WO2012131077A1

WO2012131077A1 - Somatostatin mimetics

Info

Publication number: WO2012131077A1
Application number: PCT/EP2012/055900
Authority: WO
Inventors: Jian Zhou; Paul Murphy
Original assignee: University College Dublin; National University of Ireland Galway NUI; National University of Ireland
Current assignee: University College Dublin; National University of Ireland Galway NUI; National University of Ireland
Priority date: 2011-03-30
Filing date: 2012-03-30
Publication date: 2012-10-04
Anticipated expiration: 2013-09-30

Abstract

Somatostatin is a tetradecapeptide that regulates, through binding to its receptors (SSTRs), a number of processes including the release of growth hormone and other pituitary hormones. Disclosed herein are a number of somatostatin mimetics that exhibit potential utility as therapeutic agents. Formula (I).

Description

Title

Somatostatin Mimetics Field of the Invention

[0001] The present invention relates to novel compounds that are ligands at the Somatostatin receptors. The present invention further provides for a method of synthesis of these compounds and for the use of the compounds as therapeutic agents.

Background to the Invention

[0002] Somatostatin (SST, 1) is a tetradecapeptide that regulates, through binding to its receptors (SSTRs), a number of processes including the release of growth hormone and other pituitary hormones. The side-chains of the Phe-Trp-Lys peptide fragment of 1 (residues i, i+1 and i+2 in Figure 1), which adopts a β-turn conformation, are important for the recognition of SSTRs, defining an important component of its pharmacophore. The low bioavailability and poor pharmacokinetics of somatostatin has led to the synthesis of both peptide and non-peptide mimetics of this hormone.

[0003] Sandostatin (D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-ol with a disulfide bridge) is a potent peptide based mimetic of somatostatin that has found clinical application. Sandostatin differs from 1 as it contains D-tryptophan instead of the L-tryptophan residue but it can be postulated that the pharmacophoric side-chains adopt a similar geometric arrangement in both sandostatin and somatostatin. [0004] Nothwithstanding the state of the art there remains a need for alternative peptidomimetic ligands showing affinity for SSTRs.

Summary of the Invention

[0005] In a first aspect the present invention provides for a compound of the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof:

wherein m is 0 - 4;

n is 0 - 3;

each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- Ci₀ aryl;

R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl;

R³ is selected from H, C C₅ aliphatic, and benzyl;

R⁴ is selected from H , C C₁₀ aliphatic, C(0)C C₂o aliphatic, and C(0)C₆- C₂o aromatic;

each R⁵ is independently selected from the group consisting of a halogen,

OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- C10 aryl;

W is selected from H, C C₅ aliphatic, and benzyl;

X is selected from N H, NO, S, O, CH₂, and HC=CH;

Y is C1-C5 aliphatic;

Z is selected from C C₅ aliphatic, O, N H, S, OCH₂, NHCH₂, and SCH₂; and

U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH.

[0006] When R⁴ is C(O)C Ci₀ aliphatic or C(O)C₆-Ci₀ aromatic the moiety N HR⁴ is an aliphatic amide or an aromatic amide respectively. [0007] The moiety (CH-CH)O represents an ethylene oxide (or oxirane) moiety. The moiety (CH-CH)NH represents an aziridine moiety.

[0008] As used herein the term ester includes aliphatic esters, aromatic esters and phosphate esters

[0009] As used herein, the term C_x-C_y aliphatic refers to linear, branched, saturated and unsaturated hydrocarbon chains comprising C_x-C_y carbon atoms (and includes C_x-C_yalkyl, C_x-C_y alkenyl and C_x-C_yalkynyl).

[0010] Similarly, references to C_x-C_yalkyl, C_x-C_y alkenyl and C_x-C_yalkynyl include linear and branched C_x-C_yalkyl, C_x-C_y alkenyl and C_x-C_yalkynyl.

[0011] As used herein, the term aryl/aromatic refers to a aromatic carbocyclic structure. The term heterocycle refers to cyclic compounds having as ring members atoms of at least two different elements. The term heteroaromatic refers to an aromatic heterocyclic structure having as ring members atoms of at least two different elements.

[0012] As used herein, the term "leaving group" refers to species that departs with a pair of electrons in heterolytic bond cleavage.

[0013] The compound may have the absolute stereochemistry indicated in formula (la), a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof:

wherein m is 0 - 4;

n is 0 - 3;

each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- C10 aryl;

R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl;

R⁴ is selected from H, C C₁₀ aliphatic, C(0)C C₂o aliphatic, and C(0)C₆- C₂o aromatic;

each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- C10 aryl; W is selected from H, C C₅ aliphatic, and benzyl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Y is C₁-C5 aliphatic;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

[0014] In one particular embodiment, the variables may be as follows: m is 0 - 4; n is 0-3; each R¹ is independently selected from the group consisting of halogen, OH, CF₃, Me, OMe and Ph; R² is selected from H, Me, benzyl, allyl and p-methoxybenzyl; R³ is selected from H, Me, Et, C₃H₇, C4H₉, allyl and benzyl; R⁴ is selected from H, H, Me, Et, C₃H₇, C₄H₉, C(0)Me, C(0)Et, C(0)C₃H₇, C(0)C₄H₉, and C(0)Ph; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, Me, OMe and Ph; W is selected from H or benzyl; X is selected from NH, S, O, CH₂, and HC=CH; Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂, CH₂CH₂CH₂CH₂CH₂, CH₂CH=CHCH₂; Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂,

HC=CHCH₂, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, and CH=CH.

[0015] In a further embodiment, the variables may be as follows: m is 0 - 4; n is 0; each R¹ is independently selected from the group consisting of halogen, OH, CF₃, Me, OMe and Ph; R² is selected from H, Me, benzyl, allyl and p-methoxybenzyl; R³ is selected from H, Me, Et, C₃H₇, C₄H₉, allyl and benzyl; R⁴ is selected from H, H, Me, Et, C₃H₇, C₄H₉, C(0)Me, C(0)Et, C(0)C₃H₇, C(0)C₄H₉, and C(0)Ph; W is selected from H or benzyl; X is selected from NH, S, O, CH₂, and HC=CH; Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂, CH₂CH₂CH₂CH₂CH₂, CH₂CH=CHCH₂; Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, HC=CHCH₂, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, and CH=CH.

[0016] In one embodiment, m is 0 - 4; n is 0 - 3; each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, and C C₅ aliphatic; R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl; R⁴ is selected from H, C Ci₀ aliphatic, C(O)C C₂₀ aliphatic, and C(O)C₆-C₂₀ aromatic; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, and C C₅ aliphatic, W is selected from H, C C₅ aliphatic, and benzyl; X is selected from NH, NO, S, O, CH₂, and HC=CH; Y is C C₅ aliphatic; Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, CH=CH, C≡C, and cyclopropyl.

[0017] In a further embodiment m is 0 - 4; n is 0; each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, and C C₅ aliphatic; R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl; R⁴ is selected from H, C Ci₀ aliphatic, C(O)C C₂₀ aliphatic, and C(O)C₆-C₂₀ aromatic; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, and C C₅ aliphatic, W is selected from H, C C₅ aliphatic, and benzyl; X is selected from NH, NO, S, O, CH₂, and HC=CH; Y is C C₅ aliphatic; Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, CH=CH, C≡C, and cyclopropyl

[0018] In a further embodiment m is 0 - 4; n is 0; each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-Ci₀ aryl; R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl; R⁴ is selected from H, C Ci₀ aliphatic,

C(O)Ci-C₂₀ aliphatic, and C(O)C₆-C₂₀ aromatic; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-Ci₀ aryl; W is selected from H, C C₅ aliphatic, and benzyl; X is selected from NH, NO, S, O, CH₂, and HC=CH; Y is C C₅ aliphatic; Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH.

[0019] In a further embodiment m is 0; n is 0; each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-Cio aryl; R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl; R⁴ is selected from H, C Ci₀ aliphatic, C(O)C C₂₀ aliphatic, and C(O)C₆-C₂₀ aromatic; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- Cio aryl; W is selected from H, C C₅ aliphatic, and benzyl; X is selected from NH, NO, S, O, CH₂, and HC=CH; Y is C C₅ aliphatic; Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH.

[0020] In a further embodiment m is 0 - 4; n is 0; each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-Ci₀ aryl; R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl; R⁴ is selected from H, C Ci₀ aliphatic,

C(O)Ci-C₂₀ aliphatic, and C(O)C₆-C₂₀ aromatic; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-Ci₀ aryl; W is selected from H, C C₅ aliphatic, and benzyl; X is selected from NH, NO, S, O, CH₂, and HC=CH; Y is C C₅ aliphatic; Z is C C₅ aliphatic; and U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH.

[0021] In a further embodiment m is 0; n is 0; each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-Cio aryl; R² is selected from H, C C₅ aliphatic, benzyl, and p-methoxybenzyl; R³ is selected from H, C C₅ aliphatic, and benzyl; R⁴ is selected from H, C Ci₀ aliphatic, C(O)C C₂₀ aliphatic, and C(0)C₆-C₂o aromatic; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C C₅ aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- Cio aryl; W is selected from H, C C₅ aliphatic, and benzyl; X is selected from NH, NO, S, O, CH₂, and HC=CH; Y is C C₅ aliphatic; Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH.

[0022] In yet a further embodiment, the variables may be as follows: m is 0 - 4; n is 0-3; each R¹ is independently selected from the group consisting of halogen, OH, CF₃, Me, and OMe. R² is selected from H, Me, benzyl, allyl and p-methoxybenzyl; R³ is selected from H, Me, Et, C₃H₇, C₄H₉, allyl and benzyl; R⁴ is selected from H, H, Me, Et, C₃H₇, C₄H₉, C(0)Me, C(0)Et, C(0)C₃H₇, C(0)C₄H₉, and C(0)Ph; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, Me, and OMe; W is selected from H or benzyl; X is selected from NH, S, O, CH₂, and HC=CH; Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂,

CH₂CH₂CH₂CH₂CH₂, CH₂CH=CHCH₂; Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂,

HC=CHCH₂, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, cyclopropyl and CH=CH.

[0023] In yet a further embodiment, the variables may be as follows: m is 0 - 4; n is 0-3; each R¹ is independently selected from the group consisting of halogen, OH, CF₃, Me, and OMe. R² is selected from H, Me, benzyl, allyl and p-methoxybenzyl; R³ is selected from H, Me, Et, C₃H₇, C₄H₉, allyl and benzyl; R⁴ is selected from H, C(0)Me, C(0)Et, C(0)C₃H₇, C(0)C₄H₉, and

C(0)Ph; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, Me, and OMe; W is selected from benzyl; X is selected from NH, S, O, and CH₂; Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂, CH₂CH₂CH₂CH₂CH₂, CH₂CH⁼CHCH₂; Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, HC=CHCH₂, O, NH, S, OCH₂, NHCH₂, and SCH₂; and U-U is selected from CH₂-CH₂, cyclopropyl and CH=CH.

[0024] In one particular embodiment both n and m may be 0. In a further embodiment W may be benzyl.

[0025] The compound may be

a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof. The stereodescriptors indicate absolute stereochemistry.

[0026] The compound may be:

[0027] The invention further extends to pharmaceutical composition comprising a compound according to the present invention and a pharmaceutical acceptable carrier.

[0028] The compounds of the present invention may find use in the treatment of a disorder in which somatostatin receptors are implicated. For example, use in the modulation of angiogenesis. The compounds may find use in the treatment of a disorder in which

neovascularisation or angiogenesis are implicated.

[0029] Suitable uses may include use in the treatment of acromegaly, cancer, arthritis, carcinoid tumours, and vasoactive intestinal peptide tumours.

[0030] In a further aspect the present invention provides for a method of preparing a compound according to the present invention, the method comprising:

i) peptide coupling a compound of formula (II) and a compound of formula (III) to

wherein m is 0 - 4;

n is 0 - 3;

P¹-P⁴ are oxygen protecting groups, such that P²-P⁴ can be the same or different and P¹ is different from each of P²-P⁴;

each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- C10 aryl; X is selected from NH, NO, S, O, CH₂, and HC=CH;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH; and

ii) selectively removing oxygen protecting group P¹ and alkylating the free alcohol thus formed to provide a compound of the general formula (V):

wherein m is 0 - 4;

n is 0 - 3;

P²-P⁴ are the same or different and are oxygen protecting groups;

each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- C10 aryl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; a U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH;

Y is C1-C5 aliphatic; and

R⁴ is selected from H, C C₁₀ aliphatic, C(O)C C₂₀ aliphatic, and C(0)C₆- C₂₀ aromatic.

[0031] As used herein the term peptide coupling refers to any direct or indirect method of forming a peptide bond between a carboxylic acid and an amine. For example, indirect coupling could be by means of first converting the acid to an acyl chloride or an activated

ester/anhydride, carbodiimide coupling, HOBt coupling, or HOCt coupling.

[0032] The method may further comprising the step of:

i) selectively removing oxygen protecting groups P²-P⁴ to provide a compound of the general formula (I):

wherein m is 0 - 4;

n is 0 - 3;

W is selected from H, C C₅ aliphatic, and benzyl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Y is C1-C5 aliphatic;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

In one particular embodiment, the variables may be as follows:

m is 0 - 4;

n is 0;

each R¹ is independently selected from the group consisting of halogen, OH, CF₃, Me, OMe and Ph;

R² is selected from H, Me, benzyl, ally I and p-methoxybenzyl;

R³ is selected from H, Me, Et, C₃H₇, C₄H₉, allyl and benzyl;

R⁴ is selected from H, H, Me, Et, C₃H₇, C₄H₉, C(0)Me, C(0)Et, C(0)C₃H₇, C(0)C₄H₉, and C(0)Ph;

each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, Me, OMe and Ph;

W is selected from H or benzyl; X is selected from NH, S, O, CH₂, and HC=CH;

Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂,

CH₂CH₂CH₂CH₂CH₂, CH₂CH⁼CHCH₂;

Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, HC=CHCH₂, O, NH, S,

OCH₂, NHCH₂, and SCH₂; and

U-U is selected from CH₂-CH₂, and CH=CH.

[0034] In one particular embodiment both n and m may be 0. In a further embodiment W may be benzyl.

[0035] The oxygen protecting groups P¹-P⁴ may be selected from benzyl, p-methoxybenzyl, methyl, allyl, trialkylsilyl, acetyl, tetrahydropyranyl, benzoyl, pivaloyi, substitute benzoyl, triphenyl silyl, t-butyldimethylsilyl, t-butyl-diphenylsilyl, methoxymethyl ether, methylthiomethyl ether, benzylmethoxymethyl ether, p-methoxybenzyloxymethyl, 3,4-dimethoxybenzyloxymethyl, benzyloxymethyl, t-butoxymethyl, (p-phenylphenyl)oxymethyl ether, methoxyethoxymethyl ether, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, t-butyl ether, prenyl ether, p-methoxyphenyl ether, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o- nitrobenzyl, p-nitrobenzyl, halobenzyl ether, dihalobenzyl ether, 2-naphthylmethyl ether, 4- acetoxybenzyl ether, diphenylmethyl ether, triphenylmethyl ether, methoxytriphenylmethyl ether, chloroacetyl, dichloroacetyl, trichloracetyl, trifluoroacetyl, phenoxyacetate, levulinate, halobenzoate, nitrobenzoate, allyloxycarbonate, methoxmethylcarbonate, benzylcarbonate, methoxybenzylcarbonate, t-butoxycarbonate, and fluorenylmethoxy carbonate.

[0036] With reference to the method of the present invention the step of alkylating the free alcohol thus formed may comprise:

i) alkylating the free alcohol with a molecule of the formula T— Y— T, thereby liberating an anion of one of T or T, wherein Y is C C₅ aliphatic;

T is CI, Br or I;

T is CI, Br or I; and

ii) replacing the other of T or T with NHR⁴.

[0037] The molecule of the may be

[0038] The compounds of the present invention may be found or isolated in the form of esters, salts, hydrates or solvates - all of which are embraced by the present invention.

[0039] Where suitable, it will be appreciated that all optional and/or preferred features of one embodiment of the invention may be combined with optional and/or preferred features of another/other embodiment(s) of the invention. Brief Description of the Drawings

[0040] Additional features and advantages of the present invention are described in, and will be apparent from, the detailed description of the invention and from the drawings in which:

[0041] Figure 1 illustrates the overlap of target compound 10 with the solution structure of sandostatin.

Detailed Description of the Invention

[0042] It should be readily apparent to one of ordinary skill in the art that the examples disclosed herein below represent generalised examples only, and that other arrangements and methods capable of reproducing the invention are possible and are embraced by the present invention.

Molecular Modelling Studies

[0043] A model of the target compound 10 was built with the spatial arrangement of the indole and butylamine groups found in sandostatin preserved.

10

[0044] This was then subjected to a MonteCarlo conformational search in Macromodel 8.5 which was used to generate low energy conformational isomers wherein the spatial arrangement between the indole and butylamine groups was constrained whilst allowing the conformation of the remainder of the molecule to be varied during the simulation. Subsequently the indole and butylamine groups of the lowest energy conformer of 10 generated during this search (the structure on the left hand side in Figure 1) was overlayed with those groups in the sandostatin solution structure (the light grey structure on the right hand side in Figure 1).

[0045] The outcome of this procedure suggested that although the indole and butylamine groups can potentially adopt a spatial arrangement as found in sandostatin, there was not any major overlap between the peptide backbone of sandostatin and the benzomacrolactone scaffold. There was little indication in the 3-D model of any potential for the O-benzyl group on the scaffold to overlap with the phenylalanine residue of sandostatin.

Synthesis of protected scaffolds [0046] It was proposed to generate the macrolactone (Scheme 1) via 11 which was prepared via esterification of benzoic acid 12 using alcohol 13 and a subsequent ring closure metathesis (RCM). Precursor 13 was envisaged from D-glucosamine 14. The choice of having an azide, OTIPS and OMPM (methoxyphenyl methyl) groups onto the scaffold was based on the potential of both chemoselective and regioselective functionalisation at these sites.

Scheme 1 Retrosynthetic analysis [0047] The synthesis of the orthogonally protected precursor 13 commenced as shown in

Scheme 2. Starting from the commercially available glucosamine 4, the fully acetylated 2-azido- 2-deoxy-D-glucose intermediate was obtained as a mixture of anomers (α:β, 2: 1) after a diazo transfer reaction and subsequent per-O-acetylation. A thioglycoside 6 was then obtained (admixture, 3: 1) by reaction of the peracetylated product with thiophenol in the presence of BF₃.OEt₂. De-O-acetylation and subsequent reaction of the triol intermediate with

dimethylanisaldehyde acetal in the presence of CSA gave the thioglycoside 15 (oc^-mixture, 1.8: 1). A TIPS ether protecting group was then introduced using TIPSOTf and DIPEA as base and the partial regioselective reduction of the methoxybenzylidene group of the intermediate was next achieved by treatment with Bu₂BOTf in BH₃.THF at 0 °C; this gave alcohol 16. The structure of 16 was confirmed by NMR experiments on the oc-anomer; the 2D-HMBC spectrum showed a correlation between C-4 and the CH₂ protons of the PMB group as well as a correlation between the methylene carbon of the PMB group and H-4. For this transformation the BH₃.THF-Bu₂BOTf system was found to be the most suitable in order to obtain the desired 4-O-methoxybenzyl product; the use of Cu(OTf)₂, BF₃.OEt₂, TMSOTf or TfOH as the promoters were less satisfactory and only lower yields and poor selectivity resulted. The next steps were hydrolysis of the thioglycoside and the subsequent reduction of the resulting hemiacetal in order to get the acyclic amino-deoxy-D-sorbitol derivatives. The thioglycoside 16 was hydrolyzed firstly using NBS in acetone-H₂0 (v/v, 40: 1 , α/β-mixture, 1 :2.4; 96%). The reaction time and acetone: H₂0 ratio seemed be very important. A higher proportion of water led to decomposition and a lower yield. The hemiacetal intermediate was next treated portionwise with NaBH₄ in EtOH-H₂0 to give 17. Lithium borohydride in THF was also investigated for this reduction reaction but the yields were found to be lower. Overall the triol 17 was obtained in 55% yield from 14 after 8 steps.

Scheme 2

[0048] Next the 1 ,2-diol group of 17 was protected as a benzylidene acetal in order to leave the hydroxyl group closest to the azide free; the treatment of 17 with benzaldehyde dimethylacetal in the presence of CSA gave an intermediate acetal as a mixture of diastereoisomers (86%). A pivaloyl group was next introduced at the free alcohol group and subsequent partial regioselective reductive cleavage of the benzylidene acetal gave 18. The allylation of the free alcohol was next carried out using sodium hydride (1.4 eq) and allyl iodide; there was some evidence for some TIPS protecting group migration to the primary alcohol under these conditions. The quenching procedure after the allylation reaction involved the use of satd NH₄CI; addition of methanol instead led to the premature removal of the pivalate. The pivaloyl group was then removed selectively by using freshly prepared MeONa to get the desired precursor 13 (61 % in two steps from 18).

1 3 61 %

Scheme 3 [0049] Preparation of the aromatic precursor 12 was next carried out (Scheme 4). The acetonide of 6-vinyl salicylic acid 20 was synthesized in three steps from commercially available 2,6-dihydroxybenzoic acid 19; formation of the acetonide was first carried out, then the free was converted to its triflate and a subsequent palladium-catalyzed coupling between the triflate and potassium vinyltrifluoroborate gave 20 (71 % from 19). Other palladium-catalyzed (Pd(PPh₃)₄, LiCI) couplings such as a reaction between the triflate and a vinyl tin reagent was also investigated but the vinyl product was obtained in only 50% yield. The acetonide of 20 was then hydrolyzed using KOH to give 12 (90%). The salicylic acid 12 was then converted to key macrocyclic intermediate 11. Reaction of 12 with the sorbitol derivative 13 by a Mitsunobu esterification promoted by triphenylphosphine in the presence of DIAD gave 21. It is worth noting that the yield from the esterification decreased dramatically (from 83% to 45%) if the coupling was carried out starting from the benzyl ether 22. The pKa of 12 is most likely lower than that of 22 due to intramolecular H-bonding in 12; the pKa value of salicylic acid is -2.98 while the pKa value of the corresponding methoxy ether of salicylic acid is ~ 4.10).

1 1

Scheme 4 [0050] The number of equivalents of PPh₃ used in the Mitsunobu reaction should be slightly less than that of DIAD; this prevents the Staudinger reaction of the azide and phosphine from occurring and prevents a loss in yield of 21. The phenol was then converted to its benzyl ether and then ring closure metathesis (RCM) using the Hoyveda-Grubbs II catalyst in CH₂CI₂ under argon gave 11 (85% from 21); the optimum conditions for the RCM were established after investigation of a variety of conditions where solvent and temperature were varied and the use of additives such as 2,6-dichloro-1 ,4-benzoquinone were also investigated. Also the Hoveyda- Grubbs II catalyst, a phosphine-free catalyst, was chosen as it was envisaged that a catalyst containing a phosphine ligand could react with the azide. If compound 21 was subjected to RCM reaction using the Hoveyda-Grubbs II catalyst, the yield of the ring closed product was significantly lower (-40%). This explains the preparation of the benzyl ether precursor. It was also noticed that separation of the metathesis catalyst from the product was difficult. Finally chromatography using toluene-CH₃CN (200: 1) as a solvent led to isolation of the pure 13 in high yield (92%).

[0051] In order to obtain the desired peptidomimetics, the side chains of the Trp-Lys dipeptide fragment, which are important for the recognition to somatostatin receptors, needed to be next installed onto the scaffold. This required: 1. the removal of the TIPS group followed by introduction of an alkyl amine and 2. reduction of the azide and subsequent coupling with 3- indole acetic acid. A number of attempts were investigated to achieve this goal and the sequences shown in Scheme 5 and 6 were finally successful. It was necessary to first reduce the azide of 13 which was achieved using the Staudinger reaction. The less sterically hindered PMe₃ was found more effective than the other phosphines (PBu₃, PPh₃). The resulting amine was then coupled with indol-3-ylacetic acid 22 to give compound 23 in good yield. Next the TIPS group was removed using TBAF in THF and the resulting free hydroxyl group was then alkylated using 1 ,4-dibromo- frans-2-butene 24 to give 25. Alkylations of the /V-protected alkyl halides 28 and 29 with related substrates were investigated under a wide range of conditions (e.g. from 24 using NaH, K₂C0₃, Ag₂0, Ag₂C0₃ in a variety of solvents) but all attempts to alkylate the secondary hydroxyl group using 28/29 failed. For the formation of 25 it was found that the use of Ag₂0 to promote the alkylation gave the best result (57% with unreacted 25 also recovered); the use of stronger bases (e.g NaH caused decomposition. These observations indicated that strong basic conditions needed to be avoided in subsequent steps. With the bromide compound 25 in hand, the amine surrogate then needed to be introduced. Usually, amines can be prepared using the Gabriel reagent (Potassium phthalimide) but strongly basic condition are later needed for removal of the phthalimide. N-benzyl derivatives were also considered but investigations with these derivatives were unsuccessful and thus thus another analogue of the Gabriel reagent that could be readily deprotected to give a primary amino group under acidic conditions was therefore required. The potassium salt of the less exploited potassium 5/^'s-(f-butoxycarbonyl)amine 26 (Boc₂NK) fitted these requirements extremely well and its reaction with 24 gave 26 in 77% yield in NMP as solvent. A main side product in this step was the exchange of the bromide for a hydroxyl group, which is presumably due to the presence of small amounts of KOH in the crude Boc₂NK reagent (Scheme 5).

Scheme 5 [0052] Deprotection strategies combined with reduction of the alkene groups using 27 were next investigated in order to give peptidomimetics. In order to minimize the number of deprotection steps, trifluoroacetic acid (TFA) was first chosen as the deprotection reagent as it could potentially remove the benzyl group from the phenol, the Boc and PMB protecting groups in a one-pot manner. Firstly the deprotection was investigated without any scavenger but the desired product was not obtained. The reaction with TFA in the presence of a series of cation scavengers (PhSH, anisole, thioanisole) were then screened and finally it was found that the use of thioanisole as a co-solvent with TFA was optimum and led to the formation of 29

(Scheme 6, 60%). Next reduction of the alkene group of 28 was investigated. A number of different hydrogenation conditions (5% or 10% Pd-C with AcOH or HCI in MeOH; 5% Pd(OH)₂, AcOH-MeOH; Wilkinson's catalyst EtOH etc.) led to decomposition. Moreover, it was also found for some reagents that reduction of the indole ring of 28 (as evidenced by MS analysis) was a problem; this could have been due to the presence of Boc group on the indole. Hence a variety of conditions were screened (H₂0, refluxing; Cs₂C0₃, imidazole, CH₃CN; MeONa, MeOH) in order to selectively remove the Boc group from the indole. Finally, it was found that this Boc group together with one of the Boc groups from the aminobutylene group were selectively removed under the Zemplen conditions to give 30. Subsequent attempts at hydrogenation were still problematic when Pd-C or Pd(OH)₂ were used as catalysts. Fortunately, hydrogenation using Pt0₂ gave the desired product; treatment of the intermediate with TFA and thioanisole gave the final product and the initial target compound 10. Purification of final products was difficult as side products, resulted from a Friedel-Craft reaction of carbocations generated with the indole ring, were difficult to separate from the target compounds using chromatographic methods. However sufficient material was obtained for biological tests.

29 60% 10 40%

Scheme 6

Biological evaluation

[0053] Somatostatin regulates the endocrine system and affects neurotransmission and cell proliferation via interaction with G-protein-coupled somatostatin receptors. There are five known human somatostatin receptor subtypes (hSSTR1-5). The benzomacrolactone derivatives 10 and 29 were evaluated for their binding to four of the human somatostatin repector subtypes and the results are summarized in Table 1. In general the fully reduced compound 10 was found to be more potent than alkene derivative 29. Compound 10 inhibited binding of somatostatin to each receptor subtype; Ki values ranged from 1.1 to 10 μΜ. This indicates that the salicylic acid scaffold can be utilized in peptidomimetic design. Table 1 : Binding of benzomacrolactone derivatives at somatostatin receptors

Compound hSSTRI hSSTR 2 hSSTR4 hSSTR5

(Ki, μΜ) (Ki, μΜ) (Ki, μΜ) (Ki, μΜ)

10 8.4 10 1.1 2

29 33 50 1.5 6

[0054] The words "comprises/comprising" and the words "having/including" when used herein with reference to the present invention are used to specify the presence of stated features, integers, steps or components but do not preclude the presence or addition of one or more other features, integers, steps, components or groups thereof.

[0055] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable subcombination.

Claims

1. A compound of the general formula (I), a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof:

wherein m is 0 - 4;

n is 0 - 3;

W is selected from H, C C₅ aliphatic, and benzyl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Y is C1-C5 aliphatic;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

2. A compound according to Claim 1 of the formula (la), a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof:

wherein m is 0 - 4;

n is 0 - 3;

W is selected from H, C C₅ aliphatic, and benzyl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Y is C1-C5 aliphatic;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

3. A compound according to any preceding Claim wherein

m is 0 - 4;

n is 0;

R² is selected from H, Me, benzyl, ally I and p-methoxybenzyl;

R³ is selected from H, Me, Et, C₃H₇, C₄H₉, allyl and benzyl;

R⁴ is selected from H, H, Me, Et, C₃H₇, C₄H₉, C(0)Me, C(0)Et, C(0)C₃H₇, C(0)C₄H₉, and C(0)Ph; each R⁵ is independently selected from the group consisting of a halogen, OH, CF₃, Me, OMe and Ph;

W is selected from H or benzyl;

X is selected from NH, S, O, CH₂, and HC=CH;

Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂,

CH₂CH₂CH₂CH₂CH₂, CH₂CH⁼CHCH₂;

Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, HC=CHCH₂, O, NH, S,

OCH₂, NHCH₂, and SCH₂; and

U-U is selected from CH₂-CH₂, and CH=CH.

4. A compound according to Claim 3 wherein m is 0.

5. A compound according to any preceding Claim wherein W is benzyl.

6. A compound according to any p he compound i

a pharmaceutically acceptable salt thereof, an ester thereof, a solvate thereof or a hydrate thereof.

7. A compound according to any p he compound is

8. A pharmaceutical composition comprising a compound according to any preceding Claim and a pharmaceutical acceptable carrier.

9. A compound according to any preceding Claim for use in the treatment of a disorder in which somatostatin receptors are implicated.

10. A compound according to any preceding Claim for use in the modulation of angiogenesis.

1 1. A compound according to any preceding Claim for use in the treatment of acromegaly, cancer, arthritis, carcinoid tumours, and vasoactive intestinal peptide tumours.

12. A method of preparing a compound according to any one of Claims 1 to 7 comprising: i) peptide coupling a compound of formula (II) and a compound of formula (III) to

wherein m is 0 - 4;

n is 0 - 3;

each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆-

C10 aryl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

U-U is selected from CH₂-CH₂, CH=CH, C≡C, cyclopropyl, (CH-CH)O, and (CH-CH)NH;

and

wherein m is 0 - 4;

n is 0 - 3;

P²-P⁴ are the same or different and are oxygen protecting groups;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Y is C1-C5 aliphatic; and

13. A method according to Claim 12 further comprising the step of:

iii)) sseelleeccttiivvely removing oxygen protecting groups P²-P⁴ to provide a compound of the general formula (I)

wherein m is 0

n is 0 each R¹ is independently selected from the group consisting of a halogen, OH, CF₃, C1-C5 aliphatic, C C₅ aliphatic ether, C C₅ aliphatic thioether, and C₆- C10 aryl;

W is selected from H, C C₅ aliphatic, and benzyl;

X is selected from NH, NO, S, O, CH₂, and HC=CH;

Y is C1-C5 aliphatic;

Z is selected from C C₅ aliphatic, O, NH, S, OCH₂, NHCH₂, and SCH₂; and

14. A method according to anyone of Claims 12 to 13 wherein

m is 0 - 4;

n is 0;

R² is selected from H, Me, benzyl, allyl and p-methoxybenzyl;

R³ is selected from H, Me, Et, C₃H₇, C₄H₉, allyl and benzyl;

W is selected from H or benzyl;

X is selected from NH, S, O, CH₂, and HC=CH;

Y is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, CH₂CH₂CH₂CH₂,

CH₂CH₂CH₂CH₂CH₂, CH₂CH⁼CHCH₂;

Z is selected from CH₂, CH₂CH₂, CH₂CH₂CH₂, HC=CHCH₂, O, NH, S,

OCH₂, NHCH₂, and SCH₂; and

U-U is selected from CH₂-CH₂, and CH=CH.

15. A method according to Claim 12 wherein m is 0.

16. A method according to any one of Claims 13 to 15 wherein W is benzyl.

17. A method according to Claim 12 wherein oxygen protecting groups P¹-P⁴ are selected from benzyl, p-methoxy benzyl, methyl, allyl, trialkylsilyl, acetyl, tetrahydropyranyl, benzoyl, pivaloyl, substitute benzoyl, triphenyl silyl, t-butyldimethylsilyl, t-butyl-diphenylsilyl, methoxymethyl ether, methylthiomethyl ether, benzylmethoxymethyl ether, p- methoxybenzyloxymethyl, 3,4-dimethoxybenzyloxymethyl, benzyloxymethyl, t-butoxymethyl, (p-phenylphenyl)oxymethyl ether, methoxyethoxymethyl ether, 2,2,2-trichloroethoxymethyl, tetrahydrofuranyl ether, tetrahydrothiofuranyl ether, t-butyl ether, prenyl ether, p- methoxyphenyl ether, 3,4-dimethoxybenzyl, 2,6-dimethoxybenzyl, o-nitrobenzyl, p- nitrobenzyl, halobenzyl ether, dihalobenzyl ether, 2-naphthylmethyl ether, 4-acetoxybenzyl ether, diphenylmethyl ether, triphenylmethyl ether, methoxytriphenylmethyl ether, chloroacetyl, dichloroacetyl, trichloracetyl, trifluoroacetyl, phenoxyacetate, levulinate, halobenzoate, nitrobenzoate, allyloxycarbonate, methoxmethylcarbonate, benzylcarbonate, methoxybenzylcarbonate, t-butoxycarbonate, and fluorenylmethoxy carbonate.

18. A method according to Claim 12 wherein the step of alkylating the free alcohol thus formed comprises:

iii) alkylating the free alcohol with a molecule of the formula T— Y— T, thereby liberating an anion of one of T or T, wherein Y is C C₅ aliphatic;

T is CI, Br or I;

T is CI, Br or I; and

iv) replacing the other of T or T with NHR⁴.

19. A method according to Claim 18 wherein the molecule of the formula T— Y— T is