WO1999033864A1

WO1999033864A1 - Peptide derivatives

Info

Publication number: WO1999033864A1
Application number: PCT/JP1998/005862
Authority: WO
Inventors: Shinobu Sakurada; Masaki Hagiwara; Tetsuhisa Miyamae; Toru Okayama; Tadashi Ogawa; Tomomi Oya; Eriko Nukui; Masako Yagisawa
Original assignee: Daiichi Pharmaceutical Co., Ltd.; Fuji Chemical Industries, Ltd.
Priority date: 1997-12-26
Filing date: 1998-12-24
Publication date: 1999-07-08
Also published as: TW474945B

Abstract

Compounds represented by the general formula: HN=C(R?1)-AA1-AA2-AA3-AA4-OR2¿ or salts thereof, useful in preventing and treating pains, wherein R1 represents C¿1-6? alkyl, amino, etc.; R?2¿ represents hydrogen, C¿1-6? alkyl, etc.; AA?1¿ 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(R?8)-CH(R9)-CH(R10¿)-CO- (wherein R?8, R9 and R10¿ represent each hydrogen, C¿1-6? alkyl, C2-6 alkenyl, etc.).

Description

Description Peptide derivative Technical field

The present invention relates to a peptide derivative which exerts a pharmacological action such as analgesia through an action on an obioid receptor or the like. Background art

Obioid receptors, such as morphine, to which ovioids bind, were proven to exist in the early 1970s. Opioid receptors are currently roughly classified into three types: μ, δ, and κ. Morphine mainly acts as an agonist at μ receptors, and exerts pharmacological effects such as analgesia, intestinal motility suppression, and respiratory depression. Since 1975, a series of endogenous morphine-like substances that bind to the Obioid receptor have been discovered. To date, all of these substances are peptides, collectively referred to as obioid peptides. The pharmacological effect of the obioid peptide is considered to be basically the same as that of morphine, and since it is a substance that originally exists in living organisms, it is expected that it may be a drug with a safety level higher than that of morphine. However, natural opioid peptides are not yet used as pharmaceuticals due to problems in pharmacokinetics.

In the 1980's, delmorphin, containing D-alanine, was isolated from the skin of Raiel. The analgesic effect of delmorphin was approximately 1,000 times stronger than that of morphine by ventricular administration, and was found to be relatively stable in this drug. Subsequently, synthetic Obioid peptides containing D-form amino acids have been proposed.In particular, synthetic Obioid peptides with high c-receptor selectivity are expected as analgesics without narcotic properties, and clinical trials have been conducted. I have. However, its potential as a pharmaceutical in terms of its efficacy, side effects attributed to being a / c agonist, and profitability have been questioned. Furthermore, these synthetic obiooid peptides are difficult to use as oral preparations, For example, it cannot be a substitute for MS-Contin, a sustained-release oral preparation of morphine sulfate, which is widely used as a therapeutic agent for cancer pain in recent years. The present inventors have developed an oligopeptide derivative having L-Tyr- (L or D) -Arg-Phe as a basic skeleton and having an amidino group at the N-terminus (International Publications W095 / 24421, W097 / 10261, and W097 / 10262), but even with these derivatives, the bioavailability at the time of oral administration is not always satisfactory. The daily dose of MS Contin increases to the gram unit, and it may be difficult to take it.In addition, it has to be discontinued due to the occurrence of side effects such as itch, which may be caused by histamine release. In some cases. Therefore, an orally administrable alternative drug that is safer and more effective than morphine is desired. Disclosure of the invention

The present inventors have conducted intensive studies in order to solve the above-mentioned problems, and found that, for example, the basic skeleton is L-thiomethyl-S-D-methionine sulfoxide-phenylalanine-N-methyl-β-ryanine, O-terminal tyrosine hydroxyl group acylation and C-terminal carboxyl group esterification in oligopeptide derivatives having an iminoethyl group at the terminal give excellent analgesic activity even by oral administration We found that we could get a good opioid peptide. The present inventors have further studied and completed the present invention.

That is, the present invention provides the following formula (I):

^{HN = C (R 1) -AA'} -AA'-AA:, -AA'-OR "

[Where,

R 'represents a C _{l ri} alkyl group, amino group, mono C _{l tl} alkylamino group, di C _{l fi} Arukirua amino group, or a phenylene le radical:

^ Is a hydrogen atom, (: alkyl group, halogenated ( _lti alkyl group, hydroxy (: _{| |} alkyl group, C, _lu alkoxy substituted [. Alkyl group _,. Alkoxy- _s alkoxy substituted _{Cl ri} alkyl group, Amino alkyl group, mono C, _H alkylamino _{Cl 16} Kill group, di-c, _ _s alkyl amino and _{'| 16} alkyl group, c ₃ _,. A cycloalkyl group,. Cycloalkyl-substituted c _IB alkyl group, C ₂ _{_LS} alkenyl group, Cw ₆ alkynyl group,,. § Li Ichiru group, Ariru substituted C, ₆ alkyl group, C _B _ _1B 7 Lille - _(H alkoxy substitution c _{l ri} alkyl group, also phthalidyl group which may be substituted, C _{the IH} alkoxy force / Reponiruokishi C alkyl Or a C ₂ _ ₇ alkanoyloxy C ₆ alkyl group.

AA 'has the following formula:

{Wherein, X represents a hydrogen atom, or the following formula: -CO-Y-R ³ (wherein, R ³ is a _ ₁₆ alkyl group, a hydroxy, _ ₁₆ alkyl group, an amino (: .. ₁₆ alkyl group, mono _<6 alkylene Noreamino c Bok _{| 6} Arukinore group, di-c ₆ alkylamino _<16 alkyl group, c, Shikuroa alkyl group, a cycloalkyl-substituted C ₆ alkyl group, C. ₂ - _LFI alkenyl group, (_ ₁₆ alkynyl group, C _H _ _H) 7 reel group, C _{RI | ()} aryl substituted _κ alkyl group or heterocyclic group), R 'and R ⁵ are each independently Represents a L-α-amino acid residue represented by a hydrogen atom, a C, alkyl group, a halogenated < _TI alkyl group or a halogen atom, and Y represents an oxygen atom or a single bond};

AA ² has the following formula:

(Wherein, R ^ri is an amino group, a mono C, _ ₆ alkylamino group, - ₆ Ashiruamino group, also Guanijino groups have a C _IB § alkyl group, Bok Imino _ ₆ alkyl group, C, _ _fi al Kill also Urei de group have a group, C _{l 6} alkylthio group, C, _ ₆ alkylsulfinyl Finiru group, C, alkylsulfonyl group, a C _{the IH} Ashiru group, or Bokuhi Dorokishi C _{l ti} alkyl group, _n Represents an integer of 1-4) D-α-amino acid residue represented by:

ΑΑ ³ is the following formula:

(Wherein, R ⁷ represents a hydrogen atom, a C _1-6 alkyl group, a halogenated _{Cl 6} alkyl group, or a halogen atom), and represents an α-amino acid residue represented by the formula:

Alpha alpha ⁴ is the following ^{formula: -N (R 8) -CH (} R 9) -CH (R, 0) -C0- ( wherein, RR ^9, and R ^10, respectively it independently hydrogen, C, _ ₆ alkyl group, ₍₆ alkenyl group, C _M alkynyl groups, C ₆ _,. § aryl group, or Ariru represented by substituted (indicating ₆ alkyl group)] 3 - Amino acid residue are shown:

However, R ^fi is amino group, a mono- C, _ ₆ alkylamino amino group, Ashiruamino group, also Guanijino groups have a C _{l ri} § alkyl group, 1 - having Imino C _{1 H} alkyl group, an aralkyl kill group A ureido group, an alkylthio group, a C _{1 H} alkylsulfinyl group, or a _6- alkylsulfonyl group, unless X and X are both hydrogen atoms.]

Or a salt thereof.

From another viewpoint, there is provided a medicament which contains the compound represented by the above formula (I) or a physiologically acceptable salt thereof as an active ingredient, and is useful as, for example, an analgesic. According to a preferred embodiment of the medicament, a compound represented by the above formula (I), which is an active ingredient, or The present invention provides a medicament in the form of a pharmaceutical composition comprising a physiologically acceptable salt thereof and a pharmaceutical additive. From still another viewpoint, use of the compound represented by the formula (I) or a physiologically acceptable salt thereof for the production of the above-mentioned medicament; and a method for preventing and / or treating pain, There is provided a method comprising the step of administering an effective amount of the compound represented by the above formula (I) or a physiologically acceptable salt thereof to a mammal including human. BEST MODE FOR CARRYING OUT THE INVENTION

In the above definition, an "alkyl group" or an "alkyl moiety" for a substituent containing one or more alkyl moieties (eg, a monoalkylamino group, a halogenated alkyl group, an alkoxy group, an alkoxy-substituted alkyl group, etc.) "May be a straight chain or a branched chain. For example, a C _{1 S} alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, and more specifically, a methyl group, an ethyl group, an _n- Examples include a propyl group, an isopropynole group, an n-butyl group, a sec-butyl group, a tert-butyl group, an n-pentyl group, a neopentyl group, and an n-hexyl group. For example, in the substituent containing one or more C ₆ alkyl moieties, the C, _ ₆ alkyl moieties include the above-mentioned (:, „ ₆ alkyl groups. Dialkylamino or dialkylamino). In a substituent containing a moiety (for example, a dialkylaminoalkyl group), two alkyl groups substituted on an amino group may be the same or different.

In this specification, "halogen" may be any of fluorine, chlorine, bromine, and iodine. The substitution position, number and type of the halogen atom substituted on the halogenated alkyl group are not particularly limited, and any of a monohalogenated alkyl group and a perhalogenated alkyl group can be used. When two or more halogen atoms are present, they may be the same or different. Examples of the halogenated alkyl group include a trifluoromethyl group and a 2,2,2-trifluoroethyl group. However, the present invention is not limited to these examples. Hydroxya The substitution position and number of the hydroxyl group substituted on the alkyl group are not particularly limited.For example, even when 1 to 4, more preferably 1 or 2, and particularly preferably 1 hydroxyl group is substituted at an arbitrary position. Good. As the hydroxyalkyl group, for example, a hydroxymethyl group can be used.

Examples of the alkoxy-substituted alkyl group include a methoxymethyl group, an ethoxymethyl group, a methoxethyl group, and an _n -heptoxymethyl group. Examples of the alkoxy-substituted alkyl group include a methoxymethoxymethyl group, Examples include, but are not limited to, a toxetoxymethyl group. The number of the amino groups substituted on the aminoalkyl group is preferably 1 or 2, particularly preferably 1. Although C ₃ _ _l0 number of rings of the cycloalkyl group is not particularly limited, but is preferably one to about 3, for example, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, Adamanchiru group such as Can be used. _{C: ll (,} substituent containing a cycloalkyl moiety (e.g. (- ₃ _ ₁₀ such as cycloalkyl-substituted alkyl group) of (^ _{| 0} The cycloalkyl moiety may be used cycloalkyl groups exemplified above One or more C ₆ alkyl groups may be present on the ring of these cycloalkyl groups.

The C _2-l6 alkenyl group and the alkynyl group may be either linear or branched. The number of double bonds and triple bonds contained in these groups is not particularly limited, but is preferably It is 1 to 4, more preferably 1 or 2, particularly preferably 1. In the above definition, "aryl group" or "aryl moiety" for a substituent having one or more aryl moieties (eg, an arylalkyl group, an arylalkoxy-substituted alkyl group, etc.) For example, a phenyl group, a naphthyl group and the like can be used. As an arylalkyl group, a benzyl group, a phenethyl group and the like can be used. The arylalkoxy-substituted alkyl group may be a benzyloxy group or a phenethyloxy group.The phthalidyl group may have a _c substituent.The phthalidyl group has one or more substituents on a benzene ring portion. A phthalidyl group can be used. Such a replacement As the base, for example, C _LB alkyl group, a halogenated _h alkyl groups, C an alkoxy group, a hydroxyl group, a halogen atom, an amino group, a mono- or di-alkylamino group, a carboxyl groups, C, ₆ alkoxycarbonyl group, _ ₆ alkyl Examples thereof include, but are not limited to, a phenol group and a sulfonate group. Unsubstituted phthalidyl groups are preferred. As the alkoxycarbonyloxyalkyl group, for example, an ethoxycarbonyloxymethyl group can be used, and as the alkanoyloxyalkyl group, for example, an acetooxymethyl group can be used.

The heterocyclic group represented by R ³ includes, for example, a 5- to 10-membered saturated ring containing one or more hetero atoms (eg, a nitrogen atom, an oxygen atom, a sulfur atom, etc.) as a ring-constituting atom. , Partially unsaturated, or aromatic heterocyclic groups can be used. When two or more heteroatoms are included, the types of the heteroatoms may be the same or different. In the above definition, the “acyl group” for the “acyl group” or a substituent containing an acyl moiety (eg, an acylamino group) includes, for example, an alkenyl group such as an acetyl group and a pionyl group; A halogenated alkanoyl group such as a roacetyl group, an aroyl group such as a benzoyl group and a naphthoyl group, a phenyl group, a naphthyl group, and the like can be used.

The substitution positions of R ¹ and R ⁵ in the group represented by AA ′ and R ^{7 in} the group represented by AA ^{: I} on the benzene ring are not particularly limited. Examples of the halogenated alkyl group represented by R \ R \ or R ^7, trihalogenated methyl group is preferred. Further, in this specification, the term "amino acid residue" is used in its ordinary meaning in the field of peptide chemistry, and more specifically, amino group and amino group which are in the octa position in amino acid. It means the remaining structure of the carboxyl group or the amino group and carboxyl group at the j3 position in the / 3 amino acid, excluding the hydrogen atom and / or the hydroxy group, respectively.

There ^ Ashiruamino group, C, also have a _ ₆ alkyl group: In addition, the peptide derivative represented by the above formula (I), R ^RI is amino, mono C, _rt alkylamino group, ( Guanidino group [-NH-C (N) = NH], trimino ₆ alkyl group, ureido group which may have alkyl group (-NH-CO-N), ( ₆ alkylthio group, C _1-6 Arukirusurufu Iniru group (- S0-C Bok ₆ alkyl), or an alkylsulfonyl group (. -SO厂C Bok ₆ Aruki Le), and and X is both a hydrogen atom is within the scope of the present inventionゝ

The asymmetric carbon present in the peptide derivative of the present invention represented by the above formula (I) may have any S- or R-configuration unless otherwise specified in the above definition. Good. When the sulfur atom (such as sulfoxide) substituted by an oxygen atom has an S- or R- configuration, the configuration may be any of those. For example, when M ² represents a D-methionine sulfoxide residue, a D-methionine- (RS) -sulfoxide residue, a D-methionine- (R) -sulfoxide residue, a D-methionine- Any of the (S) -sulfoxide residues are included within the scope of the present invention. It is desirable to select a peptide derivative having an appropriate configuration from the viewpoint of body stability and the like.

The peptide derivative represented by the formula (I) of the present invention includes all optically active isomers, racemic isomers, diastereoisomers, and arbitrary mixtures thereof. In addition, the peptide derivative of the present invention includes acid addition salts such as hydrochloride, acetate, and paratoluenesulfonic acid, and base addition salts such as ammonium salt and organic amine salt, as well as free forms and salts. Also included are any hydrates and solvates of the peptide derivative in the form: Furthermore, in addition to the peptide derivatives represented by the above general formula, compounds that are dimers or multimers of the above peptide derivatives, and cyclic compounds in which the C-terminal and the N-terminal of these peptide derivatives are bonded are also included. Included within the scope of the invention.

Specific examples of the compound of the present invention represented by the formula (I) include:

(1) R 'is C, _ _tt alkyl group or amino group, more preferably R' is a methyl group, Echiru group or Amino group compounds wherein:

(2) AA ¹ is a substituted or unsubstituted L- or D- phenylene Ruaranin residues, preferably There are AA ^3-phenylene Ruaranin residues, D- phenylene Ruaranin residue, L- p-fluorophenyl Compounds that are alanine residue, Dp-fluorophenylalanine residue, L-0-trifluoromethylphenylalanine residue, or D-0-trifluoromethylphenylalanine residue:

(3) Compounds in which AA ¹ is an N-methyl-0-alanine residue:

(4) AA ¹ force; shi-tyrosine residue, 2,6-dimethyl-L-tyrosine residue, 0-acyl-L-tyrosine residue, 0-alkoxycarbonyl-L-tyrosine residue, or phenoxycarboxy A compound which is a ru-L-tyrosine residue;

(5) ^AA; is D- methylol O Nin sulfoxide residues, D- arginine residues, or! )-A compound that is a citrulline residue;

Compounds in which (6) is a DN ⁵ -acetylorutin residue, a D-5-oxonorleucine residue, or a D-5 -hydroxynorleucine residue:

(7) R ^z is _(1K alkyl group. § Li Ichiru group, C ₆ _"lti Ariru substituted C, _ ₆ alkyl, C,. ₁₀ alkoxy substituted Anorekinore group, C _{l 6} alkoxycarbonyl O alkoxy C Bok ₆ A compound which is an alkynole group or a phthalidyl group: and

(8) Compound obtained by appropriately combining the specific amino acid residues or substituents described in (1) to (7) above

The compounds of the present invention are not limited to these. Among the compounds of the present invention, examples of particularly preferred compounds include:

(9) R ¹ is a methyl group, AA ′ force; L-0-acetyltyrosine residue, force; D-methionine sulfoxide residue, AA ³ is L-phenylalanine residue A compound wherein A is a N-methyl--alanine residue and is a hydrogen atom;

(10) R 'is a methyl group, AA' is a c-tyrosine residue, AA ² is a D-methionine sulfoxide residue, AA ³ is an L-phenylalanine residue, and AA ⁴ is A compound which is an N-methyl- -alanine residue and is-(CH ₂ ) ₁₅ CH _:! ;

(11) R ¹ is a methyl group, AA ′ force; L-0-acetyl tyrosine residue, AA force; D-methionine sulfoxide residue, and M ³ is L-phenylalanine residue. a group, AA ¹ force; N- methyl - - a Aranin residue, R ² is - CH _(CH:,) compound is 0C0.A; (12) R ¹ is a methyl group; AA ′ force; tyrosine residue; D-5-hydroxynorleucine residue; AA ^{: i} force; i.e. phenylalanine residue; AA ⁴ A compound having an N-methyl-alanine residue and R ^: being a hydrogen atom;

(13) R 'is a methyl group, AA' is a tyrosine residue, AA ² is a D-methionine sulfoxide residue, AA ^{: i} is an L-phenylalanine residue, AA ⁴ is N A compound which is -methyl-0-alanine residue and is a force;-(C) ₇ CE ,;

(14) R 'is a methyl group, ΑΑ' is a 2,6-dimethyl-di-tyrosine residue, AA ^; DN ⁵ -acetylorutin, AA ^{: i} is P-fluorophenyl A alanine residue, wherein AA ⁴ is an N-methyl-β-alanine residue and the force is-CH ₂ CH ₃

Can be mentioned.

The peptide derivative of the present invention has an excellent analgesic effect and is useful as an active ingredient of a medicine, preferably an active ingredient of an analgesic. The peptide derivative of the present invention has a relatively weak histamine releasing action and a lowering of heart rate associated with an analgesic action as compared with morphine, and has a low degree of cross-resistance with morphine, so that it is suitable for treating cancer pain. is expected. In addition, all of the known analgesic peptide compounds have a problem that they cannot exert sufficient efficacy by oral administration, but the peptide derivatives of the present invention can exert an excellent analgesic effect by oral administration. It has characteristics and is expected to be as useful as MS Contin, a sustained-release oral preparation of morphine sulfate.

Therefore, the medicament of the present invention containing the peptide derivative of the above formula (I) or a physiologically acceptable salt thereof as an active ingredient can be used for the prevention and / or treatment of pain. Applicable by parenteral administration such as administration and subcutaneous administration, and oral administration. It is also expected to be useful for mucosal absorption preparations including nasal absorption and transdermal absorption preparations. As the active ingredient of the medicament of the present invention, a hydrate or solvate of the peptide derivative of the above formula (I) or a physiologically acceptable salt thereof may be used. The dose is not particularly limited.For example, in the case of transdermal administration, the single dose is 0.1 to 10 mg, and in the case of oral administration, the single dose is 1 to 100 mg. It can be administered 2-3 times. The peptide derivative of the present invention can be synthesized by a solid phase method and a liquid phase method usually used for peptide synthesis. For example, a target peptide derivative can be produced by synthesizing a peptide chain having no amidino group by a solid phase method, and further introducing an amidino group to an amino group of tyrosine at the N-terminus. The C-terminus can be modified after the introduction of the group.

Various excellent protecting groups such as amino groups and condensing agents for condensation reactions are known. For example, refer to the following examples. Also, for example: Hiroshi Suzuki, “Protein Engineering—Basics and Application” Maruzen (1992) and references cited therein: M. Bondanszky, et al., "Peptide Synthesis John Wiley & Sons, NY, 1976; and JM Stewart and DJ Young," Sol id Phase Peptide Synthesis, WH Freeman and Co., San Francisco, 1969 and the like can be used as appropriate. In the solid phase method, it may be convenient to use various commercially available peptide synthesizers, for example, Model 430A manufactured by Perkin Elmer Japan (formerly Applied Biosystems). Commercially available products and the like can be easily obtained for resins and reagents used in the synthesis, and examples thereof are shown in Examples. Example

Hereinafter, the present invention will be described more specifically with reference to Examples, but the present invention is not limited to these Examples. By referring to this example, or by modifying or changing the method of this example, or by appropriately selecting starting materials or reaction reagents, the desired compound of the present invention encompassed by the general formula (I) can be obtained. The peptide derivative of the present invention can be easily produced. In the examples, the meaning of the amino acid group is the same as that usually used. When an amino acid in which the D-form and the L-form are present is referred to, particularly when the amino acid is not indicated as D-, the amino acid means an L-amino acid. In addition, the following abbreviations may be used, and similar abbreviations may be used unless otherwise indicated. The notation such as H ₂ NC (NH) -Phe-, Boc-Phe- or Z-Phe- indicates that the Ν'-terminal nitrogen atom of feniralanine is H., NC (NH)-, Boc or 1 Qualified with And amino acid residues may be shown for amino acids. Ada 1

Boc tert-butoxy canoleboninole

Bzl benzyl

cHex

DIEA disopropyl ethynoleamine

DMAP 4-dimethylaminopyridine

DMF Ν, Ν-dimethylformamide

DMT 2, 6-dimethylthicin

ECE 1-(Ethoxycarbonyloxy) ethyl

HNLE 5-Hydroxino / Releucine

HNLE (MOM) 5-Methoxy methoxynorleucine

HOBt 1-hydroxybenzotriazole

MetO methionine sulfoxide

MOM- CI Chloromethinole Metinoleate

ONLE 5-Oxonononoleucine

Phtl phthalidyl

POM pivaloyloxymethyl

_{Tyr (C0CH:!): 0} - § cetyl tyrosine

TyrCCOCH H ^) 0-Pionyl tyrosine

_{Tyr [C0 (CH) 2 CH} : i] 0- butyryl tyrosine

_{_{Tyr [C0CH (CH 3) 2}} ] 0 - I-Soviet butyryl tyrosine

Tyr (COcHex) 0 -Hex hexinole force / reponinoletyrosine

Tyr (COPh) 0-benzoyl tyrosine

Tyr [C0 (C¾), Ph] 0-3-phenylpropionyl tyrosine

Tyr [C0 (CH,) Ph] 0-4-phenylbutyrinoretyrosine Tyr [C0C (CH ₍ ) _{: t} : 0-bivaloyltyrosine

Tyr [C0 (l-Ada)]: 0-Toradamantyl carboxyltyrosine

Tyr (C0, CH,): 0-Methoxycarbyltyrosine

Tyr (C0, CH) 0-ethoxycarbodiltyrosine

Tyr [C0, CH (CH,),] 0-isopropoxycanolevonyl tyrosine

Tyr (C0, Ph) 0-phenoxycarbonyl tyrosine

Tyr (COCH h) 0-benzyl / reoxycanolevonyl tyrosine

WSCI 1-Ethyl-3- (3-dimethylaminopropyl) carbodimid hydrochloride Z Benzinoleoxycanoleboninole

(A) Production of raw material compounds

(1) Z-Phe-Me β Ala-0CH ₃

Dissolve H-Me ^ Ala-O e-HCl (6.14 g) in DMF (50 ml), and triethylamine (5.54 ml), HOBt (5.41 g), Z-Phe-OH (lOg) at -10 ° C Was added, and WSCI (8.3 g) was added, followed by stirring at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid and then with an aqueous saturated sodium bicarbonate solution. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 13 g of the desired product as a colorless oil.

(2) Boc-D-Met0-Phe-Me β Ala-0CH _{: i}

Z-Phe-MeiSAla-0CH _{: 1} (6.1 g) obtained in (1) above was dissolved in DMF (lOOinl), and 5% Pd-C (10 g) was added as a catalyst, followed by catalytic reduction at room temperature for 3 hours. . After filtering off the catalyst, Boc-D-MetO-0H (7.98 g), HOBt (4 g), and WSCI (6.7 g) were added to the filtrate at 0 ° C, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was pre-purified with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 9.1 g of the desired product as a colorless oil.

(3) Boc-Tyr-D-MetO-Phe-Me β Ala-OCH,

Obtained in the above (2) Boc- D- MetO- Phe- Me Ala- 0CH 3 a (4.5 g) was dissolved in 90% TFA (50 ml), was stirred for 30 minutes at room temperature. The residue obtained by concentrating the solvent under reduced pressure was treated with DMF (20 ml). After neutralizing this solution with triethylamine, add Boc-Tyr-0H (2.2 g), HOBt (3.5 g) and WSCI (2.5 g) at 0 ° C, and overnight at room temperature. Stirred. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 4.5 g of the desired product as a white solid.

(4) Boc-Tyr-D-MetO-Phe-Me β Ala- OH

Boc-Tyr-D-MetO-Phe-MeβAla-0CH _{: 1} (2.23 g) obtained in (3) above was dissolved in a mixed solution of methanol (20 ml) and water (10 ml). To this solution was added a 2N aqueous solution of NaOH (3.3 ml) at 0 ° C, and the mixture was stirred at room temperature for 3 hours. The pH of the reaction solution was adjusted to 2 by adding 1 N hydrochloric acid at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The obtained residue was crystallized from isopropyl ether to give 1.83 g of a white solid.

(5) Boc-D-Met0-Phe-0CH ₃

H-Phe-OMe-HCl (88 g) was dissolved in DMF (500 ml) and -10. Triethylamine (56 ml), HOBt (46 g) and Boc-D-MetO-OH (90 g) were added, and WSCI (76 g) was added, followed by stirring at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid and then with saturated aqueous sodium hydrogen carbonate. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure. The obtained residue was crystallized from hexane to obtain 117 g of the desired product as a white solid.

(6) Boc-Tyr-D-MetO-Phe-OCH,

The Boc-D-MetO-Phe-0C¾ (10 g) obtained in (5) above was dissolved in 90% TFA (100 ml) containing anisol (10 ml) and stirred at room temperature for 30 minutes. . The residue obtained by concentrating the solvent under reduced pressure was dissolved in DMF (40 ml), and neutralized by adding triethylamine. This solution was previously dissolved with Boc-Tyr-0H (5.6 g), HOBt (3.5 g) and WSCI (5.4 g) in DMF (20 ml) and stirred at 0 ° C for 30 minutes. The solution was added and stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure. The obtained residue was crystallized from hexane to obtain 11 g of the desired product as a white solid. (7) Boc-Tyr-D-MetO-Phe-OH

The Boc-Tyr-D-MetO-Phe-0C¾ (110 g) obtained in the above (6) was dissolved in methanol (187 ml). To this solution was added a 2N aqueous solution of NaOH (187 ml) at 0 ° C, and the mixture was stirred at room temperature for 30 minutes. To the reaction solution was added 1N hydrochloric acid (1 L) at 0 ° C, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to give 104 g of the desired product as a white solid.

(8) Boc-Tyr-D -MetO-Phe-Me β Ala-OC (CH:!)

Boc-Tyr-D-MetO-Phe-OH (11.5 g), H-MeβAla-0C (C) ₃ (3.82 g), HOBt (3.24 g) obtained in (7) above And WSCI (4.60 g) were added at 0 ° C, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was crystallized from isopropyl ether to obtain 12.6 g of white crystals.

(9) Z-D-HNLE (M0M) -0H

Dissolve sodium (1.17 g) in anhydrous methanol (100 ml) and add (R) -3-benzyloxycarbonyl-4- (3-oxobutyl) -5-oxazol idinone (9.90) to this solution at -12 ° C. g) [Synthesized according to the method described in JM Scoltz and PA Bartlett, Synthesis, pp. 542-544, 1989]. After stirring at this temperature for 45 minutes, 6N HCl was added dropwise to neutralize. After the separated inorganic salt was separated by filtration, sodium borohydride (1.29 g) was added at 0 ° C. After stirring the reaction solution for 5 minutes, 6N HCl was added dropwise to neutralize it. The methanol was distilled off under reduced pressure, and the residue was added with ethyl ether and washed with saturated saline. The organic layer is dried over magnesium sulfate, and the solvent is concentrated under reduced pressure. 8.88 g of -D-HNLE-OMe was obtained as a colorless oil.

Is this compound (8.50 g) dissolved in methylene chloride (25 ml)? Then, DIEA (6.1 ml) and M0M-C1 (2.62 ml) were added at 0 ° C .: After stirring at room temperature for 15 hours, methylene chloride was distilled off under reduced pressure, and the residue was added to ethyl acetate. Dissolved. This solution was washed with 10% cunic acid, saturated aqueous sodium bicarbonate, and then with saturated saline. After the organic layer is dried over magnesium sulfate, the solvent is removed. After concentration under reduced pressure, Z-HNLE (M0M) -0Me (7.83 g) was obtained as a colorless oil. This compound (7.50 g) was dissolved in methanol (20 ml), and 2N NaOH (16.5 ml) was added at 0 ° C. The solution was stirred at room temperature for 1 hour, neutralized with 1N HCl, and methanol was distilled off under reduced pressure. 1M NaHSO, was added to the residue to adjust the pH to 3, then ethyl acetate was added to separate the layers, and the organic layer was washed with saturated saline. After drying over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 7.08 g of the title compound as a colorless oil.

(B) Production of the peptide derivative of the present invention

Example 1: H ₃ C-C (NH) -Tyr-D-MetO-Phe-Me ^ Ala-0C¾ · acetate

Boc-Tyr-D-MetO-Phe-MeβAla-0CH ₃ (1.35 g) was dissolved in 90% TFA (10 ml) and stirred at 0 ° C for 30 minutes. The residue obtained by concentrating the solvent under reduced pressure was dissolved in DMF (8 ml), and ethyl acetimidoate hydrochloride (1.38 g) and triethylamine (0.84 ml) were dissolved. The solution was stirred at room temperature for 1 hour 30 minutes. The reaction solution was concentrated under reduced pressure, and the obtained residue was charged by 0DS column chromatography (Fuji Siricia DM 1020T, 50 g) and eluted with a 20% methanol / 0.1 N acetic acid solution. The fractions containing the target compound were collected and freeze-dried to obtain 0.61 g of the title compound as a white powder.

FAB mass vector m / z: 617 (M + H *)

[a] _u ^{2: i} +31.1 ^ (c = 0.97, IN 麵)

Rf: 0.66 (n-BuOH: AcOH: H0: pyridine = 15: 3: 10: 12) Examples 2 to 7

According to the method of Example 1, the compounds shown in Table 1 were synthesized. In the table, m / z indicates M + H, and the optical rotation shows the result measured at c = 0.90 to 2.00, 1N acetic acid and 23 ° C. For the measurement of Rf, n-Bu0H: Ac0H: H, 0: pyridine = 15: 3: 10: 12 was used as a developing solvent (the same applies in the following table). Orn (Ac) means N acetylethyl ordinine residue, and Phe (pF) means parafluorophenylalanine residue. Example Structural formula m / z Rf

2 H ΓΓΗ-(NH ¹ ) -Tvr-DM tD-Ph-PAT a-ΟΓΗ I3 * J + 1? «V / .uu

_{!. 3 HC-C (NH} ) -Tyr-D-Orn (Ac) - Phe- Me β Ala- 0CH: 626 +23 8 0. 65

_{! 4 H:. CC (NH} ) - Tyr - D-Orn (Ac) - Phe (pF) -Me β Ala- OCH:, 644 +23 9 0. 65

0 H _{: i} C- C (NH) -DMT-D-Orn (Ac) -Phe (pF) -Me β Ala- OC 672 +41.7 0.66

6 H _{: i} C- C (NH) -Tyr-D-MetO-Phe (pF) -Me β Ala-0CH 635 + 16.4 0.64

_{!. 7 H; CC (NH} ) - DMT- D- Me tO- Phe (pF) -Me β Ala- OCH 3 663 +38 3 0. 65 Example 8: H:, CC (NH ) - Tyr- D-MetO- Phe- Me β Ala- 0 (CH) 7 CH;! · acetate

(1) Boc-Me ^ Ala -0 (CH,) 7 CH:!

Boc-Me] 3 Ala-OH (614 g) was dissolved in methylene chloride (20 ml), and octyl alcohol (641 mg) and DMAP (10 mg) were added. Then, WSCI (1.12 g) was added, and the mixture was stirred at room temperature for 20 hours. The reaction solution was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride: methanol = 50: 1) to give a colorless oil 1 36 g were obtained.

(2) Boc-Tyr-D-MetO-Phe-Me β Ala-0 (CH,) ₇ CH ₃

The Boc-Me ^ Ala-0 (CH,) ₇ CH, (6.14 g) obtained in (1) above was dissolved in a 4N HC1 / ethyl acetate solution (20 ml), and the mixture was stirred at room temperature for 30 minutes. The crystals precipitated by adding geethylether to the reaction solution were collected by filtration. The crystals were dissolved in DMF (20 ml), neutralized by adding triethylamine, and then Boc-Tyr-D-MetO-Phe-0H (3.45 g), HOBt (0.89 g) and WSCI (1 . 72 g) was added at 0 ° C, and the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with methylene chloride: methanol = 20: 1) to obtain 3.0 g of white crystals. I got

_{_{! (3) H:! C}} - C (H) - Tyr-D- MetO- Phe- Me β Ala- 0 (C¾) 7 CH; · acetate

Boc-Tyr-D-MetO-Phe-MeβAla-0 (CH ₂ ) ₇ C¾ (1.1 g) obtained in (2) above, ethyl imidoacetyl hydrochloride (0.5 g) and triethylamine ( The reaction was carried out in the same manner as in Example 1 using 0.54 g). The resulting crude product was charged to 0DS column chromatography (Fuji Siricia DM 1020T, 40 g) and eluted stepwise with 30 to 50% methanol aqueous solution. The fractions containing the desired compound were collected and freeze-dried to obtain 0.33 g of the title compound as a white powder. FAB mass spectrum m / z: 715 (M + H ")

[α] _ΰ ^α +14.5 ° (c = 1.00, IN acetic acid)

Rf: 0.68 (n-BuOH: AcOH: H, 0: pyridine = 15: 3: 10: 12) Examples 9 to 15

According to the method of Example 8, the compounds shown in Table 2 were synthesized. Table 2 Example Structural formula m / z (a JD Rf

9 H, C- C (NH) -Tyr- D-MetO-Phe- Me fiMa- 0CH, CH:! 631 +23.7 0.66

_{10 H: 1 C- C (NH} ) -Tyr- D-MetO-Phe- Me ^ Ala- -0 (C¾):, C¾ 659 +24.4 0.68 11 H:, C- C (NH) -Tyr- D- MetO-Phe- e i5 Ala- 0 (CH,) ₅ CH _{; i} 687 +32.8 0.71

_{! 12 H: C- C (H} ) -Tyr- D - MetO- Phe - · Me ^ Ala- -0 (CH,) 9 CH :( 743 ten 15.6 0.71

13 H:, CC (N ^T H) -Tyr- D-MetO-Phe-Me ^ Ala ■ -0 (C¾) _u CH _;) 771 + 14.9 0.70

14 H:, C. -C (H) -Tyr- D-MetO-Phe- -Me Ala.-0 (CH,) ₁₅ CH, 827 + 14.6 0.73

15 H:, C -C (NH ) -Tyr- -D-MetO-Phe- -Me ^ Ala -0C (CH:!):! 659 +23.0 0.69

_{16 H: t C -C (NH} ) -Tyr- -D-MetO-Phe- -Me Ala -0CH, CF:! 685 +24.1 0.71

17 H, C -C (NH) -Tyr- -D-MetO-Phe- -Me Ala -OcHex 685 -25.0 0.70

18 H:, C -C (NH) -Tyr- -D-MetO-Phe- -Me ^ Ala -0CH, cHex 699 +25.0 0.70 _{19 H:! CC (NH)} -Tyr-D-MetO-Phe-Me β Ala- OPh 679 +25.1 0.66 0 H, CC (NH) -Tyr-D-MetO-Phe-Me β Ala-OBzl 693 +32.8 0.68 1 H _{: i} CC (NH) -Tyr-D-MetO-Phe-Me β Ala-OPht 1 735 +14.1 0.66 2 H _{: t} CC (NH) -Tyr-D-MetO-Phe-Me β Ala- OECE 719 +16.6 0.67

23 H _{: i} C- C (NH)-Tyr- D-MetO- Phe-Me β Ala- OPOM 717 +17.0 0.68

_{! 24 H; CC (NH)} - Tyr- D-MetO- Phe-Me β Ala-OCH, CH, N (CH; ¾); 674 +17.3 0.40 Example 25: H, CC (NH) -Tyr [COCH ( CH _{: t} ) ₂ ] -D-MetO- Phe-Me β Ala- OH

(1) Boc-Tyr (COCH (CH _{; i} ) J-D-MetO- Phe- Me β Ala- OC (CH ₃ ) ₃

Boc - Tyr- D- MetO- Phe-Mei3 Ala- 0C (CH 3) 3 (2.5 g) and construed dissolved in methylene chloride (30 ml), 0 ° C in chloride isobutyric acid (0.55 ml) and Toryechiruamin (0.97 ml), and the mixture was stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium bicarbonate, and then with saturated saline. The organic layer was dried over magnesium sulfate, and the solvent was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 40: 1) to obtain 1.79 g of white crystals.

(2) H ₃ C-C (NH) -Tyr [COCH (CH ₃ ) ₂ ]-D-MetO- Phe- Me β Ala- OH

Boc-Tyr [COCH (CH ₃ ) ₂ ] -D-MetO-Phe-Me j3 Ala-0C (CH ₃ ) 3 (1.56 g) obtained in (1) above, ethyl imidoate hydrochloride (1.22 g) and KHC0 _:! (1.39 g), and the reaction was carried out in the same manner as in Example 1. The obtained crude product was charged to 0DS column chromatography (Fuji Siricia DM 1020T, 150 g), and eluted stepwise with a 5 to 16% acetonitril / 0.1 acetic acid solution. The fractions containing the target compound were collected and freeze-dried to obtain 0.46 g of the title compound as a white powder.

FAB mass tank m / z: 645 (Μ + Η ')

Ca] _t) ²³ + 17.2 ° (c = 0.99, I-acetic acid)

Rf: 0.60 (n-BuOH: AcOH: H, 0: pyridine = 3:10:12) Example 26-45

According to the method of Example 25, the compounds shown in Table 3 were synthesized. In the table, Cit indicates the residue of a tetralin residue [-HN-CH (CH. Factory CH ₂ -CH Maker NH-CO-NH.-C0_)] Table 3 Example Structural formula m / _Z [α] _Β Rf

26 H ₃ CC (NH) -Tyr (C0CH) -D-MetO-Phe-Me β Ala-OH 659 +17.5 0.62

27 H _{; i} CC (NH) -Tyr (C0CH ₂ CH) -D-MetO-Phe-Me β Ala-OH 673 +20.4 0.67

28 H, CC (NH) -Tyr [CO (CH ₂ ) ₂ CH,] -D-MetO-Phe-Me β Ala-OH 729 +19.8 0.65

29 ¾C-C (NH) -Tyr [CO (CH) e CH:!] -D-MetO-Phe-Me β Ala-OH 673 +22.3 0.63

30 H, CC (NH) -Tyr (C0CH _{: i} ) -D-Arg-Phe-Me β Ala-OH 654 +21.8 0.56 31 ¾C-C (NH) -Tyr (C0CH ₃ ) -DC it -Phe-Me β Ala-OH 655 +24.1 0.68

32 HC-C (NH) -Tyr (C0CH ₃ ) -D-Orn (Ac) -Phe-Me β Ala-OH 654 +24.8 0.63

33 H ₃ CC (NH) -Tyr (COcHex) -D-MetO-Phe-Me β Ala-OH 713 +22.0 0.65

34 HC-C (NH) -Tyr (COPh) -D-MetO-Phe-Me β Ala-OH 707 +17.0 0.63

35 ¾C-C (NH) -Tyr [CO (CH ₂ ) ₂ Ph] -D-MetO-Phe-Me β Ala-OH 735 +15.4 0.65

36 H, C-C (NH) -Tyr [CO (CH,), Ph] -D-MetO-Phe-Me β Ala-OH 749 +15.3 0.65

37 H, CC (NH) -Tyr [C0C (CH 3):!] -D-Met0-Phe-Me β Ala-OH 687 +29.8 0.65

38 H _{; i} CC (NH) -Tyr [CO (1 -Ada)] -D-MetO-Phe-Me β Ala-OH 765 +25.7 0.63

39 H, CC (NH) -Tyr [C0CH;!] -D-MetO-Phe-Me β Ala-OH 661 -16.8 0.61

40 H _{; (} CC (NH) -Tyr [C0, CH ₂ CH _{: i} ] -D-MetO-Plie-Me β Ala-OH 675 +37.1 0.63 41 H _{: i} CC (NH) -Tyr [C0CH (CH _{: (} ) J -D-MetO-Phe-Me β Ala-OH 703 +39.1 0.66

42 H, C-C (NH) -Tyr (CO, Ph) -D-MetO-Phe-Me β Ala-OH 723 ÷ 27.1 0.63

43 H _{: i} CC (NH) -Tyr (C0, CH, Ph) -D-MetO-Phe-Me β Ala-OH 737 -33.0 0.64

44 H..NC (NH) -Tyr (C0CH _{; j} ) -D-MetO-Phe-Me β Ala-OH 646 -24.0 0.62

45 RN-C (NH) -Tyr (COCH,) -D-Arg-Phe-Me β Ala-OH 655 +23.9 0.52 Example 46: ¾C-C (NH) -Tyr (COCE,) -D-MetO-Phe-Me β Ala-0 (CH) ₇ CH _{: i} · acetate

(1) Boc- Tyr (C0C) -D- MetO- Phe- Me β Ala-0 (CH,) ₇ CH,

The Boc-Tyr (C0CH ₃ ) -D-MetO-Phe-Me / Ula-OH (1.00 g) obtained in Example 26 was dissolved in methylene chloride (20 ml). After adding octyl alcohol (0.64 g), DMAP (10 mg) and WSCI (1.12 g) in C, the mixture was stirred at room temperature for 20 hours. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. The organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (eluted with a chromatographic form: methanol = 50: 1) to give a white solid. 1.36 g of crystals were obtained.

_{(2) H:, CC (} NH) -Tyr (C0CH 3) -D-MetO-Phe-Me β Ala-0 (CH,) 7 C¾ · acetate

(1) obtained in _{Boc- Tyr (C0CH:,) -} D- MetO- Phe- Me / 3 Ala- 0 (01 2) 7 (¾ (1.00 g), Asetoimi de acid Echiru hydrochloride (0.30 g) And triethylamine (0.5 ml), and the reaction was carried out in the same manner as in Example 1. The obtained crude product was charged to 0DS column chromatography-(Fuji Siricia DM 1020T, 50 g) to give 10-36% acetonitrile / 0 The fraction containing the desired compound was collected and lyophilized to give 0.14 g of the title compound as a white powder.

FAB mass spectrum m / z: 757 (Μ + Η ⁺ )

[α] ₍₎ +15.0 ° (c = l.01, IN acetic acid)

Rf: 0.70 (n- BuOH: AcOH : H 2 0: pyridine = 15: 3: 10: 12) Example 47 to 50

According to the method of Example 46, the compounds shown in Table 4 were synthesized. Table 4 Example Structural formula m / z [a] _D Rf

_{_{47 H:! I CC (H}} ) -Tyr (C0CH; t) -D-MetO-Phe-Me β Ala-0 (CH,), 5 CH: 867 +10.5 0.71

_{_{(! C0CH:); 48 H}} 1 CC (NH) -Tyr -D-MetO-Phe-Me β Ala-OECE 761 +16.3 0.69

49 H.C-C (NH) -Tyr (COCH,) -D-MetO-Phe-Me β Ala-OPht 1 777 +15.0 0.67

_{50 H: i C- C (NH} ) -Tyr [CO, CH (CH:!), J - D- MetO- Phe- Me β Ala-0 (CH,), CH: 1

759 +5.6 0.71 Example 51: H, C-C (NH) -Tyr-D-HNLE-Phe-Me β Ala-OH

(1) ZD-HNLE (MOM ) -Phe- Me β Ala- OCH:,

Boc-Phe-Me β Ala- OCH:! A (9.56 g) was dissolved in 4N HC1 / acetic Echiru solution (50 ml), and stirred for 45 minutes at room temperature. The reaction solution was concentrated under reduced pressure, dissolved in methylene chloride, and washed with saturated aqueous sodium hydrogen carbonate. After the solution was dried over magnesium sulfate, the solvent was concentrated under reduced pressure, and the obtained residue was dissolved in DMF (10 ml). To this solution, add Z-D-HNLE (M0M) -0H (6.83 g), HOBt (2.97 g) and WSCI (1.72 g) at -12 ° C and stir at -12 ° C for 30 minutes and at room temperature overnight did. Ethyl acetate was added to the reaction solution, and the mixture was washed with 10% cunic acid, saturated aqueous sodium bicarbonate, and then with saturated saline. 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 (Bz 1) -D-HNLE (MOM) -Phe-Me fl Ala-0CH _{; t}

Z-D-HNLE (MOM) -Phe-MeβAla-0CH _{: i} (11.4 g) obtained in (1) above was dissolved in methanol (50 ml), and 5% Pd-C (2 g) was used as a catalyst. And catalytic reduction was carried out at room temperature for 2 hours. After filtering off the catalyst, the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in DMF (20 ml), and Z-Tyr (Bzl) -OH (7.30 g), HOBt (2.70 g), and WSCI (3.83 g) were added at -12 ° C. After stirring for an hour, the mixture was stirred at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. After the organic layer was dried over magnesium sulfate, the solvent was concentrated under reduced pressure to obtain 14.1 g of the desired product as a colorless amorphous solid. (3) Z-Tyr (Bzl)-D- HNLE-Phe- Me β Ala-OMe

Z-Tyr (Bzl) -D-HNLE (OM) -Phe-MeβAla-0CH (12.0 g) obtained in (2) above was dissolved in methanol (200 ml), and concentrated hydrochloric acid (0.3 ml) was added. In addition, the mixture was refluxed for 1 hour and 20 minutes. Ethyl acetate was added to the residue obtained by concentrating the methanol under reduced pressure, and the residue was washed with 1N hydrochloric acid, saturated aqueous sodium hydrogen carbonate, and then with saturated saline. The organic layer is dried over magnesium sulfate, the solvent is concentrated under reduced pressure, and the solvent is concentrated under reduced pressure. The resulting residue is subjected to silica gel gel chromatography (eluted with chromatoform: methanol = 100: 1). Then, 6.27 g of a white powder was obtained.

(4) Z-Tyr (Bz 1)-D- HNLE- Phe-Me β Ala- OH

Z-Tyr (Bzl) -D-HNLE-Phe-Me Ala-OMe (2.34 g) obtained in the above (3) was dissolved in methanol (33 ml). To this solution was added a 2N aqueous NaOH solution (3 ml) at 0 ° C, and the mixture was stirred at room temperature for 4 hours and further at 40 ° C for 40 minutes. The reaction mixture was adjusted to pH 2 by adding 6N hydrochloric acid at 0 ° C, and extracted with ethyl acetate. The organic layer was washed with a saturated saline solution, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 2.3 g of a colorless oil.

(5) H ₃ CC (NH) -Tyr-D-HNLE-Phe-Me β Ala- OH

Z-Tyr (Bz 1) -D-HNLE (MOM) -Phe-MeβAla-0H (2.3 g) obtained in (4) above was dissolved in methanol (30 ml), and 5% Pd-C was used as a catalyst. (1 g) was added and catalytic reduction was performed at room temperature for 3 hours. After the catalyst was removed by filtration, the filtrate was concentrated under reduced pressure .: The obtained residue was dissolved in DMF (20 ml), and ethyl acetate ethyl hydrochloride (1.11 g) and KHC0 :, (1.2 g) were added. . The second solution was stirred at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure, and the obtained residue is charged to 0DS column chromatography (Fuji Siricia DM 1020T, 125 g), and stepwise treated with 5-18% acetate nitrile / 0.1 N acetic acid solution. Fractions containing the target compound eluted with a specific gradient were collected and freeze-dried to obtain 0.66 g of the title compound as a white powder. FAB mass stake m / z: 585 (Μ + Η ')

[^ +30.2 ³ (c = 1.00, IN acetic acid)

Rf: 0.61 (n-Bu0H: Ac0H: H, 0: pyridine = 15: 3: 10: 10) Row 52: H _{: J} CC (NH) -Tyr-D-ONLE-Phe-Me β Ala-OH

(1) Z-Tyr (Bzl) -D— ONLE- Phe- Me β Ala-OMe

Example 51- Z-Tyr (Bzl) -D-HNLE-Phe-MeβAla-0CH _{: i} (12.0 g) obtained in (3) was dissolved in methylene chloride (20 ml), and PCC (1.94 g) Was added and stirred for 2 hours. The reaction solution was diluted with methylene chloride (30 ml), added with magnesium sulfate, stirred for a while and then filtered. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (eluted with chloroform: methanol = 100: 1) to give 3.1 g of a colorless oil.

(2) Z-Tyr (Bz 1)-D-ONLE- Phe- Me Ala-OH

Z-Tyr (Bzl) -D-ONLE-Phe-Me0Ala-OMe (2.34 g) obtained in (1) above was dissolved in methanol (33 ml). To this solution was added a 2N aqueous NaOH solution (3 ml) at 0 ° C, and the mixture was stirred at room temperature for 4 hours and further at 40 ° C for 40 minutes. The reaction solution was adjusted to pH 2 by adding 6N hydrochloric acid at 0 ° C, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and the solvent was concentrated under reduced pressure to obtain 2.3 g of a colorless oil.

_{(3) H;! CC (} NH) -Tyr-D-ONLE-Phe-Me β Ala-OH

Z-Tyr (Bzl) -D-ONLE-Phe-MeβAla-OH (2.65 g) obtained in the above (2) was reacted in the same manner as in Example 51- (5). The obtained crude product was charged to 0DS column chromatography (Fuji Siricia DM 1020T, 125 g), and eluted stepwise with a 5 to 20% acetate nitrile / 0.1 N acetic acid solution. The fractions containing the target compound were collected and freeze-dried to obtain 0.72 g of the title compound as a white powder.

FAB Mass Talk Tonore m / z: 583 (Μ + Η ')

[α] „· ' ^{: 1} + 23.0 ° (c = 1.05, IN acetic acid)

f: 0.64 (n-Bu0H: Ac0H: H, 0: pyridine = 15: 3: 10: 12) Examples 53 and 54

According to the method of Example 8, the compounds shown in Table 5 were synthesized. Table 5 Example Structural formula m / _Z [α] „Rf

53 HC-C (NH) -Tyr-D-Cit-Phe-Mei3Ala-0CH, 0 (CH,) 0CH, 701 +23.5 0.65

54 H _:) CC (NH) -Tyr-D-Cit-Phe-Me β Ma ~ 0 (CH,) ₇ CH 725 +18.1 0.68 Example 55: H, CC (NH) -DMT-D-Orn (Ac )-Phe (pF) -Me β Ala-OEt

Boc-DMT-D-Orn (Ac) -Phe (p-F) -MeβAla-OEt (3.0 g) was dissolved in 4N HC1 / ethyl acetate (15 ml) and stirred at room temperature for 30 minutes. To the reaction solution was added getyl ether, and the precipitated crystals were collected by filtration. The crystals were dissolved in water (25 ml), and ethyl acetate ethyl hydrochloride (1.33 g) and potassium hydrogen carbonate (1.80 g) were added. This solution was stirred at room temperature for 1 hour and 30 minutes. The reaction mixture was concentrated under reduced pressure. . The fractions containing the target compound were collected and freeze-dried to obtain 1.20 g of the title compound as a white powder.

FAB mass vector m / z: 685 (M + 1T)

[a] _D ²³ +42.3 ° (c = 1.00, IN acetic acid)

Rf: 0.67 (n-BuOH: AcOH: H _¾ 0: pyridine = 15: 3: 10: 12) 56: Analgesic activity of the peptide derivative of the present invention

The analgesic activity of the peptide derivative of the present invention was evaluated by a pressure stimulation method according to the method described in International Publication W097 / 10262. A pressure stimulus was applied to the ridge of the mouse at a rate of 10 difficult Hg / sec, and the pressure indicating a behavior such as struggling and sticking to the stimulus site was measured, and this was used as a pain response correction. In the experiments, mice that had previously responded to a pressure of 40 to 50 mmHg were used. The maximum stimulation pressure was 100 mmHg. The analgesic effect is given by the following formula:% of MPE = (Pt-Po) / (Pc-Po) × 100 (where Po is the pain response threshold before drug treatment: Pt is the pain after t minutes of drug treatment) ; Pc is the maximum stimulation pressure) (% of MPE). The results of the analgesic effect obtained by oral administration are shown in Table 5 below. Also, bioavailability one (BA) is calculated as the drug analgesic activity value obtained by subcutaneous dosing or oral administration to mice (ED ^ mg / kg) ratio [ED (oral) / ED ₅₀ (sc)] did. Morphine was used as a control. From these results, it is clear that the peptide derivative of the present invention can exert extremely excellent analgesic activity even when administered orally. Table 6 Example No. structure ED _5. (Oral) ED _sn (subcutaneous) BA

26 H _{: i} C- C (NH)-Tyr (C0CH _{: i} )-D- MetO- Phe- Me β Ala- OH

1.2 mg / kg 0.14 mg / kg 9

14 H., CC (NH) -Tyr-D-MetO-Phe-Me β Ala-0 (C¾) ₁₅ CH _{; j}

3.60.38 10

48 H ₃ CC (NH) -Tyr (C0CH ₃ )-D- MetO- Phe-Me β Ala-OECE

2.7 0.25 11

51 H ₃ CC (NH)-Tyr- D- HNLE- Phe- Me β Ala- OH 7.90.80 10 55 H _;) CC (NH) -DMT-D-Orn (Ac) -Phe (pF) -Me β Ala-OEt

<10.0.49> 20 Morphine (control) 22.2 3.37 Industrial availability

The peptide derivative of the present invention has both excellent analgesic activity and oral absorption, and is useful as an active ingredient of a medicament for preventing and / or treating cancer pain and the like.

Claims

Range of request

1. The following formula (I):

HN = C (R ')-AA to AA ² -AA ^{: i} -AA' ¹ -OR ²

[Where,

R ′ represents a C _{1 W} alkyl group, an amino group, a mono ( ₆ alkylamino group, a di ( ₆ alkylamino group, or a phenyl group;

R ² is a hydrogen atom, a C _{I 6} alkyl group, a halogenated C, _{_l} ₆ alkyl group, a hydroxy (: a ₁₆ alkyl group, an anorecoxy-substituted anorequinolene group, a C _1-6 alkoxy-C a ₆ alkoxy substituted C, _ _ti alkyl group, amino C, _ ₁₆ alkyl group, monoalkylamino C _1-16 aralkyl kill group, di (: Bok ₆ alkylamino (: City ₁₆ Anorekinore group, _{C:. i} _ ") cycloalkyl group, shea . black-substituted alkyl groups, C ₂ _ ₁₆ alkenyl group, (^ _{| 6} alkynyl, C ₆ Ariru group, C _fi _ ₁₆ 7 reel substituted C ₁₆ alkyl group, (: "_ _{| 6} Ariru - C ₁₆ alkoxy location conversion C _{l 6} alkyl group, also phthalidyl group which may be substituted, indicates (^ ₆ alkoxy force Ruboniruokishi C Bok ₆ alkyl group, or C ₂ _ ₇ alk Noi Ruo carboxymethyl _ ₆ alkyl group;

AA ¹ has the following formula:

{Wherein, X represents a hydrogen atom, or the following formula: -CO-Y-R ^{: t} (where R ^{: i} is a _Cl16alkyl group, a hydroxy C _Mt) alkyl group, amino alkyl group, mono-C, _ ₆ alkyl Ruami Bruno C Bok ₁₆ alkyl group, di _ή alkylamino C Bok _{| 6} alkyl group, C _3-l0 Shikuroa Ruquil group,. Cycloalkyl substituted C, - ₆ alkyl group, c ₂ - ₁₆ alkenyl group, (^ ₁₆ § Rukiniru group, C _ti _,. Ariru group, ₍₆ Ariru substituted (: shows the Bok ₆ alkyl group, or a heterocyclic group ) represents a group represented by, R ⁴ and R ⁵ independently represent hydrogen atom, C _iS alkyl group, a halogenated C _{the IH} alkyl group, or a halogen atom, Y represents an oxygen atom or a single bond} Represents an L-amino acid residue represented by:

KK ¹ has the following formula:

R ⁶

(CH ₂ ) _n

(Wherein, R "is an amino group, a mono C ₆ alkylamino group, C, _ ₆ Ashiruami amino group, C, - ₆ also Guanijino groups have a § alkyl group, 1-Imino _ ₆ alkyl groups, (: also Urei de group having a Bok ₆ Anore kill group, _<6 alkylthio group, C _1-6 alkylsulfinyl Fininore group, (: Bok ₆ alkylsulfonyl group, C _1-6 Ashiru group, or 1-human Dorokishi C Bok _{6 represents} an alkyl group, and _n represents an integer of 1 to 4), which represents a D-α-amino acid residue;

ΑΑ ³ is the following formula:

(Wherein, R ⁷ is a hydrogen atom, (: Bok ₆ alkyl group, a halogenated C _{l ti} alkyl group, or a halo gen atom shows a) represented by a - the amino acid residues;

AA ′ has the following formula: —N OT) —CH (R ⁹ ) —CH (R ′ ⁿ ) —CO— (wherein RR and R ¹ ″ are each independently a hydrogen atom, a C ₁₆ alkyl group, C _{2 6} alkenyl, C _{2 6} alkynyl group,. § Aryl group, or a C ₆ - ₁₆ represented by Ariru a substituted _alkyl group) / - shows the Amino acid residue;

However, R ⁶ is Amino group, mono C _{1 6} alkylamino group, C _{1 6} Ashiruami amino group, C, also Guanijino groups have a _ ₆ § alkyl group, Bok Imino C _{the IH} alkyl group, C _{1 6} Al Kill also Urei de group have a group, C _1-6 alkylthio group, (: Bok _s alkylsulfamoyl Fier group, or an alkylsulfonyl group, and and X unless both hydrogen atom

Or a salt thereof.

2. The compound or a salt thereof according to claim ^{1, wherein} R ¹ is a Cl ₆ alkyl group or an amino group.

3. The compound or a salt thereof according to claim 2, wherein R ′ is a methyl group, an ethyl group, or an amino group.

4. The compound according to any one of claims 1 to 3, wherein AA ^{: i} is a substituted or unsubstituted L-phenylalanine residue, or a substituted or unsubstituted D-phenylalanine residue. Its salt.

5. AA ³ is L- phenylene Ruaranin residues, D- phenylene Ruaranin residue, L- P- Furuorofu Eniruaranin residues, Dp Furuorofuwe two Ruaranin residues, L-0- Torifuruorome Chirufuwe two Ruaranin residues and, 5. The compound or a salt thereof according to claim 1, which is an amino acid residue selected from the group consisting of D-0-trifluoromethylphenylalanine residue, V or any one of claims 1 to 4, wherein

6. The compound or a salt thereof according to any one of claims 1 to 5, wherein AA ′ is an N-methyl-alanine residue.

. 7 AA ¹ is L- tyrosine residues, 2, 6-dimethyl -L- tyrosine residues, 0 Ashiru -L- tyrosine residues, 0-alkoxycarbonyl - L- tyrosine residue, or Fuenokishikarubo two Le - The compound according to any one of claims 1 to 6, which is an L-tyrosine residue, or a salt thereof.

8. AA is D-methionine sulfoxide residue, D-arginine residue, or D-citruri 8. The compound or a salt thereof according to any one of claims 1 to 7, which is a thiol residue.

9. Any of claims 1 to 7, wherein AA ² is a DN ⁵ -acetylorutin residue, a D-5-oxonorleucine residue or a D-5 -hydroxynorleucine residue. Or the compound or a salt thereof according to item 1.

. 1 0 ^ is C Bok _1H alkyl group, (:. _{6- | 0} Ariru group, C _{K | 6} Ariru substituted C, _s alkyl group, an alkoxy-substituted C _l alkyl group, _(TT alkoxycarbonyl O alkoxy C, _ ₆ 10. The compound or a salt thereof according to any one of claims 1 to 9, which is an alkyl group or a phthalidyl group.

1 1. R ¹ is methyl group, Echiru group, or an amino group, R ² is C _1-16 alkyl group, C ₆ _ _l0 Ariru group, § Li Ichiru substituted C ₆ alkyl group, CH. Alkoxy substitution. Alkyl group, an alkoxycarbonyl O carboxymethyl c _ti alkyl group or a phthalidyl group der, Ri, AA 'force; L - tyrosine residues, 2, 6-dimethyl -L- tyrosine residues, 0 Ashiru -L- tyrosine down residues, 0-alkoxycarbonyl -L- tyrosine residues, or Fuenokishikarubo sulfonyl - L-tyrosine residue, AA ² is D-N ⁵ - Asechiruoru two Chin residue, D-5-Okisonoru port leucine residue or a D-5-hydroxycarboxylic norleucine residue, AA ³ Offer phenylene Ruara Nin residues, D- phenylene Ruaranin residues, Lp-fluorophenyl § La Nin residue, D - P- fluorophenyl § La Nin An amino acid residue selected from the group consisting of a residue, Lo-trifluoromethylphenylalanine residue, and D-0-trifluoromethylphenylalanine residue, wherein AA ⁴ is N- The compound according to claim 1, which is a methyl-alanine residue, or a compound thereof. salt.

1 2. R ¹ is a methyl group, AA ′ is a L-0-acetyltyrosine residue, a force; D-methionine sulfoxide residue, AA ^{: i} is an L-phenylalanine residue ^2. The compound or a salt thereof according to claim 1, wherein M ⁴ is an N-methylalanine residue, and R ′ ² is a hydrogen atom.

1 3. R ¹ is a methyl group, AA ′ is a ぃ tyrosine residue, AA ² force; D-methionine sulfoxide residue, AA ³ is an L-phenylalanine residue, AA ⁴ force ; N-meth _2. The compound or a salt thereof according to claim 1, which is a-/ 3-alanine residue and has an R ² force;-(CH ₂ ) ₁₅ C¾.

14. R ¹ is a methyl group, AA ¹ is a 0-acetyl tyrosine residue, M ² is a D-methionine sulfoxide residue, and AA ³ is a phenylalanine residue. There, AA ⁴ is N- methyl - - a Aranin residue, force; - CH (CH :,) OC0 compound or a salt thereof according to claim 1 which is H _5.

15 .R ¹ is a methyl group, AA ¹ is an L-tyrosine residue, AA ² is a D-5-hydroxylnorleucine residue, M ³ is an L-phenylalanine residue, AA ⁴ force; N- methylation - beta - a Aranin residue, compound or salt thereof of according to claim 1, wherein R ^'2 is a hydrogen atom.

16. R ¹ is a methyl group, AA ′ is an L-tyrosine residue, ΑΑ ² is a D-methionine sulfoxide residue, Μ ³ is an L-phenylalanine residue, and Μ ⁴ is _{2. The} compound according to claim 1, which is a Ν-methylen-3- / 3-alanine residue, and is R ² (CH ₂ ) ₇ CH ₃ or a salt thereof.

17. R ¹ is a methyl group, M ¹ is a 2,6-dimethyl-L-tyrosine residue, M ² force; DN ⁵ -acetyl ordinine residue, AA ³ is P-fluorophenyl 2. The compound or a salt thereof according to claim 1, wherein the compound is an alanine residue, AA ⁴ is an N-methyl-] 3-alanine residue, and R ² is -CC.

18. A medicament comprising the compound according to any one of claims 1 to 17 or a physiologically acceptable salt thereof as an active ingredient.

19. The medicament according to claim 18, which is used for prevention and / or treatment of pain.

20. The medicament according to claim 18 or 19 in the form of a pharmaceutical composition for oral administration.

21. The compound or physiological substance according to any one of claims 1 to 17 for the manufacture of a medicament according to any one of claims 18 to 20. Use of that salt that is acceptable for.

22. A method for preventing and / or treating pain, comprising the steps of: A method comprising administering to a patient a prophylactically and / or therapeutically effective amount of the compound according to any one of the preceding items or a physiologically acceptable salt thereof.