WO1990012804A2 - Peptides avec des groupes n-terminaux polaires - Google Patents

Peptides avec des groupes n-terminaux polaires Download PDF

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Publication number
WO1990012804A2
WO1990012804A2 PCT/US1990/001764 US9001764W WO9012804A2 WO 1990012804 A2 WO1990012804 A2 WO 1990012804A2 US 9001764 W US9001764 W US 9001764W WO 9012804 A2 WO9012804 A2 WO 9012804A2
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WO
WIPO (PCT)
Prior art keywords
methyl
amino
carbonyl
phe
hydroxy
Prior art date
Application number
PCT/US1990/001764
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English (en)
Other versions
WO1990012804A3 (fr
Inventor
Suvit Thaisrivongs
Original Assignee
The Upjohn Company
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 The Upjohn Company filed Critical The Upjohn Company
Priority to KR1019900702636A priority Critical patent/KR920700221A/ko
Publication of WO1990012804A2 publication Critical patent/WO1990012804A2/fr
Publication of WO1990012804A3 publication Critical patent/WO1990012804A3/fr

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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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention provides novel compounds. More particularly, the present invention provides novel peptide analogs. Most particularly, the. present invention provides peptides containing a non-cleavable transition state insert corresponding to the 10,11- position of the renin substrate (angiotensinogen) and containing a novel polar group at the N-terminus of the peptide. These peptides are useful as renin inhibitors and as inhibitors of retroviral proteases. Renin inhibitors are useful for the diagnosis and control of renin-dependent hypertension, congestive heart failure, renindependent hyperaldosterism, and other renin-dependent cardiovascular disorders. Inhibitors of retroviral proteases, such as the HIV-I protease, are useful for treating diseases caused by retroviruses, such as human acquired immunodeficiency syndrome (AIDS).
  • AIDS human acquired immunodeficiency syndrome
  • U.S. Patent 4,613,676 discloses certain substituted 5-amino-4- hydroxy valeryl derivatives, having 2 amino acid residues between the hydrogen or acyl N-terminus and the transition state moiety.
  • a broad class of acyl substituents, including hydroxy-substituted alkyl and etherified sugar moieties, are disclosed.
  • U.K. Patent Application GB 2200115-A discloses renin inhibitory peptides having a sugar moiety at the N- terminus attached through an ether linkage.
  • peptides are useful as renin inhibitors and as inhibitors of retroviral proteases.
  • the present invention provides novel peptides having polar functionalities at the N-terminus.
  • the following N-terminal groups are preferred: 7-glutamic acid, ⁇ -valine and phosphoric acid. These peptides have increased water solubility and improved ADME characteristics (for example, adsorption and excretion).
  • 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.
  • the peptides of the present invention may be administered topically, parenterally, by inhalation spray, or rectally in dosage unit formulations containing conventional non- toxic pharmaceutically acceptable carriers, adjuvants and vehicles.
  • parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques.
  • the compounds of the invention are effective in the treatment of humans.
  • the peptides of this invention for renin inhibition may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • the compounds of this invention can be given in combination with such compounds or salt or other derivative forms thereof as:
  • 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) 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 occur- rence of a second symptomatic AIDS defining infection indicates alternate therapy is needed.
  • 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 renin inhibitory peptides of the present invention having ⁇ - Val as the polar N-terminal group are prepared and assembled using standard procedures known in the peptide art similar to that described in Chart A.
  • the synthesis of BOC- ⁇ -valine from ethyl 3,3- dimethylacrylate is described in Chart F below.
  • the peptides of the present invention which contain Cha-Val alcohol as the transition state insert, are prepared in a fashion exactly analogous to their LVA counterparts.
  • the synthesis of Cha-Val alcohol is described in PCT Patent Application, Serial No. PCT/US89/00247 , filed 27 January 1989, which is hereby incorporated by reference.
  • Chart G further illustrates the preparation of renin inhibitory peptides having ⁇ -Val as the polar N- terminal group.
  • the peptide of formula G-1 wherein R 30 is Ile-AMP is prepared as described in PCT patent application, Serial No. PCT/US88/03436, filed 11 October 1988, which is hereby incorporated by reference.
  • the peptide of formula G-1 wherein R 30 is Mba is prepared by procedures analogous to those described in PCT patent application, Serial No. PCT/US88/03436, filed 11 October 1988.
  • the appropriate peptide is coupled with BOC- ⁇ -Valine to give the compound of formula G-2 and then deprotected to give the compound of formula G-3, using standard procedures known in the art.
  • Treatment of the compound of formula G-3 with trifluoroacetic acid (TFA) effects removal of the BOC group to give the final peptide of formula G-4.
  • TFA trifluoroacetic acid
  • 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 dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylamine (Et3N) in methylene chloride or dimethylformamide.
  • DCC dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole
  • DEPC diethylphosphoryl cyanide
  • Et3N 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).
  • AMP is 2-(aminomethyl)pyridinyl
  • FTrp is N in- formyl-Trp
  • N-MeHis is N ⁇ -methyl histidine
  • MPLC medium pressure liquid chromatography
  • Phe is phenylalanine
  • Sta is statine
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • Tyr is tyrosine
  • the dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon.
  • renin inhibitory activity of the peptides of the present invention are determined using the in vitro test described in U.S. patent application, Serial No. 07/07/147,073, filed 20 January 1988, and in published European patent application 0173481, published 5 March 1986, pages 103-105, which are hereby incorporated by reference.
  • the in vitro IC 50 is measured in nanomolars.
  • Compounds of the present invention have also exhibited renin- inhibitory activity during in vivo testing.
  • Ethyl dimethylaerylate (641 mg) is dissolved in 10 ml of a saturated ethanolic solution of ammonia.
  • the solution is contained in a thick-walled glass vessel which is sealable by means of a Teflon Ace-thread plug.
  • the solution Is cooled to -15° in an ice-salt bath and re-saturated with ammonia from a lecture bottle.
  • the tube is sealed and heated behind a safety shield to 80. After 22 hours, the tube is cooled, and the bulk of the ammonia purged out with nitrogen. Removal of the remaining solvent under reduced pressure affords 645 mg of the title product, which is contaminated with a small amount of starting material.
  • L-Lysine N6-[N-[6-cyclohexyl-5-[[N[(l-L-7-glutamyl-L-prolyl)-L- phenylalanyl]-N-methyl-L-histidyl]amino]-4-hydroxy-2-(1-methyl- ethyl)-1-oxohexyl]-L-isoleucyl], [2S-(2R*,4R*,5R*)]-, tris(trifluoroacetate) (salt).
  • FAB-HRMS (m + H) + at 1037.642.
  • (22) ⁇ -Glu-Pro-Phe-N-MeHis-CVA-NH(CH 2 ) 4 CH(COOH)(NH 2 ) or L-Histidinamide, L- ⁇ -glutamyl-L-prolyl-L-phenylalanyl-N-[4-[[(5-amino- 5-carboxypentyl)amino]carbonyl]-1-(cyclohexylmethyl)-2-hydroxy- 5-methylhexyl]-N ⁇ -methyl-, [IS-[1R*,2R*,4R*(R*)]]-, tris(trifluoro- acetate) (salt).
  • FAB-HRMS (m + H) + at 870.5806. (34) ⁇ -Val-Phe-NC(CH 3 )His-CVA-Ile-NH(CH 2 ) 4 CH(COOH)(NH 2 ) or L-Lysine, N6- [N- [5- [ [N- [N- (3-amino-3-methyl-1-oxobutyl)-L-phenylalanyl]-N-methyl-L-histidyl]amino]-6-cyclohexyl-4-hydroxy-2-(1- methylethyl)-1-oxohexyl]-L-isoleucyl]-, [2S-(2R*,4R*,5R*)]-, tris- (trifluoroacetate) (salt) .

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Public Health (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Virology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

Peptides à insert à état transitoire non clivable correspondant à la position 10,11 du substrat rénine (angiotensinogène) et comportant un groupe polaire nouveau, correspondant à la formule (L1), où X1 est H2N-, H2NC(CH3)2-, HO2C-, (H2N)(HO2C)CH- ou (HO)2P(O)O-, à la terminaison N du peptide. Ces peptides sont utiles en tant qu'inhibiteurs de rénine et en tant qu'inhibiteurs de protéases rétrovirales. Les inhibiteurs de rénine sont utiles pour diagnostiquer et surveiller l'hypertension due à la rénine, les insuffisances cardiaques, l'hyperaldostéronisme dû à la rénine, et d'autres troubles cardiovasculaires et troubles de la vue dus à la rénine. Les inhibiteurs des protéases rétrovirales, comme la protéase HIV-I, sont utiles pour traiter des maladies provoquées par des rétrovirus, comme le SIDA.
PCT/US1990/001764 1989-04-18 1990-04-05 Peptides avec des groupes n-terminaux polaires WO1990012804A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
KR1019900702636A KR920700221A (ko) 1989-04-18 1990-04-05 극성 n-말단기들을 갖는 신규 리닌 억제인자 펩티드

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US33975089A 1989-04-18 1989-04-18
US339,750 1989-04-18

Publications (2)

Publication Number Publication Date
WO1990012804A2 true WO1990012804A2 (fr) 1990-11-01
WO1990012804A3 WO1990012804A3 (fr) 1990-11-29

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PCT/US1990/001764 WO1990012804A2 (fr) 1989-04-18 1990-04-05 Peptides avec des groupes n-terminaux polaires

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EP (1) EP0468998A1 (fr)
JP (1) JPH04504716A (fr)
KR (1) KR920700221A (fr)
AU (1) AU5407190A (fr)
WO (1) WO1990012804A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993006127A1 (fr) * 1991-09-17 1993-04-01 Warner-Lambert Company Nouveaux inhibiteurs de renine a base de promedicaments a acides amines
WO1993019059A1 (fr) * 1992-03-25 1993-09-30 Pfizer Limited Peptides antiviraux
US5424426A (en) * 1992-05-14 1995-06-13 Bayer Aktiengesellschaft Dithiolanylglycine-containing HIV protease inhibitors of the hydroxyethylene isostere type
US5430151A (en) * 1991-08-10 1995-07-04 Bayer Aktiengesellschaft Trifluoromethyl-containing pseudopeptides active against retroviruses
US5554728A (en) * 1991-07-23 1996-09-10 Nexstar Pharmaceuticals, Inc. Lipid conjugates of therapeutic peptides and protease inhibitors

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6071895A (en) * 1992-03-11 2000-06-06 Narhex Limited Polar-substituted hydrocarbons
DE69333270T2 (de) 1992-03-11 2004-08-05 Narhex Ltd. Aminderivate von oxo- und hydroxy- substituierten kohlenwasserstoffen
RU2126794C1 (ru) * 1992-03-11 1999-02-27 Нархекс Лимитед Аминопроизводные оксо- или гидроксизамещенных гидразинов, способ их получения и фармацевтические композиции для ингибирования ретровирусной протеазы
US5888992A (en) * 1992-03-11 1999-03-30 Narhex Limited Polar substituted hydrocarbons

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0104041A1 (fr) * 1982-09-15 1984-03-28 Aktiebolaget Hässle Inhibiteurs d'enzyme
DE3830825A1 (de) * 1987-09-15 1989-03-23 Sandoz Ag Hydrophile reninhemmer, ihre herstellung und verwendung
EP0312157A2 (fr) * 1987-10-13 1989-04-19 Merck & Co. Inc. Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0104041A1 (fr) * 1982-09-15 1984-03-28 Aktiebolaget Hässle Inhibiteurs d'enzyme
DE3830825A1 (de) * 1987-09-15 1989-03-23 Sandoz Ag Hydrophile reninhemmer, ihre herstellung und verwendung
EP0312157A2 (fr) * 1987-10-13 1989-04-19 Merck & Co. Inc. Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Peptides - Chemistry and Biology - Proceedings of the Tenth American Peptide Symposium, 23-28 May 1987, St. Louis, Missouri, US, edited by G.R. Marshall, published by ESCOM, (Leiden, NL), D.J. KEMPF et al.: "Renin Inhibitors based on Novel Dipeptide Analogs: Increased Efficacy through Systematic Inclusion of Polar Functionality", pages 474-475 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5554728A (en) * 1991-07-23 1996-09-10 Nexstar Pharmaceuticals, Inc. Lipid conjugates of therapeutic peptides and protease inhibitors
US5430151A (en) * 1991-08-10 1995-07-04 Bayer Aktiengesellschaft Trifluoromethyl-containing pseudopeptides active against retroviruses
WO1993006127A1 (fr) * 1991-09-17 1993-04-01 Warner-Lambert Company Nouveaux inhibiteurs de renine a base de promedicaments a acides amines
WO1993019059A1 (fr) * 1992-03-25 1993-09-30 Pfizer Limited Peptides antiviraux
US5424426A (en) * 1992-05-14 1995-06-13 Bayer Aktiengesellschaft Dithiolanylglycine-containing HIV protease inhibitors of the hydroxyethylene isostere type

Also Published As

Publication number Publication date
JPH04504716A (ja) 1992-08-20
AU5407190A (en) 1990-11-16
WO1990012804A3 (fr) 1990-11-29
KR920700221A (ko) 1992-02-19
EP0468998A1 (fr) 1992-02-05

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