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Claims for Patent: 6,123,916

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Claims 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): Krenning; Eric Paul (Rotterdam, NL), Lamberts; Steven Willem Jan (Rotterdam, NL)
Assignee: Novartis AG (Basel, CH)
Application Number:08/259,090
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 .gamma.- 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 .alpha.- or .beta.-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 C.sub.1-12 alkyl, C.sub.7-10 phenylalkyl or a group of the formula RCO--,

where

i) R is hydrogen, C.sub.1-11 alkyl, phenyl or C.sub.7-10 -phenylalkyl, or

ii) 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 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, 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 independently hydrogen or a radical of formulae (1) to (5) ##STR21## wherein R.sub.a is methyl or ethyl,

R.sub.b is hydrogen, methyl or ethyl,

m is a whole number from 1 to 4,

n is a whole number from 1 to 5,

R.sub.c is (C.sub.1-6)alkyl,

R.sub.d represents the substituent attached to the .alpha.-carbon atom of a natural or synthetic a-amino acid,

R.sub.e is (C.sub.1 5)alkyl,

R.sub.a and R.sub.b are independently hydrogen, methyl, or ethyl,

R.sub.8 and R.sub.9 are independently hydrogen, halogen, (C.sub.1-3)alkyl, or (C.sub.1-3)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, NO.sub.2, NH.sub.2, OH, C.sub.1-3 alkyl and/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, Lys in which the side chain contains O or S in the .beta.-position, .gamma.-Lys or .delta.F-Lys, optionally .alpha.-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 R.sub.7 is hydrogen or C.sub.1-3 alkyl,

R.sub.10 is hydrogen or a physiologically acceptable, physiologically acceptable, physiologically hydrolysable ester thereof,

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

R.sub.12 is hydrogen, C .sub.1-3 alkyl or a group of formula --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 a-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, and

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

R.sub.16 is hydrogen or hydroxy,

with the provisos that when R.sub.12 is --CH(R.sub.13)--X.sub.1, then R.sub.11 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 Y.sub.1 4) and Y.sub.2 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 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 or synthetic .alpha.-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 --CONR.sub.11 R.sub.11 wherein R.sub.11 and R.sub.12 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, Y.sub.1, and Y.sub.2 are as defined in claim 4, A.sub.1 is hydrogen or C.sub.1-4 alkyl, and

R.sub.1 is a diethylene triamine pentaacetic acid residue , and Z.sub.1 is the residue attached to the .alpha.-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 .gamma.- or positron-emitting radionuclide.

10. A method according to claim 2, wherein the .gamma.-emitting radionuclide is selected from .sup.67 Ga, .sup.111 In, .sup.99m Tc, .sup.169 Yb, and .sup.186 Re.

11. A method according to claim 2, wherein the positron emitting radionuclide is .sup.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 .sup.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 .alpha.- or .beta.-emitting radionuclide.

22. A method according to claim 3, wherein the .beta.-emitting radionuclide is selected from .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.

23. A method according to claim 3, wherein the .alpha.-emitting radionuclide is selected from .sup.211 At and .sup.212 Bi.
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