JPH05178890A - Compound having antagonism to endoserine - Google Patents

Abstract

PURPOSE:To obtain a new subject compound useful as a therapeutic agent for diseases such as hypertension, Raynaud disease and acute renal failure in which endoserin is participated because the compound exhibits strong antagonism through ETA, ETB receptor to endoserine. CONSTITUTION:A compound of formula I [R<1> is lower alkyl, aryl, etc.; p is 0-2; A<1> is single bond or divalent lower alkylene; R<2> is aralkyl, aryl, etc.; X<1> is O or NR<3> (R<3> is H or lower alkylene); R<4> is 5-10 membered heterocyclic lower alkyl or aryl-lower alkyl; X<3> is O or S; A<2> is formula II, formula III [Y is sulfo, phosphono, etc.; (t) is 2-6], etc.] or salt thereof. The compound of formula I wherein X<3> is O is obtained by condensing, e.g. a carboxylic acid of formula IV to an alpha-amino acid derivative of formula V (P<1> is carboxyl protecting group) to afford a compound of formula VI, deprotecting a protecting group P<1> of the compound and then condensing the deproteceted compound with a compound of the formula H-A<2>.

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 the endothelin receptor subtypes ET _A and / or ET _B receptors and, by inhibiting the action of endothelin,
It has vasodilatory action and bronchodilatory action,
In particular, multi-organ failure due to hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, endotoxin and It can be used as a therapeutic agent for 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 sustained and strong pressor action [Nature, No. 332]. Vol., Pp. 411-415 (1988)]. It is known that endothelin has three types of endothelin (endothelin-1, endothelin-2, endothelin-3) as family peptides having similar structures in animals including humans. , Both are known to have vasoconstrictor and pressor effects [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 asthma patients blood or airway lavage fluid. Have been reported to be significantly increased in comparison with normal persons [Journal of the Japanese Society of Hypertension (Japan. J. Hypertensio
n), Vol. 12, p. 79 (1989), Journal of Vascular Medicine and Biology (J. Vascular Medicine Bio).
, Vol. 2, p. 207 (1990), Diabetologia, 33.
Volume, pp. 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, 1144-114 (1990). reference].

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

Furthermore, 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, vascular relaxation factor (EDRF) derived from endothelial cells, thromboxane A ₂ , prostacyclin, noradrenaline,
It was also found that it regulates 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).
pertension, vol. 12, p. 76 (198)
9 years) and Neuroscience Letters (Neuro)
Science Letters), Volume 102, Volume 1
79-184 (1989)]. In addition, it also has an action of contracting gastrointestinal 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 it has been suggested that endothelin is associated with arterial thickening [Atherosclerosis.
Rosclerosis), 78, 225-228 (1989)]. Furthermore, it is known that endothelin receptors are present at 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 thought that it also has an important role for [Neuroscience Letters (N
euroscience Letters), 97th
Vol. 276-279 (1989)]. In particular, endothelin has been suggested to be 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 added to cultured vascular endothelial cells, the concentration of endothelin in blood or culture supernatant is significantly increased. It is considered to be one of the important mediators involved in diseases caused by [biochemical and biophysical research
Communications (Biochem.Biophy)
s. Res. Commun. ), Volume 161, 122
Page 0 (1989) and Acta Physiologica Scandinavian (Acta Physiol. Scan)
d. ), 137, 317 (1989)].

Further, cyclosporine was added to cultured kidney 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 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 by endothelin is also mediated through these two endothelin receptor subtypes [Journal・ Of Cardiovascular Pharmacology (J. Cardiovasc. Pharmac
ol. ), Vol. 17 (Suppl. 7), S119-S121 (1991)]. One of these endothelin receptor subtypes is the endothelin receptor (ET _A ) which has selectivity for ET-1 as compared to the endothelin family peptide ET-3, 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.

_A substance that specifically inhibits the binding of endothelin to these endothelin receptors ET _A and / or ET _B antagonizes various physiological actions of endothelin described above and is useful as a pharmaceutical in a wide range of fields. it is conceivable that.

[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 over-secretion 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 due to endotoxin shock or endotoxin, disseminated intravascular coagulation, and cyclosporine-induced renal damage and hypertension. ET _A receptors and ET _B receptors are known as receptors for endothelin, and ET _A receptor antagonists and / or ET _B receptor antagonists are useful as pharmaceuticals. The present invention aims 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 at ET _A and / or ET _B receptors.

[0016]

[Means for Solving the Problems] In order to solve the above problems, the present inventors have synthesized various compounds and investigated their endothelin antagonistic activity.

[0017]

[Chemical 4] {In the formula, R ¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic lower alkyl group (the lower alkyl Group, cycloalkyl group, cycloalkyl lower alkyl group, aralkyl group, aryl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heterocyclic lower alkyl group, each independently on their chain and / or Lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, nitro group, trifluoromethyl group, cyano group, formyl group, lower alkanoyl group, carboxyl group, lower alkoxycarbonyl group, amino group, mono-lower alkylamino group on the ring , Di-lower alkylamino group, formylamino group, alkanoylamino group, aroylamino group,
Carbamoyl group, N-mono-lower alkylcarbamoyl group or N, N-di-lower alkylcarbamoyl group, mercapto group, lower alkylthio group or lower alkanoylthio group may be present); p is an integer of 0 to 2; A ¹ represents a single bond or a divalent lower alkylene group which may be substituted with a lower alkyl group; R ² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group or an aryl group. A 5- to 10-membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group; X ¹
Represents an oxygen atom or a group represented by the formula: —NR ³ — [wherein, R ³ represents a hydrogen atom or a lower alkyl group]; R ⁴ represents a 5- to 10-membered heterocyclic lower alkyl group [5 The 10-membered heterocyclic lower alkyl group is a lower alkyl on the ring or has the formula: R ⁴¹ —CO— (CH ₂ ) _q — (wherein R ⁴¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group). , An aralkyloxy group, an amino group, a mono-lower alkylamino group or a di-lower alkylamino group; q represents an integer of 0 to 6)] or an aryl-lower alkyl group [The aryl lower alkyl group has a nitro group on its ring, a compound represented by the formula: R ⁴² —CO— (CH ₂ ) _r — (wherein R ⁴² is a lower alkyl group, a lower alkoxy group, an amino group, a mono-lower alkylamino group. A group or a di-lower alkylamino group, r is Groups represented by 6 an integer of)
Formula: R ⁴² —CO—X ² — (In the formula, R ⁴² has the above meaning, X ² is an oxygen atom or a formula: —NR ⁴³ — (In the formula, R ⁴³ is a hydrogen atom or a lower alkyl group. represented by (wherein, R ⁴⁴ represents a hydrogen atom or a lower alkyl group, s is an integer of ^{0~6) - R 44 O- (CH} 2) s: group or the formula represented by shown) May have a group]; X ³ represents an oxygen atom or a sulfur atom; A ² represents the following general formulas [II] to [V
II] represents an arbitrary group selected from the group consisting of groups represented by [II].

[0018]

[Chemical 5] [In the formula, Y is a hydroxy lower alkyl group, a sulfo group, a phosphono group, a group represented by the formula: -CO ₂ R ⁸¹ (wherein R ⁸¹ represents a hydrogen atom or a carboxy protecting group) or a formula: -C
ONR ⁸² R ⁸³ (wherein R ⁸² and R ⁸³ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group,
R represents a group represented by any one to five hydrogen atoms on the benzene ring each independently represent a lower alkyl group or a phenylsulfonyl group or a carboxy lower alkyl group which may be substituted with a halogen atom); ⁵¹ represents a hydrogen atom or a lower alkyl group, or represents a methylene group together with R ⁶¹ below; R ⁵³ , R ⁶¹ and R ⁶² each independently represent a hydrogen atom, a lower alkyl group, a lower alkenyl group,
Aryl group, aryl lower alkyl group, 5-10 membered heterocyclic group or 5-10 membered heterocyclic lower alkyl group (the lower alkyl group, lower alkenyl group, aryl group, aryl lower alkyl group, 5-10 membered heterocyclic group The heterocyclic group and the heterocyclic lower alkyl group each independently have a hydroxyl group, a lower alkyl group, a halogen atom, a lower alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, or a protected group on the chain and / or the ring thereof. Carboxyl group, amino group, monoalkylamino group, di-lower alkylamino group, carbamoyl group, N-mono-lower alkylcarbamoyl group, N,
N-di-lower alkylamino group, lower alkoxycarbonylamino group or aryloxycarbonylamino group), and R ⁶¹ together with R ⁵¹ may represent a methylene group. ⁶² together with R ⁵² below may represent a methylene group (provided that when R ⁵¹ represents a lower alkyl group, R ⁶¹ represents a group other than a hydrogen atom and R ⁵² represents a group other than a hydrogen atom). R ⁶² represents a hydrogen atom or a lower alkyl group when indicated); R ⁵² represents a hydrogen atom, an aryl group, an aralkyl group, a carboxyl group, a carbamoyl group, an N-mono-lower alkylcarbamoyl group, or an N, N-di-lower alkylcarbamoyl group. or a group or N- arylcarbamoyl, or represents a single bond together with R ^7; or R ⁷ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group , Or R ⁵² together with R ⁵² to represent a single bond, t represents an integer of 2 to 6; Z represents CH or N; v represents an integer of 1 to 3]} or It was found that the pharmaceutically acceptable salt thereof has a strong ET _A and / or ET _B receptor antagonistic activity, and completed the present invention.

The meanings of various abbreviations described in this specification are shown below.

Abbreviations Meaning of abbreviations DNle D-norleucine DTrp D-tryptophan DTrp (Boc) D- (N ⁱⁿ -tert-butoxycarbonyl) tryptophan DTrp (CHO) D- (N ⁱⁿ -formyl) tryptophan DTrp (COOMe) D- (N ⁱⁿ - methoxycarbonyl) tryptophan Boc tert-butoxycarbonyl Me methyl ^t Bu tert-butyl DCC N, N'-dicyclohexyl carbo di imide DMAP 4-(dimethylamino) pyridine DMF N, N-dimethylformamide DMSO Dimethyl Sulfoxide NMP N-Methylpyrrolidone NMM N-Methylmorpholine EDCI.HCl 1-Ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride HOBT.H ₂ O 1-Hide Roxy-1H-benzotriazol monohydrate HOSu N-hydroxysuccinimide mCPBA Metachloroperbenzoic acid TBAHS Tetra-n-butylammonium hydrogen sulfate TEA triethylamine TFA trifluoroacetic acid THF tetrahydrofuran TsCl p-toluenesulfonyl chloride Ts p-toluene Sulfonyl Z benzyloxycarbonyl MOPS 3-morpholinopropanesulfonic acid HEPES 2- [4- (2-hydroxyethyl) -1-piperazinyl] ethanesulfonic acid Tris tris (hydroxymethyl) aminomethane PMSF phenylmethanesulfonyl = fluoride The definitions of various terms used in the specification will be explained.

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 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 cycloalkyl lower alkyl group is 3 to
A lower alkyl group substituted with a 9-membered cycloalkyl group, for example, cyclopropylmethyl group, cyclopropylethyl group, cyclopropylpropyl group, cyclobutylmethyl group, cyclopentylmethyl group, cyclohexylmethyl group, cycloheptyl Methyl group, cyclooctylmethyl group, cyclononylmethyl group, cyclopropylbutyl group, cyclopropylpentyl group, cyclopropylhexyl group, cyclopropylheptyl group, cyclopropyloctyl group, cyclopropylnonyl group, cyclopentylethyl group, cyclohexylethyl group , Cyclopentylpropyl group, cyclohexylpropyl group and the like.

Specific examples of the aryl group include a phenyl group and a naphthyl group.

The aralkyl group means a lower alkyl group substituted with an aryl group, and specific examples thereof include a benzyl group, a phenylethyl group, a phenylpropyl group, a naphthylmethyl group and a naphthylethyl group.

The 5- to 10-membered heterocyclic group means a 5- to 10-membered monocyclic or condensed ring saturated or unsaturated cyclic group containing at least one hetero atom such as nitrogen atom, oxygen atom and sulfur atom. Means, specifically, a pyrrolyl group, a furyl group, a thienyl group, a thiazolyl group, an oxazolyl group, an imidazolyl group, a pyrrolidyl group, a tetrahydrofuryl group, a tetrahydrothienyl group, an indolyl group, a benzofuryl group, a benzothienyl group, a dihydroindolyl group. Group, pyridyl group, pyrimidyl group, quinolyl group, isoquinolyl group, piperidyl group, tetrahydropyranyl group, piperazinyl group and the like.

The 5- to 10-membered heterocyclic lower alkyl group is
Nitrogen atom, oxygen atom, a lower alkyl group having a 5- to 10-membered monocyclic or condensed ring saturated or unsaturated cyclic group containing at least one hetero atom such as a sulfur atom, for example, a pyrrolylmethyl group, Furylmethyl group, thienylmethyl group, thiazolylmethyl group, oxazolylmethyl group, imidazolylmethyl group, pyrrolinylmethyl group,
Imidazolinylmethyl group, pyrrolidylmethyl group, tetrahydrofurylmethyl group, tetrahydrothienylmethyl group, indolylmethyl group, pyridylmethyl group, pyrimidylmethyl group, quinolylmethyl group, isoquinolylmethyl group, piperidylmethyl group, tetrahydropyranylmethyl group Group, piperazinylmethyl group, pyrrolylethyl group, furylethyl group, thienylpropyl group, imidazolylbutyl group, piperidylmethyl group, piperidylpropyl group and the like.

The lower alkanol group means a lower alkylcarbonyl group having 2 to 6 carbon atoms, and specific examples thereof include acetyl group, propionyl group, butanoyl group, pentanoyl group and hexanoyl group.

The lower alkoxycarbonyl group means an alkyloxycarbonyl group having a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, a methoxycarbonyl group, an ethoxycarbonyl group, Propoxycarbonyl group, isopropoxycarbonyl group, butoxycarbonyl group, isobutoxycarbonyl group, sec-butoxycarbonyl group, tert-butoxycarbonyl group,
Pentyloxycarbonyl group, isopentyloxycarbonyl group, neopentyloxycarbonyl group, tert
Examples thereof include a pentyloxycarbonyl group and a hexyloxycarbonyl group.

The mono-lower alkylamino group has 1 carbon atom.
It means an amino group having 1 to 6 alkyl groups, and examples thereof include a methylamino group, an ethylamino group, a propylamino group, a hexylamino group, and an isopropylamino group.

The di-lower alkylamino group has 1 to 1 carbon atoms.
It means an amino group having two 6 alkyl groups, for example, dimethylamino group, ethylmethylamino group, diethylamino group, methylpropylamino group, ethylpropylamino group, butylmethylamino group, butylethylamino group, hexyl Examples thereof include a methylamino group and an ethylhexylamino group.

The lower alkoxycarbonylamino group means an amino group having an alkyloxycarbonyl group having an alkyl group having 1 to 6 carbon atoms, for example,
Methoxycarbonylamino group, ethoxycarbonylamino group, propoxycarbonylamino group, isopropoxycarbonylamino group, butoxycarbonylamino group, isobutoxycarbonylamino group, sec-butoxycarbonylamino group, tert-butoxycarbonylamino group, pentyloxycarbonylamino group Group, isopentyloxycarbonylamino group, neopentyloxycarbonylamino group, tert-pentyloxycarbonylamino group, hexyloxycarbonylamino group and the like.

The aryloxycarbonylamino group is
It means a phenyloxycarbonylamino group, a naphthyloxycarbonylamino group or the like.

The lower alkanoylamino group has 2 carbon atoms.
To an amino group having 6 lower alkylcarbonyl groups, for example, acetylamino group, propionylamino group, butanoylamino group, pentanoylamino group, hexanoylamino group, N-acetyl-N-methylamino group. , N-acetyl-N-ethylamino group, N-methyl-
Mention may be made of N-propionylamino groups.

The aroylamino group means a benzoylamino group, a naphthoylamino group and the like.

The N-mono-lower alkylcarbamoyl group means an N-monoalkylcarbamoyl group having one alkyl group having 1 to 6 carbon atoms, for example, N-methylcarbamoyl group, N-ethylcarbamoyl group, N-propylcarbamoyl group, N-isopropylcarbamoyl group, N-butylcarbamoyl group, N-pentylcarbamoyl group, N-hexylcarbamoyl group, N-cyclopropylcarbamoyl group, N-cyclopentylcarbamoyl group, N-cyclohexylcarbamoyl group, etc. Can be mentioned.

The N, N-di-lower alkylcarbamoyl group means N, N- having two alkyl groups having 1 to 6 carbon atoms.
A dialkylcarbamoyl group is meant, for example, N, N-
Dimethylcarbamoyl group, N, N-diethylcarbamoyl group, N-ethyl-N-methylcarbamoyl group, N-ethyl-N-propylcarbamoyl group, N-propyl-N
-Methylcarbamoyl group, N-cyclopropyl-N-ethylcarbamoyl group, N-butyl-N-methylcarbamoyl group, N-methyl-N-pentylcarbamoyl group, N
-Isopropyl-N-methylcarbamoyl group and the like can be mentioned.

The N-arylcarbamoyl group means N-phenylcarbamoyl group, N-naphthylcarbamoyl group and the like.

The aroyl group means an arylcarbonyl group, and specific examples thereof include a benzoyl group.

The lower alkenyl group means a linear or branched alkenyl group having 3 to 6 carbon atoms, specifically, 1-propenyl group, 2-propenyl group, 1-butenyl group, 2-butenyl group, 3-butenyl group, 1-methyl-
2-propenyl group, 1-pentenyl group, 2-pentenyl group, 3-pentenyl group, 4-pentenyl group, 3-methyl-1-butenyl group, 2-methyl-3-butenyl group, 1-
Methyl-2-butenyl group, 1-methyl-3-butenyl group, 1,1-dimethyl-2-propenyl group, 1-hexenyl group, 2-hexenyl group, 3-hexenyl group, 4-hexenyl group, 5-hexenyl group Groups and the like.

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

The lower alkoxy group has a carbon number of 1
~ 6 means an alkyloxy group having a linear or branched alkyl group, specifically, a methoxy group, an ethoxy group, a propoxy group, an isopropoxy group, a butoxy group, an isobutoxy group, a sec-butoxy group. , Tert-butoxy group, pentyloxy group, isopentyloxy group, neopentyloxy group, tert-pentyloxy group, hexyloxy group, isohexyloxy group and the like.

The aryloxy group means a phenoxy group, a naphthyloxy group and the like.

The lower alkylthio group means an alkylthio group having 1 to 6 carbon atoms, and examples thereof include a methylthio group, an ethylthio group, a propylthio group, an isopropylthio group, a butylthio group, a pentylthio group and a hexylthio group. it can.

The lower alkanoylthio group has 2 to 2 carbon atoms.
It means 6 alkanoylthio groups, and examples thereof include an acetylthio group, a propionylthio group, a butanoylthio group, a pentanoylthio group and a hexanoylthio group.

The lower alkylsulfonyl group has 1 carbon atom.
To 6 alkylsulfonyl groups, for example, methylsulfonyl group, ethylsulfonyl group, propylsulfonyl group, isopropylsulfonyl group, butylsulfonyl group, isobutylsulfonyl group, pentylsulfonyl group,
A hexyl sulfonyl group etc. can be mentioned.

The lower acyloxy group means an acyloxy group having 2 to 6 carbon atoms, and examples thereof include an acetyloxy group, a propionyloxy group, a butanoyloxy group, a heptanoyloxy group and a hexanoyloxy group. You can

The protecting group in the protected carboxyl group means a lower alkyl group such as methyl group, ethyl group and propyl group, and a benzyl group.

2 which may be substituted with a lower alkyl group
The valent lower alkylene group means a divalent alkylene group in which 1 to 6 carbon atoms are linearly linked, which may be substituted with an alkyl group having 1 to 6 carbon atoms, For example, methylene group, ethylene group, propylene group, butylene group, pentamethylene group, hexamethylene group, ethylethylene group, methylethylene group and the like can be mentioned.

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

The group represented by R ¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5- to 10-membered heterocyclic group or 5-1.
0-membered heterocyclic lower alkyl group (the lower alkyl group, cycloalkyl group, cycloalkyl lower alkyl group, aralkyl group, aryl group, 5- to 10-membered heterocyclic group and 5-1
The 0-membered heterocyclic lower alkyl group is independently a lower alkyl group, a halogen atom, a hydroxyl group, a lower alkoxy group, a nitro group, a trifluoromethyl group, a cyano group or a formyl group on the chain and / or the ring thereof. , Lower alkanoyl group, carboxyl group, lower alkoxycarbonyl group, amino group, mono-lower alkylamino group, di-lower alkylamino group, formylamino group, alkanoylamino group, aroylamino group, carbanoyl group, N-monolower alkylcarbamoyl group or N, N-di-lower alkylcarbamoyl group, mercapto group, lower alkylthio group or lower alkanoylthio group may be present). Specific examples of the lower alkyl group which may have the above substituent on the chain include 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, 1,1-
Examples thereof include a dimethylbutyl group and a 1-ethyl-1-methylpropyl group. Specific examples of the cycloalkyl group which may have the above-mentioned substituent on the ring include cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, cycloheptyl group, cyclooctyl group, cyclononyl group and the like. Specific examples of the cycloalkyl group lower alkyl group which may have the above-mentioned substituent on the chain and / or ring include cyclopropylmethyl group, 1-cyclopropylethyl group, 2-cyclopropylethyl group, 1
-Cyclopropylpropyl group, 2-cyclopropylpropyl group, 3-cyclopropylpropyl group, cyclopentylmethyl group, 1-cyclopentylethyl group, 2-cyclopentylethyl group, 1-cyclopentylpropyl group, 2
-Cyclopentylpropyl group, 3-cyclopentylpropyl group, cyclohexylmethyl group, 1-cyclohexylethyl group, 2-cyclohexylethyl group, 1-cyclohexylpropyl group, 2-cyclohexylpropyl group, 3
-Cyclohexylpropyl group, cycloheptylmethyl group, 1-cycloheptylethyl group, 1-cycloheptylpropyl group, 1-cyclopropyl-1-methylethyl group, 1-cyclobutyl-1-methylethyl group, 1-cyclopentyl-1 -Methylethyl group, 1-cyclohexyl-1-methylethyl group and the like. Specific examples of the aralkyl group which may have the above-mentioned substituent on the chain and / or ring include benzyl group, 1-phenylethyl group and 2
-Phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group, 3-phenylpropyl group, 1-naphthylmethyl group, 2-naphthylmethyl group and the like.
Specific examples of the aryl group which may have the above substituent on the ring include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like. Specific examples of the 5- to 10-membered heterocyclic group which may have the above substituents on the ring include 2-pyrrolyl group, 3-pyrrolyl group, 2-furyl group, 3-furyl group, 2-thienyl group. Group, 3-thienyl group, 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, oxazolyl group, imidazolyl group, pyrrolidino group, piperazino group,
A tetrahydroisoquinolyl group etc. are mentioned. Specific examples of the 5- to 10-membered heterocyclic lower alkyl group which may have the above-mentioned substituent on the chain and / or ring include 2-furylmethyl group, 3-furylmethyl group, 2-thienylmethyl group. Group, 3-thienylmethyl group, 2-phenylethyl group, 2
Examples thereof include a-(2-furyl) ethyl group, a 2- (3-furyl) ethyl group, a 2- (2-thienyl) ethyl group and a 2- (3-thienyl) ethyl group.

A ¹ represents a single bond or a divalent lower alkylene group which may be substituted with a lower alkyl group, and specific examples of the divalent lower alkylene group include a methylene group, an ethylene group, a propylene group, Examples thereof include butylene group.

The group represented by R ² is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5- to 10-membered heterocyclic group or 5-1.
It means a 0-membered heterocyclic 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, 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 can be mentioned. Specific examples of the cycloalkyl group include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a cyclooctyl group and a cyclononyl group. Specific examples of the cycloalkyl lower alkyl group include a cyclopropylmethyl group, 1
-Cyclopropylethyl group, 2-cyclopropylethyl group, 1-cyclopropyl-1-methylethyl group, cyclobutylmethyl group, 1-cyclobutylethyl group, 2-cyclobutylethyl group, 1-cyclobutyl-1-methyl Ethyl group, cyclopentylmethyl group, 1-cyclopentylethyl group, 2-cyclopentylethyl group, 1-cyclopentyl-1-methylethyl group, 1-cyclohexylmethyl group, 1-cyclohexylethyl group, 1-cyclohexyl-1-methylethyl group , A 1-cycloheptylmethyl group,
Examples thereof include a 1-cycloheptylethyl group, a 1-cyclooctylmethyl group and a 1-cyclooctylethyl group. Specific examples of the aralkyl group include a phenylmethyl group, a phenylethyl group, a phenylpropyl group, a 1-naphthylmethyl group, a 2-naphthylmethyl group and the like. Specific examples of the aryl group include a phenyl group and a naphthyl group. Specific examples of the 5- to 10-membered heterocyclic group include 2-
Thienyl group, 3-thienyl group, 2-thiazolyl group, 2-
A furyl group, a 3-furyl group and the like can be mentioned. Specific examples of 5- to 10-membered heterocyclic lower alkyl include 2-thienylmethyl group, 3-thienylmethyl group, 2-thienylethyl group, 2
Examples thereof include a thiazolylmethyl group and a 2-furylmethyl group.

A 5- to 10-membered heterocyclic lower alkyl group represented by R ⁴ [wherein the 5- to 10-membered heterocyclic lower alkyl group is a lower alkyl on the ring or the formula: R ⁴¹ -CO- (CH ₂ ). _q
-(Wherein R ⁴¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group,
A lower alkoxy group, an aralkyloxy group, an amino group, a mono-lower alkylamino group or a di-lower alkylamino group; q represents an integer of 0 to 6)] or aryl lower alkyl [the aryl lower alkyl group, a nitro group on the ring, the formula: R ⁴² -
CO- (CH _{2) r} - (wherein, R ⁴² is a lower alkyl group, a lower alkoxy group, an amino group, a mono-lower alkylamino group or a di-lower alkylamino group, r represents an integer of 0 to 6) A group represented by the formula: R ⁴² —CO—X ² — (wherein R ⁴² has the above meaning, X ² is an oxygen atom or a formula:
A group represented by —NR ⁴³ — (in the formula, R ⁴³ represents a hydrogen atom or a lower alkyl group) or a formula: R ⁴⁴ O— (CH ₂ ) _s —
(In the formula, R ⁴⁴ represents a hydrogen atom or a lower alkyl group, and s
Represents an integer of 0 to 6)], a specific example of a 3-indolylmethyl group, a 3-benzothienylmethyl group, a (1-oxo-3-benzothienyl) methyl group,
(1,1-dioxo-3-benzothienyl) methyl group,
(1-Methyl-3-indolyl) methyl group, (1-ethyl-3-indolyl) methyl group, (1-propyl-3-
Indolyl) methyl group, (1-butyl-3-indolyl) methyl group, (1-formyl-3-indolyl) methyl group, (1-acetyl-3-indolyl) methyl group,
(1-Methoxycarbonyl-3-indolyl) methyl group, (1-ethoxycarbonyl-3-indolyl) methyl group, (1-propoxycarbonyl-3-indolyl)
Methyl group, (1-tert-butoxycarbonyl-3-
Indolyl) methyl group, (1-benzyloxycarbonyl-3-indolyl) methyl group, (1-carbamoyl-
3-indolyl) methyl group, (1-methylcarbamoyl-3-indolyl) methyl group, (1-ethylcarbamoyl-3-indolyl) methyl group, (1-formylmethyl-3-indolyl) methyl group, [1- ( 2-oxopropyl) -3-indolyl] methyl group, (1-carboxymethyl-3-indolyl) methyl group, (1-methoxycarbonylmethyl-3-indolyl) methyl group, (1-ethoxycarbonylmethyl-3-indolyl) ) A methyl group,
(1-tert-Butoxycarbonylmethyl-3-indolyl) methyl group, (1-benzyloxycarbonylmethyl-3-indolyl) methyl group, (1-carbamoylmethyl-3-indolyl) methyl group, (1-methylcarbamoylmethyl) -3-indolyl) methyl group, (1-ethylcarbamoylmethyl-3-indolyl) methyl group,
[1- (2-Formylethyl) -3-indolyl] methyl group, [1- (2-carboxyethyl) -3-indolyl] methyl group, benzyl group, 2-nitrophenylmethyl group, 3-nitrophenylmethyl group , 4-nitrophenylmethyl group, 2-acetylphenylmethyl group, 3-acetylphenylmethyl group, 4-acetylphenylmethyl group,
2-acetylmethylphenylmethyl group, 3-acetylmethylphenylmethyl group, 4-acetylmethylphenylmethyl group, 2-methoxycarbonylphenylmethyl group, 3
-Methoxycarbonylphenylmethyl group, 4-methoxycarbonylphenylmethyl group, 2-ethoxycarboxyphenylmethyl group, 3-ethoxycarbonylphenylmethyl group, 4-ethoxycarbonylphenylmethyl group, 2
-Carbamoylphenylmethyl group, 3-carbamoylphenylmethyl group, 4-carbamoylphenylmethyl group,
2-methylcarbamoylphenylmethyl group, 3-methylcarbamoylphenylmethyl group, 4-methylcarbamoylphenylmethyl group, 2-dimethylcarbamoylphenylmethyl group, 3-dimethylcarbamoylphenylmethyl group, 4-dimethylcarbamoylphenylmethyl group, 2-
Methoxycarbonylphenylethyl group, 3-methoxycarbonylphenylethyl group, 4-methoxycarbonylphenylethyl group, 2-acetoxyphenylmethyl group, 3
-Acetoxyphenylmethyl group, 4-acetoxyphenylmethyl group, 2-methoxycarbonyloxyphenylmethyl group, 3-methoxycarbonyloxyphenylmethyl group, 4-methoxycarbonyloxyphenylmethyl group,
2-acetylaminophenylmethyl group, 3-acetylaminophenylmethyl group, 4-acetylaminophenylmethyl group, 2-methoxycarbonylaminophenylmethyl group, 3-methoxycarbonylaminophenylmethyl group,
4-methoxycarbonylaminophenylmethyl group, 2-
Hydroxyphenylmethyl group, 3-hydroxyphenylmethyl group, 4-hydroxyphenylmethyl group, 2-methoxyphenylmethyl group, 3-methoxyphenylmethyl group, 4-methoxyphenylmethyl group, 2-methoxyphenylethyl group, 3-methoxy Examples thereof include a phenylethyl group and a 4-methoxyphenylethyl group.

The group represented by R ⁵¹ represents a hydrogen atom or a lower alkyl group, or represents a methylene group together with R ^61, and specific examples of the lower alkyl group include a methyl group, an ethyl group and the like. Is mentioned.

The group represented by R ⁶¹ is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl group, an aryl lower alkyl group, a 5- to 10-membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group ( The lower alkyl group, the lower alkenyl group, the aryl group, the aryl lower alkyl group, the 5- to 10-membered heterocyclic group and the heterocyclic lower alkyl group are independently a hydroxyl group or a lower alkyl group on their chain and / or ring. , Halogen atom, lower alkoxy group, aryloxy group, acyloxy group, carboxyl group, protected carboxyl group, amino group, monoalkylamino group, dilower alkylamino group, carbamoyl group, N-monolower alkylcarbamoyl group, N , N-di-lower alkylamino group, lower alkoxycarbonylamino group or aryloxycarbonylamido Or means may also be) have a group, or together with R ⁶¹ means a methylene group.
Specific examples of the lower alkyl group which may have the above substituent on the chain include 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, hexyl group, hydroxymethyl group, 1-hydroxyethyl group, 2
-Hydroxyethyl group, 1-hydroxypropyl group, 2
-Hydroxypropyl group, 3-hydroxypropyl group,
1-hydroxy-1-methylethyl group, 2-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 2-
Examples thereof include a hydroxybutyl group, a 3-hydroxybutyl group, a 4-hydroxybutyl group, a 1-hydroxy-1-methylpropyl group and a 2-hydroxy-1-methylpropyl group. Specific examples of the lower alkenyl group which may have the above-mentioned substituent on the chain include vinyl group, allyl group and 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, 5-
Examples thereof include a pentenyl group. Specific examples of the aryl group which may have the above substituent in a ring include a phenyl group, a 1-naphthyl group, a 2-naphthyl group and the like.
Specific examples of the aryl lower alkyl group which may have the above-mentioned substituent in a ring include benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group and 3 -Phenylpropyl group, 1-methyl-2-phenylethyl group, 1-phenylbutyl group, 2-phenylbutyl group, 3-phenylbutyl group, 4-phenylbutyl group, 1-phenyl-2-methylpropyl group, 2 -Phenyl-1-methylpropyl group and the like can be mentioned. Specific examples of the heterocyclic group which may have the above-mentioned substituent in the ring include 2-thiazolyl group, 4-thiazolyl group, 5-thiazolyl group, 2-thienyl group, 3-thienyl group, 2-pyridyl group. , 3-pyridyl group, 4-pyridyl group, 2-indolyl group, 3-indolyl group, 4-imidazolyl group and the like. Specific examples of the heterocyclic lower alkyl group which may have the above-mentioned substituent in the ring include 2
-Thiazolylmethyl group, 4-thiazolylmethyl group, 5-
Thiazolylmethyl group, 2- (2-thiazolyl) ethyl group, 2- (4-thiazolyl) ethyl group, 2- (5-thiazolyl) ethyl group, 2-thienylmethyl group, 3-thienylmethyl group, 2- (2- Thienyl) ethyl group, 2- (3
Examples include -thienyl) ethyl group, 2-pyridylmethyl group, 3-pyridylmethyl group, 4-pyridylmethyl group, 2-indolylmethyl group, 3-indolylmethyl group, 4-imidazolylmethyl group and the like.

The group represented by R ⁵² is a hydrogen atom, an aryl group, an aralkyl group, a carboxy group, a carbamoyl group or an N group.
A mono-lower alkylcarbamoyl group, an N, N-di-lower alkylcarbamoyl group or an N-arylcarbamoyl group or together with R ⁷ form a single bond.

The group represented by R ⁶² is a hydrogen atom, a lower alkyl group, a lower alkenyl group, an aryl group, an aryl lower alkyl group, a 5- to 10-membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group ( The lower alkyl group, the lower alkenyl group, the aryl group, the aryl lower alkyl group, the 5- to 10-membered heterocyclic group and the heterocyclic lower alkyl group are independently a hydroxyl group or a lower alkyl group on their chain and / or ring. , Halogen atom, lower alkoxy group, aryloxy group, acyloxy group, carboxyl group, protected carboxyl group, amino group, monoalkylamino group, dilower alkylamino group, carbamoyl group, N-monolower alkylcarbamoyl group, N , N-di-lower alkylamino group, lower alkoxycarbonylamino group or aryloxycarbonylamido Means may) have a group. Specific examples of the lower alkyl group which may have the above substituent on the chain include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group and sec.
-Butyl group, tert-butyl group, pentyl group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, hydroxymethyl group, 1-hydroxyethyl group, 2-hydroxyethyl group, 1-hydroxypropyl group, 2- Hydroxypropyl group, 3-hydroxypropyl group, 1-hydroxy-1-methylethyl group, 2-hydroxy-1-methylethyl group, 1-hydroxybutyl group, 2-hydroxybutyl group, 3-hydroxybutyl group, 4- Examples thereof include a hydroxybutyl group, a 1-hydroxy-1-methylpropyl group and a 2-hydroxy-1-methylpropyl group. Specific examples of the lower alkenyl group which may have the above substituent on the chain include 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, 5-pentenyl group and the like can be mentioned. Specific examples of the aryl group which may have the above-mentioned substituent in a ring include:
Examples thereof include a phenyl group, a 1-naphthyl group and a 2-naphthyl group. Specific examples of the aryl lower alkyl group which may have the above-mentioned substituent in a ring include benzyl group, 1-phenylethyl group, 2-phenylethyl group, 1-phenylpropyl group, 2-phenylpropyl group and 3 -Phenylpropyl group, 1-methyl-2-phenylethyl group, 1-phenylbutyl group, 2-phenylbutyl group, 3-phenylbutyl group, 4-phenylbutyl group, 1-phenyl-2-
Examples thereof include a methylpropyl group and a 2-phenyl-1-methylpropyl group. Specific examples of the heterocyclic group which may have the above-mentioned substituent in the ring include 2-thiazolyl group, 4-
Thiazolyl group, 5-thiazolyl group, 2-thienyl group, 3
-Thienyl group, 2-pyridyl group, 3-pyridyl group, 4-
Pyridyl group, 2-indolyl group, 3-indolyl group, 4
—Imidazolyl group and the like. Specific examples of the heterocyclic lower alkyl group which may have the above-mentioned substituent in the ring include 2-thiazolylmethyl group, 4-thiazolylmethyl group, 5-thiazolylmethyl group, 2- (2-thiazolyl)
Ethyl group, 2- (4-thiazolyl) ethyl group, 2- (5
-Thiazolyl) ethyl group, 2-thienylmethyl group, 3-
Thienylmethyl group, 2- (2-thienyl) ethyl group, 2
-(3-thienyl) ethyl group, 2-pyridylmethyl group,
A 3-pyridylmethyl group, a 4-pyridylmethyl group, a 2-indolylmethyl group, a 3-indolylmethyl group, a 4-imidazolylmethyl group and the like can be mentioned.

The group represented by R ⁷ means a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group, or R
Together with ⁵² form a single bond. Specific examples of the lower alkyl group include a methyl group and an ethyl group, and specific examples of the lower alkoxy group include a methoxy group and an ethoxy group.

The group represented by R ⁸² is a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group, or any 1 to 5 hydrogen atoms on the benzene ring are independently substituted with a lower alkyl group or a halogen atom. It may be a phenylsulfonyl group or a carboxymethyl group, and specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group, and specific examples of the lower alkylsulfonyl group. Include a methylsulfonyl group, an ethylsulfonyl group, a propylsulfonyl group, and the like, and phenyl in which any 1 to 5 hydrogen atoms on the benzene ring may be independently substituted with a lower alkyl group or a halogen atom. Specific examples of the sulfonyl group include phenylsulfonyl group, p-tolylsulfonyl group, 2,4 6- trimethylphenyl sulfonyl group, 2,4,6-triisopropyl phenyl sulfonyl group, 2,3,4,5,6-pentafluorophenyl sulfonyl group and the like.

The group represented by R ⁸³ means a hydrogen atom or a lower alkyl group, and specific examples of the lower alkyl group include a methyl group, an ethyl group, a propyl group, an isopropyl group and a butyl group.

The group represented by R ⁵³ is a hydrogen atom, a lower alkyl group, a carboxy lower alkyl group, a formula: Ar- (C
H ₂ ) _u- (wherein Ar and u have the above-mentioned meanings). Specific examples of the lower alkyl group include a methyl group, an ethyl group and a propyl group, and specific examples of the carboxy lower alkyl group include a carboxymethyl group and a 2-carboxyethyl group.
Ar- (CH _{2) u} - Specific examples of a group represented by the benzyl group, 2-furylmethyl group, 3-furylmethyl group,
Examples thereof include 2-thienylmethyl group and 3-thienylmethyl group.

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

The compounds of the present invention generally have the general formula [VI
II] (in the formula, R ¹ , R ² , A ¹ and p have the above-mentioned meanings), a general formula [IX] (in the formula,
R ⁴ , X ¹ and X ³ have the above-mentioned meanings)
-Amino acid or α-hydroxycarboxylic acid and the general formula [X] (wherein A ² has the above meaning)

[0065]

[Chemical 6] It can be produced by sequentially condensing the compound represented by, and further, by removing the side chain and the terminal protecting group, if necessary.
Furthermore, in some cases, these novel compounds can be produced by converting them into their pharmaceutically acceptable salts.

A detailed description will be given below.

In the compound of the present invention, X in the general formula [I]
^The compound characterized in that ³ is an oxygen atom can be obtained by converting the carboxylic acid represented by the general formula [VIII] into the general formula

[0068]

[Chemical 7] (In the formula, P ¹ represents a carboxyl protecting group, and X ¹ and R ⁴
Has the above meaning) and is condensed with an α-amino acid derivative or α-hydroxycarboxylic acid derivative,

[0069]

[Chemical 8] A compound represented by the formula (wherein R ¹ , R ² , R ⁴ , A ¹ , p and P ¹ have the above-mentioned meanings) and then deprotecting the carboxyl protecting group P ¹ of the compound. Alternatively, it can be produced by converting the -OP ¹ moiety into a suitable carboxyl activating group and then condensing it with the compound represented by the general formula [X]. The condensation reaction for obtaining the compounds represented by the general formulas [XII] and [I] is performed by a known method such as DCC method, azide method, active ester method, mixed acid anhydride method [eg, M. Bodanski (M. Bodansky)
And M. Ondett
i) work, peptide synthesis, interscience,
New York (Peptide Synthesis, I
interscience, New York) 1966
Year; FM Finn and K. Hofmann, The Proteins, Volume 2, H. Nenrath and Earl L. Edited by RL Hill, Academic Press Incorporated, New York (Acade)
mic Press Inc. , New York) 1
976; Nobuo Izumiya et al., Peptide Synthesis, Maruzen Co., Ltd. 1
1975, etc.].

For example, when condensation is performed by the DCC method, the compound represented by the general formula [VIII] is DMSO, NMP, DMF, THF, 1,4-dioxane, acetonitrile, dichloromethane at about -40 ° C to room temperature. In a solvent such as chloroform, for example DCC (or EDCI.HC
1) by the action of a condensing agent such as —HOBT · H ₂ O, the compound represented by the general formula [XI] is condensed to give the compound of the general formula [XI]
I] is produced. The carboxyl protecting group is selected from methyl, ethyl, tert-butyl ester and the like, and should be selected according to the side chain functional group or protecting group so that the protecting group can be selectively removed after condensation. is there. For example, when a side chain has a functional group or a protecting group which is unstable under acidic conditions but stable under basic conditions, the carboxyl group is preferably protected as a methyl or ethyl ester. On the other hand, when the side chain has a functional group or a protecting group which is stable under acidic conditions but unstable under basic conditions, it is preferable to protect the carboxyl group as a tert-butyl ester. The tert-butyl ester can be easily removed by the action of formic acid, TsOH, TFA or the like.

The derivative thus prepared [XI
The compound obtained by removing the carboxyl protecting group P ¹ of [I] is added to a condensing agent (for example, EDCI · HCl-
The target compound can be produced by reacting the compound represented by the general formula [X] in the presence of (HOBT.H ₂ O etc.).

On the other hand, excess hydrazine is acted on the above compound [XII] in which X ¹ is —NR ⁴ — (wherein R ⁴ has the above-mentioned meaning) in a solvent such as methanol or DMF at room temperature. The desired compound can also be obtained by the azide method after the hydrazide is formed. That is, the hydrazide is treated with a reagent such as a lower alkyl nitrite (eg, tert-butyl nitrite, isoamyl nitrite) or an alkali metal nitrite (eg, sodium nitrite, potassium nitrite) in the presence of a strong acid such as hydrochloric acid or sulfuric acid. Reaction and conversion to the corresponding acid azide (this reaction is about -60 ° C to -15 ° C)
Water and / or DMF, THF or 1,4-at the temperature of
It can be carried out in the presence of a solvent such as dioxane), followed by addition of a tertiary amine such as TEA at a temperature of -70 ° C to -60 ° C, followed by addition of the compound [X] and reaction at -20 ° C to room temperature. By doing so, the desired compound [I] can be obtained. When [X] to be used contains a carboxyl group, the carboxyl group may be protected or may be used as a salt of tetrabutylammonium, triethylammonium, sodium, potassium or the like.

In the above production method, the compound [VIII],
In the condensation of [IX] and [X], the compound [X] is condensed last to produce the desired derivative. On the other hand, even if the compound [VIII] is condensed last, the desired derivative is obtained. Can be manufactured.

That is, the general formula

[0075]

[Chemical 9] [In the formula, P ² represents a hydrogen atom or an α-amino protecting group,
R ⁴ and X ¹ have the above-mentioned meanings] and the compound represented by the general formula [X] are condensed by the DCC method or the azide method to give a compound represented by the general formula

[0076]

[Chemical 10] (In the formula, R ⁴ , X ¹ , A ² and P ² have the above meanings)
A compound represented by A suitable α-amino protecting group is Z
Group, a Boc group, a urethane-type protecting group such as a p-methoxybenzyloxycarbonyl group and a p-nitrobenzyloxycarbonyl group, and when a carboxyl group is present at the terminal of [X], the carboxyl group is an ester group. Can be protected as For example, when the terminal carboxyl group is protected as tert-butyl ester, the α-amino protecting group is preferably Z group or Boc group. Z group is by catalytic hydrogenolysis, and Boc group is
It can be easily removed by allowing a mild acid such as formic acid or TFA to act under ice cooling, but the terminal carboxyl protecting group is stable under this condition.

The derivative thus prepared [XI
V], the compound obtained by removing the amino-protecting group P ² from
Similar to the above, a condensing agent (for example, EDCI.HCl-HOB
In the presence of (T.H ₂ O etc.), condensation with the carboxylic acid [VIII] can be carried out to produce the desired compound derivative.

In the compound of the present invention produced by the above method, the terminal protecting group can be removed by an appropriate method, if necessary. For example, if the carboxyl group is tert
-If protected as a butyl ester, it can be easily removed by acidolysis. That is, it can be removed by acting a mild acid such as formic acid or TFA. In the case of methyl or ethyl ester, the protecting group can be removed by alkaline hydrolysis. That is, methanol, ethanol, DM
It can be removed by acting sodium hydroxide, potassium hydroxide or the like in a solvent such as F, THF or 1,4-dioxane.

To obtain a compound characterized in that X ³ in the compound [I] of the present invention is a sulfur atom, the compound [XI
II] and the compound [X] are condensed and then reacted with Lawesson's reagent or the like to give a compound of the general formula

[0080]

[Chemical 11] [Wherein R ⁴ , X ¹ , A ² and P ² have the above meanings]
It may be converted to a compound represented by the formula (1), and then P ² is deprotected and condensed with the compound [VIII] in the same manner as described above. The reaction with the Low Esson reagent can be carried out at room temperature to the boiling point of the solvent using THF, benzene, toluene or the like as the solvent.

Among the compounds of the present invention, the compound of the general formula [I] wherein p is 1 or 2 is characterized in that p is 0 at an appropriate stage of the above synthetic method. It is also possible to produce the compound by oxidizing with a suitable oxidizing agent. Examples of the oxidizing agent used in this oxidation reaction include hydrogen peroxide, tert-butyl hydroperoxide, performic acid, peracetic acid, mCPBA, and periodic acid. The equivalent weight to be used and reaction conditions should be adjusted appropriately. Thus, the compound of the general formula [I] in which p is 1 or 2 can be selectively produced.
The oxidation reaction may be carried out on the compound [XII] or [I]. At this time, when a group unstable to the oxidation reaction exists in [XII] or [I], Those functional groups should be protected with a suitable protecting group. For example, the carboxyl group is preferably protected as a lower alkyl ester, and the indole ring is preferably protected with a formyl group or a lower alkoxycarbonyl group. The reaction is dichloromethane, chloroform,
It can be carried out in a solvent such as acetic acid or formic acid at -50 ° C to the boiling temperature of the solvent. Next, the production method of the compound [VIII] which is important for producing the compound of the present invention will be described.

The compound [VIII] can be produced generally as one having a desired stereochemistry by asymmetric synthesis or optical resolution of a racemate. Asymmetric synthesis [VI
II], the corresponding carboxylic acid can be prepared, for example, by the method of Evans et al. [Journal of
American Chemical Society (J. Am. Ch
em. Soc. ) Vol. 112, pp. 8215-8216 (1990)]

[0083]

[Chemical 12] (Wherein R ² has the above-mentioned meaning), after conversion into N-alkanoyloxazolidone, the oxazolidone derivative is converted into an equivalent amount of a Lewis acid such as titanium tetrachloride and diisopropylethylamine or sodium hexahydrate in a solvent such as dichloromethane. Treated with a base such as methyldisilazide and then treated with the general formula

[0084]

[Chemical 13] (Wherein E ¹ represents a protected hydroxyl group or a suitable leaving group, E ² represents a leaving group, and A ¹ has the above-mentioned meaning). Having the stereochemistry of

[0085]

[Chemical 14] (In the formula, E ³ represents a hydroxyl group or E ¹ , and R ² , A ¹ and E ¹
Has the above-mentioned meaning).
Further, the compound [XVIII] is represented by the general formula

[0086]

[Chemical 15] Compound [VIII] having a desired stereochemistry can be produced by reacting with a compound represented by the formula (wherein R ¹ and p have the above-mentioned meanings).

Next, a method for obtaining a compound having a desired stereochemistry by optical resolution of a racemate will be described. General formula synthesized by an appropriate method

[0088]

[Chemical 16] (Wherein R ¹ , R ² , A ¹ and p have the above-mentioned meanings)
The carboxylic acid represented by the following is converted to a salt with an optically active amine, and the diastereomeric salt is optically resolved by a known method such as recrystallization, or the carboxylic acid is
By condensation with an optically active alcohol or amine, the resulting diastereomeric ester or amide is separated by a known means such as chromatography, and the ester or amide is hydrolyzed to give a carboxylic acid having a desired stereochemistry. The acid [XX] can be produced.
At this time, if the deprotected form of the general formula [XI] or the general formula [XIV] is used as the optically active alcohol or amine,
Then, the condensate is diastereomerically decomposed to directly obtain the compound [XII] or [I] having the desired stereochemistry.

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

DL-3- (3-ethoxycarbonylphenyl) alanine and DL-3- (4-methoxycarbonylphenyl) alanine [Synthesis
s), 53 (1984)] D-3- (3-benzothienyl) alanine [Chemical
And Pharmaceutical Bulletin (Che
m. Pharm. Bull. ), 24 , 3149 (19
76)] D-S-methyl cysteine, D-S-ethyl cysteine, D-S-n-propyl cysteine [Nobuo Izumiya et al., Peptide Synthesis, Maruzen 1975] D-norleucinol [Journal of American Chemical Society. (J. Am. Chem. So
c. ), 107 , 7974 (1985). ] In addition, in Example No. corresponding to the structure of the compound manufactured by the Example. And compound No. Are shown in Table 1 below.

[0092]

[Table 1]

[0093]

[Table 2] Next, the endothelin antagonism of the peptide derivative of the present invention will be described. Endothelin binding inhibition test to ET _A receptor Porcine aortic smooth muscle tissue was treated with 10 mM MOPS at 4 ° C.
Homogenize with Polytron in pH 7.4 buffer. Add 20% sucrose to the homogenate, centrifuge at 1000Xg for 15 minutes, and add 10% supernatant.
It was centrifuged at 000 × g for 15 minutes. Add this supernatant to 9
After centrifuging at 0000Xg for 40 minutes, the resulting precipitate is 5m.
The 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) with 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 an hour, 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.

[0095]

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

As shown in Table 2, the compounds of the present invention are ET
It was found to have an extremely strong inhibitory activity on endothelin binding to the _A receptor. The test compound is the compound No. It showed with.

[0097]

[Table 3] 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) with 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 an hour, 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.

[0099]

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

[0100]

[Table 4] As shown in Table 3, the compounds of the present invention were found to have extremely strong inhibitory activity on endothelin binding to the ET _B receptor. The test compound is the compound No. It showed with.

As described above, the compound of the present invention has an excellent endothelin antagonism, and is useful as a vasodilator and a bronchodilator in the field of pharmaceuticals, and thus, hypertension, pulmonary hypertension,
Rayno's disease, acute renal failure, myocardial infarction, angina, cerebral infarction,
It can be a therapeutic drug for cerebral vasospasm, arteriosclerosis, 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. 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 additives such as auxiliary agents, stabilizers, wetting agents, emulsifiers, absorption promoters or surfactants which are usually used.
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 or talc.

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 and the like. 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, in the case of parenteral administration, 0.1 per day.
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 compounds 1A, 1B, 2A and 2B (1) Synthesis of 2-cyclohexylthiomethyl-4-methylpentanoic acid 56.5 mg of sodium hydride and 0 of cyclohexanethiol in 15 ml of ice-cooled ethanol under an argon atmosphere. 0.86 ml and 1.60 ml of ethyl 2-isobutyl-2-propenoate were added. The mixture was warmed to room temperature and stirred overnight. Saturated ammonium chloride aqueous solution (100 ml)
Was added to stop the reaction, and the mixture was extracted with ethyl acetate (30 ml × 3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by dry column flash chromatography (Merck & Co., Inc. silica gel 60 / hexane: ethyl acetate = 4: 1) to obtain 2.0 g of ethyl 2-cyclohexylthiomethyl-4-methylpentanoate as a colorless oil. .. To a solution of 1.97 g of this product in ethanol (30 ml) was added 11.6 ml of a 1N aqueous potassium hydroxide solution, and the mixture was heated under reflux for 5 hours. The reaction solution was concentrated under reduced pressure, the residue was dissolved in water (30 ml), and washed with ethyl acetate. The aqueous layer was adjusted to pH 2 with 1N hydrochloric acid and then extracted with ethyl acetate (30 ml × 3). The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the desired product (1.66 g).
Was obtained as a pale yellow oil.

FAB-MS (m / e, (C ₁₃ H ₂₄ O ₂ S
+ H) ⁺ ): 245 (2) Synthesis of DTrp (CHO) -OMe.TFA Boc-DTrp (CHO) -OH 2.05 g, DM
A solution of 75.3 mg of AP and 0.30 ml of methanol in dichloromethane (20 ml) was added to EDCI.HCl under ice cooling.
1.42 g was added, and the mixture was left for 1 hour and then at room temperature for 1 hour.
Stir for hours. After diluting the reaction solution with dichloromethane, 10
% Aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and Boc
1.97 g of -DTrp (CHO) -OMe was obtained. 1.97 g of this product was dissolved in 15 ml of TFA under ice cooling, and the mixture was stirred for 10 minutes as it was, and then TFA was distilled off under reduced pressure. Ether was added to the residue and the precipitated solid was collected by filtration to obtain the desired product 1.9.
2 g was obtained.

FAB-MS (m / e, (C ₁₃ H ₁₄ N ₂ O ₃
+ H) ⁺ ): 247 (3) (2S) -2-cyclohexylthiomethyl-4-
Synthesis of methylpentanoyl-DTrp (CHO) -OMe 2-Cyclohexylthiomethyl-4-obtained in (1)
1.31 g of methylpentanoic acid, DTr obtained in (2)
p (CHO) -OMeTFA 1.92 g and HOB
A solution of 1.03 g of T.H ₂ O in dichloromethane (40 m
l), under ice cooling TEA 0.74 ml and EDCI · H
1.30 g of Cl was added. The mixture was stirred at room temperature for 2 hours, water (50 ml) was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with 10% aqueous citric acid solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was subjected to silica gel column chromatography (Wakogel C-200 / chloroform: ethyl acetate = 20: 1).
Were isolated and purified by the procedure described above to obtain 0.144 g of the desired product as a colorless oily substance.

FAB-MS (m / e, (C ₂₆ H ₃₆ N ₂ O ₄
S + H) ⁺ ): 473 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.81 (3H, d, J = 6.2Hz), 0.86 (3
H, d, J = 6.3 Hz), 1.00-2.00 (13
H, m), 2.28-2.45 (1H, m), 2.45
-2.68 (2H, m), 2.68-2.78 (1H,
m), 3.24-3.32 (2H, m), 3.71 (3
H, s), 5.02 (1H, dt, J = 7.4Hz,
6.1 Hz), 6.28 (1H, d, J = 7.4H)
z), 7.16-7.77 (4H, m), 8.34-
8.48 (1H, m), 9.05 + 9.40 (1H, b
rs × 2) (4) (2S) -2-[(RS) -cyclohexylsulfinylmethyl] -4-methylpentanoyl-DTrp
Synthesis of -OH (2S) -2-Cyclohexylthiomethyl-4-methylpentanoyl-DTrp (CHO)-obtained in (3)
A solution of mCPBA (32.9 mg) in dichloromethane (0.8 ml) was added to a solution of OMe (88.5 mg) in dichloromethane (1 ml), and the mixture was stirred for 1 hour as it was.
The solvent was distilled off under reduced pressure, and the resulting residue was subjected to medium pressure liquid chromatography (Merck Rover Column Licroprep SI60 / hexane: ethyl acetate = 1: 5), followed by preparative thin layer chromatography (Merck silica gel 60F _254). / Hexane: ethyl acetate = 1: 5) and purified, (2S) -2-[(RS) -cyclohexylsulfinylmethyl] -4-methylpentanoyl-DTrp.
48.8 mg of (CHO) -OMe was obtained. The whole amount of this product was dissolved in 0.5 ml of methanol, 0.4 ml of a 1N sodium hydroxide aqueous solution was added, and the mixture was stirred at room temperature for 1.5 hours. The reaction mixture was adjusted to pH 2 with 1N hydrochloric acid, concentrated under reduced pressure to dryness, and the obtained solid was dissolved in chloroform, and the insoluble material was filtered off. The chloroform layer was concentrated under reduced pressure to dryness, and the target product 3
Obtained 5.6 mg as a pale yellow solid.

FAB-MS (m / e, (C ₂₄ H ₃₄ N ₂ O ₄
S + H) ⁺ ): 447 (5) Synthesis of compounds 1A and 1B (2S) -2-[(RS) -cyclohexylsulfinylmethyl] -4-methylpentanoyl-DTrp-OH 34. 4 mg, DTrp-OMe
HCl 19.8 mg and HOBT.H ₂ O 11.9
To a suspension of mg of dichloromethane (0.7 ml), 10.7 μl of TEA and EDCI.HCl 17.7 under ice cooling.
mg was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was diluted with dichloromethane (20 ml), washed successively with saturated aqueous sodium hydrogen carbonate solution, 10% aqueous citric acid solution and water, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was separated and purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / hexane: ethyl acetate = 1: 5). Among the diastereomers derived from the asymmetry of sulfoxide, the one with low polarity was designated as compound 1A and the one with high polarity was designated as compound 1B, and 15.7 mg of compound 1A and 33.8 mg of compound 1B were obtained. Compound 1A FAB-MS (m / e, as (C ₃₆ H ₄₆ N ₄ O ₅ S + H) ⁺ ): 647 Rf value: 0.49 (hexane: ethyl acetate = 1: 5) Compound 1B FAB-MS (m / e e, (as C ₃₆ H ₄₆ N ₄ O ₅ S + H) ⁺ ): 647 Rf value: 0.43 (hexane: ethyl acetate = 1: 5) (6) Synthesis of compound 2A Compound 1A obtained in (5) A solution of 14.4 mg of methanol (0.2 ml) in 1N sodium hydroxide solution 4
4 μl was added, and the mixture was stirred at room temperature for 2 hours. 1N in the reaction solution
The residue obtained by adding hydrochloric acid to pH 2 and concentrating to dryness under reduced pressure was purified by preparative thin-layer chromatography (3M company Empire silica gel sheet / chloroform: methanol: acetic acid = 10: 1: 1). Then, 9.7 mg of the desired product was obtained.

Melting point: 137-141 ° C IR (KBr, cm ^-1 ): 3412, 3064, 293
8, 2860, 1734, 1665, 1524, 145
8,1341,1233,1011,741 High resolution FAB-MS (m / e, (C ₃₅ H ₄₄ N ₄ O ₅ S +
H) ⁺ ): Calculated value 633.3111 Measured value 633.3140 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.55 (3H, d, J = 6.6Hz), 0.6
2 (3H, d, J = 6.4 Hz), 1.00-2.20
(14H, m), 2.50-2.90 (4H, m),
3.10-3.30 (3H, m), 4.45 (1H,
m), 4.68 (1H, m), 6.93-7.08 (4
H, m), 7.10 (1H, d, J = 2.2 Hz),
7.18 (1H, d, J = 2.2Hz), 7.30 (1
H, d, J = 7.9 Hz), 7.33 (1H, d, J =
7.6 Hz), 7.53 (1H, d, J = 7.9H
z), 7.58 (1H, d, J = 7.6Hz), 8.3
2 (1H, d, J = 6.7 Hz), 8.34 (1H,
d, J = 8.3 Hz), 10.77 (1H, d, J =
2.2Hz), 10.82 (1H, d, J = 2.2H
z) (7) Synthesis of compound 2B Using the compound 1B obtained in (5), the same reaction as in (6) was carried out to obtain the desired product.

Melting point: 138-142 ° C IR (KBr, cm ^-1 ): 3418, 2932, 286
0, 1665, 1581, 1530, 1458, 139
2,1341,1236,1212,1131,110
4,1008,741 High resolution FAB-MS (m / e, (C ₃₅ H ₄₄ N ₄ O ₅ S +
H) ⁺ ): Calculated value 633.3111 Measured value 633.3124 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.57 (3H, d, J = 6.3Hz), 0.6
5 (3H, d, J = 6.4 Hz), 0.79-1.37
(7H, m), 1.47-1.91 (6H, m), 2.
70-2.91 (4H, m), 3.04-3.25 (4
H, m), 4.40-4.53 (1H, m), 4.53
-4.67 (1H, m), 6.94 (1H, t, J =
7.8 Hz), 6.97 (1H, t, J = 7.9H
z), 7.03 (1H, t, J = 7.8Hz), 7.0
5 (1H, t, J = 7.9Hz), 7.10 (1H,
d, J = 2.2 Hz), 7.18 (1H, d, J = 2.
3Hz), 7.29 (1H, d, J = 7.8Hz),
7.32 (1H, d, J = 7.9Hz), 7.52 (1
H, d, J = 7.8 Hz), 7.57 (1H, d, J =
7.9 Hz), 8.05 (1H, d, J = 6.8H
z), 8.37 (1H, d, J = 8.1 Hz), 10.
77 (1H, d, J = 2.3Hz), 10.83 (1
H, d, J = 2.2 Hz) Example 2 Synthesis of compounds 3 and 4 (1) Synthesis of (2S) -2-cyclohexylsulfonylmethyl-4-methylpentanoyl-DTrp-OH Example 1- (3) (2S) -2-Cyclohexylthiomethyl-4-methylpentanoyl-DTrp obtained in
To a solution of 48.2 mg of (CHO) -OMe in dichloromethane (0.5 ml) was added 43.9 mg of mCPBA, and the mixture was stirred at room temperature for 1 hour. Then, the same operation as in Example 1- (4) was performed to obtain 41.2 mg of the desired product.

FAB-MS (m / e, (C ₂₄ H ₃₄ N ₂ O ₅
S + H) ⁺ ): 463 (2) Synthesis of compound 3 (2S) -2-cyclohexylsulfonylmethyl-4-methylpentanoyl-DTrp-OH obtained in (1).
Using the above, the same operation as in Example 1- (5) was performed to obtain the desired product.

FAB-MS (m / e, (C ₃₆ H ₄₆ N ₄ O ₆
As S + H) ⁺ ): 663 (3) Synthesis of Compound 4 Using the compound 3 obtained in (2), the same operation as in Example 1- (6) was carried out to obtain the desired product.

Melting point: 128-137 ° C. IR (KBr, cm ^-1 ): 3382, 3064, 293
8, 2866, 1734, 1662, 1581, 152
7,1461,1392,1344,1296,126
9,1233,1128,744,612 High Resolution FAB-MS (m / e, (C 35 H 44 N 4 O 6 S +
H) ⁺ ): Calculated value 649.3060 Measured value 649.3040 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp
m): 0.51 (3H, d, J = 6.4Hz), 0.6
0 (3H, d, J = 6.1Hz), 0.90-2.00
(13H, m), 2.70-2.98 (4H, m),
3.00-3.27 (4H, m), 4.39-4.52
(1H, m), 4.52-4.69 (1H, m), 6.
91-7.09 (4H, m), 7.12 (1H, d, J
= 2.0 Hz), 7.19 (1H, d, J = 2.1H
z), 7.28 (1H, d, J = 7.2 Hz), 7.3
2 (1H, d, J = 7.8Hz), 7.52 (1H,
d, J = 7.2 Hz), 7.63 (1H, d, J = 7.
8 Hz), 8.12-8.25 (1H, m), 8.46
(1H, d, J = 8.4 Hz), 10.77 (1H,
d, J = 2.1 Hz), 10.84 (1H, d, J =
2.0 Hz) Example 3 Synthesis of compounds 5A, 5B, 6A, 6B (1) Synthesis of (2S) -2-benzyloxymethyl-4-methylpentanoic acid (S)-(-)-4-benzyl-2 -A solution of 900 mg of oxazolidinone in THF (12 ml) was added to a solution of n-butyllithium in hexane (1.64 M) under an argon atmosphere.
3.16 ml was added at -78 ° C followed by 0.71 ml 4-methylpentanoic acid chloride. The reaction solution was heated to ice-cooling temperature and stirred for 30 minutes. To the reaction solution was added 5 ml of 1M potassium carbonate aqueous solution, and the mixture was stirred at room temperature for 1 hour,
The volatile components were distilled off under reduced pressure. The organic matter was extracted with dichloromethane, washed with water and saturated saline, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to obtain 1.31 g of a colorless oily substance. To a solution of 1.27 g of this oily substance in dichloromethane (12 ml), 4.85 ml of a solution of titanium tetrachloride in dichloromethane (1.0 M) was added dropwise under an argon atmosphere under ice cooling, and the mixture was stirred for 5 minutes. Next, 0.84 ml of diisopropylethylamine was added dropwise under ice cooling, and the mixture was stirred for 30 minutes. To this solution, 1.29 ml of benzyl chloromethyl ether was added dropwise under ice cooling, and the mixture was further stirred for 1.5 hours. After adding water to the reaction solution, the organic layer was diluted with ethyl acetate and separated. This solution was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (Merck, Inc. silica gel 60 / ethyl acetate: hexane = 1: 6) to obtain 1.45 g of a colorless oil. 156m of this oil
g in THF-H ₂ O (3: 1, v / v) 7.5 ml solution, 30% hydrogen peroxide aqueous solution 0.2 ml and lithium hydroxide monohydrate 33.2 mg were added under ice cooling, and 1 Stir for hours. After removing excess peroxide by adding 0.58 ml of 1.5 N sodium sulfite aqueous solution to the reaction solution under ice cooling, an aqueous sodium hydrogen carbonate solution was added to adjust the pH to 9-1.
Adjusted to 0. The THF was distilled off under reduced pressure, the aqueous layer was washed with dichloromethane, acidified with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed with saturated saline and then concentrated under reduced pressure to obtain 87.5 mg of the desired product.

¹ H-NMR (90 MHz, CDCl ₃ , δ
ppm): 0.92 (6H, d, J = 7Hz), 1.0
5-1.90 (3H, m), 2.81 (1H, m),
3.40-3.80 (2H, m), 4.53 (2H,
s), 7.17-7.40 (5H, m) (2) [(2S) -2-p-toluenesulfonyloxymethyl-4-methylpentanoyl] -DTrp (Bo
c) Synthesis of -OMe 87.5 mg of the compound obtained in (1) in dichloromethane (2
ml) solution, DTrp (Boc) -OMe.HCl
133 mg, NMM 43 μl and EDCI · HCl
78.2 mg was sequentially added under ice cooling, and the mixture was stirred for 2 hours. The reaction solution was diluted with ethyl acetate, washed with water, and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / ethyl acetate: hexane = 1: 2) to obtain a condensate 148 mg. This is methanol 1.5
It was dissolved in ml and stirred with 20 mg of 10% palladium carbon at room temperature for 20 hours under a hydrogen atmosphere at atmospheric pressure. The catalyst was filtered off, and the filtrate was concentrated under reduced pressure to obtain 117 mg of the corresponding alcohol compound. To a solution of 117 mg of this alcohol derivative in dichloromethane (1.2 ml), under argon atmosphere, 24 μl of pyridine, 57 mg of TsCl and DMA.
The amount of P catalyst was added at room temperature, and the mixture was stirred as it was for 24 hours. The reaction solution was diluted with ethyl acetate, washed successively with 10% aqueous citric acid solution and saturated brine, and dried over anhydrous magnesium sulfate. This solution was concentrated under reduced pressure, and the residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / ethyl acetate: hexane = 1: 2) to obtain 85 m of the desired product.
g was obtained.

¹ H-NMR (300 MHz, CDCl ₃ ,
δppm): 0.74 (3H, d, J = 6.4Hz),
0.75 (3H, d, J = 6.4Hz), 1.04-
1.16 (1H, m), 1.20-1.34 (1H,
m), 1.34 to 1.46 (1H, m), 1.66 (9
H, s), 2.42 (3H, s), 2.47-2.60.
(1H, m), 3.17 (1H, dd, J = 5.9H
z, 14.5 Hz), 3.24 (1H, dd, J = 4.
2Hz, 14.5Hz), 3.70 (3H, s), 3.
98 (1H, dd, J = 5.4Hz, 9.4Hz),
4.07 (1H, dd, J = 9.4Hz, 14.0H
z), 4.92 (1H, ddd, J = 4.2 Hz, 5.
9 Hz, 8.1 Hz), 6.21 (1H, d, J = 8.
1Hz), 7.22 (1H, t, J = 7.4Hz),
7.29 (2H, d, J = 8.3 Hz), 7.30 (1
H, t, J = 7.4 Hz), 7.39 (1H, s),
7.49 (1H, d, J = 7.4Hz), 7.71 (2
H, d, J = 8.3 Hz), 8.11 (1H, d, J =
7.4 Hz) (3) Synthesis of [(2S) -2-cycloheptylsulfinylmethyl-4-methylpentanoyl] -DTrp-OH Argon was added to a suspension of 4.1 mg of sodium hydride in DMF (0.5 ml) and argon. Cycloheptanethiol 23 under atmosphere
mg was added under ice cooling and stirred for 5 minutes. To this thiolate solution, 84.7 mg of DMF obtained in (2) was added.
The solution (1.5 ml) was added under ice cooling, and the mixture was further stirred for 20 minutes. A 10% aqueous citric acid solution was added to the reaction solution, and the mixture was diluted with ethyl acetate, and the organic layer was separated. The solution was washed with water, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to preparative thin-layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / ethyl acetate: hexane =
Purification at 1: 3) yielded 73.2 mg of a colorless oil.
23 mg of mCPBA was added to a solution of 72 mg of this oily substance in dichloromethane (3 ml) under ice cooling, and the mixture was stirred for 30 minutes. The reaction solution was concentrated, the residue was added, and the mixture was stirred for 30 minutes. The reaction mixture was concentrated, and the residue was purified by preparative thin layer chromatography (Merck & Co., Inc. silica gel 60F ₂₅₄ / ethyl acetate: hexane = 2: 1). 69 mg of the obtained pale yellow oily substance was cooled with formic acid under ice cooling. (1 ml) was added and the mixture was stirred at room temperature for 7 hours. This solution was concentrated under reduced pressure and methanol 0.5
Dissolve in 1 ml of 1N aqueous solution of sodium hydroxide under ice cooling 14
5 μl was added, and the mixture was stirred at room temperature for 24 hours. Methanol was distilled off under reduced pressure, water was added, acidified with 1N hydrochloric acid, extracted with ethyl acetate, and washed with saturated brine. This solution was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure, and the residue was subjected to preparative thin layer chromatography (3M Empore silica gel sheet / chloroform: methanol: acetic acid = 30: 1: 1).
23 mg of the target product was obtained by purification.

FAB-MS (m / e, (C ₂₅ H ₃₆ N ₂ O ₄
S + H) ⁺ ): 461 (4) Synthesis of compounds 5A and 5B 20 mg of the compound obtained in (3) and DTrp-OMe.
Dissolve 12 mg of HCl in 0.5 ml of dichloromethane, add 5.3 μl of NMM at room temperature, and further add H under ice cooling.
OBT · H ₂ O 6.5 mg and EDCI · HCl
9.2 mg was added, and the mixture was stirred at room temperature for 2 hours. The solution was concentrated under reduced pressure, the residue was dissolved in ethyl acetate, washed with 5% aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. This solution is concentrated under reduced pressure,
The residue was purified by preparative thin layer chromatography (Merck silica gel 60F ₂₅₄ / ethyl acetate: hexane = 4: 1) to recover purified by a sulfoxide body of interest as diastereoisomers, each 3.6 mg ( Compound 5A, low polarity), 13 mg (Compound 5B, high polarity)
Obtained. Compound 5A FAB-MS (m / e, as (C ₃₇ H ₄₈ N ₄ O ₅ S + H) ⁺ ): 661 Rf value: 0.27 (hexane: ethyl acetate = 1: 5) Compound 5B FAB-MS (m / e e, (as C ₃₇ H ₄₈ N ₄ O ₅ S + H) ⁺ ): 661 Rf value: 0.21 (hexane: ethyl acetate = 1: 5) (5) Synthesis of compounds 6A and 6B (4) Example 1 using compounds 5A and 5B
The desired product was obtained by carrying out the same reaction as in (6). Compound 6A Melting point: 103-108 ° C IR (KBr, cm ^-1 ): 3322, 3058, 292
6,2860,1734,1659,1533,146
4,134,1233,1101,1011,741 High resolution FAB-MS (m / e, (C ₃₆ H ₄₆ N ₄ O ₅ S +
H) ⁺ ): Calculated value 647.3267 Measured value 647.3234 ¹ H-NMR (300 MHz, Acetone-d ₆ , δ)
ppm): 0.62 (3H, d, J = 6.3Hz),
0.65 (3H, d, J = 6.3Hz), 0.82-
1.20 (3H, m), 1.24-2.00 (12H,
m), 2.57 (1H, dd, J = 3.5Hz, 12.
8 Hz), 2.65-2.90 (3H, m), 2.91
(1H, dd, J = 10.5Hz, 14.5Hz),
3.04 (1H, dd, J = 9.2Hz, 12.8H
z), 3.26-3.38 (2H, m), 4.66-
4.80 (2H, m), 6.98-7.13 (4H,
m), 7.15 (1H, d, J = 1.3 Hz), 7.2
1 (1H, d, J = 1.3 Hz), 7.30 (1H,
d, J = 7.3 Hz), 7.36 (1H, d, J = 8.
2Hz), 7.38 (1H, d, J = 8.2Hz),
7.54 (1H, d, J = 8.2Hz), 7.57 (1
H, d, J = 8.2 Hz), 8.17 (1H, d, J =
8.4 Hz), 10.09 (1H, d, J = 1.3H
z), 10.11 (1H, d, J = 1.3 Hz) Compound 6B Melting point: 123-128 ° C IR (KBr, cm ^-1 ): 3412, 3058, 292
6,2860, 1713, 1662, 1524, 146
4,1443,1359,1344,1230,110
1,1011,741 High resolution FAB-MS (m / e, (C ₃₆ H ₄₆ N ₄ O ₅ S +
H) ⁺ ): Calculated value 647.3267 Measured value 647.3176 ¹ H-NMR (300 MHz, Acetone-d ₆ , δ)
ppm): 0.65 (3H, d, J = 6.0Hz),
0.70 (3H, d, J = 6.0Hz), 0.80-
0.93 (1H, m), 1.05-1.20 (2H,
m), 1.25-2.00 (12H, m), 2.55
(1H, dd, J = 2.8Hz, 12.7Hz), 2.
65-2.90 (3H, m), 2.93 (1H, dd,
J = 9.8Hz, 14.9Hz), 3.02 (1H, d
d, J = 10.9 Hz, 12.7 Hz), 3.20-
3.38 (2H, m), 4.70-4.87 (2H,
m), 6.93-7.12 (4H, m), 7.15 (1
H, d, J = 1.3 Hz), 7.24 (1H, d, J =
1.3 Hz), 7.35 (1H, d, J = 8.2H
z), 7.38 (1H, d, J = 8.2 Hz), 7.4
0 (1H, d, J = 6.2Hz), 7.59 (1H,
d, J = 8.2 Hz), 7.62 (1H, d, J = 8.
2Hz), 7.80 (1H, d, J = 7.8Hz), 1
0.00 (1H, d, J = 1.3Hz), 10.12
(1H, d, J = 1.3 Hz) Example 4 Synthesis of compounds 7A, 7B, 8A, 8B (1) Synthesis of 2-acetylthiomethyl-4-methylpentanoic acid 2-isobutyl-2-pentenoic acid 4. 98 g was melt | dissolved in 5 ml of thioacetic acid, and it heat-stirred at 85 degreeC under argon atmosphere for 2 hours. The residue obtained by distilling off excess thioacetic acid under reduced pressure was purified by silica gel column chromatography (Merck & Co., Inc. silica gel 60 / chloroform → ethyl acetate) to obtain 6.46 g of the desired product as a colorless solid.

FAB-MS (m / e, (C ₉ H ₁₆ O ₃ S +
H) ⁺ ): 205 (2) (2S) -2-Acetylthiomethyl-4-methylpentanoyl-DTrp-OMe Synthesis 2-acetylthiomethyl-4-methylpentanoic acid 4 obtained in (1) 0.000 g, DTrp-OMe 4.99.
g, NMM 2.15 ml and HOBT · H ₂ O3.0
4 g of dichloromethane (65 ml) -DMF (40 m
l) To the mixed solution under ice cooling, EDCI · HCl 3.75
g was added, and the mixture was stirred as it was for 30 minutes and further at room temperature for 2.5 hours. The solvent was distilled off under reduced pressure, and the residue was dissolved in ethyl acetate. This solution was washed successively with water, a 7.5% aqueous sodium hydrogen carbonate solution, 1N hydrochloric acid and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure and the resulting residue was subjected to silica gel column chromatography (Merck & Co., Inc. silica gel 60 / hexane: ethyl acetate =
The product was purified by 2: 1 → 3: 2) to obtain 2.28 g of the desired product.

FAB-MS (m / e, (C ₂₁ H ₂₈ N ₂ O ₄
S + H) ⁺ ): 405 (3) Synthesis of (2S) -2-cyclopentylmethylthiomethyl-4-methylpentanoyl-DTrp-OMe 240 mg of the amino acid derivative obtained in (2) in methanol (2 ml) was added to -30 The mixture was cooled to ℃, and under argon atmosphere, sodium methoxide (37.6 mg) in methanol (2
ml) solution was added dropwise, and the mixture was stirred at 0 to 10 ° C for 2.5 hours. The reaction solution was cooled to −10 ° C. again, a solution of 220 mg of cyclopentylmethyl bromide in methanol (2 ml) was added, and the mixture was stirred at room temperature for 13.5 hours and further heated and stirred at 40 ° C. for 1.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution to stop the reaction, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate. The residue obtained after evaporation of the solvent under reduced pressure was subjected to silica gel column chromatography (Wakogel C-2
The product was purified with 00 / hexane: ethyl acetate = 3: 1) to obtain 175 mg of the desired product as a colorless oil.

FAB-MS (m / e, (C ₂₅ H ₃₆ N ₂ O ₃
S + H) ⁺ ): 445 (4) (2S) -2-cyclopentylmethylthiomethyl-4-methylpentanoyl-DTrp (COOMe)-
Synthesis of OMe 161 mg of amino acid derivative obtained in (3), powder 38.5 mg sodium hydroxide and TBAHS 13.6
A suspension of 70 mg of methyl chloroformate in dichloromethane (1.
5 ml) solution was added dropwise. The reaction mixture was stirred overnight at room temperature, saturated aqueous ammonium chloride solution was added to stop the reaction, and the mixture was extracted with ether. The ether layer was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (Wakogel C-200 / hexane: ethyl acetate = 4: 1) to obtain 166 mg of the desired product as a colorless powder.

FAB-MS (m / e, (C ₂₇ H ₃₈ N ₂ O ₅
S + H) ⁺ ): 503 (5) (2S) -2-[(RS) -Cyclopentylmethylthiosulfinylmethyl] -4-methylpentanoyl-DTrp (COOMe) -OMe Synthesis of amino acid derivative obtained in (4) Example 1- (4)
The desired product was obtained by reacting with mCPBA in the same manner as in.

FAB-MS (m / e, (C ₂₇ H ₃₈ N ₂ O ₆
S + H) as a ^+): 519 (6) Compound 7A, in methanol (1.0 ml) solution of the resulting amino acid derivative 29.7mg in the synthesis of 7B (5), sodium under ice-cooling 1N hydroxide solution 69μl and water 60μl And add 1.
Stir for 5 hours. 30 μl of 1N sodium hydroxide solution
Was added, and the mixture was stirred under ice cooling for another 1.5 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, followed by washing with ether and acidification of the solution with a 10% aqueous solution of citric acid. The organic matter was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and the solvent was concentrated to dryness under reduced pressure to give 26.1 mg of white powder. This powder 26.1
^{mg, DNle-O t Bu ·} HCl 15.7mg and HOBT · H ₂ O 11.6mg of DMF (0.5 m
l) To the solution, under ice cooling, 8.0 μl of NMM and EDCI.
HCl (14.2 mg) was added, and the mixture was stirred as it was for 30 minutes and further at room temperature for 3 hours. The solvent was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, washed with 10% aqueous citric acid solution, saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, and dried over anhydrous magnesium sulfate. The residue obtained by concentrating the solvent under reduced pressure was subjected to preparative thin-layer chromatography (Merck silica gel 60F ₂₅₄ / benzene: ethyl acetate = 1: 1).
Separated and purified in 1). Of the diastereomers derived from the asymmetry of sulfoxides, the less polar one was identified as compound 7
A having a high polarity and compound 7B were designated as compound 7B to obtain 7.6 mg of compound 7A and 17.3 mg of compound 7B. Compound 7A FAB-MS (m / e, as (C ₃₆ H ₅₅ N ₃ O ₇ S + H) ⁺ ): 674 Rf value: 0.46 (hexane: ethyl acetate = 1: 3) Compound 7B FAB-MS (m / e, (as C ₃₆ H ₅₅ N ₃ O ₇ S + H) ⁺ ): 674 Rf value: 0.40 (hexane: ethyl acetate = 1: 3) (7) Synthesis of compound 8A Compound 7A obtained in (6) 7.5 mg of T under ice cooling
It was dissolved in 2.2 ml of FA and stirred for 15 minutes as it was, and further for 1.5 hours at room temperature. After the TFA was distilled off under reduced pressure, the residue was reprecipitated from dichloromethane-methanol-hexane,
5.1 mg of compound 8A was obtained.

Melting point: 193-194 ° C. ¹ H-NMR (300 MHz, CDCl ₃ , δ ppm):
0.66 (3H, d, J = 6.1Hz), 0.71 (3
H, d, J = 6.1 Hz), 0.86 (3H, t, J =
6.8 Hz), 1.08-1.33 (8H, m), 1.
52-1.72 (6H, m), 1.78-1.96 (3
H, m), 2.12-2.28 (1H, m), 2.50
(1H, dd, J = 4.2Hz, 12.9Hz), 2.
59 (1H, dd, J = 8.7Hz, 12.7Hz),
2.66-2.76 (1H, m), 2.93 (1H, d
d, J = 6.4 Hz, 12.9 Hz), 3.16-3.
39 (3H, m), 4.01 (3H, s), 4.36
(1H, dt, J = 7.6Hz, 4.5Hz), 4.7
0 (1H, ddd, J = 4.2Hz, 6.4Hz, 7.
0Hz), 6.53 (1H, d, J = 7.0Hz),
7.26 (1H, t, J = 7.8Hz), 7.35 (1
H, t, J = 7.8 Hz), 7.51 (1H, s),
7.62 (1H, d, J = 7.8Hz), 7.72 (1
H, d, J = 7.8 Hz), 8.16 (1H, d, J =
7.6 Hz) (8) Synthesis of Compound 8B Using the compound 7B obtained in (6), the same operation as (7) was performed to obtain the target product.

Melting point: 194-195 ° C. ¹ H-NMR (300 MHz, CDCl ₃ , δ ppm):
0.76 (3H, d, J = 6.1Hz), 0.78 (3
H, d, J = 5.4 Hz), 0.83 (3H, t, J =
6.9 Hz), 1.14 to 1.29 (8H, m), 1.
52-1.70 (6H, m), 1.70-1.82 (1
H, m), 1.82-1.96 (2H, m), 2.22.
(1H, sept, J = 7.6 Hz), 2.54-2.
61 (2H, m), 2.83 (1H, dd, J = 6.0)
Hz, 12.7 Hz), 2.91-3.00 (1H,
m), 3.12 (1H, t, J = 12.0 Hz), 3.
21-3.33 (2H, m), 3.99 (3H, s),
4.31 (1H, dt, J = 5.4Hz, 7.4H
z), 4.82 (1H, ddd, J = 4.9 Hz, 6.
0 Hz, 7.1 Hz), 7.10 (1H, d, J = 7.
1Hz), 7.17 (1H, d, J = 7.4Hz),
7.25 (1H, t, J = 7.8Hz), 7.33 (1
H, t, J = 7.8 Hz), 7.55 (1H, s),
7.69 (1H, d, J = 7.8Hz), 8.15 (1
H, d, J = 7.8 Hz) Example 5 Synthesis of compound 9 Using DTrp-OMe.HCl, Example 4- (6)
The target compound was obtained by carrying out the same reaction as described above (diastereomer ratio derived from asymmetry of sulfoxide = 1: 3).

Melting point: 174-179 ° C. IR (KBr, cm ⁻¹ ): 3298, 2956, 174
3,1662, 1539, 1461, 1386, 126
0,1224,1092,1020,744 High resolution FAB-MS (m / e, (C ₃₈ H ₄₈ N ₄ O ₇ S +
H) ⁺ ): Calculated value 705.3322 Measured value 705.3336 ¹ H-NMR (300 MHz, CDCl ₃ , δppm):
0.64 + 0.73 (3H, d × 2, J = 6.3 Hz,
4.9 Hz), 0.68 + 0.75 (3H, d × 2, J
= 6.4 Hz, 5.4 Hz), 0.85-1.31 (4
H, m), 1.43-1.92 (7H, m), 2.12
-2.29 (1H, m), 2.40-2.58 (2H,
m), 2.70-3.01 (4H, m), 3.10-
3.34 (3H, m), 3.63 + 3.67 (3H, s
X2), 3.97 (3H, s), 4.82 (2H, d)
t, J = 7.4 Hz, 5.4 Hz), 5.90-6.0.
8 + 6.26-6.41 (1H, m × 2), 6.73−
6.80 (1H, m), 6.87 (1H, brs),
7.06 (1H, t, J = 7.5Hz), 7.15 (1
H, t, J = 7.5 Hz), 7.24 (1H, t, J =
7.8 Hz), 7.29-7.51 (3H, m), 7.
53-7.61 (2H, m), 8.15 (1H, d, J
= 7.8 Hz), 8.71-8.76 + 8.78-8.
85 (1H, brs × 2) Example 6 Synthesis of compound 10 (2S) -2-[(RS) obtained in Example 4- (5)
-Cyclopentylmethylthiosulfinylmethyl] -4
-Methylpentanoyl-DTrp (COOMe) -OM
e To a solution of 50 mg of dioxane (0.8 ml) was added 0.39 ml of 1N sodium hydroxide aqueous solution at room temperature,
The mixture was stirred as it was for 2 hours. A saturated aqueous solution of sodium hydrogen carbonate was added to the reaction solution, and the mixture was washed with ether, and then the aqueous layer was washed with 10%.
The mixture was acidified with an aqueous citric acid solution and extracted with ethyl acetate. The organic layer was washed with water and saturated saline and dried over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to dryness to obtain (2S) -2-[(RS) -cyclopentylmethylthiosulfinylmethyl] -4-methylpentanoyl-DTrp-OH (45.9 mg). This product was subjected to the same reactions as in Examples 1- (5) and (6) to obtain the desired product (diastereomer ratio derived from asymmetry of sulfoxide = 1: 3).

Melting point: 133-139 ° C. IR (KBr, cm ⁻¹ ): 3412, 3058, 295
6,2872,1731,1662,1521,146
1,1341,1233,1014,741 High resolution FAB-MS (m / e, (C ₃₅ H ₄₄ N ₄ O ₅ S +
H) ⁺ ): Calculated value 633.3111 Measured value 633.3121 ¹ H-NMR (300 MHz, DMSO-d ₆ , δpp.
m): 0.57 (3H, d, J = 5.9Hz), 0.6
4 (3H, d, J = 6.1Hz), 0.89-0.95
(1H, m), 0.95-1.02 (1H, m), 1.
06-1.15 (3H, m), 1.18-1.28 (4
H, m), 1.83-1.90 (2H, m), 2.02
-2.16 (1H, m), 2.36-2.97 (6H,
m), 3.04-3.51 (3H, m), 4.41-
4.52 (1H, m), 4.54-4.65 (1H,
m), 6.92-7.08 (4H, m), 7.11 (1
H, brs), 7.17 (1H, brs), 7.29
(1H, d, J = 8.0 Hz), 7.32 (1H, d,
J = 8.0 Hz), 7.52 (1H, d, J = 8.0H)
z), 7.58 (1H, d, J = 8.0 Hz), 8.1
3 (1H, d, J = 7.3Hz), 8.34 (1H,
d, J = 8.3 Hz), 10.76 (1H, s), 1
0.83 (1H, s), 12.40-12.50 (1
H, brs)

[0126]

INDUSTRIAL APPLICABILITY The compound of the present invention has a strong antagonistic effect on endothelin, which is an endogenous physiologically active peptide, and is therefore useful as an anti-endothelin agent. Further, it has an action of contracting blood vessels and tracheal muscle in which endothelin is involved. As a drug that antagonizes, eventually, a therapeutic drug for human hypertension, pulmonary hypertension, Raynaud's disease, bronchial asthma, arteriosclerosis, acute renal failure, myocardial infarction, angina, cerebral infarction, cerebral vasospasm, gastric ulcer and diabetes Is useful as 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.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁵ Identification code Office reference number FI Technical indication location A61K 31/22 8413-4C 31/27 8413-4C 31/40 7252-4C 31/42 7252-4C 31/66 ADP 8314-4C 37/02 AAM ABN ABR ABS ABU 8314-4C ABX ACD ACL ACV C07D 209/14 9283-4C 209/18 9283-4C 209/20 9283-4C 261/10 (72) Inventor Niiyama Kenji 2-9-3 Shimomeguro, Meguro-ku, Tokyo Banyu Pharmaceutical Co., Ltd. Central Research Institute (72) Inventor Masaki Ihara 2-3-9 Shimomeguro, Meguro-ku, Tokyo Manari Central Research Institute (72) ) Inventor Mitsuo Yano 2-9-3 Shimomeguro, Meguro-ku, Tokyo Manyu Pharmaceutical Co., Ltd. Central Research Laboratory

Claims (4)

[Claims] 1. A general formula: {In the formula, R ¹ is a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group, an aryl group, a 5-10 membered heterocyclic group or a 5-10 membered heterocyclic lower alkyl group (the lower alkyl Group, cycloalkyl group, cycloalkyl lower alkyl group, aralkyl group, aryl group, 5- to 10-membered heterocyclic group and 5- to 10-membered heterocyclic lower alkyl group, each independently on their chain and / or Lower alkyl group, halogen atom, hydroxyl group, lower alkoxy group, nitro group, trifluoromethyl group, cyano group, formyl group, lower alkanoyl group, carboxyl group, lower alkoxycarbonyl group, amino group, mono-lower alkylamino group on the ring , Di-lower alkylamino group, formylamino group, alkanoylamino group, aroylamino group,
Carbamoyl group, N-mono-lower alkylcarbamoyl group or N, N-di-lower alkylcarbamoyl group, mercapto group, lower alkylthio group or lower alkanoylthio group may be present); p is an integer of 0 to 2; A ¹ represents a single bond or a divalent lower alkylene group which may be substituted with a lower alkyl group; R ² represents a lower alkyl group, a cycloalkyl group, a cycloalkyl lower alkyl group, an aralkyl group or an aryl group. A 5- to 10-membered heterocyclic group or a 5- to 10-membered heterocyclic lower alkyl group; X ¹
Represents an oxygen atom or a group represented by the formula: —NR ³ — [wherein, R ³ represents a hydrogen atom or a lower alkyl group]; R ⁴ represents a 5- to 10-membered heterocyclic lower alkyl group [5 The 10-membered heterocyclic lower alkyl group is a lower alkyl on the ring or has the formula: R ⁴¹ —CO— (CH ₂ ) _q — (wherein R ⁴¹ is a hydrogen atom, a lower alkyl group, a hydroxyl group, a lower alkoxy group). , An aralkyloxy group, an amino group, a mono-lower alkylamino group or a di-lower alkylamino group; q represents an integer of 0 to 6)] or an aryl-lower alkyl group [The aryl lower alkyl group has a nitro group on its ring, a compound represented by the formula: R ⁴² —CO— (CH ₂ ) _r — (wherein R ⁴² is a lower alkyl group, a lower alkoxy group, an amino group, a mono-lower alkylamino group. A group or a di-lower alkylamino group, r is Groups represented by 6 an integer of)
Formula: R ⁴² —CO—X ² — (In the formula, R ⁴² has the above meaning, X ² is an oxygen atom or a formula: —NR ⁴³ — (In the formula, R ⁴³ is a hydrogen atom or a lower alkyl group. represented by (wherein, R ⁴⁴ represents a hydrogen atom or a lower alkyl group, s is an integer of ^{0~6) - R 44 O- (CH} 2) s: group or the formula represented by shown) May have a group]; X ³ represents an oxygen atom or a sulfur atom; A ² represents the following general formulas [II] to [V
II] represents an arbitrary group selected from the group consisting of groups represented by [II]. [Chemical 2] [In the formula, Y is a hydroxy lower alkyl group, a sulfo group, a phosphono group, a group represented by the formula: -CO ₂ R ⁸¹ (wherein R ⁸¹ represents a hydrogen atom or a carboxy protecting group) or a formula: -C
ONR ⁸² R ⁸³ (wherein R ⁸² and R ⁸³ are each independently a hydrogen atom, a lower alkyl group, a lower alkylsulfonyl group,
R represents a group represented by any one to five hydrogen atoms on the benzene ring each independently represent a lower alkyl group or a phenylsulfonyl group or a carboxy lower alkyl group which may be substituted with a halogen atom); ⁵¹ represents a hydrogen atom or a lower alkyl group, or represents a methylene group together with R ⁶¹ below; R ⁵³ , R ⁶¹ and R ⁶² each independently represent a hydrogen atom, a lower alkyl group, a lower alkenyl group,
Aryl group, aryl lower alkyl group, 5-10 membered heterocyclic group or 5-10 membered heterocyclic lower alkyl group (the lower alkyl group, lower alkenyl group, aryl group, aryl lower alkyl group, 5-10 membered heterocyclic group The heterocyclic group and the heterocyclic lower alkyl group each independently have a hydroxyl group, a lower alkyl group, a halogen atom, a lower alkoxy group, an aryloxy group, an acyloxy group, a carboxyl group, or a protected group on the chain and / or the ring thereof. Carboxyl group, amino group, monoalkylamino group, di-lower alkylamino group, carbamoyl group, N-mono-lower alkylcarbamoyl group, N,
N-di-lower alkylamino group, lower alkoxycarbonylamino group or aryloxycarbonylamino group), and R ⁶¹ together with R ⁵¹ may represent a methylene group. ⁶² together with R ⁵² below may represent a methylene group (provided that when R ⁵¹ represents a lower alkyl group, R ⁶¹ represents a group other than a hydrogen atom and R ⁵² represents a group other than a hydrogen atom). R ⁶² represents a hydrogen atom or a lower alkyl group when indicated); R ⁵² represents a hydrogen atom, an aryl group, an aralkyl group, a carboxyl group, a carbamoyl group, an N-mono-lower alkylcarbamoyl group, or an N, N-di-lower alkylcarbamoyl group. or a group or N- arylcarbamoyl, or represents a single bond together with R ^7; or R ⁷ is a hydrogen atom, a lower alkyl group, a lower alkoxy group or a hydroxyl group , Or R ⁵² , together with R ⁵² , represents a single bond, t represents an integer of 2 to 6; Z represents CH or N; v represents an integer of 1 to 3]} or A pharmaceutically acceptable salt thereof. 2. R¹Is a lower alkyl group, a lower alkyl group
Optionally substituted cycloalkyl group, lower alkyl
Cycloalkyl lower alkyl optionally substituted with groups
Group, aryl group, aralkyl group, 5-10 membered heteroar group
Reel group or 5-10 membered heteroaryl lower alkyl
Group (the aryl group, aralkyl group, heteroaryl group and
And heteroaryl lower alkyl groups are on their rings,
Lower alkyl group, halogen atom, hydroxyl group, lower alkoxy
Si group, nitro group, trifluoromethyl group, cyano group,
Rumil group, lower alkanoyl group, carboxyl group, lower
Alkoxycarbonyl group, amino group, formylamino
Group, lower alkanoylamino group, carbamoyl group, N-
Mono-lower alkylcarbamoyl group, N, N-di-lower alkyl
Kircarbamoyl group, mercapto group and lower alkyl group
1 to 5 identical or different selected from the group consisting of
A may have a substituent);¹Is a single bond
Or the number of carbon atoms that may be substituted with a lower alkyl group
1 to 3 divalent alkylene groups; R²Is lower al
Kill group, cycloalkyl group, cycloalkyl lower alk
Group, aryl group, 5- to 10-membered heteroaryl group,
Lille lower alkyl group, 5-10 membered heteroaryl low
A primary alkyl group; R^FourIs indole ring 1st position is lower
Alkyl group or formula: R⁴¹-CO- (CH₂)_q− (Expression
Medium, R⁴¹Is a hydrogen atom, lower alkyl group, hydroxyl group,
Lucoxy group, benzyloxy group, amino group, mono-lower group
A alkylamino group or a di-lower alkylamino group, q
Is 0 to 6), and may be substituted with a group represented by
3-indolylmethyl group, 3-benzothienylmethyl group
Group, (1-oxo-3-benzothienyl) methyl group,
(1,1-dioxo-3-benzothienyl) methyl group,
Naphthylmethyl group, aryl lower alkyl group or monocyclic
Heteroaryl lower alkyl group (the aryl lower alkyl
Group and monocyclic heteroaryl lower alkyl group are on the ring.
Nitro group, formula: R⁴³-CO- (CH₂)_r-(In the formula, R
⁴³Is a lower alkyl group, a lower alkoxy group, an amino group,
A lower alkylamino group or a dilower alkylamino group
And r is an integer of 0 to 6), a group represented by the formula: R
⁴³-CO-X²-[Wherein R⁴³Has the above meaning, X²
Is an oxygen atom or a formula: -NR⁴⁴-(In the formula, R⁴⁴Is a hydrogen atom
Or a lower alkyl group) or a group represented by the formula: R⁴⁵
O- (CH₂)_s-(In the formula, R⁴⁵Is a hydrogen atom or lower alkyl
And a s is an integer of 0 to 6)
May have the following formula]; A is the following general formula [II]
~ Any selected from the group consisting of groups represented by [VII]
It is the basis of [Chemical 3][Wherein Y is a hydroxymethyl group, a sulfo group, a phosphono group]
Group, formula: -CO₂R⁸¹(In the formula, R⁸¹Is a hydrogen atom,
A group or formula represented by the formula:
-CO NR⁸²R⁸³(In the formula, R⁸²Is a hydrogen atom, lower alk
Group, lower alkylsulfonyl group, optional on benzene ring
1 to 5 hydrogen atoms of are independently lower alkyl
A phenyl group optionally substituted by a group or a halogen atom
Is a sulfonyl group or a carboxymethyl group, R⁸³Is
A hydrogen atom or a lower alkyl group)
R; R⁵¹Is a hydrogen atom or a lower alkyl group or
R of note⁶¹Together with is a methylene group; R⁶¹Is hydrogen
Atom, hydroxyl group, lower alkoxy group or lower alkyl
A lower alkyl group optionally substituted with a thio group, a lower alkyl group
Lucenyl group, phenyl group, thienyl group, thiazolyl group,
Pyridyl group, any hydrogen atom on the benzene ring is a hydroxyl group,
Amino group, mono-lower alkylamino group, di-lower alkyl
Even if it is substituted with an amino group or a benzyloxy group
Good phenyl lower alkyl group, thienyl lower alkyl
Group, thiazolyl lower alkyl group, pyridyl lower alkyl
Group, imidazolyl lower alkyl group, indolyl lower alkyl group
Kill group, carbamoyl lower alkyl group or N-benzyl
Oxycarbonyl-ω-amino lower linear alkyl group
R or R⁵¹Together with is a methylene group (however,
R⁵¹Is a lower alkyl group, R⁶¹Is other than hydrogen atom
R); R⁵²Is hydrogen atom, phenyl group, benzyl
Group, carboxyl group, carbamoyl group or N-phenyl
A carbamoyl group or R⁷Single bond with
And R⁶²Is hydrogen atom, lower alkyl group, low phenyl
Primary alkyl group, thienyl lower alkyl group, thiazolyl low
Primary alkyl group, pyridyl lower alkyl group, indolyl low
Grade alkyl group, phenyl group, carbamoyl group or N-phenyl group
A phenylcarbamoyl group (provided that R is⁵²Is hydrogen atom or more
R is an external group⁶²Is a hydrogen atom or a lower alkyl group
R;⁵³Is a hydrogen atom, lower alkyl group, carboxy
Si lower alkyl group, formula: Ar- (CH₂)_u-(In the formula, A
r is a phenyl group, a furyl group or a thienyl group, and u is 1
Or a group represented by 2]]}.
A compound or a pharmaceutically acceptable salt thereof. 3. An endothelin antagonist, which comprises the compound according to claim 1 or a pharmaceutically acceptable salt thereof. 4. Hypertension, pulmonary hypertension, Raynaud's disease, acute renal failure, myocardium, which comprises the peptide derivative represented by the general formula [I] or the pharmaceutically acceptable salt thereof according to claim 1. Infarction, angina, cerebral infarction, cerebral vasospasm, arteriosclerosis, bronchial asthma, gastric ulcer, diabetes, endotoxin shock, multi-organ failure caused by endotoxin, disseminated intravascular coagulation and / or cyclosporine-induced renal damage, Remedy for high blood pressure.