WO1992016501A1 - Derives de tetrahydroxyalcane utiles comme inhibiteurs de la protease d'aspartyle du vih - Google Patents

Derives de tetrahydroxyalcane utiles comme inhibiteurs de la protease d'aspartyle du vih Download PDF

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WO1992016501A1
WO1992016501A1 PCT/US1992/002290 US9202290W WO9216501A1 WO 1992016501 A1 WO1992016501 A1 WO 1992016501A1 US 9202290 W US9202290 W US 9202290W WO 9216501 A1 WO9216501 A1 WO 9216501A1
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mmol
compound
straight
substituted
solution
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PCT/US1992/002290
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Roger D. Tung
David D. Deininger
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Vertex Pharmaceuticals Incorporated
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Publication of WO1992016501A1 publication Critical patent/WO1992016501A1/fr

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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
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    • C07C233/82—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/83—Carboxylic acid amides having carbon atoms of carboxamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom of an acyclic saturated carbon skeleton
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    • C07C235/12—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton being acyclic and saturated having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
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    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom 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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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems 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 carbon atoms of the nitrogen-containing ring
    • C07D217/26—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • C—CHEMISTRY; METALLURGY
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    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more 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, directly attached to ring carbon atoms
    • C07D239/32—One oxygen, sulfur or nitrogen atom
    • C07D239/38—One sulfur atom
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/36—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems
    • C07D241/38—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings condensed with carbocyclic rings or ring systems with only hydrogen or carbon atoms directly attached to the ring nitrogen atoms
    • C07D241/40—Benzopyrazines
    • C07D241/44—Benzopyrazines 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 carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
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    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three 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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    • C07D307/77—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D307/78—Benzo [b] furans; Hydrogenated benzo [b] furans
    • C07D307/82—Benzo [b] furans; Hydrogenated benzo [b] furans 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 carbon atoms of the hetero ring
    • C07D307/84—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D317/08—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3
    • C07D317/10—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms having the hetero atoms in positions 1 and 3 not condensed with other rings
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    • C07D317/48—Methylenedioxybenzenes or hydrogenated methylenedioxybenzenes, unsubstituted on the hetero ring
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    • C07C2601/10—Systems containing only non-condensed rings with a five-membered ring the ring being unsaturated

Definitions

  • HIV infection is known to manifest as a variety of diseases resulting from opportunistic infections
  • CD4+ macrophages and monocytes are known to act as a reservoir for the HIV virus and may be responsible for direct neural cytotoxicity (J. of NIH Res. 3:23-25
  • agents which interrupt the life cycle of the HIV virus can be used to treat AIDS-related complex (ARC), AIDS related dementia, and non-symptomatic HIV infection.
  • ARC AIDS-related complex
  • AIDS related dementia AIDS related dementia
  • non-symptomatic HIV infection ARC-related complex
  • anti-viral compounds have been synthesized that are designed to target various stages in the replication cycle of HIV. These include compounds that block viral attachment to CD4-positive T lymphocytes (e.g., sT4 soluble CD4), inhibit reverse transcription (e.g., zidovudine; AZT), and inhibit integration of viral DNA into cellular DNA. These compounds, however, are directed primarily to early stages of viral replication and do not block the production of infectious virions in chronically infected cells.
  • CD4-positive T lymphocytes e.g., sT4 soluble CD4
  • reverse transcription e.g., zidovudine; AZT
  • AZT zidovudine
  • This invention relates to a novel class of glycolic compounds which are potent inhibitors of the HIV aspartyl protease, as well as to therapeutic methods for inhibiting protease activity in certain aspartyl protease viruses.
  • the compounds comprise a linear backbone having four contiguous oxygen-substituted methine carbons.
  • compounds of this invention inhibit the ability of aspartyl protease from HIV to catalyze the hydrolysis of peptides.
  • These novel compounds can be used to reduce production of infectious virions from chronically infected cells and can inhibit the further infection of host cells. As such, they are useful as therapeutic agents to treat acquired immunodeficiency syndrome (AIDS), as well as AIDS-related complex (ARC), AIDS-related dementia, and non-symptomatic HIV infection.
  • AIDS acquired immunodeficiency syndrome
  • ARC AIDS-related complex
  • dementia non-symptomatic HIV infection.
  • This invention relates to a novel class of HIV aspartyl protease inhibitors which contain a linear backbone having four continguous oxygen-substituted methine carbon. These compounds are derivatives of n, n+1, n+2, n+3 - tetrahydroxyalkanes or n, n+1,
  • A is hydrogen, (C1-C4) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, phenyl, azide, hydroxyl, NH-L, O-L, CH 2 -NH-L, CH 2 -0-L,
  • L is Ar-carbonyl, Ar-oxycarbonyl or (C1-C2)-alkoxycarbonyl which may be substituted with an Ar group; wherein Ar is a benzofused heterocycle with 1-2 heteroatoms independently chosen from O, N or S;
  • morpholino phenyl, 2-naphthyl, 9-fluorenyl, 1-benzotriazole or phenyl substituted with 1-3 substituents independently selected from the group consisting of cyano, hydroxyl, amino, dimethylamino, methoxy,
  • B is H, (C1-C5) -straight or branched alkyl, (C2-C4)-straight or branched alkenyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-furyl, 3-furyl, 2-thienyl,
  • D is hydrogen or oxygen
  • E and E' are independently (C1-C2) -alkyl or C2-alkenyl;
  • G and G' are independently (C1-C4) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, (C5-C6) -cycloalkyl, (C5-C6) -cycloalkenyl, 2-furyl,
  • K is (C1-C8) -straight or branched alkane which may be substituted with one or two Ar groups,
  • A, B and D are independently selected from the groups recited above.
  • the stereochemistry at positions 1 and 2, and at the methine of K, if present, may be either (R) or (S), where (S) is preferred.
  • the stereochemistry at positions 3 may be (R) or (S).
  • the compounds will have a molecular weight from about 450 to about 1100 atomic mass units (a.m.u.) and most preferably below about 950 a.m.u.
  • B is H (C1-C5) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, (C5-C6)-cycloalkyl, (C5-C6)-cycloalkenyl, 2-furyl, 3-furyl, 2-thienyl,
  • Z is hydrogen, (C1-C4) -straight or branched alkyl, (C2-C4) -straight or branched alkenyl, phenyl, Ar-substituted (C1-C4) -straight or branched alkyl,
  • the compounds of the present invention can be used in the form of salts derived from inorganic or organic acids. Included among such acid salts are the following: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate, pectinate, persulfate, 3-phenylpropionat
  • 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.
  • the novel compounds can be synthesized using known techniques.
  • the novel compounds can be synthesized by derivatization of a precursor containing a vicinal diol or protected vicinal diol moiety, as described in the Example Section.
  • the glycols can be produced by oxidation of a precursor containing an alkene group using, for example, osmium tetraoxide either alone or catalytically with another oxidizing reagent such as 4-methyl morpholine-4-oxide (VanRheenen, V. et al., Tetrahedron Lett., 1973-1976 (1976); Evans, D.A. and S.W. Kaldor, J. Org. Chem., 55: 1698-1700 (1990)).
  • This reaction may be carried out in the presence of various ligands to promote asymmetric reaction (Wai, J.S.M. et al., J. Am. Chem.
  • novel compounds of the present invention are excellent ligands for aspartyl proteases, particularly HIV-1 and HIV-2 proteases. These compounds are designed to target and inhibit late stage events in HIV replication, i.e., the processing of the viral polyproteins by HIV encoded proteases.
  • the compounds inhibit the proteolytic processing of viral polyprotein precursors by inhibiting aspartyl protease. Since aspartyl protease is essential for production of mature virions, inhibition of this process can thereby block virus spreading by inhibiting the production of infectious virions, particularly from chronically infected mammalian cells.
  • novel protease inhibitors can be administered as a therapeutic agent for treating AIDS.
  • Table 3 summarizes the inhibition constants of the compounds listed in Table 1 against the isolated enzyme (K i ), as well as for prevention of viral spread in human T cells (IC 50 ). The inhibition constants of these compounds against HIV-1 protease can be obtained
  • T-lymphocytes H9 cells by HIV-1 virus, (HTLV-IIIb isolate)
  • HIV-1 virus HIV-1 virus
  • HTLV-IIIb isolate HIV-1 virus
  • anti-viral agents which interfere with the replication cycle of HIV can be administered to the patient as a method of potentiating the therapeutic effect of these compounds by targeting other events in the viral life cycle.
  • the co-administered anti-viral agent can be one which targets early events in the life cycle of the virus, such as cell entry, reverse transcription and viral DNA integration into cellular DNA.
  • anti-HIV agents include, zidovudine (AZT), polysulfated polysaccharides, sT4
  • soluble CD4 which blocks attachment or adsorption of the virus to host cells and other compounds which block binding of virus to CD4 receptors on CD4 bearing T-lymphocytes.
  • retroviral reverse transcriptase inhibitors such as derivatives of AZT, can also be co-administered with the compounds of this invention to provide therapeutic treatment for substantially reducing or eliminating viral infectivity and the symptoms associated therewith.
  • non-nucleoside inhibitors of reverse transcriptase such as TIBO or Neurapine may be used to potentiate the effect of these compounds, as may viral uncoating inhibitors, inhibitors of trans-activating proteins such as tat or rev, or inhibitors of the viral integrase. These compounds may also be co-administered with other inhibitors of the HIV aspartyl protease to increase the effect of the therapy against various viral mutants or members of other HIV quesi species.
  • the compounds of this invention can also be used as inhibitory agents for other viruses which depend on
  • the compounds of the present invention may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir in dosage formulations containing conventional non-toxic pharmaceutically-acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intrasternal and intracranial injection or infusion techniques.
  • compositions may be in the form of a sterile injectable preparation, for example as a sterile injectible aqueous or oleagenous suspension.
  • This suspension may be formulated according to techniques known in the 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 non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3-butanediol.
  • 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
  • any bland fixed oil may be employed including synthetic mono- or di-glycerides.
  • Fatty acids such as oleic acid and its glyceride derivatives find use in the preparation of injectables, as do natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • oils such as olive oil or castor oil, especially in their polyoxyethylated versions.
  • These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant such as Ph. Helv or similar alcohol.
  • the compounds may be administered orally, in the form of capsules or tablets, for example, or as an aqueous suspension or solution.
  • carriers which are commonly used include lactose and corn starch.
  • Lubricating agents, such as magnesium stearate, are also typically added.
  • useful diluents include lactose and dried corn starch.
  • aqueous suspensions are required for oral use, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and/or flavoring and/or coloring agents may be added.
  • compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • Such materials include cocoa
  • the compounds of this invention may also be admini- stered topically, especially when the conditions
  • the compounds can be formulated in a suitable ointment containing the compound suspended or dissolved in, for example, a
  • the compounds can be formulated in a suitable lotion or cream containing the active compound suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil.
  • Topical application for the lower intestinal tract can be effected in a rectal suppository formulation (see above) or in a suitable enema formulation.
  • Dosage levels on the order of 0.01 - 25 mg/kg per day of the active ingredient compound are useful in the treatment of the above conditions.
  • the amount of active ingredient that may be combined with the carrier is useful in the treatment of the above conditions.
  • Thick layer silica gel chromatography is also carried out using E.Merck 60 F 254 plates of 0.5, 1.0, or 2.0 mm. Detection of the compounds is carried out by treating the plate with a 10% solution of phosphomolybdic acid in ethanol followed by heating, and/or by exposure to UV light when appropriate. Thick layer silica gel chromatography is also carried out using E.Merck 60 F 254 plates of 0.5, 1.0, or 2.0 mm. Isolation of the compound is carried out by isolation of the band of silica containing the desired material, followed by elution with an appropriate solvent and concentration in vacuo.
  • Analytical HPLC is carried out using a Water Delta Pak, 5 ⁇ M silica, C18 reversed-phase column, 3.9 mm ID ⁇ 15 cm L with a flow rate of 1.5 mL/min.
  • Preparative HPLC is carried out using a Water Associates 15 ⁇ M silica, C18 reversed-phase RCM column, 25 mm ID ⁇ 10 cm L, with a flow rate of 8 mL/rnin.
  • NMR spectral data is recorded using a Bruker AMX500, equipped with either a reverse or QNP probe, at 500 MHz, and is taken in deuterochloroform or dimethylsulfoxide as solvent. Tetramethylsilane was used as an internal standard except where noted.
  • Example 1 A 4(S),5(S)-bis-((1'S)-1'-hydroxy-2'-phenylethyI)-2,2-dimethyl-1,3- dioxolane.
  • dichoromethane and filtered, washing the filter pad with additional dichloromethane.
  • Example 2 4(R),5(R)-bis-(1'(S)-((S)-N-(9-nuorenylmethoxycarbon yl)-vaIyloxy)-2'-phenylethyl))-2,2-dimethyl-1,3-dioxolane.
  • a solution of 42.4 mg (0.125 mmol) of the resultant compound of example 1A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 190 mg (0.56 mmol) of N-9-Flourenylmethoxycarbonyl-L-valine, 57.2 mg (0.3 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
  • dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 23 mg (0.092 mmol) of N-carbobenzyloxy-L-valine, 21 mg (0.107 mmol) of 1-(3-dim ethylami nopropyl)-3-ethylcarbodiimide hydrochloride, and 1 mg (0.005 mmol) of 4-pyrroIidinopyridine.
  • the rnixture was stirred for 3 days, then concentrated in vacuo to a small volume of several hundred microliters. This residue was purified by thick layer silica gel chromatography using system C chloride as eluant.
  • dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 21.0 mg ( 0.12 mmol) of quinaldic acid, 0.024 mL (0.14 mmol) diisoproplyethylamine, 8.0 mg (0.06 mmol) of 1-hydroxybenzotriazole hydrate, and 17.3 mg (0.075 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred for 48 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHCO 3 solution, saturated NaCl then dried over MgSO 4 , filtered and concentrated in vacuo.
  • Example 13 A 4(R),5(R)-bis-(1'(S)-((S)-N ⁇ -tri phenylmethyl-N ⁇ -benzyloxycarbonyl-aspari ginyIoxy)-2'-phenylethyl))-2,2-dimethyl-1,3-dioxolane.
  • dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 16.2 mg (0.094 mmol) of quinaldic acid, 0.018 mL (0.106 mmol) diisoproplyethylamine, 9.5 mg (0.071 mmol) of 1- hydroxybenzotriazole hydrate, and 13.5 mg (0.071 mmol) of 1-(3- dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. The mixture was stirred 60 h and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with water, saturated NaHCO 3 solution, saturated NaCl then dried over MgSO 4 , filtered and concentrated in vacuo.
  • Example 16 A (2S ,3 R ,4 R,5S ) -3,4 -d i hyd roxy-2,5-b is -( S )-va lyloxy- 1 ,6-diphenylhexane.
  • a solution of 96.0 mg (0.187 mmol) of the resultant compound of example 1C in tetrahydrofuran was added, at ambient
  • A. (3-(4S))-Cyclopentylacetyl-4-phenylmethyl-2-oxazolidinone A solution of 2.01 g mg (16.0 mmol) of cyclopentylacetic acid in 8 mL of methylene chloride was cooled to 0° and treated with 2.79 mL (32.0 mmol) of oxalyl chloride, followed by 40 ⁇ L (0.5 mmol) of dirnethylformamide. The mixture was stirred for 40 min and concentrated in vacuo; the resulting yellow residue was taken up in methylene chloride and again evaporated.
  • reaction mixture was stirred for 1.5 min in the cold, then quenched with 2.62 mL (46.0 mmol) of acetic acid. This mixture was removed from the cold bath and allowed to warm to ambient temperature, then concentrated in vacuo. The residue was partitioned between a mixture of 3: 1 (diethyl ether/methylene chloride) and half-saturated brine. The organic layer was separated and washed with saturated sodium bicarbonate, then brine, then dried over magnesium sulfate and concentrated to yield a yellow oil.
  • Example 18 A Compound 18.
  • a solution of 7.1 mg (0.014 mmol) of the resultant compound of example 16A in dichloromethane was treated sequentially, at ambient temperature under an atmosphere of nitrogen, with 5.4 mg (0.032 mmol) of piperonylic acid, 0.006 mL (0.035 mmol) diisoproplyemylamine, 4.0 mg (0.03 mmol) of 1-hydroxybenzotriazole hydrate, 5.7 mg (0.03 mmol) 1-(3-dimethylam ⁇ inopropyl)-3-ethylcarbodiimide
  • Example 19 A (4 R,5 S )- b i s - [ ( 1 S ) - N-ca r bo b en zyl oxyisol eu cyI oxy -2 -phen ethyl ]-2,2-di m et hyl - 1,3-d ioxolane.
  • To the resulting compound of example 1A (239 mg. 0.70 mmol) in CH 2 CI 2 (5 ml) was added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (535 mg, 2.80 mmol), carbobenzyloxy isoleucine (741 mg, 2.80 mmol), and
  • Example 20 A Compound 20.
  • a 13 mg (0.018 mmol) sample of the resultant compound of example 17F was deprotected as indicated in example 6B.
  • a white foam was obtained which was purified by thick layer silica gel chromatography using 4% isopropanol/ methylene chloride as eluant Isolation of the major product band yielded 2.8 mg of white solid.
  • Example 21 Example 21
  • Example 28 A Compound 28. To the resulting compound of example 27B (4.3 mg, 5.53 ⁇ mol) in CH 2 CI 2 (2 ml) was mixed with 1-(3-dimethylaminopropyl)-3- ethylcarbodiimide hydrochloride (4.6 mg, 24.4 ⁇ mol), 1-hydroxybenzotriazole hydrate (4 mg, 24.4 ⁇ mol), 2-pyrimidylthioacetic acid (4 mg, 22.2 ⁇ mol), and diisopropylethylamine (2 ⁇ l, 11.1 ⁇ mol).
  • Example 29 A (4R,5R)-4-((1'S)-1'-((S)-N-Carbobenzyloxvalyloxy)-2'-phenylethyl)- 5-(1 "(S)-((S)-N-Carbobenzyloxaminocyclopentylacetoxy)-2"- phenylethyI)-2,2-dimethyl-1,3-dioxoIane.
  • Example 30 A Compound 30.
  • the resulting compound of example 27B (31 mg, 0.04 mmol) in CH 2 CI 2 (2 ml) was mixed with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (69 mg, 0.36 mmol), 1-hydroxybenzotriazole hydrate (48 mg, 0.36 mmol), 4-hydroxy-3-methoxycinnamic acid (69 mg, 0.36 mmol). and diisopropylethylamine (21 ⁇ l, 0.12 mmol).
  • Example 36 (4R,5S)-4-[(1'S)-N-carbobenzyloxyisoleucyloxy-2'-phenethyl)-5-((1"S)-acetoxy-2 , '-phenethyl)]-2,2-di ⁇ nethyl-1,3-dioxolane.
  • pyridine 15 ul, 0.19 mmol
  • acetyl chloride 12 ul, 0.17 mmol
  • A. f-Butyldimethylsiloxyphenylacetic acid The title compound was prepared in two steps as follows: 1) To a solution of 2-hydroxyphenylacetic acid (137 mg, 0.9 mmol) in DMF (5 ml) was added imidazole (184 mg, 2.7 mmol) and r-butyldimethylsilyl chloride (407 mg, 2.7 mmol), and the reaction stirred at ambient temperature overnight. Dilution with EtOAc, followed by washing of the organic layer with saturated NH4CI and water (2x), provided, after drying over MgSO4. filtration and concentration, the bis-silylated hydroxy acid as a pale yellow oil which was used in the subsequent reaction without purification.

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Abstract

Une classe nouvelle de composés glycoliques contient un squelette linéaire avec quatre carbones adjacents du groupe méthine substitués par l'oxygène. Ces composés inhibent la capacité de la protéase d'aspartyle du VIH de catalyser l'hydrolyse de peptides. On peut utiliser ces nouveaux composés afin de réduire la production de virions infectieux par des cellules chroniquement infectées, ce qui permet d'inhiber l'infection de nouvelles cellules-hôtes. Ces composés sont ainsi utiles comme agents thérapeutiques du syndrom d'immunodéficience acquise (SIDA), ainsi que du para-sida, de la démence associée au SIDA et de l'infection asymptomatique par le VIH.
PCT/US1992/002290 1991-03-20 1992-03-20 Derives de tetrahydroxyalcane utiles comme inhibiteurs de la protease d'aspartyle du vih WO1992016501A1 (fr)

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WO1994013629A1 (fr) * 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Derives de mannitol et leur utilisation comme inhibiteurs de l'aspartyle-protease
US5696135A (en) * 1995-06-07 1997-12-09 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth
US5786378A (en) * 1996-09-25 1998-07-28 Gpi Nil Holdings, Inc. Heterocyclic thioesters
US5795908A (en) * 1995-06-07 1998-08-18 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US5798355A (en) * 1995-06-07 1998-08-25 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity
US5801187A (en) * 1996-09-25 1998-09-01 Gpi-Nil Holdings, Inc. Heterocyclic esters and amides
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US5804559A (en) * 1993-03-13 1998-09-08 Hoechst Aktiengesellschaft Prodrug derivatives of enzyme inhibitors having hydroxyl groups, a process for preparing them, and their use
US5846981A (en) * 1993-05-28 1998-12-08 Gpi Nil Holdings Inc. Inhibitors of rotamase enzyme activity
US6004993A (en) * 1997-06-04 1999-12-21 Gpi Nil Holdings, Inc. N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses
US6172087B1 (en) 1998-06-03 2001-01-09 Gpi Nil Holding, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6187784B1 (en) 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Pipecolic acid derivative hair growth compositions and uses
US6187796B1 (en) 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Sulfone hair growth compositions and uses
US6218424B1 (en) 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
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US6251892B1 (en) 1997-02-28 2001-06-26 Gpi Nil Holdings, Inc. N-oxides of heterocyclic esters, amides, thioesters, and ketones
US6271244B1 (en) 1998-06-03 2001-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6274602B1 (en) 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US6274617B1 (en) 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
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US6333340B1 (en) 1998-08-14 2001-12-25 Gpi Nil Holdings, Inc. Small molecule sulfonamides for vision and memory disorders
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WO1994013629A1 (fr) * 1992-12-11 1994-06-23 Vertex Pharmaceuticals Incorporated Derives de mannitol et leur utilisation comme inhibiteurs de l'aspartyle-protease
US5804559A (en) * 1993-03-13 1998-09-08 Hoechst Aktiengesellschaft Prodrug derivatives of enzyme inhibitors having hydroxyl groups, a process for preparing them, and their use
US5846981A (en) * 1993-05-28 1998-12-08 Gpi Nil Holdings Inc. Inhibitors of rotamase enzyme activity
US6140357A (en) * 1995-06-07 2000-10-31 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US7652060B2 (en) 1995-06-07 2010-01-26 Glia Med, Inc Small molecule rotamase enzyme inhibitors
US6500843B2 (en) 1995-06-07 2002-12-31 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity
US5795908A (en) * 1995-06-07 1998-08-18 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US5843960A (en) * 1995-06-07 1998-12-01 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity
US5859031A (en) * 1995-06-07 1999-01-12 Gpi Nil Holdings, Inc. Small molecule inhibitors of rotamase enzyme activity
US5696135A (en) * 1995-06-07 1997-12-09 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity effective at stimulating neuronal growth
US5798355A (en) * 1995-06-07 1998-08-25 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity
US6022878A (en) * 1995-06-07 2000-02-08 Gpi Nil Holdings, Inc. Inhibitors of rotamase enzyme activity
US7282510B2 (en) 1995-06-07 2007-10-16 Gliamed, Inc. Small molecule inhibitors of rotamase enzyme activity
US7960570B2 (en) 1995-06-07 2011-06-14 Gliamed, Inc. Small molecule inhibitors of rotamase enzyme activity
US5801197A (en) * 1995-10-31 1998-09-01 Gpi Nil Holdings, Inc. Rotamase enzyme activity inhibitors
BG64457B1 (bg) * 1996-03-22 2005-03-31 Glaxo Group Limited Фармацевтична форма за орално приложение, съдържаща hiv протеазен инхибитор
US6200972B1 (en) 1996-09-25 2001-03-13 Gpi Nil Holdings, Inc. Heterocyclic esters and amides
US6218424B1 (en) 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US5801187A (en) * 1996-09-25 1998-09-01 Gpi-Nil Holdings, Inc. Heterocyclic esters and amides
US6417209B2 (en) 1996-09-25 2002-07-09 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US5786378A (en) * 1996-09-25 1998-07-28 Gpi Nil Holdings, Inc. Heterocyclic thioesters
US5990131A (en) * 1996-09-25 1999-11-23 Gpi Nil Holdings Inc. Heterocyclic thioesters and ketones
US6984639B2 (en) 1996-09-25 2006-01-10 Gpi Nil Holdings, Inc. Heterocyclic ketone and thioester compounds and uses
US6218544B1 (en) 1996-09-25 2001-04-17 Gpi Nil Holdings, Inc. Heterocyclic esters and amides
US6251892B1 (en) 1997-02-28 2001-06-26 Gpi Nil Holdings, Inc. N-oxides of heterocyclic esters, amides, thioesters, and ketones
US6486151B2 (en) 1997-02-28 2002-11-26 Gpi Nil Holdings Inc. N-oxides of heterocyclic esters, amides, thioesters, and ketones
US6004993A (en) * 1997-06-04 1999-12-21 Gpi Nil Holdings, Inc. N-linked sulfonamide of heterocyclic thioester hair growth compounds and uses
US6177455B1 (en) 1997-06-04 2001-01-23 Gpi Nil Holdings, Inc. Pyrrolidine derivative hair growth compositions and uses
US6194440B1 (en) 1997-06-04 2001-02-27 Gpi Nil Holdings, Inc. Small molecule carbamate or urea hair growth compositions and uses
US6191125B1 (en) 1997-06-04 2001-02-20 Gpi Nil Holdings, Inc. Small molecule pipecolic acid derivative hair growth compositions and uses
US6187806B1 (en) 1997-06-04 2001-02-13 Gpi Nil Holdings N-linked sulfone of heterocyclic thioester hair growth compositions and uses
US6271244B1 (en) 1998-06-03 2001-08-07 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioester hair growth compositions and uses
US6429215B1 (en) 1998-06-03 2002-08-06 Gpi Nil Holdings, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6172087B1 (en) 1998-06-03 2001-01-09 Gpi Nil Holding, Inc. N-oxide of heterocyclic ester, amide, thioester, or ketone hair growth compositions and uses
US6187784B1 (en) 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Pipecolic acid derivative hair growth compositions and uses
US6187796B1 (en) 1998-06-03 2001-02-13 Gpi Nil Holdings, Inc. Sulfone hair growth compositions and uses
US6274602B1 (en) 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic thioester and ketone hair growth compositions and uses
US6274617B1 (en) 1998-06-03 2001-08-14 Gpi Nil Holdings, Inc. Heterocyclic ester and amide hair growth compositions and uses
US6218423B1 (en) 1998-08-14 2001-04-17 Gpi Nil Holdings, Inc. Pyrrolidine derivatives for vision and memory disorders
US7338976B1 (en) 1998-08-14 2008-03-04 Gpi Nil Holdings, Inc. Heterocyclic esters or amides for vision and memory disorders
US6333340B1 (en) 1998-08-14 2001-12-25 Gpi Nil Holdings, Inc. Small molecule sulfonamides for vision and memory disorders
US6395758B1 (en) 1998-08-14 2002-05-28 Gpi Nil Holdings, Inc. Small molecule carbamates or ureas for vision and memory disorders
US6399648B1 (en) 1998-08-14 2002-06-04 Gpi Nil Holdings, Inc. N-oxides of heterocyclic ester, amide, thioester, or ketone for vision and memory disorders
US6337340B1 (en) 1998-08-14 2002-01-08 Gpi Nil Holdings, Inc. Carboxylic acids and isosteres of heterocyclic ring compounds having multiple heteroatoms for vision and memory disorders
US6384056B1 (en) 1998-08-14 2002-05-07 Gpi Nil Holdings, Inc. Heterocyclic thioesters or ketones for vision and memory disorders
US6506788B1 (en) 1998-08-14 2003-01-14 Gpi Nil Holdings, Inc. N-linked urea or carbamate of heterocyclic thioesters for vision and memory disorders
US6376517B1 (en) 1998-08-14 2002-04-23 Gpi Nil Holdings, Inc. Pipecolic acid derivatives for vision and memory disorders
US6335348B1 (en) 1998-08-14 2002-01-01 Gpi Nil Holdings, Inc. Nitrogen-containing linear and azepinyl/ compositions and uses for vision and memory disorders
US6339101B1 (en) 1998-08-14 2002-01-15 Gpi Nil Holdings, Inc. N-linked sulfonamides of N-heterocyclic carboxylic acids or isosteres for vision and memory disorders
US6462072B1 (en) 1998-09-21 2002-10-08 Gpi Nil Holdings, Inc. Cyclic ester or amide derivatives
US6362165B1 (en) 1999-03-30 2002-03-26 Pharmacor Inc. Hydroxyphenyl derivatives with HIV integrase inhibitory properties
US6313177B1 (en) 1999-04-30 2001-11-06 Pharmacor Inc. D-mannitol derivatives as HIV aspartyl protease inhibitors
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