Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
  • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/14—Antivirals for RNA viruses
  • A61P31/18—Antivirals for RNA viruses for HIV
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/24—Radicals substituted by oxygen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
  • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
  • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
  • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
  • C07D277/28—Radicals substituted by nitrogen atoms
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
  • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

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 compositions and methods for treating a retroviral infection and in particular an HIV infection, and to processes for making such compounds and synthetic intermediates employed in these processes.
• HIV human immunodeficiency virus
• Retroviruses are those viruses which utilize a bonucleic 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.
• retroviruses from a pathological standpoint include human immunodeficiency viruses (HIV-1 and HIV-2), which cause acquired immune deficiency syndrome (AIDS) in man, hepatitis B virus, which causes hepatitis and hepatic carcinomas 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
• hepatitis B virus which causes hepatitis and hepatic carcinomas in man
• human 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 QQ ⁇ and gag gene products. See Wellink, Arch. Virol. ___ 1 (1988). Retroviral proteases most commonly process the gag precursor into core proteins, and also process the p_gj 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) and 2',3'-dideoxyinosine (DDI) and compounds which treat the opportunistic infections caused by the immunosuppression resulting from HIV infection.
• AZT 3'-azido-3'-deoxythymidine
• DDC 2',3'-dideoxycytidine
• DI 2',3'-dideoxyinosine
• None of the current AIDS treatments have proven to be totally effective in treating and/or reversing the disease.
• 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, nelfinavir, and indinavir have been approved in the U.S. for treatment of HIV infections.
• HIV protease inhibitors ritonavir, saquinavir, nelfinavir, and indinavir have been approved in the U.S. for treatment of HIV infections.
• HIV protease inhibitors ritonavir, saquinavir, nelfinavir, and indinavir have been approved in the U.S. for treatment of HIV infections.
• HIV protease inhibitors ritonavir, saquinavir, nelfinavir, and indinavir
• the present invention comprises retroviral protease inhibiting compounds having formula I.
• R 1 is a thiazolyl group having the formula
• R 2 is a group having the formula:
• R 4 group is -WR 5 .
• the R 3 group is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N.
• W is selected from the group consisting of -0-, -S-, or -(CH2)rr. where n is from 0 to 6, with the proviso that when W is O, or S then Y is CH.
• R 5 is selected from the group consisting of alkyl, and aryl.
• R 4 and the ring to which it is attached, taken together can form a bicyclic group having the formula:
• the R 6 group is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl, Z is -0-, -S-, -CH2- or -N(R 7 )- ; and R 7 is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• the present invention also comprises retroviral protease inhibiting compounds having formula M: I I wherein R 1 is a thiazolyl group having the formula
• R 2 is a group having the formula:
• R 8 N ⁇ R 8 R wherein X is -C(O)- or -S(0)2- and R 8 is alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• R 3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R 9 is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• the Z group is -0-, -S-, -CH - or -N(R 7 )-, and R 7 is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• the alkyl, aryl, heterocyclic, and heteroaryl groups in the compounds of the invention can be optionally substituted with from 1 to 5 substituents and preferrably from 1 to 3 substituents.
• the substituents are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
• the invention also includes pharmaceutically acceptable salts, esters or prodrugs of compounds I and M.
• the present invention comprises retroviral protease inhibiting compounds having formula I:
• R 1 is a thiazolyl group having the formula
• R 2 is a group having the formula:
• R 4 group is -WR 5 .
• the R 3 group is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl, and Y is CH or N.
• W is selected from the group consisting of -0-, -S-, or -(CH2)rr, where n is from 0 to
• R 5 is selected from the group consisting of alkyl, and aryl.
• R 4 and the ring to which it is attached, taken together can form a bicyclic group having the formula:
• R 6 group is hydrogen, alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl
• Z is -0-, -S-, -CH2- or -N(R 7 )-
• R 7 is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• the present invention also comprises retroviral protease inhibiting compounds having formula M:
• R 1 is a thiazolyl group having the formula:
• R 2 is a group having the formula:
• R 9 wherein X is -C(O)- or -S(0)2- and R 8 is alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• R 3 is selected from the group consisting of hydrogen, alkyl, amino, alkylamino, dialkylamino and cycloalkyl and R 9 is alkyl, cycloalkyl, aryl, (aryl)alkyl, heterocyclic, heteroaryl, or (heteroaryl)alkyl.
• the Z group is -0-, -S-, -CH2- or -N(R 7 )-, and R 7 is hydrogen, alkyl, aryl, (aryl)alkyl, heterocyclic, (heterocyclic)alkyl, heteroaryl, or (heteroaryl)alkyl.
• alkyl, aryl, heteroaryl, and heterocyclic groups of the compounds of the invention, having formula I or II, can optionally be substituted with from 1 to 5 substituents and preferrably from 1 to 3 substituents.
• the substituents are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
• the invention also includes pharmaceutically acceptable salts, esters or prodrugs of compounds i and M.
• a preferred R 3 group is alkyl or cycloalkyl. More preferred are compounds where R 3 is alkyl selected from the group consisting of methyl, ethyl, or propyl or cycloalkyl selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl. The most preferred R 3 group is isopropyl.
• the preferred Z groups are -0-, or -N(R 7 )-. When Z is -N(R 7 )- a preferred R 7 is methyl.
• R 2 is a group having the formula:
• R 5 is aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl.
• W is -(CH2)n-.
• R 5 is alkyl or aryl and n is from 0 to 6.
• a preferred W is -0-, and preferably, R 5 is alkyl, or aryl selected from the group consisting of phenyl, methylenedioxyphenyl, and heteroaryl.
• alkyl, aryl, heterocyclic, and heteroaryl groups can be substituted with from 1 to 5 substituents and preferrably from 1 to 3 substituents.
• substituents for the alkyl, aryl, heterocyclic, and heteroaryl groups, are selected from the group consisting of hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
• Preferred substituents are fluorine, hydroxy, alkoxy, or alkylthio groups.
• the preferred alkoxy is methoxy.
• the preferred halogen is fluorine in a preferred embodiment the alkyl or aryl groups can be substituted with one to three groups.
• the preferred substituents are hydroxy, methoxy or fluorine.
• the preferred aryl groups include phenyl, such as, for example, methylenedioxyphenyl, and heteroaryl such as, for example, furanyl, thienyl, benzothienyl, thiazolyl and the like.
• a preferred heteroaryl group is thiazolyl.
• n is zero, and R 5 is methyl substituted with a thiazolyl group.
• R 6 group is selected from the group consisting of alkyl, hydroxyalkyl, and cycloalkyl.
• R 6 is lower alkyl group such as, for example, methyl, ethyl, propyl, butyl and the like.
• a preferred R 6 group is tert-butyl or hydroxy- butyl.
• the R 8 group is selected from the group consisting of alkyl, aryl, (aryl)alkyl, alkylamino, dialkylamino, heterocyclic, (heterocyclic)alkyl, heteroaryl,or (heteroaryl)alkyl.
• a preferred R 8 group is (alkyl)amino, such as, for example, (ferfbutyl)amino.
• the preferred R 9 group is a lower alkyl group such as, for example propyl, butyl, pentyl and the like. More preferred R 9 groups are isopropyl, tert- butyl, isobutyl, 3-methyl-1 -butyl, and the like. Most preferred is the / ' so-butyl group.
• X is -S(0)2-, R 8 is aryl selected from the group consisting of phenyl, and heteroaryl and R 9 is iso-butyl.
• stable compound refers to a compound that is sufficiently stable to survive isolation to a useful degree of purity from a reaction mixture and formulation into a therapeutic dosage form suitable for administration.
• Preferred compounds of the invention are selected from the group consisting of:
• alkyl refers to straight or branched chain alkyl radicals containing from 1 to 12 carbon atoms.
• lower alkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including, but not limited to, methyl, ethyl, n-propyl, /so-propyl, n-butyl, /so-butyl, sec-butyl, f-butyl t?-pentyl, 1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2- dimethylpropyl, n-hexyl, and the like.
• the alkyl groups can be unsubstituted or substituted with from one to five substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
• the alkyl groups can be optionally interrupted by one or more heteroatoms selected from the group consisting of oxygen, nitrogen, sulfur, and phosphorous.
• cycloalkyl refers to an aliphatic ring system having 3 to 8 carbon atoms including, but not limited to, cyclopropyl, cyclopentyl, cyclohexyl, and the like.
• alkoxy refers to groups having the formula -OR 10 wherein R 10 is a lower alkyl group.
• thioalkyl refers to groups having the formula -SR 1 1 wherein R 1 1 is a lower alkyl group.
• alkylamino refers to groups having the formula -NHR 12 wherein R 12 is a lower alkyl group.
• dialkylamino refers to groups having the formula -N(R 13 )2 wherein each R 13 is independently a lower alkyl group.
• halo or halogen refers to F, Cl, Br or I.
• (halo)alkyl refers to a lower alkyl group in which one or more hydrogen atoms has been replaced with a halogen including, but not limited to, thfluoromethyl, trichloromethyl, difuoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl, 2,2-dichloroethyl and the like.
• 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 from one to five substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
• (aryl)alkyl refers to an aryl group as previously defined, appended to a lower alkyl radical, for example, benzyl 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, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, bistetrahydrofuranyl or benzothienyl and the like).
• Heterocyclics include: azetidinyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopipe dinyl, pyrazinyl, piperazinyl, pyrimidinyl, py dazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, tetrahydro
• X * is -CH2-, -NH- or -0-
• Y * is -C(O)- or [-C(R")2-]v
• R" is hydrogen or C1 -C4-alkyl and v is 1 , 2 or 3 and Z * is -O- or -NH-; such as 1 ,3- benzodioxolyl, 1 ,4-benzodioxanyl and the like.
• methylenedioxyphenyl refers to a substituent having the formula:
• Heterocyclic groups can be unsubstituted or substituted with from one to five substituents independently selected from hydroxy, alkoxy, alkylthio, amino, alkylamino, dialkylamino and halogen.
• nitrogen containing heterocycles can be N-protected.
• heterocyclicalkyl refers to a heterocyclic group appended to a lower alkyl radical including, but not limited to, pyrrolidinylmethyl, morpholinylmethyl and the like.
• heteroaryl refers to an heterocyclic group containing at least one aromatic ring. Examples include groups such as, for example, furanyl, thienyl, benzothienyl, thiazolyl and the like.
• heteroarylalkyl refers to a heteroaryl group appended to a lower alkyl radical including, but not limited to, thienylmethyl, thienylethyl, furanylmethyl, and the like .
• 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 undesirable reactions during synthetic procedures. Commonly used N-protecting groups are disclosed in T.H. Greene and P.G.M. Wuts, Protective Groups in Organic Synthesis. 2nd edition, John Wiley & Sons, New York (1991 ).
• N-protecting groups comprise acyl groups such as formyl, acetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromo- acetyl, trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl, ⁇ -chloro- butyryl, 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-chlorobenzyloxycar- bonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyl- oxycarbonyl,
• N-protecting groups are formyl, acetyl, benzoyl, pivaloyl, t- butylacetyl, phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl (Cbz).
• activated carboxylic acid 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.
• leaving group refers to a group which is easily displaced from the compound, such as, for example, a halide (for example, Cl, Br or I) or a sulfonate (for example, mesylate, tosylate, triflate and the like).
• a halide for example, Cl, Br or I
• a sulfonate for example, mesylate, tosylate, triflate and the like.
• 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.
• This invention is intended to encompass compounds having Formula I or Formula II when prepared by synthetic processes or by metabolic processes. Preparation of the compounds of the invention by metabolic processes include those occurring in the human or animal body (in vivo) or processes occurring in vitro.
• the reagents required for the synthesis of the compounds of the invention are readily available from a number of commercial sources such as Aldrich Chemical Co. (Milwaukee, WI, USA); Sigma Chemical Co. (St. Louis, MO, USA); and Fluka Chemical Corp. (Ronkonkoma, NY, USA); Alfa Aesar (Ward Hill, MA 01835-9953); Eastman Chemical Company (Rochester, New York 14652-3512); Lancaster Synthesis Inc. (Windham, NH 03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical) (New Brunswick, NJ 08901 ); Pfaltz and Bauer (Waterbury, CT. 06708). Compounds which are not commercially available can be prepared by employing known methods from the chemical literature.
• the compounds of the invention can be prepared as shown in Schemes MIL As outlined in Scheme I, an N-protected (for example, with a benzyloxycarbonyl group) phenylalanylepoxide 2 is coupled with an N- protected (for example, N-Boc) piperazine compound, 1 (using, for example, 1 - (3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC),1 -hydroxybenzotriazole (HOBT), and an amine, such as, triethyl amine, and the like, in an inert solvent, for example, tetrahydrofuran, methylene chloride, and the like).
• N-protected (for example, with a benzyloxycarbonyl group) phenylalanylepoxide 2 is coupled with an N- protected (for example, N-Boc) piperazine compound, 1 (using, for example, 1 - (3-dimethylaminopropy
• the protected carboxamide product, 3, is deprotected (for example, by treatment with hydrogen gas and an hydrogenation catalyst).
• the amine carboxamide 3a is then coupled with a carboxylic acid, 4, or an activated derivative thereof, using, for example, 1 -(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDAC),1 -hy- droxybenzot azole (HOBT), and triethyl amine in an inert solvent, for example, tetrahydrofuran, methylene chloride, and the like, to provide the N-protected piperazine, 5.
• the piperazine is N-deprotected, (with for example, trifluoroacetic acid (TFA), and the like) and alkylated (where X 1 is a leaving group) to provide the final product, 6.
• Example 1 2-(1 -Methyl ⁇ thyl)-4-thiazolylmethyl-[(1 SV1 -[[[(1 S.2R)-3-[f2S)-4-(1.3-benzodi- oxol-5-ylmethv ⁇ -2-f[(1 .1 -dimethylethyl)amino]carbonyl]-1 -piperazinyl]-2-hv- droxy-1 -(phenylmethv ⁇ propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• 1A 2-(1 -Methyl ⁇ thyl)-4-thiazolylmethyl-[(1 SV1 -[[[(1 S.2R)-3-[f2S)-4-(1.3-benzodi- oxol-5-ylmethv ⁇ -2-f[(1 .1 -dimethylethyl)amino]carbonyl]-1
• Example 2 2-(1 -Methylethyl)-4-thiazolylmethyl-r SH -[[[ ( 1 S.2R)-3-[(2S ) -2-[[(1.1 -dimethyl- ethvhamino]carbonvl]-4-(phenylmethyl)-1 -piperazinyl]-2-hydroxy-1 -(ph8nyl- methvnpropyl]amino1carbonyl1-2-methylpropyl]carbamate.
• Example 4 2-(1 -Methylethyl)-4-thiazolylmethyl-[(1 SV1 -[[[(1 S.2R)-3-[(2S -2-[f(1 .1 -dimethyl- ethv ⁇ amino1carbonyl]-4-f5-thienylmethv ⁇ -1 -piperazinyl]-2-hvdroxy-1 -fphenyl- methyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 5 2-(1 -Methylethyl)-4-thiazolylmethyl-f(1 S)-1 -[[f(1 S.2R ) -3-[(2S ) -2-[[(1 .1 -dimethyl- ethyl)amino]carbonyl]-4-[4-(3-hydroxyphenyl)methyl]-1 -piperazinyl]-2-hydroxy- 1 -(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 6 2- ⁇ -Methvlethvn-4-thiazolvlmethvl-r ⁇ SV1 -frr.1 S.2R -3- (2S)-2-[[(1.1 -dimethyl- ethvnamino1carbonvl]-4-(3-pvridinvlmethvh-1 -piperazinvl]-2-hvdroxv-1 - (phenylmethv ⁇ propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 7 2-(1 -Methylethvn-4-thiazolylmethvK(1 S)-1 -r[r(1 S.2R)-3-[(2S)-2-[[(1 .1 -dimethyl- ethyl)amino]carbonyl]-4-(4-pyridinylmethy0-1 -piperazinyl]-2-hydroxy-1 - (phenylmethv ⁇ propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 8 2-(1 -Methyl9thyl)-4-thiazolylmethyl-[(1 S)-1 -[[[(1 S.2R)-3-[(2S)-2-[[( 1.1 -dimsthyl- ethvhamino]carbonyl]-4-f( , 4-hvdroxyphenv ⁇ methyl]-1 -piperazinyl]-2-hvdroxy-1 - (phenvlmethv ⁇ propvl1amino]carbonvl]-2-methvlpropvl]carbamate.
• Example 9 2-(1 -Methylethvh-4-thiazolylmethyl- ⁇ S)-1 -[[[(1 S.2R)-3-f(2S 4-M H- benzimidiazol-2-ylmethyl)-2-[[f1 .1 -dimethylethvhamino]carbonyl]-1 -piperazinyl]- 2-hydroxy-1 -(phenvlmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 11 2-(1 -Methylethvh-4-thiazolylmethyl [(1 S)-1 -[[[(1 S.2R)-3-[(2S)-4-[(3.4-di- methoxylphenyl)methyl1-2-[[(1 .1 -dimethylethyl)amino]carbonyl]-1 -piperazinyl]-2- hvdroxv-1 -(phenvlmethvnpropvl]amino]carbonvl]-2-methvlpropvl]carbamate.
• Example 12 N'-[(1 S;-1 -[[[(1 S.2R)-3-[(2SV2-[f.1 .1 -Dim8thylethyl)amino]carbonyl
• Example 13 N'-[(1 S)-1 -[[[(1 S.2RV3-[(2S)-2-fr(1 .1 -Dimethylethyl)amino]carbonyl]-4- (phenylmethyl)-1 -piperazinyl]-2-hydroxy-1 -(phenylmethyl)propyl]amino]car- bonyl]-2-methylpropyl]-N-methyl-N-[2-(1-methylethyl)-4-thiazolylmethyl]urea.
• Example 14 N'-r ⁇ SV1-rrr.1 S.2RV3-[r2SV2-rr(1.1-Dimethylethvnamino1carbonyl]-4-r.4-hv- droxy-3-methoxyphenv ⁇ methyl]-1 -piperazinyl]-2-hvdroxy-1 -(phenylmethv ⁇ - propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1 -methylethv ⁇ -4-thia- zolylmethyl]urea.
• the title compound was prepared according to the method described in Example 12C substituting 3-methoxy-4-hydroxybenzyl chloride in place of 5-thiazolylmethyl chloride.
• Example 15 2-Methyl-4-thiazolylmethyl-[(1 S)-1 -[[[(1 S.2R)-3-[(2SV4-(1 .3-benzodioxol-5- ylmethyl)-2-[[(1 .1 -dimethylethyl)amino]carbonyl]-1 -piperazinyl]-2-hydroxy-1 - (phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate. 15A.
• Example 16 2-Methyl-4-thiazolylmethyl-[(1 S)-1 -[[[(1 S.2R)-3-[(2S ) -4-f (3.4-dimethoxyl- phenyl)methyl]-2-[[(1 ,1 -dimethylethyl)amino]carbonyl]-1 -piperazinyl]-2-hydroxy- 1 -(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 17 2-Msthyl-4-thiazolylmethyl-[(1 S)-1 -[[[(1 S.2R 3-[(2S 2-[[ ⁇ .1 -dimethyl- ethvnamino]carbonvl]-4-r(4-fluorophenvnmethvl]-1 -piperazinvl]-2-hvdroxv-1 - (phenvlmethynpropvl]amino]carbonvl]-2-methvlpropvl]carbamate.
• Example 18 2-Ethyl-4-thiazolylmethyl-(1 S)-1 -FrFM S.2Rl-3-f.2S -r.3.4-dimethoxyl- Dhenv ⁇ methyl]-2-[[(1 .1 -dimethylethv0amino]carbonyl]-1 -piperazinyl]-2-hvdroxy- 1 -(phenylmethv ⁇ propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• the title compound was prepared by reacting 2-ethyl-4-thiazolylmethyl- (1 S)-1 -[[[(1 S,2R)-3-[(2S)-4-[1 ,1 -dimethylethyl-oxy(carbonyl)]-2-[[(1 ,1 -dimethyl- ethyl)amino]carbonyl]-1 -piperazinyl]-2-hydroxy-1 -(phenylmethyl)propyl]amino]- carbonyl]-2-methylpropyl]carbamate, 98 mg (0.16 mmol), with 3,4- dimethoxybenzyl chloride, 30 mg (0.18 mmol), according to the method described in Example 15(B).
• Example 19 2-(1 -Methylethvn-5-thiazolylmethyl-[(1 S)-1 -[[[(1 S.2R)-3-[.2S)-4-[(3.4-di- methoxylphenyl)methyl]-2-[[(1 ,1 -dimethylethyl)amino]carbonyl]-1 -piperazinyl]-2- hydroxy-1 -(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]carbamate.
• Example 21 2-Methyl-5-thiazolylmethyl-r ⁇ SH - ⁇ U S.2R)-3-[(2S)-4-[(3.4-dimethoxyl- phenyl)m9thyl1-2-[[(1 .1 -dimethylethyl)amino
• Example 22 N'-[(1 RH - ⁇ C ⁇ S.2R)-3-[f2S)-2-[[M .1 -Dimethylethvhamino]carbonyl]-4-f5-thia- zolylmethvi ⁇ -piperazinyl]-2-hvdroxy-1 - ⁇ 'phenylmethvhpropyl1amino1carbonyl]- 2-methvlpropvl]-N-methvl-N-(5-thiazolvlmethvnurea.
• Example 23 N'-fM SH -[[[ ( 1 S.2RK3-[ ( 2S)-2-[[M .1 -Dimethylethyl)amino]carbonyl]-4-(5- thiazolylmethyl)-1 -piperazinyl]-2-hvdroxy-1 -(phenylmethyl)propyl]amino]car- bonyl]-2-methylpropyl]-N-methyl-N-(5-thiazolylmethv ⁇ urea. 23A.
• Example 24 5-Thiazolylmethyl-[(1 SH -[[[ ( 1 S.2R ) -3-[(2S)-2-[[.1.1 -dimethylethyl)amino]car- bonyl]-4-( , phenylmethvi ⁇ -piperazinyl]-2-hvdroxy-1 - henylmethv ⁇ propyl]- amino]carbonyl]-2-m ⁇ thylpropyl]carbamat ⁇ .
• the title compound was prepared according to the method described in Example 24B, by akylation of 5-thiazolylmethyl-[(1 S)-1 -[[[(1 S,2R)-3-[(2S)-2- [[(1 ,1 -dimethylethyl)amino]carbonyl]-1 -piperazinyl]-2-hydroxy-1 -(phenylmethyl)- propyl]amino]carbonyl]-2-methylpropyl]carbamate with 5-thiazolyl methyl chloride in place of benzyl bromide.
• Example 26 N'-[ ⁇ s ⁇ -rrr(1 S.2RV3-frfn .1-Dimethylethvhamino]carbonyl](2-methylethvnpro- pvlamino1-2-hvdroxv-1 -(phenvlmethvnpropvl]amino]carbonyl]-2-methylpropyl]- N-m ⁇ thyl-N-[2-f1-m ⁇ thyl ⁇ thv ⁇ -4-thiazolylm ⁇ thyl]ur ⁇ a.
• Th ⁇ titl ⁇ compound was prepared according to the method described in Example 12A, by coupling N-methyl-N-[(((2-isopropyl-4-thia- zolyl)methyl)amino)-carbonyl]-L-valine with N-(3S-amino-2R-hydroxy-4-phenyl- butyl)-N-(2-methylpropyl)-N'-(1 ,1 -dimethylethyl)urea, prepared according to the method described in J. Med. Chem., 1993, 36, 288-291.
• the title compound was prepared according to th ⁇ m ⁇ thod d ⁇ scrib ⁇ d in Exampl ⁇ 26, by coupling N-[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L- valine with N-(3S-amino-2R-hydroxy-4-phenylbutyl)-N-(2-methylpropyl)-N'-(1 ,1 - dimethyiethyl)urea, prepared according to the method described in J. Med. Chem., 1993, 36, 288-291.
• the title compound was prepared in two steps. First, N-isobutyl-2(R)-hy- droxy-3(S)-amino-4-phenyl-(4'-nitrophenyl)sulfonamide, prepared according to the method described in J. Am. Chem. Soc, 1995, 117, 1181 -1182, was coupled with [(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine according to the method described in Example 1 C. This was followed by hydrogenation of the product over Pd/C under 1 atmosphere of hydrogen . The catalyst was removed via filtration over a celite pad and the solvent was evaporated at reduced pressure to provide the title compound as a white foam.
• Example 29 N'-[(1 SH -[[[(1 S.2R)-3-[[(4-Aminophenyl)sulfonyl](1 -methylethvnamino]-2-hy- droxy-1 -(phenylmethyl)propyl]amino]carbonyl]-2-methylpropyl]-N-methyl-N-[2- (1 -methylethyl)-4-thiazolylmethyl]urea.
• the title compound was prepared in two steps. First, N-isopropyl-2(R)- hydroxy-3(S)-amino-4-phenyl-(4'-nitrophenyl)sulfonamide was coupled with N- methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl]-L-valine according to the method described in Example 12A. This was followed by hydrogenation of the product over Pd/C under 1 atmosphere of hydrogen. The catalyst was removed via filtration over a celite pad and the solvent was evaporated at reduced pressure to provide the title compound as a white foam.
• Example 30 2-(1 -Methylethyl)-5-thiazolylmethyl-[(1 S)-1 -[[[(1 S.2R)-3-[(3S)-3-[[(1.1 -dimethyl- ethv ⁇ amino]carbonyl](4a ⁇ .8a ⁇ octahvdro-2-isoquinolinyl]-2-hvdroxy-1 - henvlmethvnpropvl]amino]carbonyl]-2-methylpropyl]carbamate.
• the title compound was prepared according to the method described in Example 1 C, by coupling 2-(3(S)-amino-2(r?)-hydroxy-4-phenylbutyl)-/V-ret - butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide with [(2-isopropyl-4- thiazolyl)methyloxycarbonyl]-L-valine, prepared according to the method described in J. Org Chem., 1994, 59, 3656-3664.
• Example 31 N'-[ ( 1 S ⁇ -r[[ ( 1 S.2R ) -3-[f3SV3-rr(1 .1 -Dimethylethvnamino]carbonyl](4a ⁇ .8a )- octahydro-2-isoquinolinyl]-2-hvdroxy-1 -(phenylmethyl)propyl]amino]carbonyl]- 2-m ⁇ thylpropyl]-N-methyl-N-[2-f1 -methylethylV5-thiazolylmethyl]urea.
• Example 12A The title compound was synthesized according to the method described in Example 12A by coupling of 2-(3(S)-amino-2(/?)-hydroxy-4-phenylbutyl)-N- ret -butyldecahydro-(4aS,8aS)-isoquinoline-3(S)-carboxamide with N-methyl- N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl]-L-valine which was prepared according to the method described in J. Org Chem., 1994, 59, 3656- 3664.
• Example 32 N'-[.1 SH 417(1 S.2 -3-K2S.4m-2-ff ⁇ .1 -Dimethylethvhamino]carbonyl]-4-f5- thiazolylmethoxy ⁇ -piperidinyl]-2-hvdroxy-1 -fphenylmethvhpropyl]amino]- carbonyl]-2-methylpropyl]-N-methyl-N-[2-(1 -methylethyl)-4-thiazolyimethyl]urea.
• the title compound is prepared according to the procedure described in example 32C using N-[(2-isopropyl-4-thiazolyl)methyloxycarbonyl]-L-valine in place of N-methyl-N-[(((2-isopropyl-4-thiazolyl)methyl)amino)carbonyl]-L-valine as a coupling reagent.
• a solution of product, prepared in Example 34C in dioxane is treated with 0.50 M aqueous LiOH.
• the resulting solution is stirred at ambient temperature for about 30 minutes, treated with 1 M HCI, and concentrated in vacuo.
• the residue is taken up in dichloromethane, washed with water, dried over Na2S04, and concentrated in vacuo to provide the title compound.
• a solution of product, prepared in Example 35C in dioxane is treated with 0.50 M aqueous LiOH.
• the resulting solution is stirred at ambient temperature for about 30 minutes, treated with 8.7 ml of 1 M HCI, and concentrated in vacuo.
• the residue is taken up in dichloromethane, washed with water, dried over Na2S ⁇ 4, and concentrated in vacuo to provide the title compound.
• the inhibitory potency of the compounds of the invention can be determined by the following method:
• a compound of the invention is dissolved in DMSO.
• a small aliquot is diluted with DMSO to 100 times the final concentration desired for testing.
• the test is carried out in a 6 X 50 mm tube in a total volume of 300 microliters.
• the final concentrations of the components in the reaction buffer are: 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 reaction mixture is placed in the fluorometer cell holder and incubated at 30°C for several minutes.
• the reaction is initiated by the addition of a small aliquot of cold HIV protease.
• 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 inhibitor)/(rate in absence of inhibitor)).
• Table 1 shows the inhibitory potencies of compounds of the invention against HIV-1 protease.
• the anti-HIV activity of the compounds of the invention can be determined in MT4 cells according to the procedure of Kempf, et. al. (Antimicrob. Agents Chemother. 1991 , 35, 2209).
• the IC50 is the concentration of compound that gives 50% inhibition of the cytopathic effect of HIV.
• the LC50 is the concentration of compound at which 50% of the cells remain viable.
• 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, pect
• the basic nitrogen-containing groups can be quaternized with such agents as lower alkyl halides, such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides; dialkyl 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.
• lower alkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
• dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates
• long chain halides such
• acids which may be employed to form pharmaceutically acceptable acid addition salts include such inorganic acids as hydrochloric acid, sulfuric 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.
• esters examples include a hydroxyl-substituted compound of formula I or II which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, a hemisuccinate residue, an acyl residue of the formula R 14 C(0)- or R 14 C(S)- wherein R 14 is hydrogen, lower alkyl, haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl or haloalkoxy, or an acyl residue of the formula R a -C(R b )(R d )-C(0)- or Ra-C(R b )(R d )-C(S)- wherein Rb and Rd are independently selected from hydrogen or lower alkyl and R a is -N(R e )(R f ), OR e or -SR e wherein R e and
• 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)CH 2 NR 16 R 17 wherein R 16 and R 17 are independently selected from hydrogen and lower alkyl, or the group -NR 16 R 17 , where R 16 R 17 , taken together, forms a nitrogen containing heterocyclic ring.
• These esters serve as pro-drugs of the compounds 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 compounds.
• prodrugs include a hydroxyl-substituted compound of formula I or II wherein the hydroxyl group is functionalized with a substituent of the formula -CH(R 1 8)OC(0)R 1 9 or -CH(R 18 )OC(S)R 19 wherein R19 is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxy and R 18 is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl, aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl.
• 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 hydroxyl-substituted compound of formula I or II .
• the preparation of the prodrug esters is carried out by reacting a hydroxyl-substituted compound of formula I or II 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 (halo)alkyl esters, transacetalization with bis- (alkanoyl)acetals or condensation of the hydroxyl group with an activated aldehyde followed by acylation of the intermediate hemiacetal.
• 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 10 mg. 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 acceptable and metabolizable lipid capable of forming liposomes can be used.
• the present compositions in liposome form can contain, in addition to a compound of the present invention, stabilizers, preservatives, excipients, and the like.
• the preferred lipids are the phospholipids and phosphatidyl cholines (lecithins), both natural and synthetic.
• 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), dideoxyinosine (DDI), BCH-189, AzdU, carbovir, DDA, D4C, D4T, DP-AZT, FLT (fluorothymidine), BCH-189, 5-halo-3'-thia- dideoxycytidine, PMEA, zidovudine (AZT) and the like), non-nucleoside reverse transcriptase inhibitors (for example, R82193, L-697,661 , BI-RG-587 (nevirapine), DMP-266, and the like) retroviral protease inhibitors (for example, R82193, L-697,661 , BI-RG-587 (nevirapine), DMP-266, and the like) retroviral protease inhibitors (for
• Immunomodulators that can be administered in combination with a 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-t peptide, TP-5, erythropoietin, naltrexone, tumor necrosis facator, beta interferon, gamma interferon, interleukin-3, interleukin-4, autologous CD8+ infusion, alpha interferon immunoglobulin, IGF-1 , anti-Leu-3A, autovaccination, biostimulation, extracorporeal photophoresis, FK-565, FK-506, G-CSF, GM-CSF, hyperthermia, isopinosine, IVIG
• pentamidine isethionate Any of a variety of HIV or AIDS vaccines (for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant), VaxSyn HIV-1 (p24) can be used in combination with a compound of the present invention.
• HIV or AIDS vaccines for example, gp120 (recombinant), Env 2-3 (gp120), HIVAC-1 e (gp120), gp160 (recombinant), VaxSyn HIV-1 (gp160), Immuno-Ag (gp160), HGP-30, HIV-lmmunogen, p24 (recombinant),
• agents that can be used in combination with the compounds 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 compounds of this invention are antifungals such as amphote cin B, clotrimazole, flucytosine, fluconazole, itraconazole, ketoconazole and nystatin and the like.
• agents that can be used in combination with the compounds of this invention are antibacterials such as amikacin sulfate, azithromycin, ciprofloxacin, tosufloxacin, clarithromycin, clofazimine, ethambutol, isoniazid, pyrazinamide, rifabutin, fampin, 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, 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, bleomycin
• agents that can be used in combination with the compounds 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 compounds 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
• agents for treatment of HIV or AIDS in combination with the compounds of this invention are reverse transcriptase inhibitors and other HIV protease inhibitors. It will be understood that agents which can be combined with the compounds of the present invention for the 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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