EP0579823A1 - Neuartige hexapeptid-derivate herstellung und verwendung dieser neuen derivate als medikamente - Google Patents
Neuartige hexapeptid-derivate herstellung und verwendung dieser neuen derivate als medikamenteInfo
- 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- Withdrawn
Links
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- ZPNFWUPYTFPOJU-LPYSRVMUSA-N iniprol Chemical compound C([C@H]1C(=O)NCC(=O)NCC(=O)N[C@H]2CSSC[C@H]3C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@H](C(N[C@H](C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC=4C=CC=CC=4)C(=O)N[C@@H](CC=4C=CC(O)=CC=4)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](C)C(=O)NCC(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CC=4C=CC=CC=4)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC2=O)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](CC=2C=CC=CC=2)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H]2N(CCC2)C(=O)[C@@H](N)CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N2[C@@H](CCC2)C(=O)N2[C@@H](CCC2)C(=O)N[C@@H](CC=2C=CC(O)=CC=2)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N2[C@@H](CCC2)C(=O)N3)C(=O)NCC(=O)NCC(=O)N[C@@H](C)C(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CC=2C=CC=CC=2)C(=O)N[C@H](C(=O)N1)C(C)C)[C@@H](C)O)[C@@H](C)CC)=O)[C@@H](C)CC)C1=CC=C(O)C=C1 ZPNFWUPYTFPOJU-LPYSRVMUSA-N 0.000 description 1
- 229940102223 injectable solution Drugs 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 108010091871 leucylmethionine Proteins 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 238000004949 mass spectrometry Methods 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 210000005036 nerve Anatomy 0.000 description 1
- 230000009871 nonspecific binding Effects 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 108010091212 pepstatin Proteins 0.000 description 1
- FAXGPCHRFPCXOO-LXTPJMTPSA-N pepstatin A Chemical compound OC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)C[C@H](O)[C@H](CC(C)C)NC(=O)[C@H](C(C)C)NC(=O)[C@H](C(C)C)NC(=O)CC(C)C FAXGPCHRFPCXOO-LXTPJMTPSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 235000003270 potassium fluoride Nutrition 0.000 description 1
- 239000011698 potassium fluoride Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 125000006239 protecting group Chemical group 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000002829 reductive effect Effects 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 210000000329 smooth muscle myocyte Anatomy 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000013222 sprague-dawley male rat Methods 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 125000006253 t-butylcarbonyl group Chemical group [H]C([H])([H])C(C(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000006257 total synthesis reaction Methods 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
- 210000003556 vascular endothelial cell Anatomy 0.000 description 1
- 230000003639 vasoconstrictive effect Effects 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
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)
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| 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. |
| FR9201558 | 1992-02-12 |
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)
| 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 |
| WO2004054560A1 (en) | 2002-12-13 | 2004-07-01 | Warner-Lambert Company Llc | Alpha-2-delta ligand to treat lower urinary tract symptoms |
Family Cites Families (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5260276A (en) * | 1991-06-14 | 1993-11-09 | Warner-Lambert Company | Linear and monocyclic endothelin antagonists |
-
1992
- 1992-02-12 FR FR9201558A patent/FR2687155B1/fr not_active Expired - Fee Related
-
1993
- 1993-02-11 EP EP93905388A patent/EP0579823A1/de not_active Withdrawn
- 1993-02-11 JP JP5513852A patent/JPH06507186A/ja active Pending
- 1993-02-11 CA CA002107343A patent/CA2107343A1/fr not_active Abandoned
- 1993-02-11 US US08/133,020 patent/US5476840A/en not_active Expired - Fee Related
- 1993-02-11 WO PCT/FR1993/000145 patent/WO1993016104A1/fr not_active Ceased
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9316104A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| FR2687155A1 (fr) | 1993-08-13 |
| US5476840A (en) | 1995-12-19 |
| JPH06507186A (ja) | 1994-08-11 |
| CA2107343A1 (fr) | 1993-08-13 |
| FR2687155B1 (fr) | 1995-05-19 |
| WO1993016104A1 (fr) | 1993-08-19 |
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