EP0497835A1 - Method for treating hiv and other retroviruses and compounds useful therefor - Google Patents

Method for treating hiv and other retroviruses and compounds useful therefor

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Publication number
EP0497835A1
EP0497835A1 EP19900915950 EP90915950A EP0497835A1 EP 0497835 A1 EP0497835 A1 EP 0497835A1 EP 19900915950 EP19900915950 EP 19900915950 EP 90915950 A EP90915950 A EP 90915950A EP 0497835 A1 EP0497835 A1 EP 0497835A1
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EP
European Patent Office
Prior art keywords
amino
ile
methyl
carbonyl
hydroxy
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.)
Withdrawn
Application number
EP19900915950
Other languages
German (de)
French (fr)
Inventor
Robert Leroy Heinrikson
Alfredo Guiseppe Tomasselli
Tomi Kim Sawyer
Heinrich Josef Schostarez
Suvit Thaisrivongs
Jackson B. Hester, Jr.
John On-Ting Hui
William Gary Tarpley
Ruth Elizabeth Ten Brink
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.)
Pharmacia and Upjohn Co
Original Assignee
Upjohn Co
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Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0497835A1 publication Critical patent/EP0497835A1/en
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0207—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)4-C(=0), e.g. 'isosters', replacing two amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to a method of inhibiting a retrovirus in a human cell infected with said retrovirus which comprises treating said cell with an effective amount of a retroviral proteinase inhibitory compound of formula I.
  • the present invention also provides novel compounds which are useful in this method.
  • HTV-1 human immunodeficiency virus type I
  • HTV-1 human immunodeficiency virus type I
  • AZT zidovudine
  • U.S. Patent 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
  • HIV Human immunodeficiency virus
  • infective and non-infective HIV-isolates Sequence analysis of the complete genomes from several infective and non-infective HIV-isolates has shed considerable light on the make-up of the virus and the types of molecules that are essential for its replication and maturation to an infective species (L. Ratner, et al., Nature, 313:277-284 (1985)). HIV exhibits the same gag/pol/env organization seen in other retroviruses (L.
  • Reverse transcriptase is an enzyme unique to retroviruses that catalyzes the conversion of viral RNA into double stranded DNA. Blockage at any point during the transcription process, by AZT or any other aberrant deoxynucleoside triphosphate incapable of elongation, should have dramatic consequences relative to viral replication. Much work on the RT target is in progress based, in large measure, upon the fact that nucleosides like AZT are easily delivered to cells. However, the inefficiency of phosphorylation steps to the triphosphate, and the lack of specificity and consequent toxicity, constitute major drawbacks to use of ACT and similar nucleosides having a blocked, or missing, 3'hydroxyl group.
  • the T4 cell receptor for HTV has also been targeted as an intervention point in AIDS therapy ( R.A. Fisher, et al. , Nature, 331:76-78 (1988); R.E. Hussey, et al., Nature, 331:78-81 (1988); and K.C. Deen, et al., Nature, 331:82- 84 (1988)).
  • the exterior portion of this transmembrane protein, a molecule of 371 amino acids (sCD4) has been expressed in Chinese hamster ovary (CHO) cells and Genentech ( D.H. Smith, et al., Science, 238:1704-1707 (1987)) has had a product in clinical trials since the fall of 1987.
  • CD4 based therapy the molecules can neutralize HTV by interfering with viral attachment to T4, and other cells which express CD4 on their surfaces.
  • a variant on this theme is to attach cell toxins to CD4 for specific binding and delivery to infected cells which display glycoprotein gp-120 on their surfaces ( M.A. Till, et al., Science, 242:1166-1168 (1988); and V.K. Chaudhary, et al., Nature, 335:369-372 (1988)).
  • Another therapeutic target in AIDS involves inhibition of the viral protease (or proteinase) that is essential for processing HIV-fusion polypeptide precursors.
  • the proteolytic maturation of the gag and gag/pol fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome (Y. Yoshinaka, et al., Proc. Natl. Acad. Sci. USA, 82:1618-1622 (1985); Y. Yoshinaka, et al., J. Virol., 55:870-873 (1985); Y. Yoshinaka, et al., J. Virol., 57:826- 832 (1986); and K. von der Helm, Proc. Natl. Acad. Sci., USA, 74:911-915 (1977)).
  • protease or proteinase
  • the protease consisting of only 99 amino acids, is among the smallest enzymes known, and its demonstrated homology to aspartyl proteases such as pepsin and renin ( L.H. Pearl and W.R. Taylor, Nature, 329: 351-354 (1987); and I.
  • pepstatin A 100 ⁇ M
  • pepstatin A a general aspartyl proteinase inhibitor
  • European Published Application 0 357 332 discloses the use of renin inhibitors for the treatment of AIDS by inhibition of HTV protease.
  • These inhibitors may have a moiety of the formula R a 2 R 2 b -X-C(O)- at the N-terminus, wherein X is -O-, -S-, -CH-, or -NHCH-, and wherin R a 2 and R 2 b are the same or different and are hydrogen, C 1-4 alkyl, unsubstituted or substituted aryl, and unsubstituted and substituted C 3 ,7 -cycloalkyl.
  • this application does not disclose diol moieties as the transition state insert.
  • European Published Application 0 352 000 discloses retroviral protease binding peptides, having a variety of moieties as the transition state insert, including alcohols and diols, and having such substituents as t-butyloxycaibonyl, benzyloxycarbonyl and R"C(O)-, wherein R" is hydrogen or C 1-18 alkyl, at the N-terminus.
  • European Published Application 0 369 141 discloses specific peptides which are useful for inhibiting retroviral proteases. However, these peptides differ from the peptides of the present invention by having a ⁇ -alanineat the D 9 -position, statine analogs at the transition state insert or N-4-amino-2-methyl-5-pyri midinylmethyl amide at the C- terminus.
  • the present invention particularly provides:
  • C 8 is absent or a divalent moiety of the formula XL 1 , XL 2 , XL 2a , XL 2b or other amino acyl derivative;
  • D 9 is a divalent moiety of the formula XL 3 , XL 2a , XL 2b or other amino acyl derivative;
  • E 10 -F 11 is a divalent moiety of the formula XL 6 , XL 6b , XL 6c , XL 6d , XL 6e , II, III, or IV;
  • G 12 is absent or a divalent moiety of the formula XL 4 , XL 4a or other amino acyl derivative
  • R 4 at each occurrence is the same or different as is a) hydrogen
  • R 11 is -R or -R 2 ;
  • R 12 is -(CH 2 ) n -R 13 ;
  • j is one to three, inclusive
  • n is one or two
  • r is zero to five, inclusive
  • n is independently an integer of zero to five, inclusive; wherein q is an integer of one to five, inclusive; wherein u is an integer of zero to three, inclusive;
  • v is an integer of zero to four, inclusive
  • s is an integer of zero or one so that the sum of u plus v plus s is three or four; wherein t is an integer of zero to three, inclusive;
  • w is an integer of two or three;
  • x is an integer of two to seven, inclusive
  • y is an integer of zero to six, inclusive.
  • z is an integer of zero to six so that the sum of y plus z does not exceed six; wherein aryl is phenyl or naphthyl substituted by zero to three of the following:
  • -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any dicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and optionally substituted by zero to three of the following:
  • G 12 is present when both C 8 and D 9 are present and E 10 -F 11 is other than LPA;
  • R 5 is other than C 1 -C 6 alkyl, C 3 -C 7 cycloalkyl or aryl;
  • Z is other than N-4-amino-2-methyl-5-pyrimidinylmethyl-amide
  • X is other than benzyloxycarbonyl or butyloxycarbonyl, when E 10 -F 11 is II or IV;
  • L-Isoleucinamide N 2 -(5-amino-4-hydroxy-2-(1-methylethyl)-1-oxooctyl]-N-(2- pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-Ile-Amp;
  • Octanamide 5-[(3,3-dimethyl-1-oxobutyl)amino]-4-hydroxy-7-methyl-2-(1- methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl][2S-[1(1R*,2R- *).2R*,4R*,5R*]]- or TBA-LVA-Ile-Amp;
  • Cyclohexanehexanamide ⁇ -[(3,3-dimethyl-1-oxobutyl)amino]- ⁇ -hydroxy- ⁇ -(1- methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [ ⁇ S-[N(lR*,2R- *), ⁇ R*, ⁇ R*, ⁇ R*]]- or TBA-CVA-Ile-Amp;
  • Cyclohexanehexanamide ⁇ -amino- ⁇ -hydroxy- ⁇ -(1-methylethyI)-N-[[2-methyl-1- [[(2-pyridinylmemyl)]amino]carbonyl]butyI]-,dihydrochloride,[ ⁇ S-[N(1R*,2R*), ⁇ -R * , ⁇ - R*, ⁇ R*]]- or H-CVA-Ile-Amp;
  • Cyclohexanehexanamide ⁇ -(acetylamino)- ⁇ -hydroxy- ⁇ -(1-methylethyl)-N-[2- methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyl], [ ⁇ S-[N(lR*,2R*), ⁇ R*, ⁇ R*, ⁇ R *]]-; or Ac-CVA-Ile-Amp;
  • L-Histidinamide L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S- (1R*,2R*,4R*(1R*,2R*)]]- or H-Phe-His-LVA-Ile-Amp;
  • L-Valinamide L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl][1S-[1R*,2R*,4R*(1- R*,2R*)]]-, diacetate (salt); or H-Val-Val-LVA-Ile-Amp; or
  • Octanamide 5-[[2-(acetylammo)-3-memyl-1-oxobutyl]amino]-4-hydroxy-7-methyl- 2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S- [N(1R*,2R*),2R*,4R*.5R*(R*)]]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp;
  • L-.alpha.-Asparagine N/u 2/d-[N-[(1,1-dimethyIethoxy)carbonyl]-L-phenylala- nyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme- thyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*,4R*(1R*,2R*)]]- monoacetate (salt) or BOC-Phe-Asp-LVA-Ile-Amp;
  • L-Histidinamide N-[(1 , 1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[3,3- difluoro-2-hydroxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-4- oxo-1-(phenylmethyl)butyl]- or CH 3 -C(O)-O-CH(benzyl)-C(O)-His-LVA-Ile-Amp;
  • L-Histidinamide N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-[[[2- [(2,6-diamino-4-pyrimidinyl)amino]ethyl]amino]carbonyl]-2-hydroxy-5-methyl-1-(2- methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,6-diamino -4-pyrime- dinyl)amino-ethylamino;
  • phenyl-HC CH-(CH 2 ) n -O-C(O)-,
  • n O to five, inclusive.
  • amino acyl derivatives any of the naturally occurring amino acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof. These compounds may be in the L or D configuration and are well known and readily available to those skilled in the art.
  • the compounds of the present invention are effective and potent inhibitors of HIV protease.
  • the compounds of the present invention have also been found to inhibit HIV protease in cell cultures, as described below. Therefore, the compounds of formula I inhibit retroviral proteinases and thus inhibit the replication of the virus. They are useful for treating patients infected with human immunodeficiency virus (HTV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
  • HTV human immunodeficiency virus
  • AIDS acquired immunodeficiency syndrome
  • novel compounds of the present invention have low to moderate renin inhibitory activity but are surprisingly and unexpectedly potent retroviral protease inhibitors.
  • the peptides of the present invention are also useful as novel human retroviral protease inhibitory peptide analogs. Therefore, the peptides of the present invention inhibit retroviral proteases and thus inhibit the replication of the vims. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
  • a human retrovirus such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
  • the capsid and replicative enzymes (i.e. protease, reverse transcriptase, integrase) of retroviruses are translated from the viral gag and pol genes as polyproteins that are further processed by the viral protease (PR) to the mature proteins found in the viral capsid and necessary for viral functions and replication. If the PR is absent or nonfunctional, the virus cannot replicate.
  • the retroviral PR such as HIV-1 PR, has been found to be an aspartic protease with active site characteristics similar to those exhibited by the more complex aspartic protease, renin.
  • human retrovirus includes human immunodeficiency virus type I, human immunodeficiency virus type II, or strains thereof, as well as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) or strains apparent to one skilled in the art, which belong to the same or related viral families and which create similar physiological effects in humans as various human retroviruses.
  • Patients to be treated would be those individuals: 1) infected with one or more strains of a human retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) in the case of HIV, having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonary candidiasis including pneumocystic pneumonia iv) non- Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/m 3 in the peripheral blood.
  • a symptomatic AIDS such as i) disseminated histoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonary candidiasis including pneumocystic pneumonia iv) non- Hodgkin's lymphoma or
  • HIV human immunodeficiency virus
  • HTLV-III or LAV human immunodeficiency virus
  • AIDS human acquired immunodeficiency disease syndrome
  • HIV-I protease This enzyme, HIV-I protease, has been classified as an aspartyl protease and has a demonstrated homology to other aspartyl proteases such as renin, L.H. Pearl, et al., Nature 329:351 (1987); I. Katoh, et al.. Nature 329:654 (1987). Inhibition of HIV-I protease blocks the replication of HIV and thus is useful in the treatment of human AIDS, E.D. Clerq, J. Med. Chem. 29: 1561 (1986). Inhibitors of HIV-I protease are useful in the treatment of AIDS.
  • Pepstatin A a general inhibitor of aspartyl proteases, has been disclosed as an inhibitor of HIV-I protease, S. Seelmeier, et al, Proc. Natl. Acad. Sci. USA, 85:6612 (1986).
  • Other substrate derived inhibitors containing reduced bond isosteres or statine at the scissle position have also been disclosed, M.L. Moore, et al., Biochem. Biophys, Res. Commun. 159:420 (1989); S. Billich, et al., J. Biol. Chem. 263: 17905 (1988); Sandoz, D.E. 3812-576-A.
  • the peptides of the present invention are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS).
  • AIDS human acquired immunodeficiency disease syndrome
  • the peptides of the present invention are also useful for treating non-human animals infected with a retrovirus, such as cats infected with feline leukemia virus.
  • a retrovirus such as cats infected with feline leukemia virus.
  • viruses that infect cats include, for example, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chlamydia.
  • Exact dosages, forms and modes of administration of the peptides of the present invention to non-human animals would be apparent to one of ordinary skill in the art, such as a veterinarian.
  • the compounds of formula I of the present invention are prepared as described in the publications listed in Table I below, all of which are incorporated by reference herein, or are prepared by methods analogous thereto, which are readily known and available to one of ordinary skill in the art of peptide synthesis.
  • the compounds of the present invention can occur in several diastereomeric forms, depending on the configuration around the asymmetric carbon atoms. All such diastereomeric forms are included within the scope of the present invention.
  • the stereochemistry of the amino acids corresponds to that of the naturally occurring amino acids.
  • the present invention provides for compounds of formula I or pharmacologically acceptable salts and/or hydrates thereof.
  • Pharmacologically acceptable salts refers to those salts which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailablility.
  • the compounds of the present invention are useful for treating patients infected with human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
  • HIV human immunodeficiency virus
  • the compounds of formula I are administered by oral, nasal, transdermal and parenteral (including i.m. and i.v.) routes in doses of 1 ⁇ g to 100 mg/kg of body weight.
  • the compounds of this invention into appropriate pharmaceutical dosage forms.
  • the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
  • Solid compositions are prepared by mixing the compounds of this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers.
  • Capsules are prepared by mixing the compounds of this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule.
  • Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds of this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum.
  • Syrups are prepared by dissolving the compounds of this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives.
  • Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent.
  • Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
  • parenteral solutions are prepared by dissolving the compounds of this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule.
  • Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds of this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
  • Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia, iv) non-Hodgkin's lymphoma, or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/mm 3 in the peripheral blood.
  • Treatment would consist of maintaining an inhibitory level of the compounds of this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
  • the HTV-1 protease has been expressed in E. coli, isolated, characterized and used to determine the inhibitory constants (K i ) of potential inhibitory compounds as follows:
  • the synthetic peptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-OH serves as the substrate for the measurement of HTV-1 protease activity.
  • This peptide corresponds to the sequence from residue 128 to 135 in the HIV gag protein. Cleavage of the synthetic peptide, as well as the gag protein, takes place at the Tyr-Pro bond.
  • HTV-1 protease activity is measured at 30°C in 50 mM sodium acetate, pH 5.5, containing 10% glycerol, 5% ethylene glycol, 0.1 % Nonidet P-40 and 2.8 mM substrate in a total volume of 50 ⁇ l.
  • the screening tests are performed with primary human lymphocytes. Thereby, undesired testing of transformed cell lines is avoided in which host cell and virus may have undergone processes of mutual adaptation. Performance of cell culture in serum containing media closely mimics the in vivo situation.
  • the dose of the test compound causing half maximal suppression of virus replication is determined.
  • the screening system is standardized and automated to a high degree.
  • test compound Effects of the test compound on cell proliferation are determined by lymphocyte proliferation assays. Starting with a 100 micromolar solution, the test compound is 10 fold serially diluted. One tenth of the concentration of the test compound causing half maximal inhibition of cellular proliferation is employed for all subsequent testing.
  • Peripheral human lymphocytes are isolated by density gradient centrifugation. After stimulation by mitogen the cells are infected with a standardized preparation of
  • the infected cells are cultured in the presence of the test compound for four days. Individual cultures are established to measure viral replication two, three and four days following infection.
  • Untreated cells and AZT-treated cells are included as controls in parallel with the test compounds under investigation.
  • the amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by capture-ELISA technique on days two, three and four. By comparing with a standard preparation, the amount of protein produced by the virus infected cells will be calibrated.
  • the total amount of viral RNA synthesized by the infected lymphocytes is determined by a special nucleic acid hybridization technique on days two, three and four of culture. By including a standard preparation of HRV-RNA the amount of synthesized RNA will be quantified.
  • test compound shows antiviral effects in the primary screening, all steps of the primary screening will be repeated.
  • viability of HRV-infected cells will be determined in parallel with assays for viral p24 and RNA.
  • concentration dependency of the test compound action will be measured.
  • CV-1 cells were seeded at 2 x 10 -5 cells/well in 24 well Costar dishes and infected 6 to 12 hours later with vVK-1 at 5 PFU/cell (V. Karacostas, et al., "Human Immunodeficiency Virus-Like Particles Produced by a Vaccinia Virus Expression Vector (retrovirus/AIDS/virus assembly/reverse transcriptase, " Proc. Natl. Acad. Sci., USA, in press. 1989).
  • the test compounds were dissolved in DMEM containing 2.5% fetal bovine serum and added to triplicate wells immediately after virus addition.
  • the culture medium was removed, the monolayer washed with 1 ml of PBS and the cells lysed by the addition of 0.1 ml of loading buffer (62.5 mM Tris-Hcl pH 6.8, 2.3 % SDS, 5 % B-mercaptoethanol, 10% glycerol).
  • the cells lysates were collected individually, placed in boiling water for 3 minutes, and then 0.025 ml of each is subjected to electrophoresis on 12% SDS-polyacrylamide gels.
  • the proteins were electroblotted onto nitrocellulose and analyzed by Western blotting.
  • the primary antibodies were sheep anti-Pr24 and sheep anti-Pr17 and the secondary antibody in both cases was alkaline-phosphatase conjugated rabbit-anti sheep IgG (all obtained from Kirkegaard & Perry Laboratories, Gaithersburg, MD).
  • Pr55 to the mature viral structural proteins Pr24 and Pr17 in the above cells infected with the recombinant vaccina virus expressing the HIV-1 gag-pol genes.
  • the HIV-1 like particles released from inhibitor-treated cells contained almost exclusively Pr55 and other gag precursors, but not Pr24.
  • Pentanoic acid 5-[[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-4-[(1H-indol-2- ylcarbonyl)amino]-5-oxo-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]or1H-indol-2-yl-carbonyl- Glu-CVA-Ile-Amp;
  • L-Asparaginamide 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methyl- propyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carb- onyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- or NOA-Asp-CVA-Ile- Amp;
  • Aco is acetyloxy
  • Amp is 2-(aminomethyl) pyridine
  • Amp-NO is (2-pyridylmethyl) amino, pyridine N-oxide
  • Boc is t-butoxycarbonyl
  • BOP is benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophos- phate
  • Bz is benzyl
  • Cbz is benzyloxycarbonyl
  • CcD is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -CH 2 -cyclohexyl;
  • CCD is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is ⁇ -hydroxy R 3 is ⁇ -CH 2 -cyclohexyl and R 4 is ⁇ -hydroxy;
  • CDCl 3 is deuteriochloroform
  • Celite is a filter aid
  • CVA is Cha ⁇ [CH(OH)CH 2 ]Val of formula X wherein R 1 is cyclohexyl, R 2 is hydrogen, R 3 is ⁇ -isopropyl and R 4 is ⁇ -hydroxy;
  • chpVA is the moiety of formula X wherein R 1 is cycloheptyl, R 2 is hydrogen, and R 3 is ⁇ -isopropyl, and R 4 is ⁇ -hydroxy;
  • CLA is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is hydrogen, R 3 is - ⁇ -isobutyl, and R 4 is ⁇ -hydroxy;
  • CLD is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -isobutyl;
  • CPD is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -benzyl;
  • CVD is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is ⁇ -hydroxy, R 3 is ⁇ -isopropyl and R 4 is ⁇ -hydroxy;
  • CVD is the moiety of formula X wherein R 1 is cyclohexyl, R 2 is ⁇ -hydroxy,
  • R 4 is ⁇ -hydroxy, and R 3 is ⁇ -isopropyl
  • DANS is dansyl or 5-dimethylaminonaphthalenesulfonyl
  • DCC is dicyclohexylcarbodiimide
  • DEPC diethylphosphoryl cyanide
  • EtOAc is ethyl acetate
  • g is grams
  • ⁇ -Glu is ⁇ -glutamic acid
  • Gly is glycine
  • N-MeHis is N ⁇ -methyl histidine
  • HOBT is 1-hydroxybenzotriazole
  • HPLC high performance liquid chromatography
  • IVA is isovaleryl
  • LCA is the moiety of formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is - ⁇ -CH 2 -cyclohexyl and R 4 is ⁇ -hydroxy;
  • LFA is the difluoro version of LVA as described more fully in PCT Pub. No. WO86/06379 (6 November 1985), and is the moiety of formula IV wherein R 1 is isopropyl;
  • LLA is the moiety of formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is - ⁇ -isobutyl, and R 4 is ⁇ -hydroxy;
  • LID is the moiety of formula X wherein R, is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -isobutyl;
  • LLd is the moiety of formula X wherein R t is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy, and R 3 is ⁇ -isobutyl;
  • LLD is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy, and R 3 is ⁇ -isobutyl;
  • LPA is the moiety of formula X wherein R 1 is isopropyl, R 3 is hydrogen, R 3 is - ⁇ -benzyl and R 4 is ⁇ -hydroxy;
  • LVA is Leu ⁇ (CH(OH)CH 2 )Val with the S configuration at C4 (the hydroxyl- bearing carbon atom) of the formula X wherein R 1 is isopropyl, R 2 is hydrogen, R 3 is ⁇ -isopropyl and R 4 is ⁇ -hydroxy;
  • LVD is the diol version of LVA as described more fully in PCT Pub. No. WO87/05302 (11 September 1987) and is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -isopropyl;
  • LVDA' is the moiety of formula X wherein R 1 is isopropyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy, and R 3 is ⁇ -isopropyl;
  • Mba is 2S-methylbutylamine
  • Me is methyl
  • ml is milliliter
  • MPLC medium pressure liquid chromatography
  • MS is mass spectroscopy
  • NOA is (1-naphthyloxy)acetyl
  • Ph is phenyl
  • Phe is phenylalanine
  • POA is phenyloxyacetyl
  • PPD is the moiety of formula X wherein R 1 is phenyl, R 2 is ⁇ -hydroxy, R 4 is ⁇ -hydroxy and R 3 is ⁇ -benzyl;
  • Pro is proline
  • 2-Py-Ala is D,L-2-pyridyl-alamine.
  • RIP means a compound having the formula H-Pro-His-Phe-His-Phe-Phe-Val-
  • TBA is t-butylacetyl
  • TBAP is tetra-n-butylammonium phosphate
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TLC is thin layer chromatography
  • TsOH is p-toluenesulfonic acid
  • Tyr is tyrosine
  • (OCH 3 )Tyr is O-methyl tyrosine
  • Val is valine.
  • the wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon.
  • the dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon.
  • L-Histidinamide N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4- (cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)- amino]carbonyl]butyl]amino]-5-oxopentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc- Phe-His-LCA-Ile-Amp;
  • FABMS (found): 685.4382; (78) Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R.4R- dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CPD-Ile-Amp. FAB-MS (found): 734.4248;
  • FAB-M (found): 786.4540; (89)5-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CVA-Ile-Amp.
  • FAB-MS (found): 797:
  • reaction is quenched with 1N ammonium hydroxide, diluted with methanol and concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump - to give a black colored solid.
  • This material is dissolved in ethyl acetate and washed with brine (3X). The aqueous washes are back-extracted with ethyl acetate and the combined organic extracts are dried (Na 2 SO 4 ), filtered and concentrated to give a black colored solid (a mixture of starting diol, tosylate and desired product).
  • Section I The material of Section I is dissolved in 15 mL of dimethylformamide, treated with 0.32 mL of methyl bromoacetate (Aldrich), cooled to 0°C under a nitrogen atmosphere followed by treatment with 0.15 g of a 60% mineral oil emulsion of sodium hydride.
  • the resulting green colored mixture is stirred at 0°C for 1.5 h, quenched with saturated ammonium chloride, diluted with methanol and then concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump.
  • the resulting brown colored solid is suspended in 50 mL of water and extracted with ethyl acetate.
  • aqueous phase is back-washed with ethyl acetate and the combined organic extracts are dried (Na 2 SO 4 ), filtered and concentrated to give a brown colored oil (primarily a mixture of 4-[CH 3 (OCH 2 CH 2 ) 3 O]-1-naphthoxyaceticacid, methyl ester, 1,4-[CH 3 (OCH 2 CH 2 ) 3 O]-naphthalene and CH 3 (OCH 2 CH 2 ) 3 OTs).
  • the methyl ester of Section 2 (263 mg); is dissolved in 3 mL of methanol. Water (1 mL) and IN sodium hydroxide (1 mL) are added and the resulting solution is let stir at room temperature for 2 h. The solution is then poured into 10 mL of 1N sodium hydroxide and extracted 3X with ethyl ether. The combined organic extracts are discarded and the aqueous phase is acidified to pH 5 with aqueous hydrochloric acid and then extracted 3X with methylene chloride. The combined organic extracts are dried (Na 2 SO 4 ), filtered and concentrated to give 187 mg of 4-[CH 3 (OCH 2 CH 2 ) 3 O]-1- naphthoxyacetic acid as a brown colored oil. TLC analysis showed only a spot at the origin using 20% ethyl acetate/chloroform. This material is used without purification in the subsequent coupling experiment.
  • reaction solution is allowed to cool to room temperature and then quenched with saturated ammonium chloride, diluted with methanol and then concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump - to give a product containing mixture as a yellow solid.
  • This solid is dissolved in ethyl acetate and washed with 50 mL of water (2X). The aqueous washes are back- washed with ethyl acetate and the combined organic extracts are dried (MgSO 4 ), filtered and concentrated to give an orange colored oil.
  • TLC analysis of this oil indicates a five component mixture comprised of the desired product [5-[CH 3 (OCH 2 CH 2 ) 3 O]-1- naphthoxyaceticacid, methyl ester], an unidentified component, 1 ,5-[CH 3 (OCH 2 CH 2 ) 3 O]- naphthalene, 1,5-[CH 3 O 2 CCH 2 O]-naphthalene and 5-[CH 3 (OCH 2 CH 2 ) 3 O]-1-naphthol.
  • This mixture is chromatographed over 50 g of silica gel (63-200 ⁇ ), eluting with 20% ethyl acetate/chloroform while collecting 6 mL fractions.
  • the methyl ester of Section I (241 mg; 0.63 mmoL) is dissolved in 3 mL of methanol. Water (1 mL) and IN sodium hydroxide (1 mL) are added and the resulting solution is let stir at room temperature for 2 h. The solution is then poured into 10 mL of IN sodium hydroxide and extracted 3X with ethyl ether. The combined organic extracts are discarded and the aqueous phase is acidified to pH 5 with aqueous hydrochloric acid and then extracted 3X with methylene chloride.
  • the solution is transferred with washing with methanol to a 1-necked (24/40) 200 mL round-bottomed flask and then concentrated on a rotary evaporator - first under house vacuum and then under lower pressure using a vacuum pump - to give the crude Boc-Asn-CVA-Ile-Amp.
  • This material is suspended in a solution of 3 mL of methylene chloride and 3 mL of trifluoroacetic acid (Aldrich). The resulting yellow colored mixture is stirred at room temperature for 2 h and then concentrated under reduced pressure.

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Abstract

Procédé d'inhibition d'un retrovirus dans une cellule mammifère contaminée par ledit retrovirus, consistant à traiter ladite cellule à l'aide d'une dose efficace d'un composé de la formule (I): X-C8-D9-E10-F11-G12-Z. L'invention présente également de nouveaux composés utiles dans ce procédé.Method for inhibiting a retrovirus in a mammalian cell contaminated by said retrovirus, comprising treating said cell with the aid of an effective dose of a compound of formula (I): X-C8-D9-E10- F11-G12-Z. The invention also presents new compounds useful in this process.

Description

METHOD FOR TREATING HIV AND OTHER RETROVIRUSES
AND COMPOUNDS USEFUL THEREFOR FIELD OF THE INVENTION
The present invention relates to a method of inhibiting a retrovirus in a human cell infected with said retrovirus which comprises treating said cell with an effective amount of a retroviral proteinase inhibitory compound of formula I. The present invention also provides novel compounds which are useful in this method.
BACKGROUND OF THE INVENTION
An estimated one to one and one-half million people in the United States are infected with a human retrovirus, the human immunodeficiency virus type I, HTV-1, which is the etiological agent of acquired immunodeficiency syndrome, AIDS (C.
Norman, Science, 661-662 (1986)). Of those infected, an estimated two hundred and fifty thousands people will develop AIDS in the next five years (J.W. Curran, et al.,
Science, 1352-1357 (1985)). On March 20, 1987, the FDA approved the use of the compound, zidovudine (AZT), to treat AIDS patients with a recent initial episode of pneumocystis carinii pneumonia, AIDS patients with conditions other than pneumocystis carinii pneumonia or patients infected with the virus with an absolute CD4 lymphocyte count of less than 200/mm3 in the peripheral blood. AZT is a known inhibitor of viral reverse transcriptase, an enzyme necessary for human immunodeficiency virus replication.
U.S. Patent 4,724,232 claims a method of treating humans having acquired immunodeficiency syndrome utilizing 3'-azido-3'-deoxy-thymidine (azidothymidine, AZT).
Since the first description of the malady in the early part of this decade, acquired immunodeficiency disease syndrome (AIDS) and its devastating consequences have been subjects of continuous and intense coverage in both the lay and scientific press. Indeed, a recent edition of Scientific American was entirely devoted to AIDS (Scientific American 289, #4 (1988)), and the literature on the disease and the virus is already so vast as to defy thorough citation. At present, there is no effective treatment of the disease, and 3'-azido-3'-deoxythymidine (AZT), an inhibitor of the viral reverse transcriptase (RT) remains the therapy of choice, despite its highly toxic side effects.
Human immunodeficiency virus (HIV) has long been recognized as the causative agent in AIDS, although a minority opinion to the contrary has been expressed (e.g., P. Duesberg, Proc. Natl. Acad. Sci., USA, 86:755-764 (1989)). Sequence analysis of the complete genomes from several infective and non-infective HIV-isolates has shed considerable light on the make-up of the virus and the types of molecules that are essential for its replication and maturation to an infective species (L. Ratner, et al., Nature, 313:277-284 (1985)). HIV exhibits the same gag/pol/env organization seen in other retroviruses (L. Ratner, et al., Nature, 313:277-284 (1985)); S. Wain-Hobson, et al., Cell, 40:9-17 (1985); R. Sanchez-Pescador, et al., Science, 227:484-492 (1985); and M.A. Muesing, et al., Nature, 313: 450-458 (1985)).
Reverse transcriptase (RT) is an enzyme unique to retroviruses that catalyzes the conversion of viral RNA into double stranded DNA. Blockage at any point during the transcription process, by AZT or any other aberrant deoxynucleoside triphosphate incapable of elongation, should have dramatic consequences relative to viral replication. Much work on the RT target is in progress based, in large measure, upon the fact that nucleosides like AZT are easily delivered to cells. However, the inefficiency of phosphorylation steps to the triphosphate, and the lack of specificity and consequent toxicity, constitute major drawbacks to use of ACT and similar nucleosides having a blocked, or missing, 3'hydroxyl group.
The T4 cell receptor for HTV, the so-called CD4 molecule, has also been targeted as an intervention point in AIDS therapy ( R.A. Fisher, et al. , Nature, 331:76-78 (1988); R.E. Hussey, et al., Nature, 331:78-81 (1988); and K.C. Deen, et al., Nature, 331:82- 84 (1988)). The exterior portion of this transmembrane protein, a molecule of 371 amino acids (sCD4) has been expressed in Chinese hamster ovary (CHO) cells and Genentech ( D.H. Smith, et al., Science, 238:1704-1707 (1987)) has had a product in clinical trials since the fall of 1987. Thus far, little information on efficacy is available beyond the fact that the recombinant sCD4 appears to be relatively non-toxic. The idea behind CD4 based therapy is that the molecules can neutralize HTV by interfering with viral attachment to T4, and other cells which express CD4 on their surfaces. A variant on this theme is to attach cell toxins to CD4 for specific binding and delivery to infected cells which display glycoprotein gp-120 on their surfaces ( M.A. Till, et al., Science, 242:1166-1168 (1988); and V.K. Chaudhary, et al., Nature, 335:369-372 (1988)).
Another therapeutic target in AIDS involves inhibition of the viral protease (or proteinase) that is essential for processing HIV-fusion polypeptide precursors. In HTV and several other retroviruses, the proteolytic maturation of the gag and gag/pol fusion polypeptides (a process indispensable for generation of infective viral particles) has been shown to be mediated by a protease that is, itself, encoded by the pol region of the viral genome (Y. Yoshinaka, et al., Proc. Natl. Acad. Sci. USA, 82:1618-1622 (1985); Y. Yoshinaka, et al., J. Virol., 55:870-873 (1985); Y. Yoshinaka, et al., J. Virol., 57:826- 832 (1986); and K. von der Helm, Proc. Natl. Acad. Sci., USA, 74:911-915 (1977)).
The protease (or proteinase), consisting of only 99 amino acids, is among the smallest enzymes known, and its demonstrated homology to aspartyl proteases such as pepsin and renin ( L.H. Pearl and W.R. Taylor, Nature, 329: 351-354 (1987); and I.
Katoh, et al., Nature, 329:654-656 (1987)), led to inferences regarding the three-dimen- sional structure and mechanism of the enzyme (L.H. Pearl and W.R. Taylor, Nature, 329:351-354 (1987)) that have since been borne out experimentally. Active HTV protease has been expressed in bacteria (see, e.g., P.L. Darke, et al., J. Biol. Chem., 264:2307-2312 (1989)) and chemically synthesized ( J. Schneider and S.B. Kent, Cell, 54:363-368 (1988); and R.F. Nutt, et al., Proc. Natl. Acad. Sci., USA, 85:7129-7133 (1988)). Site directed mutagenesis (P.L. Darke, et al., J. Biol. Chem., 264: 2307-2312 (1989); and N.E. Kohl, et al., Proc. Natl. Acad. Sci., USA, 85:4686-4690 (1988) and pepstatin inhibition (P.L. Darke, et al., J. Biol. Chem., 264:2307-2312 (1989); S. Seelmeier, et al., Proc. Natl. Acad. Sci., USA, 85:6612-6616 (1988); C.-Z. Giam and I. Borsos, J. Biol. Chem., 263:14617-14720 (1988); and J. Hansen, et al., EMBO J., 7: 1785-1791 (1988)) have provided evidence for HIV protease's mechanistic function as an aspartyl protease. A recent study has demonstrated that the protease cleaves at the sites expected in peptides modeled after the regions actually cleaved by the enzyme in the gag and pol precursor proteins during viral maturation (P.L. Darke, et al., Biochem. Biophys. Res. Communs., 156:297-303 (1988)). X-ray crystallographic analysis of the HIV-protease (M.A. Navia, et al. , Nature, 337:615-620 (1989)) and a related retroviral enzyme from Rous sarcoma virus (M. Miller, et al., Nature, 337:576-579 (1989)) reveal an active site in the protease dimer that is identical to that seen in other aspartyl proteases, thus supporting the supposition (L.H. Pearl and W.R. Taylor, Nature, 329:351-354 (1987)) that the HIV enzyme is active as a dimer. To date, an effective means of inhibiting retroviruses in a human hosting such a virus, and thereby effectively treating diseases caused by such a virus, such as acquired immunodeficiency syndrome (AIDS), has not been found. The inhibition by relatively high concentrations of pepstatin A (100 μM), a general aspartyl proteinase inhibitor, of HIV replication in H9 cells is described in K. Von der Helm, et al., FEBS Letters, 247:349 (1989).
Great Britain 2,203,740 (Sandoz) claims the use of rerun inhibitors for treating diseases caused by retroviruses.
A.D. Richards, et al., FEBS Letters, 247:113 (1989) disclose tBoc-His-Pro-Phe- His-LVA-Ile-His, a potent inhibitor of another aspartyl protease human renin, which also contains a hydroxyethylene isotere, inhibits the HIV-1 protease in vitro.
Recent information from Smith-Kline-Beecham researchers has described work on the inhibition of HTV-1 replication in cell culture with synthetic protease inhibitors. Int. AIDS Symposium, Montreal, Canada, June 1989
The following patent applications disclose peptides that are useful as inhibitors of renin and retroviral proteases: International Application, Serial No. PCT/US89/-
01672, filed 24 April 1989; U.S. Patent Application, Serial No. 07/405,691, filed 11 September 1989; International Application, Serial No. PCT/US90/03754, filed 9 July
1990; and U.S. Patent Application, Serial No. 07/573,110, filed 24 August 1990.
European Published Application 0 357 332 discloses the use of renin inhibitors for the treatment of AIDS by inhibition of HTV protease. These inhibitors may have a moiety of the formula Ra 2R2 b-X-C(O)- at the N-terminus, wherein X is -O-, -S-, -CH-, or -NHCH-, and wherin Ra 2 and R2 b are the same or different and are hydrogen, C1-4 alkyl, unsubstituted or substituted aryl, and unsubstituted and substituted C3 ,7-cycloalkyl. However, this application does not disclose diol moieties as the transition state insert.
European Published Application 0 352 000 discloses retroviral protease binding peptides, having a variety of moieties as the transition state insert, including alcohols and diols, and having such substituents as t-butyloxycaibonyl, benzyloxycarbonyl and R"C(O)-, wherein R" is hydrogen or C1-18 alkyl, at the N-terminus.
European Published Application 0 369 141 discloses specific peptides which are useful for inhibiting retroviral proteases. However, these peptides differ from the peptides of the present invention by having a β-alanineat the D9-position, statine analogs at the transition state insert or N-4-amino-2-methyl-5-pyri midinylmethyl amide at the C- terminus.
European Published Applications 0337714 and 0356223 disclose HIV protease inhibitors which do not have an amino acid analog at the D-9 position in front of the transition state insert.
SUMMARY OF THE INVENTION
The present invention particularly provides:
Use of a compound of formula I
X-C8-D9-E10-F11 -G12-Z I to prepare a medicament for inhibiting a retrovirus in a mammalian cell infected with said retrovirus;
wherein X is
a) -(CH2)p-aryl,
b) -(CH2)p-Het,
c) -(CH2)p-C3-C7cycloalkyl,
d) R5-O-(CH2)q-C(O)-,
e) R5-CH2-O-C(O)-,
f) R5-O-C(O)-,
g) R5-(CH2)n-C(O)-,
h) R5-(CH2)n-C(S)-,
i) R4N(R4)-(CH2)n-C(O)-,
j) R5-SO2-(CH2)q-C(O)-,
k) R5-SO2-(CH2)q-O-C(O)-,
l) R5-(CH2)n-SO2,
m) Z-C(O)-CH(OH)-CH(CH2R1)-C(O)- n) R5-(CH2)p CH=CH-(CH2)p-C(O)-,
o) R5(CH2)p CH=CH-(CH2)p-O-C(O), or
p) R27(CH2)q-C(O)-;
wherein C8 is absent or a divalent moiety of the formula XL1, XL2, XL2a, XL2b or other amino acyl derivative;
wherein D9 is a divalent moiety of the formula XL3, XL2a, XL2b or other amino acyl derivative;
wherein E10-F11 is a divalent moiety of the formula XL6, XL6b, XL6c, XL6d, XL6e, II, III, or IV;
wherein G12 is absent or a divalent moiety of the formula XL4, XL4a or other amino acyl derivative;
wherein Z is a) -O-R10,
b) -N(R4)R14,
c) C4-C8cyclic amino,
d) -NHR120,
e) -NH-(CH2)r-pyridine, N-oxide, or
f) Het bonded via a nitrogen atom, or g) -NH(CH2)qNH Het;
wherein R is
a) -(CH2)n-isopropyl,
b) -(CH2)n-isobutyl,
c) -(CH2)n-phenyl, or
d) -(CH2)n-C3-C7cycloalkyl;
wherein R1 is
a) hydrogen,
b) C1-C5alkyl,
c) aryl,
d) C3-C7cycloalkyl,
e) -Het,
f) C1-C3alkoxy, or
g) C1-C3alkylthio;
wherein R2 is
a) hydrogen, or
b) -CH(R3)R4;
wherein R3 is
a) hydrogen,
b) hydroxy,
c) C1-C5alkyl,
d) C3-C7cycloalkyl,
e) aryl,
f) -Het,
g) C1-C3alkoxy, or
h) C1-C3alkylthio;
wherein R4 at each occurrence is the same or different as is a) hydrogen,
b) C1-C5alkyl,
c) -(CH2)p-aryl,
d) -(CH2)p-Het,
e) -(CH2)p-C3-C7cycloalkyl, or f) 1- or 2-adamantyl;
wherein R5 is
a) C1-C6alkyl,
b) C3-C7cycloalkyl,
c) aryl,
d) -Het,
e) 5-oxo-2-pyrrolidinyl, or f) 1 or 2-adamantyl;
wherein R6 is
a) hydrogen,
b) C1-C5alkyl,
c) -(CH2)p-aryl,
d) -(CH2)p-Het,
e) -(CH2)p-C3-C7cycloalkyl, or f) 1- or 2-adamantyl;
wherein R7 is
a) hydrogen,
b) C1-C5alkyl,
c) hydroxy,
d) amino C1-C4alkyl-, e) guanidinyl C1-C3alkyl-, f) aryl,
g) -Het,
h) methylthio,
i) -(CH2)p-C3-C7cycloalkyl, j) amino,
k) -(CH2)n-COOH,
l) -(CH2)n-COOC1-C6 alkyl, or m) -(CH2)n-CONR22R26;
wherein R8 is
a) hydrogen
b) C1-C5alkyl,
c) hydroxy,
d) aryl,
e) -Het,
f) guanidinyl C1-C3alkyl-, or
g) -(CH2)p-C3-C7cycloalkyl;
wherein R9 is
a) hydrogen,
b) hydroxy,
c) amino C1-C4alkyl-, or
d) guanidinyl C1-C3alkyl-;
wherein R10 is
a) hydrogen,
b) C1-C5alkyl,
c) -(CH2)nR16,
d) -(CH2)nR17,
e) C3-C7cycloalkyl,
f) a pharmaceutically acdeptable cation, g) -CH(25)-CH2-R15, or
h) -CH2-CH(R12)-R15 ;
wherein R11 is -R or -R2;
wherein R12 is -(CH2)n-R13;
wherein R13 is
a) aryl,
b) amino,
c) mono-, di- or tri-C1-C3alkylamino, d) -Het,
e) C1-C5alkyl,
f) C3-C7cycloalkyl,
g) C2-C5alkenyl, h) C3-C7cycloalkenyl,
i) hydroxy,
j) C1-C3alkoxy,
k) C1-C3alkanoyloxy,
1) mercapto,
m) C1-C3alkylthio,
n) -COOH,
o) -CO-O-C1-C6alkyl,
P) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, q) -CO-NR22R26;
r) C4-C7cyclic amino,
s) C4-C7cycloalkylamino ,
t) guanidyl,
u) cyano,
v) N-cyanoguanidyl,
w) cyanoamino,
x) (hydroxy C2-C4alkyl)amino, or y) di-(hydroxyC2-C4alkyl)amino;
wherein R14 is
a) hydrogen,
b) C1-C10alkyl,
c) -(CH2)n-R18,
d) -(CH2)n-R19,
e) -CH(R25)-CH2-R15,
f) -(CH2)q-CH(R12)-R15,
g) (hydroxy C1-C8alkyl),
h) hydroxy C1-C8 alkyaryl, or
i) (C1-C3 alkoxy) C1C8 alkyl;
wherein R15 is
a) hydroxy,
b) C3-C7cycloalkyl,
c) aryl,
d) amino, e) mono-, di-, or tri-C1-C3alkylamino, f) mono- or di-(hydroxy C2-C4alkyl)amino, g) -Het,
h) C1-C3alkoxy-,
i) C1-C3alkanoyloxy-,
j) mercapto,
k) C1-C3alkylthio-,
l) C1-C5alkyl,
m) C4-C7cyclic amino,
n) C4-C7cycloalkylamino,
o) C1-C5alkenyloxy,
p) C3-C7cycloalkenyl;
wherein R16 is
a) aryl,
b) amino,
c) mono- or di-(C1-C3alkyl)amino, d) hydroxy,
e) C3-C7cycloalkyl,
f) C4-C7cyclic amino, or
g) C1-C3alkanoyloxy;
wherein R17 is
a) -Het,
b) C1-C5alkenyl,
c) C3-C7cycloalkenyl,
d) C1-C3alkoxy,
e) mercapto,
f) C1-C3alkylthio,
g) -COOH,
h) -CO-O-C1-C6alkyl,
i) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, j) -CO-NR22R26,
k) tri-C1-C3alkyl amino,
l) guanidyl, m) cyano,
n) N-cyanoguanidyl,
o) (hydroxy C2-C4alkyl)amino,
P) di-(hydroxy C2-C4alkyl)amino, or q) cyanoamino;
wherein R18 is
a) amino,
b) mono-, or di-(C1-C3alkyl)amino, c) C4-C7cyclic amino,
d) C4-C7cycloalkylamino, or
e) -CH(NH2)(CO2H);
wherein R19 is
a) aryl,
b) -Het,
c) tri-C1-C3alkylamino,
d) C3-C7cycloalkyl,
e) C2-C5alkenyl,
f) C3-C7cycloalkenyl ,
g) hydroxy,
h) C1-C3alkoxy,
i) C1-C3alkanoyloxy,
j) mercapto,
k) C1-C3alkylthio,
l) -COOH,
m) -CO-O-C1-C6alkyl,
n) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, o) -CO-NR22R26,
p) guanidyl,
q) cyano,
r) N-cyanoguanidyl,
s) cyanoamino,
t) (hydroxy C2-C4alkyl)amino,
u) di-(hydroxy C2-C4alkyl)amino; or v) -SO3H;
wherein R20 is
a) hydrogen, b) C1-C5alkyl, or c) aryl-C1-C5alkyl; wherein R21 is
a) -NH2, or b) -OH;
wherein R22 is
a) hydrogen, or b) C1-C3alkyl;
wherein R23 is
a) -(CH2)n-OH, b) -(CH2)n-NH2, c) aryl, or d) C1-C3alkyl;
wherein R24 is
a) -R1,
b) -(CH2)n-OH, or c) -(CH2)n-NH2; wherein R25 is
a) -(CH2)n-R13, b) hydrogen, c) C1-C3alkyl, or d) phenyl-C1-C3alkyl; wherein R26 is
a) hydrogen, b) C1-C3alkyl, or c) phenyl-C1-C3alkyl; wherein R27 is
a) -COOH, b) -COOC1-C6 alkyl, c) -CONR22R26, or d) -CH(NH2)COOH;
wherein R120 is
a) R126C[(CH2)qOR121]2(CH2)q-,
b) a moiety of formula XXX
c) a moiety of formula XXXI
d) -CH2(CHOR121)xCH2OR121,
e) R121OCH2(CHOR121)yCH-(CHOR121)zCH2OR121,
f) a moiety of formula XXXII ,or
g) R121 OCH2-C(CH2OR121)2- ;
wherein R121 is
a) hydrogen,
b) C1-C6alkyl,
c) -(CH2)n-aryl, or
d) -C(O)R123;
wherein R123 is
a) C1-C5 alkyl, or
b) -(CH2)n-phenyl;
wherein R126 is
a) hydrogen, or
b) (CH2)nOR121;
wherein R128 is
a) hydrogen, or
b) -(CHOR121)tCH2OR121;
wherein Q is
a) CH2,
b) CHOR121 or
c) C(O);
wherein j is one to three, inclusive;
wherein m is one or two;
wherein p is zero to two, inclusive;
wherein r is zero to five, inclusive;
wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein q is an integer of one to five, inclusive; wherein u is an integer of zero to three, inclusive;
wherein v is an integer of zero to four, inclusive;
wherein s is an integer of zero or one so that the sum of u plus v plus s is three or four; wherein t is an integer of zero to three, inclusive;
wherein w is an integer of two or three;
wherein x is an integer of two to seven, inclusive;
wherein y is an integer of zero to six, inclusive; and
wherein z is an integer of zero to six so that the sum of y plus z does not exceed six; wherein aryl is phenyl or naphthyl substituted by zero to three of the following:
a) C1-C3alkyl,
b) hydroxy,
c) C1-C3alkoxy,
d) halo,
e) amino,
f) mono- or di-C1-C3alkylamino,
g) -CHO,
h) -COOH,
i) COOR26,
j) CONHR26,
k) nitro,
l) mercapto,
m) C1-C3alkylthio,
n) C1-C3alkylsulfinyl,
o) C1-C3alkylsulfonyl,
p) -N(R4)-C1-C3alkylsulfinyl,
q) -SO3H,
r) SO2NH2,
s) -CN, or
t) -CH2NH2;
wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any dicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and optionally substituted by zero to three of the following:
a) C1-C5alkyl.
b) hydroxy,
c) hydroxy (C1-C5alkyl),
d) halogen,
e) amino,
f) amino (C1-C5alkyl),
g) -CHO,
h) -CO2H,
i) -CO2-(C1-C5alkyl),
j) -CONH2,
k) -CONH-(C1-C5alkyl),
l) nitro,
m) mercapto,
n) mercapto (C1-C5alkyl),
o) -SO3H,
p) -SO2NH2,
q) -CN,
r) -O-C1-C5alkyl, or
s) -[O-(CH2)2]n-OCH3.
with the provisos that:
1) G12 is present when both C8 and D9 are present and E10-F11 is other than LPA;
2) when X is Z-C(O)-CH(OH)-CH(CH2R1)-C(O)-, D9 is His and G12 is Ile;
3) when X is R5-CH2-O-C(O)-or R5-(CH2)n-C(O)- and E10- F11 is XL6, XL6b, XL6c or XL6d, R5 is other than C1-C6 alkyl;
4) when X is R5-O-C(O)- and E10-F11 is XL6, XL6b , XL6c
or XL6d, R5 is other than C1-C6 alkyl, C3-C7 cycloalkyl or aryl;
5) when X is R5-(CH2)n-C(O)-wherein R5 is cycloalkyl or aryl, and E10 F11 is XL6, XL6b, XL6c or XL6d, n is other than one;
6) when X is R4N(R4)-(CH2)n-C(O)- and E10-F11 is XL6, XL6b, XL6c or XL6d, n is other than one;
7) Z is other than N-4-amino-2-methyl-5-pyrimidinylmethyl-amide;
8) X is other than benzyloxycarbonyl or butyloxycarbonyl, when E10-F11 is II or IV; and
9) when X is K5-(CH2)n-C(O)- and E10-F11 is II or IV, R5 is other than C1-C6 alkyl; and
Use of a compound selected from the group consisting of;
L-Isoleucinamide, N2-(5-amino-4-hydroxy-2-(1-methylethyl)-1-oxooctyl]-N-(2- pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-Ile-Amp;
Octanamide, 5-[(3,3-dimethyl-1-oxobutyl)amino]-4-hydroxy-7-methyl-2-(1- methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl][2S-[1(1R*,2R- *).2R*,4R*,5R*]]- or TBA-LVA-Ile-Amp;
Cyclohexanehexanamide, δ-[(3,3-dimethyl-1-oxobutyl)amino]-τ-hydroxy-α -(1- methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [αS-[N(lR*,2R- *),αR*,τR*,δR*]]- or TBA-CVA-Ile-Amp;
Cyclohexanehexanamide, δ-amino-τ-hydroxy-α -(1-methylethyI)-N-[[2-methyl-1- [[(2-pyridinylmemyl)]amino]carbonyl]butyI]-,dihydrochloride,[αS-[N(1R*,2R*),α-R * ,τ- R*,δR*]]- or H-CVA-Ile-Amp;
Cyclohexanehexanamide, δ-(acetylamino)-τ-hydroxy-α-(1-methylethyl)-N-[2- methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyl], [αS-[N(lR*,2R*),α R*,τR*,δR *]]-; or Ac-CVA-Ile-Amp;
Octanamide,5-(acetylamino)-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2-methyl- 1-[[(2-pyridinylmethyl)amino)carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*]]-, monoacetate (salt); or Ac-LVA-Ile-Amp; or
IYA-LVA-Ile-Amp.
Boc-Phe-His-Cha psi[CHOHCHOH]Val-Ile-Amp; or L-Histidinamide, N-[(1,1- dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5- memyl-4-[[[2-memyl-1-[[(2-pyridinyimethyl)amino]carbo nyl]butyl]amino]carbonyl] , [1S-[1R*,2S*,3S*,4S*(1R*,2R*)]]-; or BOC-Phe-His-CVD-Ile-Amp;
L-Histidinamide, N-[(1,1-dimemylethoxy)caιbonyl]-L-phenylalanyl-N-[2-hydroxy-
1-(2-memylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino--5- oxo-4-(phenylmethyl)pentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc-Phe-His-LPA- Ile-Amp; L-Histidinamide, N-[(1 , 1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4- (cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)- amino]carbonyl]butyl]amino]-5-oxopentyl]-, [1S-[1R*,2R*.4S*,5(1R*,2R*)]]-: or Boc- Phe-His-LCA-Ile-Amp;
L-Talonamide 6-cyclohexyl-2,5,6-trideoxy-5-[N-[N-[(1 , 1-dimethylethoxy)carbo- nyl]-L-phenylaianyl]-L-histidyI]amino]-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmet- hyl)amino]carbonyl]butyl]-, [S-(R*,R*)]-; or Boc-Phe-His-CVD'-Ile-Amp; L Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-(2,3-dihydroxy-5- methyl-1-(2-methylpropyl)-4-[[(2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]am- ino]carbonyl]hexyl]-, [1S-[1R*,2S*,3R*,4S*(1R*,2R*)]]-; or Boc-Phe-His-LVDA' -Ile- Amp;
L-HistidinamideN-[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]-L-phenylalanyl- N-[2-hydioxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]c- arbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or DANS-Phe- His-LVA-Ile-Amp;
L-Histidinamide. L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S- (1R*,2R*,4R*(1R*,2R*)]]- or H-Phe-His-LVA-Ile-Amp;
L-Valinamide.L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S- [1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-Ile-Amp;
L-Valinamide, L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl][1S-[1R*,2R*,4R*(1- R*,2R*)]]-, diacetate (salt); or H-Val-Val-LVA-Ile-Amp; or
L-Valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyI]hexyl]-, [1S- [1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp.
Nα-[(2S,4S,5S)-5-[[Nα[(S)-1-Acetoxy-1-benzyl)methylcarbonyl]-L-histidyl]- amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N- [2-pyridyl)ethyl]-L- isoleucinamide; or AcO-Phe-His-LVA-Ile-NH-(CH2)2-pyridine.
4-Morpholinebutanamide,β-hydroxy-N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl- ]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-α-(1-naphthalenylmethyl)-7-oxo-, [1S-[1R*[R*(αS*,βR*)],2R*,4R*(1R*,2R*)]]-;
1H-Imidazole-4-propanamide, α-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl- methyl)amino)carbonyl]butyl]amino]carbonyl]hexyl]-, [1S- [1R*(R*),2R*,4R*(1R*,2R*)]]-: or DANS-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide, α-amino-N-[2-hydroxy-5-methyl-1-(2-methylpro- pyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-.
[1S-[1R*(R*),2R*,4R*(1R*,2R*)]] or H-His-LVA-Ile-Amp;
Octanamide, 5-[[2-(acetylammo)-3-memyl-1-oxobutyl]amino]-4-hydroxy-7-methyl- 2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S- [N(1R*,2R*),2R*,4R*.5R*(R*)]]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp;
Ac- Asn-LV A-Ile-Amp ;
Nα-[(2S,4S,5S)-5-[[(S)-(1-Hydroxy-1-benzyl)methylcarbonyl]amino]-4-hydroxy)- 7-methyl-2-(1-methylethyl)-1-oxooctyl]-N-(2-pyridinylmethyl)-L-isoleucinamide;or HO- Phe-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[(2- hydroxy-1-oxo-3-phenylpropyl)amino]-,[1S-[1R*[R*(R*)],2R*,4R*(lR*,2R*)]]-, 2- hydroxy-1,2,3-propanetricarboxylate(12) (salt) orphenyl-CH2-CH(OH)-C(O)-His-LVA- lie-Amp;
L-α-Glutamine, N/u 2/d -[N-[[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-N- [2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]- carbonyl]butyl]amino]rarbonyl]hexyl]-,[1S-[1R*,2R*4R*(1R*,2R*)]]-,monacetate(salt) or BOC-Phe-Glu-LVA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-3-(2-pyridinyl)alanyl-N-[2- hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo- nyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]-orBOC-2-Py- Ala-His-LVA-ne-Amp;
L-.alpha.-Asparagine, N/u 2/d-[N-[(1,1-dimethyIethoxy)carbonyl]-L-phenylala- nyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme- thyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*,4R*(1R*,2R*)]]- monoacetate (salt) or BOC-Phe-Asp-LVA-Ile-Amp;
L-.alpha.-Glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-NO[1- (cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carb- onyl]butyl]amino]carbonyl]hexyl]]-,[1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp;
L-Histidinamide, N-[(1 , 1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[3,3- difluoro-2-hydroxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-4- oxo-1-(phenylmethyl)butyl]- or CH3-C(O)-O-CH(benzyl)-C(O)-His-LVA-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl- L-isoleucyl-2-pyridylmethylamide or Gly-His-CPD-Ile-Amp;
5-QuinolinylhydroxyacetyI-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CVA-Ile-Amp;
Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-Ile-Amp; N tert-Butyloxycarbonyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S-isopropyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CVA-Ile-Amp;
N-tert-Butyloxycarbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-Ile-Amp;
Benzyloxycarbonyl-L-alanyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or CBZ-Ala-Ala-CVA-Ile-Amp:
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-[[[2- [(2,6-diamino-4-pyrimidinyl)amino]ethyl]amino]carbonyl]-2-hydroxy-5-methyl-1-(2- methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,6-diamino -4-pyrime- dinyl)amino-ethylamino;
Gly-CVD-Ile-Amp, and
Gly-CPD-Ile-Amp;
to prepare a medicament for inhibiting a retrovirus in a human cell infected with said retrovirus; and
A compound of formula I
X-C8-D9-E10-F11-G12-Z I wherein X is
a) hydrogen,
b) naphthyloxyacetyl, c) t-butyloxycarbonyl,
d) toluene-sulfonyl.
e) phenyloxyacetyl.
f) pyridinyl-(CH2)n-carbonyl,
g) phenyl-(CH2)n-CH(OH)-C(O)-,
h) indolycarbonyl,
i) pyridinyl-(CH2)n-O-C(O)-,
j) phenyl-(CH2) n-so2-,
k) phenyl-O-(CH2)n-C(O)-,
l) phenyl-HC =CH-(CH2)n-C(O),
m) phenyl-HC = CH-(CH2)n-O-C(O)-,
n) HO-(CH2)n-C(O)-,
o) quinolinoylhydroxyacetyl,
p) quinolinoylcarbonyl,
q) benzyloxycarbonyl, or
r) 5-(triethyleneglycolmonomethylether) naphthyloxyacetyl; wherein C8 is
a) absent,
b) 2-Py-Ala,
c) -NH-CH2-C(O)-,
d) Phe, or
e) Ala;
wherein D9 is
a) His,
b) Glu,
c) Asp,
d) Asn,
e) -NH-CH2-C(O), or
f) Ala;
wherein E10-F11 is
a) CVA,
b) LVA,
c) CVD, d) LVD,
e) CPD,
f) CLD,
g) CcD,
h) CCD,
i) PPD,
j) LID,
k) LLd, or
1) LLD;
wherein G12 is
a) absent, or
b) lIe;
wherein Z is
a) Amp,
b) Amp-NO,
c) lysine,
d) -NH-(CH2)n-NH-pyridine,
e) -NH-(CH2)n-CH(OH)-phenyl,
f) -NH-(CH2)n-CH(OH)-C1-C5 alkyl, or
g) -NH-(CH2)n-NH-(2,6-diamino-4-pyrimidinyl).
wherein n is O to five, inclusive.
By "amino acyl derivatives" is meant any of the naturally occurring amino acids such as: glycine, alanine, valine, leucine, isoleucine, phenylalanine, lysine, proline, tryptophan, methionine, serine, threonine, cysteine, tyrosine, asparagine, glutamine, aspartic acid, glutamic acid, arginine, ornithine, and histidine, and synthetic derivatives thereof. These compounds may be in the L or D configuration and are well known and readily available to those skilled in the art.
Susprisingly and unexpectedly, the compounds of the present invention are effective and potent inhibitors of HIV protease. The compounds of the present invention have also been found to inhibit HIV protease in cell cultures, as described below. Therefore, the compounds of formula I inhibit retroviral proteinases and thus inhibit the replication of the virus. They are useful for treating patients infected with human immunodeficiency virus (HTV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
The novel compounds of the present invention have low to moderate renin inhibitory activity but are surprisingly and unexpectedly potent retroviral protease inhibitors.
The peptides of the present invention are also useful as novel human retroviral protease inhibitory peptide analogs. Therefore, the peptides of the present invention inhibit retroviral proteases and thus inhibit the replication of the vims. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (strains of HIV-1 or HIV-2) or human T-cell leukemia viruses (HTLV-I or HTLV-II) which results in acquired immunodeficiency syndrome (AIDS) and/or related diseases.
The capsid and replicative enzymes (i.e. protease, reverse transcriptase, integrase) of retroviruses are translated from the viral gag and pol genes as polyproteins that are further processed by the viral protease (PR) to the mature proteins found in the viral capsid and necessary for viral functions and replication. If the PR is absent or nonfunctional, the virus cannot replicate. The retroviral PR, such as HIV-1 PR, has been found to be an aspartic protease with active site characteristics similar to those exhibited by the more complex aspartic protease, renin.
The term human retrovirus (HRV) includes human immunodeficiency virus type I, human immunodeficiency virus type II, or strains thereof, as well as human T cell leukemia virus 1 and 2 (HTLV-1 and HTLV-2) or strains apparent to one skilled in the art, which belong to the same or related viral families and which create similar physiological effects in humans as various human retroviruses.
Patients to be treated would be those individuals: 1) infected with one or more strains of a human retrovirus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) in the case of HIV, having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isopsoriasis, iii) bronchial and pulmonary candidiasis including pneumocystic pneumonia iv) non- Hodgkin's lymphoma or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/m3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the peptide used according to this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed. More specifically, an example of one such human retrovirus is the human immunodeficiency virus (HIV, also known as HTLV-III or LAV) which has been recognized as the causative agent in human acquired immunodeficiency disease syndrome (AIDS), P. Duesberg, Proc. Natl. Acad. Sci. USA, 86:755 (1989). HIV contains a retro viral encoded protease, HIV-I protease, that cleaves the fusion polypeptides into the functional proteins of the mature virus particle, E.P. Lillehoj, et al., J. Virology, 62:3053 (1988); C. Debuck, et al., Proc. Natl. Acad. Sci., 84:8903 (1987). This enzyme, HIV-I protease, has been classified as an aspartyl protease and has a demonstrated homology to other aspartyl proteases such as renin, L.H. Pearl, et al., Nature 329:351 (1987); I. Katoh, et al.. Nature 329:654 (1987). Inhibition of HIV-I protease blocks the replication of HIV and thus is useful in the treatment of human AIDS, E.D. Clerq, J. Med. Chem. 29: 1561 (1986). Inhibitors of HIV-I protease are useful in the treatment of AIDS.
Pepstatin A, a general inhibitor of aspartyl proteases, has been disclosed as an inhibitor of HIV-I protease, S. Seelmeier, et al, Proc. Natl. Acad. Sci. USA, 85:6612 (1986). Other substrate derived inhibitors containing reduced bond isosteres or statine at the scissle position have also been disclosed, M.L. Moore, et al., Biochem. Biophys, Res. Commun. 159:420 (1989); S. Billich, et al., J. Biol. Chem. 263: 17905 (1988); Sandoz, D.E. 3812-576-A.
Thus, the peptides of the present invention are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS).
The peptides of the present invention are also useful for treating non-human animals infected with a retrovirus, such as cats infected with feline leukemia virus. Other viruses that infect cats include, for example, feline infectious peritonitis virus, calicivirus, rabies virus, feline immunodeficiency virus, feline parvovirus (panleukopenia virus), and feline chlamydia. Exact dosages, forms and modes of administration of the peptides of the present invention to non-human animals would be apparent to one of ordinary skill in the art, such as a veterinarian.
The compounds of formula I of the present invention are prepared as described in the publications listed in Table I below, all of which are incorporated by reference herein, or are prepared by methods analogous thereto, which are readily known and available to one of ordinary skill in the art of peptide synthesis. As is apparent to those of ordinary skill in the art, the compounds of the present invention can occur in several diastereomeric forms, depending on the configuration around the asymmetric carbon atoms. All such diastereomeric forms are included within the scope of the present invention. Preferably, the stereochemistry of the amino acids corresponds to that of the naturally occurring amino acids.
The present invention provides for compounds of formula I or pharmacologically acceptable salts and/or hydrates thereof. Pharmacologically acceptable salts refers to those salts which would be readily apparent to a manufacturing pharmaceutical chemist to be equivalent to the parent compound in properties such as formulation, stability, patient acceptance and bioavailablility.
The compounds of the present invention are useful for treating patients infected with human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases. For this indication, the compounds of formula I are administered by oral, nasal, transdermal and parenteral (including i.m. and i.v.) routes in doses of 1 μg to 100 mg/kg of body weight.
Those skilled in the art would know how to formulate the compounds of this invention into appropriate pharmaceutical dosage forms. Examples of the dosage forms include oral formulations, such as tablets or capsules, or parenteral formulations, such as sterile solutions.
When the compounds in this invention are administered orally, an effective amount is from about 1 μg to 100 mg per kg per day. Either solid or fluid dosage forms can be prepared for oral administration. Solid compositions are prepared by mixing the compounds of this invention with conventional ingredients such as talc, magnesium stearate, dicalcium phosphate, magnesium aluminum silicate, calcium sulfate, starch, lactose, acacia, methyl cellulose, or functionally similar pharmaceutical diluents and carriers. Capsules are prepared by mixing the compounds of this invention with an inert pharmaceutical diluent and placing the mixture into an appropriately sized hard gelatin capsule. Soft gelatin capsules are prepared by machine encapsulation of a slurry of the compounds of this invention with an acceptable inert oil such as vegetable oil or light liquid petrolatum. Syrups are prepared by dissolving the compounds of this invention in an aqueous vehicle and adding sugar, aromatic flavoring agents and preservatives. Elixirs are prepared using a hydroalcoholic vehicle such as ethanol, suitable sweeteners such as sugar or saccharin and an aromatic flavoring agent. Suspensions are prepared with an aqueous vehicle and a suspending agent such as acacia, tragacanth, or methyl cellulose.
When the compounds of this invention are administered parenterally, they can be given by injection or by intravenous infusion. An effective amount is from about 1 μg to 100 mg per kg per day. Parenteral solutions are prepared by dissolving the compounds of this invention in water and filter sterilizing the solution before placing in a suitable sealable vial or ampule. Parenteral suspensions are prepared in substantially the same way except a sterile suspension vehicle is used and the compounds of this invention are sterilized with ethylene oxide or suitable gas before it is suspended in the vehicle.
The exact route of administration, dose, or frequency of administration would be readily determined by those skill in the art and is dependant on the age, weight, general physical condition, or other clinical symptoms specific to the patient to be treated.
Patients to be treated would be those individuals: 1) infected with one or more than one strain of a human immunodeficiency virus as determined by the presence of either measurable viral antibody or antigen in the serum and 2) having either a symptomatic AIDS defining infection such as i) disseminated histoplasmosis, ii) isoporiasis, iii) bronchial and pulmonary candidiasis including pneumocystis pneumonia, iv) non-Hodgkin's lymphoma, or v) Kaposi's sarcoma and being less than sixty years old; or having an absolute CD4 lymphocyte count of less than 200/mm3 in the peripheral blood. Treatment would consist of maintaining an inhibitory level of the compounds of this invention in the patient at all times and would continue until the occurrence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
The utility of representative compounds of the present invention has been demonstrated in several biological tests as described below.
The HTV-1 protease has been expressed in E. coli, isolated, characterized and used to determine the inhibitory constants (Ki) of potential inhibitory compounds as follows:
The synthetic peptide H-Val-Ser-Gln-Asn-Tyr-Pro-Ile-Val-OH serves as the substrate for the measurement of HTV-1 protease activity. This peptide corresponds to the sequence from residue 128 to 135 in the HIV gag protein. Cleavage of the synthetic peptide, as well as the gag protein, takes place at the Tyr-Pro bond. HTV-1 protease activity is measured at 30°C in 50 mM sodium acetate, pH 5.5, containing 10% glycerol, 5% ethylene glycol, 0.1 % Nonidet P-40 and 2.8 mM substrate in a total volume of 50 μl. After 30 minutes of incubation, 75 μl of 1 % trifluoroacetic acid (TFA) is added and the reaction mixture subjected to HPLC analysis. HPLC is carried out with a Vydac C18 column (0.46 x 15 cm), eluting with a linear gradient of 0-30% acetonitrile over a period of 25 minutes at a flow rate of 1.0 ml/minute.
The Ki values of representative compounds of formula I of the present invention are listed in Table II below.
Several compounds of the present invention have been further evaluated for their ability to inhibit HIV replication in primary cultures of human peripheral blood lymphocytes. This assay is done by the following screening procedure.
The following features characterize the primary screening:
The screening tests are performed with primary human lymphocytes. Thereby, undesired testing of transformed cell lines is avoided in which host cell and virus may have undergone processes of mutual adaptation. Performance of cell culture in serum containing media closely mimics the in vivo situation.
True antiviral effects of test compounds are readily distinguished from cytostatic/ cytotoxic reactions.
By kinetic measurement of viral nucleic acids and proteins the viral replication is followed precisely.
Testing in parallel on the level of nucleic acids (total HRV-RNA intra- and extracellular) and on the level of proteins (secreted p24) allows to differentiate the test compound's effects on virus replication and on the expression of viral proteins. This leads to additional information regarding the efficacy of the test compound.
Tolerance of the cell culture against low amounts of organic solvents permits the investigation of hydrophobic substances also.
The dose of the test compound causing half maximal suppression of virus replication is determined.
The screening system is standardized and automated to a high degree.
1. TEST FOR TOXICITY
Effects of the test compound on cell proliferation are determined by lymphocyte proliferation assays. Starting with a 100 micromolar solution, the test compound is 10 fold serially diluted. One tenth of the concentration of the test compound causing half maximal inhibition of cellular proliferation is employed for all subsequent testing.
2. IN VITRO INFECTION OF LYMPHOCYTES
Peripheral human lymphocytes are isolated by density gradient centrifugation. After stimulation by mitogen the cells are infected with a standardized preparation of
HRV. Subsequently, the infected cells are cultured in the presence of the test compound for four days. Individual cultures are established to measure viral replication two, three and four days following infection.
Untreated cells and AZT-treated cells are included as controls in parallel with the test compounds under investigation.
2.1 DETECTION OF SECRETED VIRAL P24
The amount of viral core protein p24 synthesized and released by the infected cells is determined in the supernatant by capture-ELISA technique on days two, three and four. By comparing with a standard preparation, the amount of protein produced by the virus infected cells will be calibrated.
2.2 ASSAY FOR HIV-RNA
The total amount of viral RNA synthesized by the infected lymphocytes is determined by a special nucleic acid hybridization technique on days two, three and four of culture. By including a standard preparation of HRV-RNA the amount of synthesized RNA will be quantified.
In case a test compound shows antiviral effects in the primary screening, all steps of the primary screening will be repeated. In addition, viability of HRV-infected cells will be determined in parallel with assays for viral p24 and RNA. In order to evaluate the half maximal antiviral effectof the test compound, a concentration dependency of the test compound action will be measured.
The results of the testing of these compounds of the present invention in these assays is given in Table III below.
Some of the compounds of the present invention have been further evaluated in a CV-1 cellular assay described below, where it was demonstrated that the retrovirus- inhibiting effect was due to the inhibition of HTV-1 protease.
CV-1 cells were seeded at 2 x 10-5 cells/well in 24 well Costar dishes and infected 6 to 12 hours later with vVK-1 at 5 PFU/cell (V. Karacostas, et al., "Human Immunodeficiency Virus-Like Particles Produced by a Vaccinia Virus Expression Vector (retrovirus/AIDS/virus assembly/reverse transcriptase, " Proc. Natl. Acad. Sci., USA, in press. 1989). The test compounds were dissolved in DMEM containing 2.5% fetal bovine serum and added to triplicate wells immediately after virus addition. Twenty- four hours after infection the culture medium was removed, the monolayer washed with 1 ml of PBS and the cells lysed by the addition of 0.1 ml of loading buffer (62.5 mM Tris-Hcl pH 6.8, 2.3 % SDS, 5 % B-mercaptoethanol, 10% glycerol). The cells lysates were collected individually, placed in boiling water for 3 minutes, and then 0.025 ml of each is subjected to electrophoresis on 12% SDS-polyacrylamide gels. The proteins were electroblotted onto nitrocellulose and analyzed by Western blotting. The primary antibodies were sheep anti-Pr24 and sheep anti-Pr17 and the secondary antibody in both cases was alkaline-phosphatase conjugated rabbit-anti sheep IgG (all obtained from Kirkegaard & Perry Laboratories, Gaithersburg, MD).
Test compounds significantly inhibited proteolysis of the HIV-1 gag polyprotein
(Pr55) to the mature viral structural proteins Pr24 and Pr17 in the above cells infected with the recombinant vaccina virus expressing the HIV-1 gag-pol genes. The HIV-1 like particles released from inhibitor-treated cells contained almost exclusively Pr55 and other gag precursors, but not Pr24.
The following compounds of the present invention are preferred:
1-Noa-His-ChaPSI[CHOHCHOH]Val-Ile-Amp; or 1H-Imidazole-4-propanam- ide, N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]-[amino]carbonyl]hexyl]-α-[[(1-naphthalenyloxy)acetyl]- amino]-, [1S-[1R*(R*),2S*,3S*,4S*(1R*,2R*)]]-; or NOA-His-CVD-Ile-Amp;
Nα-[(2S,4S,5S)-5-[N-[Nα-(Phenoxymethylcarbonyl)-L-histidyl]amino-4- hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucinam- ide, acetic acid salt; or POA-His-LVA-Ile-NH(CH2)2NH-pyridine; or POA-His-LVA-Ile- NH(CH2)2NH-pyridine;
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α [(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-; or POA-His-CVA-Ile- Amp;
1H-Imidazole-4-propanamide, H-[1-(cycloheptylmethyl)-2-hydroxy-5-methyl-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α [(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-; or POA-His-chpVA-Ile- Amp;
Cyclohexanehexanamide, δ-(acetylamino)-τ-hydroxy-α-(1-methylethyl)-N-[2- methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyl], [αS-[N(1R*,2R* ),αR*,τR*,δR*]]-; or Ac-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα -(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα -[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl) (2-pyridinyl)alanyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl- 1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L- isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine);
Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-4-[(1H-indol-2- ylcarbonyl)amino]-5-oxo-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]or1H-indol-2-yl-carbonyl- Glu-CVA-Ile-Amp;
2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9- (1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4, 10, 13-trioxo-15-(2-pyridinyl)- 3-phenyl-2-propenyl ester, [3S-[1(E),3R*,6R*,7R*,9R*, 12R*(R*)]]- or phenyl- CH=CH-CH2-O-C(O)-His-LVA-Ile-Amp;
Phenoxyacetyl-L-histidyl-5S-am ino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CVA-Ile-Amp;
1-Naphtoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy-6-phenyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamideorNOA-His-CVD-Ile-Apr;
5-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CV A-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2R-isobutyl-7-methyl octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLd-Ile-Amp; 2-Quinolinylcarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr;
Quinolinyl-2-carbonγl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp;
L-Asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methyl- propyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carb- onyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- or NOA-Asp-CVA-Ile- Amp;
L-Asparaginamide, [5-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N- [2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]- amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl[1S-[1R*,2R*,4R*(1R*,2- R*)]]- or 5-(triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp; and
L-Asparaginamide, [4-(-riethyleneglycolmonomethylether)naphthoxy]acetyl-N- [2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]- amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl[1S-[1R*,2R*,4R*(1R*,2- R*)]]- or 4-(triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp.
The following compounds of the present invention are most preferred:
1-Noa-His-ChaPSI[CHOHCHOH]Val-Ile-Amp; or 1H-Imidazole-4-propanam- ide, N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]-[amino]carbonyl]hexyl]-α -[[(1-naphthalenyloxy)acetyl]- amino]-, [1S-[1R*(R*),2S*,3S*,4S*(1R*,2R*)]]-; or NOA-His-CVD-Ile-Amp;
Quinolinyl-2-carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp;
L-Asparaginamide, [5-(triethyleneglycol monomethyl ether)naphthoxy]acetyl-N-[2- L-Asparaginamide, [5-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N-
[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinyl- methyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R* ,2R*, - 4R*(1R*,2R*)]]- or 5-(triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp.
L-Asparaginamide ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2- memylpropyl)-4-[[[2-methyl-1-[[(2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amin- o]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- or 4-(triethylenegl- ycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl) (2-pyridinyl)alanyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα -(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl- 1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L- isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine);
2-Quinolinylcarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr; and
1-Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy-6-phenyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
In the Preparations and Examples below and throughout this document:
1H-NMR is nuclear magnetic resonance;
Ac is acetyl;
Aco is acetyloxy;
Amp is 2-(aminomethyl) pyridine;
Amp-NO is (2-pyridylmethyl) amino, pyridine N-oxide;
Apr is 2-pyridinylamino-ethylamide.
Asn is asparagine;
Boc is t-butoxycarbonyl;
BOP is benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophos- phate;
Bz is benzyl;
C is centigrade;
Cbz is benzyloxycarbonyl;
CcD is the moiety of formula X wherein R1 is cyclohexyl, R2 is α-hydroxy, R4 is α-hydroxy and R3 is β -CH2-cyclohexyl;
CCD is the moiety of formula X wherein R1 is cyclohexyl, R2 is α-hydroxy R3 is α-CH2-cyclohexyl and R4 is α-hydroxy;
CDCl3 is deuteriochloroform;
Celite is a filter aid;
CVA is Chaψ[CH(OH)CH2]Val of formula X wherein R1 is cyclohexyl, R2 is hydrogen, R3 is α-isopropyl and R4 is α-hydroxy;
chpVA is the moiety of formula X wherein R1 is cycloheptyl, R2 is hydrogen, and R3 is α-isopropyl, and R4 is α-hydroxy;
CLA is the moiety of formula X wherein R1 is cyclohexyl, R2 is hydrogen, R3 is -α-isobutyl, and R4 is α-hydroxy;
CLD is the moiety of formula X wherein R1 is cyclohexyl, R2 is α-hydroxy, R4 is α-hydroxy and R3 is α-isobutyl;
CPD is the moiety of formula X wherein R1 is cyclohexyl, R2 is α-hydroxy, R4 is α-hydroxy and R3 is α-benzyl;
CVD is the moiety of formula X wherein R1 is cyclohexyl, R2 is α-hydroxy, R3 is α-isopropyl and R4 is α-hydroxy;
CVD is the moiety of formula X wherein R1 is cyclohexyl, R2 is β-hydroxy,
R4 is α-hydroxy, and R3 is α-isopropyl;
DANS is dansyl or 5-dimethylaminonaphthalenesulfonyl;
DCC is dicyclohexylcarbodiimide;
DEPC is diethylphosphoryl cyanide;
EtOAc is ethyl acetate;
g is grams;
τ-Glu is τ-glutamic acid;
Gly is glycine;
His is histidine;
N-MeHis is Nα-methyl histidine;
HOBT is 1-hydroxybenzotriazole;
HPLC is high performance liquid chromatography;
He is isoleucine;
IR is infrared spectra;
IVA is isovaleryl;
LCA is the moiety of formula X wherein R1 is isopropyl, R2 is hydrogen, R3 is -α-CH2-cyclohexyl and R4 is α-hydroxy;
LFA is the difluoro version of LVA as described more fully in PCT Pub. No. WO86/06379 (6 November 1985), and is the moiety of formula IV wherein R1 is isopropyl;
LLA is the moiety of formula X wherein R1 is isopropyl, R2 is hydrogen, R3 is -α-isobutyl, and R4 is α-hydroxy;
LID is the moiety of formula X wherein R, is isopropyl, R2 is β -hydroxy, R4 is β-hydroxy and R3 is β -isobutyl;
LLd is the moiety of formula X wherein Rt is isopropyl, R2 is α-hydroxy, R4is α-hydroxy, and R3 is β -isobutyl;
LLD is the moiety of formula X wherein R1 is isopropyl, R2 is α-hydroxy, R4 is α-hydroxy, and R3 is α-isobutyl;
LPA is the moiety of formula X wherein R1 is isopropyl, R3 is hydrogen, R3 is -α-benzyl and R4 is α-hydroxy;
LVA is Leuψ(CH(OH)CH2)Val with the S configuration at C4 (the hydroxyl- bearing carbon atom) of the formula X wherein R1 is isopropyl, R2 is hydrogen, R3 is α-isopropyl and R4 is α-hydroxy;
LVD is the diol version of LVA as described more fully in PCT Pub. No. WO87/05302 (11 September 1987) and is the moiety of formula X wherein R1 is isopropyl, R2 is α-hydroxy, R4 is α-hydroxy and R3 is α-isopropyl;
LVDA' is the moiety of formula X wherein R1 is isopropyl, R2 is β -hydroxy, R4 is α-hydroxy, and R3 is α-isopropyl;
M or mol is mole;
Mba is 2S-methylbutylamine;
Me is methyl;
ml is milliliter;
MPLC is medium pressure liquid chromatography;
MS is mass spectroscopy;
NOA is (1-naphthyloxy)acetyl;
Ph is phenyl;
Phe is phenylalanine;
POA is phenyloxyacetyl;
PPD is the moiety of formula X wherein R1 is phenyl, R2 is α-hydroxy, R4 is α-hydroxy and R3 is α-benzyl;
Pro is proline;
2-Py-Ala is D,L-2-pyridyl-alamine.
RIP means a compound having the formula H-Pro-His-Phe-His-Phe-Phe-Val-
Tyr-Lys-OH.2(CH3C(O)OH).XH2O which is a known renin-inhibiting peptide;
TBA is t-butylacetyl;
TBAP is tetra-n-butylammonium phosphate; TEA is triethylamine;
TFA is trifluoroacetic acid;
THF is tetrahydrofuran;
TLC is thin layer chromatography;
Tos is p-toluenesulfonyl:
TsOH is p-toluenesulfonic acid;
Tyr is tyrosine;
(OCH3)Tyr is O-methyl tyrosine; and
Val is valine.
In formula X, wherein the variables are as defined above, "α" is used to indicate the substituent is below the plane of the drawing and "β" is used to indicate the substituent is above the plane of the drawing.
The wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon.
The dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon.
The following Preparations and Examples illustrate the present invention:
Examples 1 - 103.
Using the chemical procedures, starting materials, and reactants described in the publications listed in Table I below, which are incorporated by reference herein, or methods analogous thereto, all of which are readily known and available to one of ordinary skill in the art, the following compounds of the present invention, having the indicated physical characteristics, are prepared:
(1) L-Isoleucinamide, N2-(5-am ino-4-hydroxy-2-(1-methylethyl)-1-oxooctyl]- N-(2-pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-Ile-Amp;
(2) 1H-Imidazole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]- α-[(phenoxyacetyl)-amino]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- ; POA-His-LVA-Ile-Amp;
(3) 1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-3,3-difluoro-4- [[2-methyI-1-[[(2-pyridinylmethyl)a m ino]carbonyl]butyl]amino]-2,4-dioxobutyl]-α-[[(1- naphthalenyloxy)acetyl]amino]-, [1S-(1R*(αR*),2R*]]-; or NOA-His-LFA-Ile-Amp;
(4) 1H-Imidazole-4-propanamide, α-[[2-(acetyloxy)-3-(1-naphthalenyl)-1- oxopropyl]amino]-N-[1-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]amino]-2,4-dioxobutyl]-, [1S-[1R*[αR*(R*)],2R*]]-;
(5) L-Histidinamide, N-[( 1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1 - (cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]- butyl]amino]-2,4-dioxobutyl]-; or Boc-Phe-His-LFA-Ile-Amp:
(6) 1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-6- methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]- heptyl]-α-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*(1R*,2R*)]]-; or POA-His- CLA-Ile-Amp;
(7) 1H-Imidazole-4-propanamide, N-[2,3-dihydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]- carbonyl]hexyl]-α-[(phenoxyacetyl)amino]-[1S-[1R*(R*),2S*,3R*,4R*(1R*,2R*)]]-;or POA-His-LVDA-Ile-Amp;
(8) 1H-Imidazole-4-propanamide, N-[2,3-dihydroxy-5-methyl-4-[[(2-methyl- butyl)amino]carbonyl]-1-(2-methylpropyl)hexyl]-α-[(phenoxyacetyl)amino]-, [1R- [1R*(S*),2S*,3S*,4S*(S*)]]-; or POA-His-LVDA-Mba;
(9) Boc-Phe-His-Cha psi[CHOHCHOH]Val-Ile-Amp; or L-Histidinamide, N-[(1 , 1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3- dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]- carbonyl]hexyl]-, [1S-[1R*,2S*,3S*,4S*(1R* ,2R*)]]-;or BOC-Phe-His-CVD-Ile-Amp;
(10) 1-Noa-His-Cha PSI[CHOHCHOH]Val-Ile-Amp; or 1H-Imidazole-4- propanamide, N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2- pyridinylmemyl)amino]carbonyl]butyl]-[amino]carbonyl]hexyl]-α-[[(1-naphthalenyloxy)- acetyl]amino]-, [1S-[1R*(R*),2S*,3S*,4S*(1R*,2R*)]]-; or NOA-His-CVD-Ile-Amp;
(11) 1H-Imidazole-4-propanamide, N-[2-hydroxy-6-methyl-1-(2-methyl- p-Opyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]c arbonyl]butyl]amino]carbonyI]heptyl]-α-[(phenoxyacetyl)amino]-, [1S-[1R* (R*),2R*,4S*(1R*,2R*)]]-; or POA-His-LLA- Ile-Amp;
(12) 1H-Imidazole-4-propanamide, N-[2-hydroxy-1-(2-methylpropyl)-5-[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-5-oxo-4-(phenylmethyl)- pentyl]-α-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*,5(1R*,2R*)]]-; or POA-His- LPA-Ile-Amp;
(13) 1H-Imidazole-4-propanamide, N-[4-(cyclohexylmethyl)-2-hydroxy-1-(2- methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-5 oxopentyl]-α-[(phenoxyacetyI)amino]-, [1S-[1R*(R*),2R*,4S*,5(1R*,2R*)]]-; or POA- His-LCA-Ile-Amp;
(14) L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[2- hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]- amino-5-oxo-4-(phenylmethyl)pentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc-Phe- His-LPA-Ile-Amp;
(15) L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4- (cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)- amino]carbonyl]butyl]amino]-5-oxopentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc- Phe-His-LCA-Ile-Amp;
(16) L-Talonamide, 6-cyclohexyl-2,5,6-trideoxy-5-[N-[N-[(1,1-dimethyleth- oxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-(1-methylethyl)-N-[2-methyl-1-[[(2- pyridinylmethyl)amino]carbonyl]butyl]-, [S-(R*,R*)]-; or Boc-Phe-His-CVD'-Ile-Amp;
(17) L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N- (2,3-dihydroxy-5-methyl-1-(2-methylpropyl)-4-[[(2-methyl-1-[[(2-pyridinylmethyl)- amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2S*,3R*,4-Amp; or Boc-Phe- His-LVDA'-Ile-Amp; FAB-MS: [m + H]+ at 835.5084;
(18) 4-Morpholinebutanamide, β-hydroxy-N-[2-[[2-hydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]- carbonyl]hexyl]amino]-1-(1H-imidazol-4-ylmethyl)-2-oxoethyl]-α-(1-naphthalenylmethyl)- T-oxo-, [1S-[1R*[R*(αS*,βR*)],2R*,4R*(1R*,2R*)]]-;
(19) 1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-5- methyl-4-[[[2-memyl-1-[[(2-pyridinyImethyl)ammo]carb onyl]butyl]ammo]carbonyl]hexyl]- α-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-; or POA-His-CVA-Ile- Amp; FAB-MS: [m + H]+ at 746.4598;
(20) 1H-Imidazole-4-propanamide, α-[[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]amino]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2- pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*(R*),2R*,- 4R*(1R*,2R*)]]-; or DANS-His-LVA-Ile-Amp;
(21) 1H-Imidazole-4-propanamide, N-[1-(cycloheptylmethyl)-2-hydroxy-5- methyl-4-[[[2-memyl-1-[[(2-pyridinylmethyl)aιmino]carbonyl]butyl] am ino]carbonyl]hexyl]- α-[(phenoxyacetyl)amino]-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-;orPOA-His-chpVA-Ile- Amp; (22) L-Histidinamide, N-[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]-L- phenylalanyl-N-[2-hydroxy-5-methyl- 1-(2-methylpropyl)-4-[[[2-methyl-1 -[[(2- pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-[1S-[1R*,2R* ,4R*(1R*,- 2R*)]]-; or DANS-Phe-His-LVA-Ile-Amp;
(23) Octanamide 5-[(3,3-dimethyl-1-oxobutyl)amino]-4-hydroxy-7-methyl-2-
(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S- [1(1R*,2R*),2R*,4R*,5R*]]- or TBA-LVA-Ile-Amp; FAB-MS: [m + H)+ at 533;
(24) Cyclohexanehexanamide, δ-[(3,3-dimethyl-1-oxobutyl)amino]-τ-hydroxy- α-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [αS- [N(1R*,2R*),αR*,τR*,δR*]]- or TBA-CVA-Ile-Amp; FAB-MS: [m + H]+ at 573;
(25) 1H-Imidazole-4-propanamide, α-amino-N-[2-hydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]- carbonyljhexyl]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]] or H-His-LVA-Ile-Amp;
(26) L-Histidinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpro- pyl)-4-[[[2-memyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,
[1S-(1R*,2R*,4R*(1R*,2R*)]]- or H-Phe-His-LVA-Ile-Amp;
(27) Cyclohexanehexanamide, δ-amino-τ-hydroxy-α-(1-methylethyl)-N-[[2- methyl-1-[[(2-pyridinylmethyl)]amino]carbonyl]butyl]-dihydrochloride,[αS-[N(1R*,2R- *),αR*,τR*,δR*]]- or H-CVA-Ile-Amp; FAB-MS: [m + H]+ at 475;
(28) Cyclohexanehexanamide, δ-(acetylamino)-τ-hydroxy-α-(1-methylethyl)-
N-[2-methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyl], [αS-[N(1R*,2R*),αR*,τR*,- δR*]]-; or Ac-CVA-Ile-Amp; FAB-MS: [m + H]+ at 517;
(29) Octanamide, 5-(acetylamino)-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2- methyl-1-[[(2-pyridinylmemyl)a mino)carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*]]-, monoacetate (salt); or Ac-LVA-Ile-Amp; FAB-MS: [m + H]+ at 477;
(30) L-Valinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropy 1)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]- [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-Ile-Amp;
(31) Octanamide, 5-[[2-(ace-ylammo)-3-methyl-1-oxobutyl]amino]-4-hydroxy 7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-
[2S-[N(1R*,2R*),2R*,4R*,5R*(R*)]]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp; FAB-MS: [m + H]+ at 576;
(32) L-Valinamide, L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2 methyl-1-[[(2-pyridinylmethyl)amino]carbonyI]butyl]amino]carbonyl]hexyl]-, [1S- [1R*,2R*,4R*(1R*,2R*)]]-, diacetate (salt); or H-Val-Val-LVA-IIe-Amp; FAB-MS: [m + H]+ at 633;
(33) Ac-Asn-LVA-Ile-Amp; FAB-MS: [m + H]+ at 591;
(34) L-Valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylprop- yl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp; FABMS: [m + H]+ at 675;
(35) Nα-[(2S,4S,5S)-5-[N-[Nα-(Phenoxymethylcarbonyl)-L-histidyl]amino-4- hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucin- amide, acetic acid salt; or POA-His-LVA-Ile-N H(CH2)2NH-pyridine; FAB-MS: [m + H]+ at 735;
(36) IVA-LVA-Ile-Amp; FAB-MS: [m + H]+ at 519;
(37) N-[(2S ,4S ,5S)-5-[Nα-[Nα-(tert-Butoxycarbonyl)-O-methyl-L-tyrosyl]-L- histidyl]amino]-4-hydroxy-7-methyl-2-phenylmethyl-1-oxooctyl]-N-[(S)-2-hydroxy- propyl]amine; or Boc-OMeTyr-His-LPA-NH-CH2-CH(CH3)(OH); FAB-MS: [m + H]+ at 751;
(38) Nα-[(2S ,4S ,5S)-5-|N-[Nα-(Phenoxyme-hylcarbonyl)-L-histidyl]amino]-4- hydroxy-2-isopropyI-7-methyl-1-oxooctyl]-N-(2,3-dihydroxypropyl)-L-isoleucinamide; or POA-His-LVA-Ile-NH-CH,-CH(OH)-CH2OH; FAB-MS: [m + H]+ at 689;
(39) Nα-[(2S ,4S ,5S)-5-|N-[Nα-(Phenoxymemylcarbonyl)-L-histidyl]-amino-4- hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-(2-hydroxypropyl)-L-isoleucinamide; or POA-His-LVA-Ile-NH-CH2-CH(CH3)(OH); FAB-MS: [m + H]+ at 673;
(40) Nα-[(2S,4S,5S)-5-[[Nα[(S)-1-Acetoxy-1-benzyl)methylcarbonyl]-L- histidyl]arnmo]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N-[2-pyridyl)ethyl]-L- isoleucinamide; or AcO-Phe-His-LVA-He-NH-(CH2)2-pyridine; FAB-MS: [m + H]+ at 776;
(41) Nα-[(2S,4S,5S)-5-[[(S)-(1-Hydroxy-1-benzyl)meth ylcarbonyl]amino]-4- hydroxy)-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N-(2-pyridinylmethyl)-L-isoleucinamide; or HO-Phe-LVA-Ile-Amp; High Resolution MS: 583.3880;
(42) Nα-[(2S, 4S, 5S)-5-|N-[N α-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucmamide, pyridine N-oxide or NOA-His-CVA-Ile-Amp-NO. HR FAB MS [m+H]+ at m/z 812.4748;
(43) Nα-[(2S, 4S, 5S)-5-[N-[Nα-(P-toluenesulfonyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or p-Tolunesulfonyl-His-CVA-Ile-Amp. HR FAB MS [m + H]+ at m/z 766.4348;
(44) Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-
6-cyclohexyl-4-hydroxy-2-isopropyl-l-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp. HR FAB MS [m + H]+ at m/z 796.4794;
(45) Nα-[(2S , 4S , 5S)-5-[N-[Nα-(Phenoxymethylcarbonyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or POA-His-CVA-Ile-Amp-NO. HR FAB MS [m + H]+ at m/z 762.4574;
(46) Nα-[(2S, 4S, 5S)-5-[N-[Nα-(p-Toluenesulfonyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or p-Toluenesulfonyl-His-CVA-Ile-Amp-NO. HR FAB MS [m + H]+ at m/z 782.4238;
(47)Ne-[(2S,4S,5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-lysine,trifluoroacecticacid salt or NOA- His-CVA-L-lysine,trifluoroacetic acid salt. HR FAB MS [m + H]+ at m/z 721.4309;
(48) N-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino]ethyl]-amine or
NOA-His-CVA-NH-(CH2)2-NH-(2-pyridine) HR FAB MS [m + H]+ at m/z 712.4195;
(49) N-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)]ethyl]amine, pyridine N-oxide or NOA-His-CVA-NH(CH2)2-NH-(2-pyridine). HR FAB MS [m + H]+ at m/z 728.4144;
(50) Nα-[(2S,4S,5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)(2-pyridinyl)alanyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or NOA-His-CVA-Ile-Amp. HR FAB MS [m + H]+ at m/z 807.4795;
(51) Nα-[(2S, 4S, 5S)-5-[N-[Nα-[(3-Pyridinyl)-methylcarbonyl]-L-histidyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or (3-pyridinyl)-methyl-carbonyl-His-CVA-Ile-Amp. HR FAB MS [m + H]+ at m/z 731.4625;
(52) Ne-[Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-isoleuncyI]-L-lysine, trifluoroacetic acid salt or NOA-His-CVA-Ile-L-lysine, trifluoroacetic acid salt. HR FAB MS [m + H]+ at m/z 834.5151;
(53)Nα-[(2S ,4S ,5S)-5-[N-[Nα-(1-NaphthalenyloxyacetyI)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L- isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine). HR FAB MS [m+H]+ at m/z 825.5040;
(54) 1H-Imidazole-4-propana mide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[(2- hydroxy-1-oxo-3-phenylpropyl)amino]-,[1S-[1R*[R*(R*)],2R*,4R*(1R*,2R*)]]-, 2- hydroxy-1,2,3-propanetricarboxylate (12) (salt) orphenyl-CH2-CH(OH)-C(O)-His-LVA- Ile-Amp. HR FAB MS [m +H]+: 720.4456;
(55) 1H-Imidazole-4-propanamide,N-[2-hydroxy-4-[[[1-[[(2-hydroxy-2-phenylethyl)amino]carbonyl]-2-memylbutyl]amino]carbonyl]-5-methyl-1-(2-methylpropyl)hexyl]-α- [(phenoxyacetyl)amino]-, monoacetate (salt) or POA-His-LVA-Ile-NH-CH2-CH(OH)- phenyl. HR FAB MS [m +H]+: 735.4444;
(56) L-α-Glutamine, N/u 2/d -[N-[[1,1-dimethylethoxy)carbonyl]-L-phenylal- anyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*4R*(1R*,2R*)]]- monacetate (salt) or BOC-Phe-Glu-LVA-Ile-Amp. HR FAB MS [m +H]+: 811.4988;
(57) Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxy- propyl)amino]carbonyl]-5-methylhexyl]amino]-5-oxo-4-[(phenoxyacetyl)amino]-or POA- Glu-CVA-NH-CH2CH(CH3)(OH). HR FAB MS [m +H]+: 630.3146;
(58) 1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2- hydroxypropyl)amino]carbonyl]-5-methylhexyl]α-[(phenoxyacetyl)amino]-, monoacetate
(salt) or POA-His-CVA-NH-CH2-CH(OH)(CH3). HR FAB MS [m +H]+: 600.3770;
(59) Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl- 1-[[(2-pyridinylmethyl)amino]carbo nyl]butyl]amino]carbonyl]hexyl]amino]-4-[(1H-indol- 2-ylcarbonyl)amino]-5-oxo-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]- or 1H-indol-2-yl- carbonyl-Glu-CVA-Ile-Amp. HR FAB MS [m +H]+: 747.4437;
(60)L-.alpha.-Glutamine, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2- memyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N/u 2/d-L- phenylalanyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, bis(trifluoracetate) (salt) or Phe-Glu CVA-Ile-Amp. HR FAB MS [m +H]+: 751.4756;
(61)2-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyr)amino]carb onyl]butyl]-amino]carbonyl]hexyl]amino]-1-(1H- imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-or (2-Pyridyl)acetyl- His-LVA-Ile-Amp;
(62) 4-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-1- (1H-imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R* ,4R* (lR*,2R*)]]-or (4- Pyridyl)acetyl-His-LVA-Ile-Amp;
(63) L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-3-(2-pyridinyl)alanyl-
N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]c- arbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]-or BOC-2- Py-Ala-His-LVA-Ile-Amp. HR FAB MS [m +H]+: 820.5112;
(64) L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4- [[[2-[(2,6-diamino-4-pyrimidinyl)amino]ethyl]amino]carbonyl]-2-hydroxy-5-methyl-1-(2- methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,6-diamino-4-pyrime- dinyl)amino-ethylamino. HR FAB MS [m + H]+: 766.4727;
(65) L-.alpha.-Asparagine, N/u 2/d-[N-[(1,1-dimethylethoxy)carbonyl]-L- phenylalanyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme- thyl)amino]carbonyl]butyl]amino]carbonyl]hexyI]-,[1S-[1R*,2R * ,4R*(1R*,2R*)]]- monoacetate (salt) or BOC-Phe-Asp-LVA-Ile-Amp. HR FAB MS [m +H]+: 797.4857;
(66) 1H-Indole-2-carboxamide, N-[2-([2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]carbonyl]hexyl]amino]-1-(1H- imidazol-4-ylmethyl)-2-oxoethyl]-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-or N-(Indolyl-2- carbonyl)-His-LVA-Ile-Amp;
(67) L-.alpha.-Glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl- NO[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amin- o]carbonyl]butyl]amino]carbonyl]hexyl]]-,[1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp. HR FAB MS [m + H]+: 851.5297;
(68) 2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4- ylmemyl)-9-(1-memylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo-15-(2- pyridinyl)-,4-pyridinylmethyl ester, [3S-[3R*,6R*,7R*,9R*, 12R*(R*)]]- or Ioc-His- LVA-Ile-Amp; (69)L-Histidinamide.N-[( 1, 1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[3,3- difluoro-2-hydroxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-4- oxo-1-(phenylmethyl)butyl]- or CH3-C(O)-O-CH(benzyl)-C(O)-His-LVA-Ile-Amp. HR FAB MS [m + H]+: 762.4521:
(70) 1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-
4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[(1- oxo-3-phenoxypropyl)amino]-,[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-, or Phenoxy- propionyl-His-LV A-Ile-Amp ;
(71) 1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2-methyl-1-[[[(2-pyridinylmethyl)amino[carbonyl[butyl[amino[carbonyl[hexyl]-α-[(1- oxo-3phenyl-2-propenyl)amino]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]- or phenyl- CH=CH-C(O)-His-LVA-Ile-Amp. HR FAB MS [m + H]+: 702.4343;
(72) 1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2-methyl-1-[[[(2-pyridinylmethyl)amino[carbonyl][butyl]amino[carbonyl[hexyl]-α-[(1- oxo-4-phenyl-3-butenyl)amino]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]- or phenyl- CH=CH-CH2-C(O)-His-LVA-Ile-Amp. HR FAB MS [m + H]+: 716.4474;
(73) 2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4- ylmethyl)-9-(1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo-15-(2- pyridinyl)-,3-phenyl-2-proρenyl ester, [3S-[1(E),3R*,6R*,7R*,9R*,12R*(R*)]]- or phenyl-CH=CH-CH2-O-C(O)-His-LVA-Ile-Amp. HR FAB MS [m + H]+: 732.4463;
(74) 1H-Imidazole-4-propan a mide,N-[2-hydroxy-5-memyl-1-(2-memylpropyl)-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[[(2- phenylethenyl)sulfonyl]amino]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]- or phenyl -(CH2)2-SO2-His-LVA-Ile-Amp. HR FAB MS [m + H]+: 738.4061;
(75) N-tert-Butyloxycart)onyl-L-phenylalanyl-L-histidyl-5S-amino-3R,4R- dihydroxy-2R-isopropyl-7-methyl-octanoyl-2S-methylbutylamideor BOC-Phe-His-LVA- Mba. FAB-MS (found): 701.4634;
(76) Hydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CVA-Ile-Amp. FAB-MS (found): 686.4244;
(77) L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyI-2-pyridylmethylamide or Gly-His-CVA-Ile-Amp. FABMS (found): 685.4382; (78) Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R.4R- dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CPD-Ile-Amp. FAB-MS (found): 734.4248;
(79) Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R.4R dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide, N-oxide or (HO)Ac-His-CPD-
Ile-Amp. FAB-MS (found): 750.4202;
(80) Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamideor POA-His-CPD-Ile-Amp. FAB MS (found): 810.4557;
(81) L-Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy hexanoyl-L-isoleucyl-2-pyridylmethylamideor Gly-His-CPD-Ile-Amp. FAB-MS (found): 733.4409;
(82) Phenoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamideor POA-His-CVA-Ile-Amp. FAB MS (found): 762.4574;
(83)1-Naphtoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R isobutyl-hexanoyl-L-isoleucyl-2-pyridyimethylamide or NOA-His-CLD-Ile-Amp. FAB MS (found): 826;
(84) 1 -Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2R-cyclohexylmethy 3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CCD-Ile
Amp. FAB-MS (found): 866.5189;
(85) 1-Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy- phenyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp.
FAB-MS (found): 854.4230;
(86) 1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2 isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamideor NOA-His-CVD-Ile-Ap FAB-MS (found): 841.4964;
(87)-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2S-cyclohexylmethy 3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CcD-Ile-Am FAB-MS (found): 866.5194;
(88) 1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihydroxy-2S-isobutyl- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamideorNOA-His-LlD-Ile-Amp. FAB-M (found): 786.4540; (89)5-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CVA-Ile-Amp. FAB-MS (found): 797:
(90)4-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-Ile-Amp. FAB-MS (found): 797;
(91) 1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2S-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamideor NOA-His-LLd-Ile-Amp. FAB-MS (found): 786.4579;
(92) 1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4R-dihydroxy-2S-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamideor NOA-His-LLd-Ile-Amp. FAB-MS (found): 786.4556;
(93) 1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2R-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamideor NOA-His-LLD-Ile-Amp. FAB-MS (found): 786.4540;
(94) 2-Quinolinylcarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyI-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr. FAB-MS (found): 789.4670;
(95) N-tert-Butyloxycarbonyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamideor Boc-Ala-CVA-Ile-Amp. FABMS [m + H]+: 546;
(96N-tert-Butyloxycarbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamideor BOC-His-CVA-Ile-Amp. FABMS [m + H]+: 712;
(97) -Deleted-
(98) Quinolinyl-2-carbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-His-CVA-Ile-Amp. FABMS [m + H]+: 768;
(99) Quinolinyl-2-carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp.
FAB-MS [m +H]+: 744;
(100) Benzyloxycarbonyl-L-alanyl-L-alanyl-5S-anιino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamideor CBZ-Ala-Ala-CVA-Ile-Amp. FAB-MS [m +H]+: 751;
(101) 1-Naphthalenyloxyacetyl-L-histidyl-5S-amine-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucylamideorNoa-His-CVA-Ile-NH2. FAB-MS [m + H]+: 705;
(102) POA-His-CVA-NH-(CH2)4-CH(CONH)(NH2). FAB-MS [m + H]+:
671 ;
(103) L-Asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-,[1S-[1R*,2R*,4R*(lR*,2R*)]]-or NOA-Asp-CVA-Ile-Amp. Mass Spectrum: No exact mass obtained because of weak M + H+ ion. Other ions at m/z 665,535,348,354,236,222,157, 126,109,86;
Preparations 1-4
(1) Preparation of CH3(OCH2CH2)3OTs
A 100 mL two-necked round-bottomed flask, equipped with magnetic stirring bar, nitrogen inlet and reaction thermometer, is charged with 16 mL of pyridine (Mallinckrodt) and 8.0 mL of triethylene glycol monomethyl ether (Aldrich). This solution is cooled to 0°C (ice bath) under a nitrogen atmosphere and then is treated portion wise over 20 min with 11.4 g of /Moluenesulfonyl chloride so that the temperature does not exceed 5°C. About half way through the addition process a thick white precipitate began to form. Upon complete addition the resulting mixture is stirred at 0°C for two h. The mixture is poured into an ice cold solution of 30 mL of concentrated hydrochloric acid in 100 mL of water. This mixture is extracted with ethyl acetate (3 x 100 mL) and these extracts are washed with water (4 x 100 mL with the pH of the final wash being adjusted to 7 by the addition of saturated aqueous sodium bicarbonate), combined, dried (MgSO4), filtered and concentrated under reduced pressure to give 15.54 g of the desired tosylate as a colorless oil: 1H NMR (300 MHz; CDCl3) δ 7.80, 7.35, 4.16, 3.69, 3.59, 3.59, 3.54, 3.35, 2.45; mass spectrum (El), ions at m/z 318 [M]+, 286, 273, 259, 243, 229, 199, 155, 91, and 59; TLC Rf = 0.33 in 50% ethyl acetate/hexane (phosphomolybdic acid). This material is used without purification. (2) Preparation of 4-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid
I. Preparation of 4-[CH3(OC H2CH2)3O]-1-naphthol
A solution of 0.50 g of 1,4-naphthalene diol (Aldrich) and 1.0 g of CH3(OCH2- CH2)3OTs of Preparation 1 all in 10 ml of dimethylformamide is placed under a nitrogen atmosphere and then cooled to -60°C. A 60% mineral oil emulsion of sodium hydride (130 mg; 3.3 mmoL) (Aldrich)is added portionwise over two minutes. The resulting mixture is allowed to stir and gradually warm to -30ºC over 1.5 h. The cooling bath is removed and the mixture is allowed to warm to room temperature over one h at which time the mixture is then heated to 50°C and stirred for one h. The reaction is quenched with 1N ammonium hydroxide, diluted with methanol and concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump - to give a black colored solid. This material is dissolved in ethyl acetate and washed with brine (3X). The aqueous washes are back-extracted with ethyl acetate and the combined organic extracts are dried (Na2SO4), filtered and concentrated to give a black colored solid (a mixture of starting diol, tosylate and desired product). This material is chromatographed over 100 g of silica gel (63-200μ), eluting with 25% acetone/hexane while collecting 9 mL fractions (after a 100 mL solvent precut). Fractions 25-60 are combined and concentrated to give 0.51 g of impure 4-[CH3(OCH2CH2)3O]-1-naphthol: TLC Rf=0.19 in 25% acetone/hexane (UV).
II. Preparation of 4-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid, methyl ester
The material of Section I is dissolved in 15 mL of dimethylformamide, treated with 0.32 mL of methyl bromoacetate (Aldrich), cooled to 0°C under a nitrogen atmosphere followed by treatment with 0.15 g of a 60% mineral oil emulsion of sodium hydride. The resulting green colored mixture is stirred at 0°C for 1.5 h, quenched with saturated ammonium chloride, diluted with methanol and then concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump. The resulting brown colored solid is suspended in 50 mL of water and extracted with ethyl acetate. The aqueous phase is back-washed with ethyl acetate and the combined organic extracts are dried (Na2SO4), filtered and concentrated to give a brown colored oil (primarily a mixture of 4-[CH3(OCH2CH2)3O]-1-naphthoxyaceticacid, methyl ester, 1,4-[CH3(OCH2CH2)3O]-naphthalene and CH3(OCH2CH2)3OTs).
This material is chromatographed over 50 g of silica gel (63-200μ), eluting with 25% acetone/hexane while collecting 9 mL fractions. Fractions 33-49 are combined and concentrated to give 285 mg of 4-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid, methyl ester contaminated with a small amount of CH3(OCH2CH2)3OTs: Η NMR (300 MHz; CDCl3) δ 8.30-8.22, 7.56-7.50, 6.67, 6.61, 4.77, 4.25, 3.97, 3.82, 3.80, 3.69, 3.55, 3.37; TLC Rf=0.31 in 25% acetone/hexane (UV). Fractions 57-80 yielded the 1,4- [CH3(OCH2CH-)3O]-naphthalene by-product.
III. Preparation of 4-[CH3(OCH2CH2)3O]-1 -naphthoxyacetic acid
The methyl ester of Section 2 (263 mg); is dissolved in 3 mL of methanol. Water (1 mL) and IN sodium hydroxide (1 mL) are added and the resulting solution is let stir at room temperature for 2 h. The solution is then poured into 10 mL of 1N sodium hydroxide and extracted 3X with ethyl ether. The combined organic extracts are discarded and the aqueous phase is acidified to pH 5 with aqueous hydrochloric acid and then extracted 3X with methylene chloride. The combined organic extracts are dried (Na2SO4), filtered and concentrated to give 187 mg of 4-[CH3(OCH2CH2)3O]-1- naphthoxyacetic acid as a brown colored oil. TLC analysis showed only a spot at the origin using 20% ethyl acetate/chloroform. This material is used without purification in the subsequent coupling experiment.
(3) Preparation of 5-[CH3(OCH2CH2)3O]-1 -naphthoxyacetic acid
I. Preparation of 5-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid, methyl ester via 5-[CH3(OCH2CH2)3O]-1-naphthol [One pot reaction]
A solution of 0.50 g of 1 ,5 -naphthalene diol (Aldrich), 1.1 g of CH3(OCH2CH2- )3OTs of Preparation 1 and 0.27 g of a 60% sodium hydride emulsion all in 15 ml of dimethylformamide is placed under a nitrogen atmosphere and heated to 50°C. The resulting mixture is allowed to stir for 1.5 h and then treated with 0.44 mL (4.6 mmoL) of methyl bromoacetate (Aldrich). Stirring and heating is continued for an additional 1.5 h. The reaction solution is allowed to cool to room temperature and then quenched with saturated ammonium chloride, diluted with methanol and then concentrated under reduced pressure - first under house vacuum and then under lower pressure using a vacuum pump - to give a product containing mixture as a yellow solid. This solid is dissolved in ethyl acetate and washed with 50 mL of water (2X). The aqueous washes are back- washed with ethyl acetate and the combined organic extracts are dried (MgSO4), filtered and concentrated to give an orange colored oil. TLC analysis of this oil indicates a five component mixture comprised of the desired product [5-[CH3(OCH2CH2)3O]-1- naphthoxyaceticacid, methyl ester], an unidentified component, 1 ,5-[CH3(OCH2CH2)3O]- naphthalene, 1,5-[CH3O2CCH2O]-naphthalene and 5-[CH3(OCH2CH2)3O]-1-naphthol. This mixture is chromatographed over 50 g of silica gel (63-200μ), eluting with 20% ethyl acetate/chloroform while collecting 6 mL fractions. Fractions 51-60 are combined and concentrated to give 241 mg of 5-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid, methyl ester: Η NMR (300 MHz; CDCl3) δ 7.92, 7.91, 7.37 , 7.31, 6.83, 6.71, 4.78, 4.25, 3.95, 3.77, 3.79, 3.67, 3.52, 3.35; TLC Rf=0.46 in 20% ethyl acetate/chloroform (UV).
II. Preparation of 5-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid
The methyl ester of Section I (241 mg; 0.63 mmoL) is dissolved in 3 mL of methanol. Water (1 mL) and IN sodium hydroxide (1 mL) are added and the resulting solution is let stir at room temperature for 2 h. The solution is then poured into 10 mL of IN sodium hydroxide and extracted 3X with ethyl ether. The combined organic extracts are discarded and the aqueous phase is acidified to pH 5 with aqueous hydrochloric acid and then extracted 3X with methylene chloride. The combined organic extracts are dried (Na2SO4), filtered and concentrated to give 206 mg of 5-[CH3(OCH2C- H2)3O]-1-naphthoxyacetic acid as a brown colored oil. TLC analysis showed only a spot at the origin using 20% ethyl acetate/chloroform. This material is used without purification in the subsequent coupling experiment.
(4) Preparation of H-Asn-CVA-Ile-Amp.
A solution of 134 mg of Boc-L-Asparagine (Sigma) and 202 mg of H-CVA-Ile- Amp all in 10 mL of dimethylformamide is treated with 370 μL of diisopropylethylamine (Aldrich) followed by treatment with 160 μL of diethyl cyanophosphonate (Aldrich). The resulting solution is stirred under a nitrogen atmosphere for 17 h at which time TLC analysis confirmed the coupling is complete. The solution is transferred with washing with methanol to a 1-necked (24/40) 200 mL round-bottomed flask and then concentrated on a rotary evaporator - first under house vacuum and then under lower pressure using a vacuum pump - to give the crude Boc-Asn-CVA-Ile-Amp. This material is suspended in a solution of 3 mL of methylene chloride and 3 mL of trifluoroacetic acid (Aldrich). The resulting yellow colored mixture is stirred at room temperature for 2 h and then concentrated under reduced pressure. This material (preabsorbed on ~ 2 g of silica gel) is chromatographed over 55 g of silica gel (63-200μ), eluting with 10% (4M NH3/MeO- H)/CHCl3 while collecting 6 mL fractions. Fractions 51-86 are combined and concentrated to give 158 mg of product: mass spectrum (FAB) ions at mlz 589[M+H]+, 571, 481, 236, 222, 126, 109, 86 and 69. TLC Rf=0.32 in 10% (4M NH3/MeOH)/CH- Cl3 (UV).
Examples 104-105
(104) L-Asparaginamide, [5-(triethyleneglycol monomethyl ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2- (N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R* ,4R*(1R* ,2R*)]] or 5-[CH3(OCH2CH2)3O]-1-Noa-Asn-CVA-Ile-Amp.
A solution of 47.6 mg (0.131 mmoL) of 5-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid of Preparation 3 and 50.7 mg of H-Asn-CVA-Ile-Amp of Preparation 4 all in 3 mL of dimethylformamide is treated with 74 μL of diisopropylethylamine (Aldrich) followed by treatment with 32 μL of diethyl cyanophosphonate (Aldrich). The resulting solution is stirred under a nitrogen atmosphere for 13 h at which time TLC analysis confirmed the coupling is complete. The solution is transferred with washing with methanol to a 1-necked (24/40) 200 mL round-bottomed flask and then concentrated on a rotary evaporator - first under house vacuum and then under lower pressure using a vacuum pump - to give the crude product as a yellow solid. This material (preabsorbed on * 2 g of silica gel) is chromatographed over 50 g of silica gel (63-200μ), eluting with 8% (4M NH3/MeOH)/CHCl3 while collecting 6 mL fractions. Fractions 16-30 are combined and concentrated to give the desired product contaminated with a less polar impurity. This material is rechromatographed in a similar fashion using 6% (4M NH3/MeOH)/CHCl3. Fractions 44-54 are combined and concentrated to give 24.8 mg the product with a purity of > 99%: mass spectrum (FAB) [M+H]+ found: 935.5476; other ions at m/z 827, 416, 367, 348, 330, 318, 305, 236, 222, 177, 126, 109, and 86. HPLC retention time = 18.6 min. TLC Rf=0.53 in 10% (4M NH3/MeOH)/CHCl3 (UV). Fractions 34-43 afforded additional amounts of slightly less pure material.
(105) L-Asparaginamide, [4-(triethyleneglycol monomethyl ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2- (N-oxido)pyridinylmemyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]] or 4-[CH3(OCH2CH2)3O]-1-Noa-Asn-CVA-Ile-Amp
A solution of 52.6 mg of 4-[CH3(OCH2CH2)3O]-1-naphthoxyacetic acid of Preparation 2 and 51.0 mg of H-Asn-CVA-Ile-Amp of Preparation 4 all in 3 mL of dimethylformamide is treated with 75 μL of diisopropylethylamine (Aldrich) followed by treatment with 32 μL of diethyl cyanophosphonate (Aldrich). The resulting solution is stirred under a nitrogen atmosphere for 25 h at which time TLC analysis confirmed the coupling is complete. The solution is transferred with washing with methanol to a 1-necked (24/40) 200 mL round-bottomed flask and then concentrated on a rotary evaporator - first under house vacuum and then under lower pressure using a vacuum pump - to give the crude product as a yellow solid. This material (preabsorbed on 2 g of silica gel) is chromatographed over 50 g of silica gel (63-200μ). eluting with 6% (4M NH3/MeOH)/CHCl3 while collecting 6 mL fractions. Fractions 39-57 are combined and concentrated to give 70.2 mg the product with a purity of > 99% : mass spectrum (FAB) [M+H]+ found: 935.5494; other ions at m/z 827. 348. 330. 318, 305. 236. 222, 147, 126, 109, and 86. HPLC retention time = 17.6 min. TLC Rf=0.55 in 10% (4M NH3/MeOH)/CHCl3 (UV).
Examples 106-107
(106) L-Glycyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-=L-isoleucyl-2-pyridylmethylamide-or Gly-CVD-Ile-Amp. FAB-MS (found):
548.3844;
(107) L-Glycyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihy- droxy-hexanoyl L-isoleucyl-2-pyridyl-methylamide or Gly-CPD-Ile-Amp. FAB-MS (found): 596.3835.
21 1987

Claims

1. Use of a compound of formula I
X-C8-D9-E10-F 11-G 12-Z I to prepare a medicament for inhibiting a retrovirus in a mammalian cell infected with said retrovirus;
wherein X is
a) -(CH2)p-aryl,
b) -(CH2)p-Het,
c) -(CH2)p-C3-C7cycloalkyl,
d) R5-O-(CH)2q-C(O)-,
e) R5-CH2-O-C(O)-,
f) R5-O-C(O)-,
g) R5-(CH2)n-C(O)-,
h) R5-(CH2)n-C(S)-,
i) R4N(R4)-(CH2)n-C(O)-,
j) R5-SO2-(CH2)q-C(O)- ,
k) R5-SO2-(CH2)q-O-C(O)-,
l) R5-(CH2)n-SO2,
m) Z-C(O)-CH(OH)-CH(CH2R1)-C(O)- n) RHCH2)p CH=CH-(CH2)p-C(O)-,
o) R5(CH2)p CH=CH-(CH2)p-O-C(O), or
p) R27)CH2)q-C(O)-;
wherein C8 is absent or a divalent moiety of the formula XL1, XL2, XL2a, XL2b or other amino acyl derivative;
X
wherein D9 is a divalent moiety of the formula XL3, XL2a, XL2b or other amino acyl derivative;
wherein E10-F11 is a divalent moiety of the formula XL6, XL6b, XL6c, XL6d, XL6c, II , III or IV;
wherein G12 is absent or a divalent moiety of the formula XL4, XL4a or other amino acyl derivative;
wherein Z is
a) -O-R10, b) -N(R4)R14,
c) C4-C8cyclic amino,
d) -NHR120, e)
0 Het bonded via a nitrogen atom, or g) -NH(CH2)qNH Het;
wherein R is
a) -(CH2)n-isopropyl,
b) -(CH2)n-isobutyl,
c) -(CH2)n-phenyl, or
d) -(CH2)n-C3-C7cycloalkyl; wherein R1 is
a) hydrogen,
b) C1-C3alkyl,
c) aryl,
d) C3-C7cycloalkyl,
e) -Het,
0 C1-C3alkoxy, or
g) C1 -C3alkylthio;
wherein R2 is
a) hydrogen, or
b) -CH(R3)R4;
wherein R3 is
a) hydrogen,
b) hydroxy,
c) C1-C5alkyl,
d) C3-C7cycloalkyl,
e) aryl,
f) -Het, g) C1-C3alkoxy, or
h) C1-C3alkylthio:
wherein R4 at each occurrence is the same or different as is a) hydrogen.
b) C1-C5alkyl,
c) -(CH2)p-aryl.
d) -(CH2)p-Het,
e) -(CH2)p-C3-C7cycloalkyl, or
f) 1- or 2-adamantyl;
wherein R5 is
a) C1-C6alkyl,
b) C3-C7cycloalkyl,
c) aryl,
d) -Het,
e) 5-oxo-2-pyrrolidinyl, or
f) 1 or 2-adamantyl;
wherein R6 is
a) hydrogen,
b) C1-C5alkyl,
c) -(CH2)p-aryl,
d) -(CH2)p-Het,
e) -(CH2)p-C3-C7cycloalkyl, or
f) 1- or 2-adamantyl;
wherein R7 is
a) hydrogen,
b) C1-C5alkyl,
c) hydroxy,
d) amino C1-C4alkyl-,
e) guanidinyl C1-C3alkyl-,
f) aryl,
g) -Het,
h) methylthio,
i) -(CH2)p-C3-C7cycloalkyl, j) amino,
k) -(CH2)n-COOH,
l) -(CH2)n-COOC1-C6 alkyl, or m) -(CH2)n-CONR22R26;
wherein R8 is
a) hydrogen
b) C1-C5alkyl,
c) hydroxy,
d) aryl,
e) -Het,
f) guanidinyl C1-C3alkyl-, or g) -(CH2)p-C3-C7cycloalkyl;
wherein R9 is
a) hydrogen,
b) hydroxy,
c) amino C1-C4alkyl-, or
d) guanidinyl C1-C3alkyl-;
wherein R10 is
a) hydrogen,
b) C1-C5alkyl,
c) -(CH2)nR16,
d) -(CH2)nR17,
e) C3-C7cycloalkyl,
f) a pharmaceutically acdeptable cation, g) -CH(25)-CH2-R15, or
h) -CH2-CH(R 12)-R15 ;
wherein R11 is -R or -R2;
wherein R12 is -(CH2)n-R13;
wherein R13 is
a) aryl,
b) amino,
c) mono-, di- or tri-C1-C3alkylamino, d) -Het, e) C1-C5alkyl.
f) C3-C7cycloalkyl,
g) C2-C5alkenyl,
h) C3-C7Cycloalkenyl,
i) hydroxy,
j) C1-C3alkoxy,
k) C1-C3alkanoyloxy,
1) mercapto,
m) C1-C3alkylthio,
n) -COOH,
o) -CO-O-C1-C6alkyl,
P) -CO-O-CH2-(C1-C3alkyl)-N(1-C3alkyl)2, q) -CO-NR22R26;
r) C4-C7cyclic amino,
s) C4-C7cycloalkylamino,
0 guanidyl,
u) cyano,
v) N-cyanoguanidyl,
w) cyanoamino,
x) (hydroxy C2-C4alkyl)amino, or y) di-(hydroxyC2-C4alkyl)amino; wherein R14 is
a) hydrogen,
b) C1-C10alkyl,
c) -(CH2)n-R18,
d) -(CH2)n-R19,
e) -CH(R25)-CH2-R15,
f) -(CH2)q-CH(R12)-R15,
g) (hydroxy C1- C8alkyl),
h) hydroxy C1-C8 alkyaryl, or
i) (C1-C3 alkoxy) C1C8 alkyl;
wherein R15 is
a) hydroxy, b) C3-C7cycloalkyl,
c) aryl,
d) amino.
e) mono-, di-, or tri-C1-C3alkylamino,
0 mono- or di-(hydroxy C2-C4alkyl)amino, g) -Het,
h) C1-C3alkoxy-,
i) C1 -C3alkanoyloxy- ,
j) mercapto,
k) C1-C3alkylthio-,
l) C1-C5alkyl,
m) C4-C7cyclic amino,
n) C4-C7cycloalkylamino ,
o) C1-C5alkenyloxy,
P) C3-C7cycloalkenyl;
wherein R16 is
a) aryl,
b) amino,
c) mono- or di-(C1-C3alkyl)amino, d) hydroxy,
e) C3-C7Cycloalkyl,
f) C4-C7cyclic amino, or
g) C1 -C3alkanoyloxy ;
wherein R17 is
a) -Het,
b) C1-C5alkenyl,
c) C3-C7cycloalkenyl,
d) C1-C3alkoxy,
e) mercapto,
0 C1-C3alkylthio,
g) -COOH,
h) -CO-O-C1-C6alkyl,
i) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, j) -CO-NR22R26,
k) tri-C1-C3alkylamino ,
l) guanidyl,
m) cyano,
n) N-cyanoguanidyl,
o) (hydroxy C2-C4alkyl)amino,
P) di-(hydroxy C2-C4alkyl)amino, or q) cyanoamino;
wherein R18 is
a) amino,
b) mono-, or di-(C1-C3alkyl)amino, c) C4-C7Cyclic amino,
d) C4-C7cycloalkylamino, or
e) -CH(NH2)(CO2H);
wherein R19 is
a) aryl,
b) -Het,
c) tri-C1-C3alkylamino,
d) C3-C7cycloalkyl,
e) C2-C5alkenyl,
f) C3-C7cycloalkenyl ,
g) hydroxy,
h) C1-C3alkoxy,
i) C1-C3alkanoyloxy,
j) mercapto,
k) C1-C3alkylthio,
l) -COOH,
m) -CO-O-C1-C6alkyl,
n) -CO-O-CH2-(C1-C3alkyl)-N(C1-C3alkyl)2, o) -CO-NR22R26 ,
p) guanidyl,
q) cyano,
r) N-cyanoguanidyl, s) cyanoamino.
t) (hydroxy C2-C4alkyl)amino, u) di-(hydroxy C2-C4alkyl)amino; or v) -SO3H;
wherein R20 is
a) hydrogen,
b) C1-C5alkyl, or
c) aryl-C1-C5alkyl;
wherein R21 is
a) -NH2, or
b) -OH;
wherein R22 is
a) hydrogen, or
b) C1-C3alkyl;
wherein R23 is
a) -(CH2)n-OH,
b) -(CH2)n-NH2,
c) aryl, or
d) C1-C3alkyl;
wherein R24 is
a) -R1,
b) -(CH2)n-OH, or
c) -(CH2)n-NH2;
wherein R25 is
a) -(CH2)n-R13,
b) hydrogen,
c) C1-C3alkyl, or
d) phenyl-C1-C3alkyl;
wherein R26 is
a) hydrogen,
b) C1-C3alkyl, or
c) phenyl-C1-C3alkyl;
wherein R27 is a) -COOH,
b) -COOC1-C6 alkyl,
c) -CONR22R26, or
d) -CH(NH2)COOH:
wherein R120 is
a) R126C[(CH2)qOR121]2(CH2)q-, b) XXX
c) XXXI d) -CH2(CHOR121)xCH2OR121,
e) R121OCH2(CHOR121)yCH-(CHOR121)zCH2OR121,
f) XXXII ,or
g) R121OCH2-C(CH2OR121)2-;
wherein R121 is
a) hydrogen,
b) C1-C6alkyl,
c) -(CH2)n-aryl, or
d) -C(O)R123;
wherein R123 is a) C1-C5 alkyl, or
b) -(CH2)n-phenyl;
wherein R126 is
a) hydrogen, or
b) (CH2)nOR121;
wherein R128 is
a) hydrogen, or
b) -(CHOR121)tCH2OR121;
wherein Q is
a) CH2,
b) CHOR121, or
c) C(O);
wherein j is one to three, inclusive;
wherein m is one or two;
wherein p is zero to two, inclusive;
wherein r is zero to five, inclusive;
wherein for each occurrence n is independently an integer of zero to five, inclusive; wherein q is an integer of one to five, inclusive;
wherein u is an integer of zero to three, inclusive;
wherein v is an integer of zero to four, inclusive;
wherein s is an integer of zero or one so that the sum of u plus v plus s is three or four; wherein t is an integer of zero to three, inclusive;
wherein w is an integer of two or three;
wherein x is an integer of two to seven, inclusive;
wherein y is an integer of zero to six, inclusive; and
wherein z is an integer of zero to six so that the sum of y plus z does not exceed six wherein aryl is phenyl or naphthyl substituted by zero to three of the following:
a) C1-C3alkyl,
b) hydroxy,
c) C1-C3alkoxy,
d) halo,
e) amino,
f) mono- or di-C1-C3alkylamino, g) -CHO,
h) -COOH,
i) COOR26,
j) CONHR26,
k) nitro,
l) mercapto,
m) C1-C3alkylthio,
n) C1-C3alkylsulfinyl,
o) C1-C3alkylsulfonyl,
p) -N(R4)-C1-C3alkylsulfmyl,
q) -SO3H,
r) SO2NH2,
s) -CN, or
t) -CH2NH2;
wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring or another heterocycle and the ring may be connected through a carbon or secondary nitrogen in the ring or an exocyclic nitrogen; and if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and optionally substituted by zero to three of the following:
a) C1-C5alkyl,
b) hydroxy,
c) hydroxy (C1-C5alkyl),
d) halogen,
e) amino,
f) amino (C1-C5alkyl),
g) -CHO,
h) -CO-H,
i) -CO2-(C1-C5alkyl),
j) -CONH2,
k) -CONH-(C1-C5alkyl),
l) nitro, m) mercapto,
n) mercapto (C1-C5alkyl),
o) -SO3H,
p) -SO2NH2,
q) -CN,
r) -O-C1-C5alkyl, or
s) -[O-(CH2)2] n-OCH3;
with the provisos that:
1) G12 is present when both C8 and D9 are present and E10-F11 is other than LPA;
2) when X is Z-C(O)-CH(OH)-CH(CH2R1)-C(O)-, D9 is His and G12 is Ile;
3) when X is R5-CH2-O-C(O)-or R5-(CH2)n-C(O)- and E10- F11 is XL6, XL6b, XL6c or XL6d, R5 is other than C1-C6 alkyl;
4) when X is R5-O-C(O)- and E10-F11 is XL6, XL6b, XL6c
or XL6d, R5 is other than C1-C6 alkyl, C3-C7 cycloalkyl or aryl;
5) when X is R5-(CH2)n-C(O)-wherein R5 is cycloalkyl or aryl, and E10 F11 is XL6, XL6b, XL6c or XL6d, n is other than one;
6) when X is R4N(R4)-(CH2)n-C(O)- and E10-F11 is XL6, XL6b, XL6c or XL6d, n is other than one;
7) Z is other than N-4-amino-2-methyl-5-pyrimidinylmethyl-amide;
8) X is other than benzyloxycarbonyl or butyloxycarbonyl, when E10-F11 is II or IV; and
9) when X is R5-(CR2)n-C(O)- and E10-F11 is II or IV, R5 is other than C1- C6 alkyl.
2. The use of claim 1
wherein E10-F11 is a divalent moiety of the formula XL6', XL6b', XL6c', XL6d', XL6c', ll, III', or IV';
wherein the variables are as defined in claim 1.
3. The use of claim 1 wherein the cell is in a human.
4. The use of claim 3 wherein diseases caused by said retrovirus are treated in said human.
5. The use of claim 4 wherein C8, D9 and G12 are present.
6. The use of claim 5 wherein the compound of formula I is selected from the group consisting of:
1H-Imidazole-4-propanamide, α -[[2-(acetyloxy)-3-(1-naphthalenyl)-1- oxopropyl]amino]-N-[1-(cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]amino]-2,4-dioxobutyl]-, [1S-[1R*[αR*(R*)],2R*]]-;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-pheny al lanyl-N-[1- (cyclohexylmethyl)-3,3-difluoro-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]- butyl]amino]-2,4-dioxobutyl]-; or Boc-Phe-His-LFA-Ile-Amp; and
L-α-Glutamine,N/u2/d-[N-[[1, 1-dimethylethoxy)carbonyl]-L-phenylal- anyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*4R* (lR*,
-2R*)]]-,monacetate (salt) or BOC-Phe-Glu-LVA-Ile-Amp.
7. The use of claim 4 wherein C8 is absent, D9 is present and G12 is present.
8. The use of claim 7 wherein the compound of formula I is selected from the group consisting of:
1H-Imidazole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methyl- propyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]he- xyl]-α-[(phenoxyacetyl)-amino]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- ; POA-His-LVA-Ile- Amp;
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-3,3-difluoro-4- [[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-2,4-dioxobutyl]-α-[[( 1- naphthalenyloxy)acetyl]amino]-, [1S-(1R*(α R*),2R*]]-; or NOA-His-LFA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-6- methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]heptyl]-α-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*(1R*,2R*)]]-;orr POA-His-CLA- Ile-Amp;
1H-Imidazole-4-propanamide, N-[2,3-dihydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]car- bonyl]hexyl]-α -[(phenoxyacetyl)amino]- [1S-[1R*(R*),2S*,3R*,4R*(1R*,2R*)]]-; or POA-His-LVD-Ile-Amp;
1-Noa-His-Cha PSI[CHOHCHOH]Val-Ile-Amp; or 1H-Imidazole-4- propanamide, N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methyl-4-[[[2-methyl-1-[[(2- pyridinylmethyl)amino]carbonyl]butyl]-[amino]carbonyl]hexyl]-α -[[(1-naphthalenyloxy)ac- etyl]amino]-, [1S-[1R*(R*),2S*,3S*,4S*(1R*,2R*)]]-; or NOA-His-CVD-Ile-Amp;
1H-Imidazole-4-propanamide, N-[2-hydroxy-6-methyl-1-(2-methyl- propyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hep- tyl]-α -[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*(1R*,2R*)]]-; or POA-His-LLA- Ile-Amp;
1H-Imidazole-4-propanamide, N-[2-hydroxy-1-(2-methylpropyl)-5-[[2- memyl-1-[[(2-pyridinylmemyl)a mino]carbonyl]butyl]amino]-5-oxo-4-(phenylmethyl)pentyl]-α -[(phenoxyacetyl)amino]-[1S-[1R*(R*),2R*,4S*,5(lR*,2R*)]]-prPOA-His-LPA- Ile-Amp;
1H-Imidazole-4-propanamide,N-[4-(cyclohexylmethyl)-2-hydroxy-1-(2- methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]-5- oxopentyl]-α-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4S*,5(1R*,2R*)]]-; or POA- His-LCA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-5- methyl-4-[[[2-memyl-1-[[(2-pyridinylmethyl)a mino]carbonyl]butyl]ammo]carbonyl]hexyl]- α-[(phenoxyacetyl)amino]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-; or POA-His-CVA-Ile- Amp;
1H-Imidazole-4-propanamide, N-[1-(cycloheptylmethyl)-2-hydroxy-5- methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)ammo]carbonyI]butyl]am ino]ca-bonyl]hexyl]- α -[(phenoxyacetyl)amino]-,[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-prPOA-His-chpVA-Ile- Amp;
Nα -[(2S,4S,5S)-5-[N-[Nα -(Phenoxymethylcarbonyl)-L-histidyl]amino-4 hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-[2-(2-pyridinylamino)ethyl]-L-isoleucin- amide, acetic acid salt; or POA-His-LVA-Ile-NH(CH2)2NH-pyridine;
Nα -[(2S ,4S ,5S)-S-[N-[Nα-(Phenoxymemylcarbonyl)-L-histidyllainino]-4 - hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-(2,3-dihydroxypropyl)-L-isoleucinamide; or POA-His-LVA-Ile-NH-CH2-CH(OH)-CH2OH;
Nα-[(2S ,4S ,5S)-5-[N -{Nα -(Phenoxymemylcarbonyl)-L-histidyl]-amino-4- hydroxy-2-isopropyl-7-methyl-1-oxooctyl]-N-(2-hydroxypropyl)-L-isoleucinamide; or POA-His-LVA-Ile-NH-CH2-CH(CH3)(OH);
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmemyl)-L-isoleucinamide, pyridine N-oxide or NOA-His-CVA-Ile-Amp-NO;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(f-toluenesulfonyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or p-Tolunesulfonyl-His-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα-[(2S,4S,5S)-5-[N-[Nα-(Phenoxymethylcarbonyl)-L-histidyl]amino]-
6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmemyl)-L-isoleucinamide, pyridine N-oxide or POA-His-CVA-Ile-Amp-NO;
Nα-[(2S, 4S, 5S)-5-[N-[Nα -(p-Toluenesulfonyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or p-Toluenesulfonyl-His-CVA-Ile-Amp-NO;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl) (2-pyridinyl)ala- nyl]amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-[(3-Pyridinyl)-methylcarbonyl]-L-histidyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or (3-pyridinyl)-methyl-carbonyl-His-CVA-Ile-Amp;
Ne-[N2-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-isolencyl]-L-lysine, triflouroacetic acid salt or NOA-His-CVA-Ile-L-lysine, trifluoroacetic acid salt;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(l-Naphthalenyloxyacetyl)-L-histidyl]amino]-
6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L- isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine);
1H-Imidazole-4-propanamide,N-[2-hydroxy-4-[[[1-[[(2-hydroxy-2- phenylethyl)amino]carbonyl]-2-methylbutyl]amino]carbonyl]-5-methyl-1-(2-methyl- propyl)hexyl]-α-[(phenoxyacetyl)amino]-, monoacetate (salt) or POA-His-LVA-Ile-NH- CH2-CH(OH)-phenyl;
Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2- methyl-1-[[(2-pyridinylmemyhamino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-4-[(1H- indol-2-ylcarbonyl)amino]-5-oxo-,[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-or 1H-indol-2-yl- carbonyl-Glu-CVA-Ile-Amp;
L-.alpha.-Glutamine, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4- [[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N/2/d- L-phenylalanyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, bis(trifluoracetate) (salt) or Phe-Glu- CVA-Ile-Amp;
2-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2-memyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-1- (1H-imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-or (2- Pyridyl)acetyl-His-Lva-Ile-Amp;
4-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-1- (1H-imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-or (4- Pyridyl)acetyl-His-LVA-Ile-Amp;
1H-Indole-2-carboxamide, N-[2-([2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-memyl-1-[[(2-pyridinylmemyl)amino]carbonyl]butyl]carbonyl]hexyI]amino]-1- (1H-imidazol-4-ylmethyl)-2-oxoethyl]-,[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]- or N-(Indolyl- 2-carbonyl)-His-LV A-Ile-Amp;
2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4- ylmemyl)-9-(1-memylethyl)-12-(1-methylpropyl)-6-(2-memylpropyl)-4,10,13-trioxo-15-(2- pyridinyl)-,4-pyridinylmethyl ester, [3S-[3R*,6R*,7R*,9RM2R*(R*)]]- or Ioc-His- LVA-Ile-Amp;
1H-Imidazole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methyl- propyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]- carbonyl]butyl]amino]carbonyl]hexyl]-α-[(1-oxo-3-phenoxypropyl)amino]-,[1S- [1R*(R*),2R*,4R*(1R*,2R*)]]-,orPhenoxypropionyl-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-[[[2-memyl-1-[[[(2-pyridmylmemyl)amino[carbonyl[butyl[amino[carbonyl[hexyl]-α-[(1- oxo-3phenyl-2-propenyl)amino]-,[1S-[1R*[R*(E)],2R*,4R*(lR*,2R*)]]- or phenyl- CH = CH-C(O)-His-LV A-Ile- Amp ;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)- 4-[[[2-memyl-1-[[[(2-pyridinylmewyl)amino[carbonyl][butyl]amino[carbonyl[hexyl]-α-[(1- oxo-4-phenyl-3-butenyl)amino]-,[1S-[1R*[R*(E)].2R*,4R*(lR*,2R*)]]- or phenyl- CH = CH-CH2-C(O)-His-LVA-Ile-Amp;
2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4- ylmemyl)-9-(1-memylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo-15-(2- pyridinyl)-,3-phenyl-2-propenyl ester, [3S-[1(E),3R*,6R*,7R*,9R*,12R*(R*)]]- or phenyl-CH=CH-CH2-O-C(O)-His-LVA-Ile-Amp; U-77407
1H-Imidazole-4-propan am ide,N-[2-hydroxy-5-methhyl-1-(2-methylpropyl)- 4-[[[2-memyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[[(2- phenylethenyl)sulfonyl]amino]-,[1S-[1R*[R*(E)],2R*,4R*(lR*,2R*)]]-orphenyl-(CH2)- SO2-His-LVA-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CVA-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R- dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CPD-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R- dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide,N-oxideor(HO)Ac-His-CPD-Ile- Amp;
Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R- dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CPD-Ile-Amp;
Phenoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CVA-Ile-Amp;
1-Naphtoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy- 2R-isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2R-cyclohexylme- thyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamideor NOA-His-CCD-Ile- Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy-6- phenyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy- 2R-isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or NOA-His-CVD-Ile- Apr;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2S-cyclohexylme- thyl-3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamidoor NOA-His-CCD-Ile- Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihydroxy-2S-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LID-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2S-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LID-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4R-dihydroxy-2S-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LID-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3R-4R-dihydroxy-2R-isobutyl-7- methyl-octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LID-Ile-Amp;
2-Quinolinylcarbonyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr;
Q uinolinyl-2-carbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-His-CVA-Ile-Amp;
Quinolinyl-2-carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CVA-Ile-Amp;
1-Naphthalenyloxyacetyl-L-histidyl-5S-amine-6-cyclohexyl-4S-hydroxy-
2S-isopropyl-hexanoyl-L-isoleucylamide or Noa-His-CVA-Ile-NH2;
L-Asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2- methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyI]amino]carbonyl]butyl]ami- no]carbonyl]hexyl]-N-alpha-methyl-,[1S-[1R*,2R*,4R*(lR*,2R*)]]-or NOA-Asp-CVA-Ile -Amp;
L-Asparaginamide, [5-(triethyleneglycol monomethyl ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-
(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyI]-N-alpha-methyl-,
[1S-[1R*,2R*,4R*(1R*,2R*)]]-or 5-(triethyleneglycol monomethyl ether-NOA-Asp-CVA- Ile-Amp; and
L-Asparaginamide , [4-(triethyleneglycol monomethyl ether)naphthoxy]acetyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2- (N-oxido)pyridinylmemyl]amino]carb onyl]butyl]a m ino]carbo nyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- or 4-(triethyleneglycol monomethyl ether)-NOA-Asp- CVA-Ile-Amp;
9. The use of claim 4 wherein C8 is absent, D9 is present and G12 is absent.
10. The use of claim 9 wherein the compound of formula I is selected from the group consisting of:
1H-Imidazole-4-propanamide N-[2,3-dihydroxy-5-methyl-4-[[(2-methyl- butyl)amino]carbonyl]-1-(2-methylpropyl)hexyl]-α-[(phenoxyacetyl)amino]-, [1R- [1R*(S*),2S*,3S*,4S*(S*)]]-; or POA-His-LVDA-Mba;
Ne-[(2S,4S,5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyI]-L-lysine,triflouroacectic acid salt or NOA-His-CVA-L-lysine,triflouroacetic acid salt;
N-[(2S,4S,5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino]ethyl]-aminer NOA-His-CVA-NH-(CH2)2-NH-(2-pyridine);
N-[(2S,4S,5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]- 6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)]ethyl]amine,- pyridine N-oxide or NOA-His-CVA-NH(CH2)2-NH-(2-pyridine);
Pentanoic acid, 5-[ri-(cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxy- propyl)amino]carbonyl]-5-methylhexyl]amino]-5-oxo-4-[(phenoxyacetyl)amino]-or POA- Glu-CVA-NH-CH2CH(CH3)(OH);
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2- hydroxypropyl)amino]carbonyl]-5-methylhexyl]α-[(phenoxyacetyl)amino]-, monoacetate (salt) or POA-His-CVA-NH-CH2-CH(OH)(CH3);
N-tert-Butyloxycarbonyl-L-phenylalanyl-L-histidyl-5S-amino-3R,4R- dmydroxy-2R-isopropyl-7-memyl-octanoyl-2S-methylbutylamideorBOC-Phe-His-LVA- Mba; and
POA-His-CVA-N H-(CH2)4-CH(CONH)(NH2);
11. Use of a compound selected from the group consisting of:
L-Isoleucinamide, N2-(5-amino-4-hydroxy-2-(1-methylethyl)-1-oxooctyl]- N-(2-pyridinylmethyl)-, trifluoroacetate, (S,S,S)-; or H-LVA-Ile-Amp; Octanamide5-[(3.3-dimethyl-1-oxobutyl)amino]-4-hydroxy-7-methyl-2- (1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S- [1(1R*,2R*).2R*,4R*,5R*]]- or TBA-LVA-Ile-Amp;
Cyclohexanehexanamide, δ-[(3,3-dimethyl-1-oxobutyl)amino]-7-hydroxy- α-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [αS- [N(lR*,2R*),αR*,τR*,δR*]]- or TBA-CVA-Ile-Amp;
Cyclohexanehexanamide, δ-amino-τ-hydroxy-α -(1-methylethyl)-N-[[2- methyl-1-[[(2-pyridinylmethyl)]amino]carbonyl]butyl]-dihydrochloride,[αS-[N(1R*,2R- *),αR*,τR*,δR*]]- or H-CVA-Ile-Amp;
Cyclohexanehexanamide, δ-(acetylamino)-τ-hydroxy-α -(1-methylethyl)-
N-[2-methyl-1-[[(pyridinylmethyl)amino]carbonyl]butylIα S-[N(1R*,2R*),αR*,τR*,δR- *]]-; or Ac-CVA-Ile-Amp;
Octanamide, 5-(acetyla mino)-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2- memyl-1-[[(2-pyridinylmethyl)amino)carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*]]-, monoacetate (salt); or Ac-LVA-Ile-Amp; or
IVA-LVA-Ile-Amp.
Boc-Phe-His-Cha psi[CHOHCHOH]Val-Ile-Amp; or L-Histidinamide, N-[(1 , 1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[1-(cyclohexylmethyl)-2,3- dihydroxy-5-methyl-4-[[[2-meihyl-1-[[(2-pyridinylmemyl)ammo]carbonyl]butyl] amino]carbonyl]hexyl]-, [1S-[1R*,2S*,3S*,4S*(lR*.2R *)]]-; or BOC-Phe-His-CVD-Ile-Amp:
L-Histidinamide, N-[(1,1-dimethylethoxy)carb onyl]-L-phenylalanyl-N-[2- hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]- butyl]amino-5-oxo-4-(phenylmethyl)pentyl]-,[1S-[1R*,2R*,4S*,5(1R*,2R*)]]-;orBoc- Phe-His-LPA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenyla-anyl-N-[4-
(cyclohexylmethyl)-2-hydroxy-1-(2-methylpropyl)-5-[[2-methyl-1-[[(2-pyridinylmethyl)- amino]carbonyl]butyl]amino]-5-oxopentyl]-, [1S-[1R*,2R*,4S*,5(1R*,2R*)]]-; or Boc- Phe-His-LCA-Ile-Amp;
L-Talonamide, 6-cyclohexyl-2,5,6-trideoxy-5-[N-[N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-L-histidyl]amino]-2-(1-methylethyl)-N-[2-methyl-1-[[(2- pyridinylmethyl)amino]carbonyl]butyl]-, [S-(R*,R*)]-; or Boc-Phe-His-CVD'-Ile-Amp;
L-Histidinamide, N-[(1,1-d-methylethoxy)carbonyl]-L-phenylalanyl-N- (2,3-dihydroxy-5-memyl-1-(2-methylpropyl)-4-[[(2-methyl-1-[[(2-pyridinylmethyl)amino]- carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2S*,3R*,4S*(1R*,2R*)]]-;orBoc-Phe- His-LVDA'-Ile-Amp;
L-Histidinamide, N-[[5-(dimethylamino)-1-naphthalenyl]sulfonyl]-L- phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl- memyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or DANS-Phe-His-LVA-Ile-Amp;
L-Histidinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpro- pyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-(1R*,2R*,4R*(1R*,2R*)]]- or H-Phe-His-LVA-Ile-Amp;
L-Valinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropy-
1)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-Ile-Amp;
L-Valinamide, L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S- [1R*,2R*,4R*(1R*,2R*)]]-, diacetate (salt); or H-Val-Val-LVA-Ile-Amp; or
L-Valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carrx)nyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp.
Nα-[(2S,4S,5S)-5-[[Nα[(S)-1-Acetoxy-1-benzyl)methylcarbonyI]-L- histidyl]amino]-4-hydroxy-7-methyl-2-(1-methylethyl)-1-oxooctyl]-N-[2-pyridyl)ethyl] -L-isoleucinamide; or AcO-Phe-His-LVA-Ile-NH-(CH2)2-pyridine.
4-Morpholinebutanamide, β-hydroxy-N-[2-[[2-hydroxy-5-methyl-1-(2- memylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmemyl)-mιino]carbonyl]butyl]ammo]carbonyl- ]hexyl]amino]- 1 -(1H-imidazol-4-ylmethyl)-2-oxoethyl]-α-(1-naphthalenylmethyl)-7-oxo-, [1S-[1R*[R*(αS*,βR*)],2R*,4R*(lR*,2R*)]]-;
1H-Imidazole-4-propanamide, α-[[[5-(dimethyla mino)-1-naphthalenyl]sulfonyl]amino]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl- m e th y l ) a mi n o ] c arb o n y l ] b u t y l ] a m i n o ] c arb o n y l ] h ex y l ] - , [ 1 S - [1R*(R*),2R*,4R*(1R*,2R*)]]-; or DANS-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide, α -amino-N-[2-hydroxy-5-methyl-1-(2- memylpropyl)-4-[[[2-methyl-1-[[(2-pyridmylmethyl)amino]carbonyl]butyl]amino]carbonyl- ]hexyl]-, [1S-[1R*(R*),2R*,4R*(1R*,2R*)]] or H-His-LVA-Ile-Amp;
Octanamide, 5-[P-(acetylanιino)-3-memyl-1-oxobutyl]a m ino]-4-hydroxy- 7-methyl-2-(1-methylethyl)-N-[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*(R*)]]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp;
Ac-Asn-LVA-Ile-Amp;
Nα-[(2S.4S,5S)-5-[[(S)-(1-Hydroxy-1-benzyl)methylcarbonyl]amino]-4- hydroxy)-7-memyl-2-(1-memylethyI)-1-oxooctyl]-N-(2-pyridinylmemyl)-L-isoleucinamide; or HO-Phe-LVA-Ile-Amp;
1H-Imida zole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-
4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[(2- hydroxy-1-oxo-3-phenylpropyl)amino]-,[1S-[1R*p.*(R*)],2R*,4R*(lR*,2R*)]]-, 2- hydroxy-1,2,3-propanetricarboxylate (12) (salt) orphenyl-CH2-CH(OH)-C(O)-His-LVA-
Ile-Amp;
L-α-Glutamine, N/u2/d-[N-[[1,1-dimethylethoxy)carbonyl]-L-phenylal- anyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinyl- methyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*4R*(lR*,2R*)]]- monacetate (salt) or BOC-Phe-Glu-LVA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-3-(2-pyridinyl)alanyl- N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]c- arbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*[R*(E)],2R*,4R*(lR*,2R*)]]-or BOC-2- Py-Ala-His-LVA-Ile-Amp;
L-.alpha.-Asparagine, N/u 2/d-[N-[(1 ,1-dimethylethoxy)carbonyl]-L- phenylalanyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1-[[(2-pyridinylme- thyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*,4R*(lR*,2R*)]]- monoacetate (salt) or BOC-Phe-Asp-LVA-Ile-Amp; U-77808E
L-.alpha.-Glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl- N0[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amin- o]carbonyl]butyl]amino]carbonyl]hexyl]]-,[1S-[1R*,2R*,4R*(lR * ,2R* )]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-
[3,3-difluoro-2-hydroxy-4-[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]am- ino]-4-oxo-1-(phenylmethyl)butyl]-or CH3-C(O)-O-CH(benzyl)-C(O)-His-LVA-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-Ile- Amp;
L-Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy- hexanoyl-L-isoleucyl-2-ρyridylmethylamide or Gly-His-CPD-Ile-Amp;
5-Quinolinylhydroxyace-yl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-
2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-C V A-Ile- Amp;
Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-Ile-Amp;
N-tert-Butyloxyc arbonyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CVA-Ile-Amp;
N-tert-Butyloxycarrx)nyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy- 2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-Ile-Amp;
Benzyloxycarbonyl-L-alanyl-L-alanyl-5S-amino-6-cyclohexyl-4S- hydroxy-2S-isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamideor CBZ-Ala-Ala-CVA- Ile-Amp; L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-
[[[2-[(2,6-diamino-4-pyrimidinyl)amino]ethyl]amino]carbonyl]-2-hydroxy-5-methyl-1-(2- methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,6-diamino-4-pyrime- dinyl)amino-ethylamino;
Gly-CVD-Ile-Amp; and
Gly-CPD-Ile-Amp;
to prepare a medicament for inhibiting a retrovirsus in a human cell infected with said retrovirus.
12. A compound selected from the group consisting of:
Cyclohexanehexanamide, δ-(acetylamino)- τ-hydroxy-α-(1-methylethyl)- N-[2-methyl-1-[[(pyridinylmethyl)amino]carbonyl]butyI]αS-[N(IR*,2R*),αR*,TR*,δR- *]]-; or Ac-CVA-Ile-Amp;
Octanamide, 5-(acetylamino)-4-hydroxy-7-methyl-2-(1-methylethyl)-N-[2- methyl-1-[[(2-pyridinylmethyl)aimino)caibonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*]]-, monoacetate (salt); or Ac-LVA-Ile-Amp;
L-Valinamide, L-phenylalanyl-N-[2-hydroxy-5-methyl-1-(2-methylpropy- l)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-; or H-Phe-Val-LVA-Ile-Amp;
Octanamide, 5-[[2-(acetylammo)-3-methyl-1-oxobutyl]amino]-4-hydroxy- 7-memyl-2-(1-memylethyl)-N-[2-memyl-1-[[(2-pyridinylmemyl)amino]carbonyl]butyl]-, [2S-[N(1R*,2R*),2R*,4R*,5R*(R*)]]-, monoacetate (salt); or Ac-Val-LVA-Ile-Amp; L-Valinamide, L-valyI-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyI]butyl]amino]carbonyl]hexyl]-, [1S- [1R*,2R*,4R*(1R*,2R*)]]-. diacetate (salt); or H-Val-Val-LVA-Ile-Amp;
Ac-Asn-LVA-Ile-Amp;
L-Valinamide, N-acetyl-L-valyl-N-[2-hydroxy-5-methyl-1-(2-methylprop- yl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt); or Ac-Val-Val-LVA-Ile-Amp; or
N-[(2S ,4S ,5S)-5-[Nα-[Nα-(tert-Butoxycarbonyl)-O-methyl-L-tyrosyl]-L- histidyl]amino]-4-hydroxy-7-methyl-2-phenylmethyl-1-oxooctyI]-N-[(S)-2-hydroxypropyl]- amine; or Boc-OMeTyr-His-LPA-NH-CH2-CH(CH3)(OH).
13. A compound of formula I
X-C8-D9-E10-F11-G12-Z
wherein X is
a) hydrogen,
b) naphthyloxyacetyl,
c) t-butyloxycarbonyl,
d) toluene-sulfonyl,
e) phenyloxyacetyl,
f) pyridinyl-(CH2)n-carbonyl ,
g) phenyl-(CH2)n-CH(OH)-C(O)-,
h) indolycarbonyl,
i) pyridinyl-(CH2)n-O-C(O)-,
j) phenyMCHz)n -so2-,
k) phenyl-O-(CH2)n-C(O)-,
l) phenyl-HC =CH-(CH2)n-C(O) ,
m) phenyl-HC =CH-(CH2)n-O-C(O)-,
n) HO-(CH2)n-COD)-,
o) quinolinoylhydroxyacetyl,
p) quinolinoylcarbonyl,
q) benzyloxycarbonyl, or
r) 5-(triethyleneglycolmonomethylether) naphthyloxyacetyl;
wherein C8 is
a) absent, b) 2-Py-Ala,
c) -NH-CH2-C(O)-,
d) Phe, or
e) Ala;
wherein D9 is
a) His,
b) Glu,
c) Asp,
d) Asn,
e) -NH-CH2-C(O), or f) Ala;
wherein E10-F11 is
a) CVA,
b) LVA,
c) CVD,
d) LVD,
e) CPD,
f) CLD,
g) CcD,
h) CCD,
i) PPD,
j) LID,
k) LLd, or
l) LLD;
wherein G12 is
a) absent, or
b) Ile;
wherein Z is
a) Amp,
b) Amp-NO,
c) lysine,
d) -NH-(CH2)n-NH-pyridine, e) -NH-(CH2)n-CH(OH)-phenyl, f) -NH-(CH2)n-CH(OH)-C1-C5 alkyl, or
g) -NH-(CH2)n-NH-(2 , 6-diamino-4-pyrimidinyl).
wherein n is O to five, inclusive.
14. A compound of claim 13.
wherein X is
a) 1-naphthyloxyacetyl,
b) p-toluene-sulfonyl,
c) phenyloxyacetyl, or
d) 3-pyridinyl-methylcarbonyl;
wherein C8 is absent;
wherein D9 is His;
wherein E10-F11 is CVA;
wherein G12 is
a) absent, or
b) Ile;
wherein Z is
a) Amp,
b) Amp-NO
c) L-lysine, or
d) -NH-(CH2)2-NH-2-pyridine.
15. A compound of claim 14 selected from the group consisting of:
Nα-[(2S, 4S, 5S)-5-[N-[N α-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or NOA-His-CVA-Ile-Amp-NO;
Nα-[(2S,4S,5S)-5-[N-[Nα-(f-toluenesulfonyl)-L-histidyl]amino]-6-cyclohexyl-
4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or p- Tolunesulfonyl-His-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα-[(2S, 4S, 5S)-5-[N-[Nα -(Phenoxymethylcarbonyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide, pyridine N-oxide or POA-His-CVA-Ile-Amp-NO; Nα-[(2S,4S,5S)-5-[N-[Nα-(p-Toluenesulfonyl)-L-histidyl]amino]-6-cyclohexyl- 4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide,pyridineN- oxide or p-Toluenesulfonyl-His-CVA-Ile-Amp-NO;
Ne-[(2S, 4S, 5S)-5-[N-[Nα -(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-L-lysine,triflouroacecticacidsaltor NOA- His-CVA-L-lysine,triflouroacetic acid salt;
N-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino]ethyl]-amine or NOA-His-CV A-NH-(CH2)2-NH-(2-pyridine);
N-[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)]ethyl]amine,- pyridine N-oxide or NOA-His-CVA-NH(CH2)2-NH-(2-pyridine);
Nα -[(2S, 4S, 5S)-5-[N-[Nα-(1-Naphthalenyloxyacetyl) (2-pyridinyl)alanyl]- amino]-6-cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L- isoleucinamide or NOA-His-CVA-Ile-Amp;
Nα-[(2S,4S,5S)-5-[N-[N α-[(3-Pyridinyl)-methylcarbonyl]-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-(2-pyridinylmethyl)-L-isoleucinamide or (3-pyridinyl)-methyl-carbonyl-His-C V A-Ile- Amp;
Ne-[N2-[(2S,4S,5S)-5-[N-[Nα -(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyI]-L-isolencyl]-L-lysine,triflouroaceticacid salt or NOA-His-CVA-Ile-L-lysine, trifluoroacetic acid salt;
Nα-[(2S, 4S, 5S)-5-[N-[Nα -(1-Naphthalenyloxyacetyl)-L-histidyl]amino]-6- cyclohexyl-4-hydroxy-2-isopropyl-1-oxohexyl]-N-[2-(2-pyridinylamino)ethyl]-L- isoleucinamide or NOA-His-CVA-Ile-NH-(CH2)2-NH-(2-pyridine).
16. A compound of claim 13.
wherein X is
a) phenyl-CH2-CH(OH)-C(O)-,
b) phenyloxyacetyl,
c) t-butyloxycarbonyl,
d) 1H-indol-2-ylcarbonyl,
e) 2-pyridyl-acetyl,
f) 4-pyridyl-acetyl,
g) 4-pyridyl-CH2-O-C(O)-, h) phenyl-O-(CH2)2-C(O)-,
i) phenyl-HC = CH-(CH2)n-C(O)- ,
j) phenyl-HC =CH-(CH2)n-O-C(O)-. or
k) phenyl-(CH2)2-SO2-;
wherein C8 is
a) absent
b) 2-Py-Ala, or
c) Phe;
wherein D9 is
a) His,
b) Glu, or
c) Asp;
wherein E10-F11 is
a) LVA, or
b) CVA;
wherein G12 is
a) absent, or
b) Ile;
wherein Z is
a) Amp,
b) -NH-CH2-CH(OH)-phenyl,
c) -NH-CH2-CH(OH)-CH3, or
d) -NH(CH2)2NH-(2,6-diamino-4-pyrin
17. A compound of claim 16 selected from the group consisting of:
1H-Imidazole-4-propanam ide,N-[2-hyd roxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[(2- hydroxy-1-oxo-3-phenylpropyl)amino]-,[1S-[1R*[R*(R*)],2R*,4R*(1R*,2R*)]]-, 2- hydroxy-1,2,3-propanetricarboxylate(12) (salt) orρhenyl-CH2-CH(OH)-C(O)-His-LVA-Ile-Amp;
1H-I mida zole-4-propanamide,N-[2-hydroxy-4-[[[1-[[(2-hydroxy-2-phenylethyl)- amino]carbonyl]-2-methylbutyl]amino]carbonyl]-5-methyl-1-(2-methylpropyl)hexyl]-(α- [(phenoxyacetyl)amino]-,monoacetate (salt) or POA-His-LVA-Ile-NH-CH2-CH(OH)- phenyl; L-α-Glutamine,N/u2/d-[N-[[1 , 1-dimethylethoxy)carbonyl]-L-phenylalanyl]-N- [2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]- cartionyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*,2R*4R*(1R*,2R*)]]-,monacetate(salt) or BOC-Phe-Glu-LVA-Ile-Amp;
Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2-hydroxypropyl)- amino]carbonyl]-5-methylhexyl]amino]-5-oxo-4-[(phenoxyacetyl)amino]- or POA-Glu- CVA-NH-CH2CH(CH3)(OH);
1H-Imidazole-4-propanamide, N-[1-(cyclohexylmethyl)-2-hydroxy-4-[[(2- hydroxypropyl)amino]carbonyl]-5-methylhexyl]α-[(phenoxyacetyl)amino]-, monoacetate (salt) or POA-His-CVA-NH-CH2-CH(OH)(CH3);
Pentanoic acid, 5-[[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1- [[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-4-[(1H-indol-2- ylcarbonyl)aιmno]-5-oxo-,[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]or1H-indol-2-yl-carbonyl- Glu-CVA-Ile-Amp;
L-.alpha.-Glutamine, N-[1-(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2- methyl-1-[[(2-pyridinylmemyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-N/u 2/d-L- phenylalanyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]-, bis(trifluoracetate) (salt) or Phe-Glu- CVA-Ile-Amp;
2-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmemyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]amino]-1-(1H- imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-or (2-Pyridyl)acetyl- His-LVA-Ile-Amp;
4-Pyridineacetamide, N-[2-[[2-hydroxy-5-methyl-1-(2-methylpropyl)-4- [[[2methyl-1-[[(2-pyridinylmemyl)amino]carb onyl]butyl]amino]carbonyl]hexyl]amino]-1- (1H-imidazol-4-ylmethyl)-2-oxoethyl]-[1S-[1R*(R*),2R*,4R*(lR*,2R*)]]-or (4- Pyridyl)acetyl-His-LVA-Ile-Amp;
L-Histidinamide,N-[(1,1-dimethylethoxy)carbonyl]-3-(2-pyridinyl)alanyl-N-[2- hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbo- nyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*[R*(E)],2R*,4R*(lR*,2R*)]]-or BOC-2-Py- Ala-His-LVA-Ile-Amp;
L-Histidinamide, N-[(1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N-[4-[[[2- [(2,6-d iamino-4-pyrimidinyl)amino]ethyl]amino]carbonyl]-2-hydroxy-5-methyl-1-(2- methylpropyl)hexyl]-,[1S-(1R*,2R*,4R*)]- or BOC-Phe-His-LVA-(2,6-diamino-4-pyrimi dinyl)amino-ethylamino;
L-.alpha.-Asparagine,N/u2/d-[N-[(1 ,1-dimethylethoxy)carbonyl]-L-phenylalanyl]-N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2-methyl-1 -[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-,[1S-[1R*.2R*,4R*(1R*,2R*)]]- ,monoacetate (salt) or BOC-Phe-Asp-LVA-Ile-Amp;
1H-Indole-2-carboxamideN -[2-([2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]carbonyl]hexyl]amino]-1-(1H- imidazol-4-ylmethyl)-2-oxoethyl]-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-;-(Indolyl-2- carbonyl)-His-LV A-Ile- Amp;
L-.alpha.-Glutamine, N-[1,1-dimethylethoxy)carbonyl]-L-phenylalanyl-N0[1-
(cyclohexylmethyl)-2-hydroxy-5-methyl-4-[[[2-methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]1-,[1S-[1R*,2R*,4R*(1R*,2R*)]]-, monoacetate (salt) or BOC-Phe-Glu-CVA-Ile-Amp;
2,5,11,14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9- (1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10, 13-trioxo-15-(2-pyridinyl)- ,4-pyridinylmethyl ester, [3S-[3R*,6R*,7R*,9R*,12R*(R*)]]-;
1H-Imidazole-4-propanamide, N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- memyl-1-[[(2-pyridinylmethyl)anιino]carb onyl]butyl]amino]carbonyl]hexyl]-α-[(1-oxo-3- phenoxypropyl)amino]-,[1S-[1R*(R*),2R*,4R*(1R*,2R*)]]-,or Phenoxypropionyl- His-LVA-Ile-Amp;
1H-Imidazole-4-prorpanamide,N-[2-hydroxy-5-memyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[[(2-pyridinylmethyl)ammo[carbonyl[butyl[amino[carbonyl[hexyl]-α-[(1-oxo- 3phenyl-2-propenyl)amino]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]-orphenyl-CH=CH- C(O)-His-LVA-Ile-Amp;
1H-Imidazole-4-propanamide,N-[2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[[(2-pyridinylmethyl)aιmnc[carbonyl]|putyl]amino[carbonyl[hexyl]-α-[(1-oxo-4- phenyl-3-butenyl)amino]-,[1S-[1R*[ R*(E)],2R*,4R*(1R*,2R*)]]- or phenyl-CH=CH- CH2-C(O)-His-LVA-Ile-Amp;
2,5,11, 14-Tetraazapentadecanoic acid, 7-hydroxy-3-(1H-imidazol-4-ylmethyl)-9- (1-methylethyl)-12-(1-methylpropyl)-6-(2-methylpropyl)-4,10,13-trioxo-15-(2-pyridinyl)- ,3-phenyl-2-propenyl ester, [3S-[1(E),3R*,6R*,7R*,9R*,12R*(R*)]]- or phenyl- CH = CH-CH2-O-C(O)-His-LVA-Ile-Amp; and
1H-Imidazole-4-propanamide,N-[2-hydιoxy-5-methyl-1-(2-methylpropyl)-4-[[[2- methyl-1-[[(2-pyridinylmethyl)amino]carbonyl]butyl]amino]carbonyl]hexyl]-α-[[(2- phenylethenyl)sulfonyl]amino]-,[1S-[1R*[R*(E)],2R*,4R*(1R*,2R*)]]-or phenyl-
(CH2)-SO2-His-LVA-Ile-Amp;
18. A compound of claim 13.
wherein X is
a) t-butyloxycarbonyl,
b) (HO) acetyl,
c) hydrogen,
d) phenyloxyacetyl,
e) 1-naphthyloxyacetyl,
f) 5-quinolinylhydroxyacetyl,
g) 4-quinolinylhydroxyacetyl, or
h) 2-quinolinylcarbonyl;
wherein C8 is
a) absent
b) Phe, or
c) -NH-CH2C(O)-;
wherein D9 is
a) His,
b) Asn, or
c) -NH-CH2C(O)-;
wherein E10-F11 is
a) CVD,
b) LVD,
c) CPD,
d) CLD,
e) CCD,
f) CcD,
g) PPD,
h) LID,
i) CVA,
j) LLd, or
k) LLD; wherein G12 is
a) absent, or
b) Ile;
wherein Z is
a) Mba,
b) Amp,
c) Amp-NO,
d) Apr;
19. A compound of claim 18 selected from the group consisting of:
N-tert-Butyloxycaιbonyl-L-phenylalanyl-L-histidyl-5S-amino-3R,4R-dihydroxy-
2R-isopropyl-7-methyl-octanoyl-2S-methylbutylamide or BOC-Phe-His-LVA-Mba;
Hydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucy 1-2-pyridylmethylamide or (HO) Ac-His-C V A-Ile- Amp;
L-Glycyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or Gly-His-CVA-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy- hexanoyl-L-isoleucyl-2-pyridylmethylamide or (HO)Ac-His-CPD-Ile-Amp;
Hydroxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy- hexanoyl-L-isoleucyl-2-pyridylmethylamide, N-oxide or (HO)Ac-His-CPD-Ile-Amp;
Phenoxyacetyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy- hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CPD-Ile-Amp;
L-Glycyl-L-histidyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy- hexanoyl-L-isoleucyl-2-pyridyImethylamide or Gly-His-CPD-Ile-Amp;
Phenoxyacetyl-L- histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or POA-His-CVA-Ile-Amp;
1-Naphtoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isobutyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CLD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2R-cyclohexylmethyl- 3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CCD-Ile- Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-2R-benzyl-3R,4R-dihydroxy-6-phenyl- hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-PPD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R- isopropyl-hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamideor NOA-His-CVD-Ile-Apr:
1-Naphthoxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-2S-cyclohexylmethyl- 3R,4R-dihydroxy-hexanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-CcD-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-amino-3S-4S-dihydroxy-2S-isobutyl-7-methyl- octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-Lld-Ile-Amp;
5-Quinolinylhydroxyacetyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(b)-His-CV A-Ile- Amp;
4-Quinolinylhydroxyacetyl-L-lustidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Qoa(a)-His-CVA-Ile-Amp;
l-Naphthoxyacetyl-L-histidyl-5S-a mino-3R-4R-dihydroxy-2S-isobutyl-7-methyl- octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLd-Ile-Amp;
1-Naphthoxyacetyl-L-histidyl-5S-ammo-3S-4R-dihydroxy-2S-isobutyl-7-methyl- octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLd-Ile-Amp;
1-Naphmoxyacetyl-L-Wstidyl-5S-amino-3R-4R-dihydroxy-2R-isobutyl-7-methyl- octanoyl-L-isoleucyl-2-pyridylmethylamide or NOA-His-LLD-Ile-Amp;
2-Quinolinylcarbo nyl-5S-amino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl- hexanoyl-L-isoleucyl-2-pyridinylamino-ethylamide or Qc-Asn-CVD-Ile-Apr;
L-Glycyl-5S-am ino-6-cyclohexyl-3R,4R-dihydroxy-2R-isopropyl-hexanoyl-=L- isoleucyl-2-pyridylmethylamide-or Gly-CVD-Ile-Amp;
L-Glycyl-5S-amino-2R-benzyl-6-cyclohexyl-3R,4R-dihydroxy-hexanoyl-L- isoleucyl-2-pyridyl-methylamide or Gly-CPD-Ile-Amp.
20. A compound of claim 13.
wherein X is
a) t-butyloxycarbonyl,
b) 2-quinolinylcarbonyl,
c) benzyloxycarbonyl,
d) 1-naphthyloxyacetyl, or
e) phenyloxyacetyl;
wherein C8 is
a) absent, or
b) Ala;
wherein D9 is a) Ala,
b) His, or
c) Asn;
wherein E10-F11 is CVA;
wherein G12 is
a) absent or
b) Ile;
wherein Z is
a) Amp,
b) -NH2, or
c) -NH-(CH
21. A compound of claim 20 selected from the group consisting of:
N-tert-Butyloxycarbonyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or Boc-Ala-CV A-Ile- Amp;
N-tert-Butyloxycarbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or BOC-His-CVA-Ile-Amp;
Quinolinyl-2-carbonyl-L-histidyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-His-CV A-Ile- Amp;
Quinolinyl-2-carbonyl-L-asparaginyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or QC-Asn-CV A-Ile- Amp;
Benzyloxycarbonyl-L-alanyl-L-alanyl-5S-amino-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucyl-2-pyridylmethylamide or CBZ- Ala- Ala-CV A-Ile- Amp;
1-Naphthalenyloxyacetyl-L-histidyl-5S-amine-6-cyclohexyl-4S-hydroxy-2S- isopropyl-hexanoyl-L-isoleucylamide or Noa-His-CVA-Ile-NH2; and
POA-His-CVA-NH-(CH2)4-CH(CONH)(NH2).
22. A compound of claim 13
wherein X is
a) 1-naphthyloxyacetyl, or
b) 5-(triethyleneglycolmonomethyl ether) naphthoxyacetyl;
wherein C8 is absent;
wherein D9 is Asp;
wherein E10-F11 is CVA;
wherein G12 is Ile; wherein Z is Amp.
23. A compound of claim 22 selected from the group consisting of:
L-Asparaginamide, 1-(naphthoxy)acetyl-N-[2-hydroxy-5-methyl-1-(2-methyl- propyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinylmethyl]amino]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*(1R*,2R*)]]- or NOA-Asp-CVA-Ile- Amp;
L-Asparaginamide, [5-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N- [2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinyl- methyl]ammo]carbonyl]butyl]amino]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R*,2R*,4R*- (1R*,2R*)]]-or 5-(triethyleneglycol monomethyl ether-NOA-Asp-CVA-Ile-Amp; and
L-Asparaginamide, [4-(triethyleneglycolmonomethylether)naphthoxy]acetyl-N- [2-hydroxy-5-methyl-1-(2-methylpropyl)-4-[[[2-methyl-1-[[[2-(N-oxido)pyridinyl- memyl]anιino]carbonyl]butyl]ammo]carbonyl]hexyl]-N-alpha-methyl-, [1S-[1R* ,2R*,- 4R*(1R*,2R*)]]- or 4-(triethyleneglycol monomethyl ether)-NOA-Asp-CVA-Ile-Amp.
EP19900915950 1989-10-27 1990-10-16 Method for treating hiv and other retroviruses and compounds useful therefor Withdrawn EP0497835A1 (en)

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US5643878A (en) * 1991-09-12 1997-07-01 Ciba-Geigy Corporation 5-amino-4-hydroxyhexanoic acid derivatives
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
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IL129871A (en) 1994-05-06 2003-11-23 Pharmacia & Upjohn Inc Process for preparing 4-phenyl-substituted octanoyl-oxazolidin-2-one intermediates that are useful for preparing pyran-2-ones useful for treating retroviral infections
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