CC)C(=O)N[C@H]([C@H](C)O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CC(O)=O)C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCCCN)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](C(C)C)C(=O)N[C@H](C(C)C)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@H](CCC(O)=O)C(O)=O LCJVIYPJPCBWKS-NXPQJCNCSA-N 0.000 description 1
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- HBOMLICNUCNMMY-XLPZGREQSA-N zidovudine Chemical compound O=C1NC(=O)C(C)=CN1[C@@H]1O[C@H](CO)[C@@H](N=[N+]=[N-])C1 HBOMLICNUCNMMY-XLPZGREQSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
- C07H19/04—Heterocyclic radicals containing only nitrogen atoms as ring hetero atom
- C07H19/06—Pyrimidine radicals
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
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Abstract
Description
Die vorliegende Erfindung betrifft eine chemische Verbindung und ihre Verwendung sowie die Verwendung physiologisch verträglicher Salze dieser Verbindung für die therapeutische und prophylaktische Kontrolle und Behandlung des Syndroms der erworbenen Immunschwäche (AIDS), von Infektionen durch das menschliche Immunschwäche-Virus, von Hepatitis B-Infektionen und von Retrovirus-Infektionen. Außerdem betrifft die vorliegende Erfindung ein Verfahren für eine derartige Kontrolle und Behandlung in Tier und Mensch.The present invention relates to a chemical compound and its use as well as the use of physiologically acceptable salts of this compound for the therapeutic and prophylactic control and treatment of acquired immunodeficiency syndrome (AIDS), infections caused by the human immunodeficiency virus, hepatitis B infections and retrovirus infections. The present invention also relates to a method for such control and treatment in animals and humans.
In den späten siebziger Jahren wurde über eine neue Krankheit berichtet, die nachfolgend als Syndrom einer erworbenen Irnmunschwäche (AIDS) bezeichnet wurde. Es wird nun allgemein anerkannt, daß ein Retrovirus, das die Bezeichnung HIV (menschliches Irnmunschwäche- Virus) trägt und das zuvor als HTLV-III oder LAV bekannt war, für die Ätiologie von AIDS eine große Rolle spielt.In the late 1970s, a new disease was reported, subsequently called acquired immunodeficiency syndrome (AIDS). It is now generally accepted that a retrovirus called HIV (human immunodeficiency virus), previously known as HTLV-III or LAV, plays a major role in the etiology of AIDS.
AIDS ist durch eine starke Immunschwäche auf Grund geringer Zahlen einer Untergruppe von Lymphozyten T-Helferzellen, die ein Ziel für die HIV-Infektion darstellen, gekennzeichnet. Diese starke Immunschwäche in AIDS-Patienten ist dafür verantwortlich, daß diese Patienten für eine Vielzahl von opportunistischen Infektionen bakterieller, pilziger, protozoiger oder viraler Ätiologie empfänglich sind. Die ätiologischen Mittel unter den viralen opportunistischen Infektionen findet man häufig in der Gruppe der Herpesviren, das heißt Herpes simplex-Virus (HSV), Varizella Zoster-Virus (VZV), Epstein-Barr-Virus (EBV) und insbesondere Cytomegalovirus (CMV). Andere den Menschen befallende Retroviren sind HTLV-I und -II. Beispiele für Tiere befallende Retroviren sind Katzenleukämie-Virus und das infektiöse Anämie-Virus bei Pferden.AIDS is characterized by severe immunodeficiency due to low numbers of a subset of lymphocytes called T helper cells, which are a target for HIV infection. This severe immunodeficiency in AIDS patients is responsible for making these patients susceptible to a variety of opportunistic infections of bacterial, fungal, protozoal or viral etiology. The etiological agents among viral opportunistic infections are often found in the group of herpes viruses, i.e. herpes simplex virus (HSV), varicella zoster virus (VZV), Epstein-Barr virus (EBV) and especially cytomegalovirus (CMV). Other retroviruses that infect humans are HTLV-I and -II. Examples of retroviruses that infect animals are feline leukemia virus and equine infectious anemia virus.
Hepatitis B-Infektionen verursachen in einer beträchtlichen Anzahl von Personen ernsthafte Erkrankungen wie akute Hepatitis, chronische Hepatitis und fulminante Hepatitis. Man schätzt, daß es weltweit 200 Millionen Patienten mit einer chronischen Hepatitis B-Infektion gibt. Ein beträchtlicher Teil der chronischen Fälle schreitet fort zu Leberzirrhose und Lebertumor. In einigen Fällen nehmen die Hepatitis-Infektionen auch einen schnellen und ernsten Verlauf wie in der fulminanten B-Hepatitis mit einer Sterblichkeit von etwa neunzig Prozent. Gegenwärtig gibt es keine wirksame Behandlung gegen Hepatitis B-Infektionen.Hepatitis B infections cause serious diseases such as acute hepatitis, chronic hepatitis and fulminant hepatitis in a significant number of people. It is estimated that there are 200 million patients with chronic hepatitis B infection worldwide. A significant proportion of chronic cases progress to liver cirrhosis and liver tumors. In some cases, hepatitis infections also take a rapid and serious course, such as in fulminant B hepatitis, with a mortality rate of about ninety percent. There is currently no effective treatment for hepatitis B infections.
Eine große Anzahl von Nucleosid-Analoga weisen mehrere antimetabolische Aktivitäten auf. Sie tun das dadurch, daß sie natürlich vorkommende Nucleoside ersetzen oder mit diesen kompetitieren. Kürzlich sind einige Nucleosid-Analoga beschrieben worden, die die Vermehrung des menschlichen Immunschwäche-Virus (HIV, auch als HTLV-III, LAV bezeichnet), das ursächliche Agens von AIDS und dem AIDS-verwandten Komplex (ARC), inhibieren. Solche Verbindungen sind z.B. Azidothymidin, Didesoxycytidin und Didesoxyadenosin. Diese und andere beschriebene HIV-antimetabolische Nucleosid-Analoga haben dieselbe geometrische Anordnung zwischen der nucleosidischen Base und dem glykosidischen Teil wie die natürlicherweise vorkommenden Nucleoside, das heißt, sie sind ß-Anomere.A large number of nucleoside analogues exhibit multiple antimetabolic activities. They do this by replacing or competing with naturally occurring nucleosides. Recently, several nucleoside analogues have been described that inhibit the replication of the human immunodeficiency virus (HIV, also called HTLV-III, LAV), the causative agent of AIDS and the AIDS-related complex (ARC). Such compounds include azidothymidine, dideoxycytidine and dideoxyadenosine. These and other described HIV antimetabolic nucleoside analogues have the same geometric arrangement between the nucleosidic base and the glycosidic part as the naturally occurring nucleosides, i.e. they are ß-anomers.
Überraschenderweise haben wir nun herausgefunden, daß einige Nucleoside und Nucleosid-Analoga mit der entgegengesetzten geometrischen Konfiguration, nämlich die α-Anomere, potente Inhibitoren der Vermehrung von HIV, nicht jedoch der Zellteilung, sind. Anti-HIV-Aktivitäten haben vor allen Dingen solche geometrische Isomere, die entweder in dem Teil der nucleosidischen Base, dem glycosidischen Teil oder in allen beiden modifiziert worden sind. Die Strukturen dieser Verbindungen werden in dieser Erfindung offenbart.Surprisingly, we have now found that some nucleosides and nucleoside analogues with the opposite geometric configuration, namely the α-anomers, are potent inhibitors of HIV replication but not of cell division. Anti-HIV activities have, above all, those geometric isomers which have been modified either in the nucleosidic base part, the glycosidic part or in both. The structures of these compounds are disclosed in this invention.
Die folgenden Verbindungen mit einer Strukturformel ähnlich der Formel I weiter unten sind bekannt:The following compounds with a structural formula similar to formula I below are known:
1. Verbindungen der Formel 1. Compounds of the formula
wobei R³ OH ist und R¹ wie folgt ist:where R³ is OH and R¹ is as follows:
R¹ ist H und CH&sub3;: T. Nishimura, B. Shinizu, I. Iwai Chem. Pharm. Bull (Tokyo) 12 (1964), 1471;R¹ is H and CH₃: T. Nishimura, B. Shinizu, I. Iwai Chem. Pharm. Bull (Tokyo) 12 (1964), 1471;
R¹ ist C&sub2;H&sub5;: M. Swierkowski, D. Shugar J. Med. Chem. 12 (1969), 533;R¹ is C₂H�5: M. Swierkowski, D. Shugar J. Med. Chem. 12 (1969), 533;
R¹ ist n-C&sub3;H&sub7;: A Szaboles, J. S gi, L. Ötvös J. Carbohydrates, Nucleosides, Nucleotides 2 (1975), 197 - 211R¹ is n-C₃H�7: A Szaboles, J. S gi, L. Ötvös J. Carbohydrates, Nucleosides, Nucleotides 2 (1975), 197 - 211
R¹ ist i-C&sub3;H&sub7;: M. Draminski, A. Zgit-Wroblewska Polish J. Chemtstry 54 (1980), 1085;R¹ is iC₃H�7: M. Draminski, A. Zgit-Wroblewska Polish J. Chemistry 54 (1980), 1085;
R¹ ist C CH: P.J. Barr; A.S. Jones, P. Serafinowski, R. Walker; J. Chem. Soc. Perkin I (1978), 1263 - 1267;R¹ is C CH: P.J. Barr; A.S. Jones, P. Serafinowski, R. Walker; J. Chem. Soc. Perkin I (1978), 1263 - 1267;
und wobei R³ N&sub3; ist und R¹ CH&sub3; ist: M. Imezawa, E Eckstein J. Org. Chem. 43 (1978), 3044 - 3048.and wherein R³ is N₃ and R¹ is CH₃: M. Imezawa, E Eckstein J. Org. Chem. 43 (1978), 3044 - 3048.
2. Die Verbindung der Formel 2. The connection of the formula
wobei R¹ C CH ist, wird in P.J. Barr; A.S. Jones, P. Serafinowski, R. Walker J. Chem. Soc. Perkin I (1978), 1263 - 1267 beschrieben;where R¹ is C CH is described in P.J. Barr; A.S. Jones, P. Serafinowski, R. Walker J. Chem. Soc. Perkin I (1978), 1263 - 1267;
wobei R¹ H ist, wird in J.J. Fox, N.C. Yung, I. Wempen und M. Hoffer; J. Am. Chem. Soc., Bd. 83 (1961), 4066 - 4070 beschrieben.where R¹ is H is described in J.J. Fox, N.C. Yung, I. Wempen and M. Hoffer; J. Am. Chem. Soc., vol. 83 (1961), 4066 - 4070.
Beide Gruppen 1. und 2. betreffen nur Verbindungen, bei denen der Rest an der 3'-Position und die 4'-Hydroxymethyl-Gruppe in der trans-Konfiguration angeordnet sind.Both groups 1 and 2 only concern compounds in which the residue at the 3'-position and the 4'-hydroxymethyl group are arranged in the trans configuration.
Zusätzliche Verbindungen der Formel unter 2. und 1., wobei R³ OH ist, sind aus den folgenden Entgegenhaltungen bekannt:Additional compounds of the formula under 2. and 1., where R³ is OH are known from the following documents:
- J. Med. Chem 17 (1974), 269 - 273- J. Med. Chem 17 (1974), 269 - 273
- DE-A-30 02 197- DE-A-30 02 197
- DE-A-32 29 169- DE-A-32 29 169
- US-A-3,1 16,282- US-A-3,1 16,282
- Chem. Pharm. Bull. 32 (1984), 1441 - 1450 (Chem. Abst. 102, 7013q)- Chem. Pharm. Bull. 32 (1984), 1441 - 1450 (Chem. Abst. 102, 7013q)
- Vopr. Virusol. 1979 (6), 603 - 606 (Chem. Abst. 92, 208903d)- Pres. Virusol. 1979 (6), 603 - 606 (Chem. Abst. 92, 208903d)
- DE-A-29 30 904- DE-A-29 30 904
- DE-A-29 18 260- DE-A-29 18 260
- DE-A-30 45 375- DE-A-30 45 375
- US 4,247,544- US$4,247,544
- US 4,267,171- US$4,267,171
- J. Carbohydr: Nucleos. Nucleot 5 (1978), 187 - 224- J. Carbohydr: Nucleos. Nucleot 5 (1978), 187 - 224
- FR-A-2 040 177.- FR-A-2 040 177.
3. Verbindungen der Formel 3. Compounds of the formula
wobei B eine Purin- oder Cytosinbase ist, sind aus EP-O 206 497 und US 3,817,982 bekannt.where B is a purine or cytosine base, are known from EP-0 206 497 and US 3,817,982.
4. Verbindungen der Formel 4. Compounds of the formula
wobei A eine Purin- oder Pyrimidinbase ist, sind aus EP-O 217 580, EP-O 196 185 und EP-O 199 451 bekannt.where A is a purine or pyrimidine base, are known from EP-O 217 580, EP-O 196 185 and EP-O 199 451.
5. Verbindungen der Formel 5. Compounds of the formula
wobei R¹ H, CH&sub3; und C&sub2;H&sub5; sind, sind zumindest aus einer der folgenden Entgegenhaltungen EP-0 277 151, US 3,775,397, EP-0 254 268, DD 75084 oder GB 1,189,973 bekannt.where R¹ is H, CH₃ and C₂H₅ are known from at least one of the following documents EP-0 277 151, US 3,775,397, EP-0 254 268, DD 75084 or GB 1,189,973.
6. Verbindungen der Formel 6. Compounds of the formula
wobei B Thymin oder Cytosin ist, sind aus Yamauchi et al., J. Chem. Soc. Perkin Trans. 1 (1980), 2787 - 2792 bekannt.where B is thymine or cytosine, are known from Yamauchi et al., J. Chem. Soc. Perkin Trans. 1 (1980), 2787 - 2792.
7. Andere Verbindungen, die den Cytosin-Rest als die glykosidisch verknüpfte Base enthalten, sind zumindest von einer der Entgegenhaltungen Darzynkiewicz et al., Biochem. Biophys. Res. Comm. 46, 1734 (1972) und Remin und Shugar, JACS 95, 8146 (1973) bekannt. wobei X, Y und Z jeweils entweder H oder CH&sub3; sind.7. Other compounds containing the cytosine residue as the glycosidically linked base are known from at least one of the references Darzynkiewicz et al., Biochem. Biophys. Res. Comm. 46, 1734 (1972) and Remin and Shugar, JACS 95, 8146 (1973). where X, Y and Z are each either H or CH₃.
8. Schließlich ist die Verbindung 2', 3'-Didesoxy-3'-(R)-Hydroxymethyluridin mit der Strukturformel 8. Finally, the compound 2', 3'-dideoxy-3'-(R)-hydroxymethyluridine with the structural formula
aus der japanischen Offenlegungsschrift Nr. 57-146789 und aus Nucleosides & Nucleotides 1, 263 - 273 (1982) bekannt.from Japanese Laid-Open Application No. 57-146789 and from Nucleosides & Nucleotides 1, 263 - 273 (1982).
Gemäß der vorliegenden Erfindung ist gefunden worden, daß die Verbindung der Formel alpha-Anomer beta-AnomerAccording to the present invention it has been found that the compound of the formula alpha-anomer beta-anomer
wobei die Reste A und R wie folgt definiert sind: where the residues A and R are defined as follows:
und R: -CH&sub2;OH, wobei R relativ zu der -CH&sub2;OH-Gruppe an der 4'- Position entweder cis- oder trans-Konfiguration aufweisen kann, und deren therapeutisch verträgliche Salze die Vermehrung von menschlichem Immunschwäche-Virus (HIV) inhibiert. Die Verbindung der Formel I ist als therapeutisches und/oder prophylaktisches Mittel zur Kontrolle und Behandlung von Infektionen mit HI-Virus in Säugetieren und beim Menschen zu verwenden.and R: -CH₂OH, where R can have either cis or trans configuration relative to the -CH₂OH group at the 4'-position, and the therapeutically acceptable salts thereof inhibit the replication of human immunodeficiency virus (HIV). The compound of formula I is useful as a therapeutic and/or prophylactic agent for controlling and Treatment of HIV infections in mammals and humans.
Allgemeiner gesehen ist die Verbindung der Formel I als therapeutisches sund/oder prophylaktisches Mittel zur Kontrolle und Behandlung von Infektionen, die von Retroviren und dem Hepatitis B-Virus verursacht werden, in Säugetieren und beim Menschen zu verwenden.More generally, the compound of formula I is to be used as a therapeutic and/or prophylactic agent for the control and treatment of infections caused by retroviruses and hepatitis B virus in mammals and humans.
Alle Retroviren einschließlich HIV benötigen das Enzym Reverse Transkriptase in ihrem natürlichen Replikationszyklus.All retroviruses, including HIV, require the enzyme reverse transcriptase in their natural replication cycle.
Das Hepatitis B-Virus (HBV) ist ein DNA-Virus mit einem einzigartigen Genom aus zirkulärer, doppelsträngiger DNA, die teilweise einzelsträngig ist. Das Virus enthält eine spezifische DNA-Polymerase, die für die virale Replikation erforderlich ist. Diese DNA Polymerase fungiert während der Replikation der HBV-DNA über ein RNA-Intermediat auch als Reverse Transkriptase. Die Verbindung der Formel I inhibiert die Aktivität der Reversen Transkriptase von Retroviren einschließlich HIV sowie auch die Aktivität von DNA Polymerase von Hepatitis B-Virus.The hepatitis B virus (HBV) is a DNA virus with a unique genome of circular, double-stranded DNA, some of which is single-stranded. The virus contains a specific DNA polymerase that is required for viral replication. This DNA polymerase also functions as a reverse transcriptase during the replication of HBV DNA via an RNA intermediate. The compound of formula I inhibits the activity of the reverse transcriptase of retroviruses including HIV as well as the activity of DNA polymerase of hepatitis B virus.
Die vorliegende Erfindung hat verschiedene Aspekte:The present invention has several aspects:
1. die neue Verbindung der Formel I,1. the new compound of formula I,
2. pharmazeutische Zusammensetzungen, die die Verbindung der Formel I als aktiven Bestandteil enthalten,2. pharmaceutical compositions containing the compound of formula I as an active ingredient,
3. die Verbindung der Formel I für die Anwendung in der Therapie,3. the compound of formula I for use in therapy,
4. die Verbindung der Formel I für die Anwendung zur Herstellung eines Medikaments für die therapeutische und/oder die prophylaktische Behandlung von Infektionen, die von einem Retrovirus einschließlich HIV oder von dem Hepatitis B-Virus verursacht werden.4. the compound of formula I for use in the manufacture of a medicament for the therapeutic and/or prophylactic treatment of infections caused by a retrovirus including HIV or by the hepatitis B virus.
Infektionen in Säugetieren und beim Menschen, die von Retroviren einschließlich HIV oder vom Hepatitis B-Virus verursacht werden, können therapeutisch oder prophylaktisch behandelt werden, indem eine wirksame Menge der Verbindung der Formel I an einen Wirt, der eine derartige Behandlung benötigt, verabreicht wird.Infections in mammals and humans caused by retroviruses, including HIV, or by hepatitis B virus can be treated therapeutically or prophylactically by administering an effective amount of the compound of formula I to a host in need of such treatment.
Ein bevorzugter Aspekt der vorliegenden Erfindung besteht darin, HI- Virus-Infektionen beim Menschen zu bekämpfen.A preferred aspect of the present invention is to combat HIV infection in humans.
Ein Beispiel der bevorzugten Verbindungen ist: An example of preferred connections is:
wobei R CH&sub2;OH ist.where R is CH₂OH.
In dem Beispiel der bevorzugten Verbindung haben R an der 3'-Position und der Mydroxymethyl-Rest an der 4'-Position die trans-Konfiguration.In the example of the preferred compound, R at the 3'-position and the hydroxymethyl residue at the 4'-position have the trans configuration.
In der klinischen Anwendung werden die Nucleoside der Verbindung I normalerweise oral, mittels Injektion oder Infusion in Form einer pharmazeutischen Zubereitung verabreicht, die den aktiven Bestandteil in Form der ursprünglichen Verbindung oder gegebenenfalls in Form eines ihrer pharmazeutisch verträglichen Salze umfaßt, in Verbindung mit einem pharmazeutisch verträglichen Träger, der ein festes, ein halbfestes oder ein flüssiges Verdünnungsmittel oder eine unverdauliche Kapsel sein kann. Die Verbindung kann auch ohne Trägermaterial verwendet werden. Als Beispiele für pharmazeutische Zubereitungen können Tabletten, Dragees, Kapseln, Granulate, Suspensionen, Elixiere, Sirups, Lösungen etc. erwähnt werden. Üblicherweise umfaßt die aktive Substanz zwischen 0,05 und 20% der Zubereitungen für die Injektion und zwischen 10 und 90% der Zubereitungen für die orale Verabreichung.In clinical use, the nucleosides of compound I are normally administered orally, by injection or infusion, in the form of a pharmaceutical preparation comprising the active ingredient in the form of the original compound or, where appropriate, in the form of one of its pharmaceutically acceptable salts, in association with a pharmaceutically acceptable carrier which may be a solid, semi-solid or liquid diluent or an indigestible capsule. The compound may also be used without a carrier material. As examples of pharmaceutical preparations, there may be mentioned tablets, dragees, capsules, granules, suspensions, elixirs, syrups, solutions, etc. Usually, the active substance comprises between 0.05 and 20% of the preparations for injection and between 10 and 90% of the preparations for oral administration.
Bei der Behandlung von Patienten, die an Infektionen von Retroviren, insbesondere von HIV, oder vom Hepatitis B-Virus leiden, wird es bevorzugt, die Verbindung auf einem geeigneten Weg einschließlich dem oralen, dem parenteralen, dem rektalen, dem nasalen, dem topischen oder dem vaginalen Weg zu verabreichen. Der parenterale Weg umfaßt die subkutane, die intramuskuläre, die intravenöse und die sublinguale Verabreichung. Der topische Weg umfaßt die bukkale und sublinguale Verabreichung. Die Dosierung, mit der die aktiven Bestandteile verabreicht werden, können innerhalb eines weiten Bereiches variieren und hängen von verschiedenen Faktoren wie der Ernsthaftigkeit der Infektion, dem Alter des Patienten etc. ab. Dementsprechend kann es sein, daß die Dosierung individuell eingestellt werden muß. Als möglichen Bereich für die Menge der Verbindungen gemäß vorliegender Erfindung oder eines ihrer physiologisch verträglichen Salze, die pro Tag verabreicht werden muß, kann der Bereich von etwas 10 mg bis etwa 10 000 mg, vorzugsweise der von 100 - 500 mg für die intravenöse Verabreichung und vorzugsweise 100 - 3000 mg für die orale Verabreichung erwähnt werden.In the treatment of patients suffering from infections of retroviruses, particularly HIV, or hepatitis B virus, it is preferred to administer the compound by a suitable route including oral, parenteral, rectal, nasal, topical or vaginal routes. The parenteral route includes subcutaneous, intramuscular, intravenous and sublingual administration. The topical route includes buccal and sublingual administration. The dosage at which the active ingredients are administered may vary within a wide range and depend on various factors such as the severity of the infection, the age of the patient, etc. Accordingly, the dosage may have to be adjusted individually. As a possible range for the amount of the compounds according to the present invention or a of their physiologically acceptable salts to be administered per day, the range of about 10 mg to about 10 000 mg, preferably 100 - 500 mg for intravenous administration and preferably 100 - 3000 mg for oral administration may be mentioned.
Beispiele für pharmazeutisch verträgliche Salze der Verbindung der Formel I umfassen Salze organischer Carbonsäuren wie der Essigsäure, der Milchsäure, der Gluconsäure, der Zitronensäure, der Weinsäure, der Maleinsäure, der Äpfelsäure, der Panthothensäure, der Isethionsäure, der Bernsteinsäure, der Oxalsäure, der Lactobionsäure und der Bernsteinsäure; der organischen Sulfonsäuren wie der Methansulfonsäure, der Ethansulfonsäure, der Benzolsulfonsäure, der p-Chlorbenzolsulfonsäure und der p-Toluolsulfonsäure und der anorganischen Säuren wie der Salzsäure, der Iodwasserstoffsäure, der Schwefelsäure, der Phosphorsäure und der Sulfaminsäure.Examples of pharmaceutically acceptable salts of the compound of formula I include salts of organic carboxylic acids such as acetic acid, lactic acid, gluconic acid, citric acid, tartaric acid, maleic acid, malic acid, pantothenic acid, isethionic acid, succinic acid, oxalic acid, lactobionic acid and succinic acid; of organic sulfonic acids such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-chlorobenzenesulfonic acid and p-toluenesulfonic acid and of inorganic acids such as hydrochloric acid, hydriodic acid, sulfuric acid, phosphoric acid and sulfamic acid.
Die verabreichte Verbindung kann auch in Verbindung mit anderen Medikamenten wir 9-[(2-Hydroxy-1-(hydroxymethyl)ethoxy)-methyl]guanin, 9-(2-Hydroxyethoxymethyl)-guanin (Acyclovir), 2-Amino-9-(2-hydroxy-ethoxymethyl)purin, Interferon, z.B. α-Interferon, Interleukin II und Phosphonoformiat oder in Verbindung mit einer immun-modulierenden Therapie einschließlich Transplantaten von Knochenmark oder Lymphozyten oder Medikationen wie Levamisol oder Thymosin, die die Anzahl und/oder Funktion der Lymphozyten erhöhen, je nach Bedarf für die Therapie verwendet werden.The administered compound may also be used in conjunction with other medications such as 9-[(2-hydroxy-1-(hydroxymethyl)ethoxy)-methyl]guanine, 9-(2-hydroxyethoxymethyl)-guanine (acyclovir), 2-amino-9-(2-hydroxy-ethoxymethyl)purine, interferon, e.g. α-interferon, interleukin II and phosphonoformate or in conjunction with immunomodulatory therapy including bone marrow or lymphocyte transplants or medications such as levamisole or thymosin that increase the number and/or function of lymphocytes, as required for the therapy.
Die Verbindung der vorliegenden Erfindung kann mittels eines der folgenden allgemeinen Verfahren, die einen weiteren Aspekt der vorliegenden Erfindung ausmachen, hergestellt werden.The compound of the present invention may be prepared by any of the following general processes which constitute a further aspect of the present invention.
A. Kondensation eines Glykosids, wie es von der Verbindung I umfaßt ist, wobei die Hydroxyl-Gruppen gegebenenfalls geschützt sein können, an die N-1-Position eines Pyrimidin-Derivates entsprechend dem Rest A in der Verbindung I nach bekannten Verfahren, die in der Literatur beschrieben sind. Dann folgt die Abtrennung des α-Anomeren und das Entfernen eventueller Schutzgruppen. Derartige Verfahren sind z.B. in "Basic Principles in Nucleic Acid Chemistry", Bd. 1 (Academic Press, 1974, Hrsg. P.O.Ts'o), in: 'Nucleoside Analogues, Chemistry, Biology und Medical applications" (Pharma Press, 1979, Eds. R.T. Walker, E. De Clercq und F. Eckstein) und in Nucleic Acids Research Bd. 12, 1984, S. 6827 - 6837 (A.J. Hubbard, A.S. Jones und R.T. Walker) beschrieben. Ein Beispiel für ein derartiges Verfahren wird für den Fall eines Analogs einer Uracil-Base angegeben: A. Condensation of a glycoside as comprised in the compound I, where the hydroxyl groups may optionally be protected, to the N-1 position of a pyrimidine derivative corresponding to the residue A in the compound I according to known methods described in the literature. This is followed by separation of the α-anomer and removal of any protecting groups. Such procedures are described, for example, in "Basic Principles in Nucleic Acid Chemistry", Vol. 1 (Academic Press, 1974, Ed. POTs'o), in: 'Nucleoside Analogues, Chemistry, Biology and Medical applications" (Pharma Press, 1979, Eds. RT Walker, E. De Clercq and F. Eckstein) and in Nucleic Acids Research Vol. 12, 1984, pp. 6827 - 6837 (AJ Hubbard, AS Jones and RT Walker). An example of such a procedure is given for the case of an analogue of a uracil base:
wobei R CH&sub2;OR' ist, wobei R' eine Schutzgruppe ist, von der eine große Vielzahl bekannt ist, und für die Beispiele die Gruppen p- Toluoyl, Acetyl, Trityl und Benzyl sind.where R is CH₂OR', where R' is a protecting group, of which a wide variety are known and examples of which are p-toluoyl, acetyl, trityl and benzyl.
B. Anomerisierung eines ß-Anomeren der Formel B. Anomerization of a ß-anomer of the formula
wobei A wie oben definiert ist, wobei R CH&sub2;OR' ist, wobei R' H oder eine Schutzgruppe für die Hydroxy-Gruppe ist, zu einem Gemisch aus α- und ß-Anomeren, woraufhin das α-Anomer abgetrennt und eventuelle Schutzgruppen entfernt werden. Die Anomerisierung kann mittels bekannter Verfahren, z.B. mit einem gegebenenfalls geschützten ß-Nucleosid, z.B. einem silylierten Nucleosid, mit einem Katalysator wie z.B. Trimethylsilyltrifluormethansulfonat durchgeführt werden where A is as defined above, where R is CH₂OR', where R' is H or a protecting group for the hydroxy group, to a mixture of α- and β-anomers, whereupon the α-anomer is separated and any protecting groups are removed. The anomerization can be carried out by known methods, eg with an optionally protected β-nucleoside, eg a silylated nucleoside, with a catalyst such as trimethylsilyl trifluoromethanesulfonate.
wobei R und R' wie oben definiert sind.where R and R' are as defined above.
C. Eine Transglykosylierung, wobei der Zucker-Anteil, der eine α- oder ß-Bindung mit einer nucleosidischen Base bildet, auf die gewünschte Pyrimidin-Base übertragen wird. Die Reaktion wird mit einem Katalysator wie z.B. Trimethylsilyltrifluormethansulfonat durchgeführt. Anschließend erfolgt die Abtrennung der Produkte und die Abspaltung der Schutzgruppen. andere ProdukteC. A transglycosylation, where the sugar moiety that forms an α- or β-bond with a nucleosidic base is transferred to the desired pyrimidine base. The reaction is carried out with a catalyst such as trimethylsilyl trifluoromethanesulfonate. The products are then separated and the protecting groups are cleaved. other products
wobei R und R' wie oben definiert sind. Der Rest B ist eine Pyrimidin- oder Purin-Base, wobei die Wahl dieser Base nicht kritisch ist.where R and R' are as defined above. The residue B is a pyrimidine or purine base, the choice of this base not being critical.
D. Einführung der funktionellen Gruppe R- oder eines Vorläufers von R* in das α-anomere Nucleosid mittels Substitution einer geeigneten Abgangsgruppe R" und nachfolgendes Entfernen der Schutzgruppe. R' ist wie oben definiert, R" ist eine gute Abgangsgrnppe wir z.B. Trifluormethansulfonyloxy, R ist ein Synthon für die CH&sub2;OH-Gruppe wie z.B. D. Introduction of the functional group R- or a precursor of R* into the α-anomeric nucleoside by substitution of a suitable leaving group R" and subsequent removal of the protecting group. R' is as defined above, R" is a good leaving group such as trifluoromethanesulfonyloxy, R is a synthon for the CH₂OH group such as
R* ist eine geeignete Schutzgruppe.R* is a suitable protecting group.
Ein alternativer Weg für die Einführung der R -Gruppe ist der mittels Reaktion des 2',3'-Anhydro-α-Anomeren. An alternative route for the introduction of the R group is by reaction of the 2',3'-anhydro-α-anomer.
wobei R' und R wie oben definiert sind.where R' and R are as defined above.
Das Prinzip der Verfahren A bis D ist auch für die Synthese von Cytidin-Analoga der Formel I anwendbar, obwohl die Formel, die die Reaktionen beschreibt, nur Uridin-Analoga bezeichnet.The principle of processes A to D is also applicable to the synthesis of cytidine analogues of formula I, although the formula describing the reactions only refers to uridine analogues.
E. Umwandlung der Uracil-Einheit von 5-substituierten oder unsubstituierten α-Uridin-Verbindungen in eine Cytosineinheit der entsprechenden α-Cytidin-Analoga. Dies erfolgt mittels herkömmlicher Verfahren, deren Prinzip z.B. von W.L. Sung (J: Chem. Soc. Chem. Comm. 1981, S. 1089 und J. Organic Chemistry 1982, Bd. 47, S. 3623 - 3628) und von P. Herdewijn et al. (J. Medicinal Chemistry 1985, Bd. 28, S. 550 - 555) beschrieben worden ist.E. Conversion of the uracil moiety of 5-substituted or unsubstituted α-uridine compounds into a cytosine moiety of the corresponding α-cytidine analogues. This is carried out by means of conventional methods, the principle of which has been described, for example, by W.L. Sung (J: Chem. Soc. Chem. Comm. 1981, p. 1089 and J. Organic Chemistry 1982, vol. 47, pp. 3623 - 3628) and by P. Herdewijn et al. (J. Medicinal Chemistry 1985, vol. 28, pp. 550 - 555).
Claims (1)
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| SE8701605A SE8701605D0 (en) | 1987-04-16 | 1987-04-16 | NOVEL MEDICINAL COMPOUNDS |
| PCT/SE1988/000169 WO1988008001A1 (en) | 1987-04-16 | 1988-04-06 | Nucleosides and nucleoside analogues, pharmaceutical composition and processes for the preparation of the compounds |
| CA000580141A CA1336088C (en) | 1987-04-16 | 1988-10-14 | 1-(3'-substitued-2', 3'-dideoxy-d-ribofuranosyl) thymine and uracil |
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| Publication Number | Publication Date |
|---|---|
| DE3852531D1 DE3852531D1 (en) | 1995-02-02 |
| DE3852531T2 true DE3852531T2 (en) | 1995-08-10 |
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| DE3852531T Expired - Fee Related DE3852531T2 (en) | 1987-04-16 | 1988-04-06 | NUCLEOSIDES AND NUCLEOSIDE ANALOGS, PHARMACEUTICAL COMPOSITION AND METHOD FOR PRODUCING THE INGREDIENTS. |
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| JP (1) | JPH01503069A (en) |
| AT (1) | ATE115958T1 (en) |
| AU (1) | AU614082B2 (en) |
| CA (1) | CA1336088C (en) |
| DE (1) | DE3852531T2 (en) |
| DK (3) | DK168443B1 (en) |
| HU (1) | HU211547A9 (en) |
| SE (1) | SE8701605D0 (en) |
| WO (1) | WO1988008001A1 (en) |
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| GB8629892D0 (en) * | 1986-12-15 | 1987-01-28 | Wellcome Found | Antiviral compounds |
| US4950758A (en) * | 1988-01-20 | 1990-08-21 | Regents Of The University Of Minnesota | Optically-active isomers of dideoxycarbocyclic nucleosides |
| US5631370A (en) * | 1988-01-20 | 1997-05-20 | Regents Of The University Of Minnesota | Optically-active isomers of dideoxycarbocyclic nucleosides |
| US5175292A (en) * | 1988-01-20 | 1992-12-29 | Regents Of The University Of Minnesota | Intermediates for the preparation of dideoxycarbocyclic nucleosides |
| WO1989008115A1 (en) * | 1988-02-24 | 1989-09-08 | Institut De Recherches Chimiques Et Biologiques Ap | NEW DERIVATIVES OF DEOXY-2'-URIDINE SUBSTITUTED IN THE 5, 3' OR 5' POSITION BY ACYLATED alpha-AMINO GROUPS, PROCESS FOR OBTAINING THEM AND DRUGS CONTAINING THEM |
| US7119202B1 (en) | 1989-02-08 | 2006-10-10 | Glaxo Wellcome Inc. | Substituted-1,3-oxathiolanes and substituted-1,3-dioxolanes with antiviral properties |
| US5198539A (en) * | 1988-08-19 | 1993-03-30 | Burroughs Wellcome Co. | 5'-esters of 2',3'-dideoxy-3'-fluoro-5-ethynyluridine |
| US5157114A (en) * | 1988-08-19 | 1992-10-20 | Burroughs Wellcome Co. | 2',3'-dideoxy-3'-fluoro-5-ethyngluridine |
| FI95384C (en) * | 1989-04-06 | 1996-01-25 | Squibb Bristol Myers Co | Process for the preparation of 3'-deoxy-3'-substituted methyl nucleosides and intermediates used in the process |
| FR2648045B1 (en) * | 1989-06-13 | 1991-09-27 | Centre Nat Rech Scient | ALPHA ANOMERIC OLIGONUCLEOTIDE COMPOUNDS INHIBITING REPLICATION OF RETROVIRUSES |
| IE902574A1 (en) * | 1989-07-17 | 1991-02-27 | Univ Birmingham | Antiviral pyrimidine nucleosides |
| AU6401490A (en) * | 1989-09-15 | 1991-04-18 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides as antiviral and anticancer agents |
| US5591722A (en) * | 1989-09-15 | 1997-01-07 | Southern Research Institute | 2'-deoxy-4'-thioribonucleosides and their antiviral activity |
| US5728575A (en) * | 1990-02-01 | 1998-03-17 | Emory University | Method of resolution of 1,3-oxathiolane nucleoside enantiomers |
| GB9008696D0 (en) * | 1990-04-18 | 1990-06-13 | Wellcome Found | Anti-viral compounds |
| US5521163A (en) * | 1990-07-13 | 1996-05-28 | University Of Birmingham | Antiviral pyrimidine nucleosides and methods for using same |
| SE9003151D0 (en) * | 1990-10-02 | 1990-10-02 | Medivir Ab | NUCLEOSIDE DERIVATIVES |
| US6369066B1 (en) | 1990-11-13 | 2002-04-09 | Biochem Pharma, Inc. | Substituted 1,3-oxathiolanes with antiviral properties |
| AU8864191A (en) * | 1990-11-13 | 1992-06-11 | Biochem Pharma Inc. | Substituted 1,3-oxathiolanes and substituted 1,3-dithiolanes with antiviral properties |
| US5587480A (en) * | 1990-11-13 | 1996-12-24 | Biochem Pharma, Inc. | Substituted 1,3-oxathiolanes and substituted 1,3-dithiolanes with antiviral properties |
| US6228860B1 (en) | 1990-11-13 | 2001-05-08 | Biochem Pharma Inc. | Substituted 1,3-oxathiolanes with antiviral properties |
| JP3739785B2 (en) * | 1991-11-26 | 2006-01-25 | アイシス ファーマシューティカルズ，インコーポレイティド | Enhanced triple and double helix shaping using oligomers containing modified pyrimidines |
| TW393513B (en) * | 1991-11-26 | 2000-06-11 | Isis Pharmaceuticals Inc | Enhanced triple-helix and double-helix formation with oligomers containing modified pyrimidines |
| US6235887B1 (en) | 1991-11-26 | 2001-05-22 | Isis Pharmaceuticals, Inc. | Enhanced triple-helix and double-helix formation directed by oligonucleotides containing modified pyrimidines |
| US20020120130A1 (en) | 1993-09-10 | 2002-08-29 | Gilles Gosselin | 2' or 3' -deoxy and 2', 3' -dideoxy-beta-L-pentofuranonucleo-side compounds, method of preparation and application in therapy, especially as anti- viral agents |
| US5587362A (en) * | 1994-01-28 | 1996-12-24 | Univ. Of Ga Research Foundation | L-nucleosides |
| EP0763048A1 (en) * | 1994-05-31 | 1997-03-19 | Medivir Aktiebolag | Post exposure prevention of hiv |
| US5612319A (en) * | 1994-05-31 | 1997-03-18 | Medivir Ab | Postexposure prevention of HIV infection or seroconversion |
| US5703058A (en) | 1995-01-27 | 1997-12-30 | Emory University | Compositions containing 5-fluoro-2',3'-didehydro-2',3'-dideoxycytidine or a mono-, di-, or triphosphate thereof and a second antiviral agent |
| US6391859B1 (en) | 1995-01-27 | 2002-05-21 | Emory University | [5-Carboxamido or 5-fluoro]-[2′,3′-unsaturated or 3′-modified]-pyrimidine nucleosides |
| US5808040A (en) * | 1995-01-30 | 1998-09-15 | Yale University | L-nucleosides incorporated into polymeric structure for stabilization of oligonucleotides |
| EP0831852B1 (en) | 1995-06-07 | 2006-11-29 | Emory University | Nucleosides with anti-hepatitis b virus activity |
| US5869493A (en) | 1996-02-16 | 1999-02-09 | Medivir Ab | Acyclic nucleoside derivatives |
| US5753789A (en) * | 1996-07-26 | 1998-05-19 | Yale University | Oligonucleotides containing L-nucleosides |
| MXPA00008348A (en) | 1998-02-25 | 2005-07-15 | Univ Emory | 2'-fluoronucleosides. |
| KR101195019B1 (en) | 2000-10-18 | 2012-10-29 | 파마셋 인코포레이티드 | Modified nucleosides for treatment of viral infections and abnormal cellular proliferation |
| AP2009004812A0 (en) | 2006-10-10 | 2009-04-30 | Medivir Ab | HCV nucleoside inhibitor |
| WO2014109384A1 (en) * | 2013-01-10 | 2014-07-17 | 塩野義製薬株式会社 | Method for producing cross-linked nucleic acid derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| DD75084A (en) * | ||||
| US3116282A (en) * | 1960-04-27 | 1963-12-31 | Upjohn Co | Pyrimidine nucleosides and process |
| FR2040177A1 (en) * | 1969-01-31 | 1971-01-22 | Robugen Gmbh | 2-deoxyribosyl-uracil derivs |
| US3817982A (en) * | 1971-12-29 | 1974-06-18 | Syntex Inc | 2{40 ,3{40 -unsaturated nucleosides and method of making |
| DE2918260A1 (en) * | 1979-05-07 | 1980-11-27 | Robugen Gmbh | 5-alkyl-5'-deoxy-uridine deriVs. use - for normalising cancerous cell functions and accelerating wound healing |
| US4267171A (en) * | 1979-07-02 | 1981-05-12 | The Regents Of The University Of California | C-5 Substituted cytosine nucleosides |
| US4247544A (en) * | 1979-07-02 | 1981-01-27 | The Regents Of The University Of California | C-5 Substituted uracil nucleosides |
| DE2930904A1 (en) * | 1979-07-30 | 1981-02-19 | Kailash Kumar Dr Gauri | Antitumour use of 5-alkyl-pyrimidine nucleoside derivs. - as potentiators of 5-fluoro-uracil |
| DE3002197A1 (en) * | 1980-01-22 | 1981-07-23 | Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen | 5-Alkyl- and 5-alkenyl-uracil and -cytidine nucleoside derivs. - prepd. e.g. by reaction of 5'-chloro-5'-deoxy cpds. with ammonia |
| DE3045375A1 (en) * | 1980-12-02 | 1982-07-01 | Robugen Gmbh Pharmazeutische Fabrik Esslingen A.N., 7300 Esslingen | 5-Substd. pyrimidine nucleoside derivs. - useful as antiviral agents |
| DE3229169A1 (en) * | 1982-08-05 | 1984-02-09 | Robugen GmbH Pharmazeutische Fabrik, 7300 Esslingen | Use of 5-alkylpyrimidine nucleosides and their derivatives as cytostatics |
| US4724232A (en) * | 1985-03-16 | 1988-02-09 | Burroughs Wellcome Co. | Treatment of human viral infections |
| CA1285935C (en) * | 1985-03-16 | 1991-07-09 | Janet Lister Rideout | Therapeutic nucleosides |
| EP0196185B1 (en) * | 1985-03-16 | 1989-07-12 | The Wellcome Foundation Limited | Antiviral nucleosides |
| AU591125B2 (en) * | 1985-05-15 | 1989-11-30 | Wellcome Foundation Limited, The | Therapeutic nucleosides |
| DK167377B1 (en) * | 1985-09-17 | 1993-10-25 | Wellcome Found | 3'-AZIDOPYRIMIDINE NUCLEOSIDES OR PHARMACEUTICAL ACCEPTABLE SALTS OR ESTERS THEREOF USED FOR TREATMENT OR PROPHYLAXY FOR A HUMAN RETROVIRUS INFECTION |
-
1987
- 1987-04-16 SE SE8701605A patent/SE8701605D0/en unknown
-
1988
- 1988-04-06 WO PCT/SE1988/000169 patent/WO1988008001A1/en active IP Right Grant
- 1988-04-06 AT AT88903972T patent/ATE115958T1/en not_active IP Right Cessation
- 1988-04-06 AU AU16899/88A patent/AU614082B2/en not_active Ceased
- 1988-04-06 JP JP63503532A patent/JPH01503069A/en active Pending
- 1988-04-06 DE DE3852531T patent/DE3852531T2/en not_active Expired - Fee Related
- 1988-10-14 CA CA000580141A patent/CA1336088C/en not_active Expired - Fee Related
- 1988-12-15 DK DK696988A patent/DK168443B1/en not_active IP Right Cessation
-
1991
- 1991-06-07 DK DK911084A patent/DK108491D0/en not_active Application Discontinuation
-
1994
- 1994-09-13 DK DK104994A patent/DK104994A/en not_active Application Discontinuation
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1995
- 1995-05-12 HU HU95P/P00134P patent/HU211547A9/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| SE8701605D0 (en) | 1987-04-16 |
| WO1988008001A1 (en) | 1988-10-20 |
| DK168443B1 (en) | 1994-03-28 |
| DK696988D0 (en) | 1988-12-15 |
| DE3852531D1 (en) | 1995-02-02 |
| DK108491A (en) | 1991-06-07 |
| CA1336088C (en) | 1995-06-27 |
| DK108491D0 (en) | 1991-06-07 |
| DK104994A (en) | 1994-09-13 |
| DK696988A (en) | 1989-01-31 |
| AU1689988A (en) | 1988-11-04 |
| JPH01503069A (en) | 1989-10-19 |
| HU211547A9 (en) | 1995-12-28 |
| ATE115958T1 (en) | 1995-01-15 |
| AU614082B2 (en) | 1991-08-22 |
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