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WO1992006996A1 - Peptides contenant des 1,4-diamines substituees comme segments d'insertion a l'etat de transition - Google Patents

Peptides contenant des 1,4-diamines substituees comme segments d'insertion a l'etat de transition Download PDF

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Publication number
WO1992006996A1
WO1992006996A1 PCT/US1991/007047 US9107047W WO9206996A1 WO 1992006996 A1 WO1992006996 A1 WO 1992006996A1 US 9107047 W US9107047 W US 9107047W WO 9206996 A1 WO9206996 A1 WO 9206996A1
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Prior art keywords
alkyl
amino
hydrogen
aryl
het
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PCT/US1991/007047
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English (en)
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Suvit Thaisrivongs
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The Upjohn Company
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Publication of WO1992006996A1 publication Critical patent/WO1992006996A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/18—Antivirals for RNA viruses for HIV
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/04—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
    • C07D233/20—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member with substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D233/26—Radicals substituted by carbon atoms having three bonds to hetero atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/021—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)n-C(=0)-, n being 5 or 6; for n > 6, classification in C07K5/06 - C07K5/10, according to the moiety having normal peptide bonds
    • 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 provides novel compounds. More particularly, the present invention provides novel peptide analogs.
  • the peptides of the present invention contain a substituted 1,4-diamine moiety as a novel transition state insert. These peptides are useful as inhibitors of retroviral proteases. Inhibitors of retroviral proteases, such as the
  • HIV-I protease are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency disease syndrome (AIDS).
  • AIDS human acquired immunodeficiency disease syndrome
  • 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 AZT 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, etal., 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 HIV 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 HW-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. Katoh, et al., Nature, 329:654-656 (1987)), led to inferences regarding the three-dimensional 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 HIV protease has been expressed in bacteria (see, e.g., P.L. Darke, et al., J. Biol.
  • pepstatin A 100 ⁇ M
  • pepstatin A a general aspartyl proteinase inhibitor
  • the present invention particularly provides:
  • P is OH or NH 2 ;
  • Y is OH or NH 2 ;
  • a or B or both are absent or are a divalent moiety of the formula XL 1 , XL 2 or
  • n 0 to 5, inclusive
  • aryl is phenyl or naphthyl substituted by zero to three of the following:
  • -Het is a 5- or 6-membered saturated 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 if chemically feasible, the nitrogen and sulfur atoms may be in the oxidized forms; and optionally substituted by zero to three of the following:
  • 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 present invention provides for novel compounds 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.
  • Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethane-sulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobfomide, hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thi
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C i -C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (C 1 -C 4 )alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof.
  • C 4 -C 7 cyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms.
  • Examples of (C 3 -C 10 )cycloalkyl which include alkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl, 2-methylcyclopropyl,
  • aryl examples include phenyl, naphthyl, (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, 2-ethyl-tolyl,4-ethyl-o-tolyl,5-ethyl-m-tolyl, (o-, m-, orp-)propylphenyl, 2-propyl-(o-, m-, or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethylphenyl, (2,3,4- 2,3,6-, or 2,4,5-)trimethylphenyl, (o-, m-, or p-)fluorophenyl, (o-, m-, or p-trifluorometh ⁇ l)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-
  • Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl- indolyl, N in - C 1 -C 5 alkyl-C(O)-indolyl, 1,2,4-triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi- nyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolidinyl, isothiazolid
  • a heterocycle as defined herein for -Het would not be bonded through oxygen or sulfur or through nitrogen which is within a ring and part of a double bond.
  • Halo is halogen (fluoro, chloro, bromo, or iodo) or trifluoromethyl.
  • Examples of pharmaceutically acceptable cations include: pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
  • pharmacologically acceptable metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationic forms of other metals, e.g., aluminum, zinc, and iron are also within the scope of this invention.
  • Pharmacologically acceptable amine cations are those derived from primary, secondary, or tertiary amines.
  • novel peptides herein contain both natural and synthetic amino acid residues.
  • 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 HIV protease which belongs to the class of aspartyl proteases, is a C-2 symmetric homodimer, M.A. Navia et al., Science 1989, 337, 615; A. Wlodawer et al., Science 1989, 337, 616.
  • the compounds of the present invention of formula I have C-2 symmetry and thus provide complementary ligands for the C-2 symmetric active site of the enzyme.
  • the C-2 symmetric transition-state insert is depicted at -NH-CH(CH 2 R 1 )-CHP-CHY-CH(CH 2 R 2 )-NH-.
  • the symmetrical transition-state inserts 1,4-diamino-2,3- dihydroxy-1,4-dibenzyl-butane and 1,4-diamino-2,3-dihydroxy-1,4-diisobutyl-butane, are preferred.
  • the 1S,2S,3S,4S and the 1S,2R,3R,4S isomers are preferred.
  • the compounds of the present invention are effective and potent inhibitors of HIV protease. Therefore, the compounds of formula I inhibit retroviral proteases and thus inhibit the replication of the virus. They are useful for treating 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.
  • 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.
  • HTV human immunodeficiency virus
  • AIDS human acquired immunodeficiency disease syndrome
  • 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).
  • 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 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.
  • the compounds of the present invention are preferably orally administered to humans to effect HTV protease inhibition for the purpose of favorably treating diseases caused by retroviruses.
  • the compounds are administered from 0.1 mg to 100 mg per kg per dose, from 1 to 4 times daily.
  • 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 utility of the compounds of the present invention has been demonstrated in the biological test described below.
  • the HIV-1 protease has been expressed in E. coli, isolated, characterized and used to determine the inhibitory constants (K 1 ) 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 HIV-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 compounds 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 compounds 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 the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples. In these charts, the variables are as defined above.
  • Chart A describes the preparation of the insert of formula A-7 and final compounds of formulas A-8 and A-9 of Examples 1 and 2 below, respectively.
  • Vigorous basic hydrolysis of the compound of formula A-5 gives the hydroxyamine of formula A-6.
  • the acid labile protecting groups are removed with acidic methanol to give the compound of formula A-7 which is isolated as the dihydrochloride.
  • the compound of formula A-7 is treated with excess di-tert- butyldicarbonate to give the final peptide of formula A-8.
  • the amine dihydrochloride A-7 can also be coupled with tert-butyloxycarbonyl-L-valine using diethylphosphoryl cyanide, by the procedure described in S. Yamada et al., Tetrahedron Lett. 1973, 1595, to give the final peptide of formula A-9.
  • Chart B describes the preparation of the final peptide of formula B-4 of Example 3 below.
  • the amine dihydrochloride B-1 prepared as the compound A-7 in Chart A, can be coupled with tert-butyloxycarbonyl-N im -tosyl-L-histidine using diethylphosphoryl cyanide by the procedure described in S. Yamada et al., Tetrahedron Lett. 1973, 1595, to give the compound of formula B-2.
  • the tert-butyloxycarbonyl protecting group is removed with trifluoroacetic acid and the resulting amine is then coupled to 1- naphthoxyacetic acid using diethylphosphoryl cyanide, by the procedure described in S. Yamada et al., Tetrahedron Lett. 1973, 1595, to give the compound of formula B-3.
  • the tosyl protecting group is then removed with 1-hydroxybenzotriazole to give the final peptide of formula B-4.
  • Chart C describes the preparation of the insert of formula C-7 and final peptide of formula C-8 of Example 4 below.
  • the renin inhibiting polypeptides may be prepared by solution phase peptide synthetic procedures analogous to those described hereinafter or to those methods known in the art.
  • Appropriate protecting groups, reagents, and solvents for the solution phase method can be found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983; "The Practice of Peptide Synthesis", M. Bodansky and A. Bodansky, Springer- Verlag, New York, 1984; “The Principles of Peptide Synthesis", M. Bodansky, Springer- Verlag, New York, 1984.
  • the carboxylic moiety of N ⁇ -t-butyloxycarbonyl (BOC)-substituted amino acid derivatives having suitable side chain protecting groups may be condensed with the amino functionality of a suitably protected amino acid or peptide using a conventional coupling protocol such as dicyclohexyl- carbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylamine (Et 3 N) in methylene chloride or dimethylformamide.
  • DCC dicyclohexyl- carbodiimide
  • HOBT 1-hydroxybenzotriazole
  • DEPC diethylphosphoryl cyanide
  • Et 3 N triethylamine
  • N ⁇ -BOC moiety may be selectively removed with 50% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride.
  • Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropylethylamine or sodium bicarbonate in methylene chloride.
  • the compounds of the present invention may be in either free form or in protected form at one or more of the remaining (not previously protected) peptide, carboxyl, amino, hydroxy, or other reactive groups.
  • the protecting groups may be any of those known in the polypeptide art. Examples of nitrogen and oxygen protection groups are set forth in T.W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups in Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin, Organic Synthesis, Verlag Chemie (1983). Included among the nitrogen protective groups are t-butoxycarbonyl (BOC), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like.
  • BOC is t-butoxycarbonyl
  • BOPCL is bis (2-oxo-3-oxazolidinyl) phosphinic chloride
  • Celite is a filter aid
  • DCC is dicyclohexylcarbodiimide
  • DEPC diethylphosphoryl cyanide
  • ⁇ -Glu is ⁇ -glutamic acid
  • N-MeHis is N ⁇ -methyl histidine
  • HOBT 1-hydroxybenzotriazole monohydrate
  • HPLC high performance liquid chromatography
  • MPLC medium pressure liquid chromatography
  • Ph is phenyl
  • Phe is phenylalanine
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TsoH is p-toluenesulfonic acid
  • Tyr is 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.
  • Preparation 8 4S,7S-Bis-[1-Naphthoxyacetyl-N im -tosyl-L-histidyl-amino]-5S,6S- dihydroxy-2,9-dimethyldecane (Formula B-3)
  • 1 trifluoroacetic acid : dichloromethane is allowed to stir for 50 min.
  • the reaction mixture is partitioned between dichloromethane and aqueous sodium bicarbonate.
  • the organic phase is dried (sodium sulfate) and then concentrated to give 42.6 mg.
  • Example 4 4S,7S-Bis-[N ⁇ -rert-Butyloxycarbonyl-L-valyl-amino]-5R,6R- dihydroxy-2,9-dimethyldecane (Formula C-8) Refer to Chart C. To a stirred solution of 15 mg of the title product of Preparation 14 and 25.6 mg of tert-butyloxycarbonyl-L-valine in 0.5 mL dimethylformamide is added 0.038 mL of diisopropylethylamine and 48 mg of bis(2-oxo-3-oxazolidinyl)phosphinic chloride. After stirring for 18 h, the concentrated reaction mixture is chromatographed on silica gel with 3% to 5% methanol in dichloromethane to give 31 mg of the title product.
  • Example 7 4S,7S-Bis-[N ⁇ -Benzyloxycarbonyl-L-valyl-amino]-5R,6R-dihydroxy-2,9- dimethyldecane. FAB-MS (found): 699.4337.
  • Example 8 4S,7S-Bis-[N ⁇ -Benzyloxycarbonyl-L-valyl-amino]-5S,6S-dihydroxy-2,9- dimethyldecane. FAB-MS (found): 699.4337.

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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
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  • General Chemical & Material Sciences (AREA)
  • Molecular Biology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Communicable Diseases (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • AIDS & HIV (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Crystallography & Structural Chemistry (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention se rapporte à de nouveaux peptides représentés par la formule (I) et qui sont utiles comme inhibiteurs des protéases rétrovirales. Les inhibiteurs des protéases rétrovirales, comme la protéase du VIH-I, servent à traiter les maladies causées par les rétrovirus, telles que le syndrome immunodéficitaire acquis (SIDA) chez l'homme.
PCT/US1991/007047 1990-10-10 1991-10-01 Peptides contenant des 1,4-diamines substituees comme segments d'insertion a l'etat de transition WO1992006996A1 (fr)

Priority Applications (1)

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JP3517923A JPH06502403A (ja) 1990-10-10 1991-10-01 遷移状態インサートとして置換１，４−ジアミンを含有するペプチド

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US59547090A 1990-10-10 1990-10-10
US595,740 1990-10-10

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Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5362912A (en) * 1989-05-23 1994-11-08 Abbott Laboratories Process for the preparation of a substituted diaminodiol
US5436339A (en) * 1991-03-06 1995-07-25 Abbott Laboratories Process for the preparation of a substituted diaminoalcohol
US5539122A (en) * 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5541334A (en) * 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5846987A (en) * 1992-12-29 1998-12-08 Abbott Laboratories Retroviral protease inhibiting compounds
EP1039886A4 (fr) * 1997-12-08 2001-05-16 Scripps Research Inst Inhibiteurs de proteases de vih/vif presentant un petit reste p3
US8013115B1 (en) 1999-08-16 2011-09-06 Bio-Rad Pasteur Use of stabilised synthetic compounds in immunoassay

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US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons
NZ249789A (en) * 1992-03-11 1997-07-27 Narhex Ltd Hydrazine, carbazate and 1,2-diazacyclic derivatives and pharmaceutical compositions
MXPA93002392A (es) 1992-03-11 2005-02-04 Narhex Ltd Derivados amino de hidrocarburos-oxo e hidroxi-substituidos.
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
IL110898A0 (en) * 1993-09-10 1994-11-28 Narhex Australia Pty Ltd Polar-substituted hydrocarbons

Citations (4)

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WO1988004664A2 (fr) * 1986-12-22 1988-06-30 The Upjohn Company Peptides inhibiteurs de la renine ayant une partie epoxide ou glycol
EP0393445A2 (fr) * 1989-04-19 1990-10-24 Bayer Ag Utilisation de peptides inhibiteurs de la renine contre les rétrovirus
WO1991001327A1 (fr) * 1989-07-19 1991-02-07 The Upjohn Company Peptides comprenant des diaminoglycols en tant qu'imitateurs de l'etat de transition
EP0428849A2 (fr) * 1989-09-28 1991-05-29 Hoechst Aktiengesellschaft Inhibiteurs de protéases rÀ©trovirales

Patent Citations (4)

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WO1988004664A2 (fr) * 1986-12-22 1988-06-30 The Upjohn Company Peptides inhibiteurs de la renine ayant une partie epoxide ou glycol
EP0393445A2 (fr) * 1989-04-19 1990-10-24 Bayer Ag Utilisation de peptides inhibiteurs de la renine contre les rétrovirus
WO1991001327A1 (fr) * 1989-07-19 1991-02-07 The Upjohn Company Peptides comprenant des diaminoglycols en tant qu'imitateurs de l'etat de transition
EP0428849A2 (fr) * 1989-09-28 1991-05-29 Hoechst Aktiengesellschaft Inhibiteurs de protéases rÀ©trovirales

Non-Patent Citations (1)

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Title
J. Med. Chem., Vol. 33, No. 10, 1990 Ronald B. Gammill et al: "Structure-Based, C2 Symmetric Inhibitors of HIV Protease ", *

Cited By (31)

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US5616720A (en) * 1989-05-23 1997-04-01 Abbott Laboratories Retroviral protease inhibiting compounds
US5659045A (en) * 1989-05-23 1997-08-19 Abbott Laboratories Retroviral protease inhibiting compounds
US5539122A (en) * 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5541206A (en) * 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5541334A (en) * 1989-05-23 1996-07-30 Abbott Laboratories Retroviral protease inhibiting compounds
US5552558A (en) * 1989-05-23 1996-09-03 Abbott Laboratories Retroviral protease inhibiting compounds
US6531610B1 (en) 1989-05-23 2003-03-11 Abbott Laboratories Retroviral protease inhibiting compounds
US5565418A (en) * 1989-05-23 1996-10-15 Abbott Laboratories Retroviral protease inhibiting compounds
US5583233A (en) * 1989-05-23 1996-12-10 Abbott Laboratories Retroviral protease inhibiting compounds
US5583232A (en) * 1989-05-23 1996-12-10 Abbott Laboratories Retroviral protease inhibiting compounds
US5591860A (en) * 1989-05-23 1997-01-07 Abbott Laboratories Retroviral protease inhibiting compounds
US5597928A (en) * 1989-05-23 1997-01-28 Abbott Laboratories Retroviral protease inhibiting compounds
US5597927A (en) * 1989-05-23 1997-01-28 Abbott Laboratories Retroviral protease inhibiting compounds
US5608072A (en) * 1989-05-23 1997-03-04 Abbott Laboratories Retroviral protease inhibiting compounds
US5892052A (en) * 1989-05-23 1999-04-06 Abbott Labortories Process for making retroviral protease inhibiting compounds
US5362912A (en) * 1989-05-23 1994-11-08 Abbott Laboratories Process for the preparation of a substituted diaminodiol
US5679797A (en) * 1989-05-23 1997-10-21 Abbott Laboratories Retroviral protease inhibiting compounds
US5659044A (en) * 1989-05-23 1997-08-19 Abbott Laboratories Retroviral protease inhibiting compounds
US5625072A (en) * 1989-05-23 1997-04-29 Abbott Laboratories Retroviral protease inhibiting compounds
US5696270A (en) * 1989-05-23 1997-12-09 Abbott Laboratories Intermediate for making retroviral protease inhibiting compounds
US5436339A (en) * 1991-03-06 1995-07-25 Abbott Laboratories Process for the preparation of a substituted diaminoalcohol
US6667404B2 (en) 1991-08-15 2003-12-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5760036A (en) * 1992-07-20 1998-06-02 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5776933A (en) * 1992-07-20 1998-07-07 E. R. Squibb & Sons, Inc. Method of inhibiting protease
US5559256A (en) * 1992-07-20 1996-09-24 E. R. Squibb & Sons, Inc. Aminediol protease inhibitors
US5846987A (en) * 1992-12-29 1998-12-08 Abbott Laboratories Retroviral protease inhibiting compounds
US5886036A (en) * 1992-12-29 1999-03-23 Abbott Laboratories Retroviral protease inhibiting compounds
US6017928A (en) * 1992-12-29 2000-01-25 Abbott Laboratories Retroviral protease inhibiting compounds
US6150530A (en) * 1992-12-29 2000-11-21 Abbott Laboratories Retroviral protease inhibiting compounds
EP1039886A4 (fr) * 1997-12-08 2001-05-16 Scripps Research Inst Inhibiteurs de proteases de vih/vif presentant un petit reste p3
US8013115B1 (en) 1999-08-16 2011-09-06 Bio-Rad Pasteur Use of stabilised synthetic compounds in immunoassay

Also Published As

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AU8759491A (en) 1992-05-20
JPH06502403A (ja) 1994-03-17
EP0552247A1 (fr) 1993-07-28

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