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WO2009009035A1 - Analogue de la somatostatine et ses utilisations - Google Patents

Analogue de la somatostatine et ses utilisations Download PDF

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Publication number
WO2009009035A1
WO2009009035A1 PCT/US2008/008341 US2008008341W WO2009009035A1 WO 2009009035 A1 WO2009009035 A1 WO 2009009035A1 US 2008008341 W US2008008341 W US 2008008341W WO 2009009035 A1 WO2009009035 A1 WO 2009009035A1
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WO
WIPO (PCT)
Prior art keywords
human
pharmaceutically acceptable
disease
peptide
acceptable salt
Prior art date
Application number
PCT/US2008/008341
Other languages
English (en)
Inventor
Sun H. Kim
Original Assignee
Ipsen Pharma S.A.S.
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 Ipsen Pharma S.A.S. filed Critical Ipsen Pharma S.A.S.
Publication of WO2009009035A1 publication Critical patent/WO2009009035A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/31—Somatostatins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo

Definitions

  • SRIF Somatostatin
  • SRIF produces a variety of effects, including modulation of hormone release, e.g. , growth hormone, glucagon, insulin, amylin, and neurotransmitter release. Some of these effects have been associated with its binding to a specific SRIF receptor. For example, the inhibition of growth hormone has been attributed to the somatostatin type-2 receptor (SSTR- 2) (Raynor et al, Molecular Pharmacol. 43:838, 1993; Lloyd et al., Am. J. Physiol. 268:G102, 1995), while the inhibition of insulin has been attributed to the somatostatin type- 5 receptor (SSTR-5) (Rossowski, W. J. et al, Biochem. Biophys. Res. Commun.
  • Activation of types 2 and 5 have been associated with growth hormone suppression and more particularly with GH secreting adenomas (acromegaly) and TSH secreting adenomas. Activation of type 2 but not type 5 has been associated with treating prolactin secreting adenomas.
  • SRIF and analogs thereof are useful in the treatment of a great variety of diseases and/or conditions.
  • An exemplary but by no means exhaustive list of such diseases and/or conditions would include: Cushings Syndrome ⁇ see Clark, R. V. et al, Clin. Res. 38:943A, 1990); gonadotropinoma ⁇ see Ambrosi, B. et al, Acta Endocr. (Copenh.) 122:569-576, 1990); hyperparathyroidism ⁇ see Miller, D. et al, Canad. Med. Ass. J. 145:227-228, 1991); Paget's disease ⁇ see Palmieri, G. M. A. etal, J.
  • hypotension see Hoeldtke, R. D. et al, Arch. Phys. Med. Rehabil 69:895-898, 1988; Kooner, J. S. et al, Brit. J. Clin. Pharmacol. 28:735-736, 1989
  • panic attacks see Abelson, J. L. et al, Clin. Psychopharmacol. 10:128-132, 1990
  • sclerodoma see Soudah, H. et al, Clin. Res., Vol. 39, p. 3O3A, 1991
  • small bowel obstruction see Nott, D. M. et al, Brit. J. Surg. 77:A691, 1990
  • gastroesophageal reflux see Branch, M. S.
  • the present invention relates to somatostatin peptidomimetics, a process for their production and pharmaceutical preparations containing them. More particularly, the present invention features a peptide of the formula: cyclo(4(OH)Pro-Phe-DTrp-Lys-Pty-Phe), or a pharmaceutically acceptable salt thereof.
  • the peptide of the invention can be used in any application in which agonistic activity to somatostatin receptors is required.
  • the peptide of the invention can be used to inhibit the release of growth hormone or insulin in a subject (e.g., a mammal such as a human patient).
  • a subject e.g., a mammal such as a human patient.
  • the peptide is useful in the treatment of physiological conditions in which the suppression of the release of growth hormone or insulin is of benefit.
  • the peptide of the invention can also be used in enhancing wound healing or promoting angiogenesis.
  • the peptide of the invention may be able to cross the blood-brain barrier and may be useful in the treatment of various central-nervous-system disorders, such as Alzheimer's disease.
  • a method of treating a disease or condition in a human or other animal in need thereof which comprises the step of administering the compound of the formula: cyclo(4(OH)Pro-Phe-DTrp-Lys-Pty-Phe), or a pharmaceutically acceptable salt there of, to said human or other animal, wherein said disease or condition is selected from the group consisting of Cushings Syndrome, gonadotropinoma, hyperparathyroidism, Paget's disease, VIPoma, nesidioblastosis, hyperinsulinism, gastrinoma, Zollinger-Ellison Syndrome, hypersecretory diarrhea related to AIDS and other conditions, irritable bowel syndrome, pancreatitis, Crohn's Disease, systemic sclerosis, thyroid cancer, psoriasis, hypotension, panic attacks, sclerodoma, small bowel obstruction, gastroesophageal reflux, duodenogastric reflux, Graves' Disease, polycystic
  • a labeled peptide of the invention can be used either in vivo to detect cells having somatostatin receptors (e.g. , cancer cells) or in vitro as a ligand in a somatostatin receptor binding assay.
  • the peptide may be labeled with radioactivity.
  • the peptide may also be used as a vector to target cells with radioactive isotopes.
  • the present invention provides a pharmaceutical composition comprising an effective amount of cyclo(4(OH)Pro-Phe-DTrp-Lys-Pty-Phe) or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or diluent.
  • the composition is useful for treatment of physiological conditions in which the suppression of the release of growth hormone or insulin is of benefit.
  • the composition comprising the peptide of the invention can also be used in enhancing wound healing or promoting angiogenesis.
  • the composition comprising the peptide of the invention may be useful in the treatment of various central-nervous-system disorders, such as Alzheimer's disease.
  • SSTR-4 refers to the receptor originally cloned by Bruno et al
  • SSTR-5 refers to the receptor cloned by O'Carroll et al.
  • N-terminal amino acids in this disclosure stand for the structure of -NH-CH(R)-CO-, wherein R in the immediately foregoing formula is the side chain of an amino acid (e.g., CH 3 for Ala).
  • R in the immediately foregoing formula is the side chain of an amino acid (e.g., CH 3 for Ala).
  • the abbreviation stands for the structure of (R 1 R 2 J-N-CH(R)-CO-, wherein R is a side chain of an amino acid and R 1 and R 2 are as defined herein.
  • DBU 1 ,8-diazabicyclo(5.4.0)undec-7-ene
  • DCM dichloromethane
  • DIC dicyclohexylcarbodiimide
  • DIEA diisopropylethylamine
  • DMF dimethylformamide
  • Fmoc 9-Fluorenylmethoxycarbonyl MTBD, l,3,4,6,7,8-Hexahydro-l-methyl-2H-pyrimido(l,2-a)pyrimidine;
  • TBTU O-Benzorri-azol-l-yl-N,N,N ⁇ N'-terramethyluronium tetrafluoroborate
  • TFA trifluoroacetic acid
  • t-butyloxycarbonyl-hydroxyprolyl-phenylalanyl-D- tryptophanyl methylester was made and it was treated with 2N-NaOH in ethylalcohol to give t-butyloxycarbonyl-hydroxyprolyl-phenylalanyl-D-tryptophan.
  • Peptides can be made by solid phase method using oxime resin.
  • linear peptide sequences are synthesized by solid phase using 2-chlorotrityl resin and after treatment with mild acid, N-terminal free peptide acid is cyclized in solution. Final removal of the side chain protecting group of lysine yields the desired cyclic peptides.
  • the genomic clones containing the human somatostatin receptors (hSSTR-1 to hSSTR-5) (Yamada, Y. et al, Proc. Natl. Acad. ScL USA. 89:251-255, 1992; Yasuda, K. et al., J. Biol. Chem. 267:20422-20428, 1992; Yamada, Y. et al., Mol. Pharmacol. 42:2136- 2142, 1992; and Rohrer, L. et al, Proc. Natl. Acad. ScL USA. 90:4196-4200, 1993) were provided by Dr. Graeme I. Bell of the University of Chicago.
  • the hSSTR-1, hSSTR-2, hSSTR-3, hSSTR-4 and hSSTR-5 cDNAs were isolated as a 1.5-kb Pstl-Xmnl fragment, 1.7- kb Bamm-Hin ⁇ lll fragment, 2.0-kb Ncol-HindOl fragment, 1.4-kb Nhel-Ndel fragment, and a 1.2-kb HindUl-Xbal fragment, respectively, each containing the entire coding region of the full-length receptors.
  • CHO-Kl cells were maintained in ⁇ -minimum essential medium ( ⁇ -MEM; Gibco) supplemented with 10% fetal calf serum and transfected with each of the expression plasmids using calcium phosphate precipitation.
  • Clones that had inherited the expression plasmid were selected in ⁇ -MEM supplemented with 500 ⁇ g mL " ' of geneticin (G418; Gibco).
  • Independent CHO-Kl clones were picked by glass-ring cloning and expanded in culture in the selective media.
  • Membranes were prepared from the isolated clones and hSSTR expression was initially assessed for binding with ( 125 I)TyT 1 '-SRIF and ( 125 I)MK-678 (for SSTR-2).
  • Cell membranes of the five somatostatin receptor types were obtained from homogenates (Polytron setting 6, 15 sec) of the corresponding CHO-Kl cells, in ice-cold Tris-HCl (50 mM) and centrifuged (39,000 g, 2 x 10 min.), with an intermediate resuspension in fresh buffer. The final pellets were resuspended in Tris-HCl (10 mM) for assay. Aliquots of the membranes were incubated (30 min.
  • the peptide of this invention can be provided in the form of pharmaceutically acceptable salts.
  • such salts include, but are not limited to, those formed with organic acids (e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid), inorganic acids (e.g. , hydrochloric acid, sulfuric acid, or phosphoric acid), and polymeric acids (e.g. , tannic acid, carboxymethyl cellulose, polylactic, polyglycolic, or copolymers of polylactic-glycolic acids).
  • organic acids e.g., acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, methanesulfonic, toluenesulfonic, or pamoic acid
  • inorganic acids e.g. , hydrochloric acid, sulfuric acid,
  • a typical method of making a salt of the peptide of the present invention is well known in the art and can be accomplished by standard methods of salt exchange. Accordingly, the TFA salt of a peptide of the present invention (the TFA salt results from the purification of the peptide by using preparative HPLC, eluting with TFA containing buffer solutions) can be converted into another salt, such as an acetate salt, by dissolving the peptide in a small amount of 0.25 N acetic acid aqueous solution. The resulting solution is applied to a semi-prep HPLC column (Zorbax ® , 300 SB, C-8).
  • the fractions containing the peptide are collected and lyophilized to dryness.
  • the known and potential uses of peptides with SSTR receptor agonist activity are varied and multitudinous.
  • compositions comprising, as an active ingredient cyclo(4(OH)Pro-Phe-DTrp-Lys- Tyr(phenyl)-Phe) in association with a pharmaceutically acceptable carrier.
  • the dosage of active ingredient in the compositions of this invention may be varied; however, it is necessary that the amount of the active ingredient be such that a suitable dosage form is obtained.
  • the selected dosage depends upon the desired therapeutic effect, on the route of administration, and on the duration of the treatment.
  • an effective dosage for the activities of this invention is in the range of 1 x 10 ⁇ 7 to 200 mg/kg/day, preferably 1 x 10 ⁇ to 100 mg/kg/day which can be administered as a single dose or divided into multiple doses.
  • the compound of this invention can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration and can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • parenteral e.g., intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant
  • nasal, vaginal, rectal, sublingual or topical routes of administration can be formulated with pharmaceutically acceptable carriers to provide dosage forms appropriate for each route of administration.
  • Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules.
  • the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose, or starch.
  • Such dosage forms can also comprise, as is normal practice, additional substances other than such inert diluents, e.g., lubricating agents such as magnesium stearate.
  • the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
  • Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, the elixirs containing inert diluents commonly used in the art, such as water. Besides such inert diluents, compositions can also include adjuvants, such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring and perfuming agents. Preparations according to this invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles examples include propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents.
  • Preparations may be sterilized by, for example, filtration through a bacteria-retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions.
  • Preparations can also be manufactured in the form of sterile solid compositions which can be dissolved in sterile water or some other sterile injectable medium immediately before use.
  • compositions for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or a suppository wax.
  • compositions for nasal or sublingual administration are also prepared with standard excipients well known in the art.
  • the compound of this invention can be administered in a sustained release composition such as those described in the following patents and patent applications.
  • U.S. Patent No. 5,672,659 teaches sustained release compositions comprising a bioactive agent and a polyester.
  • U.S. Patent No. 5,595,760 teaches sustained release compositions comprising a bioactive agent in a gelable form.
  • U.S. Patent No. 5,821,221 teaches polymeric sustained release compositions comprising a bioactive agent and chitosan.
  • U.S. Patent No. 5,916,883 teaches sustained release compositions comprising a bioactive agent and cyclodextrin. The teachings of the foregoing patents and applications are incorporated herein by reference.
  • immediate or of sustained release compositions depends on the type of indications targeted. If the indication consists of an acute or over-acute disorder, a treatment with an immediate form will be preferred over the same with a prolonged release composition. On the contrary, for preventive or long-term treatments, a prolonged release composition will generally be preferred.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Epidemiology (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Immunology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)

Abstract

La présente invention concerne un agoniste de la somatostatine selon la formule : cyclo(4(OH)Pro-Phe-DTrp-Lys-Pty-Phe) ou l'un de ses sels acceptables sur le plan pharmaceutique ainsi que ses utilisations, qui présente des propriétés pharmaceutiques intéressantes.
PCT/US2008/008341 2007-07-06 2008-07-02 Analogue de la somatostatine et ses utilisations WO2009009035A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US95849807P 2007-07-06 2007-07-06
US60/958,498 2007-07-06

Publications (1)

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WO2009009035A1 true WO2009009035A1 (fr) 2009-01-15

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7012983B2 (en) 2000-04-28 2006-03-14 Broadcom Corporation Timing recovery and phase tracking system and method
WO2011151782A1 (fr) * 2010-06-02 2011-12-08 Preglem Sa Rôle de la somatostatine pour moduler l'initiation de la croissance folliculaire dans l'ovaire humain

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030176354A1 (en) * 1994-05-04 2003-09-18 Abajian Henry B. Therapeutic uses of tri-, tetra-, penta-, and polypeptides
US20030232807A1 (en) * 2001-10-09 2003-12-18 Poindexter Graham S. Alpha-aminoamide derivatives as melanocortin agonists
US20050014686A1 (en) * 2000-08-01 2005-01-20 Rainer Albert Somatostatin analogues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030176354A1 (en) * 1994-05-04 2003-09-18 Abajian Henry B. Therapeutic uses of tri-, tetra-, penta-, and polypeptides
US20050014686A1 (en) * 2000-08-01 2005-01-20 Rainer Albert Somatostatin analogues
US20030232807A1 (en) * 2001-10-09 2003-12-18 Poindexter Graham S. Alpha-aminoamide derivatives as melanocortin agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CRAFT S. ET AL.: "Enhancement of memory in Alzheimer disease with insulin and sornatostatin but not glucose", ARCH. GEN. PHYCHIATRY, vol. 56, no. 12, December 1999 (1999-12-01), pages 1135 - 1140 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7012983B2 (en) 2000-04-28 2006-03-14 Broadcom Corporation Timing recovery and phase tracking system and method
US7016449B2 (en) 2000-04-28 2006-03-21 Broadcom Corporation Timing recovery and frequency tracking system and method
US7058150B2 (en) 2000-04-28 2006-06-06 Broadcom Corporation High-speed serial data transceiver and related methods
WO2011151782A1 (fr) * 2010-06-02 2011-12-08 Preglem Sa Rôle de la somatostatine pour moduler l'initiation de la croissance folliculaire dans l'ovaire humain

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