Claims for Patent: 6,123,916

Summary for Patent: 6,123,916

Title:	Therapeutic use of somatostatin peptides
Abstract:	The invention relates to a new pharmaceutical use of somatostatin peptides comprising on the terminal amino group a polyamino polycarboxylic group, in free form or in a pharmaceutically acceptable salt form, particularly in the manufacture of a medicament for treating disorders with an aetiology comprising or associated with excess of GH-secretion.
Inventor(s):	Eric Paul Krenning, Steven Willem Jan Lamberts
Assignee:	Novartis AG
Application Number:	US08/259,090
Patent Claims:	1. A method for treating disorders with an aetiology comprising or associated with excess GH-secretion, for treating gastro-intestinal disorders, for inhibiting proliferation and/or keratinisation of epidermal cells, or for treating degenerative senile dementia in a subject in need of such a treatment, which comprises administering to said subject an effective amount for treating said disorders of a somatostatin peptide modified at the terminal amino group by a polyaminopolycarboxylic group attached to the terminal amino group by an amide bond, in free form or in pharmaceutically acceptable salt form. 2. A method for the in vivo detection of tuberculosis, sarcoidosis, malignant lymphoma, Merkel cell tumor of the skin, osteosarcoma, focal lymphocytic reaction, localized autoimmune disease, and organ rejection after transplantation in a subject in need thereof, which comprises a) administering to said subject a labeled somatostatin peptide modified at the terminal amino group by a polyaminopolycarboxylic group attached to the terminal amino group bv an amide bond, in free form or in pharmaceutically acceptable salt form and labeled with a γ- or positron-emitting radionuclide in an amount effective for said in vivo detection and b) recording the localization of the receptors targeted by said labeled somatostatin peptide. 3. A method for treating malignant lymphoma, Merkel cell tumor of the skin, or osteosarcoma in a subject in need of such a treatment which comprises administering to said subject a therapeutically effective amount for said treatment of a labeled somatostatin peptide modified at the terminal amino croup by a polyaminopolycarboxylic group attached to the terminal amino group by an amide bond, in free form or in pharmaceutically acceptable salt form and labeled with a α- or β-emitting radionuclide. 4. A method according to claim 1, wherein the somatostatin peptide is selected from a compound of formula I ##STR20## wherein A is C1-12 alkyl, C7-10 phenylalkyl or a group of the formula RCO--,wherei) R is hydrogen, C1-11 alkyl, phenyl or C7-10 -phenylalkyl, or ii) RCO-- isa) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, NO2 NH2, OH, C1-3 alkyl and/or C1-3 alkoxy; b) the residue of a natural or synthetic a-amino acid other than defined under a) above or of a corresponding D-amino acid; or c) a dipeptide residue in which the individual amino acid residues are the the same or different and are selected from those defined under a) and/or b) above, A' is hydrogen, C1-12 alkyl or C7-10 phenylalkyl, Y1 and Y2 represent together a direct bond or each of Y1 and Y2 is independently hydrogen or a radical of formulae (1) to (5) ##STR21## wherein Ra is methyl or ethyl, Rb is hydrogen, methyl or ethyl, m is a whole number from 1 to 4, n is a whole number from 1 to 5, Rc is (C1-6)alkyl, Rd represents the substituent attached to the α-carbon atom of a natural or synthetic a-amino acid, Re is (C1 5)alkyl, Ra and Rb are independently hydrogen, methyl, or ethyl, R8 and R9 are independently hydrogen, halogen, (C1-3)alkyl, or (C1-3)alkoxy, p is 0 or 1, q is 0 or 1, and r is 0, 1 or 2, B is --Phe-- optionally ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, or β-naphthyl-Ala, c is (L)-Trp- or (D)-Trp- optionally α-N-methylated and optionally benzene-ring-substituted by halogen, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy, D is Lys, Lys in which the side chain contains O or S in the β-position, γ-Lys or δF-Lys, optionally α-N-methylated, or a 4-aminocyclohexylAla or 4-aminocyclohexylGly residue, E is Thr, Ser, Val, Phe, Ile or an aminoisobutyric or aminobutyric acid residue, G is a group of the formula ##STR22## wherein R7 is hydrogen or C1-3 alkyl, R10 is hydrogen or a physiologically acceptable, physiologically acceptable, physiologically hydrolysable ester thereof,R11 is hydrogen, C1-3 alkyl, phenyl or C7-10 phenylalkyl, R12 is hydrogen, C 1-3 alkyl or a group of formula --CH(R13) --X1, R13 is --CH2 OH, --(CH2)2 --OH, --(CH2)3 --OH, or --CH(CH3)OH or represents the substituent attached to the α-carbon atom of a natural or synthetic a-amino acid, and X1 is a group of formula --COOR7, --CH2 OR10 or --CONR14 R15 whereinR7 and R10 have the meanings given above, R14 is hydrogen or C1-3 alkyl, and R15 is hydrogen, C1-3 alkyl, phenyl, or C7-10 ophenylalkyl, and R16 is hydrogen or hydroxy, with the provisos that when R12 is --CH(R13)--X1, then R11 is hydrogen or methyl, and A and A' being so selected that the compound contains a terminal --NH-- capable of being linked to a polyaminopolycarboxylic group, wherein the residues B, D and E have the L-configuration, and the residues in the 2-and 7-position and any residues Y1 4) and Y2 4) each independently have the (L)- or (D)- configuration; a compound of Formula II ##STR23## a compound of Formula III ##STR24## 5. Method according to claim 4, wherein in formula I A is RCO which isa) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, NO2, NH2, OH, C1-3 alkyl and/or C1-3 alkoxy; b) the residue of a natural or synthetic α-amino acid other than defined under a) above or of a corresponding D-amino acid, or c) a dipeptide residue in which the individual amino acid residues are the same or different and are selected from those defined under a) and/or b) above, B is Phe or Tyr, C is (D)Trp, D is Lys, E is Val or Thr, and G is a group of formula --CONR11 R11 wherein R11 and R12 are as defined in claim 4. 6. Method according to claim 1, wherein the polyaminopoly-carboxylic group is ethylene diaminetetraacetic acid, diethylene triamine pentaacetic acid, 1,4,7,10-tetraaza-cyclododecane-N,N',N",N'"-tetraacetic acid or 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid. 7. A method according to claim 4, wherein the labeled somatostatin peptide modified at the terminal amino group is a compound of formula Ia ##STR25## wherein B, C, D, E, G, Y1, and Y2 are as defined in claim 4, A1 is hydrogen or C1-4 alkyl, andR1 is a diethylene triamine pentaacetic acid residue , and Z1 is the residue attached to the α-carbon of an amino acid residue as defined in a) or b) of claim 4. in free form or in pharmaceutically acceptable salt form. 8. A method according to claim 1, wherein the somatostatin peptide modified at the terminal amino group is ##STR26## in free form or in pharmaceutically acceptable salt form. 9. A method according to claim 2, wherein the labeled somatostatin peptide modified at the terminal amino group is ##STR27## in free form or in pharmaceutically acceptable salt form labeled with a γ- or positron-emitting radionuclide. 10. A method according to claim 2, wherein the γ-emitting radionuclide is selected from 67 Ga, 111 In, 99m Tc, 169 Yb, and 186 Re. 11. A method according to claim 2, wherein the positron emitting radionuclide is 68 Ga. 12. The method according to claim 2, wherein the labeled somatostatin peptide modified at the terminal amino group is ##STR28## in free form or in pharmaceutically acceptable salt form labeled with 111 In. 13. The method according to claim 2 for the detection of tuberculosis. 14. The method according to claim 2 for the detection of sarcoidosis. 15. The method according to claim 2 for the detection of malignant lymphoma. 16. The method according to claim 2 for the detection of Merkel cell tumor of the skin. 17. The method according to claim 2 for the detection of osteosarcoma. 18. The method according to claim 2 for the detection of focal lymphocytic reaction. 19. The method according to claim 2 for the detection of localized autoimmune disease. 20. The method according to claim 2 for the detection of organ rejection after transplantation. 21. A method according to claim 3, wherein the labeled somatostatin peptide modified at the terminal amino group is ##STR29## in free form or in pharmaceutically acceptable salt form labeled with a α- or β-emitting radionuclide. 22. A method according to claim 3, wherein the β-emitting radionuclide is selected from 90 Y, 67 Cu, 186 Re, 188 Re, 169 Er, 121 Sn, 127 Te, 143 Pr, 198 Au, 109 Pd, 165 Dy, 32 p, and 142 Pr. 23. A method according to claim 3, wherein the α-emitting radionuclide is selected from 211 At and 212 Bi.