Title of Invention

"A 2-(SUBSTITUTED-AMINO)-BENZOXAZOLE SULFONAMIDE"

Abstract The present invention concerns the compounds having the formula (I) N-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites thereof, wherein Rl and R8 each are H, optionally substituted Cl-6alkyl, C2-6alkenyl, C3-7cycloalkyI, aryl, Hetl, Het2; Rl may also be a radical of formula (RllaRllb)NC(R10aR10b)CR9- is 0, 1 or 2; R2 is H or Cl-6alkyl; L is -C(=O)-, -O-C(=O)-, •NR8-C(=O)-, -O-Cl-6alkanediyl-C(=O)-, -NR8-Cl-6alkancdiyl-C(=O)-, -S(=O)2-, -O-S(=O)2-, -NR8-S(=O)2 ; R3 is Cl-6alkyl, aryl, C3-7cycloalkyl, C3-7eycloa]kylCl-4alkyl, or arylCl-4alkyl; R4 is H, Cl-4alkylOC(=O), carboxyl, aminoC(=Q), mono- or di(Gl-4alkyl)aminoC(=O), C3-7cycloaIkyl, C2-6alkenyl. C2-6alkynyl or optionally substituted Cl-6alkyl; A is Cl-6alkanediyl, C(=O)-, -C(=S)-, -S(=O')2-, C1-6alkanediyl-C(=O)-, Cl-6alkanediyl-C(=S)- or Cl-6alkanediyl-S(=O)2-; R5 is H, OH, Cl-6alkyl, HetlCl-6alkyl, Het2Cl-6alkyl, optionally substituted aminoCl-6alkyl; R6 is Cl-6alkylO, Hetl, HetlO, Het2, Het2O, aryl, arylO, Cl-6alkyloxycarbonylamino oramino; and in case -A- is other than Cl-6alkanediyl thenR6 may alsobeCl-6alkyl, HetlCl-4alkyl, HetlOCl-4alkyl, Het2Cl -4alkyl, Het2OCl-4alkyl, arylCl-4alkyl, arylOCl-4alkyl or aminoCl-4alkyl; whereby each of the amino groups in the definition of R6 may optionally be substituted; -A-R6 is hydroxyCl-6alkyl; R5 and -A-R6 taken together with the nitrogen atom lo which ihey are attached may also form Hetl or Hel2. Il further relates to their use as broadspectrum HTV protease inhibitors, processes for their preparation as well as pharmaceutical compositions and diagnostic kits comprising them. It also concerns combinations thereof with another anti-retroviral agent, and to their use in assays as reference compounds or as reagents.
Full Text BROADSPECTRUM2-rSUBSTITUTED-AMINO)-BENZOXAZQLE SULFONAMIDE HIV PROTEASE INHIBITORS
The present invention relates to 2-(substituted-amino)-benzoxazole sulfonamides, their use as aspartic protease inhibitor^ 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)-benzoxazole sulfonamides with another anti-retroviral agent. It further 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 IE (HTLV-IH) 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. HTV-1 and HJV-2. Hereinafter, HTV 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 HTV 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, hi particular for HIV treatment, the HIV protease is an attractive target.
HIV protease inhibitors (Pis) are commonly administered to ADDS patients in combination with other anti-HTV compounds such as, for instance nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), nucleotide reverse transcriptase inhibitors (NtRTIs) or other protease inhibitors. Despite the fact that these antiretrovirals are very useful, they have a common Limitation, namely, the targeted enzymes in the HTV 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 HTV virus creates an ever increasing resistance against the available drugs.
Resistance of retro viruses, and in particular the HTV virus, against inhibitors is a major cause of therapy failure. For instance, half of the patients receiving anti-HTV 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 earned over to newly infected individuals, resulting in severely limited therapy options for these drag-naive patients. Therefore, there is a need in the art for new
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 HTV 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 drags hi order for said antiretrovirals to regain effectivity against the mutated HTV viruses. The consequence of which is a highly undesirable increase hi 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 HTV 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 HTV 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 HTV 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-HTV compounds with good bio availability, 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-HTV 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 HTV virus with little variance in fold resistance, have a good bioavailability and experience little or no effect on their 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 retro viral protease inhibitors.
(Figure Remove)
WO 99/67254 discloses 4-substituted-phenyl sulfonamides capable of inhibiting multi-drug resistant retroviral proteases.
(Figure Remove)
Surprisingly, the 2-(substituted-amino)-benzoxazole 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 HTV viruses exhibiting resistance against known protease inhibitors.
The present invention concerns 2-(substituted-amino)-benzoxazole protease inhibitors, having the formula
(Figure Remove)and jV-oxides, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and
metabolites thereof, wherein
ri and Rg are, each independently, hydrogen, Ci-ealkyl, C2-6alkenyl, arylCi-galkyl,
o
Cs-Tcydoalkyl, C^cycloalkylCwalkyl, aryl, Het1, Het^i-gallcyl, Het2,
may also be a radical of formula
(Figure Remove)
wherein
, Rioa and Ri0b are, each, independently, hydrogen, Cwalkyloxycarbonyl, cafboxyl, aminocarbonyl, mono- or di(Ci^.aIkyl)arnin.ocarbonyl, C3-7cycloalkyl, C2-6alkenyl, Ca-ealkynyl or Ci^alkyl optionally substituted with aryl, Het1, Het2, Cs.ycycloalkyL.Ci^alkyloxycarbonyl, cafboxyl, aminocarbonyl, mono- or di(Ci^aDcyl)aminocarbonyl, aminosulfonyl, C]^alkylS(O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are each independently selected from Chalky!, aryl, arylCMalkyl, C3-7cycloalkyl, C3_7cycloalkylCMalkyl, Het1, Het2, He^Ci^alkyl and Het2CI-4aIkyl; whereby R9, Rl0a 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-6alkanediyI-C(=O)-, then Rg may also be oxo;
a is hydrogen, C2-6alkenyl, Ci^alkynyl, C3_7cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoCi^alkylcarbonyloxy optionally mono- or disubstituted, Ci^alkyloxycarbonyl, aryloxycarbonyl, HetWy-carbonyl, Het2oxycarbonyl, aryloxycarbonylC^alkyl, arylCj^alkyloxy-carbonyl, Ci^aUcylcarbonyl, Cs-ycycloalkylcafbonyl, Ca-ycycloalkyl-Ci-4alkyloxycarbonyi, Ca^cycloalkylcarbpnyloxy, carboxylCMalkyl-carbonyloxy, Ci_4alkylcarbonyloxy, arylCMalkylcarbqnyloxy, arylcarbonyloxy, aryloxycarbonyloxy, He^carbonyl, Het^arbonyloxy, Het'Ci^alkyloxycarbonyl, Het2carbonyloxy, Het2CMalkylcarbonyloxy, Het~Cj_4alkyloxycarbonyloxy or Cj^allc>i optionally substituted with, aryl, aryloxy, Het2, halogen or hydroxy; wherein the substituents on the amino groups are each independently selected from Ci^alkyl, aryl, arylC^alkyl, C3_7cycloalkyl, Cs-ycycloalkylC^alkyl, Het1, Het2, Het1 Chalky! and
1 0
Rub is hydrogen, Ca^cycloalkyl. C2-6alkenyl, Ca-^alkynyl, aryl, Het , Het~ or C[-4alkyl optionally substituted with halogen, hydroxy, Ci-4alkylS(=O)t, aryl, Cs^cycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are each independently selected from Chalky!, aryl, arylCi^alkyl, C3-7cycloaIkyl, C3-7cycloalkylCi-4alkyl, Het1, Het2, Het^Malkyl and Het2Ci.4alkyl;
whereby Rub maybe Hnked to the remainder of the molecule via a sulfonyl group; each independently, t is'zero, 1 or 2; Ro is hydrogen or Chalky!; L is -C(=O)-, -O-C(=O)-, -NR«-C(=O)-, -O-C,.salkanediyl-C(=O)-,
-NRs-Ci-6alkanediyl-C(=0)-, -S(=O)2-, -O-S(=O)2- -NRg-S(=0)2 whereby either
the C(=O) group or the S(=O)2 group is attached to the NR2 moiety; whereby the Ci-^aOcanedlyl moiety is optionally substituted with aryl, Het1, Het; rs is Ci-galkyl, aryl, Cs-vcycloalkyl, Cs^cycloalkylCi^alkyl, or arylCi-4alkyl; R4 is hydrogen, Ci^aUcyloxycarbonyl, carboxyl, aminocarboriyl, mono- or
di(Ci^alkyl)arninocarbonyl, Cs^cycloalkyl, Co-galkenyl, Ci-ealkynyl, or Ci^alkyl optionally substituted with one or more substituents each independently selected from aryl, Het1, Het2, C^ycycloalkyl, CMalkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, aminosulfonyl, Ci^alkylS(=O)t, hydroxy, cyano, halogen and amirio optionally mono- or disubstituted where the substituents are each independently selected from Cmalkyl, aryl, arylCi^alkyl, Cs-Tcycloalkyi, Cs-ycycloalkylCj^alkyl, Het1, Het2, Het1CMalkylandHet2CMalkyl; .
A is Ci-6alkanediyl, -C(=O)-, -C(=S)-, -S(=O)2-, Ci^alkanediyl-C^O)-, Ci-6alkane-diyl-C(=S)- or Ci_6alkanediyl-S(=O)2-; whereby the point of attachment to the nitrogen atom is the Cj-galkanediyl group in those moieties containing said group; R5 is hydrogen, hydroxy, Ci_6alkyl, Het1 Chalky!, Het^C^alkyl, arninoCi..6aIkyl whereby the amino group may optionally be mono- or di-substituted with CMalkyl;
Re is GVsaltyioxy, Het1, Het^xy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than Ci-salkanediyl then Re may also be Chalky!, He^Ci^alkyl, HetWyCi^alkyi, Het2CwaIkyl, Het2oxyCi^alkyl, arylCMalkyl, aryloxyC^alkyl or amiaoCi_6alkyl; whereby each of the amino groups 'in the definition of R§ may optionally be substituted with one or more substituents each independently selected from Ci^alkyl, Ci^alkylcarbonyl, CMalkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCi^alkyl, Het^Malkyl or Het2Cwalkyl; and
-A-R6 may also be hydroxyCj^alkyl;
rs and -A-R-6 taken together with the nitrogen atom to which they are attached may also form Het1 or Het2.
This invention also envisions the quatemization of the nitrogen atoms of the present compounds. A basic nitrogen can be qtiaternized 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.
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 "Chalky!" 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, and 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 Ci^alkyl and pentyl, hexyl, 2-methylbutyl, 3-methylpentyl and the
like.
The term "C^alkanediyl" 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--
1,5-diyl and the like.
The term "C2-6alkenyi" 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 examnle. ethenvl orotienvL butenvl. nentenvl. hexenvl and
a. • ^ - j. j. ^ - - ' j. - *
the like.
The term "C2-6alkynyl" 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 "C3-7cycloalkyl" 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 subsn'tuents independently
selected from Ci-salkyi, optionally mono- or disubstituted aminoCi-galkyl,
halogen, hydroxy. optionally mono- or disubstituted amino, nitro, cyano,
carboxyl, Ci-ealkoxycarbonyl, Cs^cycloalkyl, Het1, optionally mono- or disubstituted
amino carbonyl, methylthio, methylsulfonyl, and phenyl optionally substituted with one
or more substituents each independently selected from Ci^alkyl, optionally mono- or
disubstituted amrnoCi^alkyl,, Ci.6alkyloxy, halogen, hydroxy, optionally mono- or
disubstituted amino, nitro, cyano, haloCi^alkyl, carboxyl, Ci^alkoxycafbonyl.
C3-7cycloalkyl, Het1, optionally mono- or disubstituted arninocarbonyl, methylfbio and methylsulfonyl; whereby the optional substituents on any arrrmo function are independently selected from Chalky!, optionally mono- or disubstituted aminoCi-salkyi, Cwalkyloxy-A-, Het'-A-, He^Ci-galkyl, Het^i^alkyl-A-, HetWy-A-, CMakyl-A-, phenyl-A-, phenyl-oxy-A-, phenyloxyCi4alkyl-A-, phenyl-l-A-, Ci-ealkyloxycarbonylamino-A-, amino-A-, aminoCi-galkyl and amino-Ci_(jalkyl-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. An interesting subgroup in the definition of "aryl" as a group or part of a group includes phenyl and naphtyl which both may be optionally substituted with one or more substituents independently selected from Ci-galfcyl, C^galkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi-ealkyl, carboxyl, Q-ealkoxycarbonyl, Ca-vcycloaUcyl, Het1, optionally mono- or disubstituted arninocarbonyl, methylthio, methylsulfonyl, and phenyl optionally substituted with one or more substituents selected from Ci-galkyl, Ci^alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyaho, haloCi-6alkyl, carboxyl, Q. galkoxycarbonyl, Ca-vcycloalkyl, Het1, optionally mono- or disubstituted arninocarbonyl, methylthio and methylsulfonyl; whereby the optional substituents on any amino function are independently selected from Ci-ealkyl, Q-galkyloxy-A-, Het1-A-, Het'd-ealkyl, Het'Ct-gaikyl-A-, Het^xy-A-, Het^xyCj^akyl-A-, phenyl-A-, phenyl-oxy-A-, phenyloxyCi^alkyi-A-, phenylCi-galkyl-A-, Ci-salkyloxycarbonyl-amino-A-, amino-A-, aminoCi-fialkyl and aminoCi.6alkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with Cj^alkyl and whereby A is as defined above.
The term "haloCi-galkyl" as a group or part of a group is defined as Ci^alkyl substituted with one or more halogen atoms, preferably, chloro or fluoro atoms, more preferably fiuoro atoms. Preferred haloCi^allcyl groups include for instance trifluoromethyl and difluoromethyl.
The term "Het1" as a group or part of a group is defined as a saturated or partially unsaturated monocyciic, bicyclic ortricyclic 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 each independently selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by Ci.galkyl, optionally mono- or disubstituted arninoCi.galkyl, Ci^alkyloxy. halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haioCi-ealkyl, carboxyl, Cj-galkoxycafbonyl, Cs^cycloalkyl, optionally mono- or disubstituted arninocarbonyl. methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyciic, bicyclic or tricyclic heterocycle having 3 to 14 ring
members which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and whereby the optional substituents on any amino function are independently selected from Chalky!, optionally mono- or disubstituted aminoCi_6aBcyl, Ci^alkyloxy-A-, Het2-A-, Hef^Ci^alkyl, Het2Ci.6aIkyl-A-, Hei^oxy-A-, Het2oxyCt-4akyl-A-, aryl-A-, aryioxy-A-, aryloxyCi^alkyl-A-5 arylQ-salkyl-A-, Ci-galkyloxycarbonylaroino-A-, amino-A-, arnrnoCi-galkyl and aminoCi^altyl-A- whereby each of the arnino groups may optionally be mono- or where possible di-substituted with Chalky! and whereby A is as defined above. An interesting subgroup in the definition of "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 12 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-galkyl, Ci-ealkyloxy, halogen, hydroxy, oxo, optionally mono- or disubstituted amino, nitro, cyano, haloCi-salkyl, carboxyl, Ci^alkoxycarbonyl, C3.7cycloalkyl, optionally mono- or disubstituted amhiocarbonyL, methylthio, methylsulfonyl, aryl and a saturated or partially unsaturated monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 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^alkyl, C^alkyloxy-A-, Het2-A-, Het2Ci-6alkyl, Het2Ci_
9 '" 9
6alkyl-A-, Hel oxy-A-, Het oxyCi^akyl-A-, aryl-A-, aryloxy-A-, aryloxyCt^alkyl-A-, arylC].6alicyl-A-, Ci^alkyloxycarbonylarnino-A-, amino-A-, aminoCi-ealkyl and arninoCi_6alkyl-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 each independently selected from nitrogen, oxygen or sulfur and which is optionally substituted on one or more carbon atoms by C^aUcyl, optionally mono- or disubstituted aminoCi-ealkyl, Ci-galkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloC^alkyl, carboxyl, Ci-^alkoxycarbonyl, Cs^cycloallcyl, optionally mono- or disubstituted amiaocarbonyl, methylthio. methylsulfonyl. aryl, Het" 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 C^aUcyl, optionally mono- or disubstituted aminoCi^alkyl, C^alkyloxy-A-, He^-A-.
HerCi.6aIkyL, He^Ci-ealkyl-A-, Het:oxy-A-, He^oxyCi^akyl-A-, aryl-A-, aryloxy-A-, aryloxyCi^alkyl-A-, arylCi-galkyl-A-, Ci^altyloxycarbonylamino-A-, amino-A-, aminoCi-salkyl and aminoCi-salkyi-A- whereby each of the arnrno groups may optionally be mono- or where possible di-substituted with Ci^alkyl and whereby A is as defined above.
An interesting subgroup in the definition of "Her2" as a group or part of a group is defined as an aromatic monocyclic, bicyclic or tricyclic heterocycle having preferably 3 to 12 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-6alkyloxy, halogen, hydroxy, optionally mono- or disubstituted amino, nitro, cyano, haloCi-ealkyl, carboxyl, Ci-ealkoxycarbonyl, Cs.ycycloalkyl, optionally mono- or disubstituted aminocarbonyl, methylthio, methylsulfonyl, aryl, Het1 and an aromatic monocyclic, bicyclic or tricyclic heterocycle having 3 to 12 ring members; whereby the optional substituents on any amino function are independently selected from C^allcyl, C^alkyloxy-A-, Het'-A-, Het1 Chalky!, He^C^alkyl-A-, Het!oxy-A-, HetWyCi^akyl-A-, aryl-A-, aryloxy-A-, aryloxyCi-4alkyl-A-, arylCi. galkyl-A-, Ci-ealkyloxycarbonjdarnino-A-, amino-A-, aminoCi-salkyl and aminoCi-ealkyl-A- whereby each of the amino groups may optionally be mono- or where possible di-substituted with Ci^alkyl 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. The term (=O) forms a sulfoxide with the sulfur to which it is attached. The term (=0)2 forms a sulfonyl to the sulfur to which it is attached.
As used herein, the term (=S) forms a thiocarbonyl 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 Chalky!) occurs more than one time in 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
Drags", 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 hydrohaiic 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, methane-sulfonic, ethanesulfonic, benzenesulfonic, ^-toluenesulfonic, cyclamic, salicylic, ^-aminosalicylic, 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-glucamine3 hydrabamine salts, and salts with amino acids such as, for example, arginine, lysine and the Hke.
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 N-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 jV-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 stereoisomenc 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 stereoisomenc excess of at least 80% (i. e. minimum 90% of one isomer and maximum 10% of the other possible isomers) up to a stereoisomenc excess of 100% (i.e. 100% of one isomer and none of the other), more in particular, compounds or intermediates having a stereoisomenc excess of 90% up to 100%, -even more in particular having a stereoisomenc excess of 94% up to 100% and most in particular having a stereoisomenc excess of 97% up to 100%. The terms 'enantiomerically pure1 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 maybe 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 chromato graphy.
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.
(Figure Remove)
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 N-oxid.es, salts, stereoisomeric forms, racemic mixtures, prodrugs, esters and metabolites, as well as their quaternized nitrogen analogues.
A suitable group of compounds are those compounds according to formula (I) wherein : Rg , Rioa and Riob are, each independently, hydrogen, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(CMalkyl)aminocarbonyl, C3_7cycloalkyl, C2-6alkenyl, Cj-galkynyl or Ci^alkyl optionally substituted with aryl, Het1, Het2, Cs-vcycloalkyl, Ci^alkyloxycarbonyl, cafboxyl, aminocarbonyl, mono- or di(C]^aIkyI)armnocarbonyL, aminosulfonyl, C]^4alkylS(O)t, hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from Cj^alkyl, aryl, arylCMalkyl, C3_7cycloallcyl, C3.7cycloalkylCMalkyl5 Het1, Het2, HetJCi-4alkyl and Het2CMaIkyl; whereby Rg, Rioa and the carbon atoms to which they are attached may also form a C3_7cycloalkyl radical; is hydrogen, C2-6alkenyl, C2-6alkynyl, Cs-ycycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, amrnoCi^alkylcarbonyloxy optionally mono- or disubstituted, Ci^alkyloxycarbonyl, aryloxycarbonyl, Het'oxy-carbonyl, Het2oxycarbonyl, aryloxycarbonylCi^alkyl, arylCi^alkyloxy-carbonyl, Ci^alkylcafbonyl, C3-7cycloalkylcarbonyl, Cs-ycycloalkryl-C]-4aLkyloxycarbonyl, Ca.ycycloalkylcarbonyloxy, carboxylCi-4aHcyl-carbonyloxy, Ci^alkylcarbonyloxy, arylCMalkylcarbonyloxy, arylcarbonyloxy, aryloxycarbonyloxy, Het^arbonyl, He^carbonyloxy, Het1Ci^alkyloxycarbonyl, Het2carbonyloxy, Het2Ci^alkylcarbonyloxy, Het2CmaLkyloxycarbonyloxy or Ci^alkyl optionally substituted with aryl, aryloxy, Het2 or hydroxy; wherein the substituents on the amino groups are each independently selected from Ci^alkyl, aryl, arylCi^alkyl, C3_7cycloalkyl, Cs-vcycloalkylCi^alkyl, Het1, Het2, Het^Malkyl and Het2CMalkyl;
is hydrogen, Cs^cycloalkyl, Ca-ealkenyl, Co-ealkynyl, aryl, Het1, Het2 or Cj^alkyl optionally substituted with halogen, hydroxy, Ci-4.aIkylS(=O)tJ aryl, Cs^cycloalkyl, Het1, Her2, amino optionally mono- or disubstituted where the substituents are selected from Ci^allcyl, aryl, arylCi^alkyl, l, C3-7cycloalkylCMaIkyl, Het1, 'Het2, Het^i^alkyl and
whereby Rub maybe linked to the remainder of the molecule via a sulfonyl group; t is zero, 1 or 2:
L is -C(=O}-, -O-C(=O)-, -NRrC(=0>, -
-NR8-Ci.6alkanediyl-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 NRz moiety,
R4 is hydrogen, Ci^alkyloxycafbonyl. carboxyl, aminocafbonyl, mono- or
di(Ci^alkyl)aminocarbonyl, Cs-ycycloalkyl, Cs-galkenyl, C2-6alkynyl, or Chalky! optionally substituted with one or more substituents selected from, aryl, Het , Het2, C3-7cycloaUcyl, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(CMalkyl)aminocarbonyl, aminosulfonyl, Ci^alkylS(=O)t, hydroxy, cyano, halogen and amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, arylCi^alkyl, Cs-vcycloalkyl, Cs-ycycloalkyl-Ci^alkyl, Het1, Het2, He^CWalkyl and Het2Cwalkyl; and
rs is Ci^alkyloxy, Het1, He^oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than Ci^alkanediyl then Ru may also be Chalky!, Het^Mallcyl, Het^xyCi^alkyl, Het2Ci^alkyl, Het2oxyCi^alkyl, arylCi^alkyl, aryloxyC^alkyl or aminoCi_4alkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents selected from C^alkyl, Cj_4alky]lcafbonyl, Cj^alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, aryld^alkyl, Het^Malkyl or Het2CMalkyl.
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, Het^j^aJkyl, Het2Ci-6aIkyl, arylCi.6alkyl, more in particular, ri is a saturated or partially unsaturated monocyclic orbicyclic 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, or phenyl optionally substituted with one or more substituents;
R2 is hydrogen;
L is -C(=O)-, -O-C(=O)-3 -O-Ci-6alkanediyl-C(=O)-5 more in particular, L is
-O-C(=O)- or -O-Ci.6alkanediyl-C(=0)-, whereby in each case the C(=O) group is attached to the NR2 moiety;
R3 is arylCi ^alkyl. in particular, arylmethyl, more in particular phenylmethyl;
R4 is optionally substituted. Ci-galkyl. in particular unsubstituted Ci-ealkyl or
optionally substituted with one or more substituents selected from aryl. Het1, Het2, Cs-ycycloalkyl and amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, Het1 and Het2;
A is Ci-ealkanediyl, -C(=O)- or Ci-6alkanediyl-C(=O)-, in particular, A is 1.2-ethanediyl, 1.3-propanediyl or -C(=O)-;
R5 is hydrogen, Chalky!, He^Ci^alkyl, aminoCi_6alkyl whereby the amino group may
optionally be mono- or di-substituted with C^alkyl, in particular, rs is hydrogen
or Ci-galkyl; Re is Ci-galkyloxy, Het1, aryl, amino; and in case -A- is other than Q-ealkanediyl then
Re may also be Ci-ealkyl, He^Ci^alkyl, aryloxyCi^alkyl or aminoCi^alkyl;
whereby each of the amino groups may optionally be substituted; in particular, Rg
is Ci-^alkyloxy, optionally substituted amino; and in case -A- is other than
Ci-galkanediyl Re is Ci^alkyl; -A-Rfi is hydroxyCi_6alkyl; or rs and — A-Re 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 Het"1, aryl, Het2Ci_6alkyl; R2 is hydrogen; L is -C(=0)-, -O-C(=O)-, -O-CH2-C(=O)-; whereby in each case the C(=O) group is attached to the NRz moiety; R3 is phenyl-methyl; and R4 is Cj
Also a special group of compounds are those compounds of formula (I) wherein A is C^alkanediyl or -C(=O)-; rs is hydrogen or methyl; Re is Ci-galkyloxy, Het1, amino; and in case -A- is other than d-ealkanediyl then Re may also be Chalky!, He^C^ ^alkyl or aminoCj^alkyl; whereby each of the amino groups may optionally be substituted.
A suitable group of compounds are those compounds of formula (I) wherein A is Q.
r^alkanediyl or -C(=O}-; rs is hydrogen or methyl; Rg is Het"; and in case -A- is other than Cugalkanediyl then Re may also be Het2Ci_4alkyl; whereby each of the amino groups may be optionally substituted.
Yet another special group of compounds are those compounds of formula (I) wherein A is -C(=0)- and Rg is Cj^alkyloxy or Chalky!.
Another group of compounds are those compounds of formula (I) wherein wherein A is -C(=O)- and Re is Het2, Het1 or optionally mono- or disubstituted aminoCi_ealkyl.
An rnteresting group of compounds are those compounds of formula (I) wherein —A- is carbonyl and Rg is aryl, He^Cj^alkyl, aryloxyCi^alkyl or aminoCi^alkyl, whereby the amino groups may optionally be substituted; or —A- is carbonyl, Re is Ci^aUeyl and rs is He^Ci-galkyl or aminoCi-jalkyl whereby the amino group may optionally be mono-or di-substituted wifli 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
Another interesting group of compounds are those compounds of formula (I) wherein rj hydrogen, Chalky!, C2-6alkenyl, arylCi^alkyl, Cs-vcycloalkyl, Cs-vcycloalkylCi. 6alkyl, aryl, Het1, Het1 Chalky!, Het2, Het2Ci.6alkyl; wherein Het1 in the definition of R] 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-6alkanediyl-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-galkanediyl group in those moieties
containing said group; R5 is hydrogen, Ci^alkyl, He^Ci-ealkyl, Het2C1_gaIkyl, aminoCi-ealkyl whereby the
amino group may optionally be mono- or di-substituted with Chalky!; and in case —A- is — C(=O)- then R6 is CVealkyloxy, Het1, HetWy or Het2oxy, aryl,
He^Cj^alkyl, HetWyCi^alkyl, Het2Ci_4alkyl, Het2oxyCMalkyl, arylCMalkyl,
aryloxyCj^alkyl or aminoCj^alkyl; and in case —A- is C^alkanediyl then rs is amino. Ci^alkyloxy, Het1, He^oxy or Het2oxy;
and
'110
in case —A- is Ci-6alkanediyl-C(=O)- then Rg is Ci-salkyloxy, Het , Het oxy or Hefoxy,
aryl, Ci^alkyl, He^Ci^alkyl, Het^xyC^alkyl, Het2d^alkyl, 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 Chalky!, Ci^alkylcarbonyl,
Ci^alkyloxycarbonyl. aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, aryl-
CMaIkyL He^Ci^alkyl or Het2CMalkyl; and rs and — A-Re 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.
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^C^alkyl, Het2Ci-6alkyl, arylCi^alkyl, more in particular, R] is a saturated or partially unsaturated monocyclic or bicyclic heterocycle liaving 5 to 8 ring members, which contains one or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur and which is optionally substituted, or phenyl optionally substituted with one or more substituents; rz is hydrogen: L is -C(=O)-, -O-C(=O)-, -O-Ci_6aIkanediyl-C(=O)-, more in particular, L is
-O-C(=O)- or -O-Ci-6alkanediyl-C(=O)-3 whereby in each case the C(=O) group is attached to the NR2 moiety;
R^ is arylCi^alkyl, in particular, arykaethyl, more in particular phenyhnethyl; R4 is optionally substituted Ci^alkyl, in particular unsubstituted Cj^alkyl or C1_galkyl optionally substituted with one or more substituents each independently selected from aryl., Het1, Het2, Cs-ycycloalkyl and amino optionally mono- or disubstituted where the substituents are each independently selected from Ci^alkyl, aryl, Het1 and Her2; A is Cj-gaLkanediyl, -C(=O)- or Ci-galkanediyl-Cf^O)-, in particular, A is
1,2-ethanediyl,' 1,3-propanediyl or -C(=O)-;
rs is hydrogen, Ci-galkyl, He^Ci-galkyl, aminoCi-ealkyl whereby the amino group may optionally be mono- or di-substituted with.Ci^alkyl, in particular, rs is hydrogen or Ci-ealkyl;
Re is Q-salkyloxy, Het1, aryl, amino; and in case —A- is other than Cj-jgalkaaediyl then Re may also be Ci-ealkyl, He^Ci^alkyl. aryloxyCi^alkyl or aminoCi^alkyl; whereby each of the amino groups may optionally be substituted; in particular, Rg is Ci^alkyloxy, optionally substituted amino; and in case -A- is other than Ci_6alkanediyl R6 is C^alkyl; -A-Rg is hydroxyCi-gaJkyl; or
rs and — A-Rg taken together with the nitrogen atom to which they are attached may also form Het1.
Another interesting group of compounds are those compounds of formula (I) wherein -A- is Ci-galkanediyl and Rg is amino or Het1; whereby the amino group may optionally be mono- or di-srubstitnted with
Another interesting group of compounds are those compounds of formula (I) wherein A is Ci^alkanediyl. -C(=O)- or Ci-6alkanediyl-C(=O)-; whereby the point of
attachment to the nitrogen atom is the Cj-oalkanediyl group in those moieties
containing said group;
R5 is hydrogen. Chalky!, He^Ci-galkyl, Het^Ci-galkyl, aminoCi.galkyl whereby tie
amino group may optionally be mono- or di-snbstituted with Q^aliyl; and in case -A- is -C(=O)- then Re is Ci^alkyloxy, Het1, Hei^oxy or Her2oxy5 aryl,
Het'CMdiyl, HefoxyCMalkyl, HePCi^sSkyl, Het2oxyC1^aIkyl) arylC^alkjyl,
aryloxyCi^alkyl or aminoCi^alkyl; and in case —A- is Ci-galkanediyl then Rg is amino, Ci^alkyloxy, Het1, Hetjoxy or Hetpxy;
and in case -A- is Ci.salkanediyl-C(=O)- then Re is Ci-galkyloxy, Het1, HetWy or Hetroxy,
aryl, Ci-ealkyl, Het^Malkyl, HetWyCi^alkyl, Het2C^alkyl; Het2oxyCMalkyl,
arylCi^alkyl, aryloxyCi^alkyl or aminoCMalkyi; whereby each of the amino groups in the definition of R^ may optionally be substituted
with one or more substituents each independently selected from Chalky!,
Ci^alkylcarbonyl, Ci^alkyloxycarbonyl, aryl, arylcarbonyl. aryloxycarbonylj,
Het1, Het2, arylCMalkyl, He^C^alkyl or Het2Ci^.alkyl; and rs and — A-Re taken together with the nitrogen atom to which they are attached ma^
also form Het1 whereby Het1 is substituted by at least an oxo group.
Another group of compounds are those of formula (I) wherein ri is Het2Ci_6alkyl, JL is -C(=0)-, -O-C(=O)-, -O-Ci.6alkanediy]-C(=O)- ; in particular the Het2 moiety in trje definition of Rj is an aromatic heterocycle having 5 or 6 ring members, which contain one or more heteroatom ring members each independently selected from nitrogen, \ oxygen or sulfur, more in particular the Het2 moiety is an aromatic heterocycle havjng 5 or 6 ring members, which contain two or more heteroatom ring members each independently selected from nitrogen, oxygen or sulfur.
Suitably, the SO? moiety of the sulfonamide in the compounds of the present invention is para vis-a-vis the nitrogen of the benzoxazole moiety.
Another group of suitable compounds are those of formula (I) wherein A is C diyl or-C(=O)-; rs is hydrogen or methyl; and Re is C^galkyloxy, Het1, Het2, amin amino Ci-ealkyl; whereby each amino optionally may be mono- or disubstituted wh
o or re
the substituents are each independently selected from Q^alkyl, aryl, C3.7cycloalkyl; C3.7cycloalkylC]^alkyl, Het1, Het2, Het^Malkyl and Het2CwalkyL|
7
Another grotrp of suitable compounds are those of formula (I) wherein ri is Het" orj Het2Ci-6aIk:yl; wherein said Het2 in the definition of ri is an aromatic heterocycle having at least one heteroatom each independently selected from nitrogen, oxygen ajnd sulfur; L is -C(=O)-, -0-C(=O)- or -O-Ci^a]kyl-C(=O)-; A is C^alkanediyl or -C(=O)-; rs is hydrogen or methyl; and Rg is Q-ealkyloxy, Het1, Het2, amino or
aminoCi_6alkyl; whereby each arnino optionally may be mono- or disubstituted, wjiere the substituents are each independently selected from Ci^alkyl, aryl. arylCi^alkyl,! C3.7cycloallcyl, C3-7cycloalkylCi-4alkyl, Het1, Het2. HetzCi-4alkyl and Het2Ci^alky|.
Another group of suitable compounds are those of formula (Tj wherein ri is 2-thiazolyrmethyl-; and L is -O-C(=0)-.
Another group of suitable compounds are those of formula (I) wherein rs is hydroken; A is -C(=O)-; and Re is Het2; wherein said Het2 contains 5 or 6 ring members and ()>ne heteroatom selected from nitrogen, oxygen or sulfur.
Another group of compounds are those of formula (I) wherein ri is Het1, having Siring members and two heteroatoms each independently selected from nitrogen, oxygen jor sulfur; L is -O-C(=O)-; rs is hydrogen or methyl;A is —C(=O)-, Ci^alkanediyl; anji Rg is optionally mono- or disubstituted aminoCi-4aIkyl, Het1 or Her2; wherein said Hef contains 5 or 6 ring members and one heteratom selected from nitrogen, oxygen or| sulfur; wherein the amino substituents are each independently selected from aryl, aiylCMaIkyl, C3-7cycloalkyl, C3_7cycloalkylCMalkyl, Het1, Het2, Het^ and Het2Ci_4alkyl.
The compounds of formula (I) can generally be prepared using procedures analogous to those procedures described in WO 95/06030, WO 96/22287, WO 96728418, 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 krjown in the art such as, for example, extraction, crystallization, trituration and chromatography.
(Figure Remove)
The 2-acetamido-6-chlorosulfonylbenzoxazole (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 C, 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 °JC. The Boc group in the intermediate a-3 is a protective fe;^-butyloxycarbonyl group. I It may conveniently be replaced by another suitable protective group such as phtalimfdo or benzyloxycarbonyl. Using intermediate a-4 as a starting material, intermediate u-5 was deprotected using an acid such as trifiuoroacetic acid in a suitable solvent such as dichloromethane. The resulting intermediate may be further reacted with an inter­mediate of formula Ri-L-(leaving group) in the presence of a base such as Iriemylainine
I
and optionally in the presence of l-(3-dimeiiiylaminopropyl)-3-ethylcarbodii!iiide hydrochloric acid (EDC) or an alcohol such as feTt-butanol, and in a suitable solvepl 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. j
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.
The procedure described in scheme A may also be used to prepare intermediates cjf formula a-6 wherein benzoxazole is substituted with a carbamate instead of an arrjide.
(Figure Remove)
Intermediate b-4 can be prepared according to the procedure described in scheme) A. Intermediate b-5 can be prepared by for instance refluxing the 2(3H)-benzoxazolpne derivative b-4 in the presence of a base such, as, for example, sodiumhydroxide. $aid
intermediate b-5 can then be cyclized again using a reagent such as alkyi xantMc ajcid
potassium salt (alkyi dithiocarbonate potassium salt) in a suitable solvent such as, for
example, etbanol at reflux temperature, thus preparing a 2(3H)-benzoxazoletbionejof
formula b-6. Intermediate b-6 may then be derivatized with an arnine of formula EJsN-
A-Re in a suitable solvent such as acetonitrile to obtain an intermediate b-7. j
i
Debenzylation may be performed using art-known techniques such, as the use of Pd on carbon in the presence of Eb in a suitable solvent The thus formed intermediate of formula b-8 may then be reacted with an intermediate of formula Ri-L-(leaving grj^up)
in the presence of a base such as triethylamine and optionally in the presence of Elf>C
I or an alcohol such as fert-butanol, and in a suitable solvent such as dicMoromethaije,
thus obtaining an intermediate b-9.
A particular way of preparing acetamide substituted benzoxazoles is depicted in scheme C.
(Figure Remove)
Intermediate c-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 c-2. Said intermediate c-2 can further be reacted with an amine of formxla NRaRb whereby Ra and R-D are defined as the possible substituents on an arnino groiizp in the variable Re-
Another particular way of preparing acetamide substituted benzoxazoles is depicte scheme D.
in
(Figure Remove)
Intermediate d-2 can be prepared by treating intermediate d-1, prepared following the
I
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 schernej D to obtain intermediate d-6 are all analogous to reaction procedures described in the 4bove synthesis schemes.
A number of intermediates and starting materials used in the foregoing preparatiojis are known compounds, while others may be prepared according to art-known methodologies of preparing said or similar compounds.
Scheme E
(Figure Remove)
Intermediate e-2, corresponding to •intermediate a-3 in scheme A, may be prepareji by adding an amine of formula EbN-R* to an intermediate e-1 in a suitable solvent siich as isopropanol.
(Figure Remove)
A mixture of the 2-aminobenzoxazole f-1 in dichloromethane was stirred under anj inert atmosphere such as nitrogen.. Rg-COOH, EDC and HOBT (1-hydroxy-l-H-benzotriazole) were added. The mixture was stirred at room temperature for 48h. Water was added, the water layer was extracted with dichloromethane and the combined organic layers were washed with brine, dried under MgSCU and the solvent was evaporated under reduced pressure. Purification was performed on silica yielding fj~2.
The compounds of formula (I) may also be converted to the correspondin forms following art-known procedures for converting a trivalent nitrogen into its N-oxide form. Said TV-oxidation reaction may generally be carried out by reacting }fhe 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-chlorobenzenecarboperoxoic acid, peroxoalkanoic acids, e.g. peroxoacetic acid, j aUcylhydroperoxides, e.g. teTt-butyl hydroperoxide. Suitable solvents are, for exanjiple, water, lower alkanols, e.g. ethanol and the like, hydrocarbons, e.g. toluene, ketones|, e.g. 2-butanone, halogenated hydrocarbons, e.g. dichloromethane, and mixtures of bu-ch. solvents.
An interesting group of intermediates are those intermediates of formula a-8, b-8 or c-1 wherein - A-R6 is hydrogen. Said intermediates may also have pharmacological
j
properties similar to those pharmacological properties of the compounds of formul^. (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 irj the form of pharmaceutical preparations.
Furthermore, the present invention relates to pharmaceutical preparations which ajs active constituents contain an effective dose of at least one of the compounds of formula (T) in addition to customary pharmaceutically innocuous excipients and auxiliaries. The pharmaceutical preparations normally contain 0.1 to 90% by weijsht of a compound of formula (I). The pharmaceutical preparations can be prepared in 4 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 pharrnaceuticajl 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.gj, 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 fhe 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 corrig^nts, preservatives, solubilizers, agents for achieving a depot effect, buffer substances ojr colorants are also useful.
Due to their favorable pharmacological properties, particularly their activity againpt multi-drug resistant HIV protease enzymes, the compounds of the present invention are useful in the treatment of individuals infected by HTV and for the prophylaxis of tljiese individuals, rn general, the compounds of the present invention may be useful in tljie 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, ATDS-related complex) (ARC), progressive generalized lymphadenopathy (PGL), as well as chronic CNS i diseases caused by retroviruses, such as, for example HTV mediated dementia and multble 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 HTV-infected subjects of an anjount effective to combat the conditions associated with HIV and other pathogenic retroviruses. especially HTV-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 HTV virus.
In 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 HTV-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 invention 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 HTV-1 retrovirus.
In another preferred embodiment, the present invention relates to the use of formul^t (I) or any subgroup thereof in the manufacture of a medicament for inhibiting multi-drp.g resistant retroviral replication, in particular HTV-1 replication.
The compounds of the present invention may also find use hi inhibiting ex vivo samples containing HTV or expected to be exposed to HTV. Hence, the present compounds may be used to inhibit HTV present in a body fluid sample which contaijn, or is suspected to contain or be exposed to HIV.
Also, the combination of an autirerroviral compound and a compound of thepreseni 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 HTV infections, or the .infection and disease associated with HTV 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; co-receptor bidding inhibitors, such as, for example. AMD 3100 (Bicyclams), TAK 779; RT inhibitor^, such as. for example, foscarnet andprodrugs; nucleoside RTIs, such as, for example. AZT, 3TC, DDC, DDI, D4T, Abacavir, FTC, DAPD, dOTC; nucleotide RTIs, sucjh as,
I
for example, PMEA, PMPA (tenofovir): NNRTIs, such as, for example, nevirapinie, delavirdine, efavirenz, 8 and 9-C1 TffiO (tivirapine), loviride, TMC-125, TMC-12JO, MKC-442, UC 781, UC 7S2, Capraviriue, DPC 961, DPC963, DPC082, DPC083,j calanolide A, SJ-3366, TSAO, 4"-deaminated TSAO; RNAse H inhibitors, such 4, for example, SP1093V, PD126338; TAT inhibitors, such as, for example, RO-5-3335J, K12, K37; integrase inhibitors, such as, for example, L 708906, L 731988; proteasje " inhibitors, such as, for example, ampreuavir, ritonavir, nelfinavir, saquinavir, indujiavir, lopinavir, palinavir, BMS 186316, BMS 232632, DPC 681, DPC 684, tipranavir, AG1776, DMP 450, GS3333, KNI-413, KM-272, L754394, L756425, LG-71350J PD161374, PD173606, PD177298, PD178390, PD178392, PNU 140135, maslinicj acid, U-l 40690; glycosylation inhibitors, such as, for example, castanospermine, deoxynojirinaycine.
The combination may in some cases provide a synergistic effect, whereby viral infectivity and its associated symptoms may be prevented, substantially reduced, qr 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-2J methionine enkephaHn, interferon alpha, and naltrexone) with antibiotics (e.g.. pentamidine isothiorate) cytokines (e.g. Th2), modulators of cytokines, chemokin^s (e.g. CCR5) or hormones (e.g. growth hormone) to ameliorate, combat, or eliminate
HIV infection and its symptoms. \ .
'
The compounds of the present invention may also be administered in combination) with
modulators of the metabolization following application of the drug to an individuajl.
These modulators, include compounds that interfere with the metabolization at
cytochromes. such as cytochrome P450. It is known that several isoenzymes exist |of
cytochrorne P450, one of which is cytochrome P450 3A4.'Ritonavir is an example] of a
modulator of metabolization via cytochrome P450. j
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 rjieans
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, com starch. In this case the preparation can be caijried out both as dry and as moist granules. Suitable oily excipients or solvents are vegetable
j
or animal oils, such as sunflower oil or cod liver oil. Suitable solvents for aqueousl 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 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, hi addition also sugar solutions such as glucose or mannitol solutions, or alternatively mixtures of the various solvents mentioned.
Suitable pharmaceutical formulations for aobninistration 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 well as a propellant. Such a preparation customarily contains the active compound in a concentration from approximately O.iL to 50%, hi particular from approximately 0.3 to 3% by weight
In order to enhance the solubility and/or the stability of the compounds of formula (J) in pharmaceutical compositions, it can be advantageous to employ a-, ft- or y-cyclo-dextrins-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 Ci-ealkyl, particularly methyl, ethyl or isopropyl. e.g. randomly methylated J3-CD; hydroxyCi^alkyl, particularly hydroxy-
I
ethyl, hydroxypropyl or hydroxybutyl; carboxyCj.galkyl, particularly carboxyrnetl|iyl or
i
carboxyethyl; Ci-ealkyl-carbonyl, particularly acetyl; C^alkyloxycarbonylCi^al^yl or carboxyCi^alkyloxyCi-ealkyl, particularly carboxymethoxypropyl or carboxyethoixy-propyl; Ci-galkylcarbonyloxyCi-fialkyl, particularly 2-acetyloxypropyl. Especially; noteworthy as complexants.and/or solubilizers are p-CD, randomly methylated ^-]CD, 2,6-dimetiiyl-p-CD, 2-hydroxyethyl~p-CD, 2-hydroxyethyl-y-CD, 2-hydroxy-propyl-y-CD and (2-carboxymethoxy)propyl-(3-CD, and in particular 2-hydroxy-propyl-p-CD (2-HP-J3-CD).
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 equjally 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 splubilizer, an aqueous acidic medium as bulk liquid carrier and an alcoholic co-solvent that greatly simplifies the preparation of the composition. Sajd 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,
WO 98/42318, 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. j
The term "a solid dispersion" defines a system in a solid state (as opposed to a liqijjid or gaseous state) comprising at least two components, wherein one component is dispersed more or less evenly throughout the other component or components. Wljien 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 thermo-i dynamics, such a solid dispersion is referred to as "a solid solution". Solid solutiotLS 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 physicall^ 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 ^0°C
4
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 ethjer 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 dispersiojn. Various techniques exist for preparing solid dispersions inchiding melt-extrusion, spray-drying and solution-evaporation, melt-extrusion being preferred.
It may further be convenient to formulate the present compounds hi the form of j 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 nnji.. Useful surface modifiers are believed to include those which physically adhere to tfaje surface of the antrretrovrral agent hut 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 pharmja-ceutical composition whereby the present compounds are incorporated in hydrophilip polymers and applying this mixture as a coat film over many small beads, thus yielding
a composition with good bioavailabiKty which can conveniently be manufactured which is suitable for preparing pharmaceutical dosage forms for oral adrninistratiojn.
Said beads comprise (a) a central, rounded or spherical core, (b) a coating film of | hydrophilic polymer and an antiretroviral agent and (c) a seal-coating polymer lay^r.
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 inj a test or assay for determining the ability of a potential pharmaceutical to inhibit Hly 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 phenotypic resistance monitoring assays, such as known recombinant assays, in the clinical management! of resistance developing diseases such as HIV. A particularly useful resistance | 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, t The compounds of the present invention may also be linked to maleimide or derivatives thereof to form conjugates.
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 £.cute or prophylactic. Customarily, the daily dose of a compound of formula (I) in the c0.se of administration to a patient approximately 75 kg in weight is 1 mg to 3g, suitably! 1 mg to 1 g. preferably 3 mg to 0.5 g, more preferably 5 mg to 300 mg. 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 1
A mixture of 5g 2-acetarnidobenzoxazole and 20 ml chlorosulfonic acid in dicljloro-
methane was heated to 60°C for 2 hours (h). After cooling the mixture was pourejd into
ice. The organic layer was separated and dried over MgSC>4, thus yielding
2-acetamido-6-chlorosulfonylbenzoxazole (interm. 1) •
A mixture of 3.4 g of [(lS,2R)-2-hydroxy-3-[(2-methylpropyi)amino]-l-(pheny|l-
methyl)propyl] carbamic acid 1,1-dimethylethyl ester, prepared analogously to ttye
procedure described in WO 97/18205, and 2.6 g of triethylamine in 100 ml of dichWo-
methane was stirred at 0°C. Then 2.8 g of 2-acetamido-6-chlorosulfonylbenzoxaz(j)le was
added and the reaction mixture stirred overnight at room temperature. After washing with
water, the organic layer was separated, dried and evaporated. The brown solid obtained
was reslunied in warm diisopropyl ether, cooled and
filtered off, thus yielding 88% (5.1 g) of interm. 2 : bocnh
(Figure Remove)
c) To a mixture of 1.2 g of intermediate 2 in 25 ml of dichloromethane, 2.3 ml of trifiuoracetic acid were added. The reaction mixture as stirred at room temperature j for 6 hours. Extra dichloromethane was added and washed with NaHCOa solution. Th£ organic layer was dried and evaporated under reduced pressure, yielding 970 mg (99%)
(Figure Remove)of intermediate 3:
d) To a mixture of 1.1 g intermediate 3 and 364 mg triethylamine in dicMorometharJe was added 685 mg l-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbon^l]-oxyj- 2,5-pyrrolidmedione (described in W09967417). This mixture is stirred atroo|m temperature for 12 hours. After evaporation .of dichloromethane under reduced pressure, the crude product is purified on silica. Thus, 900 mg of compound 1 was obtained with a yield of 59%.
Example 2.: Preparation of compound 5
a) A mixture of 1 g of [(lS.2R)-2-hydroxy-3-[(2-methylrropyl)amiiio]-i-(pIieiiyl^ memyl)propyl]carbamic acid 1,1-dimethylethyl ester and 901 mg of rriemylamine in 40 ml of dichloromethane was stirred at 0°C. Then 1 g of 2-(Timoxycarbamoyi)-€J-chlorosulfonylbenzoxazole was added and the reaction mixture stirred overnight fit room temperature. After washing with sat NaHCOs, the organic layer was separated, dried and evaporated, yielding 1.7 g (94%) of intermediate 4
(Figure Remove)
b) To a mixture of 1.7 g of intermediate 4 in 25 ml of dichloromethane., 3.2 g of trifluoracetic acid were added. The reaction mixture as stirred at room temperatur^ for 6 hours. Extra dichloromethane was added and washed with NaHCO3 solution. Tile organic layer was dried and evaporated under reduced pressure yielding 1.4 g (99%) of
(Figure Remove)intermediate 5
c) A mixture of 380 mg of intermediate 5, 107 mg of 1 -hydroxybenzotriazole., 154 of l-(3-dimemylaminopropyI)-3-eiliylcarbodirmide hydrochloric acid and 143 mg|of 2-(2,6-dimethylphenoxy)acetic acid in 20 ml of dichloromethane, was stirred oveijnight at room temperature. The reaction mixture was then washed with 5% HC1, saturated NaHCO3 solution and brine. The organic layer was separated, dried and evaporated. The residue was purified by preparative-HP LC, yielding 141 mg (28%) of compoijmd 5.
Example 3 : Preparation of compound 3
To a mixture of 1.2g intermediate 5 and 364 mg trierhylamine in dichloromethane! was added 685 mg l-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]fbran-3-yl]oxy]carbonyl]cjxy]-2,5-pyrrolidinedione (described in W09967417). This mixture is stirred at room temperature for 12 hours. After evaporation of dichloromethane under reduced prejssure, the crude product is purified on silica, thus yielding 1.1 g (70%) of compound 3.
Exarrrole 4 : Preparation of compound 2
a) To a mixture of 8 g j3-[bis(phenylmemyl)arrimo]-a-[[(2-methylpropyl)arnino]-methyl]-, (aR,j3S)-benzenepropanol, prepared following the procedure in WO95/14653, and 3.2 g triethylamine in 150 ml dichloromethane was added at 3.9 g 6-chlorosulfonyl-benzoxazolone (prepared as described in EP 0403947). A^ter stirring for 24 hours at room temperature fhe reaction mixture was washed with salt. NaHCO3, 8 g of
(Figure Remove)intermediate 6 :
b) A. mixture of 5.2 g intermediate 6 in 60 ml 10% NaOH-solution was heated to rjsfhix overnight. After cooling the reaction mixture was acidified to pH=8 with 15% HCfl. The aqueous phase was extracted two times with ethylacetate, yielding 3 g of
(Figure Remove)intermediate?:
c) To a solution of 1 .5 g intermediate 7 in ethanol was added 361mg ethylpotassiuijn xanthate. After refluxing this mixture for 16 hours, ethanol was removed under vacuum. To the residue was added HaO. After acidification to pH=6 the precipitate was filtered of, yielding, after drying,
(Figure Remove)
1 .4 g of intermediate 8 :
d) A mixture of 500 mg intermediate 8 and 70 mg JV^-dimethylefhylenediamine inl p-xylene was heated to 110°C for 3 hours. After evaporation of the solvent and purification with column chromatography 181 mg of intermediate 9 was obtained :
(Figure Remove)
e) Debenzylation was performed with Pd/C and Ho to afford intermediate 10.
(Figure Remove)
f) To a mixture of 95 mg intermediate 10 and 27 mg triethylamine in dichlorometljiane was added 51 mg l-[[[[(3R,3aS,6aR)-hexahydrofuro[2,3-b]furan-3-yl]oxy]carbon^l]-oxy]-2,5-pyrrolidinedione (described in W09967417). This mixture is stirred at robm temperature for 12 hours. After evaporation of dichloromethane under reduced pressure, the crude product is purified on silica, yielding 83 mg of compound 2 (7(j)%).
In an analogous way, compounds 4, 6, 7 and 8 were prepared. Example5: Synthesis of compound 10
(Figure Remove)
0.23g of isonicotinic acid, 0.36g of EDC and 12mg of HOST were mixed and add^d to Ig of the 2-arninobenzoxazole intermediate 11 in 40ml of dichloromethane. The mixture was stirred under an inert atmosphere of nitrogen at room temperature for J4Sh. 50ml of water was added the water layer was extracted with dichloromethane and me combined organic layers were washed with brine, dried tinder MgSO4 and the solvent was evaporated under reduced pressure. Purification was performed on silica yielding 0.57g (48%) of compound 10.
(Figure Remove)Example 6



A mixture of 2.5g 2-aminopiienol (6-1) and 20 ml ethyl acetate was heated to 45°C- 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50°^! for 12 hours. After cooling to room temperature, 1.5g of sodium hydroxide in 15ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed.to yield 2.71g (88%) 2-aminobenzoxazol (6-2).
7.5ml of chlorosulfonic acid was stirred at room temperature under an inert atmosphere. 5g of 2-aminobenzoxazol (6-2) was added in small portions. The temperature was kept between 30-60°C during the addition of 6-2. The mixture heated to 80°C for 2 hours. 5.3 g of thionyl chloride was added drop wise, keeping! the temperature at 65°C. The mixture was stirred during 2 hours. After cooling to 0°CjlOml of ethyl acetate and 10ml of a solution of sodium carbonate (IN) were added. The j organic layer was separated from the water layer and this latter was extracted witbjethyl acetate. The combined organic layers were dried over calcium chloride, yielding 7^8g (90%) of 2-amino-6-chlorosulfonylbenzoxazole (6-3).
Example 7
(Figure Remove)
A mixture of Ig of sodium methoxide and 10 ml of toluene was stirred at 0°C undej nitrogen atmosphere . A mixture of 1.9g of methyl chloracetate (7-1) and 1.1 g of j methylformate was added drop wise keeping the temperature between 5-10°C. The mixture was stirred for 2 hours at 0°C. After washing with water, the organic layer Vas
dried and evaporated under reduced pressure yielding 2-chloro-3-oxo-propionic ajsid methyl ester (7-2).
A mixture of 2.4g of 2-chloro-3-oxo-propionic acid methyl ester (7-2), water 20nfl and 1.75g of thiourea was refluxed for 2hours. The mixture was cooled to room temperature and 0.25g of norit was added and filtered. A solution of 2.5N sodium hydroxide \fas added to the filtrate until neutral pH. The filtration yielded 1.23g (44%) of 2-aminothiazole-5-carboxylic acid methyl ester (7-3). The mixture of 2.15g of isoamyl nitrite and 10ml of dioxane was stirred at 80°C uhder a nitrogen atmosphere. A solution of 1.23g of 2-aminothiazole-5~carboxylic acid methyl ester (7-3) in 20ml of dioxane was added drop wise. The mixture was refiyxed for 2 hours. After cooling to room temperature 30ml of ethyl acetate was added. Tjhe mixture was washed with brine and dried and the solvent evaporated under reduced pressure. The crude product is purified on silica, thus yielding 0.54g (48%) of thiajzol 5-carboxyhc acid methyl ester (7-4).
A mixture of 0.54 g of thiazol 5-cafboxylic acid methyl ester (g-4) and 10ml ; tetrahydrofurane (THF) was stirred at 0°C under a nitrogen atmosphere. The mixture of 0.16g of lithium aluminium hydride and 5ml of ether was added drop wise. After f.hour at 0°C water and 20% sodium hydroxide were added, and stirred during SOminutep (min). The mixture was filtered over decalite and the solvent was removed by \ azeotropique distillation with toluene yielding 0.3g (69%) of thiazol-5-yl-merhanql (7-5).
Example 8
A mixture of 1.15g of thiazol-5-yl-methanol (8-1) and 1.2g triethylamine (TEA) hji ' 25ml of dichloromethane (DCM) was stirred at room temperature under an atmosphere of nitrogen. 2.56g of N,N'-disuccinimidyl carbonate was then added and the resulting mixture was stirred-for 10-15 minutes. The solution was stirred for an additional 2i hours. The resulting intermediate (8-2) was used directly in the subsequent reactiojn with the amine (8-3). Instead of amines also salts thereof can be used. Trierhylamine 2g and the amine 5g (8-3) were added to dichloromethane 40ml anq the resulting mixture was stirred at room temperature. Subsequently, a portion of the solution comprising 8-2 was added drop wise. The reaction mixture was stirred at jroom temperature for 2 hours. The reaction mixture was washed with water and then drifed to yield compound (8-4).
(Figure Remove)
Table 1
Compounds of the present invention prepared according to the methods described above. If no stereochemistry is indicated, the compound is present as aracemic mixture.
(Table Remove)

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 antj-HTv acti^dty against a wild type laboratory HIV strain (B3V-1 strain LAI). The cejilular 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 HIJV-infected cells have been killed by the replicating virus in the control cultures in th^ absence of any inhibitor. Cell viability- is measured by measuring the concenrratiojn- 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 ojf 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 cytopathogenic effect of tjie virus. The toxicity of the compound was measured on the mock-infected cells and I 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 CCso/ECso) is an indication of the selectivity of the anti-HIV activity of the inhibitor. Wherever results are reported as e.g. pECso °r pCCjo values, the result is expressed as the negative logarithm of the result expressed as ECso °r CCso respectively.
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 (Table 2 and 3). 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 fb|r instance saquinavir, ritonavir, nelfinavir, indinavir and amprenavir.
Table 2 List of mutations present in the protease gene of the HIV strains (A to F) usfed .
V003I, L010I, V032T, L033M: E035D, S037Y, S037D, M046I, R057R/K, Q058E, L06J3P,
K070T, A071V, I072V, IOS4V, L089V I
B
C
V003I, L010I, K020R, E035D, M0363, S037N, Q05SE, I062V, L063P, A071V, I072M,
G073S, V077I, IOS4V, I085V, L09QM . |
V003I, L010I, I015V, L019I, K020M, S037N, R041K, I054V, Q05SE, L063P, A071V,
I084V, L090M, I093L I
D V0031, L010L/I, I013V, L033I, E035D, M036I, M046L, K055R, R057K, L063P, I066FJ
A071V, I084V; ND88D, LQ90M •
(Table Remove)
As a measure of the broad spectrum activity of the present compounds, the fold resistance (FR), defined as FR = EC50(mutant strain)/EC5o(HIV-l strain LAI), w determined. Table 3 shows the results of the antiviral testing in terms of fold resistance. As can be seen hi this table, the present compounds are effective in inhibiting a broad range of mutant strains: Column A FR value towards mutant j Column B: FR towards mutant B , Column C: FR towards mutant C. Column D: towards mutant D, Column E: FR towards mutant E, Column F: FR towards mutant F. The toxicity is expressed as the pCCso value as determined with mock transfectedi cells.
Table 3. Results of the toxicity testing and the resistance testing against strain A tjo F (expressed as FR). ND indicates not determined (Table Remove)

Biovailability:
Caco-2 permeability assay for intestinal absorption
The permeability of different compounds is evaluated according to a Caco-2 test protocol as described by Augustijns et al. (Augustijns et al. (1998). Int. J. ofPharni, 166, 45-54) whereby, Caco-2 cells at cell passage number between 32 and 45 are grown in 24-well transwell cell culture plates for 21 to 25 days. The integrity of thd cell monolayer is checked by measuring the transepithelial electrical resistance (TEER)L The test is performed at pH 7.4 and at 100 uM donor compound concentration.
Aqueous solubility at different pH levels
The equilibrium solubility in simulated gastrointestirial solutions under thermodynajnaic conditions is a good measure for the solubility profile of the compound in the stomach and the different parts of the intestine. Simulated gastric fluid (SGF) (without pepsin) is set at pH of 1.5. Simulated intestinal fluids (SIF) (without bile salts) are set at pH 5sj pH 6.5, pH 7 and pH 7.5. The experimental protocol uses 96-well flat-bottom microplalfes in which 1 mg of compound is added per well (stock solution in methanol) and evaporated to dryness. The compounds are resolubilized in SGF and SIF and incubated overnight on a horizontal shaking device at 37°C. After filtration, fee compound concentrations are determined by UV-spectrophotometry.
Oral availability in the rat
'
The compounds are formulated as a 20 mg/ml solution or suspension in DMSO, PEG400 or cyclodextin 40% in water. For most experiments in the rat (mal-e and fenjiale rats), three dosing groups are formed: II single intraperitoneal (IP) dose at 20 mg/kg. using the DMSO formulation; 21 single oral dose at 20 mg/kg using the PEG400 formulation and 3/ single oral dose at 20 mg/kg using the cyclodextrin formulation. Blood is sampled at regular time intervals after dosing and drug concentrations in
serum are determined using a LC-MS bio analytical method. Serum concentratioip are expressed in ng/mg after normalization to 10 mg/kg. Serum concentration at 30 minutes (30') and at 3 hours (180') can be determined as these values reflect the Extent of absorption (30') and the speed of elimination (ISO')- The rat serum concentration at 30 min and 180 min following IP administration of 20 mg/kg of compound 4 are J1098 ng/ml and 553 ng/ml respectively.
Boosting the systemic bioavailability
With the described type of compounds (protease-inhibitors), it is known that inhibition of the metabolic degradation processes can markedly increase the systemic availability by reducing the first-pass metabolism in the liver and the metabolic clearance froija the plasma This 'boosting' principle can be applied in a clinical setting to the pharmacological action of the drug. This principle can be also explored both in thfc rat or the dog by simultaneous administration of a compound that inhibits the Cyt-p4$O metabolic enzymes. Known blockers are for example ritonavir and ketoconazole.j Dosing a single oral dose of ritonvir at 5 mg'kg in the rat and the dog may result iji an increase of the systemic availability.
Protein Binding analyses:
Human serum proteins like albumin (HSA) or a-1 acid glycoprotein (AAG) are kriovra to bind many drugs, resulting in a possible decrease in the effectiveness of those compounds. In order to determine whether the present compounds would be adversely affected by this binding, the anti-HTV activity of the compounds was measured in jhe presence of human serum, thus evaluating the effect of the binding of the protease inhibitors to those proteins.
MT4 cells are infected with HTV-1 LAI at a multiplicity of infection (MOT) of 0.001-0.01 CCIDso (50% cell culture infective dose per cell, CCED5o). After 1 h incubation, cells are washed and plated into a 96 well plate containing serial dilutions of the compound in the presence of 10% PCS (foetal calf serum), 10% PCS + 1 mg/ml AAG (cci-acid glycoprotein), 10% PCS + 45 mg/ml HSA (human serum albumin) or 50% human serum (HS). After 5 or 6 days incubation, the BCso (50% effective concentration in cell-based assays) is calculated by determining the cell viability or by quantifyinjg the level of HIV replication. Cell viability is measured using the assay described abov^. Into a 96 well plate containing serial dilutions of the compound in the presence of 10% PCS or 10% PCS + 1 mg/ml AAG, FHV (wild type or resistant strain) and MT4 cells are added to a final concentration of 200-250 CCIDso/well and 30,000 cells/well respectively. After 5 days of incubation (37°C, 5% CO?), the viability of the cells i$ determined by the tetrazolium colorimetric MTT (3-[4,5-Dimethylthiazol-2-yl]-2?5T
diphenyltetrazoli-um bromide) method (Pauwels et al. J Virol. Methods 1988,20. [309-321).
Table 4 Effect of the protein binding on the in vitro activity of compound 1
(Table Remove)

CLAIMS
1. A compound having the formula
(Figure Remove)
an N-oxide, salt, stereoisomeric form, racemic mixture, prodrug, ester or metabolite thereof, wherein ri and rs are, each independently, hydrogen, Chalky!, C2^alkenylJ
C3.7cycloalkyl, C3.7cycloalkylCi,6alkyl, aryl, Het1, Het1C1.6aBcyl, Het2,
may also be a radical of formula
(Figure Remove)

wherein
R9, Rioa and Riot are, each independently, hydrogen, Ci^aUcyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^aUcyl)aminocarbonyl, C3-7cycloalkyl, Ca-ealkenyl, Ca-ealkynyl or Ci^alkyl optionally substituted with aryl, Het1, Het2, C3-7cycloalkyl, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Ci^alkyl)aminocarbonyl, aminosulfonyl, C]-4alkylS(O)t, hydroxy, cyano, halogen or ammo optionally mono- or disubstituted where the substituents are each independently selected from Cj-^alkyl, aryl, arylCi_4alkyl, C3_7cycloalkyl, C3.7cycloaBcylCi^alkylf Het1, Het2, He^Ci^alkyl and Het2Ci^alkyl; whereby Rg, Rjoa 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 Rg may also be oxo;
Riia is hydrogen, Ci-ealkenyl, C^-ealkynyl, C3.7cycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoCi-4alkylcarbonyloxy optionally mono- or disubstituted, Ci^alkyloxycarbonyl, aryloxycarbonyl, Hetjoxy-carbonyl, Het2oxycarbonyl, aryloxycarbonylCi^.alkyl, arylCi^alkyloxy-carbonyl, Ci^alkylcarbonyl, C3.7cycloalkylcarbonyl, C3-7cycloalkyl-Ci-4alkyloxycarboriyl, C3.7cycloalkylcarbonyloxy. carboxylCi^alkyl-carbonyloxy. Ci^alkylcarbonyloxy. arylCi^alkylcarbonyloxy,
arylcarbonyloxy, aryloxycarbonyloxy, He^carbonyl, Het'cafbonyloxy,' He^Ci^alkyloxycarbonyl, Het^carbonyloxy, Het2Ci^alkylcarbonyloxy, Het^i^alkyloxycafbonyloxy or Chalky! optionally substituted with, aryi, aryloxy, Her2 , halogen or hydroxy, wherein the substituents on. the ami-no groups are each independently selected from Chalky!, aryl, arylCi C3.7cycloalkyl, C3-7cycloaIkylCMalkyl, Het1, Her2, Het^Malkyl and
is hydrogen, Cs-ycycloalkyl. C2-6alkenyl, Ca-ealkynyl, aryl, Het1, Het2 or Ci^alkyl optionally substituted with halogen, hydroxy, Ci^alkylS(=Q)t, aryl, Cs^cycloalkyl, Het1, Het2, amino optionally mono- or disubstituted where the substituents are each independently selected from Chalky!, aryl, arylCi-4alkyl, Cs^cycloalkyl, Cs-vcycloalkylCi^alkyl, Het1, Het2, Het^Malkyl and Het2CMalkyl;
whereby rub maybe linked to the remainder of the molecule via a sulfonyl group; each independently, t is zero, 1 or 2; rs is hydrogen or Chalky!; L is -C(=0)-, -0-C(=O)-, -NRs-C(-O)-, -O-Ci-6alkanediyl-C(=O)-,
-NRs-Ci_6alkanediyI-C(=O}-, -S(=O)2-, -O-S(=0)2-, -NRg-S(=O)2 whereby either the C(=O) group or the S(=O)2 group is attached to the NR2 moiety; whereby the Cj-ealkanediyl moiety is optionally substituted with aryl, Het1 or Het2; R3 is Ci-ealkyl, aryl, C3_7cycloalkyl, C3.7cycloalkylCi^alkyl, or arylCi_4alkyl; R 6^(Ci^alkyl)arninocarbonyl, Cs^cycloalkyl, Cs-salkenyl, C2-6alkynyl, or Ci_ealkyl optionally substituted with one or more substituents each independently selected from aryl, Het1, Het2, Cs-ycycloalkyl, Ci^alkyloxycarbonyl, carboxyl, amino­carbonyl, mono- or di(Ci-4alkyl)aminocarbonyl, aminosulfonyl, Ci^alkylS^O)^ hydroxy, cyano, halogen and amino optionally mono- or disubstituted where the substituents are each independently selected from Chalky!, aryl, aryl Chalky!, Cs-ycycloalkyl, C3.7cycloaIkylC]^alkyl3 Het1, Het2, Het^Malkyl and Het2CMalkyl; A is Ci_6alkanediyl, -C(=O)-, -C(=S)-3 -S(=O)2-, Ci-6aIkanediyl-C(=O)-,
Ci_6alkanediyI-C(=S)- or Ci-6alkanediyl-S(=O)?-; whereby the point of attachment to the nitrogen atom is the Ci.6alkanediyl group in those moieties containing said group;
R5 is hydrogen, hydroxy, Chalky!, He^Ci-ealkyl, Het^Ci^alkyl, aminoCi.salkyl whereby the amino group may optionally be mono- or di-substituted with
Re is Ci-ealkyloxy, Het1, Het3oxy, Her2, Het^oxy, aryl, aryloxy or ami.no; and in case -A- is other than Ci-ealkanediyl then Re may also be Ci-galkyl, Het^Malkyl, HetWyCi^alkyL, Het^Ci^alkyl, Het^xyCi^alkyl, arylCi^alkyl, aryloxyCi^alkyl or arninoCi-galkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents each independently selected from Q^alkyl, Ci^alkylcarbonyl, Ci^alkyloxycarbonyL, aryl, aryl-carbonyl, aryloxycarbonyl, Het1, Her2, arylQualkyl, He^Ci^alkyl or HerCi^alkyl; and
-A-Rg may also be hydroxyCi.galkyl;
rs and -A-Rfi taken together with the nitrogen atom to which they are attached may also form Het3 or Het2.
2. A compound according to claim 1. wherein:
R9, Rioa and Riob are, each independently, hydrogen, Ci_4alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(Cm.alkyl)aminocarbonyl, Cs.ycyclo-alkyl, C2-6alkenyl, Ca-galkynyl or C]-4alkyl optionally substituted with aryl, Het1, Her2, Cs-ycycloalkyl, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(CMalkyl)aminocarbonyl, aminosulfonyl, Ci^alkylS(O)t. hydroxy, cyano, halogen or amino optionally mono- or disubstituted where the substituents are selected from Ci^alkyl, aryl, arylCi^alkyl, C3_7cycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'Ci^aDcyl and Het2C,.4alkyl; whereby and the carbon atoms to which they are attached may also form a
kyl radical;
Riia is hydrogen, Ci-ealkenyl, C2-6alkynyl, Cs.ycycloalkyl, aryl, aminocarbonyl optionally mono- or disubstituted, aminoCMalkylcarbonyloxy optionally mono- or disubstituted, Ci^alkyloxycarbonyl, aryloxycarbonyl, Het^xy-carbon3'l, Her2oxycarbonyl, aryloxycarbonylCwalkyl, carbonyl, Chalky]carbonyl, Cs.ycycloalkylcarbonyl, C oxycarbonyl, Cs-vcycloalkylcarbonyloxy, carboxylCi^alkylcarbonyloxy, Ci^alkylcarbonyloxy, arylCMalkylcarbonyloxy, arylcarbonyloxy, aryloxy-carbonyloxy, Het^arbonyl, Het]carbonyloxy, Het^i^alkyloxycarbonyl, Het2carbonyloxy, Het2Ci4alkylcarbonyloxy, Hel^Ci^alkyloxycarbonyloxy or Ci^alkyl optionally substituted with aryl, aryloxy, Het2 or hydroxy; wherein the substituents on the amino groups are each independently selected from Ci^alkyl, aryl, arylCj^alkyl, Cs^cycloalkyl, Cs-ycycloalkylCi^alkyl, Het1, Het2, HetICi^alkyl and Het2CMalkyl;
Rub is hydrogen, Cs-ycycloalkyl, C2-6aIkenyl, Ca-fialkjoiyl, aryl, Het1. Het2 or Ci_4alkyl optionally substituted with halogen, hydroxy, Ci^alkylS^Ojt. aryl.
l, Het1, Her2, amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, arylCMalkyl, Cs.ycycloalkyl, C3-7cycloalkylCMalkyl, Het1, Her7.. Bet'C^alky! and Het2CMalkyl; whereby Rnb may be linked to the remainder of the molecule via a sulfonyl group;
t is zero, 1 or 2;
L is -C(=0)-, -0-C(=0)-, -NRs-C(=O)-, -O-d^alkanediyl-C(=O)-,
-Ml«-Ci^alkanediyl-C(=O)-, -S(=O)2-, -0-S(O)2-, -NRg-S(=O)2 whereby either the C(=O) group or the S(=O}2 group is attached to the NR2 moiety;
R di(Ci^alkyl)amiaocarbonyl, Csj/cycloalkyl, Ca-ealkenyl, C2-6aIkynyl, or Ci-galkyl optionally substituted with one or more substituents selected from aryl, Het1. Het2, Cs-vcycloalkyl, Ci^alkyloxycarbonyl, carboxyl, aminocarbonyl, mono- or di(C}^alkyl)aminocarbonyl, aminosulfonyl, Ci-4alkylS(==O)t, hydroxy. cyano, halogen and amino optionally mono- or disubstituted where the substituents are selected from Chalky!, aryl, arylCi^alkyl, Cs^cycloalkyl, C3.7cycloalkyl-CMalkyl, Het1, Het2, Het^Malkyl and Het2C]^alkyl;
Ra is Cj-galkyloxy, Het1, Het'oxy, Het2, Het2oxy, aryl, aryloxy or amino; and in case -A- is other than Ci^alkanediyl then Rg may also be Ci-galkyl, Het^Ci ^alkyl, Het'oxyCi^alkyl, Het2C)_4alkyl, Het2oxyCi_4alkyi, arylCi^alkyl, aryloxyC^alkyl or aminoCi-galkyl; whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents selected from Ci^alkyl, Ci^alkylcarbonyl, Ci-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl, Het1, Het2, arylCMalkyl, He^Ci^alkyl or Het2CMalkyl.
3. A compound according to any of claim 1 to 2 wherein
ri is hydrogen, Ci-galkyl, C2-6aIkenyL arylCi^alkyl, Cs.ycycloalkyl, Cs-vcycloalkyl-Ci_6alkyl, aryl, Het1., Het^i^alkyl, Het2 or 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 each independently selected from nitrogen, oxygen or sulfur and which is optionally ' • substituted on one or more carbon atoms.
A compound according to any of claims 1 to 3 wherein L is
C(=0>.
A compound according to any one of claims 1 to 4 wherein
A is Ci.6alkanediyl, -C(=O)- or Ci.6alkanediyl-C(=O)-; whereby the point of attachment to the nitrogen atom is the Ci-galkanediyl group in those moieties containing said group;
R5 is hydrogen, Ci.6alkyl5 He^C^alkyl, HefCi^alkyl, aminoC1.6alkyl whereby • the amino group may optionally be mono- or di-substituted with Chalky!;
and
in case -A- is -C(=0)- then R6 is Ci-ealkyloxy, Het1, HetWy or Het2oxy, aryl, HetlCwalkyl, Het'oxyC^alkyl, Het2CMaIkyl, Het2oxyCMalkyl, arylCi-4alkyl, aryloxyCi-4alkyl or aminoCi^alkyl; and in case -A- is C^galkanediyl then Re is amino, Ci-galkyloxy, Het1, He^oxy or
Het2oxy; and '
in case -A- is C^alkanediyl-C^O)- then Re is Ci-ealkyloxy, Het1, Het'oxy or Het2oxy, aryl, Ci.6alkyl, Het1CMalkyl, Het Het2oxyCi^alkyl, arylCi^alkyl, aryloxyCi^alkyl or whereby each of the amino groups in the definition of Re may optionally be substituted with one or more substituents selected from C^aUcyl, carbonyl, Ci-4alkyloxycarbonyl, aryl, arylcarbonyl, aryloxycarbonyl. Het1, Het2, arylCMalkyl, He^d^aUcy! or Het2Cwalkyl; and rs and -A-Re taken together with the nitrogen atom to which they are attached may also form HetJ whereby Het] is substituted by at least an oxo group.
6. A compound according to any of claims 1 to 3, wherein
ri is Het2 or Het Q-ealkyl; wherein said Het2 is an aromatic heterocycle having at least one heteroatom each independently selected from nitrogen, oxygen and sulfur; and L is -C(=O>, -O-C(-O)- or -O-C^aIkyl-C(=O)-.
7. A compound according to any of claims 1 to 3, wherein
ri is Het2 or Het^Cj-ealkyl; wherein said Het2 is an aromatic heterocycle having at least two heteroatom each independently selected from nitrogen, oxygen and sulfur; and L is -C(=O>, -O-C(=O)- or -O-Ci.6a]kyi-C(=O)-.
8. A compound according to any of claims 1 to 4, wherein
A is Ci-galkanediyl or-C(=O)-;
rs is hydrogen or methyl; and
Re is Ci-galkyloxy, Het1, Het2, amino or amino Ci-6aHcyl; whereby each ami-no optionally may be mono- or disubstiruted where the substituents are each independently selected from Ci^alkyl, aryl, arylCi^alkyl, Cs-ycycloalkylCi^alkyl, Het1, Her2, Het^i^taliyl and
9. A compound according to any of claims 1 to 3, wherein
ri is Het2 or Het2Ci-6alkyl; wherein said Het2 is an aromatic heterocycle having at least one heteroatom each independently selected from nitrogen, oxygen and sulfur; L is -C(=0>, -0-C(O)- or -O-C^alkyl-C(=O)-; A is Ci-ealkanediyl or -C(=O)-; Rs is hydrogen or methyl; and
R6 is Cj^alkyloxy, Het1, Het2, amino or amino Chalky!; whereby each amino optionally may be mono- or disubstituted, where the substituents are each independently selected from Chalky!, aryl, arylCi^alkyl, Cs.ycycloalkyl, C3.7cycloalkylCMalkyl, Het1, Het2, Het'd^alkyl and Het2CMalkyl.
10. A compound according to any of claims 1 to 3, wherein,
ri is 2-tfaiazolyhnethyl-; and L is -O-C(=O)-.
11. A compound according to any of claims 1 to 3, wherein
R5 is hydrogen; A is -C(=O)-; and
rs is Her; wherein said Her2 contains 5 or 6 ring members and one heteroatom
selected from nitrogen, oxygen or sulfur.
12. A compound according to any of claims 1 to 3, wherein
ri is Het, having 8 ring members and two heteroatoms each independently selected from nitrogen, oxygen or sulfur; Lis-O-C(O)-; . Rj is hydrogen or methyl; A is -C(-O)- or C]_ R.6 is optionally mono- or disubstituted aminoCi^alkyl, Het1, Het2; wherein said Her* contains 5 or 6 ring members and one heteroatom selected from nitrogen, oxygen or sulfur; wherein the amino substituents are each independently selected from Chalky!, aryl, arylCi^alkyl, Cs^cycloalkyl, Cs^cycloalkylCi^alkyl, Het1, Her2, Het^Malkyi and Het2Ci-4a]kyl.
A compound as claimed in any one of claim 1 to 12 in a prodrug form.
A compound as claimed in any one of claim 1 to 12 in a pharmaceutically tolerable
salt form.
A pharmaceutical composition, comprising an effective amount of at least one
compound as claimed in any one of claims 1 to 14, and a pharmaceutically tolerable
excipient.
16. A compound as claimed in any one of claims 1 to 14 for use as a medicine.
17. A method of inhibiting a protease of a retrovirus in a mammal infected with said
retrovirus, comprising a protease inhibiting amount of a compound according to any
one of claims 1 to 14 to said mammal in need thereof.
18. A method of treating or combating infection or disease associated with retrovirus
infection in a mammal, comprising administering an effective amount of at least one
compound according to any one of claims 1 to 14 to said mammal.
19. The methods of claim 17 or 18, wherein said mammal is a human.
20. A method of inhibiting retroviral replication, comprising contacting a retrovirus with
an effective amount of at least one compound according to any one of claims 1 to 14.
21. The method of claim 17 or 18 or 19, wherein the retrovirus is a human
immunodeficiency virus (HIV).
22. The method as claimed in claim 21, wherein the HIV virus is a multi-drug resistant
strain.
A compound as claimed in any one of claims 1 to 14 for use as a medecine.
The use of a compound as claimed in any one of claims 1 to 14 in tie manufacture
of a medicament for treating or combating infection or disease associated with
retrovirus infection in a mammal.
The use of a compound as claimed in any one of claims 1 to 14 in the manufacture
of a medicament for inhibiting a protease of a retrovirus in a mammal infected with
said retrovirus.
The use of a compound as claimed in any one of claims 1 to 14 in the manufacture
of a medicament for inhibiting retroviral replication.
The use of a compound as claimed in any one of claims 24 to 26 wherein the
retrovirus is a human immunodeficiency virus (HIV).
The use of a compound as claimed in any one of claims 24 to 26 wherein the
retrovirus is a multi-drug resistant strain.

Documents:

01589-delnp-2003-abstract.pdf

01589-delnp-2003-assignment.pdf

01589-delnp-2003-claims.pdf

01589-delnp-2003-correspondence-others.pdf

01589-delnp-2003-description (complete).pdf

01589-delnp-2003-form-1.pdf

01589-delnp-2003-form-13.pdf

01589-delnp-2003-form-18.pdf

01589-delnp-2003-form-2.pdf

01589-delnp-2003-form-3.pdf

01589-delnp-2003-form-5.pdf

01589-delnp-2003-gpa.pdf

01589-delnp-2003-pct-105.pdf

01589-delnp-2003-pct-304.pdf

01589-delnp-2003-pct-401.pdf

01589-delnp-2003-pct-409.pdf

01589-delnp-2003-pct-416.pdf

01589-delnp-2003-pct-request form.pdf

01589-delnp-2003-pct-search report.pdf

1589-DELNP-2003-Abstract-21-04-2008.pdf

1589-DELNP-2003-Claims-21-04-2008.pdf

1589-DELNP-2003-Correspondence-Others-21-04-2008.pdf

1589-DELNP-2003-Description (Complete)-21-04-2008.pdf

1589-DELNP-2003-Form-1-21-04-2008.pdf

1589-DELNP-2003-Form-2-21-04-2008.pdf

1589-DELNP-2003-GPA-21-04-2008.pdf

1589-DELNP-2003-Others Docoment-21-04-2008.pdf

1589-DELNP-2003-Petition-137-21-04-2008.pdf

1589-DELNP-2003-Petition-138-21-04-2008.pdf


Patent Number 219395
Indian Patent Application Number 01589/DELNP/2003
PG Journal Number 26/2008
Publication Date 27-Jun-2008
Grant Date 05-May-2008
Date of Filing 06-Oct-2003
Name of Patentee TIBOTEC PHARMACEUTICALS LTD.
Applicant Address
Inventors:
# Inventor's Name Inventor's Address
1 WIM GASTON VERSCHUEREN
2 SANDRINE MARIE HELENE VENDEVILLE
3 DOMINIQUE LOUIS NESTOR GHISLAIN GHISLAIN SURLERAUX
4 HERMAN AUGUSTINUS DE KOCK
5 MARIE-PIERRE T.M.M.G. DE BETHUNE AUGUSTINUS
6 MONTSERRAT ERRA SOLA
7 ABDELLAH TAHRI
PCT International Classification Number C07D 493/04
PCT International Application Number PCT/EP02/04012
PCT International Filing date 2002-04-09
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 60/287,704 2001-05-02 U.S.A.