JP2002518409A - Cyclic somatostatin analog - Google Patents

Abstract

  (57) [Summary] The present invention can be treated by cyclic derivatives containing mimics of imidazole cis amide linkages that selectively bind to the somatostatin receptor subtype, and by eliciting an agonistic or antagonistic effect from the somatostatin subtype receptor It is directed to its use in treating conditions. The present invention is also directed to a method for making the compounds of the present invention.

Description

DETAILED DESCRIPTION OF THE INVENTION

BACKGROUND OF THE INVENTION The present invention is directed to cyclic derivatives containing mimics of imidazole cis amide bonds that selectively bind to the somatostatin receptor subtype.
The present invention is also directed to a method for making the compounds of the present invention.

[0002] Somatostatin (SRIF) is a cyclic tetradecapeptide hormone containing a disulfide bond between positions 3 and 14, inhibiting the release of growth hormone (GH) and thyroid stimulating hormone (TSH), And has the property of inhibiting the release of glucagon and reducing gastric acid secretion. The action time of somatostatin is short because it is metabolized by aminopeptidase and carboxypeptidase.

[0003] Somatostatin binds with relatively high affinity for each of the five distinct receptor (SSTR) subtypes. Smaller and more stringent analogs of the present invention show high selectivity for some of this receptor subtype. Binding to different types of somatostatin subtypes has been associated with the treatment of the following conditions and / or diseases. Activation of types 2 and 5 is associated with suppression of growth hormone and, more particularly, GH-secreting adenomas (acromegaly) and TSH-secreting adenomas. Activating type 2 but not type 5 has been associated with treatment of prolactin-secreting adenomas. Other indications related to the activation of the somatostatin subtype are restenosis, inhibition of insulin and / or glucagon, more specifically diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular injury, proliferative Retinal disorders, dawn phenomenon, and renal disorders; inhibition of gastric acid secretion, more specifically peptic ulcer, intestinal and pancreatic fistula, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, AIDS-related diarrhea, Chemotherapy-induced diarrhea, acute or chronic pancreatitis, and gastrointestinal hormone-secreting tumors; treatment of cancer such as hepatoma; inhibition of angiogenesis; treatment of inflammatory disorders such as arthritis; chronic transplant rejection Angiogenesis; prevention of vascular and gastrointestinal bleeding. Somatostatin agonists can also be used to reduce the weight of a patient.

[0004] Somatostatin agonists have been disclosed to be useful in inhibiting the growth of helicobacter pylori. SUMMARY OF THE INVENTION In one aspect, the invention provides a compound of formula (I), or a pharmaceutically acceptable salt thereof.

[0005]

Embedded image

Wherein Y and Z are each independently occurrence of D- or L-natural or unnatural α-
N is independently from 0 to 50 at each occurrence (provided that both n are 0 at the same time)
M is 0 or an integer of 1 to 10; a is H or R¹B is OH, -OR¹Or -NR⁹R⁹Or a forms an amide bond with b; R¹Are independently H, (C₁-C_Four) Alkyl or aryl- (C₁-C_Four) Alkyl
R^TwoIs H or (C₁-C_Four) Alkyl, phenyl, phenyl- (C₁-C _Four ) Alkyl and heterocyclyl- (C₁-C_Four) Selected from the group consisting of alkyl
And optionally substituted components, wherein the optionally substituted components are (
C₁-C_Four) Alkyl, (C_Three-C₈) Cycloalkyl, -OR⁶, -S (O)_q−
R⁷, -N (R⁹R⁹), -NHCO-R⁶, -NHSO_TwoR⁹, -CO_TwoR⁹, -CO
NR⁹R⁹, And -SO_TwoNR⁹R⁹(Where q is 0, 1, 2 or 3)
By one or more substituents each independently selected from the group
R^ThreeAnd R^FourIs independently H, halo, or (C₁-C_Four) Alkyl, (C_Three
-C₈) Cycloalkyl, aryl and aryl- (C₁-C_Four) From alkyl
Optionally substituted components selected from the group consisting of:
OH, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, ally
Ruoxy, aryl- (C₁-C_Four) Alkoxy, -NR⁹R⁹, COOH, -CO
NR⁹R⁹And one or more substituents selected from the group consisting of
Optionally substituted; or R^ThreeAnd R^FourTogether with the carbon to which they are attached
To form an optionally substituted aryl, wherein the aryl is OH, (C₁
-C_Four) Alkyl, (C₁-C_Four) Alkoxy, aryloxy, aryl- (C₁ -C_Four) Alkoxy, -NR⁹R⁹, COOR^Five, -CONR⁹R⁹And halo
Optionally by one or more substituents each independently selected from the group
R is substituted^FiveIs independently at each occurrence H or (C₁-C_Four) Alkyl and aryl
− (C₁-C_Four) An optionally substituted component selected from the group consisting of alkyl
Wherein the optionally substituted component is (C₁-C_Four) Alkyl, OH, (
C₁-C_Four) Alkoxy, aryloxy, NO_Two, Aryl- (C₁-C_Four) Al
Coxy, -NR⁹R⁹, COOH, -CONR⁹R⁹And halo
R optionally substituted with one or more independently selected substituents; R⁶Is H, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, a
Reel-(C₁-C_Four) Alkyl and aryl- (C₁-C_Four) Consisting of alkoxy
Independently selected from the group; R⁷Is H when q is 3 or R⁷Is that q is 0, 1
Or 2, (C₁-C_Four) Alkyl, aryl or aryl- (C₁-C_Four R) is independently selected from the group consisting of alkyl;⁹Is H, NO for each occurrence_Two, (C₁-C_Four) Alkyl, aryl and aryl
− (C₁-C_Four) Is independently selected from the group consisting of alkyl.

A preferred compound of formula (I) is the compound H-Trp-D-Trp-Lys-A
bu-Phe {(4- (3-methoxyphenyl) imidazole) -Gly-OH
It is.

[0008] In another aspect, the invention provides a compound of formula (II), or a pharmaceutically acceptable salt thereof.

[0009]

Embedded image

Wherein Y and Z are each independently for each occurrence a D- or L-natural or unnatural α-
M is 0 or an integer from 1 to 10; n is independently from 0 to 6 at each occurrence; R¹Is independently H, (C₁-C_Four) Alkyl or aryl- (C₁-C _Four R) is alkyl;^TwoIs H or (C₁-C_Four) Alkyl, phenyl, phenyl- (C₁-C _Four ) Alkyl and heterocyclyl- (C₁-C_Four) Selected from the group consisting of alkyl
And optionally substituted components, wherein the optionally substituted components are (
C₁-C_Four) Alkyl, cycloalkyl, -OR⁶, -S (O)_q-R⁷, -N (
R⁹R⁹), -NHCO-R⁶, -NHSO_TwoR⁹, -CO_TwoR⁹, -CONR⁹R⁹,
And -SO_TwoNR⁹R⁹(Where q is 0, 1, 2, or 3)
Optionally substituted by one or more independently selected substituents
R^ThreeAnd R^FourIs independently H, halo, or (C₁-C_Four) Alkyl, cyclo
Alkyl, aryl and aryl- (C₁-C_Four) Selected from the group consisting of alkyl
Component that is optionally substituted; wherein the optionally substituted component is
OH, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, aryloxy, ant
-(C₁-C_Four) Alkoxy, -NR⁹R⁹, COOH, -CONR⁹R⁹And c
Optionally substituted by one or more substituents selected from the group consisting of
Or R^ThreeAnd R^FourTogether with the carbon to which they are attached
Form a substituted aryl, wherein the aryl is OH, (C₁-C_Four) Alkyl
, (C₁-C_Four) Alkoxy, aryloxy, aryl- (C₁-C_Four) Alkoki
Si, -NR⁹R⁹, COOR^Five, -CONR⁹R⁹And from the group consisting of halo
R optionally substituted with one or more independently selected substituents;^FiveIs independently at each occurrence H or (C₁-C_Four) Alkyl and aryl
− (C₁-C_Four) An optionally substituted component selected from the group consisting of alkyl
Wherein the optionally substituted component is (C₁-C_Four) Alkyl, OH, (
C₁-C_Four) Alkoxy, aryloxy, NO_Two, Aryl- (C₁-C_Four) Al
Coxy, -NR⁹R⁹, COOH, -CONR⁹R⁹And halo
R optionally substituted with one or more independently selected substituents; R⁶Is H, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, a
Reel-(C₁-C_Four) Alkyl and aryl- (C₁-C_Four) Consisting of alkoxy
Independently selected from the group; R⁷Is H when q is 3 or R⁷Is that q is 0, 1
Or 2, (C₁-C_Four) Alkyl, aryl or aryl- (C₁-C_Four R) is independently selected from the group consisting of alkyl;⁹Is H, NO for each occurrence_Two, (C₁-C_Four) Alkyl, aryl and aryl
− (C₁-C_Four) Is independently selected from the group consisting of alkyl. X¹Is a natural or unnatural D- or L-α-amino acid, where X¹Is Phe,
When Nal, Trp, Tyr, Pal or His, the aromatic ring is carbon or
R on nitrogen⁶Or optionally substituted by X¹Is Ser or Thr
And optionally the side chain oxygen may have one or more R¹X^TwoIs D- or L-Trp, N-methyl-D-Trp or N-methyl-L-Tr
p; X^ThreeIs Lys, α-N-methyl-Lys or ε-N- (C₁-C_Four) Alkyl-L
ys or ε-N- [aryl- (C₁-C_Four) Alkyl] -Lys; X^FourIs a natural or unnatural D- or L-α-amino acid, where X^FourIs Phe,
When Nal, Trp, Tyr or His, the aromatic ring is on carbon or nitrogen
R⁸Or optionally substituted by X^FourIs Ser, Tyr or Thr
And the side chain oxygen has one or more R¹Can be replaced by

The bond between X ¹ , X ² , X ³ and X ⁴ is an amide bond, X ¹ and Z, and X ⁴ and Y
Is the same. In a preferred group of compounds of formula (II), designated group A, n is 2 each; m is 0 or 1-5; R ¹ is independently at each occurrence H, methyl or aryl - (C ₁ -C ₄₎ is alkyl; R ² is phenyl - (C ₁ -C ₄₎ alkyl and heterocyclyl - is selected from (C ₁ -C ₄₎ group consisting of alkyl, optionally substituted is that component, components which are replaced by this case, (C ₁ -C ₄₎ substituted by a substituent selected from the group consisting of alkyl and -O-R ^6; R ³ and R ⁴ are each independently And optionally substituted components selected from the group consisting of H, halo, or (C ₁ -C ₄ ) alkyl and aryl; wherein the optionally substituted components are OH, (C _1- C ₄₎ alkoxy, or aryloxy, and halo Optionally substituted by a substituent selected from the group consisting of.

In a preferred group of Group A compounds, designated Group B, X ¹ is Phe, Nal, Trp, Tyr, Pal or His whose aromatic ring is optionally substituted on carbon or nitrogen by R ⁶ . X ⁴ is Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, wherein the aromatic ring of Nal, Trp, Tyr and His is optionally substituted on carbon and / or nitrogen by R ⁸ ; Or X ⁴ is Ser, Tyr or Thr
Wherein the side chain oxygen is optionally replaced by R ¹ .

[0013] In a preferred group of the group B compounds, designated group C, X ¹ is Phe, Trp or Tyr, wherein the aromatic ring is optionally substituted with R ⁶ on carbon or nitrogen; X ² is be a D-Trp or N- methyl -D-Trp; X ³ is an Lys or alpha-N- methyl -Lys; X ⁴ is Val, Thr, Abu, a Nal or Tyr, wherein Thr and T
side chain oxygen of the hydroxy groups of yr is optionally substituted with R ^1; R ¹ is independently at each occurrence H, methyl or benzyl; R ² is selected from the group consisting of phenylmethyl and heterocyclyl methyl R ³ is optionally substituted, wherein the optionally selected component is substituted by a substituent selected from the group consisting of (C ₁ -C ₄ ) alkyl and —O—R ⁶ ; C ₁ -C ₄₎ alkyl, or an optionally substituted aryl, aryl substituted by such a case, selection OH, from the group consisting of (C ₁ -C ₄₎ alkoxy, aryloxy and halo and the replaced by a substituent; R ⁴ is H; and R ^6, H and aryl in each occurrence - is independently selected from the group consisting of (C ₁ -C ₄₎ alkoxy.

In a preferred group of Group C compounds, designated Group D, X ¹ is Phe, Trp, Tyr or Tyr (OBzl); X ⁴ is Val, Thr, Abu, Nal or Tyr, Thr and T
m is 0, 2 or 4; and R ² is an optionally substituted moiety selected from the group consisting of phenylmethyl or 3-indolylmethyl. And the component selected in this case is -OR ⁶
And R ³ is 1,1-dimethylethyl or an optionally substituted aryl, wherein the optionally substituted aryl is OH, (C ₁ -C ₄ ) alkoxy and Optionally substituted by a component selected from the group consisting of halo.

In a preferred group of compounds of the group D, designated group E, R ² is phenylmethyl; R ³ is 1,1-dimethylethyl or optionally substituted phenyl, wherein Is optionally substituted by OH or OCH ₃ ; and R ⁶ is at each occurrence independently selected from the group consisting of H or benzylmethoxy.

[0016] A preferred group of Group E compounds designated as Group F are cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Tyr (OBzl ) -D-Trp-Lys-Val-PheΨ (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) 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 {(4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (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) -PheΨ (4- (
3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr-Phe} (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} (4- (3-hydroxyphenyl) imidazole) -Gly], 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) -PheΨ (4- (
3-methoxyphenyl) imidazole)-(γ) 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)-(ε) Ahx] and cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
3-hydroxyphenyl) imidazole)-([gamma]) Abu].

A preferred group of Group F compounds designated as Group G are cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Tyr (OBzl ) -D-Trp-Lys-Val-PheΨ (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) 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 {(4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (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] and cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly].

Preferred groups of Group G compounds designated as Group H include cyclo [Tyr-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) 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-Val-Phe} (4- (3-meth (Xyphenyl) imidazole) -Gly] or cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly].

Preferred groups of Group H compounds, designated Group I, include cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Trp-D -Trp-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].

Another preferred group of Group F compounds, designated Group 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) -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 {(4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
1,1-dimethylethyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Tyr] (Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole) -Gly], cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly], 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 (Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole)-(γ) 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) -PheΨ (4- (3
-Methoxyphenyl) imidazole)-(ε) Ahx] and cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (3
-Hydroxyphenyl) imidazole)-(γ) Abu].

[0021] A preferred group of Group J compounds designated as Group K are cyclo [Trp-D-Trp-Lys-Thr-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D −Trp-Lys-Tyr (Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Nal-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Tyr ( Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole)-(γ) Abu], 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) -Gly].

A preferred group of Group K compounds, designated Group L, 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)-(γ) Abu], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (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 medicament comprising an effective amount of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. A composition is provided.

In yet another aspect, the invention provides a method of eliciting a somatostatin receptor agonist in a mammal in need thereof, comprising a compound of formula (I) or (II) Or administering an effective amount of a pharmaceutically acceptable salt thereof to said mammal.

In yet another aspect, the invention provides a method of eliciting a somatostatin receptor antagonist in a mammal in need thereof, comprising a compound of formula (I) or (II) Or administering an effective amount of a pharmaceutically acceptable salt thereof to said mammal.

In another aspect, the present invention provides a method for treating prolactin-secreting adenoma restenosis, diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular injury, proliferative retinopathy, dawn phenomenon, nephropathy, gastric acid Secretion, peptic ulcer, intestinal and pancreatic fistula, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, AIDS-related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormones A method of treating a secretory tumor, cancer, hepatoma, angiogenesis, inflammatory disorder, arthritis, chronic graft rejection, angiogenesis, transplanted vascular or gastrointestinal bleeding in a mammal in need thereof, said method. Comprises administering to said mammal a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof.

[0027] In another aspect, the present invention provides a method for preparing a helicobacter from a mammal in need thereof.
Provided is a method of inhibiting the growth of pylori, the method comprising administering to the mammal a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof.

In another aspect, the invention provides a method of making a compound of the formula:

[0029]

Embedded image

The method comprises deprotecting a compound of the formula by cleaving a Prt group.

[0031]

Embedded image

Wherein Prt is a protecting group for the amino acid side chain; Y and Z are each independently a D- or L-natural or unnatural α-amino acid, wherein the protected side chain is Wherein HN ^* is the amino group of the N-terminal amino acid defined by Y, and O = C ^* is the carboxyl group of the C-terminal amino acid defined by Z; n is independent at each occurrence All other variables are as defined for formula (I) above.

In another aspect, the present invention provides a method for making a compound of the formula:

[0034]

Embedded image

The method comprises:

[0036]

Embedded image

For the compound of formula (a), the compound of formula (a ′) is reacted with a peptide coupling reagent and an additive to define the terminal amino group of the final amino acid defined by Y and Z Forming an amide bond with the terminal carboxyl group of the final amino acid; or, for compounds of formula (b), reacting the compound of formula (b ′) with a peptide coupling reagent and additives to form a terminal amino acid. Forming an amide bond between the group and the terminal carboxyl group of the final amino acid defined by Z; or for compounds of formula (c), the compound of formula (c ') is combined with a peptide coupling reagent and an additive. Reacting to form an amide bond between the terminal amino group and the terminal carboxyl group of the final amino acid defined by Y Wherein Prt is a protecting group for the amino acid side chain; and Y and Z are each independently a D- or L-natural or unnatural α-amino acid, optionally protecting the protected side chain. Wherein H-N ^* is the amino group of the N-terminal amino acid defined by Y, and O = C ^* is the carboxyl group of the C-terminal amino acid defined by Z; All other variables are as defined for formula (I) above.

In yet another aspect, the invention provides a method of making a compound of the formula:

[0039]

Embedded image

The above method comprises reacting a compound of the following formula in the presence of a base and a polar aprotic solvent until the reaction is substantially complete, with an α of the formula X′—CH (R ³ ) CO (R ⁴ ) Reacting with a haloketone;

[0041]

Embedded image

Evaporating the polar aprotic solvent to obtain a solid; dissolving the solid in an aprotic organic solvent and excess aqueous NH ₄ OAc to form a solution; and refluxing the solution and simultaneously forming the polar layer Wherein X is an amine protecting group; X 'is halo; all other variables are as defined for formula (I) as set forth above. It is on the street.

In yet another aspect, the present invention provides a method for making a compound of formula (I),

[0044]

Embedded image

The above method comprises reacting a compound of formula (B) with a Nα-protected amino acid, (Prt) -Y ( here,
The Nα-protected amino acid is in its activated ester, anhydride or acid halide form).

[0046]

Embedded image

[0047]

Embedded image

Optionally, deprotecting the amino group of the Nα-protected amino acid, (Prt) -Y, using conventional deprotection reactions, and obtaining the desired compound of formula (I) Y is independently a D- or L-natural or unnatural α-amino acid at each occurrence and optionally a protecting group. Rrt is an alkyl ester or benzyl ester; n is 1 to 100; all other variables are relative to formula (I) shown above. As defined.

In another aspect, the present invention provides a process for preparing a compound of formula (I) as defined above, said process comprising the step of preparing an active ester, anhydride or acid halide thereof. Reacting the compound of formula (B) with a N-deprotected peptide resin (A ′) prepared by methods well known to those skilled in the art of peptide synthesis, piperidine / DMF, TAEA or N-terminal Fm using similar bases
deprotecting the oc group, and using a strong acid to deprotect the resulting intermediate (B ') and cleave it from the resin. All other variables are the same as shown above (
As defined for I).

[0050]

Embedded image

In another aspect, the present invention provides a method for making a compound of formula (I),
The method comprises the steps of: converting a compound of formula (B), activated as its active ester, anhydride or acid halide, to an N-deprotected peptide prepared by methods well known to those skilled in peptide synthesis. Reacting with resin (H), piperidine / D
Deprotecting the N-terminal Fmoc group using MF, TAEA or a similar base, freeing the N-terminal Fmoc group using peptide coupling reactions familiar to those skilled in the art. Acylating the amino group with a Nα-Fmoc protected amino acid (X), repeating the base deprotection and coupling steps required to incorporate additional amino acids (X), and using strong acids And deprotecting the resulting intermediate (C ′) to cleave it from the resin. All other variables are as defined for formula (I) above.

[0052]

Embedded image

In another aspect, the present invention provides a method for making a compound of formula (I),
Said method comprises reacting a compound of formula (B) activated as its active ester, anhydride or acid halide with a tris- (alkoxy) -benzylamine resin (PAL
Resin), coupling to an amino-substituted resin such as 4- (2 ′, 4′-dimethoxyphenyl-aminomethyl) -phenoxy resin (N-deprotected Rink resin) or benzhydrylamine resin, piperidine / DMF Deprotection of the N-terminal Fmoc group using TAEA, TAEA or similar base, freed N-terminal amino acid using peptide coupling reactions well known to those skilled in the art. Acylating the group with an Nα-Fmoc protected amino acid (X), repeating the base deprotection and coupling steps required to incorporate an additional amino acid (X), and using a strong acid Deprotecting the resulting intermediate (D ') and cleaving it from the resin, all other variables being of the formula (I) shown above.
As defined above.

[0054]

Embedded image

In another aspect, the present invention provides a method for making a compound of formula (I),
The method comprises reacting a compound of formula (B) with a base such as Cs ₂ CO ₃ and reacting the resulting phenolic cesium salt (E ′) with a halomethylated polystyrene resin such as a Merrifield peptide resin. Removal of the Fmoc protecting group using piperidine or a similar organic base, and removal of the free N-terminal amino group using a peptide coupling reaction well known to those skilled in the art. Acylating with Nα-Fmoc protected amino acids (X), repeating the steps of base deprotection and coupling required to incorporate additional amino acids (X), piperidine or similar organic bases Using the N-terminus and using Tfa
Deprotection of the terminally protected peptide sequence at the terminus, using a peptide coupling reaction well known to those skilled in the art, the resulting intermediate (F ′)
) And cleaving the resulting intermediate (G ') from the resin using a strong acid. All variables are as defined for formula (I) above.

[0056]

Embedded image

In another aspect, the present invention provides a process for preparing a compound of formula (I) as defined above, said process comprising the step of preparing an active ester, anhydride or acid halide thereof. Coupling the compound of formula (B) with an N-deprotected peptide resin (A ′) prepared by methods well known to those skilled in the art, using Tfa Deprotecting the N-terminal Boc group and HF
And deprotection of the side chain protecting groups of the resulting intermediate (H ') from the resin using a strong acid such as All variables are as defined for formula (I) above.

[0058]

Embedded image

In another aspect, the present invention provides a method for making a compound of formula (I),
Said method comprises reacting a compound of formula (B) activated as its active ester, anhydride or acid halide with an N-deprotected compound prepared by methods well known to those skilled in the art. Coupling with the peptide resin (H), deprotection of the N-terminal Boc group using Tfa, free peptide coupling using well-known peptide coupling reactions familiar to those skilled in the art. Acylation of the resulting N-terminal amino group with a Nα-Boc protected amino acid (X), an additional amino acid (
X) repeating the steps of Tfa deprotection and coupling required to incorporate, and deprotecting the resulting intermediate (I ') and cleaving it from the resin using a strong acid including. All variables are as defined for formula (I) above.

[0060]

Embedded image

In another aspect, the present invention provides a method for making a compound of formula (I),
The method comprises reacting a compound of formula (B) with a base such as Cs ₂ CO ₃ and reacting the resulting phenolic cesium salt (J ′) with a halomethylated polystyrene resin such as a Merrifield peptide resin. Removal of the Boc protecting group with Tfa, Nα-Boc protection of the free N-terminal amino group using a peptide coupling reaction well known to those skilled in the art. Acylating with amino acid (X), repeating the steps of base deprotection and coupling required to incorporate additional amino acid (X), N-terminal with Tfa, and LiOH / aqueous Deprotection of the C-terminally protected peptide sequence using an inorganic base such as DMF base, a peptide coupling well known to those skilled in the art. Use grayed reaction, the resulting intermediate (K ') to cyclization, and using a strong acid, the resulting intermediate (L' comprises cleaving the) from the resin. All variables are as defined for formula (I) above.

[0062]

Embedded image

In another aspect, the present invention provides a method for making a compound of formula (I),
Said method comprises reacting a compound of formula (B) activated as its active ester, anhydride or acid halide with an N-deprotected compound prepared by methods well known to those skilled in the art. Peptide, 4-nitrobenzophenone oxime resin (M '
), Deprotection of the N-terminal Boc group using Tfa, and freed N Nα-Boc protected amino acid at terminal amino group (X)
Obtained by repeating the steps of Tfa deprotection and coupling required to incorporate an additional amino acid (X), and neutralizing with a suitable organic base. Cyclizing and cleaving the N ′ deprotected intermediate (N ′), and removing the side chain protecting groups with a strong acid such as HF. All variables are as defined for formula (I) above.

[0064]

Embedded image

DETAILED DESCRIPTION OF THE INVENTION As used herein, the term heterocycle refers to a heterocycle that may appear on the side chains of amino acids. Examples include, but are not limited to, benzothienyl, cumaryl,
Imidazolyl, indolyl, purinyl, pyridyl, pyrimidinyl, quinolinyl,
Includes thiazolyl, thienyl and triazolyl.

As used herein, the term aryl is intended to mean a stable monocyclic or bicyclic carbocyclic ring up to 7 members in each ring, wherein at least one ring Is an aromatic ring. Examples of aryl groups include biphenyl, indanyl, naphthyl,
Includes phenyl and 1,2,3,4-tetrahydronaphthalene.

In the present invention, several abbreviations are used for amino acid components, certain preferred protecting groups, reagents and solvents. Table 1 shows the meaning of such abbreviations. Abbreviation Meaning Amino acid His L-Histidine Lys L-Lysine Nal L-3- (2-naphthyl) -alanine Phe L-Phenylalanine Ser L-Serine Thr L-Threonine Trp L-Tryptophan (unless otherwise specified) Tyr L- Tyrosine Ahx 6-aminohexanoic acid protecting group Boc 1,1- (dimethylethoxy) carbonyl Cbz benzyloxycarbonyl Fmoc 9-fluorenylmethoxycarbonyl Trt triphenylmethyl solvent DMF N, N-dimethylformamide THF tetrahydrofuran EtOAc ethyl acetate reagent Tfa Trifluoroacetic acid NMM 4-Methylmorpholine DIEA Diisopropylethylamine TEA Triethylamine TAEA Tris (2-aminoethyl) amine HOAT 1-H Droxy-7-azabenzotriazole HATU [O- (7-azabenzotriazol-1-yl) -1,1,3,3-tetramethyluronium] hexafluorophosphate EDC 1- (3-dimethylaminopropyl ) -3-ethyl Le carbodiimide hydrochloride DCC dicyclohexylcarbodiimide In vitro assays human somatostatin subtype receptor 5 (respectively, sst _1, sst _2,
The affinity of the compounds for sst ₃ , sst ₄ and sst ₅ ) is determined by measuring the inhibition of [ ¹²⁵ I-Tyr ¹¹ ] SRIF-14 binding to CHO-K1 transfected cells.

[0068] was cloned human sst ₁ receptor gene as a genomic fragment. 10
0 bp of 5'-untranslated region, 1.17 Kb of total coding region and 230 bp
A 1.5 kb PstI-XmnI segment containing the 3'-untranslated region of
It was modified by adding a g1II linker. The obtained DNA fragment was used for pCMV
Subcloning into the -81 BamHI site resulted in a mammalian expression plasmid (provided by Dr. Graeme Bell, University of Chicago). Clonal cell lines stably expressing the sst ₁ receptor, using calcium phosphate co-precipitation method (1), CHO
-Obtained by transfecting into K1 cells (ATCC). Plasmid pRSV
-Neo (ATCC) was included as a selectable marker. G418 (Gibco)
Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml, ring cloned and expanded into culture.

[0069] Human sst ₂ somatostatin receptor gene, 1.7 Kb of the BamHI-Hi
The plasmid vector pG, isolated as an ndIII genomic DNA fragment
Subcloned into EM3Z (Promega) and Kindly provided by Dr. Bell (University of Chicago). A mammalian cell expression vector is constructed by inserting the 1.7 Kb BamHI-HindIII fragment into the compatible restriction endonuclease site of plasmid pCMV5. Transfect CHO-K1 cells using the calcium phosphate co-precipitation method to obtain a clonal cell line. Plasmid pRSV-neo (ATCC) is included as a selectable marker.

Human sst ₃ was isolated as a genomic fragment and had a 2.4 Kb BamHI /
The complete coding sequence was contained within the HindIII fragment. By adding a 2.0 Kb NcoI-HindIII fragment into the EcoR1 site of the pCMV vector after modifying the ends and adding an EcoR1 linker,
A mammalian expression plasmid, pCMV-h3, was constructed. Clonal cell lines stably expressing the sst ₃ receptor, using the calcium phosphate co-precipitation method, CHO
-Obtained by transfecting into K1 cells (ATCC). Plasmid pRSV
-Neo (ATCC) was included as a selectable marker. G418 (Gibco)
Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml, ring cloned and expanded into culture.

The human sst ₄ receptor expression plasmid was pCMV-HX, Dr. Graeme Bell (
(University of Chicago). 1 This vector encoding the human sst _4.
It contains a 4 Kb Nhel-Nhel genomic fragment, a 456 bp 5'-untranslated region and a 200 bp 3'-untranslated region, and the Xbal / PCMV-HX Xbal /
Clone to EcoR1 site. Clonal cell lines stably expressing the sst ₄ receptor, using the calcium phosphate co-precipitation method, CHO-K1 cells (ATCC
). Plasmid pRSV-neo (ATCC)
Was included as a selectable marker. Clonal cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), ring cloned,
Expanded to culture.

[0072] human sst ₅ gene, λ genomic clones were obtained by PCR using as a template, was kindly provided from Dr. Graeme Bell (University of Chicago). 1 obtained
. The 2 Kb PCR fragment contained 21 base pairs of the 5'-untranslated region, the entire coding region, and 55 bp of the 3'-untranslated region. Plasmid pBS
This clone was inserted into the EcoR1 site of SK (+). 1.2 Kb HindIII-Xbal for subcloning into pCVM5 mammalian expression vector
This insert was recovered as a fragment. Clonal cell lines stably expressing the sst ₅ receptor, using the calcium phosphate co-precipitation method, CHO-K1 cells (
ATCC). Plasmid pRSV-neo (A
TCC) was included as a selectable marker. G418 (Gibco) 0.5 mg /
Clonal cell lines were selected in RPMI 1640 medium containing ml, ring cloned and expanded into culture.

CHO-K1 cells stably expressing one of the human sst receptors are grown in RPMI 1640 containing 10% fetal serum and Geneticin 0.4 mg / ml. Cells are harvested using 0.5 mM EDTA and at about 4 ° C. for about 5 minutes.
Centrifuge at 500 g. Resuspend the pellet in 50 mM Tris, pH 7.4,
Centrifuge twice at 500 g for about 5 minutes at about 4 ° C. Sonicate to lyse the cells,
Centrifuge at 39000 g for about 10 minutes at about 4 ° C. Resuspend the pellet in the same buffer, centrifuge at 50,000 g for about 10 minutes at about 4 ° C, and store the resulting membrane fraction of the pellet at -80 ° C.

A competition inhibition experiment of [ ¹²⁵ I-Tyr ¹¹ ] SRIF-14 binding is performed on two identical samples in a 95-well polypropylene plate. Cell membrane (10 μg protein
/ Well) with 50 mM HEPES (pH 7.4), 0.2% BSA, 5 mM
MgCl ₂ , Trasylol 200 KIU / ml, bacitracin 0.02 m
g / ml and phenylmethylsulfonyl fluoride at 0.02 mg / ml at about 37 ° C. for about 60 minutes for about [ ¹²⁵ I-Tyr ¹¹ ] SRIF-14 (0.05 n
Incubate with M).

Using a Filtermate 196 (Packard) cell harvester, 0.1
[ ^125] by direct filtration through a GF / C glass fiber filter plate (Unifilter, Packard) soaked with 5% polyethyleneimine (PEI).
I-Tyr ¹¹ ] Separates the bound form from the free form of SRIF-14. The filters are washed with 50 mM HEPES at about 0-4 ° C. for about 4 seconds, Packard
Assay for radioactivity using Top Count.

Specific binding is obtained by subtracting non-specific binding (quantified in the presence of 0.1 μM SRIF-14) from total binding. The binding data is analyzed by computer-assisted nonlinear regression analysis (MDL) to determine inhibition constant (Ki) values.

The determination of whether a compound of the present invention is an agonist or antagonist is determined by the following assay. Functional assay: Inhibition of cAMP intracellular production: CHO- expressing human somatostatin (SRIF-14) subtype receptor
K1 cells were RPMI with 10% FCS and Geneticin 0.4 mg / ml
Seed into 24-well tissue culture multi-dish containing I 1640 medium. The medium is changed the day before the experiment.

The cells in each of the 10 ⁵ cells were subjected to 3-isobutyl-1-methylxanthine (IBMX)
0.5 ml of fresh RPMI with 0.2% BSA supplemented with 0.5 mM (1)
Wash twice with l and incubate at about 37 ° C for about 5 minutes. -Cyclic AMP production is promoted by adding 1 mM forskolin (FSK) at about 37 ° C for about 15-30 minutes. The agonist effects of the compounds were FSK (1 μM), SRIF-14 (10 ⁻¹² M to 1
0 ^-6 M) and the test compound (10 ^-10 M to ^{10 -5} M) are added simultaneously. -The antagonist effect of the compound is FSK (1 μM), SRIF-14 (1 to 10 nM)
And a test compound (10 ⁻¹⁰ M to ^{10 −5} M) are simultaneously added.

The reaction medium is removed and 200 ml of 0.1N HCl are added. CAMP is measured using a radioimmunoassay method (Kit Flash Plate S
MP001A, New England Nuclear). Radioligand binding assay CHO-K1 cells expressing the hsst receptor subtype were homogenized in ice cold 50 mM Tris-HCl (Polytron, setting 6, 15 sec).
And centrifuged twice at 39,000 g (10 minutes) and immediately resuspended in fresh buffer to obtain a membrane for in vitro receptor binding assay. The final pellet was resuspended in 10 mM Tris-HCl for the assay. hsst1, hsst3, hsst4
For the hsst5 assay, aliquots of the above membrane preparation were prepared using BSA (10 mg).
MgCl ₂ (5 mM); Trasylol (200 KIU / ml);
About 37 ° C. in 0.05 mM HEPES (pH 7.4) containing bacitracin (0.02 mg / ml) and phenylmethylsulfonyl fluoride (0.02 mg / ml) with 0.05 nM [ ¹²⁵ I-Tyr ¹¹ ] SRIF-14. About 3
Incubated for 0 minutes. Final assay volume was 0.3 ml.

For the hsst2 assay, [ ¹²⁵ I] MK-678 (0.05 nM) was used as the radioligand and the incubation time was about 90 minutes at about 25 ° C. The incubation was stopped by high speed filtration through a GF / C filter (soaked in 0.3% polyethyleneimine) using a Brandel filtration manifold. Each tube and filter was then washed three times with 5 ml aliquots of ice-cold buffer.

Specific binding was determined from total radioligand binding to 1000 nM SRIF-14 (hs
st1, 3, 4, 5) or 1000 nM MK-678 (hsst2).

The compounds of the present invention may be bound to the somatostatin receptor, including specific binding to the somatostatin subtype receptor, by methods well known to those skilled in the art, as represented by the following references: Can be assayed in vivo for uses related to: I
Shimon, et al., "Somatostatin receptor subtype specificity in human fe
tal pituitary cultures ", J. Clin. Invest., Vol. 99, No. 4, pp. 789-798,
1997; and C. Gilon, et al., "A backbone-cyclic, receptor 5-selective so
matostatin analogue: Synthesis, bioactivity, and nuclear magnetic resona
nce conformational analysis ", J. Med. Chem. 1988, 41, 919-929. As is well known to those skilled in the art, the known and potential uses of somatostatin agonists and / or antagonists vary. This diverse use of somatostatin can be summarized as follows: Somatostatin agonists inhibit growth hormone and more particularly GH-secreting adenomas (acromegaly) and TSH-secreting adenomas; Treating secretory adenomas; inhibition of insulin and / or glucagon, and more particularly diabetes, vascular injury, proliferative retinal disorders, dawn phenomena and renal impairment;
Gastric acid secretion, and more particularly peptic ulcers; enteric and pancreatic fistulas; irritable bowel syndrome; dumping syndrome; watery diarrhea syndrome; AIDS-related diarrhea; chemotherapy-induced diarrhea; acute or chronic Pancreatitis and gastrointestinal hormone-secreting tumors; treatment of cancers such as hepatomas; inhibition of angiogenesis; treatment of inflammatory disorders such as arthritis; retinal disorders; chronic graft rejection; angiogenesis; Can be used to prevent bleeding.

Accordingly, the present invention includes within its scope pharmaceutical compositions comprising, as active ingredients, at least one of the compounds of the invention as described herein, together with a pharmaceutically acceptable carrier. Include.

The compounds of the invention may be administered by oral, parenteral (eg, intramuscular, intraperitoneal, intravenous or subcutaneous injection, or implant), nasal, vaginal, rectal, sublingual or topical routes of administration, It may be formulated with a pharmaceutically acceptable carrier to provide a dosage form suitable for each route of administration.

[0085] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is admixed with at least one inert pharmaceutically acceptable carrier such as sucrose, lactose or starch. Such dosage forms will usually also contain additional substances other than such inert excipients, for example, lubricating agents such as magnesium stearate. In the case of capsules, tablets and pills, the dosage form may also comprise a buffer. Tablets and pills can additionally be prepared with enteric coatings.

[0086] Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, containing inert diluents such as water, commonly used in the art. Elixir is included. The compositions may include, in addition to such inert diluents, wetting agents, emulsifying and suspending agents, and adjuvants such as sweetening, flavoring and flavoring agents.

The preparations according to the invention for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or carriers are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate. Such dosage forms may also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They may also be sterilized by, for example, filtration through a bacterial retention filter, incorporating the sterilant into the composition, irradiating the composition, or heating the composition. They can also be manufactured in the form of solid sterile compositions that can be dissolved in sterile water, or other sterile injectable medium immediately before use.

Compositions for rectal or vaginal administration are preferably suppositories and, in addition to the active ingredient,
Excipients such as cocoa butter and suppository waxes may be included. Compositions for nasal or sublingual administration may be prepared using standard excipients that are well known in the art.

Further, the compounds of the present invention may be administered in sustained release compositions as described in the following patents. U.S. Patent No. 5,672,659 teaches a sustained release composition comprising a bioactive agent and a polyester. US Patent 5,595,7
No. 60 teaches a sustained release composition comprising a bioactive agent in a gelled form. US patent application Ser. No. 08 / 929,363, filed Sep. 9, 1997, teaches a polymeric sustained release composition comprising a bioactive agent and chitosan. 199
US patent application Ser. No. 08 / 740,778, filed Nov. 1, 6 teaches a sustained release composition comprising a bioactive agent and cyclodextrin. US patent application Ser. No. 09 / 015,394, filed Jan. 29, 1998, teaches an absorbable sustained release composition of a bioactive agent. The teachings of the above patents and applications are incorporated herein by reference.

While the dosage of the active ingredient in the compositions of the present invention may be varied, the quantity of active ingredient must be such that a suitable dosage form will be obtained. The selected dosage depends on the desired therapeutic effect, on the route of administration and on the duration of the treatment. In general, to achieve a therapeutic effect, humans and other animals, such as mammals, are treated at a rate of 0.00 per kilogram of body weight per day.
Dosage levels of 01-100 mg are administered.

A preferred dosage range is 0.01 to 5.0 mg / kg of body weight per day,
It can be administered as a single dose or can be divided into multiple doses. The compounds of the present invention can be synthesized according to the following description and Scheme I. In the first step, an amino acid whose α-amino group is protected with Boc, Cbz or another suitable group is
In a polar solvent such as H ₂ O, DMF, THF, etc., an inorganic base such as NaO
It is converted to a carboxylate with H, KOH, K ₂ CO ₃ , or most preferably Cs ₂ CO ₃ . Remove the solvent under vacuum, redissolve the residual salt in a polar aprotic solvent such as DMF, and add the appropriate α-haloketone while stirring at about −20 ° C. to about 100 ° C., most preferably at room temperature. . Stirring is continued for about 10 minutes to about 24 hours or until ester formation is complete by TLC analysis, at which time about 0 ° C. to about 100 ° C.,
Most preferably, the solution is concentrated in vacuo at about 40C to about 70C. The resulting intermediate is
Benzene is added toluene, or most preferably again dissolved in an aprotic organic solvent such as xylene, about 5-fold to about 100 fold, or most preferably an excess of NH ₄ OAc about 15 to 20 fold moles. The biphasic mixture was heated under reflux for about 1 to about 4 hours using a Dean-Stark trap to completely remove the polar layer, and the crude intermediate (A
Get) It can be used crude or purified by crystallization or column chromatography.

[0092]

Embedded image

In the second step, intermediate (A) is deprotected using catalytic hydrogenation or a strong acid such as HF, HCl, HBr or Tfa. The α-nitrogen is then removed with a base-reactive protecting group such as the Fmoc group using, for example, commercially available N- (9-fluorenylmethoxycarbonyloxy) succinimide and K ₂ CO ₃ dissolved in acetonitrile and water. Can be protected. In another approach, the Nα-Cbz protected imidazole nitrogen is alkylated with a protected carboxylic ester halide and the α-amino group is deprotected using catalytic hydrogenation to afford B ′ (V = H, W = - (CH _{2
^{) M CR 5 CO 2 R '}} , wherein R' may be obtained represents alkyl or benzyl ester). Imidazole nitrogen is commercially available triphenylmethyl chloride and 4
Protection using a tertiary amine base such as methyl morpholine, diisopropylethylamine or triethylamine to give an Fmoc protected intermediate, which in turn can be converted using a base such as TAEA The α-amino group is deprotected to obtain an intermediate (B) (V = H, W = Trt). In another approach, N-protected imidazole B "(V = H, W = H) may be used without further modification.

In the third step, the intermediate B, B ′ or B ″ is used as an anchor group for continuous liquid phase synthesis of the target peptide, ie, the anchor group is added to about 50 per liter.
About 1-5 molar equivalents of a Nα-Fmoc protected amino acid in the form of an activated ester, anhydride or acid halide, dissolved in ethyl acetate at a concentration of ~ 200 mmol;
Or more preferably, 1.1 to 1.5 molar equivalents are added. The mixture is stirred with a second layer of a weak base such as aqueous Na ₂ CO ₃ or more preferably aqueous NaHCO ₃ until the reaction is complete. The aqueous layer is removed and about 1-10 ml / mmol or more preferably about 2-4 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 (about 30 ml).
Per millimolar) and washed with 10% phosphate buffer (3 ml at approximately 10 ml / mmol).
Times) and adjust to pH = 5.5. The next cycle is performed in the same manner as the first cycle. The final amino acid may protect Nα with a Boc or Fmoc group.

In the fourth step, the N-terminal and C-terminal protecting groups are removed using an aqueous base or a strong acid, and the resulting peptide intermediate is converted to “The Practice of Peptide Synthesis”, Bod
Cyclization can be performed using standard peptide coupling techniques described in Anszky and Bodanszky, Springer-Varlag, 1984. That is, the peptide intermediate is dissolved in an aprotic solvent such as DMF, and a tertiary amine base such as 4-methylmorpholine is added to the solution to make it basic. The carboxylic acid moiety of this intermediate can be DCC or ED
Activated by adding a 1-6 fold molar excess of the carbodiimide, such as C, and an additive such as, for example, 1-hydroxybenzotriazole. The mixture is stirred at about 0 ° C. to about 100 ° C., most preferably at about room temperature, until the reaction is completed.

In the final step, the protecting group is removed from the protected peptide using catalytic hydrogenation or a strong acid such as HF, HCl, HBr or Tfa to give the final product (C). Here, R ^{1 to} R ⁵ , a, b, Y, Z and n are as defined above for formula (I).

[0097] Finnigan SSQ 70 with ESI (electrospray ionization) source
The injection mass spectrum data was measured on a 00 spectrometer. About 10 dissolved in specified solvent
Using a sample of ２０20 mg / ml concentration, 300 MHz Varian Un
NMR data was obtained on an ity spectrometer.

[0098] Alternatively, the compounds of the invention may be prepared using solid phase peptide synthesis techniques. In this manner, intermediate A (X = Boc) is alkylated, for example, in a solution of ethyl bromoacetate and a suitable base, such as K ₂ CO ₃ , in an aprotic solvent, such as DMF, to give the resulting ethyl ester intermediate: aqueous base, for example using NaOH and hydrolyzed to provide intermediate B (V = Boc, W = -CH 2 CO 2 H). Intermediate B (V = Boc, W = -CH 2 CO 2 H) is, "The Practice of Peptide Syn
thesis ", Bodanszky and Bodanszky, Springer-Varlag, 1984, can be activated using known activation techniques and can be used directly for peptide extension coupling on a solid support, or intermediate B (V = Boc, W = -CH 2 CO 2 H) is deposited directly on the solid support, it is possible to start the solid-phase synthesis. for example deprotection of the N-terminal Boc group using Tfa This makes it possible to continue peptide synthesis under conditions known to those skilled in the art.

Intermediate B (eg, V = Fmoc, W = —CH ₂ CO ₂ t-Bu) is treated with an acid, such as Tfa, to remove the t-butyl ester protecting the carboxylic acid, and the resulting intermediate is obtained. body B (e.g., V = Fmoc, W = -CH 2 CO 2 H) , and may be used in solid phase peptide synthesis utilizing the Fmoc method. Thus, intermediate B (V = Fmoc,
W = -CH ₂ CO ₂ H) is, "The Practice of Peptide Synthesis" , Bodanszky a
Activated using known activation techniques as described in nd Bodanszky, Springer-Varlag, 1984, and can be used directly for peptide extension coupling on a solid support. For example, by deprotecting the N-terminal Fmoc group using piperidine,
It is possible to continue peptide synthesis under conditions known to those skilled in the art.

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

[0101]

Embedded image

Intermediate A (X = Boc or Cbz, R ³ = 2-methoxyphenyl, 3-methoxyphenyl or 4-methoxyphenyl) was reduced to about 1 / M with 1M BBr ₃ / CH ₂ Cl ₂
For 2 h to give the free phenol ^{A (X = H, R 3} = 2- hydroxyphenyl, 3-hydroxyphenyl or 4-hydroxyphenyl) a. Then, in a mixed solvent of organic matter and water, for example, a mixture of dioxane and water, using di-t-butyl dicarbonate and a base, for example, NaOH, using an acid-reactive protecting group such as a Boc group. α-Nitrogen can be protected. For example, ethyl bromoacetate and a suitable base,
For example, in a solution of K ₂ CO ₃ in an aprotic solvent such as DMF, intermediate A (
X = Boc, R ³ = 2-hydroxyphenyl, 3-hydroxyphenyl or 4-
Alkylation of hydroxyphenyl) gives the resulting ethyl ester intermediate D. The intermediate D is then converted to its cesium salt by the action of cesium carbonate. The cesium salt is reacted with an excess amount of Merrifield resin to give intermediate E. Intermediate E is further modified using standard Boc solid phase peptide synthesis or standard Fmoc solid phase synthesis described above to provide intermediate F. When the complete amino acid sequence has been assembled, the C-terminal ethyl ester is unmasked using a suitable base, such as LiOH / aqueous DMF, and standard activation protocols such as carbodiimide (eg, hydroxybenzotriazole) and Cyclization with a tertiary amine base (eg, diisopropylethylamine) provides intermediate G. Addition of a very strong acid such as HF achieves the final side chain deprotection and cleavage from the resin to give the compounds of the present invention.

The present invention will be described by the following examples, but the present invention is not limited to the details.

[0104]

【Example】

Embodiment 1 FIG. Cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-methoxyphenyl) imidazole) -Gly]

[0105]

Embedded image

Example 1 was synthesized according to Synthesis Scheme 1 shown below.

[0107]

Embedded image

Step a: 2- (1- (S) -amino-2-phenylethyl) -4- (3-methoxyphenyl) -imidazole Cbz- (L) -phenylalanine (10.0 g, 33.4 mmol) And C
s ₂ CO ₃ (5.44 g, 16.7 mmol) in 2: 1 / DMF: H ₂ O (75 m
l) and the mixture was stirred until homogenized. The solvent was removed under reduced pressure, the residue was dissolved in DMF (70 ml), and 2-bromo-3′-methoxyacetophenone (7.65 g, 33.4 mmol) / DMF (30 ml) was added. The mixture was stirred at room temperature for about 30 minutes and concentrated under reduced pressure. The obtained ketoester was dissolved in xylene (150 ml), and CsBr was removed by filtration. Ammonium acetate (40
. 0 g, 0.52 mol) was added, Dean - using Stark trap this mixture for about 2 hours under reflux heating was removed of H ₂ O generated with excess NH ₄ OAc. The reaction was cooled, saturated NaHCO ₃ solution (50 ml) and saturated NaCl solution (50 ml).
ml). The xylene layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo.

The residue was dissolved in dioxane (30 ml), and 6N HCl (115 ml) was added.
The mixture was heated at reflux for about 3 hours. The solution was concentrated in vacuo and ethyl ether
(4 × 100 ml). Vacuum dry the residue to constant weight,
12.15 g (99%) of 1a was obtained. 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 converted to 1/1 / acetonitrile: H _Two Dissolve in O (200ml) and add K_TwoCO_Three(5.38 g, 39 mmol)
Carefully added. 9-fluorenylmethyl-succinimidyl carbonate
And the resulting mixture was stirred vigorously for about 20 minutes. EtOAc (100m
The product was extracted in 1) and the EtOAc layer was_TwoWashed with O (2 × 50 ml)
. This EtOAc layer is_TwoSO_Four, Filtered and concentrated in vacuo. silica
Purify the product by flash chromatography on a gel (150 g), 2:
2: 1 / CH_TwoCl_Two: Hexane: EtOAc, then 1: 1 / hexane: EtO
Eluted with Ac. Product fractions are pooled and concentrated in vacuo to a light yellow foam
14.77 g (85%) of intermediate 1b were obtained. Mass spectrum: 516.3MH +
. NMR (300 MHz, DMSO-d6): 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)-((fluorenyl Methoxy) carbonyl) amino-
2-phenylethyl) -4- (3-methoxyphenyl) -1-triphenylmethyl
Ruimidazole intermediate 1b (13.9 g, 26.9 mmol) was converted to N_TwoBottom, CH_TwoCl_Two(50m
l), 4-methylmorpholine (2.96 ml, 26.9 mmol) and
Chlorotriphenylmethane (7.51 g, 26.9 mmol) was added and this solution was added.
Was stirred at room temperature for about 45 minutes. The solid content was removed by filtration, and 70: 30 /
Flash chromatography of silica gel (300 g) using hexane: EtOAc
The filtrate was purified by chromatography. The product fractions were combined, concentrated in vacuo,
18.0 g (88%) of intermediate 1c were obtained as a foam. NMR (300 MHz, D
MSO-d6): 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 (
Step d: 2- (1- (S)-((Fmoc-Tyr (OBzl) -D-Trp-)
Lys (Cbz) -Val) amino-2-phenylethyl) -4- (3-methoxy
(Ciphenyl) -1-triphenylmethyl-imidazole Intermediate 1c (1.89 g, 2.50 mmol) was dissolved in EtOAc (40 ml).
Then, tris (2-aminoethyl) amine (9 ml) was added, and the mixture was added for about 1 hour.
/ 2 hours with vigorous stirring. The EtOAc layer was washed with a saturated NaCl solution (2 × 1
20 ml), then wash with 10% phosphate buffer (3 × 40 ml), pH = about
Adjusted to 5.5. The EtOAc layer was washed with saturated NaHCO_ThreeStir with solution (40 ml)
After stirring, Fmoc-Val-F (1.02 g, 3.00 mmol) was added. this
The reaction was stirred for about 1 hour and the aqueous layer was removed.

This intermediate was then converted to Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-OSu and Fmoc-Tyr (OBzl) -OSu in a manner similar to the Fmoc-Val-F cycle described above. For continuous deprotection and coupling. The EtOAc layer was diluted with 1.5 volumes of hexane and eluted first with 50: 30: 20 / CH ₂ Cl ₂ : EtOAc: hexane, then with 4: 1 / EtO.
Ac: applied to a silica gel column for purification by flash chromatography using hexane. Product fractions were pooled and concentrated in vacuo to give 1.90 g (46%) of intermediate 1d as a white foam. Mass spectrum: 1581.
2MNa +, 1559.5MH +. 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) iPr ₃ SiH (205 μ
1, 1.0 mmol) in Tfa (10 ml) and the mixture was stirred for about 15 minutes. The intermediate was precipitated by adding ethyl ether (60 ml) and collected by filtration. Mass spectrum: 1316MH +. This intermediate was dissolved in DMF (3 ml), KHCO ₃ (198 mg, 2.0 mmol) and ethyl bromoacetate (72 mg).
1 μl, 6.5 mmol) was added and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved in CH ₂ Cl ₂ (10 ml) and washed with H ₂ O (10 ml). The CH ₂ Cl ₂ 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
-Phe {(4- (3-methoxyphenyl) imidazole) -Gly] Intermediate 1e (540 mg, 0.33 mmol) was suspended in EtOAc (10 ml) and tris (aminoethyl) amine (1 ml) was added. About 1 /
Stir vigorously for 2 hours. EtOAc (10 ml) was added and the solution was saturated NaC
1 solution (2 × 25 ml), then 10% phosphate buffer (pH = 5.5, 3 × 10
ml). Hexane (40 ml) was added to precipitate the intermediate and the solvent was decanted. The residue was dissolved in methanol (10 ml), and 2.5N NaOH (0
. 5 ml) and stirred overnight at room temperature. The mixture was diluted by addition of H ₂ O until it became cloudy, and the pH was adjusted to about 6.7. The deprotected intermediate was collected by filtration and dried in vacuo. This solid was taken up in DMF (25 ml) and DCC (340 mg).
, 1.65 mmol) and HOBt (252 mg, 1.65 mmol). The mixture was stirred at room temperature for about 2 hours and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using EtOAc as eluent. The product fractions were combined and concentrated in vacuo to give intermediate 1 as a glassy material.
f (180 mg, 48% from intermediate 1d) was obtained. Mass spectrum: 1134
. 5MH +. Step g: cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-
Methoxyphenyl) imidazole) -Gly] Intermediate 1f (180 mg, 0.16 mmol) was prepared by adding 10% Pd / carbon (
24 mg) in acetic acid (10 ml), and the mixture was diluted with H ₂ (25 ps).
Shake at room temperature under i) for about 8 hours. The catalyst was removed by filtration, and the residue was concentrated in vacuo. The crude mixture contained fully deprotected material (Cbz and benzyl ether removed) and partially deprotected material (Cbz removed but benzyl ether intact). Was. 20% to 70% of CH ₃ CN gradient /
VYDAC® Protein & P using 0.1% Tfa
eptide C ₁₈ column (The Nest Group Inc., Sou
This mixture was purified by preparative HPLC (thborough, MA) over about 55 minutes. The more polar peak, the pure fraction, was pooled, concentrated, and lyophilized (0
. 5% HCl: 2 × 10 ml, then H ₂ O: 1 × 10 ml) to give 1.45 mg (29%) of the title compound of Example 1. Mass spectrum: 910.4MH +
. Embodiment 2. FIG. Cyclo [Tyr (OBzl) -D-Trp-Lys-Val-Phe} (4- (
3-Methoxyphenyl) imidazole) -Gly] Example 2 was prepared essentially according to Example 1 of Synthetic Scheme 1, except using the appropriate amino acids. Combine the less polar pure fractions from 1 g of purification,
Concentrate and freeze dry (0.5% HCl: 2 × 10 ml, then H ₂ O: 1 × 10
ml) to give 2.33 mg (21%) of the title product of Example 2. Mass spectrum: 1000.4 MH +. Embodiment 3 FIG. Cyclo [Trp-D-Trp-Lys-Val-Phe} (4- (3-methoxyphenyl) imidazole) -Gly] Example 3 was synthesized in substantially the same manner as Example 1 except for the following changes. Prepared according to Scheme 1: Step d: 2- (1- (S)-((Fmoc-Trp-D-Trp-Lys (Cb
z) -Val) amino-2-phenylethyl) -4- (3-methoxyphenyl)
-1-Triphenylmethyl-imidazole Intermediate 1c (757 mg, 1.0 mmol) was dissolved in EtOAc (20 ml), and tris (2-aminoethyl) amine (3 ml) was added.
Stir vigorously for 2 hours. Wash the EtOAc layer with saturated NaCl solution (2 × 60
ml), and then washed (3 × 20 ml) with 10% phosphate buffer, to a pH of about 5.5.
Adjusted to H. The EtOAc layer was stirred with a saturated NaHCO ₃ solution (20 ml) and Fmoc-Val-F (825 mg, 2.33 mmol) was added. The reaction was stirred for about 1 hour and the aqueous layer was removed.

This intermediate was then continuously purified using Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-OSu and Fmoc-Trp-OSu in a manner similar to the Fmoc-Val-F cycle described above. Deprotection and coupling. E
Dilute the tOAc layer with 1.5 volumes of hexane and first use 50:30:
Loaded on a silica gel column for purification by flash chromatography using 20 / CH ₂ Cl ₂ : EtOAc: Hexane, then 4: 1 / EtOAc: Hexane. Product fractions were pooled and concentrated in vacuo to give 1.02 g (68%) of intermediate 3d as a white foam. Mass spectrum: 11492.0 M Na +
, 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) -imidazole Intermediate 3d (1.00 g, 0.67 mmol) was converted to CH ₂ Cl ₂ (10 ml),
It was dissolved in a mixture of Tfa (1 ml) and iPr ₃ SiH (205 μl, 1.0 mmol), and the mixture was stirred for about 20 minutes. A mixture of 1: 1 / Et ₂ O: hexane (100 ml) was added and the intermediate was collected by filtration and dried (0.88 g).
. This intermediate was dissolved in DMF (10 ml) and KHCO ₃ (200 mg, 2.0
0 mmol) and ethyl bromoacetate were added and the mixture was stirred overnight at room temperature.
The mixture was concentrated under reduced pressure to give Intermediate 3e, which was used without further purification. Mass spectrum: 1335.7 MH +. Step f: cyclo [Trp-D-Trp-Lys (Cbz) -Val-Phe} (
4- (3-methoxyphenyl) imidazole) -Gly] Intermediate 3e (crude product, 0.67 mmol) was dissolved in methanol (10 ml), 2.5N NaOH (1.0 ml) was added, and the mixture was added at room temperature for about 45 minutes. For a minute. The mixture was diluted with H ₂ O until turbid, and the pH was adjusted to 6.9. The solvent was decanted and the residue was triturated with H ₂ O to give a pale yellow powder (650 mg, mass spectrum: 1085.5 MH +). This powder (629 mg) was added to DMF (20 m
1), 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 about 2 hours and concentrated under reduced pressure. The crude product was treated with CH ₂ Cl ₂ (1
5 ml) and washed with 10% phosphate buffer (adjusted to pH = 5.5)
. The CH ₂ Cl ₂ layer was dried over Na ₂ SO ₄ , filtered and concentrated to 2 ml. Ethyl ether was added to precipitate the product, which was collected by filtration 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 prepared by adding 10% Pd / carbon (
40 mg) in acetic acid (15 ml), and the mixture was diluted with H ₂ (25 ps).
Shake at room temperature under i) for 2 days. The catalyst was removed by filtration, and the residue was concentrated in vacuo.
HPL for the production of C ₁₈ columns (Rainin Microsorb ^™ 80-220-C5) using 20% -70% CH ₃ CN gradient / 0.1% Tfa
This crude mixture was purified by C over about 55 minutes. For good separation, 3
0% to 50% of CH ₃ CN gradient /0.1% Tfa, it was required second path to use about 55 minutes. Pure fractions are pooled, concentrated and lyophilized (0.5% HCl
: 2 × 10 ml, then H ₂ O: 1x10ml), and the title compound of Example 3 3
. 26 mg (14%) were obtained. Mass spectrum: 933.5 MH +. Embodiment 4. FIG. Cyclo [Trp-D-Trp-Lys-Val-Phe {(4- (3-hydroxyphenyl) imidazole) -Gly] Example 4 is substantially the same as Example 1 with the following changes: Prepared according to synthetic scheme 1: Step g: Cyclo [Trp-D-Trp-Lys-Val-Phe} (4- (3-
Hydroxyphenyl) imidazole) -Gly] Intermediate 3f (150 mg, was dissolved 0.14 mmol) in CH ₂ Cl ₂ (12ml), under N _2, was added 1M BBr ₃ / hexanes solution. The resulting slurry was stirred for about 1/2 hour. Methanol (10 ml) was added and the mixture was concentrated under vacuum. The C ₁₈ column preparation for HPLC using 24% to 48% of CH ₃ CN gradient 0.2% NH ₄ OAc, the crude mixture was purified over a period of about 50 minutes.
The pure fractions were combined, concentrated and lyophilized (H ₂ O: 2 × 10 ml) to give 40 mg (29%) of the title compound of Example 4. Mass spectrum: 919.4MH +. Embodiment 5 FIG. Cyclo [Trp-D-Trp-Lys-Thr (OBzl) -Phe} (4- (
3-methoxyphenyl) imidazole) -Gly] In Example 5, Fmoc-Th was substituted for Fmoc-Val-F in step d.
Prepared according to Scheme 1 in substantially the same manner as in Example 3, except using r (OBzl) -F. Mass spectrum: 1025.5 MH +. Embodiment 6 FIG. Cyclo [Trp-D-Trp-Lys-Thr-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly] In Example 6, instead of intermediate 3f in step g, intermediate 5f and cyclo [Tr
p-D-Trp-Lys (Cbz) -Thr (OBzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole) -Gly] was prepared according to Scheme 1 in substantially the same manner as in Example 4. Mass spectrum: 102
5.5 MH +. Embodiment 7 FIG. H-Trp-D-Trp-Lys-Abu-Phe {(4- (3-hydroxyphenyl) imidazole) -Gly-OH Example 7 shows that Fmoc-A was used instead of Fmoc-Val-F in step 3d.
Prepared according to Scheme 1 in substantially the same manner as in Example 3, except that bu-F was used and the cyclization with carbodiimide and HOBt in step 3f was omitted. Mass spectrum: 937.3 MH +. Embodiment 8 FIG. Cyclo [Trp-D-Trp-Lys-Abu-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly] Example 8 shows that Fmoc-A was used instead of Fmoc-Val-F in step 3d.
Prepared according to Scheme 1 in substantially the same manner as in Example 3, except using bu-F. Mass spectrum: 919.5MH +. Embodiment 9 FIG. Cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
1,1-Dimethylethyl) imidazole) -Gly] Example 9 was synthesized according to Scheme 2.

[0112]

Embedded image

Step a: 2- (1- (S) -amino-2-phenylethyl) -4- (1,1-dimethylethyl) -imidazole Boc- (L) -phenylalanine (5.31 g, 20.0 Mmol) and C
s ₂ CO ₃ (3.26 g, 10.0 mmol) in 1: 1 DMF: H ₂ O (50 m
l) and the mixture was stirred until a homogeneous mixture was obtained. The solvent was removed under reduced pressure, the residue was dissolved in DMF (50 ml) and 1-chloropinacolone (2.
63 ml, 20.0 mmol). After stirring this mixture at room temperature overnight,
Concentrated under reduced pressure. Dissolve the obtained ketoester in xylene (100 ml),
CsBr was removed by filtration. Ammonium acetate (25.0 g, 0.33 mol) was added, Dean - using Stark trap this mixture for about 2 hours under reflux heating was removed of H ₂ O generated with excess NH ₄ OAc. Cool the reaction and add saturated NaH
Washed with CO ₃ solution (50 ml), dried over Na ₂ SO ₄ , filtered and concentrated in vacuo. The protected intermediate was purified by flash chromatography on silica gel using 80: 20 / hexane: EtOAc as eluent to give 3.45 g (50%) of a crystalline intermediate (mass spectrum: 344). .3MH +). This intermediate was dissolved in methanol (30 ml), concentrated HCl (5.0 ml) was added,
The mixture was stirred for about 3 hours. The solution was concentrated under vacuum and the residue was precipitated from THF and ethyl ether. The solid content was dried under vacuum to obtain 1.89 g of Intermediate 9a.
(95%). NMR (300 MHz, DMSO-d6): 8.5-10.5 (3H, broad 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, s). Step h: 2- (1- (S)-((Fmoc-Phe-D-Trp-Lys (Bo)
c) -Tyr (OBzl))-amino-2-phenylethyl) -4- (1,1-
(Dimethylethyl) -1H-imidazole Intermediate 9a (790 mg, 2.50 mmol) was dissolved in EtOAc (40 ml), and tris (2-aminoethyl) amine (9 ml) was added.
/ 2 hours with vigorous stirring. The EtOAc layer was washed with a saturated NaCl solution (2 × 1
20 ml) and then washed (3 × 40 ml) with 10% phosphate buffer and adjusted to pH = about 5.5. The EtOAc layer was stirred with a saturated NaHCO ₃ solution (40 ml) and Fmoc-Tyr (OBzl) -OSu (1.02 g, 3.00 mmol) was added. The reaction was stirred for about 1.5 hours and the aqueous layer was removed.

This intermediate was converted to Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-O in a manner similar to the Fmoc-Tyr (OBzl) -OSu cycle described above.
Successive deprotection and coupling were performed using Su and Fmoc-Phe-OSu. This EtOAc layer was applied to a silica gel column for purification by flash chromatography using 1% acetic acid / EtOAc as eluent. Product fractions were pooled and concentrated in vacuo. The crude product was redissolved in EtOAc, precipitated by adding hexane, and collected by filtration. The solid is dried in vacuo to give intermediate 9
1.67 g (52%) of h. Mass spectrum: 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-oxo-ethyl) -imidazole Intermediate 9h (128 mg, 0.10 mmol) was dissolved in DMF (2 ml),
K ₂ CO ₃ (35 mg, 0.25 mmol) and ethyl bromoacetate (28 μl, 0
. 25 mmol) and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, dissolved in EtOAc (10 ml), washed with H ₂ O (10ml). The EtOAc 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 {(4- (3-methoxyphenyl) imidazole) -Gly] Intermediate 9e (116 mg, 0.085 mmol) was suspended in EtOAc (2 ml), and tris (aminoethyl) amine (0.5 ml) was added. The mixture was vigorously stirred for about 1/2 hour. EtOAc (10 ml) was added and the solution was saturated
aCl solution (2 × 5 ml) followed by 10% phosphate buffer (pH = 5.5, 3 × 5
ml). Hexane (40 ml) was added to precipitate the intermediate, which was collected by filtration (76 mg). The residue was dissolved in methanol (2 ml),
. 5N NaOH (0.1 ml) was added and the mixture was stirred at room temperature overnight. The mixture was diluted with H ₂ O until turbid, and the pH was adjusted to about 6.0. The deprotected intermediate was collected by filtration and dried in vacuo. This solid was taken up in DMF (20 ml) and DCC (126 mg, 0.60 mmol) and HOBt (90 mg, 0.60 mmol).
Mmol). The mixture was stirred at room temperature for about 6 hours and concentrated under reduced pressure.
Dissolved in EtOAc (5 ml) and washed with saturated NaHCO ₃ solution (1 × 5 ml) and saturated NaCl solution (5 ml). Dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give intermediate 9f. Mass spectrum: 1098.5 MH +. Step g: cyclo [Phe-D-Trp-Lys-Tyr-Phe} (4- (1,
1-Dimethylethyl) imidazole) -Gly] Intermediate 9f (crude product, 0.085 mmol) was converted to iPr ₃ SiH-containing Tfa
(9.4 ml) and H ₂ O (0.5 ml), stirred for about 20 minutes and concentrated in vacuo. Using 30% to 60% of CH ₃ CN gradient /0.1% Tfa,
This crude mixture was purified over approximately 50 minutes by preparative HPLC on a _C18 column.
For good separation, 32% to 80% of CH ₃ CN gradient 0.2% NH ₄ O
Ac, a second pass using about 50 minutes was required. The pure fractions were pooled, concentrated and lyophilized (0.5% HCl: 2 × 10 ml, then H ₂ O: 1 × 10 ml)
Then, 9.9 mg (10%) of the title compound of Example 9 was obtained. Mass spectrum: 99
8.4MH +. Embodiment 10 FIG. Cyclo [Phe-D-Trp-Lys-Val-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly] Example 10 shows that in step d, Fmoc-P was used instead of Fmoc-Trp-F
Except using he-OSu, it was manufactured according to Scheme 1 in the same manner as in Example 3. Mass spectrum: 894.4 MH +. Embodiment 11 FIG. Cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
3-methoxyphenyl) imidazole) -Gly] In Example 11, Fmoc-P was substituted for Fmoc-Trp-F in step d.
He-OH and Fmoc-Tyr (OBz) instead of Fmoc-Val-F
l) Prepared according to Scheme 1 in a similar manner to Example 3 except using -OH. Fmoc-Tyr (OBzl) -OH was activated using DCC and commercially available HOAt. The crude mixture of step g is a mixture of fully deprotected material (Cbz and benzyl ether removed) and partially deprotected material (Cbz removed but benzyl ether intact). Included. The less polar peak resulting from the partial deprotection provided the title compound of Example 11. Mass spectrum: 1048.5 MH +. Embodiment 12 FIG. Cyclo [Phe-D-Trp-Lys-Tyr-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly] Example 12 shows that in step d, Fmoc-P was used instead of Fmoc-Trp-F.
He-OH and Fmoc-Tyr (OBz) instead of Fmoc-Val-F
l) Prepared according to Scheme 1 in a similar manner to Example 3 except using -OH. Fmoc-Tyr (OBzl) -OH was activated using DCC and commercially available HOAt. The crude mixture of step g is a mixture of fully deprotected material (Cbz and benzyl ether removed) and partially deprotected material (Cbz removed but benzyl ether intact). Included. The more polar peak resulting from complete deprotection provided the title compound of Example 12. Mass spectrum: 958.4 MH +. Embodiment 13 FIG. Cyclo [Phe-D-Trp-Lys-Tyr-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly] In Example 13, cyclo [Phe- is the intermediate 11f instead of the intermediate 3f in the step g. D-Trp-Lys (Cbz) -Tyr (OBzl) -PheΨ (
Except for using 4- (3-methoxyphenyl) imidazole) -Gly], it was prepared according to Scheme 1 in the same manner as in Example 4. Mass spectrum: 944
. 6MH +. Embodiment 14 FIG. Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (3
-Methoxyphenyl) imidazole) -Gly] Example 14 was prepared according to Scheme 2 in substantially the same manner as Example 9 with the following changes: Step h: 2- (1- (S)- ((Fmoc-Trp-D-Trp-Lys (Cb
z) -Tyr (Bzl))-amino-2-phenylethyl) -4- (3-methoxyphenyl) -1- (triphenylmethyl) -imidazole using Fmoc-Trp-OSu instead of Fmoc-Phe-OSu Then F
Fmoc-Lys (Boc) -O instead of moc-Lys (Cbz) -OSu
Su, and Fmoc-Tyr (B) instead of Fmoc-Val-OSu.
Peptide synthesis was performed in a similar manner to step 9h except using zl) -OSu. Yield = 783 mg (57%). Mass spectrum: 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 performed in a similar manner to Reaction 9h. Yield = 64
0 mg (80%). Mass spectrum: 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 methanol (15 ml) and 2.5 N NaOH (1 ml, 2.5 mmol) was added. The mixture was stirred for about 1/2 hour and the pH was adjusted to about 7.0 by adding 5% HCl solution.
The methanol was removed under reduced pressure and the aqueous layer was decanted. The residue was dried completely under reduced pressure, and then dissolved in DMF (15 ml). DCC (206 mg, 1.0 mmol) and HOBt (153 mg, 1.0 mmol) were added and the reaction was stirred overnight. The reaction was concentrated under reduced pressure, dissolved in EtOAc (10 ml) and 10%
Washed twice with phosphate buffer, pH 5.5. The EtOAc layer was applied to a silica gel column and the product eluted with more EtOAc. The product 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 CH ₂ Cl ₂ (10 ml), and Tfa (10 ml) containing iPr ₃ SiH (205 μl, 1.0 mmol) was used.
) Was added. The mixture was stirred at room temperature for about 15 minutes. The CH ₂ Cl ₂ was evaporated under reduced pressure and ether was added to precipitate the crude product. Decant solvent to 30% -5
H for the production of _C18 columns using 0% CH ₃ CN gradient / 0.1% Tfa
The residue was further purified by PLC over about 55 minutes. The pure fractions were pooled, concentrated and lyophilized (0.5% HCl: 2 × 10 ml, then H ₂ O: 1 × 10 m
1) to give 25 mg (11%) of the title compound of Example 14. Mass spectrum:
1087.4 MH +. Embodiment 15 FIG. Cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly] Example 15 is a synthetic scheme in substantially the same manner as Example 4 with the following exceptions Step g: Cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-
(Hydroxyphenyl) imidazole) -Gly] Intermediate 1f (130 mg, 0.115 mmol) was dissolved in CH ₂ Cl ₂ (5 ml) and a 1 M BBr ₃ / hexane solution (5 ml) was added under N ₂ . The resulting slurry was stirred for about 1/2 hour and then cooled to 0 ° C. Methanol (10 ml)
Was added and the mixture was concentrated in vacuo. This crude mixture is applied to a _C18 column,
% NH ₄ washed with OAc solution was washed with 0.1% Tfa solution and then 20%
Use 35% of CH ₃ CN gradient /0.1% Tfa, and eluted over about 50 minutes. Pure fractions are pooled, concentrated and lyophilized (0.5% HCl: 2 × 10 ml)
) To give 60 mg (54%) of the title compound of Example 15. Mass spectrum: 8
96MH +. Embodiment 16 FIG. Cyclo [Phe-D-Trp-Lys-Nal-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly] Example 16 is substantially the same as Example 3 with the following changes: Prepared according to synthetic scheme 1: Step d: 2- (1- (S)-((Fmoc-Phe-D-Trp-Lys (Cb
z) -Nal) amino) -2-phenylethyl) -4- (3-methoxyphenyl) -1- (triphenylmethyl) -imidazole Fmoc-Nal-OAt was used instead of Fmoc-Val-F and Fmo
Intermediate 16d was prepared in substantially the same manner as Intermediate 1d, except that Fmoc-Phe-OH was used instead of c-Tyr (Bzl) -OH. Step g: cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-
[Hydroxyphenyl) imidazole) -Gly] Step 16g was performed in substantially the same manner as step 4g, to give the title compound of Example 16. Mass spectrum: Example 17 Cyclo [Phe-D-Trp-Lys-Nal-PheΨ (4- (3-methoxyphenyl) imidazole) -Gly] Example 17 is a scheme substantially similar to Example 16 with the following exceptions: Step g: Cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-
Methoxyphenyl) imidazole) -Gly] Intermediate 17f (310 mg, 0.27 mmol) was suspended in anisole (3 ml) and this suspension was treated with anhydrous HF (about 12 ml). The mixture was stirred at about 0 ° C. for about 1 hour. The HF was distilled off and ether was added to precipitate the product. The crude product was then collected filtered, 20-80% of CH ₃ CN gradient /0.1% T
Further purification by preparative HPLC using fa over approximately 40 minutes. The pure fractions were combined, concentrated and lyophilized twice from dilute hydrochloric acid. Yield = 56 mg (19%),
Mass spectrum: 992.4 MH +.

[0115]

Embedded image

Embodiment 18 FIG. Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (3
-Methoxyphenyl) imidazole)-(γ) 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 C
s ₂ CO ₃ (5.44 g, 16.7 mmol) in 2: 1 / DMF: H ₂ O (75 m
l) and the mixture was stirred until homogenized. The solvent was removed under reduced pressure, the residue was dissolved in DMF (70 ml), and 2-bromo-3'-methoxyacetophenone (7.65 g, 33.4 mmol) / DMF (30 ml) was added. The mixture was stirred at room temperature for about 1/2 hour and then concentrated under reduced pressure. The obtained ketoester was dissolved in xylene (150 ml), and CsBr was removed by filtration. Ammonium acetate (
40.0 g, 0.52 mol) was added, Dean - using Stark trap this mixture for about 2 hours under reflux heating was removed of H ₂ O generated with excess NH ₄ OAc. The reaction was cooled, saturated NaHCO ₃ solution (50 ml) and saturated NaCl solution (50 ml).
50 ml). The xylene layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to give intermediate 18i (13.8 g, 96%) as a tan solid. Mass spectrum: 428.2 (MH +). Step j: 2- (1- (S) -amino-2-phenylethyl) -1- (4- (1,
1-Dimethylethoxy) -4-oxo-butyl) -4- (4-methoxyphenyl) -imidazole Intermediate 18i (2.14 g, 5.0 mmol) was dissolved in DMF (11.5 ml) and heated at about 50 ° C. While stirring for about 18 hours, KHCO ₃ (1.50 g, 15.0 g) was added.
Mmol) and 4-bromo-t-butylbutyrate (6.69 g, 30 mmol) in three portions. The mixture is diluted with ether and saturated NaHCO ₃
Washed once with solution and once with saturated NaCl solution. The ether layer was dried over Na ₂ SO ₄ , filtered and concentrated to an oil. Column chromatography on silica gel using CH ₂ Cl ₂ as eluent gave the oily product.

The crude alkylation product was deprotected by hydrogenation with acetic acid using 10% Pd / carbon as catalyst. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was dissolved in EtOAc, washed with saturated NaHCO ₃ solution and saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated to give intermediate 18j as an oily component (
450 mg) which was used in the next step without further 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 Fmoc-Tyr (OBzl ) -Use Boc-Trp-OSu in place of OSu, and Fmoc-Tyr (OBzl)-in place of Fmoc-Val-F
Liquid phase synthesis was carried out in a similar manner to that described in step 1d, except using OAt, yielding intermediate 18k. Yield = 1.03 g (81%). Step 1: 2- (1- (S)-((H-Trp-D-Trp-Lys (Cbz)-
Val) Tfa containing amino-2-phenylethyl) -1-((4-hydroxy-4-oxo) butyl) -4- (3-methoxyphenyl) -imidazole (iPr) ₃ SiH (593 μl, 2.90 mmol) Solution (10
ml) was treated with intermediate 18k and stirred for about 1 hour. The reaction was concentrated and
Trituration with 1 ether: hexane solution afforded 18 l of intermediate as a tan solid,
Used for the next step without further purification. Mass spectrum: 1267.7 MH +. Step f: cyclo [Tyr-D-Trp-Lys (Cbz) -Tyr (Bzl)-
Phe {(4- (3-methoxyphenyl) imidazole)-(γ) Abu] Intermediate 18l was dissolved in DMF (20ml) and 4-methylmorpholine (159
μl, 1.45 mmol), HOBt (196 mg, 1.45 mmol) and E
DC (278 mg, 1.45 mmol) was added and the reaction was stirred overnight. 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
I got Yield = 220 mg (24%). Mass spectrum: 1249.7 MH +. Step g: cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (
4- (3-Methoxyphenyl) imidazole)-(γ) Abu] Intermediate 18f (220 mg, 176 μmol) was obtained at room temperature under H ₂ (30 psi) using 10% Pd / carbon as a catalyst. Partially hydrogenated in acetic acid for 14 hours. The catalyst was removed by filtration, and the filtrate was concentrated in vacuo. 0% to 75
HP for the production of _C18 columns using% CH ₃ CN gradient / 0.1% Tfa
The crude mixture was purified by LC over about 40 minutes. The pure fractions of the product peak were pooled, concentrated and lyophilized (0.5% HCl: 2 × 10 ml, then H ₂ O:
1 × 10 ml) to give 72 mg (37%) of the title compound of Example 18. Mass spectrum: 115.6 MH +. Embodiment 19 FIG. Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (4
-Methoxyphenyl) imidazole) -Gly] Example 19 was prepared according to Scheme 3 in a manner substantially similar to Example 18 with the following changes: Step j: 2- (1- (S)- Amino-2-phenylethyl) -1- (2- (1,
1-Dimethylethoxy) -2-oxo-ethyl) -4- (4-methoxyphenyl) -imidazole Intermediate 18i (854 mg, 2.0 mmol) was dissolved in DMF (10 ml) and tert-butyl bromoacetate (646 μl, 4.0 mmol) and K ₂
CO ₃ (552 mg, 4.0 mmol) was added and the reaction was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was dissolved in EtOAc and washed with a saturated NaCl solution. The EtOAc layer was dried over Na ₂ SO _4, filtered, and concentrated in vacuo to give a foam 1.02 g. Mass spectrum: 428.2MH +. NMR (300
MHz, DMSO-d6): 7.85-8.0 (1H, d), 7.6-7.75 (2H, d), 7.85-7.95 (1H
, 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). This intermediate white foam (1.02 g, 1.88 mmol) was treated with 10% Pd /
Dissolve in HOAc (50 ml) containing C, and add H ₂ (30 ps) at room temperature for 10 hours.
Hydrogenated under i). The catalyst was removed by filtration and 2N HCl (940 μL, 1.
(88 mmol). The mixture was lyophilized once and then 20% CH ₃
Lyophilized again from CN / H ₂ O and afforded intermediate 19j (862
mg) which was used without further purification. Mass spectrum: 408.2
MH +. Step g; Catalytic hydrogenation and work-up were performed in substantially the same manner as Step 18g to give the title product (22 mg, 4%) as a white solid. Mass spectrum: 1
088.2 MH +. Embodiment 20 FIG. Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe {(4- (phenyl) imidazole) -Gly] Prepared according to Scheme 3 in substantially the same manner as in Example 18, except using acetophenone. Mass spectrum: 1057.4 MH +
. Embodiment 21 FIG. Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (3
-Methoxyphenyl) imidazole)-(ε) Ahx] Example 21 was prepared according to Scheme 3 in a manner substantially similar to Example 18 with the following changes: Step j: 2- (1- (S) -Amino-2-phenylethyl) -1- (6- (ethoxy) -6-oxo-hexyl) -4- (3-methoxyphenyl) -imidazole Intermediate 21i (855 mg, 2.0 mmol) Dissolve in DMF (8.0 ml), KHCO ₃ (200 mg, 2.0 mmol) and 6 at about 120 ° C. for about 8 hours.
Treated with ethyl-bromohexanoate (3.56 ml, 20 mmol). 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).

This crude alkylation product was deprotected by hydrogenation with acetic acid using 10% Pd / carbon as catalyst. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure. The residue was dissolved in dilute hydrochloric acid, frozen and lyophilized to give Intermediate 21j (720 mg, 91%) as a pale yellow solid, which was used in the next step without further purification. Mass spectrum: 436.2 MH +. Step k and step 1: 2- (1- (S)-((H-Trp-D-Trp-Lys (
Boc) -Tyr (OBzl) -2- (1- (S) -amino-2-phenylethyl) -1- (6- (ethoxy) -6-oxo-hexyl) -4- (3-methoxyphenyl)- Fmoc-Tyr (OBzl) -OH (493 m) in 8 ml of imidazole EtOAc
g, 1.00 mmol), HOAt (136 mg, 1.0 mmol) and DCC
(206 mg, 1.0 mmol) was mixed for about 時間 hour, then dicyclohexylurea was filtered off to produce Fmoc-Tyr (OBzl) -OAt. The resulting solution was combined with intermediate 21j (457 mg, 0.9 mmol) in E
To the tOAc solution (4 ml), add saturated Na until the reaction is complete by mass spectrometry.
The mixture was stirred with HCO ₃ solution (10 ml). The aqueous layer was removed and EtOAc
The layers were dried over Na ₂ SO _4, filtered, tris (2-aminoethyl) amine (2.
7 ml). The mixture was vigorously stirred for about 1/2 hour. This EtOA
The c-layer was washed with a saturated NaCl solution (2 × 60 ml) and then the pH of the solution was adjusted to about 5.5 using 10% phosphate buffer (3 × 15 ml).

This intermediate was converted to Fmoc-Lys (Cbz) -OSu, Fmoc-DT in a manner substantially similar to the Fmoc-Tyr (OBzl) -OAt cycle described above.
Successive deprotection and coupling were performed using rp-OSu and Fmoc-Trp-OSu. Final Fmoc deprotection resulted in the intermediate ethyl ester deprotected at the N-terminus. The EtOAc layer was dried over Na ₂ SO ₄ , filtered and
Diluted with twice the amount of hexane. The solvent was drained and the residue was triturated with hexane to give the product as a solid (0.67 g, 58%). It was used without further purification. Mass spectrum: 1289.6 MH +.

A solution of the intermediate in MeOH (5.0 ml) was treated with 1.7 M NaOH (1.7 ml) overnight to remove the ethyl ester. This mixture was p-poured with 5% HCl.
H was adjusted to about 8.2 and the solvent was removed under reduced pressure. Dissolve this residue in DMF,
The NaCl was removed by filtration and the DMF solution was used for the next step without further purification.

The cyclization and deprotection were carried out in the same manner as in Example 18 to obtain 62 mg of the title compound of Example 21 as a white powder. Mass spectrum: 1143.9 MH +. Embodiment 22 FIG. Cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (3
-Hydroxyphenyl) imidazole)-(γ) Abu] Example 22 was prepared according to Scheme 3 in a manner substantially similar to Example 18 with the following changes. Step j: 2- (1- (S) -amino-2-phenylethyl) -1- (4- (ethoxy) -4-oxo-butyl) -4- (4-hydroxyphenyl) -imidazole intermediate 22i ( 2.0 g, was dissolved 4.68 mmol) in _{DMF (7.0ml), KHCO 3 (} 468mg, 4.68 mmol) and 4-bromo - treated with butyrate (6.70ml, 46.8 mmol), The mixture was stirred at about 100 ° C. for about 30 hours. The mixture is diluted with ether and once with saturated NaHCO ₃ solution,
Washed once with 1 solution. The ether layer was dried over Na ₂ SO ₄ , filtered and concentrated to an oil. Column chromatography on silica gel using CH ₂ Cl ₂ as eluent gave the product (2.53 g, 94%) as an oil.
Mass spectrum: 542.3 MH +.

A solution of the crude alkylated product (2.53 g, 4.67 mmol) in CH ₂ Cl ₂ (50 ml) was mixed with 1 M BBr ₃ / hexane (23.4 ml) / CH ₂ Cl ₂ (2
50 ml) was added dropwise to the solution at about -10 ° C over about 15 minutes. The mixture was warmed to room temperature and stirred for 2 hours. EtOH (40 ml) was added and the mixture was added to about 5
It was concentrated to 0 ml. This solution was diluted with ethanol (100 ml) and stirred at room temperature overnight. The mixture was concentrated under reduced pressure and the residue was partitioned between EtOAc and saturated NaHCO ₃ solution. The EtOAc layer was dried over Na ₂ SO ₄ , filtered and concentrated in vacuo to an oil (1.41 g, 76%) which was used without further purification in the next step. Mass spectrum: 394.3 MH ⁺ . HPLC retention time HPLC system Retention time (min) 1 A 13.65 2 A 18.503 A 16.034 B 6.975 C 20.41 6 C 11.757 D 9.538 B 11.02 9 E 7 .69 10 J 6.02 11F 4.18 12 G 4.11 13 H 5.50 14 G 6.16 15 I 17.03 16 K 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 HPLC system A. _{Gradient: 20~80% CH 3 CN / 0.1} % Tfa, 24 minutes flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (TM) Protein and Peptid e C18 B. _{Gradient: 35~50% CH 3 CN / 0.1} % Tfa, 24 minutes flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (TM) Protein and Peptid e C18 C. _{Gradient: 32~64% CH 3 CN / 0.1} % NH 4 OAc, 24 minutes flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (TM) Protein and Peptid e C18 D. _{Gradient: 20~60% CH 3 CN / 0.1} % Tfa, 24 minutes flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (TM) Protein and Peptid e C18 E. Gradient: 55-75% CH ₃ CN / 0.1% Tfa, 24 min Flow rate: 1.0 ml / min Detection: 220 nm Column: Phenomenex LICHROSPHERE (registered trademark) 5 RP18 (Phenomenex, 2320W, 205 ^th St., Torrance) , CA). Gradient: 60% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (registered trademark) Protein and Peptide C18 G. Gradient: 50% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (registered trademark) Protein and Peptide C18 H. Gradient: 38% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (registered trademark) Protein and Peptide C18 I.I. _{Gradient: 20~40% CH 3 CN / 0.1} % Tfa, 24 minutes flow rate: 1.0 ml / min Detection: 254 nm Column: VYDAC (TM) Protein and Peptid e C18 J. Gradient: 50% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: NUCLEOSIL ^™ C18, 5 microns (Alltech Associates, 2051 Waukegen Rd., Deerfield, Illinois) Gradient: 40% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: NUCLEOSIL ^™ C18, 5 microns Gradient: 52% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: NUCLEOSIL ^™ C18, 5 micron Gradient: 50% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: NUCLEOSIL ^™ C18, 5 microns Gradient: 48% CH ₃ CN / 0.1% Tfa, isocratic Flow rate: 1.0 ml / min Detection: 254 nm Column: NUCLEOSIL ^™ C18, 5 microns

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 1/04 A61P 3/10 3/06 13/12 3/10 19/02 13/12 27/02 19 / 02 29/00 27/02 31/04 29/00 35/00 31/04 37/06 35/00 43/00 37/06 C07D 233/64 105 43/00 A61K 37/02 C07D 233/64 105 37 / 24 (81) Designated countries EP (AT, BE, CH, CY, DE, DK, ES, FI, FR, GB, GR, IE, IT, LU, MC, NL, PT, SE), OA (BF , BJ, CF, CG, CI, CM, GA, GN, GW, ML, MR, NE, SN, TD, TG), AP (GH, GM, KE, LS, MW, SD, SL, SZ, UG) , ZW), EA (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM ), AE, AL, AM, AT, AU, AZ, BA, BB, BG, BR, BY, CA, CH, CN, CU, CZ, DE, DK, EE, ES, FI, GB, GE, GH , GM, HR, HU, ID, IL, IN, IS, JP, KE, KG, KP, KR, KZ, LC, LK, LR, LS, LT, LU, LV, MD, MG, MK, MN, M W, MX, NO, NZ, PL, PT, RO, RU, SD, SE, SG, SI, SK, SL, TJ, TM, TR, TT, UA, UG, US, UZ, VN, YU, ZA, ZWF term (reference) 4C084 AA02 AA07 BA09 BA16 BA17 BA32 CA59 DB11 DB70 NA14 ZA331 ZA361 ZA511 ZA531 ZA661 ZA681 ZA701 ZA811 ZA961 ZB111 ZB261 ZB351 ZC331 ZC351 ZC412 ZC422 ZC551 A03A03 MA02 A03 MA03 ZA53 ZA66 ZA68 ZA70 ZA81 ZA96 ZB11 ZB26 ZB35 ZC33 ZC35 ZC41 ZC42 Z C55 4H045 AA10 AA20 AA30 BA13 BA14 BA51 EA20 FA30

Claims (25)

[Claims] 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof. Embedded image[Wherein, Y and Z are each independently a natural or unnatural α-adhesion of D- or L-
N is independently from 0 to 50 at each occurrence (provided that both n are 0 at the same time)
M is 0 or an integer of 1 to 10; a is H or R¹B is OH, -OR¹Or -NR⁹R⁹Or a forms an amide bond with b; R¹Are independently H, (C₁-C_Four) Alkyl or aryl- (C₁-C_Four) Alkyl
R^TwoIs H or (C₁-C_Four) Alkyl, phenyl, phenyl- (C₁-C _Four ) Alkyl and heterocyclyl- (C₁-C_Four) Selected from the group consisting of alkyl
And optionally substituted components, wherein the optionally substituted components are (
C₁-C_Four) Alkyl, (C_Three-C₈) Cycloalkyl, -OR⁶, -S (O)_q−
R⁷, -N (R⁹R⁹), -NHCO-R⁶, -NHSO_TwoR⁹, -CO_TwoR⁹, -CO
NR⁹R⁹And -SO_TwoNR⁹R⁹(Where q is 0, 1, 2 or 3)
By one or more substituents, each independently selected from the group
R^ThreeAnd R^FourIs independently H, halo, or (C₁-C_Four) Alkyl, (C_Three
-C₈) Cycloalkyl, aryl and aryl- (C₁-C_Four) From alkyl
Optionally substituted components selected from the group consisting of:
OH, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, aryl
Oxy, aryl- (C₁-C_Four) Alkoxy, -NR⁹R⁹, COOH, -CON
R⁹R⁹And one or more substituents selected from the group consisting of
Optionally substituted; or R^ThreeAnd R^FourTogether with the carbon to which they are attached
To form an optionally substituted aryl, wherein the aryl is OH, (C₁
-C_Four) Alkyl, (C₁-C_Four) Alkoxy, aryloxy, aryl- (C₁ -C_Four) Alkoxy, -NR⁹R⁹, COOR^Five, -CONR⁹R⁹And halo
Optionally by one or more substituents each independently selected from the group
R is substituted^FiveIs independently H at each occurrence, or (C₁-C_Four) Alkyl and ally
Ru- (C₁-C_Four) An optionally substituted member selected from the group consisting of alkyl
And the optionally substituted component is (C₁-C_Four) Alkyl, OH, (
C₁-C_Four) Alkoxy, aryloxy, NO_Two, Aryl- (C₁-C_Four) Al
Coxy, -NR⁹R⁹, COOH, -CONR⁹R⁹And halo
Optionally substituted by one or more independently selected substituents
R⁶Is H, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, a
Reel-(C₁-C_Four) Alkyl and aryl- (C₁-C_Four) Consisting of alkoxy
Independently selected from the group; R⁷Is H when q is 3 or R⁷Is that q is 0, 1
Or 2, (C₁-C_Four) Alkyl, aryl or aryl- (C₁-C_Four R) is independently selected from the group consisting of alkyl;⁹Is H, NO for each occurrence_Two, (C₁-C_Four) Alkyl, aryl and aryl
− (C₁-C_Four) Is independently selected from the group consisting of alkyl. ] 2. A compound of formula (II) or a pharmaceutically acceptable salt thereof. Embedded image[Wherein, Y and Z are each independently a natural or unnatural α-adhesion of D- or L-
M is 0 or an integer from 1 to 10; n is independently from 0 to 6 at each occurrence; R¹Is independently H, (C₁-C_Four) Alkyl or aryl- (C₁-C _Four R) is alkyl;^TwoIs H or (C₁-C_Four) Alkyl, phenyl, phenyl- (C₁-C _Four ) Alkyl and heterocyclyl- (C₁-C_Four) Selected from the group consisting of alkyl
And optionally substituted components, wherein the optionally substituted components are (
C₁-C_Four) Alkyl, cycloalkyl, -OR⁶, -S (O)_q-R⁷, -N (
R⁹R⁹), -NHCO-R⁶, -NHSO_TwoR⁹, -CO_TwoR⁹, -CONR⁹R⁹Passing
And -SO_TwoNR⁹R⁹(Where q is 0, 1, 2, or 3)
Optionally substituted by one or more substituents, each independently selected
R^ThreeAnd R^FourIs independently H, halo, or (C₁-C_Four) Alkyl, cyclo
Alkyl, aryl and aryl- (C₁-C_Four) Selected from the group consisting of alkyl
And optionally substituted components; wherein the optionally substituted components are O
H, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, aryloxy, aryl
Ru- (C₁-C_Four) Alkoxy, -NR⁹R⁹, COOH, -CONR⁹R⁹And halo
Optionally substituted by one or more substituents selected from the group consisting of:
Or R^ThreeAnd R^FourAre optionally placed together with the carbon to which they are attached.
To form an aryl, wherein the aryl is OH, (C₁-C_Four) Alkyl,
(C₁-C_Four) Alkoxy, aryloxy, aryl- (C₁-C_Four) Alkoxy
, -NR⁹R⁹, COOR^Five, -CONR⁹R⁹From the group consisting of
Optionally substituted by one or more substituents selected from^FiveIs independently H at each occurrence, or (C₁-C_Four) Alkyl and ally
Ru- (C₁-C_Four) An optionally substituted member selected from the group consisting of alkyl
And the optionally substituted component is (C₁-C_Four) Alkyl, OH, (
C₁-C_Four) Alkoxy, aryloxy, NO_Two, Aryl- (C₁-C_Four) Al
Coxy, -NR⁹R⁹, COOH, -CONR⁹R⁹And halo
R optionally substituted with one or more independently selected substituents; R⁶Is H, (C₁-C_Four) Alkyl, (C₁-C_Four) Alkoxy, a
Reel-(C₁-C_Four) Alkyl and aryl- (C₁-C_Four) Consisting of alkoxy
Independently selected from the group; R⁷Is H when q is 3 or R⁷Is that q is 0, 1
Or 2, (C₁-C_Four) Alkyl, aryl or aryl- (C₁-C_Four R) is independently selected from the group consisting of alkyl;⁹Is H, NO for each occurrence_Two, (C₁-C_Four) Alkyl, aryl and aryl
− (C₁-C_Four) Is independently selected from the group consisting of alkyl. X¹Is a natural or unnatural D- or L-α-amino acid, where X¹Is Phe,
When Nal, Trp, Tyr, Pal or His, the aromatic ring is carbon or
R on nitrogen⁶Or optionally substituted by X¹Is Ser or Thr
And optionally the side chain oxygen may have one or more R¹X^TwoIs D- or L-Trp, N-methyl-D-Trp or N-methyl-L-Tr
p; X^ThreeIs Lys, α-N-methyl-Lys or ε-N- (C₁-C_Four) Alkyl-L
ys or ε-N- [aryl- (C₁-C_Four) Alkyl] -Lys; X^FourIs a natural or unnatural D- or L-α-amino acid, where X^FourIs Phe,
When Nal, Trp, Tyr or His, the aromatic ring is on carbon or nitrogen
R⁸Or optionally substituted by X^FourIs Ser, Tyr or Thr
And the side chain oxygen has one or more R¹Can be replaced by ] 3. n is 2 each; m is 0 or 1-5; R ¹ is independently at each occurrence H, methyl or aryl- (C ₁ -C ₄ ) alkyl. R ² is an optionally substituted moiety selected from the group consisting of phenyl- (C ₁ -C ₄ ) alkyl and heterocyclyl- (C ₁ -C ₄ ) alkyl, where optionally substituted The components are substituted by a substituent selected from the group consisting of (C ₁ -C ₄ ) alkyl and —O—R ⁶ ; R ³ and R ⁴ are each independently H, halo, or (C _1- C ₄₎ is selected from the group consisting of alkyl and aryl, optionally be a component to be replaced; component to be replaced by this _{case, OH, (C 1 -C 4} ) alkoxy, the group consisting of aryloxy and halo Depending on the substituent selected from More substituted compound of claim 2, wherein. 4. X ¹ is Phe, Nal, Trp, Tyr, Pal or His, whose aromatic ring is optionally substituted on carbon or nitrogen by R ⁶ ; X ⁴ is Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, wherein the aromatic ring of Nal, Trp, Tyr and His is optionally substituted on carbon and / or nitrogen by R ⁸ , or X ⁴ is Ser, Tyr or Thr
When oxygen of the side chain is optionally substituted by R ^1, The compound of claim 3 wherein. 5. 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, where Thr and T
side chain oxygen of the hydroxy groups of yr is optionally substituted with R ^1; R ¹ is independently at each occurrence H, methyl or benzyl; R ² is selected from the group consisting of phenylmethyl and heterocyclyl methyl ,
The optionally substituted component, wherein the optionally selected component is (C _1-
R ³ is substituted by a substituent selected from the group consisting of: C ₄ ) alkyl and —O—R ⁶ ; R ³ is (C ₁ -C ₄ ) alkyl or optionally substituted aryl; Aryl is substituted by a substituent selected from the group consisting of OH, (C ₁ -C ₄ ) alkoxy, aryloxy and halo; R ⁴ is H; and R ⁶ is at each occurrence H and aryl - (C ₁ -C ₄₎ are independently selected from the group consisting of alkoxy 5. the compound of claim 4, wherein. 6. X¹Is Phe, Trp, Tyr or Tyr (OBzl); X^FourIs Val, Thr, Abu, Nal or Tyr, where Thr and T
the hydroxy group of yr is an optionally substituted benzyl; m is 0, 2 or 4;^TwoIs selected from the group consisting of phenylmethyl or 3-indolylmethyl;
An optionally substituted component, wherein the optionally selected component is -OR ⁶ Optionally substituted by; and R^ThreeIs 1,1-dimethylethyl or an optionally substituted aryl
Yes; the optionally substituted aryl is OH, (C₁-C_Four) Alkoxy and
6. Optionally substituted by a component selected from the group consisting of:
A compound as described. 7. R ² is phenylmethyl; R ³ is 1,1-dimethylethyl or optionally substituted phenyl, wherein the optionally substituted phenyl is OH or OCH ₃ 7. The compound of claim 6, wherein R ⁶ is optionally selected from the group consisting of H or benzylmethoxy at each occurrence. 8. An H-Trp-D-Trp-Lys-Abu-PheΨ (4- (
The compound according to claim 1, which is 3-methoxyphenyl) imidazole) -Gly-OH. 9. 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-Lys-Val-Phe} (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 {(4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (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) -PheΨ (4- (
3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr-Phe} (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} (4- (3-hydroxyphenyl) imidazole) -Gly], 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) -PheΨ (4- (
3-methoxyphenyl) imidazole)-(γ) 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)-(ε) Ahx] or cyclo [Trp-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
8-hydroxyphenyl) imidazole)-(γ) Abu]. 10. 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-Lys-Val-Phe} (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 {(4- (3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (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 cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly]. Item 10. The compound according to item 9, 11. Cyclo [Tyr-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) 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-Val-Phe {(4- (3-methoxyphenyl) imidazole) -Gly] or Cycloalkyl [Tyr-D-Trp-Lys-Val-PheΨ (4- (3- hydroxyphenyl) imidazole) -Gly], 10. A compound according. 12. Cyclo [Tyr-D-Trp-Lys-Val-Phe {(4- (3-methoxyphenyl) imidazole) -Gly], Cyclo [Trp-D-Trp-Lys-Val-Phe} (4- ( 3-Hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly] or cyclo [Tyr-D-Trp-Lys-Val] The compound according to claim 11, wherein -Phe {(4- (3-hydroxyphenyl) imidazole) -Gly]. 13. Cyclo [Tyr-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) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Thr (OBzl) -PheΨ (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} (4- (
1,1-dimethylethyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr (OBzl) -Phe} (4- (
3-methoxyphenyl) imidazole) -Gly], cyclo [Phe-D-Trp-Lys-Tyr-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly], cyclo [Trp-D-Trp-Lys-Tyr] (Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole) -Gly], cyclo [Tyr-D-Trp-Lys-Val-Phe} (4- (3-hydroxyphenyl) imidazole) -Gly], 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 (Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole)-(γ) 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) -PheΨ (4- (3
-Methoxyphenyl) imidazole)-(ε) Ahx] or cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (3
-Hydroxyphenyl) imidazole)-(γ) Abu]. 14. Cyclo [Trp-D-Trp-Lys-Thr-Phe {(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) -Gly], cyclo [Trp-D-Trp-Lys-Tyr ( Bzl) -PheΨ (4- (3
-Methoxyphenyl) imidazole)-(γ) Abu], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (4
14. The compound according to claim 13, which is -methoxyphenyl) imidazole) -Gly] or cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (phenyl) imidazole) -Gly]. 15. 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)-(γ) Abu], cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (4
The compound according to claim 14, which is-[methoxyphenyl) imidazole) -Gly] or cyclo [Trp-D-Trp-Lys-Tyr (Bzl) -Phe} (4- (phenyl) imidazole) -Gly]. 16. A pharmaceutical composition comprising an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 17. A pharmaceutical composition comprising an effective amount of the compound according to claim 2 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. 18. A method for inducing a somatostatin receptor agonist in a mammal in need thereof, comprising the step of: administering an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof to said mammal. Administering to the said method. 19. A method for eliciting the effect of a somatostatin receptor agonist in a mammal in need thereof, comprising administering an effective amount of the compound of claim 2 or a pharmaceutically acceptable salt thereof to said mammal. Administering to the said method. 20. A method for eliciting the effect of a somatostatin receptor antagonist in a mammal in need thereof, comprising: administering the compound of claim 1 or an effective amount of a pharmaceutically acceptable salt thereof to the mammal. Administering to the subject. 21. A method for inducing a somatostatin receptor antagonist in a mammal in need thereof, comprising the step of: administering an effective amount of the compound according to claim 2 or a pharmaceutically acceptable salt thereof to the mammal. Administering to the said method. 22. Prolactin-secreting adenoma restenosis, diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular injury, proliferative retinal disorder, dawn phenomenon, renal disorder; gastric acid secretion, peptic ulcer, intestinal skin And pancreatic skin fistula, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, AIDS-associated diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormone-secreting tumor, cancer, hepatoma A method of treating a mammal in need of treatment for angiogenesis, inflammatory disorders, arthritis, chronic graft rejection, angiogenesis, transplanted blood vessels or gastrointestinal bleeding, wherein the compound of claim 1 or a method thereof. Administering to the mammal a pharmaceutically acceptable salt,
The method. 23. Prolactin-secreting adenoma restenosis, diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular injury, proliferative retinal disorder, dawn phenomenon, renal disorder; gastric acid secretion, peptic ulcer, intestinal skin And pancreatic skin fistula, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, AIDS-associated diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormone-secreting tumor, cancer, hepatoma A method of treating a mammal in need of treatment for angiogenesis, inflammatory disorders, arthritis, chronic graft rejection, angiogenesis, transplanted blood vessels or gastrointestinal bleeding, wherein the compound according to claim 2 or a method thereof. Administering to the mammal a pharmaceutically acceptable salt,
The method. 24. A method for inhibiting the growth of helicobacter pylori in a mammal in need thereof, comprising administering to the mammal the compound according to claim 1 or a pharmaceutically acceptable salt thereof. The method. 25. A method for inhibiting the growth of helicobacter pylori in a mammal in need thereof, comprising administering to the mammal the compound according to claim 2 or a pharmaceutically acceptable salt thereof. The method.