WO2001096300A1 - Growth hormone secretagogues - Google Patents

Growth hormone secretagogues Download PDF

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Publication number
WO2001096300A1
WO2001096300A1 PCT/EP2001/006717 EP0106717W WO0196300A1 WO 2001096300 A1 WO2001096300 A1 WO 2001096300A1 EP 0106717 W EP0106717 W EP 0106717W WO 0196300 A1 WO0196300 A1 WO 0196300A1
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Prior art keywords
group
aib
gtφ
boc
growth hormone
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PCT/EP2001/006717
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English (en)
French (fr)
Inventor
Jean Martinez
Jean-Alain Fehrentz
Vincent Guerlavais
Original Assignee
Zentaris Ag
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Priority to BRPI0111591A priority Critical patent/BRPI0111591B8/pt
Priority to SK1756-2002A priority patent/SK287169B6/sk
Priority to DK01943504T priority patent/DK1289951T3/da
Priority to DK05075086T priority patent/DK1524272T3/da
Priority to JP2002510444A priority patent/JP3522265B2/ja
Priority to HK03106131.4A priority patent/HK1054224B/en
Priority to KR1020027016614A priority patent/KR100825109B1/ko
Priority to AU6606601A priority patent/AU6606601A/xx
Priority to UA20021210562A priority patent/UA73356C2/uk
Priority to MXPA02011899A priority patent/MXPA02011899A/es
Priority to PL363081A priority patent/PL216676B1/pl
Priority to DE60112753T priority patent/DE60112753T2/de
Priority to HU0302026A priority patent/HU229233B1/hu
Priority to EP01943504A priority patent/EP1289951B1/en
Priority to NZ522280A priority patent/NZ522280A/en
Priority to AT01943504T priority patent/ATE302181T1/de
Application filed by Zentaris Ag filed Critical Zentaris Ag
Priority to CA2407659A priority patent/CA2407659C/en
Priority to AU2001266066A priority patent/AU2001266066B2/en
Priority to DK03075950T priority patent/DK1344773T3/da
Priority to IL15306701A priority patent/IL153067A0/xx
Publication of WO2001096300A1 publication Critical patent/WO2001096300A1/en
Priority to IL153067A priority patent/IL153067A/en
Priority to NO20025893A priority patent/NO323873B1/no
Priority to BG107379A priority patent/BG66130B1/bg
Priority to BG10110708A priority patent/BG66216B1/bg
Priority to BG10110771A priority patent/BG66217B1/bg
Priority to NL300999C priority patent/NL300999I2/nl
Priority to FR19C1044C priority patent/FR19C1044I2/fr

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    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D401/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing three or more hetero rings
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    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
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    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
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    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
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    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/10—Indoles; Hydrogenated indoles with substituted hydrocarbon radicals attached to carbon atoms of the hetero ring
    • C07D209/18—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0205—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -NH-(X)3-C(=0)-, e.g. statine or derivatives thereof
    • C—CHEMISTRY; METALLURGY
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    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • C07K5/0212—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link containing the structure -N-C-N-C(=0)-, e.g. retro-inverso peptides
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06026—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 0 or 1 carbon atom, i.e. Gly or Ala
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06017—Dipeptides with the first amino acid being neutral and aliphatic
    • C07K5/06034—Dipeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06008—Dipeptides with the first amino acid being neutral
    • C07K5/06078—Dipeptides with the first amino acid being neutral and aromatic or cycloaliphatic
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
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    • C07K5/06—Dipeptides
    • C07K5/06139—Dipeptides with the first amino acid being heterocyclic
    • A—HUMAN NECESSITIES
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    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates to compounds, which are useful for administration to a mammal thereby elevating the plasma level of growth hormone.
  • GH Growth hormone
  • IGF-I insulin-like growth factor-I
  • EGF epidermal growth factor
  • GH Through its action on IGF-I (somatomedin C) synthesis and secretion, GH stimulates the growth of the cartilage and the bones (structural growth), the protein synthesis and the cellular proliferation in multiple peripheral organs, including muscles and the skin. Through its biological activity, GH participates within adults at the maintenance of a protein anabolism state, and plays a primary role in the tissue regeneration phenomenon after a trauma.
  • IGF-I somatomedin C
  • GH is thus a physiological anabolic agent absolutely necessary for the linear growth of children and which controls the protein metabolism in adults.
  • GHRH GH-rel easing hormone
  • GHRP GH-releasing peptides
  • GHRPs and their antagonists are described, for example, in the following publications: C.Y. Bowers, supra, R. Deghenghi, "Growth Hormone Releasing Peptides", ibidem, 1996, pg. 85-102; R. Deghenghi et al., "Small Peptides as Potent Releasers of Growth Hormone", J. Ped. End. Metab., 8, pg. 311-313, 1996; R. Deghenghi, "The
  • Impervious Peptides as Growth Hormone Secretagogues Acta Paediatr. Suppl., 423, pg. 85-87, 1997; K. Veeraraganavan et al., "Growth Hormone Releasing Peptides (GHRP) Binding to Porcine Anterior Pituitary and Hypothalamic Membranes", Life Sci., 50, Pg. 1149-1155, 1992; and T.C. Somers et al., "Low Molecular Weight Peptidomimetic Growth Hormone Secretagogues, WO 96/15148 (May 23, 1996).
  • the human GH has been produced by genetic engineering for about ten years. Until recently most of the uses of GH were concerned with growth delay in children and now the uses of GH in adults are studied.
  • the pharmacological uses of GH, GHRPs and growth hormone secretagogues may be classified in the following three major categories.
  • Recombinant human growth hormone Treatments with recombinant human growth hormone have been shown to stimulate growth in children with pituitary dwarfism, renal insufficiencies, Turner's syndrome and short stature.
  • Recombinant human GH is presently commercialized in Europe and in the United States for children's growth retardation caused by a GH deficiency and for children's renal insufficiencies. The other uses are under clinical trial investigation.
  • GH, GHRPs and growth hormone secretagogues are also intended for veterinary pharmacological uses. GH, GHRPs and growth hormone secretagogues stimulate growth in pigs during its fattening period by favoring the deposition of muscle tissues instead of adipose tissues and increase milk production in cows, and this without any undesired side effects which would endanger the health of the animals and without any residue in the meat o or milk being produced.
  • the bovine somatotropin (BST) is presently commercialized in the United States.
  • GHRPs and growth hormone secretagogues are considered as a second generation product destined to replace in the near future the uses of GH in most instances. 5 Accordingly, the use of GHRPs and growth hormone secretagogues present a number of advantages over the use of GH per se.
  • the present invention relates to new compounds which act as growth hormone secretagogues and, in general, to a method for elevating the plasma level of growth hormone in a mammal by administering thereto one or more of the compounds according to the invention.
  • the invention also relates to methods for the treatment of growth hormone secretion deficiency, for promoting wound healing, recovery from surgery or recovery from debilitating illnesses, by administering to a mammal one of these compounds in a therapeutically effective amount.
  • GH growth hormone
  • Boc is tert-butyloxycarbonyl
  • Z is benzyloxycarbonyl
  • N-Me is N-methyl
  • Pip is 4-amino-piperidine-4-carboxylate
  • Inip is isonipecotyl, i.e.
  • Aib is ⁇ -amino isobutyryl
  • Nal is ⁇ -naphthylalanine
  • Mrp is 2-Methyl-Trp
  • Ala Lys, Phe, Tip, His, Thr, Cys, Tyr, Leu, Gly, Ser, Pro, Glu, Arg, Val and Gin are the amino acids alanine, lysine, phenylalanine, tryptophan, histidine, threonine, cysteine, tyrosine, leucine, glycine, serine, proline, glutamic acid, arginine, valine and glutamine, respectively.
  • gTrp is a group of the formula
  • * means a carbon atom which, when a chiral carbon atom, has a R or S configuration, one of R 1 and R 3 is an hydrogen atom and the other is a group of formula II
  • R 2 is a hydrogen atom, a linear or branched C,-C 6 alkyl group, an aryl group, a heterocyclic group, a cycloalkyl group, a (CH 2 ) n -aryl group, a (CH 2 ) n -heterocycIic group, a (CH 2 ) classroom-cycloalkyl group, a methylsulfonyl group, a phenylsulfonyl group, a C(O)R 8 group or a group according to one or formulas III to VIII below:
  • R 4 is a hydrogen atom or a linear or branched C r C 4 -alkyl group
  • R 5 is a hydrogen atom, a linear or branched C,-C 4 alkyl group, a (CH 2 ) n -aryl group, a (CH 2 ) n -heterocycle group, a (CH 2 ) n -cycloalkyl group or an amino group
  • R 6 and R 7 are independently from each other a hydrogen atom or a linear or branched C,-C 4 -alkyl group
  • R 8 is a linear or branched C,-C 6 -alkyl group
  • R 9 , R 10 , R u , R 12 , R 13 , R 14 , R 15 , and R 16 are independently from each other a hydrogen atom or a linear or branched C r C 4 -alkyl group
  • m is 0, 1 or 2 and n is 1 or 2.
  • a preferred embodiment of the invention are compounds wherein R 2 is hydrogen, R 3 is a group of formula II and m is 0.
  • Particularly preferred are compounds, wherein linear or branched C r C 4 alkyl is methyl, linear or branched C r C 6 alkyl is methyl, ethyl or i-butyl, aryl is phenyl or naphthyl, cycloalkyl is cyclohexyl and the heterocyclic group is a 4-piperidinyl or 3-pyrrolyl group.
  • Specifically preferred compounds of the invention include the following:
  • the compounds of the invention are useful for elevating the plasma level of growth hormone in a mammal. Furthermore the compounds of the present invention are useful for the treatment of growth hormone secretion deficiency, growth retardation in child and metabolic disorders associated with growth hormone secretion deficiency, in particular in aged subjects.
  • compositions of the invention are useful for elevating the plasma level of growth hormone in a mammal, including a human, as well for the treatment of growth hormone secretion deficiency, growth retardation in child and metabolic disorders associated with growth hormone secretion deficiency, in particular in aged subjects.
  • Such pharmaceutical compositions can comprise a compound according to the present invention or a pharmaceutically acceptable salt thereof, or combinations of compounds according to the present invention or pharmaceutically acceptable salts thereof, optionally in admixture with a carrier, excipient, vehicle, diluent, matrix, or delayed release coating.
  • a carrier excipient, vehicle, diluent, matrix, or delayed release coating.
  • examples of such carriers, excipients, vehicles, and diluents can be found in Remington's Pharmaceutical Sciences, 18th Edition, A.R. Gennaro, Ed., Mack Publishing Company, Easton, PA, 1990.
  • compositions of the invention can comprise an additional growth hormone secretagogue.
  • additional growth hormone secretagogues are Ghrelin (cf. M. Kojima et al., Nature, 402 (1999), 656-660), GHRP-1, GHRP-2 and GHRP-6.
  • Ghrelin Gly-Ser-Ser(O-n-octanoyl)-Phe-Leu-Ser-Pro-Glu-His-Gln-
  • GHRP-1 Ala-His-D- ⁇ -Nal-Ala-Trp-D-Phe-Lys-NH 2
  • GHRP-2 D-Ala-D- ⁇ -Nal-Ala-Trp-D-Phe-Lys-NH 2
  • GHRP-6 His-D-Trp-Ala-Trp-D-Phe-Lys-NH 2
  • any of the compounds according to the present invention can be formulated by the skilled in the art to provide medicaments which are suitable for parenteral, buccal, rectal, vaginal, transdermal, pulmonary or oral routes of administration.
  • the type of formulation of the medicament containing the compound can be selected o according to the desired rate of delivery. For example, if the compounds are to be rapidly delivered, the nasal or intravenous route is preferred.
  • the medicaments can be administered to mammals, including humans, at a therapeutically effective dose which can be easily determined by one of skill in the art and which can vary according to the species, age, sex and weight of the treated patient or subject 5 as well the route of administration. The exact level can be easily determined empirically.
  • Z-D-Trp-OH (8.9g; 26mmol; leq.) was dissolved in DME (25ml) and placed in an ice water bath to 0°C. NMM (3.5ml; 1.2eq.), IBCF (4.1ml; 1.2eq.) and ammonia solution 28% (8.9ml; 5eq.) were added successively. The mixture was diluted with water (100ml), and the product Z-D-Trp-NH 2 precipitated. It was filtered and dried in vacuo to afford 8.58g of a white solid.
  • Mass Spectrometry (Electrospray), m z 338 [M+H] + , 360 [M+Na] + , 675 [2M+H] + , 697 [2M+Na] + .
  • Boc-D-Trp-D-Trp-NH 2 as a white solid.
  • Boc-D-Trp-D-Trp-NH 2 (3g; 6.13mmol; leq.) was dissolved in acetonitrile (25ml).
  • di-tert-butyl-dicarbonate (3.4g; 2.5eq.) and 4-dimethylaminopyridine (150mg; 0.2eq.) were successively added.
  • the mixture was diluted with ethyl acetate (100ml) and washed with saturated aqueous sodium hydrogen carbonate (200ml), aqueous potassium hydrogen sulfate (200ml, 1M), and saturated aqueous sodium chloride (200ml).
  • Mass Spectrometry (Electrospray), m/z 690 [M+H] + , 712 [M+Na] 4 , 1379 [2M+H] + , 1401 [2M+Na] + .
  • Boc-D-(N 1' Boc)Trp-D-(N ,” Boc)Trp-NH2 (3g; 4.3mmol; leq.) was dissolved in the mixture DMF / water (18ml / 7ml). Then, pyridine (772 ⁇ l; 2.2eq.) and Bis(Trifluoroacetoxy)IodoBenzene ( 2.1 g; 1.1 eq.) were added. After 1 hr, the mixture was diluted with ethyl acetate (100ml) and washed with saturated aqueous sodium hydrogen carbonate (200ml), aqueous potassium hydrogen sulfate (200ml, 1M), and aqueous • saturated sodium chloride (200ml).
  • Boc-D-(NPBoc)Trp-D-g(N i Boc)Trp-H (4.3mmol; leq.) was dissolved in DMF (20ml). Then, N,N-diisopropylethylamine (815 ⁇ l; l.leq.) and 2,4,5-trichiorophenylformate (1.08g; l.leq.) were added. After 30 minutes, the mixture was diluted with ethyl acetate (100ml) and washed with saturated aqueous sodium hydrogen carbonate (200ml), aqueous potassium hydrogen sulfate (200ml, IM), and saturated aqueous sodium chloride (200ml).
  • Mass Spectrometry (Electrospray), m z 575 [M+H] + , 597 [M+Na] + , 1149 [2M+H] + , 1171 [2M+Na] + .
  • Boc-Aib-D-Trp-D-gTip-CHO (lg; lJmmol) was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at 0°C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated o TFA, H-Aib-D-Trp-D-gTrp-CHO was filtered.
  • Boc-N-Me-Aib-OH (327mg; 1.5mmol; 2.6eq.) was dissolved in methylene chloride (10ml) and cooled to 0°C. Then, dicyclohexylcarbodiimide (156mg; 0.75mmol; 1.3eq.) was added. The mixture, after filtration of DCU, was added to a solution containing TFA, H-D-Trp-D-gTrp-CHO (0.58mmol; leq.) and triethylamine (267 ⁇ l; 3.3eq.) in methylene chloride (5ml). The reaction mixture was slowly warmed to room temperature and stopped after 24 hr.
  • the mixture was diluted with ethyl acetate (25ml) and washed with saturated aqueous sodium hydrogen carbonate (50ml), aqueous potassium hydrogen sulfate (50ml, IM), and saturated aqueous sodium chloride (50ml).
  • the organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo.
  • the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/methancj ⁇ 9/1 ⁇ to afford 180mg (53%) of Boc-N-Me-Aib-D-Trp-D-gTrp-CHO as a white foam.
  • Boc-N-Me-Aib-D-Trp-D-gTrp-CHO (180mg; 0.3mmol) was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at 0°C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, N-Me-Aib-D-Trp-D-gTrp-CHO was filtered.
  • Boc-D-(N i Boc)Trp-D-g(N i Boc)Trp-H (0J2mmol; leq.) was dissolved in DMF
  • Boc-D-(N i Boc)Trp-D-g(N i Boc)Trp-C(O)CH 3 (350mg; 0.5mmol; leq.) was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at 0°C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-D-Trp-D-gTrp-C(O)CH 3 was filtered.
  • Boc-Aib-D-T ⁇ -D-gT ⁇ -C(O)CH 3 (249mg; 0.42mmol> was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at 0°C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Aib-D-T ⁇ -D-gT ⁇ -C(O)CH 3 was filtered.
  • Boc-N-Me-Aib-OH (1.09g; 5.04mmol; 4eq.) was dissolved in methylene chloride (10ml) and cooled to 0°C. Then, dicyclohexylcarbodiimide (520mg; 2.52mmol; 2eq.) was added. The mixture, after filtration of DCU, was added to a solution containing TFA, H-D-T ⁇ -D-gT ⁇ -C(O)CH 3 (940mg; 1.26mmol; leq.) and triethylamine (580ml; 3.3eq.) in methylene chloride (5ml). The reaction mixture was slowly warmed to room temperature and stopped after 24 h.
  • the mixture was diluted with ethyl acetate (50ml) and washed with saturated aqueous sodium hydrogen carbonate (100ml), aqueous potassium hydrogen sulfate (100ml, IM), and saturated aqueous sodium chloride (100ml).
  • the organic layer was dried over sodium sulfate, filtered and the solvent removed in vacuo.
  • the residue was purified by flash chromatography on silica gel eluting with ethyl acetate/methanol ⁇ 9/1 ⁇ to afford
  • Boc-N-Me-Aib-D-T ⁇ -D-gT ⁇ -C(O)CH 3 (530mg; 0.88mmol) was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at
  • Boc-(N 4 Boc)Pip-D-T ⁇ -D-gT ⁇ -CHO (0.31mmol) was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at 0°C. The solvents were removed in vacuo, the residue was stirred with ether and TFA, H-Pip-D-T ⁇ -D-gT ⁇ -CHO was filtered.
  • ⁇ RMN (200 MHZ, DMSO-d 6 ) : ⁇ 1.81 (m, 2H, CH 2 (Pip)); 2.3 (m, 2H, CH 2 (Pip)); 3.1 (m, 8H, 2 (CH 2 ) p et 2 CH 2 (Pip)); 4.68 (m, IH, (CH)J; 5.3 et 5.73 (2m, IH, (CH) 0 .); 6.9-7.7 (m, 10H, 2 indoles); 7.98 (2s, IH, CHO (formyl)); 8.2-9.2 (m, 6H, NH 2 et NH (Pip) et 3 NH (amides)); 10.9 (m, 2H, 2 N1H (indoles)).
  • Boc-(N 4 Boc)Pip-D-T ⁇ -D-gT ⁇ -C(O)CH 3 was dissolved in a mixture of trifluoroacetic acid (8ml), anisole (1ml) and thioanisole (1ml) for 30 minutes at 0°C. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated TFA, H-Pip-D-T ⁇ -D-gT ⁇ -C(O)CH 3 was filtered.
  • Fmoc-Isonipecotyl-D-T ⁇ -D-gT ⁇ -CHO (4.1mmol) was dissolved in a mixture of DMF (8ml) and piperidine (2ml) and allowed to stand for 30 minutes. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated 5 Isonipecotyl-D-T ⁇ -D-gT ⁇ -CHO was filtered. The product Isonipecotyl-D-T ⁇ -D-gT ⁇ -CHO (81mg; 28%) was purified by preparative HPLC (Waters, delta pak, C18, 40x100mm, 5 ⁇ m, 100 A).
  • ⁇ RMN 200 MHZ, DMSO-d 6 : ⁇ 1.65 ( , 4H, 2 CH 2 (Pip)); 2.4 (m, IH, CH (Pip)); 2.7-3.3 (m, 8H, 2 (CH 2 ) p et 2 CH 2 (Pip)); 4.6 (m, IH, (CH) J; 5.3 et 5.7 (2m, IH, (CH) ⁇ .); 6.9-7.7 (m, 10H, 2 indoles); 7.97 (2s, IH, CHO (formyl)); 8-8.8 (m, 4H, NH (Pip) et 3 NH (amides)); 10.9 (m, 2H, 2 N ⁇ (indoles)).
  • Fmoc-Isonipecotic-OH (141mg; 0.4mmol; 1.2eq.), NMM (155 ⁇ l; 4.2eq.) and BOP (178mg;
  • Fmoc-Isonipecotyl-D-T ⁇ -D-gT ⁇ -C(O)CH 3 (0.33mmol) was dissolved in a mixture of DMF (8ml) and piperidine (2ml) and allowed to stand for 30 minutes. The solvents were removed in vacuo, the residue was stirred with ether and the precipitated
  • Isonipecotyl-D-T ⁇ -D-gT ⁇ -C(O)CH 3 was filtered.
  • Example 28 N-Me-Aib-D-T ⁇ -gT ⁇ -CO-CH 2 -pyrrol-3-yl
  • Example 29 N-Me-Aib-D-T ⁇ -gT ⁇ -CO-CH 2 -CH 2 -cyclohexyl
  • Mass Spectrometry (Electrospray), m/z 505,31 [M+H] + ; 527,70 [M+Na] + .
  • ⁇ RMN 400 MHz, DMSO-d 6 : ⁇ 0.94 (t, 3H, NHCH 2 CHJ ; 1.01 (s, 3H, CH 3 (Aib)) ;
  • Pups were received on the fifth day after birth and were housed under controlled conditions (22 ⁇ 2°C, 65 % humidity and artificial light from 06.00 to 20.00 h). A standard dry diet and water were available ad libitum to the dams.
  • the minimum detectable value of rat GH was about 1.0 ng/ml, and intraassay variability was about 6 %.

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PCT/EP2001/006717 2000-06-13 2001-06-13 Growth hormone secretagogues WO2001096300A1 (en)

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NZ522280A NZ522280A (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
DK01943504T DK1289951T3 (da) 2000-06-13 2001-06-13 Væksthormon sekretionsfremmere
DK05075086T DK1524272T3 (da) 2000-06-13 2001-06-13 Væksthormonsekretionsfremmere
JP2002510444A JP3522265B2 (ja) 2000-06-13 2001-06-13 成長ホルモン分泌促進薬
HK03106131.4A HK1054224B (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
KR1020027016614A KR100825109B1 (ko) 2000-06-13 2001-06-13 성장 호르몬 분비촉진제
AU6606601A AU6606601A (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
UA20021210562A UA73356C2 (en) 2000-09-26 2001-06-13 Compounds elevating growth hormone secretion
MXPA02011899A MXPA02011899A (es) 2000-06-13 2001-06-13 Agentes secretagogos de hormona de crecimiento.
PL363081A PL216676B1 (pl) 2000-06-13 2001-06-13 Związki pobudzające wydzielanie hormonu wzrostu, kompozycja farmaceutyczna zawierająca takie związki oraz ich zastosowanie
DE60112753T DE60112753T2 (de) 2000-06-13 2001-06-13 Verbindungen zur stimulation der sekretion von wachstumshormonen
HU0302026A HU229233B1 (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
EP01943504A EP1289951B1 (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
BRPI0111591A BRPI0111591B8 (pt) 2000-06-13 2001-06-13 composto, composição farmacêutica, e, usos de um composto
DK03075950T DK1344773T3 (da) 2000-06-13 2001-06-13 Væksthormonsekretionsfremmere
AT01943504T ATE302181T1 (de) 2000-06-13 2001-06-13 Verbindungen zur stimulation der sekretion von wachstumshormonen
CA2407659A CA2407659C (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
AU2001266066A AU2001266066B2 (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
SK1756-2002A SK287169B6 (sk) 2000-06-13 2001-06-13 Zlúčeniny zvyšujúce sekréciu rastového hormónu, farmaceutický prostriedok s ich obsahom a ich použitie
IL15306701A IL153067A0 (en) 2000-06-13 2001-06-13 Growth hormone secretagogues
IL153067A IL153067A (en) 2000-06-13 2002-11-24 A stimulant that secretes growth hormone
NO20025893A NO323873B1 (no) 2000-06-13 2002-12-09 Veksthormon sekretagoga
BG107379A BG66130B1 (bg) 2000-06-13 2002-12-12 Средства, усилващи секрецията на хормона на растежа
BG10110708A BG66216B1 (bg) 2000-06-13 2010-07-21 Средства, усилващи секрецията на хормона на растежа
BG10110771A BG66217B1 (bg) 2000-06-13 2010-10-18 Средства, усилващи секрецията на хормона на растежа
NL300999C NL300999I2 (nl) 2000-06-13 2019-07-05 macimorelin
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EP2457925A1 (en) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Process for preparing a macrocyclic modulator of the ghrelin receptor and intermediates
US8138218B2 (en) * 2005-07-22 2012-03-20 Ipsen Pharma S.A.S. Growth hormone secretagogues
US8710089B2 (en) 2005-08-15 2014-04-29 Zentaris Gmbh Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
US7829724B2 (en) 2005-08-15 2010-11-09 Zentaris Gmbh Triazole derivatives as ghrelin analogue ligands of growth hormone secretagogue receptors
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EP2644618A1 (en) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. tether intermediates for the synthesis of macrocyclic ghrelin receptor modulators
EP2604594A1 (en) 2008-03-17 2013-06-19 Æterna Zentaris GmbH 1,2,4-Triazole derivatives as ghrelin analogue ligands of GHS receptors
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EP2103602A1 (en) 2008-03-17 2009-09-23 AEterna Zentaris GmbH Novel 1,2,4-triazole derivatives and process of manufacturing thereof
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ATE370119T1 (de) 2007-09-15
ES2292900T3 (es) 2008-03-16
SK287169B6 (sk) 2010-02-08
DE60130025T2 (de) 2008-05-15
DK1344773T3 (da) 2007-12-27
TW200831076A (en) 2008-08-01
US20040229823A1 (en) 2004-11-18
JP2003335752A (ja) 2003-11-28
DE60112753T2 (de) 2006-06-29
US7297681B2 (en) 2007-11-20
CA2407659A1 (en) 2001-12-20
PT1524272E (pt) 2007-07-25
CN1232507C (zh) 2005-12-21
HK1054224A1 (en) 2003-11-21
ES2250416T3 (es) 2006-04-16
EP1289951A1 (en) 2003-03-12
NZ522280A (en) 2004-09-24
NO323873B1 (no) 2007-07-16
PL363081A1 (en) 2004-11-15
HUP0302026A2 (hu) 2003-09-29
US6861409B2 (en) 2005-03-01
FR19C1044I2 (fr) 2020-07-24
AR029941A1 (es) 2003-07-23
IL153067A0 (en) 2003-06-24
KR20030007889A (ko) 2003-01-23
AU2001266066B2 (en) 2005-06-30
JP3522265B2 (ja) 2004-04-26
ATE302181T1 (de) 2005-09-15
CY1107793T1 (el) 2013-06-19
EP1289951B1 (en) 2005-08-17
HU229233B1 (en) 2013-09-30
JP2004503536A (ja) 2004-02-05
MXPA02011899A (es) 2003-04-22
KR100825109B1 (ko) 2008-04-25
ES2288724T3 (es) 2008-01-16
BG110771A (bg) 2011-03-31
DE60130025D1 (de) 2007-09-27
NO20025893D0 (no) 2002-12-09
CZ303173B6 (cs) 2012-05-16
FR19C1044I1 (GUID-C5D7CC26-194C-43D0-91A1-9AE8C70A9BFF.html) 2019-09-08
BG66216B1 (bg) 2012-05-31
DE60112753D1 (de) 2005-09-22
DE60128494D1 (de) 2007-06-28
BG107379A (bg) 2003-09-30
NL300999I2 (nl) 2019-08-28
AU6606601A (en) 2001-12-24
PL216676B1 (pl) 2014-05-30
CY1107710T1 (el) 2013-04-18
US20020165343A1 (en) 2002-11-07
BR0111591B1 (pt) 2014-02-04
CZ305279B6 (cs) 2015-07-15
CZ20024095A3 (cs) 2003-05-14
IL153067A (en) 2010-05-31
ATE362472T1 (de) 2007-06-15
BRPI0111591B8 (pt) 2021-05-25
DK1524272T3 (da) 2007-09-03
HUP0302026A3 (en) 2009-01-28
RU2270198C2 (ru) 2006-02-20
BR0111591A (pt) 2003-05-06
BG66130B1 (bg) 2011-06-30
CN1431998A (zh) 2003-07-23
JP4932132B2 (ja) 2012-05-16
NO20025893L (no) 2003-02-10
DK1289951T3 (da) 2005-12-19
BG66217B1 (bg) 2012-05-31

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