EP0910579A1 - Compounds with growth hormone releasing properties - Google Patents

Compounds with growth hormone releasing properties

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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
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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.)
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Application number
EP97919296A
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German (de)
French (fr)
Inventor
Stefan Lutz Richter
Kjeld Madsen
Henning Thoegersen
Nils Langeland Johansen
Annette Hansen
Ole Hvilsted Olsen
Peter Hoengaard Andersen
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Novo Nordisk AS
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Novo Nordisk AS
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Publication of EP0910579A1 publication Critical patent/EP0910579A1/en
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    • 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 factors (GH-RF) (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
    • 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.

Abstract

The present invention relates to truncated GHRs of general formula (I): K-(M)x-A-B-(C)w-D-E-(F)z-G-(N)y-L which have the ability to stimulate release of endogenous growth hormone.

Description

COMPOUNDS WITH GROWTH HORMONE RELEASING PROPERTIES
FIELD OF INVENTION
The present invention relates to novel compounds, compositions containing them, and their use for treating medical disorders resulting from a deficiency in growth hormone.
BACKGROUND OF THE INVENTION
Growth hormone is a hormone which stimulates growth of all tissues capable of growing. In 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) 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. For example 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. In disorders or conditions where increased levels of growth hormone is desired, the protein nature of growth hormone makes anything but parenteral administration non-viable. Furthermore, other directly acting natural secretagogues, e.g., GHRH and PACAP, are longer polypeptides for which reason oral administration of them is not viable.
The use of certain compounds for increasing the levels of growth hormone in mammals has previously been proposed, e.g. in EP 18 072, EP 83 864, WO 89/07110, WO 89/01711 , WO 89/10933, WO 88/9780, WO 83/02272, WO 91/18016, WO 92/01711 , WO 93/04081 , WO 95/17422, WO 95/17423 and WO 95/14666.
The 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.
Summary of the invention
The present invention relates to compounds of the general formula I
K-(M)x-A-B-(C)w-D-E-(F)z-G-(N)y-L (I)
wherein 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. Thus, 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.
Description of the invention
The present invention relates to a compound of the general formula I
K-(M)x-A-B-(C)w-D-E-(F)z-G-(N)y-L (I) wherein z and w are independently 0 or 1 ,
A and D are independently a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula II
(CH2),1
formula II
wherein Q1 is -CH2- or -CO-, I1 ,q1 and r1 are independently 0, 1 , 2, 3, 4, 5, or 6,
X1 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLg-dialkylamino, CLβ-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, CLg-dialkylamino, C^-alkylamino, amidino, guanidino, C,. 6-alkoxy, C1 6-alkyl group, or a valence bond,
Y1 is hydrogen, a C1-6-alkyl group, or a valence bond to X1 or T
T is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, CLg-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, C1 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
(CH2),2
formula
wherein Q2 is -CH2- or -CO-,
|2 q ~22 and r2 are independently 0, 1 , 2, 3, 4, 5, or 6,
X2 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, CLe-alkylamino, amidino, guanidino, Cv e-alkoxy, C^-alkyl group, or a valence bond,
Y2 is hydrogen, a C^-alkyl group, or a valence bond to X2or Z2,
Z2 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLβ-dialkylamino, CLβ-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;
or the residues of any of the following, non-proteinogenic amino acids (R- and S- isomer for chiral 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- thiazoleacetic acid, 2-aminothiopheneacetic acid, cis- and trans 2-amino- cyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid, 4-amino- methylbenzoic acid, aminonaphthoic aicd, aminopenicillanic acid, 3-aminopyrazole- 4-carboxylic acid, 2-amino-4-pentenoic acid, 2-aminothiopheneacetic acid, 3- aminobutyric acid, aminolevulinic acid, 8-aminocaprylic acid;
G is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula IV
(CH2)|3
formula IV
wherein Q3 is -CH,- or -CO-
, q3 and r3 are independently 0, 1 , 2, 3, 4, 5, or 6,
X3 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C1 6-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLg-dialkylamino, C1 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,
Y3 is hydrogen, a C^-alky! group, or a valence bond to X3 or Z3,
Z3 is hydrogen, or a C^-alky! group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLβ-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,. β-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
(CH2),4 formula V
wherein Q4 is -CH2- or -CO-,
I4, q4 and r4 are independently 0, 1 , 2, 3, 4, 5, or 6,
X4 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, CLβ-alkylmercapto, arylmercapto, guanidino, amidino, amino, C^-dialkylamino, CLg-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,
Y4 is hydrogen, a C^-alky! group, or a valence bond to X4 or Z4,
Z4 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLg-dialkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C1.6-dialkylamino, C^-alkylamino, amidino, guanidino, C,. e-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-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-amino- thiazoleacetic acid, 2-aminothiopheneacetic acid, cis- and trans 2-amino- cyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid, 4-amino- methylbenzoic acid, aminonaphthoic aicd, aminopenicillanic acid, 3-aminopyrazole- 4-carboxylic acid, 2-amino-4-pentenoic acid, 2-aminothiopheneacetic acid, 3- aminobutyric acid, aminolevulinic acid, 8-aminocaprylic acid ;
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
(CH2),5 formula VI
wherein Q5 is -CH,- or -CO-
|5 Λ q55 and r5 are independently 0, 1 , 2, 3, 4, 5, or 6,
X5 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, CLe-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, Cv 6-alkoxy, C^-alkyl group, or a valence bond,
Y5 is hydrogen, a C^-alkyl group, or a valence bond to X5 or Z5,
Z5 is hydrogen, or a C.,.6-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLβ-dialkylamino, CLβ-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C^-dialkylamino, CLβ-alkylamino, amidino, guanidino, C^ β-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-aminobenzoic acid, 4-aminobenzoic, 4-aminobutyric acid, beta-alanine, 3-amino-1,2,4-triazole-5- carboxylic acid, 1 ,2,3,4-tetrahyroisoquinoline-3-carboxylic acid, amino- biphenylcarboxyiic acids, pipecolic acid, nipecotinic acid, isonipecotinic acid, statine, 4-amino-3-hydroxybutyric acid, aminohexanoic acid, 2-amino-2-thiazoiine- 4-carboxylic acid, 1 ,2,3,4-tetrahyronorharman-3-carboxylic acid, 3-amino-3- methylbenzoic acid, 3-aminomethylbutanoic acid, 5-aminopentanoic acid, 2-amino- thiazoleacetic acid, 2-aminothiopheneacetic acid, cis- and trans 2-amino- cyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid, 4-amino- methylbenzoic acid, aminonaphthoic aicd, aminopenicillanic acid, 3-aminopyrazole- 4-carboxylic acid, 2-amino-4-ρentenoic acid, 2-aminothiopheneacetic acid, 3- aminobutyric acid, aminolevulinic acid, 8-aminocaprylic acid ;
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 ;
when the sidechain of an amino acid residue of either M, A, B, C, D, E, F, G, or N contains an amino group, it can optionally be connected to a sidechain of an amino acid residue of M, A, B, C, D, E, F, G, or N containing a carboxylic acid group in order to generate a linkage of the general formula VII
-[CO-(CH2)p1 -(aryl)s1 -(CH2)t1 - NH]J -
formula VII
wherein u1 and s1 are independently 0, 1 , or 2, t1 and p1 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
when a sidechain of an amino acid residue of either M, A, B, C, D, E, F, G, or N contains a mercapto group, it can optionally be connected to a side-chain of an amino acid residue of either M, A, B, C, D, E, F, G, or N containing an amino group in order to generate a linkage of the general formula VIII
- (CH2)p2 -(aryl)s2 - CO -
formula VIII
wherein p2 is 1 , 2, 3, 4, or 5, s2 is independently 0 or 1 ;
when a sidechain of an amino acid residue of either M, A, B, C, D, E, F, G, or N contains a mercapto group, it can optionally be connected to the methylene group of a dehydroalanine residue of either M, A, B, C, D, E, F, G, or N in order to generate a thioether linkage;
when the sidechains of two or more amino acid residues of M, A, B, C, D, E, F, G, or N contain a mercapto group, they can optionally be connected in order to generate a disulfide linkage;
K is W1-(CH2)v1-CO- , or Wz-(CH2)v2-NH-CO- , or W3-(CH2)v3-O-CO- , or W4- (CH2)v4-SO2-,
wherein v1, v2, v3 and v4 independently are 0, 1, 2, 3, 4, 5, or 6, W\ W2, W3 and W4 independently are hydrogen, or a hydroxy, Cv6-alkyl, aryl, amino group;
or a linkage to a sidechain of an amino acid residue of M, A, B, C, D, E, F, G, or N containing a carboxylic acid group of the general formula IX
- [CO-(CH2)p3-(aryl)s3- (CH2),3- NH]U3 -
formula IX
wherein u3 and s3 are independently 0, 1 , or 2,
t3 and p3 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
or a linkage joining K and L of the general formula X
- [CO-(CH2)p4 -(aryl)s4 - (CH2)t4 - NH]U4 - formula X
wherein u4 and s4 are independently 0, 1 , or 2,
t4 and p4 are independently 0, 1, 2, 3, 4, 5, 6, 7, or 8;
L is -O-(CH2)p5 -W5,
wherein p5 is 0, 1 , 2, 3, 4, 5, or 6, W5 is hydrogen, or a hydroxy, C^-alky!, aryl, amino group;
or L is
wherein p6 and p7 are independently 0, 1 , 2, 3, 4, 5, or 6,
p8 is 0 or 1 ,
W3 and W7 are independently hydrogen, or a hydroxy, C^-alky!, aryl, amino group, or a valence bond;
or a linkage to an amino group in the sidechain of an amino acid residue of M, A, B, C, D, E, F, G, or N of the general formula XI
- [CO-(CH2)p9 -(aryl)s9 - (CH2)t9 - NH]U9 -
formula XI
wherein u9 and s9 are independently 0, 1 or 2,
t9 and p9 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
or a pharmaceutically acceptable salt thereof.
In one embodiment of the compound of formula (I), A is a non-proteinogenic or proteinogenic amino acid of the general formula II
Z1 (CH2)|1 formula
wherein Q1 is -CH2- or -CO-,
I1 and r1 are 0 , q1 is 0, 1, 2, 3, or 4,
X1 is hydrogen, isopropyl, tert. butyl, phenyl, cyclopropyl, cyclohexyl, 2- hydroxyethyl, or amino,
Y1 is hydrogen, or methyl, and
Z1 is hydrogen;
preferably A is the residue of leucine, isoleucine, valine, phenylalanine, cyclohexylalanine or homophenylalanine, more preferably leucine.
In another embodiment of the compound of formula (I), B is a non-proteinogenic or proteinogenic alpha amino acid residue ofthe general foπnula III
(CH2),2
formula III
wherein Q2 is -CH2- or -CO-,
I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is hydrogen, phenyl, amino, guanidino, hydroxy, isopropyl, carboxy
Y2 is hydrogen, or methyl,
Z2 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;
preferably B is the residue of glycine, alanine, serine, lysine, ornithine, arginine, glutamic acid or aspartic acid, more preferably alanine. In a further embodiment of the compound of formula (I), C is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2
formula III
wherein Q2 is -CH,- or -CO-
P and i^ are O, q2 is 0, 1, 2, 3, or4,
X2 is hydrogen, imidazolyl, phenyl, amino, hydroxy, isopropyl, carboxy, aminocarbonyl, or guanidino,
Y2 is hydrogen or methyl,
Z2 is hydrogen;
preferably C is the residue of lysine, glutamine, glutamic acid, asparagine, aspartic acid, arginine, ornithine, serine or histidine, more preferably glutamine or ornithine. In a further embodiment of the compound of formula (I), D is a non-proteinogenic or proteinogenic amino acid of the general formula II
(CH2),1 formula II wherein Q1 is -CH2- or -CO-,
I1 and r1 are 0 , q1 is 0, 1 , 2, 3, or 4,
X1 is hydrogen, isopropyl, tert. butyl, phenyl, cyclopropyl, cyclohexyl, 2- hydroxyethyl, or amino,
Y1 is hydrogen, or methyl,
Z1 is hydrogen;
preferably D is the residue of leucine, isoleucine, valine, phenylalanine, cyclohexylalanine or homophenylalanine, more preferably leucine.
In a further embodiment of the compound of formula (I), E is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2 formula
wherein Q2 is -CH,- or -CO-
I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is hydrogen, phenyl, amino, guanidino, hydroxy, isopropyl, carboxy,
Y2 is hydrogen, or methyl,
Z2 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;
preferably E is the residue of glycine, alanine, serine, threonine, tyrosine, lysine, ornithine, glutamic acid, aspartic acid, homoarginine or arginine, more preferably serine. In a further embodiment of the compound of formula (I), F is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2
formula
wherein Q2 is -CH,- or -CO-
I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is hydrogen, phenyl, amino, hydroxy, isopropyl, carboxy, aminocarbonyl.or guanidino,
Y2 is hydrogen or methyl,
Z2 is hydrogen;
preferably F is the residue of alanine, phenylalanine, glycine, serine, valine, lysine, glutamine, glutamic acid, asparagine, aspartic acid or arginine, more preferably alanine. In a further embodiment of the compound of formula (I), G is a non-proteinogenic or proteinogenic amino acid residue of the general formula IV
(CH2),3
Formula IV
wherein Q3 is -CH,- or -CO-
and r3 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is amino, methylamino, dimethylamino, amidino, benzamidino, guanidino, imidazolyl, hydroxy, aminocarbonyl,
Y2 is hydrogen or methyl,
Z2 is hydrogen;
preferably G is the residue of arginine, lysine, glutamine, ornithine, histidine, serine or asparagine, more preferably arginine.
In a further embodiment of the compound of formula (I), 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.
In a further embodiment of the compound of formula (I), 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.
In a further embodiment of the compound of formula (I), 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, glutamic acid, glutamine, aspartic acid, arginine, alanine, homocysteine, leucine, isoleucine, methionine, ornithine, phenylalanine or threonine, preferably valine.
In a further embodiment of the compound of formula (I), 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, 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 fourth position of the tetrapeptide 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.
In a further embodiment of the compound of formula (I), 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, aspartic acid, cysteine, 4- aminophenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the fourth position of the pentapeptide 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 fifth position of the pentapeptide 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.
In a further embodiment of the compound of formula (I), 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-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the fourth position of the hexapeptide 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 fifth position of the hexapeptide 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 sixth position of the hexapeptide 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.
In a further embodiment of the compound of formula (I), 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, glutamine or glutamic acid, preferably alanine, the amino acid residue in the fourth position of the heptapeptide 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 fifth position of the heptapeptide 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 sixth position of the heptapeptide 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 seventh position of the heptapeptide 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.
In a further embodiment of the compound of formula (I), 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, alanine, threonine, cysteine or ornithine, preferably aspartic acid, glutamine or ornithine, the amino acid residue in the fourth position of the octapeptide 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 fifth position of the octapeptide 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 sixth position of the octapeptide 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 seventh position of the octapeptide 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 eighth position of the octapeptide 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.
In a further embodiment of the compound of formula (I), 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 or histidine, preferably threonine, the amino acid residue in the fourth position of the nonapeptide 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 fifth position of the nonapeptide 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 sixth position of the nonapeptide 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 seventh position of the nonapeptide 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 eighth position of the nonapeptide 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 ninth position of the nonapeptide 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.
In a further embodiment of the compound of formula (I), 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 fourth position of the decapeptide 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 fifth position of the decapeptide 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 sixth position of the decapeptide 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 seventh position of the decapeptide 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 eighth position of the decapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-amino¬ phenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the ninth position of the decapeptide 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 tenth position of the decapeptide 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.
In a further embodiment of the compound of formula (I), 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 phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthylalanine, cyclohexyl¬ alanine or lysine, preferably phenylalanine, the amino acid residue in the fifth position of the undecapeptide 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 sixth position of the undecapeptide 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 seventh position of the undecapeptide 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 eighth position of the undecapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthylalanine, 2-naphthylalanine, biphenyl¬ alanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in_the ninth position of the undecapeptide 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 tenth position of the undecapeptide 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 eleventh position of the undecapeptide 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.
In a further embodiment of the compound of formula (I), 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, glycine, glutamine, asparagine or histidine, preferably alanine or asparagine, the amino acid residue in the fourth position of the dodecapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the fifth position of the dodecapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthyl- alanine, cyclohexylalanine or lysine, preferably phenylalanine, the amino acid residue in the sixth position of the dodecapeptide 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 seventh position of the dodecapeptide 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 eighth position of the dodecapeptide 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 ninth position of the dodecapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthyl¬ alanine, 2-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the tenth position of the dodecapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-aminophenyl¬ alanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the eleventh position of the dodecapeptide 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 twelvth position of the dodecapeptide 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.
In a further embodiment of the compound of formula (I), 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, aspartic acid, glutamic acid, lysine, alanine, threonine, methionine, arginine, histidine or leucine, preferably aspartic acid, the amino acid residue in the fourth position of the tredecapeptide 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 fifth position of the tredecapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the sixth position of the tredecapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthyl- alanine, cyclohexylalanine or lysine, preferably phenylalanine, the amino acid residue in the seventh position of the tredecapeptide 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 eighth position of the tredecapeptide 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 ninth position of the tredecapeptide 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 tenth position of the tredecapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthyl¬ alanine, 2-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the eleventh position of the tredecapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-amino¬ phenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the twelvth position of the tredecapeptide 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 thirteenth position of the tredecapeptide 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. In a further embodiment of the compound of formula (I), 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.
In a further embodiment of the compound of formula (I), 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.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the carboxyterminal position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the carboxyterminal position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the carboxyterminal position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the carboxyterminal position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the seventh position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine, the amino acid residue in the carboxyterminal position is the residue of serine, threonine, alanine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, tyrosine or homocysteine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the seventh position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine, the amino acid residue in the eighth position is the residue of serine, threonine, alanine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, tyrosine or homo¬ cysteine, the amino acid residue in the carboxyterminal position is the residue of arginine, lysine, ornithine, histidine, glutamine, glutamic acid, asparagine, aspartic acid, serine, tyrosine, homocysteine or alanine.
In a further embodiment of the compound of formula (I), 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the seventh position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine, the amino acid residue in the eighth position is the residue of serine, threonine, alanine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, tyrosine or homocysteine, the amino acid residue in the ninth position is the residue of arginine, lysine, ornithine, histidine, glutamine, glutamic acid, asparagine, aspartic acid, serine, tyrosine, homocysteine or alanine, the amino acid residue in the carboxyterminal position is the residue of glutamine, glutamic acid, histidine, lysine, asparagine, aspartic acid, arginine, serine, threonine or tyrosine.
In a further embodiment of the compound of formula (I), K is hydrogen or a group of formula W1-(CH2)v1-CO-, wherein W1 is hydrogen, hydroxy or C^-alkyl, preferably hydrogen, and v1 is 0, 1 , 2, 3 or 4, preferably 1.
In a further embodiment of the compound of formula (I), L is
_ N ^(CH2)p6-W6 ^(CH2)p7-(O)p8-W7_ wherein p6 and p7 independently are 0, 1 or 2, preferably 0; W6 is hydrogen, hydroxy or C^-alkyl, preferably hydrogen; p8 is 0 or 1 , preferably 0; W7 is hydrogen, hydroxy or C,.6-alkyl, preferably hydrogen.
All of the above embodiments are independent of each other.
Preferred compounds of the invention are:
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2, Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2,
Asp-Ala-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2,
5
Asp-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2,
Asp-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
l o Asp-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
15
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2l
20 Cyclo(Glu9-Lys13)-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Lys-His-NH2,
Cyclo(Lys5-Glu9)-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Asp-Tyr-Arg-Lys-Val-Leu-Glu-Gln-Leu-Arg-His-NH2,
25
Asp-Ala-Tyr-Arg-Lys-Val-Phe-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Phe-Ser-Ala-Arg-His-NH2, Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Tyr-Ala-Arg-His-NH2,
Asp-Ala-Gln-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Glu-Val-Leu-Arg-Glu-Leu-Ser-Ala-Arg-His-NH2,
Cyclo(Asp1-[Gly]-Orn5)-Asp-Ala-Tyr-Arg-Orn-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His- NH2,
Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Lys-His-NH2,
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Lys-His-NH2,
Cyclo(Lys2-Glu6)-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Cyclo(Lys4-Glu8)-Lys-Val-Leu-Lys-Gln-Leu-Ser-Glu-Arg-NH2,
Cyclo(Orn2-[COCH2]-Pen6)-(Asp-Orn-Tyr-Arg-Lys-Pen-Leu-Ala-Gln-Leu-Ser-Ala- Arg-His-NH2l
Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-NH2,
Cyclo(Lys3-Glu7)-Lys-Val-Leu-Lys-Gln-Leu-Ser-Glu-Arg-His-NH2
Cyclo(Lys2-Gluβ)-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys3-Glu7)-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2 Cyclo(Glu1-Lys5)-Glu-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys4-Glu8)-Asp-Ala-Tyr-Lys-Lys-Val-Leu-Glu-Gln-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys3-Glu7)-Ala-Tyr-Lys-Lys-Val-Leu-Glu-Gln-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys4-Glu8)-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-NH2,
H-Tyr-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- His-NH2,
Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys- Leu-Leu-Gln-His-NH2,
Ac-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp2-[gly]-Orn6)-Ac-Asp-Asp-lle-Phe-Thr-Orn-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp6-[gly]-Orn10)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Orn-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp10-[gly]-Orn14)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Asp-Val-Leu-Ala-Orn- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2, or Ac-(N-Me)Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu-Gln-His-NH2.
Particular preferred compounds of the invention are:
H-Tyr-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- His-NH2,
Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys- Leu-Leu-Gln-His-NH2,
Ac-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-His-NH2>
Cyclo(Asp2-[gly]-Orn6)-Ac-Asp-Asp-lle-Phe-Thr-Orn-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp6-[gly]-Om10)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Orn-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp10-[gly]-Orn14)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Asp-Val-Leu-Ala-Orn- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2, or
Ac-(N-Me)Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu-Gln-His-NH2.
We have discovered that the rat and human GHRH receptor display different structure activity relations for the human GHRH (hGHRH) peptide. We have designed a series of truncated analogs of hGHRH. 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.
In the above structural formulas and throughout the present specification, the following terms have the indicated meanings:
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. Examples of linear alkyl are methyl, ethyl, propyl, butyl, pentyl, and hexyl. Examples of branched alkyl are isopropyl, sec-butyl, tert-butyl, isopentyl, and isohexyl. Examples of cyclic alkyl are C3.6-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. Examples of linear alkyloxy are methoxy, ethoxy, propoxy, butoxy, pentoxy, and hexoxy. Examples of branched alkoxy are isopropoxy, sec-butoxy, tert-butoxy, isopentoxy, and isohexoxy. Examples of cyclic alkoxy are cyclo- propyloxy, cyclobutyloxy, cyclopentyloxy and cyclohexyloxy.
In the present context, the term "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.
The term "halogen" is intended to include chlorine (Cl), fluorine (F), bromine (Br) and iodine (I).
Certain of the above defined terms may occur more than once in the above formula I, and upon such occurence each term shall be defined independently of the other.
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.
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.
In another aspect, the present invention relates to 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.
Pharmaceutical 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. Examples of solid carriers are lactose, terra alba, sucrose, cyclodextrin, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid or lower alkyl ethers of cellulose. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene or water.
Similarly, 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.
If a solid carrier is used for oral administration, 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. If a liquid carrier is used, 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
Colloidal silicon dioxide (Aerosil) 1.5mg
Cellulose, microcryst. (Avicel) 70mg Modified cellulose gum (Ac-Di-Sol) 7.5mg Magnesium stearate
Coating:
HPMC approx. 9mg *Mywacett 9-40 T approx. 0.9mg
*Acylated monoglyceride used as plasticizer for film coating.
For nasal administration, 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, absorption enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
Generally, 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.
It has been demonstrated that compounds of the general formula I possess the ability to release endogenous growth hormone in vivo. The compounds may therefore be used in the treatment of conditions which require increased plasma growth hormone levels such as in growth hormone deficient humans or in elderly patients or livestock.
Thus, in a particular aspect, 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.
In a further aspect, 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.
In a still further aspect, 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.
To those skilled in the art, it is well known that the current and potential uses of growth hormone in humans are varied and multitudinous. Thus, compounds of formula I can be administered for purposes stimulating release of growth hormone from the pituitary and would then have 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, 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 catabolic responses after major surgery, reducing cachexia and protein loss due to chronic illness such as cancer or AIDS; treatment of hyperinsulinemia including nesidioblastosis, adjuvant treatment for ovulation induction; to stimulate thymic development and prevent the age-related decline of thymic function, treatment of immunosuppressed patients, improvement in muscle strength, mobility, maintenance of skin thickness, metabolic homeostasis, renal homeostasis in the frail elderly, stimulation of osteoblasts, bone remodelling and cartilage growth, stimulation of the immune system in companion animals and treatment of disorder of aging in companion animals, growth promoter in livestock and stimulation of wool growth in sheep.
For the above indications the dosage will vary depending on the compound of formula 1 employed, on the mode of administration and on the therapy desired. However, generally 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. Usually, 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. Optionally, 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.
Apart from the pharmaceutical use of the growth hormone releasing hormones of formula I, they 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.
Accordingly, 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. Optionally, 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.
For the above indications, 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.
Any novel feature or combination of features described herein is considered essential to this invention.
Pharmacological Methods
Examples:
Compounds of Formula I were evaluated in vitro for their efficacy and potency to stimulate the human GHRH receptor in cell lines stably expressing this receptor. Briefly, 80 % confluent cells were scraped off and pelleted at 10,000xg for 10 min at 4°C.
1.
For binding assay the cell pellet was homogenized in 10 mM Tris-acetate buffer
(pH 7.4) and centrifuged at 50,000xg for 10 min at 4C. The pellet were rehomogenized in the same buffer and diluted to 200 ug membrane protein/ml. Assay consisted of 25 ul 125I-GHRH(1-29)NH2 (200,000cpm/tube), 900 ul Tris- acetate buffer and 25 ul 0.2 % Tween 20. This mixture was incubated for 45 min at room temperature. The reaction was terminated by rapid filtration through GF/B filters pre-wetted with 0.5 % PEI.
2.
For Adenylyl cyclase assay 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.
3.
Compounds of Formula I were evaluated in vitro for their efficacy and potency to release growth hormone in primary rat somatotrophs. 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 % NaHCO2, 10 % horse serum, 2.5 % fetal calf serum, 1 % nonessential amino acids, 1 % glutamine and 1 % pen/strep and adjusted to 1.5x105 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.
On the day of the experiments, cells were washed twice with the above medium containing 25 mM HEPES, pH 7.4. Growth hormone release were initiated by addition of medium containing 25 mM HEPES and test compound. Incubation was carried out for 15 min at 37°C. After incubation growth hormone released to the medium was measured by a standard RIA assay. EXAMPLES:
The process for preparing compounds of formula I and preparations containing them is further illustrated in the following examples, which however, are not to be construed as limiting.
The structures of the compounds are confirmed by either elemental analysis (MA) nuclear magnetic resonance (NMR) or mass spectrometry (MS). NMR shifts (d) are given in parts per million (ppm) and only selected peaks are given, mp is melting point and is given in °C. Column chromatography was carried out using the technique described by W.C. Still et al, J. Org. Chem. 1978, 43, 2923-2925 on Merck silica gel 60 (Art 9385). Compounds used as starting materials are either known compounds or compounds which can readily be prepared by methods known per se.
Abbrevations:
TLC: thin layer chromatography
DMSO: dimethylsurfoxide min: minutes h: hours
Experimental Procedures:
Method 1 :
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). Subsequently, 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.
Purifications were performed by semipreparative HPLC using a Sep-Pak C18 cartridge (Waters part.# 51910). All purified peptides were characterized by at least one analytical HPLC chromatogram on a Waters 510 system equipped with a Vydac C18 column (5 to 60% acetonitrile in water, 42°C, 0.1 M ammonium sulfate, pH adjusted to 2.5 with 4 M sulfuric acid, 50 min) and plasma desoφtion mass spectroscopy.
The following peptides were prepared by method 1 (retention time R, using a gradient of 5 to 60% acetonitrile in water, 42°C, 0.1 M ammonium sulfate, pH adjusted to 2.5 with 4 M sulfuric acid, 50 min; calculated molecular mass, found molecular mass):
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 [Rt= 20.98 min] Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2 [Rt= 21.93 min]
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 [R, = 23.75 min; calculated 1669.0, found 1669±2
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2 [Rt = 24.37 min; calculated 1670.0, found 1669.2±2
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Lys-His-NH2 [Rt = 22.85 min; calculated 1642.0, found 1640.7±2
H-Tyr-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- His-NH2 (Rt = 29.33 min, M = 2408 ± 1)
Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys- Leu-Leu-Gln-His-NH2 (Rt = 31.98 min, M = 2701 ± 3)
Ac-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-His-NH2 (Rt = 32.33 min, M = 2771 ± 3)
Ac-(N-Me)Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu-Gln-His-NH2 (Rt = 32.78 min, M = 2784 ± 3)
Method 2:
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.
Purifications were performed on a Gilson computer controlled HPLC or EM science 2 liter / min HPLC using a 15 x 50 cm Sep-tech column. All purified peptides were characterized by at least one analytical HPLC chromatogram (5 to 50% acetonitrile in water, 0.1% trifluoroacetic acid, 16 min) and laser desorption mass spectroscopy.
The following peptides were prepared by method 2 (retention time R, using a gradient of 5 to 50% acetonitrile in water, 0.1% trifluoroacetic acid, 16 min; molecular mass M+H of the singly protonated molecule):
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (R, = 9.13 min; M+H = 1624)
Asp-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (R, = 10.66 min; M+H = 1556)
Asp-Ala-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (Rt = 10.84 min; M+H = 1569)
Asp-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (R, = 8.47 min; M+H = 1108)
Asp-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (Rt = 8.03 min; M+H = 1237) Asp-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (Rt = 8.12 min; M+H = 1553)
Asp-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (R, = 5.92 min; M+H = 1009)
Asp-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2 (R, = 8.07 min; M+H = 1391)
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2 (R, = 9.07 min; M+H = 1481)
Asp-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2 (R, = 9.55 min; M+H = 1352)
Asp-Ala-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2 (R, = 9.70 min; M+H = 1423)
Tyr-Ala-Asp-Ala-lle-Phe-Thr-Gln-Ser-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala- Arg-His-NH2 (R, = 11.77 min; M+H = 2436)
Method 3:
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). In general, 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. 2nd ed., J. Wiley & Sons, New York 1991 , or in the "novabiochem catalog and Peptide Synthesis Handbook" 94/95 on pages S29 to S33 and in references 1 to 16 listed on page S33); other sidechain functionalities were protected using standard, hydrofluoric acid labile protecting groups suitable for Boc peptide synthesis (e.g., as described by Stewart and Young, Solid Phase Peptide Synthesis. 2nd ed., Rockford, Illinois, USA, 1976). For cyclization of peptides via the sidechain functionality of lysine or ornithine, 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. After formation of the cyclic structure and removal of the N-terminal Boc group, further synthesis and final cleavage are carried out under standard conditions for Boc SPPS strategy.
The crude peptide was dried and purified by HPLC on a 20 mm x 250 mm column packed with 7 μ C-18 silica which was preequilibrated with 15% CH3CN in 0.05 M (NH4)2SO4 , which was adjusted to pH 2.5 with 4 M H2SO4. The crude peptide was dissolved in 2 mL 70% CH3CN / 0.1% TFA in H2O and diluted to 100 mL with H2O. 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% CH3CN in 0.05 M (NH4)2SO4 , pH 2.5 at 10 mL/min during 47 min at 40°C. The peptide-containing fractions were collected, diluted with 3 volumes of H2O and applied to a Sep-Pak® C18 cartrtidge (Waters part. #:51910) which was equilibrated with 0.1% TFA / H2O. The peptide was eluted from the Sep-Pak® cartridge with 70% CH3CN / 0.1% TFA / H2O 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 5μ 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% CH3CN in a buffer consisting of
0.1 M (NH4)2SO4 , which was adjusted to pH 2.5 with 4 M H2SO4 , and eluted with a gradient of 5% to 60% CH3CN in the same buffer during 50 min.
B1 : The column was equilibrated with 5% CH3CN / 0.1 % TFA / H2O and eluted by a gradient of 5% CH3CN / 0.1% TFA / H2O to 60 % CH3CN / 0.1 % TFA / H2O during 50 min.
Cyclo (Asp2-[Gly]-Om6)-Ac-Asp-Asp-lle-Phe-Thr-Orn-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2 (R, A1 = 33.11 min, Rt B1 = 34.65 min, M = 2781 ± 3)
Cyclo (Asp6-[Gly]-Orn10)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Orn-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2 (R, A1 = 34.30 min, Rt B1 = 36.28 min, M = 2723 ± 3)
Cyclo (Asp10-[Giy]-Orn14)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Asp-Val-Leu-Ala- Orn-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2 (Rt A1 = 33.90 min, Rt B1 = 35.72 min, M = 2710 + 3)
Cyclo(Asp1-[Gly]-Orn5)-Asp-Ala-Tyr-Arg-Om-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His- NH2 (Rt = 23.17 min; M = 1652) Abbreviations and definitions: Pen = penicillamine, Orn = ornithine, Nleu = Norleucine, homoarg = homoarginine, SPPS = solid phase peptide synthesis, Fmoc = fluorenylmethoxycarbonyl; Boc = tert.butyloxycarbonyl
Cyclo(Glu9-Lys13) means that the sidechains of Glu9 and Lys13 are connected by an amide bond under formation of a cyclic structure;
Cyclo(Lys5-Glu9) means that the sidechains of Lys5 and Glu9 are connected by an amide bond under formation of a cyclic structure; Cyclo(Asp1-[Gly]-Orn5) means that the sidechain of Asp1 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 Orn5 under formation of a cyclic structure;
Cyclo(Asp2-[Gly]-Orn6) means that the sidechain of Asp2 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 Orn6 under formation of a cyclic structure;
Cyclo(Asp6-[Gly]-Orn10) means that the sidechain of Asp6 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 Orn10 under formation of a cyclic structure;
Cyclo(Asp10-[Gly]-Orn14) means that the sidechain of Asp10 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 Orn14 under formation of a cyclic structure; Cyclo(Lys4-Glu8) means that the sidechains of Lys4 and Glu8 are connected by an amide bond under formation of a cyclic structure;
Cyclo(Orn2-[COCH2]-Pen6) means that the sidechain of Orn2 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 Pen6 under formation of a cyclic structure;
Cyclo(Lys3-Glu7) means that the sidechains of Lys3 and Glu7 are connected by an amide bond under formation of a cyclic structure;
Cyclo(Lys2-Glu6) means that the sidechains of Lys2 and Glu6 are connected by an amide bond under formation of a cyclic structure;
Cyclo(Glu1-Lys5) means that the sidechains of Glu1 and Lys5 are connected by an amide bond under formation of a cyclic structure.

Claims

CLAIMS:
1. A compound of the general formula I
K-(M)x-A-B-(C)w-D-E-(F)z-G-(N)y-L
(I)
wherein z and w are independently 0 or 1 ,
A and D are independently a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula II
Z1 (CH2),1 formula II
wherein Q1 is -CH2- or -CO-,
I1 ,q1 and r1 are independently 0, 1 , 2, 3, 4, 5, or 6,
X1 is hydrogen, or a C,.e-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, C^-dialkylamino, CLg-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, Cv 6-alkoxy, C^-alkyl group, or a valence bond,
Y1 is hydrogen, a C^-alkyl group, or a valence bond to X1 or Z1
Z1 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^-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,
B, C, E, F are independently a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2 formula
wherein Q2 is -CH,- or -CO I2 , q2 and r2 are independently 0, 1, 2, 3, 4, 5, or 6,
X2 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^-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, Cv 6-alkoxy, C^-alkyl group, or a valence bond,
Y2 is hydrogen, a C^-alkyl group, or a valence bond to X2 or Z2,
Z2 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^-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,. 6-alkoxy, C1 6-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-aminobenzoic acid, 4-aminobenzoic, 4-aminobutyric acid, beta-alanine, 3-amino-1 ,2,4-triazole-5- carboxylic acid, 1 ,2,3,4-tetrahyroisoquinoline-3-carboxylic acid, aminobiphenylcar- boxylic acids, pipecotic 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-methylbenzoic acid, 3- aminomethylbutanoic acid, 5-aminopentanoic acid, 2-aminothiazoleacetic acid, 2- aminothiopheneacetic acid, cis- and trans 2-aminocyclohexanecarboxylic acid, 4- aminomethylcyclohexanecarboxylic acid, 4-aminomethylbenzoic acid, amino- naphthoic aicd, aminopenicillanic acid, 3-aminopyrazole-4-carboxylic acid, 2- amino-4-pentenoic acid, 2-aminothiopheneacetic acid, 3-aminobutyric acid, aminolevulinic acid, 8-aminocaprylic acid ;
G is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula IV
(CH2),3 formula IV
wherein Q3 is -CH2- or -CO-,
I3, q3 and r3 are independently 0, 1 , 2, 3, 4, 5, or 6,
X3 is hydrogen, or a C,_6-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLg-dialkylamino, C^-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C^-dialkylamino, CLβ-alkylamino, amidino, guanidino, C,. e-alkoxy, C^-alky! group, or a valence bond,
Y3 is hydrogen, a C^-alky! group, or a valence bond to X3 or Z3, Z3 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C1 6-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, C^-dialkylamino, CLg-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.,. e-alkoxy, C^-alkyl 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
(CH2),4 formula V
wherein Q4 is -CH,- or -CO- I4, q4 and r4 are independently 0, 1 , 2, 3, 4, 5, or 6,
X4 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C1-6-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLβ-dialkylamino, C^-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C1 6-dialkylamino, C^-alkylamino, amidino, guanidino, C,. 6-alkoxy, C^-alkyl group, or a valence bond,
Y4 is hydrogen, a C^-alkyl group, or a valence bond to X4 or Z",
Z4 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, C^-alkylmercapto, arylmercapto, guanidino, amidino, amino, CLβ-dialkylamino, C^-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, CLβ-dialkylamino, C^-alkylamino, amidino, guanidino, C^ 6-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-aminobenzoic acid, 4-aminobenzoic, 4-aminobutyric acid, beta-alanine, 3-amino-1 ,2,4-triazole-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- thiazoleacetic acid, 2-aminothiopheneacetic acid, cis- and trans 2-amino¬ cyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid, 4-amino- methylbenzoic acid, aminonaphthoic aicd, aminopenicillanic acid, 3-aminopyrazole- 4-carboxylic acid, 2-amino-4-pentenoic acid, 2-aminothiopheneacetic acid, 3- aminobutyric acid, aminolevulinic acid, 8-aminocaprylic acid ;
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
(CH2),5
formula VI
wherein Q5 is -CH2- or -CO-,
I5, q5 and r5 are independently 0, 1 , 2, 3, 4, 5, or 6,
X5 is hydrogen, or a C^-alkyl group optionally substituted with a halogen, hydroxy, C^-alkoxy, aryloxy, mercapto, CLβ-alkylmercapto, arylmercapto, guanidino, amidino, amino, C^-dialkylamino, CLg-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, CLg-dialkylamino, C^-alkylamino, amidino, guanidino, C^ 6-alkoxy, C,.6-alkyl group, or a valence bond, Y5 is hydrogen, a C^-alkyl group, or a valence bond to X5 or Z5,
Z5 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, CLg-alkylamino, carboxy, carbamoyl, aryl group, or an aryl group optionally substituted with a hydroxy, halogen, mercapto, carboxy, carbamoyl, amino, C^-dialkylamino, C1 6-alkylamino, amidino, guanidino, Cv 6-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-aminobenzoic acid, 4-aminobenzoic, 4-aminobutyric acid, beta-alanine, 3-amino-1,2,4-triazole-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- thiazoleacetic acid, 2-aminothiopheneacetic acid, cis- and trans 2-amino- cyclohexanecarboxylic acid, 4-aminomethylcyclohexanecarboxylic acid, 4-amino- methylbenzoic acid, aminonaphthoic aicd, aminopenicillanic acid, 3-aminopyrazole- 4-carboxylic acid, 2-amino-4-pentenoic acid, 2-aminothiopheneacetic acid, 3- aminobutyric acid, aminolevulinic acid, 8-aminocaprylic acid ;
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 ;
when the sidechain of an amino acid residue of either M, A, B, C, D, E, F, G, or N contains an amino group, it can optionally be connected to a sidechain of an amino acid residue of M, A, B, C, D, E, F, G, or N containing a carboxylic acid group in order to generate a linkage of the general formula VII
-[CO-(CH2)p1 -(aryl)s1 -(CH2)t1 - NH]J -
formula VII
wherein u1 and s1 are independently 0, 1, or 2,
t1 and p1 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
when a sidechain of an amino acid residue of either M, A, B, C, D, E, F, G, or N contains a mercapto group, it can optionally be connected to a side-chain of an amino acid residue of either M, A, B, C, D, E, F, G, or N containing an amino group in order to generate a linkage of the general formula VIII
- (CH2)p2 -(aryl)s2 - CO -
formula VIII
wherein p2 is 1 , 2, 3, 4, or 5, s2 is independently 0 or 1 ;
when a sidechain of an amino acid residue of either M, A, B, C, D, E, F, G, or N contains a mercapto group, it can optionally be connected to the methylene group of a dehydroalanine residue of either M, A, B, C, D, E, F, G, or N in order to generate a thioether linkage;
when the sidechains of two or more amino acid residues of M, A, B, C, D, E, F, G, or N contain a mercapto group, they can optionally be connected in order to generate a disulfide linkage;
K is W1-(CH2)v1-CO- , or W2-(CH2)v2-NH-CO- , or W3-(CH2)v3-O-CO- , or W4- (CH2)v4-SO2- ,
wherein v\ v2, v3 and v4 independently are 0, 1, 2, 3, 4, 5, or 6,
W1, W2, W3 and W4 independently are hydrogen, or a hydroxy, C1 6-alkyl, aryl, amino group;
or a linkage to a sidechain of an amino acid residue of M, A, B, C, D, E, F, G, or N containing a carboxylic acid group of the general formula IX
- [CO-(CH2)p3-(aryl)s3- (CH2)t3- NH]U3 -
formula IX
wherein u3 and s3 are independently 0, 1 , or 2,
t3 and p3 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
or a linkage joining K and L of the general formula X - [CO-(CH2)p4 -(aryl),4 - (CH2)t4 - NH]U4 -
formula X
wherein u4 and s4 are independently 0, 1 , or 2,
t4 and p4 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8;
L is -O-(CH2)p5 -W5
wherein p5 is 0, 1 , 2, 3, 4, 5, or 6,
W5 is hydrogen, or a hydroxy, C^-alky!, aryl, amino group;
or L is
wherein p6 and p7 are independently 0, 1 , 2, 3, 4, 5, or 6,
p8 is 0 or 1 ,
W6 and W7 are independently hydrogen, or a hydroxy, C^-alkyl, aryl, amino group, or a valence bond;
or a linkage to an amino group in the sidechain of an amino acid residue of M, A, B, C, D, E, F, G, or N of the general formula XI - [CO-(CH2)p9 -(aryl)s9 - (CH2)t9 - NH]U9
formula XI
wherein u9 and s9 are independently 0, 1 or 2,
t9 and p9 are independently 0, 1 , 2, 3, 4, 5, 6, 7, or 8; or a pharmaceutically acceptable salt thereof.
2. The compound according to claim 1 wherein A is a non-proteinogenic or proteinogenic amino acid of the general formula II
Z1 (CH2),1 formula
wherein Q1 is -CH2- or -CO-,
P and r1 are 0 , q1 is 0, 1 , 2, 3, or 4,
X1 is hydrogen, isopropyl, tert. butyl, phenyl, cyclopropyl, cyclohexyl, 2- hydroxyethyl, or amino, Y1 is hydrogen, or methyl,
Z1 is hydrogen.
3. The compound according to claim 2 wherein A is the residue of leucine, isoleucine, valine, phenylalanine, cyclohexylalanine or homophenylalanine, preferably leucine.
4. The compound according to any one of the preceeding claims wherein B is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2
formula III
wherein Q2 is -CH,- or -CO-
I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is hydrogen, phenyl, amino, guanidino, hydroxy, isopropyl, carboxy Y2 is hydrogen, or methyl,
Z2 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.
5. The compound according to claim 4 wherein B is the residue of glycine, alanine, serine, lysine, ornithine, arginine, glutamic acid or aspartic acid, preferably alanine.
6. The compound according to any one of the preceeding claims wherein C is a non-proteinogenic or proteinogenic alpha amino acid residue of the general 5 formula III
(CH2),2
formula III
o wherein Q2 is -CH2- or -CO-, I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is hydrogen, imidazolyl, phenyl, amino, hydroxy, isopropyl, carboxy, amino- carbonyl.or guanidino,
Y2 is hydrogen or methyl,
Z2 is hydrogen.
7. The compound according to claim 6 wherein C is the residue of lysine, glutamine, glutamic acid, asparagine, aspartic acid, arginine, ornithine, serine or histidine, preferably glutamine or ornithine.
8. The compound according to any one of the preceeding claims wherein D is a non-proteinogenic or proteinogenic amino acid of the general formula II
(CH2),1 formula wherein Q1 is -CH,- or -CO-,
and r1 are 0 , q1 is 0, 1 , 2, 3, or 4, X1 is hydrogen, isopropyl, tert. butyl, phenyl, cyclopropyl, cyclohexyl, 2-hydroxy¬ ethyl, or amino,
Y1 is hydrogen, or methyl,
Z1 is hydrogen.
9. The compound according to claim 8 wherein D is the residue of leucine, isoleucine, valine, phenylalanine, cyclohexylalanine or homophenylalanine, preferably leucine.
10. The compound according to any one of the preceeding claims wherein E is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2 formula III
wherein Q2 is -CH,- or -CO
I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4, X is hydrogen, phenyl, amino, guanidino, hydroxy, isopropyl, carboxy,
Y2 is hydrogen, or methyl,
Z2 is hydrogen,
or the residue of any of the following, non-proteinogenic amino acids; dehydroalanine, anthranilic acid, 3-aminobenzoic acid, 4-aminobenzoic, 4-amino¬ butyric acid, beta-alanine, cis- and trans 2-aminocyclohexanecarboxylic acid, 4- aminomethylcyclohexanecarboxylic acid or 4-aminomethylbenzoic acid.
11. The compound according to claim 10 wherein E is the residue of glycine, alanine, serine, threonine, tyrosine, lysine, ornithine, glutamic acid, aspartic acid, homoarginine or arginine, preferably serine.
12. The compound according to any one of the preceeding claims wherein z is 1 and F is a non-proteinogenic or proteinogenic alpha amino acid residue of the general formula III
(CH2),2 formula III wherein Q2 is -CH2- or -CO-,
I2 and r2 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is hydrogen, phenyl, amino, hydroxy, isopropyl, carboxy, aminocarbonyl, or guanidino,
Y2 is hydrogen or methyl,
Z2 is hydrogen.
13. The compound according to claim 12 wherein F is the residue of alanine, phenylalanine, glycine, serine, valine, lysine, glutamine, glutamic acid, asparagine, aspartic acid or arginine, preferably alanine.
14. The compound according to any one of the preceeding claims wherein G is a non-proteinogenic or proteinogenic amino acid residue of the general formula IV
(CH2),3
Formula IV wherein Q3 is -CH2- or -CO-,
I3 and r3 are 0, q2 is 0, 1 , 2, 3, or 4,
X2 is amino, methylamino, dimethylamino, amidino, benzamidino, guanidino, imidazolyl, hydroxy, aminocarbonyl,
Y2 is hydrogen or methyl,
Z2 is hydrogen.
15. The compound according to claim 14 wherein G is the residue of arginine, lysine, glutamine, ornithine, histidine, serine or asparagine, preferably arginine.
16. The compound according to any one of the preceeding claims wherein 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.
17. The compound according to any one of the claims 1-15 wherein 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.
18. The compound according to any one of the claims 1-15 wherein 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- guanidinophenylalanine 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, glutamic acid, glutamine, aspartic acid, arginine, alanine, homocysteine, leucine, isoleucine, methionine, ornithine, phenylalanine or threonine, preferably valine.
19. The compound according to any one of the claims 1-15 wherein 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, biphenyl¬ alanine, 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, 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 fourth position of the tetrapeptide 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.
20. The compound according to any one of the claims 1-15 wherein 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, aspartic acid, cysteine, 4-amino¬ phenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the fourth position of the pentapeptide 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 fifth position of the pentapeptide 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.
21. The compound according to any one of the claims 1-15 wherein 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- naphthylalanine, 2-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the fourth position of the hexapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-amino- phenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the fifth position of the hexapeptide 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 sixth position of the hexapeptide 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.
22. The compound according to any one of the claims 1-15 wherein 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, glutamine or glutamic acid, preferably alanine, the amino acid residue in the fourth position of the heptapeptide 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 fifth position of the heptapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-amino- phenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the sixth position of the heptapeptide 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 seventh position of the heptapeptide 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.
23. The compound according to any one of the claims 1-15 wherein 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, alanine, threonine, cysteine or ornithine, preferably aspartic acid, glutamine or ornithine, the amino acid residue in the fourth position of the octapeptide 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 fifth position of the octapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1-naphthyl- alanine, 2-naphthylalanine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the sixth position of the octapeptide 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 seventh position of the octapeptide 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 eighth position of the octapeptide 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.
24. The compound according to any one of the claims 1-15 wherein 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-naphthyl- alanine, cyclohexylalanine 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 or histidine, preferably threonine, the amino acid residue in the fourth position of the nonapeptide 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 fifth position of the nonapeptide 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 sixth position of the nonapeptide 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 seventh position of the nonapeptide 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 eighth position of the nonapeptide 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 ninth position of the nonapeptide 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.
25. The compound according to any one of the claims 1-15 wherein 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 fourth position of the decapeptide 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 fifth position of the decapeptide 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 sixth position of the decapeptide 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 seventh position of the decapeptide 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 eighth position of the decapeptide residue is the residue of lysine, arginine, ornithine, histidine, glutamine, alanine, serine, glutamic acid, aspartic acid, cysteine, 4-amino¬ phenylalanine, 4-guanidinophenylalanine or asparagine, preferably arginine, the amino acid residue in the ninth position of the decapeptide 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 tenth position of the decapeptide 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.
26. The compound according to any one of the claims 1-15 wherein 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 phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthylalanine, cyclo¬ hexylalanine or lysine, preferably phenylalanine, the amino acid residue in the fifth position of the undecapeptide 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 sixth position of the undecapeptide 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 seventh position of the undecapeptide 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 eighth position of the undecapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthylalanine, 2-naphthylalanine, biphenyl- alanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the ninth position of the undecapeptide 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 tenth position of the undecapeptide 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 eleventh position of the undecapeptide residue is the residue of valine, isoleucine, leucine, penicillamine, lysine, cysteine, glutamic acid, glutamine, aspartic acid, arginine, o alanine, homocysteine, leucine, isoleucine, methionine, ornithine, phenylalanine or threonine, preferably valine.
27. The compound according to any one of the claims 1-15 wherein M is an dodecapeptide residue and the amino acid residue in the aminoterminal position of 5 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, glycine, glutamine, asparagine or histidine, preferably alanine or asparagine, the amino acid residue in the fourth position of the dodecapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the fifth position of the dodecapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthylalanine, cyclohexylalanine or lysine, preferably phenylalanine, the amino acid residue in the sixth position of the dodecapeptide 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 seventh position of the dodecapeptide 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 eighth position of the dodecapeptide 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 ninth position of the dodecapeptide residue is the residue of tyrosine, phenylalanine, histidine, glutamine, lysine, tryptophane, 1 -naphthyl¬ alanine, 2-naphthylaianine, biphenylalanine, alanine, glutamic acid or cysteine, preferably tyrosine, the amino acid residue in the tenth position of the dodecapeptide 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 eleventh position of the dodecapeptide 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 twelvth position of the dodecapeptide 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.
28. The compound according to any one of the claims 1-15 wherein 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- methylalanine, the amino acid residue in the third position of the tredecapeptide 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 fourth position of the tredecapeptide 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 fifth position of the tredecapeptide residue is the residue of isoleucine, leucine, valine, alanine, threonine, phenylalanine or methionine, preferably isoleucine, the amino acid residue in the sixth position of the tredecapeptide residue is the residue of phenylalanine, tyrosine, tryptophane, histidine, 1 -naphthylalanine, 2-naphthylalanine, cyclohexylalanine or lysine, preferably phenylalanine, the amino acid residue in the seventh position of the tredecapeptide 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 eighth position of the tredecapeptide 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 ninth position of the tredecapeptide 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 tenth position of the tredecapeptide 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 eleventh position of the tredecapeptide 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 twelvth position of the tredecapeptide 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 thirteenth position of the tredecapeptide 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.
29. The compound according to any one of the claims 1-15 wherein 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.
30. The compound according to any one of the claims 1-15 wherein 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.
31. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine.
32. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the carboxyterminal position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine.
33. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the carboxyterminal position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine.
34. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the carboxyterminal position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine.
35. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the carboxyterminal position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine.
36. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the seventh position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine, the amino acid residue in the carboxyterminal position is the residue of serine, threonine, alanine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, tyrosine or homocysteine.
37. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the seventh position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine, the amino acid residue in the eighth position is the residue of serine, threonine, alanine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, tyrosine or homocysteine, the amino acid residue in the carboxyterminal position is the residue of arginine, lysine, ornithine, histidine, glutamine, glutamic acid, asparagine, aspartic acid, serine, tyrosine, homocysteine or alanine.
38. The compound according to any one of the claims 1-15 wherein 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, cysteine, valine, isoleucine, methionine, histidine, threonine or phenylalanine, preferably leucine, the amino acid residue in the fourth position is the residue of glutamine, glutamic acid, aspartic acid, asparagine, lysine, serine, arginine, ornithine, histidine, cysteine, methionine, threonine, tyrosine, alanine or leucine, preferably glutamine, the amino acid residue in the fifth position is the residue of asparagine, histidine, glutamine, aspartic acid, glutamic acid, lysine, ornithine, serine, methionine, threonine or alanine, preferably histidine, the amino acid residue in the sixth position is the "residue of isoleucine, valine, threonine, glutamic acid, aspartic acid, lysine, cysteine, penicillamine, homocysteine, methionine, histidine, leucine or alanine, the amino acid residue in the seventh position is the residue of methionine, norleucine, homocysteine, leucine, glutamine, glutamic acid, aspartic acid, lysine, ornithine, histidine, threonine, asparagine, alanine or serine, the amino acid residue in the eighth position is the residue of serine, threonine, alanine, cysteine, asparagine, aspartic acid, glutamic acid, glutamine, histidine, arginine, tyrosine or homocysteine, the amino acid residue in the ninth position is the residue of arginine, lysine, ornithine, histidine, glutamine, glutamic acid, asparagine, aspartic acid, serine, tyrosine, homocysteine or alanine, the amino acid residue in the carboxyterminal position is the residue of glutamine, glutamic acid, histidine, lysine, asparagine, aspartic acid, arginine, serine, threonine or tyrosine.
39. The compound according to any one of the preceeding claims wherein K is hydrogen or a group of formula W-(CH2)v1-CO-, wherein W1 is hydrogen, hydroxy or C^-alkyl, preferably hydrogen, and v1 is 0, 1 , 2, 3 or 4, preferably 1.
40. The compound according to any one of the preceeding claims wherein L is
wherein p6 and p7 independently are 0, 1 or 2, preferably 0; W6 is hydrogen, hydroxy or C^-alky!, preferably hydrogen; p8 is 0 or 1 , preferably 0; W7 is hydrogen, hydroxy or C^-alkyl, preferably hydrogen.
41. A compound according to claim 1 selected from the group comprising:
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2,
Asp-Ala-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2,
Asp-Tyr-Arg-Ala-Val-Leu-Ala-Gln-Leu-homoArg-His-NH2,
Asp-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2, Asp-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Cyclo(Glu9-Lys13)-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Lys-His-NH2,
Cyclo(Lys5-Glu9)-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Asp-Tyr-Arg-Lys-Val-Leu-Glu-Gln-Leu-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Phe-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Phe-Ser-Ala-Arg-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Tyr-Ala-Arg-His-NH2,
Asp-Ala-Gln-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-His-NH2,
Glu-Val-Leu-Arg-Glu-Leu-Ser-Ala-Arg-His-NH2,
Cyclo(Asp1-[Gly]-Orn5)-Asp-Ala-Tyr-Arg-Orn-Val-Leu-Ala-Gln-Leu-Ser-Ala- Arg-His-NH2> Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Lys-His-NH2,
Ac-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Lys-His-NH2,
Cyclo(Lys2-Glu6)-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2,
Cyclo(Lys4-Glu8)-Lys-Val-Leu-Lys-Gln-Leu-Ser-Glu-Arg-NH2,
Cyclo(Om2-[COCH2]-Pen8)-(Asp-Orn-Tyr-Arg-Lys-Pen-Leu-Ala-Gln-Leu-Ser-Ala- Arg-His-NH2,
Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-NH2
Cyclo(Lys3-Glu7)-Lys-Val-Leu-Lys-Gln-Leu-Ser-Glu-Arg-His-NH2
Cyclo(Lys2-Glu6)-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys3-Glu7)-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Glu1-Lys5)-Glu-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys4-Glu8)-Asp-Ala-Tyr-Lys-Lys-Val-Leu-Glu-Gln-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys3-Glu7)-Ala-Tyr-Lys-Lys-Val-Leu-Glu-Gln-Leu-Ser-Ala-Arg-His-NH2
Cyclo(Lys4-Glu8)-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Glu-Leu-Ser-Ala-Arg-His-NH2 and Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-NH2; or a pharmaceutically acceptable salt thereof.
42. A compound according to claim 1 selected from the group comprising:
H-Tyr-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- His-NH2,
Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg-Lys- Leu-Leu-Gln-His-NH2,
Ac-Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala-Arg- Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp2-[Gly]-Om6)-Ac-Asp-Asp-lle-Phe-Thr-Orn-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp6-[Gly]-Om10)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Orn-Val-Leu-Ala-Gln- Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Cyclo(Asp10-[Gly]-Orn14)-Ac-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Asp-Val-Leu-Ala- Orn-Leu-Ser-Ala-Arg-Lys-Leu-Leu-Gln-His-NH2,
Ac-(N-Me)Ala-Asp-Ala-lle-Phe-Thr-Asp-Ala-Tyr-Arg-Lys-Val-Leu-Ala-Gln-Leu-Ser-Ala- Arg-Lys-Leu-Leu-Gln-His-NH2,
or a pharmaceutically acceptable salt thereof.
43. A pharmaceutical composition comprising, as an active ingredient, a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
44. The composition according to claim 43 in unit dosage form, comprising from about 10 to about 200 mg of the compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof.
45. A pharmaceutical composition for stimulating the release of growth hormone 0 from the pituitary, the composition comprising, as an active ingredient, a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically acceptable carrier or diluent.
5 46. A pharmaceutical composition for administration to animals to increase their rate and extent of growth, to increase their milk and wool production, or for the treatment of ailments, the composition comprising, as an active ingredient, a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof together with a pharmaceutically o acceptable carrier or diluent.
47. 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 according to any one of the preceeding compound claims or a 5 pharmaceutically acceptable salt thereof or of a composition according to any one of the preceeding composition claims.
48. The method according to claim 47, wherein the effective amount of the compound according to any one of the preceeding compound claims or pharmaceutically acceptable salt or ester thereof is in the range of from about 0.0001 to about 100 mg/kg body weight per day, preferably from about 0.001 to about 50 mg/kg body weight per day.
49. A method for increasing the rate and extent of growth of animals to increase their milk and wool production, or for the treatment of ailments, the method comprising administering to a subject in need thereof an effective amount of a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof or of a composition according to any one of the preceeding composition claims.
50. Use of a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament.
51. Use of a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament for stimulating the release of growth hormone from the pituitary.
52. Use of a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament for administration to animals to increase their rate and extent of growth, to increase their milk and wool production, or for the treatment of ailments.
53. Use of a compound according to any one of the preceeding compound claims or a pharmaceutically acceptable salt thereof for the preparation of a medicament for treatment or prevention of catabolic side effects of glucocorticoids, osteoporosis, retardation, wounds, bone fractures, growth retardation, renal failure or insufficiency resulting in growth retardation, physiological short stature including growth hormone deficient children and short stature associated with chronic illness, obesity and growth retardation associated with obesity, growth retardation associated with the Prader- Willi syndrome and Turner@s syndrome; burns; intrauterine growth retardation, skeletal dysplasia, hypercortisolism and Cushings syndrome; osteochondrodysplasias, Noonans syndrome, schizophrenia, depressions, Alzheimer's disease, delayed wound healing and psychosocial deprivation; pulmonary dysfunction and ventilator dependency; cachexia and protein loss due to chronic illness such as cancer or AIDS, hyperinsulinemia including nesidioblastosis; adjuvant for ovulation induction; the age-related decline of thymic function; immunosuppressed patients; skin thickness, metabolic homeostasis, renal hemeostasis in the frail elderly; disorder of aging in companion animals.
EP97919296A 1996-04-19 1997-04-18 Compounds with growth hormone releasing properties Withdrawn EP0910579A1 (en)

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