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EP0245361A1 - Nouveaux analogues de polypeptides inhibiteurs de renine contenant s-aryl-d-cysteinyle ou l-cysteinyle ou dl-cysteinyle, de l'acide 3-(arylthio) lactique ou des moities de 3-(arylthio)-alkyl - Google Patents

Nouveaux analogues de polypeptides inhibiteurs de renine contenant s-aryl-d-cysteinyle ou l-cysteinyle ou dl-cysteinyle, de l'acide 3-(arylthio) lactique ou des moities de 3-(arylthio)-alkyl

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Publication number
EP0245361A1
EP0245361A1 EP19860906653 EP86906653A EP0245361A1 EP 0245361 A1 EP0245361 A1 EP 0245361A1 EP 19860906653 EP19860906653 EP 19860906653 EP 86906653 A EP86906653 A EP 86906653A EP 0245361 A1 EP0245361 A1 EP 0245361A1
Authority
EP
European Patent Office
Prior art keywords
alkyl
amino
hydroxy
aryl
hydrogen
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Withdrawn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
EP19860906653
Other languages
German (de)
English (en)
Inventor
Ruth E. 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
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 Upjohn Co filed Critical Upjohn Co
Publication of EP0245361A1 publication Critical patent/EP0245361A1/fr
Withdrawn legal-status Critical Current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
    • 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

Definitions

  • the present Invention provides novel compounds. More particularly, the present invention provides novel renin-inhibiting peptide analogs. Most particularly, the present invention provides renin-inhibitory compounds having S-aryl-D- or L- or DL-cysteinyl, 3- (arylthio)lactic acid or 3- (arylthio)alkyl moieties at the 8 position (as compared to the renin substrate described below).
  • the renin inhibitors provided herein are useful for the diagnosis and control of renin-dependent hypertension.
  • Renin is an endopeptidase which specifically cleaves a particular peptide bond of its substrate (angiotensinogen), of which the N-terminal sequence in equine substrate is for example:
  • Renin cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II.
  • a number of angiotensin I converting enzyme inhibitors are known to be useful in che treatment of hypertension.
  • Inhibitors of renin are also useful in the treatment of hypertension.
  • INFORMATION DISCLOSURE A number of renin-inhibitory peptides have been disclosed. Thus, U.S. patent 4,424,207, and European published applications 45,665 and 104,041 disclose certain peptides with the dipeptide at the 10,11-position containing an isostere bond.
  • statine derivatives stated to be renin inhibitors have been disclosed, see, e.g., European published applications 77,028; 81,783; and 114,993; and U.S. patents 4,478,826; 4,470,971 and 4,479,941.
  • Terminal disulfide cycles have also been disclosed in renin inhibiting peptides; see, e.g., U.S. patents 4,477,440 and 4,477,441.
  • Aromatic and aliphatic amino acid residues at the 10,11 position of the renin substrate are disclosed in U.S. patent 4,478,827.
  • C-terminal amide cycles are disclosed in U.S. patent 4,485,099.
  • the present invention particularly provides a renin inhibitory peptide of the formula X-A 6 -B 7 -C 8 -D 9 -E 10 -F 11 -G 12 -H 13 -I 14 -Z, wherein X is
  • D 9 is absent or a divalent moiety of the formula XL 3 or
  • R 18 or R 19 is hydroxy, mercapto, or amino, or a monosubstituted nitrogen containing group bonded through the nitrogen only when n is not one;
  • R 12 is -(CH 2 ) n -R 13 and n is zero and both R 13 and R 15 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen;
  • R 25 is -(CH 2 ) n -R 13 and n is zero only when R 13 is other than a primary or secondary nitrogen-containing group hydroxy or mercapto group or when R 4 of -N(R 4 )R 14 is other than hydrogen;
  • R 17 or R 19 is -COOH only when n for that moiety is other than zero;
  • R 16 or R 17 is an amino-containing substituent, hydroxy, mercapto, or -Het bonded through the hetero atom only when n for that substituent is an integer from two to five, inclusive;
  • R 13 and R 15 cannot both be -COOH; or a carboxy-, amino-, or other reactive group-protected form or a pharmaceutically acceptable acid addition salt thereof.
  • the present invention provides peptide inhibitors of renin which contain modification of the Phe 8 (angiotensinogen numbering) position. These modifications involve the insertion of a heteroatomcontaining fragment into the side chain of the residue occupying the Phe 8 position. These changes in the normal Phe side chain result in dramatic changes in the overall length and size of the side chain.
  • the hetero-atom also alters the polarity, angles, and H-bonding ability of the side chain elements. Additionally, changes in the backbone may be made such as substitution of oxygen for nitrogen in the corresponding ⁇ -amino acid.
  • Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydroiodide, 2hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate, thiocyanate
  • 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 1o )cycloalkyl which include alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2, 2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2 , 2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof.
  • aryl examples include phenyl, naphthyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-mtolyl, (o-, m-, or p-)propylphenyl, 2-propyl- (o-, m-, or p-)tolyl, 4isopropyl-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-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4- , or 3,5-)
  • Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in - ormyl-indolyl, N in -C 2 -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, pyrazolidinyl, 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.
  • 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. These residues are depicted using standard amino acid abbreviations (see, e.g., Roberts, et al., Basic Principles of Organic Chemistry, pp. 703-705 (New York 1965)) unless otherwise indicated. All the renin-inhibiting compounds of the present invention may be administered in the conventional forms, such as disclosed in
  • the dosages of the present invention are for oral administration for treatment of humans to effect renin inhibition for the purpose of favorably affecting blood pressure.
  • the compounds are administered from 0.1 mg to 1000 mg per kg per dose, administered from 1 to 4 times daily. Equivalent dosages for other routes of administration are also employed.
  • the exact dose depends on the age, weight, and condition of the patient and on the frequency and route of administration. Such variations are within the skill of the practitioner or can readily be determined.
  • the compounds of the present invention may be pharmaceutically acceptable salts both those which can be produced from the free bases by methods well known in the art and those with which acids have pharmacologically acceptable conjugate bases.
  • the compounds of the present invention are preferably orally administered in the form of pharmacologically acceptable acid addition salts.
  • Preferred pharmacologically acceptable salts for oral administration include the citrate and aspartate salts, although any pharmacologically acceptable salt is useful in this invention, including those listed above. These salts may be in hydrated form.
  • the renin inhibiting polypeptides may be prepared by either polymer assisted or solution phase peptide synthetic procedures analogous to those described hereinafter or to those methods known in the art.
  • 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, peptide or polymer-bound peptide using a conventional coupling protocol such as dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) in methylene chloride or dimethylformamide.
  • DCC dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole
  • N ⁇ Boc moiety may be selectively removed with 45% trifluoroacetic acid/2% anisole (v/v) in methylene chloride. Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropylethylamine in methylenechloride.
  • this stepwise, coupling strategy may be partially or completely automated to provide the desired peptide-polymer intermediates. Anhydrous hydrofluoric acid treatment of the peptide-polymer intermediate may then be used to effect simultaneous protecting group removal and cleavage of the peptide from its polymeric support.
  • N in -formyl-indolyl-substituted peptides in which the N in -formyl-indolyl moiety Is stable to TFA or HF but may be removed by NH 3 or NaOH. Because FTrp is somewhat unstable to base in synthetic procedures, possibly causing lower yields, it may be desirable in solution phase synthesis to introduce the FTrp-contain ing moiety late in the synthetic sequence so that it is not exposed to such conditions.
  • N ⁇ n -formyl-Trp into compounds of the present invention is easily accomplished because of the commercial availability of N ⁇ -Boc-N in -formyl-Trp-OH.
  • the N in -formyl moiety may be introduced into indolyl-substituted amino acid derivatives or related compounds by reaction with HCl-formic acid as reported in the literature, see A. Previero et al, Biochim. BiophysActa 147, 453 (1967); Y.C.S. Yang et al, Int. J. Peptide Protein Res. 15, 130 (1980).
  • 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).
  • nitrogen protective groups include t-butoxycarbonyl (Boc), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like.
  • Boc-(R.S)-3-(phenylthio)alanylHis-LeuY[CH(OH)CH 2 ]Val-IIe-2-(amldomethyl)pyridine is shown in Chart B.
  • Boc-IIe and 2-(aminomethyl)pyridine are coupled using DCC in CH 2 Cl 2 and aq. NaHCO 3 to give B-3.
  • BocLeuY[CH(OTBDMS)-CH 2 ]Val-OH is coupled to He-AMP (AMP-2- (amidomethy1)pyridine) using DEPC (diethyl cyanophosphonate) and Et 3 N in CH 2 Cl 2 to give B-4.
  • the Boc group of B-4 is removed with TFA and CH 2 Cl 2 and the resulting TFA salt is neutralized by extraction with CH 2 Cl 2 and aq. NaHCO 3 .
  • LeuY[CH(OTBDMS)-CH 2 ]Val-IIe-AMP is coupled with BocHis(Tos)-0H using DEPC and Et 3 N in C H2 Cl 2 to give B-5.
  • the Boc group and tert-butyldimethylsilyl group of B-7 are removed with TFA and CH 2 Cl 2 .
  • the resulting TFA salt is neutralized via extraction with CH 2 Cl 2 and aq. NaHCO 3 to give B-6.
  • Compound B-6 is coupled with Boc(R,S)-3-(phenylthio)alanine using DCC in CH 2 Cl 2 .
  • the tosyl protecting group on the histidine side chain is removed with l-HOBT and MeOH to give the final product, B-7.
  • the mercaptide anion of cycloalkyl-SH or alkyl-SH (formed from , for instance, the commercially available mercaptan and NaOMe or NaH) is added to A-3 and carried through the sequences of Charts A and B to give compounds such as A-5 and B-7 in which cycloalkyl-S- and alkyl-S-replace arylS-.
  • Chart E outlines the synthesis of intermediates for the preparation of compounds of this invention wherein X is R 6 -(CH 2 ) i -C(O) -from known (commercially available) halo ester E-1 or halo ester E-3.
  • Halo ester E-1 is reacted with the mercaptide anion of R 6 SH to give thio ether E-2, which is hydrolyzed to give acid E-S.
  • halo acid E-3 is converted to a salt such as the sodium salt E-4 which is reacted with the anion of R 6 SH followed by acidification to give acid E-5.
  • E-5 may be incorporated into peptides of this invention, e.g., D-5.
  • DMF dimethylformamide
  • MsCl methanesulfonyl chloride
  • Et 3 N triethylamine
  • CH 2 Cl 2 methylene chloride
  • MeOH methanol
  • TFA trifluoroacetic acid
  • DEPC diethylcyanophosphonate
  • 1-HOBT 1-hydroxybenzotriazole
  • TBDMS tert-butyldimethylsilyl
  • Tos is p-toluenesulfonyl
  • His(Tos) is histidyl protected on the imidazole nitrogen with Tos,
  • THF is tetrahydrofuran
  • AMP is (2-pyridinyl)methylamino
  • DCC is dicyclohexylcarbodiimide
  • NaHCO 3 is sodium bicarbonate
  • Na 2 SO 4 is sodium sulfate.
  • Mass spec m/z at 297 (theory , 297) .
  • Chart B (B-1 + B- 2 to B- 3) .
  • Boc-IIe-AMP (1.60 g, 4.98 mmoles) and 50% TFA-CH 2 Cl 2 (20 ml) is stirred for 30 minutes, after which TFA and CH 2 Cl 2 are removed in vacuo. The residue is exhustively extracted with CH 2 Cl 2 and aq. NaHCO 3 . The organic layers are filtered through Na 2 SO 4 and taken to dryness.
  • reaction is extracted with CHCl 3 and aq. NaHCO 3 and the organic layers are filtered through Na 2 SO 4 and concentrated. CH 2 Cl 2 and hexane are added to the residue and, after cooling in the refrigerator, the solvent is decanted. The remaining solid is stirred for 40 hours with 0.031 g of 1-HOBT in 30 ml of MeOH and 5 ml of CH 2 Cl 2 .

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  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
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Abstract

Nouveaux peptides inhibiteurs de rénine ayant comme formule X-A6-B5-C8-D9-E10-F11-G12-H13-I14-Z, où X et Z sont des groupes terminaux, C8 contient S-aryl-D-cystéinyle ou L-cystéinyle ou DL-cystéinyle, de l'acide 3-(arylthio)lactique et des moitiés de 3-(arylthio)alkyle, les variables restantes étant des résidus d'acides aminés. Ces inhibiteurs sont utiles pour le diagnostic et la régulation de l'hypertension dépendant de la rénine.
EP19860906653 1985-11-15 1986-10-21 Nouveaux analogues de polypeptides inhibiteurs de renine contenant s-aryl-d-cysteinyle ou l-cysteinyle ou dl-cysteinyle, de l'acide 3-(arylthio) lactique ou des moities de 3-(arylthio)-alkyl Withdrawn EP0245361A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US79845985A 1985-11-15 1985-11-15
US798459 1991-11-26

Publications (1)

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EP0245361A1 true EP0245361A1 (fr) 1987-11-19

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EP19860906653 Withdrawn EP0245361A1 (fr) 1985-11-15 1986-10-21 Nouveaux analogues de polypeptides inhibiteurs de renine contenant s-aryl-d-cysteinyle ou l-cysteinyle ou dl-cysteinyle, de l'acide 3-(arylthio) lactique ou des moities de 3-(arylthio)-alkyl

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EP (1) EP0245361A1 (fr)
JP (1) JPS63501364A (fr)
WO (1) WO1987002986A1 (fr)

Families Citing this family (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5268374A (en) * 1988-10-04 1993-12-07 Abbott Laboratories Non-peptide renin inhibitors
US5164388A (en) * 1988-10-19 1992-11-17 Abbott Laboratories Heterocyclic peptide renin inhibitors
US5212157A (en) * 1989-06-06 1993-05-18 Bio-Mega, Inc. Enzyme inhibitors
US5126326A (en) * 1989-06-06 1992-06-30 Bio-Mega, Inc. Enzyme inhibiting peptide derivatives
US5643878A (en) * 1991-09-12 1997-07-01 Ciba-Geigy Corporation 5-amino-4-hydroxyhexanoic acid derivatives
TW217410B (fr) * 1992-04-01 1993-12-11 Ciba Geigy
ATE343562T1 (de) 2000-03-23 2006-11-15 Elan Pharm Inc Verbindungen und verfahren zur behandlung der alzheimerschen krankheit
PE20020276A1 (es) 2000-06-30 2002-04-06 Elan Pharm Inc COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER
EP1299352B1 (fr) 2000-06-30 2005-12-28 Elan Pharmaceuticals, Inc. Composes pour traiter la maladie d'alzheimer
US6846813B2 (en) 2000-06-30 2005-01-25 Pharmacia & Upjohn Company Compounds to treat alzheimer's disease
US6982264B2 (en) 2001-06-27 2006-01-03 Elan Pharmaceuticals, Inc. Substituted alcohols useful in treatment of Alzheimer's disease

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AU537592B2 (en) * 1979-04-02 1984-07-05 E.R. Squibb & Sons, Inc. Mercaptoacyldipeptides
EP0114993B1 (fr) * 1982-12-27 1990-05-16 Merck & Co. Inc. Tripeptides, inhibiteurs de rénine
AU573735B2 (en) * 1983-02-07 1988-06-23 Aktiebolaget Hassle Peptide analogue enzyme inhibitors
US4613676A (en) * 1983-11-23 1986-09-23 Ciba-Geigy Corporation Substituted 5-amino-4-hydroxyvaleryl derivatives
US4661473A (en) * 1984-03-27 1987-04-28 Merck & Co., Inc. Renin inhibitors containing peptide isosteres
US4663310A (en) * 1984-04-04 1987-05-05 Merck & Co., Inc. Renin inhibitors containing 2-substituted statine
EP0486478A3 (en) * 1984-08-06 1992-08-12 The Upjohn Company Renin-inhibiting peptides

Non-Patent Citations (1)

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Title
See references of WO8702986A1 *

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WO1987002986A1 (fr) 1987-05-21
JPS63501364A (ja) 1988-05-26

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