TW200410986A - Pharamaceutical comiposition comprising cyclic somatostatin analogs II - Google Patents

Abstract

The Present invention is directed to cyclic derivatives containinz an imidazole cis amide bond mimetic which bind selectiveiy to sornatostatln receptor subtypes and the uses thereof in treatinz conditions which can be treated by eliciting an gorlist and antagonist effect from the somatostatin subtype receptors. This invention is also directed to methods for making the compounds of the instant invention.

Description

200410986 发明, description of the invention (invention description should be: the technical field to which the invention belongs, the prior art, the contents of the embodiment, and a brief explanation of the military) C j ^ rf Jl Derivative, which selectively binds to the growth hormone release inhibitory factor (hereinafter referred to as "growth 5 hormone") receptor subtype. The present invention also relates to a method for producing a compound of the present invention. [Previously 3 stagnation hormone (SRIF) is a cyclic tetradecapeptide hormone containing a disulfide bridge between 3 and 14 positions, and has the ability to inhibit the release of growth hormone (GH) and thyroid stimulating hormone (TSH), inhibit insulin and Glucagon release, and reduce gastric acid secretion and other properties. Somatostatin is metabolized by the amino peptide hydrolase and the slow-moon hydrolase, resulting in a short duration of action. Somatostatin binds to five discrete receptor (SSTR) subtypes and has a relative south affinity for each subtype. The smaller and stiffer analogs of the present invention are highly selective for the right dry% body isoform. The 15 different song types that bind to the somatostatin subtype are related to the treatment of the following conditions and / or diseases. Activated type 2 and 5 lines are related to growth hormone inhibition and are particularly related to growth hormone-secreting adenomas (acromegaly) and sacral gland-stimulating hormone-secreting adenomas. Activated type 2 but not type 5 can be used to treat prolactin-secreting adenomas. Other indications related to activated somatostatin subtypes include restenosis of the blood vessels, inhibition of insulin 20 and / or glucagon, and special diabetes, hyperlipidemia, insulin insensitivity, syndrome X, vascular disease, proliferative retinopathy, Tang Phenomenon and nephropathy 'inhibits gastric acid secretion and special gastric ulcers, intestinal epidermis and pancreatic epidermal pain ducts, irritable bowel syndrome, Dangpin's (Dumpin's syndrome, watery diarrhea syndrome, 200410986), invention description AIDS-associated abdominal pain, chemical Treatment induces diarrhea, acute or chronic catarrh, and gastrointestinal hormone-secreting tumors; treats cancers such as liver tumors; inhibits angiogenesis' graft rejection; angioplasty; prevents graft blood vessels and gastrointestinal bleeding. Somatostatin agonists can also 5 is used to reduce the weight of patients. Somatostatin agonists have also been disclosed to inhibit the proliferation of H. pylori. [Mei Nai 3] In one aspect, the present invention provides a compound of formula (I),

(I) or a pharmaceutically acceptable salt thereof, wherein Y and Z are DjL_natural or unnatural alpha amino acid at each occurrence; η is 0 to 50 at each occurrence, but η cannot be Also 〇; Π1 is an integer of 0 or 1 to 10; a is Η or R1; 玖, invention description b is OH, -OR1 or -NR9R9; or a and b together form a hydrazine bond; R1 is Η, (Cl-C4) alkyl or aryl_ (CkC4) alkyl; R2 is fluorene or a selectively substituted moiety selected from the group consisting of (Ci-C4) alkyl, phenyl, phenyl- (Ci-C4) alkyl and Heterocyclyl- (Ci-C4) alkyl, where the selectively substituted part is optionally from-or? Substituents are substituted, and the substituents are selected from the group consisting of (CVC4) alkyl, (C3-C8) ring group, _Q_R6 ,, 〇) q_R7, called r9r9), COf, _NHS〇2r9, even r9, thorough 9 And s〇2Nr9r9 'where q is 0,1,2, or 3; 10 15 members; R3 and R4 are fluorene atom or selective substitution part selected from the group including (CA) alkyl group (CVC8) cycloalkyl group, aromatic And aryl_ (Ci_c4) alkyl; the selective substitution part here is optionally substituted with one or more substituents, the substituents are selected from the group consisting of OH '(Cl_C4) alkyl, (Ci_C4) alkyl, Aryloxy, aryl- (qq) alkoxy '_nr9r9' C00H, _c and _Original 20 or R3 and R4 together with the carbon to which they are attached form a selectively substituted aryl group, where the aryl group is optionally selected from- Substituted by a substituent, the substituents are selected from the group consisting of OH '(C) -C4) alkynyl' oxenoxy, aryloxy, arylalkoxy, -NR9R9, COr5, _c. nr9r9 and tooth atom;] 4 R5 at each occurrence is H or the selective substitution moiety is selected from the group consisting of ClCl and mc, where the selective substitution moiety is selectively substituted by-or multiple substituents Replace They are selected from the group consisting of (CiC) alkyl, OH, (Cl-C methoxy, aryloxy, n0, and aryl melamine), 7A, hydrazone, -nr9r9 'COOH' -CONR9R9 and halogen Atom; R6 at each occurrence is selected from the group consisting of H, ((Vc4) alkyl, ((Vco), aryl- (Cl-C4) alkyl and aryl- (CKC4) alkoxy); When q is 3, R7 is Η, or when 9 is 0, 1 or 2, and 7 each occurrence is selected from the group including (Ci-c: 4) alkyl, aryl, or aryl_ (Ci- C4) alkyl; and 11 at each occurrence are selected from the group consisting of fluorene, No2, (CKC4) alkyl, aryl, and aryl- (CVC4) alkyl. The compound of formula (I) is a compound H_Tr corpse D_Trp_Lys_Abu_phe ψ oxophenyl) glutamate. Sitting)-Gly-QH. In another aspect, the invention provides a compound of formula,

Or a pharmaceutically acceptable salt thereof, wherein natural α-amines Y and Z are D _ or L _ natural or non-m at each occurrence, and m is an integer of 0 or 1 to 10; n is at each occurrence 0 to 6; 200410986 发明, description of the invention R1 is h at each occurrence, (Ci_C4) alkyl or aryl) alkyl; R2 is fluorene or a selectively substituted moiety selected from (Ci_c4) alkyl, benzene Group, phenyl-((VCO alkyl group and heterocyclyl_ (Ci_C4) group, the selectivity here

The 5 substitution part is optionally substituted by-or a plurality of substituents, and the substituents are selected from the group consisting of (CVC4) alkyl, cycloalkyl, _〇_r6, _s (〇) q_R7,-called r9r9), -NHCO WS 〇2R9, _c〇2R9, _c〇nr9ru〇2NrV, where q is 0,1,2, or 3; R3 and R4 are H, i atom or a selective substitution moiety selected from the group including 10 (c "c4) Group, cycloalkyl group, aryl group and mC4) alkyl group; the selective substitution part here is optionally substituted by-or multiple substituents, the substituents are selected from the group consisting of OH, (CVC4), and (CVC4) alkyl Oxy, aryloxy, aryl- (cvc4) alkoxy, -Nr9R9, C00H, coNm

Or R3 and R4 together with the carbon to which they are attached form a selectively substituted aryl group. These 15 aryl groups are optionally substituted with one or more substituents, and the substituents are selected from the group consisting of OH, (CrC4), and (Cl_C4 ) Alkoxy, aryloxy, aryl # 1. ^) alkoxy, -NR9R9, COORR5, -Conr9r9 &atom; R5 is selected from Η or a selectively substituted moiety at each occurrence Since (Cl-C4) alkyl and aryl- (CVC) are included, the selective substitution part here 20 is optionally substituted with one or more substituents, and the substituents are selected from the group including gamma-alkyl Na, following, n〇2, == alkoxy, -NR9R9, COOH, -conr9r9, and _ atom · R6 is selected from each occurrence including H, ⑹ heart) 9 200410986 Rose, invention description , Aryl- (Crc4) alkyl and aryl-Ci_C4) alkoxy; when q is 3, R7 is Η, or when q is 0, 1 or 2 hrs. Are included in each occurrence (cvc : 4) an alkyl group, an aryl group, or an aryl- (Ci-c4) alkyl group; and R at each occurrence is respectively selected from the group consisting of fluorene, no2, (CVQ) alkyl, 5aryl, and aryl- (Ci-oo alkyl; X1 is natural or unnatural D- or L-α-amino acid. Here, when X1 is Phe, Nal, Trp, Tyr, Pal or His, its aromatic ring system is selectively substituted by trans 6 to carbon or nitrogen, or when χ1 is Ser or Thr, Branched chain oxygen is optionally substituted by one or more R1; X2 is D- or L-Trp, N-methyl_D-Tip or N-methyl-L-Trp; X3 is Lys, α.N_fluorenyl -With ε | (C "C4) alkyl 丄 ^ or e I [aryl- (CVC4) alkyl] -Lys; x is a natural or unnatural D- or L · α amino acid, where χ4 For Phe

When Mai 'Trp' Tyr or HlS, its aromatic ring is optionally substituted by R8 with carbon or nitrogen, or when X4 is Ser, Tyr or Thr, its branched oxygen can be substituted with one or more Rl. The bonds between X, X, X3 and X4 are amine bonds, as are the bonds between χΐ and z, and the bonds between X4 and γ. A group of preferred compounds of formula (II) is labeled as group A where 20 is each η is 2; m is 0 or 1 to 5; R1 is H, methyl or aryl_ (Ci_c4) alkane at each occurrence R2 is a selectively substituted moiety selected from the group consisting of phenyl_ (C] _C4) alkyl and hetero10 玖, description of the invention cycloalkyl- (CKC4) alkyl, where the selective substituted portion is selected from a group including ( Ci-Q) alkyl and -0_R6 substituent substitution; and R3 and R4 are fluorene, halogen atom, or selective substitution part selected from (G-C4) alkyl and aryl; this choice here The sexually substituted portion is optionally substituted with a substituent selected from the group consisting of O11, (c-C4) alkoxy'aryloxy and _ atom. A group of preferred Group A compounds is labeled as Dagger where X1 is Phe, Na, Trp, Tyr, Pal or His, where the aromatic ring system is selectively substituted by R6 on charcoal or nitrogen; and X4 is Va and Abu ' Ser, Thr, Na, Trp, Tyr or His, where

The aromatic ring system of Nal, Trp, Tyr and His is selectively substituted by RS with carbon and / or nitrogen, or when X4 is Ser, Tyr or Thr, the branched oxygen system is selectively substituted with Ri. A preferred group of compounds in group B is labeled as (wherein X1 is Phe, Trp or Tyr where the aromatic ring system is selectively substituted by R6 with carbon or nitrogen; X2 is D-Trp or N-methyl-D-Trp X3 is Lys or a methyl-Lys; X4 is Val, Thr, Abu, Nal or Tyr, where the branched oxygen of the hydroxyl group of Thr and Tyr is selectively substituted by Ri; R1 is Η at each occurrence, Methyl or benzyl; R2 is a optionally substituted moiety selected from the group consisting of phenylmethyl and heterocyclyl-methyl, where the selective substituted portion is selected from the group consisting of (C ^ _C4) alkyl and -O -R6 is substituted by a substituent; 200410986 发明. Description of the invention R is (Q-C4) alkyl or optionally substituted aryl; here the selectively substituted aryl is selected from the group consisting of 0h, (Ci_C4) alkoxy R4 is Η; and 5 R at each occurrence is selected from the group consisting of a preferred group C compound including HE and aryl- (C ^ COalkoxy). Labeled as group D, where X is Phe, Trp, Tyr or Tyr (OBzl); Lu X4 is Va Bu Thr, Abu, Nal or Tyr, where Thr and Tyr hydroxyl group 10 are selective substituents; m is 0, 2 4; R2 is a selective substitution moiety selected from the group consisting of phenylfluorenyl or 3-sulphenylfluorenyl, where the selective substitution moiety is optionally substituted by _〇 氺 6; and R is 1,1-monomethyl Ethyl or optionally substituted aryl; here the optionally substituted 15 group is optionally substituted with a moiety selected from the group consisting of 0H, (Q-C4) alkoxy and halo atoms. A group of preferred Group D compounds are labeled as £ group where R2 is phenylmethyl; 'R is ι, ΐ-dimethylethyl or optionally substituted phenyl, where the selectivity, the 20-substituted phenyl OH or OCH3 substitution; and R at each occurrence is selected from the group consisting of fluorene or benzylmethoxy. A preferred group of compounds in the E group is labeled as ρ group is ring (^ 1- | but1.) 3-1 ^ * ^ 141 ^ ¥ (Heart (3-methoxyphenyl) tidazole > () 13 /] 12 200410986 玖, description of the invention ring [Tyr (OBzl) -D-Ti.p-Lys-Val-PheW ( 4- (3-Phenyloxyphenyl) imide sigma) -Gly],% ring [Trp-D-Trp-Lys-Val-Phe ¥ (4- (3-Phenyloxyphenyl) methyl ^)-Gly ] 5, Ring [Trp-D-Trp-Lys-Val-PheW (4- (3-hydroxyphenyl) imidazole) -Gly], Ring [Trp-D-Ti.p-Lys-Thr (OBzl) -PheW (4- (3-fluorenyloxyphenyl) Imidazole) -Gly], ring [Trp-D-Trp-Lys-Thr-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], 10 rings [Trp-D-Trp-Lys-Abu-Phe Ψ (4- (3 -methoxyphenyl) odor ° sitting) -Gly] ring [Phe-D-Trp-Lys-Tyi (OBzl) -PheW (4- (1,1-Difluorenylethyl)) M ^)-Gly], ring [Phe-D-Trp-Lys-Val-Phe Ψ (4- (3-fluorenoxyphenyl) imidazole) -Gly] 15, · ring [Phe-D-Trp-Lys- Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4- (3- -oxophenyl) imidazole) ) -Gly] '20 ring [Phe-D-Tip-Lys-Tyi-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Ti-pD-Ti, p_Lys-Tyi. (Bzl ) -Phe Ψ (4- (3- 曱 oxophenyl) imidazole) -Gly], ring [丁 丫 1-0- 丁 1 广 1 ^ 5- ¥ & 1-? 1 ^ ¥ (4- (3 _Hydroxyphenyl) imidazole) -01},], 13 200410986 玖, description of the invention ring [Phe-D-Trp-Lys-Nal-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [ ? 1 ^ -0- 丁 1 严 1 ^, & 1-? 1 ^ ¥ (4- (3- 曱 oxophenyl) imidazole) -0 to] ring [Trp-D-Trp-Lys-Tyr (OBzl ) -Phe ¥ (4- (3-Phenoxyphenyl) imidazole 5) (γ) -Abu]? Ring [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (4-Phenoxy Phenyl) imidazole) -Gly], ring [Trp-D-Trp-Lys-Tyr (O Bzl) _Phe ¥ (4- (phenyl) imidazole) -Gly], the ring [Trp-D-Trp_Lys-Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) 米 °° 10) _Gly ], Ring [Trp-D_Trp-Lys-Tyi '(OBzl) -Phe Ψ (4- (3-methoxyphenyl) ketone 嗤)-(ε) -Ahx] and ring [1 ^ -0-1 ^ -1 ^ 8- 丁 丫 1. ((^ 21)-? 1 ^ ¥ (4- (3-hydroxyphenyl) imidazole)-(7 ')-Abu]. 15 A group of preferred group F compounds is labeled as group G where the ring [Tyr-D-Trp_Lys-Val-PheW (4- (3-methoxyphenyl) imidazole) -Gly], and the ring [TyrCOBzlVD-Trp-Lys- Val-Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], ring [Tip-D-Trp-Lys-Val-PheW (4- (3-methoxyphenyl) imidazole) -Gly] , 20 ring [Tip-D-Trp-Lys-Val-PheW (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Trp-D-Ti.p-Lys-Thr (OBzl) -Phe ¥ (4- (3 · Hydroxyphenyl) imidazole) -Gly], ring [Ti'p-D-Tip-Lys-Thr-PheΨ (4- (3-Thrylphenyl) acetone °°) -Gly] , 14 200410986 玖, description of the invention ring [Ίϊρ-D-Trp-Lys-Abu-Phe Ψ (4_ (3_ oxophenyl) imidazole) -Gly] ring [Phe-D-Trp-Lys-Tyr (OBzl)- Phe ¥ (4- (l, l-dimethylethyl) glutamate ^)-Gly], 5-ring [Phe-D-Trp-Lys-Val-PheW (4- (3-fluorenoxyphenyl) imidazole ) -Gly] ring [Phe-D-Trp-Lys-Tyr-PheW (4- (3-hydroxyphenyl) imidazole) -Gly] and ring [Tyr-D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly]. A group of preferred compounds of group G is labeled as fluorene group 10 rings [Tyr-D-Trp-Lys-Val-Phe ¥ (4- (3-fluorenoxyphenyl) imidazole) -Gly], ring [Trp-D- Trp-Lys-Val-Phe ¥ (4- (3-methoxyphenyl) imidazole) -Gly], ring [Ti.pD-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidazole ) -Gly], ring [Trp-D-Trp-Lys-Thr-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Trp-D-Trp-Lys_Abu-Phe Ψ (4- (3_ 曱 phenyloxy) 嗤 米 嗤） -Gly]

Ring [Phe-D-Trp-Lys-Val-PheW (4- (3-amidooxyphenyl) imidazole) -Gly] or ring [Tyr-D-Tip-Lys-Val-Phe ¥ (4- (3- Hydroxyphenyl) imidazole) -Gly]. A group of preferred compounds of the hydrazone group is designated as Group I with 20 rings [Tyr-D-Ti-p-Lys-Val-Phe ¥ (4- (3-methoxyphenyl) imidazole) -Gly], ring [Trp- D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Tip-D-Trp-Lys-Thi, -Phe ¥ (4- (3-hydroxyphenyl) Imidazole) -Gly] and cyclic [butyl 71, -0-butyl 1 -1 ^ 8 ^ & 141 ^ (4- (3-hydroxyphenyl) imidazole) -01 乂]. 15 200410986 发明, description of the invention Another group of compounds of the preferred group F is labeled as group J as a ring [丁 71 ， -0-1 ^ -1 ^ 5 ^ & 1-? 1 ^ ¥ (4- (3- 曱 oxo Phenyl) imidazole) -0 to], ring [Trp-D-Trp-Lys-Val-PheW (4- (3-methoxyphenyl) imidazole) -Gly], ring [Trp-D-Trp-Lys- Val-PheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], 5-ring [Trp-D-Trp-Lys-Thr (〇Bzl) -Phe Ψ (4- (3-fluorenoxyphenyl) imidazole) ) -Gly],

Ring [Trp-D-Trp-Lys-Thr-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4- (3- Methoxyphenyl) imidazole) -Gly] 10 ring [Phe-D-Trp-Lys-Tyi (OBzl) -Phe ¥ (4- (l, l-dimethylethyl) imidazole) -Gly], ring [ Phe-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (3- 曱 oxophenyl) glutamine) -Gly], ring [Phe-D-Trp-Lys-Tyr-Phe Ψ ( 4- (3-hydroxyphenyl) imidazole) -Gly],

15 ring [Trp-D-Trp-Lys_Tyi (Bzl) -Phe Ψ (4- (3- 曱 oxophenyl) 口 °°) -Gly]], ring [Tyr-D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Phe-D-Trp-Lys-Nal-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Phe- D-Trp-Lys-Nal-PheW (4- (3-methoxyphenyl) imidazole) -Gly] 20, ring [Trp-D-Tip-Lys-Tyr (Bzl) -Phe Ψ (4- (3- (Oxyphenyl) imidazole) -Gly], ring [Trp-D-Ti'p-Lys-Tyr (Bzl) -Phe Ψ (4- (4- 曱 oxophenyl)), azo 16 200410986 玖, invention (Illustration), Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (phenyl) imidazole) -Gly]],. Ring [Trp-D-Trp-Lys-Tyr (Bzl ) -PheW (4- (3-Phenoxyphenyl) methyl))-(, ε) Ahx] and 5-ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (3- (Hydroxyphenyl) imidazole)-(τ) Abu] ° A better group of compounds is labeled as group K ring [Trp-D-Trp-Lys-Thr-PheW (4- (3-hydroxyphenyl) imidazole ) -Gly], ring [Ti'p-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-fluorenyloxyphenyl) 米 °° 10) -Gly], ring [Phe-D -Trp-Lys-NaréPheΨ (4- (3-hydroxyphenyl) imidazole) -Gly], ring [Trp-D-Trp-Lys-Tyi '(Bzl) -Phe Ψ (4- (3- 曱 oxo Phenyl) > Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4_ (4_ 曱 phenyloxy)) imidazole 15) -Gly] or Φ ring [but 1 '卩 -0_but 1卩 -1 ^^-丁 > ^ (321)-? 11 € ¥ (4- (phenyl) salari) -015 ^]. A group of preferred compounds of group K is labeled as group L as a ring [Trp-D -Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-fluorenoxyphenyl) imidazole) -Gly], 20-ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (3-fluorenylphenyl) imidazolium 9 ') Abu], ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe (4- (4-fluorenylphenyl) imidazole) -Gly] and 17 发明 Description of the invention The ring [Trp-D-Trp-LyS-Tyr (BZl) -PheW (4- (phenyl)). Sit) _Gly]. In another aspect, the present invention provides a pharmaceutical composition comprising an effective amount of a compound of Formula (I) or Formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In yet another aspect, the present invention provides a method for extracting the effect of a somatotropin receptor agonist in a mammal in need thereof, which method comprises administering to the mammal an effective amount of a compound of formula (1) or formula (11) or Its pharmaceutically acceptable salt. In another aspect, the present invention provides a method for extracting the effect of somatostatic receptor antagonists on mammals in need, the method comprising administering an effective amount of formula ⑴ to the mammal Or a compound of formula VII or a pharmaceutically acceptable salt thereof. 15

Personal Crescent Fork-A method for treating mammalian diseases in need: prolactin-secreting adenoma, re-narrowing of blood vessels, urinary disease, hyperlipidemia, insensitivity of auntrin, syndrome X, vascular disease ,, Bioretinopathy, Down's phenomenon, nephropathy, gastric acid secretion 'gastric rupture', 'intestinal epidermis and pancreatic epidermal fistula', irritable bowel syndrome, Ping's syndrome, diarrhea syndrome, 'AIDS-associated diarrhea', chemotherapy induced diarrhea J student or it's pancreatitis' gastrointestinal hormone-secreting tumor, cancer, liver tumor, blood Lüxin's' inflammatory condition 'arthritis' chronic allograft rejection, ^ angioplasty' graft blood vessel bleeding or gastrointestinal bleeding, the Method The mammal is administered a compound of formula (1) or formula (") or a drug-acceptable salt thereof. In addition, in another aspect, the present invention provides a mammal in need thereof-18 20 200410986 A method for the proliferation of Helicobacter pylori, comprising administering to the mammal a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof. ^ In another aspect, the present invention provides a method for preparing the formula Compound method

(i) (ii)

(Hi)

The method includes deprotecting a compound of the formula:

⑹ where

Prt is an amino acid branched protecting group; Y and Z are respectively D- or L- natural or non-natural α-amino acids which optionally contain protected branches, where Η-Ν * is Ν defined by Υ -The amino group of amino-terminated acid and 0 = C * is the carboxyl group of C-terminated amino-acid defined by Z;] 9 15 200410986 玖, invention 1 ¾ n in each: each occurrence is 出现; and: there are other variables Both are defined as above. Ben Tuming provides a recipe for preparing compounds of the following formula

The method contains:

For compounds of formula (a), amidine between the terminal amino group of the last amino acid defined by Y and the terminal carboxyl group of the final amino acid defined by Z is formed by reacting the compound of formula (a ') with a peptide coupling agent and an additive. Or for compounds of formula (b), via the reaction of compounds of formula (b,) with a peptide coupling agent and 15 additives to form an amido bond between the terminal amine group and the terminal carboxyl group of the last amino acid defined by Z; Or, for compounds of formula (c), via formula (c ') and peptide coupling agents and additives 20 200410986 玖, description of the invention, to form amidamine between the terminal amino group of the final amino acid defined by γ and the terminal carboxyl group Bond; wherein Prt is an amino acid branched protecting group; Y and Z are each D- or L-natural or unnatural j-amino acid optionally contains a protected branch, where Η-Ν * is Υ The amine group of the N-terminal amino acid and 0 = C * are the carboxyl groups of the C-terminal amino acid defined by Z; η is 1 to 50 in each occurrence; and all other variables are defined as the above formula (1). In another aspect, the present invention provides a method for preparing a compound of formula R2.

10 (Α) This method contains the formula

The compound reacts with the formula X, -CH (R3) CO (R) α-halone in the presence of a base and a polar aprotic solvent until the reaction is almost complete; the polar aprotic solvent is removed by evaporation to obtain a solid; Aprotic organic solvents and excess ammonium acetate aqueous solution form a solution 'and reflux solution and simultaneously remove the polar layer to obtain a compound of formula (A); where X is an amine protecting group; 15 200410986 986, invention description X is an iS atom; and all other variables The definition is as above. In another aspect, the present invention provides a method for preparing a compound of formula (I),

(I)

R2

"This method includes coupling a compound of formula (B) with 1 ^ • protected amino acid (Prt) _Y, where Nβ • protected amino acid is in the form of its active ester, anhydride or hydrazine, the reaction It is carried out in the presence of a base until the reaction is substantially completed to obtain a compound of formula (C)

co2r, (C) 10, using conventional deprotection reactions to selectively deprotect the protected amino group (Prt) -Y's and repeat the coupling reaction with another -protected amino acid to Obtain a compound of the formula ⑴; 22 200410986 玖, description of the invention Y at each occurrence is D- or L- natural or unnatural α-amino acid optionally has a chain with a protective group;

Prt is an amine protecting group; R 'is an alkyl ester or a benzyl ester; 5η is from 1 to 100; and all other variables are defined as the above formula (I).

In another aspect, the present invention provides a method for preparing a compound of formula (I), as defined above. The method comprises coupling a compound of formula (B), and the compound of formula (B) is activated to form an active ester, anhydride or halogen halide with N-deprotection. The peptide-resin (A ') and peptide-resin 10 (Α,) are prepared by methods well known to those in the peptide synthesis industry. Hexahydropyridine is used to deprotect the N-terminal Fmoc group in DMF, TAEA or similar bases, and use Intermediate (B ') obtained by strong acid deprotection and cleavage by resin. All variables are defined as in formula (I) above.

Fmoc—Ν '

Fmoc-NTR]

H: N- (y) n — (resin

(CH2) m R4 V HO ~ ^ " R5 α · Ο B 15 In another aspect, the present invention provides a method for preparing a compound of formula (I), which method comprises coupling a compound of formula (B) (activated as its active ester, Anhydride or halogen) and N-deprotected peptide-resin (树脂) (prepared by methods well known to those in the peptide synthesis industry), using hexahydropyridine to deprotect the N-terminal Fmoc group in DMF and TAEA or similar bases, Use well-known peptide coupling reactions with Nα 23 200410986 玖, description of the invention-Fmoc-protected amino acid (X) to purge the released N-terminal terminal amine group, repeat the alkali deprotection and coupling steps as necessary to combine additional Amino acid (X), using strong acid deprotection and cleavage by resin to remove the intermediate (C '). All variables are defined as in formula (I) above.

In another aspect, the present invention provides a method for preparing a compound of formula (I), which comprises coupling a compound of formula (B) (activated as its active ester, anhydride, or halogen halide) to an amine-substituted resin such as para (alkoxy) -benzyl Based amine resin (PAL resin), 4- (2 ', 4'-dimethoxyphenyl-aminomethyl) -phenoxy resin (N-deprotected Link resin)' or 10 diphenylfluorenylamine resin ; Use hexahydropyridine in DMF, TAEA or similar base to deprotect the N-terminal Fmoc group; use peptide coupling reaction well known in the industry · Na_Fmoc protected amino acid (X) should be used to triturate the released N -Terminal amine groups; repeating the alkali deprotection and coupling steps as necessary to combine additional amino acids (X); and using strong acid deprotection and cleavage to remove the resulting intermediate (D5). All ‘15 other variables are defined as above formula (I). ’24 200410986 玖, description of the invention

In another aspect, the present invention provides a method for preparing a compound of formula (I), which method comprises reacting a compound of formula (B) with a test cesium carbonate, and the obtained age series cesium salt (E ') and a halogenated polystyrene resin Such as Maryfield peptide resin reaction, using 5 hexahydrop-pyridine or a similar organic base to remove the Fmoc protecting group, NrFmoc protected amino acid (X) using a well-known peptide coupling reaction in the industry, and then released N-terminal terminal amine group; repeat the base deprotection and coupling steps as necessary to combine additional amino acid (X), use hexahydropyridine or similar organic base to remove the N-terminal final protected peptide sequence and use Tfa to remove The C-terminal protected peptide 10 sequence was cyclized using a peptide coupling reaction well known to those in the industry (F '), and the resulting intermediate (G,) was cleaved from the resin using a strong acid. All other variables are defined as in formula (I) above.

In another aspect, the present invention provides a method for preparing a compound of formula (ί) (as defined above) 25 15 200410986 玖, a method for describing the invention, which comprises coupling a compound of formula (B) (activated as its active ester, anhydride or halogen halide) to N-deprotected peptide-resin (A,) (prepared by a method well known to those in the industry) 'Use Tfa to remove the protection of the N-terminal Boc group, and use a strong acid such as HF to deprotect the branched chain protection group and remove it from the resin The obtained intermediate (h,) 5. All variables are defined as above formula (I).

In another aspect, the present invention provides a method for preparing a compound of formula VII. 10 comprises coupling a compound of formula (B) (activated as its active ester, anhydride, or sulfonium halide) and an ice-deprotected peptide prepared by a method well known in the industry. (H), using Tfa to remove the protection of the N-terminal Boc group, and using Nα-Βοο protected amino acid) using the terminal coupling of the end-month female group released by the peptide coupling reaction well known in the industry, repeat Tfa as necessary Deprotection and coupling steps to combine additional amino acids 15 (x), deprotection using strong acid and cleavage to remove the resulting intermediate (I,). All variables are defined as above formula (I). 26 200410986 发明, description of invention

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

Contains the reaction of a compound of formula (B) with a base such as cesium carbonate, and the resulting phenolic planed salt (j,) is reacted with a tooth methylated polystyrene resin such as a marfilpeptide resin. -Boc protected amino acid (X) uses the peptide coupling reaction well known in the industry to lyse the released N-terminal terminal amine group, repeat the Tfa deprotection and coupling steps as necessary to combine additional amino acids (χ), use

Tfa removes the final protected peptide sequence at the N-terminus and removes the final protected peptide sequence at the C-terminus using an inorganic base such as lithium hydroxide in an aqueous DMF solution.

The intermediates obtained by cyclization of peptide coupling reactions, which are well-known in the industry, and the intermediates obtained by cleavage and removal of the resin with a strong acid (all the variables L, h are defined as the above formula (I).

27. Description of the Invention In another aspect, the present invention provides a method for preparing a compound of formula (I), comprising coupling a compound of formula (B) (activated as its active ester, anhydride, or halogen halide) and a deprotected peptide, which is well known to those in the industry. 4 • Nitrobenzophenone S homooxime resin (M,) prepared by the method, using Tfa to remove the protection of the N-terminal boc group, "Boc protected amino acid (χ) is well known to those in the industry The N-terminal terminal amine group released by the peptide coupling reaction is repeated. If necessary, the Tfa deprotection and coupling steps are repeated to combine additional amino acid 00. The Tfa is used to remove the protection of the N-terminal B0C group. Cyclization and the use of appropriate organic Alkali cleavage removes the obtained intermediate N, _ deprotected intermediate (N,), and uses a strong acid such as hydrofluoric acid to remove the branched chain protecting group. All variables are defined as the above formula ⑴.

DETAILED DESCRIPTION The term heterocycle is used herein to mean any heterocyclic ring that may occur in an amino acid branch. Examples include, but are not limited to, benzoxenyl, coumarin, and flavor. Sit on the base,

Phenyl and triazolyl. 200410986 发明, description of the invention The term square is used here-the word is intended to mean any stable monocyclic or bicyclic charcoal, 47% of which is at least one of the rings is an aromatic ring. Examples of Fangmei include biphenyl: tetrahydrophenyl, silk, phenyl and 4-tetrahydro. In this case, the right dry abbreviation is used for the amino acid component, some preferred protecting groups, reagents and solvents. The abbreviated definitions are shown in Magic.

Thr L-serine

Trp

Tyr L-tryptophan (unless otherwise noted) 〃Tyrosine

Ahx protection base

Boc

Cbz

Fmoc

Trt 6-aminohexanoic acid U- (dimethylethoxy) carbonyl benzyloxycarbonyl 9-fluorenylfluorenyloxycarbonyl triphenylmethyl solvent

DMF N, N-dimethylformamide

THF

EtOAc tetrahydroadenosyl acetate ethyl acetate reactant

Tfa

NMM

DIEA

TEA

TAEA

HOAT

HATU

EDC Fluoroacetic acid 4-methylmorpholine diisopropylethylamine triethylamine ginseng (2-aminoethyl) amine 1-hydroxy-7-azabenzotriazole [0- (7- ° ababen And three degrees of 1--1-tetramethylurea hexafluorophosphate 1- (3-diamidoaminopropyl) -3 -ethylmethylmonoimine hydrochloride ______

DCC Dicyclohexylmethyldiamine imine 29 200410986 玖, Description of the invention Test tube test assay analysis of compounds' affinity to human somatostatin subtype receptors 1 to 5 (sst !, sst2, sst3, sst4 and sst5, respectively) via Measuring inhibition of 5 [125I-Tyrn] SRIF-14 binding to CHO-K1 metastasis-infected cells was determined.

The human ssh receptor gene was transformed into a genomic fragment. The 1.5 Kb Pwl-XmW fragment contains a 100 bp 5′-untranslated region, a 1.17 Kb overall coding region, and a 230 bp untranslated region were modified by adding the Bglll linker. The resulting DNA fragment was subtransplanted at pCMV-81 to produce mammalian performance plastids (10 courtesy of Dr. Graeme Bell, University of Chicago). A transgenic cell line capable of stably expressing the ssh receptor was obtained by transfection and infection into CHO-K1 cells (ATCC) using the calcium phosphate co-precipitation method (1). Plastid pRSV-neo (ATCC) is included as a selectable marker. Transgenic cell lines were selected in RPMI 1640 medium (Gibco) containing 0.5 mg / ml G418, circularized and transfected and expanded in culture. 15 The human sst2 somatostatin receptor gene was isolated as a 1.7 Kb genomic DNA fragment and subtransplanted into the plastid vector pGEM3Z (Promega) was kindly provided by Dr. G. Bell (University of Chicago). A mammalian cell expression vector is constructed by inserting a 1.7 Kb fragment into a compatible restriction endonuclease site of plastid pCMV5. Transgenic cell lines were obtained by transferring infection into CHO-K1 cells using calcium phosphate co-precipitation. Plastid pRSV-neo is included as a selectable marker. Human sst3 is isolated from the genomic fragment, and the complete coding sequence is contained in the 2.4 Kb BamHI / i / ζ / ^ ΙΠ fragment. Mammalian expression plastid pCMV-h3 was established on 30 200410986. Description of the invention The modified end and the EcoRl linker were added by inserting a 2.0 Kb fragment into the EcoRl position of the pCMV vector. Transgenic cell lines stably expressing the sst3 receptor were obtained by transferring infection into CHO-K1 cells (ATCC) using a calcium phosphate co-precipitation method. Plastid pRSV-neo (ATCC) is included as a 5 selectable marker. Transgenic cell lines were selected in RPMI 1640 medium containing 0.5 mg / ml G418 (Gibco), circularized and transfected and expanded in culture. The human ssU receptor-expressing plastid pCMV-YX was provided by Dr. Graeme Bell (University of Chicago). The vector contains the L4 Kb genomic fragment encoding human ssU, 456 bp 5,-untranslated region and 200 bp 3, · untranslated region 10, transfected at the heart oRl position of PCMV-QX. A transgenic cell line capable of stably expressing the sst4 receptor was obtained by transferring infected CHO-K1 cells (ATCC) using a calcium phosphate co-precipitation method. Include plastid pRSV-neo (ATCC) as a selectable marker. Transgenic cell lines were selected in RPMI lMO medium containing 0.5 mg / ml G418 (Gibco), circularized for transfection, and expanded in culture. The human SSt5 gene line was obtained by PCR using a lambda genome pure strain as a template and was kindly provided by Dr. Graeme Bei 丨 (University of Chicago). The resulting 1.2 Kb PCR fragment contains 21 base pairs 5, untranslated regions, complete coding regions, and 55 6? 3-untranslated regions. The pure plant was inserted into colony 1 ^ 88] ^ (+)] ^ 〇1 ^ 1 position 20. The insert was recovered as a 1.2 Kb fragment for subtransplantation into the pCVM5 mammalian expression vector. A transgenic cell line capable of stably expressing the sst5 receptor was obtained by infecting CHO-K1 cells (ATCC) using a calcium carbonate co-precipitation method. Including plastid pRSV-neO (ATCC) as a selectable marker 31 200410986 玖, description of the invention. Transgenic cell lines were selected on RPMI 1640 containing 0.5 mg / ml G418 (Gibco), circularized for transfection, and expanded in culture. CHO-K1 cells, which can stably express one of the human sst receptors, grow at RPMI · 1640, and the culture medium contains 10% fetal bovine serum and 0.4 mg / ml genetin 5 (geneticin). Cells were collected at 0.5 mM EDTA and centrifuged at 500 g for about 5 minutes at about 4 °. The pellet was resuspended in 50 mM Tris, pH 7.4, and centrifuged at 500 g at about 4 ° C for about 5 minutes. Cells were lysed by ultrasound and centrifuged at 39,000 g ^ for approximately 10 minutes at approximately 4 ° C. The pellets were resuspended in the same buffer and centrifuged at 50,000 g at about 4 ° C for about 10 minutes. The film of the obtained pellets was stored at -80 ° C 10 ° and repeated twice on a polypropylene 96-well plate [mi-Tyr ^ SRIF-14 competitive combination experiment. Cell membrane (10 μg protein / well) with [125I-Tyru] SRIF-14 (0.05 nM) at approximately 37 ° C at 50 mM HEPES (pH 7.4), 0.2% BSA, 5 mM MgCl2, 200 KIU / ml Trishelo 15 (Trasylol), 0.02 mg / ml bacitracin and 0.02 m 隹 g / ml phenylsulfonylsulfonium fluoride were incubated for about 60 minutes. Isolation of the conjugates derived from free [125I-Tyrn] SRIF-14 was performed using a filter 196 (Packard) cell harvester immediately through a GF / C glass fiber filter pre-soaked with 0.1% polyethyleneimine (PEI) The plates (Unifiltei · 20 Packard) were separated by filtration. The filters were washed with 50 mM HEPES at about 0-4 ° C for about 4 seconds and analyzed for radioactivity using a Packard top counter assay. Specific binding was obtained by subtracting non-specific binding (determined in the presence of 0.1 // M SRIF-14) from the total binding amount. Computer-Assisted Nonlinear Regression Analysis 32 200410986 玖, Description of Invention (MDL) analysis combines data and measures the inhibition constant (Ki) value. Whether the compound of the present invention is an agonist or an antagonist is determined by the following assay. Functional assay analysis: Inhibition of intracellular production of cAMP: 5 CHO-K1 cells (SRIF-14) subtype receptors capable of expressing human somatostatin were seeded in a 24-well tissue culture multiple orphans, seeded with 10% FCS and 0.4 mg RPMI 1640 medium per ml of Gentisine. The culture medium was changed the day before the experiment. Cells were washed twice at 105 cells / well with 0.5 ml of fresh RP MI containing 0.2% BSA and 10 supplemented with 0.5 mM (1) 3-isobutyl-1-fluorenylxanthine (IBMX), and at approximately 37 Incubate at ° C for about 5 minutes. • The production of cyclic AMP is stimulated by adding 1 mM forskolin (FSK) at about 37 ° C for about 15-30 minutes. • The agonist effect of the compound was measured by adding FSK (1 // M), 15 SRIF-14 (10 · 12 M to 1 (Γ6 M) and test compound (l < r1G M to 1 (Γ5 M)) simultaneously. • The antagonist effect of the compound is measured by adding FSK (1 // Μ), SRIF-14 (1 to 10 ηM) and test compound (10_1G Μ to 1 (Γ5 Μ) at the same time. Remove the reaction medium and add 200 ml of 0.1 Ν Hydrochloric acid. Measured using radiological 20 immunoassay analysis method (kit set rapid plate SMP001A, New England Nuclear Corporation). Radioactive ligand binding assay analysis tube test receptor binding assay analysis membrane is obtained by homogenization 33 200410986 发明, invention Explanation (Polytron, set value 6, 15 seconds) CKO-K1 cells, showing hsst receptor subtype, were centrifuged twice in ice-cold 50 mM Tris-HCl and 39,000 g (10 minutes), and resuspended in fresh medium. The final pellet was resuspended in 10 mM Tris-HCl for verification analysis. For hsst3, hsst4, hsst5 verification analysis5, each membrane product was 0.05 nM [] 25I-Tyrll] SRIF-14 at 50 mM HEPES (pH 7.4) ) Incubate at about 37 ° C for about 30 minutes. HEPES contains BSA (10 mmol / Ml); Magnesium chloride (5 mM), Tricillo (200 KIU / ml), subtilisin (0.02 mg / ml) and phenylmethanesulfonyl fluoride (0.02 mg / ml). The final assay analysis volume was 0.3 ml. 10 For hsst2 verification analysis, [125i] MK-678 (0.05 nM) was used as the radioactive ligand and the incubation time was about 25 ° C for about 90 minutes. Use Bland's filter manifold to quickly pass through GF / Filter C (pre-soaked in 0.3% polyethylenimine) to terminate the incubation. Each tube and filter were then washed three times with 5 ml of ice-cold buffer.

15 Specific binding is defined as the total radioligand binding reduced to 1000 nM SRIF-14 (hsstl, 3, 4, 5) or 1000 nM MK-678 to hsst2. The compounds of the present invention can be assayed in vivo to analyze the use of binding to somatostatin receptors, including specific binding to somatostatin subtype receptors. The methods used are well known to those in the industry, for example, refer to the following references: Shimon et al. "Somatostatin receptor subtype specificity in pituitary gland culture of human embryos", J. Clin. Invest., Vol. 99, No. 4, pp. 789-798, 1997; and C · Gilon et al. "Stem-ring, receptor 5-selective somatostatin analogues: synthesis, biological activity, and NMR configuration analysis", J. Med. 34 200410986 玖, Description of the invention

Chem. 1998, 41, 919-929. As is well known in the art, there are many variations in the known and possible uses of somatostatin agonists and / or cumin-resistant agents. The uses of somatostatin are summarized as follows: 10 15 Somatostatin enhancers can be used to inhibit growth hormone and more growth hormone-secreting adenomas (acromegaly) and TSH-secreting adenomas; to treat prolactin-secreting adenomas Inhibition of insulin and / or glucagon more specifically inhibits diabetes, vascular disease, proliferative retinopathy, Down's phenomenon and nephropathy; inhibition of gastric acid secretion and more specifically gastric ulcer; intestinal epidermis and pancreatic epidermal tumor tube; irritability Bowel Syndrome; Dang Ping's Syndrome; Water Heart Ingredients; AIDS-associated abdominal articles triggering diarrhea; pure or chronic inflammatory inflammation and gastrointestinal hormone-secreting tumors; treatment of cancers such as liver tumors; inhibition of angiogenesis; treatment of inflammatory conditions such as arthritis Retinopathy; chronic allograft rejection; angioplasty; prevention of transplanted blood vessels and gastrointestinal bleeding. As such, the scope of the present invention encompasses pharmaceutical compositions comprising at least one compound of the invention as described herein in combination with a pharmaceutically acceptable carrier as an active ingredient. The compound of the invention can be administered orally, parenterally (for example intramuscularly, intraperitoneally, intravenously or subcutaneously) or Implantation), nasal, vaginal, rectal, sublingual or topical administration 20-path administration, and can be formulated with pharmaceutically acceptable carrier formulations suitable for various administration routes. Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In a solid dosage form, the active compound is mixed with at least one inert medicine. 35. Description of the invention Drug-acceptable carriers such as sucrose, lactose or starch. These dosage forms, as usual, contain substances other than inert diluents, such as lubricants such as hard moon @@ MG. In the case of capsules, lozenges, and pills, the dosage form also includes a buffering agent. Lozenges and pills can additionally be prepared as casings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs which contain inert diluents commonly used in the industry such as water. In addition to these inert diluents, the composition also includes adjuvants such as wetting agents, emulsifying and suspending agents and sweeteners, flavoring agents and flavoring agents. Parenteral pharmaceutical preparations according to the present invention include sterile water or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and organic esters for injection such as ethyl oleate. These dosage forms also contain adjuvants such as preservatives, moisturizers, etiquettes and dispersants. It can be sterilized by, for example, filtering through a bacteria-retaining filter membrane, mixing a sterilizing agent into the composition, irradiating the composition with light, or heating the composition. It can also be manufactured in the form of a sterile solid composition, which is dissolved in sterile water or several other sterile injection media just before use. Compositions for rectal or vaginal administration are preferably suppositories which contain, in addition to the active substance, excipients such as cocoa butter or suppositories. Nasal or sublingual compositions can also be prepared using industry standard excipients. Further, the compounds of the present invention can be administered as a sustained release composition, as described in the following patents. U.S. Patent No. 5,672,659 teaches a sustained release composition comprising a bioactive agent and a polyester. U.S. Patent No. 5,595, · 200410986 (ii) Description of the invention teaches a sustained release composition comprising a bioactive agent in the form of gelatin. U.S. Patent Application No. 08 / 929,363, September 9, 1997, teaches a polymer sustained release composition comprising a bioactive agent and chitosan. U.S. Patent Application No. 08 / 740,778 Application 1996! } Month I teach that a bioactive agent and a cyclodextrin to a sustained release composition are taught. U.S. Patent No. 09 / 15,394, Application No. sl99 ^ u29 teaches an absorbable sustained release composition of a bioactive agent. The teaching contents of the aforementioned patents and applications are also incorporated herein by reference. The dosage of the active ingredient of the composition of the present invention may be varied; however, it is required that the amount of the active ingredient 10 can obtain an appropriate dosage form. The selected dose depends on the intended efficacy, the route of administration and the duration of treatment. Usually, 0.001 to 100 mg / kg body weight is administered to humans and other animals such as mammals in order to obtain a therapeutic effect. The preferred dose is from 0.01 to 5.0 mg / kg of body weight, which can be administered as a single dose or divided into multiple doses per day. 15 The compound of the present invention can be synthesized according to the description below and the reaction scheme I. In the first step, the α-amino group protects the amino acids ffiBoc, Cbz or other appropriate groups using an inorganic test such as sodium hydroxide, sodium hydroxide, carbolic acid or preferably carbonic acid in a polar solvent such as water, Qing, Ding Gan, etc. turned into Lai salt. The killer is removed in vacuo and the residual salt is redissolved in a polar aprotic solvent such as dmf at about 20-20. . To about 100. . Optimally add the appropriate ketone at room temperature with stirring. Stirring is continued for about 10 minutes to about 24 hours or sandalwood until the completion of the fermentation is confirmed by TLC analysis, at this time from about to about 10 (rc, best about about 40 to about C true shrinking solution. The intermediate is redissolved in an aprotic organic solvent such as 37 200410986, the invention description benzene, toluene, or the best dibenzobenzenes, and an ammonium acetate excess of about 5 to about 100 times or optimally about 15 to 20 times is added. The phase mixture is heated under reflux and the polar layer is completely removed using a Ding Stark trap for about 1 to about 4 hours to obtain a crude intermediate (A), which can be used in crude form or purified by crystallization or column chromatography.

10 Response diagram Ϊ

X = CBZ, BOC X-N I Rl Ο 1. Cs2C03 / DMF / H20 2. Br-CH (R3) CO (R4) 3. NH4OAc

X-N I R

1.Deprotection or derivatization 3-selective derivatization (A)

In the second step, the intermediate is deprotected using catalytic hydrogenation or a strong acid such as HF, HC1, ΗΒι · or Tfa. The α-nitrogen is then protected with a base-sensitive protecting group such as Fmoc using commercially available N- (9-fluorenylmethoxycarbonyloxy) succinimide and potassium carbonate such as acetonitrile and water. In addition, Nα-Cbz-protected imidazole nitrogen can be alkylated with protected 15 carboxylic acid esters, and protected by catalytic hydrogenation to remove α-amino groups. 38 200410986 发明, description of the invention to obtain B '(V = H, W = -(CH2) mCR5C2OR, where R represents alkyl or vinegar). Oral saliva can be protected with commercially available triphenylmethyl chloride and a third amine base such as 4-methyl-morpholin 'diisopropylethylamine or triethylamine to obtain a protected intermediate, which is subsequently The α-amino group 5 shame is removed using a base such as TAEA to obtain intermediate (B) (V = H, W = Trt). In addition, N-deprotected imidazole B, (V = H'W = H) can be used without further modification. In the second step, the intermediate B, B 'or B "is used as the actinide group for the continuous solution phase synthesis of the target peptide. In this way, the actinide group is dissolved at a concentration of about 50 to 200 millimolars per liter in Ethyl acetate and the addition of about 1 to 5 mole equivalents or better L1 to 15 mole K K N α -Fmoc protected amino acid in activated g, liver or brine. The mixture is a second layer of weak base For example, sodium carbonate aqueous solution or better sodium bicarbonate water; Valley liquid is stirred until the reaction is completed. Remove the water layer and add about 1 to 10 liters / 耄 mole or better about 2-4 ml / mmol of TAEA Or hexahydropiperidine and the mixture was stirred for about 30 minutes. Then the solution was washed with a saturated sodium chloride solution (using 15 for 30 liters / Emol twice) and then using 10% phosphate buffer solution Adjust to pH = 5.5 (three washes with about 10 ml / mole). The subsequent cycles are performed in the first cycle. The final amino acid is protected with Boc or Fmoc groups. In four steps, the N-terminal and C-terminal protecting groups are removed using an aqueous alkali solution or a strong 20 acid. The resulting peptide intermediates can be cyclized using traditional peptide coupling techniques. The embodiment described in "Peptide Synthesis Practice", Bodanszky and Bodanszky, Spnnger-Varlag, 1984. Thus, the peptide intermediate is dissolved in an aprotic solvent such as DMF, and the solution is made basic by adding a third amine base such as' methylmorpholine. 39 200410986 (ii) Description of the invention The carboxylic acid portion of the intermediate is activated by the addition of a 1 to 6-fold molar excess of dimethyldiimide such as DCC or EDC and additives such as 1- by benzotrioxane. The mixture was about 0 ° C. (: To 100 ° C, optimally stirred at about room temperature until the reaction is complete. In the final step, the protected peptide is removed by using catalytic hydrogenation or a strong acid such as HF5, Ha, HBr or Tfa to obtain the final product (. Here, RjR5, a, b, Y, Z, and η are defined as in the above formula ⑴. The immersion mass spectrometry data is provided by an ESI (electrospray ionization) source.

Measured on a Finnigan SSQ 7000 spectrometer. NMR data were obtained on a 300MHz Varian Unity spectrometer from a sample with a concentration of approximately 10-20 g / ml in the specified solvent 10. In addition, the compounds of the invention can be prepared using solid-phase peptide synthesis techniques. Thus intermediate A (X diBoc) is alkylated with, for example, ethyl bromoacetate and a suitable base such as potassium carbonate in an aprotic solvent such as DMF, and the resulting ethyl ester intermediate is hydrolyzed using an aqueous alkaline solution such as sodium hydroxide to obtain intermediate B ( V = Boc, 15 W = -CH2CO2H). Intermediate B (V = Boc, W = -CH2C02H) can be activated using known activation techniques, such as described in "Peptide Synthesis Practices", Bodanszky and Bodanszky, Springer-Varlag, 1984, and used directly for coupling to a solid support The growing peptide or intermediate B (V = Boc, W-CH2C02H) can be directly attached to the solid support and begin solid phase synthesis. Deprotection of the N-terminal Boc group such as 20 using Tfa can continue peptide synthesis under conditions known to those skilled in the art. Intermediate B (for example, V = Fmoc, W = -CH2C02t-Bu) can be treated with acid such as Tfa to remove the third butyl ester of protected carboxylic acid. The obtained intermediate B (for example, V di Fmoc, W; CH2C〇2H) can use Fmoc Strategy for solid-phase peptide synthesis. In this way, 2004200410986, the invention shows that intermediary B (V2Fmoc, W2-CH2CO2H) can be activated using known activation techniques, such as described in "Peptide Synthesis Practice", Bodanszky and Bodanszky, Springer-Varlag, 1984, Directly used for coupling to growing peptides on solid supports. Deprotection of the N-terminal Fmoc group, for example using hexahydrozidine, allows peptide synthesis to proceed under conditions known to those skilled in the art. The solid phase synthesis of cyclic analogs can also be performed according to the following reaction scheme II.

Reaction Diagram II 10

41 200410986 发明 Description of the invention Intermediate A (X = Boc or Cbz, R3 = 2-methoxyphenyl, 3-methoxyphenyl or 4-methoxyphenyl) 1M BB! · 3 can be used in dichloromethane Free-state phenol A (X = H, R3 = 2-hydroxyphenyl, 3-hydroxyphenyl, or 4-hydroxyphenyl) was obtained for about 1/2 hour of treatment. The α-nitrogen is then protected with an acid-sensitive protecting group such as a Boc group using dicarbonate-di-5-tertiary-butadiene, such as sodium hydroxide in a water-miscible organic solvent such as a mixture of dioxane and water. Intermediate A (X = Boc, R3 = 2- via phenyl, 3-hydroxyphenyl or 4-hydroxyphenyl), for example, ethyl bromoacetate and appropriate test such as potassium carbonate in an aprotic solvent such as DMF to obtain ethyl The ester intermediate E ^ and then the intermediate D are converted into shaved salt by means of carbonic acid shaving. The planed salt was reacted with an excess of Maryfield's resin to obtain Intermediate E. Intermediate E was subjected to subsequent processing, and intermediate F was obtained using the standard Boc solid phase peptide synthesis or standard Fmoc solid phase synthesis as described above. When the complete amino acid sequence is constructed, the c-terminal ethyl ester is removed from the cap using an appropriate base such as lithium hydroxide in an aqueous DMF solution, and the peptide is cyclized using a standard activation protocol, such as amidinimide and, for example, hydroxybenzene Benzotriazole and 15th triamine were tested as diisopropylethylamine to obtain intermediate G. The final branch bond deprotection and the resin cleaving system are obtained by adding a very strong acid such as decomposed gas to obtain the characterized person I of the present invention: real formula] The present invention will be illustrated by the following examples but not limited to its fine 20 Example 1 Ring [Ty 卜 D -Trp-Lys-Val-Phe ψ (Buck (3-) -Gly] 曱 oxybenzyl) taste σ sitting 42 200410986 玖, description of the invention

Example 1 was synthesized according to the synthetic reaction shown in Figure 1: Reaction Figure 1

43 200410986 发明, description of the invention

R: CBZN I R

OH 3, NH4OAc 4. 6N HC1 1. Cs2C03 / DMF / H20 2. Br-CH (R4) CO-R3

Fmoc-OSu / KjCC ^ CH3CN / H20

R3 (c) R2 Solution Synthesis R1 .N ⑷ Trt

R3

LTfa / iPr3SiH 2. Br- (CH2) mCHR5C02Et / KHCO3 / DMF

R2

(f)

1. Butadiene AEA / EtOAc 2. NaOH / H20 / MeOH 3. EDC / HOBt / DMF

(g)

44 200410986 发明. Description of the invention Step a: 2- (l- (S) -amino-2-phenylethyl) -4- (3-fluorenoxyphenyl) -imidazoline

Cbz- (L) -phenylalanine (10.0 g, 33.4 mmol, and carbonate shavings (5.44 g, 16.7 mmol)) was mixed in 2: 1 / DMF: water (75 ml) and the mixture 5 was stirred until homogeneous. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (70 ml) and 2-bromo-3'-fluorenacetophenone (7.65 g, 33.4 mmol) was added to DMF (30 ml). The mixture was stirred at room temperature. It was stirred for 30 minutes and then concentrated under reduced pressure. The obtained keto-ester was dissolved in xylene (150 ml) and filtered to remove bromide. Ammonium acetate (40.0 g, 0.52 mol) was added and the mixture was heated under reflux for about 2 hours 10 The excess ammonium acetate and released water were removed using a Ding Stark trap. The reaction was cooled and washed with a saturated sodium bicarbonate solution (50 ml) and a saturated sodium chloride solution (50 ml). The diphenylbenzene layer was sodium sulfate Dehydrate, filter and concentrate in vacuo. The residue is dissolved in dioxane (30 ml), 6ϋ hydrochloric acid (115 ml) is added and the mixture is heated under reflux for about 3 hours. The solution is concentrated in vacuo and triturated with ether (4 x 15 100 ml). The residue The material was dehydrated under vacuum to constant weight to obtain 12.15 g (99%) · Intermediate la, Mass spectrum 294.2 μM +. Step b: 2- (l- (S)-((^ ylmethoxy) hexyl) amino-2-phenylethyl) -4- (3-methoxyphenyl) -imidazole ^ Intermediate la (11.8 g, 32.2 mmol) was dissolved in 1: 1 / acetonitrile: water (200 · 20 ml) and potassium carbonate (5.38 g, 39 mmol) was added in small portions. Add 9-gadoquinone The succinimide carbonate and the resulting mixture were stirred vigorously for about 20 minutes. The product was extracted with ethyl acetate (100 ml), and the ethyl acetate layer was washed with water (2 x 50 ml). The ethyl acetate layer was with sodium sulfate Dehydrated, filtered, and concentrated in air. The product was purified by flash chromatography on silica gel (150 g) using 2: 2: 1 /-methyl chloride: hexanes: ethyl acetate and then i: 1 / Hexanes: Acetic acid acetate> Valley separation. The product dissociation fractions were concentrated and concentrated in vacuo to obtain the intermediate lb as a pale yellow foam, 14.77 g (85〇 / 〇). Mass spectrum 516.3 MU 'NMR (300MHz, DMS〇.d6) ) 5 11.8-12.0 (1H5 S)? 7.8-8.0 (3H5 d) 5 7.6-7.8 (2H? D), 7.5 (1H, s), 7.1-7.5 (12H, m) 5 6.7-6.9 (1H, d ) 4.8-5.0 (1H, 4.1-4.3 (3H, m), 3.7-3.9 (3H, s ) 5 3.0-3.4 (2H, m).: 2- (l- (S)-((fluorenyloxy) carbonyl) aminophenylethylmethoxyphenyl) -i-triphenylfluorenyl_ The imidazole intermediate lb (13.9 g, 26.9 mmol) was dissolved in dichloromethane (50 ml) under nitrogen, and 'fluorenylmorpholine (2.96 ml, 26.9 mmol) was added and chlorotriphenylphosphonium ( 7_51 g, 26.9 mmol), and the solution was stirred at room temperature for about 45 minutes. The solids were removed by filtration, and the filtrate was purified by flash chromatography on silica gel (300 g) using 70: 30 / hexanes: ethyl acetate as the eluent. The combined products were separated and concentrated in vacuo to obtain intermediate 1c as a foam, 180 g (88%). nmr (300MHz? DMSO-d6) 5 7.84-7.95 (2H? d)? 7.7-7.8 (1H? d)? 7.6-7.7 (1H? d)? 6.7-7.5 (29H? m)? 4.3-4.5 (1H m)? 3.75-3.95 (2H? m) 3.75-3.85 (3H? s)? 3.6-3.7 (1H? m) 3 2.65-2.85 (1H? d? d) 3 2.05-2.2 (1H? m). Step 遝 d: 2- (l- (S)-((Fmoc ^ Tyr (〇Bzl) -D-Trp-Lys (Cbz) -Val) amino-2-phenylethyl) -4- (3 -Phenoxyphenyl) 4-triphenylmethyl-imidazole intermediate lc (1.89 g, 2.50 mol) was dissolved in ethyl acetate (40 ml), and p- (2-aminoethyl) amine ( 9 ml) and the mixture was stirred vigorously for about half a year 200410986 玖, invention description hours. The ethyl acetate layer was washed with a saturated sodium chloride solution (2 x 120 ml) and then adjusted to about pH = 5.5 (3 x 40 ml with 10% phosphate buffer). ) Wash. The ethyl acetate layer was stirred with a saturated sodium bicarbonate solution (40 ml) and Fmoc-Val-F (1.02 g, 3.00 mmol) was added. The reaction was stirred for about 1 hour and the water-removing layer was removed. Then the intermediate It is sequentially deprotected and coupled with Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-OSu and Fmoc-Tyr (OBzl) -OSu in a manner similar to that described in the Fmoc-Val-F cycle above. Ethyl acetate layer By 1.5 times The product was diluted and applied to a silica gel column for purification by flash chromatography, first using 10 50: 30: 20 / dichloromethane: ethyl acetate: hexane and then 4: 1 / ethyl acetate: hexane It is used as a dissolving agent. The product dispersing fractions are collected and concentrated in vacuo to obtain the intermediate Id as a white foam, 1.90 g, (46%). Mass spectrum 1581.2 MNa +, 1559.5 MH +. Step e · 1-((2-ethoxy-2 -Oxy) ethyl 15) -2- (l- (SH (Fmoc-Tyr (OBzl) -D-Trp-Lys (CbzHVal) amino-2-phenylethyl) -4- (3-methoxy Phenyl)-. M. The intermediate Id (519 mg, 0.33 mmol) was dissolved in Tfa (10 ml) containing iPr3SiH (205 μl, 1.0 mmol), and the mixture was stirred for about 15 minutes. The intermediate was borrowed and added Diethyl ether (60 ml) was precipitated and filtered. Mass spec. 1316 MH +. 20 The intermediate was dissolved in DMF (3 ml), potassium hydrogen carbonate (198 mg, 2.0 mmol) and ethyl bromoacetate (721 μl, 6.5 mmol) were added. Ear), and the mixture was stirred at room temperature overnight. The mixture was concentrated in vacuo, dissolved in dioxane (10 ml) and washed with water (10 ml). The calcined dichloromethane layer was dehydrated with sodium sulfate, filtered, 47 200410986, a description of the invention, and concentrated in vacuo to obtain a crude intermediate le (540 g) which was used without further purification. Step f: ring [Tyr (OBzl) -D-Trp-Lys (Cbz) -Val-Phe Ψ (4- (3-fluorenoxyphenyl) imidazole) -Gly] 5 intermediate le (540 mg, 0.33 mmol) Ear) suspended in ethyl acetate (10

Ml) and ginsyl (aminoethyl) amine (1 ml) was added and the mixture was stirred vigorously for about half an hour. Ethyl acetate (10 ml) was added and the solution was washed with saturated sodium chloride solution (2 x 25 ml) and then washed with 10% phosphate buffer (pH 5.5, 3 x 10 ml). The intermediate was added into a simmered dish (40 ml), and the solvent was decanted. The residue was dissolved in methanol (10 ml) and stirred overnight with 2.5N sodium hydroxide (0.5 ml) at room temperature. The mixture was diluted with water to turbidity and the pH was adjusted to about 6.7. Filter to remove deprotected intermediates and vacuum dehydrate. The solids were ingested in DMF (25 ml) and added with DCC (340 mg, 1.65 mmol) and HOBt (252 mg, 1.65 mmol). The mixture was stirred at room temperature for about 2 hours and concentrated under reduced pressure. The crude product was purified by flash chromatography on silica gel using ethyl acetate as the eluent. The combined product fractions were concentrated and concentrated in vacuo to give the intermediate If as a glass (180 mg, 48% from the intermediate Id). Mass spectrum 1134.5 MH +. Step g: The ring [Tyi, -D-Trp-Lys-Val-Phe ¥ (4- (3- 曱 oxophenyl) imide. Sitting) -Gly] 20 Intermediate If (180 mg, 0.16 mmol) is dissolved Shake in acetic acid (10 ml) containing 10% palladium / carbon (24 mg) and hydrogen (25 psi) at room temperature for about 8 hours. The catalyst was removed by filtration and the residue was concentrated in vacuo. The crude mixture consists of completely deprotected substances (removal of Cbz and benzyl ether) and partial deprotection 48 200410986 玖, description of the invention negative (removal of Cbz while retaining nodal bonds). The mixture was purified by preparative HPLC on a vydac protein shell and peptide C! S column (Nestle Corporation, South Brau, Mass.) To a gradient of 70% CHfN / O. 1% Tfa by preparative HPLC for about 5 5 minutes. The purely isolated peaks of the more polar peaks were combined, concentrated and lyophilized (2 x 10 ml of 5% hydrochloric acid, then 1 x 10 ml of water) to obtain the title compound of Example 1, 45 mg (29%). Mass spectrum 910.4 MH +. Example 2 The ring [Tyr (OBzl) -D-Trp-Lys-Val-Phe Ψ (4- (3-fluorenylphenyl) hexyl. Sit: hGly] Example 2 is roughly prepared according to the example in Synthesis Figure 1 丨 but used Appropriate amino acids. The purely soluble fractions of the lower polar peaks obtained from the purified lg were combined, concentrated, and dried (2 x 10 mL of 0.5% hydrochloric acid, then 1 x 10 mL of water) to obtain the title compound of Example 2, 33 mg (21%). . Mass spectrum 1000.4 MH +. Ring [Trp-D-Tip-Lys-Val-Phe Ψ (4- (3- 曱 oxophenyl) imide. Sit _) -Gly] Example 3 is based on the synthetic reaction. Figure 1 is roughly similar to the example Method 1 is prepared with the following differences: · Step d · 2- (l- (S)-((Fmoc-Trp-D-Tip-Lys (Cbz) -Val) amino · -2-benzylethyl) -4- (3-fluorenoxyphenyl) -1- (triphenylmethyl) -πm. The intermediate lc (757 mg, 1.0 mmol) was dissolved in ethyl acetate (20 mL). Add ginseng (2-aminoethyl) amine (3 ml) and stir the mixture vigorously for about half an hour. The ethyl acetate layer was washed with a saturated sodium chloride solution (2 x 60 ml) and then 49 200410986. The invention description uses 10% The phosphate buffer solution was adjusted to a pH of about 5.5 (3 x 20 ml). The ethyl acetate layer Stir with a saturated sodium bicarbonate solution (20 ml) and add 卩 111〇 ¥ & ^ (825 mg, 2.33 mmol). The reaction is stirred for about 1 hour and the aqueous layer is removed. 5 The intermediate is then deprotected and reacted with Fmoc -Lys (Cbz) -OSu,

Fmoc-D-Trp_OSu and Fmoc-Tyr-OSu are coupled in a manner similar to the Fmoc-Val-F cycle as previously described. The ethyl acetate layer was diluted with 1.5 times the volume of hexanes and applied to a silica gel column for purification by flash chromatography, first using 50: 30: 20 / dichloromethane: ethyl acetate: hexanes and then 4: 1 / Ethyl acetate: Hexanes are used as eluents. The product fractions were pooled and concentrated in vacuo to obtain the intermediate 3d as a white foam, 1.02 g, (68%). Mass spectrum 11492.0 MNa +, 1514.2 MH +. Step e: 1-((2 · ethoxy-2-oxy) ethyl) -2- (l- (SH (Fmoc-Trp-D-Trp-Lys (Cbz) -Val ·) amino-2- Phenylethyl 15-yl:)-4- (3-methoxyphenyl) -imidazole intermediate 3d (1.00 g, 0.67 mmol) was dissolved in dichloromethane (10 ml), Tfa (1 ml) and iPr3SiH ( 205 μl, 1.0 mmol) and stir the mixture for about 20 minutes. Add 1: 1: 1 / ether: hexane (100 ml) mixture and filter out the intermediate and dehydrate (0.88 g). The intermediate is dissolved in DMF 20 (10 ml), potassium bicarbonate (200 mg, 2.00 mmol) and ethyl bromoacetate were added, and the reaction was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain intermediate 3e, which was obtained without further purification. For use. Mass spectrum 1335.7 MH + Step f •• Ring [Tip-D-Trp-Lys (Cbz) -Val-Phe Ψ (4- (3- 曱 oxobenzene 50 玖, description of the invention

Base) imidazole:)-Gly; I intermediate 3e (crude, 0.67 mmol) was dissolved in methanol (10 ml) and stirred at room temperature with 2.5 N sodium hydroxide (200 ml) for about 45 minutes. The mixture was diluted with water to turbidity and the pH was adjusted to 6.9. The solvent and residue were removed by decantation and triturated with water to obtain a pale yellow powder (650 mg, mass spectrum 1085.5 MH +). The powder (629 mg) was dissolved in DMF (20 ml), and then NMM (220 µl, 2.0 mmol), EDC (192 mg, 2.0 mmol), and HOBt (153 mg, 1.0 μmol) were added. The mixture was stirred at room temperature for about 2 hours and concentrated in vacuo. The crude product was dissolved in dichloromethane (15 ml) and washed with a 10% phosphate buffer solution (adjusted to ρΗ = 5 · 5). The dichloromethane layer was dried over sodium sulfate, filtered and concentrated to 2 ml. Diethyl ether was added to precipitate the product, which was filtered off and dehydrated to give an intermediate of 3 £ (440 mg, 71%). Mass spectrum 1067.4-11 +. Step g: Ring [Trp-D-Trp-Lys-Val-Phe ¥ (4- (3-methoxyphenyl) glutamyl) -Gly] intermediate 3f (200 mg, 0.19 mmol) was dissolved In acetic acid (15 ml) containing 10% palladium / carbon (40 mg), the mixture was shaken under hydrogen (25 pSi) at room temperature for 2 days. The catalyst was removed by filtration and the residue was concentrated in vacuo. The crude product was purified by preparative HPLC and dissolved on a C18 column (RaininMici.osorb 80-220-C5) using a gradient of 20% to 70% acetonitrile / 0.1% Tfa for about 55 minutes. It takes about 55 minutes to dissolve with 30% to 50% acetonitrile / 0.1% Tfa in the second round to obtain good separation. The pure fractions were combined, concentrated and lyophilized (2 x 10 mL of 0.5% hydrochloric acid and 1 x 10 mL of water) to obtain the title compound of Example 3, 26 mg (14%). Mass spectrum 933.5 MH +. 200410986 发明 、 Explanation of the invention Example 4 Ring [butylpyrene-0-butylpyrene-1 ^^-¥ & 141 ^ ¥ (4- (3-hydroxyphenyl) imidazole) -0 to] Example 4 is based on the synthetic reaction diagram 1 Prepared in a similar manner to Example 1 with the following differences: 5 Step g = ring [Trp-D-Trp-Lys-Val-PheW (4- (3-hydroxyphenyl) imidazole) -Gly]

The intermediate 3f (150 mg, 0.14 mmol) was dissolved in dichloromethane (12 ml) and a solution of 1 M_boron tribromide in hexane was added under nitrogen. The resulting slurry was stirred for about 1/2 hour. Methanol (10 ml) was added and the mixture was concentrated under vacuum 10. The crude mixture was purified by preparative HPLC on a C18 column using a gradient of 24% to 48% acetonitrile / 0.2% ammonium acetate for about 50 minutes. The pure fractions were combined, concentrated and lyophilized (2 x 10 ml of water) to obtain the title compound of Example 4, 40 mg (29%). Mass spectrum 919.4 MH +. Example 5

15 ring [Ti, pD-Trp-Lys-Thr (OBzl) -PheW (4- (3-methoxyphenyl) imidose) _Gly] Example 5 was prepared in a manner substantially similar to Example 3 according to Reaction Figure 1, In step d, Fmoc-Thi (OBzl) -F is used instead of Fmoc-Val_F. Mass spectrum 1025.5 MH +. 20 Example 6 Ring [Ding Jing-0-1 [Xing-1 ^ 5-Ding 111, Chong 1 ^ ¥ (4- (3-hydroxyphenyl) imidazole) -0 Bu] Example 6 is based on the reaction diagram 1 to roughly Prepared in a similar manner to Example 4, but using intermediate 5f, ring 52 200410986 in step g, description of the invention [Trp-D-Trp-Lys (Cbz) -Thr (OBzyl) -Phe Ψ (4- (3-4-oxo Phenyl) imidazole) -Gly] replaces intermediate 3f. Mass spectrum 1025.5 MH +. Example 7

H-Trp-D-Trp-Lys-Abu-Phe Ψ (4- (3-transphenyl) mouth rice mouth mouth 5) -Gly-OH

Example 7 was prepared in a manner substantially similar to Example 3 according to Reaction Figure 1, except that Fmoc-Abu-F was used in place of Fmoc-Val-F in step 3d, and cyclization with methyldiamine and HOBt was not performed in step 3f. Mass spectrum 937.3 MH +. Example 8 Example 8 was prepared according to Reaction Figure 1 in a manner substantially similar to Example 3, except that Fmoc-Abu-F was used in place of Fmoc-Val-F in step 3d. 919.5 MH + Example 9

15 ring [Phe-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (1,1-dimethylethyl) imidazole) -Gly] Example 9 was prepared according to the reaction scheme 2. 53 20 200410986 Rose, Invention Description 1. Cs2C03 / DMF / H20

Bocl ·

2. C] -CH (R4) CO (R3) R2 -OH _y Solution Synthesis 〇 3. NH4OAc 4 legs and 2 sheds (: 〆

Br (CH2) mCHR5C02Et /

Fmoc < Z) n-X1-X2-X3-X4- (Y) n-N " ^^ NNy_R3 KHC03 / DMF * R1 N-

(h) H

X

X——X——X

Fmoc-iZj ^ X1 -X2-X3-X4- (Y) n-N R * (e) R4

N

ten

1. NaOH / H20 / MeOH 2. EDC / HOBt / DMF

Step a · 2- (l- (S) -amino-2-phenylethyl) -4- (1,1-difluorenylethyl)-orally

Boc- (L) -phenylmalonic acid (5.31 g, 20.0 mmol) and cesium carbonate 54 200410986 玖, Description of the invention

(3.26 g, 10.0 mmol) was combined at 1: 1/0 ^^: water (50 ml) and the mixture was stirred until a homogeneous mixture was obtained. The solvent was removed under reduced pressure and the residue was dissolved in THF (50 ml) and 1-chlorohydrazine 11 & 0011011 (2.63 ml, 20.0 mmol) was added. The mixture was stirred at room temperature overnight and then concentrated under reduced pressure. The obtained ketone-ester was dissolved in dibenzobenzene (100 ml) and filtered to remove bromine. Ammonium acetate (25.0 g, 0.33 moles) was added and the mixture was heated at reflux for about 2 hours while using a Ding Stark trap to remove excess ammonium acetate and released water. The reaction was cooled and washed with a saturated sodium bicarbonate solution (50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The intermediate was protected in silica gel and purified by flash chromatography using 80: 20 / hexanes: ethyl acetate 10 as eluent to obtain 3.45 g (50%) of crystalline intermediate (MS 344.3 MH +). The intermediate was dissolved in methanol (30 ml) and concentrated hydrochloric acid (5.0 ml) was added and the mixture was stirred for about 3 hours. The solution was concentrated in vacuo and the residue was precipitated from THF and ether. The solid was dehydrated in vacuo to obtain 1.89 g (95%) of intermediate 9a. NMR (300MHz, DMSO-d6)? 8.5-10.5 (3H, width s) 5 15 7.3-7.4 (1H? S)? 7.15-7.35 (3H? M) 5 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- (l- (S)-((Fmoc-Phe-D-Trp-Lys (Boc) -Tyr (OBzl)) -Amino-2-phenylethyl) -4- (1,1-difluorenylethyl) -1H-taste intermediate 9a (790 mg, 2.50 mmol) is dissolved To ethyl acetate (40 20 ml), add ginseng (2-aminoethyl) amine (9 ml) and stir the mixture vigorously for about half an hour. The ethyl acetate layer was washed with a saturated sodium chloride solution (2 x 120 ml) and Then washed with 10% phosphate buffer to about pH 2.5 · 5 (3 x 40 ml). The ethyl acetate layer was stirred with saturated sodium bicarbonate solution (40 ml) and added 55 200410986 玖, description of the invention? 111 ( ^ 71 《0821） -0811 (1.02 g, 3.00 mmol). The reaction is stirred for about 1.5 hours and the water layer is removed. The intermediate is sequentially deprotected and similar to the Fmoc-Tyi (OBzl), OSu cycle method described above. Coupling with Fmoc-Lys (Cbz) -OSu, 5 Fmoc-D-Trp-OSu and Fmoc-Phe-OSu. Acetic acid acetate layer exerts force to

Silica gel columns were used for purification by flash chromatography using 1% acetic acid / ethyl acetate as eluent. The product fractions were pooled and concentrated in vacuo. The crude product was redissolved in ethyl acetate, precipitated by addition of hexane and filtered. The solid was dehydrated in vacuo to obtain the intermediate 911, 1.67 g, (52%). Mass spectrum 1280.7 ^ 411 +. 10 _c_ · 4- (1,1 -Difluorenylethyl) _2- (l- (SH (Fmoc-Phe-D-Trp-Lys (Boc) -Tyr (OBzl)-) amino-2-phenyl Ethyl) -1- (2-ethoxy-2-oxy-ethyl) -taste. Sit

Intermediate 9h (128 mg, 0.10 mmol) was dissolved in DMF (2 ml), potassium carbonate (35 mg, 0.25 mmol) and ethyl bromoacetate (28 μl 15, 0.25 mmol) were added and the mixture was added. Stir overnight at room temperature. The mixture was concentrated in vacuo, dissolved in ethyl acetate (10 ml) and washed with water (10 ml). The ethyl acetate layer was dehydrated with sodium sulfate, filtered and concentrated in vacuo to obtain the crude intermediate 9e (126 mg, 92%), which was used without further purification. Step f •• Ring [Phe-D-Trp-Lys (Boc) -Tyr (OBzl) -Phe Ψ (4- (3-20 oxophenyl) imidazole) -Gly] Intermediate 9e (116 mg, 0.085 mmol Moore) was suspended in ethyl acetate (2 ml) and ginsyl (aminoethyl) amine (0.5 ml) was added and the mixture was stirred vigorously for about 1/2 hour. Ethyl acetate (10 ml) was added and the solution was washed with saturated sodium gas solution 56 200410986 玖, description of the invention (2 x 5 ml) and then washed with 10% phosphate buffer solution (pH 5.5, 3 x 5 ml). The intermediate was precipitated by adding hexanes (40 ml) and the intermediate (76 mg) was filtered off. The residue was dissolved in methanol (2 ml) and stirred overnight with 2.5 N sodium hydroxide (0.1 ml) at room temperature. The mixture was diluted with water to turbidity and the pH 5 was adjusted to about 6.0. Filter to remove deprotected intermediates and vacuum dehydrate. Solids were ingested in DMF (20 ml) and added with DCC (126 mg, 0.60 mmol) and HOBt (90 mg, 0.60 mmol). The mixture was stirred at room temperature for about 6 hours and concentrated in vacuo. Dissolve in ethyl acetate (5 mL) and wash with saturated sodium bicarbonate solution (1 x 5 mL) and saturated sodium chloride solution (5 mL). Dehydrate with sodium sulfate, filter, and concentrate in vacuo to obtain intermediate 9f. Mass spectrum 1098.5 MH +. Step g: ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4- (1,1-dimethylethyl) imidazole) -Gly] intermediate 9f (crude, 0.085 mmol) Dissolved in Tfa (9.4 ml) containing iPr3SiH and water (0.5 ml), stirred for about 20 minutes and concentrated under reduced pressure. The crude mixture was purified by preparative HPLC on a C18 column using a gradient of 30% to 60% acetonitrile / 0.1% Tfa for about 50 minutes. A good separation was obtained in the second round using 32% to 80% acetonitrile / 0.2% ammonium acetate for about 50 minutes. The pure soluble fractions were combined, concentrated and lyophilized (2 x 10 ml of 0.5% hydrochloric acid, then 1 x 10 ml of water) to obtain the title compound of Example 9, 9 mg (10%). Mass spectrum 998.4 MH +. 20 Example 10 Ring [Phe-D-Trp-Lys-Val-Phe Ψ (4- (3-fluorenoxyphenyl) imidazole) -Gly] Example 10 was prepared in a manner similar to Example 3 according to Reaction Figure 1, but with 57 200410986 发明, description of the invention Step d uses Fmoc-Phe-OSu instead of Fmoc-Ti.pF. Mass spectrum 894.4 MH + tJUl ring [Phe-D-Trp-Lys-Tyr (OBzl) -Phe ¥ (4- (3-methoxyphenyl) imidose) -Gly] 5 Example 11 is based on reaction Figure 1 with a similar example 3 method, but in step d use Fmoc-Phe-OH instead of Fmoc-Trp-F and use

Fmoc-Tyr (OBzl) _OH replaces Fmoc-Val-F. Fmoc-Tyr (OBzl) -OH was activated with DCC and commercially available acetic acid. The crude mixture in step g is composed of a completely deprotected substance (both Cbz and benzyl ether are removed) and a partially deprotected substance ((: removed by 10 and retained by benzyl ether). The lower polarity peak obtained from partial deprotection The title compound of Example 11 was obtained. Mass spectrum 1048.5 MH +. Example 12 Ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4- (3-methoxyphenyl) methyl. Sit)-Gly] 15 Example 12 is based on Reaction Figure 1 was prepared in a manner similar to Example 3, but in step d, Fmoc-Phe-OH was used instead of Fmoc-Trp-F and used.

Fmoc-Tyi (OBzl) -OH replaces Fmoc-Val-F. Fmoc-Tyr (OBzl) -OH was activated with DCC and commercially available acetic acid. The crude mixture in step g is composed of a fully deprotected substance (both Cbz and benzyl ether are removed) and a partially deprotected substance (Cbz is removed by ~ 2 ° and benzyl ether is retained). The more polar peak obtained by complete deprotection gave the title compound of Example 12. Mass spectrum 958.4 MH +. Example 13 Ring [Phe-D-Trp-Lys-Tyr-PheW (4- (3-hydroxyphenyl) imidazole) -Gly] 58 200410986 玖, description of the invention Example 13 was prepared in a manner similar to Example 4 according to the reaction diagram 1 However, in step g, the intermediate Ilf ring [Phe-D-Trp-Lys (Cbz) -Tyi (OBzl) -Phe. Ψ (4- (3-methoxyphenyl) imidazole) -Gly] is used instead of the intermediate 3f . Mass spectrum 944.6 MH +. 〇5 Example 14 Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3- 曱 oxophenyl) spray saliva) -Gly] φ Example 14 is based on reaction Figure 2 Prepared in a manner substantially similar to Example 9, with the following differences: 10 Step h: 2- (l- (S)-((Fmoc-Trp-D-Trp-Lys (Cbz) -Tyr (Bzl))-amino group ) -2 -Phenylethyl) -4- (3- -oxophenyl) -1- (triphenylmethyl) -ρm. Sit peptide synthesis is performed in a similar manner to step 9h, but uses Fmoc-Trp-OSu instead of Fmoc-Phe-OSu, Fmoc-Lys (Boc) -OSu instead of Fmoc, Val-OSu, and 15 Fmoc_Tyr (Bzl) -OSu Replaces Fmoc-Val-OSu. Yield = 783 mg (57%) _, mass spectrometer 1370.6 ^ ore. Step e: 1-((2-ethoxy-2-oxy) ethyl) -2- (l- (S)-((Fmoc-Trp-D-Trp-Lys (Boc) -Tyr (OBzl)) -Amine) -2-phenylethyl) -4- (3-fluorenoxyphenyl) -imidazole '20 intermediate 14h alkylation was completed in a similar manner to reaction 9h, yield 640 mg (80%) ), Mass spectrum = 1456.3 MH +. Step f •• Ring [Trp-D-Ti.p-Lys (Boc) -Tyr (Bzl) -PheW (4- (3-fluorenoxyphenyl) imidazole) -Gly] 59 200410986 玖, Intermediate Description 14e (640 mg, 0.44 mmol) was dissolved in 15 ml of methanol and 2.5 N sodium hydroxide (1 ml, 2.5 mmol) was added. The mixture was stirred for about half an hour and then the pH was adjusted to about 7.0 by adding a 5% hydrochloric acid solution. The methanol was removed under reduced pressure and the aqueous layer was decanted. The residue was completely dehydrated under reduced pressure and then dissolved in 15 ml of DMF. Added DCC (206 mg, 1.0 mmol) and HOBt

(153 mg, 1.0 mmol) and allowed the reaction to stir overnight. The reaction was concentrated in vacuo, dissolved in ethyl acetate (10 ml) and washed twice with 10% phosphate buffer pH 2.5. The ethyl acetate layer was then applied to a silica gel column and the product was eluted with a larger amount of ethyl acetate. The product fractions were combined and concentrated to give 240 mg (46%) of 10 intermediate 14f. Step g •• Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3- 曱 oxophenyl) imidazole) -Gly]

Intermediate 14f (240 mg, 0.20 mmol) was dissolved in dichloromethane (10 mL) and Tfa (10 mL) was added to contain iPr3SiH (205 μl, 0.20 mmol 15 ears). The mixture was stirred at room temperature for about 15 minutes. Dichloromethane was removed by evaporation under reduced pressure and the crude product was added to an ether sink. The solvent was decanted and the residue was further purified by preparative HPLC on a C18 column using a 30% to 50% acetonitrile / 0.1% Tfa gradient to dissolve for about 55 minutes. The pure fractions were combined, concentrated and lyophilized (2 x 10 mL of 0.5% hydrochloric acid, then 1 x 10 mL of water) to obtain the title compound of Example 14, 20 mg, 25 mg (11%). Mass spectrum 1087.4 MH +. Example 15 Example 15 was prepared according to the synthetic reaction Figure 1 in a manner substantially similar to Example 4 60 200410986 玖, description of the invention with the following exceptions: Step g: ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (3- via phenyl) imidose,)-Gly] Intermediate If (130 mg, 0.115 mmol) was dissolved in dichloromethane (55 ml) and 1M boron tribromide was added under nitrogen. Alkanes (5 ml) solution. The resulting slurry was stirred for about half an hour and then cooled to about 0 ° C. Methanol (10 mL) was added and the mixture was concentrated in vacuo. The crude mixture was applied to a C18 column, washed with a 0.1% ammonium acetate solution, washed with a 0.1% Tfa solution, and then dissolved using a gradient of 20% to 35% acetonitrile / 0.1% Tfa for about 50 minutes. The pure fractions were combined, concentrated and lyophilized (2 x 10 ml of 0.5% hydrochloric acid) to obtain the title compound of Example 15, 60 mg (54 ° / °). Mass spectrum 896 MH +. Example 16 The ring [Phe-D-Trp-Lys-Nal-PheW (4_ (3_ via phenyl) glutamate ^)-Gly] Example 16 was prepared in a manner substantially similar to Example 3 according to Reaction Figure 1 but 15 has the following Difference: φ Step d: 2- (l- (SH (Fmoc-Phe-D-Trp-Lys (Cbz) -Nal-) amino) -2-phenylethyl) -4- (3-methoxybenzene Group) -1- (triphenylfluorenyl) -miso intermediate 16d was prepared in the same manner as the intermediate Id, but using Fmoc-Nal-OAt instead of Fmoc-Val-F and Fmoc-Phe- OH replaced the 20th generation Fmoc-Tyr (Bzl) -OH. Step g-· Ring [Tyr-D-Trp-Lys-Val-PheW (4- (3-Phenyl) pyridine.Sit) -Gly] Step 16g is performed in a similar manner to Step 4g to obtain Example 16 61 200410986 (Ii) Invention illustrative compounds. Mass Spec. Example 17 'Ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4- (3- 曱 oxoyl) taste) -Gly] 5 Example I7 is based on the reaction of Figure 1 in a manner substantially similar to Example 16 Pan prepared with the following exceptions: Step g: Ring [Tyr-D-Trp-Lys-Val-PheW (4- (3-Hydroxybenzyl) -mouth rice mouth sitting) -Gly] Intermediate 17f (3 10 mg, 0.27 mmol) was suspended in anisole (3 ml of 10) and the suspension was treated with about 12 ml of anhydrous hydrogen peroxide. The mixture was stirred at about 0 c for about 1 hour. The hydrogen fluoride was removed by distillation and the product was added to an ether sink. The crude product was filtered and further purified by preparative HPLC using a 20-80% acetonitrile / 0.1% Tfa gradient to dissolve for about 40 minutes. The pure fractions were combined, concentrated and lyophilized twice from a dilute hydrochloric acid solution. Yield = 56 mg (19%), mass spectrum 992.4 MH + 62 20 200410986 玖, description of the invention

R2 CB

OH 3. NH4OAc 1. Cs2C03 / DMF / H20 2. Br-CH (R4) CO-R3

1. Br- (CH (R5) C02tBu / K ^ COg / DMF 2.IVPd / carbon R2

Τ ο LTia / iPr3SiH is called (0

Example 18 Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ^^ (4- (3-methoxyphenyl) πmazole 5-(7) Abu] Example 1δ was prepared according to the synthetic reaction FIG. 3 Rabbit Step 1: 2- (1- (sHphenylmethoxy) carbonyl) -amino-2-phenylethyl) -4- (4-methoxyphenylimidazole

Cbz- (L) -phenylmalonic acid (100 g, 33.4 mmol) and carbonic acid planer 10 (5.44 g, 16.7 mmol) were combined in 2: 1 / DMF: water (75 ml) and Mixture 63 200410986 发明, description of the invention Stir until homogeneous. The solvent was removed under reduced pressure, and the residue was dissolved in DMF (70 liters) and 2-bromo-3'-methylacetophenone (7.65 g, 33.4 mmol) was added to DMF (30 liters). The mixture was stirred at room temperature for about half an hour and then concentrated under reduced pressure. The resulting keto-ester was dissolved in dibenzobenzenes (150 ml) and filtered to remove bromide. Ammonium acetate (40.0 g, 0.52 moles) was added and the mixture was heated at reflux for about 2 hours to remove excess ammonium acetate and use a Ding Stark trap to remove the released water. The reaction was cooled and washed with a saturated sodium bicarbonate solution (50 ml) and a saturated sodium vaporized φ solution (50 ml). The xylene layer was dehydrated with sodium sulfate, filtered and concentrated in vacuo to obtain intermediate 18i as a brown solid (13.8 g, 96%). Mass spectrum 428.2 10 (MH +).

Hi ·· 2- (l- (S) -amino-2-phenylethyl) -1- (4- (1,1-difluorenylethoxy) -4-oxy-butyl) -4_ (4-methoxyphenyl) -imidazole intermediate 18 (2.14 g, 5.0 mmol) was dissolved in 〇 ^^ (11.5 ml) and potassium bicarbonate (1.50 g, 15.0 mmol) and butyric acid 4 -Bromo-tert-butyl ester 15 (6.69 g, 30 mmol) was treated in triplicate with about 50. (: Stir for about 18 hrs. The mixture is diluted with ether and washed once with a saturated sodium bicarbonate solution and once with a saturated sodium chloride solution. The ether layer is dehydrated with sodium sulfate, filtered and concentrated to an oil. The layer is on a silica gel column Dichloromethane was used as the eluent to obtain the product as an oil. · 20 The crude alkylated product was deprotected by hydrogenation with acetic acid using 10% palladium / carbon as a catalyst. The catalyst was removed by filtration and the solvent was evaporated under reduced pressure to remove the solvent. Residual The product was dissolved in ethyl acetate and washed with saturated sodium bicarbonate solution and saturated sodium chloride solution, dehydrated with sodium sulfate and concentrated to obtain the intermediate 18j as an oil (45 mg), which was not 64 200410986. The invention description was further purified. That is, it is used in the next step. Step k: 2- (l- (SH (Boc-Trp-D-Trp-Lys (Cbz) -Val) -amino-2 -phenylethyl) -1-((4 -(1,1-Difluorenylethoxy) -4 -oxy-butyl) -4- (3 -fluorenylphenyl) -imidazole 5 solution synthesis is performed in a manner similar to the synthesis details described in step Id, But using Boc-Trp-OSu instead of Fmoc-Tyr (OBzl) -〇Su and Fmoc-Tyr (OBzl) -OAt instead of Fmoc_Val-F yielded an intermediate of 18k. Yield = 1.03 g (81%). Step 1 · 2- (l- (SH (H-Trp-D-Trp-Lys (Cbz) -Val ·) -amino-2-10 phenylethyl) -1-(( 4H4 -oxy-butyl) -4- (3-methoxyphenyl) -taste. For intermediates 18k, use (iPr) 3SiH (593 microliters, 2.90 mmol) in Tfa (10 liters) The solution was treated and stirred for about one hour. The reaction was concentrated and triturated with a 1: 1 ether: hexane solution to obtain intermediate 181 as a brown solid, which was used in the next step without further purification. Mass spec. 1267.7 MH + 15 Step f: The ring [Trp-D-Trp-Lys (Cbz) -Tyr (Bzl) -PheW (4- (3-methoxyphenyl) imidazole_ (T〇Abu] intermediate 181 was dissolved in DMF (20 ml) and 4- Amidinomorpholine (159 μl, 1.45 mmol), HOBt (196 mg, 1.45 mmol) and EDC (278 mg, 1.45 mmol) were added and the reaction was stirred overnight. The reaction was concentrated by evaporation for 20 min and Silica gel was purified by flash chromatography using dichloromethane: methanol (9: 1) as eluent to obtain intermediate 18f. Yield 220 mg (24%). Mass spectrum 1249.7 MH + Step g: ring [Trp-D-Trp- Lys-Tyr (Bzl) -Phe Ψ (4- (3- 曱 oxophenyl)) °°-(7〇Abu) 65 200410986 Rose, Invention Description Intermediate 18 f (220 g, Π 6 μmol) was partially hydrogenated in acetic acid at 30 psi hydrogen at room temperature using 10% palladium / carbon as a catalyst for about 4 hours. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude mixture was purified by preparative HPLC on a Cls column using 0% to? 5% acetonitrile / 01 〇 /. Tfa gradient dissociation for 40 minutes 5. The pure product dissociation peaks were combined, concentrated and lyophilized (2 x 10 mL of 0.5% _ acid, then 1 x 10 mL of water) to obtain the title compound of Example 18, 72 mg 0%). Mass spectrum 1115.6 1 ^ 11 +. Example 19 The ring [Trp-D-Trp-LyS-Tyr (Bzl) _Phe ψ (Hex (4 · fluorenylphenyl) imidazole 10 -Gly]) Example 19 was prepared in a manner substantially similar to Example 18 according to Reaction Figure 3 but There are the following differences: Panamino-2-phenylethyl) -i_ (2-i5l-dimethylethoxy) -2-oxy-ethyl) -4- (4-methoxyphenyl) -imidazole 15 Intermediate 18i (854 mg, 2.0 mmol) was dissolved in DMF (10 ml) and added with tert-butyl bromoacetate (646 μl, 4.0 mmol) and potassium carbonate (552 4 * g〇4) «Mole) 'is a reaction to warming overnight. The solvent was removed under reduced pressure and the residue was dissolved in ethyl acetate and washed with a saturated sodium chloride solution. The ethyl acetate layer was dehydrated with sodium sulfate, filtered and concentrated in vacuo to obtain 102 g of a foamed M body. Mass spectrum 428.2 MH 'NMR (300MHz, DMSO-d6), 7.85-8.0 (1H ^ d) 5 7.6-7.75 (2H? D) 5 7.85-7.95 (1H? S)? 7.1-7.35 (10H? M), 6.9 -7.0 (2H, d), 4.75-5.05 (5H, m), m 9 (3H, s), 3.1-3.4 (2H? M)? 1.3-1.5 (9H? S). 66 200410986 The white foam (L02 g, 1.88 mmol) was dissolved in acetic acid (50 ml) containing 10% 1 bar / carbon (50 g) and hydrogenated at 30 psi for 10 hours at room temperature. The catalyst was removed by filtration and 2N hydrochloric acid (940 μl, 1.88 mmol) was added. The mixture was lyophilized once and then lyophilized from 20% acetonitrile / water to obtain the intermediate 19j 5 king light brown solid (862 g), which was used without further purification. Mass spectrum 408.2 MH +. No late! : Catalytic hydrogenation and subsequent treatment were carried out in a manner substantially similar to step 18g to obtain the title product (22 mg, 4%) as a white solid. Mass spectrum 1088.2 MH +. 10 Example 20 Example 20 was prepared according to reaction FIG. 3 in a manner substantially similar to Example 18, but in step i, 2-bromoacetophenone was used instead of 2-bromo-3, -fluorenacetophenone. Mass Spec. 1057.4 MH + 15 Example 21 ^ Ring [Ti'p-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3- 曱 oxophenyl) ormidazole- (£) Ahx] Example 21 is based on Reaction Figure 3 was prepared in a manner substantially similar to Example 18, but with the following differences: 20 ° 3d: aminophenylethyl) small (6_ (ethoxy) _6_oxyqi_hexyl) -4- (3- 曱Oxyphenyl) -imidazole intermediate 21i (855 mg, 2.0 mmol) was dissolved in dmf (8.0 ml) and potassium bicarbonate (200 mg, 2.0 μmol) and ethyl 6-bromohexanoate (3% 67 200410986 发明, description of the invention (ml, 20 millimoles) at about 120 ° C for about 8 hours. The mixture was concentrated and the residue was purified by column chromatography on stone gum using 2: 1 / hexane: ethyl acetate. The ester was used as the eluent to obtain the pure product as a gum (0.94 g). The crude alkylation product was deprotected by hydrogenation in acetic acid using 10% palladium / carbon as a catalyst. The catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in dilute hydrochloric acid, and the intermediate 21j was obtained as a pale yellow solid (720 mg, 91%) by freezing and lyophilization, which was used in the next step without further purification. 0 Step k and Step 1: 2- (l- (SH (H-Trp-D-Trp-Lys (Boc) -Tyr (OBzl) -2- (l- (S) · amino 10-2-phenyl Ethyl) -1- (6- (ethoxy) -6-oxy-hexyl) -4- (3-methoxyphenyl) -methyl

Fmoc-Tyr (OBzl) -OAt is prepared by mixing Fmoc-Tyr (〇Bzl) -OH (493 mg 1.00 mmol), HOAt (136 mg, 1.0 mmol) and DCC (206 mg, 1.0 mmol) Mol) was prepared in 8 ml of ethyl 15 acetate for about half an hour and then filtered to remove dicyclohexyl urea. The resulting solution was added to a solution of the intermediate 21j (457 mg, 0.9 mmol) in ethyl acetate (4 ml), and the mixture was stirred with a saturated sodium bicarbonate solution (10 ml) until the completion of the reaction was confirmed by mass spectrometry. The aqueous layer was removed and the ethyl acetate layer was dried over sodium sulfate, filtered, and treated with ginseng (2-aminoethyl) amine (2.7 mL). The mixture was stirred vigorously for about half an hour. The ethyl acetate layer was washed with a saturated sodium chloride solution (2 x 60 mL) and then adjusted to about pH = 5.5 (3 x 15 mL) with 10% phosphate buffer. The intermediates are sequentially deprotected and roughly similar to the aforementioned 68 200410986.

Fmoc-Tyr (〇Bzl) -〇At cycles are coupled in the same way as Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-OSu and Fmoc-Trp-OSuo. Finally, Fmoc is deprotected to obtain N-terminal deprotected intermediate Ethyl ester. The ethyl acetate layer was dried over sodium sulfate, filtered and diluted with 4 times the volume of hexanes. Removal by decantation 5 The solvent and residue were triturated with hexanes to obtain the product as a solid (0.67 g, 58%), which was used without further purification. Mass spectrum 1289.6 MH +.

Ethyl acetate was removed by treating the intermediate with 1.7 M sodium hydroxide solution (1.7 mL) in methanol (5.0 mL) overnight. The mixture was adjusted to about pH 8.2 with a 5% hydrochloric acid solution and the solvent was removed under reduced pressure. The residue was taken up in DMF and filtered to remove sodium chloride and the DMF solution was used in the next step without further purification. Cyclization and deprotection were performed in the same manner as in Example 18 to obtain the title compound of Example 21 as a white powder, 62 mg. 1143.9 MH + Example 22

Ring [Ti.pD-Trp-Lys-Tyr (Bzl) -PheW (4- (3-hydroxyphenyl) imidazole- (15 7) Abu] Example 22 was prepared in a manner substantially similar to Example 18 according to Reaction Figure 3 but There are the following differences: Step 1 2- (l- (S) -amino-2-phenylethyl) -1- (4- (ethoxy) -4 -oxy-butyl) -4- (4 -Hydroxyphenyl) -imidazole 20 intermediate 22i (2.0 g, 4.68 mmol) was dissolved in DMF (7.0 ml) and potassium bicarbonate (468 mg, 4.68 mmol) and 4-bromo-butyric acid ethyl ester (6.70 ml, 46.8 mmol), and stir at about 100 ° C for about 30 hours. The mixture was diluted with ether and washed once with saturated sodium hydrogen chloride solution and washed with saturated sodium chloride 69 200410986. Once. The ether layer was dehydrated with sodium sulfate, filtered, and concentrated to an oil. Column chromatography was performed on Shi Xijiao, using methane as a eluent to obtain the product as an oil (2.53 g, 94%). Mass spectrum 542.3 MH + crude The alkylation product (2.53 g '4.67 mmol) was added dropwise to 1M boron tribromide / hexanes (23.4 ml) in dichloromethane (50 ml 5) at about -10 ° C over a period of about 15 minutes In dioxane (250 ml). Any mixture Warm to room

Gently stir for about 2 hours. Ethanol (40 ml) was added and the mixture was concentrated to about ml. The solution was diluted with ethanol (100 ml) and allowed to stir overnight at room temperature. The mixture was concentrated under reduced pressure and the residue was partitioned between acetic acid acetate and sodium hydroxide solution. The ethyl acetate layer was dehydrated with sodium sulphate, transitioned and concentrated under reduced pressure to an oil (1.41 g, 76%), which was used in the next step without protection age. Mass spectrum M. MH + 9. HPLC retention

70 200410986 Rose, description of invention 17 J 8.11 18 J 8.86 19 L 6.47 20 M 6.65 21 G 8.14 22 N 12.10 HPLC A: B: C: D: E · · F: G: H: uniformity speed measurement column speed measurement Column speed test Column speed test Column speed test Column speed test Column speed test Column speed test column Ladder detection tube Ladder detection tube 20-80% acetonitrile / 0.1% Tfa, 24 minutes 1.0 milliliter / minute 254 nanometers Vidak (VYDAC) protein and peptide C18 30-50% acetonitrile / 0.1% Tfa, 24 1.0 ml / min 254 nm Vidak protein and peptide C18 32-64% acetonitrile / 0.1% ammonium acetate, 24 minutes 1.0 ml / min 254 nm Vidak protein and peptide C18 20-60% acetonitrile / 0.1% Tfa, 1.0 ml / min for 24 minutes, 254 nm Vidak protein and peptide C18 55-75% acetonitrile / 0.1% Tfa, 1.0 liter / min for 24 minutes, 220 nm Phenomenex Likhrosphere 5 RP18 (Phenomenex , 2320, 205th Street, Dajian City, California) 60% acetonitrile / 0.1% Tfa, isometric 1.0 ml / min 254 nm Vidak protein and peptide C18 50% acetonitrile / 0.1% Tfa Isometric 1.0 ml / min 254 nm Wei Dake protein and peptide C18 38% acetonitrile /0.1% Tfa, isometric 1.0 ml / min 254 nm Wei Dake protein and peptide C18

71 200410986 发明, Description of the invention I: Gradient: I: Gradient 20-40% acetonitrile / 0.1% Tfa, 24 minutes flow rate 1.0 ml / min Detection of 254 nm Vidak protein and peptide C18 J: Gradient 50% acetonitrile /0.1% Tfa, constant angular flow rate 1.0 ml / min. Detection of 254 nm column NUCLEOSIL C18, 5 microns (Alltech, 2051 Waukegan Road, Luyuan County, Illinois) K: Gradient 40% Acetonitrile / 0.1% Tfa, isochronous flow rate 1.0 liters / min. Detection of 254 nm microcolumn Nucleo Leo C18, 5 microns L: Gradient 52% acetonitrile / 0.1% Tfa, equal angular flow rate 1.0 ml / min. Detection 254 Nanocolumn column Nucleo Leo C18, 5 microns Μ: gradient 50% acetonitrile / 0.1% Tfa, constant flow rate 1.0 ml / min detection 254 nm microcolumn column Nucleo Leo C18, 5 microns N: gradient 48% Acetonitrile / 0.1% Tfa, equiangular flow rate 1.0 ml / min. Detection of 254 nm columns. Nucleo Leo C18, 5 microns. I: Schematic description 1

None 0 72

Claims (1)

The scope of patent application is for medicinal compositions for mammals in need to treat the following diseases: prolactin-secreting adenomas, narrowing of blood vessels again, diabetes, hyperlipidemia, 'auntin insensitivity', and syndrome 'vascular disease, Proliferative retinopathy 'Don's phenomenon' Nephropathy 'Gastric acid secretion, Gastric ulcer' Intestinal epidermis and pancreatic epidermal fistula 'Irritable bowel syndrome, Ping's syndrome, Watery diarrhea syndrome, AIDS-associated abdominal pain, Chemo induced abdominal filling , Acute or chronic pancreatitis, gastrointestinal hormone-secreting tumors, cancer, liver tumors, angiogenesis, inflammatory conditions, arthritis, chronic φ xenograft rejection, angioplasty, graft vascular bleeding or gastrointestinal bleeding, the medical combination Compound of formula VII Or a pharmaceutically acceptable salt thereof, of which 15 Y is Trp-D-Trp_Lys-Abu; Z is Gly; 11 is 0 to 5 at each occurrence, but η cannot be 0 at the same time; m is 0; a is Η; b is OH; R1 is Η; 73 20 200410986 The scope of patent application for R2 is benzyl; R3 is phenyl substituted with (^-(: 4 alkoxy); r4 is Η; and R5 is Η. 2. There are 10 15 breastfeeding if necessary : Prolactin-secreting adenoma, re-constriction of blood vessels, diabetic hyperlipidemia, insulin insensitivity, χ syndrome, vascular disease, = sexual retinopathy 'Down'n phenomenon, nephropathy, gastric acid secretion, gastric cancer, intestinal epidermis and Pancreatic epidermal fistula, irritable bowel syndrome, syndrome, water syndrome, AIDS-associated diarrhea, chemical "induced diarrhea, acute or chronic pancreatitis, gastrointestinal hormone secretion & acoustic cancer, liver tumor, angiogenesis, inflammation Illness, arthritis, ^ xenograft rejection, angioplasty, graft vascularization ^ Knowing that bleeding, Xuan Yi Le composition contains an effective amount of Dry 4 ~ (Y) n-n * r1 χ3 R2 ^ VN X-wind 彳, 5 o (ii) or a pharmaceutically acceptable salt thereof, wherein Y is PheW; Z is Gly, Abu or Ahx; η is 1; 74 20 200410986, the scope of patent application m is 0; R1 is Η; R2 is benzyl; r3 is Η, C] _4 alkyl or phenyl, the phenyl is unsubstituted or substituted by a methoxy or hydroxyl group; R4 is Η; R5 is Η; X is Phe, Trp, Tyr or Tyr (OBzl); X2 is D-Trp; ίο X is Lys; X is Val, Thr, Thr (OBzl), Abu, Tyr, Tyr substituted with Bzl or OBzl, or Nal. 3. A pharmaceutical composition for inhibiting the proliferation of Helicobacter pylori in mammals in need, which comprises an effective amount of a compound of formula (I), 15 0) Or a medically acceptable salt thereof, wherein Y is Trp-D-Trp-Lys-Abu; Z is Gly; η is 0 to 5 at each occurrence, but ^^ cannot be 0 at the same time; m is 0 75 200410986 The scope of application for patents a is Η; b is OH; R] is Η; R2 is phenyl; R3 is phenyl substituted with C] -C4 alkoxy; R4 is 且; and R5 is Η 〇 之 · 4. A pharmaceutical composition for inhibiting the proliferation of Helicobacter pylori in mammals in need, which comprises an effective amount of a compound of formula (11), 10 (II) or a pharmaceutically acceptable salt thereof, wherein Υ is PheW; Z is Gly, Abu or Ahx; 15 η is 1; m is 0; R1 is Η; r2 is stupid methyl group; R3 is Η, Cw Alkyl or phenyl, the phenyl is unsubstituted or substituted with 20 methoxy or hydroxy; R4 is Η; 76 200410986, patent application scope R5 is Η; X1 is Phe, Trp, Tyr or Tyr (OBzl) X2 is D-Trp; X3 is Lys; 5 X4 is Val, Thr, Thr (OBzl), Abu, Tyr, Tyr substituted with Bzl or OBzl, or Nal. 77 200410986 Lu, (1), the representative representative of the case is: Figure __ (2), the representative symbols of the representative diagram are briefly explained: 柒 'If there is a chemical formula in this case, please reveal the chemistry that can best show the characteristics of the invention