WO1994014840A1 - Analogues peptidiques acycliques du peptide natriuretique atrial, leur procede de production et leur utilisation - Google Patents

Analogues peptidiques acycliques du peptide natriuretique atrial, leur procede de production et leur utilisation Download PDF

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Publication number
WO1994014840A1
WO1994014840A1 PCT/EP1993/003431 EP9303431W WO9414840A1 WO 1994014840 A1 WO1994014840 A1 WO 1994014840A1 EP 9303431 W EP9303431 W EP 9303431W WO 9414840 A1 WO9414840 A1 WO 9414840A1
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Prior art keywords
carbon atoms
different
hydrogen
formula
chain
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PCT/EP1993/003431
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German (de)
English (en)
Inventor
Klaus-Peter Voges
Rolf Henning
Walter Hübsch
Jan-Bernd Lenfers
Martin Beuck
Gudrun Theiss
Johannes-Peter Stasch
Claudia Hirth-Dietrich
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Bayer Aktiengesellschaft
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Priority to JP6514732A priority Critical patent/JPH08508465A/ja
Priority to EP94902694A priority patent/EP0674655A1/fr
Priority to AU56970/94A priority patent/AU5697094A/en
Publication of WO1994014840A1 publication Critical patent/WO1994014840A1/fr

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    • 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
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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 new acyclic peptides with a natriuretic effect, processes for their preparation and their use in medicaments, in particular as antihypertensive agents.
  • ANP receptors Two general classes of ANP receptors are known from many publications, the guanylate cyclase-coupled (AIB receptor) and the non-guanylate cyclase coupled (C receptor).
  • the A and B receptors are a 120-140 kDa protein with a transmembrane region which mediates the ANP effect (extracellular) on the cGMP system (intracellular) via the particulate guanylate cyclase. Both types of receptors bind ANP with high affinity; the affinities for BNP and CNP are different.
  • ANP-A / B receptors occur for example in endothelial cells, smooth vascular muscle cells as well as in glomerular, mesangial and epithelial cells.
  • the biologically silent C receptor a homodimer of a 64 kDA transmembrane protein, is common in the renal cortex, in vascular, endothelial on smooth muscle cells
  • C receptor ligands can be reduced in size over a wide range without loss of affinity if their core sequence is retained. In vivo results have shown that C receptors perform a clearance function. Infusion of C-ANF (4-23) into anesthetized or awake rats results in a reversible increase in endogenous ANP plasma levels and for lowering blood pressure (see also Maack et al., Science 238 (1987), 675-678). These effects are comparable to those caused by infusion of ANP (1-28).
  • a C receptor ligand is also known, which is an ANP molecule shortened to 15 amino acids
  • RIDRI the core sequence Arg-Ile-Asp-Arg- Ile
  • the position of the first arginine is occupied by non-basic, cyclic amino acids, which surprisingly shows a large increase in affinity
  • the present invention relates to new acyclic peptides of the general formula (I)
  • R 3 is hydrogen, straight-chain or branched alkyl having up to 4 carbon atoms or an amino protecting group
  • R 4 and R 5 are the same or different and are hydrogen or methyl, or
  • R 4 and R 5 together form a 5- or 6-membered carbocyclic, saturated ring, or
  • R 4 is hydrogen and R 5 represents a radical of the formula or
  • R 5 is cycloalkyl having 3 to 8 carbon atoms or aryl having 6 to 10 carbon atoms or hydrogen, or
  • alkyl having up to 8 carbon atoms, the alkyl optionally being substituted by cyano, hydroxy, guanidyl or by a group of the formula -NR 6 R 7 or R 8 -OC- in which
  • R 6 and R 7 independently of one another are hydrogen, formyl, straight-chain or branched acyl or alkyl each having up to 8 carbon atoms, phenyl or an amino protecting group, and
  • R 8 is hydroxyl, benzyloxy, alkoxy having up to 6 carbon atoms, cycloalkyloxy having 3 to 6 carbon atoms or the group -NR 6 R 7 mentioned above, or the alkyl optionally by cycloalkyl having 3 to 8 carbon atoms or by aryl having 6 to 10 This in turn is substituted by carbon atoms with hydroxy, halogen, nitro, alkoxy up to 8 carbon atoms or substituted by the group -NR 6 R 7 , in which R 6 and R 7 have the meaning given above, or the alkyl is optionally substituted by a 5- to 6-membered nitrogen-containing heterocycle or indolyl, in which the corresponding NH functions are optionally protected by alkyl having up to 6 carbon atoms or by an amino protecting group,
  • j is a number 0, 1, 2, 3 or 4,
  • R 9 is hydrogen or a hydroxyl protective group, g is a number 1, 2 or 3,
  • D, E and G are the same or different and have the meaning of B given above or for a radical of the formula stand,
  • R 10 has the meaning of R 3 given above and is the same or different with it
  • R 11 and R 12 have the meanings of R 4 and R 5 given above and are identical or different with these
  • R 1 represents straight-chain or branched alkyl having up to 6 carbon atoms or
  • R 13 , R 14 , R 15 , R 16 , R 19 , R 21 , R 23 , R 24 , R 25 , R 26 and R 27 are the same or different and are aryl having 6 to 10 carbon atoms, which may be up to 3 -substantially the same or different is substituted by halogen, hydroxyl, amino or straight-chain or branched alkoxy or alkoxycarbonyl, each having up to 4 carbon atoms, or
  • R 13 straight-chain or branched alkyl having up to 4 carbon atoms means h, h 'and i are identical or different and are a number 0, 1 or 2,
  • R 17 and R 18 are identical or different and are hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, phenyl or an amino protecting group,
  • R 20 is hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms
  • R 22 represents a radical of the formula HO 3 P-
  • k represents a number 0, 1 or 2
  • R 28 has the meaning of R 3 given above and is the same or different with this,
  • R 29 and R 30 have the meanings of R 4 and R 5 given above and are identical or different with these,
  • R 31 and R 32 are identical or different and represent an amino protecting group, hydrogen or straight-chain or branched alkyl having up to 8 carbon atoms, which is optionally substituted by cycloalkyl having 3 to 6 carbon atoms, phenyl, pyridyl or by the -CO-NH 2 group and their salts.
  • the compounds of the general formula (I) according to the invention have several asymmetric carbon atoms. They can exist independently of one another in the D or L form.
  • the invention includes the optical antipodes as well as the isomer mixtures or racemates. Groups A, B, D, E and G are preferably independently of one another in the optically pure, preferably in the L-form.
  • Amino protecting groups in the context of the invention are the usual amino protecting groups used in peptide chemistry.
  • benzyloxycarbonyl 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 2-nitro4,5-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl Nitrobenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, cyclohexoxycarbonyl, 1,1-dimethylethoxycarbonyl, adamantylcarbonyl, phthaloyl, 2,2,2-trichloroethoxycarbonyl, 2,2,2-trichloro-tert-butoxycarbonyl, menthyloxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluorenyl-9-methoxycarbonyl, formyl, acetyl, fluoren
  • Phthalimido isovaleroyl or benzyloxymethylene, 4-nitrobenzyl, 2,4-dinitrobenzyl or 4-nitrophenyl.
  • Physiologically acceptable salts are preferred in the context of the present invention.
  • Physiologically acceptable salts of the compounds according to the invention can be salts with mineral acids, carboxylic acids or sulfonic acids.
  • Physiologically acceptable salts of the compounds according to the invention can be salts with mineral acids, carboxylic acids or sulfonic acids.
  • Particular preference is given to Salts with hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, benzenesulfonic acid, naphthalenedisulfonic acid, acetic acid, propionic acid, lactic acid, tartaric acid, citric acid, fumaric acid, maleic acid or benzoic acid.
  • Salts in the context of the present invention are also metal salts, preferably the monovalent metals, and the ammonium salts.
  • Alkali salts such as sodium, potassium, lithium and ammonium salts are preferred.
  • Hydroxy protective group in the context of the definition given above generally represents a protective group from the series: tert-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triphenylsilyl, trimethylsilylbenzylyloxy-nitrobenzylyloxy-2-nitrobenzylyloxy-nitro-2-nitrobenzyl-nitrobenzylyl-nitro-2-nitrobenzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzyl-nitro-benzy
  • a, b, d and f are identical or different and denote a number 1 or 2, denote a number 0, 1 or 2,
  • R 3 is hydrogen, methyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl (BOC)
  • R 4 and R 5 are the same or different and are hydrogen or methyl, or
  • R 4 or R 5 together form a cyclopentyl or cyclohexyl ring, or
  • R 4 means hydrogen
  • R 5 represents a radical of the formula
  • R 5 is cyclopentyl, cyclohexyl, phenyl or hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, the alkyl being optionally substituted by cyano, hydroxy, guanidyl or by a group of the formula -NR 6 R 7 or R 8 -CO- can in what
  • R 6 and R 7 independently of one another are hydrogen, formyl, benzyloxycarbonyl, straight-chain or branched acyl or alkyl each having up to 6 carbon atoms or tert-butoxycarbonyl (BOC),
  • R 8 is hydroxy, benzyloxy, alkoxy with up to 4 carbon atoms, cyclopropyloxy, cyclopentyloxy, cyclohexyloxy or the group -NR 6 R 7 mentioned above, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which in turn is substituted by fluorine, hydroxyl, nitro or Alkoxy can be substituted with up to 4 carbon atoms, or the alkyl is substituted by indolyl, imidazolyl, pyridyl, triazolyl or pyrazolyl, the corresponding -NH functions being optionally protected by alkyl having up to 4 carbon atoms or by an amino protecting group, B for a radical of the formula
  • j is a number 0, 1, 2, or 3
  • R 9 is hydrogen, benzyl, benzoyl or straight-chain or branched acyl having up to 6 carbon atoms, g is a number 1, 2 or 3
  • D, E and G are identical or different and have the meaning of B given above, or represent a radical of the formula
  • R 10 has the meaning of R 3 given above and is the same or different with this
  • R 11 and R 12 have the meanings of R 4 and R 5 given above and are the same or different with them, represents straight-chain or branched alkyl having up to 4 carbon atoms or
  • R 13 , R 14 , R 15 , R 16 , R 19 , R 21 , R 24 , R 25 'R 26 and R 27 are the same or different and are phenyl or naphthyl, which may be up to 2 times the same or different Fluorine, chlorine, bromine, hydroxy, methoxy, methoxycarbonyl or amino are substituted, or
  • R 13 denotes methyl or ethyl, h, h 'and i are identical or different and represent a number 0, 1 or 2,
  • R 17 and R 18 are the same or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or tert. Butoxycarbonyl mean
  • R 20 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • k is a number 0, 1 or 2
  • R 28 has the meaning of R 3 given above and is the same or different with this
  • R 29 and R 30 have the meanings of R 4 and R 5 given above and are identical or different with these
  • 1 means a number 0, 1 or 2
  • R 31 and R 32 are the same or different and are benzyloxycarbonyl (Z), tert-butoxycarbonyl, pivaloyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopentyl, cyclohexyl, phenyl or pyridyl, and their salts .
  • A stands for a direct bond
  • R 3 is hydrogen, methyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl (BOC)
  • R 4 and R 5 are the same or different and are hydrogen or methyl, or
  • R 4 and R 5 together form a cyclopentyl or cyclohexyl ring, or
  • R 4 is hydrogen
  • R 5 represents a radical of the formula
  • R 5 denotes cyclopentyl, cyclohexyl or hydrogen
  • alkyl having up to 5 carbon atoms, the alkyl optionally being substituted by cyano, hydroxy, guanidyl or by a group of the formula -NR 6 R 7 or R 8 -CO-, in which
  • R 6 and R 7 independently of one another are hydrogen, formyl, benzyloxycarbonyl, straight-chain or branched alkyl or acyl each having up to 4 carbon atoms or tert-butoxycarbonyl (BOC) mean
  • R 8 is hydroxy, benzyloxy, alkoxy with up to 3 carbon atoms, cyclopentyloxy, cyclohexyloxy, or the group -NR 6 R 7 mentioned above, or the alkyl is substituted by cyclohexyl, naphthyl or phenyl, which in turn is substituted by fluorine, chlorine or alkoxy with bis can be substituted to 4 carbon atoms, or the alkyl by indolyl, imidazolyl, triazolyl, pyridyl or
  • R 9 denotes hydrogen, benzyl or straight-chain or branched acyl having up to 4 carbon atoms and g denotes a number 1, 2 or 3, D, E and G are the same or different and have the meaning of B given above, or for a radical of the formula
  • R 10 has the meanings of R 3 given above and is the same or different with this,
  • R 11 and R 12 have the meaning of R 4 and R 5 given above and are identical or different with these,
  • R 1 represents straight-chain or branched alkyl having up to 4 carbon atoms, or
  • R 13 , R 14 , R 15 , R 16 , R 19 , R 21 , R 24 , R 25 , R 26 and R 27 are the same or different and are phenyl or naphthyl, which may be identical or different up to 2 times Fluorine, chlorine, bromine, hydroxy, methoxy, methoxycarbonyl or amino are substituted, or
  • R 13 denotes methyl or ethyl, h, h 'and i are identical or different and represent a number 0, 1 or 2,
  • R 17 and R 18 are identical or different and are hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms, phenyl, benzyloxycarbonyl (Z) or tert-butoxycarbonyl,
  • R 20 is hydrogen or straight-chain or branched alkyl having up to 4 carbon atoms
  • k is a number 0, 1 or 2
  • R 28 has the meaning of R 3 given above and is the same or different with this
  • R 29 and R 30 have the meanings of R 4 and R 5 given above and are identical or different with these
  • 1 means a number 0, 1 or 2
  • R 31 and R 32 are the same or different and are benzyloxycarbonyl (Z), tert-butoxycarbonyl, pivaloyl, hydrogen or straight-chain or branched alkyl having up to 6 carbon atoms, which is optionally substituted by cyclopentyl, cyclohexyl, phenyl or pyridyl, and their salts .
  • A, B, D, E and G have the meaning given above, and L, M, Q, T and V represent one of the amino protective groups listed above, preferably Fmoc, with one another and with the head group of the formula (VII) which is present in the free acid form
  • R 1 has the meaning given above by successive and / or parallel deblocking of the amine function and activation of the respective sequence on a solid phase, or
  • R 1 has the meaning given above and
  • W represents one or more of the radicals A, B, D, E and / or G listed above with compounds of the general formula (IX)
  • R 2 has the meaning given above and Y is either hydrogen, one of the amino protective groups listed above or, depending on W, one of the residues A, B, D, E and / or G by deblocking the amine function and activation of the carboxylic acid in an inert solvent, in the presence of a base and / or of auxiliaries, by the methods customary in peptide chemistry and the substituents R 1 and R 2 optionally varied by customary methods.
  • the methods according to the invention can be illustrated by the following formula scheme:
  • Suitable solvents are the customary organic solvents which do not change under the reaction conditions. These preferably include organic solvents such as ethers, for example diethyl ether, glycol mono- or dimethyl ether, dioxane or tetrahydrofuran, or hydrocarbons such as benzene, toluene, xylene, cyclohexane or petroleum fractions or halogenated hydrocarbons such as methylene chloride, di chloroethane (DCE), chloroform, carbon tetrachloride, or dimethyl sulfoxide, dimethylformamide, hexamethylphosphoric triamide, 1,3-dimethyltetrahydro2 (1H) pyrimidone (DMPH), 1-methylpyrrolidone, ethyl acetate, pyridine, triethylamine or picoline. It is also possible to use mixtures of the solvents mentioned. Dichloromethane, dichloroethane, dimethylformamide or 1-methylpyr
  • Preferred solvents for washing out (process [A]) or recrystallization (process [B]) are alcohols, e.g. Methanol, ethanol or n-propanyl, halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, and also dimethylformamide, ethyl acetate, glacial acetic acid, formic acid and ether, e.g. Diethyl ether, diisopropyl ether used
  • Dimethylformamide is preferred for the activation and coupling steps of process [A]. Methanol, glacial acetic acid and diethyl ether are preferred for washing the resin.
  • piperidine, diisopropylethylamine and 2- (1H-benzotriazol-1-yl) -1,1,3,3-tetramethyluronium tetrafluoroborate are used as bases and / or auxiliaries.
  • the process [B] generally proceeds by reacting a corresponding fragment, consisting of one or more amino acid groups, with a free carboxyl group, optionally present in activated form, with a complementary fragment, consisting of one or more amino acid groups with a free amino group produces correspondingly larger fragments; protective groups can then optionally be split off or exchanged for other protective groups.
  • the target connections are obtained by repeating this process.
  • Condensation agents which can also be bases, are preferably used as auxiliaries for the respective peptide couplings, in particular if the carboxyl group is present as an activated anhydride.
  • Condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethyl-carbodiimide hydrochloride, N-cyclohexyl-N '(2-morpholinoethyl) carbodiimide metho-p-toluenesulfonate (CMCT), or carbonyl compounds such as carbonyldumidazole, or 1,2-oxazolium compounds such as 2-ethyl-5-phenyl-l, 2-oxazolium-3-sulfate or 2- tert-butyl-5-methyl-isoxazolium perchlorate or acylamino compounds such as 2-ethoxy-1-ethoxycarbonyl-1,2-dihydroquinoline, or n-propy
  • Process [A] generally runs in a temperature range from + 10 ° C to + 35 ° C, preferably at 20 ° C (room temperature).
  • the process [B] generally runs in a temperature range from -30 ° C to 35 ° C, preferably from -20 ° C to 25 ° C.
  • the compounds of the general formula II, III, IV, V, VI and VIII are known or can be obtained by reacting a corresponding fragment, consisting of one or more amino acid groups, with a free, optionally present in activated form, carboxyl group with a complementary fragment be produced from one or more amino acid groups with a free amino group by repeating this process with correspondingly larger fragments; protective groups can then optionally be split off or exchanged for other protective groups.
  • condensing agents such as carbodiimides, for example N, N'-diethyl, N, N'-diisopropyl, N, N'-dicyclohexylcarbodiimide, N- (3-dimethylaminoisopropyl) -N'-ethyl-carbodiimide hydrochloride, N are preferred here -Cyclo-hexyl-N '(2-morpholinoethyl) -carbodiimide-metho-p-toluenesulfonate (CMCT), or Carbonyl compounds such as carbonyldumidazole, or 1,2-oxazoumum compounds such as 2-ethyl-5phenyl-1,2-oxazoumum-3-sulfate or 2-tert-butyl-5-methyl-isoxazoumum perchlorate or acylamino compounds such as 2-ethoxy 1-ethoxycarbonyl-1,2-dihydroquinoline, or n-propy
  • the reactions can be carried out both at normal pressure and at elevated or reduced pressure (for example 0.5 to 5 bar), preferably at normal pressure.
  • the compounds according to the invention show an unforeseeable, valuable spectrum of pharmacological activity. They influence the contraction power of the heart, the tone of the smooth muscles and the electrolyte and fluid balance
  • ANP receptor ligands investigations in vivo
  • Urine was obtained via a bladder catheter.
  • the rectal temperature of the rats was kept at 37.5 + 1 ° C. using heat lamps.
  • Approximately 10 4 hANP C receptor-transfected CHO cells are sown per well on microtiter plates 2 days before the start of the experiment.
  • the culture medium is aspirated before the start of the experiment and replaced by 100 ⁇ l binding medium (DMEM / 0.1% BSA).
  • 50 ⁇ l of the prediluted test substances max. 1.0% DMSO
  • 100 ⁇ l binding medium with 25,000 cpm 125 I-ANP final conc. Approx. 3 * x10 -11 mol / l
  • the incubation medium is suctioned off, the cells are washed twice with ice-cold DMEM and then lysed overnight in 50 ⁇ l 0.2 M NaOH / 1% Triton-X-100.
  • the cell lysate is diluted with 100 ⁇ l water, in Pharmacie T-Trays transferred and mixed with 250 ul scintillator for scintillation counting in the beta plate counter
  • the raw data are analyzed using computer programs for calculating the K i or IC 50 value (K i : IC 50 value corrected for the radioactivity used; IC 50 : concentration at which the substance to be examined effects a 50% inhibition of the specific binding of the radio ligand).
  • the new active ingredient can be converted in a known manner into the customary formulations, such as tablets, dragées, pills, granules, aerosols, syrups, emulsions, suspensions and solutions, using inert, non-toxic, pharmaceutically suitable excipients or solvents.
  • the therapeutically active compound should in each case be present in a concentration of about 0.5 to 90% by weight of the total mixture, i.e. in amounts sufficient to achieve the dosage range indicated.
  • the formulations are produced, for example, by stretching the active ingredients with solvents and / or carriers, optionally using emulsifiers and / or dispersants, e.g. in the case of the use of water as a diluent, organic solvents can optionally be used as auxiliary solvents.
  • the application is carried out in the usual way, preferably orally or parenterally, in particular perlingually or intravenously.
  • HPLC systems used Mobile Phase A: 100 ml acetonitrile in 900 ml water,
  • Mobile phase B 900 ml acetonitrile in 100 ml water
  • the synthesis is carried out on a Milligen 9010 continuous flow synthesizer.
  • the synthesis column is filled with 1.6 g of dry tentagel-S-NH 2 resin
  • the column After assembly, the column is packed with a flow of 20 ml / min DMF in reverse flow. After switching to normal flow, equilibrating at 10 ml / min for 5 min
  • the 7 vials of the amino acid module are filled:
  • the resin to remove the Fmoc protecting group is washed with a 0.5 N piperidine solution in DMF at a flow of 7 ml / min for 7 min.
  • the piperidine is washed out by washing with DMF at a flow of 7 ml / min.
  • the pipetting needle is washed inside and outside with DMF and pipettes the activated Fmoc-amino acid into the sample loop. After the entire 6.4 ml sample has been taken up, the contents of the sample loop are pumped into the system at a reduced flow (6.4 ml / min). After 1.1 minutes, the mixture is then pumped in a circle at a flow of 7 ml / min for 60 minutes. After the end of the coupling period, washing out with DMF at a flow of 7 ml / min for 10 min. In parallel, the pipetting needle is rinsed inside and outside and prepared for the next synthesis step
  • the resin is rinsed out of the synthesis column and washed out on a frit
  • TFA peptide solution is then suctioned off and the resin is washed 3 times with 50 ml of TFA each.
  • the filtrate is mixed with 20 times the amount of diethyl ether and the product is precipitated. After centrifugation (3000 rpm, 5 min), the centrifugate is washed with diethyl ether, centrifuged again and dried in a desiccator
  • the polypeptide is in 10 ml of a mixture of 100 ml of acetonitrile and 900 ml

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Abstract

De nouveaux peptides acycliques à effet natriurétique ont la formule générale: R1-CO-A-B-D-E-G-R2, dans laquelle A, B, D, E, G, R1 et R2 ont la notation donnée dans la description. L'invention concerne également leur procédé de production et leur utilisation dans des médicaments, notamment comme agents antihypertenseurs.
PCT/EP1993/003431 1992-12-18 1993-12-06 Analogues peptidiques acycliques du peptide natriuretique atrial, leur procede de production et leur utilisation WO1994014840A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
JP6514732A JPH08508465A (ja) 1992-12-18 1993-12-06 新規な非環式ペプチド、それらの製造方法および薬物としてのそれらの使用
EP94902694A EP0674655A1 (fr) 1992-12-18 1993-12-06 Analogues peptidiques acycliques du peptide natriuretique atrial, leur procede de production et leur utilisation
AU56970/94A AU5697094A (en) 1992-12-18 1993-12-06 Acyclic peptide analogs of the atrial natriuretic peptide, process for producing the same and their use

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DE4242946A DE4242946A1 (de) 1992-12-18 1992-12-18 Neue acyclische Peptide, Verfahren zu ihrer Herstellung und ihre Verwendung als Arzneimittel
DEP4242946.3 1992-12-18

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WO1994014840A1 true WO1994014840A1 (fr) 1994-07-07

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WO2000061631A1 (fr) * 1999-04-12 2000-10-19 Astrazeneca Ab Antagonistes de pentapeptides modifies du recepteur de la clairance des peptides natriuretiques auriculaires

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323740A2 (fr) * 1987-12-24 1989-07-12 California Biotechnology, Inc. Analogues linéaires de peptides atrio-natriurétiques
EP0465097A2 (fr) * 1990-06-26 1992-01-08 Merck & Co. Inc. Peptides ayant une activité du facteur natriurétique atrial (ANF)

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0323740A2 (fr) * 1987-12-24 1989-07-12 California Biotechnology, Inc. Analogues linéaires de peptides atrio-natriurétiques
EP0465097A2 (fr) * 1990-06-26 1992-01-08 Merck & Co. Inc. Peptides ayant une activité du facteur natriurétique atrial (ANF)

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DE4242946A1 (de) 1994-06-23
CA2151961A1 (fr) 1994-07-07
JPH08508465A (ja) 1996-09-10
AU5697094A (en) 1994-07-19
EP0674655A1 (fr) 1995-10-04

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