BOMBESIN ANTAGONISTS

Abstract: The present invention provides a polypeptide of the formula (I): XX<1>TrpX<2>X<3>X<4>X<5>X<6>X<7>NH2, wherein X is a group X<8>Arg(or D-Arg)X<9>X<10> and X<8> is des NH2Pro,TyrPro,des NH2TyrPro, Ada, Pro, D-Pro or is deleted; X<9> is Gly, Ala, D-Ala or is deleted; X<10> is Asn, Phe, D-Phe, or Phe or D-Phe substituted by one or more halo atoms; or X is a group A-(CH2)n-CO- in which A is a group containing 1 to 3 rings of which at least one ring is aromatic, each ring system being optionally substituted; and the alkylene group is optionally substituted by one to four groups selected from amino, hydroxy, C1-4 alkoxy and C1-4 alkyl optionally substituted by halo and n is 0 to 4; or X is cyclopentyl carbonyl substituted by a group X<8>Arg(or D-Arg)X<9>X<10> as hereinbefore defined; X<1> is His, ThiAla or is deleted; X<2> is Ala, D-Ala, CPenc, D-tBuGly or Pro; X<3> is Val or Val substituted by one or more halo atoms; X<4> is Gly, Ala, D-Ala, Sarcosine, Pro, D-Pro or D-Phe; X<5> is His or ThiAla; X<6> is D-Pro psi , Pro psi , 2-pyrrolidinyl-3-hydroxypropionyl or D-Pro; X<7> is Nle, Leu, Phe, Val, Mox, D-Phe, Phe, or D-Phe substituted by one or more halo atoms or naphthylAla or naphthyl D-Ala or a hydrophobic, substituted aromatic amino acid or aralkylamine or is deleted, and the pharmaceutically acceptable salts thereof. The polypeptides possess antagonist properties against bombesin-like peptides and are of value in the treatment of malignant disease.

Description: Bombesin antagonists. The present invention relates to polypeptide compounds which possess antagonist properties against bombesin, or bombesin-like peptides, and are useful in the treatment of disease, particularly human small-cell lung cancer, Zollinger-Ellison syndrome or pancreatic cancer. The invention thus provides the polypeptides, processes - for preparing them, pharmaceutical compositions containing them, and their use in medicine. Bombesin is a tetradecapeptide originally isolated from the skin of a frog. It has the formula Glp-Gln-Arg-Gly-Asn-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 Gastrin releasing peptide is a 27 amino acid peptide isolated from the porcine gut. The last ten amino acids at the C-terminus of gastrin releasing peptide correspond with one amino acid alteration (3) to the last ten amino acids of bombesin, viz: H-Gly-Asn-His-Trp-Ala-Val-Gly-His-Leu-Met-NH 2 It has been reported (J.H. Walsh and J.R. Reeve, Peptides 6., (3), 63-68, (1985)) that bombesin and bombesin-like peptides such as gastrin releasing peptide are secreted by human small-cell lung cancer (SCLC) cells. It has been postulated (P.J. Woll and E. Rozengurt, PNAS £5. 1859-1863, (1988)) that gastrin releasing factor antagonists would bind competitively to bombesin receptors in animals and would therefore be of use in the treatment of SCLC and/or in the control of clinical symptoms associated with this disease and due to hypersecretion of this peptide hormone. Analogues of bombesin have been shown to inhibit the binding of gastrin releasing peptide to a SCLC cell line and to inhibit the growth of SCLC cells in-vitro and in-vivo (S.Mahmoud et al., Cancer Research, 51, 1798-1802 (1991). Several bombesin antagonists have been disclosed, for example [Leu 13 -Φ(CH -NH)-Leu 14 ] bombesin and [Ala 9 -Φ(CH 2 -NH)-Val 10 Leu 14 j bombesin (Coy et al, J.Biol Chem.. 1988, 261, 5056) and 4-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-His-Leu-0Me, 4-Pyridyl-CO-His-Trp-Ala-Val-D-Ala-His-Leu-NHMe, 4-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-His-MeLeu-0Me, 3-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-His-MeLeu-0Me, 4-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-Lys(Z)-MeLeu-0Me, 3-Indolyl-Co-His-Trp-Ala-Val-D-Ala-His-Leu-OMe, 4-Pyridyl-CO-His-Trp-Ala-Val-D-Ala-His-MeLeu-NHMe, 4-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-Lys(Z)-Leu-NHMe, 4-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-Lys(C0CH 2 Ph)-Leu-NHMe and 4-Pyridyl-C0-His-Trp-Ala-Val-D-Ala-Lys(C0CH 2 CH-Ph)-Leu- H e. (European Patent Application No. 345990A) . In the formula (I) below and throughout this specification, the amino acid residues are designated by their standard abbreviations (Pure and Applied Chemistry. 1974, 40, 317-331; European Journal of Biochemistry. 1984, 138, 9-37). For the avoidance of doubt it is stated that:- amino acid symbols denote the L-configuration unless otherwise indicated by D or DL appearing before the symbol and separated from it by a hyphen. (R) and (S) are the standard designations for molecular configuration. The following abbreviations are used: Φ - psi(CH 2 NH) Ada - 1-adamantanecarboxylic acid CPenc - aminocyclopentanecarboxylic acid Mox - methoxinine Des NELPro - 1-cyclopentanecarboxylic acid Des NH„Tyr - (4' -hydroxy)-3-phenylpropionic acid ThiAla - 3-(2-thienyl)-alanine β-tBuGly - D-tertiary-butyl-glycine (tertiary-D-leucine) When the Ada,CPenc,Mox,des NH„Pro,des NH„Tyr groups are in a polypeptide chain they are in the carbonyl form. It has now been discovered that a further group of polypeptides have potent bombesin antagonist activity. The compounds of the present invention inhibit the production of gastrin releasing peptide in mammalian cells and are therefore useful in controlling the clinical symptoms of diseases which cause the secretion of hypersecretion of gastrin releasing peptide (e.g., SCLC). Accordingly, the present invention provides a polypeptide of the formula (I) : XX 1 TrpX 2 X 3 X 4 X 5 X 6 X 7 NH 2 (I) 8 9 10 wherein X is a group X Arg(or £-Arg)X X a and X is des NH„Pro,TyrPro,des NH-TyrPro, Ada, Pro, D-Pro or is deleted; 9 X is Gly, Ala, D-Ala or is deleted; X is Asn, Phe, D-Phe, or Phe or D-Phe substituted by one or more halo atoms; or X is a group A-(CH„) -CO- in which A is a group containing 1 to 3 rings of which at least one ring is aromatic, each ring system being Optionally substituted; and the alkylene group is optionally substituted by one to four groups selected from amino, hydroxy C. , alkoxy and C. , alkyl optionally substituted by halo and n is 0 to 4, or X is a group A-(CH„) -CO- in which A is an optionally substituted aromatic residue containing 1 to 3 rings and the alkylene group is optionally substituted by one to four groups selected from amino, C. , alkoxy and C. , alkyl optionally substituted by halo and n is 1 to , o or X is cyclopentylcarbonyl substituted by a group X Arg (or D-Arg) 9 10 X as hereinbefore defined; X is His, ThiAla or is deleted; 2 X is Ala, D-Ala, CPenc, D-tBuGly or Pro; 3 X is Val or Val substituted by one or more halo atoms; 4 X is Gly, Ala, D-Ala, Sarcosine, Pro, D-Pro or D-Phe; X 5 is His or ThiAla; X is D-ProΦ, ProΦ, 2-pyrrolidinyl-3-hydroxypropionyl or D-Pro; X is Nle,Leu,Phe,Val,Mox, D-Phe or Phe, or D-Phe substituted by one or more halo atoms or naphthylAla or naphthyl D-Ala or a hydrophobic, substituted aromatic amino acid or aralkylamine or is deleted. Suitably A is phenyl, naphthyl, phenothiazinyl or indolyl. Preferably A is phenyl or naphthyl. Suitable substituents for the aromatic ring Ar include hydroxy, phenyl, halo, C. , alkyl or C. , alkoxy optionally substituted by halo. Preferably n is 2. Suitably X terminates in a des NH„ moiety. 8 9 Suitably X is des NH ? Tyr or des NH.Pro. Suitably X is Gly or D-Ala. 10 Suitably X is D-Phe. Preferably X is des ttt Phe, des NH„Tyr, des NH 2 TyrPro (or D-Pro) Arg (or D-Arg) Preferably X is His or ThiAla; 2 Preferably X is Ala, Pro; 3 Preferably X is Val or hexa luorovaline; 4 Preferably X is D-Ala, D-Phe; Preferably X 5 is His, ThiAla; Preferably X is n-ProΦ, ProΦ, Pro, D-Pro; Preferably X is Nle or Phe, Leu, Methoxinine, 2-Naphthyl-2- Alanine. Preferred polypeptides of the present invention include: N-((R)-2-(6-Methoxy-2-Naphthyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦNle-NH 2 N-((S)-2-(6-Methoxy-2-Naphthyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦNle-NH 2 N-((S)-3-Phenylbutyryl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH 2 N-((R)-3-Phenylbutyryl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValβ-Ala(3-(2-Thi)-Ala)D- ProΦNle-NH 2 N-((S)-3,3,3-Trifluoro-2-Methoxy-2-Phenyl-Propionyl)-HisTrpAlaValD- ProΦNle-NH 2 N-((R)-3,3,3-Trifluoro-2-Methoxy-2-Phenyl-Propionyl)-HisTrpAlaValD- ProΦNle-NH 2 N-3-(((4' -Hydroxy)Phenyl)Propionyl)-ProD-ArgGlyD-PheHisTrpAlaValGly- HisD-ProΦNle-NH. N-(((4'Hydroxy)-3-Phenyl)Propionyl)-ProD-ArgHisTrpAlaValD-AlaHisD- ProΦLeu-NH. N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦmox-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValD-ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-TrpAlaValS-AlaHisD-ProΦLeu-NH 2 N-((3-Phenyl)Propionyl)-HisTrpProValD-ProHisD-ProΦLeu-NH 2 N-3-(((3'-Trifluoromethyl)Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦLeu-NH 2 N-((3-Phenyl)Propionyl)-(3-(2-Thi)-Ala)TrpAlaValD-AlaHisD- ProΦLeu-NH 2 N-((deamino-Pro)-2-Argβ-AlaD-PheHisTrpAlaValGlyHisD- ProΦNle-NH 2 N- ( (3-Phenyl) Propionyl) -HisTrpAlaValGlyHisD-ProΦNle-NH 2 N- ( (deamino-Pro) -D-Arg£-AlaD-PheHisTrpAlaValD-AlaHisβ- ProΦNle-NH N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH 2 TyrProD-ArgGlyfi-PheHisTrpAlaValGlyHisD-ProΦNle-NH 2 D-ArgGlyD-PheHisTrpAlaValGlyHisD-ProΦNle-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProPhe-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValD- laHisD-ProΦ(3-(2-Naphthyl)- D-Ala)-NH N-((3-Phenyl)Propionyl)-HisTrpAlaValD-PheHisD-ProΦPhe-NH„ D-PheHisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-D-ProArgGlyD-PheHisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-(3-(2-Thi)-Ala)-TrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaVal-(Sarcosine)-HisD-ProΦPhe-NH N-3-(((4' -Hydroxy)Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH N-(((2' ,6'-Dichloro)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦNle-NH 2 N(((3' ,4'-Dichloro)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH 2 N-(((4' -Hydroxy)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH N-(1-Naphthoyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH N-((3,7-Dihydroxy)-2-Naphthoyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH N-(((3,4-Dihydroxy)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH 2 N-(2-(3-Pyridyl)Acetyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH 2 N-(2-(2-Thienyl)Acetyl)-HisTrpAlaValD-AlaHisD-ProΦNle-NH N-(((3-Fluoro)-3-Phenyl)Prop-ionyl)-HisTrpAlaValD-AlaHisD-ProΦNle-MU N-(((4-hydroxy-3-methoxy)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦNle-NH 2 N-(((R)-(-)-2-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((S)-(+)-2-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((Trans)-2-Phenyl)-Cyclopro-panoyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(3-(10-Phenothiazinyl)Propionyl-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-((3-Methyl-3-Phenyl)Butyryl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH N-(((2' -Trifluoromethyl)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(((3' -Trifluoromethyl)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH N-(((4'-Trifluoromethyl)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH„ N-(((2' ,3' -Difluoro)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(((2' ,4'-Difluoro)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(((2' ,6' -Difluoro)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(((2-Amino)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(1-Naphthoyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((3' ,4' ,5' -Trimethoxy)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-((6'-Methoxy)-2-(2-Naphthoyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(((3'-Trifluoromethyl)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(((S)-3-Phenyl)Butyryl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((4'-Methoxy)-3-Phenyl)Propionyl)-HisTrpAlaVal£-AlaHisD-ProΦPhe-NH 2 N-((((S)-2-Hydroxy)-2-Phenyl)Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisProΦPhe-NH 2 N-((2-Methyl-2-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(3-(1-Naphthyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((R)-3-PhenyDButyryl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-((9-Fluoroenoyl)l-Carbonyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((2'-Methoxy)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((2' ,5' -Dimethoxy)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦTyr-NH 2 N-(((2' ,3' -Dimethoxy)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHis(3-(2-Pyrrolidinyl- 3-Hydroxy)Propionyl)-Phe-NH 2 ((Isoquinolylcarbonyl)-HisTrpAlaValβ-AlaHisβ-ProΦPhe-NH 2 N-((3-Phenyl)Propionyl)-HisTrpAlaΦValD-AlaHisD-ProΦPhe-NH 2 Pharmaceutically acceptable salts or pro-drugs of polypeptides of the formula (I) are- also included within the scope of the present invention. Suitable pharmaceutically acceptable salts are acid addition salts when the polypeptide is sufficiently basic e.g., contains one or more basic residues such as histidine. A suitable pharmaceutically-acceptable acid-addition salt of the invention may be formed with an inorganic acid, for example hydrochloric acid, hydrobromic acid, sulphuric acid or phosphoric acid, or with an organic acid, for example acetic acid, citric acid, maleic acid, fumaric acid, succinic acid, tartaric acid or trifluoroacetic acid. The invention provides, as a further feature, any one or more of the preferred compounds together with their pharmaceutically acceptable acid-addition salts. The polypeptides of the invention may be prepared by any process well known in the art of peptide chemistry to be applicable to the synthesis of analogous compounds. Thus, for example, a polypeptide of the invention may be obtained by procedures analogous to those disclosed in "Solid Phase Peptide Synthesis" by Stewart and Young (published by the Pierce Chemical Company, Illinois, 1984), "Principles of Peptide Synthesis" (published by Springer-Verlag, Berlin, 1984) , "Practice of Peptide Synthesis" (published by Springer-Verlag, Berlin, 1984), and "The Synthesis of a Tetrapeptide (J.Am.Chem.Soc, 83 2149(1963)). Preferred processes for the manufacture of a polypeptide of the invention include, for example: - (a) the removal of one or more conventional peptide protecting groups from a protected polypeptide to give a polypeptide of the invention of formula I; (b) the formation of an amide bond by coupling two peptide units, one containing a carboxylic acid group, or a reactive derivative thereof, and the other containing an amino group, such that a protected or unprotected polypeptide having the sequence indicated in formula I is produced whereafter, if necessary, the protecting groups are removed using process (a) above. In process (a) there may be as many protecting groups in the starting material as there are radicals which may require protection, for example some or all of those groups which exist in the product as free hydroxy groups or basic amino groups (whether primary or secondary amino groups) . The protecting group or groups may be chosen from those described in the standard text books on peptide chemistry stated above. Various methods for the removal of the protecting group or groups are also described in those books. In process (a) a suitable protecting group for a basic amino group (whether at the JJ-terminus or in an amino acid side chain) is, for example, an arylmethoxycarbonyl group, which may be removed by hydrogenation over a catalyst, for example palladium-on-charcoal or it may be removed by treatment with an inorganic acid, for example anhydrous hydrogen fluoride or hydrogen bromide. In process (a) a particularly suitable protecting group for a basic amino group is, for example, an alkoxycarbonyl group, for example a Boc-group, which may be removed by treatment with an organic acid, for example trifluoroacetic acid, or it may be removed by treatment with an inorganic acid, for example anhydrous hydrogen chloride or hydrogen bromide; or for example a 9-fluorenylmethoxycarbonyl group, which may be removed by treatment with an organic base, for example piperidine. In process (a) a particularly suitable protecting group for the basic amino group in the side chain of Histidine is, for example, an arylsulphonyl group, for example a tosyl group, which may be removed by treatment with hydroxylamine, for example an N-hydroxytriazole, particularly 1-hydroxybenzotriazole, benzyloxymethyl or t-butyloxy- methyl. In process (a) a suitable protecting group for a hydroxy group is, for example, an arylmethyl group, for example a benzyl group, which may be removed by treatment with an inorganic acid, for example anhydrous hydrogen fluoride, or it may be removed by hydrogenation over a catalyst, for example palladium-on-charcoal; or it may be for example, an esterifying group, for example an acetyl or benzoyl group, which may be removed by hydrolysis with a base, for example sodium hydroxide. In process (a) a suitable protecting group for a carboxy group is, for example, an esterifying group, for example an arylmethyl group, for example a benzyl group, which may be removed by treatment with an inorganic acid, for example anhydrous hydrogen fluoride, or it may be removed by hydrogenation over a catalyst, for example palladium-on- charcoal; or, an alkyl group, C. . alkyl, for example a tert-butyl group which may be removed by treatment with an organic acid, for example trifluoroacetic acid. In process (a) particularly suitable protection for a carboxy group at the C-terminus is afforded by the formation of, for example, an ester, for example the ester formed by the coupling of the C-terminus amino acid and a resin, for example a hydroxymethylated styrene-divinylben- zene crosslinked resin; or by the formation of, for example, an amide, for example the amide formed by the coupling of the C-terminus amino acid and a resin, for example a methylbenzhydrylamine styrene-divin- ylbenzene crosslinked resin. In process (b) any one- of the standard peptide coupling reactions may be used, for example those described in the standard text books on peptide chemistry stated above. In process (b) it is to be understood that a peptide unit may contain- just one protected or unprotected amino acid. In process (b) a suitable coupling reaction is, for example, a solu¬ tion-phase coupling reaction, for example an active ester coupling, an azide coupling or a coupling involving N,N' -dicyclohexylcarbodiimide, 1-hydroxybenzotriazole and BOP(Benzotriazole-l-yl-oxy-tris-(dimethyl- amino)-phosphonium hexafluorophosphate. In process (b) a suitable reactive derivative of the peptide unit containing a carboxylic acid group is, for example, an acyl halide, for example an acyl chloride formed by the reaction of the acid and an inorganic acid chloride, for example thionyl chloride; a mixed anhydride, for example an anhydride formed by the reaction of the acid and a haloformate, for example isobutyl chloroformate; or an acyl azide, for example an azide formed by the reaction of the acid and am azide such as diphenylphosphoryl azide. In process (b) a particularly suitable reactive derivative of the peptide unit containing a carboxylic acid group is, for example, the product of the reaction of the acid and a carbodiimide, for example Hifi'dicyclohexylcarbodiimide or Jϋ.N' -diisopropylcarbodii ide, or it is the product of the reaction of the acid, an N-hydroxytriazole, for example 1-hydroxybenzotriazole, and a carbodiimide, for example N,£J' -dicyclohexylcarbodiimide or _{,__[' -diisopropylcarbodiimide. In process (b) a preferred strategy is, for example, to use a solid-phase synthesis wherein the amino acid which is to become the C-terminus amino acid of a polypeptide of the invention is protected at the alpha amino group and, if necessary, in the side-chain and coupled to a solid support, for example a resin, for example a hydroxymethylated or a methylbenzhdrylamine styrene-divinylbenzine crosslinked resin via an ester or amide linkage respectively, whereafter the protecting group on the alpha-amino group is removed. The amino acid which is to be attached to the C-terminus amino acid is protected at the alpha-amino group and, if necessary, in the side-chain and coupled to the C-terminus amino acid which remains attached to the solid support. The step-wise process of deprotection of the alpha-amino group and coupling to the next amino acid is repeated to give a protected or unprotected polypeptide attached to the solid support. The protected or unprotected polypeptide may be released from the hydroxymethylated resin solid support, for example, hydrolysis, for example acid hydrolysis with, for example, an organic acid, for example trifluoroacetic acid or with, for example, an inorganic acid, for example anhydrous hydrogen fluoride or hydrogen bromide; or the polypeptide is released by, for example, alcoholysis, for example methanolysis, in the presence of a base, for example an organic base, for example diisopropylethylamine whereafter, if necessary, the protecting groups are removed using process (a) above. When a me hylbenzhydrylamine resin is used, the protected or unprotected polypeptide may be released from the solid support, for example by treatment with an inorganic acid, for example hydrogen fluoride, whereafter, if necessary the protecting groups are removed using process (a) above. In process (b) a further preferred strategy is, for example, to use a solid-phase synthesis wherein an amino acid which is to become a link within the chain of amino acids forming a polypeptide of the invention is protected at the alpha-amino group and, if necessary, in the side-chain and coupled to a solid support, for example a resin as described above, whereafter the protecting group on the alpha-amino group is removed. The amino acid which is to be attached to the amino acid which has been coupled to the solid support is protected at the alpha-amino group and, if necessary, in the side-chain and coupled to the amino acid which remains coupled to the solid support. The step-wise process of deprotection of the alpha-amino group and coupling to the next amino acid is repeated to give a protected or unprotected polypeptide attached to the solid support. The protected or unprotected polypeptide may be released from the solid support, for example, using one of the methods described above whereafter a further peptide unit can be coupled using a solution- phase coupling reaction as described for process (b) above, and whereafter, if necessary, the protecting groups are removed using process (a) above. The polypeptides of the present invention have a bombesin antagonist effect, which may be demonstrated by their ability to inhibit Bombesin C stimulated mitogenesis of mouse Swiss 3T3 fibroblast cells as 3 determined by the uptake of [ H] -thymidine. According to a further feature of the invention there is provided a pharmaceutical composition which comprises a polypeptide of formula I, or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable diluent or carrier. The composition may be in a form suitable for oral use, for example a tablet, capsule, aqueous or oily solution, suspension or emulsion; for nasal use, for example, a snuff, nasal spray or nasal drops; for vaginal or rectal use, for example a suppository; for administration by inhalation, for example as a finely divided powder or a liquid aerosol; for sub-lingual or buccal use, for example a tablet or capsule; or for parenteral use (including intravenous, subcutaneous, intramuscular, intravascular or infusion), for example a sterile aqueous or oily solution or suspension. In general the above compositions may be prepared in a conventional manner using conventional excipients. However, in the case of a composition for oral administration, it may be convenient for the composition to include a coating to protect the polypeptide active ingredient from the actions of enzymes in the stomach. A composition of the invention may also contain, in addition to the polypeptide of the invention, one or more known antitumour substances selected from, for example, mitotic inhibitors, for example vinblastine; alkylating agents, for example cis-platin, carboplatin and cyclophosphamide; antimetabolites, for example, 5-fluorouracil, cytosine arabinoside and hydroxyuea; intercalating antibiotics, for example adriamycin and bleomycin; enzymes, for example asparaginase, topoisomerase inhibitors, for example etoposide and biological response modifiers, for example interferon. A preferred composition of the invention is, for example, one suitable for oral administration in unit dosage form, form example a tablet or capsule which contains from 2.5 to 500 mg, and preferably 10 to 100 mg, of polypeptide in each unit dose, or one suitable for parenteral administration which contains from 0.5 to 100 mg of polypeptide per ml, and preferably 1 to 10 mg of polypeptide per ml of solution. A parenteral composition is preferably a solution in isotonic saline or isotonic dextrose buffered if necessary to a pH of 5 to 9. Alternatively, the parenteral composition may be one designed for slow release in which case the amount of polypeptide per unit dose is in general greater than that required when a conventional injectable formulation is used. A preferred slow release formulation is, for example, a continuous release formulation, for example a formulation of the type described in US4767628 and US5004602. A preferred slow release parenteral formulation contains from 10 to 100 mg of polypeptide per unit dose. Another preferred slow release formulation is a micro-encapsulated polypeptide using a biodegradable biocompitible copolymer. These preparations are preferably administered intravenously, although administration may also be effected by means of subcutaneous, intramuscular, or intradermal injection. Polypeptides are therapeutic agents requiring specialized pharmaceutical formulations for effective, safe and convenient use by patients. Since even small oligopeptides like thyrotrophin releasing hormone (TRH) have very low oral activity, and larger molecules are inactivated by endopeptidases in the gastrointestinal tract, long-term treatment requires daily injection or administration from small portable infusion pumps. On the other hand, there are a number of potential approaches to self-administered methods, (e.g. nasal application, suppositories), or to controlled-release formulations such as injectable microcapsule suspensions and implants. Medicaments suitable for transdermal administration may take the form of an optionally buffered aqueous solution of a compound of formula (I) and may be delivered by passive diffusion or by electrically-assisted transport, for example, iontophoresis (see, for example, Pharmaceutical Research 1(6) , 318 (1986)). The composition of the invention will normally be administered such that a daily oral dose will be from 0.1 mg/kg, to 50 mg/kg, and most preferably from 0.1 mg kg to 25 mg/kg and a daily parenteral dose, will be from 20 micrograms/kg to 10 mg/kg more preferably from 100 micrograms to 10 mg/kg. According to a further feature of the invention there is provided a method for producing a bombesin antagonist effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a polypeptide of formula I or a pharmaceutically-acceptable salt thereof. The invention also provides the use of such a polypeptide of formula I or a pharmaceutically-acceptable salt thereof in the production of a new medicament for use in the treatment of a disease or medical condition mediated by bombesin or a bombesin-like peptide. The compounds of the present invention are useful for inhibiting the binding of gastrin releasing peptide in cells. The compounds of the present invention also inhibit the growth of cancer cells. A polypeptide of the invention is useful in the treatment of malignant disease, for example malignant disease in the lung, such as human small cell lung cancer, for example, malignant disease in the pituitary gland, adrenal gland, pancreas or within the skin. In particular, a polypeptide of this invention is useful for the symptomatic relief and/or treatment of exocrine pancreatic adenocarcinoma. A polypeptide of the invention is useful in the treatment of conditions associated with the over-production of bombesin or bombesin-like peptides (such as gastrin releasing factor) , for example the over-production of gastrin in the gut. The production of gastrin in animals has been linked to the suppression of the release of growth hormone and prolactin. The polypeptides of the invention may therefore be used to promote the availability of growth hormone in man or animals in need of such treatment. The polypeptides of the invention may also be used in the treatment of conditions associated with the failure of normal physiological control of the regulation of gastric acid secretion. According to further aspects of the invention, there are provided: (a) polypeptides of the invention for use in therapy; (b) pharmaceutical formulations containing polypeptides of the invention, at least one pharmaceutical carrier or excipient and, optionally, one or more other therapeutic ingredients; (c) the use of polypeptides of the invention in the manufacture of a medicament for the treatment of cancer; (d) the use of a polypeptide of the invention in the manufacture of a medicament for the treatment of: (i) Entercutaneous Fistula (ii) Type II diabetes, type I diabetes (iii) Zollinger-Ellison Syndrome (iv) Pancreatic islet carcinoma (v) Acromegaly (vi) Psoriasis e.g. Chronic Plaque Psoriasis (vii) Postoperative Small Bowel Fistula (viii) Dumping Syndrome (ix) Malignant Insulinoma (x) Pituitary Growth Hormone Cell Adenoma (xi) Thyrotropin-Secreting Pituitary Adenomas (xii) Small Cell Lung Cancer (e) a method for inhibiting the growth of cells that are sensitive to the growth promoting activity of gastrin releasing peptide in a mammal (such as a human) in need of such treatment which comprises the administration to said mammal of a growth inhibiting amount of a polypeptide of the invention to said mammal. The following examples serve to illustrate the preparation of polypeptides of the present invention and their biological properties: EXPERIMENTAL SECTION Materials: The following abbreviations are used throughout BOC - tertiary butyloxycarbonyl TLC - Thin layer Chromatography NMR - Nuclear Magnetic Resonance MS - Mass Spectrometry The following items were obtained from Advanced Chemtech, Inc., P.O. Box 1403, Louisville, KY 40201 U.S.A.: p-Methylbenzhydrylamine resin.HC1 (substitution ranges from 0.56 - 0.94 meq/g) , Trifluoroace¬ tic acid, N-Boc-D-Alanine, N-Boc-L-Alanine, N-Boc-N-Tosyl-Arginine, N-Boc-Glycine, N-Boc-L-Leucine, N-Boc-L-Leucinol, N-Boc-L-Norleucine, N-Boc-D-Phenylalanine, N-Boc-L-Phenylalanine, N-Boc-D-Proline, N-Boc- L-Proline, N-Boc-D-Prolinol, N-Boc-Sarcosine, N-Boc-L-Tryptophan, and N-Boc-L-Valine. N-Boc-L-im-CBZ-L-Histidine, N-Boc-^-Thienyl-L-Alanine, and 3-(2-Naph- thyl)-D-Alanine were acquired from Bachem, Inc., 3132 Kashiwa Street, Torrance, CA 90505, U.S.A. L-Methoxinine (O-Methyl-L-Homoserine) was obtained from Biohellas S.A., lO.Parnithos Street, 154 52 P. Phsychiko, Athens-Greece. Leucine methyl ester hydrochloride, (+)-6-Methoxy-α-methyl-2-Naphthal- eneacetic acid and (S)-6-Methoxy-α-methyl-2-Naphthaleneacetic acid were supplied from the Sigma Chemical Company, P.O. Box 14508, St. Louis, MO 63178, U.S.A. Di-tert-butyl Dicarbonate, 4-Fluorophenylalanine, 3-(4-Hydroxyphenyl)- propionic acid N-hydroxysuccinimide ester, and both (R) - and (S)-3-Phenylbutyric acid were obtained from Fluka Chemical Corp. , 980 South Street, Ronkonkoma, NY 11779, U.S.A. The following were acquired from Aldrich Chemical Co., Inc., 1001 West Saint Paul Avenue, Milwaukee, WI 53233, U.S.A.: 3-Phenylpropionic acid (Hydrocinnamic acid), (R) and (S)-3,3,3-Trifluoro-2-Methoxy-2-Phenyl- propionic acid, Dicyclohexyamine, 1-Cyclopentanecarboxylic acid, 4-Methylmorpholine, 1-Methylimidazole, Sodium cyanoborohydride and Diisopropylethylamine. One equivalent of dicyclohexylamine was added to the mixture, which was then diluted with a large excess of diethyl ether. Upon cooling, the Boc-amino acid-dicyclohexylamine salt crystallized out. The solid was filtered (20-30% yield), characterised (TLC, NMR, MS), and was used without further purification. Step II Preparation of Boc-D-Prolinal The following procedure is a variation of the reaction performed by Mancuso, et al. in J. Org. Chem. 43, 2481 (1978). Into a 500 ml three-neck flask, 25 ml of a 2.0 M solution of oxalyl chloride in methylene chloride (50 mmoles, solution obtained from Aldrich) was dissolved in 60 mL of dry CH„C1„, at -60°C, under N„. Dimethyl sulfoxide (10 ml, 140 mmoles, Aldrich) was dissolved in 25 ml dry CH„C1_, and added dropwise to the -60 C solution, by an addition funnel. This mixture was then stirred for 15 minutes after complete addition. Boc-fi-prolinol (10 g, 50 mmoles, Advanced Chemtech) was dissolved in 60 ml dry CH-C1- and chilled to -60°C in a 500 mL round-bottomed flask, under N„. To facilitate combination of the contents of both cold flasks, the N„ line was set up in series to accommodate both flasks. The oxalyl chloride/DMSO mixture was gradually added to the alcohol solution by N„-pressurized transfer through a double-tipped needle. By manually controlling the „ flow rate, the contents were transferred from one flask to the other, very slowly, but not dropwise. Upon complete addition, this mixture was stirred for 20 minutes. Lastly, 20 ml of triethylamine (140 mmoles, Kodak) was added slowly, while at -60 C. The mixture was then allowed to warm to room temperature. The mixture was washed with 50 ml of water. This aqueous layer was then extracted three times with 70 ml of CH„C1_. The organics were successively washed with 50 mL each of 5% NaHC0_, IN HC1, and water. The aqueous washings were extracted with 50 ml of CH^Cl,,, which was then combined with the other organics. After drying the organics with - - Dichloromethane (CH„C1„) , N,N-Dimethylformamide (DMF) , and N-Methyl- pyrrolidone were utilized as solvents for solid phase peptide synthesis and were obtained from Baxter Healthcare Corp., Burdick & Jackson Division, Muskegon, MI 49442, U.S.A. The BOP coupling reagent, Benzotriazol-1-yl-oxy-tris-(dimethylamino)- phosphonium hexafluorophosphate, was obtained from Richelieu Biotechnologies, Inc., 5726 Laurier Blvd., St-Hyacinthe, QC. , J2S 3V8 Canad . Hydrofluoric acid was acquired from Matheson Gas Products, P.O. Box 85, 932 Paterson Plank Road, East Rutherford, NJ 07073, U.S.A. Preparation of Peptides of the present invention Step I. Preparation of Boc-amino acids: Amino acids that were obtained without the tert-butyloxycarbonyl protecting moiety on the amino group (L-Methoxinine, 4-Fluorophenylalanine) were protected as described below. One equivalent of amino acid was dissolved in 5% aqueous Na„C0,/l,4-dioxane and cooled to 0 C. Two equivalents of Di-tert-butyl Dicarbonate, in 1,4-dioxane, was added dropwise to the cold amino acid mixture. Upon complete addition, the mixture was allowed to warm to 25 C and stirred for 12 hours. After reaction had gone to completion, as monitored by TLC, the dioxane was evaporated. The aqueous mixture was acidified with 1 N HCl until pH - 2, whereupon crystals formed, in most cases, at 60% yield. The solid was filtered and characterized by TLC, NMR, and MS as generally pure enough to continue without further purification. In those extreme cases, such as L-Methoxinine, in which the product that dropped out of the acidic, aqueous solution was a liquid, the product was removed from the aqueous solution with ethyl acetate. The organics were then dried with anhydrous sodium sulphate and the ethyl acetate was evaporated. The liquid residue was dissolved in a small portion of ethyl acetate. anhydrous sodium sulfate, the solvent was removed by rotary evaporation. The residue was dried on a vacuum pump for 3 hours. According to NMR, the characteristic -OH peak for Boc-D-prolinol (δ 4.5 ppm) was no longer visible. A sharp singlet at δ 9.4 ppm denoted the presence of the aldehydic proton of Boc-D-prolinal. TLC indicated a product mixture containing no substanial side products, so this was used without further purification. Step III Preparation of Boc-DProΦ(CH.NH)X-MBHA Resin i) Advanced Chemtech's p-methylbenzhydrylamine resin .HCl (p-MBHA) was utilized. Resin substitution ranged from 0.90-0.97 meq/g. Ten grams of p-MBHA resin (9.0-9.7 mmoles) were placed in a manual peptide shaker (Milligen) . The resin was washed twice (3 and 5 minutes) with 10% N,N-diisopropylethylamine (DIEA, Aldrich) in CH.C1- , while shaking. The resin was next rinsed twice with CH.C1„. Neutralization of the HCl on the resin was indicated by a Kaiser ninhydrin test observed as a very deep blue colour. The resin was next treated with two equivalents each of Boc-nor- leucine (Bachem, Torrance, CA) , benzotriazol-l-yloxy-tris(di- methylamino) phosphoniu hexafluorophosphate (BOP, Richelieu Biotechnologies of Canada) , and 4-methylmorpholine (Aldrich) ; all dissolved in 50 ml of N,N-dimethylformamide (DMF) . This mixture was shaken for 1 hour and then rinsed twice with CH„C1„. Coupling was verified by a Kaiser test (colourless) , compared to the previous Kaiser result (blue) . Deprotection of the Boc- group on norleucine was undertaken by shaking the resin in the presence of 50% trifluoroacetic acid (TFA, Advanced Chemtech) in CH„C1 twice, for 5 and 20 minutes. After rinsing the resin once with CH„C1_, the excess TFA was neutralized with 10% DIEA/CH C1„ solution for 3 and 5 minutes, with shaking. Following two CH 2 C1„ rinses, the resin was again qualitatively tested with ninhydrin (very deep blue) . The resin was next shaken for 2 hours with 2 equivalents of Boc-D-prolinal in 50 ml of 2% glacial acetic acid in DMF. Over the entire 2 hours, three equivalents of sodium cyanoborohydride (Aldrich) were added slowly and gradually. After rinsing twice with CH„C1-, coupling was checked with ninhydrin (colourless). The resin was now ready for standard solid phase peptide synthesis. Alternative Preparation of Boc-D-ProΦ(CH_NH)X-MBHA Resin ii) The following procedures may be used to prepare any D-ProΦ(CH„NH)X-MBHA resin, where X - any amino acid with a primary amino group. A. Boc-D-ProΦ(CH„NH)X-OH may be synthesized by the procedures of Martinez, et al. , in J. Med. Chem. , 28, 1874 (1985), or D. Tourwe, et al. , in Peptides 1988: Proceedings of the 20th European Peptide Symposium. , Ed. Jung, Bayer; Walter de Gruyter, p.562-4. B. This resin may be prepared by coupling Boc-D-ProΦ(CH-NH)X-0H to MBHA resin by shaking with BOP and 4-Methylmorpholine (or 1-Methylimidazole) in N-Methyl-pyrrolidone for 2 hours. Preparation of intermediates Preparation of Ethyl 3-(l-(Tert-Butoxycarbonyl)-2-Pyrrolidinyl -3- Hvdroxypropionate: Freshly activated zinc powder (0.79g, 12mmol, Aldrich) and benzene (50mL) were placed into a 250-mL two neck round bottom flask under N„. This flask was attached to a Dean-Stark apparatus and 25mL of benzene was distilled into the trap. Under reflux, a solution of Boc-D-Proli- nal (1.90g, 9.5mmol) and ethylbromoacetate (2.0g, 12mmol, Aldrich) was added dropwise. A crystal of iodine was added to initiate the reaction after half of the dropping solution was added. After complete addition, the mixture was refluxed for 3 hours, cooled, and carefully washed with 0.5n HCl. The aqueous solution was extracted with ether (25mL) and the combined organic solution was washed successively with water (30mL) and saturated NaHC0_ (30mL), then dried with anhydrous Na„S0, and concentrated under vacuum. A yellow oil was chromatographed on silica (with hexane/ethyl acetate) to isolate a colourless oil (1.12g, 41%). Mass spectral analysis yielded results at 288(m+l, 20%), 232 (m-tBu+1, 40%), and 188(m-C0 2 Bu+l, 100%). ^Η-NMR (CDCl- j ) : 5 4.15 (br m, 3H) ; 3.92(m, 1H); 3.48(m, 1H) ; 3.26(m, 1H) ; 2.40(m, 2H) ; 1.65-2.00(br m, 4H); 1.45(s, 9H) ; 1.25(t, 3H) . Preparation of 3-fl-(Tert-Butoxvcarbonvl)-2-Pvrrolidinvl)-3- Hvdroxypro ionic acid: A mixture of ethyl 3-(l-(tert-butoxycarbonyl)-2-pyrrolidinyl)-3-hydro- xypropionate (3.06g, 10.6mmol) and NaOH (0.80g, 20mmol) in H 2 0: THF: methanol (3: 3: 1, 35mL) was stirred at 25 C for 2 hours. The mixture was concentrated gently (30 C) under vacuum. The aqueous solution was acidified with 1.0 N HCl tp pH - 5, and was extracted with ethyl acetate. The organic washings were dried with MgSO, , filtered and vacuum concentrated. This residue was recrystallized from hexane/ethyl acetate resulting in 1.19g (47%) of a colourless solid (A, mp - 122-4 C) . The mother liquor was concentrated down to a viscous, pale yellow oil (B) . Mass spectral analysis yielded: 260(m+l, 60%); 204(m-tBu+l, 100%), 160(m-100+l, 70%). l H NMR (DMSO) : δ 4.09(m, 1H) ; 3.57(br s, 1H) ; 3.31(m, 1H); 3.15(m, 1H) : 2.10-2.40(m, 2H) ; 1.60-2.00(m, 4H) : 1.38(s, 9H). Elemental analysis: theory, 55.58% C, 8.16% H, 5.40% N; Found, 55.39% C, 8.23% H, 5.37% N. HPLC: one major peak on NOVA PAK C. 0 with 50% methanol/H 2 0/0.1% TFA/0.1% triethylamine (A - 93:7 ratio, B - 1:2 ratio observed on extended HPLC) . The two products were determined to be different stereoisomers, at the hydroxy position. Both stereoisors were used in individual peptides; the more active of the two is N-((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHis(3-(2-Pyrrolidinyl-3-Hydr¬ oxy)Propionyl)-Phe-NH„. Step IV Peptide synthesis and Purification The peptides were synthesised using an improved version of the solid phase method described by R.B. Merrifield, "Solid Phase Peptide Synthesis I. The Synthesis of a Tetrapeptide" , J. Am. Chem. Soc, 83, 2149(1963), using an Applied Biosystems Model 430A peptide synthesizer. For the synthesis of "pseudopeptides", the appropriate resin, e.g. Boc-D-ProΦ(CH-NH)Phe-MBH was loaded in the synthesizer and a standard deprotection (TFA/CH-C1„)-neutralization (diisopropylethylamine/ CH.C1 2 ) program, as supplied by Applied Biosystems (850 Lincoln Centre Drive, Foster City, CA 94404 U.S.A.) was used. Boc-protected amino acids were coupled to the resin using a modified program to suit the BOP coupling procedure, as described by Dung Le-Nguyen, Annie Heik, and Bertrand Castro, J. Chem. Soc, Perkins Trans. 1, 1915(1987). The coupling protocol involved dissolving ImMole of Boc-protected amino acid, lmMole BOP, and 1ml of 1M 1-Methylimidazole in 7 ml of DMF. The mixture was added to 0.5 mMoles of resin, mixed for 1 hour, and filtered. Afterwards, a series of DMF and CH-Cl- washes are performed. After the peptide was assembled on the resin, it was deblocked and cleaved from the resin with liquid HF containing 10% anisole, in a variation of the method described by S. Sakakibara, et al., in Bull. Chem Soc. Jap., 40, 2164(1967). The peptide and resin were next washed with ethyl acetate and then the peptide was extracted from the resin with an aqueous 1% acetic acid solution. The peptide solution was then lyophilized to obtain the dry, solid peptide. The peptides were then purified by reverse-phase liquid chromatography using a Vydac 218TP1022 column on a Waters Delta Prep 3000 system equipped with a Gilson Model 116 ultraviolet detector. Purification was achieved by equilibrating the column with 0.1% TFA in water and developing with a linear gradient of acetonitrile from 1-40% in 20 minutes at a flow rate of 20 mL/min. Samples were collected manually and checked for purity on a Spectra-Physics analytical HPLC system (including SP8700, SP8440, SP8780, and SP4200) utilizing a Vydac 218TP54 column. A flow rate of 1.5 mL/min. was employed using a 0.1% TFA/acetonitrile gradient from 10-60% ACN in 10 minutes. SYNTHESIS OF N-((3-Phenyl)Propionyl)HisTrpAlaValDAlaHisDPro-psi(CH 2 NH)Phe-NH 2 Methylbenzhydrylamine (MBHA) resin (5.0g., 4.7mmoles, Advanced Chemtech) was washed twice (3 & 5 min.) with 10% diisopropylethylamine (DIEA, Aldrich) in dichloromethane (DCM) on a Milligen Peptide Shaker. The resin was then washed with DCM and N,N-dimethylformamide (DMF). A solution containing 2.5g of Boc-Phe (9.4mmol., Chemtech), 4.3g of BOP Reagent (9.4mmol., Richilieu Biotechnologies), and 0.95mL of 4-Methylmorpholine (8.6mmol., Aldrich) were shaken on the resin for lh. The resin was then washed successively with methanol and DCM and coupling was verified via a Kaiser Ninhydrin qualitative test. A portion of the Boc-Phe-MBHA (3.06g., 2.8mmol) was deprotected by treating with 50% trifluoro-acetic acid (TFA, Chemtech) in DCM for 5 and 20 min. periods. The resin was washed twice with DCM. The acid was then neutralized by shaking for 3 and 5 min. with 10% DIEA solution and washed with DCM and DMF. The H^N-Phe-MBHA was shaken in a 1% acetic acid/N-methylpyrrolidone solution containing 1.2g of Boc-βProlinal (δ.Ommol., synthesis described previously) over 2h. Sodium cyanoborohydride (0.54g., 8.62mmol., Aldrich) was added in four portions during the 2h. (approximately every 20 min.) The resin was washed with methanol and DCM and tested with ninhydrin. Alternatively the same resin can be prepared as described in the alternative preparation above. The subsequent amino acids (Boc-His(Z), Boc-P-Ala, Boc-Val, Boc-Ala, Boc-Trp, Boc-His(Z) and 3-Phenylpropionic acid) were added to the sequence by an Applied Biosystems Automated Peptide Synthesizer (Model 430A) via the same procedure described for coupling, deprotection and neutralization involving Boc-Phe (utilizing O.Smmol. of resin and lmmol. each of amino acid, BOP, and 4-Methylmorpholine) . All amino acid couplings performed by the 430A were checked by qualitative Kaiser tests on resin samples provided by the instrument after the completion of each coupling. The peptide (approximately l.Og.) was cleaved from the MBHA resin by treating the peptide-resin with hydrogen fluoride (approximately lOmL) at 0 C for lh. The peptide was precipitated and filtered with the MBHA resin by ethyl acetate. The peptide was then extracted from the resin using 1% aqueous acetic acid and isolated upon freeze-drying this extract. A portion of the peptide (lOOmg) was purified on a Vydac C-18 preparative column (Chemtech) utilizing a 0.1% TFA/H_0:0.1% TFA/acetonitrile gradient. The collected fractions were verified by an analytical Vydao C-18 column (Chemtech) , and those samples reflecting pure peptide were combined and freeze-dried. Approximately 15mg of peptide was isolated. After characterization by FAB-Mass Spectrum (MH + - 1081.7) and Amino Acid Analysis [Ala(2.19), His(1.68), Val(1.12)], 12.2mg remained (12% yield based on HPLC) . Analytical Methods Purity was monitored by analytical HPLC using a Spectra-Physics analytical HPLC system, including SP8700, SP8440, SP8780, and SP4200. A Vydac 218TP54 column was utilized with a flow rate of 1.5 mL/min. of 1 0.1% TFA/acetonitrile gradient. The correct composition of each peptide was assessed by Amino Acid Analysis and (FAB) Mass Spectroscopy. Amino Acid Analysis was performed by the following procedure. Approximately 1-10 nanomoles of peptide were placed into an acid washed Pyrex test tube. The peptide was hydrolyzed under reduced N„ atmosphere with 6 N HCl with 1% phenol for 1 hour at 150 C. The peptide was then dried with a 2:2:1 mixture of ethanol: water: triethylamine, and derivatized with a 7:1:1:1 solution of ethanol: water: triethylamine: phenyliosothiocyanate. The derivatized amino acids then analyzed by reverse-phase chromatography. Fast atom bombardment (FAB) mass spectra were obtained on a VG 70S mass spectrometer of EBQQ geometry using a VG 11-250J Data System for data acquisition. The mass spectrometer was operated at seven kilovolts accelerating potential and a resolution of 1000 (10% valley definition) . The FAB gun used in the experiments was Ion Tech FAB11R operating at seven kilovolts potential and one milliamperes current. Xenon was used as the bombardment gas at a pressure of 1 x 10 millibars source pressure. The sample of interest was dissolved in glycerol prior to analysis by FAB-MS. Biolopical Results The peptides were evaluated in their activity to inhibit GRP binding to Swiss 3T3 cells. Antagonistic activity was measured by inhibition of the mitogenic stimulation of quiescent 3T3 ROZ cells. 3T3 ROZ cells were obtained from Enrique Rozengurt, Imperial Cancer Research Fund, P.O. Box 123, Lincoln's Inn Fields, London WC2A 3PX, England. Cells were incubated for eighteen hours with 10 ng/mL of BN either alone or in the presence of an antagonist. Cells were then 3 pulsed-labeled for 2 hours with H-thymidine and washed. The 3 incorporated H was then counted. Bombesin exposure resulted in increased cpm over media control up to a maximum response. Potency of antagonists was measured by inhibition of this maximum response down to baseline level. -^- cr , values were determined from titration curves. Analogues and available IC ςn values are listed in Table I. TABLE 1 STRUCTURE IC 50 1M1 MH "t" fFABV AAA MS -10 N-((R)-2-(6-Methoxy-2-Naphthyl) 3x10 1128 Ala(1.85), Propionyl)-HisTrpAlaValD-Ala His(1.79), HisD-ProΦNle-NH n Val(l.OO) -8 N-((S)-2-(6-Methoxy-2-Naphthyl) 1.77x10 1128 Ala(1.97), Propionyl)-HisTrpAlaValD-Ala His(1.81), HisD-ProΦNle-NH,, Val(1.00) N-((S)-3-Phenylbutyryl)-HisTrp 4.71x10 1061.6 Ala(1.92), AlaValD- laHisD-ProΦNle-NH„ His(1.71), Val(l.OO) -8 N-((R)-3-Phenylbutyryl)-HisTrp 7.54x10 1061.6 Ala(1.77), AlaValD-AlaHisD-ProΦNle-NH„ His(1.65), Val(l.OO) -7 N-((3-Phenyl)Propionyl)-HisTrp 2.35x10 1063.5 N/A AlaValD-Ala(3-(2-Thienyl)-Ala) D-ProΦNle-NH n N-((S)-3,3,3-Trifluoro-2-Methoxy- not yet 1132 Ala(2.40), 2-Phenyl-Propionyl)-HisTrpAla tested His(1.15), ValD-AlaHisD-ProΦNle-NH n Val(l.OO) N-((R)-3,3,3-Trifluoro-2-Methoxy- not yet 1131.3 Ala(1.90), 2-Phenyl-Propionyl)-HisTrpAla tested His(1.19), ValD-AlaHisD-ProΦNle-NH 2 Val(l.OO) N-(((4' -Hydroxy)-3-Phenyl) 1.99x10 -8 Ala(l.OO) Propionyl)-ProD-ArgGlyD-PheHis Arg(1.05) TrpAlaValGlyHisD-ProΦNle-NH Gly(2.15) His(1.73) Phe(1.02) Pro(l.10) Val(0.95) N-(((4'Hydroxy)-3-Phenyl) 7.96x10 -8 1508.2 Ala(0.96) Propionyl)-ProD-ArgGlyD-PheHis Arg(1.07) TrpAlaValGlyHisProΦNle-NH Gly(2.08) His(1.78) Phe(1.03) Pro(1.17) Val(0.91) N-((3-Phenyl)Propionyl)-HisTrp 3.43x10 -8 1049.4 Ala(2.09), AlaValβ-AlaHisD-ProΦMethoxinine- His(1.84), NH„ Val(1.07) -12 N-((3-Phenyl)Propionyl)-HisTrp 8.30x10 1081.7 Ala(2.19), AlaValD-AlaHisD-ProΦPhe-NH Λ His(1.68), Val(1.12) N-((3-Phenyl)Propionyl)-HisTrp 2.72x10 -8 922.0 Ala(2.02), AlaValD-AlaHisD-ProΦLeu-NH„ His(0.75), Val(1.00) N-((3-Phenyl)Propionyl)-HisTrp 6.92x10 1099.9 His(1.73), ProValD-ProHisD-ProΦLeu-NH Pro(2.06), Val(1.00) N- ( ( (3 ' -Trifluoromethyl) -3 -Phenyl) 2. 0x10 1116.0 Ala(1.92), Propionyl) -HisTrpAlaValD-AlaHisD- His(1.57), ProΦLeu-NH„ Val(l.OO) -9 N-((3-Phenyl)Propionyl)-(3-(2- 4.70x10 1064.0 Ala(1.96), Thienyl)-Ala-TrpAlaValD-AlaHisD- His(0.75), ProΦLeu-NH„ Val(l.OO) -8 N-((l-Cyclopentyl)carboxyl)-D- 1.75x10 1371.6 Ala(1.93) ArgD-AlaD-PheHisTrpAlaValGly Arg(1.04) HisD-ProΦNle-NH Λ Gly(1.03) His(1.91) Phe(1.04) Val(1.04) N-((3-Phenyl)Propionyl)-HisTrp 2.00x10 1034.1 Ala(0.99), AlaValGlyHisD-ProΦNle-NH 2 Gly(1.11), His(1.94), Val(0.96) -8 N-((l-Cycloρentyl)carboxyl)-D- 1.73x10 1386.7 Ala(2.90), ArgD-AlaD-PheHisTrpAlaValD- Arg(1.07), ProΦNle-NH„ His(1.93), Phe(1.05), Val(1.05) N-((3-Phenyl)Propionyl)-HisTrp 3.10x10 1048.2 Ala(2.02), AlaValD-AlaHisD-ProΦNle-NH n His(1.90), Val(1.08) TyrProD-ArgGlyD-PheHisTrpAla 8.54x10 " 1522.2 Ala(1.03), ValGlyHisD-ProΦNle-NH 2 Arg(0.97), Gly(2.07), His(2.03), Phe(l.OO), Pro(0.93), Tyr(0.87), Val(l.ll) P.-ArgGlyD-PheHisTrpAlaValGly 2.00x10 1262.5 Ala(0.97), HisD-ProΦNle-NH„ Arg(1.05), Gly(1.96), His(1.94), Phe(1.04), Val(1.04) N-((3-Phenyl)Propionyl)-HisTrp 7.87x10 -8 1017.0 Ala(1.87), AlaValβ-AlaHis(4-FluoroPhe)-NH 2 His(0.86), Val(l.OO) N-((3-Phenyl)Propionyl)-HisTrp 3.65x10 -8 1096 Ala(2.13), AlaValD-AlaHisD.-ProPhe-NH His(2.31), Phe(l.ll), Pro(l.24), Val(l.OO) N-((3-Phenyl)Propionyl)-HisTrp 2.65x10 " 1132.4 Ala(1.96), AlaVal£-AlaHisD-ProΦ(3-(2- His(1.42). Naphthyl)-D-Ala)-NH 2 Val(1.00) N-((3-Phenyl)Propionyl)-HisTrp 4.32x10 -8 1157.4 Ala(1.15), AlaValβ-PheHisD-ProΦPhe-NH His(1.76), Phe(0.99), Val(l.OO) D-PheHisTrpAlaValD-AlaHisD- <5.47x10-10 1093.2 Ala(1.98), ProΦPhe-NH. Phe(0.92), Val(l.OO) N-((3-Phenyl)Propionyl)-D-Pro <3.90x10 -10 1540 Ala(1.83), ArgGlyD-PheHisTrpAlaValD-Ala Arg(1.02), HisD-ProΦPhe-NH. Gly(0.94), His(1.54), Phe(0.85), Pro(0.94), Val(l.OO) N-((3-Phenyl)Propionyl)-3-(2- 3.65x10 -8 Alad.92), Thienyl)-Ala)-TrpAlaValD-Ala His(0.59), HisD-ProΦPhe-NH„ Val(l.OO) N-((3-Phenyl)Propionyl)-HisTrp <5.55xl0 •10 Ala(1.02), His(2.06), AlaVal-Sarcosine)-HisD -ProΦPhe' NH 2 Val(l.OO) N-(((4'-Hydroxy)-3-Phenyl) <5.47x10 "10 1098 Ala(2.04), Propionyl)-HisTrpAlaValD- His(1.96), AlaHisD-ProΦPhe-NH„ Val(l.OO) N-(((2' ,6' -Dichloro)-2-Phenyl) 9.07x10 -7 1103 Ala(1.85), Acetyl)-HisTrpAlaValD-AlaHisD- Hisd.83), ProΦNle-NH„ Val(1.00) N(((3',4'-Dichloro)-2-Phenyl) <5.44x10 ■10 1103.5 Ala(2.06), Acetyl)-HisTrpAlaValD-AlaHisD- His(1.79), ProΦNle-NH n Val(1.00) N-(((4'-Hydroxy)-2-Phenyl) 1.91x10 -9 1050.1 N/A Acetyl)-HisTrpAlaValD-Ala HisD-ProΦNle-NH„ N-(1-Naphthoyl)-HisTrpAlaValD- 9.35xlθ "10 1069.9 N/A AlaHisD-ProΦNle-NH Λ N-((3,7-Dihydroxy)-2-Naphthoyl)• HisTrpAlaValβ-AlaHisS-ProΦNle- NH 2 N-(((2,3-Dihydroxy)-2-Phenyl) Acetyl)-HisTrpAlaValD-AlaHisD- ProΦNle-NH N-(2-(3-Pyridyl)Acetyl)-HisTrp AlaValD-AlaHisβ-ProΦNle-NH. N-(2-(2-Thienyl)Acetyl)-HisTrp AlaValD-AlaHisD-ProΦNle-NH Λ N-(((3-Fluoro)-3-Phenyl)Prop- ionyl)-HisTrpAlaValD-AlaHisβ- ProΦNle-NH 2 N-(((3,4-Dihydroxy)-2-Phenyl) Acetyl)-HisTrpAlaValD-AlaHisβ- ProΦNle-NH 2 N-(((R)-(-)-2-Phenyl)Propionyl)• HisTrpAlaValfi-AlaHisD-ProΦPhe- NH 2 N-(((S)-(+)-2-Phenyl)Propionyl)' HisTrpAlaValD-AlaHisD-ProΦPhe- NH„ N-(((Trans)-2-Phenyl)-Cyclopro- 1.46x10 1093.1 Ala(1.99). panoyl)-HisTrpAlaValD-AlaHisD- His(1.44), ProΦPhe-NH Val(l.OO) N-(3-(10-Phenothiazinyl)Prop- 2.66x10 1202.1 Ala(2.25), ionyl-HisTrpAlaValD-AlaHisD- His(1.58), ProΦPhe-NH„ Val(l.OO) N-((3-Methyl-3-Phenyl)Butyryl)• 1.44x10 1109.5 Ala(2.07), HisTrpAlaValD-AlaHisD-ProΦPhe- His(1.63), NH Λ Val(1.00) N-(((2' -Trifluoromethyl)-2- 3.50x10 1135.4 Ala(2.10), Phenyl)Acetyl)-HisTrpAlaValD- His(1.63), AlaHisD-ProΦPhe-NH„ Val(l.OO) -8 N-(((3' -Trifluoromethyl)-2- 8.81x10 1135.4 Ala(2.10), Phenyl)Acetyl)-HisTrpAlaValD- His(1.60), AlaHisD-ProΦPhe-NH„ Val(l.OO) -7 N-(((4'-Trifluoromethyl)-2- 1.41x10 1135.5 Ala(2.24), Phenyl)Acetyl)-HisTrpAlaValD- His(1.68), AlaHisD-ProΦPhe-NH„ Val(l.OO) -7 N-(((2' ,3' -Difluoro)-2-Phenyl) 3.61x10 1103.4 Ala(2.16), Acetyl)-HisTrpAlaValD-AlaHisD- His(1.63), ProΦPhe-NH„ Val(l.OO) -7 N-(((2',4'-Difluoro)-2-Phenyl) 1.80x10 110 .2 Ala(2.16), Acetyl)-HisTrpAlaValD-AlaHisD- His(1.62), ProΦPhe-NH Λ . Val(l.OO) N-(((2' ,6' -Difluoro)-2-Phenyl) 5.71x10 1103.2 Ala(2.11), Acetyl)-HisTrpAlaValD-AlaHisD- His(1.69), ProΦPhe-NH„ Val(l.OO) N-(((2-Amino)-2-Phenyl)Acetyl) 7.30x10 1082.2 N/A HisTrpAlaValD-AlaHisD-ProΦPhe- NH„ -12 N-(1-Naphthoyl)-HisTrpAlaValD- 1.81x10 1103.9 AlaHisD-ProΨPhe-NH„ ■11 N-(((3',4' ,5' -Trimethoxy)-3- 1.11x10 1171.8 Phenyl)Propionyl)-HisTrpAla ValD-AlaHisD-ProΦPhe-NH„ •11 N-((6'-Methoxy)-2-(2-Naphthoyl) 3.44x10 1161.8 Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH„ ■11 N-(((3'-Trifluoromethyl)-3- 3.47x10 1149.8 Phenyl)Propionyl)-HisTrpAlaValD- AlaHisD-ProΦPhe-NH„ •11 N-(((S)-3-Phenyl)Butyryl)-His 5.47x10 1095.9 TrpAlaValD-AlaHisD-ProΦPhe- H 2 ■12 N-(((4'-Methoxy)-3-Phenyl) 5.40x10 1111.9 Propionyl)-HisTrpAlaValD-Ala HisD-ProΦPhe-NH 2 N-((((S)-2-Hydroxy)-2-Phenyl) 5.53x10 " 1083.8 Acetyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 -9 N-((3-Phenyl)Propionyl)-HisTrp 9.25x10 1081.5 AlaValD-AlaHisProΦPhe-NH 0 ■11 N-((2-Methyl-2-Phenyl)Propionyl) 1.46x10 1095 Ala(2.00), HisTrpAlaValD-AlaHisD-ProΦPhe- His(1.55), NH„ Val(l.OO) N-(3-(1-Naphthyl)Propionyl)-His 1.77x10 1131 Ala(2.22), TrpAlaValD-AlaHisD-ProΦPhe-NH His(1.44), Val(l.OO) N-(((R)-3-Phenyl)Butyryl)-HisTrp 9.12x10 1095 Ala(2.68), AlaValD-AlaHisD-ProΦPhe-NH 2 His(1.38), Val(l.OO) N-((9-Fluoroenoyl)1-Carbonyl)- 8.66x10 1158 Ala(2.71), HisTrpAlaValD-AlaHisD-ProΦPhe- His(1.08), Val(1.00) N-(((2' -Methoxy)-3-Phenyl) 9.00x10 1111 Ala(2.07), Propionyl)-HisTrpAlaValD-Ala His(1.35), HisD-ProΦPhe-NH„ Val(l.OO) N-(((2' ,5'-Dimethoxy)-3-Phenyl) 8.76x10 1141.7 Ala(2.23), Propionyl)-HisTrpAlaValD-AlaHisD- His(1.67), ProΦPhe-NH„ Val(l.OO) N-((3-Phenyl)Propionyl)-HisTrpAla 1.82x10 ' 1097.7 N/A ValD-AlaHisD-ProΦTyr-NH 2 -9 N-(((2' ,3'-Dimethoxy)-3-Phenyl) 3.50x10 1141.7 Ala(2.25), Propionyl)-HisTrpAlaValD-AlaHisD- His(1.66), ProΦPhe-NH„ Val(l.OO) N-((3-Phenyl)Propionyl)-HisTrpAla 1.76x10 1139.6 N/A ValD-AlaHis(3-(2-Pyrrolidiny1- 3Hydroxy)Propionyl)-Phe-NH 2 ((Isoquinolyly-Carbonyl) -HisTrp 3.44x10-9 1104.5 Ala(1.82), AlaValD-AlaHisD-ProΦPhe-NH„ His(1.32), Val(l.OO) N-((3-Phenyl)Propionyl)-HisTrp 7.50x10 1067.1 Ala(1.00, AlaΦValD-AlaHisD-ProΦPhe-NH„ His(3.17)

Claims: CLAIMS 1. A polypeptide of the formula (I): XX 1 TrpX 2 X 3 X 4 X 5 X 6 X 7 NH 2 (I) 8 9 10 wherein X is a group X Arg(or D-Arg)X X Q and X is des NH Pro,TyrPro,des NH 2 TyrPro, Ada, Pro, D-Pro or is deleted; 9 X is Gly, Ala, D-Ala or is deleted; X is Asn, Phe, D-Phe, or Phe or D-Phe substituted by one or more halo atoms; or X is a group A-(CH 2 ) -C0- in which A is a group containing 1 to 3 rings of which at least one ring is aromatic, each ring system being optionally substituted; and the alkylene group is optionally substituted by one to four groups selected from amino, hydroxy, C- , alkoxy and C. , alkyl optionally substituted by halo and n is 0 to 4; Q or X is cyclopentyl carbonyl substituted by a group X Arg (or 9 10 D-Arg) X X as hereinbefore defined; X is His, ThiAla or is deleted; 2 X is Ala, D-Ala, CPenc, D-tBuGly or Pro; 3 X is Val or Val substituted by one or more halo atoms; 4 X is Gly, Ala, D-Ala, Sarcosine, Pro, D-Pro or D-Phe; X 5 is His or ThiAla; X is D-ProΦ, ProΦ, 2-pyrrolidinyl-3-hydroxypropionyl or D-Pro; X is Nle,Leu,Phe,Val,Mox, D-Phe, Phe, or D-Phe substituted by one or more halo atoms or naphthylAla or naphthyl D-Ala or a hydrophobic, substituted aromatic amino acid or aralkylamine or is deleted, or a pharmaceutically acceptable salt thereof. A polypeptide of formula (I) as claimed in Claim 1, wherein X is a group A-(CH.) -CO- in which A is phenyl, naphthyl, phenothia- zinyl or indolyl, optionally substituted by substituents selected from hydroxy, phenyl, halo, C. , alkyl or C. alkoxy optionally substituted by halo; n is 2; 1 0 * -\ / ζ A 7 aanndd XX 1 ,, X , X , X , X , X , X as defined in Claim 1, or pharmaceutically acceptable salt thereof. 3. A polypeptide of formula (I) as claimed in Claim 1, wherein X is des NH 2 Phe, des NH j Tyr, des NH 2 TyrPro (or D-Pro) Arg (or D-Arg), and X is His or ThiAla; 2 X is Ala, Pro; 3 X is Val or hexafluorovaline; X 4 is D-Ala, D-Phe; X 5 is His, ThiAla; X is D-ProΦ, ProΦ, Pro, D-Pro; X is Nle or Phe, Leu, Methoxinine, 2-Naphthyl-2-Alanine or a pharmaceutically acceptable salt thereof. 4. A polypeptide of formula (I) as claimed in any one of Claims 1 to 3, which compound is: N((3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((4' -Hydroxy)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 N-(1-Naphthoyl)-HisTrpAlaValD-AlaHisD-ProΦPhe-NH 2 N-(((4' -Methoxy)-3-Phenyl)Propionyl)-HisTrpAlaValD-AlaHisD- ProΦPhe-NH„ N-((2-Methyl-2-Phenyl)Propionyl) -HisTrpAlaValD-AlaHisD- ProΦPhe-NH 2 or a pharmaceutically acceptable salt thereof. 5. A polypeptide of formula (I) as claimed in any of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, for use as a therapeutic agent. 6. Use of a polypeptide of formula (I) as claimed in any of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament useful for inhibiting the growth of cells that are sensitive to the growth promoting activity of GRP. 7. Use of a polypeptide of formula (I) as claimed in any of Claims 1 to 4, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment of cancer. 8. A method for inhibiting the growth of cells that are sensitive to the growth promoting activity of GRP in a mammal which comprises the administration to said mammal of a therapeutically effective amount of a polypeptide of formula (I) as claimed in any of Claims 1 to 4 or of a pharmaceutically acceptable salt thereof. 9. A method as claimed in Claim 8 for the prophylaxis or treatment of cancer. 10. A method as claimed in any of Claims 8 to 9 wherein said mammal is a human. 11. A medicament comprising a polypeptide of formula (I) as claimed in any of Claims 1 to 4 or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable carrier and, optionally, one or more other pharmaceutically active agents. 12. A medicament as claimed in Claim 11 which is in the form of a tablet or capsule. 13. A process for the preparation of a polypeptide of formula (I) according to Claims 1 to 4, the process comprising condensing amino acids and/or amino acid derivatives in the desired sequence and/or peptide fragments containing these amino acids or their derivatives in the desired sequence to give the desired peptide, either an end carboxylic acid group or an end amino group being activated for the peptide linkage and the remaining groups being protected, and optionally deprotecting the resultant peptide and/or converting the resultant peptide into a pharmaceutically acceptable salt thereof. 14. A method for inhibiting the binding of gastrin releasing peptide in cells capable of said binding which comprises exposing said cells to an inhibitory amount of a compound of Claim 1, 2, 3 or 4.

Inventors: KULL FREDERICK CHARLES, LEBAN JOHANN JAKOB, KULL, FREDERICK, CHARLES, LEBAN, JOHANN, JAKOB
Applicants: WELLCOME FOUND, THE WELLCOME FOUNDATION LIMITED
Application year: 1991
Main classification: C07K7
IPC codes: A61K38, A61P35, A61P43, C07K1, C07K7