EP0910579A1 - Composes capables de liberer une hormone de croissance - Google Patents
Composes capables de liberer une hormone de croissanceInfo
- Publication number
- EP0910579A1 EP0910579A1 EP97919296A EP97919296A EP0910579A1 EP 0910579 A1 EP0910579 A1 EP 0910579A1 EP 97919296 A EP97919296 A EP 97919296A EP 97919296 A EP97919296 A EP 97919296A EP 0910579 A1 EP0910579 A1 EP 0910579A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- residue
- acid
- alanine
- lysine
- glutamine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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- 201000006370 kidney failure Diseases 0.000 claims 2
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- 125000001637 1-naphthyl group Chemical group [H]C1=C([H])C([H])=C2C(*)=C([H])C([H])=C([H])C2=C1[H] 0.000 claims 1
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- 230000007423 decrease Effects 0.000 claims 1
- 230000002950 deficient Effects 0.000 claims 1
- 230000003111 delayed effect Effects 0.000 claims 1
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- 150000002148 esters Chemical class 0.000 claims 1
- FPIQZBQZKBKLEI-UHFFFAOYSA-N ethyl 1-[[2-chloroethyl(nitroso)carbamoyl]amino]cyclohexane-1-carboxylate Chemical compound ClCCN(N=O)C(=O)NC1(C(=O)OCC)CCCCC1 FPIQZBQZKBKLEI-UHFFFAOYSA-N 0.000 claims 1
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- 239000003862 glucocorticoid Substances 0.000 claims 1
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- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims 1
- 230000003451 hyperinsulinaemic effect Effects 0.000 claims 1
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- 125000002883 imidazolyl group Chemical group 0.000 claims 1
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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
- 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
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P19/00—Drugs for skeletal disorders
- A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
- A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
-
- 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
-
- 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 compounds, 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.
- 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) and inhibited by somatostatin. In both cases 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.
- GHRH growth hormone releasing hormone
- somatostatin somatostatin
- arginine, L-3,4-dihydroxyphenylalanine (L-Dopa), giucagon, vasopressin, PACAP (pituitary adenylyl cyclase activating peptide), muscarinic receptor agonists and a synthethic hexapeptide, GHRP (growth hormone releasing peptide) release endogenous growth hormone either by a direct effect on the pituitary or by affecting the release of GHRH and/or somatostatin from the hypothalamus.
- the protein nature of growth hormone makes anything but parenteral administration non-viable.
- other directly acting natural secretagogues e.g., GHRH and PACAP, are longer polypeptides for which reason oral administration of them is not viable.
- composition of growth hormone releasing compounds is important for their growth hormone releasing potency as well as their bioavailability. It is therefore an object of the present invention to provide novel compounds with growth hormone releasing properties.
- the present invention relates to compounds of the general formula I
- K, M, A, B, C, D, E, F, G, N, L, x, w, z and y are as defined below.
- the compounds of formula I have the ability to stimulate synthesis and/or release of endogenous growth hormone.
- these compounds can be used in the treatment of conditions which require stimulation of growth hormone production or secretion such as in humans with growth hormone deficiency or were increased growth hormone plasma levels is desired like in the elderly or in animals used for food production.
- the present invention relates to a compound of the general formula I
- a and D are independently a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula II
- Q 1 is -CH 2 - or -CO-
- I 1 ,q 1 and r 1 are independently 0, 1 , 2, 3, 4, 5, or 6,
- X 1 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C L g-dialkylamino, C L ⁇ -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C L g-dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C, . 6 -alkoxy, C 1 6 -alkyl group, or a valence bond,
- Y 1 is hydrogen, a C 1-6 -alkyl group, or a valence bond to X 1 or T
- T is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C L g-alkylmercapto, arylmercapto, guanidino, amidino, amino, C ⁇ -dialkylamino, C ⁇ -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C 1 6 -alkylamino, amidino, guanidino, C,. 6 -alkoxy, C ⁇ -alky! group, or a valence bond,
- B, C, E, F are independently a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
- X 2 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ e-alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C ⁇ -dialkylamino, C ⁇ -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C L e-alkylamino, amidino, guanidino, C v e -alkoxy, C ⁇ -alkyl group, or a valence bond,
- Y 2 is hydrogen, a C ⁇ -alkyl group, or a valence bond to X 2 or Z 2 ,
- Z 2 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C L ⁇ -dialkylamino, C L ⁇ -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C, . 6 -alkoxy, C ⁇ -alkyl group, or a valence bond;
- non-proteinogenic amino acids dehydroalanine, anthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic, 4-aminobutyric acid, beta-alanine, 3-amino-1 ,2,4-thazole-5- carboxylic acid, 1 ,2,3,4-tetrahyroisoquinoline-3-carboxylic acid, aminobiphenyl- carboxylic acids, pipecolic acid, nipecotinic acid, isonipecotinic acid, statine, 4- amino-3-hydroxybutyric acid, aminohexanoic acid, 2-amino-2-thiazoline-4- carboxylic acid, 1,2,3,4-tetrahyronorharman-3-carboxylic acid, 3-amino-3-methyl- benzoic acid, 3-aminomethylbutanoic acid, 5-aminopentanoic acid, 2-amino
- G is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula IV
- q 3 and r 3 are independently 0, 1 , 2, 3, 4, 5, or 6,
- X 3 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C 1 6 -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C L g-dialkylamino, C 1 6 -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C,_ 6 -alkoxy, C ⁇ -alky! group, or a valence bond,
- Y 3 is hydrogen, a C ⁇ -alky! group, or a valence bond to X 3 or Z 3 ,
- Z 3 is hydrogen, or a C ⁇ -alky! group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C L ⁇ -dialkylamino, C ⁇ -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C, . ⁇ -alkoxy, C ⁇ -alky! group, or a valence bond,
- M is an amino acid residue, a dipeptide residue, a tripeptide residue, a tetrapeptide residue, a pentapeptide residue, a hexapeptide residue, a heptapeptide residue, a octapeptide residue, a nonapeptide residue, a decapeptide residue, a undecapeptide residue, a dodecapeptide residue or a tredecapeptide residue, wherein the amino acid residues are independently any non-proteinogenic or proteinogenic alpha amino acid residue of the general formula V
- I 4 , q 4 and r 4 are independently 0, 1 , 2, 3, 4, 5, or 6,
- X 4 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C L ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C ⁇ -dialkylamino, C L g-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C,. 6 -alkoxy, C ⁇ -alkyl group, or a valence bond,
- Y 4 is hydrogen, a C ⁇ -alky! group, or a valence bond to X 4 or Z 4 ,
- Z 4 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C L g-dialkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C 1 . 6 -dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C,. e-alkoxy, C ⁇ -alkyl group, or a valence bond;
- non-proteinogenic amino acids dehydroalanine, anthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic, 4-aminobutyric acid, beta-alanine, 3-amino-1 ,2,4-triazole-5- carboxylic acid, 1 ,2,3,4-tetrahyroisoquinoiine-3-carboxylic acid, aminobiphenyl- carboxylic acids, pipecolic acid, nipecotinic acid, isonipecotinic acid, statine, 4- amino-3-hydroxybutyric acid, aminohexanoic acid, 2-amino-2-thiazoline-4- carboxylic acid, 1,2,3,4-tetrahyronorharman-3-carboxylic acid, 3-amino-3-methyl- benzoic acid, 3-aminomethylbutanoic acid, 5-aminopentanoic acid, 2-amin
- N is an amino acid residue, a dipeptide residue, an oligopeptide residue or an oligoamide residue which is between 1 to 10 amino acid residues long wherein the amino acid residues independently are any non-proteinogenic or proteinogenic alpha-amino acid residue of the general formula VI
- X 5 is hydrogen, or a C ⁇ -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C ⁇ -dialkylamino, C L e-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ e-dialkylamino, C ⁇ -alkylamino, amidino, guanidino, C v 6 -alkoxy, C ⁇ -alkyl group, or a valence bond,
- Y 5 is hydrogen, a C ⁇ -alkyl group, or a valence bond to X 5 or Z 5 ,
- Z 5 is hydrogen, or a C.,. 6 -alkyl group optionally substituted with a halogen, hydroxy, C ⁇ -alkoxy, aryloxy, mercapto, C ⁇ -alkylmercapto, arylmercapto, guanidino, amidino, amino, C L ⁇ -dialkylamino, C L ⁇ -alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C ⁇ -dialkylamino, C L ⁇ -alkylamino, amidino, guanidino, C ⁇ ⁇ -alkoxy, C ⁇ -alkyl group, or a valence bond; or the residues of any of the following, non-proteinogenic amino acids (R- and S- isomer for chiral amino acids) dehydroalanine, anthranilic acid, 3-
- the total number of amino acid residues of N and M is equal to or less than 17;
- x and y are independently 0 or 1 ;
- u 1 and s 1 are independently 0, 1 , or 2
- t 1 and p 1 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
- p 2 is 1 , 2, 3, 4, or 5, s 2 is independently 0 or 1 ;
- K is W 1 -(CH 2 ) v 1-CO- , or W z -(CH 2 ) v 2-NH-CO- , or W 3 -(CH 2 ) v 3-O-CO- , or W 4 - (CH 2 ) v 4-SO 2 -,
- v 1 , v 2 , v 3 and v 4 independently are 0, 1, 2, 3, 4, 5, or 6, W ⁇ W 2 , W 3 and W 4 independently are hydrogen, or a hydroxy, C v6 -alkyl, aryl, amino group;
- u 3 and s 3 are independently 0, 1 , or 2
- t 3 and p 3 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
- u 4 and s 4 are independently 0, 1 , or 2
- t 4 and p 4 are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
- L is -O-(CH 2 ) p 5 -W 5 ,
- W 5 is hydrogen, or a hydroxy, C ⁇ -alky!, aryl, amino group
- p 6 and p 7 are independently 0, 1 , 2, 3, 4, 5, or 6,
- p 8 is 0 or 1 ,
- W 3 and W 7 are independently hydrogen, or a hydroxy, C ⁇ -alky!, aryl, amino group, or a valence bond;
- u 9 and s 9 are independently 0, 1 or 2
- t 9 and p 9 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
- A is a non-proteinogenic or proteinogenic amino acid of the general formula II
- I 1 and r 1 are 0 , q 1 is 0, 1, 2, 3, or 4,
- X 1 is hydrogen, isopropyl, tert. butyl, phenyl, cyclopropyl, cyclohexyl, 2- hydroxyethyl, or amino,
- Y 1 is hydrogen, or methyl
- Z 1 is hydrogen
- A is the residue of leucine, isoleucine, valine, phenylalanine, cyclohexylalanine or homophenylalanine, more preferably leucine.
- B is a non-proteinogenic or proteinogenic alpha amino acid residue ofthe general fo ⁇ nula III
- I 2 and r 2 are 0, q 2 is 0, 1 , 2, 3, or 4,
- X 2 is hydrogen, phenyl, amino, guanidino, hydroxy, isopropyl, carboxy
- Y 2 is hydrogen, or methyl
- Z 2 is hydrogen, or the residue of any of the following, non-proteinogenic amino acids; dehydroalanine, anthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic, 4- aminobutyric acid, beta-alanine, cis- and trans 2-aminocyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid or 4-aminomethylbenzoic acid;
- B is the residue of glycine, alanine, serine, lysine, ornithine, arginine, glutamic acid or aspartic acid, more preferably alanine.
- C is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
- X 2 is hydrogen, imidazolyl, phenyl, amino, hydroxy, isopropyl, carboxy, aminocarbonyl, or guanidino,
- Y 2 is hydrogen or methyl
- Z 2 is hydrogen
- C is the residue of lysine, glutamine, glutamic acid, asparagine, aspartic acid, arginine, ornithine, serine or histidine, more preferably glutamine or ornithine.
- D is a non-proteinogenic or proteinogenic amino acid of the general formula II
- I 1 and r 1 are 0 , q 1 is 0, 1 , 2, 3, or 4,
- X 1 is hydrogen, isopropyl, tert. butyl, phenyl, cyclopropyl, cyclohexyl, 2- hydroxyethyl, or amino,
- Y 1 is hydrogen, or methyl
- Z 1 is hydrogen
- D is the residue of leucine, isoleucine, valine, phenylalanine, cyclohexylalanine or homophenylalanine, more preferably leucine.
- E is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
- I 2 and r 2 are 0, q 2 is 0, 1 , 2, 3, or 4,
- X 2 is hydrogen, phenyl, amino, guanidino, hydroxy, isopropyl, carboxy,
- Y 2 is hydrogen, or methyl
- Z 2 is hydrogen
- non-proteinogenic amino acids dehydroalanine, anthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic, 4- aminobutyric acid, beta-alanine, cis- and trans 2-aminocyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid or 4-aminomethylbenzoic acid;
- E is the residue of glycine, alanine, serine, threonine, tyrosine, lysine, ornithine, glutamic acid, aspartic acid, homoarginine or arginine, more preferably serine.
- F is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
- I 2 and r 2 are 0, q 2 is 0, 1 , 2, 3, or 4,
- X 2 is hydrogen, phenyl, amino, hydroxy, isopropyl, carboxy, aminocarbonyl.or guanidino,
- Y 2 is hydrogen or methyl
- Z 2 is hydrogen
- F is the residue of alanine, phenylalanine, glycine, serine, valine, lysine, glutamine, glutamic acid, asparagine, aspartic acid or arginine, more preferably alanine.
- G is a non-proteinogenic or proteinogenic amino acid residue of the general formula IV
- X 2 is amino, methylamino, dimethylamino, amidino, benzamidino, guanidino, imidazolyl, hydroxy, aminocarbonyl,
- Y 2 is hydrogen or methyl
- Z 2 is hydrogen
- G is the residue of arginine, lysine, glutamine, ornithine, histidine, serine or asparagine, more preferably arginine.
- M is the residue of valine, isoleucine, leucine, penicillamine, lysine, glutamic acid, glutamine, aspartic acid, arginine, alanine, cysteine, homocysteine, leucine, isoleucine, methionine, ornithine, phenylalanine or threonine, preferably valine.
- M is a dipeptide residue and the amino acid residue in the aminoterminal position of the dipeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, glutamic acid, aspartic acid, asparagine, cysteine or serine, preferably lysine, aspartic acid or ornithine, the amino acid residue in the second position of the dipeptide residue is the residue of valine, isoleucine, leucine, penicillamine, lysine, cysteine, glutamic acid, glutamine, aspartic acid, arginine, alanine, homocysteine, leucine, isoleucine, methionine, ornithine, phenylalanine or threonine, preferably valine.
- M is a tripeptide residue and the amino acid residue in the aminoterminal position of the tripeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-aminophenylalanine, 4-guanidino- phenylalanine or asparagine, preferably arginine, the amino acid residue in the second position of the tripeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, glutamic acid, aspartic acid, asparagine, cysteine or serine, preferably lysine, ornithine or aspartic acid, the amino acid residue in the third position of the dipeptide residue is the residue of valine, isoleucine, leucine, penicillamine, lysine, cysteine, gluta
- M is a tetrapeptide residue and the amino acid residue in the aminoterminal position of the tetrapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthylalanine, 2-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the second position of the tetrapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4- aminophenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the third position of the tetrapeptide residue is the residue of lysine,
- M is a pentapeptide residue and the amino acid residue in the aminoterminal position of the pentapeptide residue is the residue of serine, alanine, cysteine, threonine, lysine, valine, asparagine, aspartic acid, glutamine or glutamic acid, preferably alanine, the amino acid residue in the second position of the pentapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1- naphthylalanine, 2-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the third position of the pentapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspart
- M is a hexapeptide residue and the amino acid residue in the aminoterminal position of the hexapeptide residue is the residue of asparagine, aspartic acid, glutamine, glutamic acid, serine, lysine, alanine, threonine, cysteine or ornithine, preferably aspartic acid, glutamine or ornithine, the amino acid residue in the second position of the hexapeptide residue is the residue of serine, alanine, cysteine, threonine, lysine, valine, asparagine, aspartic acid, glutamine or glutamic acid, preferably alanine, the amino acid residue in the third position of the hexapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthyl ⁇ alanine, 2-nap
- M is a heptapeptide residue and the amino acid residue in the aminoterminal position of the heptapeptide is the residue of threonine, serine, lysine, methionine, leucine, isoleucine, alanine, asparagine, glutamine, aspartic acid, glutamic acid, cysteine or histidine, preferably threonine, the amino acid residue in the second position of the heptapeptide residue is the residue of asparagine, aspartic acid, glutamine, glutamic acid, serine, lysine, alanine, threonine, cysteine or ornithine, preferably aspartic acid, glutamine or ornithine, the amino acid residue in the third position of the heptapeptide residue is the residue of serine, alanine, cysteine, threonine, lysine, valine, asparagine, aspartic acid
- M is an octapeptide residue and the amino acid residue in the aminoterminal position of the octapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1- naphthylalanine, 2-naphthylalanine, cyclohexylalanine or lysine, preferably phenylalanine, the amino acid residue in the second position of the octapeptide residue is the residue of threonine, serine, lysine, methionine, leucine, isoleucine, alanine, asparagine, glutamine, aspartic acid, glutamic acid, cysteine or histidine, preferably threonine, the amino acid residue in the third position of the octapeptide residue is the residue of asparagine, aspartic acid, glutamine, glutamic acid, serine, lysine,
- M is a nonapeptide residue and the amino acid residue in the aminoterminal position of the nonapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the second position of the nonapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthylalanine, cyclohexyl- alanine or lysine, preferably phenylalanine, the amino acid residue in the third position of the nonapeptide residue is the residue of threonine, serine, lysine, methionine, leucine, isoleucine, alanine, asparagine, glutamine, aspartic acid, glutamic acid, cysteine
- M is a decapeptide residue and the amino acid residue in the aminoterminal position of the decapeptide residue is the residue of alanine, valine, serine, leucine, lysine, threonine, glycine, glutamine, asparagine or histidine, preferably alanine or asparagine, the amino acid residue in the second position of the decapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the third position of the decapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthylalanine, cyclohexylalanine or lysine, preferably phenylalanine, the amino acid residue in the aminoterminal position of the decapeptid
- M is an undecapeptide residue and the amino acid residue in the aminoterminal position of the undecapeptide residue is the residue of asparagine, glutamine, serine, aspartic acid, glutamic acid, lysine, alanine, threonine, methionine, arginine, histidine or leucine, preferably aspartic acid, the amino acid residue in the second position of the undecapeptide residue is the residue of alanine, valine, serine, leucine, lysine, threonine, glycine, glutamine, asparagine or histidine, preferably alanine or asparagine, the amino acid residue in the third position of the undecapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the fourth position of the undecapeptide residue is the residue of asparagine, glut
- M is an dodecapeptide residue and the amino acid residue in the aminoterminal position of the dodecapeptide residue is the residue of alanine, valine, leucine, serine, threonine, lysine, cysteine, glutamine, glutamic acid, asparagine, aspartic acid, glycine, N- methylalanine or histidine, preferably alanine or N-methylalanine, the amino acid residue in the second position of the dodecapeptide residue is the residue of asparagine, glutamine, serine, aspartic acid, glutamic acid, lysine, alanine, threonine, methionine, arginine, histidine or leucine, preferably aspartic acid, the amino acid residue in the third position of the dodecapeptide residue is the residue of alanine, valine, serine, leucine, lysine, threonine, gly
- M is an tredecapeptide residue and the amino acid residue in the aminoterminal position of the tredecapeptide residue is the residue of tyrosine, histidine, phenylalanine, tryptophane, lysine, 1 -naphthylalanine, 2-naphthylalanine, biphenylalanine, glutamine or asparagine, preferably tyrosine, the amino acid residue in the second position of the tredecapeptide residue is the residue of alanine, valine, leucine, serine, threonine, lysine, cysteine, glutamine, glutamic acid, asparagine, asparticacid, glycine, N-methylalanine or histidine, preferably alanine or N-methyl- alanine, the amino acid residue in the third position of the tredecapeptide residue is the residue of asparagine, glutamine, serine,
- N is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably histidine or lysine.
- N is a dipeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably lysine or histidine, the amino acid residue in the carboxyterminal position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine.
- N is a tripeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably lysine or histidine
- the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine
- the amino acid residue in the carboxyterminal position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid
- N is a tetrapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably lysine or histidine
- the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine
- the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid
- N is a pentapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably lysine or histidine
- the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine
- the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid,
- N is a hexapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably lysine or histidine
- the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine
- the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid
- N is a heptapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably histidine or lysine, the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid
- N is an octapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably histidine or lysine, the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid
- N is a nonapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably histidine or lysine, the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cyst
- N is a decapeptide residue and the amino acid residue in the first position is the residue of lysine, histidine, ornithine, arginine, glutamine, glutamic acid, aspartic acid, asparagine, serine, alanine, cysteine, tyrosine, tryptophane, phenylalanine or homocysteine, preferably lysine or histidine
- the amino acid residue in the second position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine
- the amino acid residue in the third position is the residue of leucine, alanine, cyclohexylalanine, glutamic acid, lysine, aspartic acid, cyst
- K is hydrogen or a group of formula W 1 -(CH 2 ) v 1-CO-, wherein W 1 is hydrogen, hydroxy or C ⁇ -alkyl, preferably hydrogen, and v 1 is 0, 1 , 2, 3 or 4, preferably 1.
- p 6 and p 7 independently are 0, 1 or 2, preferably 0; W 6 is hydrogen, hydroxy or C ⁇ -alkyl, preferably hydrogen; p 8 is 0 or 1 , preferably 0; W 7 is hydrogen, hydroxy or C,. 6 -alkyl, preferably hydrogen.
- Preferred compounds of the invention are:
- rat and human GHRH receptor display different structure activity relations for the human GHRH (hGHRH) peptide.
- hGHRH human GHRH
- the analogs activates the GHRH receptor, but does not have the disadvantages of GHRH.
- An advantage of these truncated analogs is their improved metabolic stability. Further the truncated analogs may offer advantages with respect to prolonged or modified duration of action, decreased immunogenicity, selectivity/side effects and lower cost of production.
- the C ⁇ -alkyl residues specified above are intended to include those alkyl residues 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 C 3 . 6 -cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
- the C ⁇ -alkoxy residues specified above are intended to include those alkoxy residues 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.
- cyclic alkoxy are cyclo- propyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
- 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.
- Aryl is preferably phenyl, thienyl, imidazolyl, pyridyl, indolyl, oxadiazole, quinoline or naphthyl.
- halogen is intended to include chlorine (Cl), fluorine (F), bromine (Br) and iodine (I).
- the compounds of the present invention may have one or more asymmetric centres and it is intended that stereoisomers, as separated, pure or partially purified stereoisomers or racemic mixtures thereof are included in the scope of the invention.
- the compounds of the present invention may optionally be on a pharmaceutically acceptable salt form such as the pharmaceutically acceptable acid addition salts of compounds of formula I which include those prepared by reacting the compound of formula I with an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumaric acid.
- an inorganic or organic acid such as hydrochloric, hydrobromic, sulfuric, acetic, phosphoric, lactic, maleic, phthalic, citric, glutaric, gluconic, methanesulfonic, salicylic, succinic, tartaric, toluenesulfonic, trifluoracetic, sulfamic or fumaric acid.
- 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 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 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 or 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.
- 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.
- a typical tablet which may be prepared by conventional tabletting techniques may contain: Core:
- Active compound (as free compound or salt thereof) 100mg
- the preparation may contain a compound of formula I dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application.
- a liquid carrier in particular an aqueous carrier
- the carrier may contain additives such as solubilizing agents, e.g. propylene glycol, surfactants, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
- the compounds of the present invention are dispensed in unit dosage form comprising 50-200 mg of active ingredient together with a pharmaceutically acceptable carrier per unit dosage.
- the dosage of the compounds according to this invention is suitably 0.1-500 mg/day, e.g. from about 5 to about 50 mg, such as about 10 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.
- growth hormone may be summarized as follows: stimulation of growth hormone release in the elderly; prevention of catabolic side effects of glucocorticoids, prevention and 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, Noonan's syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation, treatment of pulmonary dysfunction and ventilator dependency, attenuation of protein
- dosage levels between 0.0001 and 100 mg/kg body weight daily are administered to patients and animals to obtain effective release of endogenous growth hormone.
- dosage forms suitable for oral, nasal, pulmonal or transdermal 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 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.
- 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.
- growth hormone releasing hormones of formula I may be useful in vitro tools for investigating the regulation of growth hormone release.
- the compounds of Formula I are also 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.
- the compounds of Formula I can be administered to commercially important animals to increase their rate and extent of growth, and to increase milk production.
- the present invention include within its scope pharmaceutical compositions comprising, as an active ingredient, at least one of the compounds of Formula I in association with a pharmaceutical carrier or diluent.
- the pharmaceutical composition can comprise at least one of the compounds of Formula I combined with compounds exhibiting a different activity, e.g., an antibiotic or other pharmacologically active material.
- a further use of the compounds of Formula I is in combination with other secretagogues like GHRP's, such as GHRP (2 or 6), growth hormone and its analogues or somatomedins including IGF-1 and IGF-2.
- dosage will vary depending on the compound of Formula I employed, on the mode of administration and on the therapy desired. However, generally dose levels between 0.0001 to 100 mg/kg body weight daily are administered to patients and animals to obtain effective release of endogenous growth hormone.
- the route of administration may be any route which affectively transports the active compound to the appropriate or desired site of action, such as oral or parenteral, the oral route being the preferred.
- the cell pellet was homogenized in 10 mM Tris-acetate buffer
- the cell pellet was processed and assay performed as described previously for Dopamine D1 receptors in Pedersen et al., Eur. J. Pharmacol. 267, 85-93, 1994.
- Rat primary somatotrophs were prepared essentially as described previously (Chen et al., Endocrinology 129, 3337-3342, 1991 and Chen et al., Endocrinology, 124, 2791-2798, 1989). Briefly, rats were killed by decapitation. The pituitary were quickly removed. The pituitaries were digested with 0.2 % collagenase n 0.2% hyaluronidase in Hanks balanced salt solution.
- the cells were resuspended in Dulbecco@s modified eagles medium containing 0.37 % NaHCO 2 , 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % pen/strep and adjusted to 1.5x10 5 cells/ ml.
- Dulbecco@s modified eagles medium containing 0.37 % NaHCO 2 , 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % pen/strep and adjusted to 1.5x10 5 cells/ ml.
- One ml of this suspension was placed in each well of 24-well trays and left for 2-3 days before release experiments were performed.
- Linear peptides were synthesized with an ABI 431A peptide synthesizer using standard protocols according to the Fmoc SPPS strategy (as substantially described by Fields et al., Int. J. Pept. Protein Res. 35, 1990, 161) on Rink amide polystyrene resin [4-((4 ⁇ 2'-dimethoxyphenyl)-(Fmoc-amino)methyl)-phenoxy resin, e.g. Novabiochem, Bad Soden, Germany, cat.# 01-64-0013].
- the peptides were cleaved from resin using standard cleavage cocktails containing a mixture of trifluoroactic acid and common scavengers (e.g., a mixture of trifluoroacetic acid (4 mL), phenol (300 mg), ethanedithiol (0.10 mL), thioanisole (0.20 mL) and water (0.20 mL), or as substantially described in the "novabiochem catalog and Peptide Synthesis Handbook" 94/95 on pages S34 to S36 and in references 1 to 15 listed on page S39).
- a mixture of trifluoroactic acid and common scavengers e.g., a mixture of trifluoroacetic acid (4 mL), phenol (300 mg), ethanedithiol (0.10 mL), thioanisole (0.20 mL) and water (0.20 mL
- the cleavage mixture was concentrated to 1 mL using a stream of nitrogen, and the crude peptides were precipitated from this oil with diethyl ether (45 mL), washed with diethyl ether ( 3 portions of 50 mL) and dried.
- Linear peptides were synthesized using standard protocols according to the Fmoc SPPS strategy (as substantially described by Fields et al., Int. J. Pept. Protein Res. 35, 1990, 161) and to method 1 on either an Abimed 422 MPS, Milligen 9050 continuous flow, or ACT Model 90 2 vessel machine.
- the peptides were cleaved from resin using standard cleavage cocktails containing a mixture of trifluoroactic acid and common scavengers (similar to method 1 , or as substantially described in the "novabiochem catalog and Peptide Synthesis Handbook" 94/95 on pages S34 to S36 and in references 1 to 15 listed on page S39). Subsequently, the cleavage mixture was concentrated, and the crude peptides were precipitated with diethyl ether and dried, similar to method 1.
- Cyclic peptides by sidechain to sidechain cyclization from an amino to a carboxy group were synthesized using 4-methylbenzhydryl (MBHA) polystyrene resin and an ABI 430 peptide synthesizer employing standard protocols according to the Boc SPPS strategy (e.g, as substantially described by Stewart and Young, Solid Phase Peptide Synthesis. 2nd ed., Rockford, Illinois, USA, 1976).
- sidechain functionalities intended for cyclization were protected using a base-labile protecting group (Fmoc-protection for amino groups, fluorenylmethylester-protection for carboxy groups, as described in T.W. Greene, P.G.M. Wuts, Protective Groups in Organic Synthesis.
- the amino group in the sidechain can be acylated with an Fmoc protected spacer amino acid (e.g., FmocGly); subsequently, the amino group of the spacer amino acid can be used for formation of the amide bond with the sidechain functionality of glutamic acid or aspartic acid.
- Fmoc protected spacer amino acid e.g., FmocGly
- the amino group of the spacer amino acid can be used for formation of the amide bond with the sidechain functionality of glutamic acid or aspartic acid.
- the crude peptide was dried and purified by HPLC on a 20 mm x 250 mm column packed with 7 ⁇ C-18 silica which was preequilibrated with 15% CH 3 CN in 0.05 M (NH 4 ) 2 SO 4 , which was adjusted to pH 2.5 with 4 M H 2 SO 4 .
- the crude peptide was dissolved in 2 mL 70% CH 3 CN / 0.1% TFA in H 2 O and diluted to 100 mL with H 2 O. This solution was divided into two equal portions and each of them were injected on the column in two separate runs.
- the column was eluted with a gradient of 15% - 25% CH 3 CN in 0.05 M (NH 4 ) 2 SO 4 , pH 2.5 at 10 mL/min during 47 min at 40°C.
- the peptide-containing fractions were collected, diluted with 3 volumes of H 2 O and applied to a Sep-Pak ® C18 cartrtidge (Waters part. #:51910) which was equilibrated with 0.1% TFA / H 2 O.
- the peptide was eluted from the Sep-Pak ® cartridge with 70% CH 3 CN / 0.1% TFA / H 2 O and isolated from the eluate after dilution with water.
- the final product obtained was characterized by analytical RP-HPLC (retention time) and by plasma desorption mass spectrometry (molecular mass). Mass spectrometry ageed with the expected structure within the experimental error of the method.
- the RP-HPLC analysis was performed using UV-detection at 214 nm and a Vydac 218TP544.6 mm x 250 mm 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:
- Cyclo(Glu 9 -Lys 13 ) means that the sidechains of Glu 9 and Lys 13 are connected by an amide bond under formation of a cyclic structure
- Cyclo(Lys 5 -Glu 9 ) means that the sidechains of Lys 5 and Glu 9 are connected by an amide bond under formation of a cyclic structure
- Cyclo(Asp 1 -[Gly]-Orn 5 ) means that the sidechain of Asp 1 is connected by an amide bond to the amino group of Gly by an amide bond and that the carboxylate of Gly is connected by an amide bond to the amino group of Orn 5 under formation of a cyclic structure;
- Cyclo(Asp 2 -[Gly]-Orn 6 ) means that the sidechain of Asp 2 is connected by an amide bond to the amino group of Gly by an amide bond and that the carboxylate of Gly is connected by an amide bond to the amino group of Orn 6 under formation of a cyclic structure;
- Cyclo(Asp 6 -[Gly]-Orn 10 ) means that the sidechain of Asp 6 is connected by an amide bond to the amino group of Gly by an amide bond and that the carboxylate of Gly is connected by an amide bond to the amino group of Orn 10 under formation of a cyclic structure;
- Cyclo(Asp 10 -[Gly]-Orn 14 ) means that the sidechain of Asp 10 is connected by an amide bond to the amino group of Gly by an amide bond and that the carboxylate of Gly is connected by an amide bond to the amino group of Orn 14 under formation of a cyclic structure; Cyclo(Lys 4 -Glu 8 ) means that the sidechains of Lys 4 and Glu 8 are connected by an amide bond under formation of a cyclic structure;
- Cyclo(Orn 2 -[COCH 2 ]-Pen 6 ) means that the sidechain of Orn 2 is connected by an amide bond to the carboxylate of an acetic acid moiety and that the methylene group of the acetic acid moiety is connected by a thioether bond to the sulfur atom of Pen 6 under formation of a cyclic structure;
- Cyclo(Lys 3 -Glu 7 ) means that the sidechains of Lys 3 and Glu 7 are connected by an amide bond under formation of a cyclic structure
- Cyclo(Lys 2 -Glu 6 ) means that the sidechains of Lys 2 and Glu 6 are connected by an amide bond under formation of a cyclic structure
- Cyclo(Glu 1 -Lys 5 ) means that the sidechains of Glu 1 and Lys 5 are connected by an amide bond under formation of a cyclic structure.
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Abstract
Cette invention concerne des composés tronqués libérant une hormone de croissance (GHR), lesquels correspondent à la formule générale (I): K-(M)x-A-B-(C)w-D-E-(F)z-G-(N)y-L et sont capables de stimuler la libération d'hormone de croissance endogène.
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK46896 | 1996-04-19 | ||
DK46896 | 1996-04-19 | ||
PCT/DK1997/000175 WO1997040071A1 (fr) | 1996-04-19 | 1997-04-18 | Composes capables de liberer une hormone de croissance |
Publications (1)
Publication Number | Publication Date |
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EP0910579A1 true EP0910579A1 (fr) | 1999-04-28 |
Family
ID=8093893
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP97919296A Withdrawn EP0910579A1 (fr) | 1996-04-19 | 1997-04-18 | Composes capables de liberer une hormone de croissance |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0910579A1 (fr) |
JP (1) | JP2000510453A (fr) |
AU (1) | AU2382097A (fr) |
WO (1) | WO1997040071A1 (fr) |
Families Citing this family (16)
Publication number | Priority date | Publication date | Assignee | Title |
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KR100699404B1 (ko) | 1999-02-18 | 2007-03-23 | 가켄 세야쿠 가부시키가이샤 | 성장 호르몬 분비촉진제로서의 신규 아미드 유도체 |
DE60140285D1 (de) | 2000-05-31 | 2009-12-10 | Pfizer Prod Inc | Verwendung von Wachstumshormonsekretagoga zur Förderung der Beweglichkeit des Verdauungstrakts |
JP4754731B2 (ja) * | 2001-07-31 | 2011-08-24 | コスモ石油株式会社 | 豚成育促進剤及び豚成育促進方法 |
WO2004063221A1 (fr) | 2002-12-26 | 2004-07-29 | Takeda Pharmaceutical Company Limited | Derive de la metastine et son utilisation |
WO2004080479A1 (fr) | 2003-03-12 | 2004-09-23 | Takeda Pharmaceutical Company Limited | Agents ameliorant la fonction gonadique |
US7476653B2 (en) | 2003-06-18 | 2009-01-13 | Tranzyme Pharma, Inc. | Macrocyclic modulators of the ghrelin receptor |
NZ552029A (en) | 2004-06-25 | 2009-01-31 | Takeda Pharmaceutical | Metastin derivatives and use thereof |
US8404643B2 (en) | 2005-12-22 | 2013-03-26 | Takeda Pharmaceutical Company Limited | Metastin derivatives and use thereof |
TWI386417B (zh) | 2005-12-22 | 2013-02-21 | Takeda Pharmaceutical | 轉移抑素衍生物及其用途 |
CU23558A1 (es) | 2006-02-28 | 2010-07-20 | Ct Ingenieria Genetica Biotech | Compuestos análogos a los secretagogos peptidicos de la hormona de crecimiento |
JO3048B1 (ar) | 2006-10-25 | 2016-09-05 | Takeda Pharmaceuticals Co | مشتقات متاستين واستخدامها |
ES2602789T3 (es) | 2007-02-09 | 2017-02-22 | Ocera Therapeutics, Inc. | Productos intermedios conectores para la síntesis de moduladores macrocíclicos del receptor de la grelina |
US9119832B2 (en) | 2014-02-05 | 2015-09-01 | The Regents Of The University Of California | Methods of treating mild brain injury |
WO2017075535A1 (fr) | 2015-10-28 | 2017-05-04 | Oxeia Biopharmaceuticals, Inc. | Méthodes de traitement de troubles neurodégénératifs |
AU2017273857B2 (en) | 2016-06-01 | 2021-08-19 | Athira Pharma, Inc. | Compounds |
US11806405B1 (en) | 2021-07-19 | 2023-11-07 | Zeno Management, Inc. | Immunoconjugates and methods |
Family Cites Families (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4649131A (en) * | 1984-09-24 | 1987-03-10 | Hoffmann-La Roche Inc. | Growth hormone releasing factor analogs |
WO1992018531A1 (fr) * | 1991-04-09 | 1992-10-29 | F. Hoffmann-La Roche Ag | Analogues de somatocrinine |
WO1994011396A1 (fr) * | 1992-11-13 | 1994-05-26 | The Administrators Of The Tulane Educational Fund | Agonistes de l'hormone de liberation de l'hormone de croissance |
-
1997
- 1997-04-18 AU AU23820/97A patent/AU2382097A/en not_active Abandoned
- 1997-04-18 EP EP97919296A patent/EP0910579A1/fr not_active Withdrawn
- 1997-04-18 WO PCT/DK1997/000175 patent/WO1997040071A1/fr not_active Application Discontinuation
- 1997-04-18 JP JP09537615A patent/JP2000510453A/ja active Pending
Non-Patent Citations (1)
Title |
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See references of WO9740071A1 * |
Also Published As
Publication number | Publication date |
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JP2000510453A (ja) | 2000-08-15 |
AU2382097A (en) | 1997-11-12 |
WO1997040071A1 (fr) | 1997-10-30 |
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