JP6980874B2 - Transdermal delivery system for peptides and related compounds - Google Patents

Description

The present invention relates to transdermal delivery systems for peptides and related compounds by transferring the peptides to positively charged water-soluble prodrugs, and for treating conditions treatable by the peptides and related compounds in humans or animals. Regarding pharmaceutical use. More specifically, the present invention is to allow rapid penetration of peptides and related compounds so that they can be transdermally administered.

All peptides are polymers and the monomers that bind to form polymers are amino acids. 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 a huge variety of roles in all living organisms. Peptide hormones are the largest group of hormones. The number of peptide hormones identified and synthesized continues to grow. They have an interesting role in the process of controlling life. When one nanogram of thyrotropin releasing hormone (hyrotropin-releasing hormone) is injected into mice, increase the uptake of iodide into the thyroid from the blood (RL Kisliuk, Principles of Medicinal Chemistry , 4 th Ed., Etc. WO Foye, Eds., Williams & Wilkins, 4 th Ed. 1995, p.606). Tuftsin (Thr-Lys-Pro-Arg) stimulates phagocytosis and promotes antibody-dependent cytotoxicity (VA Najjar, Mol. Cell. Biochem. 41. 1, 1981), brain and Met-enkephalin (Tyr-Gly-Gly-Phe-Met) isolated from the small intestine acts like morphine in that it binds to the same receptor and has an analgesic effect (JR Jaffe and WR Martin). , in Pharmacological Basis of Therapeutics, AG Gilman, etc., 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) 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) Etc., Annu. Rev. Biochem., 47, 89, 1978), Dynorfin (MG Weisskopf et al., Nature, 362, 423, 1993), Endoserin (AM Doherty, J. Med. Chem., 35, 1493, 1992). , Secretin (E. Jorper, Gastroenterology, 55, 157, 1968), Calcitonin (MVL Ray, etc., Biotechnology, 11, 64, 1993), Insulin (F. Sanger, Br. Med. Bull., 16. 183, 1960) , And many others are peptides with estimated structures, which are used for the treatment of many diseases.

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

An alternative method of drug administration is local delivery. Topical drug delivery has several advantages. This method helps to avoid drug inactivation caused by first-pass metabolism in the liver and gastrointestinal tract. It may provide local delivery of the appropriate concentration of drug to the intended site of action without systemic exposure. Fishman (Fishman; Robert, US Pat. No. 7,052,715) noted additional challenges associated with oral drug treatment. That is, the concentration level that must be achieved in the bloodstream must be significant in order to effectively treat the painful or inflamed end. These levels are often much higher than those required if it is possible to accurately target a particular site of pain or injury. _{Yeager attempted to use an osmotic 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 that is present in protonated form at physiological pH. They found that prodrugs (TSBH) diffuse through human skin ~ 60 times faster than the drug (TS) itself [Susan Milosovich et al., J. Pharm. Sci., 82, 227 (1993)].

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

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 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 _{n 1} represents H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , where R _n is the aliphatic side chain of the amino acid, the hydroxyl- or sulfur-containing side chain of the amino acid, the amino acid. Any one of the aromatic side chains of amino acids, amino, imidazolyl, or quanidino group-containing side chains, or the carboxyl or carboxamide group-containing side chains of amino acids, H, alkyl, alkyl having 1-12 carbon atoms. oxy, any one alkenyl or alkynyl 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, alkyl Any one of oxy, alkenyl or alkynyl residues, aryl or heteroaryl residue, or the following groups,

Or nothing, R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn is an H, O, alkyl, alkyloxy, alkenyl, or alkynyl residue with 1-12 carbon atoms. 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 ..., and all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched chains or It is linear and may contain C, H, O, S, or N atoms and may have single, double, and triple bonds. Any CH ₂ group may be substituted with O, S or NH. One or more amino acid residues in the sequence are replaced with unnatural amino acids such as β-amino acid, 2-naphthylalanine, and any one of alkyl, alkyloxy, alkenyl or alkynyl, aryl or heteroaryl residue. obtain. The amino and carboxyl functional groups of the amino acids on the peptide chain may form a lactam bridge to form a homodetic cyclic peptide. 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. 1. Prodrugs are primary, secondary or tertiary amine groups, quanidino groups, or monoprotected quanidino groups (hydrophilic) that are present in lipophilic moieties and in protonated form at physiological pH. Must have a sex part). 2. 2. All prodrugs of the peptide have only one or two (preferably one) primary, secondary or tertiary amine groups, quanidino groups, which are present in protonated form at physiological pH. Or one should have a protected quanidino group (hydrophilic moiety). 3. 3. The primary, secondary or tertiary amine group, quanidino group, or one protected quanidino group can be the N-terminal, C-terminal, or side chain of the peptide. The N-terminal or C-terminal portion is preferable. 4. To make the peptide lipophilic, carboxyl groups, amino groups, guanidine groups or other hydrophilic groups can be protected with alkyl, aryl, or heteroaryl esters or amide groups.

The following are examples of these prodrugs.

In the formula, R is H, a branched chain or a straight chain,-(CH ₂ ) _n- , and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., Represents an aryl or heteroaryl residue, where 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 are any of alkyl, alkyloxy, alkenyl or alkynyl residues having H, O, 1-12 carbon atoms. one, 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 where Ar represents a phenyl, 2'-naphthyl, 4-iodophenyl, or other aryl or heteroaryl residue, all R,-(CH _2). ) _n -or-(CH ₂ ) _m -groups are branched or linear, may contain C, H, O, S, or N atoms and have single, double, and triple bonds. Either CH ₂ group may be substituted with O, S or NH.

Drug absorption requires the drug to pass across the barrier membrane in molecular form, whether from the gastrointestinal tract or elsewhere. The drug must first dissolve, and if the drug has the desired biopharmaceutical properties, it crosses the membrane from the high concentration region to the low concentration region, blood circulation or the body. Will enter the cycle. All biological membranes contain lipids as a major constituent. Molecules that play a major role in membrane formation all have a phosphate-containing head group, often with two highly hydrophobic hydrocarbon tails. The membrane is a bimolecular membrane, the two hydrophilic head groups facing outward to the aqueous regions on either side. Very hydrophilic drugs (most peptides) cannot cross the hydrophobic layer of the membrane, and very hydrophobic drugs stay in the hydrophobic layer as part of the membrane due to their similarity, it. Therefore, it will not be possible to efficiently enter the inner cytoplasmic sol.

An object of the present invention is to allow 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 have two structural features in common. That is, they are formed by (using a lipophilic alcohol to protect the carboxyl group and using a lipophilic acid to protect an amino, hydroxyl, or guanidine group, or other hydrophilic group of the peptide. (Possible) lipophilic moieties, and primary, secondary or tertiary amine groups, quanidino groups, or one protected quanidino groups (hydrophilic moieties) that are present in a protonated form at physiological pH. have. Such a hydrophilic lipophilic balance is required for efficient passage through the membrane barrier [Susan Milosovich et al., J. Pharm. Sci., 82, 227 (1993)]. Positively charged amino groups greatly increase the solubility of the drug, and the lipophilic moiety will help the prodrug enter the lipophilic membrane and skin barrier. These novel prodrugs will dissolve immediately 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 combine with the negative charge on the phosphate head group of the membrane. Therefore, the local concentration on the outside of the membrane will be very high, facilitating the passage of these prodrugs from the high concentration region to the low concentration region. 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.

Penetration of some prodrugs through human skin was measured in vitro using modified Franz cells. Modified Franz cells were isolated from human skin tissue (thickness 360-400 μm) in the anterior and posterior thighs. The receiving fluid consisted of 2 ml of 2% bovine serum albumin in physiological saline and stirred at 600 rpm. Cumulative amounts of these prodrugs and their parent drugs that penetrate the skin over time were measured by specific high performance liquid chromatography. Results obtained using a donor consisting of a 10% solution of some prodrug and peptide in 2 mL of pH 7.4 phosphate buffer (0.2 M) are shown in FIG. 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 that diffuses through human skin} 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 explicit flow velocity values of 0.52 mg, 0.55 mg, 0.46 mg, 0.34 mg, 0.50 mg, 0.60 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 results show that the positive charge on the dialkylaminoethyl group has a very important role in the passage of the drug across the membrane or skin barrier.

A good prodrug should change quickly in plasma and return to the drug itself. The peptide prodrug in the present invention can change very quickly in human plasma in good yield to return to the parent peptide. In 1 ml of whole blood, 120 mg of Ac-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HC was incubated at 37 ° C. for 30 minutes. 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% Ac-Tyr-Gly-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _2. HC1, 8% Ac-Tyr-Gly-Gly-Phe-Met-OH, 60% H-Tyr-Gly-Gly-Phe-Met-OH, 27% Other by-products (amino acids, dipeptides, tripeptides, tetrapeptides) were observed. 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 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 , 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% other by-products were observed. Cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OCH ₂ CH ₂ N (CH ₂ CH _{3 ) 2.} 4% cyclo (1) to HCl , 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 by-products were observed. The results show that most of the peptide prodrugs are altered back to the parent peptide, and thus the transdermal delivery system of the peptide is successful.

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 terminal of the later procolipase and belongs to the family of intestinal-brain peptides. They may be used to regulate fat intake and for the treatment of obesity (Erlanson-Albertsson C, York D, Obes. Rev. 1997 Jul; 5 (4): 360-72 and Sorhe de M, Mei J, Erlanson. -Albertsson C., J Physiol. 87: 273-275, 1993). Intraperitoneal administration of H-Val-Pro-Asp-Pro-Arg-OH to overnight starved Osborne-Mendel rats resulted in a dose-dependent reduction in food intake. This suppression of feeding was observed when rats were fed a high-fat diet, but not in rats fed a high-carbohydrate, low-fat diet (Physiol Behav., 1991, such as Okada S.). Jun; 49 (6): 1185-9). At the beginning of the dark-onset feeding time, 5 mg / kg of Ac-Val-Pro-Asp (OEt)-Pro-Arg (diAc)-in 0.5 ml of water applied to the rat back. OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .HCl was transdermally administered to rats (n = 5) (n = 5 respectively) given food and fed overnight fasted rats and occasional food. 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 Palatin's (AMEX: PTN) new drug candidate for the treatment of male and female sexual dysfunction. First of all, in a novel classification of treatments 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 in doing so. Melanocortin II acts through mechanisms related to the central nervous system rather than directly related to the vascular system. As a result, it may offer significant safety and efficacy advantages over currently available products. The novel prodrugs of the 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 women. It may provide a method of enhancing sexual stimulation. 2 mg / kg cyclo (1,6) -Ac-Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OCH ₂ CH _{2 in 0.2 ml of pH 7.0 phosphate buffer (0.1 M)} 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 backs of male rats (30 animals) once a day for 5 days. As a result, rats given Peptide A or Peptide B showed a 5-fold increase in peptide A and a 6-fold increase in peptide B and mating in solicitation compared to rats not given it. Both Peptide A and Peptide B showed a 3-fold increase in. In 0.2 ml of pH 7.0 phosphate buffer (0.1 M), 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 backs of both male and female rats (30) once daily for 5 days, the result is Peptide A or Peptide B. Rats given the were shown a 6-fold increase in solicitation and a 5-fold increase in mating compared to rats not given it.

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, etc. exert a morphine-like analgesic effect. The number of writhing that occurred when the acetic acid solution was administered intraperitoneally to the mice was counted, and the suppression 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 (10 mg / kg, C), and HCl. H-Tyr (Ac) -D-Ala-Gly-Phe-Met (O) -OL (10 mg) / Kg, D) was transdermally administered to the neck of the mouse 30 minutes before administration of the tyrosine solution. Group A is a control group. The results are shown in Table 1.
Table 1. Rising inhibition rate by prodrugs of enkephalin and related compounds

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

Peptides and related compounds are very hydrophilic and cannot penetrate the skin barrier. When the peptide is taken orally, the peptide and related compounds are rapidly proteolytically degraded in the gastrointestinal tract by proteolytic enzymes in minutes. In the case of injection, administration of the peptide is painful and often requires frequent and costly visits to treat chronic symptoms. When the peptide prodrugs are applied topically to the skin, they will dissolve immediately in the skin's waters. The positive charge on the amino groups of these prodrugs will combine with the negative charge on the phosphate heads of the skin membrane. Therefore, the local concentration on the outside of the membrane will be very high, facilitating the passage of these prodrugs from the high concentration region to the low concentration region. When these prodrugs enter the membrane, the hydrophilic moiety will push the prodrug into the cytosol.

The compound represented by structure 1 can be prepared by a standard peptide synthesis protocol. In the preparation of cyclopeptides and related compounds represented by structure 4-C, peptide chains can be synthesized by standard peptide synthesis protocols, and the side chains of lysine are protected by 2- or 4-Pyoc protecting groups and peptides. The cyclization was performed on the resin.

The prodrugs of these peptides and related compounds in the present invention have lipophilic and hydrophilic moieties (amine groups present in protonated form at physiological pH). The positively charged amino groups of these prodrugs have two excellent advantages. First, the prodrug is dissolved in water. That is, when these novel prodrugs are transdermally administered in dosage forms such as liquids, sprays, lotions, ointments, emulsions or gels, they are immediately skin, eye, genital, mouth, nose, or. Will mix with water in other parts of the body. Second, the positive charges on the amino groups of these prodrugs will combine with the negative charges on the phosphate head groups of the membrane. Therefore, the local concentration on the outside of the membrane will be very high, facilitating the passage of these prodrugs from the high concentration region to the low concentration region. The lipophilic portion of the prodrug (by modifying the polar group with a lipophilic alkyl group) 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 a short residue on the skin, eyes, genitals, mouth, nose, or other parts of the body, prodrugs itch and tingle on the skin, eyes, genitals, mouth, nose, or other parts of the body. Or will not cause pain. Experimental results show that over 40% of the prodrug changed in minutes and returned to the parent peptide. Prodrugs can even easily penetrate the blood-brain barrier. Transdermal delivery systems for peptides and related compounds may allow peptide hormones to be used pharmaceuticalally. Another major advantage of transdermal administration of these prodrugs is that they will be easier to administer, especially to children.

Crossing isolated human skin tissue at Franz cells (n = 5), 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 -The _{cumulative amount 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 _{n 1} represents H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , where R _n is the aliphatic side chain of the amino acid, the hydroxyl- or sulfur-containing side chain of the amino acid, the amino acid. Aromatic side chains of amino acids, amino, imidazolyl, or quanidino group-containing side chains, or carboxyl or carboxamide group-containing side chains of amino acids, alkyl, alkyloxy, alkenyl or alkynyl having 1-12 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 or alkynyl Any one of the residues, aryl or heteroaryl residue, R _x3 R _x4 R _x5 N ⁺ A ^- 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 Cl ^{-, br -, F -, I -} , AcO -, citrate, or represents any anion, n = 0,1,2,3,4,5,6,7,8,9,10 ... a and all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or linear and may contain C, H, O, S, or N atoms, single bond, double. It may have a bond and a triple bond. Any CH ₂ group may be substituted with O, S or NH. One or more amino acid residues in the sequence are replaced with unnatural amino acids such as β-amino acid, 2-naphthylalanine, and any one of alkyl, alkyloxy, alkenyl or alkynyl, aryl or heteroaryl residue. obtain. The amino and carboxyl functional groups of the amino acids on the peptide chain may form lactam bridges to form homodetic cyclic peptides. The thiol groups of cysteine, homecysteine, or other amino acids may form disulfide bridges to form heterodetic cyclic peptides.

(Best form)
Ac-Val-Pro-Asp (OEt) -Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _2. Preparation of HCl 1. Preparation of H-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂
30.8 g of Z-Arg-OH was dissolved in 500 ml of acetone. 200 ml of 20% NaOH was added to the reaction mixture. 40 g of acetic anhydride was added drop by drop 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 x 100 ml). The ethyl acetate layer was dried over sodium sulfate. The ethyl acetate solution was evaporated and dried. The residue (Z-Arg (diAc) -OH, 30 g) was dissolved in 300 ml of acetonitrile. The mixture was cooled to 0 ° C. in 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 at 0 ° C. for 1 hour and at room temperature overnight. The solids were removed by filtration and the solution was evaporated to dryness. The residue was extracted with ethyl acetate (2 x 250 ml). The ethyl acetate solution was washed with 5% sodium bicarbonate (1 x 500 ml) and water (3 x 100 ml). The ethyl acetate solution was dried over sodium sulfate. Evaporate the solution and dry. The residue [Z-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ , 28 g] was dissolved in 300 ml of methanol. 10% Pd / C 2g was added to the solution. The mixture was stirred under hydrogen at room temperature for 10 hours. Pd / C was removed by filtration. The solution was evaporated and dried. To obtain a _{H-Arg (diAc) -OCH 2} CH 2 N (CH 2 CH 3) 2 22g.

2. 2. Preparation of Boc-Asp (OEt) -Pro-OSu
15 g of L-proline was 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 x 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-cooled 3NHCl. The ethyl acetate layer was collected and washed with water (3 x 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 25 g of the residue (Boc-Asp (OEt) -Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 ml of dichloromethlene. 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 dichloromethane solution was washed with 5% sodium bicarbonate (1 x 200 ml) and water (3 x 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 28 g of Boc-Asp (OEt) -Pro-OSu was obtained.

3. 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 was added to the mixture. The ethyl acetate solution was washed with water (3 x 100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. The residue was dissolved in 250 ml of dichloromethane. 250 ml of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated and dried. 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 was dissolved in 300 ml of 10% sodium bicarbonate. 150 ml of acetone and 26 g of Ac-VaI-OSu were added to the reaction mixture. The mixture was stirred at room temperature for 5 hours. The mixture was washed with ether (1 x 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-cooled 3NHCl. The ethyl acetate layer was collected and washed with water (3 x 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 20 g of 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 dichloromethane solution was washed with 5% sodium bicarbonate (1 x 200 ml) and water (3 x 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 20 g of Ac-Val-Pro-OSu was obtained.

5. Preparation of Ac-Val-Pro-Asp (OEt) -Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _{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 was added to the mixture. The organic layer is washed with water (3 x 100 ml). The ethyl acetate layer was dried over sodium sulfate. Remove sodium sulfate by filtration. Add 3.5 g of HCl gas in dioxane (50 ml) to the solution. The solids are collected and washed with ether (3 x 50 ml). After drying, 20 g of the desired hygroscopic product was obtained. Solubility in water: 150 mg / ml, Elemental analysis: C ₃₉ H ₆₆ ClN ₉ O ₁₁ , Molecular weight: 872.45, Calculated% 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 invention)
Ac-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _2. Preparation of HCl 1. 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 dichloromethane. The mixture was cooled to 0 ° C. in 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 at 0 ° C. for 1 hour and at room temperature overnight. The solids were removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 500 ml) and water (3 x 100 ml). The ethyl acetate solution was dried over sodium sulfate. Evaporate the solution and dry. The residue [Boc-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ , 30 g] was dissolved in 250 ml of dichloromethane. Add 250 ml of trifluoroacetic acid to the mixture and stir the mixture for 30 minutes. The solution was evaporated and dried. H-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .TFA 26 g was obtained.

2. 2. Preparation of Boc-Gly-Phe-OSu
20 g of L-Phenylalanine was 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 x 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-cooled 3NHCl. The ethyl acetate layer was collected and washed with water (3 x 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 22 g of the residue (Boc-Gly-Phe-OH) and 10 g of N-hydroxysuccinimide were dissolved in 300 ml of 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 dichloromethane solution is washed with 5% sodium bicarbonate (1 x 200 ml) and water (3 x 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 25 g of Boc-Gly-Phe-OSu was obtained.

3. 3. Preparation of H-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _{2 .TFA}
H-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .TFA 25 g was dissolved in 300 ml of 5% NaHCO _3. 22 g of Boc-Gly-Phe-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 was added to the mixture. The ethyl acetate solution was washed with water (3 x 100 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. The residue was dissolved in 250 ml of dichloromethane. 200 ml of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated and dried. H-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .TFA 25 g 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 x 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-cooled 3NHCl. The ethyl acetate layer was collected and washed with water (3 x 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 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 dichloromethane solution is washed with 5% sodium bicarbonate (1 x 200 ml) and water (3 x 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 20 g of Ac-Tyr (Ac) -Gly-OSu was obtained.

5. Preparation of Ac-Tyr (Ac) -Gly-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _{2. HCl}
H-Gly-Phe-Met-OCH ₂ CH ₂ N (CH ₂ CH ₃ ) ₂ .TFA 24 g was dissolved in 300 ml of 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 was added to the mixture. The organic layer is washed with water (3 x 100 ml). The ethyl acetate layer was dried over sodium sulfate. Remove sodium sulfate by filtration. Add 3.5 g of HCl gas in dioxane (50 ml) to the solution. The solids are collected and washed with ether (3 x 50 ml). After drying, 18 g of the desired hygroscopic product was obtained. Solubility in water: 200 mg / ml, Elemental analysis: C ₃₇ H ₅₃ ClN ₆ O ₉ S, Molecular weight: 793.37, Calculated% C: 56.01; H: 6.73; Cl: 4.47; N: 10.59; O: 18.15; S : 4.04, measured% C: 55.96; 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.

Ac-Val-Pro-Gly-Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _2. Preparation of HCl 1. Preparation of Boc-Gly-Pro-OSu
15 g of L-proline was 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 x 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-cooled 3NHCl. The ethyl acetate layer was collected and washed with water (3 x 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 21 g of residue (Boc-Gly-Pro-OH) and 11 g of N-hydroxysuccinimide were dissolved in 300 ml of 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 dichloromethane solution is washed with 5% sodium bicarbonate (1 x 200 ml) and water (3 x 200 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. Boc-Gly-Pro-OSu 23g was obtained.

2. 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 was added to the mixture. The ethyl acetate solution was washed with water (3 x 100 ml). The organic solution was dried over sodium sulfate. Remove sodium sulfate by filtration. The solution was evaporated and dried. The residue was dissolved in 250 ml of dichloromethane. 250 ml of trifluoroacetic acid was added to the mixture and the mixture was stirred for 30 minutes. The mixture was evaporated and dried. It was obtained H-Gly-Pro-Arg ( diAc) -OCH 2 CH 2 N (CH 2 CH 3) 2 .2TFA28g.

3. 3. Preparation of Ac-Val-Pro-Gly-Pro-Arg (diAc) -OCH ₂ CH ₂ N (CH ₂ CH ₃ ) _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 was added to the mixture. The organic layer is washed with water (3 x 100 ml). The ethyl acetate layer was dried over sodium sulfate. Remove sodium sulfate by filtration. Add 3.5 g of HCl gas in dioxane (50 ml) to the solution. The solids were collected and washed with ether (3 x 50 ml). After drying, 18 g of the desired hygroscopic product was obtained. Solubility in water: 150 mg / ml, Elemental analysis: C ₃₅ H ₆₀ ClN ₉ O ₉ , Molecular weight: 786.36, Calculated% C: 53.46; H: 7.69; Cl: 4.51; N: 16.03; O: 18.31, Measured% 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 1. 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 x 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-cooled 3NHCl. The ethyl acetate layer was collected and washed with water (3 x 300 ml). The organic solution was dried over sodium sulfate. The solution was evaporated and dried. 42 g of Ac-Nle-Asp (OFm) -OH was obtained.

2. 2. Preparation of Fmoc-Trp-Lys (4-Pyoc) -OH
References to H-Lys (4-Pyoc) -OH (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 was 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 x 500 ml). Add 500 ml of ethyl acetate to the mixture and adjust the pH of the mixture to 2.2-2.3 with ice-cooled 3NHCl. The ethyl acetate layer was collected and washed with water. The organic solution was dried over sodium sulfate. The organic solution was evaporated and dried. Fmoc-Trp-Lys (4-Pyoc) -OH 55g was obtained.

3. 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. Fmoc-Trp-Lys (4-Pyoc) -OH 50 g, 1-hydroxybenzotriazole 13 g, 4-dimethylaminopyridine 2 g, and N, N'-diisopropylcarbodiimide 12 g. The mixture was stirred at room temperature overnight. The resin was collected by filtration and washed with DMF (3 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). DMF 700 ml, Fmoc-Arg (diAc) -OH 48 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazole-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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). DMF 700 ml, Fmoc-Phe-OH 39 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluronium 38 g as resin added. The mixture was stirred at room temperature for 2 hours. The resin was collected by filtration and washed with DMF (3 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). DMF 700 ml, Fmoc-His (Fmoc) -OH 60 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazole-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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). DMF 700 ml, Ac-Nle-Asp (OFm) -OH 60 g, 1-hydroxybenzotriazole 13 g, triethylamine 35 ml, and O- (benzotriazole-1-yl) -N, N, N', N'-tetramethyluro 38 g of nium 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). The peptide (peptided) resin was suspended in 700 ml of 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). 700 ml of DMF, 13 g of 1-hydroxybenzotriazole, 35 ml of triethylamine, and 38 g of O- (benzotriazole-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 x 400 ml), methanol (3 x 400 ml), and dichloromethylene (3 x 400 ml). 500 ml of trifluoroacetic acid was 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 dry. The residue was washed with ether (3 x 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. Preparation of HCl Cyclo (1,6) -Ac -Nle-Asp-His-Phe-Arg (diAc) -Trp-Lys-OH 10 g was dissolved in 300 ml of DMF. The mixture was cooled to 0 ° C. in 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 at 0 ° C. for 1 hour and at room temperature overnight. The solids were removed by filtration and the dichloromethylene solution was washed with 5% sodium bicarbonate (1 x 500 ml) and water (3 x 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 solids were collected and washed with ether (3 x 30 ml). 8 g of product was obtained.

The prodrug represented by structure 1 can easily penetrate the skin membrane. Transdermal delivery systems for peptides and related compounds provide for many diseases in humans or animals, such as pain, fever, erectile dysfunction in men, sexual dysfunction in women, systemic blood pressure, hypotension, resulting from rheumatoid arthritis and osteoarthritis. Peptide hormones can be useful in the treatment of hypotensive control, suppression of platelet aggregation, lung disease, digestive disorders, inflammation, shock, reproduction, fertility and the like.

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 aspects of the present invention, for example, there are the following.
1. 1. It is a compound represented by the structure 1 of the following formula, and 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 _{n 1} represents H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , where R _n is the aliphatic side chain of the amino acid, the hydroxyl or sulfur-containing side chain of the amino acid, or the amino acid. Aromatic side chains, amino acid amino, imidazolyl, or quanidino group-containing side chains, or any one of the amino acid carboxyl or carboxamide group-containing side chains, alkyl, alkyloxy, alkenyl, or alkynyl residues with 1-12 carbon atoms. One of the groups, an aryl or heteroaryl residue, or none, where Y _x1 , Y _x2 , or Y _n is H, an alkyl, alkyloxy, alkenyl or alkynyl residue with 1-12 carbon atoms. Any one of the groups, an aryl or heteroaryl residue, or the following group,

Or nothing, R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn is an alkyl, alkyloxy, alkenyl or alkynyl residue with H, O, 1-12 carbon atoms. 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 … And all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or linear compounds.
2. 2. In structure 1, R _n , R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn groups contain C, H, O, S, or N atoms, or single or double bonds. Alternatively, the compound according to 1 above, which has a triple bond.
3. 3. The compound according to 1 above, wherein the CH ₂ group is substituted with O, S or NH in the structure 1.
4. The compound according to 1 above, wherein the amino acid in the structure 1 is L-type or D-type.
5. 1 above, wherein in structure 1 one or more amino acid residues in the sequence are substituted with an unnatural amino acid or any one of alkyl, alkyloxy, alkenyl, alkynyl, aryl or heteroaryl residues. Compound.
6. The compound according to 1 above, wherein in the 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 1 above, wherein in the structure 1, the thiol group of the amino acid forms a disulfide bridge to form a heterodetic cyclic peptide.
8. The ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate compound according to claim 1.

9. A transdermal delivery composition of a prodrug of a peptide, wherein the prodrug is a primary, secondary or tertiary amine group, or a primary, secondary or tertiary amine group present in a protonated form at a lipophilic moiety and physiological pH. The primary, second, having a quanidino group or one protected quanidino group (hydrophilic moiety), said prodrug is present in only one or two, protonated form at physiological pH. A transdermal delivery composition comprising a tertiary or tertiary amine group, or a quanidino group or one protected quanidino group (hydrophilic moiety).
10. 9. The transdermal delivery composition according to 9 above, wherein the primary, secondary or tertiary amine group, quanidino group, or one protected quanidino group is the N-terminal, C-terminal, or side chain of the peptide. thing.
11. 9. Percutaneous according to 9 above, wherein the carboxyl group, amino group, guanidine group or other hydrophilic group is protected with an alkyl, aryl, or heteroaryl ester, or amide group in order to make the peptide oil-friendly. 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. A compound represented by the following structure 2-C.

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 Heteroaryl residues, where X stands for CO, SO, SO ₂ , or nothing, where X ₁ stands for CH ₃ SCH ₂ CH ₂ , CH ₃ SOCH ₂ CH ₂ , or (CH ₃ ) ₂ CHCH ₂ . Represents X ₂ for H, CH ₃ or CF ₃ , X ₃ for H, CH ₃ , C ₂ H ₅ , or CF ₃ , and R ₁ , R ₂ , R ₃ , R ₄ , or R ₅ 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 ... and all R, R n} ,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are minutes. It is a branched chain or a straight chain.
13. In the structure 2-C, or the amino acid is L- type or the _{D-, R, R 1, R 2} , R 3, R 4, or R ₅ groups are C, H, O, S, or N atoms 12. The compound according to 12 above, which comprises, has a single bond, a double bond or a triple bond, or has _two CH groups substituted with O, S or NH.
14. The ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate The compound according to above 12.
15. Use of the compounds according to 12 above for the manufacture of agents for the treatment of pain resulting 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. A compound represented by the following structure 3-C.

In the formula, R ₁ or R ₂ represents H, any one of alkyl, alkyloxy, alkenyl or alkynyl residues having 1-12 carbon atoms, aryl or heteroaryl residue, or none. ₃ represents H or CH ₃ , A ⁻ represents an anion, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, ..., And all R, R _n ,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or straight.
17. In the structure 3-C, or the amino acid is L- type or the D-, R _1, R _2, or R ₃ groups include C, H, O, S, or N atoms, or a single bond, a 16. The compound according to 16 above, which has a double bond or a triple bond, or has _{two CH groups substituted with O, S or NH.}
18. The ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate, the compound according to the above 16.
19. Use of the compounds according to 16 above for the manufacture of agents for the treatment of pain resulting 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. A compound represented by the following structure 4-C.

In the formula, R is a branched or straight chain,-(CH ₂ ) _n- , and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., Aryl or hetero. Represents an aryl residue, where 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 any one of the alkyl, alkyloxy, alkenyl or alkynyl residues having H, O, 1-12 carbon atoms. Aryl or heteroaryl residue, or nothing, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., where Ar is an aryl or heteroaryl residue. And all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or linear.
21. In the structural 4-C, or the amino acid is L- type or the _{D-, R, R 1, R 2} , R 3, R 4, R 5, R 6, R 7, R 8, or R ₉ groups 20 above, wherein the C, H, O, S, or N atom is contained, or has a single bond, a double bond, or a triple bond, or the CH ₂ group is substituted with O, S, or NH. Compound.
22. The compound according to 20 above, wherein the Ar group is phenyl, 2'-naphthyl or 4-iodophenyl.
23. Use of the compounds according to 20 above for the manufacture of agents for treating erectile dysfunction in men, sexual dysfunction in women, or skin diseases.
24. 23. The use according to 23 above, 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. A compound represented by the following structure 5-C.

In the formula, R is a branched or straight chain,-(CH ₂ ) _n- , and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., Aryl or hetero. 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 group is a branched chain or a straight chain.
26. In structure 5-C, R, R ₁ , R ₂ , R ₃ , R ₄ , R ₅ , or R ₆ groups contain C, H, O, S, or N atoms, or are single-bonded or double-bonded. Alternatively, the compound according to 25 above, which has a triple bond or has _two CH groups substituted with O, S or NH.
27. The ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate, the compound according to the above 25.
28. Use of the compounds according to 25 above for the manufacture of agents for treating obesity.
29. The method for preparing a cyclopeptide represented by the structure 4-C according to 20 above, 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 peptide cyclization is carried out on a resin, protected by.

30. A pharmaceutical composition for treating a condition treatable by a peptide in a human or an animal, which comprises the compound represented by the structure 1 according to 1 above as an active ingredient.
31. 30. The pharmaceutical composition according to 30 above, which is orally or transdermally administered.
32. Conditions that can be treated with the peptide include glaucoma, ocular hypertension, erectile dysfunction in men, sexual dysfunction in women, systemic blood pressure, obesity, antihypertensive control, suppression of platelet aggregation, lung disease, digestive disorders, inflammation, shock, etc. 30. The pharmaceutical composition according to 30 above, which is selected from the group consisting of fertility, fertility, and obesity.
33. 30. The pharmaceutical composition according to 30 above, which is transdermally administered to a part of the body in the form of a solution, spray, lotion, ointment, emulsion or gel.
34. A transdermal therapeutic application system comprising a matrix layer containing a compound represented by the structure 1 according to 1 above and a non-permeable support layer for treating a peptide-treatable condition in humans or animals. ..
35. The transdermal therapeutic application system according to 34 above, which is a bandage or patch.
36. 34. The transdermal therapeutic application system according to 34 above, which is an active substance storage and has a permeable bottom surface 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. It is a compound represented by the structure 1 of the following formula, and 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 _{n 1} represents H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , where R _n is the aliphatic side chain of the amino acid, the hydroxyl- or sulfur-containing side chain of the amino acid, the amino acid. Aromatic side chains of amino acids, amino, imidazolyl, or quanidino group-containing side chains, or carboxyl or carboxamide group-containing side chains of amino acids, alkyl, alkyloxy, alkenyl or alkynyl having 1-12 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 or alkynyl Any one of the residues, an aryl or heteroaryl residue, or the following group,

Or nothing, R _x1 , R _x2 , R _x3 , R _x4 , R _x5 , or R _xn is an H, O, alkyl, alkyloxy, alkenyl, or alkynyl residue with 1-12 carbon atoms. 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 ..., and all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or direct. It is a chain and may contain a C, H, O, S, or N amino acid, may have a single bond, a double bond, and a triple bond, and the CH ₂ group is substituted with O, S or NH. Also, the amino acid may be L- or D-type, and one or more amino acid residues in the sequence are unnatural amino acids such as β-amino acids, 2-naphthylalanine, and alkyl, alkyloxy, alkenyl or alkynyl. Any one of these may be substituted with an aryl or heteroaryl residue, and the amino and carboxyl functional groups of the amino acids on the peptide chain may form a lactam bridge to form a homodetic cyclic peptide, cysteine, The thiol groups of homecysteine, or other amino acids, may form disulfide bridges to form heterodetic cyclic peptides.
2-2. In the design of transdermal delivery systems for peptides and related compounds, the principles for designing these prodrugs of peptides or related compounds are: Prodrugs are primary, secondary or tertiary amine groups, quanidino groups, or one protected quanidino groups (hydrophilic moieties) that are present in lipophilic moieties and in protonated form at physiological pH. Must have 2. All prodrugs of the peptide have only one or two (preferably one) primary, secondary or tertiary amine groups, quanidino groups, or groups present in protonated form at physiological pH. One should have a protected quanidino group (hydrophilic moiety). 3. 3. The primary, secondary or tertiary amine group, quanidino group, or one protected quanidino group can be the N-terminal, C-terminal, or side chain of the peptide, preferably the N-terminal or C-terminal moiety. 4. To make the peptide lipophilic, carboxyl groups, amino groups, guanidine groups or other hydrophilic groups can be protected with alkyl, aryl, or heteroaryl esters or amide 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 resulting from toothache, headache, arthritis, other inflammatory, fever, cancer, dysmenorrhea, and acute migraine.

In the formula, R is a branched or straight chain,-(CH ₂ ) _n- , and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., aryl or hetero. Represents an aryl residue, where X represents CO, SO, SO ₂ or nothing, where X ₁ represents CH ₃ SCH ₂ CH _2- , CH ₃ SOCH ₂ CH _2- , or (CH ₃ ) ₂ CHCH ₂ -, X ₂ stands for H, CH ₃ or CF ₃ , X ₃ stands for 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 represents any anion, n = 0,1,2,3,4,5,6,7,8,9,10 ... an and the amino acid is L Can be −-type or D-type, and all R, R _n ,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or linear, C, H, O, S. , Or may contain N atoms, may have a single bond, a double bond, and a triple bond, and the CH ₂ group may be substituted with O, S or NH.
4-2. Compounds represented by structure 3-C of the following formula, and their use for treating pain resulting from toothache, headache, arthritis, other inflammatory, fever, cancer, dysmenorrhea, and acute migraine.

In the formula, R ₁ or R ₂ represents H, any one of alkyl, alkyloxy, alkenyl or alkynyl residues having 1-12 carbon atoms, aryl or heteroaryl residue, or none. ₃ represents H or CH _3, a ^- is ^{Cl -, Br -, F -} , I -, AcO -, citrate, or represents any anion, n = 0,1,2,3,4,5 , 6, 7, 8, 9, 10 ..., amino acids can be L- or D-type, and all R, R _n ,-(CH ₂ ) _n- or-(CH ₂ ) _m -groups. Is a branched or straight chain, may contain C, H, O, S, or N atoms, may have single, double, and triple bonds, and the _two CH groups are O, S. Alternatively, it may be replaced 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 men, sexual dysfunction in women, leukoderma, and other skin diseases.

In the formula, R is a branched or straight chain,-(CH ₂ ) _n- , and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., Aryl or hetero. Represents an aryl residue, where 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 any one of the alkyl, alkyloxy, alkenyl or alkynyl residues having H, O, 1-12 carbon atoms. 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 represents phenyl, 2'-naphthyl, 4-iodophenyl, or other aryl or heteroaryl residue, and the amino acid is L-. It can be of type or D-type, and all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or straight, C, H, O, S, or N atoms. May contain 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 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 -groups are branched or linear and may contain C, H, O, S, or N atoms, single bonds, It may have a double bond and a triple bond, and the CH ₂ group may be substituted with O, S or NH.

7-2. A method for preparing a cyclopeptide represented by structure 4-C and related compounds according to 5-2 above, wherein the peptide chain can be synthesized by a standard peptide synthesis protocol, and the side chain of lysine is 2-, Alternatively, a method in which the peptide is protected by a 4-Pyoc protecting group and the cyclization of the peptide is carried out on the resin.
8-2. A composition comprising the compound represented by the structure 1 or at least the compound represented by the structure 1 as an active ingredient according to the above 1-2, which can be treated with a peptide and related compounds in humans or animals. A compound or composition that can be orally or transdermally administered to treat glaucoma or ocular hypertension, male erectile dysfunction and female sexual dysfunction, systemic blood pressure, abortion, hypotension. Compounds or compositions including, but not limited to, control, suppression of platelet aggregation, lung disease, digestive disorders, inflammation, shock, fertility, fertility, obesity, etc.
9-2. A method of treating a treatable condition of a peptide and related compounds in humans or animals, described above by transdermal administration (in the form of a solution, spray, lotion, ointment, emulsion or gel) to a part of the body. 1-2. A method comprising delivering a therapeutically effective plasma level of a composition comprising the compound represented by structure 1 or at least the compound represented by structure 1 as an active ingredient.
10-2. A composition comprising, as an active ingredient, the compound represented by the structure 1 or at least the compound represented by the structure 1 described in 1-2 above for treating a therapeutic condition of a peptide and a related compound in humans or animals. A transdermal therapeutic application system for an object, which may 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 provides a permeable bottom surface facing the skin. Having and controlling the rate of release allows peptides and related compounds to constantly reach optimal therapeutic blood levels, increase efficacy and reduce side effects of peptides and related compounds. A system featuring.

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 the structure 1 of the following 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 _{n 1} represents H, Represents CH ₃ , C ₂ H ₅ , C ₃ H ₇ , CF ₃ , C ₂ F ₅ , or C ₃ F ₇ , where R _n is the aliphatic side chain of the amino acid, the hydroxyl or sulfur-containing side chain of the amino acid, or the amino acid. Aromatic side chains, amino acid amino, imidazolyl, or quanidino group-containing side chains, or any one of the amino acid carboxyl or carboxamide group-containing side chains, alkyl, alkyloxy, alkenyl, or alkynyl residues with 1-12 carbon atoms. Any one of the groups, an aryl or heteroaryl residue, or none, where Y _x1 or Y _x2 is H, any one of an alkyl, alkenyl or alkynyl residue with 1-12 carbon atoms. Aryl or heteroaryl residues, or the following groups,

Or nothing, where Y _n is H, any one of an alkyl, alkyloxy, alkenyl or alkynyl residues with 1-12 carbon atoms, an aryl or heteroaryl residue, or the following group,

Or nothing, where R _x1 or R _x2 is H, O, any one of alkyl, alkenyl or alkynyl residues with 1-12 carbon atoms, aryl or heteroaryl residue, or nothing. _Represents R x3, R _x4 , or R _xn is H, O, any one of alkyl, alkyloxy, alkenyl or alkynyl residues having H, O, 1-12 carbon atoms, 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 linear compound, the compound being a prodrug of a peptide, one or two primary, secondary or secondary present in a protonated form at the lipophilic moiety and physiological pH. A primary, secondary or tertiary amine having a tertiary amine group, a quanidino group, or a hydrophilic moiety having one protected quanidino group and present in a protonated form at said physiological pH. The group is the following group,

A compound that is.
[2] In the structure 1, one or more amino acid residues in the sequence are substituted with any one of an unnatural amino acid or an alkyl, alkyloxy, alkenyl, alkynyl, aryl or heteroaryl residue. The compound according to [1].
[3] In Structure 1, the amino and carboxyl groups of the amino acid on the peptide chain form a lactam bridge to form a homodetic cyclic peptide, or the thiol group of the amino acid forms a disulfide bridge to form a heterodetic cyclic peptide. The compound according to the above [1], which forms the above-mentioned compound.
[4] A compound represented by the 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, where 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 . , X ₂ stands for H, CH ₃ or CF ₃ , X ₃ stands for H, CH ₃ , C ₂ H ₅ , or CF ₃ , and R ₁ , R ₂ , R ₄ , or R ₅ stands for H, 1 to 1. 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 according to the above [4] for producing a drug for treating pain resulting 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, any one of alkyl, alkyloxy, alkenyl or alkynyl residues having 1-12 carbon atoms, aryl or heteroaryl residue, or none. ₃ represents H or CH _3, a ^- represents an anion, all R groups are branched or straight chain.
[7] Use of the compound according to the above [6] for producing a drug for treating pain resulting 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, where 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, any one of alkyl, alkyloxy, alkenyl or alkynyl residues with 1-12 carbon atoms, 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 a branched or straight chain.
[9] Use of the compound according to the above [8] for the production of a drug for treating erectile dysfunction in men, sexual dysfunction in women, or skin diseases.
[10] The use according to the above [9], wherein the skin disease is albinism.
[11] A method for preparing a cyclopeptide represented by the structure 4-C according to the above [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 peptide cyclization is carried out on a resin, protected by a 4-Pyoc protecting group.
[12] In humans or animals containing the compound represented by the structure 1 according to the above [1] as an active ingredient, glaucoma, ocular hypertension, erectile dysfunction in men, sexual dysfunction in women, systemic blood pressure, fertility, 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 disorders, inflammation, shock, fertility, fertility, and obesity.
[13] The pharmaceutical composition according to the above [12], which is orally or transdermally administered.
[14] The pharmaceutical composition according to the above [12], which is transdermally administered to a part of the body in the form of a solution, spray, lotion, ointment, emulsion or gel.
[15] In humans or animals, glaucoma, ocular hypertension, erectile dysfunction in men, sexual dysfunction in women, systemic blood pressure, abortion, antihypertensive control, suppression of platelet aggregation, lung disease, digestive disorders, inflammation, shock, reproduction Peptide selected from the group consisting of ability, fertility, and obesity From a matrix layer and a non-permeable support layer containing the compound represented by the structure 1 according to the above [1] for treating a treatable state. A transdermal treatment application system characterized by becoming.
[16] The transdermal therapeutic application system according to the above [15], which is a bandage or a patch.
[17] The transdermal therapeutic application system according to the above [15], which is an active substance storage and has a permeable bottom surface facing the skin.
[18] In Structure 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 groups contain C, H, O, S, or N atoms or have single, double or triple bonds, said [1], [ 4], [6] or [8].
[19] In the structure 1, 2-C, 3-C or 4-C, _two CH groups are substituted with O, S or NH, as described above [1], [4], [6] or [8]. The compound described in.
[20] The above-mentioned [1], [4], [6] or [8], wherein the amino acid is L-type or D-type in the structures 1, 2-C, 3-C or 4-C. Compound.
[21] the ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate, the above [1], [4] The compound according to [6] or [8].
Another aspect of the present invention may be as follows.
[1'] A compound represented by the structure 2-C of the following formula.

In the formula, R is a branched or straight chain,-(CH ₂ ) _n- , and n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., Aryl or hetero. Represents an aryl residue, where X represents CO, SO, SO ₂ , or nothing, where 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 , and 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 ^- represents an anion, n = 0 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., and all R,-(CH ₂ ) _n -or-(CH ₂ ) _m -groups are branched or direct. It is a chain.
[2 '] or an amino acid is L- type or the D-, R, or _{R 1, R 2, R 3} , R 4, or R ₅ include C, H, O, S, or N atoms, Or the compound according to the above [1'], which has a single bond, a double bond or a triple bond, or has _{two CH groups substituted with O, S or NH.}
[3 '] wherein ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate, the [1' compounds described].
[4'] The above-mentioned [1] for producing a drug for treating pain derived from at least one disease selected from toothache, headache, inflammation, fever, cancer, dysmenorrhea, and acute migraine. '] Use of the compounds described.
[5'] A compound represented by the structure 3-C of the following formula.

In the formula, R ₁ or R ₂ represents H, any one of alkyl, alkyloxy, alkenyl or alkynyl residues having 1-12 carbon atoms, aryl or heteroaryl residue, or none. ₃ represents H or CH ₃ , A ⁻ represents an anion, n = 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 ..., And all R,-( CH ₂ ) _n- or-(CH ₂ ) _m -groups are branched or straight.
[6 '] or the amino acid is L- type or the D- or R _1, R _2, or R ₃ comprises C, H, O, S, or N atoms, or a single bond, double bond or The compound according to the above [5'], which has a triple bond or has _{two CH groups substituted with O, S or NH.}
[7 '] the ^{anions, Cl -, Br -, F} -, I -, AcO -, or citrate, the [5' compounds described].
[8'] The above-mentioned [5] for producing a drug for treating pain derived from at least one disease selected from toothache, headache, inflammation, fever, cancer, dysmenorrhea, and acute migraine. '] Use of the compounds described.
[9'] of the above [1'] to [3'] and [5'] to [7'] for use in the treatment of peptide-treatable conditions in humans or animals by oral or transdermal administration. A composition containing the compound according to any one of the above items or the compound according to any one of the above [1'] to [3'] and [5'] to [7'] as an active ingredient.
[10'] The 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 containing the compound according to any one of [1'] to [3'] and [5'] to [7'] as an active ingredient, wherein the compound or the composition is a solution. , The compound or the composition, in the form of a spray, lotion, ointment, emulsion or gel.
[11'] A transdermal therapeutic application system for use in the treatment of peptide-treatable conditions in humans or animals, wherein the above [1'] to [3'] and [5'] to [7']. The above-mentioned composition comprising the compound according to any one item or the compound according to any one of [1'] to [3'] and [5'] to [7'] as an active ingredient. system.
[12'] The system according to [11'] above, which is a bandage or patch composed of an active substance-containing matrix layer and an impermeable support layer.
[13'] The system according to [11'] or [12'] above, wherein the system has an active substance storage having a permeable bottom surface facing the skin.
[14'] Controlling means that control the rate of release, allowing peptides and related compounds to constantly reach optimal therapeutic blood levels, increasing efficacy and reducing side effects of peptides and related compounds. The system according to any one of [11'] to [13'] above, further comprising.
[15'] At least one prodrug selected from the following structures 2, structure 3, structure 4, structure 7, structure 8, structure 9 and structure 10.

Claims (3)

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

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

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