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WO1988004664A2 - Peptides inhibiteurs de la renine ayant une partie epoxide ou glycol - Google Patents

Peptides inhibiteurs de la renine ayant une partie epoxide ou glycol Download PDF

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Publication number
WO1988004664A2
WO1988004664A2 PCT/US1987/003007 US8703007W WO8804664A2 WO 1988004664 A2 WO1988004664 A2 WO 1988004664A2 US 8703007 W US8703007 W US 8703007W WO 8804664 A2 WO8804664 A2 WO 8804664A2
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formula
amino
hydrogen
absent
alkyl
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PCT/US1987/003007
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English (en)
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WO1988004664A3 (fr
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Suvit Thaisrivongs
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The Upjohn Company
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Priority to JP88501531A priority Critical patent/JPH02501140A/ja
Publication of WO1988004664A2 publication Critical patent/WO1988004664A2/fr
Publication of WO1988004664A3 publication Critical patent/WO1988004664A3/fr

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    • 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
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/04—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C07D263/06—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hydrocarbon radicals, substituted by oxygen atoms, attached to ring carbon 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
    • C07D295/18—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 carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/185—Radicals derived from carboxylic acids from aliphatic carboxylic acids
    • 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
    • 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
    • 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 renin inhibitory peptides and intermediates thereto . Most particularly, the present invention provides renin- inhibitory peptides containing C- terminus truncated epoxy or azido or cyano groups or containing a position 10- ll diol and a position 11-12 retro bond as compared to the renin substrate . These renin- inhibitory peptides are useful for the diagnosis and control of renin- dependent hypertension. The present invention further provides novel transition- state analogue inserts which are useful as intermediates to renin- inhibitory peptides .
  • 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 substrate has a different sequence as recently discovered by D .A. Tewkesbury et al . , Biochem. Biophys . Res . Comm. 99 , 1311 (1981) . It may be represented as follows : Renin
  • 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 the treatment of hypertension.
  • Inhibitors of renin are also useful in the treatment of hypertension.
  • E.P. 189,203 discloses new N-dihydroxyalkyl peptide derivatives which are useful as inhibitors of renin for treating hypertension.
  • E.P. 184,855 discloses new hydroxy substituted-statine peptide derivatives which are useful as inhibitors of renin for treating hypertension.
  • the present invention particularly provides: A renin inhibitory peptide of the formula I
  • N-proline-Y-R 6 N-proline-Y-R 6 ; wherein m is one or two; wherein for each occurrence n Is independently an integer of zero to five, inclusive; wherein p is zero to 2, inclusive; wherein q is 1 to 5, inclusive; wherein Q Is
  • the present invention provides peptide inhibitors of renin which contain right-hand-terminating epoxy or azido or cyano groups or containing a position 10-11 diol and a position 11-12 retro bond as compared to the renin substrate.
  • Examples of pharmaceutically acceptable acid addition salts include: acetate, adipate, alginate, aspartate, benzoate, benzenesulf onate, bisulfate, butyrate, citrate, camphorate, camphorsulfonate, cyclopentanepropionate, dlgluconate, dodecylsulf ate, ethanesulf onate, fumarate, glucoheptanoate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide, hydro iodide, 2- hydroxyethanesulf onate, lactate, maleate, me thanesulf onate, 2- naphthalenesulf onate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate
  • 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, 2,2-dimethylcyclopropyl, 2,3- diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methyl- cyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof.
  • aryl examples include phenyl, naphthyl, (o-, m-, or p-)tolyl, (o-, m-, or p-)ethylphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyI, 5- ethyl-m-tolyl, (o-, m-, or p-)propylphenyl, 2-ppropyl-(o-, m-, or p-)tolyl, 4-isopropyI-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-,
  • 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, pyrrollnyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, qui
  • 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. These residues are depicted using standard amino acid abbreviations (see, e.g., IUPAC-IUB Joint Commission on Biochemical Nomenclature (JCBN) , "Nomenclature and Symbolism for Amino Acids and Peptides," Eur. J. Biochem. 138:9-37 (1984) unless otherwise indicated.
  • JCBN IUPAC-IUB Joint Commission on Biochemical Nomenclature
  • the renin inhibitors of this invention are useful for treating any medical condition-for which it is beneficial to reduce the levels of active circulating renin.
  • examples of such conditions include renin-dependent hypertension, hypertension, hypertension under treatment with another antihypertensive and/or a diuretic agent, congestive heart failure, renin-dependent hyperaldosterism, angina, post-myocardial infarction and other renin-dependent cardiovascular disorders.
  • the renin-angiotension system may play a role in maintenance of Intracellular homeostasls: see Clinical and Experimental Hypertension, 86, 1739-1742 (1984) at page 1740 under Discussion.
  • the compounds of the present invention are preferably orally administered to 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 in the form of 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 or solvated form.
  • the compounds of the present invention may be administered 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 pharmaceutical compositions may be in the form of a sterile injectable preparation, for example as a sterile injectable aqueous or oleagenous suspension.
  • This suspension may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1,3- butanediol.
  • the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the peptides of this invention 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 nonirritating 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 nonirritating 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 renin-inhibiting compounds of this invention may be administered in combination with other agents used in antihypertensive therapy such as diuretics, o and/or ⁇ -adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and the like as described for example in published European patent application 156,318.
  • agents used in antihypertensive therapy such as diuretics, o and/or ⁇ -adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and the like as described for example in published European patent application 156,318.
  • the present invention is also directed to combinations of the novel renin-inhibitory peptides of Formula I with one or more antihypertensive agents selected from the group consisting of diuretics, ⁇ and/or ⁇ -adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and other antihypertensive agents.
  • one or more antihypertensive agents selected from the group consisting of diuretics, ⁇ and/or ⁇ -adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and other antihypertensive agents.
  • the compounds of this invention can be given in combination with such compounds or salt or other derivative forms thereof as: Diuretics: acetazolamide; amlloride; bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; i ⁇ dacrinone (racemic mixture, or as either the (+) or (-) enantlomer alone, or a manipulated ratio, e.g., 9:1 of said enantiomers, respectively); metolazone; methyclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironolactone; ticrynaten; trimaterene; trichlormethiazide; ⁇ -Adrene
  • Angiotensin I Converting Enzyme Inhibitors 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline (captopril); (1-(4-ethoxycarbonyl-2,4(R,R)-dimethylbutanoyl)indoline-2(S)-carboxylic acid);
  • the individual daily dosages for these combinations can range from, about one-fifth of the minimally recommended clinical dosages to the maximum recommended levels for the entities when they are given singly.
  • Coadministration is most readily accomplished by combining the active ingredients into a suitable unit dosage form containing the proper dosages of each. Other methods of coad ministration are, of course, possible.
  • novel peptides of the present invention possess an excellent degree of activity in treating renin-associated hypertension and hyperaldosteronlsm.
  • the compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples.
  • Chart A Chart A describes the preparation of compounds which are useful as intermediates for the preparation of renin inhibitory peptides.
  • Chart B Chart B describes the incorporation of amino acids into the compound of formula A-3 of Chart A.
  • the compound of formula B-1 (A-3) is deprotected with acidic methanol to the corresponding free amine which is coupled to Boc- His(Ts)-OH to give an epimeric mixture.
  • the mixture is separated into the compounds of formulas B-2A and B-2B.
  • the stereochemistry at the hydroxyl group at C-2 has not been assigned.
  • the compound of formula B-2A Is deprotected and the resulting amine coupled to Boc- Phe-OH to give the compound of formula B-3A.
  • Chart C describes the preparation of the acid of formula C-4. Diastereoselective alkylation of the known dianion of the diester of formula C-1 with 1-bromomethylnaphthalene gives the compound of formula C-2. Selective ester hydrolysis, followed by amide formation with morpholine, gives the ester of formula C-3. Hydrolysis of the ester then affords the acid of formula C-4. Chart D
  • Chart D describes the preparation of a representative renininhibitory peptide of formula D-4.
  • the compound of formula D-1 (B-3A) is hydrogenolyzed to the amine of formula D-2. Reaction with isopropylisocyanate gives the compound of formula D-3. Removal of the tosyl group affords the peptide of formula D-4.
  • Chart E Chart E describes the preparation of the compound of formula E-2 and its incorporation into a representative renin-inhibitory peptide.
  • the epimeric epoxides of formula E-1 (A-2) are opened with cyanide to give a mixture of nitriles of formula E-2.
  • the mixture is then deprotected with acidic methanol to give the corresponding free amine which is coupled to Boc-His(Ts)-OH to give an epimeric mixture.
  • the mixture is separated into the compounds of formulas E-3A and E- 3B.
  • the assignment of stereochemistry of the C-3 hydroxyl group is tentative.
  • Compound E-3A is deprotected with trifluoroacetic acid in dichloromethane.
  • the corresponding free amine is coupled to Boc-Phe- OH to give the compound of formula E-4A. Removal of the tosyl group affords the renin-inhibitory peptide of formula E-5A.
  • Chart F describes the incorporation of the acid of formula C-4 of Chart C into a representative renin-inhibitory peptide of formula F-3.
  • renin-inhibitory peptides of this invention can be prepared according to the processes of these charts by using different amino acids known in the art.
  • 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 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 dicyclohexylcarbodiimide and 1-hydroxybenzotriazole or diethylphosphoryl cyanide and trialkylamine in methylene chloride or dimethylformamide.
  • a conventional coupling protocol such as dicyclohexylcarbodiimide and 1-hydroxybenzotriazole or diethylphosphoryl cyanide and trialkylamine in methylene chloride or dimethylformamide.
  • 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.
  • N in -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 hydrochloric-formic acid as reported in the literature, see A. Previero et al, Biochim. Biophys. Acta 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.V. 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 an G. Benzlin, Organic Synthesis, Verlag Chemie (1983).
  • nitrogen protective groups are t-butoxycarbonyl (Boc), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl an the like.
  • 1H-NMR is proton nuclear magnetic resonance ( ⁇ is relative to tetramethylsilane); 1 3 C-NMR is carbon-13 nuclear magnetic resonance; BOC is t-butoxycarbonyl; C is centigrade;
  • CDCl 3 is deuteriochloroform
  • Celite is a filter aid
  • g grams
  • His is histidine
  • IR infrared spectra
  • M or mol is mole
  • min is minute
  • ml is milliliter
  • FAB HRMS is fast-atom bombardment high-resolution mass spectroscopy
  • Phe is phenylalanine
  • Ts is p-toluenesulfonyl.
  • the wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon.
  • the dotted line indicates a bond which extends below the plane of the paper relative to the plane of the compound thereon.
  • the aqueous phase is extracted with four portions of dichloromethane. The combined organics are dried (magnesium sulfate), filtered and concentrated. The residue is purified by flash chromatography on silica gel using 5% ethyl acetate in hexane to afford 2.7 g of the title product as a mixture of isomers.
  • the peptide of formula B-2A of Preparation 3, 193.9 mg, is dissolved in 1.0 ml of dichloromethane and 1.0 ml of trifluoroacetic acid. After 45 min at room temperature, the reaction mixture is slowly pipetted into a stirred solution containing 1.5 g of solid sodium bicarbonate in 15 ml of water. After 10 min, the aqueous phase is extracted with five portions of dichloromethane. The combined organic phases are dried (magnesium sulfate), filtered and concentrated to afford 150.4 mg of the free amine.
  • the reaction mixture is flushed with nitrogen and evacuated several times, and then filled with hydrogen to an initial pressure of 55 psi.
  • the reaction mixture is hydrogenated on a Parr shaker overnight.
  • the reaction mixture is filtered through a pad of Celite.
  • the catalyst is washed with several portions of methanol.
  • the filtrate is concentrated and the residue is purified on 11 g of silica gel using 7% methanol saturated with ammonia in dichloromethane to afford 58.2 mg of the title product.
  • Chart E By the same procedure as in the preparation of the compounds of formula B-3A of Preparation 4, 95.1 mg of the compound of formula E- 3A of Preparation 11 is treated with trifluoroacetic acid and dichloromethane to give the free amine.
  • Priority Country US (81) Designated States: AT (European patent), AU, BE ( ropean patent), CH (European patent), DE (Eu pean patent), DK, FI, FR (European patent),
  • the present invention furt provides novel transition-state analogue inserts which are useful as intermediates for the preparation of renin-inhibit peptides.

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Abstract

La présente invention fournit de nouveaux peptides inhibiteurs de la rénine de formule X-A6-B7-C8-D9-E10-F11 et contenant des groupes époxy ou azido ou cyano tronqués en C terminal ou qui contiennent un diol en position 10-11 et une rétroliaison en position 11-12. La présente invention fournit de nouveaux inserts analogues à l'état de transition qui sont utiles comme intermédiaires dans la préparation des peptides inhibiteurs de la rénine.
PCT/US1987/003007 1986-12-22 1987-11-23 Peptides inhibiteurs de la renine ayant une partie epoxide ou glycol WO1988004664A2 (fr)

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JP88501531A JPH02501140A (ja) 1986-12-22 1987-11-23 エポキシドまたはグリコール基を有するレニン‐抑制ペプチド

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US94534086A 1986-12-22 1986-12-22
US945,340 1986-12-22

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WO1988004664A2 true WO1988004664A2 (fr) 1988-06-30
WO1988004664A3 WO1988004664A3 (fr) 1988-08-11

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006996A1 (fr) * 1990-10-10 1992-04-30 The Upjohn Company Peptides contenant des 1,4-diamines substituees comme segments d'insertion a l'etat de transition

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0173481A3 (fr) * 1984-08-06 1988-12-21 The Upjohn Company Peptides
DK34086A (da) * 1985-01-23 1986-07-24 Abbott Lab Peptidylaminodioler

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1992006996A1 (fr) * 1990-10-10 1992-04-30 The Upjohn Company Peptides contenant des 1,4-diamines substituees comme segments d'insertion a l'etat de transition

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WO1988004664A3 (fr) 1988-08-11
AU1243888A (en) 1988-07-15
JPH02501140A (ja) 1990-04-19
EP0344189A1 (fr) 1989-12-06

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