EP0415981A1 - Inhibiteurs de protease retrovirale - Google Patents

Inhibiteurs de protease retrovirale

Info

Publication number
EP0415981A1
EP0415981A1 EP89905856A EP89905856A EP0415981A1 EP 0415981 A1 EP0415981 A1 EP 0415981A1 EP 89905856 A EP89905856 A EP 89905856A EP 89905856 A EP89905856 A EP 89905856A EP 0415981 A1 EP0415981 A1 EP 0415981A1
Authority
EP
European Patent Office
Prior art keywords
loweralkyl
amino
alkyl
mmol
substituted
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP89905856A
Other languages
German (de)
English (en)
Other versions
EP0415981A4 (en
Inventor
Dale J. Kempf
Jacob J. Plattner
Daniel W. Norbeck
Steven A. Boyd
William R. Baker
John W. Erickson
Anthony K. L. Fung
Steven R. Crowley
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Abbott Laboratories
Original Assignee
Abbott Laboratories
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Publication of EP0415981A1 publication Critical patent/EP0415981A1/fr
Publication of EP0415981A4 publication Critical patent/EP0415981A4/en
Ceased legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D239/06—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D239/08—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine 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 directly attached in position 2
    • C07D239/10—Oxygen or sulfur atoms
    • 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
    • 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
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C317/00—Sulfones; Sulfoxides
    • C07C317/44—Sulfones; Sulfoxides having sulfone or sulfoxide groups and carboxyl groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/50—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton
    • C07C323/51—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C323/60—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and carboxyl groups bound to the same carbon skeleton having the sulfur atoms of the thio groups bound to acyclic carbon atoms of the carbon skeleton with the carbon atom of at least one of the carboxyl groups bound to nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/28—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole 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
    • C07D233/30—Oxygen or sulfur atoms
    • C07D233/32—One oxygen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon atoms
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—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
    • 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—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
    • 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/22—Oxygen atoms attached in position 2 with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, directly attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—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
    • 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/24—Oxygen atoms attached in position 2 with hydrocarbon radicals, substituted by oxygen atoms, attached to other ring carbon atoms
    • C—CHEMISTRY; METALLURGY
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    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/08—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
    • 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
    • C07D263/18—Oxygen atoms
    • C07D263/20—Oxygen atoms attached in position 2
    • C07D263/26—Oxygen atoms attached in position 2 with hetero atoms or acyl radicals directly attached to the ring nitrogen atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D265/00—Heterocyclic compounds containing six-membered rings having one nitrogen atom and one oxygen atom as the only ring hetero atoms
    • C07D265/04—1,3-Oxazines; Hydrogenated 1,3-oxazines
    • C07D265/06—1,3-Oxazines; Hydrogenated 1,3-oxazines not condensed with other rings
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D273/00—Heterocyclic compounds containing rings having nitrogen and oxygen atoms as the only ring hetero atoms, not provided for by groups C07D261/00 - C07D271/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • 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
    • C07D295/205—Radicals derived from carbonic acid
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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
    • C07D295/215—Radicals derived from nitrogen analogues of carbonic acid
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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
    • C07D307/58—One oxygen atom, e.g. butenolide
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    • 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
    • C07D307/68—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
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    • C07D317/00—Heterocyclic compounds containing five-membered rings having two oxygen atoms as the only ring hetero atoms
    • 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
    • C07D317/32—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 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
    • C07D317/34—Oxygen atoms
    • C07D317/36—Alkylene carbonates; Substituted alkylene carbonates
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/26—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur 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
    • C07D333/38—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
    • C07K5/06043—Leu-amino acid
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
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    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1016—Tetrapeptides with the first amino acid being neutral and aromatic or cycloaliphatic
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    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • patent application Serial No. 194,678, filed May 13, 1988 is also a continuation-in-part of U.S. patent application Serial No. 943,566, filed December 31, 1986, which is a continuation-in-part of U.S. patent application Serial No. 818,715, filed January 16, 1986, now abandoned, which is a continuation-in-part of U.S. patent application Serial No. 693,951, filed January; 23, 1985, now abandoned.
  • U.S. patent application Serial No. 194,678, filed May 13, 1988 is also a continuation-in-part of U.S. patent application Serial No. 946,883, filed January 9, 1987, which is a continuation-in-part of U.S. patent application Serial No.
  • the present invention relates to novel compounds and a composition and method for inhibiting retroviral proteases and in particular for inhibiting human immunodeficiency virus (HIV) protease, a composition and method for treating a retroviral infection and in particular an HIV infection, processes for making such compounds and synthetic intermediates employed in these processes.
  • HIV human immunodeficiency virus
  • 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, 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.
  • retroviral protease should provide a therapeutic agent for diseases caused by the retrovirus.
  • the genomes of retroviruses encode a protease that is responsible for the proteolytic processing of one or more polyprotein precursors such as the pol and ga ⁇ gene products. See Wellink, Arch. Virol. 981 (1988).
  • Retroviral proteases most commonly process the gag precursor into core proteins, and also process the pol precursor into reverse transciptase and retroviral protease. In addition, retroviral proteases are sequence specific. See Pearl, Nature 328482 (1987).
  • U.S. Patent No. 4,652,552 discloses methyl ketone derivatives of tetrapeptides as inhibitors of viral proteases.
  • U.S. Patent No. 4,644,055 discloses halomethylketone derivatives of peptides as inhibitors of viral proteases.
  • European Patent Application No. EP0246630 discloses antiviral peptides for treating herpes.
  • PCT Patent Application No. WO87/07836 discloses L-glutamic acid gamma-monohydroxamate as an antiviral agent.
  • the ability to inhibit retroviral proteases, and in particular HIV protease provides a method for blocking viral replication and therefore a treatment for retroviral diseases, and AIDS in particular, that has fewer or no side effects when compared to current treatments . Disclosure of the Invention
  • R 14 is hydrogen, loweralkyl or aminoalkyl
  • Functionalized alkyl groups include:
  • R 15 and R 16 are independently selected from hydrogen, loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, (N-protected) aminoalkyl,
  • Functionalized carbonyl and functionalized sulfonyl include R 17 C(O)B- and R 17 S (O) 2 B-, respectively, wherein B is NH, -N (alkyl)-, S, O, CH 2 or CHOH, and
  • R 3 is (substituted alkyl) amino .
  • (Substituted alkyl) amino includes wherein m is 1 to 5 ;
  • R 6 is hydroxy, alkoxy or -NR 15 R 16 wherein R 15 and R 16 are independently as defined above and R 75 is -NHCH(R")C(O)-, -NHCH (R")C(O) NHCH (R''')C(O)-, -NHCH(R")C(O)NHCH(R''') C (O) -R 220 - or -NHCH (R") C (O) NHCH (R' ' ' ) C (O) -R 220 -R 221 - wherein R" is hydrogen, loweralkyl, cycloalkylalkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is independently as defined above, (naphthyl) alkyl or (substituted naphthyl) alkyl wherein substituted naphth
  • R 7 is hydrogen, amino or hydroxy and R 8 is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, azido, azidoalkyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, (N-protected) amino, (N-protected) aminoalkyl, (N-protected) (alkyl) amino, (N-protected) (alkyl) aminoalkyl, thioalkoxy, thioalkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, thioaryloxy, thioaryloxyalkyl, phenyl, substituted phenyl independently as defined above, naphthyl, substituted naphthyl independently as defined above, heterocyclic, substituted heterocycl
  • R 200 is an alkylene group
  • R 201 is S, S (O) , S(O) 2 , O, NH or -N (alkyl)-
  • R 202 is an alkylene group
  • R 203 is phenyl, substituted phenyl independently as defined above, naphthyl or substituted naphthyl independently as defined above;
  • R 5 is independently as defined above,
  • G is O, S, -N (R 11 ) - or -C (R 11 ) (R 70 ) - wherein R 11 is hydrogen or loweralkyl and R 70 is hydrogen or loweralkyl,
  • L is N or -C(R 5 )- wherein R 5 is independently as defined above,
  • R 81 is N or -C(R 11 )- wherein R 11 is independently as defined above, R 71 is N or -C(R 11 )- wherein R 11 is independently as defined above,
  • R 80 is absent, -C (R 11 ) (R 70 ) - or -N(R 11 )- wherein R 11 and R 70 are independently as defined above, R 80 is absent, or one or two substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide,
  • Q is O or -C(R 11 ) (R 70 )- wherein R 11 andR 70 are independently as defined above,
  • X is O, S, -N(R 11 )-, -C(R 11 ) (R 70 )-,
  • R 11 and R 70 are independently as defined above,
  • R 12 is independently as defined above or
  • R 5 is independently as defined above.
  • R 13 is hydrogen or loweralkyl.
  • R 1 is loweralkyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl) methyl or (2-naphthyl) methyl and R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is as defined above and R 3 is
  • R 4 is loweralkyl, cycloalkylmethyl or benzyl and E is -CH(R 7 ) (R 8 ) wherein R 7 is hydroxy or amino and R 8 is loweralkyl, phenylalkyl, (substiututed phenyl) alkyl, naphthylalkyl or (substituted naphthyl) alkyl have been disclosed as renin inhibitors in copending U.S. patent applications, USSN 217,106, filed July 11, 1988 and USSN 132,356, filed December 18, 1987, both of which are hereby incorporated by reference.
  • R 1 is loweralkyl, phenylalkyl, (substituted phenyl) alkyl, naphthylalkyl and (substituted naphthyl) alkyl and R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is hydrogen, loweralkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is as defined above, (naphthyl) alkyl, (substituted naphthyl) alkyl wherein substituted naphthyl is as defined above, -OR 14 wherein R 14 is hydrogen or loweralkyl, -NR 15 R 16 wherein R 1 and R 16 are independently selected from hydrogen and loweralkyl or R 17 C(O)B- wherein B is NH, O or CH 2 and R 17 is loweralkyl, alkoxy, (phenyl)
  • R 4 is loweralkyl, cycloalkyl, cycloalkylalkyl, naphthylmethyl, benzyl or substituted benzyl and E is - CH 2 R 8 wherein R 8 is loweralkyl, alkoxy, alkylamino, (N-protected) amino, thioalkoxy, alkylsulfonyl, thioaryloxy or (phenyl) sulfonyl, (substituted phenyl) sulfonyl wherein substituted phenyl is as defined above, (naphthyl) sulfonyl, or (substituted naphthyl) sulfonyl wherein substituted naphthyl is as defined above have been disclosed as renin inhibitors in copending U.S. patent application USSN 946,881, filed January 9, 1987, which is hereby incorporated by reference.
  • R 1 is loweralkyl, benzyl, 4-methoxybenzyl, halobenzyl, (1-naphthyl) methyl or (2-naphthyl) methyl and R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is hydrogen, loweralkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is as defined above, (naphthyl) alkyl, (substituted naphthyl) alkyl wherein substituted naphthyl is as defined above, -OR- .
  • R 14 is hydrogen, loweralkyl or aminoalkyl, -NR 15 R 16 wherein R 15 and R 16 are independently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl or hydroxyalkyl, R 17 C(O)B- or R 17 S(O) 2 B- wherein B is NH, -N (alkyl)-, S, O, CH 2 or CHOH and R 17 is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl, substituted naphthyl as defined above,
  • substituted naphthyl alkyl wherein substituted naphthyl is as defined above, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, (phenyl) alkoxy, (substituted phenyl) alkoxy wherein substituted phenyl is as defined above,
  • R 4 is loweralkyl, cycloalkylmethyl or benzyl and E is -CH(OH)R 8 wherein R 8 is hydroxyalkyl, alkoxyalkyl, azidoalkyl, aminoalkyl, (N-protected) aminoalkyl, alkylaminoalkyl, (N-protected) (alkyl) aminoalkyl, thioalkoxyalkyl, alkylsulfonylalkyl, thioaryloxyalkyl or (phenyl) sulfonylalkyl, (substituted phenyl) sulfonylalkyl wherein substituted phenyl is as defined above, (naphthyl) sulfonylalkyl, or (substituted naphthyl) sulfonylalkyl wherein substituted naphthyl is as defined above; or E is -CHR 7 R 48 wherein R 7 R
  • R 1 is loweralkyl, benzyl, 4-methoxybenzyl, halobenzyl,
  • R 2 is loweralkyl, heterocyclic alkyl or (substituted heterocyclic) alkyl and A is hydrogen, loweralkyl,
  • substituted phenyl alkoxy wherein substituted phenyl is as defined above, (naphthyl) alkoxy, (substituted naphthyl) alkoxy wherein substituted naphthyl is as defined above, (phenyl) alkoxyalkyl, (substituted phenyl) alkoxyalkyl wherein substituted phenyl is as defined above,
  • naphthyl alkoxyalkyl
  • substituted naphthyl is as defined above, amino, alkylamino, dialkylamino, (hydroxyalkyl) (alkyl) amino,
  • alkyl aminoalkyl, dialkylaminoalkyl.
  • carboxyalkyl alkoxycarbonylalkyl, aminocycloalkyl, aminoalkylamino, dialkylaminoalkylamino,
  • phenyl alkyl (alkyl) amino (substituted phenyl) alkyl (alkyl) amino wherein substituted phenyl is as defined above, (naphthyl) alkyl (alkyl) amino, (substituted naphthyl) alkyl (alkyl) amino wherein substituted naphthyl is as defined above, alkoxyalkyl (alkyl) amino;
  • R 5 is hydrogen
  • R 80 is absent, -CH 2 - or -N(R 11 )- wherein R 11 is as defined above, X is O, S or NH, Y is
  • R 5 is hydrogen or loweralkyl
  • R 11 is hydrogen or loweralkyl
  • R 70 is hydrogen or loweralkyl
  • Z is -N(R 12 )- wherein R 12 is hydrogen or loweralkyl, X is O, S, -C(R 11 ) (R 70 )- or -N(R 11 )-, and R 80 is absent, -C(R 11 ) (R 7 0)- or -N(R 11 )-; or
  • R 80 is -N(R 11 )-, X is O, S, -C(R 11 ) (R 70 )- or -
  • N(R 11 )- and Z is O, S, -C(R 11 ) (R 70 )- or -N(R 12 )- wherein R 12 is hydrogen or loweralkyl; or (2 ) E is
  • R 11 is hydrogen or loweralkyl and R 70 is hydrogen or loweralkyl;
  • R 5 is hydrogen or loweralkyl and R 11 is hydrogen or loweralkyl
  • L is N and R 82 is hydrogen or loweralkyl; or (ii) wherein L is -C(R 5 )- wherein R 5 is hydrogen or loweralkyl, G is -N(R 11 )- wherein R 11 is hydrogen or loweralkyl and R 82 is hydrogen or loweralkyl have been disclosed as renin inhibitors in European Patent Application No. EP0231919, published August 12, 1987.
  • the chiral centers of the compounds of the invention may have either the "R” or "S” configuration.
  • the terms "S” and “R” configuration are as defined by the IUPAC 1974 Recommendations for Section E, Fundamental Stereochemistry, Pure Appl. Chem. (1976) 45, 13 - 30.
  • N-protecting group or “N-protected” as used herein refers to those groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures or to prevent the attack of exopeptidases on the final compounds or to increase the solubility of the final compounds and includes but is not limited to acyl, acetyl, pivaloyl, t-butylacetyl, t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) or benzoyl groups or an L- or D- aminoacyl residue, which may itself be N-protected similarly.
  • loweralkyl refers to straight or branched chain alkyl radicals containing from 1 to 6 carbon atoms including but not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, n-pentyl, 1-methylbutyl, 2, 2-dimethylbutyl, 2-methylpentyl, 2, 2-dimethylpropyl, n-hexyl and the like.
  • loweralkenyl refers to a loweralkyl radical which contains at least one carbon-carbon double bond.
  • alkylene refers to straight or branched chain spacer radicals containing 2 to 6 carbon atoms such as -CH 2 -, -CH(CH 3 )-, -CH 2 CH 2 -, -CH 2 CH(CH 3 )- and the like.
  • substituted phenyl refers to a phenyl ring substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • substituted naphthyl refers to a naphthyl ring substituted with one, two or three substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide.
  • (phenyl) alkyl refers to a phenyl ring appended to a loweralkyl radical, including but not limited to benzyl and the like.
  • (substituted phenyl) alkyl refers to a substituted phenyl ring as defined above appended to a loweralkyl radical, including but not limited to 4-hydroxybenzyl, 4-methoxybenzyl and 4-chlorobenzyl.
  • (naphthyl) alkyl refers to a naphthyl ring appended to a loweralkyl radical, including but not limited to 1-naphthylmethyl and 2-naphthylmethyl.
  • substituted naphthyl alkyl refers to a substituted naphthyl ring as defined above appended to a loweralkyl radical.
  • aminoalkyl refers to -NH 2 appended to a loweralkyl radical.
  • cyanoalkyl refers to -CN appended to a loweralkyl radical.
  • hydroxyalkyl refers to -OH appended to a loweralkyl radical.
  • alkylamino refers to a loweralkyl radical appended to an NH radical.
  • cycloalkyl refers to an aliphatic ring having 3 to 7 carbon atoms.
  • cycloalkylalkyl refers to a cycloalkyl group appended to a loweralkyl radical, including but not limited to cyclohexylmethyl.
  • alkoxy and thioalkoxy refer to R 18 O- and R 18 S-, respectively, wherein R 18 is a loweralkyl group.
  • alkenyloxy refers to R 19 O- wherein R 19 is a loweralkenyl group.
  • hydroxyalkoxy refers to -OH appended to an alkoxy radical.
  • dihydroxyalkoxy refers to an alkoxy radical which is disubstituted with -OH groups.
  • (phenyl) alkoxy refers R 90 O- wherein R 90 is a (phenyl) alkyl group as defined above.
  • (substituted phenyl) alkoxy refers to R 91 O- wherein R 91 is a (substituted phenyl) alkyl group as defined above.
  • R 92 O- wherein R 92 is a (naphthyl) alkyl group as defined above.
  • (substituted naphthyl) alkoxy refers to R 93 O- wherein R 93 is a (substituted naphthyl) alkyl group as defined above.
  • (phenyl) alkoxyalkyl refers to a (phenyl) alkoxy group as defined above appended to a loweralkyl radical.
  • (substituted phenyl) alkoxyalkyl refers to a (substituted phenyl) alkoxy group as defined above appended to a loweralkyl radical.
  • (naphthyl) alkoxyalkyl refers to a (naphthyl) alkoxy group as defined above appended to a loweralkyl radical.
  • (substituted naphthyl) alkoxyalkyl refers to a (substituted naphthyl) alkoxy group as defined above appended to a loweralkyl radical.
  • (thioalkoxy) alkyl refers to thioalkoxy appended to a loweralkyl radical.
  • dialkylamino refers to -NR 20 R 21 wherein R 20 and R 21 are independently selected from loweralkyl groups.
  • (alkoxy) alkoxy) alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
  • (hydroxyalkyl) (alkyl) amino refers to -NR 22 R 23 wherein R 22 is hydroxyalkyl and R 23 is loweralkyl.
  • N-protected aminoalkyl refers to -NHR 24 appended to a loweralkyl group, wherein R 24 is an N-protecting group.
  • alkylaminoalkyl refers to NHR 25 appended to a loweralkyl radical, wherein R 25 is a loweralkyl group.
  • (N-protected) (alkyl) aminoalkyl refers to -NR 24 R 25 , which is appended to a loweralkyl radical, wherein R 24 and R 25 are as defined above.
  • dialkylaminoalkyl refers to -NR R which is appended to a loweralkyl radical wherein R 26 and R 27 are independently selected from loweralkyl.
  • Carboxamidoalkyl refers to a -C(O)NH 2 group appended to a loweralkyl radical.
  • N-hydroxycarboxamidoalkyl refers to a -C(O)NHOH group appended to a loweralkyl radical.
  • azidoalkyl refers to a -N 3 group appended to a loweralkyl radical.
  • carboxyalkyl refers to a carboxylic acid group (-COOH) appended to a loweralkyl radical.
  • alkoxycarbonylalkyl refers to R 28 C(O)R 29 - wherein R 28 is an alkoxy group and R29 is a loweralkyl radical.
  • carboxyalkoxyalkyl refers to a carboxylic acid group (-COOH) appended to an alkoxy group which is appended to a loweralkyl radical.
  • alkoxycarbonylalkoxyalkyl refers to an alkoxycarbonyl group (R 30 C(O)- wherein R 30 is an alkoxy group) appended to an alkoxy group which is appended to a loweralkyl radical.
  • (amino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an amino group (-NH 2 ).
  • (N-protected) amino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NHR 31 wherein R 31 is an N-protecting group.
  • (alkylamino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an alkylamino group.
  • (N-protected) alkylamino) carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and an -NR 31 R 32 wherein R 31 is as defined above and R 32 is a loweralkyl group.
  • dialkylamino carboxyalkyl refers to a loweralkyl radical to which is appended a carboxylic acid group (-COOH) and -NR 32 R 32 wherein R 32 is as defined above.
  • (amino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an amino group (-NH 2 ).
  • ((N-protected) amino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NHR 31 wherein R 31 is as defined above.
  • alkylamino alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and an alkylamino group as defined above.
  • (N-protected) alkylamino) alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 31 R 32 wherein R 31 and R 32 are as defined above.
  • dialkylamino alkoxycarbonylalkyl refers to a loweralkyl radical to which is appended an alkoxycarbonyl group as defined above and -NR 32 R 32 wherein R 32 is as defined above.
  • carboxyalkylamino refers to -NHR 33 wherein R 33 is a carboxyalkyl group.
  • alkoxycarbonylalkylamino refers to -NHR 34 wherein R 34 is an alkoxycarbonylakyl group.
  • (amino) carboxyalkylamino refers to -NHR 35 wherein R 35 is an (amino) carboxyalkyl group.
  • (N-protected) amino) carboxyalkylamino refers to -NHR 36 wherein R 36 is an [ (N- protected) amino] carboxyalkyl group.
  • (alkylamino) carboxyalkylamino refers to -NHR 37 wherein R 37 is an (alkylamino) carboxyalkyl group .
  • ((N-protected) alkylamino)-carboxyalkylamino refers to -NHR 38 wherein
  • R 38 is an ( (N-protected) alkylamino) carboxyalkyl group.
  • dialkylamino carboxyalkylamino refers to -NHR 39 wherein R 39 is a (dialkylamino) carboxyalkyl group.
  • (amino) alkoxycarbonylalkylamino refers to -NHR 40 wherein R 40 is an (amino) alkoxycarbonylalkyl group.
  • (N-protected) amino) alkoxycarbonylalkylamino refers to -NHR 41 wherein R 41 is an ( (N-protected) amino)-alkoxycarbonylalkyl group.
  • (alkylamino) alkoxycarbonylalkylamino refers to -NHR 42 wherein R 42 is an (alkylamino) alkoxycarbonylalkyl group.
  • (N-protected) alkylamino) alkoxycarbonylalkylamino refers to -NHR 43 whereinR 43 - is an ( (N-protected) alkylamino)-alkoxycarbonylalkyl group.
  • dialkylamino alkoxycarbonylalkylamino refers to -NHR 44 wherein R 44 is a (dialkylamino) alkoxycarbonylalkyl group.
  • ammocycloalkyl refers to an NH « appended to a cycloalkyl radical.
  • (alkoxy) alkoxy) alkyl refers to an alkoxy group appended to an alkoxy group which is appended to a loweralkyl radical.
  • polyalkoxyalkyl refers to a polyalkoxy residue appended to a loweralkyl radical.
  • polyalkoxy refers to -OR 45 wherein R 45 is a straight or branched chain containing 1-5,
  • n and n' are independently selected from 1 to 3, including but not limited to methoxyethoxymethoxy, methoxymethoxy and the like.
  • (phenyl) alkylamino refers to R 100 NH- wherein R 100 is a (phenyl) alkyl group as defined above .
  • (substituted phenyl) alkylamino refers to R 101 NH- wherein R 101 is a (substituted phenyl) alkyl group as defined above.
  • (naphthyl) alkylamino refers to R 102 NH- wherein R 100 is a (naphthyl) alkyl group as defined above.
  • (substituted naphthyl) alkylamino refers to R 103 NH- wherein R 103 is a (substituted naphthyl) alkyl group as defined above.
  • (phenyl) alkyl (alkyl) amino refers to R 104 R 105 N- wherein R 104 is a (phenyl) alkyl group as defined above and R 105 is a loweralkyl group.
  • (substituted phenyl) alkyl (alkyl) amino refers to R 106 R 107 N- wherein R 106 is a
  • R 107 is a loweralkyl group.
  • (naphthyl) alkyl (alkyl) amino refers to R 108 R 109 N- wherein R 108 is a (naphthyl) alkyl group as defined above and R 109 is a loweralkyl group.
  • (substituted naphthyl) alkyl (alkyl)- amino refers to R 110 R 111 N- wherein R 100 is a (substituted naphthyl) alkyl group as defined above and R 111 is a loweralkyl group.
  • dialkylaminoalkyl (alkyl) amino refers to -NR 49 R 50 wherein R 49 is a dialkylamino residue appended to a loweralkyl residue and R 50 is a loweralkyl residue.
  • alkylaminoalkylamino refers to -NHR 50a wherein R 50a is an alkylaminoalkyl group as previously defined.
  • dialkylaminoalkylamino refers to -NHR 50b wherein R 50b is a dialkylaminoalkyl group as previously defined.
  • aminoalkylamino refers to - NHR 51 wherein R 51 is an aminoalkyl residue.
  • (dihydroxyalkyl) (alkyl) amino refers to a loweralkyl group which is disubstituted with - OH radicals, appended to an amino group, which amino group also has appended another loweralkyl group, including but not limited to N- (2,3-dihydroxypropyl) - N- (methyl) amine.
  • di- (hydroxyalkyl) amino refers to -NR 52 R 53 , wherein R 52 and R 53 are hydroxyalkyl residues.
  • alkoxyalkyl (alkyl) amino refers to -NR 54 R 55 wherein R 54 is an alkoxyalkyl group andR 55 is a loweralkyl group.
  • di- (alkoxyalkyl) amino refers to -NR 56 R 57 wherein R 56 and R 57 are alkoxyalkyl groups.
  • di- (polyalkoxyalkyl) amino refers to -NR 58 R 59 wherein R 58 and R 59 are polyalkoxy residues appended to loweralkyl residues.
  • (polyalkoxy) alkyl) (alkyl) amino refers to -NR 60 R 61 wherein R 60 is a polyalkoxy residue appended to a loweralkyl residue and R 61 is a loweralkyl residue.
  • halo or halogen as used herein refers to -Cl, -Br, -I or -F.
  • haloalkyl refers to a loweralkyl radical in which one or more of the hydrogen atoms are replaced by halogen including, but not limited to, chloromethyl, trifluoromethyl, 1-chloro-2-fluoroethyl and the like.
  • thioalkoxyalkyl refers to a thioalkoxy group appended to a loweralkyl radical.
  • alkylsulfonyl refers to R 62 SO 2 - wherein R 62 is loweralkyl group.
  • alkylsulfonylalkyl refers to an alkylsulfonyl group appended to a loweralkyl radical.
  • thioaryloxy refers to R 63 S- wherein R 63 is a substituted or unsubstituted phenyl or naphthyl group as defined above, including but not limited to phenyl, naphthyl, halophenyl and alkoxyphenyl.
  • thioaryloxyalkyl refers to a thioaryloxy group appended to a loweralkyl radical.
  • arylsulfonyl refers to R 63 SO - wherein R 63 is as defined above.
  • arylsulfonylalkyl refers to an arylsulfonyl group appended to a loweralkyl radical.
  • heterocyclic ring refers to any 3- or 4-membered ring containing a heteroatom selected from oxygen, nitrogen and sulfur, or a 5- or 6-membered ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; wherein the 5-membered ring has 0-2 double bonds and the 6-membered ring has 0-3 double bonds; wherein the nitrogen and sulfur heteroatoms are optionally oxidized; wherein the nitrogen heteroatoms are optionally quaternized; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring. Heterocyclics in which nitrogen is the heteroatom are preferred.
  • heterocyclics are: pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl and benzothienyl.
  • b is 1 or 2 and T is N, NH, O, S, provided that T is the point of connection only when T is N, wherein R 72 is NH, N-loweralkyl, N-haloalkyl, O, S, or SO 2 , or
  • substituted heterocyclic refers to saturated heterocyclics which are monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl or loweralkyl; or unsaturated heterocyclics which are monosubstituted with hydroxy, oxo, amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, haloalkyl or loweralkyl.
  • heterocyclic alkyl refers to a heterocyclic group appended to a loweralkyl radical. including but not limited to imidazolylmethyl and thiazolylmethyl.
  • substituted heterocyclic alkyl refers to a substituted heterocyclic group as defined above appended to a loweralkyl radical.
  • heterocyclic carbonyloxy refers to R 205 C(O)O- wherein R 205 is a heterocyclic group.
  • (substituted heterocyclic) carbonyloxy refers to R 206 C(O)O- wherein R 206 is a substituted heterocyclic group.
  • heterocyclic carbonylamino refers to R 207 C(O)NH- wherein R 207 is a heterocyclic group.
  • (substituted heterocyclic) carbonylamino refers to R 208 C(O)NH- wherein R 208 is a substititued heterocyclic group.
  • amino acyl residue refers to a residue of the type -NHCH (R*) C (O) - wherein R* represents the side chain of one of the twenty naturally occuring alpha amino acids including, but not limited to alanyl, prolyl, leucyl, phenylalanyl, aspartyl and the like.
  • Al Al
  • Gin Leu
  • Phe He
  • Ser He
  • Pro Pro
  • the compounds of the invention can be prepared as shown in Scheme I .
  • the syntheses of segments containing substituents R 3 and A-CHR 1 -CO- are described in the Examples.
  • the process shown in Scheme 1 discloses the carbodiimide coupling of acid (1) to substituent R 3 to give the peptide (2).
  • carbodiimide coupling of protected amino acid (3) to substituent R 3 followed byhydrogenolytic deprotection provides the amine (4).
  • Reaction of (4) with the mixed anhydride (5) gives the peptide (2).
  • acid halide and other activated ester derivatives of the carboxylic acid are useful for the coupling reactions with amines.
  • Acid halide derivatives include the acid chloride.
  • Activated ester derivatives include activated esters commonly used by those skilled in the art for activating carboxylic acid groups for coupling with an amine to form a peptide bond 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 and the like.
  • H-R 3 represents compounds of the formula:
  • m 1 to 5;
  • R 6 is hydroxy, alkoxy or -NR 15 R 16 wherein R 15 and R 16 are independently as defined above and R 75 is -NHCH(R")C(O)-, -NHCH (R")C(O) NHCH (R' ' ')C(O)-, -NHCH (R")C(O) NHCH (R' ' ' )C(O)-R 220 - or -NHCH(R") C (O) NHCH (R' ' ' ) C (O) -R 220 -R 221 - wherein R" is hydrogen, loweralkyl, cycloalkylalkyl, (phenyl) alkyl, (substituted phenyl) alkyl wherein substituted phenyl is independently as defined above, (naphthyl) alkyl or (substituted naphthyl) alkyl wherein substitute
  • R 7 is hydrogen, amino or hydroxy and R 8 is loweralkyl, hydroxy, hydroxyalkyl, alkoxy, alkoxyalkyl, azido, azidoalkyl, amino, aminoalkyl, alkylamino, alkylaminoalkyl, dialkylamino, dialkylaminoalkyl, (N-protected) amino, (N-protected) aminoalkyl, (N-protected) (alkyl) amino, (N-protected) (alkyl) aminoalkyl, thioalkoxy, thioalkoxyalkyl, alkylsulfonyl, alkylsulfonylalkyl, thioaryloxy, thioaryloxyalkyl, phenyl, substituted phenyl independently as defined above, naphthyl, substituted naphthyl independently as defined above, heterocyclic, substituted heterocycl
  • R 200 is an alkylene group
  • R 201 is S, S (O) , S(O)2, O, NH or -N (alkyl)-
  • R 202 is an alkylene group
  • R 203 is phenyl, substituted phenyl independently as defined above, naphthyl or substituted naphthyl independently as defined above;
  • R 5 is independently as defined above,
  • G is O, S, -N(R 11 )- or -C(R 11 ) (R 70 )- wherein R 11 is hydrogen or loweralkyl and
  • R 70 is hydrogen or loweralkyl
  • L is N or -C(R 5 )- wherein R 5 is independently as defined above
  • R 81 is N or -C(R 11 )- wherein R 11 is independently as defined above
  • R 71 is N or -C(R 11 )- wherein R 11 is independently as defined above
  • R 80 is absent, -C(R 11 ) (R 70 )- or -N(R 11 )- wherein R 11 and R 70 are independently as defined above, R 82 is absent, or one or two substituents independently selected from loweralkyl, alkoxy, thioalkoxy, hydroxy, halogen, mercapto, nitro, amino, loweralkylamino, dialkylamino, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide,
  • Q is P or -C(R 11 ) (R 70 )- wherein R 11 and
  • R 70 are independently as defined above,
  • X is O, S, -N(R 11 )-, -C(R 11 ) (R 70 )-,
  • R 11 and R 70 are independently as defined above,
  • R 12 is independently as defined above or
  • H-R 3 can optionally be obtained from the N-protected form of the compound.
  • Example 1 N-Methyl-6-(2-(t-butyloxycarbonyl) amino-1-hydroxy- 3-phenyl) propyl-1-cyclohexenecarboxamide.
  • a solution of 0.88 g (6.4 mmol) of N-methyl-1-cyclohexenecarboxamide in 30 ml of anhydrous tetrahydrofuran was cooled under nitrogen atmosphere to -78oC and treated with 5.2 ml (13.1 mmol) of n-butyllithium.
  • the resulting solution was warmed to 0oC for 30 mm, recooled to -78oC, and treated with 6.4 ml (6.4 mmol) of chlorotitanium triisopropoxide in hexane.
  • Example 2 N-Methyl-6-(2-amino-1-hydroxy-3-phenylpropyl)- 1-cyclohexenecarboxamide Hydrochloride.
  • the resultant compound of Example 1 (0.23 g) was treated with 8 ml of 4 M HCl in dioxane. After 1 h, the solution was concentrated in vacuo to give the desired compound.
  • Boc-Leu-Asn-OH A solution of 10 g (40 mmol) of Boc-Leu-OH and 4.4 ml (40 mmol) of 4-methylmorpholine in 200 ml of anhydrous tetrahydrofuran was cooled under N 2 atmosphere to -10oC and treated with 5.2 ml (40 mmol) of isobutyl chloroformate. After 15 min, the solution was treated with a mixture of 5.30 g (40 mmol) of asparagine and 25 ml of 3 N NaOH in 50 ml of tetrahydrofuran and 200 ml of water.
  • Example 5 N-(3-Methylbutyl)-1-cyclopentenecarboxamide.
  • 1-Cyclopentenecarboxylic acid (7.17 g, 64 mmol) was coupled to isoamylamine using the procedure of Example 4 to give, after silica gel chromatography using 7:3 hexane/ethyl acetate, 7.86 g (68%) of the desired compound as a white crystalline solid.
  • Example 6 N-(3-Methylbutyl)-5-(2-(t-butyloxycarbonyl)amino- 1-hydroxy-3-phenyl)propyl-1-cyclopentenecarboxamide. Using the procedure of Example 1 but replacing N-methyl-1-cyclohexenecarboxamide with the resultant compound of Example 5 gives the desired compound as a mixture of diastereomers .
  • Example 7 Boc-Leu-Asn Amide of N-(3-Methylbutyl)-5- (2-amino-1-hydroxy-3-phenyl)propyl- 1-cyclopentenecarboxamide. Using the procedures of Examples 2 and 4 with the resultant compound of Example 6 gives the desired compound.
  • Example 8 ( (4-Moroholinyl) carbonyl) -Leu Methyl Ester.
  • a suspension of L-leucine methyl ester hydrochloride (6 g).in toluene (125 ml) is heated to 100°C while phosgene gas is bubbled into the reaction mixture. After approximately 1.5-2 h, the mixture becomes homogeneous. The passage of phosgene is continued for an additional 15 min, keeping the temperature at 90-100°C. The toluene is then evaporated and the residue chased several times with benzene.
  • Example 9 (4-Morpholinyl) carbonyl) -Leu-OH.
  • a solution of lithium hydroxide (0.174 g, 4.15 mmol) in water (7.5 ml).
  • the reaction mixture is diluted with cold water and extracted 2X with ether.
  • the aqueous portion is acidified with 6N HCl and extracted with ether.
  • the organic extract is washed with brine and evaporated to give the desired compound.
  • Example 10 3-Benzyloxycarbonylamino-3-methylbutanoic Acid.
  • a solution of 2,2-dimethyl-3-carbomethoxypropionic acid (LeMaul, Bull. Soc. Chim. Fr., 828 (1965), 20 g, 0.125 mol), diphenylphosphorylazide (34.3 g, 0.125 mol) and triethylamine is heated in toluene (150 ml) at 100°C for 2 h. After cooling to 5°C, the toluene solution is washed successively with 0.5 M HCl, aqueous NaHCO 3 and brine. Evaporation of the dried solution gave a residue which is chromatographed on silica gel eluting with 60/40 hexane-ether. There is obtained 13 g of methyl 3-
  • Example 11 Cbz-(( ⁇ , ⁇ -di-Me)- ⁇ -Ala)-Leu-OCH 3 .
  • a 4.0 g sample of 3-benzyloxycarbonylamino-3-methylbutanoic acid is coupled to leucine methyl ester hydrochloride using the mixed anhydride procedure described in Example 4. Purification of the crude product by flash chromatography gives the desired compound.
  • Example 12 Cbz-(( ⁇ , ⁇ -di-Me)- ⁇ -Ala)-Leu-OH.
  • a solution of Cbz-(( ⁇ , ⁇ -di-Me)- ⁇ -Ala)-Leu-OMe (3.63 mmol) in dioxane (15 ml) is added a solution of lithium hydroxide (0.174 g, 4.15 mmol) in water (7.5 ml). After stirring for 1 h at 0-5°C, the reaction mixture is diluted with cold water and extracted 2X with ether. The aqueous portion is acidified with 6N HCl and extracted with ether. The organic extract is washed with brine and evaporated to give the desired compound.
  • Example 13 (4R)-3-(4-Methylpentanoyl)-4- (2-propyl)oxazolidine-2-one.
  • 4-(2-propyl)-oxazolidine-2-one in anhydrous tetrahydrofuran (250 ml) under a nitrogen atmosphere at -78°C is added in a dropwise fashion a solution of a-butyllithium in hexane (50 ml, 77.4 mmol) over 5 to 10 min.
  • 4-methylpentanoyl chloride (85.2 mmol) is added neat. The reaction is warmed to room temperature and stirred 1 to 2 h at the temperature.
  • reaction is quenched by adding 100 ml of saturated aqueous ammonium chloride and the volatiles are removed by rotary evaporation.
  • the resulting aqueous residue is extracted three times with ether and the combined organic phases. are washed with brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo. Recrystallization from hexanes/ethyl acetate provides the desired compound.
  • Example 14 (4R)-3-((2-R)-2-(t-Butyloxycarbonyl)methyl-4- methylpentanoyl)-4-(2-propyl)oxazolidine-2-one.
  • a stirred solution of the product resulting from Example 13 (8.72 mmol) in anhydrous tetrahydrofuran (30 ml) under a nitrogen atmosphere at -78°C is added a solution of sodium hexamethyldisilylamide (9.6 ml, 9.59 mmol) in tetrahydrofuran.
  • t-butyl bromoacetate (2.21 g, 11.34 mmol) is added in anhydrous tetrahydrofuran and the resulting solution stirred 1 h at -78°C.
  • the reaction is quenched by adding 20 ml of saturated aqueous ammonium chloride and partitioned between water and ether. The aqueous layer is drawn off and extracted with ether. The combined organic phases are washed with 10% aqueous HCl, saturated aqueous NaHCO 3 , and brine, dried (Na 2 SO 4 ), filtered, and concentrated in vacuo. Recrystallization from acetone/hexanes provides the desired compound.
  • Example 15 Benzyl-(2R)-2-(t-Butyloxycarbonyl)methyl- 4-methylpentanoate.
  • benzyl alcohol 0.55 ml, 5.33 mmol
  • anhydrous tetrahydrofuran 18 ml
  • n-butyllithium 2.58 ml; 4.00 mmol
  • To this solution is added the product from Example 55 in anhydrous tetrahydrofuran (10 ml). After stirring 1 h at 0°C the reaction is quenched by adding excess saturated aqueous ammonium chloride.
  • Example 16 Benzyl-(2R)-2-(Carboxymethyl)-4-methylpentanoate.
  • the resultant compound from Example 15 (1.47 mmol) is dissolved in a 1:1 (v:v) solution (6 ml) of trifluoroacetic acid and dichloromethane and stirred at room temperature for 1 h.
  • the volatiles are removed in vacuo to provide the desired compound.
  • the unpurified material is of sufficient purity to employ in subsequent steps.
  • Example 17 Benzyl (2R) -2-Isobutyl-3-morpholinocarbonylpropionate.
  • the resultant compound of Example 16 is coupled to morpholine using the mixed anhydride procedure as described in Example 4 to give the desired compound.
  • Example 18 (3, 4-cis-Dihydroxypyrrolidinylcarbonyl)-Leu Methyl Ester.
  • a suspension of L-leucine methyl ester hydrochloride (10 g) in toluene (f200 ml) is heated to 100°C while phosgene gas was bubbled into the reaction mixture. After approximately 2 h the mixture becomes homogeneous. The bubbling of phosgene is continued for 15 more minutes keeping the temperature at 100°C. The toluene is then evaporated and the residue chased with benzene several
  • Example 19 ( (4-Thiomorpholinyl)carbonyl)-Leu Methyl Ester.
  • a suspension of L-leucine methyl ester hydrochloride (6 g) in toluene (125 ml) is heated to 100°C and phosgene gas is bubbled into the reaction mixture. After approximately 1.5 h, the mixture becomes homogeneous. The bubbling of phosgene is continued for 10 more min. The solvent is then evaporated and the residue chased with benzene several times. The residue is then dissolved in 100 ml of methylene chloride and cooled to 0°C, and 1.1 equivalent of thiomorpholine is added dropwise. After 10 min the solution is washed with 1N HCl and the organic layer was dried with MgSO 4 . Evaporation of solvent gives the desired compound.
  • Example 21 Boc-6-aminohexanoic acid.
  • a mixture of 3.0 g (0.02 mol) of 6-aminohexanoic acid, 5.04 g (0.02 mol) of di-t-butyldicarbonate and 3.84 g (0.05 mol) of NaHCO 3 in 160 ml of 1:1 H 2 O/tetrahydrofuran is stirred vigorously for 24 h. After concentration of the solvent, the mixture is acidified with HCl, saturated with NaCl, extracted with ethyl acetate, dried over MgSO 4 and concentrated in vacuo to give the desired product (R f 0.48, 9:1 chloroform/methanol).
  • Example 22 Boc-6-aminohexanoyl-Leu benzyl ester.
  • Example 23 Boc-6-aminohexanoyl-Leu-OH.
  • a mixture of 1.07 mmol of the resultant compound of Example 22 and 30 mg of 10% palladium on carbon in 50 ml of methanol is stirred under an H 2 atmosphere for 3.5 h. After filtration through Celite, concentration in vacuo gives the desired compound.
  • Example 24 N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl- leucine methyl ester.
  • a solution of 2.1 mmol of a-isocyanoto-leucine methyl ester in 50 ml of dichloromethane is cooled to 0°C and treated with 0.3 ml (2.3 mmol) of N,N,N'-trimethylethylenediamine. After being allowed to stir for 16 h, the solution is concentrated and the desired compound is isolated by flash column chromatography.
  • Example 25 N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl- leucine lithium salt.
  • a solution of the resultant compound of Example 24 in dioxane is cooled to 0°C, treated with 1.05 equiv. of aqueous lithium hydroxide (0.5 M) and stirred for 1.5 h.
  • the resulting solution is concentrated in vacuo to give the desired compound as a white solid.
  • Example 26 (2R)-2-Isobutyl-3-morpholinocarbonylpropionic Acid.
  • the resultant compound of Example 17 is a hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
  • Example 27 (3.4-cis-Dihydroxypyrrolidinylcarbonyl)-Leu-OH.
  • the resultant compound of Example 18 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
  • Example 28 (4-Thiomorpholinylcarbonyl)-Leu-OH.
  • the resultant compound of Example 19 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
  • Example 29 (4-Sulphonylmorpholinylcarbonyl)-Leu-OH.
  • the resultant compound of Example 20 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
  • Example 31 (((4-Morpholinyl) carbonyl) oxy)-4-methylpentanoic Acid.
  • the resultant compound of Example 30 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
  • Example 32 Benzyl-(2R)-2-isobutyl-3- ( ( (4-morpholinyl) carbonyl) amino)-propionate.
  • the product from Example 16 (1.47 mmol), diphenylphosphoryl azide (1.47 mmol), and triethylamine (1.47 mmol) in dry benzene (6 ml) are refluxed for 3 to 5 h to provide a solution of the derived isocyanate which is cooled to 0°C and treated with morpholine (1.6 mmol).
  • the cooling bath is removed and the reaction stirred for 1 h.
  • the reaction mixture is poured into 10% aqueous HCl and extracted two times with ether.
  • the combined organic layers are washed successively with saturated aqueous NaHCO 3 and brine, dried (Na 2 SO 4 ), filtered and concentrated in vacuo to provide the unpurified product.
  • the desired product is obtained in pure form after chromatography on SiO 2 .
  • Example 33 Benzyl-(2R)-2-isobutyl-3- ( (ethoxvcarbonyl) amino)-propionate. Using the procedure of Example 32 but replacing morpholine with ethanol gives the desired compound.
  • Example 34 (2R)-2-Isobutyl-3- (((4-morpholinyl) carbonyl) amino) propionic Acid.
  • the resultant compound of Example 32 is hydrolyzed according to the procedures of Example 9 to give the desired compound.
  • Example 35 (2R)-2-Isobutyl-3- ( (ethoxycarbonyl) amino) propionic Acid.
  • the resultant compound of Example 33 is hydrolyzed according to the procedures of Example 9 to give the desired compound.
  • Example 36 1-Benzyloxycarbonylamino-2,3-propanediol.
  • 1-Amino-2,3-propanediol (15.2 g, 167 mmol) and NaOH (8.1 g, 204 mmol) in water (70 ml) at -10°C was treated dropwise with benzyl chloroformate (28.5 ml, 200 mmol) in ether (30 ml) over 20 min. The reaction was stirred at 0°C for 30 min then at room temperature for 2 h. The mixture was acidified with 2 M HCl and extracted with ethyl acetate which was washed with 0.5 M H 3 PO 4 and brine, then dried over Na 2 SO 4 and evaporated.
  • Lithium aluminum hydride (7.20 g, 189 mmol) in tetrahydrofuran (THF, 300 ml) was heated to reflux and the resultant compound from Example 36 (17.0 g, 75.5 mmol) in THF (150 ml) was added dropwise over 10 min.
  • the mixture was refluxed for 2 h, cooled, quenched sequentially with water (10 ml), 3 M NaOH (40 ml) and water (20 ml), then filtered and concentrated. The residue was dissolved in water which was washed with ether and evaporated. Bulb to bulb distillation of the residue afforded 2.0 g (25%) of the desired compound as an oil.
  • Example 19 Using the procedure of Example 19 but replacing thiomorpholine with the resultant compound of Example 37 gives the desired compound.
  • Example 38 is hydrolyzed according to the procedures of Example 9 to give the desired compound.
  • Example 40 5-(Methoxycarbonyl) pentanoyl-leucine Benzyl Ester.
  • Adipic acid monomethyl ester is coupled to leucine benzyl ester hydrochloride using the mixed anhydride procedure described in Example 4 to provide the desired compound.
  • Example 41 5-(Methoxycarbonyl) pentanoyl-leucine.
  • the resultant compound of Example 40 is hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
  • aqueous phase is acidified with concentrated HCl then extracted with ethyl acetate which is dried over Na 2 SO 4 and evaporated. Trituration with hot ethyl acetate affords the desired compound.
  • Example 43 N-Benzyloxycarbonyl-N-methyl-2-aminoethanol. To N-methylethanolamine (149 mmol) in methylene chloride (100 ml) at 0°C was added benzyl chloroformate (70 mmol). The mixture was stirred at 0°C for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2 M HCl, saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 and evaporated to provide the desired compound.
  • 1 H NMR (CDCl 3 ,TMS) ⁇ 7.36 (m,5H), 5.14 (s,2H), 3.78 (m,2H), 3.47 (m,2H), 3.01 (s,3H).
  • Example 44 1-Methoxyethoxymethoxy-2-(N-methyl- N-benzyloxycarbonylamino) ethane.
  • diisopropylethylamme 138 mmol
  • 2-methoxyethoxymethyl chloride 132 mmol
  • the mixture was evaporated, dissolved in ethyl acetate, washed with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 , and evaporated to afford the desired product as an oil, b.p. 150-170°C (0.3 mm).
  • Example 45 1-Methylamino-2-methoxyethoxymethoxyethane.
  • the resultant compound from Example 44 (31 mmol) and 10% palladium on carbon (3 g) in methanol (60 ml) were stirred under a hydrogen atmosphere for 24 h.
  • the mixture was filtered, evaporated and distilled to afford the desired product as an oil, b.p. 130-140°C (45 mm).
  • the resultant compound of Example 16 is coupled to the resultant compound of Example 45 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 47 (2R)-2-Isobutyl-3-(N-methyl-N-(2-methoxyethoxy methoxyethyl) aminocarbonyl) propionic Acid.
  • the resultant compound of Example 46 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 48 N-(2-Cyanoethyl) leucine Methyl Ester.
  • a solution of leucine methyl ester (0.590 mmol) in acrylonitrile (2 ml) is heated at reflux. Evaporation provides a residue which is chromatographed on silica gel to give desired compound.
  • Example 49 N-(3-Benzyloxycarbonylaminopropyl) leucine Methyl Ester.
  • the resultant compound of Example 48 (0.135 mmol) is hydrogenated (4 atmospheres H 2 ) over Raney Nickel (85 mg) in anhydrous methanol/ammonia (20 ml/5 ml) for 3 h. Filtration and evaporation provide the crude amine which is taken up in dichloromethane and treated with 0.14 mmol of N-(benzyloxycarbonyloxy) succinimide. After 2 h, the solution is washed with aqueous NaHCO 3 , dried over Na 2 SO 4 , and concentrated. Silica gel chromatography gives the desired compound.
  • Example 50 N-(3-Benzyloxycarbonylaminopropyl) leucine.
  • the resultant compound of Example 49 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 51 Cbz-Sar-Leu Methyl Ester.
  • Cbz-sarcosine is coupled to leucine methyl ester using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 52 Cbz-Sar-Leu-OH.
  • the resultant compound of Example 51 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 53 (N,N-Dimethyl)-Gly-Leu-OCH 3 .
  • the resultant product of Example 51 (0.243 mmol) is hydrogenated (1 atmosphere H 2 ) with 10% Pd/C (39 mg) in methanol/formalin (12 ml/5 ml) for 8 h. Filtering and evaporating (high vacuum) provides a residue which is chromatographed on silica gel to give the desired- compound.
  • Example 54 (N,N-Dimethyl)-Gly-Leu-O-Li + The resultant compound of Example 53 is hydrolyzed according to the procedure of Example 25 to give the desired compound.
  • Example 55 (N-(Benzyloxycarbonyl)pipiridin-4-yl) carbonyl- leucine Methyl Ester.
  • Cbz-isonipecotic acid is coupled to leucine methyl ester using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 56 (N-(Benzyloxycarbonyl) pipiridin-4-yl) carbonyl-ieucine.
  • the resultant compound of Example 55 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 57 N-(Allyloxycarbonyl)-leucine Methyl Ester.
  • a solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) is cooled to 0°C and treated dropwise with allyl chloroformate. After addition, the solution is stirred at ambient temperature for 2 h, diluted with dichloromethane, washed successively with 1 N HCl and aqueous NaHCO 3 , dried over Na 2 SO 4 , and concentrated to give the desired compound.
  • Example 58 N-(Allyloxycarbonyl)-leucine Methyl Ester.
  • a solution of leucine methyl ester (5 mmol) and triethylamine (10 mmol) in dichloromethane (50 ml) is cooled to 0°C and treated dropwise with allyl chloroformate. After addition, the solution is stirred at ambient temperature for 2 h
  • Example 59 N-(3-Hydroxypropyloxycarbonyl)-leucine.
  • the resultant compound of Example 58 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 60 N-(2,3-Dihydroxypropyloxycarbonyl)-leucine Methyl Ester.
  • OsO 4 2.8 ml of a 2.5% solution in t-butanol
  • N-methylmorpholine N-oxide 68.7 mmol.
  • the mixture is partitioned between ether (200 ml) and brine (100 ml).
  • the aqueous layer is back-extracted with ether (2x100 ml), and the combined organic phase is washed with 10% Na 2 SO 3 , 0.1 M H 3 PO 4 , and brine. Drying (MgSO 4 ) and evaporating provides a residue which is chromatographed on silica gel to give the desired compound.
  • Example 61 3-Benzyloxycarbonyl-4-(4-carboxybutyl) oxazolidin-5-one.
  • a solution of 3.0 g (17.1 mmol) of d1- ⁇ -aminopimelic acid in 30 ml of dioxane and 10 ml of water was treated simultaneously in a dropwise fashion with 4.8 g (18.8 mmol) of N-(benzyloxycarbonyloxy) succinimide in 10 ml of dioxane and 17 ml (51 mmol) of 3 N NaOH. After the addition was complete, the reaction mixture was stirred for 1.5 h and concentrated in vacuo.
  • Example 63 N-(3-Benzyloxypropanoyl)-leucine.
  • the resultant compound of Example 62 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 64 N-(2,3-Dihydroxypropyloxycarbonyl)-leucine.
  • the resultant compound of Example 60 is hydrolyzed according to the procedure of Example 9 to give the desired compound.
  • Example 65 (3S.5S,1'R,2'S)-5-(2-Amino-3-cyclohexyl- 1-hydroxypropyl)-3-methyldihydrofuran- 2(3H)-one Hydrochloride.
  • the resultant compound of Example 106 (1.13 g, 2.86 mmol) was dissolved in 10 ml of anhydrous ethanol.
  • the resulting solution was treated with 75 ml of HCl in dioxane (4 M) and stirred at ambient temperature for 1 h. Concentration of the solution in vacuo gave the desired compound as an off-white foam.
  • Example 66 (3S.5S,1'R,2'S)-5-(2-Amino-3-cyclohexyl- 1-hydroxypropyl)-3-methyldihydrofuran- 2(3H)-one Hydrochloride.
  • the resultant compound of Example 106 (1.13 g, 2.86 mmol) was dissolved in 10 ml of anhydrous ethanol.
  • Boc-Leu-Asn Amide of (3S, 5S.1 'R.2'S)-5-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3-methyldihydrofuran- 2(3H)-one A solution of 0.20 g (0.69 mmol) of the resultant compound of Example 65, 0.24 g (2.1 mmol) of 1-hydroxybenzotriazole and 0.15 ml (1.4 mmol) of 4-methylmorpholine in 5 ml of dimethylformamide was cooled under N 2 atmosphere to -23°C and treated with 0.13 g (0.69 mmol) of N-ethylN'-(dimethylaminopropyl) carbodiimide.
  • Example 68 Cbz-Leu-Asn-OH Cbz-Leu-OH (19.8 g, 75 mmol) was coupled to asparagine (9.9 g, 75 mmol) using the mixed anhydride procedure described in Example 3. After extraction into chloroform and washing with water, the product formed a white precipitate in the organic layer. The mixture was filtered, and the residue was washed with chloroform and dried in vacuo at 50°C to provide 10.37 g (37%) of the desired compound.
  • Example 69 Cbz-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2(S)-amino- 1(R)-hydroxy-3-phenylpropyl) furan-3-carboxamide.
  • the resultant 1' (R) ,2' (S) -diastereomer of Example 102 was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to provide, after silica gel chromatography using 7.5% methanol in chloroform, the desired compound in 87% yield.
  • Example 104 Boc-Leu-Asn Amide of N-(1-Hydroxy-3-methylpent-2-yl)- 2-(2-amino-1-hydroxy-3-phenylpropyl) thiophene- 3-carboxamide.
  • the resultant compound of Example 104 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 71 Boc-Leu-Asn Amide of (5S, 1 'R, 2 ' S)-5-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)- 3-methylenedihydrofuran-2(4H)-one.
  • the resultant compound of Example 105 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 72 Boc-Leu-Asn Amide of (2S, 3R.4S, 6S)-2-Amino- 1-cyclohexyl-6-methyl-3,4,7-trihydroxyheptane.
  • the resultant compound of Example 107 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 73 Boc-Leu-Asn Amide of (5S, 1 'R, 2 'S)-5-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3,3- dimethyldihydrofuran-2(3H)-one.
  • the resultant compound of Example 169 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 74 Boc-Leu-Asn Amide of (2S, 3R, 4S)-2-Amino-1- cyclohexyl-6,6-dimethyl-3,4,7-trihydroxyheptane.
  • the resultant compound of Example 170 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 75 2N-Boc-Leu-Asn Amide of (2S, 3R, 4S,6S)- 2-Amino-7-(benzylamino)-1-cyclohexyl-3,4- dihydroxy-6-methylheptane.
  • the resultant compound of Example 109B is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 76 2N-Boc-Leu-Asn Amide of (2S, 3R, 4S, 6S)-1-Cyclohexyl- 2,7-diamino-3,4-dihydroxy-6-methylheptane.
  • the resultant compound of Example 75 is hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
  • Example 77 Cbz-Asn Amide of (2S , 4S, 1 'R, 2 ' S) -2-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)- 4-methyltetrahydrofuran.
  • the resultant compound of Example 108 is deprotected according to the procedure of Example 55 and coupled to Cbz-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 78 Boc-(6-aminohexanoyl) Leu-Asn Amide of (2S, 4S.1 'R, 2'S)- 2-(2-Amino-3-cyclohexyl-1-hydroxypropyl)- 4-methyltetrahydrofuran.
  • the resultant compound of Example 77 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 23 according to the procedure of Example 4 to provide the desired compound.
  • Example 79 (6-Aminohexanoyl) Leu-Asn Amide of (2S, 4S, 1 'R,2'S)- 2-(2-Amino-3-cyclohexyl-1-hydroxypropyl)- 4-methyltetrahydrofuran.
  • the resultant compound of Example 78 is deprotected according to the procedure of Example 2.
  • the crude product is partitioned between ethyl acetate and aqueous NaHCO 3 , dried over MgSO 4 , and concentrated. Chromatography on silica gel provides the desired compound.
  • Example 80 Cbz-Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
  • the resultant compound of Example 110 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 81 (N-Methyl-N-(2-(N,N-dimethylamino) ethyl) carbamoyl)- Leu-Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
  • the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 25 according to the procedure of Example 4 to provide the desired compound.
  • Example 82 2-(((4-Morpholinyl) carbonyl) oxy)-4-methylpentanoyl- Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
  • the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 31 according to the procedure of Example 4 to provide the desired compound.
  • Example 83 (2R)-2-Isobutyl-3- ( ( (4-morpholinyl) carbonyl) amino) propanoyl)-Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy-3-phenylpropane.
  • the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 34 according to the procedure of Example 4 to provide the desired compound.
  • Example 84 (2R)-2-Isobutyl-3-((ethoxycarbonyl) amino) propanoyl)- Asn Amide of 2-Amino-1-cyclopentyl-1-hydroxy- 3-phenylpropane.
  • the resultant compound of Example 80 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 35 according to the procedure of Example 4 to provide the desired compound.
  • Example 85 Boc-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino- 3-cyclohexyl-1-hydroxypropyl) cyclopentanecarboxamide.
  • the resultant compound of Example 111 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 86 Boc-Leu-Asn Amide of (1 'R, 2 'S.5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-ethyloxazolidin-2-one.
  • the resultant compound of Example 118 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 87 Boc-Leu-Asn Amide of (1 'R,2'S , 5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-methoxyoxazolidin-2-one.
  • the resultant compound of Example 119 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 120 Boc-Leu-Asn Amide of (1 'R.2 ' S, 5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-(N-benzyloxycarbonyl- N-methylamino)oxazolidin-2-one.
  • the resultant compound of Example 120 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 89 Boc-Leu-Asn Amide of (1 'R, 2 ' S, 5S)-5-(2-Amino-3-cyclohexyl- 1-hydroxypropyl)-3-(methylamino) oxazolidin-2-one.
  • the resultant compound of Example 88 is hydrogenolyzed according to the procedure of Example 23 to provide the desired compound.
  • Example 128 Boc-Leu-Asn Amide of (1 'R, 2 ' S , 4S) -4-(2-Amino- 3-cyclohexyl-1-hydroxypropyl) dioxolan-2-one.
  • the resultant compound of Example 128 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 91 Boc-Leu-Asn Amide of (1 'R, 2 ' S, 5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-ethylimidazolidin-2-one.
  • the resultant compound of Example 124 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 92 Boc-Leu-Asn Amide of (1 'R, 2 'S, 6S)-6-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-aza-2-oxotetrahydrooyran.
  • the resultant compound of Example 127 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 93 Boc-Leu-Asn Amide of (1 'R, 2'S, 4S)-4-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3-azapiperidin-2-one.
  • the resultant compound of Example 132 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 94 Boc-Leu-Asn Amide of (1 'R, 2 'S.6S)-6-(2-Amino- 3-cyclohexyl-1-hydroxypropyl)-3.4-diaza-2-oxo- 4-methyltetrahydropyran.
  • the resultant compound of Example 135 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 139 Boc-Leu-Asn Amide of (1 'R.2'S.5S)-5-(2-Amino-3- cyclohexyl-1-hydroxypropyl)-3-(hydroxyethyl) oxazolidin- 2-one.
  • the resultant compound of Example 139 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 96 Boc-Leu-Asn Amide of (2S, 3R, 4S)-(2-Amino- 1-cyclohexyl-3,4-dihydroxy-6-methylheptane.
  • the resultant compound of Example 141 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 97 Boc-Leu-Asn Amide of 3-Amino-4-cyclohexyl- 2-hydroxy-1-(isopropylmercapto) butane.
  • the resultant compound of Example 144 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 98 Boc-Leu-Asn Amide of 3-Amino-4-cyclohexyl- 2-hydroxy-1-(isopropylsulfonyl) butane.
  • the resultant compound of Example 145 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 99 Boc-Leu-Asn Amide of (2S, 3R.4S) -4-Amino-1-azido- 5-cyclohexyl-2,3-dihydroxypentane.
  • the resultant compound of Example 149 is deprotected according to the procedure of Example 65 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 100 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) pyrrole.
  • the resultant compound of Example 150 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 102 N-(3-Methylbutyl)-2-(2-(t-butyloxycarbonylamino)- 1-hydroxy-3-phenylpropyl) furan-3-carboxamide. Using the procedure of Example 1 but replacing N-methyl-1-cyclohexenecarboxamide with the resultant compound of Example 102 gives the desired compound.
  • Example 103 N-(1-Hydroxy-3-methylpent-2-yl) thiophene- 3-carboxamide. Thiophene-3-carboxylic acid is coupled to isoleucinol using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 104 N-(1-Hydroxy-3-methylpent-2-yl)-2- (2-(t-butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)thiophene-3-carboxamide. Using the procedure of Example 1 but replacing N-methyl-1-cyclohexenecarboxamide with the resultant compound of Example 103 and using one additional equivalent of n-butyllithium gives the desired compound.
  • Example 105 (5S,4'S.5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2.2-dimethyloxazolidin-5-yl)- 3-methylenedihydrofuran-2(4H)-one.
  • a solution of 16.52 g (51 mmol) of the resultant compound of Example 241 in 15 ml of anhydrous tetrahydrofuran was treated with 3.98 g (61 mmol) of freshly activated zinc dust. With vigorous stirring, the mixture was treated with 10 g (56 mmol) of methyl 2- (bromomethyl) aerylate at a rate which maintained the temperature at 50-60°C.
  • Example 106 (3S,5S,4'S.5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2,2-dimethyloxazolidin-5-yl)- 3-methyldihydrofuran-2(3H)-one.
  • Example 107 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5- (1,4-dihydroxy-3-methylbutyl)-2,2-dimethyloxazolidine.
  • a mixture of 0.50 g (1.26 mmol) of the resultant compound of Example 106 and 0.15 g (4 mmol) of sodium borohydride in 50 ml of tetrahydrofuran was heated at reflux under N 2 atmosphere for 48 h. After being allowed to cool, the mixture was treated cautiously with aqueous NH 4 Cl, extracted with ether, washed with saturated brine, dried over MgSO 4 , and concentrated in vacuo.
  • Example 108 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2- dimethyl-5-(4-methyltetrahydrofuran-2- yl)oxazolidine.
  • a solution of 51 mg (0.13 mmol) of the resultant compound of Example 107 and 0.037 ml (0.27 mmol) of triethylamine in 2 ml of dichloromethane was cooled to 0°C under N 2 atmosphere and treated with 0.012 mol (0.15 mmol) of methanesulfonyl chloride.
  • Example 109 A (3S,5S,4'S,5'R)-5-(3-(t-Butyloxycarbonyl)- 4-(cyclohexylmethyl)-2,2-dimethyloxazolidin-5-yl)- 2-hydroxy-3-methyItetrahydrofuran.
  • a solution of 1.00 g (2.5 mmol) of the resultant compound of Example 106 in 30 ml of anhydrous dichloromethane was cooled under N 2 atmosphere to -78°C and treated dropwise with 3.03 ml (3.0 mmol) of precooled diisobutylaluminum hydride (1.0 M in dichloromethane).
  • Example 110 2-(t-Butyloxycarbonylamino)-1-cyclopentyl- 1-hydroxy-3-phenylpropane.
  • a solution of Boc-phenylalininal (1 mmol) in dry tetrahydrofuran is cooled under N 2 atmosphere to -78°C and treated dropwise with 1.2 mmol of cyclopentylmagnesium chloride (2.0 M in diethylether). After 2 h, the solution is neutralized, extracted with ether, washed with saturated brine, dried over MgSO 4 , and concentrated in vacuo. Silica gel chromatography using hexane/ethyl acetate gives the desired compound.
  • Example 111 N-(3-Methylbutyl)-2-(2-(t-butyloxycarbonylamino)- 1-hydroxy-3-phenylpropyl) cyclopentane-1-carboxamide.
  • a mixture of the resultant compound of Example 6 and 10% palladium on carbon in methanol is shaken under four atmospheres of H 2 for 4 h. Filtration and concentration of the resulting solution gives the desired compound.
  • Example 115 (3S, 4S)-3-Hydroxy-4-tert-butyloxycarbonylamino- 5-cyclohexyl-1-pentene.
  • methylene chloride 20 ml
  • di-tert-butyldicarbonate 1.93 g, 8.84 mmol
  • the mixture was stirred for 14 h, diluted with ethyl acetate, washed sequentially with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution and brine, then dried over Na 2 SO 4 and evaporated to afford 2.51 g (100%) of the desired compound.
  • Example 116 (3S, 4S)-3-Methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexyl-1-pentene.
  • diisopropyl ethylamine (4.60 ml, 26.4 mmol)
  • methoxyethoxy chloromethane (3.00 ml, 26.3 mmol).
  • the mixture was concentrated, diluted with ethyl acetate, washed with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution, then brine, dried over Na 2 SO 4 , and evaporated. Chromatography on silica gel with ethyl acetate/hexane mixtures afforded 2.63 g (80%) of the desired product as an oil.
  • Example 117 (2RS, 3R, 4S)-3-Methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexyl-1,2-oxopentane.
  • To the resultant compound from Example 116 (5.41 g, 14.56 mmol) in methylene chloride (50 ml) was added 3-chloroperbenzoic acid (6.28 g).
  • Example 119 (2'S,1'R,5S)-3-Methoxy-5-(1'-methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- oxazolidin-2-one.
  • Example 120 (2 'S, 1 'R.5S)-3-(Benzyloxycarbonylmethylamino)-5- (1'-methoxyethoxymethoxy)-2'-tert-butyloxycarbonylamino- 3'-cyclohexylpropyl)-oxazolidin-2-one. Prepared from the resultant compound of Example 117 using the procedure of Example 118 and replacing the ethyl amine with one equivalent of 1-methyl-1-benzyloxycarbonylhydrazine.
  • Example 116 To the resultant compound from Example 116 (1.00 g, 2.69 mmol) in tetrahydrofuran (20 ml) at 0°C was added osmium tetroxide (0.75 ml of a 2.5% solution in tert-butanol) and N-methylmorpholine N-oxide (347 mg, 2.95 mmol). The mixture was stirred at room temperature 16 h, diluted with ethyl acetate, washed with NaHSO 3 solution, saturated NaHCO 3 solution and brine, then dried over Na 2 SO 4 and evaporated. Chromatography of the residue on silica gel with methanol/methylene chloride mixtures provided 887 mg (81%) of the desired product.
  • Example 124 (2'S, 1'R, 5S)-3-Ethyl-5-(1 , -methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- imidazolidin-2-one.
  • Example 125 (3S, 4R, 5S)-3-Hydroxy-4-methoxyethoxymethoxy-5-tert- butyloxycarbonylamino-6-cyclohexylhexane nitrile.
  • potassium cyanide 320 mg, 4.91 mmol
  • the mixture was stirred for 32 h, concentrated, diluted with ethyl acetate, washed with water and brine, then dried over Na 2 SO 4 and evaporated. Chromatography on silica gel with 2:1 hexane/ethyl acetate afforded 209 mg (31%) of the desired 3S-isomer as a solid followed by 150 mg (22%) of the 3R-isomer.
  • Example 127 ( 6S, 1'R,2'S)-3-Aza-2-oxo-6-(1'-methoxyethoxymethoxy- 2'-tert-butyloxycarbonylamino-3'- cyclchexylpropyl) tetrahydropyran.
  • the resultant compound from Example 126 (59.0 mg, 0.141 mmol) in methylene chloride (2 ml) at 0°C was treated with triethylamine (100 ) 1, 0.71 mmol) then phosgene in toluene (0.22 mmol in 180 ) 1).
  • Example 128 (2'S,1'R,4S)-2-Oxo-4-(1'-methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- dioxolane.
  • the resultant compound of Example 121 was treated according to the procedure of Example 127 to provide the desired product as an oil.
  • Example 129 (3R, 4R, 5S)-1-Amino-3-hvdroxy-4-methoxyethoxymethoxy-5- tert-butyloxycarbonylamino-6-cyclohexylhexane.
  • the resultant 3R-isomer from Example 125 was treated according to the procedure for Example 126 to provide the desired product.
  • Example 129 The resultant compound from Example 129 was treated according to the procedure for Example 127 except that the phosgene in toluene was replaced with benzyl chloroformate to provide the desired product.
  • Example 131 (3S,4R,5S)-1-Benzyloxycarbonylamino-3-azido- 4-methoxyethoxymethoxy-5-tert-butyloxycarbonylamino- 6-cyclohoxylpentane.
  • the resultant compound from Example 130 was treated according to the procedure of Example 123 to provide the desired product.
  • Example 132 (4S,1'R,2'S)-3-Aza-4-(1'-methoxyethoxymethoxy-2'- tert-butyloxycarbonylamino-3'-cyclohexylpropyl)- piperidin-2-one.
  • the resultant compound from Example 131 was treated according to the procedure of Example 124 to provide the desired product.
  • Example 133 (2S, 3R, 4S)-1-(Benzyloxycarbonylamino) methylamino- 2-hydroxy-3-methoxyethoxymethoxy-4-tert- butyloxycarbonylamino-5-cyclohexylpentane.
  • the desired product was isolated by chromatography on silica gel.
  • Example 134 (2S, 3R, 4S)-1-(Amino)methylamino-2-hydroxy- 3-methoxyethoxymethoxy-4-tert-butyloxycarbonylamino- 5-cyclohexylpentane.
  • the resultant compound from Example 133 and an equal weight of 10% palladium on carbon in methanol were stirred under a hydrogen atmosphere for 6 h.
  • the mixture was filtered and evaporated to provide the desired product.
  • Example 135 ( 6S, 1'R,2'S)-3,4-Diaza-2-oxo-4-methyl-6- (1'-methoxyethoxymethoxy-2'-tert-butyloxycarbonylamino- 3'-cyclohexylpropyl) tetrahydropyran.
  • the resultant compound from Example 134 was treated according to the procedure of Example 118 to provide the desired product.
  • Example 136 N-Benzyloxycarbonyl-2-aminoethanol.
  • benzyl chloroformate 10.0 ml, 70 mmol.
  • the mixture was stirred at 0°C for 30 min, then at room temperature for 1 h, poured into ethyl acetate, washed with 2 M HCl, saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 and evaporated to provide 12.91 g (94%) of the desired compound as a white solid.
  • 1 H NMR (CDCl 3 ,TMS) ⁇ 7.47 (m, 5H) , 5.11 (s,2H), 3.73 (m,2H), 3.38 (m, 2H).
  • Example 137 1-Methoxymethoxy-2-benzyloxycarbonylaminoethane. To the resultant compound from Example 136 (12.91 g, 66.1 mmol) in methylene chloride (100 ml) was added diisopropylethylamine (24.0 ml, 138 mmol) and chloromethylmethylether (10.0 ml, 132 mmol). After 4 h the mixture was evaporated, dissolved in ethyl acetate, washed with 0.5 M H 3 PO 4 , saturated NaHCO 3 solution, and brine, then dried over Na 2 SO 4 , and evaporated to afford 15.27 g (97%) of the desired product as an oil.
  • Example 138 1-Methoxymethoxy-2-aminoethane.
  • the resultant compound from Example 137 (7.60 g, 31.2 mmol) and 10% palladium on carbon (3 g) in methanol (60 ml) were stirred under a hydrogen atmosphere for 24 h. The mixture was filtered, evaporated and distilled to afford 2.02 g (60%) of the desired product as an oil.
  • Example 139 (2 'S,1'R,5S)-3-(2-Methoxymethoxyethyl)-5'- (1'-methoxyethoxymethoxy-2'-tert-butyloxycarbonylamino- 3'-cyclohexylpropyl)-oxazolidin-2-one.
  • Example 117 The resultant compound from Example 117 was treated accordingly to the procedure for Example 118 except that the ethyl amine was replaced with three equivalents of the resultant compound from Example 138 to provide the desired product as an oil.
  • Example 140 (S)-t-Butyloxycarbonylamino-1-cyclohexyl- 6-methylhept-3-ene.
  • Boc-cyclohexylalanine methyl ester 40 g, 140 mmol
  • diisobutylaluminum hydride 130 M%, 1.5 M solution in toluene, 121.4 ml
  • the -78°C aldehyde solution prepared above was then added via cannula. After stirring at -78°C for 15 minutes, the mixture was allowed to slowly warm to room temperature and then heated to 40°C for 12 hours. The mixture was then cooled to room temperature and quenched with methanol (7.65 ml) followed by aqueous Rochelle salts (100 ml saturated solution and 500 ml H 2 O). The mixture was then extracted with ethyl acetate (2x). The combined extracts were washed with water and brine.
  • Example 141 2 (S)-t-Butyloxycarbonylamino-1-cyclohexyl-3,4-dihydroxy- 6-methylheptane : The 3 (R) 4 (S), 3 (S) 4 (S), 3 (R) 4 (R), and 3(S)4(R) Diastereomers.
  • Example 140 To a solution of the resultant compound of Example 140 (8.50, 27.5 mmol) in dry THF (150 ml) were added OsO 4 (2.8 ml of a 2.5% solution in t-butanol and N-methylmorpholine N-oxide (9.28 g, 68.7 mmol). After 4 days the mixture was partitioned between ether (200 ml) and brine (100 ml). The aqueous layer was back-extracted with ether (2 ⁇ 100 ml), and the combined organic phase was washed with 10% Na 2 SO 3 , 0.1 M H 3 PO 4 , and brine. Drying (MgSO 4 ) and evaporating provided a residue (10.81 g) which was chromatographed on silica gel to elute a 60% yield of the 4 diols in the following order.
  • OsO 4 2.8 ml of a 2.5% solution in t-butanol and N-methylmorpholine N-oxid
  • Example 142 2-t-Butyloxycarbonylamino-1-cyclohexylbut-3-ene.
  • methyltriphenyl phosphonium bromide 10.97 g, 30.70 mmol
  • n-butyllithium (19.8 ml of a 1.55 M hexane solution) dropwise over the course of 5 min.
  • the -78°C bath was replaced with a 0°C bath for .5 h, at which time the resulting orange solution was cooled again to -78°C.
  • Example 143 3-t-Butyloxycarbonylamino-4-cyclohexyl-1,2-oxobutane.
  • dichloromethane 20 ml
  • MCPBA m-chloroperbenzoic acid
  • Example 144 3-t-Butyloxycarbonylamino-4-cyclohexyl- 2-hydroxy-1-isopropylmercaptobutane.
  • methanol 8.7 ml
  • isopropyl mercaptan 0.87 mmol
  • triethylamine 0.87 mmol
  • the resultant solution was refluxed for 2 h and then evaporated to give a residue which was chromatographed on 15 g of 40 ) SiO 2 (7/3, hexane/ether) to give the desired compound.
  • Mass spectrum: (M+H) + 346.
  • Example 146 (3S, 4S)-3-tert-Butyldimethylsilyloxy-4-tert- butoxycarbonylamino-5-cyclohexyl-1-pentene.
  • tert- butyldimethylsilyl chloride (0.300 g, 1.99 mmol)
  • imidazole 0.269 g, 3.95 mmol.
  • Example 147 (2RS,3R,4S)-3-tert-Butyldimethylsilyloxy-4-tert- butoxycarbonylamino-5-cyclohexyl-1,2-oxopentane.
  • the resultant compound from Example 146 (0.355 g, 0.893 mmol) in methylene chloride (8 ml) was treated with m-chloroperbenzoic acid (0.758 g, 3.51 mmol) and stirred at ambient temperature for 14 hours.
  • the mixture was concentrated, dissolved in ethyl acetate, washed sequentially with cold 10% aqueous Na 2 SO 3 solution, saturated NaHCO 3 solution and brine, and then dried over
  • Example 148 (2RS, 3R, 4S)-3-Hydroxy-4-tert-butoxycarbonylamino- 5-cyclohexyl-l,2-oxopentane.
  • the resultant compound from Example 147 (2.10 g, 5.07 mmol) was treated with 1 M tetrabutylammonium fluoride in tetrahydrofuran (10 ml) .
  • the mixture was stirred at 0°C for 1 hour, poured into ethyl acetate, washed with water and brine, then dried over Na 2 SO 4 and evaporated. Chromatography on silica gel (u.5% methanol in chloroform) afforded 1.3 g (74%) of the desired compound.
  • Mass spectrum: (M+H) + 300.
  • Example 149 (2S, 3R, 4S) -1-Azido-2,3-dihydroxy-4-tert- butoxycarbonylamino-5-cyclohexylpentane.
  • the resultant compound from Example 148 (1.12 g, 3.74 mmol), ammonium chloride (0.374 g, 6.98 mmol) and sodium azide (0.580 g, 8.92 mmol) were refluxed in methanol (25 ml) for 12 hours. The mixture was concentrated, then taken up in ethyl acetate, washed with water and brine, dried over Na 2 SO 4 and evaporated.
  • Example 150 1-(t-Butyloxycarbonyl)-2-(2-(t-butyloxycarbonylamino)- 1-hydroxy-3-phenylpropyl) pyrrole.
  • a solution of 1-Boc-2-lithiopyrrole (J. Org. Chem. 1981, 46, 157) is cooled to -78°C and treated with Boc-phenylalaninal (Chem. Pharm. Bull. 1982, 30 , 1921). After 0.5 h, the solution is treated with saturated NH 4 Cl, extracted with ether, dried over MgSO 4 , and concentrated to the crude product which is purified by silica gel chromatography to give the desired compound.
  • Example 151 5-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylprnpyl)-1-methylpyrrazole Using the procedure of Example 150, 5-lithio-1-methylpyrrazole (Justus Liebigs Ann. Chem. 1959, 625, 55) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 152 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-1-methylimidazole. Using the procedure of Example 150, 2-lithio-1-methylimidazole (J. Org. Chem. 1973, 15., 3762) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 153 5-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-1-methyltetrazole. Using the procedure of Example 150, 5-lithio-1-methyltetrazole (Can. J. Chem. 1971, 49, 2139) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 154 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-4.5-dihydrofuran. Using the procedure of Example 150, 2-lithio-4,5- dihydrofuran (Tetrahedron Lett. 1977, 4187) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 155 6-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-3,4-dihydro(2H) pyran. Using the procedure of Example 150, 6-lithio-3,4-dihydro (2H)pyran (Acad. Sci., Paris, Ser. C, 1977, 284. 281) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 156 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl)-4,4-dimethyloxazoline. Using the procedure of Example 150, 2-lithio-4,4-dimethyloxazoline (J. Amer. Chem. Soc. 1970, 92, 6676) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 157 5-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl) isothiazole-4-carboxylic Acid. Using the procedure of Example 150, lithium 5-lithioisothiazole-4-carboxylate (J. Chem. Soc. 1964, 446) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 158 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl) thiazole. Using the procedure of Example 150, 2-lithiothiazole (Bull. Soc. Chim. Fr. 1962, 2072) is condensed with Boc-phenylalaninal to give the desired compound.
  • Example 159 2-(2-(t-Butyloxycarbonylamino)-1-hydroxy- 3-phenylpropyl) tetrahydrofuran. Using the procedure of Example 106, the resultant compound of Example 154 is hydrogenated to give the desired compound.
  • Example 160 2-(2-(t-Butyloxycarbonylaminot-1-hydroxy- 3-phenylpropyl) tetrahydro (2H) pyran. Using the procedure of Example 106, the resultant compound of Example 155 is hydrogenated to give the desired compound.
  • Example 162 (3S,4S)-4-t-Butyloxycarbonylamino-3-hydroxy- 6-methyl-1-heptene.
  • Boc-leucinal 1.5 g, 6.97 mmol
  • THF tetrahydrofuran
  • a -78°C solution of vinyl magnesium bromide 7 mmol
  • anhydrous THF 40 ml
  • the organic phase was separated, washed with brine (2 ⁇ 10 ml) and dried (Na 2 SO 4 ). Filtration and evaporation provided an oil which was purified by flash chromatography on silica gel with 7/3 hexane-ether. There was obtained a 53% yield of product, mp 57-59°C.
  • Example 163 4 (S) -Isobutyl-5 (S)-vinyl-2-oxazolidinone. To a solution of (3S,4S)-4-t-butyloxycarbonylamino-3-hydroxy-6-methyl-1-heptane (10.5 g, 0.043 mol) in dimethylformamide (DMF) (100 ml) was added sodium hydride
  • Example 164 4 (S)-Isobutyl-5(S)-(2-mesyloxyethyl)-2-oxazolidinone.
  • 4 (S) -isobutyl-5(S)-vinyl-2-oxazolidinone (4.7 g, 0.028 mol) in THF (20 ml) was added 9-BBN (9-borabicyclo(3.3.1)nonane, 75 ml, 0.0375 mol in THF) by dropwise addition. After stirring for 5 h at room temperature, the reaction was quenched by the addition of water (1 ml).
  • Example 166 4 (S)-Isobutyl-5(S)-(2-(phenethylsulfonyl) ethyl)- 2-oxazolidinone.
  • 4 (S)-isobutyl-5(S)-(2-(phenethylmercapto) ethyl)-2-oxazolidinone (0.49 g, 1.59 mmol) in methylene chloride (6 ml) was added 0.756 g (3.5 mmol) of in-chloroperoxybenzoic acid. After stirring for 1 h at room temperature, the methylene chloride solution was washed successively with aqueous NaHS03 and aqueous NaOH. The organic layer was dried and evaporated to a solid product.
  • Example 168 (3S,4S)-4-Amino-3-hydroxy-6-methyl- 1-phenethylsulfonylheotane. Using the procedure of Example 167 with the resultant compound of Example 166, gave the desired compound, mp 153-154°C.
  • Example 170 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5-(1,4- dihydroxy-3,3-dimethylbutyl)-2,2-dimethyloxazolidine.
  • Example 107 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5-(1,4- dihydroxy-3,3-dimethylbutyl)-2,2-dimethyloxazolidine.
  • Example 107 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-5-(1,4- dihydroxy-3,3-dimethylbutyl)-2,2-dimethyloxazolidine.
  • Example 171 Boc-Gly-Asn Amide of 5-(2-Amino-1-hydroxy- 3-phenylpropyl)-1-methylpyrrazole.
  • the resultant compound of Example 151 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine according to the procedure of Example 66. After purification, the resulting compound is hydrogenolyzed according to the procedure of Example 23 and coupled to Boc-glycine according to the mixed anhydride procedure of Example 4 to provide the desired compound.
  • Example 172 Cbz-Ser-Ile Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl)-1-methylimidazole.
  • the resultant compound of Example 152 is deprotected according to the procedure of Example 2 and coupled to Boc-Ile-OH according to the procedure of Example 4. After purification, the resulting compound is deprotected according to the procedure of Example 2 and coupled to Cbz-serine according to the procedure of Example 66 to provide the desired compound.
  • Example 173 Boc-Leu-Asn Amide of 5-(2-Amino-1-hydroxy- 3-phenylpropyl)-1-methyltetrazole.
  • the resultant compound of Example 153 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 174 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl)-4,5-dihydrofuran.
  • the resultant compound of Example 154 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 175 Boc-Leu-Asn Amide of 6-(2-Amino-1-hydroxy- 3-phenylpropyl)-3,4-dihydro (2H) pyran.
  • the resultant compound of Example 155 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 176 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl)-4,4-dimethyloxazoline.
  • the resultant compound of Example 156 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 177 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) thiazole.
  • the resultant compound of Example 158 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 178 Boc-Gln-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) tetrahydro (2H) pyran.
  • the resultant compound of Example 160 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine according to the procedure of Example 66. After purification, the resulting compound is hydrogenolyzed according to the procedure of Example 23 and coupled to Boc-glutamine according to the procedure of Example 66 to provide the desired compound.
  • Example 179 Boc-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 4-methylpentyl)benzothiazole.
  • the resultant compound of Example 161 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 167 The resultant compound of Example 167 is coupled to
  • Example 181 Boc-Leu-Asn Amide of (3S,45)-4-Amino-3-hydroxy- 6-methyl-1-(phenethylsulfonyl) heptane.
  • the resultant compound of Example 168 is coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 182 Cbz-Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) tetrahydrofuran.
  • the resultant compound of Example 159 is deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to provide the desired compound.
  • Example 183 (5-(3-(Benzyloxycarbonyl) oxazolidin-5-on- 4-yl)pentanoyl)-Leu-Asn Amide of 2-(2-Amino- 1-hydroxy-3-phenylpropyl) tetrahydrofuran.
  • the resultant compound of Example 182 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 61 according to the procedure of Example 4 to provide the desired compound.
  • Example 184 Boc-Leu-Asn Amide of 5-(2-Amino-1-hydroxy- 3-phenylpropyl) isothiazole-4-carboxylic Acid.
  • the resultant compound of Example 157 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 3 to provide the desired compound.
  • Example 185 Boc-Leu-Asn Amide of (2S, 4 S , 5S)-N-(3-Methylbutyl)- 5-amino-6-cyclohexylhexan-2,4-diol-2-carboxamide.
  • Example 186 Boc-Leu-Asn Amide of (4S,5S)-N-Methvl-5-amino- 6-phenylhexan-1,4-diol-2-carboxamide.
  • (4S,5S)-N-Methyl-5-(t-butyloxycarbonylamino)-6-phenyl-hexan-1,4-diol-2-carboxamide J. Org. Chem. 1986, 51, 3921
  • Example 2 was deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Mass spectrum: (M+H) + 576.
  • Example 187 Boc-Leu-Asn Amide of (2S, 4S, 5S)-N-Isobutyl-5-amino- 1-chloro-6-cyclohexylhexan-2,4-diol-2-carboxamide.
  • (2R, 4S, 5S)-5-(t-Butyloxycarbonylamino)-6-cyclohexyl-2- (N-isobutylcarboxamido)-1-hexen-4-ol-1,2-oxide J. Med. Chem. 1987, 30, 1978
  • Example 188 Boc-Leu-Asn Amide of (2R, 4S, 5S)-N-Isobutyl-5-amino- 1-azido-6-cyclohexylhexan-2,4-diol-2-carboxamide.
  • (2R,4S,5S)-N-Isobutyl-1-azido-5-(t-butyloxycarbonyl-amino)-6-cyclohexylhexan-2,4-diol-2-carboxamide J. Med. Chem. 1987, 30, 1978
  • Example 2 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 189 6-Carboxy-6-(dimethylamino) hexanoyl-Leu-Asn Amide of 2-(2-Amino-1-hydroxy-3-phenylpropyl) tetrahydrofuran.
  • the resulting mixture is filtered through Celite, diluted with chloroform, dried over Na 2 SO 4 , and concentrated.
  • the crude product is purified by silica gel chromatography to give the desired compound.
  • Example 190 6-(Benzyloxycarbonyl) amino-6-carboxyhexanoyl-Leu-Asn Amide of 2-(2-Amino-1-hydroxy-3- phenyloropyl) tetrahydrofuran.
  • a solution of 0.042 mmol of the resultant compound of Example 183 in 2 ml of tetrahydrofuran and 1 ml of water is treated with 1.9 mg (0.046 mmol) of lithium hydroxide monohydrate. After completion of the reaction, the solution is acidified with HCl, extracted with chloroform, dried over MgSO 4 , and concentrated to give the desired compound.
  • Example 191 6-(Benzyloxycarbonylamino)-6-(methoxycarbonyl) hexanoic Acid.
  • a solution of 0.20 g (0.62 mmol) of the resultant compound of Example 61 in methanol was treated with sodium methoxide and stirred at ambient temperature for 2 h.
  • the solvent was removed in vacuo, and the residue was acidified with 1N HCl, extracted with chloroform, and concentrated to give 159 mg of the desired compound.
  • Example 192 6-(Benzyloxycarbonylamino)-6-(methoxycarbonyl)hexanoyl- Leu-Asn Amide of 2-(2-Amino-1-hydroxy- 3-phenylpropyl) tetrahydrofuran.
  • the resultant compound of Example 182 is hydrogenolyzed according to the procedure of Example 23 and coupled to the resultant compound of Example 191 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 193 6-Amino-6-(methoxycarbonyl) hexanoyl-Leu-Asn Amide of 2-(2-Amino-1-hydroxy-3-phenylpropyl) tetrahydrofuran.
  • the resultant compound of Example 192 is hydrogenated using the procedure of Example 23 to give the desired compound.
  • Example 194 6-Amino-6-carboxyhexanoyl-Leu-Asn Amide of 2-(2-Amino- 1-hydroxy-3-phenylpropyl) tetrahydrofuran. Using the procedure of Example 190 with the resultant compound of Example 193 gives a crude lithium salt which is neutralized to pH 7 and extracted with chloroform to give the desired compound.
  • Example 195 Cbz-Ile-Ser-OMe.
  • H-Ser-OMe-HCl 5.7 g, 36.6 mmol
  • DMF dimethylformamide
  • 4-methylmorpholine 3.7 g, 36.6 mmol
  • Cbz-Ile-OH 9.8 g, 37 mmol
  • 1-hydroxybenzotriazole (HOBT) monohydrate 5.4 g, 40 mm
  • EDAC N-ethyl-N'- (dimethylaminopropyl) carbodiimide
  • Example 196 H-Ile-Ser-OMe HCl
  • the resultant compound of Example 195 (3.4 g, 9.29 mmol) was hydrogenated at 4 atm H 2 with 20% Pd/C in methanol/HCl to obtain 2 g (80%) of the desired product.
  • 1 H NMR (DMSO, TMS) ⁇ 0.8-1.0 (m, 6H) , 3.65 (s,3H), 3.8 (m, 2H), 4.4 (m, 1H) , 5.3 (t,1H).
  • Mass spectrum: (M+H) + 233.
  • Example 197 Cbz-Phe-Pro-O-t-Bu.
  • a mixture of Cbz-Phe-OH (3.89 g, 13 mmol) and H-Pro-O-t-Bu (2 g, 11.7 mmol) in 50 ml anhydrous DMF was added with HOBT monohydrate (2 g, 15 mmol) and EDAC (2.2 g, 11.9 mmol) at 0°C.
  • the mixture was stirred at 0-5°C for 3 h and then at room temperature for 16 h.
  • the mixture was poured into ethyl acetate, washed with citric acid, dilute NaHCO 3 solution, and then water.
  • Example 198 Cbz-Phe- R Pro-OH
  • the resultant compound of Example 197 (3.3 g, 7.29 mmol) was dissolved in 300 ml anhydrous tetrahydrofuran (THF) and 14 ml of 1 M BH 3 in THF (14 mmol) was added at - 20°C. After addition was complete, the reaction mixture was stirred at -20°C for 4 h, and at room temperature for 12 h. The reaction mixture was cooled back to -20°C and methanol was added dropwise until H 2 ceased to evolve. The solvent was evaporated under reduced pressure to a residual liquid. Some methanol was added and evaporated again. The residual oil was chromatographed on silica gel* eluting with ethyl acetate:hexane (1:4) to afford 1.4 g (37.6%) of pure product.
  • Example 199 Cbz-Phe- R Pro-Ile-Ser-OMe.
  • the resultant compounds of Example 198 600 mg, 1.43 mmol) and Example 196 (376 mg, 1.4 mmol) were mixed in 8 ml anhydrous DMF. After cooling to 0°C, 4-methylmorpholine (303 mg, 3.0 mmol) was added followed by HOBT monohydrate (270 mg, 2 mmol) and EDAC (287 mg, 1.5 mmol). The mixture was stirred at 0-5°C for 3 h and at room temperature for 12 h. The mixture was poured into ethyl acetate, washed with dilute NaHCO 3 solution, water, dried, and filtered.
  • Example 199 The resultant compound of Example 199 (300 mg, 0.5 mmol) was hydrogenated with 20% Pd/C at 4 atm H2 in methanol/HCl to obtain 180 mg (69.8%) of the deprotected product which was used in the next step without further purification.
  • Example 202 Boc-Leu-Asn-Phe- R Pro-NHCH 2 Ph.
  • the resultant compound from Example 201 is deprotected and coupled as described in Example 200 to give the desired compound.
  • Example 203 Boc-L ⁇ u-Asn-Phe- R Pip-NHCH 2 Ph.
  • Cbz Phe- R Tip-OH is prepared starting from (L) - pipecolinic acid t-butyl ester (Pip-O-t-Bu) using the procedures described in Examples 197 and 198. This material is coupled sequentially to benzylamine and then to Boc-Leu-Asn-OH as described in Examples 199 and 200 to give the desired compound.
  • Example 204 Boc-Leu-Asn-Phe- R Azd-NHCH 2 Ph.
  • Example 198 replacing Pro-O-t-Bu in Examples 197 and 198 with (S)-(-)-2-azetidine carboxylic acid tert-butyl ester (Azd-O-t-Bu) gives Cbz-Phe- R Azd-OH. This is coupled as described in Examples 199 and 200 with benzylamine and Boc-Leu-Asn-OH to give the desired product.
  • Example 205 3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2- dimethyl-4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)- 2(S)-chloro-3-hydroxy-1-oxopropyl)-4(S)- (phenylmethyl)-2-oxazolidinone.
  • the cooling bath was removed after 5 min, and the resulting mixture was stirred at ambient temperature for 2 hr.
  • the mixture was recooled to -78°C, then treated dropwise with a solution of the resultant compound from Example 241 (1.30 g, 3.98 mmol) in 10 ml ether.
  • the reaction is quenched with 20 ml 0.5 M aqueous NaHS04 and 30 ml Et 2 O at 0°C.
  • the aqueous phase is further extracted with 2 X 20 ml Et 2 O, and the combined organic phases are washed with 20 ml H 2 O, and the organic phase concentrated under reduced pressure.
  • aqueous phase was further extracted with CH 2 Cl 2 (2 X 10 ml), and the combined organic phases were washed with 15 ml brine, dried (MgSO 4 ), filtered and concentrated under reduced pressure to produce 109 mg of crude mixture of products (oxazolidinone plus carboxylic acid).
  • This mixture was dissolved in 5 mL dry DMF, the solution was cooled to 0° under an argon atmosphere, and a solution of potassium tert-butoxide (0.90 ml, 1.0 M in THF, 0.90 mmol) was introduced into the reaction.
  • Example 208 5 (S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-4(R)-(n- butylcarboxamido)-3-ethyl-2-oxazolidinone.
  • the resultant compound from Example 207 (34.3 mg, 0.0755 mmol) was coupled to n-butylamine (7.4 mg, 0.10 mmol) to provide the desired compound.
  • Example 209 5 (S)-(2(S)-Amino-3-cyclohexyl-1-hydroxypropyl)-4(R)-(n- butylcarboxamido)-3-ethyl-2-oxazolidinone.
  • the resultant compound from Example 208 (6.4 mg, 0.013 mmol) was dissolved in 0.6 ml dry CH 2 CI 2 , cooled to -10° (N 2 ), and the resulting solution treated with 0.6 ml trifluoroacetic acid. After 1.5 h at -10° to 0°, the solvent was removed under reduced pressure without warming, then the residue was dissolved in 1 ml THF and 0.5 ml H 2 O.
  • the resulting solution was stirred at ambient temperature for 2.5 hr, at which time the solution was concentrated under reduced pressure and the residue partitioned between 15 ml CH 2 CI 2 and 10 ml 1.0 M Na 2 CO 3 .
  • the aqueous phase was further extracted (2 X 10 ml CH 2 CI 2 ) 1 and the combined organic phases were washed with 15 ml brine, dried (Na2S04) and concentrated to yield 5.1 mg (109%) of the desired product as a viscous oil.
  • the resultant compound of Example 209 is coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 211 3-(3(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-2(R)-bromo- 3-hydroxy-1-oxopropyl)-4(R)-(phenylmethyl)- 2-oxazolidinone.
  • the boryl enolate derived from the resultant compound from Example 206 is allowed to react with the resultant compound from Example 241, to provide the desired product.
  • Example 208 3-(3(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-2(R)-bromo- 3-(N-methylcarbamoyloxy)-1-oxopropyl)-4(R)- (phenylmethyl)-2-oxazolidinone.
  • the resultant compound from Example 211 is treated with methyl isocyanate to provide the desired compound.
  • Example 213 3(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-2(R)-bromo-3- (N-methylcarbamoyloxy) propanoic acid.
  • the resultant compound from Example 212 is hydrolyzed with lithium hydroxide-monohydrate to afford the desired product.
  • Example 213 5(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-4(S)-carboxyl-3- methyl-2-oxazolidinone.
  • the resultant compound from Example 213 is cyclized with potassium tert- butoxide in DMF, affording the desired compound.
  • reaction is quenched with 1 ml pH 7 phosphate buffer, and the resulting mixture is partitioned between 15 ml CH 2 Cl 2 and 5 ml water.
  • the aqueous phase is extracted (2 X 5 ml CH 2 Cl 2 ), and the combined organic phases are washed (5 ml saturated aqueous CuSO 4 , 5 ml water, 5 ml brine), dried over MgSO 4 , filtered and concentrated under reduced pressure. The residue is further dried under high vacuum to afford the crude mesylate.
  • the mesylate is then dissolved in 2 ml DMF, cooled to 0°C and treated with sodium hydride (16 mg, 0.40 mmol). The reaction mixture is allowed to warm to room temperature and stir until TLC indicates complete reaction.
  • the DMF is removed under high vacuum, and the residue is partitioned between 15 ml CH 2 Cl 2 and 5 ml H 2 O.
  • the aqueous phase is extracted (2 X 5 ml CH 2 Cl 2 ), and the combined organic phases are washed with 5 ml brine, dried over MgSO 4 , and! the filtrate concentrated under reduced pressure. Purification by column chromatography produces the desired compound.
  • Example 216 3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(4-methoxyphenyl) methyl)-5(R)-oxazolidinyl)- 3-hydroxy-2(R)-(2-propenyl)-1-oxooropyl)-4(R)-methyl- 5(S)-phenyl-2-oxazolidinone.
  • the resultant compound from Example 243 is allowed to react with the boryl enolate derived from the resultant compound from Example 215 to afford the desired product.
  • a solution of the resultant compound from Example 220 (292 mg, 0.500 mmol) in 2 ml ether is treated with 2 ml of saturated aqueous NaHCO 3 , cooled to 0°C, and a solution of iodine (127 mg, 0.500 mmol) in 0.5 ml ether.
  • the iodomethyl-tetrahydrofuran is isolated by extraction with Et 2 O, and the ether extract is washed with 5% aqueous NaHCO 3 , brine, then concentrated under reduced pressure.
  • Example 2 (R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-5(R,S)-methyl- 2,3,4,5-tetrahydrofuran-3(R)-carboxylic Acid.
  • the resultant compound from Example 221 is hydrolyzed with lithium hydroxide-monohydrate to produce the desired compound.
  • a solution of the resultant compound from Example 216 (175 mg, 0.299 mmol) is dissolved in 0.7 ml dry CH 2 Cl 2 and 0.7 ml dry methanol, cooled to 0°C under a nitrogen atmosphere, and treated with a mixture resulting from the addition of methylmagnesium bromide (1.31 mmol) to 2.0 ml methanol.
  • the resulting mixture is stirred at 0°C for 3 hr, and at room temperature for 0.5 hr.
  • the mixture is quenched with pH 7 phosphate buffer and extracted with CH 2 Cl 2 (4 X 25 ml).
  • the combined organic phases were dried over MgSO 4 , and the filtrate is concentrated in vacuo. The residue is purified by column chromatography to afford the desired compound.
  • Example 225 Methyl 3 (R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-3-hydroxy- 2(R)-(3-hydroxypropyl) propionate.
  • the procedure of D.A. Evans and A.E. Weber J. Am. Chem. Soc. 1987, 109, 7151) is adapted.
  • To a 0°C suspension of di-cyclohexylborane (1.5 equivalents) in dry CH 2 Cl 2 is added a solution of the resultant compound from Example 224 (1.0 equivalents).
  • the cooling bath is removed, and the resulting mixture is stirred at room temperature for 5 hr.
  • the mixture is recooled to 0°C and treated with 30% aqueous H 2 O 2 in 1.0 M NaOH. After 1 hr, the mixture is partitioned between H 2 O and CH 2 Cl 2 , then the organic phase dried over MgSO 4 , and the filtrate concentrated under reduced pressure. Purification of the residue by column chromatography affords the desired product.
  • Example 226 2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-3(R)- (methoxycarbonyl)-2,3,4,5-tetrahydropyran. Using the procedure of Example 218, the resultant compound from Example 225 is cyclized to afford the desired compound.
  • Example 210 The resultant compound of Example 210 is coupled to H-Ile-Ser-OMe according to the procedure of Example 66 to give the desired compound.
  • Example 227 N-(Boc-Leu-Asn Amide of 5(S)-(2(S)-Amino- 3-cyclohexyl-1(R)-hydroxypropyl)-3-methyl- 2-oxazolidinon-4(R)-carbonyl)- Ile-Ser Methyl Ester.
  • the resultant compound of Example 227 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 229 5(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- (cyclohexylmethyl)-5(R)-oxazolidinyl)-3-methyl- 4(S)-(N-(2-methylbutyl) carbamoyl)-2-oxazolidinone.
  • the resultant compound of Example 214 is coupled to (2-methylbutyl) amine according to the procedure of Example 66 to give the desired compound.
  • Example 229 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 26 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 231 N-(2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-(cyclohexylmethyl)-5(R)-oxazolidinyl)-2,3,4,5- tetrahydrofuran-3(R)-carbonyl)-Ile-Ser Methyl Ester.
  • the resultant compound of Example 219 is coupled to H- Ile-Ser-OMe according to the procedure of Example 66 to give the desired compound.
  • Example 232 N-(2(R)-((3,4-cis-Dihydroxypyrrolidinylcarbonyl)- Leu-Asn Amide of 2(S)-Amino-3-cyclohe ⁇ yl-1(R)- hydroxypropyl)-2,3,4,5-tetrahydrofuran-3(R)- carbonvl)-Ile-Ser Methyl Ester.
  • the resultant compound of Example 231 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 27 using the procedure of Example 66 to give the desired compound.
  • Example 233 N-(2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-((4-methoxyphenyl) methyl)-5(R)-oxazolidinyl)- 5-methyl-2,3,4,5-tetrahydrofuran-3(R)-carbonyl)- Ile-Ser Methyl Ester.
  • the resultant compound of Example 222 is coupled to H-Ile-Ser-OMe according to the procedure of Example 66 to give the desired compound.
  • Example 235 2(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- ((4-hydroxyphenyl) methyl)-5(R)-oxazolidinyl)- 5-methyl-3(R)-(N-(2-methylbutyl) carbamoyl)- 2,3,4,5-tetrahydrofuran.
  • the resultant compound of Example 223 is coupled to (2- methylbutyl) amine according to the procedure of Example 66 to give the desired compound.
  • Example 236 2 (R)-((3-Benzyloxycarbonylaminopropyl)-Leu-Asn Amide of 2(S)-Amino-1(R)-hydroxy-3- (4-methoxyphenyl) propyl)-5-methyl-3(R)-(N-(2- methylbutyl) carbamoyl)-2,3,4,5-tetrahydrofuran.
  • the resultant compound of Example 235 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 50 using the procedure of Example 66 to give the desired compound.
  • Example 237 2(R)-(Cbz-Sar-Leu-Asn Amide of 2(S)-Amino- 3-cyclohexvl-1(R)-hydroxypropyl)-3(R)- methoxycarbonyl-2,3,4,5-tetrahydropyran.
  • the resultant compound of Example 226 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 52 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 236 is deprotected according to the procedure of Example 23 to give the desired compound.
  • Example 237 (R)-(H-Sar-Leu-Asn Amide of 2 (S)-Amino-3-cyclohexyl- 1(R)-hydroxypropyl)-3(R)-methoxycarbonyl-2,3,4,5- tetrahydropyran.
  • the resultant compound of Example 237 is deprotected according to the procedure of Example 23 to give the desired compound.
  • Example 240 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)- 2,2-dimethyl-5-vinyloxazolidine.
  • the procedure of S. Thaisrivong J. Med. Chem. 1987, 30, 976) was employed.
  • a solution of 40 g of the resultant compound of Example 112 and 102 g of 2-methoxypropene in 250 ml of dichloromethane was stirred at room temperature.
  • Solid pyridinium p-toluenesulfonate (PPTS) (177 g) was added slowly to the reaction mixture. After addition was complete, the reaction was stirred for 1 h and neutralized by addition of solid sodium bicarbonate. The solids were filtered and the filtrate was concentrated.
  • PPTS Solid pyridinium p-toluenesulfonate
  • Example 241 3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2- dimethyloxazolidine-5-carboxaldehyde.
  • the reaction mixture was cannulated into a suspension of 8 g zinc dust, 8 ml glacial acetic acid, 200 ml water, and 200 ml of methanol cooled to -45°C.
  • Example 242 3-(t-Butyloxycarbonyl)-2,2-dimethyl-4-(phenylmethyl)- oxazolidine-5-carboxaldehyde. Using the procedures of Examples 112, 240, and 241 but replacing Boc-cyclohexylalanine methyl ester with Boc-phenylalanine methyl ester gives the desired compound.
  • Example 243 3- (t-Butyloxycarbonyl)-2,2-dimethyl-4- ((4-methoxyphenyl)methyl)-oxazolidine- 5-carboxaldehyde. Using the procedures of Examples 112, 240, and 241 but replacing Boc-cyclohexylalanine methyl ester with Boc-(4-methoxy)phenylalanine methyl ester gives the desired compound.
  • Example 246 3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-2(S),3- dihydroxy-1-oxopropyl)-4(S)-isopropyl- 2-oxazolidinone.
  • a solution of the resultant compound from Example 245 (0.5 mmol) in 5 ml ethanol is exposed to 1 atmosphere of hydrogen gas in the presence of 0.5 g of 10% palladium on carbon at ambient temperature. The mixture is stirred for 18 hr, then filtered through a pad of celite, and the filtrate is concentrated under reduced pressure to give the desired product.
  • Example 247 3-((5(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-1,3-dioxolan- 2-one-4(S)-yl)carbonyl)-4(S)-isopropyl- 2-oxazolidinone.
  • the solution is cooled, diluted with 40 ml CH 2 Cl 2 , and washed with 20 ml 0:1 M NaHSO 4 .
  • the organic phase is washed with 20 ml brine, dried (Na 2 SO 4 ), and the filtrate is concentrated under reduced pressure to afford the desired product.
  • Example 249 (4R, 5S)-4-Methyl-5-phenylpxazolidine-2-one.
  • the flask was fitted for distillation through a 12" Vigreux column and placed in an oil bath pre-equilibrated to 150°C. The stirred solution was heated until ethanol distillation ceased (overnight).
  • Example 250 5 (S)-(3-(tert-Butyloxycarbonyl)-2.2-dimethyl-4(S)- benzyl-5(R)-oxazolidinyl)-4(R)-carboxy-1,3- dioxolan-2-one.
  • Example 251 3-(Bromoacetyl)-4(S)-isopropyl-2-oxazolidinone. Using the procedure of Example 244, 4 (S) -isopropyl-2-oxazolidinone was acylated with bromoacetyl bromide to give the desired product.
  • 1 H NMR (CDCl 3 ) ⁇ 0.92 (d,3H), 0.95 (d,3H), 2.42 (m, 1H) , 4.27 (dd, 1H), 4.35 (t,1H), 4.43 (d,1H), 4.47 (m,1H), 4.61 (d, 1H).
  • Mass spectrum: (M+NH 4 ) + 267.
  • Example 253 3-(5(S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)- 2-thionooxazolidinyl)-4(S)-carbonyl)- (4S) -isopropyl-2-oxazolidinone.
  • the procedure of D.A. Evans and A.E. Weber J. Am. Chem. Soc. 1987, 109, 7151) is adapted.
  • Example 224 Using the procedure of Example 224 with the resultant compound of Example 253 gives the desired compound.
  • Example 255 5 (S)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl- 4 (S)-cyclohexylmethyl-5(R)-oxazolidinyl)- 4 (S)-methoxycarbonyl-2-oxazolidinone.
  • the procedure of D. Hoppe and R. Follmann (Chem. Ber. 1976, 109. 3047) is adapted.
  • a 1 M solution of the resultant compound from Example 254 in formic acid is cooled to 0°C and treated with 2 equivalents of 30% aqueous H 2 O 2 .
  • Example 248 is coupled to H-Ile-Ser-OMe according to the procedure of Example 66.
  • the resulting compound from that coupling is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 257 N- (Boc-Leu-Asn Amide of 5 (S)-(2(S)-Amino- 3-phenyl-1 (R)-hydroxypropyl)-1,3-dioxolan-2-on- 4(S)-carbonyl)-Ile-Ser Methyl Ester.
  • the resultant compound of Example 250 is. coupled to H-Ile-Ser-OMe according to the procedure of Example 66.
  • the resulting compound from that coupling is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 258 Boc-Leu-Asn Amide of 5 (S) - (2 (S) -Amino-3-cyclohexyl- 1 (R) -hydroxypropyl)-4(S)-(methoxycarbonyl)-2- thionooxazolidine.
  • the resultant compound of Example 254 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 259 Boc-Leu-Asn Amide of 5 (S)-(2(S)-Amino-3-cyclohexyl- 1(R)-hydroxypropyl)-4(S)-(methoxycarbonyl)- oxazolidine-2-one.
  • the resultant compound of Example 255 is deprotected according to the procedure of Example 2 and coupled to Boc-Leu-Asn-OH according to the procedure of Example 66 to give the desired compound.
  • Example 260 (N-Methyl-2,3-dihydroxypropylamino) carbonyl-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino- 1-hydroxy-3-phenylpropyl) furan-3-carboxamide.
  • the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 39 using the procedure of Example 66 to give the desired compound.
  • Example 261 5-(Methoxycarbonyl)pentanoyl-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
  • the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 41 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 261 The resultant compound of Example 261 is hydrolyzed according to the procedure of Example 9 to provide the desired compound.
  • Example 263 2-Methylpropanoyl-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
  • the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 42 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 264 (2R)-2-Isobutyl-3-(N-methyl-N- (2-methoxyethoxymethoxyethyl) aminocarbonyl) propannyl- Asn Amide of N-(3-Methylbutyl)-2-(2-amino- 1-hydroxy-3-phenylpropyl) furan-3-carboxamids.
  • the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the. resultant compound of Example 47 using the mixed anhydride procedure of Example 4 to give the desired compound.
  • Example 265 (3-Hydroxypropyloxycarbonyl)-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
  • the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 59 using the procedure of Example 66 to give the desired compound.
  • Example 102 (2,3-Dihydroxypropyloxycarbonyl)-Leu-Asn Amide of N-(3-Methylbutyl)-2-(2-amino-1-hydroxy- 3-phenylpropyl) furan-3-carboxamide.
  • the resultant compound of Example 102 is deprotected according to the procedure of Example 2 and coupled to Cbz-Asn-OH according to the procedure of Example 66. After purification, the above compound is deprotected according to the procedure of Example 23 and coupled to the resultant compound of Example 64 using the procedure of Example 66 to give the desired compound.
  • Example 269 2-(3-Phenyl-2-azido-1-hydroxyprop- 1-yl) cyclopentanecarboxylic Acid Methvl Ester.
  • Example 270 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-hydroxyprop-1-yl) cyclopentanecarboxylic Acid Methyl Ester.
  • a stirred solution of 30.3 g (100 mmol) of the resultant compound of Example 269 in 500 ml of MeOH is hydrogenated over 1 g of 10% Pd-C.
  • the reaction is degassed, the catalyst removed by filtration, and the filtrate treated with a slight excess of di-t-butyldicarbonate. Removal of the solvent and chromatography of the residue on silica gel affords the desired product.
  • Example 271 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
  • To a stirred solution of 37.7 g (100 mmol) of the resultant compound of Example 270 in 500 ml of dichloromethane is added 23.0 ml of t-butyldimethylsilyl trifluoromethane sulfonate and 12.8 ml of 2,6-lutidine. After 6 h, the solution is washed with water, dried over MgSO 4 , and concentrated. Chromatography of the residue on silica gel affords the desired product.
  • Example 274 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl) cyclohexanecarboxylic Acid Methyl Ester. Using the procedures of Examples 267, 268, 269, 270, and 271 but substituting 2-formylcyclohexanecarboxylic acid methyl ester for 2-formylcyclopentanecarboxylic methyl ester affords the desired product.
  • Example 275 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl)cyclobutanecarboxylic Acid Methyl Ester. Using the procedures of Examples 267, 268, 269, 270, and 271 but substituting 2-formylcyclobutanecarboxylic acid methyl ester for 2-formylcyclopentanecarboxylic acid methyl ester affords the desired product.
  • Example 276 2-(3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl)benzenecarboxylic Acid. To a stirred solution of 2.01 g (10 mmol) of 2-bromobenzoic acid in 100 ml of THF at -100°C is added 20 ml of 1 M n-BuLi in hexane. After 15 m, a solution of 2.49 g (10 mmol) N-t-butyloxycarbonylphenylalaninal is added, and the solution allowed to warm to -78°C.
  • Example 277 2- (3-Phenyl-2-t-butyloxycarbonylamino- 1-t-butyldimethylsilyloxyprop- 1-yl) cyclopent-1-enecarboxylic Acid. Using the procedure described in Example 276, but substituting 2-bromocyclopent-1-enecarboxylic acid for 2-bromobenzoic acid affords the desired product .
  • Example 279 6-Phenyl-5-t-butyloxycarbonylamino- 4-t-butyldimethylsilyloxy-2-hexenoic Acid. Using the procedure described in Example 276, but substituting 2-bromo ⁇ ropenoic acid for 2-bromobenzoic acid affords the desired product.
  • Example 280 2-(3-(4-Benzyloxy-1-phenyl)-2-t-butoxycarbonylamino- 1-t-butyldimethylsilyloxvprop-1-yl) cyclopent- 1-enecarboxylic Acid. Using the procedure described in Example 277, but substituting N-t-butyloxycarbonyl-0-benzyltyrosinal for N-t-butyloxycarbonylphenylalaninal affords the desired product.
  • Example 281 2-(3-Pheny1-2-t-butyloxycarbonylamino-1-azidoprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
  • Example 282 ( 4-Morpholinyl) carbonyl)-Leu-Asn-Amide of 2-(3-Phenyl-2-amino-1-hydroxyprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
  • the resultant compound of Example 271 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66.
  • the resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 9 using the mixed anhydride method of Example 4 to provide the desired compound.
  • Example 283 Cbz-(( ⁇ , ⁇ -di-Me) ⁇ -Ala)-Leu-Asn-Amide of 2- (3-(4-hydroxyphenyl)-2-amino-1-hydroxyprop- 1-yl) cyclopentanecarboxylic Acid Methyl Ester.
  • the resultant compound of Example 272 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66.
  • the resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 12 using the mixed anhydride method of Example 4 to provide the desired compound.
  • Example 284 ( ⁇ , ⁇ -di-Me) ⁇ -Ala)-Leu-Asn-Amide of 2-(3- Phenyl-2-amino-1-hydroxyprop-yl) cyclopropanecarboxylic
  • Example 273 The resultant compound of Example 273 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 12 using the mixed anhydride method of Example 4. The resultant compound is then hydrogenolyzed according to the procedure of Example 23 to afford the desired compound.
  • Example 274 The resultant compound of Example 274 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 54 using the procedure of Example 66 to provide the desired compound.
  • Example 286 N-((N-Cbz-4-piperidinyl) carbonyl)-Leu-Asn Amide of 2-(3-Phenyl-2-amino-1-hydroxyprop- 1-yl) cyclobutanecarboxylic Acid Methyl Ester.
  • the resultant compound of Example 275 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66.
  • the resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 56 using the mixed anhydride method of Example 4 to provide the desired compound .
  • Example 276 The resultant compound of Example 276 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 56 using the mixed anhydride method of Example 4. The resulting compound is then hydrogenolyzed according to the procedure of Example 23. Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to afford the desired compound.
  • Example 277 The resultant compound of Example 277 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 63 using the mixed anhydride procedure of Example 4. Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to provide the desired compound.
  • Example 278 The resultant compound of Example 278 is deprotected according to the procedure of Example 2 and coupled to Cbz-asparagine using the carbodiimide coupling procedure of Example 66. The resulting compound is then hydrogenolyzed according to the procedure of Example 23 and then coupled to the resultant compound of Example 63 using the mixed anhydride method of Example 4. Hydrogenolysis of the resulting compound according to the procedure of Example 23 followed by treatment under the conditions of Example 9 effects hydrolysis to afford the desired compound.
  • Example 290 Boc-Gln-Ala Amide of 6-Phenyl-5-amino-4-hydroxy- 2-hexenoic Acid.
  • the resultant compound of Example 279 is deprotected according to the procedure of Example 2 and coupled to Boc-alanine using the mixed anhydride coupling procedure of Example 4.
  • the resulting compound is then deprotected according to the procedure of Example 2 and then coupled to Boc-glutamine using the carbodiimide coupling procedure of Example 66.
  • Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to afford the desired compound.
  • Example 291 Boc-Leu-Asn Amide of 2 (3-(4-Hydroxyphenyl)-2-amino-1- hydroxypr ⁇ p-1-yl) cyclopent-1-enecarboxylic Acid.
  • the resultant compound of Example 280 is deprotected according to the procedure of Example 2 and coupled to the resultant compound of Example 3 using the carbodiimide coupling procedure of Example 66.
  • Treatment of the resulting compound under the conditions of Example 9 effects hydrolysis to afford the desired compound.
  • Example 292 Boc-Leu-Asn-3-Amide of 2-(3-Phenvl-2,3-diaminoprop- 1-yl)cyclopentanecarboxylic Acid Methvl Ester.
  • the resultant compound of Example 281 is deprotected according to the procedure of Example 2 and coupled to Boc—Leu-Asn-OH using the carbodiimide coupling procedure of Example 66. Hydrogenolysis under the conditions of Example 23 affords the desired compound.
  • Example 106 Cbz-Leu-Asn Amide of 5 (S)-(2(S)-Amino-3-cyclohexyl- 1(R)-hydroxy)-3(S)-methyl-2,3,4,5-tetrahydrofuran- 2-one.
  • the resultant compound of Example 106 was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to provide, after silica gel chromatography using 5% methanol in chloroform, a 70% yield of the desired compound.
  • Example 295 N-(5-(Methoxycarbonyl)pentanoyl)-Leu-Asn Amide of 5 (S) - (2 (S) -Amino-3-cyclohexyl-1(R)-hydroxy)-3(S)- methyl-2,3.4.5-tetrahydrofuran-2-one.
  • the resultant compound of Example 294 (0.51 g, 0.83 mmol) was added to a mixture of 0.06 g of 10% palladium on carbon in 15 ml of methanol and stirred under 1 atmosphere of H 2 for 24 h.
  • the mixture was filtered through Celite and concentrated to the crude amine, a portion (0.30 g, 0.62 mmol) of which was taken up in 10 ml of dichloromethane and 0.5 ml of dimethylformamide, treated with 0.20 g (0.80 mmol) of N-(5- (methoxycarbonyl)pentanoyloxy) succinimide, and stirred at ambient temperature for 16 h.
  • the resulting mixture was concentrated in vacuo, taken up in ethyl acetate, washed sequentially with 10% citric acid, water, aqueous NaHCO 3 , and saturated brine, dried over MgSO 4 , and concentrated.
  • Example 296 2-(t-Butyloxycarbonylamino)-1,5-diphenylpent-3-ene, A suspension of 20 g (53 mmol) of phenyl 2-(t- butyloxycarbonylamino)-3-phenylpropyl sulfone (Tetrahedron Lett. 1986, 27, 2095) in 500 ml of dry tetrahydrofuran was cooled under inert atmosphere to - 78°C and treated with 65 ml (135 mmol) of n-butyllithium. The resulting suspension was warmed to 0°C and stirred for 5 min during which the solution became homogenous.
  • the crude residue was taken up in 500 ml of dry dichloromethane, treated sequentially with 0.8 g (7.3 mmol) of 4-dimethylaminopyridine, 13 mi (93 mmol) of triethylamine, and 7.5 ml (80 mmol) of acetic anhydride.
  • the resulting solution was stirred for 2 h at ambient temperature, treated with water, stirred for 10 min, washed sequentially with 10% aqueous citric acid and aqueous NaHCO 3 , dried over MgSO 4 , and concentrated in vacuo.
  • the resulting crude mixture was taken up in 500 ml of methanol, cooled to 0°C, and treated with 150 g (0.32 mol) of 5% sodium amalgam.
  • Example 296A 160 mg, 0.47 mmol was deprotected according to the procedure of Example 2 and coupled to Ac-Val-Val-OH according to the procedure of Example 66 to give a crude product which was triturated with ether, filtered, and air-dried to give 111 mg (49%) of the desired compound.
  • Mass spectrum (M+l)+ 478.
  • Example 297 A 1-(2-Furanyl)-1-hydroxy-3-phenyl-2- (triphenylmethyl) aminopropane.
  • a solution of 18 mmol of n-butyllithium in 40 ml of tetrahydrofuran/hexane was cooled to -78°C and treated with 1.3 ml (18 mmol) of furan.
  • the resulting solution was stirred at -23°C for 4 h, recooled to -78°C, and treated with a solution of 2.35 g (6 mmol) of N-(triphenylmethyl)-phenylalaninal in 20 ml of tetrahydrofuran.
  • Example 297B C. Cbz-Leu-Asn Amide of 2-amino-1-(2-tetrahydrofuranyl)- 1-hydroxy-3-phenylpropane.
  • the resultant compound of Example 297B (26 mg, 0.08 mmol) was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to give, after purification by flash chromatography using 6.5% methanol in chloroform, 34 mg (72%) of the desired compound, m.p. 198-200°C.
  • Mass spectrum (M+1) + 583.
  • Example 299 A 4-Benzyl-3-(t-butyloxycarbonyl)-2,2-dimpthyl-5- (hydroxymethyl)-oxazolidine.
  • a precooled (0°C) solution of sodium borohydride (40 mg, 1.05 mmol) in 2 ml of methanol was treated with a solution of 218 mg (0.68 mmol) of the resultant compound of Example 242 in 3 ml of 1:1 methanol:tetrahydrofuran. After being allowed to stir at ambient temperature for 2 h, the solution was quenched with aqueous NH 4 CI, extracted with ether, washed with 1 N NaOH and saturated brine, dried oyer MgSO 4 , and concentrated.
  • Example 299A Cbz-Leu-Asn Amide of 3-Amino-1,2-dihydroxy-4- phenylbutane.
  • the resultant compound of Example 299A was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to give, after trituration with 2% methanol in chloroform, filtration, washings with chloroform, and air-drying, the desired compound (41 mg, 48%) as a white solid, m.p. 214-215°C.
  • Mass spectrum: (M+H) + 543.
  • Example 300B (cis) -N-(3-Methylbutyl)-3-(4-benzyl-3-(t- butyloxycarbonyl)-2.2-dimethyl-oxazolidin-5- yl)propenamide.
  • the resultant compound of Example 300B was coupled to isoamylamine to give 251 mg (100%) of the desired compound as a colorless oil.
  • the resulting suspension was treated with 9 ml of dry tetrahydrofuran, allowed to warm to 0°C for 20 min, recooled to -78°C, and treated with a solution of 1.0 g (2.5 mmol) of N- (triphenylmethyl)- phenylalaninal in 10 ml of tetrahydrofuran.
  • the resulting solution was stirred at - 78°C for 10 min, warmed to 0°C for 5 min, and quenched cautiously with aqueous ammonium chloride.
  • the product was extracted with ether, dried over MgSO 4 , and concentrated in vacuo to give the desired compound as a crude foam.
  • Example 302A 2-(2-Amino-1-hydroxy-3-phenyl) propyl-2-hydroxy- 2,3,4,5-tetrahydrofuran.
  • the resultant compound of Example 302A (1.37 g, 2.5 mmol) was treated with 50 ml of tetrahydrofuran and 50 ml of 1 N HCl and heated at reflux for 0.5 h. After being allowed to cool, the mixture was concentrated in vacuo, taken up in dilute aqueous HCl, washed with three portions of hexane, concentrated in vacuo, taken up in methanol/chloroform, and concentrated to a brown foam.
  • Example 303 A N-Methyl-2-(1-hydroxy-3-phenyl-2- (triphenylmethylamino) propyl-benzamide.
  • a solution of 0.29 g (2.1 mmol) of N-methylbenzamide in 15 ml of tetrahydrofuran was cooled under inert atmosphere to -78°C and treated with 2.1 ml (4.4 mmol) of n-butyllithium.
  • the resulting solution was warmed to 0°C for 30 min, recooled to -78°C, and treated with a solution of 0.42 g (1.1 mmol) of N- (triphenylmethyl)-phenylalaninal in 5 ml of tetrahydrofuran.
  • Example 304 Cbz-Leu-Asn Amide of 2-Amino-1-cyclohexyl-3.4-dihydroxy- 6-methylheptane.
  • the resultant compound of Example 141 (1.39 mmol) was deprotected according to the procedure of Example 2 and coupled to Cbz-Leu-Asn-OH according to the procedure of Example 66 to give a crude product, which crystallized from ethyl acetate to give 204 mg (24%) of the desired compound as a white solid, m.p. 189-190°C.
  • Mass spectrum: (M+H) +
  • Example 305 (5 (S)-(3-tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-2-thionoxazolidinon- 4(S)-carbonyl)-Ile-Ser Methyl Ester.
  • the resultant compound from Example 253 (1.18 g, 2.13 mmol) was reacted according to the procedure of Example 213 to provide 865 mg (92%) of the desired compound.
  • Example 306 N-Boc-Leu-Asn Amide of (5 (S)-(3-tert-Butyloxycarbonyl)- 2,2-dimethyl-4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-2- thionooxazolidinon-4(S)-carbonyl)-Ile-Ser Methyl Ester.
  • the resultant compound from Example 305 (183 mg, 0.279 mmol) was dissolved in 2 ml methanol and treated with acetyl chloride (0.119 ml, 131 mg, 1.67 mmol). The resulting solution was stirred overnight at room temperature.
  • Example 307 3-(5(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-2-thionooxazolidnyl)- 4(R)-carbonyl)-4(R)-phenylmethyl-2-oxazolidinone.
  • the procedure of D.A. Evans and A. E. Weber J. Am . Chem . Soc. 1987, 109. 7151) is adapted.
  • Example 309 (5 (R) - (3- (tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)- cyclohexylmethyl-5(R)-oxazolidinyl)-2-thioxazolidinon- 4(R)-carbonyl)-Ile-Ser Methyl Ester.
  • the resultant compound of Example 308 (174 mg, 0.393 mmol) was coupled to H-Ile-Ser-OMe (105 mg, 0.393 mmol) to provide 73 mg (28%) of the desired compound after column chromatography (2% MeOH-CHCl 3 ).
  • Example 310 N-(Boc-Leu-Asn Amide of 5 (R) -(3-(tert-Butyloxycarbonyl)- 2,2-dimethyl-4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-2- thioxazolidinon-4(R)-carbonyl)-Ile-Ser Methyl Ester.
  • the resultant compound from Example 309 (307 mg, 0.467 mmol) was dissolved in 5 ml methylene chloride, cooled to 0° under a nitrogen atmosphere, and 5 ml trifluoroacetic acid was added.
  • Example 66 Using the procedure of Example 66, in which the above crude amino alcohol replaced the resultant compound from Example 196, the desired compound (30mg, 40%) was obtained after column chromatography on silica gel (7% MeOH-CH 2 Cl 2 ).
  • Mass spectrum: (M+H) + 844.
  • 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, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, pa
  • the basic nitrogen-containing groups can be quaternized with such agents as loweralkyl 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.
  • loweralkyl halides such as methyl, ethyl, propyl, and butyl chloride, bromides, and iodides
  • dialkyl 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.
  • the compounds of the present invention can also be used in the form of esters.
  • esters include a hydroxyl-substituted compound of formula I which has been acylated with a blocked or unblocked amino acid residue, a phosphate function, or a hemisuccinate residue.
  • the amino acid esters of particular interest are glycine and lysine; however, other amino acid residues can also be used.
  • 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 pro-drugs are metabolized in vivo to provide the hydroxyl- substituted compound of formula I.
  • the preparation of the pro-drug esters is carried out by reacting a hydroxyl- substituted compound of formula I with an activated amino acyl, phosphoryl or hemisuccinyl derivative. The resulting product is then deprotected to provide the desired pro-drug ester.
  • novel compounds of the present invention are inhibitors of retroviral proteases and in particular are inhibitors of HIV-1 protease and HIV-2 protease.
  • Compounds of the invention inhibit HIV-1 protease in the range of 22-91% at concentrations of 04-1.0 mM.
  • the novel compounds of the present invention are useful for the treatment or prophylaxis of diseases caused by retroviruses, especially acquired immune deficiency syndrome or an HIV infection.
  • Total daily dose administered to a host in single or divided doses may be in amounts, for example, from 0.001 to 10 mg/kg body weight daily and more usually 0.01 to 1 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, 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 i ⁇ j.ectable solution or suspension in a nontoxic 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 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 invention can be administered as the sole active pharmaceutical agent, they can also be used in combination with one or more immunomodulators, antiviral agents or other antiinfective agents.
  • 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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Abstract

L'invention concerne un composé inhibiteur de protéase rétrovirale de la formule (I), ou un sel, un promédicament ou un ester pharmaceutiquement acceptable de celui-ci.
EP19890905856 1988-05-13 1989-05-12 Retroviral protease inhibitors Ceased EP0415981A4 (en)

Applications Claiming Priority (2)

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US19467888A 1988-05-13 1988-05-13
US194678 1988-05-13

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EP0415981A1 true EP0415981A1 (fr) 1991-03-13
EP0415981A4 EP0415981A4 (en) 1991-10-09

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EP19890108590 Pending EP0342541A3 (fr) 1988-05-13 1989-05-12 Inhibiteurs de protéases rétrovirales
EP19890905856 Ceased EP0415981A4 (en) 1988-05-13 1989-05-12 Retroviral protease inhibitors

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JP (1) JPH03504247A (fr)
AU (1) AU3566089A (fr)
IL (1) IL90218A0 (fr)
WO (1) WO1989010752A1 (fr)

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JP5598489B2 (ja) 2011-03-28 2014-10-01 信越化学工業株式会社 ビフェニル誘導体、レジスト下層膜材料、レジスト下層膜形成方法及びパターン形成方法

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Also Published As

Publication number Publication date
EP0342541A2 (fr) 1989-11-23
IL90218A0 (en) 1989-12-15
WO1989010752A1 (fr) 1989-11-16
AU3566089A (en) 1989-11-29
EP0415981A4 (en) 1991-10-09
EP0342541A3 (fr) 1991-11-06
JPH03504247A (ja) 1991-09-19

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