MXPA00000455A - Therapeutic peptide derivatives - Google Patents

Abstract

Peptide derivatives containing one or more substituents separately linked by an amide, amino or sulfonamide bond to an amino group on either the N-terminal end or side chain of a biologically active peptide moiety. The peptide derivatives have relatively enhanced biological activity when compared to the corresponding peptide alone.

Description

DERIVATIVES OF THERAPEUTIC PEPTIDES Background of the Invention This invention relates to therapeutic peptides. Several attempts have been made to prolong the activity of biologically active peptides. For example, peptides have been chemically modi by synthetically adding fractions of sugar to increase the period during which the peptide is active (Sandoz, WO 88/02756, Sandoz, WO 89/09786, DE 3910667 A1, EPO 0 374 089 A2 (1990 ), and Breipohl, U.S. Patent No. 4,861,755 (1989)). The addition of cationic anchors (EPO 0 363 589 A2 (1990)) and lipid fractions (Whittaker, WO 91/09837; Jung, U.S. Patent No. 4,837,303 (1989)) has also been used to increase the life of the peptides. Summary of the Invention In general, the present invention provides biologically active peptide derivatives that contain one or more substituents linked separately to an amino group located at the N-terminus or a side chain of the peptide moiety. In this modi form, the derivatives have a more potent and prolonged biological activity than the corresponding unmodi peptide. Peptide derivatives are advantageous in that they are inexpensive, highly biocompatible, lack of negative side effects, and are compatible with different forms of therapeutic administration. In particular, many of the derivatives that have somatostatin as the peptide fraction have potency and selectively highly improved compared to unmodi somatosta-tina. In one aspect, the invention relates to a peptide derivative containing a biologically active peptide moiety and at least one substituent attached to the peptide moiety; the substituent is selected from the group including the compounds I, II and III, wherein the compound I is: where R "is O, S or NR5, where Rs is H or alkyl (Ci-Cg); each Rt and R2 is, independently, II, (CH2) mOR6, or CH (0R7) Cil2ORBI where R6 is H or acyl (C2-C7), and each R7 and Re is, independently, H, acyl (C2-C7) or C (R9) (R10), wherein each R9 and R10 is, independently, H or alkyl (CÍ-CJ); or each Rx and R2 is = CHCH2ORu, where in Ru, each Rt and R2 is independently H or acyl (C2-C7), and m is an integer between 1 and 5, inclusive; and one of R3 and R "is (CII2)" R12 or (CH2) nCH (OH) R12, where R12 is CO, CH2 or S02, and n is an integer between 1 and 5, inclusive; and the other R3 and R "is H, hydroxyalkyl ((Cj), or acyl (C2-C7); and compound II is: where each Rn, R ^ and R1S is, independently, H or acyl (C2 C2 «>; R16 is NH or is absent; R17 is CO, O, or absent; Rie is CO, CH2, S02, or is absent; and m is an integer between 1 and 5, inclusive; and n is an integer between 0 and 5, inclusive; and compound III is: (CH2) p-R25- (CH2) q-R26 wherein: R19 is II, NH2, an aromatic functional group, OH, hydroxyalkyl (Cn-C6), H (R27) (R2B), S03H, or is absent, where each R "and R2e, independently, is H or alkyl ( Cx-C6); R20 is O or is absent; R21 is alkyl or is absent; R22 is N, CH, 0, or C; -R2J- is alkyl ((CJ, or is absent; R "is N, CH, or C; R25 is H, O, or is absent; m is an integer between 0 and 5, inclusive; n is an integer between 0 and 5, inclusive; p is an integer between 0 and 5, inclusive; and q is an integer between 0 and 5, inclusive. In the compounds, II and III, the peptide moiety is linked to each of the substituents by means of a CO-N, CH2-N, or S02-N bond between the substituent and a nitrogen atom of the N-terminus or a chain side of said peptide fraction. In preferred embodiments, -R23- is alkyl (Ci-Cg); R22 is N, C, or CH; and R24 is C. Alternatively, R22 is O; R19, R20, R21 and -R23- are absent; and the sum of m and n is 3, 4 or 5. In other preferred embodiments of the invention, the substituent is compound I; in this embodiment, R12 is preferably CH2 or S02. Alternatively, the substituent may be compound II, in which case R18 is preferably CH2 or S02; R13, R14 and R15 are H; and R17 is absent. In particularly preferred embodiments, the substituent is (HOCH2) 3C-NH- (CH) 2-S02 or (HOCH2) 3C-CH2. In still other embodiments of the invention, the substituent is compound III; preferably, in this embodiment, -R23- is absent and at least one of R22 and R24 is N. Alternatively, both R22 and R24 may be N. In other embodiments, the substituent is one from : Y HO (C] I2) 2 - (Cfl2) 2S02- Preferably, the peptide moiety is selected from the group including: somatostatin, bombesin, calcitonin, the peptide related to the calcitonin gene (CGRP), amylin, parathyroid hormone (PTH), gastrin-releasing peptide (GRP) , melanocyte-stimulating hormone (MS1I), adrenocorticotropic hormone (ACT11), parathyroid-related peptide (PTHrP), hormone-releasing hormone luteniziante (LHRH), growth hormone-releasing factor (GI-1RF), peptide-releasing hormone Growth Hormone (GHRP), Cholecystokinin (CCK), Glycoagon, Bradykinin, Glycogon-Like Peptide (GLP), Gastrin, Encephalitis, Neuromedins, Endothelin, Substance P, Neuropeptide Y (NPY), YY Peptide (PYY), Vasoactive Intestinal Peptide (VIP), guaniline, pituitary adenylate cyclase activating polypeptide (PACAP), tropin of beta cells, adrenomedullin, and derivatives, fragments and analogs thereof. The peptide moiety is preferably somatostatin or a derivative, fragment or analog thereof. More preferably, the somatostatin analog is one of: H-D-Phe-c [Cys-Tyr-D-Trp- Lys-Abu-Cys] -Thr-NHa (II-D-Phe-c tCys-Tyr-D-Trp-Lys-Thr-Cys) -Nal-NH2, and HD-Nal-c [Cya-Tyr-D- Trp-Lys-Val-Cys] -Thr-NH2 Alternatively, the peptide moiety is bombesin or a derivative, fragment or analogue thereof In still other preferred embodiments, the peptide derivative is one of: (CH2) 2 - n - (c || 2 JCO-D-P e-c (Cys-lYr-D-Trp-Lys-Abu-Cys | -Tlir-HH2 > 2 ~ N ^ ^ N- < a, 2.2S02"D-Plie-c {Vs- -Trp-Lys-Abu-Cys | -'nir-NI.

In another aspect, the invention provides a dimeric peptide derivative containing two biologically active peptide moieties, and at least one substituent attached to each of the peptide moieties. The substituent is selected from the group consisting of compounds IV and V, wherein compound IV has a generic structure equivalent to compound I, and compound V has a generic structure equivalent to compound III. In the dimer, each of the peptide moieties is linked to the substituents by a CO-N, CH2-N, or S02-N bond between the substituent and a nitrogen atom of the N-terminus or a side chain of one of the fractions peptide. In still another aspect, the invention provides a method for treating a disease, such as cancer, in a patient; the method includes the step of administering the patient a therapeutic amount of the peptide derivatives described herein. In preferred embodiments, the peptide moiety used in the treatment is somatostatin. By "biologically active", as used herein, a natural, recombinant or synthetic peptide having physiological or therapeutic activity is indicated. In general, this term covers all derivatives, fragments and analogues of biologically active peptides that exhibit a qualitatively similar or opposite effect to that of the unmodified peptide. Brief Description of the Drawings Figure 1 is a graph of two growth curves of AR42J cells in the presence of different somatostatin derivatives. Description of the Preferred Embodiments of Peptide Derivatives In general, the peptide derivatives of the invention contain two separate components: 1) a biologically active peptide; and 2) at least one substituent having the structure of compounds I, II and III. Peptide derivatives made in accordance with the methods described herein include the following compounds. Derivatives based on Compound I p'-Nii-R12aMau (cn2) ° ~ (aí2 ^ nai { OH'R12 - ^ - £ " where R0, R1 # R2, R3, R4, R12 and n are as defined herein, and H-P 'is the biologically active peptide moiety. In these embodiments, the NH group is located at the N-terminal or side chain of the peptide and P 'represents the remainder of the peptide. Derivatives based on Compound II ) m-R16-R17- (cil2) irRle-NII-P ' where Rl3, R14, i5, Rie, Rn, R1B, ra, n and NH-P 'are as defined herein. Derivatives based on Compound III R «-R20-R21-¾2" R23"2 -R25- (C» 2) p-R26-N »-P ' where R ", R20, R21, R22, R23, 2« »« 25 »« 26 »'» »p and NH-P' are as defined herein. In addition to the structures shown above, the Compounds made in accordance with the invention include peptide derivatives that contain two or more substituents attached to a peptide moiety. These embodiments of the invention are derivatives of biologically active peptides having more than one free amino group, for example a lysine residue. The invention also provides peptide derivatives that contain two peptide moieties linked to a single substitutent, for example two Bradykinin analogs linked to a substituent of compound V. The peptide derivatives of the invention are biologically active peptide derivatives selected from the following group: somatostatin, bombesin, calcitonin, peptide related to the calcitonin gene (CGRP), amylin, parathyroid hormone (PTH), gastrin-releasing peptide (GRP), melanocyte-stimulating hormone (MSH), adrenocorticotropic hormone (ACTH), peptide related parathyroid hormone (PTHrP), luteinizing hormone releasing hormone (LHRH), growth hormone releasing factor (GRF), growth hormone releasing peptide (GHRP), cholecystokinin (CCK), glycoagon, Bradykinin, peptide similar to Glucose (GLP), gastrin, encephalin, neuromedins, endothelin, substance P, neuropeptide Y (NPY), peptide YY (PYY), vasoactive intestinal peptide (VIP), guaniline, pituitary adenylate cyclase activating polypeptide (PACAP), tropin of beta cells, adrenomedullin, or derivatives, fragments or analogs of any of the foregoing.

In especially preferred embodiments, the peptide moiety is somatostatin or a somatostatin derivative, fragment or analogue. Somatostatin analogs that can be used according to the present invention include, but are not limited to the following compounds: H-D-beta-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-beta-Nal-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-befea-Nal-NH2; H-D-Betar Nal-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-H2; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Pen-Thr; H-Gly-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr; H-Phe-Pen-Tyr-D-Trp-Lys-Thr-Cys-Thr; H-Phe-Pen-Phe-D-Trp-Lys-Thr-Pen-Thr; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol; H-D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-H2 H-D-Trp-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Trp-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH 2 H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH 2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-Phe-Lys * -Tyr-D-Trp-Lys-Val-Asp-Thr-NH2; Ac-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Bu) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-L-hArg (Et) 2-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 Ac-D-hArg (CH2CF3) 2-Cys-Phe-D-Trp-Lys-Thr-Cys -Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys -Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHE; Ac-L-hARg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hARg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NH2 Ac-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys (Me) -Thr-Cys-Thr-NHEt; Ac-hArg (CH3, hexyl) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; H-hArg (hexyl2) -Gly-Cys-.Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (E) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NHEt; Ac-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Phe-NH2; Propionyl-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys (iPr) -Thr-Cys-Thr-NH2 Ac-D-beta-Nal-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Gly-hArg (Et) 2-NH2; Ac-D-Lys (iPr) -Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys Thr-NH2; Ac-D-hArg (CH2CF3) 2-D-hArg (CH2CF3) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys Phe-NH2; Ac-D-hArg (Et) 2-D-hArg (Et) 2-Gly-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 Ac-Cys-Lys-Asn-4-Cl-PheTPhe -D-Trp-Lys-Thr-Phe-Thr-Ser-D-Cys-NH2 Bmp-Tyr-D-rp-Lys-Va1-Cys-Thr-H2; Bmp-Tyr-D-Tr-Lys-Va1 -Cys-Phe-H2; Bmp-Tyr-D-Trp-Lys-Val-Cys-p-Cl-Phe-NH2; Bmp-Tyr-D-Trp-Lys- al-Cys-beta-Nal-NH2; H-D-beta-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-beta-Nal-NH2; H-pentafluoro-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2; Ac-D-beta-Nal-Cys-pentafluoro-Phe-D-Trp-Lys-Val-Cys-Thr-NH2; H-D-beta-Nal-Cys-Tyr-D-Trp-Lys-Val-Cys-beta-Nal-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-beta-Nal-NH2; H-D-beta-Nal-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; Ac-D-p-Cl-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H-D-Phe-Cys-beta-Nal -D-Trp-Lys-Val-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Cys-Thr-NH2; cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp-N-Me-Lys-Thr-Phe) cycle (Pro-Phe-D-Trp- Lys-Thr-N-Me-Phe) Cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Thr-Phe) Cycle (Pro-Try-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe); Cyclo (Pro-Phe-L-Trp-Lys-Thr-Phe); cycle (Pro-Phe-D-Trp (F) -Lys-Thr-Phe); cycle (Pro-Phe-Trp (F) -Lys-Thr-Phe); cycle (Pro- Phe-D-Trp-Lys-Ser-Phe); [Pro-Phe-D-Trp-Lys-Thr-p-Cl-Phe); ! D-Ala-N-Me-D-Phe-D-Thr-D-Lys-Trp-D-Phe) D-Ala-N-eD-Phe-D-Val-Lys-D-Trp-D-Phe )! D-Ala-N-Me-D-Phe-D-Thr-Lys-D-Trp-D-Phe)! D-Abu-N-Me-D-Phe-D-Val-Lys-D-Trp -D-Tyr) N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe); Pro-Tyr-D-Trp-4-amfe-Thr-Phe) Pro-Phe-D-Trp-4-amfe-Thr-Phe); N-Me-Ala-Tyr-D-Trp-4-amfe-Thr-Phe); Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba); Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba-Gaba); Asn-Phe-D-Trp-Lys-Thr-Phe); Asn-Phe-Phe-D Trp-Lys-Thr-Phe-NH (CH2) 4C0) Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-beta-Ala); Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-D-Gly) -0H Phe-Phe-D-Trp-Lys-Thr-Phe) Phe-Phe-D-Trp-Lys-Thr-Phe- Gly); ! Phe-Phe-D-Trp-Lys-Th-Phe-Gaba); Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gly); ! Asn-Phe-Phe-D-Trp (F) -Lys-Thr-Phe-Gaba); Asn-Phe-Phe-D-Trp (N02) -Lys-Thr-Phe-Gaba); Asn-Phe-Phe-Trp (Br) -Lys-Thr-Phe-Gaba); Asn-Phe-Phe-D-Trp-Lys-Thr-Phe (I) -Gaba)! Asn-Phe-Phe-D-Trp-Lys-Thr-Ty (But) -Gaba); ! Bmp-Lys-Asn-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-Pro-Cys) -0H; cycle (Bmp-Lys -Asn-Phe-Phe-D-Trp-Lys -Thr-Phe-Thr|-Pro-Cys) -OH; cycle (Bmp-Lys -Asn-Phe-Phe-D-Trp-Lys -Thr-Phe-Thr| -Pro-Cys) -OH; cycle (Bmp-Lys -Asn-Phe-Phe-D-Trp-Lys -Thr-Phe-Thr -Tpo-Cys) -OH; cycle (Bmp-Lys -Asn-Phe-Phe-D-Trp-Lys -Thr-Phe-Thr| -MeLeu-Cys) -OH; Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-Phe-Gaba); Cyclo (Phe-Phe-D-Trp-Lys-Thr-Phe-D-Phe-Gaba) / Cyclo (Phe-Phe-D-Trp (5F) -Lys-Thr-Phe -Phe-Gaba); Cyclo (Asn -Phe -Phe-D-Trp-Lys (Ac) -Thr -Phe-NH- (CH2) 3-CO); Cyclo (Lys-Phe -Phe-D-Trp-Lys-Thr-Phe-Gaba); Cyclo (Lys-Phe -Phe-D-Trp-Lys-Thr-Phe-Gaba); and cycle (Orn-Phe-Phe-D-Trp-Lys-Thr-Phe-Gaba), where Lys * indicates an amide bridge formed between Lys * and Asp. The peptide compounds listed above are described in the following background, each of which is incorporated herein by reference: European Patent Application No. P5 164 EU; Van Binst, G. and collaborators; Peptide Research 5: 8 (1992); Horvath, A. et al., Abstract, "Conformations of Somatostatin Analogs Having Anti-Tumor Activity", 22 European Symposium on Peptides, 13-19 September 1992, Interlaken, Switzerland; European patent application 0 363 589 A2 (1990); European patent application 0 203 031 A2 (1986); U.S. Patent Nos. 4,904,642; 4,871,717; 4,853,371; 4,725,577; 4,684,620; 4,650,787; 4,603,120; 4,585,755; 4,522,813; 4,486,415; 4,485,101; 4,435,385; 4,395,403; 4,369,179; 4,360,516; 4,358,439; 4,328,214; 4,316,890; 4,310,518; 4,291,022; 4,423,481; 4,235,190; 4,211,693; 4,190,648; 4,146,612; and 4, 133, 782. In the somatostatin analogs listed above, each amino acid residue has the structure of NH-C (R) H-CI-, where R is the side chain; The lines between amino acid residues represent peptide bonds that bind amino acids. When the amino acid residue is optically active, it is the configuration in the L-form that is intended, unless the D-form is expressly designated. When two Cys residues are present in the peptide, a bisulfide bridge is formed between the two fractions. However, this link is not shown in the listed waste. Additionally, preferred somatostatin analogs of the invention are of the following formula: where is a D or L isomer of beta-Nal, Trp, beta-pyridyl-Ala, Phe, Phe substituted, or deleted; and each of A2 and A7, independently, is Cys, Asp or Lys. These fractions are covalently bound together via a bisulfide bridge or an amide bridge. In addition, A3 is beta-Nal, Phe, or X-Phe o-, m- or p-substituted, where X is a halogen, OH, NH2, N02 or alkyl CÍ-CJ, - A6 is Val, Thr, Ser , Ala, Phe, beta-Nal, Abu, lie, Nle or Nva; and A "is Phe, Thr, Tyr, Trp, Ser, beta-Nal, an alcohol group, or it is deleted; each of Rj and R2, independently, is H, lower acyl or lower alkyl; and R3 is OH, NH2 or is deleted. Preferably, when one of A2 and A7-is Cys, the other also s Cys; when A8 is an alpha-amino alcohol, R3 is deleted; and when neither A2 nor A7 is Cys, A2 is different from A7. Especially preferred somatostatin analogs of this embodiment are: M-D-he-Cys-yr-Ty -D-Trp-Lys-Va1-Cys-hr-NH2; H-D-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2; H-D-Nal-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-NH2; H-D-Phe-Cys-Tyr-D-Trp-Lys-Abu-Cys-Thr-NH2; H7D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Nal-NH2; and H-D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-ol. In other embodiments, linear somatostatin analogs of the invention have the following structure: A1-A2-A3-D-Trp-Lys-A6-A7-A8-R3 where A1 is a D or L isomer of Ala, Leu, Lie, Val, Nle, Thr, Ser, beta-Nal, beta-pyridyl-Ala, Trp, Phe, 2,4-dichloro-Phe, pentafluoro-Phe, pX -Phe or oX-Phe, where X is CH3, Cl, Br, F, OH, OCH3 or N02; A2 is Ala, Leu, Lie, Val, Nle., Phe, beta-Nal, pyridyl-Ala, Trp, 2-4-dichloro-Phe, pentafluoro-Phe, o-X-Phe, or p-X-Phe, where X is CH3, Cl, Br, F, OH, OCH3 or N02; A3 is pyridyl-Ala, Trp, Phe, beta-Nal, 2-dichloro-Phe, pentafluoro-Phe, oX-Phe, or pX-Phe, where X is CH3, Cl, Br, F, OH, OCH3, or N02; A6 is Val, Ala, Leu, Lie, Nle, Thr, Abu or Ser; A7 is Ala, Leu, Lie, Val, Nle, Phe, beta-Nal, pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, oX-Phe, or pX-Phe, where X is CH3, Cl, Br, F, OH, OCH3 or N02; A8 is a D or L isomer of Ala, Leu, Lie, Val, Nle, Thr, Ser, Phe, Beta-Nal, Pyridyl-Ala, Trp, 2,4-dichloro-Phe, pentafluoro-Phe, pX-Phe, or oX-Phe, where X is CH3, Cl, Br, F, OH, OCH3 or N02, or an alcohol thereof; and each of Rt and R2, independently, is H, lower acyl or lower alkyl; and R3 is OH, NH2, or is deleted. Preferably, at least one of A1 and A8 and one of A2 and A7 must be an aromatic amino acid; and when A8 is an alcohol, R3 is deleted. Additionally, A1, A2, A7 and A8 can not all be aromatic amino acids. Particularly preferred analogs of this aspect of the invention include: H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-p-N02-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Nal-p-chloro-Phe-TyrTD-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-Phe-Phe-D-Trp-Lys-Thr-Phe-Thr-NH2; H-D-Phe-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; H-D-Phe-p-chloro-Phe-Tyr-D-Trp-Lys-Val-Phe-Thr-NH2; Y H-D-Phe-Ala-Tyr-D-Trp-Lys-Val-Ala-D-beta-Nal-NH2. In still other preferred embodiments, the peptide moiety is bombesin or a bombesin derivative, fragment or analogue. Bombesin analogs that can be used for the practice of the present invention include, but are not limited to neuromedin C, neuromedin B, litorin and gastrin-releasing peptide (GRP), which has the following amino acid sequence: H-Ala-Pro-ValrSer-Val-Gly-Gly-Gly-Thr-Val - Leu-Ala-Lys-Met-Tyr-Pro-Arg-Gly-Asn-His -Trp-Ala-Val-Gly-His-Leu-Met-NH2. Other bombesin analogs that can be used in the present invention include the compounds described in the following background, the content of which is incorporated herein by reference: Coy et al., Peptides, Proceedings of the Eleventh Amer. Peptide Symposium, edited by Rivier et al., ESCOM, pp. 65-67 (1990); Wang et al., J. Biol. Chem. 265: 15695 (1990); Mahmoud et al., Cancer Research 51: 1798 (1991); Wang et al., Biochemistry 29: 616 (1990); Heimbrook et al., "Synthetic Peptides: Approaches to Biological Problems", UCLA Symposium on Mol. and Cell. Biol. New Series, vol. 86, editors Tam and Kaiser; Martínez et al., J. Med. Chem. 28: 1874 (1985); Gargosky et al., Biochem. j. 247: 427 (1987); Dubreuil et al., Drug Design and Delivery, vol. 2:49, Harwood Academic Publishers, GB (1987); Heikkila et al., J. Biol. Chem. 262: 16456 (1987); Caranikas et al., J. Med. Chem. 25: 1313 (1982); Saeed et al., Peptides 10: 597 (1989); Rosell et al., Trends in Pharmacological Sciences 3: 211 (1982); Lundberg et al., Proc. Nat. Acad. Sci 80: 1120 (1983); Engberg et al., Nature 293: 222 (1984); Mizrahi et al., Euro. J. Pharma. 82: 101 (1982); Leander et al., Nature 294: 467 (1981); Woll et al., Biochem. Biophys. Res. Comm. 155: 359 (1988); Rivier et al., Biochem. 17: 1766 (1978); Cuttitta et al., Cancer Surveys 4: 707 (1985); Aumelas et al., Int. J. Peptide Res. 30: 596 (1987); Szepeshazi et al., Cancer Research 51: 5980 (1991); Jensen et al., Trends Pharmacol. Sci. 12:13 (1991); U.S. Patent Nos. 5,028,692; 4,943,561; 4,207,311; 5,068,222; 5,081,107; 5,084,555; European patent applications Nos. 0 315 367 A2 (1989); 0 434 979 Al (1991); 0 468 497 A2 (1992); 0 313 158 A2 (1989); 0 339 193 Al (1989); PCT applications Nos. WO 90/01037 (1990); 90/02545 (1992); and UK Patent Application GB 1 231 051 A (1990). The peptides of the invention can be provided in the form of pharmaceutically acceptable salts. Examples of preferred salts are those with therapeutically acceptable organic acids, for example acetic, lactic, maleic, citric, malic, ascorbic, succinic, benzoic, salicylic, methanesulfonic, toluenesulfonic, or pamoic, as well as polymeric acids such as tannic acid or carboxymethyl cellulose, and salts with inorganic acids such as hydrohalic acids, including hydrochloric acid, sulfuric acid and phosphoric acid. Synthesis of Compounds The synthesis of compounds I, II and III is now described. The following abbreviations are used to describe the synthesis of compounds according to the present invention: naphthylalanine (1 or 2) alpha-aminobutyric acid dextrorotatory levogyral acid acetic acid benzotriazole-1-yloxytris (dimethyl amino) phosphonium hexafluoro-phosphate tert-butyloxycarbonyl dicyclohexyl carbodiimide 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide diethyl cyanophosphonate dimethylformamide dichloromethane methanol ethanol N, -diisoproylethylamine HOBT: 1-hydroxybenzotriazole HBTU: o-benzotriazole-l-yl-N, N, N ',' - tetramethyluronium hexafluorophosphate THF: tetrahydrofuran TFA: trifluoroacetic acid The starting materials and intermediates for compounds I, II and III are commercially available. Alternatively, the initial materials can be easily prepared by methods that are well known and included in the literature. For example, the chemistry of derivatives related to ascorbic acid can be found in J. Chem. Soc. , Perkin (translator) 1: 1220 (1974); Carbohvd. Res., £ 7: 127 (1978); Yakuqaku Zasshi. 6: 376 (1966); U.S. Patent No. 4,552,888; J. Med. Chem. 31: 793 (1988); ibid. 34 = 2152 (1991); and ibid. 3_5: 1618 (1992), the content of which is incorporated herein by reference. The chemistry of derivatives related to tris can be found in Arch. Biochem. Biophv .. 96.:653 (1962), Biochem. , 5: 46.7 (1966), the content of which is also incorporated herein by reference. Synthesis of Peptide Derivatives In a general sense, the coupling of compounds I, II or III to a free, appropriate amino group of a protected amino acid or peptide can be achieved according to well-known methods employed for the synthesis of peptides (e.g. , DCC, DCC-HOBT, DIC-HOBT PPA, EDC-HOBT, DEPT, BOP, HBTU) using a base (for example DIEA) in an inert solvent (for example DMF, THR or CH2C12 ethyl acetate or combinations thereof). The unblocking of the protected groups can also be carried out by well-known methods (for example, removal of the group by the addition of an acid or base, TFA, dioxane-HCl, ammonia, NaOMe, piperidine). In most cases, the reaction temperature should vary from -30 ° C to room temperature. In general, the first step of the synthesis involves the reaction between an epoxide and a free amino group of a protected amino acid or peptide; complex formation and deprotection can be achieved using well-known methods, such as those described by McManus et al., Synth. Communications. 3 .: 177 (1973), the content of which is incorporated herein by reference. Following the synthesis, the purification of intermediates and products can be achieved by conventional methods such as chromatography or HPLC. The identification of the compounds can be determined by conventional techniques such as NMR, amino acid analysis and mass spectrometry. The following examples illustrate the preferred methods for forming the compounds of the invention. Example 1 - Synthesis of Somatostatin Derivatives The following somatostatin derivative, also referred to herein as BIM-23118, was synthesized according to the invention: Example 1.1 - 3-0- (Benzyloxycarbonylmethyl) -2.5.6-triacetyl-ascorbic acid Acetic anhydride (6 tnl) was added dropwise to a solution of 3-0- (benzyloxycarbonylmethyl) -ascorbic acid (2.2 g) in pyridine (30 mi); the mixture was then stirred overnight at room temperature. The pyridine was evaporated under reduced pressure, leaving a residue which was then partitioned between ethyl acetate and 1N HCl. The ethyl acetate layer was washed in 1N HCl, and then in water. After drying (gS04), the ethyl acetate was evaporated under reduced pressure; Traces of pyridine and acetic anhydride that still remained were removed by multiple co-evaporations with toluene. The resulting 3-0- (benzyloxycarbonylmethyl) -2,5,6-triacetyl-ascorbic acid was dried under vacuum to give a viscous gel remaining in the residue (2.4 g). TLC (silica gel: CHCl3 / acetone [9: 1], f = 0.52). Example 1.2 - 3-0- (Carboxymethyl) -2,5,6-triacetyl-aBCORBIC acid A suspension of Pd-C (100 mg) in water (2 ml) was added to a solution of 3-0- (benzyloxycarbonylmethyl) - 2, 5, 6-triacetyl-ascorbic (2.4 g) in ethanol (30 ml), and the suspension was stirred under hydrogen (17 psi) for six hours.

The catalyst was then removed by filtration through a pad of celite and the filtrate was evaporated under reduced pressure to give 3-0- (carboxymethyl) -2,5,6-triacetyl-ascorbic acid. TLC (silica gel: CHCl3 / MeOH / HOAc [9: 1: -0.1], Rf = 0.2). Example 1.3 - Acid 5, 6. O-Isopropilidenoascorbic Acetyl chloride (0.67 ml) was added to a vigorously stirred suspension of ascorbic acid (8.0 g) in acetone (80 ml), and the mixture was stirred at room temperature overnight . The precipitate was collected by filtration, washed with ethyl acetate, and dried under reduced pressure to give 8.29 g of acid 5.6-0. isopropylideno-ascorbic, as a colorless solid. TLC (silica gel: CHCl3 / MeOH / HOAc [3: 1: 0.1], Rf = 0.54). Example 1.4 - 3-0- (Ethoxycarbonylpropyl) -5.6-isopropylidene-ascorbic acid A solution of 5,6-isopropylidene-ascorbic acid (2.0 g) in 10 ml of DMF was added dropwise to a suspension of NaH (0.44 g of dispersion). of NaH in mineral oil, washed with hexane several times) in 5 ml of DMF. After the evolution of gas ceased, a solution of 1.43 ml of ethyl 4-bromobutyrate in 5 ml of DMF was added dropwise and the mixture was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the resulting residue was subjected to chromatography on silica gel (55 g) using CHCl3 / MeOH (19: 1) as eluent. The appropriate fractions were taken and solvents were removed under reduced pressure to give a viscous residue containing 3-0- (ethoxycarbonylpropyl) -5,6-isopropylidene-ascorbic acid (1.1 g). Example 1.5 - 3-0- (Carboxypropyl) -5,6-isopropylidene-ascorbic acid 4.6 ml of 2N NaOH was added to a solution of 3-0- (ethoxycarbonylpropyl) -5,6-isopropylidene-ascorbic acid (1.02 g) in 15 g. my EtOH. After one hour, most of the ethanol was removed under reduced pressure and the residue was diluted with water (10 ml) and acidified with dilute HCl (pH 3). The solution was then saturated with NaCl and extruded several times with ethyl acetate; the extracts were then dried using MgSO4. The solvent was evaporated under reduced pressure to give a viscous residue containing 3-0- (carboxypropyl) -5,6-isopropylidene-ascorbic acid (0.85 g). TLC: (silica gel: CHCl3 / MeOH / HOAc [5: 1: -0.1], Rf = 0.55). EXAMPLE 1-6 - D-Nal-c [Cvs-Tyr-D-Trp-Lvs (BOC) -Val-Cvsl -Thr-NH, A solution of di-tert-butyl-bicarbonate (0.36 g) was added dropwise at 10 ° C. mi of DMF, to a solution of D-Nal-c [Cys-Tyr-D-Trp-Lys-Val-Cys] -Thr-NH 2 acetate (2 g, BIM-23014) in 45 ml of DMF. After two hours at room temperature, the solvent was removed under reduced pressure to give a residue, which was then subjected to chromatography on silica gel (150 g), using CHCl 3 / MeOH (9: 1), as eluent. Fractionals were taken The solvents were removed under reduced pressure to give a residue containing D-Nal-c [Cys-Tyr-D-Trp-Lys (BOC-Val-Cys) -Thr-NH2 (1.45 g). silica: CHCl, / Me01I [3: 1], Rf = 0.52) Example 1.7 0.2 nil of diisopropylethylamine was added to a solution of D-Nal-cyclo- [Cys-Tyr-D-Trp-Lys (BOC) -Val-Cys] -Thr-NHj (300 mg), 3-0- (carboxypropyl) ) -5, 6-isopropylidene-ascorbic (56 mg) and 11BTU (113 mg) in 5 ml of DMF. The mixture was then stirred at room temperature overnight, and solvent was removed under reduced pressure. The residue was partitioned between a mixture of ethyl acetate / MeOH and an aqueous solution, saturated with NaCl, and the ethyl acetate layer was washed with saturated aqueous NaCl, then aqueous NaCl, saturated, and then dried (MgSO 4). The solvent was evaporated under reduced pressure, and the residue was subjected to preparative TLC using a mixture of CHClj / MeOH (0: 1) as a developing solvent. The appropriate UV-positive zone was isolated and extracted with CHCl3 / MeOH. The solvents were removed under reduced pressure to give the product identified above (0.20 g). TLC (silica gel: CHC13 / - eOH [5: 1], Rf «0.54).

Example 1.0 - Removal of the BOC Group The ascorbic acid derivative containing D-Nal-c [Cys-Tyr-D-Trp-Lys (BOC) -Val-Cys] -Thr-.N1I2 (95 mg) shown above was treated with 25% TFA in CHClj for 45 minutes at room temperature. The volatiles were removed under reduced pressure to give a dry residue which was purified using Vydac C1B HPLC and CHjCN / 0.1% aqueous TFA. The final yield was 90 mg (FAB-MS (m / e) 1341). Example 1.9 - Other Forms of Realization The following somatostatin derivatives were also synthesized in an analogous way: The following somatostatin derivative, also referred to as BIM-23107, was synthesized according to the invention: (Aco-CH2) 3-C-NH-CO- (CH2) 2-CO-D-Nal-c [Cys-Tyr -D-Trp-Lys-Val-Cys] -Thr-NH2. E-example 2.1 - (Aco-CH.) T-C-NH-CO- (CH7). CO-D-Nal-c rCvs-Tyr-D-Trp-Lys-Val-Cvs] -Thr-NH. 0.03 ml of DIEA was added to an ice-cooled solution of 2-N- (succinyl) amino-2- (acetoxymethyl) -1,3-propanediol diacetate (83 mg) and HBTU (92 mg) in 2 ml of DMF. . After stirring at 0-5 ° C for 30 minutes, a solution of D-Nal-c [Cys-Tyr-D-Trp-Lys (BOC) -Val-Cys] -Thr-NH2 (100 mg) was added 2 ml of DMF, containing 0.03 ml of DIEA. The mixture was first stirred at 0-5 ° C for one hour and then stirred at room temperature overnight. The solvent was removed under reduced pressure to give a dry residue which was partitioned between ethyl acetate and saturated aqueous NaCl, and the EtOAc layer washed with 5% aqueous NaHCO and finally saturated NaCl, aqueous; the resulting solution was then dried using MgSO4. The solvent was evaporated under reduced pressure, leaving a residue containing (AcO-CH2) 3-C-NH-CO- (CH2) 2-CO-D-Nal-c [Cys-Tyr-D-Trp-Lys (BOC) -Val-Cys] -Thr-NH2 (0.14 g). TLC (silica gel: CHCl3 / MeOH / HOAc = 4: 1: 0.1, Rf = 0.82). Example 2.2 - Removal of the BOC Group 30 mg of the compound identified above were treated with 50% TFA in CHC13 for 45 minutes, at room temperature; then the volatile substances were removed, under reduced pressure, to give a residue. Traces of TFA were co-evaporated with ethanol, several times, and the residue was subjected to titration with ether and then dried to give 30 mg of the product (30 mg). TLC (silica gel: CHCl3 / MeOH / HOAc = 3: 1: 1, Rf = 0.24). Example 2.3 - Other Forms of Embodiment The following somatostatin derivatives were also synthesized, analogously. (HO-CH-) 3-C-NH-CO- (CH2) 2-CO-D-Nal-c [Cys-Tyr-D-Trp-Lys-Val-Cys] -Thr-NH2 BIM-23158 (H0 -CH2) 3-C-NH-CO- (CH2) 2-C0-D-Phe-c [Cys-Tyr-D-Trp-Lys-Thr-Cys] -Nal-NH2 BIM-23167 (H0-CH2) 3-C-NH-C0- (CH2) 2-CO-D-Phe-c [Cys-Tyr-D-Trp-Lys-Abu-Cys] -Thr-NH2 BIM-23173 (H0- | CH2) 3- C-NH-CO-CH2-CO-D-Phe-c [Cys-Tyr-D-Trp-Lys -Thr-Cys] -Nal BIM-23179 (HO-1CH2) 3-C-NH-CO-CH2-CO-D-Phe-c [Cys-Tyr-D-Trp-Lys -Abu-Cys] -Thr BIM-23182 Example 3 - Synthesis of BIM-23201 The following somatostatin derivative, also referred to as (BIM-23201), was synthesized in accordance with the present invention. (HO-CH2) 3-C-CH2-D-Phe-c [Cys-Tyr-D-Trp-Lys-Thr-Cys] -Nal-NH2 Example 3.1 - (HO-CH-) 3-C-CH. -D-Phe-c rCvs-Tyr-D-Trp-Lvs-Thr-Cvsl -Nal-NH. Two grams of molecular sieve of 3 Angstroms, followed by NaCNBH3 (36 mg) were added in portions, in increments of 15 minutes, to a solution of D-Phe-c [Cys-tyr (OBt) -D-Trp-Lys ( BOC) -Thr (OBt) Cys] Nal-NH2 (250 mg) and tris (acetoxymethyl) acetaldehyde (120 mg), obtained by oxidation of triacetyl pentaerythritol with pyridinium dichromate or DMSO / oxalyl chloride / -trietylamine ) in methanol (10 ml) containing 10% acetic acid. The mixture was then stirred at room temperature for 30 minutes and heated for 4 hours. After filtration, the residue was partitioned between ethyl acetate and water. The ethyl acetate layer was washed with water, then aqueous NaHCO 3, and then dried (MgSO 4). The solvent was evaporated under reduced pressure, to give a residue (0.4 g) which was then dissolved in methanol (5 ml), treated with a solution of NaOMe / MeOH (pH 10), stirred for 1 hour and finally neutralized with 1N HCl. at a pH of 5-6. After evaporation of the solvent, the residue was dissolved in 90% aqueous TFA (5 ml) and stirred for 30 minutes. The volatile materials were removed under reduced pressure and traces of TFA and water were removed in the resulting residue by co-evaporation with alcohol (2x). The residue was dried, then titrated with ether, and finally purified by HPLC using conditions similar to those described above, to give 41 mg of. { 110-CHX), -C-ClU-D-P e -c tCys-yr-D-Trp-Lys-Tlir-Cys] -Na1-NIl;,, as a colorless solid. MS (m / e) 1,262.8. Example 3.2 - Other Forms of Embodiment The following somatostatin derivative, also referred to as BIM-23195, was synthesized in an analogous manner. (HO-CHa), C-CHa-D-Phe-c [Cys-Tyr-D-Trp-Lys-Abu-Cys] -Thr-NH2 BIM-23195 Example 4 - Synthesis of BIM-23197 The following somatostatin derivative , also referred to as BIM-23197, was synthesized in accordance with the invention.

Example 4.1 - 2-Bromoethanesulfonyl Chloride Sodium 2-bromoethanesulfonate (4.0 g) was treated with PC15 (11.0 g) while cooling in an ice bath. After reaching the liquid phase, the solution was heated at 90-120 ° C for 1.5 hours in oil, cooled to room temperature, poured into 50 g of shredded ice, and then stirred for 15 minutes. The mixture was extracted with CH2C12 (3 x 30 mL) and the combined extracts were washed with M20 (2 x), NalICÜ, 5% (2 x), and again II20 (2 x). Drying over anhydrous MgS0 and distilling under reduced pressure gave 2-bromoethacrylate nosulfonyl, as a colorless liquid (1.95 g, 42-44 ° C / 1 mm Hg). Example 4-2 - Br- (CU.).-SO, -D-Phe-c tCvs-Tyr (tBu) -D-Trp-Lvs (Boc) - Abu-Cvsl -Thr (bBu) -NH (1- cyclopropyl-1-methyl) -ethyl A solution of 2-bromoethane sulfonyl chloride (30 mg) in DMF (1 ml) was added dropwise to a solution of II-D-Phe-c [Cys-Tyr (tBu ) -D-Trp-Lys (Boc) -Abu-Cys] -Thr (tBu) - (1-cyclopropyl-1-methyl) -ethyl (150 mg) and DIEA (55 mg) in DMF (2 ml) under Na at 0 ° C. The reaction mixture was stirred at 0-5 ° C for 3 hours; solvent was then removed under reduced pressure. The residue was dissolved in ethyl acetate and washed with 5% citric acid (2 x), 5% NaHCO 3 (2 x) and saline (2 x). The solution was then dried over anhydrous MgSO 4, filtered, and condensed to dryness under reduced pressure. The product was further purified by a short silica gel column, eluted with ethyl acetate. Fractions containing the product were separated and the solvent was removed under reduced pressure, giving 105 mg of Br- (CH2) 2-S02-D-Phe-c [cys-Tyr (tBu) -D- Trp-Lys (Boc) - Abu-Cys] -Thr (tBu) -NH (1-cyclopropyl-1-methyl) -ethyl as a slightly yellow solid. (Silica gel, CHClj / MeOH- / HOAc (9: 1: 0.1), f = 0.36). EH emolo 4.3 HOfCH, > , -HH- í CU,), -SO, -D-Plie-c t Cva-Tyr I tBu) -D-Trp-LvB (Boc) -A u- ^ 'CYBl-T r (tBm-HH ( l-cvcloDroDyl-l-methvH-ethvL A solution of I3r -. (CII2) 2-S02-D-Phe-c [Cys-Tyr (tBu) -D- Trp-Lys (Boc) -Abu-Cys] -Thr (tUu) -NH (1. Cyclopropyl -l-methyl) -ethyl (100 tng) and 2-hydroxyethylpiperazine (55 mg) in 2 ml of 1-propanol was refluxed under N2 for 2.5 hours. The solution was then cooled to room temperature, and the solvent was removed under reduced pressure. The residue was then dissolved in ethyl acetate containing 5% HeOH and washed with saline (3 x). Finally, the solution was dried over anhydrous MgSO 4, filtered and condensed to dryness under reduced pressure, resulting in 110 mg of the solid identified above. Without further purification, this compound was used directly in the next step. Example 4.4 110 mg of the protected somatostatin derivative obtained in the previous step was dissolved in 10 ml of 90% aqueous TFA solution and stirred at room temperature under N2 for one hour. TFA and 1120 were removed under reduced pressure, and the residue was titrated with cold ether (3 x 10 ral). A slightly yellow solid was obtained; this material was further purified in preparative HPLC in inverted phase, eluting with: 1) an aqueous solution of NH < 0Ac; and 2) an aqueous IIOAc solution. The lyophilization of the fractions containing the The above-identified product gave a white solid (lü mg, ESI-MS ((m + l) / e) 1252.7). Example 4.5 - Other Forms of Realization The following derivatives of .somatostatin were also synthesized in an analogous fashion: / ~ \ IIO (CII2) 2-ll M- (CII2) -CO-D-Pha-c l Cye-Tyr- D-Trp-LyB-Abu-CyB j -Thr-HH2 DIH-23190 HO (CHz) 2-N ^ ^ H (CH2) -CO-D-Plie-c l Cy e-Ty r-D-Trp-Ly e-Tlir-Cye J -Hal-Illlj DIM-23191 (IIO-CII2) jC-MIl- (CII2) 2-S02-D-Phe-c (Cy B-Ty r-D-Trp-Ly B -Abu-C B] -Thr-Hll2 DIH-23196 H0- (CH2) 2-0- (Cll2) 2-H H- (CH2) -CO-D-Plie-c l Cy B-Ty rD-Trp-Ly B-Abu-Cy BJ - \ - / Thr- HH2 DIM-23202 Example 5 - Synthesis of Bombesin Derivatives 131 The following bombesin derivative, also referred to as BIM-2G333, was synthesized in a manner analogous to that described above: ai -ai2-ai2-CO-D -? !! e-Gliipp-Ala-Val-Gly-His-Leu-Leu-N! Other peptide derivatives of the invention can be synthesized in an analogous manner, using synthetic modifications known in the art. Results of Test Peptide Assays Example 6 - Ligation Assays In order to demonstrate the binding affinity of somatostatin analogues (SRIF). To the somatostatin receptor, the purified compounds described above were tested in ligation assays involving measurements of the inhibition of ligation of [125 I-Tyr] SRIF-14 to rat pancreas membranes AR42J. As indicated in Table I, the purified somatostatin analogs of this invention demonstrated high binding affinities to these receptors. Additionally, the molecular weight, determined by mass spectrometry and estimated from the molecular structure, is listed in the table for each somatostatin derivative. Similarly, the described purified bombesin analog described was tested in a bombesin ligation assay. The ligation assay consisted of measurements of the inhibition of t125I-Trylx] bombesin binding to rat pancreas membranes AR42J; of the assay, the binding affinity of the bombesin analog to the GRP receptor of about 21 nM was determined. Example 7 - Test of Growth Hormone Inhibition (GH) Groups of five male Sprague Dawley rats (each weighing between 250 and 300 g) were injected subcutaneously with a somatostatin derivative or saline solution. 30 minutes before the selected post-medication time periods, shown in Table II (2 hours, 4 hours, 6 hours, 8 hours), the rats were anaesthetized with Nembutal via i.p. (50 mg / kg). 15 minutes after anesthesia, an aliquot of blood was removed by cardiac puncture on heparin to measure basal GH. Additionally, a s.c. injection was given. of D-Ala2-GRF (10 g kg). 15 minutes later, the blood was withdrawn to quantify the stimulated GH, which was measured in plasma using a radioimmunoassay supplied by NIADDKD. The percentage of GH inhibition was calculated from differences obtained between basal and stimulated GH values. Table II shows the effect of various purified somatostatin analogues as a function of time. The efficacy of D-Phe-c [Cys-Tyr-D-Trp-Lys-Thr-Cys] -Nal-NH2 (BIM-23060) in the inhibition of growth hormone in rats is compared with other somatostatin derivatives (BIM -23167, BIM-23179, and BIM-23181) of the invention. All derivatives demonstrate a surprisingly long duration of action, which is reduced in a time-dependent manner. Additional experiments were conducted on D-Phe-c [Cys-Tyr-D-Trp-Lys-Abu-Cys] -Thr-NH2, a somatastine analog, and BIM-23190, BIM-23195 and BI -23197, to determine the ED50 (it's to say, the concentration of each compound required to inhibit 50% of the release of growth hormone after a specified time) of the respective compound. Experiments were conducted at a dose range of between 25 and 0.25 g kg. Table III shows the surprising improvement of the somatostatin derivatives on the unmodified peptide at various time intervals, indicating the time-dependent inhibition of GH release stimulated by the compounds of the invention. Example 8 Antiproliferative Assay The purified somatostatin analogs described above were also tested for activity against rapidly proliferating cells. Table IV describes the effect of these peptides on the growth of tumor pancreas cells of rats AR42J. In contrast to natural somatostatin, the derivatives of the invention demonstrate substantial anti-proliferative activity. Referring to Figure 1, both BIM-23014C (a somatostatin analogue) and BI -23118 (a derivative of BIM-23014) inhibit the growth of rat pancreas tumor cells AR42J in a concentration-dependent manner, being BIM -23118 the most effective of the two compounds. Both compounds inhibit tumor cell growth to a greater extent than unmodified somatostatin analogues at equivalent concentrations. Example 9 - Timidine Taking Test In this assay, Swiss 3T3 cell cultures are cultured in Dulbecco's modified Eagles medium (DMEM) and supplemented with 10% fetal calf serum in a humidified atmosphere of 10% CO 2 and 90% air at 37 ° C. Cells were plated in 24-well dishes and used fdays after the last media change. In order to stop the cells in the G1 / G0 phase of the cell cycle, serum-free DMEM was used 24 h before the assay of thymidine uptake; the cells were then washed twice with aliquots of 1 ml of DMEM (without serum, 0.5 μm) and [tnethyl-3H] thymidine (20 Ci / mmoles, New England Nuclear). The bombesin derivatives were initially tested at 0.001, 0.01, 1, 10, 100, 100 nM. After 28 h at 37 ° C, the incorporation of [methyl-3H] thymidine in insoluble acid fractions was tested as follows. The cells were first washed twice with 0.9% NaCl, cold (aliquots of 1 ml); acid-soluble radioactivity was then removed by incubation for 30 minutes at 40 ° C by 5% trichloroacetic acid (TCA). The cultures were then washed once (1 ml) with 95% ethanol and solubilized by incubation for 30 minutes with 1 ml of 0.1 N NaOH. The solubilized material was transferred to flasks containing 10 ml of ScintA (Packard), and the radioactivity was determined by liquid scintillation spectrometry. This assay demonstrates the ability of bombesin derivatives to stimulate thymidine uptake into cells. The EC50 was calculated as 0.48 nm, demonstrating in this way that the Bombesin derivatives of the invention are potent simulators of thymidine uptake. Methods of Use Peptide derivatives of the invention can be administered to a mammal, particularly a human, in one of the traditional modes (eg, oral, parenteral, . transdermally or transmucosally), in a sustained release formulation using a biodegradable, biocompatible polymer, or by delivery to the site (eg, in the case of anti-cancer bombesin or somatostatin derivatives, to the lungs), using mycelia, gels and liposomes. The doses are generally the same as those currently used for therapeutic peptides in humans. Additionally, the peptide derivatives of the invention are suitable for the improved treatment of diseases that are susceptible to treatment by the corresponding unmodified peptide. In particular, • Somatostatin derivatives described above are suitable for the treatment of cancer, acromegaly, pancreatitis, trauma-induced proliferation, diabetes, diabetic retinopathy, restenosis following angioplasty, AIDS, neurogenic inflammation, arteritis and intestinal problems, including diarrhea.

Table I - Affinities of In Vitro Ligature and Molecular Weights of Derivatives of Somatostatin Peptides.

Table II - Inhibition of Stimulated Release of Growth Hormone in Rats by Derivatives of Somatostatin Peptides.

Table III - Inhibition of Stimulated Release of Growth Hormone in Rats by Derivatives of Somatostatin Peptides Administered S.C.

Table IV - Anti-Proliferating Activity of Somatostatin Peptide Derivatives.

CELLULAR GROWTH (PERCENTAGE OF CONTROL) 1 SRIF - 14 91.3 SRIF - 28 98.0 BIM - 23014C 74.1 BIM - 23107 67.5 BIM - 23109 72.1 BIM - 23118 61.0 BIM - 23135 62.9 BIM - 23167 60.2 BIM - 23173 67.9 BIM - 23181 69.1 BIM - 23182 68.7 BIM - 23183 69.1 BIM - 23195 69.2 BIM - 23197 66.4 1 Concentration 100 nM, tumor cells of rat pancreas

Claims (6)

1. CLAIMS 1. A dimeric peptide derivative, comprising: two biologically active peptide moieties, and at least one substituent attached to one of said peptide moieties, wherein said substituent is one of compounds IV and V, wherein compound IV is: where: 0 is 0, S or NR5, where R5 is H or (C ^ -Cg) alkyl; each j and R2, independently, is H, (CH2) mOR6, or CH (0R7) CH2OR8, where R6 is H or (C2-C7) acyl, and each R7 and RB, independently, is H, (C2-C7) acyl , or C (R9) (R10), wherein each R9 and Ri independently, is H or (Cj-Cg) alkyl; or each Rx and R2 is = CHCH2Rn, Ru in Rx and Rz, independently, is H or (C2-C7) acyl, and m is an integer between 1 and 5, inclusive; and each R3 or R4, independently, is (CH2) nR12 or (CH2) nCH (OH) R12, where Ra2 is CO, CH2 or S02, and n is an integer between 1 and 5, (CH2) p-R25- (CH2) where: R19 is S02, CO or CH2; R20 is 0, or is absent; R2i is (Ci-Cg) alkyl or is absent; R22 is N, CH, 0, or C; -R23- is (Ci-Cg) alkyl or is absent; R24 is N, CH, or C; R25 is NH, 0, or absent; R26 is S02, CO, or CH2, or is absent; m is an integer between 0 and 5, inclusive; n is an integer between 0 and 5, inclusive; p is an integer between 0 and 5, inclusive; q is an integer between 0 and 5, inclusive; wherein at least one of said peptide moieties is linked to each of said substituents by a CO-N, CH2-N, or S02-N bond between said substituent and a nitrogen atom of either the N-terminus or a side chain of one of said peptide fractions.
2. 2. The dimeric peptide derivative of claim 1, wherein -R23- is (C ^ -C ^ alkyl; R22 is N, C, or CH; and R24 is C.
3. 3. The dimeric peptide derivative of claim 1 where R22 is 0, R19, R20, R21 and -R23- are absent, and the sum of m and n is 3, or 5. A method to treat a disease in a Patient, comprising the step of administering to said patient a therapeutic amount of the peptide derivative of claim 1. The method of claim 4, wherein said peptide moiety is somatostatin or an analogue thereof. 6. The method of claim 4, wherein said disease is cancer.