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WO1990006947A1 - Nouveaux peptides derives du facteur de necrose de tumeurs (tnf) - Google Patents

Nouveaux peptides derives du facteur de necrose de tumeurs (tnf) Download PDF

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Publication number
WO1990006947A1
WO1990006947A1 PCT/EP1989/001475 EP8901475W WO9006947A1 WO 1990006947 A1 WO1990006947 A1 WO 1990006947A1 EP 8901475 W EP8901475 W EP 8901475W WO 9006947 A1 WO9006947 A1 WO 9006947A1
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WIPO (PCT)
Prior art keywords
group
peptide
val
protecting group
amino
Prior art date
Application number
PCT/EP1989/001475
Other languages
German (de)
English (en)
Inventor
Hans-Joachim Boehm
Lothar Daum
Andreas Haupt
Bernhard Schmied
Nigel Walker
Johann-Christian Zechel
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 WO1990006947A1 publication Critical patent/WO1990006947A1/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
    • C07K14/52—Cytokines; Lymphokines; Interferons
    • C07K14/525—Tumour necrosis factor [TNF]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • 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 tumor necrosis factor (TNF), their production and their use as medicaments.
  • TNF tumor necrosis factor
  • TNF TNF-related protein kinase
  • mice In addition to its cytotoxic properties, TNF is one of the main participants in inflammatory reactions (Pharmac. Res. 5, 129, 1988). The involvement of TNF in septic shock (Science 229, 869, 1985) and graft versus host disease (J. Exp. Med. 166, 1280, 1987) was shown in the animal model.
  • the invention relates to peptides of the formula I
  • A is Ser, Ala or Thr
  • B means Glu, Asp or Ser, X for a group G-, G-NH-CHM-CO-, G-NH-CHM-CO-W-, GR-NH-CHM-CO- or GR-NH-CHM- CO-W and
  • Y stands for a group Z-, -NH-CHQ-CO-Z, -V-NH-CHQ-CO-Z, -NH-CHQ-CO-UZ or -V-NH-CHQ-CO-UZ, where in X and Y
  • G represents a hydrogen atom or an amino protecting group
  • Z represents an OH or NH 2 group or a carboxyl protecting group
  • M and Q are hydrogen atoms or one of the groups
  • M and Q together form a - (CH 2 ) c -SS- (CH 2 ) d -, - (CH 2 ) e -CO-NH- (CH 2 ) f - or - (CH 2 ) e -NH-CO- (CH 2 ) g -NH-CO- (CH 2 ) f bridge (with c and d meaning a number from 1 to 4, e and f a number from 1 to 6 and g a number from 1 to 12) mean, and their salts with physiologically acceptable acids.
  • the peptides of formula I are made up of L-amino acids, but they can contain 1 to 2 D-amino acids.
  • the side chains of the trifunctional amino acids can carry protective groups or be unprotected.
  • Methanesulfonic acid acetic acid, formic acid, maleic acid, fumaric acid, malic acid, succinic acid, malonic acid, sulfuric acid, L-glutamic acid, L-aspartic acid, pyruvic acid, mucic acid, benzoic acid,
  • Glucuronic acid oxalic acid, ascorbic acid, acetylglycine.
  • the new compounds can be prepared by methods known in peptide chemistry.
  • the fragments in turn being able to be 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
  • HSu N-hydroxysuccinimide
  • 2-hydroxypyridine 2-hydroxypyridine
  • Protective groups can be dispensed with, 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 polymers 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 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.
  • 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.
  • the new peptides show good cytotoxic properties. Another part of the peptides has a high affinity for the cellular TNF receptor without, however, having any cytotoxic activity. They therefore represent TNF antagonists. In competition with natural TNF, they bind to the cellular TNF receptor and thus suppress the TNF effect.
  • the new peptides prove to be valuable medicinal products that are used for
  • neoplastic diseases and autoimmune diseases Treatment of neoplastic diseases and autoimmune diseases as well as for the control and prophylaxis of infections, inflammation and
  • Rejection reactions can be used in transplants. Simple experiments can be used to determine the mode of action of the individual peptides.
  • Simple experiments can be used to determine the mode of action of the individual peptides.
  • Cytotoxicity of the peptide was determined by incubating the cell line in the presence of the peptide. In a second experiment, you incubate the
  • the agonistic evaluation of the new peptides is based on their cytotoxic effects on TNF-sensitive cells (e.g. L929, MCF-7,
  • the L929 and MCF-7 test was performed as follows: 1. 100 ⁇ l of culture medium with 3 to 5 ⁇ 10 3 freshly trypsinized, exponentially growing L929 cells (mouse) or MCF-7 cells (human) were placed in the wells of a
  • the L929 culture medium contained 500 ml MEM Earle 1 ⁇ (Boehringer, Mannheim), 50 ml heat-inactivated (30 min, 56 ° C.) fetal calf serum (FCS), 50 ml L-glutamine (200 mM), 5 ml 100 ⁇
  • non-essential amino acids 3 ml 1M Hepes buffer pH 7.2 and 50 ml gentamycin (50 mg / ml).
  • the MCF-7 culture medium contained 500 ml of MEM Dulbecco 1x
  • the percentage of surviving cells in the cultures treated with peptide dilution was determined by means of crystal violet staining.
  • the liquids were removed from the wells by knocking off the test plate. 50 ⁇ l of crystal violet solutions were pipetted into each well.
  • the crystal violet solution had the following composition:
  • the antagonistic evaluation of the peptides is based on their
  • TNF-sensitive cells e.g. L929, MCF-7, A204, U937.
  • the L929 culture medium contained 500 ml of MEM Earle lx (Boehringer, Mannheim), 50 ml of FCS heat-inactivated for 30 min at 56 ° C., 5 ml of L-glutamine (200 mM), 5 ml of 100 ⁇ nonessential amino acids, 3 ml of IM Hepes Buffer pH 7.2 and 500 ⁇ l gentamycin (50 mg / ml).
  • the MCF-7 culture medium contained 500 ml MEM Dulbecco 1 ⁇ (Boehringer, Mannheim), 100 ml heat-inactivated (30 min, 56 ° C) FCS, 5 ml L-glutamine (200 mM) and 5 ml 100x nonessential amino acids.
  • the culture plate was then incubated for 48 hours at 37 ° C. in an atmosphere of water vapor-saturated air with 5 vol.% CO 2 .
  • the percentage of surviving cells in the solution-treated cultures was determined by crystal violet staining.
  • the liquids were removed from the wells by knocking off the test plate. 50 ⁇ l of crystal violet solutions were pipetted into each well.
  • the crystal violet solution had the one given in II.3
  • the crystal violet solution remained in the wells for 20 min and was then also knocked off.
  • the plates were then washed 5 times each by immersion in water to remove the non-cell-bound dye.
  • cell-bound dye was added by adding 100 ul
  • Reagent solution (50% ethanol, 0.1% glacial acetic acid, 49.9% water) extracted from the cells into each well. 4. By shaking the plates for 5 min each was obtained
  • rhu-TNF control defined the 50% competition value and the sample concentration, which leads to 50% competition of the rhu-TNF cytotoxicity at the presented rhu-TNF concentration, was determined as the antagonistic activity of the examined sample.
  • Indicator cells (eg U937) compete.
  • the medium contained 500 ml PBS (Boehringer, Mannheim), 10 ml heat-inactivated (30 min, 56 ° C) FCS and 100 mg sodium azide.
  • rhu-TNF lactoperoxidase method according to Bolton
  • NBS nonspecific binding
  • the 125 iodine-labeled rhu-TNF (1 ng 125 J-rhu-TNF in 100 ⁇ l medium) with a 200-fold excess of non-radioactively labeled rhu-TNF (200 ng rhu-TNF mixed in 100 ul medium).
  • 100 ⁇ l of medium with 2 ⁇ 10 6 u937 cells (human) were pipetted into the reaction vessels and mixed.
  • the reaction vessels (test volume 300 ⁇ l) were incubated at 0 ° C. for 90 min. After 45 minutes, the reaction batches were mixed again.
  • proteogenic amino acids are abbreviated in the examples with the well-known three-letter code.
  • Aad ⁇ -aminoadipic acid
  • Ac acetic acid
  • Ade 10-aminodecanoic acid
  • Ahp 7-aminoheptanoic acid
  • Ahx 6-aminohexanoic acid
  • Ano 9-aminononanoic acid
  • Aoc 8-aminooctanoic acid
  • Ape 5-aminopentanoic acid
  • Bai ß-alanine
  • Hey homocysteine
  • peptide resin (Pam or Merrifield resin) was suspended in DMF (15 ml / g resin) and, after addition with hydrazine hydrate (20 equivalents), stirred for 2 days at room temperature. For working up, the resin was filtered off and the filtrate
  • the peptide resin obtained according to Ib was dried in vacuo and then, depending on the amino acid composition, subjected to one of the following cleavage procedures (Wade, Tregear, Howard Florey Fmoc-Workshop Manual, Melbourne 1985).
  • the purity of the end products obtained was determined using analytical HPLC (stationary phase: 100 ⁇ 2, 1 mm VYDAC C-18, 5 ⁇ , 300 ⁇ ; mobile phase CH 3 CN / H 2 O gradient, buffered with 0.1% TFA, 40 ° C). Amino acid analysis and fast atom bombardment mass spectroscopy were used for characterization.
  • step 1-6 and 14-16 were carried out according to Ala).
  • the peptide resin was dried in vacuo; the yield was 1.14 g.
  • Boc-Glu (0Chx) -OH Boc-Cys (pMB) -OH implemented.
  • the resin was subjected to an HF cleavage according to All and the lyophilized crude product was taken up in 2 l of 0.1% acetic acid and the pH was then adjusted to 8.4 with aqueous ammonia. 0.01 N K 3 [Fe (CN) 6 ] solution was slowly added dropwise under an argon atmosphere until the yellowish-green color persisted for more than 15 min. The mixture was stirred for a further 1 h, then acidified to pH 4.5 with glacial acetic acid and 15 ml of an aqueous suspension of an anion exchanger (BIORAD 3 ⁇ 4A, chloride form) were added. After 30 minutes, the ion exchange resin was filtered off, the filtrate was concentrated to 100 ml on a rotary evaporator and then lyophilized.
  • an anion exchanger BIORAD 3 ⁇ 4A, chloride form
  • Example 28 Analogously to Example 28 can be prepared (for the synthesis of
  • Fmoc-Glu (OBzl) -OH implemented. After the synthesis was complete, the N-terminus was deprotected and acetylated (steps 2-4 and 8-9 were carried out according to Alb). The peptide resin was dried in vacuo; Yield 1.38 g.
  • the crude product (288 mg) obtained after the TFA cleavage according to AIII was dissolved in 500 ml degassed DMF. After addition of 0.2 ml of NEt 3 , 0.2 ml of diphenylphosphoryl azide was added at -25 ° C. and the mixture was stirred at -25 ° C. for 2 hours. The mixture was then stored at -20 ° C, 2 days at 4 ° C and 2 days at room temperature.
  • Fig. 1 The Boc protection group technique on the polymeric carrier
  • Boc t-butyloxycarbonyl protecting group
  • Fig. 2 The Fmoc protection group technique on the polymeric carrier

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
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Abstract

L'invention concerne de nouveaux peptides ayant la formule: X-Pro-A-B-Y, dans laquelle A, B, X et Y ont la signification donnée dans la description, et leur procédé de production. Ces nouveaux peptides sont utiles pour traiter des maladies.
PCT/EP1989/001475 1988-12-12 1989-12-02 Nouveaux peptides derives du facteur de necrose de tumeurs (tnf) WO1990006947A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DEP3841763.4 1988-12-12
DE3841763A DE3841763A1 (de) 1988-12-12 1988-12-12 Neue tnf-peptide

Publications (1)

Publication Number Publication Date
WO1990006947A1 true WO1990006947A1 (fr) 1990-06-28

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ID=6368958

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PCT/EP1989/001475 WO1990006947A1 (fr) 1988-12-12 1989-12-02 Nouveaux peptides derives du facteur de necrose de tumeurs (tnf)

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EP (1) EP0447430A1 (fr)
JP (1) JPH04502309A (fr)
CA (1) CA2005050A1 (fr)
DE (1) DE3841763A1 (fr)
WO (1) WO1990006947A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002267A1 (fr) * 1994-06-29 1996-02-01 Vladislav Isakovich Deigin Peptide, son procede d'obtention et compose pharmaceutique a base dudit peptide

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5827821A (en) * 1987-12-10 1998-10-27 The Burnham Institute Conformationally stabilized cell adhesion peptides
ATE140926T1 (de) * 1987-12-10 1996-08-15 Jolla Cancer Res Found Verfahren zur herstellung von conformationnell stabilisierten zelladhäsionspeptiden
US6521594B1 (en) 1990-04-06 2003-02-18 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
JPH05509294A (ja) * 1990-04-06 1993-12-22 ラ　ホヤ　キャンサー　リサーチ　ファウンデーション 血栓症治療のための方法および組成物
US5612311A (en) * 1990-04-06 1997-03-18 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
US5648330A (en) * 1990-04-06 1997-07-15 La Jolla Cancer Research Foundation Method and composition for treating vascular graft occlusion
US5780303A (en) * 1990-04-06 1998-07-14 La Jolla Cancer Research Foundation Method and composition for treating thrombosis
DE4340111A1 (de) * 1993-11-22 1995-05-24 Schering Ag Tumor-Nekrose-Faktor-alpha inaktivierende Peptide
US7173110B2 (en) * 2004-11-08 2007-02-06 New York University Peptide anti-tumor agent

Citations (5)

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Publication number Priority date Publication date Assignee Title
US4415491A (en) * 1980-01-14 1983-11-15 The Regents Of The University Of California Synthetic vaccine peptide epitomes of hepatitis B surface antigen
US4518527A (en) * 1983-08-16 1985-05-21 Mitsubishi Chemical Industries Limited Polypeptides related to the pre-acetylcholine receptor-α of the electric organ of Torpedo californica
EP0154902A2 (fr) * 1984-03-07 1985-09-18 New York Blood Center, Inc. Peptides codés par le gène pré-S immunogènes de l'hépatite B, vaccins, diagnostics et supports vésiculaires lipidiques synthétiques
EP0247906A2 (fr) * 1986-02-04 1987-12-02 Mizuno, Den'Ichi ADN codant pour des polypeptides antitumoraux, les polypeptides et les agents antitumoraux contenant ces polypeptides
WO1988003950A1 (fr) * 1982-11-30 1988-06-02 Marc Girard PEPTIDES COMPORTANT UN SITE IMMUNOGENE DU POLIOVIRUS ET ADNs CONTENANT DES SEQUENCES NUCLEOTIDIQUES CODANT POUR CES PEPTIDES

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JPS5245290A (en) * 1975-10-08 1977-04-09 Hitachi Ltd Integrated circuit of semiconductor and method for its fabrication
JPS60160125A (ja) * 1984-01-30 1985-08-21 Mitsubishi Electric Corp 半導体装置の製造方法
US4556585A (en) * 1985-01-28 1985-12-03 International Business Machines Corporation Vertically isolated complementary transistors
JPS6231153A (ja) * 1985-08-02 1987-02-10 Matsushita Electric Ind Co Ltd Ｍｉｓ型半導体集積回路の製造方法
JPS6296390A (ja) * 1985-10-21 1987-05-02 Nec Corp 気相エピタキシヤル成長法

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4415491A (en) * 1980-01-14 1983-11-15 The Regents Of The University Of California Synthetic vaccine peptide epitomes of hepatitis B surface antigen
WO1988003950A1 (fr) * 1982-11-30 1988-06-02 Marc Girard PEPTIDES COMPORTANT UN SITE IMMUNOGENE DU POLIOVIRUS ET ADNs CONTENANT DES SEQUENCES NUCLEOTIDIQUES CODANT POUR CES PEPTIDES
US4518527A (en) * 1983-08-16 1985-05-21 Mitsubishi Chemical Industries Limited Polypeptides related to the pre-acetylcholine receptor-α of the electric organ of Torpedo californica
EP0154902A2 (fr) * 1984-03-07 1985-09-18 New York Blood Center, Inc. Peptides codés par le gène pré-S immunogènes de l'hépatite B, vaccins, diagnostics et supports vésiculaires lipidiques synthétiques
EP0247906A2 (fr) * 1986-02-04 1987-12-02 Mizuno, Den'Ichi ADN codant pour des polypeptides antitumoraux, les polypeptides et les agents antitumoraux contenant ces polypeptides

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
Chemical Abstracts, Band 102, no. 1, 7 Januar 1985, (Columbus, Ohio, US), Radmila Micanovic et al : "Purification and sequence of a non-opioid peptide derived from ovine proenkephalin: implications for possible species specific processing. ", siehe Seite 678, Zusammenfassung 678b, & Peptides (Fayetteville, N.Y.) 1984, 5( 5), 853-6 *
Chemical Abstracts, Band 108, no. 5, 1 Februar 1988, (Columbus, Ohio, US), Robert Benoit et al : "A new prosomatostatin-derived peptide reveals a pattern for prohormone cleavage at monobasic sites. ", siehe Seite 124, Zusammenfassung 32370k, & Science (Washington, D.C., 1883-) 1987, 238(4830), 1126-9 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996002267A1 (fr) * 1994-06-29 1996-02-01 Vladislav Isakovich Deigin Peptide, son procede d'obtention et compose pharmaceutique a base dudit peptide

Also Published As

Publication number Publication date
DE3841763A1 (de) 1990-06-13
EP0447430A1 (fr) 1991-09-25
CA2005050A1 (fr) 1990-06-12
JPH04502309A (ja) 1992-04-23

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