WO1990014362A1 - Derives de peptides atriaux - Google Patents

Derives de peptides atriaux Download PDF

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Publication number
WO1990014362A1
WO1990014362A1 PCT/US1990/002917 US9002917W WO9014362A1 WO 1990014362 A1 WO1990014362 A1 WO 1990014362A1 US 9002917 W US9002917 W US 9002917W WO 9014362 A1 WO9014362 A1 WO 9014362A1
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WO
WIPO (PCT)
Prior art keywords
arg
ile
cys
gly
phe
Prior art date
Application number
PCT/US1990/002917
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English (en)
Inventor
Scott D. Lucas
Todd W. Rockway
Steven K. Davidsen
A. Mitchell Thomas
Thomas W. Von Geldern
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Abbott Laboratories
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Publication date
Application filed by Abbott Laboratories filed Critical Abbott Laboratories
Priority to KR1019910700087A priority Critical patent/KR920701244A/ko
Publication of WO1990014362A1 publication Critical patent/WO1990014362A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/58—Atrial natriuretic factor complex; Atriopeptin; Atrial natriuretic peptide [ANP]; Cardionatrin; Cardiodilatin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/10—Antioedematous agents; Diuretics
    • 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
    • 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 relates to derivatives of atrial natriuretic polypeptides (ANP) which exhibit useful
  • hypotensive, natriuretic, diuretic, renovasodilating
  • hypertension has been classified as either hypertension having clear factor disease or hypertension
  • kidney disease is also known as secondary hypertension and involves mainly hypertension caused by kidney disease
  • the conditions of secondary hypertension can be improved by treatment of the factor disease.
  • vasodilators which provide symptomatic relief.
  • alpha-human atrial polypeptide (alpha-hANP) has been isolated from human atrium and identified as a polypeptide consisting of twenty eight amino acids having the following formula:
  • Alpha-hANP is a peptide hormone which reacts with
  • alpha-hANP is about 1000 times as strong as that of furosemide which is used as a hypotensive diuretic.
  • alpha-hANP or derivatives thereof which are chemically and enzymatically stable and have therapeutically useful potency and duration of action have not been commercially
  • novel peptides which exhibit useful hypotensive, natriuretic, diuretic, renovasodilating, reno-protective, smooth muscle
  • R 1 is selected from hydrogen
  • R 2 is a sulfur-containing group
  • R 3 is a hydrophobic amino acid or dipeptide
  • R 4 is a dipeptide spacer, or a tripeptide containing a
  • R 5 is a hydrophobic amino acid
  • R 6 is a peptide of up to three amino acids
  • R 7 is selected from Cha, Phe, Cha-Arg, Phe-Arg, (D)Phe-Arg,
  • the present invention also relates to the use of the atrial peptide derivatives of formula (I) in the treatment of ANP-related diseases.
  • the invention further relates to compositions comprising a therapeutically effective amount of the polypeptide of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • the present invention provides novel peptides which exhibit useful hypotensive, natriuretic, diuretic,
  • the compounds of the invention comprise peptides having the following amino acid sequence:
  • Cit, His, Lys, Orn and Ser-Ser and is preferably hydrogen
  • R 2 is Mpa or a basic ammo acid
  • R 2 is a sulfur-containing group
  • R 3 is a hydrophobic amino acid or dipeptide, examples of which include Phe, (D)Phe, Phe-Gly, Phg, (D)Phg, Cha, (D)Cha, Chg,
  • R 4 is a dipeptide spacer such as Gly-Gly or (D) Ala-Ala, or a tripeptide of the formula X-Y where X is a dipeptide spacer and Y is a basic amino acid, as for example Gly-Gly-Arg, Gly- Gly- (D) Arg, Gly-Gly-Lys, Gly-Arg-Arg, (D) Ala-Arg-Arg, (D)Ala- Ala-Arg and (D)Ala- (D) Ala-Arg;
  • R 5 is a hydrophobic ammo acid;
  • R 6 is a peptide of up to three amino acids, such as Asp-Arg-
  • R 7 is selected from Cha, Phe, Cha-Arg, Phe-Arg, (D)Phe-Arg,
  • the methods of the present invention comprise the use of atrial peptide derivatives of formula (I) in the treatment of ANP-related diseases including, for example, congestive heart failure, renal failure and hypertension.
  • compositions of the invention include compositions comprising a therapeutically effective amount of a polypeptide of formula (I) and a pharmaceutically acceptable carrier or diluent.
  • polypeptides as well as their pharmaceutically acceptable salts, esters and amides:
  • Arg-Cys-3 5-l 2 Tyr-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Phe-Arg-Cys-NH 2 ; Arg-Cys-Cha-Gly-Gly-Arg-Ile-Asp-Arg-Ile-Arg-Cys-NH 2 ;
  • Preferred compounds of this invention include the
  • amino acid components of the above compounds are designated by conventional abbreviations as follows :
  • All of the above amino acids can be either in the L or D configuration as well as mixtures thereof including a racemic mixture of the two isomers. Unless expressly stated otherwise, all of the amino acids are optically active and have the L- configuration.
  • AcetylArg refers to a group wherein an acetyl group is attached through the carbonyl carbon of the acetyl group to the alpha amino group of the amino acid arginine.
  • acidic amino acid refers to amino acids which have a group, in addition to the alpha- carboxylic acid group, which exists in ionized form in neutral aqueous solution, as for example Asp, Glu and the like.
  • basic amino acid refers to amino acids which have a group, in addition to the alpha-amino group, which exists in protonated form in neutral aqueous solution, as for example Lys, Orn, Arg and the like.
  • cycloalkyl refers to a three to seven carbon cyclic radical. These radicals can be
  • hydrophobic amino acid refers to amino acids which lack an affinity for water, such as Ala, lie, Leu, Val, Met, Nva, Phe, Phg, Cha, Chg, Tic, and the like.
  • sulfur-containing group refers to a group having a sulfur substituent which is available to participate in bonding to form a disulfide bridge, as for example Cys, Mpa, Pen and hCys.
  • salts, esters, or amides pharmaceutically acceptable salts, esters, or amides
  • pharmaceutically acceptable, nontoxic addition salts are salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid.
  • salts include nitrate, bisulfate, formate, valerate, lactate, fumarate, oleate, palmitate, stearate, laurate, borate, benzoate, mesylate, ascorbate, p-toluene-sulfonate, glucoheptonate, lactobioate, lauryl sulfate and the like or metal salts such as sodium, potassium, calcium or magnesium salts or amino salts such as ammonium, triethylamine salts, and the like and they may be prepared according to conventional methods.
  • pharmaceutically acceptable, non-toxic esters of the compounds of Formula (I) include C1 to C6 alkyl esters wherein the alkyl group is straight or branched chain.
  • Acceptable esters also include C5 to C7 cycloalkyl esters. C1 to C4 alkyl esters are preferred. Esters of the compounds of Formula (I) may be prepared according to conventional methods.
  • Examples of pharmaceutically acceptable, nontoxic amides of the compounds of Formula (I) include amides derived from ammonia, primary C1 to C6 alkyl amines and secondary C1 to C6 dialkyl amines wherein the alkyl groups are straight or branched chain. In the case of secondary, amines the amine may also be in the form of a five or six membered heterocycle containing one nitrogen atom. Amides derived from ammonia, C1 to C3 alkyl primary amines and C1 to C2 dialkyl secondary amines are preferred. Amides of the compounds of Formula (I) are prepared according to the conventional methods.
  • the daily dose of the compounds of the present invention may be suitably defined, according to the condition of the patient, by those skilled in the art, but generally may be administered in an amount of 0.2 - 250 mg/kg body weight.
  • Unit dosage compositions may contain such amounts of submultiples thereof to make up the daily dose.
  • the amount of active ingredient that may be combined with carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed; the age, body weight, general health, sex and diet of the patient; the route of administration and the rate of excretion of the specific compound; drug combination used and the severity of the particular disease being treated.
  • the compounds of the present invention may be
  • parenteral as used herein includes subcutaneous injections, intravenous,
  • Injectable preparations as for example sterile
  • injectable aqueous or oleaginous suspensions may be any suitable injectable aqueous or oleaginous suspensions.
  • the sterile injectable preparation may also be a sterile
  • injectable solution or suspension in a nontoxic parenterally acceptable diluent or solvent as for example a solution in 1,3-butanediol.
  • a nontoxic parenterally acceptable diluent or solvent as for example a solution in 1,3-butanediol.
  • acceptable vehicles and solvents that may be employed are water. Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed including synthetic mono- or
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • Suppositories for rectal administration of the drug can be prepared by mixing the drug with a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • a suitable nonirritating excipient such as cocoa butter and polyethylene glycol which are solid at ordinary temperature but liquid at the rectal temperature and will therefore melt in the rectum and release the drug.
  • Solid dosage forms for oral administration may include capsules, tablets, pills, powders and granules.
  • the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch.
  • Such dosage forms may also comprise, as is normal practice,
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration may include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art such as water. Such compositions may also comprise adjuvants, such as wetting agents; emulsifying and suspending agents; and sweetening, flavoring and perfuming agents.
  • adjuvants such as wetting agents; emulsifying and suspending agents; and sweetening, flavoring and perfuming agents.
  • novel polypeptides and salts thereof of the invention can be utilized effectively as vasorelaxant agents, diuretics, natriuretic agents, renovasodilators or renoprotective agents. Accordingly the present invention further relates to
  • vasorelaxant diuretic, natriuretic, renovasodilating or renoprotective compositions comprising a novel polypeptide having the general formula (I) or salts thereof as an active component.
  • polypeptides of the invention may be prepared by the synthetic method of elongation of a peptide chain through condensation of one amino acid by one, or several amino acids, or by a combination of these methods in accordance with conventional peptide synthesis methods.
  • condensation of two amino acids may be effected in accordance with conventional condensation methods such as the azide method, the mixed acid anhydride method, the DCC
  • detachable bond by reacting with a carboxyl group in a C- terminal amino acid, as for example halomethyl resins such as chloromethyl or bromomethyl resins; hydroxymethyl resin;
  • branched chain amino and carboxyl groups at alpha and omega positions in amino acids may be protected and deprotected if necessary.
  • the protecting groups for amino groups which can be used involve, for example, benzyloxycarbonyl (Z), o-chloro- benzyloxycarbonyl ((2-Cl)Z), p-nitrobenzyloxycarbonyl (Z (NO 2 )), p-methoxybenzyloxycarbonyl (Z(OMe)), t-butoxycarbonyl (Boc), t-amyloxycarbonyl (Aoc), isobornealoxycarbonyl,
  • Ppt diphenylphosphinothioyl
  • Mpt dimethylphosphino-thioyl
  • protecting groups for carboxyl groups involve, for example, benzyl ester (OBzl), cyclohexyl ester, 4-nitrobenzyl ester (OBZINO 2 ), t-butyl ester (OtBu), 4- pyridylmethyl ester (OPic) and the like.
  • the guanidino group (N G ) in arginine may be protect with nitro, p-toluenesulfonyl (Tos), benzyloxycarbonyl (Z), adamantyloxycarbonyl (Adoc), p-methoxybenzenesulfonyl, 4- methoxy-2,6-dimethyl-benzenesulfonyl (Mts) and the like, and the thiol group in cysteine may be protected with benzyl, p- methoxybenzyl, triphenylmethyl, acetamidomethyl,
  • ethylcarbamyl 4-methylbenzyl (4-MeBzl), 2,4,6,- trimethylbenzyl (Tmb) and the like
  • hydroxy group in serine may be protected with benzyl (Bzl), t-butyl, acetyl, tetrahydropyranyl (THP) and the like.
  • the compounds of the invention are prepared by standard solid phase peptide synthesis conditions as described in
  • the compounds of the invention may also be prepared by partial solid phase synthesis, fragment condensation methods and classical solution methods as exemplified by the methods described in "Peptide Synthesis", Second Edition, M. Bodansky, Y.S. Klausner and M.A. Ondetti (1976).
  • Resin p-methylbenzhydrylamine functionalized styrene- divinylbenzene copolymer, 0.5 g, commercially available from Bachem, Inc.
  • Boc-Cys (4-MeBzl) Boc- Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta- cyclohexyl), Boc-Leu, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc- (D)Ala, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Arg(N G -Tos), according to the protocol outlined in Agenda A to yield the protected peptide resin: Arginyl-Cysteinyl (4-MeBzl)-Cyclohexylalanyl-
  • Step 3 in DMF; 0.2 M diisopropylcarbodiimide in CH 2 CI 2 , reaction time 60 min.
  • the excess iodine was removed from the solution by first adjusting the pH to about 5.5 with 50 mL glacial acetic acid and then adding 3-6 mL of 0.01N sodium thiosulfate solution. The combined aqueous solution was applied to a column containing 300 g XAD-16 molecular adsorbent resin
  • the sample was desalted by first washing the column with 3 L distilled water. The sample was eluted from the column with 1.5 L 50% aqueous ethanol. The combined ethanol fractions were concentrated to approximately 100 mL in vacuo, taken up in an additional 100 mL distilled water and lyophilized to a dry amorphous powder. The dry powder was purified by High
  • HPLC Performance Liquid Chromatography
  • TFA trifluoroacetic acid
  • acetonitrile organic modifiers.
  • the preparative HPLC was performed using a Dynamax (RAININ) C 18 reverse-phase column (2.1 cm i.d. X 25 cm) at a flow rate of 12-15 mL/min.
  • the sample was purified by linear solvent-gradient elution from 10% acetonitrile/90% aq. solvent (0.1% TFA in H 2 O) to 35% acetonitrile/65% aqueous solvent.
  • Analytical HPLC was performed using a VYDAC 218 TP 10 micron C 18 reverse-phase column (0.46 cm i.d. X 20 cm). There was obtained 2.5 mg of the title compound as a white powder.
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • the title compound was obtained as a white powder, 17 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from Boc-Cys (4-MeBzl)-O-Merrifield resin and the amino acids added sequentially in the following order: Boc- Arg (N G -Tos), Boc-Cha, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta- cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc- Cha, Boc-Cys (4-MeBzl), Boc-Ser (Bzl), Boc-Ser (Bzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 18.1 mg.
  • Boc-Arg (N G -Tos) Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp(beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly,
  • Boc-N G -Tos Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta- cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-N G -N-
  • Boc-N G -Tos Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta- cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-N G -N-
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly,
  • Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Arg (N G -Tos), was treated with HF (liquid) and purified as described in Example 2.
  • the title compound was obtained as a white powder, 12.4 mg.
  • Boc-Arg (N G -Tos) Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Ala, Boc-(D)Ala, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Arg (N G -Tos), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 40 mg.
  • Boc-Arg (N G -Tos) Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos) , Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly,
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Asp beta-cyclohexyl
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-His (N-Im-Tos), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 13 mg.
  • Boc-Asp (beta-cyclohexyl), Boc-Phe, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Arg (N G -Tos), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 25.1 mg.
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Asp beta-cyclohexyl
  • Boc-Ile Boc-Arg (N G -Tos)
  • Boc-Gly Boc-Gly
  • Protected peptide resin (0.37 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys, Boc-Orn (Cbz), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 20.0 mg.
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Asp beta-cyclohexyl
  • Boc-Ile Boc-Arg (N G -Tos)
  • Boc-Gly Boc-Gly
  • Example 1 The title compound was obtained as a white powder,
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Cit, was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 24.9 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos) , Boc-Asp (beta- cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Gly, Boc-
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Asp beta-cyclohexyl
  • Boc-Ile Boc-Arg (N G -Tos)
  • Boc-Gly Boc-Gly
  • Example 2 Iodination of the tyrosine occurred during the oxidation (i.e. cyclization) of the peptide with 0.01 N iodine solution as described in Example 2. The title compound was obtained as a white powder, 25 mg.
  • Boc-Lys-Ile-Asp Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Arg (N G -Tos)
  • HF liquid
  • the side chain amino group of lysine in the tripeptide Lys-Ile-Asp was cyclized with the side chain carboxylic acid group of aspartic acid by standard DPPA coupling techniques.
  • the tripeptide was incorporated during the solid phase synthesis as the Boc-protected cyclized tripeptide acid dissolved in N-methyl pyrrolidone.
  • the title compound was obtained as a white powder, 2.8 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Ala, Boc-Gly, Boc-Ile, Boc-Arg (N G -Tos), Boc- Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-
  • Boc-Gly Boc-Gly,
  • Boc-Cha Boc-Cys (4-MeBzl), Boc-Arg (N G -Tos), was treated with
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-(D)Arg(N G -Tos), was treated with HF (liquid) and purified as described in Example
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg(N -Tos), Boc-Gly,
  • the title compound was obtained as a white powder, 30 mg.
  • Boc-Cys (4-MeBzl) Boc-
  • Boc-N G -Tos Boc-Phe, Boc-Ala, Boc-Arg (N G -Tos), Boc-Asp (beta- cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Asp beta-cyclohexyl
  • Boc-Ile Boc-Arg (N G -Tos)
  • Boc-Gly Boc-Gly
  • Boc-Ala Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Ala Boc- Ile
  • Boc-Arg N G -Tos
  • Boc-Gly Boc-Gly
  • Boc-Cha Boc-Cys (4-
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2.
  • the title compound was obtained as a white powder, 27.0 mg.
  • Boc-Arg (N G -Tos) Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (beta- cyclohexyl), Boc-Ile, Boc- (D)Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), Boc-Arg (N G -Tos), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 40 mg.
  • Boc-Asp (alpha-Bzl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc- Gly, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 50.0 mg.
  • Boc-Asp (beta-cyclohexyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Boc-Cys (4-MeBzl), was treated with HF
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Nva, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -Bzl), Boc-Nva, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly,
  • Boc-Cha, Boc-Cys (4-MeBzl) was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 23 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -Bzl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly,
  • Boc-(D)Phg, Boc-Cys (4-MeBzl) was treated with HF (liquid) and purified as described in Example 2.
  • the title compound was obtained as a white powder, 25 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-(D)Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -tert-butyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc- Gly, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 19.1 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-(D) Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -benzyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly,
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -tert-butyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Arg (N G -
  • Boc-(D)Ala, Boc-Cha, Mpa (4-MeBzl) was treated with HF (liquid) and purified as described in Example 2.
  • the title compound was obtained as a white powder, 51 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl) , Boc-Arg (N G -Tos), Boc-Leu, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -Bzl), Boc-Leu, Boc-Arg (N G -Tos), Boc-Arg (N G -Tos),
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Glu(Bzl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc- Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 140 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -Bzl), Boc-Ile, Boc-(D) Arg (N G -Tos), Boc-Gly, Boc-Gly,
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-(D)Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp ( ⁇ -tert-butyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc- Gly, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 12.0 mg.
  • Boc-Arg N G -Tos
  • Boc-Phe Boc-Ile
  • Boc-Arg N G -Tos
  • Boc-Asp ⁇ -Bzl
  • Boc-Ile Boc-Arg (N G -Tos)
  • Boc-(D)Ala Boc-(D)Ala
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-His(Nim-Tos), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 10.0 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg(N G -Tos), Boc-Asp ( ⁇ -Bzl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Gly, Boc-Gly,
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-(D) Cys (4- MeBzl), Boc-Arg (N G -Tos), Boc-Phe, Boc-Ile, Boc-Arg (N G -Tos), Boc-Asp (b-tert-butyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Ala, Boc- (D)Ala, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 33.1 mg.
  • Protected peptide resin (0.50 g), prepared (as described in Example 1) from p-methylbenzhydrylamine resin and the amino acids added sequentially in the following order: Boc-(D) Cys (4- MeBzl), Boc-Phe-Arg (N G -Tos) reduced amide, Boc-Ile, Boc- Arg (N G -Tos), Boc-Asp ( ⁇ -tert-butyl), Boc-Ile, Boc-Arg (N G -Tos), Boc-Ala, Boc-(D)Ala, Boc-Cha, Mpa (4-MeBzl), was treated with HF (liquid) and purified as described in Example 2. The title compound was obtained as a white powder, 7.4 mg.
  • peptides of the invention which can be synthesized according to the methods of Examples 1 and 2 include the following:
  • Adrenal cell membranes were prepared for use in binding assays as follows: Weighed frozen mature rabbit adrenals (Pel-Freez) were pulverized in a liquid-nitrogen-cooled mortar. The plasma membrane powder was transferred to assay buffer (50mM HEPES (4-(2-hydroxyethyl)-1-piperazine- ethanesulfonic acid), 100 mM NaCl, 5 mM EGTA (ethylene glycol bis (.beta.-aminoethyl ether)-N,N,N',N'-tetraacetic acid), 1 mM PMSF (phenyl methylsulfonyl fluoride), 0.01% Brij-35
  • assay buffer 50mM HEPES (4-(2-hydroxyethyl)-1-piperazine- ethanesulfonic acid
  • 100 mM NaCl 100 mM NaCl
  • 5 mM EGTA ethylene glycol bis (.beta.-amino
  • Binding data was analyzed by computer assisted non-linear regression analysis using the LIGAND program (Munson, P.J. and M. Rodbard, Analytical
  • test compounds were infused intravenously in 0.1% bovine serum albumin (BSA) in saline solution at a rate of 1 mL per hour for 15 minutes at each dose level.
  • BSA bovine serum albumin
  • Example 11 The ability of the compound of Example 11 to improve renal function after ischemically-induced renal failure was studied as follows: Male Sprague-Dawley rats were
  • test compound was infused intravenously at a dose of 10 ⁇ g/kg/min for two hours.

Abstract

L'invention concerne des nouveaux peptides présentant des activités hypotensive, natriurétique, diurétique, de rénovasodilatation, réno-protective, relaxant les fibres lisses, et vasorelaxantes. Les nouveaux peptides atriaux de l'invention on la formule générale (I), ou bien un sel, un ester ou un amide pharmaceutiquement acceptable de celle-ci, dans laquelle R1 est choisi entre hydrogène, AcétylArg, Aha, Arg, Cit, His, Lys, Orn et Ser-Ser; R2 représente un groupe contenant du soufre; R3 représente un acide aminé hydrophobe ou un dipeptide; R4 représente un élément d'espacement de dipeptides ou un tripeptide de la formule X-Y, dans laquelle X représente un élément d'espacement de dipeptides et Y représente un acide aminé basique; R5 représente un acide aminé hydrophobe; R6 représente un peptide ayant jusqu'à trois acides aminés; R7 est choisi parmi Cha, Phe, Cha-Arg, Phe-Arg, (D)Phe-Arg, Phe-(D)Arg, PheγArg, Leu-Arg, Ala-Arg, Arg et Gly-Ala; R8 représente un groupe contenant du soufre.
PCT/US1990/002917 1989-05-24 1990-05-23 Derives de peptides atriaux WO1990014362A1 (fr)

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US356,980 1989-05-24

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KR (1) KR920701244A (fr)
AU (1) AU5827690A (fr)
CA (1) CA2033198A1 (fr)
GR (1) GR1001018B (fr)
IL (1) IL94487A0 (fr)
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Cited By (8)

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US5208218A (en) * 1988-09-19 1993-05-04 Ludwig Institute For Cancer Research T cell growth factor glycoproteins
US5665704A (en) * 1993-11-12 1997-09-09 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5846932A (en) * 1993-11-12 1998-12-08 Genentech, Inc. Receptor specific atrial natriuretic peptides
US6525022B1 (en) 1993-11-12 2003-02-25 Genentech, Inc. Receptor specific atrial natriuretic peptides
WO2007115175A2 (fr) 2006-03-30 2007-10-11 Palatin Technologies, Inc. Constructions de peptides natriurétiques cycliques
US7795221B2 (en) 2006-03-30 2010-09-14 Palatin Technologies, Inc. Linear natriuretic peptide constructs
WO2011098095A1 (fr) * 2010-02-09 2011-08-18 Aplagen Gmbh Peptides se liant au récepteur de tpo
US8580746B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Amide linkage cyclic natriuretic peptide constructs

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2003246500A1 (en) * 2002-07-31 2004-02-16 Conjuchem Biotechnologies Inc. Long lasting natriuretic peptide derivatives

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US4721704A (en) * 1986-05-09 1988-01-26 Peninsula Laboratories, Inc. Potent synthetic atrial peptide analogs
US4757048A (en) * 1985-11-05 1988-07-12 Biotechnology Research Associates J.V. Synthetic analogs of atrial natriuretic peptides
US4804650A (en) * 1986-10-28 1989-02-14 Biotechnology Research Associates, J.V. Analogs of atrial natriuretic peptides
US4935492A (en) * 1987-12-24 1990-06-19 California Biotechnology Inc. Cyclic analogs of atrial natriuretic peptides

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IE862891L (en) * 1985-11-05 1987-05-05 Behringwerke Ag Analogs of atrial natriuretic peptides
EP0271041A3 (fr) * 1986-12-10 1990-04-11 Abbott Laboratories Dérivés de peptides atriaux
EP0292256A3 (fr) * 1987-05-19 1990-10-03 Merck & Co. Inc. Peptides à activité d'ANF

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US4757048A (en) * 1985-11-05 1988-07-12 Biotechnology Research Associates J.V. Synthetic analogs of atrial natriuretic peptides
US4721704A (en) * 1986-05-09 1988-01-26 Peninsula Laboratories, Inc. Potent synthetic atrial peptide analogs
US4804650A (en) * 1986-10-28 1989-02-14 Biotechnology Research Associates, J.V. Analogs of atrial natriuretic peptides
US4935492A (en) * 1987-12-24 1990-06-19 California Biotechnology Inc. Cyclic analogs of atrial natriuretic peptides

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Bio/Technology, Volume 6, published May 1988, "Atrial Natriuretic Peptide", (BAXTER et al), pgs. 529-541. see especially page 536. *
See also references of EP0431113A4 *

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5208218A (en) * 1988-09-19 1993-05-04 Ludwig Institute For Cancer Research T cell growth factor glycoproteins
US5665704A (en) * 1993-11-12 1997-09-09 Genentech, Inc. Receptor specific atrial natriuretic peptides
US5846932A (en) * 1993-11-12 1998-12-08 Genentech, Inc. Receptor specific atrial natriuretic peptides
US6525022B1 (en) 1993-11-12 2003-02-25 Genentech, Inc. Receptor specific atrial natriuretic peptides
WO2007115175A2 (fr) 2006-03-30 2007-10-11 Palatin Technologies, Inc. Constructions de peptides natriurétiques cycliques
US7622440B2 (en) 2006-03-30 2009-11-24 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US7795221B2 (en) 2006-03-30 2010-09-14 Palatin Technologies, Inc. Linear natriuretic peptide constructs
US8580747B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Cyclic natriuretic peptide constructs
US8580746B2 (en) 2006-03-30 2013-11-12 Palatin Technologies, Inc. Amide linkage cyclic natriuretic peptide constructs
WO2011098095A1 (fr) * 2010-02-09 2011-08-18 Aplagen Gmbh Peptides se liant au récepteur de tpo

Also Published As

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EP0431113A1 (fr) 1991-06-12
NZ233795A (en) 1992-07-28
GR900100396A (en) 1991-10-10
JPH04500363A (ja) 1992-01-23
EP0431113A4 (en) 1992-01-22
AU5827690A (en) 1990-12-18
CA2033198A1 (fr) 1990-11-25
GR1001018B (el) 1993-03-31
IL94487A0 (en) 1991-03-10
KR920701244A (ko) 1992-08-11

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