EP0437469A1 - Derives de nucleoside - Google Patents

Derives de nucleoside

Info

Publication number
EP0437469A1
EP0437469A1 EP89911035A EP89911035A EP0437469A1 EP 0437469 A1 EP0437469 A1 EP 0437469A1 EP 89911035 A EP89911035 A EP 89911035A EP 89911035 A EP89911035 A EP 89911035A EP 0437469 A1 EP0437469 A1 EP 0437469A1
Authority
EP
European Patent Office
Prior art keywords
groups
formula
group
hydrogen atom
compounds
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.)
Pending
Application number
EP89911035A
Other languages
German (de)
English (en)
Inventor
Jo Klaveness
Kjell Undheim
Frode Rise
Jostein Hatlelid
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.)
GE Healthcare AS
Original Assignee
Nycomed AS
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Nycomed AS filed Critical Nycomed AS
Publication of EP0437469A1 publication Critical patent/EP0437469A1/fr
Pending legal-status Critical Current

Links

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
    • 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
    • C07H19/16—Purine radicals

Definitions

  • This invention relates to antiviral compounds and more particularly to esters and amides of nucleoside derivatives which are active against human immuno ⁇ deficiency virus (HIV) , the retrovirus which causes the disease AIDS.
  • HIV human immuno ⁇ deficiency virus
  • AIDS is a relatively new disease. It was discovered in 1981 and several thousand cases of the disease have been diagnosed since then. It is anticipated that the number will increase to at least several hundred thousand in the next few years. The situation is especially severe in several Central African countries. AIDS is fatal, and about 40% of all diagnosed cases have ended in death. Of those diagnosed as having AIDS three or more years ago it is estimated that 85% are now dead.
  • Clinical symptoms are weight loss, chronic diarrhoea, persisting fever and opportunistic infections due to loss of T-cells, thus upsetting the overall balance of the immune system. The patient loses his/her ability to combat otherwise insignificant infections.
  • European Patent Application No. 0196185A describes pharmaceutical compositions containing AZT, a known compound which has shown great promise in the treatment of AIDS and AIDS- related complex. It is believed that AZT works by inhibiting reverse transcriptase, a vital enzyme in the life cycle of retroviruses.
  • European Patent Application No 0206497A discloses 2' ,3'-dideoxyribofuranoside derivatives of cytosine or purine bases as antiviral compounds. While there is reference to esters of these compounds as possible metabolic precursors, there is no suggestion that esters would possess any advantageous properties compared with the parent 5'-hydroxy compounds and no esters are specifically named or their synthesis exemplified. There is no reference to any corresponding thymidine compounds or of any nucleoside derivatives having N-acylated amino groups.
  • Y is a hydrogen atom or a physiologically acceptable group of the formula R 1 (O) n CO(OCR 2 R 3 ) -
  • n 0 or 1
  • m 0 or 1
  • R is an optionally substituted alkyl or aryl group or, where n is 0, a hydrogen atom.
  • R 2 and R3 are independently hydrogen atoms or lower alkyl groups; and
  • X is a group selected from
  • R4 is a hydrogen atom or a group -NY 3Y4, where Y3 and Y4 have the above meanings and R is a hydrogen atom or a lower alkyl group, with the proviso that at least one of the groups
  • Y , Y , Y and Y is other than hydrogen, and that
  • any groups Y 1, Y3, and Y4 which are present are either hydrogen atoms or groups R 1 (O) CO(OCR2R3) where m is 0 then Z is an azido group) and/or salts thereof.
  • compositions for the treatment or prophylaxis of retrovirus infections in particular neurotropic viruses and especially HIV infections.
  • Such compositions also form part of the invention.
  • the group R is preferably an alkyl group containing 1-20 carbon atoms which may be straight or branched, or an aryl group which may contain 6 to 20 carbon atoms and may be mono- or poly-cyclic.
  • Substituents which may be present on the alkyl groups R include aryl groups preferably having 6-10 carbon atoms (as in aralkyl groupings) , hydroxy and carboxy groups.
  • Aryl groups include heterocyclic aryl groups such as pyridinyl and thienyl groups.
  • Substituents which may be present on aryl groups include alkyl groups, e.g. having 1-6 carbon atoms, hydroxy and carboxy groups. Examples of such groups include methyl, ethyl, propyl, t-butyl, pentyl, stearyl, palmityl, carboxyethyl and benzyl groups.
  • the lower alkyl groups R 2, R3 and R5 preferably
  • R 2 contain 1-6 carbon atoms.
  • R preferably represents a hydrogen atom.
  • R 3 i.s preferably a hydrogen atom or more preferably a methyl group
  • R is preferably a hydrogen atom or a methyl group.
  • the compounds of the invention may carry more than one of the groups Y 1, Y2, Y3 and Y4.
  • the compounds of formula 1 may carry more than one of the groups Y 1, Y2, Y3 and Y4.
  • Groups Y2 are preferably of the formula
  • R 1 .CO- R 1 CO.O.CR 2 R 3 or R ⁇ -.O.CO.O.CR ⁇ 3 -.
  • the salts of the compounds of formula (I) may be acid addition salts with organic or inorganic acids, for instance hydrochloric or phosphoric acid or methanesulphonic acid, ethane disulphonic acid, 2-naphthylsulphonic acid, pivalic acid and pamoic acid.
  • Antiviral counter-ions such as phosphono- formate or suramin may also be used.
  • Organic or inorganic base salts may be formed with acidic groups present in the molecule; suitable counter- ions include alkali metal ions such as sodium and potassium ions, divalent ions such as calcium and zinc ions and organic ions such as tetraalkylammonium and choline or ions derived from meglumine or ethylene- diamine. Salts according to the invention may be formed by reaction of the compound of formula (I) with an appropriate acid or base.
  • compositions according to the invention may be used in the treatment and/or prophylaxis of retrovirus infections, in particular HIV infections, and such a method forms a further feature of the - 6 - invention.
  • They may be formulated in conventional manner by admixture of one or more compounds of formula (I) as defined above with excipients and/or carriers.
  • the compounds of formula (I) are not themselves inhibitors of reverse transcriptase but are converted J i vivo to the 5-hydroxy-2' ,3'- dideoxynucleosides. Nevertheless the substitution at the respective 0- and N- atoms gives surprising advantages in terms of uptake and sustained activity.
  • the compounds of formula (I) are more lipophilic than the parent compounds and this permits rapid and efficient absorption from the gastro-intestinal tract; the absorption rate may be optimised by careful choice of the substituent group to give the desired balance of lipophilicity and hydrophilicity.
  • the lipophilic nature of the compunds of formula (I) also gives the molecules the ability to penetrate the cell membranes more easily and leads to higher intracellular concentrations, giving an improved dose/effect ratio.
  • the steady hydrolysis of the compounds ensures a sustained concentration of the active compound in the cell and thereby permits longer intervals between doses, overcoming a significant drawback of the prior art compounds such as AZT.
  • the compounds according to the invention can penetrate the blood-brain barrier and thus permit treatment of the neurological disorders which have been observed to be related to the presence of neurotropic viruses, e.g. retroviruses such as HIV, and lentiviruses (Yarchoan et al, The Lancet, January 17, 1987, page 132).
  • neurotropic viruses e.g. retroviruses such as HIV, and lentiviruses
  • This is a significant advantage compared to the corresponding unsubstituted compounds or other antiviral compounds and is not referred to anywhere in the prior art, for instance in EP-A-0196185 or in EP-A-0206497. Attempts have been made to treat these neurological disorders with AZT but with limited success.
  • the invention thus further provides a method of treatment of neurological disorders caused by neurotropic viruses wherein an effective dose of a compound of formula (I) or a salt thereof is administered to a patient suffering from such a disorder.
  • X is as hereinbefore defined for X except that any of the groups Y 1, Y2, Y3 and Y4 may each additionaly represent a protecting group, with the proviso that at least one of Y 1, Y2, Y3 and Y4 is a hydrogen atom] with a reagent serving to introduce a group
  • Y , Y , Y and Y remain as hydrogen atoms, it may be desirable to protect the latter first, to form a compound of formula (I) in which one or more of Y 1, Y2, Y3 and Y4 are protecting groups, these being removed after introduction of the desired acyl or ether group.
  • Such protecting groups may, in fact, be conventional N- or O-protecting groups including groups R OCO- which may be selectively removed in the presence of the group(s) intended to remain.
  • an N-benzyloxycarbonyl may be used to protect an exocylic amino group and if the group which is intended to remain is not one which is removable by reduction, for example a straight chain alkoxycarbonyl group, the N-benzyloxycarb group can readily be removed selectively using hydrogen and a noble metal catalyst such as palladium.
  • Trisubstituted silyl groups may also be used as protecting groups, especially for the 5'-oxygen atom, and include trialkylsilyl e.g. trimethylsilyl, dimeth 1-t-butylsilyl, and thexyldimethyl silyl groups.
  • trialkylsilyl e.g. trimethylsilyl, dimeth 1-t-butylsilyl, and thexyldimethyl silyl groups.
  • Y and Y are hydrogen, and a mixture of compounds is produced, the individual components may readily be separated, for example by chromatography.
  • 5'-0-monoalkylation is to be effected (i.e. introduction of a group Y in which m is 1) it is especially effective to form a dianion of the nucleoside (e.g. by reacting with sodium hydride) and to react this with one equivalent of the alk lating agent. It is of course, still possible to use protected forms of the nucleoside, for example by acylation of a nucleophilic nitrogen atom before salt formation with sodium hydride.
  • Suitable acylating agents for use in the reaction have the formula Ac-L where L is a leaving group.
  • suitable acylating agents include the acid halides and acid anhydrides advantageously in the presence of a base; when the acyl group is derived from a carbonic acid, i.e. is of formula R .0.C0-, then acylating agents include the haloformate esters and reactive carbonic acid diesters.
  • the halogen may, for example, be chlorine or bromine.
  • the base for use in the reaction with the acid halide or anhydride may, for example, be a heterocyclic base such as pyridine or 4-dimethylaminopyridine.
  • a heterocyclic base such as pyridine or 4-dimethylaminopyridine.
  • the latter increases the speed of the reaction and may be used advantageously with pyridine.
  • the reaction will normally be carried out in the presence of an inert solvent e.g. a substituted amide solvent such as dimethylformamide, dimethyl- acetamide or a halogenated hydrocarbon such as dichloromethane.
  • N-acyl groups R CO- may be removed selectively, for example by reaction with a phenol such as p- methyl-phenol. where multiple substitution is to be effected, a stronger base such as sodium hydride may be advantageous.
  • Suitable acyloxyalkylating agents for use in the invention will in general be of the formula R 1 C0.0.CR 2 R 3 L or R 1 0.C0.0.CR 2 R 3 L, where L is a leaving group.
  • the group L may for example, be a halogen atom such as a chlorine or bromine atom or a hydrocarbon-sulphonyloxy group such as a tosyloxy or mesyloxy group.
  • the alkylation reaction will normally be effected in the presence of a base, conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
  • a base conveniently an inorganic carbonate such as potassium carbonate or an alkali metal hydride such as sodium hydride.
  • Bases as used for acylation may also be useful.
  • Y 1, Y2, Y3 and Y4 are all hydrogen atoms are well described in the literature - see, for instance,
  • Y are other than hydrogen may be prepared by preliminary reactions as described above.
  • the pharmaceutical compositions according to the invention may be formulated conventionally by means well known in the art, and may be administered by any convenient route, for instance orally, rectally, vaginally, intraveneously or intramuscularly.
  • suitable formulations include tablets and capsules, aqueous formulations for intravenous injection and oil-based formulations for intramuscular injection. Suitable dosages will lie in the range 0.1 to lOOmg per kilogram of bodyweight per 24 hour period.
  • the compositions according to the invention may also contain other active antivirals for instance acyclovir, phosphonoformate, suramin, Evans Blue, inte ferons or AZT.
  • 2' ,3 '-dideoxycytidine (0.2 mmol) is added to a suspension of 5% palladium on charcoal (25 mg) in ethanol (25 ml) , the air removed under vacuum and the mixture hydrogenated at atmospheric pressure until the hydrogenolysis is completed (ca. 3 hours) .
  • the stirred suspension is subjected to hydrogenolysis at atmospheric pressure using a Brown apparatus where the H 2 ⁇ gas is generated in a controlled manner by the addition of 3N HC1 to a solution of sodium borohydride in a separate compartment.
  • reaction is run for 1 hour at room temperature, the mixture filtered through a thin bed of Celite, the filtrate evaporated and the product purified by chromatography on a silica gel column using
  • 5'-O-propionyl-3 '-deoxythymidine (0.063 g, 0.223 mmol) and potassium carbonate (0.0339 g, 0.245 mmol) were suspended in DMF (2ml) and stirred at room temperature under nitrogen for 1.5 hours.
  • the powder is mixed and filled into hard gelatin capsules (Capsugel Size 00) .
  • White soft paraffin is melted and incorporated into the liquid paraffin and stirred until the mixture is cold.
  • Active compound is triturated with a portion of the basis and gradually the remainder of the basis was incorporated.
  • the ointment is filled into lacquered aluminium tubes (20 g) and sealed. The ointment contains 0.1 % active compound. - 23 -
  • Polysorbate 80, Sorbitol and benzyl alcohol are dissolved in 500 ml distilled water. Active compound is screened through a 0.15 mm sieve and dispersed in the solution under vigorous stirring. The pH is adjusted to 4.5 by dropwise addition of 1M HC1. Water is added to 1000 ml, the suspension was filled in 1 ml vials The vials are sterilized by y -radiation. Each vial contains 200 mg active compound.
  • Active compound and lactose are screened through a 0.15 mm sieve and mixed together for 10 minutes.
  • the mixed powder is wetted with an aqueous solution of polyvinyl-pyrrolidone.
  • the mass is granulated, and the dried (40 °C) granulate is mixed with starch, talcum powder and magnesium stearate.
  • the granulate is compressed into tablets.
  • the tablet diameter is 11 mm, the tablet weight is 350 mg and each tablet contains 200 mg active compound.
  • Methyl £-hydroxybenzoate (70 mg) and propyl £-hydroxy- benzoate (15 mg) are dissolved in water (100 ml) at 90 °C. After cooling to 30 °C methyl cellulose (2g) is added and the mixture is agitated for 3 hours. 1 gram active compound are screened through a 0.15 mm sieve, and dispersed in the solution under vigorous stirring. The suspension is filled in a 100 ml tube. The suspension contain 10 mg active compound/ml.
  • Carboxymethyl cellulose, sorbitol and sodium benzoate are dissolved in water with stirring _for 2 hours. A solution of the essences in ethanol is added. Active compound is screened through a 0.15 mm sieve and dispersed in the solution under vigorous stirring. The suspension (10 gram) is filled in a 20 ml tube. Each tube contains 200 mg active compound.
  • Pharmaceutical Example G Preparation of injection solution
  • Active compound hydroxypropyl-methylcellulose and lactose are mixed together for 20 minutes and granulated with a solution of povidone. Magnesium stearate is added and the mixture is compressed into tablets.
  • the tablet diameter is 13 mm
  • the tablet weight is 700 mg
  • each tablet contains 500 mg active compoun .

Abstract

Les composés décrits sont représentés par la formule (I), où Y1 représente un atome d'hydrogène ou un groupe acyle ou acyloxyalkyle; Z représente un atome d'hydrogène ou un groupe azido; et X représente une base de purine ou de pyrimidine ou un dérivé ester, amide ou acyloxyalkyle d'une telle base. Ces composés ont une action antivirale.
EP89911035A 1988-10-05 1989-10-05 Derives de nucleoside Pending EP0437469A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB888823320A GB8823320D0 (en) 1988-10-05 1988-10-05 Chemical compounds
GB8823320 1988-10-05

Publications (1)

Publication Number Publication Date
EP0437469A1 true EP0437469A1 (fr) 1991-07-24

Family

ID=10644727

Family Applications (2)

Application Number Title Priority Date Filing Date
EP89911035A Pending EP0437469A1 (fr) 1988-10-05 1989-10-05 Derives de nucleoside
EP89202508A Expired - Lifetime EP0362967B1 (fr) 1988-10-05 1989-10-05 Dérivés de nucléosides

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP89202508A Expired - Lifetime EP0362967B1 (fr) 1988-10-05 1989-10-05 Dérivés de nucléosides

Country Status (14)

Country Link
EP (2) EP0437469A1 (fr)
JP (1) JPH04500968A (fr)
AT (1) ATE111104T1 (fr)
AU (1) AU617543B2 (fr)
DE (1) DE68918036T2 (fr)
DK (1) DK58791A (fr)
ES (1) ES2058481T3 (fr)
FI (1) FI92491C (fr)
GB (1) GB8823320D0 (fr)
NO (1) NO176052C (fr)
NZ (1) NZ230919A (fr)
OA (1) OA09642A (fr)
WO (1) WO1990004602A1 (fr)
ZA (1) ZA897594B (fr)

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2841074A (en) * 1954-09-23 1958-07-01 Thorell & Persson Ab Sausage grilling and vending machine
DK156450C (da) * 1986-08-29 1990-01-15 Autochef Aps Apparat til successiv tilberedning og udlevering af foedevareportioner, navnlig moentbetjent burgerautomat med mikroboelgeovn
ATE108183T1 (de) * 1987-03-24 1994-07-15 Nycomed Imaging As 2',3'-dideoxyribofuranoxid-derivate.
GB8815241D0 (en) * 1988-06-27 1988-08-03 Wellcome Found Antiviral combinations & compounds therefor
GB8823319D0 (en) * 1988-10-05 1988-11-09 Nycomed As Chemical compounds
GB8904855D0 (en) * 1989-03-03 1989-04-12 Beecham Group Plc Pharmaceutical treatment
KR910007655A (ko) * 1989-10-03 1991-05-30 엠. 피. 잭슨 치료용 뉴클레오시드
EP0500610A1 (fr) * 1989-11-06 1992-09-02 Nycomed Imaging As Derives de nucleosides
WO1991015498A2 (fr) * 1990-04-04 1991-10-17 Nycomed Imaging As Derives nucleosidiques
DE4110977A1 (de) * 1991-04-05 1992-10-08 Bayer Ag Substituierte 2',3'-didesoxy-5-trifluormethyluridine, verfahren zu ihrer herstellung und ihre verwendung in arzneimitteln

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2181128A (en) * 1985-09-17 1987-04-15 Wellcome Found 3'-azidonucleosides
DE3705794A1 (de) * 1987-02-24 1988-09-01 Bayer Ag Verfahren zur herstellung von 1-(3-azido-2,3-didesoxy-ss-d- erythropentofuranosyl)pyrimidinen sowie neue zwischenprodukte
ATE108183T1 (de) * 1987-03-24 1994-07-15 Nycomed Imaging As 2',3'-dideoxyribofuranoxid-derivate.
GB8712691D0 (en) * 1987-05-29 1987-07-01 Wellcome Found Therapeutic nucleosides
ZA886890B (en) * 1987-10-09 1989-05-30 Hoffmann La Roche Novel dideoxycytidine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9004602A1 *

Also Published As

Publication number Publication date
AU4333889A (en) 1990-05-14
DE68918036T2 (de) 1995-01-26
EP0362967B1 (fr) 1994-09-07
DK58791D0 (da) 1991-04-03
ATE111104T1 (de) 1994-09-15
GB8823320D0 (en) 1988-11-09
FI911621A0 (fi) 1991-04-04
DE68918036D1 (de) 1994-10-13
ZA897594B (en) 1990-07-25
NO911322L (no) 1991-06-04
EP0362967A1 (fr) 1990-04-11
AU617543B2 (en) 1991-11-28
NO176052B (no) 1994-10-17
NZ230919A (en) 1991-10-25
ES2058481T3 (es) 1994-11-01
OA09642A (en) 1993-04-30
FI92491C (fi) 1994-11-25
DK58791A (da) 1991-04-03
NO911322D0 (no) 1991-04-04
JPH04500968A (ja) 1992-02-20
FI92491B (fi) 1994-08-15
WO1990004602A1 (fr) 1990-05-03
NO176052C (no) 1995-01-25

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