EP0946205A2 - Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production - Google Patents

Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production

Info

Publication number
EP0946205A2
EP0946205A2 EP97951940A EP97951940A EP0946205A2 EP 0946205 A2 EP0946205 A2 EP 0946205A2 EP 97951940 A EP97951940 A EP 97951940A EP 97951940 A EP97951940 A EP 97951940A EP 0946205 A2 EP0946205 A2 EP 0946205A2
Authority
EP
European Patent Office
Prior art keywords
ile
asp
cys
leu
ser
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Withdrawn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
EP97951940A
Other languages
German (de)
English (en)
Inventor
Ludger Dinkelborg
Ulrich Speck
Christoph-Stephan Hilger
Friedhelm Blume
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.)
Bayer Pharma AG
Original Assignee
Schering AG
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 Schering AG filed Critical Schering AG
Publication of EP0946205A2 publication Critical patent/EP0946205A2/fr
Withdrawn legal-status Critical Current

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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
    • C07K14/57536—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
    • A61P9/10—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
    • 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 in particular to the use of conjugates from endothelin derivatives, partial sequences of endothelin, endothelin analogs or endothelin antagonists and an active group for the therapy of vascular diseases.
  • Another aspect of the invention relates to new endothelin conjugates, agents containing these compounds and methods for their preparation.
  • Cardiovascular diseases are one of the most widespread diseases in the industrialized countries. They are one of the most common causes of death. In the vast majority of cases, cardiovascular diseases are caused by atherosclerosis. This is an inflammatory, fibroproliferative disease that is responsible for 50% of all deaths in the United States, Europe and Japan (Ross 1993, Nature 362: 801-809). With its peripheral characteristics, it threatens the preservation of the
  • Atherosclerosis is currently treated in different ways. In addition to the conservative measures (e.g. lowering the rate of the blood pressure).
  • An alternative method of treating atherosclerotic diseases uses ionizing radiation. It is known, for example, that ionizing radiation inhibits the proliferation of cells. A variety of neoplastic and non-neoplastic diseases have been treated in this way (Fletcher, Textbook of Radiotherapy, Philadelphia, P.A: Lea and Febiger, 1980, Hall, Radiobiology for the Radiologist, Philadelphia, P.A: Lippincott, 1988).
  • neointimal hyperplasia a number of other therapeutic strategies for inhibiting neointimal hyperplasia (restenosis) are also used. These include classic drugs for restenosis suppression such as antithrombotics, platelet aggregation inhibitors, calcium antagonists, anti-inflammatory and anti-proliferative substances, but also gene therapy approaches. It is possible to inhibit growth stimulators, for example by means of antisense oligonucleotides, or to amplify inhibiting factors by means of expression vector plasmids and virus-mediated gene integration. Aptamer oligonucleotides can also be used to inhibit a wide variety of receptor-mediated processes that play a crucial role in restenosis.
  • PTK inhibition is not free of side effects, since PTKs are also responsible for normal proliferation and metabolic processes (eg insulin receptor or NGF receptor) (Levitzki 1992, FASEB 6, 3275-3282).
  • Another unsolved problem is the insufficient length of stay of the PTK blockers and their lack of selectivity.
  • all PTK blockers must be able to cross the cell membrane in order to be effective.
  • cytostatics such as Cis-diaminedichloroplatin (cisplatin) used for the therapy of neoplastic diseases (Rozencweig et al., 1977. Ann. Intern. Med., 86, 803-812).
  • cisplatin proves to be a very effective therapeutic agent for the application mentioned, its broad application is prohibited, since the therapeutic window of this substance is very limited due to the various, in some cases drastic, systemic side effects. Above all, the nephrotoxic effect of renally eliminated cisplatin is responsible for the limited clinical use of this substance (Dentino et al. 1987, Cancer 41, 1274-1281, Groth et al. 1986, Cancer Chemofher. Pharmacol. 17, 191-196).
  • endothelin conjugate also means conjugates of endothelin derivatives, partial sequences of endothelin, endothelin analogs or endothelium-antagonists.
  • the invention thus relates to the use of endothelin conjugates for the therapeutic treatment of vascular diseases.
  • Another aspect of the invention relates to new conjugates from endothelins, endothelin derivatives, partial sequences of endothelins, endothelin analogs or endothelin antagonists and at least one active group, processes for their preparation, agents containing these conjugates and their use in diagnostics and therapy. It has been found that conjugates of endothelins, endothelin derivatives, partial sequences of endothelin, endothelin analogs or endothelin antagonists and an active group accumulate in cells and tissues in which endothelin receptors are increasingly expressed. These receptors are particularly found in atherosclerotic deposits (plaques).
  • the endotheline despite being coupled to an active group, maintains its high specificity towards these receptors, so that a therapeutically effective enrichment of the active group at the target site can be achieved even at low doses.
  • the residence time of the conjugates is also long enough to achieve the desired therapeutic effect.
  • the concentration in other tissues does not reach a toxic range at this dosage, in particular because the conjugates not containing the active muscle groups that bind to the smooth muscle cells are quickly eliminated from the body and the burden on the patient caused by the unbound conjugate is minimal. The systemic side effects observed are therefore minor.
  • conjugates according to the invention are also absorbed into the cell as a substance-receptor complex after binding to the receptors. So it is not only possible to target the target groups
  • endotheline endotheline, endothelin derivatives, partial sequences of endothelin, endothelin analogs or endothelin antagonists:
  • chemotherapeutics include vinblastine, doxorubicin, bleomycin, methotrexate, 5-fluorouracil, 6-thioguanine, cytarabine, cyclophosphoamide and cisplatin, as well as other conventional chemotherapeutics (see, for example, Cancer: Principles and Practice of Oncology. 2nd ed., VT De Vita, Jr., S. Hellman, SA Rosenberg, JB Lippincot Co., Philadelphia, PA, 1985, Chapter 14). Preferred among the cisplatin mentioned.
  • the radionuclide is bound to the endothelin residue either directly or - in particular in the case of metallic radionuclides, such as e.g. a nuclide of the elements Ag, As, Au, Bi, Cu, Ga, Gd, Hg, Ho, In, Ir, Lu, Pb, Pd, Pm, Pr, Re, Rh, Ru, Sb, Sc, Se, Sm, Sn, Tb, Tc or Y - via an appropriate complexing agent which is coupled to the endothelin.
  • metallic radionuclides such as e.g. a nuclide of the elements Ag, As, Au, Bi, Cu, Ga, Gd, Hg, Ho, In, Ir, Lu, Pb, Pd, Pm, Pr, Re, Rh, Ru, Sb, Sc, Se, Sm, Sn, Tb, Tc or Y - via an appropriate complexing agent which is coupled to the endothelin.
  • the radionuclide of the elements At, Ba, Br, C, F, N, O or P may be mentioned as active group W 1 .
  • chemotherapeutic agents are vinblastine, doxorubicin, bleomycin, methotrexate, 5-fluorouracil, 6-thioguanine, cytarabine, cyclophosphoamide and preferably cisplatin.
  • Examples of medicines are mercaptopurine, N-methyl-formamide, 2-amino-l, 3,4-thiadiazole, melphalan, hexamethylmelanine, dichloromethotrexate, mitoguazone, sumarin, bromodeoxyuridine, iodine deoxyuridine, semustine, 1- (2-chloroethyl) -3 - (2,6-dioxo-3-piperidyl) -l-nitrosourea, N, N'-hexamethylene-bis-acetamide, azacitidine, dibromodulcitol, Erwinia asparaginase, ifosfamide, 2-mercaptoethanesulfonate, teniposide, taxol, 3-deazauridine, soluble Baker's folic acid antagonist, homoharringtonine, cyclo-cytidine, acivicin, ICRF-187, spiromustine, levamisole, chlorozotocin
  • Anti-inflammatory drugs such as corticoids or non-steroidal anti-inflammatory drugs
  • Ca antagonists such as verapamil, nifedipine or diltiazem
  • Lipid-lowering agents such as simvastatin or probucol
  • Anti-proliferatives such as colchicine, angiopeptin, estradiol or ACE inhibitors (eg Ramipril ® );
  • Antisense oligonucleotides; Aptamer oligonucleotides; PTK blockers such as
  • PTK blockers such as Ty ⁇ hostine, S-aryl-benylidene malononitrile compounds or benzylidene malononitrile (BMN) compounds.
  • the active groups are linked to the endothelines in a manner known per se.
  • tyrosine kinase inhibitors of the type Ty ⁇ hostine e.g. are bound via their phenolic OH groups to the peptides of the endothelin type by first esterifying them with cyclic anhydrides of aliphatic and aromatic dicarboxylic acids and then amide-linking them to the N-terminus of the peptide.
  • compositions comprising an endothelin conjugate dissolved, suspended or emulsified in water and the additives and stabilizers customary in galenics. If the endothelin conjugate carries a complex with a short-lived radioisotope as the active group, the corresponding agents are provided as a kit, the endothelin compound being present in a container coupled to the metal-free complexing agent. The desired radioisotope is added to this immediately before administration.
  • the substances according to the invention are outstandingly suitable for being applied in large quantities and over a long period of time to the wall of a blood vessel via an application catheter.
  • the amount applied depends on the respective active group and the extent of the deposits.
  • a value that can also be used when the pure active substance is administered can be assumed as an orienting upper limit. Based on the effect-enhancing effect and the possibility However, to introduce the active substance specifically (via a catheter), the required dose is generally far below this upper limit.
  • the systemic tolerance of highly potent active ingredients is also improved by binding to the endothelin receptor-affine substances and endothelin derivatives.
  • the endothelin conjugates are not only suitable for the treatment of cardiovascular diseases such as myocardial ischemia, congestive heart failure, cardiac arrhythmia, unstable angina, heart attack, high blood pressure, atherosclerosis and restenosis, but also for example the treatment of bronchoconstructive diseases such as pulmonary hypertension and asthma, neuronal diseases such as cerebral infarction, cerebral vasospasm and subarachnoid hemorrhages, endocrinal diseases such as preeclampsia, renal diseases, vascular diseases such as Buergers disease, the Takay ashes arteritis, the Raynaud and macro phenomenon Forms of diabetic diseases, neoplastic diseases in particular the leiomyoma, pulmonary and prostate carcinomas, gastric mucosal injuries, gastrointestinal changes, endotoxic shock, septicemia as well as bacterial and other inflammation Oritions, that is, in all diseases in which the endothelin level and the expression of cardiovascular diseases such as myocardial ischemia
  • diethylene triamine (prepared as described in Example la) is added and the reaction mixture is stirred for 6 h at room temperature, then filtered and the solvent is evaporated off under a fine vacuum
  • the white residue is mixed with 150 ml of a mixture of trifluoroacetic acid: Anisole: ethanedithiol (95: 2.5: 2.5), then concentrated in a fine vacuum at room temperature (about 15-20 ml) and poured onto 150 ml of absolute diethyl ether, the white precipitate is filtered off and chromatographed on silica gel RP-18 (eluent: A: water / 0.1% trifluoroacetic acid B: acetonitrile / 0.1% trifluoroacetic acid; gradient: 0% B to 100% B).
  • N- (8-amino-l-oxo-octyl) -Phe- (D-T ⁇ ) -Leu-Asp-Ile-Ile-T ⁇ -OH was carried out by solid phase synthesis in analogy to E. Atherton and R.C. Sheppard (Solid phase Peptide synthesis, a practical approach, IRL Press, Oxford, New York, Tokyo, 1989).
  • Trifluoroacetic acid anisole: ethanedithiol (95: 2.5: 2.5) treated. It is then concentrated under a fine vacuum at room temperature (approx. 15-20 ml) and poured onto 150 ml of absolute diethyl ether. The white precipitate is filtered off and purified by chromatography on silica gel RP-18 (eluent: A: water / 0.1% trifluoroacetic acid B: acetonitrile / 0.1% trifluoroacetic acid; gradient: 0% B to 100% B). Yield: 135.2 mg (17.9%) white powder. Molecular weight: calc.: 1508.74 found. : 1509 (FAB-MS)
  • Example 3 1 mg of N- [N ', N', N '", N"' tetrakis (hydroxycarboxymethyl) -N '' - (carboxy
  • the A. carotis speciis dextra was exposed on anesthetized white New Zealand rabbits (3.5 kg).
  • a 2 F balloon catheter (Baxter) was introduced cranially over a cut and an approximately 5 cm long vessel area was denuded twice with 0.9% saline after inflation of the catheter. Then a
  • FIG. 1 shows an anterior summation scintigram of the dynamic study 0-1 h after local application of the Tc-99m complex of NH2-Asp-Gly-Gly-Cys-Gly-Cys-Phe- (D-T ⁇ ) -Leu-Asp-Ile -Ile-T ⁇ -OH (picture A), as well as Tc-99m pertechnetate (picture B). While the locally applied Tc-99m-NH2-Asp-Gly-Gly-Cys-Gly-Cys-Phe- (D-T ⁇ ) -Leu-Asp-Ile-Ile-T ⁇ -OH after 1 h after
  • Tc-99m pertechnetate (Fig. B) is flushed out of the vessel wall immediately after restoration of blood flow and accumulates in the salivary glands and the thyroid gland.
  • FIG. 2 shows the course of the activity (cpm / s) of Tc-99m-NH2-Asp-Gly-Gly-Cys-Gly-Cys-Phe- (D-T ⁇ ) -Leu-Asp-Ile-Ile-T ⁇ -OH in the common carotid artery after local application over time. The activity was recorded over a period of 1 h after local application by means of a dynamic study. The amount of Tc-99m-NH2-Asp-Gly-Gly-Cys-Gly-Cys-Phe- (D-T ⁇ ) -Leu-Asp-Ile-Ile-T ⁇ -OH applied only decreased marginally during the investigation period.
  • the rabbit was sacrificed 5 hours after the application and both autoradiography of the aorta and Sudan III staining were carried out.
  • the atherosclerotic plaques in the area of the aortic arch of WHHL rabbits could be visualized 10 min pi in vivo.
  • the subsequent autoradiography showed an accumulation of 3930 cpm / mm 2 atherosclerotic lesions and an accumulation of 380 cpm / mm 2 in the macroscopically unchanged aorta.
  • the enrichment factor between normal and atherosclerotic wall areas was 14.
  • the precipitated dicyclohexylurea is filtered off, the filtrate is washed twice with 1% citric acid and once with saturated sodium bicarbonate solution, dried with magnesium sulfate and concentrated. The residue is dissolved in a little methylene chloride and the remaining precipitated dicyclohexylurea is filtered off. The filtrate is concentrated and the residue is taken up in DMF. 10.5 g (0.01 mol) of H2N-Gly-Phe- (DT ⁇ ) -Leu-Asp-Ile-Ile-T ⁇ -OH are added and the mixture is stirred overnight at room temperature.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Vascular Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Engineering & Computer Science (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Endocrinology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Urology & Nephrology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Cardiology (AREA)
  • Public Health (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Veterinary Medicine (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Peptides Or Proteins (AREA)
  • Medicinal Preparation (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)

Abstract

L'invention concerne l'utilisation de conjugués constitués d'endothélines et de groupes actifs pour le traitement de maladies vasculaires, ainsi que de nouveaux conjugués d'endothélines, des agents contenant ces composés et leurs procédés de production.
EP97951940A 1996-12-04 1997-11-24 Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production Withdrawn EP0946205A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE19652374A DE19652374A1 (de) 1996-12-04 1996-12-04 Verwendung von Endothelin-Konjugaten in der Therapie, neue Endothelin-Konjugate, diese enthaltende Mittel, sowie Verfahren zu deren Herstellung
DE19652374 1996-12-04
PCT/EP1997/006518 WO1998024482A2 (fr) 1996-12-04 1997-11-24 Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production

Publications (1)

Publication Number Publication Date
EP0946205A2 true EP0946205A2 (fr) 1999-10-06

Family

ID=7814923

Family Applications (1)

Application Number Title Priority Date Filing Date
EP97951940A Withdrawn EP0946205A2 (fr) 1996-12-04 1997-11-24 Utilisation de conjugues d'endothelines en therapie, nouveaux conjugues d'endothelines, agents les contenant, et leurs procedes de production

Country Status (6)

Country Link
US (1) US20030119719A1 (fr)
EP (1) EP0946205A2 (fr)
JP (1) JP2001504841A (fr)
AU (1) AU5554598A (fr)
DE (1) DE19652374A1 (fr)
WO (1) WO1998024482A2 (fr)

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DE19743143A1 (de) * 1997-09-30 1999-04-01 Knoll Ag Pharmazeutische Kombinationspräparate
DE19916417A1 (de) * 1999-04-01 2000-10-19 Schering Ag Amyloidspezifisches Aptamer
US7741431B2 (en) * 2005-02-01 2010-06-22 The United States Of America As Represented By The Secretary Of The Army Liposomes containing novel targeting and/or fusogenic peptides, preparations containing them and therapeutic use thereof
US20090220587A1 (en) * 2005-02-01 2009-09-03 United State Army Liposomal drug delivery constructs targeted by lipid-conjugated peptide ligands

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Also Published As

Publication number Publication date
JP2001504841A (ja) 2001-04-10
US20030119719A1 (en) 2003-06-26
WO1998024482A2 (fr) 1998-06-11
DE19652374A1 (de) 1998-06-10
AU5554598A (en) 1998-06-29
WO1998024482A3 (fr) 1999-04-01

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