CN1200000C

CN1200000C - Somatostatin analogs

Info

Publication number: CN1200000C
Application number: CNB998075027A
Authority: CN
Inventors: 汤玛斯·D·高登
Original assignee: Societe de Conseils de Recherches et dApplications Scientifiques SCRAS SAS
Current assignee: Ipsen Pharma SAS
Priority date: 1998-06-16
Filing date: 1999-06-11
Publication date: 2005-05-04
Anticipated expiration: 2019-06-11
Also published as: AR021161A1; WO1999065942A8; TWI242442B; TW527361B; AU4822399A; JP2002518409A; PL345037A1; NO20006320L; HUP0102902A2; EP1086131A1; WO1999065942A1; TWI242441B; CN1305496A; RU2242481C2; HUP0102902A3; NO20006320D0; TW200410986A; CA2335184A1; AU745493B2

Abstract

The present invention relates to cyclic derivatives containing imidazole cis amide bond mimetics that selectively bind to somatostatin receptor subtypes and to the use of such compounds in the treatment of diseases treatable by the induction of agonist or antagonist action from somatostatin subtype receptors. The invention also relates to methods of preparing the compounds of the invention.

Description

Somatostatin analogs

Background of invention

The present invention relates to contain the cyclic derivatives of imidazoles cis amido linkage stand-in, this compound optionally combines with the somatostatin receptor hypotype.The invention still further relates to the method for preparing The compounds of this invention.

Somatostatin (SRIF) is a kind of ring-type tetradecapeptide hormone that contains disulfide linkage between 3 and 14, and it can suppress the secretion of the release of tethelin (GH) and thyrotropin (TSH), the release that suppresses Regular Insulin and hyperglycemic-glycogenolytic factor and minimizing stomach.Somatostatin is by aminopeptidase and carboxypeptidase metabolism, and action time is very short.

Somatostatin can with the combination of five kinds of different acceptors (SSTR) hypotype, each hypotype is all had higher affinity.The present invention is less, that rigidity is stronger, and analogue demonstrates very high selectivity to multiple receptor subtype.Relevant with dissimilar somatostatin hypotype combinations with following illness of treatment and/or disease.2 is relevant with TSH secretion adenoma with tethelin inhibition, particularly GH secretion adenoma (acromegaly) with the activation of 5 types.Activate 2 types but do not activate 5 types with the treatment prolactin-secreting adenoma relevant.Other indication relevant with activating the somatostatin hypotype is the inhibition of restenosis, Regular Insulin and/or hyperglycemic-glycogenolytic factor, particularly diabetes, hyperlipidaemia, insulin insensitivity, X syndrome, vascular disease, proliferating retinopathy, dawn phenomenon and ephrosis; The inhibition of gastric acid secretion, particularly peptide ulceration, intestines fistula of skin and pancreas fistula of skin, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, the diarrhoea relevant, the diarrhoea that chemotherapy causes, acute or chronic pancreatitis and gastrointestinal hormone ` secreting tumor with AIDS; The treatment of cancer such as hepatoma; The inhibition of vasculogenesis, inflammatory diseases such as arthritic treatment; Chronic allograft rejection reaction; Angioplasty; Prevention grafting vessel and gastrointestinal hemorrhage.Somatostatin agonists also can be used for reducing patient's body weight.

It is reported that somatostatin agonists also can be used for suppressing the propagation of Hp.

Summary of the invention

On the one hand, the invention provides compound or its pharmaceutically useful salt of formula (I),

Wherein,

Y and Z are D-or the natural or non-natural a-amino acid of L-when occurring at every turn independently of one another;

N is 0 to 50 when occurring at every turn independently of one another, and condition is that two n can not be 0 simultaneously;

M is 0 or 1 to 10 integer;

A is H or R ¹

B be OH ,-OR ¹Or-NR ⁹R ⁹

Perhaps a and b lump together the formation amido linkage;

R ¹Be H, (C independently of one another ₁-C ₄) alkyl or aryl-(C ₁-C ₄) alkyl;

R ²Be H or be selected from (C ₁-C ₄) alkyl, phenyl, phenyl-(C ₁-C ₄) alkyl and heterocyclic radical-(C ₁-C ₄) part that the selectivity of alkyl replaces, wherein, the part that selectivity replaces is optionally replaced by one or more substituting group, and described substituting group is independently from each other (C ₁-C ₄) alkyl, (C ₃-C ₈) cycloalkyl ,-O-R ⁶,-S (O) _q-R ⁷,-N (R ⁹R ⁹) ,-NHCO-R ⁶,-NHSO ₂R ⁹,-CO ₂R ⁹,-CONR ⁹R ⁹With-SO ₂NR ⁹R ⁹, wherein q is 0,1,2 or 3;

R ³And R ⁴Be H, halogen independently of one another or be selected from (C ₁-C ₄) alkyl, (C ₃-C ₈) cycloalkyl, aryl and aryl-(C ₁-C ₄) part that replaces of the selectivity of alkyl; Wherein, the part that selectivity replaces is optionally replaced by one or more substituting group, and described substituting group is independently from each other OH, (C ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, aryloxy, aryl-(C ₁-C ₄) alkoxyl group ,-NR ⁹R ⁹,-COOH ,-CONR ⁹R ⁹And halogen; Perhaps R ³And R ⁴The carbon that is connected with them lumps together and forms the aryl that selectivity replaces, and aryl is wherein optionally replaced by one or more substituting group, and described substituting group is independently from each other OH, (C ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, aryloxy, aryl-(C ₁-C ₄) alkoxyl group ,-NR ⁹R ⁹,-COOR ⁵,-CONR ⁹R ⁹And halogen;

R ⁵Be H at every turn independently of one another when occurring or be selected from (C ₁-C ₄) alkyl and aryl-(C ₁-C ₄) part that the selectivity of alkyl replaces, wherein, the part that selectivity replaces is optionally replaced by one or more substituting group, and described substituting group is independently from each other (C ₁-C ₄) alkyl, OH, (C ₁-C ₄) alkoxyl group, aryloxy, NO ₂, aryl-(C ₁-C ₄) alkoxyl group ,-NR ⁹R ⁹, COOH ,-CONR ⁹R ⁹And halogen;

R ⁶When occurring, be independently from each other H, (C at every turn ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, aryl-(C ₁-C ₄) alkyl and aryl-(C ₁-C ₄) alkoxyl group;

When q is 3, R ⁷Be H; Perhaps when q is 0,1 or 2, R ⁷When occurring, be independently from each other (C at every turn ₁-C ₄) alkyl, aryl or aryl-(C ₁-C ₄) alkyl;

R ⁹When occurring, be independently from each other H, NO at every turn ₂, (C ₁-C ₄) alkyl, aryl and aryl-(C ₁-C ₄) alkyl.

A preferred formula (I) compound is compound H-Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly-OH.

On the other hand, the invention provides compound or its pharmaceutically useful salt of formula (II),

Wherein,

M is 0 or 1 to 10 integer;

N is 0 to 6 when occurring at every turn independently of one another;

R ¹Be H, (C independently of one another when occurring at every turn ₁-C ₄) alkyl or aryl-(C ₁-C ₄) alkyl;

R ²Be H or be selected from (C ₁-C ₄) alkyl, phenyl, phenyl-(C ₁-C ₄) alkyl and heterocyclic radical-(C ₁-C ₄) part that the selectivity of alkyl replaces, wherein, the part that selectivity replaces is optionally replaced by one or more substituting group, and described substituting group is independently from each other (C ₁-C ₄) alkyl, cycloalkyl ,-O-R ⁶,-S (O) _q-R ⁷,-N (R ⁹R ⁹) ,-NHCO-R ⁶,-NHSO ₂R ⁹,-CO ₂R ⁹,-CONR ⁹R ⁹With-SO ₂NR ⁹R ⁹, wherein q is 0,1,2 or 3;

R ³And R ⁴Be H, halogen independently of one another or be selected from (C ₁-C ₄) alkyl, cycloalkyl, aryl and aryl-(C ₁-C ₄) part that replaces of the selectivity of alkyl; Wherein, the part that selectivity replaces is optionally replaced by one or more substituting group, and described substituting group is selected from OH, (C ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, aryloxy, aryl-(C ₁-C ₄) alkoxyl group ,-NR ⁹R ⁹,-COOH ,-CONR ⁹R ⁹And halogen; Perhaps R ³And R ⁴The carbon that is connected with them lumps together and forms the aryl that selectivity replaces, and aryl is wherein optionally replaced by one or more substituting group, and described substituting group is independently from each other OH, (C ₁-C ₄) alkyl, (C ₁-C ₄) alkoxyl group, aryloxy, aryl-(C ₁-C ₄) alkoxyl group ,-NR ⁹R ⁹,-COOR ⁵,-CONR ⁹R ⁹And halogen;

R ⁹When occurring, be independently from each other H, NO at every turn ₂, (C ₁-C ₄) alkyl, aryl and aryl-(C ₁-C ₄) alkyl;

X ¹Be natural or non-natural D-or L-a-amino acid, wherein, work as X ¹When being Phe, Nal, Trp, Tyr, Pal or His, its aromatic ring on carbon or nitrogen optionally by R ⁶Replace, perhaps work as X ¹When being Ser or Thr, its side chain oxygen selective ground is by one or more R ¹Replace;

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

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

X ⁴Be natural or non-natural D-or L-a-amino acid, wherein, work as X ⁴When being Phe, Nal, Trp, Tyr or His, its aromatic ring on carbon or nitrogen optionally by R ⁸Replace, perhaps work as X ⁴When being Ser, Tyr or Thr, its side chain oxygen can be by one or more R ¹Replace.

X ¹, X ², X ³And X ⁴Between key and X ¹And key between the Z and X ⁴And the key between the Y equally is an amido linkage.

One group of preferred formula (II) compound (be appointed as A group) is, wherein,

N is 2;

M is 0 or 1 to 5;

R ¹Be H, methyl or aryl-(C independently of one another when occurring at every turn ₁-C ₄) alkyl;

R ²Be to be selected from phenyl-(C ₁-C ₄) alkyl and heterocyclic radical-(C ₁-C ₄) part that the selectivity of alkyl replaces, wherein, the part that selectivity replaces is selected from (C ₁-C ₄) alkyl and-O-R ⁶Substituting group replace;

R ³And R ⁴Be H, halogen independently of one another or be selected from (C ₁-C ₄) part that replaces of the selectivity of alkyl and aryl; Wherein, the part of selectivity replacement optionally is selected from OH, (C ₁-C ₄) substituting group of alkoxyl group, aryloxy and halogen replaces.

In the A group, one group of preferred compound (being appointed as the B group) is, wherein,

X ¹Be Phe, Nal, Trp, Tyr, Pal or His, wherein, their aromatic ring on carbon or nitrogen optionally by R ⁶Replace;

X ⁴Be Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, wherein, the aromatic ring of Nal, Trp, Tyr and His on carbon and/or nitrogen optionally by R ⁸Replace, perhaps work as X ⁴When being Ser, Tyr or Thr, side chain oxygen selective ground is by R ¹Replace.

In the B group compound, one group of preferred compound (being appointed as the C group) is, wherein,

X ¹Be Phe, Trp or Tyr, wherein, their aromatic ring on carbon or nitrogen optionally by R ⁶Replace;

X ²Be D-Trp or N-methyl D-Trp;

X ³Be Lys or α-N-methyl-Lys;

X ⁴Be Val, Thr, Abu, Nal or Tyr, wherein the side chain oxygen selective ground of the hydroxyl of Thr and Tyr is by R ¹Replace;

R ¹Be H, methyl or benzyl independently of one another when occurring at every turn;

R ²Be the part that is selected from the selectivity replacement of phenmethyl and heterocyclic radical-methyl, wherein, the part that selectivity replaces is selected from (C ₁-C ₄) alkyl and-O-R ⁶Substituting group replace;

R ³Be (C ₁-C ₄) aryl that replaces of alkyl or selectivity; Wherein, the aryl of selectivity replacement is selected from OH, (C ₁-C ₄) substituting group of alkoxyl group, aryloxy and halogen replaces;

R ⁴Be H;

R ⁶When occurring, be independently from each other H and aryl-(C at every turn ₁-C ₄) alkoxyl group.

In the C group compound, one group of preferred compound (being appointed as the D group) is, wherein

X ¹Be Phe, Trp, Tyr or Tyr (Bzl);

X ⁴Be Val, Thr, Abu, Nal or Tyr, wherein the hydroxyl of Thr and Tyr is optionally replaced by benzyl;

M is 0,2 or 4;

R ²Be to be selected from the part that the selectivity of phenmethyl or 3-indyl methyl replaces, wherein, the part that this selectivity replaces is optionally by-O-R ⁶Replace;

R ³Be 1, the aryl that 1-dimethyl ethyl or selectivity replace; Wherein, the aryl of selectivity replacement optionally is selected from OH, (C ₁-C ₄) group of alkoxyl group and halogen replaces;

In the D group compound, one group of preferred compound (being appointed as the E group) is, wherein

R ²It is phenmethyl;

R ³Be 1, the phenyl that 1-dimethyl ethyl or selectivity replace, wherein, the phenyl that selectivity replaces is optionally by OH or OCH ₃Replace;

R ⁶When occurring, be independently from each other H or benzyl methoxyl group at every turn.

In the E group compound, one group of preferred compound (being appointed as the F group) is,

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Tyr (Bzl)-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(1, the 1-dimethyl ethyl) imidazoles) Gly],

Ring [Phe-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-(γ) Abu],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(4-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(phenyl) imidazoles)-Gly],

The ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-(ε) Ahx] and

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-(γ) Abu].

In the F group compound, one group of preferred compound (being appointed as the G group) is,

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Tyr (Bzl)-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

The ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly] and

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly].

In the G group compound, one group of preferred compound (being appointed as the H group) is,

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

The ring [Phe-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly] or

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly].

In the H group compound, one group of preferred compound (being appointed as the I group) is,

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

The ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly] and

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly].

In the F group compound, another is organized preferred compound (being appointed as the J group) and is,

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(1, the 1-dimethyl ethyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(4-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(phenyl) imidazoles)-Gly],

In the J group compound, one group of preferred compound (being appointed as the K group) is,

Ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly],

The ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(4-p-methoxy-phenyl) imidazoles)-Gly] and

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(phenyl) imidazoles)-Gly].

In the K group compound, one group of preferred compound (being appointed as the L group) is,

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly],

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(phenyl) imidazoles)-Gly].

On the other hand, the invention provides the formula (I) that contains significant quantity or the pharmaceutical composition of formula (II) compound or pharmaceutically acceptable salt thereof and pharmaceutically acceptable carrier.

On the other hand, the present invention also provides the method for inducing the effect of the somatostatin receptor agonist in having the Mammals that needs, and this method comprises, to the formula (I) or formula (II) compound or pharmaceutically acceptable salt thereof of described administration significant quantity.

On the other hand, the present invention also provides the method for inducing the somatostatin receptor antagonist action in having the Mammals that needs, and this method comprises, to the formula (I) or formula (II) compound or pharmaceutically acceptable salt thereof of described administration significant quantity.

On the other hand, the present invention also provides treatment prolactin-secreting adenoma restenosis in the Mammals of needs treatment, diabetes, hyperlipidaemia, insulin insensitivity, X syndrome, vascular disease, proliferating retinopathy, dawn phenomenon, ephrosis, gastric acid secretion, peptide ulceration, intestines fistula of skin and pancreas fistula of skin, irritable bowel syndrome, dumping syndrome, watery diarrhea syndrome, the diarrhoea relevant with AIDS, the diarrhoea that chemotherapy causes, acute or chronic pancreatitis, the gastrointestinal hormone ` secreting tumor, cancer, hepatoma, vasculogenesis, inflammatory diseases, sacroiliitis, chronic allograft rejection reaction, angioplasty, the method of the hemorrhage or gastrointestinal hemorrhage of grafting vessel, this method comprises, to described administration formula (I) or formula (II) compound or pharmaceutically acceptable salt thereof.

On the other hand, the present invention also provides the method that suppresses Hp propagation in the Mammals of needs treatment, and this method comprises, to described administration formula (I) or formula (II) compound or pharmaceutically acceptable salt thereof.

On the other hand, the invention provides the method for compound in the following formula of preparation

Or

This method comprises, by cracking Prt group with the compound deprotection in the following formula,

Or

Wherein,

Prt is the amino acid side chain protecting group;

Y and Z are the D-of the selectivity side chain that has protection or L-is natural or non-natural a-amino acid, wherein H-N independently of one another ^*Be the amino acid whose amino of the defined N-end of Y, O=C ^*It is the carboxyl of the defined C-end amino acid of Z;

N is 1 to 50 when occurring at every turn independently of one another;

Other all variablees all define in as shown above the formula (I).

On the other hand, the invention provides the method for compound in the following formula of preparation,

Or

This method comprises:

Or

For formula (a) compound, compound and peptide coupling agent and additive reaction by with formula (a ') form amido linkage between defined last the amino acid whose terminal amino group of Y and defined last the amino acid whose terminal carboxyl(group) of Z; Perhaps,

For formula (b) compound, compound and peptide coupling agent and additive reaction by with formula (b ') form amido linkage between defined last the amino acid whose terminal carboxyl(group) of amino and Z endways; Perhaps,

For formula (c) compound, compound and peptide coupling agent and additive reaction by with formula (c ') form amido linkage between defined last amino acid whose terminal amino group of Y and terminal carboxyl(group); Wherein, Prt is the amino acid side chain protecting group;

N is 1 to 50 when occurring at every turn independently of one another;

Other all variablees all define in as shown above the formula (I).

On the other hand, the invention provides the method for preparing following formula: compound,

This method comprises, with formula

Compound and formula X '-CH (R ³) CO (R ⁴) α-Lu Daitong in the presence of alkali and polar aprotic solvent, react until reaction is basic and finish; Steaming removes the polarity aprotic solvent and obtains solid; Solid is dissolved in aprotic organic solvent and excessive N H ₄The OAc aqueous solution is to form solution; Also removing polar layer simultaneously obtains formula (A) compound with the solution backflow;

Wherein

X is an amine protecting group;

X ' is a halogen;

Other all variablees all define in as shown above the formula (I).

On the other hand, the present invention relates to the method for preparation formula (I) compound,

This method comprises, with the compound of formula (B)

With N _αThe amino acid of-protection, (Prt)-Y, in the presence of alkali coupling until the basic compound that finishes production (C) of reaction, wherein, N _αThe amino acid of-protection is the form of its active ester, acid anhydrides or carboxylic acid halides,

Optionally pass through conventional deprotection reaction with N _αThe amino deprotection of amino acid (the Prt)-Y of-protection is then with another N _αThe amino acid of-protection repeats linked reaction until obtaining required formula (I) compound;

Y is that selectivity has the D-of the side chain that contains protecting group or L-is natural or the non-natural a-amino acid when occurring at every turn independently of one another;

Prt is an amino protecting group;

R ' is alkyl ester or benzyl ester;

N is 1 to 100;

Other all variablees all define in as shown above the formula (I).

On the other hand; the invention provides the method for formula (I) compound of the above definition of preparation; this method comprises; formula (B) compound that will activate with the form of its active ester, acid anhydrides or carboxylic acid halides and peptide-resin by being familiar with the N-deprotection that method that peptide synthetic technician knows prepares (A ') coupling; with piperidines DMF, TAEA or similarly in the alkali with the Fmoc group deprotection of N-end, then with strong acid with the intermediate that forms (B ') deprotection and from the resin cracking get off.All variablees all define in as shown above the formula (I).

On the other hand; the invention provides the method for preparation formula (I) compound; this method comprises; formula (B) compound that will activate with the form of its active ester, acid anhydrides or carboxylic acid halides with by being familiar with peptide-resin (H) coupling of the N-deprotection that method that peptide synthetic technician knows prepares; with piperidines DMF, TAEA or similarly in the alkali with the Fmoc group deprotection of N-end, with the amino N of the N-end that discharges _αAmino acid (x) and the peptide linked reaction acidylate well known in the art of-Fmoc-protection repeat alkali deprotection and coupling step as required, mixing other amino acid (x), with strong acid with the intermediate of formation (C ') deprotection and from the resin cracking get off.All variablees all define in as shown above the formula (I).

On the other hand; the invention provides the method for preparation formula (I) compound; this method comprises; formula (B) compound that will activate with the form of its active ester, acid anhydrides or carboxylic acid halides and the amino resin that replaces are as three-(alkoxyl group)-benzyl polyimide resin (PAL resin), 4-(2 '; 4 '-Dimethoxyphenyl-amino methyl)-phenoxy resin (the Rink resin of N-deprotection) or benzhydrylamine resin coupling; with piperidines DMF, TAEA or similarly in the alkali with the Fmoc group deprotection of N-end, with the amino N of the N-end that discharges _αThe amino acid (x) of-Fmoc-protection is by peptide linked reaction acidylate well known to those skilled in the art; repeat alkali deprotection and coupling step as required mixing other amino acid (x), with strong acid with the intermediate that forms (D ') deprotection and from the resin cracking get off.All variablees all define in as shown above the formula (I).

On the other hand, the invention provides the method for preparation formula (I) compound, this method comprises, with formula (B) compound and alkali such as Cs ₂CO ₃Reaction, with polystyrene resin such as the Merrifield peptide resin reaction of the cesium salt of the phenol that forms (E ') with halogenated methylation, with piperidines or similarly organic bases remove the Fmoc protecting group, with the amino N of the N-end that discharges _αThe amino acid (x) of-Fmoc-protection is by peptide linked reaction acidylate well known to those skilled in the art; repeat alkali deprotection and coupling step as required to mix other amino acid (x); also use Tfa at the terminal deprotection of C-with piperidines or similar organic bases at the terminal deprotection of the N-of the peptide sequence of final protection; the intermediate that forms (F ') by peptide linked reaction well known to those skilled in the art cyclisation, is got off the intermediate of formation (G ') cracking from the resin with strong acid.All variablees all define in as shown above the formula (I).

On the other hand; the invention provides the method for formula (I) compound of the above definition of preparation; this method comprises; peptide-the resin of formula (B) compound that will activate with the form of its active ester, acid anhydrides or carboxylic acid halides and the N-deprotection for preparing by method well known to those skilled in the art (A ') coupling; with the Boc group deprotection of Tfa with the N-end, then with strong acid such as HF with the Side chain protective group deprotection and with the intermediate that forms (H ') cracking from the resin.All variablees all define in as shown above the formula (I).

On the other hand; the invention provides the method for preparation formula (I) compound; this method comprises; peptide-resin (H) coupling of formula (B) compound that will activate and the N-deprotection for preparing by method well known to those skilled in the art with the form of its active ester, acid anhydrides or carboxylic acid halides; with the Boc group deprotection of Tfa, with the amino N of the N-end that discharges with the N-end _αThe amino acid (x) of-Boc-protection is by peptide linked reaction acidylate well known to those skilled in the art; repeat Tfa deprotection and coupling step as required mixing other amino acid (x), with strong acid with the intermediate that forms (I ') deprotection and cracking from the resin.All variablees all define in as shown above the formula (I).

On the other hand, the invention provides the method for preparation formula (I) compound, this method comprises, with formula (B) compound and alkali such as Cs ₂CO ₃Reaction with polystyrene resin such as the Merrifield peptide resin reaction of the cesium salt of the phenol that forms (J ') with halogenated methylation, is removed the Boc protecting group with Tfa, with the amino N of the N-end that discharges _αThe amino acid (x) of-Boc-protection is by peptide linked reaction acidylate well known to those skilled in the art; repeat Tfa deprotection and coupling step as required to mix other amino acid (x); with Tfa the terminal deprotection of the N-of the peptide sequence of final protection and with mineral alkali such as LiOH in moisture DMF to the terminal deprotection of C-; with the intermediate that forms (K ') by peptide linked reaction well known to those skilled in the art cyclisation, with strong acid with the intermediate of formation (L ') cracking from the resin.All variablees all define in as shown above the formula (I).

On the other hand; the invention provides the method for preparation formula (I) compound; this method comprises; the peptide of formula (B) compound that will activate with the form of its active ester, acid anhydrides or carboxylic acid halides and the N-deprotection for preparing by method well known to those skilled in the art, 4-nitro diphenyl-ketoxime resin (M ') coupling; with the Boc group deprotection of Tfa, with the amino N of the N-end that discharges with the N-end _αThe amino acid (x) of-Boc-protection is by peptide linked reaction acidylate well known to those skilled in the art; repeat Tfa deprotection and coupling step as required to mix other amino acid (x); with the Boc group deprotection of Tfa with the N-end; by with in the suitable organic bases and, remove Side chain protective group with strong acid such as HF then with the intermediate of N '-deprotection of forming (N ') cyclisation and cracking.All variablees all define in as shown above the formula (I).

Describe in detail

Term used herein " heterocycle " is meant any heterocycle that can appear on the amino acid side chain.Its example includes but are not limited to, heterocycles such as benzothienyl, benzofuryl (coumaryl), imidazolyl, indyl, purine radicals, pyridyl, pyrimidyl, quinolyl, thiazolyl, thienyl and triazolyl.

Term used herein " aryl " is meant any stable monocycle or the two ring carbocyclic rings that contain maximum 7 carbon atoms in each ring, and wherein having a ring at least is aromaticity.The example of aryl comprises xenyl, indenyl, naphthyl, phenyl and 1,2,3,4-naphthane.

In this application, aminoacid component, some preferred protecting group, reagent and solvent have been adopted the symbol of abbreviation.The implication of these dummy suffix notations is as shown in table 1.

Table 1

Dummy suffix notation		Implication
Dummy suffix notation		Implication	Amino acid	His	The L-Histidine
	Lys	L-Methionin	Amino acid	His	The L-Histidine
	Lys	L-Methionin		Nal	L-3-(2-naphthyl)-L-Ala
	Phe	The L-phenylalanine		Nal	L-3-(2-naphthyl)-L-Ala
	Phe	The L-phenylalanine		Ser	The L-Serine
	Thr	The L-Threonine		Ser	The L-Serine
	Thr	The L-Threonine		Trp	L-tryptophane (except as otherwise noted)
	Tyr	L-tyrosine		Trp	L-tryptophane (except as otherwise noted)
	Tyr	L-tyrosine		Ahx	6-oxygen base caproic acid
	Abu	The 2-aminobutyric acid		Ahx	6-oxygen base caproic acid
	Abu	The 2-aminobutyric acid	Protecting group	Boc	1,1-(dimethyl oxyethyl group) carbonyl
	Cbz	Carbobenzoxy-(Cbz)	Protecting group	Boc	1,1-(dimethyl oxyethyl group) carbonyl
	Cbz	Carbobenzoxy-(Cbz)		Fmoc	9-fluorenyl methoxy carbonyl
	Trt	Trityl group		Fmoc	9-fluorenyl methoxy carbonyl
	Trt	Trityl group		Bzl	Benzyl

Solvent	DMF	N, dinethylformamide
Solvent	DMF	N, dinethylformamide		THF	Tetrahydrofuran (THF)
	EtOAc	Ethyl acetate		THF	Tetrahydrofuran (THF)
	EtOAc	Ethyl acetate	Reagent	Tfa	Trifluoroacetic acid
	NMM	The 4-methylmorpholine	Reagent	Tfa	Trifluoroacetic acid
	NMM	The 4-methylmorpholine		DIEA	Diisopropyl ethyl amine
	TEA	Triethylamine		DIEA	Diisopropyl ethyl amine
	TEA	Triethylamine		TAEA	Three (2-amino-ethyl) amine
	HOAT	1-hydroxyl-7-azepine benzotriazole		TAEA	Three (2-amino-ethyl) amine
	HOAT	1-hydroxyl-7-azepine benzotriazole		HATU	[O-(7-azepine benzo triazol-1-yl)-1,1,3,3-tetramethyl-urea hexafluorophosphate
	EDC	1-(3-dimethylaminopropyl)-3-ethyl-carbodiimide hydrochloride		HATU
	EDC			DCC	Dicyclohexyl carbodiimide

In vitro tests

By measure to [ ¹²⁵I-Tyr ¹¹] SRIF-14 and CHO-K1 transfectional cell bonded restraining effect determine that compound (is respectively sst to human somatotropin's statin subtype acceptor 1 to 5 ₁, sst ₂, sst ₃, sst ₄And sst ₅) affinity.

With people sst ₁Acceptor gene is with the form clone of genomic fragment.By adding the Bg1II joint 1.5Kb Pstl-Xmn1 of 3 '-non-translational region of the complete coding region that contains 100bp 5 '-non-translational region, 1.17Kb and 230bp is modified.With the dna fragmentation subclone that obtains to the BamHl site of pCMV-81 to produce Mammals expression plasmid (Chicago University is provided by Dr.Graeme Bell).By in CHO-K1 cell (ATCC), obtaining stably express sst with coprecipitation of calcium phosphate method (1) transfection ₁The cloned cell line of acceptor.Contain plasmid pRSV-neo (ATCC) as selectable mark.Select cloned cell line in the RPMI RPMI-1640 that contains the G418 of 0.5mg/ml (Gibco), ring the clone expand in the substratum then.

People sst ₂The somatostatin receptor gene separates as 1.7Kb BamHI-HindIII genomic DNA fragment, and subclone is in the plasmid vector pGEM3Z (Promega) that is provided by Dr.G.Bell (Chicago University) then.Make up mammalian cell expression vector by the consistency limiting acid endo enzyme site that 1.7Kb BamH1-HindII fragment is inserted into plasmid pCMV5.In the CHO-K1 cell, obtain cloned cell line with the transfection of coprecipitation of calcium phosphate method.Contain plasmid pRSV-neo as selectable mark.

With people sst ₃Separate as genomic fragment, in 2.4Kb BamHI/HindIII fragment, contain complete encoding sequence.After modifying terminal and adding the EcoR1 joint, make up Mammals expression plasmid pMCV-h3 by the EcoR1 site of the 2.0KbNcoI-HindIII fragment being inserted the pCMV carrier.In CHO-K1 cell (ATCC), obtain stably express sst with the transfection of coprecipitation of calcium phosphate method ₃The cloned cell line of acceptor.Contain plasmid pRSV-neo (ATCC) as selectable mark.Select cloned cell line in the RPMI RPMI-1640 that contains the G418 of 0.5mg/ml (Gibco), ring the clone expand in the substratum then.

Provide the people sst by Dr.Graeme Bell (Chicago University) ₄Expression of receptor plasmid pCMV-HX.This carrier contains 1.4Kb NheI-NheI coding people sst ₄Genomic fragment, 5 '-non-translational region of 456bp and 3 '-non-translational region of 200bp, be cloned into the XbaI/EcoR1 site of PCMV-HX then.In CHO-K1 cell (ATCC), obtain stably express sst with the transfection of coprecipitation of calcium phosphate method ₄The cloned cell line of acceptor.Contain plasmid pRSV-neo (ATCC) as selectable mark.Select cloned cell line in the RPMI RPMI-1640 that contains the G418 of 0.5mg/ml (Gibco), ring the clone expand in the substratum then.

Obtain people sst as template by PCR with going into genomic clone ₅Gene is provided by Dr.GraemeBell (Chicago University).The 1.2Kb PCR fragment of gained contains the 55bp of 21 base pair and 3 '-non-translational regions of 5 '-non-translational region.Described clone is inserted the EcoR1 site of plasmid pBSSK (+).Reclaim this insertion fragment with 1.2Kb HindIII-XbaI fragment, subclone is in the pCVM5 mammalian expression vector then.In CHO-K1 cell (ATCC), obtain stably express sst with the transfection of coprecipitation of calcium phosphate method ₅The cloned cell line of acceptor.Contain plasmid pRSV-neo (ATCC) as selectable mark.Select cloned cell line in the RPMI RPMI-1640 that contains the G418 of 0.5mg/ml (Gibco), ring the clone expand in the substratum then.

The CHO-K1 cell of one of stably express people sst acceptor is grown in the RPMI 1640 that contains 10% foetal calf serum and 0.4mg/ml Geneticin.With 0.5mM EDTA collecting cell, descended centrifugal about 5 minutes at about 4 ℃ with 500g.Settling is suspended among 50mM Tris, the pH7.4 again and twice with 500g about 4 ℃ centrifugal about 5 minutes down.Made cytolysis by supersound process and with 39000g down in centrifugal about 10 minutes at about 4 ℃.Settling is suspended in the identical damping fluid and with 50000g to descend centrifugal about 10 minutes at about 4 ℃ again, the film in the settling that obtains is deposited under-80 ℃.

[ ¹²⁵I-Tyr ¹¹] SRIF-14 bonded competitive inhibition experiment carries out in polypropylene 96 orifice plates in duplicate.With cytolemma (10 μ g protein/hole) with [ ¹²⁵I-Tyr ¹¹] SRIF-14 (0.05nM) together under about 37 ℃ at the MgCl of 50mM HEPES (pH7.4), 0.2%BSA, 5mM ₂, the 200KIU/ml Trypsin inhibitor,Trasylol, in 0.02mg/ml bacitracin and the 0.02mg/ml phenylmethylsulfonyl fluoride insulation about 60 minutes.

By immediately with the GF/C glass fibre filter plate of using 0.1% polymine (P.E.I.) to soak in advance (Unifilter Packard) filters, usefulness Filtermate 196 (Packard) cell harvestor separate by free [ ¹²⁵I-Tyr ¹¹] combination that produces of SRIF-14.Filter paper was washed for 4 seconds with 50mM HEPES at about 0-4 ℃, use Packard Top Count detection of radioactive then.

From total combination, deduct non-specific binding (in the presence of 0.1 μ M SRIF-14, measuring) and obtain the specificity combination.Binding data is analyzed by computer assisted nonlinear regression analysis (MDL) and definite constant (Ki) value that suppresses.

Determine that by following test compound of the present invention is agonist or antagonist.

Function test: the restraining effect that produces in the cAMP cell:

In the RPMI RPMI-1640 that contains 10%FCS and 0.4mg/ml Geneticin of CHO-K1 cell inoculation in the tissue culturing plate of 24-hole with expressing human somatostatin (SRIF-14) subtype acceptor.Change nutrient solution the day before yesterday in experiment.

With cell (10 ⁵Cells/well) contains the fresh RPMI washed twice of 0.2%BSA and 0.5mM (1) 3-isobutyl-1-methylxanthine (IBMX) with 0.5ml, then about 5 minutes of about 37 ℃ of insulations.

By adding 1mM forskolin (FSK) in about 37 ℃ of productions that stimulated ring AMP in about 15-30 minute down.

By adding FSK (1 μ M), SRIF-14 (10 simultaneously ^-12M to 10 ^-6M) and test compound (10 ^-10M to 10 ^-5M) the agonist effect of mensuration compound.

By adding FSK (1 μ M), SRIF-14 (1 to 10nM) and test compound (10 simultaneously ^-10M to 10 ^-5M) antagonist action of mensuration compound.

Remove reaction solution and add the HCl of 200ml 0.1N.Measure cAMP with radioimmunoassay method (KitFlashPlate SMP001A, New England Nuclear).

Radioligand is in conjunction with test

Being used for extracorporeal receptor makes by the following method in conjunction with the film of testing: the CHO-K1 cell that will express the hsst receptor subtype is at ice-cold 50mM Tris-HCl homogenize (Polytron, be provided with 6,15 seconds), then with 39,000g (10 minutes) is centrifugal twice, suspends again with fresh damping fluid between twice.With final settling be suspended in again be used among the 10mM Tris-HCl test.For hsst1, hsst3, hsst4, hsst5 test, with the aliquots containig of membrane prepare thing about 37 ℃ down with 0.05nM[125I-Tyr11] SRIF-14 containing BSA (10mg/ml), MgCl ₂(5mM)), be incubated about 30 minutes among the 50mM HEPES (pH7.4) of Trypsin inhibitor,Trasylol (200KIU/ml), bacitracin (0.02mg/ml) and phenylmethylsulfonyl fluoride (0.02mg/ml).Final test volume is 0.3ml.

For the hsst2 test, adopt [125I] MK-678 (0.05nM) as radioligand, be incubated about 90 minutes down at about 25 ℃.Stop insulation by rapid the filtration with the Brandel filter manifold with GF/C filter paper (in 0.3% polyethylene industry amine, soaking in advance).Then each test tube and filter paper are washed 3 times with every portion of ice-cold damping fluid of 5ml.

The specificity bonded is defined as, and total radioligand is in conjunction with the combination that deducts in the presence of 1000nM SRIF-14 (hsst1,3,4,5) or 1000nM MK678 (hsst2).

Can be by detecting The compounds of this invention and the somatostatin receptor in the method body well known to those skilled in the art in conjunction with relevant application, comprise with the specificity of somatostatin subtype acceptor and combining, the example of described method well known to those skilled in the art can be referring to I.Shimon etc., " the somatostatin receptor hypospecificity in human fetal pituitary gland culture ", " Journal of Clinical Investigation " (J.Clin.Invest.), 99 volumes, No.4,789-798 page or leaf, 1997; With C.Gilon etc., " skeleton-ring-type, acceptor 5-selectivity somatostatin analogs: synthetic, biological activity and nucleus magnetic resonance conformational analysis ", " pharmaceutical chemistry magazine " (J.Med.Chem.) 1998,41,919-929.

As well-known to those skilled in the art, it is diversified that the known and potential of somatostatin agonists and/or antagonist is used.The different purposes of these of somatostatin can be summarized as follows:

Somatostatin agonists can be used for suppressing tethelin, particularly GH secretion adenoma (acromegaly) and TSH secretion adenoma; The treatment prolactin-secreting adenoma; Suppress Regular Insulin and/or hyperglycemic-glycogenolytic factor, particularly diabetes, vascular disease, proliferating retinopathy, dawn phenomenon and ephrosis; Gastric acid inhibitory secretion, particularly peptide ulceration; Intestines fistula of skin and pancreas fistula of skin; Irritable bowel syndrome; Dumping syndrome; Watery diarrhea syndrome; The diarrhoea relevant with AIDS; The diarrhoea that chemotherapy causes; Acute or chronic pancreatitis and gastrointestinal hormone ` secreting tumor; Treatment cancer such as hepatoma; Suppress vasculogenesis; Treatment inflammatory diseases such as sacroiliitis; Retinopathy; Chronic allograft rejection reaction; Angioplasty; Prevention grafting vessel and gastrointestinal hemorrhage.

Therefore, the present invention includes and contain the pharmaceutical composition of the The compounds of this invention described at least a literary composition as activeconstituents and pharmaceutically acceptable carrier.

Compound of the present invention can be by (for example intramuscular, intraperitoneal, intravenously or the subcutaneous injection of oral, parenteral, or implant), nose, vagina, rectum, hypogloeeis or topical approach carry out administration, and can be mixed with the dosage form that is suitable for various route of administration with pharmaceutically acceptable carrier.

The solid dosage form that is used for oral administration comprises capsule, tablet, pill, powder and granule.In described solid dosage form, active compound mixes with at least a inertia pharmaceutically acceptable carrier such as sucrose, lactose or starch.Usually, described dosage form can also contain other material except that described inert diluent, for example lubricant such as Magnesium Stearate.Under the situation of capsule, tablet and pill, dosage form can contain buffer reagent.Tablet and pill can also prepare with enteric coating.

The liquid dosages form that is used for oral administration comprises and contains this area inert diluent commonly used for example pharmaceutically acceptable emulsion, solution, suspension, syrup, the elixir of water.Except that described inert diluent, also can contain assistant agent in the composition, for example wetting agent, emulsifying agent and suspending agent, and sweeting agent, correctives and perfuming agent.

The preparation of the present invention that is used for parenteral admin comprises aseptic moisture or non-aqueous solution, suspension or emulsion.The example of non-aqueous solvent or carrier is for example sweet oil and Semen Maydis oil, gelatin, an injectable organic ester ethyl oleate for example of propylene glycol, polyoxyethylene glycol, vegetables oil.Described dosage form can also contain assistant agent such as sanitas, wetting agent, emulsifying agent and dispersion agent.They can pass through, for example, and with filter paper filtering that can retain bacteria, in composition, mix sterilant, composition is shone or the composition heating is sterilized.Can also be made into and to face the form that is dissolved in the aseptic solid composite of sterilized water or other sterile injectable solvent at once with preceding.

Be used for the preferred suppository of composition of rectum or vagina administration, described suppository also contains vehicle such as theobroma oil or suppository wax except that active substance.

The composition that is used for nose or sublingual administration also can prepare with conventional excipients well known in the art.

In addition, compound of the present invention can also be with the form administration of the slow releasing composition described in the following patent.United States Patent (USP) 5,672,659 have instructed the slow releasing composition that contains biologically active agent and polyester.United States Patent (USP) 5,595, but 760 instructed the slow releasing composition that contains biologically active agent of gelation form.U.S. application number 08/929,363 (September 9 1997 applying date) has been instructed the polymeric slow releasing composition that contains biologically active agent and chitosan.U.S. application number 08/740,778 (November 1 1996 applying date) has been instructed the slow releasing composition that contains biologically active agent and cyclodextrin.U.S. application number 09/015,394 (January 29 1998 applying date) has been instructed the absorbable slow releasing composition that contains biologically active agent.The instruction of above-mentioned patent and patent application is incorporated herein by reference.

The dosage of the activeconstituents in the present composition can change; But the amount of activeconstituents must can obtain the appropriate dosage form.Selected dosage depends on the time length of required therapeutic action, route of administration and treatment.Usually, to the every day of people and other animal, for example administration 0.0001 to 100mg/kg body weight dosage to reach therapeutic action.

The preferred dosage scope is 0.01 to 5.0mg/kg body weight/day, and described dosage can single-dose or is divided into multiple dosing.

Compound of the present invention can be synthetic according to the description among the reaction scheme I.In the first step, will be on alpha-amino group with Boc, Cbz or other suitable radical protection amino acid with mineral alkali such as NaOH, KOH, K ₂CO ₃Perhaps Shou Xuan CsCO ₃For example be transformed into carboxylate salt among water, DMF, the THF etc. at polar solvent.Vacuum is steamed and to be desolventized, the salt of remnants is dissolved among polar aprotic solvent such as the DMF again and under-20 ℃ to about 100 ℃ approximately, first-selected room temperature, stir in add the α-Lu Daitong that suits.Continued stir about 10 minutes to about 24 hours, it is complete perhaps to analyze the formation that confirms ester until TLC, at this moment, with solution at the about 40 ℃ of about 70 ℃ of following vacuum concentration extremely of about 0 ℃ to about 100 ℃, first-selection.Intermediate is dissolved in aprotic organic solvent such as benzene, toluene or the first-selected dimethylbenzene again, adds about 5 times to 100 times, the NH of first-selected about 15-20 times molar excess then ₄OAc.With this two-phase mixture reflux and thoroughly remove polar layer by the Dean-Stark water trap obtain crude product intermediate (A) in about 1 to about 4 hours time, the form that this intermediate can crude product is used, perhaps by crystallization or column chromatography purifying.

Reaction scheme I

In second step, adopt catalytic hydrogenation or strong acid such as HF, hydrochloric acid, HBr or Tfa that intermediate (A) is carried out deprotection.Then, can protect, can adopt alkali susceptibility blocking group such as Fmoc group, N-(the 9-fluorenyl methoxy carbonyl oxygen base) succinimide that use is purchased and the acetonitrile and the aqueous solution of salt of wormwood α-nitrogen.Perhaps, N _αThe imidazoles nitrogen of-Cbz-protection can carry out alkylation and with catalytic hydrogenation the alpha-amino group group be carried out deprotection with the carboxylicesters halogenide of protection, obtains B ' (V=H, W=-(CH ₂) _mCR ⁵-CO ₂R ', wherein, R ' expression alkyl or benzyl ester).Imidazoles nitrogen can adopt the trityl group muriate that is purchased and tertiary amine base such as 4-methyl-morpholine, diisopropyl ethyl amine or triethylamine to protect to obtain the intermediate of Fmoc-protection; it can adopt alkali subsequently; for example TAEA carries out deprotection to alpha-amino group; obtain intermediate (B) (V=H, W=Trt).Perhaps, the imidazoles B of N-deprotection " (V=H W=H) can use without further modification.

At the 3rd step, intermediate B, B ' or B " anchor group that is combined to as the successive soln of target peptide.Therefore, anchor group is dissolved in the ethyl acetate, concentration is about 50-200mmol/L, and the about 1-5 molar equivalent that adds Acibenzolar, acid anhydrides or carboxylic acid halides form, or the N of 1.1-1.5 molar equivalent more preferably _αThe amino acid of-Fmoc protection.At weak base such as aqueous sodium carbonate, perhaps more preferably stir the second layer of sodium hydrogen carbonate solution top, finishes until reaction with mixture.Remove water layer, add about 1-10ml/mmol, the perhaps more preferably from about TAEA of 2-4ml/mmol or piperidines were with mixture stir about 30 minutes.Then, solvent is adjusted to pH=5.5 (3 times, about 10ml/mmol) with 10% phosphate buffer soln then with saturated nacl aqueous solution washing (2 times, about 30ml/mmol).Subsequently, to carry out subsequently circulation with the similar mode of first circulation.Last amino acid can be with Boc or Fmoc group to N _αProtect.

In the 4th step; the N-end can adopt the aqueous solution of alkali or strong acid to remove with the protecting group C-end; the peptide intermediate that forms can adopt typical peptide coupling technology to carry out cyclisation; as described in following document: " synthetic put into practice (the The Practice of Peptide Synthesis) of peptide "; Bodanszky and Bodanszky; Springer-Varlag, 1984.After this, again the peptide intermediate is dissolved among aprotic solvent such as the DMF, solution is alkalized by adding tertiary amine base such as 4-methyl-morpholine.The carboxylic moiety of intermediate can be by adding 1 to 6 times of molar excess carbodiimide such as DCC or EDC and a kind of additive such as I-hydroxybenzotriazole activate.Mixture is stirred down at about 0 ℃ to 100 ℃, more preferably, finish until reaction approximately stirring under the room temperature.

In the end a step, adopt catalytic hydrogenation or strong acid such as HF, hydrochloric acid, HBr or Tfa that the peptide of protection is removed protecting group, get product (C) to the end, wherein, R ¹To R ⁵, a, b, Y, Z and n all define suc as formula (I).

Employing has Finnigan SSQ 7000 spectrometers in ESI (electrospray ionization) source and measures the injection mass-spectrometric data.The NMR data are to adopt the Varian Unity spectrograph of 300MHz to obtain, and sample is the sample in designated solvent in about 10-20mg/ml concentration range.

Perhaps, compound of the present invention can adopt the preparation of solid-phase peptide synthetic technology.Therefore, intermediate A (X=Boc) is for example carried out alkylated reaction with ethyl bromoacetate and suitable alkali as the salt of wormwood in aprotic solvent such as DMF, the ethyl ester intermediate that forms adopts alkali aqueous solution such as aqueous sodium hydroxide solution to be hydrolyzed, and obtains intermediate B (V=Boc, W=-CH ₂CO ₂H).Intermediate B (V=Boc, W=-CH ₂CO ₂H) can adopt known activating technology activation, described technology is as described in the following document: " synthetic put into practice (the The Practice of Peptide Synthesis) of peptide ", Bodanszky and Bodanszky, Springer-Varlag, 1984, and be directly used in solid carrier on the growth peptide carry out coupling, perhaps, intermediate B (V=Boc, W=-CH ₂CO ₂H) also can directly relatedly be combined to the beginning solid with solid carrier.The Boc group of N-end for example can adopt that Tfa carries out deprotection, well known to a person skilled in the art that to proceed peptide under the condition synthetic.

Intermediate B (for example, V=Fmoc, W=-CH ₂CO ₂T-Bu) usable acid such as Tfa handle removing the tertiary butyl ester of carboxylate salt protection, and the intermediate B (for example, V=Fmoc, the W=-CH that form ₂CO ₂H) can be used for utilizing the solid-phase peptide of Fmoc strategy synthetic.Therefore, intermediate B (V=Fmoc, W=-CH ₂CO ₂H) can adopt known activating technology activation, described technology is as described in the following document: " synthetic put into practice (the ThePractice of Peptide Synthesis) of peptide ", M.Bodanszky and A.Bodanszky, Springer-Varlag, 1984, and be directly used in solid carrier on the growth peptide carry out coupling.The Fmoc group of N-end for example can adopt that piperidines carries out deprotection, well known to a person skilled in the art that to proceed peptide under the condition synthetic.

The solid of cyclic analogs is combined to also and can carries out according to following reaction scheme II.

Intermediate A (X=Boc or Cbz, R ³=2-p-methoxy-phenyl, 3-p-methoxy-phenyl or 4-p-methoxy-phenyl) BBr of available 1M ₃Dichloromethane solution handled about 1/2 hour, obtain free phenol A (X=H, R ³=2-hydroxy phenyl, 3-hydroxy phenyl or 4-hydroxy phenyl).Then, α-nitrogen usable acid susceptibility blocking group such as Boc group are protected, and adopt di-tert-butyl dicarbonic acid ester and a kind of alkali such as the solution of sodium hydroxide in the mixture of the immiscible solvent of organic water such as diox and water.Intermediate A (X=Boc, R ³=2-hydroxy phenyl, 3-hydroxy phenyl or 4-hydroxy phenyl) for example carry out alkylated reaction as the salt of wormwood in aprotic solvent such as DMF, the ethyl ester intermediate D that obtains forming with ethyl bromoacetate and suitable alkali.Then, with intermediate D by changing into its cesium salt with the cesium carbonate effect.Cesium salt excessively with the Merrifield resin reaction, obtain intermediate E.Intermediate E adopts standard Boc solid-phase peptide synthetic technology or foregoing standard Fmoc solid phase synthesis to process again, obtains intermediate F.When having made up complete aminoacid sequence; the ethyl ester of C-end adopts suitable alkali such as the moisture DMF solution of LiOH to carry out deprotection (unmask); peptide adopts the activation method of standard to carry out cyclisation; for example; adopt carbodiimide and for example hydroxybenzotriazole and tertiary amine base; for example, diisopropyl ethyl amine obtains intermediate G.Last side chain deprotection and be to realize from resin division by adding very strong acid, as adding HF, obtain compound of the present invention.

Further specify the present invention by the following examples, but be not in order to limiting the scope of the invention.

Embodiment 1

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

Embodiment 1 synthesizes according to following building-up reactions route 1:

Reaction scheme 1

Step a:2-(1-(S)-amino-2-phenylethyl)-4-(3-p-methoxy-phenyl)-imidazoles

With Cbz-(L)-phenylalanine (10.0g, 33.4mmol) and cesium carbonate (5.44g 16.7mmol) is incorporated in 2: 1 DMF: in the water (75ml), mixture is stirred until evenly.Removal of solvent under reduced pressure is dissolved in resistates among the DMF (70ml), adds 2-bromo-3 '-methoxyacetophenone (7.65g, DMF 33.4mmol) (30ml) solution.With mixture stir about 30 minutes at room temperature, then, concentrating under reduced pressure.Ketone-the ester that forms is dissolved in the dimethylbenzene (150ml), leaches CsBr.(40.0g 0.52mol), refluxed mixture heating up about 2 hours again, adopted the Dean-Stark water trap to remove excessive N H to add ammonium acetate ₄OAc also discharges water outlet.Reaction mixture is cooled off, and wash with saturated sodium bicarbonate solution (50ml) and saturated nacl aqueous solution (50ml).Dimethylbenzene layer dried over sodium sulfate, filtration and vacuum concentration.

Resistates is dissolved in the diox (30ml), adds the hydrochloric acid (115ml) of 6N, mixture is refluxed heated about 3 hours down.With solution for vacuum concentration, and with ether (4 * 100ml) development.Again resistates is dried to constant weight under vacuum, obtains the intermediate 1a of 12.15g (99%), mass spectrum 294.2MH+.

Step b:2-(1-(S)-((fluorenyl methoxy) carbonyl) amino-2-phenylethyl)-4-(3-p-methoxy-phenyl)-imidazoles

With intermediate 1a (11.8g, 32.2mmol) be dissolved in 1: 1/ acetonitrile: in the water (200ml), add carefully continuously in batches salt of wormwood (5.38g, 39mmol), add 9-fluorenyl methyl-succinimidyl carbonate, with about 20 minutes of the mixture vigorous stirring that forms.Product extracts with ethyl acetate (100ml), (2 * 50ml) washings of ethyl acetate layer water.Ethyl acetate layer is used dried over sodium sulfate, filtration, vacuum concentration again.With product with silica gel flash chromatography purifying (150g), with 2: 2: 1 methylene dichloride: hexane: ethyl acetate drip washing, use 1: 1 hexane then: ethyl acetate drip washing.The product cut is merged and vacuum concentration, obtain intermediate 1b, be a kind of light yellow foam thing, 14.77g (85%).Mass spectrum 516.3MH+, and NMR (300MHz, DMSO-d6), 11.8-12.0 (1H, s), and 7.8-8.0 (3H, d), 7.6-7.8 (2H, d), 7.5 (1H, s), 7.1-7.5 (12H, m), and 6.7-6.9 (1H, d), 4.8-5.0 (1H, m), and 4.1-4.3 (3H, m), 3.7-3.9 (3H, s), and 3.0-3.4 (2H, m).

Step c:2-(1-(S)-((fluorenyl methoxy) carbonyl) amino-2-phenylethyl)-4-(3-methoxyl group-phenyl)-1-trityl group-imidazoles

Under nitrogen atmosphere, with intermediate 1b (13.9g 26.9mmol) is dissolved in the methylene dichloride (50ml), add the 4-methylmorpholine (2.96ml, 26.9mmol) and the chloro triphenyl methane (7.51g, 26.9mmol), with solution stir about 45 minutes at room temperature.Solids removed by filtration is used silica gel flash chromatography purifying (300g) with filtrate, and adopt 70: 30 hexane: ethyl acetate is as eluent.The product cut is merged, and vacuum concentration obtains intermediate 1c, is a kind of foam thing, 18.0g (88%), NMR (300MHz, DMSO-d6), 7.84-7.95 (2H, d), 7.7-7.8 (1H, d), and 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), and 3.6-3.7 (1H, m), 2.65-2.85 (1H, d, d), 2.05-2.2 (1H, m).

Steps d: 2-(1-(S)-((Fmoc-Tyr (Bzl)-D-Trp-Lys (Cbz)-Val) amino-2-phenylethyl)-4-(3-p-methoxy-phenyl)-1-(trityl group)-imidazoles

(1.89g 2.50mmol) was dissolved in the ethyl acetate (40ml), adds three (2-amino-ethyl) amine (9ml), with about 1/2 hour of mixture vigorous stirring with intermediate 1c.(2 * 120ml) washings are adjusted to about pH=5.5 (3 * 40ml) with 10% phosphate buffer soln to ethyl acetate layer again with saturated nacl aqueous solution.Ethyl acetate layer uses saturated sodium bicarbonate solution (40ml) to stir again, and adding Fmoc-Val-F (1.02g, 3.00mmol).With reaction mixture stir about 1 hour, remove water layer.

Then, intermediate carries out deprotection and coupling in proper order, employing be Fmoc-Lys (Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Tyr (Bzl)-OSu, to carry out with the above-mentioned Fmoc-Val-F similar mode that circulates.Ethyl acetate layer dilutes with the hexane of 1.5 times of volumes, and carries out purifying by the silicagel column of flash chromatography, and at first adopt 50: 30: 20 methylene dichloride: ethyl acetate: hexane, adopt 4: 1 ethyl acetate then: hexane is as eluent.Merge product cut and vacuum concentration, obtain intermediate 1d, be a kind of white foam thing, 1.90g (46%).Mass spectrum 1581.2 MNa+, 1559.5MH+.

Step e:1-((2-oxyethyl group-2-oxo) ethyl)-2-(1-(S)-((Fmoc-Tyr (Bzl)-D-Trp-Lys (Cbz)-Val) amino-2-phenylethyl)-4-(3-p-methoxy-phenyl)-imidazoles

(519mg 0.33mmol) is dissolved in and comprises iPr with intermediate 1d ₃(205 μ l are among Tfa 1.0mmol) (10ml), with mixture stir about 15 minutes for SiH.Add ether (60ml) and be settled out intermediate, filter.Mass spectrum 1316MH+.Intermediate is dissolved among the DMF (3ml), add saleratus (198mg, 2.0mmol) and ethyl bromoacetate (721 μ l 6.5mmol), at room temperature stir mixture and to spend the night.With the mixture vacuum concentration, be dissolved in the methylene dichloride (10ml) water (10ml) washing.The dichloromethane layer dried over sodium sulfate is filtered and vacuum concentration, obtains the crude product (540mg) of intermediate 1e, and it need not purifying and can use.

Step f: ring [Tyr (Bzl)-D-Trp-Lys (Cbz)-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

(540mg 0.33mmol) was suspended in the ethyl acetate (10ml), adds three (amino-ethyl) amine (1ml), with about 1/2 hour of mixture vigorous stirring with intermediate 1e.Add ethyl acetate (10ml), (10% phosphate buffer soln (pH=5.5,3 * 10ml) washings are used in 2 * 25ml) washings to solution again with saturated nacl aqueous solution.Add hexane (40ml) and be settled out intermediate, decantation goes out solvent.Resistates is dissolved in the methyl alcohol (10ml), at room temperature stirs and spend the night with 2.5N sodium hydroxide (0.5ml).With the agent of mixture dilute with water to muddy, and with pH regulator to about 6.7.Leach the intermediate and the vacuum-drying of deprotection.Solid is absorbed among the DMF (25ml), add DCC (340mg, 1.65mmol) and HOBt (252mg, 1.65mmol).With mixture at room temperature stir about 2 hours and concentrating under reduced pressure.With silica gel flash chromatography purifying, adopt ethyl acetate crude product as eluent.The product cut is merged, and vacuum concentration obtains intermediate 1f, is a kind of glassy mass (180mg, 48%, by intermediate 1d meter).Mass spectrum 1134.5MH+.

Step g: ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

(180mg 0.16mmol) is dissolved in the acetate (10ml) that comprises 10%Pd/C (24mg), and under nitrogen atmosphere (25psi), jolting is about 8 hours under room temperature with mixture with intermediate 1f.Leach catalyzer, with the resistates vacuum concentration.Crude mixture is made up of the material (all having removed Cbz and benzylic ether) of complete deprotection and the material of part deprotection (remove Cbz and benzylic ether is complete).Mixture is passed through preparative chromatography HPLC purifying, at VYDAC  Dan Baizhi ﹠amp; Peptide C ₁₈(The Nest GroupInc., Southborough carry out on MA) post, adopt 20% to 70% CH ₃The CN/0.1%Tfa gradient elution, the time is about 55 minutes.The purifying cut that will have more polarity peak merges, concentrated, lyophilize (2 * 10ml, 0.5% hydrochloric acid, 1 * 10ml water then), obtains the title compound of embodiment 1,45mg (29%).Mass spectrum 910.4MH+.

Embodiment 2

Ring [Tyr (Bzl)-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

Substantially the building-up reactions route 1 according to embodiment 1 carries out embodiment 2, just adopts suitable amino acid.Merge the purifying cut that hangs down polarity peak of 1g, concentrate and lyophilize (2 * 10ml, 0.5% hydrochloric acid, 1 * 10ml water then), obtain the title product of embodiment 2,33mg (21%) from purge process.Mass spectrum 1000.4MH+.

Embodiment 3

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly mode of embodiment 1, carry out embodiment 3 according to building-up reactions route 1, its difference is as follows:

Steps d: 2-(1-(S)-((Fmoc-Trp-D-Trp-Lys (Cbz)-Val-) amino-2-phenylethyl)-4-(3-p-methoxy-phenyl)-1-(trityl group)-imidazoles

(757mg 1.0mmol) was dissolved in the ethyl acetate (20ml), adds three (2-amino-ethyl) amine (3ml), with about 1/2 hour of mixture vigorous stirring with intermediate 1c.(2 * 60ml) washings, be adjusted to pH with 10% phosphate buffer soln then is about 5.5 (3 * 20ml) to ethyl acetate layer with saturated nacl aqueous solution.Ethyl acetate layer is stirred with saturated sodium bicarbonate solution (20ml), and adding Fmoc-Val-F (825mg, 2.33mmol).With reaction mixture stir about 1 hour, remove water layer again.

With with similar mode as previously mentioned, the intermediate order is carried out deprotection and coupling, adopt Fmoc-Lys (Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Trp-OSu.Ethyl acetate layer is with the dilution of the hexane of 1.5 times of volumes, the silicagel column purifying by flash chromatography at first, employing be 50: 30: 20 methylene dichloride: ethyl acetate: hexane is as eluent, and adopt 4: 1 ethyl acetate then: hexane is as eluent.The product cut is merged, and vacuum concentration obtains intermediate 3d, is a kind of white foam thing, 1.02g (68%).Mass spectrum 11492.0MNa+, 1514.2MH+.

Step e:1-((2-oxyethyl group-2-oxo) ethyl)-2-(1-(S)-((Fmoc-Trp-D-Trp-Lys (Cbz)-Val-) amino-2-phenylethyl)-4-(3-p-methoxy-phenyl)-imidazoles

(1.00g 0.67mmol) is dissolved in methylene dichloride (10ml), Tfa (1ml) and iPr with intermediate 3d ₃(205 μ l are in mixture 1.0mmol), with mixture stir about 20 minutes for SiH.The ether that adds 1: 1: the mixture of hexane (100ml), filter intermediate and dry (0.88g).Intermediate is dissolved among the DMF (10ml), (200mg 2.00mmol) and bromoethyl acetate, at room temperature stirs reaction mixture and to spend the night to add saleratus again.With the mixture concentrating under reduced pressure, obtain intermediate 3e again, it can not purified direct use.Mass spectrum 1335.7MH+.

Step f: ring [Trp-D-Trp-Lys (Cbz)-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With intermediate 3e (crude product 0.67mmol) is dissolved in the methyl alcohol (10ml), will be at room temperature with 2.5N sodium hydroxide (10ml) stir about 45 minutes.Mixture is diluted with water to muddiness, the pH value is adjusted to 6.9.Decantation goes out solvent, with the development of resistates water, obtains a kind of lurid powder (650mg, mass spectrum 1085.5MH+).This powder (629mg) is dissolved among the DMF (20ml), then, add NMM (220 μ l, 2.0mmol), EDC (192mg, 1.0mmol) and HOBt (153mg, 1.0mmol).With mixture stir about 2 hours at room temperature, vacuum concentration.Crude product is dissolved in the methylene dichloride (15ml), washs with 10% phosphate buffer soln (being adjusted to pH=5.5).Dichloromethane layer with dried over sodium sulfate, filtration, is concentrated into 2ml then.Add ether sedimentation and go out product,, obtain intermediate 3f (440mg, 71%) its filtration and drying.Mass spectrum 1067.4MH+.

Step g: ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

(200mg 0.19mmol) is dissolved in the acetate (15ml) that comprises 10%Pd/C (40mg), and under nitrogen atmosphere (25psi), jolting is about 2 days under room temperature with mixture with intermediate 3f.Leach catalyzer, with the resistates vacuum concentration.Crude mixture is passed through preparative chromatography HPLC purifying, at C ₁₈Post (Rainin Microsorb ^TMCarry out 80-220-C5), adopt 20% to 70%CH ₃The CN/0.1%Tfa gradient elution, the time is about 55 minutes.Pass through for the second time, adopt 30% to 50%CH ₃The CN/0.1%Tfa gradient elution, the time is about 55 minutes, to obtain good separating effect.The purifying cut is merged, concentrate, lyophilize (2 * 10ml, 0.5% hydrochloric acid, 1 * 10ml water then), obtain the title compound of embodiment 3,26mg (14%).Mass spectrum 933.5MH+.

Embodiment 4

Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

With with the basic similarly mode of embodiment 1, carry out embodiment 4 according to building-up reactions route 1, its difference is as follows:

Step g: ring [Trp-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

(150mg 0.14mmol) is dissolved in the methylene dichloride (12ml), adds the BBr of 1M under nitrogen atmosphere with intermediate 3f ₃Hexane solution.With the slurries stir about that forms 1/2 hour.Add methyl alcohol (10ml), with the mixture vacuum concentration.Crude mixture is passed through preparation HPLC at C ₁₈Purifying on the post adopts 24% to 48% CH ₃CN/0.2%NH ₄The OAC gradient elution, the time is about 50 minutes.Merge the purifying cut, concentrate, lyophilize (2 * 10ml water), obtain the title compound of embodiment 4,40mg (29%).Mass spectrum 919.4MH+.

Embodiment 5

Ring [Trp-D-Trp-Lys-Thr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 3, carry out embodiment 5 according to building-up reactions route 1, just in steps d, adopt Fmoc-Thr (Bzl)-F to replace Fmoc-Val-F.Mass spectrum 1025.5MH+.

Embodiment 6

Ring [Trp-D-Trp-Lys-Thr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 4, carry out embodiment 6 according to building-up reactions route 1, just adopt intermediate 5f, ring [Trp-D-Trp-Lys (Cbz)-Thr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly] replaces the intermediate 3f in the step g.Mass spectrum 1025.5MH+.

Embodiment 7

H-Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly-OH

With with the basic similarly modes of embodiment 3, carry out embodiment 7 according to building-up reactions route 1, just in step 3d, adopt Fmoc-Abu-F to replace Fmoc-Val-F, and carry out cyclisation, and do not carry out step 3f with carbodiimide and HOBt.Mass spectrum 937.3MH+.

Embodiment 8

Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 3, carry out embodiment 8 according to building-up reactions route 1, just in step 3d, adopt Fmoc-Abu-F to replace Fmoc-Val-F.Mass spectrum 919.5MH+.

Embodiment 9

Ring [Phe-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(1, the 1-dimethyl ethyl) imidazoles)-Gly]

Embodiment 9 is according to reaction scheme 2 preparations.

Reaction scheme 2

Step a:2-(1-(S)-amino-2-phenylethyl)-4-(1, the 1-dimethyl ethyl)-imidazoles

With Boc-(L)-phenylalanine (5.31g, 20.0mmol) and cesium carbonate (3.26g 10.0mmol) is incorporated in 1: 1/DMF: in the water (50ml), mixture is stirred until obtaining uniform mixture.Removal of solvent under reduced pressure is dissolved in resistates among the DMF (50ml), and adding 1-chlorine Pinacolone (2.63ml, 20.0mmol).Mixture at room temperature stirred spend the night concentrating under reduced pressure.Ketone-the ester that forms is dissolved in the dimethylbenzene (100ml) filtering CsBr.(25.0g 0.33mol), refluxes mixture heating up about 2 hours, adopts the Dean-Stark water trap, removes excessive ammonium acetate and discharges water outlet to add ammonium acetate.With the reaction mixture cooling, with saturated sodium bicarbonate solution (50ml) washing, with dried over sodium sulfate, filtration and vacuum concentration.The silicagel column of intermediate by flash chromatography to protection carries out purifying, and adopt 80: 20 hexane: ethyl acetate obtains the crystallization of intermediate (mass spectrum 344.3MH+) of 3.45g (50%) as eluent.This intermediate is dissolved in the methyl alcohol (30ml), adds concentrated hydrochloric acid (5.0ml), with mixture stir about 3 hours.With solution for vacuum concentration, resistates is precipitated out from THF and ether.With solid vacuum-drying, obtain the intermediate 9a of 1.89g (95%).NMR (300MHZ, DMSO-d6), 8.5-10.5 (3H, wide 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 (Boc)-Tyr (OBzl))-amino-2-phenylethyl)-4-(1, the 1-dimethyl ethyl)-1H-imidazoles

(790mg 2.50mmol) was dissolved in the ethyl acetate (40ml), adds three (2-amino-ethyl) amine (9ml), with about 1/2 hour of mixture vigorous stirring with intermediate 9a.(2 * 120ml) washings are adjusted to pH=5.5 (3 * 40ml) with 10% phosphate buffer soln to ethyl acetate layer then with saturated nacl aqueous solution.Ethyl acetate layer stirs with saturated sodium bicarbonate solution (40ml), and adding FmocTyr (OBzl)-OSu (1.02g, 3.00mmol).With reaction mixture stir about 1.5 hours, remove water layer.

With with aforementioned similar mode, the intermediate order is carried out deprotection and coupling, adopt Fmoc-Lys (Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Phe-OSu.The silicagel column of ethyl acetate layer by flash chromatography carried out purifying, adopt 1% acetate/ethyl acetate as eluent.The product cut is merged vacuum concentration.Crude product is dissolved in the ethyl acetate again, adds hexane and precipitate, filter.Solid is carried out vacuum-drying, obtain intermediate 9h, 1.67g (52%).Mass spectrum 1280.7MH+.

Step e:4-(1, the 1-dimethyl ethyl)-2-(1-(S)-((Fmoc-Phe-D-Trp-Lys (Boc)-Tyr (Bzl)) amino-2-phenylethyl)-1-(2-oxyethyl group-2-oxo-ethyl)-imidazoles

With intermediate 9h (128mg 0.10mmol) is dissolved among the DMF (2ml), add salt of wormwood (35mg, 0.25mmol) and ethyl bromoacetate (28 μ l 0.25mmol), at room temperature stir mixture and to spend the night.With the mixture vacuum concentration, be dissolved in the ethyl acetate (10ml) water (10ml) washing again.With the ethyl acetate layer dried over sodium sulfate, filter and vacuum concentration, obtain thick intermediate 9e (126mg, 92%), it can not purified direct use.

Step f: ring [Phe-D-Trp-Lys (Boc)-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

(116mg 0.085mmol) was suspended in the ethyl acetate (2ml), adds three (amino-ethyl) amine (0.5ml), with about 1/2 hour of mixture vigorous stirring with intermediate 9e.Add ethyl acetate (10ml), (10% phosphate buffer soln (pH=5.5,3 * 5ml) washings are used in 2 * 5ml) washings then with saturated nacl aqueous solution with solution.Add hexane (40ml) and be settled out intermediate, (76mg) filters to intermediate.Resistates is dissolved in the methyl alcohol (2ml), at room temperature spends the night with sodium hydroxide (0.1ml) stirring of 2.5N.Mixture is diluted with water to muddiness, the pH value is adjusted to about 6.0.The intermediate of deprotection is filtered and vacuum-drying.Solid is absorbed among the DMF (20ml), add DCC (126mg, 0.60mmol) and HOBt (90mg, 0.60mmol).With mixture stir about 6 hours at room temperature, vacuum concentration.It is dissolved in the ethyl acetate (5ml), and (saturated nacl aqueous solution (5ml) washing is used in 1 * 5ml) washing again with saturated sodium bicarbonate aqueous solution.With dried over sodium sulfate, filtration and vacuum concentration, obtain intermediate 9f.Mass spectrum 1098.5MH+.

Step g: ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(1, the 1-dimethyl ethyl) imidazoles)-Gly]

(crude product 0.085mmol) is dissolved in and comprises iPr with intermediate 9f ₃In the Tfa of SiH (9.4ml) and the water (0.5ml), stir about 20 minutes, vacuum concentration.With crude mixture at C ₁₈Be prepared the HPLC purifying on the post, adopt 30% to 60%CH ₃CN/0.1%Tfa carries out gradient elution, and the time is about 50 minutes.For the second time usually, adopt 32% to 80%CH ₃The CN/0.2% ammonium acetate carries out gradient elution, and the time is about 50 minutes, to obtain good separating effect.Merge the purifying cut, concentrate and lyophilize (2 * 10ml, 0.5% hydrochloric acid, 1 * 10ml water then), obtain the title compound of embodiment 9,9mg (10%).Mass spectrum 998.4MH+.

Embodiment 10

Ring [Phe-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 3, carry out embodiment 10 according to building-up reactions route 1, just in steps d, adopt Fmoc-Phe-OSu to replace Fmoc-Trp-F.Mass spectrum 894.4MH+.

Embodiment 11

Ring [Phe-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 3, carry out embodiment 11 according to building-up reactions route 1, just in steps d, adopt Fmoc-Phe-OH to replace Fmoc-Trp-F, adopt Fmoc-Tyr (Bzl)-OH to replace Fmoc-Val-F.Fmoc-Tyr (Bzl)-OH activates with DCC and the HOAt that is purchased.Crude mixture in step g is made up of the material (Cbz and benzylic ether are all removed) of complete deprotection and the material of part deprotection (Cbz removes and benzylic ether is complete).The low polarity peak that is formed by the part deprotection obtains the title compound of embodiment 11.Mass spectrum 1048.5MH+.

Embodiment 12

Ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 3, carry out embodiment 12 according to building-up reactions route 1, just in steps d, adopt Fmoc-Phe-OH to replace Fmoc-Trp-F, adopt Fmoc-Tyr (Bzl)-OH to replace Fmoc-Val-F.With DCC and HOAt activation Fmoc-Tyr (the Bzl)-OH that is purchased.Crude mixture in step g is made up of the material (Cbz and benzylic ether are all removed) of complete deprotection and the material of part deprotection (Cbz removes and benzylic ether is complete).The high polarity peak that is formed by complete deprotection obtains the title compound of embodiment 12.Mass spectrum 958.4MH+.

Embodiment 13

Ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 4, carry out embodiment 13 according to building-up reactions route 1, just in step g, adopt intermediate 11f, ring [Phe-D-Trp-Lys (Cbz)-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly] replaces intermediate 3f.Mass spectrum 944.6MH+.

Embodiment 14

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 9, carry out embodiment 14 according to building-up reactions route 2, its difference is as follows:

Step h:2-(1-(S)-((Fmoc-Trp-D-Trp-Lys (Cbz)-Tyr (Bzl))-amino)-2-phenylethyl)-4-(3-p-methoxy-phenyl)-1-(trityl group)-imidazoles

Synthesize to carry out peptide, just adopt Fmoc-Trp-OSu to replace Fmoc-Phe-OSu, adopt Fmoc-Lys (Boc)-OSu to replace Fmoc-Lys (Cbz)-OSu and employing Fmoc-Tyr (Bzl)-OSu to replace Fmoc-Val-OSu with the similar mode of step 9h.Obtain 783mg (57%), mass spectrum=1370.6MH+.

Step e:1-((2-oxyethyl group-2-oxo) ethyl)-2-(1-(S)-((Fmoc-Trp-D-Trp-Lys (Boc)-Tyr (OBzl))-amino)-2-phenylethyl)-4-(3-p-methoxy-phenyl) imidazoles

The alkylated reaction of intermediate 14h obtains 640mg (80%), mass spectrum=1456.3MH+ to finish with the similar mode of reaction 9h.

Step f: ring [Trp-D-Trp-Lys (Boc)-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With intermediate 14e (640mg 0.44mmol) is dissolved in the 15ml methyl alcohol, add 2.5N sodium hydroxide (1ml, 2.5mmol).With mixture stir about 1/2 hour, add 5% hydrochloric acid soln then the pH value is adjusted to about 7.0.Methyl alcohol, decantation water-yielding stratum are removed in decompression.With resistates thorough drying under reduced pressure, then, be dissolved in again among the 15ml DMF.Add DCC (206mg, 1.0mmol) and HOBt (153mg 1.0mmo), spends the night the reaction mixture stirring.With the reaction mixture vacuum concentration, be dissolved in again in the ethyl acetate (10ml), with 10% phosphate buffered saline buffer (pH=5.5) washed twice.Ethyl acetate layer is placed on the silicagel column, and product is with more ethyl acetate drip washing.Merge product cut and concentrated, obtain the intermediate 14f of 240mg (46%).

Step g: ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

(240mg 0.20mmol) is dissolved in the methylene dichloride (10ml), adds to comprise iPr with intermediate 14f ₃SiH (205 μ l, Tfa 1.0mmol) (10ml).With mixture stir about 15 minutes at room temperature.Decompression steams methylene dichloride, adds ether and is settled out crude product.Decantation goes out solvent, with resistates further at C ₁₈By preparation HPLC purifying, adopt 30% on the post to 50%CH ₃CN/0.1%Tfa carries out gradient elution, and the time is about 55 minutes.Merge the purifying cut, concentrate and lyophilize (2 * 10ml0.5% hydrochloric acid, 1 * 10ml water then), obtain the title compound of embodiment 14,25mg (11%).Mass spectrum 1087.4MH+.

Embodiment 15

Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 4, carry out embodiment 15 according to building-up reactions route 1, its difference is as follows:

Step g: ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

(130mg 0.115mmol) is dissolved in the methylene dichloride (5ml), under nitrogen atmosphere, adds 1M BBr with intermediate 1f ₃Hexane solution (5ml).With the slurries stir about that forms 1/2 hour, be cooled to about 0 ℃ then.Add methyl alcohol (10ml), with the mixture vacuum concentration.Crude mixture is put in C ₁₈On the post,, use the 0.1%Tfa solution washing again, use 20% then to 35%CH with the washing of 1% ammonium acetate solution ₃CN/0.1%Tfa carries out gradient elution, and the time is about 50 minutes.Merge the purifying cut, concentrate and lyophilize (2 * 10ml, 0.5% hydrochloric acid), obtain the title compound of embodiment 15,60mg (54%).Mass spectrum 896MH+.

Embodiment 16

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 3, carry out embodiment 16 according to building-up reactions route 1, its difference is as follows:

Steps d: 2-(1-(S)-((Fmoc-Phe-D-Trp-Lys (Cbz)-Nal) amino)-2-phenylethyl)-4-(3-p-methoxy-phenyl)-1-(trityl group)-imidazoles

To prepare intermediate 16d, just adopt Fmoc-Nal-OAt to replace Fmoc-Val-F and employing Fmoc-Phe-OH to replace Fmoc-Tyr (Bzl)-OH with the basic similarly mode of intermediate 1d.

Step g: ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-Gly]

To carry out step 16g, obtain the title compound of embodiment 16 with the essentially identical mode of step 4g.Mass spectrum 980.0MH ⁺

Embodiment 17

Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 16, carry out embodiment 17 according to reaction scheme 1, its difference is as follows:

Step g: ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-Gly]

(310mg 0.27mmol) is suspended in the phenylmethylether (3ml), and suspension is handled in the anhydrous HF of about 12ml with intermediate 17f.With mixture about 0 ℃ of following stir about 1 hour.Steam HF, be settled out product by adding ether.With filtration of crude product, be further purified with preparation HPLC again, adopt 20-80%CH ₃CN/0.1%Tfa carries out gradient elution, and the time is about 40 minutes.Merge the purifying cut, concentrate and lyophilize twice in dilute hydrochloric acid solution, obtain product 56mg (19%), mass spectrum 992.4MH+.

Reaction scheme 3

Embodiment 18

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-(γ) Abu]

Carry out embodiment 18 according to building-up reactions route 3.

Step I: 2-(1-(S)-((phenyl methoxyl group) carbonyl)-amino-2-phenylethyl)-4-(4-p-methoxy-phenyl)-imidazoles

With Cbz-(L)-phenylalanine (10.0g, 33.4mmol) and cesium carbonate (5.44g 16.7mmol) integrates with 2: 1/DMF: in the water (75ml), mixture is stirred until obtaining uniform mixture.Removal of solvent under reduced pressure is dissolved in resistates among the DMF (70ml), adds 2-bromo-3 '-methoxyacetophenone (7.65g, DMF 33.4mmol) (30ml) solution.With mixture at room temperature stir about 1/2 hour, concentrating under reduced pressure then.Ketone-the ester that forms is dissolved in the dimethylbenzene (150ml) filtering CsBr.(40.0g 0.52mol), refluxes mixture heating up about 2 hours, adopts the Dean-Stark water trap, removes excessive ammonium acetate and discharges water outlet to add ammonium acetate.With the reaction mixture cooling, with saturated sodium bicarbonate solution (50ml) and saturated nacl aqueous solution (50ml) washing.With dried over sodium sulfate dimethylbenzene layer, filter and vacuum concentration, obtain intermediate 18i, be a kind of brown solid (13.8g, 96%).Mass spectrum 428.2 (MH+).

Step j:2-(1-(S)-amino-2-phenylethyl)-1-(4-(1,1-dimethyl oxyethyl group)-4-oxo-butyl)-4-(4-p-methoxy-phenyl)-imidazoles

With intermediate 18i (2.14g, 5.0mmol) be dissolved among the DMF (11.5ml), (1.50g is 15.0mmol) with butyric acid 4-bromo-tertiary butyl ester (4-bromo-t-butylbutyrate) (6.69g with saleratus, 30mmol) divide and to handle for three times, about 50 ℃ of following stir abouts 18 hours.Mixture is diluted with ether, once and with saturated nacl aqueous solution wash once with the saturated sodium bicarbonate solution washing.A kind of oil of formation is filtered and concentrated to ether layer dried over sodium sulfate.Handle with silica gel column chromatography, adopt methylene dichloride, obtain a kind of oily product as eluent.

Alkylating crude product is carried out hydrogenation and deprotection by adopt 10%Pd/C in acetate as catalyzer.Filtration catalizer, decompression steams solvent.Resistates is dissolved in the ethyl acetate,, carries out drying and concentrate obtaining intermediate 18j, be a kind of oil (450mg) that it can promptly be used for next step without being further purified with sodium sulfate with saturated sodium bicarbonate solution and saturated nacl aqueous solution washing.

Step k:2-(1-(S)-((Boc-Trp-D-Trp-Lys (Cbz)-Val)-amino-2-phenylethyl)-1-((4-(1,1-dimethyl oxyethyl group)-4-oxo) butyl)-4-(3-p-methoxy-phenyl)-imidazoles

Carry out solution in the mode identical and synthesize, just adopt Boc-Trp-OSu to replace Fmoc-Tyr (Bzl)-OSu and employing Fmoc-Tyr (Bzl)-OAt to replace Fmoc-Val-F, obtain intermediate 18k with the building-up process of step 1d detailed description.Obtain product 1.03g (81%).

Step 1:2-(1-(S)-((H-Trp-D-Trp-Lys (Cbz)-Val)-amino-2-phenylethyl)-1-((4-hydroxyl-4-oxo) butyl)-4-(3-p-methoxy-phenyl)-imidazoles

Intermediate 18k is with containing (iPr) ₃SiH (593 μ l, Tfa 2.90mmol) (10ml) solution-treated, stir about 1 hour.Reaction mixture is concentrated, and with 1: 1 ether: hexane solution was developed, and obtains intermediate 181, is a kind of brown solid, and it can promptly can be used for next step without being further purified.Mass spectrum 1267.7MH+.

Step f: ring [Trp-D-Trp-Lys (Cbz)-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-(γ) Abu]

Intermediate 181 is dissolved among the DMF (20ml), add the 4-methylmorpholine (159 μ l, 1.45mmol), HOBt (196mg, 1.45mmol) and EDC (278mg 1.45mmol), spends the night the reaction mixture stirring.With the reaction mixture vacuum concentration, with silica gel flash chromatography purifying, adopt methylene dichloride: methyl alcohol (9: 1) obtains intermediate 18f as eluent, obtains product 220mg (24%) again.Mass spectrum 1249.7MH+.

Step g: ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-(γ) Abu]

Under the hydrogen atmosphere of 30psi, in room temperature, with intermediate 18f (220mg, 176 μ mol) partial hydrogenation 14 hours in acetate, the catalyzer of employing is 10%Pd/C.Filtration catalizer carries out vacuum concentration with filtrate.With crude mixture at C ₁₈Be prepared the HPLC purifying on the post, adopt 0% to 75%CH ₃CN/0.1%Tfa carries out gradient elution, and the time is 40 minutes.The purifying cut that merges the product peak concentrates and lyophilize (2 * 10ml, 0.5% hydrochloric acid, 1 * 10ml water then), obtains the title compound of embodiment 18,72mg (37%).Mass spectrum 1115.6MH+.

Embodiment 19

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(4-p-methoxy-phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 18, carry out embodiment 19 according to building-up reactions route 3, its difference is as follows:

Step j:2-(1-(S)-amino-2-phenylethyl)-1-(2-(1,1-dimethyl oxyethyl group)-2-oxo-ethyl)-4-(4-p-methoxy-phenyl)-imidazoles

With intermediate 18i (854mg 2.0mmol) is dissolved among the DMF (10ml), add the monobromo-acetic acid tert-butyl ester (646 μ l, 4.0mmol) and salt of wormwood (552mg 4.0mmol), at room temperature stirs reaction mixture and to spend the night.Removal of solvent under reduced pressure is dissolved in resistates in the ethyl acetate, washs with saturated nacl aqueous solution.The ethyl acetate layer dried over sodium sulfate is filtered and vacuum concentration, obtains the foam thing of 1.02g.Mass spectrum 428.2MH+, and NMR (300MHZ, 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), and 3.7-3.9 (3H, s), 3.1-3.4 (2H, m), 1.3-1.5 (9H, s).

(1.02g 1.88mmol) is dissolved among the HOAc (50ml) that comprises 10%Pd/C (50mg), carries out hydrogenation 10 hours under the hydrogen atmosphere of 30psi with intermediate white foam thing.Filtration catalizer, and adding 2N hydrochloric acid (940 μ L, 1.88mmol).With the mixture lyophilize once, and then at 20%CH ₃Lyophilize in the CN/ water obtains intermediate 19j, is a kind of light brown solid (862mg), and it can be without being further purified direct use.Mass spectrum 408.2MH+.

Step g: to carry out catalytic hydrogenation and processing, obtain title product (22mg, 4%), be a kind of white solid with the basic similarly mode of step 18g.Mass spectrum 1088.2MH+.

Embodiment 20

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(phenyl) imidazoles)-Gly]

With with the basic similarly modes of embodiment 18, carry out embodiment 20 according to building-up reactions route 3, just in step I, adopt the 2-bromoacetophenone replace 2-bromo-3 '-methoxyacetophenone.Mass spectrum 1057.4MH+.

Embodiment 21

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-p-methoxy-phenyl) imidazoles)-(ε) Ahx]

With with the basic similarly modes of embodiment 18, carry out embodiment 21 according to building-up reactions route 3, its difference is as follows:

Step j:2-(1-(S)-amino-2-phenylethyl)-1-(6-(oxyethyl group)-6-oxo-hexyl)-4-(3-p-methoxy-phenyl)-imidazoles

(855mg 2.0mmol) is dissolved among the DMF (8.0ml), and (200mg, 2.0mmol) (3.56ml 20mmol) handled about 8 hours down at about 120 ℃ with 6-bromocaproic acid ethyl ester with saleratus with intermediate 21i.Mixture is concentrated, resistates is carried out purifying by silica gel column chromatography, adopt 2: 1 hexane: ethyl acetate obtains purified product as eluent, is a kind of jelly (0.94g).

By in acetate, carrying out the hydrogenation deprotection, adopt 10%Pd/C alkylating crude product as catalyzer.Filtration catalizer, decompression steams solvent.Resistates is dissolved in the dilute hydrochloric acid, and freezing and lyophilize obtains intermediate 21j, is a kind of light yellow solid (720mg, 91%) that it promptly can be used for next step without being further purified.Mass spectrum 436.2MH+.

Step k and step 1:2-(1-(S)-((H-Trp-D-Trp-Lys (Boc)-Tyr (Bzl)-2-(1-(S)-amino-2-phenylethyl)-1-(6-(oxyethyl group)-6-oxo-hexyl)-4-(3-p-methoxy-phenyl)-imidazoles

By with Fmoc-Tyr (Bzl)-OH (493mg, 1.00mmol), HOAt (136mg, 1.0mmol) and DCC (206mg 1.0mmol) mixed in the 8ml ethyl acetate about 1/2 hour, removed dicyclohexylurea (DCU) then and made Fmoc-Tyr (Bzl)-OAt.The solution that forms is added to intermediate 21j, and (457mg in ethyl acetate 0.9mmol) (4ml) solution, stirs mixture and saturated sodium bicarbonate solution (10ml), finishes until showing through mass spectroscopy to react.Remove water layer, the processing of three (2-amino-ethyl) amine (2.7ml) is filtered and used to the ethyl acetate layer dried over sodium sulfate.With about 1/2 hour of mixture vigorous stirring.(2 * 60ml) washings are regulated the pH value to about 5.5 (3 * 15ml) with 10% phosphate buffer soln to ethyl acetate layer then with saturated nacl aqueous solution.

With with the similar mode that circulates of Fmoc-Tyr (Bzl)-OAt as mentioned above, the intermediate order is carried out deprotection and coupling, adopt Fmoc-Lys (Cbz)-OSu, Fmoc-D-Trp-OSu and Fmoc-Trp-OSu.Last Fmoc deprotection obtains the intermediate ethyl ester of the deprotection of N-end.With the ethyl acetate layer dried over sodium sulfate, filter and dilute with the hexane of 4 times of volumes.Pour out solvent, resistates is developed with hexane, obtain a kind of solid state product (0.67g, 58%), it can use without being further purified.Mass spectrum 1289.6MH+.

Spend the night the intermediate of processing in methyl alcohol (5.0ml) to remove ethyl ester by sodium hydroxide solution (1.7ml) with 1.7M.With 5% hydrochloric acid soln the pH value of mixture is adjusted to about 8.2, removal of solvent under reduced pressure.Resistates is absorbed among the DMF, removes by filter sodium-chlor, DMF solution can be used for next step without being further purified.

Carry out cyclization and deprotection in mode similar to Example 18, obtain the title compound of embodiment 21, be a kind of white powder, 62mg.Mass spectrum 1143.9MH+.

Embodiment 22

Ring [Trp-D-Trp-Lys-Tyr (Bzl)-Phe Ψ (4-(3-hydroxy phenyl) imidazoles)-(γ) Abu]

With with the basic similarly modes of embodiment 18, carry out embodiment 22 according to building-up reactions route 3, its difference is as follows:

Step j:2-(1-(S)-amino-2-phenylethyl)-1-(4-(oxyethyl group)-4-oxo-butyl)-4-(4-hydroxy phenyl)-imidazoles

With intermediate 22i (2.0g 4.68mmol) is dissolved among the DMF (7.0ml), with saleratus (468mg, 4.68mmol) and 4-bromo-ethyl butyrate (6.70ml 46.8mmol) handled, about 100 ℃ of following stir abouts 30 hours.Mixture is diluted with ether, with the saturated sodium bicarbonate solution washing once, more once with the saturated nacl aqueous solution washing.Ether layer dried over sodium sulfate filtered and concentrated and obtain a kind of oil.Carry out silica gel chromatography, adopt methylene dichloride, obtain a kind of oily product (2.53g, 94%) as eluent.Mass spectrum 542.3MH+.

In 15 minutes, under approximately-10 ℃, will (2.53g 4.67mmol) be added drop-wise to 1M BBr at the alkylating crude product in the methylene dichloride (50ml) ₃In methylene dichloride (250ml) solution of/hexane (23.4ml).Mixture is warming up to room temperature, stir about 2 hours.Add ethanol (40ml), again mixture is concentrated into about 50ml.Solution with ethanol (100ml) dilution, is at room temperature stirred and spends the night.With the mixture concentrating under reduced pressure, resistates is distributed between ethyl acetate and saturated sodium bicarbonate solution.The ethyl acetate layer dried over sodium sulfate is filtered and concentrating under reduced pressure, obtains a kind of oil (1.41g, 76%), and it can promptly can be used for next step without the phenol protection.Mass spectrum 394.3MH+.

The HPLC residence time

Embodiment number	The HPLC system	The residence time (minute)
Embodiment number	The HPLC system	The residence time (minute)	1	A	13.65
2	A	18.50	1	A	13.65
2	A	18.50	3	A	16.03
4	B	6.97	3	A	16.03
4	B	6.97	5	C	20.41
6	C	11.75	5	C	20.41
6	C	11.75	7	D	9.53
8	B	11.02	7	D	9.53
8	B	11.02	9	E	7.69
10	J	6.02	9	E	7.69
10	J	6.02	11	F	4.18
12	G	4.11	11	F	4.18
12	G	4.11	13	H	5.50
14	G	6.16	13	H	5.50
14	G	6.16	15	I	17.03
16	K	9.12	15	I	17.03
16	K	9.12	17	J	8.11
18	J	8.86	17	J	8.11
18	J	8.86	19	L	6.47
20	M	6.65	19	L	6.47
20	M	6.65	21	G	8.14
22	N	12.10	21	G	8.14

The HPLC system:

A gradient: 20-80% CH ₃CN/0.1% Tfa, 24 minutes

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

B gradient: 35-50% CH ₃CN/0.1% Tfa, 24 minutes

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

C gradient: 32-64% CH ₃The CN/0.1% ammonium acetate, 24 minutes

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

D gradient: 20-60% CH ₃CN/0.1% Tfa, 24 minutes

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

E gradient: 55-75% CH ₃CN/0.1% Tfa, 24 minutes

Flow velocity: 1.0ml/ minute

Detect: 220nm

Post: Phenomenex LICHROSPHERE  5 RP18 (Phenomenex,

2320W，205 ^th St.，Torrance，CA)

F gradient: 60% CH ₃CN/0.1% Tfa isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

G gradient: 50% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

H gradient: 38% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

I gradient: 20-40% CH ₃CN/0.1% Tfa, 24 minutes

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: VYDAC  protein and peptide C18

J gradient: 50% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: NUCLEOSIL ^TMC18,5 microns (Alltech Associates, 2051

Waukegan Rd.，Deerfield，Illinois)

K gradient: 40% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: NUCLEOSIL ^TMC18,5 microns

L gradient: 52% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: NUCLEOSIL ^TMC18,5 microns

M gradient: 50% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: NUCLEOSIL ^TMC18,5 microns

N gradient: 48% CH ₃CN/0.1% Tfa, isocratic elution

Flow velocity: 1.0ml/ minute

Detect: 254nm

Post: NUCLEOSIL ^TMC18,5 microns

Claims

1. A compound of formula (I) or a pharmaceutically acceptable salt thereof,

in,

Y and Z independently of each other at each occurrence are D- or L-natural or unnatural α-amino acids;

n is independently 0 or 4 at each occurrence, provided that both n cannot be 0 at the same time;

The amino acid constitutes a chain: X ¹ -X ² -X ³ -X ⁴ , wherein

X ¹ is Tyr or Trp, and the amino acid can be protected by a Boc group;

^X2 is D-Trp;

X ³ is Lys, which can be protected by a Boc group;

X ⁴ is Nal, Tyr or Thr;

m is 0;

a is H or R ¹ ;

b is OH or -OR ¹ ;

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

R ² is H or phenyl-(C ₁ -C ₄ ) alkyl;

R ³ and R ⁴ are independently H or a substituted aryl group substituted by one or more substituents selected from OH, (C ₁ -C ₄ )alkyl, (C ₁ -C ₄ ) alkoxy; and

R ⁵ is H in every occurrence.

2. A compound of formula (II) or a pharmaceutically acceptable salt thereof,

in,

m is 0;

n is independently 0 or 1 at each occurrence;

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

R ² is phenyl-(C ₁ -C ₄ )alkyl;

R ³ and R ⁴ are independently of each other H or the following groups optionally substituted: (C ₁ -C ₄ )alkyl and aryl, wherein the optionally substituted groups are selected from one or more of - OH and (C ₁ -C ₄ ) alkoxy substituents are substituted;

^R is independently H at each occurrence;

R ⁶ is independently at each occurrence aryl-(C ₁ -C ₄ )alkyl;

^X is a D- or L-isomer of natural or unnatural Phe, Trp or Tyr, wherein, when ^X is Tyr, the aromatic ring on its side chain is optionally substituted by ^R ;

X ² is a D- or L-isomer of Trp;

^X3 is Lys;

X ⁴ is a natural or unnatural D- or L-α-amino acid Nal, Thr, Tyr or Ser, wherein, when X ⁴ is Tyr, the aromatic ring on its side chain is optionally substituted by R ⁶ , or when When X ⁴ is Ser or Thr, the oxygen atom on its side chain can be optionally substituted by one or more R ¹ .

3. The compound according to claim 1, wherein said compound is:

H-Trp-D-Trp-Lys-Abu-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly-OH.

4. The compound according to claim 2, wherein said compound is:

Cyclo[Tyr-D-Trp-Lys-Val-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly],

Cyclo[Tyr(Bzl)-D-Trp-Lys-Val-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly],

Cyclo[Trp-D-Trp-Lys-Val-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly],

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

Cyclo[Trp-D-Trp-Lys-Thr(Bzl)-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly],

Cyclo[Trp-D-Trp-Lys-Thr-PheΨ(4-(3-hydroxyphenyl)imidazole)-Gly],

Cyclo[Trp-D-Trp-Lys-Abu-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly],

Cyclo[Phe-D-Trp-Lys-Tyr(Bzl)-PheΨ(4-(1,1-dimethylethyl)imidazole)Gly],

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

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

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

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

Cyclo[Trp-D-Trp-Lys-Tyr(Bzl)-PheΨ(4-(3-methoxyphenyl)imidazole)-Gly],

Cyclo[Tyr-D-Trp-Lys-Val-PheΨ(4-(3-hydroxyphenyl)imidazole)-Gly],

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

Cyclo[Phe-D-Trp-Lys-Nal-PheΨ(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)-PheΨ(4-(4-methoxyphenyl)imidazole)-Gly],

Cyclo[Trp-D-Trp-Lys-Tyr(Bzl)-PheΨ(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)-PheΨ(4-(3-hydroxyphenyl)imidazole)-(γ)Abu].

5. A pharmaceutical composition comprising an effective amount of the compound of claim 1 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

6. A pharmaceutical composition comprising an effective amount of the compound of claim 2 or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier.

7. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a somatostatin receptor agonist.

8. The use of the compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof in the preparation of a somatostatin receptor agonist.

9. The use of the compound of claim 1 or a pharmaceutically acceptable salt thereof in the preparation of a somatostatin receptor antagonist.

10. The use of the compound as claimed in claim 2 or a pharmaceutically acceptable salt thereof in the preparation of a somatostatin receptor antagonist.

11. The application of the compound or pharmaceutically acceptable salt thereof of claim 1 in the preparation of medicines for the treatment of diseases associated with somatostatin receptors, said diseases comprising prolactin-secreting adenoma restenosis, diabetes, hyperlipidemia syndrome, insulin insensitivity, syndrome X, vascular disease, proliferative retinopathy, dawn phenomenon, nephropathy; gastric acid secretion, peptic ulcer, enterocutaneous and pancreaticocutaneous fistula, irritable bowel disease, dumping syndrome, watery diarrhea syndrome AIDS-related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormone-secreting tumors, cancer, hepatoma, angiogenesis, inflammatory disease, arthritis, chronic allograft rejection, Angioplasty, graft bleeding, or gastrointestinal bleeding.

12. The application of the compound or pharmaceutically acceptable salt thereof of claim 2 in the preparation of medicines for the treatment of diseases associated with somatostatin receptors, said diseases comprising prolactin-secreting adenoma restenosis, diabetes, hyperlipidemia syndrome, insulin insensitivity, syndrome X, vascular disease, proliferative retinopathy, dawn phenomenon, nephropathy; gastric acid secretion, peptic ulcer, enterocutaneous and pancreaticocutaneous fistula, irritable bowel disease, dumping syndrome, watery diarrhea syndrome AIDS-related diarrhea, chemotherapy-induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormone-secreting tumors, cancer, hepatoma, angiogenesis, inflammatory disease, arthritis, chronic allograft rejection, Angioplasty, graft bleeding, or gastrointestinal bleeding.

13. The compound of claim 1 or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for treating the proliferation of Helicobacter pylori associated with a somatostatin receptor.

14. The compound of claim 2 or a pharmaceutically acceptable salt thereof is used in the preparation of a medicament for treating the proliferation of Helicobacter pylori associated with a somatostatin receptor.