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EP1261626A1 - Analogues de bombesine utilises dans le traitement du cancer - Google Patents

Analogues de bombesine utilises dans le traitement du cancer

Info

Publication number
EP1261626A1
EP1261626A1 EP00952333A EP00952333A EP1261626A1 EP 1261626 A1 EP1261626 A1 EP 1261626A1 EP 00952333 A EP00952333 A EP 00952333A EP 00952333 A EP00952333 A EP 00952333A EP 1261626 A1 EP1261626 A1 EP 1261626A1
Authority
EP
European Patent Office
Prior art keywords
peptide
trp
leu
aib
ala
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Withdrawn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
EP00952333A
Other languages
German (de)
English (en)
Inventor
Anand C. Burman
Sudhanand Prasad
Rama Mukherjee
Manu Jaggi
Anu T. Singh
Archna Mathur
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.)
Fresenius Kabi Oncology Ltd
Original Assignee
Dabur Research Foundation
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 Dabur Research Foundation filed Critical Dabur Research Foundation
Publication of EP1261626A1 publication Critical patent/EP1261626A1/fr
Withdrawn legal-status Critical Current

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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
    • C07K7/04—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 encompasses novel peptides that are antagonists to bombesin and bombesin like peptides and are useful in the treatment of cancer.
  • the invention particularly relates to the design and synthesis of the novel peptides incorporating ⁇ , ⁇ -amino acids in a site specific manner.
  • the invention encompasses methods for the generation of these peptides, compositions containing the peptides and the pharmacological applications of these peptides especially in the treatment and prevention of cancer.
  • Bombesin is a 14 amino acid peptide which was first isolated from the skin of the frog Bombina bombina (Anastasi et al., Experientia, 1971, 27, 166) and has the sequence: pGlu-Gln-Arg-Leu-Gly-Asn-Gln-Trp-Ala-Val-Gly-His- Leu-Met-NH 2 (SEQ ID NO: 1)
  • Gastrin releasing peptide is a 27 amino acid peptide isolated from the porcine gut. The last ten amino acids at the C-terminus of gastrin releasing peptide correspond with one amino acid alteration (3) to the last ten amino acids of bombesin, viz: H-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH 2
  • Analogues of bombesin / GRP have been shown to inhibit the binding of gastrin releasing peptide to a SCLC cell line and to inhibit the growth of SCLC cells in-vitro and in-vivo (S. Mahmoud et al., Cancer Research, 1991, 51, 1798; Moody TW et al., Life Sci., 1995, 56, 521; Moody TW et al., 1996, 17, 1337).
  • Bombesin/GRP cell receptors were established on SCLC cells, receptors were also found to be present on human prostate cells.
  • a Bombesin/GRP antagonist (RC-3940-II) was found to inhibit the proliferation of SW-1990 human pancreatic adenocarcinoma cells in vivo and in vitro (Qin, Y. et al., 1995, Int. J. Cancer, 63, 257). Similar effect was seen with bombesin/GRP antagonist RC-3095 on the growth of CFPAC-1 human pancreatic cancer cells transplanted to nude mice or cultured in vitro (Qin Y et al., Can Res, 1994, 54(4): 1035-41).
  • bombesin/GRP antagonists such as [Psi 13,14] bombesin.
  • bombesin analogues were solid phase synthesized and incubated with intact SCLC cells at 37°C in RPMI medium in a time course fashion (0-1080 minutes) to determine enzymatic stability. The proteolytic stability of the compounds was determined by subsequent HPLC analysis.
  • This invention describes the preparation and use of peptide analogs of bombesin/GRP using constrained amino acids and their use for cancer therapy, alone, or in combination or as an adjunct to or with other chemotherapeutic agents and compounds.
  • the design of conformationally constrained bioactive peptide derivatives has been one of the widely used approaches for the development of peptide-based therapeutic agents.
  • Non-standard amino acids with strong conformational preferences may be used to direct the course of polypeptide chain folding, by imposing local stereochemical constraints, in de novo approaches to peptide design.
  • the conformational characteristics of ⁇ , ⁇ -dialkylated amino acids ' have been well studied.
  • conformational properties of the higher homologs of ⁇ , ⁇ -dialkylated amino acids such as diethylglycine (Deg), di-n- propylglycine (Dpg) and di-n-butylglycine (Dbg) as well as the cyclic side chain analogs of , ⁇ -dialkylated amino acids such as 1-aminocyclopentane carboxylic acid (Ac5c), 1-aminocyclohexane carboxylic acid (Ac6c), 1-aminocycloheptane carboxylic acid (Ac7c) and 1-aminocyclooctane carboxylic acid (Ac8c) have also been shown to induce folded conformation (Prasad et al., (1995), Biopolymers 35, 11-20; Karle et al., (1995); J.
  • the present invention exploits the conformational properties of , ⁇ - dialkylated amino acids for the design of biologically active peptide derivatives, taking bombesin as the model system under consideration. Furthermore, it has been shown that lipophilization of bioactive peptides improves their stability, bioavailability and the ability to permeate biomembranes (Dasgupta, P et al; 1999, Pharmaceutical Res. 16, 1047-1053; Gozes, I, et al 1996, Proc. Natl. Acad. Sci. USA, 93, 427-432). In the present invention, we have also synthesized peptide derivatives having N-terminal alkanoyl groups from C2-C1 carbon atoms, which retain anticancer activity.
  • the present invention exploits the conformational properties of ⁇ , ⁇ - dialkylated amino acids for the design of biologically active peptide derivatives, taking bombesin as the model system under consideration. Furthermore, it has been shown that lipophilization of bioactive peptides improves their stability, bioavailability and the ability to permeate biomembranes (Dasgupta, P et al; 1999, Pharmaceutical Res. 16, 1047-1053; Goes, L, et al., 1996, Proc. Natl. Acad. Sci. USA, 93, 427-432).
  • HBTU O-Benzotriazole-N,N,N',N'-tetramethyl-uronium- hexofluoro-phosphate
  • HOBt 1-Hydroxy Benzotriazole
  • DCC Dicyclohexyl carbodiimide
  • the present invention provides novel polypeptides of the following general formula,
  • X-D-Phe-Gln-Rl-R2-Val-R3-His-R4-NH 2 wherein X is acetyl or straight, branched, or cyclic alkanoyl group from 3-16 carbon atoms, or X is deleted,
  • Rl is Trp or D-Trp
  • R2 is Ala, Aib or Deg
  • R3 is Gly, Aib, Deg, Dpg or Ac5c
  • R4 is Leu or He or a hydrolyzable carboxy protecting group; or a pharmaceutically acceptable salt of the polypeptide. At least one of R2 or R3 is a non-standard amino acid.
  • the invention also encompasses methods for making the peptides, compositions containing the peptides and use of the peptides. DETAILED DESCRIPTION OF THE INVENTION The present invention provides novel polypeptides of the following general formula,
  • Rl is Trp or D-Trp
  • R2 is Ala, Aib or Deg
  • R3 is Gly, Aib, Deg, Dpg or Ac5c,
  • R4 is Leu or He or a hydrolyzable carboxy protecting group; or a pharmaceutically acceptable salt of the polypeptide. At least one of R2 or R3 is a non-standard amino acid.
  • a hydrolyzable carboxy protecting group are those groups which on hydrolysis converts to carboxylic group such as -COONH 2 , -COOMe, etc.
  • the preferred alkanoyl groups are acetyl, n-butanoyl, n-hexanoyl, n- octanoyl, lauroyl, myristoyl, palmitoyl, isohexanoyl, cyclohexanoyl, cyclopentyl- carbonyl, n-heptanoyl, n-decanoyl, n-undecanoyl and 3,7-dimethyloctanoyl.
  • Salts encompassed within the term "pharmaceutically acceptable salts" refer to non-toxic salts of the compounds of this invention.
  • Representative salts and esters include: acetate, ascorbate, benzenesulfonate, benzoate, bicarbonate, bisulfate, bitartrate, borate, camsylate, carbonate, citrate, dihydrochloride, methanesulfonate, ethanesulfonate, p-toluenesulfonate, cyclohexylsulfamate, quinate, edetate, edisylate, estolate, esylate, fumaxate, gluconate, glutamate, glycerophophates, hydrobromide, 5 hydrochloride, hydroxynaphthoate, lactate, lactobionate, laurate, malate, maleate, mandelate, mesylate, mucate, napsylate, nitrate, n-
  • salts include Ca, Li, Mg, Na and K salts; salts of amino acids such lysine or arginine; guanidine, diethanolamine or choline; ammonium, substituted ammonium salts or aluminum salts.
  • the salts can be prepared by standard techniques.
  • Preferred peptides of this invention are:
  • D-Phe-Gln-Trp-Ala-Val-Aib-His-Leu-NH 2 (SEQ ID NO:3) D-Phe-Gln-Trp-Aib-Val-Gly -His-Leu-NH 2 (SEQ ID NO:4) D-Phe-Gln-D-Trp-Ala-Val-Aib-His-Leu-NH 2 (SEQ ID NO:5) D-Phe-Gln-Trp-Aib-Val-Gly-His-Ile-NH 2 (SEQ ID NO:6) D-Phe-Gln-Trp-Ala-Val-Aib-His-Ile-NH 2 (SEQ ID NO:7)
  • the present invention also envisages methods of prevention and treatment of cancer using the polypeptides of the present invention, pharmaceutical compositions comprising such polypeptides and processes for their preparation. These peptides possess antagonist properties against bombesin and bombesin-like peptides and are useful in the prevention and treatment of malignant diseases.
  • Suitable routes for administration of the peptides are those known in the art and include oral, rectal, transdermal, vaginal, transmucosal, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intradedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections.
  • compositions suitable for use in present invention include compositions wherein the active ingredients are contained in an effective amount to achieve its intended purpose.
  • these pharmaceutical compositions may contain suitable pharmaceutically acceptable carriers, excipients, diluents, solvents, flavorings, colorants etc.
  • the preparations may be formulated in any form including but not limited to tablets, dragees, capsules, powders, syrups, suspensions, slurries, time released formulations, sustained release formulations, pills, granules, emulsions, patches, injections, solutions, liposomes or nanoparticles.
  • the exact formulation, route of administration and dosage can be chosen by the individual physician in view of the patient's condition.
  • an effective amount means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought. Toxicity and therapeutic efficacy of the peptides of this invention can be determined by standard pharmaceutical procedures in cell cultures or experimental animals.
  • the novel peptide analogs embodied in the present invention contain amino acids, namely ⁇ , ⁇ -dialkylated amino acids, which have been known to induce highly specific constraints in the peptide backbone.
  • the ⁇ , -dialkylated amino acids, used in the present invention are synthesized from the corresponding ketones.
  • the ketones are first converted into the corresponding hydantoins which are hydrolyzed using a strong acid or base, preferably H 2 SO 4 , HC1, NaOH or Na 2 CO 3 to yield the aforesaid amino acids.
  • 60% sulphuric acid has been employed as the hydrolyzing agent.
  • the present invention also provides a solid phase synthesis process for the preparation of peptide analogs of the general formula (I):
  • X-D-Phe-Gln-Rl-R2-Val-R3-His-R4-NH 2 wherein X is acetyl or straight, branched, or cyclic alkanoyl group from 3-16 carbon atoms or X is deleted, Rl is Trp or D-Trp,
  • R2 is Ala, Aib or Deg
  • R3 is Gly, Aib, Deg, Dpg or Ac5c
  • R4 is Leu or He which comprises sequentially loading the corresponding protected ⁇ , ⁇ -dialkylated amino acids in sequential cycles to the amino terminus of a solid phase resin, coupling the amino acids in the presence of conventional solvents and reagents to assemble a peptide-resin assembly, removing the protecting groups and cleaving the peptide from the resin to obtain a crude peptide analog.
  • novel peptides in the present invention have been generated by using solid phase techniques or by a combination of solution phase procedures and solid phase techniques or by fragment condensation. These methods for the chemical synthesis of polypeptides are well known in the art (Stewart and Young, 1969, Solid Phase Peptide Synthesis, W.H. Freeman & Co.).
  • the peptides were synthesized using the Fmoc strategy, on a semi automatic peptide synthesizer (CS Bio, Model 536), using optimum side chain protection.
  • the peptides were assembled from C-terminus to N-terminus.
  • Peptides amidated at the carboxy-terminus were synthesized using the Rink Amide resin.
  • the loading of the first Fmoc protected amino acid was achieved via an amide bond formation with the solid support, mediated by Diiopropylcarbodiimide (DIPCDI) and HOBt.
  • DIPCDI Diiopropylcarbodiimide
  • Substitution levels for automated synthesis were preferably between 0.2 and 0.6 mmole amino acid per gram resin.
  • the resin employed for the synthesis of carboxy-terminal amidated peptide analogs was 4-(2', 4'-Dimethoxyphenyl-Fmoc-aminomethyl)-phenoxymethyl derivatized polystyrene 1% divinylbenzene (Rink Amide) resin (100-200 mesh), procured from Calbioichem-Novabiochem Corp., La Jolla, U.S.A., (0.47 milliequivalent NH 2 /g resin).
  • the N-terminal amino group was protected by 9-fluorenylmethoxy- carbonyl (Fmoc) group.
  • Trityl (trt) or t-butyloxycarbonyl (Boc) were the preferred protecting groups for imadazole group of Histidine residue.
  • Trityl was the preferred protecting group for Asparagine and Glutamine and tertiary butyl group (tBu) was the preferred protecting group for Aspartic acid and Glutamic acid.
  • the tryptophan residue was either left unprotected or used with Boc protection.
  • the side chain amino group of Lysine was protected using Boc group preferably.
  • a preferred embodiment of the invention 2-8 equivalents of Fmoc protected amino acid per resin nitrogen equivalent were used.
  • the activating reagents used for coupling amino acids to the resin, in solid phase peptide synthesis are well known in the art. These include DCC, DIPCDI, DIEA, BOP, PyBOP, HBTU, TBTU, or HOBt. Preferably, DCC, DIPCDI/HOBt or HBTU/HOBT and DIEA were used as activating reagents in the coupling reactions.
  • the protected amino acids were either activated in situ or added in the form of preactivated esters known in the art such as NHS esters, Opfp esters etc. Atherton, E. et. al, 1988, J. Chem. Soc, Perkin Trans.I, 2887; Bodansky, M. in
  • the coupling reaction was carried out in DMF, DCM or NMP or a mixture of these solvents and was monitored by Kaiser test (Kaiser et al., Anal. Biochem., 34, 595-598 (1970)). In case of a positive Kaiser test, the appropriate amino acid was re-coupled using freshly prepared activated reagents.
  • the ammo-terminal Fmoc group was removed and then the peptide-resin was washed with methanol and dried.
  • the peptides were then deprotected and cleaved from the resin support by treatment with trifluoroacetic acid, crystalline phenol, ethanedithiol, thioanisole and de-ionized water for 1.5 to 5 hours at room temperature.
  • the crude peptide was obtained by precipitation with cold dry ether, filtered, dissolved, and lyophilized.
  • the resulting crude peptide was purified by preperative high performance liquid chromatography (HPLC) using a LiChroCART® C,8 (250. Times.
  • a peptide of the present invention can be made by exclusively solid phase techniques, by partial solid phase/solution phase techniques and/or fragment condensation.
  • Preferred, semi-automated, stepwise solid phase methods for synthesis of peptides of the invention are provided in the examples discussed in the subsequent section of this document.
  • EXAMPLE 1 First loading on Rink Amide Resin A typical preparation of the Fmoc-Leu-Rink Amide Resin was carried out using 0.5g of 4-(2',4'-Dimethoxyphenyl-Fmoc-aminomethyl)phenoxymethyl derivatized polystyrene 1% divinylbenzene (Rink Amide) resin (0.7 mM/g) (100-200 mesh), procured from Advanced Chemtech, Louisville, KY, U.S.A., (0.7 milliequivalent NH 2 resin). Swelling of the resin was typically carried out in dichloromethane measuring to volumes 10-40 ml/g resin.
  • the resin was allowed to swell in methylene chloride (2 X 25 ml, for 10 min.). It was washed once in dimethylformamide (DMF) for 1 min. All solvents in the protocol were added in 20 ml portions per cycle.
  • the Fmoc-protecting group on the resin was removed by following steps 3-7 in the protocol. The deprotection of the Fmoc group was checked by the presence of blue beads in Kaiser test.
  • the first amino acid, Fmoc-Leu- OH was weighed in three to six fold excess, along with a similar fold excess of HOBt, in the amino acid vessel of the peptide synthesizer.
  • the peptide- resin was washed twice with methanol, dried and weighed to obtain 0.649g. This was subjected to cleavage in a cleavage mixture consisting of trifiuoroacetic acid and scavengers, ethanedithol, crystalline phenol and thioanisole and water for a period of 1.5 to 5 hours at room temperature with continuous stirring. The peptide was precipitated using cold dry ether to obtain ⁇ 330 mg of crude peptide.
  • the crude peptide was purified on a C18 preperative reverse phase HPLC column (250 X 10) on a gradient system comprising acetonitrile and water in 0.1 % TFA as described previously in the art.
  • the prominent peaks were collected and lyophilized, reanalyzed on analytical HPLC and subjected to mass spectrometry. There was a good agreement between the observed molecular weight and calculated molecular weight (Calculated Mass ⁇ 983; Observed Mass ⁇ 984.2 ).
  • the pure peptide was then used for bioassays.
  • MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazoliurn bromide] assay.
  • MTT assay is based on the principle of uptake of MTT, a tetrazolium salt, by metabolically active cells where it is metabolized by active mitochondria into a blue colored formazon product, which can be read spectrometrically (J. of Immunological Methods 65: 55-63, 1983).
  • MTT MTT was dissolved in phosphate buffered saline with a pH of 7.4 to obtain an MTT concentration of 5 mg/ml; the resulting mixture was filtered through a 0.22 micron filter to sterilize and remove a small amount of insoluble residue. This filtered mixture was the MTT stock solution.
  • Rl (absorbance of the untreated control at 540nm) - (absorbance of the blank at 540nm).
  • EXAMPLE 12 The biological activity of synthesized peptide SEQ ID NO:3 was tested on different human tumor cell lines such as HT-29 & PTC (colon), A549 (non small lung cell), KB (oral squamous cell), MCF7 & MDA.MB.453 (Breast), HuTu80 (duodenum), PA-1 (ovary), MOLT-4 (leukemia) and MIAPaCa2 (Pancreas) at various molar concentrations.
  • the percentage cytotoxicity induced by different concentrations of the peptide SEQ ID NO: 3 is summarized in the following table.
  • EXAMPLE 13 The cytotoxic activity of other synthesized bombesin analogs was tested on eight human tumor cell lines namely HT-29, SW620, PTC (all colon), PA- 1 (ovary), A549 (lung), HBL100 (breast), MOLT-4 (leukemia) and DU145 (prostate).
  • the tumor cells were collected at exponential growth phase and resuspended in medium (1.5 x 10 6 ) cells/ml in RPMI 1640 containing 10% FBS). 150 ⁇ l of medium was added to the wells of a 96-well tissue culture plate (Nunc, Denmark) followed by 30 ⁇ l of cell suspension. The plate was left in incubator (37°C, 5% CO 2 overnight.
  • EXAMPLE 14 The cytotoxic effect of peptide sequences SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 11 and SEQ ID NO: 12, were studied by MTT assay which is based on the principle of uptake of MTT[3-[4,5-dimethylthiazol-2-yl]-2,5- diphenyl tetrazolium bromide], a tetrazolium salt by the metabolically active cells where it is metabolized by active mitochondria into a blue colored formazan product which can be read spectrophotometrically.
  • Tumor cells KB oral squamous
  • HuTu80 Stomach
  • PTC and SW620 colon
  • U87MG Glioblastoma
  • HBL 100 Breast
  • HeP2 laryngeal
  • LI 32 LI 32 (Lung) were incubated with the peptide analogs for 48 hours at 37°C in a 96-well culture plate, followed by the addition of 100 ⁇ g MTT and further incubation of 1 hour.
  • the formazan crystals formed inside the cells were dissolved with a detergent comprising 10% Sodium dodecyl sulfate and 0.01 N HC1 and optical density read on a multiscan ELISA reader. The optical density was directly proportional to the number of proliferating and metabolically active cells. Percent cytotoxicity of peptide analogs is shown in the following Table.

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  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
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  • Genetics & Genomics (AREA)
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  • Public Health (AREA)
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Abstract

La présente invention concerne de nouveaux peptides, en l'occurrence des antagonistes de la bombésine et des peptides du type bombésine, qui sont utiles dans le traitement du cancer. L'invention concerne, en particulier, la conception et la synthèse de ces nouveaux peptides qui comprennent des α,α-acides aminés d'une manière spécifique au site. L'invention concerne, en outre, des procédés de génération desdits peptides, des compositions les renfermant et les applications pharmacologiques de ces peptides, notamment dans le traitement et la prévention du cancer.
EP00952333A 2000-02-24 2000-07-31 Analogues de bombesine utilises dans le traitement du cancer Withdrawn EP1261626A1 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
INDE00014700 2000-02-24
IN147DE2000 2000-02-24
PCT/US2000/020873 WO2001062777A1 (fr) 2000-02-24 2000-07-31 Analogues de bombesine utilises dans le traitement du cancer

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EP1261626A1 true EP1261626A1 (fr) 2002-12-04

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Publication number Priority date Publication date Assignee Title
US7173006B2 (en) * 2002-12-23 2007-02-06 Dabur Research Foundation Drug comprising synthetic peptide analogs for the treatment of cancer
US8420050B2 (en) 2003-01-13 2013-04-16 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US7611692B2 (en) 2003-01-13 2009-11-03 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US7226577B2 (en) 2003-01-13 2007-06-05 Bracco Imaging, S. P. A. Gastrin releasing peptide compounds
US7922998B2 (en) 2003-01-13 2011-04-12 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
US7850947B2 (en) 2003-01-13 2010-12-14 Bracco Imaging S.P.A. Gastrin releasing peptide compounds
AU2004314112A1 (en) * 2003-12-24 2005-07-28 Bracco Imaging S.P.A. Improved gastrin releasing peptide compounds
WO2009040019A2 (fr) * 2007-09-11 2009-04-02 Mondobiotech Laboratories Ag Utilisation d'un peptide comme agent thérapeutique

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Publication number Priority date Publication date Assignee Title
AU618029B2 (en) * 1987-11-02 1991-12-12 Imperial Chemical Industries Plc Polypeptide compounds
GB8813356D0 (en) * 1988-06-06 1988-07-13 Ici Plc Polypeptide compounds
AU641789B2 (en) * 1990-07-26 1993-09-30 Aventisub Ii Inc. Peptides
US6492330B1 (en) * 1996-08-16 2002-12-10 National Institute Of Immunology Antiangiogenic drugs

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Title
See references of WO0162777A1 *

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CA2405704A1 (fr) 2001-08-30
CA2405704C (fr) 2010-11-16
WO2001062777A1 (fr) 2001-08-30

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