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Claims for Patent: 5,776,894

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Claims for Patent: 5,776,894

Title: Chelated somatostatin peptides and complexes thereof, pharmaceutical compositions containing them and their use in treating tumors
Abstract:Somatostatin peptides bearing at least one chelating group for a detectable element, said chelating group being linked to an amino group of said peptide, and said amino group having no significant binding affinity for somatostatin receptors, in free or salt form, are complexed with a detectable element and are useful as a pharmaceutical, e.g. a radiopharmaceutical for in vivo imaging of somatostatin receptor positive tumors or for therapy.
Inventor(s): Albert; Rainer (Basel, CH), Krenning; Eric P. (Rotterdam, NL), Lamberts; Steven W. J. (Rotterdam, NL), Pless; Janos (Basel, CH)
Assignee: Novartis AG (Basel, CH)
Application Number:08/479,052
Patent Claims: 1. A somatostatin peptide having a physiologically acceptable chelating group for a detectable element covalently linked directly or indirectly to the N-terminal amino group of the somatostatin peptide, in free form or in pharmaceutically acceptable salt form.

2. A somatostatin peptide according to claim 1, wherein the chelating group is covalently linked indirectly to the N-terminal amino group of said peptide through a spacer or bridging group.

3. A somatostatin peptide according to claim 1, wherein the chelating group is covalently linked by an amide bond to said peptide.

4. A somatostatin peptide according to claim 1, wherein the chelating group is covalently linked by a thiourea bond to said peptide.

5. A somatostatin peptide according to claim 1 having a physiologically acceptable chelating group for a detectable element covalently linked to the N-terminal amino group of the somatostatin peptide, wherein the somatostatin peptide is a compound of formula I ##STR55## wherein A is a group of formula RCO--,

where RCO-- is

a) an L- or D-phenylalanine residue optionally ring-substituted by F, Cl, Br, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy;

b) the residue of a natural and/or synthetic .alpha.-amino acid other than defined under a) above or of a corresponding D-amino acid, or

c) 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,

the .alpha.-amino group of amino acid residues a) and b) and the N-terminal amino group of dipeptide residues c) being optionally mono-C.sub.1-12 alkylated,

A' is hydrogen, C.sub.1-12 alkyl or C.sub.7-10 phenylalkyl, Y.sub.1 and Y.sub.2 represent together a direct bond or each of Y.sub.1 and Y.sub.2 is hydrogen,

B is -Phe- optionally ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl or C.sub.1-3 alkoxy; or .beta.-naphthyl-Ala,

C is (L)-Trp- or (D)-Trp- optionally .alpha.-N-methylated and optionally benzene-ring-substituted by halogen, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/or C.sub.1-3 alkoxy,

D is Lys, 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 formula ##STR56## wherein R.sub.7 is hydrogen or C.sub.1-3 alkyl,

R.sub.10 is hydrogen or the residue of a pharmaceutically acceptable, physiologically hydrolyzable ester,

R.sub.11 hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl,

R.sub.12 hydrogen, C.sub.1-3 alkyl or --CH(R.sub.13)--X.sub.1,

R.sub.13 is --CH.sub.2 OH, --(CH.sub.2).sub.2 --OH, --(CH.sub.2).sub.3 --OH, or --CH(CH.sub.3)OH or represents the substituent attached to the .alpha.-carbon atom of a natural or synthetic .alpha.-amino acid and

X.sub.1 is a group of formula --COOR.sub.7, --CH.sub.2 OR.sub.10 or --CONR.sub.14 R.sub.15

wherein

R.sub.7 and R.sub.10 have the meanings given above,

R.sub.14 is hydrogen or C.sub.1-3 alkyl,

R.sub.15 is hydrogen, C.sub.1-3 alkyl, phenyl or C.sub.7-10 phenylalkyl, and

R.sub.16 is hydrogen or hydroxy, with the proviso that when R.sub.12 is --CH(R.sub.13)--X.sub.1 then R.sub.11 is hydrogen or methyl,

wherein the residues B, D and E have the L-configuration, and the residues C and in the 2-and 7-position independently have the L- or D- configuration, in free form or in pharmaceutically acceptable salt form.

6. A somatostatin peptide according to claim 5, wherein the somatostatin peptide is ##STR57##

7. A somatostatin peptide according to claim 5, wherein the chelating group is selected from the group consisting of iminodicarboxylic groups, polyaminopolycarboxylic groups, groups derived from macrocyclic amines, groups of formula IV or V ##STR58## wherein each of R.sub.1, R.sub.2 and R.sub.3 independently is C.sub.1-6 alkyl, C.sub.6-8 aryl or C.sub.7-9 arylalkyl, each optionally substituted by OH, C.sub.1-4 alkoxy, COOH or SO.sub.3 H,

n' is 1 or 2,

i is an integer from 2 to 6, and

TT are independently .alpha. or .beta. amino acids linked to each other by amide bonds,

groups derived from bis-aminothiol derivatives, from dithiasemicarbazone derivatives, from propylene amine oxime derivatives, from diamide dimercaptides, from porphyrins or from Deferoxamine, in free form or in pharmaceutically accepted salt form.

8. A somatostatin peptide according to claim 5, wherein the chelating group is derived from ethylene diaminetetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), ethylene glycol-0,0'-bis(2-aminoethyl)-N,N,N',N'-tetraacetic acid (EGTA), N,N'-bis(hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED), triethylenetetramine hexaacetic acid (TTHA), substituted EDTA or -DTPA 1,4,7,10-tetra-azacyclododecane-N,N',N",N'"-tetraacetic acid (DOTA) and 1,4,8,11-tetraazacyclotetradecane-N,N',N",N'"-tetraacetic acid (TETA), in free form or in pharmaceutically accepted salt form.

9. A somatostatin peptide according to claim 5, wherein the chelating group is derived from 1,4,7,10-tetraazacyclotridecane-1,4,7,10-tetraacetic acid (TITRA), 1,4,8,11-tetraazacyclotetradecane (TETRA); EDTA, DTPA, DOTA, TETA, TITRA, TETRA or 3,3,9,9-tetramethyl-4,8-diazaundecane-2,10-dione dioxime (HMPAO) substituted by p-isothiocyanato-phenyl-C.sub.1-3 alkyl, in free form or in pharmaceutically accepted salt form.

10. A somatostatin peptide according to claim 5 which is ##STR59## in free form or in pharmaceutically accepted salt form.

11. A somatostatin peptide according to claim 1 which is complexed by the chelating group with a detectable element, in free form or in pharmaceutically acceptable salt form.

12. A somatostatin peptide according to claim 1 which is complexed by the chelating group with a .alpha.-, .beta.-, .gamma.- or positron-emitting radionuclide.

13. A peptide according to claim 12 complexed with a gamma-emitting radionuclide.

14. A peptide according to claim 13 wherein the gamma-emitting radionuclide is selected from the group consisting of .sup.67 Ga, .sup.111 In, .sup.99 Tc, .sup.169 Yb, .sup.90 Y, and .sup.186 Re.

15. A peptide according to claim 12 complexed with an .alpha.- or .beta.-emitting radionuclide.

16. A peptide according to claim 15 wherein the .alpha. or .beta.-emitting radionuclide is selected from the group consisting of .sup.211 At, .sup.212 Bi, .sup.88 Y, .sup.90 Y, .sup.67 Cu, .sup.186 Re, .sup.188 Re, .sup.169 Er, .sup.121 Sn, .sup.127 Te, .sup.143 Pr, .sup.198 Au, .sup.109 Pd, .sup.165 Dy, .sup.32 P, and .sup.142 Pr.

17. A somatostatin peptide according to claim 5 which is .sup.111 In or ##STR60## in free form or in salt form.

18. A pharmaceutical composition comprising a somatostatin peptide as defined in claim 1 complexed by the chelating group with a detectable element, in free form or in pharmaceutically acceptable salt form in association with a pharmaceutically carrier or diluent.

19. A method for in vivo treatment of somatostatin receptor positive tumors and metastases in a subject in need of such treatment which comprises administering to said subject a therapeutically effective amount of a somatostatin peptide as defined in claim 1 and complexed with a detectable element, the detectable element being selected from the group consisting of .alpha.- and .beta.-emitting radionuclide.
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