Title of Invention

"A 2-(SUBSTITUTED-AMINO)-BENZOTHIAZOLE SULFONAMIDE COMPOUND AND PROCESS THEREOF"

Abstract

A 2-(substituted-amino)-benzothiazole sulfonamide compound having the formula (I) and N-oxides, salts, steroisomeric forms, racemic mixtures and esters, wherein R1 and R8, are each independently hydrogen, C1-6alkyl, C2-6alkenyl, arylC1-6alkyl, C3- 7cycloalkylC1-6alkyl, aryl, Het1, Het1C1-6alkyl, Het2, Het2C1-6alkyl; R1 may also be a radical of formula R2 is hydrogen or C1-6alkyl; R3 is hydrogen, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkyl optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl) aminocarbonyl, aminosulfonyl, C1-4alkylS(=0)t, hydroxyl, cyano, halogen or amino optionally mono-or disubstituted where the substituents are selected from C1-4alkyl, aryl, aryl-C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Det2C1-4alkyl.

Full Text

The present invention relates to a 2-(substituted-amino)-benzothiazole sulfonamide compound and process thereof. The present invention relates to 2-(substituted-amino)-benzothiazole sulfonamides, men-use as aspartic protease inhibitors, in particular as broadspectrum HIV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. The present invention also concerns combinations of the present 2-(substituted-amino)-benzothiazole sulfonamides with another anti-retroviral agent. It farther relates to their use in assays as reference compounds or as reagents. The virus causing the acquired immunodeficiency syndrome (AIDS) is known by different names, including T-lymphocyte virus III (HTLV-III) or lymphadenopathy-associated virus (LAV) or AIDS-related virus (ARV) or human immunodeficiency virus (HIV). Up until now, two distinct families have been identified, i.e. HIV-1 and HIV-2. Hereinafter, HIV will be used to generically denote these viruses. One of the critical pathways in a retroviral life cycle is the processing of polyprotein precursors by aspartic protease. For instance with the HIV virus the gag-pol protein is processed by HIV protease. The correct processing of the precursor polyproteins by the aspartic protease is required for the assembly of infectious virions, thus making the aspartic protease an attractive target for antiviral therapy. In particular for HIV treatment, the HIV protease is an attractive target. HIV protease inhibitors (PIs) are commonly administered to AIDS patients in combination with other anti-HIV compounds such as, for instance nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) or other protease inhibitors. Despite the fact that these antiretrovirals are very useful, they have a common limitation, namely, the targeted enzymes in the HIV virus are able to mutate in such a way that the known drugs become less effective, or even ineffective against these mutant HIV viruses. Or, in other words, the HIV virus creates an ever increasing resistance against the available drugs. Resistance of retroviruses, and in particular the HIV virus, against inhibitors is a major cause of therapy failure. For instance, half of the patients receiving anti-HIV combination therapy do not respond fully to the treatment, mainly because of resistance of the virus to one or more drugs used. Moreover, it has been shown that resistant virus is carried over to newly infected individuals, resulting in severely limited therapy options for these drug-naive patients. Therefore, there is a need in the art for new CONFIRMATION COPY compounds for retrovirus therapy, more particularly for AIDS therapy. The need in the art is particularly acute for compounds that are active not only on wild type HIV virus, but also on the increasingly more common resistant HIV viruses. Known antiretrovirals, often administered in a combination therapy regimen, will eventually cause resistance as stated above. This often may force the physician to boost the plasma levels of the active drugs in order for said antiretrovirals to regain effectivity against the mutated HIV viruses. The consequence of which is a highly undesirable increase in pill burden. Boosting plasma levels may also lead to an increased risk of non-compliance with the prescribed therapy. Thus, it is not only important to have compounds showing activity for a wide range of HIV mutants, it is also important that there is little or no variance in the ratio between activity against mutant HIV virus and activity against wild type HIV virus (also defined as fold resistance or FR) over a broad range of mutant HIV strains. As such, a patient may remain on the same combination therapy regimen for a longer period of time since the chance that a mutant HIV virus will be sensitive to the active ingredients will be increased. Finding compounds with a high potency on the wild type and on a wide variety of mutants is also of importance since the pill burden can be reduced if therapeutic levels are kept to a minimum. One way of reducing this pill burden is finding anti-HIV compounds with good bioavailability, i.e. a favorable pharmacokinetic and metabolic profile, such that the daily dose can be minimized and consequently also the number of pills to be taken. Another important characteristic of a good anti-HIV compound is that plasma protein binding of the inhibitor has minimal or even no effect on its potency. Thus, there is a high medical need for protease inhibitors that are able to combat a broad spectrum of mutants of the HIV virus with little variance in fold resistance, have a good bioavailability and experience little or no effect on then: potency due to plasma protein binding. Up until now, several protease inhibitors are on the market or are being developed. One particular core structure (depicted below) has been disclosed in a number of references, such as, WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. The compounds disclosed therein are described as retroviral protease inhibitors. WO 99/67254 discloses 4-substituted-phenyl sulfonamides capable of inhibiting multidrug resistant retroviral proteases. Surprisingly, the 2-(substituted-amino)-benzothiazole sulfonamides of the present invention are found to have a favorable pharmacological and pharmacokinetic profile. Not only are they active against wild-type HIV virus, but they also show a broadspectrum activity against various mutant HIV viruses exhibiting resistance against known protease inhibitors. Though some of the present 2-(substituted-amino)-benzothiazole sulfonamides appear to fall within the generic description of some of the above cited patent publications, they are not specifically disclosed, suggested or claimed therein, nor would a person skilled in the art have been motivated to design them as broadspectrum protease inhibitors. The present invention concerns 2-(substituted-amino)-benzotbiazole protease inhibitors, having the formula and JV-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein RI and Rg are, each independently, hydrogen, Chalky!, C2-6alkenyl, C3-7cycloalkyl, Cs^cycloalkylCi-ealkyl, aryl, Het1, Her2Ci.6alkyl; RI may also be a radical of formula Het or wherein and Riob are, each independently, hydrogen, Ci^alkyloxycarbonyl, carboxyl, , aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, C3-7cycloalkyl, Ca-ealkenyl, Ca-ealkynyl or Ci-4alkyl optionally substituted with aryl, Het1, Het2, Cs.ycycloalkyl, Cj^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, aminosulfonyl, Ci-4alkyiS(O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from Ci^alkyl, aryl, aryld_4alkyl, C3-7cycloalkyl, C3_7cycloalkylCi_4alkyl, Het1, Het2, Het'Ci^alkyl and Het2Ci-4alkyl; whereby Rp, Rioa and the carbon atoms to which they are attached may also form a C3_7cycloalkyl radical; when L is -O-Ci_6alkanediyl-C(=O)- or -NR8-Ci.6alkanediyl-C(=O)-, then R9 may also be oxo; Riiais hydrogen, C2-6alkenyl, C2-6alkynyl, C3.7cycloalkyl, aryl, arylCi^alkyl, aminocarbonyl optionally mono- . or disubstituted, arm'noCi-4alkylcarbonyloxy optionally mono- or disubstituted, CMalkyloxycarbonyl, aryloxycarbonyl, HetWycarbonyl, Het2oxycarbonyl, aryloxycarbonylCi- 4alkyl, arylCMalkyloxycarbonyl, Ci.4alkylcarbonyl, Cs^cycloalkylcarbonyl, Cs^cycloalkylCi^alkyioxycarbonyl, Cs.ycycloalkylcarbonyloxy, carboxylCi-4alkylcarbonyloxy, Ci_4alkylcarbonyloxy, arylCi^alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, He^carbonyl, He^carbonyloxy, Het'Ci^alkyloxycarbonyl, Het2carbonyloxy, Het2Ci4alkylcarbonyloxy, Het2Ci4alkyloxycarbonyloxy or optionally substituted with aryl, aryloxy, Het2 , halogen or hydroxy; wherein the substituents on the amino groups are each independently selected from Chalky!, aryl, arylCi_4alkyl, Cs^cycloalkyl, Cs- 7cycloalkylCMalkyl, Het1, Het2, Het^Malkyl and Het2CMalkyl; Rub is hydrogen, C3.7cycloalkyl, C2.6alkenyl, C2-6alkynyl, aryl, Ci.6alkyloxycarbonyl, Het1, Het2 or Chalky! optionally substituted with halogen, hydroxy, Ci-4alkylS(=O)t, aryl, C3-7cycloalkyl, Het1, Her2, amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, arylCi-4alkyl, C3.7cycloalkyl, C3_7cycloalkylCi_4alkyl, Het1, Het2, Het^Malkyl and Het^CMalkyl; whereby Rub maybe linked to the remainder of the molecule via a sulfonyl group; each independently t is zero, 1 or 2; R2 is hydrogen or Ci-ealkyl; Lis -C(=0)-, -0-C(=O)-, -NR8-C(=O)-, -O-Ci.6alkanediyl-C(=O>, -NR8-Ci.6- alkanediyl-C(=0)-, -S(=O)2-, -O-S(=O)2-, -NR8-S(=O)2 whereby either the C(=O) group or the S(=O)2 group is attached to the NR2 moiety; and whereby the alkanediyl moiety is optionally substituted with aryl, arylCi^alkyl, C3.7cycloalkyl, C3-7cycloalkylCMalkyl5 Het1, Het2, Het'c^alkyl and Het2Ci_ 4alkyl; Ra is Ci-ealkyl, aryl, C3-7cycloalkyl, Ca^cycloalkylCi^alkyl, or arylCi^alkyl; R4 is hydrogen, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, Ca-ealkynyl or Q-ealkyl optionally substituted with aryl, Het1, Het2, C3_7cycloalkyl, Ci^alkyloxycaibonyl, carboxyl, aminocarbonyl, mono- or di(Ci_4alkyl)aminocarbonyl, aminosulfonyl, CMalkylS(=O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from d-4alkyl, aryl, aryl- CMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Her2, Het^Malkyl and Het2CMalkyl; A is Ci.6alkanediyl, -C(=O)-, -C(=S)-, -S(=O)2-, C'i-6alkanediyl-C(=O)-, C].6alkanediyl- C(=S)- or Ci-6alkanediyl-S(=0)2-; whereby the point of attachment to the nitrogen atom is the d-galkanediyl group hi those moieties containing said group; RS is hydrogen, hydroxy, Chalky!, Het1 Chalky!, Het2Ci_6alkyl, aminoCi-salkyl whereby the amino group may optionally be mono- or di-substiruted with Ci-4alkyl; Re is Ci-ealkyloxy, Het1, He^oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than Ci-ealkanediyl then R6 may also be Ci-ealkyl, Het^i^alkyl, Het^xyCMalkyl, Het2CMalkyl, Het2oxyCi_4alkyl, arylCi.4alkyl, aryloxyCi-4alkyl or aminoCMalkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents selected from Ci^alkyl, C[-4alkylcarbonyl, Ci-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCMalkyl, Het^Malkyl or Het2CMalkyl; and R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1 or Het2. According to one embodiment, the present invention concerns 2-(substituted-amino)- benzothiazole protease inhibitors of formula (I),-and W-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein RI and Rg are, each independently, hydrogen, Ci^alkyl, C2-6alkenyl, arylCi-ealkyl, C3.7cycloalkyl, C3.7cycloalkylCi.6alkyl, aryl, Het1, Het'Ci^alkyl, Het2, Het2Ci.6alkyl; RI may also be a radical of formula wherein Rg , Rioa and Riob are, each independently, hydrogen, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci.4alkyl)aminocarbonyl, C3_7cycloalkylj C2-ealkenyl, Ca-ealkynyl or Chalky! optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(CMalkyl)aminocarbonyl, aminosulfonyl, Ci_4alkylS(O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, arylCi-4alkyl, Cs-Tcycloalkyl, C3.7cycloalkylCi_4alkyl, Het1, Het2, Het'Ci-ialkyl and Het2Ci^alkyl; whereby R9, Rioa and the carbon atoms to which they are attached may also form a Ca.ycycloalkyl radical; is hydrogen, C2-6alkenyl, C2-6alkynyl, Ca^cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoCi^alkylcarbonyloxy optionally mono- or disubstituted, Ci^alkyloxycarbonyl, aryloxycarbonyl, He^oxycarbonyl, Het2oxycarbonyl, aryloxycarbonylCi^alkyl, arylCi_4alkyloxycarbonyl, CMalkylcarbonyl, Cs-vcycloalkylcarbonyl, C3-7cycloalkylCi-4alkyloxycarbonyl, Ca.ycycloalkylcarbonyloxy, carboxylCi^alkylcarbonyloxy, Ci^alkylcarbonyloxy, arylCi. 4alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het^arbonyl, Het^arbonyloxy, Het!CMalkyloxycarbonyl, Hel^carbonyloxy, Het2Ci- 4alkylcajbonyloxy, Het2Ci^alkyloxycarbonyloxy or Ci^alkyl optionally A substituted with aryl, aryloxy, Het or hydroxy; wherein the substituents on the amino groups are each independently selected from Ci^alkyl, aryl, arylCMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, He^Ci. 4alkyl and Het2CMalkyl; Rub is hydrogen, C3_7cycloalkyl, C2-ealkenyl, C2-6alkynyl, aryl, Het1, Het2 or Ci_4alkyl optionally substituted with halogen, hydroxy, Ci-4alkylS(=0)t, 1 0 aryl, Cs.vcycloalkyi, Het , Het , amino optionally mono- or disubstituted where the substituents are selected from Cj^alkyl, aryl, arylCj^alkyl, C3-7cycloalkyl, C3.7cycloalkylCMalkyls Het1, Her2, Het'C^alkyl and Het2CMalkyl; whereby Rub maybe linked to the remainder of the molecule via a sulfonyl group; each independently t is zero, 1 or 2; R2is hydrogen or Ci^alkyl; L is -C(=O)-, -0-C(=O)-, -NR8-C(^O>, -O-Ci.6alkanediyl-C(=O)-, -NRg-Ci-ealkanediyl- C(=O)-, -S(=O)2-, -O-S(=O)2-, -NR8-S(=O)2 whereby either the C(=O) group or the S(=O)2 group is attached to the NR2 moiety; R3 is Ci-ealkyl, aryl, C3-7cycloalkyl, C3.7cycloalkylCMalkyl, or arylCi^alkyl; R^is hydrogen, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci_4alkyl)aminocarbonyl, Ca^cycloalkyl, C2_6alkenyl, C2_6alkynyl or Chalky! optionally substituted with aryl, Het1, Het2, C3.7cycloalkyls Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, aminosulfonyl, Ci-4alkylS(=O)t, hydroxy, cyano, halogen or ammo optionally mono- or disubstiruted where the substituents are selected from Ci^alkyl, aryl, aryl- CMalkyl, C3.7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, He^C^alkyl and Het2CMalkyl; A is Ci-ealkanediyl, -C(=O)-, -C(=S)-, -S(=O)2-, Ci.6alkanediyl-C(=O)-, Ci-6alkanediyl- C(=S)- or Ci-6alkanediyl-S(:=O)2-; whereby the point of attachment to the nitrogen atom is the d-ealkanediyl group in those moieties containing said group; RS is hydrogen, hydroxy, Ci^alkyl, He^Ci-galkyl, Het2Ci_6alkyl, aminoCi-ealkyl whereby the amino group may optionally be mono- or di-substituted with Re is Ci-ealkyloxy, Het1, Het^xy, Het2, Hej^oxy, aryl, aryloxy or ammo; and in case -A- is other than Ci-ealkanediyl then R6 may also be Cj.galkyl, Het^i^alkyl, HetWyCi^alkyl, Het2CMalkyl, Het2oxyCi^alkyl, arylCi^alkyl, aryloxyCi^alkyl or aminoCi^alkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents selected from Ci.4alkyl, Ci_4alkylcarbonyl, Ci^alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCMalkyl, Het^Malkyl or Het2CMalkyl; and R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1 or Het2. This invention also envisions the quaternization of the nitrogen atoms of the present compounds. A basic nitrogen can be quaternized with any agent known to those of ordinary skill in the art including, for instance, lower alkyl halides, dialkyl sulfates, long chain halides and aralkyl halides. -8- Whenever the term "substituted" is used in defining the compounds of formula (I), it is meant to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group, provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a chemically stable compound, i.e. a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into a therapeutic agent. As used herein, the term "halo" or "halogen" as a group or part of a group is generic for fluoro, chloro, bromo or iodo. The term "CiJtalkyl" as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 4 carbon atoms, such as, for example, methyl, ethyl, propyl, butyl and 2-methyl-propyl, the like. The term "Chalky!" as a group or part of a group defines straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as the groups defined for Chalky! and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the like. The tenn "Ci-galkanediyl" as a group or part of a group defines bivalent straight and branched chained saturated hydrocarbon radicals having from 1 to 6 carbon atoms such as, for example, methylene, ethan-l,2-diyl, propan-l,3-diyl, propan-l,2-diyl, butan-1,4- diyl, pentan-l,5-diyl, hexan-l,6-diyl, 2-methylbutan-l,4-diyl, 3-methylpentan-l,5-diyl and the like. The term "C2-6alkenyl" as a group or part of a group defines straight and branched chained hydrocarbon radicals having from 2 to 6 carbon atoms containing at least one double bond such as, for example, ethenyl, propenyl, butenyl, pentenyl, hexenyl and the like. The term "Ca-ealkynyl" as a group or part of a group defines straight and branched chained hydrocarbon radicals having from 2 to 6 carbon atoms containing at least one triple bond such as, for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl and the like. The term "Ca-vcycloalkyl" as a group or part of a group is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. The term "aryl" as a group or part of a group is meant to include phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from Ci-salkyl, Q-ealkyloxy, halogen, hydroxy, optionally mono- or disubstituted arnino, nitro, cyano, haloQi-ealkyl, carboxyl, Ci-ealkoxycarbonyl, C3.7cycloalkyl, Het1, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminoCi-ealkyl, methylthio, methylsulfouyl, and phenyl optionally substituted with one or more substituents selected from Chalky!, Ci_ galkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi_6alkyl, carboxyl, C^alkoxycarbonyl, Cs-vcycloallcyl, Het1, optionally mono- or disubstituted aminocarbonyl, methylthio and methylsulfonyl; whereby the optional substituents on any amino function are independently selected from Chalky!, Ci- 6alkylcarbonyl, Ci.6alkyloxy-A-, HetJ-A-, Het'C^alkyl, Het'Cualkyl-A-, Het'oxy-A-, He^oxyCMakyl-A-, phenyl-A-, phenyl-oxy-A-, phenyloxyCi^alkyl-A-, phenylCiealkyl- A-, Ci-ealkyloxycarbonylamino-A-, amino-A-, aminoCLgalkyl and aminoCiealkyl- A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with Chalky! and whereby. A is as defined above. The term "haloCi-galkyl" as a group or part of a group is defined as C^alkyl substituted with one or more halogen atoms, preferably, chloro or fluoro atoms, more preferably fluoro atoms. Preferred haloCj-galkyl groups include for instance trifluoromethyl and difiuoromethyl. The term "Het1" as a group or part of a group is defined as a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by Ci-ealkyi, Ci^alkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloCj-salkyl, carboxyl, Q-ealkoxycarbonyl, Cs^cycloalkyl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminoCi-ealkyl, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from Ci-salkyl, Ci-ealkylcarbonyl, Ci-ealkyloxy-A-, Het2-A-, Het2Ci.6alkyl, Het2Ci.6alkyl-A-, Het2oxy-A-, Het2oxyCwakyl-A-, aryl-A-, aryloxy-A-, aryloxyCi-4alkyl-A-, arylCi.6alkyl-A-, Ci-ealkyloxycarbonylamino-A-, amino-A-, aminoCi-ealkyl and aminoCi-ealkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with Chalky! and whereby A is as defined above. The term "Het2" as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 14 ring members, more preferably 5 to 10 ring members and more preferably 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by Chalky!, Ci-ealkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi-ealkyl, carboxyl, Cualkoxycarbonyl, Cs^cycloalkyl, optionally mono- or disubstituted aminocarbonyl, optionally mono- or disubstituted aminoCusalkyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 14 ring members; whereby the optional substituents on any amino function are independently selected from Chalky!, Ci-ealkylcarbonyl, Ci_6alkyloxy-A-, Het'-A-, Het'Ci-ealkyl, Het'Ci-salkyl-A-, HetWy-A-, HetWy- Ci.4akyl-A-, aryl-A-, aryloxy-A-, aryloxyCi_4alkyl-A-, arylCi-ealkyl-A-, Ci-ealkyloxycarbonylamino- A-, amino-A-, amrnoCi^alkyl and aminoC^alkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with and whereby A is as defined above. As used herein, the term (=O) forms a carbonyl moiety with the carbon atom to which it is attached. As used herein before, the term "one or more" covers the possibility of all the available C-atoms, where appropriate, to be substituted, preferably, one, two or three. When any variable (e.g. halogen or Ci^alkyl) occurs more man one time hi any constituent, each definition is independent. The term "prodrug" as used throughout this text means the pharmacologically acceptable derivatives such as esters, amides and phosphates, such that the resulting in vivo biotransformation product of the derivative is the active drug as defined in the compounds of formula (I). The reference by Goodman and Oilman (The Pharmacological Basis of Therapeutics, 8th ed, McGraw-Hill, Int. Ed. 1992, "Biotransformation of Drugs", p 13-15) describing prodrugs generally is hereby incorporated. Prodrugs of a compound of the present invention are prepared by modifying functional groups present in the compound in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds of the present invention wherein a hydroxy group, for instance the hydroxy group on the asymmetric carbon atom, or an amino group is bonded to any group that, when the prodrug is administered to a patient, cleaves to form a free hydroxyl or free amino, respectively. Typical examples of prodrugs are described for instance in WO 99/33795, WO 99/33815, WO 99/33793 and WO 99/33792 all incorporated herein by reference. Prodrugs are characterized by excellent aqueous solubility, increased bioavailability and are readily metabolized into the active inhibitors in vivo. For therapeutic use, the salts of the compounds of formula (I) are those wherein the counterion is pharmaceutically or physiologically acceptable. However, salts having a pharmaceutically unacceptable counterion may also find use, for example, in the preparation or purification of a pharmaceutically acceptable compound of formula (I). All salts, whether pharmaceutically acceptable or not are included within the ambit of the present invention. The pharmaceutically acceptable or physiologically tolerable addition salt forms which the compounds of the present invention are able to form can conveniently be prepared using the appropriate acids, such as, for example, inorganic acids such as hydrohalic acids, e.g. hydrochloric or hydrobromic acid; sulfuric; nitric; phosphoric and the like acids; or organic acids such as, for example, acetic, propanoic, hydroxyacetic, lactic, pyruvic, oxalic, malonic, succinic, maleic, fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic, benzenesulfonic, j>-toluenesulfonic, cyclamic, salicylic, p-amino-salicylic, pamoic and the like acids. Conversely said acid addition salt forms can be converted by treatment with an appropriate base into the free base form. The compounds of formula (I) containing an acidic proton may also be converted into their non-toxic metal or amine addition salt form by treatment with appropriate organic and inorganic bases. Appropriate .base salt forms comprise, for example, the ammonium salts, the alkali and earth alkaline metal salts, e.g. the lithium, sodium, potassium, magnesium, calcium salts and the like, salts with organic bases, e.g. the benzathine, N-methyl, -D-glucamine, hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the like. Conversely said base addition salt forms can be converted by treatment with an appropriate acid into the free acid form. The term "salts" also comprises the hydrates and the solvent addition forms which the compounds of the present invention are able to form. Examples of such forms are e.g. hydrates, alcoholates and the like. The A^-oxide forms of the present compounds are meant to comprise the compounds of formula (I) wherein one or several nitrogen atoms are oxidized to the so-called TV-oxide. The present compounds may also exist in their tautomeric forms. Such forms, although not explicitly indicated in the above formula are intended to be included within the scope of the present invention. The term stereochemically isomeric forms of compounds of the present invention, as used hereinbefore, defines all possible compounds made up of the same atoms bonded by the same sequence of bonds but having different three-dimensional structures which are not interchangeable, which the compounds of the present invention may possess. Unless otherwise mentioned or indicated, the chemical designation of a compound encompasses the mixture of all possible stereochemically isomeric forms which said compound may possess. Said mixture may contain all diastereomers and/or enantiomers of the basic molecular structure of said compound. All stereochemically isomeric forms of the compounds of the present invention both in pure form or in admixture with each other are intended to be embraced within the scope of the present invention. Pure stereoisomeric forms of the compounds and intermediates as mentioned herein are defined as isomers substantially free of other enantiomeric or diastereomeric forms of the same basic molecular structure of said compounds or intermediates. In particular, the term 'stereoisomerically pure' concerns compounds or intermediates having a stereoisomeric excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomeric excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomeric excess of 90% up to 100%, even more in particular having a stereoisomeric excess of 94% up to 100% and most in particular having a stereoisomeric excess of 97% up to 100%. The terms 'enantiomerically pure' and 'diastereomerically pure' should be understood in a similar way, but then having regard to the enantiomeric excess, respectively the diastereomeric excess of the mixture in question. Pure stereoisomeric forms of the compounds and intermediates of this invention may be obtained by the application of art-known procedures. For instance, enantiomers may be separated from each other by the selective crystallization of their diastereomeric salts with optically active acids. Alternatively, enantiomers may be separated by chromatographic techniques using chiral stationary phases. Said pure stereochemically isomeric forms may also be derived from the corresponding pure stereochemically isomeric forms of the appropriate starting materials, provided that the reaction occurs stereospecifically. Preferably, if a specific stereoisomer is desired, said compound will be synthesized by stereospecific methods of preparation. These methods will advantageously employ enantiomerically pure starting materials. The diastereomeric racemates of formula (I) can be obtained separately by conventional methods. Appropriate physical separation methods which may advantageously be employed are, for example, selective crystallization and chromatography, e.g. column chromatography. It is clear to a person skilled in the art that the compounds of formula (I) contain at least one asymmetric center and thus may exist as different stereoisomeric forms. This asymmetric center is indicated with a asterisk (*) in the figure below. The absolute configuration of each asymmetric center that may be present in the compounds of formula (I) may be indicated by the stereochemical descriptors R and S, this R and S notation corresponding to the rules described in Pure Appl. Chem. 1976, 45, 11-30. The carbon atom marked with the asterisk (*) preferably has the R configuration. The present invention is also intended to include all isotopes of atoms occurring on the present compounds. Isotopes include those atoms having the same atomic number but different mass numbers. By way of general example and without limitation, isotopes of hydrogen include tritium and deuterium. Isotopes-of carbon include C-13 and C-14. Whenever used hereinafter, the term "compounds of formula (I)", or "the present compounds" or similar term is meant to include the compounds of general formula (I), their JV-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, as well as their quatemized nitrogen analogues. A particular group of compounds are those compounds of formula (I) wherein one or more of the following restrictions apply : Ri is hydrogen, Het1, Het2, aryl, He^Ci-ealkyl, Het2Ci-6alkyl, arylCi.6alkyl, more in particular, RI is hydrogen, a saturated or partially unsaturated monocyclic or bicyclic heterocycle having 5 to 8 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted, phenyl optionally substituted with one or more suhstituents, an aromatic monocyclic heterocycle having 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms, or Chalky! substituted with an aromatic monocyclic heterocycle having 5 to 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms; is H, alkyloxycarbonyl; Rub is C1-4 alkyl optionally substituted with aryl; R2 is hydrogen; Lis -C(=O)-, -O-C(=O)-,-O-Ci.6alkanediyl-C(=O)-, -NR8-Ci-6alkanediyl-C(=O), more in particular, L is -C(=O)-, -O-C(=O)-,-O-CH2-C(==O)-, whereby in each case the C(=O) group is attached to the NR2 moiety; Ra is arylCi-4alkyl, in particular, arylmethyl, more in particular phenylmethyl; R4 is optionally substituted Ci-galkyl, in particular Ci_6alkyl optionally substituted with aryl, Het1, Het2, Cj.ycycloalkyl or amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, Het1 and Het2; A is Ci-salkanediyl, -C(=O)- or Ci-6alkanediyl-C(=O)-, in particular, A is methylene, 1,2-ethanediyl, 1,3-propanediyl, -C(=O)- or -CH2-C(=O)-; RS is hydrogen, d-ealkyl, Het'Ci^alkyl, aminoCi-saUcyl whereby the amino group may optionally be mono- or di-substituted with Ci^alkyl; RS is Cj-ealkyloxy, Het1, aryl, amino; and in case -A- is other than Ci-salkanediyl then R6 may also be Ci-galkyl, He^Ci^alkyl, aryloxyCi^alkyl or aminoCi^alkyl; whereby each of the amino groups may optionally be substituted; or R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1. A special group of compounds are those compounds of formula (I) wherein RI is Het1, aryl, Het2Ci.6alkyl; R2 is hydrogen; L is -C(=O)-, -O-C(=O)-, -O-CH2-C(=O)-, whereby in each case the C(=O) group is attached to the NR2 moiety; RS is phenylmethyl; and R4 is Chalky!. Also a special group of compounds are those compounds of formula (I) wherein A is Ci.galkanediyl or -C(=O)-; RS is hydrogen, methyl, He^Ci-ealkyl, aminoCi-salkyl whereby the amino group may optionally be mono- or di-substituted with Cj^alkyl; R« is Ci-ealkyloxy, Het1, amino; and in case -A- is other than Ci-ealkanediyl then R6 may also be Ci-galkyl, Het1Ci4alkyl or aminoCMalkyl; whereby each of the amino groups may optionally be substituted. An interesting group of compounds are those compounds of formula (I) wherein-A- is carbonyl and Re is aryl, Het^Malkyl, aryloxyCi.4alkyl or arninoCi-4alkyl, whereby the amino groups may optionally be substituted; or -A- is carbonyl, Rg is Chalky! and R$ is Het'Ci-ealkyl or aminoCi.galkyl whereby the amino group may optionally be monoor di-substituted with Chalky!. Another interesting group of compounds are those compounds of formula (I) wherein - A- is Ci-galkanediyl and Rg is amino and Het1; whereby the amino group may optionally be mono- or di-substituted with Ci_4alkyl. Another interesting group of compounds are those compounds of formula (I) wherein RI hydrogen, Ci^alkyl, C2-6alkenyl, arylCi-ealkyl, Ca^cycloalkyl, Cs^cycloalkylCi. galkyl, aryl, Het1, He^Q.galkyl, Het2, Het2Ci.6alkyl; wherein Het1 is a saturated or partially unsaturated monocyclic heterocycle having 5 or 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms. Another interesting group of compounds are those compounds of formula (I) wherein L is -O-Ci-ealkanediyl-C^O)-. Another interesting group of compounds are those compounds of formula (I) wherein A is Ci-galkanediyl, -C(=O)- or Ci-6alkanediyl-C(=O)-; whereby the point of attachment to the nitrogen atom is the Ci^alkanediyl group in those moieties containing said group; RS is hydrogen, d-galkyl, He^Ci-galkyl, Het2Ci_6alkyl, aminoCi-ealkyl whereby the amino group may optionally be mono- or di-substituted with Ci^alkyl; and in case -A- is -C(=O)- then R6 is Ci-ealkyloxy, Het1, Het!oxy or Hel^oxy, aryl, Het'CMalkyl, Het'oxyCMalkyl, Het2CMalkyl, Het2oxyCMalkyl, arylCMalkyl, aryloxyCi-4alkyl or aminoCMalkyl; and in case -A- is Ci-galkanediyl then R*5 is amino, Ci-galkyloxy, Het1, HetWy or Het2oxy; and in case -A- is Ci_6alkanediyl-C(=O)- then R6 is Ci-galkyloxy, Het1, Het'oxy or Het2oxy, aryl, Ci.6alkyl, Het]CMalkyl, Het^xyCMalkyl, Het2CMalkyl, Het2oxyCMalkyl, arylCi^alkyl, aryloxyCi^alkyl or aminoCi^alkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents selected from Ci_4alkyl, Ci^alkylcarbonyl, Ci-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCi. 4alkyl, Het^Malkyl or Het2CMalkyl; and R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1 whereby Het1 is substituted by at least an oxo group. Interesting compounds are those wherein L is -O-Ci_6alkanediyl-C(=O)- or -'. alkanediyl-C(=O)- and RI is a radical of formula Rioa and Riob are, each independently, hydrogen or Ci^alkyl optionally substituted with aryl, Het1, Het2, Ci_4alkyloxycarbonyl, carboxyl, aminocarbonyl, hydroxy, or amino optionally mono- or disubstituted where the substituents are selected from Ci-4alkyl, Riia is arylCi-4alkyl, or Ci^alkyl optionally substituted with aryl or halogen and Riib is hydrogen, or Cj-ealkyloxycarbonyl. Also interesting compounds are those wherein L is -O-Ci_6alkanediyl-C(=O)- or -NR«- Ci_6alkanediyl-C(=O)- and RI is a radical of formula wherein Rg is oxo , Rioa and Riob are hydrogen, Rna is w-fluorobenzyl and Rub is hydrogen, or Ci-ealkyloxycarbonyl. Yet other interesting compounds are those wherein L is -O-Ci-6alkanediyl-C(=O)- or -NR8-Ci-6alkanediyl-C(=O)- and RI is a radical of formula wherein Rg is oxo, Rioa and Riob are hydrogen, Rna is m-fluorobenzyl and Rut is hydrogen. Other interesting compounds are those wherein L is -O-Ci_6alkanediyl-C(=O)- or -NRg- Ci-6alkanediyl-C(=O)- and RI is a radical of formula wherein Rg is oxo, Rioa and Riob are hydrogen, Rna is m-fluorobenzyl and Rub is tertbutyloxycarbonyl. Interestingly, the compounds of the present invention may comprise chemically reactive moieties capable of forming covalent bonds to localized sites such that said compound have increased tissue retention and half-lives. The term "chemically reactive group" as used herein refers to chemical groups capable of forming a covalent bond. Reactive groups will generally be stable in an aqueous environment and will usually be carboxy, phosphoryl, or convenient acyl group, either as an ester or a mixed anhydride, or an imidate, or a maleimidate thereby capable of forming a covalent bond with functionalities such as an amino group, a hydroxy or a thiol at the target site on for example blood components. 4 Upon administration to an individual in need thereof, said compound is capable of forming covalent bonds to localized sites, with blood component for example, such that said compound according to the invention has increased tissue retention and half-lives. Usually, the covalent bond that is formed should be able to be maintained during the lifetime of the blood component, unless it is intended to be a release site. A major advantage of said new compound is the small amount of compound necessary to provide an effective effect. The reasons for this advantage are explained by the targeting of the delivery, the high yield of reaction between the reactive entity Y and reactive functionality and the irreversible nature of the bond formed after reaction. Furthermore, once bound to the membrane or tissue said compound according to the invention is not susceptible to liver metabolism, kidney filtration and excretion, and may even be protected from protease (inclusive of endopeptidase) activity which usually leads to loss of activity and accelerated elimination. "Blood components" as used herein refers to either fixed or mobile blood components. Fixed blood components are non-mobile blood components and include tissues, membrane receptors, interstitial proteins, fibrin proteins, collagens, platelets, endothelial cells, epithelial cells and their associated membrane and membranous receptors, somatic body cells, skeletal and smooth muscle cells, neuronal components, osteocytes and osteoclasts and all body tissues especially those associated with the circulatory and lymphatic systems. Mobile blood components are blood components that do not have a fixed situs for any extended period of time, generally not exceeding 5, more usually one minute. These blood components are not membrane-associated and are present in the blood for extended periods of time and are present in a minimum concentration of at least 0.1 |j,g/ml. Mobile blood components include serum albumin, transferrin, ferritin and immunoglobulins such as IgM and IgG. The half-life of mobile blood components is at least about 12 hours. The compounds of formula (I) can generally be prepared using procedures analogous to those procedures described in WO 95/06030, WO 96/22287, WO 96/28418, WO 96/28463, WO 96/28464, WO 96/28465 and WO 97/18205. Particular reaction procedures to make the present compounds are described below. In the preparations described below,the reaction products may be isolated from the medium and, if necessary, further purified according to methodologies generally known in the art such as, for example, extraction, crystallization, trituration and chromatography. The 2-acetamido-6-chlorosulfonylbenzothiazole (intermediate a-2) was prepared following the procedure described in EP-A-0,445,926. Intermediates a-4 were prepared by reacting an intermediate a-3, prepared according to the procedure described in WO97/18205 and also depicted in scheme F, with an intermediate a-2 in a reaction-inert solvent such as dichloromethane, and in the presence of a base such, as triethylamine and at low temperature, for example at 0 °C. The Boc group in the intermediate a-3 is a protective tert-butyloxycarbonyl group. It may conveniently be replaced by another suitable protective group such as phtalimido or benzyloxycarbonyl. Using intermediate a-4 as a starring material, intermediate a-5 was deprotected using an acid such as trifluoro acetic acid in a suitable solvent such as dicloromethane. The resulting intermediate may be further reacted with an intermediate of formula Ri-L-(leaving group) in the presence of a base such as triethylamine and optionally in the presence of l-(3-dimethylaminopropyl)-3-ethylcafbodiimide hydrochloric acid (EDC) or an alcohol such as terf-butanol, and in a suitable solvent such as dichloromethane; thus forming intermediates a-6. Particularly, intermediates of formula Ri-C(=O)-OH are suitable to further react with an intermediate a-5. Alternatively, intermediates a-4 may be deprotected with a strong acid such as hydrochloric acid in isopropanol, in a suitable solvent such as a mixture of ethanol and dioxane, thus preparing an intermediate a-7. 'Intermediates a-8 can be prepared analogously to the procedure described for the preparation of intermediates a-6. Intermediate b-5 can be prepared according, to the procedure described in scheme A. The aminobenzothiazole derivative b-5 can be de-aminated by for instance treatment with sodium nitrite in combination with phosphoric acid, and subsequently with copper sulphate and sodium chloride, thus obtaining an intermediate b-6. Intermediate b-6 may then be reacted with an intermediate of formula Ri-L-(leaving group) in the presence of a base such as triethylamine and optionally in the presence of EDC or an alcohol such as t-butanol, and in a suitable solvent such as dichloromethane, thus obtaining an intermediate b-8. Intermediate b-8 may further be derivatized with an amine of formula FLjN-A-Re in a suitable solvent such as acetonitrile to obtain an intermediate b-9. Alternatively, intermediates b-6 may first be reacted with H^N-A-Re and then with formula Ri-L-(leaving group) as is shown in scheme B. Intermediate b-9 can finally be further reacted with R5COC1 or a functional equivalent thereof in the presence of a base such as triethylamine and in a suitable solvent such as dichloromethane. Conveniently, said reaction is carried out under an inert atmosphere. - An alternative way of preparing compounds of formula (I) is exemplified in scheme C. Intermediate c-1, prepared according to the procedure described in US 6,140,505, was reacted with thiocarbonyldiimidazole in* a reaction inert solvent such as tetrahydrofuran, and the resulting intermediate was further reacted with an amine such as for instance dimethylethylamine, thus obtaining the thiourea derivative c-2. Said intermediate c-2 was then cyclized with bromine in the presence of an acid such as acetic acid, thus obtaining a benzthiazole derivative c-3. The following two steps in scheme C are analogous as those described for the preparation of intermediates a-5 and a-6 in scheme A. If so desired, intermediate c-5 can be TV-oxidized using for example meta chloroperbenzoic acid in dichloromethane. A particular way of preparing acetamide substituted benzothiazoles is depicted in scheme D. Scheme D hitermediate d-1, prepared following the procedure as described in Scheme A, may be reacted with chloroacetylchloride, or a functional analogue, in the presence of a base such as triethylamine and in a solvent such as 1,4-dioxane in order to obtain an amide of formula d-2. Said intermediate d-2 can further be reacted with an amine of formula NRaRb whereby Ra and Rb are defined as the possible substituents on an amino group in the variable RS. Another particular way of preparing acetamide substituted benzothiazoles is depicted in Intermediate e-2 can be prepared by treating intermediate e-1, prepared following the procedure described in scheme A, with a base such as sodiumcarbonate in an aqueous medium such as a water dioxane mixture. The synthesis steps depicted in scheme E to obtain intermediate e-6 are all analogous to reaction procedures described in the above synthesis schemes. A. number of intermediates and starting materials used in the foregoing preparations are known compounds, while others may be prepared according to art-known methodologies of preparing said or similar compounds. Scheme F Intermediate f-2, corresponding to intermediate a-3 in scheme A, may be prepared by adding an amine of formula tySf-Ri to an intermediate f-1 in a suitable solvent such as isopropanol. The compounds according to the present invention may also be prepared according to the method as depicted in scheme G. The benzothiazole derivative g-1 may be reacted with chlorosulfonic acid and subsequently treated with thionylchloride to yield intermediate g-2. Said intennediate g-2 may be further reacted with intermediate g-3 yielding an intermediate g-4 wherein PG means a suitable protecting group such as for example Boc,. Said reaction may be performed in a suitable solvent such as for example 2-methyltetrahydrofuran and optionally in the presence of a suitable base such as triethylamine, The intermediate g-4 may then be reacted with a suitable reagent such as metachloroperoxybenzoic acid (mCPBA) or magnesium monoperoxyphtalate hexahydrate (MMPP) in the presence of a suitable solvent such as 2-methyltetrahydrofuran in ethanol thereby producing intermediates g-5 and g-6. Intermediates g-S and g-6 may be further derivatized with a compound of formula HN(Rs)A-Re yielding intermediate g-7 after a deprotection reaction. Intermediate g-7 may then be reacted with an intermediate of formula Ri-L-(leaving group) in the present of a base such as triethylarnine and optionally in the presence of EDC or an alcohol such as t-butanol, and in a suitabl^ solvent such as dichloromethane, thus obtaining the compound g-8 which is compound of formula (I). Another particular way of preparing some compounds according to the invention is depicted in scheme H. After deprotection of the protective group ofh-1 using methods known in the art, such as HCl in isopropanol when PG is a Boc group, the free amine is reacted with a carboxylic acid , in the presence of a coupling agent such as EDC and HOBt, in an organic solvent such as dichloromethane, to yield h-2. hi one preferred embodiment, the carboxylic acid is the Boc-protected L-tert-Leucine. h-2 is then deprotected as previously described and reacted with chloroacetic acid in the presence of EDC and HOBt, in dichloromethane, to give intermediate h-3, which is further substituted by a primary amine in an organic solvent such as dimethyl formamide (DMF), under heating conditions, then protected by an adequate protective group such as Boc, to give intermediate h-4. Intermediate h^4 is reacted with mefa-chloroperoxybenzoic acid in dichloromethane to give the sulfoxide h-5. further substituted by an amine of formula NHRsR4 in an organic solvent such as acetonitrile, under heating conditions. The final compound h-6 is obtained after removal of the protective group as previously described. The compounds of formula (I) may also be converted to the corresponding JV-oxide forms following art-known procedures for converting a trivalent nitrogen into its Noxide form as is shown for instance for intermediate c-6 in scheme C. Said W-oxidation reaction may generally be carried out by reacting the starting material of formula (I) with an appropriate organic or inorganic peroxide. Appropriate inorganic peroxides comprise, for example, hydrogen peroxide, alkali metal or earth alkaline metal peroxides, e.g. sodium peroxide, potassium peroxide; appropriate organic peroxides may comprise peroxy acids such as, for example, benzenecarboperoxoic acid or halo substituted benzenecarboperoxoic acid, e.g. 3-chloro-benzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, alkylhydroperoxides, e.g. tert-bntyl hydroperoxide. Suitable solvents are, for example, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketpnes, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of such solvents. An interesting group of intermediates are those intermediates of formula a-8, b-9 or d-1 wherein -A-Re is hydrogen. Said intermediates may also have pharmacological properties similar to those pharmacological properties of the compounds of formula (I). The present compounds can thus be used in animals, preferably in mammals, and in particular in humans as pharmaceuticals per se, in mixtures with one another or in the form of pharmaceutical preparations. Furthermore, the present invention relates to pharmaceutical preparations which as active constituents contain an effective dose of at least one of the compounds of formula (I) in addition to customary pharmaceutically innocuous excipients and auxiliaries. The pharmaceutical preparations normally contain 0.1 to 90% by weight of a compound of formula (I). The pharmaceutical preparations can be prepared in a manner known per se to one of skill in the art. For this purpose, at least one of a compound of formula (I), together with one or more solid or liquid pharmaceutical excipients and/or auxiliaries and, if desired, in combination with other pharmaceutical active compounds, are brought into a suitable administration form or dosage form which can then be used as a pharmaceutical in human medicine or veterinary medicine. Pharmaceuticals which contain a compound according to the invention can be administered orally, parenterally, e.g., intravenously, rectally, by inhalation, or topically, the preferred administration being dependent on the individual case, e.g., the particular course of the disorder to be treated. Oral administration is preferred. The person skilled in the art is familiar on the basis of his expert knowledge with the auxiliaries which are suitable for the desired pharmaceutical formulation. Beside solvents, gel-forming agents, suppository bases, tablet auxiliaries and other active compound carriers, antioxidants, dispersants, emulsifiers, antifoams, flavor corrigents, preservatives, solubilizers, agents for achieving a depot effect, buffer substances or colorants are also useful. Due to their favorable pharmacological properties, particularly their activity against multi-drug resistant HIV protease enzymes, the compounds of the present invention are useful in the treatment of individuals infected by HIV and for the prophylaxis of these individuals. In general, the compounds of the present invention may be useful in the treatment of warm-blooded animals infected with viruses whose existence is mediated by, or depends upon, the protease enzyme. Conditions which may be prevented or treated with the compounds of the present invention, especially conditions associated with HIV and other pathogenic retroviruses, include AIDS, AIDS-related complex (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS diseases caused by retroviruses, such as, for example HIV mediated dementia and multiple sclerosis. The compounds of the present invention or any subgroup thereof may therefore be used as medicines against above-mentioned conditions. Said use as a medicine or method of treatment comprises the systemic administration to HFV-infected subjects of an amount effective to combat the conditions associated with HIV and other pathogenic retroviruses, especially HIV-1. Consequently, the compounds of the present invention can be used in the manufacture of a medicament useful for treating conditions associated with HIV and other pathogenic retroviruses, in particular medicaments useful for treating patients infected with multi-drug resistant HIV virus. hi a preferred embodiment, the invention relates to the use of a compound of formula (I) or any subgroup thereof in the manufacture of a medicament for treating or combating infection or disease associated with multi-drug resistant retrovirus infection in a mammal, in particular HIV-1 infection. Thus, the invention also relates to a method of treating a retroviral infection, or a disease associated with multi-drug resistant retrovirus infection comprising administering to a mammal in need thereof an effective amount of a compound of formula (I) or a subgroup thereof. In another preferred embodiment, the present inyention relates to the use of formula (I) or any subgroup thereof in the manufacture of a medicament for inhibiting a protease of a multi-drug resistant retrovirus in a mammal infected with said retrovirus, in particular HIV-1 retrovirus. In another preferred embodiment, the present invention relates to the use of formula (I) or any subgroup thereof in the manufacture of a medicament for inhibiting multi-drug resistant retroviral replication, in particular HIV-1 replication. The compounds of the present invention may also find use in inhibiting ex vivo samples containing HIV or expected to be exposed to HIV. Hence, the present compounds may be used to inhibit HIV present in a body fluid sample which contains or is suspected to contain or be exposed to HIV. Also, the combination of an antiretroviral compound and a compound of the present invention can be used as a medicine. Thus, the present invention also relates to a product containing (a) a compound of the present invention, and (b) another antiretroviral compound, as a combined preparation for simultaneous, separate or sequential use in treatment of retroviral infections, in particular, in the treatment of infections with multi-drug resistant retroviruses. Thus, to combat or treat HIV infections, or the infection and disease associated with HIV infections, such as Acquired Immunodeficiency Syndrome (AIDS) or AIDS Related Complex (ARC), the compounds of this invention may be co-administered in combination with for instance, binding inhibitors, such as, for example, dextran sulfate, suramine, polyanions, soluble CD4; fusion inhibitors, such as, for example, T20, T1249, SHC-C, PRO542; coreceptor binding inhibitors, such as, for example, AMD 3100 (Bicyclams), TAK 779; RT inhibitors, such as, for example, foscarnet and prodrugs, MIV-310; nucleoside RTIs, such as, for example, AZT, 3TC, DDC, DDI, D4T, Abacavir, FTC, DAPD, dOTC; nucleotide RTIs, such as, for example, PMEA, PMPA, tenofovir; NNRTIs, such as, for example, nevirapine, delavirdine, efavirenz, 8 and 9-C1 TIBO (tivirapine), loviride, TMC-125, TMC-120, MKC-442, UC 781, Capravirine, DPC 961, DPC963, DPC082, DPC083, calanolide A, SJ-3366, TSAO, 4"-dearninated TSAO; RNAse H inhibitors, such as, for example, SP1093V, PD126338; TAT inhibitors, such as, for example, RO-5-3335, K12, K37; integrase inhibitors, such as, for example, L 708906, L 731988; protease inhibitors, such as, for example, amprenavir, ritonavir, nelfinavir, saquinavir, indinavir, lopinavir, BMS 232632, BMS 186316, DPC 681, DPC 684, tipranavir, AG1776, DMP 450, L 756425, PD178390, PNU 140135; glycosylation inhibitors, such as, for example, castanospermine, deoxynojirimycine. The combination may provide a synergistic effect, whereby viral infectivity and its associated symptoms may be prevented, substantially reduced, or eliminated completely. The compounds of the present invention may also be administered in combination with immunomodulators (e.g., bropirimine, anti-human alpha interferon antibody, IL-2, methionine enkephalin, interferon alpha, and naltrexone) antibiotics (e.g., pentamidine isothiorate) , vaccines or hormones (e.g growth hormone) to ameliorate, combat, or eliminate HIV infection and its symptoms. For an oral administration form, compounds of the present invention are mixed with suitable additives, such as excipients, stabilizers or inert diluents, and brought by means of the customary methods into the suitable administration forms, such as tablets, coated tablets, hard capsules, aqueous, alcoholic, or oily solutions. Examples of suitable inert carriers are gum arabic, magnesia, magnesium carbonate, potassium phosphate, lactose, glucose, or starch, in particular, corn starch. In this case the preparation can be carried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueous or alcoholic solutions are water, ethanol,. sugar solutions, or mixtures thereof. Polyethylene glycols and polypropylene glycols are also useful as further auxiliaries for other administration forms. For subcutaneous or intravenous administration, the active compounds, if desired with the substances customary therefor such as solubilizers, emulsifiers or further auxiliaries, are brought into solution, suspension, or emulsion. The compounds of formula (I) can also be lyophilized and the lyophilizates obtained used, for example, for the production of injection or infusion preparations. Suitable solvents are, for example, water, physiological saline solution or alcohols, e.g. ethanol, propanol, glycerol, in addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned. Suitable pharmaceutical formulations for administration in the form of aerosols or sprays are, for example, solutions, suspensions or emulsions of the compounds of formula (I) or their physiologically tolerable salts in a pharmaceutically acceptable solvent, such as ethanol or water, or a mixture _of such solvents. If required, the formulation can also additionally contain other pharmaceutical auxiliaries such as surfactants, emulsifiers and stabilizers as weir as a propellant. Such a preparation customarily contains the active compound in a concentration from approximately 0.1 to 50%, in particular from approximately 0.3 to 3% by weight. In order to enhance the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions, it can be advantageous to employ a-, P- or y-cyclodextrins or their derivatives. Also co-solvents such as alcohols may improve the solubility and/or the stability of the compounds of formula (I) in pharmaceutical compositions. In the preparation of aqueous compositions, addition salts of the subject compounds are obviously more suitable due to their increased water solubility. Appropriate cyclodextrins are a-, (3- or y-cyclodextrins (CDs) or ethers and mixed ethers thereof wherein one or more of the hydroxy groups of the anhydroglucose units of the cyclodextrin are substituted with Chalky!, particularly methyl, ethyl or isopropyl, e.g. randomly methylated p-CD; hydroxyCi-ealkyl, particularly hydroxyethyl, hydroxypropyl or hydroxybutyl; carboxyCi-ealkyl, particularly carboxymethyl or carboxyethyl; C^galkylcarbonyl, particularly acetyl; CiealkyloxycarbonylCi- ealkyl or carboxyCi-galkyloxyCi-galkyl, particularly carboxymethoxypropyl or carboxyethoxypropyl; Ci-galkylcarbonyloxyCi-galkyl, particularly 2-acetyloxypropyl. Especially noteworthy as complexants and/or solubilizers are P-CD, randomly methylated (3-CD, 2,6-dimethyl-p-CD, 2-hydroxyethyl-p-CD, 2-hydroxyethyl-y-CD, 2-hydroxypropyl-y-CD and (2-carboxymethoxy)propyl-p-CD, and in particular 2-hydroxypropyl-p-CD (2-HP-PCD). The term mixed ether denotes cyclodextrin derivatives wherein at least two cyclodextrin hydroxy groups are etherified with different groups such as, for example, hydroxy-propyl and hydroxyethyl. An interesting way of formulating the present compounds in combination with a cyclodextrin or a derivative thereof has been described in EP-A-721,331. Although the formulations described therein are with antifungal active ingredients, they are equally interesting for formulating the compounds of the present invention. The formulations described therein are particularly suitable for oral administration and comprise an antifungal as active ingredient, a sufficient amount of a cyclodextrin or a derivative thereof as a solubilizer, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition. Said formulations may also be rendered more palatable by adding pharmaceutically acceptable sweeteners and/or flavors. Other convenient ways to enhance the solubility of the compounds of the present invention in pharmaceutical compositions are described in WO-94/05263, PCT application No. PCT/EP98/01773, EP-A-499,299 and WO 97/44014, all incorporated herein by reference. More in particular, the present compounds may be formulated in a pharmaceutical composition comprising a therapeutically effective amount of particles consisting of a solid dispersion comprising (a) a compound of formula (I), and (b) one or more pharmaceutically acceptable water-soluble polymers. The term "a solid dispersion" defines a system in a solid state (as opposed to a liquid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. When said dispersion of the components is such that the system is chemically and physically uniform or homogenous throughout or consists of one phase as defined in thermodynamics, such a solid dispersion is referred to as "a solid solution". Solid solutions are preferred physical systems because the components therein are usually readily bioavailable to the organisms to which they are administered. The term "a solid dispersion" also comprises dispersions which are less homogenous throughout than solid solutions. Such dispersions are not chemically and physically uniform throughout or comprise more than one phase. The water-soluble polymer in the particles is conveniently a. polymer that has an apparent viscosity of 1 to 100 mPa.s when dissolved in a 2 % aqueous solution at solution. Preferred water-soluble polymers are hydroxypropyl methylcelluloses or HPMC. HPMC having a methoxy degree of substitution from about 0.8 to about 2.5 and a hydroxypropyl molar substitution from about 0.05 to about 3.0 are generally water soluble. Methoxy degree of substitution refers to the average number of methyl ether groups present per anhydroglucose unit of the cellulose molecule. Hydroxy-propyl molar substitution refers to the average number of moles of propylene oxide which have reacted with each anhydroglucose unit of the cellulose molecule. The particles as defined hereinabove can be prepared by first preparing a solid dispersion of the components, and then optionally grinding or milling that dispersion. -32- Various techniques exist for preparing solid dispersions including melt-extrusion, spray-drying and solution-evaporation, melt-extrusion being preferred. It may further be convenient to formulate the present compounds in the form of nanoparticles which have a surface modifier adsorbed on the surface thereof in an amount sufficient to maintain an effective average particle size of less than 1000 nm. Useful surface modifiers are believed to include those which physically adhere to the surface of the atitiretro viral agent but do not chemically bond to the antiretroviral agent. Suitable surface modifiers can preferably be selected from known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Preferred surface modifiers include nonionic and anionic surfactants. Yet another interesting way of formulating the present compounds involves a pharmaceutical composition whereby the present compounds are incorporated in hydrophilic polymers and applying this mixture as a coat film over many small beads, thus yielding a composition with good bioavailability which can conveniently be manufactured and which is suitable for preparing pharmaceutical dosage forms for oral administration. Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of a hydrophilic polymer and an antiretroviral agent and (c) a seal-coating polymer layer. Materials suitable for use as cores in the beads are manifold, provided that said materials are pharmaceutically acceptable and have appropriate dimensions and firmness. Examples of such materials are polymers, inorganic substances, organic substances, and saccharides and derivatives thereof. Another aspect of the present invention concerns a kit or container comprising a compound of formula (I) in an amount effective for use as a standard or reagent in a test or assay for determining the ability of a potential pharmaceutical to inhibit HIV protease, HIV growth, or both. This aspect of the invention may find its use in pharmaceutical research programs. The compounds of the present invention can be used in high-throughput target-analyte assays such as those for measuring the efficacy of said compound in HIV treatment. The compovmds of the present invention can be used in phenotypic resistance monitoring assays, such as known recombinant assays, in the clinical management of resistance developing diseases such as HIV. A particularly useful resistance TK/f monitoring system is a recombinant assay known as the Antivirogram . The Antivirogram™ is a highly automated, high throughput, second generation, recombinant assay that can measure susceptibility, especially viral susceptibility, to the compounds of the present invention. (Hertogs K, de Bethune MP, Miller V et al. Antimicrob Agents Chemother, 1998; 42(2)-.269-276, incorporated by reference). The dose of the present compounds or of the physiologically tolerable salt(s) thereof to be administered depends on the individual case and, as customary, is to be adapted to the conditions of the individual case for an optimum effect. Thus it depends, of course, on the frequency of administration and on the potency and duration of action of the compounds employed in each case for therapy or prophylaxis, but also on the nature and severity of the infection and symptoms, and on the sex, age, weight and individual responsiveness of the human or animal to be treated and on whether the therapy is acute or prophylactic. Customarily, the daily dose of a compound of formula (I) in the case of administration to a patient approximately 75 kg in weight is 1 mg to Ig, preferably 3 mg to 0.5 g. The dose can be administered in the form of an individual dose, or divided into several, e.g. two, three, or four, individual doses. Experimental Part Preparation of the compounds of formula (I) and their intermediates Example 1 : Preparation of compound 29 A mixture of 1.56 g of intermediate a-3 (R2= H and R4 = -CH2-CH2-NH-(2-pyridinyl)) and 0.59 g of triethylamine in 50 ml of dichloromethane was stirred at 0°C. Then 1.25 g of 2-(acetylamino)-6-benzotniazolesulfonyl chloride, was added and the reaction mixture stirred overnight at room temperature. After washing with water, the organic layer was separated, dried and the solvent evaporated. The brown solid obtained was re-dissolved in methanol at 70°C, cooled and filtered off, yielding 1.9 g (75 %) of intermediate a-4 (R2 = H, IU = -CH2-CH2-NH-(2-pyridinyl) and -A-R6 = H). To a mixture of 6 g of intermediate a-4 (R2 = H, IU = -CH2-CH2-NH-(2-pyridinyl) and -A-Rg = H) in 50 ml of dichloromethane, 7.3 ml of trifluoracetic acid were added. The reaction mixture was stirred at room temperature for 6 hours. Extra dichloromethane was added and washed with NaHCOs solution. The organic layer was dried and the solvent evaporated under reduced pressure, yielding 4.1 g (81%) of intermediate a-5 (R2 = H, R4 = -CH2-CH2-NH-(2-pyridinyI) and -A-R6 = H). A mixture of 0.60 g of intermediate a-5 (R2 = H, R4 = -CH2-CH2-NH-(2-pyridmyl) and -A-R6 = H), 0.29 g of l-[[[[(3S,3aR,6aS)+(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3- yl]oxy]carbonyl]oxy]- 2,5-pyrrolidinedione (prepared analogously to the procedure described in WO9967417) and 0.33g of triethylamine in 15 ml of dichloromethane was stirred at room temperature for 24 hours. Solvents were evaporated and the solid obtained was redissolved in methanol at 70°C, cooled and filtered off, yielding 0.53 g (69%) of compound 29. Mass Spectral data: m/z = 711 (M+H) Example 2 : Preparation of compound 31 compound 31 A mixture of 540 mg of intermediate a-5 (R2 = H, Rt = -CH2-(2-pyridinyl) and —A-Re = H), 135 mg of tert-butanol, 192 mg of EDC and 101 mg of triethylamine in 5 ml of dichloromethane, was stirred overnight at room temperature. The reaction mixture was then washed with a Na2CC>3 solution and brine. The organic layer was separated, dried and the solvent evaporated. The residue was purified by preparative-HPLC, yielding 184 mg (26%) of compound 31. Mass spectral data: m/z = 702 (M+H) Example 3 : Preparation of compound 33 compound 33 A mixture of 540 mg of intermediate a-5 (R2 = H, R4 = -CH2-(2~pyridinyl) and —A-Re = H), 271 mg of l-[[[t(3S,3aR56aS)+(3R,3aS,6aR)-hexahydrofuro[2)3-b]furan-3- yl]oxy]carbonyl]oxyj- 2,5-pyrrolidinedione and 101 mg of triethylamine in 5 ml of -35- dichloromethane was stirred at room temperature for 24 hours. The reaction mixture was then washed with a Na2COs solution and brine. The organic layer was separated, dried and the solvent evaporated. The residue was purified by preparative-HPLC, yielding 161 mg (23%) of compound 33. Mass spectral data: m/z = 696 (M+H) Example 4 : Preparation of compound 2 compound 2 -C O—CHj—CH3 To a mixture of 0.3g of racemic intermediate a-8 (R2= H, R»= isobutyl, -A-Re = H and -L-Ri = [[hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) and 0.06Ig triethylamine in anhydrous dioxane is added in several portions 0.18g ethyl chloroformate. The reaction mixture was heated overnight to 60° C. To the mixture is added 10ml water and 0.4g potassium carbonate followed by 2 hours of stirring. Dioxane was removed in vacuo. The aqueous phase was extracted with dichloromethane. The combined organic phase was concentrated and the obtained residue purified by chromatography yielded 0.23g (68%) of compound 2. Example 5 : Preparation of compound 56 compound 56 A mixture of 19.66 g of [2R-hydroxy-3-[(2-methylpropyl)amino]-lS-(phenylmethyl)- propyl]-carbamic acid, 1,1-dimethylethyl ester (described in WO97/18205) and 17.76 g of triethylamine in 200 ml of dichloromethane is stirred at 0°C for 20 minutes under inert atmosphere. 18.72 g of 2-(acetylamino)-6-benzothiazolesulfonyl chloride was added in small portions and the mixture was then stirred at room temperature for 2 hours. After washing with 5% HCl solution, saturated sodium bicarbonate solution and brine, the organic layer was dried and the solvent evaporated under reduced pressure. The crude product was purified on silica gel eluting with 4% methanol in dichloromethane yielding 30.82 g (90%) of intermediate b-4 (R2= H and R4= isobutyl). To a mixture of 13.75 g of intermediate b-4 (R2= H and R4= isobutyl) in 130 ml of ethanol/dioxane (1:1) 65 ml of HCl (5 to 6 N hi isopropanol) was added. The reaction was stirred at 50°C for 22 hours. After evaporating, the salt was treated with saturated sodium bicarbonate solution and extracted with dichloromethane. The organic layer was dried, the solvent evaporated and the residue purified on silica gel eluting with 3% methanol in dichloromethane yielding 18.36 g (72%) of intermediate b-5 (R2= H and R A solution of 1.81 g of sodium nitrite in 10 ml of water was added over a 40-min period to a mixture of 9.80 g of intermediate b-5 (R.2= H and R4= isobutyl) in 180 ml of 85% phosphoric acid held at -10°C. After being stirred for 1.5 hour, the mixture was added to a stirred solution of 10.90 g of copper sulphate pentahydrate and 12.67 g of sodium chloride in 80 ml of water at -10°C. The mixture was stirred for 1.5 hour , being allowed to warm to room temperature, and then made alkaline (pH = 8) with an ammonium hydroxide solution under cooling. The resulting solution was extracted with ethylacetate. After drying and evaporating the solvent, 7.59 g (74%) of intermediate b- 6 (Ra= H and Rr= isobutyl) was obtained. A mixture of 1.63g of intermediate b-6 (R2= H and R4= isobutyl), 0.80 g of 1-[[[[(3S)- tetrahydro-3-furanyl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione and 0.53 g 6f triethylamine in 50 ml of dichloromethane was stirred at room temperature for 5 hours. After evaporation of dichloromethane under reduced pressure, the crude product was purified on silica gel eluting with 3% of methanol in dichloromethane yielding 0.58 g (29%) of intermediate b-8 (R2= H, Rj= isobutyl, RX-L- = [[(3S)-tetrahydro-3- furanyl] oxy] carbonyl). To a solution of 0.23 g of intermediate b-8 (R2= H, R4= isobutyl, RrL- = [[(3S)- tetrahydro-3-furanyl]oxy]carbonyl) in 30 ml of acetonitrile was added 0.20 g of 7V,7V-dimethylethylenediamine. This solution was stirred at 80°C for 4 hours. After evaporation of acetonitrile under reduced pressure, the crude product was purified on silica gel eluting with 2% of methanol in dichloromethane yielding 0.12 g (50%) of compound 56. Mass spectral data: m/z = 634 (M+H) Example 6 : Preparation of compound 44 "' compound 44 N To a solution of 0.90 g of intermediate b-6 (Ra= H and R4= isobutyl) in 20 ml of acetonitrile was added 0.85 g of N,N-dimethylethylenediamine. This solution was stirred at 80°C for 3 hours. After evaporation of acetonitrile under reduced pressure, the product was washed with 2% sodium carbonate and extracted with ethylacetate. The silica gel eluting with 1% of ammonia in dichloromethane, yielding 0.57 g (58%) of intermediate b-7 (R2= H, R^ isobutyl and -A-R6 = CH2CH2N(CH3)2). A mixture of 0.65 g of (± trans)- 4-(dimethylammo)tetrahydro-3-furanol (synthesis described in US 3,265,711), 3.78 g of disuccinimidyl carbonate and 1.50 g of triethylamine in 30 ml of dichloromethane was stirred at room temperature for 24 hours. After washing the resulting solution with saturated sodium bicarbonate, the organic layer was dried and the solvent evaporated under reduced pressure to give 0.52 g (38%) of (± ?rara)-l-[[[[4 carbonyl]oxy]-2,5-pyrrolidinedione. A mixture of 0.25g of intermediate b-7 (Ri - H, R2 = CH2CH2N(Me)2), 0.13 g (± trans)-1 -[ [ [[4-(dimethylamino)-tetrahydro-furan-3 -yl]oxy] carbonyl] oxy] -2,5- pyrrolidinedione and 0.07 g of triethylamine in 15 ml of dichloromethane was stirred at room temperature for 24 hours. After evaporation of dichloromethane under reduced pressure, the crude product was purified on silica gel eluting with 4% of ammonia in dichloromethane, yielding 0.14 g (43%) of compound 44. Mass spectral data : m/z = 677 (M+H) Example 7 : Preparation of compound 19 To a solution of 0.83 g of intermediate b-6 (R2= H and R4= isobutyl) in 20 ml of acetonitrile was added 0.40 g of N-(2-aminoethyl)-pyrrolidine. This solution was stirred at 80°C for 4 hours. After evaporation of acetonitrile under reduced pressure, the product was washed with 2% sodium carbonate and extracted with ethylacetate. The organic layer was dried, evaporated under reduced pressure and purified on silica gel eluting with 1% of ammonia in dichloromethane, yielding 0.47 g (49%) of intermediate b-7 (R2= H, R4= isobutyl and -A-R6 = CH2CH2-(l-pyrrolidinyl)). A mixture of 0.47g of intermediate b-7 (R2= H, R4= isobutyl and -A-R6 = CH2CH2-(1- pyrrolidinyl)) 0.24 g of l-[[[[(3R,3aS36aR)-hexahydrofijro[2,3-b]furan-3-yl]oxy]- carbonyljoxy]- 2,5-pyrrolidinedione and 0.10 g of triethylamine in 20 ml of -38- dichloromethane was stirred at room temperature for 24 hours. After evaporation of dichloromethane under reduced pressure, the crude product was purified on silica gel eluting with 2% of ammonia in dichloromethane, yielding 0.54 g (88%) of intermediate b-9 (R2= H, R4= isobutyl, -A-R6 = CH2CH2-(l-pyrrolidinyl) and -L-Ri = [[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl). To a solution of 0.54 g of intermediate b-9 (R2= H, R4= isobutyl, -A-R6 = CH2CH2-(1- pyrrolidinyl) and -L-Ri = [[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]- carbonyl) and 0.16 g of triethylamine in 40 ml of dichloromethane under inert atmosphere was added 0.22 g of acetyl chloride. After stirring at room temperature for 2 hours and washing with water, the organic layer was dried and evaporated under reduced pressure to give 0.50 g (87%) of compound 19. Mass spectral data : m/z = 744 (M+H) Example 8 : Preparation of compound 16 To a solution of 4.91 g of [(lS,2R)-3-[[(4-aminophenyl)sulfonyl](2-methylpropyl>- amino]-2-hydroxy-l-(phenylmethyl)propyl]-carbaniic acid, 1,1-dimethylethyl ester (prepared as described in US 6,140,505) in 40 ml of anhydrous tetrahydrofuran, was added 1.78 g of l,l'-thiocarbonyldiimidazole. This solution was refluxed 4 hours. After cooled at 25°C, 0.88 g of N,N-dimethylethylamine was added and then this solution was again refluxed 16 hours. After cooling at 25°C, evaporation of tetrahydrofuran under reduced pressure, dichloromethane was added, washed with water, the organic phase was dried and concentrated. This crude product was purified on silica gel eluting with 5% of methanol in dichloromethane, yielding 3.8 g (62%) of intermediate c-2 (R.2~ H, Rj= isobutyl). Mass spectral data : m/z = 622 (M+H), 566, 532. To a solution of 2.5 g of the intermediate c-2 (R2= H, R4= isobutyl) in 10 ml of acetic acid was added a solution of 0.64g of bromine in 10ml acetic acid. After 2 hours, this crude product was concentrated, dichloromethane added and this organic phase washed with a saturated potassium carbonate solution. The organic phase was dried on magnesium sulfate, filtered and concentrated, yielding intermediate c-3 (R2= H, R4= isobutyl). Mass spectral data : m/z = 620 (M+H), 564, 520, 261. The intermediate c-3 (R2= H, R4= isobutyl) was diluted with 20 ml of dichloromethane and 5 ml of trifuoroacetic acid were added. This solution was stirred for 1 hour and then concentrated. This residue was washed with a potassium carbonate solution and extracted with dichloromethane. This crude material was purified on silica gel eluting with 5% of methanol in dichloromethane yielding 1.5 g (72%) of the intermediate c-4 (R2= H, R4= isobutyl). 1.5 g of the intermediate c-4 (R2= H, R4- isobutyl), 0.81 g of ]-[[[[(3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]-2,5-pyrrolidinedione 0.67 g of triethylamine in 5 ml of dichloromethane was stirred for 4 hours at room temperature. This crude product was directly purified on silica gel eluting with 5% methanol in dichloromethane, yielding 0.80 g (39%) of compound 16. Example 9 : Preparation of compound 27 compound 27 To 0.34 g of compound 16 in 5ml of dichloromethane was added 0.08g of sodium bicarbonate and 0.15g (75%) of meta chloroperbenzoic acid. This solution was stirred 2 hours at room temperature. Water was added and the residue was extracted with dichloromethane. The organic phase was dried on magnesium sulfate, filtered and concentrated. This crude material was purified on silica gel eluting with 5% of methanol in dichloromethane yielding 0.09 g (26%) of compound 27, Mass spectral data : m/z = 692 (M+H) Example 10 : Preparation of compound 11 To a mixture of 2.32g 2-amino-N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2- methylpropyl)-6-benzothiazolesulfonamide and l.Og triethylamine in dichloromethane was added 1.47g l-[[[[(3R,3aS)6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]- oxy]- 2,5-pyrrolidinedione. After overnight stirring the reaction mixture was washed with a saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated. The obtained, residue was purified by column (dichloromethanemethanol 95:5) to afford 2.76g intermediate d-1 (R2= H, R4= isobutyl, -A-Re = H and -L-Ri = [[(3R,3aS,6aR)-hexahydroruro[2,3-b]furan-3- yl]oxy]carbonyl) (88%). To a mixture of intermediate d-1 (R2= H, R^= isobutyl, -A-Rs = H and —L-Ri = [[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) (2.0g; 3.3 mmole) and triethylamine (1.16g; 11.5 mmole) in dry 1,4-dioxane is added chloroacetylchloride (429 mg; 3.8 mmole). The resulting mixture was stirred at rt for 3 hours. Another portion of chloroacetylchloride (180mg; 1.5 mmole) was added and stirring was continued for 3 hours. After evaporation of the solvent the residue was purified by chromatography (dichloromethanermethanol 98:2) to afford 1.57 g (70%) of intermediate d-2 (R2= H, R4= isobutyl, -A-Rg = H and -L-R] = [[(3R,3aS,6aR> hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl). Mass spectral data : (ES+): 681/683(M+H). To a solution of the intermediate d-2 (R2= H, R4= isobutyl, -A-Re = H and -L-Ri = [[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) (0.45g; 0.66 mmole) in tetrahydrofuran was added 4.6ml of an 40% wt aqueous dimethylamine solution. After stirring for two hours tetrahydrofuran was evaporated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate. Concentration in vacuo yielded 0.42g (92%) of compound 11. Mass spectral data: (ES+): 690 (M+H), 560. Example 11 : Preparation of compound 12 compound 12 To a solution of the intermediate d-2 (Rj= HJ, R4= isobutyl, -A-R^ = H and -L-Ri = [[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl) in dichloromethane was 1.5 eq. of pyrrolidine together with sodium carbonate as a base. After overnight stirring at room temperature the solvent was removed in vacuo. The residue was purified by chromatography (dichloromethane:methanol) to yield 76% of compound 12. Mass spectral data : (ES+) 715 (M+H) Example 12 : Preparation of compound 43 A mixture of 6.13g of intermediate e-1 (R2= H, R4= isobutyl and -A-R$ = H) and lOg sodium carbonate in water/dioxane (1/2) was heated to 80°C for 48 hours. Dioxane was removed in vacuo. The resulting aqueous phase was extracted twice with ethyl acetate. After drying over magnesium sulfate and filtration the combined organic phase was concentrated to yield 5.08g of intermediate e-2 (R2= H, R»= isobutyl and — A-Re = H). Mass spectral data (ES+): 549(M+H), 449. To a mixture of 3.0g 2-aminobenzothiazole intermediate e-2 (R2= H, R4= isobutyl and — A-R.6 — H) and l.lg triethylamine in dry 1,4-dioxane was added 0.77 'g chloroacetylchloride. The resulting mixture was stirred overnight. After evaporation of the solvent the residue was purified by chromatography (dichloromethanermethanol 98:2) to afford 2.7g (78%) of intermediate e-3 (R2= H, R4= isobutyl and -A-R6 = H). Mass spectral data (ES+): 625/627(M+H). To a solution of 0.8g intermediate e-3 (R$= H, R4= isobutyl and — A-Re = H) in tetrahydrofuran was added 8 ml of an 40% wt aqueous dimethylamine solution. After stirring for three hours tetrahydrofuran was evaporated. The aqueous layer was extracted with dichloromethane. The combined organic layers were dried over magnesium sulfate. Concentration in vacuo provided 0.58g (85%) of intermediate e-4 (R2= H, Ri= isobutyl, -A-R& = H and Ra=Rb =CH3). Mass spectral data (ES+): 634(M+H), 534. To a solution of intermediate e-4 (Rr= H, RA~ isobutyl, -A-Re = H and Ra=Rb ^CHs) in dichloromethane was added trifluoracetic acid (10 equivalents). After overnight stirring the organic phase was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, filtered and concentrated to afford the intermediate e-5 (R2= H, R4= isobutyl, -A-Re = H and Ra=Rt =CH3). To a solution of 0.35g 4-amino-2-methylbenzoic acid in dichloromethane was added at 0°C 0.09g 1-hydroxybenzotriazole and 0.13g EDC. After one half hour of stirring the temperature was allowed to rise to room temperature and stirring was continued for one more hour. After addition of the intermediate e-5 (R2= H, RI= isobutyl, -A-Re = H and Ra=Rb =CH3) the reaction mixture was stirred at room temperature for two days. Then the solvent was removed in vacuo and the obtained residue was purified by chromatography (dichloromethane:methanol 97:3) to afford 0.12g (29%) of compound 43. Mass spectral data (ES+): 667(M+H). Example 13 : Preparation of the intermediate f-2 (R?= H and R^= -CH7-(2-pvridinvD) 25 g of 2-pyridyknethylamine was stirred at reflux in 400 ml of isopropanol. Then a solution of 21 g of the 2S,3S-l,2-epoxy-3-(ter^butoxycarbonylammo)-4-phenylbutane, commercially available, in 200 ml of isopropanol was added dropwise. The reaction mixture was stirred overnight at reflux. After evaporation of the solvent, the residue was redissolved in dichloromethane and washed 4 times with water. The organic layer was dried and evaporated. The residue obtained was purified by chromatography (dichloromethane:7N NH3 in methanol, 98:2) to afford 24 g (84%) of intermediate f-2 (R2= H and 1*4= -CH2-(2-pvridinyl)). Example 14 : Preparation of compound 20 Compound 20 may also be prepared according to the method depicted in scheme G. The specific method is illustrated hereunder in scheme I. CISOjH O SMe S(0)Me 20 Chlorosulfonic acid (0.193 kg; 1.65 mol) was stirred at 10°C under nitrogen, i-1 was added carefully. The reaction mixture was stirred for 3 hours at 90°C. The heating was stopped and thionylchloride (0.079 kg; 0.66 mol) was added slowly. The reaction mixture was stirred for another hour at 90°C. The reaction mixture was cooled until 35°C and then 200 ml ethylacetate was added slowly. Another 200 ml of ethylacetate was added quickly after the beginning of the product precipitation. The precipitate was filtered and washed twice with 200 ml ethylacetate and twice with 1000 ml cold water. The precipitate was then stirred in a NaHCOa solution until pH = 7. This mixture was filtered and the white solid i-2 was dried in a vacuum oven at 50°C. (0.123 kg, 80%). (LC/MS MW+; 280,282) A mixture of 0.120 kg (0.36 mol) of intermediate i-3 and 0.073 kg (0.72 mol) of triethylamine in 2-methyltetrahydrofuran (1.150 kg) was stirred at 35 °C until dissolution of the reactants. Then 0.100 kg (0.36 mol) of intermediate i-2 was added and the reaction mixture was stirred for 1.5 hours at 55°C. After washing the reaction mixture with water (0.500 kg), the organic layer was separated and washed with 0.500 kg 1.5 N HC1 solution. Then the organic layer was separated, dried and evaporated yielding i-4; 0.208 kg ( 100%). (LC/MS MW4; 480,481,482) 0.208 kg (0.36 mol) of intermediate i-4 was stirred in a mixture of 1 kg 2-methyltetrahydrofuran, 0.060 kg H2O and 0.110 kg ethanol at 40°C until dissolution of all the reactants. Then magnesium monoperoxyphtalate hexahydrate 0.200 kg (0.4 mol) was added. The mixture was stirred arid heated for 15 min at 60°C. The reaction mixture was made alkaline with 0.400 kg Na2CC>3 until pH = 10. Intermediates i-5 and i-6. (about 70% i-5 and 30% i-6). (LC/MS M^i-5; 496,497,498 MW+i-6; 511,513) To this reaction mixture was added at 60°C 0.050 kg (0.43 mol) N-(2- aminoethylpyrrolidine. This mixture was stirred for 20 hours at 70°C. Then the slurry was cooled to 40°C and HC1 concentrated (12N) was added dropwise until pH = 7-8. A phase precipitation was then observed. The organic layer was separated, evaporated and dried in the vacuum oven at 50°C yielding Boc N-protected i-7; 0.217 kg (93%). (LC/MS MW"; 646,647,648) 0.217 kg (0.36 mol) of intermediate Boc N-protected i-7 was dissolved in 1.4 kg isopropanol at 50°C. Then 0.370 L HC1 5 a 6 N (2 mol) was added and the mixture was heated and stirred for 2.5 hours at 70°C. This hot reaction mixture was added dropwise to 0.50 kg cold (0°C-15°C) isopropanol. The precipitate was filtered and washed with diisopropyl ether. The slightly brown solid was triturated in a DIPE/toluene (50/50) mixture and then filtered and dried in the vacuum oven at 50°C, yielding 0.170 kg (76%) of i-7 HCl-salt. (LC/MS MW*; 546,547,548). A mixture of 1.3g of intermediate i-7 ,0.774 g of !-[[[[(3S,3aR,6aS)+(3R,3aS,6aR)- hexahydrofuro[2,3-b]furan-3-yl]oxy]carbonyl]oxy]- 2,5-pyrrolidinedione (prepared analogously to the procedure described in WO9967417) and 0.33g of triethylamine in 100 ml of dichloromethane was stirred at room temperature for 24 hours. This crude product was wahed with NaHCO3 solution. The organic layer was dried and the solvant evaporated under reduced pressure. The residue was purified on silica gel, yielding 0.74g (45%) of compound 20. Mass spectra data : m/z=702(M+H). Example 15 : Preparation of the compound 85 and its intermediatesR^ = isobutyl) This compound was prepared following the procedure depicted in scheme H. 11 g of intermediate h-1 (PG = Hoc, RI = isobutyl) [(!S,2R)-2-hydroxy-3-[(2- methylpropyl)[[2-(methylthio)-benzothiazol-6-yl]sulfonyl]amino]-l-(pheiiyl methyl)propyl]carbamic acid, 1,1-dimethylethyl ester were dissolved in 300 mL of HC1 in isopropanol and 100 mL of dichloromethane and the solution was stirred at room temperature overnight. The reaction mixture was then concentrated and treated with a mixture of dichloromethane and sodium hydroxide in water. The organic layer was then dried over MgSO4 and evaporated to give 8.8 g (97%) of the deprotected intermediate N-[(2R,3S)-3-amino-2-hydroxy-4-phenylbutyl]-N-(2-methylpropyl)[2-(methylthio)- benzothiazol-6-yl]sulfonamide, as a free base. Mass spectral data : m/z = 480 (M+H). 4.15 g of the previous intermediate, 2 g of Boc-L-fer/-Leucine, 1.17 g of HOBt and 1.66 g of EDC were dissolved in 150 mL of dichloromethane and stirred at room temperature overnight. The reaction mixture was then successively washed with a solution of NaHCO3 in water, brine, dried over MgSC>4 and evaporated to give 6 g (100 %) of intermediate h-2 [(lS)-l-[[[(lS,2R)-2-hydroxy-3-[(2-methylpropyl)[(2- (methylthio)-berizotMazol-6-yl)sulfonyl]arnino]-l-(phenymiethyl)propyl]aniino]- carbonyl]-2,2-dimethylpropyl]carbamic acid, 1,1-dimethylethyl ester. Mass spectral data: m/z = 693 (M+H). room temperature during 2h. The reaction mixture was then concentrated and treated with a mixture of dichloromethane and a solution of sodium carbonate in water. The organic phase was then washed with brine, dried over MgSCU and evaporated to give 3.9 g (76%) of the deprotected intermediate as a free base. Mass spectral data : m/z = 593 (M+H). 3.9 g of the previous intermediate, 0.69 g of chloroacetic acid, 0.98 g of HOBt, and 1.38 g of EDC were dissolved in 100 mL of dichloromethane and stirred at RT overnight. The reaction mixture was then washed with brine, dried over MgSCU and evaporated. The crude compound was purified on silica gel eluting with 0 to 5% methanol in dichloromethane, yielding 3.72 g (85%) of the desired intermediate h-3 2- [(cMoroacetyl)amino]-3,3-dimet3iyl-N-[(lS,2R)-2-hydi-oxy-3-[(2-methylpropyl)[[2- (methyltm'o)-be:nzotruazol-6-yl]sulfonyl] butanamide. Mass spectral data : m/z = 669 (M+H). 3.72 g of intermediate h-3 and 1.27 mL of meta-fluorobenzylamine were dissolved in DMF and stirred at 60°C during 2h. The reaction mixture was then concentrated and treated with a mixture of dichloromethane and a solution of sodium carbonate in water. The organic phase was then dried over MgSCU and evaporated to yield 4.3 g (100%) of the desired intermediate N'-[(3-fluorophenyl)methyl]glycyl-N-[(lS,2R)-2-hydroxy-3- [(2-methylpropyl)[[2-(methyltMo)benzothiazol-6-yl]sulfonyl]amino]-l-(phenyknethyl) propyl]-3-metiiyl-L-Valinamide. Mass spectral data: m/z = 758 (M+H). 4.2 g of the previous intermediate, 1.2 g of BocaO and 0.77 mL of triethylamine were dissolved in 50 mL of dichloromethane. The reaction mixture was stirred overnight at room temperature and 1.2 g of Boc2O were added. After 5h, the reaction mixture was successively washed with a solution of sodium carbonate in water, brine, dried over MgSO4 and evaporated. The crude compound was purified on silica gel eluting with 2 to 5% methanol in dichloromethane, yielding 3.2 g (67%) of the desired intermediate h^ 4N'-[(l,l-dimethylethoxy)carbonyl]-N'-[(3-fluorophenyl)methyl]gtycyl-N-[(lS,2R)-2- hydroxy-3-[(2-methylpropyl)[[2-(methylthio)benzo1:hiazol-6-yl]sulfonyl] amino]-!- (phenylmethyl)propyl]-3-methyl-L-Valinamide. Mass spectral data : m/z = 858 (M+H). 3.2 g of intermediate h-4 and 0.92 g of meta-chloroperoxybenzoic acid (mCPBA) were reacted in 100 mL of dichloromethane, at room temperature, during Ih30. The reaction mixture was then washed with a solution of sodium carbonate in water, dried over MgSO4 and evaporated to yield 3.45 g (100%) of the desired intermediate h-5 N'-[(l,ldimethylethoxy) carbonyl]-N'-[(3-fluorophenyl)met:hyl]glycyl-N-[(lS,2R)-2-hydroxy- 3-[(2-methylpropyl)[[2-(methylsulfinyl)benzothiazol-6-yl]sulfonyl]amino]-l-- (phenyhnethyl)propyl]-3-methyl-L-Valinarnide. Mass spectral data : m/z = 874 (M+H). 0.5 g of intermediate h-5 was reacted with 0.16 mL of N-(2-aminoethyl)pyrrolidine in 10 mL of acetonitrile, at 60°C, during Ih30. The reaction mixture was then evaporated and purified on silica gel eluting with 5 to 10% meiianol in dichloromethane, yielding 0.24 g (46%) of the desired intermediate N'-[(l,l-dimethylethoxy)carbonyl]-N'-[(3- fluorophenyl)methyl]glycyl-N-[(lS,2R)-2-hydroxy-3-[(2-methylpropyl)[[2-[2- (pyrrolidin-1 -yl)ethylamino]benzothiazol-6-yl] sulfonyl]amino]-1 - (phenyhnethyl)propyl]-3-methyl-L-Valinamide. Mass spectral data: m/z = 924 (M+H). 0.15 g of the previous intermediate was dissolved in 5 mL of HC1 in isopropanol. The reaction mixture was stirred at room temperature during 2h, then evaporated. The crude compound was purified by preparative HPLC, yielding 60 mg of the desired final compound 85 N'-[(3-fluorophenyl)methyl]giycyl-N-[(l S,2R)-2-hydroxy-3-[(2- methylpropyl)[[2-[2-(pyrrolidin-1 -yl)ethylamino]benzothiazol-6-yl]sulfonyl]amino] - (phenyhnethyl)propyl]-3-meHiyl-L-Valinamide, bis-trifiuoroacetate, obtained as a TFA salt. Mass spectral data : m/z = 824 (M+H). Example 16 : Preparation of the compound 86Rj = isobutyD 0.5 g of intermediate h-5 was reacted with 0.16 mL of 3-(dimethylamino)propylamine in 10 mL of acetonitrile, at 60°C, during 2h. The reaction mixture was then evaporated, yielding 0.54 g (100%) of the desired intermediate N'-[(l,l-dimethylethoxy)carbonyl]- N'-[(3-fluorophenyl)methyl]glycyl-N-[(lS,2R)-2-hydroxy-3-[[[2-[3- (dimethylamino)propylarnino]benzothiazol-6-yl]sulfonyl](2-methyl propyl)amino]-1 - (phenylmethyl)propyl]-3-methyl-L-Valinamide. Mass spectral data : m/z = 912 (M-t-H). 0.54 g of the previous intermediate was dissolved in 10 mL of HC1 in isopropanol. The reaction mixture was stirred at room temperature during 2h, then evaporated. The crude compound was purified by preparative HPLC, yielding 83 mg of the desired final compound 86 N'-[(3-fiuorophenyl)methyl]glycyl-N-[(lS,2R)-2-hydroxy-3-[[[2-[3- (dimethylamino)propylamino]benzothiazol-6-yl] sulfonyl] (2-methylpropyl)aminoj -1 - (phenylmelhyl)propylJ-3-methyl-L-Valinamide, bis-trifluoroacetate, obtained as a TFA salt. Mass spectral data : m/z = 812 (M+H). Example 17 : Preparation of the compounds 87 (Ri_ = isoburvF) 0.5 g of intermediate h-5 was reacted with 0.18 mg of N-methyl, N-(2-morpholin-4- ylethyl)amine in 10 mL of acetonitrile, at 60°C, overnight. 0.9 g of //-methyl, N-(2- morpholin-4-ylethyl)amine was then added again to the reaction mixture, which was further stirred during two days. The reaction mixture was then evaporated and purified on silica gel eluting with 5% methanol in dichloromethane, yielding 0.6 g (100%) of the desired intermediate N'-[(l,l-dimethylethoxy)carbonyl]-N'-[(3-fluorophenyl) methyl]glycyl-N-[(lS,2R)-2-hydroxy-3-[[[2-[^-methyl^V-(2-morphoUn-4-ylethyl) anuno]berjz;otbiazol-6-yl]sulfonyl](2-memylpropyl)amino]-l-(phenyknethyl)propyl]-3- methyl-L-Valinamide. Mass spectral data : m/z = 954 (M+H). 10 -48- 0.6 g of the previous intermediate was dissolved in 100 mL of HC1 in isopropanol. The reaction mixture was stirred at room temperature during 2h, then evaporated and treated with a mixture of dichloromethane and a solution of sodium carbonate in water. The organic phase was then dried over MgSC>4 and evaporated. The crude compound was purified by preparative HPLC, yielding 424 mg (60%) of the desired final compound 87 N'-[(3-fluorophenyl)methyl]glycyl-N-[(lS32R)-2-hydroxy-3-[[[2-[N-methyl,N-(2- morpholin-4-ylemyl)arnino]benzothiazol-6-yl]sulfonyl](2-methylpropyl)amino]-l- (phenylmethyl)propyl]-3-methyl-L-Valinamide, bis-trifluoroacetate, obtained as a TFA salt. Mass spectral data: m/z = 854 (M+H). The following tables list the compounds of formula (I) which were prepared following one of the above reaction schemes. Co Structure Co Structure Co Structure 04 •M 16 90 (l-Benzyl-3-{[2-(2- dimethylaminoetb. ylamino)-ben2;othiazole- 6-sulfonyrJ-isobutylamino}- 2-hydroxy-propyl)- carbatnic acid hexahydrofuro[ 2,3-b] furan-3-yl ester (l-Benzyl-3-{[2-(2- dimethylaminoethylainino)- benzothiazole- 6-sulfonyl]-isobutylarnino} -2-hydroxy-propyl)- carbamic acid tetrahydro- Euran-3-yl ester l-Benzyl-2-hydroxy-3- {isobutyl-[2-(2-pyrrolidin- 1-yl-ethylamino)- 3enzotbiazole-6-sulfonyl]- amiao}-propyl)-carbamic acid hexahydro-furo[2,3-b] iuran-3-yl ester 3 [l-Benzyl-3-({2-[(3- dimethylamino-propyl)- methyl-amino]- )enzotbiazole-6-sulfonyl} - sobutyl-amino)-2-hydroxyjropylj- carbamic acid hexahydro-furof2,3-b] turan-3-yl ester l-Benzyl-3-({2-[Oethylpyrrolidin- 2-ylmeliyl)- amino]-benzothiazole-6- sulfonyl) -isobutyl-amino)- 2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b] iiran-3-yl ester N'-[(3-fluorophenyl)methyl] ;lycyl-N-t(lS,2R)-2- hydroxy-3-[[[2-[Nmethyl, N-(2-morpholin-4- 'lethyl)amino]benzothiazol- 6-yl]sulfonyl](2- methylpropyl)arnino]-1- phenylmethyl)propyl]-3- methyl-L-Valinamide, bistrifluoroacetate "^'-[(3-fluorophenyl) methyl]glycyl-N-t(l S.2R)- 2-hydroxy-3-[[[2-[3- dimethylamitio)propylamia >]benzothiazol-6- methylpropyl)amino]- 1- methyl-L-Valinamide, bistrifluoroacetate. luorophenyl)raethyl]glycyl- NH(lS,2R)-2-liydroxy-3- (2-methylpropyl)[[2-[2- pyrrolidin-1- rl)ethylambo]benzothiazoli- yl]sulfonyl]amiao]-1 - j3henylmethyl)propyl]-3- metbyl-L-Valinamide, bistrifluoroacetate Table 6 The following compounds were also prepared. The compounds were evaluated according to the methods described infra. Column 3 displays the results as pECSO against wild type viras (IIIB). Column 4 displays the results as pECSO against wild virus strain F (R13025). Column 5 displays the results as pECSO against wild virus strain S(R13080). Compound Antiviral analyses: The compounds of the present invention were examined for anti-viral activity in a cellular assay. The assay demonstrated that these compounds exhibited potent anti- HIV activity against a wild type laboratory HIV strain (HIV-1 strain LAI). The cellular assay was performed according to the following procedure. Cellular Assay Experimental Method; HIV- or mock-infected MT4 cells were incubated for five days in the presence of various concentrations of the inhibitor. At the end of the incubation period, all HIVinfected cells have been killed by the replicating virus in the control cultures in the absence of any inhibitor. Cell viability is measured by measuring the concentration of MTT, a yellow, water soluble tetrazolium dye that is converted to a purple, water insoluble formazan in the mitochondria of living cells only. Upon solubilization of the resulting formazan crystals with isopropanol, the absorbance of the solution is monitored at 540nm. The values correlate directly to the number of living cells remaining in the culture at the completion of the five day incubation. The inhibitory activity of the compound was monitored on the virus-infected cells and was expressed as ECso and ECgo. These values represent the amount of the compound required to protect 50% and 90%, respectively, of the cells from the cytopathogenie effect of the virus. The toxicity of the compound was measured on the mock-infected cells and was expressed as CCso, which represents the concentration of compound required to inhibit the growth of the cells by 50%. The selectivity' index (SI) (ratio CC5o/EC5o) is an indication of the selectivity of the anti-HIV activity of the inhibitor. The compounds 1-4, 7, 9-19, 21, 24-26, 28, 33-35, 37-43, 45, 46, 49, 50, 56, 61-64, 66, 68, 70, 71, 75, 79-83 and 88-93 all have an EC50 value against HIV-1 strain LAI of than 50 nM. The SI for these compounds ranges between about 400 up to more than 47000. The compounds 5, 6, 20, 22, 23, 29, 36, 44, 47, 48, 51-55, 58, 59, 69, 72-74, 76-78 and 84 all had an EC50 value against HIV-1 strain LAI between 50 nM and 500 nM. The SI for these compounds ranges between about 26 up to more than 1900. The compounds 27, 30, 31, 57 and 60 have an EC5o against HIV-1 strain LAI of more than 500 nM. The SI for these compounds ranges between more than 13 up to more than 183. Antiviral spectrum: Because of the increasing emergence of drug resistant HIV strains, the present compounds were tested for their potency against clinically isolated HIV strains harboring several mutations. These mutations are associated with resistance to protease inhibitors and result in viruses that show various degrees of phenotypic cross-resistance to the currently commercially available drugs such as for instance saquinavir, ritonavir, nelfinavir, indinavir and amprenavir. Results: As a measure of the broad spectrum activity of the present compounds, the fold resistance (FR) defined as FR = EC50(mutant strain)/EC50(HrV-l strain LAI). Table 7 shows the results of the antiviral testing hi terms of fold resistance. As can be seen in this table, the present compounds are effective in inhibiting a broad range of mutant strains. presence of human serum, thus evaluating the effect of the binding of the protease inhibitors to those proteins. Pharmacokinetic data The pharmacokinetic properties of compounds 20, 88 and 90 were tested on rats and dogs. The compounds were evaluated in Whistar rats, source Iffa Credo, weighing approximately 350 g. Before dosing the animals were fasted overnight (approximately 12 h fasting period). The compounds were dissolved in DMSO. The results represented in the table concern the results from the oral dosing of the compounds. Blood was sampled at 30 min, Ih, 2h, 3h, no pre-dose sample was taken. The amount of the compound in the biological sample was determined using LC-MS. In the table below "or" means oral dosing, "mpk" means mg per kilogram. The results are illustrated in Table 8. A high plasma level can be observed for these compounds and more specifically for the compound such as compound 20, which is due to the good solubility of said Resistance associated mutations LI 01, L24I, G48V, L54V, V77I, V82T; L90M L10I, L24I, M36I, I54V, L63P, V82T, L90M L10I, M46I, I54V, L63P, A71V, V82A, L90M LI 01, L24I, M36I, I54V, L63P, A71V, I84V LI 01, D30N, L63P, V77I, N88D LI01, K20R, I54L, L63P, A71V, G73S, L90M L10I, M46I, I54V, L63P, A71T, V77I, V82A, L9QM ,10F, M46I, L63P, A71V, I84V V32I, M36I, M46I, I47V, I50V, L63P, L90M LI OF, M46I, I47V, L63P, A71V, I84V Biovailabilitv: The bioavailability of the present compounds was measured in rats. The compounds were administered orally or intra peritoneal. Animals were sacrificed at different time points after administration, whole blood was collected and serum prepared by standard methods. Concentration of the compound in serum was determined by titrating the anti-HIV activity present in the sample according to the procedure described above. Serum concentrations were also measured by HPLC-MS. Protein Binding analyses: Human serum proteins like albumin (HSA) or alpha-1 acid glycoprotein (AAG) are known to bind many drugs, resulting in a possible decrease in the effectiveness of those compounds. In order to determine whether the present compounds would be adversely effected by this binding, the anti-HIV activity of the compounds was measured in the WE CLAIM: 1. A 2-(substituted-amino)-benzothiazole sulfonamide compound having the formula (I) (Formula Removed) and N-oxides, salts, steroisomeric forms, racemic mixtures and esters, wherein R1 and R8, are each independently hydrogen, C1-6alkyl, C2-6alkenyl, arylC1- 6alkyl, C3-7cycloalkylC1-6alkyl, aryl, Het1, Het1C1-6alkyl, Het2, Het2C1- 6alkyl; R1 may also be a radical of formula (Formula Removed) wherein R9, R10a and R10b are each independently, hydrogen, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-4alkyl optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, C1-4alkylS(0))t, hydroxyl, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl,C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2- Het1C1-4alkyl and Het2C1-4alkyl; whereby R9, R10a and the carbon atoms to which they are attached may also form a C3-7cycloalkyl radical; when L is -0-C1-6alkanediyl-C(=0)- or -NR8-C1-6alkanediyl-C(=0)-, then R9 may also be oxo; R11a is hydrogen, C2-6alkenyl, C2-6alkenyl, C3-7cycloalkyl, aryl, arylC1-4alkyl, aminocarbonyl optionally mono- or disubstituted, aminoC1-4alkyl- carbonyloxy optionally mono- or disubstituted, C1-4alkyloxycarbonyl, aryloxycarbonyl, Het1 oxycarbonyl, Het2 oxycarbonyl, aryloxycarbonyl- C1-4alkyl, arylC1-4alkyloxycarbonyl, C1-4alkylcarbonyl, C3- 7cycloalkylcarbonyl, C3-7cycloalkylC1-4alkyloxycarbonyl, C3-7cycloalkyl-carbonyloxy, carboxylC1-4alkylcarbonyloxy, C1-4alkylcarbonyloxy, arylC1-4alkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het1 carbonyl, Het1 carbonyloxy, Het1C1-4alkyloxycarbonyl, Het2 carbonyl-oxy, Het2C1-4alkylcarbonyloxy, Het2C1-4alkyloxycarbonyloxy or C1-4alkyl optionally substituted with aryl, aryloxy, Het2, halogen or hydroxy; wherein the substituents on the amino groups are each independently selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; R11b is hydrogen, C3-7cycloalky, C2-6alkenyl, C2-6alkynyl, aryl, C1-6alkyloxycarbonyl, Het1, Het2 or C1-4alkyl optionally substituted with halogen hydroxy, C1-4alkylS(=O)t, aryl, C3-7cycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; whereby R11b may be linked to the remainder of the molecule via a sulfonyl group; each independently t is zero, 1 or 2; R2 is hydrogen or C1-6alkyl; L is -C(=O)-, -O-C(=O)-, -NR8-C(=O)-, -O-C1-6alkanediyl-C(=O)-, -NR8-C1-6alkanediyl-C(=O)-, -S(=O)2-, -O-S(=O)2-, -NR8-S(=O)2 whereby either the C(=O) group or the S(=O)2 group is attached to the NR2 moiety; and whereby the alkanediyl moiety is optionally substituted with aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4 and Het2C1-4alkyl; R3 is C1-6alkyl, aryl, C3-7cycloakyl, C3-7cycloalkylC1-4alkyl, or arylC1-4alkyl; R4 is hydrogen, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkyl optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, C1-4alkylS(=O)t, hydroxyl, cyano, halogen or amino optionally mono-or disubstituted where the substituents are selected from C1-4alkyl, aryl, aryl-C1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; A is C1-ealkanediyl, -C(=O)-, -C(=S)-, -S(=O)2, C1-6alkanediyl-C(=O)-, C1-6alkanediyl-C(=S)- or C1-6alkanediyl-S(=O)2; whereby the point of attachment to the nitrogen atom is the C1-6alkanediyl group in those moieties containing said group; R5 is hydrogen, hydroxyl, C1-6alky, Het1C1-6alkyl, Het2C1-6alkyl, aminoC1-6alkyl whereby the amino group may optionally be mono or disubstituted with C1-4alkyl; R6 is C1-6alkyloxy, Het1, He^oxy, Het2, Het2oxy, aryl, aiyloxy or amino; and in case -A- is other than C1-6alkanediyl then R6 may also be C1-6alkyl, Het1C1-4alkyl, Het1 oxyC1-4alkyl, Het2C1-4alkyl, Het2oxyC1-4alkyl, arylC1-4alkyl, aryloxyC1-4alkyl or aminoC1-4alkyl; whereby each of the amino groups in the definition of R6 may optionally be substituted with one or more substituents selected from C1-4alkyl, C1- 4alkylcarbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylC1-4alky, Het1C1-4alkyl or Het2C1-4alkyl; and R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1 or Het2. 2. A compound as claimed in claim 1, wherein R1 and R8 are each independently, hydrogen, C1-6alky, C2-6alkenyl, arylC1-6alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-6alkyl, aryl, Het1, Het1C1-6alkyl, Het2, Het2C1-6alkyl; R1 may also be a radical of formula (Formula Removed) wherein R9, R10a and R10b are each independently, hydrogen, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-4alkyl optionally substituted with aryl, Het1, Het2 C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, C1-4alkylS(0)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl and Het2C1-4alkyl; whereby R9, Rioa and the carbon atoms to which they are attached may also form a C3-7cycloalkyl radical; R11a is hydrogen, C2-6alkenyl, C2-6alkynyl, C3-7cycloalkyl, aryl, aminocarbonyl optionally mono-or disubstituted, aminoC1-4alkylcarbonyloxy optionally mono- or disubstituted, C1-4alkyloxycarbonyl, aryloxycarbonyl, Het1oxycarbonyl, Het2oxycarbonyl, aryloxycarbonylC1-4alkyl, arylC1-4alkyloxycarbonyl, C1-4alkylcarbonyl, C3-7cycloalkylcarbonyl, C3-7cycloalkylC1-4alkyloxycarbonyl, C3- 7cycloalkylcarbonyloxy, carboxylC1-4alkylcarbonyloxy, C1- 4alkylcarbonyloxy, arylC1-4alkyl-carbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het1carbonyl, Het1carbonyloxy, Het1C1-4alkyloxycarbonyl, Het2carbonyloxy, Het2C1-4alkylcarbonyloxy, Het2C1-4alkyloxycarbonyloxy or C1-4alkyl optionally substituted with aryl, aryloxy, Het2C1-4alkyloxycarbonyloxy or C1-4alkyl optionally substituted with aryl, aryloxy, Het2 or hydroxy; wherein the substituents on the amino groups are each independently selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; R11b is hydrogen, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl, aryl, Het1, Het2 or C1-4alkyl optionally substituted with halogen, hydroxy, C1-4alkylS(=0)t, aryl, C3-7cycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; whereby R11b may be linked to the remainder of the molecule via a sulfonyl group; each independently t is zero, 1 or 2; R2 is hydrogen or C1-6alkyl; L is -C(=0)-, -0-C(=0)-, NR8-C(=0)-, -0-C1-6alkanediyl-C(=0)-, NR8-C1-6alkane-diyl-C(=0)-, -S(=0)2-, -0-S(-0)2-, -NR8-S(=0)2 whereby either the C(=0) group or the S(=0)2 group is attached to the NR2 group to the NR2 moiety; R3 is C1-6alkyl, aryl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, or arylC1-4alkyl; R4 is hydrogen, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C1-4alkyl)aminocarbonyl, C3-7cycloalkyl, C2-6alkenyl, C2-6alkynyl or C1-6alkyl optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono or di(C1-4alkyl)aminocarbonyl, aminosulfonyl, C1-4alkylS(=0)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, aryl, arylC1-4alkyl, C3-7cycloalkyl, C3-7cycloalkylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4alkyl; A is C1-6alkanediyl, -C(=0)-, -C(=S)-, -S(=0)2-, C1-6alkanediyl-C(=0)-, C1-6alkanediyl-C(=S)- or C1-5alkanediyl-S(=0)2-; whereby the point of attachment to the nitrogen atom is the C1-6alkanediyl group is those moieties containing said group; R5 is hydrogen, hydroxyl, C1-6alkyl, Het1C1-4alkyl, Het2C1-6alkyl, aminoC1-6alkyl whereby the amino group may optionally be mono- or di-substituted with C1-4alkyl; R6 is C1-6alkyloxy, Het1, Het1oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than C1-6alkanediyl then R6 may also be C1-6alkyl, Het1C1-4alkyl Het1oxyC1-4alkyl, Het2C1-4alkyl, Het2oxyC1-4alkyl, arylC1-4alkyl, aryloxyC1-4alkyl or amino C1-4alkyl; whereby each of the amino groups in the definition of R6 may optionally be substituted with one or more substituents selected from C1-4alkyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylC1-4alkyl, Het1C1-4alkyl or Het2C1-4alkyl; and R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1 or Het2. 3. A compound as claimed in any of claims 1 or 2, wherein Ri hydrogen, C1-6alkyl, C2-6alkenyl, arylC1-6alkyl, C3-7cycloalkly, C3-7cycloaklyC1-6alkyl, aryl, Het1, Het1C1-6alkyl, Het2, Het2C1-6alkyl; wherein Het1 is a saturated or partially unstaturated monocyclic heterocycle having 5 or 6 ring members, which contains one or more heteroatom ring members selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms. 4. A compound as claimed in any or claims 1 to 3, wherein L is -O-C1-6 alkanediyl-C(=0)-. 5. A compound as claimed in any one of claims 1 to 3, wherein L is -O-C(=0)-. 6. A compound as claimed in any one of claims 1 to 3, wherein L is -NR8-C1-6alkanediyl-C(=0)-, whereby the alkanediyl moiety is optionally substituted with, aryl, arylC1-4alkyl, Het1, Het2, Het1C1-4alkyl and Het2C1-4 alkyl. 7. A compound as claimed in any one of claims 1 to 6, wherein R1 is Het1, Het1C1-6alkyl, Het2 or Het2C1-6alkyl. 8. A compound as claimed in claim 7, wherein R1 is Het1 or Het2. 9. A compound as claimed in claim 8, wherein R1 is Het1. 10. A compound as claimed in claim 9, wherein R1 is hexahydro=furo[2,3-b]-furanyl. 11. A compound as claimed in claim 10, wherein R1 is tetrahydrofuranyl. 12. A compound as claimed in any one of claims 1 to 6, wherein L is -O-C1-6alkanediyl-C(=0)- or -NR8-C1-6alkanediyl-C(=0)- and R1 is a radical of formula (Formula Removed) wherein R9 is oxo, R10a and R10b are, each independently, hydrogen or C1-4alkyl optionally substituted with aryl, Het1, Het2, C1-4alkyloxycarbonyl, carboxyl, aminocarbonyl, hydroxyl, or amino optionally mono- or disubstituted where the substituents are selected from C1-4alkyl, R11a is arylC1-4alkyl, or C1-4alkyl optionally substituted with aryl or halogen and R11b is hydrogen, or C1-6alkyloxycarbonyl. 13. A compound as claimed in claim 12, wherein L is -0-C1-6alkanediyl-C(=0)- or -NR8-C1-6alkanediyl-C(=0)- and R1 is a radical of formula (Formula Removed) wherein R9is oxo, R10and R10b are hydrogen, R11is arylC1-4alkyl wherein the aryl group is substituted with a halogen and R11is hydrogen, or C1-6alkyloxycarbonyl. 14. A compound as claimed in claim 13, wherein L is -0-C1-6alkanediyl- C(=0)- or -NR8-C1-6alkanediyl-C(=0)- and R1 is a radical of formula (Formula Removed) wherein R9 is oxo, R10a and R10h are hydrogen, R11a is m-fluorobenzyl and R11b is hydrogen, or C1-6alkyloxycarbonyl. 15. A compound as claimed in claim 14, wherein L is -0-C1-6alkanediyl- C(=0)- or -NR8-C1-6alkanediyl-C(=0)- and R1 is a radical of formula (Formula Removed) wherein R9is oxo, R10a and R10b are hydrogen, R11a is m-fluorobenzyl and R11b is hydrogen. 16. A compound as claimed in claim 14, wherein L is -0-C1-6alkanediyl- C(=0)- or -NR8-C1-6alkanediyl-C(=0)- and R1 is a radical of formula wherein R9 is oxo, R10a and R`0b are hydrogen, R11a is m-fluoroben2yl and R11b is tert-butyloxycarbonyl. 17. A compound as claimed in any one of claims 1 to 6, wherein R3 is arylC1-4alkyl. 18. A compound as claimed in claim 17, wherein R3 is arylCH2-. 19. A compound as claimed in claim 18, wherein R3 is benzyl. 20. A compound as claimed in claims 1 to 19, wherein R4 is C1-6alkyl. 21. A compound as claimed in claim 20, wherein R4 is butyl. 22. A compound as claimed in claim 21, wherein R4 is isobutyl. 23. A compound as claimed in any one of claims 1 to 22, wherein A is C1-6alkanediyl, -C(=0)- or C1-6alkanediyl-C(=0)-; whereby the point of attachment to the nitrogen atom is the C1-6alkanediyl group is those moieties containing said group; R5 is hydrogen, C1-6alkyl, Het1C1-6alkyl, Het2C1-6alkyl, aminoC1-6alkyl whereby the amino group may optionally be mono- or di-substituted with C1-4alkyl; and in case -A- is -C(=0)- then R6 is C1-6alkyloxy, Het1, Het1oxy or Het2oxy, aryl, Het1C1-4alkyl, Het1oxyC1-4alkyl, Het2C1-4alkyl, Het2oxyC1-4alkyl, arylC1- 4aryloxy, aryloxyC1-4alkyl or aminoC1-4alkyl; and in case -A- is C1-6alkanediyl then R6 is amino, C1-6alkyloxy, Het1, Het1oxy or Het2oxy; and in case -A- is C1-6alkanediyl-C(=0)- then R6 is C1-6alkyloxy, Het1, Het1oxy or Het2oxy, aryl, C1-ealkyl, Het1C1-4alky, Het1oxyC1-4aalkyl, Het2C1-4alkyl, Het2oxyC1-4alkyl, arylC1-4alkyl, aryloxyC1-4alkyl or aminoC1-4alkyl; whereby each of the amino groups in the definition or R6 may optionally be substituted with one or more substituents selected from C1-4alkyl, C1- 4alkyl-carbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylC1-4alkyl, Het1C1-4alkyl; and R5 and -A-R6 taken together with the nitrogen atom to which they are attached may also form Het1 whereby Het1 whereby Het1 is substituted by at least an oxo group. 24. A compound as claimed in claim 23, wherein Rs is hydrogen or C1-6alkyl. 25. A compound as claimed in claim 24, wherein Rs is hydrogen. 26. A compound as claimed in claim 24, wherein Rs is methyl or ethyl. 27. A compound as claimed in claim 26, wherein Rs is methyl. 28. A compound as claimed in claim 23, wherein A is C1-6alkanediyl. 29. A compound as claimed in claim 28, wherein A is ethylenediyl. 30. A compound as claimed in claims 1 to 29, wherein R6 is Het1. 31. A compound as claimed in claim 30, wherein R6 is Het1C1-4aalkyl. 32. A compound as claimed in claim 30, wherein R6 is pyrrolidinyl or pyrrolidinylC1-4aalkyl. 33. A compound as claimed in claim 32, wherein R6 is pyrrolidinylethyl. 34. A compound as claimed in claim 1 to 29, wherein R6 is an amino; whereby each of the amino groups may optionally be substituted with one or more substituents selected from C1-4alkyl, C1-4alkylcarbonyl, C1-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCh 4alkyl, Het1C1-4alkyl or Het2C1-4alkyl. 35. A compound as claimed in claim 34, wherein R6 is an amino; whereby each of the amino group is substituted with two substitutents selected from C1-4alkyl. 36. A compound as claimed in claim 35, wherein R6 is dimethylamino. 37. A compound as claimed in claim 1, having the formula (Formula Removed) wherein the formula I is: (l-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]- isobutyl-amino}-2-hydroxy-propyl)-carbamic acid hexahydro-furo[2,3-b] furan-3-yl ester, (l-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]- isobutyl-amino}-2-hydroxy-propyl)-carbamic acid tetrahydro-furan-3-yl ester, 1-Benzyl-2-hydroxy-3-(isobutyl-[2 - (2-pyrrolidin-yl-ethylamino)- benzothiazole-6-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3- b] furan-3-yl ester, [ 1-Benzyl-3-({2-[(3-dimethylamino-propyl)-methyl-amino]-benzothiazole-6- sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro- furo[2,3-b] furan-3-yl ester, [ 1 -Benzyl-3-({2-[( 1 -ethyl-pyrrolidin-2-ylmethyl)-amino]-benzothiazole-6-sulfonyl)-isobutyl-amino)-2-hydroxy-propyl]carbarnic acid hexahydro-furo[2,3-b] furan-3-yl ester. 38. Method for the preparation of a compound as claimed in claim 1, (Formula Removed) comprising the steps of a) reacting benzothiazole derivative g-1 with chlorosulfonic acid, and subsequently with thionylchloride to yield intermediate g-2, b) reacting said intermediate g-2 with intermediate g-3 yielding an intermediate g-4 wherein PG is a protecting group such as Boc, c) reacting intermediate g-4 into intermediates g-5 and g-6, d) intermediates g-5 and g-6 are derivatized with a compound of formula HN(R5)A-R6 yielding and subsequently deprotected yielding intermediate g-7, e) g-7 may then be reacted with an intermediate of formula Ri-L-(leaving group) resulting in the compound g-8. 39. A method as claimed in any one of claims 38, wherein step (c) is performed with a suitable reagent selected from the group comprising metachloroperoxybenzoic acid or magnesium monoperoxyphtalate hexahydrate. 40. A pharmaceutical composition as and when prepared by using at least one compound as claimed in any one of claims 1 to 37, and a pharmaceutically tolerable excipient. 41. A compound as claimed in claim 1, wherein the compound is 1 -Benzyl-2-hydroxy-3-{isobutyl-[2-(2-pyrrolidin-1 -yl-ethylamino)-benzothiazole-6-sulfonyl]-amino}-propyl)-carbamic acid hexahydro-furo[2,3-b] furan-3-yl ester; or [l-Ben2yl-3-({2-[(3-dimethylamino-propyl)-methyl-amino]-benzothiazole-6-sulfonyl}-isobutyl-amino)-2-hydroxy-propyl]-carbamic acid hexahydro-furo[2,3-b] furan-3-yl ester; or (l-Benzyl-3-{[2-(2-dimethylamino-ethylamino)-benzothiazole-6-sulfonyl]-isobutyl-amino}-2-hydroxy-propyl)-carbamic acid tetrahydro-furan-3-yl ester.

Documents:

01269-DELNP-2003-Abstract(07-10-2008).pdf

01269-delnp-2003-abstract.pdf

01269-DELNP-2003-Claims(07-10-2008).pdf

01269-delnp-2003-claims.pdf

01269-delnp-2003-correspondence-others.pdf

01269-delnp-2003-description (complete)-07-10-2008.pdf

01269-delnp-2003-description (complete)-12-08-2008.pdf

01269-delnp-2003-description (complete).pdf

01269-delnp-2003-form-1.pdf

01269-delnp-2003-form-13.pdf

01269-delnp-2003-form-18.pdf

01269-delnp-2003-form-2.pdf

01269-delnp-2003-form-3.pdf

01269-delnp-2003-form-5.pdf

01269-delnp-2003-gpa.pdf

01269-delnp-2003-pct-304.pdf

1269-DELNP-2003-Abstract-(12-08-2008).pdf

1269-DELNP-2003-Claims-(12-08-2008).pdf

1269-delnp-2003-claims-(19-03-2009).pdf

1269-DELNP-2003-Correspondence-Others-(12-08-2008).pdf

1269-DELNP-2003-Correspondence-Others-(18-08-2008).pdf

1269-DELNP-2003-Form-1-(12-08-2008).pdf

1269-DELNP-2003-Form-2-(12-08-2008).pdf

1269-DELNP-2003-Form-3-(12-08-2008).pdf

1269-DELNP-2003-Form-3-(18-08-2008).pdf

1269-DELNP-2003-GPA-(12-08-2008).pdf

1269-DELNP-2003-Others-Document-(12-08-2008).pdf

1269-DELNP-2003-Petition-137-(12-08-2008).pdf

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