EP0426823A1 - Novel thimine derivatives - Google Patents

Novel thimine derivatives

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Publication number
EP0426823A1
EP0426823A1 EP90908614A EP90908614A EP0426823A1 EP 0426823 A1 EP0426823 A1 EP 0426823A1 EP 90908614 A EP90908614 A EP 90908614A EP 90908614 A EP90908614 A EP 90908614A EP 0426823 A1 EP0426823 A1 EP 0426823A1
Authority
EP
European Patent Office
Prior art keywords
group
formula
hydrogen atom
hexopyranosyl
compound
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Withdrawn
Application number
EP90908614A
Other languages
German (de)
French (fr)
Inventor
Ferenc Sztaricskai
Lajos Gergely
Gyula Szegedi
József FACHET
István CSERNUS
Sándor JANCS
Katalin Marossy
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Teva Pharmaceutical Works PLC
Original Assignee
Biogal Gyogyszergyar Rt
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Filing date
Publication date
Application filed by Biogal Gyogyszergyar Rt filed Critical Biogal Gyogyszergyar Rt
Publication of EP0426823A1 publication Critical patent/EP0426823A1/en
Withdrawn legal-status Critical Current

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Classifications

    • 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
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to novel thimine derivatives of formula I ,
  • A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, and at least one of the hydroxy group is protected with a protecting group.
  • the compounds of formula I which are free of protecting groups, are useful against retrovirus (HIV) therefore they can be used for the treatment of AIDS.
  • the invention also relates to pharmaceutical compositions comprising the said compounds of formula I as active ingredient and to the preparation of the novel compounds.
  • the most effective drugs useful against DNA and RNA virus infections can be classified to the group of nucleosides.
  • the most widely used drug against AIDS is 3,- azido-3'-deoxy-thimidine (AZT) of formula II
  • the anti-AIDS activity of AZT can be explained by the fact that it is able to inhibit the formation of the DNA of the virus either by competitive inhibition or by closing the DNA-chain of the virus.
  • AZT is phosphorilated and activated in the form of AZT-triphosphate, which is the analogon of timidine-triphosphate being one of the most important compound for building the DNA-chain.
  • AZT-triphosphate competes with other nucleoside triphosphates for binding to reverse transcriptase and inhibits the building of nucleoside triphosphates into the DNA-chain. If AZT-triphosphate is built into the DNA chain, the enlargement of the chain is ceased and the inactive form of the virus is formed.
  • AZT comprises an azido group in position C-3' in contradistinction to thimidine which azido group is not suitable for forming phosphate esters.
  • thimidin was modified not only at the aglicone, but at the -D-ribofuranosyl moiety
  • the above-listed derivatives are pyrimidine nucleosides which sugar moiety is in the form of ⁇ -D-pentofuranosyl ring and they are substituted in position C-3, with such substituent which is not suitable for forming phosphate esters thus these derivatives are not useful for the further enlargement of the DNA chain of the virus.
  • siginificant anti-HIV effect could be achieved only by AZT.
  • AZT is effective against HIV even in a concentraion of 1 to 5 ⁇ M, while it is atoxic under 20 to 50 ⁇ M.
  • the acyclic derivative obtained by opening the pyranoside ring is completely ineffective (J. Med. Che 32, 73-76, 1989).
  • the therapeutic effect also depends on the penetration of the compound into the cell and on the measure of the phosphorilation of the molecule, which results in the activation of the compound.
  • the phosphorilation of the different derivatives is carried out with different efficicacy, e.g. the 2',3'-dideoxy derivative is phosphorilated at significantly lower extent, thus its lower therapeutic activity may be attributed to this fact,
  • novel thimine derivatives of formula I wherein A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, are thermodinamically more stable than the known thimidine derivatives, they are more effective against HIV and their toxicity is lower.
  • the compounds of formula I which are not substituted with protecting group in the sugar moiety are active ingredients of antiviral compositions, while the compounds of formula I which are substituted with protecting group in the sugar moiety are intermediates for the preparation of the said compounds.
  • the acyloxy groups can be referred to.
  • the acyl moiety thereof may be an acyl moiety derived from substituted or unsubstituted aliphatic, aromatic, araliphatic or heterocyclic carboxylic acids, e.g. from acetic acid, benzoic acid, pyridine carboxylic acid or sulphonic acids.
  • the preferred protecting group is p-nitrobenzoyloxy group.
  • the 1-hexopyranosyl group of formula A may be a group derived from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, and/or any optical antipode (enantiomer) and/or anomer thereof.
  • the 1-hexopyranosyl group of formula A may carry hydrogen atom, halogen atom, azido group, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms substituted by halogen or alkoxy having 1 to 4 carbon atoms instead of one or more hydroxy groups being in position 2, 3 and/or 6.
  • the 1-hexopyranosyl group of formula A carries hydrogen atoms instead of hydroxy groups in positions 2 or 2 and 6 and azido group instead of hyroxy group in position 3.
  • the 1-hexopyranosyl ring of formula A may represent a group of formula A 1 ,
  • R 1 and R 2 may be the same or different, they
  • R 3 and R 4 are different, they stand for hydrogen atom or azido group
  • R 5 and R 6 are the same or different, they represent hydrogen atom, hydroxy, straight or branched alkyl having 1 to 4 carbon atoms with the provision that if R 5 and R 6 are the same, they represent hydrogen atom, R 7 is methyl optionally substituted by one or more halogen atoms or it is straight or branched alkoxy group having 1 to 4 carbon atoms
  • halogen atom fluorine, chlorine, bromine and iodine atom is understood.
  • alkyl having 1 to 4 carbon atoms examples include the methyl, ethyl, propyl, isopropyl, butyl, i- butyl, t-butyl, sec-butyl groups, from which methyl is preferred.
  • alkoxy having 1 to 4 carbon atoms the methoxy, ethoxy, propoxy, i-propoxy, butoxy, t- butoxy. sec-butoxy, i-butoxy groups can be mentioned, from which methoxy is preferred.
  • the preferred compounds of formula I are those, wherein A represents a group of formula A 1 , wherein
  • R 1 and R 2 are hydrogen
  • R 3 and R 4 are different, they represent hydrogen or azido, R 5 and R 6 are different, they represent hydrogen and
  • R 7 represents methyl
  • the most preferred compound of formula I are ⁇ - and ⁇ -1-(3-azido-2,3-6-trideoxi- ⁇ -L-ribo-hexopyranosyl)- thimine.
  • SZ 1-(3-azido-2,3-6- trideoxi- ⁇ -L-ribo-hexopyranosyl)-thimine
  • the infection with HIV was carried out by adding H9 cells infected with HTLV-III B cells to the uninfected H9 cells The ratio of the infected to the uninfected cells was 1:9. The density of the cultures was adjusted to 3x10 5 /ml. The multiplication of HIV was examined by indirect citoplasm immunofluorescence test The cultures were treated with an aqueous solution of SZ and AZT of a concentration of 25 and 100 ⁇ M four hours before the infection. The control cultures were not treated at all. The percentile rate of the cells comprising HIV antigene in the samples taken 4, 12, 20 and 28 after the infection was measured.
  • the 100 % of the cells was infected on the 12th day.
  • the ratio of the infected cells in the cultures treated with AZT and SZ was 50 % and 10 %, respectively.
  • the ratio of the infected cells was 100 %
  • this ratio was 70 % and 50 %, respectively.
  • the ratio of the infected cells increased to 100 % even in the cultures treated with SZ. According to this test SZ could more durably and more effectively inhibit the multiplication of HIV and the spreading of the infection than AZT.
  • the MT4 cells are characterized by growing in so-called clusters Due to the HIV-infection. such clusters disappear. In the presence of an effective active ingredient, the protection against the infection is indicated by the reappearance of the clusters.
  • mice treated with SZ have survived the mice treated with AZT with about 3 to 4 weeks.
  • the compounds of formula I are prepared by a) removing the protecting group(s) from a compound of formula I, wherein A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6 and at least one of the free hydroxy groups is protected with a protective group, and if desired separating the optical isomers in a manner known per se, or
  • A represents a substituted 1-hexopyranosyl ring which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, and optionally at least one of the free hydroxy groups is protected with a protective group
  • R is alkyl having 1 to 4 carbon atoms
  • R 1 and R 2 may be the same or different, they
  • R 3 and R 4 are different, they stand for hydrogen atom or azido group
  • R 5 and R 6 are the same or different, they represent hydrogen atom, hydroxy group or a protecting group for the hydroxy or straight or branched alkyl having 1 to 4 carbon atoms with the provision that if R 5 and R 6 are the same, they cannot be different from hydrogen atom,
  • R 7 is methyl optionally substituted by
  • halogen atoms or it is straight or branched alkoxy group having 1 to 4 carbon atoms
  • the monosacharide of formula A-OR may be of L or D configuration, preferably of L-configuration.
  • the reaction between the thimine and the compound of formula A-OR is preferably carried out in the presence of a sylilating agent, e.g. hexamethyl disylasane, trimethyl chlorosylane.
  • a sylilating agent e.g. hexamethyl disylasane, trimethyl chlorosylane.
  • the reaction is carried out in the presence of an inert organic solvent, e.g. acetone at a temperature of 60 to 150°C, preferably at the boiling point of the solvent.
  • the reaction can be facilitated by the addition of a promoter, e.g. trifluoromethane sulphonic acid trimethylsylil ester.
  • the product thus obtained is usually in racemic form and the optically active isomers can be separated from each-other before or after the splitting off of the protecting groups.
  • the removal of the protecting group(s) may be carried out by any conventional technique, e.g. by reduction or hydrolysis.
  • the protecting group is p-nitro-benzoyloxy group
  • it can be splitted off e. g. by the addition of sodium methylate in methanolic medium at a temperature of 10-50°C within 0.5 to 6 hours.
  • reaction is carried out by using a compound of formula A 1 -OR, wherein one of R 5 and R 6 is hydrogen atom, the other is p-nitrobenzoyloxy group, the other substituents are the same as defined hereinabove.
  • thimine and the compound of formula A 1 -OR are kept at a temperature of 100 to 150°C in the presence of an excess of sylilating agent, preferably hexamethyl disylasane and trimethyl chlorosylane, until a homogenous phase is formed.
  • the glycosylation can be carried out directly after the removal of the excess of sylilating agent in a suitable solvent, preferably in dry acetonitrile, preferably in the presence of promoter, e.g. trifluoromethane sulfonic acid trimethylsylil ester at the boiling point of the reaction mixture by eliminating air.
  • a suitable solvent preferably in dry acetonitrile, preferably in the presence of promoter, e.g. trifluoromethane sulfonic acid trimethylsylil ester at the boiling point of the reaction mixture by eliminating air.
  • reaction temperature is preferably 90 to 95°C.
  • the ⁇ -anomer of the protected compound of formula I thus obtained can be isolated in crystalline form from the reaction mixture and it can be separated from the ⁇ -anomer remaining in the solution.
  • the protected derivative of compound of formula I is purified on silicagel coloumn by using a 9:1 mixture of benzene and methanol as eluent, then the (6 -anomer recovered in crystalline form, is dissolved in dry methanol and the protective group is eliminated in the presence of catalytic amount of sodium methylate.
  • the product thus obtained can be further purified by coloumn chromatography .
  • the solvent is removed from the product obtained after glycosylation, then the acyloxy protecting group is saponified with the aid of dry methanolic ammonia solution or sodium methylate and the racemic product is separated to optically isomers by coloumn chromatography according to the above-described method.
  • the acyloxy group is removed at a temperature of 20 to 25°C within 2 to 6 hors, then the pH of the reaction mixture is adjusted between 5-6 by the addition of diluted mineral acid, acetic acid or cation exchange resin being in OH- cycle.
  • the solution is evaporated to dryness in vacuo, the residue is dried and if desired purified by e.g. coloumn chromatography.
  • the antiviral agents of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjuction with pharmaceuticals. They are generally admnistered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Usually they are administered orally or parenterally. In the latter case, the pharmaceutical composition should be in a sterile form.
  • Dosage forms (compositions) suitable for internal administration contain from about 10 to 500 milligramms, preferably 50 to 300 milligramms, more preferably 150 to 250 milligramms of active ingredient per unit.
  • the active ingredient will ordinarily be present in an amount of about 0.5 to 95 % by weight based on the total weight of the composition.
  • the dosage admnistered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration, age, health and weight of the recipient, nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, etc.
  • a daily dosage of active ingredient can be about 0.1 to 200 mg per kilogram of body weight.
  • a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • excipients such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like.
  • Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
  • subcutaneous, intramuscular or intravenous injections can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions.
  • Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
  • compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitane monolaurate, triethanolamine oleat ⁇ , etc.
  • non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitane monolaurate, triethanolamine oleat ⁇ , etc.
  • 0.3 millimoles of thimine and 0.15 millimoles of methyl-3-azido-4-0-p-nitrobenzoyl-2,3,6-trideoxy- ⁇ -L-ribo- hexopyranoside are treated with the mixture of 1.5 ml of hexamethyl disylazane and 0.15 ml of trimethyl chlorosylane at a temperature of 120 to 130°C for 3 hours until the reaction mixture turns to homogenous. Then the reaction mixture is dissolved in 3 ml of dry acetonitrile and the reaction is continued in the presence of 0.15 ml of trifluoromethane sulphonic acid trimethylsylil ester at a temperature of 90°C for 3 hours. Then further 0,15 ml of trifluoromethane sulphonic acid trimethylsylil ester are added and the reaction is followed for further 2 hours.
  • the glycosylation reaction is completed by this time.
  • the crude product obtained according to Example 1 is dissolved in a 9:1 mixture of benzene and methanol, then slowly filtered through a silica gel 60 bed, then the solvent is removed in vacuo The mixture of the - and - anomers is isolated, and the p-nitrobenzoyl group is removed in anhydrous methanolic medium with the aid of sodium methylate according to Example 1.
  • the saponified product is chromatographed on a silica gel 60 (40 x 2 cm) coloumn with a 9:1 mixture of benzene and methanol at a flow rate of 1 ml/30 minutes. The ⁇ -anomer formed in small amount left the coloumn in fractions 77 to 105.
  • the ⁇ -L-isomer is obtained after evaporation fractions 119 to 137 in vacuo.
  • the active ingredient is sieved and blended with the excipients
  • the mix is then filled into hard gelatine capsules using suitable machinery.
  • the active ingredient is blended with about 10 h of the microcrystalline cellulose then blended with the remaining microcrystalline cellulose and magnesium stearate. The blend is then compressed using 6 mm diameter punches into tablets on a suitable machine.
  • the tablets may be film coated with suitable film forming materials e.g. methyl cellulose or hydroxypropyl methylcellulose using standard techniques.
  • suitable film forming materials e.g. methyl cellulose or hydroxypropyl methylcellulose using standard techniques.

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Abstract

La présente invention concerne de nouveaux dérivés de thimine de formule (I), ses épimères et anomères, où A représente un composé cyclique de 1-héxopyranosyle substitué, lequel porte un substituant ne convenant pas à la formation d'esters de phosphate, à la place d'au moins un des groupes hydroxy en position 2, 3 et 6, et au moins un des groupes hydroxy est protégé à l'aide d'un groupe protecteur. Les composés de formule (I), qui sont exempts de groupes protecteurs, sont utiles contre le rétrovirus (VIH) et peuvent donc s'utiliser pour le traitement du SIDA.The present invention relates to new thimine derivatives of formula (I), its epimers and anomers, where A represents a cyclic compound of substituted 1-hexopyranosyl, which carries a substituent which is not suitable for the formation of phosphate esters, with the places at least one of the hydroxy groups in positions 2, 3 and 6, and at least one of the hydroxy groups is protected with the aid of a protective group. The compounds of formula (I), which are free of protective groups, are useful against the retrovirus (HIV) and can therefore be used for the treatment of AIDS.

Description

NOVEL THIMINE DERIVATIVES
Technical field
The present invention relates to novel thimine derivatives of formula I ,
their epimers and anomers, wherein
A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, and at least one of the hydroxy group is protected with a protecting group.
The compounds of formula I which are free of protecting groups, are useful against retrovirus (HIV) therefore they can be used for the treatment of AIDS.
The invention also relates to pharmaceutical compositions comprising the said compounds of formula I as active ingredient and to the preparation of the novel compounds.
Background art
The spreading of AIDS means gradually higher and higher problem all over the world.
The most effective drugs useful against DNA and RNA virus infections can be classified to the group of nucleosides. The most widely used drug against AIDS is 3,- azido-3'-deoxy-thimidine (AZT) of formula II
which is marketed by Wellcome under the trade mark Retrovir (J Org. Chem. 29, 2076, 1964: J . Med. Chem. 21, 109, 1978).
The anti-AIDS activity of AZT can be explained by the fact that it is able to inhibit the formation of the DNA of the virus either by competitive inhibition or by closing the DNA-chain of the virus.
In the cell AZT is phosphorilated and activated in the form of AZT-triphosphate, which is the analogon of timidine-triphosphate being one of the most important compound for building the DNA-chain. During the biological processes AZT-triphosphate competes with other nucleoside triphosphates for binding to reverse transcriptase and inhibits the building of nucleoside triphosphates into the DNA-chain. If AZT-triphosphate is built into the DNA chain, the enlargement of the chain is ceased and the inactive form of the virus is formed.
The reason is that AZT comprises an azido group in position C-3' in contradistinction to thimidine which azido group is not suitable for forming phosphate esters.
During the last years thimidin was modified not only at the aglicone, but at the -D-ribofuranosyl moiety
as well. As regarding the anti-HIV activity especially the dideoxy derivatives were promising, such thimidine derivatives were prepared wherein the C-3, hydroxy group of the sugar moiety is subsituted by azido or nitril groups (Proc Natl. Acad. Sci., USA, 83, 1911, 1986) or fluorine atom (Tetrahedron Letters, 44, 625, 1988). A β -D-glyceropenteno-furanosyl derivative, wherein the C-2, and C-3, carbon atoms are connected to each-other with double bond, was also prepared (Biochem. Pharmacol. 36 , 311, 1987),
The above-listed derivatives (including AZT) are pyrimidine nucleosides which sugar moiety is in the form of β -D-pentofuranosyl ring and they are substituted in position C-3, with such substituent which is not suitable for forming phosphate esters thus these derivatives are not useful for the further enlargement of the DNA chain of the virus. However, especially siginificant anti-HIV effect could be achieved only by AZT. According to in vitro experiments in T-cell culture, AZT is effective against HIV even in a concentraion of 1 to 5 μ M, while it is atoxic under 20 to 50 μ M. Surprisingly the acyclic derivative obtained by opening the pyranoside ring, is completely ineffective (J. Med. Che 32, 73-76, 1989).
The reason may be that the therapeutic effect also depends on the penetration of the compound into the cell and on the measure of the phosphorilation of the molecule, which results in the activation of the compound. According to the experiments the phosphorilation of the different derivatives is carried out with different efficicacy, e.g. the 2',3'-dideoxy derivative is phosphorilated at significantly lower extent, thus its lower therapeutic activity may be attributed to this fact,
In the course of our experiments our aim was to find such compounds which are more effective against HIV than the known compounds and which are less toxic, therefore they can more preferably be used for therapeutic treatment.
In order to achieve this aim we have targeted our efforts for preparing such molecules which are suitable for connecting to the reverse-transcriptase and for building into the DNA chain of the virus and simultaneously they are well phosphorilated in the cells.
Summary of the invention
Surprisingly it was found that the novel thimine derivatives of formula I, wherein A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, are thermodinamically more stable than the known thimidine derivatives, they are more effective against HIV and their toxicity is lower.
Contrary to the known anti-HIV agents, in the compounds of formula I not a five-membered sugar moiety, but a six-membered sugar moiety is attached to thimine. It could have been supposed by a man skilled in the art that a compound comprising a six-membered sugar moiety (therefore needs more space) can more difficultly penetrate into the cells than a compound comprising a five- membered sugar moiety. On the other hand, it could also have not been expected that this molecule will be phosphorilated as well or better than AZT.
Detailed description of the invention
The compounds of formula I which are not substituted with protecting group in the sugar moiety are active ingredients of antiviral compositions, while the compounds of formula I which are substituted with protecting group in the sugar moiety are intermediates for the preparation of the said compounds.
As optional protecting groups those groups can be mentioned, which can easily be removed by the conventional techniques. As an example for such protecting groups, the acyloxy groups can be referred to. The acyl moiety thereof may be an acyl moiety derived from substituted or unsubstituted aliphatic, aromatic, araliphatic or heterocyclic carboxylic acids, e.g. from acetic acid, benzoic acid, pyridine carboxylic acid or sulphonic acids. The preferred protecting group is p-nitrobenzoyloxy group.
The 1-hexopyranosyl group of formula A may be a group derived from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, and/or any optical antipode (enantiomer) and/or anomer thereof.
The 1-hexopyranosyl group of formula A may carry hydrogen atom, halogen atom, azido group, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms substituted by halogen or alkoxy having 1 to 4 carbon atoms instead of one or more hydroxy groups being in position 2, 3 and/or 6.
Preferably the 1-hexopyranosyl group of formula A carries hydrogen atoms instead of hydroxy groups in positions 2 or 2 and 6 and azido group instead of hyroxy group in position 3.
Preferably the 1-hexopyranosyl ring of formula A may represent a group of formula A1 ,
wherein
R1 and R2 may be the same or different, they
represent hydrogen atom or halogen atom with the provision that if R1 = R2, then both represent hydrogen atom,
R3 and R4 are different, they stand for hydrogen atom or azido group,
R5 and R6 are the same or different, they represent hydrogen atom, hydroxy, straight or branched alkyl having 1 to 4 carbon atoms with the provision that if R5 and R6 are the same, they represent hydrogen atom, R7 is methyl optionally substituted by one or more halogen atoms or it is straight or branched alkoxy group having 1 to 4 carbon atoms
Under the term "halogen atom" fluorine, chlorine, bromine and iodine atom is understood.
As examples for "alkyl having 1 to 4 carbon atoms", the methyl, ethyl, propyl, isopropyl, butyl, i- butyl, t-butyl, sec-butyl groups can be mentioned, from which methyl is preferred.
As examples for "alkoxy having 1 to 4 carbon atoms", the methoxy, ethoxy, propoxy, i-propoxy, butoxy, t- butoxy. sec-butoxy, i-butoxy groups can be mentioned, from which methoxy is preferred.
The preferred compounds of formula I are those, wherein A represents a group of formula A1 , wherein
R1 and R2 are hydrogen,
R3 and R4 are different, they represent hydrogen or azido, R5 and R6 are different, they represent hydrogen and
hydroxy. or both represent hydrogen, R7 represents methyl.
The most preferred compound of formula I are α- and β -1-(3-azido-2,3-6-trideoxi-β -L-ribo-hexopyranosyl)- thimine.
The biological activity of 1-(3-azido-2,3-6- trideoxi-β -L-ribo-hexopyranosyl)-thimine (referred to as SZ) was examined as follows:
A/ Inhibition of the multiplication of HIV The HIV multiplication inhibiting effect of SZ and AZT vas compared in vitro systems and in vivo test suitable for the modelling of HIV-infection.
The in vitro tests were carried out in H9 lymphoid cell cultures being susceptible to HIV-infection and on MT4 cells.
a) The infection with HIV was carried out by adding H9 cells infected with HTLV-III B cells to the uninfected H9 cells The ratio of the infected to the uninfected cells was 1:9. The density of the cultures was adjusted to 3x105/ml. The multiplication of HIV was examined by indirect citoplasm immunofluorescence test The cultures were treated with an aqueous solution of SZ and AZT of a concentration of 25 and 100 μ M four hours before the infection. The control cultures were not treated at all. The percentile rate of the cells comprising HIV antigene in the samples taken 4, 12, 20 and 28 after the infection was measured.
In the control cultures administered with no antiviral active ingredient, the 100 % of the cells was infected on the 12th day. On the 12th day the ratio of the infected cells in the cultures treated with AZT and SZ was 50 % and 10 %, respectively. On the 20th day in the cultures treated with AZT the ratio of the infected cells was 100 % , while in the cultures treated with 25 μ M and 100 μ M of SZ, this ratio was 70 % and 50 %, respectively. On the 28th day the ratio of the infected cells increased to 100 % even in the cultures treated with SZ. According to this test SZ could more durably and more effectively inhibit the multiplication of HIV and the spreading of the infection than AZT.
b) The MT4 cells are characterized by growing in so-called clusters Due to the HIV-infection. such clusters disappear. In the presence of an effective active ingredient, the protection against the infection is indicated by the reappearance of the clusters.
The phenomenon of reclustering of MT4 cells in the presence of SZ and AZT of a concentration of 1, 25, and 100 μ M, was examined once a day. As negative control, MT4 cells being not infected with HIV, were used. The maximume of the reclustering-inhibiting effect of HIV was observed on the 3rd day.
When SZ and AZT were used in a concentration of 100 μ M, there was no difference between the activites of SZ and AZT. This fact can probably be attributed to the slightly toxic effect of these compounds as the reclustering could be observed in only 75 % even in the uninfected cultures.
When SZ and AZT were used in a concentration of 25 μ m, SZ was more effective in provoking the reclustering. However, in the control culture only 75 % of the expected clusters reappeared.
When SZ and AZT were used in a concentration of 1 μM, both active ingredient inhibited the HIV-infection in 50 h.
2. In vivo experiment As there is no unambigously reliable animal model for examining HIV infection in animals, it is generally accepted, that the anti-AIDS active ingredients are tested on mice with the aid of an other retrovirus. the Rouscher- leukemia virus (RLV). The antiviral effect of AZT and SZ was tested on BaLB/c mice infected with RLV RLV causes splenomegalia in mice and the animals dye within 4 to 6 weeks due to erythroleukaemia.
6 week old, female BaLB/c mice were i.p. infected with 20 % RLV spleen suspension. SZ and AZT were given to the animals in the drinking water in a concentration of 0.1 mg/ml (it corresponds to about 145 mg/kg/day) 4 hours after the infection.
According to the results, AZT was able the inhibit the splenomegalia in some cases, while SZ has not shown such effect. However, the mice treated with SZ have survived the mice treated with AZT with about 3 to 4 weeks.
The above experiments clearly show that the antiviral effect of SZ exceeds that of AZT, and the survival of RLV-infected mice is lenghthened with about 3 to 4 weeks if SZ is given to them in the drinking water.
The compounds of formula I are prepared by a) removing the protecting group(s) from a compound of formula I, wherein A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6 and at least one of the free hydroxy groups is protected with a protective group, and if desired separating the optical isomers in a manner known per se, or
b) reacting thimine and a compound of formula A-OR, wherein A represents a substituted 1-hexopyranosyl ring which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, and optionally at least one of the free hydroxy groups is protected with a protective group, R is alkyl having 1 to 4 carbon atoms,
and if desired, removing the optional protecting groups from the compound of formula I thus obtained and/or if desired, separating the optical isomers in a manner known per se,
The preferred compounds of formula I can be prepared by
a) removing the protecting group from a compound of formula I, wherein A represents a group of formula A1 , wherein
R1 and R2 may be the same or different, they
represent hydrogen atom or halogen atom but both cannot represent halogen atom, R3 and R4 are different, they stand for hydrogen atom or azido group,
R5 and R6 are the same or different, they represent hydrogen atom, hydroxy group or a protecting group for the hydroxy or straight or branched alkyl having 1 to 4 carbon atoms with the provision that if R5 and R6 are the same, they cannot be different from hydrogen atom,
R7 is methyl optionally substituted by
one or more halogen atoms or it is straight or branched alkoxy group having 1 to 4 carbon atoms,
and if desired, separating the optical isomers, or
b) reacting thimine and a compound of formula A1-OR, wherein A1 is the same as defined hereinabove, R is alkyl having 1 to 4 carbon atoms, and if desired, removing the optional protecting groups from the compound of formula I thus obtained and/or separating the optical isomers in a manner known per se.
The monosacharide of formula A-OR may be of L or D configuration, preferably of L-configuration.
The reaction between the thimine and the compound of formula A-OR is preferably carried out in the presence of a sylilating agent, e.g. hexamethyl disylasane, trimethyl chlorosylane. The reaction is carried out in the presence of an inert organic solvent, e.g. acetone at a temperature of 60 to 150°C, preferably at the boiling point of the solvent. The reaction can be facilitated by the addition of a promoter, e.g. trifluoromethane sulphonic acid trimethylsylil ester.
The product thus obtained is usually in racemic form and the optically active isomers can be separated from each-other before or after the splitting off of the protecting groups. The removal of the protecting group(s) may be carried out by any conventional technique, e.g. by reduction or hydrolysis.
If the protecting group is p-nitro-benzoyloxy group, it can be splitted off e. g. by the addition of sodium methylate in methanolic medium at a temperature of 10-50°C within 0.5 to 6 hours.
If the reaction is carried out by using a compound of formula A1-OR, wherein one of R5 and R6 is hydrogen atom, the other is p-nitrobenzoyloxy group, the other substituents are the same as defined hereinabove. thimine and the compound of formula A1-OR are kept at a temperature of 100 to 150°C in the presence of an excess of sylilating agent, preferably hexamethyl disylasane and trimethyl chlorosylane, until a homogenous phase is formed.
The glycosylation can be carried out directly after the removal of the excess of sylilating agent in a suitable solvent, preferably in dry acetonitrile, preferably in the presence of promoter, e.g. trifluoromethane sulfonic acid trimethylsylil ester at the boiling point of the reaction mixture by eliminating air.
It is advantageous if the reaction is carried out in the presence of a molecular sieve and the promoter is added to the reaction mixture in small portions. The reaction temperature is preferably 90 to 95°C.
The β -anomer of the protected compound of formula I thus obtained can be isolated in crystalline form from the reaction mixture and it can be separated from the α -anomer remaining in the solution.
According to a preferred embodiment of the process, the protected derivative of compound of formula I is purified on silicagel coloumn by using a 9:1 mixture of benzene and methanol as eluent, then the (6 -anomer recovered in crystalline form, is dissolved in dry methanol and the protective group is eliminated in the presence of catalytic amount of sodium methylate. The product thus obtained can be further purified by coloumn chromatography .
According to an other embodiment of the process, the solvent is removed from the product obtained after glycosylation, then the acyloxy protecting group is saponified with the aid of dry methanolic ammonia solution or sodium methylate and the racemic product is separated to optically isomers by coloumn chromatography according to the above-described method.
The acyloxy group is removed at a temperature of 20 to 25°C within 2 to 6 hors, then the pH of the reaction mixture is adjusted between 5-6 by the addition of diluted mineral acid, acetic acid or cation exchange resin being in OH- cycle. The solution is evaporated to dryness in vacuo, the residue is dried and if desired purified by e.g. coloumn chromatography.
The antiviral agents of this invention can be administered by any means that produces contact of the active agent with the agent's site of action in the body of a mammal. They can be administered by any conventional means available for use in conjuction with pharmaceuticals. They are generally admnistered with a pharmaceutical carrier selected on the basis of the chosen route of administration and standard pharmaceutical practice. Usually they are administered orally or parenterally. In the latter case, the pharmaceutical composition should be in a sterile form.
Dosage forms (compositions) suitable for internal administration contain from about 10 to 500 milligramms, preferably 50 to 300 milligramms, more preferably 150 to 250 milligramms of active ingredient per unit. In these pharmaceutical compositions the active ingredient will ordinarily be present in an amount of about 0.5 to 95 % by weight based on the total weight of the composition.
The dosage admnistered will, of course, vary depending upon known factors, such as the pharmacodynamic characteristics of the particular agent, and its mode and route of administration, age, health and weight of the recipient, nature and extent of symptoms, kind of concurrent treatment, frequency of treatment, etc. Usually a daily dosage of active ingredient can be about 0.1 to 200 mg per kilogram of body weight.
For oral administration, a pharmaceutically acceptable composition is formed by the incorporation of any of the normally employed excipients, such as, for example pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talcum, cellulose, glucose, sucrose, magnesium, carbonate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.
For parenteral administration, subcutaneous, intramuscular or intravenous injections can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, glycerol, ethanol or the like.
In addition, if desired, the pharmaceutical compositions to be administered may also contain minor amounts of non-toxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, such as for example, sodium acetate, sorbitane monolaurate, triethanolamine oleatε, etc.
The invention is illustrated by the following, non-limiting examples.
Example 1
1-(3-azido-2,3,6-trideoxy-β-L-ribo-hexopyranosyl)-thimine
0.3 millimoles of thimine and 0.15 millimoles of methyl-3-azido-4-0-p-nitrobenzoyl-2,3,6-trideoxy- β-L-ribo- hexopyranoside are treated with the mixture of 1.5 ml of hexamethyl disylazane and 0.15 ml of trimethyl chlorosylane at a temperature of 120 to 130°C for 3 hours until the reaction mixture turns to homogenous. Then the reaction mixture is dissolved in 3 ml of dry acetonitrile and the reaction is continued in the presence of 0.15 ml of trifluoromethane sulphonic acid trimethylsylil ester at a temperature of 90°C for 3 hours. Then further 0,15 ml of trifluoromethane sulphonic acid trimethylsylil ester are added and the reaction is followed for further 2 hours.
According to the thin-layer chromatographic analysis, the glycosylation reaction is completed by this time.
Then the solvent is evaporated from the reaction mixture with the aid of benzene under vacuum and the evaporation residue is chromatographed on silicagel 60 coloumn (30 x 3 cm) by using a 9:1 mixture of benzene and methanol as eluent with a flow rate of 3-4 ml/30 minutes.
The fractions Nos. 24 to 32 are unified and evaporated under vacuum, thus the product precipitates from the solution in crystalline form and it is filtered off.
Yield: 85 %.
Melting point: 166-169°C.
Rf: 0.54 (with a 96:4 mixture of chloroform and ethanol) Elemεntar analysis for C18H18N6O7:
Calculated: N : 19.52 %
Found: N : 19.34 %.
IR (KBr, cm-1): 2100 (azido group), 1600-1720 (thimin carbo- nyl and ester carbonyl), 1605 (C=C), 1522,
1345 (nitro group), 945 (thimine skeleton).
H1 NMR and COSY (200 MHz, MeOD) δppm:
3,41-8,23 (4H,m,cλD2-fenil); 7,54 (1H,g, -CH=;, 4JCH,CH3=1,2 Hz;
6,02 (1H ,dd,H-1), 3J1,2ax=11,0 Hz, 3J1,Zeq=2,7 Hz: 5,11 (1H,dd,H-4, 3J3,4=3,2 Hz, 3J4,5= 9,8 Hz; 4,54 (1H,ddd,H-3) ; 4,33 (1H, dq, H-5); 2,35 (1H. ddd, H-2ax), 3Jax , 3=3,2 Hz, 2J2ax , 2eq= 13,9 Hz; 2,12 (1H,ddd, H-2eq); 1,90 (3H,d,timin-CH3); 1,29 (3H,d,CH3-5'), 3JMe,M-5=6,1 Hz. 0.80 Millimoles of the p-nitroherzoyl derivative
thus obtained are dissolved in 50 ml of dry methanol and 1.5 ml of 0,1 N methanolic sodium methylate solution are added, then the solution is left to stand for 2 hours. Then the pH of the solution is adjusted to 6 by acetic acid, then evaporated to dryness in vacuo. The ressidue is dried over potassium hydroxide and anhydrous calcium chloride in a vacuum desiccator. The white cristallyne substance thus obtaianed is washed with small amount of anhydrous ether and eluted on a silicagel 60 column by a 9:1 mixture of benzene and methanol.
Yield: 72 %.
Melting point: 199-201°C
[α ] 20 D : -24.5° (c = 0.51, methanol)
Rf: 0,20 (with a 9:1 mixture of benzene and methanol)
Water solubility: 5 mg/ml
Elementar analysis for C11H15N5O4.C6H6 (M = 359.40):
Calculated: C: 56.80 % H: 5-82 % N: 19.49,
Found: C: 54.82 H: 5.73 N: 19.79.
IR (KBr): 3400-3370 (OH), 3320 (NH), 2982 (CH3), 22930
(CH2), 1680-1610 (C=O, C=C), 940 (thimine skeleton) cm -1
H1 NMR (200 MHz, MeOD) δ ppm:
5,48 (1H,c,CH=), 4JH,CH3=1,2 Hz; 5,86 (1H,dd,H-1), 3J1,2ax=12 Hz, 3J1 2eq=2,5 Hz; 4,12 (1H, ddd H-2),3J3, 4=3,2 Hz, 3J3,2eq=3 Hz, 3J3,2eq=3 Hz; 3,51 (1H,dd,H-4), 34,5=9,5 Hz; 2,13 (1H, ddd, H-2ax), 2J2ax,2eq=12 Hz; 1,97 (1H, ddd, H-2 eq); 1,87 (3H,d,timin CH3); 1,27(3H,d,CH3-5). Example 2
Separation of 1-(3-azido-2,3,6-trideoxi-α and -β-L-ribo- hexopyranosyl)-thimine
The crude product obtained according to Example 1 is dissolved in a 9:1 mixture of benzene and methanol, then slowly filtered through a silica gel 60 bed, then the solvent is removed in vacuo The mixture of the - and - anomers is isolated, and the p-nitrobenzoyl group is removed in anhydrous methanolic medium with the aid of sodium methylate according to Example 1. The saponified product is chromatographed on a silica gel 60 (40 x 2 cm) coloumn with a 9:1 mixture of benzene and methanol at a flow rate of 1 ml/30 minutes. The α-anomer formed in small amount left the coloumn in fractions 77 to 105.
Yield: 15 % .
[α] 20D = +21 80° ( c = 0 83, methanol)
The β-L-isomer is obtained after evaporation fractions 119 to 137 in vacuo.
Yield: 65 %.
Melting point: 199 - 202°C
[α] 20D = -21.6° (c = 0.50, methanol)
Rf = 0.27 (9:1 mixture of benzene and methanol)
Example 3
Capsule for oral administration mg/capsule
Active ingredient 100 mg
Starch+ 75 mg
Magnesium stearate 2.5 mg
(+starch = a form of directly compressible starch)
The active ingredient is sieved and blended with the excipients The mix is then filled into hard gelatine capsules using suitable machinery.
Example 4
Tablet for oral administration
Active ingredient 5.0 mg
Magnesium stearate, BP 1.5 mg
Microcrystalline cellulose 150.0 mg
The active ingredient is blended with about 10 h of the microcrystalline cellulose then blended with the remaining microcrystalline cellulose and magnesium stearate. The blend is then compressed using 6 mm diameter punches into tablets on a suitable machine.
The tablets may be film coated with suitable film forming materials e.g. methyl cellulose or hydroxypropyl methylcellulose using standard techniques.

Claims

Patent claims
1 Novel thimine derivatives of formula I,
the. epimers and anomers thereof, wherein
A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6 and at least one of the free hydroxy groups is optionally protected with a protecting group.
2 The compound as claimed in claim 1 wherein the 1-hexopyranosyl group of formula A is a group derived from allose, altrose, glucose, mannose, gulose, idose, galactose, talose, and/or any optical antipode (enantiomer) and/or anomer thereof
3. The compound as claimed in claim 1 or 2 wherein A represents a 1-hexopyranosyl group which carries hydrogen atom, halogen atom, azido group, alkyl having 1 to 4 carbon atoms, alkyl having 1 to 4 carbon atoms substituted by halogen or alkoxy having 1 to 4 carbon atoms instead of one or more hydroxy groups being in position 2, 3 and 6.
4 The compound as claimed in any of the preceeding claims wherein A stands for a 1-hexopyranosyl group which carries hydrogen atoms instead of hydroxy groups in positions 2 and 6 and azido group instead of hyroxy group in position 3
5 The compound as claimed in any of the preceeding claims wherein A stands for a 1-hexopyranosyl ring of formula A1,
wherein
R1 and R2 may be the same or different, they
represent hydrogen atom or halogen atom with the provision that if R1 = R2, then both represent hydrogen atom,
R3 and R4 are different, they stand for hydrogen atom or azido group,
R5 and R6 are the same or different, they represent hydrogen atom, hydroxy, straight or branched alkyl having 1 to 4 carbon atoms or hydroxy-protecting group,
with the provision that if R5 and R6 are the same, they represent hydrogen atom, R7 is methyl optionally substituted by
one or more halogen atoms or it is straight or branched alkoxy group having 1 to 4 carbon atoms.
6. Racemic and optically active 1-(3-azido-2,3- 6-trideoxi-β-L-ribo-hexopyranosyl)-thimine
7. Antiviral pharmaceutical composition which comprises an antivirally effective amount of compound of formula I together with one or more pharmaceutically active carriers and/or excipients
8. The composition as claimed in claiam 7 which comprises a compound of formula I, wherein
R1 and R2 may be the same or different, they
represent hydrogen atom or halogen atom with the provision that if R1 = R2, then both represent hydrogen atom,
R3 and R4 are different, they stand for hydrogen atom or azido group,
R5 and R6 are the same or different, they represent hydrogen atom, hydroxy, straight or branched alkyl having 1 to 4 carbon atoms with the provision that if R5 and R6 are the same, they represent hydrogen atom,
R7 is methyl optionally substituted by
one or more halogen atoms or it is straight or branched alkoxy group having 1 to 4 carbon atoms, as active ingredient.
9. The composition as claimed in claim 7 or 8 which comprises racemic or optically active 1-(3-azido-2,3- 6-tridecxi- -L-ribo-hexopyranosyl)-thimine as active ingredient.
10. Process for the preparation of compounds of formula I,
their epimers and anomers thereof, wherein
A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6 and at least one of the free hydroxy groups is optionally protected with a protecting group
which comprises
a) removing the protecting group(s) from a compound of formula I, wherein A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6 and at least one of the free hydroxy groups is protected with a protective group, and if desired separating the epimers and/or anomers in a manner known per se, or
b) reacting thimine and a compound of formula A-OR, wherein A represents a substituted 1-hexopyranosyl ring, which carries a substituent being not suitable for forming phosphate esters instead of at least one of the hydroxy groups being in position 2, 3 and 6, and optionally at least one of the free hydroxy groups is protected with a protective group, R is alkyl having 1 to 4 carbon atoms, and if desired, removing the optional protecting groups from the compound of formula I thus obtained and/or if desored, separating the epimers and/or anomers in a manner known per se
EP90908614A 1989-05-31 1990-05-31 Novel thimine derivatives Withdrawn EP0426823A1 (en)

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HU278189 1989-05-31

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JPS60190791A (en) * 1984-03-09 1985-09-28 Kanto Ishi Pharma Co Ltd Sialic acid derivative and its preparation
EP0199451B1 (en) * 1985-03-16 1996-03-06 The Wellcome Foundation Limited Therapeutic nucleosides
PT82199B (en) * 1985-03-16 1990-11-07 Wellcome Found PROCESS FOR THE PREPARATION OF ANTIVIRAL NUCLEOSIDES AND PHARMACEUTICAL COMPOSITIONS CONTAINING THEM

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