CZ20004654A3 - Somatostatin cyclic analogs - Google Patents

Abstract

New cyclic analogs of somatostatin containing in the molecule an imidazole group representing cis amidic bond, which binds selectively to different somatostatin receptors, and which can therefore be used for the manufacture of pharmaceutical compositions suitable for the treatment of a variety of somatostatin-related diseases in the body.

Description

Technical field

BACKGROUND OF THE INVENTION The present invention relates to cyclic derivatives containing an imidazole mimetic cisamide bond that selectively bind to somatostatin receptor subtypes. The invention further relates to processes for preparing the compounds of this invention.

Background Art

Somatostatin (SRIF) is a cyclic tetradecapeptide hormone containing a disulfide bridge between positions 3 and 14 and possessing the ability to inhibit the release of growth hormone (GH) and thyroid stimulating hormone, as well as the ability to inhibit insulin and glucagon release and reduce gastric secretion. The metabolism of somatostatin by amidopeptidases and carboxypeptidases leads to a short duration of action.

Somatostatins bind to five different receptor subtypes (SSTRs) with relatively high affinity for each subtype. Smaller, more rigid analogs of the invention exhibit high selectivity for some of the receptor subtypes. Binding to various types of somatostatin subtypes is associated with the treatment of the following diseases. Activation of types 2 and 5 is associated with suppression of growth hormone and more specifically with the secretion of GH adenomas and TSH adenomas. Type 2 activation, however, without type 5 activation is associated with the treatment of prolactin secreting adenomas. Other indications associated with somatostatin subtype activation are retinose, insulin and / or glucagon inhibition, and more particularly diabetes mellitus, hyperlipidemia, insulin insensitivity, syndrome X, angiopathy, proliferative retinopathy, Dawn syndrome, and nephropathia, inhibition of gastric acid secretion, and more particularly peptic ulcers, enterocutaneous and pancreatic acute fistulas, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, AIDS-induced diarrhea, chemotherapy-induced diarrhea, cancer treatment such as hepatomia, angiogenesis inhibition, treatment of inflammatory diseases such as arthritis, chronic graft rejection, angioplasty, graft vessel rejection, and gastrointestinal bleeding. Somatostatin agonists can also be used to reduce body weight in patients.

I • .. ·· ··· • · · · ···· ··· ··· ································································ · ·

Somatostatin agonists have been reported to be useful in inhibiting proliferation of heliobacter pylori.

SUMMARY OF THE INVENTION

In one aspect, the invention provides a compound of Formula I,

O

O) or a pharmacologically acceptable salt thereof, wherein Y and Z are each independently D- or L- natural or non-natural α-amino acid; n are independently 0 to 50, provided that both n cannot be 0; m is 0 or an integer from 1 to 10;

a is H or R ¹ ;

b is OH, -OR ¹ or-NR ⁹ R ⁹ ;

or and together form an amide bond;

R ¹ is independently H, (C 1 -C ₄ ) alkyl or aryl (C 1 -C ₄ ) alkyl;

R ² is H or an optionally substituted group selected from the group consisting of (C 1 -C 4) alkyl, phenyl, phenyl (C 1 -C 4) alkyl or heterocyclyl (C 1 -C 4) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents each independently selected from the group consisting of (C 1 -C 4) alkyl, (C 3 -C ⁶ cycloalkyl, -OR ⁶ , -S (O) q R ⁷ , -N (R ⁹ R ⁹ ), -NHCO-R ⁶ , -NHSO ² R ⁹ , -CO ² R ⁹ , -CONR ⁹ R ⁹ and -SO ₂ NR ⁹ R ⁹ where q is 0, 1, 2 or 3;

R ³ and R ⁴ are each independently H, halo or an optionally substituted group selected from the group consisting of (C 1 to C ₄ ) alkyl, (C ₃ to C ₈ ) cycloalkyl, aryl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents selected from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, N ( R ⁹ R ⁹ ), -COOH, -CONR ⁹ R ⁹ and halo;

or R ³ and R ⁴ are taken together with the carbons to which they are attached to form an optionally substituted aryl, wherein the aryl is optionally substituted with one or more substituents selected independently from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C , to C ₄ alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -NR ⁹ R ⁹ , -COOR ⁵ , -CONR ⁹ R ⁹ and halo;

R ⁵ at each occurrence is independently H or is an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl, OH, (C 1 -C ₄ ) alkoxy, aryloxy, NO ₂ , aryl (C 1 to C ₄ ) alkoxy, NR ⁹ R ⁹ , -COOH, -CONR ⁹ R ⁹ and halo;

R ⁶ at each occurrence is independently selected from the group consisting of H, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryl (C 1 -C ₄ ) alkyl, and aryl (C 1 -C ₄ ) alkoxy,

R ⁷ is H when q is 3 or R ⁷ is at each occurrence independently selected from the group consisting of (C 1 -C ₄ ) alkyl, aryl, or aryl (C 1 -C ₄ ) alkyl when q is 0, 1, or 2, and

R ⁹ at each occurrence is independently selected from the group consisting of H, NO ₂ , (C 1 -C ₄ ) alkyl, aryl, and aryl (C 1 -C ₄ ) alkyl.

A preferred compound of Formula I is H-Trp-D-Trp-Lys-Abu-Phe (4-methoxyphenyl) imidazole-Gly-OH.

In another aspect, the invention provides a compound of Formula II,

or a pharmaceutically acceptable salt thereof, wherein Y and Z are each independently D- or L- natural or unnatural α-amino acid; m is 0 or an integer from 1 to 10; n is for each occurrence independently 0 to 6, b is OH, -OR ¹ or-NR ⁹ R ⁹ ;

R ¹ at each occurrence is independently H, (C 1 -C ₄ ) alkyl or aryl (C 1 -C ₄ ) alkyl;

R ² is H or an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl, phenyl, phenyl (C 1 -C ₄ ) alkyl or heterocyclyl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group

is optionally substituted with one or more substituents each independently selected from the group consisting of (C 1 -C ₄ ) alkyl, cycloalkyl, -OR ⁶ , -S (O) q R ⁷ , -N (R ⁹ R ⁹ ), - NHCO-R ⁶ , NHSO ² R ⁹ , -CO ² R ⁹ , -CONR ⁹ R ⁹ and -SO ² NR ⁹ R ⁹ , wherein q is 0, 1, 2 or 3;

R ³ and R ⁴ are each independently H, halo or an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl, cycloalkyl, aryl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents selected from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -N (R ⁹ R ⁹ ) , COOH, -CONR ⁹ R ⁹ and halo;

or R ³ and R ⁴ are taken together with the carbons to which they are attached to form an optionally substituted aryl, wherein the aryl is optionally substituted with one or more substituents selected independently from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C , to C ₄ alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -NR ⁹ R ⁹ , -COOR ⁵ , -CONR ⁹ R ⁹ and halo;

R ⁵ at each occurrence is independently H or is an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents wherein each independently selected from the group consisting of (C 1 -C ₄ ) alkyl, OH, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -NR ⁹ R ⁹ , -COOR ⁵ , -CONR ⁹ R ⁹ and halo;

R ⁶ at each occurrence is independently selected from the group consisting of H, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryl (C 1 -C ₄ ) alkyl, and aryl (C 1 -C ₄ ) alkoxy ,

R ⁷ is H when q is 3 or R ⁷ is at each occurrence independently selected from the group consisting of (C 1 -C ₄ ) alkyl, aryl, or aryl (C 1 -C ₄ ) alkyl when q is 0, 1, or 2, and

R ⁹ at each occurrence is independently selected from the group consisting of H, NO ₂ , (C 1 -C ₄ ) alkyl, aryl, and aryl (C 1 -C ₄ ) alkyl.

X ¹ is a natural or unnatural D- or La-amino acid, wherein X ¹ is Phe, Nal, Trp, Tyr, Pal or His, whose aromatic ring is optionally substituted on carbon or nitrogen by R ⁶ or when Ser or Thr is oxygen of the side a chain optionally substituted with one or more R ';

X ² is D- or L-Trp, N-methyl-D-Trp or N-methyl-L-Trp;

X ³ is Lys, α-N-methyl-Lys or ε-Ν- (C 1 -C ₄ ) alkyl-Lys or εN- [aryl- (C 1 -C ₄ ) alkyl] -Lys;

X ⁴ is a natural or unnatural D- or La-amino acid, wherein X ⁴ is Phe, Nal, Trp, Tyr or His, whose aromatic ring is optionally substituted on carbon or nitrogen by R ⁸

or when X ⁴ is Ser, Tyr or Thr the oxygen of the side chain may be substituted with one or more substituents R ¹ .

The bonds between X ¹ , X ² , X ³ and X ⁴ are amide bonds as well as the bond between X ¹ and Z and the bond between X ⁴ and Y.

A preferred group of compounds of Formula II, designated A, is wherein each n is 2, m is 0 or 1 to 5,

R ¹ at each occurrence is independently H, methyl or aryl (C 1 -C ₄ ) alkyl,

R ² is an optionally substituted group selected from the group consisting of phenyl- (C 1 -C ₄ ) alkyl, and heterocyclyl- (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is substituted with a substituent selected from the group consisting of (C 1 to C ₄₎ ) alkyl and -OR ^6a

R ³ and R ⁴ are each independently H, halo, or an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl and aryl, wherein the optionally substituted group is optionally substituted with a substituent selected from the group consisting of OH, (C 1 to C ₄ ) alkoxy, aryloxy and halo.

A preferred group B in group A of the compounds of this invention is one wherein X ¹ is Phe, Nal, Trp, Tyr, Pal or His, wherein the aromatic ring is optionally substituted on carbon or nitrogen by R ⁶ , and

X ⁴ is Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, wherein the aromatic ring in Nal, Trp, Tyr and His is optionally substituted on carbon and / or nitrogen by R ⁸ or wherein X ⁴ is Ser, Tyr or Thr, the side chain oxygen of which is optionally substituted with R ¹ .

A preferred group C in the group of compounds B is one wherein X ¹ is Phe, Trp or Tyr, the aromatic ring of which is optionally substituted on carbon or nitrogen by R ⁶ ,

X ² is D-Trp or N-methyl-D-Trp,

X ³ is Lys or a N-methyl-Lys,

X ⁴ is Val, Thr, Abu, Nal or Tyr, wherein the oxygen in the side chain hydroxyl group of Thr and Tyr is optionally substituted with R ¹ ;

R ¹ for each occurrence is independently H, methyl or benzyl;

R ² is an optionally substituted group selected from phenylmethyl and heterocyclylmethyl, wherein the optionally substituted group is substituted with a substituent selected from the group consisting of (C 1 -C ₄ ) alkyl and -OR ⁶ ;

R ³ is (C 1 -C ₄ ) alkyl or optionally substituted aryl wherein the optionally substituted aryl is substituted with a substituent selected from OH, (C 1 -C 6 alkoxy, aryloxy and halo;

R ⁴ is H, a

R ⁶ for each occurrence is independently selected from the group consisting of H and aryl (C 1 -C ₄ ) alkoxy.

A preferred group D in the group of compounds C is one wherein X ¹ is Phe, Trp, Tyr or Tyr (Obzl);

X ⁴ is Val, Thr, Abu, Nal or Tyr, wherein the hydroxy group in Thr and Tyr is optionally substituted with benzyl;

M is 0, 2 or 4;

R ² is an optionally substituted group selected from the group consisting of phenylmethyl or 3-indoles of methyl, wherein the optionally substituted group is optionally substituted with -OR ⁶ ; and R ³ is 1,1-dimethylethyl or optionally substituted aryl wherein optionally substituted aryl is optionally substituted with a group selected from OH, (C 1 -C ₄ ) alkoxy and halo.

A preferred group E from the group of compounds D is one wherein R ² is phenylmethyl;

R ³ is 1,1-dimethylethyl or optionally substituted phenyl, wherein optionally substituted phenyl is optionally substituted with OH or OCH ₃ and

R ⁶ for each occurrence is independently selected from the group consisting of H or benzylmethoxy.

A preferred group of F from the group of compounds E is:

Cyclo [Tyr-D-Trp-Lys-Val-Phe- (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Tyr (OBzl) -D-Trp-Lys-Val-Phe] (4- (3 -methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-1-y-Val-Phe- (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-1 ys-Val] -Phe Ψ (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidamle) Gly], cyclo [Trp] -D-Trp-Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-Phe (4- (3-methoxyphenyl) imidazole) - Gly), cyclo [Phe-D-Trp-Iy-Tyr (OBzl) -Phe Ψ (4- (1,1-dimethylethyl) imidazole-Gly), cyclo [Phe-D-Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidazole-Gly), cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe- (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp] -Lys-Tyr-Phe (4- (3-methoxyphenyl) imidazoh-Gly), cyclo [Phe-D-Trp-Lys-Tyr-Phe] (4- (3-hydroxyphenyl) imidazole-Gly), cyclo [Trp] -D-Trp-lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole-Gly), · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· · Cyclo [Tyr-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole-Glyj, cyclo [Phe-D-Trp-Lys-Nal-Phe] (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe- (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4 - (3-methoxyphenyl) imidazole (s) Abu), cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe- (4- (4-methoxyphenyl) imidazole-Gly], cyclo [Trp-D-Trp] -Lys-Tyr (OBzl) -Phe Ψ (4- (phenyl) imidazole-Gly), cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole-ř And Ahx] and cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (3-hydroxyphenyl) imidazole- (γ) Abu).

A preferred group of skypines of compounds F, designated G, is cyclo [Tyr-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazoyl) -Gly], cyclo [Tyr (OBzl) -D-Trp -Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly, cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole} -Gly), cyclo [ Trp-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazo) -Glyl, Cyclo [Trp-D-Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) 1) imidazole) -Gy], cyclo [Trp-D-Trp-Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-Phe] (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (1,1-dimethylethyl) imidazole-Gly], cyclo [Phe- D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidamle-Gly), cyclo [Phe-D-Trp-Lys-Tyr-Phe] (4- (3-hydroxyphenyl) imidazole-Gly) and Cyclo [Tyr-D-Trp-Lys-VahPhe Ψ (4- (3-hydroxyphenyl) imidazole-Glyj).

A preferred group of compounds G, referred to as group H, is cyclo [Tyr-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly], cyclo-Trp-D-Trp-Lys-Val -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Yal-PheΨ (4- (3-hydroxyphenylimidazoyl) -Gly], cycto [Trp-D-Trp -Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-Phe (4- (3-methoxyphenyl) imidazole) -Gly], cyclic [Phe-D-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole-Gly] or cyclo [Tyr-D-Trp-Lys-Yal-Phe] (4- (3-hydroxyphenyl) imidazole-GlyJ).

A preferred group of compounds H, group I, is cyclo [Tyr-D-Trp-Lys-Val-Phe- (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Lys-Va]. (4- (3-hydroxyphenyl) imidazole) -Gly], · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Cyclo [Trp-D-Trp-Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly] and Cyclo [Tyr \ t -D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly].

Another preferred group of compounds F, designated J, is cyclo [Tyr-D-Trp-Lys-Val-Phe- (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys- Val-Phe (4- (3-methoxyphenyl) imidazole) -Glyl, cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D] -Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-Phe (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-lys-Tyr (OBzl) -Phe Ψ ( 4- (1,1-dimethylethyl) imidazole-Gly], cyclo [Phe-D-Trp-γ-Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe-D] -Trp-Lys-Tyr-Phe- (4- (3-hydroxyphenyl) imidazole-Glyj, cyclo [Trp-D-Trp-1-ys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole-Glyj) , cyclo [Tyr-D-Trp-Lys-Val-Phe- (4- (3-hydroxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-1-ys-Nal-Phe] (4- (3-hydroxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe] (4- (3-methoxyphenyl) imidazole-Gly), cyclo [Trp-D-Trp-Lys-Tyr (Bzl ) -Phe Ψ (4- (3-methoxyphenyl) imidazole- () Abu], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (4-methoxyphenyl) imidazole-Gly), cyclic [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (phenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3- methoxyphenyl) imidazole- (8) Ahx] and cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-hydroxyphenyl) imidazole- () Abu].

A preferred group of compounds J, referred to as Group K, is cyclo [Trp-D-Trp-Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Tyr] (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole-Gly), cyclo [Phe-D-Trp-Lys-Nal-Phe 3 (4- (3-hydroxyphenyl) imidazole-Gly], cyclo [Trp- D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole- (y) Abu), cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- ( 4-methoxyphenyl) imidazole-Glyj or cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (phenyl) imidazole-Glyj).

A preferred group of compounds of formula K, designated L, is cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazoyl-Glyc, cyclopro-D-Trp-Lys- Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole- (Y) Abu), · ···· ···· ··· Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (4-methoxyphenyl) imidazole-Gly) and Cyclo (Trp-D-Trp-Lys-Tyr ( Bzl) -Phe (4- (phenyl) imidazole-Gly).

In another aspect, the invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula I or Formula II, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

In another aspect, the invention provides a method of provoking a somatostatin receptor agonist effect in a mammal comprising administering an effective amount of a compound of Formula I or II, respectively. a pharmaceutically acceptable carrier therefor.

In another aspect, the invention provides a method of provoking a somatostatin receptor antagonist effect in a mammal comprising administering an effective amount of a compound of Formula I or II. a pharmaceutically acceptable carrier therefor.

In another aspect of the invention there is provided a method of treating prolactin adenomas, diabetes mellitus, hyperlipidemia, insensitivity to insulin, Syndrome X, angiopathy, proliferative retinopathy, dawn syndrome, neuropathy, gastric acid secretion, peptic ulcer, enterocutaneous and pancreatic acute fistula, irritable bowel syndrome, Dumping syndrome, watery diarrhea syndrome, AIDS-induced diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, hormone-secreting gastrointestinal tumors, cancers, hepatoma, angiogenesis, inflammatory diseases, arthritis, chronic graft rejection, angioplasty, grafted vessel bleeding or gastrointestinal bleeding in mammals, comprising administering to said mammal a compound of Formula I or II or a pharmaceutically acceptable salt thereof.

In another aspect of the invention, there is provided a method of inhibiting the proliferation of heliobacter pylori in a mammal, comprising administering to said mammal a compound of Formula I or II, or a pharmaceutically acceptable salt thereof.

In another aspect of the present invention, a method of making a compound of Formula I is provided

H-N '

R ¹ χ-W.— Ν '(«% · o = c' ~ v '' o

(and)

(ii)

which includes deprotection of compounds of formula

cleavage of the Prt group where

Prt is an amino acid chain protecting group,

Y and Z are each independently D- or L-natural or non-natural α-amino acid having an optionally protected side chain wherein HN * is an amino group of the N-terminal amino acid defined by Y and O = C * is a carboxyl group of the C-terminal amino acid defined using Z;

n for each occurrence is independently 1 to 50;

and all other variables are as defined above in Formula I.

In another aspect, the invention provides a process for preparing a compound of formula

which includes

<γ-Ρη) "- Ν". you you

HOOC (ΦΑ. ^R λν <tf) for compounds of formula a, forming an amide bond between the terminal amino group of the last amino acid defined by Y and the terminal carboxyl group of the last amino acid defined by Z, reacting a compound of formula a 'with a peptide capping agent and an additive; or for compounds of formula b, forming an amide bond between the terminal amino group and the terminal carboxyl group of the last amino acid defined by Z, reacting the compound of formula b 'with a peptide capping agent and an additive; or for compounds of formula c, forming an amide bond between the terminal amino group of the last amino acid defined by Y and the terminal carboxyl group, by reacting a compound of formula c 'with a peptide capping agent and an additive;

wherein Prt is an amino acid side chain protecting group;

Y and Z are each independently D- or L-natural or unnatural α-amino acids having an optionally protected side chain wherein HN * is an amino group of the N-terminal amino acid defined by Y and O = C * is a carboxyl group of the C-terminal amino acid defined using Z;

n for each occurrence is independently 1 to 50;

all other variables are the same as in the above definition of compound of formula I.

In another aspect, the invention provides a process for preparing a compound of formula

R °

which involves reacting a compound of formula f with an α-haloketone of formula

X'-CH (R ³ ) CO (R ⁴ ) in the presence of a base and a polar aprotic solvent until said reaction is complete, evaporating the polar aprotic solvent to form a solid, dissolving the solid in an aprotic organic solvent and excess aqueous NH ₄ OAc to forming a solution and boiling the solution while simultaneously removing the polar layer to form a compound of formula A wherein

X is an amino protecting group,

X 'is halo, and the other variables are as defined above for Formula I.

In another aspect, the invention provides a process for the preparation of a compound of Formula I, comprising linking a compound of Formula B to an Unprotected amino acid, (Prt) -Y, wherein the unprotected amino acid is in the form of its activated ester, anhydride or acid halide, in the presence of a base up to practical

·· 0 00 0 • 0 0 0 0 0 0 0 0

0 0 0 0 0 0

0 0 0 000 0 0

000 000

Reaction to produce a compound of formula C, optionally deprotecting the amino group N _{and the} protected amino acid, (Prt) -Y, using conventional deprotection reactions and repeating the coupling reaction with another unprotected amino acid until the desired a product of formula I;

Y is for each occurrence independently D- or L-natural or non-natural α-amino acid having a side chain with a protecting group;

Prt is an amino protecting group

R 1 is an alkyl ester or benzyl ester, n is 1 to 100;

and all other variables are the same as in the above definition of compound of formula I.

In another aspect, the invention provides a process for preparing a compound of Formula I, as defined above, comprising capping a compound of Formula B, activated as an actively ester, anhydride or chloride thereof, with an N-deprotected peptide resin (A ') prepared by methods well known in the art. those skilled in the art of peptide synthesis, depleting the N-terminal Fmoc moiety using piperidine in DMF, TAEA or the like and deprotecting and cleaving the resulting B 'intermediates from the resin using a strong acid. All variables are the same as in the above definition of compound I.

r M ' ^R1

Fmoc — N

⁰ B

H, N- (y) n-resin

AND'

In another aspect, the invention provides a process for preparing a compound of Formula I comprising coupling a compound of Formula B, activated as an active ester, anhydride or halide thereof, with an N-deprotected peptide resin (H), prepared by a method well known to those skilled in the art of peptide synthesis, deprotection. N-terminal Fmoc groups using piperidine in DMF, TAEA or similar base, acylating the deprotected N-terminal amino group with N _and -Fmoc-protected amino acids using peptide capping reaction well known to those skilled in the art, repeating base deprotection and capping step as needed up to to build more

99 9

9 9 ··

9 9 9

9 9 9 9

9 9 9

999 99 9 * 9

99 9 · 9 9 9 9 · 9 9 · 9 · 99 · 9 · 9 · 9 9 9 · 9 9 · 9 · 99 · 9 · 9 · 9 9 · 9 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9, 9, 9, 9, 9, 9, 9, 9 All variables are the same as in the above definition of compound of formula I.

In another aspect, the invention provides a process for preparing a compound of Formula I comprising capping a compound of Formula B, activated as an active ester, anhydride or halide thereof, with an amino-substituted resin such as Tris (alkoxy) -benzylamine resin (PAL resin); (2 ', 4'-dimethoxyphenylaminomethyl) phenoxy resin (N-deprotected Rink resin) or benzhydrylamine resin, deprotection of the N-terminal Fmoc group using piperidine in DMF, TAEA or similar base, acylation of the released N-terminal amino group with N _and -Fmoc -protected amino acid x using a peptide capping reaction well known to those of skill in the art, repeating the basic deprotection and capping step as necessary to introduce additional amino acids x, deprotecting and cleaving the resulting intermediate D 'from the resin using strong acid, and all other variables being the same as above. the above definition of merger I.

In another aspect, the present invention provides a process for the preparation of a compound of Formula I comprising reacting a compound of Formula B with a base such as Cs ₂ CO ₃ , reacting the resulting phenolic cesium salt E 'with halomethylated polystyrene resin such as Merrifield peptide resin, removing Fmoc protecting group with piperidine or a similar organic base, acylation of the released N-terminal amino group with N _and -Fmoc protected by the phyto · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

ΦΦΦ Φ · Φ

Χ · · · ΦΦΦ · ΦΦΦ amino acid χ using a coupling reaction well known to those skilled in the art, repeating deprotection and capping step as necessary until incorporation of additional amino acids x, deprotection of the final N-terminal protected peptide sequence with piperidine or similar organic base and at the C-terminus with Tfa, cyclization of the resulting intermediate F 'using a coupling reaction well known to those skilled in the art and cleavage of the resulting G'z intermediate with a strong acid. All variables are the same as in the above definition of Formula I.

EP

In another aspect, the invention provides a process for the preparation of a compound of Formula I, as defined above, comprising combining a compound of Formula B, activated as its active ester, anhydride or halide, with an N-deprotected peptide resin A 'prepared using methods well known in the art. in the art, deprotecting the N-terminal Boc group using Tfa and deprotecting the side chain protecting groups and cleaving the resulting intermediate H 'from the resin with a strong acid such as HF. All variables are the same as in the above definition of Formula I.

In another aspect, the invention provides a method of making a compound of Formula I comprising coupling a compound of Formula B, activated in the form of an active ester, anhydride or acyl halide, with an N-deprotected peptide resin H, prepared by methods well known in the art, deprotection of N-terminal Boc groups using Tfa, acylating the released N-terminal amino group with N _and -Boc-protected amino acid x using peptide capping reaction well known to those skilled in the art, repeating Tfa deprotection and capping • · · · · ······· Step up as necessary until the introduction of additional amino acids x, deprotection and cleavage of the resulting intermediate Γ from the resin using a strong acid. All variables are the same as in the above definition of Formula I.

H- (x | n — N

In another aspect, the present invention provides a process for preparing a compound of Formula I comprising reacting a compound of Formula B with a base such as C ₂ CO ₃ , reacting the resulting phenolic cesium salt J 'with a halomethylated polystyrene resin such as Merrifield peptide resin, removing Boc protecting group with Tfa, acylating the released N-terminal amino group with N "-Boc protected amino acid x using a coupling reaction well known to those skilled in the art, repeating Tfa deprotection and capping step as necessary until additional amino acids x are incorporated, deprotecting the final protected peptide sequence at the N-terminus with Tfa and at the C-terminus with an inorganic base such as LiOH in aqueous DMF, cyclization of the resulting intermediate K 'using a peptide capping reaction well known to those skilled in the art and cleavage of the resulting intermediate L'z of the resin using a strong acid. All variables are the same as in the above definition of Formula I.

In another aspect, the invention provides a method of making a compound of Formula 1, comprising coupling a compound of Formula B, activated in the form of its active ester, anhydride or acyl halide, with an N-deprotected peptide 4-nitrobenzophenone oxime resin M ', prepared by methods well known in the art, deprotection N-terminal Boc group · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 94 9 using Tfa, acylation of the released N-terminal amino group with N _and -Boc-protected amino acid x using a peptide capping reaction well known to those skilled in the art, repeating Tfa deprotection and capping step as needed until further introduction amino acids x, deprotection of the N-terminal Boc group with Tfa, cyclization and cleavage of the resulting N'protected intermediate N 'by neutralization with a suitable organic base and deprotection side chains using a strong acid such as HF. All variables are the same as in the above definition of Formula I.

M '

Detailed description

The term "heterocycle" in this invention refers to any heterocycle that may be present in the amino acid side chain. Examples include (but are not limited to) such heterocycles such as benzothienyl, cumaryl, imidazolyl, indolyl, purinyl, pyridyl, pyrimidinyl, quinolinyl, thiazolyl, thienyl and triazolyl.

The term aryl refers to any stable monocyclic or bicyclic carbon ring of up to seven in each ring wherein at least one ring is aromatic. Examples of aryl groups include biphenyl, indanyl, naphthyl, phenyl and 1,2,3,4-tetrahydronaphthalene.

Several abbreviations for amino acid components, certain preferred protecting groups, reagents and solvents are used in the present invention. The meaning of these abbreviations is shown in Table 1.

Abbreviated designation Importance Amino acids His L-Histidine Lys L-Lysine Nal L-3- (2-naphthyl) alanine Phe L-Phenylalanine

Ser L-Serin Thr L-Threonine Trp L-Tryptophan (unless otherwise indicated) Tyr L-Tyrosine Ahx 6-Aminohexanoic acid Protecting groups Boc 1,1- (Dimethylethoxy) carbonyl Cbz Benzyloxycarbonyl Fmoc 9-fluorenylmethoxycarbonyl Trt Triphenylmethyl Solvents DMF N, N-dimethylformamide THF T etrahydrofuran EtOAc Ethyl acetate Reagents Tfa Trifluoroacetic acid NMM 4-methylmorpholine DIEA Diisopropylethylamine TEA Triethylamine TAEA Tris (2-aminoethyl) amine HOAT 1-Hydroxy-7-azabenzotriazole HATU [O- (7-azabenzotrazol-1-yl) -1,1,3,3-tetramethyluronium hexafluorophosphate EDC 1- (3-Dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride DCC Dicyclohexylcarbodiimide

In vitro assay

The affinity of the compound for human somatostatin subtype 1 to 5 receptors (ssf, sst ₂ , sst ₃ , sst ₄ and sst ₅ ) is determined by measuring the inhibition of [ ¹²⁵ I-Tyr ¹¹ ] SRIF-14 binding to CH0-K1 cells.

The human sst receptor gene was cloned as a genomic fragment. Pst | -Xmn | segment (1.5 Kb) containing 5'-untranslated region (100 bp), 1.17 Kb large total coding region and 230 bp of 3'-untranslated region was modified by addition of BglII | linker. The resulting DNA fragment was subcloned into the BamHI region of pCMV-81 to form a mammalian expression fragment.

9 • 9 plasmids (provided by Dr. Graeme Bell of the University of Chicago). A clonal cell line stably expressing sst receptor was obtained by transferring to CHO-K1 cells (ATCC) using a calcium phosphate precipitation method (1). Plasmid pRSV-neo (ATCC) was included as a selectable label. Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), the ring cloned and expanded into culture.

Human somatostin receptor sst ₂ gene isolated as 1.7 Kb BamHI HindIII the genomic fragment and subcloned into the plasmid vector pGEM3Z (Promega) was kindly provided by Dr. G. Bell of the University of Chicago). The mammalian cell expression vector was constructed by inserting 1.7Kb BamHI-HindIII fragment into a compatible restriction endonuclease site in pCMV5. The clonal cell line was obtained by transfer to CHO-K1 cells using a calcium phosphate precipitation method. Plasmid pRSV-neo was included as a selectable label.

Human sst was isolated on a genomic fragment and the complete coding sequence was contained in 2.4 Kb BamHI HindIII | fragment. The mammalian expression plasmid pCMV-h3 was constructed by inserting 2.0 Kb of NcoI -Hindi I fragment into the EcoR1 site of the pCMV vector after modification of the ends and addition of EcoR1 linkers. A clonal cell line stably expressing sst receptor was obtained by transfer to CHO-K1 cells (ATCC) using a calcium phosphate precipitation method. Plasmid pRSV-neo (ATCC) was included as a selectable label. Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), the ring was tilted and expanded into culture.

A plasmid expressing the human sst ₄ receptor, pCMV-ΗΧ, was provided by Dr. Graem Bell of University Chicago). Vector containing 1.4 Kb Nhe | -Hne | the genomic fragment encoding human sst ₄ , 456 bp 5'-untranslated region and 200 bp 3'-untranslated region was cloned into the XbaI / EcoR1 region of PCMV-HX. The clonal cell line expressing the sst ₄ receptor was obtained by transfer to CHO-K1 cells (ATCC) using a calcium phosphate precipitation method. Plasmid pRSV-neo (ATCC) was included as a selectable label. Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), the ring cloned and expanded into culture.

The human sst ₅ gene was obtained by PCR using the λ genomic clone as a template, and was kindly provided by Dr. Graem Bell of University Chicago). The resulting 1.2 Kb PCR fragment contains 21 pairs in the 5'-untranslated region, the fully coding region and 55 bp of the 3 'untranslated region. The clone was inserted into the EcoR1 site of the pBSSK (+) plasmid. Insert was

· • 4 ·

4 was regenerated as a 1.2 Kb Hindi Ixbal fragment for subcloning into pCVM5 mammalian expression vector. A clonal cell line stably expressing the sst ₅ receptor was obtained by converting to CHO-K1 cells (ATCC) using a calcium phosphate precipitation method. Plasmid pRSV-neo (ATCC) was included as a selectable label. Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), the ring was tilted and expanded into culture.

CHO-K1 cells stably expressing one of the human sst receptors were grown in RPMI 1640 containing 10% calf serum and 0.4 mg / ml geneticin. Cells were collected with 0.5 mM EDTA and centrifuged at 500 g for 5 min at 4 ° C. The pellet was dissolved in 50 mM Tris, pH 7.4 and centrifuged twice at 500 g for 5 minutes at 4 ° C. Cells were lysed by sonication and centrifugation at 39,000 g for 10 min at 4 ° C. The pellet was resuspended in the same buffer and centrifuged at 50,000 g for 10 min at 4 ° C and the pellet membranes stored at -80 ° C.

Comparative Binding Inhibition Experiments [ ¹²⁵ I-Tyr ^H ] SRIF-14 were performed in duplicate in a 96-well polypropylene plate. Cell membranes (10 µg protein per well) were incubated with [ ¹²⁵ I-Tyr ^H ] SRIF-14 (0.05 nM) for 60 min at 37 ° C in 50 mM HEPES (pH 7.4), 0.2 % BSA, 5 mM MgCl ₂ , 200 KIU / mL Trasylol, 0.02 mg / mL Bactracin and 0.02 mg / mL Phenylmethylsulfonylfluoride.

Bound [ ¹²⁵ I-Tyr ^H ] SRIF-14 is separated from free by direct filtration through a GF / C glass filter plate (Unifilter, Packard) pre-impregnated with 0.1% Ethylenimine (PEI) using Filtermate 196 (Packard) cellular pickers. The filters were washed with 50 mM HEPES at 0-4 ° C for 4 sec and determined for radioactivity using a Packard Top Count.

Specific binding is obtained by subtracting non-specific binding (determined in the presence of 0.1 µM SRIF-14) from total binding. Binding data are analyzed by computerized nonlinear regression analysis (MDL) and Ki inhibition constant values are determined.

Determining whether a compound of the invention is an agonist or antagonist is performed by the following measurements.

CHO-K1 cells expressing human somatostatin receptor subtypes (SRIF-14) are seeded into 24-well culture plates in RPMI 1640 medium with 10% FCS and 0.4% mg / ml geneticin. The media changes the day before the experiment.

Cells at 10 ⁵ cells per well are washed twice with 0.5 ml fresh RPMI s

0.2% BSA supplemented with 0.5 mM (1) 3-isobutyl-1-methylxanthine (IBMX) and incubated for min at 37 ° C.

Cyclic AMP production is stimulated by the addition of 1 mM forskolin (FSK) for 15-30 min at 37 ° C.

• The agonist effect of a compound is measured by the simultaneous addition of FSK (1 μΜ), SRIF-14 (10 ^-12 M to 10 ^-6 M) of test compound (10 ^-10 M to 10 ^-5 M).

• The antagonist effect of a compound is measured by the simultaneous addition of FSK (1 μΜ), SRIF-14 (1 to 10 nM) and test compound (ΙΟ ^-10 M to 10 ^-5 M).

The reaction medium was removed and 200 mL of 0.1 N HCl was added. Radioimmunoassay cAMP was measured (Kit FlashPlate SMP001A, New England Nuclear).

Determination of radioligand binding

Membranes for in vitro receptor binding assays were obtained by homogenization (Polytron, 6, 15 sec setting) of CHO-K1 cells expressing hsst receptor subtypes, in ice-cooled 50 mM Tris-HCl and centrifugation twice at 39,000 g (10 min) with immediate by subsequent suspension in fresh buffer. The final pellets were suspended in 10 mM Tris-HCl for assay. For the determination of hsst1, hsst3, hsst4, hsst5, aliquots of membrane preparation were incubated (for 30 min at 37 ° C with 0.05 nM [ ¹²⁵ I-Tyr ¹¹ ] SRIF-14 in 50 mM HEPES (pH 7.4) containing BSA) (10 mg / ml); MgCl ₂ (5 mM)), Trasylol (200 KlU / ml), bacitracin (0.02 mg / ml) and phenylmethylsulfonyl fluoride (0.02 mg / ml). The final assay volume was 0.3 ml.

[ ¹²⁵ I] MK-678 (0.05 nM) was used as the radioligand for the hsst2 assay and incubation was performed at 25 ° C for 90 minutes. Incubations were interrupted by rapid filtration through GF / C sequins (pre-impregnated with 0.3% ethylenimine poles) using a Brandel filter device. Each tube and filter were then washed three times with 5 ml aliquots of ice-cold buffer.

Specific binding was defined as total radioligand minus ligand bound in the presence of 1000 nM SRIF-14 (hsst1, 3.4.5) or 1000 nM MK-678 for hsst2.

The compounds of the invention can be determined in vivo for their use associated with binding to the somatostatin receptor, including specific binding to somatostatin receptor subtypes according to a method well known to those skilled in the art, as described, for example, by I. Shimon, et al., "Somatostatin Receptor subtype specifically in human fetal pituitary cultures ", J. Clin. Invest., Vol. 99, No. 4, pp. 789-798, 1997 and C. Gilon et al., &Quot; A backbone22 cyclic receptor 5-selective somatostatin analogue: Synthesis, bias and magnetic resonance conformational analysis &quot;, J. Med. . Chem., 1998, 41, 919-929.

As is well known to those skilled in the art, the known and potential uses of somaztostatin antagonists and / or agonists are numerous and diverse. These different uses of somatostatin can be summarized as follows:

Somatostatin agonists can be used to suppress growth hormone, and more specifically, GH (acromegaly) and TSH-secreting endomases; treating prolactin secreting adenomas, inhibiting insulin and / or glucagon, and more particularly diabetes mellitus, angiopathy, proliferative retinopathy, Dawn syndrome, and nephropathia; inhibiting gastric acid secretion and more particularly gastric ulcers; enterocutaneous and pancreatic-acute fistulas, irritable bowel syndrome, chemotherapy-induced diarrhea, acute or chronic pancreatitis, and gastrointestinal hormone-secreting tumors; treating cancer as a hepatoma; inhibiting angiogenesis; treating inflammatory diseases such as arthritis; retinopathy; chronic graft rejection; angioplasty, prevention of graft rejection and gastrointestinal bleeding.

Thus, the invention also encompasses the preparation of pharmaceutical compositions comprising as active ingredient at least one compound of the invention together with a pharmaceutically acceptable carrier.

The compound of the invention may be administered orally, parenterally (eg, intramuscularly, intraperitoneally, intravenously or subcutaneously by injection or implant), nasally, vaginally, rectally, sublingually or by local routes of administration and may be formulated with a pharmaceutically acceptable carrier to form the appropriate dosage form. for each route of administration.

Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In these solid dosage forms, the active compound is mixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. These dosage forms may also include, as is common practice, additional substances other than these inert diluents, e.g., lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also include buffering agents. Tablets and pills can be further prepared with an enteric coating.

Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs containing inert diluents commonly used in the art, such as water. In addition to these inert solvents, the compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, perfuming and flavoring agents.

Formulations of the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. These dosage forms may also contain adjuvants such as preservatives, wetting, emulsifying and dispersing agents. They can be sterilized by, for example, filtering through a bacteria-retaining filter, introducing sterilizing agents, introducing the agent into the formulation, irradiating the composition, or heating the composition. They can also be made in the form of a sterile solid which can be dissolved in sterile water or some other sterile injectable medium before use.

Formulations for rectal or vaginal administration are preferably suppositories which may contain, in addition to the active substance, excipients such as cocoa butter or suppository wax.

Formulations for nasal or sublingual administration are prepared with standard excipients known in the art.

In addition, the compounds of this invention may be administered in sustained release formulations, such as those described in the following patents. US Patent No. 5,672,659 discloses sustained release formulations comprising bioactive agent and polyester, US Patent No. 5,595,760 discloses sustained release formulations comprising a bioactive agent in gel form. U.S. Application No. 08 / 929,383 filed September 9, 1997 discloses sustained release polymeric compositions comprising a bioactive agent and chitosan. U.S. Application No. 08 / 740,778 filed November 1, 1996 discloses sustained release formulations comprising a bioactive agent and a cyclodextrin. U.S. Application No. 09 / 015,394 filed January 29, 1998 discloses absorbable sustained release formulations of a bioactive agent. Refills of all previous patents and applications are incorporated herein by reference.

The dosage of the active ingredient in the compositions of this invention may vary, but it is essential that the amount of active ingredient is such that a suitable dosage form is obtained. The selected doses depend on the desired therapeutic effect, the mode of administration, the duration of treatment. In general, dosage levels range from 0.0001 to 100 mg per kg body weight per day for humans and other animals, e.g., mammals, to achieve the desired effect.

The preferred range is from 0.01 to 5.0 mg / kg body weight per day, which can be administered in a single dose or divided into multiple doses.

The compound of the present invention can be synthesized according to the following description and Scheme 1. In a first step, an amino acid protected at the α-amino group with Boc, Cbz or another suitable group is converted to a carboxylate salt with an inorganic base such as NaOH, KOH, K ₂ CO. ₃ or most preferably Cs ₂ CO ₃ in a polar solvent such as H ₂ O, DMF, THF and the like. The solvent is removed in vacuo and the remaining salt is redissolved in a polar aprotic solvent such as DMF and the appropriate α-haloketone is added with stirring at -20 ° C to 100 ° C, most preferably at room temperature. Stirring is continued for 10 minutes to 24 hours or until ester formation is complete by TLC analysis, whereupon the solution is concentrated in vacuo at 0 ° C to about 100 ° C, most preferably at 40 ° C to 70 ° C. The intermediate is then redissolved in an aprotic organic solvent such as benzene, toluene or, most preferably, xylenes, and 5 to 100 times or more preferably about 15-20 times molar excess of NH ₄ OAc is added. The biphasic mixture is heated to reflux and the polar layer is removed within 1 to 4 hours using an azeotropic attachment to give crude intermediate A which can be used crude or purified by crystallization or column chromatography.

Scheme 1

X = eg CBZ, BOC

1. Cs 2 CO 3 / DMF / H 2 O

2. Br-CH (R ³ ) CO (R ⁴ )

3. NH ₄ OAc

1. Deprotection or derivatization

2. Repeated protection if necessary

3. Derivatization, if any

(B) (A)

Peptide synthesis in solution

2. cyclization and deprotection

In a second step, intermediate A is deprotected using catalytic hydrogenation or a strong acid such as HF, HCl, HBr or Tfa. The α-amino group can then be protected with a base-sensitive protecting group such as the Fmoc group using commercially available N- (9-fluorenylmethoxycarbonyloxy) succinimide and K ₂ CO ₃ , for example in acetonitrile and water. Alternatively, N _and -Cbz protected imidazole nitrogen may be alkylated with a carboxyl ester halide and deprotected by α-amino group using catalytic hydrogenation. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · To form Β '(V = H, W = - (CH ₂ ) _m CR ⁵ CO ₂ R', where R 'represents alkyl or benzyl ester). The imidazole nitrogen can be protected using commercially available triphenylmethyl chloride and a tertiary amine base such as 4-methylmorpholine, diisopropylethylamine or triethylamine to form an Fmoc-protected intermediate which is subsequently deprotected at the α-amino group using bases such as TAEA to give intermediate Β ( V = H, W = Trt). Alternatively, N-deprotected imidazole Β ”(V = H, W = H) may be used without further modification.

In the third step, the intermediate Β, B 'or B "is used as an anchor group to continue the synthesis of the target peptide in the solution phase. Thus, the anchoring group is dissolved in ethyl acetate at a concentration of about 50 to 200 mmol per liter and 1 to 5 molar equivalents, more preferably 1.1 to 1.5 molar equivalents of N _and -Fmoc protected amino acid in the form of its activated ester, anhydride or acyl halide are added . The mixture is mixed with a second layer of a weak base such as aqueous Na ₂ CO ₃ or more preferably an aqueous solution of NaHCO ₃ until the reaction is complete. The aqueous layer is removed and about 1 to 10 ml / mmol or more preferably about 2 to 4 ml / mmol of TAEA or piperidine is added and the mixture is stirred for about 30 minutes. The solution is then washed with a saturated NaCl solution (twice with about 30 ml / mmol) and then the pH of the solution is adjusted to 5.5 (three times with 10 ml / mmol) with 10% phosphate buffer solution. The following cycles are performed in a similar manner to the first cycle. The final amino acid can be protected by N 'using the Boc or Fmoc group.

In a fourth step, the N-terminal and C-terminal protecting groups are removed with an aqueous base or with a strong acid and the resulting peptide intermediate can be cyclized using classical peptide coupling techniques as described in "The Practice of Peptide Synthesis", Bodanszky and Bodanszky, Springer Verlag, 1984. The peptide intermediate is dissolved in an aprotic solvent such as DMF and the solution is basified by addition of a tertiary amine base such as 4-methylmorpholine. The carboxyl moiety of the intermediate is activated by the addition of a 1 to 6-fold molar excess of a carbodiimide such as DCC or EDC and addition of, e.g., 1-hydroxy benzotriazole. The mixture is stirred at 0 ° C to 100 ° C, most preferably at room temperature until complete reaction.

In the final step, the protected peptide is released from the protecting groups using catalytic hydrogenation or strong acids such as HF, HCl, HBr or Tfa to give final product C where R ¹ to R ⁵ , a, b, Y, Z and n are the same as has been defined above for the compound of formula I.

• 0 0 000 0 0 000 «000

0 0 · 0,000

0 0 · 0 0 ·

000 0000 00 000 00 000

Infusion mass spectra were measured on a Finnigan SSQ 7000 spectrometer equipped with ESI (electrospray ionization) source. NMR data was obtained on a 300 MHz Varian Unity spectrometer on samples at concentrations from 10 to 20 mg / ml in the indicated solvents.

Alternatively, the compounds of the invention may be prepared by solid phase peptide synthesis techniques. Thus, intermediate A (X = Boc) is alkylated with, for example, ethyl bromoacetate and a suitable base such as K ₂ CO ₃ in an aprotic solvent such as DMF and the resulting ethyl ester intermediate is hydrolyzed using an aqueous base such as NaOH to give intermediate Β ( V = Boc, W = -CH ₂ CO ₂ H). Intermediate Β (V = Boc, W = -CH ₂ CO ₂ H) can be activated using known activation techniques as described in "The Practice of Peptide Synthesis", Bodanszky and Bodanszky, Springer-Verlag, 1984, and can be used directly for coupling to a growing peptide on a solid support or intermediate Β (V = Boc, W = CH ₂ CO ₂ H) can be attached directly to the solid support at the start of solid phase synthesis. Deprotection of the n-terminal Boc group with, for example, Tfa, permits the continuation of peptide synthesis under conditions known to those skilled in the art of peptide synthesis.

Intermediate Β (V = Fmoc, W = -CH ₂ CO ₂ t -Bu eg) can be reacted with an acid such as Tfa to remove the protecting tert-butyl ester group and the resulting intermediate Β (V = Fmoc, W = -CH ₂ CO) ₂ H, e.g., can be used for solid phase peptide synthesis by Fmoc. Intermediate Β (V = Fmoc, W = -CH ₂ CO ₂ H) can be activated using known activation techniques as described in "The Practice of Peptide Synthesis", by M. Bodanszky and A. Bodanszky, Springer-Verlag, 1984 and may to be used directly for coupling to a growing peptide on a solid support. Deprotection of the N-terminal Fmoc moiety with, e.g., piperidine allows for continuation of peptide synthesis under conditions known to those skilled in the art.

Solid state synthesis of cyclic analogs can also be performed according to Scheme II below.

SCHEME II

Ε-

ν # - \ t

O-Resin (F)

R '= alkyl, benzyl R * = Boc, Fmoc

Intermediate A (X = Boc or Cbz, R ³ = 2-methoxyphenyl, 3-methoxyphenyl or 4-methoxyphenyl) can be reacted with 1 M BBr 3 in CH 2 Cl 2 for 0.5 h to give free phenol A (X = H, R ³ = 2 -hydroxy phenyl, 3-hydroxyphenyl or 4-hydroxyphenyl). α-Nitrogen can be protected with an acid-sensitive protecting group such as a Boc group using di-tert-butyl dicarbonate and a base such as NaOH in a mixture of an organic water-miscible solvent such as dioxane and water. Intermediate A (X = Boc, R ³ = 2-hydroxyphenyl, 3-hydroxyphenyl, and 4-hydroxyphenyl) is alkylated with ethyl bromoacetate and a suitable base such as K ₂ CO ₃ in an aprotic solvent such as DMF to afford the ethyl ester intermediate D. then converted to the cesium salt by the action of cesium carbonate. The organic salt is reacted with excess Merrifield resin to form intermediate E. Intermediate E is then subjected to standard Boc solid phase synthesis or standard Fmoc solid phase synthesis as • 9 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · • 9 9 9 · · 9 9 • · 9 9 «* · 9

9 9 9 9 9 9 9 • 99 9999 99 ··· 9,999 described previously to give intermediates F. When the complete C-terminal amino acid sequence is constructed, it is unmasked using a suitable base such as LiOH in aqueous DMF and the peptide cyclized using a standard activation protocol such as carbodiimide with hydroxybenzotriazole and a tertiary base such as diisopropylethylamine to form intermediates G. Final deprotection of the side chains and cleavage of the resin is accomplished by adding a very strong acid such as HF to form the compounds of this invention.

The invention is further illustrated by the following examples which are not intended to be limiting.

EXAMPLES OF THE INVENTION

Example 1 Cyclo [Tyr-D-Trp-Lys-Val-Phe] (4- (3-methoxyphenyl) imidazole) -Glyl

Example 1 was synthesized according to synthetic scheme 1 as shown below:

*

0 «

3. NH ₄ OAc

4. 6N HCl

1. CSjCOj / DMF / Η, Ο

2. Br-CH (R) CO-R ³

Fmoc-OSu / K, CO ₃ CHC / HjO · »

R ·

FmocN

R 'VVk

H

Trityl-Cl / NMM

CH, CI, (b)

Solution synthesis

R '

Fmoc-IZVX ^ X ^ -X ^ YVN ^^ (d)

RN Trt

1. Tfa / iPr ₃ SiH

2. Br- (CH ₂ ) CHR ⁵ CO ₂ Et / KHCO / DMF

1. TAEA / EtOAc

2. NaOH / H2O / MeOH

3. EDC / HOBt / DMF

HYPd on carbon HOAc

O

(G)

O (f)

Step a: 2- (1- (S) -amino-2-phenylethyl) -4- (3-methoxyphenyl) imidazole

Cbz- (L) -Phenylalanine (10.0 g, 33.4 mmol) and Cs ₂ CO ₃ (5.44 g, 16.7 mmol) were mixed with 2: 1 DMF: water (75 mL) and it was stirred until homogenized. The solvent was removed under reduced pressure, the residue was dissolved in DMF (70 mL) and 7.65 g of 2-bromo-3'-methoxyacetophenone (33.4 mmol) in 30 mL of DMF was added. The mixture was stirred at room temperature for 30 min and then concentrated under reduced pressure. The resulting ketoester has dissolved · · · · · · · · · · · · · · · · · · · · · · · · · · ·

· φ φφφ φφ _φφφ φφφφ φφ φ φ in xylene (150 ml), CsBr was filtered off. Ammonium acetate (40.0 g, 0.52 mol) was then added and the mixture was heated to reflux for 2 h by removing excess AcONH ₄ and the resulting water by means of an azeotropic attachment. The reaction was cooled and washed with saturated NaHCO ₃ (50 mL) followed by saturated NaCl (50 mL). The xylene layer was dried over Na ₂ SO ₄ , filtered concentrated in vacuo.

The residue was dissolved in 30 mL of dioxane, 6N HCl (115 mL) was added, and the mixture was heated to reflux for about 3 h. The solution was concentrated under reduced pressure and triturated with diethyl ether (4 x 100 mL). The residue was dried under vacuum to constant weight to give 12.15 g (99%) of intermediate 1a, mass spectrum 294.2 MH ⁺ .

Step b: 2- (1- (S) - ((Fluorenylmethoxy) carbonyl) amino-2-phenylethyl) -4- (3-methoxyphenyl) imidazole

Intermediate 1a (11.8 g, 32.2 mmol) was dissolved in 200 mL of acetonitrile: water (1: 1) and then K ₂ CO ₃ (5.38 g, 39 mmol) was carefully added in portions. Then 9-fluorenylmethylsuccinimidyl carbonate was added and the resulting mixture was vigorously stirred for 20 minutes. The product was extracted with ethyl acetate (100 mL) and the ethyl acetate layer was washed with water (2 x 50 mL). The ethyl acetate layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The product was purified by flash chromatography on silica gel (150 g) eluting with 2: 2: 1 / CH ₂ Cl ₂ : hexane: EtOAc and then 1: 1 / hexane: EtOAc. The product fractions were combined and concentrated in vacuo to give intermediate 1b as a pale yellow foam, 14.77 g (85%). Mass spectrum 516.3 MH ⁺ NMR (300 MHz, DMSO-d ₆ ), 11.8-12.0 (1H, s), 7.8-8.0 (3H, d), 7.6-7 , 8 (2H, d), 7.5 (1H, s), 7.1-7.5 (12H, m), 6.7-6.9 (1H, d), 4.8-5.0 (1H, m), 4.1-4.3 (3H, m), 3.7-3.9 (3H, s), 3.0-3.4 (2H, m).

Step c: 2- (1- (S) - ((Fluorenylmethoxy) carbonyl) amino-2-phenylethyl) -4- (3-methoxyphenyl) -1-triphenylmethylimidazole

Intermediate 1b (13.9 g, 26.9 mmol) was dissolved in 50 mL of CH ₂ Cl ₂ under N ₂ , then 4-methylmorpholine (2.96 mL, 26.9 mmol) and chlorotrifenylmethane (7.51) were added. g, 26.9 mmol) and the solution was stirred at room temperature for 45 minutes. The solids were removed by filtration and the filtrate was purified by flash chromatography on silica gel (300 g) using 70:30 / hexane: EtOAc as eluent. Product containing fractions were combined and concentrated in vacuo to give intermediate 1c as a foam, 18.0 g (88%), NMR (300 MHz, DMSO-d ₆ ), 7.84-7.95 (2H, d),

7.7-7.8 (1H, d), 7.6-7.7 (1H, d), 6.7-7.5 (29H, m), 4.3-4.5 (1H, m ), 3.75-3.95 (2H, m), 3.75-3.85 (3H, s), 3.6-3.7 (1H, m), 2.65-2.85 (1H) , dd), 2.05-2.2 (1H, m).

Step d: 2- (1- (S) - ((Fmoc-Tyr (OBzl) -D-Trp-Lys (Cbz) -Val) amino-2-phenylethyl) -4- (3-methoxyphenyl) -1- ( triphenylmethyl) imidazole

Intermediate 1c (1.89 g, 2.50 mmol) was dissolved in 40 mL of ethyl acetate, then 9 mL of tris (2-aminoethyl) amine was added and the mixture was vigorously stirred for about 30 min. The ethyl acetate layer was washed with saturated NaCl solution (2 x 120 mL) and then adjusted to pH = 5.5 (3 x 40 mL) with 10% phosphate buffer. The ethyl acetate layer was stirred overnight with saturated NaHCO ₃ solution (40 mL) and Fmoc-Val-F (1.02 g, 3.00 mmol) was added. The reaction mixture was stirred for 1 h and the aqueous layer was removed.

The intermediate was then sequentially deprotected and capped with Fmoc-Lys (Cbz) -Os, Fmoc-DTrp-Osu and Fmoc-Tyr (OBzl) -Os in a similar manner to that described above for the Fmoc-Val-F cycle. The ethyl acetate layer was diluted with 1.5 times the volume of hexane and applied to a silica gel column by flash chromatography using a 50: 30: 20 / CH ₂ Cl ₂ : EtOAc: hexane mixture followed by 4: 1 / EtOAc: hexane as the eluent. eluent. Product containing fractions were combined and concentrated in vacuo to give intermediate 1d as a white foam, 1.90 g (46%). Mass Spectroscopy 1581.2 MNa ⁺ , 1559.5 MH ⁺ .

Step e: 1 - ((2-Ethoxy-2-oxo) ethyl) -2- (1- (S) - ((Fmoc-Tyr (OBzl) -D-Trp-Lys (Cbz) -Val) amino-2-phenylethyl ) -4- (3-methoxyphenyl) imidazole

Intermediate 1d (519 mg, 0.33 mmol) was dissolved in 10 mL of Tfa containing i-Pr ₃ SiH (205 µL, 1.0 mmol) and stirred for 15 min. The intermediate was precipitated by the addition of diethyl ether (60 mL) and filtered. Mass spectroscopy: 1316 MH ⁺ . The intermediate was dissolved in 3 mL of DMF, then KHCO ₃ (198 mg, 2.0 mmol) and ethyl bromoacetate (721 µL, 6.5 mmol) were added and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, dissolved in 10 mL of CH ₂ Cl ₂ and washed with 10 mL of water. The dichloromethane layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude intermediate 1e (540 mg) which was used without further purification.

Step f: Cyclo [Tyr (OBzl) -D-Trp-Lys (Cbz) -Val-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly · · · · · · · · · · · · · · ·· · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ·

Intermediate 1e (540 mg, 0.33 mmol) was suspended in 10 mL of ethyl acetate, 1 mL of tris (aminoethyl) amine was added and the mixture was vigorously stirred for 30 minutes. Ethyl acetate (10 mL) was then added and the solution was washed with saturated NaCl solution (2 x 25 mL) and then adjusted to pH 5.5 (3 x 10 mL) with 10% phosphate buffer. The intermediate was precipitated by addition of hexane (40 mL) and the solution was decanted. The residue was dissolved in 10 mL of methanol and stirred overnight at room temperature with 2.5 N NaOH (0.5 mL). The mixture was diluted to turbidity with water and the pH adjusted to pH = 6.7. The deprotected intermediate was filtered off and dried in vacuo. The solid was dissolved in DMF (25 mL) and DCC (340 mg, 1.65 mmol) and HOBt (252 mg, 1.65 mmol) were added. The mixture was stirred at room temperature for 2 h and then concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using AcOEt as eluent. Product containing fractions were combined and concentrated in vacuo to give intermediate 1f as a glass (180 mg, 48% of intermediate 1d). Mass Spectroscopy:

1134.5 MH ⁺ .

Step g: Cyclo [Tyr-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Intermediate 1f (180 mg, 0.16 mmol) was dissolved in 10 mL of acetic acid

10% palladium on carbon (24 mg) and shaken under H ₂ (25 psi) at room temperature for 8 h. The catalyst was then filtered and the residue concentrated in vacuo. The crude mixture was composed of fully deprotected material (both CBz and benzyl ethers removed) and partially deprotected material (Cbz de-scrubbed, benzyl ether remaining). The mixture was purified by preparative HPLC on a VYDAC® Protein & Peptide _{C] 8} (The Nest Group, Inc., Southborough, MA) using a gradient of 20% to 70% CH ₃ CN / 0% TFA over 55 minutes. 4 fractions of more polar peak were pooled, concentrated and lyophilized (2 x 10 mL 0.5% HCl, then 1 x 10 mL water) to afford the title compound of Example 1 (1.45 mg, 29%). MS: 910.4 MH ⁺ .

Example 2 Cyclo [Tyr (OBzl) -D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Example 2 was prepared according to synthetic scheme 1 in Example 1, but using the appropriate amino acids. Pure Less Polar Peak Fractions of Purification 1 g of the substance were combined, concentrated and lyophilized (2 x 10 mL 0.5% HCl, then 1 x 10 mL water) to give the product of Example 2, 33 mg (21%). Mass spectroscopy: 1000.4 MH ⁺ .

AA · AA · AAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAAA

And AAA AAA

AAA AA AAA AA AAA

Example 3 Cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Example 3 was prepared according to Synthetic Scheme 1 in Example 1, but with the following differences:

Step d: 2- (1- (S) - ((Fmoc-Trp-D-Trp-Lys (Cbz) -Val) amino-2-phenylethyl) -4- (3-methoxyphenyl) -1 (triphenylmethyl) imidazole

Intermediate 1c (757 mg, 1.0 mmol) was dissolved in 20 mL of AcOEt, then tris (2-aminoethyljamin (3 mL) was added and the mixture was stirred vigorously for half an hour. The ethyl acetate layer was washed with saturated NaCl solution (2 x 60 mL) and the pH of the mixture was adjusted to 5.5 (3 x 20 mL) with 10% phosphate buffer, and the ethyl acetate layer was stirred overnight with saturated NaHCO ₃ (20 mL) and Fmoc-Val-F (825 mg, 2) was added. 33 mmol) The reaction was stirred for 1 h and the aqueous phase was removed.

The intermediate was sequentially deprotected and capped with Fmoc-Lys (Cbz) -OSu, Fmoc-D-TrpOSu and Fmoc-Trp-OSu in a similar manner as described for the Fmoc-Val-F cycle. The ethyl acetate layer was diluted with 1.5 times the volume of hexane and column chromatographed first using 50: 30: 20 / CH ₂ Cl ₂ : EtOAc: hexane and then 4: 1 / EtOAc as eluent. Product containing fractions were combined and concentrated under reduced pressure to afford intermediate 3d as a white foam, 1.02 g, (68%). Mass Spectroscopy: 11492.0 (MNa ⁺ ), 1514.2 (MH ⁺ ).

Step e: 1 - ((2-Ethoxy-2-oxo) ethyl) -2- (1- (S) - ((Fmoc-Trp-D-Trp-Lys (Cbz) -Val) amino-2-phenylethyl) ) -4- (3-methoxyphenyl) -1- (triphenylmethylamidazole

Intermediate 3d (1.00 g, 0.67 mmol) was dissolved in a mixture of CH ₂ Cl ₂ (10 mL), Tfa (1 mL) and i-Pr ₃ SiH (205 µL, 1.0 mmol) and the mixture was stirred. 20 minutes. A 1: 1 / Et ₂ O: hexane mixture (100 mL) was added and the intermediate was filtered off and dried (0.88 g). The intermediate was dissolved in 10 mL of DMF, then KHCO ₃ (200 mg, 2.00 mmol) and ethyl bromoacetate were added and the reaction mixture was stirred overnight at room temperature. The mixture was then concentrated under reduced pressure to give intermediate 3e, which was used without further purification. MS: 1335.7 MH ⁺ .

Step f: Cyclo [Trp-D-Trp-Lys (Cbz) -Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Intermediate 3e (crude, 0.67 mmol) was dissolved in 10 mL of methanol and stirred for 45 min at room temperature with 2.5 N NaOH (1.0 mL). The mixture was diluted with water until turbidity and pH was adjusted to 6.9. The solvent was decanted and the residue was triturated with water to give a solvent. · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · 999 «« »light yellow powder (650 mg, 1085.5 MH ⁺ ). Powder (629 mg) was dissolved in 20 mL of DMF, NMM (220 µL, 2.0 mmol), EDC (192 mg, 1.0 mmol) and HOBt (153 mg, 1.0 mmol) were added. The mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The crude product was dissolved in 15 mL of CH2C12 and washed with 10% phosphate buffer ^- (pH was adjusted to 5.5). The dichloromethane layer was dried over Na 2 SO ₄ , filtered and concentrated to 2 mL. Ethyl ether was then added to precipitate the product, which was filtered off and dried to give intermediate 3f (440 mg, 71%). Mass spectrum: 1067.4 MH ⁺ .

Step g: Cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Intermediate 3f (200 mg, 0.19 mmol) was dissolved in 15 mL of acetic acid

10% palladium on carbon (40 mg) and the mixture was shaken under a hydrogen atmosphere (25 psi) for 2 days at room temperature. The catalyst was then filtered off and the residue was concentrated in vacuo. The crude mixture was purified using preparative HPLC on a C ₁₈ column (Rainin Microsorb ™ 80220-C5) using a gradient of 20% to 70% CH ₃ CN / 0.1% Tfa over 55 minutes. A slow passage using a gradient of 30% to 50% CH ₃ CN / 0.1% Tfa over 55 minutes was required to obtain good separation. Pure fractions were combined, concentrated, and lyophilized (2 x 10 mL 0.5% HCl, then 1 x 10 mL water) to afford the title compound of Example 3, 26 mg, (14%). Mass spectroscopy: 933.5 MH ⁺ .

Example 4:

Cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Example 4 was prepared according to synthetic scheme 1 similar to that described in Example 1 with the following differences:

Step g: Cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Intermediate 3f (150 mg, 0.14 mmol) was dissolved in 12 mL of CH ₂ Cl ₂ and BBr ₃ in hexane under a nitrogen atmosphere. The resulting slurry was stirred for 0.5 h. Methanol (10 mL) was then added and the mixture was concentrated in vacuo. The crude mixture was purified by preparative HPLC on C, _g column using a gradient from 24% to 48% CH ₃ CN / 0.2 / NH ₄ OAc over 50 minutes. Pure fractions were combined, concentrated, and lyophilized (2 x 10 mL water) to afford the title compound of Example 4, 40 mg (29%). Mass Spectroscopy: 919.4 MH ⁺ .

Example 5 • 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 000 000 00 0000 00 000 00 00 cyclo [Trp-D-Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Glyl

Example 5 was prepared according to Scheme 1 in a manner similar to that described for Example 3 except that Fmoc-Thr (OBzl) -F was used in place of Fmoc-Val-F in step d. Mass spectrometry: 1025.5 MH ⁺ .

Example 6 Cyclo [Trp-D-Trp-Lys-Thr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Example 6 was prepared according to Scheme 1 in a similar manner to that described for Example 4 except that intermediate 5f, cyclo [Trp-D-Trp-Lys (Cbz) -Thr (Obzyl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) ) -Gly] was used in place of intermediate 3f in step g. Mass spectroscopy: 1025.5 MH ⁺ .

Example 7 Cycl [Trp-D-Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly]

Example 7 was prepared according to Scheme 1 in a manner similar to that described for Example 3 except that Fmoc-Abu-F was used in place of Fmoc-Val-F in step d and cyclodiimide and HoBt cyclization was not performed in step 3f. Mass Spec 937.3 MH ⁺ .

Example 8 Cyclo [Trp-D-Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly]

Example 8 was prepared according to Scheme 1 in a manner similar to that described for Example 3 except that Fmoc-Abu-F was used in place of Fmoc-Val-F in step d. Mass Spec: 919.5 MH ⁺ .

Example 9 Cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe- (4- (1,1-dimethylethyl) imidazole) -Gly]

Example 9 was prepared according to Scheme 2.

• fl fl ·· • · «• • fl • • «fl • fl • • • fl • • • · • • • • fl • • flfl flflfl * • fl flflfl • · • flfl

SCHEME 2

BocNH

Ø ', ν *

solution synthesis

R *

Fmoc- (Z) _n -X '

(h)

R

Br (CH ₂ ) _OT CHR ⁵ CO ₃ Et /

KHCO ₃ / DMF

Step a: 2- (1- (S) -amino-2-phenylethyl) -4- (1,1-dimethylethyl) imidazole

Boc- (L) -phenylalanine (5.31 g, 20.0 mmol) and Cs ₂ CO ₃ (3.26 g, 10.0 mmol) were combined in 1: 1 / DMF: H ₂ O (50 mL ) and the mixture was stirred until a homogeneous mixture was obtained. The solvent was removed under reduced pressure and the residue was dissolved in 50 mL of DMF and 1chlorpinacolone (2.63 mL, 20.0 mmol) was added. The mixture was stirred overnight at room temperature and then concentrated under reduced pressure. The resulting ketoester was dissolved in 100 mL of xylene and CsBr was filtered off. Ammonium acetate (25.0 g, 0.33 mol) was then added and the mixture was added

• ·· ·· • 99 • · 9 9 9 • 9 9 9 99 • 9 9 · • 9 9 • · * • • • • 9 9 • 9 • 9 9 t 9 99 9999 99 999 99 99

heating with 2 h reflux while removing excess AcONH ₄ and released water using an azeotropic attachment. The reaction was cooled and washed with saturated NaHCO 3 solution (50 mL), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. Purification of the protected intermediate was accomplished by flash chromatography on silica gel using 80:20 / hexane: EtOAc as eluent to give 3.45 g (50%) of the crystalline intermediate (344.3 MH ⁺ ). This intermediate was dissolved in 30 mL of methanol and concentrated sulfuric acid (5.0 mL) was added and the mixture was stirred for about 3 h. The solution was concentrated in vacuo and the residue was precipitated from THF and diethyl ether. The solid was dried under vacuum to give 1.89 g (95%) of intermediate 9a. NMR (300 MHz, DMSO-d ₆₎ 8.5 to 10.5 (3H, br s), 7.3-7.4 (1H, s), 7.15-7.35 (3H, m) , 7.0-7.1 (2H, m), 4.9-5.1 (1H, t), 3.5-3.65 (2H, d), 1.2-1.3 (9H, m), with).

Step h: 2- (1- (S) - ((Fmoc-Phe-D-Trp-Lys (Boc) -Tyr (Obzl)) amino-2-phenylethyl) -4- (1,1-dimethylethyl) - 1H-imidazole

Intermediate 9a (790 mg, 2.50 mmol) was dissolved in 40 mL of AcOEt, tris (2-aminoethyl) amine (9 mL) was added and the mixture was stirred vigorously for 0.5 h. The ethyl acetate layer was washed with saturated NaCl solution ( 2 x 120 ml) and then with 10% phosphate buffer adjusted to pH = 5.5 (3 x 40 ml). The ethyl acetate layer was stirred with saturated NaHCO ₃ solution (40 mL) and FmocTyr (OBzl) -OSu (1.02 g, 3.00 mmol) was added. The reaction was stirred for 1.5 h and the aqueous layer was removed.

The intermediate was sequentially deprotected and capped with Fmoc-Lys (Cbz) -OSu, Fmoc-D-TrpOSu and Fmoc-Phe-OSu in a manner similar to that described above for the Fmoc-Tyr (OBzl) -OSu cycle. The ethyl acetate layer was applied to a silica gel column by flash chromatography using 1% acetic acid / EtOAc as eluent. The product-containing fractions were combined and concentrated in vacuo. The crude product was dissolved in AcOEt, precipitated by the addition of hexane and filtered. The solid was dried under vacuum to give intermediates 9h, 1.67 g (52%). Mass spectroscopy: 1280.7 MH ⁺ .

Step e: 4- (1,1-dimethylethyl) -2- (1- (S) - ((Fmoc-Phe-D-Trp-Lys (Boc) -Tyr (Obzl)) - amino-2-phenylethyl) - 1- (2-ethoxy-2-oxoethyl) imidazole

Intermediate 9h (128 mg, 0.10 mmol) was dissolved in 2 mL of DMF, K ₂ CO ₃ (35 mg, 0.25 mmol) and ethyl bromoacetate (28 µL, 0.25 mmol) were added and the mixture was stirred overnight. at room temperature. The mixture was concentrated in vacuo, dissolved in 10 mL of AcOEt and washed with water (10 mL). The ethyl acetate layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give crude intermediate 9e (126 mg, 92%) which was used without further purification.

Step f: Cyclo [Phe-D-Trp-Lys (Boc) -Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly]

Intermediate 9e (116 mg, 0.085 mmol) was suspended in 2 mL of AcOEt and tris (aminoethyl) amine (0.5 mL) was added and the mixture was stirred vigorously for 0.5 h. the solution was washed with saturated NaCl solution (2 x 5 mL) followed by 10% phosphate buffer solution (pH = 5.5, 3 x 5 mL). The intermediate was precipitated by the addition of 40 mL of hexane and the intermediate was filtered (76 mg). The residue was dissolved in 2 mL of methanol and stirred overnight at room temperature with 2.5 N NaOH (0.1 mL). The mixture was diluted with turbidity with water and adjusted to pH 6.0. The deprotected intermediate was filtered off and dried in vacuo. The solid was dissolved in DMF (20 mL) and DCC (126 mg, 0.60 mmol) and HOBt (90 mg, 0.60 mmol) were added. The mixture was stirred at room temperature for 6 h and then concentrated in vacuo. It was then dissolved in 5 mL of EtOAc and washed with saturated NaHCO ₃ solution (1 x 5 mL) and saturated NaCl solution (5 mL). The mixture was dried over Na ₂ SO ₄ , filtered and concentrated under vacuum to give intermediate 9f. Mass Spectroscopy: 1098.5 MH ⁺ .

Step g: Cyclo [Phe-D-Trp-Lys-Tyr-Phe (4- (1,1-dimethylethyl) imidazole) -Gly]

Intermediate 9f (crude, 0.085 mmol) was dissolved in Tfa (9.4 mL) containing i-Pr ₃ SiH and water (0.5 mL), the mixture was stirred for 20 min and then concentrated in vacuo. The crude mixture was purified by preparative HPLC on a C ₁₈ column using a gradient of 30% to 60% CH ₃ CN / 0.1% Tfa over 50 min. A second pass using a gradient of 32% to 80% CH ₃ CN / 0.2% NH ₄ OAc over 50 minutes was required for good separation. Pure fractions were combined, concentrated, and lyophilized (2 x 10 mL 0.5% HCl, then 1 x 10 mL water) to afford the title compound of Example 9, 9 mg (10%). Mass Spectroscopy: 998.4 MH ⁺ .

Example 10 Cyclo [Phe-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Example 10 was prepared according to Scheme 1, similar to Example 3 except that Fmoc-Phe-Osu was used in place of Fmoc-Trp-F in step d. Mass spectroscopy: 894.4 MH ⁺ .

Example 11 Cycle [Phe-D-Trp-Lys-T yr (OBzl) -Phe Ψ (4- (3-Methoxyphenyl) imidazole) -Gly] · · · · · · · · · · · · · · · Example · 11 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · prepared according to Scheme 1 in a manner similar to that described in Example 3 except that Fmoc-Phe-OH was used instead of Fmoc-Trp-F and FmocTyr (OBzl) -OH was used in place of Fmoc-Val-F in step d. -Tyr (OBzl) -OH was activated with DCC and commercially available HOAt. The crude mixture in step g consisted of fully deprotected material (both Cbz and benzyl ether removed) and partially deprotected material (Cbz was removed, benzyl ether remained). The less polar peak formed by partial deprotection gave the title compound of Example 11. Mass spectroscopy: 1048.5 MH ⁺ .

Example 12 Cyclo [Phe-D-Trp-Lys-Tyr-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Example 12 was prepared according to Scheme 1 in a manner similar to that described in Example 3 except that Fmoc-Phe-OH was used in place of Fmoc-Trp-F and FmocTyr (OBzl) -OH was used in place of Fmoc-Val-F in step d. Fmoc-Tyr (OBzl) -OH was activated with DCC and commercially available HOAt. The crude mixture in step g consisted of fully deprotected material (both Cbz and benzyl ether removed) and partially deprotected material (Cbz was removed, benzyl ether remained). The more polar peak formed by partial deprotection gave the title compound of Example 12. Mass spectroscopy: 958.4 MH ⁺ .

Example 13 Cyclo [Phe-D-Trp-Lys-Tyr-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Example 13 was prepared according to Scheme 1 in a manner similar to that described in Example 4 except that intermediate 11f, cyclo [Phe-D-Trp-Lys (Cbz) -Tyr (OBzl) -Phehe (4- (3-methoxyphenyl) imidazole) -Gly] was used in place of intermediate 3f in step g. Mass Spec: 944.6 MH ⁺ .

Example 14 Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole) -Gly]

Example 14 was prepared according to Scheme 2 in a manner similar to that described in Example 9, with the following differences:

Step h: 2- (1- (S) - ((Fmoc-Trp-D-Trp-Lys (Cbz) -Tyr (Bzl)) - amino-2-phenylethyl) -4- (3-methoxyphenyl) -1- ( triphenylmethyl) imidazole · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · ··· ···· ·· ··· ··

Peptide synthesis was performed in a similar manner to step 9h except that Fmoc-Trp-OSu was used instead of Fmoc-Phe-OSu, Fmoc-Lys (Boc) -OSu was used in place of Fmoc-Lys (Cbz) -OSu and Fmoc -Tyr (Bzl) -OSu was used instead of Fmoc-Val-OSu. Yield = 783 mg (57%). Mass Spectroscopy: 1370.6 MH ⁺ .

Step e: 1 - ((2-Ethoxy-2-oxo) ethyl) -2- (1- (S) - ((Fmoc-Trp-D-Trp-Lys (Boc) -Tyr (OBzl)) - amino- 2-Phenylethyl) -4- (3-methoxyphenyl) imidazole

Alkylation of intermediate 14h was carried out in a similar manner to reaction 9h, yield = 640 mg (80%), mass spectroscopy: 1456.3 MH ⁺ .

Step f: Cyclo [Trp-D-Trp-Lys (Boc) -Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole) -Gly]

Intermediate 14e (640 mg, 0.44 mmol) was dissolved in 15 mL of methanol and 2.5 N NaOH (1 mL, 2.5 mmol) was added. The mixture was stirred for 0.5 h and then the pH was adjusted to 7.0 with 5% HCl solution. The methanol was removed under reduced pressure and the aqueous layer was decanted. The residue was dried well under reduced pressure and then dissolved in 15 mL of DMF. DCC (206 mg, 1.0 mmol) and HOBt (153 mg, 1.0 mmol) were added and the mixture was allowed to stir overnight. The reaction was concentrated in vacuo, dissolved in 10 mL of AcOEt and washed twice with 10% phosphate buffer solution, pH = 5.5. The ethyl acetate layer was applied to a silica gel column and the product was eluted with ethyl acetate. Product containing fractions were combined and concentrated to give 240 mg (46%) of intermediate 14f.

Step g: Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole) -Gly]

Intermediate 14f (240 mg, 0.20 mmol) was dissolved in 10 mL CH ₂ Cl ₂ and Tfa (10 mL) containing i-Pr ₃ SiH (205 µL, 1.0 mmol) was added. The mixture was stirred at room temperature for 15 minutes. The dichloromethane layer was evaporated under reduced pressure and the crude product was precipitated by the addition of ether. The solvents were decanted and the residue was further purified by preparative HPLC on a C ₁₈ column using a gradient of 30% to 50% CH ₃ CN / 0.1% Tfa over 55 min. Pure fractions were combined, concentrated, and lyophilized (1 x 10 mL 0.5% HCl, then 1 x 10 mL water) to afford the title compound of Example 14, 25 mg (11%). Mass Spectroscopy: 1087.4 MH ⁺ .

Example 15 Cyclo [Tyr-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Example 15 was prepared according to Synthetic Scheme 1 in a manner similar to Example 4, with the following exceptions:

• 99 ·· · · · · · · · · · · · · · · ··· ··· ··· ··· ···

Intermediate 1f (130 mg, 0.115 mmol) was dissolved in 5 mL of dichloromethane and IM BBr ₃ in hexane (5 mL) was added under N ₂ . The resulting slurry was stirred for 0.5 h and then cooled to 0 ° C. Then methanol (10 mL) was added and the mixture was concentrated in vacuo. The crude mixture was applied to C _I8 column, washed with 1% NH ₄ OAc, washed with 0.1% TFA and then eluted with a gradient of 20% to 35% CH ₃ CN / 0% TFA over 50 minutes. Pure fractions were combined, concentrated and lyophilized (2 x 10 mL 0.5% HCl) to afford the title compound of Example 15, 60 mg (54%). Mass spectroscopy: 896 MH ⁺ .

Example 16 Cyclo [Phe-D-Trp-Lys-Nal-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Example 16 was prepared according to Scheme 1 in a manner similar to that described in Example 3, with the following exceptions:

Step d: 2- (1- (S) - ((Fmoc-Phe-D-Trp-Lys (Cbz) -Nal) -amino) -2-phenylethyl) -4- (3-methoxyphenyl) -1 (triphenylmethyl) -imidazole

Intermediate 16d was prepared similarly to intermediate ld except that Fmoc-Nal-OAt was used in place of Fmoc-Val-F and Fmoc-Phe-OH was used in place of Fmoc-Tyr (Bzl) -OH.

Step g: Cyclo [Phe-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly]

Step 16g was performed in a similar manner to Step 4g to give the title compound of Example 16.

Example 17 Cyclo [Phe-D-Trp-Lys-Nal-Phe (4- (3-methoxyphenyl) imidazole) -Gly]

Example 17 was prepared according to schemes similar to those described for analogous Example 16 with the following exceptions:

Intermediate 17f (310 mg, 0.27 mmol) was suspended in 3 mL of anisole and 12 mL of anhydrous HF was added. The mixture was stirred for 1 h at 0 ° C. The HF was distilled off and the product was precipitated by the addition of ether. The crude product was filtered off and further purified by preparative HPLC using a 20-80% CH ₃ CN / 0.1% Tfa gradient over 40 min. Pure fractions were combined, concentrated, and lyophilized twice with HCl. Yield = 56 mg (19%). Mass Spec 992.4 MH ⁺ .

Scheme 3

HN '

R 'JU ω fe *

IN

3. NH ₄ OAc solution synthesis ► φ φφφφφφφφ · φ · · *

1. CS3 CO3 / DMF / H2 O

2. Br-CH (R ⁴ ) CO-R ³

(and)

First Br- (CH (R ⁵⁾ CO, tBu / KaCQj / DMF

2. H / PdonC

R *

Οοο-ίΖ ^ -Χ'-χΤχίχ ^ χ.Ν ''> A_- _R ³ (k)

'KJ ^{R <}

R '

R '

O

1. EDCZHOBt / DMF

3.Tfa / iPr, SiH -Χ'-Χ'-Χ ^ Υ)

0) <V;

RN /

HIM

O

strong Hj / Pd acid on carbon HAc

Example 18 Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole) - (y) Abu]

Example 18 was prepared according to synthetic scheme 3.

Step i: 2- (1- (S) - ((Phenylmethoxy) carbonyl) amino-2-phenylethyl) -4- (4-methoxyphenyl) imidazole

Cbz- (L) -Phenylalanine (10.0 g, 33.4 mmol) and Cs ₂ CO ₃ (5.44 g, 16.7 mmol) were mixed in a 2: 1 / DMF: water (75 mL) mixture and the mixture was stirred until a homogeneous mixture was formed. The solvent was removed under reduced pressure and the residue was dissolved in 70 mL of DMF and 243 bromo-3'-methoxy acetophenone (7.65 g, 33.4 mmol) in 30 mL of DMF was added. The mixture was stirred at room temperature for 0.5 h and then concentrated under reduced pressure. The resulting ketoester was dissolved in 150 mL of xylene and CsBr was filtered off. Ammonium acetate (40.0 g, 0.52 mol) was then added and the mixture was heated to reflux for 2 h while removing excess ammonium acetate and water released using an azeotropic adapter. The reaction was cooled and washed with saturated NaHCO ₃ solution (50 mL) and saturated NaCl solution (50 mL). The xylene layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to afford intermediate 18i as a tan solid (13.8 g, 96%). MS: 428.2 (MH ⁺ ).

Step j: 2- (1- (S) -amino-2-phenylethyl) -1- (4- (1,1-dimethylethyloxy) -4-oxobutyl-4- (4-methoxyphenyl) imidazole)

Intermediate 18i (2.14 g, 5.0 mmol) was dissolved in 11.5 mL DMF and KHCO ₃ (1.50 g, 15.0 mmol) and 4-bromo-tert-butyl butyrate (6.69 g) were added. , 30 mmol) in three portions and the mixture was stirred at 50 ° C for 18 h. The mixture was then diluted with ether and washed once with saturated NaHCO ₃ solution and once with saturated NaCl solution. The ether layer was removed, dried over Na ₂ SO ₄ , filtered and concentrated to an oil. Silica gel column chromatography using CH ₂ Cl ₂ as eluent gave the product as an oil.

The crude alkylated product was deprotected by hydrogenation in acetic acid using 10% Pd on carbon as catalyst. The catalyst was then filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in AcOEt and washed with saturated NaHCO ₃ solution and saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated to give intermediate 18j as an oil (450 mg) which was used without subsequent purification.

Step k: 2- (1- (S) - ((Boc-Trp-D-Trp-Lys (Cbz) -Val) -amino-2-phenylethyl) -1 - ((4- (1,1-dimethylethoxy)) -4-oxo) butyl-4- (3-methoxyphenyl) imidazole

Solution synthesis was performed in a manner analogous to that described in Step 1d except that Boc-Trp-OSu was used in place of Fmoc-Tyr (OBzl) -OSu and Fmoc-Tyr (OBzl) OAt was used in place of Fmoc-Val-F to yield intermediate 18k. Yield = 1.03 g (81%).

Step 1: 2- (1- (S) - ((H-Trp-D-Trp-Lys (Cbz) -Val) -amino-2-phenylethyl) -1 - ((4-hydroxy-4-oxo) butyl-4 - (3-methoxyphenyl) imidazole

Intermediate 18k was reacted with a solution containing (i-Pr) ₃ SiH (593 μΐ, 2.90 mmol) in 10 ml Tfa and allowed to react for 1 h. The reaction was concentrated and triturated.

0 · 0 0 * 000 • 0 0 0 0 0 0 • 000 000 0 0 • 0 0 · 0 0 0

With 1: 1 ether: hexane to give intermediate 181 as a tan solid which was used in the next step without subsequent purification. Mass Spec 1267.7 MH ⁺ .

Step f: Cyclo [Trp-D-Trp-Lys (Cbz) -Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole) - (y) Abu]

Intermediate 181 was dissolved in 20 mL of DMF and 4-methylmorpholine (159 µL, 1.45 mmol), HOBt (196 mg, 1.45 mmol) and EDC (278 mg, 1.45 mmol) were added and the reaction was stirred through night. The reaction was concentrated in vacuo and purified by flash chromatography on silica gel using CH ₂ Cl ₂ : MeOH (9: 1) as eluent to afford intermediate 18f. Yield = 220 mg (24%). Mass Spec 1249.7 MH ⁺ .

Step g: Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole) - (y) Abu]

Intermediate 18f (220 mg, 176 pmol) was partially hydrogenated in acetic acid under H ₂ 30 psi pressure at room temperature using 10% Pd on carbon catalyst for 14 h. The catalyst was filtered off and the filtrate was concentrated in vacuo. The crude mixture was purified by preparative HPLC on a C ₁₈ column using a gradient of 0% to 75% CH ₃ CN / 0.1% Tfa over 40 min. Pure product fractions were combined, concentrated, and lyophilized (2 x 10 mL 0.5% HCl, then 1 x 10 mL water) to afford the title compound of Example 18, 72 mg (37%). Mass spectroscopy: 1115.6 MH ⁺ .

Example 19 Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (4-methoxyphenyl) imidazole) -Gly]

Example 19 was prepared according to Scheme 3 in a manner similar to that described in Example 18 with the following differences:

Step j: 2- (1- (S) -amino-2-phenylethyl) -1- (2- (1,1-dimethylethyloxy) -2-oxo-ethyl) -4- (4-methoxyphenylimidazole)

Intermediate 181 (854 mg, 2.0 mmol) was dissolved in 10 mL of DMF and tert-butyl bromoacetate (646 μΐ, 4.0 mmol) and K ₂ CO ₃ (552 mg, 4.0 mmol) were added and the reaction was stirred overnight at room temperature. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with saturated NaCl solution. The ethyl acetate layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give 1.02 g as a foam. Mass Spec 428.2 MH ⁺ . NMR (300 MHz, _DMSO-d6), 7.85-8.0 (IH, d), 7.6-7.75 (2H, d), 7857.95 (IH, s), 7.1- 7.35 (10H, m), 6.9-7.0 (2H, d), 4.75-5.05 (5H, m), 3.7-3.9 (3H, s), 3, 1-3.4 (2H, m), 1.3-1.5 (9H, s).

The white foam of the intermediate (1.02 g, 1.88 mmol) was dissolved in acetic acid (50 mL) containing 10% Pd on carbon (50 mg) and hydrogenated at room temperature under a hydrogen atmosphere (30 psi) for 10 h. The catalyst was then filtered off and 2N HCl (940 μΐ, 1.88 mmol) was added. The mixture was lyophilized once and then lyophilized again with 20% CH ₃ CN / H ₂ O to afford intermediate 19j as a light brown solid (862 mg) which was used without further purification. Mass Spectroscopy: 408.2 MH ⁺ .

Step g: Catalytic hydrogenation and work up similar to Step 18g to give the title compound (22 mg, 4%) as a white solid. Mass Spectroscopy: 1088.2 MH ⁺ .

Example 20 Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (phenyl) imidazole) -Gly]

Example 20 was prepared according to Scheme 3 in a manner similar to that described in Example 18 except that 2-bromoacetophenone was used in place of 2-bromo-3'-methoxyacetophenone in step i. Mass spectroscopy: 1057.4 MH ⁺ .

Example 21 Cycle [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) - (s) Ahx]

Example 21 was prepared according to Scheme 3 in a manner similar to that described in Example 18, with the following differences:

Step j: 2- (1- (S) -Amino-2-phenylethyl) -1- (6- (ethoxy) -6-oxohexyl) -4- (3-methoxyphenyl) imidazole

Intermediate 21i (855 mg, 2.0 mmol) was dissolved in 8.0 mL of DMF and treated with KHCO ₃ (200 mg, 2.0 mmol) and ethyl 6-bromohexanoate (3.56 mL, 20 mmol) 8 h at 120 ° C. The mixture was concentrated and the residue was purified by column chromatography on silica gel using 2: 1 / hexane: EtOAc as eluent to give the pure product as a gum (0.94 g).

The crude alkylated product was deprotected by hydrogenation in acetic acid using 10% Pd on carbon as catalyst. The catalyst was then filtered off and the solvent was evaporated under reduced pressure. The residue was dissolved in dilute HCl, precipitated and lyophilized to give intermediate 21j as a light yellow solid, (720 mg, 91%) which was used in the next step without further purification. MS: 436.2 MH ⁺ .

· · · · · · · · ···· · · · · · · · · · · · · · · · · · · · · · · ·

Step k and step 1: 2- (1- (S) - ((H-Trp-D-Trp-Lys (Boc) -Tyr (OBz1) -2- (1- (S) -amino-2-phenylethyl) - 1 (6- (ethoxy) -6-oxohexyl) -4- (3-methoxyphenyl) imidazole

Fmoc-Tyr (OBzl) -OAt was prepared by stirring Fmoc-Tyr (OBzl) -OH (493 mg, 1.00 mmol), HOAt (136 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) in 8 ml of ethyl acetate for 0.5 h and then filtering out the dicyclohexylurea. The resulting solution was added to a solution of intermediate 2lj (457 mg, 0.9 mmol) in 4 mL of EtOAc, and the mixture was stirred with saturated NaHCO ₃ solution (10 mL) until complete by mass spectrometry. The aqueous layer was removed and the EtOAc layer was dried over Na ₂ SO ₄ , filtered and treated with tris (2-aminoethyl) amine (2.7 mL). The mixture was stirred vigorously for 0.5 h. The ethyl acetate layer was washed with saturated NaCl solution (2 x 60 mL) and then with 10% phosphate buffer adjusted to pH = 5.5 (3 x 15 mL).

The intermediate was sequentially deprotected and capped with Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-Oss and Fmoc-Trp-Oss in a similar manner to that described above for Fmoc-Tyr (OBzl) -OAt cycle. The final Fmoc deprotection yielded an N-terminally deprotected intermediate as the ethyl ester. The ethyl acetate layer was dried over Na ₂ SO ₄ , filtered and diluted with four volumes of hexane. The solvent was cast and the residue was triturated with hexane to give the product as a solid (0.67 g, 58%) which was used without further purification. Mass Spectroscopy:

1289.6 MH ⁺ .

The ethyl ester was removed by reaction of the intermediate in 5 mL of methanol with 1.7 M NaOH (1.7 mL) overnight. The mixture was adjusted to pH = 8.2 with 5% HCl solution and the solvents were removed under reduced pressure. The residue was dissolved in DMF, NaCl was removed by filtration and the DMF solution was used in the next step without further purification.

Cyclization and deprotection were carried out in a manner analogous to Example 18 to give the title compound of Example 21 as a white powder, 62 mg. Mass Spectroscopy:

1143.9 MH ⁺ .

Example 22 Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-hydroxyphenyl) imidazole) - (y) Abu]

Example 22 was prepared according to Scheme 3 in a manner similar to Example 18 with the following differences:

Step j: 2- (1- (S) -Amino-2-phenylethyl) -1- (4- (ethoxy-4-oxobutyl) -4- (4-hydroxyphenyl) imidazole • · · · 9

9 9 9

9 9

9 9 • 99

9 9 99

A »9 ·

Intermediate 22i (2.0 g, 4.68 mmol) was dissolved in 7.0 mL DMF and treated with KHCO ₃ (468 mg, 4.68 mmol) and with ethyl 4-bromobutyrate (6.70 mL, 46, 8 mmol) and the mixture was stirred at 100 ° C for 30 h. The mixture was diluted with ether and washed once with saturated NaHCO 3 solution, and once with saturated NaCl solution. The ether layer was dried over Na ₂ SO ₄ , filtered and concentrated to give an oil. Silica gel column chromatography using dichloromethane as eluent gave the product as an oil (2.53 g, 94%). Mass spectroscopy: 542.3 MH ⁺ .

The crude alkylated product (2.53 g, 4.67 mmol) in 50 mL of dichloromethane was added dropwise over 15 min at -10 ° C to a 1M BBr ₃ / hexane solution (23.4 mL) in 250 mL of dichloromethane. The mixture was allowed to warm to room temperature and stirred for 2 h. Ethanol (40 mL) was then added and the mixture was concentrated to about 50 mL. The solution was diluted with 100 mL of ethanol and allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was distributed between EtOAc and saturated NaHCO ₃ . The ethyl acetate layer was dried over Na ₂ SO ₄ , filtered and concentrated under reduced pressure to give an oil (1.41 g, 76%) which was used for the next reaction without protecting the phenolic group. Mass Spec. 394.3 MH ⁺ .

· · 9

9 9 9

9 9

9 9

9 9

9 *

9

9

HPLC retention time

Example number: HPLC system Retention time (minutes) 1 AND 13.65 2 AND 18.50 3 AND 16.03 4 B 6.97 5 C 20.41 6 C 11.75 7 D 9.53 8 B 11.02 9 E 7.69 10 J 6.02 11 F 4.18 12 G 4.11 13 H 5.50 14 G 6.16 15 AND 17.03 16 TO 9,12 17 J 8.11 18 J 8.86 19 L 6.47 20 M 6.65 21 G 8.14 22 N 12.10

«A

49 • A · A · AAA • A HPLC systems: AND. Gradient: 20-80% CH 3 CN / 0.1% Tfa, 24min. Flow rate: 1.0 mL / min. Detection: 254nm Column: VYDAC® Protein and Peptide Cl8 B. Gradient: 35-50% CH 3 CN / 0.1% Tfa, 24min. Flow rate: 1.0 mL / min. Detection: 254nm Column: VYDAC® Protein and Peptide Cl8 C. Gradient: 32-64% CH 3 CN / 0.1% NH 4 OAC, 24min. Flow rate: 1.0 mL / min. Detection: 254nm Column: VYDAC® Protein and Peptide Cl8 D. Gradient: 20-60% CH 3 CN / 0.1% Tfa, 24min. Flow rate: 1.0 mL / min. Detection: 254nm Column: VYDAC® Protein and Peptide Cl8 E. Gradient: 55-75% CH 3 CN / 0.1% TFA, 24 min. Flow rate: 1.0 mL / min. Detection: 220nm Column: Phenomenex LICHROSPHERE® 5 RP18 (Phenomenex, 2320 W) 205 * St., Torrance, CA) F. Gradient: 60. CH3CN / 0.1% Tfa, isocratic Flow rate: 1.0 mL / min. Detection: 254nm Column: VYDAC® Protein and Peptide C18 G: Gradient: 50% CH 3 CN / 0.1% Tfa, isocratic Flow Rate: 1.0 mL / min. Detection: 254nm Column: VYDAC® Protein and Peptide C18

9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9 · 9

999 9999 99 999 99 9

. Gradient: 38% CH 3 CN / 0.1% Tfa, isocratic Flow rate: 1.0 mL / min.

Detection: 254nm

Column: VYDAC® Protein and Peptide Cl8

I. Gradient: 20-40% CH 3 CN / 0.1% Tfa, 24 min Flow Rate: 1.0 mL / min.

Detection: 254nm

Column: VYDAC® Protein and Peptide C18

J. Gradient: 50% CH 3 CN / 0.1% Tfa, isocratic Flow Rate: 1.0 mL / min.

Detection: 254nm

Column: NUCLEOSIL ™ Cl 8.5 micron (Alltech Associates, 2051,

Waukegan Rd., Deerfield, Illinois

K. Gradient: 40% CH 3 CN / 0.1% Tfa, isocratic Flow Rate: 1.0 mL / min.

Detection: 254nm

Column: NUCLEOSIL ™ C18, 5 micron

L. Gradient: 52% CH 3 CN / 0.1% Tfa, isocratic Flow Rate: 1.0 mL / min.

Detection: 254nm

Column: NUCLEOSIL ™ Cl8, 5 micron

M. Gradient: 50% CH 3 CN / 0.1% Tfa, isocratic Flow Rate: 1.0 mL / min.

Detection: 254nm

Column: NUCLEOSIL ™ Cl8, 5 micron

N. Gradient: 48% CH 3 CN / 0.1% Tfa, isocratic Flow Rate: 1.0 mL / min.

Detection: 254nm

Column: NUCLEOSIL ™ Cl8, 5 micron

; )

Industrial usability

The compounds of this invention are useful in the manufacture of pharmaceutical products useful for treating a variety of somatostatin-related diseases in the body.

Claims (25)

PATENT CLAIMS A compound of formula I or a pharmacologically acceptable salt thereof, wherein Y and Z for each occurrence are each independently D- or L- natural or non-natural amino acid; n is independently 0 to 50 for each occurrence, provided that both n cannot be 0 at the same time; m is 0 or an integer from 1 to 10; a is H or R ¹ ; b is OH, -OR ¹ or -NR ⁹ R ⁹ ; or a together with a b amidic bond; R ¹ is independently H, (C 1 -C ₄ ) alkyl or aryl (C ₁ -C ₄ ) alkyl; R ² is H or an optionally substituted group selected from the group consisting of (C 1 -C 4) alkyl, phenyl, phenyl (C 1 -C 4) alkyl or heterocyclyl (C 1 -C 4) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents each independently selected from the group consisting of (C 1 -C 4) alkyl, (C 3 -C 8) cycloalkyl, -OR ⁶ , -S (O) q R ⁷ , -N (R ⁹ R ⁹ ), -NHCO-R ⁶ , -NHSO ² R ⁹ , -CO ² R ⁹ , -CONR ⁹ R ⁹ and -SO ₂ NR ⁹ R ⁹ , wherein q is 0, 1, 2 or 3; R ³ and R ⁴ are each independently H, halogen or an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl, (C ₃ -C ₈ ) cycloalkyl, aryl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents selected from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, N ( R ⁹ R ⁹ ), -COOH, -CONR ⁹ R ⁹ and halogen; ·· ·· · ·· · 4 4 4 9 9 9 9 9 9 9 4 9 9 4 9 4 4 4 4 9 9 9 4 4 5 Or R ³ and R ⁴ together with the carbons to which they are attached form an optionally substituted aryl, wherein the aryl is optionally substituted with one or more substituents independently selected from the group consisting of OH, (C 1 to C ₄₎ alkyl, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -NR ⁹ R ⁹ , COOR ⁵ , -CONR ⁹ R ⁹ and halogen; R ⁵ at each occurrence is independently H or an optionally substituted group is selected from the group consisting of (C 1 -C ₄ ) alkyl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents, wherein each independently selected from the group consisting of (C 1 -C ₄ ) alkyl, OH, (C ₁ -C ₄ ) alkoxy, aryloxy, NO ₂ , aryl (C 1 -C ₄ ) alkoxy, NR ⁹ R ⁹ , -COOH, -; CONR ⁹ R ⁹ and halogen; R ⁶ at each occurrence is independently selected from the group consisting of H, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryl (C 1 -C ₄ ) alkyl, and aryl (C 1 -C ₄ ) alkoxy, R ⁷ is H when q is 3 or R ⁷ is at each occurrence independently selected from the group consisting of (C ₁ to C ₄ ) alkyl, aryl or aryl (C 1 to C ₄ ) alkyl when q is 0,1 or 2, and R ⁹ at each occurrence is independently selected from the group consisting of H, NO _{2, (C}} to C ₄₎ alkyl, aryl and aryl (C, to C ₄₎ alkyl. A compound of formula II, or a pharmaceutically acceptable salt thereof, wherein Y and Z are each independently D- or L- natural or non-natural amino acids for each occurrence; m is 0 or an integer from 1 to 10; n is independently 0 to 6 for each occurrence, R ¹ at each occurrence is independently H, (C 1 -C ₄ ) alkyl or aryl (C 1 -C ₄ ) alkyl; • 99 ·· 9 99 · 9 9 9 9 9 9 999 999 99 999 99 » 999 9999 99 999 99 999 R ² is H or an optionally substituted group selected from the group consisting of (C 1 to C 4) alkyl, phenyl, phenyl (C 1 to C 4) alkyl or heterocyclyl (C 1 to C 4) alkyl, wherein the optionally substituted group is optionally substituted with one or a plurality of substituents each independently selected from the group consisting of (C 1 to C 4) alkyl, cycloalkyl, -OR ⁶ , -S (O) q R ⁷ , -N (R ⁹ R ⁹ ), -NHCO-R ⁶ , NHSO ² R ⁹ -CO ² R ⁹ , -CONR ⁹ R ⁹ and -SO ₂ NR ⁹ R ⁹ wherein q is 0, 1, 2 or 3; R ³ and R ⁴ are each independently H, halo or an optionally substituted group selected from the group consisting of (C 1 -C ₄ ) alkyl, cycloalkyl, aryl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents selected from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -N (R ⁹ R ⁹ ), COOH, -CONR ⁹ R ⁹ and halogen; or R ³ and R ⁴ together with the carbons to which they are attached form an optionally substituted aryl, wherein the aryl is optionally substituted with one or more substituents each independently selected from the group consisting of OH, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -NR ⁹ R ⁹ , -COOR ⁵ , -CONR ⁹ R ⁹ and halogen; R ⁵ at each occurrence is independently H or an optionally substituted group is selected from the group consisting of (C 1 -C ₄ ) alkyl and aryl (C 1 -C ₄ ) alkyl, wherein the optionally substituted group is optionally substituted with one or more substituents, wherein each is independently selected from the group consisting of (C 1 -C ₄ ) alkyl, OH, (C ₁ -C ₄ ) alkoxy, aryloxy, aryl (C 1 -C ₄ ) alkoxy, -NR ⁹ R ⁹ , -COOR ⁵ , -CONR ⁹ R ⁹ and halogen; R ⁶ is at each occurrence independently selected from the group consisting of H, (C 1 -C ₄ ) alkyl, (C 1 -C ₄ ) alkoxy, aryl (C 1 -C ₄ ) alkyl and aryl (C 1 -C ₄ ) alkoxy , R ⁷ is H when q is 3 or R ⁷ at each occurrence is independently selected from the group consisting of (C 1 -C ₄ ) alkyl, aryl or aryl (C 1 -C ₄ ) alkyl when q is 0, 1 or 2, and R ⁹ is at each occurrence independently selected from the group consisting of H, NO ₂ , (C 1 -C ₄ ) alkyl, aryl and aryl (C 1 -C ₄ ) alkyl. X ¹ is a natural or unnatural D- or La-amino acid, wherein X ¹ is Phe, Nal, Trp, Tyr, Pal or His, the aromatic ring of which is optionally substituted on carbon or nitrogen by R ⁶ or when X ¹ is Ser or Thr the side chain oxygen is optionally substituted with one or more R ¹ ; X ² is D- or L-Trp, N-methyl-1-D-Trp or N-methyl-L-Trp; X ³ is Lys, α-N-methyl-Lys or ε-Ν- (C 1 -C ₄ ) alkyl-Lys or 8-N- [aryl- (C 1 -C ₄ ) alkyl] -Lys; 00 00 ♦ · · 00 0 0 · 0 0 0 0 0 0 0 • 0 0 0 0 0 0 0 • 0 0 0 0 · ♦ · Φ 0 X ⁴ is a natural or unnatural D- or La-amino acid, wherein X ⁴ is Phe, Nal, Trp, Tyr or His, the aromatic ring of which is optionally substituted on carbon or nitrogen substituent ^R8 or when ^X4 is Ser, Thr or Tyr may be oxygen of the side chain substituted with one or more substituents ^R! . A compound of formula II according to claim 2, wherein each n is 2; m is 0 or 1 to 5; R ¹ at each occurrence is independently H, methyl or aryl (C ₁ -C ₄ ) alkyl; R ² is an optionally substituted group selected from the group consisting of phenyl- (C 1 to C ₄ ) alkyl, and heterocyclyl- (C 1 to C ₄ ) alkyl, wherein the optionally substituted group is substituted with a substituent selected from the group consisting of (C 1 to C ₄₎ ) alkyl and -OR ^6a ; R ³ and R ⁴ are each independently H, halogen or an optionally substituted group selected from the group consisting of (C 1 to C ₄ ) alkyl and aryl, wherein the optionally substituted group is optionally substituted with a substituent selected from the group consisting of OH, (C 1 to C) ₄ ) alkoxy, aryloxy and halo. A compound of formula II according to claim 3, wherein X 'is Phe, Nal, Trp, Tyr, Pal or His, wherein the aromatic ring is optionally substituted on carbon or nitrogen with R ⁶ , and X ⁴ is Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, wherein the aromatic ring in Nal, Trp, Tyr and His is optionally substituted on carbon and / or nitrogen with R ⁸ or when X ⁴ is Ser, Tyr or Thr, the oxygen in their side chain is optionally substituted with R ¹ . A compound of formula II according to claim 4, wherein X ¹ is Phe, Trp or Tyr, the aromatic ring of which is optionally substituted on carbon or nitrogen by R ⁶ , X ² is D-Trp or N-methyl-D-Trp, X ³ is Lys or α-N-methyl-Lys, X ⁴ is Val, Thr, Abu, Nal or Tyr, wherein the oxygen in the hydroxyl group of the side chain of Thr and Tyr is optionally substituted with R ¹ ; R ¹ for each occurrence is independently H, methyl or benzyl; • «· ·· · 44 4 4 9 4 49 4 9 4 4 4 4 4 5 4 9 4 4 4 4 4 4 4 5 4 4 4 9 4 449 4444 44 444 44 444 R ² is an optionally substituted group selected from the group consisting of phenylmethyl and heterocyclylmethyl, wherein the optionally substituted group is substituted with a substituent selected from the group consisting of (C 1 to C ₄ ) alkyl and -OR ⁶ ; R ³ is (C 1 -C ₄ ) alkyl or optionally substituted aryl, wherein the optionally substituted aryl is substituted with a substituent selected from the group consisting of OH, (C 1 -C ₄ ) alkoxy, aryloxy and halogen; R ^{4 is} H, and R ⁶ for each occurrence is independently selected from the group consisting of H and aryl (C 1 -C ₄ ) alkoxy. A compound of formula II according to claim 5, wherein X 1 is Phe, Trp, Tyr or Tyr (Obzl); X ⁴ is Val, Thr, Abu, Nal or Tyr, wherein the hydroxy of Thr and Tyr is optionally substituted with benzyl; m is 0, 2 or 4; R ² is an optionally substituted group selected from the group consisting of phenylmethyl or 3-indolylmethyl, wherein the optionally substituted group is optionally substituted with -OR ⁶ ; and R ³ is 1,1-dimethylethyl or optionally substituted aryl, wherein the optionally substituted aryl is optionally substituted with a group selected from the group consisting of OH, (C 1 -C ₄ ) alkoxy and halogen. A compound of formula II according to claim 6, wherein R ² is phenylmethyl; R ³ is 1,1-dimethylethyl or optionally substituted phenyl, wherein optionally substituted phenyl is optionally substituted with OH or OCH _3, and R ⁶ for each occurrence is independently selected from the group consisting of H or benzylmethoxy. A compound of formula I according to claim 1, wherein said compound is H-Trp-D-Trp-Lys-Abu-Phe (4- (3-methoxyphenyl) imidazole) -Gly-OH. A compound of formula I according to claim 7, wherein said compound is cyclo [Tyr-D-Trp-Lys-Val-Phe 2 - (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Tyr (OBzl) -D -Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], • 0 0 · • 0 0 0 0 0 0 0 0 00 Cyclo [Trp-D-Trp-Lys-Val- PheΨ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Val-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D- Trp-Lys-Thr (OBzl) -Phe- (4- (3-methoxyphenyl) imidazole) -Glyj, cyclo [Trp-D-Trp-Lys-Thr-Phe- (4- (3-hydroxyphenyl) imidazole) -Gly ], cyclo [Trp-D-Trp-Lys-Abu-Phee (4- (3-methoxyphenyl) imidazole) -Gly), cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -PheΨ (4- (1,1-dimethylethyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Val-Phe (4- (3-methoxyphenyl) imidazole-Gly), cyclo [Phe-D-Trp-Lys-Tyr] (OBzl) -Phe 4- (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Tyr-Phe Ψ (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe- D-Trp-Lys-Tyr-Phe - (4- (3-hydroxyphenyl) imidazole-Gly), cyclo [Trp-D-Trp-lys-Tyr (Bzl) -Phe - (4- (3-methoxyphenyl) imidazole-Gly), cyclo [Tyr-D-Trp-Lys-Val-Phee (4- (3-hydroxyphenyl) imidazole-Gly]), cyclo [Phe-D-Trp-Lys-Nal-PheΨ (4- (3-hydroxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe] (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (OBzl) ) -Phe- (4- (3-methoxyphenyl) imidazole (s) Abu), cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe- (4- (4-methoxyphenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe (4- (phenyl) imidazole-Gly]), cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe (4- (3-)) methoxyphenyl) imidazole- (c) Ahx] or cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe- (4- (3-hydroxyphenyl) imidazole- (s) Abu). A compound of formula I according to claim 9, wherein said compound is cyclo [Tyr-D-Trp-Lys-Val-Phe 2 - (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Tyr (OBzl) -D -Trp-Lys-Val-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly, cyclo [Trp-D-Trp-Lys-Val-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Val-Phe (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr (OBzl) -Phe (4- (3 -methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr-Phe [4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-Phe] Ψ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (1,1-dimethylethyl) imidazole-Gly], cyclo [Phe -D-Trp-Lys-Val-Phe - (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Tyr-Phe - (4- (3-hydroxyphenyl) imidazole-Gly]) or 9 99 9 9 9 9 9 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 3-hydroxyphenyl) imidazole-Gly]. A compound of formula I according to claim 10, wherein said compound is cyclo [Tyr-D-Trp-Lys-Val-Phe 2 - (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp- Lys-Val-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Val-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [ Trp-D-Trp-Lys-Thr-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-PheΨ (4- (3-methoxyphenyl) imidazole)) -Gly], cyclo [Phe-D-Lys-Val-Phe - (4- (3-methoxyphenyl) imidazole-Gly]) or cyclo [Tyr-D-Trp-Lys-Val-Phe - (4- (3-hydroxyphenyl) ) imidazole-Gly]. A compound of formula I according to claim 11, wherein said compound is cyclo [Tyr-D-Trp-Lys-Val-Phe 2 - (4- (3-methoxyphenyl) imidazole) -Glyj, cyclo [Trp-D-Lys-Val] -Phe- (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr-Phe- (4- (3-hydroxyphenyl) imidazole) -Gly] and cyclo [Tyr-D] -Trp-Lys-Val-Phe - (4- (3-hydroxyphenyl) imidazole) -Gly]. A compound of formula I according to claim 9, wherein said compound is cyclo [Tyr-D-Trp-Lys-Val-Phe 2 - (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp- Lys-Val-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Val-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [ Trp-D-Trp-Lys-Thr (OBzl) -Phe- (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr-PheΨ (4- (3-hydroxyphenyl) (imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Abu-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) - PheΨ (4- (1,1-dimethylethyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -PheΨ- (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe] -D-Trp-Lys-Tyr-Phe - (4- (3-hydroxyphenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe - (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Tyr-D-Trp-Lys-Val-Phe 1 - (4- (3-hydroxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe 1 - (4- (3 -hydroxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe] (4- (3-methoxyphenyl) imidazole-Gly]) Cyclo (Trp-D-Trp-Lys-Tyr (Bzl) -Phe) (4- (3-methoxyphenyl) imidazole) - (y) Abu], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe-4- (4-methoxyphenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) ) -Phe- (4- (phenyl) imidazole-Gly], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole- (s) Ahx) or cyclo [ Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-hydroxyphenyl) imidazole (s) Abu). A compound of formula I according to claim 13, wherein said compound is cyclo [Trp-D-Trp-Lys-Thr-Phe 2 - (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp- Lys-Tyr (Bzl) -Phe - (4- (3-methoxyphenyl) imidazole-Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe - (4- (3-hydroxyphenyl) imidazole-Glyj), cyclo [ Trp-D-Trp-Lys-Tyr (Bzl) -Phe (4- (3-methoxyphenyl) imidazole- (s)) Abuj, cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe (4-) (4-methoxyphenyl) imidazole-Glyj or cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (phenyl) imidazole-Gly]). A compound of formula I according to claim 14, wherein said compound is cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole-Gly]), cyclo [Trp-D- Trp-Lys-Tyr (Bzl) -Phe- (4- (3-methoxyphenyl) imidazole- (s) Abuj, cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe) (4- (4-methoxyphenyl) imidazole-Gly] or cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe- (4- (phenyl) imidazole-Glyj. 16. A pharmaceutical composition comprising an effective amount of a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 17. A pharmaceutical composition comprising an effective amount of a compound of claim 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 18. A method of eliciting a somatostatin receptor agonist effect in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of claim 1 or a pharmaceutically acceptable salt thereof. ft ft ft 9 ft ft ft ft ft e e ft ft ft A A ft ft ·· ··· ·· ft ·· 19. A method of eliciting a somatostatin receptor agonist effect in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 2 or a pharmaceutically acceptable salt thereof. 20. A method of eliciting a somatostatin receptor antagonist effect in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound according to claim 1 or a pharmaceutically acceptable salt thereof. 21. A method of eliciting a somatostatin receptor antagonist effect in a mammal in need thereof, comprising administering to said mammal an effective amount of a compound of claim 2 or a pharmaceutically acceptable salt thereof. 22. A method of treating prolactin secreting adenomas of restenosis, diabetes mellitus, hyperlipidemia, insensitivity to insulin, Syndrome X, angiopathia, proliferative retinopathy, dawns syndrome, neuropathy, gastric acid secretion, peptic ulcers, enterocutaneous and pancreaticocutromic pustules, watery diarrhea syndrome, AIDS-induced diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, hormone-secreting gastrointestinal tumors, cancer, hepatoma, angiogenesis, inflammatory diseases, arthritis, chronic graft rejection, angioplasty, bleeding from graft vascular bleeding or graft vascular bleeding, characterized in that said mammal is administered with a compound of claim 1 or a pharmaceutically acceptable salt thereof. 23. A method of treating prolactin secreting adenomas of restenosis, diabetes mellitus, hyperlipidemia, insensitivity to insulin, syndrome X, angiopathia, proliferative retinopathy, dawns syndrome, neuropathy, gastric acid secretion, peptic ulcers, enterocutaneous and pancreaticocutromic stroke, pustreaticocutaneous pustules, watery diarrhea syndrome, AIDS-induced diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, hormone-secreting gastrointestinal tumors, cancer, hepatoma, angiogenesis, inflammatory diseases, arthritis, chronic graft rejection, angioplasty, bleeding from graft vascular bleeding or graft vascular bleeding, characterized in that said mammal is administered with a compound according to claim 2 or a pharmaceutically acceptable salt thereof. 24. A method of inhibiting helicobacter pylori proliferation in a mammal, comprising administering to said mammal the compound of claim 1 or a pharmaceutically acceptable salt thereof. 25. A method of inhibiting helicobacter pylori proliferation in a mammal, comprising administering to said mammal the compound of claim 2 or a pharmaceutically acceptable salt thereof.