Title:
LABELED NEUROTENSIN DERIVATIVES WITH IMPROVED RESISTANCE TO ENZYMATIC DEGRADATION
Document Type and Number:
WIPO Patent Application WO/2000/078796
Kind Code:
A2
Abstract:
Peptide analogs of neurotensin are disclosed which are resistant to enzymatic degradation and which retain high binding affinity for neurotensin receptors. Pharmaceutical compositions of these compounds are useful for diagnostic and therapeutic purposes.
Inventors:
SRINIVASAN ANANTHACHARI (US)
ERION JACK L (US)
SCHMIDT MICHELLE A (US)
ERION JACK L (US)
SCHMIDT MICHELLE A (US)
Application Number:
PCT/US2000/017509
Publication Date:
December 28, 2000
Filing Date:
June 22, 2000
Export Citation:
Assignee:
MALLINCKRODT INC (US)
SRINIVASAN ANANTHACHARI (US)
ERION JACK L (US)
SCHMIDT MICHELLE A (US)
SRINIVASAN ANANTHACHARI (US)
ERION JACK L (US)
SCHMIDT MICHELLE A (US)
International Classes:
A61K47/48; A61K51/00; A61K51/08; C07K7/06; C07K7/08; A61K38/00; (IPC1-7): C07K7/00
Domestic Patent References:
| WO1995022341A1 | 1995-08-24 |
Foreign References:
| EP0606804A2 | 1994-07-20 |
Other References:
CHEMICAL ABSTRACTS, vol. 131, no. 8, 23 August 1999 (1999-08-23) Columbus, Ohio, US; abstract no. 99344, CHAVATTE, K. ET AL: "Rhenium (Re) and technetium (Tc)-99m oxocomplexes of neurotensin(8-13)" XP002156749 & J. LABELLED COMPD. RADIOPHARM. (1999), 42(5), 415-421 , 1999,
Attorney, Agent or Firm:
Boone, Jeffrey S. (675 McDonnell Boulevard P.O. Box 584, St. Louis MO, US)
Download PDF:
Claims:
WHAT IS CLAIMED IS:
| 1. | A peptide of structure CMR3 (CA) nAA,AA2AA3AA4AA5AA6OH, wherein said peptide has a selective affinity for neurotensin receptors and wherein CM is a chelating moiety or metal binding site; R3 is Dlysine, Dphenylalanine, any Damino acid, glycineglycineglycine, GlySerGly, TyrGluAsn, DTyrGluAsn, PheGluAsn, DPheGluAsn, piperidinyl glycine, aminomethylcyclohexylalanine, amino acid containing a cycloalkyl ring at the aor P position with an amine group or an alkyl amino substituent either externally or as a part of the ring, or a spacer unit; CA is a cyclic amino acid selected from the group consisting of proline, hydroxyproline, 4oxoproline, pipecolic acid, azetidinecarboxylic acid, and other amino acid containing a cycloalkyl ring at the aor pposition with an amine group or an alkyl amino substituent either externally or as a part of the ring; n = 0,1 or 2; AA, is an amino acid which comprises a guanidino group and wherein the acarbon is either Lor D, with the proviso that AA, is not arginine; AA, is arginine, lysine, piperidinylglycine, or other amino acid containing a cycloalkyl ring at the aor (3position with an amine group or alkyl amino substituent either externally or as a part of the ring, wherein the amino acid can have the Lor D configuration at the acarbon, or AA, is an amino acid which comprises a guanidino group wherein the acarbon is either Lor D ; AA3 is a cyclic amino acid selected from proline, hydroxyproline, 4oxoproline, pipecolic acid, azetidinecarboxylic acid, or other amino acid containing a cycloalkyl ring at the aor (3position with an amine group or alkyl amino substituent either externally or as a part of the ring, wherein the amino acid can have the Lor Dconfiguration at the acarbon; AA4 is phenylalanine, tyrosine, an isomer of tyrosine, polyhydroxylated phenylalanine, or other aromatic amino acid, wherein the amino acid can have the Lor Dconfiguration at the acarbon; AA, is isoleucine; and AA6 is leucine. |
| 2. | The peptide of claim 1 wherein AA, is wherein <BR> m = 06;<BR> p 17 ; q = 17; and R4 is cycloalkyl C3Cl0, phenyl, aralkyl, substituted phenyl or substituted aralkyl comprising an electron withdrawing or electron donating group with the proviso that said guanidino group is at a position different from said electron withdrawing or electron donating group. |
| 3. | The peptide of claim 1 wherein said peptide is labeled with a radioisotope. |
| 4. | The peptide of claim 3 wherein said label is 99mTc, 203Pb, 67Ga, 111In, 97Ru, 62Cu, 64Cu, 186Re, 188Re, 90Y, 121Sn, 161Tb, 153Sm, 166Ho, 105Rh, 177Lu or a radioactive halogen isotope. |
| 5. | The peptide of claim 4 wherein if said label is a metal then CM is a chelating group for said metal and if said label is a halogen then said halogen is bound to an aromatic ring. |
| 6. | The peptide of claim 1 wherein CM is ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), cyclohexyl 1,2diamine tetraacetic acid (CDTA), ethyleneglycolO, O'bis (2aminoethyl)N, N, N', N'diacetic acid (HBED), triethylene tetraamine hexaacetic acid (TTHA), 1,4,7,10tetraazacyclododecane N, N', N", N"'tetraacetic acid (DOTA), 1,4,7triazacyclononaneN, N', N"triacetic acid (NOTA), 1,4,8,11tetraazacyclotetradecaneN, N', N", N"'tetraacetic acid (TETA) or a compound of formula wherein PG is a sulfur protecting group selected from the group consisting of alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl; Y', Y", and Y"'are hydrogen or oxygen with the proviso that at least one of them is an O; R, and R2 are hydrogen or alkyl (ClC3); X = NH or S with the proviso that Y"'is hydrogen when X is S; ZisPGifXisS; and Z is hydroxyalkyl, aminoalkyl or carboxyalkyl. |
| 7. | The peptide of claim 1 wherein said peptide is. |
| 8. | A peptide of structure CMR3 (CA) nAAlAA2AA3AA4AA5AA6OH, wherein said peptide has a selective affinity for neurotensin receptors and wherein CM is a chelating moiety or metal binding site; R3 is Dlysine, Dphenylalanine, any Damino acid, glycineglycineglycine, GlySerGly, TyrGluAsn, DTyrGluAsn, PheGluAsn, DPheGluAsn, piperidinyl glycine, aminomethylcyclohexylalanine, other amino acid containing a cycloalkyl ring at the a or pposition with an amine group or an alkyl amino substituent either externally or as a part of the ring, or a spacer unit; CA is a cyclic amino acid selected from the group consisting of proline, hydroxyproline, 4oxoproline, pipecolic acid, azetidinecarboxylic acid, other amino acid containing a cycloalkyl ring at the aor (3position with an amine group or an alkyl amino substituent either externally or as a part of the ring; n = 0,1 or 2; AA, is an amino acid which comprises a guanidino group and wherein the acarbon is either Lor D, with the proviso that AA, is not arginine; AA2 is arginine, lysine, piperidinylglycine, or other amino acid containing a cycloalkyl ring at the aor pposition with an amine group or alkyl amino substituent either externally or as a part of the ring, wherein the amino acid can have the Lor D configuration at the acarbon, or AA2 is an amino acid which comprises a guanidino group wherein the acarbon is either Lor D ; AA3 is proline, hydroxyproline, 4oxoproline, pipecolic acid, azetidinecarboxylic acid, or other amino acid containing a cycloalkyl ring at the aor (3position with an amine group or alkyl amino substituent either externally or as a part of the ring, wherein the amino acid can have the Lor Dconfiguration at the acarbon; AA4 is phenylalanine, tyrosine, an isomer of tyrosine, polyhydroxylated phenylalanine, or other aromatic amino acid wherein said amino acid can have the Lor Dconfiguration at the acarbon; AA5 is tbutylglycine, 1aminocyclohexylcarboxylic acid, cyclohexylglycine, trimethylsilylalanine, isoleucine, or other amino acid containing a branched or cyclic hydrocarbon substituent at the side chain at the aor (3position, wherein the amino acid can have the Lor Dconfiguration at the acarbon; and AA6 is cyclopropylalanine, cyclohexylalanine, tbutylalanine, leucine, or other amino acid containing a branched or cyclic hydrocarbon substituent at the side chain at the aor ß position, wherein the amino acid can have the Lor Dconfiguration at the acarbon. |
| 9. | The peptide of claim 8 wherein AA, is m = 06; p 17 ; q= 17; and R4 is cycloalkyl C3Cl, phenyl, aralkyl, substituted phenyl or substituted aralkyl comprising an electron withdrawing or electron donating group with the proviso that said guanidino group is at a position different from said electron withdrawing or electron donating group. |
| 10. | The peptide of claim 8 wherein said peptide is labeled with a radioisotope. |
| 11. | The peptide of claim 10 wherein said label is 99mTc, 203Pb, 67Ga,"lIn, 97Ru, 62Cu, 64Cu, 186Re, 188Re, 121Sn, 161Tb, 153Sm, 166Ho, 105Rh, 177Lu or a radioactive halogen isotope. |
| 12. | The peptide of claim 11 wherein if said label is a metal then CM is a chelating group for said metal and if said label is a halogen then said halogen is bound to an aromatic ring. |
| 13. | The peptide of claim 8 wherein CM is ethylene diamine tetraacetic acid (EDTA), diethylene triamine pentaacetic acid (DTPA), cyclohexyl 1,2diamine tetraacetic acid (CDTA), ethyleneglycolO, O'bis (2aminoethyl)N, N, N', N'diacetic acid (HBED), triethylene tetraamine hexaacetic acid (TTHA), 1,4,7,10tetraazacyclododecane N, N', N", N"'tetraacetic acid (DOTA), 1,4,7triazacyclononaneN, N', N"triacetic acid (NOTA), 1,4,8,11tetraazacyclotetradecaneN, N', N", N"'tetraacetic acid (TETA) or a compound of formula wherein PG is a sulfur protecting group selected from the group consisting of alkanoyl, arylcarbonyl, arylalkanoyl, acetamidomethyl, tetrahydropyranyl and tetrahydrofuranyl; Y', Y", and Y"'are hydrogen or oxygen with the proviso that at least one of them is an O; R, and R2 are hydrogen or alkyl (C,C3); X = NH or S with the proviso that Y"'is hydrogen when X is S; ZisPGifXisS, and Z is hydroxyalkyl, aminoalkyl or carboxyalkyl. |
| 14. | The peptide of claim 8 wherein said peptide is DTPAArgArgProTyrIleLeuOH (SEQ ID NO: 3), DTPADLysProArg (4Gu) PheProTyrIleLeuOH, DTPADLysPro (4Gu) PheArgProTyrIleLeuOH (Compound I), DTPADLysPro (4Gu) Phe (4Gu) PheProTyrIleLeuOH, DTPADLysProArgAba (Apy)ProTyrIleLeuOH, DTPADLysProAba (Apy)ArgProTyrIleLeuOH, DTPADLysProAba (Apy)Aba (Apy)ProTyrIleLeuOH, DTPADLysPro (4Gu) PheArgProTyrtBuGlyLeuOH (Compound IX), DTPADLysPro (4Gu) PheArgProTyrLeu (TCH2NH) LeuOH, DTPADLysProGly (PipAm)ArgProTyrIleLeuOH (Compound II), DTPADLysProGly (PipAm)ArgProTyrtBuGlyLeuOH (Compound X), DTPADLysProGly (PipAm)Arg (4oxo) ProTyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgPro (2,6diMe) TyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgPromTyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgProROCOTyrtBuGlyLeuOH, DTPADLysProGly (PipAm)PipGlyProTyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgAzeCATyrtBuGlyLeuOH, DTPADLysAzeCAGly (PipAm)ArgProTyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgProTyrAchcLeuOH, DTPADLysProGly (PipAm)ArgProTyrtBuGlyCpaOH, DTPADLysProGly (PipAm)ArgProTyrtBuGlyChaOH, DTPADLysProGly (PipAm)ArgProTyrtBuGlytBuAlaOH, DTPADLysProGly (PipAm)ArgPipCATyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgDPipCATyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgProTyrChgLeuOH, DTPADLysProGly (PipAm)ArgProTyrIleROCOLeuOH, DTPA (Pip) AlaProGly (PipAm)ArgProTyrtBuGlyLeuOH (SEQ ID NO: 6), DTPADLysProGly (PipAm)ArgProDTyrtBuGlyLeuOH, DTPADLysProAla (PipAm)ArgProTyrtBuGlyLeuOH, DTPADLysProhomoAla (PipAm)ArgProTyrtBuGlyLeuOH, DTPADLysProGly (PipAm)ArgProTyrtBuGlyLeuHA, DTPAPipGlyProGly (PipAm)ArgProTyrtBuGlyLeuOH (Compound XI) (SEQ ID NO: 4), DTPAtransCha (4CH2NH2)ProGly (PipAm)ArgProTyrtBuGlyLeuOH (Compound XII) (SEQ ID NO: 5), DTPADTyrGluAsnLysProGly (PipAm)ArgProTyrtBuGlyLeuOH (Compound XIII), DTPADTyrGluAsnLysProGly (PipAm)ArgProTyrtBuGlyChaOH (Compound XIV), or DTPADTyrGluAsnLysProGly (PipAm)ArgProTyrtBuGlytBuAlaOH (Compound XV). A method for diagnosing a patient for a tumor by administering an effective amount of a peptide of claim 1. |
| 15. | The method of claim. |
| 16. | wherein said tumor is a small cell lung carcinoma, exocrine pancreatic cancer, Ewing sarcoma, meningioma, medulloblastoma, or astrocytoma. A method for diagnosing a patient for a tumor by administering an effective amount of a peptide of claim 8. The method of claim 17 wherein said tumor is a small cell lung carcinoma, exocrine pancreatic cancer, Ewing sarcoma, meningioma, medulloblastoma, or astrocytoma. A method for treating a patient for a tumor by administering an effective amount of a peptide of claim 1. The method of claim 19 wherein said tumor is a small cell lung carcinoma, exocrine pancreatic cancer, Ewing sarcoma, meningioma, medulloblastoma, or astrocytoma. A method for treating a patient for a tumor by administering an effective amount of a peptide of claim 8. The method of claim 21 wherein said tumor is a small cell lung carcinoma, exocrine pancreatic cancer, Ewing sarcoma, meningioma, medulloblastoma, or astrocytoma. |
Description:
INTERNATIONAL SEARCH REPORT Inter-rnal Application No PCT/US 00/17509 C. (Continuation) DOCUMENTS CONSIDERED TO BE RELEVANT Category ° Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. P, A CHEMICAL ABSTRACTS, vol. 131, no. 8,1-22 23 August 1999 (1999-08-23) Columbus, Ohio, US; abstract no. 99344, CHAVATTE, K. ET AL:"Rhenium (Re) and technetium (Tc)-99m oxocomplexes of neurotensin (8-13)" XP002156749 A & J. LABELLED COMPD. RADIOPHARM. (1999), 1-22 42 (5), 415-421, 1999, abstract 1 INTERNATIONAL SEARCH ------------------- Inter bnal Applicatlon No formation on patent family members PCT/US 00/17509 Patent document Publication Patent family Publication cited in search report date member (s) date WO 9522341 A 24-08-1995 CA 2183421 A 24-08-1995 EP 0752873 A 15-01-1997 JP 11514329 T 07-12-1999 US 5952464 A 14-09-1999 EP 606804 A 20-07-1994 CA 2086453 A 01-07-1994