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WO1988007053A1 - Inhibiteurs de la rennine contenant un acide amino cyclopropylique ou un cycloalkyle de transition analogue - Google Patents

Inhibiteurs de la rennine contenant un acide amino cyclopropylique ou un cycloalkyle de transition analogue Download PDF

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Publication number
WO1988007053A1
WO1988007053A1 PCT/US1988/000547 US8800547W WO8807053A1 WO 1988007053 A1 WO1988007053 A1 WO 1988007053A1 US 8800547 W US8800547 W US 8800547W WO 8807053 A1 WO8807053 A1 WO 8807053A1
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Prior art keywords
alkyl
amino
hydrogen
aryl
cycloalkyl
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PCT/US1988/000547
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English (en)
Inventor
Ronald B. Gammill
Jackson B. Hester, Jr.
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The Upjohn Company
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Publication of WO1988007053A1 publication Critical patent/WO1988007053A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/64—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms, e.g. histidine
    • 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
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10

Definitions

  • Renin inhibitors containing a cyclopropyl amino acid and/or a cycloalkyl transition-state analogue Renin inhibitors containing a cyclopropyl amino acid and/or a cycloalkyl transition-state analogue.
  • the present invention provides novel compounds. More particularly, the present invention provides novel renin-inhibiting peptide analogs. Most particularly, the present invention provides renininhibitory compounds having non-cleavable transition state inserts and having at least one cyclopropyl amino acid and/or a cycloalkyl non- cleavable transition state insert.
  • the renin inhibitors provided herein are useful for the diagnosis and control of renin- dependent hypertension and other related diseases.
  • 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
  • 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.
  • Phenylcyclopropane carboxylic acids and esters as hypotensive agents are disclosed in U.S. Patent 4,293,760 (1967) Kaiser; U.S. Patent 3,068,283 (1962) Kaiser; U.S. Patent 3,313,842 (1967) Smith Kline.
  • the present invention particularly provides:
  • halogen wherein p is zero to two, inclusive; wherein r is zero to three, inclusive; wherein t is zero to three, Inclusive; wherein aryl is phenyl or naphthyl substituted by zero to 3 of the following: (a) C 1 -C 3 alkyl,
  • ( t) -CH 2 NH 2 wherein -Het is a 5- or 6-membered saturated or unsaturated ring containing from one to three heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur; and including any bicyclic group in which any of the above heterocyclic rings is fused to a benzene ring, which heterocyclic moiety is substituted with zero to 3 of the following:
  • renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10 , 11-position of a renin substrate (angiotensinogen) , the improvement which comprises inclusion in the renin inhibitory peptide of:
  • renin inhibitors of the present invention of formula I are: wherein X is
  • R 18 or R 1g is hydroxy, mercapto, or amino, or a mono-substituted nitrogen containing group bonded through the nitrogen only when n is not one;
  • R 12 is -(CH 2 ) n -R 13 and n is zero and both R 13 and R 15 are oxygen-, nitrogen-, or sulfur-containing substituents bonded through the hetero atom, only when the hetero atom is not also bonded to hydrogen;
  • R 17 or R 19 is -COOH only when n for that moiety is other than zero;
  • R 16 or R 17 is an amino-containing substituent, hydroxy, mercapto, or -Het bonded through the hetero atom only when n for that substituent is an integer from two to five, inclusive;
  • R 17 or R 19 is -Het, only when -Het is other than cyclic amino; or a carboxy-, amino-, or other reactive group-protected form thereof; or a pharmaceutically acceptable acid addition salt thereof.
  • R 110 and R 111 are attached to the same carbon atom of the cycloalkyl ring.
  • renin inhibitory peptide is meant a compound capable of inhibiting the renin enzyme in mammalian metabolism and having thre 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.
  • 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:
  • 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 E isomer of the cyclopropyl amino acids is preferred.
  • the trans isomer of the cycloalkyl transition state inserts is preferred.
  • the stereochemistry of the other amino acids corresponds to that of the naturally-occurring amino acids.
  • Renin inhibitory peptides commonly have protecting groups at the
  • cyclopropyl amino acid of the formula XL 2b of the present Invention may occur at the N-terminus of the renin inhibitory peptide and, as such, will, when coupled with a suitable protecting group, assume the ending position.
  • the present invention provides peptide inhibitors of renin which contain at least one cyclopropane amino acid and have transition state inserts.
  • 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, hydr ⁇ iodide, 2-hydroxyethanesulfonate, lactate, maleate, methanesulfonate, 2-naphthalenesulfonate, nlcotinate, oxalate, palmoate, pectinate, persulfate, 3-phenylpropionate, plcrate, pivalate, propionate, succinate, tartrate, thi
  • the carbon atom ccntent 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 (G i -C j ) indicates a moiety of the integer "i” to the integer "j" carbon atoms, inclusive.
  • the prefix (G 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 )cycloallcyl which include alkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclo ⁇ ropyl, 2,3-diethylcyclopropyl, 2-butylcyclopro ⁇ yl, cyclobutyl, 2-methylcyclobutyl, 3- propylcyclobutyl, cyclopentyl, 2,2-dimethylcyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl and isomeric forms thereof.
  • aryl examples include phenyl, naphthyl, (o-, m-, p-)tolyl, (o-, m-, p-)ethylphenyl, 2-ethyl- tolyl, 4-ethyl-o-tolyl, 5-ethyl-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-, or 3,5-
  • 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, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidi- nyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolidin
  • a heterocycle as defined herein for -Het would not be bonded through oxygen or sulfur or through nitrogen which is within a ring and part of a double bond.
  • Halo is halogen (fluoro, chloro, bromo, or iodo) or trifluoromethyl.
  • pharmaceutically acceptable cations include: pharmacologically acceptable metal cations, ammonium, amine cations, or quaternary ammonium cations.
  • pharmacologically acceptable metal cations are those derived from the alkali metals, e.g., lithium, sodium, and potassium, and from the alkaline earth metals, e.g., magnesium and calcium, although cationlc 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., Eur. J. Biochem., 138, 9 (1984)) unless otherwise indicated.
  • the compounds of the Invention are effective In the treatment of humans.
  • 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-associated hypertension and hyperaldosteronism, hypertension, hypertension under treatment with another antihypertensive and/or a diuretic agent, congestive heart failure, angina, and post-myocardial infarction.
  • the renin-anglotension 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 renin inhibitors of this invention may be useful in the treatment of cerebrovascular disorders and disorders of intracellular homeotasis.
  • the possible role of the renin-angiotensin system in the maintenance of intracellular homeostasis is disclosed in Clinical and Experimental Hypertension, 86:1739-1742 (1984).
  • the renin inhibitors of this invention potentiate the antithrombotic activity of a thromboxane antagonist (U.S. patent 4,558,037).
  • the antihypertensive effect of the renin inhibitors of this invention are potentiated by combination with a thromboxane synthetase inhibitor.
  • 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.
  • 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.
  • parenteral 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 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 injectibles.
  • 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 renin-inhibiting compounds of this invention may be administered in combination with other agents used in antihypertensive therapy such as diuretics, or 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, or 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 salts or other derivative forms thereof as :
  • Diuretics acetazolamide; amiloride; bendroflumethiazide; benzthiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethlazide; 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; trichlormethlazide; ⁇ -Adrenergic Blocking Agents: dibenamine; phentolamine; phenoxybenzamine; prazosin; to
  • Angiotensin I Converting Enzyme Inhibitors 1-(3-mercapto-2-methyl-1-oxopro ⁇ yl)-L-proline (captopril);
  • 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.
  • Chart A The synthesis of both (Z) and (E) cyclopropylphenylalanine derivatives is reported in the literature and is outlined in Chart A.
  • the (Z) benzyldineoxazoline A-2 is prepared from hippuric acid A-1 via an Org. Syn. procedure, J.S. Buck and W.S. Ide, Org. Syn., Coll. Vol. II, 55 (1943).
  • a standard means of isomerizing (Z) arylidineoxazolones is with saturated hydrobromic acid, Y.S. Rao, Synthesis, 1975:749 (1975).
  • the oxazolone B-1 or C-1 is opened with 4- dimethylaminopyridine in methanol to afford the compounds B-2 or C-2.
  • This is followed by removal of the benzoyl group with freshly prepared Meerwein's salt via the procedure of Stammer (S.W. King, J.M. Riordan, E.M. Holt, and CH. Stammer, J. Org. Chem., 47:3270, 1982; also see CH. Stammer, CA, 103(25) : 215811w) to afford the compounds B-3 or C-
  • Stammer S.W. King, J.M. Riordan, E.M. Holt, and CH. Stammer, J. Org. Chem., 47:3270, 1982; also see CH. Stammer, CA, 103(25) : 215811w
  • the amine is protected with a Boc group and the ester saponified to afford the compounds B-4 or C-4.
  • the cyclopropyl amino acids B-4 or C-4 are incorporated into a peptide using standard coupling procedures. Should the peptide exist in a protected form, the protecting groups are removed prior to coupling. For example, a Boc group is removed from an N-terminus with trifluoroacetic acid in methylene chloride and then the cyclopropyl amino acid is introduced. After coupling, any remaining protecting groups are removed under standard conditions. For example a tosyl group is removed from histidine using 1-hydroxybenzotriazole in dimethylformamide.
  • the phenylalaninol of formula D-1 is commercially available.
  • the allylic alcohol of formula D-5 is protected as its acetonide of formula D-6 by standard procedures.
  • any of these diastereomeric cyclopropane products can be utilized in the following reaction steps to achieve the peptides of this invention.
  • the trans diastereomeric cyclopropane products are preferred.
  • Fraction B is treated with catalytic tosic acid in methanol at 60°C to remove the acetonide and to afford the alcohol of formula D-8.
  • the compound of formula D-8 is saponified using 50% methanol/2N LiOH (aq) at 40°C to afford the acid of formula D-9.
  • the D-9 acid and isoleucyl-2-pyridyl-methylamide are coupled in dimethylformamide (DMF) using diethylcyanophosphonate and triethylamine (TEA) to afford the D-10 compound.
  • the D-10 compound is dissolved in methylene chloride/trifluoroacetic acid (TFA) at -20°C and stirred for 19 h. Work-up with saturated sodium bicarbonate yields the amino intermediate of formula D-11 which is coupled to Boc-His(Tos) in DMF in the presence of diethylcyanophosphonate and TEA to yield the compound of formula D-12.
  • Deprotection of the compound of formula D-12 is conducted in the same manner as described above for the compound of formula D-10 and the resulting amine of formula D-13 is coupled to Boc-Phe, in the same manner as described above for the compound of formula D-11, to yield the compound of formula D-14.
  • the Tos group is removed from the compound of formula D-14 by treatment with 1-hydroxybenzotriazole in methanol to yield the finnal product of formula D-15.
  • Chart E describes the preparation of peptides of this invention containing two cyclopropyl amino acid groups.
  • Chart F The synthesis of the cyclobutane transition state inserts originates with the olefin of formula F-1, prepared as the compound of formula D-5 in Chart D. Conversion of the compound of formula F-1 to the allylic ester of formula F-2 is accomplished in straightforward fashion via esterification. The compound of formula F-2 is submitted to a photochemical 2+2 cycloaddition. M. Tanaka et al., Tetrahedron Letters (1985) 3035. Both the compounds of formula F-3a and F-3b are formed in the cycloadditon reaction and are separable by chromatographic means.
  • Chart G illustrates an additional method for the synthesis of the cyclobutane transition state inserts.
  • Epoxidation of the compound of formula G-2, using the directing influence of the protected nitrogen, provides the desired epoxide of formula G-3.
  • Deprotonation of the compound of formula G-3 effects an intramolecular cyclization giving rise to the desired target "compound of formula G-4.
  • Chart H Chart H illustrates another method for the synthesis of the cyclobutane transition state inserts.
  • Addition of ylid P(Ph) 3 CCH 2 C ⁇ C to the compound of formula H-1, prepared as the compound of formula D-4 In Chart D, affords the enyne of formula H-2.
  • Carbomethoxylation o the compound of formula H-2 gives the compound of formula H-3 whic upon addition of lithium dimethyl cuprate, and then a higher order cuprate, B.H. Lipshutz et al., Tetrahedron (1984) 40, 5005 and references therein, for the introduction of the second methyl group, yields the compound of formula H-4.
  • Charts G and H described above provide entry to the syn series.
  • the cis olefins corresponding to formula G-2 and H-2 must be used.
  • transition state inserts can readily be coupled to amino acids to build the desired peptides through the use of standard procedures.
  • the renin Inhibiting polypeptides may be prepared by either polymer assisted or solution phase peptide synthetic procedures analogous to those described hereinafter or to those methods known in the art.
  • the carboxylic moiety of N ⁇ - t-butyloxycarbonyl (Boc)-substituted amino acid derivatives having suitable side chain protecting groups may be condensed with the amino functionality of a suitably protected amino acid, peptide or polymer-bound peptide using a conventional coupling protocol such as dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBT) or diethylphosphoryl cyanide (DEPC) and triethylamine (Et 3 N) in methylene chloride or dimethylformamide.
  • DCC dicyclohexylcarbodiimide
  • HOBT 1-hydroxybenzotriazole
  • DEPC diethylphosphoryl cyanide
  • Et 3 N triethylamine
  • N ⁇ -Boc moiety may be selectively removed with 45% trifluoroacetlc 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.
  • this stepwise, coupling strategy may be partially or completely automated to provide the desired peptide-polymer intermediates. Anhydrous hydrofluoric acid treatment of the peptide-polymer intermediate may then be used to effect simultaneous protecting group removal and cleavage of the peptide from its polymeric support.
  • N in -formyl- indolyl-substituted peptides in which the N in -formyl- indolyl moiety is stable to TFA or HF but may be removed by NH 3 or NaOH. Because FTrp is somewhat unstable to base in synthetic procedures, possibly causing lower yields, it may be desirable in solution phase synthesis to introduce the FTrp-containing moiety late in the synthetic sequence so that it is not exposed to such conditions.
  • 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 HCl-formic acid as reported in the literature, see A. Previero et al, Biochim. Biophys. Acta 147, 453 (1967); Y.C ang et al, Int. J. Peptide Protein Res. 15, 130 (1980).
  • methods of alkylation useful in alkylating histidine for use in the present invention are found in Cheung, S.T.
  • peptides may also be prepared by the standard solid phase techniques of Merrifleld. 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.
  • the compounds of the present invention may be in either free form or In protected form at one or more of the remaining (not previously protected) peptide, carboxyl, amino, hydroxy, or other reactive groups.
  • the protecting groups may be any of those known in the polypeptide art. Examples of nitrogen and oxygen protection groups are set forth in T.W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York, (1981); J.F.W. McOmie, ed. Protective Groups in Organic Chemistry, Plenum Press (1973); and J. Fuhrhop and G. Benzlin, Organic Synthesis, Verlag Chemie (1983).
  • nitrogen protective groups include t-butoxycarbonyl (Boc), benzyloxycarbonyl, acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like.
  • Boc t-butoxycarbonyl
  • benzyloxycarbonyl acetyl, allyl, phthalyl, benzyl, benzoyl, trityl and the like.
  • AMP is 2-(aminomethyl)pyridinyl; BOC is t-butoxycarbonyl; BOM is benzyloxymethyl; Bz is benzyl;
  • C centigrade
  • Celite is a filter aid
  • CVDA is "Cha-Val diol" where Cha is 3-cyclohexylalanyl, i.e. the moiety of the formula XL 6 wherein R 1 is cyclohexyl and R 11 is isopropyl and the configuration at each carbon atom with a * is (R);
  • DCC is dicyclohexylcarbodiimide
  • DMF is dimethylformamide
  • EtOAc is ethyl acetate; g. is grams;
  • GEA is 2- (quanidylethyl)amino
  • GMPMA is (3-(guanidylmethyl)phenyl)methylamino
  • HPLC high performance liquid chromatography
  • I 2 is iodine
  • IR is infra red spectra
  • a Lindlar catalyst is a modified 5% palladium on calcium carbonate catalyst, obtained from Engelhard Industries and used for reduction;
  • LVDA is "Leu-Val diol,” i.e., the moiety of the formula XL 6 wherein R 1 and R 11 are isopropyl and the configuration at each carbon atom with a * is (R) ;
  • MBA is 2-methylbutylamino (racemic or optically active);
  • MBAS is 2S-methylbutylamino; Me is methyl; min. is minute; ml is milliliter;
  • MS is mass spectroscopy
  • NMHis is N ⁇ -methyl-L-histidine; NMR is nuclear magnetic resonance;
  • NOAl is (1-naphthyloxy)acetyl
  • p-TSA salt is para-toluene sulfonic acid salt
  • Ph is phenyl
  • POA is phenoxyacetyl
  • 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.
  • Skellysolve B is as defined in the Merck Index, 10th edition;
  • TBDMS is t-butyldimethylsilyl
  • TFA is trifluoroacetic acid
  • THF is tetrahydrofuran
  • TLC is thin layer chromatography
  • Tos is p-toluenesulfonyl
  • Tr is trityl (triphenylmethyl); 2HPA is ( ⁇ )-(2-hydroxypropyl)amino; and UV is ultraviolet.
  • Benzaldehyde (51 g), hlppuric acid (96 g), and sodium acetate (arih. 40 g) are suspended in acetic anhydride (140 ml) in a 1 1 Ehrlenmeyer flask. This is heated on a hot plate with shaking. After becoming a solid mass, it begins liquifying. Once all of the material is a yellow liquid, the flask is maintained at 100° C for 2 hours. Ethanol (200 ml) is added at 0°C. After sitting overnight, the crystals are collected and washed two times with 50 ml of cold ethanol and boiling water to afford 88.25 g of crude material.
  • Diazomethane (formed from 30 g of N-methyl-N'-nitro-N-nitrosoguanidine over 160 ml 45% potassium hydroxide in 400 ml ether and dried over potassium hydroxide pellets) is added to a solution of the title product of Preparation 1 (12 g) in methylene chloride (200 ml) at ambient temperature. Nitrogen evolution is immediate. After stirring overnight, excess diazomethane is destroyed by adding solid calcium chloride. Filtration and evaporation of the filtrate affords 19.8 g of crude product. Flash chromatography over silica gel (1.2 kg, toluene) affords 1.24 g of a mixture of starting material and the first title product. Further elution affords 2.59 g of the first title product. An analytical sample is prepared by recrystallization from methylene chloride to give yellow crystals.
  • IR cm -1 , mull.: 2954, 2925, 2855, 1805, 1635, 1453, 1322, 1255, 1017, 994, 985, 877, 710, 696, 689.
  • 1H-NMR ⁇ , CDCI 3 ): 7.98-7.85, 7.47-7.30, 3.22, 2.36, 2.25.
  • Mass spectrum (ions at m/e): 263, 219, 218, 130, 115, 106, 105, 78, 77, 51.
  • Diazomethane (formed from 30 g of N-methyl-N'-nitro-N-nitrosoguanidine over 160 ml 45% potassium hydroxide in 400 ml ether and dried over potassium hydroxide pellets) is added to a solution of the title product of Preparation 2 (12 g) in methylene chloride (200 ml) at ambient temperature. Nitrogen evolution is immediate. After stirring overnight, excess diazomethane is destroyed by adding solid calcium chloride. Filtration and evaporation of the filtrate affords 15.1 g of crude product.
  • Mass spectrum (ions at m/e): 264, 263, 106, 105, 103, 78, 77, 76, 51, 50.
  • IR cm -1 , mull: 3275, 2950, 2923, 2867, 2855, 1716, 1667, 1648, 1552, 1455, 1437, 1338, 1274, 1162, 713, 696.
  • Mass spectrum (ions at m/e): 191, 159, 132, 131, 130, 117, 115, 104, 103, 91, 77.
  • Mass spectrum (ions at m/e): 191, 159, 132, 131, 130, 115, 104, 103, 91, 77, 51.
  • the crude methyl ester is dissolved in methanol (6.5 ml) and 2N sodium hydroxide (6.5 ml). After stirring at ambient temperature for 23 h, the reaction solution is reduced to half volume in vacuo and the residue transferred to a separatory funnel with ethyl acetate/water. Acidification with 2N hydrochloric acid to pH 5, extracting with ethyl acetate, washing the combined organic layers with brine, and filtering through sodium sulfate affords 0.60 g of the title product after evaporation of the solvent. An analytical sample is prepared by recrystallization from ethyl acetate/hexane. Physical characteristics are as follows: Mp : 163-173°C decomposed.
  • Isomer B is eluted from the column in fractions 145-250 and amounts to 0.020 g.
  • the high resolution FAB mass spectrum has [M + H] + at m/z 985. Theory for C 52 H 73 N 8 O 9 S: 985.5221. Measured: 985.5195. 3.
  • a solution of the product (Isomer A) prepared In paragraph 2 (0.018 g) in dimethylformamide (0.21 ml) and tetrahydrofuran (1.2 ml) under a nitrogen atmosphere is treated with 1-hydroxybenzotriazole (0.025 g) and stirred at room temperature for 20 hr.
  • IR cm -1 , mull: 3357, 3319, 2958, 2925, 2870, 2855, 1687, 1670, 1528 , 1454, 1444, 1366, 1315, 1270, 1253, 1185, 1170, 1007, 701.
  • Preparation 14 (S-(R*,R*))-(1-(Cyclohexylmethyl-2-hydroxy-4-methyl-3- pentenyl)-carbamic acid, 1,1-dimethylethyl ester (Formula D-5) Refer to Chart D. 1-Bromo-2-methylpropene (17.7 g) is added dropwise to a refluxing mixture of Mg (turnings, 3.05 g), 1,2-dibromo-ethane ( 25 ml), and iodine (0.1 g) in tetrahydrofuran (135 ml).
  • IR (mull, cm -1 ): 3440, 2977, 2923, 2853, 1717, 1695, 1502, 1449, 1392, 1366, 1248, 1173, 1044, 1022.
  • IR cm- 1 , mull: 2976, 2952, 2926, 2855, 1729, 1715, 1698, 1456, 1447, 1389, 1377, 1363, 1202, 1185, 1172, 1095, 1055, 769.
  • 1H-NMR (CDCl 3 , ⁇ ): 4.25, 3.5, 3.20, 1.9-1.0, 1.45, 1.28, 1.25, 1.21.
  • IR (mull, cm -1 ): 2983, 2955, 2926, 2916, 2867, 2854, 1723, 1686, 1463, 1456, 1395, 1389, 1378, 1373, 1366, 1253, 1180, 1175, 1157, 1116, 1089, 1022, 844, 770.
  • 1H-NMR ( ⁇ , CDCI 3 ): 4.15, 3.95, 3.60, 2.2-0.7, 1.50.
  • Tosic acid (0.2 g) Is added to a stirring solution of the title product of formula D- 7b of Preparation 16 (218 mg) in methanol (6 . 7 ml) at ambient temperature . After 4.5 h, the reaction is quenched with solid sodium bicarbonate . After evaporation, the residue Is added to a column.
  • Chart D A solution of the title product of Preparation 23 (0.2 g) in methylene chloride (8 ml) and trifluoroacetlc acid (8 ml), is placed at -20°C After 19 h, the reaction solution is transferred to a separatory funnel containing saturated sodium bicarbonate. Extracting 2 times with methylene chloride and drying over magnesium sulfate affords 139.2 mg of the title product.

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Abstract

Nouveaux peptides inhibiteurs de la rennine possédant des insertions de transition insécables correspondant à la position 10,11 d'un substrat de rennine (angiotensinogène) et comprenant au moins un acide amino cyclopropylique à la place d'un reste d'acide aminé correspondant à la position 6, 8, 9, 12, 13 ou 14 du substrat de rennine; et/ou une insertion de transition insécable acide amino cycloalkyle à la place d'un reste d'acide aminé correspondant à la position 10 et 11 du substrat de rennine. De tels inhibiteurs sont utiles pour le diagnostic et le contrôle de l'hypertension due à la rennine et autres maladies apparentées.
PCT/US1988/000547 1987-03-09 1988-03-02 Inhibiteurs de la rennine contenant un acide amino cyclopropylique ou un cycloalkyle de transition analogue WO1988007053A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0361341A3 (fr) * 1988-09-28 1991-07-03 Miles Inc. Agents thérapeutiques contre le SIDA basés sur des inhibiteurs des protéases du HIV
EP0452587A1 (fr) * 1989-09-15 1991-10-23 E.R. SQUIBB & SONS, INC. Dihydroxy sulfonamides et sulfinamides comme inhibiteurs de rénine
WO1992000972A1 (fr) * 1990-07-11 1992-01-23 Abbott Laboratories Composes inhibiteurs de renine

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985000809A1 (fr) * 1983-08-16 1985-02-28 University Of Georgia Research Foundation, Inc. Synthese de peptides et d'acides amines de cyclopropane
EP0173481A2 (fr) * 1984-08-06 1986-03-05 The Upjohn Company Peptides

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1985000809A1 (fr) * 1983-08-16 1985-02-28 University Of Georgia Research Foundation, Inc. Synthese de peptides et d'acides amines de cyclopropane
EP0173481A2 (fr) * 1984-08-06 1986-03-05 The Upjohn Company Peptides

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
Chemical and Pharmaceutical Bulletin, vol. 18, no. 11, November 1970 S. Kimoto et al.: "Stereochemistry of decahydroisoquinolines and related compounds. VIII. Syntheses of trans-4-hydroxy-2-methyldecahydroisoquinolines", see pages 2141-2145 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0361341A3 (fr) * 1988-09-28 1991-07-03 Miles Inc. Agents thérapeutiques contre le SIDA basés sur des inhibiteurs des protéases du HIV
EP0452587A1 (fr) * 1989-09-15 1991-10-23 E.R. SQUIBB & SONS, INC. Dihydroxy sulfonamides et sulfinamides comme inhibiteurs de rénine
US5098924A (en) * 1989-09-15 1992-03-24 E. R. Squibb & Sons, Inc. Diol sulfonamide and sulfinyl renin inhibitors
US5545838A (en) * 1989-09-15 1996-08-13 E. R. Squibb & Sons, Inc. Diol sulfonamide and sulfinyl renin inhibitors
WO1992000972A1 (fr) * 1990-07-11 1992-01-23 Abbott Laboratories Composes inhibiteurs de renine

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JPH02502457A (ja) 1990-08-09
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