JP2019081772A - Transdermal delivery system of peptide and relative compounds - Google Patents

Abstract

To provide novel positive charge prodrug of peptide and relative compounds.SOLUTION: A compound represented by structure 1 may be synthesized by a standard peptide synthesis protocol. Amino group having positive charge in prodrug of peptide contributes to not only dissolving of medicament into water, but also bond to negative charge on phosphate head group of membrane to introduce prodrug into cytosol. The prodrug diffuses through human skin 100 to 1000 times faster than peptide and relative compounds. The prodrug may be used in therapy for condition capable of being treated with peptide and relative compounds in human and animal. The prodrug may be transdermally administered for any type of medicament therapies to avoid protein degradation by protein degradation enzyme in gastrointestinal tract.SELECTED DRAWING: Figure 2

Description

  The present invention relates to a transdermal delivery system of peptides and related compounds by converting the peptides into positively charged water soluble prodrugs, and in treating conditions treatable by the peptides and related compounds in humans or animals. It relates to medical use. More specifically, the present invention is to allow for the rapid penetration of peptides and related compounds and to allow them to be administered transdermally.

All peptides are polymers, and the monomers that combine to make a polymer are amino acids. The chains containing 2 to 50 amino acid residues are collectively referred to as peptides. If the chains are more than 50 amino acid residues, they are called proteins. Peptides play an enormous variety of roles in all organisms. Peptide hormones are the largest group of hormones. The number of peptide hormones identified and synthesized continues to increase. They have an interesting role in the process of controlling life. Injection of 1 nanogram of thyrotropin-releasing hormone into mice increases iodide uptake from blood to the thyroid (RL Kisliuk, Principles of Medicinal Chemistry, 4 ^th Ed., WO Foye, etc.) Eds., Williams & Wilkins, 4 th Ed. 1995, p.606). Taftsin (Thr-Lys-Pro-Arg) stimulates phagocytosis and promotes antibody-dependent cytotoxicity (V.A. Najjar, Mol. Cell. Biochem. 41. 1, 1981), brain and Met-enkephalin (Tyr-Gly-Gly-Phe-Met) isolated from the small intestine acts on morphine action in that it binds to the same receptor and has analgesia (JRJaffe and WR Martin , in Pharmacological Basis of Therapeutics, AG Gilman et al., Eds., New York, Pergamon Press, 1990, p. 481). Oxytocin (Pierce et al., J. Biol. Chem. 199, 929, 1952), vasopressin (Kamm et al., J. Am. Chem. Soc. 50, 573, 1928), angiotensin (JC Garrison and MJ Peach, in Pharmacological Basis of of Therapeutics, AG Gilman et al., Eds., New York, Pergamon Press, 1990, p. 749), Gastrin (PC Emson and BEB Sandberg, Annu, Rep. Med. Chem., 18, 31, 1983), somatostatin (AV Schally Et al, Annu. Rev. Biochem., 47, 89, 1978), Dynorphin (MG Weisskopf et al., Nature, 362, 423, 1993), endothelin (AM Doherty, J. Med. Chem., 35, 1493, 1992). Secretin (E. Jorper, Gastroenterology, 55, 157, 1968), calcitonin (MVL Ray et al., Biotechnology, 11, 64, 1993), insulin (F. Sanger, Br. Med. Bull., 16. 183, 1960) , And many others are peptides whose structure has been deduced, and they are used for the treatment of many diseases.

  Unfortunately, peptides and related compounds are rapidly proteolytically degraded by proteolytic enzymes. When the peptides are taken orally, they are destroyed in a few minutes. In the case of injection, administration of the peptide is painful and often requires frequent and costly visits to treat chronic conditions.

One alternative to drug administration is local delivery. Local drug delivery has several advantages. This method serves to avoid inactivation of the drug caused by first pass metabolism in the liver and gastrointestinal tract. It can provide localized delivery of an appropriate concentration of drug at the intended site of action without systemic exposure. Fishman (Fishman; Robert, US Pat. No. 7,052,715) pointed out additional issues associated with oral drug treatment. That is, to effectively treat the painful or inflamed end, the concentration level that must be achieved in the bloodstream must be significant. These levels are often much higher than would be required if it were possible to accurately target certain sites of pain or damage. Yeager attempted to use a penetration enhancer to deliver PGE ₁ for the treatment of male erectile dysfunction (Yeager, James L. US Pat. No. 6,693,135). Susan Milosovich et al. Designed and prepared testosteronyl-4-dimethylaminobutyrate.HCl (TSBH). It has a lipophilic moiety and a tertiary amine group present in protonated form at physiological pH. They found that the prodrug (TSBH) diffuses through human skin ~ 60 times faster than the drug (TS) itself [Susan Milosovich et al., J. Pharm. Sci., 82, 227 (1993)].

Peptides play an enormous variety of roles in all organisms, which are used for the treatment of many diseases.
Unfortunately, peptides and related compounds are rapidly proteolytically degraded by proteolytic enzymes. When the peptides are taken orally, they are destroyed in a few minutes. In the case of injection, administration of the peptide is painful and often requires frequent and costly visits to treat chronic conditions.

The present invention relates to the preparation of novel positively charged prodrugs of peptides and related compounds, and their pharmaceutical uses. Prodrugs of peptides and related compounds have the structure 1 of the following formula:

又は何もないことを表し、Ｒ_x1、Ｒ_x2、Ｒ_x3、Ｒ_x4、Ｒ_x5、又はＲ_xnはＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-はＣｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、シトラート、又はいずれの陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０……であり、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖であり、Ｃ、Ｈ、Ｏ、Ｓ、又はＮ原子を含んでもよく、単結合、二重結合、及び三重結合を有してもよい。いずれのＣＨ₂基はＯ、Ｓ又はＮＨと置換されてもよい。配列中の１種以上のアミノ酸残基は非天然アミノ酸、例えば、β−アミノ酸、２−ナフチルアラニン、及びアルキル、アルキルオキシ、アルケニル若しくはアルキニルのいずれか一つ、アリール又はヘテロアリール残基により置換され得る。ペプチド鎖上のアミノ酸のアミノ及びカルボキシル官能基は、ラクタムブリッジを形成しホモデティック(homodetic)な環状ペプチドを形成してもよい。システイン、ホメシステイン(homecysteine)、又は他のアミノ酸のチオール基は、ジスルフィドブリッジを形成しヘテロデティックな(heterodetic)環状ペプチドを形成してもよい。 In the formula, X represents O, S or NH, X ₁ or X _n represents CO, SO, SO ₂ , PO (OR), NO or nothing, and Z _n or Z _n1 is H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , wherein R _n is an aliphatic side chain of an amino acid, a hydroxyl- or sulfur-containing side chain of an amino acid, an amino acid Aromatic side chain, amino acid amino, imidazolyl, or quanidino group-containing side chain, or any one of amino acid carboxyl or carboxamido group-containing side chain H, alkyl having 1 to 12 carbon atoms, alkyl Represents any one of an oxy, alkenyl or alkynyl residue, an aryl or heteroaryl residue or nothing, Y _x1 , Y _x2 or Y _n is H, alkyl having 1 to 12 carbon atoms, alkyl Oxy, Any one of alkenyl or alkynyl residues, aryl or heteroaryl residues, or the following groups:

Or R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn is H, O, alkyl having 1 to 12 carbon atoms, any of alkyloxy, alkenyl or alkynyl residue or one, represents no aryl or heteroaryl residues, or nothing, a ^- is ^{Cl -, Br -, F -} , I -, AcO -, citrate, or represents any anion, n = 0 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ..., all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or It may be linear and contain C, H, O, S, or N atoms, and may have single bonds, double bonds, and triple bonds. Any CH ₂ group may be substituted with O, S or NH. At least one amino acid residue in the sequence is substituted by a non-naturally occurring amino acid, such as a β-amino acid, 2-naphthylalanine, and any one of alkyl, alkyloxy, alkenyl or alkynyl, aryl or heteroaryl residues obtain. The amino and carboxyl functional groups of amino acids on the peptide chain may form lactam bridges to form homocyclic cyclic peptides. The thiol groups of cysteine, homecysteine or other amino acids may form disulfide bridges to form heterodetic cyclic peptides.

  The principles for designing these prodrugs of peptides or related compounds are as follows. 1. Prodrugs may be lipophilic moieties and primary, secondary or tertiary amine groups present in protonated form at physiological pH, guanidino groups, or monoprotected guanidino groups (hydrophilic Must have a sex part). 2. All prodrugs of the peptide may have only one or two, preferably one, primary, secondary or tertiary amine groups present in protonated form at physiological pH, guanidino groups, Or one should have a protected guanidino group (hydrophilic moiety). 3. The primary, secondary or tertiary amine group, the guanidino group, or the one protected guanidino group may be the N-terminus, C-terminus, or side chain of the peptide. N-terminal or C-terminal moieties are preferred. 4. In order to make the peptide lipophilic, carboxyl, amino, guanidine or other hydrophilic groups may be protected with alkyl, aryl or heteroaryl ester or amido groups.

The following are examples of these prodrugs.

Wherein, R is H, branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ......, X represents an aryl or heteroaryl residue; X ₄ , X ₅ , X ₆ , X ₇ , X ₈ or X ₉ represents CO, SO ₂ , PO (OR), NO or none, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ is H, O, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl or alkynyl residue A represents an aryl or heteroaryl residue, A ⁻ represents Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , citrate, or any anion; n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, Ar is phenyl, 2'-naphthyl, 4-iodophenyl, or other aryl or heteroaryl All R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or straight and contain C, H, O, S or N atoms. And may have a single bond, a double bond, and a triple bond, and any CH ₂ group may be substituted with O, S or NH.

  Drug absorption, whether from the gastrointestinal tract or from other sites, requires the drug to pass across the barrier membrane in molecular form. The drug must first dissolve, and if the drug has desirable biopharmaceutical properties, it will cross the membrane from the area of high concentration to the area of low concentration, blood circulation or body It will go into circulation. All biological membranes contain lipids as the main component. The molecules that play a major role in film formation all have phosphate-containing highly polar head groups and in most cases have two highly hydrophobic hydrocarbon tails. The membrane is a bilayer membrane, the two hydrophilic head groups pointing outwards to the aqueous region on both sides. Very hydrophilic drugs (most peptides) can not pass through the hydrophobic layer of the membrane and very hydrophobic drugs stay in the hydrophobic layer as part of the membrane due to their similarity, So you will not be able to get into the inner cytosol efficiently.

  The object of the present invention is to allow the transdermal administration (topical application) of peptides and related compounds by increasing their permeability through membranes and skin barriers. These novel prodrugs of peptides and related compounds share two structural features in common. That is, they are formed by using (a lipophilic alcohol to protect the carboxyl group and a lipophilic acid to protect the amino, hydroxyl or guanidine group, or other hydrophilic groups of the peptide ) Lipophilic moieties, and primary, secondary or tertiary amine groups present in protonated form at physiological pH, guanidino groups, or one protected guanidino group (hydrophilic part) have. Such a hydrophilic-lipophilic balance is required in order to pass efficiently through the membrane barrier [Susan Milosovich et al., J. Pharm. Sci., 82, 227 (1993)]. The positively charged amino group greatly increases the drug's solubility, and the lipophilic moiety will help the prodrug to enter the lipophilic membrane and skin barrier. These novel prodrugs will readily dissolve in the water on the skin surface when administered transdermally in dosage forms such as solutions, sprays, lotions, ointments, emulsions or gels. The positive charge on the amino group of these prodrugs will bind to the negative charge on the phosphate head group of the membrane. Thus, the local concentration outside the membrane will be very high, which will facilitate the passage of these prodrugs from the high concentration area to the low concentration area. When these prodrugs enter the membrane, the hydrophilic moiety will push the prodrug into the cytosol, which is a semi-liquid concentrated aqueous solution or suspension.

The penetration of some prodrugs through human skin was measured in vitro by using modified Franz cells. Modified Franz cells were isolated from human skin tissue (360-400 μm thick) in the anterior and posterior thighs. The receiving fluid consisted of 2 ml of 2% bovine serum albumin in saline and stirred at 600 rpm. The cumulative amount of these prodrugs and their parent drugs that penetrate the skin versus time was determined by a specific high performance liquid chromatography method. The results obtained using a donor consisting of several prodrugs and a 10% solution of the peptide in 2 mL of pH 7.4 phosphate buffer (0.2 M) are shown in FIG. It diffuses through human skin, Ac-Tyr (Ac) -Gly -Gly-Phe-Met-OCH 2 CH 2 N (CH 2 CH 3) 2 .HC1, HC1. (CH 3) 2 NCH 2 CH 2 CH 2 CO-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ CH ₂ CH ₃ , cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys- OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl, cyclo (1,6) -Ac-Nle-Asp-His-D-Phe (4-I) -Arg (Ac) -Trp-Lys-NH ₂ HCl, cyclo (1,6) -Ac-Nle-Asp-His-D-Ala (2-naphthyl) -Arg-Trp-Lys-NH ₂ .HCl, Ac-Val-Pro-Gly-Pro-Arg ( diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl, Ac-Tyr-Gly-Gly-Phe-Met-OH, cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg -Trp-Lys-OH, cyclo (1,6) -Ac-Nle-Asp -His-D-Phe (4-I) -Arg-Trp-Lys-NH 2, and H-Val-Pro-Gly- Pro Calculate distinct flow rate values of 0.52 mg, 0.55 mg, 0.46 mg, 0.34 mg, 0.50 mg, 0.50 mg, 0.001 mg, 0.001 mg, 0.001 mg, and 0.001 mg / cm ² / h for -Arg-OH did. The results show that prodrugs diffuse through human skin 340-600 times faster than peptides and related compounds. The present results show that the positive charge on the dialkylaminoethyl group has a very important role in passing the drug across the membrane or skin barrier.

A good prodrug should change quickly in plasma back to the drug itself. Prodrugs of the peptides in the present invention can change very quickly in human plasma with good yield back to the parent peptide. 120 mg of Ac-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HC was incubated for 30 minutes at 37 ° C. in 1 ml whole blood. The mixture was analyzed by HPLC. 3% Ac-Tyr (Ac) -Gly- Gly-Phe-Met-OCH 2 CH 2 N (CH 2 CH 3) 2 .HC1,2% of Ac-Tyr-Gly-Gly- Phe-Met-OCH 2 _{CH 2 N (CH 2 CH 3} ) in _{2 .HC1,8% Ac-Tyr-Gly} -Gly-Phe-Met-OH, 60% of H-Tyr-Gly-Gly- Phe-Met-OH, 27% of Other byproducts (amino acids, dipeptides, tripeptides, tetrapeptides) were observed. HC1. Relative to _{(CH 3) 2 NCH 2 CH} 2 CH 2 CO-Tyr (Ac) -Gly-Gly-Phe-Met-OCH 2 CH 2 CH 2 CH 3, of _{5% HC1. (CH 3)} 2 _{NCH 2 CH 2 CH 2 CO-} Tyr (Ac) -Gly-Gly-Phe-Met-OCH 2 CH 2 CH 2 CH 3, of _{6% (CH 3) 2 NCH} 2 CH 2 CH 2 CO-Tyr-Gly- Gly-Phe-Met-OCH ₂ CH ₂ CH ₂ CH ₃ , 10% (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ CO-Tyr-Gly-Gly-Phe-Met-OH, 55% H-Tyr- Gly-Gly-Phe-Met-OH and 24% of other byproducts were observed. Cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl, 4% cyclo (1 , 6) -Ac-Nle-Asp -His-Phe-Arg (diAc) -Trp-Lys-OCH 2 CH 2 N (CH 2 CH 3) 2 .HCl, 8% of cyclo (1,6) -Ac- Nle-Asp-His-Phe-Arg (Ac) -Trp-Lys-OH, 10% cyclo (1,6) -Nle-Asp-His-Phe-Arg-Trp-Lys-OH, 45% cyclo ( 1,6) -Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH, 33% of other side products were observed. The present results show that most of the prodrugs of the peptide change back to the parent peptide, thus the transdermal delivery system of the peptide is a success.

Enterostatin [Val-Pro-Asp-Pro-Arg (VPDPR), Val-Pro-Gly-Pro-Arg (VPGPR) and Ala-Pro-Gly-Pro-Arg (APGPR)] is a tryptic cleavage. It is a pentapeptide derived from the NH ₂ -terminus of later procolipase and belongs to the family of gut-brain peptides. They regulate fat intake and may be used for the treatment of obesity (Erlanson-Albertsson C, York D, Obes. Rev. 1997 Jul; 5 (4): 360-72 and Sorhede M, Mei J, Erlanson -Albertsson C., J Physiol. 87: 273-275, 1993). Intraperitoneal administration of H-Val-Pro-Asp-Pro-Arg-OH overnight to starved Osborne-Mendel rats resulted in a dose-dependent decrease in food intake. This feeding suppression was observed when rats were fed a high fat diet but not in rats fed a high carbohydrate, low fat diet (Okada S. et al., Physiol Behav., 1991). Jun; 49 (6): 1185-9). 5 mg / kg of Ac-Val-Pro-Asp (OEt) -Pro-Arg (diAc)-in 0.5 ml of water applied to the back of the rat at the beginning of the dark-onset feeding time OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl was transdermally administered to rats (n = 5) (n = 5 each presented food and fasted overnight and fed food ad libitum) Both rats).
This selective suppression of fat intake was observed.

Melanocortin II is a cyclic lactam peptide, cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH. It is a novel drug candidate of Palatin's (AMEX: PTN) for treating male and female sexual dysfunction. First of all, in a new class of treatment called melanocortin agonists, melanocortin II treats erectile dysfunction (ED) and female sexual dysfunction without the cardiovascular effects seen in currently available ED drugs Showed the prospect of being effective. Melanocortin II acts through mechanisms related to the central nervous system, rather than directly to the vasculature. As a result, it can provide the benefits of significant safety and efficacy over currently available products. The novel prodrugs of the present invention can diffuse through human skin at very high rates (~ 0.3-0.5 mg / h / cm ² ) with few side effects, treating erectile dysfunction or in females Methods may be provided to enhance sexual stimulation. pH7.0 phosphate buffer (0.1 M) in 0.2 ml, cyclo (1,6) of the 2mg / kg -Ac-Nle-Asp -His-Phe-Arg (diAc) -Trp-Lys-OCH 2 CH 2 _{N (CH 2 CH 3) 2} .HCl ( peptide A) and cyclo (1,6) -Ac-Nle-Asp -His-Phe-Arg (NO 2) -Trp-Lys-OCH 2 CH 2 N (CH 2 CH ₃ ) ₂ .HCl (peptide B) was applied to the back of male rats (30) once a day for 5 days. As a result, in rats given peptide A or peptide B, peptide A shows a 5-fold increase and peptide B shows a six-fold increase in solicitation, compared with rats not given it, and copulation , Both peptide A and peptide B showed a 3-fold increase. pH7.0 phosphate buffer (0.1 M) in 0.2 ml, the same amount of cyclo (1,6) -Ac-Nle-Asp -His-Phe-Arg (diAc) -Trp-Lys-OCH 2 CH 2 N (CH ₂ CH ₃ ) ₂ .HCl (Peptide A) and cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (NO ₂ ) -Trp-Lys-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _{2. When} HCl (peptide B) is applied to the back of both male rats (30) and female rats (30) once a day for 5 days, as a result, peptide A or peptide B The rats given had a 6-fold increase in solicitation and a 5-fold increase in mating as compared to the rats that were not given.

本結果は、ペプチドプロドラッグを使用する経皮送達システムは、肥満及び疼痛の治療、並びに男性及び女性の性機能障害の治療に対して非常によく作用する、ということを示す。 Opioid peptides, such as Met-enkephalin (H-Tyr-Gly-Gly-Phe-Met-OH), Leu-enkephalin (H-Tyr-Gly-Gly-Phe-Leu-OH), H-Tyr-D-Ala -Gly-N-Me-Phe-Met (O) -OL, H-Tyr-D-Ala-Gly-Phe-Leu-OH and the like exert morphine-like analgesic action. The number of writhing that occurred when the acetic acid solution was intraperitoneally administered to mice was counted, and the inhibition rate based on the control group was calculated. HCl.H-Tyr (Ac) -D-Ala-Gly-Phe-Leu-OCH ₂ (CH ₂ ) ₄ CH ₃ (10 mg / kg, B), Ac-Tyr (Ac) -D-Ala-Gly-Phe _{-Leu-OCH 2 CH 2 N (} CH 2 CH 3) .HCl (10mg / kg, C), and HCl.H-Tyr (Ac) -D- Ala-Gly-Phe-Met (O) -OL (10mg / Kg, D) was transdermally administered to the neck of the mouse 30 minutes prior to administration of the acetic acid solution. Group A is a control group. The results are shown in Table 1.
Table 1. Rising inhibition rate of enkephalin and related compounds by prodrugs

The present results show that transdermal delivery systems using peptide prodrugs work very well for the treatment of obesity and pain, as well as the treatment of male and female sexual dysfunction.

  The peptides and related compounds are very hydrophilic and can not penetrate the skin membrane barrier. When the peptide is taken orally, the peptide and related compounds are rapidly proteolytically degraded by proteolytic enzymes in a few minutes in the digestive tract. In the case of injection, administration of the peptide is painful and often requires frequent and costly visits to treat chronic conditions. When prodrugs of peptides are applied topically to the skin, they will dissolve in the skin's water immediately. The positive charge on the amino group of these prodrugs will bind to the negative charge on the phosphate head group of the skin film. Thus, the local concentration outside the membrane will be very high, which will facilitate the passage of these prodrugs from the high concentration area to the low concentration area. When these prodrugs enter the membrane, the hydrophilic moiety will push the prodrug into the cytosol.

  Compounds represented by structure 1 can be prepared by standard peptide synthesis protocols. For preparation of cyclopeptides and related compounds represented by structure 4-C, the peptide chain can be synthesized by standard peptide synthesis protocols, the side chain of lysine is protected by a 2- or 4-Pyoc protecting group, the peptide Cyclization was performed on the resin.

  Prodrugs of these peptides and related compounds in the present invention have a lipophilic moiety and a hydrophilic moiety (an amine group present in protonated form at physiological pH). The positively charged amino groups of these prodrugs have two distinct advantages. First, the prodrug is dissolved in water. That is, when these novel prodrugs are administered transdermally in dosage forms such as liquids, sprays, lotions, ointments, emulsions or gels, they are immediately applied to the skin, eyes, genital area, mouth, nose or It will mix with water in other parts of the body. Second, the positive charge on the amino group of these prodrugs will bind to the negative charge on the phosphate head group of the membrane. Thus, the local concentration outside the membrane will be very high, which will facilitate the passage of these prodrugs from the high concentration area to the low concentration area. The lipophilic moiety (by modifying the polar group with a lipophilic alkyl group) of the prodrug will help the drug enter the skin membrane. When these prodrugs enter the membrane, the hydrophilic moiety will push the prodrug into the cytosol, which is a semi-liquid concentrated aqueous solution or suspension. Due to its short retention in the skin, eyes, genital area, mouth, nose, or other parts of the body, the pro-drug is itching on the skin, eyes, genital area, mouth, nose or other parts of the body Or will not cause pain. The experimental results show that more than 40% of the prodrug changed in a few minutes back to the parent peptide. Prodrugs can even easily penetrate the blood-brain barrier. Transdermal delivery systems for peptides and related compounds may allow the peptide hormone to be used medicinally. Another major advantage of transdermal administration of these prodrugs is that drug administration, especially to children, will be easier.

Traversing in cells (n = 5) Franz, isolated human skin tissue, Ac-Tyr (Ac) -Gly -Gly-Phe-Met-OCH 2 CH 2 N (CH 2 CH 3) 2 .HC1 , HC 1. (CH ₃ ) ₂ NCH ₂ CH ₂ CH ₂ CO-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ CH ₂ CH ₃ , cyclo (1,6) -Ac-Nle-Asp -His-Phe-Arg (diAc) -Trp-Lys-OCH 2 CH 2 N (CH 2 CH 3) 2 .HCl, cyclo (1,6) -Ac-Nle-Asp -His-D-Phe (4- I) -Arg (Ac) -Trp- Lys-NH 2 .HCl, cyclo (1,6) -Ac-Nle-Asp -His-D-Ala (2- naphthyl) -Arg-Trp-Lys-NH 2. HCl, Ac-Val-Pro-Gly-Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl, Ac-Tyr-Gly-Gly-Phe-Met-OH, cyclo (1,1) 6) -Ac-Nle-Asp-His-Phe-Arg-Trp-Lys-OH, cyclo (1,6) -Ac-Nle-Asp-His-D-Phe (4-I) -Arg-Trp-Lys Cumulative amounts of -NH ₂ and H-Val-Pro-Gly-Pro-Arg-OH. In each case, the medium was pH 7.4 phosphate buffer (0.2 M). Structure 1. In the formula, X represents O, S or NH, X ₁ or X _n represents CO, SO, SO ₂ , PO (OR), NO or nothing, and Z _n or Z _n1 is H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , wherein R _n is an aliphatic side chain of an amino acid, a hydroxyl- or sulfur-containing side chain of an amino acid, an amino acid The aromatic side chain, amino acid of amino acid, imidazolyl, or guanidino group-containing side chain, or any one of carboxyl or carboxamido group-containing side chain of amino acid, alkyl, alkyloxy, alkenyl or alkynyl having 1 to 12 carbon atoms one of residues, represents no aryl or heteroaryl residues, or nothing, Y _x1, Y _x2, or Y _n is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl Properly is one of alkynyl residues, aryl or heteroaryl _{residue, R x3 R x4 R x5 N} + A - indicates that or _{nothing, R x1, R x2, R} x3, R x4, R x5 , or R _xn represents H, O, alkyl having 1 to 12 carbon atoms, alkyloxy, any one alkenyl or alkynyl residue, aryl or heteroaryl residues, or that nothing, a ^- is Represents Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , citrate, or any anion, and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 Yes, all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or straight and may contain C, H, O, S or N atoms, single bond , A double bond, and a triple bond. Any CH ₂ group may be substituted with O, S or NH. At least one amino acid residue in the sequence is substituted by a non-naturally occurring amino acid, such as a β-amino acid, 2-naphthylalanine, and any one of alkyl, alkyloxy, alkenyl or alkynyl, aryl or heteroaryl residues obtain. The amino and carboxyl functional groups of amino acids on the peptide chain may form lactam bridges to form homocyclic cyclic peptides. The thiol groups of cysteine, homecysteine or other amino acids may form a disulfide bridge to form a heterodetic cyclic peptide.

(Best form)
Preparation of Ac-Val-Pro-Asp (OEt) -Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl _{H-Arg (diAc) -OCH 2} CH 2 N (CH 2 CH 3) Preparation of ₂
30.8 g of Z-Arg-OH was dissolved in 500 ml of acetone. 200 ml of 20% NaOH were added to the reaction mixture. 40 g of acetic anhydride was added dropwise to the reaction mixture. The mixture was stirred at room temperature for 2 hours. The solvent was evaporated. The residue was extracted with 500 ml of ethyl acetate. The ethyl acetate solution was washed with water (3 × 100 ml). The ethyl acetate layer was dried over sodium sulfate. The ethyl acetate solution was evaporated to dryness. The residue (Z-Arg (diAc) -OH, 30 g) was dissolved in 300 ml of acetonitrile. The mixture was cooled to 0 ° C. with an ice water bath. 12 g of N, N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture is stirred for 1 hour at 0 ° C. and overnight at room temperature. The solids were removed by filtration and the solution was evaporated to dryness. The residue was extracted with ethyl acetate (2 × 250 ml). The ethyl acetate solution was washed with 5% sodium bicarbonate (1 × 500 ml) and water (3 × 100 ml). The ethyl acetate solution was dried over sodium sulfate. The solution is evaporated to dryness. The residue [Z-Arg (diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2, 28g] was dissolved in methanol 300 ml. 2 g of 10% Pd / C was added to the solution. The mixture was stirred at room temperature under hydrogen for 10 hours. The Pd / C was removed by filtration. The solution was evaporated to dryness. To obtain a _{H-Arg (diAc) -OCH 2} CH 2 N (CH 2 CH 3) 2 22g.

2. Preparation of Boc-Asp (OEt) -Pro-OSu
15 g of L-proline were dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 36 g of Boc-Asp (OEt) -OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with ether (1 × 300 ml). 500 ml of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 × 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 25 g of the residue (Boc-Asp (OEt) -Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene. The mixture was cooled to 0 ° C. 16 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 ° C. for 1 hour. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 × 200 ml) and water (3 × 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 28 g of Boc-Asp (OEt) -Pro-OSu was obtained.

3. Preparation of H-Asp (OEt) -Pro- Arg (diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA
Were dissolved _{H-Arg (diAc) -OCH 2} CH 2 N (CH 2 CH 3) 2 22g in 5% NaHCO ₃ 300ml. 24 g of Boc-Asp (OEt) -Pro-OSu in 150 ml of acetone was added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. 500 ml of ethyl acetate were added to the mixture. The ethyl acetate solution was washed with water (3 × 100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue is dissolved in 250 ml of dichloromethylene. 250 ml of trifluoroacetic acid were added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness. It was obtained H-Asp (OEt) -Pro- Arg (diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA32g.

4. Preparation of Ac-Val-Pro-OSu
15 g of L-proline were dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 26 g of Ac-Val-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with ether (1 × 300 ml). 500 ml of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 × 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 20 g of the residue (Ac-Val-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene. The mixture was cooled to 0 ° C. 16 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 ° C. for 1 hour and at room temperature for 1 hour. The solids were removed by filtration. The dichloromethylene solution was washed with 5% sodium bicarbonate (1 × 200 ml) and water (3 × 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 20 g of Ac-Val-Pro-OSu was obtained.

5. Ac-Val-Pro-Asp ( OEt) -Pro-Arg (diAc) -OCH 2 CH 2 N (CH 2 CH 3) Preparation of ₂ .HCl
Were dissolved H-Asp (OEt) -Pro- Arg (diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA31g into 10% sodium bicarbonate 300 ml. 150 ml of acetone and 15 g of Ac-Val-Pro-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. 500 ml of ethyl acetate were added to the mixture. The organic layer is washed with water (3 × 100 ml). The ethyl acetate layer was dried over sodium sulfate. Sodium sulfate is removed by filtration. 3.5 g of HCl gas in dioxane (50 ml) are added to the solution. The solid is collected and washed with ether (3 × 50 ml). After drying, 20 g of the desired hygroscopic product are obtained. Solubility in water: 150 mg / ml, elemental analysis: C ₃₉ H ₆₆ ClN ₉ O ₁₁ , molecular weight: 872.45, calculation% C: 53.69; H: 7.62; Cl: 4.06; N: 14.45; O: 20.17, measured% C: 53.61; H: 7.67; Cl: 4.10; N: 14.40, O: 20.22, MS: m / e: 836.4; m / e + 1: 836.4.

(Form of the Invention)
Preparation of Ac-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl Preparation of H-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .TFA
25 g of Boc-Met-OH was dissolved in 300 ml of dichloromethylene. The mixture was cooled to 0 ° C. with an ice water bath. 12 g of N, N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture is stirred for 1 hour at 0 ° C. and overnight at room temperature. The solids were removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 × 500 ml) and water (3 × 100 ml). The ethyl acetate solution was dried over sodium sulfate. The solution is evaporated to dryness. The residue _{[Boc-Met-OCH 2 CH} 2 N (CH 2 CH 3) 2, 30g] was dissolved in dichloromethylene 250 ml. 250 ml of trifluoroacetic acid are added to the mixture and the mixture is stirred for 30 minutes. The solution was evaporated to dryness. H-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .26 g of TFA was obtained.

2. Preparation of Boc-Gly-Phe-OSu
20 g of L-phenylalanine were dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 28 g of Boc-Gly-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with ether (1 × 300 ml). 500 ml of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 × 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue (Boc-Gly-Phe-OH) 22 g and 10 g N-hydroxysuccinimide were dissolved in 300 ml dichloromethylene. The mixture was cooled to 0 ° C. 15 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 ° C. for 1 hour. The solids were removed by filtration. The dichloromethylene solution is washed with 5% sodium bicarbonate (1 × 200 ml) and water (3 × 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 25 g of Boc-Gly-Phe-OSu was obtained.

3. Preparation of H-Gly-Phe-Met- OCH 2 CH 2 N (CH 2 CH 3) 2 .TFA
25 g of H-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .TFA were dissolved in 300 ml of 5% NaHCO ₃ . 22 g of Boc-Gly-Phe-OSu in 150 ml of acetone were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. 500 ml of ethyl acetate were added to the mixture. The ethyl acetate solution was washed with water (3 × 100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue is dissolved in 250 ml of dichloromethylene. 200 ml of trifluoroacetic acid were added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness. H-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .25 g of TFA was obtained.

4. Preparation of Ac-Tyr (Ac) -Gly-OSu
11 g of L-glycine was dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 36 g of Ac-Tyr (Ac) -OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with ether (1 × 300 ml). 500 ml of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 × 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 28 g of the residue (Ac-Tyr (Ac) -Gly-OH) and 13 g of N-hydroxysuccinimide were dissolved in 300 ml of dichloromethylene. The mixture was cooled to 0 ° C. 18 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 ° C. for 1 hour. The solids were removed by filtration. The dichloromethylene solution is washed with 5% sodium bicarbonate (1 × 200 ml) and water (3 × 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 20 g of Ac-Tyr (Ac) -Gly-OSu was obtained.

5. Ac-Tyr (Ac) -Gly- Gly-Phe-Met-OCH 2 CH 2 N (CH 2 CH 3) Preparation of ₂ .HCl
H-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .24 g TFA was dissolved in 300 ml 10% sodium bicarbonate. 150 ml of acetone and 15 g of Ac-Tyr (Ac) -Gly-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. 500 ml of ethyl acetate were added to the mixture. The organic layer is washed with water (3 × 100 ml). The ethyl acetate layer was dried over sodium sulfate. Sodium sulfate is removed by filtration. 3.5 g of HCl gas in dioxane (50 ml) are added to the solution. The solid is collected and washed with ether (3 × 50 ml). After drying, 18 g of the desired hygroscopic product are obtained. Solubility in water: 200 mg / ml, elemental analysis: C ₃₇ H ₅₃ ClN ₆ O ₉ S, molecular weight: 793.37, calculation% C: 56.01; H: 6.73; Cl: 4.47; N: 10.59; O: 18.15; H: 6.76; Cl: 4.52; N: 10.54, O: 18.19; S: 4.03, MS: m / e: 757.4; m / e + 1: 758.4.

Preparation of Ac-Val-Pro-Gly-Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl Preparation of Boc-Gly-Pro-OSu
15 g of L-proline were dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 27.2 g of Boc-Gly-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with ether (1 × 300 ml). 500 ml of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 × 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. The residue (Boc-Gly-Pro-OH) 21 g and 11 g N-hydroxysuccinimide were dissolved in 300 ml dichloromethylene. The mixture was cooled to 0 ° C. 17 g of 1,3-dicyclohexylcarbodiimide was added to the reaction mixture. The mixture was stirred at 0 ° C. for 1 hour. The solids were removed by filtration. The dichloromethylene solution is washed with 5% sodium bicarbonate (1 × 200 ml) and water (3 × 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 23 g of Boc-Gly-Pro-OSu was obtained.

2. Preparation of H-Gly-Pro-Arg ( diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA
Were dissolved _{H-Arg (diAc) -OCH 2} CH 2 N (CH 2 CH 3) 2 22g in 5% NaHCO ₃ 300ml. 20 g of Boc-Gly-Pro-OSu in 150 ml of acetone was added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. 500 ml of ethyl acetate were added to the mixture. The ethyl acetate solution was washed with water (3 × 100 ml). The organic solution was dried over sodium sulfate. Sodium sulfate is removed by filtration. The solution was evaporated to dryness. The residue is dissolved in 250 ml of dichloromethylene. 250 ml of trifluoroacetic acid were added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated to dryness. It was obtained H-Gly-Pro-Arg ( diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA28g.

3. Ac-Val-Pro-Gly- Pro-Arg (diAc) -OCH 2 CH 2 N (CH 2 CH 3) Preparation of ₂ .HCl
Were dissolved H-Gly-Pro-Arg ( diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA26g into 10% sodium bicarbonate 300 ml. 150 ml of acetone and 15 g of Ac-Val-Pro-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. 500 ml of ethyl acetate were added to the mixture. The organic layer is washed with water (3 × 100 ml). The ethyl acetate layer was dried over sodium sulfate. Sodium sulfate is removed by filtration. 3.5 g of HCl gas in dioxane (50 ml) are added to the solution. The solid was collected and washed with ether (3 × 50 ml). After drying, 18 g of the desired hygroscopic product are obtained. Solubility in water: 150 mg / ml, elemental analysis: C ₃₅ H ₆₀ ClN ₉ O ₉ , molecular weight: 786.36, calculation% C: 53.46; H: 7.69; Cl: 4.51; N: 16.03; O: 18.31, found% C: 53.43; H: 7.73; Cl: 4.55; N: 16.01, O: 18.29, MS: m / e: 750.4; m / e + 1: 751.4.

Preparation of cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl Preparation of Ac-Nle-Asp (OFm) -OH
43 g of H-Asp (OFm) -OH.TFA and 27 g of Ac-Nle-OSu were suspended in 300 ml of acetone. 300 ml of 5% NaHCO ₃ was added to the reaction mixture. The mixture was stirred at room temperature overnight. The mixture was washed with ether (1 × 300 ml). 500 ml of ethyl acetate was added to the aqueous layer. The pH of the mixture was adjusted to 2.4-2.5 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water (3 × 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated to dryness. 42 g of Ac-Nle-Asp (OFm) -OH was obtained.

2. Preparation of Fmoc-Trp-Lys (4-Pyoc) -OH
H-Lys (4-Pyoc) -OH is described in the reference (H. Kunz and S. Birnbach, Tetrahedron Lett., 25, 3567, 1984; H. Kunz and R. Barthels, Angew. Chem., Int. Ed. Engl , 22, 783, 1983). 33 g of H-Lys (4-Pyoc) -OH were suspended in 300 ml of 5% NaHCO ₃ . 300 ml of acetone and 52 g of Fmoc-Trp-OSu were added to the reaction mixture. The mixture was stirred at room temperature overnight. The mixture was washed with ether (1 × 500 ml). 500 ml of ethyl acetate are added to the mixture and the pH of the mixture is adjusted to 2.2-2.3 with ice cold 3N HCl. The ethyl acetate layer was collected and washed with water. The organic solution was dried over sodium sulfate. The organic solution was evaporated to dryness. 55 g of Fmoc-Trp-Lys (4-Pyoc) -OH was obtained.

3. Preparation of cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OH
100 g of Wang resin was suspended in 700 ml of DMF. 50 g of Fmoc-Trp-Lys (4-Pyoc) -OH, 13 g of 1-hydroxybenzotriazole, 2 g of 4-dimethylaminopyridine, and 12 g of N, N'-diisopropylcarbodiimide. The mixture was stirred at room temperature overnight. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). DMF 700 ml, Fmoc-Arg (diAc) -OH 48 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium 38 g Was added to the resin. The mixture was stirred at room temperature for 2 hours. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of DMF, 39 g of Fmoc-Phe-OH, 13 g of 1-hydroxybenzotriazole, 35 ml of triethylamine, and 38 g of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium to a resin added. The mixture was stirred at room temperature for 2 hours. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). DMF 700 ml, Fmoc-His (Fmoc) -OH 60 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium 38 g Was added to the resin. The mixture was stirred at room temperature for 2 hours. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of 20% piperidine was added to the resin. The mixture was stirred for 30 minutes. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). DMF 700 ml, Ac-Nle-Asp (OFm) -OH 60 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluro 38 g of nickel were added to the resin. The mixture was stirred at room temperature for 2 hours. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). The peptide resin was suspended in 700 ml DMF. 50 g of MeI was added to the reaction mixture. The mixture was stirred at room temperature for 1 hour and at 50 ° C. for 1 hour. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of 30% piperidine was added to the resin. The mixture was stirred for 60 minutes. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 700 ml of DMF, 13 g of 1-hydroxybenzotriazole, 35 ml of triethylamine, and 38 g of O- (benzotriazol-1-yl) -N, N, N ', N'-tetramethyluronium were added to the resin. The mixture was stirred at room temperature for 10 hours. The resin was collected by filtration and washed with DMF (3 × 400 ml), methanol (3 × 400 ml), and dichloromethylene (3 × 400 ml). 500 ml of trifluoroacetic acid were added to the resin and the mixture was stirred at room temperature for 1 hour. The resin is removed by filtration and the solution is evaporated to dryness. The residue was washed with ether (3 × 100 ml).

4. Cyclo (1,6) -Ac-Nle-Asp -His-Phe-Arg (diAc) -Trp-Lys-OCH 2 CH 2 N (CH 2 CH 3) 2 .HCl Preparation cyclo (1, 6) -Ac 10 g of Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OH were dissolved in 300 ml of DMF. The mixture was cooled to 0 ° C. with an ice water bath. 12 g of N, N-diethylaminoethanol, 2 g of 4-dimethylaminopyridine and 22 g of 1,3-dicyclohexylcarbodiimide were added to the reaction mixture. The reaction mixture is stirred for 1 hour at 0 ° C. and overnight at room temperature. The solids were removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 × 500 ml) and water (3 × 100 ml). The ethyl acetate solution was dried over sodium sulfate. 2 g of HCl in dioxane (20 ml) was added to the solution. The solid was collected and washed with ether (3 × 30 ml). 8 g of product were obtained.

  The prodrug represented by structure 1 can easily penetrate the skin film. Transdermal delivery systems for peptides and related compounds have been used to treat many diseases in humans or animals, such as pain from rheumatoid arthritis and osteoarthritis, fever, male erectile dysfunction, female sexual dysfunction, systemic blood pressure, antihypertensive The peptide hormone may be useful in the treatment of hypotensive control, inhibition of platelet aggregation, lung disease, digestive disease, inflammation, shock, reproduction, fertility, etc.

式中、ＸはＯ、Ｓ、又はＮＨを表し、Ｘ₁又はＸ_nはＣＯ、ＳＯ、ＳＯ₂、ＰＯ（ＯＲ）、ＮＯ、又は何もないことを表し、Ｚ_n又はＺ_n1はＨ、ＣＨ₃、Ｃ₂Ｈ₅、Ｃ₃Ｈ₇、ＣＦ₃、Ｃ₂Ｆ₅、又はＣ₃Ｆ₇を表し、Ｒ_nはアミノ酸の脂肪族側鎖、アミノ酸のヒドロキシル若しくは硫黄含有側鎖、アミノ酸の芳香族側鎖、アミノ酸のアミノ、イミダゾリル、若しくはクアニジノ基含有側鎖、又はアミノ酸のカルボキシル若しくはカルボキサミド基含有側鎖のいずれか一つ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｙ_x1、Ｙ_x2、又はＹ_nはＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は以下の基、

又は何もないことを表し、Ｒ_x1、Ｒ_x2、Ｒ_x3、Ｒ_x4、Ｒ_x5、又はＲ_xnはＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-は陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である化合物。
２．構造１中、Ｒ_n、Ｒ_x1、Ｒ_x2、Ｒ_x3、Ｒ_x4、Ｒ_x5、又はＲ_xn基がＣ、Ｈ、Ｏ、Ｓ、又はＮ原子を含むか、又は単結合、二重結合、若しくは三重結合を有する、上記１に記載の化合物。
３．構造１中、ＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、上記１に記載の化合物。
４．構造１中、アミノ酸がＬ−型若しくはＤ−型である、上記１に記載の化合物。
５．構造１中、配列中の１種以上のアミノ酸残基が非天然アミノ酸、又はアルキル、アルキルオキシ、アルケニル、アルキニル、アリール又はヘテロアリール残基のいずれか一つにより置換されている、上記１に記載の化合物。
６．構造１中、ペプチド鎖上のアミノ酸のアミノ及びカルボキシル基がラクタムブリッジを形成しホモデティックな環状ペプチドを形成している、上記１に記載の化合物。
７．構造１中、アミノ酸のチオール基がジスルフィドブリッジを形成しヘテロデティックな環状ペプチドを形成している、上記１に記載の化合物。
８．前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、上記１に記載の化合物。 As an aspect of this invention, there exist the following, for example.
1. A compound represented by structure 1 of the formula:

In the formula, X represents O, S or NH, X ₁ or X _n represents CO, SO, SO ₂ , PO (OR), NO or nothing, and Z _n or Z _n1 is H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ or C ₃ F ₇ , wherein R _n is an aliphatic side chain of an amino acid, a hydroxyl or sulfur containing side chain of an amino acid, an amino acid Aromatic side chain, amino acid of amino acid, imidazolyl or guanidino group-containing side chain, or any one of carboxyl or carboxamido group-containing side chain of amino acid, alkyl, alkyloxy, alkenyl or alkynyl residue having 1 to 12 carbon atoms one of groups, represents no aryl or heteroaryl residues, or nothing, Y _x1, Y _x2, or Y _n is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl young Ku is one of alkynyl residues, aryl or heteroaryl residue, or the following group,

Or R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn is H, O, alkyl having 1 to 12 carbon atoms, any of alkyloxy, alkenyl or alkynyl residue or one, represents no aryl or heteroaryl residues, or nothing, a ^- represents an anion, n = 0,1,2,3,4,5,6,7,8,9,10 Compounds in which all R, — (CH ₂ ) _n — or — (CH ₂ ) _m — groups are branched or linear.
2. In structure 1, R _n , R _x1 , R _x2 , R _x3 , R _x4 , R _x5 or R _xn group contains a C, H, O, S or N atom, or a single bond or a double bond, Or a compound according to the above 1 having a triple bond.
3. A compound according to claim 1 wherein in structure 1 the CH ₂ group is substituted with O, S or NH.
4. A compound according to claim 1, wherein in structure 1 the amino acid is in L- or D-form.
5. In structure 1, one or more of the amino acid residues in the sequence are substituted by a non-naturally occurring amino acid, or any one of alkyl, alkyloxy, alkenyl, alkynyl, aryl or heteroaryl residues. Compounds.
6. A compound according to claim 1, wherein in structure 1 the amino and carboxyl groups of the amino acids on the peptide chain form a lactam bridge to form a homodetic cyclic peptide.
7. The compound according to claim 1, wherein in structure 1, the thiol group of the amino acid forms a disulfide bridge to form a heterodetic cyclic peptide.
8. The compound according to 1 above, wherein the anion is Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , or citrate.

9. Transdermal delivery compositions for prodrugs of peptides, wherein the prodrug comprises a lipophilic moiety and a primary, secondary or tertiary amine group present in protonated form at physiological pH, or It has a guanidino group or one protected guanidino group (hydrophilic moiety), said prodrugs being present in one or two, protonated forms at physiological pH, primary, secondary Transdermal delivery composition characterized in that it has a secondary or tertiary amine group, or a guanidino group or one protected guanidino group (hydrophilic part).
10. The transdermal delivery composition according to the above 9, wherein the primary, secondary or tertiary amine group, guanidino group, or one protected guanidino group is N-terminal, C-terminal or side chain of peptide object.
11. Transdermal according to claim 9, wherein the carboxyl group, amino group, guanidine group or other hydrophilic group is protected by an alkyl, aryl or heteroaryl ester, or an amide group to make the peptide lipophilic. Delivery composition.

式中、Ｒは分枝鎖若しくは直鎖、又は-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基を表し、ＸはCO、SO、SO₂、又は何もないことを表し、Ｘ₁はCH₃SCH₂CH₂、CH₃SOCH₂CH₂、又は(CH₃)₂CHCH₂を表し、Ｘ₂はH、CH₃又はCF₃を表し、Ｘ₃はH、CH₃、C₂H₅、又はCF₃を表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、又はＲ₅はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-は陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、Ｒ_n、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である。
１３．構造２−Ｃ中、アミノ酸がＬ−型若しくはＤ−型であるか、Ｒ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、又はＲ₅基がＣ、Ｈ、Ｏ、Ｓ、若しくはＮ原子を含むか、又は単結合、二重結合若しくは三重結合を有するか、又はＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、上記１２に記載の化合物。
１４．前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、上記１２に記載の化合物。
１５．歯痛、頭痛、炎症、熱、癌、月経困難症、又は急性片頭痛に由来する疼痛を治療するための薬剤の製造のための、上記１２に記載の化合物の使用。 12. The compound represented by structure 2-C of a following formula.

In the formula, R represents a branched or straight chain, or - (CH _{2) n} - A n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or Represents a heteroaryl residue, X represents CO, SO, SO ₂ or nothing, X ₁ represents CH ₃ SCH ₂ CH ₂ , CH ₃ SOCH ₂ CH ₂ or (CH ₃ ) ₂ CHCH ₂ X ₂ represents H, CH ₃ or CF ₃ , X ₃ represents H, CH ₃ , C ₂ H ₅ or CF ₃ , R ₁ , R ₂ , R ₃ , R ₄ or R ₅ represents H, indicates that no alkyl, alkyloxy, any one alkenyl or alkynyl residue, aryl or heteroaryl residues, or anything having 1 to 12 carbon atoms, a ^- represents an anion, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ..., all R, R _n ,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are It is branched or linear.
13. In structure 2-C, the amino acid is L-type or D-type, or R, R ₁ , R ₂ , R ₃ , R ₄ or R ₅ group is a C, H, O, S or N atom comprising or a single bond, double bond or one having a triple bond, or a CH ₂ group is O, it is replaced with S or NH, a compound according to the above 12.
14. The compound according to the above 12, wherein the anion is Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , or citrate.
15. Use of a compound according to the above 12 for the manufacture of a medicament for treating pain derived from toothache, headache, inflammation, fever, cancer, dysmenorrhea or acute migraine.

式中、Ｒ₁又はＲ₂はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ₃はＨ又はＣＨ₃を表し、Ａ^-は陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、Ｒ_n、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である。
１７．構造３−Ｃ中、アミノ酸がＬ−型若しくはＤ−型であるか、Ｒ₁、Ｒ₂、又はＲ₃基がＣ、Ｈ、Ｏ、Ｓ、若しくはＮ原子を含むか、又は単結合、二重結合若しくは三重結合を有するか、又はＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、上記１６に記載の化合物。
１８．前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、上記１６に記載の化合物。
１９．歯痛、頭痛、炎症、熱、癌、月経困難症、又は急性片頭痛に由来する疼痛を治療するための薬剤の製造のための、上記１６に記載の化合物の使用。 16. The compound represented by structure 3-C of a following formula.

In the formula, R ₁ or R ₂ represents H, an alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, an aryl or heteroaryl residue or nothing. ₃ represents H or CH ₃ , A ⁻ represents an anion, and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, all R, R _n The — (CH ₂ ) _n — or — (CH ₂ ) _m — groups are branched or linear.
17. In structure 3-C, the amino acid is in L- or D-form, or the R ₁ , R ₂ or R ₃ group contains a C, H, O, S or N atom, or a single bond, or having a double bond or triple bond, or a CH ₂ group is O, is replaced with S or NH, a compound according to the above 16.
18. The ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate, the compound according to the above 16.
19. The use of a compound according to the above 16 for the manufacture of a medicament for treating pain from toothache, headache, inflammation, fever, cancer, dysmenorrhea or acute migraine.

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基を表し、Ｘ₄、Ｘ₅、Ｘ₆、Ｘ₇、Ｘ₈、又はＸ₉はＣＯ、ＳＯ₂、ＰＯ（ＯＲ）、ＮＯ、又は何もないことを表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、Ｒ₈、又はＲ₉はＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、Ａｒはアリール若しくはヘテロアリール残基を表し、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である。
２１．構造４−Ｃ中、アミノ酸がＬ−型若しくはＤ−型であるか、Ｒ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、Ｒ₈、又はＲ₉基がＣ、Ｈ、Ｏ、Ｓ、若しくはＮ原子を含むか、又は単結合、二重結合若しくは三重結合を有するか、又はＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、上記２０に記載の化合物。
２２．前記Ａｒ基が、フェニル、２’−ナフチル又は４−ヨードフェニルである、上記２０に記載の化合物。
２３．男性の勃起不全、女性の性機能障害、又は皮膚病を治療するための薬剤の製造のための、上記２０に記載の化合物の使用。
２４．前記皮膚病が、白皮症である、上記２３に記載の使用。 20. The compound represented by structure 4-C of a following formula.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or heteroaryl Represents an aryl residue, and X ₄ , X ₅ , X ₆ , X ₇ , X ₈ or X ₉ represents CO, SO ₂ , PO (OR), NO or nothing, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ is H, O, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl or an alkynyl residue, Represents an aryl or heteroaryl residue or nothing, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ..., Ar is an aryl or heteroaryl residue And all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or linear.
21. In structure 4-C, the amino acid is in L- or D-form, or R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ group is 20. A compound as described in 20 above comprising C, H, O, S, or N atoms, or having a single bond, double bond or triple bond, or wherein a CH ₂ group is substituted with O, S or NH. Compound.
22. The compound according to claim 20, wherein the Ar group is phenyl, 2'-naphthyl or 4-iodophenyl.
23. Use of a compound according to the above 20 for the manufacture of a medicament for treating male erectile dysfunction, female sexual dysfunction or skin disease.
24. The use according to the above 23, wherein the skin disease is albinism.

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基、又は何もないことを表し、Ｘ₁はＨ又はＲ₁ＯＣＯＣＨ₂−を表し、Ｘ₂はＨ又は（ＣＨ₃）₂ＣＨ−を表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、又はＲ₆はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基を表し、Ａ^-は陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、Ｒ_n、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である。
２６．構造５−Ｃ中、Ｒ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、又はＲ₆基がＣ、Ｈ、Ｏ、Ｓ、若しくはＮ原子を含むか、又は単結合、二重結合若しくは三重結合を有するか、又はＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、上記２５に記載の化合物。
２７．前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、上記２５に記載の化合物。
２８．肥満を治療するための薬剤の製造のための、上記２５に記載の化合物の使用。
２９．上記２０に記載の構造４−Ｃで表されるシクロペプチドを調製する方法であって、ペプチド鎖が標準的なペプチド合成プロトコルにより合成され、リシンの側鎖が２−，又は４−Ｐｙｏｃ保護基により保護され、ペプチドの環化が樹脂上で行われる方法。 25. The compound represented by structure 5-C of a following formula.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or heteroaryl Represents an aryl residue or nothing, X ₁ represents H or R ₁ OCOCH _2- , X ₂ represents H or (CH ₃ ) ₂ CH-, R ₁ , R ₂ , R ₃ , R _4, R _5, or R ₆ represents H, alkyl having 1 to 12 carbon atoms, alkyloxy, any one alkenyl or alkynyl residues, aryl or heteroaryl residue, a ^- represents an anion , n = 0,1,2,3,4,5,6,7,8,9,10 ... a is, all _{R, R n, - (CH} 2) n - or - (CH _{2) m} - The groups are branched or linear.
26. In the structure 5-C, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ or R ₆ group contains a C, H, O, S or N atom, or a single bond or a double bond 26. The compound according to 25 above, wherein the compound has a triple bond or the CH ₂ group is substituted with O, S or NH.
27. 26. The compound according to 25 above, wherein the anion is Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ or citrate.
28. Use of a compound according to the above 25 for the manufacture of a medicament for treating obesity.
29. A method of preparing a cyclopeptide represented by structure 4-C according to the above 20, wherein the peptide chain is synthesized by a standard peptide synthesis protocol, and the side chain of lysine is a 2-, or 4-Pyoc protecting group A method in which the cyclization of the peptide is carried out on a resin.

30. A pharmaceutical composition for treating a condition treatable by a peptide in a human or an animal, comprising the compound represented by the structure 1 described in 1 above as an active ingredient.
31. The pharmaceutical composition according to the above 30, which is orally or transdermally administered.
32. The conditions treatable by the peptide include glaucoma, hypertonia, male erectile dysfunction, female sexual dysfunction, systemic blood pressure, abortion, antihypertensive control, inhibition of platelet aggregation, lung disease, digestive disease, inflammation, shock, The pharmaceutical composition according to claim 30, selected from the group consisting of fertility, fertility and obesity.
33. The pharmaceutical composition according to claim 30, which is transdermally administered to the body part in the form of a solution, spray, lotion, ointment, emulsion or gel.
34. Transdermal therapeutic application system comprising a matrix layer containing a compound represented by the structure 1 according to the above 1 and a non-permeable support layer for treating a peptide-treatable condition in humans or animals .
35. 35. The transdermal therapeutic application system of 34, which is a bandage or a patch.
36. The transdermal therapeutic application system according to Claim 34, which is an active substance storage and has a permeable bottom facing the skin.

式中、ＸはＯ、Ｓ、又はＮＨを表し、Ｘ₁又はＸ_nはＣＯ、ＳＯ、ＳＯ₂、ＰＯ（ＯＲ）、ＮＯ、又は何もないことを表し、Ｚ_n又はＺ_n1はＨ、ＣＨ₃、Ｃ₂Ｈ₅、Ｃ₃Ｈ₇、ＣＦ₃、Ｃ₂Ｆ₅、又はＣ₃Ｆ₇を表し、Ｒ_nはアミノ酸の脂肪族側鎖、アミノ酸のヒドロキシル−若しくは硫黄含有側鎖、アミノ酸の芳香族側鎖、アミノ酸のアミノ、イミダゾリル、若しくはクアニジノ基含有側鎖、又はアミノ酸のカルボキシル若しくはカルボキサミド基含有側鎖のいずれか一つ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｙ_x1、Ｙ_x2、又はＹ_nはＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は以下の基、

又は何もないことを表し、Ｒ_x1、Ｒ_x2、Ｒ_x3、Ｒ_x4、Ｒ_x5、又はＲ_xnはＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-はＣｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、シトラート、又はいずれの陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖であり、Ｃ、Ｈ、Ｏ、Ｓ、又はＮ原子を含んでもよく、単結合、二重結合、及び三重結合を有してもよく、ＣＨ₂基はＯ、Ｓ又はＮＨと置換されてもよく、アミノ酸はＬ−型でもＤ−型でもよく、配列中の１種以上のアミノ酸残基は非天然アミノ酸、例えば、β−アミノ酸、２−ナフチルアラニン、及びアルキル、アルキルオキシ、アルケニル若しくはアルキニルのいずれか一つ、アリール又はヘテロアリール残基により置換されてもよく、ペプチド鎖上のアミノ酸のアミノ及びカルボキシル官能基は、ラクタムブリッジを形成しホモデティックな環状ペプチドを形成してもよく、システイン、ホメシステイン、又は他のアミノ酸のチオール基は、ジスルフィドブリッジを形成しヘテロデティックな環状ペプチドを形成してもよい。
２−２．ペプチド及び関連化合物の経皮送達システムのデザインであって、ペプチド又は関連化合物のこれらのプロドラッグをデザインするための原則は、１．プロドラッグは、親油性部分及び生理学的ｐＨにおいてプロトン化された形態で存在する第１級、第２級若しくは第３級アミン基、クアニジノ基、又は１つが保護されたクアニジノ基（親水性部分）を有していなければならず、２．ペプチドの全てプロドラッグは１つ又は２つだけ（好ましくは１つ）の、生理学的ｐＨにおいてプロトン化された形態で存在する第１級、第２級若しくは第３級アミン基、クアニジノ基、又は１つが保護されたクアニジノ基（親水性部分）を有するべきである。３．第１級、第２級若しくは第３級アミン基、クアニジノ基、又は１つが保護されたクアニジノ基は、Ｎ末端、Ｃ末端、又はペプチドの側鎖であり得、Ｎ末端又はＣ末端部分が好ましく、４．ペプチドを親油性にするために、カルボキシル基、アミノ基、グアニジン基又は他の親水性基は、アルキル、アリール、若しくはヘテロアリールエステル又はアミド基で保護され得る。 1-2. A compound represented by structure 1 of the formula:

In the formula, X represents O, S or NH, X ₁ or X _n represents CO, SO, SO ₂ , PO (OR), NO or nothing, and Z _n or Z _n1 is H, CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , wherein R _n is an aliphatic side chain of an amino acid, a hydroxyl- or sulfur-containing side chain of an amino acid, an amino acid The aromatic side chain, amino acid of amino acid, imidazolyl, or guanidino group-containing side chain, or any one of carboxyl or carboxamido group-containing side chain of amino acid, alkyl, alkyloxy, alkenyl or alkynyl having 1 to 12 carbon atoms one of residues, represents no aryl or heteroaryl residues, or nothing, Y _x1, Y _x2, or Y _n is H, alkyl having 1 to 12 carbon atoms, alkyloxy, alkenyl Any one of properly alkynyl residues, aryl or heteroaryl residue, or the following group,

Or R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn is H, O, alkyl having 1 to 12 carbon atoms, any of alkyloxy, alkenyl or alkynyl residue or one, represents no aryl or heteroaryl residues, or nothing, a ^- is ^{Cl -, Br -, F -} , I -, AcO -, citrate, or represents any anion, n = 0 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ..., all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or straight A chain, which may contain C, H, O, S, or N atoms, may have a single bond, a double bond, and a triple bond, and a CH ₂ group is substituted with O, S or NH The amino acids may be L- or D-type, and one or more amino acid residues in the sequence may be non-naturally occurring amino acids, for example It may be substituted by 2-naphthylalanine and any one of alkyl, alkyloxy, alkenyl or alkynyl, aryl or heteroaryl residues, and the amino and carboxyl functional groups of the amino acids on the peptide chain form a lactam bridge And homophilic cyclic peptides may be formed, and thiol groups of cysteine, homecysteine or other amino acids may form disulfide bridges to form heterocyclic cyclic peptides.
2-2. The design of transdermal delivery systems for peptides and related compounds, the principles for designing these prodrugs of peptides or related compounds are: Prodrugs may be lipophilic moieties and primary, secondary or tertiary amine groups present in protonated form at physiological pH, guanidino groups, or one guanidino group protected (hydrophilic moiety) Have to have All prodrugs of the peptide may be only one or two (preferably one) primary, secondary or tertiary amine groups present in protonated form at physiological pH, guanidino groups, or One should have a protected guanidino group (hydrophilic moiety). 3. The primary, secondary or tertiary amine group, guanidino group, or one protected guanidino group may be N-terminal, C-terminal or side chain of peptide, preferably N-terminal or C-terminal part , 4. In order to make the peptide lipophilic, carboxyl, amino, guanidine or other hydrophilic groups may be protected with alkyl, aryl or heteroaryl ester or amido groups.

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基を表し、ＸはCO、SO、SO₂、又は何もないことを表し、Ｘ₁はCH₃SCH₂CH₂-、CH₃SOCH₂CH₂-、又は(CH₃)₂CHCH₂-を表し、Ｘ₂はH、CH₃又はCF₃を表し、Ｘ₃はH、CH₃、C₂H₅、又はCF₃を表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、又はＲ₅はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-はＣｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、シトラート、又はいずれの陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、アミノ酸はＬ−型又はＤ−型であり得、全てのＲ、Ｒ_n、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖であり、Ｃ、Ｈ、Ｏ、Ｓ、又はＮ原子を含んでもよく、単結合、二重結合、及び三重結合を有してもよく、ＣＨ₂基はＯ、Ｓ又はＮＨと置換されてもよい。
４−２．次式の構造３−Ｃで表される化合物、及び歯痛、頭痛、関節炎、他の炎症性、熱、癌、月経困難症、及び急性片頭痛に由来する疼痛を治療するためのそれらの使用。

式中、Ｒ₁又はＲ₂はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ₃はＨ又はＣＨ₃を表し、Ａ^-はＣｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、シトラート、又はいずれの陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、アミノ酸はＬ−型又はＤ−型であり得、全てのＲ、Ｒ_n、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖であり、Ｃ、Ｈ、Ｏ、Ｓ、又はＮ原子を含んでもよく、単結合、二重結合、及び三重結合を有してもよく、ＣＨ₂基はＯ、Ｓ又はＮＨと置換されてもよい。 3-2. Compounds represented by structure 2-C of the following formula and their use for treating pain from toothache, headache, arthritis, other inflammatory, fever, cancer, dysmenorrhea and acute migraine.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or heteroaryl Represents an aryl residue, X represents CO, SO, SO ₂ or nothing, and X ₁ represents CH ₃ SCH ₂ CH _2- , CH ₃ SOCH ₂ CH _2- , or (CH ₃ ) ₂ CHCH ₂ And X ₂ represents H, CH ₃ or CF ₃ , X ₃ represents H, CH ₃ , C ₂ H ₅ or CF ₃ , R ₁ , R ₂ , R ₃ , R ₄ or R ₅ is H, indicates that no alkyl, alkyloxy, any one alkenyl or alkynyl residue, aryl or heteroaryl residues, or anything having 1 to 12 carbon atoms, a ^- is Cl ^-, Br ^- , F ⁻ , I ⁻ , AcO ⁻ , citrate, or any of the anions, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, and the amino acid is L -Or D-type, all _{R, R n, - (CH} 2) n - or - (CH _{2) m} - group is branched or straight chain, C, H, O, may contain S, or N atom, a single bond, It may have a double bond and a triple bond, and the CH ₂ group may be substituted with O, S or NH.
4-2. Compounds of structure 3-C of the following formula and their use for treating pain from toothache, headache, arthritis, other inflammatory, fever, cancer, dysmenorrhea, and acute migraine.

In the formula, R ₁ or R ₂ represents H, an alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, an aryl or heteroaryl residue or nothing. ₃ represents H or CH ₃ , A ⁻ represents Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , citrate or any anion, and n = 0, 1, 2, 3, 4, 5 , 6, 7, 8, 9, 10, ..., the amino acids may be in L- or D-form and all R, R _n ,-(CH ₂ ) _n- or-(CH ₂ ) _m -groups Is a branched or straight chain, and may contain a C, H, O, S, or N atom, and may have a single bond, a double bond, and a triple bond, and a CH ₂ group is O, S Or may be substituted with NH.

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基を表し、Ｘ₄、Ｘ₅、Ｘ₆、Ｘ₇、Ｘ₈、又はＸ₉はＣＯ、ＳＯ₂、ＰＯ（ＯＲ）、ＮＯ、又は何もないことを表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、Ｒ₈、又はＲ₉はＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-はＣｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、シトラート、又はいずれの陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、Ａｒはフェニル、２’−ナフチル、４−ヨードフェニル、又は他のアリール若しくはヘテロアリール残基を表し、アミノ酸はＬ−型又はＤ−型であり得、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖であり、Ｃ、Ｈ、Ｏ、Ｓ、又はＮ原子を含んでもよく、単結合、二重結合、及び三重結合を有してもよく、ＣＨ₂基はＯ、Ｓ又はＮＨと置換されてもよい。
６−２．次式の構造５−Ｃで表される化合物、及び肥満を治療するためのそれらの使用。

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基、又は何もないことを表し、Ｘ₁はＨ又はＲ₁ＯＣＯＣＨ₂−を表し、Ｘ₂はＨ又は（ＣＨ₃）₂ＣＨ−を表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、Ｒ₅、又はＲ₆はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基を表し、Ａ^-はＣｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、シトラート、又はいずれの陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、Ｒ_n、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖であり、Ｃ、Ｈ、Ｏ、Ｓ、又はＮ原子を含んでもよく、単結合、二重結合、及び三重結合を有してもよく、ＣＨ₂基はＯ、Ｓ又はＮＨと置換されてもよい。 5-2. Compounds represented by structure 4-C of the following formula and their use for treating erectile dysfunction in males, sexual dysfunction in females, albinism and other skin diseases.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or heteroaryl Represents an aryl residue, and X ₄ , X ₅ , X ₆ , X ₇ , X ₈ or X ₉ represents CO, SO ₂ , PO (OR), NO or nothing, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ is H, O, an alkyl having 1 to 12 carbon atoms, an alkyloxy, an alkenyl or an alkynyl residue, indicates no aryl or heteroaryl residues, or nothing, a ^- is ^{Cl -, Br -, F -} , I -, AcO -, citrate, or represents any anion, n = 0, 1, 2 , 3, 4, 5, 6, 7, 8, 9, 10, ..., Ar is phenyl, 2'-naphthyl, 4-iodophenyl, or other aryl groups. Represents a heteroaryl residue, the amino acids may be in L- or D-form, all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or linear And may contain C, H, O, S, or N atoms, may have single bonds, double bonds, and triple bonds, and the CH ₂ group may be substituted with O, S or NH.
6-2. Compounds represented by structure 5-C of the following formula: and their use for treating obesity.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or heteroaryl Represents an aryl residue or nothing, X ₁ represents H or R ₁ OCOCH _2- , X ₂ represents H or (CH ₃ ) ₂ CH-, R ₁ , R ₂ , R ₃ , R _4, R _5, or R ₆ represents H, alkyl having 1 to 12 carbon atoms, alkyloxy, any one alkenyl or alkynyl residues, aryl or heteroaryl residue, a ^- is Cl ^-, Br ^{-, F -, I -,} AcO -, citrate, or represents any anion, n = 0,1,2,3,4,5,6,7,8,9,10 ... a is, all _{R, R n, - (CH} 2) n - or - (CH _{2) m} - group is branched or straight chain, C, H, O, may contain S, or n atom, a single bond, Double bond, and may have a triple bond, CH ₂ group is O, may be replaced with S or NH.

7-2. A method for preparing a cyclopeptide represented by structure 4-C and a related compound described in 5-2 above, wherein the peptide chain can be synthesized by a standard peptide synthesis protocol, and the side chain of lysine is 2-, Or the method protected by 4-Pyoc protecting group and the cyclization of a peptide is performed on resin.
8-2. A composition comprising, as an active ingredient, the compound represented by structure 1 or the compound represented by at least structure 1 as described in 1-2 above, which is treatable by a peptide and related compounds in humans or animals. A compound or composition that can be administered orally or percutaneously to treat the disease, wherein the condition is glaucoma or hypertonia, male erectile dysfunction and female sexual dysfunction, systemic blood pressure, abortion, hypotension A compound or composition including, but not limited to, control, suppression of platelet aggregation, lung disease, digestive disease, inflammation, shock, reproductive ability, fertility, obesity and the like.
9-2. A method of treating a treatable condition for peptides and related compounds in humans or animals, comprising: transdermally administering (in the form of a solution, spray, lotion, ointment, emulsion or gel) to a part of the body A method comprising delivering a therapeutically effective plasma level of a compound represented by Structure 1, or a composition comprising at least a compound represented by Structure 1 as an active ingredient described in 1-2.
10-2. Composition containing the compound represented by structure 1 or the compound represented by at least structure 1 as described in the above 1-2 for treating a treatable condition for peptides and related compounds in humans or animals Transdermal therapeutic application system, which can be a bandage or patch consisting of an active substance-containing matrix layer and a non-permeable support layer, most preferably an active substance reservoir, which has a permeable bottom facing the skin And controlling the release rate to allow the peptide and related compounds to constantly reach optimal therapeutic blood levels, to increase efficacy and to reduce side effects of the peptide and related compounds. A system characterized by

式中、ＸはＯ、Ｓ、又はＮＨを表し、Ｘ₁又はＸ_nはＣＯ、ＳＯ、ＳＯ₂、ＰＯ（ＯＲ）、ＮＯ、又は何もないことを表し、Ｚ_n又はＺ_n1はＨ、ＣＨ₃、Ｃ₂Ｈ₅、Ｃ₃Ｈ₇、ＣＦ₃、Ｃ₂Ｆ₅、又はＣ₃Ｆ₇を表し、Ｒ_nはアミノ酸の脂肪族側鎖、アミノ酸のヒドロキシル若しくは硫黄含有側鎖、アミノ酸の芳香族側鎖、アミノ酸のアミノ、イミダゾリル、若しくはクアニジノ基含有側鎖、又はアミノ酸のカルボキシル若しくはカルボキサミド基含有側鎖のいずれか一つ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｙ_x1又はＹ_x2はＨ、１〜１２炭素原子を有するアルキル、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は以下の基、

又は何もないことを表し、Ｙ_nはＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は以下の基、

又は何もないことを表し、Ｒ_x1又はＲ_x2はＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ_x3、Ｒ_x4、又はＲ_xnはＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ_x5はＨを表し、Ａ^-は陰イオンを表し、ｎ＝２、３、４、５、６、７、８、９又は１０であり、全てのＲ基は分枝鎖若しくは直鎖である化合物であって、該化合物はペプチドのプロドラッグであり、親油性部分及び生理学的ｐＨにおいてプロトン化された形態で存在する１つ又は２つの第１級、第２級若しくは第３級アミン基、クアニジノ基、又は１つが保護されたクアニジノ基を有する親水性部分を有し、前記生理学的ｐＨにおいてプロトン化された形態で存在する第１級、第２級若しくは第３級アミン基が、以下の基、

である化合物。
〔２〕構造１中、配列中の１種以上のアミノ酸残基が非天然アミノ酸、又はアルキル、アルキルオキシ、アルケニル、アルキニル、アリール又はヘテロアリール残基のいずれか一つにより置換されている、前記〔１〕に記載の化合物。
〔３〕構造１中、ペプチド鎖上のアミノ酸のアミノ及びカルボキシル基がラクタムブリッジを形成しホモデティックな環状ペプチドを形成しているか、又はアミノ酸のチオール基がジスルフィドブリッジを形成しヘテロデティックな環状ペプチドを形成している、前記〔１〕に記載の化合物。
〔４〕次式の構造２−Ｃで表される化合物。

式中、Ｒは分枝鎖若しくは直鎖、又は-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９又は１０、アリール又はヘテロアリール残基を表し、ＸはCO、SO、SO₂、又は何もないことを表し、Ｘ₁はCH₃SCH₂CH₂、CH₃SOCH₂CH₂、又は(CH₃)₂CHCH₂を表し、Ｘ₂はH、CH₃又はCF₃を表し、Ｘ₃はH、CH₃、C₂H₅、又はCF₃を表し、Ｒ₁、Ｒ₂、Ｒ₄、又はＲ₅はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ₃はＨを表し、Ａ^-は陰イオンを表し、全てのＲ、又は-(CH₂)_n-基は分枝鎖若しくは直鎖である。
〔５〕歯痛、頭痛、炎症、熱、癌、月経困難症、又は急性片頭痛に由来する疼痛を治療するための薬剤の製造のための、前記〔４〕に記載の化合物の使用。
〔６〕次式の構造３−Ｃで表される化合物。

式中、Ｒ₁又はＲ₂はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ₃はＨ又はＣＨ₃を表し、Ａ^-は陰イオンを表し、全てのＲ基は分枝鎖若しくは直鎖である。
〔７〕歯痛、頭痛、炎症、熱、癌、月経困難症、又は急性片頭痛に由来する疼痛を治療するための薬剤の製造のための、前記〔６〕に記載の化合物の使用。
〔８〕次式の構造４−Ｃで表される化合物。

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９又は１０、アリール又はヘテロアリール残基を表し、Ｘ₄、Ｘ₅、Ｘ₆、Ｘ₇、Ｘ₈、又はＸ₉はＣＯ、ＳＯ₂、ＰＯ（ＯＲ）、ＮＯ、又は何もないことを表し、Ｒ₁、Ｒ₂、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、Ｒ₈、又はＲ₉はＨ、Ｏ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ₃はＨを表し、Ａｒはアリール若しくはヘテロアリール残基を表し、Ａ^-は陰イオンを表し、全てのＲ、又は-(CH₂)_n-基は分枝鎖若しくは直鎖である。
〔９〕男性の勃起不全、女性の性機能障害、又は皮膚病を治療するための薬剤の製造のための、前記〔８〕に記載の化合物の使用。
〔１０〕前記皮膚病が、白皮症である、前記〔９〕に記載の使用。
〔１１〕前記〔８〕に記載の構造４−Ｃで表されるシクロペプチドを調製する方法であって、ペプチド鎖が標準的なペプチド合成プロトコルにより合成され、リシンの側鎖が２−，又は４−Ｐｙｏｃ保護基により保護され、ペプチドの環化が樹脂上で行われる方法。
〔１２〕前記〔１〕に記載の構造１で表される化合物を活性成分として含む、人又は動物において、緑内障、高眼圧症、男性の勃起不全、女性の性機能障害、全身血圧、堕胎、降圧コントロール、血小板凝集の抑制、肺疾患、消化器疾患、炎症、ショック、生殖能、受精能、及び肥満からなる群から選択されるペプチドにより治療可能な状態を治療するための医薬組成物。
〔１３〕経口投与又は経皮投与される、前記〔１２〕に記載の医薬組成物。
〔１４〕身体の一部に溶液、スプレー、ローション、軟膏、エマルジョン又はゲルの形態で経皮投与される、前記〔１２〕に記載の医薬組成物。
〔１５〕人又は動物において、緑内障、高眼圧症、男性の勃起不全、女性の性機能障害、全身血圧、堕胎、降圧コントロール、血小板凝集の抑制、肺疾患、消化器疾患、炎症、ショック、生殖能、受精能、及び肥満からなる群から選択されるペプチド治療可能な状態を治療するための、前記〔１〕に記載の構造１で表される化合物を含むマトリックス層及び非透過性支持層からなることを特徴とする経皮治療応用システム。
〔１６〕包帯又はパッチである、前記〔１５〕に記載の経皮治療応用システム。
〔１７〕活性物質貯蔵庫であり、皮膚に面する透過性底面を有する、前記〔１５〕に記載の経皮治療応用システム。
〔１８〕構造１、２−Ｃ、３−Ｃ又は４−Ｃ中、Ｒ_n、Ｒ_x1、Ｒ_x2、Ｒ_x3、Ｒ_x4、Ｒ_xn、Ｒ、Ｒ₁、Ｒ₂、Ｒ₄、Ｒ₅、Ｒ₆、Ｒ₇、Ｒ₈、又はＲ₉基がＣ、Ｈ、Ｏ、Ｓ、又はＮ原子を含むか、又は単結合、二重結合、若しくは三重結合を有する、前記〔１〕、〔４〕、〔６〕又は〔８〕に記載の化合物。
〔１９〕構造１、２−Ｃ、３−Ｃ又は４−Ｃ中、ＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、前記〔１〕、〔４〕、〔６〕又は〔８〕に記載の化合物。
〔２０〕構造１、２−Ｃ、３−Ｃ又は４−Ｃ中、アミノ酸がＬ−型若しくはＤ−型である、前記〔１〕、〔４〕、〔６〕又は〔８〕に記載の化合物。
〔２１〕前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、前記〔１〕、〔４〕、〔６〕又は〔８〕に記載の化合物。
本発明のまた別の態様は、以下のとおりであってもよい。
〔１'〕次式の構造２−Ｃで表される化合物。

式中、Ｒは分枝鎖若しくは直鎖、-(CH₂)_n-であってｎ＝０、１、２、３、４、５、６、７、８、９、１０…、アリール又はヘテロアリール残基を表し、ＸはCO、SO、SO₂、又は何もないことを表し、Ｘ₁はCH₃SCH₂CH₂、CH₃SOCH₂CH₂、又は(CH₃)₂CHCH₂を表し、Ｘ₂はH、CH₃又はCF₃を表し、Ｘ₃はH、CH₃、C₂H₅、又はCF₃を表し、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、又はＲ₅はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ａ^-は陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である。
〔２'〕アミノ酸がＬ−型若しくはＤ−型であるか、Ｒ、Ｒ₁、Ｒ₂、Ｒ₃、Ｒ₄、又はＲ₅がＣ、Ｈ、Ｏ、Ｓ、若しくはＮ原子を含むか、又は単結合、二重結合若しくは三重結合を有するか、又はＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、前記〔１'〕に記載の化合物。
〔３'〕前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、前記〔１'〕に記載の化合物。
〔４'〕歯痛、頭痛、炎症、熱、癌、月経困難症、及び急性片頭痛から選択される少なくとも１種の疾患に由来する疼痛を治療するための薬剤の製造のための、前記〔１'〕に記載の化合物の使用。
〔５'〕次式の構造３−Ｃで表される化合物。

式中、Ｒ₁又はＲ₂はＨ、１〜１２炭素原子を有するアルキル、アルキルオキシ、アルケニル若しくはアルキニル残基のいずれか一つ、アリール又はヘテロアリール残基、又は何もないことを表し、Ｒ₃はＨ又はＣＨ₃を表し、Ａ^-は陰イオンを表し、ｎ＝０、１、２、３、４、５、６、７、８、９、１０…であり、全てのＲ、-(CH₂)_n-又は-(CH₂)_m-基は分枝鎖若しくは直鎖である。
〔６'〕アミノ酸がＬ−型若しくはＤ−型であるか、Ｒ₁、Ｒ₂、又はＲ₃がＣ、Ｈ、Ｏ、Ｓ、若しくはＮ原子を含むか、又は単結合、二重結合若しくは三重結合を有するか、又はＣＨ₂基がＯ、Ｓ若しくはＮＨと置換されている、前記〔５'〕に記載の化合物。
〔７'〕前記陰イオンが、Ｃｌ^-、Ｂｒ^-、Ｆ^-、Ｉ^-、ＡｃＯ^-、又はシトラートである、前記〔５'〕に記載の化合物。
〔８'〕歯痛、頭痛、炎症、熱、癌、月経困難症、及び急性片頭痛から選択される少なくとも１種の疾患に由来する疼痛を治療するための薬剤の製造のための、前記〔５'〕に記載の化合物の使用。
〔９'〕経口投与又は経皮投与での人又は動物におけるペプチド治療可能な状態の治療における使用のための、前記〔１'〕〜〔３'〕及び〔５'〕〜〔７'〕のいずれか１項に記載の化合物、又は前記〔１'〕〜〔３'〕及び〔５'〕〜〔７'〕のいずれか１項に記載の化合物を活性成分として含む組成物。
〔１０'〕人又は動物におけるペプチド治療可能な状態の治療における使用のための、前記〔１'〕〜〔３'〕及び〔５'〕〜〔７'〕のいずれか１項に記載の化合物、又は前記〔１'〕〜〔３'〕及び〔５'〕〜〔７'〕のいずれか１項に記載の化合物を活性成分として含む組成物であって、該化合物又は該組成物が溶液、スプレー、ローション、軟膏、エマルジョン又はゲルの形態である、前記化合物又は前記組成物。
〔１１'〕人又は動物におけるペプチド治療可能な状態の治療における使用のための経皮治療応用システムであって、前記〔１'〕〜〔３'〕及び〔５'〕〜〔７'〕のいずれか１項に記載の化合物、又は前記〔１'〕〜〔３'〕及び〔５'〕〜〔７'〕のいずれか１項に記載の化合物を活性成分として含む組成物を含む、前記システム。
〔１２'〕活性物質含有マトリックス層及び非透過性支持層からなる包帯又はパッチである、前記〔１１'〕に記載のシステム。
〔１３'〕皮膚に面する透過性底面を有する活性物質貯蔵庫を有することを特徴とする、前記〔１１'〕又は〔１２'〕に記載のシステム。
〔１４'〕放出の割合を制御し、ペプチド及び関連化合物が絶えず最適治療血中レベルに達することを可能にし、効能を増大させ、ペプチド及び関連化合物の副作用を減少させることを可能にする制御手段を更に含む、前記〔１１'〕〜〔１３'〕のいずれか１項に記載のシステム。
〔１５'〕以下の構造２、構造３、構造４、構造７、構造８、構造９及び構造１０から選択される少なくとも１種のプロドラッグ。

Another aspect of the present invention may be as follows.
[1] A compound represented by structure 1 of the following formula, which is

In the formula, X represents O, S or NH, X ₁ or X _n represents CO, SO, SO ₂ , PO (OR), NO or nothing, and Z _n or Z _n1 is H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ or C ₃ F ₇ , wherein R _n is an aliphatic side chain of an amino acid, a hydroxyl or sulfur containing side chain of an amino acid, an amino acid Aromatic side chain, amino acid of amino acid, imidazolyl or guanidino group-containing side chain, or any one of carboxyl or carboxamido group-containing side chain of amino acid, alkyl, alkyloxy, alkenyl or alkynyl residue having 1 to 12 carbon atoms Represents any one of the groups, an aryl or heteroaryl residue, or nothing, and Y _x1 or Y _x2 is H, any of alkyl, alkenyl or alkynyl residues having 1 to 12 carbon atoms An aryl or heteroaryl residue, or the following groups:

Or Y represents nothing, and Y _n is H, alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, aryl or heteroaryl residues, or the following groups:

Or R _x1 or R _x2 is H, O, any one of alkyl, alkenyl or alkynyl having 1 to 12 carbon atoms, aryl or heteroaryl, or none R _x3 , R _x4 , or R _xn is H, O, alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, aryl or heteroaryl residues, or nothing indicates no, R _x5 represents H, a ^- represents an anion, a n = 2,3,4,5,6,7,8,9 or 10, all of the R groups is a branched Or a straight-chain compound, which is a prodrug of the peptide and which has a lipophilic moiety and one or two primary, secondary or secondary, which exist in the protonated form at physiological pH Tertiary amine group, A primary, secondary or tertiary amine group having a hydrophilic moiety having an anidino group, or one protected guanidino group, and which is present in protonated form at said physiological pH is Group,

A compound that is
[2] In the structure 1, one or more amino acid residues in the sequence are substituted by any one of non-natural amino acids or alkyl, alkyloxy, alkenyl, alkynyl, aryl or heteroaryl residues. The compound as described in [1].
[3] In structure 1, the amino and carboxyl groups of the amino acids on the peptide chain form a lactam bridge to form a homodetic cyclic peptide, or the thiol group of an amino acid forms a disulfide bridge to form a heterocyclic cyclic peptide The compound according to the above [1], which is
[4] A compound represented by structure 2-C of the following formula.

In the formula, R represents a branched or straight chain, or - (CH _{2) n} -, a and n = 0,1,2,3,4,5,6,7,8,9 or 10, aryl or heteroaryl Represents an aryl residue, X represents CO, SO, SO ₂ or nothing, X ₁ represents CH ₃ SCH ₂ CH ₂ , CH ₃ SOCH ₂ CH ₂ or (CH ₃ ) ₂ CHCH ₂ , X ₂ represents H, CH ₃ or CF ₃ , X ₃ represents H, CH ₃ , C ₂ H ₅ or CF ₃ , R ₁ , R ₂ , R ₄ or R ₅ represents H, 1 to alkyl having 12 carbon atoms, one of alkyloxy, alkenyl or alkynyl residues, represents no aryl or heteroaryl residues, or nothing, R ₃ represents H, a ^- represents an anion , All R or-(CH ₂ ) _n -groups are branched or linear.
[5] Use of the compound of the above-mentioned [4] for the manufacture of a medicament for treating pain derived from toothache, headache, inflammation, fever, cancer, dysmenorrhea or acute migraine.
[6] A compound represented by the structure 3-C of the following formula.

In the formula, R ₁ or R ₂ represents H, an alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, an aryl or heteroaryl residue or nothing. ₃ represents H or CH ₃ , A ⁻ represents an anion, and all R groups are branched or linear.
[7] Use of the compound of the above-mentioned [6] for the manufacture of a medicament for treating pain derived from toothache, headache, inflammation, fever, cancer, dysmenorrhea or acute migraine.
[8] A compound represented by the structure 4-C of the following formula.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9 or 10, aryl or heteroaryl Represents a residue, and X ₄ , X ₅ , X ₆ , X ₇ , X ₈ or X ₉ represents CO, SO ₂ , PO (OR), NO or nothing, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ is H, O, alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, aryl or heteroaryl indicates no residue, or nothing, R ₃ represents H, Ar represents an aryl or heteroaryl residue, a ^- represents an anion, all R, or - (CH _{2) n} - group Is branched or linear.
[9] Use of the compound of the above-mentioned [8] for the manufacture of a medicament for treating male erectile dysfunction, female sexual dysfunction or skin disease.
[10] The use according to [9] above, wherein the skin disease is albinism.
[11] A method for preparing a cyclopeptide represented by structure 4-C according to the above-mentioned [8], wherein the peptide chain is synthesized by a standard peptide synthesis protocol, and the side chain of lysine is 2-, or A method in which the 4-Pyoc protecting group is used and cyclization of the peptide is carried out on a resin.
[12] A glaucoma, ocular hypertension, male erectile dysfunction, female sexual dysfunction, systemic blood pressure, abortion, in a human or animal comprising the compound represented by the structure 1 according to the above [1] as an active ingredient A pharmaceutical composition for treating a condition treatable by a peptide selected from the group consisting of antihypertensive control, suppression of platelet aggregation, lung disease, digestive disease, inflammation, shock, fertility, fertility and obesity.
[13] The pharmaceutical composition of the above-mentioned [12], which is orally or transdermally administered.
[14] The pharmaceutical composition of the above-mentioned [12], which is transdermally administered to the body part in the form of a solution, spray, lotion, ointment, emulsion or gel.
[15] glaucoma, hypertonia, male erectile dysfunction, female sexual dysfunction, systemic blood pressure, abortion, antihypertensive control, suppression of platelet aggregation, suppression of platelet aggregation, lung disease, digestive disease, inflammation, shock, reproduction in humans or animals [15] From the matrix layer and the impermeable support layer containing the compound represented by the structure 1 described in the above [1], for treating a peptide-treatable condition selected from the group consisting of Transdermal therapeutic application system characterized by becoming.
[16] The transdermal therapeutic application system according to [15] above, which is a bandage or a patch.
[17] The transdermal therapeutic application system according to [15] above, which is an active substance storage and has a permeable bottom facing the skin.
[18] In the structures 1, 2-C, 3-C or 4-C, R _n , R _x1 , R _x2 , R _x3 , R _x4 , R _xn , R, R ₁ , R ₂ , R ₄ , R ₅ , R ₆ , R ₇ , R ₈ or R ₉ contains a C, H, O, S or N atom, or has a single bond, a double bond or a triple bond, as described in the above [1], [A] 4], the compound as described in [6] or [8].
[19] In the structures 1, 2-C, 3-C or 4-C, the CH ₂ group is substituted with O, S or NH, the above [1], [4], [6] or [8] The compound as described in.
[20] The structure according to the above [1], [4], [6] or [8], wherein the amino acid is in L-form or D-form in the structures 1, 2-C, 3-C or 4-C. Compound.
[21] The compound according to the above [1], [4], [6] or [8], wherein the anion is Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , or citrate.
Another aspect of the present invention may be as follows.
[1 '] a compound represented by structure 2-C of the following formula.

In the formula, R represents a branched or straight chain, - (CH _{2) n} - is a by n = 0,1,2,3,4,5,6,7,8,9,10 ..., aryl or heteroaryl Represents an aryl residue, X represents CO, SO, SO ₂ or nothing, X ₁ represents CH ₃ SCH ₂ CH ₂ , CH ₃ SOCH ₂ CH ₂ or (CH ₃ ) ₂ CHCH ₂ , X ₂ represents H, CH ₃ or CF ₃ , X ₃ represents H, CH ₃ , C ₂ H ₅ or CF ₃ , R ₁ , R ₂ , R ₃ , R ₄ or R ₅ represents H indicates that no alkyl, alkyloxy, any one alkenyl or alkynyl residue, aryl or heteroaryl residues, or anything having 1 to 12 carbon atoms, a ^- represents an anion, n = 0 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ..., all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or straight It is a chain.
[2 ′] amino acid is L-type or D-type, or R, R ₁ , R ₂ , R ₃ , R ₄ or R ₅ contains a C, H, O, S or N atom, or Or a compound according to the above [1 ′], having a single bond, a double bond or a triple bond, or wherein a CH ₂ group is substituted with O, S or NH.
[3 ′] The compound according to the above [1 ′], wherein the anion is Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , or citrate.
[4 '] for the manufacture of a medicament for treating pain derived from at least one disease selected from toothache, headache, inflammation, fever, cancer, dysmenorrhea, and acute migraine; Use of a compound described in '].
[5 '] A compound represented by structure 3-C of the following formula.

In the formula, R ₁ or R ₂ represents H, an alkyl having 1 to 12 carbon atoms, any one of alkyloxy, alkenyl or alkynyl residues, an aryl or heteroaryl residue or nothing. ₃ represents H or CH _3, a ^- represents an anion, a n = 0,1,2,3,4,5,6,7,8,9,10 ..., all R, - ( CH ₂ ) _n- or-(CH ₂ ) _m -group is branched or linear.
[6 ′] amino acid is L-form or D-form, or R ₁ , R ₂ or R ₃ contains C, H, O, S or N atom, or single bond, double bond or The compound according to the above [5 '], which has a triple bond or in which a CH ₂ group is substituted with O, S or NH.
[7 ′] The compound according to the above [5 ′], wherein the anion is Cl ⁻ , Br ⁻ , F ⁻ , I ⁻ , AcO ⁻ , or citrate.
[8 '] for the manufacture of a medicament for treating pain derived from at least one disease selected from toothache, headache, inflammation, fever, cancer, dysmenorrhea, and acute migraine, [5] Use of a compound described in '].
[9 '] for use in the treatment of a peptide-treatable condition in humans or animals for oral or transdermal administration, as described in [1'] to [3 '] and [5'] to [7 '] The composition containing the compound as described in any one term, or the compound as described in any one of said [1 ']-[3'] and [5 ']-[7'] as an active ingredient.
[10 '] A compound according to any one of the above [1'] to [3 '] and [5'] to [7 '] for use in the treatment of a peptide-treatable condition in humans or animals Or a composition comprising the compound according to any one of the above [1 '] to [3'] and [5 '] to [7'] as an active ingredient, wherein the compound or the composition is a solution Said compound or said composition, which is in the form of a spray, a lotion, an ointment, an emulsion or a gel.
[11 '] A transdermal therapeutic application system for use in the treatment of peptide-treatable conditions in humans or animals, comprising the above-mentioned [1'] to [3 '] and [5'] to [7 '] A compound according to any one of the above, or a composition comprising as an active ingredient the compound according to any one of the above [1 '] to [3'] and [5 '] to [7'] system.
[12 '] The system according to the above [11'], which is a bandage or patch consisting of an active substance-containing matrix layer and an impermeable support layer.
[13 '] The system according to the above [11'] or [12 '], which comprises an active substance storage having a permeable bottom facing the skin.
[14 '] Control means to control the rate of release and allow the peptide and related compounds to constantly reach optimal therapeutic blood levels, increase efficacy and reduce side effects of the peptide and related compounds The system according to any one of the above [11 '] to [13'], further comprising
[15 '] At least one prodrug selected from the following structure 2, structure 3, structure 4, structure 7, structure 8, structure 9, and structure 10.

Claims (3)

At least one compound selected from the following structure 3, structure 4, structure 7, structure 9 and structure 10.

  A composition comprising, as an active ingredient, at least one compound according to claim 1 for use in the treatment of peptide-treatable conditions.   The composition according to claim 2, which is administered transdermally in the form of a solution, spray, lotion, ointment, emulsion or gel.

Images