PT93094B

Substituted-1,3-oxathiolanes with antiviral properties

Abstract

Disclosed are compounds of the formula <CHEM> wherein R1 is hydrogen; R2 is a purine or pyrimidine base or an analogue or derivative thereof; Z is S, S=O or SO2; and pharmaceutically acceptable derivatives thereof. Also described are use of the compounds as antiviral agents, pharmaceutical formulations, and methods for the preparation of the compounds.

PT93094B, drawing sheet 1 — Sheet 1 of 73

Term

Term ended

Expired 8 February 2005, 21.6 years ago.

15 claims: 4 independent, 11 dependent

1
- Process for the preparation of compounds of general formula in which 1.- Processo para a preparaçao de compostos de fórmula geral na qual R representa um átomo de hidrogénio, r2 representa uma base purínica ou pirimidínica ou um seu análogo ou derivado, R represents a hydrogen atom, r2 represents a purine or pyrimidine base or an analogue or derivative thereof, Z representa um átomo de enxofre ou um grupo S=0 ou so2, dos seus isómeros geométricos e ópticos e misturas destes isómeros e ainda derivados de todos estes compostos, aceitáveis sob o ponto de vista farmacêutico, caracterizado pelo facto (a) de se fazer reagir um composto de fórmula geral Rl° (VIII) Z represents a sulfur atom or a group S = 0 or so2, its geometric and optical isomers and mixtures of these isomers and still derived from all these compounds, pharmaceutically acceptable, characterized by the fact (a) that a compound of general formula is reacted Rl (VIII) -58in which -58na qual R ^ represents a hydrogen atom or a hydroxy protecting group, R^ representa um átomo de hidrogénio ou um grupo protector do radical hidroxi, L representa um átomo ou um grupo eliminãvel, L represents an atom or a leaving group, Z has the meanings defined before, on a general formula basis Z tem os significados definidos antes, com uma base de fórmula geral R ^-H in which R^-H na qual R2 has the meanings defined before; R2 tem os significados definidos antes; (b) de se realizar uma interconversão no grupo da base de um composto de fórmula geral I em um outro composto de fórmula geral I; (b) performing an interconversion in the base group of a compound of formula I into another compound of formula I; (c) de se fazer reagir um composto de fórmula geral (c) reacting a compound of the general formula HO (IX) HO (IX) HZ in which HZ na qual R2 and Z have the meanings defined before, with a compound of general formula R2 e Z têm os significados definidos antes, com um composto de fórmula geral PO. POWDER. (X) (X) CHO in which CHO na qual P representa um grupo protector, ou (d) de se converter um composto de' fórmula geral na qual P represents a protecting group, or (d) to convert a compound of the general formula in which R ^ and Z have the meanings defined above, in a compound of formula I; R^ e Z têm os significados definidos antes, em um composto de fórmula geral I; and, if necessary, subjecting the compound prepared in stages (a) to (d) to one or two of the following reactions:e de se submeter, eventualmente, o composto preparado nas fases (a) a (d) a uma ou ãs duas reacções seguintes: (i) elimination of any protecting group;(i) eliminação de qualquer grupo protector;(ii) conversão de um composto de fórmula geral I ou um seu sal em um sal aceitável sob o ponto de vista farmacêutico. (ii) converting a compound of formula I or a salt thereof into a pharmaceutically acceptable salt.
10
- Process for the preparation of intermediate compounds of general formula 10.- Processo para a preparação de compostos intermédios de fórmula geral R, 0 (VIII) in which R,0 (VIII) na qual R4 represents a hydrogen atom or a hydroxy radical protecting group;R^ representa um átomo de hidrogénio ou um grupo protector do radical hidroxi;L representa um átomo de iodo, bromo ou cloro, um grupo alcoxicarbonilo ou um grupo de fórmula geral —OR na qual R representa um- grupo alquilo eventualmente substituído ou eventualmente saturado ou acilo aromático ou alifático eventualmente saturado ou eventualmente substituído;e L represents an iodine, bromine or chlorine atom, an alkoxycarbonyl group or a group of the general formula —OR in which R represents an optionally substituted or optionally saturated or optionally saturated or optionally substituted aromatic or aliphatic acyl group;and Z has the meanings defined above, characterized by the fact that an aldehyde of formula Z tem os significados definidos antes, caracterizado pelo facto de se fazer reagir un aldeído de fórmula C6H5COOCK2CHO (VII) com um mercapto-acetal de fórmula hsch2ch(oc2h5)2 (VI) no seio de um dissolvente orgânico compatível como, por exemplo, tolueno e na presença de um catalisador ãcido como, por exemplo, o ácido p-toluenosulfónico ou um ãcido de Lewis como, por exemplo, cloreto de zinco. Ç6H5COOCK2CHO (VII) with a mercapto-acetal of formula hsch2ch (oc2H5)2 (VI) in a compatible organic solvent such as, for example, toluene and in the presence of an acid catalyst such as, for example, p-toluenesulfonic acid or a Lewis acid such as, for example, zinc chloride.
11
- Process for the preparation of compounds of general formula (IV) in which 11.- Processo para a preparação de compostos de fórmula geral (IV) na qual W representa um anião PO.- ou SPOr ou um gruoo de fórmula W represents a PO anion.- or SPOr or a formula group 0 0 4 3 0 0 4 3 II II qeral -O-C-(CH_) -C-0- na aual n representa um numero 2 n * inteiro de 1 a 10; II qeral -OC- (CH_) -C-0- naual n represents an integer 2 n * number from 1 to 10; J representa um nucleosido ou um seu análogo ou derivado; J represents a nucleoside or an analogue or derivative thereof; Z representa um átomo de enxofre ou um grupo S=0 ou SO?:e R2 representa uma base purínica ou pirimidínica ou um seu análogo ou derivado, caracterizado pelo facto de se esterificar cada grupo carboxilo ,ζ de um ãcido policarboxílico com um composto de fórmula geral I ou outros nucleosidos ou análogos e os seus derivados. Z represents a sulfur atom or a group S = 0 or SO ?: and R2 represents a purine or pyrimidine base or an analog or derivative thereof, characterized in that each carboxyl group is esterified, ζ of a polycarboxylic acid with a compound of formula I or other nucleosides or analogs and their derivatives.
14
Process according to any of the claims 14. - Processo de acordo com uraa qualquer das reivindicações 1 to 9 and 13, characterized in that a compound of general formula VIII, mentioned above, is reacted in step (a) with a silylated purine or pyrimidine base in a compatible solvent and in the presence of an acid Lewis or trimethylsilyltriflate. 1 a 9 e 13, caracterizado pelo facto de se fazer reagir na fase (a) um composto de fórmula geral VIII, citada antes, com uma base purínica ou pirimidínica sililada no seio de um dissolvente comf -67- patível e na presença de um ãcido de Lewis ou de trimetilsililtriflato.

Independent claims4

613 paragraphs in 23 sections, as filed

PROCESS FOR THE PREPARATION OF REPLACED 1,3-ΟΧATIOLANS

AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM

The present invention relates to new cyclic 1,3-oxathiolane compounds substituted with pharmacological activity, to processes for preparing intermediates used in their preparation, to pharmaceutical compositions containing them and to the application of these compounds in the antiviral treatment of mammals.

Retroviral infections are a serious cause of illness, especially in acquired immunodeficiency syndrome (AIDS). The human immunodeficiency virus (HIV) has been recognized as the etiologic agent of AIDS and compounds that exhibit an inhibiting effect on HIV multiplication have been actively sought.

Mitsuaya et al., 3'-azido-3idesoxythymidine (BW A509U): An antiviral agent that inhibits the infectivity and cytopathic effect of human type III T-lymphotropic virus / virus associated with lymphadenopathy in vitro, Proc. Natl. Acad. Know. USA, 82;

(1985) pp. 7096-7100, refers to a compound of formula (A), 3'-azido-2 ', 3'-dideoxythymidine, commonly referred to as AZT. This compound is said to be applicable to provide some pro. protection for people with AIDS against the cytopathogenic effect of the immunodeficiency virus (HIV).

/ f

Mitsuya et al., In vitro inhibition of infectivity and cytopathic effect of human T-lymphotropic virus type III / virus associated with lymphadenopathy (HTL V / 111 / LAV) by 2'p'-didesoxynucleosides, Proc. Natl. Acad. Know. USA, 86, pp. 1911-15 (1986), also refers to a group of 2'3 '-didesoxynucleosides represented by formula (B) which is said to have a protective activity against the cytopathogenic effect induced by HIV.

(B)

Balzarini ti-HTLV-III / LAV de

-didesoxycytidine et al., Potent and selective an2 activity, '3' -didesoxycytidine, the derivative of 2 ', 3' -

Biochem. Biophys. Comm. Res., 140, pp. 735-42 (1986), refer to an unsaturated analogue of these nucleosi. of the 2 'f 3 '-didesoxycytidine represented by formula (C) as

s * characterized by antiretroviral activity.

(Ç)

Baba et al., 2j3'-didesoxythymidine and its unsaturated derivative 2 ', 3' (2 ', 3 1-didesoxythymidinene) are potent selective inhibitors of human immunodeficiency virus replication in vitro. Biochem. Biophys. Res. Comm., 142, pp. 128-34 (1987), refers to analogue 2 ', 31-insaturated, represented by the formula (D) of 2 ', 3'-didesoxythymidine. This analogue is supposed to be a potent selective inhibitor of ΗIV replication.

O

(D)

AZT analogs known as 3'-azido-2 ', 3 1 -didesoxyuridine represented by the general formula (E) in which V represents a bromine or iodine atom, have been reported to have an inhibitory activity against Moloney's murine leukemia in TS Lin et al., Synthesis and antiviral activity of several 3 'analogs -azido, 3'-amino, 23'-unsaturated and 2 ', 3'

-pyrimidine dideoxy, deoxy-ribonucleosides against viruses, J. · Med. Chem. , 30, pp. 440-41 (1987).

retroFinally, the 3'-fluorine analogs of 2 ', 3 1-didesoxycytidine, represented in formula (F) and 2 ', 3' -didesoxythymidine represented by formula (G), are reported by Herdwijn et al. ; 31-substituted 2 ', 31 -dideoxynuc1eoside analogues as potential anti-Η IV (ΗTLV-111 / LAV agents; J. Med. Chem., 30; (1987)

P. 1270-41 as having potent antiviral activity.

The most potent anti-HIV compounds listed below are 2 ', 3 1-didesoxynucleosides and more particularly 2 ', 3'-didesoxycytidine (ddCyd) and 3'-azido-2', 3 1 -didesoxythymidine (AzddThd or AZT). These compounds are also active against other types of retroviruses such as the murine leukemia virus

of Moloney. Due to the increased incidence and life-threatening characteristics of AIDS, efforts have been made to discover and develop new potent and non-toxic HIV inhibitors and blockers of their infectivity. It is therefore an object of this invention to provide effective anti-HIV compounds of low toxicity and a synthesis of these new compounds easily achievable.

A structurally distinct class of compounds known as 2,5-substituted 1,3-oxathiolans has now been discovered and has been found to have antiretroviral activity.

In particular, these compounds have been found to act as non-toxic inhibitors of HIV-1 replication in T-lymphocytes for extended periods.

In this way, it is provided, in a first aspect, with posts of general formula

in which,

R1 represents a hydrogen atom;

R4 represents a purine or pyrimidine base or an analog or derivative thereof;

Z represents a sulfur atom or a group S = 0 or SO2; and their pharmaceutically acceptable salts.

Those skilled in the art understand that compounds of formula I contain at least two chiral centers marked with a

asterisk in general formula I and therefore exists in the form of two pairs of optical isomers, that is, enantiomers, and their racemic mixtures. Therefore, compounds of general formula I may be either cis isomers, as represented by general formula II, or trans isomers as represented by general formula III or mixtures thereof. Each of the cis or trans isomers can exist in the form of one or two enantiomers or mixtures thereof including the rhemic mixtures. All of these isomers and mixtures thereof, including z ·; racemic mixtures are within the scope of the present invention.

The compounds of formula I are preferably in the form of cis isomers.

It will also be understood that when the symbol Z represents a group S = 0, the compounds exist in two more isomeric forms as shown by the general formulas lia and Ilb,

.- »· which differ in the configuration of the oxide oxygen atom relative to the 2,5 substituents. The compounds of the present invention further embrace these isomers and mixtures thereof.

(There is)

(Ilb)

The purine or pyrimidine bases or their analogues or derivatives represented by the symbol will be linked in position 9 or 1, respectively.

By purine or pyrimidine base or its analog or derivative is meant a purine or pyrimidine base that is found in natural nucleosides or an analog that mimics these bases because their structures (types of atoms and their arrangement) are identical to the bases but may or may not additionally have certain functional properties of the natural bases. These analogs include those derived from the substitution of a group CH2 P ° r a nitrogen atom, for example 5-azapif

rimidines such as 5-azacytosine or vice versa, for example 7-diazapurines (for example 7-diazadenoside or 7-deazaguanosine or both, for example 7-deaza, 8-azapurines).

Derivatives or analogs of these bases refer to compounds in which the substituents on the nucleus are included or removed or modified by known conventional substituents, for example, halogen atoms, hydroxyl groups, amine, alkyl C. These purine bases or pyrimidine, its analogs and derivatives are well known.

Conveniently the R group2 is chosen from a formula formula

Where it represents a hydrogen atom, a hydroxymethyl group or an optionally unsaturated C ^ _ alqu alkyl group;

R ^ and R ^ each independently represent a hydrogen, bromine, chlorine, fluorine or iodine atom or a hydroxymethyl, trifluoromethyl or (C1 -C) alkyl groupz) eventually replaced and unsaturated;

Rg represents a hydrogen atom or a cyano, carboxy, ethoxycarbonyl, carboxamido or thiocarbamus group 1 and

X and Y each independently represent a hydrogen, bromine, chlorine, fluorine or iodine atom or a preferred amino or hydroxy group represented by the symbol R4 is a group of general formula

O'

in which,

Rj and R ^ have the meanings defined above;

Z preferably represents a sulfur atom.

By a pharmaceutically acceptable derivative is meant any pharmaceutically acceptable salt, ester or salt of that ester, of a general formula I compound or of another compound which, after administration to a receptor, is capable of providing directly or indirectly a compound of formula I or an active antiviral metabolite or a residue thereof.

Those skilled in the art will realize that those with general formula I posts can be modified to provide their pharmaceutically acceptable derivatives in the functional groups in the two base radicals, R1 and in the hydroxy group of the nucleus oxathiolane.

Modification in all of these functional groups is within the scope of the present invention. However, its pharmaceutically acceptable derivatives, of particular esters, obtained by modifying the 2-hydroxymethyl group of the oxathiolane nucleus are of particular interest.

Preferred esters of the compounds of formula I include those compounds in which R 4 represents a carboxyl function of general formula R-C in which R represents the non-carbonyl fraction of the ester group chosen from a hydrogen atom, or a straight or branched alkyl group such as methyl, ethyl, n-propyl, t-butyl, n-butyl; alkoxyalkyl, such as methoxymethyl; aralkyl, for example benzyl; aryloxyalkyl, for example phenoxy methyl; aryl, for example phenyl possibly containing

as a substituted halogen atom or a substituted C 1-4 alkyl or dihydro-pyridinyl alkoxy group, for example N-methyl-dihydro-pyridyl, sulphonate esters such as alkyl- or aralkylsulfonyl, for example methanesulfonyl; sulfate esters; amino acid esters, for example L-valyl or L-isoleucyl; and mono-, di- or triphosphated esters.

Also included within the scope of the present invention are esters from polyfunctional acids such as carboxylic acids, comprising more than one carboxyl group, for example, dicarboxylic acids of general formula HC ^ C (CH ^ ^ CC ^ H in in which the symbol n represents an integer from 1 to 10, for example succinic acid, or phosphoric acids The methods for preparing these esters are known. See for example Hahn et al., Nucleotide Dimers as Anti Human Immunodeficiency Virus Agents, Nucleotides Analogues; (1989) p. 156-159 and Busso et al., Nucleotide Dimers Suppress HIV Expression In Vitro; AIDS Research and Human Retroviruses; 4 (6); (1988);

P. 449-455. When esters are derived from these acids, each acid group is preferably esterified by a compound of formula I or other nucleosides or analogues or derivatives thereof to provide esters of formula

(IV)

in which, W represents a group of general formula 0 0

-0-C- (CH „) -C-Ó en represents a zn number

II to 10 or represents a -0-P-0- or I group

0 “integer of

II

-0-P-0-,

J represents any nucleoside or an analog or derivative thereof and Z and have the meanings defined above. Preferred nucleosides and nucleoside analogs include 3'-azido-2 '5' -didesoxythymidine, 2 ', 3' -didesoxy ^ thymidine, 2l/ 3'-didesoxycytidine, 2 ', 3'-didesoxyadenosine, 2', 3'-didesoxy-inosine, 2 ', 3' -didesoxy-2 ', 3 1 - dides-hydro-1imidine and 1 , 3 '-didesoxy-2 1 ,3 1-dides-hydrocytidine or ribavirin and those nucleosides whose bases are described on pages 7 and 8 of this specification. A homodimer mainly consisting of two nucleosides of general formula I is preferred.

With respect to the aforementioned esters, unless otherwise specified, any alkyl group present should advantageously contain 1 to 16 carbon atoms, preferably 1 to 4 carbon atoms and may contain one or more double bonds. Any aryl group present in these esters advantageously contains a phenyl group.

In particular, these esters can be alkyl C esters or possibly substituted benzoyl esters containing

1-16 - at least 1 halogen atom (bromine, chlorine, fluorine or iodine), possibly unsaturated alkyl groups or C alkoxy, optionally unsaturated, nitro or tri-fluoromethyl as substituents.

Pharmaceutically acceptable salts of compounds of formula I include those derived from organic acids or

inorganic and pharmaceutically acceptable bases. Examples of suitable acids include hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, perchloric acid, fumaric acid, maleic acid, phosphoric acid, glycolic acid, lactic acid, salicylic acid, succinic acid, p-toluenesulfonic acid, tartaric acid, acetic acid, citric acid, methanesulfonic acid, formic acid, benzoic acid, malonic acid, 2-naphthalenesulfonic acid or benzenesulfonic acid. Other acids such as oxalic, although not pharmaceutically acceptable in themselves, can be useful in the preparation of salts applicable as intermediates for obtaining the compounds of the present invention and their acceptable acid addition salts from the pharmacist view.

Salts derived from appropriate bases include the alkali metal salts, for example sodium, alkaline earth metals, for example magnesium, ammonium and of the general formula NR ^ + in which R represents a C ^ _ alkyl group.

Subsequent references to the compounds according to the present invention include the compounds of formula I and their pharmaceutically acceptable derivatives.

Specific compounds of general formula I include: cis-2hydroxymethyl-5 - (cytosin-1'-yl) -1, 3-oxathiolane, trans-2-hydroxymethyl1-5- (cytosin-1 1 -i1) -1,3-oxathiolane and mixtures thereof; cis-2-benzoyloxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolane, trans-2-benzyloxymethyl1-5- £ itosin-1'-i1) -1,3-oxathiolane and its mixtures ;

cis-2-hydroxymethyl-5- (N ^l-acetyl-cytosin-l'-yl) -1,3-oxathiolane, trans-2-hydroxymethyl-5- (i-acetyl-cytosin-1'-yl) -1,3-oxathiolane and mixtures thereof;

cis-2-benzoyloxymethyl-5- (N4 '-acetyl-cytosin-1' - yl) -1,3-oxathio1 year, trans-2-benzoyloxymethyl-5 - ('- acetyl-cytosin-11-yl) -1,3-oxathiolane and mixtures thereof; and cis-2-hydroxymethyl-5- (cytosin-1'-yl) -3-oxo-1,3-oxathiolane; cis-2-hydroxymethyl-5- (N-dimethylamino-methylenocytosin-1'-yl) -1,3-oxathiolane;

bis-cis-2-succinyloxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolane; cis-2-benzoyloxymethyl-5- (6'-chloropurin-N-9'-yl) -1,3-oxathiolane, trans-2-benzoyloxymethyl-5- (6Ichloropurin-N-9'-yl) -l, 3 -oxathiolane and mixtures thereof;

cis-2-hydroxymethyl-5- (6'-chloropurin-N-9'-yl) -1,3-oxathiolane; cis-2-benzoyloxymethyl-5 (uracil-N-l'-yl) -1,3-oxathiolane, trans-2-benzoyloxymethyl 1-5-uracil-Ν-1'-i1) -1,3-oxathiolan and the their mixtures;

cis-2-benzoyloxymethyl-5- (timin-Nl '-yl) -1,3-oxathiolane, trans-2-benzoyloxymethyl-5 cis-2-hydroxymethyl-5- (uracyl-Nl' -yl) -1, 3-oxathiolane;

(timin-N-1'-yl) -1,3-oxathiolane and mixtures thereof;

cis-2-hydroxymethyl-5- (timin-N-1'-yl) -1,3-oxathiolane;

in the form of a racemic mixture or a single enantiomer.

The compounds of the present invention alone or the metabolizable compounds therein have antiviral activity.

In particular, these compounds are effective in inhibiting replication of retroviruses including human retroviruses such as human immunodeficiency virus Η IV, causative agents of AIDS.

Therefore, as a further aspect of this invention, compounds of formula I or their pharmaceutically acceptable derivatives are provided as active therapeutic agents usable in particular as antiviral agents.

-15 rich, for example in the treatment of retroviral infections.

In another aspect or an alternative aspect, a method is provided for the treatment of a viral infection, in particular an infection caused by a retrovirus, such as HIV, in a mammal, including man, which consists of administering a quantity effectiveness of an antiviral compound of formula I or a pharmaceutically acceptable derivative thereof.

It is also provided, in another alternative aspect of this invention, the application of a compound of general formula I or a pharmaceutically acceptable derivative for the preparation of drugs for the treatment of viral infections.

The compounds of this invention are also applicable in the treatment of AIDS-related conditions such as the AIDS-related complex referred to as ARC, persistent generalized infectious disease (PGL), AIDS-related neurological diseases such as dementia, positive conditions of anti-HIV or HIV-positive antibodies, Kaposi's sarcoma, purplish thrombocythemia and opportunistic infections.

The compounds of this invention are also useful in the prevention or progression of clinical disease in individuals whose HIV antibody or HIV antigen is positive and in the prophylaxis following exposure to HIV.

Compounds of general formula I or their pharmaceutically acceptable derivatives can also be used to prevent viral contamination of biological fluids such as blood or semen in vitro.

Some of the compounds of formula I are still applicable.

- suitable as intermediates in the preparation of other compounds of this invention.

Those skilled in the art will recognize that the references made here to treatment embrace prophylaxis as well as the designated treatment for infections or symptoms.

It should also be recognized that the amount of the compound of this invention required for application in treatment will vary not only with the particular compound chosen but depending on the route of administration, the nature and situation to be treated and the age and condition of the patient and how The latter circumstance will be at the discretion of the attending physician or veterinarian.

In general, however, an appropriate dose should be between about 1 and about 750 mg / kg of body weight per day, as well as between 3 and about 120 mg / kg of body mass per day, depending on preferably between 6 and 90 mg / kg per day and even more preferably between 15 and 60 mg / kg per day.

The appropriate dose can conveniently be presented in a single dose or in divided doses administered at appropriate intervals, for example 2,3,4 or more sub-doses per day.

<td></td><td>The</td><td>compounds are conveniently administered</td><td>in</td>

<td>form</td><td>dose</td><td>unitary; for example containing from 10 to 1500</td><td>mg,</td>

<td>of a</td><td>form</td><td>convenient 20 to 1000 mg, and even more</td><td>more</td>

50 to 700 mg of active ingredient per unit dosage form is appropriate.

Ideally, the active component should be administered in order to achieve the maximum plasma concentration of the active component between about 1 and 75 µM, preferably about

at 50 æM, still more preferably between 3 and about 30 This can be achieved, for example, by intravenous injection of a solution between 0.1 and 5% of active component, possibly in sodium chloride solution or administered in bolus with about 0.1 to about 110 mg / kg of the active component. Desirable blood levels can be maintained by continuous infusion to provide about 0.01 to about 5.0 mg / kg / hour or by intermittent infusion containing about 0.4 to about 15 mg / kg of active ingredient .

Although it is possible that for therapeutic application. ca, a compound of this invention can be administered in chemical form as it is, it is preferable to present the active component in the form of a pharmaceutical composition.

This invention, therefore, further provides a pharmaceutical composition containing the compound of general formula I or a pharmaceutically acceptable derivative thereof together with one or more acceptable pharmaceutical carriers and, where appropriate, other therapeutic and / or prophylactic components. The vehicles may be acceptable in the sense of being compatible with the other components of the composition and not harmful to their container.

The single pharmaceutical compositions include compositions suitable for oral, rectal, nasal, topical (including oral and sublingual), vaginal or parenteral (including intramuscular, subcutaneous and intravenous) administration or in an appropriate form for administration by inhalation or insufflation. The compositions may, where appropriate, be conveniently presented in independent dosage form, and may pre. stop by any method known in pharmaceutical technology. All methods include the association formation phase

-18 of the active compound with liquid vehicles or very divided solid vehicles or both and then, if necessary, the formation of the product in the appropriate formulation. Pharmaceutical compositions suitable for oral administration may be conveniently presented in the form of separate units, such as capsules, cachets or tablets, each containing a predetermined amount of the active component; in the form of powder or granules; or a solution; or suspension; or even an emulsion. The active component may also be in the form of a bolus, electuary or paste.

Tablets and capsules for oral administration may contain conventional excipients such as binding agents, fillers, lubricating agents, disintegrating agents or wetting agents. The tablets can be coated according to conventional methods well known to those skilled in the art. Liquid oral preparations may be in the form, for example, of aqueous or oily suspensions, solutions, emulsions, syrups or elixirs, or they may be in the form of a dry product for reconstitution with water or another suitable vehicle, before of use. These liquid preparations can contain conventional additives such as suspending agents, emulsifying agents, non-aqueous vehicles that can include edible oils, or preserving agents.

The compounds according to the present invention can also be prepared for parenteral administration, for example by injection or by bolus injection or by continuous infusion, and can be presented in the form of unit doses in ampoules, pre-filled syringes, infusion small volume in multidose containers added with a preservative. Make up /

The sections may also be in the form of suspensions, solutions or emulsions, in oily or aqueous vehicles and, where appropriate, contain formulation agents such as suspending agents, stabilizing agents and / or dispersing agents. Alternatively, the active component may be a powder obtained by aseptic isolation of the sterile solid or by lyophilization of a solution for reconstitution with a suitable vehicle, for example sterile pyrogen-free water, before use.

For topical administration to the epidermis, the compounds according to the present invention may be in the form of ointments, creams or lotions or in the form of a transdermal patch. Ointments and creams can, for example, be composed of an aqueous or oily base in addition to thickening and / or gelling agents. Lotions can be formulated with oily or aqueous bases and generally can contain one or more emulsifying agents, stabilizing agents, dispersing agents, suspending agents, thickening agents and coloring agents.

Compositions suitable for topical administration in the mouth include lozenges containing the active ingredient in a flavored base, usually sucrose, acacia or tragacanth; the tablets contain the active ingredient and an inert base such as gelatin, glycerin or sucrose and acacia; and mouthwashing elixirs comprise the active ingredient in an appropriate liquid carrier.

Pharmaceutical compositions suitable for administration; rectal traction in which the vehicle is a solid, are preferably presented in the form of suppositories in unit doses.

-20/ /

Suitable carriers include cocoa butter and other commonly used materials and suppositories can be conveniently formed by mixing the active component with a mild or melting vehicle followed by cooling and molding.

Compositions suitable for vaginal administration may be presented in pessaries, tampons, creams, gels, pastes, foams or sprays containing, in addition to the active component, vehicles known to be suitable.

For intranasal administration, the compounds of the present invention may be used in the form of a liquid spray or dispersible powder or in the form of a drop.

The drops can be prepared with an aqueous or non-aqueous base and also contain one or more dispersing agents, solubilizing agents or suspending agents.

Liquid sprays are generally packaged in pressurized packaging.

For administration by inhalation, compounds according to

L with the present invention are presented in a convenient way

-'4 te in an insufflator, nebulizer, or in a pressurized package or other convenient means of dispersing an aerosol. Pressurized packages may contain an appropriate propellant such as dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other appropriate gas In the case of a pressurized aerosol the unit dosage can be determined to provide a valve device to release a valve established quantity.

Alternatively, for administration by inhalation or insufflation, the compounds according to the present invention may be in the form of a dry powder composition, for example

-21 for a powder mixture consisting of a compound and an appropriate powder as a base, such as lactose or starch. The powder compositions can be presented in unit dosage form, for example in capsules or in cartridges or for example in blister or gelatin packaging from which the powder can be administered with the aid of an inhaler or insufflator.

Where appropriate, the aforementioned compositions can be used to adapt to provide controlled release of the active component.

The pharmaceutical compositions, according to the present invention, can also contain other active components such as antimicrobial agents or preservative agents.

The compounds of the present invention can be used in combination with other therapeutic agents, for example other anti-infective agents. In particular, the compounds of this invention can be applied in conjunction with known antiviral agents.

This invention, therefore, provides, in another aspect, an association consisting of a compound of general formula I or a physiologically compatible derivative thereof together with another therapeutically active agent, in particular with an antiviral agent.

The aforementioned preparations can conveniently be presented for application in the form of a pharmaceutical composition and therefore the compositions contain an association, as defined above, with a pharmaceutically acceptable carrier, which therefore consists of in another aspect of this invention.

Suitable therapeutic agents for use in these combinations include acyclic nucleosides such as acyclovir, ganci clovir, interferons such as alpha-, beta- and gamma-interferon; glucuronidation inhibitors such as probenicid; nucleoside transport inhibitors such as dipyridamole; nucleoside analogs such as 3'-azido-2 ', 3'-didesoxythymidine, 2', 3'-didesoxycytidine, 2 ', 3-dideoxyadenosine, 21 , 3'-didesoxy-inosine, 2 ', 3'-didesoxythymidine, 2', 3'-didesoxy-2 ', 3'-dideshydrothymidine and 2', 3'-didesoxy-2 ', 3'-didesidrocytidine or ribavirin; immunomodulators such as interleukin II (IL2) and granulocyte macrophage colony stimulating factor (GM-CSF), erythropoietin, ampligene, thymomodulin, thymopentin, phoscarnet, glycosylation inhibitors such as 2-deoxy-D-glucose, castanoespermin, 1 -deoxynorjirimycin, and inhibitors of HIV binding to CD4 receptors such as CD4 fragments, soluble CD4 and hybrid molecules

CD4.

The individual components of these combinations can be administered either sequentially or simultaneously in isolation or associated with pharmaceutical compositions.

When the compound of formula I or a pharmaceutically acceptable derivative thereof is used in combination with a second therapeutic agent active against the same virus, the dose of each compound may be the same or different from that used when the compound is used alone. Appropriate doses can be easily determined by a technician.

The compounds of general formula I and their pharmaceutically acceptable derivatives can be prepared by methods known in the art for the preparation of compounds of similar structure.

The symbols and R2, used later, have the meaning defined before, unless otherwise specified.

In one of these processes (A) a 1,3-oxathiolane of general formula

(VIII) in which R1 represents a hydrogen atom or a hydroxyl protecting group, as defined above and the anomeric group represented by L is an eliminable atom or group, is reacted with an appropriate base. Suitable groups represented by L include the alkoxycarbonyl groups such as ethoxycarbonyl or the halogen atoms, for example iodine, bromine or chlorine or groups of the general formula -OR in which R represents an optionally unsubstituted and unsaturated alkyl group, for example an alkyl group like metyl or R symbol represents an optionally substituted aliphatic or aromatic acyl group, for example an aliphatic acyl group C, -Cz such as acetyl and an aromatic acyl group such as benzoyl.

The compounds of general formula VIII are reacted in a convenient manner with an appropriate purine or pyrimidine base, of general formula R2-H (previously silylated with a silylating agent such as hexamethyldisilazane) in a compatible dissol-24 , such as methylene chloride, using a Lewis acid (such as titanium tetrachloride or stannous chloride) or trimethylsilitrifact.

The 1,3-oxathiolans of general formula VIII can pre. stop, for example, by comparing an aldehyde of general formula VII to a mercaptoacetal of general formula VI, in a dissol. suitable organic solvent, such as toluene, in the presence of an acid catalyst with p-1oluenesulfonic acid or a Lewis acid, for example zinc chloride.

(vi) hsch2ch (oc2H5)2 ç6H5cooch2cho (VII)

Mercaptoacetals of general formula VI can be prepared by known methods, for example G. Hesse and I. Jorder, Mercaptoacetaldehyde and dioxy-1,4-dithiane; Chem. Ber; 85; 1952; P. 924-932.

Aldehydes of general formula VII can be prepared by known methods, for example EG Halloquist and H. Hibbert;

Studies on reactions relating to carbohydrates and polysaccarides. Part XLIV: Synthesis of isomeric bicyclic acetal ethers, Can.

J. Research 8; 1933; P. 120-136.

In a second process (B), a compound of formula I can be converted into another compound of formula I by base interconversion. This interconversion can be carried out by simple chemical transformation, for example the conversion of the uracil base to cytosine or by an enzymatic conversion using, for example, a deoxy-ribosyl transferase. These methods and conditions for base interconversions are known in the chemical technology of nucleosides.

/ -25In a third process (C), compounds of general formula I can be prepared by reacting a compound of general formula

HO

(IX)

HZ with a compound of general formula

POWDER.

(X)

CHO in which P represents a protecting group, followed by the elimination of this group.

Compounds of general formula IX can be prepared by reacting an appropriate epoxide of general formula

(XI) with an appropriate sulfur-containing compound, for example sodium thioacetate. The compounds of general formula XI are known or can be obtained by similar processes.

In a fourth process (D) a compound of the general formula

it can be converted to a compound of general formula I by converting an anomeric NH ^ group to the required base, by methods known in nucleoside chemistry.

Many of the reactions described above have often been referred to in the context of purine nucleoside synthesis, for example in Nucleoside Analogues - Chemistry, Biology and Medical Applications; RT Walker et al. , Eds. Plenum Press, New York (1979) on pages 193-223, text whose reference is incorporated here.

It should be considered that the reactions mentioned above may require the use of, or the convenient application of starting materials with protected functional groups and deprotection should therefore be necessary as an intermediate or final phase to obtain the desired compound. . The protection and deprotection of the functional groups can be carried out by conventional means. Thus, for example, amino groups can be protected by a group chosen from aralkyl groups, for example benzyl, acyl or aryl, for example 2,4 - dinitrophenyl, subsequent removal of the protecting group carried out, where appropriate, by hydrolysis or hydrogenolysis using standard conditions. Hydroxyl groups can be protected using any conventional hydroxyl protecting group, for example, as described in Protective Groups in Organic Chemistry, Ed. JFW McOmie (Plenum Press, 1973) or Protective Groups in Organic

-2 7Synthesis by Theodora W. Greene (John Wiley and Sons, 1981). Examples of suitable hydroxyl protecting groups include groups chosen from alkyl groups, for example methyl, t-butyl or methoxymethyl, aralkyl, for example benzyl, diphenylmethyl or triphenylmethyl, heterocyclic groups such as tetrahydropyranyl, acyl such as acetyl or benzoyl, and silyl groups such as trialkylsilyl, for example t-butyldimethylsilyl. The hydroxyl protecting groups can be removed by conventional techniques. Thus, for example, alkyl, silyl, acyl and heterocyclic groups can be eliminated by solvolysis, for example by hydrolysis under acidic or basic conditions. Aralkyl groups such as triphenylmethyl can similarly be eliminated by solvolysis, for example by hydrolysis under acidic or basic conditions. Aralkyl groups such as benzyl can be split, for example, by treatment with boron trifluoride / etherate and acetic anhydride followed by the elimination of the acetate groups formed in this way at the appropriate stage of the synthesis. Silyl groups can also be eliminated in a convenient way by applying a fluoride ion source such as tetra-n-butylammonium fluoride.

In the processes mentioned above, the compounds of the general formula I are generally obtained in the form of cis or trans isomers.

These isomers can be separated, for example, by acetylation, for example with acetic anhydride, followed by separation by physical means, for example by chromatography on silica gel, and deacetylation, for example with methanolic ammonia or by fractional crystallization.

Pharmaceutically acceptable salts of

-28 compounds of the present invention can be prepared as described in United States Patent No. 4,383,114, the description of which is incorporated herein by reference. Thus, for example, when an acid addition salt of a compound of formula I is to be prepared, the product of any of the processes mentioned above can be converted into a salt by treating the resulting free base with an appropriate acid using conventional methods. Pharmaceutically acceptable acid addition salts can be prepared by reacting the free base with an appropriate acid, possibly in the presence of a suitable solvent, such as an ester, for example ethyl acetate or an alcohol, for example methanol, ethanol or isapropanol. Basic inorganic salts can be prepared by reacting the free base with an appropriate base such as an alkoxide, such as sodium methoxide, possibly in the presence of a solvent such as alcohol, for example methanol. Pharmaceutically acceptable salts can be prepared from other salts including other pharmaceutically acceptable salts of the compounds of formula I by application of conventional means.

The compounds of formula I can be converted to a pharmaceutically acceptable phosphate or other ester by reaction with a phosphorylating agent, such as phosphoryl trichloride or with an appropriate esterifying agent such as a halide or suitable acid anhydride. An ester or a salt of a compound of formula I can be converted into the main compound, for example, by hydrolysis.

When a compound of formula I is desired under

.¾

The simple isomeric form can be obtained by resolution of the final product or by stereospecific synthesis of the isomerically pure starting material or any suitable intermediate compound.

The resolution of the final product or of an intermediate or starting material can therefore be carried out according to any appropriate known method. See, for example, Stereochemistry of Carbon Compouds, by ELEliel (Mcgraw Hill, 1962) and Tables of Resolving Agents, by SH Wilen.

The present invention will be more fully described by the following examples which are not intended to limit this invention in any sense. All temperatures are given in degrees Celsius.

EXAMPLES

Example 1 2-thiobenzoyl acetaldehyde-diethyl1acet16H5cos-ch2ch (oc2H5)2 (V)

To a solution consisting of 11.5 potassium t-butoxide (0.11 mole) in 100 ml of dimethylformamide, 17 g (0.11 mole) of thiobenzoic acid were added and evaporated evenly. the solution in a vacuum. Benzene was added in two consecutive 30 ml potions and evaporated each time in a vacuum.

Dehyde bromoacetal diethyl acetal (20.3 g, 0.1 mole) was added to the residual dimethylformamide solution and the mixture was stirred for 15 hours at 120 ° C. After cooling, it was poured into 500 ml of water and the product was extracted three times with 200 ml of diethyl ether. The extract was washed with

-30 an aqueous solution of sodium hydrogen carbonate, followed by water and then the solvent was removed in vacuo. The residue was distilled in vacuo to obtain 17.2 g of the pure formula V compound, with a boiling point of 131 ° -33 ° / 0.07 mm. It was characterized

<td> 97</td><td>(d,</td><td>2H;</td><td>aromatic)</td>

<td> 7,</td><td> 47</td><td>(m,</td><td>3H;</td><td>aromatic)</td>

Example 2 mercaptoacetaldehyde hsch diethylacetal2ch (oc2H5)2 (SAW )

The previous thiobenzoic derivative (V) was dissolved in the amount of 17.2 g in 100 ml of tetrahydrofuran followed by the addition of 6 g of sodium hydroxide in 20 ml of water. The mixture was refluxed under nitrogen for 15 hours, then cooled and diluted with 200 ml of water and the product was extracted three times with 200 ml of ethyl ether. The extract was dried, the solvent was removed in vacuo and the residue was also distilled in vacuo to obtain 7.1 g of pure VI compound, eg 60 ° -62 ° / 18 mm. It was characterized by H NMR

Example 3 benzoyloxyacetaldehyde c6H5cooch2cho (VII)

This known intermediate was prepared by the method described above from 1-benzoyl-glycerol also known. Therefore, 50 g of the latter, in a mixture of 500 ml of methylene chloride and 25 ml of water, was subjected to treatment with 80 g portions of sodium periodate under vigorous stirring at room temperature. After the addition, stirring was continued for 2 hours after which 100 g of magnesium sulfate was added and another 50 minutes were stirred. The mixture was filtered and the filtrate was evaporated in vacuo and the residue was also distilled in vacuo to obtain 26 g of pure compound VII, eg 92 ° -94 ° / 0.25 mm. H NMR (200 MH ^; TMS as an internal reference)

S (ppm on CDCl3):

<td> 8,11</td><td>(d,</td><td>2H;</td><td>aromatic)</td>

<td> 7,60</td><td>(m,</td><td>1H;</td><td>aromatic)</td>

<td> 7,46</td><td>(m,</td><td>2H;</td><td>aromatic</td>

Example 4

2-benzoyloxymethyl-5-ethoxy-1,5-oxathiolane

CeHsCOOCHz

OCrt (XIII) /

-3 2 Ί g of the previous mercaptoacetaldehyde acetal (VI) were mixed in 100 ml of toluene with 7 g of the benzoyloxyacetaldehyde described above (VII), a few crystals of p-toluenesulfonic acid were added and the mixture was added in an oil bath at a temperature of 120 ° in a nitrogen atmosphere. The formed ethanol was distilled and the mixture was kept at 120 ° C for a further 30 minutes after which it was cooled and washed with an aqueous solution of sodium hydrogen carbonate, dried and evaporated in vacuo. The residue was distilled in vacuo to obtain 9.8 g of pure compound XIII as a mixture of cis and trans isomers, eg 140 ° -143 ° / 0.1 mm; RfO, 51 (hexane-EtOAc).

S NMR (ppm in CDCl-j):

<td> 8,05</td><td>(m,</td><td>2H;</td><td>aromatic)</td>

<td> 7,57</td><td>(m,</td><td>1H;</td><td>aromatic)</td>

<td> 7,43</td><td>(m,</td><td>2H;</td><td>aromatic)</td>

<td> 3,76</td><td>(m,</td><td>1H;</td><td>ç5-ochch3) H</td>

-33Example 5 cis- and trans-2-benzoyloxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolanes

It was subjected to heating at reflux temperature and anhydrous nitrogen atmosphere until a clear solution (3 hours) was obtained, a mixture of 2.7 g of cytosine, 30 ml of hexamethyldisilazane (HMDS) and 0.3 ml of trimethylsiline chloride and excess reagents were evaporated in vacuo. The remaining volatiles were removed in a powerful vacuum for 15 minutes and the solid residue was extracted with 250 ml of 1,2-dichloroethane and 5 g of the aforementioned key intermediate (XIII) was added in 50 ml of dichloroethane, under an argon atmosphere, followed by 4.7 ml of trimethylsilyl triflate (TMST). After 3 days of heating to the reflux temperature and argon atmosphere, it was cooled and poured into 300 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was collected, the aqueous phase was extracted twice with

100 ml of methylene chloride and the combined extracts were washed with water, dried and evaporated in vacuo. The residue was purified by silica gel chromatography using 9: 1 methylene chloride: methyl 1 as the eluant to obtain 2.5 g of a pure mixture in a cis- and trans- (XIV) 1: 1 ratio as determined by proton nuclear magnetic resonance. The isomers were separated as N-acetyl derivatives as described in the following example.

-'3 4

Example 6

Cis- and trans- isomers of 2-benzoyloxymethyl-5- (N/ il-acetyl-cytosin - 1 '-yl) —I, 3-oxathiolane

CçHsCOOCHb

(XV)

The previously obtained mixture (XIV) (2.5 g) was treated in 100 ml of anhydrous pyridine containing 0.1 g of 4-dimethylaminopyridine (DMAP), with 7 ml of acetic anhydride at room temperature and after 16 hours , the mixture was poured into cooled water followed by extraction with 3x150 ml of methylene chloride. The extract was washed with water, dried and evaporated in vacuo. Toluene was added to the residue, then evaporated in vacuo and the residual oil was purified by chromatography on silica gel using a 99: 1 ethyl acetate: methyl alcohol mixture as eluent to obtain 1.35 g of the pure trans— (XV) compound as the product of greatest mobility and 1.20 g of cis- (XV) as the product of least mobility. They were characterized by proton nuclear magnetic resonance spectroscopy.

trans- (XV): mp 158 ° -160 °; Rf: 0.48 EtOA: CH3OH 95: 5

UV: (CHjOH) Lambda max: 297 nm

<td> 8</td><td> , 06</td><td>(m,</td><td>2H;</td><td>aromatic</td>

<td> 7</td><td> ,56</td><td>(m,</td><td>1H;</td><td>aromatic</td>

<td> 7</td><td> ,56</td><td>(m,</td><td>1H;</td><td>aromatic)</td>

-3 5-

<td> 7,45</td><td>(m,</td><td>2H;</td><td>aromatic)</td>

Cis- (XV): mp 150 ° -152 °; Rf: 0.40 Et0Ac: Me0H 95: 5)

<td colspan="4">UV: (CH ^ OH) Lambda max: 297 nm</td>

<td> 8,05</td><td>(m,</td><td>2H;</td><td>aromatic)</td>

<td> 7,60</td><td>(m,</td><td>1H;</td><td>aromatic)</td>

<td> 7,50</td><td>(m,</td><td>2H;</td><td>aromatic)</td>

Z * 5 »

Example 7 cis- and trans-2-hydroxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolanes

(XVI)

a) Trans- (XVI): From this 1, 375 mg of trans- (XV) previously obtained were obtained in 100 ml of methanolic ammonia at 24 ° and, after stirring for 16 hours, the solvent was removed in a vacuum and crystallized the residue in diethyl ether. It was only recrystallized from ethanol / diethyl ether to obtain 174 mg of the pure product mp> 220 ° (with decomposition). It was characterized as follows. and NMR.

1H NMR S (ppm in DMSO-d ^):

UV: (CH ^ OH) Lambda max: 270 nm 13C NMR (DMS0-d6, Varian XL-300); $ in ppm:

ç2'c · c5' ç6' ç5 ç4 ç2 çh2oh

154,71 165,70 93,47 140,95 87,77 36,14 86,80 64,71

b) Cis- (X VI): 375 mg of Cis - (X V-) were treated by the procedure described above, obtaining 165 mg of the pure product after recrystallization from ethanol / ether, mp 171 ° -173 °. It was characterized by H and 1 C NMR.

NMR: S (ppm in DMSO-d ^):

7.80 (d, 1H; C ^ -H)

7.20 (d, 2H; C ^ -NH?)

6.18 (t, 1H; C5-H)

5.70 (d, 1H; C ^ -H)

5.14 (t, 1H; C2-Ch2OH)

3.71 (m, 2H; C2-Ch20H)

3.40 (dd, 1H; C ^ -K)

2.99 (dd, 1H; C3 -H).

UV (CH-jOH) Lambda max: 270 nm

<td>Example</td><td> 8</td><td></td>

cis-2-hydroxymethyl-5- (cytosin-11 - i1) -3-oxo-I, 3-oxathiolane

The previously obtained cis- (XVI) compound was treated,

100 mg in 30 ml of ice-cooled methanol, was treated with 93 mg of meta-chloroperbenzoic acid and after stirring for

minutes a white solid was separated and collected and washed with 10 ml of methanol to obtain 45 mg of the pure southern isoxide a isomer. The methanol filtrates were incorporated in vacuo and the residue was washed with 15 ml of ethanol / diethyl ether 1: 1 and then with 30 ml of diethyl ether to obtain 50 mg of the pure sulfoxide R isomer. Isomers were characterized by1H NMR.

Isomer (XVII) a: PF> 270 ° (dec); Rf:0730 (0Η? Cl £-Me OH -3: 1)

UV: (CH ^ OH) Lambda max: 270 nm 1H NMR S (ppm in DMS0-d.):

O

Isomer (XVII) b: PF> 220 ° (dec); Rf: 0.32 CH2Cl2: MeOH 3: 1 1H NMR S (ppm in DMSO-d ^):

5.45 (t, 1H; C2-Ch20H)

4.64 (t, 1H; C2-H)

3.77 (t, 2H; C2-Ch20H)

3.65 (dd, 1H; C ^ H)

3.17 (dd, 1H; C4~ H)

Example 9 cis-2-hydroxymethyl-5- (N-dimethylamino-methylene-cytosin-1'-yl) -1,3-oxathiolane

(XVIII)

A suspension of 300 mg of cis-2-hydroxymethyl-5- (cyto si η-1 1 -i1) -1,3-oxathium 1 year in 10 ml of dimethylformamide-dimethylacetal (DMF-dimethyl acetate 1). The mixture was stirred at room temperature overnight (18 hours). Volatile material was removed by evaporation under reduced pressure. The residue was crystallized from ethanol / diethyl ether to obtain 345 mg of the pure product (yield 93%). MP 162 ° -164 ° C; R ^ 0.56 in CH Cl ^ MeOH 4: 1

UV: Lambda max: 325 nm

H NMR 8 (ppm in DMS 0 - d ^):

8.64 (s, 1H N = CH-N)

8.04 (d, 1H, C6 '-H, J = 7.2 Hz)

6.22 (t, 1H, C5-H, J = 4.9 Hz)

5.97 (d, 1H, C '-H, J = 7.2 Hz)

5.37 (t, 1H, -0H, J = 5.8 Hz, D0 ^ exchange

-4 0 ζ

Example 10 bis-cis-2-succinyloxymethyl-5- (cytosin-1'-yl) -1,3-oxathiolane

284 mg of cis-2-hydroxymethyl 1-5- (N, N-dimethylamino-methylene-cytosin-1 '-yl) -1, 3-oxathiolan were dissolved in 10 ml of anhydrous pyridine and cooled to 0 ° C with an ice bath. 60 µl of succinyl chloride was added via syringe. The mixture was stirred overnight, 18 hours and poured into 50 ml of a saturated aqueous solution of sodium hydrogen carbonate. The mixture was extracted with 3x50 ml of methylene chloride. The methylene chloride solution was washed, washed with water twice with 50 ml and dried with magnesium sulfate. After filtration, the solvent was removed by evaporation under reduced pressure. A residual foam was dissolved in 10 ml of methylene chloride containing 5 ml of methanol. 2 ml / -41 of aqueous acetic acid was added at 80 ° and the mixture was stirred at room temperature overnight. The mixture was evaporated to dryness and the solid residue was purified on silica gel using 4: 1 methylene chloride-methyl alcohol as eluent. 145 mg of the pure product were obtained (54% yield).

PF Dec> 230 ° C; Rf: 0.23 (in CH2Cl2: MeOH 4: 1)

UV: (MeOH) Lambda max: 271 nm '' H-NMR S (ppm in DMSO-d ^)

<td> 7,28</td><td>(d,</td><td>4H,</td><td>2 x</td><td>NH2, J - 24.9Hz, D20 exchange)</td>

Example 11 cis-etr ans-2-benzo i 1 ox ime ti 1 - 5- (6 1-cl oropur i η - N-9 1 - i 1) -1, 3-oxathiolane

N

K /

-42 1.7 g of 6-chloropurine in 50 ml of hexamethyldysilane (HMDS) containing 50 mg of ammonium sulfate were heated to reflux until a clear solution was obtained (1 hour). Excess HMDS was removed under reduced pressure, the oily residue was dried in a powerful vacuum for 1 hour and then dissolved in 100 ml of anhydrous 1,2-dichloroethane.

2.7 g of 2-benzoyl oxymethyl 1-5-ethoxy-1,3-oxytiolane (XIII) were dried in a 500 ml round-bottom flask by evaporation twice with 50 ml of benzene and dissolved in 200 ml. ml of anhydrous 1,2-dichloroethane.

Then the silylated 6-chloropurine solution was transferred to a solution of 1,3-oxathiolane, through a tube in an argon atmosphere. To the reaction vessel, 11 ml of 1M trimethylsulphine sulfate (TMS — triflate) were added. The mixture was heated to reflux for 5 hours and then cooled to room temperature. The mixture was poured into 300 ml of a saturated solution of sodium carbonate with stirring. The organic phase was collected and the aqueous phase was extracted twice with 100 ml of methylene chloride. The combined organic phases were washed with water, dried with magnesium sulfate, filtered and evaporated under reduced pressure. The residue was purified and separated on silica gel using 7: 3 hexane-ethyl acetate as the eluent. 1.05 g of the product with the least polarity (yield 28%) were obtained, which was identified as the alpha- or trans- isomer in the form of a foam and 710 mg of the product with the least polarity identified with beta or cis-isomer. The total yield was 46.1% in the cis: trans ratio of 1: 1.4.

/ -43

Rf .: 0.43 in Hexane: EtOAc 1: 1 isomer - trans (0 (UV-isomer: (MeOH) Lambda max 264.7 nm 1h-RMn5 (ppm in CDCl4):

isomer

<td> 8,06</td><td>(m, 2H,</td><td>aromatic)</td><td></td><td></td>

<td> 7,56</td><td>(m, 1H,</td><td>aromatic)</td><td></td><td></td>

<td> 7,45</td><td>(m, 2H,</td><td>aromatic)</td><td></td><td></td>

<td>cis</td><td colspan="2">(beta-isomer): Rf :</td><td> 0:35</td><td>in</td>

U. V. : (MeOH) Lambda max 264 ^, 7 nm H - R Μ N 5 (ppm on CD C1,):

<td> 8 , 00</td><td>(m,</td><td>2H,</td><td>aromatic)</td><td></td>

<td> 7,56</td><td>(m,</td><td>1H,</td><td>aromatic)</td><td></td>

<td> 7,44</td><td>(m,</td><td>2H,</td><td>aromatic)</td><td></td>

Example 12 cis-2-hydroxymethyl-5- (6 '-hydroxipurin-N-9'-yl) -1,3-oxathiolane (derived from inosine)

(XXI)

533 mg of cis-2-benzoyloxymethyl-5 - (6 '- chlorophorium η-N-9' -i 1) -1, 3-ox were dissolved for 1 year in 25 ml of methanol. Add. 5 g of sodium hydroxide and 3 ml of water were added to the solution. The mixture was heated to reflux for 5 hours and cooled to room temperature. Then the solution was diluted with 100 ml of water, neutralized with effective pyridinium resin. The resin residue was filtered with 100 ml of methanol.

the combined filtrate was evaporated under reduced pressure. The residue was purified on silica gel using 4: 1 methylene chloride / methanol as eluent. 183 mg of the pure product (51% yield) were obtained, which was identified as the inosine derivative. MP: 208 ° -210 ° C; Rf: 0.27 in Et0Ac: Me0H 4: 1

UV: (MeOH) Lambda max: 246 nm ^ H-NMR: & (ppm in DMSO-d ^)

<td> 12</td><td> ,42</td><td>(s ,</td><td>, 1H,</td><td>, -NH, D0</td><td>exchange )</td>

/-4 5-

<td> 5,29</td><td>(t,</td><td>1H,</td><td>-0H, J = 6.0 Hz, D20 exchange)</td>

Example 13 cis- and trans-2-benzoyloxymethyl-5- (uracil-N1 '-yl) -1,3-oxathiolanes

760 mg of uraci were heated to the reflux temperature. it in 30 ml of HMDS in the presence of 50 mg of ammonium sulphate until a clear solution is obtained. The mixture was evaporated under reduced pressure, the residue was dried in vacuo for 1 hour and dissolved in 100 ml of 1,2 - dichloride in the anhydrous.

1.5 g of 2-b and η zoi 1 ox ime ti 1 - 5-ethoxy i-1,3-ox aioli were dried by evaporation twice with 50 ml of benzene each time in a 500 ml flask of round bottom and dissolved in 150 ml of 1,2-dichlorohydrate in the anhydrous.

The silylated uracil solution was transferred to an oxathiolan solution through an argon tube and 1.5 trimethyl triflate in 20 ml of 1,2-dichloroethane was added. The reaction mixture was heated at reflux temperature and under an argon atmosphere for 48 hours, cooled to room temperature and poured into 300 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was collected. The aqueous phase was extracted twice with 100 ml of methylene estrogen-46. The combined organic phases were washed twice with 200 ml of water, once with 150 ml of sodium chloride solution and dried with magnesium sulfate. After filtration, the solvent was removed by vacuum evaporation and the residue was purified on silica gel using 1: 1 hexane / ethyl acetate as the eluent. 594 mg of pure product (32% yield) were obtained. 0 product showed only one spot on thin layer chromatography. However, the H1-NMR spectrum indicated the presence of two cis and trans isomers in the proportion of 1: 1.2 and which at this stage were not separated.

R ^: 0.35 in Hexane: EtoAc 3: 7

UV: (MeOH) Lambda max: 261 nm ^ H-NMR S (ppm in CDCl ^)

<td> 8,05</td><td>(m,</td><td>2H,</td><td>aromatic)</td><td></td><td></td>

<td> 7,57</td><td>(m,</td><td>1H,</td><td>aromatic)</td><td></td><td></td>

<td> 7,45</td><td>(m,</td><td>5H,</td><td>aromatic and</td><td>N3·</td><td>-H)</td>

<td> 6, 55</td><td>(dd</td><td>, 1H,</td><td>C ^ -H trans,</td><td>J</td><td>= 2.4 and 5.4 Hz)</td>

<td> 5,79</td><td>(t,</td><td>1H,</td><td>Ç Q - H trans,</td><td>J =</td><td>5.4 Hz)</td>

<td> 5,73</td><td>(d,</td><td>1H,</td><td>C ^ '- H trans,</td><td>J</td><td>= 8.2 Hz)</td>

<td> 4,73</td><td>(d,</td><td>2H,</td><td>-Ch2O-COCgH5</td><td> )</td><td></td>

Example 14 cis-2-hydroxymethyl-5- (uracil-Nll-yl) -l, 3-oxathiolane

HO

(XXIII)

300 mg of a mixture of cis- and trans-2-benzoyloxymethyl1-5- (uraci1-Nl '-i1) -1, 3-oxathiolans and 75 ml of methanolic ammonia were dissolved. The mixture was stirred at room temperature overnight. The solution was evaporated to dryness. The residue was purified and the two isomers were separated on silica gel using 98: 2 ethyl acetate / methanol as eluent.

The top product was isolated as a solid product and identified as the cis isomer

Cisisomer mp 162 ° -164 ° C; Rf 0.57 in EtoAc: MeOH 95: 5

UV: (MeOH) Lambda majç 261.4 nm

1H-RΜN è (ppm in DMSO-d ^:

11.36 (s, 1H, N3'-H)

<td> 5,17</td><td>(t,</td><td>1H,</td><td>-OH, D20</td><td>exchange )</td><td></td>

Example 15 cis and trans-2-benzoyloxymethyl1-5- (timin-N-1 1 -i1) -1,3-oxathiolanes

1.7 g of thymine were heated at reflux temperature in 50 ml of hexamethyldisilazane containing 50 mg of ammonium sulfate until a clear solution was obtained. The mixture was evaporated under reduced pressure. The residue was dried in vacuo for 1 hour and dissolved in 150 ml of 1,2-dichloroethane.

3 g of 2-benzoyloxymethyl 1-5-ethoxy-1,3-oxathiolane were dried by evaporation twice with 75 ml of benzene and dissolved in 150 ml of anhydrous 1,2-dichloroethane.

The silylated thymine solution was transferred to oxa thiol through a tube in an argon atmosphere.

3.3 ml of trimethylsilyl triflate in 30 ml of anhydrous 1,2-dichloroethane were introduced into the reaction mixture through a tube in an argon atmosphere. The solution was heated at reflux in an argon atmosphere for 36 hours, cooled to room temperature and poured into 300 ml of a saturated aqueous solution of sodium hydrogen carbonate. The organic phase was collected and the aqueous phase was extracted twice with 100 ml of methylene chloride each time. The combined organic phases were washed twice with 200 ml of water

-4 9-

each time and once with 150 ml of sodium chloride solution and dried over magnesium sulfate. The solution was filtered, the filtrate was evaporated in vacuo and the residue was purified on silica gel using 1: 1 hexane / ethyl acetate as the eluent. 1.3 g of the pure product were obtained (35% yield).

The product exhibited only one spot on thin layer chromatography but the H-NMR spectrum indicated the presence of two cis and trans isomers in the proportion of 1: 1.2.

Rf .: 0.30 in Hexane: EtOAc 2: 3

UV: (MeOH) Lambda max: 266 nm

1H-RΜN & (ppm on CD C1 ^):

8.60 (broad singlet, Ν ^ '- Η)

<td>8.06 (m, 2H,</td><td>aromatic)</td>

<td>7.59 (m, 1H,</td><td>aromatic)</td>

<td>7.49 (m, 2H,</td><td>aromatic)</td>

<td>7.28 (d, 1H,</td><td>1 -H-trans, J = 1.3 Hz)</td>

<td>6.55 (dd, 1H</td><td>, C ^-H-trans isomer, J = 3.1 and 5,</td>

<td>6.38 (t, 1H,</td><td>C ^ -H-cis isomer, J = 5.5 Hz)</td>

<td>5.78 (dd, lH, C?</td><td>-H-trans, J = 4.4 and 6.4 Hz)</td>

<td>5.46 (t, 1H,</td><td>Çn-H -cisisomer, J = 4.3 Hz)</td>

<td>1.93 (d, 1H,</td><td>Çç1 -CH ^ -Trans isomer J = 1.2 Hz)</td>

<td>1.78 (d, 1H,</td><td>Cr'-CHO-isomer isomer, J = 1.2 Hz)</td>

Example 16 cis-2-hydroxymethyl-5- (timin-N-l'-yl)-1,3-oxathiolanes

HN

(XXV)

500 mg of a cis and trans mixture of 2-benzoyloxymethyl1-5- (timin-Nl '-i1) -1,3-oxathium 1 years (XXIV) were dissolved in 100 ml of saturated methanolic ammonia. The mixture was stirred at room temperature overnight (18 hours). Then the mixture was evaporated to dryness under reduced pressure. The residue was separated on silica gel using 98: 2 ethyl acetate / methanol as eluent. The product with the least polarity was identified as the cis isomer, mp 167 ° -168 ° C; R ^: in EtOAc: MeOH 95: 5

UV: (MeOH) Lambda max: 266 nm 'H-NMR & (ppm in DMSO-d ^)

<td> 5,</td><td> 14</td><td>(t,</td><td>1H,</td><td>0H, D20 change</td><td> )</td>

1.75 (d, 3H, C5 '-CH-j, J = 1.7 Hz)

Example 17

Compositions of tablets

A. The following composition was prepared by wet granulation of the components with an aqueous solution of povidone, drying and calibration, followed by addition of magnesium stearate and compression.

mg / tablet

<td>(The)</td><td>Active ingredient</td><td> 250</td>

<td>(B)</td><td>Lactose Β.P.</td><td> 210</td>

<td>(ç )</td><td>Povidone Β.P.</td><td> 15</td>

<td>(d)</td><td>Starch and sodium glycolate</td><td> 20</td>

<td>(and )</td><td>Magnesium stearate</td><td> 5</td>

500

Β. The following composition was prepared by direct compression; lactose was of the direct compression type.

mg / tablet

<td>Ingredient</td><td>active</td><td> 250</td>

<td>Lactose</td><td></td><td> 145</td>

<td>Avicel</td><td></td><td> 100</td>

<td>Stearate</td><td>magnesium</td><td> 5 500</td>

<td>Ç.</td><td>Controlled release composition.</td><td>The composition</td>

it was prepared by wet granulation of the components listed below, with an aqueous solution of povidone, drying and calibration followed by addition of magnesium stearate and compression.

/ mg / tablet

<td>(a) Active ingredient</td><td> 500</td>

<td>(b) Hydroxypropylmethylcellulose</td><td></td>

<td>(Methocel K4M Premium)</td><td> 112</td>

<td>(c) Lactose BP</td><td> 53</td>

<td>(d) Povidone BP</td><td> 28</td>

<td>(e) Magnesium stearate</td><td> 7</td>

<td>Example 18</td><td></td>

<td>Capsule composition</td><td></td>

<td>The composition of a capsule</td><td>a is prepared by mixing</td>

<td>of the components listed below and</td><td>capsule filling</td>

<td>two-part hard gelatin.</td><td>mg / capsule</td>

<td>Active ingredient</td><td> 125</td>

<td>Lactose</td><td> 72,5</td>

<td>Avicel</td><td> 50</td>

<td>Magnesium stearate</td><td> 2,5</td>

250

Example 19

Injectable composition

Active component 0.200 g

0.1M sodium hydroxide solution qbp ^ im pH of about 11. Sterile water qbp 10 ml.

The active component is suspended in a part of the water, which may be heated, and the pH is adjusted to about 11 with the sodium hydroxide solution. Then he prepared

The batch was adjusted by adjusting the volume and filtering through a sterile membrane into a sterile 10 ml vial and closed with sterile closures and sent.

Example 20

Suppositories mg / suppository

Active component 250

Hard fat, BP 1770

2020

One fifth of the hard fat material is melted in a steam bath at a maximum temperature of 45 ° C. The active component is passed through a 200 yum sieve and added to the molten base with stirring using a high speed agitator until a good dispersion is obtained. Keeping the mixture at 45 ° C, the remaining hard fat material is added to the suspension and stirred until homogeneity is obtained. The entire suspension is passed through a 250 µm stainless steel mesh and, with continuous stirring, keeps cooling to 40 ° C. The mixture is filled at a temperature between 38 ° -40 ° C, with a distribution of 2.02 g for each 2 ml plastic mold. Suppositories are allowed to cool to room temperature.

Example 21

Antiviral activity

The in vitro assay of several of the compounds of the present invention was conducted to determine their inhibitory capabilities. The results are shown in Tables 1 and 2. The mentioned concentrations are in µg / ml in the incubation media, which affects the susceptibility of a continuous T cell line developed at the Lady Davis Institute for Medical Research (Montreal) by Dr. Mark A. Wainberg, regarding HIV infection following a protocol identical to that described by H. Mitsuya and S. Broder; Inhibition of the in vitro infectivity and cytopathic effect of human T-lymphotropic virus type III / / lymphadenopathy-associated virus (HTLV-111 / LAV) by 2 ^ 3'-dideoxy nucleosides. Proc. Natl. Acad. Know. USA, 83; 1986 p. 1911-15. Protection of cell line infection was controlled by staining with monoclonal antibodies against viral proteins in a conventional manner (Table 1). In all experiments, comparisons were made with the drug AZT as a control.

In order to confirm the results, the effects of the drug were monitored by evaluating the reverse transcriptase (TI) activity in the human monocytic cell line U-937, according to the usual assay method with tritiated thymidine triphosphate (TTP) , Table 2). Finally, the drug's effects on cell viability were measured by the well-known cytolytic effects of HIV-1 on the MT-4 cell line assessed in the usual manner (Table 1).

Toxicity

In the tests mentioned above, no toxic effects were observed.

Table 1

Inhibition of HIV-1 by compounds of formula I in MT-4 cells

a) Counting of viable cells (in a 6-day culture), using 2 µg / ml of compound.

-5 5-

Compound_ Cell viability%

<td>trans-XVI</td><td></td><td></td><td> 24</td><td></td>

<td>cis-XXIII</td><td></td><td></td><td> 14</td><td></td>

<td colspan="3">b) P-24 immunofluorescence</td><td></td><td></td>

<td>Culture time</td><td></td><td colspan="3">Immunofluorescent cells</td>

<td>c) Test with</td><td>transcriptase</td><td>reverse</td><td></td><td></td>

<td>Culture time</td><td></td><td>Activity of</td><td>YOU</td><td>(CPM X 1000) / ml</td>

Table 2

Inhibition of HIV-1 production by compounds of formula I in H-9 cells

Reverse transcriptase assay

Culture time IT activity (CPM X 1000) / ml

Dias_Num drug_2pg / ml AZT 2 pg / ml cis-XVI

153 members in 45 offices

This recordMember, by publication datePriority claim35 more offices are in the list below

Priority claims7

Priority claims
Document	Office	Kind	Date
30810189	United States of America	A	1989-02-08
30810189	United States of America	A	1989-02-08
2152269	Canada	A	1992-12-21
2152269	Canada	A	1992-12-21
308101	–	–	–
CA19922152269	–	–	–
US19890308101	–	–	–

Members153

Family members, oldest first
Document	Office	Kind
DK172089D0	Denmark	D0	1989-04-10
IE891136L	Ireland	L	1989-10-11
AU3264489A	Australia	A	1989-10-12
DK172089A	Denmark	A	1989-10-12
EP0337713A2	European Patent Office (EPO)	A2	1989-10-18
KR890016046A	Republic of Korea	A	1989-11-28
IL89921A0	Israel	A0	1989-12-15
IL89921D0	Israel	D0	1989-12-15
JPH01316375A	Japan	A	1989-12-21
ZA892645B	South Africa	B	1989-12-27
FI900631A0	Finland	A0	1990-02-08
NO900619D0	Norway	D0	1990-02-08
HU900708D0	Hungary	D0	1990-04-28
AP9000163A0	African Regional Intellectual Property Organization (ARIPO)	A0	1990-04-30
CA2009637A1	Canada	A1	1990-08-08
IE900452L	Ireland	L	1990-08-08
IE960758L	Ireland	L	1990-08-08
NO900619L	Norway	L	1990-08-09
AU4920190A	Australia	A	1990-08-16
EP0382526A2	European Patent Office (EPO)	A2	1990-08-16
CN1044817A	China	A	1990-08-22
PT93094A	Portugal	A	1990-08-31
KR900012932A	Republic of Korea	A	1990-09-03
HUT53362A	Hungary	A	1990-10-28
ZA90943B	South Africa	B	1990-10-31
EP0337713A3	European Patent Office (EPO)	A3	1990-11-22
JPH037282A	Japan	A	1991-01-14
AP136A	African Regional Intellectual Property Organization (ARIPO)	A	1991-08-05
US5041449A	United States of America	A	1991-08-20
US5047407A	United States of America	A	1991-09-10
NZ228645A	New Zealand	A	1991-09-25
YU24390A	Yugoslavia, later Serbia and Montenegro (until 2006)	A	1991-10-31
EP0382526A3	European Patent Office (EPO)	A3	1992-01-02
OA09193A	African Intellectual Property Organization (OAPI)	A	1992-06-30
CS410991A3	Czechoslovakia (until 1993)	A3	1992-07-15
US5151426A	United States of America	A	1992-09-29
AU630913B2	Australia	B2	1992-11-12
OA09470A	African Intellectual Property Organization (OAPI)	A	1992-11-15
AU631786B2	Australia	B2	1992-12-10
MX19437A	Mexico	A	1993-05-01
IL89921A	Israel	A	1993-08-18
HU208134B	Hungary	B	1993-08-30
NZ232421A	New Zealand	A	1993-10-26
US5270315A	United States of America	A	1993-12-14
CA2152269A1	Canada	A1	1994-07-07
WO9414802A1	World Intellectual Property Organization (WIPO)	A1	1994-07-07
AU3154993A	Australia	A	1994-07-19
MY105523A	Malaysia	A	1994-10-31
PL164785B1	Poland	B1	1994-10-31
HU210537A9	Hungary	A9	1995-04-28
IL93318A	Israel	A	1995-07-31
HU9501825D0	Hungary	D0	1995-08-28
EP0674634A1	European Patent Office (EPO)	A1	1995-10-04
EP0337713B1	European Patent Office (EPO)	B1	1995-10-18
US5466806A	United States of America	A	1995-11-14
AT129247T	Austria	T	1995-11-15
ATE129247T1	Austria	T1	1995-11-15
DE68924549D1	Germany	D1	1995-11-23
ES2078234T3	Spain	T3	1995-12-16
PT93094BThis record	Portugal	B	1995-12-29
HK5996A	Hong Kong, China	A	1996-01-19
GR3017812T3	Greece	T3	1996-01-31
DE68924549T2	Germany	T2	1996-04-04
LV5730A4	Latvia	A4	1996-04-20
JPH08504212A	Japan	A	1996-05-07
JPH08119967A	Japan	A	1996-05-14
EP0382526B1	European Patent Office (EPO)	B1	1996-05-15
EP0711771A2	European Patent Office (EPO)	A2	1996-05-15
KR960007531B1	Republic of Korea	B1	1996-06-05
AT138065T	Austria	T	1996-06-15
ATE138065T1	Austria	T1	1996-06-15
DE69026971D1	Germany	D1	1996-06-20
ES2086371T3	Spain	T3	1996-07-01
EP0711771A3	European Patent Office (EPO)	A3	1996-07-10
NO179518B	Norway	B	1996-07-15
DK0382526T3	Denmark	T3	1996-08-05
LV5730B4	Latvia	B4	1996-08-20
GR3019919T3	Greece	T3	1996-08-31
DE69026971T2	Germany	T2	1996-09-12
HUT73655A	Hungary	A	1996-09-30
SI9010243A	Slovenia	A	1996-10-31
CN1033640C	China	C	1996-12-25
FI98065B	Finland	B	1996-12-31
LU88809I2	Luxembourg	I2	1997-01-03
NL960025I1	Netherlands (Kingdom of the)	I1	1997-01-06
IE71225B1	Ireland	B1	1997-02-12
NL960025I2	Netherlands (Kingdom of the)	I2	1997-03-03
IE72184B1	Ireland	B1	1997-03-26
FI98065C	Finland	C	1997-04-10
HRP940040A2	Croatia	A2	1997-04-30
HK51997A	Hong Kong, China	A	1997-05-02
JP2644357B2	Japan	B2	1997-08-25
CZ282720B6	Czechia	B6	1997-09-17
CA2009637C	Canada	C	1997-10-07
RU2092485C1	Russian Federation	C1	1997-10-10
US5684164A	United States of America	A	1997-11-04
CA1339609C	Canada	C	1997-12-30
CY2036A	Cyprus	A	1998-02-20
KR0137023B1	Republic of Korea	B1	1998-04-25
SG48737A1	Singapore	A1	1998-05-18

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2008-05-23	Change of proprietorshipPD4A	PD4A
2006-09-29	Change of address (patent)TE3A	TE3A
2002-08-30	Change of proprietorshipPD3A	PD3A
1995-12-29	Patent granted, date of grantingGrantedFG3A	FG3A