NZ246195A - Peptides useful as therapeutic agents particularly in feeding inhibition and compositions thereof - Google Patents

Description

New Zealand Paient Spedficaiion for Paient Number £46195 246195 New Zealand No. 246195 International No. PCT/GB/92/02369 TO BE ENTERED AFTER ACCEPTANCE AND PUBLICATION Priority dates; ^.c»-ci-c?2.) International filing date: 9.1 • «7.- <vz_ Classification: c<=.-> o=>n«-»4.l lQfolt^>8 i©8,2Z, Publication date: 2 7 NOV 1995 Journal No.: NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION Title of invention: PEPTIDE COMPOUNDS HAVING THERAPEUTIC ACTIVITY Name, address and nationality of applicant^) as in international application form: FISONS CORPORATION, of Jefferson Road, Rochester, New York 14603, United States of America. A U-S CcVipo^'C^'hoK^ 1 Peptide compounds having therapeutic activity This invention relates to peptide compounds having therapeutic activity (in particular feeding inhibition), their use as pharmaceutical and cosmetic therapeutic agents, and 5 formulations comprising them.

CCK-8 (a peptide having the structure Asp-Tyr(S03H)-Met-Gly-Trp-Met-Asp-Phe-NH2) is known to have feeding inhibition properties [see for example J E Morley, Minireview: 'The ascent of cholecystokinin - from gut to brain', Life Sciences, vol 30 (6), pp479-493, International Patent Application WO 91/08225 (to Fisons Corporation) discloses a number of peptide compounds which are indicated for use in the inhibition of feeding. is A group of peptide compounds have now been found which are particularly advantageous.

According to the present invention, there is provided a compound of formula I: 1982]. 0 M-G-T r p-X-J -L-NH2 wherein R1 is OH or 0S03H; M is Met, Ahx or lie; G is Gly or Sar; X is Met, Ahx, lie, Phe or Lys(R2); J is Asp, Asp(OBn), Dasp, MeAsp, or MeDAsp; and L is Phe or MePhe; wherein R2 is a group of formula II, 2 c R f \« R I I wherein E is NH, CH=CH or CH2CH2; and R3, R4, R5, R6 and R7 are independently H, OH, halogen, alkyl C1-6 or 0S03H; provided that when R1 is 0S03H, G is Gly and: (a) J is Asp, L is MePhe and M is Ahx, then X is not Ahx; (b) J is Asp, L is MePhe and M is lie, then X is not He; (c) J is Asp, L is MePhe and M is fle, then X is not Ahx; (d) J is Asp, L is Phe and M is Met, then X is not Met; (e) J is Asp, L is MePhe and M is Met, then X is not Met; or (f) J is Dasp, L is MePhe and M is Met, then X is not Met; or a pharmaceutically acceptable derivative thereof (hereinafter referred to en bloc as "the compounds of the invention").

The compounds of the invention, amino acids, peptides and protecting groups are represented by symbols commonly used in the art, for example those defined by IUPAC and IUB.

All optically active amino acids have the L-configuration unless otherwise indicated.

Examples of symbols are given below: Ahx 2-aminohexanoic acid Asn asparagine Asp aspartic acid Asp(OBn) aspartic acid beta-benzyl ester Asp(OtBu) aspartic acid beta-tert-butyl ester Boc tert-butyloxycarbonyl BrCH2-Pam 4-(bromomethyl)phenyl-acetamidomethyl DAsp D-aspartic acid 3 Fmoc 9-fluorenylmethyloxycarbonyl Gly glycine HOBt 1-hydroxybenzotriazolyl Hpa 4-hydroxyphenylacetic acid s Hpa(S03H) O-sulpho-4-oxyphenylacetic acid lie isoleucine Lys lysine MeAsp N-methylaspartic acid MePhe N-methylphenylalanine MePhe-NH2 N-methylphenylalanine amide Met methionine Nle norleucine (or 2-aminohexanoic acid) OBt 1-benzotriazolyl ester OCH2-Pam 4-oxymethylphenylacetamidomethyl OSu succinimidyloxy ester OtBu tert-butylester Phe phenylalanine Phe-NH2 phenylalanine amide resin polystyrene Sar sarcosine Tbu tert-butyl Tyr(S03H) O-sulphotyrosine 2 Thus, Hpa-Met-Gly-Trp-Met-Asp-MePhe-NH2 is the compound of formula I 25 R1 is OH, M is Met, G is Gly, X is Met, J is Asp and L is MePhe: 246195 By Lys(R2) we mean a lysine residue in which the e-amino group forms an amide bond with a group of formula II, as defined above. Two particular groups of formula II which may be mentioned are the group in which E is NH, R3 is methyl and R4"7 are each hydrogen, ie (2-methylphenyl)aminocarbonyl, also referred to herein as 'Tac"; and the s group in which E is trans-CH-CH, R5 is OH and R3, R4, R6 and R7 are each hydrogen.

Pharmaceutically acceptable derivatives of the compounds of formula I include esters and amides of any carboxylic acid groups which may be present, and pharmaceutically acceptable salts. Pharmaceutically acceptable derivatives which may be mentioned 10 include unsubstituted amides of carboxylic acid groups (for example Asp may be present as its unsubstituted amide derivative Asn) and alkyl (for example methyl) esters of carboxylic acid groups. Pharmaceutically acceptable salts which may be mentioned include sodium and ammonium salts. Pharmaceutically acceptable derivatives of compounds of formula I may be prepared from the corresponding compound of formula 15 I by conventional methods.

The term "pharmaceutically acceptable" used herein should be construed to mean that the compound, derivative, salt or other substance to which it refers is suitable for administration to the body as a pharmaceutical or cosmetic therapeutic agent. Similarly, 20 terms such as "use as a pharmaceutical" and "pharmaceutical formulation" include use as a cosmetic therapeutic agent and a cosmetic therapeutic formulation respectively.

Preferably M is Ahx or lie; G is Gly; X is Ahx, He or Lys(R2); J is Asp, Dasp, MeAsp or MeDAsp; and R1 is 0S03H.

According to a further aspect of the invention, there is provided a process for the preparation of a compound of formula I, or a pharmaceutically acceptable derivative thereof, which comprises: a) preparing a compound of formula I in which R1 represents 0S03H by 30 sulphating a compound of formula III, 246 1 I I I 0 M-G-Trp-Xa-J a-L-Z. m wherein M, G and L are as defined above; Ja has the same definition as J above, except % that the 0-carboxyl group of any Asp, Dasp, MeAsp or MeDAsp residue present is optionally protected; Xa has the same definition as X above, except that it may additionally represent Lys and any hydroxy or amino group is present in protected form 10 (except for any hydroxy groups to be converted to a sulphate ester); and Za is NH2 or a carboxyl protecting group; and, if necessary, deprotecting the resulting compound; b) removing one or more protecting groups from a compound of formula IV, is IV "M-G-Trp-Xa-J a-L-Za wherein R\ L, M, G, Xa, Ja, and Za are as defined above, and at least one of Xa, Ja, 20 and Za is present in protected form; c) preparing a compound of formula I in which R1 represents OH and X represents Lys(R2) wherein R2 is a group of formula II, C(0)-E I I wherein R3, R4, R5, R6 and R7 are independently H, OH, halogen, alkyl or 0S03H; and E is NH by reacting a compound of formula V, 246 1 M-G-Trp-Xb-J-L-NH2 wherein M, G, J and L are as defined above, and Xb is Lys, with a compound of * formula VI, 0-C-N V I wherein R3, R4, Rs, R6 and R7 are as defined above; or d) preparing a compound of formula I in which R1 represents OH and X 15 represents Lys^2) wherein R2 is a group of formula II, C ( 0 ) - E 11 wherein R3, R4, R5, R6 and R7 are independently H, OH, halogen, alkyl or 0S03H; and E is CH2CH2 or CH=CH by coupling a compound of formula V as defined above with a compound of formula VII, HO-C ( 0 ) -E (C^}/ V [ I wherein E is CH2CH2 or CH=CH and R3, R4, R5, R6 and R7 are as defined above.

The invention provides intermediate compounds of formula IV per se. 24-6195 6A In process (a), the sulphating agent may be, for example, sulphur trioxide or a complex thereof such as sulphur trioxide pyridine. We particularly prefer to carry out the sulphation in a polar aprotic solvent, for example, dimethylformamide or pyridine. The reaction is preferably carried out using an excess of sulphating agent, for example a 1-40 molar excess, preferably a 5 molar excess.

In processes (a) and (b), protecting groups for peptides and methods for their removal are well known in the art, see for example, T W Greene, Protective Groups in Organic Synthesis, Wiley-Interscience (1981). The choice of protecting groups and the methods employed for their removal will depend, inter alia, on the method of synthesis employed for the preparation of the peptide and the amino acids in the peptide. Suitable amino protecting groups include, for example, benzyloxycarbonyl, which may readily be removed by hydrogenolysis or hydrogen bromide in acetic acid; t-butyloxycarbonyi, (Boc), which is removed by standing the peptide in cold trifluoroacetic acid; Fmoc, which may be removed by treatment with dilute piperidine (20% in DMF); (4-methoxybenzyl)oxycarbonyl and 2-nitrophenylsulphenyl. The Boc and Fmoc groups are particularly preferred. 246195 WO 93/13126 PCT/GB92/02369 7 . - Suitable carboxyl protecting groups that Za may include are, for €xampie, methyl, tert-butyl, benzyl and 4-methoxybenzyl. We panicularly prefer benzyl, which may be readily removed by treatment with alcoholic amine or ammonia to give the corresponding amides. Similar groups may be used to protect the amino group in lysine s and the carboxyl group in aspartic acid.

When the peptide is prepared using solid phase techniques, for example those in which the carboxyl end of the peptide is attached to a solid phase resin, linkage of the peptide to the resin acts as a carboxyl protecting group. Cleavage of the peptidyl-resin linkage io will deprotect the carboxyl terminus of the peptide. Since the peptide end products of this invention are carboxyl terminal amides, the chemical link which connects the peptide chain to the resin must be such that its cleavage with suitable reagents readily provides amides. Due to the lability of the sulphate ester group to strong acids (for example, liquid hydrogen fluoride), the peptidyl-resin linkage may be cleavable with 15 either weaker acids (for example, brief treatment with trifluoroacetic acid, TFA) and/or nucleophiles (for example, ammonia, amines, hydroxide, and alkoxides).

Process (c) may be carried out in an inert solvent, for example DMF, in the presence of a base such as N-methylmorpholine, and at a temperature of, for example, from 0°-20 50°C.

Process (d) may be carried out using an activated ester derivative of the acid. A suitable activated ester derivative is the N-hydroxy succinimidyl ester. The reaction may be carried out in the presence of a base such as N-methylmorpholine, under similar 25 conditions to those described for process (c) above.

Among suitable resin derivatives may be mentioned oxymethyl-polystyrene, 4-(oxymethylphenyl)-(CH2)n-aminomethyl-polystyrene(n=0-3)and4-(oxymethylphenyl)-oxymethyl-polystyrene. Similarly substituted polyacrylamide resins are equally well suited 30 as the above polystyrene based resins. The term "polystyrene" includes copolymers with minor amounts, usually 1%, of unsaturated monomers such as divinylbenzene.

PCT/GB92/i)236P . 8 f 4-(Oxymethylphenyl)-CH2CO-aminomethyl-polystyrene [herein referred to as 4-(oxymethyiphenyl)-acetamidomethylpolystyrene or OCH2-Pam-resin] is particularly preferred for the generation of peptide amides. This linkage may readily be cleaved to give the peptides of formula I by reaction with methanolic solutions of ammonia, s alkylamines or dialkylamines as required.

Another resin which may be mentioned is a polystyrene resin (P) in which the backbone linkage to the peptide is, and herein referred to as [ [5-[(4-Fmoc-aminomethyl)-3,5-dimethoxyphenoxy]valeroyl]norleucyl]-4'-methylbenzhydrylamine divinylbenzene polystyrene or PAL resin. PAL resin is particularly preferred for the generation of peptide amides in which X is not Lys. The linkage between the assembled peptide and this resin may be cleaved readily by reaction with the reagent formed by mixing TFA 20 (trifluoroacetic acid), phenol, thioanisole, water and ethanedithiol in the proportions 8.5:0.5:0.5:0.5:0.2.

Another resin which may be substituted for the PAL resin is a polystyrene resin (P) in which the backbone linkage to the peptide is Fmoc-NH-CH2 och3 'CCH234-CO-N i e-N 0ch3 0-p Fmoc-N ch3o och3 93/13126 fRCTVGB92/0?36^ W and referred to as 4-[(2,4-dimethoxyphenyl)(Fmoc-amino)methyl]phenoxydivinylbenzene polystyrene or Rink resin. The linkage may be readily cleaved in the same manner as for PAL resin.

The peptides of formulae III, IV and V may be prepared by methods well known to those skilled in the art. For example, they may be prepared by combining individual amino acids on a solid phase resin on a step-by-step basis, or alternatively, by combining groups of amino acids on a solid phase resin to yield the desired peptidyl-resin intermediate. Such additions are accomplished by protecting the amino group of the 10 amino acid or group of amino acids by converting it to, for example, its tert-butyloxycarbonyl (Boc) or 9-fluorenylmethyl-oxycarbonyl (Fmoc) derivative, and then activating the carboxylic group of such amino acid or group of amino acids by converting it, for example, to its 1-hydroxybenzotriazole (HOBt) or N-hydroxysuccinimide (HOSu) ester derivative. Such a protected-activated intermediate is then allowed to react with is an amino acid resin or peptidyl-resin with a free amino group, thus extending the peptide chain to provide the desired peptidyl-resin.

The C-terminal amino acid of the peptide to be prepared may be attached to the OCH2-Pam-resin in several ways. For example, Boc-protected N-methylphenylalanine, 20 may be reacted with a suitable 4-(bromomethyl)-phenylacetate ester (for example, phenacyl ester) and processed further to provide Boc-MePhe-(4-oxymethylphenyl)acetic acid which may be coupled to aminomethyl-polystyrene to provide Boc-MePhe-(4-oxymethylphenyl)acetamidomethylpolystyrene (Boc-MePhe-OCH2-Pam-resin). Alternatively, 4-(bromomethyl)phenylacetic acid may be coupled to 25 aminomethylpolystyrene to provide 4-(bromomethyl)phenylacetamidomethylpolystyrene (BrCH2-Pam-resin) which may be reacted with the caesium salt of Boc-MePhe-OH to provide Boc-Phe-OCH2-Pam-resin.

The C-terminal amino acid may be attached to the PAL resin by removal of the Fmoc 30 protecting group with base, for example, piperidine, in a suitable solvent or mixture of solvents, for example, DMF and toluene, and then coupling the protected activated amino acid in the normal manner for solid phase synthesis. A particularly preferred method of activating the carboxyl group is to form the N-hydroxybenzotriazole (HOBt) - / ester in the presence of diisopropylcarbodiimide (DIPCDI). Suitable solvent systems, for example, dimethylformamide (DMF) and dichloromethane (DCM) may be used for this preactivation procedure. s Among the suitable activating groups may be mentioned any combination of groups which causes the acid function of the amino acid to become more reactive, such as acid chlorides, mixed and symmetrical anhydrides, reaction product with carbodiimide (for example, dicyclohexylcarbodiimide, DCC), and active esters (for example, esters derived from HOBt, HOSu, 2- or 4-nitrophenol, and 2,4,5-trichlorophenol). The use of DCC io and esters of HOBt and HOSu is particularly preferred from the standpoint of yield, lack of by-products, and consequent ease of purification.

An automatic peptide synthesizer may be used for the solid phase synthesis of the sulphated peptide amides of this invention. The sulphate ester containing peptides of is formula I may be desalted and purified by the usual methods. For example, the product may be purified by ion-exchange chromatography with the use of Trisacryl M DEAE, DEAE-cellulose or the like, partition chromatography with the use of Sephadex LH-20, Sephadex G-25 or the like, reverse phase chromatography with the use of Amberlite XAD-2 (or Biorad SM-2), ODS-silica gel or the like, normal phase chromatography with 20 the use of silica gel or the like, or high-performance liquid chromatography (HPLC).

The protocol of coupling onto an aminomethyl-resin or peptidyl-OCH2-Pam-resin (1 mmole of available nitrogen), deprotection, sulphation, cleavage, and product purification is set forth in Table 1.

Table 1 Protocol for Solid Phase Synthesis of Sulphated Peptide Amides on Pam-resin (lmmole scaled Step Reagent or Solvent 1 DCM 2 Go to step 3, 5 or 8 3 Add filtered, pre- Purpose Mix Time Wash 1 min Pre- 2-15 hr activated (0°C, 1 hr) mixture of protected amino acid (or protected dipeptide, 3mmole), 5 HOBt (4.5mmole), and DCC (3mmole) in 1:4 DMF/DCC 4 Go to step 10, 16, 21 or 26 Add protected amino acid io (or protected dipeptide, 3mmole) in and HOBt (4.5mmole) in 30ml 1:2 DMF/DCM then DCC (3mmole) in 20ml DCM is 6 2-propanol 7 Go to step 10, 16, 21 or 26 8 Add active ester or anhydride (3mmole) in DCM, DMF or a mixture thereof 9 Go to step 10, 16, 21 or 26 DCM 11 Treat with 49:1:50 TFA/ 25 anisole/DCM 12 DCM 13 Treat with 1:19 DIEA'/DCM 14 DCM Go to step 10, 16, 21 30 or 26 16 DMF 17 Treat with 1:4 piperidine/DMF 211 B92/023fe9 11 activated DCC/HOBt coupling In situ activated DCC/HOBt coupling 2-15 hr Wash 1 min Non DCC/HOBt 2-15 hr activated coupling Wash Boc and tBu removal Wash Neutralise Wash 1 min 30 min 1 min 1 min 1 min Wash Fmoc removal 1 min 3 min tl.z. patent office 1 4 JUN 1994 18 Treat with 1:4 piperidine/DMF 19 DMF Go to step 10, 16, 21 5 or 26 21 DMF 22 1:2 pyridine/DMF 23 Add sulphur trioxide pyridine complex (40mmole) io in 60ml 1:2 pyridine/DMF 24 DMF 12 Fmoc removal Wash Wash Wash Sulphation 24-1 7 min 1 min 1 min 1 min 20-24 hr Wash 1 min Go to step 10, 16, 21 or 26 is 26 Methanol 27 Ammonia saturated (-20°C) methanol or 20% methanolic amine (250ml) 28 Methanol :o 29 Combine and concentrate filtrates from steps 27-28 Chromatograph residue on column(s) of Amberlite XAD-2 (Rohm and Haas, 25 2.5 x 60 cm, methanol gradient 0.1M in ammonia), Trisaciyl M DEAE (LKB Inc., 2.5 x 47 cm, ammonium bicarbonate gradient), 30 and/or P-40 ODS-3 (Whatman, 4.8 x 50 cm, methanol gradient 0.2% in ammonium acetate).

Wash Resin cleavage Wash Isolation Purification 1 min 2-5 days 1 min * DIEA is diisopropylethylamine 246195 13 A general procedure for the synthesis of non-sulphated peptide amides on PAL-resin (lg scale) is set out in Table 2.

Step Reagent or Solvent 1 2 3 DCM DCM/DMF (1:1) 30% Piperidine 10 35% DMF % Toluene 4 Repeat 3 DCM/DMF (1:1) is 6 Go to step 7 or 11 7 Preactivated-protected amino acid [room temperature, Fmoc-aa-OH, DIPCDI (1 eq), HOBt (1 eq), 20 in DMF:DCM(1:4)] 8 Add to resin or resin-peptide is 9 DCM/DMF (1:1) 10 Go to step 3 [Repeat sequence 3-10 as necessary to complete peptide sequence] 30 11 Preactivated Hpa-Osu [Hpa-OH (1 eq), HO-Su (1 eq), DMF] 12 Add to resin-peptide Table 2 Purpose wash wash Fmoc removal Fmoc removal wash (lOx) Mix Time 1 min 1 min 3 min 7 min sec Pre- 10 min activation [Omit HOBt if preceding amino acid is MeAsp-, MeDAsp or MePhe-] Coupling 1-2 hr.

Wash (4x) 1 min Pre- activation Coupling min 1-2 hr 2461 13 14 16 17 18 19 DCM MeOH TFA/phenol/thioanisole/ water/ethanedithiol [8.5:0.5:0.5:0.5:0.2] TFA 14 Wash (4x) Wash (4x) Cleavage from resin Filter resin and wash Isolation of peptide Purification 1 min 1 min 2-3 hr.

Combine and concentrate filtrates from step 16 Chromatograph residue on column(s) of Amberlite XAD-2 (Biorad SM-2 200-400 mesh, MeOH gradient 0.1M in ammonia) and/or C-18 (ODS-3 Amicon, MeOH gradient, 0.1% in triethylamine, 0.1% in glacial acetic acid) and/or Amberlite XAD-2 (MeOH gradient).

Combine and concentrate purified fractions by freeze drying from 0-1M NH3 Modifications of the protocols in Tables 1 and 2 which may be applicable may readily be determined by experimentation.

Isolation Analogous procedures, wherein the reactions are carried out without the solid phase 30 component (resin), are well known in the art and are well suited to large scale production (see for example US Patent No 3,892,726). 246195 WO 93/13126 PCT/GB92/02369 The compounds of the invention inhibit feeding activity in mammals, and to bind to cholecystokinin receptors. Distinct CCK receptors in peripheral and brain tissues have been classified as CCK-A and CCK-B receptors respectively. Differentiation between agonist and antagonist interactions at CCK receptors can also be determined by s functional assays. Activation of CCK-A receptors in peripheral tissues plays an important role in the control of pancreatic secretion, gut motility and gall bladder contraction. Thus compounds with agonist activity at CCK-A receptors have utility in the treatment of obesity and motility disorders and compounds with antagonist activity at CCK-A receptors may have utility in gastrointestinal disorders such as irritable bowel io syndrome, ulcers, excess pancreatic or gastric secretion, acute pancreatitis and motility disorders. Therefore, compounds intended for use as therapeutic agents in the inhibition of feeding are likely to lack unwanted side-effects if they bind selectively to CCK-A receptors (rather than CCK-B receptors). is Pharmacological activity of the compounds of the invention can be demonstrated in Tests A-D below.

Test A Feeding inhibition Male Sprague-Dawley rats (weighing 300-350g) are individually caged and maintained on a 12 hour light/dark cycle and trained for at least 14 days to feed during a three hour period of the dark cycle but not the 21 hours preceding that three hour period. On the day of the study, rats are dosed intraperitoneally with saline (controls) or test compound (dissolved in saline; usually at a concentration of 0.3 to 300/ig of test compound per kg 2s of rat weight). Food is introduced 10 minutes after administration of saline or test compound. A test compound is deemed to be active if the test group consumes significantly less food than the saline controls during the feeding period, which ends either 0.5 or three hours after presentation of the food.

Test B CCK-A Binding Evaluation of a test compound for its ability to bind to CCK-A receptors in rat pancreatic membranes is measured against the binding of Bolton Hunter 125I-CCK-8 and WO 93/13126 PCT/GB92/02369 16 . . 3H-L364718 to rat pancreas according to the procedures of Cha&g,sJLoty, Cfian^ncM Kunkel (Molecular Pharmacolgy, 30:212-216, 1986).

Test C 5 CCK-B Binding Evaluation of a test compound for its ability to bind to CCK-B receptors in rat cerebral cortex membranes is measured against 125I-CCK-8 according to the procedures of Chang and Lotti (Proc, Natl. Acad. Sci. Vol. 83, 4923-4926). io Test D Functional Assay For CCK-A Agonist/Antagonist Activity The evaluation of a test compound for its ability to inhibit or stimulate amylase release by rat pancreatic tissue fragments (acinar cells) is measured according to the procedures of Lin et al (J Pharm & Exper Therapeutics, 1986, 729-734) and Jung (Clinica Chema is Acta, 1980, 100, 7-11).

Therefore, the invention also provides the use of a compound of the invention as a pharmaceutical.

According to a further aspect of the invention there is provided the use of a compound of the invention in the manufacture of a medicament for the treatment of obesity.

According to the invention there is also provided a method of treatment of obesity which comprises administering a therapeutically effective amount of a compound of the 25 invention to a patient in need of such treatment; and also a method of improving the bodily appearance of a mammal which comprises administering to that mammal a compound of the invention until a cosmetically beneficial loss of body weight has occurred. The mammals of greatest interest are human beings.

According to a further aspect of the invention there is also provided a pharmaceutical formulation comprising (preferably less than 80%, and more preferably less than 50% by weight of) a compound of the invention in combination with a pharmaceutically acceptable adjuvant, diluent or carrier. 24-01 95 WO 93/13126 PCT/GB92/02369 17 - ' ' ' The compounds of the invention may be administered by a variety of routes, for example, orally, intraperitoneally, intravenously, intramuscularly, subcutaneously or intranasally. The dosage of the compounds of the invention will depend on several factors, including the requirements of the recipient, but will typically be in the range 5 0.3pig to 3.0mg per kg of body weight per day, either in a single dose or divided among two to four doses.

Examples of suitable adjuvants, diluents or carriers are: for tablets and dragees; lactose, starch, talc or stearic acid; io for capsules; tartaric acid or lactose; for injectable solutions; water, alcohols, glycerin or vegetable oils.

The compositions may also contain suitable preserving, stabilising and wetting agents, solubilisers (eg a water-soluble cellulose polymer such as hydroxypropyl methylcellulose, is or a water-soluble glycol such as propylene glycol), sweetening and colouring agents and flavourings. The compositions may, if desired, be formulated in sustained release form.

The compounds of the invention have the advantage that they are more efficacious, more potent, longer acting, more stable (particularly to enzymatic degradation), more 20 selective, less toxic, give rise to fewer side effects, are more readily absorbed, are quicker acting, or have other advantageous pharmacological effects, in comparison with the compounds of the prior art.

The invention is illustrated by the following examples, in which an automatic peptide 25 synthesizer was used for solid phase synthesis.

Example 1 Boc-MePhe-f4-oxvmethvlphenvDacetic acid To a solution of Boc-MePhe-OH (27.93g) and 4-(bromomethyl)phenylacetic acid 30 phenacyl ester (33.32g) in acetonitrile (11) was added potassium fluoride dihydrate (18.28g). The suspension was stirred overnight, filtered and the filtrate evaporated to dryness. The residue, Boc-MePhe-(4-oxymethylphenyl)acetic acid phenacyl ester, was dissolved in 85% acetic acid (1.21), treated with zinc dust (128g), and stirred for 2-4 WO 93/13126 PCT/GB92/0^369 18 hours. Concentration of the filtered reaction mixture to about 400ml and dilution with 3.2ml of water gave an oil which was dissolved in ethyl acetate and treated with dicyclohexylamine (DCHA) to give 41.31g of the DCHA salt of the title compound, mp 120-122°C.

Example 2 H-MePhe-OCH-,-Pam-resin Boc-MePhe-(4-oxymethylphenyl)acetic acid (the product of Example 1, 1.82g, 3mmole of its DCHA salt) and HOBt (6.9g, 4.5mmole) in 40ml of 1:3 DMF/DCM io (dimethylformamide/dichloromethane) followed by DCC (1,3-dicyclohexylcarbodiimide, 0.62g, 3mmole) in 20ml of DCM were added to aminomethylpolystyrene resin (1.34g, lmmole available nitrogen) to give a suspension which was shaken for 2 to 15 hours. Boc-MePhe-OCH2-Pam-resin was isolated by filtration, washed with 2-propanol and DCM, and treated according to Table 1 (steps 10-14) to give the title compound as the 15 free base.

Example 3 H-Phe-OCH^-Pam-resin Boc-Phe-(4-oxymethylphenyl)acetic acid (prepared by the method of Example 1, 0.83g, 20 2mmole), 1-hydroxybenzotriazole (HOBt, 0.46g, 3mmole) and DCC (0.41g, 2mmole) were dissolved in 50ml of 4:1 DCM/DMF and stirred at 0°C for 1 hour. Aminomethylpolystyrene resin (1.34g, lmmole available nitrogen) was suspended in the filtered reaction mixture (precipitated DCU removed) and shaken for 2-15 hours. The product, Boc-Phe-OCH2-Pam-resin, was isolated by filtration and treated according to 25 Table 1 (steps 10-14) to give the title compound.

Example 4 Fmoc-Met-Aspf OtBuVOH Fmoc-Met-OSu was prepared in situ by the reaction of Fmoc-Met-OH (14.87g), HOSu 30 (5.52g) and DCC (8.26g) in THF (tetrahydrofuran, 200ml) at 0°C for 3.5 hours. Precipitated dicyclohexylurea (DCU) was removed by filtration and the THF filtrate was added to a cold solution of H-Asp(OtBu)-OH in 220ml of 10:1 water/THF to which had been added 40ml of IN sodium hydroxide. After stirring the reaction mixture at room ; WO 93/13126 PCT/GB92/02369 i 19 - ■ - ; - temperature overnight, solid citric acid (20g) was added along with ethyl acetate (600ml). The ethyl acetate layer was separated, washed with 10% citric acid and brine, then dried (MgS04). Evaporation of the ethyl acetate solution gave a residue which was dissolved in ethyl acetate (200ml) and treated with DCHA (7.84ml) to precipitate 17.93g s of the DCHA salt of the title compound, mp 159-162°C.

Example 5 HpafSC^HI-Ahx-Giv-Trp-Ahx-Asp-Phe-NH, (SEQ ID NO 1) H-Phe-OCH2-Pam-resin (the product of Example 3) was sequentially coupled with io Fmoc-Asp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH according to Table 1 (coupling steps 5-7 followed by Fmoc removal steps 16-20) to provide H-Ahx-Gly-Trp-Ahx-Asp(OtBu)-Phe-OCH2-Pam-resin which was coupled with Hpa-OSu according to Table 1 (coupling steps 8-9) to give Hpa-Ahx-Gly-Trp-Ahx-Asp(OtBu)-Phe-OCH2-Pam-resin which was deprotected, sulphated and cleaved from is the resin according to Table 1 (steps 10-15, steps 21-25 and then steps 26-29 with ammonia) to give the title compound which was chromatographically purified on SM-2 and ODS-3 columns sequentially according to Table 2 (step 18). Amino acid analysis following acid decomposition gave Asp 1.03(1), Gly 1.05(1), Ahx 1.94(2), Phe 0.99 (1), Trp 0.74 (1), NH3 2.16. MS (FAB): m/e 961 (M-H)\ Example 6 Hpa-Met-Glv-Trp-Met-DAsp-Phe-NH-, PAL-resin was deprotected and sequentially coupled according to Table 2 with Fmoc-Phe-OH, Fmoc-DAsp(OtBu)-OH, Fmoc-Met-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-25 Met-OH and Hpa-OSu to provide the title compound. Amino acid analysis following acid decomposition gave Asp 1.04(1), Gly 1.07(1), Met 1.79(2), Phe 1.10(1), Trp 0.71(1.0), NH3 1.40. MS (FAB): m/e 919 (M+H)+.

Example 7 Hpa-Ahx-Glv-Trp-Ahx-Asp-Phe-NH7 (SEQ ID NO 2) PAL-resin was deprotected and sequentially coupled according to Table 2 with Fmoc-Phe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu to provide the title compound. Amino acid analysis following WO 93/13126 PCI7GB92/0236? acid decomposition gave Asp 1.00(1), Gly 1.08(1.0), Ahx 1.85(2), Phe 1.10(1), Trp 0.68(1), NH3 1.00. MS (FAB): m/e 883 (M+H)+.

Example 8 Hpa-Ahx-Glv-Trp-Ahx-MeAsp-Phe-NH-, (SEQ ID NO 3) PAL-resin was deprotected and sequentially coupled according to Table 2 with Fmoc-Phe-OH, Fmoc-MeAsp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, to give the title compound. Amino acid analysis following acid decomposition gave Gly 0.89(1), MeAsp 1.04(1), Ahx 1.99(2), Phe 1.09(1), Trp io 0.71(1), NH3 0.91. MS (FAB): m/e 897 (M+H)\ Example 9 Hpa-Ile-Glv-Trp-Ile-DAsp-MePhe-NH7 PAL-resin was deprotected and sequentially coupled according to Table 2 with Fmoc-is MePhe-OH, Fmoc-DAsp(OtBu)-OH, Fmoc-Iie-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ile-OH and Hpa-OSu, to give the title compound. Amino acid analysis following acid decomposition gave Asp 1.00(1), Gly 1.14(1), lie 1.91(2), MePhe 0.96(1), Trp 0.64(1), NH3 1.44. MS (FAB): m/e 897 (M+H)+.

Example 10 Hpaf SO,HV Met-Glv-T rp-Met-D Asp-Phe-NH-, Hpa-Met-Gly-Trp-Met-DAsp-Phe-NHj (the product of Example 6,114mg) was dissolved in pyridine (1.4ml) and sulphur trioxide pyridine complex (130mg) was added. The reaction was stirred for 2 hours then an additional 80mg of sulphur trioxide pyridine 25 complex was added. After 4 hours the reaction was diluted with 5% NH4OH (20ml) and concentrated to dryness. The crude residue was purified by chromatography on SM-2, ODS-3, SM-2 sequentially according to Table 2, step 18. The resulting product was freeze dried from 0.1M NH3 to give the title compound (89mg). Amino acid analysis following acid decomposition gave Asp 1.03(1), Gly 1.11(1), Met 1.83(2), Phe jo 1.04(1), Trp 0.59(1), NH3 2.2. MS (FAB): m/e 997 (M-H)".

Example 11 HpaCSOiHVAhx-Glv-Trp-Ahx-MeAsp-Phe-NH-, (SEQ ID NO 4) 2fi WO 93/13126 PCT/GB92/02369 21 r " Hpa-Ahx-Gly-Trp-Ahx-MeAsp-Phe-NH2 (the product of Example 8, 55mg) was sulphated essentially according to the method of Example 10 to give purified title compound (15mg). Amino acid analysis following acid decomposition gave MeAsp 1.07(1), Gly 1.04(1), Ahx 1.90 (2), Phe 0.98 (1), Trp 0.61 (1), NH3 0.79. MS (FAB): m/e 5 975 (M-H)\ Example 12 HpafSO,HVIle-Glv-Trp-Ile-DAsp-MePhe-NH, Hpa-Ile-Gly-Trp-Ile-DAsp-MePhe-NH2 (the product of Example 9,58mg) was sulphated io essentially according to the method of Example 10 to give purified title compound (16mg). Amino acid analysis following acid decomposition gave Asp 1.08(1), Gly 1.08(1), lie 1.97(2), MePhe 0.87(1), Trp 0.75(1) NH3 1.39. MS (FAB): m/e 975 (M-H)\ Example 13 is Hpa-Met-Glv-Trp-Met-Asp-MePhe-NH-, (SEQ ID NO 5) The title compound was prepared following the method of Table 2, sequentially coupling Fmoc-MePhe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Met-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Met-OH and Hpa-OSu. Amino acid analysis following acid decomposition gave Asp 1.06 (1). Gly 1.04 (1), MePhe 1.00 (1), Met 1.90 (2), Trp 0.84 (1), NH3 0.51. 20 MS (FAB): m/e 931 (M-H)-.

Example 14 Hpa-Ahx-Glv-T rp- Ahx-D Asp-MePhe-NH, PAL resin was sequentially coupled according to Table 2 with Fmoc-MePhe-OH, Fmoc-25 DAsp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, to give the title compound. Amino acid analysis following acid decomposition gave Asp 1.03(1), Gly 1.04(1), Ahx 1.95(2), MePhe 0.99(1), Trp 0.77(1), NH, 0.94. MS (FAB): m/e 895 (M-H)".

Example 15 Hpa-Ahx-Glv-T rp-Ile-D Asp-Phe-NH? PAL resin was sequentially coupled according to Table 2 with Fmoc-Phe-OH, Fmoc-DAsp(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and 24-61 WO 93/13126 PCT/GB92/02369 * - 22 Hpa-OSu, to give the title compound. Amino acid analysis following acid decomposition gave Asp 1.03(1), Gly 1.04(1), Ahx 0.96(1), lie 0.98(1), Phe 1.00(1), Trp 0.67(1), NH3 0.99. MS (FAB): m/e 881 (M-H)\ s Example 16 Hpa-Ahx-Glv-Tro-Ile-MeAsp-Phe-NH, (SEQ ID NO 6) PAL resin was sequentially coupled according to Table 2 with Fmoc-Phe-OH, Fmoc-MeAsp(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, to give the title compound. Amino acid analysis following acid decomposition io gave MeAsp 1.19(1), Gly 1.00(1), Ahx 1.02(1), Phe 0.91(1), lie 0.89(1), Trp 0.65(1), NH3 0.60. MS (FAB): m/e 895 (M-H)\ Example 17 Hpa-Ahx-Glv-Trp-Ile-Asp-MePhe-NH, (SEQ ID NO 7) is PAL resin was sequentially coupled according to Table 2 with Fmoc-MePhe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, to give the title compound. Amino acid analysis following acid decomposition gave Asp 1.10(1), Gly 1.09(1), Ahx 1.06(1), He 1.05(1), MePhe 0.71(1), Trp 0.76(1), NH3 0.80. MS (FAB): m/e 895 (M-H)\ Example 18 Hpaf SO-.HV Ahx-Glv-T rp-Ile-D Asp-Phe-NH7 Hpa-Ahx-Gly-Trp-Ile-DAsp-Phe-NH2 (the product of Example 15, 41mg) prepared according to Table 2 was sulphated essentially according to the method of Example 10 25 to give purified title compound (22mg). Amino acid analysis following acid decomposition gave Asp 1.07(1), Gly 1.04(1), lie 0.97(1), Phe 0.80(1), Trp 0.46(1) NH3 1.88. MS (FAB): m/e 961 (M-H)\ Example 19 Hpa-Met-Glv-Trp-Met-AspCOBnVMePhe-NH. (SEQ ID NO 8) By following essentially the procedures of Table 2 and sequentially coupling with Fmoc-MePhe-OH, Fmoc-Asp(OBn)-OH, Fmoc-Met-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, wo 93/13126 PCT/G B92/02369 23 Fmoc-Met-OH and Hpa-OSu, the title compound was prepared. MS (FAB): m/e 1023 (M+H)+.

Example 20 s HpafSO,HVMet-Glv-Trp-Met-AspfOBnVMePhe-NH. fSEQ ID NO 9^ Hpa-Met-Gly-Trp-Met-Asp(OBn)-MePhe-NH2 (the product of Example 19) was sulphated essentially according to the procedures of Example 10 to give the purified title compound. Amino acid analysis following acid decomposition gave Asp 1.07(1), Gly 0.99(1), Met 1.91 (2), MePhe 1.02(1), Trp 0.47(1). MS (FAB): m/e 1101 (M-H)\ Example 21 Hpa-Ahx-Glv-Trp-Ile-DAsp-MePhe-NH7 By following essentially the procedure of Table 2 and sequentially coupling Fmoc-MePhe-OH, Fmoc-DAsp(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, is Fmoc-Ahx-OH and Hpa-OSu, the title compound was prepared. Amino Acid analysis following acid decomposition gave Asp 0.96 (1), Gly 1.04 (1), lie 0.96 (1), MePhe 1.07 (1), Ahx 0.98 (1), Trp 0.61 (1), NH3 0.89. MS (FAB): m/e 895 (M-H)\ Example 22 HpafSO,H>Ahx-Glv-Trp-Ile-DAsp-MePhe-NH? Hpa-Ahx-Gly-Trp-Ue-DAsp-MePhe-NH2 (the product of Example 21) was sulphated essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave Asp 0.98 (1), Gly 1.07 (1), lie 0.95 (1), MePhe 1.41 (1), Ahx 0.81 (1). MS (FAB): m/e 975 (M-H)\ m/e 895 (M-25 S03H)\ Example 23 HpafSO^HVAhx-Glv-Tro-Ile-Asp-MePhe-NH, (SEQ ID NO 10) Hpa-Ahx-Gly-Trp-Ile-Asp-MePhe-NH2 (the product of Example 17) was sulphated 30 essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave Asp 0.98 (1), Gly 1.08 (1), lie 0.96 (1), MePhe 1.55 (1), Ahx 0.84 (1). MS (FAB): m/e 975 (M-H)\ m/e 895 (M-S03H)\ WO 93/13126 PCT/GB92/02369 24 Example 24 ~^ , HpaCSOiH V Ahx-Glv-T rp- Ahx-D Asp-MePhe-NH, Hpa-Ahx-Gly-Trp-Ahx-D Asp-MePhe-NH2 (the product of Example 14) was sulphated essentially according to the procedures of Example 10 to give the title compound, s Amino Acid analysis following acid decomposition gave Asp 1.00 (1), Gly 0.98 (1), MePhe 1.10 (1), Ahx 1.93 (2), Trp 0.96 (1), NH3 0.30. MS (FAB): m/e 975 (M-H)\ Example 25 Hpa-Ile-Glv-T rp-Ile-D Asp-Phe-NH-, io By following essentially the procedure of Table 2 and sequentially coupling Fmoc-Phe-OH, Fmoc-DAsp(OtBu)-OH, Fmoc-Ile-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ile-OH and Hpa-OSu, the title compound was prepared. Amino Acid analysis following acid decomposition gave Asp 1.02 (1), Gly 1.03 (1), Phe 1.01 (1), lie 1.94 (2), Trp 0.72 (1), NH3 0.85. MS (FAB): m/e 881 (M-H)\ is Example 26 HparSO,HVIle-Glv-Trp-Ile-DAsp-Phe-NH-, Hpa-Ile-Gly-Trp-Ile-DAsp-Phe-NHj (the product of Example 25) was sulphated essentially according to the procedures of Example 10 to give the title compound. 20 Amino Acid analysis following acid decomposition gave Asp 0.92 (1), Gly 1.03 (1), Phe 0.99 (1), lie 1.93 (2). MS (FAB): m/e 961 (M-H)\ m/e 881 (M-S03H)-.

Example 27 Hpa-Ahx-Glv-Trp-Phe-DAsp-MePhe-NH, By following essentially the procedure of Table 2 and sequentially coupling Fmoc-MePhe-OH, Fmoc-DAsp(OtBu)-OH, Fmoc-Phe-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, the title compound was prepared. Amino Acid analysis following acid decomposition gave Asp 1.01 (1), Gly 0.99 (1), MePhe 1.06 (1), Ahx 1.02 (1), Trp 1.06 (1), Phe 0.94 (1), NH3 0.82. MS (FAB): m/e 931 (M-H)\ Example 28 HpafSO-,HVAhx-Glv-Trp-Phe-DAsp-MePhe-NH? WO 93/13126 PCT/GB92/02369 » 25 " ' Hpa-Ahx-Gly-Trp-Phe-DAsp-MePhe-NH2 (the product of Example 27) was sulphated essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave Asp 0.98 (1), Gly 1.06 (1), MePhe 0.97 (1), Ahx 0.95 (1), Trp 0.61 (1), Phe 1.04 (1), NH3 1.10. MS (FAB): m/e s 1009 (M-H)-, m/e 929 (M-S03H)\ Example 29 Hpaf SO-.H V Ahx-Glv-T rp-Ahx-D Asp-Phe-NH-, Hpa-Ahx-Gly-Tip-Ahx-DAsp-Phe-NH2 was prepared by the method of Table 2, and io sulphated essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave Asp 1.02 (1), Gly 1.05 (1), Phe 1.02 (1), Ahx 1.92 (2), Trp 0.81 (1), NH31.48. MS (FAB): m/e 961 (M-H)" , 881 (M-S03H)\ is Example 30 HparSO,HVAhx-Glv-Tro-Ile-MeAsp-MePhe-NH, (SEQ ID NO 11) Hpa-Ahx-Gly-Trp-Ile-MeAsp-MePhe-NH2 (SEQ ID NO 12) was prepared by the method of Table 2, and sulphated essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave 20 MeAsp 0.92 (1), Gly 1.00 (1), MePhe 1.29 (1), Ahx 0.77 (1), lie 1.02 (1). MS (FAB): m/e 989 (M-H)", 909 (M-S03H)\ Example 31 HpafSO,HVIle-Glv-Tro-Ile-MeAsp-Phe-NH-, (SEQ ID NO 13) 2s Hpa-Ile-Gly-Trp-Ile-MeAsp-Phe-NH2 (SEQ ID NO 14) was prepared by the method of Table 2, and sulphated essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave MeAsp 1.11 (1), Gly 1.00 (1), Phe 1.06 (1), lie 1.83 (2), Trp 0.73 (1), NH3 1.48. MS (FAB): m/e 975 (M-H)\ 897 (M-S03H)\ Example 32 Hpa-Ahx-Glv-T rp-Ahx-MeDAsp-Phe-NH-, WO 93/13126 PCT/GB92/02369 26 By following essentially the procedure of Table 2 and sequentially coupling Fmoc-Phe-OH, Fmoc-MeDAsp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, the title compound was prepared. Amino Acid analysis following acid decomposition gave MeAsp 0.78 (1), Gly 1.10 (1), Phe 1.05 (1), Ahx 2.07 s (2), Trp 0.76 (1), NH3 0.71. MS (FAB): m/e 895 (M-H)\ Example 33 Hpaf SO,HV Ahx-Glv-T rp-Ahx-MeD Asp-Phe-NH? Hpa-Ahx-Gly-Trp-Ahx-MeDAsp-Phe-NH2 (the product of Example 32) was sulphated io essentially according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition gave MeAsp 1.00 (1), Gly 1.02 (1), Phe 1.06 (1), Ahx 1.91 (2), Trp 0.86 (1), NH31.48. MS (FAB): m/e 975 (M-H)", m/e 896 (M-SOjH)-.

Example 34 Hpa-Ahx-Glv-T rp- Ahx-Me Asp-MePhe-NH, (SEQ ID NO 15) By following essentially the procedure of Table 2 and sequentiaUy coupling Fmoc-MePhe-OH, Fmoc-MeAsp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, the title compound was prepared. Amino Acid analysis 20 following acid decomposition gave MeAsp 1.01 (1), Gly 1.05 (1), MePhe 0.91 (1), Ahx 2.02 (2), Trp 0.84 (1), NH3 0.82. MS (FAB): m/e 909 (M-H)'.

Example 35 Hpa-Ahx-Glv-Trp-LvsfTacVAsp-MePhe-NH7 (SEQ ID NO 16) Following the procedure of Table 2, Fmoc-MePhe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Lys(Boc)-OH and Hpa-OSu were sequentially coupled to the Rink amide resin. Following removal of the peptide from the resin using standard procedures the 2-methylphenylacetamide group was added to the e-amino of Lys using o-tolylisocyanate. Amino Acid analysis following acid 30 decomposition gave Asp 1.01 (1), Gly 1.03 (1), MePhe 0.98 (1), Lys 0.94 (1), Ahx 1.04 (1), Trp 0.96 (1). MS (FAB): m/e 1046 (M-H)+.

Example 36 0 Example 37 Hpa-Ahx-Glv-T rp- Ahx- Asp-MePhe-NH? (SEQ ID NO 18) Following the procedure of Table 2 and sequentially coupling Fmoc-MePhe-OH, Fmoc-io Asp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Gly-OH, Fmoc-Ahx-OH and Hpa-OSu, to the resin, the title compound was prepared. Amino Acid analysis following acid decomposition gave Asp 1.00 (1), Gly 1.02 (1), MePhe 1.05 (1), Ahx 2.1 (2), Trp 0.53 (1), NH3 0.69. MS (FAB): m/e 897 (M+H)+.

Example 38 Hpa-Ahx-Sar-Trp-Ahx-Asp-MePhe-NH-, (SEQ ID NO 19) Following the procedure of Table 2 and sequentially coupling Fmoc-MePhe-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Ahx-OH, Fmoc-Trp-OH, Fmoc-Sar-OH, Fmoc-Ahx-OH and Hpa-OSu, to the resin, the title compound was prepared. Amino Acid analysis following 20 acid decomposition gave Asp 0.93 (1), Sar 1.12 (1), MePhe 0.95 (1), Ahx 1.99 (2), Trp 1.06 (1), HN3 0.88. MS (FAB): m/e 909 (M-H)'.

Example 39 HpafSO-.H V Ahx-Sar-T rp-Ahx-Asp-MePhe-NH-, (SEQ ID NO 20) 25 Hpa-Ahx-Sar-Trp-Ahx-Asp-MePhe-NH2 (the product of Example 38) was sulphated according to the procedures of Example 10 to give the title compound. Amino Acid analysis following acid decomposition Asp 1.04 (1), Sar 0.87 (1), MePhe 0.86 (1), Ahx 2.23 (2), Trp 0.89 (1), NH3 1.31, MS(FAB) m/e 989 (M-H)\ Example 40 The compound of Example 32 was tested in Test B above, and found to bind to CCK-A receptors with a binding constant (Kj) of 0.03nM. 28 Secnience Listing (Total of 20 sequences) (1) INFORMATION FOR SEQ ID NO 1: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 IS (D) OTHER INFORMATION: Xaa is N-[2-(O-SUlpho-4- oxyphenyl)ethanoyl]-Nle (ix) FEATURE: (A) NAME/KEY: misc-feature :o (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: (A) NAME/KEY: misc-feature 25 (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is phenylalanine amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 1 Xaa Gly Trp Leu Asp Xaa 1 5 (2) INFORMATION FOR SEQ ID NO 2: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear 40 (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 45 (D) OTHER INFORMATION: Xaa is N-[2-(4- hydroxyphenyl)ethanoyl]-Nle (ix) FEATURE: (A) NAME/KEY: misc-feature so (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: (A) NAME/KEY: misc-feature 55 (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is phenylalanine amide 24-6195 WO 93/13126 PCT/G B92/02369 29 (xi) SEQUENCE DESCRIPTION: SEQ ID NO 2 Xaa Gly Trp Leu Asp Xaa 1 5 s (3) INFORMATION FOR SEQ ID NO 3: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues io (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide is (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxypheny1)ethanoyl] -Nle 2S 40 (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl aspartic acid (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is phenylalanine amide (xi) SEQUENCE DESCRIPTION: SEQ ID NO 3 Xaa Gly Trp Leu Xaa Xaa 1 5 (4) INFORMATION FOR SEQ ID NO 4: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues 45 (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide so (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(O-sulpho-4-oxyphenyl)ethanoyl]-Nle 55 (ix) FEATURE: (A) NAME/KEY: misc-feature 2*6 195 WO 93/13126 PCT/GB92/02369 (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: s (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: io (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is phenylalanine amide is (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 4 Xaa Gly Trp Leu Xaa Xaa 1 5 (5) INFORMATION FOR SEQ ID NO 5: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear 2S (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature so (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[4-hydroxypheny1)ethanoyl]-Met (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide 40 (xi) SEQUENCE DESCRIPTION: SEQ ID NO 5 Xaa Gly Trp Met Asp Xaa 1 5 45 (6) INFORMATION FOR SEQ ID NO 6: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid 50 (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: 55 (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[4- 2f619 WO 93/13126 PCT/GB92/02369 31 hydroxyphenyl)ethanoyl]-Nle (ix) FEATURE: (A) NAME/KEY: misc-feature s (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: (A) NAME/KEY: misc-feature io . (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is phenylalanine amide (xi) SEQUENCE DESCRIPTION: SEQ ID NO 6 is Xaa Gly Trp lie Xaa Xaa 1 5 (7) INFORMATION FOR SEQ ID NO 7: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[4- hydroxypheny1)ethanoyl]-Nle (ix) FEATURE: (A) NAME/KEY: misc-feature 35 (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide 40 45 50 (xi) SEQUENCE DESCRIPTION: SEQ ID NO 7 Xaa Gly Trp lie Asp Xaa 1 5 (8) INFORMATION FOR SEQ ID NO 8: (!) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature 55 (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxypheny1)ethanoyl]-Met 2*619 WO 93/13126 PCT/GB92/02369 32 (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is Asp 0-benzyl ester s (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine io amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 8 Xaa Gly Trp Met Xaa Xaa is 1 5 (9) INFORMATION FOR SEQ ID NO 9: (i) SEQUENCE CHARACTERISTICS 20 (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(0-sulphO-4-30 oxypheny 1) ethanoy 1 ] -Met (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is Asp 0-benzyl ester (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 40 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 9 45 Xaa Gly Trp Met Xaa Xaa 1 5 (10) INFORMATION FOR SEQ ID NO 10: so (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear ss (ii) MOLECULE TYPE: peptide (ix) FEATURE: 2f6l WO 93/13126 PCT(GB?2/02369 f 33 (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[O-sulpho-4-oxyphenyl)ethanoyl]-Nle (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine io amide (xi) SEQUENCE DESCRIPTION: SEQ ID NO 10 Xaa Gly Trp lie Asp Xaa is 1 5 (11) INFORMATION FOR SEQ ID NO 11: (i) SEQUENCE CHARACTERISTICS 20 (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(O-sulpho-4-30 oxypheny 1) ethanoyl ] -Nle (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 40 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide (xi) SEQUENCE DESCRIPTION: SEQ ID NO 11 45 Xaa Gly Trp lie Xaa Xaa 1 5 (12) INFORMATION FOR SEQ ID NO 12: so (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear 55 (ii) MOLECULE TYPE: peptide (ix) FEATURE: 24-619 WO 93/13126 PCT/GB92/02369 ► 34 (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxyphenyl)ethanoyl]-Nle s (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine is amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 12 Xaa Gly Trp lie Xaa Xaa 1 5 (13) INFORMATION FOR SEQ ID NO 13: (i) SEQUENCE CHARACTERISTICS 25 (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(0-sulpho-4-35 oxyphenyl) ethanoyl ] -lie (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 5 40 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 45 (D) OTHER INFORMATION: Xaa is phenylalanine amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 13 Xaa Gly Trp lie Xaa Xaa 50 1 5 (14) INFORMATION FOR SEQ ID NO 14: (i) SEQUENCE CHARACTERISTICS 55 (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear 2f61 9 WO 93/13126 PCT/GB92/02369 (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature 5 (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxyphenyl)ethanoyl]-lie (ix) FEATURE: io (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: is (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is phenylalanine amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 14 Xaa Gly Trp lie Xaa Xaa 1 5 (15) INFORMATION FOR SEQ ID NO 15: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature 35 (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxyphenyl)ethanoyl]-Nle (ix) FEATURE: 40 (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: 45 (A) NAME/KEY: misc-feature (B) LOCATION: 5 (D) OTHER INFORMATION: Xaa is N-methyl-Asp (ix) FEATURE: so (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide ss (xi) SEQUENCE DESCRIPTION: SEQ ID NO 15 2*6195 WO 93/13126 PCT/G B92/02369 36 r Xaa Gly Trp Leu Xaa Xaa 1 5 s (16) INFORMATION FOR SEQ ID NO 16: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature is (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxyphenyl)ethanoyl]-Nle (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Xaa is e-N-[(2-methylphenyl)aminocarbony1]-Lys (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 16 Xaa Gly Trp Xaa Asp Xaa 1 5 (17) INFORMATION FOR SEQ ID NO 17: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues 40 (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 45 (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(O-sulpho-4-oxyphenyl)ethanoyl]-Nle 50 . (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Xaa is e-N-[(2-55 methylphenyl)aminocarbonyl]-Lys (ix) FEATURE: 1 WO 93/13126 PCI7 GB92/02369 37 - • (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide s (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 17 Xaa Gly Trp Xaa Asp Xaa 1 5 50 (18) INFORMATION FOR SEQ ID NO 18: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues is (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-hydroxypheny1)ethanoyl]-Nle (ix) FEATURE; (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine 35 amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 18 Xaa Gly Trp Leu Asp Xaa 40 1 5 (19) INFORMATION FOR SEQ ID NO 19: (i) SEQUENCE CHARACTERISTICS 45 (A) LENGTH: 6 residues (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(4-55 hydroxypheny 1) ethanoyl ] -Nle (ix) FEATURE:

Claims (18)

2f6195 WO 93/13126 PCT/GB92/02369 38 r ' (A) NAME/KEY: misc-feature (B) LOCATION: 2 (D) OTHER INFORMATION: Gly is sarcosine s (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle io (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine amide is 20 35 45 (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 19 Xaa Gly Trp Leu Asp Xaa 1 5 (20) INFORMATION FOR SEQ ID NO 20: (i) SEQUENCE CHARACTERISTICS (A) LENGTH: 6 residues 25 (B) TYPE: amino acid (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide 30 (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 1 (D) OTHER INFORMATION: Xaa is N-[2-(O-sulpho-4-oxyphenyl)ethanoyl]-Nle 40 (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 2 (D) OTHER INFORMATION: Gly is sarcosine (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 4 (D) OTHER INFORMATION: Leu is Nle (ix) FEATURE: (A) NAME/KEY: misc-feature (B) LOCATION: 6 (D) OTHER INFORMATION: Xaa is N-methyl-phenylalanine so amide (Xi) SEQUENCE DESCRIPTION: SEQ ID NO 20 Xaa Gly Trp Leu Asp Xaa 55 1 5 39 Claims:

1. A compound of formula I: 2461 M-G-Trp-X-J-L-NH2 10 15 20 25 30 wherein R1 is OH or 0S03H; M is Met, Ahx or lie; G is Gly or Sar, X is Met, Ahx, He, Phe or Lys^2); J is Asp, Asp(OBn), DAsp, MeAsp, or MeDAsp; and L is Phe or MePhe; wherein R2 is a group of formula II, C(0)-E I I wherein E is NH, CH=CH or CH2CH2; and R3, R4, R5, R6 and R7 are independently H, OH, halogen, alkyl Cw or 0S03H; provided that when R1 is 0S03H, G is Gly and: (a) J is Asp, L is MePhe and M is Ahx, then X is not Ahx; (b) J is Asp, L is MePhe and M is lie, then X is not He; (c) J is Asp, L is MePhe and M is lie, then X is not Ahx; (d) J is Asp, L is Phe and M is Met, then X is not Met; ^ (e) J is Asp, L is MePhe and M is Met, then X is not Met; or (f) J is DAsp, L is MePhe and M is Met, then X is not Met; or a pharmaceutically acceptable derivative thereof. 246195' 40

2. A compound of formula I as claimed in claim 1, or a pharmaceutically acceptable derivative thereof, wherein M is Ahx or lie.

3. A compound of formula I as claimed in claim 1 or claim 2, or a pharmaceutically acceptable derivative thereof, wherein X is Ahx, lie or Lys(R2) and R2 is a group of wherein E is NH, CH=CH or CH2CH2; and R3, R4, Rs, R6 and R7 are independently H, OH, halogen, alkyl or 0S03H.

4. A compound of formula I as claimed in any one of the preceding claims, or a pharmaceutically acceptable derivative thereof, wherein J is Asp, DAsp, MeAsp or 15 MeDAsp.

5. A compound of formula I, as claimed in any one of the preceding claims, or a pharmaceutically acceptable derivative thereof, wherein R1 is 0S03H.

6. A compound of formula I as claimed in claim 1, which is: Hpa(S03H)-Ahx-Gly-Trp-Ahx-Asp-Phe-NH2 (SEQ ID NO 1); 20 Hpa-Met-Gly-T rp-Met-DAsp-Phe-NH2; Hpa-Ahx-Gly-Trp-Ahx-Asp-Phe-NH2 (SEQ ID NO 2); Hpa-Ahx-Gly-Trp-Ahx-MeAsp-Phe-NH2 (SEQ ID NO 3); Hpa-Ile-Gly-Trp-Ile-DAsp-MePhe-NH2; Hpa(S03H)-Met-Gly-Trp-Met-DAsp-Phe-NH2; 25 Hpa (S03H)-Ile-Gly-T rp-Ile-D Asp-MePhe-NH2; Hpa-Met-Gly-Trp-Met-Asp-MePhe-NH2 (SEQ ID NO 5); Hpa-Ahx-Gly-Trp-Ahx-D Asp-MePhe-NH2; Hpa-Ahx-Gly-Trp-Ue-DAsp-Phe-NH2; Hpa-Ahx-Gly-Trp-Ile-MeAsp-Phe-NH2 (SEQ ID NO 6); 30 Hpa-Ahx-Gly-Trp-Ile-Asp-MePhe-NH2 (SEQ ID NO 7); H pa (S03H)-Ahx-G ly-Trp-Ile-D Asp-Phe-NH2; 5 formula II, I I 10 246195 41 Hpa-Met-Gly-Trp-Met-Asp(OBn)-MePhe-NH2 (SEQ ID NO 8); Hpa(S03H)-Met-Gly-Trp-Met-Asp(0Bn)-MePhe-NH2 (SEQ ID NO 9); Hpa-Ahx-Gly-T rp-Ile-D Asp-MePhe-NH2; Hpa(S03H)-Ahx-Gly-Trp-Ile-DAsp-MePhe-NH2; 5 Hpa(S03H)-Ahx-Gly-Trp-Ile-Asp-MePhe-NH2 (SEQ ID NO 10); Hpa(S03H)-Ahx-Gly-Trp-Ahx-D Asp-MePhe-NH2; Hpa-De-Gly-T rp-Ile-D Asp-Phe-NH2; Hpa(S03H)-Ile-Gly-Trp-Ile-DAsp-Phe-NH2; Hpa-Ahx-Gly-Trp-Phe-D Asp-MePhe-NH2; 10 Hpa(S03H)-Ahx-Gly-T rp-Phe-D Asp-MePhe-NH2; Hpa(S03H)-Ahx-Gly-Trp-Ahx-DAsp-Phe-NH2; Hpa-Ahx-Gly-T rp-Ahx-D Asp-Phe-NH2; Hpa(S03H)-Ahx-Gly-Trp-Ile-MeAsp-MePhe-NH2 (SEQ ID NO 11); Hpa-Ahx-Gly-Trp-Ile-MeAsp-MePhe-NH2 (SEQ ID NO 12); 15 Hpa(S03H)-Ile-Gly-Trp-Ile-MeAsp-Phe-NH2 (SEQ ID NO 13); Hpa-Ile-Gly-Trp-Ile-MeAsp-Phe-NH2 (SEQ ID NO 14); Hpa-Ahx-Gly-T rp-Ahx-MeD Asp-Phe-NH2; Hpa(S03H)-Ahx-Gly-Trp-Ahx-MeDAsp-Phe-NH2; Hpa-Ahx-Gly-T rp-Ahx-Me Asp-MePhe-NH2 (SEQ ID NO 15); 20 Hpa-Ahx-Gly-Trp-Lys(Tac)-Asp-MePhe-NH2 (SEQ ID NO 16); Hpa(S03H)-Ahx-Gly-Trp-Lys(Tac)-Asp-MePhe-NH2 (SEQ ID NO 17); Hpa-Ahx-Gly-Trp-Ahx-Asp-MePhe-NH2 (SEQ ID NO 18); Hpa-Ahx-Sar-Trp-Ahx-Asp-MePhe-NH2 (SEQ ID NO 19); Hpa(S03H)-Ahx-Sar-Trp-Ahx-Asp-MePhe-NH2 (SEQ ID NO 20); 25 or a pharmaceutically acceptable derivative of any one thereof.

7. A compound of formula I, as claimed in claim 1, which is Hpa(S03H)-Ahx-Gly-Trp-Ahx-MeAsp-Phe-NH2 (SEQ ID NO 4) or a pharmaceutically acceptable derivative thereof.

8. A compound of formula I, as defined in any one of claims 1 to 7, or a pharmaceutically acceptable derivative thereof, for use as a pharmaceutical. 30

9. A compound of formula I, as defined in any one of claims 1 to 7, or a 246195 42 pharmaceutically acceptable derivative thereof, for use in the manufacture of a medicament for the treatment of obesity.

10. A pharmaceutical formulation comprising a compound of formula I, as defined in any one of claims 1 to 7, or a pharmaceutically acceptable derivative thereof, in admixture 5 with a pharmaceutically acceptable adjuvant, diluent or carrier.

11. A cosmetic method of improving the bodily appearance of a mammal which comprises administering to that mammal a compound of formula I, as defined in any one of claims 1 to 7, or a pharmaceutically acceptable derivative thereof, until a cosmetically beneficial loss of body weight has occurred. 10

12. A process for the preparation of a compound of formula I, as defined in any one of claims 1 to 7, or a pharmaceutically acceptable derivative thereof, which comprises: a) preparing a compound of formula I in which R1 represents 0S03H by sulphating a compound of formula III, wherein M, G and L are as defined in claim 1; Ja has the same definition as J in claim 1 20 except that the /3-carboxyl group of any Asp, DAsp, MeAsp or MeDAsp residue present is optionally protected; Xa has the same definition as X in claim 1 except that it may additionally represent Lys and any hydroxy or amino group is present in protected form (except for any hydroxy groups to be converted to a sulphate ester); and Za is NH2 or a carboxyl protecting group; 25 and, if necessary, deprotecting the resulting compound; b) removing one or more protecting groups from a compound of formula IV, HO 15 i i i M-G-Trp-Xa-Ja-L-Za 30 0 M-G-T rp-Xa-Ja-L-Za I V n.z. PATENT OFFICE 1 2 SEP 1995 received 43 246195 wherein R1, L, M and G are as defined in claim 1; Xa, Ja, and Za are as defined in process alternative (a), and at least one of Xa, Ja, and Z is present in protected form; c) preparing a compound of formula I in which R1 represents OH and X represents 5 Lys(R2) wherein R2 is a group of formula II, C ( 0 ) - E 10 I I wherein R3, R4, R5, R6 and R7 are independently H, OH, halogen, alkyl or 0S03H; and E is NH by reacting a compound of formula V, HO 15 0 M-G-Trp-Xb-J-L-NH2 wherein M, G, J and L are as defined in claim 1, and Xb is Lys, with a compound of formula VI, 20 0 = C - N V I 25 wherein R3, R4, R5, R6 and R7 are as defined in claim 1; or d) preparing a compound of formula I in which R1 represents OH and X represents Lys(R2) wherein R2 is a group of formula II, 30 N ?. OFFICE 1 2 SEP 1995 RloEiv'EO 44 246195 C(0)-E I I wherein R3, R4, Rs, R6 and R7 are independently H, OH, halogen, alkyl or 0S03H; and E is CH2CH2 or CH=CH by coupling a compound of formula V as defined in process alternative (c) with a compound of formula VII, , 4 10 HO -C(0 ) -E V [ I wherein E is CH2CH2 or CH=CH and R3, R4, R5, R6 and R7 are as defined in claim 1. 15

13. A compound of formula IV, as defined in claim 12.

14. A compound of formula I as claimed in claim 1 substantially as herein described with reference to any example thereof.

15. A pharmaceutical formulation as claimed in claim 10 substantially as herein described with reference to any example thereof. 20

16. A cosmetic method for improving the bodily appearance of a mammal substantially as herein described with reference to any example thereof.

17. A process for the preparation of a compound of formula I as defined in claim 1 substantially as herein described with reference to any example thereof.

18. A compound of formula IV as claimed in claim 13 substantially as herein described 25 with reference to any example thereof. Fim s Corporation the authorised n.jsnis Per N.Z. Pfr-.yr OFFICE t 2 SEP 1995