EP0452447A1 - Antagonistes irreversibles reduits de bombesine - Google Patents

Antagonistes irreversibles reduits de bombesine

Info

Publication number
EP0452447A1
EP0452447A1 EP90915774A EP90915774A EP0452447A1 EP 0452447 A1 EP0452447 A1 EP 0452447A1 EP 90915774 A EP90915774 A EP 90915774A EP 90915774 A EP90915774 A EP 90915774A EP 0452447 A1 EP0452447 A1 EP 0452447A1
Authority
EP
European Patent Office
Prior art keywords
gly
residue
leu
ala
group
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.)
Ceased
Application number
EP90915774A
Other languages
German (de)
English (en)
Inventor
Roberto De Castiglione
Luigia Gozzini
Fabio Corradi
Marina Ciomei
Isabella Molinari
Cristina Franzetti
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.)
Pfizer Italia SRL
Original Assignee
Farmitalia Carlo Erba SRL
Carlo Erba SpA
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
Priority claimed from GB898925024A external-priority patent/GB8925024D0/en
Priority claimed from GB909006413A external-priority patent/GB9006413D0/en
Application filed by Farmitalia Carlo Erba SRL, Carlo Erba SpA filed Critical Farmitalia Carlo Erba SRL
Publication of EP0452447A1 publication Critical patent/EP0452447A1/fr
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/02—Linear peptides containing at least one abnormal peptide link
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • C07K7/086—Bombesin; Related peptides
    • 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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to peptide derivatives, to pharmaceutical compositions containing them, to processes for their preparation, and to their application as therapeutic agents.
  • AA amino acid
  • Ac acetyl
  • AcOEt ethylacetate
  • BBS bombesin
  • Boc t-butoxycarbonyl
  • BuOH n-butyl alcohol
  • BOP benzotriazolyloxy-tris[dimethylamino]phosphonium hexafluorophosphate
  • DMAP 4-dimethylaminopyridine
  • DMF freshly distilled dimethylformamide
  • DMSO dimethylsulfoxide
  • Dnp 2,4-di- nitrophenyl
  • EGF epidermal growth factor
  • EtOH ethyl alcohol
  • FAB epidermal growth factor
  • EtOH
  • the invention provides a peptide of the formula I:
  • R represents a group of the formula
  • CH 2 CBrCO- (either cis or trans isomers);
  • CH 2 -CH-CH 2 -CO-; CH C-CO-; ClCH 2 CH 2 CH 2 N(NO)CO-;
  • A represents a valence bond, or a Gly, Leu-Gly, Arg-Leu-Gly, or
  • B represents a valence bond or a Asn, Thr or phe residue
  • C represents a Gin or His residue
  • X represents a Gly or ala residue
  • Y represents a valence bond, or a His(R 3 ), his(R 3 ), Phe, phe, Ser, ser, Ala or ala residue;
  • T represents a valence bond, or a Leu, leu, Phe or phe residue
  • W represents a group of the formula OR 2 , NH 2 , NH(CH 2 ) 4 CH 3 ,
  • R 1 represents a hydrogen atom, a Boc group or an acyl group having from 1 to 11 carbon atoms.
  • R 2 represents a hydrogen atom, a linear or branched alyphatic chain having from 1 to 11 carbon atoms, a benzyl or a phenyl group.
  • Preferred alyphatic chains which R 2 may represent include methyl, ethyl, n-propyl-, iso-propyl, n-butyl and iso-butyl groups.
  • R 3 represents a hydrogen atom or a Tos, Dnp or Bzl group
  • R 4 represents NH 2 , NH-NH 2 or OR 2 .
  • one or more peptide bonds are replaced by reduced peptide bonds (CH 2 NH).
  • Preferred acyl group which R 1 may represent are aliphatic acyl group such as acetyl, formyl, propionyl and butirryl or aromatic such as benzoyl optionally substituted by nitro, methoxy, amino group or halogen atoms.
  • R represents pMel or Cab
  • R 1 represents hydrogen atom, Boc or acetyl group
  • A represents a valence bond
  • B represents a valence bond or phe residue
  • C represents a Gin residue
  • X represents a His (Dnp), His or Gly residue most preferably Gly
  • Y represents a valence bond
  • T represents a Leu residue
  • W represents a group of the formula Leu-NH 2 or Nle-NH 2
  • the reduced peptide bond (CH 2 NH) is that between T and W. Salts of these peptides with pharmaceutically acceptable acids are within the scope of the invention.
  • Such acid addition salts can be derived from a variety of inorganic and organic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, nitric, sulfamic, citric, lactic, pyruvic, oxalic, maleic, succinic, tartaric, cinnamic, acetic, trifluoracetic, benzoic, salicylic, gluconic, ascorbic and related acids.
  • inorganic and organic acids such as sulfuric, phosphoric, hydrochloric, hydrobromic, hydroiodic, nitric, sulfamic, citric, lactic, pyruvic, oxalic, maleic, succinic, tartaric, cinnamic, acetic, trifluoracetic, benzoic, salicylic, gluconic, ascorbic and related acids.
  • the synthesis of the peptides of the invention may be accomplished by classical solution methods.
  • the synthesis consists essentially of appropriate successive condensations of protected amino acids or peptides. The condensations are carried out so that the resulting peptides have the desired sequence of amino acid residues.
  • amino acids and peptides which can be condensed according to methods known in peptide chemistry, have the amino and carboxyl groups, not involved in peptide bond formation, blocked by suitable protecting groups capable of being removed by acid or alkali treatment or by hydrogenolysis.
  • the following protective groups may, for example, be employed: benzyloxycarbonyl, t-butoxycarbonyl, trityl, formyl, trifluoracetyl, o-nitrophenylsulphenyl, 4-methyloxybenzyloxycarbonyl, 9-fluorenylmethoxycarbonyl, 3,5-dimethoxy- ⁇ - ⁇ '-dimethylbenzyloxycarbonyl or methylsulphonylethoxycarbonyl.
  • the following protective groups may, for example, be employed: methyl, ethyl, t-butyl, benzyl, p-nitrobenzyl or fluorenylmethyl, amide, hydrazide, t-butoxycarbonyl hydrazide or benzyloxycarbonyl hydrazide.
  • the hydroxy functions of hydroxy amino acids and the imino function of histidine may be protected by suitable protecting groups (throughout all the synthesis or only during a few steps) or may be unprotected.
  • the following protective groups may, for example, be employed; t-butyl, benzyl, acetyl.
  • the following groups may, for example, be used: 2,4-dinitrophenyl, tosyl, benzyl.
  • De-protecting reactions are carried out according to methods known per se in peptide chemistry.
  • the condensation between an amino group of one molecule and a carboxyl group of another molecule to form the peptidic linkage may be carried out through an activated acyl-derivative such as a mixed anhydride, an azide or an activated ester, or by direct condensation between a free amino group and a free carboxyl group, in the presence of a condensing agent such as dicyclohexylcarbodiimide, alone or together with a racemization preventing agent, such as N-hydroxysuccinimide or 1-hydroxybenzotriazole, or together with an activating agent such as 4-dimethylamino-pyridine.
  • the condensation may be carried out in a solvent such as dimethylformamide, dimethylacetamide, pyridine, acetonitrile, tetrahydrofuran or N-methyl-2-pyrrolidone.
  • the formation of a reduced peptide bond is accomplished by condensation of an N-protected amino acid aldehyde with a C-protected amino acid or peptide in the presence of a reducing agent, such as NaBH 3 CN.
  • the aldehyde is usually obtained by condensing an N-protected amino acid with N,O-dimethylhydroxylamine, and reducing the resulting amide with a suitable reducing agent, such as LiAlH 4 .
  • the reaction temperature may be from -30°C to room temperature.
  • the reaction time is generally from 1 to 120 hours.
  • the scheme of synthesis, the protecting groups and condensing agents are selected so as to avoid the risk of racemization.
  • the peptides of the present invention are endowed with potent antagonism versus "in vitro” and "in vivo” effects induced by bombesin, such as contraction of smooth musculature, modification of behaviour of central origin and mitogenesis.
  • Bombesin is a tetradecapeptide of formula Glp-Gln-Arg-Leu- Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 , originally isolated from the skin of a frog.
  • the biological activity resides in the C-terminal part of the molecule: BBS(6-14)nonapeptide is as active as the parent compound.
  • the human counterpart of bombesin is a 27 amino acid peptide, known as gastrin-releasing peptide (h-GRP). Bombesin and bombesin-like peptides display a number of biological activities (J.H.
  • the compounds of the present invention due to the alkylating moiety, display greater receptor affinity than the parent peptides, and behave as receptor antagonists either when given in combination with bombesin or when administered 24 hours before bombesin challenge. In addition, owing to the presence of reduced peptide bonds, water solubility and, in many cases, also antagonistic properties are increased.
  • the peptides of the formula I therefore, find application in the therapy of human neoplasms which are modulated in their growth and progression by peptides of the GRP family, either directly or in concert with other growth factors.
  • alkylating analogues can be used in the management of the clinical symptoms associates with these deseases and due to hypersecretion of GRP-like peptides.
  • the compounds of the invention can be administered by the usual routes, for example, parenterally, e.g. by intravenous injection or infusion, or by intramuscular, subcutaneous, intracavity and intranasal administration.
  • the dosage depends on the age, weight and condition of the patient and on the administration route.
  • the toxicity of the peptides of the present invention is quite negligible.
  • the invention also provides pharmaceutical compositions containing a compound of formula (I) as the active substance, in association with one or more pharmaceutically acceptable excipients.
  • compositions of the invention are usually prepared following conventional methods and are administered in a pharmaceutically suitable form.
  • solutions for intravenous injection or infusion may contain as carrier, for example, sterile water or, preferably, they may be in the form of sterile aqueous isotonic saline solutions.
  • Suspensions or solutions for intramuscular injections may contain, together with the active compound, a pharmaceutically acceptable carrier, e.g., sterile water, olive oil, ethyl oleate, glycols (e.g., propylene glycol) and, if desired, a suitable amount of lidocaine hydrochloride.
  • neuroendocrine neoplasms such as small cell lung carcinoma and prostatic carcinoma
  • a method of treating neuroendocrine neoplasms comprising administering to the said patients a composition of the invention.
  • B KH 2 PO 4 20 mM, pH 3.5/acetonitrile 3/7 by volume.
  • the elution was programmed with a linear gradient from 60% to 90% B over a period of 20 min (System A) or from 30 to 70% B over a period of 15 min (System B), and then isocratically for 15 min, with a flow rate of 1 ml/min.
  • peptides were characterized by their retention time (RT).
  • reaction mixture was kept for 60 min at -12°C, then for 30 min at 0°C.
  • the solvent was removed in vacuo and the residue was dissolved in AcOEt, washed with 5% NaHCO 3 and then brine to neutrality. After drying over Na 2 SO 4 , the solvent was evaporated and the oily residue purified by flash-chromatography on silica gel, eluting with AcOEt containing increasing amount of MeOH (from 0.5% to 10%).
  • the product was recovered by evaporation of the solvents and trituration with Et 2 O: 1.23 g (70.7% yield) of compound Im were obtained: m.p. 70°C (mod.) - 90°C (dec); FD-MS: m/z 651 (100, MH + ) ; Rf c 0.57; RT A 12.0.
  • Boc-pMel-OSu [prepared extemporaneously from 259 mg (0.64 mmol) of Boc-pMel-OH (see our UK Pat. Appl. No 8906000.9), 77 mg (0.67 mmol) of HOSu and 132 mg (0.64 mmol) of DCC in 5 ml of DMF] were added dropwise to a cooled solution (0°C) of 500 mg (0.43 mmol) of H-Gln-Trp-Ala-Val-Gly-His(Dnp)-Leu ⁇ (CH 2 NH) Met-NH 2 ⁇ 2 H HCl (Ip) and 0.096 ml (0.87 mmol) of NMM in 10 ml of DMF.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Saccharide Compounds (AREA)
  • Transition And Organic Metals Composition Catalysts For Addition Polymerization (AREA)
  • Steroid Compounds (AREA)

Abstract

Peptide de la formule (I): R-A-B-C-Trp-Ala-Val-X-Y-T-W, dans laquelle R représente un groupe de la formule 4-(ClCH2CH2)2N-C6H4-CH2CH(NHR1)CO-; 3-(ClCH2CH2)2N-C6H4CH2CH(NHR1)CO-; 4-(ClCH2CH2)2N-C6H4-CO-; 3-(ClCH2CH2)2N-C6H4-CO-; ClCH2CH2NHCO-; ClCH=CH-CO-, BrCH=CH-CO-, CH2=CClCO-, CH2=CBrCO- (isomères soit cis soit trans); (a); CH=C-CO-; ClCH2CH2CH2N(NO)CO-; ClCH2CO-CH(R2)NHCO(CH2)2CO-; A représente une liaison de valence ou un reste Gly, Leu-Gly, Arg-Leu-Gly, ou Gln-Arg-Leu-Gly, B représente une liaison de valence ou un reste Asn, phe ou Thr; C représente un reste Gln or His, X représente un reste Gly ou ala; Y représente une liaison de valence ou un reste His(R3), his(R3), Phe, phe, Ser, ser, Ala ou ala; T représente une liaison de valence, ou un reste Leu, leu, Phe, phe; W représente un groupe de la formule OR2, NH2, NH(CH2)4CH3, NH(CH2)2C6H5, Met-R4, Leu-R4, Ile-R4, ou Nle-R4; R1 représente un atome d'hydrogène, un groupe Boc ou un groupe acyle, R2 représente un atome d'hydrogène, une chaîne alyphatique linéaire ou ramifiée comportant 1 à 11 atomes, un groupe benzyle ou un groupe phényle contenant un à 21 atomes de carbone, R3 représente un atome d'hydrogène ou un groupe Tos, Dnp ou Bzl, R4 représente NH2, NH-NH2 ou OR2, une ou plusieurs liaisons peptidiques (CONH) sont remplacées par des liaisons peptidiques réduites (CH2NH), ainsi que leurs sels pharmaceutiquement acceptables et des sels pharmaceutiquement acceptables représentent des antagonistes de bombésine. Leur préparation et les compositions pharmaceutiques les contenant sont également décrites.
EP90915774A 1989-11-06 1990-11-02 Antagonistes irreversibles reduits de bombesine Ceased EP0452447A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
GB898925024A GB8925024D0 (en) 1989-11-06 1989-11-06 Reduced irreversible bombesin antagonists
GB8925024 1989-11-06
GB909006413A GB9006413D0 (en) 1990-03-22 1990-03-22 Reduced irreversible bombesin antagonists
GB9006413 1990-03-22

Publications (1)

Publication Number Publication Date
EP0452447A1 true EP0452447A1 (fr) 1991-10-23

Family

ID=26296160

Family Applications (1)

Application Number Title Priority Date Filing Date
EP90915774A Ceased EP0452447A1 (fr) 1989-11-06 1990-11-02 Antagonistes irreversibles reduits de bombesine

Country Status (9)

Country Link
EP (1) EP0452447A1 (fr)
JP (1) JPH04502629A (fr)
KR (1) KR920701242A (fr)
AU (1) AU6610390A (fr)
CA (1) CA2045494A1 (fr)
HU (1) HUT58763A (fr)
IE (1) IE903958A1 (fr)
IL (1) IL96216A0 (fr)
WO (1) WO1991006563A1 (fr)

Families Citing this family (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5834433A (en) * 1990-07-26 1998-11-10 Merrell Pharmaceuticals Inc. Compounds and pharmaceutical uses of peptides of bombesin and GRP
WO1992020707A1 (fr) * 1991-05-23 1992-11-26 Merrell Dow Pharmaceuticals Inc. Analogues de bombesine
JPH07505865A (ja) * 1992-02-07 1995-06-29 メレルダウファーマスーティカルズ　インコーポレイテッド ボンベシンのフェニルアラニン類似体類
JP4578470B2 (ja) 2003-04-22 2010-11-10 イプセン ファルマ ソシエテ パール アクシオン サンプリフィエ ソマトスタチンベクター
US20120329730A1 (en) * 2010-01-25 2012-12-27 Institut De Recherches Cliniques De Montreal Aromatic-cationic peptides and uses of same
KR102190005B1 (ko) 2012-09-25 2020-12-15 어드밴스드 액셀러레이터 애플리케이션즈 유에스에이, 인코퍼레이티드. Grpr-양성 암의 검출, 진단과 치료를 위한 grpr-길항제

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2795449B2 (ja) * 1987-09-24 1998-09-10 ジ・アドミニストレーターズ・オブ・ザ・ツーレイン・エデュケイショナル・ファンド 治療用ペプチド
GB8808768D0 (en) * 1988-04-14 1988-05-18 Erba Carlo Spa Peptide ligands for bombesin receptors
GR1000608B (el) * 1988-07-21 1992-08-31 Erba Carlo Spa Μεθοδος για την παρασκευη ανταγωνιστων bombesin.
MC2144A1 (fr) * 1988-10-14 1992-02-19 Univ Tulane Peptides therapeutiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9106563A1 *

Also Published As

Publication number Publication date
CA2045494A1 (fr) 1991-05-07
HUT58763A (en) 1992-03-30
HU912604D0 (en) 1992-01-28
WO1991006563A1 (fr) 1991-05-16
JPH04502629A (ja) 1992-05-14
IE903958A1 (en) 1991-05-08
IL96216A0 (en) 1991-08-16
AU6610390A (en) 1991-05-31
KR920701242A (ko) 1992-08-11

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