EP0523160A1 - Derives de carbo-nucleoside - Google Patents

Derives de carbo-nucleoside

Info

Publication number
EP0523160A1
EP0523160A1 EP91907828A EP91907828A EP0523160A1 EP 0523160 A1 EP0523160 A1 EP 0523160A1 EP 91907828 A EP91907828 A EP 91907828A EP 91907828 A EP91907828 A EP 91907828A EP 0523160 A1 EP0523160 A1 EP 0523160A1
Authority
EP
European Patent Office
Prior art keywords
group
alkyl
derivative
mmol
mixture
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Withdrawn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
EP91907828A
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German (de)
English (en)
Inventor
Jo Klaveness
Kjell Undheim
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.)
FROUD Clive
GE Healthcare AS
Original Assignee
FROUD Clive
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 FROUD Clive, Nycomed AS filed Critical FROUD Clive
Publication of EP0523160A1 publication Critical patent/EP0523160A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/47—One nitrogen atom and one oxygen or sulfur atom, e.g. cytosine
    • 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
    • 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
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/52—Two oxygen atoms
    • C07D239/54—Two oxygen atoms as doubly bound oxygen atoms or as unsubstituted hydroxy radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D473/00—Heterocyclic compounds containing purine ring systems

Definitions

  • This invention relates to carbo-nucleoside derivatives; more particularly, it relates to antiviral esters, ethers and amides of carbo-nucleoside derivatives which, inter alia are active against human immunodeficiency virus (HIV) , the retrovirus which causes the disease acquired immunodeficiency syndrome (AIDS) .
  • HIV human immunodeficiency virus
  • AIDS disease acquired immunodeficiency syndrome
  • 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.
  • EP-A- 196185 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.
  • EP 277599 (Asahi) ; EP 325460 (Minnesota) ; EP 346132 (Minnesota) ; AIDS research and human retroviruses, 4., 457, (1988); Biochem. Pharmacol., 37., 2847, (1988); J. Med. Chem., 31, 2040, (1988); J. Med. Chem., 32., 1743, (1988); and J. Med. Chem., 3_C), 2131, (1987) .
  • acylation or alkylation of oxygen atoms in the 5'-position or in the purine or pyrimidine ring and/or acylation or alkylation of exocyclic or endocyclic nitrogen atoms present in the purine or pyrimidine ring may give significant advantages in terms of uptake, overall activity and site of action.
  • WO 88/07532 describes certain esters and amides of this type carrying acyl groups on the oxygen in at the 5' position or in the heterocycle or on exocyclic or endocyclic nitrogens; this principle has been extended to a wider range of related compounds.
  • the present invention provides carbo-nucleoside derivatives which correspond to the following general formula (I) :
  • A represents H or a substituent which is F or OH
  • B represents H or a substituent which is F
  • Y 1 represents H or a physiologically-acceptable group corresponding to the formula:
  • R 1 represents an optionally unsaturated and/or optionally substituted alkyl, alkyloxyalkyl or ' aryl group or an N-(C 1 -c 7 alkyl)-1,4-dihydropyridin-3-yl group or, when n represents 0, H;
  • R 2 and R 3 independently represents H, C 1 -C 6 alkyl C 2 -C 5 alkenyl or alkynyl or aryl; alternatively, two of such substituents may be replaced by an alkylidene group; and
  • X represents a group selected from:
  • Y 2 ,Y 3 and Y 4 independently have the same definition as Y 1 ;
  • R 4 represents H or -NY 3 Y 4 , Y 3 and Y 4 being as defined above; and
  • R 5 represents H or halogen, ⁇ -Cg alkyl, C 2 -C 6 alkenyl or alkynyl or trifluoromethyl; provided that at least one of Y 1 , Y 2 , Y 3 and Y 4 represents other than H and that, when all of Y 2 , Y 3 and Y 4 present represent H, then Y 1 represents R 1 (0) n CO(OCR 2 R 3 ) m wherein n and/or m represents
  • Preferred stereochemistry in the 1- and 4-position in the cyclopentenyl or cyclopentyl ring is cis, herein designated .
  • the preferred fluorine substitution in the 2-position preferably has the ⁇ -configuration and a hydroxy1 in the 3-position has the ⁇ -configuration.
  • the ring system thus corresponding to a 2'-deoxy-2-fluoroarabinoside.
  • a fluorine substitution in the 3-position preferably has the ⁇ - configuration corresponding to a 3'-deoxy-3-fluoro-riboside.
  • R 1 preferably represents an optionally unsaturated and/or optionally substituted alkyl or alkyloxyalkyl group containing from 1 to 20 carbon atoms which may be straight or branched, or an aryl group containing from 6 to 20 carbon atoms which may be mono- or poly-cyclic.
  • Substituents which may be present on the alkyl groups R 1 include aryl groups preferably having from 6 to 10 carbon atoms (as in aralkyl groupings) , hydroxy and carboxy groups.
  • Aryl groups include 5- or 6-membered heterocyclic aryl groups having one or more heteroatoms selected from 0, N and S, such as furyl, imidazolyl, pyrrolyl, pyridinyl and thienyl groups.
  • Substituents which may be present on such aryl groups include alkyl groups, e.g. having from 1 to 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 alkyl groups R 2 , R 3 and R 5 contain from 1 to 6 carbon atoms.
  • R 2 preferably represents a hydrogen atom.
  • R 3 preferably represents a hydrogen atom or more preferably a methyl or a phenyl group.
  • R 5 represents a halogen atom, it may be fluorine, chlorine, bromine or iodine.
  • R 5 preferably represents a hydrogen or chlorine atom or a methyl group.
  • R 1 in any of the groups Y 1 , Y 2 , Y 3 or Y 4 represents an N-alkyl- l,4-dihydropyridin-3-yl group
  • the alkyl group is preferably methyl .
  • the present compounds may carry more than one of the groups Y 1 , Y 2 , Y 3 and Y 4 .
  • m in the group Y 4 represents 0.
  • Groups Y 2 are preferably
  • the salts of the compounds (I) may be acid addition salts with organic or inorganic acids, for instance hydrochloric or phosphoric acid or methanesulphonic acid, ethanedisulphonic acid, 2-naphthalene sulphonic acid, pivalic acid and pal oic acid.
  • Antiviral counter-ions such as phosphonoformate 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.
  • Such salts may be formed by reaction of the compound (I) with an appropriate acid or base.
  • the present invention also relates to the use of above compounds (I) and/or salts therof in the manufacture of a composition for the treatment or prophylaxis of virus infections, in particular neurotropic retro viruses and especially HIV infections.
  • the present invention further relates to such compositions. They may be formulated in conventional manner by admixture of one or more compounds (I) and/or salts thereof with one or more excipients and/or carriers.
  • the present compounds (I) may not themselves be inhibitors of reverse transcriptase and may be converted in vivo to the parent nucleoside, for example.
  • Cleavage of the acyl substituents in the heterocycle is by esterases or amidases. The rate of cleavage will depend on the nature of the substituents or whether the acyl group is present on an ester, amide or urethane.
  • the heterocyclic substituted nucleosides with a free 5'-OH group may be substrates for the kinases as such or may be phosphorylated after initial acyl cleavage. Nevertheless, the substitution at the respective 0- and N- atoms gives surprising advantages in terms of uptake and sustained activity.
  • the compounds (I) are
  • the absorption rate may be optimised by careful choice of the substituent group to give the desired balance of lipophilicity and hydrophilicity.
  • the present compounds may penetrate the blood-brain barrier and thus permit treatment of the neurological disorders
  • neurotropic viruses e.g. retroviruses, such as HIV, and lentiviruses (Yarchoan et al.. The Lancet, January 17, 1987, page 132) .
  • retroviruses such as HIV
  • lentiviruses Yarchoan et al.. The Lancet, January 17, 1987, page 132
  • the present invention further relates to a method of treatment 30 of neurological disorders caused by neurotropic viruses wherein an effective dose of a compound (I) or a salt thereof is administered to a patient suffering from such a disorder.
  • compounds (I) may be prepared '35 in any convenient way, for example, by reaction of a compound corresponding to the following general formula (II) :
  • X 1 is as defined above for X, except that any of Y 1 , Y 2 , Y 3 and Y 4 may each additionally represent a protecting group; provided that at least one of Y 1 , Y 2 , Y 3 and Y 4 represents H; with a reagent serving to introduce a group R 1 (0) n C0. (0CR 2 R 3 ) m as defined above, followed, where required, by removal of any protecting group(s) and/or unwanted substituent(s) so introduced.
  • acylation or alkylation is effected while one or more groups Y 1 , Y 2 , Y 3 and Y 4 remain as hydrogen atoms
  • 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 alkoxycarbony1 group, the N-benzyloxycarbonyl group in cyclopentyl may readily be removed selectively using hydrogen and a noble metal catalyst, such as palladium.
  • Silyl protecting groups may also be used, especially for the 5'-oxygen atom, and include trialkylsilyl e.g.
  • 5'-0-monoalkylation is to be effected (i.e. introduction of a group Y 1 wherein m represents 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 alkylating agent.
  • a second OH group in the cyclopentyl prior protection of either OH group must be carried out.
  • 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 wherein L represents a leaving group.
  • 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. corresponds to the formula R-'-.O.CO-, then acylating agents include the haloformate esters, anhydrides 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.
  • 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, such as dimethylformamide and dimethylacetamide, or a halogenated hydrocarbon, such as dichloromethane.
  • Suitable acyloxyalkylating agents for the present purposes will in general correspond to the formula R 1 CO.O.CR 2 R 3 L or R 1 0-CO- OCR 2 R 3 L, wherein L represents a leaving group.
  • the group L may, for example, be a halogen atom, such as chlorine or bromine 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.
  • compositions according to the present 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 intraveneous injection and oil-based formulations for intramuscular injection. Suitable dosages will lie in the range of from 0.1 to 100 mg per kilogram of bodyweight per 24 hour period.
  • the present compositions may also contain other active antivirals for instance acyclovir, phosphonoformate, suramin, Evans Blue, interferons, AZT or the other example mentioned above.
  • the present invention is further illustrated by the following Examples:
  • the mixture is extracted with diethyl ether, the ether extracts washed (saturated NaCl) , dried, evaporated and the product fractionated by silica gel chromatography.
  • the desired product is eluated by chloroform:methanol (98:2 v/v).
  • the silyl group is removed by dissolution of the thus-obtained product (1 mmol) in THF (1 ml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (1 ml) .
  • the mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10 ml) , washed with water (2 ml) , dried (MgS0 4 ) , evaporated, and the product purified by chromatorgraphy on silica gel using chloroform:methanol (95:5 v/v).
  • the silyl group is removed by dissolution of the thus-obtained product (1 mmol) in THF (1 ml) and adding 0.25 M solution of tetrabutylammonium fluoride in THF (1 ml) .
  • the mixture is stirred at ambient temperature for 30 minutes, the solvent evaporated, the residue dissolved in chloroform (10 ml) , washed with water (2 ml) , dried (MgS0 4 ) , evaporated, and the product purified by chromatography on silica gel using chloroform:methanol (95:5 v/v) .
  • the 2-fluoro carbocyclic nucleosides are analogues of 2- fluoroarabinosyl pyrimidine or purine nucleosides:
  • the solvent was distilled off at reduced pressure, the product extracted into 15% ethanol in chloroform, the mixture filtered, the filtrate evaporated and the residue subjected to chromatography on silica gel using 15% ethanol in chloroform. Besides the title compound another product due to further alkylation was formed (described below) and was eluated before the title compound.
  • the product was a white solid, yield 8 mg.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Virology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Communicable Diseases (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Oncology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Molecular Biology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Saccharide Compounds (AREA)

Abstract

L'invention se rapporte à un dérivé de carbo-nucléoside, qui se caractérise en ce qu'il correspond à la formule générale (I), où: les pointillés représentent une insaturation éventuelle; A représente H ou un substituant pouvant être F ou OH; B représente H ou un substituant pouvant être F; Y1 représente H ou un groupe physiologiquement acceptable correspondant à la formule: R1(O)nCO(OCR2R3)m-, où n est égal à 0 ou à 1; m est égal à 0 ou à 1; R1 représente un groupe alkyle, alkyloxyalkyle ou aryle éventuellement substitué et/ou éventuellement insaturé ou un groupe N-(alkyle C1-C7)-1,4-dihydropyridine-3-yle ou lorsque n est égal à 0, R1 représente H; R2 et R3 représentent séparément H, un alkyle C1-C6, un alcényle C2-C6 ou un alkynyle ou un aryle; ou, deux de ces substituants peuvent remplacés par un groupe alkylidène; et X représente un groupe choisi parmi (A), (B), (C), (D), (E), (F), (G), (H), (I) et (J), où Y2, Y3 et Y4 ont séparément la même définition que Y1; R4 représente H ou -NY3Y4, Y3 et Y4 sont définis ci-dessus; et R5 représente H ou un halogène, un alkyle C1-C6, un alcényle C2-C6 ou un alkynyle ou un trifluorométhyle; à condition qu'au moins l'un des éléments Y1, Y2, Y3 et Y4 représentent d'autres composés que H et à condition que, lorsque tous les éléments Y2, Y3 et Y4 présents représentent H, alors Y1 représente R1(O)nCO(OCR2R3)m où n et/ou m est égal à 1; et/ou à des sels d'un tel dérivé.
EP91907828A 1990-04-04 1991-04-04 Derives de carbo-nucleoside Withdrawn EP0523160A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB9007569 1990-04-04
GB909007569A GB9007569D0 (en) 1990-04-04 1990-04-04 Carbo-nucleoside derivatives

Publications (1)

Publication Number Publication Date
EP0523160A1 true EP0523160A1 (fr) 1993-01-20

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Family Applications (1)

Application Number Title Priority Date Filing Date
EP91907828A Withdrawn EP0523160A1 (fr) 1990-04-04 1991-04-04 Derives de carbo-nucleoside

Country Status (7)

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EP (1) EP0523160A1 (fr)
JP (1) JPH05507267A (fr)
AU (1) AU7695991A (fr)
CA (1) CA2079815A1 (fr)
GB (1) GB9007569D0 (fr)
OA (1) OA09670A (fr)
WO (1) WO1991015488A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0630897A3 (fr) * 1993-06-25 1995-03-01 Bristol Myers Squibb Co 3-Hydroxy-4-hydroxyméthyl-2-methylène-cyclopentyl purines et pyrimidines.
EP2390257A1 (fr) * 1998-02-25 2011-11-30 Emory University 2'-Fluoronucléosides
JP2003508533A (ja) * 1999-09-10 2003-03-04 スティヒティング・レガ・ヴェー・ゼット・ウェー 炭素環式ヌクレオシドとその製造方法
KR101005299B1 (ko) * 2000-10-18 2011-01-04 파마셋 인코포레이티드 바이러스 감염 및 비정상적인 세포 증식의 치료를 위한 변형된 뉴클레오시드
CA2463719A1 (fr) 2003-04-05 2004-10-05 F. Hoffmann-La Roche Ag Analogues de nucleotides possedant des cycles a six chainons
WO2009009625A2 (fr) * 2007-07-09 2009-01-15 Eastern Virginia Medical School Dérivés nucléosidiques substitués ayant des propriétés antivirales et antimicrobiennes
JP5732453B2 (ja) 2009-06-25 2015-06-10 アルカーメス ファーマ アイルランド リミテッド Ｎｈ酸性化合物のプロドラッグ
US11273158B2 (en) 2018-03-05 2022-03-15 Alkermes Pharma Ireland Limited Aripiprazole dosing strategy

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NZ197458A (en) * 1980-06-23 1983-11-30 Univ Minnesota O-alkoxyalkanoyl derivatives of adenine nucleosides
US4396623A (en) * 1981-08-26 1983-08-02 Southern Research Institute Carbocyclic analogs of uracil nucleosides as antiviral agents
US4719214A (en) * 1985-07-25 1988-01-12 Southern Research Institute Carbocyclic analogues of thymine nucleosides
ATE108183T1 (de) * 1987-03-24 1994-07-15 Nycomed Imaging As 2',3'-dideoxyribofuranoxid-derivate.
US5015739A (en) * 1988-04-22 1991-05-14 Schering Corporation Processes for preparation of cyclopentyl purine derivatives

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9115488A1 *

Also Published As

Publication number Publication date
AU7695991A (en) 1991-10-30
OA09670A (en) 1993-05-15
JPH05507267A (ja) 1993-10-21
GB9007569D0 (en) 1990-05-30
WO1991015488A1 (fr) 1991-10-17
CA2079815A1 (fr) 1991-10-05

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