EP0468998A1 - Peptides avec des groupes n-terminaux polaires - Google Patents

Peptides avec des groupes n-terminaux polaires

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Publication number
EP0468998A1
EP0468998A1 EP90905979A EP90905979A EP0468998A1 EP 0468998 A1 EP0468998 A1 EP 0468998A1 EP 90905979 A EP90905979 A EP 90905979A EP 90905979 A EP90905979 A EP 90905979A EP 0468998 A1 EP0468998 A1 EP 0468998A1
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EP
European Patent Office
Prior art keywords
methyl
amino
carbonyl
phe
hydroxy
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Withdrawn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
EP90905979A
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German (de)
English (en)
Inventor
Suvit Thaisrivongs
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Pharmacia and Upjohn Co
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Upjohn Co
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Publication date
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Publication of EP0468998A1 publication Critical patent/EP0468998A1/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
  • Renin I is an endopeptidase which specifically cleaves a par- ticular peptide bond of its substrate (angiotensinogen), of which the N-terminal sequence in equine substrate is for example:
  • Human 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 cleaves angiotensinogen to produce angiotensin I, which is converted to the potent pressor angiotensin II.
  • a number of an giotensin 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.
  • 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. patents 4,478,827 and 4,455,303.
  • C-terminal amide cycles are disclosed in U.S. patent 4,485,099 and European published applications 156,320 and 156,318.
  • Certain tetrapeptides are disclosed in European publications 111,266 and 77,027. Further, European pub- lished application No.
  • Isosteric bond modifications at positions 11-12 and 12-13 have been disclosed in European published application 179,352.
  • Certain peptides containing 2-substituted statine analogues have been disclosed in European published application 157,409.
  • Certain peptides containing 3-aminodeoxystatine have been disclosed in European published application 161,588.
  • Certain peptides containing 1-amino-2-hydroxybutane derivatives at positions 10-11 have been disclosed in European published application 172,346.
  • Certain peptides containing 1-amino-2-hydroxypropane derivatives at positions 10-11 have been disclosed in European published application 172,347.
  • Certain peptides containing N- terminal amide cycles have been disclosed in U.S. patent application, Serial No. 844,716, filed 27 March 1986.
  • Certain peptides containing dihalostatine have been disclosed in PCT application, Serial No. 000,713, filed 7 April 1986.
  • 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.S. Patent 4,729,985 discloses renin inhibitors having a protecting group with a molecular weight less than 500, including, e.g., a (tris-hydroxy)-(t-butyluriedo).
  • U.S. Patent 4,668,770 generically discloses renin inhibitory tripeptides having a poly-hydroxy group at the C-terminus.
  • U.K. Patent Application GB 2200115-A discloses renin inhibitory peptides having a sugar moiety at the N- terminus attached through an ether linkage.
  • the present invention particularly provides:
  • n is one to five, inclusive.2
  • peptides are useful as renin inhibitors and as inhibitors of retroviral proteases.
  • renin inhibitory peptide is meant a compound capable of inhibiting the renin enzyme in mammalian metabolism and having three or more amino acid residues linked by peptidic or pseudo-peptidic bonds.
  • a non-cleavable transition state insert is meant a transition state insert which is not cleavable by a hydrolytic enzyme in mammalian metabolism.
  • a variety of such transition state inserts, corresponding to the 10,11-position of the renin substrate, are known in the art, including those disclosed in the following references, which are hereby incorporated by reference:
  • polyhydroxy-substituted-alkyl moiety is meant a cyclic or acyclic, branched or unbranched alkyl derivative having from three to nine carbon atoms and from two to eight hydroxyl substituents which are attached to the C-terminus of the renin inhibiting peptide by means of a bond or by amide, or ester linkages.
  • These polyhydroxysubstituted-alkyl moieties include sugars and other linear or branched polyhydroxy-substituted-alkyl derivatives which are coupled to the C-terminal of the renin inhibitor peptide by means of an amino or a hydroxyl substituent on the polyhydroxy-substituted-alkyl moiety.
  • Suitable amino-substituted polyhydroxy-substituted-alkyl derivatives include the aminodesoxy- aldoses and the aminodesoxyketoses and their cyclic and reduced derivatives, 2,3-dihydroxy-2- (hydroxymethyl)propylamine, 2-hydroxy- 1,1-bis(hydroxymethyl)ethylamine, 3-hydroxy-2,2-bis(hydroxymethyl)- propylamine, 3-amino-1,2-propanediol, 2-amino-1,3-propanediol, 4- hydroxy-3,3-bis(hydroxymethyl)butylamine, and 2,3,4-trihydroxybutyl- amine.
  • suitable carboxylic acid substituted polyhydroxysubstituted-alkyl derivatives include the onic and uronic acid sugars such as gluconic and glucuronic acids, glyceric acid, 3-hydroxy-2,2- bis(hydroxymethyl)propionic acid, 2-hydroxy-2,2-bis(hydroxymethyl)- acetic acid, 4-hydroxy-3,3-bis(hydroxymethyl)butyric acid, 2,3,4- trihydroxybutyric acid.
  • suitable aldehyde or ketone sub- stituted sugars include the aldoses and ketoses which can be condensed directly with the C-terminal of renin inhibitory peptides by means of an esterification. Examples of this and other reactions suitable for incorporating sugars onto peptides having a free amine are set forth in WO published PCT application 87/02756.
  • derivatives of amino acids is meant the well known amino acid derivatives commonly employed in renin inhibitors as set forth in the references above.
  • peptides of the present invention are represented by formula I.
  • the non-cleavable transition state insert corresponding to the 10,11-position of the renin substrate, is designated E 10 -F 11 .
  • 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).
  • the peptides 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.
  • Renin inhibitory peptides commonly have protecting groups at the C-terminus. These protecting groups are known in the polypeptide art. Examples of these protecting groups are given below. Any of these protecting groups are suitable for the peptides of the present invention.
  • 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, 2- hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2- naphthalenesulfonate, nicotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, picrate, pivalate, propionate, succinate. tartrate, thio
  • 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 -Cycyclic 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-tolyl, 5- ethyl-m-tolyl, (o-, m-, or p-)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-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(0)-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, pyridazin- yl, 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 tri- fluoromethyl.
  • 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 peptides 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, other renin-dependent cardiovascular disorders and ocular disorders.
  • the renin-angiotension system may play a role in maintenance of intracellular homeostasis: see Clinical and Experimental Hypertension, 86, 1739-1742 (1984) at page 1740 under Discussion.
  • the peptides 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 100 mg per kg per dose, administered from 1 to 4 times daily. Equivalent dosages for other routes of administration are also employed.
  • renin-associated hypertension and hyperaldosteronism are effectively treated by the administration of from 0.5 to 50 milligrams of the compound per kilogram of body weight per day.
  • 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 peptides of the present invention to effect renin inhibition 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 peptides of the present invention to effect renin inhibition 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 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.
  • compositions of the peptides of the present invention for renin inhibition 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 digly- cerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • 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 peptides of this invention may be administered in combination with other agents used in antihypertensive therapy such as diuretics, a 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, a 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 compounds of this invention can be given in combination with such compounds or salt or other derivative forms thereof as:
  • Diuretics acetazolamide; amiloride; bendroflumethiazide; benzthia- zide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiomer 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; ⁇ -Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxyben- zamine; pr
  • ⁇ -Adrenergic Blocking Agents atenolol; metoprolol; nadolol; propranolol; timolol;
  • N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxopropyl)glycine (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-merca ⁇ topropionyl)-4-thiazolidinecarboxylic acid);
  • Other Antihypertensive Agents aminophylline; cryptenamine acetates and tannates; deserpidine; meremethoxylline procaine; pargyline; trimethaphan camsylate; and the like, as well as admixtures and combinations thereof.
  • 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 coadministration are, of course, possible.
  • novel peptides of the present invention possess an excellent degree of activity in treating renin-associated hypertension and hyperaldosteronism.
  • Renin inhibitors have also been disclosed to control the rise in intraocular pressure associated with the use of steroidal anti- inflammatory drugs as described in International Application PCT/-
  • the peptides of the present invention are also useful as novel human retroviral protease inhibitory peptide analogs. Therefore, the peptides of the present inventions inhibit retroviral proteases and thus inhibit the replication of the virus. They are useful for treating human patients infected with a human retrovirus, such as human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
  • a human retrovirus such as human immunodeficiency virus (HIV) which results in acquired immunodeficiency syndrome (AIDS) and related diseases.
  • the capsid and nonstructural proteins of recroviruses are translated from the viral genes gag and pol 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 there- of, 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) 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.
  • HIV human immunodeficiency virus
  • HTLV-III or LAV human immunodeficiency virus
  • AIDS human acquired immunodeficiency disease syndrome
  • HIV-I protease a retro viral encoded protease
  • 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 328:351 (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), using dosages, forms and modes of adminstration equivalent to those described above for renin inhibition.
  • AIDS human acquired immunodeficiency disease syndrome
  • Exact dosages, forms and mode of administration would be apparent to one of ordinary skill in the art such as a physician or pharmacologist.
  • 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 renin inhibitory peptides having 7-glutamic acid as the polar N-terminal groupp.
  • BOC-Pro-Phe-N-MeHis-LVA-Ile-AMP i.e., Pro-Phe-N-MeHis- LVA-Ile-AMP, of formula A-l is coupled with N(a)-BOC- ⁇ -benzyl-L-glut- amic acid, which is commercially available, using diethylcyano- phosphonate to afford peptide of formula A-2.
  • the preparation of BOC-Pro-Phe-N-MeHis-LVA-Ile-AMP is described in U.S. patent application, Serial No. 147,073, filed 20 January 1988, and in published European patent application 0173481, published 5 March 1986, which are hereby incorporated by reference.
  • Oxidation of the peptide of formula A-3 with m-chloroperbenzoic acid affords the N-oxide of formula A-4.
  • peptides of the present invention having ⁇ -glutamic acid as the polar N- terminal group are prepared in an analogous manner to the procedures described above.
  • 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 B illustrates the preparation of renin inhibitory peptides having ⁇ -Val as the polar N- terminal group.
  • the peptide of formula B-1 wherein R 20 is Ile-AMP is prepared as described in U.S. patent application, Serial No. 147,073, filed 20 January 1988, and in published European patent application 0173481, published 5 March 1986, which are hereby incorporated by reference.
  • the peptide of formula B-1 wherein R 20 is Mba is prepared by procedures analogous to those described in U.S. patent application, Serial No. 07/147,073, filed 20 January 1988, and in published European patent application 0173481, published 5 March 1986, which are hereby incorporated by reference.
  • the appropriate peptide is coupled with BOC- ⁇ -Valine to give the compound of formula B-2 and then deprotected to give the compound of formula B-3, using standard procedures known in the art.
  • Treatment of the compound of formula B-3 with trifluoroacetic acid (TFA) effects removal of the BOC group to give the final peptide of formula B-4.
  • TFA trifluoroacetic acid
  • Chart E illustrates the assembly of a renin inhibitory peptide having a phosphoric acid residue as the polar N-terminal group.
  • the peptide of formula E-1 (A-l) is coupled with the acid of formula C-4, prepared as described in Chart C, using DEPC or DIC to provide the product of formula E-2.
  • m-Chloroperbenzoic acid (MCPBA) oxidation proceeds smoothly at the pyridine nitrogen to afford the N-oxide of formula E-3.
  • peptides of the present invention having a phosphoric acid residue as the polar N-terminal group are prepared in an analogous manner to the procedures desdribed above.
  • Chart F describes the synthesis of the BOC- ⁇ -Valine residue from ethyl 3,3-dimethylacrylate.
  • ethyl 2,2-dimethylacrylate of formula F-1 is heated in a saturated ethanolic solution of ammonia, the amino ester of formula F-2 is formed by Michael addition of ammonia. Although this reaction is slow (half life of about 10 hours at 80°C), no aminolysis of the ester is observed.
  • a BOC group is added to give the compound of formula F-3, and hydrolysis of the ester provides the acid of formula F-4.
  • 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 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 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).
  • nitrogen protective groups include t-butoxycarbonyl (BOC) , benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like.
  • ⁇ -Val-Phe-N-MeHis-LVA-MBA or L-histidinamide N- (3-amino-3- methyl-1-oxobutyl)-L-phenylalanyl-N-[2-hydroxy-5-methyl-4-[[(2- methylbutyl)amino]carbonyl]-1-(2-methylpropyl)hexyl]-N ⁇ -methyl-, [1S- [1R*,2R*,4R*(R*)]]-, bis(trifluoroacetate) (salt);
  • ⁇ -Glu-Pro-Phe-N-MeHis-CVG or L-Histidinamide L- ⁇ -glutamyl-L- prolyl-L- phenylalanyl-N-[1-(cyclohexylmethyl)-2,3-dihydroxy-5-methylhexyl]-N ⁇ -methyl-, [1S-(1R*,2S*,3R*) bis (trifluoroacetate) (salt); ⁇ -Glu-Pro-Phe-N-MeHis-CVA-MBA or L-Histidinamide, L- ⁇ -glutam- yl-L-prolyl-L-phenylalanyl-N-cyclohexylmethyl)-2-hydroxy-5-methyl-4- [[(2-methylbutyl)aminoicarbonyl]hexyl]-N ⁇ -methyl-, [1S-[1R*.2R*,4R*- (R*)]]-. bis(trifluoroacetate) (
  • AMP is 2-(aminomethyl)pyridinyl
  • AMP-NO is (2-pyridylmethyl)amino, pyridine N-oxide
  • Ampip is 4-(aminomethyl)piperidine
  • ⁇ -Asp is ⁇ -asparagine
  • BOC is t-butoxycarbonyl
  • Celite is a filter aid
  • CVG is 2S-amino-1-cyclohexyl-3R,4S-dihydroxy-6-methylheptane
  • DCC is dicyclohexylcarbodiimide
  • DEPC diethylphosphoryl cyanide
  • FTrp is N in- formyl-Trp
  • ⁇ -Glu is ⁇ -glutamic acid
  • N-MeHis is N ⁇ -methyl histidine
  • HOBT is 1-hydroxybenzotriazole
  • HPLC high performance liquid chromatography
  • Iba is isobutylamine
  • LVA is Leu ⁇ (CH(OH)CH 2 )Val with the S configuration at C4 (the hydroxyl-bearing carbon atom).
  • MBA is 2-methylbutylamino (racemic or optically active)
  • MPLC medium pressure liquid chromatography
  • Ph is phenyl
  • Phe is phenylalanine
  • RIP means a compound having the formula H-Pro-His-Phe-His-Phe- Phe-Val-Tyr-Lys-OH.2(CH 3 C(O)OH) .XH 2 O which is a known renin-inhibiting peptide.
  • Sta is statine
  • TBS is tert-butyldimethylsilyl
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TsOH is p-toluenesulfonic acid
  • Tyr is tyrosine
  • (OCH 3 )Tyr is O-methyl 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.
  • HPLC high pressure liquid chromatography and k is the partition ratio obtained.
  • the solvent system used is indicated in parentheses after the partition ratio: A is 50% methanol, 50% aqueous phosphate pH 3 buffer; B is 55% methanol, 45% aqueous phosphate pH 3 buffer; C is 60% methanol, 40% aqueous phosphate pH 3 buffer; and D is 65% methanol, 35% aqueous phosphate pH 3 buffer.
  • the flow rates were at 1.5 ml/min.
  • the detector was set at 225 or 254 nm.
  • 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.
  • Example 1 ⁇ -Glu-Pro-Phe-(N-Me)His-LVA-Ile-AMP tris trifluoroacetate (Formula A-5) Refer to Chart A.
  • This material in 20 ml of ether, is saturated with gaseous hydrogen chloride; volatiles are then removed under a stream of nitrogen and the residue is dried in vacuo to give 1.2 g of the title product.
  • reaction mixture is given an aqueous workup, with sodium bisulfite washes, and the material is flashed on silica gel with 8% acetone-dichloromethane to afford 978 mg of the title product as a colorless oil.
  • reaction mixture is given an aqueous workup, with sodium bisulfite washes, and the material is flashed on silica gel with 5-10% acetone-dichloromethane to afford 1.46 g of the title product as a colorless oil.
  • Example 10 (HO) 2 P(O)OCH 2 CO-Pro-Phe- (N-Me)His-LVA-Ile-AMP N-oxide bis hydrochloride (Formula E-5) Refer to Chart E. A solution of 47 mg of the title product of Preparation 35 in 1 ml of 4 M aqueous hydrochloric acid is allowed to stand for one h, then the solvent is pumped off under high vacuum via a potassium hydroxide trap. The residue is dissolved in absolute ethanol, which is then carefully pumped off, and this treatment is repeated once. The residue is then dissolved in water and the solution lyophilized to provide 41 mg of the title product as a fluffy white solid.
  • 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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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.
EP90905979A 1989-04-18 1990-04-05 Peptides avec des groupes n-terminaux polaires Withdrawn EP0468998A1 (fr)

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US339750 2003-01-09

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US5554728A (en) * 1991-07-23 1996-09-10 Nexstar Pharmaceuticals, Inc. Lipid conjugates of therapeutic peptides and protease inhibitors
DE4126485A1 (de) * 1991-08-10 1993-02-11 Bayer Ag Trifluormethyl-haltige pseudopeptide
WO1993006127A1 (fr) * 1991-09-17 1993-04-01 Warner-Lambert Company Nouveaux inhibiteurs de renine a base de promedicaments a acides amines
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
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
BR9306138A (pt) * 1992-03-25 1998-06-23 Pfizer Peptídeos antivirais
DE4215874A1 (de) * 1992-05-14 1993-11-18 Bayer Ag Dithiolanylglycinhaltige HIV-Proteaseinhibitoren vom Hydroxyethylenisostertyp

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DE3377497D1 (en) * 1982-09-15 1988-09-01 Haessle Ab Enzyme inhibitors
DE3830825A1 (de) * 1987-09-15 1989-03-23 Sandoz Ag Hydrophile reninhemmer, ihre herstellung und verwendung
EP0312157A3 (fr) * 1987-10-13 1990-07-25 Merck & Co. Inc. Inhibiteurs tétrapeptidiques de la rénine, ayant des amides d'acides aminés C-terminaux

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Title
See references of WO9012804A2 *

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KR920700221A (ko) 1992-02-19

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