JPH0741498A - New endothelin antagonist - Google Patents

Abstract

PURPOSE:To obtain a new endathelin antagonist useful as a therapeutic agent for hypertension, myocardial infarction, angina pectoris, gastric ulcer, etc., inhibiting action of endothelin, having vasodilator action and bronchodilator action, comprising a peptide derivative containing tryptophan residue. CONSTITUTION:An alpha-amino acid derivative of formula I [R is R<1>OC=O (R<1> is a lower alkyl or aryl) or alpha-amino protecting group; R<3> is H or a lower alkyl; R<4> is a (substituted) lower alkyl, lower alkenyl, etc.] is condensed with a tryptophan derivative of formula II (X<1> is H, a halogen or lower alkyl; R<51> is H, a lower alkyl or indole NH protecting group; P<1> is alpha-carboxyl protecting group) at about -40 deg.C to room temperature in a solvent in the presence of a condensation agent and then condensed with a compound of formula III (Y<1> is hydroxymethyl or protecting carboxyl; (n) is 0 or 1; R<6> is H, OH, a lower alkoxy, lower alkyl, etc.) to give the compound of formula IV (Y is a halogen or lower alkyl; Y is as shown for Y<1>: A is as shown for T).

Description

Detailed Description of the Invention

[0001]

FIELD OF THE INVENTION The present invention relates to three types of endothelins (endothelins) which are endogenous potent bioactive peptides.
1, a novel compound having an antagonistic action against endothelin-2 and endothelin-3), a process for producing the same, and a use thereof.

The compounds of the present invention have a high affinity for both receptors of the endothelin receptor subtypes ET _A and ET _B , and by inhibiting the action of endothelin, they have a vasodilatory action and a bronchodilatory action. In the field of medicine, especially hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure,
Myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis,
It can be used as a therapeutic agent for bronchial asthma, gastric ulcer, diabetes, endotoxin shock, multi-organ failure caused by endotoxin, disseminated intravascular coagulation and / or cyclosporine-induced renal damage, hypertension and the like.

[0003]

Endothelin is a polypeptide consisting of 21 amino acids, which is produced by human and porcine endothelial cells and has a strong vasoconstrictor action and a persistent and strong pressor action [Nature, No. 332]. Vol., Pp. 411-415 (1988)]. It is known that endothelin has three types of endothelins (endothelin-1, endothelin-2, endothelin-3) as family peptides having similar structures in animals including humans. , Both are known to have vasoconstrictor and pressor actions [Proceeding National Academy of
Science (Proc. Natl. Acad. Sc
i. USA), 86, 2863-2867 (1989).
reference].

Endothelin is clinically found in essential hypertensive patients, acute myocardial infarction patients, pulmonary hypertension patients, Raynaud's disease patients, diabetic patients, atherosclerotic patients 'blood and asthmatic patients' blood or airway lavage fluid. It has been reported in Japan that the increase is clearly higher than that in normal subjects [Jpn.
n), Vol. 12, p. 79 (1989), Journal of Vascular Medicine and Biology (J. Vascular Medicine Bio).
, Vol. 2, p. 207 (1990), Diabetologia, 33.
Volume 306-310 (1990), Journal of American Medical Association (J. Am. Med. Association), 2nd.
64, 2868 (1990) and The Lancet, Volume 2, 747-748 (1989) and Volume 2, 1144- 1147 (1990). reference].

In addition, in an experimental cerebral vasospasm model,
Increased sensitivity of cerebral blood vessels to endothelin [Japan Society for Cerebral Circulation and Metabolism (Japan. Soc. Cereb.
odFlow & Metabol. ), Volume 1, Volume 7
3 (1989)], Improvement of renal function by endothelin antibody in acute renal failure model [Journal of the
Clinical Investigation (J. Clin.
Invest. ), 83, 1762-176.
7 (1989)] and suppression of gastric ulcer development by endothelin antibody in gastric ulcer model [Abstracts of the 19th Annual Meeting of the Japanese Society for Experimental Ulcers, page 50 (1991)]. It is considered to be one of the causative agents of cerebral vasospasm and acute renal failure after subarachnoid hemorrhage.

Further, it has been revealed that endothelin is released not only from vascular endothelial cells but also from tracheal epithelial cells or renal parenchymal cells [Febs Letters (FEB).
S Letters), Vol. 255, pp. 129-13.
Page 2 (1989) and Febs Letters (FEBS)
Letters), 249, 42-46 (1989)].

Endothelin is an endogenous physiologically active peptide such as renin and atrial natriuretic hormone, and further endothelial cell-derived vasorelaxant factor (EDRF), thromboxane A2, prostacyclin, noradrenaline,
It was also found to regulate the release of physiologically active substances such as angiotensin II and substance P [Biochemical and Biophysical Research Communications (Biochem. Biophys. R).
es. Commun. ), Vol. 157, p. 1164-
Pp. 1168 (1988), Biochemical and Biophysical Research Communications (Biochem. Biophys. Res. Comm.
un. ), 155, 167-172 (19)
1989), Proceeding of the National
Academy of Science of USA (Proc. Natl. Acad. Sci. USA),
Volume 85, pp. 9797-9800 (1989)
Year), Journal of Cardiovascular Pharmacology (J. Cardiovasc. Pharm
acol. ), Vol. 13, pages S89-S92 (1
989), Journal of Japanese Society for Hypertension (Japan. J. Hy.
volume, page 12, page 76 (198).
9 years) and Neuroscience Letters (Neuro)
Science Letters), Volume 102, Volume 1
79-page 184 (1989)]. In addition, it also has an action of contracting digestive tract smooth muscle and uterine smooth muscle [FEBS Letters, No. 24
Volume 7, pp. 337-340 (1989), European Journal of Pharmacology (Eu
r. J. Pharmacol. ), Vol. 154, vol. 22
Pages 7-228 (1988) and Biochemicals
And Biophysical Research Communications (Biochem. Biophys. Res. C)
ommun. ), 159, 317-323 (1989)].

[0008] Endothelin was also found to promote the proliferation of rat vascular smooth muscle cells, and its association with arterial thickening has been suggested [Atherosclerosis (Athel)
Rosclerosis), 78, 225-228 (1989)]. Furthermore, it is known that endothelin receptors are present in high concentrations not only in peripheral tissues but also in central tissues, and that endothelin administered in the brain causes changes in animal behavior. It is believed that it also has an important role for [Neuroscience Letters (N
euroscience Letters), 97th
Vol. 276-279 (1989)]. In particular, it has been suggested that endothelin is a kind of pain mediator [Life Sciences (Li
fe Sciences), Vol. 49, PL-61-PL-65 (1991)].

On the other hand, endotoxin is one of the strong candidate substances that promote the release of endogenous endothelin. It has been found that when endotoxin is exogenously administered to animals or when added to cultured vascular endothelial cells, the concentration of endothelin in blood or culture supernatant is significantly increased. Is considered to be one of the important mediators involved in diseases caused by [Biochemical and biophysical research
Communications (Biochem.Biophy)
s. Res. Commun. ), Vol. 161, 122
Page 0 (1989) and Acta Physiologica Scandinavian (Acta Physiol. Scan)
d. ), 137, 317 (1989)].

Furthermore, cyclosporine was added to cultured renal cells (LL
It has been reported that the secretion of endothelin is remarkably enhanced when added to C-PK1 cells [European Journal of Pharmacology (Eur.
J. Pharmacol. ), 180, 191
P.-p. 192 (1990)]. When cyclosporin was administered to rats, a decrease in glomerular filtration rate and an increase in blood pressure were observed, and at this time, the circulating endothelin level showed a marked increase. This cyclosporine-induced nephropathy is suppressed by the administration of endothelin antibodies [Kidney International (Kidney International).
Int. ), 37, 1487-1491 (1990)]. Thus, it has been suggested that endothelin plays an important role in these cyclosporine-induced diseases.

It is known that various actions of these endothelins are caused by the binding of endothelin receptors widely distributed in the living body with the endothelin [American Journal of Physiology (Am.
J. Physiol. ), Vol 256, page R856-
R 866 (1989)].

[0012] At least two subtypes of the endothelin receptor exist from the studies to date, and it is known that the vasoconstrictor action of endothelin is also mediated through these two endothelin receptor subtypes [Journal・ Of Cardiovascular Pharmacology (J. Cardiovasc. Pharmac
ol. ), Vol. 17 (Supp. 7), S119-S121 (1991)]. One of these endothelin receptor subtypes is the endothelin receptor (ET _A ) which has selectivity for ET-1 compared to ET-3 of the endothelin family peptide, and the other is ET.
-1 and ET-3 are endothelin receptors (ET _B ) having almost the same activity, and it has been shown that the respective receptor proteins are different [Nature (N
Nature), vol. 348, p. 730-p. 735 (1990)].

The distribution of two endothelin receptor subtypes with different selectivities among these endothelin family peptides is different in the tissue, and ET _A receptors are mainly present in the cardiovascular system, whereas ET _B receptors are The body is the brain, the kidneys,
It is known to be distributed in a wide range of tissues such as lungs, heart and blood vessels.

Substances that specifically inhibit the binding of endothelin to these endothelin receptors are considered to be useful as pharmaceuticals in a wide range of fields by antagonizing the various physiological actions of endothelin described above. The present inventors have previously disclosed a strong antagonism of endothelin through the ET _A receptor of peptides (Japanese Patent Application No. 3-160023). However, since the action of endothelin is expressed not only by the ET _A receptor but also by the ET _B receptor, in order to effectively antagonize the action of endothelin in various diseases, ET _A , ET _B receptors have been desired to be invented.

[0015]

Endothelin is an endogenous physiologically active substance that directly or indirectly (regulates the release of various endogenous substances) continuously contracts vascular and non-vascular smooth muscle. Yes, its overproduction and hypersecretion are the etiological factors of hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, acute renal failure, myocardial infarction, angina, cerebral vasospasm and cerebral infarction. Considered to be one. Further, it has been suggested that endothelin acts as an important mediator for diseases such as multi-organ failure caused by endotoxin shock or endotoxin, disseminated intravascular coagulation, and renal damage and hypertension induced by cyclosporine. The receptors of endothelin are known ET _A receptor and ET _B receptors, with ET _A receptor antagonists, ET _B receptor antagonists are useful as pharmaceuticals. The present invention is intended to provide a novel therapeutic method for the above-mentioned various pathological conditions, which has never been achieved by the invention of a substance having a strong antagonistic activity against both ET _A receptor and ET _B receptor. ..

[0016]

The present inventors have synthesized various peptide derivatives in order to solve the above-mentioned problems,
As a result of examining the endothelin antagonistic activity, the general formula

[0017]

[Chemical 2] [Wherein A is a group represented by the formula: R ¹ O—C (═O) (wherein R ¹ represents a lower alkyl group or an aryl group) or a formula: R ²¹ R ²² N—C (= O) (wherein R ²¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, or any 1 to 2 hydrogen atoms on the ring is a lower alkyl group, a lower alkoxy group, Represents an aryl group or a heteroaryl group which may be substituted with any group selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, an amino group and a formylamino group, and R ²² represents a hydrogen atom or a hydroxyl group. It represents a lower alkyl group which may be substituted, a cycloalkyl group or a cycloalkyl lower alkyl group, or both R ²¹ and R ²² are bonded to each other to form an adjacent nitrogen atom and have 4 to 4 carbon atoms. 8 to 5 A nitrogen-containing saturated heterocycle of a member ring may be formed, and at this time, among the methylene groups forming the ring, any one methylene group not adjacent to the above nitrogen atom is substituted with a thio group. Further, any 1 to 4 hydrogen atoms on the carbon atoms of the heterocycle may be independently substituted with a lower alkyl group or a hydroxy lower alkyl group, and the heterocycle may be adjacent to each other. Which may form a benzo-condensed ring at two carbon atoms), R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ may be substituted with a lower alkylthio group. A lower alkyl group, a lower alkenyl group, a cycloalkyl group in which any 1 to 4 hydrogen atoms on the ring may be independently substituted with a lower alkyl group, a cycloalkyl lower alkyl group, or an aryl group , A heteroaryl group, an aryl lower alkyl group or a heteroaryl lower alkyl group; X represents a halogen atom or a lower alkyl group; R ⁵ represents a hydrogen atom or a lower alkyl group;
R ⁶ represents a hydrogen atom, or a lower alkyl group or a lower alkenyl group which may have a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an aryl group and a heteroaryl group; 0 or 1
Y is a hydroxymethyl group, a group represented by the formula: CO ₂ R ⁷¹ (wherein R ⁷¹ represents a hydrogen atom or a lower alkyl group), a formula: CONR ⁷² R ⁷³ (wherein R ⁷² , R ⁷³ each independently represents a hydrogen atom, an aryl group, a heteroaryl group, or a lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group). Group, 1H-tetrazol-5-yl group, sulfo group or phosphono group] or a pharmaceutically acceptable salt thereof has a strong antagonistic activity against both ET _A receptor and ET _B receptor. The present invention has been completed by finding out that

The meanings of various abbreviations described in this specification are shown below. Abbreviation Meaning of abbreviation DβAbu D-3-aminobutyric acid Cpeg L-cyclopentylglycine Cprg L-cyclopropylglycine Ile L-isoleucine DIle D-isoleucine Leu L-leucine γMeLeu γ-methyl-L-leucine DMet D-methionine D-methionine -(1-naphthyl) alanine Nle L-norleucine DNle D-norleucine Nva L-norvaline DNva D-norvaline DTrp D-tryptophan DTrp (2-Br) D- (2-bromo) tryptophan DTrp (2-Cl) D- ( 2-chloro) tryptophan DTrp (1-Me, 2-Cl) D- (2-chloro-1-methyl) tryptophan DTrp (1-Boc, 2-Cl) D- (1-t-butoxycarbonyl-2- Chloro) Liptophan DTrp (1-Boc, 2-Br) D- (1-t-butoxycarbonyl-2-bromo) tryptophan DTrp (2-Me) D- (2-methyl) tryptophan DTrp (2-Et) D- ( 2-ethyl) tryptophan DTrp (1-Me, 2-Me) D- (1,2-dimethyl) tryptophan Ac acetyl Boc tert-butoxycarbonyl Et ethyl Me methyl nPr n-propyl iPr isopropyl nBun n-butyl tBu tert-butyl. Ph phenyl Bzl benzyl c-Pent cyclopentyl CDI 1,1′-carbonyldiimidazole DCC N, N′-dicyclohexylcarbodiimide DMAP 4- (dimethylamino) pyridine DMF N, N-dimethylformamide DMSO dimethy. Sulfoxide NMP N-methylpyrrolidone NMM N-methylmorpholine EDCI · HCl 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBT · H ₂ O 1-hydroxy -1H- Benzotoria tetrazole monohydrate HOSu N-hydroxysuccinimide TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TsOH p-toluenesulfonic acid Ts p-toluenesulfonyl Z benzyloxycarbonyl MOPS 3-morpholinopropanesulfonic acid HEPES 2- [4- (2-hydroxyethyl) -1-piperazinyl ] Ethanesulfonic Acid Tris Tris (hydroxymethyl) aminomethan PMSF Phenylmethanesulfonyl Fluoride Then, as used in this specification To explain the definition of that various terms.

In the present specification, the lower alkyl group means
It means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a sec-butyl group, a tert. -Butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, 1-methylbutyl group, 2-methylbutyl group, 1,2-dimethylpropyl group, 1-ethylpropyl group, hexyl group, isohexyl group, 1- Methylpentyl group, 2-methylpentyl group, 3-methylpentyl group, 1,1-dimethylbutyl group, 1,2-dimethylbutyl group, 2,2-dimethylbutyl group, 1-ethylbutyl group, 1,1,2 -Trimethylpropyl group, 1,2,2-trimethylpropyl group, 1-ethyl-2-methylpropyl group, 1-ethyl-1-methylpropyl group and the like. It is.

The lower alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, and specific examples thereof include a methoxy group, an ethoxy group, a propoxy group and an isopropoxy group. To be

The cycloalkyl group means a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group, a cyclononyl group and the like.

The term "cycloalkyl lower alkyl group" means an alkyl group having 1 to 6 carbon atoms which is substituted with a cycloalkyl group having 3 to 6 carbon atoms, specifically, a cyclopropylmethyl group, 1 -Cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropylpropyl group,
Examples thereof include a 2-cyclopropylpropyl group, a 3-cyclopropylpropyl group, a cyclopentylmethyl group, a 2-cyclopentylethyl group, a cyclohexylmethyl group, a 2-cyclohexylethyl group and a 3-cyclohexylpropyl group.

The hydroxy lower alkyl group means a lower alkyl group in which 1 to 3 hydrogen atoms of the lower alkyl group defined above are substituted with a hydroxyl group, and examples thereof include a hydroxymethyl group, a 1-hydroxyethyl group, and a 2 hydroxy group. -Hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1,2-dihydroxyethyl group, 1,3-dihydroxypropyl group , 1,
2,3-trihydroxybutyl group and the like can be mentioned.

The aryl group means a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like.

The aryl lower alkyl group means a lower alkyl group in which the hydrogen atom of the lower alkyl group defined above is substituted with the aryl group defined above, and examples thereof include benzyl group, phenylethyl group and 1-naphthylmethyl group. Base, 2
Examples thereof include -naphthylmethyl group and 1-naphthylethyl group.

The heteroaryl group means a heteroaryl group or a condensed heteroaryl group containing at least one hetero atom such as oxygen, nitrogen or sulfur atom, and specifically, it is a thienyl group, a furyl group or a thiazolyl group. Group, imidazolyl group, pyridyl group, indolyl group, benzothienyl group and the like.

The heteroaryl lower alkyl group means a lower alkyl group in which the hydrogen atom of the lower alkyl group defined above is substituted with the heteroaryl group defined above, and examples thereof include 2-thienylmethyl group and 3-thienyl group. Methyl group, 2- (2-thienyl) ethyl group, 2-thiazolylmethyl group, 2-furylmethyl group, 3-furylmethyl group, 2
-Pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-indolylmethyl group, 3-indolylmethyl group, 2-benzothienylmethyl group and the like can be mentioned.

The lower alkenyl group means a linear or branched alkenyl group having 2 to 6 carbon atoms, specifically, vinyl group, allyl group, 2-propenyl group, isopropenyl group, 3-butenyl group, 2-butenyl group, 1-butenyl group, 1-methyl-2-propenyl group, 1-methyl-
1-propenyl group, 1-ethyl-1-ethenyl group, 2-
Examples thereof include a methyl-2-propenyl group, a 2-methyl-1-propenyl group and a 4-pentenyl group.

The halogen atom means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.

The lower alkylthio group has 1 to 6 carbon atoms.
Means a linear or branched alkylthio group, specifically, a methylthio group, an ethylthio group, a propylthio group,
Examples thereof include isopropylthio group.

Next, the present invention will be described in more detail by explaining the meaning of the symbols used in the general formula [I] with a specific example.

The group represented by R ¹ in A means a lower alkyl group or an aryl group. Specific examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group. , 1,1-
Examples thereof include a dimethylbutyl group, a 1-ethyl-1-methylpropyl group, and a 1,1,2-trimethylpropyl group. Specific examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like.

The group represented by R ²¹ in A is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, any one or two hydrogen atoms on the ring may be a halogen atom or trifluoromethyl. Group, a nitro group, an amino group and a formylamino group means an aryl group or a heteroaryl group which may be substituted with any group selected from the group consisting of, a group bonded to R ²² , and an adjacent nitrogen atom. Together, they mean the heterocyclic group described below. Specific examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert.
-Pentyl group, 1,1-dimethylbutyl group, 1-ethyl-1-methylpropyl group, 1,1,2-trimethylpropyl group and the like. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. Specific examples of the cycloalkyl lower alkyl group include a cyclopropylmethyl group, a 1-cyclopropylethyl group, a 2-cyclopropylethyl group, a 1-cyclopropylpropyl group, a 2-cyclopropylpropyl group and a 3-cyclopropylpropyl group. , Cyclopentylmethyl group, 2
-Cyclopentylethyl group, cyclohexylmethyl group,
Examples thereof include 2-cyclohexylethyl group and 3-cyclohexylpropyl group. Any one or two hydrogen atoms on the ring may be halogen atom, trifluoromethyl group, nitro group,
Specific examples of the aryl group or heteroaryl group which may be substituted with any group selected from the group consisting of an amino group and a formylamino group, include a phenyl group, a 2-fluorophenyl group, a 2-chlorophenyl group and a 2-chlorophenyl group. Bromophenyl group, 3-fluorophenyl group, 3-chlorophenyl group, 3-bromophenyl group, 4-fluorophenyl group,
4-chlorophenyl group, 4-bromophenyl group, 2,6
-Difluorophenyl group, 2,6-dichlorophenyl group, 2,6-dibromophenyl group, 2-aminophenyl group, 2-formylaminophenyl group, 2-trifluoromethylphenyl group, 2-nitrophenyl group, 3-amino Examples thereof include a phenyl group, 3-formylaminophenyl group, 2-pyridyl group, 3-pyridyl group, 4-pyridyl group, 2-thienyl group and 3-thienyl group.

In A, the group represented by R ²² means a hydrogen atom, a lower alkyl group optionally substituted with a hydroxyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, or a group bonded to R ²¹ ; In addition, it means a heterocyclic group described later together with the adjacent nitrogen atom. Specific examples of the lower alkyl group which may be substituted with a hydroxyl group include a methyl group, an ethyl group, a hydroxyethyl group, a propyl group,
Hydroxypropyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group,
Pentyl group, isopentyl group, neopentyl group, ter
Examples thereof include t-pentyl group. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group and a cycloheptyl group. Specific examples of the cycloalkyl lower alkyl group include a cyclopropylmethyl group, a 1-cyclopropylethyl group, a 2-cyclopropylethyl group, a 1-cyclopropylpropyl group, a 2-cyclopropylpropyl group and a 3-cyclopropylpropyl group. , Cyclopentylmethyl group, 2-cyclopentylethyl group, cyclohexylmethyl group, 2-cyclohexylethyl group, 3-cyclohexylpropyl group and the like.

In A, both R ²¹ and R ²² are bonded to form a nitrogen-containing saturated heterocyclic ring having 4 to 8 carbon atoms and a 5 to 9 membered ring together with the adjacent nitrogen atom. Well,
At this time, among the methylene groups forming a ring, any one methylene group not adjacent to the above nitrogen atom may be substituted with a thio group, and further, any one of the methylene groups on the carbon atom of the heterocycle may be substituted. To 4 hydrogen atoms may be each independently substituted with a lower alkyl group or a hydroxy lower alkyl group, and may form a benzo-fused ring at two adjacent carbon atoms of the heterocycle. Good groups include pyrrolidino group, piperidino group, perhydroazepin-1-yl group, perhydroazocin-1-yl group, perhydroazonin-1-yl group, 1,3-thiazolidin-1-yl group. , Indoline-1-yl group, isoindoline-2-yl group, 3-pyrrolin-1-yl group, 1,5-dihydro-
2H-pyrrol-1-yl group, perhydro-1,4-thiazin-4-yl group, 1,2,3,4-tetrahydroquinolin-1-yl group, 1,2,3,4-tetrahydroisoquinoline-2 -Yl group, 1,2,3,4-tetrahydropyridin-1-yl group, 1,2,3,6-tetrahydropyridin-1-yl group, perhydro-1,4-thiazepin-4-yl group, 2 , 3,4,5-Tetrahydro-1
-Benzazepin-1-yl group, 2,3,4,5-tetrahydro-2-benzazepin-2-yl group, 1,2,
4,5-Tetrahydro-3-benzazepin-3-yl group, 2,3,4,5-tetrahydro-1H-azepine-
1-yl group, 2,3,6,7-tetrahydro-1H-azepin-1-yl group, 1,3,4,7-tetrahydro-
2H-azepin-1-yl group, perhydro-1,4-thiazocin-4-yl group, 1,2,3,4,5,6-hexahydro-1-benzazocin-1-yl group, 1,2,
3,4,5,6-hexahydro-2-benzazocine-
2-yl group, 1,2,3,4,5,6-hexahydro-
3-benzazocin-3-yl group, 1,2,3,4
5,6-hexahydroazocin-1-yl group, 1,2,
3,4,7,8-hexahydroazocin-1-yl group,
1,2,3,4,5,8-hexahydroazocin-1-
It means a heterocyclic group such as an yl group or a heterocyclic group in which any 1 to 4 hydrogen atoms on the carbon atoms of the heterocycle are independently substituted with a lower alkyl group or a hydroxy lower alkyl group. Among the substituents on the heterocyclic carbon atom, specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group,
Examples thereof include sec-butyl group and tert-butyl group. Specific examples of the hydroxy lower alkyl group include hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 2-hydroxypropyl group, 3-hydroxypropyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4-hydroxybutyl group, 1,2-dihydroxyethyl group, 1,3-dihydroxypropyl group,
Examples include 1,2,3-trihydroxybutyl group.

The group represented by R ³ means a hydrogen atom or a lower alkyl group, and specific examples of the lower alkyl group include a methyl group and an ethyl group.

The group represented by R ⁴ is a lower alkyl group optionally substituted with a lower alkylthio group, a lower alkenyl group, or any 1 to 4 hydrogen atoms on the ring are independently substituted with a lower alkyl group. And an optionally substituted cycloalkyl or cycloalkyl lower alkyl group, an aryl group, a heteroaryl group, an aryl lower alkyl group, or a heteroaryl lower alkyl group. Specific examples of the lower alkyl group which may be substituted with a lower alkylthio group include methyl group, ethyl group, methylthioethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-butyl group. , Pentyl group, isopentyl group, neopentyl group, tert-pentyl group and the like. Specific examples of the lower alkenyl group include vinyl group, allyl group, 1-propenyl group, isopropenyl group, 3-butenyl group, 2-butenyl group, 1-
Butenyl group, 1-methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group,
A 2-methyl-2-propenyl group, a 2-methyl-1-propenyl group, a 4-pentenyl group and the like can be mentioned. Specific examples of the cycloalkyl group or cycloalkyl lower alkyl group in which any 1 to 4 hydrogen atoms on the ring may be independently substituted with a lower alkyl group, include cyclopropyl group and 2-methylcycloalkyl group. Propyl group, 2-ethylcyclopropyl group, 2-propylcyclopropyl group,
2,2-dimethylcyclopropyl group, 2,3-dimethylcyclopropyl group, 2,2,3,3-tetramethylcyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cyclopropylmethyl group, 2-methylcyclo Propylmethyl group, 2-ethylcyclopropylmethyl group, 2-propylcyclopropylmethyl group, 2,2
-Dimethylcyclopropylmethyl group, 2,3-dimethylcyclopropylmethyl group, 2,2,3,3-tetramethylcyclopropylmethyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, 1-
Cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropyl-1-methylethyl group, 1-cyclobutylethyl group, 2-cyclobutylethyl group, 1-
Cyclobutyl-1-methylethyl group, 1-cyclopentylethyl group, 2-cyclopentylethyl group, 1-cyclopentyl-1-methylethyl group, 1-cyclohexylethyl group, 1-cyclohexyl-1-methylethyl group, 1
Examples include -cycloheptylethyl group and 1-cyclooctylethyl group. Specific examples of the aryl group include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like, and specific examples of the heteroaryl group include a 2-thienyl group, a 3-thienyl group, a 2-thiazolyl group, 4 Examples thereof include a thiazolyl group, a 5-thiazolyl group, a 2-furyl group and a 3-furyl group. Specific examples of the aryl lower alkyl group include benzyl group, phenylethyl group, 1-naphthylmethyl group, 2-naphthylmethyl group and 2- (1-naphthyl).
Examples thereof include an ethyl group, and specific examples of the heteroaryl lower alkyl group include a 2-thienylmethyl group, a 3-thienylmethyl group, a 2-thienylethyl group, a 2-thiazolylmethyl group, a 2-furylmethyl group, and a 3-furyl group. Methyl group, 2
-Pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-indolylmethyl group, 3-indolylmethyl group, 2-benzothienylmethyl group, 3-benzothienylmethyl group and the like can be mentioned.

X represents a halogen atom or a lower alkyl group. Specific examples of the halogen atom include a fluorine atom,
Examples thereof include chlorine atom, bromine atom and iodine atom. Specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and the like.

The group represented by R ⁵ means a hydrogen atom or a lower alkyl group, and specific examples of the lower alkyl group include:
Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, tert-
Examples thereof include a butyl group.

The group represented by R ⁶ is a hydrogen atom, or a lower alkyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an aryl group and a heteroaryl group, or A lower alkenyl group means a lower alkyl group or a lower alkenyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an aryl group and a heteroaryl group. , Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, te
rt-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, hydroxymethyl group, 1-hydroxyethyl group, methoxymethyl group, 1-methoxyethyl group, methylthiomethyl group, ethylthiomethyl group , Propylthiomethyl group, butylthiomethyl group, 2-methylthioethyl group, 2-ethylthioethyl group, phenylmethyl group, 3-indolylmethyl group,
4-imidazolylmethyl group, 2-pyridylmethyl group, 3
-Pyridylmethyl group, 4-pyridylmethyl group, vinyl group, allyl group, 2-propenyl group, isopropenyl group,
3-butenyl group, 2-butenyl group, 1-butenyl group, 1
-Methyl-2-propenyl group, 1-methyl-1-propenyl group, 1-ethyl-1-ethenyl group, 2-methyl-2
-Propenyl group, 2-methyl-1-propenyl group, 4-
Pentenyl group, 1-hydroxy-2-propenyl group, 1
-Methoxy-2-propenyl group, 1-methylthio-2-
Propenyl group, 2-hydroxy-3-butenyl group, 2-
An ethylthio-3-butenyl group etc. can be mentioned.

The group represented by R ⁷¹ means a hydrogen atom or a lower alkyl group. Specific examples of the lower alkyl group include methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, sec-butyl group, te.
Examples thereof include rt-butyl group, pentyl group, isopentyl group, neopentyl group and hexyl group.

The groups represented by R ⁷² and R ⁷³ may be independently substituted with a hydrogen atom, an aryl group, a heteroaryl group, or a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group. Means a good lower alkyl group, and specific examples of the aryl group include a phenyl group and 1-
Examples thereof include a naphthyl group and a 2-naphthyl group, and specific examples of the heteroaryl group include a thienyl group, a thiazolyl group,
Furyl group, pyridyl group, indolyl group, benzothienyl group and the like, and specific examples of the lower alkyl group which may be substituted with a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group, Methyl group, ethyl group, propyl group, isopropyl group, butyl group, isobutyl group, tert-butyl group, pentyl group, hexyl group, 2-hydroxyethyl group, carboxymethyl group, 1
-Carboxyethyl group, 2-carboxyethyl group, sulfomethyl group, 2-sulfoethyl group and the like.

Next, a method for producing the novel peptide derivative of the present invention will be described.

The peptide derivative represented by the general formula [I] of the present invention is generally prepared by condensing the amino acids or amino acid derivatives constituting the peptide derivative one by one and, if necessary, protecting the C-terminal or the side chain. It can be produced by deprotecting the group (Production Method 1). Further, the compound of the present invention is obtained by removing (1) the N-terminal α-amino protecting group of the compound obtained by the production method 1 or an intermediate thereof, and then subjecting the amino group to alkoxycarbonylation, aryloxycarbonylation or carbamoylation. Do (manufacturing method 2, 3),
(2) Halogenating the indole ring 2-position of the tryptophan residue (Production method 4), (3) Amidating the C-terminal carboxyl group (Production method 5), etc.
Furthermore, it can optionally be produced by forming a pharmaceutically acceptable salt thereof.

Each manufacturing method will be specifically described below. [Production method 1] Production method 1 is a general method for producing a peptide derivative, and is a method for producing a desired peptide derivative by condensing amino acids or amino acid derivatives one by one. Further, it is a method of removing the protecting group at the C-terminal of the peptide by alkaline hydrolysis, catalytic hydrogenolysis or acidolysis, if necessary. The condensation reaction is a DCC method,
Known methods such as the azide method, the active ester method, the mixed acid anhydride method, etc. [eg, M. Bodanski]
y) and M. A. Ondetti (MA Onde)
by Ttti, Peptide Synthesis, Interscience, New York (Peptide Synthesi)
s, Interscience, New York) 1
966; FM Finn
And K. Hofmann, The Proteins, Volume 2,
Edited by H. Nenrath and RL Hill, Academic Press Incorporated, New York (Ac)
acoustic Press Inc. , NewYor
k) 1976; Nobuo Izumiya et al., Peptide Synthesis, Maruzen Co., Ltd. 1975, etc.].

For example, when the condensation is carried out by the DCC method, the general formula

[0047]

[Chemical 3] [In the formula, T represents A or an α-amino protecting group, and A, R ³
And R ⁴ have the above-mentioned meanings], an α-amino acid derivative represented by the formula: DMSO, NMP,
In a solvent such as DMF, THF, 1,4-dioxane, acetonitrile, dichloromethane, or chloroform, by the action of a condensing agent such as DCC (or EDCI.HCl) -HOBT.H ₂ O, a general formula

[0048]

[Chemical 4] [In the formula, X ¹ represents X or a hydrogen atom, R ⁵¹ represents R ⁵ or an indole NH protecting group, P ¹ represents an α-carboxyl protecting group, and X and R ⁵ have the above meanings] By condensation with an α-amino acid derivative having a suitable α-carboxyl protecting group represented by the general formula

[0049]

[Chemical 5] A dipeptide derivative represented by the formula: wherein T, R ³ , R ⁴ , R ⁵¹ , X ¹ and P ¹ have the above meanings is prepared. The indole NH protecting group is selected from formyl group, Boc group and the like. The α-amino protecting group is generally selected from those well known to those skilled in the art, for example, urethane type protecting groups such as Z group, Boc group, p-methoxybenzyloxycarbonyl group and p-nitrobenzyloxycarbonyl group. . On the other hand, the α-carboxyl protecting group is selected from methyl, ethyl, benzyl, tert-butyl ester and the like, and is selected according to the N-terminal protecting group so that each protecting group can be selectively removed after condensation. Should. For example, when the N-terminal protecting group is a Boc group, the C-terminal side is preferably protected as methyl, ethyl or benzyl ester. The Boc group is easily removed by the action of a relatively mild acid such as formic acid and TFA, but under these conditions, these carboxyl protecting groups are stable. on the other hand,
Methyl, ethyl ester and benzyl ester are easily removed by alkaline hydrolysis and benzyl ester by catalytic hydrogenolysis, but the Boc group is stable under these conditions.

When T is an α-amino protecting group, it is deprotected and then N-alkoxycarbonylated, N-aryloxycarbonylated or N-carbamoylated to protect the N-terminal. The group can also be converted to A. Where N-alkoxycarbonylation,
The N-aryloxycarbonylation, N-carbamoylation and the like can be carried out under the conditions described in the production method 2 or 3 described later.

Further, in the general formula [IV], when X ¹ is a hydrogen atom, the 2-position of the indole ring can be halogenated under the conditions described in the following production method 4.

A general formula obtained by deprotecting the C-terminal carboxyl protecting group of the dipeptide derivative [IV] thus produced

[0053]

[Chemical 6] [Wherein T, R ³ , R ⁴ , X ¹ , and R ⁵¹ have the above-mentioned meanings], a dipeptide represented by the above-mentioned conditions and the same condensing agent (for example, EDCI · HCl-HOBT) can be used.・
H ₂ O etc.)

[0054]

[Chemical 7] [Wherein Y ¹ represents Y or COOP ² , P ² represents an α-carboxyl protecting group, and R ⁶ , n and Y have the above-mentioned meanings], and condensed with a compound represented by the general formula

[0055]

[Chemical 8] A tripeptide derivative represented by the formula [wherein T, R ³ , R ⁴ , X ¹ , R ⁵¹ , R ⁶ , Y ¹ and n have the above-mentioned meanings] can be produced.

In the general formula [VII], when T is an α-amino protecting group, it is deprotected and then N-
It is also possible to convert the N-terminal protecting group into A by alkoxycarbonylation, N-aryloxycarbonylation or N-carbamoylation. Here, N-alkoxycarbonylation, N-aryloxycarbonylation, N-carbamoylation and the like can be carried out under the conditions described in the production method 2 or 3 described later.

Further, in the general formula [VII], when X ¹ is a hydrogen atom, the 2-position of the indole ring can be halogenated under the conditions described in the production method 4 described later.

The tripeptide derivative produced as described above is subjected to deprotection of the C-terminal or side chain protecting group, if necessary, to produce the desired peptide derivative represented by the general formula [I]. can do.

On the other hand, the dipeptide derivative represented by the general formula [V] is condensed with HOSu, p-nitrophenol or the like at about -40 ° C to room temperature in a solvent such as DMF by the action of EDCI · HCl or the like. The desired peptide derivative can also be obtained by reacting the compound represented by the general formula [VI] with the active ester.
Such an active ester can be once isolated and purified and then used in the next reaction. However, after being produced in the system, it is reacted with the compound represented by the general formula [VI] without isolation and purification. It is also possible to react. Further, when the compound represented by the general formula [VI] is an amino acid, salts of the amino acid such as tetrabutylammonium, triethylammonium, sodium and potassium can be used.

In the above-described method for producing a peptide derivative, the C of the desired peptide derivative is condensed in the condensation of amino acids.
A target peptide derivative is produced by finally condensing a terminal amino acid or a C-terminal dipeptide, while a target peptide derivative is produced even by finally condensing an N-terminal side amino acid. You can

That is, the general formula

[0062]

[Chemical 9] [Wherein P ³ represents an α-amino protecting group, R ⁵¹ and X ¹ have the above meanings] and a compound represented by the general formula

[0063]

[Chemical 10] [Wherein Y ¹ represents Y or COOP ² , P ² represents an α-carboxyl protecting group, and R ⁶ , n and Y have the above-mentioned meanings] with a DCC method or an active ester The peptide derivative having N-terminal protection is obtained by condensation by a method or the like. Suitable α-amino protecting groups are selected from the urethane type protecting groups described above, and the C-terminal carboxyl group can be protected as an ester. For example, when the C-terminal carboxyl group is protected as tert-butyl ester, the N-terminal amino protecting group is Z group or Boc.
Groups are preferred. The Z group is formed by catalytic hydrogenolysis
The c group can be easily removed by allowing a mild acid such as formic acid or TFA to act under ice cooling, but the C-terminal carboxyl protecting group is stable under this condition.

The dipeptide obtained by removing the N-terminal amino-protecting group of the dipeptide derivative thus produced is added to a condensing agent (for example, EDCI.HCl-H) in the same manner as above.
OBT.H ₂ O, etc.) is allowed to act to condense with the α-N-substituted amino acid to produce the desired peptide derivative.

In the peptide derivative produced by the above method, the C-terminal protecting group can be deprotected by an appropriate method if necessary. For example, if the carboxyl group is t
When protected as an ert-butyl ester, it can be easily deprotected by acidolysis. That is, deprotection can be achieved by acting a mild acid such as formic acid and TFA. In the case of benzyl ester, the protective group can be deprotected by catalytic hydrogenolysis. That is, methanol, ethanol, DMF,
Deprotection can be performed by catalytic hydrogenolysis in a solvent such as THF, 1,4-dioxane, acetic acid or the like in the presence of a catalyst such as palladium carbon or palladium black in a hydrogen atmosphere at 1 to 4 atm. [Production Method 2] In Production Method 2, after removing the N-terminal amino-protecting group of the amino acid ester derivative or the dipeptide derivative or the tripeptide derivative produced by Production Method 1, it is preferable that the C-terminal carboxyl group is protected as an ester. ) To the amino group of chloroformate (R ¹ OCOC
l), an acid chloride such as carbamoyl chloride (R ²¹ R ²² NCOCl) or the like is reacted in the presence of a base, or an isocyanate (R ²¹ NCO) is reacted so that the N-terminals are each alkoxycarbonylated, aryloxy. Producing a carbonylated or carbamoylated peptide derivative,
After that, if necessary, the C-terminal protecting group is removed by alkali hydrolysis, catalytic hydrogenolysis or acid decomposition. In the above formula, R ¹ , R ²¹ and R ²² have the above-mentioned meanings.

The N-terminal amino protecting group is easily removed by catalytic hydrogenolysis, for example in the case of the Z group. The Boc group can be removed by the action of a relatively mild acid such as TFA. The peptide derivative obtained by removing the N-terminal amino protecting group and the chloroformate (R ¹ O
COCl), carbamoyl chloride (R ²¹ R ²² NCOC
The reaction with an acid chloride such as l) is carried out in a solvent such as chloroform, dichloromethane, THF, 1,4-dioxane, toluene and pyridine in the presence of a base such as TEA, DMAP, NMM and pyridine from 0 ° C to a solvent. It can be carried out at the boiling temperature. In addition, the reaction with isocyanate (R ²¹ NCO) is performed using chloroform, dichloromethane, THF, 1,4-
It can be carried out in a solvent such as dioxane or toluene at 0 ° C to the boiling point of the solvent.

In the peptide derivative obtained by the present production method, the C-terminal protecting group can be removed by alkali hydrolysis, catalytic hydrogenolysis or acidolysis in the same manner as in the production method 1, if necessary. [Production method 3] Production method 3 is an amino acid derivative or production method 1 or 2.
And a peptide derivative having an aryloxycarbonyl group at the N-terminus and a primary or secondary amine R ²¹ NHR ²²
(Wherein R ²¹ and R ²² have the above-mentioned meanings) to produce an amino acid or peptide derivative whose N-terminal is a carbamoyl group, and then, if necessary, alkali-hydrolyze the C-terminal protecting group. , Catalytic hydrogenolysis or acid decomposition.

That is, a peptide derivative having an aryloxycarbonyl group at the N-terminal is dissolved in a solvent such as chloroform, dichloromethane, THF, 1,4-dioxane, toluene, pyridine, etc., and the primary or secondary amine is added thereto. Further, a tertiary amine such as TEA or DMAP is further added if necessary, and the reaction is carried out at room temperature to the boiling temperature of the solvent, whereby the desired peptide derivative having a carbamoyl group at the N-terminal can be produced. In the compound, if necessary, the C-terminal protecting group can be removed by alkali hydrolysis, catalytic hydrogenolysis or acid decomposition in the same manner as in Production Method 1. [Production Method 4] Production Method 4 is a method of halogenating the indole ring 2-position of the compound when the peptide derivative produced in Production Method 1 contains an unsubstituted tryptophan residue at the 2-position of the indole ring.

Manufactured by arbitrarily combining the manufacturing methods 1, 2 and 3
Tryptophan-containing dipeptide or tripeptide
Derivatives, or tryptophan-protected forms of the raw materials,
For example, in a solvent such as acetic acid or carbon tetrachloride, for example, N-bromo.
N-has such as succinimide and N-chlorosuccinimide
Locosuccinimide was added to 2,2'-azobis as needed.
To act in the presence of (isobutyronitrile), etc.
Makes it possible to halogenate the 2-position of the indole ring.
It [Production method 5] Production method 5 is a pep produced by production methods 1 to 4.
In the tide derivative, the C-terminal is an unprotected carboxyl group
A compound of the general formula R⁷²R⁷³NH  [IX] [wherein R⁷²Has the above meaning]
To DCC method, active ester method, etc.
By further condensing to obtain the desired peptide derivative
is there.

The reaction intermediate and the desired product in the above production method can be purified by a known purification method (eg, recrystallization, reprecipitation, partitioning operation, normal phase or reverse phase chromatography, ion exchange chromatography, etc.). it can.

Commercially available compounds can be used as the raw material compounds used in the above production method, but the following raw material compounds were those produced by known methods.

D-Norleucinol [Journal of the American Chemical Society (JA
m. Chem. Soc. ), 107, 7974 (198)
It was synthesized according to 5). ] D-3-Cyclopropylalanine [Journal of
The American Chemical Society (J. Am.
Chem. Soc. ), 111, 6354 (198)
9)] D-Cyclopropylglycine [Journal of the
American Chemical Society (J. Am. Ch
em. Soc. ), 111, 6354 (1989)] D- (2-methylcyclopropyl) glycine [Journal of the American Chemical Society.
(J. Am. Chem. Soc.), 111, 6354.
(1989). ] DL- (2,2-dimethylcyclopropyl) glycine
t-Butyl ester [Tetrahedron Letters (Te
trahedron Lett. ), 30, 3069
(1989). ] DL-cyclobutylglycine t-butyl ester [Tetrahedron L (Tetrahedron L
ett. ), 30, 3069 (1989)] D-cyclopentylglycine [Journal of Organic Chemistry (J. Org. Chem.),
30, 1320 (1965)] α-N- (trifluoroacetyl) -2-chloro-D-
Tryptophan methyl ester, α-N- (trifluoroacetyl) -2-bromo-D-tryptophan methyl ester and α-N- (trifluoroacetyl)-
1-Methyl-2-chloro-D-tryptophan [Journal of the American Chemical Society (J. Am. Chem. Soc.), 108, 2023.
It was synthesized according to (1986). ] 2-methyl-DL-tryptophan [Journal of Chemical Society (J. Chem. So
c. ), 705 (1948)] α-N-benzyloxycarbonyl-2-methyl-D-
Tryptophan methyl ester [Tetrahedron Letters, 3
It was synthesized according to 0,4073 (1989). ] In addition, in Example No. corresponding to the structure of the compound manufactured by the Example. And compound No. Are shown in Tables 1 to 3 below.

[0073]

[Table 1]

[0074]

[Table 2]

[0075]

[Table 3]

[0076]

[Table 4]

[0077]

[Table 5]

[0078]

[Table 6]

[0079]

[Table 7]

[0080]

[Table 8]

[0081]

[Table 9] Compound 45 is a mixture of diastereomers and is compound 7
1, 72 is a mixture of trans diastereomers, and compounds 46 and 47, 48 and 49, 72 and 73, 7
4 and 75 are respectively one and the other of the two diastereomers.

Next, the endothelin antagonism of the cyclic pentapeptide of the present invention will be described.

Trial of inhibition of endothelin binding to ET _A receptor
Test pig aortic smooth muscle tissue was 10 mM MOPS at 4 ° C.
Homogenize with Polytron in pH 7.4 buffer. Add 20% sucrose to the homogenate, centrifuge at 1000 xg for 15 minutes, and add 10% supernatant.
It was centrifuged at 000 × g for 15 minutes. Add this supernatant to 9
Centrifuge at 0000 xg for 40 minutes and the resulting precipitate is 5m
A membrane fraction was prepared by suspending it in MHEPES / Tris pH 7.4 buffer to give 25 mg / ml.

16 μl of this membrane fraction was added to 50 mM Tris
/ HCl pH 7.4 buffer A (10 μM calcium chloride, 10 μM magnesium chloride, 0.1 mM PM
SF, 1 μM pepstatin A, 2 μM leupeptin, 1 mM 1,10-phenanthroline, 0.1%
Suspension in 340 μl of bovine serum albumin).
To this suspension, (A) unlabeled endothelin-1 (for non-specific binding) having a final concentration of 0.2 μM, (B) buffer A (for total binding), or (C) a final concentration of 1 Add 4 μl of each test compound to give 1 μM, and add ¹²⁵
I-endothelin-1 (12000-18000cp
m) 40 μl was added. Add these mixtures at 25 ° C for 4
Incubate for hours, glass filter GF / C
Filtration at 5 mM HEPES / Tris pH
After washing with 7.4 (containing 0.3% bovine serum albumin), the ¹²⁵ I-endothelin-1 binding inhibition rate D (%) at 1.1 μM of the compound of the present invention was determined by the following formula by measuring the radioactivity on a glass filter. Sought by.

[0085]

[Equation 1] All these tests were performed in triplicate.

As shown in Table 4, the compounds of the present invention are ET
_It showed extremely strong inhibitory activity against endothelin binding to _A receptor. The test compound is the compound No. Indicated by.

[0087]

[Table 10] Assay for inhibition of endothelin binding to ET _B receptor Porcine cerebellum was homogenized with Polytron in 10 mM MOPS pH 7.4 buffer at 4 ° C. Add 20% sucrose to the homogenate and add 1000X
g for 15 minutes, and the supernatant was centrifuged at 10,000 × g for 15 minutes. This supernatant was further centrifuged at 90,000 × g for 40 minutes, and the resulting precipitate was washed with 5 mM HEPES.
/ Tris 3.3 mg suspended in pH 7.4 buffer
The membrane fraction was prepared so that it would be / ml.

16 μl of this membrane fraction was added to 50 mM Tris
/ HCl pH 7.4 buffer A (10 μM calcium chloride, 10 μM magnesium chloride, 0.1 mM PM
SF, 1 μM pepstatin A, 2 μM leupeptin, 1 mM 1,10-phenanthroline, 0.1%
Suspension in 340 μl of bovine serum albumin).
To this suspension, (A) unlabeled endothelin-1 (for non-specific binding) having a final concentration of 0.2 μM, (B) buffer A (for total binding), or (C) a final concentration of 1 Add 4 μl of each test compound to give 1 μM, and add ¹²⁵
I-endothelin-1 (12000-18000cp
m) 40 μl was added. Add these mixtures at 25 ° C for 4
Incubate for hours, glass filter GF / C
Filtration at 5 mM HEPES / Tris pH
After washing with 7.4 (containing 0.3% bovine serum albumin), the ¹²⁵ I-endothelin-1 binding inhibition rate D (%) at 1.1 μM of the compound of the present invention was determined by the following formula by measuring the radioactivity on a glass filter. Sought by.

[0089]

[Equation 2] All these tests were performed in triplicate.

As shown in Table 5, the compounds of the present invention are ET
_It showed extremely strong inhibitory activity against endothelin binding to _B receptor. The test compound is the compound No. Indicated by.

[0091]

[Table 11] On the other hand, the representative compounds of endothelin antagonistic peptides described in Japanese Patent Application No. 3-160023 (reference compounds 1, 2, and 3) are E at a concentration of 1.1 μM.
¹²⁵ I-ET-in porcine aortic membrane fraction rich in T _A receptors
It inhibits 1 binding by 69, 77, and 86%, respectively, while ¹²⁵ I-to the porcine cerebellar membrane fraction ET _B receptor in this study.
For ET-1 binding, 6.
It inhibited only 4, 3.8, 10.1%.

[0092]

[Chemical 11] Endothelin contraction (ET) in pig isolated coronary artery preparation
After excised coronary effects pigs against shrinkage) which via the _A receptor, to produce a spiral specimen width 1 mm, length 10 mm. 95 specimens with peeled endothelial cells
It was suspended in a Magnus tube 5 filled with a Krebs-Henseleit solution saturated with a mixed gas of% O ₂ and 5% CO ₂ , and the change in tension was measured isometrically.

The effect of the compound of the present invention on the dose-response curve obtained by cumulatively adding endothelin-1 into the Magnus tube was examined. The compound of the present invention was added to the Magnus tube 20 minutes before the addition of endothelin-1 so that the final concentration was 10 μM.

As shown in FIGS. 1 and 2, Compound No. 1
No. 4 compound (FIG. 1) and compound No. The 16 compounds (Fig. 2) moved markedly to the right in the endothelin-1 dose-response curve and did not affect its maximal response. Further, the compound of the present invention alone did not show any action on the above blood vessel specimen. As described above, the compound of the present invention exhibited a marked antagonistic action on endothelin contraction in the above blood vessel specimen.

Endoseri in porcine isolated basilar artery preparation
Effect on contraction (contraction via ET _A receptor) After removing the basilar artery of the pig, a ring-shaped specimen having a width of 4 mm was prepared. After the endothelial cells were detached, the cells were suspended in a Magnus tube 5 filled with a Krebs-Henseleit solution saturated with a mixed gas of 95% O ₂ , 5% CO ₂ , and the change in tension was measured isometrically.

The effect of the compound of the present invention on the dose-response curve obtained by cumulatively adding endothelin-1 into the Magnus tube was examined. The compound of the present invention was added to the Magnus tube 20 minutes before the addition of endothelin-1 so that the final concentration was 1 μM.

As shown in FIG. 3, compound No. Sixteen compounds moved markedly to the right in the endothelin-1 dose response curve and did not affect its maximal response. Further, the compound of the present invention alone did not show any action on the above blood vessel specimen. As described above, the compound of the present invention exhibited a marked antagonistic action on endothelin contraction in the above blood vessel specimen.

Ends in Guinea Pig Isolated Bronchial Specimens
Action on serine contraction (contraction via ET _B receptor) After removing the bronchus of guinea pig, a ring specimen with an outer diameter of 2 mm and a width of 4 mm was prepared, and Krebs saturated with a mixed gas of 95% O ₂ and 5% CO ₂ -Suspended in a 5 ml Magnus tube filled with Henseleit solution. The change in tension was measured isometrically and recorded.

The effect of the compound of the present invention on the dose-response curve obtained by cumulatively adding endothelin-1 into the Magnus tube was examined. The compound of the present invention was added to the Magnus tube 20 minutes before the addition of endothelin so that the final concentration was 10 μM.

As shown in FIGS. 4 to 5, Compound No. 1
No. 4 compound (FIG. 4) and compound No. 16 compounds (Fig. 5) were endothelin-in isolated bronchial muscle specimens.
The dose-response curve of 1 shifted significantly to the right. Further, the compound of the present invention alone did not show any action on the above-mentioned specimen. As described above, the compound of the present invention showed a remarkable antagonistic effect on endothelin contraction in the above-mentioned specimen.

As described above, the compound of the present invention has an excellent endothelin antagonism against both ET _A and ET _B receptors, and is useful as a vasodilator and bronchodilator in the field of pharmaceuticals, and is useful for hypertension, pulmonary Hypertension, Rayno's disease, acute renal failure, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, dissemination of multiple organs caused by endotoxin It can be a therapeutic agent for intravascular coagulation and / or cyclosporine-induced renal damage, hypertension and the like. When used as a therapeutic agent for such diseases, the compound of the present invention can be used alone or in combination with other therapeutic agents.

The compound of the present invention can be mixed with a solid or liquid excipient carrier known in the art and used in the form of a pharmaceutical preparation suitable for parenteral administration, oral administration or external administration. Examples of the pharmaceutical preparation include liquid preparations such as injections, inhalants, syrups and emulsions, solid preparations such as tablets, capsules and granules, and external preparations such as ointments and suppositories. In addition, these preparations may optionally contain commonly used additives such as auxiliaries, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants.
Examples of the additive include distilled water for injection, Ringer's solution, glucose, sucrose syrup, gelatin, edible oil, cocoa butter, ethylene glycol, sucrose, corn starch, magnesium stearate, talc and the like.

The dose of the compound of the present invention as an endothelin antagonist varies depending on the administration method, the age and weight of the patient, the condition of the patient to be treated, etc., but typical administration methods for adults are oral administration and non-administration. Oral administration: 0.1 to 100 m per day for oral administration to adult patients
g / Kg body weight, and is 0.1 per day for parenteral administration.
01 to 10 mg / Kg body weight.

[0104]

The present invention will be described in more detail with reference to the following examples, but the present invention is not limited to these examples. Example 1 Synthesis of Compound 1 (1-a) α-N, 1-bis- (t-butoxycarbo)
Nyl) -α-N-trifluoroacetyl-2-chloro-
Synthesis of D-tryptophan methyl ester 283 mg of α-N-trifluoroacetyl-2-chloro-D-tryptophan methyl ester was dissolved in 5 ml of acetonitrile, 0.89 g of di-t-butyl dicarbonate and 20 mg of DMAP were added, and the mixture was stirred at room temperature. It was stirred for 23 hours. The reaction solution was concentrated under reduced pressure, and the residue was purified by medium-pressure liquid chromatography (Merck & Co., Ltd., Rover column Licroprep SI60 / hexane: ethyl acetate = 5: 1) to obtain 265 mg of the desired product.

FAB-MS (m / e, (C ₂₄ H ₂₈ F ₃ C
1N ₂ O ₇ ) ⁺ ): 548,550 (1-b) α-N, 1-bis- (t-butoxycarbo)
Nyl) -2-chloro-D-tryptophan synthesis α-N, 1-bis- (t-butoxycarbonyl) -α-N-trifluoroacetyl-2 obtained in Example (1-a).
-Chloro-D-tryptophan methyl ester 255
mg was dissolved in 5 ml of methanol, 1.03 ml of 1N aqueous sodium hydroxide solution was added, and the mixture was stirred at room temperature for 7 hours.
Water (50 ml) was added to the reaction mixture to dilute it, and 10% aqueous citric acid solution was added to acidify the mixture, followed by ethyl acetate (30 ml).
Extracted with × 3). The combined organic layers were saturated saline (3
(0 ml) and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 206 mg of the desired product.

FAB-MS (m / e, (C ₂₁ H ₂₇ ClN
₂ O ₆ ) ⁺ ): 438,440 (1- c) Boc-DTrp (1-Boc, 2-C)
1) Synthesis of -DNle-OtBu α-N, 1-bis- (t-butoxycarbonyl) -2-chloro-D-tryptophan 2 obtained in Example (1-b)
06 mg and H-DNle-OtBu.HCl 125 m
g in 10 ml of dichloromethane and NMM under ice cooling.
62 μl, HOBT · H ₂ O 86 mg, EDCI ·
HCl (107 mg) was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. Dichloromethane (20 ml) was added to the reaction mixture to dilute it, and saturated aqueous sodium hydrogen carbonate solution (10 m
l) It was washed successively with 10% citric acid aqueous solution (10 ml) and saturated saline (10 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (Merck silica gel 60).
/ Hexane: Ethyl acetate = 5: 1)
35 mg was obtained.

FAB-MS (m / e, (C ₃₁ H ₄₆ ClN
_{As 3} O ₇ + H) ⁺ ): 608,610 (1-d) H-DTrp (1-Boc, 2-Cl)-
DNle-OtBu and H-DTrp (2-Cl)-
Synthesis of DNle-OtBu Boc-DTrp (1-Bo) obtained in Example (1-c)
c, 2-Cl) -DNle-OtBu (252 mg) was dissolved in formic acid (10 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 ml), washed with saturated aqueous sodium hydrogen carbonate solution (50 ml × 2) and saturated brine (50 ml), dried over anhydrous magnesium sulfate, and then under reduced pressure. The solvent was distilled off. Preparative thin layer chromatography (Merck silica gel 60)
F ₂₅₄ / chloroform: methanol = 30: 1) to give, H-DTrp (1-Boc , 2-Cl) -DNl
e-OtBu (116 mg) and H-DTrp (2-
Cl) -DNle-OtBu (35 mg) was obtained.

FAB-MS (m / e, (C ₂₆ H ₃₈ ClN
_{As 3} O ₅ + H) ⁺ ): 508, 510 [H-DTr
p (1-Boc, 2-Cl) -DNle-OtBu] FAB-MS (m / e, (C ₂₁ H ₃₀ ClN ₃ O ₃ + H) ⁺
As :) 408.410 [H-DTrp (2-C
l) -DNle-OtBu] (1-e) 2,6-dimethylpiperidinocarbonyl-
Synthesis of Val-OH 3.79 g of H-Val-OBzl.TsOH and C
1.78 g of DI was added to a dry THF (20 m
l), and TEA (1.53 ml) was added dropwise over 5 minutes under ice cooling, followed by stirring at the same temperature for 10 minutes. 2,6
-Dimethylpiperidine (1.48 ml) was added under ice-cooling, and then the mixture was stirred at room temperature overnight. Water (100 ml) in the reaction solution
Was added, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic layers were combined, washed successively with 1N hydrochloric acid (50 ml × 2), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated brine (50 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (silica gel 60 manufactured by Merck / ethyl acetate: hexane = 2: 1) to obtain 3.09 g of 2,6-dimethylpiperidinocarbonyl-Val-OBzl. This was dissolved in methanol (30 ml) and 10% Pd-
C 0.15 g was added, and the mixture was vigorously stirred at room temperature for 1 hour under a hydrogen atmosphere at 1 atm. The catalyst was removed by filtration, and the filtrate was dried under reduced pressure to give 2.20 g of the desired product as a colorless amorphous substance.

FAB-MS (m / e, (C ₁₃ H ₂₄ N ₂ O ₃
+ H) ⁺ ): 257 (1-f) 2,6-dimethylpiperidinocarbonyl-
Val-DTrp (1-Boc, 2-Cl) -DNle
Synthesis of -OtBu H-DTrp (1-Boc, 2) obtained in Example (1-d)
-Cl) -DNle-OtBu 17.4 mg and (1
2,6-dimethylpiperidinocarbonyl obtained in -e)
Val-OH (13 mg) was dissolved in dichloromethane (3 ml), and HOBT.H ₂ O (8 mg) and EDCI.
HCl (10 mg) was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. The reaction solution was diluted with dichloromethane (30 ml), washed successively with saturated aqueous sodium hydrogen carbonate solution (20 ml), 10% aqueous citric acid solution (20 ml) and saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 24.4 mg of the desired product.

FAB-MS (m / e, (C ₃₉ H ₆₀ ClN
₅ O ₇ + H) as a ^{+): 746,748 (1-g} ) Compound Synthesis Example of 1 (1-f) obtained in 2,6-dimethyl-piperidinocarbonyl -Val-DTrp (1-Boc, 2 -Cl)
-DNle-OtBu 23.6 mg was added to TFA (1 m
It was dissolved in 1) and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / chloroform: methanol: acetic acid = 30: 1: 1) to give the title compound as a pale yellow powder, 10.4 mg. Obtained.

Melting point: 142-146 ° C. IR (KBr, cm ^-1 ): 3398, 3297, 296
2,2935,2868,2362,1720,165
5,1624,1522,1450,1389,134
0,1232,1128,743 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ ClN ₅ O ₅
+ H) as a ^+): calculated 590.3109 measured ^{590.3086 1 H-NMR (300MHz,} CDCl 3, δppm):
0.78 (3H, t, J = 7.1Hz), 0.86 (3
H, d, J = 6.3 Hz), 0.96 (3H, d, J =
6.3 Hz), 1.16 (3H, d, J = 7.1H)
z), 1.19 (3H, d, J = 7.1 Hz), 1.0
0-1.82 (12H, m), 1.93-2.10 (1
H, m), 3.17 (1H, dd, J = 5.6Hz, 1
4.3 Hz), 3.34 (1H, dd, J = 5.8H)
z, 14.3 Hz), 3.81-3.93 (1H,
m), 3.98-4.24 (2H, m), 4.28-
4.43 (1H, m), 4.51 to 4.73 (1H,
m), 5.12-5.32 (1H, m), 6.74-
6.90 (1H, m), 7.12 (1H, t, J = 7.
4Hz), 7.17 (1H, t, J = 7.4Hz),
7.06-7.21 (1H, m), 7.25 (1H,
d, J = 7.4 Hz), 7.63 (1H, d, J = 7.
4 Hz), 8.78 (1H, brs) In Examples 2 to 4 below, 2,6-dimethylpiperidine and H-Val-OBzl in Example (1-e) were used.
-Compounds 2 to 4 were obtained by replacing TsOH with the corresponding amine and amino acid ester, and carrying out the same reaction as in Example 1. Example 2 Compound 2 Melting point: 145-149 ° C. IR (KBr, cm ⁻¹ ): 3290, 2956, 236
0, 1646, 1618, 1533, 1247, 112
8,743 High resolution FAB-MS (m / e, (C ₃₂ H ₄₈ ClN ₅ O ₅
+ H) ⁺ as): Calculated value 618.3422 Measured value 618.3431 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78 (3H, t, J = 7.2Hz), 0.91 (9
H, s), 1.13 (3H, d, J = 6.9 Hz),
1.16 (3H, d, J = 6.9Hz), 0.96-
1.88 (14H, m), 3.20 (1H, dd, J =
5.7 Hz, 15.0 Hz), 3.39 (1H, dd,
5.7 Hz, 15.0 Hz), 3.90-4.08 (2
H, m), 4.08-4.20 (1H, m), 4.20
-4.33 (1H, m), 4.48-4.64 (1H,
m), 4.90-5.05 (1H, m), 6.49-
6.63 (1H, m), 7.10 (1H, t, J = 8.
0Hz), 7.17 (1H, t, J = 8.0Hz),
7.25 (1H, d, J = 8.0 Hz), 7.59 (1
H, d, J = 8.0 Hz), 7.33-7.48 (1
H, m), 8.61 (1H, brs) Example 3 Compound 3 Melting point: 142-147 ° C IR (KBr, cm ^-1 ): 3402, 2956, 287
0,2360,1653,1622,1522,138
7,1340,1238,1128,743 High resolution F
AB-MS (m / e, (C ₃₁ H ₄₆ ClN ₅ O ₅ + H) ⁺ ): Calculated value 604.3266 Measured value 604.3260 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.79 (3H, t, J = 7.2Hz), 0.86 (3
H, d, J = 4.9 Hz), 0.88 (3H, d, J =
4.9 Hz), 1.15 (3H, d, J = 6.9H)
z), 1.16 (3H, d, J = 6.9Hz), 0.9
3-1.87 (15H, m), 3.21 (1H, dd,
J = 6.3 Hz, 14.4 Hz), 3.38 (1H, d
d, 6.3 Hz, 14.4 Hz), 3.91-4.07.
(2H, m), 4.07-4.20 (1H, m), 4.
20-4.34 (1H, m), 4.52-4.73 (1
H, m), 4.82-5.02 (1H, m), 6.52
-6.70 (1H, m), 7.11 (1H, t, J =
7.1 Hz), 7.17 (1H, t, J = 7.1H)
z), 7.26 (1H, d, J = 7.1 Hz), 7.5
9 (1H, d, J = 7.1 Hz), 7.31-7.49
(1H, m), 8.63 (1H, brs) Example 4 Compound 4 Melting point: 127-130 ° C IR (KBr, cm ^-1 ): 3300, 2929, 286
4,1647,1529,1452,1342,121
7,743 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ ClN ₅ O ₅
+ H) as ⁺ ): Calculated value 590.3109 Measured value 590.3067 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78 (3H, t, J = 7.2Hz), 0.86 (3
H, d, J = 4.4 Hz), 0.88 (3H, d, J =
4.4Hz), 0.92-1.87 (17H, m),
3.05-3.47 (6H, m), 3.92-4.06
(1H, m), 4.23-4.38 (1H, m), 4.
51-4.70 (1H, m), 4.92-5.08 (1
H, m), 6.50-6.70 (1H, m), 7.11
(1H, t, J = 7.6 Hz), 7.17 (1H, t,
J = 7.6 Hz), 7.26 (1H, d, J = 7.6H)
z), 7.59 (1H, d, J = 7.6 Hz), 7.3
7-7.52 (1H, m), 8.60 (1H, brs) Example 5 Synthesis of compound 5 (5-a) 2,6-dimethylpiperidinocarbonyl-
Cpeg-DTrp (2-Cl) -DNle-OtBu
H-DTrp (2-Cl) -D obtained in Synthesis Example (1-d)
30 mg of Nle-OtBu and 2,6-dimethylpiperidinocarbonyl-Cpeg-OH (H-Val-OBzl.TsOH in (1-e) was replaced with H-Cpeg-O.
22 mg (synthesized in the same manner as in (1-e) instead of Bzl.HCl) was dissolved in 3 ml of dichloromethane, and 17 mg of HOBT.H ₂ O and EDCI were cooled with ice.
-Add 22 mg of HCl at the same temperature for 15 minutes at room temperature for 30 minutes.
Stir for minutes. The reaction solution was diluted with dichloromethane (30 ml), washed successively with saturated aqueous sodium hydrogen carbonate (20 ml), 10% aqueous citric acid solution (20 ml) and saturated brine (20 ml), and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / chloroform: methanol = 30: 1) to give the desired product 3
8.3 mg was obtained.

FAB-MS (m / e, (C ₃₂ H ₄₆ ClN
₅ O ₅ + H) as a ^{+): 615,617 (5-b} ) obtained in Synthesis Example of Compound 5 (5-a) 2,6- dimethyl-piperidinocarbonyl -Cpeg-DTrp (2-Cl) - DNle
-OtBu 36 mg was added to 4N hydrogen chloride / dioxane (3
ml) and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, ethyl ether was added to the residue, and the precipitated crystals were collected by filtration and dried to give the title compound as pale yellow crystals (31.2 mg).
Obtained.

Melting point: 199 ° C. dec. IR (KBr, cm ^-1 ): 3396, 3236, 295
6,2869,1774,1646,1540,145
4, 1228, 1002, 744 High resolution FAB-MS (m / e, (C ₃₂ H ₄₆ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 616.3266 Measured value 616.3276 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp.
m): 0.85 (3H, t, J = 7.1Hz), 1.0
3 (3H, d, J = 6.8Hz), 1.05 (3H,
d, J = 6.8 Hz), 0.65-1.85 (21H,
m), 2.85 (1H, dd, J = 10.7Hz, 1
4.6 Hz), 3.20-3.45 (1H, m), 3.
62 (1H, dd, J = 6.3Hz, 9.3Hz),
4.05-4.20 (3H, m), 4.65-4.75
(1H, m), 6.01 (1H, d, J = 6.3H
z), 6.97 (1H, t, J = 7.6Hz), 7.0
5 (1H, t, J = 7.6Hz), 7.21 (1H,
d, J = 7.6 Hz), 7.61 (1H, d, J = 7.
6 Hz), 8.14 (1H, d, J = 7.8 Hz),
8.14 (1H, d, J = 7.8Hz), 11.55
(1H, s), 12.35 (1H, brs) In Examples 6 to 11 below, 2,6-dimethylpiperidinocarbonyl-Cpeg-O in Example (5-a) was used.
Example (5) by replacing H with a corresponding carboxylic acid compound
Compounds 6 to 11 were obtained by performing the same reaction as in (a) and (5-b). Example 6 Compound 6 Melting point: 180 ° C. dec. IR (KBr, cm ^-1 ): 3261, 2956, 177
4,1654,1523,1454,1340,114
7,933,744 High resolution FAB-MS (m / e, (C 30 H 42 ClN 5 O 5
+ H) ⁺ ): Calculated value 588.2953 Measured value 588.2954 ¹ H-NMR (300 MHz, CD ₃ OD, δppm):
0.12-0.53 (4H, m), 0.83-1.00
(3H, m), 1.02-1.95 (12H, m),
1.21 (6H, d, J = 6.7Hz), 2.94-
3.60 (2H, m), 3.90-4.28 (3H,
m), 4.32 (1H, dd, J = 5.2Hz, 8.6)
Hz), 4.80-5.05 (1H, m), 7.02
(1H, dt, J = 1.2Hz, 7.5Hz), 7.1
0 (1H, dt, J = 1.2Hz, 7.5Hz), 7.
24 (1H, dd, J = 1.2Hz, 7.5Hz),
7.58 (1 H, dd, J = 1.2 Hz, 7.5 Hz) Example 7 Compound 7 Melting point: 160 ° C. dec. IR (KBr, cm ^-1 ): 3232, 2935, 177
4,1652, 1623, 1454, 1340, 114
9,931,744 High resolution FAB-MS (m / e, (C ₃₁ H ₄₄ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 602.3109 Measured value 602.30961 ¹ H-NMR (300 MHz, CD ₃ OD, δ ppm):
-0.18--0.03 (2H, m), 0.12-0.
38 (3H, m), 0.80-0.95 (3H, m),
0.97-1.91 (20H, m), 3.02-3.4
0 (2H, m), 3.75-4.25 (3H, m),
4.33 (1H, dd, J = 5.4Hz, 8.8H
z), 4.80-5.00 (1H, m), 7.01 (1
H, dt, J = 1.4 Hz, 7.6 Hz), 7.08
(1H, dt, J = 1.4Hz, 7.6Hz), 7.2
2 (1H, dd, J = 1.4Hz, 7.6Hz), 7.
57 (1 H, dd, J = 1.4 Hz, 7.6 Hz) Example 8 Compound 8 Melting point: 140 ° C. dec. IR (KBr, cm ^-1 ): 3305, 2931, 171
6,1635,1519,1454,1340,122
2,1145,742 High-resolution FAB-MS (m / e, (C ₂₉ H ₄₂ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 576.2953 Measured value 576.2946 ¹ H-NMR (300 MHz, CD ₃ OD, δ ppm):
0.57 (3H, d, J = 6.9Hz), 0.65 (3
H, d, J = 6.9 Hz), 0.84-0.96 (3
H, m), 1.20 (3H, d, J = 6.4 Hz),
1.21 (3H, d, J = 6.4Hz), 1.26-
2.22 (11H, m), 3.10 (1H, dd, J =
9.9 Hz, 14.8 Hz), 3.25-3.35 (1
H, m), 3.81-4.05 (3H, m), 4.33.
(1H, dd, J = 4.7Hz, 8.3Hz), 4.8
0-4.95 (1H, m), 5.42 (1H, d, J =
8.1Hz), 7.02 (1H, dt, J = 1.4H
z, 7.1 Hz), 7.09 (1H, dt, J = 1.4)
Hz, 7.1 Hz), 7.22 (1H, dd, J = 1.
4Hz, 7.1Hz), 7.59 (1H, dd, J =
1.4Hz, 7.1Hz), 7.95 (1H, d, J =
8.8 Hz) Example 9 Compound 9 Melting point: 165 ° C. dec. IR (KBr, cm ^-1 ): 3384, 3261, 295
8, 1776, 1654, 1527, 1454, 114
7,744,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 590.3109 Measured value 590.3135 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.62 (3H, t, J = 7.2Hz), 0.8
5 (3H, t, J = 6.8Hz), 0.70 to 1.80
(16H, m), 1.02 (3H, d, J = 6.4H
z), 1.05 (3H, d, J = 6.4Hz), 2.8
5 (1H, dd, J = 10.3Hz, 14.5Hz),
3.24 (1H, dd, J = 3.6Hz, 14.5H
z), 3.79-3.94 (1H, m), 4.00-
4.20 (3H, m), 4.50-4.68 (1H,
m), 6.00-6.13 (1H, m), 6.97 (1
H, t, J = 7.4 Hz), 7.05 (1H, t, J =
7.4 Hz), 7.21 (1H, d, J = 7.4H)
z), 7.63 (1H, d, J = 7.4 Hz), 8.1
0 (1H, d, J = 8.8Hz), 8.11 (1H,
d, J = 6.1 Hz), 11.58 (1 H, s) Example 10 Compound 10 Melting point: 117-122 ° C. IR (KBr, cm ⁻¹ ): 3386, 3236, 296
4,1778,1639,1535,1457,115
3,1095,931,746,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 604.3266 Measured value 604.3287 ¹ H-NMR (300 MHz, CD ₃ OD, δppm):
0.47 (3H, d, J = 6.8Hz), 0.73 (3
H, t, J = 7.2 Hz), 0.82-1.94 (18
H, m), 1.17 (3H, d, J = 6.8 Hz),
1.18 (3H, d, J = 6.8Hz), 3.08 (1
H, dd, J = 10.1 Hz, 14.8 Hz), 3.2
4-3.42 (1H, m), 3.91 (1H, br
s), 4.00-4.28 (2H, m), 4.32 (1)
H, dd, J = 5.4 Hz, 8.8 Hz), 4.80-
5.00 (1H, m), 7.03 (1H, dt, J =
1.3Hz, 7.5Hz), 7.09 (1H, dt, J
= 1.3 Hz, 7.5 Hz), 7.23 (1H, dd,
J = 1.3 Hz, 7.5 Hz), 7.59 (1H, d
d, J = 1.3 Hz, 7.5 Hz) Example 11 Compound 11 Melting point: 128-139 ° C. IR (KBr, cm ⁻¹ ): 3398, 3291, 295
6,2935,2869,1722,1656,161
9, 1519, 1454, 1240, 1147, 112
6,742 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 604.3266 Measured value 604.3217 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.71 (3H, t, J = 7.1Hz), 0.8
4 (3H, t, J = 6.9Hz), 1.03 (3H,
d, J = 5.9 Hz), 1.05 (3H, d, J = 5.
9Hz), 0.65-1.80 (18H, m), 2.8
6 (1H, dd, J = 10.3Hz, 14.1Hz),
3.39 (1H, dd, J = 4.6Hz, 14.1H
z), 3.81-3.98 (1H, m), 3.98-
4.20 (3H, m), 4.50-4.64 (1H,
m), 6.04 (1H, d, J = 6.6 Hz), 6.9
7 (1H, t, J = 7.7Hz), 7.05 (1H,
t, J = 7.7 Hz), 7.21 (1H, d, J = 7.
7Hz), 7.62 (1H, d, J = 7.7Hz),
8.05 (1H, brs), 8.07 (1H, d, J =
9.0 Hz), 11.57 (1 H, s) Example 12 Synthesis of compound 12 (12-a) α-N-trifluoroacetyl-2-quat
Synthesis of loro-1-methyl-D-tryptophan α-N- (trifluoroacetyl) -2-chloro-1-
Methyl-D-tryptophan methyl ester 525m
g was dissolved in 10 ml of methanol, 1.70 ml of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 6 hours.
The reaction mixture was diluted with water (50 ml), acidified with 1N hydrochloric acid, and then diethyl ether (30 ml × 3).
It was extracted in. The combined organic layers are saturated saline (30m
After washing with 1) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 344 mg of the desired product.

FAB-MS (m / e, (C ₁₄ H ₁₂ ClF
_{As 3} N ₂ O ₃ + H) ⁺ ): 349,351 (12-b) α-N-trifluoroacetyl-DTr
Synthesis of p (1-Me, 2-Cl) -DNle-OtBu α-N-trifluoroacetyl-2-chloro-1-methyl-D-tryptophan 34 obtained in Example (12-a).
0 mg and H-DNle-OtBu.HCl 230 mg
Is dissolved in 20 ml of dichloromethane and NMM is added under ice cooling.
0.12 ml, HOBT · H ₂ O 180 mg, EDC
I-HCl (225 mg) was added, and the mixture was stirred at the same temperature for 1 hr and at room temperature overnight. Ethyl acetate (100 ml) was added to the reaction solution to dilute it, and saturated aqueous sodium hydrogen carbonate solution (100 m
l) 1N hydrochloric acid (100 ml), saturated saline solution (100 m
It was washed successively with 1) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Merck silica gel 60 / hexane: ethyl acetate = 4: 1) to obtain 571 mg of the desired product.
Got (12-c) H-DTrp (1-Me, 2-Cl)-
Synthesis of DNle-OtBu α-N-trifluoroacetyl-DTrp (1-Me, 2-Cl) -DNle-Ot obtained in Example (12-b).
84 mg of Bu was dissolved in 1,4-dioxane (3.0 ml), 1M aqueous sodium carbonate solution (3.0 ml) was added, and the mixture was stirred at 50 ° C. overnight. The reaction mixture was diluted with water (30 ml) and extracted with ethyl acetate (10 ml x 3). The organic layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed under reduced pressure. Was distilled off. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / hexane: ethyl acetate = 3: 7) to give the desired product 47 mg.

FAB-MS (m / e, (C ₂₂ H ₃₂ ClN
_{As 3} O ₃ + H) ⁺ ): 422,424 (12-d) 2,6-dimethylpiperidinocarbonyl
-ΓMeLeu-DTrp (1-Me, 2-Cl) -D
Synthesis of Nle-OtBu H-DTrp (1-Me, 2) obtained in Example (12-c)
-Cl) -DNle-OtBu 47 mg and 2,6-
Dimethylpiperidinocarbonyl-γMeLeu-OH
Dissolve 38 mg in DMF 2.0 ml, and HO under ice cooling.
BT · H ₂ O 22mg and EDCI · HCl 27mg
Was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours.
The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed successively with saturated aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / hexane: ethyl acetate = 1: 1) to obtain 73 mg of the desired product.

FAB-MS (m / e, (C ₃₇ H ₅₈ ClN
₅ O ₅ + H) as a ^{+): 688,690 (12-e} ) Compound Synthesis Example of 12 (12-d) obtained in 2,6-dimethyl-piperidinocarbonyl -γMeLeu-DTrp (1-Me, 2 −
Cl) -DNle-OtBu 28 mg to TFA 3 m
It was dissolved in 1 and stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol =
Purification by 9: 1) yielded 19 mg of the desired product.

Melting point: 103-108 ° C. IR (KBr, cm ^-1 ): 3300, 2954, 293
7,1652,1647,1541,1533,152
2,741 High resolution FAB-MS (m / e, (C ₃₃ H ₅₀ ClN ₅ O ₅
+ H) ⁺ ): Calculated value 632.3578 Measured value 632.3564 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78 (3H, t, J = 7.4Hz), 0.86 (9
H, s), 1.14 (3H, d, J = 5.8Hz),
1.15 (3H, d, J = 5.8Hz), 0.91-
1.92 (14H, m), 3.34 (1H, dd, J =
5.7 Hz, 14.6 Hz), 3.44 (1H, dd,
6.2 Hz, 14.6 Hz), 3.73 (3H, s),
3.84-4.19 (3H, m), 4.30 (1H, d
dd, J = 5.7 Hz, 6.2 Hz, 7.6 Hz),
4.66-4.74 (1H, m), 4.90 (1H,
d, J = 5.5 Hz), 6.41 (1H, d, J = 7.
6 Hz), 7.11 (1H, t, J = 7.8 Hz),
7.22 (1H, t, J = 7.8Hz), 7.25 (1
H, d, J = 7.8 Hz), 7.58 (1H, d, J =
7.8 Hz), 7.62 (1 H, d, J = 6.9 Hz) Example 13 Synthesis of Compound 13 (13-a) 2,6-Dimethylpiperidinocarbonyl
-ΓMeLeu-DTrp (2-Br) -DNle-O
Synthesis of tBu 2,6-Dimethylpiperidinocarbonyl-γMeLeu
320 mg of -DTrp-DNle-OtBu was dissolved in 1.0 ml of acetic acid, and a solution of N-bromosuccinimide (107 mg) in acetic acid (3.0 ml) was added dropwise thereto over 10 minutes, and then stirred at room temperature for 20 hours. did. The reaction solution was diluted with dichloromethane (50 ml), and this solution was washed successively with water (25 ml × 2), saturated aqueous sodium hydrogen carbonate solution (25 ml) and saturated brine (25 ml), and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol = 30: 1) to give the desired product was obtained 15 mg.

FAB-MS (m / e, (C ₃₆ H ₅₆ BrN
₅ O ₅ + H) as a ^{+): 718,720 (13-b} ) Synthesis Example of Compound 13 (13-a) obtained in 2,6-dimethyl-piperidinocarbonyl over γMeLeu-DTrp (2-Br)
-DNle-OtBu 14 mg, TFA 1.0 ml
And was stirred for 3 hours under ice cooling. The reaction mixture was concentrated under reduced pressure, residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol:
Purification with acetic acid = 30: 1: 1) gave 8.4 mg of the desired product.

Melting point: 145-148 ° C IR (KBr, cm ^-1 ): 2954, 2868, 172
4, 1659, 1620, 1514, 1247, 113
6,743 High resolution FAB-MS (m / e, (C ₃₂ H ₄₈ BrN ₅ O ₅
+ H) as ⁺ ): Calculated value 662.2917 Measured value 662.2944 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78 (3H, t, J = 7.1Hz), 0.91 (9
H, s), 1.13 (3H, d, J = 7.1 Hz),
1.16 (3H, d, J = 7.1Hz), 0.98-
1.86 (14H, m), 3.19 (1H, dd, J =
6.2Hz, 14.6Hz), 3.39 (1H, dd,
5.7 Hz, 14.6 Hz), 3.93-4.20 (3
H, m), 4.20-4.35 (1H, m), 4.50
-4.66 (1H, m), 4.90-5.07 (1H,
m), 6.54-6.66 (1H, m), 7.09 (1
H, t, J = 7.6 Hz), 7.15 (1H, t, J =
7.6 Hz), 7.25 (1H, d, J = 7.6H
z), 7.62 (1H, d, J = 7.6 Hz), 7.3
0-7.44 (1H, m), 8.74 (1H, brs) Example 14 Synthesis of compound 14 α-N-trifluoroacetyl-2-chloro-D-tryptophan methyl in Example (1-a) The ester was replaced with α-N-trifluoroacetyl-2-bromo-D-tryptophan methyl ester and the procedure of Example (1-
H-Val-OBzl.TsOH in e) is HL
eu-OBzl.TsOH was replaced with the same procedures as in Example 1 to obtain the title compound.

Melting point: 107-111 ° C. IR (KBr, cm ⁻¹ ): 3277, 2956, 287
0, 1655, 1618, 1522, 1450, 134
0,1236,1126,743 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 648.2761 Measured value 648.2739 ¹ H-NMR (300 MHz, CD3COCD3, δp
pm): 0.76 (6H, d, J = 5.8Hz), 0.
87 (3H, t, J = 6.6Hz), 1.15 (6H,
d, J = 7.2 Hz), 1.10-1.88 (15H,
m), 3.19 (1H, dd, J = 9.3 Hz, 14.
6Hz), 3.42 (1H, dd, J = 4.5Hz, 1
4.6 Hz), 3.95-4.10 (1H, m), 4.
15-4.35 (3H, m), 4.75-4.85 (1
H, m), 5.72-5.80 (1H, m), 7.04.
(1H, t, 7.5 Hz), 7.11 (1H, t, 7.
5 Hz), 7.33 (1H, d, 7.5 Hz), 7.5
0 (1H, brs), 7.69 (1H, d, J = 7.5
Hz), 7.95 (1H, d, J = 6.9Hz), 1
0.69 (1H, s) Example 15 Synthesis of compounds 15 and 16 (15-a) α-N, 1-bis- (t-butoxycal)
Bonyl) -2-bromo-D-tryptophan methyl ester
Synthesis of Stell 2.37 g of α-N-trifluoroacetyl-2-bromo-D-tryptophan methyl ester was dissolved in 15 ml of acetonitrile, and 6.60 g of di-t-butyl dicarbonate was dissolved.
And DMAP (74 mg) were added, and the mixture was stirred at room temperature for 4 hours.
The reaction mixture was ice-cooled, 3-dimethylaminopropylamine (3.02 ml) was added, the mixture was stirred at room temperature for 5 min, and concentrated under reduced pressure. Dissolve the residue in ethyl acetate (100 ml),
10% citric acid aqueous solution (50 ml), saturated aqueous sodium hydrogen carbonate (50
ml) and saturated saline (50 ml), and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 3.00 g of the desired product.

FAB-MS (m / e, (C ₂₂ H ₂₉ BrN
₂ O ₆ ) ⁺ ): 496, 498 (15-b) α-N- (t-butoxycarbonyl)-
Synthesis of 2-bromo-D-tryptophan 3.00 g of α-N, 1-bis- (t-butoxycarbonyl) -2-bromo-D-tryptophan methyl ester obtained in Example (15-a) was added to 36 ml of methanol. It melt | dissolved, 18 ml of 1N sodium hydroxide aqueous solution was added, and it stirred at room temperature for 2 days. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (30 ml) and ethyl ether (30 ml x 2).
It was extracted in. The aqueous layer was acidified by adding 10% aqueous citric acid solution, and then extracted with ethyl acetate (50 ml × 3). The ethyl acetate extract layer was washed with saturated brine (30 ml) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to obtain 2.30 g of the desired product.

FAB-MS (m / e, (C ₁₆ H ₁₉ BrN
₂ O ₄ ) ⁺ ): 382, 384 (15-c) Boc-DTrp (2-Br) -DNl
Synthesis of e-OMe 2.30 g of α-N- (t-butoxycarbonyl) -2-bromo-D-tryptophan and H-DNle-OMe.HCl obtained in Example (15-b) were added to 20 ml of dichloromethane. And NMM 0.73 under ice cooling
ml, HOBT · H ₂ O 1.11 g and EDCI · H
1.39 g of Cl was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1.5 hours. The reaction solution was saturated aqueous sodium hydrogen carbonate (20 m
l) It was washed successively with 10% aqueous citric acid solution (20 ml) and saturated saline (20 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Merck silica gel 6
After purification with 0 / ethyl acetate: hexane = 1: 2),
Recrystallization from hexane-ethyl acetate gave 2.62 g of the desired product.

FAB-MS (m / e, (C ₂₃ H ₃₂ BrN
_{As 3} O ₅ + H) ⁺ ): 510, 512 (15-d) H-DTrp (2-Br) -DNle-
Synthesis of OMe Boc-DTrp (2-B) obtained in Example (15-c)
r) -DNle-OMe 2.08 g was added to 98% formic acid 30 m.
After dissolving in 1 and stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (60 ml), washed with saturated aqueous sodium hydrogen carbonate (40 ml × 2) and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (1.60 g).

FAB-MS (m / e, (C ₁₈ H ₂₄ BrN
_{As 3} O ₃ + H) ⁺ ): 410,412 ( 15-e) H-DTrp (2-Br) -DNle-
Synthesis of OMe.HCl H-DTrp (2-Br) -obtained in Example (15-d)
0.65 g of DNle-OMe was added to ethyl ether (10
ml), 4N hydrogen chloride / dioxane 0.40 ml was added under ice cooling, and the precipitated crystals were collected by filtration and dried to give the desired product
64 g was obtained. (15-f) Synthesis of Compound 15 H-DTrp (2-Br)-obtained in Example (15-d)
DNle-OMe 960 mg and 2,6-dimethylpiperidinocarbonyl-Cprg-OH (H-Val-OBzl.TsOH in (1-e) was replaced with H-Cprg-
540 mg of OBzl.HCl (synthesized in the same manner as in (1-e)) was dissolved in 10 ml of dichloromethane, and HOBT.H ₂ O (390 mg and E) was cooled with ice.
DCI / HCl (490 mg) was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 1 hour. Dichloromethane (30
ml) and diluted to give saturated sodium bicarbonate water (20 ml), 10 ml.
% Aqueous citric acid solution (20 ml), saturated saline solution (20 m
It was washed successively with 1) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (Merck & Co. Rover Column Licroprep SI60 / hexane: ethyl acetate = 1: 2) to obtain 1.25 g of the title compound.

FAB-MS (m / e, (C ₃₁ H ₄₄ BrN
_{As 5} O ₅ + H) ⁺ ): 646 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.21-0.35 (2H, m), 0.40-0.52
(2H, m), 0.79 (3H, t, J = 7.0H
z), 1.00-1.80 (13H, m), 1.18
(3H, d, J = 6.9 Hz), 3.24 (1H, d
d, J = 6.7 Hz, 14.6 Hz), 3.36 (1
H, dd, J = 10.0 Hz, 14.6 Hz), 3.3
0-3.44 (1H, m), 3.63 (3H, s),
4.00-4.22 (2H, m), 4.35-4.46
(1H, m), 4.73-4.84 (1H, m), 5.
04 (1H, d, J = 5.6 Hz), 6.37 (1H,
d, J = 8.6 Hz), 7.05 (1H, d, J = 9.
6Hz), 7.09 (1H, dt, J = 1.3Hz,
7.1 Hz), 7.16 (1H, dt, J = 1.3H)
z, 7.1 Hz), 7.27 (1H, dd, J = 1.3)
Hz, 7.1 Hz), 7.64 (1H, dd, J = 1.
3 Hz, 7.1 Hz), 8.35 (1 H, s) (15-g) Synthesis of compound 16 1.13 g of compound 15 obtained in Example (15-f) was dissolved in 6 ml of methanol, and the mixture was cooled with ice. 2.9 ml of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 3.5 hours. Water (10 ml) was added to the reaction solution,
Methanol was distilled off under reduced pressure. 1N Hydrochloric acid was added to the obtained aqueous solution under ice cooling, and the precipitated crystals were collected by filtration and dried to give the title compound (1.02 g) as colorless crystals.

Melting point: 142-152 ° C. dec. IR (KBr, cm ^-1 ): 3394, 3291, 293
5,2869, 1724, 1658, 1619, 151
3,1450,1340,1226,1145,744 High Resolution FAB-MS (m / e, (C 30 H 42 BrN 5 O 5
+ H) ⁺ ): Calculated value 632.2433 Measured value 632.2476 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): -0.13-0.22 (4H, m), 0.83
(3H, t, J = 6.9Hz), 0.72-1.76
(13H, m), 1.04 (3H, d, J = 6.6H
z), 1.05 (3H, d, J = 6.6Hz), 2.8
8 (1H, dd, J = 9.9Hz, 14.5Hz),
3.24 (1H, dd, J = 3.9Hz, 14.5H
z), 3.22-3.40 (1H, m), 3.94-
4.20 (3H, m), 4.50-4.65 (1H,
m), 6.20 (1H, d, J = 5.8 Hz), 6.9
6 (1H, t, J = 7.4Hz), 7.04 (1H,
t, J = 7.4 Hz), 7.22 (1H, d, J = 7.
4Hz), 7.64 (1H, d, J = 7.4Hz),
8.01 (1H, d, J = 9.3 Hz), 8.01 (1
H, d, J = 9.3 Hz), 11.56 (1 H, s) Optical rotation: [α] ²⁰ _D = + 19.9 ° (C1.0, MeO)
H) Elemental analysis (as _{C 30 H 42 BrN 5 O 5} · 3 / 4H 2 O): Calculated C55.77%, H6.78%, N10.83
% Measured value C56.00%, H6.96%, N11.06
% (15-h) Synthesis of Compound 16 Na Salt 921 mg of Compound 16 obtained in Example (15-g) was dissolved in 10 ml of methanol, and a solution of 122 mg of sodium hydrogen carbonate in water (3 ml) was added dropwise under ice cooling. The solution was dried under reduced pressure to give the title compound as a colorless powder (951 mg).

Melting point: 172 ° C. dec. IR (KBr, cm ^-1 ): 3396, 3307, 293
5,2869,1650,1596,1515,145
0,1340,1247,1143,742 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp
m): -0.01-0.20 (4H, m), 0.78
(3H, t, J = 6.8Hz), 0.86-0.95
(1H, m), 1.05 (3H, d, J = 6.6H
z), 1.06 (3H, d, J = 6.6Hz), 1.0
0-1.75 (12H, m), 2.92 (1H, dd,
J = 8.5 Hz, 14.4 Hz), 3.09 (1H, d
d, J = 5.1 Hz, 14.4 Hz), 3.63-3.
72 (1H, m), 3.77 (1H, t, J = 7.3H
z), 4.03-4.18 (2H, m), 4.45-
4.55 (1H, m), 5.98 (1H, d, J = 7.
3Hz), 6.94 (1H, t, J = 7.5Hz),
7.03 (1H, t, J = 7.5Hz), 7.21 (1
H, d, J = 7.5 Hz), 7.37 (1H, d, J =
5.4 Hz), 7.60 (1H, d, J = 7.5H
z), 8.06 (1H, d, J = 8.3 Hz), 11.
58 (1H, s) Elemental analysis (as _{C 30 H 41 BrN 5 O 5} Na · 3 / 4H 2 O): Calculated C53.93%, H6.41%, N10.48
%, Na3.44% Measured value C54.11%, H6.86%, N10.75
%, Na 3.25% Example 16 Synthesis of Compound 17 (16-a) 2,6-Dimethylpiperidinocarbonyl
Synthesis of -Met -OH H-Met-OMe.HCl 601 mg and CDI
537 mg of dry THF (12 ml) under a nitrogen atmosphere
Then, 0.50 ml of TEA was added dropwise over 5 minutes under ice cooling, and then the mixture was stirred at the same temperature for 30 minutes. 0.62 ml of 2,6-dimethylpiperidine was added under ice cooling and then stirred at room temperature overnight. 1N hydrochloric acid (60 ml) in the reaction solution
Was added, and the mixture was extracted with ethyl acetate (60 ml + 30 ml × 2). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (manufactured by Merck & Co., Inc., silica gel 60 / ethyl acetate: hexane = 1: 1) to obtain 610 mg of 2,6-dimethylpiperidinocarbonyl-Met-OMe. This product (580 mg) was dissolved in methanol (16 ml), 1N aqueous sodium hydroxide solution (4.0 ml) was added under ice cooling, and the mixture was stirred at the same temperature for 1 hr and at room temperature for 2.5 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (80 ml), and a 10% aqueous citric acid solution was added to acidify the mixture, followed by ethyl acetate (50 m).
It was extracted with 1 × 3). The organic layers were combined, washed with saturated brine (50 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 520 mg of the desired product.

FAB-MS (m / e, (C ₁₃ H ₂₄ N ₂ O ₃
S + H) ⁺ as): 289 (16-b) 2,6-dimethylpiperidinocarbonyl
-Met-DTrp (2-Br) -DNle-OMe
H-DTrp (2-Br) -obtained in Synthesis Example (15-e)
DNle-OMe.HCl 39 mg and Example (16)
-2,6-dimethylpiperidinocarbonyl obtained in a)
Met-OH (30 mg) was dissolved in dichloromethane (3 ml), and NMM (10 μl) and HOBT · H ₂ O 1 were cooled with ice.
6 mg and EDCI.HCl 20 mg were added, and 1 at the same temperature
For 1.5 hours at room temperature. Ethyl acetate (30 ml) was added to the reaction mixture to dilute it, and saturated aqueous sodium hydrogen carbonate (10 ml) was added.
X3) The solution was washed successively with 10% citric acid aqueous solution (10 ml x 3) and saturated saline (10 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol = 20: 1) to give 54.5mg of the desired product.

FAB-MS (m / e, (C ₃₁ H ₄₆ BrN
₅ O ₅ S + H) as a ^{+): 680,682 (16-c} ) obtained in Synthesis Example of Compound 17 (16-b) 2,6- dimethyl piperidinocarbonyl -Met-DTrp (2-Br) - DNle
-OMe (46 mg) was dissolved in methanol (1.5 ml), and ice-cooled, 1N aqueous sodium hydroxide solution (0.25 ml).
Was added, and the mixture was stirred at the same temperature for 1.5 hours and at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure, 1N hydrochloric acid (1 ml) was added to the residue, and the precipitated crystals were collected by filtration and dried to give the title compound (35.9 mg) as a colorless powder.

Melting point: 118-124 ° C. IR (KBr, cm ^-1 ): 3294, 2937, 236
0,1726,1659,1620,1529,145
0, 1390, 1342, 1277, 1227, 112
6,1078,742,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
S + H) ⁺ ): Calculated value 666.2325 Measured value 666.2316 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp.
m): 0.85 (3H, t, J = 7.1Hz), 1.0
3 (3H, d, J = 7.3Hz), 1.05 (3H,
d, J = 7.3 Hz), 1.23-1.73 (14H,
m), 1.90 (3H, s), 2.04-2.10 (1
H, m), 2.16-2.20 (1H, m), 2.86
(1H, dd, J = 10.3Hz, 14.5Hz),
3.22 (1H, dd, J = 3.7Hz, 14.5H
z), 3.96-4.01 (1H, m), 4.07-
4.14 (3H, m), 4.53-4.60 (1H,
m), 6.20 (1H, d, J = 6.8 Hz), 6.9
6 (1H, t, J = 7.7 Hz), 7.04 (1H,
t, J = 7.7 Hz), 7.22 (1H, d, J = 7.
7 Hz), 7.66 (1 H, d, J = 7.7 Hz),
8.09 (1H, d, J = 9.3 Hz), 8.10 (1
H, d, J = 6.4 Hz), 11.57 (1 H, s),
12.04 (1H, brs) In Examples 17 to 19 below, 2,6-dimethylpiperidinocarbonyl-Met- in Example (16-b) was used.
Compounds 18 to 20 were obtained by replacing OH with the corresponding carboxylic acid compound and carrying out the same reaction as in Examples (16-b) and (16-c). Example 17 Compound 18 Melting point: 178-182 ° C IR (KBr, cm ^-1 ): 3396, 3304, 310
5,2937,2870,2359,1659,162
0,1502,1450,1390,1342,123
6,1124,1078,742,700,611 High resolution FAB-MS (m / e, (C ₃₃ H ₄₂ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 668.2448 Measured value 668.2424 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.80 (3H, t, J = 6.8Hz), 1.0
7 (3H, d, J = 6.7Hz), 1.09 (3H,
d, J = 6.7 Hz), 1.10-1.18 (12H,
m), 2.88 (1H, dd, J = 8.8Hz, 14.
4Hz), 3.08 (1H, dd, J = 5.4Hz, 1
4.4 Hz), 3.76-3.84 (1H, m), 4.
13-4.19 (2H, m), 4.48-4.52 (1
H, m), 5.39 (1H, d, J = 7.6 Hz),
6.39 (1 H, d, J = 7.6 Hz), 6.93 (1
H, t, J = 7.5 Hz), 7.04 (1H, t, J =
7.5 Hz), 7.21 (1H, d, J = 7.5H
z), 7.24-7.27 (5H, m), 7.59 (1
H, d, J = 7.5 Hz), 7.64 (1H, d, J =
6.6 Hz), 8.46 (1H, d, J = 8.6H
z), 11.56 (1H, s) Example 18 Compound 19 Melting point: 143-1475C IR (KBr, cm- ¹ ): 3398, 3292, 295
8,2872,1624,1518,1452,140
8,1340,743,609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₈ BrN ₅ O ₅
+ H) as ⁺ ): Calculated value 662.2917 Measured value 662.2903 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.66 (3H, d, J = 6.3Hz), 0.7
0 (3H, d, J = 6.3Hz), 0.77 (3H,
t, J = 7.3 Hz), 0.81 (3H, t, J = 6.
6Hz), 0.95-1.74 (19H, m), 2.8
8 (1H, dd, J = 9.3Hz, 14.1Hz),
2.88-3.06 (2H, m), 3.09 (1H, d
d, J = 4.3 Hz, 14.1 Hz), 3.79-3.
86 (1H, m), 4.04-4.14 (2H, m),
4.46-1.54 (1H, m), 5.89 (1H,
d, J = 7.8 Hz), 6.95 (1H, t, J = 7.
8Hz), 7.03 (1H, t, J = 7.8Hz),
7.21 (1H, d, J = 7.8Hz), 7.58 (1
H, d, J = 5.3 Hz), 7.63 (1H, d, J =
7.8 Hz), 8.00 (1H, d, J = 8.8H
z), 11.59 (1H, s) Example 19 Compound 20 Melting point: 152-155 ° C IR (KBr, cm ^-1 ): 3398, 3294, 295
6,2872,1624,1518,1450,140
6,1340,743,609 High resolution FAB-MS (m / e, (C ₃₃ H ₅₀ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 676.3074 Measured value 676.3084 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.66 (3H, d, J = 6.3Hz), 0.7
1 (3H, d, J = 6.3Hz), 0.80 (3H,
t, J = 6.6 Hz), 0.84 (3H, t, J = 7.
2Hz), 1.00-1.72 (21H, m), 2.8
4-3.10 (4H, m), 3.71-3.76 (1
H, m), 4.07-4.22 (2H, m), 4.42.
-4.52 (1H, m), 5.86 (1H, d, J =
8.0 Hz), 6.95 (1H, t, J = 7.6H
z), 7.03 (1H, t, J = 7.6 Hz), 7.2
1 (1H, d, J = 7.6Hz), 7.46 (1H,
d, J = 7.8 Hz), 7.62 (1H, d, J = 7.
6 Hz), 8.01 (1H, d, J = 8.8 Hz), 1
1.59 (1H, s) Example 20 Synthesis of Compound 21 (20-a) α-N-trifluoroacetyl-2-yo
Synthesis of dehydro-D-tryptophan methyl ester α-N-trifluoroacetyl-D-tryptophan
1.26 g of methyl ester was suspended in 30 ml of carbon tetrachloride, 1.12 g of N-iodosuccinimide and 5 mg of 2,2′-azobis (isobutyronitrile) were added thereto, and the mixture was stirred at room temperature for 19 hours. The reaction solution is concentrated under reduced pressure,
The residue was dissolved in ethyl acetate (20 ml) and added with hexane (4
0 ml) was added and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure and the residue was subjected to medium pressure liquid chromatography (Merck).
Rover column Licroprep SI60 / hexane:
The product was purified with ethyl acetate = 3: 1) to obtain 156 mg of the desired product.

FAB-MS (m / e, (C ₁₄ H ₁₂ F ₃ I
As N ₂ O ₃ ) ⁺ ): 440 (20-b) Synthesis of Compound 21 α-N-trifluoroacetyl-2-chloro-D-tryptophan methyl ester in Example (1-a) was used in Example (20-). The α-N-trifluoroacetyl-2-iodo-D-tryptophan methyl ester obtained in a) was replaced with H-Val-in Example (1-e).
OBzl / TsOH to H-Leu-OBzl / TsOH
In place of this, the same operation as in Example 1 was carried out to obtain the title compound.

Melting point: 145-153 ° C. IR (KBr, cm ^-1 ): 3392, 3300, 295
8, 2867, 1655, 1622, 1520, 144
4,1390,1340,1244,1126,74
3,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₄ IN ₅ O ₅ +
H) As ^+): calculated 696.2622 measured ^{696.2627 1 H-NMR (300MHz,} CD 3 OD, δppm):
0.77 (6H, d, J = 6.4Hz), 0.89 (3
H, t, J = 6.9 Hz), 0.82-0.99 (1
H, m), 1.14 (3H, d, J = 6.3Hz),
1.16 (3H, d, J = 6.3Hz), 1.08-
1.91 (14H, m), 3.10 (1H, dd, J =
9.3 Hz, 14.7 Hz), 3.24-3.35 (1
H, m), 4.03-4.44 (4H, m), 4.80.
-4.93 (1H, m), 6.97 (1H, dt, J =
1.6Hz, 7.6Hz), 7.02 (1H, dt, J
= 1.6 Hz, 7.6 Hz), 7.25 (1H, dd,
J = 1.6 Hz, 7.6 Hz), 7.60 (1H, d
d, J = 1.6 Hz, 7.6 Hz) Synthesis of Example 21 Compound 22 (21-a) 2,6-Dimethylpiperidinocarbonyl
Synthesis of -Leu-DTrp (2-Br) -OMe Boc-DTrp (1-Bo) obtained in Example (15-a).
c, 2-Br) -OMe (1.09 g) with 98% formic acid 15
It was dissolved in ml and stirred at room temperature for 7 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (50 ml), washed with saturated aqueous sodium hydrogen carbonate (50 ml) and saturated brine (50 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Then, 666 mg of a pale yellow oily substance was obtained. Dissolve this in dichloromethane (30 ml), and under ice cooling 2,
6-Dimethylpiperidinocarbonyl-Leu-OH 5
54 mg, HOBT.H ₂ O 338 mg, EDCI.
HCl 479 mg was added and then stirred at room temperature for 4 hours. The reaction mixture was washed with saturated aqueous sodium hydrogen carbonate (30 ml), 10% aqueous citric acid solution (30 ml) and saturated brine (30 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to medium-pressure liquid chromatography (Merck Rover Column Licroprep SI).
The product was purified with 60 / hexane: ethyl acetate = 1: 1) to obtain 512 mg of the desired product. (21-b) 2,6-dimethylpiperidinocarbonyl
Synthesis of -Leu-DTrp (2-Br) -OH 2,6-Dimethylpiperidinocarbonyl-Leu-DTrp (2-Br) -OMe obtained in Example (21-a).
270 mg was dissolved in methanol (10 ml), 2N aqueous sodium hydroxide solution (2.0 ml) was added under ice cooling,
The mixture was stirred at the same temperature for 2 hours and at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (50 ml), acidified by adding 1N hydrochloric acid, and then extracted with ethyl acetate (25 ml × 3). The organic layers were combined, washed with saturated brine (25 ml) and dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure to give the desired product as a pale yellow amorphous.
47 mg was obtained.

FAB-MS (m / e, (C ₂₅ H ₃₅ BrN
₄ O ₄ + H) as a ^{+): 535,537 (21-c} ) Synthesis Example of Compound 22 (21-b) obtained in 2,6-dimethyl-piperidinocarbonyl -Leu-DTrp (2-Br) - OH 5
3.5 mg and HOSu 17.3 mg were added to DMF (1.
0 ml), and under ice cooling, EDCI.HCl 21.
1 mg was added, and the mixture was stirred at the same temperature for 3 hours and at room temperature for 2 hours.
To D-β-aminobutyric acid (12.4 mg) and NMM
A solution of (16 μl) in water (1 ml) was added, and the mixture was stirred overnight at room temperature. 1N Hydrochloric acid (10 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 ml × 3). The organic layers were combined, washed with saturated brine (10 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure.
The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol = 10:
Purified in 1), the title compound as a colorless powder, 9.5 m
g was obtained.

Melting point: 129-133 ° C. IR (KBr, cm ^-1 ): 3305, 2935, 165
1,1539, 1452, 1389, 1340, 124
0,1126,1092,743,609 High resolution FAB-MS (m / e, (C ₂₉ H ₄₂ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 620.2448 Measured value 620.2424 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, d, J = 6.1Hz), 0.84 (3
H, d, J = 6.1 Hz), 0.86-0.93 (1
H, m), 0.97 (3H, d, J = 6.4 Hz),
1.17 (3H, d, J = 6.8Hz), 1.18 (3
H, d, J = 6.8 Hz), 1.10-1.80 (8
H, m), 2.10-2.45 (2H, m), 3.26.
(1H, dd, J = 6.3Hz, 14.6Hz), 3.
39 (1H, dd, J = 6.2Hz, 14.6Hz),
4.00-4.22 (4H, m), 4.73-4.90
(2H, m), 6.52-6.60 (1H, m), 7.
04-7.17 (3H, m), 7.30 (1H, d, J
= 7.9 Hz), 7.62 (1H, dd, J = 7.6H)
z), 9.05 (1H, brs) Example 22 Synthesis of compound 23 (22-a) 2,6-dimethylpiperidinocarbonyl
-Leu-DTrp (2-Br) -DTrp-OMe
2,6-Dimethylpiperidinocarbonyl-Leu-DTrp (2-Br) -OH 5 obtained in Synthesis Example (21-b)
3.5 mg and H-DTrp-OMe.HCl 25.5
Dissolve mg in dichloromethane (5 ml) and add N under ice cooling.
MM 14 μl, HOBT · H ₂ O 19 mg, EDC
I · HCl (24 mg) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (30 ml), saturated aqueous sodium hydrogen carbonate (30 ml) and 10% aqueous citric acid solution (30 m).
It was washed with 1) and saturated saline (30 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Preparative thin-layer chromatography (Merck)
Silica gel 60 F ₂₅₄ / chloroform: methanol = 3
The product was purified by 0: 1) to obtain 45.2 mg of the desired product.

FAB-MS (m / e, (C ₃₇ H ₄₇ BrN
₆ O ₅ + H) ⁺ ): 735,737 (22-b) Synthesis of compound 23 2,6-Dimethylpiperidinocarbonyl-Leu-DTrp (2-Br) -obtained in Example (22-a). DTrp
-OMe (36.6 mg) was dissolved in methanol (5 ml), and 2N aqueous sodium hydroxide solution (0.5 m) was added under ice cooling.
1) was added, and then the mixture was stirred at room temperature for 2.5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (50 ml), and 1N
After adding hydrochloric acid to acidify, ethyl acetate (25 ml x
Extracted in 3). The organic layers are combined and saturated saline (25
(ml) and dried over anhydrous magnesium sulfate, the solvent was evaporated under reduced pressure to give the title compound (32.2 mg) as a pale yellow amorphous substance.

Melting point: 118-124 ° C. IR (KBr, cm ⁻¹ ): 3392, 3293, 293
1,1652, 1519, 1454, 1340, 123
2,742,609 High resolution FAB-MS (m / e, (C ₃₆ H ₄₅ BrN ₆ O ₅
+ H) As ⁺ ): Calculated value 721.2713 Measured value 721.2707 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, d, J = 6.5Hz), 0.82 (3
H, d, J = 6.5 Hz), 0.85-0.91 (1
H, m), 1.10-1.90 (8H, m), 1.15
(3H, d, J = 7.0 Hz), 1.16 (3H, d,
J = 7.0 Hz), 3.10-3.21 (3H, m),
3.28 (1H, dd, J = 4.9Hz, 15.5H
z), 3.80-3.88 (1H, m), 3.98-
4.12 (2H, m), 4.66-4.81 (3H,
m), 6.23 (1H, d, J = 7.9 Hz), 6.7
3 (1H, s), 7.04-7.20 (4H, m),
7.27 (1H, d, J = 8.1Hz), 7.34 (1
H, d, J = 8.1 Hz), 7.40-7.46 (2
H, m), 7.53 (1H, d, J = 8.4 Hz),
8.19 (1H, brs), 8.27 (1H, brs) Example 23 Synthesis of compound 24 30 mg of compound 16 obtained in Example (15-g) and 5.3 mg of aniline were dissolved in DMF (3 ml). , Under ice cooling, HOBT · H ₂ O 11 mg, EDCl · HCl 1
4 mg was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature overnight.
Water (30 ml) was added to the reaction solution, and ethyl acetate (10 ml x
Extracted in 3). The organic layers were combined, washed with 10% aqueous citric acid solution (30 ml), saturated aqueous sodium hydrogen carbonate (30 ml) and saturated brine (30 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Preparative thin layer chromatography (Merck silica gel 60F)
_The product was purified with ₂₅₄ / chloroform: methanol = 30: 1) to obtain 20.6 mg of the title compound.

Melting point: 136-141 ° C. IR (KBr, cm ⁻¹ ): 3399, 2933, 286
9,1662, 1614, 1523, 1442, 133
8,1241,1126,1025,744,694 High resolution FAB-MS (m / e, (C ₃₆ H ₄₇ BrN ₆ O ₄
+ H) as ⁺ ): Calculated value 707.2920 Measured value 707.29511 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.20-0.41 (2H, m), 0.48-0.68
(2H, m), 0.75 (3H, t, J = 7.2H
z), 0.97 (3H, d, J = 7.1 Hz), 1.0
5 (3H, d, J = 7.1 Hz), 0.80-1.68
(12H, m), 1.99-2.07 (1H, m),
2.94-3.06 (1H, m), 3.37 (1H, d
d, J = 5.1 Hz, 14.8 Hz), 3.50 (1
H, dd, J = 6.2 Hz, 14.8 Hz), 3.65
-3.80 (1H, m), 3.90-4.04 (1H,
m), 4.48-4.60 (1H, m), 4.73 (1
H, q, J = 5.8 Hz), 5.00 (1H, d, J =
3.9 Hz), 6.26 (1H, d, J = 5.2H
z), 7.00 (1H, t, J = 7.5 Hz), 7.0
6-7.32 (5H, m), 7.64 (1H, d, J =
7.8 Hz), 7.70-7.88 (1 H, m), 7.
83 (2H, d, J = 7.5 Hz), 8.36 (1H,
s), 8.36 (1H, s) Example 24 Synthesis of compound 25 30 mg of compound 16 obtained in Example (15-g) and H
9 mg of OSu was dissolved in DMF (1 ml), 14 mg of EDCl.HCl was added under ice cooling, and the mixture was stirred at the same temperature for 2 hours. Concentrated aqueous ammonia (0.1 ml) was added to the reaction solution,
Stir for 10 minutes at room temperature. Water (20 ml) was added to the reaction solution, and the mixture was extracted with dichloromethane (10 ml × 2).
The combined organic layers were 10% aqueous citric acid solution (10 ml),
The extract was washed with saturated aqueous sodium hydrogen carbonate (10 ml) and saturated brine (10 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol: acetic acid = 30: 1: 1) to give 19.8mg of the title compound.

Melting point: 135-139 ° C. IR (KBr, cm ^-1 ): 3398, 3291, 293
5,2869,1662,1618,1519,145
0, 1386, 1340, 1249, 1126, 74
2,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₃ BrN ₆ O ₄
+ H) As ⁺ ): Calculated value 631.2607 Measured value 631.2623 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): -0.02-0.35 (4H, m), 0.82
(3H, t, J = 6.8Hz), 1.04 (3H, d,
J = 6.7 Hz), 1.05 (3H, d, J = 6.7H)
z), 0.61-1.80 (13H, m), 2.99
(1H, dd, J = 8.9Hz, 14.5Hz), 3.
12-3.62 (2H, m), 3.95-4.21 (3
H, m), 4.32-4.51 (1H, m), 6.48.
(1H, d, J = 5.7 Hz), 6.59 (1H,
s), 6.92-7.12 (3H, m), 7.24 (1)
H, d, J = 7.8 Hz), 7.62 (1H, d, J =
7.8 Hz), 7.96 (1H, d, J = 8.3H)
z), 8.11 (1H, d, J = 8.1 Hz), 11.
63 (1H, s) Example 25 Synthesis of Compound 26 (25-a) Boc-Leu-DTrp (2-Br)
-Synthesis of DNle-OMe H-DTrp (2-Br) -obtained in Example (15-e)
DNle-OMe. HCl 415 mg and Boc-L
eu-OH.H ₂ O 278 mg was added to dichloromethane 15
Dissolve in 0.1 ml, NMM 0.12 ml under ice cooling, HOB
T · H ₂ O 171 mg and EDCl · HCl 214
mg was added and the mixture was stirred at the same temperature for 1.5 hours and at room temperature for 2.5 hours. Dichloromethane (30 ml) was added to the reaction solution to dilute it, and the mixture was washed successively with saturated aqueous sodium hydrogen carbonate (20 ml x 2), 10% aqueous citric acid solution (20 ml x 2) and saturated saline (20 ml), and dried over anhydrous magnesium sulfate. After drying, the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Merck silica gel 60 / chloroform: methanol = 20: 1) to obtain 564 mg of the desired product.
Obtained.

FAB-MS (m / e, (C ₂₉ H ₄₃ BrN
₄ O ₆ + H) as a ^{+): 623,625 (25-b} ) Synthesis Example of Compound 26 (25-a) with Boc-Leu-DTrp obtained
(2-Br) -DNle-OMe 24 mg was melt | dissolved in methanol (1 ml), 2N sodium hydroxide aqueous solution 0.2 ml was added under ice-cooling, and it stirred at the same temperature for 1 hour and room temperature for 3.5 hours. . The reaction solution is concentrated under reduced pressure, and the residue is 1N.
Hydrochloric acid was added, and the formed precipitate was collected by filtration and dried to give the title compound as a colorless powder (15 mg).

Melting point: 139-143 ° C. IR (KBr, cm ^-1 ): 3400, 3304, 295
8,2872,1664,1595,1512,145
2,1392, 1367, 1340, 1250, 116
8,1047,743,609 High resolution FAB-MS (m / e, (C ₂₈ H ₄₁ BrN ₄ O ₆
+ H) ⁺ ): Calculated value 609.2287 Measured value 609.2267 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.65 (3H, d, J = 6.4Hz), 0.7
0 (3H, d, J = 6.4Hz), 0.82 (3H,
t, J = 6.8 Hz), 0.86-0.94 (1H,
m), 1.02-1.13 (1H, m), 1.20-
1.35 (5H, m), 1.33 (9H, s), 1.5
0-1.70 (2H, m), 2.87 (1H, dd, J
= 9.8 Hz, 14.4 Hz), 3.08 (1H, d
d, J = 4.4 Hz, 14.4 Hz), 3.83-3.
95 (2H, m), 4.52-4.56 (1H, m),
6.74 (1H, d, J = 7.8Hz), 6.95 (1
H, t, J = 7.6 Hz), 7.03 (1H, t, J =
7.6 Hz), 7.21 (1H, d, J = 7.6H
z), 7.58-7.61 (1H, m), 7.64 (1
H, d, J = 7.6 Hz), 7.97 (1H, d, J =
8.8 Hz), 11.59 (1 H, s) In Examples 26 to 27 below, the same reaction as in Example 24 was carried out by replacing the concentrated aqueous ammonia in Example 24 with a methylamine methanol solution or a dimethylamine methanol solution, respectively. Compounds 27 to 28 were obtained by carrying out. Example 26 Compound 27 Melting point: 136-141 ° C IR (KBr, cm ^-1 ): 3388, 3305, 293
5,2869,1656,1618,1529,145
0, 1338, 1276, 1249, 1126, 74
2,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₅ BrN ₆ O ₄
+ H) ⁺ ): Calculated value 645.2764 Measured value 645.2787 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.17-0.40 (2H, m), 0.40-0.67
(2H, m), 0.73 (3H, t, J = 7.2H
z), 0.80-1.99 (13H, m), 1.12
(3H, d, J = 6.9 Hz), 1.15 (3H, d,
J = 6.9 Hz), 2.70 (3H, d, J = 4.3H)
z,), 2.91-3.03 (1H, m), 3.34.
(1H, dd, J = 5.1Hz, 14.9Hz), 3.
46 (1H, dd, J = 6.4Hz, 14.9Hz),
3.91-4.11 (2H, m), 4.30-4.47
(1H, m), 4.60-4.72 (1H, m), 4.
99 (1H, d, J = 4.3Hz), 6.25 (1H,
d, J = 6.6 Hz), 6.70 (1H, d, J = 5.
0Hz), 7.10 (1H, t, J = 7.7Hz),
7.18 (1 H, t, J = 7.7 Hz), 7.29 (1
H, d, J = 7.7 Hz), 7.52 (1H, d, J =
8.5 Hz), 7.61 (1H, d, J = 7.7H
z), 8.47 (1H, s) Example 27 Compound 28 Melting point: 120-126 ° C IR (KBr, cm ^-1 ): 3399, 3270, 293
5,2869,1631,1502,1452,134
0, 1126, 742, 609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₇ BrN ₆ O ₄
+ H) as ⁺ ): Calculated value 659.2920 Measured value 659.2925 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.20-0.58 (4H, m), 0.82 (3H,
t, J = 6.8 Hz), 1.00-1.90 (13H,
m), 1.21 (3H, d, J = 6.7Hz), 1.2
3 (3H, d, J = 6.7Hz), 2.80 (3H,
s), 2.89 (3H, s), 3.10 (1H, dd,
J = 8.2 Hz, 14.3 Hz), 3.29 (1H, d
d, J = 6.5 Hz, 14.3 Hz), 3.83 (1
H, dd, J = 6.3 Hz, 8.3 Hz), 4.07-
4.30 (2H, m), 4.60-4.75 (2H,
m), 5.24 (1H, d, J = 6.3 Hz), 6.6
5 (1H, d, J = 7.9 Hz), 6.94 (1H,
d, J = 7.8 Hz), 7.04 (1H, dt, J =
1.3Hz, 7.4Hz), 7.11 (1H, dt, J
= 1.3 Hz, 7.4 Hz), 7.25 (1H, dd,
J = 1.3 Hz, 7.4 Hz), 7.57 (1H, d
d, J = 1.3 Hz, 7.4 Hz), 8.78 (1H,
s) Synthesis of Example 28 Compounds 29 and 30 (28-a) H-Leu-DTrp (2-Br) -D
Synthesis of Nle-OMe Boc-Leu-DTrp obtained in Example (25-a)
98% of 360 mg of (2-Br) -DNle-OMe
After dissolving in 15 ml of formic acid and stirring at room temperature for 2 hours, the reaction solution was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (50 ml), washed with saturated aqueous sodium hydrogen carbonate (30 ml × 2), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (278 mg).

FAB-MS (m / e, (C ₂₄ H ₃₅ BrN
₄ O ₄ + H) as a ^{+): 523,525 (28-b} ) Synthesis Example of Compound 29 (28-a) obtained in H-Leu-DTrp (2-
Br) -DNle-OMe 42 mg of THF (2 m
l-Methoxyphenyl isocyanate (12 μl) was added to the solution under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours.
The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (30 ml), 1N hydrochloric acid (20 ml) and saturated aqueous sodium hydrogen carbonate (20 m).
l) and saturated brine (20 ml) were successively washed, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol = 20: 1) to give 48mg of the title compound.

Melting point: 221-223 ° C. IR (KBr, cm ⁻¹ ): 3294, 2956, 173
8,1643,1547,1460,1435,125
1,1219,744 High resolution FAB-MS (m / e, (C ₃₂ H ₄₂ BrN ₅ O ₆
+ H) ⁺ ): Calculated value 672.2397 Measured value 672.2421 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.66 (3H, d, J = 6.4Hz), 0.7
0 (3H, d, J = 6.4Hz), 0.82 (3H,
t, J = 7.0 Hz), 0.86-1.32 (7H,
m), 1.63-1.70 (2H, m), 2.87 (1
H, dd, J = 10.3 Hz, 14.3 Hz), 3.1
6 (1H, dd, J = 4.3Hz, 14.3Hz),
3.52 (3H, s), 3.79 (3H, s), 3.9
8-4.06 (1H, m), 4.22-4.26 (1
H, m), 4.54-4.62 (1H, m), 6.76
(1H, t, J = 7.8Hz), 6.85 (1H, t,
J = 7.8 Hz), 6.92 (1H, d, J = 7.8H)
z), 6.96 (1H, t, J = 7.7 Hz), 7.0
2 (1H, d, J = 7.1Hz), 7.04 (1H,
t, J = 7.7 Hz), 7.22 (1H, d, J = 7.
7Hz), 7.67 (1H, d, J = 7.7Hz),
7.99 (1H, d, J = 7.8Hz), 8.02 (1
H, d, J = 7.6 Hz), 8.02 (1H, s),
8.26 (1H, d, J = 9.0Hz), 11.58
(1H, s) (28-c) Synthesis of Compound 30 40 mg of the compound 29 obtained in Example (28-b) was dissolved in a mixed solvent of methanol (1 ml) and THF (0.5 ml), and the mixture was cooled with ice. 2N sodium hydroxide aqueous solution 0.3
ml was added, and the mixture was stirred at the same temperature for 1.5 hours and at room temperature for 4 hours. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the formed precipitate was collected by filtration and dried to obtain 35 mg of the title compound as a colorless powder.

Melting point: 162-167 ° C. IR (KBr, cm ^-1 ): 3340, 2956, 165
1,1601,1549,1252,744 High resolution FAB-MS (m / e, (C ₃₁ H ₄₀ BrN ₅ O ₆
+ H) ⁺ ): Calculated value 658.2240 Measured value 658.2275 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp.
m): 0.64 (3H, d, J = 6.6Hz), 0.7
2 (3H, d, J = 6.6Hz), 0.74 (3H,
t, J = 6.8 Hz), 0.79-1.35 (7H,
m), 1.54-1.70 (2H, m), 2.92 (1
H, dd, J = 10.0 Hz, 14.4 Hz), 3.0
5 (1H, dd, J = 4.1Hz, 14.4Hz),
3.78 (3H, s), 3.77-3.82 (1H,
m), 4.15-4.20 (1H, m), 4.45-
4.50 (1H, m), 6.78 (1H, t, J = 7.
7Hz), 6.82 (1H, t, J = 7.7Hz),
6.91 (1H, d, J = 7.7 Hz), 6.93 (1
H, t, J = 7.4 Hz), 7.01 (1H, t, J =
7.4 Hz), 7.21 (1H, d, J = 7.4H)
z), 7.20-7.25 (1H, brs), 7.47.
-7.51 (1H, brs), 7.67 (1H, d, J
= 7.4 Hz), 8.03 (1H, d, J = 7.8H)
z), 8.15-8.20 (1H, brs), 8.44
(1H, brs), 11.58 (1H, s) In Examples 29 to 30 below, the 2-methoxyphenyl isocyanate in Example (28-b) was replaced with the corresponding isocyanate. -B) and (2
Compound 31-
34 was obtained. Example 29 Compound 31 Melting point: 229-232 ° C IR (KBr, cm ^-1 ): 3292, 2929, 287
0,1738,1641,1549,1444,122
3,742 High-resolution FAB-MS (m / e, (C ₃₁ H ₄₀ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 642.2291 Measured value 642.2266 ¹ H-NMR (300 MHz, CDCl ₃ + CD ₃ OD,
δppm): 0.81 (3H, t, J = 7.2Hz),
0.83 (3H, d, J = 6.0Hz), 0.84 (3
H, d, J = 6.0 Hz), 1.06-1.67 (9
H, m), 3.20-3.27 (2H, m), 3.52
(3H, s), 4.12-4.18 (1H, m), 4.
35-4.43 (1H, m), 4.72-4.80 (1
H, m), 6.94-7.32 (8H, m), 7.58.
(1H, d, J = 7.1 Hz) Compound 32 Melting point: 196-198 ° C. IR (KBr, cm ⁻¹ ): 3305, 2958, 292
5,1722, 1651, 1552, 1443, 123
6,744 High resolution FAB-MS (m / e, (C ₃₀ H ₃₈ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 628.2133 Measured value 628.2136 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp.
m): 0.62 (3H, d, J = 6.6Hz), 0.6
9 (3H, d, J = 6.6Hz), 0.82 (3H,
t, J = 7.1 Hz), 0.79-1.75 (9H,
m), 2.88 (1H, dd, J = 10.6Hz, 1
4.6 Hz), 3.14 (1H, dd, J = 3.9H)
z, 14.6 Hz), 4.04-4.19 (2H,
m), 4.60-4.67 (1H, m), 6.20 (1
H, d, J = 7.9 Hz), 6.86 (1H, t, J =
7.8Hz), 6.97 (1H, t, J = 7.5H
z), 7.04 (1H, t, J = 7.5 Hz), 7.1
7 (2H, t, J = 7.8Hz), 7.22 (1H,
d, J = 7.5 Hz), 7.30 (2H, d, J = 7.
8Hz), 7.69 (1H, d, J = 7.5Hz),
7.94 (1H, d, J = 7.3 Hz), 8.27 (1
H, d, J = 9.0 Hz) 8.46 (1H, s), 1
1.58 (1 H, s) Example 30 Compound 33 Melting point: 224-228 ° C. IR (KBr, cm ⁻¹ ): 3304, 3076, 295
6,2870,2362,2343,1738,164
3,1587,1547,1439,1225,74
4,609 High resolution FAB-MS (m / e, (C ₃₁ H ₃₉ BrClN
₅ O ₅ + H) ⁺ ): Calculated value 676.1902 Measured value 676.1890 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp
m): 0.66 (3H, d, J = 6.8Hz), 0.7
1 (3H, d, J = 6.8Hz), 0.81 (3H,
t, J = 7.1 Hz), 0.83 to 1.04 (2H,
m), 1.16-1.34 (5H, m), 1.60-
1.65 (2H, m), 2.88 (1H, dd, J = 1
0.3 Hz, 14.4 Hz), 3.14 (1H, dd,
J = 4.4 Hz, 14.4 Hz), 3.54 (3H,
s), 4.05-4.11 (1H, m), 4.19-
4.26 (1H, m), 4.58-4.64 (1H,
m), 6.92 (1H, t, J = 7.9 Hz), 6.9
7 (1H, t, J = 7.6Hz), 7.05 (1H,
t, J = 7.6 Hz), 7.16 (1H, t, J = 7.
9Hz), 7.21 (1H, d, J = 6.8Hz),
7.23 (1H, d, J = 7.6Hz), 7.36 (1
H, d, J = 7.9 Hz), 7.68 (1H, d, J =
7.6 Hz), 8.04 (1H, d, J = 7.3H)
z), 8.08 (1H, d, J = 7.9 Hz), 8.3
1 (1H, d, J = 8.8Hz), 10.09 (1H,
s), 11.59 (1H, s) compound 34 melting point: 131-135 ° C IR (KBr, cm ^-1 ): 3305, 2958, 165
7, 1547, 1439, 1230, 744 High resolution FAB-MS (m / e, (C ₃₀ H ₃₇ BrClN
₅ O ₅ + H) ⁺ ): Calculated value 662.1745 Measured value 662.1718 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.64 (3H, d, J = 6.6Hz), 0.7
0 (3H, d, J = 6.6Hz), 0.81 (3H,
t, J = 7.1 Hz), 0.85-1.35 (7H,
m), 1.76-1.75 (2H, m), 2.89 (1
H, dd, J = 10.6 Hz, 14.6 Hz), 3.1
6 (1H, dd, J = 4.0Hz, 14.6Hz),
4.03-4.20 (2H, m), 4.59-4.67
(1H, m), 6.91 (1H, t, J = 7.9H
z), 6.97 (1H, t, J = 7.5 Hz), 7.0
4 (1H, t, J = 7.5 Hz), 7.13-7.24
(3H, m), 7.36 (1H, d, J = 7.9H
z), 7.69 (1H, d, J = 7.5 Hz), 7.9
1 (1H, d, J = 7.6 Hz), 8.08 (1H,
d, J = 7.8 Hz), 8.10 (1H, s), 8.2
7 (1H, d, J = 8.7 Hz), 11.58 (1H,
s), 12.51 (1H, brs) Example 31 Synthesis of compound 35 H-Leu-DTrp (2-) obtained in Example (28-a)
Br) -DNle-OMe 422 mg of pyridine (3
phenyl chloroformate (0.2 m
1) was added, and the mixture was stirred at the same temperature for 1.5 hours. Water (1 drop) was added to the reaction solution, and the mixture was concentrated under reduced pressure. Water (40m) on the residue
l) was added and ethyl acetate (40 ml x 1, 20 ml x
Extracted in 2), the combined ethyl acetate layers are 10%
Aqueous citric acid solution (40 ml), saturated aqueous sodium hydrogen carbonate (40 ml)
Then, the extract was washed successively with saturated saline (40 ml), dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Merck silica gel 60 / chloroform: methanol = 50:
Purification in 1) yielded 472 mg of the title compound.

IR (KBr, cm ^-1 ): 3296, 30
62, 2956, 2870, 1730, 1649, 15
37,1211,742,689 High resolution FAB-MS (m / e, (C ₃₁ H ₃₉ BrN ₄ O ₆
+ H) ⁺ ): Calculated value 643.2131 Measured value 643.2103 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.77 (3H, t, J = 7.1Hz), 0.89 (3
H, d, J = 6.0 Hz), 0.90 (3H, d, J =
6.0 Hz), 0.80-1.70 (9H, m), 3.
14 (1H, dd, J = 7.7Hz, 14.6Hz),
3.31 (1H, dd, J = 6.6Hz, 14.6H
z), 3.64 (3H, s), 4.13-4.19 (1
H, m), 4.36-4.43 (1H, m), 4.69
-4.77 (1H, m), 5.47 (1H, d, J =
8.1 Hz), 6.32 (1H, d, J = 7.6H)
z), 6.58 (1H, d, J = 7.9 Hz), 7.0
7-7.22 (5H, m), 7.28 (1H, d, J =
7.5 Hz), 7.32 (2H, t, J = 7.5H
z), 7.65 (1H, d, J = 7.6 Hz), 8.1
5 (1H, s) Example 32 Synthesis of Compounds 36 and 37 (32-a) Synthesis of Compound 36 Compound 35 obtained in Example 31 was converted into chloroform (1.6 m).
1) and THF (1.0 ml) mixed solvent,
Heptamethyleneimine (75 μl) and triethylamine (118 μl) were added, and the mixture was stirred at 50 ° C. for 4.5 hours. Dilute the reaction mixture with ethyl acetate (30 ml) and
The mixture was washed successively with N hydrochloric acid (20 ml), saturated aqueous sodium hydrogen carbonate (20 ml) and saturated brine (20 ml), dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / hexane: ethyl acetate = 2: 3) to obtain 33mg of the title compound.

IR (KBr, cm ^-1 ): 3280, 29
56, 2927, 2866, 1741, 1659, 16
30, 1527, 1439, 1342, 1279, 12
19,742 High-resolution FAB-MS (m / e, (C ₃₂ H ₄₈ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 662.2917 Measured value 662.2930 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, t, J = 7.4Hz), 0.83 (3
H, d, J = 6.3 Hz), 0.84 (3H, d, J =
6.3 Hz), 1.07-1.75 (19H, m),
3.23 (1H, dd, J = 6.6Hz, 14.7H
z), 3.34 (1H, dd, J = 6.5 Hz, 14.
7 Hz), 3.18-3.41 (4H, m), 3.63
(3H, s), 4.03-4.09 (1H, m), 4.
37-4.46 (1H, m), 4.61 (1H, d, J
= 7.1 Hz), 4.75-4.83 (1H, m),
6.43 (1H, d, J = 7.1Hz), 7.02 (1
H, d, J = 7.8 Hz), 7.09 (1H, t, J =
7.5 Hz), 7.15 (1H, t, J = 7.5H
z), 7.27 (1H, d, J = 7.5 Hz), 7.6
3 (1H, d, J = 7.5Hz), 8.23 (1H,
s) (32-b) Synthesis of compound 37 28 mg of the compound 36 obtained in Example (32-a) was dissolved in methanol (0.8 ml), and 0.2 ml of 2N sodium hydroxide aqueous solution was added under ice cooling, The mixture was stirred at the same temperature for 1 hour and at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, and 1 was added to the residue.
N hydrochloric acid was added, and the formed precipitate was collected by filtration and dried to obtain 13 mg of the title compound as a colorless powder.

Melting point: 158-163 ° C. IR (KBr, cm ^-1 ): 3408, 3304, 292
7, 1659, 1632, 1529, 1450, 74
2,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 628.2760 Measured value 628.2775 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.68 (3H, d, J = 7.4Hz), 0.7
1 (3H, d, J = 7.3Hz), 0.82 (3H,
t, J = 6.7 Hz), 1.01-1.68 (19H,
m), 2.87 (1H, dd, J = 9.4 Hz, 14.
5Hz), 3.00 (1H, dd, J = 4.4Hz, 1
4.5 Hz), 3.14-3.47 (4H, m), 3.
80-3.86 (1H, m), 4.03-4.09 (1
H, m), 4.43-4.52 (1H, m), 5.88.
(1H, d, J = 7.8Hz), 6.94 (1H, t,
J = 7.4 Hz), 7.03 (1H, t, J = 7.4H
z), 7.21 (1H, d, J = 7.4 Hz), 7.5
9 (1H, d, J = 7.1Hz), 7.63 (1H,
d, J = 7.4 Hz), 7.97 (1H, d, J = 8.
5 Hz), 11.58 (1 H, s) In Examples 33 to 36 below, heptamethyleneimine in Example (32-a) was replaced with a corresponding amine, and Examples (32-a) and (32-) were used. Compounds 38 to 45 were obtained by performing the same reaction as in b). Example 33 Compound 38 IR (KBr, cm ^-1 ): 3284, 2954, 293
1,2767,1741,1659,1626,152
9, 1439, 1213, 742 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 648.2761 Measured value 648.2740 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, t, J = 7.2Hz), 0.83 (3
H, d, J = 5.7 Hz), 0.84 (3H, d, J =
5.7 Hz), 1.05-1.74 (17H, m),
3.19-3.43 (6H, m), 3.63 (3H,
s), 3.99-4.06 (1H, m), 4.38-
4.45 (1H, m), 4.58 (1H, d, J = 7.
5 Hz), 4.75-4.83 (1H, m), 6.42
(1H, d, J = 8.2 Hz), 7.02 (1H, d,
J = 8.2 Hz), 7.09 (1H, t, J = 7.8H
z), 7.16 (1H, t, J = 7.8Hz), 7.2
6 (1H, d, J = 7.8Hz), 7.63 (1H,
d, J = 7.8 Hz), 8.12 (1H, s) compound 39 melting point: 122-126 ° C. IR (KBr, cm ⁻¹ ): 3396, 3288, 295
6,2929,2868,1658,1632,152
9, 1450, 1217, 742 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 634.2604 Measured value 634.2586 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.66 (3H, d, J = 6.4Hz), 0.6
7 (3H, d, J = 6.3Hz), 0.85 (3H,
t, J = 7.1 Hz), 0.87-0.91 (1H,
m), 1.13-1.54 (14H, m), 1.68-
1.72 (2H, m), 2.85 (1H, dd, J = 1
0.5Hz, 14.4Hz), 3.21 (1H, dd,
J = 3.7 Hz, 14.4 Hz), 3.24-3.28.
(4H, m), 3.84-3.90 (1H, m), 4.
06-4.13 (1H, m), 4.50-4.56 (1
H, m), 6.01 (1H, d, J = 6.8 Hz),
6.95 (1H, t, J = 7.4Hz), 7.04 (1
H, t, J = 7.4 Hz), 7.22 (1H, d, J =
7.4 Hz), 7.66 (1H, d, J = 7.4H)
z), 8.03 (1H, d, J = 10.7Hz), 8.
05 (1H, d, J = 7.8Hz), 11.56 (1
H, s), 12.39 (1H, brs) Example 34 Compound 40 IR (KBr, cm ^-1 ): 3296, 2954, 293
1,2856, 1741, 1659, 1626, 153
7,1443,1270,1257,1236,74
2,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 634.2609 Measured value 634.2596 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, t, J = 7.2Hz), 0.82 (3
H, d, J = 5.6 Hz), 0.84 (3H, d, J =
5.6 Hz), 1.07-1.73 (15H, m),
3.17-3.37 (6H, m), 3.63 (3H,
s), 4.00-4.05 (1H, m), 4.37-
4.46 (1H, m), 4.70 (1H, d, J = 7.
7 Hz), 4.73-4.81 (1H, m), 6.46
(1H, d, J = 8.3 Hz), 6.94 (1H, d,
J = 7.6 Hz), 7.09 (1H, t, J = 7.7H
z), 7.19 (1H, t, J = 7.7 Hz), 7.2
7 (1H, d, J = 7.7Hz), 7.63 (1H,
d, J = 7.7 Hz), 8.16 (1 H, s) compound 41 melting point: 161-164 ° C. IR (KBr, cm ⁻¹ ): 3398, 3296, 295
4,2860,1635,1533,1450,127
0,1238,742,609 High resolution FAB-MS (m / e, (C ₂₉ H ₄₂ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 620.2448 Measured value 620.2449 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp
m): 0.67 (3H, d, J = 6.8Hz), 0.6
9 (3H, d, J = 7.3Hz), 0.82 (3H,
t, J = 6.8 Hz), 0.95-1.00 (1H,
m), 1.14-1.68 (14H, m), 2.87.
(1H, dd, J = 9.5Hz, 14.4Hz), 3.
12 (1H, dd, J = 4.1Hz, 14.4Hz),
3.20-4.24 (4H, m), 3.87-4.00
(2H, m), 4.47-4.53 (1H, m), 6.
27 (1H, d, J = 7.3 Hz), 6.95 (1H,
t, J = 7.6 Hz), 7.03 (1H, t, J = 7.
6Hz), 7.21 (1H, d, J = 7.6Hz),
7.64 (1H, d, J = 7.6Hz), 7.63-
7.69 (1H, m), 7.95 (1H, d, J = 8.
8 Hz), 11.58 (1 H, s) Example 35 Compound 42 IR (KBr, cm ^-1 ): 3274, 2956, 287
0,1741, 1659, 1632, 1524, 143
9,1340,1230,744 High resolution FAB-MS (m / e, (C ₂₉ H ₄₂ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 620.2447 Measured value 620.2457 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, t, J = 6.7Hz), 0.83 (3
H, d, J = 6.2 Hz), 0.84 (3H, d, J =
6.2 Hz), 1.03-1.75 (9H, m), 1.
85-1.92 (4H, m), 3.19-3.37 (6
H, m), 3.63 (3H, s), 4.03-4.11.
(1H, m), 4.39-4.47 (2H, m), 4.
73-4.82 (1H, m), 6.55 (1H, d, J
= 8.6 Hz), 7.00 (1H, d, J = 7.2H)
z), 7.09 (1H, t, J = 7.8Hz), 7.1
6 (1H, t, J = 7.8Hz), 7.26 (1H,
d, J = 7.8 Hz), 7.63 (1H, d, J = 7.
8 Hz), 8.21 (1H, s) Compound 43 Melting point: 148.5-154 ° C IR (KBr, cm ^-1 ): 3406, 3304, 293
3, 1658, 1641, 1529, 742, 609 High resolution FAB-MS (m / e, (C ₂₈ H ₄₀ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 606.2291 Measured value 606.2294 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.67 (3H, d, J = 6.1Hz), 0.6
9 (3H, d, J = 5.6Hz), 0.83 (3H,
t, J = 7.0 Hz), 0.97-1.03 (1H,
m), 1.14-1.34 (6H, m), 1.60-
1.78 (6H, m), 2.88 (1H, dd, J = 1
0.2 Hz, 14.5 Hz), 3.11-3.23 (5
H, m), 3.92-4.02 (2H, m), 4.46.
-4.54 (1H, m), 5.90 (1H, d, J =
7.8 Hz), 6.94 (1H, t, J = 7.3H)
z), 7.04 (1H, t, J = 7.4Hz), 7.2
2 (1H, d, J = 7.4Hz), 7.64 (1H,
d, J = 7.4 Hz), 7.80 (1H, d, J = 6.
2Hz), 8.00 (1H, d, J = 8.7Hz), 1
1.58 (1H, s) Example 36 Compound 44 Melting point: 97-101 ° C IR (KBr, cm ^-1 ): 3398, 3280, 305
9,2954,2868,2358,1741,165
9, 1620, 1529, 1439, 1340, 127
4,1236,1186,1151,743,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 648.2761 Measured value 648.2732 ¹ H-NMR (400 MHz, CDCl ₃ , δppm):
0.79-0.90 (10H, m), 1.09 + 1.1
4 (3H, d2, J = 6.8Hz, J = 6.8Hz),
1.07-1.78 (14H, m), 2.80-2.8
9 (1H, m), 3.20-3.27 (1H, m),
3.29-3.38 (1H, m), 3.63 (3H,
s), 3.65-3.70 (1H, m), 4.00-
4.08 (1H, m), 4.12-4.18 (1H,
m), 4.38-4.45 (1H, m), 4.67+
4.71 (1H, d2, J = 6.8Hz, J = 7.3H
z), 4.74-4.83 (1H, m), 6.42+
6.48 (1H, d2, J = 8.8Hz, J = 8.3H
z), 6.93 + 7.00 (1H, d2, J = 7.3H
z, J = 7.8 Hz), 7.10 (1H, t, J = 7.
3Hz), 7.16 (1H, t, J = 7.3Hz),
7.27 (1H, d, J = 7.3 Hz), 7.63 (1
H, d, J = 7.3 Hz), 8.19 (1 H, s) Compound 45 Melting point: 167-170 ° C. IR (KBr, cm ⁻¹ ): 3396, 3294, 295
6,2868,1659,1620,1529,144
1,1402,1342,1275,743,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 634.2604 Measured value 634.2585 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp.
m): 0.66 (3H, d, J = 6.8Hz), 0.7
0 (3H, d, J = 7.3Hz), 0.80 (3H,
t, J = 6.6 Hz), 0.98 + 0.99 (3H, d
2, J = 7.7 Hz, J = 7.3 Hz), 1.18-
1.70 (15H, m), 2.65-2.73 (1H,
m), 2.84-2.90 (1H, m), 3.05-
3.13 (1H, m), 3.69-3.83 (2H,
m), 4.03-4.10 (1H, m), 4.20-
4.28 (1H, m), 4.45-4.52 (1H,
m), 6.15 + 6.21 (1H, d2, J = 8.3H
z, J = 7.9 Hz), 6.95 (1H, t, J = 7.
7Hz), 7.03 (1H, t, J = 7.7Hz),
7.21 (1H, d, J = 7.7 Hz), 7.50-
7.59 (1H, m), 7.63 (1H, d, J = 7.
7 Hz), 7.94-7.96 (1H, m), 11.5
8 (1H, s) Example 37 Compound 46 Melting point: 85-92 ° C IR (KBr, cm ^-1 ): 3294, 1741, 165
7, 1630, 1450, 1275, 1240, 105
1,743 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₆
+ H) as ⁺ ): Calculated value 664.2709 Measured value 664.2731 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.77-0.85 (9H, m), 0.86-0.91
(1H, m), 1.00-1.72 (14H, m),
2.62-2.71 (1H, m), 3.24 (1H, d
d, J = 6.1 Hz, 14.8 Hz), 3.35 (1
H, dd, J = 6.4 Hz, 14.8 Hz), 3.44
-3.50 (1H, m), 3.66 (3H, s), 3.
90-4.22 (5H, m), 4.45-4.53 (1
H, m), 4.71-4.79 (1H, m), 5.60.
(1H, d, J = 8.5 Hz), 6.68 (1H, d,
J = 8.4 Hz), 7.08 (1H, t, J = 7.6H
z), 7.15 (1H, t, J = 7.6 Hz), 7.2
5-7.27 (2H, m), 7.61 (1H, d, J =
7.6 Hz), 8.22 (1H, brs) compound 47 Melting point: 89-93 ° C IR (KBr, cm ^-1 ): 3294, 2954, 173
8, 1659, 1620, 1450, 1275, 105
2,742,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₆
+ H) ⁺ ): Calculated value 664.2709 Measured value 664.2682 ¹ H-NMR (500 MHz, CDCl ₃ , δppm):
0.83 (3H, t, J = 7.3Hz), 0.84 (3
H, d, J = 6.6 Hz) 0.85 (3H, d, J =
6.6 Hz), 1.10-1.77 (15H, m),
2.92-3.00 (2H, m), 3.28 (1H, d
d, J = 6.1 Hz, 14.6 Hz), 3.43 (1
H, dd, J = 7.3 Hz, 14.6 Hz), 3.50
-3.56 (2H, m), 3.67 (3H, s), 3.
70-4.77 (1H, m), 3.96-4.00 (1
H, m), 4.32-4.38 (1H, m), 4.43.
-4.49 (1H, m), 4.61-4.67 (1H,
m), 4.85 (1H, d, J = 6.4 Hz), 6.5
5 (1H, d, J = 8.3 Hz), 7.09 (1H,
t, J = 8.1 Hz), 7.16 (1H, t, J = 8.
1Hz), 7.20 (1H, m), 7.27 (1H,
d, J = 8.1 Hz), 7.61 (1H, d, J = 8.
1Hz), 8.22 (1H, s) compound 48 Melting point: 104-109 ° C IR (KBr, cm ^-1 ): 3388, 3302, 296
6,2931,1722,1657,1535,145
0, 1275, 1240, 1049, 742 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₆
+ H) ⁺ ): Calculated value 650.2555 Measured value 650.25571 ¹ H-NMR (400 MHz, DMSO-d ₆ , δpp
m): 0.64 (3H, d, J = 6.3Hz), 0.6
5 (3H, d, J = 6.4Hz), 0.86 (3H,
t, J = 6.8 Hz), 0.87-0.92 (1H,
m,), 1.06-1.75 (14H, m), 2.61
-2.68 (1H, m), 2.84 (1H, dd, J =
10.5Hz, 14.5Hz), 3.22 (1H, d
d, J = 3.9 Hz, 14.5 Hz), 3.42-3.
48 (2H, m), 3.78-3.89 (2H, m3.
93-3.99 (1H, m), 4.04-4.12 (1
H, m), 4.54-4.58 (1H, m), 4.63.
-4.67 (1H, m), 6.15 (1H, d, J =
7.3 Hz), 6.95 (1H, t, J = 7.6H
z), 7.04 (1H, t, J = 7.6 Hz), 7.2
1 (1H, d, J = 7.6 Hz), 7.65 (1H,
d, J = 7.6 Hz), 8.00 (1H, d, J = 7.
3Hz), 8.07 (1H, d, J = 8.8Hz), 1
1.56 (1H, s) Compound 49 Melting point: 107-113 ° C IR (KBr, cm ^-1 ): 3305, 2956, 293
1,1722, 1659, 1632, 1535, 145
0,1269,1240,742 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₆
+ H) As ⁺ ): Calculated value 650.2555 Measured value 650.25560 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.66 (3H, d, J = 6.3Hz), 0.6
7 (3H, d, J = 6.3Hz), 0.85 (3H,
t, J = 7.0 Hz), 0.90-0.95 (1H,
m,), 1.09-1.72 (14H, m), 2.58
-2.64 (1H, m), 2.86 (1H, dd, J =
10.3 Hz, 14.3 Hz), 3.19 (1 H, d
d, J = 3.8 Hz, 14.3 Hz), 3.35-3.
45 (2H, m), 3.76-4.11 (4H, m4.
50-4.58 (2H, m), 6.14 (1H, d, J
= 7.3 Hz), 6.96 (1H, t, J = 7.3H)
z), 7.04 (1H, t, J = 7.3 Hz), 7.2
2 (1H, d, J = 7.3 Hz), 7.65 (1H,
d, J = 7.3 Hz), 7.97 (1H, d, J = 9.
0 Hz), 8.01 (1H, d, J = 7.1 Hz), 1
1.56 (1H, s), 12.39 (1H, brs) Synthesis of Example 38 Compound 50 H-DTrp-OMe.H in Example (22-a)
Example in which Cl was replaced with D-norleucinol (22-
Compound 50 was obtained by performing the same reaction as in a).

Melting point: 106-109 ° C. IR (KBr, cm ⁻¹ ): 3392, 3278, 295
4,2933, 2868, 1653, 1618, 152
5,1126,743,608 High resolution FAB-MS (m / e, (C ₃₁ H ₄₈ BrN ₅ O ₄
+ H) ⁺ ): Calculated value 634.2968 Measured value 634.2968 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.77-0.92 (9H, m), 1.18 (6H,
d, J = 6.8 Hz), 1.15-1.80 (15H,
m), 3.36 (2H, d, J = 6.0 Hz), 3.4
2-3.62 (2H, m), 3.74-3.88 (3
H, m), 3.92-4.03 (1H, m), 4.05.
-4.17 (1H, m), 4.60 (1H, d, J =
6.4 Hz), 4.78 (1H, ddd, J = 6.4H
z, 6.4 Hz, 8.3 Hz), 6.01 (1H, d,
J = 8.3 Hz), 7.03 (1H, d, J = 8.1H
z), 7.11 (1H, t, J = 7.7 Hz), 7.1
8 (1H, t, J = 7.7 Hz), 7.28 (1H,
d, J = 7.7 Hz), 7.65 (1H, d, 7.7H)
z), 8.11 (1H, s) Example 39 Synthesis of compound 51 D-β-aminobutyric acid in Example (21-c) was replaced with D-
Compound 51 was obtained by performing the same reaction as in Example (21-c) instead of Met.

Melting point: 117-122 ° C. IR (KBr, cm ⁻¹ ): 3290, 2931, 171
8,1651, 1618, 1522, 1450, 138
9, 1340, 1126, 744, 608 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
S + H) ⁺ ): Calculated value 666.2325 Measured value 666.2328 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.87 (6H, d, J = 6.6Hz), 1.16 (6
H, d, J = 6.8 Hz), 1.20-2.23 (13
H, m), 1.98 (3H, s), 3.24 (1H, d
d, J = 6.2 Hz, 14.5 Hz), 3.39 (1
H, dd, J = 6.1 Hz, 14.5 Hz), 3.96
-4.18 (3H, m), 4.36-4.46 (1H,
m), 4.67-4.78 (1H, m), 4.90-
5.00 (1H, m), 6.64-6.76 (1H,
m), 7.08-7.19 (2H, m), 7.29 (1
H, d, J = 7.6 Hz), 7.46 (1H, d, J =
7.4 Hz), 7.61 (1H, d, J = 7.6H
z), 8.78 (1H, s) In Examples 40 to 47 below, H-DTrp-OMe.HCl in Example (22-a) was replaced with a corresponding amino acid methyl ester hydrochloride. 22-a)
Compounds 52 to 67 were obtained by performing the same reaction as in (22-b). Example 40 Compound 52 Melting point: 103-107 ° C IR (KBr, cm ^-1 ): 3273, 2958, 174
5,1653,1620,1522,743,608 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 648.2761 Measured value 648.2759 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.79-0.88 (9H, m), 1.10-1.30
(2H, m), 1.17 (3H, d, J = 7.1H
z), 1.18 (3H, d, J = 7.1Hz), 1.3
6-1.77 (11H, m), 3.25 (1H, dd,
J = 6.6 Hz, 14.7 Hz), 3.33 (1H, d
d, J = 6.8 Hz, J = 14.7 Hz), 3.63
(3H, s), 3.96-4.08 (2H, m), 4.
09-4.20 (1H, m), 4.43 (1H, dd
d, J = 5.6 Hz, 7.9 Hz, 7.9 Hz), 4.
70 (1H, d, J = 6.7Hz), 4.80 (1H,
ddd, J = 6.6 Hz, 6.8 Hz, 8.5 Hz),
6.39 (1H, d, J = 8.5 Hz), 7.03 (1
H, d, J = 7.5 Hz), 7.10 (1H, t, J =
7.5 Hz), 7.16 (1H, t, J = 7.5H
z), 7.27 (1H, d, J = 7.5 Hz), 7.6
3 (1H, d, J = 7.5Hz), 8.10 (1H,
s) Compound 53 Melting point: 145-152 ° C. IR (KBr, cm ⁻¹ ): 3294, 2958, 287
2,1718,1653,1622,1521,145
0,743,608 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 634.2604 Measured value 634.2571 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78 (3H, t, J = 7.3Hz), 0.84 (3
H, d, J = 6.6 Hz), 0.86 (3H, d, J =
6.6 Hz), 1.00-1.15 (2H, m), 1.
15 (3H, d, J = 7.1Hz), 1.16 (3H,
d, J = 7.1 Hz), 1.40-1.82 (11H,
m), 3.25 (1H, dd, J = 6.3 Hz, 14.
8Hz), 3.37 (1H, dd, J = 6.5Hz, J
= 14.8 Hz), 3.92-4.05 (2H, m),
4.05-4.17 (1H, m), 4.24-4.35
(1H, m), 4.66-4.76 (1H, m), 4.
82-4.92 (1H, m), 6.55 (1H, d, J
= 6.6 Hz), 7.10 (1H, t, J = 7.7H)
z), 7.17 (1H, t, J = 7.7 Hz), 7.2
7 (1H, d, J = 7.7Hz), 7.41 (1H,
s), 7.61 (1H, d, J = 7.7 Hz), 8.5
8 (1H, s) Example 41 Compound 54 Melting point: 86-90 ° C. IR (KBr, cm ⁻¹ ): 3388, 3275, 295
3,2937,2870,1743,1655,161
8, 1520, 1437, 1387, 1340, 114
7, 1126, 744, 608 High resolution FAB-MS (m / e, (C ₃₁ H ₄₄ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 646.2604 Measured value 646.2589 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.82 (3H, d, J = 6.1Hz), 0.83 (3
H, d, J = 6.1 Hz), 1.17 (3H, d, J =
7.1 Hz), 1.18 (3H, d, J = 7.1H)
z), 1.36-1.82 (9H, m), 2.34-
2.55 (2H, m), 3.24 (1H, dd, J =
6.6 Hz, 14.6 Hz), 3.31 (1H, dd,
J = 6.8 Hz, J = 14.6 Hz), 3.63 (3
H, s), 3.98-4.21 (3H, m), 4.51
(1H, ddd, J = 6.2Hz, 7.5Hz, 7.5
Hz), 4.74 (1H, d, J = 7.3 Hz), 4.
79 (1H, ddd, J = 6.6Hz, 6.8Hz,
8.2 Hz), 4.89-5.00 (2H, m), 5.
52 (1H, dddd, J = 7.1Hz, 7.1Hz,
10.0 Hz, 17.1 Hz), 6.46 (1 H, d,
J = 8.2 Hz), 7.04 (1H, d, J = 7.5H
z), 7.09 (1H, t, J = 7.5 Hz), 7.1
6 (1H, t, J = 7.5 Hz), 7.27 (1H,
d, J = 7.5 Hz), 7.62 (1H, d, J = 7.
5 Hz), 8.34 (1 H, s) compound 55 Melting point: 134-137 ° C IR (KBr, cm ^-1 ): 3392, 3290, 295
4,2935,2870,1714,1653,162
0,1524,1392,1340,1126,74
4,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₂ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 632.2448 Measured value 632.2453 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81-0.89 (6H, m), 1.16 (3H,
d, J = 7.2 Hz), 1.17 (3H, d, J = 6.
8 Hz), 1.30-1.90 (9H, m), 2.29
-2.61 (2H, m), 3.21 (1H, dd, J =
6.5 Hz, 14.8 Hz), 3.34 (1H, dd,
J = 6.5 Hz, J = 14.8 Hz), 3.95-4.
20 (3H, m), 4.29-4.39 (1H, m),
4.64-4.75 (1H, m), 4.79-4.97
(3H, m), 5.35-5.50 (1H, m), 6.
55-6.73 (1H, m), 7.07-7.20 (3
H, m), 7.28 (1H, d, J = 7.8 Hz),
7.62 (1H, d, J = 7.8Hz), 8.75 (1
H, s) Example 42 Compound 56 Melting point: 125-129 ° C IR (KBr, cm ^-1 ): 3265, 2931, 286
8,1741, 1655, 1618, 1524, 143
9,1126,744,609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₄ BrN ₇ O ₅
+ H) ⁺ ): Calculated value 6866.2666 Measured value 686.2694 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.826 (3H, d, J = 6.1Hz), 0.833
(3H, d, J = 6.1 Hz), 1.14 (3H, d,
J = 7.1 Hz), 1.18 (3H, d, J = 7.1H)
z), 1.20-1.80 (9H, m), 2.96 (1
H, dd, J = 9.0 Hz, 14.8 Hz), 3.15
-3.30 (3H, m), 3.67 (3H, s), 3.
97-4.11 (3H, m), 4.46-4.55 (1
H, m), 4.68-4.75 (1H, m), 4.81
(1H, d, J = 6.7 Hz), 6.70 (1H,
s), 6.72 (1H, d, J = 8.0 Hz), 7.0
8 (1H, t, J = 7.5 Hz), 7.14 (1H,
t, J = 7.5 Hz), 7.30 (1H, d, J = 7.
5Hz), 7.30 (1H, d, J = 7.5Hz),
7.48 (1H, s), 7.54 (1H, d, J = 7.
5 Hz), 8.79 (1 H, s) compound 57 melting point: 188-195 ° C. IR (KBr, cm ⁻¹ ): 3390, 2929, 164
7,1616,1516,1454,1394,134
2,744,608 High resolution FAB-MS (m / e, (C ₃₁ H ₄₂ BrN ₇ O ₅
+ H) ⁺ ): Calculated value 672.2509 Measured value 672.2512 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.68 (3H, d, J = 6.4Hz), 0.7
3 (3H, d, J = 6.4Hz), 0.76-1.75
(9H, m), 1.05 (6H, d, J = 6.8H
z), 2.75-3.35 (4H, m), 3.80-
3.92 (1H, m), 4.08-4.25 (3H,
m), 4.41-4.49 (1H, m), 6.03 (1
H, d, J = 7.8 Hz), 6.58 (1 H, s),
6.94 (1H, t, J = 7.1Hz), 7.03 (1
H, t, J = 7.1 Hz), 7.21 (1H, d, J =
7.1 Hz), 7.39 (1H, s), 7.50-7.
61 (1H, m), 7.64 (1H, d, J = 7.1H
z), 8.06 (1H, s), 11.59 (1H, s) Example 43 Compound 58 Melting point: 97-105 ° C IR (KBr, cm ^-1 ): 3271, 2954, 287
0,1736,1651,1620,1522,112
6,743,608 High resolution FAB-MS (m / e, (C ₃₃ H ₅₀ BrN ₅ O ₅
+ H) as a ^+): calculated 676.3074 measured ^{676.3068 1 H-NMR (300MHz,} CDCl 3, δppm):
0.75-0.90 (9H, m), 1.00-1.82
(15H, m), 1.17 (3H, d, J = 7.1H
z), 1.19 (3H, d, J = 7.2 Hz), 2.1
6 (1H, dd, J = 7.2Hz, 15.3Hz),
2.40 (1H, dd, J = 5.1Hz, 15.3H
z), 3.24 (1H, dd, J = 6.6 Hz, 14.
6Hz), 3.32 (1H, dd, J = 6.9Hz, 1
4.6 Hz), 3.58 (3H, s), 3.95-4.
27 (4H, m), 4.69-4.79 (2H, m),
6.37 (1H, d, J = 8.5Hz), 6.88 (1
H, d, J = 8.8 Hz), 7.08 (1H, t, J =
7.5Hz), 7.14 (1H, t, J = 7.5H
z), 7.25 (1H, d, J = 7.5 Hz), 7.6
3 (1H, d, J = 7.5Hz), 8.51 (1H, b
rs) Compound 59 Melting point: 133-139 ° C IR (KBr, cm ^-1 ): 3292, 2956, 286
8, 1713, 1651, 1620, 1524, 112
6,743,608 High resolution FAB-MS (m / e, (C ₃₂ H ₄₈ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 662.2917 Measured value 662.2909 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78-0.87 (9H, m), 1.06-2.36
(17H, m), 1.18 (3H, d, J = 6.8H
z), 1.19 (3H, d, J = 6.8Hz), 3.2
0-3.35 (2H, m), 3.92-4.14 (3
H, m), 4.14-4.25 (1H, m), 4.66.
-4.77 (1H, m), 5.01 (1H, brs),
6.55 (1H, brs), 7.00-7.17 (3
H, m), 7.28 (1H, d, J = 7.6 Hz),
7.61 (1H, d, J = 7.6Hz), 8.65 (1
H, brs) Example 44 Compound 60 Melting point: 92-95 ° C IR (KBr, cm ^-1 ): 3270, 2956, 174
1,1657,1620,1524,743,609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₈ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 662.2917 Measured value 662.2916 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.78-0.87 (12H, m), 0.92-0.9
6 (1H, m), 1.16 (3H, d, J = 6.8H
z), 1.17 (3H, d, J = 7.1Hz), 1.2
5-1.80 (11H, m), 3.24-3.35 (2
H, m), 3.63 (3H, s), 3.94-4.06.
(2H, m), 4.10-4.20 (1H, m), 4.
43-4.51 (1H, m), 4.72 (1H, d, J
= 6.8 Hz), 4.83 (1H, ddd, J = 6.5)
Hz, 6.9 Hz, 8.8 Hz), 6.35 (1H,
d, J = 8.8 Hz), 7.06-7.18 (3H,
m), 7.27 (1H, d, J = 7.6 Hz), 7.6
2 (1H, d, J = 7.6Hz), 8.28 (1H,
s) Compound 61 Melting point: 149-153 ° C IR (KBr, cm ^-1 ): 3664, 3265, 323
8,2953,2870,1726,1657,162
2,1525,1448,1383,744 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 648.2761 Measured value 648.2756 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.74-0.88 (12H, m), 1.16 (6H,
d, J = 7.1 Hz), 1.20-1.75 (12H,
m), 3.26-3.40 (2H, m), 3.90-
4.04 (2H, m), 4.08-4.20 (1H,
m), 4.35-4.46 (1H, m), 4.72-
4.82 (1H, m), 4.88-4.96 (1H,
m), 6.58 (1H, d, J = 7.0Hz), 7.1
0 (1H, t, J = 7.5Hz), 7.17 (1H,
t, J = 7.5 Hz), 7.29 (1H, d, J = 7.
5Hz), 7.45 (1H, d, J = 7.6Hz),
7.61 (1H, d, J = 7.5Hz), 8.50 (1
H, s) Example 45 Compound 62 Melting point: 85-89 ° C IR (KBr, cm ^-1 ): 3275, 2954, 293
5,2870,1745,1657,1618,152
2,1450,1437,1340,1126,74
4,608 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
S + H) ⁺ ): Calculated value 680.2481 Measured value 680.2467 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.80 (3H, d, J = 6.1Hz), 0.81 (3
H, d, J = 6.1 Hz), 0.88 (3H, t, J =
7.3 Hz), 1.16 (3H, d, J = 7.3H)
z), 1.18 (3H, d, J = 7.2 Hz), 1.1
5-1.80 (9H, m), 2.44 (2H, q, J =
7.3 Hz), 2.80 (1H, dd, J = 7.2H
z, 14.0 Hz), 2.93 (1H, dd, J = 5.
8 Hz, 14.0 Hz), 3.29 (2H, d, J =
7.0 Hz), 3.66 (3H, s), 3.97-4.
20 (3H, m), 4.63 (1H, ddd, J = 5.
8Hz, 7.2Hz, 7.5Hz), 4.71 (1H,
d, J = 7.1 Hz), 4.84 (1H, ddd, J =
7.0 Hz, 7.0 Hz, 8.5 Hz), 6.50 (1
H, d, J = 8.5 Hz), 7.10 (1H, t, J =
7.5 Hz), 7.16 (1H, t, J = 7.5H
z), 7.27 (1H, d, J = 7.5 Hz), 7.2
9 (1H, d, J = 7.5 Hz), 7.63 (1H,
d, J = 7.5 Hz), 8.22 (1H, s) compound 63 melting point: 144-149 ° C. IR (KBr, cm ⁻¹ ): 3392, 3274, 295
6,2933,2870,1657,1618,152
0,1450,1437,1389,1340,123
8,1126,743 High resolution FAB-MS (m / e, (C ₃₀ H ₄₄ BrN ₅ O ₅
S + H) ⁺ ): Calculated value 666.2325 Measured value 666.2349 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.72-0.90 (10H, m), 1.16 (3H,
d, J = 7.1 Hz), 1.18 (3H, d, J = 7.
1 Hz), 1.20-1.80 (8H, m), 2.42
(2H, q, J = 7.4Hz), 2.83 (1H, d
d, J = 7.6 Hz, 13.0 Hz), 2.97-3.
05 (1H, m), 3.18-3.31 (2H, m),
3.97-4.20 (3H, m), 4.40-4.45
(1H, m), 4.72-4.93 (2H, m), 6.
72-6.92 (1H, m), 7.09 (1H, t, J
= 7.5 Hz), 7.14 (1H, t, J = 7.5H)
z), 7.27 (1H, d, J = 7.5 Hz), 7.3
0-7.50 (1H, m), 7.65 (1H, d, J =
7.5 Hz), 8.80 (1 H, s) Example 46 Compound 64 Melting point: 86-90 ° C IR (KBr, cm ^-1 ): 3365, 2956, 293
5,2870,1745,1657,1618,152
2,1452,1437,1340,1126,74
4,608 High resolution FAB-MS (m / e, (C ₃₂ H ₄₈ BrN ₅ O ₅
S + H) ⁺ ): Calculated value 694.2638 Measured value 694.2657 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.79 (3H, d, J = 6.4Hz), 0.81 (3
H, d, J = 6.1 Hz), 0.94 (3H, t, J =
7.3 Hz), 1.16 (3H, d, J = 7.1H)
z), 1.18 (3H, d, J = 7.1Hz), 1.2
4-1.76 (11H, m), 2.40 (2H, t, J
= 7.3 Hz), 2.78 (1H, dd, J = 7.3H)
z, 14.0 Hz), 2.90 (1H, dd, J = 5.
8 Hz, 14.0 Hz), 3.21-3.34 (2H,
m), 3.66 (3H, s), 3.96-4.21 (3
H, m), 4.62 (1H, ddd, J = 5.8 Hz,
7.3 Hz, 7.3 Hz), 4.71 (1H, d, J =
7.1 Hz), 4.79-4.87 (1H, m), 6.
49 (1H, d, J = 8.5 Hz), 7.09 (1H,
t, J = 7.3 Hz), 7.15 (1H, t, J = 7.
3Hz), 7.26 (1H, d, J = 7.3Hz),
7.29 (1H, d, J = 7.3 Hz), 7.62 (1
H, d, J = 7.3 Hz), 8.28 (1 H, s) compound 65 melting point: 137-143 ° C. IR (KBr, cm ⁻¹ ): 3386, 3275, 295
8, 2927, 2870, 1651, 1610, 152
2,1452,1435,1392,1340,112
6,743,608 High resolution FAB-MS (m / e, (C ₃₁ H ₄₆ BrN ₅ O ₅
S + H) ⁺ ): Calculated value 680.2481 Measured value 680.2498 ¹ H-NMR (300 MHz, CD ₃ OD, δppm):
0.747 (3H, d, J = 6.2Hz), 0.753
(3H, d, J = 5.8Hz), 0.84-1.72
(11H, m), 0.95 (3H, t, J = 7.1H
z), 1.16 (6H, d, J = 6.9 Hz), 2.4
6 (2H, t, J = 7.2 Hz), 2.78-3.35.
(4H, m), 4.05-4.28 (3H, m), 4.
40-4.85 (2H, m), 7.01 (1H, t, J
= 7.3 Hz), 7.07 (1H, t, J = 7.3H)
z), 7.24 (1H, d, J = 7.3 Hz), 7.6
0 (1H, d, J = 7.3 Hz) Example 47 Compound 66 Melting point: 82-86 ° C. IR (KBr, cm ⁻¹ ): 3275, 2931, 174
3,1653, 1618, 1522, 1452, 138
7,1340,1126,743 High resolution FAB-MS (m / e, (C ₃₄ H ₅₂ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 690.3230 Measured value 690.3245 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81-0.89 (9H, m), 1.10-1.82
(19H, m), 1.17 (3H, d, J = 6.8H
z), 1.18 (3H, d, J = 6.8Hz), 3.2
4 (1H, dd, J = 6.6Hz, 14.6Hz),
3.33 (1H, dd, J = 6.8Hz, 14.6H
z), 3.63 (3H, s), 3.98-4.10 (2
H, m), 4.10-4.19 (1H, m), 4.36.
-4.44 (1H, m), 4.74 (1H, d, J =
7.1 Hz), 4.76-4.84 (1H, m), 6.
44 (1H, d, J = 8.6 Hz), 7.03 (1H,
d, J = 7.6 Hz), 7.09 (1H, t, J = 7.
5Hz), 7.15 (1H, t, J = 7.5Hz),
7.27 (1H, d, J = 7.5 Hz), 7.62 (1
H, d, J = 7.5 Hz), 8.27 (1 H, s) compound 67 Melting point: 119-125 ° C. IR (KBr, cm ⁻¹ ): 3294, 2929, 171
6,1653,1525,1450,1389,134
0,1240,1126,743 High resolution FAB-MS (m / e, (C ₃₃ H ₅₀ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 676.3074 Measured value 676.30641 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81-0.91 (9H, m), 1.02-1.84
(19H, m), 1.16 (6H, d, J = 7.1H
z), 3.27 (1H, dd, J = 6.6 Hz, 14.
6Hz), 3.37 (1H, dd, J = 6.3Hz, 1
4.6 Hz), 3.95-4.08 (2H, m), 4.
08-4.20 (1H, m), 4.27-4.35 (1
H, m), 4.74-4.82 (1H, m), 4.94.
(1H, d, J = 6.3 Hz), 6.68 (1H, d,
J = 7.7 Hz), 7.07-7.18 (2H, m),
7.28 (1H, d, J = 7.5Hz), 7.30 (1
H, brs), 7.62 (1H, d, J = 7.5H
z), 8.64 (1H, s) Example 48 Synthesis of compounds 68 and 69 (48-a) 2,6-dimethylpiperidinocarbonyl
Synthesis of -DL-cyclobutylglycine DL-Cyclobutylglycine t-butyl ester Hydrochloride 150 mg and CDI 165 mg were suspended in dry THF (5 ml) under a nitrogen atmosphere, and TEA was cooled with ice.
0.14 ml was added dropwise over 5 minutes, and then the mixture was stirred at the same temperature for 1 hour. 2,6-dimethylpiperidine 0.23 ml
Was added under ice-cooling and then stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (30 ml), 10% citric acid (30 ml) and saturated aqueous sodium hydrogen carbonate (30 ml).
Then, it was washed successively with saturated saline (30 ml), dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. This was dissolved in TFA (10 ml) and stirred at room temperature for 1 hour. The reaction solution was evaporated to dryness under reduced pressure to obtain 224 mg of a target crude product as a pale yellow powder.

FAB-MS (m / e, (C ₁₄ H ₂₄ N ₂ O ₃
+ H) ⁺ ): 269 (48-b) Synthesis of Compound 68 48 mg of 2,6-dimethylpiperidinocarbonyl-DL-cyclobutylglycine obtained in Example (48-a) and Example (15-d) H-DTrp (2-Br) -obtained in
53 mg of DNle-OMe was added to dichloromethane (3 m
l) and adjusted to pH 7 by adding NMM under ice-cooling, then HOBT · H ₂ O 25 mg and EDCI · HC
l 31 mg was added, and the mixture was stirred under ice cooling for 30 minutes and at room temperature for 1.5 hours. 30 ml of reaction solution in dichloromethane
Diluted with saturated aqueous sodium hydrogen carbonate (15 ml), 1N hydrochloric acid (15
ml) and saturated brine (15 ml), and dried over anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck, Inc. silica gel 60F ₂₅₄ / hexane: ethyl acetate = 1: 2) to obtain 36 mg of the title compound as a pale yellow powder.

Melting point: 99-108 ° C. IR (KBr, cm ⁻¹ ): 3282, 2933, 286
0,1743,1655,1620,1508,145
0, 1387, 1340, 743, 609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 660.2761 Measured value 660.2736 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, t, J = 7.2Hz), 1.17 (3
H, d, J = 7.1 Hz), 1.18 (3H, d, J =
7.1 Hz), 1.02-1.97 (18H, m),
2.43-2.61 (1H, m), 3.22 (1H, d
d, J = 7.0 Hz, 14.6 Hz), 3.30 (1
H, dd, J = 7.0 Hz, 14.6 Hz), 3.62
(3H, s), 3.95-4.05 (2H, m), 4.
12-4.22 (1H, m), 4.35-4.44 (1
H, m), 4.70-4.81 (2H, m), 6.43
(1H, d, J = 8.6 Hz), 6.96 (1H, d,
J = 7.6 Hz), 7.10 (1H, t, J = 7.4H)
z), 7.16 (1H, t, J = 7.4 Hz), 7.2
7 (1H, d, J = 7.4Hz), 7.64 (1H,
d, J = 7.4 Hz), 8.15 (1H, s) (48-c) Synthesis of Compound 69 30 mg of Compound 68 obtained in Example (48-b) was dissolved in methanol (1 ml), and cooled under ice-cooling. To the above, 0.2 ml of 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 5 hours. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 26 mg of the title compound as a colorless powder.

Melting point: 151-161 ° C IR (KBr, cm ^-1 ): 3396, 3271, 293
7,2868,1718,1657,1620,151
6,1450,1388,1340,1247,74
3,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₄ BrN ₅ O ₅
+ H) as ⁺ ): Calculated value 646.2604 Measured value 646.2601 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.84 (3H, t, J = 6.8Hz), 1.0
4 (3H, d, J = 6.7Hz), 1.05 (3H,
d, J = 6.7 Hz), 1.12-1.79 (18H,
m), 2.21-2.39 (1H, m), 2.85 (1
H, dd, J = 10.0 Hz, 14.4 Hz), 3.1
8 (1H, dd, J = 4.1Hz, 14.4Hz),
3.88-4.17 (4H, m), 4.50-4.65
(1H, m), 5.90 (1H, d, J = 6.8H
z), 6.96 (1H, t, J = 7.4 Hz), 7.0
4 (1H, t, J = 7.4Hz), 7.21 (1H,
d, J = 7.4 Hz), 7.63 (1H, d, J = 7.
4Hz), 7.95 (1H, d, J = 5.8Hz),
8.06 (1H, d, J = 9.0Hz), 11.55
(1H, s) Example 49 Synthesis of Compounds 70 and 71 H-Cprg-OBzl · in Example (15-f)
Example (15-f) using (2-methylcyclopropyl) glycine benzyl ester hydrochloride instead of HCl.
And the same reaction as (15-g) was performed to obtain the title compound.

Compound 70 IR (KBr, cm ^-1 ): 3396, 3280, 295
2,2869, 1741, 1658, 1619, 150
2,1450,1371, 1340,1247,114
5,1126,1047,742,609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₆ BrN ₅ O ₅
+ H) as a ^+): calculated 660.2761 measured ^{660.2752 1 H-NMR (300MHz,} CDCl 3, δppm):
0.16-0.28 (1H, m), 0.39-0.51
(2H, m), 0.61-1.80 (13H, m),
0.79 + 0.80 (3H, t × 2, J = 7.1H
z), 0.89 + 0.98 (3H, d × 2, J = 6.0
Hz), 1.17 (3H, d, J = 6.9Hz), 1.
19 (3H, d, J = 6.9 Hz), 3.18-3.4.
6 (3H, m), 3.63 (3H, s), 3.98-
4.23 (2H, m), 4.34-4.45 (1H,
m), 4.71-4.83 (1H, m), 4.93+
5.00 (1H, d × 2, J = 6.3 Hz), 6.33
(1H, d, J = 8.0 Hz), 6.98 + 7.04
(1H, d × 2, J = 7.9 Hz), 7.07-7.2
0 (2H, m), 7.28 (1H, d, J = 7.3H
z), 7.65 (1H, d, J = 7.3 Hz), 8.1
9 (1H, s) Compound 71 Melting point: 167-175 ° C. IR (KBr, cm ⁻¹ ): 3398, 3293, 293
5,2869,1650,1616,1510,138
8, 1340, 1247, 1143, 1126, 74
2,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₄ BrN ₅ O ₅
+ H) as ⁺ ): Calculated value 646.2604 Measured value 646.2595 ¹ H-NMR (500 MHz, CDCl ₃ , δppm):
-0.28-0.12 (1H, m), 0.10-0.
20 + 0.20-0.32 (1H, m × 2), 0.39
-0.50 (1H, m), 0.50-0.68 (1H,
m), 0.61 + 0.74 (3H, d × 2, J = 6.0
Hz), 0.80 (3H, t, J = 6.1Hz), 1.
05 (3H, d, J = 6.9Hz), 1.06 (3H,
d, J = 6.9 Hz), 1.00-1.75 (12H,
m), 2.82-2.95 (1H, m), 3.12+
3.14 (1H, dd × 2, J = 4.8 Hz, 14.6
Hz), 3.60-3.71 (1H, m), 3.77-
3.88 (1H, m), 4.04-4.18 (2H,
m), 4.46-4.60 (1H, m), 5.95+
6.03 (1H, d × 2, J = 7.5 Hz), 6.96
(1H, t, J = 7.7 Hz), 7.03 (1H, t,
J = 7.7 Hz), 7.22 (1H, d, J = 7.7H
z), 7.55 (1H, d × 2, J = 7.5 Hz),
7.63 + 7.64 (1H, d × 2, J = 7.7H
z), 8.04 + 8.08 (1H, d × 2, J = 8.7.
Hz), 11.61 + 11.62 (1H, s × 2) Example 50 Synthesis of compounds 72, 73, 74 and 75 DL-cyclobutylglycine t-butyl ester hydrochloride in Example (48-a) (2,2-Dimethylcyclopropyl) glycine t-butyl ester Hydrochloride was replaced with the same reaction as in Examples (48-a), (48-b) and (48-c) to obtain the title compound.

Compound 72 High resolution FAB-MS (m / e, (C ₃₃ H ₄₈ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 674.2917 Measured value 674.2929 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.23 (1H, t, J = 4.6Hz), 0.46 (1
H, dd, J = 4.6 Hz, 8.3 Hz), 0.83
(3H, t, J = 7.1Hz), 0.92 (3H,
s), 1.02 (3H, s), 1.19 (6H, d, J
= 6.8 Hz), 0.88-1.84 (13H, m),
3.18-3.37 (2H, m), 3.62 (3H,
s), 3.68 (1H, dd, J = 5.8Hz, 10.
2 Hz), 4.00-4.25 (2H, m), 4.36
-4.58 (1H, m), 4.74-4.85 (1H,
m), 4.98 (1H, d, J = 5.8Hz), 6.6
2 (1H, d, J = 8.1Hz), 6.83 (1H,
d, J = 7.5 Hz), 7.09 (1H, t, J = 7.
3Hz), 7.15 (1H, t, J = 7.3Hz),
7.26 (1H, d, J = 7.3 Hz), 7.66 (1
H, d, J = 7.3 Hz), 8.26 (1 H, s) compound 73 IR (KBr, cm ⁻¹ ): 3405, 3272, 293
7,2869,1741,1654,1619,151
7, 1450, 1340, 1145, 1124, 74
2,609 High resolution FAB-MS (m / e, (C ₃₃ H ₄₈ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 674.2917 Measured value 674.2936 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.16 (1H, t, J = 5.0Hz), 0.42 (1
H, dd, J = 5.0 Hz, 8.6 Hz), 0.80
(3H, t, J = 7.1Hz), 1.03 (3H,
s), 1.07 (3H, s), 1.16 (3H, d, J
= 7.2 Hz), 1.19 (3H, d, J = 7.2H)
z), 0.83-1.80 (13H, m), 3.27.
(1H, dd, J = 6.2Hz, 14.7Hz), 3.
38 (1H, dd, J = 6.5Hz, 14.7Hz),
3.32-3.40 (1H, m), 3.63 (3H,
s), 3.90-4.02 (1H, m), 4.13-
4.26 (1H, m), 4.36-4.47 (1H,
m), 4.75-4.85 (2H, m), 6.26 (1
H, d, J = 8.5 Hz), 7.09 (1H, t, J =
7.2 Hz), 7.16 (1H, t, J = 7.2H
z), 7.22-7.30 (1H, m), 7.27 (1
H, d, J = 7.2 Hz), 7.65 (1H, d, J =
7.2 Hz), 8.14 (1H, s) Compound 74 Melting point: 150 ° C. dec. IR (KBr, cm ^-1 ): 3398, 3276, 293
7,2869,1718,1656,1619,151
7, 1450, 1241, 1139, 1126, 74
2,686,609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₆ BrN ₅ O ₅
+ H) as a ^+): calculated 660.2761 measured ^{660.2752 1 H-NMR (300MHz,} DMSO-d 6, δpp
m): 0.02 (1H, t, J = 4.5Hz), 0.2
6 (1H, dd, J = 4.5Hz, 9.0Hz), 0.
75 (3H, s), 0.84 (3H, s), 0.82
(3H, t, J = 4.5Hz), 1.03 (3H, d,
J = 7.0 Hz), 1.06 (3H, d, J = 7.0H
z), 0.68-1.75 (13H, m), 2.92
(1H, dd, J = 9.0Hz, 14.5Hz), 3.
15 (1H, dd, J = 4.7Hz, 14.5Hz),
3.50-3.64 (1H, m), 3.92-4.20
(3H, m), 4.58-4.70 (1H, m), 6.
37 (1H, d, J = 6.8Hz), 6.94 (1H,
t, J = 7.6 Hz), 7.03 (1H, t, J = 7.
6Hz), 7.21 (1H, d, J = 7.6Hz),
7.58 (1H, d, J = 7.6Hz), 7.63 (1
H, d, J = 8.8 Hz), 8.03 (1H, d, J =
3.4 Hz), 11.57 (1 H, s) compound 75 melting point: 160 ° C. dec. IR (KBr, cm ^-1 ): 3394, 3291, 293
7,2869,1716,1652,1621,151
7, 1450, 1340, 1241, 1143, 112
4,742,609 High resolution FAB-MS (m / e, (C ₃₂ H ₄₆ BrN ₅ O ₅
+ H) ⁺ ): Calculated value 660.2761 Measured value 660.2792 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): -0.21 -0.10 (1H, m), -0.0
4 ~ 0.10 (1H, m), 0.59-0.73 (1
H, m), 0.83 (3H, t, J = 6.9Hz),
0.89 (3H, s), 0.96 (3H, s), 1.0
6 (6H, d, J = 6.8Hz), 0.80-1.78
(12H, m), 2.87 (1H, dd, J = 9.8H
z, 14.4 Hz), 3.15-3.52 (2H,
m), 3.90-4.05 (1H, m), 4.05-
4.23 (2H, m), 4.45-4.58 (1H,
m), 6.36 (1H, d, J = 6.1Hz), 6.9
5 (1H, t, J = 7.5Hz), 7.04 (1H,
t, J = 7.5 Hz), 7.22 (1H, d, J = 7.
5Hz), 7.64 (1H, d, J = 7.5Hz),
8.00 (2H, d, J = 9.2Hz), 11.56
(1H, s) Example 51 Synthesis of Compound 76 (51-a) H-DTrp (2-Me) -DNle-
Synthesis of OMe α-Nt-butoxycarbonyl-2-methyl-DL-
Tryptophan 63.7 mg and H-DNle-OM
e • HCl 36.3 mg with dichloromethane (1 ml)
Dissolve in water, and under ice cooling, NMM 22 μl, HOBT · H ₂
O 30.6 mg and EDCI.HCl 42.2 mg
Was added and the mixture was stirred at the same temperature for 1 hour and at room temperature for 1 hour. Dichloromethane (20 ml) was added to the reaction mixture to dilute it, and saturated aqueous sodium hydrogen carbonate (20 ml) and 10% aqueous citric acid solution (20 m) were added.
l) and saturated saline (20 ml) were sequentially washed, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (Merck & Co., Inc. silica gel 60 / hexane: ethyl acetate = 2: 1) and Boc-DL-Trp (2-Me) -DNle.
59.7 mg of -OMe was obtained. This product (57.8 mg) was dissolved in formic acid (3.3 ml), and the mixture was stirred at room temperature for 1 hr. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in dichloromethane (20 ml), washed with saturated aqueous sodium hydrogen carbonate (20 ml) and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel chromatography (Merck silica gel 6
The product was purified with 0 / chloroform: methanol = 50: 1) to obtain 19.6 mg of the desired product.

FAB-MS (m / e, (C ₁₉ H ₂₇ N ₃ O ₃
+ H) as ⁺ ): 346 (51-b) 2,6-dimethylpiperidinocarbonyl
-Leu-DTrp (2-Me) -DNle-OMe
H-DTrp (2-Me) -obtained in Synthesis Example (51-a)
DNle-OMe (19.5 mg) and 2,6-dimethylpiperidinocarbonyl-Leu-OH (15.3 mg) were dissolved in dichloromethane (0.6 ml), and HOBT was cooled with ice.
· H ₂ O 8.7 mg, and EDCI · HCl 13.0
mg was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 3 hours.
Dichloromethane was added to the reaction mixture (20 ml),
Saturated sodium bicarbonate water (20 ml), 10% citric acid aqueous solution (20
ml) and saturated saline (20 ml), and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by medium pressure liquid chromatography (Merck Rover Column Licroprep SI60 / hexane: ethyl acetate = 1: 2) to give the title compound 1.
25 g was obtained. The residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / ethyl acetate) to obtain 24.3 mg of the desired product.

FAB-MS (m / e, (C ₃₃ H ₅₁ N ₅ O ₅
+ H) ⁺ ): 598 (51-c) Synthesis of Compound 76 2,6-Dimethylpiperidinocarbonyl-Leu-DTrp (2-Me) -DNle obtained in Example (51-b).
-OMe (23.3 mg) was dissolved in methanol (0.48 ml), and 1N aqueous sodium hydroxide solution (0.12 m) was added under ice cooling.
1 was added and the mixture was stirred at the same temperature for 10 minutes and at room temperature for 3 hours. After adding 0.12 ml of 1N hydrochloric acid to the reaction solution, it was concentrated under reduced pressure. The residue was dissolved in 1 ml of water, passed through a Sepppack C18 cartridge, the cartridge was washed with water, and then the desired product was eluted with methanol. The eluent was evaporated to dryness under reduced pressure to obtain 22.4 mg of the title compound as a pale yellow powder.

Melting point: 118-125 ° C. IR (KBr, cm ^-1 ): 3388, 2956, 293
7,1657,1622,1524,1464,743 High resolution FAB-MS (m / e, (C ₃₂ H ₄₉ N ₅ O ₅ +
H) as ⁺ ): Calculated value 584.3812 Measured value 584.3787 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.70 (3H, d, J = 6.9Hz), 0.7
3 (3H, d, J = 6.9Hz), 0.85 (3H,
t, J = 6.8 Hz), 1.03 (3H, d, J = 6.
3Hz), 1.05 (3H, d, J = 6.3Hz),
1.00-1.80 (15H, m), 2.30 (3H,
s), 2.80 (1H, dd, J = 10.1Hz, 1
4.4 Hz), 3.17 (1H, dd, J = 3.6H)
z, 14.4 Hz), 3.90-4.00 (1H,
m), 4.00-4.20 (3H, m), 4.40-
4.45 (1H, m), 6.07 (1H, d, J = 6.
7Hz), 6.87 (1H, t, J = 7.4Hz),
6.93 (1H, t, J = 7.4Hz), 7.16 (1
H, d, J = 7.4 Hz), 7.51 (1H, d, J =
7.4 Hz), 7.96 (1H, d, J = 9.0H
z), 8.08 (1H, d, J = 7.3 Hz), 10.
62 (1H, s) In Examples 52 to 53 below, 2,6-dimethylpiperidinocarbonyl-Leu- in Example (51-b) was used.
OH was replaced by the corresponding carboxylic acid, and
-Compounds 77 to 80 were obtained by performing the same reaction as in (b) and (51-c). Example 52 Compound 77 Melting point: 79-83 ° C IR (KBr, cm ^-1 ): 3294, 2954, 292
9,1741,1651, 1626,1535,146
4,1439,1211,741 High resolution FAB-MS (m / e, (C ₃₂ H ₄₉ N ₅ O ₅ +
H) ⁺ ): Calculated value 684.3812 Measured value 684.38311 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.82 (3H, t, J = 7.2Hz), 0.86 (3
H, d, J = 5.9 Hz), 0.87 (3H, d, J =
6.2 Hz), 1.07-1.73 (17H, m),
2.39 (3H, s), 3.19-3.39 (4H,
m), 3.12 (1H, dd, J = 7.4 Hz, 14.
6Hz), 3.40 (1H, dd, J = 5.2Hz, 1
4.6 Hz), 3.60 (3H, s), 3.94-3.
99 (1H, m), 4.34-4.41 (1H, m),
4.62 (1H, d, J = 7.0Hz), 4.71-
4.78 (1H, m), 6.49 (1H, d, J = 8.
6 Hz), 6.93 (1 H, d, J = 7.5 Hz),
7.04 (1H, t, J = 7.3Hz), 7.10 (1
H, t, J = 7.3 Hz), 7.25 (1H, d, J =
7.3 Hz), 7.53 (1H, d, J = 7.3H)
z), 7.87 (1H, s) compound 78 melting point: 136-142 ° C IR (KBr, cm ^-1 ): 3321, 954, 162
5,1529,1464,1302,742 High resolution FAB-MS (m / e, (C ₃₁ H ₄₇ N ₅ O ₅ +
H) ⁺ ): Calculated value 570.3655 Measured value 570.3652 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.73 (3H, d, J = 6.1Hz), 0.7
5 (3H, d, J = 5.4Hz), 0.82 (3H,
t, J = 6.7 Hz), 1.09-1.71 (17H,
m), 2.27 (3H, s), 2.83 (1H, dd,
J = 8.8Hz, 14.5Hz), 3.08 (1H, d
d, J = 4.5 Hz, 14.5 Hz), 3.18-3.
33 (4H, m), 3.86-3.92 (1H, m),
4.03-4.11 (1H, m), 4.38-4.46
(1H, m), 6.02 (1H, d, J = 7.8H
z), 6.85 (1H, t, J = 7.1 Hz), 6.9.
2 (1H, t, J = 7.1Hz), 7.15 (1H,
d, J = 7.1 Hz), 7.48 (1H, d, J = 7.
1Hz), 7.70 (1H, d, J = 5.5Hz),
7.89 (1H, d, J = 8.8Hz), 10.64
(1H, s), Example 53 Compound 79 Melting point: 88-93 ° C IR (KBr, cm ^-1 ): 3396, 3304, 293
7,1741,1651, 1620,1524,150
2,742 High resolution FAB-MS (m / e, (C ₃₂ H ₄₇ N ₅ O ₅ +
H) ⁺ ): Calculated value 582.3655 Measured value 582.3681 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.28-0.35 (2H, m), 0.50-0.57
(2H, m), 0.81 (3H, t, J = 7.1H
z), 0.86-0.91 (1H, m), 1.04-
1.76 (12H, m), 1.17 (3H, d, J =
7.1 Hz), 1.18 (3H, d, J = 7.1H)
z), 2.40 (3H, s), 3.13 (1H, dd,
J = 7.4 Hz, 14.5 Hz), 3.22-3.27.
(1H, m), 3.47 (1H, dd, J = 4.7H
z, 14.5 Hz), 3.60 (3H, s), 4.02
-4.16 (2H, m), 4.32-4.40 (1H,
m), 4.73-4.81 (1H, m), 5.03 (1
H, d, J = 5.9 Hz), 6.39 (1H, d, J =
8.5 Hz, 6.98 (1H, d, J = 7.6H
z), 7.06 (1H, t, J = 7.0Hz), 7.1
0 (1H, t, J = 7.0Hz), 7.26 (1H,
d, J = 7.0 Hz), 7.56 (1H, d, J = 7.
0 Hz), 7.87 (1 H, s) compound 80 Melting point: 137-141 ° C IR (KBr, cm ^-1 ): 3396, 2937, 172
6,1658,1626,1514,743,609 High resolution FAB-MS (m / e, (C ₃₁ H ₄₅ N ₅ O ₅ +
H) as ⁺ ): Calculated value 568.3499 Measured value 568.3527 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.03-0.25 (4H, m), 0.82 (3
H, t, J = 6.8 Hz), 0.83-0.90 (1
H, m), 1.05 (6H, d, J = 6.9Hz),
1.06-1.73 (12H, m), 2.30 (3H,
s), 2.83 (1H, dd, J = 9.1 Hz, 14.
5Hz), 3.18 (1H, dd, J = 4.0Hz, 1
4.5 Hz), 3.54 to 3.60 (1 H, m), 3.
99-4.16 (3H, m), 4.44-4.49 (1
H, m), 6.21 (1H, d, J = 6.9 Hz),
6.87 (1H, t, J = 7.4Hz), 6.93 (1
H, t, J = 7.4 Hz), 7.16 (1H, d, J =
7.4 Hz), 7.49 (1H, d, J = 7.4H)
z), 7.94-8.01 (2H, m), 10.64
(1H, s) Example 54 Synthesis of compounds 81 and 82 H-DNle-OMe.H in Example (51-a)
The title compound was obtained by performing the same reactions as in Examples (51-a), (51-b) and (51-c) by replacing Cl with H-DMet-OMe.HCl.

Compound 81 Melting point: 86-89 ° C IR (KBr, cm ^-1 ): 3398, 3294, 293
7,1741, 1659, 1614, 1524, 112
6,742 High resolution FAB-MS (m / e, (C ₃₂ H ₄₉ N ₅ O ₅ S +
H) as ⁺ ): Calculated value 616.3532 Measured value 616.35311 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.86 (3H, d, J = 6.1Hz), 0.88 (3
H, d, J = 6.1 Hz), 1.14 (3H, d, J =
7.1 Hz), 1.16 (3H, d, J = 7.1H)
z), 1.23-1.71 (9H, m,), 1.85-
2.10 (2H, m), 1.99 (3H, s), 2.2
3-2.33 (2H, m), 2.41 (3H, s),
3.13 (1H, dd, J = 7.3Hz, 14.6H
z), 3.45 (1H, dd, J = 5.1 Hz, 14.
6 Hz), 3.62 (3H, s), 3.88-4.12.
(3H, m), 4.48-4.56 (1H, m), 4.
68 (1H, d, J = 6.8Hz), 4.75-4.8
2 (1H, m), 6.41 (1H, d, J = 9.1H
z), 7.05 (1H, t, J = 7.1Hz), 7.1
1 (1H, t, J = 7.1Hz), 7.21 (1H,
d, J = 7.2 Hz), 7.27 (1H, d, J = 7.
1Hz), 7.51 (1H, d, J = 7.1Hz),
7.91 (1H, s) Compound 82 Melting point: 139-143 ° C IR (KBr, cm ^-1 ): 3396, 3305, 293
7,1651, 1614, 1440, 1389, 743 High resolution FAB-MS (m / e, (C ₃₁ H ₄₇ N ₅ O ₅ S +
H) ⁺ ): Calculated value 602.3376 Measured value 602.3389 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.72 (3H, d, J = 5.9Hz), 0.7
4 (3H, d, J = 5.6Hz), 0.76-0.84
(1H, m), 1.04 (3H, d, J = 6.5H
z), 1.05 (3H, d, J = 6.9Hz), 1.2
2-1.75 (8H, m,), 1.88-1.98 (2
H, m), 2.00 (3H, s), 2.28 (3H,
s), 2.43 (2H, t, J = 7.8Hz), 2.8
1 (1H, dd, J = 9.3Hz, 14.4Hz),
3.13 (1H, dd, J = 4.1Hz, 14.4H
z), 3.99-4.18 (4H, m), 4.38-
4.46 (1H, m), 6.08 (1H, d, J = 7.
3Hz), 6.86 (1H, t, J = 7.4Hz),
6.93 (1H, t, J = 7.4Hz), 7.16 (1
H, d, J = 7.4 Hz), 7.48 (1H, d, J =
7.4 Hz), 7.84 (1H, d, J = 7.1H
z), 7.96 (1H, d, J = 8.6 Hz), 10.
65 (1H, s) Example 55 Synthesis of compounds 83 and 84 H-DNle-OMe.H in Example (51-a)
Cl in H-DMet-OMe.HCl, Example (51
In Example (51-a), (5), 2,6-dimethylpiperidinocarbonyl-Leu-OH in -b) was replaced with 2,6-dimethylpiperidinocarbonyl-Cprg-OH.
The title compound was obtained by performing the same reaction as in 1-b) and (51-c).

Compound 83 IR (KBr, cm ^-1 ): 3269, 2949, 174
0,1660,1599,1435,1375,134
0,1076,833,752,606 High resolution FAB-MS (m / e, (C ₃₁ H ₄₅ N ₅ O ₅ S +
H) ⁺ ): Calculated value 600.3220 Measured value 600.3223 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.20-0.63 (4H, m), 1.16 (3H,
d, J = 7.1 Hz), 1.17 (3H, d, J = 7.
1 Hz), 1.03-1.21 (1H, m), 1.42
-1.78 (6H, m), 1.83-2.12 (2H,
m), 1.98 (3H, s), 2.18-2.33 (2
H, m), 2.41 (3H, s), 3.10-3.18.
(2H, m), 3.51 (1H, dd, J = 4.9H
z, 14.7 Hz), 3.61 (3H, s), 3.97.
-4.17 (2H, m), 4.48-4.55 (1H,
m), 4.76-4.83 (1H, m), 4.99 (1
H, d, J = 5.4 Hz), 6.31 (1H, d, J =
8.7 Hz), 7.07 (1H, dt, J = 1.5H
z, 7.3 Hz), 7.11 (1H, dt, J = 1.5)
Hz, 7.3 Hz), 7.26-7.30 (2H,
m), 7.54 (1H, dd, J = 1.5Hz, 7.3)
Hz), 7.90 (1H, s) compound 84 Melting point: 118-121 ° C IR (KBr, cm ^-1 ): 3294, 2927, 172
2,1659,1614,1520,1381,134
0,1074,748,606 High resolution FAB-MS (m / e, (C ₃₀ H ₄₃ N ₅ O ₅ S +
H) As ^+): calculated 586.3063 measured ^{586.3055 1 H-NMR (400MHz,} DMSO-d 6, δpp
m): 0.00-0.34 (4H, m), 0.84-
0.88 (1H, m), 1.04 (3H, d, J = 6.
8Hz), 1.06 (3H, d, J = 6.8Hz),
1.20-1.66 (6H, m), 1.95-1.98
(2H, m), 2.01 (3H, s), 2.32 (3
H, s), 2.32-2.54 (2H, m), 2.81.
(1H, dd, J = 9.6Hz, 14.5Hz), 3.
16-3.33 (2H, m), 4.09-4.15 (2
H, m), 4.24-4.27 (1H, m), 4.43.
-4.49 (1H, m), 6.26 (1H, d, J =
6.4 Hz), 6.89 (1H, t, J = 7.8H
z), 6.94 (1H, t, J = 7.8Hz), 7.1
7 (1H, d, J = 7.8Hz), 7.49 (1H,
d, J = 7.8 Hz), 7.99 (1H, d, J = 8.
8 Hz), 8.15 (1H, d, J = 7.3 Hz), 1
0.64 (1H, s) Example 56 Synthesis of compounds 85 and 86 (56-a) Synthesis of compound 85 α-Nt-butoxycarbonyl-2-methyl-DL-
Tryptophan 100 mg and H-DHis-OMe.
91 mg of 2HCl was dissolved in DMF (5 ml), 86 μl of NMM, 58 mg of HOBT · H ₂ O and 72 mg of EDCI · HCl were added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 4 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in chloroform (20 ml), and saturated aqueous sodium hydrogen carbonate (20 m) was added.
l) and saturated saline (20 ml) were sequentially washed, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (Merck silica gel 60 / chloroform: methanol = 30:
Purified in 1) and Boc-DL-Trp (2-Me) -D
105 mg of His-OMe was obtained. This thing 100mg
Was dissolved in 5 ml of formic acid and stirred at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in methanol, 81 mg of p-toluenesulfonic acid monohydrate was added, and the solution was dried under reduced pressure. 69 mg of the above product and 2,6-dimethylpiperidinocarbonyl-Leu-OH in DMF (5 m
l), dissolve in ice-cooled NMM 47 μl, HOBT.
H ₂ O (39 mg) and EDCI · HCl (49 mg) were added, and the mixture was stirred at the same temperature for 3 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in chloroform (50 ml), and saturated aqueous sodium hydrogen carbonate solution (20
ml) and saturated saline (20 ml), and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol =
The product was purified by 10: 1) to obtain 40 mg of the title compound as a pale yellow powder.

Melting point: 119-124 ° C. IR (KBr, cm ^-1 ): 3278, 2937, 287
0,1741,1651, 1620,1527,743 High resolution FAB-MS (m / e, (C ₃₃ H ₄₇ N ₇ O ₅ +
H) ⁺ ): Calculated value 622.3717 Measured value 622.3710 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.90 (3H, d, J = 6.5Hz), 0.94 (3
H, d, J = 6.1 Hz), 1.12 (3H, d, J =
7.1 Hz), 1.18 (3H, d, J = 6.8H)
z), 1.22-1.75 (9H, m,), 2.15.
(3H, s), 2.88 (1H, dd, J = 10.7H
z, 14.7 Hz), 3.11 (1H, dd, J = 6.
4Hz, 14.7Hz), 3.22 (1H, dd, J =
3.7 Hz, 14.7 Hz), 3.38 (1H, dd,
J = 4.6 Hz, 14.7 Hz), 3.68 (3H,
s), 3.73-3.80 (1H, m), 3.95-
4.08 (2H, m), 4.42-4.51 (1H,
m), 4.62-4.69 (1H, m), 4.74 (1
H, d, J = 6.4 Hz), 6.50 (1H, d, J =
7.1 Hz), 6.76 (1 H, s), 7.06 (1
H, t, J = 6.9 Hz), 7.06 (1H, s),
7.12 (1H, t, J = 6.9Hz), 7.25 (1
H, d, J = 6.9 Hz), 7.35 (1H, d, J =
7.5 Hz), 7.46 (1H, d, J = 6.9H)
z), 8.39 (1H, brs) (56-b) Synthesis of compound 86 35 mg of compound 85 obtained in Example (56-a) was dissolved in methanol (0.4 ml), and 1N hydroxylated under ice cooling. 85 μl of an aqueous sodium solution was added, and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 3 hours. After adding 85 μl of 1N hydrochloric acid to the reaction solution, it was concentrated under reduced pressure. Suspend the residue in water and use SEPPACK
After passing through a C18 cartridge and washing the cartridge with water, the target substance was eluted with methanol. The eluent was evaporated to dryness under reduced pressure to obtain 32 mg of the title compound as a pale yellow powder.

Melting point: 163-166 ° C. IR (KBr, cm ⁻¹ ): 3406, 3296, 295
1,1643, 1618, 1513, 1390, 742 High resolution FAB-MS (m / e, (C ₃₂ H ₄₅ N ₇ O ₅ +
H) as ⁺ ): Calculated value 608.3560 Measured value 608.3558 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.72 (3H, d, J = 6.2Hz), 0.7
3 (3H, d, J = 6.2Hz), 1.04 (3H,
d, J = 6.7 Hz), 1.06 (3H, d, J = 6.
7 Hz), 0.80-1.75 (9H, m,), 2.2
9 (3H, s), 2.78 (1H, dd, J = 10.3)
Hz, 14.4 Hz), 2.87-3.01 (2H,
m), 3.13 (1H, dd, J = 3.6 Hz, 14.
4 Hz), 4.01-4.18 (3H, m), 4.28
-4.35 (1H, m), 4.45-4.50 (1H,
m), 6.07 (1H, d, J = 6.5 Hz), 6.8
0 (1H, s), 6.87 (1H, t, J = 7.2H
z), 6.93 (1H, t, J = 7.2 Hz), 7.1
6 (1H, d, J = 7.2 Hz), 7.51 (1H,
d, J = 7.2 Hz), 7.53 (1 H, s), 7.9
9 (1H, d, J = 8.6Hz), 8.20 (1H,
d, J = 6.5 Hz), 10.63 (1 H, s) Example 57 Synthesis of compounds 87 and 88 (57-a) α-N-1-bis-t-butoxycarbo
Nyl-2- (2-trimethylsilylethynyl) -D-to
Synthesis of liptophan methyl ester α-N, 1-bis-t-butoxycarbonyl-2-bromo-D-tryptophan methyl ester obtained in Example (15-a) 994 mg, copper (I) iodide 115 mg and tetrakis ( 232 mg of triphenylphosphine) palladium (0) was dissolved in 10 ml of dry diethylamine, and trimethylsilylacetylene 0.85 was added under a nitrogen atmosphere.
ml was added, and the mixture was stirred at 40 ° C. for 9 hours and at room temperature overnight. Dry ether (60 ml) was added to the reaction solution, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue is ether (60 m
l), washed with 10% aqueous citric acid solution (50 ml), saturated aqueous sodium hydrogen carbonate (50 ml) and saturated brine (50 ml) successively, dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. . The residue was subjected to medium pressure liquid chromatography (Merck Rover Column Licroprep).
The product was purified with SI60 / hexane: ethyl acetate = 10: 1) to obtain 782 mg of the desired product.

FAB-MS (m / e, (C ₂₇ H ₃₈ N ₂ O ₆
Si) +): 514 (57-b) α-Nt-butoxycarbonyl-2-
Synthesis of ethynyl-D-tryptophan α-N-1-bis-t-butoxycarbonyl-2- (2-trimethylsilylethynyl) -D-tryptophan methyl ester obtained in Example (57-a) 400 mg
Was dissolved in methanol (10 ml), 4N aqueous sodium hydroxide solution (5 ml) was added under an argon atmosphere, and the mixture was stirred under ice cooling for 1 hr and at room temperature overnight. Methanol was distilled off under reduced pressure, citric acid was added to the residue to adjust the pH to 3, and the mixture was extracted with ethyl acetate (30 ml × 3). The ethyl acetate extraction layers were combined, washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure.
280 mg of the desired product was obtained.

FAB-MS (m / e, (C ₁₈ H ₂₀ N ₂ O ₄
+ H) as ⁺ ): 329 (57-c) Boc-DTrp (2-Et) -DNl
Synthesis of e-OMe 280 mg of α-Nt-butoxycarbonyl-2-ethynyl-D-tryptophan obtained in Example (57-b) and 156 mg of H-DNle-OMe · HCl were dissolved in 10 ml of dichloromethane and cooled under ice-cooling. To NMM 94μ
1, HOBT · H ₂ O 179 mg and EDCI · HC
1 224 mg was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 0.5 hour. The reaction mixture was diluted with ethyl acetate (60 ml), washed successively with saturated aqueous sodium hydrogen carbonate (30 ml), 10% aqueous citric acid solution (30 ml) and saturated brine (30 ml), and dried over anhydrous magnesium sulfate, The solvent was distilled off under reduced pressure. The residue was subjected to medium-pressure liquid chromatography (Merck Rover Column Licroprep SI6).
The product was purified with 0 / hexane: ethyl acetate = 2: 1) to obtain 303 mg of a pale yellow powder. 180 mg of the above product was dissolved in methanol (4 ml), 50 mg of 5% palladium / barium sulfate was added, and the mixture was stirred at room temperature for 3.5 hours under a hydrogen atmosphere at 1 atm. The catalyst was filtered off, and the filtrate was dried under reduced pressure to give the desired product (166 mg).

FAB-MS (m / e, (C ₂₅ H ₃₇ N
₃ O ₄₎ as a ^{+): 459 (57-d} ) obtained in Synthesis Example of Compound 87 (57-c) Boc- DTrp (2-E
t) -DNle-OMe 160 mg was dissolved in formic acid 5 ml and stirred at room temperature for 1.5 hours. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in ethyl acetate (20 ml), washed with saturated aqueous sodium hydrogen carbonate (20 ml × 2) and dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure to give a pale yellow amorphous substance (123 mg). Got 120 mg and 2.6 of this product
-Dimethylpiperidinocarbonyl-Leu-OH 10
Dissolve 0 mg in 5 ml of dichloromethane and add HO under ice cooling.
BT · H ₂ O 62 mg and EDCI · HCl 78 m
g was added, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. The reaction mixture was diluted with ethyl acetate (60 ml) and saturated aqueous sodium hydrogen carbonate (3
(0 ml), 10% aqueous citric acid solution (30 ml) and saturated brine (30 ml) were successively washed, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by medium-pressure liquid chromatography (Merck & Co., Ltd. Rover column Licroprep SI60 / hexane: ethyl acetate = 1: 2) to obtain 143 mg of the title compound as a pale yellow amorphous substance.

IR (KBr, cm ^-1 ): 3396, 32
93, 2956, 1743, 1652, 1619, 15
17,1465,1386,1149,1128,74
2,609 High resolution FAB-MS (m / e, (C ₃₄ H ₅₃ N ₅ O ₅ +
H) As ^+): calculated 612.4125 measured ^{612.4098 1 H-NMR (300MHz,} CDCl 3, δppm):
0.75-0.90 (9H, m), 1.16 (3H,
d, J = 7.1 Hz), 1.17 (3H, d, J = 7.
1Hz), 1.27 (3H, t, J = 7.8Hz),
1.02-1.82 (15H, m), 2.70-2.9
1 (2H, m), 3.15 (1H, dd, J = 7.5H
z, 14.5 Hz), 3.38 (1H, dd, J = 5.
9 Hz, 14.5 Hz), 3.60 (3H, s), 3.
91-4.20 (3H, m), 4.29-4.40 (1
H, m), 4.67-4.80 (2H, m), 6.44.
(1H, d, J = 8.5 Hz), 6.92 (1H, d,
J = 7.5 Hz), 7.05 (1H, dt, J = 1.2)
Hz, 7.6 Hz), 7.11 (1H, dt, J = 1.
2Hz, 7.6Hz), 7.21 (1H, dd, J =
1.2Hz, 7.6Hz), 7.53 (1H, dd, J
= 1.2 Hz, 7.6 Hz), 7.90 (1 H, s) (57-e) Synthesis of compound 88 43.4 mg of the compound 87 obtained in Example (57-d) was dissolved in methanol (2 ml), 1 ml of 1N sodium hydroxide aqueous solution was added under ice cooling, and the mixture was stirred at the same temperature for 1 hour and at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, 1N hydrochloric acid was added to the residue, and the precipitated crystals were collected by filtration and dried to obtain 36 mg of the title compound as a pale yellow powder.

Melting point: 140 ° C. dec. IR (KBr, cm ^-1 ): 3386, 3311, 295
8, 2871, 1716, 1654, 1621, 152
1, 1465, 1386, 1126, 742, 609 High resolution FAB-MS (m / e, (C ₃₃ H ₅₁ N ₅ O ₅ +
H) as ⁺ ): Calculated value 598.3968 Measured value 598.3964 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.71 (6H, d, J = 6.8Hz), 0.8
3 (3H, t, J = 6.7Hz), 1.03 (3H,
d, J = 6.3 Hz), 1.05 (3H, d, J = 6.
3Hz), 1.19 (3H, t, J = 7.6Hz),
0.95-1.76 (15H, m), 2.59-2.8
9 (3H, m), 3.18 (1H, dd, J = 4.8H
z, 14.6 Hz), 3.94-4.20 (4H,
m), 4.40-4.48 (1H, m), 6.07 (1
H, d, J = 7.3 Hz), 6.87 (1H, t, J =
7.4 Hz), 6.94 (1H, t, J = 7.4H
z), 7.18 (1H, d, J = 7.4 Hz), 7.5
3 (1H, d, J = 7.4Hz), 7.89 (1H, b
rs), 7.98 (1H, d, J = 9.8Hz), 1
0.64 (1H, s) Example 58 Synthesis of Compound 89 2,6-Dimethylpiperidinocarbonyl-Leu-OH in Example (57-d) was converted to 2,6-dimethylpiperidinocarbonyl-Cprg-OH. Example (57)
The title compound was obtained by performing the same reaction as in (d) and (57-e).

Melting point: 118-128 ° C. IR (KBr, cm ⁻¹ ): 3390, 3324, 293
5,2871, 1716, 1652, 1621, 151
9,1463,1375,1247,1143,74
2,607 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): -0.01 to 0.30 (5H, m), 0.84
(3H, t, J = 6.8Hz), 1.05 (3H, d,
J = 6.8 Hz), 1.06 (3H, d, J = 6.8H)
z), 1.20 (3H, t, J = 7.7Hz), 1.0
0-1.80 (12H, m), 2.55-2.90 (3
H, m), 3.14-3.52 (2H, m), 4.00.
-4.21 (3H, m), 4.40-4.53 (1H,
m), 6.23 (1H, d, J = 6.1Hz), 6.8
8 (1H, t, J = 7.4Hz), 6.95 (1H,
t, J = 7.4 Hz), 7.19 (1H, d, J = 7.
4Hz), 7.53 (1H, d, J = 7.4Hz),
7.98 (1H, d, J = 8.8Hz), 8.10 (1
H, d, J = 7.3 Hz), 10.64 (1H, s),
12.35 (1H, brs) Example 59 Synthesis of compounds 90 and 91 (59-a) 2,6-dimethylpiperidinocarbonyl
Synthesis of -Cprg-DTrp (2-Me) -OH 133 mg of Z-DTrp (2-Me) -OMe was dissolved in methanol (5 ml), and 10 mg of Pd-C was 30 mg.
Was added and the mixture was vigorously stirred at room temperature for 8 hours under a hydrogen atmosphere of 1 atm. The catalyst was filtered off, and the filtrate was evaporated to dryness under reduced pressure to obtain 96.2 mg of a pale yellow amorphous substance. This product was 92.6 mg and 2,6-dimethylpiperidinocarbonyl-Cprg.
-OH was dissolved in DMF (5 ml), and HOBT was cooled with ice.
· H ₂ O73mg and EDCI · HCl 92 mg was added at the same temperature for 1 hour, and stirred at room temperature overnight. The reaction mixture was diluted with ethyl acetate (50 ml), water (50 ml), 10%
Aqueous citric acid solution (50 ml), saturated aqueous sodium hydrogen carbonate (50 m
l), and washed with saturated saline (50 ml) successively,
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by medium-pressure liquid chromatography (Merck Rover Column Licroprep SI60 / Hexane: Ethyl acetate = 1: 1) to obtain colorless amorphous. This product was dissolved in methanol (2 ml), 0.5 ml of a 1N sodium hydroxide aqueous solution was added under ice cooling, and the mixture was stirred at the same temperature for 2.5 hours and at room temperature for 2 hours.
The reaction solution was concentrated under reduced pressure, and 10% citric acid (30 m
1) was added, and the mixture was extracted with ethyl acetate (15 ml × 3). The combined ethyl acetate extracts were saturated saline (15m).
After washing with 1) and drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure to obtain 75.9 mg of the desired product.

FAB-MS (m / e, (C ₂₅ H ₃₄ N ₄ O ₄
+ H) ⁺ ): 455 (59-b) Synthesis of Compound 90 2,6-Dimethylpiperidinocarbonyl-Cprg-DTrp (2-Me) -OH obtained in Example (59-a).
24.9 mg and H-DHis-OMe.2HCl
Dissolve 19.9 mg in DMF (1 ml) and add N under ice cooling.
MM 23 μl, HOBT · H ₂ O 12.6 mg and EDCI · HCl 15.8 mg were added, and the same temperature was applied for 3 hours.
Stir at room temperature for 6 hours. The reaction solution is ethyl acetate (50 m
l) diluted, washed with saturated aqueous sodium hydrogen carbonate (50 ml),
After drying over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / chloroform: methanol = 10: 1) to give the purified title compound 9.9mg at.

High resolution FAB-MS (m / e, (C ₃₂ H
₄₃ N ₇ O ₅ + H) ⁺ ): Calculated value 606.3404 Measured value 606.3390 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.23-0.33 (1H, m), 0.44-0.70
(3H, m), 1.13 (3H, d, J = 7.1H
z), 1.18 (3H, d, J = 7.1Hz), 1.0
7-1.28 (1H, m), 1.38-1.82 (6
H, m), 2.11 (3H, s), 2.89 (1H, d
d, J = 10.6 Hz, 14.7 Hz), 2.85-
2.98 (1H, m), 3.14 (1H, dd, J =
6.6 Hz, 14.7 Hz), 3.23 (1H, dd,
J = 4.0 Hz, 14.7 Hz), 3.45 (1H, d
d, J = 3.9 Hz, 14.7 Hz), 3.69 (3
H, s), 3.93-4.12 (2H, m), 4.38.
-4.50 (1H, m), 4.62-4.73 (1H,
m), 5.03 (1H, d, J = 5.2 Hz), 6.2
3 (1H, d, J = 7.5 Hz), 6.79 (1H,
s), 7.03-7.19 (3H, m), 7.23-
7.40 (1H, m), 7.33 (1H, d, J = 7.
4Hz), 7.49 (1H, d, J = 7.4Hz),
8.24 (1H, s) (59-c) Synthesis of Compound 91 9.2 mg of the compound 90 obtained in Example (59-b) was dissolved in methanol (0.3 ml), and 1N sodium hydroxide was added under ice cooling. 80 μl of an aqueous solution was added and the mixture was stirred at the same temperature for 30 minutes and at room temperature for 3 hours. After adding 85 μl of 1N hydrochloric acid to the reaction solution, it was concentrated under reduced pressure. The residue was suspended in water and passed through a Seppak C18 cartridge to wash the cartridge with water, and then the target product was eluted with methanol. The eluent was evaporated to dryness under reduced pressure to obtain 9.0 mg of the title compound as a pale yellow powder.

Melting point: 165-171 ° C. IR (KBr, cm ^-1 ): 3396, 3303, 315
5,2939,1648,1608,1513,138
8,1076,835,750,605 High resolution FAB-MS (m / e, (C ₃₁ H ₄₁ N ₇ O ₅ +
H) ⁺ ): Calculated value 592.3247 Measured value 592.3232 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.00-0.28 (4H, m), 0.80-
0.95 (1H, m), 1.06 (3H, d, J = 6.
6Hz), 1.07 (3H, d, J = 6.6Hz),
1.31-1.77 (6H, m), 2.30 (3H,
s), 2.70-3.60 (5H, m), 4.06-
4.21 (2H, m), 4.30-4.53 (2H,
m), 6.18 (1H, d, J = 6.3 Hz), 6.8
0 (1H, s), 6.86 (1H, t, J = 7.5H
z), 6.94 (1H, t, J = 7.5 Hz), 7.1
7 (1H, d, J = 7.5Hz), 7.51 (1H,
d, J = 7.5 Hz), 7.53 (1 H, s), 8.0
2 (1H, d, J = 8.6Hz), 8.27 (1H,
d, J = 7.0 Hz), 10.62 (1H, s) Example 60 Synthesis of compounds 92 and 93 HD-His-OMe in Example (59-b)
2HCl was replaced with D-3- (2-pyridyl) alanine methyl ester dihydrochloride to carry out the same reaction as in Examples (59-b) and (59-c) to obtain the title compound.

Compound 92 High resolution FAB-MS (m / e, (C ₃₄ H ₄₄ N ₆ O ₅ +
H) as ⁺ ): Calculated value 617.3451 Measured value 617.3441 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.28-0.37 (2H, m), 0.43-0.53
(2H, m), 0.98-1.12 (1H, m), 1.
18 (3H, d, J = 7.0Hz), 1.21 (3H,
d, J = 7.0 Hz), 1.40 to 1.80 (6H,
m), 2.28 (3H, s), 3.04-3.33 (4
H, m), 3.43 (1H, dd, J = 5.9 Hz,
8.9 Hz), 3.60 (3H, s), 4.05-4.
23 (2H, m), 4.69-4.83 (2H, m),
5.08 (1H, d, J = 5.9Hz), 6.55 (1
H, d, J = 8.1 Hz), 6.99 (1H, d, J =
7.7 Hz), 7.03-7.15 (3H, m), 7.
22-7.30 (1H, m), 7.35 (1H, d, J
= 7.3 Hz), 7.46 (1H, dt, J = 1.8H)
z, 7.7 Hz), 7.60 (1H, d, J = 7.3H)
z), 7.73 (1H, s), 8.25 (1H, dd,
J = 1.8 Hz, 3.8 Hz) Compound 93 Melting point: 150-157 ° C. IR (KBr, cm ⁻¹ ): 3403, 3307, 293
5,1652, 1619, 1513, 1388, 111
0,1078,837,752 High resolution FAB-MS (m / e, (C ₃₃ H ₄₂ N ₆ O ₅ +
H) as ⁺ ): Calculated value 603.3295 Measured value 603.3280 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.00-0.25 (4H, m), 0.78-
0.91 (1H, m), 1.07 (3H, d, J = 6.
7Hz), 1.08 (3H, d, J = 6.7Hz),
1.32-1.76 (6H, m), 2.28 (3H,
s), 2.68-2.82 (2H, m), 3.02-
3.23 (2H, m), 3.46-3.58 (1H,
m), 4.08-4.21 (2H, m), 4.38-
4.59 (2H, m), 6.14 (1H, d, J = 6.
8Hz), 6.87 (1H, t, J = 7.2Hz),
6.92 (1H, t, J = 7.2 Hz), 7.11-
7.25 (3H, m), 7.48 (1H, d, J = 7.
2Hz), 7.62 (1H, dt, J = 1.8Hz,
5.8 Hz), 7.94 (1H, d, J = 9.1H
z), 8.10 (1H, brs), 8.43 (1H, d
d, J = 1.8 Hz, 4.3 Hz), 10.62 (1
H, s) Example 61 Synthesis of Compounds 94 and 95 HD-His-OMe in Example (59-b)
The title compound was obtained by replacing 2HCl with D-β-aminobutyric acid methyl ester hydrochloride and carrying out the same reactions as in Examples (59-b) and (59-c).

Compound 94 Melting point: 99-104 ° C IR (KBr, cm ^-1 ): 3390, 3295, 293
7,1733,1650,1619,1513,137
3,1143,742,609 High resolution FAB-MS (m / e, (C ₃₀ H ₄₃ N ₅ O ₅ +
H) ⁺ ): Calculated value 554.3342 Measured value 554.3335 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.18-0.33 (2H, m), 0.47-0.59
(2H, m), 1.07 (3H, d, J = 6.5H
z), 1.01-1.21 (1H, m), 1.18 (3
H, d, J = 6.9 Hz), 1.19 (3H, d, J =
6.9 Hz), 1.41-1.79 (6H, m), 2.
05 (1H, dd, J = 8.3Hz, 15.5Hz),
2.41 (3H, s), 2.46 (1H, dd, J =
4.4Hz, 15.5Hz), 3.08 (1H, dd,
J = 5.4 Hz, 9.3 Hz), 3.15 (1H, d
d, J = 7.2 Hz, 14.6 Hz), 3.47 (1
H, dd, J = 5.0, 14.6 Hz), 3.60 (3
H, s), 4.00-4.32 (3H, m), 4.64.
-4.73 (1H, m), 4.98 (1H, d, J =
5.4 Hz), 6.20 (1H, d, J = 8.5H
z), 6.97 (1H, d, J = 8.4 Hz), 7.0
6 (1H, t, J = 7.5 Hz), 7.11 (1H,
t, J = 7.5 Hz), 7.25 (1H, d, J = 7.
5Hz), 7.53 (1H, d, J = 7.5Hz),
7.86 (1H, s) Compound 95 Melting point: 131-134 ° C IR (KBr, cm ^-1 ): 3390, 3295, 293
9,1712,1648,1625,1517,146
1,1386,1137,744,609 High resolution FAB-MS (m / e, (C ₂₉ H ₄₁ N ₅ O ₅ +
H) ⁺ ): Calculated value 540.3186 Measured value 540.3210 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.00-0.36 (4H, m), 0.80-
0.94 (1H, m), 1.08 (9H, d, J = 6.
4 Hz), 1.33-1.80 (6H, m), 2.01
(1H, dd, J = 9.7Hz, 15.6Hz), 2.
28 (1H, dd, J = 4.5Hz, 15.6Hz),
2.33 (3H, s), 2.83 (1H, dd, J =
8.8Hz, 14.3Hz), 3.17 (1H, dd,
J = 4.6 Hz, 14.3 Hz), 3.23-3.45.
(1H, m), 4.01-4.37 (4H, m), 6.
33 (1H, d, J = 5.7 Hz), 6.88 (1H,
t, J = 7.4 Hz), 6.93 (1H, t, J = 7.
4Hz), 7.17 (1H, d, J = 7.4Hz),
7.48 (1H, d, J = 7.4Hz), 7.79 (1
H, d, J = 8.3 Hz), 7.97 (1H, d, J =
8.8Hz), 10.65 (1H, s)

[0172]

EFFECT OF THE INVENTION Since the peptide derivative of the present invention has a strong antagonism against endothelin which is an endogenous physiologically active peptide, it can be used as a drug that antagonizes the contraction action of endothelin-related blood vessels and tracheal muscles and eventually humans. It is useful as a therapeutic drug for hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, arteriosclerosis, acute renal failure, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, gastric ulcer and diabetes.
It is also useful as a therapeutic drug for endotoxin shock, multi-organ failure caused by endotoxin, disseminated intravascular coagulation, and cyclosporine-induced renal damage and hypertension.

[Brief description of drawings]

FIG. 1 shows compound No. 14 compounds 10 μM
3 shows the effects on endothelin-1 contraction in pig isolated coronary artery preparations (◯) and the absence of drug (●).

FIG. 2 shows compound No. 16 compounds 10 μM
3 shows the effects on endothelin-1 contraction in pig isolated coronary artery preparations (◯) and the absence of drug (●).

FIG. 3 shows compound No. 16 compounds 1 μM
3 shows the effects on endothelin-1 contraction in porcine isolated basilar artery preparations (◯) and drug-free (●).

FIG. 4 shows compound No. 14 compounds 10 μM
3 shows the effects on endothelin-1 contraction in guinea pig isolated bronchial specimens in (◯) and in the absence of drug (●).

FIG. 5 shows compound No. 16 compounds 10 μM
3 shows the effects on endothelin-1 contraction in guinea pig isolated bronchial specimens in (◯) and in the absence of drug (●).

Continuation of front page (51) Int.Cl. ⁶ Identification number Internal reference number FI Technical location A61K 38/00 ABR ABU ABX ACB ACF ACL ACV ADP C07D 209/14 9284-4C 209/30 9284-4C A61K 37 / 02 ABU ABX ACB 8314-4C ACF ACL ACV ADP (72) Inventor Yu Nishikibe 3 Okubo Okubo, Tsukuba City, Ibaraki Prefecture Banyu Research Institute Ltd. (72) Mitsuo Yano 3 Okubo Okubo, Tsukuba City Ibaraki Prefecture Tsukuba Research Institute, a pharmaceutical stock company

Claims (8)

[Claims] 1. A general formula: [Wherein A is a group represented by the formula: R ¹ O—C (═O) (wherein R ¹ represents a lower alkyl group or an aryl group) or a formula: R ²¹ R ²² N—C (= O) (wherein R ²¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, or any 1 to 2 hydrogen atoms on the ring is a lower alkyl group, a lower alkoxy group, Represents an aryl group or a heteroaryl group which may be substituted with any group selected from the group consisting of a halogen atom, a trifluoromethyl group, a nitro group, an amino group and a formylamino group, and R ²² represents a hydrogen atom or a hydroxyl group. It represents a lower alkyl group which may be substituted, a cycloalkyl group or a cycloalkyl lower alkyl group, or both R ²¹ and R ²² are bonded to each other to form an adjacent nitrogen atom and have 4 to 4 carbon atoms. 8 to 5 A nitrogen-containing saturated heterocycle of a member ring may be formed, and at this time, among the methylene groups forming the ring, any one methylene group not adjacent to the above nitrogen atom is substituted with a thio group. Further, any 1 to 4 hydrogen atoms on the carbon atoms of the heterocycle may be independently substituted with a lower alkyl group or a hydroxy lower alkyl group, and the heterocycle may be adjacent to each other. Which may form a benzo-condensed ring at two carbon atoms), R ³ represents a hydrogen atom or a lower alkyl group, and R ⁴ may be substituted with a lower alkylthio group. A lower alkyl group, a lower alkenyl group, a cycloalkyl group in which any 1 to 4 hydrogen atoms on the ring may be independently substituted with a lower alkyl group, a cycloalkyl lower alkyl group, or an aryl group , A heteroaryl group, an aryl lower alkyl group or a heteroaryl lower alkyl group; X represents a halogen atom or a lower alkyl group; R ⁵ represents a hydrogen atom or a lower alkyl group;
R ⁶ represents a hydrogen atom, or a lower alkyl group or a lower alkenyl group which may have a substituent selected from the group consisting of a hydroxyl group, a lower alkoxy group, a lower alkylthio group, an aryl group and a heteroaryl group; 0 or 1
Y is a hydroxymethyl group, a group represented by the formula: CO ₂ R ⁷¹ (wherein R ⁷¹ represents a hydrogen atom or a lower alkyl group), a formula: CONR ⁷² R ⁷³ (wherein R ⁷² , R ⁷³ each independently represents a hydrogen atom, an aryl group, a heteroaryl group, or a lower alkyl group which may have a substituent selected from the group consisting of a hydroxyl group, a carboxyl group and a sulfo group). Group, 1H-tetrazol-5-yl group, sulfo group or phosphono group] or a pharmaceutically acceptable salt thereof. 2. The peptide derivative according to (1), wherein X is a halogen atom, or a pharmaceutically acceptable salt thereof. 3. The peptide derivative according to (1), wherein X is a lower alkyl group, or a pharmaceutically acceptable salt thereof. 4. X is a halogen atom and A is of the formula: R ¹ O
A group represented by —C (═O) (wherein R ¹ represents a lower alkyl group or an aryl group) or a formula: R ²¹ R ²² N—C (=
O) (wherein R ²¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, or any one hydrogen atom on the ring is a lower alkoxy group or a halogen atom) R ²² represents an aryl group which may be substituted with any selected group, R ²² represents a hydrogen atom, a lower alkyl group which may be substituted with a hydroxyl group, a cycloalkyl group or a cycloalkyl lower alkyl group, or Both R ²¹ and R ²² may be bonded to each other to form a nitrogen-containing saturated heterocyclic ring having 4 to 8 carbon atoms and having 5 to 9 membered ring together with the adjacent nitrogen atom. Among the methylene groups forming a, any one methylene group not adjacent to the above nitrogen atom may be substituted with a thio group, and further, any one to four methylene groups on the carbon atom of the heterocycle may be substituted. Each hydrogen atom of May be vertically substituted with a lower alkyl group or a hydroxy lower alkyl group, or may form a benzo-fused ring at two adjacent carbon atoms of the heterocycle). R ⁴ is a lower alkyl group optionally substituted with a lower alkylthio group, a cycloalkyl group optionally having 1 to 4 hydrogen atoms on the ring independently substituted with a lower alkyl group, or Represents a cycloalkyl lower alkyl group, an aryl group or a heteroaryl group; R ⁶ represents a lower alkyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a lower alkylthio group, an aryl group and a heteroaryl group. Or a lower alkenyl group (1)
The peptide derivative described or a pharmaceutically acceptable salt thereof. 5. X is a lower alkyl group and A is of the formula: R ¹
A group represented by O—C (═O) (wherein R ¹ represents a lower alkyl group or an aryl group) or a formula: R ²¹ R ²² N—C
(= O) (In the formula, R ²¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, a 1-adamantyl group, or any one hydrogen atom on the ring is a lower alkoxy group and a halogen atom. Represents an aryl group which may be substituted with any group selected from the group, R ²² represents a hydrogen atom, a lower alkyl group which may be substituted with a hydroxyl group,
A cycloalkyl group or a cycloalkyl lower alkyl group is shown, or both R ²¹ and R ²² are bonded to each other to form an adjacent nitrogen atom and have a 5 to 9 membered ring having 4 to 8 carbon atoms. A nitrogen-saturated heterocycle may be formed, and among the methylene groups forming a ring at this time, any one methylene group not adjacent to the above-mentioned nitrogen atom may be substituted with a thio group, Furthermore, any 1 to 4 hydrogen atoms on the carbon atoms of the heterocycle may be independently substituted with a lower alkyl group or a hydroxy lower alkyl group, and
The heterocyclic ring may form a benzo-condensed ring at two adjacent carbon atoms); R ⁴ is a lower alkyl group optionally substituted with a lower alkylthio group; Represents a cycloalkyl group, a cycloalkyl lower alkyl group, an aryl group or a heteroaryl group each optionally having 1 to 4 hydrogen atoms independently substituted with a lower alkyl group; R ⁶ is a lower alkoxy group , A lower alkylthio group, an aryl group and a heteroaryl group, which is a lower alkyl group or a lower alkenyl group which may have a substituent selected from the group consisting of (1), or a pharmaceutically acceptable salt thereof. . 6. X is a halogen atom and A is of the formula: R ¹ O
A group represented by —C (═O) (wherein R ¹ represents a lower alkyl group or an aryl group) or a formula: R ²¹ R ²² N—C (=
O) (wherein R ²¹ is a lower alkyl group, a cycloalkyl group, or any one hydrogen atom on the ring may be substituted with any group selected from the group consisting of a lower alkoxy group and a halogen atom). Represents a good aryl group, R ²² represents a hydrogen atom, a lower alkyl group which may be substituted with a hydroxyl group or a cycloalkyl group, or both R ²¹ and R ²² are bonded to each other to form an adjacent nitrogen atom. Has 4 to 4 carbon atoms
It may form 7 nitrogen-containing saturated heterocycles having 5 to 8 members, and further, any 1 to 4 hydrogen atoms on the carbon atoms of the heterocycle are independently a lower alkyl group or a hydroxy group. a group represented by lower alkyl may be substituted with a group); R ³ represents a hydrogen atom; R ⁴ is a lower alkyl group which may be substituted with a lower alkylthio group, any one of the ring ~ Represents a cycloalkyl group or a cycloalkyl lower alkyl group or an aryl group, each of which may have two hydrogen atoms independently substituted with a lower alkyl group;
R ⁶ represents a lower alkyl group or a lower alkenyl group which may have a substituent selected from the group consisting of a lower alkoxy group, a lower alkylthio group and a heteroaryl group; Y represents a hydroxymethyl group, a formula: CO ₂ R ⁷¹ (where
R ⁷¹ represents a hydrogen atom or a lower alkyl group), a formula: CONR ⁷² R ⁷³ (in the formula, R ⁷² and R ⁷³ each independently represent a hydrogen atom, an aryl group or a lower alkyl group) The peptide derivative according to (1) or a pharmaceutically acceptable salt thereof, which is a group represented by: 7. X is a lower alkyl group, and A is of the formula: R ¹
A group represented by O—C (═O) (wherein R ¹ represents a lower alkyl group or an aryl group) or a formula: R ²¹ R ²² N—C
(= O) (in the formula, R ²¹ is a lower alkyl group, a cycloalkyl group, or any one hydrogen atom on the ring is substituted with an arbitrary group selected from the group consisting of a lower alkoxy group and a halogen atom. Optionally represents an aryl group, R ²² represents a hydrogen atom, a lower alkyl group which may be substituted with a hydroxyl group, or a cycloalkyl group, or a nitrogen atom adjacent to both R ²¹ and R ²² by bonding. Together with, carbon number 4
~ 7 to form a 5- to 8-membered nitrogen-containing saturated heterocycle, wherein any 1 to 4 hydrogen atoms on the carbon atoms of the heterocycle are independently a lower alkyl group or A lower alkyl group which may be substituted with a hydroxy lower alkyl group); R ³ represents a hydrogen atom; R ⁴ represents a lower alkyl group optionally substituted with a lower alkylthio group; 1 to 2 hydrogen atoms each independently represent a cycloalkyl group, a cycloalkyl lower alkyl group or an aryl group which may be substituted with a lower alkyl group; R ⁶ is a lower alkoxy group, a lower alkylthio group or a heteroaryl Represents a lower alkyl group or a lower alkenyl group optionally having a substituent selected from the group consisting of a group; Y is a hydroxymethyl group, a formula: CO ₂ R ⁷¹ (wherein R ⁷¹ is a hydrogen atom) Or a lower alkyl group), a group represented by the formula: CONR ⁷² R ⁷³ (in the formula, R ⁷² and R ⁷³ each independently represent a hydrogen atom, an aryl group or a lower alkyl group). (1) The peptide derivative according to (1) or a pharmaceutically acceptable salt thereof. 8. Hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, which comprises an effective amount of the peptide derivative represented by the general formula [I] or the pharmaceutically acceptable salt thereof according to (1). , Myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, multiple organ failure caused by endotoxin and disseminated intravascular coagulation and / or cyclosporine-induced kidney Remedy for disorders and high blood pressure.