JP2005170950A - N-terminus modified analog of lhrh - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a medicine inhibiting activity of luteinizing hormone releasing hormone (LHRH) as a remedy for sex steroid much related diseases. <P>SOLUTION: Decapeptides and undecapeptides substituted on the N-terminal nitrogen atom by acyl groups (which include furo-2-yl, isonicotinyl, nicotinyl, 2-quinolinecarbonyl, 3-quinolinecarbonyl, and 4-quinolinecarbonyl, shikimyl, dihydroshikimyl and tetrahydrofur-2-oyl) are potent antagonists of LHRH. The antagonists of LHRH are useful for suppressing the levels of sex hormones in mammals. <P>COPYRIGHT: (C)2005,JPO&NCIPI

Description

  The present invention relates to an organic compound having biological activity, a composition containing the compound, and a medical treatment method. In particular, the present invention relates to certain N-terminal modified decapeptides and undecapeptides having LHRH antagonist activity, pharmaceutical compositions comprising such peptides, and methods for inhibiting LHRH activity in mammals in need of treatment. Related.

  Gonadotropins, follicle stimulating hormone (FSH), luteinizing hormone (LH) and chorionic gonadotropin (CG) are required for ovulation, spermatogenesis and sex steroid biosynthesis. One hypothalamic hormone, gonadotropin-releasing hormone (GnRH, also known as luteinizing hormone-releasing hormone (LHRH)), serves to regulate the secretion of both FSH and LH in mammals.

The structure of LHRH is A.I. V. Schally, et al. Science 173: 1036-1037 (1971). Early attempts to prepare peptides with LHRH-like activity have focused on the synthesis of compounds that are LHRH agonists. However, in 1976, it was discovered that individual administration of LHRH stimulates gonadotropin release, whereas continuous administration of small doses of LHRH or long-term administration of LHRH agonists has the opposite effect. This discovery has facilitated research to discover both agonist and antagonist analogs of LHRH as drugs that can be used to regulate mammalian sex steroids. Among the published literature, many patents and articles act as LHRH agonists (ie, act to stimulate the release of LH and FSH) or act as LHRH antagonists (ie, release of LH and FSH). Analogs of LHRH are disclosed. In most cases, such compounds contain 9 or 10 aminoacyl residues that replace natural or non-natural amino acid residues at one or more positions in the native sequence of LHRH. In some cases, active antagonists of LHRH containing fewer than 10 amino acid residues have been reported.

  Treatment of various diseases in which sex steroid suppression plays an important role, such as contraception, treatment of delayed sexual maturation, treatment of benign prostatic hyperplasia, palliative treatment or remission of hormone-dependent tumors of the breast and ovary, Promising treatment or remission of hormone-dependent tumors of the prostate, treatment of cryptorchidism, treatment of female hirsutism, treatment of gastric motility abnormalities, treatment of dysmenorrhea, treatment of endometriosis It has been reported in the literature that LHRH antagonists can be used.

SUMMARY OF THE INVENTION The present invention, in its first embodiment, comprises a group of LHRH decaylates modified at the N-terminus by adding an acyl functional group or by adding an acyl functional group with an additional aminoacyl residue. And undecapeptide antagonist analogs are provided. The compounds of the present invention inhibit gonadotropin secretion by the pituitary gland and inhibit steroid release by the gonads.

  In particular, the peptides of the present invention have the structure:

式中の文字ＡからＫはアミノアシル残基を表し、ＸはＮ末端改変アシル基を表す。本発明では、上記残基は次のものから選択される。

Letters A to K in the formula represent an aminoacyl residue, and X represents an N-terminal modified acyl group. In the present invention, the residue is selected from:

  X represents (a) dihydroshikimyl, (b) 2-furoyl, (c) 3-furoyl, (d) tetrahydrofuro-2-yl, (e) tetrahydrofuro-3-yl, (f) (thien- 2-yl) carbonyl, (g) (thien-3-yl) carbonyl, (h) (tetrahydrothien-2-yl) carbonyl, (i) (tetrahydrothien-3-yl) carbonyl, (j) (pyrrole- 2-yl) carbonyl, (k) (pyrrol-3-yl) carbonyl, (l) prolyl, (m) N-acetyl-prolyl, (n) 3- (indoline-3-yl) propionyl, (o) ( Indoline-3-yl) acetyl, (p) (indoline-2-yl) carbonyl, (q) (indoline-3-yl) carbonyl, (r) benzo [b] fur-2-yl) carbonyl, (s) ( Hydrobenzo [b] flu-2-yl) carbonyl, (t) (tetrahydropyran-2-yl) carbonyl, (u) (tetrahydropyran-3-yl) carbonyl, (v) (piperidin-3-yl) carbonyl, (W) (N-acetylpiperidin-3-yl) carbonyl, (x) (optionally substituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, or hydroxy Nicotinyl, (y) isonicotinyl (optionally substituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen or hydroxy), (z) picolinyl, (Aa) (optionally substituted with alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen or hydroxy) 2- , 3- or 4-quinolinecarbonyl, (bb) salicyl, (cc) shikimyl, (dd) p-toluenesulfonyl.

  A is absent or β-alanyl, D-alanyl, 3-aminopropionyl, 4-aminobutyryl, 5-aminovaleryl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-aminooctanoyl, 11- An aminoacyl residue selected from the group consisting of aminoundecanoyl, azaglycyl, glycyl, sarkosyl, D-seryl.

B is D-phenylalanyl, D-3- (4-chlorophenyl) alanyl, D-3- (4-fluorophenyl) alanyl, D-3- (quinolin-3-yl) alanyl, sarkosyl, glycyl, azaglycyl Aminoacyl residue selected from the group consisting of D-3,3-diphenylalanyl, N ^α -methyl-D-3- (naphth-2-yl) alanyl, D-3- (naphth-2-yl) alanyl It is a group.

  C is D-3- (4-chlorophenyl) alanyl, D-3,3-diphenylalanyl, D-3- (4-fluorophenyl) alanyl, D-3- (naphth-2-yl) alanyl, D -Aminoacyl residue selected from phenylalanyl, D-3- (quinolin-3-yl) alanyl.

  D is D-alanyl, D-3- (benzo [b] thien-2-yl) alanyl, glycyl, D-3- (naphth-1-yl) alanyl, D-3- (pyrid-3-yl) An aminoacyl residue selected from alanyl, D-3- (quinolin-3-yl) alanyl, D-3- (thiazol-2-yl).

E is glycyl, L-seryl, L-homoseryl, L-seryl (O-benzyl), N ^α (R ¹ ) -L-seryl (wherein R ¹ is alkyl of 1 to 4 carbon atoms) An aminoacyl residue selected from:

F is N ^α (R ¹ ) -alanyl, N ^α (R ¹ )-(3- (4- (3-amino-1,2,4-triazol-5-yl) amino) phenyl) alanyl, N ^α (R ¹ )-(3- (4-((3-Amino-1,2,4-triazol-5-yl) amino) methyl) phenyl) alanyl, N ^α (R ¹ )-(3- (4- (3-Amino-1,2,4-triazol-5-yl) amino) cyclohexyl) alanyl, N ^α (R ¹ )-(3- (4- (nicotinyl) amino) cyclohexyl) alanyl, N ^α (R ¹ )-(N-ε-nicotinyl) lysyl, N ^α (R ¹ )-(N-ε- (3-amino-1,2,4-triazol-5-yl) lysyl, N ^α (R ¹ ) -3 -(4-Nitrophenyl) alanyl, N ^α (R ¹ ) -3- (4-aminophenyl) a ^{Ranil, N α (R 1) -3-} (4- aminocyclohexyl) alanyl, N α ^{(R 1)} - tyrosyl, N α ^{(R 1)} - tyrosyl (O-methyl), N α ^{(R 1)} - phenyl alanyl, N α ^{(R 1)} - cyclohexyl alanyl, N α ^{(R 1)} - glycyl, N α ^{(R 1)} - arginyl, N α ^{(R 1)} - histidyl, N α ^{(R 1)} - Homoaruginiru ( In which R ¹ is an aminoacyl residue selected from hydrogen or alkyl of 1 to 4 carbon atoms.

  G is glycyl, D-citrulyl, D-homocitryl, β-alanyl, an aminoacyl residue having the structure

から成るグループから選択されるアミノアシル残基である。

An aminoacyl residue selected from the group consisting of

X in the previous formula is selected from the group consisting of — (CH ₂ ) _n — (where n is 1 to 6) and a group of the formula:

Y is absent or D-alanyl, L-alanyl, 4-aminobutyryl, 5-aminopentanoyl, 6-aminohexanoyl, 7-aminoheptanoyl, 8-amino-octanoyl, 11-aminoundeca Noyl, azaglycyl, D-3- (benzo [b] thien-2-yl) alanyl, L-3- (benzo [b] thien-2-yl) alanyl, D-3- (4-chlorophenyl) alanyl, D -Cyclohexylanalyl, glycyl, D-histidyl, D-histidyl (benzyl), D-leucyl, D-3- (naphth-2-yl) alanyl, D-phenylalanyl, D-3- (pyrido-3- Yl) alanyl, sarcosyl, ceryl, D-seryl, D-threonyl, D-3- (thiazol-4-yl) alanyl, D-tryptyl, D-tyrosyl D- Torioshiru (O-methyl), an amino acyl residue selected from the group consisting of D- valyl,
Z is absent or D-alanyl, L-alanyl, azaglycyl, D-cyclohexylalanyl, glycyl, D-histidyl, D-phenylalanyl, 3-((4- (3-amino-1, 2,4-triazol-5-yl) amino) phenyl) alanyl, (3- (4-((3-amino-1,2,4-triazol-5-yl) amino) methyl) phenyl) alanyl, sarkosyl, D-seryl, L-seryl, groups of formula

（ｍは１から１２までの整数（１、１２を含む）である）から成るグループから選択されるアミノアシル残基であり、
Ｒ^２は、３−アミノ−１，２，４−トリアゾール−５−イルであるか、又は、アセチル、（４−アセチルピペラジン−１−イル）カルボニル、（アダマント−１−イル）カルボニル、（１個から４個の炭素原子のアルキル、１個から４個の炭素原子のアルコキシ、又は、ハロゲンで随意に置換された）ベンゾイル、ブチリル、シクロヘキシルカルボニル、ジヒドロシキミル、ホルミル、ニコチニル、２−フロイル、２−及び６−ヒドロキシニコチニル、（インドール−２−イル）カルボニル、イソニコチニル、（４−メチルピペラジン−１−イル）カルボニル、（モルフィリン−１−イル）カルボニル、２−及び６−メチルニコチニル、（１個から４個の炭素原子のアルキル、１個から４個の炭素原子のアルコキシ、又は、ハロゲンで随意に置換された）１−及び２−ナフトイル、ピコリル、（ピペラジン−１−イル）カルボニル、プロピオニル、ピラジノイル、ピリジルアセチル、（ピロリル）カルボニル、（キノリニル）カルボニル、サリチル、シキミル、２−（テトラヒドロフロイル）、（チエン−２−イル）カルボニルから成るグループから選択されるアシル基である。

An aminoacyl residue selected from the group consisting of (where m is an integer from 1 to 12 inclusive).
R ² is 3-amino-1,2,4-triazol-5-yl, or acetyl, (4-acetylpiperazin-1-yl) carbonyl, (adamanto-1-yl) carbonyl, (1 Benzoyl, butyryl, cyclohexylcarbonyl, dihydroshikimyl, formyl, nicotinyl, 2-furoyl, optionally substituted with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen. 2- and 6-hydroxynicotinyl, (indol-2-yl) carbonyl, isonicotinyl, (4-methylpiperazin-1-yl) carbonyl, (morphin-1-yl) carbonyl, 2- and 6-methylnicotinyl, (Optionally with alkyl of 1 to 4 carbon atoms, alkoxy of 1 to 4 carbon atoms, or halogen. 1- and 2-naphthoyl, picolyl, (piperazin-1-yl) carbonyl, propionyl, pyrazinoyl, pyridylacetyl, (pyrrolyl) carbonyl, (quinolinyl) carbonyl, salicyl, shikimyl, 2- (tetrahydrofuroyl) , An acyl group selected from the group consisting of (thien-2-yl) carbonyl.

H is L-leucyl, N (R ¹ ) -L-leucyl, glycyl, sarcosyl, prolyl, L-valyl, L-cyclohexylalanyl, N ^α (R ¹ ) -L-cyclohexylalanyl (R ¹ is An aminoacyl residue selected from the group consisting of hydrogen or alkyl of 1 to 6 carbon atoms.

I is L-citrulyl, L-homocitryl, L-histidyl, L- (N-ε-isopropyl) lysyl, L-arginyl, N ^α (R ¹ ) -L-arginyl, L-homoarginyl, L-2-amino ^{-6-N g} - ethyl guanidino hexanoyl, L-2-amino ^{-6-N g,} N g - is a amino acyl residue selected from the group consisting of diethyl guanidino-hexanoyl.

J represents L-prolyl, 4-hydroxy-L-prolyl, L-pipecolyl, L-azetidinyl, L-2,8-tetrahydroisoquinoline-2-carbonyl, N (R ¹ ) -L-leucyl, sarkosyl, glycyl, N ^(R 1)-L-alanyl ^{(R 1} is hydrogen or from one to six of the alkyl carbon atoms) is aminoacyl residue selected from the group consisting of.

K is —NH (CH ₂ CH ₃ ), or D-alanylamide, D-alanyl (OH), D-glutamyl (OH), L-glutamyl (OH), N (R ¹ ) -L— ^{alanylamide, N} (R 1)-D-alanylamide, Sarukosamido, D- Seriruamido aza glycyl amide, Gurishiruamido ^{(R 1} is as defined above) is an amino acyl residue selected from the group consisting of.

However, when K is -NH _(CH 2 _{CH 3)} is, J is L- prolyl.

  In another embodiment of the present invention, there is provided a pharmaceutical composition for use in suppressing the level of sex hormones in a mammal comprising an effective amount of a sex hormone suppressing compound as defined above in combination with a pharmaceutically acceptable base carrier. Provided.

  In yet another embodiment of the present invention, there is provided a method for suppressing the level of mammalian sex hormone comprising administering to a mammal in need of treatment a therapeutically effective amount of a compound as defined above.

DETAILED DESCRIPTION Throughout this specification and the appended claims, the term “halide” means bromo (Br), chloro (Cl), fluoro (F), or iodo (I).

  The term “resin” or “peptide resin” means a type of resin commonly used in the field of synthetic peptide preparation. Examples of such resins include, but are not limited to, methylbenzhydrylamine (MBHA), benzhydrylamine (BHA), or Merrifield resin (ie, chloromethylated polystyrene).

  The term “alkyl” means a divalent straight or branched chain group derived from a saturated hydrocarbon by removing one hydrogen atom. Examples of this alkyl include, but are not limited to, methyl, ethyl, propyl, iso-propyl, butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, hexyl and the like.

The term “alkylene” means a divalent linear or branched group derived from a saturated hydrocarbon by removing two hydrogen atoms. Examples of this alkylene include, but are not limited to, —CH ₂ —, —CH ₂ CH ₂ —, —CH (CH ₃ ) CH ₂ —, and the like.

  The term “azetidinyl” refers to a cyclic aminoacyl residue obtained from azetidine-2-carboxylic acid.

  The term “cycloalkyl” means a monovalent cyclic hydrocarbon group obtained from a saturated cyclic hydrocarbon group by removing one hydrogen atom. Examples of this cycloalkyl group include cyclopropyl, cyclobutyl, cyclohexyl, cycloheptyl, bicyclo [2.2.2] octane and the like.

  The term “cycloalkylene” refers to a divalent group derived from a saturated cyclic hydrocarbon group by removing two hydrogen atoms. Examples of this cycloalkylene include cyclopentylene, cyclohexylene and the like.

  The term “isonicotinyl” refers to an acyl group derived from isonicotinic acid (ie, pyridine-4-carboxylic acid).

  The term “nicotinyl” refers to an acyl group derived from nicotinic acid (ie, pyridine-3-carboxylic acid).

  The term “picolinoyl” refers to an acyl group derived from picolinic acid (ie, 2-pyridinecarboxylic acid).

  The term “shikimyl” means an acyl residue obtained from shikimic acid or [3R- (3α, 4α, 5β) -3,4,5-trihydroxy-1-cyclohexene-1-carboxylic acid, and the term “dihydro “Shikimyl” means a fully saturated analog of shikimic acid.

Unless indicated with the prefix “D”, the stereochemical structure of the alpha-carbon atom of the amino acid and aminoacyl residues of the peptides described herein and in the appended claims is in the natural configuration, ie “L” configuration. The “R” and “S” designations according to the Cahn-Ingold-Prelog nomenclature are used to identify the stereochemical structure of the chiral center of a particular acyl substituent at the N-terminus of the peptides of the invention. The designation “R, S” is intended to represent a racemic mixture of the two enantiomer forms. This terminology is described in R.A. S. Cahn, C.I. K. Ingold, and V.A. Prelog, Angew. Chem. , Int. Ed. Engl. 5: 385-415 (1966).

The names of natural aminoacyl residues and non-natural aminoacyl residues are most often referred to as “Nomenclature of α-Amino Acids (Recommendations, 1974),” Biochemistry , 14 (2): 1975. Follow the conventions shown in the Commission on the Nomenclature of Organic Chemistry and the IUPAC-IUB Commission on Biochemical Nomenclature. The names and abbreviations of amino acids and aminoacyl residues used in this specification and the appended claims are different from those in the above terminology, and will be described below.

  “Atz” or “Atza” means the substituent “3-amino-1,2,4-triazol-5-yl”. “Bal” represents 3- (benzo [b] thien-2-yl) alanine, “Thial” represents 3- (thien-2-yl) alanine, and “Thiaz” represents 3- (thiazolyl) alanine. Represents.

“Cha” represents 3-cyclohexylalanine, and the various amino acids obtained from phenylalanine by substitution of the phenyl group are “D4ClPhe”, D-3- (4-fluoro, which represents D-3- (4-chlorophenyl) alanine. Table abbreviations such phenyl) represents alanine "D4FPhe", D-3- (4-nitrophenyl) represents alanine "D4NO ₂ Phe" represents the D-3- (4-aminophenyl) alanine "D4NH ₂ Phe" Is done.

  “Cit” and “HCit” each represent citrullyl and homocitryl (or L-2-amino- (6-aminocarbonylamino) hexanoic acid).

  “Cha (4AmPyz)” represents a 3-((4-aminopyrazine-2-carbonyl) cyclohexyl) -alanylaminoacyl residue.

  “DLys (Nic)” or “D-Lys (N-epsilon-nicotinyl)” represents a D-lysine amino acid or aminoacyl residue substituted on the epsilon nitrogen atom of the side chain with a nicotinyl acyl group. Similarly, “DLys (Isonic)” represents D-lysine acylated on the epsilon nitrogen atom with an isonicotinyl group, and “DLys (Shik)” is D acylated on the epsilon nitrogen atom with a shikimyl group. -Represents lysine, "DLys (Fur)" represents D-lysine acylated on the epsilon nitrogen atom with a fur-2-oil group, and "DLys (THF)" represents a tetrahydroflu-2-oil group Represents D-lysine acylated on the epsilon nitrogen atom. “DLys (Isp)”, “DLys (Nisp)” or “D-Lys (N-epsilon-isopropyl)” represents a lysine substituted on the epsilon amino group of the lysine side chain with an isopropyl group.

“Harg” represents homoarginyl or L-2-amino-6-guanidinohexanoyl. “HargEt” represents L-2-amino-6-N ^g -ethylguanidinohexanoic acid, and “HargEt ₂ ” represents L-2-amino-6-N ^g , N ^g -diethylguanidinohexanoic acid.

  “Aha” represents 4-aminoheptanoic acid, “Aca” represents 6-aminocaproic acid, “Gaba” represents 4-aminobutyric acid, “Bala” represents beta-aminoalanine or 3-amino Represents propionic acid.

  “D1Nal” represents D-3- (naphth-1-yl) alanine, and “D2Nal” represents D-3- (naphth-2-yl) alanine. “D3Pal” represents D-3- (pyrid-3-yl) alanine, and “D3Qal” or “D3Qual” represents D-3- (quinol-3-yl) alanine. “D- (4-Atza) Phe” or “DAtzPhe” represents D-3- (4- (3-amino-1H-1,2,4-triazol-5-yl) amino) phenyl) alanine; “D- (4-Atzame) Phe” or “D- (AtzMe) Phe” is D-3- (4-(((3-amino-1H-1,2,4′-triazol-5-yl) Represents amino) methyl) phenyl) alanine.

“Sar” represents sarcosine and “SarNH ₂ ” represents an amide of sarcosine.

  The term “Aze” represents L-2-azetidinylcarbonyl, while “4- (p-OMeBzOl) Hala” represents 4- (4-methoxybenzoyl) homoalanyl and “DLys (COdiAmpropShik)” , D-lysyl (N-ε-carbonyl-N ′, N ″ -diaminopropaneshikimyl) aminoacyl residue.

The phrase “pharmaceutically acceptable salts” refers to salts that are recognized in the pharmaceutical formulation art as being suitable for use in formulations for use in the treatment of humans and animals and are non-toxic. Suitable acids and bases that can be used for this purpose are shown, for example, in the article “Pharmaceutical Salts” (SN Berge, et al., J. Pharm. Sci. , 66: 1-19 (1977)) . ing.

  Representative examples of compounds considered to be included within the scope of the present invention include, but are not limited to, the following compounds:

N-dihydroshikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-2-furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-3-furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-picolyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-isonicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-salicyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-[(R, S) -tetrahydroflu-2-oil] -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-[(S) -tetrahydroflu-2-oil] -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-[(R) -tetrahydroflu-2-oil] -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-3aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-cychymyl-3aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-4aminobutyryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-shikimyl-4aminobutyryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-5 aminovaleryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-shikimyl-5aminovaleryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-shikimyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2-furoyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N- (R, S) tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N- (R, S) tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N- (R, S) tetrahydro-flu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N- (R, S) tetrahydro-flu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (AzaGly-furoyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-succinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-DAla-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-Sikimyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-Sar-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-Siquimyl-Sar-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-DAla-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-Siquimil-DAla-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-Sikimyl-Dser-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-DLys (Nic) -DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-DLys (Nic) -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-DLys (Shik) -DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-DLys (Shik) -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N- (S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N- (R) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (DSer-Nic) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D1Nal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Ile-Arg-Pro-DAlaNH ₂ ,
N-Sikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -NMeLeu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Aze-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (GlyGlyNic) -Leu-Arg-Pro-DAlaNH ₂ ,
N- (L-Glonyl) -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-L-Glonyl) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Ile-Arg-Pro-DAlaNH ₂ ,
Nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Sikimyl) -NMeLeu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Arg-Aze-DAlaNH ₂ ,
N-nicotinyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Harg-Pro-DAlaNH ₂ ,
N (2-Furoyl) -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Harg-Pro-DAlaNH ₂ ,
N- (3-quinolinyl) -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (NO ₂ ) -DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (NO ₂ ) -DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Arg-Pro-DAlaNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Arg-Aze-DAlaNH ₂ ,
N-nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-3-aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-shikimyl-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (GlyNic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-Azagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-Azagly-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (2-Furoyl) -Azagly-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-isonicotinyl-Azagly-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-Azagly-D4ClPhe-D1Nal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-Sar-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
Nic-Gly-Sar-D4ClPhe-D1Nal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
Nic-Gly-Sar-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-DBal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N-nicotinyl-Azagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-salicyl-Azagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-isonicotinyl-Azagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-tosyl-Azagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-Arg-Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Arg-Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Arg-D4 (pOMeBzol) Hala-Leu-Arg-Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHarg (Et ₂ ) -Leu-Harg (Et ₂ ) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Phe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2Fur) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ ,
N-Sikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Atz) -DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D3Qal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmplopShik) -Leu-Harg-Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmplopShik) -Leu-Harg-Pro-SarNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropShik) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropShik) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N-nicotinyl-Gly-D3Qal-D4ClPhe-D3Pal-Ser-cis-Cha (4AmPrz) -DLys (Pic) -Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-dihydroshikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-2 furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-3 furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-picolyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-isonicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-salicyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ ,
N-tosyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N- (S) -tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (R) -tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (S) -tetrahydrofur-3-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) t-Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (R) -tetrahydrofur-3-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) t-Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) t-Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-2-furoyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-3-furoyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-thienyl-2-carbonyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-picolinoyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (6-hydroxy) nicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-isonicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (3-pyridylacetyl) -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-nicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (S) -tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N- (R) -tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N- (R) -5-oxo-tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N- (S) -5-oxo-tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-2-furoyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-isonicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-picolinoyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N-nicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,
N- (3-pyridylacetyl) -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH ₂ ,as well as,
N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ .

  In one embodiment of the present invention, no aminoacyl residue A is present, and the peptide of the present invention is a decapatide modified with an acyl group at the N-terminus and has a structure of the following formula:

式中で、Ｘ、Ｂ、Ｃ、Ｄ、Ｅ、Ｆ、Ｇ、Ｈ、Ｉ、Ｊ、Ｋは上記定義の通りである。

In the formula, X, B, C, D, E, F, G, H, I, J, and K are as defined above.

  Preferred compounds of the present invention have the structure:

^{X-Gly-D2Nal-D4ClPhe-} D3Pal-Ser-AA 6 -AA 7 -Leu-AA 9 -Pro-AA 11
In the formula, X represents tetrahydrofur-3-oil, (tetrahydrothien-2-yl) carbonyl, (pyrrol-2-yl) carbonyl, prolyl, (indoline-2-yl) carbonyl, 3- (indoline-3- Yl) propionyl, (dihydrobenzo [b] fur-2-yl) carbonyl, (tetrahydropyran-2-yl) carbonyl, an acyl group selected from the group consisting of
AA ⁶ is tyrosyl, arginyl, N ^α -methyltyrosyl, lysyl (N-epsilon- (3′-amino-1H-1 ′, 2 ′, 4′-triazol-5-yl)), N ^α -methyl-3. An aminoacyl residue selected from the group consisting of-(4- (3'-amino-1H-1 ', 2', 4'-triazol-5-ylmethyl) phenyl) alanyl;
AA ⁷ is D-citrulyl, D-homocitryl, D-lysyl (N-epsilon-nicotinyl), D-lysyl (N-epsilon-glycyl-nicotinyl), D-lysyl (N-epsilon-azaglycyl-nicotinyl), D -Lysyl (N-epsilon-shikimyl), D-lysyl (N-epsilon-glycyl-shikimyl), D-lysyl (N-epsilon-azaglycyl-shikimyl), D-lysyl (N-epsilon-dihydroshikimyl), D -Lysyl (N-epsilon-glycyl-dihydroshikimyl), D-lysyl (N-epsilon-azaglycyl-dihydroshikimyl), D-lysyl (N-epsilon-fur-2-oil), D-lysyl (N- Epsilon-glycyl-flu-2-oil), D-lysyl (N-epsilon-azaglycyl-flu-2-) Oil), D-lysyl (N-epsilon-tetrahydro-fur-2-oil), D-lysyl (N-epsilon-glycyl-tetrahydrofur-2-oil), D-lysyl (N-epsilon-azaglycyl-tetrahydrofur) -2-oil) an aminoacyl residue selected from the group consisting of
AA ⁹ is an aminoacyl residue selected from the group consisting of lysyl (N-epsilon-isopropyl), arginyl, L- (N ^g , N ^g -diethylhomoarginyl), homoarginyl;
AA ¹¹ is an aminoacyl residue selected from the group consisting of D-alanylamide, D-sarcosamide.

  Examples of this type of compound include the following compounds:

N- Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Azagly- nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Gly- nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydro - fur-2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2,
N- Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2,
N- Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 , and,
N- nicotinyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH 2.

  In a particularly preferred embodiment, the compounds of the invention have the structure:

X-Gly-D2Nal-D4ClPhe- D3Pal-Ser-N α MeTyr-AA 7 -Leu-Lys (Isp) -Pro-AA 11
Wherein X is an acyl group selected from the group consisting of tetrahydrofuro-2-yl ^**
AA ⁷ is D-citryl, D-lysyl (N-epsilon-nicotinyl), D-lysyl (N-epsilon-glycyl-nicotinyl), D-lysyl (N-epsilon-azaglycyl-nicotinyl), D-lysyl (N -Epsilon-shikimyl), D-lysyl (N-epsilon-glycyl-shikimyl), D-lysyl (N-epsilon-azaglycyl-shikimyl), D-lysyl (N-epsilon-dihydroshikimyl), D-lysyl (N -Epsilon-glycyl-dihydroshikimyl), D-lysyl (N-epsilon-azaglycyl-dihydroshikimyl), D-lysyl (N-epsilon-fur-2-oil), D-lysyl (N-epsilon-glycyl-) Full-2-oil), D-lysyl (N-epsilon-azaglycyl-flu-2-oil), D-lysyl (N-epsilon-tetrahydrofur-2-oil), D-lysyl (N-epsilon-glycyl-tetrahydrofur-2-oil), D-lysyl (N-epsilon-azaglycyl-tetrahydrofur-2-oil) An aminoacyl residue selected from the group;
AA ¹¹ is an aminoacyl residue selected from the group consisting of D-alanylamide and D-sarcosamide.

  Specific compounds of this embodiment are as follows.

N [(R, S) - tetrahydrofurfuryl 2-Oil] -Gly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys ( nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N [(S) - tetrahydrofurfuryl 2-Oil] -Gly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys ( nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N [(R) - tetrahydrofurfuryl 2-Oil] -Gly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys ( nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Azagly-2 full) -Leu-Lys (Isp) -Pro -DAlaNH 2,
N-Shik-D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N-Shik-D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Azagly-2 full) -Leu-Lys (Isp) -Pro -DAlaNH 2,
N-(2-furoyl) -Azagly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys (-Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -SarNH 2,
N- (S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -SarNH 2,
N- (R) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -SarNH 2,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp) -Pro-SarNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Lys (Nic) -DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DCit-Leu-Arg-Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Arg-Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Arg-D4 (pOMeBzol) Hala-Leu-Arg-Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil _{-Gly-D2Nal-D4ClPhe-D3Pal-} Ser-Tyr-DHarg (Et 2) -Leu-Harg (Et 2) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMePhe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Phe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Gly-2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- DSer-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-3DPal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaOH,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-Lys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-3DPal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -DLeu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -DPro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-DLys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-DNMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ ,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DHcit-Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-DPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Arg-Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Bala-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Gaba-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Aha-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Sar-D2Nal-D4ClPhe-3DPal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Gly-DAla-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (S) -2- tetrahydrofuroyl -Gly-Sar-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 and,
N- (S) -2- tetrahydrofuroyl -Aca-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2.

LHRH antagonist activity LHRH antagonist potency (pA ₂ ) of representative compounds of the present invention was evaluated in an in vivo test. In this test, F.R. Haviv, et al. J. et al. Med. Chem . 32: 2340-2344 (1989). The pA ₂ value is the negative logarithm of the concentration of the individual antagonist test compound required to shift the response curve generated by the agonist leuprolide to a 2-fold higher concentration. (Leuprolide is an LHRH agonist having the structure “5-Oxo-Pro ¹ -His ² -Trp ³ -Ser ⁴ -Tyr ⁵ -D-Leu ⁶ -Leu ⁷ -Arg ⁸ -Pro ⁹ -NHEt”, US Patent (Disclosed and claimed in US Pat. No. 4,005,063.) Typically, a pA ₂ value of 9.5 or higher indicates good LHRH antagonist potency. A pA ₂ value of 10.0 or greater is preferred.

  The results of the above tests for representative compounds according to the present invention are shown in Table 1.

  The compounds of the present invention act as LHRH antagonists and are effective in suppressing gonadotropin and androgen levels in mammals.

  In practicing the method of the present invention, a pharmaceutical composition comprising an amount of a compound of the present invention or an antagonist thereof effective to suppress the level of sex hormone in a mammal is administered to a host in need of such treatment. Such compounds or compositions may be administered orally, parenterally (including subcutaneous, intramuscular, intravenous), vaginal (especially for contraception), rectal, buccal (including sublingual), It can be administered by various routes depending on the individual end use, including transdermal administration and intranasal administration. In any case, the optimum administration route is determined based on the use, individual active ingredients, the subject to be treated, and the judgment of the actual doctor in charge. The compounds or compositions can also be administered using sustained release depot or implant formulations, as described in more detail below.

  In general, to vary the sex hormone levels of male or female mammals for the above uses, an amount in the range of about 0.01 mg to 10 mg per kg body weight per day, preferably 1 It is appropriate to administer the active ingredient in an amount in the range of about 0.1 mg to 5.0 mg per kg body weight per day. This administration can be done by one administration per day, by multiple administrations or by sustained release to obtain the most effective results.

  The exact dose and regimen for administration of the compound or composition will be determined according to the subject to be treated, the type of treatment, the degree of disease and urgency, and the judgment of the attending physician. In general, parenteral administration requires less dosage than other methods of administration that are more affected by absorption.

  Yet another aspect of the present invention relates to a pharmaceutical composition comprising a compound of the present invention as an active ingredient together with a pharmaceutically acceptable non-toxic base. As mentioned above, such compositions can be prepared in particular in the form of liquid solutions or suspensions for use in parenteral administration (including subcutaneous, intramuscular and intravenous administration) For use in vaginal or rectal administration, it can be prepared in particular in the form of semi-solids (eg creams, suppositories), especially for tablets or capsules for use in oral or buccal administration. It can be prepared in a form, or for use in intranasal administration, in particular in the form of powders, nasal drops, aerosols.

  Suitably, the composition is administered in unit dosage form, eg, Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA. , 1970, and can be prepared by any of the methods known in the pharmaceutical arts. Formulations for parenteral administration may also include sterile water or saline, polyalkylene glycols (eg, polyethylene glycol), vegetable oils, hydrogenated naphthalene, and the like as conventional adjuvants. Formulations for inhalation administration may be solid, may contain, for example, lactose as an adjuvant, or may be an aqueous or oily solution for administration in the form of nasal drops Is possible. Typical adjuvants for buccal administration include sugar, calcium stearate, magnesium stearate, pregelatinized starch and the like.

It is particularly desirable to deliver the compounds of the invention over an extended period of time, for example, from a single dose to a week to a year. A variety of sustained release depot formulations or implant dosage forms can be used. For example, such dosage forms may have low solubility in bodily fluids, pharmaceutically acceptable non-toxic salts of the compounds of the invention, such as (a) polybasic acids (eg, phosphoric acid, sulfuric acid, citric acid, tartaric acid, tannic acid) Acid addition salt with pamoic acid, alginic acid, polyglutamic acid, naphthalene monosulfonic acid, naphthalene disulfonic acid, polygalacturonic acid, etc., (b) polyvalent metal cation (zinc, calcium, bismuth, barium, magnesium, aluminum, copper) , Cobalt, nickel, cadmium, etc.), or a salt with an organic cation formed from, for example, N, N′-dibenzylethylenediamine or ethylenediamine, or (c) a combination of (a) and (b) ( For example, zinc tannic acid salt) can be included. In addition, a compound of the invention, or preferably a salt that is relatively insoluble, such as those described above, is formulated in a gel suitable for injection (eg, aluminum monostearate gel) using, for example, sesame oil. It is possible. Particularly preferred salts are zinc salts, zinc tannic acid salts, pamoate salts, and the like. Another type of sustained release depot formulation for injection is a sustained disintegrating non-toxic non-antigenic polymer such as disclosed in US Pat. No. 3,773,919 (eg, polylactic acid / polyglycolic acid). The above compounds or salts can be included dispersed or encapsulated in a polymer. The compounds of the present invention, or preferably salts that are relatively insoluble, such as the salts described above, can also be formulated in the form of cholesterol matrix pellets, particularly for use in mammals. Still other sustained release depot or implant formulations (eg liposomes) are known in the literature. For example, Sustained and Controlled Release Drug Delivery Systems , J. MoI . R. Edited by Robinson, Marcel Dekker Inc. , New York, 1978. See, for example, US Pat. No. 4,010,125 for LHRH type compounds.

Synthesis of the Compounds of the Invention In general, the compounds of the invention are synthesized by techniques known to those skilled in the art, for example by so-called “solid phase” peptide synthesis or by the usual methods of solution phase chemistry. For an overview of available solid phase peptide synthesis methods, see J. Am. M.M. StewaR _t and J.M. D. Young, Solid Phase Peptide Synthesis, W.M. H. Freeman Co. San Francisco, 1963; Meienhofer, Hormonal Proteins and Peptides, Vol. 2. , P. 46, Academic Press (New York), 1973. For conventional solution synthesis methods, see G.C. Schroder and K.C. Lupke, The Peptides, vol. 1, Academic Pres (New York), 1965.

  In general, such methods involve the sequential addition of one or more amino acids or appropriately protected amino acids to a growing peptide chain bound to a suitable resin. Starting amino acids are commercially available, but new compounds of the invention are synthesized from readily available starting materials by the methods described in detail below.

  In general, the amino group or carboxyl group of the first amino acid is protected by a suitable protecting group. Thereafter, the protected or derivatized amino acid can be coupled to an inert solid support (resin), or appropriately protected complementation under conditions that allow the formation of an amide bond. It can be used in solution by adding the next amino acid in the sequence with a typical (amino or carboxyl) group. The protecting group is then removed from the newly added amino acid residue, the next (appropriately protected) amino acid is added, and the procedure is repeated. After all the necessary amino acids have been attached in the correct sequence, all remaining protecting groups are removed either sequentially or simultaneously, and the peptide chain is detached from the solid support (in the case of solid phase synthesis). To obtain the final polypeptide. By simply modifying this general procedure, for example, a protected tripeptide can be conjugated with a properly protected dipeptide (under conditions that do not racemize the chiral center) and the pentapeptide after deprotection By forming, it is possible to add one or more amino acids to the growing chain at one time.

  A particularly preferred method for preparing peptides includes solid phase peptide synthesis. In this peptide preparation method, the alpha-amino group of an amino acid is protected by a group sensitive to acids or bases. These protecting groups have the property that they are stable against peptide bond formation conditions while being easily removed without breaking the growing peptide chain or without racemizing the chiral centers contained therein. Must have. Suitable protecting groups are tert-butyloxycarbonyl (BOC), benzyloxycarbonyl (Cbz), biphenylisopropyloxycarbonyl, tert-amyloxycarbonyl, isobornyloxycarbonyl, (alpha, alpha) -dimethyl-3.5 Dimethoxybenzyloxycarbonyl, o-nitrophenylsulfenyl, 2-cyano-tert-butyloxycarbonyl, 9-fluorenylmethyloxycarbonyl and the like. Tertiary butyloxycarbonyl (“BOC” or “t-BOC”) protecting groups are preferred.

  Particularly preferred side chain protecting groups are nitro, p-toluene-sulfonyl, 4-methoxybenzene-sulfonyl, Cbz, BOC, adamantyloxycarbonyl for side chain amino groups as in lysine and arginine, and for tyrosine Are benzyl, o-bromo-benzyloxycarbonyl, 2,6-dichlorobenzyl, isopropyl, cyclohexyl, cyclopentyl, acetyl, for serine, benzyl, tetrahydropyranyl, for histidine, benzyl, Cbz, p -Toluenesulfonyl, 2,4-dinitrophenyl, and for tryptophan it is formyl.

In this solid phase peptide synthesis method, the C-terminal amino acid is bound to a suitable solid support. Suitable solid supports that can be used for this synthesis are materials that are inert to the reagents and reaction conditions of the stepwise "condensation-deprotection" reaction and that are insoluble in the solvent used. Suitable solid supports are chloromethyl polystyrene-divinylbenzene polymer, hydroxymethyl-polystyrene-divinylbenzene polymer, and the like. Chloromethyl polystyrene-1% divinylbenzene polymer is particularly preferred. In the special case where the C-terminus of the compound is glycinamide, a particularly preferred support is P.I. Rivail, et al. Helv. Chim. Acta. , 54, 2772 (1971), a benzhydrylamino-polystyrene-divinylbenzene polymer. Binding to resins of the “chloromethylpolystyrene-divinylbenzene” type is alpha as a salt such as cesium salt, tetramethylammonium salt, triethylammonium salt, 1,5-diazabicyclo [5.4.0] undec-5-ene. It is generated by the reaction of N-protected amino acids (especially BOC-amino acids). This conjugation reaction is carried out at a high temperature (eg, a temperature in the range of about 40 ° C. to 60 ° C.) in a solvent such as ethanol, acetonitrile, N, N-dimethylformamide (DMF), etc. for about 12 to 48 hours. In the meantime, it is carried out using chloromethyl resin. Preferred reagents and reaction conditions include conjugation of alpha-N-BOC-amino acid cesium salt and the resin in DMF at about 50 ° C. for about 24 hours. With 1-hydroxybenzotriazole (HOBt), benzotriazol-1-yloxy-tris (dimethylamino) phosphonium-hexafluorophosphate (BOP), or bis (2-oxo-3-oxazolidinyl) phosphine chloride (BOPCl) With or without N, N′-dicyclohexylcarbodiimide (DCC) or N, N′-diisopropylcarbodiimide (DIC), the alpha-N-BOC-amino acid is coupled to the benzhydrylamine resin for about 1 hour. Of solvent such as dichloromethane or DMF (preferably dichloromethane) at a temperature in the range of about 10 ° C. to about 50 ° C. (most preferably 25 ° C.) over about 24 hours (preferably about 12 hours). Combine in. In addition to the carbodiimide reagent, a catalytic action by 4-dimethylaminopyridine (DMAP) is required for the binding of the carboxyl group to N-methyl-Ser (OBzl) bound to the peptide resin.

  Sequentially protected amino acid linkages can be performed on automated polypeptide synthesizers as is known in the art. Removal of the alpha-N-protecting group is generally at ambient temperature, for example, a solution containing trifluoroacetic acid in methylene chloride, a solution containing hydrogen chloride in dioxane, a solution containing hydrogen chloride in acetic acid, or other It can be carried out in the presence of a strong acid solution, preferably a solution containing 50% trifluoroacetic acid in dichloromethane. It is preferred that each protected amino acid is introduced at a concentration of 0.4M and in an excess of about 3.5 molar, generally at ambient temperature, in dichloromethane, dichloromethane / DMF mixtures, DMF, etc., especially in methylene chloride. It is possible to perform the above combination. The binder is usually DCC in dichloromethane, but N, N'-di-isopropylcarbodiimide (DIC) alone or in the presence of HOBt, N-hydroxysuccinimide, other N-hydroxyimides or oximes. ) Or other carbodiimides. Alternatively, protected amino acid active esters (eg, p-nitrophenyl, pentafluorophenyl, etc.) or symmetric anhydrides can be used.

  The side chain of the peptide of the present invention can be modified by the method described in detail in “Preparation A” and “Preparation B” below.

Preparation A
N -trifluoroacetyl-N-methyl-phenylalanine (1 equivalent) and zinc chloride (0.9 equivalents ) in N- (t-butoxycarbonyl) -N-methyl- (4-FMOC-aminomethyl) phenylalanine chloromethyl ether To 2.2 equivalents) is heated to 65 ° C. for 10 to 24 hours. Excess reagent is removed in vacuo and the residue is dissolved in CH ₂ Cl ₂ and washed with saturated NaHCO ₃ solution followed by saturated sodium chloride solution. The organic phase is dried (Na ₂ SO ₄ ) and concentrated. The crude product is purified by column chromatography to give 4- (chloromethyl) phenylalanine methyl ester. This is treated with aqueous hydrochloric acid to cleave the methyl ester. N-methyl- (4-chloromethyl) phenylalanine hydrochloride is di-tert-butyl carbonate (1.2 eq) in the presence of triethylamine (1 eq) in THF at 0 ° C. for 1 h. ). After work-up and purification, BOC-N-methyl- (4-chloromethyl) phenylalanine is obtained.

  BOC-N-Me- (4-chloromethyl) phenylalanine is heated to reflux with an excess of sodium azide and a catalytic amount of sodium iodide in methanol over 4 to 24 hours. The residue is treated with dilute hydrochloric acid to pH 6 and extracted with ethyl acetate. The organic extract is dried and concentrated to obtain BOC-N-methyl- (4-azidomethyl) phenylalanine. This is hydrogenated in methanol over a Pd / C catalyst to give BOC-N-methyl- (4-aminomethyl) phenylalanine. M.M. Bodanszky and A.B. This compound is treated with 9-fluorenylmethyl chlorocarbonate under basic conditions as described on page 24 of Bodanzky's “The Practice of Peptide Synthesis”. After workup and purification, N- (t-butoxycarbonyl) -N-methyl- (4-FMOC-aminomethyl) phenylalanine is obtained (see Scheme 1).

Preparation B
N- (t-butoxycarbonyl) -D- (4-FMOC-aminomethyl) phenylalanine BOC-D- (4-chloromethyl) phenylalanine is synthesized according to Preparation A above. The product is first treated with sodium azide in methanol using conditions similar to those described above, followed by hydrogenation to give N-BOC-D- (4-aminomethyl) phenylalanine, as described above, FMOC. To give N- (t-butoxycarbonyl) -D- (4-FMOC-aminomethyl) phenylalanine.

The Atz or 3-amino-1,2,4-triazol-5-yl group is converted to 3 by the method detailed in Scheme 2 below showing the process for N ^α -methyl-3- (4-aminophenyl) alanine. It can be attached to the 4-amino group of-(4-aminophenyl) alanine or the terminal amino group of the omega-aminoalkyl side chain of any alpha, omega-diaminocarboxylic acid amino acid.

As shown in Scheme 2 below, N ^alpha - methyl-3- (4-aminophenyl) upon completion of the synthesis of the peptide resin containing an alanine residue in 30% over the peptide resin from 2 hours to 24 hours Treat with piperidine / DMF to cleave the FMOC group from the N-4-amino position of the N-Me-Phe residue. The peptide-resin is washed 3 times with methylene chloride, 3 times with DMF, and reacted overnight with a 10 to 20-fold excess of diphenylcyanocarboimidate in DMF (see the scheme below). 2), washed 3 times with methylene chloride, 3 times with DMF, and further reacted with a 20 to 100-fold excess of hydrazine in DMF overnight. The peptide-resin is washed as above, dried over P ₂ O ₅ overnight and treated with HF / anisole as described above.

Ａｔｚ基を、例えば、リジンの側鎖内のイプシロン−アミノ基、又は、オメガ−アミノアルキル側鎖基を有する類似のアミノアシル残基に結合するために、上記図式２のプロセスを同様に使用する。

The process of Scheme 2 above is similarly used to attach an Atz group to, for example, an epsilon-amino group in the side chain of lysine or a similar aminoacyl residue having an omega-aminoalkyl side chain group.

N-Ac-DTyr-D2Nal- D4ClPhe-D3Pal-Ser-NMeTyr-Dlys ( nicotinyl) -Leu-Lys (N-epsilon - isopropyl) -Pro-DAlaNH ₂ (Compound 1)
In a reaction vessel of a Milligen-Biosearch 9500 peptide synthesizer, 1 g (0.6 mmol) of D-Ala-NH-resin (4-methyl-benzhydrylamine resin) was placed. Amino acids were added sequentially according to the following synthesis cycle.
1. Deblocking to remove the t-BOC group from the alpha-amino functional group of the peptide was performed using 45% trifluoroacetic acid (TFA), 2.5% anisole, 2.0% dimethyl phosphite and 50.5. Performed using a solution with% methylene chloride. The resin was prewashed with the above deblocking solution for 1 minute, after which the deblocking reaction was allowed to proceed for 20 minutes.
2. A base wash to remove and neutralize the TFA used for deprotection was performed using a 10% N, N'-diisopropylethylamine solution in methylene chloride. Each time the deblocking step was completed, the resin was washed 3 times with base for 1 minute.
3. The coupling reaction was carried out with a 3-fold molar excess of “solution containing 0.3 M diisopropylcarbodiimide in methylene chloride” (as activator) and a 3-fold molar excess of “t-BOC protected amino acid derivative in DMF. .3M solution ”. The activated amino acid was then coupled to the free alpha amino group of the peptide-resin. The reaction time is as described in the following synthesis protocol.
4). Washing : After each reaction step, wash once with methylene chloride for 1 minute, (1: 1) once with methylene chloride / DMF for 1 minute, and then once with DMF. Wash for 3 minutes (3 washes).

Synthesis Protocol The amino protected amino acid was coupled to the resin according to the following sequence, number of couplings and coupling time.

Upon completion of the synthesis, the resin was dehydrated overnight over P ₂ O _{5 in} vacuo, then treated with anhydrous HF in the presence of anisole for 1 hour at 0 ° C. The peptide was cleaved. Excess reagent was removed in vacuo. The resin was first washed with ether, then stirred with water / acetonitrile / acetic acid solution (50 mL) at room temperature (1: 1: 0.1) for 15 minutes and filtered. The filtrate was lyophilized to obtain the crude peptide as a fluffy powder. The crude peptide was purified using (25 × 2.5 cm) DynamaxC − using various gradient solvent mixtures from 89% H ₂ O / 11% CH ₃ CN / 0.1% TFA over 20 minutes. Purified by HPLC using 18 column (8 microns). The UV detector was set at 260 nm. The product was eluted as a single peak at 37.80 minutes, collected and lyophilized to give pure NAc-DTyr-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu- Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (1) was obtained as the trifluoroacetate salt. FAB mass spectrum m / e 1697 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.99 Pro; 0.99 Lys; 1.01 Leu; 0.99 NMeTyr; 0.49 Ser; 0.94 Tyr

  The following compounds are illustrated in Example 1 except that BOC-Gly was used in place of BOC-DTyr (O-2,6-diCl-Bzl) and a suitable carboxylic acid was used in place of acetic acid. Prepared using a procedure similar to the procedure. After completion of treatment, lyophilization and purification, the following compound was obtained:

Example 2a N-Siquimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 26)
R _t = 23.17 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.01 Pro; 1.04 Lys (Isp); 1.00 Leu; 0.99 Lys; 0.78 NMeTyr; 0.54 Ser; 0.99 3Pal; 1.06 4ClPhe 0.99 Gly
Example 2b N-dihydroshikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 27)
R _t = 17.45 minutes,
FAB mass spectrum m / e 1707 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 0.88 Pro; 0.96 Lys (Isp); 0.93 Leu; 0.98 Lys; 0.40 NMeTyr; 0.56 Ser; 0.80 3Pal; 0.97 4ClPhe 1.22 Gly
Example 2c N-2-furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 28),
R _t = 28.57 minutes,
FAB mass spectrum m / e 1643 (M + H) ⁺ ,
Amino acid analysis: 1.05 Ala; 0.97 Pro; 0.95 Lys (Isp); 0.97 Leu; 1.00 Lys; 0.56 NMeTyr; 0.44 Ser; 0.74 3Pal; 0.91 4ClPhe 1.02 Gly
Example 2d N-3-furoyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 29)
R _t = 28.82 minutes,
FAB mass spectrum m / e 1643 (M + H) ⁺ ,
Amino acid analysis: 1.06 Ala; 1.00 Pro; 0.90 Lys (Isp); 1.00 Leu; 0.97 Lys; 0.60 NMeTyr; 0.46 Ser; 0.72 3Pal; 0.72 4ClPhe 0.95 Gly
Example 2e N-picolyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 30), R _t = 29.25 minutes,
FAB mass spectrum m / e 1654 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.04 Pro; 1.01 Lys (Isp); 1.01 Leu; 0.96 Lys; 1.03 NMeTyr; 0.50 Ser; 1.01 3Pal; 1.07 4ClPhe 0.98 Gly
Example 2f N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 31), R _t = 26.65 minutes,
FAB mass spectrum m / e 1654 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.01 Pro; 0.88 Lys (Isp); 1.01 Leu; 0.96 Lys; 0.99 NMeTyr; 0.45 Ser; 1.08 3Pal; 1.16 4ClPhe 1.00 Gly
Example 2g N-isonicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 32)
R _t = 22.77 minutes,
FAB mass spectrum m / e 1654 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.02 Pro; 0.97 Lys (Isp); 1.03 Leu; 0.97 Lys; 1.02 NMeTyr; 0.43 Ser; 1.01 3Pal; 1.04 4ClPhe 0.97 Gly
Example 2h N-salicyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 33), R _t = 31.25 minutes,
FAB mass spectrum m / e 1669 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.02 Pro; 0.99 Lys (Isp); 1.02 Leu; 0.98 Lys; 1.10 NMeTyr; 0.47 Ser; 0.98 3Pal; 1.02 4ClPhe 0.98 Gly

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 23 )
Example 1 with the exception that BOC-Gly was used in place of BOC-DTyr (O-2,6-diCl-Bzl) and (R, S) -tetrahydro-2-furoyl was used in place of acetic acid. The title compound was prepared in a similar procedure as described. After treatment completion, lyophilization and HPLC purification, N [(R, S) -tetrahydroflu-2-oil] -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon) - isopropyl) -Pro-DAlaNH ₂ (23) was obtained as the trifluoroacetic acid salt.
R _t = 26.95 minutes,
FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.04 Pro; 0.94 Lys (Isp); 1.02 Leu; 0.96 Lys; 1.10 NMeTyr; 0.49 Ser; 1.00 3Pal; 1.07 4ClPhe 0.98 Gly

N- (S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 24)
The title compound was prepared by a procedure similar to that described in Example 3 except that (S) -tetrahydro-2-furoic acid was used instead of (R, S) -tetrahydro-2-furoic acid. . After treatment completion, lyophilization and HPLC purification, N [(S) -tetrahydroflu-2-oil] -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl ) -Pro-DAlaNH ₂ (24) was obtained as the trifluoroacetate salt.
R _t = 27.08 minutes,
FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.99 Pro; 0.93 Lys (Isp); 0.99 Leu; 1.03 Lys; 0.90 NMeTyr; 0.55 Ser; 0.98 3Pal; 1.00 4ClPhe 1.00 Gly

N- (R) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 25)
The title compound was prepared by a procedure similar to that described in Example 3 except that (R) -tetrahydro-2-furoic acid was used instead of (R, S) -tetrahydro-2-furoic acid. . After treatment completion, lyophilization and HPLC purification, N [(R) -tetrahydro-flu-2-oil] -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (N-epsilon- Isopropyl) -Pro-DAlaNH ₂ (25) was obtained as the trifluoroacetate salt.
R _t = 18.32 minutes,
FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 0.96 Ala; 0.98 Pro; 1.01 Lys (Isp); 0.99 Leu; 1.07 Lys; 0.93 NMeTyr; 0.67 Ser; 1.16 3Pal; 1.11 4ClPhe 1.13 Gly

  Same procedure as described in Example 1 except that a suitable BOC-amino acid was used instead of BOC-DTyr (O-2,6-diCl-Bzl) and a suitable carboxylic acid was used instead of acetic acid. The following compounds were prepared using the procedure: After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 6a N-nicotinyl-3aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 35)
R _t = 22.32 minutes,
FAB mass spectrum m / e 1668 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.02 Pro; 0.92 Lys (Isp); 1.02 Leu; 0.95 Lys; 1.04 NMeTyr; 0.40 Ser; 1.00 3Pal; 1.05 4ClPhe
Example 6b N-Cycymyl-3aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 36)
R _t = 22.25 minutes,
FAB mass spectrum m / e 1719 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.00 Pro; 1.02 Lys (Isp); 1.00 Leu; 1.00 Lys; 0.71 NMeTyr; 0.50 Ser; 1.00 3Pal; 1.00 4ClPhe
Example 6c N-nicotinyl-4aminobutyryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 38)
R _t = 22.75 minutes,
FAB mass spectrum m / e 1682 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.00 Pro; 0.89 Lys (Isp); 1.03 Leu; 0.96 Lys; 0.89 NMeTyr; 0.44 Ser; 0.70 3Pal; 0.75 4ClPhe 0.97 4-aminobutyric acid Example 6d N-Siquimyl-4aminobutyryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro- DAlaNH ₂ (compound 39),
R _t = 22.50 minutes,
FAB mass spectrum m / e 1733 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 0.99 Pro; 0.89 Lys (Isp); 1.05 Leu; 0.97 Lys; 0.83 NMeTyr; 0.44 Ser; 0.71 3Pal; 0.76 D4ClPhe 0.95 4-aminobutyric acid Example 6e N-nicotinyl-5 aminovaleryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-; DAlaNH ₂ (compound 41),
R _t = 14.02 minutes,
FAB mass spectrum m / e 1695 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.00 Pro; 0.93 Lys (Isp); 1.00 Leu; 0.96 Lys; 0.94 NMeTyr; 0.43 Ser; 0.99 3Pal; 1.06 4ClPhe 0.76 5-aminovaleric acid Example 6f N-Cycymyl-5-aminovaleryl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro -DAlaNH ₂ (compound 42),
R _t = 13.82 minutes,
FAB mass spectrum m / e 1747 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.01 Pro; 0.93 Lys (Isp); 1.00 Leu; 0.96 Lys; 1.01 NMeTyr; 0.45 Ser; 1.01 3Pal; 1.07 4ClPhe 0.80 5-aminovaleric acid

N-shikimyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 47)
The procedure described in Example 1 with the exception that BOC-D-Ser (OBzl) was used instead of BOC-DTyr (O-2,6-diCl-Bzl) and shikimic acid was used instead of acetic acid. The title compound was prepared in a similar procedure. After processing, lyophilization and HPLC purification, N-Siquimyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro- DAlaNH ₂ (47) was obtained.
R _t = 13.73 minutes,
FAB mass spectrum m / e 1735 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 0.99 Pro; 0.97 Lys (Isp); 0.98 Leu; 0.99 Lys; 0.82 NMeTyr; 0.97 Ser; 1.01 3Pal; 1.05 4ClPhe

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (Compound 49)
NicGly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys described in Example 2 except that BOC-DLyr (N-epsilon-FMOC) was used instead of BOC-DLyr (N-epsilon-nicotinyl) (N- epsilon - nicotinyl) -Leu-Lys - at (N- epsilon-isopropyl) procedure analogous to that for the synthesis of -Pro-DAlaNH _2, the title compound was prepared. After completion of this synthesis, the peptide-resin was treated with 20% piperidine / DMF overnight, washed 3 times with methylene chloride / DMF, then “2-2 hours” as described in Example 1. A binding protocol was used to first bind BOC-Gly and then nicotinic acid. The peptide-resin was dehydrated and treated with HF / anisole as described above. After processing, lyophilization and HPLC purification, N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (49) was obtained.
R _t = 13.88 minutes,
FAB mass spectrum m / e 1711 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.98 Pro; 0.92 Lys (Isp); 0.98 Leu; 0.97 Lys; 0.65 NMeTyr; 0.45 Ser; 0.92 3Pal; 0.98 4ClPhe 2.06 Gly.

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 50)
NicGly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys described in Example 2 except that BOC-DLyr (N-epsilon-FMOC) was used instead of BOC-DLyr (N-epsilon-nicotinyl) (N- epsilon - nicotinyl) -Leu-Lys - at (N- epsilon-isopropyl) procedure analogous to that for the synthesis of -Pro-DAlaNH _2, the title compound was prepared. After completion of this synthesis, the peptide-resin was treated with 20% piperidine / DMF overnight, washed 3 times with methylene chloride / DMF, and then washed with a marked excess of carbonyldiimidazole in DMF. Processed for minutes. The peptide-resin was washed 3 times with a (1: 1) DMF / DCM mixture and then reacted overnight with a significant excess of nicotinyl hydrazide in DMF. The peptide-resin was dehydrated and treated with HF / anisole as described above. After processing, lyophilization and HPLC purification, N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (50) was obtained.
R _t = 14.05 minutes,
FAB mass spectrum m / e 1712 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.03 Pro; 0.92 Lys (Isp); 1.00 Leu; 0.96 Lys; 1.00 NMeTyr; 0.45 Ser; 0.99 3Pal; 1.03 4ClPhe 1.01 Gly.

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2 furoyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 51)
The title compound was prepared by a procedure similar to that described in Example 9 except that 2-furoyl hydrazide was used instead of nicotinyl hydrazide. After processing completion and lyophilization and HPLC purification, N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2furoyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (51) was obtained.
R _t = 16.35 minutes,
FAB mass spectrum m / e 1700 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.00 Pro; 0.95 Lys (Isp); 1.00 Leu; 0.95 Lys; 0.87 NMeTyr; 0.48 Ser; 0.97 3Pal; 1.02 4ClPhe 1.03 Gly

N- (R, S) tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 52)
The title compound was prepared by a procedure similar to that described in Example 3 and Example 9, except that the appropriate amino acid and N-terminal acid were used instead. After processing, lyophilization and HPLC purification, N- (R, S) tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-nicotinyl) -Leu-Lys (N - epsilon - isopropyl) was obtained -Pro-DAlaNH ₂ (52).
R _t = 23.33 minutes,
FAB mass spectrum m / e 1706 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.98 Pro; 1.02 Lys (Isp); 0.98 Leu; 1.05 Lys; 0.97 NMeTyr; 0.53 Ser; 0.95 3Pal; 1.01 4ClPhe 1.01 Gly.

N- (R, S) tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 53)
The title compound was prepared by a procedure similar to that described in Example 3, except that BOC-D2Nal was followed by (R, S) -tetrahydro-2-furoic acid. After processing, lyophilization and HPLC purification, N- (R, S) tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-nicotinyl) -Leu-Lys (N-epsilon) - isopropyl) was obtained -Pro-DAlaNH ₂ (53).
R _t = 26.70 min, 26.77 min FAB, mass spectrum m / e 1704 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 0.97 Pro; 0.93 Lys (Isp); 0.99 Leu; 0.95 Lys; 0.86 NMeTyr; 0.50 Ser; 1.05 3Pal; 1.11 4ClPhe 2.02 Gly.

  BOC-Gly is used instead of BOC-DTyr (O-2,6-diCl-Bzl), BOC-DCit is used instead of BOC-DLys (N-epsilon-FMOC), and BOC-Lys (N- Same procedure as described in Example 1 except that BOC-Arg (Tos) was used instead of epsilon-CBZ, isopropyl) and the appropriate BOC-amino acid and acid were used instead of acetic acid. The following compounds were prepared using the procedure. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 13a N- (R, S) tetrahydro - fur-2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 (Compound 80) as a trifluoroacetic acid salt Obtained.
R _t = 36.10 minutes,
FAB mass spectrum m / e 1557 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.99 Pro; 0.99 Arg; 1.02 Leu; 1.03 Cit; 0.49 Ser; 1.05 3Pal; 1.06 4ClPhe; 0.98 Gly.
Example 13b N-Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 81) was obtained as the trifluoroacetic acid salt.
R _t = 32.35 minutes,
FAB mass spectrum m / e 1615 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.03 Pro; 0.96 Arg; 1.04 Leu; 0.98 Cit; 0.47 Ser; 0.69 3Pal; 0.97 4ClPhe; 0.95 Gly.
Example 13c N-nicotinyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 82) was obtained as the trifluoroacetic acid salt.
R _t = 32.20 minutes,
FAB mass spectrum m / e 1565 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.01 Pro; 1.00 Arg; 1.03 Leu; 1.02 Cit; 0.86 NMeTyr; 0.44 Ser; 1.03 3Pal; 1.01 4ClPhe; 95 Gly.
Example 13d N-succinyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 83) was obtained as the trifluoroacetic acid salt.
R _t = 38.05 minutes,
FAB mass spectrum m / e 1559 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.00 Pro; 0.96 Arg; 0.99 Leu; 1.00 Cit; 1.04 NMeTyr; 0.53 Ser; 0.97 3Pal; 1.04 4ClPhe; 05 Gly.
Example 13e N-Shikimiru -DAla-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 84) was obtained as the trifluoroacetic acid salt.
R _t = 31.25 minutes,
FAB mass spectrum m / e 1629 (M + H) ⁺ ,
Amino acid analysis: 1.99 Ala; 1.03 Pro; 0.94 Arg; 1.03 Leu; 1.04 Cit; 1.05 NMeTyr; 0.51 Ser; 0.70 3Pal; 0.88 4ClPhe.
Example 13f N-Shikimiru -DSer-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 85) was obtained as the trifluoroacetic acid salt.
R _t = 31.25 minutes,
FAB mass spectrum m / e 1646 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.04 Pro; 0.97 Arg; 1.00 Leu; 0.98 Cit; 0.90 NMeTyr; 1.02 Ser; 0.99 3Pal; 1.02 4ClPhe.

  BOC-Gly is used instead of BOC-D-Tyr (O-2,6-diCl-Bzl), BOC-Cit is used instead of BOC-DLys (N-epsilon-FMOC), and BOC-Lys ( Using a procedure similar to that described in Example 1 except that BOC-Arg (Tos) was used instead of N-epsilon-Cbz, isopropyl) and the appropriate acid was used, the following compound: Was prepared. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 14a N-nicotinyl -Sar-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 86) was obtained as the trifluoroacetic acid salt.
R _t = 31.35 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.02 Pro; 1.01 Arg; 1.04 Leu; 0.93 Lys; 1.19 NMeTyr; 0.48 Ser; 1.14 3Pal; 1.23 4ClPhe; 97 Sar.
Example 14b N-Shikimiru -Sar-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys the (Shik) -Leu-Arg-Pro -DAlaNH 2 ( Compound 87) was obtained as the trifluoroacetic acid salt.
R _t = 31.35 minutes,
FAB mass spectrum m / e 1757 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.02 Pro; 0.99 Arg; 1.03 Leu; 0.97 Lys; 0.97 NMeTyr; 0.51 Ser; 1.12 3Pal; 1.24 ClPhe; 90 Sar.
Example 14c N-nicotinyl -DAla-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys the (Shik) -Leu-Arg-Pro -DAlaNH 2 ( Compound 88) was obtained as the trifluoroacetic acid salt.
R _t = 31.15 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 1.98 Ala; 1.02 Pro; 0.98 Arg; 1.02 Leu; 0.92 Lys; 1.10 NMeTyr; 0.47 Ser; 1.12 3Pal; 1.20 4ClPhe.
Example 14d N-Shikimiru -DAla-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 89) was obtained as the trifluoroacetic acid salt.
R _t = 30.75 minutes,
FAB mass spectrum m / e 1756 (M + H) ⁺ ,
Amino acid analysis: 1.98 Ala; 1.05 Pro; 1.00 Arg; 1.03 Leu; 0.94 Lys; 1.01 NMeTyr; 0.47 Ser; 1.11 3Pal; 1.19 4ClPhe.
Example 14e N-nicotinyl -DSer-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys the (Shik) -Leu-Arg-Pro -DAlaNH 2 ( Compound 90) was obtained as the trifluoroacetic acid salt.
R _t = 31.35 minutes,
FAB mass spectrum m / e 1722 (M + H) ⁺ ,
Amino acid analysis: 0.97 Ala; 1.03 Pro; 0.96 Arg; 1.02 Leu; 0.96 Lys; 1.02 NMeTyr; 1.01 Ser; 1.10 3Pal; 1.14 4ClPhe.
Example 14f N-Shikimiru -DSer-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 91) was obtained as the trifluoroacetic acid salt.
R _t = 30.60 minutes,
FAB mass spectrum m / e 1773 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.03 Pro; 0.95 Arg; 0.99 Leu; 0.93 Lys; 1.02 NMeTyr; 0.96 Ser; 1.06 3Pal; 1.12 4ClPhe.
EXAMPLE 14 g N-nicotinyl -DLys (Nic) -D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 92) was obtained as the trifluoroacetic acid salt.
R _t = 29.25 minutes,
FAB mass spectrum m / e 1867 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.01 Pro; 0.97 Arg; 1.03 Leu; 1.85 Lys; 1.05 NMeTyr; 0.49 Ser; 1.13 D3Pal; 1.20 D-4ClPhe.
Example 14h N-Shikimiru -DLys (Nic) -D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 93) was obtained as the trifluoroacetic acid salt.
R _t = 28.65 minutes,
FAB mass spectrum m / e 1918 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.00 Pro; 0.99 Arg; 1.02 Leu; 1.79 Lys; 1.09 NMeTyr; 0.45 Ser; 1.11 3Pal; 1.19 4ClPhe.
Example 14i N-nicotinyl -DLys (Shik) -D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 94) was obtained as the trifluoroacetic acid salt.
R _t = 29.05 min,
FAB mass spectrum m / e 1918 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.04 Pro; 1.01 Arg; 1.06 Leu; 1.88 Lys; 1.12 NMeTyr; 0.57 Ser; 1.16 3Pal; 1.23 4ClPhe.
Example 14j N-Shikimiru -DLys (Shik) -D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 95) was obtained as the trifluoroacetic acid salt.
R _t = 28.35 minutes,
FAB mass spectrum m / e 1969 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.02 Pro; 0.96 Arg; 1.02 Leu; 1.80 Lys; 1.01 NMeTyr; 0.49 Ser; 1.12 3Pal; 1.19 4ClPhe.
Example 14k N-nicotinyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 96) was obtained as the trifluoroacetic acid salt.
R _t = 30.85 minutes,
FAB mass spectrum m / e 1691 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.04 Pro; 1.00 Arg; 1.02 Leu; 0.95 Lys; 0.92 NMeTyr; 0.47 Ser; 1.03 3Pal; 1.08 4ClPhe; 84 Gly.
Example 14l N-Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 97) was obtained as the trifluoroacetic acid salt.
R _t = 30.85 minutes,
FAB mass spectrum m / e 1743 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.06 Pro; 1.00 Arg; 1.03 Leu; 0.97 Lys; 0.92 NMeTyr; 0.49 Ser; 1.05 3Pal; 1.10 4ClPhe; 92 Gly.
Example 14m N-(S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH trifluoroacetate ₂ (Compound 98) Got as.
R _t = 38.40 minutes,
FAB mass spectrum m / e 1683 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.02 Pro; 0.98 Arg; 1.01 Leu; 0.96 Lys; 1.02 NMeTyr; 0.52 Ser; 1.00 3Pal; 1.09 4ClPhe; 02 Gly.
Example 14n N-(R) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH trifluoroacetate ₂ (Compound 99) Got as.
R _t = 41.15 minutes,
FAB mass spectrum m / e 1683 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.02 Pro; 0.98 Arg; 1.01 Leu; 0.96 Lys; 1.02 NMeTyr; 0.52 Ser; 1.00 3Pal; 1.09 4ClPhe; 02 Gly.

  Using a procedure similar to that described in Example 14 except that instead of BOC-DLys (Shik), an appropriate BOC-amino acid was used at the G position and an acid was used at the X position, The compound was prepared. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 15a N-Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys the (Nic) -Leu-Arg-Pro -DAlaNH 2 ( Compound 100) was obtained as the trifluoroacetic acid salt.
R _t = 32.85 minutes,
FAB mass spectrum m / e 1692 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.03 Pro; 0.97 Arg; 1.03 Leu; 1.00 Lys; 1.14 NMeTyr; 0.52 Ser; 1.12 3Pal; 0.97 Gly.
Example 15b N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu-Arg-Pro-DAlaNH ₂ (Compound 101) was obtained as the trifluoroacetate salt.
R _t = 34.75 minutes,
FAB mass spectrum m / e 1750 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.03 Pro; 0.98 Arg; 1.01 Leu; 0.97 Lys; 1.04 NMeTyr; 0.53 Ser; 1.00 3Pal; 1.09 4ClPhe; 01 Gly.
Example 15c N-Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys the (DSer-Nic) -Leu-Arg -Pro-DAlaNH 2 ( Compound 102) was obtained as the trifluoroacetic acid salt.
R _t = 34.45 minutes,
FAB mass spectrum m / e 1778 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 1.00 Pro; 0.94 Arg; 1.00 Leu; 1.02 Lys; 1.12 NMeTyr; 1.28 Ser; 1.02 3Pal; 1.06 4ClPhe; 15 Gly.
Example 15d N-Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Gly-Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 103) was obtained as the trifluoroacetic acid salt.
R _t = 18.59 minutes,
FAB mass spectrum m / e 1799 (M + H) ⁺ ,
Amino acid analysis: 1.13 Ala; 0.98 Pro; 0.99 Arg; 1.03 Leu; 0.96 Lys; 0.85 NMeTyr; 0.44 Ser; 0.69 3Pal; 0.76 4ClPhe; 91 Gly.

N-shikimyl-Gly-D2Nal-D4ClPhe-D1Nal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ (compound 104)
N-Siquimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH as described in Example 14 except that BOC-D1Nal was used instead of BOC-D3Pal. _The title compound was prepared using a procedure similar to that for the preparation of ₂ . After processing completion, lyophilization and HPLC purification, N-shikimyl-Gly-D2Nal-D4ClPhe-D1Nal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ was obtained.
R _t = 40.55 minutes,
FAB mass spectrum m / e 1791 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 1.00 Pro; 0.94 Arg; 0.99 Leu; 0.99 Lys; 0.61 NMeTyr; 0.58 Ser; 1.06 4ClPhe; 1.02 Gly.

N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ (Compound 105)
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys described in Example 14 except that BOC-NMePhe was used instead of BOC-NMeTyr (O-2,6-diClBzl) Shik) using a procedure similar to that of -Leu-Arg-Pro-DAlaNH preparation of ₂ for, the title compound was prepared. After treatment completion, lyophilization and HPLC purification, N-shikimyl-Gly-D2Nal-D4ClPhe-D1Nal-Ser-NMePhe-DLys (Shik) -Leu-Arg-Pro-DAlaNH ₂ was obtained.
R _t = 35.05 minutes,
FAB mass spectrum m / e 1726 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.02 Pro; 0.98 Arg; 1.00 Leu; 0.52 Ser; 1.03 Pal; 1.07 4ClPhe; 0.97 Gly.

N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu as described in Example 14 except that BOC-Ile and BOC-NMeLeu were used instead of BOC-Leu, respectively. using procedures similar to those for the preparation of -Arg-Pro-DAlaNH _2, the following compounds were prepared. After processing, lyophilization and HPLC purification, the following compound was obtained:

Example 18a N-Siquimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Ile-Arg-Pro-DAlaNH ₂
R _t = 32.05 minutes,
FAB mass spectrum m / e 1742 (M + H) ⁺ ,
Amino acid analysis: 1.06 Ala; 1.07 Pro; 0.99 Arg; 0.93 Ile; 0.52 Ser; 1.06 3Pal; 1.06 4ClPhe; 1.00 Gly. (Compound 106)
Example 18b N-Siquimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -NMeLeu-Arg-Pro-DAlaNH ₂
R _t = 33.4 minutes,
FAB mass spectrum m / e 1756 (M + H) ⁺ ,
Amino acid analysis: 1.09 Ala; 1.02 Pro; 0.97 Arg; 0.94 Lys; 0.75 NMeTyr; 0.51 Ser; 1.03 3Pal; 1.09 4ClPhe; 0.97 Gly (Compound 107 )

N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Aze-DAlaNH ₂ (compound 108)
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH as described in Example 14 except that BOC-Aze was used instead of BOC-Pro. _The title compound was prepared using a procedure similar to that for the preparation of ₂ . After processing completion, lyophilization and HPLC purification, N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Arg-Aze-DAlaNH ₂ was obtained.
R _t = 14.13 minutes,
FAB mass spectrum m / e 1728 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 0.96 Arg; 0.98 Leu; 0.99 Lys; 1.41 NMeTyr; 0.51 Ser; 0.95 3Pal; 1.00 4ClPhe; 1.05 Gly.

N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (GlyGlyNic) -Leu-Arg-Pro-DAlaNH ₂ (Compound 109)
N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu- described in Example 15 except that it was conjugated twice with BOC-Gly prior to nicotinic acid binding. using procedures similar to those for the preparation of arg-Pro-DAlaNH _2, the title compound was prepared. After treatment completion, lyophilization and HPLC purification, N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (GlyGlyNic) -Leu-Arg-Pro-DAlaNH ₂ was obtained.
R _t = 14.77 minutes,
FAB mass spectrum m / e 1805 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.00 Arg; 1.03 Leu; 1.02 Lys; 1.10 NMeTyr; 0.47 Ser; 1.17 3Pal; 0.91 4ClPhe; 2.90 Gly.

N- (L-Glonyl) -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-L-Glonyl) -Leu-Arg-Pro-DAlaNH ₂ (Compound 110)
Boc-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Boc) -Leu-Arg-Pro-DAla-N-Siquimyl-Gly-D2Nal-D4ClPhe described in Example 15 for synthesis of resin use -D3Pal-Ser-NMeTyr-DLys ( Gly-Shik) -Leu-Arg-Pro-DAlaNH similar to the procedure for preparation of _2, the title compound was prepared. The peptide was cleaved with HF / anisole and lyophilized, leaving free glycine amine residues at positions 0 and 6. The crude peptide (0.24 g, 0.17 mmol) and L-gulonic acid lactone (0.30 g, 1.7 mmol) were heated in DMF at 85 ° C. for 48 hours. The solution is concentrated in vacuo, the residue is purified by HPLC, N- (L-Glonyl) -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-L-Glonyl) -Leu-Arg-Pro-DAlaNH ₂ was obtained.
R _t = 17.16 minutes,
FAB mass spectrum m / e 1843 (M + H) ⁺ ,
Amino acid analysis: 1.14 Ala; 0.97 Pro; 1.00 Arg; 1.06 Leu; 0.96 Lys; 0.87 NMeTyr; 0.45 Ser; 0.69 3Pal; 0.75 4ClPhe; 85 Gly.

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Arg-Pro-DAlaNH ₂ (compound 111)
Using nicotinic acid instead of shikimic acid, the N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Arg-Pro-DAlaNH ₂ described in Example 15 was used. The title compound was prepared using a procedure similar to the procedure for preparation. After processing, lyophilization and HPLC purification, N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Arg-Pro-DAlaNH ₂ was obtained.
R _t = 23.82 minutes,
FAB mass spectrum m / e 1748 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 0.99 Pro; 0.94 Arg; 0.98 Leu; 1.01 Lys; 0.93 NMeTyr; 0.50 Ser; 1.06 3Pal; 1.13 4ClPhe; 08 Gly.

  The following compounds were prepared using procedures similar to those described in Example 14 except that BOC-Ile and BOC-NMeLeu were used for each instead of BOC-Leu. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 23a N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Ile-Arg-Pro-DAlaNH ₂ (Compound 112)
R _t = 14.27 minutes,
FAB mass spectrum m / e 1691 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 1.04 Pro; 1.00 Arg; 0.95 Ile; 0.96 Lys; 1.79 NMeTyr; 0.47 Ser; 0.99 D3Pal; 1.05 D4ClPhe; 01 Gly.
Example 23b N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimil) -NMeLeu-Arg-Pro-DAlaNH ₂ (Compound 113)
R _t = 15.15 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 1.08 Ala; 1.01 Pro; 0.97 Arg; 0.92 Lys; 1.33 NMeTyr; 0.47 Ser; 0.95 3Pal; 1.01 4ClPhe; 1.06 Gly.

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Arg-Aze-DAlaNH ₂ (Compound 114)
The title compound was prepared using a procedure similar to that described in Example 19 using BOC-Aze instead of BOC-Pro. After processing, lyophilization and HPLC purification, nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Arg-Aze-DAlaNH ₂ was obtained.
R _t = 14.00 minutes,
FAB mass spectrum m / e 1678 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.00 Arg; 0.97 Lys; 0.46 Ser; 1.15 3Pal; 0.89 4ClPhe; 1.0 Gly.

The following compounds were prepared using procedures similar to those described in Example 14 except that BOC-Harg (NO ₂ ) was used in place of BOC-Arg (Tos). After processing, lyophilization and HPLC purification, the following compound was obtained:

Example 25a N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (Compound 115)
R _t = 30.45 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.00 Pro; 1.04 Leu; 0.96 Lys; 1.06 NMeTyr; 0.54 Ser; 1.13 3Pal; 1.20 4ClPhe; 1.02 Gly.
Example 25b N-nicotinyl-DSer-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Harg-Pro-DAlaNH ₂ (Compound 116)
R _t = 33.85 minutes,
FAB mass spectrum m / e 1735 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 0.99 Pro; 1.00 Leu; 0.98 Lys; 1.04 NMeTyr; 1.05 Ser; 0.97 3Pal; 1.04 4ClPhe.
Example 25c N-(2-furoyl) -Gly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 ( Compound 117)
R _t = 40.60 minutes,
FAB mass spectrum m / e 1694 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.03 Pro; 1.01 Leu; 0.93 Lys; 1.28 NMeTyr; 0.47 Ser; 0.97 3Pal; 1.04 4ClPhe; 0.88 Gly.
Example 25d N-Sichymyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (Compound 118)
R _t = 31.95 minutes,
FAB mass spectrum m / e 1756 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.03 Pro; 1.04 Leu; 0.94 Lys; 1.15 NMeTyr; 0.49 Ser; 1.15 3Pal; 1.20 4ClPhe; 0.97 Gly.
Example 25e N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Shik) -Leu-Harg-Pro-DAlaNH ₂ (Compound 119)
R _t = 30.27 minutes,
FAB mass spectrum m / e 1762 (M + H) ⁺ ,
Amino acid analysis: 1.07 Ala; 1.00 Pro; 0.99 Leu; 0.99 Lys; 1.14 NMeTyr; 0.50 Ser; 0.97 3Pal; 1.04 4ClPhe; 2.01 Gly.
Example 25f N-nicotinyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys ( nicotinyl) -Leu-Harg-Pro-DAlaNH 2 ( Compound 120)
R _t = 18.91 minutes,
FAB mass spectrum m / e 1655 (M + H) ⁺ ,
Amino acid analysis: 1.07 Ala; 1.00 Pro; 1.03 Leu; 0.99 Lys; 1.01 NMeTyr; 0.46 Ser; 1.04 3Pal; 1.10 4ClPhe; 0.96 Gly.
Example 25g N- (3-quinolinylcarbonyl) -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Harg-Pro-DAlaNH ₂ (Compound 124)
R _t = 17.77 minutes,
FAB mass spectrum m / e 1755 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.92 Pro; 0.98 Leu; 1.01 Lys; 1.41 NMeTyr; 0.49 Ser; 0.93 3Pal; 098 4ClPhe; 1.04 Gly.

  Procedure described in Example 22 except that instead of BOC-NMeTyr (O-2,6-diCl-Bzl), the appropriate BOC-amino acid and the appropriate BOC-amino acid were used at the A and X positions. The following compounds were prepared using a similar procedure to: After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 26a N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (Compound 121)
R _t = 16.79 minutes,
FAB mass spectrum m / e 1689 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.96 Pro; 0.96 Leu; 1.03 Lys; 0.54 Ser; 0.92 3Pal; 0.97 4ClPhe; 1.05 Gly.
Example 26b N-nicotinyl _{-Gly-D2Nal-D4ClPhe-D3Pal-} Ser-NMePhe (NO 2) -DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 ( Compound 122)
R _t = 17.83 minutes,
FAB mass spectrum m / e 1736 (M + H) ⁺ ,
Amino acid analysis: 1.07 Ala; 0.99 Pro; 1.00 Leu; 0.94 Lys; 0.40 Ser; 0.98 3Pal; 1.04 4ClPhe; 1.00 Gly
Example 26c N-Shikimiru _{-Gly-D2Nal-D4ClPhe-D3Pal-} Ser-NMePhe (NO 2) -DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 ( Compound 123)
R _t = 17.37 minutes,
FAB mass spectrum m / e 1785 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 0.99 Pro; 1.00 Leu; 0.97 Lys; 0.48 Ser; 0.99 3Pal; 1.03 4ClPhe; 0.99 Gly

  The following compounds were prepared using procedures similar to those described in Example 14 except for substitution with the appropriate BOC-amino acid and acid at the X, A, G and J positions. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 27a N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Arg-Pro-DAlaNH ₂ (Compound 125)
R _t = 15.11 minutes,
FAB mass spectrum m / e 1640 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 0.99 Pro; 0.99 Leu; 1.00 Lys; 1.47 NMeTyr; 0.46 Ser; 0.99 3Pal; 1.06 4ClPhe; 1.02 Gly.
Example 27b N- (R, S) -tetrahydroflu-2 oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu-Arg-Pro-DAlaNH ₂ (compound 126)
R _t = 18.27 minutes,
FAB mass spectrum m / e 1690 (M + H) ⁺ ,
Amino acid analysis: 1.07 Ala; 1.00 Pro; 1.01 Leu; 0.99 Lys; 1.40 NMeTyr; 0.39 Ser; 0.97 3Pal; 1.09 4ClPhe; 1.97 Gly.
Example 27c N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Arg-Aze-DAlaNH ₂ (Compound 127)
R _t = 14.77 minutes,
FAB mass spectrum m / e 1678 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.02 Leu; 1.01 Lys; 1.07 NMeTyr; 0.43 Ser; 1.15 3Pal; 0.90 4ClPhe; 0.98 Gly.
Example 27d N-nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shikimyl) -Leu-Arg-Pro-DAlaNH ₂ (Compound 128)
R _t = 30.75 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.98 Pro; 0.95 Arg; 1.04 Leu; 0.96 Lys; 0.90 NMeTyr; 0.55 Ser; 1.13 3Pal; 1.19 4ClPhe.
Example 27e N-Shikimiru 3-amino-propionylamino -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2 ( Compound 129)
R _t = 30.95 minutes,
FAB mass spectrum m / e 1756 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.03 Pro; 0.99 Arg; 1.04 Leu; 0.95 Lys; 0.35 NMeTyr; 0.50 Ser; 1.12 3Pal; 1.18 4ClPhe.

N-nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (compound 132)
The title compound was prepared using a procedure similar to that described in Example 8 except that BOC-Harg (NO ₂ ) was used instead of BOC-Arg (Tos). After treatment completion, lyophilization and HPLC purification, nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ was obtained.
R _t = 34.20 minutes,
FAB mass spectrum m / e 1719 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.99 Pro; 0.99 Leu; 1.00 Lys; 1.02 NMeTyr; 0.57 Ser; 0.98 3Pal; 1.04 4ClPhe.

N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (GlyNic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 135)
The title compound was prepared using a procedure similar to that described in Example 8 except that the appropriate BOC-amino acids and acids were used in place of 6 and 0 instead. After treatment completion, lyophilization and HPLC purification, N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (GlyNic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 31.31 minutes,
FAB mass spectrum m / e 1705 (M + H) ⁺ ,
Amino acid analysis: 0.96 Ala; 1.00 Pro; 0.96 Lys (Isp); 1.00 Leu; 0.85 Lys; 1.08 Gly; 1.08 NMeTyr; 0.49 Ser; 1.13 3Pal 1.15 4ClPhe (135).

  The following compounds were prepared using procedures similar to those described in Example 11 except that the appropriate BOC-amino acids and acids were used instead at the 6 and 0 positions. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 30a N- (R, S) -Tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2Fur) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (compound 136)
R _t = 27.47 min, 27.58 min FAB mass spectrum m / e 1694 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.02 Pro; 0.95 Lys (Isp); 1.01 Leu; 0.93 Lys; 1.07 NMeTyr; 0.47 Ser; 1.07 3Pal; 1.13 4ClPhe 1.03 Gly.
Example 30b N-Shik-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 139)
R _t = 31.21 min FAB mass spectrum m / e 1707 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.02 Pro; 0.94 Lys (Isp); 1.02 Leu; 0.87 Lys; 0.87 NMeTyr; 0.5 Ser; 0.97 3Pal; 1.05 ClPhe .
Example 30c N-Shik-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2Fur) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 140)
R _t = 30.87 min FAB mass spectrum m / e 1696 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.03 Pro; 0.92 Lys (Isp); 1.01 Leu; 0.96 Lys; 1.16 NMeTyr; 0.5 Ser; 1.05 3Pal; 1.06 ClPhe .

N-nicotinyl-Azagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 141)
The title compound was prepared using a procedure similar to that described in Example 30 except that it was replaced with Nic-Azagly at position 0 using the same method as described above for position 6. . After treatment completion, lyophilization and HPLC purification, NicAzagly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 25.92 minutes,
FAB mass spectrum m / e 1565 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 0.98 Pro; 0.91 Lys (Isp); 1.00 Leu; 1.00 Lys; 1.44 NMeTyr; 0.50 Ser; 1.01 3Pal; 1.0 4ClPhe .

N-nicotinyl-Azagly-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 142)
Explained in Example 31 except that BOC-DLys (Nic) was used instead of BOC-DLys (FMOC), BOC-DBal was used instead of BOC-D3Pal, and the BOC-D2Nal coupling reaction was omitted. The title compound was prepared using a procedure similar to that described above. Nic-Azagly-D4ClPhe-DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained after treatment completion, lyophilization and HPLC purification.
R _t = 19.17 minutes,
FAB mass spectrum m / e 1513 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.03 Pro; 0.99 Leu; 1.57 Lys; 1.08 NMeTyr; 0.45 Ser.

  The following compounds were prepared using procedures similar to those described in Example 32 except for replacing with the appropriate BOC-amino acid and acid at the 3 and 0 positions. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 33a N-(2-furoyl) -Azagly-D4ClPhe-DBal-Ser -NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 143).
R _t = 20.41 minutes,
FAB mass spectrum m / e 1502 (M + H) ⁺ ,
Amino acid analysis: 0.96 Ala; 1.02 Pro; 1.6 Lys (Isp); 1.02 Leu; 0.94 Lys; 1.16 NMeTyr; 0.48 Ser.
Example 33b N-isonicotinyl -Azagly-D4ClPhe-DBal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 145).
R _t = 17.23 minutes,
FAB mass spectrum m / e 1513 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 1.03 Pro; 0.88 Lys (Isp); 0.99 Leu; 0.94 Lys; 1.23 NMeTyr; 0.63 Ser; 0.86 4ClPhe.
Example 33c N-nicotinyl -Azagly-D4ClPhe-D1Nal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 146).
R _t = 18.60 min,
FAB mass spectrum m / e 1507 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.02 Pro; 0.95 Lys (Isp); 1.00 Leu; 0.96 Lys; 1.09 NMeTyr; 0.41 Ser; 1.00 4ClPhe.

N- nicotinyl -Sar-D4ClPhe-DBal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 147)
Instead of introducing NicAzagly after conjugation with BOC-D4ClPhe, the procedure was similar to that described in Example 33 except that the peptide-resin was conjugated with BOC-Sar and then nicotinic acid. Used to prepare the title compound. After the process is completed the freeze-dried and the HPLC purification gave the NicSar-D4ClPhe-DBal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2.
R _t = 17.80 minutes,
FAB mass spectrum m / e 1526 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 1.01 Pro; 0.90 Lys (Isp); 0.99 Leu; 0.96 Lys; 1.22 NMeTyr; 0.41 Ser; 0.74 4ClPhe.

  Using a procedure similar to that described in Example 34 except that it was coupled to BOC-Gly and nicotinic acid after conjugation with BOC-Sar and replaced with the appropriate BOC-amino acid at position 3. The following compounds were prepared: After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 35a Nic-Gly-Sar-D4ClPhe -D1Nal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 148)
R _t = 17.25 min FAB mass spectrum m / e 1578 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.02 Pro; 0.88 Lys (Isp); 1.03 Leu; 1.05 Lys; 1.07 NMeTyr; 0.48 Ser; 1.15 4ClPhe; 0.92 Sar 0.92 Gly.
Example 35b Nic-Gly-Sar-D4ClPhe -DBal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 149)
R _t = 16.30 min FAB mass spectrum m / e 1584 (M + H) ⁺ ,
Amino acid analysis: 1.10 Ala; 1.02 Pro; 094 Lys (Isp); 0.97 Leu; 0.96 Lys; 1.10 NMeTyr; 0.41 Ser; 1.03 Sar; 0.95 Gly.

  Procedure similar to that described in Example 2 except that BOC-3-aminopropanoic acid was used in place of BOC-Gly and BOC-D-Bal was used in place of BOC-D-3-Pal. The following compounds were prepared using After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

N-nicotinyl-3-aminopropionyl-D2Nal-D4ClPhe-DBal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 151)
R _t = 18.39 min FAB mass spectrum m / e 1726 (M + H) ⁺ ,
Amino acid analysis: 0.92 Ala; 0.98 Pro; 1.01 Lys (Isp); 1.02 Leu; 1.08 Lys; 1.18 NMeTyr; 0.36 Ser; 1.04 4ClPhe.

  The following compounds were prepared using procedures similar to those described in Example 31 except that the appropriate BOC-amino acids and acid hydrazides were used instead. After completion of treatment, lyophilization and HPLC purification, the following compound was obtained:

Example 37a N-(2-furoyl) -Azagly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 155)
R _t = 21.49 min FAB mass spectrum m / e 1644 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.02 Pro; 1.64 Lys; 1.01 Leu; 0.82 NMeTyr; 0.56 Ser.
Example 37b N-nicotinyl -Azagly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 156)
R _t = 17.60 min FAB mass spectrum m / e 1655 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.03 Pro; 1.60 Lys; 1.01 Leu; 1.12 NMeTyr; 0.46 Ser.
Example 37c N-salicylic -Azagly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 157)
R _t = 20.35 min FAB mass spectrum m / e 1671 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.01 Pro; 0.98 Lys; 1.01 Leu; 1.12 NMeTyr; 0.46 Ser.
Example 37d N-isonicotinyl -Azagly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 158)
R _t = 19.30 min FAB mass spectrum m / e 1655 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.02 Pro; 0.87 Lys (Isp); 1.04 Leu; 0.95 Lys; 1.04 NMeTyr; 0.46 Ser; 1.06 3Pal; 1.04 4ClPhe .
Example 37e N-tosyl -Azagly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 160)
R _t = 21.17 min FAB mass spectrum m / e 1704 (M + H) ⁺ ,
Amino acid analysis: 1.07 Ala; 1.01 Pro; 0.90 Lys (Isp); 1.01 Leu; 0.94 Lys; 1.04 NMeTyr; 0.51 Ser.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ (Compound 165)
The title compound was prepared using a procedure similar to that described in Example 3, except that BOC-SarNH-resin was used instead of BOC-DAlaNH-resin. After processing, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro -SarNH ₂ (165) was obtained as the trifluoroacetate salt.
R _t = 17.03 min, 18.04 min FAB mass spectrum m / e 1646 (M + H) ⁺ ,
Amino acid analysis: 1.01 Sar; 1.0 Pro; 1.23 Lys (Isp); 1.01 Leu; 1.02 Lys; 1.12 NMeTyr; 0.51 Ser; 1.13 3Pal; 1.31 4ClPhe .

N- (S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 166)
A procedure similar to that described in Example 4 was used, except that BOC-SarNH-resin was used instead of BOC-DAlaNH-resin. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (N-epsilon-isopropyl ) -Pro-SarNH ₂ (166) was obtained as the trifluoroacetate salt.
R _t = 19.75 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 0.90 Sar; 0.99 Pro; 1.0 Lys (Isp); 0.99 Leu; 0.99 Lys; 1.03 NMeTyr; 0.39 Ser; 0.97 D3Pal; 1.03 D4ClPhe 1.02 Gly.

N- (R) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 167)
A procedure similar to that described in Example 5 was used, except that BOC-SarNH-resin was used instead of BOC-DAlaNH-resin. After processing completion, lyophilization and HPLC purification, (R) -tetrahydroflu-2-ol-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ (167) was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 168)
A procedure similar to that described in Example 1 was used, except that BOC-Tyr (O-2,6diClBzl) was used instead of BOC-NMe-Tyr (O-2,6Cl-Bzl). After processing completion, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (nicotinyl) -Leu-Lys (Isp) -Pro -SarNH ₂ (168) was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (nicotinyl) -Leu-Lys (Isp) -Pro-SarNH ₂ (Compound 169)
A procedure similar to that described in Example 41 was used, except that BOC-Lys (Nic) was used instead of BOC-Tyr (O-2,6Cl-Bzl). After processing completion, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (nicotinyl) -Leu-Lys (Isp ) -Pro-SarNH ₂ (169) was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DCit-Leu-Arg-Pro-SarNH ₂ (compound 170)
Same procedure as described in Example 41, except that BOC-DCit was used instead of BOC-DLys (Nic) and BOC-Arg (Tos) was used instead of BOC-Lys (Cbz, Isp). Procedure was used. After the process is completed the freeze-dried and HPLC purification, (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DCit-Leu-Arg-Pro-SarNH 2 (170) Was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Arg-Pro-SarNH ₂ (Compound 171)
A procedure similar to that described in Example 41 was used except that BOC-DHcit was used instead of BOC-DLys (Nic). After the process is completed the freeze-dried and HPLC purification, (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Arg-Pro-SarNH 2 (171) Was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys (Isp) -Pro-SarNH ₂ (Compound 172)
A procedure similar to that described in Example 44 was used except that BOC-Lys (Isp, Cbz) was used in place of BOC-Arg (Tos). After processing, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys (Isp) -Pro-SarNH ₂ (172) was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Arg-D4 (pOMeBzol) Hala-Leu-Arg-Pro-SarNH ₂ (compound 173)
The use of BOC-Arg (Tos) instead of BOC-Tyr (O-2,6-diClBzl) and BOC-D-4- (p-OMe-benzoyl) homoalanyl instead of BOC-DCit Except for the procedure described in Example 43, the same procedure was used. After completion of treatment, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Arg-D4 (pOMeBzol) -Leu-Arg-Pro-SarNH ₂ (173) was obtained as the trifluoroacetate salt.

N- (R, S) - tetrahydrofurfuryl 2-Oil _{-Gly-D2Nal-D4ClPhe-D3Pal-} Ser-Tyr-DHarg (Et 2) -Leu-Harg (Et 2) -Pro-SarNH 2 ( Compound 174)
BOC-DCit instead of BOC-DHarg (Et ₂₎ using and BOC-Arg instead BOC-Harg (Et ₂₎ Procedure same as those described in Example 43 except using the (Tos) Procedure was used. After the process is completed the freeze-dried and HPLC purification, (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHarg (Et 2) -Leu-Harg (Et 2) -Pro-SarNH ₂ the (174) as the trifluoroacetic acid salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 175)
The procedure described in Example 38, except that BOC-NMePhe (4NFMOC) and BOC-DPhe (4NFMOC) were used instead of BOC-NMeTyr (O-2,6-ClBzl) and BOC-DLys (Nic). A similar procedure was used. The peptide-resin was treated with 30% piperidine in DMF for 2 hours, then washed three times with (1: 1) DMF / DCM, and diphenylcyanocarbonimidate (0.43 g in DMF (15 mL)). ) Treated with solution and aerated the mixture for 16 hours. The resin was washed 3 times each with DCM / DMF, MeOH and DCM and then treated with hydrazine (10 mL) for 8 hours. The resin was washed again as above and dried under vacuum over P ₂ O ₅ overnight. The peptide was cleaved from the resin using HF and after processing, lyophilization, HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Atz) -DPhe (Atz) -Leu-Lys ( Isp) -Pro-SarNH 2 the (175) as the trifluoroacetic acid salt.

N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Phe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-SarNH 2 ( Compound 176)
A procedure similar to that described in Example 48 was used except that BOC-Phe (4NFMOC) was used instead of BOC-NMePhe (4NFMOC). After processing completion, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Phe (Atz) -DPhe (Atz) -Leu-Lys (Isp ) -Pro-SarNH ₂ (176) was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ (Compound 177)
The procedure described in Example 48, except that BOC-NMePhe (4Me-NFMOC) and BOC-DPhe (4Me-NFMOC) were used instead of BOC-NMePhe (4NFMOC) and BOC-DPhe (4NFMOC). A similar procedure was used. After completion of the treatment, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu -Lys the _{(Isp) -Pro-SarNH 2 (} 177) was obtained as the trifluoroacetic acid salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ (Compound 178)
Explained in Example 48 except that BOC-Lys (FMOC) was used in place of BOC-NMePhe (4N-FMOC) and BOC-DLys (NFMOC) was used instead of BOC-DPhe (4NFMOC). Similar procedures were used. After treatment completion, lyophilization and HPLC purification, (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp ) -Pro-SarNH ₂ (178) was obtained as the trifluoroacetate salt.

  A procedure similar to that described in Examples 41-49 was used, except that BOC-DAla-NH-resin was used instead of BOC-Sar-NH-resin. After processing, lyophilization and HPLC purification, the following compound was obtained as the trifluoroacetate salt.

Example 52a N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -DAlaNH 2 ( Compound 179) .

Example 52b N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (nicotinyl) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ( Compound 180).

Example 52c N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 181).

Example 52d N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Arg-Pro-DAlaNH 2 ( Compound 182).

Example 52e N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 183).

Example 52f N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Arg-D4 (pOMeBzol) Hala-Leu-Arg-Pro-DAlaNH 2 ( Compound 184).

Example 52g N- (R, S) - tetrahydrofurfuryl 2-Oil _{-Gly-D2Nal-D4ClPhe-D3Pal-} Ser-Tyr-DHarg (Et 2) -Leu-Harg (Et 2) -Pro-DAlaNH 2 ( Compound 185).

Example 52h N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ( Compound 186).

Example 52i N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Phe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ( Compound 187).

Example 52j N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu-Lys (Isp) -Pro -DAlaNH ₂ (compound 188).

Example 52k N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp) -Pro-DAlaNH ₂ ( Compound 189).

  A procedure similar to that described in Example 31 was used, except that BOC-SarNH-resin was used instead of BOC-DAlaNH-resin and replaced with the appropriate amino acid and acid at the 6-position. After processing, lyophilization and HPLC purification, the following compound was obtained as the trifluoroacetate salt.

Example 53a N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-2Fur) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 190).

Example 53b N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 191).

Example 53c N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Gly-Nic) -Leu-Lys (Isp) -Pro-SarNH ₂ (compound 192).

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ (Compound 193)
Appropriate BOC-amino acids were used instead of BOC-Gly, BOC-DLys-FMOC was used instead of BOC-DCit, and BOC-Sar-NH-resin was used instead of BOC-DAla-NH-resin A procedure similar to that described in Example 1 was used. After processing, lyophilization and HPLC purification, Nic-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ was obtained as the trifluoroacetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (compound 194)
A procedure similar to that described in Example 54 was used, except that BOC-DAlaNH-resin was used instead of BOC-SarNH-resin. After completion of the process lyophilized and HPLC purification, N- (R, S) 4H2Fur -Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 trifluoroacetic acid Obtained as a salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ (Compound 195)
A procedure similar to that described in Example 55 was used except that (R, S) -tetrahydro-2-furoic acid was used instead of nicotinic acid. After processing, lyophilization, and HPLC purification, N- (R, S) 4H2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ is converted to trifluoroacetic acid. Obtained as a salt.

N-shikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ (Compound 196)
A procedure similar to that described in Example 54 was used except that shikimic acid was used instead of nicotinic acid. After treatment completion, lyophilization and HPLC purification, Shik-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-SarNH ₂ was obtained as the trifluoroacetate salt.

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (4AmAtz) -DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (compound 197)
A procedure similar to that described in Example 54 was used except that the appropriate BOC-amino acids and acids were replaced at positions 0, 6 and 8. After completion of the process lyophilized and HPLC purification gave the Nic-Gly-D2Nal-D4ClPhe- D3Pal-Ser-NMePhe (4AmAtz) -DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 as the trifluoroacetate salt .

N-nicotinyl-Gly-D3Qal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ (Compound 198)
A procedure similar to that described in Example 14 was used except that BOC-3Qal was used instead of BOC-D2Nal. After completion of the process lyophilized and HPLC purification gave the Nic-Gly-D3Qal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 as the trifluoroacetate salt.

N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmplopShik) -Leu-Harg-Pro-SarNH ₂ (Compound 199)
The procedure described in Example 54 was used to obtain Nic-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (FMOC) -Leu-Harg-Pro-SarNH-resin. This was then treated with 1,1'-N, N'-carbonyldiimidazole (excess) in DMF for 20 minutes. The resin was washed 3 times with (1: 1) DMF / DCM and treated with diaminoproplan (excess) in DMF for 1 hour. The resin was washed again as above and reacted with shikimic acid in DMF by performing the coupling twice for 6 hours each. After processing, lyophilization and HPLC purification, Nic-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropShik) -Leu-Harg-Pro-SarNH ₂ was obtained as the trifluoroacetate salt.

(R, S) 4H2Fur-Gly -D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropShik) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 200)
To obtain (R, S) -4H2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (FMOC) -Leu-Lys (Isp) -Pro-DAlaNH-resin, the procedure described in Example 60 was used. used. This was then treated with 1,1'-N, N'-carbonyldiimidazole (excess) in DMF for 20 minutes. The resin was washed 3 times with (1: 1) DMF / DCM and treated with diaminoproplan (excess) in DMF for 1 hour. The resin was washed again as above and reacted with shikimic acid in DMF by performing the coupling twice for 6 hours each. After processing, lyophilization and HPLC purification, trifluoro (R, S) 4H2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmplopShik) -Leu-Lys (Isp) -Pro-DAlaNH ₂ Obtained as the acetate salt.

N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropShik) -Leu-Harg-Pro-SarNH ₂ (Compound 201)
A procedure similar to that described in Example 61 was used, except that SarNH-resin was used instead of BOC-DAlaNH-resin. After processing, lyophilization and HPLC purification, trifluoro (R, S) -4H-2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmplopShik) -Leu-Harg-Pro-SarNH ₂ Obtained as the acetate salt.

(R, S) 4H2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropNic) -Leu-Lys (Isp) -Pro-SarNH ₂ (Compound 202)
A procedure similar to that described in Example 62 was used except that nicotinic acid was used in place of shikimic acid. After processing, lyophilization and HPLC purification, trifluoro (R, S) 4H2Fur-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (COdiAmpropNic) -Leu-Lys (Isp) -Pro-SarNH ₂ Obtained as the acetate salt.

Nic-Gly-D3Qal-D4ClPhe- D3Pal-Ser-cis-Cha (4AmPrz) -Dlys (Pic) -Leu-Arg-Pro-DAlaNH 2 ( Compound 203)
Explained in Example 59 except that BOC-cis-Cha (4Am-Prz) was used instead of BOC-NMeTyr (O-2,6-Cl-Bzl) and picolinic acid was used instead of nicotinic acid. Similar procedures were used. After completion of the process lyophilized and HPLC purification, the Nic-Gly-D3Qal-D4ClPhe- D3Pal-Ser-cis-Cha (4AmPrz) -Dlys (Pic) -Leu-Arg-Pro-DAlaNH 2 as the trifluoroacetate salt Obtained.

  A procedure similar to that described in Example 2 was used, except that BOC-Sar-NH-resin was used instead of BOC-DAla-NH-resin. After processing, lyophilization and HPLC purification, the following compound was obtained:

Example 65a N-Siquimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ (Compound 207)
Example 65b N-dihydroshikimyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ (compound 208)
Example 65c N-2-furoyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N-epsilon - isopropyl) -Pro-SarNH ₂ (Compound 209)
Example 65d N-3-furoyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N-epsilon - isopropyl) -Pro-SarNH ₂ (Compound 210)
Example 65e N-picolyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ (compound 211)
Example 65f N-nicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ (compound 212)
Example 65g N-isonicotinyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-SarNH ₂ (compound 213)

N- tosyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 10c)
Procedure of Example 1 except that the resin-peptide was reacted overnight with a 10-fold excess of p-toluenesulfonyl chloride and a 1-fold excess of pyridine in DMF instead of conjugation with acetic acid. A similar procedure was used. After completion of the process lyophilized and HPLC purification to give N- tosyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2.
R _t = 43.35 min FAB mass spectrum m / e 1556 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.00 Pro; 0.98 Arg; 0.99 Leu; 0.91 Cit; 1.01 NMeTyr; 0.50 Ser; 0.98 3Pal; 1.02 4ClPhe.

N- (S) - tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 12b)
The procedure of Example 1 except that (S) -tetrahydro-2-furoic acid was used instead of BOC-DTyr (O-2,6-Cl-Bzl) and the coupling with acetic acid was omitted. A similar procedure was used. After processing, lyophilization and HPLC purification, N- (S) -tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 28.38 min FAB mass spectrum m / e 1591 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.00 Pro; 1.01 Leu; 1.69 Lys; 0.69 NMeTyr; 0.51 Ser.

N- (R) - tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 13b)
A procedure similar to that of Example 67 was used except that (R) -tetrahydro-2-furoic acid was used instead of (S) -tetrahydro-2-furoic acid. After processing, lyophilization and HPLC purification, N- (R) -tetrahydroflu-2-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 29.51 min FAB mass spectrum m / e 1591 (M + H) ⁺ ,
Amino acid analysis: 0.97 Ala; 1.01 Pro; 0.81 Leu; 1.66 Lys; 0.81 NMeTyr; 0.52 Ser.

N- (S) -tetrahydrofur-3-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) t-Leu-Lys (Isp) -Pro-DAlaNH ₂ (compound 14b)
A procedure similar to that of Example 67 was used except that (S) -tetrahydro-3-furoic acid was used instead of (S) -tetrahydro-2-furoic acid. After treatment completion, lyophilization and HPLC purification, N- (S) -tetrahydroflu-3-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 26.41 min FAB mass spectrum m / e 1591 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 0.99 Pro; 0.95 Lys (Isp); 1.0 Leu; 0.99 Lys; 0.86 NMeTyr; 0.50 Ser; 0.99 3Pal; 1.05 4ClPhe .

N- (R) - tetrahydrofurfuryl-3 oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 15b)
A procedure similar to that of Example 69 was used except that (R) -tetrahydro-3-furoic acid was used instead of (S) -tetrahydro-2-furoic acid. After processing, lyophilization and HPLC purification, N- (R) -tetrahydroflu-3-oil-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 26.88 min FAB mass spectrum m / e 1591 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.01 Pro; 0.93 Lys (Isp); 1.0 Leu; 1.00 Lys; 1.00 NMeTyr; 0.58 Ser; 1.03 3Pal; 1.05 4ClPhe .

N- Shikimiru -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 16b)
A procedure similar to that of Example 67 was used except that shikimic acid was used instead of (S) -tetrahydro-2-furoic acid. After processing, lyophilization and HPLC purification, N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 23.53 min FAB mass spectrum m / e 1648 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.0 Pro; 0.81 Leu; 1.64 Lys; 0.76 NMeTyr; 0.56 Ser.

  A procedure similar to that described in Example 71 was used except that the appropriate acid was used instead of shikimic acid. After processing, lyophilization and HPLC purification, the following compound was obtained:

Example 72a N-2-furoyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 17b)
R _t = 29.51 min FAB mass spectrum m / e 1586 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.01 Pro; 1.01 Leu; 1.63 Lys; 0.89 NMeTyr; 0.53 Ser.
Example 72b N-3- furoyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 18b)
R _t = 30.75 min FAB mass spectrum m / e 1586 (M + H) ⁺ ,
Amino acid analysis: 1.04 Ala; 0.97 Pro; 1.26 Lys (Isp); 1.05 Leu; 0.97 Lys; 1.04 NMeTyr; 0.53 Ser; 0.96 3Pal; 0.96 4ClPhe .
Example 72c N-thienyl-2-carbonyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 19b)
R _t = 31.01 min FAB mass spectrum m / e 1602 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 0.99 Pro; 0.93 Lys (Isp); 1.01 Leu; 0.94 Lys; 0.97 NMeTyr; 0.50 Ser; 1.08 3Pal; 1.15 4ClPhe .
Example 72d N-nicotinyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 20b)
R _t = 23.63 min FAB mass spectrum m / e 1597 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.01 Pro; 0.95 Lys (Isp); 1.02 Leu; 0.97 Lys; 1.06 NMeTyr; 0.48 Ser; 1.01 3Pal; 1.07 4ClPhe .
Example 72e N-picolinoyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 21b)
R _t = 30.9 min FAB mass spectrum m / e 1597 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.03 Pro; 0.94 Lys (Isp); 1.01 Leu; 0.95 Lys; 1.07 NMeTyr; 0.50 Ser; 0.99 3Pal; 1.06 4ClPhe .
Example 72f N-(6- hydroxy) nicotinyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 22b)
R _t = 23.80 min FAB mass spectrum m / e 1613 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.02 Pro; 0.95 Lys (Isp); 1.01 Leu; 0.96 Lys; 0.98 NMeTyr; 0.51 Ser; 0.98 3Pal; 1.06 4ClPhe .
EXAMPLE 72 g N-isonicotinyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 23b)
R _t = 22.71 min FAB mass spectrum m / e 1597 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.01 Pro; 0.93 Lys (Isp); 1.02 Leu; 0.97 Lys; 1.10 NMeTyr; 0.42 Ser; 1.02 3Pal; 1.07 4ClPhe .
Example 72h N-(3- pyridyl acetyl) -D2Nal-D4ClPhe-D3Pal-Ser -NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 24b)
R _t = 22.71 min FAB mass spectrum m / e 1611 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 0.99 Pro; 0.92 Lys (Isp); 1.01 Leu; 0.94 Lys; 1.07 NMeTyr; 0.50 Ser; 1.08 3Pal; 1.13 4ClPhe .

N- Shikimiru -D2Nal-D4ClPhe-D3Pal-Ser- Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 31b)
A procedure similar to that described in Example 71 was used except that BOC-Lys (Nic) was used instead of BOC-NMeTyr (O-2,6-Cl-Bzl). After processing, lyophilization and HPLC purification, N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 18.66 min FAB mass spectrum m / e 1704 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.03 Pro; 0.94 Lys (Isp); 1.03 Leu; 1.97 Lys; 0.59 Ser; 0.97 3Pal; 1.00 4ClPhe.

N- nicotinyl -D2Nal-D4ClPhe-D3Pal-Ser- Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 32 b)
A procedure similar to that described in Example 71 was used except that BOC-Lys (Nic) was used instead of BOC-NMeTyr (O-2,6-Cl-Bzl). After processing, lyophilization and HPLC purification, N-nicotinyl-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 20.05 min FAB mass spectrum m / e 1652 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.01 Pro; 1.08 Lys (Isp); 1.05 Leu; 1.92 Lys; 0.56 Ser; 0.95 3Pal; 0.97 4ClPhe.

N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (compound 33b)
A procedure similar to that described in Example 73 was used except that BOC-Tyr (O-2,6-Cl-Bzl) was used instead of BOC-Lys (Nic). After processing, lyophilization and HPLC purification, N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained.
R _t = 23.38 min FAB mass spectrum m / e 1634 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.99 Pro; 1.04 Lys (Isp); 1.00 Leu; 1.00 Lys; 0.92 Tyr; 0.55 Ser; 0.97 3Pal; 0.97 4ClPhe .

N- (S) - tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 41b)
The procedure is similar to that described in Example 67, except that BOC-DCit is used instead of BOC-DLys (Nic) and BOC-Arg (Tos) is used instead of BOC-Lys (Isp, Cbz). Procedure was used. After completion of the process lyophilized and HPLC purification, N- (S) - to obtain a tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2.
R _t = 37.15 min FAB mass spectrum m / e 1501 (M + H) ⁺ ,
Amino acid analysis: 1.05 Ala; 0.97 Pro; 0.98 Arg; 0.99 Leu; 1.05 Cit; 0.61 NMeTyr; 0.59 Ser; 1.00 3Pal; 0.98 4ClPhe.

N- (R) - tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 42b)
A procedure similar to that described in Example 76 was used except that (R) -tetrahydro-2-furoic acid was used instead of (S) -tetrahydro-2-furoic acid. After completion of the process lyophilized and HPLC purification, N- (R) - to obtain a tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2.
R _t = 38.20 min FAB mass spectrum m / e 1501 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.99 Pro; 0.99 Arg; 1.01 Leu; 1.04 Cit; 0.68 NMeTyr; 0.50 Ser; 1.05 3Pal; 1.03 4ClPhe.

  A procedure similar to that described in Example 77 was used except that the appropriate acid was used instead of (R) -tetrahydro-2-furoic acid. After processing, lyophilization and HPLC purification, the following compound was obtained:

Example 78a N- (R) -5- oxo - obtain tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 (Compound 43 b).
R _t = 37.40 min FAB mass spectrum m / e 1514 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.02 Pro; 0.97 Arg; 0.98 Leu; 0.94 Cit; 0.68 NMeTyr; 0.51 Ser; 1.00 3Pal; 1.05 4ClPhe.
Example 78b N- (S) -5- oxo - obtain tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 (Compound 44b).
R _t = 37.80 min FAB mass spectrum m / e 1514 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.02 Pro; 0.98 Arg; 0.99 Leu; 0.91 Cit; 0.57 NMeTyr; 0.48 Ser; 1.01 3Pal; 1.05 4ClPhe.
To afford Example 78c N-Shikimiru -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 45b).
R _t = 32.45 min FAB mass spectrum m / e 1558 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.03 Pro; 0.91 Arg; 1.04 Leu; 1.04 Cit; 0.94 NMeTyr; 0.52 Ser; 0.72 3Pal; 1.01 4ClPhe.
To give Example 78d N-2-furoyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 46b).
R _t = 38.30 min FAB mass spectrum m / e 1498 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.07 Pro; 0.97 Arg; 1.00 Leu; 0.93 Cit; 0.60 NMeTyr; 0.60 Ser; 0.93 3Pal; 0.94 4ClPhe.
To give Example 78e N-isonicotinyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 47b).
R _t = 32.80 min FAB mass spectrum m / e 1507 (M + H) ⁺ ,
Amino acid analysis: 1.02 Ala; 1.02 Pro; 0.96 Arg; 1.00 Leu; 0.99 Cit; 0.82 NMeTyr; 0.40 Ser; 1.04 3Pal; 1.09 4ClPhe.
To give Example 78f N-picolinoyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 48b).
R _t = 39.55 min FAB mass spectrum m / e 1507 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.03 Pro; 0.93 Arg; 1.04 Leu; 1.03 Cit; 1.07 NMeTyr; 0.50 Ser; 0.68 3Pal; 0.95 4ClPhe.
To give Example 78 g N-nicotinyl -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 49b).
R _t = 32.10 min FAB mass spectrum m / e 1507 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.00 Pro; 0.99 Arg; 1.01 Leu; 0.99 Cit; 1.00 NMeTyr; 0.45 Ser; 1.01 3Pal; 1.00 4ClPhe.
To give Example 78h N-(3- pyridyl acetyl) -D2Nal-D4ClPhe-D3Pal-Ser -NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2 ( Compound 50b).
R _t = 32.0 min FAB mass spectrum m / e 1521 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.02 Pro; 0.96 Arg; 1.02 Leu; 0.98 Cit; 0.93 NMeTyr; 0.45 Ser; 1.14 3Pal; 1.19 4ClPhe.

N- Shikimiru -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH 2 ( Compound 52 b)
Shikimic acid is used in place of 5-oxo-tetrahydroflu-2-oleic acid, BOC-Harg (NO ₂ ) is used in place of BOC-Arg (Tos), and BOC-DLys (instead of BOC-DCit ( A procedure similar to that described in Example 78 was used except that FMOC) was used. After the synthesis was complete, it was treated with 30% piperidine in DMF, washed, and conjugated with shikimic acid using a “2-2 hour” binding protocol. After processing, lyophilization and HPLC purification, N-shikimyl-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH ₂ was obtained.
R _t = 15.54 min FAB mass spectrum m / e 1699 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 0.99 Pro; 0.99 Leu; 1.00 Lys; 1.02 NMeTyr; 0.57 Ser; 0.98 3Pal; 1.04 4ClPhe.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-AlaNH ₂ (compound 214)
A procedure similar to that described in Example 4 was used, except that BOC-AlaNH-resin was used instead of BOC-DAlaNH-resin. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- Epsilon-isopropyl) -Pro-AlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 18.88 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.98 Pro; 1.18 Lys (Isp); 1.01 Leu; 1.00 Lys; 0.99 NMeTyr; 0.44 Ser; 1.14 D3Pal; 1.24 D4ClPhe 0.98 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 215)
A procedure similar to that described in Example 4 was used except that BOC-2Nal was used instead of BOC-D2Nal. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 20.38 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.00 Pro; 1.25 Lys (Isp); 1.02 Leu; 1.00 Lys; 1.01 NMeTyr; 0.39 Ser; 1.13 D3Pal; 1.22 D4ClPhe 0.97 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-DSer-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 216)
A procedure similar to that described in Example 4 was used except that BOC-DSer (OBzl) was used instead of BOC-Ser (OBzl). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-DSer-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 20.35 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.99 Pro; 1.16 Lys (Isp); 1.01 Leu; 1.01 Lys; 0.98 NMeTyr; 0.48 Ser; 1.15 D3Pal; 1.23 D4ClPhe 0.99 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 217)
A procedure similar to that described in Example 4 was used except that BOC-3Pal was used instead of BOC-D3Pal. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 20.24 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.00 Pro; 1.23 Lys (Isp); 1.01 Leu; 1.01 Lys; 1.01 NMeTyr; 0.44 Ser; 1.14 D3Pal; 1.24 D4ClPhe 0.98 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaOH (compound 218) )
A procedure similar to that described in Example 4 was used, except that BOC-DAla-O-resin (Merrifield) was used instead of BOC-DAla-NH-resin (benzhydrylamine). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- Epsilon-isopropyl) -Pro-DAlaOH was obtained as the trifluoroacetate salt.
R _t = 19.92 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.00 Pro; 1.26 Lys (Isp); 1.02 Leu; 1.01 Lys; 1.02 NMeTyr; 0.42 Ser; 1.14 D3Pal; 1.25 D4ClPhe 0.97 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-Lys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 219)
A procedure similar to that described in Example 4 was used except that BOC-Lys (Nic) was used instead of BOC-DLys (Nic). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-Lys (N-epsilon-nicotinyl) -Leu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 19.60 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.07 Pro; 1.25 Lys (Isp); 1.01 Leu; 1.01 Lys; 1.07 NMeTyr; 0.40 Ser; 1.13 D3Pal; 1.25 D4ClPhe 0.96 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 220)
A procedure similar to that described in Example 4 was used except that BOC-4ClPhe was used instead of BOC-D4ClPhe. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-4ClPhe-3DPal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 19.85 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.01 Pro; 1.24 Lys (Isp); 1.01 Leu; 1.07 Lys; 1.06 NMeTyr; 0.42 Ser; 1.14 D3Pal; 1.27 D4ClPhe 0.97 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -DLeu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 221)
A procedure similar to that described in Example 4 was used except that BOC-DLeu was used instead of BOC-Leu. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -DLeu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 19.96 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 1.01 Pro; 1.24 Lys (Isp); 1.01 Leu; 1.01 Lys; 1.04 NMeTyr; 0.37 Ser; 1.13 D3Pal; 1.26 D4ClPhe 0.97 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -DPro-DAlaNH ₂ (compound 222)
A procedure similar to that described in Example 4 was used except that BOC-DPro was used instead of BOC-Pro. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- Epsilon-isopropyl) -DPro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 19.71 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.01 Pro; 1.23 Lys (Isp); 1.01 Leu; 1.01 DLys; 1.06 NMeTyr; 0.41 Ser; 1.14 D3Pal; 1.26 D4ClPhe; 0.98 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-DLys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 223)
A procedure similar to that described in Example 4 was used except that BOC-DLys (Isp, Cbz) was used instead of BOC-Lys (Isp, Cbz). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (N-epsilon-nicotinyl) -Leu-DLys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 15.15 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.99 Pro; 0.95 Lys (Isp); 1.01 Leu; 1.02 Lys; 1.00 NMeTyr; 0.42 Ser; 0.93 D3Pal; 1.10 D4ClPhe 0.98 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-DNMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 224)
A procedure similar to that described in Example 4 was used except that BOC-DNMeTyr (O-2,6ClBzl) was used instead of BOC-NMeTyr (O-2,6ClBzl). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-DNMeTyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N- epsilon - isopropyl) a -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 19.60 min FAB mass spectrum m / e 1647 (M + H) ⁺ ,
Amino acid analysis: 1.03 Ala; 1.00 Pro; 0.64 Lys (Isp); 1.00 Leu; 1.00 Lys; 0.79 NMeTyr; 0.29 Ser; 0.98 D3Pal; 1.03 D4ClPhe 0.96 Gly.

N- (R, S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (N-epsilon-nicotinyl) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (Compound 225)
A procedure similar to that described in Example 3 was used except that BOC-Tyr (O-2,6ClBzl) was used instead of BOC-NMeTyr (O-2,6ClBzl). After processing completion, lyophilization and HPLC purification, N- (R, S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DLys (N-epsilon-nicotinyl) -Leu-Lys ( N- epsilon - isopropyl) -Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 19.14 min FAB mass spectrum m / e 1633 (M + H) ⁺ ,
Amino acid analysis: 0.99 Ala; 1.00 Pro; 1.00 Lys (Isp); 1.00 Leu; 1.00 Lys; 1.02 Tyr; 0.46 Ser; 0.98 D3Pal; 1.02 D4ClPhe 0.96 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DHcit-Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 226)
A procedure similar to that described in Example 4 was used except that BOC-DHcit was used instead of BOC-DLys (Nic). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DHcit-Leu-Lys (N-epsilon-isopropyl) -Pro- DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 20.58 min FAB mass spectrum m / e 1585 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.01 Pro; 0.99 Lys (Isp); 1.01 Leu; 0.87 NMeTyr; 0.48 Ser; 0.99 D3Pal; 1.04 D4ClPhe; 0.98 Gly .

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 227)
A procedure similar to that described in Example 92 was used except that BOC-Tyr (O-2,6ClBzl) was used instead of BOC-NMeTyr (O-2,6ClBzl). After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Lys (N-epsilon-isopropyl) -Pro- DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 19.73 min FAB mass spectrum m / e 1571 (M + H) ⁺ ,
Amino acid analysis: 1.00 Ala; 0.98 Pro; 0.87 Lys (Isp); 1.01 Leu; 0.99 Tyr; 0.52 Ser; 0.91 D3Pal; 1.02 D4ClPhe; 0.98 Gly .

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-DPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (N-epsilon-isopropyl) -Pro-DAlaNH ₂ (compound 228)
A procedure similar to that described in Example 4 was used except that BOC-DPhe was used instead of BOC-D4ClPhe. N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-DPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (N-epsilon-isopropyl)-after treatment completion, lyophilization and HPLC purification the Pro-DAlaNH ₂ as a trifluoroacetate salt.
R _t = 17.61 min FAB mass spectrum m / e 1613 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 0.98 Pro; 0.87 Lys (Isp); 1.00 Leu; 0.97 NMeTyr; 1.02 Lys (Nic); 0.43 Ser; 0.89 D3Pal; 1 .05 Phe; 0.95 Gly.

N- (S) -2-tetrahydrofuroyl-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Tyr-DHcit-Leu-Arg-Pro-DAlaNH ₂ (compound 230)
BOC-Tyr (O-2,6ClBzl) is used instead of BOC-NMeTyr (O-2,6ClBzl), BOC-DHcit is used instead of DLys (Nic), and BOC-Lys (Isp, Cbz) A procedure similar to that described in Example 4 was used except that BOC-Arg (NO ₂ ) was used instead. After completion of the process lyophilized and HPLC purification N- (S) -2- tetrahydrofuroyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Arg-Pro-DAlaNH 2 as the trifluoroacetate salt Obtained.
R _t = 19.61 min FAB mass spectrum m / e 1557 (M + H) ⁺ ,
Amino acid analysis: 1.01 Ala; 1.04 Pro; 0.96 Arg; 1.04 Leu; 0.93 Tyr; 0.5 Ser; 1.01 D3Pal; 1.08 D4ClPhe; 1.01 Gly; 01 Hcit.

N- (S) -2-tetrahydrofuroyl-Bala-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 231)
A procedure similar to that described in Example 4 was used except that BOC-Bala was used instead of BOC-Gly. After processing completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Bala-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 19.37 min FAB mass spectrum m / e 1661 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.00 Pro; 0.89 Lys (Isp); 1.01 Leu; 1.01 Lys; 1.05 NMeTyr; 0.40 Ser; 0.99 D3Pal; 1.09 D4ClPhe .

N- (S) -2-tetrahydrofuroyl-Gaba-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 232)
A procedure similar to that described in Example 96 was used except that BOC-Gaba was used instead of BOC-Bala. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gaba-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 20.02 min FAB mass spectrum m / e 1675 (M + H) ⁺ ,
Amino acid analysis: 0.97 Ala; 1.00 Pro; 0.90 Lys (Isp); 1.01 Leu; 1.05 NMeTyr; 0.37 Ser; 0.98 D3Pal; 1.08 D4ClPhe.

N- (S) -2-tetrahydrofuroyl-Aha-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 233)
A procedure similar to that described in Example 96 was used except that BOC-Aha was used instead of BOC-Bala. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Aha-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 22.11 min FAB mass spectrum m / e 1717 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.00 Pro; 0.91 Lys (Isp); 1.01 Leu; 1.01 Lys; 1.06 NMeTyr; 0.38 Ser; 0.98 D3Pal; 1.08 D4ClPhe .

N-(S)-2-tetrahydrofuroyl -Sar-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 234)
A procedure similar to that described in Example 96 was used except that BOC-Sar was used instead of BOC-Bala. After processing completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Sar-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 20.266 min FAB mass spectrum m / e 1661 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.00 Pro; 0.87 Lys (Isp); 1.00 Leu; 1.01 Lys; 1.02 NMeTyr; 0.42 Ser; 1.00 D3Pal; 1.08 D4ClPhe 0.89 Sar.

N-(S)-2-tetrahydrofuroyl -Gly-DAla-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 235)
A procedure similar to that described in Example 4 was used except that BOC-DAla was used instead of BOC-D2Nal. After treatment completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-DAla-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 10.94 min FAB mass spectrum m / e 1521 (M + H) ⁺ ,
Amino acid analysis: 1.96 Ala; 1.01 Pro; 0.91 Lys (Isp); 1.02 Leu; 1.02 Lys; 1.10 NMeTyr; 0.38 Ser; 0.99 D3Pal; 1.09 D4ClPhe 1.00 Gly.

N-(S)-2-tetrahydrofuroyl -Gly-Sar-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2 ( Compound 236)
A procedure similar to that described in Example 4 was used except that BOC-Sar was used instead of BOC-D2Nal. After processing completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Gly-Sar-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 11.49 min FAB mass spectrum m / e 1521 (M + H) ⁺ ,
Amino acid analysis: 0.98 Ala; 1.01 Pro; 0.91 Lys (Isp); 1.02 Leu; 1.01 Lys; 1.09 NMeTyr; 0.36 Ser; 0.99 D3Pal; 1.09 D4ClPhe 0.93 Sar; 0.99 Gly.

N- (S) -2-tetrahydrofuroyl-Aca-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ (Compound 237)
A procedure similar to that described in Example 4 was used except that BOC-Aca was used instead of BOC-Gly. After processing completion, lyophilization and HPLC purification, N- (S) -2-tetrahydrofuroyl-Aca-D2Nal-D4ClPhe-D3Pal-Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH ₂ was obtained as the trifluoroacetate salt.
R _t = 20.45 min FAB mass spectrum m / e 1703 (M + H) ⁺ ,
Amino acid analysis: 0.97 Ala; 1.00 Pro; 0.89 Lys (Isp); 1.01 Leu; 1.01 Lys; 1.07 NMeTyr; 0.44 Ser; 1.11 D3Pal; 1.08 D4ClPhe 1.01 Aca.

Claims (7)

A peptide having structure I of the formula: or a pharmaceutically acceptable salt thereof,

X in the previous formula is
(A) dihydroshikimyl,
(B) 2-Floyl,
(C) 3-Furoyl,
(D) tetrahydrofuro-2-yl,
(E) tetrahydrofuro-3-yl,
(F) (thien-2-yl) carbonyl,
(G) (thien-3-yl) carbonyl,
(H) (tetrahydrothien-2-yl) carbonyl,
(I) (tetrahydrothien-3-yl) carbonyl,
(J) (pyrrol-2-yl) carbonyl,
(K) (pyrrol-3-yl) carbonyl,
(L) prolyl,
(M) N-acetyl-prolyl,
(N) 3- (Indoline-3-yl) propionyl,
(O) (Indoline-3-yl) acetyl,
(P) (Indolin-2-yl) carbonyl,
(Q) (Indoline-3-yl) carbonyl,
(R) (benzo [b] flu-2-yl) carbonyl,
(S) (dihydrobenzo [b] flu-2-yl) carbonyl,
(T) (tetrahydropyran-2-yl) carbonyl,
(U) (tetrahydropyran-3-yl) carbonyl,
(V) (piperidin-3-yl) carbonyl,
(W) (N-acetylpiperidin-3-yl) carbonyl,
(X) alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, halogen, or nicotinyl optionally substituted with hydroxy,
(Y) alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, isonicotinyl optionally substituted with halogen or hydroxy,
(Z) Picolinoyl,
(Aa) alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, 2-, 3- or 4-quinolinecarbonyl optionally substituted with halogen or hydroxy;
(Bb) salicyl,
(Cc) shikimyl, and (dd) an acyl group selected from the group consisting of p-toluenesulfonyl,
A is absent or
D-alanyl,
3-aminopropionyl,
4-aminobutyryl,
5-aminovaleryl,
6-amino-hexanoyl,
7-aminoheptanoyl,
8-aminooctanoyl,
11-aminoundecanoyl,
Azaglycyl,
Glycyl,
An aminoacyl residue selected from the group consisting of sarkosyl and D-seryl;
B
D-phenylalanyl,
D-3- (4-chlorophenyl) alanyl,
D-3- (4-fluorophenyl) alanyl,
D-3- (quinolin-3-yl) alanyl,
Sarkosyl,
Glycyl,
Azaglycyl,
D-3,3-diphenylalanyl,
An aminoacyl residue selected from the group consisting of N ^α -methyl-D-3- (naphth-2-yl) alanyl, and D-3- (naphth-2-yl) alanyl;
C
D-3- (4-chlorophenyl) alanyl,
D-3,3-diphenylalanyl,
D-3- (4-fluorophenyl) alanyl,
D-3- (naphth-2-yl) alanyl,
An aminoacyl residue selected from the group consisting of D-phenylalanyl and D-3- (quinolin-3-yl) alanyl;
D is
D-alanyl,
D-3- (benzo [b] thien-2-yl) alanyl,
Glycyl,
D-3- (naphth-1-yl) alanyl,
D-3- (pyrid-3-yl) alanyl,
An aminoacyl residue selected from the group consisting of D-3- (quinolin-3-yl) alanyl, and D-3- (thiazol-2-yl) alanyl;
E
Glycyl,
L-seryl,
L-homoceryl,
L-seryl (O-benzyl), and N ^α (R ¹ ) -L-seryl (R ¹ is alkyl of 1 to 4 carbon atoms)
An aminoacyl residue selected from the group consisting of
F is
N ^α (R ¹ ) -alanyl,
N ^α (R ¹ )-(3- (4- (3-amino-1,2,4-triazol-5-yl) amino) phenyl) alanyl,
N ^α (R ¹ )-(3- (4- (3-amino-1,2,4-triazole-5-amino) methyl) phenyl) alanyl,
N ^α (R ¹ )-(3- (4- (3-amino-1,2,4-triazol-5-yl) amino) cyclohexyl) alanyl,
N ^α (R ¹ )-(3- (4- (nicotinyl) amino) cyclohexyl) alanyl,
N ^α (R ¹ )-(N-ε-nicotinyl) lysyl,
N ^α (R ¹ )-(N-ε- (3-amino-1,2,4-triazol-5-yl) lysyl,
N ^α (R ¹ ) -3- (4-nitrophenyl) alanyl,
N ^α (R ¹ ) -3- (4-aminophenyl) alanyl,
N ^α (R ¹ ) -3- (4-aminocyclohexyl) alanyl,
N ^α (R ¹ ) -tyrosyl,
N ^α (R ¹ ) -tyrosyl (O-methyl),
N ^α (R ¹ ) -phenylalanyl,
N ^α (R ¹ ) -cyclohexylalanyl,
N ^α (R ¹ ) -glycyl,
N ^α (R ¹ ) -arginyl,
N ^α (R ¹ ) -histidyl, and N ^α (R ¹ ) -homoarginyl (R ¹ is hydrogen or alkyl of 1 to 4 carbon atoms)
An aminoacyl residue selected from the group consisting of
G is
Glycyl,
D-citrulyl,
D-homocitryl,
β-alanyl,
D-lysyl (N-epsilon-glycyl-nicotinyl),
D-lysyl (N-epsilon-azaglycyl-nicotinyl),
D-lysyl (N-epsilon-shikimyl),
D-lysyl (N-epsilon-glycyl-shikimyl),
D-lysyl (N-epsilon-azaglycyl-shikimyl),
D-lysyl (N-epsilon-dihydroshikimyl),
D-lysyl (N-epsilon-glycyl-dihydroshikimyl),
D-lysyl (N-epsilon-azaglycyl-dihydroshikimyl),
D-lysyl (N-epsilon-fur-2-oil),
D-lysyl (N-epsilon-glycyl-fur-2-oil),
D-lysyl (N-epsilon-azaglycyl-flu-2-oil),
D-lysyl (N-epsilon-tetrahydrofur-2-oil),
D-lysyl (N-epsilon-glycyl-tetrahydrofur-2-oil),
D-lysyl (N-epsilon-azaglycyl-tetrahydrofur-2-oil),
D-lysyl (N-epsilon- (3-amino-1,2,4-triazol-5-yl) amino), and D-3- (4- (3-amino-1,2,4-triazole-5) An aminoacyl residue selected from the group consisting of -yl) amino) phenylalanyl;
H is
L-Leucyl,
N ^α (R ¹ ) -L-Leucyl,
Glycyl,
Sarkosyl,
Prolyl,
L-baryl,
L-cyclohexylalanyl, and N ^α (R ¹ ) -L-cyclohexylalanyl (R ¹ is hydrogen or alkyl of 1 to 6 carbon atoms)
An aminoacyl residue selected from the group consisting of
I
L-citrulyl,
L-homocitrulyl,
L-histidyl,
L- (N-ε-isopropyl) lysyl,
L-arginyl,
N ^α (R ¹ ) -L-arginyl,
L-homoarginyl,
L-2-amino ^{-6-N g} - ethyl guanidino hexanoyl, and L-2-amino ^{-6-N g,} N g - a amino acyl residue selected from the group consisting of diethyl guanidino-hexanoyl,
J
L-prolyl,
4-hydroxy-L-prolyl,
L-pipecholyl,
L-azetidinyl,
L-2,8-tetrahydroisoquinoline-2-carbonyl,
N ^α (R ¹ ) -L-Leucyl,
Sarkosyl,
Glycyl, and N ^(R 1)-L-alanyl ^{(R 1} is hydrogen, or a 6 alkyl carbon atoms from 1)
An aminoacyl residue selected from the group consisting of
K is —NH (CH ₂ CH ₃ ), or
D-alanylamide,
D-alanyl (OH),
D-glutamyl (OH),
L-glutamyl (OH),
N ^α (R ¹ ) -L-alanylamide,
N ^α (R ¹ ) -D-alanylamide,
Sarcosamide,
D-serylamide,
Azaglycylamide, and glycylamide (R ¹ is as defined above)
The peptide or a pharmaceutically acceptable salt thereof, wherein the peptide is an aminoacyl residue selected from the group consisting of (wherein J is L-prolyl when K is —NH (CH ₂ CH ₃ )). In the previous formula, X is
Tetrahydroflu-2-oil,
Tetrahydrofur-3-oil,
Full-2-oil,
Nicotinyl,
Isonicotinyl,
Shikimil,
Dihydroshikimyl,
(Tetrahydrothien-2-yl) carbonyl,
(Pyrrol-2-yl) carbonyl,
Prolyl,
(Indol-2-yl) carbonyl,
3- (Indol-3-yl) propionyl,
The peptide according to claim 1 or a pharmaceutically acceptable salt thereof, selected from the group consisting of (dihydrobenzo [b] flu-2-yl) carbonyl and (tetrahydropyran-2-yl) carbonyl. A peptide having the following structure or a pharmaceutically acceptable salt thereof:
^{X-Gly-D2Nal-D4ClPhe-} D3Pal-Ser-AA 6 -AA 7 -Leu-AA 9 -Pro-AA 11
In the previous formula, X is
Tetrahydroflu-2-oil,
Tetrahydrofur-3-oil,
Full-2-oil,
Nicotinyl,
Isonicotinyl,
Shikimil,
Dihydroshikimyl,
(Tetrahydrothien-2-yl) carbonyl,
(Pyrrol-2-yl) carbonyl,
Prolyl,
(Indoline-2-yl) carbonyl,
3- (indoline-3-yl) propionyl,
An acyl group selected from the group consisting of (dihydrobenzo [b] fur-2-yl) carbonyl and (tetrahydropyran-2-yl) carbonyl;
AA ⁶
Tyrosyl,
Arginyl,
N α ^- Mechiruchiroshiru,
Lysyl (N-epsilon- (3′-amino-1H-1 ′, 2 ′, 4′-triazol-5-yl)), and N ^α -methyl-3- (4- (3′-amino-1H— 1 ', 2', 4'-triazol-5-ylmethyl) phenyl) alanyl, an aminoacyl residue selected from the group consisting of
AA ⁷
D-citrulyl,
D-lysyl (N-epsilon-nicotinyl),
D-lysyl (N-epsilon-glycyl-nicotinyl),
D-lysyl (N-epsilon-azaglycyl-nicotinyl),
D-lysyl (N-epsilon-shikimyl),
D-lysyl (N-epsilon-glycyl-shikimyl),
D-lysyl (N-epsilon-azaglycyl-shikimyl),
D-lysyl (N-epsilon-dihydroshikimyl),
D-lysyl (N-epsilon-glycyl-dihydroshikimyl),
D-lysyl (N-epsilon-azaglycyl-dihydroshikimyl),
D-lysyl (N-epsilon-fur-2-oil),
D-lysyl (N-epsilon-glycyl-fur-2-oil),
D-lysyl (N-epsilon-azaglycyl-flu-2-oil),
D-lysyl (N-epsilon-tetrahydrofur-2-oil),
D-lysyl (N-epsilon-glycyl-tetrahydrofur-2-oil) and D-lysyl (N-epsilon-azaglycyl-tetrahydrofur-2-oil)
An aminoacyl residue selected from the group consisting of
AA ⁹ is
Lysyl (N-epsilon-isopropyl),
Arginyl,
An aminoacyl residue selected from the group consisting of L- (N ^g , N ^g -diethyl) homoarginyl, and homoarginyl;
AA ¹¹ is
The peptide or a pharmaceutically acceptable salt thereof, which is an aminoacyl residue selected from the group consisting of D-alanylamide and D-sarcosamide. N- Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (N- epsilon - nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Azagly- nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -D2Nal-D4ClPhe-D3Pal-Ser- NMeTyr-DLys (Gly- nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH _2,
N- (R, S) - tetrahydro - fur-2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2,
N- Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DCit-Leu-Arg-Pro-DAlaNH 2,
N- Shikimiru -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Arg-Pro-DAlaNH 2,
N- nicotinyl -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Shik) -Leu-Harg-Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Azagly-2Fur) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N-Shik-D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Azagly-Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N-Shik-D2Nal-D4ClPhe- D3Pal-Ser-NMeTyr-DLys (Azagly-2Fur) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N-(2-furoyl) -Azagly-D2Nal-D4ClPhe-D3Pal -Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-SarNH 2,
N- (S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-SarNH 2,
N- (R) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMeTyr-DLys (Nic) -Leu-Lys (Isp) -Pro-SarNH 2,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu-Lys (Isp) -Pro-SarNH ₂ ,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp) -Pro-SarNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DLys ( nicotinyl) -Leu-Lys (Isp) -Pro -DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Lys (Nic) -DLys (Nic) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DCit-Leu-Arg-Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Arg-Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Tyr-DHcit-Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil _{-Gly-D2Nal-D4ClPhe-D3Pal-} Ser-Tyr-DHarg (Et 2) -Leu-Harg (Et 2) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-NMePhe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) - tetrahydrofurfuryl 2-Oil -Gly-D2Nal-D4ClPhe-D3Pal- Ser-Phe (Atz) -DPhe (Atz) -Leu-Lys (Isp) -Pro-DAlaNH 2,
N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-NMePhe (Me-Atz) -DPhe (Me-Atz) -Leu-Lys (Isp) -Pro-DAlaNH ₂ N- (R, S) -tetrahydroflu-2-oil-Gly-D2Nal-D4ClPhe-D3Pal-Ser-Lys (Atz) -DLys (Atz) -Leu-Lys (Isp) -Pro-DAlaNH ₂
3. A compound according to claim 2 or a pharmaceutically acceptable salt thereof selected from the group consisting of: An undecapeptide having an LHRH antagonist activity or a pharmaceutically acceptable salt thereof having the structure:
X-Gly-D2Nal-D4ClPhe-D3Pal-Ser-N ^α
MeTyr-AA7-Leu-Lys (Isp) -Pro-AA ¹¹
In the previous formula, X is
Tetrahydroflu-2-oil,
Full-2-oil,
Nicotinyl,
Isonicotinyl,
Shikimyl and dihydroshikimyl,
An acyl group selected from the group consisting of:
AA ⁷
D-citrulyl,
D-homocitryl,
D-lysyl (N-epsilon-nicotinyl),
D-lysyl (N-epsilon-glycyl-nicotinyl),
D-lysyl (N-epsilon-azaglycyl-nicotinyl),
D-lysyl (N-epsilon-shikimyl),
D-lysyl (N-epsilon-glycyl-shikimyl),
D-lysyl (N-epsilon-azaglycyl-shikimyl),
D-lysyl (N-epsilon-dihydroshikimyl),
D-lysyl (N-epsilon-glycyl-dihydroshikimyl),
D-lysyl (N-epsilon-azaglycyl-dihydroshikimyl),
D-lysyl (N-epsilon-fur-2-oil),
D-lysyl (N-epsilon-glycyl-fur-2-oil),
D-lysyl (N-epsilon-azaglycyl-flu-2-oil),
D-lysyl (N-epsilon-tetrahydrofur-2-oil),
D-lysyl (N-epsilon-glycyl-tetrahydrofur-2-oil) and D-lysyl (N-epsilon-azaglycyl-tetrahydrofur-2-oil)
An aminoacyl residue selected from the group consisting of
AA ¹¹ is
The undecapeptide or a pharmaceutically acceptable salt thereof, which is an aminoacyl residue selected from the group consisting of D-alanylamide and D-sarcosamide. N [(R, S) - tetrahydrofurfuryl 2-Oil] -Gly-D2Nal-D4ClPhe-D3Pal -Ser-N α MeTyr-DLys ( nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH ₂ ,
N [(S) - tetrahydrofurfuryl 2-Oil] -Gly-D2Nal-D4ClPhe-D3Pal -Ser-N α MeTyr-DLys ( nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH ₂ and, N [(R) - tetrahydrofurfuryl 2-oil] -Gly-D2Nal-D4ClPhe-D3Pal -Ser-N α MeTyr-DLys ( nicotinyl) -Leu-Lys (N- epsilon - isopropyl) -Pro-DAlaNH ₂
5. A compound according to claim 4 or a pharmaceutically acceptable salt thereof selected from the group consisting of:   A pharmaceutical composition for inhibiting luteinizing hormone (LH) levels in mammals comprising a therapeutically effective amount of the compound of claim 1 in combination with a pharmaceutically acceptable base.