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WO1991008223A1 - Nouveaux peptides derives du neuropeptide y - Google Patents

Nouveaux peptides derives du neuropeptide y Download PDF

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Publication number
WO1991008223A1
WO1991008223A1 PCT/EP1990/001997 EP9001997W WO9108223A1 WO 1991008223 A1 WO1991008223 A1 WO 1991008223A1 EP 9001997 W EP9001997 W EP 9001997W WO 9108223 A1 WO9108223 A1 WO 9108223A1
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WO
WIPO (PCT)
Prior art keywords
arg
tyr
ile
asn
ser
Prior art date
Application number
PCT/EP1990/001997
Other languages
German (de)
English (en)
Inventor
Johann-Christian Zechel
Sabine Schult
Liliane Unger
Original Assignee
Basf Aktiengesellschaft
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Basf Aktiengesellschaft filed Critical Basf Aktiengesellschaft
Publication of WO1991008223A1 publication Critical patent/WO1991008223A1/fr

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Classifications

    • 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
    • C07K14/57545—Neuropeptide Y
    • 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 invention relates to new peptides derived from neuropeptide Y (NPY), their preparation and their use as medicaments.
  • NPY was isolated from pig brain in 1982 (Nature 296 (1982) 659) and has now been detected in a number of mammalian species. Human NPY has the following sequence:
  • the peptide which is widely used in the peripheral and central nervous system, is one of the most potent known vasoconstrictors. It also increases the blood pressure-increasing effects of norepinephrine and is able to cause cardiac and cerebral vasospasm. All of these observations indicate that NPY is significantly involved in the neuronal regulation of blood pressure.
  • H is a dipeptide residue composed of lipophilic amino acids
  • Z represents a hydrogen atom, an amino protecting group, a benzyl radical, a C 2-10 acyl radical or a C 1-5 alkyl radical, k, l, m, n, o, p and q denote the numbers 0 or 1, but k + 1 + m + n + o + p + q> l and two possibly present Cys residues can be connected to one another via a disulfide bridge, as well as their salts with physiologically compatible acids.
  • the partially structurally modified N- and C-terminal fragments of the NPY are connected to each other via a spacer (E) which replaces the central sequence section of the NPY.
  • the lengths of the N- and C-terminal ends and the spacer are variable.
  • Suitable protecting groups are the following: t-butyloxycarbonyl, benzyloxycarbonyl, fluorenylmethyloxycarbonyl.
  • Hydrochloric acid citric acid, tartaric acid, lactic acid, phosphoric acid, methanesulfonic acid, acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid,
  • p-Hydroxyphenylacetyl- or p-Hydroxyphenylpropionylrest mean.
  • Z is a hydrogen atom, an acetyl, p-hydroxybenzoyl,
  • p-Hydroxyphenylacetyl-, p-Hydroxyphenylpropionylrest mean and A, B, D, K and k-q have the meanings given.
  • the new compounds can be prepared by methods known in peptide chemistry.
  • the peptide chain is gradually extended by one amino acid each, starting at the C terminus.
  • fragments of different lengths can be linked to one another, the fragments in turn being obtained by sequential construction from amino acids or, in turn, by fragment coupling.
  • the cyclic peptides are obtained by a cyclization reaction carried out in high dilution. Both in the sequential structure and in the fragment coupling, the building blocks must be linked by forming an amide bond. Enzymatic and chemical methods are suitable for this.
  • the coupling reagents can be used alone or in combination with additives such as N, N'-dimethyl-4-aminopyridine (DMAP), N-hydroxybenzotriazole (HOBt), N-hydroxybenzotriazine (HOOBt), N-hydroxysuccinimide (HOSu) or 2-hydroxypyridine .
  • DMAP N, N'-dimethyl-4-aminopyridine
  • HOBt N-hydroxybenzotriazole
  • HOOBt N-hydroxybenzotriazine
  • HOSu N-hydroxysuccinimide
  • 2-hydroxypyridine 2-hydroxypyridine
  • While protective groups can normally be dispensed with in enzymatic peptide synthesis, reversible protection of the reactive functional groups of the two reactants which are not involved in the formation of the amide bond is required for chemical synthesis.
  • three protecting group techniques known from the literature are preferred: the benzyloxycarbonyl (Z), the t-butyloxycarbonyl (Boc) and the 9-fluorenylmethyloxycarbonyl (Fmoc) protective group technique.
  • the protective group of the ⁇ -amino function of the chain-extending building block is designated in each case.
  • the side chain protecting groups of the trifunctional amino acids are chosen so that they are not necessarily split off together with the ⁇ -amino protecting group.
  • the peptide is typically built up sequentially on the polymeric support using the Boc or Fmoc protective group technique, the growing peptide chain at the C-terminus being covalently linked to the insoluble resin particles (see Figs. 1 and 2). This procedure allows reagents and by-products to be removed by filtration, making recrystallization of intermediate products unnecessary.
  • the protected amino acids can be bound to any suitable polymer, which are only insoluble in the solvents used and must have a stable physical form which enables easy filtration.
  • the polymer must contain a functional group to which the first protected amino acid can be bound by a covalent bond.
  • a wide variety of polymers are suitable for this purpose, e.g.
  • All solvents which prove inert under the reaction conditions are particularly suitable for peptide synthesis in solution, in particular water, N, N'-dimethylformamide (DMF), dimethyl sulfoxide (DMSO), acetonitrile, dichloromethane (DCM), 1,4- Dioxane, tetrahydrofuran (THF), N-methyl-2-pyrrolidone (NMP) and mixtures of the solvents mentioned.
  • DMF N, N'-dimethylformamide
  • DMSO dimethyl sulfoxide
  • DCM dichloromethane
  • THF tetrahydrofuran
  • NMP N-methyl-2-pyrrolidone
  • the peptide synthesis on the polymeric support can be carried out in all inert organic solvents in which the amino acid derivatives used are soluble; however, solvents which additionally have resin-swelling properties, such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents are preferred.
  • solvents which additionally have resin-swelling properties such as DMF, DCM, NMP, acetonitrile and DMSO, and mixtures of these solvents are preferred.
  • the peptide is split off from the polymeric carrier.
  • the conditions under which the peptides can be split off from the various types of resin are known from the literature.
  • Acid and palladium-catalyzed cleavage reactions are most commonly used, in particular the cleavage in liquid anhydrous hydrogen fluoride, in anhydrous trifluoromethanesulfonic acid, in dilute or concentrated trifluoroacetic acid or the palladium-catalyzed cleavage in THF or THF-DCM mixture in the presence of a weak base such as, for example, morpholine.
  • a weak base such as, for example, morpholine.
  • these can be retained under the cleavage conditions or can also be split off. Partial deprotection of the peptide can also be useful if certain derivatization reactions or a cyclization are to be carried out.
  • the new peptides bind with high affinity to NPY receptors, but without triggering the physiological effect of the NPY, are therefore competitive antagonists and suppress the effect of the endogenous NPY.
  • the new peptides have hypotensive properties and are valuable medicinal products that are suitable for the treatment of circulatory diseases, in particular high blood pressure, and vascular spasms. They can be combined with ACE inhibitors, Ca antagonists or diuretics.
  • the new peptides are also valuable diagnostic and analytical reagents for biochemical and medical research, for researching hypertension and especially for studying the biochemistry and pathophysiology of NPY.
  • Receptor binding assay (rabbit kidney cortex)
  • Rabbit renal cortex was prepared immediately after the kidney was removed and homogenized in 0.32 M sucrose solution (4 ° C.). The homogenate was filtered and then centrifuged at 480 g (5 min, 4 ° C), the supernatant collected and centrifuged at 45,000 g (10 min, 4 ° C). The resulting residue was washed by resuspension and recentrifugation twice with incubation buffer (25 mM Tris, 5 mM MgCl 2 , 0.5% bovine serum albumin and 0.1% bacitracin, pH 7.4) and taken up in incubation buffer.
  • incubation buffer 25 mM Tris, 5 mM MgCl 2 , 0.5% bovine serum albumin and 0.1% bacitracin, pH 7.4
  • test batches (1 ml) were composed of: 100 ⁇ g membrane protein (BCA protein assay, Pierce, Rockford, Illinois, USA), 0.5 nM 3H-NPY (Amersham, Braunschweig, specific radioactivity 3 TBq / mmol) in incubation buffer (total binding) or a) with an additional 0.3 ⁇ M NPY (non-specific binding) or b) with test substance.
  • the batches were made as triplicates.
  • the batches were filtered through glass fiber filters (Whatman GF / B) and washed with ice-cold washing buffer (50 mM Tris, 0.5 mM EDTA, 0.2% bovine serum ibumin, pH 7.4) .
  • the radioactivity retained on the filters was determined by means of liquid scintillation measurement.
  • the nonspecific binding was approx. 20 to 30% of the total binding at 0.5 nM 3H-NPY.
  • the competition curves are evaluated using iterative nonlinear regression analysis based on the "Ligand" program (Munson and Rodbard: Anal. Biochem. 107, 220, 1980).
  • NPY injections (3 ⁇ g / kg IV) were given 15 min before and 5 min after substance administration.
  • the blood pressure in the carotid artery was measured with Statham pressure transducers, the amplifiers and recording devices were from Hellige.
  • the relative inhibition ( ⁇ %) of the increase in blood pressure caused by NPY was measured.
  • mice Male Sprague-Dawley rats of 250 to 300 g body weight were used for the experiments. The feeding was 16 to Suspended 24 h before the start of the experiment, water was available ad libitum. The animals were anesthetized with urethane 1.7 g / kg ip 30 to 40 min before the start of the experiment. Breathing was spontaneous via tracheal cannula.
  • the trachea, carotid artery and jugular vein were dissected 20 minutes after induction of anesthesia. Subcutaneous electrode needles were used to record the ECG. The mean carotid pressure MAP (mmHg) was measured via Statham transducer P23Db. The heart rate HR (min -1 ) was determined from the blood pressure amplitude. Both parameters were registered with Heilige writers.
  • proteogenic amino acids are abbreviated in the examples with the three-letter code (according to Eur. J. Biochem. 138, 1984, 9-37).
  • Abs 4-aminobutyric acid
  • Abu 2-aminobutyric acid
  • Ac acetic acid
  • Ahx aminohexanoic acid
  • Aoc 8-aminooctanoic acid
  • Ape 5-aminopentanoic acid
  • HBz p-hydroxybenzoic acid
  • Hpac p-hydroxyphenylacetic acid
  • Hpp p-hydroxyphenylpropionic acid
  • Boc-Tyr (Br-Z) -p-methylbenzhydrylamine resin with a substitution of 0.49 mmol / g, corresponding to a batch size of 0.25 mmol, were, according to A, with 1 mmol of Boc-Arg (Tos) - OH Boc-Ile-OH
  • the peptide resin obtained (1.06 g) was subjected to HF cleavage (10 ml HF / 1 ml anisole; 0 ° C, 45 min). HF and most of the anisol were removed in vacuo, the resin was washed with ethyl acetate, and extracted the peptide with 10% acetic acid. The extract was lyophilized. The crude peptide was purified by medium pressure chromatography (HD-SIL® reversed phase C 18 material, 100 ⁇ , 25-45 ⁇ grain size) with a gradient of 50-70% B in 80 min
  • Boc-Asn-OH Hpp-OH implemented.
  • the peptide resin obtained (1.01 g) was subjected to HF cleavage (10 ml HF, 1 ml m-cresol; 0 ° C., 45 min).
  • the HF was in a vacuum

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Il est décrit des peptides ayant la formule Z-Ak-Bl-Cm-Dn-Eo-Fp-Gq-H-Thr-I-Gln-J-K-NH2, dans laquelle A - K, Z et k - q ont la notation donnée dans la description, ainsi que leur procédé de fabrication. Ces peptides conviennent pour combattre des maladies.
PCT/EP1990/001997 1989-12-01 1990-11-22 Nouveaux peptides derives du neuropeptide y WO1991008223A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3939797.1 1989-12-01
DE19893939797 DE3939797A1 (de) 1989-12-01 1989-12-01 Neue vom neuropeptid y abgeleitete peptide

Publications (1)

Publication Number Publication Date
WO1991008223A1 true WO1991008223A1 (fr) 1991-06-13

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Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1990/001997 WO1991008223A1 (fr) 1989-12-01 1990-11-22 Nouveaux peptides derives du neuropeptide y

Country Status (3)

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EP (1) EP0502874A1 (fr)
DE (1) DE3939797A1 (fr)
WO (1) WO1991008223A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012139A1 (fr) * 1991-12-19 1993-06-24 Garvan Institute Of Medical Research Nouvelle molecule inhibant la fonction biologique du neuropeptide tyrosine
FR2701480A1 (fr) * 1993-02-15 1994-08-19 Sanofi Elf Composés à groupe sulfamoyle et amidino, leur procédé de préparation et les compositions pharmaceutiques les contenant.
US5714497A (en) * 1993-02-15 1998-02-03 Sanofi Compounds bearing sulphamoyl and amidino radicals, their preparation process and pharmaceutical compositions containing them

Families Citing this family (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE462432T1 (de) 2003-05-05 2010-04-15 Probiodrug Ag Glutaminylcyclase-hemmer
US20050137142A1 (en) 2003-11-03 2005-06-23 Probiodrug Ag Combinations useful for the treatment of neuronal disorders
CA2554809C (fr) 2004-02-05 2014-04-29 Probiodrug Ag Nouveaux inhibiteurs de la glutaminyl-cyclase comportant de la n thiouree alkyle et de l'imidazolyl substitue par thioamide
JP5379692B2 (ja) 2006-11-09 2013-12-25 プロビオドルグ エージー 潰瘍、癌及び他の疾患の治療のためのグルタミニルシクラーゼの阻害薬としての３−ヒドロキシ−１，５−ジヒドロ−ピロール−２−オン誘導体
DK2091948T3 (da) 2006-11-30 2012-07-23 Probiodrug Ag Nye inhibitorer af glutaminylcyclase
CA2679446C (fr) 2007-03-01 2016-05-17 Probiodrug Ag Nouvelle utilisation d'inhibiteurs de la glutaminyl cyclase
WO2008128985A1 (fr) 2007-04-18 2008-10-30 Probiodrug Ag Dérivés de thio-urée utilisés comme inhibiteurs de la glutaminyl cyclase
BR112012008346B1 (pt) 2009-09-11 2021-12-21 Vivoryon Therapeutics N.V. Derivados heterocíclicos, seu processo de preparação, e composição farmacêutica
JP6026284B2 (ja) 2010-03-03 2016-11-16 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤
BR112012022478B1 (pt) 2010-03-10 2021-09-21 Probiodrug Ag Inibidores heterocíclicos de glutaminil ciclase (qc, ec 2.3.2.5), seu processo de preparação, e composição farmacêutica
JP5945532B2 (ja) 2010-04-21 2016-07-05 プロビオドルグ エージー グルタミニルシクラーゼの阻害剤としてのベンゾイミダゾール誘導体
US8530670B2 (en) 2011-03-16 2013-09-10 Probiodrug Ag Inhibitors
EP3461819B1 (fr) 2017-09-29 2020-05-27 Probiodrug AG Inhibiteurs de la glutaminyl-cyclase

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3811193A1 (de) * 1988-04-01 1989-10-19 Boehringer Ingelheim Kg Neue peptide, verfahren zu ihrer herstellung und diese peptide enthaltende pharmazeutische zusammensetzungen

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3811193A1 (de) * 1988-04-01 1989-10-19 Boehringer Ingelheim Kg Neue peptide, verfahren zu ihrer herstellung und diese peptide enthaltende pharmazeutische zusammensetzungen

Cited By (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993012139A1 (fr) * 1991-12-19 1993-06-24 Garvan Institute Of Medical Research Nouvelle molecule inhibant la fonction biologique du neuropeptide tyrosine
EP0672054A1 (fr) * 1991-12-19 1995-09-20 Garvan Institute Of Medical Research Nouvelle molecule inhibant la fonction biologique du neuropeptide tyrosine
EP0672054A4 (fr) * 1991-12-19 1996-02-07 Garvan Inst Med Res Nouvelle molecule inhibant la fonction biologique du neuropeptide tyrosine.
FR2701480A1 (fr) * 1993-02-15 1994-08-19 Sanofi Elf Composés à groupe sulfamoyle et amidino, leur procédé de préparation et les compositions pharmaceutiques les contenant.
EP0614911A1 (fr) * 1993-02-15 1994-09-14 Sanofi Composés à groupe sulfamoyle et amidino, leur procédé de préparation et les compositions pharmaceutiques les contenant
US5506258A (en) * 1993-02-15 1996-04-09 Elf Sanofi Compounds bearing sulphamoyl and amidino radicals, their preparation process and pharmaceutical compositions containing them
US5674890A (en) * 1993-02-15 1997-10-07 Sanofi Compounds bearing sulphamoyl and amidino radicals, their preparation process and pharmaceutical compositions containing them
US5714497A (en) * 1993-02-15 1998-02-03 Sanofi Compounds bearing sulphamoyl and amidino radicals, their preparation process and pharmaceutical compositions containing them

Also Published As

Publication number Publication date
EP0502874A1 (fr) 1992-09-16
DE3939797A1 (de) 1991-06-06

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