TW458958B - Compound with growth hormone releasing properties - Google Patents

Abstract

Compounds of the formula A-B-C-D(E)<p> are used to stimulate the release of growth hormone from the pituitary. A compound of general formula I A-B-C-D-(-E)p, wherein p is 0 or 1; A is hydrogen or R1-(CH2)q-(X)r-(CH2)s-CO-, wherein q is 0 or 1; r is 0 or 1; s is 0; R1 is piperidino or N(R2)-R3, wherein each of R2 and R3 is independently hydrogen or lower alkyl; and X, when r is 1, is -C(R16)(R17)-, wherein each of R16 and R17 is independently lower alkyl; B is (G)t-(H)u wherein each of t and u independently is 0 or 1; G and H are amino acid residues selected from the group consisting of natural L-amino acids or their corresponding D-isomers such as His or Ala, or non-natural amino acids such as amino-isobutyric acid, 3-aminomethylbenzoic acid, nipecotic acid or iso-nipecotic acid; C is a D-amino acid of formula -NH-CH((CH2)W-R4)-CO- wherein W is 1, and R4 is selected from the group consisting of D, when p is 1, is a D-amino acid of formula -NR20-CH((CH2)k-R5)-CO- or, when p is 0, D is -NR20-CH((CH2)k-R5)-CH2-R6 or -NR20-CH((CH2)m-R5)-COR6, wherein k is 1; I is 1; m is 1; R20 is selected from the group consisting of lower alkyl; R5 is selected from the group consisting of each of which is optionally substituted with halogen, and R6 is -OH or -N(R7)-R8, wherein each of R7 and R8 is independently hydrogen or lower alkyl; E, when p is 1, is -NH-CH(R10)-(CH2)v-R9, wherein v is 0 or an integer selected from the group; 1, 2, 3, 4; R9 is hydrogen, morpholino, -N(R11)-R12, wherein n is 0, and R19 is hydrogen or lower alkyl, each of R11 and R12 is independently hydrogen or lower alkyl, and R10, when p is 1, is selected from the group consisting of H or -CO-R13, wherein R13 is -N(R14)-R15, wherein each of R14 and R15 is hydrogen; all amide bonds within formula I with the exception of the bond between C and D may independently be replaced by -Y-NR18-, wherein Y is -CO-, and R18 is hydrogen, lower alkyl; or a pharmaceutically acceptable salt thereof; and with the exception of the compounds, (3-aminomethylbenzoyl)-D-2Nal-N-Me-D-Phe-Lys-NH2, H-Aib-His-D-2Nal-N-Me-D-Phe-Lys-NH2, H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH2, 3-(H-Aib-His-D-2Nal-N-Me-D-Phe-NH)-1-morpholinopropane, 2-(H-Aib-His-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl)ethane, ((3R)-piperidinecarbonyl)-N-Me-D-2Nal-N-Me-D-Phe-Lys-NH2, 3-((3-aminomethylbenzoyl)-D-2Nal-N-Me-D-Phe-NH)1-morpholinopropane, 2-(H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl)ethane, 2-(((3R)-piperidinecarbonyl)-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl)ethane, 2-((3-aminomethylbenzoyl)-N-Me-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl)ethane, 3-(H-Aib-His-N-Me-D-2Nal-N-Me-D-Phe-NH)-1-morpholinopropane, 3-(((3R)-piperidinecarbonyl)-N-Me-D-2Nal-N-Me-D-Phe-NH)-1-morpholinopropane, 3-((3-aminomethylbenzoyl)-N-Me-D-2Nal-N-Me-D-Phe-NH)-1-morpholinopropane, 2-((3-aminomethylbenzoyl)-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl)ethane, 2-(((3R)piperidinecarbonyl)-D-2Nal-N-Me-D-Phe-NH)-(1-methyl-2-pyrrolidinyl)ethane.

Description

Printed by the Central Bureau of quasi-Ministry of Economic Affairs, Shellfish Consumer Cooperative Co., Ltd. 458958 A7 ΒΊ_ V. Description of the invention (ί) Scope of the invention The present invention is related to novel peptide derivatives. The use of overdose disorders due to growth hormone deficiency. BACKGROUND OF THE INVENTION Somatotropin is a hormone that stimulates growth of all tissues that can grow. In addition, somatotropin is known to have multiple effects on metabolic pathways * For example, it stimulates protein synthesis and sleep fatty acid fixation and causes energy metabolism to change from carbohydrates to fatty acid metabolism. Lack of growth hormone can cause many serious medical disorders, such as dwarfism. Hormones are released from the inferior glands. The release is tightly controlled either directly or indirectly via hormones and neurotransmitting substances. Growth hormone release can be stimulated via growth hormone release hormone (GHRH) and inhibited through growth hormone release inhibitory factors (somat t sta t i η). In both cases, the hormone is released from the hypothalamus, but its effect is mainly through a specific receptor located in the hypothalamus plus K mediator. Other compounds that stimulate growth hormone release from the sub-brain gland have been described. For example, arginine, L-3, 4 ~ dihydroxyphenylalanine (L-Dopa), glycemic hormone, vasopressin, PACAP (subadenosine adenylate cyclase activating peptide), This paper size applies to China National Standards (CNS) A4 (210X297 mm) ------------ ά ------ it ------ (Please read the back first Please pay attention to this page and fill in this page again) Consumption Cooperation between Employees of the Central Bureau of the Ministry of Economic Affairs of the People ’s Republic of China Du Yincha Λ 5 895 8 Α7 _Β7 _ V. Description of the invention Γν) Buscarinic receptor activator and a synthetic hexapeptide, GHRP (growth hormone-releasing peptide) can release endogenous growth hormone by directly affecting the hypothalamus or by affecting the release of GHRH and / or somatostatin from the hypothalamus. In disorders or situations where it is desired to increase the level of growth hormone, the protein properties of growth hormone must be administered in the intestine. Furthermore, other natural secretagogues, such as GHRH and PACAP, are relatively large molecular weight polypeptides. For this reason, parenteral administration is preferred. The use of short peptides to increase growth hormone levels in mammals has been previously proposed, for example in EP 1 8 0 7 2, EP 83 864 * W0 89/07110, W0 89 / 01711- W0 89/10933, W0 88 / 9780 ， W0 8 3/0 2 2 7 2 * W0 9 1/1 80 1 6 ， W0 9 2/0 1 7 1 1 and WO 9 3/0 4 0 8 1 ° Growth hormone releasing peptides or peptide derivatives The structure of the substance is important for the growth hormone release efficiency and its bioavailability. It is therefore an object of the present invention to provide novel peptides having somatogenesis-releasing properties which have improved properties relative to known peptides of this type. Summary of the invention This paper is applicable to China National Standards (CNS) Α4 size (2 丨 0X297 mm) ------- r ——- installation ------ order ------ line (Please read the note on the back before filling out this page) 9,95 8 Α7 Β7 V. Description of the invention (&gt;) Compound of general formula I

A— B — C— D (— Ε) ρ I where P is 0 or 1; A is hydrogen or R1 — (CH2) q- (X) r — (CB2) s — CO-, where q is 0 or select An integer from the following group: 1, 2, 3, 4, 5; r is ί) or 1; S is 0 or an integer selected from the following sister: 1, 2, 3, 4, 5; R1 is hydrogen, Oxazolyl, guanidino * donazinyl, morpholinyl, donidinyl or N (R2) -R3 * wherein R2 and R3 are independently hydrogen or optionally via one or more hydroxyl, pyridyl or peptide Lower alkyl groups substituted by alkynyl groups; and X, when Γ is 1, is ΝΗ-, -CH2-,-CH = CH-, -5- This paper standard applies to China National Standards (CNS) A4 specification (210X297 mm) ...... I nn --1---4---- ϋ----Order · · ........ (Please read the precautions on the back first (Fill in this page) Printed by the Consumers' Cooperatives of the Central Procurement Bureau of the Ministry of Economic Affairs 458958 A7 B7 V. Description of the invention (

C (R R1 7) from .A _zhong

Where R1. And R1 7th independently are hydrogen or lower alkyl, B is (G) t- (H) u where t and u are each independently 0 or 1; G and Η are selected from a group of natural L-amines Amino acid or its corresponding D-isomer amino acid residue, or a non-natural amino acid such as 1,4-diaminobutyric acid, amino-isobutyric acid, 1,3 ** diamine Propanoic acid, 4-monoaminobenzylalanine, 3-pyridylalanine, 1,2,3,4-tetrahydroisoquinoline 3-carboxylic acid, 1,2,3,4-tetrazolidine Nor harman 3-carboxylic acid, N-methylaminoanilic acid, aminanilic acid, N-benzylglycine, 3-aminomethylbenzoic acid * 3-aminomethyl 3-methyl Butyric acid, sarcosinic acid, nalidic acid or isopiperidic acid; and where t and u are both amine bonds with hydrazone -------- k .-- (please first Read the notes on the reverse side and fill out this page) -5 —line. The shellfish consumer cooperative of the Central Bureau of Standards of the Ministry of Economy has printed it selectively-NR 1 s one is replaced, where Y is _ C 〇 1 or CH 2 and Ri 3 is hydrogen, and the lower fluorenyl or lower aralkyl C is D of the formula NH — CH ((CH2) w — I? 4.)-C0 — Amino acids of which -6- This paper is scaled to the size of China National Cricket (CNS) A4 (210X 297 gong) Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4 5 895 8 A7 B7 V. Description of the invention (tr ) w is G, 1 or 2; and R4 is selected from the group consisting of

They are each optionally substituted with halogen, lower alkyl, lower alkyl, lower alkylamino, amine or hydroxyl plus M; D, when P is 1, * is formula 1 NR2 0-CH ((CH2) k-Rs) -CO- of D-amino acid or, when P is 0, D is -NRZ 0 — CH ((CH2) 1—) ~ C Η 2 — R6 or- NR2 0-CH ((CH2) m— R5)-C0-R6, where k is 0, 1 or 2; 1 is 0, 1 or 2; This paper uses the Chinese National Standard (CNS) A4 specification (210X297) Li) -------- Raid ------ iT ------ Φ, (Please read the precautions on the back before filling out this page) 45 895 8 Employees of the Central Procurement Bureau of the Ministry of Economic Affairs Cooperative printed A7 B7 V. Description of the invention (（) ill is 0, 1 or 2; R2 ° is a group of self-contained lower alkyl groups or lower aralkyl groups &gt;

Rs is a group selected from the group consisting of ρ, Pl I χο, ~, which are each optionally substituted with halogen, lower alkyl, lower alkyloxy, amine or hydroxyl plus K; and R6 Is morphazinyl, morpholinyl, imididinyl, —0Η or —N (R7)-Ji 8 · where R7 and R 8 are independently hydrogen or lower alkyl; Ε, when ρ is 1, it is one NH— CH (R 1) — (CHZ) ν— R 3, where V is 0 or choose an integer of the next group: 1, 2, 3, 4 '5' 6, 7, 8; R9 is hydrogen, Oxazolyl, fluorenyl, piperazinyl, morpholinyl, morphinyl, -NCR1 1) -R12--8- This paper size applies to China National Standards (CNS) A4 specifications (210 X 297 mm &gt; II nn II Order II ί I — Line (please read the notes on the back before filling this page) 458958 A7 B7 V. Description of the invention ((CH2) n

N I R or 19 where η is 0, 1 or 2 'and R1 9 is hydrogen or lower alkyl'

R 11

R 11 (CH2) 0—N 312 where 0 is an integer selected from the group of M: 1 ·

Vx ^ (CH2) 0— 'α r12 R1 1 and R1 2 are each independently hydrogen or lower alkyl, or

The Ministry of Economic Affairs, Central Bureau of Standards, Work and Consumption Cooperation Du Du printed its individual via selective halogen * lower alkyl, lower alkyloxy, amine, alkylamine, hydroxyl, or derived from amine Group and hexacyclohexose or hexacyclohexosyl-Amadori recombination product of hexacyclohexose plus W to replace denier R1 0, when P is 1, to select self-contained one H, one C00H, one CHz-R1 3 ' _C0— R1 3 or one of CHz ~ 〇H ', where R1 3 is piperazinyl, manganyl, oxidyl, 0H or ~ N (R1 -9 This paper standard applies Chinese National Standard (CNS) A4 Specifications (210 X 297 male shame) IH ^ I n I line (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs 4b 895 8 A7 B7 V. Description of the invention (t) 4) — R1 5, wherein R i 4 and E are each independently hydrogen or lower alkyl; all amine bonds in formula I, except for the bond between C and D, can be independently passed through a Y ™ NR 1 8 _ is substituted, wherein Y is a C0-or a CIU —, and R1 8 is S, a lower alkyl group or a lower aralkyl group; or a pharmaceutically acceptable salt thereof; the following Except for compounds (3-aminomethylbenzylmethyl) -D-2 N a 1-N-Me- D-P he -Lys- NH2 H- Aib-His- D — 2Nal — N — He — D ~ Phe — Lys — NHz H — Aib — His — N — He — D — 2Nal — N — Me — D — Phe — Lys -NHz 3- (H-Aib-His-D-2Nal-N- Me-D- Phe-NH) 1 1 morpholinyl propane 2 — (Η — Aib — His ~ D — 2Nal — N — Me — D — Phe — ίί) — 2 — (1 monomethyl-2 —pyrrolidinyl) ethyl Ethane-1 0-This paper size applies to China National Standard (CNS) Α4 size (210 × 297 cm) -------- ^ ------ 1Τ ------ Φ (Please read the back first Please note this page, please fill in this page) Printed by the Consumers' Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs β 9 5 8 Α7 Β7 V. Description of Invention (p)

((3 R) —Donton steep basis) —N — Me — D-2Nal — N — Me — D -Phe- Lys- NHZ

3- ((3-Aminomethylbenzylidene) -D-2Nai-N-He-D-Phe-NH)-1-morpholinylpropane 2- (H-Aib-His-N-Me- D — 2fial — N—Me — D — Phe —NH)-1-(1 —Methyl-2 —Pyridinyl) ethane 2- (((3R) —Neridinecarbonyl) —N-He—D — 2Nal-N-

Me- D- Phe-NH) — 1 mono (1-methylmonopyrrolidinyl) ethane 2-((3-aminomethylbenzylidene) -N — M e — D — 2 fJ a 1-—Me- D— Phe— NH) — 1 mono (1 —methyl_ 2 -pyrrolidine 棊) ethane 3 — (H — Aib — His — N — Me — D — 2Nal — N — Μθ — D — Phe —NH) — 1 — Do you ask Ji Bingyuan to install -------- IT ------ # (Please read the precautions on the back before filling this page) A7 458958 ΒΊ_ V. Description of the invention (丨 〇)

3— ((. 3 -aminomethylbenzyl) &gt; -N- Me-D-2Nal — N —Me — D — Phe — NH) — 1 —Morinyl Houses 2- ((3 — Aminomethylbenzylidene) -D-2Nal-N—Me— D -Phe- NH) -1 — (1 —formamidine-2 —pyrrolidinyl) ethane 2- (((3R) pyridine Carbonyl) -D- 2Nal- N- He- D- Phe-NH)-1- (1-methyl-2-pyrrolidinyl) ethane. Peptide derivatives of formula I for proteolytic degradation of enzymes 圼Improved resistance * because the adjacent D-amino acid in the peptide sequence is optionally accompanied by a substituted amine bond (_CO-NH-) such as amine, such as amine Modification of methylidene (-CH2-NH-), and / or the N- or C-terminus of the peptide terminus. Increased bioavailability of peptide derivatives of the present invention * as suggested in the prior art In comparison, peptides are considered to be caused by the combination of resistance to proteolytic degradation and small size. In the structural formula M on K and throughout this specification, proper nouns under M have indications Significance: the lower alkane referred to above The group is intended to include linear or branched or cyclic configurations of alkyl groups with a design length, preferably from 1 to 6 -12- This paper size applies to the Chinese Standard (CNS) A4 (210 X 297 cm) (Li) -------- ¾ ------ 1T ------ ^ (Please read the notes on the back before filling out this page) Central Standards Bureau, Ministry of Economic Affairs, Consumer Cooperatives, Printing Economy Ministry of Economics and Standards Bureau of the People's Republic of China Consumer Cooperatives 4 5 8 9 5 8 A7 B7 V. Description of the invention () carbon atom. Examples of linear alkyl groups are methyl, ethyl, propyl • butyl, pentyl, Examples of branched alkyl groups are isopropyl, second to butyl * third monobutyl, isopentyl, and isohexyl. Examples of fluorene-like alkyl groups are cyclopropyl * ring Butyl, cyclopentyl and cyclohexyl. The above-mentioned lower alkoxy groups are intended to include linear or branched or cyclic configurations of alkoxy groups of design length, preferably having 1 to 6 carbons Atoms. Examples of linear alkoxy are methoxy, ethoxy, propoxy, butoxy, pentoxy | and hexyloxy. Examples of branched alkoxy are isopropyl Oxygen, second to butoxy, tertiary butoxy, isoamyloxy * and isohexyloxy. Examples of cyclic alkane groups are cyclopropyloxy, cyclobutyloxy, cyclopentyloxy And cyclohexyloxy. The above-mentioned lower alkylamine groups are intended to include linear or branched or cyclic configurations of alkylamine groups of designed length, preferably having 1 to 6 carbon atoms. Straight Examples of type alkylamino groups are methylamino, ethylamino, propylamino, butylamino, pentylamino, and hexylamino. Yellow examples of branched alkylamino groups are isopropylamino, second-butylamino, third-butylamino, isoamylamino, and isohexylamino. Examples of cyclic alkylamino groups are cyclopropylamino, cyclobutylamino, cyclopentylamino and cyclohexylamino. In this article &lt; proprietary term &quot; aryl &quot; intends to contain aromatic rings, -13- This paper size is applicable to China National Standard (CNS) A4 size (210X 297 cm) (Please read the first Note: Please fill in this page again) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 4 5 8 9 5 8 Α7 Β7 V. Description of the invention (/ w Such as carbocyclic and heterocyclic aromatic rings, which are selected from the group consisting of Phenyl, naphthyl,

Bt pyridyl * 1-H-tetrazol-5-yl, oxazolyl, oxazolyl, indoxyl 1 pyrimidinyl, pyrazolyl, pyrazolyl, isoxazolyl, isoxazolyl, thiophene Group, quinolinyl, pyrazinyl, or isothiazolyl, which is optionally substituted via one or more ec t_alkyl, Cl-alkanoyl, halogen, amine, or aryl groups. Aryl preference is phenyl * sialyl, oxazolyl, pyridyl, indolyl, quinoline or naphthyl, which is optionally via halogen, amine, hydroxyl, Ci ~ alkyl or C! _6 — Alkoxy substituted

C The above-mentioned lower aralkyl group is composed of a lower alkyl group and an aryl group, wherein the lower alkyl group and the aryl group are as defined above. The proper term &quot; halogen &quot; is intended to include C1, F, B r and I. Common three-letter codes are used for natural amino acids, such as Ala for alanine. Detailed description of the invention In the specific matter of preference of the formula lib compound, A is hydrogen, 3_N-Me-AMB, 3-AMB or Aib. When t is 1, the preference of G in the compound of formula I is Ala, Gly, sarcosinate, 3-aminomethyl benzyl, ϋ -14- This paper size applies to China National Standard (CNS) A4 specification (210X297 Mm) Order I-m I (please read the note on the back before filling this page) 4 5 895 8 A7 __B7_ V. Description of the Invention (丨)) A meal of nicoticotinyl, iridoidic acid or isopropyl Piperidinecarboxylic acid, more preferably 3-aminomethylbenzyl, R- # pyridylcarboxylate (nipecotinyl), 1,2 formic acid or isotonic acid. When u is 1, the fi preference is His, Phe * Tic, Phe (4-NH2) 3 — Pya 1 1 iHy, Ala, Sar, Pro, Tyr &gt; Arg, 0 rn-3 -aminomethylbenzoic acid Or D—Phe, prefer H for His, Phe or Ala, and most prefer H for His or Ala. In the compounds of formula I, C prefers D-2 -naphthylalanine (D-2Mal), D-1 -alanyl alanine (D-INal), D-Phe or D-Trp, more preferably D-2Nal or D-Phe and the preference is N — He — D — 2 N a 1 &gt; D — 2 S a 1 »D — Phe, 5¾ N — Me — D —

Phe. In the compounds of formula I, D preference is -NR2 ° — CH ((CH2) k— R 5) — c0_ *, where k preference is 1 and R2. Is a lower alkyl group, and D is more preferably D-Phe or D-2Nal. The most preferred D is N-Me-D — Phe — leaven, (ΐ — Me — D — Phe N — Me — D — 2Nal — leaven 'N — Me — D — Phe — NH2, N — He — D — Phe— NH—Me &gt; or N — Me — D-(4-1) Phe-NB — Me ° When P is 1 in the compound of formula I, E prefers Lys-NH2, Ser — NH2, NH — (2— ( 1-donazinyl) ethyl), NH- (3- (1-morpholinyl) propyl), NH- (2-aminoethyl), NH- (4-aminomethylbenzyl), NH- (benzyl); Lys — OH, NH — (1-hydroxy-6-amino- 2S-hexyl), NH- (2- (1-methyl-2-pyrrolidinyl) ethyl), or 3— N, N -dimethyl monoaminopropyl-1 5- This paper size is applicable to China National Standard (CNS) A4 specification (2 丨 〇Χ2ί &gt; 7 mm) -------- Raid- ------ II ------. ^ (Please read the precautions on the back before filling out this page) Printed by the Consumer Standards Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Central Standards Bureau of the Ministry of Economic Affairs Printed by the Bayer Consumer Cooperatives 458958 A7 B7 V. Description of the invention (/ f), the most preferred E is NH— (2 _ (1 _methyl- 2-pyrrolidinyl) ethyl), 3-N Ν-dimethyl-aminopropyl, Lys-ΝΗ2, or Ser-NH2 or a compound of formula I, R4 prefers 2-naphthyl. R5 prefers phenyl. ¥ prefers 2 to 6, and R9 is NΗ2. 2 —Moryl ethyl, 3 -morpholinylpropyl or (丨 methylpyrrolidinyl) ethyl «preferred to —C Ο Ο Η» — CH2 _〇Η, — Η *-CONH2 or —CON (CHs) 2 An example of a special compound of the present invention is (2R) — 2- ((3-aminomethylbenzyl))-N—He — D-2Nal-(j-Me) — 3 — (2 —Czech) Propanol:

(3 -Aminomethylbenzylidene) -N-He-D-2Nal— N-Me-D-Phe- NHz: -1 6- This paper size is applicable to Chinese Standard (CNS) A4 (210X297) (Mm) -------- install ------ iT ------ ^ (Please read the notes on the back before filling this page) 458958 A7 B7 V. Description of the invention (Μ) 〇 I CH, ο 3-((3 -aminomethylbenzyl:)-N-Me- D-2Nal-NMe D- Phe- NH) -N, S -dimethylaminopropane: (Please read first (Notes on the back then fill out this page)

Printed by the Shellfish Consumer Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs (3-Aminomethylbenzyl) -N-Me-D- 2Nal — N-He D-Phe-Lys-KHz:

-17-

This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 458958 A7 B7 V. Description of the invention (/ fe) H—Aib ^ Ala — D — 2Nal — N — Me — D — Phe — Lys — NHz H_ Aib — His ~~ i) — 2Nal — N — Me — D_ Phe — NHz 2 — ((3-aminomethylbenzyl) _N ™ Me-D— 2Nal

Me— D— Phe-NH) — 1 monomorphoethane:

(Please read the notes on the back before filling out this page) 〇 (3-Aminomethylbenzyl) -N—Me— D — 2Nal-N-Me D- Phe- NH- Me

Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China 3— ((3-methylaminomethylbenzyl) -N-Me-D—2Nal-K-Me-D-Phe-NH) —N, N-Dimethylaminopropane: -18- This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 5 895 8 A7 B7 Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

(3-Aminomethylbenzyl) -N- Me-D — 2Nal— N-Me —D-Phe-K- He 2.

H-Aib-His-N-Me-D-2Nal-fi-Me- D-Phe NHMe:

3-Methylaminomethyl-Nate- D — 2Nal— Nme = D — Phe — NH CH3 -19- This paper size applies to China National Standard (CNS) A4 specification {210 X 297 mm). Order line ( Please read the notes on the back before filling this page) 458958 A7 B7 V. Description of the invention (

Methylaminomethylamidino) _2 — (2 —Czeky) ethyl) -N-methylamidamine

Structure of unnatural amino acid residues: D 2Nal

Alb {Please read the notes on the back before filling out this page) Printed by the Consumers ’Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs

0

3Pyal N

Tic

Abbreviation used for the substitution of peptide -20-20- This paper size is applicable to the Chinese National Standard (CNS) AA specification (210X297 mm) 45 895 8 A7 B7 Printed by the Consumer Cooperatives of the Central Government Bureau of the Ministry of Economic Affairs v /) -N-Me ~ Ο

Compounds of formula I can be prepared via conventional methods of solution or solid phase peptide synthesis. For example, solid-phase synthesis can basically be performed as described by Stewart and Young, Solid Phase Peptide Synthesis, Second Edition, Rockford, Illinois * USA · 1 976. Solution peptide synthesis can basically be performed, for example, as described by Bodansky et al. * Peptide Synthesis' Second Edition, New York-USA, 1976. The substituted amine bond aminomethylene can be incorporated according to the method described in Y. Sasaki and D.H, Coy-Peptides 8 (1)-1987, pages 119-121. Peptide derivatives containing single or hexacyclohexose-derived amine groups can be substantially described via R. Albert et al. * Life Sciences 53, 1 9 9 3 '5 1 7-5 2 5 Way to

Amador i was prepared recombinantly. Examples of suitable mono- or hexacyclohexoses are glucose * galactose, maltose, lactose or cellobiose. Derivatives used as starting materials in the synthesis can be purchased from commercial products and provided with appropriate protective groups plus K when needed, or used in general formula I to prepare the starting materials for the 〃 A 〃 group. Well-known methods are prepared and selectively protected in a manner known per se. ~ 2 1-This paper size is in accordance with Chinese National Standard (CNS) A4 specification (210X25 »7mm) 'I line (please read the notes on the back before filling in this I) 458958 A7 B7 V. Description of the invention (&gt; A) Abbreviations used for protecting groups: Trt- _ Dod- Bom

The pharmaceutically acceptable acid addition salts of the Si 彳 b complex include lithium prepared by reacting the peptide with an inorganic or organic acid, such as hydrochloric acid'hydroxamic acid, sulfuric acid, and acetic acid. , O-acid, lactic acid, maleic acid, peptidic acid, glutamic acid, glutaric acid, gluconic acid, methanesulfonic acid, salicylic acid, succinic acid 'tartaric acid, oxalic acid, toluenesulfonic acid, trifluoroacetic acid, amines Sulfonic acid and fumaric acid. ^^ 1 ^^^ 1 In In m 1 ^ 1 HI w · (Please read the precautions on the back before filling out this page) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs On the other hand, the present invention is related to »s in A medical composition comprising, as an active ingredient, a compound of the general formula I or its pharmaceutically acceptable ffi M and a pharmaceutically acceptable carrier or diluent. Pharmaceutical products containing the compounds of the present invention can be prepared by conventional techniques *, for example, as described in Remington's Pharmaceutical Sciences * 1985. The composition can be presented in conventional forms, such as capsules, tablets, sprays, solutions, suspensions, patches or topical applications. -22- The size of this paper applies to Chinese National Standard (CNS) A4 (2 丨 0 X m mm) Printed by the Consumers' Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 8y 5 8 A7 B7 V. Description of the invention The agent or diluent may be a conventional solid or liquid warm carrier. Examples of solid carriers are lactose, stone powder, sucrose, cyclodextrin, talc, gelatin, agar, pectin, gum arabic, magnesium stearate, stearic acid or lower androgen Alkyl ethers. Examples of liquid carriers are syrup • peanut oil, olive oil, butter fat, fatty acids, fatty acid amines, polyethylene oxide and water. Likewise * the carrier or diluent can include any reading-release material known in the art, such as glyceryl monostearate or glyceryl distearate, which is present alone or mixed with wax . When a solid carrier is used for oral administration • The formulation may be tabletted, in powder or precipitated form in a hard gelatin capsule or it may be in the form of a troche or tablet. The amount of solid carrier will vary greatly but is usually from about 25 mg to about 1 g. A typical lozenge prepared by traditional tablettiug techniques may include: Core: Active compound (is a compound or its salt) 1〇 [) mg colloidal silica (Aerosil) 1.5 mg-2-this Paper size applies Chinese National Standard (CNS) Α4 specification (210X297 mm) -------- Λ ------ ΐτ ------ ^ (Please read the notes on the back before filling This page) 4b 89b 8 A7 B7 V. Description of the invention (1 cellulose, microcrystalline (A vice 1) modified cellulose gum (Ac-Di-Sol) magnesium stearate 70 mg. 5 mg

Covering: HPMC * Mywacett 9-40 T, about 3 watts, about 0.9 gram, printed by the Central Labor Bureau of the Ministry of Economic Affairs, printed by Shellfish Consumer Cooperative * * Glycerol monolayer is used as a plasticizer for thin coating. When a liquid carrier is used, the preparation may be in the form of a syrup, emulsion, soft gelatin capsule or sterile injectable liquid, such as an aqueous or non-aqueous liquid suspension or solution. For classical cavity or pulmonary administration, the formulation may comprise a compound of formula I dissolved or floated in a carcass carrier, particularly an aqueous carrier, such as for spray application. The carrier may contain additives such as ribosolvents such as propylene glycol, surfactants such as cholates * polyethylene glycols or polyoxyethylene higher enzyme ethers * absorption Accelerators such as lecithin (phospholipidylcholine) or cyclodextrin, or preservatives such as parabenes. For transdermal application, the preparation can be in a form suitable for patch or iontophoresis * 24 This paper size applies the Chinese National Standard (CNS) A4 specification (210X297 mm) -------- Attack- ---- ΪΤ ------ ^ (Please read the notes on the back before filling this page) 4 5 895 8 a7 B7 V. Description of the invention (v &quot; j) Generally, the compounds of the present invention The dosage form is divided into parts, which include 0.00 D1 to 100 mg of active ingredient per unit dose and a pharmaceutically acceptable carrier. When administered to a patient, such as a human, as a medicament, the agent of the compound of the present invention is most suitably 1-50 Qg / day, for example, about 100 dg per dose. The compounds of general formula I have been shown to have the ability to release endogenous growth hormones in vivo. This class of compounds can therefore be used to treat conditions that require elevated plasma growth hormone levels, for example in patients with growth hormone deficiency or in elderly patients or livestock. Therefore, in a particular aspect, the present invention relates to a saponin drug composition K for release of stimulating growth hormone from the hypothalamus, the composition comprising a compound of the general formula I or a pharmaceutically acceptable salt thereof M and K are pharmaceutically acceptable carriers or diluents as active ingredients. In a further aspect, the present invention relates to a method for stimulating the release of growth hormone from the hypothalamus, which method comprises administering an effective amount of a compound of formula I or a pharmaceutically acceptable salt thereof to a subject in need thereof . This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) ----------------- 1T ------ line (please read the precautions on the back before filling (This page) Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives. Printed by the Central Government of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives. Du Printed 45 895 8 at B7 V. Description of the invention (&gt; 4) In a further aspect * This invention is related Use of a compound of the general formula I or an acceptable lavatory on it for the preparation of a drug for stimulating the release of growth hormone from the inferior gland. The compounds of formula I have interesting physiological properties. An example of this property is the release of stimulating growth hormone from the sub-brain gland, which has a similar effect or use as growth hormone itself. The use of growth hormone can be summarized as follows: stimulate the release of growth hormone in the elderly; prevent the metabolic side effects of glucocorticoids, the treatment of osteoporosis, stimulate the immune system, accelerate wound healing, accelerate #fold recovery, Treatment of dysphoria, renal failure or insufficiency caused by delayed growth, physiological shortness, including growth hormone deficient children and short form associated with chronic diseases, treatment of obesity and obesity-related Growth Chi Yuan * Treats growth retardation related to Prader-Willi syndrome and Turner's syndrome; accelerates recovery of patients with sunburn and reduces hospitalization time; treats growth retardation in the uterus, skeletal dysplasia, hyperfunction of epithelium Cushing's syndrome; induces pulsatile growth hormone release; restores growth hormone in stressed patients, treats osteochondral dysplasia, Noonan's syndrome, schizophrenia, depression, Alzheimer's disease * delayed wound healing and Psychosocial dissociation, treatment of pulmonary function loss and respirator dependence, reduction after major surgery Proteolytic response, reducing anorexia and protein loss due to chronic diseases such as cancer or AIDS; treatment of hyperinsulinemia * including adjuvant treatment of islet blast proliferation, ovulation promotion; stimulation of thymus development and preparation Paper size applies to China's National Standard (CNS) A4 specification (210 X 297 mm) in— binding III line {please read the note on the back before filling out this page) Printed by the Central Ministry of Economic Affairs of the Ministry of Economic Affairs for consumer cooperation 4 5 3 9 5 8 A7 B7 V. Description of the invention &lt;) Prevent age-related decline of thymus function, treat immunosuppressed patients, muscle strength, exercise change * maintain skin thickness, metabolic stability, debilitating old age Human constancy * stimulates osteoblasts, bone reconstruction and cartilage growth, stimulates the pet's immune system and treats aging disorders of pets, promotes breeding of livestock and stimulates wool growth of sheep. For such stresses, the dosage will depend on the compound of formula I used, the mode of administration and the desired treatment. However, usually daily dose levels ranging from 0.1 to 100 mg / kg body weight are administered to patients and animals to obtain effective release of endogenous growth hormone. In general, dosage forms suitable for oral or nasal administration include from about 0.00 mg to about 100 mg mixed with a pharmaceutically acceptable carrier or diluent, with preference from about 0.001 gram to about 50 mg of a compound of formula I. The compounds of formula I may be administered in the form of pharmaceutically acceptable acid addition salts or, where appropriate, in the form of alkali metal or alkaline earth metal or lower alkyl ammonium. This salt form is believed to exhibit approximately the same level of activity as the free base form. Alternatively, the pharmaceutical composition of the present invention may include a compound of formula I in combination with one or more compounds exhibiting different activities, for example, in combination with an antibiotic or other medically active substance. This may be another secretagogue, such as GHR1 (1 or 6) or GHRH or this paper ruler and applicable China National Standard (CNS &gt; A4 size (210X297 mm) -------- 'Pack-C Please read the notes on the back before filling this page) Thread A7 d5 895 8 _B7_ V. Description of the invention (7 L) its analogues, growth hormone or its analogues or soaatonedin * Such as IGF-1 or IGF-2. The route for pickling can be any route that effectively transports the active compound to a suitable or desired site of action, such as oral, nasal, pulmonary, percutaneous or parenteral administration, with the oral route being preferred. In addition to the medicinal use of compounds of formula I, they can be used as useful in vitro tools to study the regulation of growth hormone release. Out ability. For example, serum samples taken before or after the application of these compounds to humans can be tested for growth hormone. Comparing growth hormone in each serum sample can directly determine the ability of the patient's subgland to release growth hormone. Compounds of formula I can be applied to commercially important animals to increase their growth rate and extent, and to increase milk production. Pharmacological methods The compounds of formula I can be used to evaluate the effect and ability of somatotrophin release in primary rat somatotroph cells in vitro-28 * This paper size applies Chinese National Standard (CNS) A4 specifications ( 2 丨 0X297 public address) I 1-^ n H &lt; line (please read the precautions on the back before filling this page) Printed by A7 Λ5 B958 B7 of the Central Labor Bureau of the Ministry of Economic Affairs, Consumer Cooperative __ V. Description of the invention ( y /) evaluation. Somatotrophs in rats can basically be prepared as previously described (Chen et al., Endocrinology 1991, 129, 3337-3342 and Chen et al., Endocrinology 1989, 124 * 2791-2798). Simply put * Rat K is beheaded and killed. The underbrain glands are quickly removed. The hypothalamus was cut with 0.2% collagenase and 0.2% hyaluronidase in Hanks' balanced salt solution. Shed cells were resuspended in Dulbecco's Modified Eagle's Peigang Foundation, which contained 0.37% sodium bicarbonate * 10% horse serum, 2, 5% fetal bovine serum, 1% non-essential amino acids * 1% Glutamate M and 1% penicillin / streptavidin * and adjusted to 1.5 X 1D5 cells / ml. Prior to performing the release experiment, 1 ml of this suspension was placed in each well of a 24-well plate and allowed to stand for 2 to 3 days. On the first day of the experiment, cells were washed twice with K medium containing 25 dim HEPES, pH 7.4 and K twice. Growth hormone release was initiated by adding a medium containing 25 m Η Η E P E S and test compounds. Incubation was performed at 37 C for 15 minutes. The growth hormone released into the culture medium after incubation was measured using a standardized RI Α. Compounds of formula I can be anesthetized female rats with pentobarbital as previously described (Bercu et al. Endocrinology 1991 * 129, 2592— -29- This paper has a Chinese standard (CNS) A4 specification (210 X 297) (Li) -------- d ------ ΐτ ------ φ. (Please read the notes on the back before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economic Affairs, Consumer Cooperatives « A7 458958 B7__ V. Description of the invention In 2598), their in vivo effects on the release of growth hormone are evaluated. fg alone, male mature Sprague-Dawley rats were anesthetized with pentobarbital in an intraperitoneal manner at 50 mg / kg. Rats were fully anesthetized and implanted with tracheal cannulas and catheters in the carotid and jugular veins. After 15 minutes of recovery, blood samples were taken at time 0. Intrarenal hormones were administered intravenously and arterial blood samples were placed on ice for 15 minutes and centrifuged at 12, GGG X g for 2 minutes. The serum was discarded and the amount of auxin was determined using standard RI A. The invention is further described in the examples below, which are in no way intended to limit the scope of the invention as claimed. The compounds prepared in the following examples are K trifluoroacetic acid (TFA) lithium plus K single ion. Example 1 Preparation of 2 (R)-2-((3-aminomethylbenzyl) -N-Me-D-2Nal-N-Me) -3-phenylpropionase

The size of this paper applies to the Chinese Standard (CNS) Α4 size (210 X 297 mm) ---------------- ΐτ ------ 0 (Please read the note on the back first Please fill in this page again) Printed by the Central Standards Bureau of the Ministry of Economy Shellfish Consumer Cooperative A7 458953 _B7_____ V. Description of the invention ('ί) 165.7 mg of Boc-N-Me — D-2Nal-〇H and 165.2 mg of (R) —Methylamino—3 —phenyl-propan-1 1

McKennon * MJ; Meyers5 AIJ Org. Che®. 1993 »58, 3568—71 (Η—N — — Phe — OH Jin Ting® ^ Preparation) and 68.1 g of HOAt were dissolved in 2 ml of DMF and 4 In a mixture of D CM. 11 5 mg of EDAC was added and the mixture was stirred at 0 ° C for 1 hour and then limp at room temperature for 18 hours. After 5Q ml of EtOAc was added, DCK was removed from the mixture using a nitrogen stream, and the resulting mixture was Extraction was performed sequentially with 5% aqueous NaHC0 3, 100 mL 0, 100 mL of 5% aqueous RHS 04 and 1QQ mL of HZ0. The resulting organic phase was dry-refined with Na2S04 and fed into a vacuum on a rotary volatilizer. An oily substance. 50 0 2.6 mg of 3-Boc-aminomethylbenzoic acid was dissolved in 10 ml of DCM by adding 2 drops of DMF ', and then converted to a symmetrical hydrazone by stirring with 191.6 mg of EDAC for 10 minutes. 2 (R)-(Η- N- Me- D- 2Nal- H-

He) — 3 ~ Phenylpropionase 342 microliters of DIEA in 5 ml of DCM was added to this compound and then reacted at room temperature for 20 hours-3 1- This paper is for China 圉Furniture Standard (CNS) A4 Specification (210X297mm) -------- Raid ----- 1T ------ line (please read the precautions on the back before filling this page) Central Government Bureau of the Ministry of Economic Affairs, Industrial and Consumer Cooperatives, A7 458958 B7__ 5. Description of Invention (p). The reaction mixture was then reduced to an oil and redissolved in 50 mL of EtOAc. This solution was sequentially extracted with 5% aqueous Sa HC 0 3 * 1 0 0 ml Hz 〇, 100 ml 5% aqueous OS 0 4 and 100 liters fl 2 〇 Extraction 3 The organic phase produced by Na 2 S04 It was dried and concentrated in a vacuum on a rotary evaporator to an oil. The oil was then dissolved in 4 ml of DCM / TFA 1: 1 and mixed. After 1Q minutes, the mixture was condensed via a stream of nitrogen and the resulting oil was redissolved in 2G ml of 70% CHs CN / 0.03 H HC1 and 480 ml of Η20 was added. The crude product was then purified using semi-preparative HPLC, which was performed 7 times on a 25 a.m. X 250 mm column packed with 7 a C-18 silicone gel, which was adjusted to Η 2 · 5 with 4H H2 S〇4 Pre-equilibration with 28% CH3 CN in 0.05M (NH4) 2 S04 0 The column is used in a gradient of 28% to 38% in 0.05M (ΝΗ4) 2 S04, pH 2_5 CH3CN, K 1G ml / min Elution in 47 minutes at 40¾ and collection in peptide-containing tubes * Dilute with 3 volumes of ϋ and fill into Sep- Pak® C18 (

Waters part.ί: 51910), it was equilibrated with 0.1% TFA plus Μ. The peptide was extracted from Sep-Pak © column using 70% CH3 CN 0.1% TFA and lyophilized and self-extracted with water dilution after dilution -32- The standard of this paper is applicable to China National Standard (CNS) A4 specification (2ΙΟχ297) (Li) -------- install ------ ΐτ ------ ^ (please read the precautions on the back before filling out this page) Printed on 45 89B 8 A7 A7 B7 by the Central Laboratories Bureau of the Ministry of Economic Affairs. 5. Description of the invention (5 丨) The final product obtained by single isolation 0 is analyzed by RP-Η PLC (retention time) and by plasma desorption mass spectrometry. Analysis (molecular mass) to characterize. Mass spectrometry analysis was consistent with the expected structure and was within the experimental error of the method (mass spectrometer 0.9 atomic mass position). RP-HPLC analysis was performed using UV detection at 2 14 rtm and Vydac 218TP54 4.6 mm x 250 mm C-18 silicone column (T he S e ρ parati 〇ns G r 〇up, Hespe I * ia). It was eluted at 4 ml at 1 ml / min. Two different elution conditions were used: A1: The column was used for a 0.1 M (NH4) 2 S04 element balance solution, which was adjusted to pH 2.5 by 4 M H2S04, and 5% CH3 CN was equilibrated and used for the same. A gradient of 5% to 60% Cfh CK in the wash was eluted over a period of 50 minutes. B1: The column is equilibrated with 5% CH3 CN / 0 · 1% TFA / H20 and a gradient of 5% CH3 CN / 0.1% TFA / H20 to 60% CH3 CN / 0.1% TFA / H2 0 in 50 minutes Perform elution. -33- This paper size is applicable to Chinese National Standard (CNS) A4 (210 X 297 mm) Order IIII-Line (Please read the precautions on the back before filling this page) Crack 458958 A / B7 V. Description of the invention (): 0} The residence time of the elution conditions A 1 and B 1 were found to be 29.90 minutes and 31.52 minutes, respectively. Synthesis of 3-Boc-aminomethylbenzoic acid 25 grams of 3-cyanoblylcarboxylic acid was dissolved in 70 ml of 25% NH3 0 and 200 ml of Hz 〇 and 5 g of 10% Pd / C was removed under nitrogen. Join. The mixture was hydrogenated at room temperature and atmospheric pressure while the pH was adjusted to 10.5 by adding 12% NH3 / H2O. After 18 hours of grazing, approximately 4 liters of salamander 2 were reacted * and the palpitation was removed by filtration. The filtrate was concentrated in vacuo to 20 ml and the unreacted starting material was extracted with K 200 liters of 1.5 M hydrogen acid and M acidified ethyl acetate and removed. The aqueous phase was concentrated to dryness and redissolved in 400 ml of THF and 343 ml of 1 M NaOH. A solution of 30 g of Boc- 酑 in 1 G0 ml of THF was added and the mixture was searched overnight. The reaction mixture was then acidified with 1 N ffCl plus M to pH 3 and extracted with 3 x 300 mL of EtOAc. The organic phase was volatilized to a foam. The yield was 22 grams. Abbreviations: r. T. Room temperature-34- This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 1 — — — ——— • Install III __ Order III, line (please read the note on the back first) Please fill in this page again) 458958 A7 B7 V. Description of the invention (M) EDAC: N-ethyl-N '-(3-dimethylaminopropyl) -carbodiimide hydrochloride E tOAc: ethyl acetate ester

Boc: t-butyloxycarbonylammonium N-Me-D- 2Hal: N-methyl-D-2-Zeidyl alanine DC M: dichloromethane DIEA: diisopropylethylamine DHF: Ν · Ν —Dimethylformamide HOAt ： 1 —Hydroxy-7-azabenzotriazole -------- A ------ IT ------ φ (Please read the Please fill in this page for further details.) N-Me-D-Phe, ol: N-methyl-D-phenylalanine fermentation by the Central Consumers Bureau of the Ministry of Economic Affairs FA: Trifluoroacetic acid THF: Tetrachlorofuran Paper size applies Chinese National Standard (CNS) A4 specification (210 X 297 mm) 458958 A7 B7 V. Description of the invention ((/) Implementation valve 2 3-((3-aminomethylbenzyl)) -N — M e — D -N- Me- D- Phe- KH)-K * N -dimethylaminopropane PH, N, CH,

2Nal

Boc ™ N-Me-D-Phe-OH (279 mg) was dissolved in dMF (4 liters) and stirred with HGBt (168 mg) and EDAC (2 3 0 «g) for 1Q minutes. 3-Dimethylamino-1,1-propylamine (188 liters) was added and the mixture was stirred at room temperature for 18 hours. Then a 5% aqueous solution of sodium bicarbonate (50 ml) was added and the resulting mixture was extracted with EtOAc (50 ml) plus M and dried with Na 2 phase and concentrated in vacuo to an oil. S 〇4 on the --------, install ------ order ------ line (please read the notes on the back before filling this page) Co-printed this oil with TFA / DCM 1: 1 (6 ml) and stirred at room temperature for 1 minute at room temperature for 1 minute. After that, TFA / DC Μ was used to dissolve the P &amp; raw oil and re-dissolve it in 70% CH3 CN (10 ml) '1 々 strict HC1 (3 ml j and water (37 ml) mixture and The product is immediately frozen and freeze-dried. -36- This paper size applies Chinese National Standard (CNS) A4 (210X297 mm) A7 458958 B7 V. Description of the invention ο The freeze-dried product is dissolved in DMF (6 Ml) and DCM (12 ml). Boc— Ν — Me-D— 2Nal-0Η (4 9 4 mg), HOAt (2 0 4 鼍), DI EA (1 7 1 μl) ) Was added to this mixture, and after cooling to 0 ° C, EDAC (288 mg) was added. After stirring at room temperature for 18 hours, DC was volatilized with a stream of nitrogen and EtOAc (100 ml) was added. This mixture was made with 5% carbonic acid Sodium hydrogen (100 drafts) and extraction twice with water (100 ml) plus M and dried over Na2S04 and concentrated in vacuo to an oil (480 mg). This oil was at room temperature Stir with TFA / (6 mL) for 10 minutes. After that, TFA / DCM is evaporated with a nitrogen roller and The resulting oil was dissolved in 70% CH3 CN (10 ml). IN HC1 (1 ml) and water (47 ml) were added and the resulting mixture was immediately frozen and freeze-dried to form an oil. (2 HC1, D-2 N a 1-N-Me- D- Phe- NH- (CH2) 3-N (CHa) 2) 0 The above oil (2 HC1 * Η-N-Me-D-2Nal -N-Me- D -Phe- NH- (CH2) 3-N (CH3) 2) is dissolved in DCM (9 ml) and 2 drops of DMF and DIEA (342 μl) are added to this solution. Added to the solution of Boc-3AMB-OH (503 mg) and ED AC (i 9 2 mg) in DC Μ (5 ml) * It has been applied to Chinese paper standard (CNS) A4 (210X297) (Mm) -------- i ------ IT ------ 0 (Please read the notes on the back before filling out this page) Printing 4 Printed by the Consumer Cooperatives of the Central Bureau of Vehicles of the Ministry of Economic Affairs 5 895 8 A7 _B7_ V. Description of the invention (] L) Stir at temperature for 15 minutes. After stirring for 20 minutes, the reaction mixture was concentrated to a oily substance using a thoron gas stream and stirred with a 5% aqueous solution of sodium bicarbonate (100 ml) for 15 minutes. Then E 10 A c (50 ml) was added, and the phases were separated and extracted with 5% aqueous sodium bicarbonate solution (100 ml) and extracted with water (100 ml). Then dried on Na 2 S04 and dried on The thread was filled in vacuo to an oil (340 mg). This oil was searched with TFA / DCM 1: 1 (6 pulls) at room temperature for 10 minutes. TFA / DCM was then evaporated using a stream of nitrogen and the resulting oil was dissolved in Cih CM (10 mL) and diluted with K water to a final volume of 5Q mL. The crude product was then passivated via semi-preparative ΗPLC in 8 operations and freeze-dried using similar procedures as described in Example 1. The final product obtained was qualitatively analyzed by analytical R P — Η P L C (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular weight found (ΜΗ +: 6G8.2 atomic mass units) is consistent with the expected structure (te 〇r. Η 61 + 61) 8,8 atomic mass units), which is located in the method _ 3 3-This paper is not easy to use China National Standard (CNS) A4 Specification (210X29? Mm) --------- Raid ------ 1T ------ 0 (Please read the precautions on the back before filling this page ) A7 B7 of the Consumer Cooperatives of the Central Sample Rate Bureau of the Ministry of Economic Affairs 5. Description of the invention (^) Examination error. U P-Η P L C residence times using the elution conditions A1 and B1 as defined in Example 1 were found to be 25.23 minutes and 26.58 minutes, respectively. Example 3

3- (((3R)-3-imididinecarbonyl) -N-Me- D- 2Nal- H -Me- D- Phe- NH) -1-N &lt; N -dimethylaminopropane

Half the amount of 2 HC1-Η- Ν-Me- D- 2Nal- N- Me- D- Phe-NH- (CH2) 3-N (C83) 2, which was obtained as an oil in Example 2 and was Dissolved in DC M (9 ml) and 2 drops of DMF and D EA (3 42 μl) were added. This solution was added to a solution of Boc- (R) -piperidinecarboxylic acid (459 mg) and EDAC (192 g) in DCM (5 ml), which had been stirred at room temperature for 15 minutes. -39- This paper size applies to Chinese National Standard (CNS) Α4 specification (210X297 mm) ---------------- ΐτ ------ 0 (Please read the note on the back first Please fill in this page again) Printed by the Employees Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs 458958 A7 _B7 V. Description of the invention Π) After stirring for 213 hours, the reaction mixture was concentrated to an oil by nitrogen flow and mixed with 5% carbonic acid Aqueous hydrogen hydrogen solution (100 ml) was stirred for 15 minutes. EtOAc (50 mL) was then added, and the organic phase was separated and extracted with 5% aqueous sodium bicarbonate solution (100 liters) and extracted with water (1Q0 mL), then dried over Na 2 S 04 and in vacuo. Sprinkle into an oil. This oil was stirred with TFA / DCM 1: 1 (6 ml) at room temperature for 10 minutes. Thereafter, TFA / DCM was volatilized using a nitrogen stream and the resulting oil was dissolved in 70% CH3 CN (10 ml) And diluted with water to a final volume of 5D ml. The crude product was then purified via 5 steps of semi-prepared fiPLC M and freeze-dried using similar steps as described in Example 1. The final product obtained was analytical R Ρ Η Η PLC (retention time) and qualitative analysis by plasma desorption mass spectrometry (molecular mass). The molecular mass found (MΗ +: 586.3 units in atomic mass) and the expected structure (te 〇.. Η Η + 585.8 atomic mass Although the unit is the same, it is within the test error of the method.-4 0 — This paper size applies the Chinese National Standard (CNS) A4 specification (210 × 297 mm) -------- attack ------ ΐτ ------ 0 (Please read the precautions on the back before filling out this page) 5 895 8 Printed by the Consumer Affairs Cooperative of the Central Bureau of the Ministry of Economic Affairs A7 B7 5. The use of the invention is as defined in Example 1. Elution conditions A1 and B1 RP-HPLC retention time Were 25.33 minutes and 26.35 minutes. Example 4

I-(((3R) — 3-N-pyridinylcarbonyl) -N- Me- D_ 2Nal- N -Me-D- Phe- NH) -1- (1-methyl-2-pyrrolidinyl) ethane

Boc-N-Me-D-Phe-OH (27.9 mg) was dissolved in DHF (10 ml) and searched with HOBt (168 grams) and EDAC (384 ^ g) for 10 minutes. 2- (Aminoethyl) -1,1-methyl-pyrrolidine (29Q liters) and IHEA (171 microliters) were added and the warmed mixture was stirred at room temperature for 2 G hours. The mixture was then concentrated to an oil, which was dissolved in 50 ml of water and freeze-dried. The product was re-dissolved in 25 ml of water and then filled into a Sep-Pak® C18 cylinder (Waters part.ti: 43345) -41- This paper size is applicable to the Chinese standard (CNS) A4 specification (210X297 mm)- ------- Ί ------ ΐτ ------ ^. (Please read the notes on the back before filling out this page) Printed by the Shellfish Consumer Cooperative of the Central Bureau of Quasi-Ministry of Economic Affairs 45 895 8 A7 B7 V. Description of the invention (p), which uses ο. I) 3 N hydrochloric acid for equilibrium ° This product is used in 0 * 0 3 ti of hydrochloric acid 7 096 CH3 CN from Sep-P ak ® The column was eluted and diluted with water and isolated from the eluate by freeze drying. The resulting material was stirred with TFA (6 ml) at room temperature for 10 minutes. TFA / DCM was then evaporated using a stream of nitrogen and the resulting oil was dissolved in 70% CH3 CN (10 liters) and 1 N hydrochloric acid (2 mL) was added. The product was diluted with water (50 ml) and then freeze-dried to obtain a single chicken. The resulting material was dissolved in DMF (3 ml) after adding BoeN-Me_l) -2NaI-OH (329 mg), HOAt (136 mg), EDAC (230 mg) and DIEA (171 w 1). Stir at room temperature for 18 hours. E10 A c (50 ml) was then added and the mixture was extracted with a 5% aqueous solution of sodium bicarbonate (50 ml), with a 5% aqueous solution of potassium hydrogen sulfate (50 ml) and with water (50 ml). The organic phase was dried with sodium sulfate and condensed in vacuo to an oil. This oil was stirred with TFA / DCM 1: 1 (6 ml) at room temperature for 10 minutes. TFA / DCM was then evaporated with nitrogen gas and the resulting oil was dissolved in 70% CH3CN (10 mL) and added with 1 N hydrochloric acid (2 mL). The product was K water (50 drafts ) Diluted by freeze-drying after dilution. This paper has been oversized using Chinese National Standard (CNS) A4 size (210 X 297 mm) --------. Loading— (Please read the notes on the back first Please fill in this page again) Printed by the Consumers Cooperative of Central Standards Bureau, Ministry of Economic Affairs, printed 458958 A7 _____B7 V. Invention Description (V) 28 6 mg of this freeze-dried product was dissolved in DCM (15 drafts) and DIEA ( 171 μl). This solution was added to a solution of Boc- (R) -imidamic acid (459 mg) and EDAC (192 * g) in DCH (10 ml), which had been stirred at room temperature for 25 minutes. After stirring for 20 hours, the reaction mixture was condensed into an oil using a stream of nitrogen and then redissolved in EtOAc (100 mL) and 5% aqueous sodium bicarbonate solution (50 mL) was used. Aqueous potassium hydrogen acid solution (5 β ml) and extraction with water (50 ml). Sulfur phase uses sulfur The oil was dried and concentrated in vacuo to an oily bark. This oil was stirred with TFA / DCM 1: 1 (6 liters) at room temperature for 10 minutes. Thereafter, TFA / DCM was evaporated using a nitrogen stream and The resulting oil was dissolved in 70% CH3CN (10 mL) and diluted with MW water to a final draw of 50. The crude product was then purified via semi-preparative HPLC Μ 3 operations and used as in Example 1 Lyophilization was performed similarly to the procedure described in the above. The final product obtained was qualitatively analyzed via analytical RP — HPLC (retention time) and plasma desorption mass spectrometry (molecular mass). The molecular mass found (ΜΗ +: 612.2 atoms) Quality military position) and expected structure -43- This paper size is in accordance with the Chinese National Standard (CNS) A4 specification (210X297 mm) ---------- Raid -------- ΐτ ----- -Φ (Please read the note f on the back before filling in this page)

5. The description of the invention (qM t teor .ΜΗ +: 612.39 atomic mass unit) is consistent, and lies within the experimental error of the method. The RP-HPLC retention time using elution conditions A1 as defined in Example 1 was found to be 25.8 G minutes. Example 5 (2R) — 2 — ((3-Aminomethylbenzylidene) -N-Me-D -2Nal-N-Me) — 3— (2-naphthyl) propionase

(1) — 2— (N-tris-butoxycarbonyl-methylamino)-3— (2-naphthyl) propanoic acid methyl ester

(R) — 2-tertiary monobutoxycarbonylamino — 3- (2-naphthyl) propanoic acid (5.0 g; 16.4 mmol) was dissolved in anhydrous DMF (50-44 * This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -------- d ------ IT ------ 0 (Please read the Please fill in this page again for attention) 458958 Printed A7 B7 (Fifth, the invention description (ML) ml) by the Central Working Group of the Ministry of Economic Affairs, the Peasant Poverty Alleviation Cooperative. Methyl iodide (6.2 ml; 38.4 mmol) and silver oxide (1) (u. 3 g; 57.4 mmol) were added and the mixture was stirred overnight. The reaction mixture was subjected to mashing and the filtrate was extracted with dichloromethane (200 draft) plus M. The organic phase was washed with potassium cyanide (2 X 50 ml; 5%.) And water (3 X 75 ml). The organic phase was dried (H g S 0 4) and the solvent was removed in vacuo. The residue was subjected to chromatographic analysis (silicon, 5 X 4 cm) using ethyl acetate and hexane (1: 2) as eluents to obtain 4.98 g of (R) 2-(N-tertiary monobutoxycarbonyl group -N-methylamino) _3- (2-Cequiyl :) methyl propionate. 1 H-NMR (CDC13): 1.30, 1.35 (two s, 9H); 2.71 · 2.75 (two s, 3H); 3.19 * 3.47 (two 1, 2H); 3.74, 3.77 (two s, 3H); 4.65 * 5.05 (didd, 1 Η); 7.29-7.82 (m-7H) (mixture of rotamers) (R) — 2_ (N ~ tertiary—butanecarbonyl—methylamino) —3— ( 2-naphthyl) propionic acid

β〇〇-νΛ ° Η ch5 ° (R) — 2 — (S —tris-butyroylcarbonyl —N —methylamino) —3- (2-denyl) propanoic acid methyl ester (21.73 g; 65.57 MM-45- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------- 'Meal ------ 1T ------ 0 (Please read the precautions on the back before filling this page) Printed by the Consumer Affairs Cooperation Department of the Central Bureau of the Ministry of Economic Affairs 5 895 8 A7 B7 V. Description of the invention (Dou. &Lt; 4.)) Was dissolved in 1, 4 Dioxane (200 ml) and water (2Q ml) were added. The reaction mixture was cooled on an ice bath and lithium hydroxide (1.73 g; 72.13 mmol) was added. After 15 minutes, water (140 mL) was added and the reaction mixture was then stirred at room temperature for an additional 3 hours. Ethyl acetate (400 ml) and water (300 ml) were added and the pH was adjusted to 2.5 using sodium bisulfate 1 M (110 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (200 ml) plus K. The confluent phase was washed with water (300 liters), dried (MgS〇4 *), and the solvent was removed in vacuo. K was obtained to obtain 20.1 g of (R) 2 — (N — three-stage one Oxycarbonyl-N-methylamino) -3- (2-acryl) propionic acid. J H-NMR (DMS0) 1.18, 1.21 (two s, 9H); 2.62, 2.66 (two s, 38); 3.11- 3.58 (a &gt;2H); 4.75 · 4.90 (two dd, 1H); 7.48-7.88 (m ， 7H) ； 1.85 (s (br) · 1H) (a mixture of rotamers) (R) 2 ~ formamido-3- (2-naphthyl) propionic acid

ηΎ Η Ο (ΙΟ-2-Amino ~ 3 — (2-naphthyl) propionic acid (8.11 g; -46 ™) This paper size applies to China National Standard (CNS) A4 size (2 丨 0 X 29?) (Li) -------- Attack ------ ΪΤ ------ ^ (Please read the precautions on the back before filling out this page) 458958 A7 B7 V. Description of the invention 0 84.14 millimoles ) Was dissolved in formic acid (204 ml) and acetic anhydride (70 ml) was added dropwise. The reaction mixture was heated to 55C and stirred at room temperature for 3 1/2 hours. Ice cold water (70 ml) was Add human dropwise and stir under Of for 20 minutes. The reaction mixture was filtered and washed with ice-cold water (20 mL) plus M to obtain 2 G. 2 β g of (R) 2-methylamido_ 3 (2-naphthyl) propanoic acid 1 Η-NKR (BMS0): 3.05 (dd, 1H); 3.27 (dd 1 Η); 4,64 (nt-1Η); 7.4 8-7.8 7 (m, 7H ); .95 (s * 1H); 8.45 (d, 1H); 12.9 (s (br) 1H). (Ϋ) —methylamino_3— (2 —acyl) propan-1-ol— ------ 袅 ------ ΐτ ------ 0 (Please read the notes on the back before filling this page) (R)-2-methylamidoamino 3- (2-naphthyl) propanoic acid (4.37 g; 18 mmol) was dissolved in anhydrous tetrahydrofuran (100 ml) by Fe Cooperative and hydrogen Sodium boride (1.6 g; 43.2 mmol) was added. Iodine (4.57 g; 18 mmol) was dissolved in anhydrous tetrahydrofuran (40 ml) and added dropwise to the reaction at less than 4 (TC) Mixture. Reaction mixture-4 7-The paper size is in accordance with Chinese National Standard (CNS) A4 specification {210X297 gong) A7 458958 B7 V. Description of the invention (to) Heat to the state of flow for 12 hours. Potassium hydroxide (5Q ml; 20%) was added. The aqueous phase was extracted with methyl tertiary butyl ether (4 X 50 ml). The combined organic layers were washed with saturated sodium chloride (15ϋml) plus K and dried ( MgSO +) and the solvent was removed in vacuo-the residue was analyzed by I) cM / methanol / ammonia (100: 1 0: 1) chromatographic analysis (silicon; 5 x 4 cm) M to obtain 1.81 g of (R) Methylamino-3 (2-naphthyl) two one one alcohol. 1 H-NMR (CDC 13): 2.43 (s, 3H); 2.88- 3.05 (m-3H); 3.10 (s (br) * 2H); 3.42 (dd, 1H); 3.69 (dd, 1H); 7.3 0-7.8 2 (m &gt; 7H) 〇N— {(1 R)-1- [N— ({1R) — 2 -hydroxy-1 — ((2_Cequiyl) methyl) ethyl) -N -Methylaminomethylamidino] -2 — (2-naphthyl) ethyl} —N-methylaminocarboxylic acid tertiary monobutyl

(R) _ (N-tertiary-butoxycarbonyl-N-methylamino) -3- (2-acryl) propanoic acid (0.55 g; 1,67 mmol) and (R) methyl Amine —3-(2 —Czechyl) Propane-1 (0,38 g; 2,00 -48-) This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) --- ----- d ------ IT ------ 0 (Please read the notes on the back before filling in this page) Printed by the Industrial and Commercial Cooperatives 45 895 8 A7 B7 V. Description of the invention (^ /) Millimolar) was dissolved in dichloromethane (15 ml) and dimethylformamide (7.5 ml). The reaction mixture was cooled on an ice bath. 1-Hydroxy-7-azabenzotriazole (0.24 g; 2.09 mmol) and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (0.38 g; 2.0 walmor) was added. The mixture was stirred at room temperature for 12 hours. The reaction mixture was condensed in vacuo. Ethyl acetate (2QQl) was added and the organic solution was made up of water (100 ml), sodium bicarbonate / sodium carbonate (Ph 9) (75 ml), sodium bisulfate (75 ml; 1G%) water (100 ml) was washed with M and dried (MgS04). The solvent was removed in vacuo and the residue was chromatographed using ethyl acetate (silica, 2 X 45cb). 0.25 g of (1 R)

Mono (N — [(1 R) — 2 —hydroxy — 1 — ((2-naphthyl) methyl) ethyl) —N —methylaminomethylamidino] — 2 — (2-naphthyl) ethyl } -N Trimethylmonobutylaminocarbamate. 1 H-NMR (DMSO): 〇 80-1. 99 (several s, 9Η); 2. 4 5-4.. 2 0 (1 &gt;12Η); 4.70-5.12 (a · 2Η) 丨 peak of choice , A mixture of rotamers) (2ii) ((1R) hydroxy-l-((2-naphthyl) methyl) ethyl) -N-methyl-2-methylamino-3- (2- Naphthyl) propylamine. -49 This paper size applies to China National Standard (CNS) A4 specification {210 X 297 mm) ^^ 1 ^^^ 1 m d.— ^^^ 1 ^^^^ 1 τ II— ^^ i · — J —, I (Please read the notes on the back before filling in this page} 4 5 895 8 at _B7 V. Description of Invention P)

Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs ην, ΛγΝΥ ^ 〇η -0¾ Ν ί 1R) -1— (Ν-[(1R)-2-hydroxy-1-((2-naphthyl) methyl) Ethyl) -N_methylaminomethylamidino] _2_ (2-naphthyl) ethyl) _N_methylaminocarbamic acid tertiary monobutyl ester (0,25 g-0.75 mil) Dissolved in DCM (3 mL). Trifluoroacetic acid (1 mL) was added and the reaction mixture was stirred for 20 minutes. The solvent was removed in vacuo. DCM (5 mL) was added and removed in vacuo and repeated. The residue was dissolved in methanol (5 mL). Sodium bicarbonate / sodium carbonate (5 ml; pH 9) was added and the solution was extracted with ethyl acetate (.2 x 10 ml) plus M. The organic phase was dried (MgSO 4) and the solvent was removed. K gave 0.22 g of (2 R)-(ί — ((1 R) — 2 —hydroxyl 1 — ((2-naphthyl) methyl) ethyl ) -N-methyl- 2 -methylamino_ 3 _ (. 2 -naphthyl) propanamide. 1 Η-NMR (CDC13): 1.70 * 2,37- 2.45- 2.93 (four s, 6Η) ; 2.5 6-3.0 5 (i-2H), 3.52-3.85 (m · 7 Η); 4 _ 2 5, 4. 97 (two m, 1H); 6.86- 7.78 (n-14 H) (peak of choice , A mixture of rotational isomers)

(2R) -2— ((3-Aminomethylbenzyl) -N—Me— D -50- This paper size applies to China National Standard (CNS) A4 (210X297 mm) ----- --- Raid ------ 1T ------ ^ (Please read the precautions on the back before filling out this page) 458958 A7 B7 Printing Policy of Employee Consumer Cooperatives of the Central Bureau of the Ministry of Economic Affairs Winter f) -2Nal-N- Me)-3- (2 -naphthyl) propionate

3-Bo c-Aminomethyl stearic acid (502.6 mg) was dissolved in DCM (6 ml) and stirred with OAC (191.6 g) for 15 minutes to convert to symmetrical anhydride. (2R)-ti- ((1 R)-2-hydroxy-1-((2-naphthyl) methyl) ethyl) -N-methyl ~ 2-methylamino- 3-(2 -naphthalene A solution of propyl) amidine (20 [mg]) in DCM (5 ml) was added to the mixture and the reaction was then carried out at room temperature for 2 hours. The reaction mixture was then concentrated to an oil and redissolved in EtOAc (100 mL). This solution was sequentially extracted with a 5% NaHC03 (2 X 50 mL) aqueous solution, a 5% KHS04 (2 X 50 mL) aqueous solution, and H20 (2 X 50 mL). The resulting organic phase was dried over Na2S04 and concentrated on a rotary volatilizer in vacuo to an oil. The oil was then dissolved in DCM / TFA 1: 1 (6 mL) and searched. After 1Q minutes, the mixture was concentrated by nitrogen flow and the resulting oil was re-dissolved in 70% CH3 CN / 0.1 This paper size is applicable to China National Standard (CNS) A4 (2Ι0 × 297 mm) ----- --- Wei ------ ΐτ ------ ^ (Read the precautions on the back before filling in this page) 458958 Imprint A7 _B7_ by the Consumer Cooperatives of the Central Government of the Ministry of Economic Affairs θ)% TFA (5 ml) and diluted with K water to a volume of 100 ml. This crude product was then purified via semi-preparative HPLC K 2 operations and freeze-dried using similar procedures as described in Example 1. The final product obtained was qualitatively analyzed by analytical R P-HP LC (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular weight found (HH +: 559.5 atomic mass military rank) is consistent with the expected structure Ueor.MH + 560.72 atomic mass unit) and is within the experimental error of the method. KP-HPLC retention times using elution conditions A1 and B1 as defined in Example 1 were found to be 33.07 minutes and 34.63 minutes, respectively. Example 6 H—Aib—His—D—2Nal—N—He—D—Phe—NH2

This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) --------- installation ------ IT ------ ^ (Please read the note on the back first Please fill in this page again for details) 45 89S Β Shellfish Consumer Cooperation of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China “Soyinjia A7 Β7” V. Description of the invention Synthesis was performed using the FastMocUV method provided by the manufacturer, which uses the coupling of HBTU-dominated SHP and UV monitoring Fmoc protecting groups to deprotect. The starting resin used for the synthesis was obtained from Bacheai Feinctieaiikalien AG, Bubendorf * Switzerland Cat. No. D — 1675 (427) mg, which is a Faoc _2,4-dimethoxy-4 '-(carboxymethyloxy) -diphenylmethyl monoamine attached to an aminomethyl polystyrene resin via ammonium hydrazone This substitution ability is 0.55 mmol / g. The protected amino acid derivative used is Fmoc- S -Me-D-Phe-OH * Fioc-D-2Nal-OH * Fmoc-His (Trt) And Fbioc-Aib — 0 H ° Fmoc — Me — D — Phe — OH coupling is double coupling After synthesis, the mixture was searched at room temperature with 8 ml of TFA, 600 mg of phenol, 2 G0 of ethylenedisulfide * 400 microliters of phenylthiomethane, and 400 microliters of 0 for 18G minutes. Pg of peptide resin was cut off. The cut mixture was filtered and the filtrate was condensed to about 2 ml via a stream of nitrogen. The crude peptide was precipitated from the oil using 5 CI ml of diethyl ether and 50 ml of ethyl ether was added to M Wash 2 times. The crude peptide was purified from 1 operation via semi-preparative HPLC and freeze-dried using similar procedures as described in Example 1. The final product obtained was analyzed via analytical RP — Η PLC (retention time ) -53- This paper size applies the Chinese National Standard (CNS) A4 grid (210X297 mm) -------- ά ------ IT ------ 0 (Please read the back first Please fill in this page again) Printed by the Consumers Cooperative of the Central Bureau of Standards, Ministry of Economic Affairs, 458958 A7 B7 V. Description of the invention (b) and qualitative analysis by plasma desorption mass spectrometry (molecular mass) ΜΗ +: 538.5 atomic mass units) and expected structure (te ο r · Η Η + 5 9 8. 7 3 atomic mass units) are consistent and within the experimental error of the method. Using the elution conditions A1 and Bit RP-HPLC retention times as defined in Example I, it was found to be 24.68 minutes and 25.68 minutes, respectively. Example 7 H — Aib — His ~ D — 2Nal — He — D — Phe — Ser — NH2

This compound was synthesized using a similar procedure as described in Example 6. The final product obtained was qualitatively analyzed by analytical R P-Η P L C (retention time) and by plasma desorption mass spectrometry (molecular mass). The found molecular mass (M Η +: 6 8 5.6 atomic mass units) is consistent with the expected structure (teor. Μ Η + 6 8 5. 8 1 atomic mass unit) and is within the experimental error of the method. -54- This paper size is applicable to China Standard (CNS) ΑΊ size (210X29? Mm) -------- Ί ------, 1T ------ 0 (Please read first Note on the back, please fill in this page again.) Seal of the Central Government Bureau of the Ministry of Economic Affairs, Zhenggong Consumer Cooperative Co., Ltd. «. 45 895 8 A7 B7 V. Description of the invention (M) Use the elution conditions A1 as defined in Example 1 and The RP-HPLC retention time of Β1 was found to be 24.42 minutes and 25.92 minutes, respectively. Example 8 (3-Aminomethylanisole) -D-2Nal — N — Me — D-Phe —N Η 2

This compound was synthesized using similar procedures as described in Example S. The only exception is the coupling of F m 〇 c — D ~ 2 N a 1 _ 〇 Η using HATU as the activator. Η — Ν-Me-D — Phe — resin (0.23 mmol) with 1 ml of Fmoc-D-2Nai-0H in the presence of DIEA (2 mmol), using 1 mmol of HATU for coupling up to 1 5 minutes. The final product obtained was qualitatively analyzed by analytical R P-fi P LC (retention time) and by plasma desorption mass spectrometry (molecular mass). FA-55- This paper size is applicable to China National Standard (CNS) A4 (210 X 297 mm) -------------- 1T ------ ^ (Please read first Note on the back, please fill out this page again) 4 8 9 5 8 A7 _B7 V. Description of the invention C &lt; ^) Current molecular mass (HH +: 511.2 atomic mass military position) and expected structure (teor.HH +: 509.6 atomic mass unit) Consistent within the experimental error of the method. The retention times of E P-滞 P L C using elution conditions A1 and B1 as defined in Example 1 were found to be 30. 7 minutes and 3 2. 47 minutes, respectively. Example 9 4-Pyridinylcarbonyl) -D-2Nal-N- Me- D-Phe-NH2

This compound was synthesized using similar procedures as described in Example 8. The final product obtained was analyzed qualitatively via analytical 0-Η P L C (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular weight found (ΜΗ +: 486.8 atomic mass units) is consistent with the expected structure (te 〇r. MH +: 4 87.6 atomic mass units), which is within the experimental error of the method. Standard (CNS) Α4 Specification (210 × 297 cm) --------. ^ ------ 1Τ ------ 0 (Please read the precautions on the back before filling this page) Ministry of Economy Printed by the Central Bureau of Standards for Consumer Cooperatives 458958 Printed by the Central Government Bureau of the Ministry of Economics and Labor Cooperatives for Consumers Cooperatives A7 B7 V. Description of the invention (0) RP-HPLC using elution conditions A1 and B1 as defined in Example 1 Retention times were 27.0 3 minutes and 28. 48 minutes, respectively. Example 10 t (3R) -3-¾-pyridylcarbonyl) -D- 2Nal-N- He- D- Phe -NHz

This compound was synthesized using similar procedures as described in Example 8. The final product obtained was qualitatively analyzed by analytical R P-Η P L C (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular weight found (ΜΗ +: 486.9 atomic mass units) was consistent with the expected structure (teor. MH +: 487.6 atomic mass units) and was within the experimental error of the method. The KP-HPLC retention times using the elution conditions A1 and 81 as defined in Example 1 were issued as 28.G3 minutes and 29.50 minutes, respectively. -5 7-This paper size is in accordance with Chinese Standard (CNS) A4 (210X29? Mm)-Thread setting (Please read the precautions on the back before filling this page) 458958 Α7 Β7

Consumer Co-operation of the Central Government Bureau of the Ministry of Economic Affairs of the People's Republic of China. Printed by the Society I. Description of Invention (‘d) Example 11 (3-aminomethylbenzyl) -Me-D-2Nal-N—Me D ~ Phe ™ NH2

This compound was synthesized using similar procedures as described in Example 8, except that the last residue was incorporated using symmetry coupling plus K. Boc-3 —Aminomethylbenzoic acid (251 μg) and EDAC (96 mg) were stirred in DCM for 15 minutes. The resin (429 mg) was then added and stirred continuously for 18 hours. Another exception is that the time required to cleave the peptide from the resin with M is reduced to 6 G minutes. The final product obtained was qualitatively analyzed by analytical R P-HP LC (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular mass found (Μ Η +: 5 2 2.9 atomic mass units) is consistent with the expected structure (.te 〇 r, Μ Η +: 5 2 3.6 atomic mass units), which is within the test error of the method . Using the RP-calculated LC retention time as defined in Example 1 of U. chinensis / U and B1, it was found that the retention times of the LC were 28.83 minutes and 3Q. 13 minutes-58- This paper standard is applicable to the Chinese Standard (CNS) Α4 Specifications (210 × 297 mm) ----------------- ΐτ ------. ^ (Please read the notes on the back before filling this page) ^ 5 895 8 A7 B7 Consumption Cooperation between Employees of the Central Sample Rate Bureau of the Ministry of Economic Affairs Du Yinzhuang 5. Description of Invention (: vp bell.:. Implementation M 1 2

Η-Aib ~ His-N- Me-D-2Sal-N- Me-D ~ Phe-NH 2

This compound was synthesized using a phase bismuth step as described in Example 8, where Frac-N-Me ~ D -2Nal-0H and Fic-His (Trt) were combined using HATU and the resin The time to cleave the peptide was reduced to 60 minutes. The final product obtained was qualitatively analyzed by analytical RP-Η P L C (retention time) and by plasma desorption mass spectrometry (molecular mass). Although the molecular mass found (M H +: 612.3 atomic mass unit) is consistent with the expected structure: 612 · 8 atomic mass unit, it is within the spring error of the method. The RP-HPLC retention times for the elution conditions A1 and B1, as defined in Example 1, were found to be 24, 33 minutes, and 26.20 minutes, respectively. -59- The size of this paper is in accordance with the Chinese National Standard (CNS) A4 (210X297 mm). Order, line (please read the notes on the back before filling this page) 4 ^ 8958 A7 B7 V. Description of the invention (#) Example 13 (3-Aminomethylbenzyl)-D — Phe — N — Me ™ D — Phe — Lys-O 2

Printed by Shellfish Consumer Cooperative, Central Bureau of Economic Affairs, Ministry of Economic Affairs This compound was synthesized using similar procedures as described in Example 8. The final product obtained was qualitatively analyzed by analytical K P-H P LC (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular weight found (MH +: 5δ7.2 atomic mass units) is consistent with the expected structure (te e r · Μ Η +: 5 8 7.7.4 atomic mass units), which is within the experimental error of the method. The RP-Η PLC retention times using the elution conditions A1 and B1 as defined in Example 1 were found to be 21.13 minutes and 2 2.60 minutes, respectively. Example 14, ^ 54 Please read the notes on the back before filling this page) This paper size is applicable to Chinese national standard (CNS) Α4 size (210 X 297 mm) 453958 A7 _B7 _ ______ V. Description of the invention (1) (3-aminomethyl Benzamidine) -N-Me—D—Phe-! Ί-Me-D — Phe — Lys-NH2

Printed by the Central Bureau of Standards, Ministry of Economic Affairs and Consumer Cooperatives. This compound was synthesized using the phase M procedure described in Example 1. The final product obtained was qualitatively analyzed via analytical R P — Η PLC (retention time>) and by plasma desorption mass spectrometry (molecular mass). The molecular mass found (ΜΗ +: 6G1.6 atomic mass unit) and the expected structure (Teor. ΜΗ +: 6 0 1. 7 7 atomic mass unit) are consistent, and are within the spring error of the method. Using the elution conditions A1 and B1 R RP-Η PLC as defined in Jin Example 1, it stays The time was found to be 20.4 minutes and 21.7 minutes. Example 15 (f 3 R.) _3-ton 0 $ Satoki) —N_Me — D_Phe — N ~ Me_ D-Phe ~ Lys- NH2 -61- --------- Λ ------ IT ------ Φ. (Please read the precautions on the back before filling this page) This paper size is applicable to Chinese standards (CNS) A4 specification (210X 297 mm) Printed by the Shell Specimen Consumer Cooperative of the Central Sample Bureau of the Ministry of Economic Affairs 4 5 8 9 bc, A7 ___B7 5. Description of the invention

This compound was synthesized using similar procedures as described in Example 11. The final product obtained was qualitatively analyzed by analytical R P — Η P L C (retention time :) and by plasma desorption mass spectrometry (molecular mass). The molecular mass found (ΜΗ +: 579.4 atomic mass units) is consistent with the expected structure (te e r · Μ Η +: 5 79.8 atomic mass military position), which is within the test error of the method. RP-HPLC retention times using elution conditions A1 and B1 as defined in Example 1 were found to be 19 · M minutes and 2 1.20 minutes, respectively. Example 16 H ~ Aib—His—N—Me—D — Phe —? I — Me — D — Phe — Lys -NHz -62- This paper size is applicable to China National Standard (CNS) Α4 specification (210 X 29 &quot;? mm) -------- • xiang-- ---- ΐτ ------. ^ (Please read the notes on the back before filling this page) 458958 A7 B7 V. Description of the invention ((ί)

This policy was synthesized using similar procedures as in Example 12 of Spring. The final product obtained was qualitatively analyzed by analytical R P-Η P L C (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular mass found (ΜΗ +: 690.6 atomic mass units) is consistent with the expected structure (teor .MH +: 690.9 atomic mass units), which is within the error of the method. Use the elution conditions as defined in Example 1. The RP-HPLC retention times of A1 and B1 were found to be 15,71 minutes and 17.82 minutes, respectively. Example 17 !, (3R) — 3 -pyridine carbon-based)-N-Me-N-Me -D-Phe — NHz -63 A paper size is applicable to China National Standard (CNS) A4 (210X297 mm) ---------. Meal ------ IT ------ 0 (please first (Please read the notes on the back and fill in this page) 45 895 A7 Printed by the Central Labor Bureau of the Ministry of Economy

This compound was synthesized using a similar procedure as described in Example 11 * using Fntoc_N_Me_D — P he — Ο Η 5 Faioc — Ν — Me ~ D — 2Nal — OH and Boc- (R) -piperidinecarboxylic acid. Among them, Fnioc-N — Ne- D — 2NaI — OH and Boc — (R) —piperidinecarboxylic acid were coupled using HATU. The final product obtained was qualitatively analyzed by analytical RP-HPLC (retention time) and by plasma desorption mass spectrometry (molecular mass). The molecular mass of the hairpin (MH +: 50D.7 Atomic Mass Military Rank) is consistent with the expected structure (teor. MH +: 5G1. 7 Atomic Mass Unit), which is within the experimental error of the method. Use it as in Example 1 The RP-HPLC retention times of the defined elution conditions A1 and B1 were found to be 28.1 8 minutes and 29.5 5 minutes, respectively. Example 18 H—Aib—Ala—D—2Nal—N—He ~ D — Phe — Lys ~ NHe

-64- This paper size applies the Chinese National Standard (CNS) ΑΊ specifications (210X297 mm &gt; --II-n-n 1-n tf --- TI _ _ _ _.,-&Amp; Mai (Please read first Note on the back, please fill out this page again) A5 B9 A7 B7 V. Description of the invention ([7 The compound was synthesized using the phase M step as described in Example 6. The final product obtained was analyzed by RP-HP LC ( Retention time) and qualitative analysis by plasma desorption mass spectrometry (molecular mass). The molecular mass found (MH +: 66G.7 atomic mass unit) is consistent with the expected structure (teor. MEi +: 66G.8 atomic mass unit), located at The test error is within the method.

The RP-HPLC retention times using the elution conditions A1 and B1 as defined in Example 1 were found to be 25.63 minutes and 26.75 minutes, respectively. G Example 19 Η 3 -aminomethylbenzyl-N- Me-D— 2Nal-N— Me D- Phe- NH- CH3 -------- Wei -------- ΪΤ ------ ^ (Please read the notes on the back before filling in this page)

Central Government Bureau of the Ministry of Economy

65 This paper size is in accordance with Chinese National Standard (CNS) A4 (210X297 mm). Printed by Shelley Consumers Cooperation Department of the Central Bureau of Standards of the Ministry of Economic Affairs. 458958 A7 ___B7 V. Description of Invention (6 ^ ·)

Boc—3ΑΗΒ-0Η (115 mg, (5.458 mol), 1-hydroxy-7-azabenzotriazole (62 罨, 0.458 mmol) and 1 ~ ethyl-1 3 &lt; 3--2 Methylaminopropyl) carbodiimide chloride (97 psi, 0.504 mmol) was dissolved in DCM (8 mL) and DMF (1 mL) and stirred for is minutes. N-methyl-2-methylamino-((1R) -1-(methylaminomethylamido) -2-phenylethyl) -3- (2 —Acridyl) Propamide (185 mg, 0.458 mmol) was added, followed by diisopropylethylamine (80 mL, 0.458 ¾ mole) and the mixture was stirred for 20 hours. The organic phase was washed with sodium bicarbonate (50 ml * 5%) &gt; H2 0 (50 ml) and saturated NaCl / H2 0 (50 ml) plus M, dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in DCM (2 mL) and treated with K TFA (2 mL) plus M for 10 minutes. Volatile materials were removed using N 2 gas flow. The residue was dissolved in 50 ml of 20% MeCN and diluted with K 升 2 0 to 500 draft

Semi-preparative HPLC _ 6 6-This paper's standard is applicable to China Solid Standard (CNS) Α4 specification (210 × 297 male shame) -------- Wei -------- ΐτ ------ 0 (Please read the precautions on the back before filling this page) α5 89 5 8 A7 B7 V. Description of the invention (b 10ml / min, 5 operations, 30-40% MeCN / 0.1 Μ (NH4) z S04 * pH 2.5

Detection 276 ηπ, Sep- Pals ^ 70% HeCN / 0.1% TFA, freeze-dried PD — MS theoretical value 5 3 6. 7 hair value 5 3 5. 7 soil 1 Η PLCA 1 rt 3 1, 20 minutes B 1 rt 3 6. 3 5 minutes Example 2 0 —Aib — His ™ N — Me — D — 2Nal — N ~ Me — Γ — Phe -------- '参 ------ IT- ----- it (Please read the notes on the back before filling out this page) NHHe Male Labor Consumers Cooperatives Printed

-67- This paper size applies to Chinese National Standard (CNS) A4 specification (2 丨 OX297 mm) A7 458958 B7 V. Description of invention (β)

Futoc—L—His (tribenzyl) -OH (1.54 g, 2.48 mmol) (BACHEM B-1570) and 1-hydroxyaza-benzotriazole (3 3 8 mg * 2. 4 8 Dymol) was dissolved in 9 ml of DMF. 1 Cooled to 0-4C and 1_ethyl-3_ (3-dimethylaminopropyl) carbodiimide hydrochloride (475 mg. 2.48 Dymol Ear) was added. The reaction mixture was searched at G_4 ° C for 15 minutes. N-methyl-1, 2-methylamino-1 ((1 R) — 1- (methylaminomethylmethyl)-2 ~ phenylethyl) -3 dissolved in dichloromethane (18 ml) — (2-naphthyl) propanamide (500 mg, 1.24 mmol) is cooled to G-4t: and added and stirred for 1 hour, followed by diisopropylethylamine (0.425 Ml, 2.48 millimoles). The temperature of the mixture was slowly raised to room temperature and the mixture was stirred for 72 hours. DCM was evaporated in a stream of N2 and 100 liters of ethyl acetate was added to the mixture and washed with sodium bicarbonate (2 x 100 mL, 5%) and potassium hydrogen sulfate (100 mL, 5%) plus M. The phases were separated and the organic phase was dried over sodium sulfate and evaporated in vacuo. The residue was dissolved in DMF (8 ml) and treated with pyridine for 15 minutes, diluted with Hz 0 (100 ml) plus K and quenched with acetic acid (1.5 ml). Acetonitrile was added and the mixture was diluted with iH0 to 25Q ml. The clarification solution is filled to 10 grams &quot; Seppaks -6 8 _ This paper size applies to China National Standard (CNS) A4 specification (210X297 mm) --------. Packing -------- II ------ ^ (Please read the notes on the back before filling out this page) Printed by the Central Laboratories of the Ministry of Economic Affairs, Shellfish Consumer Cooperatives, printed by the Central Laboratories of the Ministry of Economic Affairs, Consumer Consumption Cooperatives * '45 895 8 A7 __________B7_ V. Description of the invention (tj) &quot; Sample Water, washing with H2 0 / 0. 3 M HC i and eluting with 50 ml of 35% MeCN / 0.G3 M HC1. Dilute to 200 ml with Η20 and freeze-dry.

Boc-α —aminoisobutyric acid (756 mg, 3.72 moles), 1-hydroxyazabenztriazole hydrate (506 mg, 3.72 mmol) and 1-ethyl-3 (3 — Dimethylaminopropyl) carbodiimide hydrochloride (7.13 mg, 3.7 2 mol) was dissolved in DMF (6 ml) and after 15 minutes, dissolved in DCMU 2 ml ) Η-L-His (tribenzyl)-NMe!) 2tial-NMeDPhe-NliCH3, 2 HCL was added, followed by diisopropylethylamine (0.6 6 7 ml) and carried out Stir for 72 hours. DC was evaporated in a stream of N 2 and 100 ml of ethyl acetate was added to the mixture and washed with sodium bicarbonate (2 × 50 ml, 5%) and potassium hydrogen sulfate (5 ml, 5%) plus K. The phases were separated and organically dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in DCM (6¾ liters), cooled to 0-4 and treated with TFA (6 ml) at 0-4 &quot; C for 10 minutes. The volatiles are removed using a gas stream. The oily residue was dissolved in 35 ml of 70% acetonitrile, diluted to 50 ml with H20 and 10 ml of concentrated hydrochloric acid (12 molar concentration) was added and searched for 72 hours: the mixture was treated with Η 2 〇 Add M to dilute to 2 GG ml and neutralize with solid sodium carbonate plus M. Finally, M Η 20 to 40 卩 ml. -69- This paper scale is applicable to Chinese National Standard (CNS) A4 (210X29 · 7mm) I n n * I n n n cable (Please read the note on the back before filling this page)

4 5 8 y 5 8 A7 _B7 V. Description of the invention 6)

Semi-preparative HPLC PD — MS, theoretical: 5 5 0.7, found 5 5 0. 1 Η PLCA 1 rt 3 1. 7 5 minutes Birt 3 6. 15 minutes Example 21 3-methylamine Methylmethyl benzamidine-N-M e-D — 2 N a 1-N — M e — D — Phe — NH ~ CH3

Boc- NMe3A.MB ™ OH (358 mg, 2.48 mmol), 1-hydroxyazabenzobenzotriazole hydrate (338 mg, 2.48 mmol) and 1_ethyl-3— (3_ Dimethylaminodiyl) carbodiimide hydrochloride (475 mg, 2, 48 mmol) was dissolved in 6 ml of DMF -70- This paper size applies to Chinese National Standards (CNS) Α4 specifications (210X29 &quot;? mm) ---------- Refer to --- ΐτ ------ line (please read the precautions on the back before filling this page) Ministry of Economic Affairs A7 458958 B7_ printed by the Consumer Standards Cooperative of the Central Bureau of Standards (5. Description of the invention) and stirred for minutes. N-methyl-2-methylamino-N- ((1R) —1- (methylaminomethylamidino) -2-phenylethyl) —dissolved in dichloromethane (12 ml) 3- (2-naphthyl) propanidine (500 mg, 1.24 mmol) was added * followed by diisopropylethylamine (0.425 ml, 2.48 mmol). The mixture was searched for 2 ϋ hours. DCM was evaporated in a stream of N2 * and 75 ml of ethyl acetate was added to the mixture and washed with sodium bicarbonate (2 X 50 ml, 5%) and potassium hydrogen sulfate (50 ml, 5%) plus M. The phases were separated and the organics were dried with sodium sulfate and evaporated in vacuo. The residue was dissolved in 10 ml of dichloromethane * cooled to 0-4 ° C and treated with TFA (10 ml) at 0-4 ° C for 10 minutes. The volatiles were removed using a stream of N2. The oily residue was dissolved in 25 ml of 70% He C N /0.1% TFA and diluted to 600 ml with fi20.

Semi-preparative H P L C large column, 40 ml / min * S operations 2 8-4 0 &amp; P 1 1 (.N Η 4) 2 S 0 4 '2 7 6 η Μ °

Seppak, freeze-drying -71- This paper size is applicable to China National Standard (CNS) A4 (2IOX297mm) --------- d ------ IT ------ line ( #Read the precautions on the back before filling this page) Printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and printed by the Consumer Cooperatives of the Central Standards Bureau of the Ministry of Economic Affairs and printed by 458958 A7 B7. 5 5 0 .7, found value 5 5 0. 1 Η PLCA 1 rt 3 1. 7 5 minutes Birt 3 6. 1 5 minutes Example 2 2 Perinedin 4 monocarboxylic acid fi- ((1R) — 1 — (N— ((1R) — 2-(4-iodophenyl) -1— (methylaminomethylamidino) ethyl) —S-methylaminomethylamidino) _2 — (2 —naphthalene ) Ethyl &gt; -N-methylamidamine

(2R) — 2— (N-tris-butoxycarbonyl-N-methylamino) —3 _ (4 _iodophenyl) propionic acid

Prepared according to Can J. Cheai. (1377), 55, 906. -72- This paper size applies to Chinese National Standard (CNS) Α4 specification {210X297 mm) --------- I ------ ΐτ ------ 0 (Please read the (Please fill in this page for attention) Printed by the Consumer Cooperatives of the Central Bureau of Standards of the Ministry of Economic Affairs

d5 895 B A7 B7 V. Description of the invention (W) 1 II-NMR: (CDC 1 3) d 1.34 (s, 4.5 H), 1.38 (s * 4.5H), 2.70 (s, 1.5H), 2.75 (s, 1.5H); 2.85-3.10 (tn-1H), 3.2-3.4 (m, 1H); 4.4-4,6 (nt 0. 5H), 6.9-7. 0 (m, 2H) ， 7.62 (d, J = 10Hz, 21? Z) &gt; 9.5-10 (bs, 1H) N— ((1 R)-2- (4 1 捵 benzyl) -1 1- (methylaminoformamidine ) Ethyl) -N-methylaminocarboxylic acid tertiary-butyl ester

(2R)-2- (N-tertiary-butoxycarbonyl-N-methylamino)-: 3- (4-iodophenyl) propionic acid (_2.00 g, 4.9 mmol) was dissolved In dichloromethane (20 ml). Hydroxybenzotriazole hydrate (G.67 g, 4.9 mmol) and 1-ethyl- 3 ™ (3-dimethylaminopropyl) -carbodiimide hydrochloride (0.99 g, 4 3 millimoles) was added and the mixture was stirred for 15 minutes. Methylamine ((38 grams of a 40% solution in methanol, 4.9 mmol) was added and the mixture was stirred overnight. Dimethane (40 ml) was added and the mixture was saturated with carbonic acid Sodium hydrogen solution (53 ml) M and sodium bisulfate (10%, 50 ml) solution plus M. The organic phase is dried (M g S 04) and the solvent is true-73- This paper size applies to Chinese national standards (CNS ) A4 size (210 X 297 mm) --------- ¾ .------ ΐτ ------. Ii (Please read the notes on the back before filling in this K) Economy The Ministry of Central Government of the Taiwan Bureau of Shellfish Consumer Cooperatives Co., Ltd. 45 895 8 A7 B7 V. Description of the invention Ql) Removed from the air. The residue uses ethyl acetate / hexane (2: 1) as the eluent on silicone (2. 5 X 20 cm) Chromatographic analysis K yielded 1.77 g of N — ((1 R) — 2— (4-iodophenyl) -1- (methylaminomethylmethyl) ethyl) -N-methyl Tris-monobutylaminocarbamate. 1 H-NMR: (CDCls) (selected peaks for the main rotational isomers) d 1 · 39 (s, 3H); 2.75 (s, 3H); 2.80 (d, 3H ); 3.2 B (dd, 1H) 4.88 (t, 1H). (2 R)-3-(4 -iodophenyl) -fi monomethyl-2-(methylamino) propanamide! Xx Ο Ν— ((im — 2— (4-Iodophenyl)-1- (methylaminomethylmethyl) ethyl) -N-methylaminocarboxylic acid tertiary-butyl ester (1.7 g; 4.Q mmol) was dissolved in Dichloromethane (10 ml) and trifluoroacetic acid (5 ml) were added. The mixture was stirred for 1 hour. Dichloromethane (30 ml) and water (31) ml) were added. Solid Sodium bicarbonate was added to pH 8. The organic phase was separated, dried (MgS04) and evaporated in vacuo to give 1.22 g of (2ΙΠ — 3-(4-iodophenyl) —N —methyl — 2 — (Methylamino) propanamide. This paper uses Chinese National Standard (CNS) AA specifications (210X297 mm). ---- ^ (Please read the back &amp; notes before filling out this page) Printed by the Central Standards Bureau of the Ministry of Economy, Shellfish Consumer Cooperative, 458958 A7 B7 V. Description of the invention (V-point 1 H-NMR: (CDCI3) d 2 · 2δ (S, 3H); 2.68 ί dd, 1 Η); 2.81 (d * 3HJ; 3,08-3.19 (®, 2H); 6.95 (d-2H); 7.63 (d, 2H) N-methyl-N- ((1R) -1- (N -methyl_N- ((IE) ~ 1 ~ (methylamine Formamyl)-2_ (4-iodophenyl) ethyl) aminomethyl)-2 ~ (2-naphthyl) ethyl) aminocarboxylic acid tertiary monobutyl ester

(2R) — 2_ (N-tertiary monobutoxycarbonyl monomethylamino) -3- (2-naphthyl) propanoic acid (1-10 g; 3.3G mmol) was dissolved in dichloromethane (10 ml ) And H0At (0.45 grams, 3.1 penicillin) and EDAC (G. 66 grams, 3.5 millimoles) were added. After 15 minutes of searching, (2R)-3- (4-iodophenyl) -fj-methyl-2-(methylamino) propanamide (1.0 g * 3.1 mmol) and diiso Propylethylamine (045 g, 3.4 mTorr) was added and the mixture was allowed to stir overnight. Dichloromethane (30 liters) was added and the mixture was saturated with sodium bicarbonate aqueous solution (3G ml) and sodium bisulfate solution (10%, 30 ml) and the M supernatant. The organic phase was dried (M g S 0 4) and the solvent was removed in vacuo. The residue uses ethyl acetate / hexane (2: 1) as -75- This paper is about the standard of China National Standard (CNS) A4 {210X297 mm) -II f I Order II, thread (please first listen (Please read the notes on the back and fill in this page) Printed by the Consumer Cooperative of the Central Government Bureau of the Ministry of Economic Affairs

458958 A7 _B7_ V. Description of the invention (The eluent is analyzed on silica gel (2.5 X 2 [I cm]) for color layer analysis to obtain 1.74 g of N—methyl—N— {(1R) — 1 — (S —A -N — ((1 R) »1— (methylaminomethylamidino) —2- (4-iodophenyl) ethyl) aminomethylamido) —2- (2-naphthyl) ethyl Tris-butylaminocarbamate. 1 Η-NMR: (CDCU) (peak for the selection of rotational isomers) d 1.38 (s, 9H); 2.18 (d, 3H); 2.45 (s, 3H); 2.75 (s, 3H) 5.05 {m- 1H); 5.42 (m, 1 H)-'(2R)-N- f (1R}-2- (4-iodophenyl) -1-1- (methylaminomethylmethyl) ethyl) -N- Methyl-2-methylamino-3-(2-naphthyl) propanamine N -methyl-N- ((1R) -1- (N -methyl-N-((1R) -1- (Methylaminomethylamidino) -1- (4-monoiodophenyl) ethyl) aminomethylamido) _2_ (2-naphthyl) ethyl) aminocarboxylic acid tertiary monobutyl-76-benzyl Paper size applies Chinese National Standard (CNS) A4 (210X297 mm) --------- ¾ .------ 1T ------ 0 (Please read the precautions on the back before (Fill in this page) 458958 A7 B7

V. Description of the invention (9 D is dissolved in a mixture of dichloromethane and trifluoroacetic acid and stirred for 15 minutes. Dichloromethane (20 ml) and water (30 ml) are added. Solid carbonic acid Sodium hydrogen was added to pH 8. The organic phase was separated, dried (MgStU) and evaporated in vacuo to give 1.4 g of (2 R) — N-((1R) — 2- (4-iodophenyl). )-1- (methylaminomethylamidino) ethyl) _N-methyl-2-methylamino (2-naphthyl) propanamide. 1 Η-NMR: (CDC 1 3) ((for The peak of rotation isomer selection) dl'79 (s · 3Ii); 2.02 (d-3H); 2.55 (s, 3H); 3.78 (dd · 1H); 5.44 (dd · 1H) 〇nn HI n II — I— I t Ding ---- I m! AK, 0¾. ， V * ^ (Please read the notes on the back before filling this page) Printed by the Consumer Cooperative of the Central Standards Bureau of the Ministry of Economic Affairs AJ = 广 U-

The size of this paper applies to Chinese National Standard (CMS) A1 2 3 specifications (210X294 mm) 1 (N— ((1R) -1- (N- ((1R)-1- (4 -iodine 2 phenyl)) 1 — (Methylaminomethylamidino) ethyl) _N_methylaminomethyl 3methyl)-2_ (2-naphthyl) ethyl) ~ N_methylaminomethylmethyl) # 4 pyridine_ 1 Tris (tributyl) carboxylic acid monoester Printed by the Central Sample Rates Bureau Shellfish Consumer Cooperative of the Ministry of Economic Affairs 458958 A7 B7 V. Description of the invention (W) 1-tertiary—butoxycarbonylpyridine—4-carboxylic acid (143 mg 0.66 mmol) was dissolved in dichloromethane (10 ml) and HOAt (90 mg, 0.66 mmol) and EDAC (140 mg, 0.73 mmol) were added after stirring for 15 minutes * ( 2 R)-N — ((1R) _2 — (4 —fluorenyl J — 1_ (methylaminomethylmethyl) ethyl) —N-methyl-2-methylamino- 3— (2 —Napthyl) propanamide (350 mg, 0.66 mmol) and diisopropylethylamine (85 mg, 0.66 mmol) were added and the warmed mixture was stirred overnight. Dichloromethane ( 20 ml) was added and the mixture was made up of a saturated aqueous solution of sodium bicarbonate (2 0 ml) and sodium bisulfate (10% &gt; 20 ml) were washed. The organic phase was dried (M g S) and the solvent was removed in vacuo. The residue used ethyl acetate as eluent on silicone (2 5 X 2 0 cm) chromatographic analysis K yielded 412 mg of 4 a (N — ((1R)-1-(N — ((1R)-2-(4 -iodophenyl)) 1 ~ (A Methylaminomethylmethyl) ethyl) -methylaminomethylmethyl)-2-(. 2 -naphthyl) ethyl) -N-methylaminomethylmethylmethyl) pyridine_1 monocarboxylic acid Tertiary butyl butyl. 4- (N-((1R)-1-(N-((1R) -2- (4-iodophenyl)-1- (methylaminomethylmethyl) ethyl ) -N-methylaminomethylamidino)-2_ (2-naphthyl) ethyl.)-N-methylaminomethylamidino) Sodium-1-carboxylic acid tertiary-butyl ester (412 (Mg Q.56 mmol) is dissolved in a mixture of dichloromethane (5 ml) and trifluoroacetic acid (5 ml) and stirred for 5 minutes. Dichloromethane (213 ml) and saturation National Standard (CNS) Α4 specification (210 × 297 males) --------- equipment -------- ΐτ ---- -^ (Please read the notes on the back before filling out this page) 9 9 Printed by the Employees' Cooperative of the Central Bureau of Standards of the Ministry of Economic Affairs A7 _B7_ V. Description of the invention (7 Li's sodium bicarbonate solution (2Q ml) was added. Solid sodium argon carbonate was added to pH 8. The phases were separated and the hydration phase was dried (MgS04) and evaporated to give 255 mg of the title compound. 1 Η-NHR: (CDC 1 3) (t peak for the selection of rotational isomers) d 2 '32 (d * 3H); 2.58 (s, 3 Η); 2.68 (s, 3 Η); 5.33 (at -1Η); 5. δ4 (t, 1Η) HPLC: rt = 3 3. 3.5 minutes (A 1) PDMS: m / z 640.8 f M + H) + abbreviation HBTU: hexafluorophosphate 0- (benzotris Azole-1—1) _1,1 * 3,3_tetramethylenteric gun NMP: N-methylpyrrolidone HATU: hexafluorophosphate 0- (7-azabenzotriazolyl) -1 , 1,3,3-tetramethylurea

Tr t —: Tribenzylyl-7 9-This paper uses Chinese National Standard (CNS) A4 (210X297 mm) for this paper. I Thread (please read the precautions on the back before filling this page) Λβδ ^ 58 Α7 _Β7 V. Description of the invention (; $ HOBT: 7 ~ hydroxybenzotriazole hydrate 3 ~ ΑιΒ: 3-aminomethyl benzamidine N-Me- 3- AMB: 3-methylamino group Methyl benzamidine --------- I ------ ΪΤ ------ 0 (Please read the precautions on the back before filling out this page) Staff Consumption of Central Bureau of Standards, Ministry of Economic Affairs Printed by the cooperative -80- This paper size applies to China National Standard (CNS) A4 (210X297 mm)

Claims (1)

Λ Α845 89 | 8 The scope of patent application. A generalized formula H '(please read the description on the back before filling out this page) A- B-C-D {-E) p where P is G or 1; A is lotus or R1 — (CH2) q— (JO Γ— (Cfi2) S— CO. Where Γ is 0 or 1; 1 is piperidinyl or N (R2) — R3 is an employee cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Printed where R2 and R3 are independently hydrogen or Ci alkyl; and when r is 1, it is -C (R1S) (R 1 7) A The size of the private paper applies the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 458958 AS B8 CS D8 6. Application scope of patents where P 6 and R 1 7 are each independently G-4 alkyl, S is (G) t — (Γ) U, where t and u are each independently 0 or 1 and t + U is 0 or 1; G and Η are amino acid residues selected from the group consisting of natural L-amino acids or their relative D-isomers such as His or Ala, or non-natural amines Basic acids such as amino-isobutyric acid, 3-aminomethylbenzoic acid * nepicolinic acid or isopiperidic acid; C is the formula of —fiH — CH ((CK2) w — R4) — C0 —D -Amino acids, where w is 1; and R4 is selected Contains one of the following groups 〆〆D, when P is 1, it is the D-amino acid of the formula -NRZ 0 —CH ((CH2) k— R5) —CO— or, when P is 0, D is— NR: 0-CH ((CH2) 1 — ip -2-This paper size applies to China National Standard (CNS) A4 (210 X 297 public love) ^^ 1 HJ:. 』^^ 1. _ 1 ^ 1 I -·: In ^^ 1 S. —II Order --------- ·% (Please read the precautions on the back before filling out this page) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Λ 5 8 0 ^ ρ · AS BS CS D8 patent application scope) -CH2-R (or one.-CH ((CH2) m- R5)-COR6, where k is 1; i; si is 1; R2 ° In order to select one group Rs of self-containing Ci-4 alkyl group, to select one group M of self-contained M, which is selectively replaced by halogen accumulation M; and ------------ ϊ * --------- ^ ------- 1 II (Please read the notes on the back before filling in this page) Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 别 R6 is a 0Η or a N (R7) — R8, where R7 and R3 are independently hydrogen or C i -4 alkyl; E, when p is 1, it is -NH-CtMR1 0) — {CH2) v R9, of which -3- paper Standards are applicable to Chinese National Standard (CNS) A4 specifications (2) ϋ X 297 mm. Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed by 458958, reserved for CS D8. 6. The scope of patent application is 0 or an integer of the following group: 1 , 2, 3, 4; ίϊ3 is hydrogen, morpholinyl, iMR1-R1 · ^, Wherein η is G denier, R1 9 is hydrogen or "-4 alkyl group. S1 1 and R1 2 are each independently hydrogen or C ^ -4 alkyl group, and a1 °, when P is 1, the stem is optional and contains one Η Or a group of CO—R1 3, where Ri3 is a NUI4) —R15, where and is hydrogen; all amidine bonds in formula I, except for the bond between C and D, can be independently passed through a bond — NR 1 S — Replaced, where Υ is --C0— and R1 3 is hydrogen Ci-4 alkyl; or an acceptable salt thereof; and the following chemical inclusions are excluded—4 This paper is applicable to China Standard (CNS) A4 specification (210 X 297 mm) 1 III n I- H---J ^.-Iin ft-one nJI 1 1 n ϋ il Γ— I (Fill in this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 458958 g D8 6. Scope of patent application (3-aminomethylbenzyl)-D--N-Me-D-Phe-Lys-NH2, ϋ — Aib — His— 0-2Nai — H — Me — D — Phe— Lys— 9 H— Aib — His — S — Μθ— D — 2Nal — N — He — D — Phe — Lys 1 2, 3 — F H — Aib — His — D — 2Nal — S — Me — D — Phe — flH) — 1 — Morphine, 2 — (H — Aib — His — D — 2Nal — N — He ^ D — Phe— NB) _ (i —methyl—2 —fttrolyl) ethane, ((3R) —piperidinylcarbonyl) —N-Me-D— Mal—N-Me-D—Phe ** Lys — NH2, 3-C (3-aminomethylbenzyl) -D- 2 N a 1-S-He-D -Phe- NH) _ 1-morpholinyl propane, 2-(ti-Aib — His — N — Me — D — 2Nal — N — Me — D — Phe -5- This paper size applies to China® Home Standard (CNS) A4 (210x 297 mm) n I n tl I —1 I «^ 1 I— I— I 4 J n In I) aJt. —I KK n! I (Please read the precautions on the back before filling out this page) The Employees ’Cooperatives' Seal of the Intellectual Property Bureau of the Ministry of Economy-4 5 8 9 5 P § D8 VI. Application scope of patents_NH)-(1-Methyl-2-pyrrolidinyl) ethane, 2-i ((3R) -piperidinecarbonyl) -N-Me-D- 2Nal-N-M e — D — P he — Ν Η) — (1 -methyl- 2-® pyrrolidinyl) ethane, 2 — ((3 — Methylmethyl benzamidine) -N-Me-D-2fial— S -Me-D-Phe- NH) _ (1 monomethyl-2 -pyrrolidinyl) ethane, 3-f H-Aib ~ His — ί — He — D — 2Nal — N — He — D — Phe _SH) -1 —morpholinylpropane, 3- (((3R) —piperidinylcarbonyl)-^ 6-0-2! ^ 1- wish-Me-D-Phe- NH) -1 -morpholinylpropane, 3-((3-aminomethylbenzyl) -N-Me-i)-2 N a 1-N -Me-D- Phe- NH) — 1 -morpholinylpropane, 2- ((3-aminomethylbenzyl) -D — 2Nal-f) -Me-D -P he-N Η)-( 1-methyl-2-pyrrolidinyl) ethane, 2- (((3β) pyridinylcarbonyl) -D-2Nal-N-Me-D-Phe_NH)-(1-methyl-1 2-ffi; Pyridine) ethane Applies to China National Standards (CNS) A4 specifications (21ϋ χ 297g t) ----- ϊ-Ε Γ---I · 1, I n: I tl -1 -、 Ί H «^ 1 ^^ 1 ^! ·· I—-Γ (please read the meanings on the back before filling out this page) 458958 A8 B8 CS D8 VI. Application scope f [-----I. in ('II-u 1 一 · OJ_ n I tr-] n ϋ I (Please read the following:-Italian matter before filling out this page) Intellectual Property Bureau, Ministry of Economic Affairs, Consumer Consumption Cooperative Printing 2. The compound according to item 1 of the application patent, in which A is S, 3 — A Μ B * ί — H e — 3 — ΑΜΒ or A ib 0 3. According to the scope of the application, Compounds, where t is 1 denier, U is 0 denier, G is selected from the group consisting of 3-aminomethylbenzyl, piperidinecarboxylic acid and isotrenic acid. 4. According to the first patent application circle Compound, of which C is selected. This paper size applies Chinese National Standard (CNS) A4 specifications (210 * 297 mm). Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs. 4 5 B 9 5 f B8 D8. 1)-2-N ai and D — P he. 5. The compound according to item 1 of the scope of patent application, wherein when p is 1, D is D—Phe or D—2Nai. The compound according to item 1 of the patent application circle, where &gt; When? When it is 0, D is D — Phe— ΝΗ2 or D-2Nal —. 7. According to the application of the patent application of the patent application, it is between k and B * between B and C, between D (E) p, K, and at least one between G and K Amidine is replaced by a CO-S (CH3)-plus M. 3. The compound according to item 1 of the patent application, which is a compound selected from any of the following (R) — 2 — ((3-aminomethylbenzyl) —N—kD-2Nal-S — He) -3-phenylpropanol, or its TFA salt; 3- ((3-aminomethylbenzyl)) N—Me-D—2Nal-N —Me—i) _Phe — NH) — —Dimethylaminopropane, or its TFA salt; -S- This paper size applies to China National Standard (CNS) A4 (210 X 297 male S) ------------ ------- Order '-------- (Please read the notes on the back before filling in this page) d 5 895 8 Λ8 R8 CS D8 f. Application scope 3— (((3R) — 3- # Pyridylcarbonyl) —N ~ Me — D— 2Nal-N -Me- D- Phe- SH) —1— (ΐ, N-dimethylaminopropane, or its TFA salt; 2 ~ (( (3 R)-3 -N-pyridinylcarbonyl) -N — H e-D — 2 N ai — N —Me— β- Phe— NH) — (1 —methyl-2-pyrrolidinyl) ethane, or Its TFA salt; H — Aib — His — D — 2Nal — N — Me — D — Phe — Ser — NH2, or its TFA salt; (3 — Junylmethyl cage carpentyl) — D — 2Nal — N — fie— D ~ Phe —Lys— NH2, or its TFA salt; (4-Nanidinecarbonyl) -D-2Sal-N-He-D-Phe-NH2, or its TFA salt; ((3R) — 3 — Pai Pao Mito) — U — 2Nal — H — Me — D — Phe — Take 2 or its TFA salt; (3 —Waistylmethylbenzyl) — β — P hs — S — H 0 — D — P h θ —NH2 * or its TFA salt; this paper size applies the Chinese National Standard (CNS) A4 (210 X 297: 坌) f. 'II 1 · i I ------. I — I — ---- &quot; '^ &gt; f (Please read the left-hand items on the back before filling this page >> Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, ABCD 458958, Fan Li, please apply for N Six Economy Ministry of Intellectual Property Bureau—Industrial and Consumer Cooperative Cooperatives &quot; (3-Fujinomethyl: ¢: Jiamuji)-Ke-β-Phe--β-Phe-Lys-NHz, or its TFA salt; f (3R ) — 3 -piperidine carbonyl) Ue-β- Phe-N-Me- D- Phe- Lys- 02, or its T FA salt; H — Aib— His-N — He — D — Phe — ίί — Me- D — Phe— Lys 1, or its TFA 翳; ((3R) — 3-cheek Carbonyl) -N-Me-D—2Sal-N—Me —D-Phe— 〇2, or its TFA salt; (2R) — 2— ((3-aminomethylbenzylmethyl))-(i- Me— D -2NaI — N — Me) — 3— (2-naphthyl) propanol, or its TFA salt; (j —methylmethylbenzyl) —N — Me— D — 2Nal — N — fie -D-Piie-NH2, or its TFA salt; ((3-aminoaminobenzyl) -N-Ke-D-Phe-NH) -1-dimethylaminopropane, H-Aib- His--Me-D-2NaI-N-Me-D ~ Phe-NK 2, or its TFA salt; Ί〇- This paper size applies to Chinese national standard (CNSU4 specification (210 χ 297 mm)! &Gt; III —1 ! Ϊ1 II nn I f I-m _—Γ--n. 1 I I ϋ I— _ I (Please read the $ I-matter on the back before filling this page) 458 ^ 58 A8 B8 C8 D8 VI. Application scope (3 ™ Banylmethylbenzyl) -fj — He — D — 2Nal — N — He —D — Phe ™ Lys — NH2 'H-Aib— Ala ™ D — 2Nal — N — Me — D — Phe- * Lys — SHz, or its TFA salt; H — Aib-fiis — D-2Nal — S — Me-β — Phe_, or Its TFA salt; 3-((3-aminomethylbenzyl) -N-Me-D-2Nal-N-He-D-Phe-NH)-1-morpholinyl complex, (3- Limyl methyl sylmethionine)-N-Me — D — 2Nal — N — Ke ™ D — Phe — Nfi ~ He * 3 — ((3-methylaminomethylbenzyl)) ^ | — 1 ^ _1)-ZSal-N-Me-D-Phe-NH) -1_N, N-dimethylaminopropane * (3-limylmethylmethanoyl) -N — Me— D — 2Hal — N — Me —Fhe — Ν — Μθ2, -11- This paper size applies the Chinese National Standard (CNS) A4 specification (2.10 χ 297 Male S) ----- 1 ri 3 1-ni &lt; ^ in I m ο · , I [n. Ii I ^ '(Please read the back; please fill in this page before filling out this page) Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs printed 5 458958 A8 Β8 C3 D8 t, patent application scope H ~ Aib ~- His-N — Me — D — 2Nal — N — Me — D — Phe — NH 3 -Waistylmethylbenzylidene-N-Me-D ~ 2Nal-N—Me-D-Phe-NH— CH3, Or its TFA salt; 3-methylaminomethylbenzylidene-N-Me-D-2Nal-N-Ke-B-Phe-NH-CH3, Its TFA salt; H—Aib—His—N—He—D— 2Nal—N—Me ~ D—Phe-NΗH e, or its HC 1 salt; K and piperidine-4—carboxylic acid—N— { (1R)-1- (N — ((1R) -2- (4 ~ fluorenyl) -1- (methylaminomethylmethyl) ethyl) -N′-methylaminomethylmethyl) 2- (2-naphthyl) ethyl) -N-methylamidamine, or a pharmaceutically acceptable salt thereof. 3. — An extinction composition for stimulating the release of growth hormone from the lower brain gland, which comprises a compound according to any one of the applied patent scope Nos. 丨 8 or an extinction acceptable salt thereof and a Pour an acceptable carrier or diluent together as an active ingredient. -1 2-This paper size applies to China National Standard (CNS) A4 (210 X 297 male S) ------------------- Order --------- --- line (Please read the precautions on the back before filling out this page) Printed by the Employees' Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs, printed 458958 Α8 Β8 CS D8 The pesticide composition claimed in item 9 of the patent range is a military dosage form comprising from 10 to 200 mg of a compound according to any one of the items 1 to 8 of the patents or the above Accepted salt. U. The K composition according to item 9 or 10 of the patent application, which is applied as D-coat, transdermally, nasally, lung, or parenterally. 12. The compound according to any one of claims 1 to 8 of the patent application or its pharmaceutically acceptable salt, which is used as K 蕖. 13. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 of the scope of the patent application, which is a B medicine released from the inferior gland as a preparation for the spinal growth hormone. 14. The compound according to any one of claims 1 to δ or a peony acceptable salt thereof, which is pseudo-used as a preparation for application to an animal to increase its growth rate and extent and increase its milk Or wool production, or treatment of cyanosis with κ. -13- This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) -------- ---- ---- IIII Order '11111 — *: ^ (Please read first Please fill in this page on the back of the matter) Λ Α845 89 | 8 The scope of patent application. A generalized formula I '(Please read the notice on the back before filling out this page) A- Β-C-D {- E) p where P is G or 1; A is lotus or R1 — (CH2) q— (JO Γ— (Cfi2) S—CO. Where Γ is 0 or 1; 1 is piperidinyl or N (R2) — R3 Printed by the staff of the Intellectual Property Bureau of the Ministry of Economic Affairs, the cooperative, where R2 and R3 are independently hydrogen or Ci alkyl; and when r is 1, it is -C (R1S) (R 1 7) A Private paper size applies to China National Standard (CNS) A4 specification (210 X 297 cm)