TW474945B - Peptide derivatives having analgesic activity and capable of orally admistration - Google Patents

Abstract

Compounds represented by the general formula: HN=C(R1)-AA1-AA2-AA3-AA4-OR2 or salts thereof, useful in preventing and treating pains, wherein R1 represents C1-6 alkyl, amino, etc; R2 represents hydrogen, C1-6 alkyl, etc; AA1 represents an optionally substituted O-acyl-L-tyrosine residue, etc; AA2 represents a D-5-oxonorleucine or D-5-hydroxynorleucine residue, etc; AA3 represents an optionally substituted L-phenylalanine residue, etc; and AA4 represents a β-amino acid residue represented by the formula: -N(R8)-CH(R9)-CH(R10)-CO- (wherein R8, R9 and R10 represent each hydrogen, C1-6 alkyl, C2-6 alkenyl, etc.).

Description

474945 A7 B7 V. Description of the invention (1) Detailed description of the technical field Please read the notes on the back and then fill out this page. The present invention relates to a peptide derivative that exerts pharmacological effects such as pain by acting on opioid receptors and the like. Technical background In the first half of the 1970s, it has been proven that opioid receptors capable of binding to opiates such as morphine exist. The opioids are now divided into three categories: μ, δ and κ. It was found that morphine mainly acts as a stimulant on μ receptors, and can exhibit pharmacological effects such as nausea, inhibition of bowel movement, and inhibition of breathing. After 1975, endogenous morphine substances bound to opioid receptors were successively discovered. So far, all of these substances are peptides, collectively known as opioid peptides. The pharmacological effect of opioid peptides is basically the same as that of morphine, but because of the substances originally present in the living body, it is expected to be a safer drug than morphine. However, natural opioid peptides also have problems with their dynamics in the body and are not used as pharmaceuticals. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs. In the 1980s, morphine containing D-alanine was isolated from frog skin. It has been confirmed that the substitution of morphine into the ventricle is about 1,000 times stronger than that of morphine, and it is also more stable in the body. Later, a synthetic opioid peptide containing D-amino acid was proposed, and a synthetic opioid peptide with high / c receptor selectivity was particularly expected as a non-narcotic pain medicine, and clinical trials were carried out immediately. . However, there are still doubts about its properties, especially the side effects caused by κ stimulants, and economic considerations as to whether it can be used as a pharmaceutical. In addition, the synthetic opioid peptides are used as oral agents. 3 I 031 1 This paper size is applicable to the Chinese National Standard (CNS) A4 specification (210 × 297 mm) 474945

Α7 '\ B7 I Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (difficulty) For example, it has not become an MS homologous drug that replaces the morphine sulfate protonation D dosage widely used in cancer pain treatment drugs in recent years Instead, the present inventors have provided an oligopeptide derivative having L-Tyr- (L or D) -Arg-Phe as a basic skeleton and an N-terminal fluorenyl group (International Publication WO 95/24421). (Same as W097 / 10261 and same as W097 / 10262), but it does not mean that its derivatives will necessarily meet its biological effectiveness when administered orally. When the daily dosage of MS homologues is increased to more than 1 g, taking will occur. In difficult cases, side effects such as pruritus due to histamine free action have also been found, and the administration has to be discontinued. Therefore, alternative medicines with higher safety and efficacy than morphine and oral administration can be expected. DISCLOSURE OF THE INVENTION The inventors of the present invention have made intensive research in order to solve the above-mentioned problems. For example, they used L-tyrosine-D-methionine imine-phenylalanine-N-methyl-β-alanine Is the basic skeleton, in the oligopeptide derivative with iminoethyl group at the N-terminus, The hydroxyl group of the 1-position tyrosine is amidated and / or the C-terminal carboxyl group is esterified, which can provide opiate peptides that can exhibit superior pain-relieving activity when administered orally. The present invention has been further studied and completed. That is, the present invention provides a compound represented by the following formula (I) or a compound thereof: HN = C (R1) -AA1-AA2-AA3-AA4-〇R2 [wherein R1 is Cm alkyl, amine, mono Cm alkylamino, diCV6 alkylamino, or phenyl; R2 represents a hydrogen atom, (V16 alkyl, halogenated (V16 alkyl, hydroxyl 0 ^ 16 alkyl, Cm. Alkoxy) Cm, alkyl, CV6 alkoxy, Cm substituted by the group This paper size applies to Chinese National Standard (CNS) A4 (210 X 297 mm) 2 (correction page) 310311 ^^ 1 II 1 I _ ι_ϋ I— I ϋ, L, SS < Hi 1 > n an -ϋ _ ^ ϋ ϋ I βκβ * 1 ^^ 1 ^^ 1 ^^ 1 I 丨 ^ (Please read the notes on the back before filling this page) 474945 A7 B7

V. Description of the invention (3) Alkoxy substituted (^ _6 alkyl, amine 0 \ .16 alkyl, monoalkylamino C ii 6 fluorenyl, di C i-6 amine amine C it 6 , C 3.! 0 cyclofluorenyl, C 3 · i❶ cycloalkyl substituted Cm alkyl, C2-16 alkenyl, C2.16 alkynyl, c6. &Quot; aryl, Cfu aryl substituted Cm alkyl C6-16 aryl-(^, alkoxy-substituted Cw alkyl, phthalone group which may have a substituent, Cp, alkoxycarbonyloxy Cu alkyl, or C2_7 alkoxyoxy Cm alkyl; AA1 Is the L-cc-amino acid residue represented by the formula: X 0

(Please read the notes on the back before filling this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs {where X is a hydrogen atom or the formula: -CO-Y-R3 is shown in the formula (where R3 is shown Cm6 alkyl, hydroxy Cm6 alkyl, amine Cm6 alkyl, mono 6 alkylamino < ^. 16 alkyl, di cv6 alkylamino (ν16 alkyl, C3_1 () cycloalkyl, Cp.cycloalkyl Substituted Cm alkyl, C2.16 alkenyl, C2.16 alkynyl, Cm. Aryl, C6_1 () aryl substituted Cl6 alkyl, or heterocyclyl, R4 and Rs each represent a hydrogen atom, (V6 Alkyl, halogenated Cm alkyl, or halogen atom, Y represents an oxygen atom or a single bond}; AA2 is a D_oc-amino acid residue represented by the following formula:

This paper size applies Chinese National Standard (CNS) A4 specification (210X 297 mm) 03 1? 474945 A7 B7 V. Description of the invention (4 R6 I (CH2) n

(In the formula, R6 represents an amine group, a mono-Cm alkylamino group, a ^ -6-amino group, a guanidino group which may have a <^ 6 alkyl group, a 1-imino group Cm alkyl group, or a urea which may have an alkyl group. (V6 alkylthio, C ^ 6 alkylsulfinyl fluorenyl, Cm alkyl sulfonate, Cm fluorenyl, or 1-hydroxy Cm alkyl, η is an integer of 1-4); AA3 is the following formula Α · amino acid residues shown:

(Please read the precautions on the back before filling this page)

NH I

CHO Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs (where R7 represents a hydrogen atom, a Cm alkyl group, a halogenated Cm alkyl group, or a halogen atom); AA4 is of the formula-N (R8) -CH (R9) -CH Β-amino acid residue represented by (Rie) -CO (wherein R8, R9, and R1D are each independently shown with a hydrogen atom, a Cm alkyl group, a C2 "alkenyl group, a C2-6 alkynyl group, and a Cq. Aryl group Or a C6_16 aryl substituted Cl6 alkyl group); however, R6 is an amine group, a single q, an alkylamino group, a Cm amine group, a guanidyl group that may have a Cm alkyl group, a 1-imino Cm alkyl group, may have (U6 alkyl ureido, &lt; ^ 6 alkylthio, C ^ 6 alkylsulfinamidinyl, or Cle6 alkylsulfinyl, and R2 and X are not included in the case of hydrogen atom].

This paper size applies the Chinese National Standard (CNS) A4 specification (210X 297 mm) 4 310311 474945 A7 B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (5) 4 From another perspective, this The present invention can provide a useful pharmaceutical product containing the compound represented by the above formula (I) or a physiologically acceptable hydrazone as an active ingredient, for example, it can be used as a painkiller. In a preferred form of the pharmaceutical product, it is a pharmaceutical product in the form of a medicinal composition which can provide the compound represented by the above formula (I) or a physiologically acceptable hydrazone as an active ingredient and a pharmaceutical additive. In another aspect, the present invention also provides the use of the compound of formula (I) or a physiologically acceptable puppet thereof used in the manufacture of the above-mentioned pharmaceuticals; and a method for preventing and / or treating pain, including A method comprising administering an effective amount of a compound represented by the above formula (I) or a physiologically acceptable tadpole to a mammalian mammal. Best Mode for Carrying Out the Invention In the above definition, "alkyl" or a substituent containing one or more alkyl moieties (such as monoalkylamino, haloalkyl, alkoxy, Moxy substituted The "alkyl moiety" in the "alkyl group" may be either straight or branched. For example, the so-called Ci.6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and more specifically, examples include methyl, ethyl, n-propyl, isopropyl, n-butyl, Second butyl, third butyl, n-pentyl, neopentyl, n-hexyl and the like. For example, in a substituent having one or more Cl6 alkyl portions, the Ci.6 alkyl portion may be a Cp6 alkyl group as exemplified above. In a dialkylamino group or a substituent containing a diamidoamino moiety (e.g., a dialkylaminoalkyl group), the two alkyl groups substituted on the amino group may be the same or different. The term "halogen" in this specification means any one of fluorine, chlorine, bromine or iodine. There are no particular restrictions on the number and type of halogen atoms substituted on the halogenated alkyl group, and any one of the monohalogenated alkyl group to the fully halogenated alkyl group can be read on the back of this page.

This paper size applies to China National Standard (CNS) A4 specifications (210X 297 mm) 31031t 474945 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 B7 V. Description of invention 发明) Use. When two or more halogen atoms are present, they may be the same or different. The halogenated alkyl group may be, for example, trifluoromethyl group, '2,2,2-trifluoroethyl group, but it is not limited to the above examples. The substitution position and number of hydroxyl groups on the hydroxyalkyl group are not particularly limited. For example, 1 to 4, preferably 1 to 2, and most preferably 1 hydroxyl group may be substituted at any position. As the hydroxyalkyl group, for example, hydroxymethyl can be used. Examples of the alkoxy-substituted ethane group include methoxymethyl, ethoxymethyl, methoxyethyl, and n-heptyloxymethyl. Examples of the alkoxy-alkoxy-substituted alkyl group include Such as methoxymethoxymethyl, methoxyethoxymethyl, these groups are not made of special P. The number of amino groups substituted on the aminoalkyl group is preferably one or two, and most preferably one. Although the number of rings of c3.1 () cycloalkyl is not particularly limited, it is preferably 1 to 3, and examples thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and auryl. The C3.1_1 cycloalkyl group-containing substituent (for example, C3_1Q cycloalkyl substituted Cp6 alkyl, etc.) may have a C3_1Q cycloalkyl portion as a cycloalkyl group as exemplified above. 6. These cycloalkyl rings may also have one or more C i. 6 alkyl groups on the ring. The C2-16 alkenyl group and &lt; 2.16 alkynyl group may be either straight or branched. Although the number of double or triple bonds contained in each of these groups is not particularly limited, it is preferably one to four, more preferably one or two, and most preferably one. In the above definition, the "alkyl moiety" in "aryl" or a substituent containing one or more aryl moieties (for example, aralkyl, arylalkoxy substituted alkyl, etc.) may be, for example, , Phenyl, * 1 and so on. The arylalkoxy group may be a Toxy group, a phenethyl group, or the like. The arylalkoxy group may be benzyloxy, phenethyloxy, and the like. The phthalone group which may have a substituent may be one or two of a benzene ring part. Applicable to the national paper (CNS) A4 specification (210X297 mm) at this paper size. 6 310311 474945 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs A7 _ B7 V. Description of the invention (7) The phthalone group on the substituent. Examples of such substituents include Ci-6 alkyl, halogenated alkyl, Ci.6 alkoxy, hydroxyl, halogen atom, amine, mono- or di-G6 alkylamino, carboxyl, Ci.6 alkoxycarbonyl, Cu Alkylcarbonyl, sulfonic acid, etc. are not limited thereto. The phthalone group is preferably unsubstituted. The alkoxycarbonyloxyalkyl group may be, for example, an ethoxycarbonyloxymethyl group, and the alkoxycarbonyl group may be, for example, an ethoxymethyl group. The heterocyclic group represented by R3 may be, for example, a saturated or partially unsaturated group containing 5 to 10 members of 1 to 2 heteroatoms (eg, nitrogen, oxygen, sulfur, etc.) as ring constituent atoms. Or, when the aromatic heterocyclic group ❶ contains two or more heteroatoms, the types of the heteroatoms may be the same or different. In the above definition, the "fluorenyl group" in the "fluorenyl group" or the substituent containing a fluorenyl moiety (for example, fluorenyl group, etc.) may use, for example, an alkyl fluorenyl group such as ethyl fluorenyl and propionyl, and trifluoroacetamidine Halogenated alkyl fluorenyl, phenyl fluorenyl, aryl fluorenyl and the like, phenyl, fluorenyl and the like. The substitution positions of R4 and R5 in the group shown by AA1 and R7 in the group shown by AA3 on the benzene ring are not particularly limited. The halogenated alkyl group represented by R4, R5 or R7 is preferably a trihalogenated methyl group. In addition, in the present specification, the term "amino acid residue" has the same meaning as commonly used in the field of peptide chemistry, and more specifically means an amino group and a carboxyl group related to an oc position from an α amino acid, or β -Structures left in the amine group and the carboxyl group associated with the β position in the amino acid with hydrogen atoms and / or hydroxyl groups removed, respectively. However, in the peptide derivative represented by the above formula (I), R6 is an amine group, a mono Cm alkylamino group, a Cm amine group, and a guanidino group which may have a Cm alkyl group NH-C (NH2) = NH] , 1-imino C, _6 alkyl, may have C!-, Alkyl This paper size is applicable to Chinese National Standard (CNS) A4 specification (210X297 mm) 7 310311 474945 A7 B7 5. Description of the invention (8) Read the notes on the back and fill in the ureido (-NH-CO-NH2), Cm alkylthio, Cle6 alkylsulfinyl (-SO-C ^ alkyl) or 〇ν6 alkylsulfonyl group (-S02-CM alkyl), and R2 and X are not included in the scope of the present invention when they are both hydrogen atoms. The peptide derivative of the present invention represented by the above formula (I) has an asymmetric carbon atom. Except for those specifically mentioned in the above definition, it may have any stereo configuration of S- or R-. When a sulfur atom (such as a fluorene) substituted with an oxygen atom has an S- or R-stereo configuration, the stereo configuration may be either. As an example, when A-A2 shows D-methionine sulfonium residue, D-methionine- (RS) -sulfonium residue, D-methionine- (R) -sulfonium residue, Any of the D-methionine- (S) -fluorene residues is included within the scope of the present invention. A peptide derivative having an appropriate stereo configuration can be selected from the viewpoints of in vivo stability and the like. Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs The peptide derivative represented by formula (I) of the present invention includes any optically active or racemic form, diastereoisomeric form, or any mixture of the above compounds. In addition, the peptide derivatives of the present invention include free form and amidine form in addition to acid addition amidine, ammonium amidine, or organic amine amidine, such as osmium osmium, osmium acetate, or p-toluenesulfonic acid. Any hydrate and solvate of the peptide derivative. In addition, in addition to the peptide derivative represented by the general formula described above, the dimer to polymer compound of the peptide derivative described above, and the peptide derivative obtained by combining the C-terminus with the N-terminus Cyclic compounds are also included within the scope of the invention. Compounds of the present invention represented by formula (I); ^ Specific examples include: (1) a compound in which R1 is a Ci.6 alkyl group or an amine group, preferably a compound in which R1 is a methyl group, an ethyl group, or an amine group; (2) ) A A3 is a substituted or unsubstituted L- or D-phenylalanine residue. Compared with the standard of this paper, the Chinese National Standard (CNS) A4 specification (210X 297 mm) 474945 A7 B7 V. Description of the invention (9 ) AA3 is preferably L-phenylalanine residue, D-phenylalanine residue, LP-fluorophenylalanine residue, DP-fluorophenylalanine residue, L-0-trifluoro Compounds of methylphenylalanine residues or D-O-trifluoromethylphenylalanine residues; (3> AA4 is a compound of N-methylalanine residues; (4) AA1 is L · casein Amino acid residues, 2,6-dimethyl-L · tyrosine residues, 0-fluorenyl-L-tyrosine residues, 0-alkoxycarbonyl-L-tyrosine residues or phenoxy Compounds with carbonyl-L-tyrosine residues; (5) AA2 is a compound with D-methionine residue, D-arginine residue or D-citrulline residue; (6) AA2 Compounds which are D-N5-acetamidoguanine residues, D-5-oxohexyl amino acid residues or D-5-hydroxyhexyl amino acid residues; (7 ) R2 is (V〗 6 alkyl, C6.1 () aryl, C "16 aryl substituted (: Bu 6 alkyl, alkoxy substituted alkyl, C] -6 alkoxycarbonyloxy Ci. 6 alkyl or phthalone-based compounds; and (8) compounds in which the specific amino acid residues or substituents in the above (1) to (7) are appropriately combined, but the present invention is not limited to the above compounds. Ministry of Economic Affairs Intellectual Property Among the best-printed compounds of the present invention printed by the Bureau's Consumer Cooperative, the following are listed: (WR1 is methyl, AA1 is L-0 -ethyryl tyrosine residue, and AA2 is D-methionine sulfonium residue Compounds where AA3 is L-phenylalanine residue, AA4 is N-methyl-Ling-alanine residue, and R2 is a hydrogen atom; (10 ^ R1 is methyl, and AA1 is L-tyrosine residue AA2 is a compound of D-methionine sulfonium, AA3 is an L-phenylalanine residue, AA4 is an N-methyl- / 5-alanine residue, and R2 is a compound of (CH2) 15CH3; This paper size applies to Chinese National Standard (CNS) A4 specification (210X297 mm) q 1 / J 1 1 474945 A7 _ B7 V. Description of the invention (10) Please read the precautions on the back before (11) R1 is methyl, AA1 is L-0-ethytyrosine Residue, AA2 is a D-methionine sulfonium residue, AA3 is an L-phenylalanine residue, AA4 is an N-methyl-ys-alanine residue, and R2 is a compound of -ch (ch3oco2c2h5; (12) Ri is methyl, AA1 is L-tyrosine residue, AA2 is D-5-hydroxyhexylamine residue, AA3 is L-phenylalanine residue, and AA4 is N-methyl-Lu -Alanine residues, compounds where R2 is a hydrogen atom; (13) ν is methyl, AA1 is an L-tyrosine residue, AA2 is a D-methionine sulfonium residue, and A A3 is L-benzene Alanine residue, A A4 is a compound of N-methyl · cold-alanine residue, R2 is-(CH2) 7CH3; (M) R1 is methyl, AA1 is 2,6-dimethyl-L -Tyrosine residue, AA2 is D-N5-acetamidoguanine residue, AA3 is P-fluorophenylalanine residue, AA4 is N-methyl-dot-alanine residue, R2 is CH2CH3 The Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs has printed a copy of this book. No sexual promise. In the case of divorce therapy, the content is used for the treatment of sub-tours. Study, the effect of weaving pain pain peptides to be treated by the enemy, and the 4 wins are effective, «A kind of painkillers can be weaker than Yiming, ^ or pain and use it as the source Is it possible to use morphine as a natural alternative to make a difference? S can be combined to make the pain more periodical, using M-shaped U should be U-shaped questions for _㈣ ㈣ 随 对 g wins asking pain 3S Zhi U is more associated with sexual intercourse for 1 life, sex {, using low-pain, heterogeneous K-type substance as the result of Dongying. The effectiveness of the two compounds is low. Do you know that the hair has pharyngeal content and the number of peptides that it has been used for? Is the chemical medicine better than the previous hair? It can be used for filling and using hair. 3 丨 0 3J 1 This paper size is applicable to China National Standard (CNS) A4 (210X297 mm) 474945 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 2. Description of the invention (U) The pharmaceutical product of the present invention as an active ingredient can be used for the purpose of preventing and / or treating pain. In addition to parenteral administration such as intravenous administration and subcutaneous administration, it can also be applied to Oral administration. It is also expected to be used in a mucosal absorbent preparation and a transdermal absorbent preparation containing a nasal absorbent. The medicinal active ingredient of the present invention may also use the peptide derivative of the formula (I) or a physiologically acceptable hydrazone or solvate thereof. The dose is not particularly limited, and may be, for example, 0.1 to 10 mg per dose when administered transdermally, 1 to 10 mg each time during oral administration, or 2 to 3 times per day. The peptide derivative of the present invention can be synthesized by solid phase method and liquid phase method commonly used in peptide synthesis. For example, an amidine-free peptide chain is synthesized by a solid phase method, and then an amidine group is introduced into the amine group of tyrosine at the N-terminus to produce the desired peptide. In addition, an amidine group is first introduced and then the C-terminus is modified. Yes. Protective groups such as amine groups and condensation agents for condensation reactions are known, and reference can be made to the following examples. For example, refer to the "Study of Protein Engineering-Basics and Applications" edited by Suzuki Aya. (Co., Ltd.) (1992) and references cited therein; M. Bondanszky, et al., 44 Peptide Synthesis ^ John Wiley &amp; Sons * N. Y., 1976; and J. M. Stewart &amp; D. J_ Young, "Solid Phase Peptide Synthesis", W · H · Freeman and Co., San Francisco, 1969, etc. are appropriately selected and used. The solid phase method can use various commercially available peptide synthesis devices, such as manufactured by Kashiwa Emma Japan. (Perkin Elmer Japan, Applied Bio-systems of the old company) Model 430A can be easily synthesized. The resins and reagents used in the synthesis are readily available commercially available products, and examples are shown in the examples. Standards are applicable to Zhongguanjia Standard (CNS) A4 (210X297mm) ~ 11 Jing311 (Please read the precautions on the back before filling this page)

474945 A7 ____B7 .. V. Description of the Invention (12) Examples The present invention will be described more specifically with reference to the following examples, but the present invention is not limited to the following examples. With reference to this example, or by modifying or changing the method of this example, or by appropriately selecting starting materials or reaction reagents, the objective peptide derivative of the present invention included in the general formula (1) can be easily prepared. In the examples, the meaning of the amino group is the same as that of the commonly used ones. When referring to the amino acids present in the D-form and the L-form, if d- is not specifically indicated, the amino acid refers to the L-amino acid. In addition, abbreviations are used below. If there is no special mark, the same abbreviations are used. Among them, the symbols such as H2NC (NH) -Phe, Boc-Phe- or Z-Phe- indicate that the N-terminal nitrogen atom of phenylalanine is modified by H2NC (NH) ·, Boc or Z, respectively. The amino acid is Shown as base acid residues 消费 Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 1 -Ada: 1-Gold steel alkyl Bo c: Third butoxycarbonyl Bz 1: benzyl CHe x: cyclohexyl DIEA: diiso Propylethylamine DMAP: 4-dimethylaminopyridine DMF: Ν, Ν · dimethylformamide DMT: 2,6-dimethyltyrosine ECE: 1 ((ethoxycarbonyloxy HNLE: 5 -Hydroxy-hexylamine HNLE (MOM): 5-methoxymethoxyhexyl! HOB t: 1-Hydroxybenzotriazole Me t 0: Methionine sulfonium 12 This paper size applies Chinese national standard (CNS) A4 specification (210X297 mm) 474945 A7 B7 V. Description of the invention b) Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economy M0M-C1: Chloromethyl methyl ether 0NLE: 5 -Oxo € amine Pht 1: Phthaloketo POM: Trimethylacetoxymethyl Tyr (C0CH3): 0-Ethyl tyrosine Tyr (C0CH2CH3): 0-Propyl tyrosine Tyr [C0 (CH) 2CH3] : 0-butyryl tyrosine Tyr [C0CH (CH3) 2]: 0-isobutyryl tyramine Ty r [COcHex]: 0-cyclohexylcarbonyl Tyr [COPh]: 0-phenylfluorenyl Tyr [C0 (CH2) 2Ph]: 0-3-phenylpropylfluorenyl Ty r [C0 (CH2) 3Ph]: 0 -4-Phenylbutanoyl Tyr [C0C (CH3) 3]: 0-trimethylethylfluorenyl Ty r [C0 (1-Ada)]: 0-Bu Jingang alkylcarbonyl Tyr (C02CH3): 0-formyl Oxycarbonyltyrosine Tyr (C02C2H5): 0-ethoxycarbonyltyrosine Tyr [C02CH (CH3) 2]: 0-isopropoxy Tyr (C02Ph): 0-phenoxy Tyr (C0CH2Ph): 〇-Benzyloxy WSCI: 1-ethyl-3 · (3-dimethylaminopropyl) carbodiimide sulfonic acid 塩 Z: Benzyloxycarbonyl (A) Manufacture of raw material compounds (1) Z- Phe-Me A 1 a-OCH3 Dissolve Η-Me Lu A1a-OMe HC1 (6 · 14g) in DMF (5Om1). This paper size applies Chinese National Standard (CNS) A4 specification (210XM7 mm) 13 (Please (Read the precautions on the back before filling out this page): 5

T

1031 474945 A7 ____ B7 5. Description of the invention (14) at -10. (: Triethylamine (5.5 41111), 11.0 [(5.41)), 2-? ^-OH (10g) were added below, then WSCI (8.3g) was added and stirred at room temperature for 20 hours. In the reaction solution Ethyl acetate was added to the solution, and the solution was washed with 1N osmic acid, followed by saturated sodium bicarbonate water. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 13 g of a colorless oil. (2) Boc- D-MctO-Phc-Mc) S Ala-0CH3

Page-order: Dissolve the Z-Phe-Me ^ S Ala-OCH3 (6.1g) obtained in (1) above in DMF (100ml), and add 5% pd-C (10g) as a catalyst. The contact reduction reaction was carried out for 3 hours. After the catalyst was filtered off, Boc-D-Met0-0H (7.98g), HOBt (4g), WSCI (6.7g) was added to the filtrate at 0 ° C, and the mixture was stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N acetic acid, saturated sodium bicarbonate water, and then with saturated aqueous sodium chloride. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 9. lg of a colorless oily object.

(3) Boc-Tyr-D-MetO-Phe-MeilingAla-0CH3 Printed by Boc-D-MetO-Phe-Me yS Ala-〇CH3 (2) 4.5 g) was dissolved in 90% TFA (50 ml) and stirred at room temperature for 30 minutes. The residue obtained after concentration and removal of the solvent under reduced pressure was dissolved in I &gt; MF (20 ml). After adding triethylamine to the solution for neutralization, add 80 (: -Tyr-OH (2.2g), HOB t (3.5g), WSCI (2.5g) at 0 ° C, and stir at room temperature for one Overnight. To the reaction solution was added ethyl acetate / washed with IN ethyl acid, saturated sodium bicarbonate aqueous solution, followed by saturated sodium bicarbonate water. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 4.5 g of the target compound. White solid.

(4) Boc-Tyr-D-MetO-Phe-MeySAla-OH This paper size is applicable to Chinese National Standard (CNS) A4 specification (2 丨 〇 &gt; &lt; 297 mm) 14 0 311 · Employees of Intellectual Property Bureau, Ministry of Economic Affairs Printed by the Consumer Cooperative 474945 A7 _____ B7 V. Description of the invention (15) The Boc-Tyr-D-MetO-Phe-Me) 5 Ala-OCH3 (2.23g) obtained above was dissolved in methanol (20ml) and water (10ml) ). 2N NaOH aqueous solution (3.3ml) was added to the solution, and the mixture was stirred at room temperature for 3 hours. The reaction solution was adjusted to Ph2 by adding 1N osmic acid at 0 ° C, and extracted with ethyl acetate. The organic layer was saturated with sodium bicarbonate. After washing with water, the stomach was dried with magnesium sulfate, and the solvent was concentrated under reduced pressure to remove the solvent. The obtained residue was crystallized from isopropyl ether to obtain a white solid 1.83ge (5) Boc-D-MetO-Phe-OCH3 and H-Phe-OMe. HCl (88g) was dissolved in DMF (500ml). Triethylamine (56ml), HOBt (46g), Boc-D-Met0-0H (90g) were added at -10, and then WSCI (76g) was added and stirred at room temperature. 20 hours. Ethyl acetate was added to the reaction solution, and the solution was washed with 1 N osmic acid, followed by saturated aqueous sodium hydrogen carbonate solution. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was crystallized from hexane. Thus, 1 17 g of the target substance was obtained as a white solid. (6) Boc-Tyr-D-MetO-Phe-OCH3 The Boc-D-MetO-Phe-OCH3 (10 g) obtained in the above (5) was dissolved in anisole ( 10ml) in 90% TFA (100ml) and stirred at room temperature for 30 minutes. The residue obtained by removing the solvent by concentration under reduced pressure was dissolved in DMF (40ml). Triethylamine was added to neutralize it. Boc-Ty r-OH (5.6g), HOB t (3.5g) and WSCI (5.4g) were dissolved in DMF (20ml), and the solution stirred at 30 ° C for 30 minutes was added to the above solution, and stirred at a warm temperature Overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N acetic acid, a saturated aqueous sodium hydrogen carbonate solution, and then with saturated aqueous sodium bicarbonate. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to remove the solvent. Crystallized to obtain llg target (please read the precautions on the back before filling this page)

This paper size applies to Chinese National Standard (CNS) A4 (210X297 mm) 15 3-031 474945 A7 ___B7_ 5. Description of the invention u) White solid.

(7) Boc-Tyr-D-MetO-Phe-OH The Boc-Tyr-D-MetO-Phe-OCH3 (110g) obtained in (6) above was dissolved in methanol (187ml). A 2N Na OH aqueous solution (187 ml) was added to the solution at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. After IN acetic acid (1 L) was added to the reaction solution at 0 ° C, it was extracted with ethyl acetate. The organic layer was washed with saturated edible water, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 104 g of a white solid as a target substance. (8) Boc-Ty rD-Me tO-Phe-Me yS Ala-OC (CH3) 3 is added to Boc-Tyr-D-MetO-PheOH (11.5g) obtained in (7) above, added at 0 ° C H-Me) SAla-OC (CH3) 3 (3.82g), HOBt (3.24g) and WSCI (4.60g), and stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, and the solution was washed with 1N acetic acid, a saturated aqueous solution of sodium hydrogencarbonate, and then with saturated water. 6g。 After the organic layer was dried over magnesium sulfate, concentrated under reduced pressure to remove the solvent, the resulting residue was crystallized from isopropyl ether to give white crystals 12.6g.

(9) ZD-HNLE (MOM) -0H Printed by the Consumer Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs Sodium (1.17) was dissolved in anhydrous methanol (1001111) 'at -12 ° &lt;: added below this solution (R) -3 -benzyloxycarbonyl-4-(3-oxobutyl) -5 -solimone (9.90 g) [according to J. M. Scoltz and P. A. Bartlett, Synthesis, pp -542-544, synthesized by the method described in 1989]. After stirring at this temperature for 45 minutes, 6N osmic acid was added dropwise to neutralize it. After the precipitated inorganic thorium was filtered off, sodium hydroxide (1.29 g) was added at 0 ° C. After the reaction solution was stirred for 5 minutes, 6NHC1 was added dropwise to neutralize it. Distilled from the methanol 'residue under reduced pressure, diethyl ether was added, and the strip was washed with saturated food. The organic layer is dried with magnesium sulfate. The paper size is in accordance with the Chinese National Standard (CNS) A4 (210X 297 mm)% 3 1 〇3 1 1 474945 Μ B7 V. Description of the invention (17 After drying, the solvent is removed by concentration under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 dissolution) to obtain a colorless oily substance of ZD-HNLE = Ome. 8 · 8 8 g ^ This compound (8.50 g) was dissolved in dichloromethane ( 25ml), DIEA (6.1ml) and MOM-Cl (2.62ml) were added at 0 ° C. After stirring at room temperature for 15 hours, dichloromethane was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. This solution It was sequentially washed with 10% citric acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated sodium bicarbonate water. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 2-bie 1 ^ (»« 01 ^)-〇11 ^ ( 7.83 £) as a colorless oil. The compound (7.50) was dissolved in methanol (20 ml), and 2NNaOH (16 · 5 ml) was added at (ΓC). The resulting solution was stirred at room temperature for 1 hour, and then IN HC1 was neutralized and the methanol was distilled off under reduced pressure. After adding 1M NaHS04 to Ph = 3 to the residue, ethyl acetate was added and the solution was separated. The organic layer was saturated with sodium bicarbonate. Wash. After drying over magnesium sulfate, remove the solvent by concentration under reduced pressure to obtain 7.08 g of the target compound as a colorless oil. (B) Production Example 1 of the peptide derivative of the present invention: H3C-C (NH) -Ty rD-Me tO-Phe-Me yS A1 a-OCH3 Acetate Acetate Dissolve Boc-Tyr-D-MetO-Phe-Me A Ala-OCH3 (1.35g) in 90% TFA (10ml) and stir at 0 ° C for 30 minutes The residue obtained by removing the solvent by concentrating under reduced pressure was dissolved in DMF (8 ml), and gadolinium acetimidate (K38 g) and triethylamine (0.84 ml) were added. The solution was stirred at room temperature for 1 hour and 30 minutes. After that, the reaction solution was concentrated under reduced pressure, and the resulting residue was injected into an ODs column (DM 1 020T, Fuji Silesia, 50 g) for chromatography, and washed out with a 20% methanol 10.1N acetic acid solution. The target substance containing the object was collected and frozen. The size of this paper is in accordance with China National Standard (CNS) A4 (210X297 mm). Please read the note on the back page printed by the Intellectual Property Bureau Employee Consumption Cooperative of the Ministry of Economic Affairs. 17 3 IQ 3 1 1 474945 Cooperatives print &quot; Ά7 • 一一 — ·] ΒZ '(is), and obtain the target compound white Color powder 0.61g. FAB mass spectrum m / z: 617 (M + H +) [a] D23 + 31 · 1 ° (C = 0.97, IN acetic acid)

Rf: 0 · 66 (n-BuOH: ACOH: H20: pyridine = 15: 3: 10: 12) Examples 2 to 7 The compounds shown in Table 1 were synthesized according to the method shown in 1. In the table, m / z indicates M + H +, and the optical rotation is 00.90 to 2.00 g / 10 0 ml, 1N acetic acid, and the results are measured at 23 ° C. Rf is measured using n-Bu0H: AC0H: H20: pyridine = 15: 3: 10: 12 as the developing solvent (the same applies to the following table) e〇rn (Ac) means N5-ethylamidoguanine residue Group, Phe (Pf) means a perfluorophenylalanine residue. Table 1 Example structural formula m / z [α] D Rf 2 H3CCH2-C (NH) -Tyr-D-Meto-Phe- Me β Ala-〇CH3 631 +12.8 0. 65 3 H3C-C (ΝΗ) -Tyr -D-Orn (Ac) -Phe- Me j3 Ala-0CH3 626 +23.8 0. 65 4 H3C-C (NH) -Tyr-D-〇rn (Ac) -Phe (pF) -Me] 3 Ala-0CH3 644 +23.9 0.65 5 H3OC (NH) -DMT-D-Orn (Ac) -Phe (pF) -Me J3 Ala-0CH3 672 +41.7 0. 66 6 H3C-C (NH) -Tyr-D-MetO-Phe (pF) -Me] 3 Ala-0CH3 635 +16.4 0.64 7 H3C-C _ -DMT-D-Met〇-Phe (pF)-Me) 3 Ala-0CH3 663 + 38 · 3 0.65 Example 8: H3C-C (NH) -Tyr-D-MetO-Phe-Mei3Ala-〇 (CH2) 7CH3 Acetic acid (1) BoC-Me β A1a-0 (CH2) 7CH3

Boc-MeiSAla-0H (6.14g) was dissolved in dichloromethane (20ml), octanol (641mg) and DMAP (10mg) were added, and WSCI (1.12g) was added at 0 ° C, followed by stirring at room temperature for 20 hours. The reaction solution is sequentially based on IN acid, saturated bicarbonate. The paper size is applicable to the Chinese National Standard (CNS) A4 (210 X 297 mm) 18 (correction page) 310311 I --.--------- · 11 --- · --Order --------- 7- · (Please read the notes on the back before filling out this page) Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 474945 A7 B7 __ V. Invention Note (19) The solvent was removed by concentration, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 50: 1 washing out) to obtain colorless oil i.36g. (2) Boc-Tyr-D-MctO-Phc-Me ^ S Ala-0 (CH2) 7 ^^ 3 Boc-Me ^ Ala-0 (CH2) 7CH3 (6.14g) obtained in (1) above is dissolved In a 4N HC1 / ethyl acetate solution (20 ml), stir at room temperature for 30 minutes. Diethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration. This crystal was dissolved in DMF (20 mg), and after neutralization with triethylamine, Boc-Tyr-D-Met0-Phe-0H (3.45 g), HOBt (0.89 g), and WSC 1 ( 1.72g), and stirred overnight at room temperature. Ethyl acetate was added to the reaction solution, followed by washing with 1N osmic acid, a saturated aqueous sodium hydrogen carbonate solution, and a saturated aqueous solution of sodium bicarbonate in this order. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (dichloromethane: methanol = 20: 1) to obtain 3.0 g of white crystals. (3) H3C-C (NH) -Tyr-D-Met0-Phe-Me / 9Ala-0 (CH2) 7CH3 Acetyl Acetate Use the above (2) K.iBoc-Tyr-D-MetO-Phe-MeiSAla-0 ( CH2) 7CH3 (Klg), ethyl acetimidate (0.5 g) and triethylamine (0.54 g) were reacted in the same manner as in Example 1. The obtained crude product was injected into an 0DS column (DM 1 020T, manufactured by Fuji Silesia, 40 g) and subjected to chromatography ', and was washed out with a gradient of 30 to 50% methanol in water. The fractions containing the target compound were collected and freeze-dried to obtain a white powder of the target compound (0.33 g). FAB mass spectrum m / z: 715 (M + H +). [a] D23 + 14.5 ° (C = 1.00, IN acetic acid) This paper size applies Chinese National Standard (CNS) A4 specification (210X297 mm) 19 3] ι; 3 1 1 (Please read the notes on the back before filling (This page)

4/4945 A7 B7 V. Description of the invention (20) 1 ^: 0.68 (11-811〇 ^ (: 〇11: 112〇: pyridine = 15: 3: 10: 12) Examples 9 to 24, according to Example 8 Method to synthesize the compounds shown in Table 2. Table 2 (Please read the precautions on the back before filling this page), τ

Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs m / z [a] D Rf 9 H3C ~ C (NH) -Tyr-D-MetO-Phe-Me β Ala-0CH2CH3 631 +23.7 0. 66 10 H3C -C (NH) -Tyr-D ~ Met〇-Phe ~ Me j3 Ala-0 (CH2) 3CH3 659 +24.4 0. 68 11 H3C-C (NH) -Tyr-D-MetO-Phe-Me jS Ala- 0 (CH2) 5CH3 687 +32.8 0.71 12 H3C ~ C (NH) -Tyr ~ D-MetO ~ Phe ~ Me j3 Ala-0 (CH2) 9CH3 74.3 +15.6 0.71 13 H3C-C (NH) -Tyr ~ D- Met〇- * Phe-Me] 3 Ala-0 (CH2) nCH3 771 +14.9 0. 70 14 H3C-C (NH) -Tyr-D ~ MetO-Phe-Me β Ala-0 (CH2) 15CH3 827 +14.6 0. 73 15 H3C-C (NH) -Tyr-D-MetO-Phe ~ Me jS Ala-OC (CH3) 3 659 +23.0 0. 69 16 H3C-C (NH) -Tyr-D-MetO-Phe- Me jS Ala ~ 0CH2CF3 685 +24. 1 0.71 17 H3C-C (NH) -Tyr-D-Met〇-Phe-Me βAla-OcHex 685 +25.0 0. 70 18 H3C-C (NH) -Tyr-D- MetO-Phe-Me / 3 Ala-〇CH2cHex 699 +25.0 0. 70 19 HnC-C (NH) -Tyr-D-Met〇-Phe-Me βAla-OPh 679 +25. 1 0. 66 20 H3C-C (NH) -Tyr-D-MetO-Phe ~ Me jS Ala-OBzl 693 +32.8 0. 68 21 H3C-C (NH) -Tyr-D-MetO-Phe-Me βAla-OPhtl 735 +14. 1 0. 66 22 H3C-C (NH) -Tyr-D-MetO-Phe-Me j3 Ala ~ 0ECE 719 +16.6 0.67 23 H3C-C (NH) -Tyr ~ D-Met〇-Phe ~ Me βAla-OPOM 717 + 17.0 0. 68 24 H3C ~ C (NH) -Tyr-D-MetO-Phe-Me β Ala ~ 0CH2CH2N (CHn ) 2 674 +17.3 0. 40 25: H3C-C (NH) -Tyr- [COCH (CH3) 2] -D-MetO -Phe-This paper size applies to China National Standard (CNS) A4 (2i〇x 297 Mm) 2 03 1 G 31 1 474945 A7 B7 V. Description of the invention (21)

Me Cold A1 a-OH (1) Boc-Tyr [COCH (CH3) 2] -D-MetO-Phe-Me) S Ala-OC (CH3) 3 Boc-Tyr-D-MetO-Phe-MeiS AU-0C (CH3) 3 (2.5 g) was dissolved in dichloromethane (30 ml), and isostearic acid chloride (0.55 ml) and triethylamine (0.9 7 ml) were added at 0 ° C, followed by stirring at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the solution was washed sequentially with a 1N aqueous solution of sodium bicarbonate 'and a saturated aqueous solution of sodium bicarbonate. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to remove the solvent. The obtained residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1 washing out) to obtain white crystals 1.79ge (2) H3C-C (NH ) -Ty r [C0CH (CH3) 2]-D-MetO-Phe-Me) S Ala-OH Use 60 (:-丁 丫 1: [(: 0 &lt;: 11 ((: 113) 2] -0-] ^ 10-Phe-MeiSAla-OC (CH3) 3 (1.56g), ethyl acetimidate ethyl sulfonate (1.22 g) and KHC03 (1.39 g), as in Example 1 The reaction was performed in the same way. The obtained crude product was injected into an 0DS column (DM 1 020T, Fuji Silesia, 150g) and subjected to chromatography, and was washed out with a gradient of 5 to 16% acetonitrile / 0.1N acetic acid solution. The fractions containing the target compound were collected. It was freeze-dried to obtain 0.46 g of a white powder of the target compound. FAB mass spectrum m / z: 645 (M + H +). [A] d23 + 17.2. (C = 0.99, IN acetic acid)

Rf: 0.60 (n-BuOH: ACOH: H20: pyridine = 15: 3: 10: 12) Examples 26 to 45 The compounds shown in Table 3 were synthesized according to the method of Example 25. Cit in the table shows citrulline residue [-NH-CH (CH2-CH2-CH2-NH-CO-NH2) -CO ·]. This paper size applies to China National Standard (CNS) A4 (210X 297 mm) Please read the note on the back page printed by the Intellectual Property Bureau Employee Consumer Cooperative of the Ministry of Economic Affairs 21 3 1 C 3 1 1 474945 A7 B7 V. Description of the invention (22 Table 3 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs

Example Structural formula 26 HjC-C (NH) -Tyr (C0CH3) -D ~ MetO ~ Phe-Me β Ala-〇H 27 H3C-C (NH) -Tyr (C0CH2CH3) -D-MetO-Phe-Me j3 Ala -〇H 28 H3C-C (NH) -Tyr [C0 (CH2) 2CH3] -D-Met0-Phe-Me β Ala-〇H 29 H3C ~ C (NH) -Tyr [C0 (CH2) 6CH3] -D -Met0-Phe * -Me β Ala ~ OH 30 H / X (NH) -Tyr (C0CH3) -D-Arg-Phe-Me P Ala-OH 31 H3C-C (NH) -Tyr (C0CH3) -D- Cit-Phe-Me β Ala-OH 32 H3C-C (NH) -Tyr (C0CH3) -D-Orn (Ac) -Phe-Me] 3 Ala-OH 33 H3C-C (NH) -Tyr (COcHex)- D-MetO-Phe-Me βAla-OH 34 H3C-C (NH) -Tyr (COPh) -D-Met〇-Phe-Me βAla-OH 35 H3C-C (NH) ~ Tyr [C0 (CH2) 2Ph] -D-MetO-Phe-Me / 3 Ala-OH 36 H3C-C (NH) -Tyr [CO (CH2) 3Ph] -D-Met〇-Phe-Me jS Ala-OH 37 HUC-C (NH)- Tyr [COC (CH:]) 3] -D-Met〇-Phe-Me β Ala-OH 38 H3C-C (NH) -Tyr [C0 (l-Ada)]-D-MetO-Phe ~ Me βAla- OH 39 H.JC-C (NH) ~ Tyr [C02CH3] -D-Met〇--Phe-Me j3 Ala-OH 40 H3C-C (NH) -Tyr [C02CH.2CH3] -D-Met0-Phe- Me j3 Ala-OH 41 H3OC (NH) -Tyr [C02CH (CH3〉 2] -D-MetO-Phe-Me jS Ala-OH 42 HUC-C (NH) -Tyr (C02Ph) -D-MetO-Phe- Me / 3 Ala-OH 43 H3C-C (NH) -Tyr (C02CH2Ph) -D-MetO-Phe-Me β Ala-OH 44 H2N-C (NH)- Tyr (COCHu) -D-Met〇-Phe-Me β Ala-QH 45 H2N-C (NH) -Tyr (C0CH3) -D-Arg-Phe-Me j3 Ala-OH m / z [α], Rf 659 + 17.5 0. 62 673 +20.4 0.67 729 + 19.8 0.65 673 +22.3 0. 63 654 +21.8 0. 56 655 + 24 · 1 0. 68 654 +24.8 0.63 713 +22.0 0.65 707 + 1 · 0 0. 63 735 + 15.4 0.65 749 + 15.3 0.65 687 +29. 8 0.65 765 +25.7 0. 63 661 + 16.8 0.61 675 + 37 · 1 0. 63 703 +39. 1 0. 66 723 + 27 · 1 0.63 737 +33.0 0. 64 646 +24.0 0. 62 655 +23.9 0.52 Please-read the precautions on the back first

This paper size applies the Chinese National Standard (CNS) A4 specification (21 ×× 297 mm) 22 474945 A7 B7 V. Description of the invention (23) Example 46:% 〇 (: (_- 丁 7): (〇〇3) -〇 ， 0 {〇-? 1 ^, 4 六 1 &amp; -〇 细 2) 7〇13. 塩 (1) Boc-Tyr (C0CH3) -D-Met0-Phe-Me β Ala-0 (CH2) 7CH3 Please Read the precautions on the reverse side and fill out the Boc-Tyr (COCH3) -D-MetO-Phe-Me yS Ala-OH (1,000 g) obtained in Example 26 on this page, dissolved in dichloromethane (30ml), 0 ° C After adding octanol (0.64 g>, DMAP (10 mg), and WSCI (1.12 g), the mixture was stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, followed by IN acetic acid, a saturated aqueous sodium hydrogen carbonate solution, The organic layer was dried over magnesium sulfate, concentrated under reduced pressure to remove the solvent, and the obtained residue was purified by silica gel column chromatography (chloroform: methanol = 50: 1 washed out) to obtain 1.36 g of white crystals. (2 ) H3C-C (NH) -Tyr (COCH3) -D-MetO-Phe-Me / S Ala-0 (CH2) 7CH3 Acetate Acetate Printed using the Boc produced in (1) above by the Consumer Consumption Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs -Tyr (COCH3) -D-MetO-Phe-Me / 3 A1 a-0 (CH2) 7CH3 (1.00 g) Ethyl acetimidate (0.30 g) and triethylamine (0.5 ml) were reacted in the same manner as in Example 1. The obtained crude product was injected into an 0DS column (DM 1020T manufactured by Fuji Silesia, 50 g). Chromatography 'Wash out with a gradient of 10 to 3 6% acetonitrile / 0.1N acetic acid solution. Collect the fractions containing the target compound and freeze-dried to obtain the target compound as a white powder 0 · 14 g 〇 FAB mass spectrum m / z: 75 7 (M + H +). [A] d23 + 15.0 ° (C = l · 01, IN acetic acid)

Rf: 0.70 (ϋ-ΒιιΟΗ: AC0H: H20: pyridine = 15: 3: 10: 12) Examples 47 to 50 The compounds shown in Table 4 were synthesized according to the method of Example 46. 23 3 1 0 3 1 1 This paper size applies to Chinese National Standard (CNS) A4 (210X 297 mm) 474945 A7 B7 V. Description of the invention (24 m / z [a] D Rf 867 +10.5 0.71 761 +16.3 0.6 ί 777 +15. 0 0.67 Printed by the Consumer Property Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs 47 H3C-C (NH) -Tyr (C0CH3) -D-MetO-Phe-Me j3 Ala-0 (CH2) l5CH3 48 H3C -C (NH) -Tyr (C0CH3) -D-MetO-Phe-Me jS Ala-OECE 49 H3C-C (NH) -Tyr (C0CH3) -D-Met〇-Phe-Me β Ala-OPht 1 50 H3C -C (NH) -Tyr [C02CH (CH3) 2] -D-MetO-Phe-Me) 3 Ala-0 (CH2) 2CH3 759 +5.6 0.7 ^ Example 51: H3C-C (NH) -Tyr-D- HNLE-Phe-Me / 3 Ala-OH (1) ZD-HNLE (MOM) -Phe-Me / 3 Ala-OCH3 Dissolve Boc-Phe-MeySAla-OCH3 (9.56g) in 4NHC1 / ethyl acetate solution (50ml The reaction solution was stirred at room temperature for 45 minutes. The reaction solution was concentrated under reduced pressure, dissolved in dichloromethane, and washed with a saturated sodium bicarbonate aqueous solution. After the solution was dried over magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the resulting residue was dissolved in DMF (10 ml). ZD-HNLE (MOM) -OH (6.83g), H0Bt (2.97g) and ffSCI (1.72g) were added to the solution at -12 ° C, stirred at -12 ° C for 30 minutes, and then stirred at room temperature. One night. Ethyl acetate was added to the reaction solution, followed by washing with 10% citric acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride in this order. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 11.9 g of a colorless oil. (2) Z-Tyr (Bzl) -D-HNLE (MOM) -Phe-Me LingA1a-0CH3 The ZD-HNLE (MOM) -Phe-Me yS A 1 a-0CH3 (11.4g) obtained from the above (1) ) Is dissolved in methanol (50ml), and 5% Pd-C (2g) is added as a catalyst to perform a contact reduction reaction at room temperature for 2 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in DMF (20 mg), and Z-Tyr (Bz 1) -0H (7 · 30g), HOBt (2 · 70g), WSCI (3 · 83g) were added at -12 ° C, please Read the notes on the back first

This paper size is in accordance with Chinese National Standard (CNS) A4 specification (21 × 297 mm) 24 0311 474945 A7 B7 V. Description of the invention (25) Stir for 1 hour and stir overnight at room temperature. Ethyl acetate 'was added to the reaction solution, followed by washing with 1N osmic acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 14.1 g of a target substance as a colorless amorphous solid. (3) Z-Tyr (Bzl) -D-HNLE-Phe-Me β Ala-OMe The Z-Tyr (Bzl) -D-HNLE (MOM) -Phe-Me stone AU-〇CH3 obtained in the above (2) (12.0 g) was dissolved in methanol (200 ml), and concentrated osmic acid (0.3 ml) was added and refluxed for 1 hour and 20 minutes. Methanol was removed by concentration under reduced pressure, and ethyl acetate was added to the resulting residue, followed by washing with 1N osmic acid, a saturated aqueous sodium hydrogen carbonate solution, and saturated aqueous sodium chloride. After the organic layer was dried over magnesium sulfate, the solvent was removed by concentration under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 washing out) to obtain 6.27 g of a white powder.

(4) Z-Tyr (Bzl) -D-HNLE-Phe-Mey3Ala-0H The Z-Tyr (Bzl) -D-HNLE-Phe-Me A Ala-〇Me (2.34 g) obtained in (3) above is dissolved In methanol (33 ml). A 2N NaOH aqueous solution (3 ml) was added to the solution at 0 ° C, and the mixture was stirred at room temperature for 4 hours and then at 40 ° C for 40 minutes. The reaction solution was adjusted to Ph2 by adding 6N osmic acid at 01, and then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate, dried over magnesium sulfate, and concentrated under reduced pressure to remove the solvent to obtain 2.3 g of a colorless oil.

(5) H3C-C (NH) -Tyr-D-HNLE-Phe-Me β A1a-OH Z-Tyr (Bzl) -D-HNLE (MOM) -Phe-Me cold Ala- OH (2.3g) was dissolved in methanol (30ml), and 5% Pd-C (lg) was added as a catalyst to perform a contact reduction reaction at room temperature for 3 hours. After the catalyst was filtered off, the filtrate was concentrated under reduced pressure. The obtained residue is dissolved in DMF (20mg), add (please read the precautions on the back before filling this page)

T

The paper size printed by the Employees' Cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs applies to the Chinese National Standard (CNS) A4 specification (210X297 mm) 25 31 1 474945 A7 _B7_ V. Description of the invention (26) Please read the precautions before filling in this document Pyrene acetimidate (1.1 g) and KHC03 (1.2 g) were added. After the solution was stirred at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure, and the resulting residue was injected into an ODS column (DM 1 020T manufactured by Fuji Silesia, 125g) for chromatography, with 5 to 18% acetonitrile / 0. The IN acetic acid solution was washed out in a gradient. The fractions containing the target compound were freeze-dried to obtain 0.66 g of the target compound as a white powder. FAB mass spectrum m / z: 585 (M + H +) ❶ [a] d23 + 30.2 ° (C = l · 00, IN acetic acid)

Rf: 0.61 (n-BuOH: ACOH: H20: pyridine = 15: 3: 10: 12)

Example 52: H3C-C (NH) -Tyr-D-ONLE-Phe-MeySAla-OH (1) Z-Tyr (Bzl) -D-0NLE-Phe-Mey9Ala-0Me The Z obtained in Example 51- (3) -Tyr (Bzl) -D-HNLE-Phe-Me ^ A 1 a-0CH3 (1 2.0 g) was dissolved in dichloromethane (20 ml), and PCC (1.94 g) was added and stirred for 2 hours. The reaction solution was diluted with dichloromethane (30 ml), and magnesium sulfate was added, followed by short stirring, followed by filtration. The filtrate was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1 washed out) printed by the Employees' Cooperative of Intellectual Property Bureau of the Ministry of Economics to obtain a colorless oil 3.1 g °

(2) Z-Tyr (Bzl) -D-0NLE-Phe-Mei8Ala-0H dissolve the Z-Tyr (Bzl) -D-ONLE-Phe-Me $ A1a-OMe (2.34g) obtained in the above (1) Methanol (33mi). Π Na OH aqueous solution (3ml) was added to the solution at 0 ° C, stirred at room temperature for 4 hours, and then stirred at 40 ° C for 40 minutes. The reaction solution was added 6N at 0 ° C After the osmic acid was adjusted to Ph2, it was extracted with ethyl acetate. The organic layer was washed with saturated sodium bicarbonate water and then with magnesium sulfate 26 3 1 〇3. This paper is in accordance with China National Standard (CNS) A4 specification (2 丨 〇'〆297). (Centi) 474945 A7 B7 V. Description of the invention b) It was dried and concentrated under reduced pressure to remove the solvent to obtain 2.3 g of colorless oil.

(3) H3C-C (NH) -Ty rD-ONLE-Phe-Me A1 a-OH Z-Tyr (Bzl) -D-ONLE-Phe-Me Θ Ala-〇H (2.65) g) The same reaction was performed as in Example 51- (5). The obtained crude product was injected into a 0DS column (DM 1 020T, manufactured by Fuji Silesia, 125 g) and subjected to chromatography, and was washed out in a gradient of 5 to 20% acetonitrile / 0.1N acetic acid solution. The fractions containing the target compound were collected and freeze-dried to obtain a white powder of the target compound. 0.72 g β FAB Mass spectrum m / z: 58 3 (Μ + Η +). [a] d2 3 + 2 3.0 ° (C = 1.05, IN acetic acid)

Rf: 0 · 64 (n-BuOH: ACOH: H20: pyridine = 15: 3: 10: 12) Examples W and 54 The compounds shown in Table 5 were synthesized according to the method of Example 8 Table 5 Example structural formula m / z [a ] D Rf 53 H3C-C (NH) -Tyr-D-Cit-Phe-Me β Ala-0CH20 (CH2) 20CH3 701 +23.5 0. 65 54 H3C-C (NH) -Tyr-D-Cit-Phe- Me β Ala-0 (CH2) 7CK3 725 +18. 1 0. 68 M55: H3C-C (NH) -DMT-D-Orn (Ac) -Phe (pF)- MeySAla-Oet acetic acid, dissolve Boc-DMT-D-0rn (Ac) -Phe (pF) -Mei9 Ala-Oet (3.0g) in 4N HC1 / ethyl acetate solution (15ml), and stir at room temperature for 30 minutes . Diethyl ether was added to the reaction solution, and the precipitated crystals were collected by filtration. This crystal was dissolved in water (25 mg), and ethyl phosphonium acetimidate (1.33 g) and KHC03 (1.80 g) were added. After the solution was stirred at room temperature for 1 hour and 30 minutes, the paper size was in accordance with Chinese National Standard (CNS) A4 (210X 297 mm) 27 3 1 0 3 1 ί 474945 A7 B7 V. Description of the invention (28) The mixture was concentrated under reduced pressure, and the resulting residue was injected into an ODS column (DM 1 020T, Fuji Silesia, 140 g) for chromatography, and washed out with a 12 to 16% acetonitrile / 0.1N acetic acid solution in a gradient. The fractions containing the target compound were collected and freeze-dried to obtain 1.20 g of the target compound as a white powder. FAB mass spectrum m / z: 685 (M + H +). [a] D2 3 + 42 · 3 ° (C = l · 00, IN acetic acid)

Rf: 0.6 7 (n-BuOH: AC0H: H20: pyridine = 15: 3: 10: 12) Example 56 The pain activity of the peptide derivative of the present invention The consumer property cooperative of the Intellectual Property Bureau of the Ministry of Economic Affairs printed the peptide derivative of the present invention The painful activity of the substance was evaluated by the pressure stimulation method according to the method described in International Publication W097 / 10262. A pressure stimulus of about 10 mmHg / sec was applied to the tail root of the rat, struggling with it; the behavior of the irritation site determined the pressure, which is the critical threshold of pain response. The mice used in the experiments were those who responded to a pressure of 40 to 5 OmmHg. The maximum stimulation pressure was 100 mmHg. The pain effect is based on the following formula of MPE = (Pt-Po) / (Pc-Po) X100 (where P0 is the threshold for pain response before drug treatment; Pt is the threshold for pain response after drug treatment. ; Pc maximum stimulation pressure), calculated, expressed as the percentage of maximum possible effect (% of MPE). Table 5 shows the painful effects when administered via 0. In addition, bioavailability (BA) was calculated as the ratio of ED5 () (mg / kg) of pain activity (ED5 (), mg / kg) obtained by subcutaneous or oral administration to mice [ED5Q (oral) / ED50 (subcutaneous)]. Morphine was used as a control. From the results, it can be seen that the peptide derivative of the present invention can also exhibit extremely excellent pain-relieving activity when administered orally. This paper size applies the side standard (CNS) M specification (brief 2 gift) -31〇311 474945 A7-B7 Printed by the Consumer Cooperatives of the Intellectual Property Bureau of the Ministry of Economic Affairs 5. Description of the invention (29) Table 6 Example Να Structure ED50 (| H3C-C (NH) -Tyr-D-MetO-Phe-Me] S Ala-0 (CH2) 7CH3 8 (Please read the notes on the back before filling this page) ED50 (Subcutaneous) BA 0.24 mg / kg 25 0. 14 9 0. 38 10 0. 25 11 0. 80 10 0. 49 &gt; 20 3.3 7 H3C-C (NH) -Tyr (C0CH3) -D-Met〇-Phe-Me j3 Ala-OH 1. 2 H3C-C (NH) -Tyr-D-MetO-Phe-Me] 3 Ala-0 (CH2) 15CH33.6 H3C-C (NH) -Tyr (C0CH3) -D-MetO-Phe-Me β Ala- OECE 2.7 H3C-C (NH) -Tyr-D-HNLE-Phe-Me β Ala-OH 7.9 H3C-C (NH) -DMT-D-Orn (Ac) -Phe (pF) -Me j3 Ala-OEts &lt; 10.0 mm mm 22 · 2 Possibility of industrial utilization The peptide derivative of the present invention has both excellent pain-relieving effect and absorption through the body, and can be used as a medicine for the prevention and / or treatment of cancer pain and the like. Effective ingredients: 485155 This paper size applies to China National Standard (CNS) A4 (210 X 297 mm) 29 (correction page) 310311

Claims (1)

474945 H3 Attachment No. 87121678 Patent Application Amendment to the Patent Scope (January 14, 89) 1. The compound represented by the following formula (I) or its hydrazone: HN ^ CCR ^ -AA'-AA'-AA'-AA ^ OR2 [wherein R1 represents a CY6 alkyl group and an amine group; R2 represents a hydrogen atom, a CV16 alkyl group, a halogenated CV16 alkyl group, and a Cm alkoxy group substituted with it. Alkyl, CV6 alkoxy, Ci_6 alkoxy substituted (^ _6 alkyl, mono 0v6 alkylamino cv16 alkyl, di cv6 alkylamino (v16 alkyl, .cycloalkyl, C3_1 () cycloalkane Ci-6 alkyl substituted with phenyl, CVe alkyl substituted with phenyl, Cu alkyl substituted with phenyl-CV6 alkoxy, phthalone group which may have substituents, CV6 alkoxycarbonyloxy (^ _6 alkyl Or C2_7 alkylfluorenyloxy Cm alkyl; AA1 is an L-cx-amino acid residue represented by the formula: X \ 0 Printed by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs —NT 'C— Η δ {wherein X represents a hydrogen atom or a formula: -CO-Y-R3 (wherein 113 represents a q 16 alkyl group, a C3_1Q cycloalkyl group, or a C3_1Q cycloalkyl group substituted with &lt; ^ _ 6 alkyl, phenyl, and phenyl substituted (^ _6 alkyl), R4 and R5 each represent a hydrogen atom, the size of the alkyl paper is applicable to China National Standard (CNS) A4 (210 X 297 cm) 31031Γ 474945 H3 group, halogenated Ci-6 alkyl group, or halogen atom, Y represents oxygen atom or single bond}; ΑΑ2 is a D-α-amino acid residue represented by the formula: R6 I (CH2) n (wherein, R6 represents an amine group, a mono-CV6 alkylamino group, a CV6 amido group, a guanidyl group which may have a CV alkyl group, a 1-imino group (^ -6 alkyl group, a ureido group which may have a CV6 alkyl group, a Ci-6 alkylthio group, Alkyl sulfinyl, Ci-6 alkylsulfonyl, fluorenyl, or 1-hydroxy CV6 alkyl, η is an integer of 1 to 4); ΑΑ3 is an a-amino acid residue represented by the following formula: Printed by the Staff Welfare Committee of the Central Standards Bureau of the Ministry of Economic Affairs (where R7 represents a hydrogen atom, a trifluoromethyl group, or a halogen atom); AA4 is the formula -N (R8) -CH (R9) -CH (R1G) -CO Β_amino acid residues shown (wherein R8, R9, and R1Q each represent a hydrogen atom and (^ _6 alkyl group); however, R6 is an amine group, a mono Ci_6 alkylamino group, a Ci_6 alkylamino group, and may have Guanidine group of CV6 alkyl group, 1-imino Cr6 alkyl group, ureido group which may have Cm alkyl group, Ci-6 alkylthio group, (6-6 alkylsulfinamilide group or (6-6 alkylsulfonyl group) and Cases where R2 and X are both hydrogen atoms are not included]. 2. If the compound of the scope of application for patent No. 1 or its 塩 group, where R1 is methyl, the paper size applies the Chinese National Standard (CNS) A4 specification ( 210 X 297 male sauce) 310311 474945 H3 ethyl or amine group. 3. If the compound or any of its compounds of any one of the scope of the patent application item 1 or 2, or AA3 is a substituted or unsubstituted L- Phenylalanine residues, or D-phenylalanine residues that are substituted by $ π or unsubstituted. 4. If a compound or any of its compounds of any one of item 1 or 2 of the scope of patent application, which ΑΑ3 is selected from the group consisting of L-phenylalanine residue, D-phenylalanine residue, L-fluorophenylalanine residue, DP-fluorophenylalanine residue, and L-0-trifluoromethylpropylamine Acid residues and D-O-trifluoromethylphenylalanine residues as a group &amp; amino acid residues. 5. A compound as claimed in any one of the first or second scope of the patent application Or a compound thereof, in which AA4 is an N-methyl-methyl-alanine residue. 6. A compound or a compound thereof in any one of the items 1 or 2 of the scope of patent application, wherein AA1 is L-tyramine Acid residue, 2,6-dimethyl-L-tyrosine residue, octayl-L-tyrosine residue, 0-alkoxycarbonyl-L-tyrosine residue, or phenoxy Those with carbonyl-L-tyrosine residues. Printed by the Staff Welfare Committee of the Central Bureau of Standards of the Ministry of Economic Affairs 7. If the scope of patent application is one of the 1st or 2nd * compounds or their 塩, where AA2 is D- Methionine residues, D-arginine residues, or!) _ Citrulline residues. 8. If a compound or any of its compounds in any one of the first or second scope of the patent application Where AA2 is D-N5-acetamidoguanine residue, D-5-oxo Amino acid residues, or D-5-hydroxyhexyl amino acid residues. 9. For example, the compound of any one of the scope of claims 1 or 2, or a hydrazone thereof, wherein R2 is a CV16 alkyl group, a phenyl group , C6_16 aryl substituted CV6 alkyl, CV10 alkoxy substituted. Alkyl, alkoxycarbonyloxy (^ _6 alkyl, or phthalate paper size applies Chinese National Standard (CNS) A4 specifications (210X 297 cm) ) 3 310311 H3 keto. 10. If the compound in the scope of application for item i and its hydrazones, wherein R1 is methyl, ethyl or amine, R2 is Cb16 alkyl, phenyl, phenyl substituted CV6 alkyl, CV6 alkoxy substituted Cb6 alkyl, Ci-6 alkoxycarbonyloxy (^ -6 alkyl, or phthalone group, AA1 is L-tyrosine residue, 2,6-dimethyl-L-tyrosine residue, 0- 醯Tyrosine residue, 0-alkoxycarbonyl-L-tyrosine residue, or phenoxycarbonyl-L-tyrosine residue, AA2 is D-N5-acetamidoguanine residue, D -5-oxohexylamine residue, or D-5-hydroxyhexylamine residue, AA1 is selected from L-phenylalanine residue, D-phenylalanine residue, LP-fluorobenzene Groups of propylalanine residues, DP-fluorophenylalanine residues, L-0-trifluoromethylphenylalanine residues, and D-0-trifluoromethylphenylalanine residues For amino acid residues, AA2 is an N-methyl-methyl-alanine residue. 11. For example, for the compounds and their hydrazones in the scope of patent application, R1 is methyl and AA1 is L-0-B. Amidinotyrosine residue, AA2 is D-methionine sulfonium residue, AA1 is L-phenylalanine residue, AA2 is N-methyl- / 8- Those who have alanine residues and R2 are hydrogen atoms. Printed by the Staff Welfare Committee of the Central Bureau of Standards of the Ministry of Economic Affairs. For example, for compounds and their derivatives of item 1 in the scope of patent application, where R1 is methyl and AA1 is L-tyrosine residue. Those in which AA2 is a D-methionine residue, AA1 is an L-phenylalanine residue, AA2 is an N-methyl-glutamic acid residue, and R2 is-(CH2) 15CH3. 13 For example, the compound and its stilbene category 1 in the scope of patent application, in which R1 is methyl, AA1 is L-0-ethylammonium tyrosine residue, AA2 is D-methionine sulfonate residue, and AA1 is L-phenylalanine residues, AA2 is N-methyl-methyl-alanine residues, and R2 is -CH (CH30C02C2H5. 1) This paper size applies to China National Standard (CNS) A4 specifications (210 X 297 cm) ) 2 310311 H3 14 · As for the compound and its stilbene in item 1 of the scope of patent application, where ... is methyl, AAI is L-tyrosine residue, AA2 is D-5-hydroxyhexylamine residue, and AA3 is L-phenylalanine residues, AA4 is N-methyl-A-alanine residues, and R2 is a hydrogen atom. 15. For example, the compound and its stilbene of item 1 in the scope of patent application, where ... is methyl, AAi to L- Those having an amino acid residue, AA2 being a D-methionine sulfonate residue, aa3 being an L-phenylalanine residue, AA4 being an N-methyl-alanine residue, and R2 being-(Ch2) 7CH3. 16. The compound and its hydrazones according to item 丨 in the scope of patent application, wherein ... is methyl, AAI% is 2,6-dimethyl-L-tyrosine residue, AA2 is DN, and ethinoguanine The residue, AA3 is a P-fluorophenylalanine residue, AA4 is an N-methyl-cold-alanine residue, and R2 is -CH2CH3. * 17. · 'A pharmaceutical composition for preventing and / or treating pain, which contains the compound of any one of the scope of claims 1 to 16 of the patent application or its physiologically acceptable 塩 as an active ingredient. 18. If the pharmaceutical composition in the scope of application for item π is in the form of a pharmaceutical composition for oral use. · Printed by the Staff Welfare Committee of the Central Bureau of Standards of the Ministry of Economic Affairs of the People's Republic of China 19 · If the compound of any one of the scope of patent application items 1 to 16 or the physiologically acceptable species thereof is used for manufacturing Item to any one of item 18 to item 18. Λ This paper size applies to Chinese National Standard (CNS) Α4 specification (210 X 297 public love) 5 31031Γ