EP0364493A1 - Peptides inhibiteurs de la renine a liaisons non peptidiques - Google Patents

Peptides inhibiteurs de la renine a liaisons non peptidiques

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Publication number
EP0364493A1
EP0364493A1 EP88906552A EP88906552A EP0364493A1 EP 0364493 A1 EP0364493 A1 EP 0364493A1 EP 88906552 A EP88906552 A EP 88906552A EP 88906552 A EP88906552 A EP 88906552A EP 0364493 A1 EP0364493 A1 EP 0364493A1
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Prior art keywords
alkyl
aryl
zero
absent
amino
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EP88906552A
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German (de)
English (en)
Inventor
Ruth E. Ten Brink
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Pharmacia and Upjohn Co
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Upjohn Co
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C321/00—Thiols, sulfides, hydropolysulfides or polysulfides
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/18—Compounds having one or more C—Si linkages as well as one or more C—O—Si linkages
    • C07F7/1804—Compounds having Si-O-C linkages
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0227—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the (partial) peptide sequence -Phe-His-NH-(X)2-C(=0)-, e.g. Renin-inhibitors with n = 2 - 6; for n > 6 see C07K5/06 - C07K5/10

Definitions

  • the present invention provides novel compounds. More particularly, the present invention provides novel renin-inhibiting peptide analogs with nonpeptide linkages. Most particularly, the present invention provides renin-inhibitory compounds which contain modifications of the Phe 8 -His 9 (angiotensinogen numbering) positions. The modifications involve substitution of nonproteinogenic (non ⁇ -amino acid) moieties for the usual ⁇ -amino acid residues. Specifically, aryl acid derived moieties are substituted for Phe 8 -His 9 .
  • 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 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. 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 published application No.
  • 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.
  • European published applications 045 665, 118 223, and 104 041 disclose isosteric replacements of the "reduced" ( ⁇ [CH 2 NH]) kind at one or both of the Pro-Phe or Phe-His links in compounds of the formula X- Y-Pro 7 -Phe 8 -His 9 -A 10 ' 11 -B-Z-W.
  • European published application 206 090 discloses hydroxyethylene- type isosteres to the left of the transition state insert of renin inhibitors.
  • the present invention particularly provides: A renin inhibitory peptide having a non-cleavable transition state insert corresponding to the 10,11-position of a renin substrate (angiotensinogen) and having a moiety of the formula XL 2b in place of amino acid residues normally found at the 8,9- position of the renin substrate; wherein R 50 is
  • R 51 NHCH(R 52 )(CO)-, or (e) R 51 CH(R 52 )NH(CO)-; provided that R 50 is the substituent in (d) only when r, t, and u are all zero; provided that R 50 is the substituent in (e) only when r, t, u and v are all zero; wherein R 51 is
  • R 5 (i) R 5 -SO 2 -(CH 2 ) q -O-C(O)-, or (j) R 6 -(CH 2 ) i -C(O)-; wherein R 52 is (a) aryl, (b) -(C 1 -C 4 )alkylaryl,
  • 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 other amino acids corresponds to that of the naturally-occurring amino acids.
  • Renin inhibitory peptides commonly have protecting groups at the
  • non ⁇ -amino acid moieties 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 non ⁇ -amino acid moiety and have transition state inserts.
  • 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, per
  • the carbon atom content of various hydrocarbon-containing moieties is indicated by a prefix designating the minimum and maximum number of carbon atoms in the moiety, i.e., the prefix (C i -C j ) indicates a moiety of the integer "i" to the integer "j" carbon atoms, inclusive.
  • (C 1 -C 4 )alkyl refers to alkyl of one to 4 carbon atoms, inclusive, or methyl, ethyl, propyl, butyl, and isomeric forms thereof.
  • C 4 -C 7 cyclic amino indicates a monocyclic group containing one nitrogen and 4 to 7 carbon atoms.
  • Examples of (C 3 -C 10 )cycloalkyl which include alkyl-substituted cycloalkyl containing a total of up to 10 total carbon atoms, are cyclopropyl, 2-methylcyclopropyl, 2,2-dimethylcyclopropyl, 2,3-diethylcyclopropyl, 2-butylcyclopropyl, cyclobutyl, 2-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-)ethyIphenyl, 2-ethyl-tolyl, 4-ethyl-o-tolyl, 5-ethyl-m-tolyl, (o-, m-, or p-)propyIphenyl, 2-propyl- (o-, m-, or p-)tolyl, 4-isopropyl-2,6-xylyl, 3-propyl-4-ethyIphenyl, (2,3,4- 2,3,6-, or 2,4,5-)- trimethyIphenyl, (o-, m-, or p-) fluorophenyl, (o-, m-, or p-trifluoromethyl)phenyl, 4-fluoro-2,5-xylyl, (2,4-, 2,5-, 2,6-, 3,4-
  • Examples of -Het include: 2-, 3-, or 4-pyridyl, imidazolyl, indolyl, N in -formyl-indolyl. N in -C 1 -C 5 alkyl-C(O) -indolyl, [1,2,4]- triazolyl, 2-, 4-, or 5-pyrimidinyl, 2- or 3-thienyl, piperidinyl, pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, pyrazinyl, piperazinyl, pyridazinyl, oxazolyl, oxazolidlnyl, isoxazclyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolidinyl, isothiazolidinyl, iso
  • 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.
  • the 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 reninassociated 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-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 compounds will also be useful as molecular probes for the diagnosis and study of the physiology of blood pressure regulation or other physiological functions.
  • Inhibitors containing these "non-natural" residues are potent inhibitors of human plasma renin.
  • the novel non-peptidic nature of these inhibitors is expected to alter their absorption, distribution, metabolism, and elimination.
  • the new residues make the inhibitor unrecognizable to proteinases, such as chymotrypsin, elastase, or aminopeptidase, which normally would rapidly degrade a substrate-based peptidic inhibitor.
  • proteinases such as chymotrypsin, elastase, or aminopeptidase
  • 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, transdermally 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. Equivalent dosages for such other routes of administration are thus employed. The exact dose depends on the age, weight, and condition of the patient and on the frequency and route of administration. Such variations are within the skill of the practitioner or can readily be determined.
  • the compounds of the present invention may be in the form of pharmaceutically acceptable salts both those which can be produced from the free bases by methods well known in the art and those with which acids have pharmacologically acceptable conjugate bases.
  • the renin-inhibiting compounds of this invention may be administered in combination with other agents used in antihypertensive therapy such as diuretics, ⁇ 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, ⁇ 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; amilorlde; bendroflumethiazide; benz thiazide; bumetanide; chlorothiazide; chlorthalidone; cyclothiazide; ethacrynic acid; furosemide; hydrochlorothiazide; hydroflumethiazide; indacrinone (racemic mixture, or as either the (+) or (-) enantiome 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; phenoxybenzamine; prazosin;
  • 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 the compound of formula A-5 is shown in Chart A.
  • m-Toluic acid (formula A-1) is photolyzed with bromine to give 3- (bromomethyl) benzoic acid (formula A-2).
  • 3- (Bromomethyl) benzoic acid (formula A-2) is then stirred with two equivalents of sodium thiophenoxide to give m-(phenylthiomethyl)benzoic acid (formula A-3).
  • the acid is coupled to LVA(O-t-BDMS) -Ile-Amp using diethylphosphorylcyanide to give the compound of formula A-4. Removal of the t-butyldimethylsilyl protecting group with tetrabutylammonium fluoride gives the compound of formula A-5.
  • cycloalkyl compounds of the present invention containing the formula XL 2b moiety wherein R 50 is cycloalkyl may be prepared by synthetic procedures similar to that described above.
  • CHART G LVA-Ile-Amp (formula G-8) and LVA(O-t-BDMS) -Ile-Amp (formula G-7) are synthesized in the following manner: Boc-Ile (formula G-1) and 2- (aminomethyl) pyridine (formula G-2) are coupled using dicyclohexylcarbodiimide to give Boc-Ile-Amp (formula G-3).
  • the Boc group is removed with trifluoroacetic acid in methylene chloride and the resulting trifluoroacetate salt is neutralized via extraction from aq. sodium bicarbonate with methylene chloride to give Ile-Amp (formula G-4).
  • Ile-Amp (formula G-4) is coupled with Boc-LVA(O-t-BDMS) -OH (formula G- 5), prepared as described in U.S. application Serial No. 825,250, filed 3 February 1986, to give Boc-LVA(O-t-BDMS) -Ile-Amp (formula G-6).
  • the Boc group is removed with trifluoroacetic acid in methylene chloride to give, after neutralization and chromatography, LVA-Ile-Amp (formula G- 8) and LVA(O-t-BDMS) -Ile-Amp (formula G-7).
  • 3-Hydroxypicolinic acid (formula J-1) is esterified with methanol using concentrated sulfuric acid as the acid catalyst to give methyl 3- hydroxypicolinate (formula J-2).
  • Methyl 3-hydroxypicolinate (formula J-2) is O-alkylated with chloromethylphenylsulfide (formula J-3) using potassium carbonate in dimethylformamide to give the compound of formula J-4.
  • the compound of formula J-4 is hydrolyzed using 1.5 equivalents of 1 N potassium hydroxide in methanol, followed by acidification with 2 N hydrochloric acid to give the compound of formula J-5.
  • the compound of formula J-5 is coupled with Leu ⁇ [CH(OH) -
  • the compound(s) of formula M-3 and/or M-4 are coupled with 2HCl-LVA- Ile-Amp (formula M-5) using diethylphosphorylcyanide and triethylamine In methylene chloride and dimethylformamide to give the compound(s) of formula(s) M-6 and/or M-7.
  • the compound of formula P-4 is coupled with the compound of formula P-5 (see Chart B) using diethylphosphorylcyanide, triethylamine, and methylene chloride to give the compound of formula P-6.
  • the silyl protecting group of the compound of formula P-6 is removed with tetra-n-butylammonium fluoride in tetrahydrofuran to give the compound of formula P-7.
  • 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.
  • the carboxylic moiety of N ⁇ -t-butyloxycarbony-1 (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 (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% trifluoroacetic acid with or without 2% anisole (v/v) in methylene chloride.
  • Neutralization of the resultant trifluoroacetate salt may be accomplished with 10% diisopropylethylamine or sodium bicarbonate in methylene chloride.
  • N in -formyl-Trp into compounds of the present invention is easily accomplished because of the commercial availability of N ⁇ -Boc-N in -formyl-Trp-OH.
  • the N in -formyl moiety may be introduced into indolyl-substituted amino acid derivatives or related compounds by reaction with HCl-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.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.
  • the following compounds of the present invention are preferred: 2-(Boc-Phe-amido)benzoyl-LVA-Ile-Amp; 2-(Boc-Phe-amido)nicotinoyl-LVA- Ile-Amp; and 2-(Phenylthiomethyleneoxy)benzoyl-LVA-Ile-Amp.
  • 1-HOBt is 1-hydroxybenzotriazole;
  • HPLC high performance liquid chromatography;
  • I 2 is iodine;
  • Ile is isoleucine;
  • IR is infra red spectra;
  • LVA is Leu ⁇ [CH(OH)CH 2 ]Val;
  • LVDA is Leu ⁇ [CH(OH)CH(OH)]Val;
  • M or mol is mole;
  • 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 renininhibiting peptide.
  • Skellysolve B is as defined in the Merck Index, 10th edition; t-BDMS 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.
  • 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.
  • statine The synthesis of statine is disclosed in Evans et al., J. Org. Chem. 47: 3016 (1982).
  • the synthesis of moieties at the E 10 F 11 osition is disclosed in the following: U.S. patent application, Serial No. 825,250, filed 3 February 1986 (synthesis of LVA); U.S. patent application. Serial No. 000,291, filed 13 February 1987 (synthesis of dihydroxy-LVA; and published European Patent Application 189,203 (synthesis of amino-diol).
  • reaction mixture is partitioned between methylene chloride and hexane to give 0.58 g of the title product.
  • Preparation 5 m-(Phenylthiomethyleneoxy)benzoic Acid (Formula B-4) Refer to Chart B. To 0.1052 g of the title product of Preparation 4 in 5 ml of methanol is added 0.44 ml of 1 N sodium hydroxide. After 30 min, an additional 0.11 ml of 1 N sodium hydroxide is added and after 3 hrs, 0.22 ml of 1 N sodium hydroxide is added. The reaction is stirred overnight, methanol is then removed in vacuo, and the residue is partitioned between diethyl ether, aq. hydrochloric acid, and brine. The organic layers are dried over magnesium sulfate and taken to dryness in vacuo.
  • Preparation 16 2-(Boc-Phe-amido)benzoic acid (Formula D-4) Refer to Chart D. To 0.46 g of the title product of Preparation 15 in 25 ml of ethanol is added dropwise over several minutes 1.67 ml of 1 N sodium hydroxide. After stirring for 1 h, the reaction is concentrated, acidified with aq. hydrochloric acid, and partitioned between ethyl acetate and brine. The organic layers are dried over magnesium sulfate and concentrated In vacuo. The residue is crystallized from ethyl acetate and hexane to give 0.227 g of the title product. Physical characteristics are as follows: M.P.: 188-189°C.
  • Methyl 2-aminonicotinate Refer to Chart F. A solution of 0.78 g of 2-amino nicotinic acid in 70 ml of methanol/methylene chloride is stirred for 4 days. The solvent is then removed in vacuo and the residue is partitioned with methylene chloride and aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate and taken to dryness to give 0.38 g of the title product.
  • Example 8 2-(Boc-Phe-amido)nlcotinoyl-LVA-Ile-Amp (Formula F-5) Refer to Chart F. To 0.060 g of the title product of Preparation 19 (impure) and 0.078 g of LVA-Ile Amp-2HC1 in 10 ml of methylene chloride is added 0.072 ml of triethylamine, followed by 0.031 ml of diethylphosphorylcyanide. After stirring for 2 days at room temperature, the reaction mixture is partitioned with chloroform and aq. sodium bicarbonate.
  • LVA-Ile-Amp ⁇ 2HCl and 30 ml of methylene chloride are added 0.106 ml of triethylamine, followed by 0.0445 ml of diethylphosphorylcyanide. After about a minute, 2 ml of dimethylformamide is added to obtain a homogeneous solution. After 2.5 h, the reaction mixture is partitioned between methylene chloride and aq. sodium bicarbonate and brine. The organic layers are filtered through sodium sulfate, concentrated, and the residue chromatographed on silica gel using 3% methanol-methylene chloride (ammonium hydroxide sat'd) to give 0.1305 g of the title product.
  • N ⁇ - (4-Carboxy)nicotinoyl-D-phenylalanine tert-butyl ester and/or N ⁇ -(3-Carboxy)isonicotinoyl-D-phenylalanine tert-butyl ester Refer to Chart L. To 0.2007 g of D-Phe-O-t-Bu in 10 ml of tetrahydrofuran and 2 ml of methylene chloride is added 0.1444 g of 3,4-pyridine bicarboxylic anhydride. After stirring for 3.5 hrs, the reaction mixture is partitioned between diethyl ether and brine.
  • Example 10 4-[(1'R-tert-Butoxycarbonyl)phenethylaminocarbonyl]- nicotinoyl-LVA-Ile-Amp and/or 3-[(l'R-tert-Butoxycarbonyl)phenethylaminocarbonyl]isonicotinoyl-LVA-Ile-Amp (Formula L-6 and/or Formula L-7) Refer to Chart L.
  • N ⁇ -(3-Carboxy)picolinoyl-D-phenylalanine tert-butyl ester and/or N ⁇ -(2-Carboxy)nicotinoyl-D-phenylalanine tert-butyl ester Refer to Chart M. To 0.2347 g of D-Phe-O-t-Bu in 5 ml of tetrahydrofuran is added 0.1688 g of 2, 3-pyridine dicarboxylic anhydride. After stirring for 1.75 hrs, the reaction mixture is partitioned between diethyl ether and brine.
  • Preparation 28 5S-Amino-4S-tert-butyldimethylsilyloxy-2S-isopropyl-7- methyloctanoyl-2S-methylbutylamide (Formula H-4: X is 2(S)methylbutyl)
  • X is 2(S)methylbutyl
  • a solution of 0.413 g of the title product of Preparation 27 in 10 ml of trifluoroacetic acid-methylene chloride (1:1) is stirred at room temperature for 10 minutes. Trifluoroacetic acid and methylene chloride are removed in vacuo and the residue is extracted four times with methylene chloride and two times with aq. sodium bicarbonate. The organic layers are filtered through sodium sulfate and taken to dryness to give 0.323 g of the title product and a small amount of the desilylated material.
  • Preparation 32 2-(Phenylthiomethyleneoxy)benzoyl-Leu ⁇ [CH(O-t-BDMS)CH 2 ]- Val-methylamlde (Formula 1-6) Refer to Chart I. To 0.0500 g of 2-(phenylthiomethyleneoxy)benzoic acid, 0.05740 g of the title product of Preparation 31, and 5 ml of methylene chloride are added 0.028 ml of triethylamine and 0.030 ml of diethylphosphorylcyanide. After stirring overnight, the reaction mixture is partitioned between methylene chloride and aq. sodium bicarbonate.
  • Methyl 3-(phenylthiomethyleneoxy)plcolinate (Formula J- 4) Refer to Chart J. A mixture of 0.18 g of methyl 3-hydroxypIcolinate, 0.17 mi of chloromethyIphenyl sulfide, 0.178 g of potassium carbonate, and 10 ml of dimethylformamide is stirred at room temperature for 20 hours. The dimethylformamide is then removed in vacuo and the residue is partitioned between methylene chloride and 1 N sodium hydroxide. The organic layers are filtered through sodium sulfate, concentrated, and the crude material is chromatographed on silica gel using 2% methanolmethylene chloride to give 0.1222 g of the title product.
  • Preparation 42 2-(Phenylthiomethyleneoxy)benzoyl-5S-amino-4S-tert- butyldimethyIsilyloxy-2S-isopropyl-6-cyclohexylhexanoylmethylamide (Formula P-6) Refer to Chart P. To 0.0376 g of 2-(phenylthiomethyleneoxy) benzoic acid, 0.048 g of the title product of Preparation 41, and 2 ml of methylene chloride are added 0.022 ml of triethylamine and 0.024 ml of diethylphosphorylcyanide. After stirring at room temperature for 1.5 hours, the reaction mixture is partitioned between methylene chloride and aq.
  • Example 19 2-(Phenylthiomethyleneoxy)benzoyl-2S-amino-1-cyclohexyl- 3R,4-dihydroxy-6-methylheptane (Formula Q-5) Refer to Chart Q. To 0.012 g of the title product of Preparation 44, 0.0192 g of 2- (phenylthiomethyleneoxy) benzoic acid, and 2 ml of methylene chloride are added 0.011 ml of triethylamine and 0.012 ml of diethylphosphorylcyanide. After stirring for 2 hours, the reaction mixture is partitioned between methylene chloride and aq. sodium bicarbonate.

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Abstract

Nouveaux peptides inhibiteurs de la rénine de formule X-A6-B7-C8-D9-E10-F11-G12-H13-I14-Z, contenant des parties dérivées de l'acide d'aryle de formule XL2b, qui sont substituées au Phe8-His9, X et Z sont des groupes en fin de chaîne, et les variables restantes sont absentes ou bien sont des résidus aminoacides. Ces inhibiteurs sont utiles pour le diagnostic et la maîtrise de l'hypertension liée à la rénine et d'autres maladies apparentées.
EP88906552A 1987-08-07 1988-07-11 Peptides inhibiteurs de la renine a liaisons non peptidiques Withdrawn EP0364493A1 (fr)

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JPH04500963A (ja) * 1988-09-26 1992-02-20 ジ・アップジョン・カンパニー マレアミド置換基を含有するレニン抑制ペプチド類
US6403587B1 (en) 1997-02-26 2002-06-11 Pfizer Inc. Heteroaryl-hexanoic acid amide derivatives, their preparation and their use as selective inhibitors of MIP-1-α binding to its CCR 1 receptor
EP1666452A2 (fr) 2000-06-30 2006-06-07 Elan Pharmaceuticals, Inc. Composés pour le traitement de la maladie d'Alzheimer
PE20020276A1 (es) 2000-06-30 2002-04-06 Elan Pharm Inc COMPUESTOS DE AMINA SUSTITUIDA COMO INHIBIDORES DE ß-SECRETASA PARA EL TRATAMIENTO DE ALZHEIMER
KR100787131B1 (ko) 2006-07-04 2007-12-21 한국생명공학연구원 Ｈｉｆ―１ 활성을 저해하는 화합물, 이의 제조방법 및이를 유효성분으로 함유하는 약학적 조성물
US11174229B2 (en) * 2018-10-29 2021-11-16 Kempharm, Inc. D-amphetamine compounds, compositions, and processes for making and using the same

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DE3418491A1 (de) * 1984-05-18 1985-11-21 Merck Patent Gmbh, 6100 Darmstadt Diaminosaeurederivate
FI88400C (fi) * 1984-08-06 1993-05-10 Upjohn Co Foerfarande foer framstaellning av renin inhiberande peptider
US4665055A (en) * 1985-06-17 1987-05-12 Merck & Co., Inc. Peptide renin inhibitors
DE3538749A1 (de) * 1985-10-31 1987-05-07 Merck Patent Gmbh Peptide
EP0236734A3 (fr) * 1986-02-07 1988-05-11 Ciba-Geigy Ag Dérivés d'amino-5-hydroxy-4-valeryl substitués par des groupes contenant du soufre

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JPH02504509A (ja) 1990-12-20
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