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  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D207/34—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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  • C07D263/16—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Definitions

• the present invention relates to novel compounds, compositions and methods for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease.
• the present invention also relates to a method of overcoming acquired resistance to certain HIV protease inhibitors.
• Retroviruses are those viruses which utilize a ribonucleic acid (RNA) intermediate and a RNA-dependent deoxyribonucleic acid (DNA) polymerase, reverse transcriptase, during their life cycle. Retroviruses include, but are not limited to, the RNA viruses of the Retroviridae family, and also the DNA viruses of the Hepadnavirus and Caulimovirus families. Retroviruses cause a variety of disease states in man, animals and plants.
• RNA ribonucleic acid
• DNA RNA-dependent deoxyribonucleic acid
• retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, human T-cell lymphotrophic viruses I, II, IV and V, which cause human acute cell leukemia, and bovine and feline leukemia viruses which cause leukemia in domestic animals.
• HIV-1 and HIV-2 human immunodeficiency viruses
• HIV-2 acquired immune deficiency syndrome
• T-cell lymphotrophic viruses I, II, IV and V which cause human acute cell leukemia
• bovine and feline leukemia viruses which cause leukemia in domestic animals.
• Proteases are enzymes which cleave proteins at specific peptide bonds. Many biological functions are controlled or mediated by proteases and their complementary protease inhibitors. For example, the protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I. Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angiotensin II. Inhibitors of renin and ACE are known to reduce high blood pressure in vivo. An inhibitor of a retroviral protease will provide a therapeutic agent for diseases caused by the retrovirus.
• protease renin cleaves the peptide angiotensinogen to produce the peptide angiotensin I.
• Angiotensin I is further cleaved by the protease angiotensin converting enzyme (ACE) to form the hypotensive peptide angioten
• retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and gqg gene products. See Wellink, Arch. Virol. 9_8_ 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the ⁇ oj precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328 482 (1987).
• Current treatments for viral diseases usually involve administration of compounds that inhibit viral DNA synthesis.
• Current treatments for AIDS involve administration of compounds such as 3'-azido-3'-deoxythymidine (AZT), 2',3'-dideoxycytidine (DDC), 2',3'-dideoxyinosine (DDI), d4T and 3TC and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection. None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease. In addition, many of the compounds currently used to treat AIDS cause adverse side effects including low platelet count, renal toxicity and bone marrow cytopenia.
• HIV protease inhibitors ritonavir, saquinavir and indinavir have been approved in the U.S. for treatment of HIV infections.
• a problem associated with use of existing HIV protease inhibitors is the diminishing effectiveness of those drugs with prolonged use as monotherapy.
• the long-term administration of ritonavir as onotherapy leads to mutations in the amino acid residue sequence of HIV protease, which mutant HIV proteases have reduced susceptibility to the effects of the inhibitor. Similar results have been reported for other HIV protease inhibitors. There is still a need in the art, therefore, for new and improved HIV protease inhibitors.
• the present invention provides HIV protease inhibiting compounds.
• oxo 0
• S thioxo
• the inhibitor preferably binds to the active site of the protease.
• the compound of the invention when bound to the HIV protease, further contains a non-hydrogen atom in either the S1 or S1 ' subsite of the HIV protease and lacks a non-hydrogen atom in both the S3 and S3' subsites of the HIV protease, which S3 and S3' subsites do not include any of the S1 and S1 ' subsites, respectively.
• the present invention further provides pharmaceutical compositions comprising an HIV protease inhibitor of the invention and the use of inhibitors to inhibit HIV protease or HIV infection alone or in combination with other anti-HIV treatments such as other HIV protease inhibitors or reverse transcriptase inhibitors.
• the compounds of the present invention are active as inhibitors of mutant HIV proteases, which proteases are resistant to inhibition by ritonavir and other HIV protease inhibitors which promote the development of mutantions in HIV protease of the type promoted by ritonavir. Therefore, the compounds of the present invention are useful in combination with ritonavir and/or other HIV protease inhibitors which promote the development of mutantions in HIV protease of the type promoted by ritonavir.
• the present invention provides inhibitors of HIV protease.
• the inhibitors when bound to the HIV protease, are characterized by a unique three- dimensional conformation and orientation relative to the HIV protease.
• the presently claimed inhibitors are less susceptible to the development of mutational changes in the HIV protease of the type caused by monotherapy with ritonavir (or other HIV protease inhibitors which promote the development of mutantions in HIV protease of the type promoted by ritonavir) and which result in loss of inhibitor activity.
• compounds of the present invention are active as inhibitors of mutant HIV proteases, which proteases are resistant to inhibition by ritonavir and other HIV protease inhibitors which promote the development of mutantions in HIV protease of the type promoted by ritonavir.
• an inhibitor of the present invention can be used alone or together with other HIV protease inhibitors to treat HIV infection.
• a compound of the present invention binds to HIV protease and inhibits the catalytic activity of that protease enzyme.
• the inhibitor binds to the active site of the HIV protease, which active site is well known in the art (See, e.g., Miller et al., Science, 246:1 149-1 152, 1989).
• An inhibitor of the present invention can be either a peptidomimetic or a non-peptide inhibitor as those terms are known and understood in the art (HIV Protease Inhibitors, Kempf, D.J. and Sham, H.L., Current Pharmaceutical Design, 2:225-246, 1996).
• the inhibitor When bound to the active site, the inhibitor preferably comprises at least one non- hydrogen atom in a first spherical volume.
• the first spherical volume (and all other spherical volumes referred to herein) is defined by locating the center point of the spherical volume together with a defined radius around that center point.
• the center points of the spherical volumes are defined by the point of intersection of vectors of a certain length (loci) emanating from particular alpha carbon atoms of the bound protease.
• loci the point of intersection of vectors of a certain length emanating from particular alpha carbon atoms of the bound protease.
• loci certain length
• the center point of the first and all other spherical volumes herein is defined by the intersection of at least three vector loci of given lengths (i.e., at least three reference alpha carbons are needed).
• the reference points for location of the center point of the first spherical volume herein include the alpha carbon atoms of residues 27, 127, 50 and 150 of the HIV protease.
• HIV protease consists of two identical subunits, each of which has 99 amino acid residues.
• ordinal numbers 1 -99 indicate residues (the N-terminal residue is 1 ) on one subunit and ordinals 101 - 199 indicate the corresponding residues on the other subunit.
• the center point of the first spherical volume is defined by at least three loci selected from the group of first loci consisting of 5.0 A to 6.0 A from the alpha carbon of residue 27 of the protease, 5.0 A to 6.0 A from the alpha carbon of residue 127 of the protease, 6.3 A to 7.5 A from the alpha carbon of residue 50 of the protease, and 6.3 A to 7.5 A from the alpha carbon of residue 150 of the protease.
• the center point of the first spherical volume is determined using four loci from the first loci group.
• the radius of the first spherical volume is about 3.0 A.
• An inhibitor compound of the present invention comprises a particular heterocycle, which heterocycle is uniquely spatially oriented to subsites of the HIV protease, when the inhibitor is bound to the protease.
• the heterocycle component of the inhibitor can contain from 4 to 7 ring atoms.
• the ring atoms must include at least one ring nitrogen (N) atom.
• the heterocycle of the compound contains five or six ring atoms.
• At least one of the ring N atoms preferably has the structure NH and the ring preferably has from 0 to 2 double bonds.
• the ring N atom of the NH structure is located within a range of from about 2.4 A to about 3.7 A of the backbone nitrogen atom of either residue 30 or residue 130 of the protease when the compound is bound to the protease.
• both of the above conditions are satisfied.
• a preferred heterocycle has the structure:
• n is 1 , 2 or 3, m is 1 , 2 or 3, m' is 1 or 2,
• X is O, S or NH
• Y is -CH 2 -, -0-, -S- or -N(Rg)- wherein R 6 is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, Y" is -CH 2 - or -N(R 6 ..)- wherein R 6 ., is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, Y' is -N(R 6 .)- wherein R 6 . is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, and Z is O, S or NH;
• heterocycle More preferred structures of the heterocycle have the structure:
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• m 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or
• n 1 or 2
• X is 0 or S and Y is -CH 2 or -NH-
• the inhibitor When bound to the HIV protease, the inhibitor is characterized by the presence of at least one heterocyclic ring atom in the S2 or S2' subsite of the protease.
• the locations of the S2 and S2' subsites of the protease are well known to one of skill in the art (See, e.g., Miller et al., Science, 246:1 149-1152, 1989).
• any number of the ring atoms up to and including the total number of ring atoms (4, 5, 6 or 7), can be located therein. It is preferred that more than one ring atom be located in the S2 or S2' subsite.
• At least one ring atom of the heterocyclic ring of the inhibitor is located in either a second or third spherical volume.
• the second spherical volume has a radius in the range of from about 2.5 A to about 4.0 A. More preferably, that radius is from about 3.0 A to about 4.0 A and, even more preferably in the range of from about 3.5 A to about 4.0 A. Most preferably, the radius of the fourth spherical volume is about 4.0 A.
• the center point of the second spherical volume is defined by at least three loci selected from a second group of loci consisting of 3.8 A to 4.2 A from the alpha carbon of residue 28 of the protease, 4.3 A to 4.7 A from the alpha carbon of residue 30 of the protease, 7.7 A to 8.1 A from the alpha carbon of residue 32 of the protease, and 6.5 A to 6.9 A from the alpha carbon of residue 48 of the protease.
• the radius of the third spherical volume is in the range of from about 2.5 A to about 4.0 A. More preferably, that radius is from about 3.0 A to about 4.0 A and, even more preferably in the range of from about 3.5 A to about 4.0 A.
• the radius of the third spherical volume is about 4.0 A.
• the center point of the third spherical volume is defined by at least three loci selected from a group of third loci consisting of 3.8 A to 4.2 A from the alpha carbon of residue 128 of the protease, 4.3 A to 4.7 A from the alpha carbon of residue 130 of the protease, 7.7 A to 8.1 A from the alpha carbon of residue 132 of the protease, and 6.5 A to 6.9 A from the alpha carbon of residue 148 of the protease.
• the second and third spherical volumes are related by symmetry to the two subunits of the protease.
• the alpha carbons at residues 28 (128), 30 (130), 32 (132) and 48 (148) are typically Ala, Asp, Val and Gly, respectively.
• the precise identity of those residues is not, however, critical to their use as reference points for defining the second and third spherical volumes.
• each of those residues can be any of the twenty naturally occurring amino acid residues. In other words, mutations in the protease will not affect the location of the defined volumes or the relationship of the inhibitor to that volume.
• the center points of the second and third spherical volumes be defined by more than three loci.
• these center points are each independently preferably defined by at least four, more preferably at least five, even more preferably at least six and, most preferably all seven of their respective loci groups.
• an inhibitor of the present invention is preferably also spatially constrained relative to the S1 and S1 ' subsites of the protease.
• the inhibitor when bound to the protease, has at least one non-hydrogen atom in either the S1 or SV subsite of the protease. More particularly, the inhibitor, when bound to the protease, contains a non-hydrogen atom in either a fourth or a fifth spherical volume.
• the center point of the fourth spherical volume is defined by the point of intersection of at least three vector loci selected from the group of fourth loci consisting 3.2 A to 3.7 A from the alpha carbon of residue 49 of the protease, 4.1 A to 4.5 A from the alpha carbon of residue 50 of the protease, 12.4 A to 12.8 A from the alpha carbon of residue 108 of the protease, 13.0 A to 13.4 A from the alpha carbon of residue 110 of the protease, 11.0 A to 11.4 A from the alpha carbon of residue 125 of the protease, 5.7 A to 6.1 A from the alpha carbon of residue 182 of the protease, and 8.4 A to 8.8 A from the alpha carbon of residue 184 of the protease
• the radius of the fourth spherical volume is in the range of from about 2.5 A to about 4.0 A More preferably, that radius is from about 3 0 A to about 4.0 A and, even more preferably in the range of from about 3.5 A
• the fifth spherical volume (the symmetrical counterpart of the fourth spherical volume but relative to the second subunit of the protease) has a radius in the range of from about 2.5 A to about 4.0 A and a center point defined by at least three loci selected from the group of fifth loci consisting of 3.2 A to 3 7 A from the alpha carbon of residue 149 of the protease, 4 1 A to 4 5 A from the alpha carbon of residue 150 of the protease, 12 4 A to 12 8 A from the alpha carbon of residue 8 of the protease, 13.0 A to 13 4 A from the alpha carbon of residue 10 of the protease, 1 1.0 A to 1 1 4 A from the alpha carbon of residue 25 of the protease, 5 7 A to 6 1 A from the alpha carbon of residue 82 of the protease, and 8.4 A to 8.8 A from the alpha carbon of residue 84 of the protease
• a preferred radius for the fifth spherical volume is the same as
• ammo acid residues at the indicated alpha carbon locations are not critical and they can be any of the twenty naturally occurring ammo acid residues
• an inhibitor of the present invention is spatially constrained relative to the S3 and S3' subsites of the protease.
• the inhibitor when bound to the protease, lacks a non-hydrogen atom in both the S3 and S3' subsites of the protease.
• a non-hydrogen atom there is overlap between the S3 and S1 subsites as well as between the S3' and S1 ' subsites.
• the absence of a non-hydrogen atom in the S3 and S3 subsites is intended to exclude those portions of the S3 and S3' subsites overlapping with the S1 and S1 ' subsites, respectively.
• an inhibitor of the present invention can contain a non-hydrogen atom in that portion of S3 overlapping with S1 and that portion of S3' overlapping with S1 '.
• the inhibitor when bound to the protease, lacks a non- hydrogen atom in both a sixth and seventh spherical volume
• the sixth spherical volume has a radius in the range of from about 2.5 A to about 4 0 A and a center point defined by at least three loci selected from the group of sixth loci consisting of 7.7 A to 8.2 A from the alpha carbon of residue 49 of the protease, 9.8 A to 10.2 A from the alpha carbon of residue 50 of the protease, 9 6 A to 10.0 A from the alpha carbon of residue 108 of the protease, 10.4 A to 10.8 A from the alpha carbon of residue 110 of the protease, 12.7 A to 13.1 A from the alpha carbon of residue 125 of the protease, 5 4 A to 5.8 A from the alpha carbon of residue 182 of the protease, and 10.1 A to 10.6 A from the alpha carbon of residue 184 of the protease
• the sixth spherical volume overlaps
• the seventh spherical volume has a radius in the range of from about 2.5 A to about 4.0 A and a center point defined by at least three loci selected from the group of seventh loci consisting of 7.7 A to 8.2 A from the alpha carbon of residue 149 of the protease, 9.8 A to 10.2 A from the alpha carbon of residue 150 of the protease, 9.6 A to 10.0 A from the alpha carbon of residue 8 of the protease, 10.4 A to 10.8 A from the alpha carbon of residue 10 of the protease, 12.7 A to 13 1 A from the alpha carbon of residue 25 of the protease, 5.4 A to 5.8 A from the alpha carbon of residue 82 of the protease, and 10 1 A to 10.6 A from the alpha carbon of residue 84 of the protease, wherein the seventh spherical volume does not include any of the fifth spherical volume The exclusion of any of the volume of the fifth spherical volume is in keeping with the overlap between the
• Preferred values for the radii of the sixth and seventh spherical volumes are the same as set forth above with regard to the fourth and fifth spherical volumes. Similarly, the preferred number of loci used to identify the centerpoints of the sixth and seventh spherical volumes are the same as set forth above relative to the fourth and fifth spherical volumes.
• R 1 and R 2 are independently selected from the group consisting of loweralkyi, cycloalkylalkyi and arylalkyl;
• R 3 is loweralkyi, hydroxyalkyi or cycloalkylalkyi
• R 4 is aryl or heterocyclic
• n is 1 , 2 or 3, m is 1 , 2 or 3, m' is 1 or 2,
• X is O, S or NH
• Y is -CH 2 -, -0-, -S- or -N(Rg)- wherein R 6 is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl
• Y" is -CH 2 - or -N(R 6 victim)- wherein R 6 ..
• R 6 is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, and Z is O, S or NH;
• L 1 is a) -0-, b) -S-, c) -N(R 7 )- wherein R 7 is hydrogen, loweralkyi, cycloalkyl or cycloalkylalkyi, d) -O-alkylenyl-, e) -S-alkylenyl- f) -S(0)-alkylenyl-, g) -S(0) 2 -alkylenyl-, h) -N(R 7 )-alkylenyl- wherein R 7 is defined as above, i) -alkylenyl-O-, j) -alkylenyl-S-, k) alkylenyl-N(R 7 )- wherein R 7 is defined as above,
• Preferred compounds are compounds of the formula I wherein R-, and R 2 are arylalkyl, R 3 is loweralkyi, R 4 is aryl, R 5 is
• More preferred compounds are compounds of the formula I wherein R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is loweralkyi, R 3 is loweralkyi, R 4 is (a) phenyl which is substituted with two loweralkyi groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyi, hydroxy, amino and halo or (b) pyridyl or pyrimidinyl either of which is substituted with two loweralkyi groups and which is optionally substituted with a third substituent selected from the group consisting of loweralkyi, hydroxy, amino and halo, R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-, wherein m is 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or
• L 1 is -0-CH 2 -.
• R 1 and R 2 are benzyl or R-
• R 3 is loweralkyl
• R 4 is 2,6-d ⁇ methylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyi and halo
• R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• m 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or wherein X is O and Rg,. is hydrogen
• L 1 is -0-CH 2 -.
• R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is loweralkyi, R 4 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• L 1 is -0-CH 2 -
• R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is loweralkyi, R 4 is 2,6-dimethylphenyl which is optionally substituted with a third substituent selected from the group consisting of loweralkyi and halo, R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH- and
• L 1 is -0-CH 2 -.
• the most highly preferred compound of the formula I is (2S, 3S, 5S)-2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2- onyl)-3-methyl butanoyl] amino-1 ,6-diphenylhexane; or a pharmaceutically acceptable salt, ester or prodrug thereof.
• Such an amorphous solid can be prepared by dissolving (2S, 3S, 5S)-2-(2,6- Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2-onyl)- 3-methyl butanoyl] amino-1 ,6-diphenylhexane in an organic solvent (for example, ethanol, isopropanol, acetone, acetonitrile and the like) and then adding the solution to water.
• an organic solvent for example, ethanol, isopropanol, acetone, acetonitrile and the like
• (2S, 3S, 5S)-2-(2,6- Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2-onyl)- 3-methyl butanoyl] amino-1 ,6-diphenylhexane is dissolved in ethanol (from about 2 to about 4 mL/g) and the ethanolic solution is added with stirring to water (from about 10 about 100 mL/g) to provide amorphous (2S, 3S, 5S)-2- (2,6-Dimethylphenoxyacetyl) amino-3-hydroxy-5-[2S-(1 -tetrahydro-pyrimid-2- onyl)-3-methyl butanoyl] amino-1 ,6-diphenylhexane.
• the compounds of the invention can comprise asymmetrically substituted carbon atoms.
• all stereoisomers of the compounds of the invention are meant to be included in the invention, including racemic mixtures, mixtures of diastereomers, as well as single diastereomers of the compounds of the invention.
• N-protecting group or “N-protected” as used herein refers to those groups intended to protect the N-terminus of an amino acid or peptide or to protect an amino group against undersirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in Greene and Wuts, "Protective Groups In Organic Synthesis,” (John Wiley & Sons, New York (1991)), which is hereby incorporated by reference.
• N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl, 4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl, p-toluenesulfonyl and the like; carbamate forming groups such as benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzy
• N-protecting groups are formyl, acetyl, benzoyl, pivaloyi, t-butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
• activated ester derivative refers to acid halides such as acid chlorides, and activated esters including, but not limited to, formic and acetic acid derived anhydrides, anhydrides derived from alkoxycarbonyl halides such as isobutyloxycarbonylchloride and the like, N- hydroxysuccinimide derived esters, N-hydroxyphthalimide derived esters, N- hydroxybenzotriazole derived esters, N-hydroxy-5-norbornene-2,3- dicarboxamide derived esters, 2,4,5-trichlorophenol derived esters, thiophenol derived esters, propylphosphonic acid derived anhydrides and the like.
• alkanoyl refers to R 19 C(0)- wherein R 19 is a loweralkyi group.
• alkenylenyl refers to a divalent group derived from a straight or branched chain hydrocarbon containing from 2 to 10 carbon atoms and also containing at least one carbon-carbon double bond.
• alkoxy and thioalkoxy as used herein refer to - j c O- and R 15 S-, respectively, wherein R 1 5 is a loweralkyi group.
• alkoxyalkoxy refers to R22O-R23O- wherein R22 is loweralkyi as defined above and R23 is an alkylenyl group.
• Representative examples of alkoxyalkoxy groups include methoxymethoxy, ethoxymethoxy, t-butoxymethoxy and the like.
• alkoxyalkyl refers to an alkoxy group appended to a loweralkyi radical.
• alkoxycarbonyl refers to R 20 C(O)- wherein R 20 is an alkoxy group.
• alkylamino refers to -NHR 16 wherein R 16 is a loweralkyi group.
• alkylaminocarbonyl refers to R 21 C(0)- wherein R 2 ⁇ is an alkylamino group.
• aminocarbonyl refers to -C(0)NH 2 .
• aryl refers to a mono- or bicyclic carbocyclic ring system comprising 6 to 12 carbon atoms and having one or two aromatic rings including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl indenyl and the like.
• Aryl groups can be unsubstituted or substituted with one, two or three substituents independently selected from loweralkyi, halo, haloalkyl, haloalkoxy, alkoxy, alkoxycarbonyl, thioalkoxy, amino, alkylamino, dialkylamino, aminocarbonyl, mercapto, nitro, carboxaldehyde, carboxy and hydroxy.
• arylalkyl refers to an aryl group as previously defined, appended to a loweralkyi radical, for example, benzyl and the like.
• cycloalkyl refers to an aliphatic ring system having 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• cycloalkylalkyi refers to a cycloalkyl group appended to a loweralkyi radical, including but not limited to cyclohexylmethyl
• dialkylamino refers to -NR 1 6 R 1 7 wherein R 1 ⁇ and R 1 7 are independently selected from loweralkyi groups.
• dialkylammocarbonyl refers to R 22 C(0)- wherein R 22 is a dialkylamino group
• halo or halogen as used herein refers to -Cl, -Br, -I or -F
• haloalkoxy refers to R-igO- wherein R 18 is a haloalkyl group.
• haloalkyl refers to a loweralkyi group in which one or more hydrogen atoms are replaced by halogen, for example, chloromethyl, chloroethyl, trifluoromethyl and the like
• heterocyclic ring or “heterocyclic” or “heterocycle” as used herein refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5-, 6- or 7-membered ring containing one, two or three heteroatoms independently selected from the group consisting of nitrogen, oxygen and sulfur or a 5-membered ring containing 4 nitrogen atoms; and includes a 5-, 6- or 7-membered ring containing one, two or three nitrogen atoms, one oxygen atom; one sulfur atom, one nitrogen and one sulfur atom; one nitrogen and one oxygen atom; two oxygen atoms in non- adjacent positions, one oxygen and one sulfur atom in non-adjacent positions, two sulfur atoms in non-adjacent positions; two sulfur atoms in adjacent positions and one nitrogen atom, two adjacent nitrogen atoms and one sulfur atom, two non-adjacent nitrogen atoms and one sulfur atom, two non-adjacent nitrogen
• heterocyclic also includes bicyclic groups in which any of the above heterocyclic rings is fused to a benzene ring or a cyclohexane ring or another heterocyclic ring (for example, indolyl, qumolyl, isoqumolyl, tetrahydroqumolyl, benzofuryl, bistetrahydorfuranyl or benzothienyl and the like) Heterocyclics include azetidinyl, pyrrolyl, pyrro nyl, pyrrolidinyl, pyrazolyl, pyrazolmyl, pyrazolidmyl, imidazolyl, imidazolmyl, imidazolidinyl, pyridyl, piperidinyl, homopipe ⁇ diny
• X * is -CH 2 -, -NH- or -0-
• Y * is -C(O)- or [-C(R") 2 -] V
• R" is hydrogen or C-
• nitrogen containing heterocycles can be N-protected.
• hydroxyalkyi refers to a loweralkyi radical to which is appended an hydroxy group.
• loweralkyi refers to a straight or branched chain alkyl radical containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, t-butyl, n- pentyl, 1 -methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl, n- hexyl and the like.
• thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyi radical.
• the compound of the invention of formula I can be prepared as shown in Schemes l-IV.
• intermediates 1 and 2 (wherein P 1 is an N-protecting group, for example, t-butyloxycarbonyl) can be coupled using standard peptide coupling reagents and methods, for example, reaction of 1 and 2 in the presence of 1 -hydroxybenzotriazole and a diimide such as dicyclohexylcarbodiimide (DCC) or N-ethyl-N'-dimethylaminopropyl carbodiimide (EDAC) and the like to give 2-
• a salt or an activated ester derivative of intermediate 1 for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride
• Compound 2 can be N-deprotected to give compound 4. N-deprotection of 3 wherein P 1 (especially wherein P 1 is t-butyloxycarbonyl) is an acid labile
• N-protecting group can lead to formation of impurities resulting from migration of the acyl group R 4 -L.,-C(0)- from the amino group to the hydroxyl group.
• the formation of this impurity can be minimized or eliminated by performing the deprotection using (1 ) trifluoroacetic acid in methylene chloride or (2) concentrated hydrochloric acid (from about 2 molar equivalents to about 6 molar equivalents, preferably, from about 2 molar equivalents to about 4 molar equivalents) in acetic acid at about room temperature.
• a preferred N-deprotection method comprises reacting compound 3 (wherein P 1 is t-butyloxycarbonyl) with concentrated hydrochloric acid (from about 10 to about 20 molar equivalents) in acetonitrile (from about 2 to about 10 liters/kilogram of compound 2 ) at a temperature of from about 0°C to about 5°C.
• Compound 5 or an activated ester derivative thereof can then be coupled to compound _ to give the compound of the formula I (i.e., 5).
• Scheme IIB shows a preferred alternative process wherein the N- protected amino alcohol 7a.
• P 3 is hydrogen and P 4 is an N-protecting group or both P 3 and P 4 are N-protecting groups, preferably, P 3 and P 4 are benzyl
• carboxylic acid 5 or a salt or an activated ester derivative thereof for example, the acid chloride, prepared by reaction of the carboxylic acid with thionyl chloride in ethyl acetate or THF or oxalyl chloride in toluene/DMF and the like
• an organic amine base for example, imidazole, 1 -methylimidazole, 2-methylimidazole, 2-isopropylimidazole, 4-methylimidazole, 4-nitroimidazole, pyridine, N,N-
• N-Debenzylation of a (for example, using hydrogen and a hydrogenation catalyst or Pd/C and a formic acid salt (for example, ammonium formate and the like) or Pd/C and formic acid and the like) provides 9_.
• Compound 9_ can be advantageously purified by crystallization with an organic carboxylic acid (for example, S-pyroglutamic acid, succinic acid or fumaric acid and the like).
• an organic carboxylic acid for example, S-pyroglutamic acid, succinic acid or fumaric acid and the like.
• a preferred organic carboxylic acid is S-pyroglutamic acid.
• Compound 9. (or an organic carboxylic acid salt of compound 9_) is reacted with from about 1.0 to about 1.3 molar equivalents of carboxylic acid 1 or a salt or an activated ester derivative thereof (for example, the acid chloride) in the presence of (1 ) from about 4 to about 8 molar equivalents (preferably, from about 5 to about 7 molar equivalents) of an inorganic base (for example, NaHC0 3 , Na 2 C0 3 , KHC0 3 , K 2 C0 3 , NaOH or KOH and the like) in an inert solvent (for example, 1 :1 ethyl acetate/water or isopropyl acetate/water or toluene/water or THF/water and the like) at about room temperature or (2) from about 1.0 to about 4.0 molar equivalents (preferably, from about 2.5 to about 3.5 molar equivalents) of an organic amine base (for example, imidazole, 1 -methylimidazole, 2-methylimi
• intermediate compound 5 has the formula of compound 1_Q_ (R 3 is as defined for the compound of formula I and is preferably isopropyl).
• Compound W can be prepared in variety ways as shown in Scheme III. In one method, amino acid 1 1 (either as the free carboxylic acid or as the carboxylic acid ester (i.e., loweralkyi ester)) is converted to carbamate Y ⁇ (R" is phenyl, loweralkyl- substituted phenyl, halo-substituted phenyl, nitro-substituted phenyl, trifluoromethylphenyl and the like) by reaction with the appropriate chloroformate ester and the like.
• Reaction of carbamate 12 with from about 1.0 to about 1.5 molar equivalents of amine 13 or an acid addition salt thereof (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, methyl t-butyl ether, dimethoxyethane, THF/water, dimethoxyethane/water, toluene or heptane and the like) in the presence of a base (for example, LiOH, NaOH, Li 2 C03, Na 2 C0 3 , lithium phenoxide or sodium phenoxide and the like) in the amount of from about 2.5 to about 3.5 molar equivalents provides urea 14.
• Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as
• Urea 14 can be isolated and reacted further or can be converted in situ to cyclic urea 10 by reaction in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) with a base (for example, potassium t-butoxide, sodium hydride, potassium hydride or dimethylaminopyridine and the like) in the amount of from about 2.0 to about 5.0 molar equivalents. If the amino acid ester of JJ . was the starting material, the ester is then hydrolyzed to provide the carboxylic acid £.
• an inert solvent for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like
• a base for example, potassium t-butoxide, sodium hydride, potassium hydride or dimethylaminopyridine and the like
• amino acid JJ. (either as the free carboxylic acid or as the carboxylic acid ester) is converted to urea J ⁇ by reaction with from about 1.0 to about 1.5 molar equivalents of isocyanate Jj> (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p- toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base.
• an inert solvent for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like
• ammo acid H (either as the free carboxylic acid or as the carboxylic acid ester) is converted to diamme 12 by reaction with from about 1.0 to about 1.5 molar equivalents of amme 12 or an N-protected derivative thereof (Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulfonate, triflate, p-toluenesulfonate, benzenesulfonate and the like) in an inert solvent (for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like) in the presence of a base (for example, NaH or potassium t-butoxide and the like) in the amount of from about 1 0 to about 4.0 molar equivalents.
• Q is a leaving group, for example, Cl, Br or I, or a sulfonate such as methanesulf
• N-deprotection is required if the N-protected derivative of 13 was used
• a carbonyl equivalent 17 for example, phosgene, carbonyldiimidazole and the like wherein Q' and Q" are leaving groups such as Cl, Br, I, -O-loweralkyl, -O-aryl or imidazolyl and the like
• an inert solvent for example, THF, dimethoxyethane, methyl t-butyl ether, toluene or heptane and the like
• a base for example, NaH or potassium t-butoxide and the like and the like
• acrylonitnle can be replaced with 3-chloroprop ⁇ on ⁇ tr ⁇ le to provide J ⁇ N-protection of ammonitrile 18 as the carbamate (R 30 is loweralkyi or phenyl or haloalkyl (for example, 2-chloroethyl, 2-bromoethyl and the like) and the like) using standard conditions (for example, reaction of the amme with the appropriate chloroformate ester (CIC(O)OR 30 wherein R 30 is loweralkyi, phenyl, haloalkyl and the like) neat or in an inert solvent (for example, water, THF and the like) in the presence of an inorganic base (for example, NaOH, KOH, K 2 C0 3 and the like) or an organic base (for example, an alkylamine or dialkylamine and the like) and the like) provides compound 19 Hydrogenation of 19 in the presence of a
• compound 12 is hydrogenated in the presence of a Ni-AI alloy catalyst in an inert solvent (for example, water or methanol or ethanol or THF and the like) in the presence of a base (for example, KOH or NaOH or LiOH or an organic amine base and the like) in the amount of from about 1.1 to about 5 molar equivalents to provide cyclic urea 10. If the amino acid ester of Jl was the starting material, the ester is then hydrolyzed to provide the carboxylic acid 1Q_.
• an inert solvent for example, water or methanol or ethanol or THF and the like
• a base for example, KOH or NaOH or LiOH or an organic amine base and the like
• R 3 is loweralkyi, hydroxyalkyi or cycloalkylalkyi
• n is 1 , 2 or 3, m is 1 , 2 or 3, m' is 1 or 2,
• X is O, S or NH
• Y is -CH 2 -, -0-, -S- or -N(Rg)- wherein R 6 is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl
• Y" is -CH 2 - or -N(R 6 seemingly)-
• R 6 .. is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl
• Y' is -N(R g ,)- wherein R ⁇ . is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl
• Z is O, S or NH.
• Preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R 3 is loweralkyi and R 5 is
• More preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R 3 is loweralkyi and R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• m is 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• m' is 1
• X is O
• Z is O
• Y is -NH-
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-, wherein m is 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• Most preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R 3 is isopropyl and R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• m * is 1 , X is O, Y" is -NH- and Y' is -NH- or
• Most highly preferred compounds are compounds of the formula III or an activated ester derivative thereof wherein R 3 is isopropyl and R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-.
• Key intermediates for the preparation of the compounds of the invention also include compounds of the formula IV:
• P 3 and P 4 are independently selected from hydrogen or an
• R 1 and R 2 are independently selected from the group consisting of loweralkyi, cycloalkylalkyi and arylalkyl;
• R 3 is loweralkyi, hydroxyalkyi or cycloalkylalkyi
• n is 1 , 2 or 3, m is 1 , 2 or 3, m' is 1 or 2,
• X is O, S or NH
• Y is -CH 2 -, -0-, -S- or -N(R 6 )- wherein R 6 is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, Y" is -CH 2 - or -N(R 6 ..)- wherein R 6 .. is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, Y' is -N(R 6 .)- wherein R 6 . is hydrogen, loweralkyi, cycloalkyl, cycloalkylalkyi, aryl or arylalkyl, and Z is O, S or NH.
• Preferred compounds are compounds of the formula IV wherein P 3 and P 4 are hydrogen or benzyl, R 1 and R 2 are arylalkyl, R 3 is loweralkyi and R 5 is
• X, Y, Y', Y", Z, Rg.., n, m and m' are defined as above.
• More preferred compounds are compounds of the formula IV wherein R-
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-, wherein m is 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or
• R-, and R 2 are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is loweralkyi and R 5 is wherein n is 1 or 2, X is O or S and Y is -CH 2 or -NH-,
• m 1 or 2
• X is O
• Y is -CH 2 - and Z is O
• m' is 1 , X is O, Y" is -NH- and Y' is -NH- or
• R 1 and R are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is loweralkyi and R 5 is
• n 1 or 2
• X is O or S and Y is -CH 2 or -NH-
• R 1 and R 2 are benzyl or R 1 is benzyl and R 2 is isopropyl, R 3 is loweralkyi and R 5 is wherein n is 1 or 2, X is O or S and Y is -CH 2 or -NH-.
• Preferred salts of the compound of formula IV are organic carboxylic acid salts, especially the (S)-pyroglutamic acid salt.
• A. N.N-Dibenzyl-(L)-phenylalanine Benzyl Ester A solution containing L-phenylalanine (161 kg, 975 moles), potassium carbonate (445 kg, 3220 moles), water (675 L), ethanol (340 L), and benzyl chloride (415 kg, 3275 moles) was heated to 90 ⁇ 15°C for 10-24 hours. The reaction mixture was cooled to 60°C and the lower aqueous layer was removed. Heptane (850 L) and water (385 L) were added to the organics, stirred, and the layers separated. The organics were then washed once with a water/methanol mixture (150 L/150 L). The organics were then stripped to give the desired product as an oil.which was carried on in the next step without purification.
• the organics were then washed three times with 900 mL of a 5% (w/v) sodium chloride solution, two times with 900 mL of a 10% methanolic water solution, one time with 900 mL of a 15% methanolic water solution, and then one time with 900 mL of a 20% methanolic water solution.
• the organics were stripped and the resulting material dissolved into 700 mL of hot ethanol. Upon cooling to room temperature, the desired product precipitated. Filtration gave the desired product in 59% yield from the L- phenylalanine.
• the solution was stirred under nitrogen at 60 °C for three hours and then at 75 °C for 12 hours.
• An additional amount of ammonium formate (6 g) and 10% palladium on carbon (1.5 g) was added as well as 1 mL of glacial acetic acid.
• the reaction was driven to completion within 2 hours at a reflux temperature.
• the reaction mixture was then cooled to room temperature and then filtered through a bed of celite.
• the filter cake was washed with methanol (75 mL) and the combined filtrates were concentrated under reduced pressure.
• the residue was taken up in 1 N NaOH (300 mL) and extracted into methylene chloride (2 X 200 mL).
• the combined organic layers were washed with brine (250 mL) and dried over sodium sulfate.
• N-Cbz-aminoethanol in 40 ml of CH2CI2 was added. After 15 minutes at -78°C and 2 minutes at 0°C, the solution was cooled to -78°C and triethylamine (6.14 ml) was added dropwise. The solution was stirred at -78°C for 30 minutes and poured into 50 ml of cold 10% aq. citric acid and extracted with ether (150 ml). The combined organic layer was washed with brine and dried with anhydrous Na2S ⁇ 4; filtered and concentrated in vacuo. Purification of the crude product by silica gel column chromatography (10% EtOAc/CH2Cl2) provided the desired compound (42%).
• Example 8 ⁇ , 2S.3S.5Sl-2-t2.6-Dimethylphenoxyacetvhamino-3-hvdroxy-5-(2S- ⁇ '1 - imidazolidin-2-onyl)-3.3-dimethyl butanoyl)amino-1.6-diphenylhexane.
• A. 2.6-Dimethyl-4-nitro phenoxyacetic acid ethyl ester To a solution of 10.5 g (54.6 mmole) of ethyl 2,6-dimethylphenoxy acetate and 7.5 g (109 mmole) of sodium nitrite in 100 ml of methylene chloride was added 50 ml of trifluoroacetic acid slowly. The reaction mixture became solid after addition. Additional 35 ml of trifluoroacetic acid was added. After the reaction mixture was stirred at room temperature for 3 h, it was carefully partitioned between saturated sodium bicarbonate solution and methylene chloride.
• Example 12 imidazolidin-2-onv0-3-methyl-butanoyl) amino-1 .6-diphenylhexane.
• Example 15 (2S.3S.5S 2-(2.4-Dimethyl-pyridin-3-oxy-acetvn amino-3-hvdroxy-5-[ ' 2S- ⁇ '1 - imidazolidin-2-onv ⁇ -3-methyl-butanoyl) amino-1.6-diphenylhexane.
• Cis ( ⁇ )-2- ⁇ sopropvl-3-hvdroxv-tetrahvdroth ⁇ ophene To a solution of ethyl-3-mercaptopropionate (27.25 ml, 0.246 mole) in 200 ml of ethanol was added carefully sodium ethoxide (16.75 g, 0 246 mole) in several portions The resulting suspension was then cooled to -20°C and ethyl-2-bromo ⁇ sovalerate (50 g, 0.239 mole) in 50 ml of ethanol was added dropwise over 2 h. After addition was complete, the reaction was warmed to ambient temperature and stirred for 3 h.
• the crude product was added to 500 ml of aqueous 10% sulfuric acid and the resulting mixture heated to reflux for several hours, and then cooled to RT and neutralized with 6N sodium hydroxide and extracted with ethyl acetate (3 x 300 ml) The combined organic layer was dried, filtered and concentrated in vacuo to give a dark burgundy oil.
• the crude product (ketone) was purified by vacuum distillation at 75°-80°C.
• N- ⁇ '2-Ethoxvacrvlovl N l -('1 S-carbomethoxy-2-methyl-propyn-urea.
• 2-ethoxy-acryloyl chloride in 18 ml of toluene was added 3.90 g (0.026 mole) of silver cyanate.
• the mixture was heated to reflux for 0.75 h.
• the mixture was allowed to cool to RT and the precipitate allowed to settle.
• the supernatant (9.6 ml) was withdrawn and added to 18 ml of dry PMF and 5 ml of Et2 ⁇ , cooled to -15°C for 45 minutes and left in freezer overnight.
• Oxallyl chloride (36.3 ml, 0.42 mol) was added to a slurry of 2-6 dimethylphenoxyacetic acid (50 g, 0.28 mol) in 500 ml toluene followed by addition of 5 drops of DMF and stirred at room temperature for 30 min, then at 55°C for 1.5 hours.
• the toluene was removed on a rotary evaporator and remaining volatiles were removed in vacuo to afford 2,6-dimethyl- phenoxyacetyl chloride as an amber oil, 55 grams, 100%.
• Example 24F 120g, 0.372mol
• methanol 1 L
• This solution was allowed to stir in the presence of Raney Nickel (180g) for 1 h .
• Pd(OH)2 24g
• the solution was allowed to stir under 60 psi of a hydrogen atmosphere for 12h.
• the solution was purged with nitrogen and repressurized with 60 psi of hydrogen for an additional 1 h.
• the solution was filtered and concentrated to give 63g of an oil (90%). To this oil toluene (120mL) was added and the solution was again concentrated in vacuo to give the desired product.
• Example 24H 126g, 0.588mol
• water 1.3L
• THF 3.9L
• the solution was cooled to 0°C in an ice-water bath and lithium hydroxide monohydrate (74g, 1.76mol, 3.0eq) was added in one portion with rapid stirring.
• the solution was allowed to stir at 0°C for 14h. It was then acidified to pH 11 by slow addition of 50% aq phosphoric acid and the THF was removed in vacuo.
• the aqueous phase was washed with isopropyl acetate (2L) and was subsequently acidified to pH by slow addition of 35% aq HCl.
• Example 24C 100 g, 0.22 mol
• the product of Example 24I 44.8 g, 0.22 mol
• 750 ml DMF 750 ml DMF
• HOBT 90.9 g, 0.67 mol
• EDAC 86 g, 0.45 mol
• triethylamine 62.5 ml, 0.45 mol
• the reaction was diluted with 1000 ml of IPAC and quenched with 1000 ml of water. The mixture was shaken and separated, the aq.
• Example 2A using standard coupling procedure provided the desired compound. 300 MHz 1 H NMR (CPCI 3 ) ⁇ 0.88 (m, 12H), 1.67 (m, 2H),
• Example 28 l / 2S.3S.5S)-2-(2.6-Pimethylphenoxyacetyl) amino-3-hvdroxy-5-r2S-(1 - tetrahvdro-pvrimid-2.4-dionvl)-3-methvlbutanovl]amino-1 -phenvl-6- methvlheptane.
• Example 31 cis-N-tert-butyl-decahvdro-2-r 2 )-hvdroxy-4-phenyl-3fS)-(2S-(1 - tetrahvdropyrimid-2-onvl)-3-m9thvlbutanoyl)aminobutvl]-/4aS.8aS ) - isoquinoline-3fS)-carboxamide
• the title compound can be prepared by coupling the product of Example 2A with cis-N-tert-butyl-decahydro-2-[ 2(R)-hydroxy-4-phenyl-3(S)-aminobutyl]- (4aS,8aS)-isoquinoline-3(S)-carboxamide (disclosed in PCT Patent Application No. W09426749 and U.S. Patent No. 5,196,438, issued March 23, 1993, both of which are incorporated herein by reference) using a standard coupling procedure (EPAC in PMF
• Example 32 cis-N-tert-butyl-decahvdro-2-[ 2(R)-hvdroxy-4-thiophenyl-3fS)-(2S-(1 tetrahvdropvrimid-2-onvl ) -3-methvlbutanovl)aminobutyl]-f4aS.8aS)- isoquinoline-3 ⁇ / S)-carboxamirie
• the title compound can be prepared by coupling the product of Example 2A with cis-N-tert-butyl-decahydro-2-[ 2(R)-hydroxy-4-thiophenyl-3(S)- aminobutyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide (disclosed in PCT Patent Application No. WO95/09843, published April 13, 1995 and U.S. Patent No. 5,484,926, issued January 16, 1996, both of which are incorporated herein by reference) using a
• Example 33 4-Amino-N-(( 2svn. 3S)-2-hvdroxy-4-phenyl-3- ⁇ / 2S-( 1 -tetrahvdropyrimid-2- onyl)-3-methylbutanoylamino)-butyl)-N-isobutyl-benzenesulfonamide
• the title compound can be prepared by coupling the product of Example 2A with 4-Amino-N-(( 2syn, 3S)-2-hydroxy-4-phenyl-3-amino)-butyl)-N-isobutyl- be ⁇ zenesulfonamide (disclosed in PCT Patent Application No. WO94/05639, published March 17, 1994, which is incorporated herein by reference) using a standard coupling procedure (EPAC in PMF).
• reaction flask was immersed in an ice bath and a NaOH solution (16 mL, 0.198 mol) was added at a rate to maintain the internal temperature of the flask below 30 °C.
• Water 200 mL was added and the mixture extracted with 4 x 200 mL of Isopropyl Acetate. The combined organic layers were washed with 2.5M NaOH (2 x 200 L), 100 mL H2O, brine, dried over Na2S ⁇ 4, filtered and evaporated in vacuo to yield 39.7g (94% crude) of product as a colorless solid in greater than 95% purity by HPLC.
• N-phenoxycarbonyl-L-valine may be prepared according to the procedures disclosed in U.S. Patent Application No. 08/08/671 ,893, filed June 28, 1996, which is incorporated herein by reference, and which include the following method.
• lithium chloride (15.6 kg, 368 moles)
• L-valine (26.0 kg, 222 moles)
• neutral alumina 8.1 kg, 150 mesh, Aldrich
• the heterogeneous mixture was stirred and cooled to -14°C + 5°C.
• the pH was adjusted to 10.1 with 10% aqueous lithium hydroxide.
• Precooled (-20°C) phenylchlorformate (36.6 kg, 234 moles) was added while maintaining a temperature of not more than -9 °C and the pH was controlled during the reaction (maintaining a pH within the range of 9.5 to 10.5 with a target of 10.0) using a continuous addition of 10% aqueous lithium hydroxide.
• the reaction was stirred for 2 hours at about -14°C.
• the reaction mixture was filtered through Celite and the filter cake was washed with 42 kg of distilled water.
• the aqueous filtrate was extracted with methyl t-butyl ether (65 kg) to remove residual phenol.
• the aqueous phase was then cooled to 0-5°C and mixed with 200 kg of toluene.
• the stirred biphasic solution was adjusted to pH 1.8-2.0 with 25% (w/w) sulfuric acid.
• the toluene layer was concentrated at not more than 40 °C to approximately 120 L, filtered (30 kg rinse of toluene) and then concentrated again at not more than 40 °C to approximately 120 L.
• the resulting white slurry was cooled to 14 °C + 5°C and stirred for not less than 3 hours.
• the white slurry was filtered and the solid washed with 41 kg of 1 :1 toluene/heptane.
• the solid product was dried at not more than 50 °C to provide the desired product (47.8 kg) as a white powder.
• the reaction mixture was quenched with 200 mL of distilled water and then acidified to pH 9 using 26.2 g of concentrated hydrochloric acid, keeping the temperature below 30°C.
• the aqueous layer was separated and washed with another 125 mL of THF.
• Ethanol 3A 75 mL was added to the separated aqueous layer and the mixture was acidified to pH ⁇ 3 with 12.3 g of concentrated hydrochloric acid, keeping the temperature below 25°C.
• the acidified mixture was extracted twice with ethyl acetate (250 mL and 150 mL). The combined organic layers were evaporated to dryness on a rotary evaporator at a temperature below 50°C.
• the residual solids were flushed with 250 mL of ethyl acetate.
• the residual solid was dissolved in 150 mL of ethanol 3A at reflux temperature and filtered through a 5 g Darco-G60 bed over filteraid, followed by a 50 mL hot ethanol rinse.
• the filtrate was evaporated to dryness on a rotary evaporator at a temperature below 50°C.
• Ethyl acetate (75 mL) was added to the residue and refluxed for 30 minutes.
• the suspension was cooled to below 10°C for 2 hours.
• the solid was collected by filtration and washed with 20 mL of cold ethyl acetate (5-8°C). After drying at 40°C for 72 hours the desired product was obtained as a white solid (15.6 g, 74%).
• Example 36 Alternative Preparation of 2S-(1 -Tetrahvdro-pyrimid-2-onyl)-3-methvl butanoic acjd.
• a mixture of phenoxycarbonyl-L-valine (250 g, 1.05 mol; prepared according to the procedure disclosed in U.S. Patent Application No. 08/671 ,893, filed June 28, 1996, which is incorporated herein by reference) and 3-chloropropylamine hydrochloride (151 g, 1.16 mol) in THF (2.5 L) is cooled to 2°C.
• Sodium hydroxide 127 g, 3.2 mol
• reaction is stirred at 1 -5°C for 2 hours. Additional 3-chloropropylamine (10 g, 0.08 mol) is added and stirring is continued for 1 hour. A solution of potassium t-butoxide (296 g, 2.6 mol) in 1.25 L of THF is then added over 30 minutes, followed by a 100 mL THF rinse. The temperature of the reaction mixture was allowed to rise to 20°C during the addition. The reaction mixture is stirred at room temperature for 12-16 hours.
• the reaction mixture is quenched with 2 L of distilled water and cooled to 12°C and then acidified to pH 9 using 258 g (2.6 mol) of concentrated hydrochloric acid, keeping the temperature below 30°C.
• the aqueous layer is separated.
• Ethanol 3A (625 mL) is added to the separated aqueous layer and the mixture was acidified to pH ⁇ 3 with 116 g (1.2 mol) of concentrated hydrochloric acid, keeping the temperature below 25°C.
• the acidified mixture is extracted twice with ethyl acetate (2.5 L and 1 .5 L).
• the combined organic layers are evaproated to dryness on a rotary evaporator at a temperature below 50°C.
• the residual solids are dried by repeated distillation with ethyl acetate (4 x 1 L).
• the residual solid is dissolved in 750 mL of methanol and treated with decolorizing carbon (10 g Darco-G60 bed) at room temperature overnight.
• the carbon is removed by filtration through diatomaceous earth.
• the filtrate is evaporated to dryness on a rotary evaporator at a temperature below 50°C.
• Ethyl acetate (1.5 L) is added to the residue and approximately 500 mL is removed on the rotary evaporator.
• the suspension is cooled to below 10°C for > 1 hour.
• the solid is collected by filtration and washed with 2 x 100 mL of cold ethyl acetate (5-8°C). After drying at 50°C for 72 hours the desired product is obtained.
• the reaction was quenched with a dilute solution of HCl (36.75 g concentrated HCl in 225 mL of water) and stirred 20 minutes.
• the biphasic mixture was filtered with a 100 mL ethyl acetate rinse.
• the organic layer was separated and washed with 3 x 125 mL 5% NaCl.
• the organic layer was separated and washed with 3 x 225 mL 5% NaCl and 2 x 225 mL 5% NaHC0 3 .
• the organic solution was concentrated by rotary evaporation to provide the desired product as a thick syrup.
• Example 38P The product of Example 38P (20 g, 31.7 mmole, corrected for dioxane content), sodium bicarbonate (16.5 g, 197 mmole), ethyl acetate (150 mL) and water (150 mL) were combined in a flask and stirred until the product of Example 38P had dissolved (some salt remains undissolved).
• the solution of acid chloride prepared above was added over 5 minutes, followed by an ethyl acetate rinse (5 mL). Addition was mildly exothermic (maximum temperature 23 °C). The mixture was stirred overnight.
• Example 38E The product of Example 38E (2.5 g) was dissolved in 6 mL of absolute ethanol. This solution was added slowly dropwise to 31 mL of chilled water at 7-9°C with vigorous stirring. A white solid appeared. The stirring was continued for 20 minutes and the solids were collected by filtration. Vacuum drying at 50°C for 12 hours provided 2.24 g of the desired product as an amorphous solid.
• Example 38E The product of Example 38E (0.5 g) was dissolved in 8 mL of isopropanol. This solution was added slowly dropwise to 100 mL of chilled water at 10-15°C with vigorous stirring. A white solid appeared. The stirring was continued for 20 minutes and the solids were collected by filtration. Air drying provided 0.48 g of the desired product as an amorphous solid.
• Example 38E The product of Example 38E (0.5 g) was dissolved in 8 mL of acetone and 0.2 mL of absolute ethanol. This solution was added slowly dropwise to 100 mL of chilled water at 10-15°C with vigorous stirring. A white solid appeared. The stirring was continued for 10 minutes and the solids were collected by filtration. Air drying provided 0.46 g of the desired product as an amorphous solid.
• Example 38E The product of Example 38E (0.5 g) was dissolved in 2 mL of acetonitrile. This solution was added slowly dropwise to 100 mL of chilled water at 10-15°C with vigorous stirring. A white solid appeared. The stirring was continued for 20 minutes and the solids were collected by filtration. Air drying provided 0.46 g of the desired product as an amorphous solid.
• Example 40 N-O-Chloro p ropylaminocarbonvD-valine methyl ester 3-Chloropropylisocyanate (0.31 mL, 3.0 mmol) was added to a slurry of L-valine methyl ester hydrochloride (0.5 g, 3.0 mmol) and triethylamine (0.42 mL, 3.0 mmol) in THF (10 mL). The reaction mixture was stirred for 4 hours at room temperature and was then quenched with the addition of aqueous sodium bicarbonate. The quenched reaction mixture was extracted with ethyl acetate. The organic layer was separated, dried and evaporated to give the desired product.
• Example 42 f2S. 3S. 5S)-2-(2.6-Pimethylphenoxyacetyl) amino-3-hvdroxy-5-f2S- ⁇ - tetrahydro-6-hvdroxy-pyrimid-2-onyl)-3-methyl butanoyl] amino-1 .6- diphenylhexane
• the inhibitory potency of the compound of the invention can be determined by the following method.
• the compound of the invention is dissolved in DMSO and a small aliquot further diluted with DMSO to 100 times the final concentration desired for testing
• the reaction is carried out in a 6 X 50 mm tube in a total volume of 30Q microliters
• the final concentrations of the components in the reaction buffer are.
• reaction mixture 125 mM sodium acetate, 1 M sodium chloride, 5 mM dithiothreitol, 0.5 mg/ml bovine serum albumin, 1.3 ⁇ M fluorogenic substrate, 2% (v/v) dimethylsulfoxide, pH 4 5
• the fluorescence intensity (excitation 340 nM, emmision 490 nM) is recorded as a function of time
• the reaction rate is determined for the first six to eight minutes
• the observed rate is directly proportional to the moles of substrate cleaved per unit time
• the percent inhibition is 100 X (1 - (rate in presence of ⁇ nh ⁇ b ⁇ tor)/(rate in absence of inhibitor)).
• the anti-HIV activity of the compound of the invention can be determined in MT4 cells according to the following procedure.
• MT4 cells were infected with cell-free supernatant of HIVIIIB (previously frozen with known 50% tissue culture infectious dose (TCIP50) at 0.003 multiplicity of infection (MOI) for one hour. After one hour infection, cells were washed twice to remove residual viruses, resuspended in culture media and seeded into 96-well tissue culture plates at 1 x10 ⁇ 4 cells per well with various half-log dilutions of compounds. Uninfected celts are included as toxicity and cell controls. RPMI 1640 media (Gibco ) with 10% fetal bovine serum were used as culture media.
• the 50% effective concentration was calculated by the median effect equation (Chou, 1975, Proc. Int. Cong. Pharmacol. 6th p. 619) to determine the efficacy of compound.
• the 50% lethal concentration (LC50) was calculated using uninfected MT4 cells.
• Passage MT4 cells were infected with the wild-type HIV clone pNL4-3, and the virus was serially passaged in the presentee of increasing concentrations of the compound of Example 2B to select for the compound of Example 2B resistant virus strains.
• Virus was initially grown in the presence of 0.02 ⁇ M the compound of Example 2B (passage P1 ), and during the course of the five month selection procedure, the concentration of the compound of Example 2B was increased to 3.0 ⁇ M (Passage P17). While it took more than 110 days in culture to increase the drug concentration from 0.02 ⁇ M to 0.80 ⁇ M, the drug concentration could be rapidly escalated from 0.80 ⁇ M to 3.0 ⁇ M during the subsequent six weeks.
• Table 3 The results of these selection studies are shown in Table 3 below.
• the above data clearly demonstrates that the use of a compound of the present invention elicits a different profile of HIV protease mutations, and, therefore a different profile of the development of resistance.
• the data shows that a compound of the present invention can be used to effectively inhibit HIV protease activity in patients that have already developed resistance to one or more other protease inhibitors which promote an HIV protease mutation pattern of the type promoted by ritonavir.
• the data demonstrate the value of using a compound of the invention in combination with ritonavir or an HIV protease inhibitor which promotes an HIV protease mutation pattern of the type promoted by ritonavir.
• the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids.
• These salts include but are not limited to the following: acetate, adipate, alginate, citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxy- ethanesulfonate (isethionate), lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pamoate, pectinate
• the basic nitrogen- containing groups can be quatemized with such agents as loweralkyi halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyi sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates, long chain halides such as decyl, lauryl, myristyl and stearyl chlorides, bromides and iodides, aralkyl halides like benzyl and phenethyl bromides, and others. Water or oil- soluble or dispersible products are thereby obtained.
• loweralkyi halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
• dialkyi sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
• acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulphuric acid and phosphoric acid and such organic acids as oxalic acid, maleic acid, succinic acid and citric acid.
• Other salts include salts with alkali metals or alkaline earth metals, such as sodium, potassium, calcium or magnesium or with organic bases.
• Preferred salts of the compounds of the invention include hydrochloride, methanesulfonate, sulfonate, phosphonate and isethionate.
• the compounds of the present invention can also be used in the form of esters. Examples of such esters include compounds wherein a hydroxyl group in the compound of this invention has been acylated with an N-protected or unprotected amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R * C(0)- or R * C(S)- wherein R * is hydrogen, loweralkyi, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula R a -C(Rb)(Rd)-C(0)- or R a -C(Rb)(R ⁇ j)-C(S)- wherein Rb and Rd are independently
• amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used, including those wherein the amino acyl group is -C(0)CH2NR2ooR20i wherein R200 and R201 are independently selected from hydrogen and loweralkyi or the group -NR200R201 forms a nitrogen containing heterocyclic ring.
• These esters serve as pro-drugs of the compound of the present invention and serve to increase the solubility of these substances in the gastrointestinal tract.
• These esters also serve to increase solubility for intravenous administration of the compound.
• prodrugs include compounds wherein a hydroxyl group in the compound of this invention is functionalized with a substituent of the formula -CH(R g )OC(0)R-
• Such prodrugs can be prepared according to the procedure of Schreiber (Tetrahedron Lett. 1983, 24, 2363) by ozonolysis of the corresponding methallyl ether in methanol followed by treatment with acetic anhydride.
• the prodrugs of this invention are metabolized in vivo to provide the compound of this invention .
• the preparation of the prodrug esters is carried out by reacting the compound of the invention with an activated amino acyl, phosphoryl, hemisuccinyl or acyl derivative as defined above. The resulting product is then deprotected to provide the desired pro-drug ester.
• Prodrugs of the invention can also be prepared by alkylation of the hydroxyl group with (haioalkyl)esters, transacetalization with bis-(alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
• Means for determining the spatial orientation of a compound of this invention are well known in the art.
• One preferred method is determination of the HIV protease/inhibitor complex by the technique of X-ray crystallography.
• the process of determining the structures of protein/inhibitor complexes using the X-ray technique is well known (See T. L. Blundel and L. N. Johnson, Protein Crystallography, Academic Press, (1976) and Methods in Enzymology, volumes 114 and 115, H. W. Wyckoff et al., eds., Academic Press (1985)).
• This technique can employ, for instance, a highly purified preparation of HIV protease complexed with an inhibitor of interest in a buffered solution (typically at a pH of between about 4.5 and about 8.0).
• a buffered solution typically at a pH of between about 4.5 and about 8.0.
• the complex is allowed to crystallize in the presence of a precipitation agent (such as ammonium sulfate) under conditions which yield single crystals of the complex.
• a precipitation agent such as ammonium sulfate
• a concentrated X-ray beam (from rotating anode X-ray generator or synchrotron) to an appropriately prepared and mounted crystal will yield a diffraction pattern from the reflected X-ray beam.
• Detection of the diffracted rays may be carried out by using a multiwire area detector (such as that manufactured by Siemmens Analytical X-ray Instruments, Inc. (Madison, Wl)() or an R-axis II image plate system from Rigaku Corporation, The Woodlands, TX).
• Visualization of the complex of HIV protease and an inhibitor may be carried out using computer software such as Insightll (Biosym/Molecular Simulations, INC., San Piego) or Quanta (Molecular Simulations, Inc., Burlington MA), and distances and spherical volumes may be generated using tools available within those programs
• a second means for determining spatial orientation is the technique of Nuclear Magnetic Resonance (NMR) Spectroscopy
• NMR Nuclear Magnetic Resonance
• This technique can employ, for instance, a preparation of HIV protease complexed with an inhibitor of interest in a buffered solution (typically at a pH of between about 3 0 and about 8 0) Either single or multi ⁇ dimensional techniques may be applied.
• the enzyme and/or the inhibitor may be enriched with stable isotopes such as 13 C, 15 N, or 2 H to more easily determine the binding conformation and proximity
• stable isotopes such as 13 C, 15 N, or 2 H
• the NMR technique will yield a structure which has no distance violation greater than about 0.3 A and an RMS deviation between the family of structures generated from the average structure of about 0 6 A
• these values are adequate to determine the interactions between HIV protease and a given compound such that it will be clear if the claimed features are present.
• Visualization of the complex of HIV protease and an inhibitor may be carried out using computer software such as Insightll (Biosym/Molecular Simulations, Inc , San Piego) or Quanta (Molecular Simulations, Inc , Burlington, MA), and distances and spherical volumes may be generated using tools available within those programs
• a third means is Molecular Modeling. This process of creating theoretical models of protein-inhibitor complexes is well known (see G L Seibel and P A Kollman, "Molecular Mechanics and the Modeling of Prug Structures, Ch 18.2 in Comprehensive Medicinal Chemistry, C Hansch, Ed., Pergammon Press, (1990) and T J Perun and C. L Propst, Eds Computer- Aided Prug Pesign, Marcel Pekker, Inc. (1989)).
• Computer software such as Insight II (Biosym/Molecular Simulations, Inc., San Piego) or Quanta (Molecular Simulations, Inc., Burlington, MA) is used to construct a possible 3P arrangement of inhibitor and protein.
• coordinates for the protein are derived from prior X-ray or NMR structures taken from the Protein Data Base (Brookhaven National Laboratories, New York). Coordinates for the inhibitor are adopted which use standard bond lengths and angles derived from structures of organic compounds (for example, data found within the Cambridge Crystallographic Database (University Chemical Laboratory, Cambridge, United Kingdom).
• the candidate inhibitor is aligned in 3- dimensional space with other, related inhibitors whose bound conformations have previously been determined by either X-ray crystallography or NMR spectroscopy. Both Van der Waals volume and electrostatic potentials are used to direct the alignment process.
• the protein and inhibitor molecules are allowed to achieve conformations that are lower in energy from the initial starting geometry by energy minimization in which a force field is used to mathematically search for the lowest energy conformation.
• Suitable force fields such as AMBER (S. J. Weiner et al., Journal of Computational Chemistry, 7, 230-252 (1986) or CVFF (J. R. Maple et al., Journal of Computational Chemistry 15:162-182 (1994)) are available within the software listed above.
• energy minimization of the inhibitor is initially carried out with the enzyme atoms held fixed in space followed by more extensive energy minimization of the entire protein/inhibitor complex.
• Conformational searching (torsion driver, rotor library, or dynamics/Monte Carlo methods are available within the software listed above) is carried out to explore additional or alternative binding modes of the inhibitor within the active site of HIV protease.
• Water molecules may be added during this analysis to more closely simulate the aqueous environment.
• the accuracy of these theoretical models is frequently comparable to the accuracy of structures determined by X-ray or NMR methods, particularly when the candidate inhibitor compound is closely related to the previously studied inhibitor compounds.
• a specific example of the use of theoretical molecular modeling methods in the successful prediction of an HIV protease/inhibitor complex is found in H. L.
• Visualization of the complex of HIV protease and an inhibitor may be carried out using computer software such as Insight II (Biosym/Molecular Simulations, Inc., San Diego) or Quanta (Molecular Simulations, Inc., Burlington MA), and distances and spherical volumes may be generated using tools available within those programs.
• the compounds of the invention are useful for inhibiting retroviral protease, in particular HIV protease, in vitro or in vivo (especially in mammals and in particular in humans).
• the compounds of the present invention are also useful for the inhibition of retroviruses in vivo, especially human immunodeficiency virus (HIV).
• the compounds of the present invention are also useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection in a human or other mammal.
• Total daily dose administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 20 mg/kg body weight daily. Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
• the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
• the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination, and the severity of the particular disease undergoing therapy.
• the compounds of the present invention may be administered orally, parenterally, sublingually, by inhalation spray, rectally, or topically in dosage unit formulations containing conventional nontoxic pharmaceutically acceptable carriers, adjuvants, and vehicles as desired. Topical administration may also involve the use of transdermal administration such as transdermal patches or iontophoresis devices.
• parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques.
• sterile injectable preparations for example, sterile injectable aqueous or oleagenous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
• the sterile injectable preparation may also be a sterile injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-propanediol.
• acceptable vehicles and solvents that may be employed are water, Ringer's solution, and isotonic sodium chloride solution.
• sterile, fixed oils are conventionally employed as a solvent or suspending medium.
• any bland fixed oil may be employed including synthetic mono- or diglycerides.
• fatty acids such as oleic acid find use in the preparation of injectables.
• Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
• a suitable nonirritating excipient such as cocoa butter and polyethylene glycols which are solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
• Solid dosage forms for oral administration may include capsules, tablets, pills, powders, and granules.
• the active compound may be admixed with at least one inert diluent such as sucrose lactose or starch.
• Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., lubricating agents such as magnesium stearate.
• the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
• Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents commonly used in the art, such as water. Such compositions may also comprise adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
• the compounds of the present invention can also be administered in the form of liposomes.
• liposomes are generally derived from phospholipids or other lipid substances. Liposomes are formed by mono- or multi-lamellar hydrated liquid crystals that are dispersed in an aqueous medium.
• any non-toxic, physiologically aceptable and metabolizable lipid capabale of forming liposomes can be used.
• the present compositions in liposome form can contain, in addition to the compound of the present invention, stabilizers, preservatives, excipients, and the like.
• the preferred lipids are the phospholipids and phosphatidyt cholines (lecithins), both natureal and synthetic.
• a preferred dosage form for the compounds of this invention comprises a solution of (a) a compound of the formula I in the amount of from about 1 % to about 50% (preferably, from about 5% to about 30%) by weight of the total solution and (b) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1 ) oleic acid in the amount of from about 20% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and (2) ethanol or propylene glycol or a mixture thereof in the amount of from about 0% to about 12% (preferably, about 10%) by weight of the total solution.
• a most preferred composition of the invention comprises a solution of (a) a compound of the formula I in the amount of about 30% by weight of the total solution and (b) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of (1 ) oleic acid in the amount of about 50% by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution.
• the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01 % to about 0.08% by weight of the total solution (preferably, from about 0.01 % to about 0.05% by weight of the total solution).
• SEC soft elastic gelatin capsule
• BHT butylated hydroxytoluene
• the mixing tank was purged with nitrogen. Oleic acid (499.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The Compound of Example 2B (300 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g)was added to the tank and mixed. The resulting solution was filled into soft elastic capsules (0.333 g of solution/SEC) to provide a dosage of 100 mg of compound of Example 2B/SEC or 0.667 g/SEC to provide a dosage of 200 mg of compound of Example 2B/SEC.
• antiviral agents to be administered in combination with a compound of the present invention include AL-721 , beta interferon, polymannoacetate, reverse transcriptase inhibitors (for example, dideoxycytidine (ddC; zaicitabine), dideoxyinosine (ddl; didanosine), BCH-189, AzdU, carbovir, ddA, d4C, d4T (stavudine), 3TC (lamivudine) DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia-dideoxycytidine, PMEA, bis- POMPMEA, zidovudine (AZT), nevirapine, delvihdine, MSA-300, trovirdine and the like),
• AL-721 beta interferon
• polymannoacetate reverse transcriptase inhibitors
• reverse transcriptase inhibitors for example, dideoxycytidine (ddC
• Immunomodulators that can be administered in combination with the compound of the present invention include bropirimine, Ampligen, anti-human alpha interferon antibody, colony stimulting factor, CL246.738, lmreg-1 , lmreg-2, diethydithiocarbamate, interleukin-2, alpha- interferon, inosine pranobex, methionine enkephalin, muramyl-tripeptide, TP-5, erythropoietin, naltrexone, tumor necrosis factor, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1 , anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, cyclosporin, rapamycin, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia
• Any of a variety of HIV or AIDS vaccines for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp1 0), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV- Immunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with the compound of the present invention.
• agents that can be used in combination with the compound of this invention are ansamycin LM 427, apurinic acid, ABPP, AI-721 , carrisyn, AS- 101 , avarol, azimexon, colchicine, compound Q, CS-85, N-acetyl cysteine, (2- oxothiazolidine-4-carboxylate), D-penicillamine, diphenylhydantoin, EL-10, erythropoieten, fusidic acid, glucan, HPA-23, human growth hormone, hydroxchloroquine, iscador, L-ofloxacin or other quinolone antibiotics, lentinan, lithium carbonate, MM-1 , monolaurin, MTP-PE, naltrexone, neurotropin, ozone, PAI, panax ginseng, pentofylline, pentoxifylline, Peptide T, pine cone extract, polymannoacetate, reticulose
• agents that can be used in combination with the compound of this invention are antifungals such as amphotericin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin and the like.
• agents that can be used in combination with the compound of this invention are antibacterials such as amikacin sulfate, azithromycin, ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin, rifampin, streptomycin and TLC G-65 and the like.
• anti-neoplasties such as alpha interferon, COMP (cyclophosphamide, vincristine, methotrexate and prednisone), etoposide, mBACOD (methotrexate, bleomycin, doxorubicin, cyclophosphamide, vincristine and dexamethasone), PRO-MACE/MOPP(prednisone, methotrexate (w/leucovin rescue), doxorubicin, cyclophosphamide, taxol, etoposide/mechlorethamine, vincristine, prednisone and procarbazine), vincristine, vinblastine, angioinhibins, pentosan polysulfate, platelet factor 4 and SP-PG and the like.
• COMP cyclophosphamide, vincristine, methotrexate and prednisone
• etoposide mBACOD (methotrexate,
• agents that can be used in combination with the compound of this invention are drugs for treating neurological disease such as peptide T, ritalin, lithium, elavil, phenytoin, carbamazipine, mexitetine, heparin and cytosine arabinoside and the like.
• agents that can be used in combination with the compound of this invention are anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, fansidar, furazolidone, L,671 ,329, letrazuril, metronidazole, paromycin, pefloxacin, pentamidine, piritrexim, primaquine, pyrimethamine, somatostatin, spiramycin, sulfadiazine, trimethoprim, TMP/SMX, trimetrexate and WR 6026 and the like.
• anti-protozoals such as albendazole, azithromycin, clarithromycin, clindamycin, corticosteroids, dapsone, DIMP, eflornithine, 566C80, fansidar, furazolidone, L,671 ,329, letraz
• AZT zidovudine
• ddl didanosine
• ddC zaicitabine
• d4T stavudine
• 3TC lamivudine
• nevirapine delvihdine
• trovirdine PMEA, bis-POMPMEA and MSA-300.
• HIV protease inhibitors especially, ABT-538 (ritonavir) and related compounds, disclosed in U.S. Patent No. 5,541 ,206, issued July 30, 1996 and U.S. Patent No.
• a compound of this invention is administered in combination with ritonavir
• a combination is especially useful for inhibiting HIV protease in a human
• a combination is also especially useful for inhibiting or treating an HIV infection in a human
• the compound of this invention and ritonavir can be administered as separate agents at the same or different times or they can be formulated as a single composition comprising both compounds
• ritonavir When administered in combination with a compound of this invention, ritonavir causes an improvement in the pharmacokinetics (i.e., increases half- life, increases the time to peak plasma concentration, increases blood levels) of the compound of this invention
• Preferred dosage forms for ritonavir include (a) a liquid dosage form for oral administration as disclosed in U.S Patent No 5,484,801 , issued January 19, 1996, which is incorporated herein by reference, (b) an encapsulated solid or semi-solid dosage form as disclosed in PCT Patent Application No WO95/07696, published Mar ⁇ h 23, 1995 and U.S. Serial No 08/402,690, filed March 13, 1995, both of whi ⁇ e incorporated herein by reference and (c) an encapsulated solid dosage form as disclosed in PCT Patent Application No WO95/09614, published April 13, 1995 and U.S Patent No. 5,559,158, issued September 24, 1996, both of which are incorporated herein by reference.
• Other examples of preferred dosage forms for ritonavir are disclosed in
• a preferred composition for ritonavir comprises a solution of (a) ritonavir in the amount of from about 1 % to about 30% (preferably, from about 5% to about 25%) by weight of the total solution and (b) polyoxyl 35 castor oil in the amount of from about 0% to about 20% (preferably, from about 5% to about 10%) by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises (i) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution or (ii) a mixture of (1 ) oleic acid in the amount of from about 15% to about 99% (preferably, from about 30% to about 70%; more preferably, from about 40% to about 65%) by weight of the total solution and (2) ethanol or propylene glycol or a mixture thereof in the amount of from about 0% to about 12% (preferably, about 10%) by weight of the total solution.
• the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01 % to about 0.08% by weight of the total solution (preferably, from about 0.01 % to about 0.05% by weight of the total solution).
• SEC soft elastic gelatin capsule
• BHT butylated hydroxytoluene
• the mixing tank was purged with nitrogen. Oleic acid (649.9 g) and ethanol (100g) were mixed in the tank. This solution was warmed to about 33°C (29-37°C) and maintained at that temperature. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (200 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (50 g) was added to the tank and mixed. Heating was discontinued and the solution allowed to cool to amibient temperature (20-30°C).
• the resulting solution was filled into soft elastic capsules (0.5 g of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC or 1.0 g/SEC to provide a dosage of 200 mg of ritonavir/SEC.
• the mixing tank was purged with nitrogen. Oleic acid (599.9 g) and ethanol (100g) were mixed in the tank. This solution was warmed to about 33°C (29-37°C) and maintained at that temperature. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (200 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g)was added to the tank and mixed. Heating was discontinued and the solution allowed to cool to amibient temperature (20-30°C).
• the resulting solution was filled into soft elastic capsules (0.5 g of solution/SEC) to provide a dosage of 100 mg of ritonavir/SEC or 1.0 g/SEC to provide a dosage of 200 mg of ritonavir/SEC.
• a preferred composition for a single dosage form comprising both ritonavir and a compound of the formula I comprises a solution of (a) a mixture of ritonavir in the amount of from about 1 % to about 30% (preferably, from about 5% to about 25%) by weight of the total solution and a compound of the formula I in the amount of from about 1% to about 50% (preferably, from about 5% to about 40%) by weight of the total solution and (b) polyoxyl 35 castor oil in the amount of about 10% by weight of the total solution, in a pharmaceutically acceptable organic solvent which comprises a mixture of (1 ) oleic acid in the amount of from about 10% to about 88% (preferably, from about 40% to about 65%) by weight of the total solution and (2) ethanol in the amount of about 10% by weight of the total solution.
• the solution is encapsulated in a soft elastic gelatin capsule (SEC) or a hard gelatin capsule and the solution also comprises an antioxidant (preferably, BHT (butylated hydroxytoluene)) in the amount of from about 0.01 % to about 0.08% by weight of the total solution (preferably, from about 0.01% to about 0.05% by weight of the total solution).
• SEC soft elastic gelatin capsule
• BHT butylated hydroxytoluene
• the mixing tank was purged with nitrogen. Oleic acid (549.9 g) and ethanol (100g) were mixed in the tank. The butylated hydroxytoluene (0.1 g) was charged into the tank and mixed until the solution was clear. The ritonavir (150 g) was slowly charged into the tank and mixed until the solution was clear. Compound Example 2B (150 g) was slowly charged into the tank and mixed until the solution was clear. The polyoxyl 35 castor oil (100 g) was added to the tank and mixed. The resulting solution was filled into soft elastic capsules (1.0 g of solution/SEC) to provide a dosage of 150 mg each of ritonavir and compound Example 2B/SEC.
• Total daily dose of ritonavir (administered in combination with a compound of this invention) to be administered to a human or other mammal host in single or divided doses may be in amounts, for example, from 0.001 to 300 mg/kg body weight daily and more usually 0.1 to 10 mg of ritonavir.
• Dosage unit compositions may contain such amounts of submultiples thereof to make up the daily dose.
• the ratio (w/w) of ritonavir to the compound of Example 2B ranges from about 1 :16 to about 5:1 (preferably, from about 1 :6 to about 3:1 ).
• a compound of this invention is administered in combination with ritonavir and one or more reverse transcriptase inhibitors (preferably, one or more compounds selected from the group consisting of AZT (zidovudine), ddl (didanosine), ddC (zaicitabine), d4T (stavudine) and 3TC (lamivudine)).
• AZT zidovudine
• ddl didanosine
• ddC zaicitabine
• d4T stavudine
• 3TC lamvudine
• a particularly preferred therapeutic combination comprises a compound of the formula I (especially, the compound of Example 2B) in combination with ritonavir, AZT and 3TC.
• agents which can be combined with the compound of the present invention for the inhibition, treatment or prophylaxis of AIDS or an HIV infection are not limited to those listed above, but include in principle any agents useful for the treatment or prophylaxis of AIDS or an HIV infection.
• the therapeutic agents When administered as a combination, the therapeutic agents can be formulated as separate compositions which are given at the same time or different times, or the therapeutic agents can be given as a single composition.

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• 1996
  • 1996-12-06 EP EP02026856A patent/EP1295874A3/de not_active Withdrawn
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