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WO1995019958A1 - Inhibiteurs de la protease aspartique du paludisme - Google Patents

Inhibiteurs de la protease aspartique du paludisme Download PDF

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Publication number
WO1995019958A1
WO1995019958A1 PCT/US1995/000017 US9500017W WO9519958A1 WO 1995019958 A1 WO1995019958 A1 WO 1995019958A1 US 9500017 W US9500017 W US 9500017W WO 9519958 A1 WO9519958 A1 WO 9519958A1
Authority
WO
WIPO (PCT)
Prior art keywords
radicals
amino
group
carbonyl
compound
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/US1995/000017
Other languages
English (en)
Inventor
Mark A. Russell
Richard A. Mueller
Martin L. Bryant
Gunnar H. Hanson
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.)
GD Searle LLC
Original Assignee
GD Searle LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by GD Searle LLC filed Critical GD Searle LLC
Priority to JP7519566A priority Critical patent/JPH09508365A/ja
Priority to EP95907965A priority patent/EP0741696A1/fr
Priority to AU15968/95A priority patent/AU1596895A/en
Publication of WO1995019958A1 publication Critical patent/WO1995019958A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • 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
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P33/00—Antiparasitic agents
    • A61P33/02—Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/02—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C215/04—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated
    • C07C215/20—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being saturated the carbon skeleton being saturated and containing rings
    • 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
    • C07C271/16—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 singly-bound oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/20—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carbonic acid, or sulfur or nitrogen analogues thereof
    • C07D295/205—Radicals derived from carbonic acid
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • R 11 is selected from the group consisting of hydrogen, alkoxycarbonyl, aralkoxycarbonyl, alkylcarbonyl, cycloalkylcarbonyl, cycloalkylalkoxycarbonyl, cycloalkylalkanoyl, alkanoyl, aralkanoyl, aroyl, aryloxycarbonyl, aryloxyalkanoyl, heterocyclylcarbonyl, heterocycloalkoxycarbonyl, heterocycloalkylalkanoyl, heterocycloalkylalkoxycarbonyl, heteroaralkoxycarbonyl, heteroaryloxycarbonyl, heteroaralkanoyl, heteroaroyl, alkyl, aryl, aralkyl, aryloxyalkyl, heteroaryloxyalkyl, hydroxyalkyl, aminocarbonyl, aminoaralkanoyl, aminocycloalkylalkanoyl, aminoalkanoyl, and mono- and disub
  • cycloalkylalkyl means an alkyl radical as defined above which is substituted by a cycloalkyl radical containing from about 3 to about 10, preferably from about 3 to about 8, and more preferably from about 3 to about 6, carbon atoms.
  • cycloalkyl radicals include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, adamantyl and the like.
  • cycloalkylalkoxycarbonyl means an acyl group derived from a cycloalkylalkoxycarboxylic acid of the formula cycloalkylalkyl-O-COOH wherein cycloalkylalkyl has the significance given above.
  • aryloxyalkanoyl means an acyl radical of the formula aryl-O-alkanoyl wherein aryl and alkanoyl have the significance given above.
  • heterocycloalkoxycarbonyl means an acyl group derived from heterocycloalkyl-O-COOH wherein heterocycloalkyl is as defined above.
  • the ketone or aldehyde can be reacted with the ittig reagent of formula
  • the unsaturated ester can then be reduced under hydrogenation conditions, such as 5% Pt/C in methanol in the presence of 2 pounds per square inch of hydrogen (H ) , to produce the saturated ester of formula
  • R 1 , R 2 , R 5 , G 1 and G 2 are as defined above.
  • the saturated ester can then be converted into a lactone of the formula
  • the R 2 group can be introduced after the lactone formation.
  • the above ketone or aldehyde can be reacted with the Wittig reagent of formula
  • Deprotection of the amine can be accomplished using the standard conditions well known in the art and appropriate for the particular protecting group, such as hydrolysis with base, acid treatment of a t- butoxycarbonyl group or reductive hydrogenation.
  • the conditions selected must not affect the remaining portion of the molecule.
  • a carbobenzoxy group can be removed by hydrogenolysis utilizing palladium on carbon in a suitable solvent system such as an alcohol, acetic acid, and the like or mixtures thereof, and a t-butoxycarbonyl group can be removed utilizing an inorganic or organic acid, such as HCl or trifluoroacetic acid, in a suitable solvent system, such as dioxane or methylene chloride.
  • R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are as defined above,
  • R 1 , R 2 , R 3 , R 4 , R 5 and R ⁇ are as de'fined above.
  • SUBSTITUTE SHEET (RULE 2 ⁇ obtain mono-alkanoyl compounds (i.e., where one of P 1 or P 2 is a hydrogen radical) .
  • P 1 and P 2 taken together form a carbonyl the addition can be accomplished by reaction of the alcohol groups with phosgene or a phosgene equivalent, followed by removal of any N-protecting groups as disclosed above.
  • P. falciparum clone HB3 was grown at 37° C under 3% oxygen/3% carbon dioxide in RPMI medium using 5% human red blood cells (Trager and Jensen, Science 193:673-675, 1976, incorporated herein by reference) supplemented with 10% human plasma (Hui, et al., Trans. Roy. Soc. Trop. Med. Hyg. 625:625-626, 1984, incorporated herein by reference) . Synchronization was attained by treatment with sorbitol (Lambros and Vanderberg, J. Para ⁇ itol. 65:418-420, 1979, incorporated herein by reference) . Aspartic Protease Purification
  • Aspartic hemoglobinase was purified as previously described (Goldberg et al., J. Exp. Med. 173:961-969, 1991, incorporated herein by reference) with the following modifications. 1) Digestive vacuoles isolated by sorbitol lysis/differential centrifugation (Goldberg et al., Proc. Natl. Acad. Sci. USA 87:2931- 2935, 1990, incorporated herein by reference) omitting Percoll separation, were used as enzyme source. 2) Hydroxylapetite chromatography was performed by HPLC (Vander Jagt et al., Biochim. et Biophys.
  • the second aspartic protease was isolated as an earlier-migrating activity peak on the hydroxylapetite chromatography described above. A small amount of cysteine protease contamination was observed, which could be removed by repeating the DEAE chromatography.
  • reaction mixtures contained 150mM sodium acetate pH 5.0, 60,000 cpm (6.25 ⁇ M) 14 C-methylated globin (Dot avio-Martin and Ravel, Anal. Biochem. 87:562-565, 1978), lO ⁇ l vacuole extract or purified enzyme, and varying concentrations of inhibitor compound in a 40 ⁇ l final volume.
  • Late ring-stage cultures (10% parasitemia) were allowed to mature in the presence or absence of 10 ⁇ M inhibitor. At various time points, 24 ml aliquots of culture were harvested, brought to 1% Triton X-100, vortexed well, and centrifuged for 40,000 g-hours. The pellets were washed in water, then solubilized and heme content measured by the pyridine-hemochrome method (Slater and Cerami, Nature 355:167-169, 1992, incorporated herein by reference) .
  • the inhibitors to be tested were dissolved in DMSO.
  • the stock solutions were kept at -20°C.
  • Working solutions were prepared by diluting the stock solutions with DMSO.
  • the inhibitor, in l ⁇ l DMSO, was added to microtiter wells containing 250 ⁇ l medium to give a constant final concentration of 0.4% DMSO.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Biochemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Peptides Or Proteins (AREA)
  • Furan Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Cette invention concerne des composés d'inhibiteurs de la protéase 2,5-diolpentylamine qui sont efficaces comme inhibiteurs de la protéase aspartique du paludisme. Ces composés et les compositions contenant ces derniers sont efficaces pour traiter ou prévenir les infections provoquées par le paludisme.
PCT/US1995/000017 1994-01-25 1995-01-12 Inhibiteurs de la protease aspartique du paludisme Ceased WO1995019958A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP7519566A JPH09508365A (ja) 1994-01-25 1995-01-12 マラリア原虫アスパラギン酸プロテアーゼ阻害剤
EP95907965A EP0741696A1 (fr) 1994-01-25 1995-01-12 Inhibiteurs de la protease aspartique du paludisme
AU15968/95A AU1596895A (en) 1994-01-25 1995-01-12 Malarial aspartic protease inhibitors

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US18637994A 1994-01-25 1994-01-25
US08/186,379 1994-01-25

Publications (1)

Publication Number Publication Date
WO1995019958A1 true WO1995019958A1 (fr) 1995-07-27

Family

ID=22684720

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/US1995/000017 Ceased WO1995019958A1 (fr) 1994-01-25 1995-01-12 Inhibiteurs de la protease aspartique du paludisme

Country Status (6)

Country Link
EP (1) EP0741696A1 (fr)
JP (1) JPH09508365A (fr)
CN (1) CN1139427A (fr)
AU (1) AU1596895A (fr)
CA (1) CA2181551A1 (fr)
WO (1) WO1995019958A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0202577A2 (fr) * 1985-05-15 1986-11-26 G.D. Searle & Co. N-(acyldipeptidyl)-aminoglycols
EP0391179A2 (fr) * 1989-04-05 1990-10-10 F. Hoffmann-La Roche Ag Dérivés peptidiques d'acides aminés avec effet inhibiteur de la rénine
WO1992003429A1 (fr) * 1990-08-15 1992-03-05 Abbott Laboratories Inhibiteurs de la renine
US5229518A (en) * 1991-03-06 1993-07-20 Abbott Laboratories Isomerically pure 2-piperidone compounds
WO1994004172A1 (fr) * 1992-08-20 1994-03-03 Prototek, Inc. Inhibiteurs cetoniques actives par peptidyle et contenant des sequences peptidiques naturelles et non naturelles

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0202577A2 (fr) * 1985-05-15 1986-11-26 G.D. Searle & Co. N-(acyldipeptidyl)-aminoglycols
EP0391179A2 (fr) * 1989-04-05 1990-10-10 F. Hoffmann-La Roche Ag Dérivés peptidiques d'acides aminés avec effet inhibiteur de la rénine
WO1992003429A1 (fr) * 1990-08-15 1992-03-05 Abbott Laboratories Inhibiteurs de la renine
US5229518A (en) * 1991-03-06 1993-07-20 Abbott Laboratories Isomerically pure 2-piperidone compounds
WO1994004172A1 (fr) * 1992-08-20 1994-03-03 Prototek, Inc. Inhibiteurs cetoniques actives par peptidyle et contenant des sequences peptidiques naturelles et non naturelles

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
E. A. LUNNEY ET. AL.: "Analysis of Ligand Binding in Five Endothiapepsin Crystal Complexes and Their Use in the design and Evaluation of Novel Renin Inhibitors.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 36, no. 24, 26 November 1993 (1993-11-26), WASHINGTON US, pages 3809 - 20 *
M. W. HOLLIDAY ET. AL.: "Synthetic and Enzyme Inhibition studies of Pepstatin Analogues Containing Hydroxyethylene and Ketomethylene Dipeptide Isosteres.", JOURNAL OF MEDICINAL CHEMISTRY, vol. 30, no. 2, February 1987 (1987-02-01), WASHINGTON US, pages 374 - 83 *
W. R. BAKER ET. AL.: "dipeptide Isosteres. 2. Synthesis of Hydroxyethylene Dipeptide Isostere diastereomers from a Common gamma-Lactone Intermediate. Preparation of Renin and HIV-I Protease Inhibitor Transition State Mimics.", TETRAHEDRON, (INCL. TETRAHEDRON REPORTS), vol. 49, no. 39, 24 September 1993 (1993-09-24), OXFORD GB, pages 8739 - 56 *

Also Published As

Publication number Publication date
JPH09508365A (ja) 1997-08-26
EP0741696A1 (fr) 1996-11-13
CA2181551A1 (fr) 1995-07-27
AU1596895A (en) 1995-08-08
CN1139427A (zh) 1997-01-01

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