EP0321497A1 - Renin inhibitory peptides having novel c-terminal moieties - Google Patents

Renin inhibitory peptides having novel c-terminal moieties

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Publication number
EP0321497A1
EP0321497A1 EP87906262A EP87906262A EP0321497A1 EP 0321497 A1 EP0321497 A1 EP 0321497A1 EP 87906262 A EP87906262 A EP 87906262A EP 87906262 A EP87906262 A EP 87906262A EP 0321497 A1 EP0321497 A1 EP 0321497A1
Authority
EP
European Patent Office
Prior art keywords
amino
hydroxy
alkyl
aryl
het
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Withdrawn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
EP87906262A
Other languages
German (de)
English (en)
French (fr)
Inventor
Heinrich J. Schostarez
Jackson B. Hester, Jr.
Tomi K. Sawyer
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
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Filing date
Publication date
Application filed by Upjohn Co filed Critical Upjohn Co
Publication of EP0321497A1 publication Critical patent/EP0321497A1/en
Withdrawn legal-status Critical Current

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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
    • 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
    • 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
    • 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 renin-inhibiting peptides which have novel moieties at the C- terminus. Most particularly, the present invention provides novel renin-inhibiting peptide analogs which are derived from (1S, 3S, 4S)-1,4-diamino-1,4-disubstituted-3- hydroxy-butane. The present invention also provides renin-inhibitory compounds containing a C-terminal hydroxamate function as compared to the renin substrate. 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 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. patent 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 77,029. Further, European published application No .
  • published European Applications 45,161 and 53,017 disclose amide derivatives useful as inhibitors of angiotensin converting enzymes. Certain dipeptide and trlpeptides are disclosed in U.S. patents 4,514,332; 4,510,085; and 4,548,926 as well as in European published applications 128,762; 152,255; and 181,110. Eepstatin derived renin inhibitors have been disclosed in U.S. patent 4,481,192. Retroinverso bond modifications at positions 10-11 have been disclosed in U.S. patent 4,560,505 and in European published applications 127,234 and 127,235.
  • isosteric bond replacements at positions 10-11 have been disclosed in European published applications 143,746 and 144,290; and U.S. patent application, Serial No. 833,993, filed 27 February 1986.
  • 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 l-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. INFORMATION DISCLOSURE
  • renin inhibitor compounds were disclosed by S.H. Rosenberg, et. al., at an American Chemical Society meeting in New York City on April 13-18, 1986. These peptidic compounds have a transition state moiety of the formula -NH-CH(CH 2 R) -CH(OH)CH 2 - (CH 2 ) n - NH-, wherein n is 0 or 1.
  • Published British patent application 2,167,759A discloses certain compounds useful for treating angiotensin related hypotension containing a moiety of the formula NHCHR 2 - CHOH-CH 2 N-.
  • patent 4,599,198 discloses renin-inhibitor compounds having a moiety -N-CH(CH 2 -cyclohexyl)-CHOH-CH 2 -NR 4 -.
  • European patent application 181,071 discloses renin inhibitor compounds having a moiety of the formula -NH-CHR 2 -CHOH-CH 2 -NR 1 - .
  • 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 -V,
  • a renin inhibitory peptide having a noncleavable transition state insert corresponding to the 10,11-position of the renin substrate (angiotensinogen) and having a moiety of the formula V, wherein V is (a) -C( Y)-G 12 -H 13 -Z,
  • 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 airyl is phenyl or naphthyl substituted by zero to 3 of the following :
  • 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:
  • the renin inhibitory peptides of the present invention can occur in several isomeric forms, depending on the configuration around the asymmetric carbon atoms . All such isomeric 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.
  • 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, palmitate, pectinate
  • 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 ( Ci -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 3 to 7 carbon atoms.
  • Examples of (C 3 -C 10 )cycloalkyl which include alkyl-substituted cycloalkyl, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethyl- cyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-methylcyclobutyl, 3-propylcyclobutyl, cyclopentyl, 2,2-dimethyl- cyclopentyl, and cyclohexyl.
  • aryl examples include phenyl, naphthyl, (o-, m- , p-)tolyl, (o-, m-, 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-
  • Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl-indolyl, N in -C 2 -C 5 alkyl-C(O)-Indolyl, [1,2,4]- triazolyl, 2-, 4-, 5-pyrimidinyl.
  • 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., TUPAC-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 TUPAC-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.
  • renin-dependent hypertension examples include renin-dependent hypertension, hypertension, hypertension under treatment with another antihypertensive and/or a diuretic agent, congestive heart failure, renin-dependent hyperaldosterism, angina, post-mycardial infarction and other renin-dependent cardiovascular disorders.
  • the renin-angiotension system may play a role in maintenance of intracellular hemeostasis: 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.
  • renin-associated hypertension and hyperaldosteronism are effectively treated by the administration of from 1.0 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 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-butanedlol.
  • a non-toxic parenterally-acceptable diluent or solvent for example as a solution in 1,3-butanedlol.
  • 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 non- irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature
  • the renin-inhibiting compounds 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 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, a and/or ⁇ -adrenergic blocking agents, CNS-acting agents, adrenergic neuron blocking agents, vasodilators, angiotensin I converting enzyme inhibitors, and other antihypertensive agents.
  • antihypertensive agents selected from the group consisting of diuretics, a 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 salts or other derivative forms thereof as:
  • Diuretics acetazolamide; amiloride; bendroflumethiazide; benzthiazide; 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; methylclothiazide; muzolimine; polythiazide; quinethazone; sodium ethacrynate; sodium nitroprusside; spironolacetone; ticrynaten; trimaterene; trichlormethiazide; ⁇ -Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; tol
  • N-cyclopentyl-N-(3-(2,2-dimethyl-1-oxopropyl)thiol-2-methyl-1-oxo- propyl)glycine) (pivalopril); ((2R,4R)-2-(2-hydroxyphenyl)-3-(3-mercaptopropionyl)-4-thlazolidine- carboxylic acid);
  • Other Antihypertensive Agents aminophylline ; cryptenamine acetates and tannates ; deserpidine ; meremethoxylline procaine ; pargyline ; tri- methaphan 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.
  • 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 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.
  • micronization of the compounds of this invention may be advantageous for optimal drug delivery .
  • the compounds of the present invention are prepared as depicted in the charts and as described more fully in the Preparations and Examples .
  • the compounds of formula A-1 are treated with isobutyl chloroformate and triethylamine to give the mixed anhydrides (A-2) which without Isolation are allowed to react with sodium azide.
  • the resulting acyl azides (A-3) are isolated from the aqueous reaction mixture, dried and warmed with benzyl alcohol to give the carbamates A-4 via the isocyanates A-5. Both A-4 and A-5 are useful intermediates for compounds of formula I.
  • CHART B Chart B describes the preparation of the fully protected peptidic acid, Bob-Phe-His(Tos)-OH, which is useful as an intermediate in the synthesis of renin inhibitors.
  • the compound of formula B-l is treated with p-nitrophenol and dicyclohexylcar- bodiimide in ethyl acetate at 0°C for about one hour.
  • Other activating reagents such as N-hydroxysuccimide or 1,1-carbonyldlimidizole may be utilized with condensing reagents known in the art such as diisopropylcarbodiimide, diethylphosphoryl cyanide or N-methyl-2- halopyridiniua salts.
  • Suitable solvents include tetrahydrofuran, glyme, and halocarbons such as dichloromethane and chloroform.
  • the compound of formula B-2 is isolated by standard procedures known in the art.
  • the compound of formula B-2 is reacted with His-methyl ester hydrochloride and base in dimethylformamide at room temperature for about eighteen hours.
  • Suitable bases include hindered tertiary amines such as triethylamine or diisopropylethylamine.
  • the compound of formula B-3 is isolated by standard procedures known in the art. The compound of formula B-3 is treated with tosyl chloride and base in methylene chloride at room temperature for about one hour. Bases suitable in this transformation are similar to those described above, tertiary amines.
  • Suitable solvents include tetrahydrofuran, ethyl acetate, diethyl ether, glyme, and halocarbons such as dichloromethane and chloroform.
  • the compound of formula B-4 Is Isolated by standard procedures known in the art. The compound of formula B-4 is treated with lithium hydroxide in tetrahydrofuran/water at room temperature for about thirty minutes. The compound of formula B-5 is isolated by standard procedures known in the art.
  • CHART C Chart C illustrates the preparation of renin-inhibitory peptides containing a C- terminal hydroxamate function.
  • the compounds of formula C-1 and C-1A are treated with a condensing reagent and base in methylene chloride at 0oC to room temperature for 30 min. to 24 hrs.
  • Suitable solvents include tetrahydrofuran, ethyl acetate, diethyl ether, glyme, and halocarbons such as dichloromethane and chloroform.
  • Suitable bases include hindered tertiary amines such as triethylamine or diisopropylethylamine.
  • the compound of formula C-2 is isolated by standard procedures known in the art.
  • the compound of formula C-2 is deprotected using acidic conditions. Those most commonly employed include 2:1 to 1:1 mixtures of methylene chloride : trifluoroacetic acid or dry hydrochloric acid in 1,4-dioxane or diethyl ether.
  • Condensation with the next reactant is carried out as described above. Namely, the compounds are treated with a condensing reagent and base in methylene chloride at 0oC to room temperature for 30 min. to 24 hrs.
  • Suitable solvents include tetrahydrofuran, ethyl acetate, diethyl ether, glyme, and halocarbons such as dichloromethane and chloroform.
  • Suitable bases include hindered tertiary amines such as triethylamine or diisopropylethylamine.
  • the compound of formula C-3 is isolated by standard procedures known in the art.
  • This procedure may be repeated to deliver the compounds of formula C-4.
  • the compound of formula C-4 is isolated by standard procedures known in the art.
  • Removal of the p-toluenesulfonyl protecting group on histidine may be accomplished by nucleophilic displacement. This may be carried out with nucleophiles such as 1-hydroxybenzotriazole in protic solvents such as methanol, or with reagents such as tetra-N- butylammonium fluoride in aprotic solvents such as tetrahydrofuran. Times range from 30 min. to 48 hrs. at temperatures ranging from 20o to 50°C. The compound of formula C-5 is isolated by standard procedures known in the art.
  • 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.
  • Appropriate protecting groups, reagents, and solvents for both the solution and solid phase methods can be found in "The Peptides: Analysis, Synthesis, and Biology," Vols. 1-5, eds. E. Gross and T. Meienhofer, Academic Press, NY, 1979-1983; "Solid Phase Peptide Synthesis", J.M. Stewart and J.D. Young, Pierce Chemical Company, Rockford, 111., 1984; "The Practice of Peptide Synthesis", M. Bodansky and A.
  • the carboxylic moiety of EP-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 50% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride.
  • Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropyl- ethylamine or sodium bicarbonate in methylene chloride.
  • 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 intermediates 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 hydrogen fluoride but may be removed by ammonia or sodium hydroxide.
  • FTrp N in -formyl- tryptophane
  • 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.W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J.F.ff. 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-Phe-His-Sta-Ile-NHOCH 3 or L-Histldinamide, N-[(1-dimethyl- ethoxy)carbonyl]-L-phenylalanyl-N-[2-hydroxy-4-[[-[(methoxyamino)carbonyl]-2-methylbutyl]amino]-1-(2-methylpropyl)-(4-oxobutyl]-, [1S- [1R*,2R*,4(1R*,2R*)]]-;
  • LVA is Leu ⁇ (CH(OH)CH 2 )Val with the S configuration at C4 (the hydroxyl-bearing carbon atom) M or mol is mole Me is methyl min. is minute ml is milliliter
  • MPLC medium pressure liquid chromatography
  • MS mass spectroscopy
  • 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 or TBDI7S is tert-butyldimethylsilyl
  • TEA is triethylamine
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TLC is thin layer chromatography
  • Tos is p-toluenesulfonyl
  • TsOH is p-toluenesulfonic acid.
  • the wedge-shape line indicates a bond which extends above the plane of the paper relative to the plane of the compound thereon.
  • Procedure B Coupling of an acid to an amine using Mukaiyama conditions.
  • a 5% solution of the Boc protected amine in an equal volume of methylene chloride and trifluoroacetic acid is allowed to stand at room temperature and then concentrated in vacuo.
  • the residue is dissolved in methylene chloride or ethyl acetate and washed once with aqueous sodium bicarbonate and dilute aqueous sodium chloride, dried over magnesium sulfate and concentrated in vacuo.
  • the residue is either chromatographed over silica gel or used as is in the next step.
  • Procedure D Coupling an acid to an amine using diethyl cyanophosphonate.
  • a 5% solution of the Boc protected amine in an equal volume of methylene chloride and trifluoroacetic acid is allowed to stir at room temperature for 1 hour and then concentrated in vacuo.
  • a solution of the residue in methylene chloride is washed once with aqueous sodium bicarbonate. The aqueous wash is backwashed twice with methylene chloride. The combined organic fractions are dried over magnesium sulfate and concentrated in vacuo. The residue is then used as is in the next step without further purification.
  • Example 1 (3S,5S,6S)-3-(Benzyloxycarbonylamino)-6-[[N ⁇ -[N ⁇ -(t- butoxycarbonyl)phenylalanyl]-L-histidyl]amino]-2,8- dimethyl-5-hydroxynonane.
  • Part A By the general procedure C for Boc group removal, 0.209 g (0.379 mmol) of the Boc amino urethane (Preparation 1) yields 0.204 g of the crude free amine. The amine is then coupled (procedure B) with Boc(tosyl)histidine. The chromatography is carried out using 1.8% MEOH:CH 2 Cl 2 containing 0.18% of NH 4 OH to yield 0.254 g (79.6%) of coupled product. The structure is supported by NMR and high resolution FAB mass spec.
  • Example 2 (3S,5S,6S)-3-Amino-6-[[N ⁇ [N ⁇ -(t-butoxycarbonyl-)L- phenylalanyl]-L-histidyl]amino]-2,8-dimethyl-5- hydroxynonane.
  • a mixture of 0.096 g (0.133 mmol) of the CBZ peptide (Example 1) and 0.05 g of 10% Pd/C catalyst in 10 ml of EtOH is stirred under H 2 at atmospheric pressure for 2 hrs 15 min. An additional 0.05 g of 10% Pd/C catalyst is added and stirring is continued for an additional 18 hrs. The catalyst is removed by filtration and the filtrate concentrated in vacuo. The residue is chromatographed over silica gel using 30% MEOH:CH 2 Cl 2 containing 0.5% NH 4 OH to yield 0.062 g (79.4%) of the title compound.
  • the structure is supported by high resolution FAB mass spec.
  • Part B To a N 2 covered, ice bath cooled solution of 0.092 g (0.221 mmol) of the free amine (Part A) and 0.077 ml of triethylamine in 4 ml of THF is added 0.055 ml of isopropylchloroformate. The ice bath is allowed to melt and the mixture is then stirred at room temperature for 16 hrs. The reaction mixture is then pipetted into 10 ml of ice water and then extracted three times with CH 2 Cl 2 . The combined extracts are dried over MgSO 4 and concentrated in vacuo.
  • Example 3 Part A is coupled with CBZ-D-valine and chromatographed with 15% EtOAc:hexane to yield 0.131 g (84.0%) of the coupled product.
  • the structure is supported by NMR and high resolution FAB mass spec.
  • Example 7 (3S,5S,6S)-3-[[N ⁇ -[(3-Aminomethyl)benzoyl]-D-valyl]- amino]-6-[[N ⁇ [N ⁇ -(t-butoxycarbonyl)-L-phenylalanyl)-L- histidyl]amino]-2,8-dimethyl-5-hydroxynonane. Part A.
  • Part B By the general procedure F for Boc group removal 0.218 g (0.421 mmol) of the Boc peptide (Part A) yields 0.164 g of the free amine.
  • the amine is then coupled (coupling procedure D) with Boc-im-tosyl- histidine and chromatographed using 1.25% MeOH:methylene chloride containing 0.125% NH 4 OH to yield 0.293 g (86.1%) of coupled product.
  • the structure is supported by NMR and high resolution FAB mass spec. Found: [m + H] + at m/z 808; Theory for C 40 H 70 N 5 O 8 SSi, 808.4714; Measured, 808.4722. Part C.
  • Part B By the general procedure F for Boc group removal 0.219 g (0.447 mmol) of the Boc peptide (Part A) yielded 0.176 g of the free amine. The amine is then coupled (coupling procedure D) with Boc- im-tosyl- histidine and chromatographed using 2% MeOH:CH 2 Cl 2 containing 0.2% NH4OH to yield 0.294 g (84.2%) of coupled product. The structure is supported by NMR and FAB mass spec. Found: [m. + H] + at m/z 781. Part C.
  • Boc-Ile-NHOCH 3 (260 mg) of Part A in 5 ml of trifluoroacetic acid/aethylene chloride (50%) is stirred at room temperature for 30 min. The solution is then concentrated in vacuo and residue is dissolved in methylene chloride (20 ml). To this solution is added Boc-Sta (275 mg), 1-hydroxybenzotriazole (135 mg), dicyclohexylcarbodiiaide (415 mg) and triethylamine (200 mg) and the resulting solution is stirred for 18 hours. The above solution is filtered and washed with methylene chloride.
  • a solution of Boc-Ile-NHOCH 2 -phenyl (200 mg) of Part A in 5 ml of 50% trifluoroacetic acid/methylene chloride is stirred at room temperature for 30 min.
  • the solution is then concentrated in vacuo and residue is dissolved in 5 ml of methylene chloride.
  • diethylcyanophosphonate 100 ⁇ l
  • Boc-Sta 165 mg
  • triethylamine 200 ⁇ l
  • Boc-Sta-Ile-NHO-phenyl (Formula C-3: R is phenyl).
  • the resulting solution is stirred at room temperature for 18 hours.
  • the mixture is then diluted with 20 ml of methylene chloride and washed with 10% sodium bicarbonate, water, saturated sodium chloride solution, dried (sodium sulfate) and concentrated in vacuo giving a crude oil.
  • the oil is purified by column chromatography on silica gel using 4% methanol/chloroform as eluent and affords white crystalline title product.
  • Boc-Phe-His-Sta-Ile-NHO-phenyl (Formula C-5: R is phenyl).
  • a solution of Boc-Phe-His(Tos)-Sta-Ile-NHO-phenyl (75 mg) of Part C and 1-hydroxybenzotriazole (75 mg) in 2 ml of methanol is stirred at room temperature for 72 hours.
  • the mixture is diluted with 20 ml of methylene chloride, washed with 10% sodium bicarbonate, water, saturated sodium chloride, dried (sodium sulfate) and concentrated in vacuo to give a crude oil.
  • the oil on trituration with anhydrous ether gives the title product.
  • Boc-Sta-lie-NHOC 2 H 5 (Formula C-3: R is ethyl).
  • a solution of Boc-Ile-NHOC 2 Hg (275 mg) of Part A in 5 ml of trifluoroacetic acid/methylene chloride (50%) is stirred at room temperature for 30 min.
  • the solution is then concentrated in vacuo and the residue is dissolved in methylene chloride (20 ml).
  • Boc-Sta 275 mg
  • 1-hydroxybenzotriazole (135 mg)
  • dicyclohexylcarbodiimide (415 mg) and triethylamine (200 mg)
  • the resulting solution is stirred for 18 hours.
  • the solution is filtered and washed with methylene chloride.
  • Boc-Phe-His(Tos)-Sta-Ile-NHOC 2 H 5 (Formula C-4: R is ethyl).
  • a solution of Boc-Sta-lie-NHOC 2 H 5 (215 mg) of Part B in 50% trifluoroacetic acid/methylene chloride is stirred for 30 min.
  • the solution is then concentrated in vacuo and residue is dissolved in 5 ml of methylene chloride.
  • Boc-Phe- His(Tos)-COOH (278 mg), diethylcyanophosphonate (80 ⁇ l) and triethyl- amine (100 ⁇ l).
  • the resulting solution is stirred at room temperature for 18 hours.
  • the mixture is then diluted with 20 ml of methylene chloride and washed with 10% sodium bicarbonate, water, saturated sodium chloride solution, dried (sodium sulfate) and concentrated in vacuo giving an oil.
  • the oil is purified by column chromatography on silica gel using 4% methanol/chloroform as eluent and affords white crystalline title product.
  • Boc-Phe-His-Sta-Ile-NHOC 2 H 5 (Formula C-5: R is ethyl).
  • a solution of Boc-Phe-His(Tos)-Sta-Ile-NHOC 2 H 5 (100 mg) of Part C and 1-hydroxybenzotrlazole (100 mg) in 5 ml of methanol is stirred at room temperature for 72 hours.
  • the mixture is diluted with 20 al of methylene chloride, washed with 10% sodium bicarbonate, water, saturated sodium chloride solution, dried (sodium sulfate) and concentrated in vacuo to give a crude oil.
  • the oil on trituration with anhydrous ether gives the title product.
  • Priority Country US FI, FR (European patent), GB (European patent), IT ( pean patent), JP, KR, LU (European patent), NL (Eur patent), NO, SE (European patent), US, US, US.

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EP87906262A 1986-09-30 1987-09-10 Renin inhibitory peptides having novel c-terminal moieties Withdrawn EP0321497A1 (en)

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US91349086A 1986-09-30 1986-09-30
US913490 1986-09-30
US92583086A 1986-10-30 1986-10-30
US925830 1986-10-30
US707987A 1987-01-27 1987-01-27
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AU619222B2 (en) * 1987-10-21 1992-01-23 Upjohn Company, The Renin inhibitors containing a (1-amino-2-hydroxy-2- heterocyclic)ethyl moiety
DE3814325A1 (de) * 1988-04-28 1989-11-09 Merck Patent Gmbh Aminosaeurederivate
SE8802428D0 (sv) * 1988-06-28 1988-06-28 Haessle Ab New compounds
WO1990002137A1 (en) * 1988-08-19 1990-03-08 The Upjohn Company Renin inhibitory peptides containing suleptanic acid or derivatives thereof
US5164388A (en) * 1988-10-19 1992-11-17 Abbott Laboratories Heterocyclic peptide renin inhibitors
US5539122A (en) * 1989-05-23 1996-07-23 Abbott Laboratories Retroviral protease inhibiting compounds
US5354866A (en) * 1989-05-23 1994-10-11 Abbott Laboratories Retroviral protease inhibiting compounds
US5554783A (en) * 1989-05-23 1996-09-10 Abbott Laboratories Retroviral protease inhibiting compounds
US5643878A (en) * 1991-09-12 1997-07-01 Ciba-Geigy Corporation 5-amino-4-hydroxyhexanoic acid derivatives
TW217410B (da) * 1992-04-01 1993-12-11 Ciba Geigy
CA2170020C (en) * 1992-12-29 2005-08-02 Dale J. Kempf Retroviral protease inhibiting compounds
US5786500A (en) * 1993-10-22 1998-07-28 Abbott Laboratories Process for the preparation of a substituted 2.5-diamino-3-hydroxyhexane
US5491253A (en) * 1993-10-22 1996-02-13 Abbott Laboratories Process for the preparation of a substituted 2,5-diamino-3-hydroxyhexane
DK0708085T3 (da) * 1994-10-19 2002-11-11 Novartis Ag Antivirale ethere af aspartatproteasesubstrat-isostere

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US4595677A (en) * 1982-12-03 1986-06-17 Ciba-Geigy Corporation Substituted tetrapeptides
EP0163237A3 (en) * 1984-05-29 1988-04-27 Merck & Co. Inc. Di- and tri-peptidal renin inhibitors
DK356085A (da) * 1984-08-06 1986-02-07 Upjohn Co Reninhaemmende peptid eller et farmaceutisk acceptabelt syreadditionssalt deraf

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