EP0579823A1 - Neuartige hexapeptid-derivate herstellung und verwendung dieser neuen derivate als medikamente - Google Patents

Neuartige hexapeptid-derivate herstellung und verwendung dieser neuen derivate als medikamente

Info

Publication number
EP0579823A1
EP0579823A1 EP93905388A EP93905388A EP0579823A1 EP 0579823 A1 EP0579823 A1 EP 0579823A1 EP 93905388 A EP93905388 A EP 93905388A EP 93905388 A EP93905388 A EP 93905388A EP 0579823 A1 EP0579823 A1 EP 0579823A1
Authority
EP
European Patent Office
Prior art keywords
residue
trp
series
alanine
derivatives
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP93905388A
Other languages
English (en)
French (fr)
Inventor
Pierre Broto
Gilles Hamon
Eve 825 avenue du Comté-de-Nice MAHE
Dung Le-Nguyen
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanofi Aventis France
Original Assignee
Roussel Uclaf SA
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 Roussel Uclaf SA filed Critical Roussel Uclaf SA
Publication of EP0579823A1 publication Critical patent/EP0579823A1/de
Withdrawn legal-status Critical Current

Links

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
    • C07K14/57536—Endothelin, vasoactive intestinal contractor [VIC]
    • 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
    • A61P9/08—Vasodilators for multiple indications
    • 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
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present application relates to new hexapep ⁇ tidic derivatives, the process for the preparation and the application as a medicament of these new derivatives.
  • endothelin is a potent vasoconstrictor extracted from aortic endothelium from pigs.
  • This recently isolated peptide contains 21 amino acids, has 2 disulfide bridges and has the formula:
  • X 1 represents a hydrogen atom or a residue of histidine, acetyl-histidine, or D-histidine
  • X 2 represents a residue of alanine, leucine, tryptophane, phenylalanine and their D-series counterparts
  • X 3 represents an alanine residue as well as its D-series counterpart
  • X 5 represents a residue of isoleucine, alanine, valine, norleucine, leucine and aspartic acid as well as their D-series counterparts,
  • X 6 represents a residue of tryptophan, leucine, isoleu ⁇ cine, norleucine and their D-series counterparts
  • X- ⁇ represents a hydrogen atom, a residue of histidine or of D-histidine,
  • X 2 represents an alanine or leucine residue, as well as their D-series counterparts
  • X 3 represents an alanine residue as well as its D-series counterpart
  • X 5 represents an isoleucine residue as well as its D-series counterpart
  • X 6 represents a tryptophan residue, as well as its homolog in series D.
  • the peptide derivatives are preferably used in which:
  • X- j _ represents a hydrogen atom or a histidine residue
  • X 2 represents an alanine residue
  • X 3 represents an alanine or aspartic acid residue
  • X 5 represents an isoleucine residue
  • X 6 represents a residue of tryptophan or of D-tryptophan.
  • X 6 represents a residue of tryptophan or of D-tryptophan.
  • the invention also relates to a process for the preparation of new hexapeptide derivatives as defined above, characterized in that a solid phase synthesis is carried out by sequentially introducing them onto a support of crosslinked polystyrene type. duly protected ino-acids, using a coupling agent, deprotects the amino acids, and releases from the resin the peptide chain thus formed, to obtain the peptide derivative of formula (I) thus sought.
  • the process described above is characterized in that: the support of the crosslinked polystyrene type is a resin of the "Boc-Trp-CM” type or of the “Boc-D-Trp- type CM "in which Boc is a tert-butyloxycarbonyl group, Trp is a tryptophyl group and D-Trp is a D-tryptophyl group and CM denotes the crosslinked polystyrene support,
  • the coupling agent is (benzotriazol-1-yloxy) tris (dimethylamino) phosphoniu hexafluorophosphate or Bop,
  • the new hexapeptide derivatives which are the subject of the present invention have very interesting pharmacological properties; there is in particular a remarkable practically pure antagonistic effect against hypertension induced by endothelin and an anti-dry effect, the vasoconstrictive activity of endothelin being abolished.
  • a subject of the present invention is thus also the application, as medicaments, of the new hexapeptide derivatives as defined by the general formula (I) above.
  • the drugs which are the subject of the invention there are in particular the drugs, characterized in that they consist of the products of formula (I) in which X- ⁇ represents a hydrogen atom, a histidine residue or of D-histidine, X 2 represents an alanine or leucine residue, as well as their D-series counterparts,
  • X 3 represents an alanine residue, as well as its D-series counterpart
  • X ⁇ represents an isoleucine residue, as well as its D-series counterpart
  • X 6 represents a residue of tryptophan, or of D-tryptophan.
  • the drugs containing the new peptide derivatives such as defined above, in which:
  • X 1 represents a hydrogen atom or a histidine residue
  • X 2 represents an alanine or leucine residue
  • X 3 represents an alanine residue
  • X 5 represents an isoleucine residue
  • Xg represents a residue of tryptophan or of D-tryptophan.
  • These drugs find, for example, their use in the treatment of all vascular spasms, in the treatment of cerebral post-hemorrhages, in the treatment of coronary spasms, peripheral vascular spasms as well as in the treatment of renal insufficiencies.
  • These drugs can also be used in the treatment of myocardial infarction, in the prevention of post-angioplasty restenosis, in the treatment of atherosclerosis, certain forms of hypertension, as well as in the treatment of asthma.
  • the usual dose which varies depending on the product used, the subject treated and the condition in question, may for example be from 1 to 300 g per day intravenously in humans.
  • a subject of the invention is also pharmaceutical compositions which contain at least one aforementioned derivative as active principle.
  • the peptide derivatives corresponding to the general formula (I) can be incorporated into pharmaceutical compositions intended for the digestive or parenteral route.
  • These pharmaceutical compositions may be, for example, solid or liquid and be in the pharmaceutical forms commonly used in human medicine, such as, for example, simple or coated tablets, capsules, capsules, granules, suppositories, injections, aerosols; they are prepared according to the usual methods.
  • the active ingredient (s) can be incorporated into excipients usually used in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • excipients usually used in these pharmaceutical compositions such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous vehicles or not, fatty substances of animal or vegetable origin, paraffinic derivatives, glycols, various wetting agents, dispersants or emulsifiers, preservatives.
  • a support of the “Boc-Trp-CM-support” type is used in which Boc is a tert-butyloxycarbonyl group, Trp represents a tryptophyl group and CM-support denotes the crosslinked polystyrene support.
  • the support containing 0.6 mol Trp / g was prepared by the potassium fluoride method according to the technique described by Horiki K., Igano K. & Inouye K. (1978) Che istry Lett. , 165-168. All the amino acids are N-protected by the tert-butylcarbonyl group, the protective groups for the side chains were as follows:
  • the fraction obtained is lyophilized and finally 30 mg of expected product is collected.
  • excipient q.s.p. one tablet finished at 150 mg (composition of the excipient: lactose, starch, talc, magnesium stearate). 5
  • a membrane preparation is carried out from the posterior cortex plus the rat cerebellum.
  • the non-specific binding is determined by adding endothelin at 10 ⁇ 6 M (in triplicate). Incubate at 25 ° C for 60 minutes, return to a water bath at 0 ° C for 5 minutes, filter under reduced pressure, rinse with Tris 7.4 buffer and count the radioactivity in the presence of the scintillant Triton.
  • IC50 inhibitory concentration 50%
  • the animals receive endothelin 1 or the test compound in cumulative injections by venous route, the administrations being spaced 2 minutes apart.
  • the increase in mean arterial pressure (BP) induced by each compound is measured and expressed as a percentage change from the initial pressure.
  • the antagonistic activity is expressed as a percentage of inhibition of the pressure response of endothelin administered alone, at doses of 3 and 10 ⁇ g / kg. Results:
  • New hexapeptide derivatives process for the preparation and application as medicaments of these new derivatives.
  • New hexapeptide derivatives process for the preparation and application as medicaments of these new derivatives.
  • New hexapeptide derivatives process for the preparation and application as medicaments of these new derivatives.
  • New hexapeptide derivatives process for the preparation and application as medicaments of these new derivatives.
  • New hexapeptide derivatives process for the preparation and application as medicaments of these new derivatives.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Genetics & Genomics (AREA)
  • Toxicology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Endocrinology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Animal Behavior & Ethology (AREA)
  • Molecular Biology (AREA)
  • Urology & Nephrology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
EP93905388A 1992-02-12 1993-02-11 Neuartige hexapeptid-derivate herstellung und verwendung dieser neuen derivate als medikamente Withdrawn EP0579823A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
FR9201558 1992-02-12
FR9201558A FR2687155B1 (fr) 1992-02-12 1992-02-12 Nouveaux derives hexapeptidiques, procede de preparation et application a titre de medicaments de ces nouveaux derives.

Publications (1)

Publication Number Publication Date
EP0579823A1 true EP0579823A1 (de) 1994-01-26

Family

ID=9426559

Family Applications (1)

Application Number Title Priority Date Filing Date
EP93905388A Withdrawn EP0579823A1 (de) 1992-02-12 1993-02-11 Neuartige hexapeptid-derivate herstellung und verwendung dieser neuen derivate als medikamente

Country Status (6)

Country Link
US (1) US5476840A (de)
EP (1) EP0579823A1 (de)
JP (1) JPH06507186A (de)
CA (1) CA2107343A1 (de)
FR (1) FR2687155B1 (de)
WO (1) WO1993016104A1 (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5382569A (en) * 1991-05-16 1995-01-17 Warner-Lambert Company Endotherlin antagonists
RU2213747C2 (ru) * 1999-03-11 2003-10-10 Институт биоорганической химии им. акад. М.М.Шемякина и Ю.А. Овчинникова РАН Пептид, обладающий противоопухолевой, протекторной и нормализующей активностью, и фармацевтическая композиция
JP2006511606A (ja) 2002-12-13 2006-04-06 ワーナー−ランバート・カンパニー、リミテッド、ライアビリティ、カンパニー 下部尿路症状を治療するα−２−δリガンド

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5260276A (en) * 1991-06-14 1993-11-09 Warner-Lambert Company Linear and monocyclic endothelin antagonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9316104A1 *

Also Published As

Publication number Publication date
JPH06507186A (ja) 1994-08-11
FR2687155B1 (fr) 1995-05-19
WO1993016104A1 (fr) 1993-08-19
US5476840A (en) 1995-12-19
FR2687155A1 (fr) 1993-08-13
CA2107343A1 (fr) 1993-08-13

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