JPH09157253A - Novel amino acid derivative - Google Patents

Abstract

(57) [Summary] (Modified) [PROBLEMS] To provide a novel amino acid derivative having excellent NPY receptor affinity. A novel amino acid derivative represented by the general formula (I) or a salt thereof. [In the formula, R ₁ -AB represents a tert-butoxycarbonyl group, 2-naphthylsulfonyl group, or the like; X represents CH ₂ , N
H, S or O; R ₂ , R ₃ is a hydrogen atom or a lower alkyl group; R ₄ is a hydrogen atom, a cyano group, a nitro group or the like;
R ₅ and R _{6 each} represent a hydrogen atom, a lower alkyl group or the like, or a nitrogen-containing heterocycle in combination with each other;
Is 0 or an integer of 1 to 4; m is 0 or 1.]

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel amino acid derivative having an affinity for a neuropeptide Y (hereinafter referred to as NPY) receptor.

[0002]

NPY is a peptide consisting of 36 amino acid residues belonging to pancreatic peptides and widely distributed in central and peripheral tissues of humans and animals. NPY in the central nervous system
Has a feeding promoting action, an antispasmodic action, a learning promoting action, an anxiety action, an antistress action and the like.

It is also known that in depression, Alzheimer's disease and Parkinson's disease, the amount of NPY in the cerebrospinal cord decreases, and further, the amount of NPY in the brain increases with head trauma. On the other hand, in peripheral tissues, NP
Y is also called a vasoconstrictor peptide and controls contraction of smooth muscles such as blood vessels, regulation of cardiac contractility, and secretion control of blood pressure regulating hormones such as renin.

NPY receptor affinity substances (NPY receptor agonists and antagonists) are various diseases associated with the physiological actions of NPY, namely bulimia nervosa and anorexia nervosa, anxiety, senile dementia, Alzheimer's disease, It is considered to be useful as a therapeutic drug for diseases such as Parkinson's disease, depression, hypertension and hypotension.

As NPY receptor antagonists, antihistamines H derived from benextramine, inositol phosphate PP56, and guanidinoalkylimidazole
Although e90481 has been reported, none of them has a weak NPY inhibitory action and cannot be said to be a specific antagonist [Drugs of the Future, Vol. 17, No. 1, pp. 39-45 (1992)]. Further, the compound having the structure of amidinophenylalanine described in French Patent Publication No. 2701480 and the amino acid derivative described in German Patent Publication No. 4326465 are said to have NPY receptor affinity.

[0006]

The object of the present invention is to provide a novel compound having excellent NPY receptor affinity.

[0007]

Means for Solving the Problems The inventors of the present invention have conducted diligent studies on a compound having a high affinity for the NPY receptor, and as a result, have found a compound having a chemical structure different from that of a conventional compound, that is, a novel amino acid derivative. Heading The present invention has been completed.

That is, the present invention relates to a novel amino acid derivative represented by the general formula (I) or a salt thereof.

[0009]

Embedded image

(The symbols in the formulas have the following meanings.

A: 5- or 6-membered nitrogen-containing heterocyclic ring which may be condensed with an aryl ring or a benzene ring, or a lower alkylene group B: Formula --SO _2- , --C (= O)-, --OC (= O)-
Or _{-CHR 7 C (= O) -} R 7: a hydrogen atom, a lower alkyl group, or an aryl group X: a lower alkyl group a methylene group which may have a substituent, a nitrogen atom, a sulfur atom, or oxygen atom R ₁ : hydrogen atom, amino group, or mono- or di-lower alkylamino group R ₂ and R ₃ : identical or different hydrogen atom, or lower alkyl group R ₄ : hydrogen atom, cyano group, nitro group, carbamoyl group, thio Carbamoyl group, amino group or mono- or di-lower alkylamino group, or

[0012]

Embedded image

The group represented by Y: NH, sulfur atom, or oxygen atom R ₈ and R ₉ : the same or different, a hydrogen atom, a lower alkyl group, a cycloalkyl group, or R ₈ and R ₉ together Nitrogen-containing heterocycle optionally having oxygen atom p: 0 or 1 R ₅ and R ₆ : hydrogen atom, lower alkyl group which may be the same or different, aralkyl group or aryl group optionally having substituent (s), Or, R ₅ and R ₆ may have an oxygen atom as a unit and may be condensed with a benzene ring, and may be a nitrogen-containing heterocycle n: 0 or an integer of 1 to 4 m: 0 or 1) preferably Is R ₄

[0014]

[Chemical 6]

(The symbols in the formulas have the following meanings.

Y: NH, sulfur atom, or oxygen atom R ₈ and R ₉ : the same or different, a hydrogen atom, a lower alkyl group, a cycloalkyl group, or R ₈ and R ₉ together have an oxygen atom. And optionally a nitrogen-containing heterocycle p: 0 or 1).

[0017]

BEST MODE FOR CARRYING OUT THE INVENTION The general formula (I) will be described in detail below.

In the definition of the general formulas herein, the term "lower" means a straight or branched carbon chain having 1 to 6 carbon atoms unless otherwise specified. Therefore, the "lower alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, specifically, for example, methyl group, ethyl group, propyl group, isopropyl group, butyl group. , Isobutyl group, sec-butyl group, tert-butyl group, pentyl (amyl) group, isopentyl group, neopentyl group, tert-pentyl group, hexyl group, isohexyl group, etc., and "lower alkylene group" means the number of carbon atoms. Is 1
To 6 linear or branched alkylene groups, specifically, methylene group, ethylene group, ethylidene group, propylidene group, isopropylidene group, propylene group, trimethylene group, tetramethylene group, 1,1- Examples thereof include a dimethylethylene group, a 1,2-dimethylethylene group, an ethylethylene group, a pentamethylene group and a hexamethylene group.

"Mono- or di-lower alkylamino group"
Examples thereof include a methylamino group, an ethylamino group, a dimethylamino group, a diethylamino group and the like.

The "aryl ring" of A specifically means a carbon aryl ring, and examples thereof include phenyl, tolyl, xylyl, naphthyl, anthryl, phenanthryl and the like, with preference given to naphthyl.

"A which may be condensed with a benzene ring 5"
Examples of the “6-membered nitrogen-containing heterocycle” include pyrrole, pyridine, indole, benzimidazole, isoindole, quinoline, isoquinoline, tetrahydroquinoline, tetrahydroisoquinoline and the like, and indole is preferable.

The "cycloalkyl group" of R ₈ or R ₉ is a monocyclic hydrocarbon ring group having 3 to 8 ring atoms, and specifically, cyclopropyl group, cyclobutyl group, cyclopentyl group, cyclohexyl group, Examples thereof include a cycloheptyl group and a cyclooctyl group, and a cyclopropyl group is preferable.

The "nitrogen-containing heterocycle in which R ₈ and R ₉ may be combined with each other to have an oxygen atom" means a 3- to 6-membered saturated nitrogen-containing heterocycle, and specifically, Aziridine,
Azetidine, pyrrolidine, oxazolidine, piperidine, morpholine and the like can be mentioned, preferably piperidine,
It is morpholine.

The "aralkyl group" of R ₅ or R ₆ is a lower alkyl group having an aryl group as a substituent, specifically, benzyl group, phenethyl group, methylbenzyl group, methylphenethyl group, dimethyl group. Examples thereof include benzyl group, dimethylphenethyl group, benzhydryl group, naphthylmethyl group, naphthylethyl group, anthrylmethyl group, anthrylethyl group, trityl group, phenanthrylmethyl group and phenanthrylethyl group, and preferably benzyl group. It is a base.

Examples of the “substituent” of the “aralkyl group or aryl group which may have a substituent” of R ₅ or R ₆ include a hydrogen atom, a hydroxyl group, a lower alkoxy group and the like, preferably a hydroxyl group. is there.

The "lower alkoxy group" includes methoxy group, ethoxy group, propoxy group, isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group, te.
Examples thereof include rt-butoxy group.

The term "nitrogen-containing heterocycle in which R ₅ and R ₆ may together have an oxygen atom and which may be condensed with a benzene ring" means the above-mentioned saturated 3 to 6-membered saturated ring. A nitrogen heterocycle and a group in which the heterocycle is condensed with a benzene ring, specifically, aziridine, azetidine, pyrrolidine,
Examples thereof include oxazolidine, piperidine, morpholine, indoline, isoindoline, tetrahydroquinoline, tetrahydroisoquinoline, benzomorpholine, and the like, with morpholine and tetrahydroisoquinoline being preferred.

Specific examples of the compound (I) of the present invention include the following compounds in addition to the compounds of Examples described later.

(2RS, 4'RS) -2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- (4-hydroxyphenyl) -N
^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide, (2RS, 4'RS) -1- [2- (6 '
-Amidino-1'-methyl-1 ', 2', 3 ', 4'-
Tetrahydroquinolin-4′-yl) -N- [N- (2
-Naphthylsulfonyl) glycyl] glycyl] piperidine, (2RS, 4'RS) -1- [2- (6'-amidino-1 ', 2', 3 ', 4'-tetrahydroquinoline-
4'-yl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] piperidine, (2RS, 4'R
S) -1- [2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N-
(N-nicotinoylglycyl) glycyl] piperidine,
(2RS, 4'RS) -1- [2- (6'-amidino-
3 ', 4'-dihydro-2'H-benzothiopyran-
4'-yl) -N- [N- (4-dimethylaminobenzoyl) glycyl] glycyl] piperidine, (2RS,
4'RS) -1- [2- (6'-amidino-3 ', 4'
-Dihydro-2'H-benzothiopyran-4'-yl)
-N- [N- (benzimidazol-5-yl) carbonylglycyl] glycyl] piperidine, (2RS, 4 '
RS) -1- [2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N
-[N- (1H-indol-2-yl) carbonylglycyl] glycyl] piperidine, (2RS, 4'RS)
-1- [2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- [N
-(2-naphthoyl) glycyl] glycyl] piperidine, (2RS, 4'RS) -1- [2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- [N- (1,2,3,4-tetrahydro-8-quinolylsulfonyl) glycyl] glycyl] piperidine, (2RS, 4'RS) -1- [2-
(6'-amidino-3 ', 4'-dihydro-6'-2'
H-benzothiopyran-4'-yl) -N- [N- (8
-Quinolylsulfonyl) glycyl] glycyl] piperidine, (2RS, 4'RS) -1- [2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl)- N- [N- (1-naphthylsulfonyl) glycyl] glycyl] piperidine, (2RS, 4 ′
RS) -1- [2- (3 ', 4'-dihydro-6'-guanidino-2'H-benzothiopyran-4'-yl)-
N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine, (2RS, 4'RS) -1- [2-
(3 ', 4'-dihydro-7'-guanidino-2'H-
Benzothiopyran-4′-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine,
(2RS, 4'RS) -4- [2- (6'-amidino-
3 ', 4'-dihydro-2'H-benzothiopyran-
4′-yl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] morpholine, (2RS, 4'R
S) -2- [2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N-
[N- (2-naphthylsulfonyl) glycyl] glycyl] -1,2,3,4-tetrahydroisoquinoline,
(2RS, 1'RS) -2- (7'-amidino-1 ',
2 ', 3', 4'-Tetrahydro-1'-naphthyl)-
N- (4-hydroxybenzyl) -N ^α- [N- (2-
Naphthylsulfonyl) glycyl] glycinamide, (2
RS, 1'RS) -2- (6'- amidino-1'indanyl) -N- (4- hydroxybenzyl) -N ^alpha -
[N- (2-naphthylsulfonyl) glycyl] glycinamide, (2RS, 1'RS) -2- (2'-amidino-5 ', 6', 7 ', 8',-tetrahydro-9'H-
Benzocyclohepten-9′-yl) -N- (4-hydroxybenzyl) -N ^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide, (2RS, 1′R
S) -2- (7'-amidino-1 ', 2', 3 ', 4'
-Tetrahydro-1'-naphthyl) -N- (4-hydroxybenzyl) -N [ ^alpha] -(N-dansylglycyl) glycinamide.

The compound (I) of the present invention has an asymmetric carbon and has an optically active substance or diastereomer based on the asymmetric carbon, and a mixture of these optically active substances or diastereomers or an isolated one Also includes.

The compound (I) of the present invention can form a salt with an acid. Specifically, mineral acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, tartaric acid, carbonic acid, picric acid, methanesulfone. Examples thereof include acid addition salts with acids, ethanesulfonic acid, glutamic acid and other organic acids. Furthermore, the compound (I) of the present invention can form hydrates, solvates with ethanol and the like, and polymorphism, and the present invention also includes these compounds.

(Production Method) The compound (I) of the present invention is produced by the following typical methods, but is not limited to these production methods.

[0033]

Embedded image

(Wherein D is a leaving group such as a halogen atom and a hydroxyl group, E is a hydroxyl group, a lower alkoxy group, an amino group, a mono- or di-lower alkylamino group, an arylamino group, or a lower alkylarylamino group. The groups are Z ₁ , Z ₂
Are the same or different and each represents a hydrogen atom or an amino-protecting group. R ₁₀ represents R ₄ or a halogen atom. R ₁ , R
₂ , R ₃ , R ₄ , R ₅ , R ₆ , A, B, X, and n have the above-mentioned meanings. ) Here, as the “halogen atom”, a chlorine atom, a fluorine atom, a bromine atom, and an iodine atom are “amino group-protecting groups”.
Examples thereof include a tert-butoxycarbonyl group, a benzyloxycarbonyl group, a diphenylmethylene group and the like.

The compound (I) of the present invention is the compound (II),
An amine and an acid or acid halide such as N- (arylsulfonyl) glycine, N- (acyl) glycine, arylsulfonyl halide, or acyl halide is added to the glycine derivative (V) obtained from (III) or (IV) by a conventional method. It is produced by introducing by an amidation reaction. The details will be described below. Compound (V) was prepared according to J. D. Mi
lkowski et al. , J. et al. Med. Che
m. , 13, 741-742 (1970), E.I. Rei
mann et al. Arch. Pharm, 31
0, 102-109 (1977) and the like, its manufacturing method is shown. Besides, it can be produced by a known amino acid production method. For example, compound (II) and a glycine equivalent such as diethyl acetamidomalonate, a glycine derivative (eg, imidic acid ester), or a nitroacetic acid ester in an amount corresponding to the reaction thereof in the presence of a base (alkoxide, sodium hydride, butyllithium, etc.) or After reacting in the presence of an acid catalyst such as Lewis acid or the like under cooling to heating without adding anything, the substituent is converted by decarboxylation, hydrolysis, reduction, or the compound (III) is used as a starting material. S
The amino group is directly activated by subjecting it to the trecker method or the Bucherer method, and further activating the α-position of the carbonyl group of the compound (IV) with the same base or acid (for example, hydrochloric acid) as described above or by halogenation. It is obtained by introducing or by introducing a substituent that can be converted to an amino group such as an azido group or a hydroxyimino group, and then converting it to an amino group by treatment such as reduction.

When R _{10 of} compounds (II) to (V) is a hydrogen atom, a nitro compound can be obtained at any stage by carrying out ordinary nitration conditions. Further, the nitro group can be derivatized to an arbitrary substituent such as an amino group and a cyano group by a known method (reduction, Sandmeyer method, etc.).

When R _{10 of} compounds (II) to (V) is a halogen atom, a cyano group or the like can be introduced at any stage by a known method (for example, reaction between a halogen compound and CuCN).

Compound (I) can be produced by a known method (for example, M.
Bodanszky, Peptide Chemis
try, 55-73 (1988), Nobuo Izumiya et al.,
Fundamentals and Experiments of Peptide Synthesis, 89-142 (1985)
Etc.), compound (V) or its N-protected form, or any salt thereof (for example, sodium salt, potassium salt, cesium salt, etc.) and a reaction amount of amine with a suitable solvent (dimethylformamide). , Tetrahydrofuran, etc.), the protecting group is removed by, for example, treatment with an acid (hydrobromic acid, hydrochloric acid, etc.), and the N-unprotected glycine derivative and N- (arylsulfonyl) glycine are obtained. , N- (acyl) glycine, arylsulfonyl halide, or acyl halide or the like, or by reacting with an appropriate N
After the reaction with glycine protected by a protecting group (eg, t-butoxycarbonyl group), the protecting group is removed by the same method as described above, and the acid halide such as arylsulfonyl halide or acyl halide is converted into a base (triethylamine, potassium carbonate). , Sodium hydroxide, etc.). In addition, after compound (V) is esterified or introduced into a solid carrier (Melfield resin etc.), N-
(Arylsulfonyl) glycine, N- (acyl) glycine, arylsulfonyl halide, or an acyl halide, or the like, or a compound obtained by reacting the obtained compound with a carboxylic acid and then reacting with an amine. You can

When R ₁₀ of the compound (I) is a cyano group, a known method (for example, GD Nelson, T.
he Chemistry of amidines
and imidates, Patai and R
appport, Ed. , Wiley and
Sons, Vol. 1, 238-348 (19
75), Vol. 2, 339-366 (199
1); S. Garigipati, Tetr
ahedron Lett. , 31, 1969-19
72 (see 1990, etc.) can convert a cyano group into an amidino group.

When R ₁₀ of compound (I) is an amino group, aminoiminomethyl chloride, S-methylisothiourea, 1-amidino-3,5-dimethylpyrazole,
A salt such as nitroguanidine (eg, hydrochloride, sulfate, nitrate, etc.) is reacted as it is or in the presence of a base such as sodium hydroxide or triethylamine without solvent or in a solvent such as dimethylformamide, dioxane or tetrahydrofuran. By doing so, it can be converted into a guanidino group.

The optical isomer of compound (I) is compound (I)
Alternatively, an optical resolution method such as a fractional recrystallization method, an enzyme method, silica gel column chromatography, or high performance liquid chromatography in an intermediate and a compound (I
I) or a reaction of the optically active substance with an optically active glycine equivalent (for example, Scholkopf method, Willams method or Oppolzer method), and a method using a compound (IV) having an optically active center (for example, Ev
ans method), an asymmetric synthesis method such as an asymmetric Strecker method, or a combination thereof (for example, RO Duthaler, Tetrah).
edron, 50, 1539-1650 (1994)).

The compound (I) of the present invention thus produced is isolated and purified as a free compound, its salt, hydrate, various solvates and the like. Compound (I) of the present invention
The pharmaceutically acceptable salt of can also be produced by subjecting to a conventional salt-forming reaction.

[0043]

EXAMPLES The present invention is described in detail below with reference to examples, but the present invention is not limited to the examples. It should be noted that reference is made to those with new raw material compounds.

Reference Example 1 Diethyl acetamidomalonate 65.2 g (0.3 mo)
l) and tert-butanol (350 ml) in a mixed solution of t
34.8 g of ert-butoxy potassium (0.31 mo
l) was added and stirred for 1 hour, and then 11 g of sodium iodide
(75 mmol), 1-chloro-1,2,3,4-tetrahydronaphthalene (51.7 g, 0.31 mol) and tert-butanol (100 ml) were added at 50 ° C.
And stirred overnight. 400 ml of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The extract was washed with water and saturated saline and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. Hexane was added to the residue and the crystals were collected by filtration. The crystals were subjected to silica gel column chromatography and eluted with 25-33% ethyl acetate-hexane to give 2-acetylamino-2-.
59.9 g (56%) of diethyl (1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) malonate was obtained.

¹ H-NMR (δ ppm in CDCl
₃ ): 1.14 (3H, t), 1.24 (3H,
t), 1.4-2.3 (4H, m), 1.96 (3
H, s), 2.64 (2H, br-t), 3.8-
4.4 (5H, m), 7.0-7.4 (4H, m) Reference Example 2 2-Acetylamino-2- (1 ', 2', 3 ', 4'-
Tetrahydro-1'-naphthyl) malonate diethyl 5
To a mixed solution of 6.1 g (0.161 mol), 300 ml of acetic anhydride and 20 ml of acetic acid, 28 ml (2.5 equivalents) of concentrated nitric acid was added at 20 ° C or lower under ice-cooling stirring, and the mixture was stirred at 20 ° C or lower for 1.5 hours. The reaction solution was added to 1.8 l of ice water, and the precipitated crystals were filtered, washed with cold ether-hexane (4: 1), and 2-acetylamino-2- (7'-nitro-).
33.8 g (53%) of diethyl 1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) malonate was obtained. The solvent of the mother liquor was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography and eluted with 33% ethyl acetate-hexane to give 2-acetylamino-2- (7'-nitro-1 ', 2', 7.53 g (12%) of diethyl 3 ', 4'-tetrahydro-1'-naphthyl) malonate, 2-
Acetylamino-2- (5'-nitro-1 ', 2',
9.1 g (14%) of diethyl 3 ', 4'-tetrahydro-1'-naphthyl) malonate was obtained.

7'-nitro form: Rf = 0.36 (50%
Ethyl acetate-hexane) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.02 (3H, t), 1.13 (3H, t),
1.55 (1H, m), 1.8-2.0 (3H,
m), 1.81 (3H, s), 2.76 (2H,
t), 3.95 (2H, m), 4.06 (1H,
t), 4.13 (2H, q), 7.32 (1H,
d), 7.97 (1H, dd), 8.34 (1H,
d), 8.43 (1H, s) 5'-nitro form: Rf = 0.49 (50% ethyl acetate-
Hexane) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.02 (3H, t), 1.10 (3H, t),
1.5 (1H, m), 1.8-2.0 (3H, m),
1.81 (3H, s), 2.73 (2H, t),
3.95 (2H, m), 4.05 (1H, t),
4.10 (2H, q), 7.31 (1H, t),
7.70 (1H, d), 7.73 (1H, d),
8.43 (1H, s) Reference Example 3 2-Acetylamino-2- (7′-nitro-1 ′,
41 g (105 mmol) of diethyl 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) malonate, acetic acid 100
10% palladium-carbon powder was added to a mixed solution of 100 ml of ethanol and 300 ml of ethanol, and the mixture was vigorously stirred in a hydrogen gas atmosphere for 6 hours. The catalyst in the reaction solution was removed and the solvent was distilled off under reduced pressure. The residue was crystallized from ether-hexane to give 2-acetylamino-2- (7'-amino-1 ', 2', 3 ', 4'-tetrahydro- Diethyl 1'-naphthyl) malonate 34.
6 g (91%) were obtained.

¹ H-NMR (δ ppm in CDCl
₃ ): 1.17 (3H, t), 1.24 (3H,
t), 1.4-3.2 (4H, m), 1.96 (3
H, s), 2.53 (2H, br-t), 3.8-
4.4 (5H, m), 6.50 (1H, dd),
6.65 (1H, d), 6.84 (1H, br-d) Reference Example 4 2-Acetylamino-2- (7'-amino-1 ',
34.1 g (94 mmol) of diethyl 2 ', 3', 4'-tetrahydro-1'-naphthyl) malonate and water 1
To a mixed solution of 50 ml, 10 ml of concentrated sulfuric acid (2 equivalents) was added and dissolved, and sodium nitrite 7.1 was added under cooling with a methanol-ice bath.
An aqueous solution prepared by dissolving g (103 mmol) in 100 ml of water was added dropwise so as not to exceed 5 ° C, and the mixture was stirred for 1.5 hours. After adding 100 ml of toluene to the reaction solution and neutralizing it with sodium hydrogencarbonate under stirring with ice cooling, it was added all at once to the solution A which was subjected to the following operation.

Solution A is 21 g of cuprous chloride (235 mm
solution) and a mixture of 100 ml of water under cooling with a methanol-ice bath, a mixture of 40 g (611 mmol) of potassium cyanide and 100 ml of water was added at 5 ° C. or lower and stirred for 1.5 hours, and then 100 ml of ethyl acetate was added.

Subsequently, the temperature was raised to room temperature over 30 minutes and the mixture was stirred at 60 ° C. for 1.5 hours. 100 ml of water was added to the reaction solution, and the mixture was extracted twice with ethyl acetate. The extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography, eluted with 50% ethyl acetate-hexane to remove the vicinity of the origin, and recrystallized with ether-hexane to give 2-acetylamino-2- (7'-cyano-1 ', 2. ', 3', 4'-
Tetrahydro-1'-naphthyl) malonate diethyl 1
Obtained 7.2 g (49%). Furthermore, the mother liquor is treated to 5.
2 g (15%) was obtained.

¹ H-NMR (δ ppm in CDCl
₃ ): 1.13 (3H, t), 1.31 (3H, t
t), 1.5-2.2 (4H, m), 1.98 (3
H, s), 2.71 (2H, br-t), 3.7-
4.4 (5H, m), 7.12 (1H, br-d),
7.40 (1H, dd), 7.85 (1H, br-
s) Reference example 5 2-acetylamino-2- (5'-nitro-1 ',
Diethyl 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) malonate was treated in the same manner as in Reference Example 3 and Reference Example 4, and 2-acetylamino-2- (5′-cyano-1 ′,
Diethyl 2 ', 3', 4'-tetrahydro-1'-naphthyl) malonate was obtained (yield 78%).

¹ H-NMR (500 MHz, δ ppm
in CDCl ₃ ): 1.07 (3H, t),
1.28 (3H, t), 1.7-2.0 (4H,
m), 1.91 (3H, s), 2.8-2.9 (2
H, m), 3.9 (1H, m), 4.1 (1
H, m), 4.2-4.3 (3H, m), 6.
62 (1H, s), 7.18 (1H, t),
7.49 (1H, d), 7.88 (1H, d) Reference Example 6 1-Chloroindane was treated in the same manner as in Reference Example 1 to obtain diethyl 2-acetylamino-2- (1′-indanyl) malonate. Was obtained (yield 50%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.25 (3H, t), 1.26 (3H,
t), 1.97 (3H, s), 2.2-2.9 (4)
H, m), 4.1-4.5 (5H, m), 6.4
(1H, br), 7.0-7.4 (4H, m) Reference Example 7 Diethyl 2-acetylamino-2- (1′-indanyl) malonate was used as Reference Examples 2, 3 and 4. By the same treatment, 2-acetylamino-2- (6'-cyano-
Diethyl 1'-indanyl malonate was obtained (yield 40
%, 3 strokes).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.20 (3H, t), 1.27 (3H,
t), 1.99 (3H, s), 2.1-2.5 (2
H, m), 2.8 (2H, m), 4.1-4.3.
(4H, m), 4.41 (1H, dd), 6.53
(1H, s), 7.27 (1H, d), 7.47
(1H, d), 7.61 (1H, s) Reference Example 8 5-Chloro-5,6,7,8, -tetrahydro-9H-
Benzocycloheptene was treated as in Reference Example 1 to give 2-
Acetylamino-2- (5 ', 6', 7 ', 8',-tetrahydro-9'H-benzocyclohepten-5'-yl) malonate diethyl was obtained (yield 19%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.0-2.1 (5H, m), 1.06
(3H, t), 1.27 (3H, t), 2.01
(3H, s), 2.3-3.0 (3H, m), 4.
0-4.5 (5H, m), 6.64 (1H, br),
7.1 (4H, m) Reference Example 9 2-Acetylamino-2- (5 ′, 6 ′, 7 ′, 8 ′,
-Tetrahydro-9'H-benzocycloheptene-5 '
2-yl) diethyl malonate was treated as in Reference Examples 2 and 3 to give 2-acetylamino-2- (2′-amino-5 ′, 6 ′, 7 ′, 8 ′,-tetrahydro-9 ′. H
-Diethyl benzocycloheptene-9'-yl) malonate was obtained (47% yield, 2 strokes).

¹ H-NMR (δ ppm in DMSO
_{-D 6): 0.93 (3H,} t), 1.1-1.
3 (2H, m), 1.15 (3H, t), 1.5
(1H, br), 1.7 (2H, br), 1.95
(3H, s), 2.25 (1H, m), 2.6 (2
H, m), 3.78 (1H, d), 3.98 (2
H, q), 4.1 (2H, m), 4.59 (2H,
s), 6.27 (1H, dd), 6.46 (1H,
d), 6.73 (1H, d), 8.04 (1H,
s) Reference example 10 2-acetylamino-2- (2'-amino-5 ',
Diethyl 6 ', 7', 8 ',-tetrahydro-9'H-benzocyclohepten-9'-yl) malonate was treated in the same manner as in Reference Example 4 to give 2-acetylamino-2- (2'-.
Cyano-5 ', 6', 7 ', 8',-tetrahydro-
Diethyl 9'H-benzocyclohepten-9'-yl) malonate was obtained (yield 72%).

¹ H-NMR (δ ppm in CDCl
₃ ): 0.9-2.1 (5H, m), 1.05 (3
H, t), 1.28 (3H, t), 2.03 (3
H, s), 2.3-2.7 (1H, m), 2.8-
3.0 (2H, m), 4.13 (2H, q), 4.
29 (2H, q), 4.2-4.5 (1H, m),
6.8 (1H, br), 7.0-7.3 (1H,
m), 7.3-7.6 (2H, m) Reference Example 11 4-Chloro-6-cyano-3,4-dihydro-2H-benzopyran was treated in the same manner as in Reference Example 1 to give 2-acetylamino-. 2- (6'-cyano-3 ', 4'-dihydro-
Diethyl 2'H-benzopyran-4'-yl) malonate was obtained (yield 79%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.10 (3H, t), 1.27 (3
H, t), 2.00 (3H, s), 2.0-
2.1 (1H, m), 2.2-2.3 (1H,
m), 3.9-4.0 (1H, m), 4.1-4.
3 (6H, m), 6.70 (1H, s), 6.
82 (1H, d), 7.40 (1H, dd),
7.77 (1H, d) Reference Example 12 N- (diphenylmethylene) glycine ethyl ester 7.7 g (28.8 mmol), tetrahydrofuran 4
To a mixed solution of 8 ml and hexamethylphosphoric triamide 12 ml, 18 ml of 1.6 M butyllithium-hexane solution (2 ml at −68 ° C. or lower under cooling with dry ice-acetone bath).
8.8 mmol) was added dropwise and the mixture was stirred for 15 minutes.
A mixture of 2.98 g (16 mmol) of chloro-6-cyano-3,4-dihydro-2H-benzothiopyran and 4 ml of tetrahydrofuran was added dropwise at −68 ° C. or below, and −2.
The mixture was stirred at 0 to -10 ° C for 1.5 hours and at 4 ° C overnight. The reaction solution was added to 200 ml of saturated aqueous ammonium chloride and extracted twice with ethyl acetate. The extract was washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, 1
Elute with 0-15% ethyl acetate-hexane (2RS,
4'RS) and (2RS, 4'SR) -2- (6'-
Cyan-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- (diphenylmethylene) glycine ethyl ester 3.22 g (47%) and 2.
Obtained 14 g (31%).

(2RS, 4'RS) body: Rf = 0.57
(33% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.30 (3H, t), 1.95 (1H, br),
2.3 (1H, br), 2.80 (1H, dt),
2.91 (1H, dt), 3.72 (1H, dt),
4.25 (2H, m), 4.31 (1H, d),
6.49 (2H, br), 7.07 (1H, d),
7.2-7.4 (7H, m), 7.43 (1H,
S), 7.56 (1H, S), 7.57 (1H,
d) (2RS, 4′SR) form: Rf = 0.67 (33% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.24 (3H, t), 0.7-1.6 (1H, m),
1.7-2.3 (1H, m), 2.4-3.1 (2
H, m), 3.4-3.8 (1H, m), 3.9-
4.4 (2H, m), 4.25 (2H, m), 4.
41 (1H, d), 6.7-6.9 (2H, m),
6.9-7.8 (11H, m) Reference Example 13 1-chloro-7-cyano-1,2,3,4-tetrahydronaphthalene was treated in the same manner as in Reference Example 12 to give 2- (7 ′).
-Cyano-1 ', 2', 3 ', 4'-tetrahydro-
1'-Naphthyl) -N- (diphenylmethylene) glycine ethyl ester was obtained (yield 35%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.27 (3H, t), 1.45 (1H, b
r), 1.6 (1H, br), 1.85 (2H,
br), 2.5 (1H, br), 3.65 (1
H, br), 4.2 (3H, m), 6.5 (2H,
br), 7.08 (1H, d), 7.2-7.4
(8H, m), 7.41 (1H, S), 7.60
(1H, d) Reference Example 14 1-chloro-6-cyano-1,2,3,4-tetrahydronaphthalene was treated in the same manner as in Reference Example 12 to give 2- (6 ′).
-Cyano-1 ', 2', 3 ', 4'-tetrahydro-
1'-Naphthyl) -N- (diphenylmethylene) glycine ethyl ester was obtained (88% yield).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.2-1.3 (3H, m), 1.5 (1
H, br), 1.65 (1H, br), 1.85
(2H, br), 2.5 (1H, br), 2.65
(1H, br), 3.65 (1H, br), 4.2
(3H, m), 6.45 (2H, br), 7.2-
7.4 (9H, m), 7.58 (2H, d) Reference Example 15 1-chloro-7-nitro-1,2,3,4-tetrahydronaphthalene was treated in the same manner as in Reference Example 12 (2RS ，
1'RS) and (2RS, 1'SR) -2- (7'-
Nitro-1 ', 2', 3 ', 4'-tetrahydro-1'
-Naphthyl) -N- (diphenylmethylene) glycine ethyl ester was obtained (yield 36% and 23%).

(2RS, 1'RS) body: Rf = 0.64
(33% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.28 (3H, t), 1.5 (1H, br), 1.
65 (1H, br), 1.85 (2H, br),
2.55 (1H, br), 2.7 (1H, br),
3.75 (1H, br), 4.22 (2H, q),
4.26 (1H, d), 6.55 (2H, br),
7.13 (1H, d), 7.2-7.4 (6H,
m), 7.59 (1H, s), 7.60 (1H,
d), 7.91 (1H, dd), 8.14 (1H,
d) (2RS, 1′SR) form: Rf = 0.70 (33% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.28 (3H, t), 1.7 (1H, br), 2.
0 (1H, br), 2.1 (1H, br), 2.45
(1H, br), 2.7-2.9 (2H, m),
3.67 (1H, dd), 4.25 (2H, m),
4.55 (1H, d), 6.85 (2H, d),
7.17 (1H, d), 7.26 (2H, t),
7.3-7.5 (6H, m), 7.74 (1H,
s), 7.88 (1H, dd) Reference Example 16 4-chloro-6-cyano-3,4-dihydro-2H-benzothiopyran and 1- [N- (diphenylmethylene) glycyl] piperidine were used as in Reference Example 12. To 1- [2- (6'-cyano-3 ', 4'-dihydro-
2'H-benzothiopyran-4'-yl) -N- (diphenylmethylene) glycyl] piperidine was obtained (yield 8
8%).

IR (KBr, cm ^-1 ): 500,
698, 782, 1012, 1070, 113
6, 1250, 1446, 1476, 159
8, 1638, 2228, 2864, 2848 Reference Example 17 4-chloro-6-cyano-2,2-dimethyl-3,4-
Dihydro-2H-benzothiopyran and 1- [N-
(Diphenylmethylene) glycyl] piperidine was treated as in Reference Example 12 to give (2RS, 4′RS) and (2RS
RS, 4'SR) -1- [2- (6'-cyano-2 ',
2'-Dimethyl-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- (diphenylmethylene) glycyl] piperidine was obtained (yield 18% and 4
3%).

(2RS, 4'RS) body: Rf = 0.37
(33% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.0-1.6 (11H, m), 2.21 (2H,
t), 2.5-2.7 (4H, m), 3.3 (1)
H, br), 3.65 (1H, br), 5.31
(1H, s), 6.55 (3H, m), 7.0-
7.5 (7H, m), 7.69 (2H, d), 8.6
98 (1H, s) (2RS, 4′SR) body: Rf = 0.32 (33% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.15 (2H, br), 1.37 (3H, s),
1.4-1.6 (4H, m), 1.51 (3H,
s), 2.10 (1H, dd), 2.78 (1H,
dd), 3.0 (1H, br), 3.2 (1H, b)
r), 3.4-3.6 (3H, m), 4.86 (1
H, d), 7.09 (2H, dd), 7.10 (1
H, d), 7.17 (1H, d), 7.25 (3
H, m), 7.34 (1H, m), 7.5 (5H,
m) Reference Example 18 (2RS, 4′RS) -2- (6′-cyano-3 ′,
4'-dihydro-2'H-benzothiopyran-4'-yl) -N- (diphenylmethylene) glycine ethyl ester 3 g (6.8 mmol), and ethanol 21 m
7 ml of concentrated hydrochloric acid was added to the mixed solution of 1 and stirred at room temperature for 2 hours.
After distilling off the solvent of the reaction solution under reduced pressure, the residue was dissolved in 28 ml of 75% aqueous dioxane, and sodium hydrogencarbonate under ice cooling.2.
86 g (34 mmol) and di-tert-butyl dicarbonate 1.63 g (7.5 mmol) were added, and the mixture was stirred at room temperature overnight. 50 ml of water was added to the reaction solution, and the mixture was concentrated under reduced pressure, extracted twice with ethyl acetate, the extract was washed with water and saturated saline, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and eluted with 15-25% ethyl acetate-hexane (2RS, 4'RS) -N-tert-butoxycarbonyl-2- (6'-cyano-3 ', 4. '-Dihydro-
2.12 g (83%) of 2'H-benzothiopyran-4'-yl) glycine ethyl ester was obtained.

¹ H-NMR (δ ppm in CDCl
₃ ): 1.24 (3H, t), 1.37 (9H,
s), 2.05 (1H, t), 2.29 (1H, d
d), 2.96 (1H, dt), 3.30 (2H,
dt), 4.21 (2H, m), 4.57 (1H,
t), 5.10 (1H, d), 7.20 (1H, d
d), 7.34 (1H, d), 7.35 (1H,
s) Reference Example 19 (2RS, 4'SR) -2- (6'-cyano-3 ',
4′-dihydro-2′H-benzothiopyran-4′-yl) -N- (diphenylmethylene) glycine ethyl ester was treated as in Reference Example 18 (2RS, 4 ′S).
R) -N-tert-butoxycarbonyl-2- (6 ′
-Cyano-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) glycine ethyl ester was obtained (yield 71%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.03 (3H, t), 1.44 (9H,
s), 1.9 (1H, br), 2.4 (1H, b)
r), 3.00 (1H, dt), 3.13 (1H, d
d), 3.4 (1H, br), 3.9-4.1 (2
H, m), 4.58 (1H, t), 5.14 (1
H, br), 7.21 (1H, d), 7.23 (1
H, s), 7.34 (1H, dd) Reference Example 20 2- (7′-cyano-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) -N- (diphenylmethylene) Glycine ethyl ester was treated in the same manner as in Reference Example 18 to give N-tert-butoxycarbonyl-2- (7′-).
Cyano-1 ', 2', 3 ', 4'-tetrahydro-1'
-Naphthyl) glycine ethyl ester was obtained (yield 74
%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.12 (3H, t), 1.41 (9H,
s), 1.75 (2H, br), 2.8 (2H, b)
r), 3.33 (1H, q), 4.1 (2H,
m), 4.62 (1H, dd), 5.18 (1H,
d), 7.17 (1H, d), 7.40 (1H,
d), 7.54 (1H, s) Reference Example 21 2- (6'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) -N- (diphenylmethylene) glycine ethyl The ester was treated as in Reference Example 18 (2RS, 1'RS) and (2RS, 1'SR)
-N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-
Naphthyl) glycine ethyl ester was obtained (44% yield)
And 40%).

(2RS, 1'RS) body: Rf = 0.39
(20% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.08 (3H, t), 1.42 (9H, s), 1.
6-2.0 (4H, m), 2.74 (2H, t),
3.45 (1H, br), 4.1 (2H, m),
4.68 (1H, dd), 5.17 (1H, d),
7.3-7.5 (3H, m) (2RS, 1'SR) body: Rf = 0.34 (20% ethyl acetate-hexane) ¹ H-NMR (δppm in CDCl ₃ ):
1.19 (3H, t), 1.36 (9H, s), 1.
6-1.9 (3H, m), 2.0 (1H, br),
2.8 (2H, m), 3.35 (1H, br),
4.0-4.3 (2H, m), 4.85 (1H, b
r), 5.00 (1H, d), 7.3-7.4 (3
H, m) Reference Example 22 (2RS, 1'RS) -2- (7'-nitro-1 ',
2 ', 3', 4'-Tetrahydro-1'-naphthyl)-
N- (diphenylmethylene) glycine ethyl ester was treated as in Reference Example 18 to give (2RS, 1′RS) -N.
-Tert-Butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycine ethyl ester was obtained (yield 75%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.15 (3H, t), 1.38 (9H,
s), 1.75 (2H, m), 1.95 (2H,
m), 2.83 (2H, br), 3.43 (1H,
q), 4.15 (2H, m), 4.67 (1H, d
d), 5.15 (1H, d), 7.24 (1H,
d), 7.98 (1H, dd), 8.11 (1H,
s) Reference Example 23 (2RS, 1'SR) -2- (7'-nitro-1 ',
2 ', 3', 4'-Tetrahydro-1'-naphthyl)-
N- (diphenylmethylene) glycine ethyl ester was treated as in Reference Example 18 to give (2RS, 1′SR) -N.
-Tert-Butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycine ethyl ester was obtained (yield 91%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.17 (3H, t), 1.37 (9H,
s), 1.8 (3H, m), 2.05 (1H,
m), 2.7-3.0 (2H, m), 3.35 (1
H, m), 4.0-4.3 (2H, m), 4.79.
(1H, t), 5.05 (1H, br), 7.23
(1H, d), 7.97 (1H, dd), 8.10
(1H, d) Reference Example 24 2-Acetylamino-2- (7'-cyano-1 ',
Diethyl 2 ', 3', 4'-tetrahydro-1'-naphthyl) malonate 22.4 g (60 mmol), acetic acid 80
A mixed solution of 1 ml of 3 ml hydrochloric acid and 160 ml of 3N hydrochloric acid was heated under reflux for 3.5 hours. The reaction solution was allowed to cool, 6 g of activated carbon was added and stirred, the activated carbon was removed, the solvent was distilled off under reduced pressure, 150 ml of toluene was added to the residue, and the solvent was further distilled off under reduced pressure. After adding 150 ml of dioxane to the residue and cooling with ice, 150 ml of a 1N sodium hydroxide aqueous solution and 13 g (60 mmol) of di-tert-butyl dicarbonate were added, and the mixture was stirred at room temperature for 5 hours. The reaction mixture was concentrated under reduced pressure, 100 ml of water was added, and the mixture was washed with ether. The aqueous layer was made weakly acidic with 1N hydrochloric acid and extracted twice with ethyl acetate. The extract was washed with water and saturated brine and dried over anhydrous sodium sulfate. After removing the solvent under reduced pressure,
13.2 g (67%) of a crude product of N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) glycine was obtained. A part was recrystallized from ethyl acetate.

¹ H-NMR (δ ppm in CDCl
₃ ): 1.39, 1.42 (9H, s × 2),
1.6-2.1 (4H, m), 2.8 (2H, m),
3.4 (1H, m), 4.65 (1H, br-t),
4.9, 5.1 (1H, br × 2), 7.18,
7.20 (1H, d × 2), 7.41, 7.42 (1
H, d × 2), 7.53, 7.59 (1H, s × 2) Reference Example 25 2-Acetylamino-2- (5′-cyano-1 ′,
Diethyl 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) malonate was treated as in Reference Example 24 to give N-te.
rt-butoxycarbonyl-2- (5′-cyano-
1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycine was obtained (yield 61%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.26, 1.41 (9H, s × 2),
1.7-2.1 (4H, m), 2.8-3.5 (3
H, m), 4.4-5.1 (1H, m), 6.9-
7.5 (4H, m) Reference Example 26 2-Acetylamino-2- (6'-cyano-3 ', 4'
Di-dihydro-2'H-benzopyran-4'-yl) malonate diethyl was treated as in Reference Example 24 to give N-ter.
t-butoxycarbonyl-2- (6′-cyano-3 ′,
4'-dihydro-2'H-benzopyran-4'-yl)
Glycine was obtained (yield 55%).

¹ H-NMR (δ ppm in DMSO
_{-D 6): 1.2-1.4 (9H,} m), 1.9
-2.1 (2H, m), 3.1-3.2 (1H,
m), 4.1-4.4 (3H, m), 6.9 (1H,
d), 7.4 (1H, d), 7.6 (1H, dd),
7.7 (1H, d), 12.9 (1H, br) Reference Example 27 (2RS, 4′RS) -N-tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro −
2'H-benzothiopyran-4'-yl) glycine ethyl ester 2 g (5.3 mmol) and methanol 2
8 ml of 1N sodium hydroxide aqueous solution was added to the mixed liquid of 4 ml under ice-cooling stirring, and the mixture was stirred overnight at room temperature. Cool the reaction mixture with ice to 1N
8 ml of hydrochloric acid was added and the precipitated crystals were filtered (2RS,
4'RS) -N-tert-butoxycarbonyl-2-
1.83 g (yield quant.) Of (6′-cyano-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl) glycine was obtained.

¹ H-NMR (δ ppm in CDCl
₃ ): 1.25 (9H, s), 1.86 (1H,
t), 2.19 (1H, dd), 3.0-3.2.
(2H, m), 3.31 (1H, dt), 4.08
(1H, t), 5.10 (1H, d), 7.2 (1
H, m), 7.47 (1H, d), 7.66 (1
H, d) Reference Example 28 (2RS, 4'SR) -N-tert-butoxycarbonyl-2- (6'-cyano-3 ', 4'-dihydro-
2′H-benzothiopyran-4′-yl) glycine ethyl ester was treated as in Reference Example 27 (2RS,
4'SR) -N-tert-butoxycarbonyl-2-
(6′-Cyano-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl) glycine was obtained (yield 82
%).

¹ H-NMR (δ ppm in CDCl
₃ ): 1.38 (9H, s), 1.7 (1H, b)
r), 2.36 (1H, dd), 3.0 (2H,
m), 3.25 (1H, m), 4.25 (1H,
t), 7.42 (1H, d), 7.60 (1H,
s), 7.66 (1H, dd) Reference Example 29 N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) glycine ethyl The ester was treated as in Reference Example 27 to give N-tert-butoxycarbonyl-2-
(7'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycine was obtained (yield 92%).

Reference Example 30 (2RS, 1'RS) -N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) glycine ethyl ester was treated as in Reference Example 27 (2RS, 1′RS).
-N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-
Naphthyl) glycine was obtained (yield 84%).

Melting point: 180 to 182 ° C. Reference Example 31 (2RS, 1′SR) -N-tert-butoxycarbonyl-2- (6′-cyano-1 ′, 2 ′, 3 ′, 4′-
Tetrahydro-1′-naphthyl) glycine ethyl ester was treated as in Reference Example 27 (2RS, 1′SR).
-N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-
Naphthyl) glycine was obtained (yield 60%).

FAB-MS: 331 (M + 1) Reference Example 32 (2RS, 1'RS) -N-tert-butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) glycine ethyl ester was treated as in Reference Example 27 (2RS, 1′RS).
-N-tert-butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-tetrahydro-1'-
Naphthyl) glycine was obtained (yield 91%).

Melting point: 161-164 ° C Reference Example 33 (2RS, 1'SR) -N-tert-butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) glycine ethyl ester was treated as in Reference Example 27 (2RS, 1′SR).
-N-tert-butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-tetrahydro-1'-
Naphthyl) glycine was obtained (yield 89%).

Melting point: 176 to 177 ° C. (decomposition point) Example 1 N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) To a mixed solution of 3.3 g (10 mmol) of glycine, 1 ml (12 mmol) of piperidine and 20 ml of dimethylformamide, 2.6 ml (12 mmol) of diphenylphosphoric acid azide and 1.7 ml (12 mmol) of trierylamine were added under cooling with ice. Stir for 3 hours at room temperature overnight. To the reaction mixture was added 33% toluene-ethyl acetate (150 ml), and the mixture was washed with 10% aqueous citric acid solution, water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, 25-33
% Ethyl acetate-hexane to elute (2RS, 1'R
S) and (2RS, 1'SR) -1- [N-tert.
-Butoxycarbonyl-2- (7'-cyano-1 ',
2.33 g (50%) and 0.2 of 2 ', 3', 4'-tetrahydro-1'-naphthyl) glycyl] piperidine.
52 g (21%) was obtained.

(2RS, 1'RS) body: Rf = 0.63
(50% ethyl acetate-hexane) Melting point: 178 to 181 ° C. Elemental analysis value (as C ₂₃ H ₃₁ N ₃ O ₃ 0.25H ₂ O) C% H% N% Theoretical value 68.72 7.90 10.45 Found 68.67 7.85 10.74 ¹ H-NMR (δ ppm in CDCl ₃ ):
1.2-1.9 (10H, m), 1.34 (9H,
s), 2.7-2.9 (2H, m), 3.1-3.
7 (5H, m), 4.77 (1H, t), 5.45
(1H, d), 7.16 (1H, d), 7.40
(1H, dd), 7.57 (1H, s) (2RS, 1'SR) body: Rf = 0.71 (50% ethyl acetate-hexane) Melting point: 188-189 ° C ¹ H-NMR (δppm in CDCl) ₃ ):
0.75 (1H, m), 1.2-1.9 (9H, m),
1.42 (9H, s), 2.65 (1H, m),
2.8-3.2 (4H, m), 3.4-3.6 (2
H, m), 4.89 (1H, t), 5.49 (1
H, d), 7.18 (1H, d), 7.40 (1
H, s), 7.41 (1H, d) Example 2 Diethyl 2-acetylamino-2- (6′-cyano-1′-indanyl) malonate was used as Reference Example 24 and Example 1.
(2RS, 1'RS) and (2R
S, 1′SR) -1- [N-tert-butoxycarbonyl-2- (6′-cyano-1′-indanyl) glycyl] piperidine was obtained (yield 46% and 25%).

(2RS, 1'RS) body: Rf = 0.31
(33% ethyl acetate-hexane) Melting point: 180 to 182 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
1.3-1.7 (6H, m), 1.40 (9H,
s), 2.05 (1H, br), 2.3 (1H, b)
r), 2.8-3.1 (2H, m), 3.4-3.
7 (5H, m), 4.78 (1H, dd), 5.3
2 (1H, d), 7.30 (1H, d), 7.48
(1H, d), 7.54 (1H, s) (2RS, 1′SR) form: Rf = 0.38 (33% ethyl acetate-hexane) FAB-MS: 384 (M + 1) ¹ H-NMR (δppm in CDCl ₃ ):
1.09 (1H, br), 1.3-1.7 (5H,
m), 1.39 (9H, s), 2.15 (2H,
m), 2.9 (1H, br), 3.1 (2H,
m), 3.3 (1H, m), 3.4-3.7 (4
H, m), 4.82 (1H, t), 5.39 (1
H, d), 7.31 (1H, d), 7.47 (1
H, d), 7.51 (1H, s) Example 3 2-Acetylamino-2- (2'-cyano-5 ',
Diethyl 6 ′, 7 ′, 8 ′,-tetrahydro-9′H-benzocyclohepten-9′-yl) malonate was treated as in Reference Example 24 and Example 1 (2RS, 1′R).
S) -1- [N-tert-butoxycarbonyl-2-
(2′-Cyano-5 ′, 6 ′, 7 ′, 8 ′,-tetrahydro-9′H-benzocyclohepten-9′-yl) glycyl] piperidine was obtained (yield 46%) Melting point: 189 ~ 193 ° C ¹ H-NMR (δppm in CDCl ₃ ):
1.1-1.8 (12H, m), 1.27 (9H,
s), 2.8-3.1 (2H, m), 3.4-3.
8 (5H, m), 4.93 (1H, d), 5.21
(1H, t), 7.17 (1H, d), 7.40
(1H, d), 7.49 (1H, s) Example 4 N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl ) Glycine and morpholine were treated as in Example 1 to give (2RS, 1′RS) and (2RS, 1 ′S).
R) -4- [N-tert-butoxycarbonyl-2-
(7'-Cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycyl] morpholine was obtained (yield 51% and 18%).

(2RS, 1'RS) body: Rf = 0.11
(33% ethyl acetate-hexane) Melting point: 157-159 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
1.35 (9H, s), 1.7-1.9 (4H, m),
2.7-3.0 (2H, m), 3.2-3.8 (9
H, m), 4.71 (1H, t), 5.45 (1
H, d), 7.18 (1H, d), 7.42 (1
H, d), 7.59 (1H, s) (2RS, 1'SR) body: Rf = 0.15 (33% ethyl acetate-hexane) Melting point: 162-163 ° C ¹ H-NMR (δppm in CDCl ₃ ):
1.43 (9H, s), 1.7 (1H, br), 1.
9 (1H, br), 2.1 (2H, br), 2.5
(1H, br), 2.8-3.7 (10H, m),
4.82 (1H, t), 5.43 (1H, d),
7.20 (1H, d), 7.38 (1H, s),
7.44 (1H, dd) Example 5 N-tert-butoxycarbonyl-2- (7'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycine and 1,2. 2,3,4-Tetrahydroisoquinoline was treated as in Example 1 to give 2- [N-
tert-butoxycarbonyl-2- (7'-cyano-
1 ', 2', 3 ', 4'-Tetrahydro-1'-naphthyl) glycyl] -1,2,3,4-tetrahydroisoquinoline was obtained (yield 82%).

Melting point: 184-186 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
1.34 (9H, s), 1.6-1.9 (4H, m),
2.6-2.9 (4H, m), 3.3 (1H, b
r), 3.6-4.0 (2H, m), 4.51,
4.75 (2H, dd × 2), 4.85, 4.87
(1H, t × 2), 5.40, 5.47 (1H, d ×
2), 6.9-7.3 (5H, m), 7.35,
7.41 (1H, d × 2), 7.59, 7.62 (1
H, s × 2) Example 6 N-tert-butoxycarbonyl-2- (5′-cyano-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) glycine was used as in Example 1. To 1- [N
-Tert-Butoxycarbonyl-2- (5'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield quan.
t. ).

FAB-MS: 398 (M + 1) ¹ H-NMR (δppm in CDCl ₃ ):
1.3-2.1 (10H), 1.34, 1.41 (9
H, s × 2), 2.8-3.0 (1H, m),
3.0-3.2 (1H, m), 3.2-3.4 (2
H, m), 3.5-3.6 (2H, m), 4.
8-4.9 (1H, m), 5.4-5.5 (1H,
m), 7.1-7.3 (2H, m), 7.3
7.4 (1H, m), 7.5-7.6 (1H,
m) Example 7 (2RS, 1'RS) -N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) glycine was treated as in Example 1 to give (2RS, 1′RS) -1- [N-te.
rt-butoxycarbonyl-2- (6′-cyano-
1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield 86%).

Melting point: 157-158 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
1.2-1.7 (6H, m), 1.35 (9H,
s), 1.7-2.0 (4H, m), 2.7-2.
9 (2H, m), 3.2-3.4 (3H, m),
3.5-3.6 (2H, m), 4.81 (1H, d
d), 5.46 (1H, d), 7.38 (2H,
d), 7.41 (1H, s) Example 8 (2RS, 1'SR) -N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) glycine was treated as in Example 1 to give (2RS, 1′SR) -1- [N-te.
rt-butoxycarbonyl-2- (6′-cyano-
1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield 78%).

Melting point: 181-183 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
0.85 (1H, br), 1.3-2.1 (9H,
m), 1.41 (9H, s), 2.6 (1H,
m), 2.7-2.9 (2H, m), 3.0-3.
2 (2H, m), 3.3 (1H, m), 3.55
(1H, m), 4.94 (1H, t), 5.42
(1H, d), 7.21 (1H, d), 7.34
(1H, d), 7.38 (1H, s) Example 9 N-tert-butoxycarbonyl-2- (7′-nitro-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl ) Glycine was treated as in Example 1 (2R
S, 1'RS) and (2RS, 1'SR) -1- [N
-Tert-Butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield 45% and 25%).

(2RS, 1'RS) body: Rf = 0.19
(25% ethyl acetate-hexane) Melting point: 177 to 179 ° C ¹ H-NMR (δppm in CDCl ₃ ):
1.27 (9H, s), 1.4-2.0 (10H,
m), 2.7-3.0 (2H, m), 3.4-3.
7 (7H, m), 4.81 (1H, t), 5.46
(1H, d), 7.22 (1H, d), 7.97
(1H, dd), 8.12 (1H, s) (2RS, 1′SR) body: Rf = 0.26 (25% ethyl acetate-hexane) Melting point: 162-164 ° C. Elemental analysis value (C ₂₂ H ₃₁ N ₃ O ₅ 0.1H as _{2 O) C% H% N} % theoretical value 63.02 7.50 10.02 Found ^{62.71 7.58 10.33 1 H-NMR (} δppm in CDCl 3):
0.82 (1H, br), 1.2-1.6 (5H,
m), 1.41 (9H, s), 1.6-1.9 (2
H, m), 2.0-2.2 (2H, m), 2.6-
2.7 (1H, m), 2.8-3.0 (2H, m),
3.1-3.2 (2H, m), 3.3-3.4 (1
H, m), 3.6 (1H, br), 4.93 (1
H, t), 5.45 (1H, d), 7.23 (1
H, d), 7.98 (1H, dd), 7.99 (1
H, s) Example 10 N-tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-2′H-benzopyran-
4′-yl) glycine was treated as in Example 1 (2
RS, 4′RS) -1- [N-tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-
2'H-benzopyran-4'-yl) glycyl] piperidine was obtained (yield 15%).

APCI-MS: 400 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.06 (1H, s), 1.24 (9H, s),
1.4-1.7 (6H, m), 1.9-2.1
(1H, m), 2.25 (1H, br), 3.
0-3.2 (3H, m), 3.56 (2H, b
r), 3.84 (1H, dd), 4.28 (1
H, dd), 4.88 (1H, br), 6.9
8 (1H, d), 7.64 (1H, dd), 8.
11 (1H, d), 8.66 (3H, br) Example 11 (2RS, 4'RS) -N-tert-butoxycarbonyl-2- (6'-cyano-3 ', 4'-dihydro-
2′H-benzothiopyran-4′-yl) glycine and 4-hydroxybenzylamine were treated as in Example 1 to give (2RS, 4′RS) -N ^α -tert-butoxycarbonyl-2- (6′-. Cyano-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N-
(4-Hydroxybenzyl) glycinamide was obtained (yield 76%).

Melting point: 218 to 219 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
1.24 (9H, s), 1.75 (1H, t), 1.
96 (1H, dd), 2.92 (1H, d), 3.
3. 10 (1H, d), 3.42 (1H, dt), 4.
10 (1H, t), 4.2 (2H, m), 6.69
(2H, d), 7.06 (2H, d), 7.16
(1H, d), 7.21 (1H, d), 7.45
(1H, dd), 7.64 (1H, s), 8.68
(1H, t), 9.28 (1H, s) Example 12 (2RS, 4'SR) -N-tert-butoxycarbonyl-2- (6'-cyano-3 ', 4'-dihydro-
2′H-benzothiopyran-4′-yl) glycine and 4-hydroxybenzylamine were treated as in Example 1 to give (2RS, 4′SR) -N ^α -tert-butoxycarbonyl-2- (6′-. Cyano-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N-
(4-Hydroxybenzyl) glycinamide was obtained (yield 83%).

Melting point: 204 to 206 ° C. Elemental analysis value (as C ₂₄ H ₂₇ N ₃ O ₄ S 0.25H ₂ O) C% H% N% S% Theoretical value 62.93 6.05 9.17 7. 00 Found ^{63.18 5.97 8.79 6.56 1 H-NMR} (δppm in CDCl 3):
1.37 (9H, s), 1.70 (1H, t), 2.
29 (1H, br), 3.0-3.2 (2H, m),
3.25 (1H, br), 4.0 (2H, m),
4.33 (1H, t), 6.64 (2H, d),
6.85 (2H, d), 7.16 (1H, d),
7.26 (1H, d), 7.32 (1H, s),
7.48 (1H, d), 8.22 (1H, t),
9.23 (1H, s) Example 13 (2RS, 1′RS) -1- [N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′,
10 ml of 4N hydrochloric acid-dioxane was added to 1.39 g (3.5 mmol) of 4'-tetrahydro-1'-naphthyl) glycyl] piperidine, and the mixture was stirred at room temperature for 1 hour. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was washed with ether to obtain 1.2 g of a white powder.

To a mixture of the white powder obtained above, N- (2-naphthylsulfonyl) glycine 1.11 g (4.2 mmol) and dimethylformamide 10 ml, 0.91 ml (4.2 mmo of diphenylphosphoric acid azide was stirred with ice cooling.
l) and 1.2 ml triarylamine (8.4 mmo
l) ml was added, and the mixture was stirred under ice cooling for 3 hours and at room temperature overnight. 100 ml of a mixed solution of ethyl acetate-water (1: 1) was added to the reaction solution, and the crystals were collected by filtration, washed with water and ethanol, and then (2RS, 1′RS) -1- [2- (7′-cyano). −
1.42 g (74%) of 1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained.

Melting point: 261-263 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2 (2H, br), 1.4 (3H, br),
1.5 (1H, br), 1.65 (4H, br),
2.6-2.9 (2H, m), 3.1 (2H, b)
r), 3.2-3.4 (1H, m), 3.4-3.
6 (2H, m), 4.03 (2H, s), 4.81
(1H, t), 7.21 (1H, d), 7.47
(1H, dd), 7.55 (1H, s), 7.7
(2H, m), 7.76 (1H, dd), 8.05
(3H, m), 8.12 (1H, d), 8.39
(1H, s), 8.40 (1H, d) Example 14 (2RS, 1′SR) -1- [N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3) ',
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine was treated as in Example 13 (2RS, 1 ′S).
R) -1- [2- (7'-cyano-1 ', 2', 3 ',
4'-tetrahydro-1'-naphthyl) -N- [N-
(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 81%).

Melting point: 207 to 212 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.4 (1H, br), 1.2 (2H, br),
1.4 (5H, br), 1.7 (2H, br),
2.6-3.2 (6H, m), 3.5-3.6 (3
H, m), 4.99 (1H, t), 7.26 (1
H, d), 7.33 (1H, s), 7.55 (1
H, dd), 7.7 (2H, m), 7.82 (1
H, dd), 8.1 (4H, m), 8.20 (1
H, d), 8.42 (1H, s) Example 15 (2RS, 1'RS) -1- [N-tert-butoxycarbonyl-2- (6'-cyano-1'-indanyl).
Glycyl] piperidine was treated as in Example 13 to give (2RS, 1′RS) -1- [2- (6′-cyano-
1'-Indanyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 9
3%).

Elemental analysis value (as C ₂₉ H ₃₀ N ₄ O ₄ S 0.25H ₂ O) C% H% N% S% Theoretical value 65.09 5.74 10.47 5.99 Found value 65.14 5.62 10.41 6.12 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.3 (2H, br), 1.4 (2H, br),
1.5 (2H, m), 1.75 (1H, m), 2.
1 (1H, m), 2.8 (1H, m), 2.9 (1
H, m), 3.2-3.6 (7H, m), 4.77.
(1H, t), 7.38 (1H, d), 7.5-
7.8 (4H, m), 7.79 (1H, d), 8.
03 (1H, d), 8.08 (2H, d), 8.1
2 (1H, d), 8.28 (1H, d), 8.40
(1H, s) Example 16 (2RS, 1′SR) -1- [N-tert-butoxycarbonyl-2- (6′-cyano-1′-indanyl)
Glycyl] piperidine was treated as in Example 13 to give (2RS, 1′SR) -1- [2- (6′-cyano-
1'-Indanyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 9
2%).

FAB-MS: 531 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.88 (1H, br), 1.2-1.6 (4H,
m), 1.75 (1H, m), 1.9 (1H,
m), 2.6-2.9 (2H, m), 3.0-3.
6 (6H, m), 4.84 (1H, t), 7.37
(1H, d), 7.45 (1H, s), 7.58 (1
H, d), 7.65 (2H, d), 7.81 (1
H, d), 8.0-8.2 (4H, m), 8.29.
(1H, d), 8.40 (1H, s) Example 17 (2RS, 1′RS) -1- [N-tert-butoxycarbonyl-2- (2′-cyano-5 ′, 6 ′, 7) ',
8 ',-Tetrahydro-9'H-benzocyclohepten-9'-yl) glycyl] piperidine was treated as in Example 13 to give (2RS, 1'RS) -1- [2- (2'.
-Cyano-5 ', 6', 7 ', 8',-tetrahydro-
9'H-benzocycloheptene-9'-yl) -N-
[N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 86%).

Melting point: 242 to 246 ° C. Elemental analysis value (as C ₃₁ H ₃₄ N ₄ O ₄ S 0.25H ₂ O) C% H% N% S% Theoretical value 66.11 6.17 9.95 5. 69 Found 65.94 6.02 9.75 6.02 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2-1.7 (12H, m), 2.7-3.1
(3H, m), 3.2-3.6 (6H, m), 5.3
3 (1H, t), 7.19 (1H, d), 7.40
(1H, s), 7.44 (1H, d), 7.7 (3
H, m), 7.91 (1H, t), 8.03 (1H,
d), 8.07 (1H, d), 8.11 (1H,
d), 8.16 (1H, d), 8.34 (1H, s) Example 18 (2RS, 1′RS) -1- [N-tert-butoxycarbonyl-2- (7′-cyano-1) ', 2', 3 ',
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine and N-dansylglycine were treated as in Example 13 to give (2RS, 1′RS) -1- [2- (7′-
Cyano-1 ', 2', 3 ', 4'-tetrahydro-1'
-Naphthyl) -N- (N-dansylglycyl) glycyl] piperidine was obtained (yield 82%).

FAB-MS: 588 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.1-1.7 (10H, m), 2.6-2.9
(2H, m), 2.86 (6H, s), 3.1
(1H, m), 3.2-3.6 (6H, m),
4.83 (1H, t), 7.23 (1H, d
d), 7.5-7.6 (4H, m), 8.08 (1
H, dd), 8.18 (1H, t), 8.24
(1H, d), 8.38 (1H, d), 8.44
(1H, d) Example 19 (2RS, 1′RS) -1- [N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′,
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine and N-tert-butoxycarbonylglycine were treated as in Example 13 (2RS, 1′RS).
-1- [N- (N-tert-butoxycarbonylglycyl) -2- (7'-cyano-1 ', 2', 3 ', 4'
-Tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield 76%).

Melting point: 203 to 206 ° C. Elemental analysis value (as C ₂₅ H ₃₄ N ₄ O ₄ 0.75H ₂ O) C% H% N% Theoretical value 64.14 7.64 11.97 Actual value 64.02 7.36 11.93 ¹ H-NMR (δppm in CDCl ₃ ):
1.2-2.0 (10H, m), 1.45 (9H,
s), 2.7-2.9 (2H, m), 3.2-3.
4 (3H, m), 3.5-3.8 (4H, m),
5.06 (1H, br), 5.17 (1H, t),
7.16 (1H, d), 7.40 (1H, dd),
7.69 (1H, s) Example 20 (2RS, 1'RS) -1- [N- (N-tert-butoxycarbonylglycyl) -2- (7'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) glycyl] piperidine and diphenylacetic acid were treated as in Example 13 to give (2RS, 1′RS) -1-
[2- (7'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) -N- (N-diphenylacetylglycyl) glycyl] piperidine was obtained (yield 8
4%).

Melting point: 220-224 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.3-1.8 (10H, m), 2.7-2.9.
(2H, m), 3.2 (1H, m), 3.4-3.
5 (5H, m), 3.83 (1H, dd), 4.9
3 (1H, t), 5.00 (1H, s), 7.2-
7.3 (11H, m), 7.51 (1H, dd),
7.64 (1H, s), 8.33 (1H, t),
8.56 (1H, d) Example 21 (2RS, 1'RS) -1- [N- (N-tert-butoxycarbonylglycyl) -2- (7'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) glycyl] piperidine and indole-3-carboxylic acid were treated as in Example 13 (2RS, 1′R
S) -1- [2- (7'-cyano-1 ', 2', 3 ',
4'-tetrahydro-1'-naphthyl) -N- [N-
(1H-Indol-3-yl) carbonylglycyl]
Glycyl] piperidine was obtained (yield 88%).

Melting point: 136-139 ° C. Elemental analysis value (as C ₂₉ H ₃₁ N ₅ O ₃ 1.5H ₂ O) C% H% N% Theoretical value 66.39 6.53 13.35 Actual value 66.39 6.25 12.92 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.3-1.8 (10H, m), 2.7-2.9.
(2H, m), 3.26 (1H, d), 3.4-
3.6 (5H, m), 3.98 (1H, dd),
4.97 (1H, t), 7.0-7.2 (3H,
m), 7.42 (1H, d), 7.50 (1H,
d), 7.70 (1H, s), 8.0 (2H,
m), 8.09 (1H, d), 8.40 (1H, d
d), 11.52 (1H, br) Example 22 (2RS, 1′RS) -4- [N-tert-butoxycarbonyl-2- (7′-cyano-1 ′, 2 ′, 3 ′,
4′-Tetrahydro-1′-naphthyl) glycyl] morpholine was treated as in Example 13 (2RS, 1′R).
S) -4- [2- (7'-cyano-1 ', 2', 3 ',
4'-tetrahydro-1'-naphthyl) -N- [N-
(2-Naphthylsulfonyl) glycyl] glycyl] morpholine was obtained (yield 91%).

Melting point: 265-270 ° C. (decomposition point) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.65 (4H, m), 2.6-2.9 (2H,
m), 3.1-3.6 (11H, m), 4.80.
(1H, t), 7.21 (1H, d), 7.47
(1H, d), 7.59 (1H, s), 7.7 (2
H, m), 7.77 (1H, dd), 8.0 (2
H, m), 8.10 (2H, dd), 8.40 (1
H, s), 8.44 (1H, d) Example 23 2- [N-tert-butoxycarbonyl-2- (7 ′).
-Cyano-1 ', 2', 3 ', 4'-tetrahydro-
1′-naphthyl) glycyl] -1,2,3,4-tetrahydroisoquinoline was treated as in Example 13 to give 2
-[2- (7'-cyano-1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] -1,2, Three
4, -tetrahydroisoquinoline was obtained (yield 80
%).

Melting point: 241-245 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.5-1.8 (4H, m), 2.6-2.9 (4
H, m), 3.1-3.2 (1H, m), 3.4-
3.8 (3H, m), 4.51, 4.59 (2H, d
d × 2), 4.92, 4.96 (1H, t × 2),
6.9-7.2 (5H, m), 7.44, 7.48
(1H, d × 2), 7.6-7.8 (4H, m),
7.9-8.2 (4H, m), 8.3-8.5 (2
H, m) Example 24 1- [N-tert-butoxycarbonyl-2- (5 '
-Cyano-1 ', 2', 3 ', 4'-tetrahydro-
1′-naphthyl) glycyl] piperidine was treated as in Example 13 to give 1- [2- (5′-cyano-1 ′,
2 ', 3', 4'-Tetrahydro-1'-naphthyl)-
N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 76%).

FAB-MS: 545 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.5-1.8 (10H), 2.7-3.6 (9
H), 4.81, 4.91 (1H, t), 7.1-
8.5 (12H) Example 25 (2RS, 1'RS) -1- [N-tert-butoxycarbonyl-2- (6'-cyano-1 ', 2', 3 ',
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine was treated as in Example 13 (2RS, 1′R).
S) -1- [2- (6'-cyano-1 ', 2', 3 ',
4'-tetrahydro-1'-naphthyl) -N- [N-
(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 69%).

Melting point: 215 to 220 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2 (2H, br), 1.4 (3H, br),
1.5 (1H, br), 1.65 (4H, br),
2.6-2.8 (2H, m), 3.0-3.4 (5
H, m), 3.4-3.6 (2H, m), 4.82.
(1H, t), 7.30 (1H, d), 7.40 (1
H, d), 7.49 (1H, s), 7.7 (2H,
m), 7.77 (1H, dd), 7.99 (1H, dd)
t), 8.03 (1H, d), 8.08 (1H,
d), 8.13 (1H, d), 8.38 (1H,
s), 8.45 (1H, d) Example 26 (2RS, 1′SR) -1- [N-tert-butoxycarbonyl-2- (6′-cyano-1 ′, 2 ′, 3 ′,
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine was treated as in Example 13 (2RS, 1 ′S).
R) -1- [2- (6'-cyano-1 ', 2', 3 ',
4'-tetrahydro-1'-naphthyl) -N- [N-
(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 69%).

Melting point: 244-247 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.55 (1H, br), 1.1-1.6 (7H,
m), 1.7 (2H, m), 2.6-2.8 (3
H, m), 2.95 (1H, m), 3.05 (1
H, m), 3.2 (1H, m), 3.4 (1H,
m), 3.55 (2H, d), 4.99 (1H,
t), 7.13 (1H, d), 7.48 (1H,
d), 7.54 (1H, s), 7.7 (2H,
m), 7.82 (1H, dd), 8.05 (2H,
t), 8.10 (1H, d), 8.14 (1H,
d), 8.20 (1H, d), 8.41 (1H,
s) Example 27 (2RS, 1′RS) -1- [N-tert-butoxycarbonyl-2- (7′-nitro-1 ′, 2 ′, 3 ′,
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine was treated as in Example 13 (2RS, 1′R).
S) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (7′-nitro-1 ′, 2 ′, 3 ′,
4'-Tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield 82%).

Elemental analysis value (as C ₂₉ H ₃₂ N ₄ O ₆ S) C% H% N% S% Theoretical value 61.69 5.71 9.92 5.68 Found 61.60 5.72 9. ^{90 5.63 1 H-NMR (δppm} in DMSO-d 6):
1.2 (2H, br), 1.4 (3H, br),
1.5 (1H, br), 1.65 (4H, br),
2.75 (1H, m), 2.85 (1H, m),
3.05 (1H, m), 3.1-3.4 (4H,
m), 3.55 (2H, m), 4.82 (1H,
d), 7.28 (1H, d), 7.6-7.7 (3
H, m), 7.90 (2H, dd), 8.05 (3
H, m), 8.10 (1H, d), 8.32 (1
H, s), 8.54 (1H, d) Example 28 (2RS, 1'SR) -1- [N-tert-butoxycarbonyl-2- (7'-nitro-1 ', 2', 3 '. ，
4′-Tetrahydro-1′-naphthyl) glycyl] piperidine was treated as in Example 13 (2RS, 1 ′S).
R) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (7′-nitro-1 ′, 2 ′, 3 ′,
4'-Tetrahydro-1'-naphthyl) glycyl] piperidine was obtained (yield 93%).

Melting point: 241-243 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.4 (1H, br), 1.0 (1H, br),
1.15 (1H, br), 1.3 (3H, br),
1.5 (2H, m), 1.7 (2H, br), 2.
7-2.9 (4H, m), 3.1 (2H, m),
3.45 (1H, m), 3.58 (2H, d),
4.96 (1H, t), 7.35 (1H, d),
7.65 (2H, m), 7.80 (1H, d),
7.82 (1H, dd), 7.98 (1H, dd),
8.0-8.1 (4H, m), 8.26 (1H,
d), 8.42 (1H, s) Example 29 (2RS, 4′RS) -1- [N-tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-2 ′] H-benzopyran-4′-yl) glycyl] piperidine was treated as in Example 13 (2RS, 4 ′).
RS) -1- [2- (6'-cyano-3 ', 4'-dihydro-2'H-benzopyran-4'-yl) -N- [N
-(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 55%).

FAB-MS: 547 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.1-1.2 (2H, m), 1.3-1.5
(4H, m), 1.72 (1H, dd), 1.9
-2.0 (1H, m), 3.1-3.2 (2H,
m), 3.2-3.4 (3H, m), 3.4-.
3.5 (1H, m), 3.59 (1H, dd),
4.08 (1H, t), 4.27 (1H, t
d), 4.86 (1H, t), 6.85 (1H,
d), 7.48 (1H, dd), 7.56 (1
H, d), 7.6-7.7 (2H, m), 7.
77 (1H, dd), 8.0-8.1 (3H,
m), 8.12 (1H, d), 8.40 (1H,
s), 8.50 (1H, d) Example 30 (2RS, 4′RS) -N ^α -tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-
2'H-benzothiopyran-4'-yl) -N- (4-
Hydroxybenzyl) glycinamide was treated as in Example 13 to give (2RS, 4′RS) -2- (6′-cyano-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl). -N- (4-hydroxybenzyl) -N
^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide was obtained (yield 67%).

Melting point: 262-265 ° C. Elemental analysis value (as C ₃₁ H ₂₈ N ₄ O ₅ S ₂ 0.5H ₂ O) C% H% N% S% Theoretical value 61.07 4.79 9.19 10 .52 measured value 61.31 4.64 8.98 10.24 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.73 (1H, t), 1.95 (1H, m),
2.87 (1H, d), 3.09 (1H, d),
3.28 (1H, dd), 3.40 (1H, dd),
3.50 (1H, dd), 4.07 (1H, d
d), 4.20 (1H, dd), 4.44 (1H,
t), 6.69 (2H, d), 7.02 (2H,
d), 7.18 (1H, d), 7.40 (1H,
d), 7.51 (1H, s), 7.6-7.8 (3
H, m), 7.98 (1H, t), 8.03 (2
H, t), 8.11 (1H, d), 8.26 (1
H, d), 8.39 (1H, s), 8.81 (1
H, t), 9.28 (1H, s) Example 31 (2RS, 4′SR) -N ^α -tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-
2'H-benzothiopyran-4'-yl) -N- (4-
Hydroxybenzyl) glycinamide was treated as in Example 13 to give (2RS, 4′SR) -2- (6′-cyano-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl). -N- (4-hydroxybenzyl) -N
^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide was obtained (yield 72%).

FAB-MS: 601 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.51 (1H, t), 2.05 (1H, m),
2.69 (1H, d), 3.03 (1H, dt),
3.13 (1H, d), 3.57 (2H, dd),
3.93 (1H, dd), 3.99 (1H, dd),
4.52 (1H, t), 6.62 (2H, d),
6.75 (2H, d), 7.22 (1H, d),
7.45 (1H, d), 7.7 (3H, m), 7.
83 (1H, d), 8.03 (1H, d), 8.0
9 (2H, d), 8.14 (1H, d), 8.20
(1H, d), 8.33 (1H, t), 8.41
(1H, s), 9.25 (1H, br) Example 32 (2RS, 4′RS) -N ^α -tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-
2'H-benzothiopyran-4'-yl) -N- (4-
Hydroxybenzyl) glycinamide and diphenylacetic acid were treated as in Example 13 (2RS, 4′R).
S) -2- (6'-cyano-3 ', 4'-dihydro-
2′H-benzothiopyran-4′-yl) -N ^α -diphenylacetyl-N- (4-hydroxybenzyl) glycinamide was obtained (yield 75%).

Melting point: 261-265 ° C. Elemental analysis value (as C ₃₃ H ₂₉ N ₃ O ₃ S 0.5H ₂ O) C% H% N% S% Theoretical value 71.20 5.43 7.55 5. 76 Found 71.26 5.33 7.41 5.52 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.75 (1H, t), 2.0 (1H, m),
2.94 (1H, d), 3.22 (1H, d),
3.46 (1H, dt), 4.07 (1H, dd),
4.25 (1H, dd), 4.56 (1H, t),
5.04 (1H, s), 6.64 (2H, d),
6.89 (2H, d), 6.95 (2H, d),
7.1-7.3 (9H, m), 7.39 (1H, d
d), 7.66 (1H, s), 8.83 (1H,
d), 8.92 (1H, t), 9.26 (1H,
s) Example 33 (2RS, 4′SR) -N ^α -tert-butoxycarbonyl-2- (6′-cyano-3 ′, 4′-dihydro-
2'H-benzothiopyran-4'-yl) -N- (4-
Hydroxybenzyl) glycinamide and diphenylacetic acid were treated as in Example 13 (2RS, 4 ′S).
R) -2- (6'-cyano-3 ', 4'-dihydro-
2′H-benzothiopyran-4′-yl) -N ^α -diphenylacetyl-N- (4-hydroxybenzyl) glycinamide was obtained (yield 75%).

Melting point: 251 to 255 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.66 (1H, t), 2.1 (1H, m),
2.85 (1H, m), 3.09 (1H, dt),
3.3 (1H, m), 4.02 (2H, dd),
4.73 (1H, t), 5.16 (1H, s),
6.61 (2H, d), 6.78 (2H, d),
7.2-7.4 (11H, m), 7.35 (1H,
s), 7.47 (1H, d), 8.39 (1H,
t), 8.74 (1H, d), 9.25 (1H, b
r) Example 34 (2RS, 4'RS) -1- [2- (6'-cyano-
2 ', 2'-dimethyl-3', 4'-dihydro-2'H
-Benzothiopyran-4'-yl) -N- (diphenylmethylene) glycyl] piperidine 0.66 g (1.3 m
mol) and 4 ml of methanol to a mixture of concentrated hydrochloric acid 1.3
ml was added and the mixture was stirred at room temperature for 2 hours. 30 ml of ethyl acetate was added to the reaction solution, and the mixture was extracted twice with water. The extract was neutralized by adding sodium hydroxide under ice-cooling and then extracted twice with chloroform. The extract was dried over anhydrous sodium sulfate and the solvent was distilled off under reduced pressure. . The residue was dissolved in 4 ml of dimethylformamide and dissolved in N
0.4 g of (2-naphthylsulfonyl) glycine (1.
5 mmol) was added, and 0.32 ml (1.5 mmol) of diphenylphosphoric acid azide and 0.21 ml (1.5 mmol) of triarylamine were added under stirring with ice cooling, and the mixture was stirred under ice cooling for 3 hours and at room temperature overnight. 100 ml of a mixed solution of ethyl acetate-water (1: 1) was added to the reaction solution, and the crystals were collected by filtration and washed with water and ethanol (2RS, 4'RS).
-1- [2- (6'-cyano-2 ', 2'-dimethyl-
3 ', 4'-dihydro-2'H-benzothiopyran-
4'-yl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] piperidine 0.42 g (55
%)Obtained. Melting point: 248 to 251 ° C. Elemental analysis value (as C ₃₁ H ₃₄ N ₄ O ₄ S ₂ 0.75H ₂ O) C% H% N% S% Theoretical value 61.62 5.92 9.27 10.61 Actual measurement Value 61.66 5.74 9.26 10.48 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2-1.6 (6H, m), 1.23 (3H,
s), 1.34 (3H, s), 1.89 (1H, d
d), 1.91 (1H, dd), 3.1-3.5.
(5H, m), 3.44 (2H, dd), 5.16
(1H, t), 7.24 (1H, d), 7.47 (1
H, dd), 7.6-7.7 (3H, m), 7.7.
8 (1H, dd), 8.0-8.2 (4H, m),
8.36 (1H, d), 8.38 (1H, s) Example 35 (2RS, 4'SR) -1- [2- (6'-cyano-
2 ', 2'-dimethyl-3', 4'-dihydro-2'H
-Benzothiopyran-4'-yl) -N- (diphenylmethylene) glycyl] piperidine was treated as in Example 34 to give (2RS, 4'SR) -1- [2- (6'-cyano-2 ', 2'-dimethyl-3 ', 4'-dihydro-
2'H-benzothiopyran-4'-yl) -N- [N-
(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (88% yield).

Melting point: 208 to 209 ° C. ¹ H-NMR (δ ppm in CDCl ₃ ):
1.1 (1H, br), 1.2-1.3 (1H, m),
1.30 (3H, s), 1.40 (3H, s),
1.49 (4H, br), 1.84 (1H, dd),
2.04 (1H, dd), 3.1-3.3 (4H,
m), 3.5 (1H, br), 3.61 (1H, d
d), 3.70 (1H, dd), 5.58 (1H,
t), 6.04 (1H, t), 7.16 (1H,
d), 7.20 (1H, d), 7.33 (1H, d
d), 7.54 (1H, s), 7.63 (2H,
m), 7.85 (1H, dd), 7.91 (1H,
d), 7.98 (2H, d), 8.43 (1H,
s) Example 36 1- [2- (6'-cyano-3 ', 4'-dihydro-
2'H-benzothiopyran-4'-yl) -N- (diphenylmethylene) glycyl] piperidine was treated as in Example 34 to give 1- [2- (6'-cyano-3 ', 4'.
-Dihydro-2'H-benzothiopyran-4'-yl)
-N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 62%).

FAB-MS: 563 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.2-1.8 (7H, m), 2.1-2.2
(1H, m), 2.7-3.0 (4H, m),
3.1-3.7 (4H, m), 4.85, 4.99
(1H, t × 2), 7.2-7.9 (10H,
m), 8.0-8.4 (5H, m) Example 37 (2RS, 1'RS) -1- [2- (7'-cyano-
1 ', 2', 3 ', 4'-Tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine 1.36 g (2.5 mmo
l), triethylamine 8 ml and pyridine 40 ml
Hydrogen sulfide gas was passed through the mixed solution for 15 minutes under ice cooling, and then the mixture was stirred at room temperature for 9 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was washed with acetone to obtain (2RS, 1′RS) -1- [N.
-[N- (2-naphthylsulfonyl) glycyl] -2-
1.43 g (99%) of (1 ′, 2 ′, 3 ′, 4′-tetrahydro-7′-thiocarbamoyl-1′-naphthyl) glycyl] piperidine was obtained.

Melting point: 242-245 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.0 (1H, br), 1.1 (1H, br),
1.2-1.5 (4H, m), 1.65 (4H, b
r), 2.6-2.8 (2H, m), 2.92 (1
H, t), 3.0-3.2 (3H, m), 3.43.
(1H, dd), 3.5 (1H, br), 3.62
(1H, dd), 4.89 (1H, t), 7.03
(1H, d), 7.59 (1H, dd), 7,65
(2H, m), 7.77 (1H, dd), 7.79
(1H, s), 7.92 (1H, t), 8.02
(1H, d), 8.07 (1H, d), 8.13
(1H, d), 8.32 (1H, d), 8.37
(1H, s), 9.25 (1H, s), 9.71
(1H, s) Example 38 (2RS, 1′SR) -1- [2- (7′-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 (2RS, 1 'SR) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1', 2 ',
3 ', 4'-tetrahydro-7'-thiocarbamoyl-
1′-naphthyl) glycyl] piperidine was obtained (yield q
uant. ).

Melting point: 260-263 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.45 (1H, br), 1.0-1.6 (7H,
m), 1.7 (2H, br), 2.6-3.2 (6
H, m), 3.4 (1H, m), 3.57 (2H,
d), 4.96 (1H, t), 7.07 (1H,
d), 7.50 (1H, s), 7, 61 (1H, d
d), 7.7 (2H, m), 7.83 (1H, d
d), 8.0-8.2 (5H, m), 8.43 (1
H, s), 9.29 (1H, s), 9.66 (1H,
s) Example 39 (2RS, 1'RS) -1- [2- (6'-cyano-
1′-Indanyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 to give (2RS, 1′RS) -1- [N- [N.
-(2-naphthylsulfonyl) glycyl] -2- (6 '
-Thiocarbamoyl-1'-indanyl) glycyl] piperidine was obtained (yield 85%).

Melting point: 249 to 252 ° C. (decomposition point) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.1-1.6 (6H, m), 1.8 (1H, b
r), 2.05 (1H, br), 2.7 (1H, b)
r), 2.8 (1H, br), 3.0-3.7 (7
H, m), 4.75 (1H, t), 7.17 (1
H, d), 7.6-7.7 (3H, m), 7.80.
(1H, d), 7.869 (1H, s), 7.9-
8.1 (3H, m), 8.12 (1H, d), 8.
31 (1H, d), 8.39 (1H, s), 9.3
0 (1H, s), 9.70 (1H, s) Example 40 (2RS, 1'SR) -1- [2- (6'-cyano-
1'-Indanyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 to give (2RS, 1'SR) -1- [N- [N.
-(2-naphthylsulfonyl) glycyl] -2- (6 '
-Thiocarbamoyl-1'-indanyl) glycyl] piperidine was obtained (yield 76%).

Melting point: 244-247 ° C. (decomposition point) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.85 (1H, br), 1.15 (1H, b
r), 1.4 (4H, m), 1.65 (1H, b
r), 1.85 (1H, br), 2.6 (1H, b)
r), 2.7 (1H, br), 2.9-3.6 (7
H, m), 4.68 (1H, t), 7.19 (1
H, d), 7.60 (1H, s), 7.6-7.7.
(3H, m), 7.82 (1H, dd), 8.0-
8.1 (4H, m), 8.30 (1H, d), 8.
41 (1H, s), 9.31 (1H, s), 9.6
7 (1H, s) Example 41 (2RS, 1′RS) -1- [2- (2′-cyano-
5 ', 6', 7 ', 8',-Tetrahydro-9'H-benzocyclohepten-9'-yl) -N- [N- (2-
Naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 to give (2RS, 1′RS)-
1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (5 ', 6', 7 ', 8',-tetrahydro-2'-thiocarbamoyl-9'H-benzocycloheptene- 9'-yl) glycyl] piperidine was obtained (yield 91%).

FAB-MS: 593 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.2-1.8 (12H, m), 2.6-3.1
(3H, m), 3.2-3.6 (6H, m), 5.3
0 (1H, t), 7.00 (1H, d), 7.55
(1H, d), 7, 56 (1H, s), 7.7 (3
H, m), 7.82 (1H, t), 8.0-8.2.
(4H, m), 8.31 (1H, s), 9.16
(1H, s), 9.70 (1H, s) Example 42 (2RS, 1'RS) -1- [2- (7'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- (N-dansylglycyl) glycyl] piperidine was treated as in Example 37 (2RS, 1′R
S) -1- [N- (N-dansylglycyl) -2-
(1 ′, 2 ′, 3 ′, 4′-Tetrahydro-7′-thiocarbamoyl-1′-naphthyl) glycyl] piperidine was obtained (yield 59%).

FAB-MS: 622 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.1-1.7 (10H, m), 2.6-2.8
(2H, m), 2.86 (6H, s), 3.1
(2H, m), 3.2-3.3 (3H, m),
3.40 (1H, dd), 3.4-3.5 (1H,
m), 3.59 (1H, dd), 4.93 (1
H, t), 7.04 (1H, dd), 7.23
(1H, dd), 7.5-7.6 (3H, m),
7.79 (1H, s), 8.05 (1H, d
d), 8.24 (1H, dd), 8.29 (1
H, dd), 8.43 (1H, dd), 9.24
(1H, s), 9.69 (1H, s) Example 43 (2RS, 1'RS) -1- [2- (7'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- (N-diphenylacetylglycyl) glycyl] piperidine was treated as in Example 37 (2R
S, 1′RS) -1- [N- (N-diphenylacetylglycyl) -2- (1 ′, 2 ′, 3 ′, 4′-tetrahydro-7′-thiocarbamoyl-1′-naphthyl) glycyl ] Piperidine was obtained (yield quant.).

Melting point: 152-155 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2 (1H, br), 1.3-1.6 (5H,
m), 1.6-1.8 (4H, m), 2.6-2.
8 (2H, m), 3.2 (1H, br), 3.3-
3.5 (5H, m), 3.85 (1H, dd),
5.00 (1H, s), 5.02 (1H, t),
7.05 (1H, d), 7.2-7.3 (10H,
m), 7.63 (1H, d), 7.84 (1H,
s), 8.29 (1H, t), 8.43 (1H,
d), 9.25 (1H, s), 9.71 (1H,
s) Example 44 (2RS, 1'RS) -1- [2- (7'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- [N- (1H-indol-3-yl) carbonylglycyl] glycyl] piperidine was treated as in Example 37. (2RS, 1'RS) -1- [N- [N
-(1H-Indol-3-yl) carbonylglycyl] -2- (1 ', 2', 3 ', 4'-tetrahydro-
7'-thiocarbamoyl-1'-naphthyl) glycyl]
Piperidine was obtained (94% yield).

Melting point: 161 to 163 ° C. Elemental analysis value (as C ₂₉ H ₃₃ N ₅ O ₃ SH ₂ O) C% H% N% S% Theoretical value 63.37 6.42 12.74 5.83 Actual measurement Value 63.25 6.41 12.69 5.89 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2 (1H, br), 1.3-1.6 (5H,
m), 1.6-1.8 (4H, m), 2.6-2.
8 (2H, m), 3.2-3.4 (4H, m),
3.5 (1H, br), 3.61 (1H, dd),
3.98 (1H, dd), 5.07 (1H, t),
7.04 (1H, d), 7.1 (2H, m), 7.
42 (1H, d), 7.66 (1H, dd), 7.
89 (1H, d), 8.0 (2H, m), 8.32
(1H, d), 9.32 (1H, s), 9.76
(1H, s), 11.53 (1H, s) Example 45 (2RS, 1'RS) -4- [2- (7'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] morpholine was treated as in Example 37 (2RS, 1 'RS) -4- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1', 2 ',
3 ', 4'-tetrahydro-7'-thiocarbamoyl-
1'-naphthyl) glycyl] morpholine was obtained (yield 8
6%).

Melting point: 264-269 ° C. Elemental analysis value (as C ₂₉ H ₃₂ N ₄ O ₅ S ₂ 0.75H ₂ O) C% H% N% S% Theoretical value 58.61 5.68 9.43 10 .79 measured value 58.72 5.52 9.40 10.49 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.6-1.8 (4H, m), 2.6-2.8 (2
H, m), 3.0-3.5 (10H, m), 3.60.
(1H, dd), 4.89 (1H, t), 7.05
(1H, d), 7.59 (1H, d), 7.6-
7.8 (4H, m), 7.95 (1H, t), 8.
08 (3H, dt), 8.36 (1H, d), 8.
38 (1H, s), 9.28 (1H, s), 9.7
1 (1H, s) Example 46 2- [2- (7'-cyano-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] -1,2,
3,4, -Tetrahydroisoquinoline was treated as in Example 37 to give 2- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ', 4'-tetrahydro. -7'-thiocarbamoyl-1'-naphthyl)
Glycyl] -1,2,3,4-tetrahydroisoquinoline was obtained (yield quant.). Melting point: 250 to 252 ° C. (decomposition point) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.4-1.7 (4H, m), 2.2-2.8 (3
H, m), 3.15 (1H, br), 3.2-3.
7 (5H, m), 4.32, 4.54 (2H, ddx
2), 4.98, 5.05 (1H, t × 2), 6.
9-7.2 (5H, m), 7.6 (3H, m),
7.7-8.1 (6H, m), 8.3-8.5 (2
H, m), 9.26, 9.32 (1H, s × 2),
9.72, 9.73 (1H, sx2) Example 47 1- [2- (5'-cyano-1 ', 2', 3 ', 4'-
Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 to give 1- [N- [N- (2-naphthylsulfonyl) glycyl]. -2- (1 ', 2',
3 ', 4'-tetrahydro-5'-thiocarbamoyl-
1'-naphthyl) glycyl] piperidine was obtained (yield 4
8%).

FAB-MS: 579 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.7-1.8 (10H, m), 2.6-3.1
(4H, m), 3.2-3.6 (5H, m),
4.85, 4.96 (1H, t), 6.8-7.2
(3H, m), 8.0-8.2 (4H, m),
8.4 (1H, m), 9.32, 9.37 (1H,
s × 2), 9.7, 9.92 (1H, s × 2) Example 48 (2RS, 1′RS) -1- [2- (6′-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 (2RS, 1 'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1', 2 ',
3 ', 4'-tetrahydro-6'-thiocarbamoyl-
1′-naphthyl) glycyl] piperidine was obtained (yield q
uant. ).

FAB-MS: 579 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.1-1.7 (10H, m), 2.6-2.8
(2H, m), 3.0-3.4 (5H, m), 3.5
(1H, br), 3.57 (1H, dd), 4.8
4 (1H, t), 7.19 (1H, d), 7.57
(1H, d), 7.62 (1H, s), 7.7 (2
H, m), 7.76 (1H, dd), 8.0 (2
H, m), 8.07 (1H, d), 8.13 (1H,
d), 8.38 (1H, s), 8.40 (1H,
d), 9.34 (1H, s), 9.73 (1H,
s) Example 49 (2RS, 1'SR) -1- [2- (6'-cyano-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 (2RS, 1 'SR) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1', 2 ',
3 ', 4'-tetrahydro-6'-thiocarbamoyl-
1′-naphthyl) glycyl] piperidine was obtained (yield q
uant. ).

FAB-MS: 579 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.6 (1H, br), 1.0-1.8 (9H,
m), 2.6-2.8 (3H, m), 3.0 (2
H, m), 3.2-3.4 (2H, m), 3.56.
(2H, d), 5.00 (1H, t), 6.95
(1H, d), 7.57 (1H, d), 7.62
(1H, s), 7.7 (2H, m), 7.83 (1
H, dd), 8.0-8.2 (5H, m), 8.4.
2 (1H, s), 9.37 (1H, s), 9.75
(1H, s) Example 50 (2RS, 4′RS) -1- [2- (6′-cyano-
3 ', 4'-dihydro-2'H-benzopyran-4'-
Yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine is treated as in Example 37 to give (2RS, 4′RS) -1- [2- (3 ′, 4′-dihydro. -6'-thiocarbamoyl-2'H-benzopyran-4'-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 84
%).

FAB-MS: 581 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.9-1.5 (6H, m), 1.7-2.0
(2H, m), 2.9-3.7 (7H, m),
3.9-4.3 (2H, m), 4.8-4.9 (1
H, m), 6.7-6.9 (1H, m), 7.
5-8.2 (9H, m), 8.4-8.5 (2H,
m), 9.18 (1H, s), 9.58 (1
H, s) Example 51 1- [2- (6'-cyano-3 ', 4'-dihydro-
2'H-benzothiopyran-4'-yl) -N- [N-
(2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37 to give (2RS, 4′R
S) and (2RS, 4'SR) -1- [2- (3 ',
4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 23 and 76%). .

(2RS, 4'RS) body: Rf = 0.31
(66% ethyl acetate-hexane) FAB-MS: 597 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.10 (1H, br), 1.34 (2H, b
r), 1.47 (1H, br), 1.7-1.8.
(1H, m), 2.11 (1H, dd), 2.
8-3.0 (3H, m), 3.1-3.3 (2H,
m), 3.31 (2H, dd), 3.5-3.7.
(2H, m), 3.58 (1H, dd), 4.
87 (1H, t), 7.02 (1H, d),
7.57 (1H, dd), 7.6-7.7 (4H,
m), 7.8 (1H, m), 7.95 (1H,
d), 8.04 (1H, d), 8.3-8.4
(2H, m), 9.20 (1H, s), 9.6
7 (1H, s) (2RS, 4′SR) form: Rf = 0.15 (66% ethyl acetate-hexane) FAB-MS: 597 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.19 (1H, m), 0.9-1.1 (2H,
m), 1.2 (1H, m), 1.50 (1H,
t), 2.19 (1H, d), 2.69 (1H, d
d), 2.8-2.9 (4H, m), 3.18.
(1H, d), 3.52 (1H, d), 3.62
(2H, ddd), 4.50 (1H, t),
7.11 (1H, d), 7.50 (1H, d),
7.62 (21H, dd), 7.7 (2H,
m), 7.84 (1H, dd), 8.0-8.2.
(4H, m), 8.34 (1H, d), 8.4
3 (1H, s), 9.29 (1H, s), 9.
62 (1H, s) Example 52 (2RS, 4'RS) -2- (6'-cyano-3 ',
4'-dihydro -2'H- benzothiopyran-4'-yl) -N- (4- hydroxybenzyl) -N α - ^[N-
(2-Naphtylsulfonyl) glycyl] glycinamide was treated as in Example 37 to give (2RS, 4′RS)-
2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N- (4
-Hydroxybenzyl) -N ^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide was obtained (yield 8
7%).

FAB-MS: 635 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.72 (1H, t), 1.96 (1H, dd),
2.82 (1H, d), 3.08 (1H, d),
3.3-3.4 (2H, m), 3.57 (1H, d
d), 4.05 (1H, dd), 4.20 (1H,
dd), 4.53 (1H, t), 6.69 (2H,
d), 7.01 (3H, d), 7.60 (1H,
d), 7.65 (5H, m), 7.84 (1H,
t), 8.01 (2H, t), 8.11 (1H,
d), 8.19 (1H, d), 8.35 (1H,
s), 8.69 (1H, t), 9.15 (1H,
s), 9.26 (1H, s), 9.66 (1H,
s) Example 53 (2RS, 4'SR) -2- (6'-cyano-3 ',
4'-dihydro -2'H- benzothiopyran-4'-yl) -N- (4- hydroxybenzyl) -N α - ^[N-
(2-Naphthylsulfonyl) glycyl] glycinamide was treated as in Example 37 to give (2RS, 4′SR)-
2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N- (4
-Hydroxybenzyl) -N ^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide was obtained (yield 6
5%).

FAB-MS: 635 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.53 (1H, t), 2.1 (1H, m),
2.65 (1H, m), 2.99 (1H, dt),
3.15 (1H, d), 3.55 (1H, dd),
3.61 (1H, dd), 3.83 (1H, dd),
3.99 (1H, dd), 4.52 (1H, t),
6.61 (2H, t), 6.78 (2H, d),
7.04 (1H, d), 7.65 (4H, m),
7.84 (1H, dd), 8.0-8.2 (6H,
m), 8.44 (1H, s), 9.19 (1H,
s), 9.24 (1H, s), 9.62 (1H,
s) Example 54 (2RS, 4'RS) -2- (6'-cyano-3 ',
4′-Dihydro-2′H-benzothiopyran-4′-yl) -N ^α -diphenylacetyl-N- (4-hydroxybenzyl) glycinamide was treated as in Example 37 (2RS, 4′RS). -2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N ^α -diphenylacetyl-N-
(4-Hydroxybenzyl) glycinamide was obtained (yield 92%).

FAB-MS: 582 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.78 (1H, t), 2.03 (1H, d),
2.92 (1H, d), 3.25 (1H, d),
3.44 (1H, dt), 4.08 (1H, dd),
4.23 (1H, dd), 4.60 (1H, t),
4.99 (1H, s), 6.64 (2H, d),
6.74 (2H, d), 6.94 (2H, d),
7.0-7.1 (3H, m), 7.2-7.3 (5
H, m), 7.39 (1H, dd), 7.76 (1
H, dd), 7.93 (1H, d), 8.54 (1
H, d), 8.58 (1H, d), 8.79 (1
H, t), 9.13 (1H, s), 9.26 (1
H, s), 9.70 (1H, s) Example 55 (2RS, 4'SR) -2- (6'-cyano-3 ',
4′-Dihydro-2′H-benzothiopyran-4′-yl) -N ^α -diphenylacetyl-N- (4-hydroxybenzyl) glycinamide was treated as in Example 37 (2RS, 4′SR). -2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N ^α -diphenylacetyl-N-
(4-Hydroxybenzyl) glycinamide was obtained (yield 96%).

FAB-MS: 582 (M + 1) Example 56 (2RS, 4'RS) -2- (6'-cyano-2 ',
2′-Dimethyl-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37. (2RS, 4'RS) -1-
[2- (2 ', 2'-Dimethyl-3', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N- [N- (2-naphthylsulfonyl) glycyl ] Glycyl] piperidine was obtained (yield qu
ant. ).

FAB-MS: 625 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.1-1.6 (6H, m), 1.19 (3H,
s), 1.34 (3H, s), 1.95 (2H,
m), 2.9-3.4 (4H, m), 3.4-3.
7 (3H, m), 5.27 (1H, t), 7.07
(1H, d), 7.58 (1H, dd), 7.7 (2
H, m), 7.81 (1H, dd), 7.88 (1
H, s), 8.0-8.2 (4H, m), 8.38.
(1H, d), 8.40 (1H, s), 9.33
(1H, s), 9.71 (1H, s) Example 57 (2RS, 4'SR) -2- (6'-cyano-2 ',
2′-Dimethyl-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 37. (2RS, 4'SR) -1-
[2- (2 ', 2'-Dimethyl-3', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'-yl) -N- [N- (2-naphthylsulfonyl) glycyl ] Glycyl] piperidine was obtained (yield 78
%).

Melting point: 243-246 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.05 (1H, br), 1.1-1.5 (5H,
m), 1.28 (3H, s), 1.29 (3H,
s), 1.75 (2H, m), 3.0-3.7 (7
H, m), 5.40 (1H, t), 7.12 (1
H, d), 7.6-7.7 (4H, m), 7.81
(1H, dd), 8.0-8.2 (4H, m),
8.31 (1H, d), 8.41 (1H, s),
9.27 (1H, s), 9.72 (1H, s) Example 58 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ' , 2 ', 3',
4'-tetrahydro-7'-thiocarbamoyl-1'-
Naphthyl) glycyl] piperidine 1.1 g (1.9 mm
0.1 ml (10 equivalents) of methyl iodide was added to a mixture of 33 ml of acetone) and acetone, and the mixture was heated under reflux for 2 hours. The solvent of the reaction solution was distilled off under reduced pressure, and 0.22 g (2.85 mmol) of ammonium acetate and 33 of methanol were added to the residue.
After adding ml and heating under reflux for 3 hours, 0.15 g (1.9 mmol) of ammonium acetate was further added, and the mixture was heated under reflux overnight. The solvent of the reaction solution was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, eluted with 10% methanol-chloroform, and the obtained powder was washed with acetonitrile (2RS, 1'RS) -1- [2- (7 '
-Amidino-1 ', 2', 3 ', 4'-tetrahydro-
0.93 g (71%) of 1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained.

Melting point: 169-174 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.1 (1H, br), 1.2 (1H, br),
1.4 (3H, br), 1.5 (1H, br),
1.7 (4H, br), 2.7-2.9 (2H,
m), 3.05 (1H, br), 3.1-3.4.
(3H, m), 3.38 (2H, dd), 3.5
(1H, br), 4.94 (1H, t), 7.26
(1H, d), 7.54 (1H, d), 7, 7 (5
H, m), 8.04 (1H, d), 8.09 (1H,
d), 8.13 (1H, d), 8.26 (1H,
d), 8.36 (1H, s), 8.8 (2H, b
r), 9.1 (2H, br) Example 59 (2RS, 1'SR) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ' ，
4'-tetrahydro-7'-thiocarbamoyl-1'-
Naphthyl) glycyl] piperidine was treated as in Example 58 to give (2RS, 1′SR) -1- [2- (7′-amidino-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1 ′.
-Naphthyl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] piperidine hydroiodide was obtained (yield 54%).

Melting point: 205 to 210 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.5 (1H, br), 1.0-1.2 (2H,
m), 1.35 (3H, br), 1.5 (2H, b)
r), 1.75 (2H, br), 2.7-3.2.
(6H, m), 3.4 (1H, br), 3.54
(2H, dd), 5.05 (1H, t), 7.30
(1H, d), 7.44 (1H, s), 7.54
(1H, dd), 7,7 (3H, m), 7.82 (1
H, dd), 8.05 (1H, d), 8.13 (1
H, dd), 8.20 (1H, d), 8.41 (1
H, s), 8.9 (4H, br) Example 60 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (6'-thiocarbamoyl- 1′-Indanyl) glycyl] piperidine was treated as in Example 58 to give (2RS, 1′RS) -1-
[2- (6'-amidino-1'-indanyl) -N-
[N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained (yield 67.
%).

FAB-MS: 548 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2-1.6 (6H, m), 1.9 (1H, b
r), 2.1 (1H, br), 2.7-2.9 (2
H, m), 3.1-3.6 (9H, m), 4.88.
(1H, t), 7.36 (1H, d), 7.59 (1
H, d), 7, 7 (3H, m), 7.79 (1H,
d), 8.1 (4H, m), 8.24 (1H, d),
8.39 (1H, s), 8.8 (2H, br),
9.2 (2H, br) Example 61 (2RS, 1'SR) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (6'-thiocarbamoyl-1'-indanyl). Glycyl] piperidine was treated as in Example 58 (2RS, 1′SR) -1-
[2- (6'-amidino-1'-indanyl) -N-
[N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained (yield 49
%).

Melting point: 167 to 170 ° C. FAB-MS: 548 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.75 (1H, br), 1.2 (2H, br),
1.4 (3H, br), 1.75 (1H, br),
1.95 (1H, br), 2.75 (1H, b
r), 2.85 (1H, br), 3.0-3.4.
(4H, m), 3.4-3.6 (2H, m), 3.
53 (2H, dd), 4.81 (1H, t), 7.
42 (1H, d), 7.491H, s), 7, 7
(2H, m), 7.81 (1H, dd), 8.04
(1H, d), 8.10 (1H, d), 8.13 (1
H, d), 8.33 (1H, d), 8.40 (1
H, s), 8.6-9.3 (4H, br) Example 62 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (5 '. , 6 ', 7',
8 ',-tetrahydro-2'-thiocarbamoyl-9'
H-benzocycloheptene-9′-yl) glycyl] piperidine was treated as in Example 58 (2RS, 1 ′).
RS) -1- [2- (2'-amidino-5 ', 6',
7 ', 8',-Tetrahydro-9'H-benzocycloheptene-9'-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained. 65%).

Elemental analysis value (as C ₃₁ H ₃₇ N ₅ O ₄ S HI H ₂ O) C% H% N% S% I% Theoretical value 51.60 5.59 9.70 4.44 17.58 Actual measurement Value 51.47 5.47 9.51 4.44 17.68 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2-1.8 (12H, m), 2.7-3.0
(3H, m), 3.1-3.6 (6H, m), 5.3
8 (1H, t), 7.23 (1H, d), 7.48
(1H, d), 7.55 (1H, s), 7, 7 (3
H, m), 7.8-8.2 (5H, m), 8.30
(1H, s), 8.9 (4H, br) Example 63 (2RS, 1'RS) -1- [N- (N-dansylglycyl) -2- (1 ', 2', 3 ', 4'-Tetrahydro-7'-thiocarbamoyl-1'-naphthyl) glycyl] piperidine was treated as in Example 58 (2R
S, 1'RS) -1- [2- (7'-amidino-1 ',
2 ', 3', 4'-Tetrahydro-1'-naphthyl)-
N- (N-dansylglycyl) glycyl] piperidine
A hydroiodide salt was obtained (74% yield).

FAB-MS: 605 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.1-1.3 (2H, m), 1.3-1.5
(4H, m), 1.6-1.8 (4H, m),
2.7-2.9 (2H, m), 2.82 (6H,
s), 3.2-3.5 (7H, m), 4.95.
(1H, t), 7.2-7.3 (2H, m),
7.5-7.6 (3H, m), 7.67 (1H,
s), 8.02 (1H, dd), 8.21 (1
H, d), 8.25 (1H, d), 8.44
(1H, d), 8.89 (4H, br) Example 64 (2RS, 1'RS) -1- [N- (N-diphenylacetylglycyl) -2- (1 ', 2', 3 ' , 4′-Tetrahydro-7′-thiocarbamoyl-1′-naphthyl) glycyl] piperidine was treated as in Example 58 to give (2RS, 1′RS) -1- [2- (7′-amidino-1). ', 2', 3 ', 4'-Tetrahydro-1'-naphthyl) -N- (N-diphenylacetylglycyl) glycyl] piperidine hydroiodide was obtained (yield 69
%).

Melting point: 182-187 ° C. Elemental analysis value (as C ₃₄ H ₃₉ N ₅ O ₃ HI 0.5H ₂ O) C% H% N% I% Theoretical value 58.12 5.88 9.97 18. 06 Found 57.88 5.87 9.89 18.41 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.25 (1H, br), 1.3-1.6 (5H,
m), 1.7-1.8 (4H, m), 2.7-2.
9 (2H, m), 3.3-3.5 (6H, m),
3.73 (1H, dd), 5.01 (1H, s),
5.04 (1H, t), 7.1-7.3 (11H,
m), 7.54 (1H, dd), 7.72 (1H,
s), 8.34 (1H, t), 8.41 (1H,
d), 8.78 (2H, br), 9.08 (2H,
br) Example 65 (2RS, 1'RS) -1- [N- [N- (1H-indol-3-yl) carbonylglycyl] -2-
(1 ′, 2 ′, 3 ′, 4′-Tetrahydro-7′-thiocarbamoyl-1′-naphthyl) glycyl] piperidine was treated as in Example 58 to give (2RS, 1′RS)-
1- [2- (7'-amidino-1 ', 2', 3 ', 4'
-Tetrahydro-1'-naphthyl) -N- [N- (1H
-Indol-3-yl) carbonylglycyl] glycyl] piperidine hydroiodide was obtained (yield 47
%).

Melting point: 254-257 ° C. Elemental analysis value (as C ₂₉ H ₃₄ N ₆ O ₃ HI 0.25H ₂ O) C% H% N% I% Theoretical value 53.83 5.53 12.99 19. 61 Found ^{53.50 5.51 12.87 20.04 1 H-NMR} (δppm in DMSO-d 6):
1.2-1.9 (10H, m), 2.7-2.9.
(2H, m), 3.3-3.6 (5H, m), 3.7
5 (2H, dd), 5.09 (1H, t), 7.1
5 (2H, dt), 7.28 (1H, d), 7.4
4 (1H, d), 7.57 (1H, d), 7.80
(1H, s), 8.02 (1H, s), 8.05
(2H, m), 8.35 (1H, s), 8.7-
9.3 (4H, br), 11.56 (1H, br) Example 66 (2RS, 1'RS) -4- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ' , 2 ', 3',
4'-tetrahydro-7'-thiocarbamoyl-1'-
Naphthyl) glycyl] morpholine was treated as in Example 58 to give (2RS, 1'RS) -4- [2- (7'-amidino-1 ', 2', 3 ', 4'-tetrahydro-1'.
-Naphthyl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] morpholine hydroiodide was obtained (yield 38%).

Melting point: 190 to 200 ° C. Elemental analysis value (as C ₂₉ H ₃₃ N ₅ O ₅ S HI 0.5CH ₃ CN) C% H% N% S% I% Theoretical value 50.60 5.02 10. 82 4.50 17.82 Found 50.40 5.03 10.92 4.42 17.69 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.6-1.8 (4H, m), 2.6-2.9 (2
H, m), 3.1-3.6 (11H, m), 4.94.
(1H, t), 7.28 (1H, d), 7.53
(1H, d), 7.6-7.8 (4H, m), 8.0
4 (1H, d), 8.11 (2H, dd), 8.3
1 (1H, d), 8.37 (1H, s), 8.78
(2H, br), 9.10 (2H, br) Example 67 2- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ', 4'-tetrahydro −
7'-thiocarbamoyl-1'-naphthyl) glycyl]
-1,2,3,4-Tetrahydroisoquinoline was treated as in Example 58 to give 2- [2- (7'-amidino-
1 ', 2', 3 ', 4'-Tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] -1,2,3,4-tetrahydroisoquinoline hydrogen iodide The acid salt was obtained (yield 78%).

Elemental analysis value (as C ₃₄ H ₃₅ N ₅ O ₄ S HI 0.75H ₂ O) C% H% N% S% I% Theoretical value 54.36 5.03 9.32 4.27 16. 89 Found 54.11 5.02 9.01 4.18 17.26 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.5-1.8 (4H, m), 2.4-2.9 (4
H, m), 3.2-3.7 (5H, m), 4.31,
4.57 (2H, dd × 2), 5.03, 5.11
(1H, t × 2), 6.8-7.3 (5H, m),
7.49, 7.54 (1H, dd × 2), 7.6-
7.8 (4H, m), 7.9-8.1 (4H, m),
8.2-8.4 (2H, m), 8.7-9.2 (4
H, br) Example 68 1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ', 4'-tetrahydro-
5'-thiocarbamoyl-1'-naphthyl) glycyl]
Piperidine was treated as in Example 58 to give 1- [2-
(5′-amidino-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained. (Yield 15%).

FAB-MS: 562 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
0.7-1.8 (10H, m), 2.7-2.8
(2H, m), 3.0-3.6 (7H, m),
4.85, 5.04 (1H, t × 2), 7.16,
7.38 (1H, d × 2), 7.5-7.8 (5
H, m), 8.0-8.2 (3H, m), 8.4
0, 8.47 (1H, s × 2), 9.0 (4H, b
r) Example 69 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ',
4'-tetrahydro-6'-thiocarbamoyl-1'-
Naphthyl) glycyl] piperidine was treated as in Example 58 to give (2RS, 1'RS) -1- [2- (6'-amidino-1 ', 2', 3 ', 4'-tetrahydro-1'.
-Naphthyl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] piperidine hydroiodide was obtained (yield 44%).

Melting point:> 290 ° C. Elemental analysis (as C ₃₀ H ₃₅ N ₅ O ₄ S HI 0.25H ₂ O) C% H% N% I% Theoretical 51.91 5.30 10.09 18. 28 measured value 51.88 5.11 9.99 18.11 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2 (2H, br), 1.35 (3H, br),
1.5 (1H, br), 1.7 (4H, br),
2.6-2.9 (2H, m), 3.0-3.4 (4
H, m), 3.45 (2H, dd), 3.5 (1
H, br), 4.86 (1H, t), 7.38 (1
H, d), 7.47 (1H, d), 7.52 (1
H, s), 7.7 (2H, m), 7.77 (1H,
dd), 8.04 (1H, d), 8.08 (2H,
d), 8.13 (1H, d), 8.39 (1H,
s), 8.48 (1H, d), 8.6-9.2 (4
H, br) Example 70 (2RS, 1'SR) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ',
4'-tetrahydro-6'-thiocarbamoyl-1'-
Naphthyl) glycyl] piperidine was treated as in Example 58 to give (2RS, 1′SR) -1- [2- (6′-amidino-1 ′, 2 ′, 3 ′, 4′-tetrahydro-1 ′.
-Naphthyl) -N- [N- (2-naphthylsulfonyl)
Glycyl] glycyl] piperidine hydroiodide was obtained (60% yield).

Melting point: 280 to 282 ° C. (decomposition point) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.75 (1H, br), 1.1-1.6 (7H,
m), 1.75 (2H, br), 2.6-2.9.
(3H, m), 3.1 (2H, br), 3.2-
3.4 (2H, m), 3.54 (1H, dd),
5.05 (1H, t), 7.17 (1H, d),
7.49 (1H, d), 7.55 (1H, s),
7.7 (2H, m), 7.82 (1H, d), 8.
04 (1H, d), 8.11 (2H, d), 8.1
4 (1H, d), 8.19 (1H, d), 8.42
(1H, s), 8.6-9.3 (4H, br) Example 71 (2RS, 4'RS) -1- [2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2. 'H-benzopyran-4'-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 58 to give (2RS, 4'RS) -1- [2- (6 '
-Amidino-3 ', 4'-dihydro-2'H-benzopyran-4'-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained (yield 19%).

FAB-MS: 564 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.0-1.1 (1H, m), 1.1-1.2
(1H, m), 1.2-1.5 (4H, m),
1.8-1.9 (2H, m), 3.0-3.6 (7
H, m), 4.0-4.1 (1H, m), 4.
2-4.3 (1H, m), 4.99 (1H, m
t), 6.92 (1H, d), 7.58 (1H,
d), 7.6-7.8 (4H, m), 8.0-
8.2 (3H, m), 8.3-8.4 (2H,
m), 8.9 (3H, br) Example 72 (2RS, 4'RS) -1- [2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'. -Yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 58 to give (2RS, 4'RS) -1- [2-
(6′-amidino-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained. (Yield 74%). ^{FAB-MS: 580 (M +} 1) 1 H-NMR (δppm in DMSO-d 6):
1.18 (1H, br), 1.3-1.4 (2H,
m), 1.48 (1H, br), 1.8 (1
H, m), 2.12 (1H, dd), 3.0
(2H, m), 3.1-3.3 (2H, m),
3.17 (1H, d), 3.3-3.4 (3H,
m), 3.45 (1H, d), 4.94 (1H,
t), 7.25 (1H, d), 7.50 (1H,
dd), 7.6-7.7 (4H, m), 8.0
3 (1H, d), 8.07 (1H, d), 8.
12 (1H, d), 8.26 (1H, d),
8.33 (1H, s), 8.79 (4H, br) Example 73 (2RS, 4'SR) -1- [2- (3 ', 4'-dihydro-6'-thiocarbamoyl-2'. H-benzothiopyran-4′-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 58 to give (2RS, 4′SR) -1- [2-
(6′-amidino-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained. (Yield 55%).

FAB-MS: 580 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.20 (1H, m), 0.81 (1H, m),
1.11 (1H, m), 1.29 (1H, m
m), 1.53 (1H, t), 2.24 (1H,
d), 2.78 (1H, d), 2.8-3.0.
(4H, m), 3.26 (1H, d), 3.3
2 (1H, br), 3.48 (1H, d),
3.58 (1H, d), 3.66 (1H, d),
5.01 (1H, t), 7.3-7.4 (2H,
m), 7.54 (1H, dd), 7.6-7.
7 (2H, m), 7.84 (1H, dd),
8.05 (1H, d), 8.1-8.2 (2H,
m), 8.40 (1H, d), 8.43 (1H,
s), 8.80 (4H, br) Example 74 (2RS, 4'RS) 2- (3 ', 4'-dihydro-
6'-thiocarbamoyl-2'H-benzothiopyran-
4′-yl) -N- (4-hydroxybenzyl) -N ^α
-[N- (2-naphthylsulfonyl) glycyl] glycinamide was treated as in Example 58 (2RS, 4 ').
RS) -2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- (4
-Hydroxybenzyl) -N ^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide hydroiodide was obtained (yield 65%).

FAB-MS: 618 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.75 (1H, t), 2.00 (1H, d),
2.91 (1H, d), 3.17 (1H, d),
3.22 (1H, d), 3.44 (1H, d),
3.48 (1H, dd), 4.07 (1H, dd),
4.19 (1H, dd), 4.51 (1H, t),
6.69 (2H, d), 7.01 (2H, d),
7.25 (1H, d), 7.49 (1H, dd),
7.6-7.8 (4H, m), 8.04 (2H,
t), 8.11 (2H, d), 8.32 (1H,
d), 8.75 (2H, br), 8.79 (1H,
t), 8.99 (2H, br), 9.28 (1H,
s) Example 75 (2RS, 4'SR) -2- (3 ', 4'-dihydro-
6'-thiocarbamoyl-2'H-benzothiopyran-
4′-yl) -N- (4-hydroxybenzyl) -N ^α
-[N- (2-naphthylsulfonyl) glycyl] glycinamide was treated as in Example 58 (2RS, 4 ').
SR) -2- (6'-amidino-3 ', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- (4
-Hydroxybenzyl) -N ^α- [N- (2-naphthylsulfonyl) glycyl] glycinamide hydroiodide was obtained (yield 32%).

FAB-MS: 618 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.57 (1H, t), 2.14 (1H, d),
2.74 (1H, d), 3.0 (1H, br),
3.25 (1H, br), 3.59 (2H, dd),
3.78 (1H, dd), 4.59 (1H, t),
6.63 (2H, d), 6.78 (2H, d),
7.29 (1H, d), 7.46 (1H, s),
7.53 (1H, d), 7.7 (2H, m), 7.
83 (1H, d), 8.0-8.4 (6H, m),
8.43 (1H, s), 8.69 (2H, br),
9.10 (2H, br), 9.24 (1H, br) Example 76 (2RS, 4'RS) -2- (3 ', 4'-dihydro-
6'-thiocarbamoyl-2'H-benzothiopyran-
4′-yl) -N ^α -diphenylacetyl-N- (4-
Hydroxybenzyl) glycinamide was treated as in Example 58 to give (2RS, 4′RS) -2- (6′-amidino-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl). -N ^α -diphenylacetyl-N-
(4-Hydroxybenzyl) glycinamide hydroiodide was obtained (yield 44%).

FAB-MS: 565 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.78 (1H, t), 2.05 (1H, d),
2.98 (1H, d), 3.27 (1H, d),
3.53 (1H, dd), 4.09 (1H, dd),
4.24 (1H, dd), 4.63 (1H, t),
4.99 (1H, s), 6.65 (2H, d),
6.75 (2H, t), 6.95 (2H, d),
7.1-7.3 (9H, m), 7.49 (1H,
d), 7.75 (1H, s), 8.60 (1H,
d), 8.70 (2H, br), 8.87 (2H,
br), 8.93 (1H, t), 9.27 (1H,
s) Example 77 (2RS, 4'SR) -2- (3 ', 4'-dihydro-
6'-thiocarbamoyl-2'H-benzothiopyran-
4′-yl) -N ^α -diphenylacetyl-N- (4-
Hydroxybenzyl) glycinamide was treated as in Example 58 to give (2RS, 4′SR) -2- (6′-amidino-3 ′, 4′-dihydro-2′H-benzothiopyran-4′-yl). -N ^α -diphenylacetyl-N-
(4-Hydroxybenzyl) glycinamide hydroiodide was obtained (yield 7%).

FAB-MS: 565 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.69 (1H, t), 2.1-2.2 (1H,
m), 2.85 (1H, br), 3.05 (1H, br)
br), 3.9 (1H, br), 3.89 (1H,
dd), 4.09 (1H, dd), 4.79 (1
H, t), 5.17 (1H, s), 6.62 (2
H, d), 6.81 (2H, d), 7.16 (2
H, d), 7.1-7.4 (9H, m), 7.52
(1H, d), 7.53 (1H, s), 8.33 (1
H, t), 8.71 (2H, br), 8.79 (1
H, d), 9.06 (2H, br), 9.25 (1
H, br) Example 78 (2RS, 4'RS) -1- [2- (2 ', 2'-dimethyl-3', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4. '-Il) -N- [N
-(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 58 (2RS, 4 ').
RS) -1- [2- (6'-amidino-2 ', 2'-dimethyl-3', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- [N- (2- Naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained (yield 61%).

FAB-MS: 608 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.1-1.6 (6H, m), 1.23 (3H,
s), 1.37 (3H, s), 2.0 (2H, b
r), 3.0-3.6 (5H, m), 3.47 (2)
H, dd), 5.35 (1H, t), 7.31 (1
H, d), 7.51 (1H, d), 7.7 (3H,
m), 7.80 (1H, dd), 8.05 (1H,
d), 8.11 (1H, d), 8.13 (1H,
d), 8.3-8.4 (3H, m), 9.9 (4H,
br) Example 79 (2RS, 4'SR) -1- [2- (2 ', 2'-dimethyl-3', 4'-dihydro-6'-thiocarbamoyl-2'H-benzothiopyran-4'- Ill) -N- [N
-(2-Naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 58 (2RS, 4 ').
SR) -1- [2- (6'-amidino-2 ', 2'-dimethyl-3', 4'-dihydro-2'H-benzothiopyran-4'-yl) -N- [N- (2- Naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained (yield 69%).

Melting point:> 260 ° C. FAB-MS: 608 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.1-1.6 (6H, m), 1.32 (3H,
s), 1.34 (3H, s), 1.8 (2H, b
r), 3.1-3.7 (5H, m), 3.46 (2)
H, dd), 5.57 (1H, dd), 7.30
(1H, d), 7.51 (1H, d), 7.7 (4
H, m), 7.79 (1H, dd), 8.1 (3
H, m), 8.31 (1H, d), 8.37 (1
H, s), 8.9 (4H, br) Example 80 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ',
4'-tetrahydro-7'-thiocarbamoyl-1'-
Naphthyl) glycyl] piperidine 0.22 g (0.38
mmol) and acetone 7 ml, methyl iodide 0.36 ml (15 equivalents) was added, and the mixture was heated under reflux for 3 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was cyclopropylamine 0.05 ml (0.7 mmol), acetic acid 0.0
5 ml and 7 ml of methanol were added and the mixture was heated under reflux for 5 hours. The solvent of the reaction solution was distilled off under reduced pressure, and the residue was subjected to silica gel column chromatography to give 3-6% methanol-
Elute with chloroform and wash the resulting powder with chloroform to obtain (2RS, 1'RS) -4- [2- [7'-
(N'-cyclopropylamidino) -1 ', 2',
3 ', 4'-tetrahydro-1'-naphthyl) -N-
0.2 g (72%) of [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide
Obtained.

Melting point: 147 to 149 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.75 (2H, br), 0.9 (2H, br),
1.1-1.6 (6H, m), 1.7 (4H, b
r), 2.7-2.9 (3H, m), 3.1-3.
4 (5H, m), 3.45 (2H, br), 4.90
(1H, t), 7.25 (1H, d), 7.46
(1H, d), 7.56 (1H, s), 7.7 (3
H, m), 7.89 (1H, br), 8.05 (1
H, d), 8.11 (2H, dd), 8.31 (1
H, d), 8.36 (1H, s), 9.01 (1
H, br), 9.42 (1H, br), 9.68
(1H, br) Example 81 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (1 ', 2', 3 ',
4'-tetrahydro-7'-thiocarbamoyl-1'-
Naphthyl) glycyl] piperidine and morpholine were treated as in Example 80 to give (2RS, 1′RS) -4-.
[2- [7 '-[(morpholino) (imino) methyl]-
1 ′, 2 ′, 3 ′, 4′-tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine hydroiodide was obtained (yield 45%). .

FAB-MS: 632 (M + 1) ¹ H-NMR (δ ppm in DMSO-d ₆ ):
1.2 (2H, br), 1.3-1.6 (4H,
m), 1.7 (4H, br), 2.7-2.9 (2
H, m), 3.1-3.5 (9H, m), 3.6-
3.8 (4H, m), 4.90 (1H, t), 7.
29 (1H, d), 7.36 (1H, d), 7.4
4 (1H, s), 7.7 (2H, m), 7.79
(1H, dd), 7.97 (1H, br), 8.0
5 (1H, d), 8.12 (2H, dd), 8.3
5 (1H, d), 8.38 (1H, s), 9.14
(1H, br), 9.42 ((1H, br) Example 82 (2RS, 1'RS) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (7'-nitro) −
1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) glycyl] piperidine 0.8 g (1.4 mmo
l), 10 ml of a mixture of 7 ml of acetic acid and 7 ml of ethanol.
% Palladium-carbon powder was added, and the mixture was vigorously stirred in a hydrogen gas atmosphere for 6 hours. The catalyst in the reaction solution was removed, the solvent was distilled off under reduced pressure, 40 ml of a saturated aqueous sodium carbonate solution was added to the residue, the mixture was extracted twice with chloroform, dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. The residue was washed with ether and (2RS, 1'RS) -1- [2- (7'-amino-
0.68 g (91%) of 1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained.

Melting point: 173-174 ° C. Elemental analysis value (as C ₂₉ H ₃₄ N ₄ O ₄ S) C% H% N% S% Theoretical value 65.15 6.41 10.48 6.00 Found 65. 03 6.39 10.36 5.97 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.95 (1H, br), 1.15 (1H, b
r), 1.25 (1H, br), 1.3-1.6
(6H, m), 1.7 (1H, br), 2.4-
2.5 (2H, m), 2.85 (1H, br), 3.
0 (1H, br), 3.15 (2H, br), 3.
4-3.6 (3H, m), 4.64 (2H, s),
4.86 (1H, t), 6.35 (1H, dd),
6.48 (1H, d), 6.66 (1H, d),
7.7 (2H, m), 7.81 (1H, dd),
8.03 (1H, d), 8.09 (2H, d),
8.13 (1H, d), 8.17 (1H, d),
8.41 (1H, s) Example 83 (2RS, 1'SR) -1- [N- [N- (2-naphthylsulfonyl) glycyl] -2- (7'-nitro-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) glycyl] piperidine was treated as in Example 82 to give (2RS, 1′SR) -1- [2- (7′-amino). −
1 ', 2', 3 ', 4'-tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was obtained (yield 85%).

Melting point: 240-244 ° C. ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.55 (1H, br), 1.1 (1H, br),
1.2-1.5 (6H, m), 1.65 (2H,
m), 2.5 (2H, m), 2.85 (1H, b
r), 3.1 (1H, br), 3.56 (3H, b
r), 4.69 (2H, s), 4.92 (1H,
t), 6.15 (1H, d), 6.35 (1H, d
d), 6.68 (1H, d), 7.7 (2H,
m), 7.82 (1H, dd), 8.04 (2H,
d), 8.06 (1H, d), 8.10 (1H,
d), 8.14 (1H, d), 8.43 (1H,
s) Example 84 (2RS, 1'RS) -1- [2- (7'-amino-
1 ', 2', 3 ', 4'-Tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine 0.59 g (1.1 mmo
Aminoiminomethyl chloride hydrochloride (0.5 g, 4 equivalents) was added to a mixed solution of 1) and dioxane (6 ml), and the mixture was stirred at 90 ° C. overnight. The solvent of the reaction solution was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography, and eluted with 2-6% methanol-chloroform (2RS, 1'RS).
-1- [2- (7'-guanidino-1 ', 2', 3 ',
4'-tetrahydro-1'-naphthyl) -N- [N-
0.46 g (64%) of (2-naphthylsulfonyl) glycyl] glycyl] piperidine dihydrochloride was obtained.

FAB-MS: 577 (M + 1) ¹ H-NMR (δppm in DMSO-d ₆ ):
1.0-1.7 (10H, m), 2.6-2.8
(2H, m), 3.0-3.2 (2H, m), 3.2
-3.6 (5H, br), 4.86 (1H, t),
6.97 (1H, dd), 7.03 (1H, d),
7.10 (1H, d), 7.35 (4H, m),
7.7 (2H, m), 7.79 (1H, dd),
8.03 (2H, d), 8.09 (1H, d),
8.14 (1H, d), 8.40 (1H, s),
9.8 (1H, br) Example 85 (2RS, 1'SR) -1- [2- (7'-amino-
1 ′, 2 ′, 3 ′, 4′-Tetrahydro-1′-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] piperidine was treated as in Example 84 (2RS, 1 'SR) -1- [2- (7'-guanidino-1', 2 ', 3', 4'-tetrahydro-1'-naphthyl) -N- [N- (2-naphthylsulfonyl) glycyl] glycyl] Piperidine 1.5 hydrochloride hydrate was obtained (yield 55%).

Elemental analysis value (C ₃₀ H ₃₆ N ₆ O ₄ S 1.5HCl H ₂ O C% H% N% S% Cl% Theoretical value 55.48 6.13 12.94 4.94 8.19 Actual measurement Value 55.70 6.19 13.08 4.80 8.05 ¹ H-NMR (δ ppm in DMSO-d ₆ ):
0.8 (1H, br), 1.2-1.8 (9H,
m), 2.5-2.8 (2H, m), 2.95 (1
H, br), 3.05 (2H, m), 3.2-3.
6 (4H, m), 5.04 (1H, t), 6.95
(2H, m), 7.09 (1H, d), 7.38 (4
H, br), 7.7 (2H, m), 7.81 (1
H, dd), 8.0-8.2 (5H, m), 8.0
9 (1H, d), 8.41 (1H, s), 9.81
(1H, s) The chemical structural formulas of the compounds obtained in the examples are shown below.

[0162]

Embedded image

[0163]

[Table 1]

[0164]

Embedded image

[0165]

[Table 2]

[0166]

[Table 3]

[0167]

Embedded image

[0168]

[Table 4]

[0169]

Embedded image

[0170]

[Table 5]

[0171]

Embedded image

[0172]

[Table 6]

[0173]

[Table 7]

[0174]

Embedded image

[0175]

[Table 8]

[0176]

Embedded image

[0177]

[Table 9]

[0178]

Embedded image

[0179]

[Table 10]

[0180]

[Table 11]

[0181]

Embedded image

[0182]

[Table 12]

[0183]

Embedded image

[0184]

[Table 13]

[0185]

Embedded image

[0186]

[Table 14]

[0187]

INDUSTRIAL APPLICABILITY The compounds of the present invention are various diseases related to the physiological function of NPY, namely hyperphagia, anorexia nervosa, obesity, epilepsy, anxiety, senile dementia, depression, Parkinson's disease, head. Cerebral tissue degeneration due to trauma, various physical symptoms due to stress, hypertension, hypotension, heart failure, angina, myocardial infarction, subarachnoid hemorrhage, coronary artery disease, syndrome X, renal disease, asthma, diarrhea , It is useful as a remedy for hormone disorders. INDUSTRIAL APPLICABILITY The compound of the present invention is useful as an adjunct to diet therapy in diabetic patients, as a drug used for blood pressure management during surgery, after surgery, during shock or in pheochromocytoma, and as an immunomodulator.

The action of the compound of the present invention was confirmed by the following test methods.

1) Binding Experiments Membrane preparations prepared from human neuroblastoma cell line SK-N-MC cells or porcine hippocampus were treated with the compound of the present invention and 50 p.
M [ ¹²⁵ I] -peptide YY (PYY), 10 mM
Magnesium chloride, 1 mM phenylmethylsulfonyl fluoride, 1 mg / ml bacitracin, and 5 mg / m
After incubation in 25 mM Tris-hydrochloric acid buffer (pH 7.4) containing 1 bovine serum albumin at 25 ° C. for 180 minutes, the membrane-bound labeled ligand was separated by centrifugation at 10,000 × g for 3 minutes. Non-specific binding is 1 μM NP
It was measured in the presence of Y.

2) Y1 receptor antagonism Using a Japanese white male rabbit having a body weight of 3 to 5 Kg, exsanguination was performed under light anesthesia with thiopental, and the saphenous veins on both sides were excised. After peeling adipose tissue and the like in Krebs nutrient solution, 8 to 12 ring specimens having a length of about 5 mm were prepared. Each section was suspended in a Magnus tank filled with 10 ml of Krebs nutrient solution at 37 ° C., and a static tension of about 1 g was applied. A mixed gas (95% O ₂ + 5% CO ₂ ) was constantly aerated in the tank. 9
After leaving it for 0 minutes to stabilize the sample, 10-8M NP
Y was administered and the resulting contractions were recorded on a recorder via an FD pickup and amplifier. NP at 1 hour intervals
After Y was administered and the contraction height became constant, the effect of the test substance was examined. The test substance was administered 30 minutes before the administration of NPY, and the inhibition rate was calculated by comparing the NPY contraction after administration with the NPY contraction before administration, which was used as an index of the Y1 receptor antagonistic action.

In these pharmacological tests, the compound of the present invention showed a high affinity for the NPY receptor.

To use the compound of the present invention, a non-toxic salt thereof, or a solvate thereof, for example, a hydrate, for the above purpose, it is usually administered orally or parenterally. The dose varies depending on the age, body weight, symptoms, therapeutic effect, administration method, treatment time, etc., but is usually 0.1 mg per adult per day
100 mg, preferably in the range of 1 mg to 10 mg, orally administered once a day in several divided doses, or in the range of 0.1 mg to 100 mg per adult per day, once to several times a day The drug is either parenterally administered or divided into 1 to 24 hours per day and continuously administered intravenously. Since the dose varies depending on various conditions, a dose smaller than the above dose range may be sufficient.

As the solid composition for oral administration according to the present invention, tablets, powders, granules and the like are used. In such solid compositions, the one or more active substances comprises at least one inert diluent such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone, metasilicic acid. It is mixed with magnesium aluminate. According to a conventional method, the composition may be an additive other than an inert diluent, for example, a lubricant such as magnesium stearate, a disintegrating agent such as calcium fibrin glycolate, a stabilizer such as lactose, glutamic acid or asparagine. It may contain a solubilizing agent such as an acid. If necessary, the tablets or pills may be coated with a film of a gastric or enteric substance such as sucrose, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate.

Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs and the like, commonly used inert diluents, For example, it contains purified water and ethanol. In addition to the inert diluent, this composition may contain an auxiliary agent such as a wetting agent and a suspending agent, a sweetening agent, a flavoring agent, an aromatic agent and a preservative.
Parenteral administration includes sublingual, buccal, intratracheal, intranasal, subcutaneous, intramuscular or intravenous administration and rectal administration. Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of the aqueous solution and suspension include distilled water for injection and physiological saline. Examples of the water-insoluble solutions and suspensions include propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, and surfactants such as polysorbate 80 (trade name). Such compositions may further contain adjuvants such as preservatives, wetting agents, emulsifiers, dispersants, stabilizers (eg lactose), solubilizers (eg glutamic acid, aspartic acid). These are sterilized by, for example, filtration through a bacteria retaining filter, blending of a bactericide, or irradiation. They can also be used by preparing a sterile solid composition and dissolving it in sterile water or a sterile solvent for injection before use.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical indication location A61K 31/40 A61K 31/40 31/445 AAE 31/445 AAE AAF AAF AAM AAM ACN ACN AED AED AED 31 / 47 ABC 31/47 ABC 31/535 ACR 31/535 ACR 38/00 AAB C07D 217/06 AAK 295/18 Z ABU 311/58 ABV 335/06 C07D 217/06 C07K 5/062 295/18 A61K 37 / 02 AAB 311/58 AAK 335/06 ABU C07K 5/062 ABV (72) Inventor Junji Togami 2-18-43 Daijuku, Toride City, Toride City, Ibaraki Prefecture No. 2-103, Toride No. 2-72 (72) Inventor Shinichi Tsukamoto, Tsukuba, Ibaraki Prefecture 4-14 Onogawa, Ichi

Claims (2)

[Claims] 1. A novel amino acid derivative represented by the general formula (I) or a salt thereof. Embedded image (The symbols in the formulas have the following meanings: A: Aryl ring, 5- or 6-membered nitrogen-containing heterocyclic ring which may be condensed with benzene ring, or lower alkylene group B: Formula -SO _2- , -C ( = O)-, -OC (= O)-
Or _{-CHR 7 C (= O) -} R 7: a hydrogen atom, a lower alkyl group, or an aryl group X: a lower alkyl group which may have as a substituent a methylene group or a nitrogen atom, a sulfur atom, or oxygen atom R ₁ : hydrogen atom, amino group, or mono- or di-lower alkylamino group R ₂ and R ₃ : same or different hydrogen atom, or lower alkyl group R ₄ : hydrogen atom, cyano group, nitro group, carbamoyl group, thio Carbamoyl group, amino group or mono- or di-lower alkylamino group, or A group represented by Y: NH, a sulfur atom, or an oxygen atom R ₈ and R ₉ : the same or different, a hydrogen atom, a lower alkyl group, a cycloalkyl group, or R ₈ and R ₉ together form an oxygen atom. Nitrogen-containing heterocycle which may have p: 0 or 1 R ₅ and R ₆ : hydrogen atom, lower alkyl group which may be the same or different, aralkyl group or aryl group which may have a substituent, or R ₅ And R ₆ together may have an oxygen atom and may be condensed with a benzene ring. Nitrogen-containing heterocycle n: 0 or an integer of 1 to 4 m: 0 or 1) 2. R ₄ is (The symbols in the formulas have the following meanings: Y: NH, sulfur atom, or oxygen atom R ₈ and R ₉ : the same or different, a hydrogen atom, a lower alkyl group, a cycloalkyl group, or R ₈ and R ₉ ; Is a nitrogen-containing heterocycle optionally having an oxygen atom, p: 0 or 1), the novel amino acid derivative or a salt thereof according to claim 1.