WO1997000894A1 - Compounds with growth hormone releasing properties - Google Patents

Compounds with growth hormone releasing properties Download PDF

Info

Publication number
WO1997000894A1
WO1997000894A1 PCT/DK1996/000266 DK9600266W WO9700894A1 WO 1997000894 A1 WO1997000894 A1 WO 1997000894A1 DK 9600266 W DK9600266 W DK 9600266W WO 9700894 A1 WO9700894 A1 WO 9700894A1
Authority
WO
WIPO (PCT)
Prior art keywords
phe
2nal
aminomethylbenzoyl
acid
aib
Prior art date
Application number
PCT/DK1996/000266
Other languages
English (en)
French (fr)
Inventor
Nils Langeland Johansen
Jesper Lau
Kjeld Madsen
Henning Thoegersen
Behrend Friedrich Lundt
Bernd Peschke
Thomas Kruse Hansen
Birgit Sehested Hansen
Original Assignee
Novo Nordisk 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 Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to PL96324200A priority Critical patent/PL186520B1/pl
Priority to JP1997503521A priority patent/JP4173541B6/ja
Priority to AU61882/96A priority patent/AU711104B2/en
Priority to UA97126188A priority patent/UA61056C2/uk
Priority to BR9608909A priority patent/BR9608909A/pt
Priority to EP96920742A priority patent/EP0833845A1/en
Publication of WO1997000894A1 publication Critical patent/WO1997000894A1/en
Priority to MXPA/A/1997/010377A priority patent/MXPA97010377A/xx
Priority to NO975992A priority patent/NO975992L/no

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/60—Growth hormone-releasing factor [GH-RF], i.e. somatoliberin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/06—Drugs for disorders of the endocrine system of the anterior pituitary hormones, e.g. TSH, ACTH, FSH, LH, PRL, GH
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton
    • C07C237/22—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atoms of the carboxamide groups bound to acyclic carbon atoms of the carbon skeleton having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/02—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing at least one abnormal peptide link
    • 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
    • C07K5/06078—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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/08—Tripeptides
    • C07K5/0802—Tripeptides with the first amino acid being neutral
    • C07K5/0812—Tripeptides 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
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1002—Tetrapeptides with the first amino acid being neutral
    • C07K5/1005—Tetrapeptides with the first amino acid being neutral and aliphatic
    • C07K5/101—Tetrapeptides with the first amino acid being neutral and aliphatic the side chain containing 2 to 4 carbon atoms, e.g. Val, Ile, Leu
    • 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
    • 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 novel peptide derivatives, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
  • Growth hormone is a hormone which stimulates growth of all tissues capable of growing, ln addition, growth hormone is known to have a number of effects on metabolic processes, e.g., stimulation of protein synthesis and free fatty acid mobilization and to cause a switch in energy metabolism from carbohydrate to fatty acid metabolism. Deficiency in growth hormone can result in a number of severe medical disorders, e.g., dwarfism.
  • Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone
  • GHRH somatostatin
  • somatostatin somatostatin
  • the hormones are released from the hypothalamus but their action is mediated primarily via specific receptors located in the pituitary.
  • Other compounds which stimulate the release of growth hormone from the pituitary have also been described. For example arginine,
  • L-Dopa L-3,4-dihydroxyphenylaIanine
  • glucagon glucagon
  • vasopressin PACAP (pituitary adenylyl cyclase activating peptide)
  • muscarinic receptor agonists and a synthethic hexapeptide
  • GHRP growth hormone releasing peptide
  • growth hormone releasing peptides or peptide derivatives are important for their growth hormone releasing potency as well as their bioavailability. It is therefore the object of the present invention to provide novel peptides with growth hormone releasing properties which have improved properties relative to known peptides of this type.
  • A is hydrogen or R 1 -(CH 2 )q-(X) r -(CH 2 ) s -CO-, wherein q is 0 or an integer selected from the group: 1 , 2, 3, 4, 5; r is O or l; s is 0 or an integer selected from the group: 1 , 2, 3, 4, 5;
  • R ⁇ is hydrogen, imidazolyl, guanidino, piperazino, morpholino, piperidino or N(R ⁇ )- R3, wherein each of R ⁇ and R ⁇ is independently hydrogen or lower alkyl optionally substituted by one or more hydroxyl, pyridinyl or furanyl groups; and
  • each of R 1 ⁇ and R ⁇ is independently hydrogen or lower alkyl;
  • B is (G) t -(H) U wherein each of t and u independently is 0 or 1;
  • G and H are amino acid residues selected from the group consisting of natural L- amino acids or their corresponding D-isomers, or non-natural amino acids such as 1 ,4-diaminobutyric acid, amino-isobutyric acid, 1,3-diaminopropionic acid, 4- aminophenylalanine, 3-pyridylalanine, 1 ⁇ .S ⁇ -tetrahydroisoquinoline-S-carboxylic acid, I ⁇ S ⁇ -tetrahydronorharman-S-carboxylic acid, N-methylanthranilic acid, anthranilic acid, N-benzylglycine, 3-aminomethylbenzoic acid, 3-amino-3-methyl butanoic acid, sarcosine, nipecotic acid or
  • C is a D-amino acid of formula -NH-CH((CH 2 ) w -R )-CO- wherein w is 0, 1 or 2;
  • R 4 is selected from the group consisting of
  • D when p is 1, is a D-amino acid of formula -NR 20 -CH((CH 2 ) k -R 5 )-CO- or, when p is 0, D is -NR 20 -CH((CH 2 ) r R 5 )-CH 2 -R 6 or -NR 20 -CH((CH 2 ) m -R 5 )-CO-R 6 , wherein k is O, 1 or 2; l is O, 1 or 2; m is 0, 1 or 2; R 2 ⁇ is selected from the group consisting of lower alkyl or lower aralkyl;
  • R5 is selected from the group consisting of
  • R 6 is piperazino, mo ⁇ holino, piperidino, -OH or -N(R 7 )-R 8 , wherein each of R 7 and R 8 is independently hydrogen or lower alkyl;
  • E when p is 1 , is -NH-CH(R 10 )-(CH 2 ) v -R 9 , wherein v is 0 or an integer selected from the group: 1 ⁇ 2, 3, 4, 5, 6, 7, 8;
  • R is hydrogen, imidazolyl, guanidino, piperazino, mo ⁇ holino, piperidino, -N(R1 1 )-
  • n 0, 1 or 2
  • R-' ⁇ is hydrogen or lower alkyl
  • o is an integer selected from the group: 1 , 2, 3, each of R 1 1 and R ⁇ 2 is independently hydrogen or lower alkyl, or
  • R ⁇ is piperazino, mo ⁇ holino, piperidino, -OH or -N(R ⁇ )-R ⁇ , wherein each of R ⁇ 4 and R ⁇ is independently hydrogen or lower alkyl;
  • I 8 is hydrogen, lower alkyl or lower aralkyl; or a pharmaceutically acceptable salt thereof;
  • the peptide derivatives of formula I exhibit an improved resistance to proteolytic degradation by enzymes due to the presence of adjacent D-amino acids in the peptide sequence, optionally combined with the substitution of an amide bond (-
  • the lower alkyl moities specified above are intended to include those alkyl moities, preferably with 1-6 carbon atoms, of the designated length in either a linear or branched or cyclic configuration.
  • linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl.
  • branched alkyl are isopropyl, sec-butyl, tert- butyl, isopentyl, and isohexyl.
  • Examples of cyclic alkyl are cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • the lower alkoxy moities specified above are intended to include those alkoxy moities preferably with 1-6 carbon atoms, of the designated length in either a linear or branched or cyclic configuration.
  • linear alkyloxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy.
  • branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy.
  • Examples of cyclic alkoxy are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
  • the lower alkylamino moities specified above are intended to include those alkylamino moities preferably with 1-6 carbon atoms, of the designated length in either a linear or branched or cyclic configuration.
  • linear alkylamino are methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino.
  • branched alkylamino are isopropylamino, sec-butylamino, tert-butylamino, isopentylamino, and isohexylamino.
  • cyclic alkylamino examples include cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino.
  • aryl is intended to include aromatic rings, such as carbocyclic and heterocyclic aromatic rings selected from the group consisting of phenyl, naphthyl, pyridyl, 1-H-tetrazol-5-yl, thiazolyl, imidazolyl, indolyl, pyrimidinyl, thiadiazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiopheneyl, quinolinyl, pyrazinyl, or isothiazolyl, optionally substituted by one or more d-6-alkyl, halogen, amino or aryl.
  • Aryl is preferably phenyl, thienyl, imidazolyl, pyridyl, indolyl, quinoline or naphthyl optionally substituted with halogen, amino, hydroxy, or C ⁇ - 6 -alkoxy.
  • the lower aralkyl moities specified above are composed of a lower alkyl moity and a aryl moiety, wherein the lower alkyl moiety and aryl moiety are as defined above.
  • halogen is intended to include Cl, F, Br and I.
  • the common three-letter code is used for natural amino acids, e.g. Ala for alanine.
  • A is hydrogen, 3-N-Me- AMB, -3-AMB or Aib.
  • G in the compund of formula I is preferably Ala, Gly, sarcosine, 3-aminomethylbenzoyl, R-nipecotinyl, nipecotic acid or isonipecotic acid, more preferably 3-aminomethylbenzoyl, R-nipecotinyl, nipecotic acid or isonipecotic acid.
  • H is preferably His, Phe, Tic, Phe(4-NH 2 ), 3-Pyal, Gly, Ala, Sar, Pro, Tyr, Arg, Orn, 3-aminomethylbenzoic acid or D-Phe, more preferably H is His, Phe or Ala, most preferably H is His or Ala.
  • C in the compound of formula I is preferably D-2-naphthylalanine (D-2Nal), D-1-naphthylalanine (D- 1 Nal), D-Phe or D-T ⁇ , more preferably D-2Nal or D-Phe and most preferably N- Me-D-2Nal, D-2Nal, D-Phe, or N-Me-D-Phe.
  • D in the compound of formula I is preferably -NR 20 -CH((CH 2 ) k -R 5 )-CO-, wherein k is preferably 1 and R 20 is lower alkyl, more preferably D is D-Phe or D-2Nal. Most preferably D is N-Me-D-Phe-ol, N-Me-D-Phe, N-Me-D-2Nal-ol, N-Me-D-Phe-NH 2 , N-Me-D-Phe-NH-Me, or N-Me-D- . (4-l)Phe-NH-Me.
  • E is preferably Lys-NH , Ser-NH 2 , NH-
  • R 4 in the compound of formula I is preferably 2-naphthyl.
  • R 5 is preferably phenyl.
  • v is preferably 2-6, and R is NH 2 ,2-mo ⁇ holinoethyl , 3-morpholinopropyl
  • R 10 is preferably -COOH, -CH 2 -OH, -H, -CONH 2 or
  • Examples of specific compounds of the present invention are (2R)-2-((3-Aminomethylbenzoyl))-N-Me-D-2Nal-N-Me)-3-(2-naphthyl) ⁇ ropanol:
  • Solid phase synthesis may be carried out substantially as described by Stewart and Young, Solid Phase Peptide Svnthesis, 2nd. Ed., Rockford, Illinois, USA, 1976.
  • Solution peptide synthesis may for instance be carried out substantially as described by Bodansky et al., Peptide Synthesis. 2nd. Ed., New York, New York, USA, 1976.
  • Aminomethylene as a substitution of an amide bond may be introduced according to the method described by Y. Sasaki and D.H. Coy, Peptides 8(1 ), 1987, pp. 119-
  • Peptide derivatives containing a mono- or di-hexapyranose derivatised amino group may be prepared by an Amadori rearrangement substantially by the method described by R. Albert et al., Life Sciences 53, 1993, pp. 517-525.
  • suitable mono- or di-hexapyranoses are glucose, galactose, maltose, lactose or cellobiose.
  • Derivatives used as starting materials in the synthesis may either be obtained commercially and, when required, provided with suitable protecting groups, or starting materials used to prepare the "A" moiety in general formula I may be prepared by well-known methods and optionally protected in a manner known perse.
  • Pharmaceutically acceptable acid addition salts of compounds of formula I include those prepared by reacting the peptide with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, oxalic, •toluenesulfonic, trifluoracetic, sulfamic and fumaric acid.
  • an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, oxalic, •toluenesulfonic, trifluoracetic, sulfamic and fumaric acid.
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • compositions containing a compound of the present invention may be prepared by conventional techniques, e.g. as described in Remington's Pharmaceutical Sciences. 1985.
  • the compositions may appear in conventional forms, for example capsules, tablets, aerosols, solutions, suspensions, patches or topical applications.
  • the pharmaceutical carrier or diluent employed may be a conventional solid or liquid carrier.
  • solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose.
  • liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water.
  • the carrier or diluent may include any sustained release material known in the art, such as glyceryl monostearate or glyceryl distearate, alone or mixed with a wax.
  • the preparation may be tabletted, placed in a hard gelatin capsule in powder or pellet form or it can be in the form of a troche or lozenge.
  • the amount of solid carrier will vary widely but will usually be from about 25 mg to about 1 g.
  • a typical tablet which may be prepared by conventional tabletting techniques may contain:
  • Active compound (as free compound or salt thereof) 100 mg
  • the preparation may be in. the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid such as an aqueous or non-aqueous liquid suspension or solution.
  • the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
  • the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants such as bile acid salts polyethylene glycols, polypropylene glycols or polyoxyethylene higher alcohol ethers, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
  • solubilizing agents e.g. propylene glycol
  • surfactants such as bile acid salts polyethylene glycols, polypropylene glycols or polyoxyethylene higher alcohol ethers
  • absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin
  • preservatives such as parabenes.
  • the preparation may be in a form suitable for patches or iontophoresis.
  • the compounds of the present invention are dispensed in unit dosage form comprising 0.0001-100 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
  • the dosage of the compounds according to this invention is suitably 1-500 mg/day, e.g. about 100 mg per dose, when administered to patients, e.g. humans, as a drug.
  • the present invention relates to a pharmaceutical composition for stimulating the release of growth hormone from the pituitary, the composition comprising, as an active ingredient, a compound of the general formula I or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
  • the present invention relates to a method of stimulating the release of growth hormone from the pituitary, the method comprising administering to a subject in need thereof an effective amount of a compound of the general formula I or a pharmaceutically acceptable salt thereof.
  • the present invention relates to the use of a compound of the general formula I or a pharmaceutically acceptable salt thereof for the preparation of a medicament for stimulating the release of growth hormone from the pituitary.
  • the compounds of formula I have interesting pharmacological properties. Examples of such properties are the stimulation of release of growth hormone from the pituitary which has similar effects or uses as growth hormone itself.
  • the uses of growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids, treatment of osteoporosis, stimulation of the immune system, acceleration of wound healing, accelerating bone fracture repair, treatment of growth retardation, treating renal failure or insufficiency resulting from growth retardation, treatment of physiological short stature including growth hormone deficient children and short stature associated with chronic illness, treatment of obesity and growth retardation associated with obesity, treating growth retardation associated with the Prader-Willi syndrome and Turner's syndrome; accelerating the recovery and reducing hospitalization of burn patients; treatment of intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushing's syndrome; induction of pulsatile growth hormone release; replacement of growth hormone in stressed patients, treatment of osteochondrodysplasias, No
  • the dosage may vary depending on the compound of formula I employed, on the mode of administration and on the therapy desired. However, generally dosage levels between 0.0001 and 100 mg/kg body weight per day may be administered to patients and animals to obtain effective release of endogenous growth hormone.
  • dosage forms suitable for oral or nasal administration comprise from about 0.0001 mg to about 100 mg, preferably from about 0.001 mg to about 50 mg of the compounds of formula I admixed with a pharmaceutically acceptable carrier or diluent.
  • the compounds of formula I may be administered in pharmaceutically acceptable acid addition salt form or, where appropriate, as a alkali metal or alkaline earth metal or lower alkylammonium salt. Such salt forms are believed to exhibit approximately the same order of activity as the free base forms.
  • the pharmaceutical composition of the invention may comprise a compound of formula I combined with one or more compounds exhibiting a different activity, e.g., an antibiotic or other pharmacologically active material.
  • This might be another secretagogue, such as GHRP (1 or 6) or GHRH or an analogue thereof, growth hormone or an analogue thereof or a somatomedin such as IGF-1 or IGF-2.
  • the route of administration may be any route which effectively transports the active compound to the appropriate or desired site of action, such as oral, nasal, pulmonary, transdermal or parenteral, the oral route being preferred.
  • the compounds of formula I may also be useful in vivo tools for evaluating the growth hormone releasing capability of the pituitary. For example, serum samples taken before and after administration of these compounds to humans can be assayed for growth hormone. Comparison of the growth hormone in each serum sample would directly determine the ability of the patients pituitary to release growth hormone.
  • Compounds of formula I may be administered to commercially important animals to increase their rate and extent of growth, and to increase milk production.
  • Compounds of formula I may be evaluated in vitro for their efficacy and potency to release growth hormone in primary rat somatotrophs.
  • Rat primary somatotrophs may be prepared essentially as described previously (Chen et al., Endocrinology 1991 , 129, 3337-3342 and Chen et al., Endocrinology 1989, 124, 2791-2798). Briefly, rats are killed by decapitation. The pituitary is quickly removed. The pituitaries are digested with 0.2 % collagenase n 0.2 % hyalurinidase in Hanks balanced salt solution.
  • the cells are resuspended in Dulbecco's Modified Eagle's medium containing 0.37 % NaHCO3, 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % penicillin/streptomycin and adjusted to 1.5 x 105 cells/ml.
  • Dulbecco's Modified Eagle's medium containing 0.37 % NaHCO3, 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % penicillin/streptomycin and adjusted to 1.5 x 105 cells/ml.
  • One ml of this suspension is placed in each well of 24-well trays and left for 2-3 days before release experiments are performed.
  • the peptide was eluted from the Sep-Pak ® cartridge with 70% CH 3 CN 0.1% TFA and isolated from the eluate by lyophilisation after dilution with water.
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma deso ⁇ tion mass spectrometry (molecular mass). Mass spectrometry agreed with the expected structure within the experimental error of the method (mass spectrometry ⁇ 0.9 amu).
  • the RP-HPLC analysis was performed using UV detection at 214 nm and a Vydac 218TP54 4.6mm x 250mm 5 ⁇ C-18 silica column (The Separations Group, Hesperia) which was eluted at 1 ml/min at 42 °C. Two different elution conditions were used: A1: The column was equilibrated with 5% CH 3 CN in a buffer consisting of 0JM
  • the retention time using elution conditions A1 and B1 was found to be 29.90 min and 31.52 min, respectively.
  • the aqueous phase was concentrated to dryness and redissolved in 400 ml THF and 343 ml 1 M NaOH. A solution of 30g Boc-anhydride in 100 ml THF was added and the mixture was stirred overnight. Then the reaction mixture was acidified to pH 3 with 1 N HCl and extracted with 3 x 300 ml of EtOAc. The organic phase was evaporated to a foam. The yield was 22 g.
  • N-Me-D-2Nal N-methyl-D-2-naphtylalanine
  • DCM dichloromethane
  • DIEA diisopropylethyl amine
  • Boc-N-Me-D-Phe-OH (279 mg) was dissolved in DMF (4 ml) and stirred 10 min with HOBt (168 mg) and EDAC (230 mg ). 3-Dimethylamino-1 -propylamine (188 ⁇ l) was added and the mixture was stirred 18h at r.t. Then 5% aqueous sodium hydrogen carbonate (50 ml) was added and the resulting mixture was extracted with EtOAc (50 ml) and the organic phase was dried over Na 2 SO and concentrated in vacuum to an oil.
  • reaction mixture was concentrated to an oil with a stream of nitrogen and stirred for 15 min with 5% aqueous sodium hydrogen carbonate (100 ml).
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
  • the molecular mass found (MH + :608.2 amu) agreed with the expected structure (teor. MH +: 608.8 amu) within the experimental error of the method.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 25.23 min and 26.58 min, respectively.
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
  • the molecular mass found (MH + : 586.3 amu) agreed with the expected structure (teor. MH +: 585.8 amu) within the experimental error of the method.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1 was found to be 25.33 min and 26.35 min, respectively.
  • Boc-N-Me-D-Phe-OH (279 mg) was dissolved in DMF (10 ml) and stirred 10 min with HOBt (168 mg) and EDAC (384 mg ).
  • 2-(Aminoethyl)-1-methyl-pyrrolidine (290 ⁇ l) and DIEA (171 ⁇ l) were added and the mixture was stirred for 20 h at r.t. Then the mixture was concentrated to an oil which was dissolved in 50 ml water and lyophilized. The product was redissolved in 25 ml water and then applied to a Sep-Pak® C18 cartridge (Waters part. #:43345 ) which was equilibrated with 0.03 N hydrochloric acid .
  • the product was eluted from the Sep-Pak® cartridge with 70% CH 3 CN in 0.03 N hydrochloric acid and isolated from the eluate by lyophilisation after dilution with water.
  • the resulting material is stirred 10 min at r.t. with TFA / DCM 1 : 1 (6 ml). After this the TFA / DCM was evaporated by a stream of nitrogen and the resulting oil was dissolved in 70% CH 3 CN (10 ml) and 1 N hydrochloric acid (2 ml) was added.
  • the product was isolated by lyophilisation after dilution with water (50 ml).
  • the resulting material was dissolved in DMF (3 ml) and stirred 18h at r.t.
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
  • the molecular mass found (MH + : 612.2 amu) agreed with the expected structure (teor. MH +: 612.39 amu) within the experimental error of the method.
  • the RP-HPLC retention time using elution condition A1 as defined in example 1. was found to be 25.80 min.
  • N- ⁇ (1 R)-1 -(N-[(1 R)-2-hydroxy-1 -((2-naphthyl)methyl)ethyl)-N-methylcarbamoyl]-2- (2-naphthyl)ethyl ⁇ -N-methylcarbamic acid tert-butyl ester (0,25 g; 0,475 mmol) was dissolved in DCM (3 ml). Triflouroacetic acid (1 ml) was added and the reaction mixture was stirred for 20 min. The solvent was removed in vacuo. DCM (5 ml) was added and removed in vacuo and repeated. The residue was dissolved in methanol (5 ml).
  • the resulting organic phase was dried with Na 2 SO 4 and concentrated in vacuum on a rotary evaporator to an oil.
  • the oil was then dissolved in DCM / TFA 1 :1 (6 ml) and stirred. After 10 min the mixture was concentrated by a stream of nitrogen and the resulting oil was redissolved in 70% CH 3 CN / 0J % TFA (5 ml) and diluted with water to a volume of 100 ml.
  • the peptide was synthesized according to the Fmoc strategy on an Applied Biosystems 431 A peptide synthesizer in 0.22 mmol scale using the manufacturer supplied FastMoc UV protocols which employ HBTU mediated couplings in NMP and UV monitoring of the deprotection of the Fmoc protection group.
  • the starting resin used for the synthesis was cat. #: D-1675 from Bachem Feinchemikalien AG, Bubendorf, Switzerland (427) mg which is a Fmoc-2,4-dimethoxy-4'- (carboxymethyloxy)-benzhydryl-amine linked to amino methyl polystyrene resin through an amide bond.
  • the substitution capacity was 0.55 mmol / g .
  • the protected amino acid derivatives used were Fmoc-N-Me-D-Phe-OH, Fmoc-D-2Nal- OH, Fmoc-His(Trt) and Fmoc-Aib-OH.
  • the coupling of Fmoc-N-Me-D-Phe-OH was carried out as a double coupling.
  • the peptide was cleaved from 750 mg of the peptide resin by stirring for 180 min at room temperature with a mixture of 8 ml TFA , 600 mg phenol, 200 ⁇ l ethanedithiol, 400 ⁇ l thioanisole and 400 ⁇ l H 2 O.
  • the cleavage mixture was filtered and the filtrate was concentrated to approximately 2 ml by a stream of nitrogen.
  • the crude peptide was precipitated from this oil with 50 ml diethyl ether and washed 2 times with 50 ml diethyl ether.
  • the crude peptide was dried and purified by semipreparative HPLC in one run and lyophilized using similar procedures as described in example 1.
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass).
  • the molecular mass found (MH + :598.5 amu) agreed with the expected structure (teor. MH +: 598.73 amu) within the experimental error of the method.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1 was found to be 24.68 min and 25.58 min, respectively.
  • This compound was synthesized using similar procedures as described in example 6. The only exception was that the coupling of Fmoc-D-2Nal-OH was performed using HATU as the activating reagent. H-N-Me-D-Phe-resin (0.23 mmol) was coupled for 150 min with 1 mmol Fmoc-D-2Nal-OH using 1 mmol HATU in the presence of DIEA (2 mmol).
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma deso ⁇ tion mass spectrometry (molecular mass).
  • the molecular mass found (MH + :511.2 amu) agreed with the expected structure (teor. MH +: 509.6 amu) within the experimental error of the method.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 30.73 min and 32.47 min, respectively.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 21.13 min and 22.60 min, respectively.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 15.71 min and 17.82 min, respectively.
  • This compound was synthesized using similar procedures as described in example 11. using Fmoc-N-Me-D-Phe-OH, Fmoc-N-Me-D-2Nal-OH and Boc-(R)-Nipecotic acid, where both Fmoc-N-Me-D-2Nal-OH and Boc-(R)-Nipecotic acid were coupled using HATU.
  • the final product obtained was characterised by analytical RP-HPLC (retention time) and by Plasma desorption mass spectrometry (molecular mass). The molecular mass found (MH + :500.7 amu) agreed with the expected structure (teor. MH +: 501.7 amu) within the experimental error of the method.
  • the RP-HPLC retention time using elution conditions A1 and B1 as defined in example 1. was found to be 28J 8 min and 29.55 min, respectively.
  • Boc-3AMB-OH 115 mg, 0.458 mmol
  • 1 -hydroxy-7-azabenzotriazole 62 mg, 0.458 mmol
  • 1-ethyl-3(3-dimethylaminopropyl)carbodiimide hydrochloride 97 mg, 0.504 mmol
  • N-methyl-2-methylamino-N-((1R)-1-(methylcarbamoyI)-2-phenylethyl)-3-(2- naphthyl)propionamide (185 mg, 0.458 mmol) dissolved in DCM (5 ml) was added followed by addition of diisopropylethylamine (80 ml, 0.458 mmol) and the mixture was stirred for 20 hours.
  • Fmoc-L-His(Trityl)-OH (1,54 g, 2.48 mmol) (BACHEM B-1570) and 1-hydroxyaza- benzotriazol (338 mg, 2.48 mmol) were dissolved in 9 ml of DMF, cooled to 0-4°C and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (475 mg, 2.48 mmol) was added. The reaction mixture was stirred for 15 min. at 0-4° C.
  • N-Methyl-2-methylamino-N-((1 R)-1-(Methylcarbamoyl)-2-phenylethyl)-3-(2- naphthyl)propionamid 500 mg, 1.24 mmol
  • methylen chloride (18 ml) was cooled to 0-4° C and added and stirred for 1 hour at 0-4° C followed by addition of diisopropylethylamine (0.425 ml, 2.48 mmol). The temperature of the mixture was slowly raised to room temperature and the mixture was stirred for 72 hours.
  • DCM was evaporated in a stream of N 2 and to the mixture was added 100 ml ethyl acetate and washed with sodium hydrogen carbonate (2 x 100 ml, 5%) and potassium hydrogen sulfate (100 ml, 5%). The phases were separated and the organic phase was dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in DMF (8 ml) and treated with piperidine for 15 min., diluted with H 2 O (100 ml) and quenched with acetic acid (1 ,5 ml). Acetonitrile was added and the mixture was diluted with H 2 O to 250 ml.
  • Boc- ⁇ aminoisobutyric acid (756 mg, 3.72 mmol), 1-hydroxyazabenzotriazole hydrate (506 mg, 3.72 mmol) and 1-ethyI-3(3-dimethylaminopropyl)carbodiimide hydrochloride (713 mg, 3.72 mmol) were dissolved in DMF (6 ml) and after 15 min. was added H-L- His(trityl)-NMeD2Nal-NMeDPhe-NHCH 3 , 2 HCL dissolved in DCM (12 ml) followed by addition of diisopropylethylamine (0.637 ml) and stirred for 72 hours.
  • DCM was evaporated in a stream of N 2 and the mixture was added 100 ml ethyl acetate and washed with sodium hydrogen carbonate (2 x 50 ml, 5%) and potassium hydrogen sulfate (50 ml, 5%). The phase were separated and the organic phase was dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in DCM (6 ml), cooled to 0 ⁇ ° C and treated with TFA (6 ml) for 10 min. at 0-4° C. With a stream of N 2 the volatiles was removed.
  • Boc-NMe3AMB-OH (658 mg, 2.48 mmol), 1-hydroxyazabenzotriazole hydrate (338 mg, 2.48 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (475 mg, 2.48 mmol) were dissolved in 6 ml of DMF and stirred for 15 min.
  • N-Methyl-2-methylamino-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-3-(2- naphthyl)propionamid 500 mg, 1.24 mmol
  • methylene chloride (12 ml) was added, followed by addition of diisopropylethylamine (0,425 ml, 2.48 mmol). The mixture was stirred for 20 hours.
  • N-((1 R)-2-(4-lodophenyl)-1 -(methylcarbamoyl)ethyl)-N-methylcarbamic acid tert-butylester (1.7 g; 4.0 mmol) was dissolved in methylene chloride (10 ml) and trifluoroacetic acid (5 ml) was added. The mixture was stirred for 1 h. Methylene chloride (30 ml) and water (30 ml) was added. Solid sodium hydrogen carbonate was added to pH 8. The organic phase was separated, dried (MgSO 4 ) and evaporated in vacuo to afford 1.22 g of (2R)-3-(4-iodo ⁇ henyl)-N-methyl-2-(methylamino)propionamide.
  • N-Methyl-N-((1 R)-1 -(N-methyl-N-((1 R)-1 -(methylcarbamoyl)-2-(4- iodophenyl)ethyl)carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butylester was dissolved in a mixture of methylene chloride and trifluoroacetic acid and stirred for 15 min.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Endocrinology (AREA)
  • Biochemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • General Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Diabetes (AREA)
  • Toxicology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Reproductive Health (AREA)
  • Urology & Nephrology (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
PCT/DK1996/000266 1995-06-22 1996-06-19 Compounds with growth hormone releasing properties WO1997000894A1 (en)

Priority Applications (8)

Application Number Priority Date Filing Date Title
PL96324200A PL186520B1 (pl) 1995-06-22 1996-06-19 Związk o właściwościach uwalniania hormonu wzrostu, kompozycja farmaceutyczna zawierająca ten związek i jego zastosowanie
JP1997503521A JP4173541B6 (ja) 1995-06-22 1996-06-19 成長ホルモン放出特性を有する化合物
AU61882/96A AU711104B2 (en) 1995-06-22 1996-06-19 Compounds with growth hormone releasing properties
UA97126188A UA61056C2 (en) 1995-06-22 1996-06-19 Componuds with properties of growth hormone release, as pharmaceutical composition, a method for stimulating the growth hormone release from the pituitary and a method for increasing animal growth rate
BR9608909A BR9608909A (pt) 1995-06-22 1996-06-19 Composto composição farmacêutica processos para estimular a liberação do hormônio do crescimento da patuitária e aumentar a velocidade e extensão do crescimento dos animais para aumentar a produção de leite ou lã de animais ou para para doenças e uso do composto
EP96920742A EP0833845A1 (en) 1995-06-22 1996-06-19 Compounds with growth hormone releasing properties
MXPA/A/1997/010377A MXPA97010377A (en) 1995-06-22 1997-12-18 Compounds with releasing properties of growth hormone
NO975992A NO975992L (no) 1995-06-22 1997-12-19 Forbindelser med veksthormonfrigjörende egenskaper

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK71995 1995-06-22
DK719/95 1995-06-22
DK1371/95 1995-12-04
DK137195 1995-12-04

Publications (1)

Publication Number Publication Date
WO1997000894A1 true WO1997000894A1 (en) 1997-01-09

Family

ID=26064522

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/DK1996/000266 WO1997000894A1 (en) 1995-06-22 1996-06-19 Compounds with growth hormone releasing properties

Country Status (12)

Country Link
EP (1) EP0833845A1 (pl)
KR (1) KR19990028303A (pl)
AU (1) AU711104B2 (pl)
BR (1) BR9608909A (pl)
CA (1) CA2224434A1 (pl)
CZ (1) CZ287948B6 (pl)
HU (1) HUP9802821A3 (pl)
IL (1) IL122371A0 (pl)
NO (1) NO975992L (pl)
PL (1) PL186520B1 (pl)
TW (1) TW458958B (pl)
WO (1) WO1997000894A1 (pl)

Cited By (26)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998008492A1 (en) * 1996-08-29 1998-03-05 Novo Nordisk A/S Transdermal delivery of peptides
WO1998058950A1 (en) 1997-06-20 1998-12-30 Novo Nordisk A/S Compounds with growth hormone releasing properties
WO1999058505A2 (en) * 1998-05-12 1999-11-18 Warner-Lambert Company Combinations of protein farnesyltransferase and hmg coa reductase inhibitors and their use to treat cancer
US6127341A (en) * 1997-06-20 2000-10-03 Novo Nordisk A/S Compounds with growth hormone releasing properties
EP1159964A2 (en) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions and methods for stimulating gastrointestinal motility
JP2002519436A (ja) * 1998-06-30 2002-07-02 ノボ ノルディスク アクティーゼルスカブ 成長ホルモン放出特性を有する化合物
US6468974B1 (en) 1998-08-14 2002-10-22 The Administrators Of The Tulane Educational Fund Compounds having growth hormone releasing activity
US6528529B1 (en) 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
US6706712B2 (en) 2000-12-20 2004-03-16 Bristol-Myers Squibb Pharma Company Cyclic derivatives as modulators of chemokine receptor activity
EP1506969A1 (en) 1998-01-16 2005-02-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6864250B1 (en) 1997-08-22 2005-03-08 Kaken Pharmaceutical Co., Ltd. N-acylated lipophilic amino acid derivatives
US6919315B1 (en) 1998-06-30 2005-07-19 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6974836B2 (en) 2000-12-20 2005-12-13 Bristol-Myers Squibb Pharma Company Diamines as modulators of chemokine receptor activity
WO2007098716A1 (es) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Compuestos analogos a los secretagogos peptidicos de la hormona de crecimiento y preparaciones que los contienen
EP1930021A2 (en) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Novel amide derivatives as growth hormone secretagogues
US7678363B2 (en) 2005-08-26 2010-03-16 Braincells Inc Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs
EP2258359A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
EP2457893A1 (en) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermediates for macrocyclic modulators of the ghrelin receptor
US8377865B2 (en) 2002-08-09 2013-02-19 Ipsen Pharma S.A.S. Growth hormone releasing peptides
EP2644618A1 (en) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. tether intermediates for the synthesis of macrocyclic ghrelin receptor modulators
WO2013190520A2 (en) 2012-06-22 2013-12-27 The General Hospital Corporation Gh-releasing agents in the treatment of vascular stenosis and associated conditions
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
WO2017075535A1 (en) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Methods of treating neurodegenerative conditions
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993004081A1 (en) * 1991-08-22 1993-03-04 Administrators Of The Tulane Educational Fund Peptides having growth hormone releasing activity
WO1995017423A1 (en) * 1993-12-23 1995-06-29 Novo Nordisk A/S Compounds with growth hormone releasing properties
WO1996015148A2 (en) * 1994-11-16 1996-05-23 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1993004081A1 (en) * 1991-08-22 1993-03-04 Administrators Of The Tulane Educational Fund Peptides having growth hormone releasing activity
WO1995017423A1 (en) * 1993-12-23 1995-06-29 Novo Nordisk A/S Compounds with growth hormone releasing properties
WO1996015148A2 (en) * 1994-11-16 1996-05-23 Genentech, Inc. Low molecular weight peptidomimetic growth hormone secretagogues

Cited By (47)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1998008492A1 (en) * 1996-08-29 1998-03-05 Novo Nordisk A/S Transdermal delivery of peptides
WO1998058950A1 (en) 1997-06-20 1998-12-30 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6127341A (en) * 1997-06-20 2000-10-03 Novo Nordisk A/S Compounds with growth hormone releasing properties
US7279573B2 (en) 1997-08-22 2007-10-09 Kaken Pharmaceutical Co., Ltd. Amide derivatives
US7064121B2 (en) 1997-08-22 2006-06-20 Kaken Pharmaceutical Co., Ltd. N-acylated lipophilic amino acid derivatives
US6864250B1 (en) 1997-08-22 2005-03-08 Kaken Pharmaceutical Co., Ltd. N-acylated lipophilic amino acid derivatives
EP1506969A1 (en) 1998-01-16 2005-02-16 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6528529B1 (en) 1998-03-31 2003-03-04 Acadia Pharmaceuticals Inc. Compounds with activity on muscarinic receptors
US7485651B2 (en) 1998-03-31 2009-02-03 Acadia Pharmaceuticals, Inc. Compounds with activity on muscarinic receptors
WO1999058505A3 (en) * 1998-05-12 2000-01-06 Warner Lambert Co Combinations of protein farnesyltransferase and hmg coa reductase inhibitors and their use to treat cancer
WO1999058505A2 (en) * 1998-05-12 1999-11-18 Warner-Lambert Company Combinations of protein farnesyltransferase and hmg coa reductase inhibitors and their use to treat cancer
EP1100824B1 (en) * 1998-06-30 2011-03-02 Novo Nordisk A/S Compounds with growth hormone releasing properties
JP2002519436A (ja) * 1998-06-30 2002-07-02 ノボ ノルディスク アクティーゼルスカブ 成長ホルモン放出特性を有する化合物
US6919315B1 (en) 1998-06-30 2005-07-19 Novo Nordisk A/S Compounds with growth hormone releasing properties
US7576062B2 (en) 1998-06-30 2009-08-18 Novo Nordisk A/S Compounds with growth hormone releasing properties
US6468974B1 (en) 1998-08-14 2002-10-22 The Administrators Of The Tulane Educational Fund Compounds having growth hormone releasing activity
US7250399B2 (en) 1998-08-14 2007-07-31 The Administrators Of The Tulane Educational Fund Compounds having growth hormone releasing activity
EP1930021A2 (en) 1999-02-18 2008-06-11 Kaken Pharmaceutical Co., Ltd. Novel amide derivatives as growth hormone secretagogues
EP1159964A2 (en) 2000-05-31 2001-12-05 Pfizer Products Inc. Compositions and methods for stimulating gastrointestinal motility
US7572813B2 (en) 2000-12-20 2009-08-11 Bristol-Myers Squibb Company Cyclic derivatives as modulators of chemokine receptor activity
US6706712B2 (en) 2000-12-20 2004-03-16 Bristol-Myers Squibb Pharma Company Cyclic derivatives as modulators of chemokine receptor activity
US7045521B2 (en) 2000-12-20 2006-05-16 Bristol-Myers Squibb Pharma Company Cyclic derivatives as modulators of chemokine receptor activity
US6974836B2 (en) 2000-12-20 2005-12-13 Bristol-Myers Squibb Pharma Company Diamines as modulators of chemokine receptor activity
US7449493B2 (en) 2000-12-20 2008-11-11 Bristol-Myers Squibb Pharmaceutical Company Diamines as modulators of chemokine receptor activity
US9409948B2 (en) 2002-08-09 2016-08-09 Ipsen Pharma S.A.S. Growth hormone releasing peptides
US8859729B2 (en) 2002-08-09 2014-10-14 Ipsen Pharma S.A.S. Growth hormone releasing peptides
US8377865B2 (en) 2002-08-09 2013-02-19 Ipsen Pharma S.A.S. Growth hormone releasing peptides
EP2457925A1 (en) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Process for preparing a macrocyclic modulator of the ghrelin receptor and intermediates
EP2457893A1 (en) 2004-06-18 2012-05-30 Tranzyme Pharma, Inc. Intermediates for macrocyclic modulators of the ghrelin receptor
EP2258357A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2275095A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis by muscarinic receptor modulation
EP2258358A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis with acetylcholinesterase inhibitor
EP2258359A2 (en) 2005-08-26 2010-12-08 Braincells, Inc. Neurogenesis by muscarinic receptor modulation with sabcomelin
US7678363B2 (en) 2005-08-26 2010-03-16 Braincells Inc Methods of treating psychiatric conditions comprising administration of muscarinic agents in combination with SSRIs
EP2275096A2 (en) 2005-08-26 2011-01-19 Braincells, Inc. Neurogenesis via modulation of the muscarinic receptors
WO2007098716A1 (es) 2006-02-28 2007-09-07 Centro De Ingeniería Genética Y Biotecnología Compuestos analogos a los secretagogos peptidicos de la hormona de crecimiento y preparaciones que los contienen
US9284275B2 (en) 2007-01-11 2016-03-15 Critical Outcome Technologies Inc. Inhibitor compounds and cancer treatment methods
EP2644618A1 (en) 2007-02-09 2013-10-02 Tranzyme Pharma, Inc. tether intermediates for the synthesis of macrocyclic ghrelin receptor modulators
US8895556B2 (en) 2007-12-26 2014-11-25 Critical Outcome Technologies Inc. Compounds and method for treatment of cancer
US8987272B2 (en) 2010-04-01 2015-03-24 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9422282B2 (en) 2010-04-01 2016-08-23 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
US9624220B2 (en) 2010-04-01 2017-04-18 Critical Outcome Technologies Inc. Compounds and method for treatment of HIV
WO2013190520A2 (en) 2012-06-22 2013-12-27 The General Hospital Corporation Gh-releasing agents in the treatment of vascular stenosis and associated conditions
US10105416B2 (en) 2014-02-05 2018-10-23 The Regents Of The University Of California Methods of treating mild brain injury
US10617740B2 (en) 2014-02-05 2020-04-14 The Regents Of The University Of California Methods of treating mild brain injury
US11241483B2 (en) 2014-02-05 2022-02-08 The Regents Of The University Of California Methods of treating mild brain injury
WO2017075535A1 (en) 2015-10-28 2017-05-04 Oxeia Biopharmaceuticals, Inc. Methods of treating neurodegenerative conditions

Also Published As

Publication number Publication date
IL122371A0 (en) 1998-06-15
PL324200A1 (en) 1998-05-11
TW458958B (en) 2001-10-11
CZ287948B6 (cs) 2001-03-14
JPH11507928A (ja) 1999-07-13
KR19990028303A (ko) 1999-04-15
JP4173541B2 (ja) 2008-10-29
HUP9802821A2 (hu) 1999-03-29
CA2224434A1 (en) 1997-01-09
NO975992L (no) 1998-02-20
HUP9802821A3 (en) 2000-03-28
NO975992D0 (no) 1997-12-19
PL186520B1 (pl) 2004-01-30
AU711104B2 (en) 1999-10-07
BR9608909A (pt) 1999-03-02
MX9710377A (es) 1998-03-29
AU6188296A (en) 1997-01-22
EP0833845A1 (en) 1998-04-08
CZ408197A3 (cs) 1998-05-13

Similar Documents

Publication Publication Date Title
AU711104B2 (en) Compounds with growth hormone releasing properties
US5767085A (en) Compounds with growth hormone releasing properties
US5854211A (en) Compounds with growth hormone releasing properties
US5990084A (en) Compounds with growth hormone releasing properties
KR20010043422A (ko) 성장호르몬 방출성을 가진 화합물
WO1997040071A1 (en) Compounds with growth hormone releasing properties
WO1996024580A1 (en) Compounds with growth hormone releasing properties
WO1996024587A1 (en) Compounds with growth hormone releasing properties
JP2003504369A (ja) アミドスピロピペリジン類による成長ホルモン放出の促進
JP2002509156A (ja) 成長ホルモン放出特性を有する化合物
JP4173541B6 (ja) 成長ホルモン放出特性を有する化合物
MXPA97010377A (en) Compounds with releasing properties of growth hormone
EP1093463A1 (en) A method for preparing a compound with growth hormone releasing properties

Legal Events

Date Code Title Description
WWE Wipo information: entry into national phase

Ref document number: 96194947.3

Country of ref document: CN

AK Designated states

Kind code of ref document: A1

Designated state(s): AL AM AT AU AZ BB BG BR BY CA CH CN CZ DE DK EE ES FI GB GE HU IL IS JP KE KG KP KR KZ LK LR LS LT LU LV MD MG MK MN MW MX NO NZ PL PT RO RU SD SE SG SI SK TJ TM TR TT UA UG US UZ VN AM AZ BY KG KZ MD RU TJ TM

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): KE LS MW SD SZ UG AT BE CH DE DK ES FI FR GB GR IE IT LU MC NL PT SE BF BJ CF CG CI CM GA

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
WWE Wipo information: entry into national phase

Ref document number: 1996920742

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2224434

Country of ref document: CA

Ref document number: 2224434

Country of ref document: CA

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: PV1997-4081

Country of ref document: CZ

WWE Wipo information: entry into national phase

Ref document number: PA/a/1997/010377

Country of ref document: MX

ENP Entry into the national phase

Ref document number: 1997 503521

Country of ref document: JP

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 1019970709617

Country of ref document: KR

WWP Wipo information: published in national office

Ref document number: 1996920742

Country of ref document: EP

REG Reference to national code

Ref country code: DE

Ref legal event code: 8642

WWP Wipo information: published in national office

Ref document number: PV1997-4081

Country of ref document: CZ

WWP Wipo information: published in national office

Ref document number: 1019970709617

Country of ref document: KR

WWG Wipo information: grant in national office

Ref document number: PV1997-4081

Country of ref document: CZ

WWR Wipo information: refused in national office

Ref document number: 1019970709617

Country of ref document: KR