TWI242441B - Pharmaceutical composition comprising cyclic somatostatin analogs - Google Patents

Abstract

The present invention is directed to cyclic derivatives containing an imidazole cis amide bond mimetic which bind selectively to somatostatin receptor subtypes and the uses thereof in treating conditions which can be treated by eliciting an agonist and antagonist effect from the somatostatin subtype receptors. This invention is also directed to methods for making the compounds of the instant invention.

Description

1242441

5. Description of the invention (1) The present invention relates to a cyclic derivative containing mimetic imidazolamide linkages, which selectively binds to a growth hormone release inhibitory factor (hereinafter referred to as "stagnation hormone") receptor subtype. The present invention also relates to a method for producing a compound of the present invention. Somatostatin (SRIF) is a cyclic tetradecapeptide hormone containing a disulfide bridge between the 3 and 14 positions, and has the ability to inhibit the release of growth hormone (GH) and thyroid stimulating hormone (TSH), and inhibit insulin and glucagon Release, and reduce the secretion of moon acid. Somatostatin is metabolized by amino peptide hydrolase and serotonin, resulting in short duration of action. Somatostatin binds to five discrete receptor (SSTR) subtypes and has a relative amphipathic affinity for each subtype. The smaller and stiffer analogs of the invention are highly selective for several receptor subtypes. The different types that bind to the somatostatin subtype are related to the treatment of the following conditions and / or diseases ^ Activated Types 2 and 5 are related to growth hormone inhibition and specifically to growth hormone-secreting adenomas (acromegaly) and thyroid stimulation Hormone-secreting adenomas are involved, and activating 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 melanin and / or glucagon, and special diabetes, hyperlipidemia, insulin-insensitive 'X syndrome, vascular disease, proliferative retinopathy, Down's phenomenon and nephropathy, inhibition of gastric acid secretion and special gastric ulcer, intestinal epidermis and pancreatic epidermal fistula 'irritable bowel syndrome, Dumping syndrome, Shuiwen syndrome, AIDS-associated diarrhea, chemotherapy-induced diarrhea, acute or Chronic pancreatitis and gastrointestinal hormone-secreting tumors; treatment of cancers such as liver tumors; inhibition of this paper size applies Chinese National Standard (CNS) A4 specifications (210 X 297 public love) (Please read the precautions on the back before filling this page)- -III ί I order --- 1 ί ^ Winning the clothing of the Intellectual Property Bureau of the Ministry of Economic Affairs, consumer clothing cooperatives, printing 4 1242441 L · η f L · A7 V. Description of the invention (2) Angiogenesis, treatment of inflammatory conditions such as arthritis; slow blood vessels Angioplasty to prevent rejection of graft vessels and body transplants; the agent can also be used to reduce patient weight. Wins bleeding. Somatostatin-promoting growth somatostatin agonists have also been disclosed for inhibiting Helicobacter pylori. In one aspect, the present invention provides a compound of formula (I), p1 a- (Y) n— or a pharmaceutically acceptable Salt, where Y and Z are D_4L_ natural or non-natural Q amino acid at each occurrence; η is 0 to 50 at each occurrence, but η cannot be 0 at the same time; m is 0 or An integer from 1 to 10; a is fluorene or R1; b is OH, -OR1 or -NR9R9; or a and b together form a hydrazine bond; R1 is fluorene, (CrCd alkyl or aryl-(CrC4) Alkyl; This paper size applies to China National Standard (CNS) A4 (210 X 297 mm)

------------ Μ ·! (Please read the notes on the back before filling in this page) Order · -line-5 Description of the invention (3) R is Η or the optional substitution part is selected from the group consisting of (C "c", "benzyl", "benzyl-xin c4"), silk and heterocyclyl ^, the selective substitution part here is optionally substituted by-or multiple substituents, the substituents are selected from the group consisting of ( CVC,) alkyl, (C3_C8) cycloalkyl, _〇_R6, _s (〇) q_R7,, -NHC0-R6 ', cco2R9, _coNR9R9 and which nr9r9, where q is 0, 1, 2 or 3; R3 and R4 are each a Η 'atom or a selectively substituted moiety selected from the group consisting of fluorene), ((3)) cyclofluorenyl, aryl, and arylamino, select here The optional substituent is optionally substituted by one or more substituents. The substituents are selected from the group consisting of OH, (CVC, (c 丨 _C4) oxy, aryloxy'aryl- (CVQ) oxy Group, _NR9R9, c〇〇H, _c〇Nw and halogen atom; ... 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 substituted by one or more substituents, The substituents are selected from the group consisting of oh, (cvq), and (cvc4) Group, aryloxy group, aryl_ (C 「C4) alkoxy group '-NR9R9, COOR5, -CONR9R9 and self-atom; R5 is H in each occurrence or the optionally substituted part is selected from (crC4) alkane And aryl_ (CrC: 4) alkyl, where the selective substitution part is selectively substituted by one or more substituents, the substituents are selected from the group consisting of ((VQ) alkyl, 0H, (C "C4) alkoxy, aryloxy, NO2, aryl · (ίν €; 4) alkoxy, -NR9R9, COOH, -CONR9R9 and its atoms; R6 is selected from each occurrence including η (CrC4) alkyl, (c "C4) alkoxy, aryl- (Crc4) alkyl and aryl_ (crc4) alkoxy; when q is 3, R7 is H, or when q is 0, At 1 or 2 when R7 appears, the paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 6 1242441 A7 V. Description of the invention (4) Each is selected from the group consisting of (crc: 4) alkyl , Aryl or aryl- (CrC4) alkyl; and R9 at each occurrence is selected from the group consisting of H, No2, alkyl '^' and aryl- (CVC4) alkyl. (I) The compound is the compound rp_D-Trp-Lys-Abu-Phe ψ (4- (3-methoxyphenyl) Yl) -Gly-〇H 'another aspect, the present invention provides a method of formula (II) compound,

0 (II) or a pharmaceutically acceptable salt thereof, in which Y and Z are D_ * L_ natural or non-natural α-amino acid in each occurrence; m is an integer of 0 or 1 to 10; η is 0 to 6 in each occurrence; R1 is Η in each occurrence, (CrC4) alkyl or aryl- (CrC4) alkyl; R2 is Η or a selectively substituted moiety is selected from the group consisting of (C "C4) alkyl, phenyl'phenyl- (CVC4) alkyl, and heterocyclylalkyl. The selectivity here applies to the Chinese National Standard (CNS) A4 specification (21,297 mm>)- ------------ Equipment --- (Please read the precautions on the back before filling out this page)-Line · 7 1 1242441 Printed by A7 of the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs ~ — _B7 5 5. Description of the invention (5) The substituted part is optionally substituted by-or a plurality of substituents, and the substituents are selected from the group consisting of (CVC4), cyclyl, -0_R6, _s (〇) q_R7, _n < r9r9 ), -NHC0-R6, · NΗ3〇2Ϊι9, _C〇2R9, _c〇Nr9, and · s〇2Nr9r9 'where q is 0, 1, 2 or 3; R3 and R4 are fluorene, halogen atom or selectivity The substituted part is selected from the group consisting of (q-C4) alkyl, cycloalkyl, And aryl_ (Ci_c4) alkyl; the selective substitution part here is optionally substituted by one or more substituents, the substituents are respectively selected from the group including OH., (CVQ) alkyl '(Ci_C4) alkoxy , Aryloxy = aryl- (CVC4) alkoxy, -NW, C00H, -Conr9r9 and by atom; or R3 and R4 together with the carbon to which they are attached form a selectively substituted aryl group, here the aryl system The selectivity is taken from one or more substituents, and the substituents are selected from the group consisting of OH '(CVC4): ^, (C "C4) alkoxy, aryloxy, arylalkoxy, -NR9R9, C00R5 , -CONR9R9 and halogen atom; R5 at each occurrence is fluorene or the optionally substituted part is selected from the group consisting of (crc: 4) alkyl and aryl_ (CrC4) alkyl. Is substituted by one or more substituents, each of which is selected from the group consisting of: (CrC4) fluorenyl, OH, (cvc4) oxy, aryloxy, NO2, aryl_ (C1_C4) alkoxy, -NR9R9, coog, -CONR9m _ atom; R6 at each occurrence is selected from the group consisting of H, (Ci < 4) alkyl, C4) alkoxy, aryl- (Ci_C4) alkyl and aryl- (Ci_C4 ) Alkoxy; R is H when q is 3, or When q is 0, 1 or 2 o'clock in each occurrence, it is selected from (crc: 4) alkyl, aryl or aryl_ (Ci_C4) alkyl; and ι (please read the precautions on the back before (Fill in this page)

1242441 A7 -------- —_B7 ____ 5. Description of the invention (6) R9 is selected from each occurrence including Η, N02, (CVC4) alkyl'aryl and aryl- (CrC4) alkyl ; X1 is a natural or unnatural D- or L_a-amino acid, where should it be? ", When Nal, Trp, Tyr, pai or His, the aromatic ring system is selectively substituted by trans 6 to fluorene or nitrogen, or when X1 is Ser or Thr, the branched chain oxygen is selectively substituted by one or more R1; X2 is D- or L-Trp, N-methyl-D-Trp or N-methyl-L-Trp; X3 is Lys, α-N-methyl- ^ or £ -N_ (Ci_c4) alkyl 忒^ Or ε-N- [aryl- (CVC4) system] -Lys; X4 is Λran or unnatural D- or L-α amino acid, where X4 is Phe, Nal, Trp, Tyr or His When its aromatic ring is selectively substituted by carbon or nitrogen from R8, or when X4 is Ser, Tyr or Thr, the branched chain oxygen may be substituted by one or more R1. — Bonding between X, X, X3 and X4 It is a hydrazine bond, like the hydration between X! And ζ, and the bond between X4 and hydrazone. A group of preferred compounds of formula (II) are labeled as group A, where each η is 2;-m is 0 Or 1 to 5;. R1 is 出现 at each occurrence, methyl or aryl group CrC4) alkyl 'R is a selective substitution moiety selected from the group consisting of phenylalkyl and heterocyclyl- (CrC4) alkyl Here, the selective substitution part is substituted by a substituent selected from the group consisting of (CrC4) alkyl and -0-R6; and R and R are Η and _ atoms, respectively. Or optional replacement part is selected from the paper size of the package. Applicable to China National Standard (CNS) A4 specification (210 X 297 mm). Please fill in this page for the matters needing attention} σi line · 9! 242441 A7 B7 V. Employees of the Intellectual Property Bureau of the Ministry of Economic Affairs and the cooperative printed the description of the invention (7) Including (CrC: 4) tombs and aryl groups; The selective substitution moiety is optionally substituted by a substituent selected from the group consisting of 0H, (< ^-(: 4) alkoxy, aryloxy and halogen atoms. A group of preferred group A compounds are labeled For group B, where X1 is Phe, Nal, Trp 'Tyr, Pal or His, and its aromatic ring system is selectively substituted by carbon or nitrogen with r6; and X4 is Val, Abu, Ser, Thr, Nal, Trp, Tyr or His, in which the aromatic ring system of Nal, Tirp, Tyr and His is selectively substituted by R8 with carbon and / or nitrogen, or when X4 is Ser, Tyr or Thr, the branched chain oxygen system is selectively substituted with ruler 1. A good group of compounds in group B is labeled as group c where X1 is Phe, T 卬 or Tyr where the aromatic 瓖 system is selectively substituted by R6 for carbon or nitrogen; X2 is D-Trp Or N-methyl-D-Trp; X3 is Lys or a-N-methyl-Lys; X4 is Va Bu Thr, Abu, Nal or Tyr, where the branched oxygen of the hydroxyl groups of Thr and Tyr is selected by Rl Substitution; R is Η, methyl or benzyl at each occurrence; R2 is a selective substitution moiety selected from the group consisting of phenylmethyl and heterocyclyl-methyl ', where the selective substitution moiety consists of- Is selected from the group consisting of (c, c4) alkyl and -0-R6; R3 is ((VC4) or a substituted aryl | '(Cl-C is substituted with aryloxy and halogen atom substituents; (Please read the notes on the back before filling this page) Applicable to China National Standard (CNS) A4 specification (210 X 297 Public Love 1 10 1242441 A7 _____ _B7 ^ ___ V. Description of the invention (8) R4 is Η "and R is selected from each occurrence including Η and aryl_ (CrC4) alkoxy. A group of preferred group C compounds are labeled] ^^ where X1 is Phe, Trp, Tyr or Tyr (OBzl); X4 is Va Bu Thr, Abu, Nal or Tyr, where the hydroxyl- · groups of Thr and Tyr are selected M is 0, 2 or 4; R2 is a selective substitution moiety selected from the group consisting of phenylmethyl or 3-πindolylmethyl ', where the selective substitution moiety is selected from -0- R6 is substituted; and R3 is 1,1-difluorenylethyl or optionally substituted aryl; here, the optionally substituted aryl is optionally selected from the group consisting of OH, (Ci-c4) alkoxy And partial replacement of halogen atoms. — A group of preferred group D compounds is labeled as ε where R2 is phenylfluorenyl; R3 is 1,1-dimethylethyl or optionally substituted phenyl, which is a selective substitution for phenyl Is substituted by 〇Η or 〇CH3; and "R0 at each occurrence is selected from the group consisting of fluorene or benzylfluorenyloxy, respectively. , A group of preferred group E compounds is labeled as group F as ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (3- 曱 oxophenyl) imidazole) · Gly], ring [TyrCOBzlhD-Trp- Lys-Val-PheW (4- (3-methoxybenzyl) wow) -Gly], ring [Trp-D-Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidium ） · This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) -------------- Loading --- (Please read the precautions on the back before filling in this Page) Order:-line · 11 1242441 A7 ___B7_ 5. Description of the invention (9)

Gly], · ring [Trp-D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxybenzyl) imidazole) -Gly], ring [Ti: pD-Trp-Lys-Thr (OBzl) -Phe Ψ (4- (3-methoxybenzyl) mizolium) -Gly], ring [Trp-D-Trp-Lys-Thr-PheW (4- (3-transphenyl) imidium) -Gly], Ring [Trp-D-Trp-Lys-Abu-PheW (4- (3-methoxyphenyl) imido) -Gly] Ring [Phe-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (l, l-dimethylethyl) imine) -Gly], ring [Phe-D-Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imide) -Gly] ring [Phe-D-Trp-Lys-Tyr (OBzl) -Phe ¥ '(4- (3-_oxophenyl) imidazole) -Gly], ring [Phe-D_Trp-Lys-Tyr-PheW (4- (3- Phenoxyphenyl) glutamyl) -Gly],… · ring [Phe-D-Trp-Lys-Tyr-PheΨ (4- (3-Thrylphenyl) Weitu) -Gly], ring [Trp-D -Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], ring [Tyr-D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxy Phenyl) imidazole) -Gly], ring [Phe-D-Trp-Lys-Nal-Phe ¥ (4- (3-transphenyl) imide) -Gly], ring [Phe-D-Trp-Lys- Nal-Phe ¥ (4- (3-methoxyphenyl) imido) -Gly] ring [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (3- 曱 oxyphenyl) imide Saliva) (.7) -Abu], this paper is applicable in National Standard (CNS) A4 Specification (210 X 297 mm) (Please read the notes on the back before filling out this page) ϋ ϋ ϋ n ϋ ϋ n 1: WJ · nnnnn-Printed by the Intellectual Property Bureau of the Ministry of Economic Affairs and Consumer Cooperatives Preparation 12 1242441 A7 > _B7_ V. Description of the invention (10) ring [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (4-methoxyphenyl) imido) -Gly], ring [Trp-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (phenyl) σmiσ sitting) -Gly] ring [Trp-D-Trp-Lys-Tyi: (OBzl) -Phe ¥ ( 4- (3-Fluorophenyl) imidazole —) -Gly], • Ring [Ti * pD-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole)-( ε) -Αίιχ] and ring [Trp-D-Trp-Lys-Tyr (OBzl) -Phe ¥ (4- (3-Thrylphenyl) imidone) _ (7) -Abu] ° A better group F The compounds are labeled as group G where the ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (3-, methoxyphenyl) σ glutamate) -Gly], and the ring [Tyr (OBzl) -D- Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], ring [丁 印 -0-1 ^ -1 ^^-\ ^ 1-? 1 ^ ¥ (4- (3, methoxyphenyl) Mizolite) -01; /] '-ring [Trp-D-Trp-Lys-Val-PheW (4- (3-hydroxyphenyl) acetal) -Gly], Ring [Trp-D-Trp-Lys-Thr (〇Bzl) -PheW (4- (3-methoxyphenyl) miso) -Gly], ring [Trp-D-Trp-Lys-Thr-PheW (4- (3-transphenyl) imidyl) -Gly], ring [ Trp-D-Trp-Lys-Abu-PheW (4- (3-fluorenyloxy) methyl) -Gly] ring [? 1 ^ -〇- 丁 卬 -1 ^ 5- 丁 740321)-? 1 ^ ¥ (4- (1,1-dimethylethyl) This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ------------- Package- ------- Order --------- line (please read the notes on the back before filling this page) 13 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 1242441 A7 _______B7______ V. Description of the invention ( 11) Imidazole) -01} ^],-ring [Phe-D-Trp-Lys-Val-Phe Ψ (4- (3-fluorenoxyphenyl) imidazole) -Gly] ring [Phe-D-Trp-Lys -Tyr-PheW (4- (3-hydroxyphenyl) imidazole) _Gly] and the ring [Tyr-D-Trp-Lys-Val-PheΨ (4- (3-hydroxyphenyl) imidazole) _Gly]. A preferred group of compounds in the G group is designated as the ring [TyrD-Trp-Lys-Val-Phe P (4- (3-fluorenoxyphenyl) imidazole) -Gly] ring [Trp-D-Trp-Lys_Val- Phe Ψ (4- (3-methoxyphenyl) imidazole) _Gly], ring [Trp_D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Gly], private * [丁印 -1)-丁 印-£ / 3 ^ -1 [111 >? 116 see (4- (3-light phenyl) flavor 17 sitting) -〇17], ring [Trp ^ D-Trp-Lys-Abu -Phe ¥ (4- (3-methoxyphenyl) imide) -Gly] 1 ring [Phe-D-Trp-Lys-Val-Phe ¥ (4 · (3-methoxyphenyl) imidazole) _Gly ] Or ring [丁 > ^ *-〇_ 丁 印 -1 ^ 5-\ ^ 1-? 1] ^ ¥ (4- (3-Transphenyl) imidium) _ (315 ^) 0 Compounds in the Jiayu Group are labeled as Group I as a ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly]

J ring [Trp_D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidazole) -Giy], ring [Trp-D-Trp-Lys-Thr-PheW (4- (3- Hydroxyphenyl) usazole) _Gly] and the ring [1> 1]> [^ -1 ^-\ ^ 1-? 1 ^ ¥ (4- (3-hydroxyphenyl) ourazol) -〇17] . Another group of better F compounds is marked as J group. This paper size applies Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page). ---- Order ---------. 14 1242441 A7 _____B7__ 5. Description of the invention (l2) ring [Tyr-G-Trp-Lys-Val-PheW (4- (3-fluorenoxyphenyl) Imidazole) -Gly] y ring [Trp-D-Trp-Lys-Val-Phe Ψ (4- (3- 曱 oxophenyl) imidal) -Gly] bad [Trp-D-Trp-Lys-Val-Phe (4- (3- (phenyl)) ^^-Gly], ring [Trp-D-Trp-Lys-Thr (OBzl) -PheW (4- (3-methoxyphenyl) imidazole-)-Gly ], Ring [Trp-D-Trp-Lys-Thr-PheW (4- (3-transphenyl) miso) -Gly], ring [Trp-D-Trp-Lys-Abu-PheW (4- (3 -Methoxyphenyl) imidium) -Gly] ring [Phe-D-Trp-Lys, Tyr (0Bzl) -Phe ¥ (4- (l, l · dimethylethyl) taste) -Gly], , Ring [Phe-D-Trp-Lys-Tyr (OBzl) -Phe ¥ (4- (3- 曱 oxophenyl) methyl])-Gly] 'ring [Phe-D-Trp-Lys-Tyr-PheW (4- (3-Transphenyl) imidium) -Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (3-methoxyphenyl) imidazole) -Gly] ，-Ring [Tyr-D-Trp-Lys-Val-PheW (4- (3-Thrylphenyl) ketone), Gly], [Phe-D-Trp-Lys-Nal-Phe ¥ (4- (3 · Phenyl) Salary) -Gly], ring [Phe-D-Trp-Lys-Nal-PheW (4- (3- -A Oxyphenyl) imidazole) -Gly] ring [Trp-D-Trp-Lys-Tyi: (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole) -Gly], ring [Trp-D- Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (4-methoxyphenyl) imidazole)-This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------ -------- Installation --- (Please read the precautions on the back before filling this page) Order:, 丨 line-15 1242441 A7 B7_ V. Description of the invention (13)

Gly], _ ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (phenyl) imidium) -Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl)- Phe ¥ (4- (3-methoxyphenyl) imidal)-(ε) Ahx] and ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-Ethylphenyl)) Misal)-(7 ") Abu] 〇 A group of compounds more than Group J is marked as Group K as a ring [Trp-D-Trp-Lys-Thr-PheW (4- (3-Phenyl) taste))- Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (3-methoxyphenyl) imido) -Gly], ring [Phe-D-Trp-Lys-Nal-PheΨ (4- (3-_Phenyl-Homisa) -Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3- 曱 oxophenyl) imidazole) -Gly] , Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (4-methoxyphenyl) glutamate) -Gly] or-ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (phenyl) miso) -Gly]. A group of preferred compounds of group K is labeled as group L as ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (3-methoxyphenyl) orbital) -Gly], ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole)-(r) Abu], ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (4-methoxyphenyl) pyran))-Gly] and ring [1 ^ -0-1 ^ -1 ^^ -丁) ^ (621)-? 1 ^ ¥ (4- (phenyl) 口 米 ° ) -01; 7]. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page). -------- Order- -------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 16 1242441 A7 ---_ B7 V. Invention Description (I4) On the other hand, the present invention provides a pharmaceutical composition containing an effective amount of the formula (I ) Or a compound of formula (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. In another aspect, the present invention provides a method for extracting the effect of a somatotropin receptor agonist in a mammal in need thereof. The method comprises administering an effective amount of a compound of formula (I) or formula (11) or a pharmaceutically acceptable salt thereof to the mammal. In another aspect, the present invention provides a mammal in need of extracting a growth-restoring form. A method including the effect of an antagonist, which method comprises administering a compound of formula (I) or formula (II) or a pharmaceutically acceptable salt thereof to cough and mammals. In another aspect, the present invention provides a method for treating the following diseases in mammals in need and need: prolactin-secreting adenoma, re-narrowing of blood vessels, diabetic 'salilipidemia', insulin insensitivity, syndrome X, vascular disease, proliferative Retinopathy, Down's phenomenon, nephropathy, gastric acid secretion, gastric ulcer, 'intestinal epidermis and tense epidermal fistula, irritable bowel syndrome, Dang's syndrome, watery diarrhea syndrome, AIDS-related diarrhea, chemotherapy-induced diarrhea' Acute or chronic gastritis, gastrointestinal hormone-secreting tumors, cancer, liver tumors, angiogenesis, inflammatory diseases, arthritis, chronic allograft rejection 'angioplasty, graft vascular bleeding or gastrointestinal bleeding, this method contains The mammal is administered a compound of formula (I) or formula (II) or a pharmaceutically acceptable inclusion thereof ^ --- (please read the precautions on the back before filling this page) ·-丨 line-salt 'The present invention provides a Mammals in need-A method for inhibiting H. pylori proliferation, including administering to the mammals. On the other hand, this paper applies to China Standard (CNS) A4 (210 X 297 mm) 17 1242441 A7 B7 V. Description of the invention (i5 compound of formula (I) or formula (iiy or a pharmaceutically acceptable salt thereof). In another aspect, the present invention provides a preparation Method of compound of formula

0 = (i) 0 (...)

The method includes deprotecting a compound of the formula:

-^ R1 o = c R3 0 (b) or

R3 -----: ------- install -------- order --------- line (please read the precautions on the back before filling this page) Ministry of Economy Wisdom Printed by Property Consumer Cooperatives

Prt is an amino acid branched concord; Y and Z are respectively D- or l-natural or non-natural α-amino groups, which optionally contain protected branches, where Η-Ν * is defined by Υ The amino group of the N-terminal amino acid and 0 = C * are the carboxyl groups of the c-terminal amino acid as defined by Z; η is 1 to 50 in each occurrence; and all other variables are defined as above formula (1 ). The paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 18 1242441 A7 B7 V. Description of the invention (16) Its __ ancient aspects The present invention provides a method for preparing a compound of the following formula

The method contains:

HOOC (Z-Prt): ^ R1

wr] CO

HOOC Can rS (c ·) or (b.) For the compound of formula (a), react the compound of formula (a,) with the peptide coupling agent and additives to form the terminal amino group defined by the terminal amino group of Y and the terminal group defined by Z. The amine bond between the terminal carboxyl groups of the last amino acid; or for the compound of formula (b) 'reacting through a compound of formula (b') with a skin coupling agent and additives to form the final amine defined by the terminal amine group and Z Ammonium amine bond between the terminal carboxyl groups of the basic acid; or for compounds of formula (c), react with the peptide coupling agent and additives via formula (c ') to form the terminal amino group and terminal terminal of the final amino acid defined by γ The paper size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page)

19 Sui Zou Zhicai ^ Qi Employee Consumption Co., Ltd. ^ 1242441 A7 V. The amine bond of the invention description (17); where Prt is an amino acid branched protective group; Y and Z are each D- or L-natural or unnatural α-amino acid optionally contains protected branched chains, where Η-Ν * is the amine group of an N-terminal amino acid as defined by 及 and 0 = C * is the c-terminal as defined by Z Carboxyl group of amino acid; η is 1 to 50 in each occurrence; and all other variables are defined as above formula (I). In another aspect, the present invention provides a method for preparing a compound of the formula

The method comprises reacting a compound of formula R 0 with a compound of formula X, -CH (R3) C〇 (R4) α-halone in the presence of a polar aprotic solvent in the presence of a polar aprotic solvent until the reaction is substantially completed; Solid; dissolved solid in aprotic organic solvent and excess ammonium acetate aqueous solution to form a solution; and refluxing the solution and removing the polar layer at the same time to obtain a compound of formula (A); where X is an amine-protecting group; X 'is an atomic generator; Applicable to China National Standard (CNS) A4 (210 X 297 mm) r. --------- ^ --------- (Please read the precautions on the back before filling this page) 1242441 A7 B7 Description of the invention (18 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,

Prt-⑺n > vRl R2

N,

R3 0) (Please read the notes on the back before filling this page)

η- > τ N

R5_pmV co2r · (B), the method includes coupling a compound of formula (B) with Nα-protected amino acid (Prt) -Y, where the protected amino acid is its active ester, anhydride or hydrazone_ Form, the reaction proceeds in the presence of the test until the reaction is substantially complete to obtain a compound of formula (C)

(Prt) -Y-N

R1 N, Α) Λ4

R · 5., R5- co2r · (C), using conventional deprotection reactions to selectively deprotect the amino group of Na_protected amino acid (Prt) -Y, and repeat with another Na -Coupling reaction of the protected amino acid to obtain the predetermined compound of formula (I); 21 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) 1242441 A7 _______B7 V. Description of the invention (19) γ in each The next occurrence is D-aL_ natural or non-natural α • amino acid optionally has a chain with a protective group;

Prt is an amine-protecting group; W is an S or G group; η is 1 to 100; and all other variables are defined as in the above formula ⑴. In another aspect, the present invention provides a method for preparing a compound of formula VII, as defined above. The method comprises coupling a compound of formula (B), and the compound of formula (B) is activated to its active ester, anhydride, or halide and N-deprotected peptide. -Resin (a,), Peptide-Resin (A ') is prepared by peptide synthesis methods well known to those in the industry, using hexahydropyridine in DMF, TAEA or similar base to deprotect the N-terminal Fmoc group, and using strong acid The intermediate (B,) obtained by deprotection and cleavage by the resin ^ All variables are defined as the above formula (I). —

In another aspect, the present invention provides a method for preparing a compound of formula VII. The method comprises coupling a compound of formula (B) (activated as its active ester, anhydride or dentition) with N-deprotected peptide-resin (h) (borrowed Peptide synthesis industry well-known method), using hexahydropyridine in DMF and TAEA or similar bases to deprotect the N-terminal Fmoc group, using peptide coupling well known in the industry. This paper applies Chinese National Standards (CNS) A4 size (210 X 297 mm) (Please read the notes on the back before filling out this page) -—— — — — — — I— ^ · 1111111 ·. Printed by the Intellectual Property Bureau Employees Consumer Cooperatives of the Ministry of Economic Affairs 22 1242441 1 丄A7

^ _BL V. Description of the invention (20) The N-terminal terminal amine group to be liberated with N α -Fmox-protected amino acid (X) should be repeated as necessary to dealk and decouple the base to combine additional amine groups. Acid (X), using strong acid to deprotect and remove the intermediate (C ') obtained by resin cleavage. 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 gins (alkoxy) -benzyl Amine, resin (PAL resin), 4- (2 ', 4'-dioxophenyl-aminomethyl) -phenoxy resin (N-deprotected Link resin), or benzhydrylamine resin ; Use hexahydropyridine in DMF, TAEA or similar base to deprotect the N-terminal Fmoc group; use well-known peptide coupling reaction to cleavate the released N with N α -Fmoc protected amino acid (X) -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 (D,). All other variables are defined as in formula (I) above. ------------- ^ --------- ^ --------- (Please read the notes on the back before filling this page)

This paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 23 1242441 A7 ~ ^ --- B7____, invention description (21) In another aspect, the present invention provides a method for preparing a compound of formula ⑴ The method comprises reacting a compound of formula (B) with a base such as carbonic acid, and the obtained phenolic absolute salt (E ') is reacted with a halomethylated polystyrene resin such as Maryfield peptide resin, using hexahydrofuridine or a similar organic base. Remove? 1110 (: protecting group, using Nα-Fmoc protected amino acid (χ) to brew the released N-terminal terminal amine group using a peptide coupling reaction well known in the industry; repeat the alkali deprotection and coupling steps as necessary to combine Additional amino acids, using hexaargine or similar organic base to remove the final protected peptide sequence at the N-terminus and using Tfa to remove the protected peptide sequence at the C-terminus, cyclization using peptide coupling reactions well known in the industry The obtained intermediate (F,), and the obtained intermediate (G ') was removed by cleaving from the resin using a strong acid. All other variables are defined by the above formula.

In another aspect, the present invention provides a method for preparing a compound of formula (I) (as defined above), which method comprises coupling a compound of formula (B) (activated as its active ester, anhydride or halogen halide) with N-deprotected peptide-resin ( A,) (prepared by a method well known to those in the industry), using Tfa to remove the protection of the N-terminal Boc group, and using a strong acid such as HF to deprotect the branched chain protecting group, and cleave the resin to remove the intermediate (H,). All variables are defined as above formula (I). This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page) -------- Order · 丨 丨 丨 丨 丨 丨 ·· Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 24 1242441 A7 B7 V. Description of the invention (22 Η2Ν ·-(resin

Boc one; R2

HO-/ ^ O A,

Boc-N " R1 (CH2) m R4 0 =, R5 NH- (y) n «

H. 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) and N-desulfurization prepared by methods well known to those in the industry. Protecting peptide-resin (H), using Tfa to remove the protection of the N-terminal Boc group, and using Na-Boc-protected amino acid (X) to release the N- For terminal amine groups, repeat the Tfa deprotection and coupling steps as necessary to combine additional amino acids (X), use strong acid deprotection and cleave the resin to remove the intermediate (Γ). All variables are defined as above formula (I). Η · (χ) η—N’Rl

This paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm). Packing --- t Please read the notes on the back before filling out this page) • Line · 25 1242441 A7 B7 V. Description of the invention (23) In another aspect, the present invention provides a method for preparing a compound of formula (I), which comprises reacting a compound of formula (B) with a base, such as carbonic acid, to obtain a phenolic cesium salt (Γ) and a halomethylated polystyrene resin such as Maryfield. Peptide resin reaction, using Tfa to remove the Boc protecting group, and using Na-Boc protected amino acid (X) to peptide the N-terminal terminal amine group, which is well known in the industry, using a peptide coupling reaction. Protection and coupling steps to combine additional amino acids 00, use Tfa to remove the final protected peptide sequence at the N-terminus and remove the final protected peptide sequence at the C-terminus using an inorganic base such as lithium hydroxide in aqueous DMF, The intermediate (K ') obtained by cyclization of a peptide coupling reaction, which is well known to those in the industry, is used, and the intermediate (L') obtained by cleavage of the resin with a strong acid is used. All variables are defined as in formula (I) above. (Please read the notes on the back before filling this page)

Boc—N ^ R1 (C ^) m R4

OEt

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. On the other hand, the present invention provides a method for preparing a compound of formula (I), which comprises coupling a compound of formula (B) (activated to its active purpose, anhydride, or halogen) and N- Deprotected peptide, that is, 4-nitrobenzophenone oxime resin (M,) prepared by a method well known in the industry, using butyl fa to remove the protection of the N-terminal Boc group, and using Nα-Boc protected amine The basic acid (X) uses the N-terminal terminal amine group released by the peptide coupling reaction well-known in the industry, and repeats the Tfa release if necessary. The paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 26 1242441 A7 B7

Μ · Ν ·

V. Description of the invention) Combine the additional amino acid (X) in the protection and coupling steps, use Tfa to remove the protection of the N-terminal Boc group, cyclize and remove the intermediate N-deprotected edge by using appropriate organic bases to cleave Intermediate (N ')' and the use of strong acids such as hydrofluoric acid to remove branched protecting groups. All the variables are defined as above formula (1). (CH2) m R4 NH- (x) n Detailed description The term heterocycle is used herein to mean any heterocyclic ring that can occur in an amino acid branch bond. Examples include, but are not limited to, benzothienyl, coumaryl, and the like. Misalyl, indolyl, purinyl, amidinyl, pyrimidinyl, fluorinyl, thiazolyl, σsedenyl and trisigma. The use of the term aryl herein is intended to mean a stable monocyclic or bicyclic carbocyclic ring having up to 7 members in each ring, at least one of which is an aromatic ring. Examples of aryl groups include biphenyl, tetrahydroacyl, naphthyl, phenyl, and ^, ^ tetrahydro felt. In this case, several abbreviations are used for amino acid components, certain preferred protecting groups, reactants, and Solvent. Definitions of abbreviations are shown in Table 1. This paper size applies to Zhongguanjiaqun (CNS) A4 specification (210X297 mm) C Please read the notes on the back before filling in this page}; ··· 27 1242441 A7 B7 V. Inventive Note) The label does not define amine His L-Histidine Lys L -Nal L-3- (2-naphthyl) -alanine Phe L-phenylalanine Ser L-serine Thr L-threonine Trp L-color Amino acid (unless otherwise noted) Tyr L-Tyrosylic acid Ahx 6-Aminocaproic acid protecting group Boc 1,1- (difluorenylethoxy) carbonyl Cbz Benzyloxycarbonyl Fmoc 9 -fluorenylmethoxychityl Trt III Phenylmethyl solvent DMF N, N-dimethylamidamine THF tetrahydroadenosine Λ: 'Et〇Ac ethyl acetate reactant Tfa trifluoroacetic acid NMM 4-methylmorpholine DIEA diisopropylethyl Amine TEA Triethylamine TAEA Phen (2-aminoethyl) amine HOAT 1-Hydroxy-7-azepinebenzotriazole HATU [0- (7-Acebenzotriazol-1-yl) -1,1 , 3,3-Tetrafluorenylurea hexafluorophosphate EDC 1- (3-Difluorenylaminopropyl) -3-ethylformamidineimine hydrochloride DCC Dicyclohexylformamide (Please read the notes on the back first (Fill in this page again.) Test tube assay assays show that the affinities of compounds to human somatostatin subtype receptors 1 to 5 (respectively ssq, sst2, sst3, sst4, and sst5) are measured by inhibiting [125Ι-Tyrn] SRIF-14 binding Transfer to CH0-K1 was determined for infected cells. The size of this paper applies the Chinese National Standard (CNS) A4 (210X297 mm) 1242441 A7 B7 V. Description of the invention (26) The human 381: 1 receptor gene is transformed into a genomic fragment. The 1.5 Kb PW1-Xmwl fragment contains a 100 bp 5, -untranslated region, a 1.17 Kb overall coding region, and a 230 bp 3'-untranslated region were modified by adding the Bglll linker. The resulting DNA fragments were transfected at pCMV-81 to produce mammalian performance plastids (courtesy of Dr. Graeme Bell, University of Chicago). A transgenic cell line stably expressing the sst! Receptor was obtained by transfection and infection into CHO-K1 cells (ATCC) using the acid-filled 4 bow co-precipitation method (1). Plastid pRSV-neo (ATCC) is included as a selectable marker. The transgenic cell line was selected in RPMI 1640 medium (Gibco) containing 0.5 mg / ml G4 18, circularized for transfection and expanded in culture. The human sst2 somatostatin receptor gene was isolated at 1.7 Kb as mHI- / The / hi / III genomic DNA fragment and pGEM3Z (Promega) subtransformed into the plastid vector were kindly provided by Dr. G. Bell (University of Chicago). The mammalian cell expression vector is constructed by inserting 1.7 Kb in a III fragment into the pCMV5 compatible restriction endonuclease site. Transgenic cell lines were obtained by transferring infection into CHO-K1 cells using a co-precipitation method of calcium phosphate. Plastid pRSV-neo is included as a selectable marker. Human sst3 is isolated from the genome fragment, and the complete coding sequence is contained in the 2.4 Kb fragment. The mammalian expression plastid pCMV-h3 is modified by inserting a 2.0 Kb iVcoI-// Μί / ΙΙΙ fragment into the EcoRl position of the pCMV vector after modifying the end and adding the EcoRl linker. Transgenic cell lines stably expressing the sst3 receptor were obtained by transfer infection into CHO-K1 cells (ATCC) using a calcium phosphate coprecipitation method. Plastid pRSV-neo (ATCC) is included as a selectable marker. The transgenic cell line contains 0.5 亳 g / ml G418. The paper size is applicable to the Chinese National Standard (CNS) Α4 size (210X297 mm) (please read the precautions on the back before filling this page). — 29 1242441 Α7 Β7 V. Description of the invention (27) (Gibco) RPMI 1640 medium selection, circularization transfection and expansion in culture. The human sst4 receptor expression plastid pCMV-HX was provided by Dr. Graeme Bell (University of Chicago). The vector contains a j 4 Kb genomic fragment encoding human ss%, 456 bp 5, _ untranslated region and 200 bp 3, _untranslated region 'which is transfected at the aUcoR1 position of PCMV-HX. 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 1640 medium containing 0.5 mg / ml G418 (Gibco), circularized for transfection, and expanded in culture. The human SSts gene was obtained by PCR using a lambda-based, inbred strain of the genome as a template and was kindly provided by (The Postmaster of the University of Chicago Postdoctoral. The resulting 1.2 Kb PCR fragment contains 21 base pairs 5, Complete coding region and 55 bp untransfected region. Pure plant was inserted into the EcoRl position of pBSSK (+). Inserts were recovered as Kb fragments for subtransplantation.

Enter PCVM5 mammalian performance vector. Transgenic cell lines capable of stably expressing s-porphyrin receptors are known to be transferred to cH0_K1 cells (ATCC) by co-precipitation of calcium discoate. Include plastid pRSV-neO (ATCC) as a selectable marker. Transgenic cell lines were selected at 0.5 g / ml G418 (Gibco) tRpMI 1640, circularized for transfection, and expanded in culture. CH0_K1 cells, which can stably express one of the human sst receptors, grow on RPMI 1640, and the culture medium contains 10% fetal bovine blood and 0.4 g / ml genetlcin. Cells were collected at 0.5 mM EDTA and at 500 g. Approx. 4 paper sizes. Applicable to Chinese national standards. Ο: ι ^ μ ^ Γ ^ 〇χ 297 public love) 乂 Please read the precautions on the back first # < Fill this page ) ^ Installed ------- ordering! ------ · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 30 1242441 A7 B7 was «Lr 卩 -03 才 ln57lL. 肖 ίΟτΛι Zhatu.:PΞ C. Invention Description (28) C centrifugation for about 5 minutes -bell. The pellet was resuspended in 50 mM Tds, pH 7.4, and centrifuged at 500 g for about 5 minutes at about 4 ° C. Cells were lysed by ultrasound and centrifuged at 39000 g at about 4 ° C for about 10 minutes. The pellets were resuspended in the same buffer 'and centrifuged at 5000 for about 10 minutes at about 4 minutes, and the film of the resulting pellets was stored there. ^ Repeatedly performed [mi-Tyr ^ SRIF-M one of competitive binding experiments on a polypropylene 96-well plate twice. Cell membrane (10 μg protein / well) with [125I-

Tyrn] SRlF-i4 (0.05 μm) at about 37 ° C at 50 mM HEPES (pH 7.4),-〆〆—- ~~ 0.2% BSA, 5 mM MgCl2, 200 KIU / ml) Trasylol ), 0.02 μg / liter bacitracin and 0.02 μg / ml phenylmethylcontinium fluoride were incubated for about 60 minutes. Separation of the free material from [125I-Tyrn] SRIF-14 was performed immediately using a filter 196 (Packard) cell harvester. ▲ GF / C pre-soaked with 0.1% polyethyleneimine (PE 丄) Glass fiber filter plates (Unifilter, Packard) were separated by filtration. Filters were washed with 50 mM HEPES at approximately 0-4 ° C for approximately 4 seconds and analyzed for radioactivity using a Packard top counter assay. Non-specific binding was deducted from the total binding amount (stored in 〇 # 1 SRIF-14. Determined below) to obtain specific binding. Computer-assisted nonlinear regression analysis (MDL) was used to analyze the combined data and determine the inhibition constant (Ki) value. Whether the compound of the present invention is an agonist or a holding agent is determined by the following analysis. Functional assay analysis: Inhibition of intracellular production of cAMP: Can express human growth. This subtype receptor of CH0, -K1 cells (SRIF-U) is sown in a 24-well tissue culture multiplex, sown in 10% FCS and 0.4 copies. Paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 31 ------------- Installation -------- Order -------- -Line (Please read the precautions on the back before filling this page) A7 B7 1242441 V. Description of the invention (29) RPMI 1640 medium of mg / ml gentisine. The culture medium was changed the day before the experiment. Cells were washed twice at 0.5 cells / well with 0.5 ml of fresh RPMI containing 0.2% BSA and supplemented with 0.5 mM (1) 3-isobutyl-1-methylxanthine (IBMX), and incubated at about 37 ° C for about 5 minutes. minute. • The production of cyclic AMP is stimulated by adding 1 mM forskolin (FSK) at about 37 ° C for about 15-30 minutes. • The compound's agonist effect is measured by adding FSK (1 // M), SRIF-14 (10 · 12 Μ to IO · 6 M) and test compounds (IO · 10 Μ to IO · 5 M) at the same time. • The antagonist effect of the compound is measured by adding FSK (1 / ζM), SRIF-14 (1 to 10 ηM) and the test compound (10.1 ·) to 10 · 5 Μ simultaneously. Remove the reaction medium and add 200 ml of 0.1 N hydrochloric acid. Measured using radioimmunoassay analysis method (kit set rapid plate SMP001A, New England Nuclear Corporation). Radioligand binding assay

The method of obtaining the membrane for the analysis of the receptor binding assay in test tubes was homogenization (Polytron, set value of 6, 15 seconds) of CK0-K1 cells, showing the hsst receptor subtype, under ice-cold 50 mM Tris-HCl, and at 39,000 g ( Centrifuge twice (10 minutes) and resuspend in fresh medium. The final pellet was resuspended in 10 mM Tris-HCl for assay analysis. Used for hsst3, hsst4, hsst5 verification analysis. Each membrane product is incubated with 0,05 nM [125I_Tyrll] SRIF-14 at 50 mM HEPES (pH 7.4) for about 30 minutes at 37 ° C. HEPES contains BSA. China National Standard (CNS) A4 (210 X 297 mm)

------- Line · (Please read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 32 1242441 A7 ____B7_ V. Description of the invention (3〇) (10 mg / ml · ); Magnesium chloride (5 mM), Tricillo (200 KIU / ml), subtilisin (0.02 mg / ml) and phenylmethanesulfonyl fluoride (0.02 mg / ml). The final analytical volume was 0.3 ml. For hsst2 assay, [125Ι] ΜΚ-678 (0.05 nM) was used as the radioactive ligand and the incubation time was about 25 ° C for about 90 minutes. The incubation was stopped by quickly passing the cloth-blue filter manifold through a GF / C filter (pre-soaked in 0.3% polyethylenimine). The tubes and filters were then washed three times with 5 ml of ice-cold buffer. · Specific binding is defined as the total radioligand binding reduced to 1000 nM SRIF-14 (1 ^ 311, 3, 4, 5) or 100〇11] ^] ^ 〖-678 binding amount to 1153 {2. The compounds of the invention can be assayed and analyzed in vivo for their use in binding to somatostatin receptors, including specific binding to somatostatin subtype receptors. The methods used are well known in the industry, for example, refer to the following references: I. Shimon et al. Human "Somatostatin Receptor Subtype Specificity in Human Embryonic Pituitary Gland", J. Clin. Invest., Vol. 99, No. 4, pp. 789-798, 1997; and C. Gilon et al. "Stem-Cycle, Receptor 5-Selection 'Somatostatin Analogues: Synthesis, Biological Activity, and NMR Configuration Analysis", J. Med. Chem. 1998, 41, 919-929. As is well known in the art, there are many variations of known and possible uses of somatostatin agonists and / or antagonists. The uses of somatostatin are summarized as follows: Somatostatin enhancers can be used to inhibit growth hormone and more specifically growth hormone secreting adenomas (acromegaly) and TSH secreting adenomas; the treatment of this paper applies Chinese national standards (CNS) A4 specifications (210 X 297 mm) -------------- installation -------- order --------- line (please read first Note on the back page, please fill in this page) 33 1242441 A7 B7 V. Description of the invention (31) Prolactin-secreting adenoma; Inhibition of insulin and / or glucagon more specifically inhibits sugar-guided disease, vascular disease, proliferative retinopathy, Tang Phenomenon and nephropathy; inhibition of gastric acid secretion and more particularly gastric ulcer; intestinal epidermal and pancreatic epidermal fistulas; irritable bowel syndrome; Dangpin syndrome; hydrodiarrhea syndrome; AIDS-associated diarrhea; chemotherapy-induced diarrhea; acute or chronic pancreatitis 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; golden angioplasty; prevention of transplanted blood vessels and gastrointestinal bleeding. The scope of the invention thus encompasses pharmaceutical compositions comprising at least one compound of the invention as described herein in combination with a pharmaceutically acceptable carrier. The compound of the present invention can be administered orally, parenterally (for example, intramuscularly, intraperitoneally, intravenously or subcutaneously or implanted), nasally, vaginally, rectum: sublingually or locally. The carrier formulation results in a dosage form suitable for various routes of administration. _ 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 pharmaceutically acceptable carrier such as sucrose, lactose or starch. These dosage forms contain substances other than inert diluents, such as lubricants such as magnesium stearate, as normal practice. In the case of capsules, tablets, and pills, the dosage forms also include buffering agents. Lozenges and pills can additionally be prepared as casings. Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs containing inert diluents such as water commonly used in the industry. In addition to these inert diluents, the composition also includes adjuvants. If the paper size is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) (please read the precautions on the back before filling this page) --- ----- ^ --------- ^-Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 34 V. Description of the Invention (32) Wetting agent, emulsifier and suspending agent, sweetener and flavoring agent And fragrance. Parenteral pharmaceutical preparations according to the present invention include sterile aqueous or non-aqueous solutions, suspensions or emulsions. Examples of non-aqueous solvents or vehicles are propylene glycol 'polyethylene glycol, vegetable oils such as olive oil and corn oil, gelatin and organic esters for injection such as ethyl oleate. These dosage forms also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents. It can be sterilized by, for example, filtering through a bacterial retention filter membrane, mixing a sterilizing agent in the composition, irradiating the composition, 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 injectable media just before use. Rectal or vaginal axe compositions are preferably suppositories which contain excipients such as cocoa butter or suppository waxes in addition to the active substance. Compositions for nasal or sublingual administration can also be prepared using industry standard excipients. Further, the compounds of the present invention can be administered as a sustained release composition, for example, as described in the following patent, US Patent No. 5,672,659 teaches a sustained release composition comprising a bioactive agent and a polyester. U.S. Patent No. 5,595,76G teaches a sustained release composition comprising a bioactive agent in the form of gelatin. U.S. Patent Application No. 08 / 929,363, filed September 9, 1997, teaches a polymer sustained release composition comprising a bioactive agent and methylose. U.S. Patent Application No. 08 / 74〇, 778, "" January 1st, "teaches a composition comprising a bioactive agent and a cyclodextrin to a sustained release. U.S. Patent No. 09 / 015,394, filed on Jan. 29, 1998, teaches absorbent sustained release compositions of bioactive agents. The teaching contents of the aforementioned patents and patent applications are described herein for reference. 1242441 Α7 B7 1. Description of the invention (33) The dosage of the active ingredient of the composition of the present invention may vary; however, the amount of the active ingredient is required to 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 at a dose per day to obtain a therapeutic effect. The preferred dose is 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. 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 amine group is protected by Boc, cbz or other suitable group. The inorganic acid is used, such as sodium hydroxide, potassium hydroxide, carbonic acid, or preferably carbonic acid in a polar solvent such as water, DMF. , THF, etc. into complete acid salt. The solvent is removed in vacuo, and the residual salt is redissolved in a polar aprotic solvent such as dmf 'at about -20 C to about 100 ° C, preferably at room temperature. Stirring is continued for about 10 minutes to about 24 hours or until the formation of the ester is confirmed by tLC analysis. At this time, the solution is concentrated in vacuo at about 40 ° C to about 70 ° C, preferably at about 40 ° C to about 70 ° C. The intermediate is re-dissolved in an aprotic organic solvent such as benzene, toluene or optimal xylenes, and ammonium acetate is added in an amount of about 5 to about j times, or preferably about 15 to 20 times. The two-phase mixture is heated under reflux and the polar layer is completely removed using butytaxel 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. This paper size applies to China National Standard (CNS) A4 specifications (2) 0 X 297 mm (Please read the precautions on the back before filling this page) Order --------- Line-Ministry of Economics Intellectual Property Printed by the Bureau's Consumer Cooperatives 36 1242441 A7 B7 V. Description of Invention (34)

Reaction diagram I

X-N

I 丨 »1 R1 Ο: e.g. CBZ, BOC 1. C, C03 / DMF / H20 OH 2. Br.CH (R3) CO (R4) 3. NH.OAc

X-l-N: R

R3 (A) iS '

1. Deprotection or derivatization 3. Selective derivation .Rl

V-N

R1, N W 1 ·· Solution peptide 4 synthesis

R3 R2

2.cyclization and deprotection (B) b- (Z),

N

R3 -------------- Packing --- (Please read the notes on the back before filling this page) (C) Order · 丨 Line-In the second step, the intermediate is catalytically hydrogenated Or strong acids such as HF, HC1, HBr or Tfa are deprotected. 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, -Cbz_protected imidazolium nitrogen can be calcined using a protected ammonium acid ester and the protection of α-amino group by catalytic hydrogenation to obtain B, (V = H, W =-(CH2) mCR5C2OR, here R represents a thio group or a benzoate). Imidazole nitrogen can be protected with commercially available triphenylphosphonium chloride and a third amine such as 4-methyl-morpholine, diisopropylethylamine or triethylamine to obtain a Fmoc protected intermediate, which is subsequently used Deprotection of the α-amino group by a base such as TAEA gives the intermediate (B) (v == h, W = Trt). In addition, the N-deprotected microphone t »sit b" (V = H, W = H) can be used without further modification. In the third step, the intermediate B, B, or B "is used as the target peptide. The size of continuous dissolving paper is in accordance with Chinese National Standard (CNS) A4 (210 X 297 mm) 37 1242441 A7 _________B7 V. Description of the invention (35) Actinide for liquid phase synthesis. In this way, the spinyl group is dissolved in ethyl acetate at a concentration of about 50-200 millimoles per liter, and about 1-5 to 5 mol equivalent or better hl to 15 mol equivalent is added. ^ 411100 The protected amino acid is activated. Ester, anhydride or halogen form. The mixture is stirred with a second layer of a weak base such as an aqueous sodium carbonate solution or more preferably a sodium bicarbonate bath until the reaction is complete. Remove the aqueous layer and add about 1 to 10 ml / mmol or more preferably about 2-4 ml / mmol of 3TAEA or hexahydropyridine and stir the mixture for about 30 minutes. The solution was then washed with a saturated sodium gas solution (twice with about 30 ml /. Millimolar) and then adjusted to pH = 5.5 using a 10% phosphate buffer solution (using about 10 ml / mmol). Wash three times). The subsequent cycles are then performed in the manner of the first cycle. The final amino acid is protected with Noc using a Boc or Fmoc group. In the fourth step, the N-terminal and C-terminal end protecting and protecting groups are removed using an alkaline aqueous solution or a strong acid. The resulting peptide intermediates can be cyclized using traditional peptide coupling techniques, as described in "Peptide Synthesis Practices", Bodanszky and Bodanszky, Springer -Varlag, 1984. In this way, the peptide intermediate is dissolved in an aprotic solvent such as DMF, and the solution is adjusted to be basic by adding a third amine base such as' fluorenylmorpholine. The slow acid portion of the intermediate is activated by the addition of a 1 to 6-fold molar excess of methylenedimine, such as DCC or EDC, and additives such as 1-benzobenzoate. The mixture is stirred at about 0 ° C to 100 ° C, preferably at about room temperature, until the reaction is complete. In the final step, the protected peptide is protected by catalytic hydrogenation or strong acid such as HF, HC1, HBr or Tfa to remove the protecting group to obtain the final product (c), where ... to ^, a, b, Y, Z and η are defined as above formula ⑴ . Immersion mass spectrometry data were obtained from an ESI (electrospray ionization) source

Measured on a Finnigan SSQ 7000 spectrometer. The NMR data is at 300MHz. This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page) 1_1 —1 ϋ nn Ί n Order ---- --- ——Printed by the Consumers' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 38 A7 1242441 ____B7___ V. Description of the Invention (36)

The Varian Unity spectrometer was obtained from a sample at a concentration of about 10-20 mg / ml in the specified solvent. In addition, the compounds of the invention can be prepared using solid-phase peptide synthesis techniques. Thus intermediate A (X = Boc) is, for example, alkylated with 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 test solution such as sodium hydroxide to obtain intermediate B ( V = Boc, W = -CH2C02H). Intermediate B (V = Boc, λν = -0: Η2 (ΙΌ2Η) can be activated using known activation techniques. For example, described in "Peptide Synthesis Practices", Bodanszky and Bodanszky, Springer-Varlag, 1984, and used directly for coupling As for the peptides grown on the solid support, or the intermediate B (V = Boc, W = _CH2CO2H) can be directly attached to the solid support to start the solid phase synthesis. The N-terminal terminal Boc group can be deprotected using Tfa, for example. Peptide synthesis is continued under conditions known to those in the industry. ^ Intermediate B, for example (V = Fmoc, W = -CH2C02t-Bu), can be treated with an acid such as Tfa to remove the third butyl protected carboxylic acid, and the resulting intermediate B (for example, V = Fmoc 'W = -CH2C〇2H) can be used for solid-phase peptide synthesis using the Fmoc strategy. Thus intermediate B (V = Fmoc, W = -CH2C02H) can be activated using known activation techniques, such as described in "Peptide Synthesis Practices Bodanszky and Bodanszky, Springer-Varlag, 1984, are used directly to couple peptides growing on solid supports. Deprotection of N-terminal Fmoc groups, such as using hexahydropyridine, allows peptides under conditions known to those in the industry. The synthesis continues. The solid phase synthesis of cyclic analogs can also be performed as follows Figure Η. This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) ------------- ^ · I ------- ^ --- ------ line (please read the precautions on the back before filling this page) 39 1242441 A7 B7 V. Description of Invention (37)

I should map II

R ... R--NR

0-shuyue · alkyl, benzyl 588 Boc, Fmoc (Please read the notes on the back before filling out this page) II 1 I I--Order ·------- ·-Employees of Intellectual Property Bureau, Ministry of Economic Affairs Intermediate A printed by Xiaoxian Cooperative (X = Boc or Cbz, R3 = 2-methoxybenzyl, 3-methoxyphenyl or 4-methoxyphenyl) can be treated with 1M Βγ3 in digas methane. Free state A was obtained in 2 hours (X = H, R3 = 2- via benzyl, 3- via phenyl or 4- via phenyl). The α-nitrogen is then protected with an acid-sensitive protecting group such as a Boc group using a dicarbonate-di-third-butyl ester and a base such as sodium hydroxide in a water-miscible organic solvent such as a dioxane and water mixture. Intermediate A (X = Boc, R3 = 2-Mphenyl, 3-hydroxyphenyl or 4-hydroxyphenyl), for example, ethyl bromoacetate and appropriate tests such as breaking acid in aprotic solvents such as DMF to obtain ethyl The purpose of this paper is to apply the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 40 1242441 A7 B7 V. Description of the invention (38)

物 D。 Object D. Then Shenma D is converted into shaved salt by carbonation shaving. Excessive reaction of the shaved salt with the Maryfield resin gave Intermediate E. Intermediate E was subjected to post-reed treatment, 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 stripped off with a suitable base such as lithium hydroxide in an aqueous DMF solution, and the skin is cyclized using a standard activation scheme such as formamidine and e.g. hydroxybenzene Benzotriazole and a third amine base such as diisopropylethylamine give intermediate G. Finally, the branched chain is deprotected and the resin is cleaved to obtain the compound of the present invention by adding a very strong acid such as hydrogen fluoride. The invention will be illustrated by the following examples but not limited to the details. Example 1 Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (f methoxyphenyl) imidazole) _

Gly] -------------- install— (Please read the precautions on the back before filling this page) ij ·

—Line— Example 1 is synthesized according to the synthesis reaction shown in Figure 1. The paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) 41

I 1242441 A7 B7 V. Explanation of the invention (39) Reaction diagram 1 ·

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

Fmoc-OSu / i ^ COj CH3CN / H20

FmocN

Trityl-Cl / NMM r3 ch2ci2

FmocN ^ R3 R1 Trt

(c) Solution synthesis

Fmoc- (Z) -X, -X2-X3-X4H

Tit

1. Tfe / iPr3SiH 2. Br- (CH2) mCHR5C02Et / KHCO3 / DMF (Please read the precautions on the back before filling this page)

Fm〇C- (Z) n-X 丨-× 2- × 3- × 4 · (Υ) η々, ((e) WL R4 (from 0 to 0) R1.

1. Ding AEA / £ tOAc 2. NaOH / H20 / McOH 3. EDC / HOBt / DMF 〒4- (Y) „— N · L R2 R3 Hj / Pd / Carbon X HOAc (CH2) m-(z) r

〇

(g) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs (f)

This paper size is in accordance with Chinese National Standard (CNS) A4 (210 x 297 mm) 42 1242441 A7 21 ______B7___ 5. Description of the invention (4〇) Step a-: ⑻-amino-2-phenylethyl ) -4- (3-methoxyphenyl) -mizole (Please read the precautions on the back before filling in this page)

Cbz- (L) -phenylalanine (10.0 grams, 33.4 millimoles and cesium carbonate (5.44 grams, 16.7 millimoles) combined in 2: 1 / 〇1 / ?: water (75 mL) and mixture Stir until homogeneous. Remove the solvent under storage pressure, dissolve the residue in kDMF (70 ml) and add 2-bromo_3'_oxoacetophenone (7.65 g, 33.4 mmol) to DMF (30 Ml). The mixture was stirred at room temperature for 30 minutes and then concentrated under reduced pressure. The resulting ketone vinegar was dissolved in xylene (150 ml) and filtered to remove bromide. Ammonium acetate (40.0 g, 0.52 Mol) and the mixture was heated under reflux for about 2 hours, using a Ding Stark trap to remove excess ammonium acetate and released water. The reaction was cooled and saturated with sodium bicarbonate solution (50 liters) and residual sodium chloride solution. (50 ml) washing. The xylene layer was dehydrated with sodium sulfate, filtered and the concentrated residue was dissolved in dihumane (30 ml), 6 迓 hydrochloric acid (115 ml) was added and the mixture was heated under reflux for about 10 hours. The solution was vacuumed Concentrated and triturated with diethyl ether (4 to XI00 ml). The residue was dehydrated in vacuo to constant weight to obtain 1215 g (99%) of intermediate la , Mass spectrum 294.2 MH +. ▲ 2- (l- (SH (fluorenylmethoxy) amido) aminophenylethyl) _ 4- (3-fluorenoxybenzyl) -imidazole intermediate la (11.8 g, 32 · 2 mmoles) dissolved in 1: 1 / acetonitrile: water (200 liters) and carefully divided into carbon dioxide (5.38 g, 39 mmoles). Add 9-methylmethyl-butanediol The aminocarbonate 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 × 50 ml). The ethyl acetate layer was dehydrated with sodium sulfate and passed through the paper The scale is applicable to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 43 1242441 A7 _____B7____ V. Description of the invention (41) 遽 and vacuum '/ agricultural shrinkage. The product is purified by flash chromatography (150 grams) by flash chromatography Use 2: 2: 1 / digas methane •• hexanes: ethyl acetate and then use 1: 1 / hexanos: ethyl acetate to dissolve. The product dissociation fractions are concentrated and concentrated in vacuo to obtain the intermediate lb with a pale yellow hair. Foam, 14.77 g (85%). Mass spectrum 516.3 MH +, NMR (300 MHz, DMS0-d6), 11.8-12.0 (1H, S), 7 · 8-8 · 0 (3H, d), 7 · 6-7 · 8 (2Η, d), 7.5 (1Η, s), 7.1-7.5 (12Η, m), 6.7-6.9 (1Η, d) 4.8-5.0 (1H, m), 4.1-4.3 (3H, m), 3.7-3.9 (3H, s), 3.0-3.4 (2H, m) · static c.: 2- (l- (S)-((fluorenylmethoxy) carbonyl) amino-2-phenylethyl) -4- (3- Methoxyphenyl) -1-triphenylmethyl-imidazole intermediate lb (13.9 g, 26.9 mmol) was dissolved in dichloromethane (50 ml) under nitrogen, and 4-methylmorpholine ( 2.96 milli #, 26.9 millimoles) and triphenylpyridine (7.51 grams, 26.9 millimoles), and the solution was allowed to stir at room temperature for about 45 minutes. The solid was removed by filtration, and the filtrate was purified by flash chromatography on silica gel (300 g) using 70: 30 / hexane. Type: Ethyl acetate as the eluent. The combined product dissolution fractions and vacuum concentration gave the intermediate lc as a foam, 18.0 g (88%). NMR (300MHz, DMSO-d6), 7.84-7.95 (2H, d), 7.7-7.8 (1H, d), 7.6--7 · 7 (1H, d), 6.7-7 · 5 (29H, m), 4 · 3-4 · 5 (1H, m), 3.75-3.95 (2H? m) 3.75-3.85 (3H, s), 3.6-3.7 (1H, m) 5 2.65-2 · 85 (1H, d, d), 2.05-2.2 (1H, m). ^^ _ d: 2- (l- (S)-((Fmoc-Tyr (OBzl) -D-Trp-Lys (Cbz) -Val) Amino group- 2-phenylethyl) -4- (3-methoxyphenyl) -1-triphenylmethyl-imidazole intermediate lc (1.89 g, 2.50 mol) was dissolved in ethyl acetate (40 liters) ), Add ginseng (2-aminoethyl) amine (9 ml) and stir the mixture vigorously. This paper size applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back first) (Fill in this page) The layer was washed with a saturated sodium gas solution (2 x 120 ml), and then washed with a 10% phosphate buffer adjusted to approximately pH = 5.5 (3 x 40 ml). The ethyl acetate layer was washed with a saturated sodium bicarbonate solution (40 mmol). Liter) Stir and add Fmoc-Val-F (1.02 g, 3.00 mmol). The reaction is stirred for about H, and the water layer is removed. Then the intermediates are sequenced in a manner similar to that described in the Fmoc-Val-F cycle described above. Deprotected and coupled with Fmoc-Lys (Cbz) -OSu, Fmoc-D-Trp-OSu, and Fmoc-Tyr (OBzl) -OSu. The ethyl acetate layer was diluted with ι · 5 times the volume of hexane and applied to silicone The column was purified by flash chromatography, using 50: 30: 20 / digas methane: ethyl acetate: hexanes and then 4: 1 / ethyl acetate: hexanes as eluents. Concentrated in vacuo to obtain Intermediate 1 (1 was a white foam, 190 g, (46%). Mass spectrum 1581.2] ^ +, 1559.5 Μ. +. Bunny: κ (2-ethoxy-2-oxy) Ethyl) -2- (l- (SH (Fmoc-

Tyr (OBzl) -D-Trp-Lys (Cbz)-(Val) amino-2-phenylethyl) -4- (3-methoxybenzyl) -taste intermediate Id (519 mg, • 33 mol) was dissolved in Tfa (10 liter) containing iPhSiH (205 μl, ΐ0 mmol), and the mixture was stirred for about 15 minutes. 'The intermediate was precipitated by adding ether (60 liters) and filtered. Mass spectrum 1316 MH +. The intermediate was dissolved in DMF (3 ml), potassium bicarbonate (198 mg, 2.0 mmol) and ethyl bromoacetate (721 µl, 6.5 mmol) were added, and the mixture was stirred overnight at room temperature. The mixture was concentrated in vacuo, dissolved in dichloromethane (100 mL) and washed with water (10 mL). The dichloromethane layer was dehydrated with sodium sulfate, and was subjected to vacuum shrinkage to obtain a crude intermediate 1 e (540 mg), which has not been printed in a paper. The Chinese National Standard (CNS) A4 specification (210 X 297 mm) has been applied. ------------- install -------- order --------- line (please read the precautions on the back before filling this page) 45 1242441 A7- --- B7 V. Description of the invention (43) Step purification is for 4 uses. Step-Comfort • Cycle [Tyr (0Bzl) -D-Trp-Lys (Cbz) -Val-Phe ¥ (4- (3-methoxyphenyl) imidazole: l-Glyl intermediate le (540 mg, 〇 · 33 mmol) suspended in ethyl acetate (10 liters) and added ginsyl (aminoethyl) amine (1 ml) and the mixture was stirred vigorously for about half an hour. Ethyl acetate (10 ml) and the solution were added to Saturated sodium chloride solution

(2 X 25 ml) washes and then washed with 10% phosphate buffer (pH = 5.5, 3 X 10 ml). -The intermediate was precipitated by adding hexanes (40 ml) and the solvent was decanted. The residue was dissolved in methanol (10 ml) and stirred in a chamber with 2.5 与 sodium hydroxide (0.5 ml) overnight. 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 DCC (3 ^ 0 mg, 1.65 mmol) and HOBt (252 mg, 1.65 mmol) were added. 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 products were separated and concentrated in vacuo to give the intermediate If as a glass (180 mg, 48% from the intermediate Id). Mass spectrum 1134.5 MH + 〇 Step g: Ring [Tyr-D-Trp-Lys-Val-Phe ¥ (4- (3-methoxyphenyl) imidazole) -Gly] 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 (removing Cbz and benzyl ether) and partially deprotected substances (removing Cbz while retaining benzyl ether). The size of the mixture on the VYDAC egg paper is in accordance with the Chinese National Standard (CNS) A4 (210 X 297 mm) (Please read the precautions on the back before filling this page). Loading -------- Order ---- -----. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs -46 1242441 A7 ________B7___; 5. Description of the invention (44) White matter and peptide columns (Nestle Corporation, South Blau, Mass.) Use 20% to 70%. The% CH / N / Ol% Tfa gradient was prepared by preparative but HPLC purification took approximately 55 minutes. The purely isolated fractions of the more polar peaks were combined, concentrated and lyophilized (2 < 10% 0.5% hydrochloric acid, then 1 × 10 ml of water) to obtain the title compound of Example 1, 45 mg (29%). Mass spectrum 910.4 μ +. Example 2 The ring [Tyr (OBzl) -D-Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidose) -Gly] Example 2 was prepared roughly according to the synthesis of Figure 1, Example 1, but Use the appropriate amino acid. The purely isolated fractions of the less polar peaks obtained by the purification of lg were combined, concentrated and lyophilized (2 × 10 ml of 0.5% hydrochloric acid, then 1 × 10 ml of water) to obtain the title compound of Example 2, 33 mg (21%). Mass spectrum 100 · 4, MΗ +. Example 3 The ring [Trp-D-Trp-Lys-Val-Phe Ψ (4- (3-methoxyphenyl) imidazole) · Gly] · Example 3 was prepared in a manner similar to Example 1 according to the synthetic reaction FIG. 1 but There are the following differences: Step d: 2- (l- (S)-((Fmoc-Trp-D-Trp-Lys (Cbz) -Val) amino-2-benzylethyl) -4- (3-methyl Oxyphenyl) -1- (triphenylfluorenyl) -miso intermediate lc (757 mg, 1.0 mol) dissolved in ethyl acetate (2. 亳 liter) 'added ginseng (2-amine Methyl ethyl amine (3 ml) and 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 a pH of about 5.5 using a 10% phosphate buffer solution. (3X20ml). The ethyl acetate layer is stirred with a saturated sodium bicarbonate solution (20ml) and added to the paper. The size of the paper is applicable to China National Standard (CNS) A4 (210 X 297mm) (Please read the precautions on the back first) (Fill in this page) Binding · Thread · 47 1242441 A7 __________wr_ V. Description of the invention (45) Fmoc-Val-F (825 mg, 2.33 亳 Mor). The reaction is stirred for about j hours, and the water layer is removed The subsequent deprotection of the intermediates and Fmo c-Ly ^ Cbz ^ OSu, FmoccD-Trp-OSu and Fmoc-Tyr-OSu are coupled in a similar manner to the previous cycle. The ethyl acetate layer is diluted with ½ times the volume of hexanes and applied to the stone tube The column was purified by flash chromatography, first using 50: 30: 20 / dichloromethane, ethyl acetate, and hexanes and then 4: 1 / ethyl acetate: hexanes as the eluent. The product was separated and concentrated in vacuo to obtain Intermediate 3 (1 as a white foam, 1.02 g, (68%). Mass spectrum 11492.0 MNa +, 1514.2 MΗ, rabbit_-e: 1 ((2 • ethoxy_2_oxy ) Ethyl) -2- (l- (SH (Fmoc-Trp-D-Trp-LyS (Cbz) -Val-) amino_2_benzyl'ethylfluorenoxyphenyl) -imidazole intermediate 3d ( 1.00 g of '0.67 mol) was dissolved in a mixture of dichloromethane (10 liters)' Tfa (1 ml) and iPhSiH (205 μl, 1.0 mmol) and the mixture was stirred for about 20 minutes. Add 1: 1: 1 / ether: hexanes (100 ml) mixture and the intermediate was filtered off and dehydrated (088 g). The intermediate was dissolved in DMF (10 ml) and potassium bicarbonate (200 mg, 2 · 〇〇mmol) and > ethyl acetate, reaction It was stirred at room temperature overnight. The mixture was concentrated under reduced pressure to obtain an intermediate 3e, i.e., for which was used without further purification. Mass spectrum 1335 7 MH + rabbit step f •• ring [TrP-D-Trp-Lys (Cbz) -Val-Phe Ψ (4- (3-methoxybenzyl) ranosa) -Gly] Intermediate 3e (crude, 0.67 Millimolar) dissolved in methanol (10 ml) and this paper size applies Chinese National Standard (CNS) A4 specifications (210 x 297 public love) (Please read the precautions on the back before filling this page) Packing .-- ----- Order ---------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 48 1242441 A7 ____B7__ V. Description of the invention (46) at room temperature with 2.5N sodium hydroxide (1.0 亳) L) Stir 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 g, mass spectrum 1085 · 5 mh +). The powder (629 mg) was dissolved in DMF (20 μl) and then αNM (22 μl '2.0 mmol), EDC (192 mg, ι · 0 μmol ^ H〇Bt (153 mg, 1.0 Millimoles). The mixture was stirred at room temperature for about 2 hours and concentrated in vacuo. The crude product was dissolved in one gas methylbenzene (15 liters) and a 10% salt buffer solution (adjusted to ρΗ = 5 · 5). ) Washed. The methane layer was dehydrated with sodium sulfate, filtered and concentrated to 2 ml. Diethyl ether was added to precipitate the product. The product was obtained by filtration and dehydration. Intermediate 3f (44.0 mg, 7.1%). Mass spectrum 1067.4 ΜΗ +. Step Huan: ring [TrP-D-Trp-Lys-Val-Phe Ψ (4 · (3-methoxyphenyl) glutamate) -Gly] intermediate 3f (200 mg, 0.19 mol) 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 on a C18 column ( RaininMicrosorb 80-220-C5) dissolves in a gradient of 20% to 70% acetonitrile / 0.1% Tfa for about 55 minutes. It takes about 50 minutes to dissolve in the second round using 30% to 50% acetonitrile / 0.1% Tfa Good separation was obtained. The pure fractions were combined, concentrated and lyophilized (2 × 10 ml of 0.5% hydrochloric acid and 1 × 10 ml of water) to obtain the title compound of Example 3, 26 mg (14%). Mass spectrum 933.5 MH, Example 4 Ring [Trp- D-Trp-Lys-Val-PheW (4- (3-hydroxyphenyl) imidazole) -Gly] Example 4 is based on the synthetic reaction. Figure 1 uses approximately the same formula as Example 1. The paper size applies the Chinese National Standard (CNS). A4 specifications (210 X 297 public love) -------------- install i I (Please read the precautions on the back before filling in this page) Order · -line-49 1242441 Formula but with the following differences: Shoulderguard · Ring [Trp-D-Trp-Lys-Val-Phe Ψ (4- (3-hydroxyphenyl) imidazole) -Gly] soil ', intermediate 3f (150 mg Om mol) was dissolved in dioxane (12 liters) and a solution of grade 1 boron tribromide in hexane was added under nitrogen. The resulting slurry was stirred for about 1/2 hour. Add methanol (1〇 Ml) and the mixture was concentrated under vacuum. The crude mixture was purified by a preparative HPLC ^ Ci8 column and dissolved in a gradient of 24% to 48% acetonitrile / 0.2% ammonium acetate for about 50 minutes. The pure dissociation fractions were combined and wave frozen dry 2 × 10 ml of water) to obtain the title compound of Example 4, 40 mg (29%). Mass spectrum 919.4 1 ^ +. Example 5 Ring [Trp-D-Trp-Lys-Thr (〇Bzl) -Phe Ψ (4- (3- Methoxyphenyl) imidazole) -Gly] Example 5 was prepared in a manner substantially similar to Example 3 according to reaction FIG. 1, but Fmoc-Thr (OBzl) -F was used instead of Fmoc-Val-F in step d. . Mass spectrum 1025.5 MH +. Example 6 The ring [Trp-D-Trp-Lys-Thr-PheW (4- (3-hydroxyphenyl) imidazole) -Gly] Example 6 was prepared in a manner substantially similar to Example 4 according to Reaction Figure 1, but in step g Intermediate 5f was replaced with ring [butyl rp-D-Trp-LyS (CbZ) -Thr (OBzyl) -PheW (4- (3--oxophenyl) imidazole) -Gly] instead of intermediate 3f. Mass spectrum 1025.5 MH +. Example 7 — Η-Ίϊρ-D-Trp-Lys-Abu-Phe Ψ (4- (3-methoxyphenyl) imidazole) The paper size is applicable to the Chinese national standard (0 ^) A4 size (210X297 mm) (please first (Read the notes on the back and fill in this page)

50 1242441 A7 __B7_ V. Detailed description of the invention)

Gly-OH (Please read the notes on the back before filling this page) Example 7 was prepared in a manner similar to Example 3 according to the reaction diagram 1, but in step 3d, Fmoc-Abu-F was used instead of Fmoc-Val-F and in Step 3f did not perform the cyclization using fluorenediamine and 1103. Mass spectrum 93 7.3 ^ «1+. Example 8 Ring [Trp-D-Trp-Lys-Abu-Phe Ψ (4- (3- 曱 oxophenyl) miso)-

Gly] Example 8 was prepared in a manner substantially similar to Example 3 according to Reaction Figure 1, but using Fmoc-Abu-F instead of Fmoc-Val-F in step 3d. Mass spectrum 919.5 MH + 〇 Example 9 Ring [Phe-D-Trp-Lys-Tyr (OBzl) -PheW (4- (l, l-dimethylethyl) imidazole) -Gly] Example 9 was prepared according to reaction FIG. 2. This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) 51 1242441 A7 B7 V. Description of invention (49

Boot

OH O 1. Cs2C03 / DMF / H20 2. Cl-CH (R4) CO (R3) 3. NH4OAc 4. MeOH ^ O / HCl

HN

Solution Synthesis R *

Fmoc- (Z) n-X1-X2-X3-X4- (Y) n-N

BrCC ^^ CHR ^ OjEt / KHC03 / DMF ·

Fmoc- (Z) n-Xl-X2-X3-X4- (Y) n-]

R · / N ⑻ wn one. lR5 0

1. Na0H / H20 / Me0H 2. EDC / HOBt / DMF (Please read the precautions on the back before filling this page) Ώ 1

H2 / Pd / Carbon HOAc

Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Step a · 2- (1-(S) -Amine Storm-2-phenylethyl) -4- (1,1-dimethylethyl) -Miye

Combine Boc- (L) -phenylmalonic acid (5.31 g, 20.0 mmol) with cesium carbonate (3.26 g, 10.0 mmol) at 1: 1 / DMF: water (50 mL) and stir the mixture to obtain Homogeneous mixture. Remove solvents and residues under reduced pressure, dissolve in DMF (50ml) and add 1-air pinacolone (2.63ml, 20.0m) This paper size is applicable to China National Standard (CNS) A4 (210 X 297mm) 52 1242441 A7 — ______ B7__ 5. Description of the invention (50) Moore). Mix ^ Do not let it fall overnight before concentrating under reduced pressure. The obtained ketone-S was dissolved in xylenes (100 ml) and filtered to remove cesium bromide. Add acetic acid: (25.0 g, 0.33 mole) and heat the mixture at reflux for about 2 hours while using a Ding Stark trap to remove excess acetic acid and the water released. 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 as eluent to obtain 3.45 g (50%) of crystalline intermediate (MS: 344.3 MΗ +). 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 the intermediate 9aNMR (300 MHz, DMSO-d6), 8.5-10.5 (3H, width s), 7.3-7.4 (1H, s), 7.15-7.35 0H, m), 7 · 0-7 · 1 (2H, m), 4.9-5.1 (1H, t), 3.5-3.65 (2H, d), 1.2-1 · 3 (9H, s). ^^ _ iL_ 2- (1-(S)-((Fmoc-Phe-D-Trp-Lys (Boc) -Tyr (OBzl))-amino-2-phenylethyl · yl) -4- (1,1- Dimethylethyl) _iH-imidazole intermediate 9a (790 mg, 2.50 mmol) was dissolved in ethyl acetate (40 ml). Added ginseng (2-aminoethyl) amine (9 ml) and The mixture was stirred vigorously for about half an hour. The ethyl acetate layer was washed with saturated sodium carbonate solution (2 X 120 ml) and then adjusted to about ρΗ = 5 · 5 (3 X 40 亳 L) with 10% phosphate buffer. Wash. The ethyl acetate layer was stirred with a saturated sodium bicarbonate solution (40 liters) and FmocTyr (OBzl) -OSu (1.02 g, 3.00 mmol) was added. The reaction was stirred for about 1.5 hours and the aqueous layer was removed. Intermediate Sequential deprotection and similar Fm0C-

Tyr (OBzl) -OSu cycle method and Fmoc-Lys (Cbz) -OSu, Fmoc · This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) ^ -------- t --------- (Please read the notes on the back before filling out this page) 53 1242441 A7 B7 V. Description of the invention (51) D-Trp-OSu and Fmoc-Phe-OSu are coupled. An ethyl acetate layer was applied to a Shixi gel column for purification by flash chromatography using 1% acetic acid / ethyl acetate as the eluent. The product fractions were pooled and concentrated in vacuo. The crude product was re-dissolved in ethyl acetate, and the hexane-burning sink and transition were added. The solid was dehydrated in vacuo to obtain the intermediate 9h, 1.67 g, (52%). Mass spectrum 1280.7 MH +. Step e: 4- (1,1-dimethylethyl) -2- (l- (S)-((Fmoc-Phe-D-Trp-Lys (Boc) -Tyr (OBzl)-) amine 2-Phenylethyl) -1- (2-ethoxy-2-oxy-ethyl) -imidazole intermediate 9h (128 mg, 0.10 mmol) was dissolved in DMF (2 ml) and carbonic acid was added Potassium (35 mg, 0.25 mol) and ethyl bromoacetate (28 μl '0.25 mmol) and the mixture were allowed to stand overnight at room temperature. The mixture was concentrated in vacuo and dissolved in ethyl acetate (10 liter) and It was 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. 1 [phe-D- Trp-Lys (Boc) -Tyr (〇Bzl) -Phe (4- (3-methoxyphenyl) imidazole) -Gly] intermediate 9e (116 g, 0.085 mmol) was suspended in ethyl acetate ( 2 ml) and ginsyl (aminoethyl) amine (0.5 ml) and the mixture was stirred vigorously for about 1/2 hour. Ethyl acetate (10 ml) and the solution were added to saturate sodium vaporized solution (2X5 Ml) and then washed with 10% phosphate buffer solution (ρΗ = 5.5, 3 × 5 ml) The intermediate was precipitated by adding hexanes (40 liters) and the intermediate (76 mg) was filtered off. The residue was dissolved in methanol (2 liters) and allowed to react with sodium hydroxide (0.1 ml) at room temperature. Overnight. The mixture was diluted with water to turbidity and adjusted to about 6.0. Intermediate removal of deprotected intermediates and vacuum removal (please read the precautions on the back before filling this page). Loading -------- Order- -------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 54 1242441 A7 ____B7_ V. Description of the invention (52) -------------- Installation-- (Please read first Note on the back, please fill out this page again) Water. Solid Dare to DMF (20 ml) and add DCC (126 mg, 0.60 mmol) and HOBt (90 mg, 0.60 mmol). Stir the mixture at room temperature for about 6 Hours and concentrated in vacuo. Dissolved in ethyl acetate (5 ml) and washed with saturated sodium bicarbonate solution (1 X 5 ml) and saturated sodium gas solution (5 ml). Dehydrated with sodium sulfate, filtered and concentrated in vacuo to obtain the middle 9f. Mass spectrum 1098.5 MH +. 'Step g: ring [Phe-D-Trp-Lys-Tyr-PheW (4- (l, l-dimethylethyl) imide Azole) -Gly] · Intermediate 9f (crude, 0.085 mmol) was 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 prepared on a C18 column. Purification by HPLC using a gradient of 30% to 60% acetonitrile / 0.1% Tfa for about 50 minutes. The second 'round uses 32% to 80% acetonitrile / 0.2% ammonium acetate to dissolve for about 50 minutes to obtain a good separation. The pure fractions were combined, concentrated and lyophilized (2 X 10 ml of 0.5% hydrochloric acid, then IX 10 ml of water) to obtain the title compound of Example 9, 9 mg (10%). Mass spectrum 998.4 MH + 〇 Example 10 Ring [Phe-D-Trp-Lys-Val-Phe Ψ (4- (3- 曱 oxophenyl) imidazole)--G1y] 〆 Example 10 is based on the reaction Figure 1 and is similar to Example 3 Was prepared by the method, but Fmoc-Phe-OSu was used instead of Fmoc-Trp-F in step d. Mass spectrometry 894.4 MH + Example Π ring [Phe-D-Trp-Lys-Tyr (OBzl) -Phe Ψ (4- (3-methoxyphenyl)) microphone This paper size is applicable to China National Standard (CNS) A4 specifications (210 X 297 (Mm) 55 1242441 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the Invention (53) Jun)-Gly] Example J1 was prepared in a manner similar to Example 3 according to the reaction diagram 1, but using Fmoc in step d -Phe-OH instead of Fmoc-Trp-F and Fmoc-Tyr (OBzl) -OH instead of 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 completely deprotected substances (both Cbz and benzyl ether are removed) and partially deprotected substances (Cbz is removed and benzyl ether is retained). The title compound of Example 11 was obtained from the less polar peak obtained by partial deprotection. Mass spectrum 1 (M8 · 5 MH +. F Example 12 ring [Phe-D-Trp-Lys-Tyr-Phe Ψ (4- (3-fluorenoxyphenyl) imidazole)-

Gly] Example 12 was prepared in a similar manner according to Reaction Figure 1 but with Fmoc_Phe-OH instead of Fmoc-Trp-F and Fmoc-Tyr (OBzl) -OH instead of Fmoc-Val-F in step d . Fmoc-Tyr (OBzl) -OH was activated with DCC and commercially available acetic acid. The crude mixture in step g is composed of completely deprotected substances (both Cbz and benzyl ether are removed) and partially deprotected substances (Cbz is removed 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] Example 13 was prepared in a manner similar to Example 4 according to Reaction Figure 1, but using an intermediate in step g The Ilf ring [Phe-D-Trp-Lys (Cbz) -Tyr (OBzl) -PheW (4- (3-methoxyphenyl) amizole) -Gly] replaces the intermediate 3f. Mass spectrum 944.6 MH +. This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) (Please read the precautions on the back before filling this page) Loading -------- Order -------- -Line at 56 A7 1242441 __B7_ V. Description of the Invention (54) Example 14-Ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (3-methoxyphenyl) pyran))-Gly] Example I4 was prepared in a manner substantially similar to Example 9 according to Reaction Figure 2, but with the following differences: Step h: 2- (l- (S)-((Fmoc-Trp-D-Trp-Lys (Cbz) -Tyr ( Bzl)) • -Amino) -2-phenylethyl) -4- (3-methoxyphenyl) -1- (triphenylmethyl) -imidazole peptide synthesis is performed in a similar manner to step 9h, However, Fmoc-Trp-OSu is used instead of Fmoc-Phe-OSu, Fmoc-Lys (Boc) -OSu is used instead of Fmoc-Val-OSu, and Fmoc-Tyr (Bzl) -OSu is used instead of Fmoc-Val_ :, ... OSu. Yield = 783 mg (57%), mass spectrum = 1370.6 MH +. Step e: 1-((2-ethoxy-2-oxy) ethyl) -2- (1- (S)-((Finoc-Trp_D-Trp-Lys (Boc) -Tyr (OBzl))-amine Alkyl) -2-phenylethyl) -4- (3-methoxyphenyl) -imidazole intermediate was synthesized in 14h in a manner similar to the reaction for 9h. Yield = 640 mg (80%). Mass spectrum. = 1456.3 MH +. Step f •• Ring [Trp-D-Trp-Lys (Boc) -Tyr (Bzl) -Phe Ψ (4- (3- 曱 oxobenzyl) 嗦 σ sitting) -Gly]. Intermediate 14e (640 mg, 0.44 mmol) was dissolved in 15 ml of methanol and 2.5N 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. DCC (206 mg, 1.0 mmol) and HOBt (153 g, 1.0 mmol) were added and the reaction was allowed to stir overnight. The size of the paper is in accordance with the Chinese National Standard (CNS) A4 (210 X 297 mm) ------- I ^ -------- ^ · III I ---- (Please read the back first Please note this page and fill in this page again) 57 1242441 A7 __B7__ V. Description of the invention (55) Concentrated in vacuum, dissolved in ethyl acetate (10 ml) and washed twice with 10% phosphate buffer solution ρΗ = 5.5. The ethyl acetate layer was then applied to a silica gel column and the product was dissolved with a larger amount of ethyl acetate. The product fractions were combined and concentrated to give 240 mg (46%) of intermediate 14f. Step g: The ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-amidooxyphenyl) imidazole) -Gly] intermediate 14f (240 mg, 0.20 mmol) was dissolved in Digas methane (10 ml) and Tfa (10 ml) was added to contain iPr3SiH (205 μl, 0.20 mmol). The mixture was stirred at room temperature for about 15 minutes. The dichloromethane was removed by evaporation under reduced pressure and the crude product was precipitated by adding ether. The solvent was decanted and the residue was further purified by preparative HPLC on a C1S column using a gradient of 30% to 50% acetonitrile / 0.1% Tfa for about 55 minutes. The pure solvents were combined, concentrated and lyophilized (2 × 10 ml of 0.5% hydrochloric acid, then 1 × 10 ml of water) to obtain the title compound of Example 14, 25 mg (11 ° / °). Mass spectrum 1087.4 MH +. Example 15 · Ring [Tyr-D-Trp-Lys-Val-Phe ¥ (4- (3-hydroxyphenyl) imidium) -Gly] Example 15 was prepared in a manner substantially similar to Example 4 according to the synthetic reaction FIG. 1 but There are the following exceptions: Step g: Ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (3-transphenyl) imidium) -Gly] Intermediate If (130 mg, 0.115 mmol) is dissolved 1M boron tribromide in hexanes (5 ml) was added to methane (5 ml) under nitrogen. 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 is applied to the C18 column. The paper size applies to the Chinese National Standard (CNS) A4 (210 X 297 mm) (please read the precautions on the back before filling this page). Order --------- Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 58-1242441 A7 B7 V. Description of the invention and) Wash the strips with 1% acetic acid > Wash the strips with 0.1% T fa The solution was washed and then dissolved using a gradient of 20% to 35% acetonitrile / 0.1% Tfa for about 50 minutes. The pure soluble fractions were combined, concentrated and lyophilized (2 x 10 ml of 0.5% hydrochloric acid) to obtain Example 5 of the title compound, 60 mg (54%). Mass spectrum 896 MH +. Example 16 The ring [Phe-D-Trp-Lys-Nal-PheW (4- (3-hydroxyphenyl) amizole) -Gly] Example 16 was prepared in a manner substantially similar to Example 3 according to Reaction Figure 1 with the following differences : Step d: 2- (l- (S)-((Fmoc-Phe-D-Trp-Lys (Cbz) -Nal-) amino) -2-phenylethyl) -4- (3- -oxo Phenyl) -1- (triphenylfluorenyl) -crmisal

•. V intermediate 16d is prepared in the same way as the intermediate Id,

However, Fmoc-Nal-OAt is used instead of Fmoc-Val-F and Fmoc-Phe-OH is used instead of Fmoc-Tyr (Bzl) -OH. Step g • Ring [Tyr-D-Trp-Lys-Val-Phe he (4- (3-Thrylphenyl) -salary) -Gly] Step 16g was performed in a similar manner to Step 4g to obtain the compound of Example 16. Mass spec. 980.0 MHT. umi ring [Phe-D-Trp-Lys-Nal-Phe Ψ (4- (3-methoxyphenyl) Weiwa)-

Gly] Example 17 was prepared in a manner substantially similar to Example 16 according to Reaction Figure 1 with the following exceptions. · Free from g-: ring [Tyr-D-Trp-Lys-Val-Phe Ψ (4- (3- 曱(Oxyphenyl) imidazole) -Gly] This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) (Please read the precautions on the back before filling this page) • Packing 丨 'Order — -59-1242441 A7 -------- B7 _— 15. Description of the invention (57) Intermediate 17f (310 g, 0.27 mmol) is suspended in anisole (3 ml) and the suspension is about 12 ml anhydrous Treatment with hydrogen fluoride. Mix for about 1 hour at about ye. Distillation removes hydrogen fluoride and the product is added to the 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 dissociated fractions were combined, concentrated and dried twice with dilute hydrochloric acid solution. Yield = 56 mg (19%). Mass spectrum 992.4 MH +. (Please read the precautions on the back before filling out this page) Packing ---------- Order --- I ----- line Standard (CNS) A4 specification (210 X 297 mm) 60 1242441 A7 B7 V. Description of invention (58)

CBZN

Ο 1, C ^ CCVDMF / I ^ O R2 2. Br-CH (R4) COR3 CBZ,

(0

1. Br- (CH (R5) C02tBu / KjCOj / DMF 3. NH4OAc 2.H2 / Pd / carbon K4

Packing --- (Please read the precautions on the back before filling this page) Line Example 18 Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (3-methoxyphenyl) imidazole- (7) Abu] Example 18 was prepared according to the synthetic reaction Figure 3. Step: 2- (l- (SH phenylmethoxy) carbonyl) -amino-2-phenylethyl) 4- (4-methyl Oxyphenyl) -imidazole

L

Cbz- (L) -phenylmalonic acid (10.0 grams, 33.4 millimoles) and carbon paper shavings are sized according to Chinese National Standard (CNS) A4 (210 X 297 mm) 61 1242441 A7 ^ _____ B7____ V. Description of the invention (59) (5.44 g, 16.7 mol) Combined in 2: 1/0! ^ ?: water (75 ml) and stir the mixture until homogeneous. The solvent was removed under reduced pressure, and the residue was dissolved in dmf (70 liters) and 2- < -3'-pyroxyphenylethyl (7.65 g, 33.4 mmol) was added to DMF (30 ml). The mixture was stirred at room temperature for about half an hour and then concentrated under reduced pressure. The obtained keto-ester was dissolved in xylenes (10.5 liters) and filtered to remove the brominated agar. Ammonium acetate (40.0 g, 0.52 mol) was added and the mixture was heated at reflux for about 2 hours to remove excess ammonium acetate and use a Buter Stark trap to remove released water. The reaction was cooled and washed with a saturated sodium bicarbonate solution (50 liters) and a saturated sodium chloride solution (50 ml). The xylene layer was dehydrated with sodium sulfate, filtered and concentrated in vacuo to obtain the intermediate 18i as a brown solid (13.8 g, 96%). Mass spectrum 428.2 (ΜΗ +) 〇 ± Al: 2- (l- (S) -amino-2-phenylethyl) -U (4- (l, l-dimethylethoxy) -4-oxy -Butyl) -4- (4-methoxyphenyl) -imidazole · Intermediate 18i (2.14 g, 5.0 mol) was dissolved in DMF (11.5 ml) and potassium bicarbonate (1.50 g ·, 15.0 Mmol) and 4-bromo-tert-butyl butyrate (6.69 g, 30 mmol) were processed in three portions with stirring at about 50 ° C for about 18 hours. The mixture was diluted with ether and washed once with a saturated sodium bicarbonate solution and once with a saturated sodium gas solution. The ether layer was dehydrated with sodium sulfate, filtered and concentrated to an oil. The product was obtained as oil by column chromatography on silica gel using methane as eluent. The crude alkylated product was deprotected using 10% palladium / carbon as a catalyst in hydrogen acetic acid. The catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in ethyl acetate and washed with a saturated sodium bicarbonate solution and a saturated sodium chloride solution, and dehydrated and concentrated with sodium sulfate to obtain an intermediate 18j as an oil (450 mg). This paper is in accordance with Chinese National Standard (CNS) A4 Specifications (210 X 297 mm) (Please read the precautions on the back before filling out this page) --------- Line · Printed by the Employee Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 62 1242441 A7 ______B7____ 5. Description of the Invention (60) It was used in the next step without further purification. Step ϋ: O.OaBoc-Trp-D-Trp-LysCCbzhVal) -amino-2-phenylethyl) -1-((4- (1,1-dimethylethoxy) -4-oxy- The synthesis of butyl)-'(3-methoxyphenyl) -imidazole solution was performed in a manner similar to the synthesis details described in step Id, but using Boc-Trp-OSu instead of Fmoc-Tyr (OBzl) -OSu and using FmooTyr (OBzl) _OAt replaces Fmoc-Val-F to obtain 18k intermediate. Yield = 1.03 g (81%). Step 1: 2- (l- (S)-((H-Trp-D-Trp-Lys (Cbz ) -Val) -amino-2-phenylethyl) -1-((4-hydroxy-4-oxy-butyl) -4- (3-amidophenyl) -imidazole intermediate 18k using containing (IPr) 3SiH (593 μl, 2.90 mol) was treated with Tfa (10 ml) solution and stirred for about one hour. The reaction was concentrated and triturated with a 1: 1 ether: hexane solution to obtain intermediate 181 which was brown. Solid, which was used in the next step without further purification. Mass spec. 1267 · 7 MH + Step f: Ring [Trp-D-Trp-Lys (Cbz) -Tyr (Bzl) -Phe Ψ (4- (3-Formaldehyde Lactyl) Misal_ (7) Abu] Intermediate 181 was dissolved in DMF (20 ml) and 4-methylmorpholine (159 µl '1.45 mmol), and HOBt (196 mg, 1.45 mmol) was added Mol) and EDC (278 mg,丨 .45 millimolar) and the reaction was stirred overnight. The reaction was concentrated by evaporation and purified by flash chromatography on Shixi gum using dichloromethane: methanol (9: 1) as the eluent to obtain the intermediate 18f. Yield = 220 亳 g (24%). Mass spectrum 1249.7 MH + Free: ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe Ψ (4- (3-methoxyphenyl) imidazole- (7) Abu] Paper) Standards are applicable to China National Standard (CNS) A4 specifications (21 × 297 mm) (Please read the > I on the back before filling in the unpaged pages)-Compare: Order:; Line-63 1242441 A7 B7 V. Invention Note (61) The intermediate l * 8f (220 mg, 176 μmol) was partially hydrogenated in acetic acid at 30 pSi hydrogen at room temperature using 10% palladium / carbon as the catalyst for about 14 hours. The catalyst was removed by filtration and the Concentrated in vacuo. The crude mixture was purified by preparative HPLC on a c18 column using 0% to 75% acetonitrile / 〇 ″% dimethyme gradient for 40 minutes. The pure product was separated and the peaks were combined, concentrated and lyophilized (2 × 10 ml. 5% hydrochloric acid 'followed by 1 x 10 ml of water) to obtain the title compound of Example 18, 72 mg (37%). Mass spectrum 1115.6] ^ 11 +. Example 19 Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (4-methoxyphenyl) imidazole-Gly] Example 19 was prepared in a manner substantially similar to Example 18 according to Reaction Figure 3 but There are the following differences:… ± Mλ ·· 2- (l- (S) -amino-2-phenylethyl) -l- (2-i, i-dimethylethoxy) -2-oxy- Ethyl) -4- (4-fluorenoxyphenyl) -imidazole intermediate 18i (854 mg, 2.0 mmol) was dissolved in DMF (10 mL) and tert-butyl bromoacetate (646 μL, 4.0) was added Mmol) and potassium carbonate (552 mg, 4.0 mmol), and the reaction was stirred at room temperature overnight. The solvent and residue were removed under reduced pressure, dissolved in ethyl acetate and washed with saturated sodium gas solution. The ethyl acetate layer was dehydrated with sodium sulfate, filtered and concentrated in vacuo to obtain 0.12 g of foam. Mass spectrum 428.2 MH +, NMR (300 MHz, DMSO-d6), 7.85-8.0 (1H, d), 7.6-7.75 (2H, d), 7.85-7.95 (1H, s), 7.1-7.35 (10H, m), 6.9 -7.0 (2H, d), 4.75-5.05 (5H, m), 3.7-3.9 (3H, s), 3.1-3.4 (2H, m) 5 1.3-1.5 (9H5 s). Intermediate white foam ( 1.02 grams, 1.88 millimolars) dissolved in 10% of this paper size Applies to Chinese National Standard (CNS) A4 specifications (210 X 297 mm) (Please read the precautions on the back before filling this page) Order ---- ----- Line · Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economy 64 1242441 A7, ___B7 ___ V. Description of the invention (62) Put / carbon (50 mg,) acetic acid (50 ml) and room temperature at 30 psi Hydrogenated for 10 hours under hydrogen. 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 as a light brown solid (862 mg), which was used without further purification. Mass spectrum 408.2 MH +. Step g: Catalytic hydrogenation and subsequent treatment were performed 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 + 9 Example 20 Ring [Trp-D-Trp-Lys-Tyr (Bzl) -PheW (4- (phenyl) weititu-Gly]] Example 20 was prepared in a manner substantially similar to Example 18 according to reaction FIG. 3, However, in step i, 2-bromobenzone was used instead of 2-bromo ~ -_3 and methoxyacetophenone. Mass spectrum 1057.4 MH + ^ Example 21 Ring [Trp-D-Trp-LysTTyr (Bzl) -Phe ¥ (4- ( 3-methoxyphenyl) imidamine- (ε) Ahx] Example 21 was prepared in a manner substantially similar to Example 18 according to reaction FIG. 3, but with the following differences: Mianhui_1: 2- (1- (S)- Amino-2-phenylethyl) -1- (6- (ethoxy) -6-oxy-hexyl) -4- (3-fluorenylphenyl) -imidazole intermediate 21i (855 mg, 2.0 mmol Mol) was dissolved in DMF (8.0 ml) and treated with potassium bicarbonate (200 g, 2.0 mmol) and ethyl 6-bromohexanoate (3.56 ml, 20 mmol) at about 120 ° C for about 8 minutes. Hours. The mixture was concentrated and the residue was purified by silica gel column chromatography using 2: 1 / hexane. This paper is sized for China National Standard (CNS) A4 (210 X 297 public love) 65 1242441 A7 B7

V. Description of the invention (63): Ethyl acetate was used as the eluent to obtain the pure product as a gum (0.94 g). The crude calcined product was deprotected by hydrogenation using 10% carbon / carbon catalyst in acetic acid. The catalyst was removed by filtration and the solvent was removed by evaporation under reduced pressure. The residue was dissolved in dilute hydrochloric acid, frozen and lyophilized to obtain the intermediate 21j • as a pale yellow solid (720 mg, 91%), which was used in the next step without further purification. Free, ... and Step 1: 2- (l- (S)-((H-TrP-D-TrP-LyS (BOC) -Tyr (OBzl) -2- (l- (S) -amino 2-phenylethyl) -1- (6- (ethoxy) -6-oxymonohexyl) -4- (3-methoxyphenyl) -σm

Fmoc-Tyr (〇Bzl) -OAt is prepared by mixing Fmoc-TyaoBzW OH (493 mg 1.00 mmol), HOAt (136 mg, 1.0 mmol) and DCC (206 mg, 1.0 mg) (Ear) prepared at 8 liters of ethyl acetate for about half an hour and then filtered to remove dicyclohexyl urea. The resulting solution was added to a solution of intermediate 21j (4 57 mg '0.9 mmol) in ethyl acetate (4 ml), and the mixture was stirred with a saturated sodium bicarbonate solution (10 ml) until confirmed by mass spectrometry. The reaction is complete. The aqueous layer was removed and the ethyl acetate layer was dehydrated with 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 vaporized solution (2 × 60 ml) and then adjusted to approximately pH = 5.5 (3 × 15 ml) with 10% phosphonate buffer. The intermediates are sequentially deprotected and coupled with Fmoc-Lys (Cbz:) _ 〇Su in a manner substantially similar to the aforementioned Finoc-Tyr (OBzl) -OAt cycle,

Fmoc-D-Trp-OSu and Fmoc-Trp-OSu. Finally, Fmoc was deprotected to obtain the N-terminal deprotected intermediate ethyl ester. The ethyl acetate layer was dehydrated with sodium sulfate, filtered and diluted with 4 times the volume of hexanes. Solvents and residues are removed by pouring. The size of this paper is applicable to China National Standard (CNS) A4 (210 X 297 public love). --- [I ------- ^ 装 --- (Please read the note on the back first Please fill in this page again for details) Order · 4 Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 66

1242441 V. Description of the invention (64) The product obtained as a solid (0.67 g, 58%) was prepared from hexane, and it was used without further purification. Mass spectrum 1289.6 MΗ +. Ethyl acetate was removed overnight by treating the intermediate with 1.7 M sodium hydroxide solution (L7 mL) in methanol (5.0 mL). The mixture was adjusted to about ρΗ = 8.2 with a 5% hydrochloric acid solution and the solvent was removed under reduced pressure. The residue was taken up by mDmf, and the sodium carbonate and DMF solution was removed by filtration and used in the next step without further purification. The% reduction and deprotection were obtained in the same manner as in Example 18. Example 21 The title compound was a white powder, 62 g. Mass Specimen i143.9 Example 22 Ring [Trp-D-Trp-Lys-Tyr (Bzl) -Phe ¥ (4- (3-hydroxybenzyl) tidazole_ (7) Abu]… Example 22 is based on reaction Figure 3 Prepared in a manner substantially similar to Example 18, with the following differences: 1- 2-0-0) -fluorenyl-2-phenylethyl) -ΐ · (4- (ethoxy) _4_oxy -Butyl) -4- (4-transphenyl) -pyridine intermediate 22i (2.0 g, 4.68 mol) was dissolved in DMF (7.0 ml) and dehydrated with bicarbonate (468 mg, 4.68 mmol) Ear) and 4-bromo-butyric acid ethyl ester (6.70 ml, 46.8 mmol), and stirred at about 100 ° C for about 30 hours. The mixture was diluted and washed once with a saturated sodium bicarbonate solution and once with a saturated sodium carbonate solution. The ether layer was dehydrated with sodium sulfate, filtered and concentrated to an oil. Column chromatography was performed on silica gel, and the product was obtained as an oil (2.53 g, 94%) using dioxane as a eluent. Mass spectrum 542.3 MH + Crude alkylation product (2.53 g, 4.67 mmol) in dioxane (50 mmol) This paper is in accordance with China National Standard (CNS) A4 (210 X 297 mm) ------ -------- Installation --- (Please read the precautions on the back before filling out this page) Ηδτ · --line · 67 1242441 A7 V. Description of the invention (65 liters) is about -1 (TC to Add dropwise to a solution of dendritic rotten / hexane burned (23.4 ml) in digas-fired (25.0 ml) in about 15 minutes. Allow the mixture to warm to room temperature and search for about 2 hours. Add people Ethanol (40 ml) and the mixture were concentrated to about 50 ml. The solution was diluted with ethanol (100 ml) and allowed to stir overnight at room temperature.::⑤The mixture was concentrated under reduced pressure and the residue was partitioned into acetic acid Ethyl acetate and saturated sodium bicarbonate solution. The ethyl acetate layer was dehydrated with sodium sulfate, filtered and concentrated under reduced pressure to an oil (1.41 g, 76%), which was used in the next step without protected phenol. Mass spectrum 394.3 MH + HPLC Asking when staying ---- installed --- (Please read the precautions on the back before filling this page) Example No. HPLC system residence time (pounds of pounds) 1 A 13.65 '2 A 18.S〇3 A 16.03 B 6.97 ^-~~ 5 C 20.4Ϊ ^ ™ ^^ 6 C 11.7? ~~ 7 D 9.53 8 B 11.02 9 E 7.69 ^-10 J 6.02 11 F 4. lT ~ 12 G 4 · ΐΤ '~' 13 H 5.S〇 " ~ 14 G 6.16 ^ 15 I 17.03-16 K 9.12 ~ ~~ ~~ — 17 J 8.11 18 J 8.86 19 L 6.47 20 M 6.6? '~ 21 G 8.ΪΤ —'-22 N 12.10 Η ^ τ * -line · This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 68 1242441 A7 B7 (66 HPLC A: B: C: D: E: uniform speed measurement column speed measurement column speed measurement column speed measurement column speed measurement column system ladder flow detection ladder flow detection tube ladder flow detection tube ladder flow detection Pipe Ladder Detecting and Printing Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economics G Η Degrees Quick Test Columns Quick Test Columns Quick Test Columns Quick Test Columns Ladder Detection Ladder Ladder Detection Ladder Ladder 20-80% acetonitrile / 0.1% Tfa, 1.0 liters / min 254 nm in 24 minutes * Vidak (乂 〇〇〇0) protein and peptide (18: 30-50% acetonitrile / 0.1% Tfa, 24 minutes) 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, 24 minutes 1.0 ml / min 254 nm Vidak protein and peptide C18 55-75% acetonitrile / 0.1% Tfa, 1.0ml / min 220nm Phenomenex 24 minutes Phichmenex Lichrosphere 5 RP18 (Phenomenex, 2320, 205th Street, Doron, California) 60% acetonitrile / 0.1% Tfa, isocratic 1.0ml / min 254mmol Micron Vidak protein and peptide C18 50% acetonitrile / 0.1% Tfa, isometric 1.0 ml / min 254 nm Vidak protein and peptide C18 38% acetonitrile / 0.1% Tfa, isometric 1.0 ml / min 254 nanometers Vidak protein and peptide C18 20-40% acetonitrile / 0.1% Tfa, 1.0 ml / min for 24 minutes 254 nm Vidak protein and peptide C18 50% acetonitrile / 0.1% Tfa, isometric --- ^ --- ------- Packing --- (Please read the precautions on the back before filling this page) · .1 Order: This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 69 [ 242441 A7 B7 V. Description of the invention (67)

KLMN Quick Test Column Quick Test Column Quick Test Column Quick Test Column Quick Test Column Flow Detection Ladder Flow Detection Ladder Flow Detection Ladder Flow Detection Ladder Flow Detection Ladder 1.0 ml / min 254 nm (NUCLEOSIL) C18, 5 microns (Alltech Corporation, 2051 Waukegan Road, Luyuan County, Illinois) 40% acetonitrile / 0.1% Tfa, equal angle 1.0 ml / min 254 nm Nucleo Leo C18, 5 microns 52% acetonitrile /0.1% Tfa, equal angle 1.0 ml / min 254 亳 μm Nucleo Leo C18, 5 microns 50% acetonitrile / 0.1% Tfa, equal angle 1.0 ml / min 254 nm Nucleo Leo C18, 5 μm 48% acetonitrile /0.1% Tfa, equiangular 1.0 ml / min 254 μm ... Nucleo Leo C18, 5 μm _ (Please read the precautions on the back before filling this page) i Order ---- Line-Intellectual Property of Qin Economic Ministry Bureau of the Consumer Cooperatives printed clothing paper standards applicable to the Chinese National Standard (CNS) A4 (210x297 mm) 70

Claims (1)

1242441 f Jingjing profit scope brother 9 1 1 1 5 0 〇3 patent towel ^ Ann & T Ming patent application scope amendments 1. A need to feed 94 · 8 · 2 animal growth hormone release F-factor receptor agonist, a medicinal composition with the effect of a dagger-resistant anti-Flying dagger, J: an effective amount of a compound of formula ⑴, including a '(V) nir ^ R (cf) m R b * (2) n \ AR5 or its medically acceptable, j where (丨) 〇 sex salt and a medically acceptable carrier ________J printed by the staff member of the Intellectual Property Bureau of the Ministry of Economic Affairs ¾ 2 · γ is TrPm [Lys-Abu; Z is Gly; n is 0 to m at each occurrence; a is Η; b is OH; R1 is Η; R2 is phenylfluorenyl; R3 is substituted with alkoxy; R4 is Η; and R5 is Η. 5, but η cannot be 0 at the same time; the base;-, mammals are required to elicit factor receptor agonists phantoms ... 丨 々 Changshodin release inhibition is called a pharmaceutical combination of several effects. Sixth, the Intellectual Property Bureau of the Ministry of Economic Affairs, the Consumer Cooperative Cooperative Print 1242441, the scope of application for a patent, an effective amount of the compound of formula (II), X4—mn- ^ Rl X3 R2 ^ > N 3 丨 2 f (弋 上 R4 X— (Z) n ^ R5 〇 (II) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, wherein Y is PheU /; Z is Gly, Abu or Ahx; η is 1; m is 0; R 丨 is Η • R2 is benzyl; R is fluorene, C μ alkyl or phenyl, the phenyl is unsubstituted or substituted by a methoxy or hydroxyl; R4 is Η; R5 is Η; X1 is Phe, Trp , Tyr or Tyr (OBzl); X. is D-Ti, p; (·; X '' is Lys; X is Val, Thr, Thr (OBzl), Abu, Tyr, Tyr substituted by Bzl or OBzl, Or Nal. No paper rule. Ruler. 'Another: ⑷Η 千' said 舀 家 捽 半 (CNS) A · ·; specifications (2j〇297. Male) 1 ^ 11,1 ----- «· install- --ΊΤ1 Order --------- (Please note the back of 83 technology before filling this page)