JP2001187790A - 2-alkoxybenzene derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a compound having excellent antagonistic action on NK1 receptor, NK2 receptor and NK3 receptor, high peroral absorbability and good internal kinetics. SOLUTION: The objective 2-alkoxybenzene derivative is a compound expressed by general formula (1) or its pharmacologically permissible salt, ester or other derivative [R1 is an alkyl; R2 is a (substituted)nitrogen-containing 5-membered heteroaryl group or a (substituted)nitrogen-containing 5-membered heterocyclic group; R3 is a (substituted)aryl or a (substituted)heteroaryl; A is CO or SO2; E is CH2, O or S; G is a (substituted)cycloalkane ring, a (substituted) cycloalkene ring or a (substituted)saturated heterocyclic group; Ar is a (substituted)aryl ring or a (substituted)heteroaryl ring; (m) is 1 or 2; and (n) is 2-4].

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

BACKGROUND OF THE INVENTION The present invention is, NK ₁ receptor, N
The present invention relates to an alkoxybenzene derivative having excellent antagonism to K ₂ receptor and NK ₃ receptor.

[0002]

BACKGROUND ART Compounds having tachykinin antagonistic activity include, for example, EP7766893 and WO98 / 270.
86, but the following compounds are disclosed, for these compounds remain in effect for the NK ₁ receptor and NK ₂ receptors have been disclosed, NK ₁ receptor,
There is a demand for the development of a compound that has a better antagonism to the NK ₂ receptor and NK ₃ receptor, has better oral absorbability, and has better pharmacokinetics.

[0003]

Embedded image

[0004]

The present inventors have found 0005] As a result of extensive studies on compounds having tachykinin antagonism, alkoxy benzene derivatives of the present application is NK ₁ receptor, the NK ₂ receptors and NK ₃ receptors The present invention has been found to exhibit strong antagonism against all, to have excellent oral absorbability, and to have excellent pharmacokinetics (in particular, stability against drug metabolism), thereby completing the present invention.

[0005]

SUMMARY OF THE INVENTION The present invention relates to (1) a compound having the following general formula (I) or a pharmaceutically acceptable salt, ester or other derivative thereof:

[0006]

Embedded image In the formula, R ¹ represents a lower alkyl group; R ² is a 5-membered heteroaryl group containing at least one nitrogen atom, which is substituted with 1 to 3 groups selected from a substituent group α; A 5-membered heteroaryl group containing at least one nitrogen atom, a 5-membered heterocyclyl group containing at least one nitrogen atom, or at least one nitrogen atom substituted with 1 to 3 groups selected from a substituent group α. Represents a 5-membered heterocyclyl group containing one, and R ³ is selected from an aryl group, an aryl group substituted by 1 to 3 groups selected from a substituent group α, a heteroaryl group, or a substituent group α. A heteroaryl group substituted by 1 to 3 groups with
Represents a carbonyl group or a sulfonyl group, E represents a methylene group, an oxygen atom or a sulfur atom, and cyclic group G represents a cycloalkane ring having 5 to 8 carbon atoms, a group selected from substituent group α. A cycloalkane ring having 5 to 8 carbon atoms substituted with 1 or 2 carbon atoms, a cycloalkene ring having 5 to 8 carbon atoms, and 5 carbon atoms substituted with 1 or 2 carbon atoms selected from a substituent group α. A cycloalkene ring, a 5- to 8-membered saturated heterocyclic ring, or a 5- to 8-membered saturated heterocyclic ring substituted by 1 or 2 groups selected from a substituent group α, and a cyclic group Ar Is an aryl ring, a heteroaryl ring, an aryl ring substituted by 1 to 3 groups selected from a substituent group α, or a heteroaryl ring substituted by 1 to 3 groups selected from a substituent group α. Show.

M represents 1 or 2, and n represents an integer of 2 to 4. ｝. [Substituent group α] halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano Base.

In the above, preferred compounds include
(2) a compound wherein R ¹ is methyl, ethyl or n-propyl; (3) R ² is imidazolyl, triazolyl,
A compound which is tetrazolyl, pyrrolidinyl or imidazolyl, triazolyl, tetrazolyl or pyrrolidinyl substituted by 1 to 3 groups selected from the substituent group α, (4) wherein R ² is 1-imidazolyl, 2-triazolyl, 1- 1-imidazolyl, 2-triazolyl, 1-trizolyl, 2-tetrazolyl, 1-pyrrolidinyl, or 1- to 3-substituted with a group selected from substituent group α
A compound which is tetrazolyl, 2-tetrazolyl or 1-pyrrolidinyl; (5) a compound wherein R ² is 1-tetrazolyl; and (6) a compound wherein R ³ is substituted by 1 to 3 groups selected from the substituent group α. Wherein R ³ is an aryl group, a heteroaryl group, or a heteroaryl group substituted by 1 to 3 groups selected from a substituent group α, (7) R ³ is
A compound which is an aryl group substituted by 1 to 3 groups selected from the substituent group α, (8) a compound wherein R ³ is an aryl group substituted by 1 to 3 halogen atoms,
(9) a compound wherein A is carbonyl; (10) a compound wherein E is an oxygen atom and m is 2; (11) a compound wherein E is a methylene group and m is 1; A compound of 2 or 3, (13) a cycloalkane ring having 5 to 6 carbon atoms, and 5 to 6 carbon atoms substituted by 1 or 2 groups selected from a substituent group α. A compound which is a cycloalkane ring, a 5- or 6-membered saturated heterocyclic ring, or a 5- or 6-membered saturated heterocyclic ring substituted by one or two groups selected from a substituent group α, (14) a cyclic group G is a substituent group α
A cycloalkane ring having 5 or 6 carbon atoms substituted with 1 or 2 carbon atoms, a 5- or 6-membered saturated heterocyclic ring, or 1 or 2 carbon atoms substituted with a group selected from substituent group α. (15) a compound having 5 to 6 carbon atoms in which cyclic group G is substituted with one or two hydroxyl groups.
(16) the cyclic group Ar is an aryl ring, a heteroaryl ring, or a group selected from a substituent group α of 1 to 3 A compound which is a substituted aryl ring, (17) a compound wherein the cyclic group Ar is an aryl ring or an aryl ring substituted by 1 to 3 groups with a group selected from the substituent group α.
(18) a compound in which the cyclic group Ar is a benzene ring or a benzene ring substituted by 1 to 3 groups selected from a group selected from the substituent group α, (19) a compound represented by the following partial structure in the general formula (I): I
I):

[0009]

Embedded image But,

[0010]

Embedded image Or (20) the following partial structure (II) in the general formula (I):

[0011]

Embedded image But,

[0012]

Embedded image Or a pharmacologically acceptable salt, ester or other derivative thereof.

More preferred compounds include (21) compounds selected from the following or pharmaceutically acceptable salts, esters or other derivatives thereof: 1- {2-[(3R)- (3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) pyrrolidin-3-yl] ethyl {spiro [((2S) -hydroxy) indan-1,4'-
Piperidine], 1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) pyrrolidin-3-yl] ethyl}-
3-oxo-3,4-dihydrospiro [isoquinoline-
1 (2H), 4'-piperidine], 1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) pyrrolidin-3-yl] ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,4′-piperidine], 1- {2-[( 3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) pyrrolidin-3-yl] ethyl} spiro [benzo [c] thiophene-1 (3H), 4'-piperidine]-(2S) -oxide; 1- {2-[(2R)-(3 , 4-Dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [((2S) -hydroxy) indane-1,4'-
1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) morpholin-2-yl] ethyl}-
3-oxo-3,4-dihydrospiro [isoquinoline-
1 (2H), 4'-piperidine], 1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,4′-piperidine]; and 1- {2- [ (2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [benzo [c] thiophen-1 (3H), 4'-piperidine]-(2S) -oxide.

Further, the novel medicine of the present invention can be obtained from the above (1)
Or a pharmacologically acceptable salt, ester or other derivative thereof as an active ingredient, and a novel use of the present invention is to produce a medicament. Or a pharmacologically acceptable salt, ester or other derivative thereof according to any one of the above (1) to (21), and The method of treatment comprises administering to a patient an effective amount of the compound according to any one of the above (1) to (21) or a pharmaceutically acceptable salt, ester or other derivative thereof. Prophylactic and / or therapeutic methods.

In the general formula (I), the term “lower alkyl group” in the definition of R ¹ and [substituent group α] represents a straight-chain or branched-chain alkyl having 1 to 6 carbon atoms.
Such groups include methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, s-butyl, te
rt-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methylpentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl,
3,3-dimethylbutyl, 2,2-dimethylbutyl,
1,1-dimethylbutyl, 1,2-dimethylbutyl,
Examples include 1,3-dimethylbutyl, 2,3-dimethylbutyl and 2-ethylbutyl. It is preferably an alkyl group having 1 to 4 carbon atoms, more preferably methyl, ethyl or propyl, particularly preferably methyl or ethyl, and most preferably methyl.

In the definition of R ² , “a 5-membered heteroaryl group containing at least one nitrogen atom” and “1 to 3 nitrogen atoms substituted with 1 to 3 groups selected from a substituent group α” 5-membered heteroaryl group containing
Of the "5-membered heteroaryl group containing at least one nitrogen atom" is pyrrolyl, pyrazolyl, imidazolyl,
A 5-membered aromatic heterocyclic group containing 1 to 4 nitrogen atoms such as oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl and tetrazolyl, preferably a heteroatom such as pyrrolyl, pyrazolyl, imidazolyl, triazolyl, tetrazolyl Is a 5-membered aromatic heterocyclic group containing only a nitrogen atom. More preferably, it is imidazolyl, triazolyl, tetrazolyl, and even more preferably, 1-imidazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl,
Most preferably, it is 1-tetrazolyl.

In the definition of R ² , “a 5-membered heterocyclyl group containing at least one nitrogen atom” and “at least one nitrogen atom substituted by 1 to 3 groups selected from a substituent group α” Containing 5-membered heterocyclyl group "
The "5-membered heterocyclyl group containing at least one nitrogen atom" is a 5-membered non-aromatic heterocyclic group containing 1 to 3 nitrogen atoms, such as pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, and pyrazolinyl. Show. Preferably, 1-pyrrolidinyl, 1-pyrrolinyl, 1-imidazolidinyl, 1-imidazolinyl,
1-pyrazolidinyl, 1-pyrazolinyl, more preferably 1-pyrrolidinyl, 1-pyrolinyl, 1-imidazolinyl, 1-pyrazolinyl, most preferably
1-pyrrolidinyl.

In the definition of R ³ , the “aryl group” and the “aryl group” in the “aryl group substituted by 1 to 3 groups selected from the substituent group α” include, for example, phenyl, naphthyl, It represents an aromatic hydrocarbon group having 6 to 14 carbon atoms such as phenanthryl and anthracenyl, and is preferably phenyl or naphthyl, and most preferably phenyl.

The "aryl group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples of such a group include 5-indanyl.

In the definition of R ³ , “heteroaryl group” and “heteroaryl group” of “heteroaryl group substituted by 1 to 3 groups selected from substituent group α”
Is defined as a sulfur atom, an oxygen atom and / or a nitrogen atom such as furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, tetrazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl. And represents a 5- to 7-membered aromatic heterocyclic group containing from 4 to 4, and preferably furyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl or pyrazinyl.

The above "heteroaryl group" may be condensed with another cyclic group, and examples of such a group include indolyl, benzofuranyl, benzothienyl,
Isoquinolyl, quinolyl and the like can be mentioned.

In the definition of cyclic group G, "cycloalkane ring having 5 to 8 carbon atoms" and "cycloalkane ring having 5 to 8 carbon atoms substituted by 1 or 2 groups selected from substituent group α" are used. Examples of the “cycloalkane ring having 5 to 8 carbon atoms” of the “cycloalkane ring” include a cyclopentane ring, a cyclohexane ring, a cycloheptane ring, and a cyclooctane ring. Preferably, it is a "cycloalkane ring having 5 to 6 carbon atoms", more preferably a cyclopentane ring.

In the above-mentioned “cycloalkane ring of 5 to 8 carbon atoms substituted by 1 or 2 groups selected from substituent group α”, preferably “cycloalkane ring substituted by 1 or 2 hydroxyl groups” A cycloalkane ring having 5 to 8 carbon atoms ".

In the definition of cyclic group G, "cycloalkene ring having 5 to 8 carbon atoms" and "cycloalkene ring having 5 to 8 carbon atoms substituted by 1 or 2 groups selected from substituent group α" Examples of the “cycloalkene ring having 5 to 8 carbon atoms” of the “cycloalkene ring” include a cyclopentene ring, a cyclohexene ring, a cycloheptene ring, and a cyclooctene ring. Preferably, it is a "cycloalkene ring having 5 to 6 carbon atoms", more preferably a cyclopentene ring.

In the definition of the cyclic group G, "5- to 8-membered saturated heterocyclic ring" and "1
Alternatively, the “5- to 8-membered saturated heterocyclic ring” of the “2- or 5-substituted 5- to 8-membered saturated heterocyclic ring” refers to a sulfur atom, an oxygen atom or /
And a 5- to 8-membered saturated heterocyclic ring containing 1 to 3 nitrogen atoms (when the ring contains a sulfur atom, the sulfur atom may be a sulfoxide or a sulfone). 5 to 6-membered saturated heterocyclic ring containing 1 to 3 atoms, oxygen atoms and / or nitrogen atoms, and most preferably 1 to 2 sulfur atoms, oxygen atoms and / or nitrogen atoms.
Is a 5-membered saturated heterocyclic ring. As such a ring,
For example, a ring such as an imidazolidine ring, an oxazolidine ring, a pyrrolidine ring, a tetrahydrofuran ring, a tetrahydrothiophene ring, a tetrahydrothiophene-S-oxide ring, a tetrahydrothiophene-S, S-dioxide ring and a piperidine ring can be exemplified.

The carbon atom of the "5- to 8-membered saturated heterocyclic ring" may have an oxo group and / or a thioxo group. Examples of such a group include, for example, 2-oxo Examples thereof include a piperidine ring and a 2-oxo-2,4,5,6-tetrahydrooxazine ring.

In the definition of the cyclic group Ar, the “aryl ring” and the “aryl ring” of the “aryl ring substituted by 1 to 3 groups selected from the substituent group α” include a benzene ring and a naphthalene An aromatic hydrocarbon ring having 6 to 14 carbon atoms, such as a ring, a phenanthrene ring or an anthracenyl ring, and preferably a benzene ring.

In the definition of the cyclic group Ar, “heteroaryl ring” and “heteroaryl ring” of “heteroaryl ring substituted by 1 to 3 groups selected from substituent group α” are sulfur One atom, oxygen atom and / or nitrogen atom
Represents a 5- to 7-membered aromatic heterocyclic ring containing from 3 to 3, for example,
Furan ring, thiophene ring, pyrrole ring, azepine ring, pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, 1,
Rings such as a 2,3-oxadiazole ring, a triazole ring, a tetrazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring and a pyrazine ring can be mentioned, and it preferably contains at least one nitrogen atom. Represents a 5- to 7-membered aromatic heterocyclic group which may contain an oxygen atom or a sulfur atom, for example, a pyrrole ring, an azepine ring,
Pyrazole ring, imidazole ring, oxazole ring, isoxazole ring, thiazole ring, isothiazole ring, 1,
Examples of such groups include a 2,3-oxadiazole ring, a triazole ring, a tetrazole ring, a thiadiazole ring, a pyridine ring, a pyridazine ring, a pyrimidine ring, and a pyrazine ring. More preferably, a pyridine ring, an imidazole ring,
An oxazole ring, a pyrazine ring and a thiazole ring.

The following general formula (II):

[0030]

Embedded image (In the formula, the cyclic group G and the cyclic group Ar have the same meanings as described above.)

[0031]

Embedded image And more preferably,

[0032]

Embedded image Can be mentioned.

The "halogen atom" in the definition of the [substituent group α] represents a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. Preferably, they are a fluorine atom and a chlorine atom.

The “halogeno lower alkyl group” in the definition of [Substituent group α] is a group in which one or more hydrogen atoms of the above “lower alkyl group” are substituted by the above “halogen atom”. . It is preferably a halogenoalkyl group having 1 to 4 carbon atoms, more preferably trifluoromethyl, trichloromethyl, difluoromethyl, dichloromethyl, dibromomethyl, fluoromethyl, 2,2,2
-Trichloroethyl, 2,2,2-trifluoroethyl, 2-bromoethyl, 2-chloroethyl, 2-fluoroethyl, 2,2-dibromoethyl, more preferably trifluoromethyl, trichloromethyl, difluoro Methyl, fluoromethyl, most preferably
Trifluoromethyl.

The term "lower alkoxy group" in the definition of [substituent group α] refers to a group in which an oxygen atom is bonded to the above "lower alkyl group", and is preferably a straight-chain or straight-chain having 1 to 4 carbon atoms. It is a branched alkoxy group, more preferably methoxy, ethoxy, propoxy, isopropoxy, butoxy, even more preferably methoxy, ethoxy, propoxy, and most preferably a methoxy group.

The "lower alkoxycarbonyl group" in the definition of [substituent group α] is the above-mentioned "lower alkoxy group"
Represents a group having a carbonyl bonded thereto, such as methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, butoxycarbonyl, s-
Butoxycarbonyl, t-butoxycarbonyl, isobutoxycarbonyl and the like can be mentioned. Preferably, it is an alkoxycarbonyl group having 2 to 5 carbon atoms, and more preferably, methoxycarbonyl, ethoxycarbonyl or propoxycarbonyl.

The “lower aliphatic acyl group” and the “lower aliphatic acyl group” of the “lower aliphatic acylamino group” in the definition of [substituent group α] are an aliphatic acyl group having 1 to 7 carbon atoms. And such groups include, for example, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and isovaleryl. Preferably, it is acetyl or propionyl.

The "pharmacologically acceptable salt thereof" means that the compound (I) of the present invention is reacted with an acid when it has a basic partial structure such as an amino group and / or an imino group. When the compound has an acidic partial structure such as a carboxy group, it can be converted into a salt by reacting with a base.

The salt based on the basic partial structure is preferably a hydrohalide such as hydrofluoride, hydrochloride, hydrobromide, hydroiodide, nitrate, peroxide, etc. Inorganic salts such as chlorates, sulfates and phosphates; lower alkanesulfonates such as methanesulfonate, trifluoromethanesulfonate and ethanesulfonate; benzenesulfonate; p-toluenesulfonate Such as aryl sulfonate, acetate, malate, fumarate, succinate, citrate, ascorbate, tartrate,
Organic acid salts such as oxalate and maleate; and amino acid salts such as glycine, lysine, arginine, ornithine, glutamate and aspartate.

On the other hand, the salt based on the acidic partial structure is preferably an alkali metal salt such as a sodium salt, a potassium salt or a lithium salt, an alkaline earth metal salt such as a calcium salt or a magnesium salt, or an aluminum salt. , Iron salts and other metal salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine alkyl ester salts,
Ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzylphenethylamine salt,
Amine salts such as organic salts such as piperazine salt, tetramethylammonium salt and tris (hydroxymethyl) aminomethane salt; and amino acids such as glycine salt, lysine salt, arginine salt, ornithine salt, glutamate and aspartate. Salts may be mentioned.

The compound having the general formula (I) of the present invention is
By leaving in the air or recrystallizing,
In some cases, water may be absorbed, adsorbed water may be formed, or a hydrate may be formed. Such a hydrate is also included in the present invention.

The “ester or other derivative” refers to a functional group (eg, a hydroxyl group,
A compound obtained by modifying a carboxy group, an amino group, an imino group, etc.) with a protecting group according to a conventional method, which is converted into the compound (I) of the present invention by administering to a living body Is shown. Whether or not such a derivative is used is determined by administering the compound intravenously or orally to experimental animals such as rats or mice, and then examining the body fluid of the animal to determine whether the compound (I) of the present invention or a pharmaceutically acceptable compound thereof is acceptable. It can be determined by detecting the salt.

That is, the “ester or other derivative” means that the functional group (eg, hydroxyl group, carboxy group, amino group, imino group, etc.) of the compound of the present invention is a “general protecting group” or “in vivo. A compound modified by a "protecting group that can be cleaved by a biological method such as hydrolysis."

"General protecting group" refers to a protecting group that can be cleaved by a chemical method such as hydrogenolysis, hydrolysis, electrolysis, or photolysis.

As the “general protecting group” for the “ester or other derivative of a hydroxyl group”, preferably, formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, Decanoyl, 3-methylnonanoyl, 8-methylnonanoyl, 3-ethyloctanoyl, 3,7-dimethyloctanoyl, undecanoyl, dodecanoyl, tridecanoyl, tetradecanoyl, pentadecanoyl, hexadecanoyl, 1-methylpentadecanoyl, 14 -Methylpentadecanoyl,
Alkanoyl groups such as 13,13-dimethyltetradecanoyl, heptadecanoyl, 15-methylhexadecanoyl, octadecanoyl, 1-methylheptadecanoyl, nonadecanoyl, eicosanoyl, henicosanoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trichloroacetyl Halogenated alkylcarbonyl groups such as fluoroacetyl, lower alkoxyalkylcarbonyl groups such as methoxyacetyl, unsaturated alkylcarbonyl such as acryloyl, propioloyl, methacryloyl, crotonoyl, isocrotonoyl, (E) -2-methyl-2-butenoyl An aliphatic acyl group such as a group (preferably a lower aliphatic acyl group having 1 to 6 carbon atoms); aryl such as benzoyl, α-naphthoyl and β-naphthoyl Arylcarbonyl groups such as bonyl group, 2-bromobenzoyl and 4-chlorobenzoyl; 2,4,6-trimethylbenzoyl;
A lower alkylated arylcarbonyl group such as toluoyl and a lower alkoxylated aryl such as 4-anisoyl;
Nitrated arylcarbonyl groups such as 4-carbonylbenzoyl, 2-nitrobenzoyl and 2-nitrobenzoyl;
"Aromatic acyl group" such as lower alkoxycarbonylated arylcarbonyl group such as (methoxycarbonyl) benzoyl and arylated arylcarbonyl group such as 4-phenylbenzoyl; the above "lower alkoxycarbonyl group" , 2,2,2-trichloroethoxycarbonyl,
An "alkoxycarbonyl group" such as a "lower alkoxycarbonyl group" substituted with a halogen such as 2-trimethylsilylethoxycarbonyl or a tri-lower alkylsilyl group; tetrahydropyran-2-yl, 3-bromotetrahydropyran-2-yl, "Tetrahydropyranyl or tetrahydrothiopyranyl group" such as 4-methoxytetrahydropyran-4-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydrothiopyran-4-yl; tetrahydrofuran-2-yl, tetrahydro "Tetrahydrofuranyl or tetrahydrothiofuranyl group" such as thiofuran-2-yl; trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t Tri-lower alkylsilyl groups such as butylsilyl and triisopropylsilyl, and tri-lower alkylsilyl groups substituted with one or two aryl groups such as diphenylmethylsilyl, diphenylbutylsilyl, diphenylisopropylsilyl and phenyldiisopropylsilyl “Silyl group” such as methoxymethyl,
Lower alkoxymethyl groups such as 1,1-dimethyl-1-methoxymethyl, ethoxymethyl, propoxymethyl, isopropoxymethyl, butoxymethyl and t-butoxymethyl, lower alkoxylated lower alkoxymethyl groups such as 2-methoxyethoxymethyl Groups, "alkoxymethyl groups" such as halogeno lower alkoxymethyl such as 2,2,2-trichloroethoxymethyl, bis (2-chloroethoxy) methyl; 1-ethoxyethyl, 1- (isopropoxy) ethyl and the like Lower alkoxylated ethyl group,
“Substituted ethyl group” such as halogenated ethyl group such as 2,2,2-trichloroethyl; benzyl, α-naphthylmethyl, β-naphthylmethyl, diphenylmethyl, triphenylmethyl, α-naphthyldiphenylmethyl, 9- Lower alkyl group substituted with 1 to 3 aryl groups such as anthrylmethyl, 4-methylbenzyl, 2,4,
6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-methoxyphenyldiphenylmethyl, 2-nitrobenzyl, 4-nitrobenzyl, 4-chlorobenzyl, 4-bromobenzyl, 4-
"Aralkyl groups" such as lower alkyl such as cyanobenzyl, lower alkoxy, nitro, halogen, lower alkyl groups substituted with one to three aryl groups having an aryl ring substituted with a cyano group; vinyl “Alkenyloxycarbonyl group” such as oxycarbonyl, allyloxycarbonyl; benzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, 4-nitrobenzyloxycarbonyl like,
An "aralkyloxycarbonyl group" in which the aryl ring may be substituted with one or two lower alkoxy or nitro groups may be mentioned.

The “general protecting group” for the “ester or other derivative of a carboxy group” is preferably the aforementioned “lower alkyl group”; ethenyl, 1-propenyl, 2-propenyl, 1-methyl- 2-propenyl, 1
-Methyl-1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 2-ethyl-2-propenyl, 1-butenyl, 2-butenyl, 1-methyl-
2-butenyl, 1-methyl-1-butenyl, 3-methyl-2-butenyl, 1-ethyl-2-butenyl, 3-butenyl, 1-methyl-3-butenyl, 2-methyl-3-butenyl, 1- Ethyl-3-butenyl, 1-pentenyl,
2-pentenyl, 1-methyl-2-pentenyl, 2-methyl-2-pentenyl, 3-pentenyl, 1-methyl-
3-pentenyl, 2-methyl-3-pentenyl, 4-pentenyl, 1-methyl-4-pentenyl, 2-methyl-
4-pentenyl 1-hexenyl, 2-hexenyl, 3-
Lower alkenyl groups such as hexenyl, 4-hexenyl, 5-hexenyl; ethynyl, 2-propynyl, 1-methyl-2-propynyl, 2-butynyl, 1-methyl-2
-Butynyl, 1-ethyl-2-butynyl, 3-butynyl, 1-methyl-3-butynyl, 2-methyl-3-butynyl, 1-ethyl-3-butynyl, 2-pentynyl, 1
-Methyl-2-pentynyl, 3-pentynyl, 1-methyl-3-pentynyl, 2-methyl-3-pentynyl, 4
Lower alkynyl groups such as -pentynyl, 1-methyl-4-pentynyl, 2-methyl-4-pentynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl; the above-mentioned "halogeno lower alkyl"; Hydroxy "lower alkyl group" such as hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl; "lower aliphatic acyl" such as acetylmethyl-
"Lower alkyl group";"aralkylgroup";"silylgroup".

The term "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" means that it is cleaved in a human body by a biological method such as hydrolysis to produce a free acid or a salt thereof. It refers to a protecting group, and whether such a derivative is administered by intravenous injection to experimental animals such as rats and mice,
Subsequent examination of the body fluids of the animals allows the determination of the ability to detect the original compound or a pharmacologically acceptable salt thereof, such as "esterification of hydroxyl groups or other derivatives" such as "hydrolysis in vivo". As the `` protecting group which can be cleaved by a biological method '', preferably, formyloxymethyl, acetoxymethyl, dimethylaminoacetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, Isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl , 1-formyl propyl, 1-acetoxy propyl, 1-propionyloxy-propyl, 1-butyryloxy-propyl, 1-pivaloyloxymethyl-propyl, 1-valeryl propyl, 1-
Isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl,
1-("lower aliphatic acyl" oxy), such as 1-pivaloyloxypentyl, 1-pivaloyloxyhexyl
"Lower alkyl group", cyclopentylcarbonyloxymethyl, cyclohexylcarbonyloxymethyl, 1-
1-("cycloalkyl" carbonyl, such as cyclopentylcarbonyloxyethyl, 1-cyclohexylcarbonyloxyethyl, 1-cyclopentylcarbonyloxypropyl, 1-cyclohexylcarbonyloxypropyl, 1-cyclopentylcarbonyloxybutyl, 1-cyclohexylcarbonyloxybutyl Oxy)
1- (acyloxy) "lower alkyl group" such as 1-("aromatic acyl" oxy) "lower alkyl group" such as "lower alkyl group" and benzoyloxymethyl; methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, Propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxy (cyclohexyl) methyl, -(Methoxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy)
Ethyl, 1- (propoxycarbonyloxy) ethyl,
1- (isopropoxycarbonyloxy) ethyl, 1-
(Butoxycarbonyloxy) ethyl, 1- (isobutoxycarbonyloxy) ethyl, 1- (t-butoxycarbonyloxy) ethyl, 1- (pentyloxycarbonyloxy) ethyl, 1- (hexyloxycarbonyloxy) ethyl, 1- (Cyclopentyloxycarbonyloxy) ethyl, 1- (cyclopentyloxycarbonyloxy) propyl, 1- (cyclohexyloxycarbonyloxy) propyl, 1- (cyclopentyloxycarbonyloxy) butyl, 1- (cyclohexyloxycarbonyloxy) butyl, (Cyclohexyloxycarbonyloxy) ethyl, 1- (ethoxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) propyl, 1- (ethoxycarbonyloxy) propyl, 1- (p Po butoxycarbonyl) propyl, 1- (isopropoxycarbonyloxy) propyl, 1- (butoxycarbonyl) propyl, 1-
(Isobutoxycarbonyloxy) propyl, 1- (pentyloxycarbonyloxy) propyl, 1- (hexyloxycarbonyloxy) propyl, 1- (methoxycarbonyloxy) butyl, 1- (ethoxycarbonyloxy) butyl, 1- (propoxy Carbonyloxy) butyl, 1- (isopropoxycarbonyloxy)
Butyl, 1- (butoxycarbonyloxy) butyl, 1
-(Isobutoxycarbonyloxy) butyl, 1- (methoxycarbonyloxy) pentyl, 1- (ethoxycarbonyloxy) pentyl, 1- (methoxycarbonyloxy) hexyl, 1- (ethoxycarbonyloxy)
Hexyl-like (lower alkoxycarbonyloxy)
Alkyl group; (5-phenyl-2-oxo-1,3-dioxolen-4-yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5
-(4-fluorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, ( 2-oxo-1,3-dioxolen-4
-Yl) methyl, (5-methyl-2-oxo-1,3-
Dioxolen-4-yl) methyl, (5-ethyl-2-
Oxo-1,3-dioxolen-4-yl) methyl,
(5-propyl-2-oxo-1,3-dioxolene-
4-yl) methyl, (5-isopropyl-2-oxo-)
Carbonyloxyalkyl groups such as oxodioxorenylmethyl groups such as 1,3-dioxolen-4-yl) methyl and (5-butyl-2-oxo-1,3-dioxolen-4-yl) methyl; ": Phthalidyl group such as phthalidyl, dimethylphthalidyl, dimethoxyphthalidyl": the above "lower aliphatic acyl group": the above "aromatic acyl group": "half ester salt residue of succinic acid": "phosphate ester""Saltresidue":"ester-forming residue such as amino acid": carbamoyl group: carbamoyl group substituted with one or two lower alkyl groups: and "1- (acyloxy) such as pivaloyloxymethyloxycarbonyl. )
An "alkyloxycarbonyl group" can be mentioned, and is preferably a "carbonyloxyalkyl group".

On the other hand, the "protecting group which can be cleaved in vivo by a biological method such as hydrolysis" as the "protecting group which can be cleaved by a biological method such as hydrolysis" is preferably methoxyethyl, 1- Ethoxyethyl, 1-methyl-1-methoxyethyl, 1- (isopropoxy) ethyl, 2-methoxyethyl, 2-ethoxyethyl, 1,1
-Dimethyl-1-methoxyethyl, ethoxymethyl, n
-Lower alkoxy lower alkyl groups such as propoxymethyl, isopropoxymethyl, n-butoxymethyl, t-butoxymethyl, lower alkoxylated lower alkoxy lower alkyl groups such as 2-methoxyethoxymethyl, and "aryl" such as phenoxymethyl "Oxy" lower alkyl groups "," alkoxy lower alkyl groups "such as halogenated lower alkoxy lower alkyl groups such as 2,2,2-trichloroethoxymethyl and bis (2-chloroethoxy) methyl; like methoxycarbonylmethyl "" Lower alkoxy "carbonyl" lower alkyl group ";" cyano "lower alkyl group" such as cyanomethyl and 2-cyanoethyl; "" lower alkyl "thiomethyl group" such as methylthiomethyl and ethylthiomethyl; phenylthio Methyl, naphthylch “Aryl” thiomethyl group such as methyl; “lower alkyl optionally substituted by halogen” “lower alkyl group” such as 2-methanesulfonylethyl and 2-trifluoromethanesulfonylethyl; 2- Benzenesulfonylethyl, 2-
“Aryl” sulfonyl “lower alkyl group” such as toluenesulfonylethyl; “1- (acyloxy)“ lower alkyl group ””; “phthalidyl group”; “aryl group”; “lower alkyl group” "Carboxyalkyl groups" such as carboxymethyl; and "amide-forming residues of amino acids" such as phenylalanine. When the compound (I) of the present invention has an amino group and / or an imino group, examples of the “ester or other derivative” include compounds in which the amino group or the imino group is protected by a “general protecting group”. Can be.

"General protecting group" for amino group or imino group
Is a "protecting group in a reaction" that can be cleaved by chemical methods such as hydrogenolysis, hydrolysis, electrolysis, and photolysis.
For example, the "lower aliphatic acyl group"; the "aromatic acyl group"; the "lower alkoxycarbonyl group"; the "alkenyloxycarbonyl group"; the "aralkyloxycarbonyl group"; or the "silyl". Group ", preferably a lower alkoxycarbonyl group, and more preferably tert-butoxycarbonyl.

The compound having the general formula (I) of the present invention is
Since there is an asymmetric carbon atom in the molecule, various isomers (eg, enantiomers, diastereomers) may exist, and the present invention relates to these isomers and mixtures of these isomers in any proportion. Are all included.

Specific examples of the compound having the general formula (I) of the present invention include the compounds shown in Table 1 below.

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Table 1 Table 1 −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− Compound No. ZR ¹ R ² R ³ AE mn −−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−−− 1 Place 1 Me 1-Tez 3,4-di- Cl-Ph CO CH ₂ 1 2 2 Place 2 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 3 Place 3 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 4 App 4 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 5 App 5 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 6 App 6 Me 1-Tez 3 , 4-di-Cl-Ph CO CH ₂ 1 2 7 place 7 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 8 place 8 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 9 place 9 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 10 place 10 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 11 place 11 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 12 place 12 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 13 place 13 Me 1-Tez 3,4- di-Cl-Ph CO CH ₂ 1 2 14 Place 14 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 15 Place 15 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 16 Place 16 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 17 Place 1 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 18 Place 2 Me 1- Tez 3,4 -di-F-Ph CO CH ₂ 1 2 19 Place 3 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 20 Place 4 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 12 Place 5 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 22 Place 6 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 23 Place 7 Me 1 -Tez 3,4-di-F-Ph CO CH ₂ 1 2 24 Place 8 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 25 Place 9 Me 1-Tez 3,4-di- F-Ph CO CH ₂ 1 2 26 Place 10 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 27 Place 11 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 28 Place 12 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 29 Place 13 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 30 Place 14 Me 1-Tez 3 , 4-di-F-Ph CO CH ₂ 1 2 31 Place 15 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 32 Place 16 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 2 33 Place 1 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 34 Place 2 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 35 Place 3 Me 1-Tez 4-Cl- Ph CO CH ₂ 1 2 36 place 4 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 37 place 5 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 38 place 6 Me 1-Tez 4-Cl -Ph CO CH ₂ 1 2 39 Place 7 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 40 Place 8 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 41 Place 9 Me 1-Tez 4- Cl-Ph CO CH ₂ 1 2 42 Place 10 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 43 Place 11 Me 1-Tez 4-Cl-Ph C O CH ₂ 1 2 44 Place 12 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 45 Place 13 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 46 Place 14 Me 1-Tez 4-Cl- Ph CO CH ₂ 1 2 47 place 15 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 48 place 16 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 2 49 place 1 Me 1-Tez 4-F -Ph CO CH ₂ 1 2 50 Place 2 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 51 Place 3 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 52 Place 4 Me 1-Tez 4- F-Ph CO CH ₂ 1 2 53 position 5 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 54 position 6 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 55 position 7 Me 1-Tez 4 -F-Ph CO CH ₂ 1 2 56 position 8 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 57 position 9 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 58 position 10 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 59 Place 11 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 60 Place 12 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 61 Place 13 Me 1- Tez 4-F-Ph CO CH ₂ 1 2 62 set 14 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 63 set 15 Me 1-Tez 4-F-Ph CO CH ₂ 1 2 64 set 16 Me 1 -Tez 4-F-Ph CO CH ₂ 1 2 65 position 4 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 66 position 5 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 67 unit 6 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 68 unit 7 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 1 2 69 unit 4 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 2 70 5 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 2 71 Place 6 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 2 72 Place 7 Me 2-Tez 3,4- di-F-Ph CO CH ₂ 1 2 73 position 4 Me 2-Tez 4-Cl-Ph CO CH ₂ 1 2 74 position 5 Me 2-Tez 4-Cl-Ph CO CH ₂ 1 2 75 position 6 Me 2- Tez 4-Cl-Ph CO CH ₂ 1 2 76 6 7 Me 2-Tez 4-Cl-Ph CO CH ₂ 1 2 77 6 4 Me 2-Tez 4-F-Ph CO CH ₂ 1 2 78 5 Me 2 -Tez 4-F-Ph CO CH ₂ 1 2 79 place 6 Me 2-Tez 4-F-Ph CO CH ₂ 1 2 80 place 7 Me 2-Tez 4-F-Ph CO CH ₂ 1 2 81 place 4 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 2 82 5Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 2 83 6Me 2-Trz 3,4-di -Cl-Ph CO CH ₂ 1 2 84 position 7 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 2 85 position 4 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 2 86 location 5 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 2 87 location 6 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 2 88 location 7 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 2 89 place 4 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 2 90 place 5 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 2 91 place 6 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 2 92 Place 7 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 2 93 Place 4 Me 2-Trz 4-F-Ph CO CH ₂ 1 2 94 location 5 Me 2-Trz 4-F -Ph CO CH 2 1 2 95 location 6 Me 2-Trz 4-F -Ph CO CH 2 1 2 96 7 Me 2-Trz 4-F -Ph CO CH 2 1 2 95 location 4 Me 2-Imd 3,4-di -Cl-Ph CO CH 2 1 2 96 location 5 Me 2-Imd 3,4-di -Cl -Ph CO CH ₂ 1 2 97 place 6 Me 2-Imd 3,4-di-Cl-Ph CO CH ₂ 1 2 100 place 7 Me 2-Imd 3,4-di-Cl-Ph CO CH ₂ 1 2 101 4 Me 2-Imd 3,4-di-F-Ph CO CH ₂ 1 2 102 5 Me 2-Imd 3,4-di-F-Ph CO CH ₂ 1 2 103 6 Me 2-Imd 3, 4-di-F-Ph CO CH ₂ 1 2 104 position 7 Me 2-Imd 3,4-di-F-Ph CO CH ₂ 1 2 105 position 4 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 2 106 Set 5 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 2 107 Set 6 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 2 108 Set 7 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 2 109 Place 4 Me 2-Imd 4-F-Ph CO CH ₂ 1 2 110 Place 5 Me 2-Imd 4-F-Ph CO CH ₂ 1 2 111 Place 6 Me 2-Imd 4-F-Ph CO CH ₂ 1 2 112 Place 7 Me 2-Imd 4-F-Ph CO CH ₂ 1 2 113 Place 4 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 2 114 Place 5 Me 1-Pyd 3,4 -di-Cl-Ph CO CH ₂ 1 2 115 Place 6 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 2 116 Place 7 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 2 117 Place 4 Me 1-Pyd 3,4-di-F-Ph CO CH ₂ 1 2 118 Place 5 Me 1-Pyd 3,4-di-F-Ph CO CH ₂ 1 2 119 Place 6 Me 1 -Pyd 3,4-di-F-Ph CO CH ₂ 1 2 120 Place 7 Me 1-Pyd 3,4-di-F-Ph CO CH ₂ 1 2 121 Place 4 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 2 122 Place 5 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 2 123 Place 6 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 2 124 Place 7 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 2 125 Place 4 Me 1-Pyd 4-F-Ph CO CH ₂ 1 2 126 Place 5 Me 1-Pyd 4-F- Ph CO CH ₂ 1 2 127 Place 6 Me 1-Pyd 4-F-Ph CO CH ₂ 1 2 128 Place 7 Me 1-Pyd 4-F-Ph CO CH ₂ 1 2 129 Place 4 Me 1-Tez 3,4 -di-Cl-Ph CO CH ₂ 1 3 130 Place 5 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 3 131 Place 6 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 3 132 Unit 7 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 1 3 133 Unit 4 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 3 134 Unit 5 Me 1 -Tez 3,4-di-F-Ph CO CH ₂ 1 3 135 Place 6 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 1 3 136 Place 7 Me 1-Tez 3,4-di- F-Ph CO CH ₂ 1 3 137 Set 4 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 3 138 Set 5 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 3 139 Set 6 Me 1-Tez 4 -Cl-Ph CO CH ₂ 1 3 140 Place 7 Me 1-Tez 4-Cl-Ph CO CH ₂ 1 3 141 Place 4 Me 1-Tez 4-F-Ph CO CH ₂ 1 3 142 Place 5 Me 1-Tez 4-F-Ph CO CH ₂ 1 3 143 Place 6 Me 1-Tez 4-F-Ph CO CH ₂ 1 3 144 Place 7 Me 1-Tez 4-F-Ph CO CH ₂ 1 3 145 Place 4 Me 2- Tez 3,4-di-Cl-Ph CO CH ₂ 1 3 146 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 1 3 147 Place 6 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 1 3 148 Place 7 Me 2-Tez 3,4- di-Cl-Ph CO CH ₂ 1 3 149 Place 4 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 3 150 Place 5 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 3 151 Station 6 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 3 152 Station 7 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 1 3 153 Station 4 Me 2- Tez 4-Cl-Ph CO CH ₂ 1 3 154 position 5 Me 2-Tez 4-Cl-Ph CO CH ₂ 1 3 155 position 6 Me 2-Tez 4-Cl-Ph CO CH ₂ 1 3 156 position 7 Me 2 -Tez 4-Cl-Ph CO CH ₂ 1 3 157 position 4 Me 2-Tez 4-F-Ph CO CH ₂ 1 3 158 position 5 Me 2-Tez 4-F-Ph CO CH ₂ 1 3 159 position 6 Me 2-Tez 4-F-Ph CO CH ₂ 1 3 160 Place 7 Me 2-Tez 4-F-Ph CO CH ₂ 1 3 161 Place 4 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 3 162 Place 5 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 3 163 Place 6 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 3 164 Place 7 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 1 3 165 position 4 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 3 166 position 5 Me 2-Trz 3,4-di-F- Ph CO CH ₂ 1 3 167 position 6 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 3 168 position 7 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 1 3 169 position 4 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 3 170 Place 5 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 3 171 Place 6 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 3 172 Place 7 Me 2-Trz 4-Cl-Ph CO CH ₂ 1 3 173 Place 4 Me 2-Trz 4-F-Ph CO CH ₂ 1 3 174 Set 5 Me 2-Trz 4-F-Ph CO CH ₂ 1 3 175 Set 6 Me 2-Trz 4-F-Ph CO CH ₂ 1 3 176 Set 7 Me 2-Trz 4-F-Ph CO CH ₂ 1 3 177 unit 4 Me 2-Imd 3,4-di-Cl-Ph CO CH ₂ 1 3 178 unit 5 Me 2-Imd 3,4-di-Cl-Ph CO CH ₂ 1 3 179 unit 6 Me 2-Imd 3,4-di-Cl-Ph CO CH ₂ 1 3 180 Place 7 Me 2-Imd 3,4-di-Cl-Ph CO CH ₂ 1 3 181 Place 4 Me 2-Imd 3,4-di -F-Ph CO CH ₂ 1 3 182 Place 5 Me 2-Imd 3,4-di-F-Ph CO CH ₂ 1 3 183 Place 6 Me 2-Imd 3,4-di-F-Ph CO CH ₂ 1 3 184 Station 7 Me 2-Imd 3,4-di-F-Ph CO CH ₂ 1 3 185 Station 4 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 3 186 Station 5 Me 2-Imd 4-Cl- Ph CO CH ₂ 1 3 187 Place 6 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 3 188 Place 7 Me 2-Imd 4-Cl-Ph CO CH ₂ 1 3 189 Place 4 Me 2-Imd 4-F -Ph CO CH ₂ 1 3 190 Place 5 Me 2-Imd 4-F-Ph CO CH ₂ 1 3 191 Place 6 Me 2-Imd 4-F-Ph CO CH ₂ 1 3 192 Place 7 Me 2-Imd 4- F-Ph CO CH ₂ 1 3 193 Place 4 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 3 194 Place 5 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 3 195 Place 6 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 3 19 6 App 7 Me 1-Pyd 3,4-di-Cl-Ph CO CH ₂ 1 3 197 App 4 Me 1-Pyd 3,4-di-F-Ph CO CH ₂ 1 3 198 App 5 Me 1-Pyd 3 , 4-di-F-Ph CO CH ₂ 1 3 199 Place 6 Me 1-Pyd 3,4-di-F-Ph CO CH ₂ 1 3 200 Place 7 Me 1-Pyd 3,4-di-F-Ph CO CH ₂ 1 3 201 Place 4 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 3 202 Place 5 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 3 203 Place 6 Me 1-Pyd 4-Cl- Ph CO CH ₂ 1 3 204 Place 7 Me 1-Pyd 4-Cl-Ph CO CH ₂ 1 3 205 Place 4 Me 1-Pyd 4-F-Ph CO CH ₂ 1 3 206 Place 5 Me 1-Pyd 4-F -Ph CO CH ₂ 1 3 207 Place 6 Me 1-Pyd 4-F-Ph CO CH ₂ 1 3 208 Place 7 Me 1-Pyd 4-F-Ph CO CH ₂ 1 3 209 Place 4 Me 1-Tez 3, 4-di-Cl-Ph CO CH ₂ 2 2 210 Place 5 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 2 2 211 Place 6 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 2 2 212 location 7 Me 1-Tez 3,4-di -Cl-Ph CO CH 2 2 2 213 location 4 Me 1-Tez 3,4-di -F-Ph CO CH 2 2 2 214 location 5 Me 1-Tez 3,4-di-F -Ph CO CH 2 2 2 215 location 6 Me 1-Tez 3,4-di -F-Ph CO CH 2 2 2 216 location 7 Me 1-Tez 3,4-di -F-Ph CO CH ₂ 2 2 217 Place 4 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 2 2 218 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 2 2 219 Station 6 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 2 2 220 Station 7 Me 2-Tez 3,4- _{di-Cl-Ph CO CH 2} 2 2 221 location 4 Me 2-Tez 3,4-di -F-Ph CO CH 2 2 2 222 location 5 Me 2-Tez 3,4-di -F-Ph CO CH 2 2 2 223 location 6 Me 2-Tez 3,4-di -F-Ph CO CH 2 2 2 224 location 7 Me 2-Tez 3,4-di -F-Ph CO CH 2 2 2 225 location 4 Me 2- trz 3,4-di-Cl-Ph CO CH 2 2 2 226 location 5 Me 2-trz 3,4-di -Cl-Ph CO CH 2 2 2 227 location 6 Me 2-trz 3,4-di -Cl -Ph CO CH _{2 2 2} 228 location 7 Me 2-Trz 3,4-di -Cl-Ph CO CH 2 2 2 229 location 4 Me 2-Trz 3,4-di -F-Ph CO CH 2 2 2 230 location 5 Me 2-Trz 3,4-di -F-Ph CO CH 2 2 2 231 location 6 Me 2-Trz 3,4-di -F-Ph CO CH 2 2 2 232 location 7 Me 2-Trz 3, 4-di-F-Ph CO CH ₂ 2 2 233 Place 4 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 234 Place 5 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 235 device 6 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 236 device 7 Me 1-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 237 device 4 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 2 3 238 5Me 1-Tez 3,4-di-F-Ph CO CH ₂ 2 3 239 6Me 1-Tez 3,4-di -F-Ph CO CH ₂ 2 3 240 Place 7 Me 1-Tez 3,4-di-F-Ph CO CH ₂ 2 3 241 Place 4 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 242 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 243 Place 6 Me 2-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 24 4 Me 7-Tez 3,4-di-Cl-Ph CO CH ₂ 2 3 245 4 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 2 3 246 5 Me 2-Tez 3 , 4-di-F-Ph CO CH ₂ 2 3 247 Place 6 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 2 3 248 Place 7 Me 2-Tez 3,4-di-F-Ph CO CH ₂ 2 3 249 Unit 4 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 2 3 250 Unit 5 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 2 3 251 Unit 6 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 2 3 252 Place 7 Me 2-Trz 3,4-di-Cl-Ph CO CH ₂ 2 3 253 Place 4 Me 2-Trz 3,4- di-F-Ph CO CH ₂ 2 3 254 position 5 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 2 3 255 position 6 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 2 3 256 Station 7 Me 2-Trz 3,4-di-F-Ph CO CH ₂ 2 3 257 Station 4 Me 1-Tez 3,4-di-Cl-Ph CO O 1 2 258 Station 5 Me 1-Tez 3,4-di-Cl-Ph CO O 1 2 259 Place 6 Me 1-Tez 3,4-di-Cl-Ph CO O 1 2 260 Place 7 Me 1-Tez 3,4-di-Cl-Ph CO O 1 2 261 Place 4 Me 1-Tez 3,4-di-F-Ph CO O 1 2 262 Place 5 Me 1-Tez 3,4-di-F-Ph CO O 1 2 263 Place 6 Me 1-Tez 3,4-di-F-Ph CO O 1 2 264 Place 7 Me 1-Tez 3,4-di-F-Ph CO O 1 2 265 Place 4 Me 2-Tez 3,4-di-Cl-Ph CO O 1 2 266 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO O 1 2 267 Place 6 Me 2-Tez 3,4-di-Cl-Ph CO O 1 2 268 Place 7 Me 2-T ez 3,4-di-Cl-Ph CO O 1 2 269 Place 4 Me 2-Tez 3,4-di-F-Ph CO O 1 2 270 Place 5 Me 2-Tez 3,4-di-F-Ph CO O 1 2 271 Place 6 Me 2-Tez 3,4-di-F-Ph CO O 1 2 272 Place 7 Me 2-Tez 3,4-di-F-Ph CO O 1 2 273 Place 4 Me 2- Trz 3,4-di-Cl-Ph CO O 1 2 274 Place 5 Me 2-Trz 3,4-di-Cl-Ph CO O 1 2 275 Place 6 Me 2-Trz 3,4-di-Cl-Ph CO O 1 2 276 Place 7 Me 2-Trz 3,4-di-Cl-Ph CO O 1 2 277 Place 4 Me 2-Trz 3,4-di-F-Ph CO O 1 2 278 Place 5 Me 2- Trz 3,4-di-F-Ph CO O 1 2 279 Place 6 Me 2-Trz 3,4-di-F-Ph CO O 1 2 280 Place 7 Me 2-Trz 3,4-di-F-Ph CO O 1 2 281 Place 4 Me 1-Tez 3,4-di-Cl-Ph CO O 1 3 282 Place 5 Me 1-Tez 3,4-di-Cl-Ph CO O 1 3 283 Place 6 Me 1- Tez 3,4-di-Cl-Ph CO O 1 3 284 unit 7 Me 1-Tez 3,4-di-Cl-Ph CO O 1 3 285 unit 4 Me 1-Tez 3,4-di-F-Ph CO O 1 3 286 Place 5 Me 1-Tez 3,4-di-F-Ph CO O 1 3 287 Place 6 Me 1-Tez 3,4-di-F-Ph CO O 1 3 288 Place 7 Me 1- Tez 3,4-di-F-Ph CO O 1 3 289 Place 4 Me 2-Tez 3,4-di-Cl-Ph CO O 1 3 290 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO O 1 3 291 Place 6 Me 2-Tez 3,4-di-Cl-Ph CO O 1 3 292 Place 7 Me 2-Tez 3,4-di-Cl-Ph CO O 1 3 293 Place 4 Me 2- Tez 3,4-di-F- Ph CO O 1 3 294 App 5 Me 2-Tez 3,4-di-F-Ph CO O 1 3 295 App 6 Me 2-Tez 3,4-di-F-Ph CO O 1 3 296 App 7 Me 2 -Tez 3,4-di-F-Ph CO O 1 3 297 position 4 Me 2-Trz 3,4-di-Cl-Ph CO O 1 3 298 position 5 Me 2-Trz 3,4-di-Cl- Ph CO O 1 3 299 Place 6 Me 2-Trz 3,4-di-Cl-Ph CO O 1 3 300 Place 7 Me 2-Trz 3,4-di-Cl-Ph CO O 1 3 301 Place 4 Me 2 -Trz 3,4-di-F-Ph CO O 1 3 302 Place 5 Me 2-Trz 3,4-di-F-Ph CO O 1 3 303 Place 6 Me 2-Trz 3,4-di-F- Ph CO O 1 3 304 Place 7 Me 2-Trz 3,4-di-F-Ph CO O 13 3 305 Place 1 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 306 Place 2 Me 1 -Tez 3,4-di-Cl-Ph CO O 2 2 307 Place 3 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 308 Place 4 Me 1-Tez 3,4-di-Cl- Ph CO O 2 2 309 Place 5 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 310 Place 6 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 311 Place 7 Me 1 -Tez 3,4-di-Cl-Ph CO O 2 2 312 Place 8 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 313 Place 9 Me 1-Tez 3,4-di-Cl- Ph CO O 2 2 314 device 10 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 315 device 11 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 316 device 12 Me 1 -Tez 3,4-di-Cl-Ph CO O 2 2 317 Place 13 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 318 Place 14 Me 1-Tez 3,4-di-Cl- Ph CO O 2 2 319 Place 15 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 320 Place 16 Me 1-Tez 3,4-di-Cl-Ph CO O 2 2 321 Place 1 Me 1- Tez 3,4-di-F-Ph CO O 2 2 322 Place 2 Me 1-Tez 3,4-di-F-Ph CO O 2 2 323 Place 3 Me 1-Tez 3,4-di-F-Ph CO O 2 2 324 Unit 4 Me 1-Tez 3,4-di-F-Ph CO O 2 2 325 Unit 5 Me 1-Tez 3,4-di-F-Ph CO O 2 2 326 Unit 6 Me 1- Tez 3,4-di-F-Ph CO O 2 2 327 Place 7 Me 1-Tez 3,4-di-F-Ph CO O 2 2 328 Place 8 Me 1-Tez 3,4-di-F-Ph CO O 2 2 329 Place 9 Me 1-Tez 3,4-di-F-Ph CO O 2 2 330 Place 10 Me 1-Tez 3,4-di-F-Ph CO O 2 2 331 Place 11 Me 1- Tez 3,4-di-F-Ph CO O 2 2 332 Place 12 Me 1-Tez 3,4-di-F-Ph CO O 2 2 333 Place 13 Me 1-Tez 3,4-di-F-Ph CO O 2 2 334 Unit 14 Me 1-Tez 3,4-di-F-Ph CO O 2 2 335 Unit 15 Me 1-Tez 3,4-di-F-Ph CO O 2 2 336 Unit 16 Me 1- Tez 3,4-di-F-Ph CO O 2 2 337 position 1 Me 1-Tez 4-Cl-Ph CO O 2 2 338 position 2 Me 1-Tez 4-Cl-Ph CO O 2 2 339 position 3 Me 1-Tez 4-Cl-Ph CO O 2 2 340 Place 4 Me 1-Tez 4-Cl-Ph CO O 2 2 341 Place 5 Me 1-Tez 4-Cl-Ph CO O 2 2 342 Place 6 Me 1- Tez 4-Cl-Ph CO O 2 2 343 Place 7 Me 1-Tez 4-Cl-Ph CO O 2 2 344 Place 8 Me 1-Tez 4-Cl-Ph CO O 2 2 345 Place 9 Me 1-Tez 4-Cl-Ph CO O 2 2 346 Place 10 Me 1-Tez 4-Cl-Ph CO O 2 2 347 Place 11 Me 1-Tez 4-Cl-Ph CO O 2 2 348 Place 12 Me 1-Tez 4-Cl-Ph CO O 2 2 349 Place 13 Me 1-Tez 4-Cl-Ph CO O 2 2 350 Place 14 Me 1-Tez 4-Cl-Ph CO O 2 2 351 Place 15 Me 1-Tez 4-Cl-Ph CO O 2 2 352 Place 16 Me 1-Tez 4-Cl-Ph CO O 2 2 353 Place 1 Me 1-Tez 4-F-Ph CO O 2 2 354 Place 2 Me 1 -Tez 4-F-Ph CO O 2 2 355 position 3 Me 1-Tez 4-F-Ph CO O 2 2 356 position 4 Me 1-Tez 4-F-Ph CO O 2 2 357 position 5 Me 1-Tez 4-F-Ph CO O 2 2 358 Place 6 Me 1-Tez 4-F-Ph CO O 2 2 359 Place 7 Me 1-Tez 4-F-Ph CO O 2 2 360 Place 8 Me 1-Tez 4- F-Ph CO O 2 2 361 Place 9 Me 1-Tez 4-F-Ph CO O 2 2 362 Place 10 Me 1-Tez 4-F-Ph CO O 2 2 363 Place 11 Me 1-Tez 4-F- Ph CO O 2 2 364 Place 12 Me 1-Tez 4-F-Ph CO O 2 2 365 Place 13 Me 1-Tez 4-F-Ph CO O 2 2 366 Place 14 Me 1-Tez 4-F-Ph CO O 2 2 367 O 15 Me 1-Tez 4-F-Ph CO O 2 2 368 O 16 Me 1-Tez 4-F-Ph CO O 2 2 369 O 4 Me 2-Tez 3,4-di-Cl- Ph CO O 2 2 370 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO O 2 2 371 Place 6 Me 2-Tez 3,4-di-Cl-Ph CO O 2 2 372 Place 7 Me 2 -Tez 3,4-di-Cl-Ph CO O 2 2 373 App 4 Me 2-Tez 3,4-di-F-Ph CO O 2 2 374 App 5 Me 2-Tez 3,4-di-F-Ph CO O 2 2 375 App 6 Me 2-Tez 3,4 -Di-F-Ph CO O 2 2 376 Place 7 Me 2-Tez 3,4-di-F-Ph CO O 2 2 377 Place 4 Me 2-Tez 4-Cl-Ph CO O 2 2 378 Place 5 Me 2-Tez 4-Cl-Ph CO O 2 2 379 Place 6 Me 2-Tez 4-Cl-Ph CO O 2 2 380 Place 7 Me 2-Tez 4-Cl-Ph CO O 2 2 381 Place 4 Me 2- Tez 4-F-Ph CO O 2 2 382 position 5 Me 2-Tez 4-F-Ph CO O 2 2 383 position 6 Me 2-Tez 4-F-Ph CO O 2 2 384 position 7 Me 2-Tez 4 -F-Ph CO O 2 2 385 place 4 Me 2-Trz 3,4-di-Cl-Ph CO O 2 2 386 place 5 Me 2-Trz 3,4-di-Cl-Ph CO O 2 2 387 place 6 Me 2-Trz 3,4-di-Cl-Ph CO O 2 2 388 Place 7 Me 2-Trz 3,4-di-Cl-Ph CO O 2 2 389 Place 4 Me 2-Trz 3,4-di -F-Ph CO O 2 2 390 6 5 Me 2-Trz 3,4-di-F-Ph CO O 2 2 391 6 Me 2-Trz 3,4-di-F-Ph CO O 2 392 7 Me 2-Trz 3,4-di-F-Ph CO O 2 393 4 Me 2-Trz 4-Cl-Ph CO O 2 2 394 5 Me 2-Trz 4-Cl-Ph CO O 2 2 395 installation 6 Me 2-Trz 4-Cl-Ph CO O 2 2 396 installation 7 Me 2-Trz 4-Cl-Ph CO O 2 2 397 installation 4 Me 2-Trz 4-F-Ph CO O 2 2 398 installation 5 Me 2-Trz 4-F-Ph CO O 2 2 399 Place 6 Me 2-Trz 4-F-Ph CO O 2 2 400 Place 7 Me 2-Trz 4-F-Ph CO O 2 2 1 401 4 Me 2-Imd 3,4-di-Cl-Ph CO O 2 2 402 2 5 Me 2-Imd 3,4-di-Cl-Ph CO O 2 2 403 Place 6 Me 2-Imd 3,4-di-Cl-Ph CO O 2 2 404 Place 7 Me 2-Imd 3,4-di-Cl-Ph CO O 2 2 405 Place 4 Me 2-Imd 3,4-di-F-Ph CO O 2 2 406 Place 5 Me 2-Imd 3,4-di-F-Ph CO O 2 2 407 Place 6 Me 2-Imd 3,4-di-F-Ph CO O 2 2 408 Place 7 Me 2-Imd 3,4-di-F-Ph CO O 2 2 409 Place 4 Me 2-Imd 4-Cl-Ph CO O 2 2 410 Place 5 Me 2-Imd 4-Cl- Ph CO O 2 2 411 Place 6 Me 2-Imd 4-Cl-Ph CO O 2 2 412 Place 7 Me 2-Imd 4-Cl-Ph CO O 2 2 413 Place 4 Me 2-Imd 4-F-Ph CO O 2 2 414 Place 5 Me 2-Imd 4-F-Ph CO O 2 2 415 Place 6 Me 2-Imd 4-F-Ph CO O 2 2 416 Place 7 Me 2-Imd 4-F-Ph CO O 2 2 417 Place 4 Me 1-Pyd 3,4-di-Cl-Ph CO O 2 2 418 Place 5 Me 1-Pyd 3,4-di-Cl-Ph CO O 2 2 419 Place 6 Me 1-Pyd 3, 4-di-Cl-Ph CO O 2 2 420 Place 7 Me 1-Pyd 3,4-di-Cl-Ph CO O 2 2 421 Place 4 Me 1-Pyd 3,4-di-F-Ph CO O 2 2 422 Place 5 Me 1-Pyd 3,4-di-F-Ph CO O 2 2 423 Place 6 Me 1-Pyd 3,4-di-F-Ph CO O 2 424 Place 7 Me 1-Pyd 3, 4-di-F-Ph CO O 2 2 425 Place 4 Me 1-Pyd 4-Cl-Ph CO O 2 2 426 Place 5 Me 1-Pyd 4-Cl-Ph CO O 2 2 427 Place 6 Me 1-Pyd 4-Cl-Ph CO O 2 2 428 Place 7 Me 1-Pyd 4-Cl-Ph CO O 2 2 429 Place 4 Me 1-Pyd 4-F-Ph CO O 2 2 430 5 Me 1-Pyd 4-F-Ph CO O 2 2 431 6 Me 1-Pyd 4-F-Ph CO O 2 2 432 7 7 Me 1-Pyd 4-F-Ph CO O 2 2 433 4 Me 1-Tez 3,4-di-Cl-Ph CO O 2 3 434 Place 5 Me 1-Tez 3,4-di-Cl-Ph CO O 2 3 435 Place 6 Me 1-Tez 3,4-di- Cl-Ph CO O 2 3 436 place 7 Me 1-Tez 3,4-di-Cl-Ph CO O 2 3 437 place 4 Me 1-Tez 3,4-di-F-Ph CO O 2 3 438 place 5 Me 1-Tez 3,4-di-F-Ph CO O 2 3 439 Place 6 Me 1-Tez 3,4-di-F-Ph CO O 2 3 440 Place 7 Me 1-Tez 3,4-di- F-Ph CO O 2 3 441 Place 4 Me 1-Tez 4-Cl-Ph CO O 2 3 442 Place 5 Me 1-Tez 4-Cl-Ph CO O 2 3 443 Place 6 Me 1-Tez 4-Cl- Ph CO O 2 3 444 Place 7 Me 1-Tez 4-Cl-Ph CO O 2 3 445 Place 4 Me 1-Tez 4-F-Ph CO O 2 3 446 Place 5 Me 1-Tez 4-F-Ph CO O 2 3 447 Place 6 Me 1-Tez 4-F-Ph CO O 2 3 448 Place 7 Me 1-Tez 4-F-Ph CO O 2 3 449 Place 4 Me 2-Tez 3,4-di-Cl- Ph CO O 2 3 450 Place 5 Me 2-Tez 3,4-di-Cl-Ph CO O 2 3 451 Place 6 Me 2-Tez 3,4-di-Cl-Ph CO O 2 3 452 Place 7 Me 2 -Tez 3,4-di-Cl-Ph CO O 2 3 453 4Me 2-Tez 3,4-di-F-Ph CO O 2 3 454 App 5 Me 2-Tez 3,4-di-F-Ph CO O 2 3 455 App 6 Me 2-Tez 3,4-di-F-Ph CO O 2 3 456 App 7 Me 2-Tez 3,4 -di-F-Ph CO O 2 3 457 position 4 Me 2-Tez 4-Cl-Ph CO O 2 3 458 position 5 Me 2-Tez 4-Cl-Ph CO O 2 3 459 position 6 Me 2-Tez 4 -Cl-Ph CO O 2 3 460 Place 7 Me 2-Tez 4-Cl-Ph CO O 2 3 461 Place 4 Me 2-Tez 4-F-Ph CO O 2 3 462 Place 5 Me 2-Tez 4-F -Ph CO O 2 3 463 Place 6 Me 2-Tez 4-F-Ph CO O 2 3 464 Place 7 Me 2-Tez 4-F-Ph CO O 2 3 465 Place 4 Me 2-Trz 3,4-di -Cl-Ph CO O 2 3 466 unit 5 Me 2-Trz 3,4-di-Cl-Ph CO O 2 3 467 unit 6 Me 2-Trz 3,4-di-Cl-Ph CO O 2 3 468 unit 7 Me 2-Trz 3,4-di-Cl-Ph CO O 2 3 469 Place 4 Me 2-Trz 3,4-di-F-Ph CO O 2 3 470 Place 5 Me 2-Trz 3,4-di -F-Ph CO O 2 3 471 unit 6 Me 2-Trz 3,4-di-F-Ph CO O 2 3 472 unit 7 Me 2-Trz 3,4-di-F-Ph CO O 2 3 473 unit 4 Me 2-Trz 4-Cl-Ph CO O 2 3 474 setting 5 Me 2-Trz 4-Cl-Ph CO O 2 3 475 setting 6 Me 2-Trz 4-Cl-Ph CO O 2 3 476 setting 7 Me 2-Trz 4-Cl-Ph CO O 2 3 477 position 4 Me 2-Trz 4-F-Ph CO O 2 3 478 position 5 Me 2-Trz 4-F-Ph COO 2 3 479 position 6 Me 2- Trz 4-F-Ph CO O 2 3 480 Place 7 Me 2-Trz 4-F-Ph CO O 2 3 481 Place 4 Me 2-I md 3,4-di-Cl-Ph CO O 2 3 482 Place 5 Me 2-Imd 3,4-di-Cl-Ph CO O 2 3 483 Place 6 Me 2-Imd 3,4-di-Cl-Ph CO O 2 3 484 Place 7 Me 2-Imd 3,4-di-Cl-Ph CO O 2 3 485 Place 4 Me 2-Imd 3,4-di-F-Ph CO O 2 3 486 Place 5 Me 2- Imd 3,4-di-F-Ph CO O 2 3 487 Place 6 Me 2-Imd 3,4-di-F-Ph CO O 2 3 488 Place 7 Me 2-Imd 3,4-di-F-Ph CO O 2 3 489 Place 4 Me 2-Imd 4-Cl-Ph CO O 2 3 490 Place 5 Me 2-Imd 4-Cl-Ph CO O 2 3 491 Place 6 Me 2-Imd 4-Cl-Ph CO O 2 3 492 Place 7 Me 2-Imd 4-Cl-Ph CO O 2 3 493 Place 4 Me 2-Imd 4-F-Ph CO O 2 3 494 Place 5 Me 2-Imd 4-F-Ph CO O 2 3 495 Place 6 Me 2-Imd 4-F-Ph CO O 2 3 496 Place 7 Me 2-Imd 4-F-Ph CO O 2 3 497 Place 4 Me 1-Pyd 3,4-di-Cl-Ph CO O 2 3 498 Place 5 Me 1-Pyd 3,4-di-Cl-Ph CO O 2 3 499 Place 6 Me 1-Pyd 3,4-di-Cl-Ph CO O 2 3 500 Place 7 Me 1-Pyd 3 , 4-di-Cl-Ph CO O 2 3 501 Place 4 Me 1-Pyd 3,4-di-F-Ph CO O 2 3 502 Place 5 Me 1-Pyd 3,4-di-F-Ph CO O 2 3 503 Place 6 Me 1-Pyd 3,4-di-F-Ph CO O 2 3 504 Place 7 Me 1-Pyd 3,4-di-F-Ph CO O 2 3 505 Place 4 Me 1-Pyd 4 -Cl-Ph CO O 2 3 506 Place 5 Me 1-Pyd 4-Cl-Ph CO O 2 3 507 Place 6 Me 1-Pyd 4-Cl-Ph CO O 2 3 50 8 place 7 Me 1-Pyd 4-Cl-Ph CO O 2 3 509 place 4 Me 1-Pyd 4-F-Ph CO O 2 3 510 place 5 Me 1-Pyd 4-F-Ph CO O 2 3 511 place 6 Me 1-Pyd 4-F-Ph CO O 2 3 512 Place 7 Me 1-Pyd 4-F-Ph CO O 2 3 −−−−−−−−−−−−−−−−−−−−− In the above table, `` Imd '' indicates imidazolyl, `` Me '' indicates methyl, `` Ph '' indicates phenyl, and `` Pyd '' indicates pyrrolidinyl. , “Tez” indicates tetrazolyl and “Tr
"z" represents triazolyl. In the section of "Z", "position 1" to "position 16" each represent a group represented by the following formula.

[0054]

Embedded image In the above table, the preferred compound is Compound No. 1
To 32, 257 to 264, and 305 to 336. More preferred compounds are Compound Nos. 1 to 16, 257 to 260, and 3
05 to 320.

Particularly preferred are: 1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) pyrrolidin-3-yl] ethyl {spiro [((2S) -hydroxy) indan-1,4'-
1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) pyrrolidin-3-yl] ethyl}-
3-oxo-3,4-dihydrospiro [isoquinoline-
1 (2H), 4'-piperidine] (Exemplary Compound No. 5), 1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) pyrrolidin-3-yl] ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,4′-piperidine] (Exemplary Compound No. 6); -{2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) pyrrolidin-3-yl] ethyl} spiro [benzo [c] thiophene-1 (3H), 4′-piperidine]-(2S) -oxide (exemplary compound number 7); 1- {2- [ (2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [((2S) -hydroxy) indane-1,4'-
Piperidine] (exemplary compound number 308), 1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) morpholin-2-yl] ethyl}-
3-oxo-3,4-dihydrospiro [isoquinoline-
1 (2H), 4′-piperidine] (Exemplary Compound No. 30
9), 1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,4′-piperidine] (exemplified compound number 310); and 1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [benzo [c] thiophen-1 (3H), 4′-piperidine]-(2S) -oxide (Exemplified Compound No. 31)
1) can be mentioned.

[0056]

BEST MODE FOR CARRYING OUT THE INVENTION The compound having the general formula (I) of the present invention can be produced, for example, according to the following [Method A] and [Method B]. [Method A]

[0057]

Embedded image (In the above formula, R ¹ , R ² , R ³ , A, E, the cyclic group G, the cyclic groups Ar, m and n have the same meanings as described above, and R ⁴ is a protecting group for the imino group. X represents a leaving group.

"Protecting group for imino group" in the definition of R ⁴
Is a general protecting group for an amino group or an imino group described above in the description of the "ester or other derivative"
Represents the same group as, preferably, the `` lower alkoxycarbonyl group '' or the `` aralkyloxycarbonyl group '', more preferably tert-butoxycarbonyl or benzyloxycarbonyl, most preferably,
tert-butoxycarbonyl.

The "leaving group" in the definition of X is usually
There is no particular limitation as long as it is a group leaving as a nucleophilic residue,
Preferably, a halogen atom such as chlorine, bromine or iodine; a lower alkoxycarbonyloxy group such as methoxycarbonyloxy or ethoxycarbonyloxy; a halogen atom such as chloroacetyloxy, dichloroacetyloxy, trichloroacetyloxy or trifluoroacetyloxy Halogenated alkylcarbonyloxy groups; lower alkanesulfonyloxy groups such as methanesulfonyloxy and ethanesulfonyloxy; halogeno lower alkanesulfonyloxy groups such as trifluoromethanesulfonyloxy and pentafluoroethanesulfonyloxy; benzenesulfonyloxy, p-toluene Sulfonyloxy, p-
It represents an arylsulfonyloxy group such as nitrobenzenesulfonyloxy, and more preferably a lower alkanesulfonyloxy group or an arylsulfonyloxy group. ) Step A1 comprises compound (II) and compound (I)
II) is reacted with a solvent in the presence of a base to produce a compound (IV).

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate; Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexane Ketones such as xanone; nitro compounds such as nitroethane and nitrobenzene; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide, N-methyl-2 −
Amides such as pyrrolidone, N-methylpyrrolidinone, hexamethyl phosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; and more preferably amides, ethers and nitriles. , Most preferably amides.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. Preferably, a metal iodide such as potassium iodide is used.
Alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; such as lithium hydride, sodium hydride and potassium hydride Alkali metal hydrides; inorganic bases such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide or alkali metal fluorides such as sodium fluoride and potassium fluoride; Or N-methylmorpholine,
Triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t- Butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N,
N-diethylaniline, 1,5-diazabicyclo [4.
3.0] Nona-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8
Organic bases such as -diazabicyclo [5.4.0] undec-7-ene (DBU); more preferably, a combination of a metal iodide and an inorganic base; Are combinations of metal iodides and alkali metal bicarbonates.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 30 minutes to 48 hours, preferably 1 hour to 12 hours.

Step A2 is a compound represented by the formula ( ⁴ ):
After removing the group, the resulting compound and compound (V) are mixed with a “condensing agent” in a solvent in the presence or absence of a base.
In which the compound (I) of the present invention is produced.

The removal of the protecting group R ⁴ depends on its type, but is generally carried out by a method well known in the art as follows.

When a silyl group is used as R ⁴ , it is usually treated with a compound which generates a fluorine anion, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride. Or acetic acid,
It can be removed by treatment with an organic acid such as methanesulfonic acid, paratoluenesulfonic acid, trifluoroacetic acid, trifluoromethanesulfonic acid, B-bromocatecholborane or an inorganic acid such as hydrochloric acid.

In the case of removal by fluorine anion,
By adding an organic acid such as formic acid, acetic acid or propionic acid, side reactions may be suppressed.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent. Preferably, it is preferably diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxy. Ethers such as ethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; water; organic acids such as acetic acid and mixed solvents thereof.

The reaction temperature and the reaction time are not particularly limited, but are usually 0 ° C. to 150 ° C. (preferably 10 ° C. to 1 ° C.).
(00 ° C.) for 1 hour to 48 hours (preferably 2 hours to 12 hours).

When R ⁴ is an aralkyl group or an aralkyloxycarbonyl group, it is usually removed by contact with a reducing agent in a solvent (preferably catalytic reduction at room temperature under a catalyst) or A method of removing with an oxidizing agent is preferred.

The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the present reaction, but alcohols such as methanol, ethanol and isopropanol, and diethyl ether Ethers such as ter, tetrahydrofuran, dioxane, toluene,
Aromatic hydrocarbons such as benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, dimethylacetamide, N
Preferred are amides such as -methyl-2-pyrrolidone and hexamethyl phosphorotriamide, fatty acids such as formic acid and acetic acid, water, and mixed solvents thereof, and more preferably alcohols and fatty acids. , A mixed solvent of alcohols and ethers, a mixed solvent of alcohols and water, or a mixed solvent of fatty acids and water.

The catalyst to be used is not particularly limited as long as it is usually used for a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, Rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used.

The pressure is not particularly limited, but is usually 1000
The reaction is performed at hPa to 10,000 hPa.

The reaction temperature and the reaction time vary depending on the starting material, the solvent and the type of the catalyst, but are usually from 0 ° C. to 10 ° C.
0 ° C. (preferably 20 ° C. to 70 ° C.), 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal by oxidation is not particularly limited as long as it does not participate in the present reaction, but is preferably a water-containing organic solvent.

Preferred examples of such organic solvents include ketones such as acetone, methylene chloride, chloroform, halogenated hydrocarbons such as carbon tetrachloride, nitriles such as acetonitrile, diethyl ether, tetrahydrofuran, and the like. Mention may be made of ethers such as dioxane, amides such as dimethylformamide, dimethylacetamide, hexamethylphosphorotriamide and sulfoxides such as dimethylsulfoxide.

The oxidizing agent to be used is not particularly limited as long as it is a compound used for oxidation. Preferably, potassium persulfate, sodium persulfate, ammonium cerium nitrate (CAN), 2,3- Dichloro-5,6-
Dicyano-p-benzoquinone (DDQ) is used.

The reaction temperature and the reaction time vary depending on the starting material, the solvent, the type of the catalyst and the like.
C. for 10 minutes to 24 hours.

In liquid ammonia or methanol
In alcohols such as ethanol and ethanol.
It can also be removed by applying alkali metals such as metallic lithium and metallic sodium at a temperature of from -20 ° C to -20 ° C.

Further, it can also be removed by using an alkylsilyl halide such as aluminum chloride-sodium iodide or trimethylsilane iodide in a solvent.

The solvent used is not particularly limited as long as it does not participate in the present reaction, but is preferably a nitrile such as acetonitrile, a halogenated hydrocarbon such as methylene chloride or chloroform, or a halogenated hydrocarbon such as these. Is used.

The reaction temperature and the reaction time vary depending on the starting material, solvent and the like, but are usually 0 to 50 ° C. and 5 minutes to 3 minutes.
Implemented for days.

When the reaction substrate has a sulfur atom,
Preferably, aluminum chloride-sodium iodide is used.

When R ⁴ is an aliphatic acyl group, an aromatic acyl group or a lower alkoxycarbonyl group, it is removed by treating with a base in a solvent.

The base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide; sodium carbonate, potassium carbonate, carbonate Alkali metal carbonates such as lithium; alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, barium hydroxide or ammonia such as ammonia water and concentrated ammonia-methanol are used. .

The solvent to be used is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol , Tetrahydrofuran, dioxane
An organic solvent such as ters or a mixed solvent of water and the above organic solvent is preferable.

The reaction temperature and the reaction time vary depending on the starting material, solvent and base used, and are not particularly limited.
In order to suppress side reactions, usually at 0 to 150 ° C., 1
For 10 to 10 hours.

When R ⁴ is t-butoxycarbonyl, it can be removed by treating it with an acid in a solvent.

The acid used is not particularly limited as long as it is usually used as a Bronsted acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or Bronsted acids such as organic acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid, and p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cations such as Dowex 50W Exchange resins can also be used.

The solvent used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate; Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol , Isopropanol, n-butanol , Isobutanol - Le, tert
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water, or And a mixed solvent thereof, and more preferably, a halogenated hydrocarbon, an ester or an ether.

The reaction temperature and reaction time vary depending on the starting material, the solvent and the type and concentration of the acid used, but are usually -10 to 100 ° C (preferably -5 to 50 ° C).
5 minutes to 48 hours (preferably 30 minutes to 10 hours).

When R ⁴ is a lower alkoxymethyl group, a tetrahydropyranyl group, a tetrahydrothiopyranyl group, a tetrahydrofuranyl group, a tetrahydrothiofuranyl group or a substituted ethyl group, it is usually added to an acid in a solvent. And is removed by treating with

The acid used is not particularly limited as long as it is generally used as a Bronsted acid or Lewis acid, and is preferably hydrogen chloride; an inorganic acid such as hydrochloric acid, sulfuric acid or nitric acid; or Bronsted acids such as acetic acid, trifluoroacetic acid, methanesulfonic acid and organic acids such as p-toluenesulfonic acid: Lewis acids such as boron trifluoride, but strongly acidic cations such as Dowex 50W Exchange resins can also be used.

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate; Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; methanol, ethanol, n-propanol , Isopropanol, n-butano- , Isobutanol - Le, tert
Alcohols such as butanol, isoamyl alcohol, diethylene glycol, glycerin, octanol, cyclohexanol, methyl cellosolve; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, isophorone, cyclohexanone; water, or And a mixed solvent thereof, and more preferably, a halogenated hydrocarbon, an ester or an ether.

The reaction temperature and reaction time vary depending on the starting material, the solvent and the type and concentration of the acid used, but are usually -10 to 100 ° C (preferably -5 to 50 ° C).
5 minutes to 48 hours (preferably 30 minutes to 10 hours).

When R ⁴ is an alkenyloxycarbonyl group, the removal reaction is usually carried out in the same manner as in the removal reaction when R ⁴ is an aliphatic acyl group, an aromatic acyl group or a lower alkoxycarbonyl group. , And a base.

In the case of allyloxycarbonyl, palladium (II) chloride bistriphenylphosphine complex or bis (methyldiphenylphosphine) (1,
The removal method using a transition metal catalyst such as 5-cyclooctadiene) iridium (I) hexafluorophosphate is simple and can be carried out with few side reactions.

"Condensing agent" used in the subsequent reaction
(1) a combination of a phosphoric ester such as diethylphosphoryl cyanide or diphenylphosphoryl azide with the following base; (2) 1,3-dicyclohexylcarbodiimide,
3-diisopropylcarbodiimide, 1-ethyl-3-
Carbodiimides such as (3-dimethylaminopropyl) carbodiimide; combinations of the carbodiimides with the following bases; the carbodiimides and N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-di Combinations of N-hydroxys such as carboximides; (3) 2,2′-dipyridyl disulfide, 2,
Combination of disulfides such as 2'-dibenzothiazolyl disulfide and phosphines such as triphenylphosphine and tributylphosphine; (4) N, N'-disuccinimidyl carbonate, di-2-pyridyl carbonate , S, S'-bis (1-
Carbonates such as phenyl-1H-tetrazol-5-yl) dithiocarbonate; (5) phosphinic chlorides such as N, N′-bis (2-oxo-3-oxazolidinyl) phosphinic chloride; 6) N, N'-disuccinimidyl oxalate,
N, N'-diphthalimide oxalate, N, N'-bis (5-norbornene-2,3-dicarboximidyl) oxalate, 1,1'-bis (benzotriazolyl) oxalate, 1,1 Oxalates such as' -bis (6-chlorobenzotriazolyl) oxalate and 1,1'-bis (6-trifluoromethylbenzotriazolyl) oxalate; (7) the phosphines and diethyl azodicarboxylate;
Combinations of azodicarboxylic acid esters such as 1,1 '-(azodicarbonyl) dipiperidine or azodicarboxamides; combinations of the above phosphines with the following bases; (8) N-ethyl-5-phenylisoxazolium −
N-lower alkyl-5-arylisoxazolium-3'-sulfonates such as 3'-sulfonate; (9) diheteroaryldiselenides such as di-2-pyridyldiselenide; (10 ) Arylsulfonyltriazolides such as p-nitrobenzenesulfonyltriazolide; (11) 2-halo-1-lower alkylpyridinium halides such as 2-chloro-1-methylpyridinium iodide; 1'-oxalyldiimidazole, N,
Imidazoles such as N'-carbonyldiimidazole; (13) 3-lower alkyl-2-halogen-benzothiazolium fluoroborates such as 3-ethyl-2-chloro-benzothiazolium fluoroborate (14) 3-lower alkyl-benzothiazole-2-cellones such as 3-methyl-benzothiazole-2-cellone; (15) phosphates such as phenyldichlorophosphate and polyphosphate ester; (16) chloro; (17) halogenosilanes such as trimethylsilyl chloride and triethylsilyl chloride; (18) combinations of lower alkanesulfonyl halides such as methanesulfonyl chloride and the following bases; (19) N, N, N, N, N ', N'-tetra-lower alkylhalogenoformamidium chlorides such as N', N'-tetramethylchloroformamidium chloride; ).

The solvent to be used is not particularly limited as long as it does not hinder the reaction and dissolves the starting materials to some extent, but is preferably an aliphatic hydrocarbon such as hexane or heptane; Aromatic hydrocarbons such as toluene and xylene; methylene chloride, chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; diethyl ether, diisopropyl ether, tetrahydrofuran; Ethers such as dioxane, dimethoxyethane and diethylene glycol dimethyl ether; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-dimethylformamide, N, N-dimethylacetamide;
Examples include amides such as N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. Preferably, N-methylmorpholine, triethylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine,
Pyridine, 4-pyrrolidinopyridine, picoline, 4-
(N, N-dimethylamino) pyridine, 2,6-di (te
rt-butyl) -4-methylpyridine, quinoline, N, N
Organic bases such as -dimethylaniline and N, N-diethylaniline.

It is to be noted that 4- (N, N-dimethylamino) pyridine and 4-pyrrolidinopyridine may be used in combination with other bases in a catalytic amount. , Dehydrating agents such as molecular sieves, quaternary ammonium salts such as benzyltriethylammonium chloride, tetrabutylammonium chloride, crown ethers such as dibenzo-18-crown-6, 3,4-dihydro-2H- Pyrido [1,
2-a] An acid scavenger such as pyrimidin-2-one can also be added.

The reaction is carried out at a temperature from -20 ° C to 80 ° C, preferably from 0 ° C to room temperature.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 10 minutes to 3 days, preferably 30 minutes to 1 day. [Method B] Method B is a method for producing a compound of the formula (I) wherein R ² is tetrazol-5-yl.

[0104]

Embedded image (Wherein, R ¹ , R ³ , A, E, cyclic group G, cyclic group A
r, m and n are as defined above. ) Step B1 removes the R ⁴ group of compound (IV),
Next, in the step of producing the compound (VII), the produced compound and the compound (VI) are reacted with a "condensing agent" in a solvent in the presence or absence of a base.

The reaction at the first stage (removal of the R ⁴ group) and the reaction at the second stage (condensation reaction) of this step are respectively Step A2
The method is performed in the same manner as described in the above.

Step B2 is a compound of the present invention obtained by reacting a cyano group of compound (VII) with sodium azide or tributyltin azide in a solvent in the presence or absence of an acid to form a tetrazole group. Compound (I)
This is the step of manufacturing.

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but is preferably water; methanol, ethanol, n
Alcohols such as propanol, aliphatic hydrocarbons such as hexane, heptane, ligroin, petroleum ether; aromatic hydrocarbons such as benzene, toluene, xylene; methylene chloride, chloroform, carbon tetrachloride, dichloroethane, Halogenated hydrocarbons such as chlorobenzene and dichlorobenzene; esters such as ethyl formate, ethyl acetate, propyl acetate, butyl acetate and diethyl carbonate; such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether Ethers; ketones such as acetone, methyl ethyl ketone, isophorone and cyclohexanone; nitriles such as acetonitrile and isobutyronitrile; formamide, N, N-di Chill acetamide, N- methyl-2
Amides such as -pyrrolidone, N-methylpyrrolidinone, hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; more preferably, alcohols, aromatic hydrocarbons and amides. , Ethers, most preferably,
Aromatic hydrocarbons.

Examples of the acid to be used include Lewis acids such as aluminum chloride, aluminum bromide, aluminum iodide, boron trifluoride-ether complex, dibutyltin oxide and tributyltin chloride; ammonium chloride, trimethylamine hydrochloride, triethylamine Tertiary amine hydrochloride or sulfate such as hydrochloride, tributylamine hydrochloride, ammonium sulfate, trimethylamine sulfate, triethylamine sulfate, tributylamine sulfate; lithium chloride, lithium perchlorate, lithium trifluoromethanesulfonate, chloride Metal salts such as zinc can be mentioned. Preferably, they are Lewis acids or tertiary amine hydrochlorides.

The reaction can be carried out at a temperature of 0 ° C. to 200 ° C., preferably 20 ° C. to 150 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 30 minutes to 200 hours, preferably 1 hour to 50 hours. [Method C] Method C is a method for producing compound (V ′) in which A is a carbonyl group and R ² is 1-pyrrolidinyl in compound (V).

[0111]

Embedded image (In the formula, R ¹ and R ⁵ represents the same meanings as defined above, R ⁵
Represents a protecting group for a carboxyl group, and Y represents
Represents a leaving group.

The term “protecting group for carboxyl group” in the definition of R ^{5 represents} the same group as the above-mentioned “general protecting group” for “ester or other derivative of carboxy group”. It is a lower alkyl group, a lower alkenyl group, a lower alkynyl group, a silyl group or an aralkyl group.

The term "leaving group" in the definition of Y represents the same group as the leaving group represented by Y, and is preferably a halogen atom,
Or a lower alkanesulfonyloxy group. ) Step C1 comprises compound (VIII) and compound (I)
X) is reacted with a solvent in the presence of a base to produce a pyrrolidinylbenzoic acid derivative (X).

The solvent to be used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting materials to some extent. Preferably, the solvent is an aliphatic hydrocarbon such as hexane, heptane, ligroin or petroleum ether. Hydrogens; aromatic hydrocarbons such as benzene, toluene and xylene; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane, chlorobenzene and dichlorobenzene; ethyl formate, ethyl acetate, propyl acetate; Esters such as butyl acetate and diethyl carbonate; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane and diethylene glycol dimethyl ether; ketones such as acetone, methyl ethyl ketone, isophorone and cyclohexanone ; Acetonitrile, nitriles such as isobutyronitrile; formamide,
Amides such as N, N-dimethylacetamide, N-methyl-2-pyrrolidone, N-methylpyrrolidinone, and hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide and sulfolane; Amides, ethers and nitriles, most preferably amides.

The base to be used is not particularly limited as long as it is used as a base in a usual reaction. Preferably, the base is a metal iodide such as potassium iodide.
Alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; alkali metal hydrogen carbonates such as sodium hydrogen carbonate, potassium hydrogen carbonate and lithium hydrogen carbonate; such as lithium hydride, sodium hydride and potassium hydride Alkali metal hydrides; inorganic salts such as alkali metal hydroxides such as sodium hydroxide, potassium hydroxide, barium hydroxide and lithium hydroxide or alkali metal fluorides such as sodium fluoride and potassium fluoride. Or N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine, picoline, 4- (N, N-dimethylamino ) Pyridine, , 6- di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO),
1,8-diazabicyclo [5.4.0] undec-7-
Organic bases such as ene (DBU) can be mentioned, more preferably a combination of a metal iodide and an inorganic base, and most preferably a combination of a metal iodide and an alkali metal bicarbonate. Combination.

The reaction is carried out at a temperature of 0 ° C. to 150 ° C., preferably 20 ° C. to 120 ° C.

The reaction time mainly depends on the reaction temperature, the starting compound,
Depending on the type of reaction reagent or solvent used,
Usually, it is 30 minutes to 48 hours, preferably 1 hour to 12 hours. Step C2 is a step of producing a carboxylic acid derivative (V ′) by removing the protecting group R ⁵ of the compound (X).

This reaction depends on the type of R ⁵ ,
Generally, it is performed as follows by methods well known in the art.

When R ⁵ is a lower alkyl group, a lower alkenyl group, a lower alkynyl group or a silyl group, it can be removed by treating with an acid or a base.

As the acid, hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid is used. The base is not particularly limited as long as it does not affect the other parts of the compound. And alkali metal carbonates such as potassium carbonate, alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide, or concentrated ammonia-methanol solution.

The solvent used is not particularly limited as long as it does not inhibit the reaction, and is not particularly limited as long as it does not inhibit the reaction. Water or methanol, ethanol, n
A mixed solvent of water and an organic solvent such as alcohols such as propanol or ethers such as tetrahydrofuran and dioxane is preferred.

The reaction temperature and the reaction time vary depending on the starting material, the solvent and the reagent to be used and are not particularly limited.
For 10 to 10 hours.

When R ⁵ is a silyl group, it is treated with a compound which generates a fluorine anion, such as tetrabutylammonium fluoride, hydrofluoric acid, hydrofluoric acid-pyridine and potassium fluoride. Can also be removed.

When R ⁵ is an aralkyl group, it is usually reduced by contact with a reducing agent in a solvent (preferably catalytic reduction at room temperature under a catalyst) or with a base in a solvent. It is removed by processing.

The solvent used in the removal by catalytic reduction is not particularly limited as long as it does not participate in the present reaction, but alcohols such as methanol, ethanol and isopropanol, and diethyl ether Ethers such as ter, tetrahydrofuran, dioxane, toluene,
Aromatic hydrocarbons such as benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and propyl acetate, formamide, dimethylformamide, dimethylacetamide, N
Preferred are amides such as -methyl-2-pyrrolidone and hexamethyl phosphorotriamide, fatty acids such as formic acid and acetic acid, water, and mixed solvents thereof, and more preferably alcohols and fatty acids. , A mixed solvent of alcohols and ethers, a mixed solvent of alcohols and water, or a mixed solvent of fatty acids and water.

The catalyst to be used is not particularly limited as long as it is usually used in a catalytic reduction reaction, but is preferably palladium carbon, palladium black, Raney nickel, platinum oxide, platinum black, Rhodium-aluminum oxide,
Triphenylphosphine-rhodium chloride, palladium-
Barium sulfate is used.

Although the pressure is not particularly limited, it is usually 1000.
The reaction is performed at hPa to 10,000 hPa.

The reaction temperature and the reaction time vary depending on the starting material, the solvent, the type of the catalyst, and the like.
0 ° C. (preferably 20 ° C. to 70 ° C.), 5 minutes to 48 hours (preferably 1 hour to 24 hours).

The solvent used in the removal with a base is not particularly limited as long as it is used in a usual hydrolysis reaction. Water; alcohols such as methanol, ethanol and n-propanol; tetrahydrofuran; dioxane Preferred is an organic solvent such as ethers or a mixed solvent of water and the above-mentioned organic solvent.

The base used is not particularly limited as long as it does not affect the other parts of the compound, but is preferably a metal alkoxide such as sodium methoxide; sodium carbonate, potassium carbonate, or the like. Alkali metal carbonates such as lithium carbonate; alkali metal hydroxides such as sodium hydroxide and barium hydroxide or ammonia water, and ammonia such as concentrated ammonia-methanol are used.

The reaction temperature and reaction time vary depending on the starting material, solvent, base used and the like, and are not particularly limited.
In order to suppress a side reaction, the temperature is usually 1 to 0 to 150 ° C.
For 10 to 10 hours.

Compounds used as starting materials in the above methods A to C, ie, compounds (II), (III),
(V), (VI), (VIII) and (IX) are compounds known per se or compounds easily obtained from known compounds according to known methods.

For example, in the production of compound (II), EP776893A1 can be referred to, and in the production of compound (III), EP776893A1 can be referred to.
And U.S. Pat. No. 5,578,593,
For the production of compounds (V), (VI), (VIII) and (XI), reference may be made to WO 98/27086.

After completion of each of the above reactions, the target compound is collected from the reaction mixture according to a conventional method.

For example, the reaction mixture is appropriately neutralized, and if there is any insoluble matter, it is removed by filtration, an immiscible organic solvent such as water and ethyl acetate is added, and the mixture is washed with water and the like. An organic layer containing the compound is separated, dried over anhydrous magnesium sulfate or the like, and then obtained by distilling off the solvent.

If necessary, the obtained target compound can be obtained by a conventional method.
For example, recrystallization, reprecipitation, or a method commonly used for separation and purification of organic compounds, for example, adsorption column chromatography using a carrier such as silica gel, alumina, and magnesium-silica gel type florisil; Sephadex LH-20 (manufactured by Pharmacia), Amberlite XAD-11 (manufactured by Rohm and Haas),
A method using a synthetic adsorbent such as distribution column chromatography using a carrier such as Diaion HP-20 (manufactured by Mitsubishi Chemical Corporation), a method using ion exchange chromatography,
Alternatively, separation and purification can be performed by appropriately combining a normal phase / reverse phase column chromatography method with silica gel or alkylated silica gel (preferably high performance liquid chromatography) and eluting with a suitable eluent. .

The compound having the general formula (I) of the present invention or a pharmaceutically acceptable salt, ester or other derivative thereof has potent NK ₁ receptor, NK ₂ receptor and NK ₃ receptor. Since it has an excellent antagonism, has good oral absorbability, and has excellent pharmacokinetics, it can be used as a medicine. Diseases to which such medicines can be applied include, for example, diseases of the central nervous system including anxiety, depression, psychiatric disorders and schizophrenia; dementia in AIDS, senile dementia of the Alzheimer type, Alzheimer's disease, Down's syndrome, demyelination Neurodegenerative diseases including sexual diseases, amyotrophic lateral sclerosis, neuropathy, peripheral neuropathy, and neuralgia; respiratory diseases including chronic obstructive pulmonary disease, bronchitis, pneumonia, bronchoconstriction, asthma, cough; Inflammatory diseases including inflammatory bowel disease (IBD), psoriasis, fibrositis, osteoarthritis, degenerative arthritis, and rheumatoid arthritis; allergic diseases including eczema; and rhinitis; hypersensitivity diseases including sensitivity to vines Ophthalmologic diseases including conjunctivitis, spring conjunctivitis, spring catarrh, destruction of blood-aqueous humor barrier, increased intraocular pressure, miosis associated with various inflammatory eye diseases; contact dermatitis, atopic skin Skin diseases including urticaria, hives and other eczema-like dermatitis; dementia including alcoholism; somatic diseases due to stress; reflex sympathetic dystrophy including shoulder-hand syndrome; mood swings; transplant rejection Diseases associated with unwanted immune response and immune enhancement or immune suppression, including systemic lupus erythematosus; diseases due to abnormalities in the nerves regulating the internal organs, gastrointestinal tract including colitis, ulcerative colitis, Crohn's disease Diseases; X-ray irradiation and side effects associated with chemotherapeutic agents, toxic substances, toxins, pregnancy, vestibular disorders, postoperative illness, gastrointestinal obstruction, gastrointestinal motility, visceral pain, migraine, increased intracranial pressure, decreased intracranial pressure, or administration of various drugs Vomiting, including vomiting induced by bladder; cystitis, bladder dysfunction including urinary incontinence; collagen disease, scleroderma, eosinophilia due to fluke infection; including angina, migraine, and Raynaud's disease Vasodilation, or Abnormality due to the disease of the blood flow by condensation; migraine, pain pain nociceptive including headache, toothache; can be exemplified sleep apnea syndrome. In particular, the novel medicament of the present invention can be used as a prophylactic or therapeutic agent for the chronic obstructive pulmonary disease, asthma and / or bronchitis, rhinitis, allergy, urinary incontinence and ulcerative colitis as described in the above general formula (I) )), For example, tablets, capsules, granules,
Oral administration by powder or syrup or the like, or parenteral administration by injection or suppository or the like can be mentioned. These preparations include excipients (eg, lactose, sucrose, glucose,
Sugar derivatives such as mannitol and sorbit; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose, low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium Cellulose derivatives such as sodium internally-crosslinked carboxymethylcellulose; gum arabic; dextran; organic excipients such as pullulan: and silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, magnesium metasilicate aluminate; Inorganic excipients such as phosphates such as calcium; carbonates such as calcium carbonate; sulfates such as calcium sulfate can be exemplified. ), Lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as veegum, gay wax; boric acid; adipic acid; Sodium sulfate; DL leucine; fatty acid sodium salt; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as anhydrous silicic acid and silicic acid hydrate; Derivatives, etc.), binders (for example, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), disintegrants (for example, the same as the above-mentioned excipients) Compound and croscarmellose sodium, carboxymethyl starch sodium And chemically modified starch celluloses such as cross-linked polyvinylpyrrolidone), stabilizers (paraoxybenzoic acid esters such as methylparaben and propylparaben; chlorobutanol, benzyl alcohol, phenylethyl alcohol and the like) Alcohols; benzalkonium chloride; phenols such as phenol and cresol; thimerosal; dehydroacetic acid; and sorbic acid), flavoring agents (eg, commonly used sweeteners, sourness). , Fragrance, etc.), and a known method using additives such as a diluent.

The amount used depends on the condition, age, administration method and the like. For example, in the case of oral administration,
As a lower limit, 0.005 mg / kg body weight (preferably, 0.
01 mg / kg body weight), as an upper limit, 100 mg / kg body weight (preferably, 50 mg / kg body weight), and in the case of intravenous administration, a lower limit is 0.0005 mg / kg body weight (preferably, 0 mg / kg body weight). 0.001 mg / kg body weight).
100 mg / kg body weight (preferably 50 mg / kg body weight)
It is desirable to administer once or several times a day depending on the symptoms.

Hereinafter, the present invention will be described more specifically with reference to Examples, Preparation Examples, and Test Examples, but the present invention is not limited thereto.

[0140]

Example 1 1- {2-[(2R)-(3,4-dic)
Lorophenyl) -4- (2-methoxy-5- (tetrazo
1-yl) benzoyl) morpholin-2-yl]
Ethyl dispiro [benzo [c] thiophene-1 (3
H), 4'-Piperidine]-(2S) -oxide (Exemplified Compound No. 311) (1) 2- [4- (t-butoxycarbonyl)-(2
R)-(3,4-Dichlorophenyl) morpholine-2-
6.00 g (21.7 mmol) of yl] ethanol 2-[(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethanol are dissolved in 100 ml of methylene chloride and 4.54 ml of triethylamine under ice-cooling. (32.6 mmol) and 7.11 g of di-t-butyl dicarbonate (3
(2.6 mmol) and stirred at room temperature for 6 hours. The reaction mixture was washed with ice-cooled 10% hydrochloric acid and then with saturated saline, and then dried over anhydrous magnesium sulfate. After evaporating the solvent under reduced pressure, the residue was subjected to silica gel column chromatography (eluent: n-hexane: ethyl acetate = 2: 1 → 1: 5).
And purified the title compound as white amorphos 7.1.
6 g was obtained (yield: 86%).

Infrared absorption spectrum νmax cm ^-1 (CHC
l ₃ ): 2980, 1688, 1460, 1430, 1368, 1285, 1168. Mass spectrum FAB (m / z): 376 ([M + H] ⁺ ). (2) 2- [4- (t-butoxycarbonyl)-(2
R)-(3,4-Dichlorophenyl) morpholine-2-
Yl] ethanol 7.07 g of 2- [4- (t-butoxycarbonyl)-(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethanol obtained with methanesulfonate (1) (18. 8 mmol) was dissolved in 100 ml of methylene chloride, and under ice-cooling, 3.93 ml (28.2 mmol) of triethylamine and 2.18 ml (21.8 ml) of methanesulfonyl chloride were added.
8.2 mmol) and stirred for 1 hour. The reaction mixture was washed with ice-cooled 10% hydrochloric acid and then with saturated saline, and then dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (developing solvent; n).
-Hexane: ethyl acetate = 2: 1 → 1: 3),
7.96 g of the title compound was obtained as white amorphos (yield: 93%).

Infrared absorption spectrum νmax cm ^-1 (thin film method): 2976, 1694, 1428, 1365, 1176, 1138, 1094. Mass spectrum FAB (m / z): 454 ([M + H] ⁺ ). (3) 1- {2- [4- (t-butoxycarbonyl)
-(2R)-(3,4-dichlorophenyl) morpholine
-2-yl] ethyl @ spiro [benzo [c] thiophene
-1 (3H), 4'-piperidine]-(2S) -oxy
De obtained in (2) 2- [4- (t- butoxycarbonyl) - (2R) - (3,4- dichlorophenyl) morpholin-2-yl] ethanol methanesulfonate
4.27 g (9.40 mmol), spiro [benzo [c] thiophene-1 (3H), 4'-piperidine]-
2.66 g (10.3 mmol) of (2S) -oxide hydrochloride, 2.37 g (28.2 mmol) of sodium hydrogen carbonate and 2.34 g (14.1 mmol) of potassium iodide are added to 50 ml of anhydrous dimethylformamide. The suspension was stirred at 80 ° C. for 8 hours under a nitrogen atmosphere. The reaction mixture was diluted with 150 ml of ethyl acetate, washed with saturated saline, and then the organic layer was dried over anhydrous magnesium sulfate. After the solvent was distilled off under reduced pressure, the residue was subjected to silica gel column chromatography (elution solvent: methylene chloride: methanol = 20: 1).
→ 10: 1) to give 7.96 g of the title compound as white amorphos (yield: 93%).

Mass spectrum FAB (m / z): 579 ([M + H] ⁺ ). (4) 1- {2-[(2R)-(3,4-dichlorofuran)
Enyl) morpholin-2-yl] ethyl} spiro [ben
Zo [c] thiophene-1 (3H), 4'-piperidine]
1- {2- [4- (t-butoxycarbonyl)-(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethyl} spiro [benzo obtained with-(2S) -oxide (3) [C] thiophene-1 (3H), 4'-piperidine]-(2S)
1.70 g (2.90 mmol) of the oxide are dissolved in 17 ml of dichloromethane and 8.0 m of trifluoroacetic acid are dissolved.
1 was added. After stirring at room temperature for 2 hours, saturated aqueous sodium hydrogen carbonate was added to make the mixture alkaline, and dichloromethane was added.
Extracted times. After drying over sodium sulfate, the solvent was distilled off under reduced pressure to obtain 1.20 g of the title compound as white crystals (yield: 94%).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 1.57-2.45 (10H, m), 2.78-3.06 (6H, m), 3.29 (1H,
d, J = 12.9Hz), 3.62-3.77 (2H, m), 4.01 (1H, d, J = 12.
9Hz), 4.33 (1H, d, J = 6.7Hz), 7.22-7.53 (7H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3691, 2956,
1672, 1471, 1033. Mass spectrum FAB (m / z): 479 ((M + H) ⁺ ). (5) 1- {2-[(2R)-(3,4-dichlorofu)
Enyl) -4- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) morpholin-2-yl] ethy
Ruspiro [benzo [c] thiophene-1 (3H),
1- {2-[(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethyl} spiro [benzo [c] thiophene obtained with 4'-piperidine]-(2S) -oxide (4) -1 (3H), 4'-piperidine]-(2S) -oxide 47.9 mg (0.1
0 mmol) and 2-methoxy-5- (tetrazole-
24.2 mg (0.11 mmol) of 1-yl) benzoic acid was dissolved in 1.0 ml of tetrahydrofuran, and 0.030 ml of diethyl cyanophosphonate (0.1 ml) was dissolved.
20 mmol) and 0.027 ml of triethylamine
(0.20 mmol) was added and the mixture was stirred at room temperature for 15 hours.
Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the residue was separated by preparative thin-layer chromatography (developing solvent; methylene chloride: methanol = 1).
0: 1) to give 46.4 mg of the title compound as white amorphos (yield: 68%).

[Α] _D ²⁵ +12.8 (c = 0.06, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.86-2.52 (8H, m), 2.72-5.18 (15H, m), 6.94-7.91
(10H, m), 8.86-8.94 (1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3453, 3073,
2924, 1734, 1638, 1508, 1473, 1259, 1091, 1047. Mass spectrum FAB (m / z): 681 ([M + H] ⁺ ) Elemental analysis; (C ₃₃ H ₃₄ Cl ₂ N ₆ O ₄ S %) Calculated: C: 58.15, H: 5.03, N: 12.33, S: 4.70,
Cl: 10.40 Observed value: C: 57.26, H: 5.32, N: 11.36, S: 4.09,
Cl: 9.02.

[0146]

Example 2 1- {2-[(2R)-(3,4-dic)
Lorophenyl) -4- (2-methoxy-5- (tetrazo
1-yl) benzoyl) morpholin-2-yl]
Ethyl dispiro [((2S) -hydroxy) indane-
1,4′-piperidine] (Exemplary Compound No. 308) (1) 1- {2- [4- (t-butoxycarbonyl)
-(2R)-(3,4-dichlorophenyl) morpholine
-2-yl] ethyl} spiro [((2S) -hydroxy
B) Indane-1,4'-piperidine] 2- [4- (t-butoxycarbonyl)-(2R)-
(3,4-dichlorophenyl) morpholin-2-yl]
3.50 g of ethanol methanesulfonate (7.7 g)
0 mmol) and spiro [((2S) -hydroxy) indane-1,4-piperidine] hydrochloride 1.93 g
(8.48 mmol) was used to carry out a reaction in the same manner as in "Example 1- (3)" to obtain 3.03 g of the title compound as white amorphos (yield: 70%).

Infrared absorption spectrum νmax cm ^-1 (KBr):
3445, 2930, 1693, 1427, 1169. Mass spectrum FAB (m / z): 561 ([M + H] ⁺ ). (2) 1- {2-[(2R)-(3,4-dichlorofuran)
Enyl) morpholin-2-yl] ethyl @ spiro
[((2S) -hydroxy) indane-1,4′-pipe
Lysine] 1- {2- [4- (t-butoxycarbonyl)-(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethyl} spiro [((2S)-obtained in (1) Hydroxy) indane-1,4'-piperidine] 2.5
Using 0 g (4.45 mmol), “Example 1-
(4) "to give 1.95 g of the title compound as white crystals (yield: 95%).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 1.57-2.42 (11H, m), 2.76-3.01 (7H, m),
3.22 (1H, d, J = 12.8Hz), 3.27 (1H, dd, J = 5.7, 16.5H
z), 3.63-3.78 (2H, m), 4.41 (1H, dd, J = 3.0, 5.7Hz),
7.17-7.24 (5H, m), 7.46 (1H, d, J = 8.6Hz), 7.52 (1
H, d, J = 1.8Hz). Infrared absorption spectrum νmax cm ^-1 (KBr): 3614, 2953,
1672, 1472, 1138. Mass spectrum FAB (m / z): 461 ([M + H] ⁺ ). (3) 1- {2-[(2R)-(3,4-dichlorofu)
Enyl) -4- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) morpholin-2-yl] ethy
Ruspiro [((2S) -hydroxy) indane-1,
4′-piperidine] 1- {2-[(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethyl} spiro [((2S) -hydroxy) indane-1, obtained in (2), 4'-piperidine] 46.1 mg (0.10 mmol) and 2
The reaction was carried out in the same manner as in "Example 1- (5)" using 24.2 mg (0.11 mmol) of -methoxy-5- (tetrazol-1-yl) benzoic acid to give the title compound as a white amorphous compound. 0.8 mg (yield: 57)
%).

[Α] _D ²⁵ +26.2 (c = 0.75, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.37-2.41 (10H, m), 2.57-4.03 (12H, m), 4.30-4.52
(2H, m), 4.96 (1H, br.s), 6.96-7.92 (10H, m), 8.86-
9.08 (1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3435, 2925,
1733, 1634, 1508, 1475, 1440, 1376, 1259, 1091, 10
51. Mass spectrum FAB (m / z): 663 ([M + H] ⁺ ) Elemental analysis; (% as C ₃₄ H ₃₆ Cl ₂ N ₆ O ₄ + H ₂ O) Calculated: C: 59.91, H : 5.62, N: 12.33, Cl: 10.40 Found: C: 60.05, H: 5.69, N: 11.26, Cl: 9.79.

[0150]

Example 3 1- {2-[(3R)-(3,4-dic)
Lorophenyl) -1- (2-methoxy-5- (tetrazo)
1-yl) benzoyl) pyrrolidin-3-yl]
Ethyl dispiro [benzo [c] thiophene-1 (3
H), 4'-Piperidine]-(2S) -oxide (Exemplary Compound No. 7) (1) 2- [1- (t-butoxycarbonyl)-(3
S)-(3,4-Dichlorophenyl) pyrrolidine-3-
[Il] ethanol in 100 ml of 1 N aqueous sodium hydroxide solution,
[(3S)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethanol (2R, 3R) -di- (4-
7.54 g (11.1 mmol) of methoxy) benzoyl tartrate, 3.63 g of di-tert-butyl dicarbonate
(16.6 mmol) was added under ice-cooling, followed by stirring at room temperature for 2 hours, and the reaction solution was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure.
The residue was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3: 1 to 1: 2) to give the title compound as a white amorphous 2.43.
g was obtained (yield: 61%).

[Α] _D ²⁴ +54.3 (c = 1.32, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.15-1.25 (1H, m), 1.46 and 1.49 (total 9H, s), 1.86-1.
97 (1H, m), 2.20-2.26 (3H, m), 3.20-3.75 (6H, m),
7.08 (1H, dd, J = 2.4, 8.4Hz), 7.32 (1H, d, J = 2.8Hz),
7.40 (1H, d, J = 8.4Hz). Infrared absorption spectrum νmax cm ^-1 (thin film method): 3426, 297
7, 2934, 2885, 1677, 1476, 1415, 1174, 1142, 1051,
1029. Mass spectrum FAB (m / z): 360 ([M + H] ⁺ ). (2) 2- [1- (t-butoxycarbonyl)-(3
S)-(3,4-Dichlorophenyl) pyrrolidine-3-
2- [1- (t-butoxycarbonyl)-(3S)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethanol obtained with methanesulfonate (1) 2.96 g (8. 19 mmol) was dissolved in 40 ml of methylene chloride, and 1.70 ml (12.2 mmol) of triethylamine and 0.82 ml (10.6 mmol) of methanesulfonyl chloride were added under ice cooling. After stirring under ice-cooling for 2 hours under a nitrogen atmosphere, water was added to the reaction solution, and the aqueous layer was extracted with methylene chloride. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3: 1 to 1:
Purification according to 1) gave 3.15 g of the title compound as white amorphos (yield: 88%).

[Α] _D ²⁴ +39.0 (c = 1.02, methanol).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 1.46 and 1.50 (total 9H, s), 2.04-2.30 (4H,
m), 2.91 and 2.92 (3H, s), 3.26-3.52 (2H, m), 3.5
2-3.80 (2H, m), 3.85-4.10 (2H, m), 7.08 (1H, dd, J =
2.4, 8.4Hz), 7.30-7.35 (1H, m), 7.44 (1H, d, J = 8.4H
z), infrared absorption spectrum νmax cm ^-1 (KBr): 2977, 1690,
1476, 1406, 1358, 1176, 1143. Mass spectrum FAB (m / z): 438 ([M + H] ⁺ ). (3) 1- {2- [1- (t-butoxycarbonyl)
-(3R)-(3,4-dichlorophenyl) pyrrolidine
-3-yl] ethyl} spiro [benzo [c] thiophene
-1 (3H), 4'-piperidine]-(2S) -oxy
De (2) 2 obtained in [1-(t-butoxycarbonyl) - (3S) - (3,4-dichlorophenyl) pyrrolidin-3-yl] ethanol methanesulfonate 4
75 mg (1.08 mmol), spiro [benzo [c]
Thiophene-1 (3H), 4'-piperidine]-(2
308 mg (1.19 mmol) of S) -oxide hydrochloride, 273 mg (3.25 mmol) of sodium hydrogen carbonate and 273 mg (1.64 mmol) of potassium iodide were suspended in 7.0 ml of dimethylacetamide, and the suspension was added under a nitrogen atmosphere. Stirred at C for 8 hours. The reaction solution was poured into water, extracted with ethyl acetate, and the organic layer was washed with saturated saline. After the organic layer was dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure. The residue was subjected to silica gel chromatography (elution solvent: hexane / ethyl acetate = 1: 1 to ethyl acetate /
Purification by methanol (20: 1) gave 136 mg of the title compound as white amorphos (yield: 22).
%).

[Α] _D ²⁵ +32.3 (c = 0.48, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.47 and 1.57 (total 9H, s), 1.45-1.65 (2H, m), 1.80-2.
45 (10H, m), 2.70-2.95 (2H, m), 3.25-3.68 (4H, m),
3.97 (1H, d, J = 16.8Hz), 4.31 (1H, d, J = 16.8Hz), 7.04
-7.10 (1H, m), 7.25-7.37 (5H, m), 7.39-7.43 (1H,
m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3446, 2929,
1694, 1474, 1402, 1256, 1170, 1142. Mass spectrum FAB (m / z): 563 ([M + H] ⁺ ). (4) 1- {2-[(3S)-(3,4-dichlorofuran)
Enyl) pyrrolidin-3-yl] ethyl} spiro [ben
Zo [c] thiophene-1 (3H), 4'-piperidine]
1- {2- [1- (t-Butoxycarbonyl)-(3R)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethyl} obtained with-(2S) -oxide dihydrochloride (3). Spiro [benzo [c] thiophene-1 (3H), 4'-piperidine]-(2S)
120 mg (0.21 mmol) of -oxide was dissolved in 3.0 ml of ethanol, and 4N hydrochloric acid in dioxane.
20 ml (4.80 mmol) was added under ice-cooling, followed by stirring at room temperature for 24 hours. The reaction solution was distilled off under reduced pressure to obtain 110 mg of the title compound as white crystals (yield: 96).
%). (5) 1- {2-[(3R)-(3,4-dichlorofuran)
Enyl) -1- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) pyrrolidin-3-yl] ethyl
Ruspiro [benzo [c] thiophene-1 (3H),
1- {2-[(3S)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethyl} spiro [benzo [c] thiophene obtained with 4'-piperidine]-(2S) -oxide (4) -1 (3H), 4'-piperidine]-(2S) -oxide dihydrochloride 53.6m
g (0.10 mmol) and 2-methoxy-5- (tetrazol-1-yl) benzoic acid 24.2 mg (0.1
(1 mmol), and the reaction was carried out in the same manner as in "Example 1- (5)".
3.3 mg were obtained (yield: 65%).

[Α] _D ²⁵ +4.69 (c = 0.15, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.79-2.48 (10H, m), 2.68-3.15 (3H, m), 3.19-3.52
(2H, m), 3.57-4.38 (8H, m), 7.04-7.84 (10H, m), 8.8
6-8.94 (1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3448, 3072,
2946, 1733, 1635, 1508, 1472, 1456, 1441, 1257, 10
47, 1029. Mass spectrum FAB (m / z): 665 ([M + H] ⁺ ) Elemental analysis; (% as C ₃₃ H ₃₄ Cl ₂ N ₆ O ₃ S + H ₂ O) Calculated: C: 57.98, H: 5.31, N: 12.29, S: 4.69,
Cl: 10.37 Found: C: 58.62, H: 5.48, N: 11.52, S: 4.29,
Cl: 9.98.

[0156]

Example 4 1- {2-[(3R)-(3,4-dic)
Lorophenyl) -1- (2-methoxy-5- (tetrazo)
1-yl) benzoyl) pyrrolidin-3-yl]
Ethyl dispiro [((2S) -hydroxy) indane-
1,4'-piperidine] (Exemplary Compound No. 4) (1) 1- {2- [1- (t-butoxycarbonyl)]
-(3R)-(3,4-dichlorophenyl) pyrrolidine
-3-yl] ethyl} spiro ((2S) -hydroxy)
Indane-1,4'-piperidine 2- [1- (t-butoxycarbonyl)-(3S)-
(3,4-dichlorophenyl) pyrrolidin-3-yl]
469 mg of ethanol methanesulfonate (1.
07 mmol), 283 mg of spiro ((2S) -hydroxy) indane-1,4′-piperidine hydrochloride (1.
Using 18 mmol), the reaction was carried out in the same manner as in "Example 3- (3)" to obtain 181 mg of the title compound as white amorphos (yield: 31%).

[Α] _D ²⁵ +52.0 (c = 0.46, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.46 and 1.50 (9H, s in total), 1.55-1.75 (3H, m), 1.80-2.3
5 (10H, m), 2.55-2.85 (3H, m), 3.20-3.75 (5H, m),
4.38-4.45 (1H, m), 7.04-7.10 (1H, m), 7.13-7.32 (5
H, m), 7.40 (1H, d, J = 8.8Hz). Infrared absorption spectrum νmax cm ^-1 (KBr): 3432, 2929,
1695, 1476, 1405, 1256, 1170, 1143. Mass spectrum FAB (m / z): 545 ([M + H] ⁺ ). (2) 1- {2-[(3S)-(3,4-dichlorofuran)
Enyl) pyrrolidin-3-yl] ethyl} spiro ((2
S) -Hydroxy) indane-1,4'-piperidine
1- {2- [1- (t-Butoxycarbonyl)-(3R)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethyl} spiro ((2S)-obtained by dihydrochloride (1) 166 mg of hydroxy) indane-1,4'-piperidine
(Example 3- (4)) using (0.32 mmol)
The reaction was carried out in the same manner as in to give 156 mg of the title compound as white crystals (yield: 99%). (3) 1- {2-[(3R)-(3,4-dichlorofuran)
Enyl) -1- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) pyrrolidin-3-yl] ethyl
Ruspiro [((2S) -hydroxy) indane-1,
4′-piperidine] 1- {2-[(3S)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethyl} spiro [((2S) -hydroxy) indane-1, obtained in (2), 4′-piperidine] dihydrochloride 51.8 mg (0.10 mmol) and 2-methoxy-5- (tetrazol-1-yl) benzoic acid 24.2 mg (0.11 mmol) were used to prepare “Example 1- (5) "to give 46.6 mg of the title compound as white amorphous (yield: 72%).

[Α] _D ²⁴ +30.7 (c = 0.39, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.85-2.38 (12H, m), 2.53-3.88 (4H, m), 3.18-4.03
(8H, m), 4.31-4.45 (1H, m), 7.00-7.81 (10H, m), 8.9
5 (1H, br.s). Infrared absorption spectrum νmax cm ^-1 (KBr): 3420, 2936,
1733, 1630, 1509, 1474, 1459, 1441, 1257, 1092, 10
27, 820. Mass spectrum FAB (m / z): 647 ([M + H] ⁺ ) Elemental analysis; (% as C ₃₄ H ₃₆ Cl ₂ N ₆ O ₃ + 3 / 2H ₂ O) Calculated: C : 60.53, H: 5.87, N: 12.46, Cl: 10.51 Found: C: 62.05, H: 5.87, N: 11.86, Cl: 10.5
2.

[0159]

Example 5 1- {2-[(2R)-(3,4-dic)
Lorophenyl) -4- (2-methoxy-5- (tetrazo
1-yl) benzoyl) morpholin-2-yl]
Ethyl {-3-oxo-3,4-dihydrospiro [iso
Quinoline-1 (2H), 4'-piperidine] (Exemplary Compound No. 309) (1) 1- {2- [4- (t-butoxycarbonyl)]
-(2R)-(3,4-dichlorophenyl) morpholine
-2-yl] ethyl} -3-oxo-3,4-dihydro
Spiro [isoquinoline-1 (2H), 4'-piperidi
Down] 2- [4- (t- butoxycarbonyl) - (2R) -
(3,4-dichlorophenyl) morpholin-2-yl]
909 mg of ethanol methanesulfonate (2.
00 mmol) and -3-oxo-3,4-dihydrospiro [isoquinoline-1 (2H), 4'-piperidine]
Example 1 using 476 mg (2.20 mmol)
-(3) "to give 483 mg of the title compound as white amorphos (yield: 42%).

Infrared absorption spectrum νmax cm ^-1 (KBr):
1694, 1669, 1427, 1169, 1135, 1092.

Mass spectrum FAB (m / z): 574 ([M + H] ⁺ ). (2) 1- {2-[(2R)-(3,4-dichlorofuran)
Enyl) morpholin-2-yl] ethyl} -3-oxo
-3,4-dihydrospiro [isoquinoline-1 (2
H), 4'-Piperidine] 1- {2- [4- (t-butoxycarbonyl)-(2R)-(3,4-dichlorophenyl) morpholin-2-yl] obtained with dihydrochloride (1). Ethyl} -3-oxo-3,4-
483 mg (0.84 mmol) of dihydrospiro [isoquinoline-1 (2H), 4′-piperidine] is dissolved in 5.0 ml of ethanol, 1.0 ml of a 4N hydrochloric acid in dioxane solution is added at 0 ° C., and the solution is added at room temperature. Stirred for hours.
After evaporating the solvent under reduced pressure, the residue was washed with hexane to obtain 483 mg of the title compound as white crystals (yield: 95%).

¹ H-nuclear magnetic resonance spectrum (400 MHz, DMS
O) δ ppm: 1.82-1.99 (2H, m), 2.18-4.07 (18H, m),
7.16-8.12 (7H, m), 9.08-9.42 (2H, m), 9.97-10.8 (1
H, m), 11.34 (1H, br.s). Mass spectrum FAB (m / z): 474 ([M +
H] ⁺ ). (3) 1- {2-[(2R)-(3,4-dichlorofu)
Enyl) -4- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) morpholin-2-yl] ethy
Ru-3-oxo-3,4-dihydrospiro [isoquino
Phosphorus-1 (2H), 4′-piperidine] 1- {2-[(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethyl} -3 obtained in (2).
-Oxo-3,4-dihydrospiro [isoquinoline-1
(2H), 4'-piperidine] dihydrochloride 54.7 mg
(0.10 mmol) and 2-methoxy-5- (tetrazol-1-yl) benzoic acid 24.2 mg (0.11 mmol)
The reaction was carried out in the same manner as in "Example 1- (5)" using
0.6 mg was obtained (yield: 60%).

[Α] _D ²⁴ -0.385 (c = 0.27, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.68-1.82 (2H, m), 1.91-2.39 (8H, m), 2.67-2.94 (2
H, m), 3.10-4.01 (10H, m), 4.46-5.12 (1H, m), 6.29
(1H, br.s), 6.92-7.78 (10H, m), 8.85-8.96 (1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3084, 2926,
1668, 1642, 1508, 1473, 1440, 1382, 1259, 1091, 75
4. Mass spectrum FAB (m / z): 676 ([M + H] ⁺ ) Elemental analysis; (% as C ₃₄ H ₃₅ Cl ₂ N ₇ O ₄ + 3 / 2H ₂ O) Calculated: C: 58.04 , H: 5.44, N: 13.93, Cl: 10.51 Found: C: 58.42, H: 5.49, N: 13.55, Cl: 9.03.

[0164]

Embodiment 61- {2-[(2R)-(3,4-dic)
Lorophenyl) -4- (2-methoxy-5- (tetrazo
1-yl) benzoyl) morpholin-2-yl]
Ethyl dispiro [1,4-dihydrobenzo [d] [1.
3] Oxazin-2-one-1,4'-piperidine]
(Exemplary Compound No. 310) (1)1- {2- [4- (t-butoxycarbonyl)
-(2R)-(3,4-dichlorophenyl) morpholine
-2-yl] ethyl} spiro [1,4-dihydrobenzo
[D] [1.3] Oxazin-2-one-1,4'-pi
Peridine] 2- [4- (t-butoxycarbonyl)-(2R)-
(3,4-dichlorophenyl) morpholin-2-yl]
590 mg of ethanol methanesulfonate (1.
30 mmol) and spiro [1,4-dihydrobenzo
[D] [1.3] Oxazin-2-one-1,4'-pi
Peridine] using 311 mg (1.43 mmol)
The reaction was carried out in the same manner as in "Example 1- (3)" to give the title.
285 mg of the compound was obtained as white amorphos (yield:
38%).

Infrared absorption spectrum νmax cm ^-1 (KBr):
3258, 2972, 2929, 1721, 1699, 1428, 1244, 1169. Mass spectrum FAB (m / z): 576 ([M + H]) ⁺ ). (2) 1- {2-[(2R)-(3,4-dichlorophene)
Nyl) morpholin-2-yl] ethyl} spiro [1,4
-Dihydrobenzo [d] [1.3] oxazin-2-o
1- {2-[(2R)-(3,4-dichlorophenyl) -4- (t-butoxycarbonyl) morpholin-2-yl ] obtained with dihydrochloride (1) ] Ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,
4'-piperidine] 285 mg (0.49 mmol)
Was used to carry out the same reaction as in "Example 5- (2)" to obtain 252 mg of the title compound as white crystals (yield: 93%).

¹ H-nuclear magnetic resonance spectrum (400 MHz, DMS
O) δ ppm: 2.07-3.60 (16H, m), 3.78-3.91 (1H, m), 4.01-4.14
(1H, m), 6.89-7.34 (7H, m), 9.10-10.16 (2H, m), 10.
42 (1H, br.s), 11.38 (1H, br.s). Infrared absorption spectrum νmax cm ^-1 (KBr): 3419, 3262,
3127, 2956, 2928, 1724, 1637, 1599, 1506, 1472, 12
57,1091, 1049, 755. Mass spectrum FAB (m / z): 476 ([M +
H] ⁺ ). (3) 1- {2-[(2R)-(3,4-dichlorofu)
Enyl) -4- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) morpholin-2-yl] ethy
Ruspiro [1,4-dihydrobenzo [d] [1.3]
Oxazin-2-one-1,4'-piperidine] 1- {2-[(2R)-(3,4-dichlorophenyl) morpholin-2-yl] ethyl} spiro [1,4 obtained in (2). -Dihydrobenzo [d] [1.3] oxazin-2-one-1,4'-piperidine] dihydrochloride 5
4.9 mg (0.10 mmol) and 2-methoxy-5
-(Tetrazol-1-yl) benzoic acid 24.2 mg
(0.11 mmol), and the reaction was carried out in the same manner as in "Example 1- (5)" to obtain 42.1 mg of the title compound as white amorphous (yield: 62%).

[Α] _D ²⁴ -0.739 (c = 0.33, methanol) ¹ H-nuclear magnetic resonance spectrum (400 MHz, CDCl ₃ ) δ ppm:
1.91-2.17 (4H, m), 2.21-2.82 (6H, m), 3.13-4.04 (1
0H, m), 4.43-5.08 (1H, m), 6.74-7.78 (11H, m), 8.88
-8.97 (1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3419, 3262,
3127, 2956, 2928, 1724, 1637, 1599, 1506, 1472, 12
57, 1091, 1049, 755. Mass spectrum FAB (m / z): 678 ([M + H] ⁺ ) Elemental analysis; (% as C ₃₃ H ₃₃ Cl ₂ N ₇ O ₅ + 2H ₂ O) Calculated value : C: 55.47, H: 5.22, N: 12.72, Cl: 9.42 Found: C: 55.20, H: 5.22, N: 12.44, Cl: 9.23.

[0168]

Example 7 1- {2-[(3R)-(3,4-dic)
Lorophenyl) -1- (2-methoxy-5- (tetrazo)
1-yl) benzoyl) pyrrolidin-3-yl]
Ethyl {-3-oxo-3,4-dihydrospiro [iso
Quinoline-1 (2H), 4'-piperidine] (Exemplary Compound No. 5) (1) 1- {2- [1- (t-butoxycarbonyl)]
-(3R)-(3,4-dichlorophenyl) pyrrolidine
-3-yl] ethyl} -3-oxo-3,4-dihydro
Spiro [isoquinoline-1 (2H), 4'-piperidi
Down] 2- [1- (t- butoxycarbonyl) - (3S) -
(3,4-dichlorophenyl) pyrrolidin-3-yl]
964 mg of ethanol methanesulfonate (2.
20 mmol) and -3-oxo-3,4-dihydrospiro [isoquinoline-1 (2H), 4'-piperidine]
Using 523 mg (2.42 mmol) of "Example 3-
(3) "to give 246 mg of the title compound as white amorphous (yield: 20.0).
%). (2) 1- {2-[(3S)-(3,4-dichlorofu)
Enyl) pyrrolidin-3-yl] ethyl} -3-oxo
-3,4-dihydrospiro [isoquinoline-1 (2
H), 4'-Piperidine] 1- {2- [1- (t-butoxycarbonyl)-(3R)-(3,4-dichlorophenyl) pyrrolidin-3-yl] obtained with dihydrochloride (1). Ethyl} -3-oxo-3,4-
The reaction was carried out in the same manner as in "Example 3- (4)" using 220 mg (0.39 mmol) of dihydrospiro [isoquinoline-1 (2H), 4'-piperidine] to give 205 mg of the title compound as white crystals. (Yield: 98.
0%). (3) 1- {2-[(3R)-(3,4-dichlorofuran)
Enyl) -1- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) pyrrolidin-3-yl] ethyl
Ru-3-oxo-3,4-dihydrospiro [isoquino
Phosphorus-1 (2H), 4′-piperidine] 1- {2-[(3S)-(3,4-dichlorophenyl) pyrrolidin-3-yl] ethyl} -3 obtained in (2).
-Oxo-3,4-dihydrospiro [isoquinoline-1
(2H), 4'-piperidine] dihydrochloride 53.1 m
g (0.10 mmol) and 2-methoxy-5- (tetrazol-1-yl) benzoic acid 24.2 mg (0.1
(1 mmol), and the reaction was carried out in the same manner as in "Example 1- (5)".
9.6 mg were obtained (yield: 60%).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 1.50-2.35 (12H, m), 2.65-2.90 (2H, m),
3.20-4.20 (9H, m), 6.25-6.40 (1H, m), 7.00-7.80 (1
0H, m), 8.90-9.00 (1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3409, 3246,
3083, 2926, 1668, 1508, 1258. Mass spectrum FAB (m / z): 660 ([M + H] ⁺ ).

[0170]

Embodiment 81- {2-[(3R)-(3,4-dic)
Lorophenyl) -1- (2-methoxy-5- (tetrazo)
1-yl) benzoyl) pyrrolidin-3-yl]
Ethyl dispiro [1,4-dihydrobenzo [d] [1.
3] Oxazin-2-one-1,4'-piperidine]
(Exemplary Compound No. 6) (1)1- {2- [1- (t-butoxycarbonyl)
-(3R)-(3,4-dichlorophenyl) pyrrolidine
-3-yl] ethyl} spiro [1,4-dihydrobenzo
[D] [1.3] Oxazin-2-one-1,4'-pi
Peridine] 2- [1- (t-butoxycarbonyl)-(3S)-
(3,4-dichlorophenyl) pyrrolidin-3-yl]
911 mg of ethanol methanesulfonate (2.
08 mmol) and spiro [1,4-dihydrobenzo
[D] [1.3] Oxazin-2-one-1,4'-pi
Peridine] using 500 mg (2.29 mmol)
The title compound was converted to white in the same manner as in “Example 3- (3)”.
210 mg was obtained as amorphos (yield: 18.0).
%). (2)1- {2-[(3S)-(3,4-dichlorofu)
Enyl) pyrrolidin-3-yl] ethyl} spiro [1,
4-dihydrobenzo [d] [1,3] oxazine-2-
On-1,4'-piperidine] dihydrochloride 1- {2- [1- (t-butoxycal) obtained in (1)
Bonyl)-(3R)-(3,4-dichlorophenyl) pi
Loridin-3-yl] ethyl} spiro [1,4-dihydride
Lobenzo [d] [1.3] oxazin-2-one-1,
4'-piperidine] 200 mg (0.36 mmol)
And the reaction was carried out in the same manner as in "Example 3- (4)".
This gave 188 mg of the title compound as white crystals (yield
Rate: 99.0%). (3)1- {2-[(3R)-(3,4-dichloroph
Enyl) -1- (2-methoxy-5- (tetrazole-
1-yl) benzoyl) pyrrolidin-3-yl] ethyl
Ruspiro [1,4-dihydrobenzo [d] [1.3]
Oxazin-2-one-1,4'-piperidine] 1- {2-[(3S)-(3,4-dichlorophenyl)
Pyrrolidin-3-yl] ethyl} spiro [1,4-dihi
Drobenzo [d] [1.3] oxazin-2-one-
1,4'-piperidine] dihydrochloride 53.3 mg
(0.10 mmol) and 2-methoxy-5- (tetra
Zol-1-yl) benzoic acid 24.2 mg (0.11
In the same manner as in "Example 1- (5)"
To give the title compound as white amorphous
1.7 mg was obtained (yield: 63%).

¹ H-nuclear magnetic resonance spectrum (400 MHz, CDC
l ₃ ) δ ppm: 1.80-2.85 (14H, m), 3.20-4.10 (7H, m),
6.77-6.82 (1H, m), 7.00-7.95 (10H, m), 8.95-9.00
(1H, m). Infrared absorption spectrum νmax cm ^-1 (KBr): 3421, 3252,
3101, 2928, 1725, 1631, 1507, 1472, 1256. Mass spectrum FAB (m / z): 662 ([M + H] ⁺ ).

[0172]

Formulation Example: The compound of the present invention having the general formula (I),
A preparation containing the pharmacologically acceptable salt or derivative as an active ingredient can be produced, for example, by the following method.

[0173]

Formulation Example 1 Powder 5 g of the compound of Example 1, 895 g of lactose, and 100 g of corn starch are mixed with a blender.
A powder is obtained.

[0174]

Formulation Example 2 Granules 5 g of the compound of Example 2, 865 g of lactose and 100 g of low-substituted hydroxypropylcellulose are mixed, and then a 10% aqueous solution of hydroxypropylcellulose 30
Add 0 g and knead. This is granulated using an extrusion granulator and dried to obtain a granule.

[0175]

Formulation Example 3 Capsule 5g of the compound of Example 3, lactose 115g, corn starch 58g and magnesium stearate
After mixing 2 g using a V-type mixer, 180 mg is filled into No. 3 capsules to obtain capsules.

[0176]

Formulation Example 4 Tablets 5 g of the compound of Example 4, 90 g of lactose, 34 g of corn starch, 20 g of crystalline cellulose and 1 g of magnesium stearate are mixed in a blender and then tableted with a tablet machine to obtain tablets.

[0177]

[Test example]

[0178]

[Test Example 1] was prepared Somaku specimens from lung Preparation Male Hartley guinea pigs NK ₁ receptor binding test (a) Sohaimaku specimen. That is, under chloroform anesthesia, the blood was killed by exsanguination from the abdominal vena cava, and the pulmonary airway tissue was immediately removed.

The isolated lung was perfused with a buffer solution (50 mM Tris-HCl, pH 7.4), minced, and further in a buffer solution (buffer containing 120 mM sodium chloride and 5 mM potassium chloride) using a polytron. Homogenized.

From the homogenate, a nylon mesh (5
(0 μm), the tissue mass was removed by filtration and centrifuged (3
000 xg, 30 minutes, 4 ° C).

The pellet was washed with ice-cold buffer (10 mM E
The suspension was resuspended in DTA and a buffer containing 300 mM potassium chloride), allowed to stand at 4 ° C. for 60 minutes, and then centrifugally washed twice (30,000 × g, 15 minutes, 4 ° C.).

The crude membrane specimen was stored at -80 ° C until use. (B) Receptor binding test A test drug and [ ³ H] -substance P (final concentration 1 n
M) 250 μl (50 mM Tris-HCl, pH
7.4, 6 mM manganese chloride, 800 μg / ml BS
A, 8 μg / ml chymostatin, 8 μg / ml leupeptin, 80 μg / ml bacitracin, 20 μg / ml phosphoramidone), 250 μl of crude lung membrane specimen was added, and incubated at room temperature for 30 minutes.

After the reaction, the membrane components were collected on a GF / B glass fiber filter (Whatman) using an automatic filtration device (Brandel).

[0184] In order to suppress non-specific binding, the glass filter is made up of about 4% with a 0.1% polyethyleneimine solution.
It was used after time pretreatment.

[0185] The membrane component recovery filter was set to a pico flow of 4 m.
1 to a mini plastic vial containing a liquid scintillation counter (Beckman, LSC350).
Radioactivity was measured in 0). The 50% binding concentration (IC ₅₀ ) was determined based on the measured values in the test drug added group and the test drug non-added group.

[0186]

Test Example 2 NK ₂ Receptor Binding Test (a) Preparation of Coarse Ileum Membrane Specimens Coarse membrane specimens were prepared from the ileum of Hartley male guinea pigs. That is, under chloroform anesthesia, the blood was killed by exsanguination from the abdominal vena cava, and the ileum was immediately removed.

The isolated ileum was rubbed and peeled off the contents of the lumen, secretions, and epithelium using a slide glass, cut into small pieces in a buffer solution (50 mM Tris-HCl, pH 7.4), and further buffered. The solution was homogenized in a liquid (a buffer containing 120 mM sodium chloride and 5 mM potassium chloride) using a polytron.

From the homogenate, a nylon mesh (5
(0 μm), the tissue mass was removed by filtration and centrifuged (3
000 xg, 30 minutes, 4 ° C).

The pellet was washed with ice-cold buffer (10 mM E
The suspension was resuspended in DTA and a buffer containing 300 mM potassium chloride), allowed to stand at 4 ° C. for 60 minutes, and then centrifugally washed twice (30,000 × g, 15 minutes, 4 ° C.).

The crude membrane specimen was stored at -80 ° C until use. (B) Receptor binding test 250 μl (50 mM Tris-HCl, pH 7.4, 6 mM manganese chloride, 800 mM) of a mixture of the test drug and [ ³ H] -SR-48968 (Amersham, 1 nM final concentration)
μg / ml BSA, 8 μg / ml chymostatin, 8 μ
g / ml leupeptin, 80 μg / ml bacitracin,
20 μg / ml phosphoramidone) and crude ileal membrane sample solution 2
50 μl was added and incubated at room temperature for 30 minutes.

After the reaction, the membrane components were collected on a GF / B glass fiber filter (Whatman) using an automatic filter (Brandel).

[0192] In order to suppress non-specific binding, the glass filter is made up of about 4% with 0.1% polyethyleneimine solution.
It was used after time pretreatment.

[0193] The membrane component recovery filter was
1 to a mini plastic vial containing a liquid scintillation counter (Beckman, LSC350).
Radioactivity was measured in 0). The 50% binding concentration (IC ₅₀ ) was determined based on the measured values in the test drug added group and the test drug non-added group.

[0194]

[Test Example 3] Inhibition Test Healthy guinea pigs (body weight 400g longitudinal, Hartley male guinea pigs) vascular hyperpermeability is used, NK ₁ receptor agonist substan
The inhibitory effect of ce P (SP) on vascular hyperpermeability was examined using the amount of leaked dye as an index. Dye (Evans blue: 40 mg / kg, i.p.) was injected into the femoral vein of a guinea pig anesthetized with pentobarbital (30 mg / kg, ip).
v. ) Was administered and SP (1 μg / kg) was immediately injected intravenously to induce an increase in vascular permeability. Fifteen
A minute later, the guinea pig was killed under chloroform anesthesia, and the amount of the dye leaked to the main trachea was determined by the Harada method (J. Phar
m. Pharmacol. 23, 218 (1971)). The test drug was suspended in a 0.5% tragacanth suspension and SP
Was orally administered one hour prior to induction by

The inhibitory action was determined from the amount of dye leaked from the guinea pig to which the test drug was administered.

[0196]

[Test Example 4] Inhibition Test Healthy guinea pigs (body weight 500g longitudinal, Hartley male guinea pigs) of bronchoconstriction is used, NK ₂ receptor agonist neuroki
The inhibitory effect of a test drug on airway constriction by nin A (NKA) was determined by Konzet-Roessler (Naunyn-S
chmiedebergs Arch.Exp.Pathol.pharmakol.195, 71
(1940)), the airway pressure was used as an index.

That is, pentobarbital (30 mg / k
g, i. p. ), An airway cannula was attached to a guinea pig anesthetized with gallamine (galamine 20 mg).
/ Kg, i. v. ), And immediately after 8 ml / k
g, 60 breaths / min positive pressure breathing (Ugo-Basile, 7
025). The airway pressure during artificial respiration is amplified and sensed through a pressure transducer (Nippon Denko, TP-200T) attached to the side branch of the tracheal cannula.
AP-601G) and recorder (Nippon Denko, WT-
685 G). Atropine (1 mg / kg,
i. v. ) And propranolol (1 mg / kg, i.
v. ), And 5 minutes later, NKA was intravenously administered at 4 μg / kg to induce airway constriction, and then the airway pressure for 10 minutes was measured. The test drug was prepared in the same manner as in Test Example 3;
Oral administration was performed 1 hour before KA induction.

The inhibitory action was determined from the airway pressure area values of the test drug-administered group and the non-administered group.

[0199]

Test Example 5 NK ₃ Receptor Binding Test (a) Preparation of Coarse Membrane Specimens Coarse membrane specimens were prepared from Hartley male guinea pig brains.

That is, male Hartley guinea pigs were exsanguinated and killed from the abdominal vena cava under chloroform anesthesia, and a buffer solution (50 mM Tris-HCl, pH
After perfusion in 7.4), the brain was immediately removed. The excised brain was subjected to polytron (Kine) in buffer (buffer containing 120 mM sodium chloride and 5 mM potassium chloride).
After homogenization using the same method as described above, the mixture was filtered through a gauze and nylon mesh (50 μm) to remove a tissue mass, and the filtrate was centrifuged (30,000 g, 30 minutes,
4 ° C). The obtained pellet (membrane component) was suspended in an ice-cooled buffer (a buffer containing 10 mM EDTA and 300 mM potassium chloride), allowed to stand at 4 ° C. for 60 minutes, and then centrifuged (30,000 g, 15 minutes, 4 minutes). 2 ° C.). This was suspended in a buffer to form a crude membrane sample, and stored at -80 ° C until used for a receptor binding test. (B) Receptor binding test The test tube used for the reaction was pretreated in advance with a buffer containing 5 mg / ml bovine serum albumin (BSA). [ ³ H] -senktide, 6 mM manganese chloride, 800 μg / ml BSA, 8 μg / ml chymostatin, 8 μg / ml leupeptin, 80 μg / ml
400 μg / ml in 100 μl of buffer containing bacitracin and 20 μg / ml phosphoramidon
150 μl of a buffer containing BSA and a test drug were added, and a cerebral sclera membrane sample (protein concentration was 1 mg / ml)
The reaction was started by adding 250 μl (at this time, the final concentration of [ ³ H] -senktide in the reaction phase was 2.5 nM).

After incubating at room temperature for 60 minutes,
Using an automatic filtration device (Brandel), the membrane components were collected on a GF / B glass fiber filter (Whatman) pretreated with 0.1% polyethyleneimine for 4 hours or more, and then ice-cooled buffer ( 5 mM containing 400 μg / ml BSA and 0.01% sodium dodecyl sulfate
(Tris-hydrochloric acid, pH 7.4) Washed 3 times with 5 ml.

The GF / B glass fiber filter having the membrane component attached thereto was transferred to a mini plastic vial containing 4 ml of Picoflow, and the radioactivity was measured with a liquid scintillation counter (Aloka, LSC3500).

To determine the radioactivity due to non-specific binding of [ ³ H] -senktide (binding to a site other than the receptor (eg, a filter)), an excess amount of senktide (final concentration: 10 μM) was added. The test was conducted to measure the radioactivity.

The senktide-receptor binding inhibition rate by the test drug was determined by the following equation.

Inhibition rate (%) = [1- (CA) / (B-
A)] × 100 A: Radioactivity due to non-specific binding B: Radioactivity in a test performed without adding a test drug C: Radioactivity in a test with a test drug added

[0206]

[Test Example 6] Stability test on drug metabolism 20 mg / ml human liver microsomes (International
18 μl of the fraction obtained from the Institute for the Advancement of Medicine was added to an Eppendorf centrifuge tube, and β-nicotine adenine dinucleotide phosphate (β-N
ADP), 870 μl of a phosphate buffer (pH 7.4) containing D-glucose-6-phosphate, D-glucose-6-phosphate dehydrogenase and magnesium chloride, and
Incubated at 37 ° C. for 3 minutes.

To this mixture, add 30 μl of the test compound solution.
The reaction was started by adding l.

In this reaction solution, the protein concentration of human liver microsomes was 0.4 mg / ml and β-NAD
The concentration of P is 1 mM, the concentration of D-glucose-6-phosphate is 10 mM / ml, the concentration of D-glucose-6-phosphate dehydrogenase is 1 unit / ml, the concentration of magnesium chloride is 5 mM, and the concentration of phosphoric acid (phosphorus Acid buffer) is 10
0 mM.

Immediately after the start of the reaction (after 0 minutes), and at 3, 5, 10, 30, and 60 minutes after the start of the reaction, 100 μl of the reaction solution was taken, and this was used as the internal standard substance. The reaction was stopped by adding to the tube containing the methanol solution. This was centrifuged at 15,000 rpm for 5 minutes, and the obtained supernatant was analyzed by high performance liquid chromatography (HPLC).

Separately, 6 μl of the human liver microsomal fraction (20 mg / ml) was placed in an Eppendorf centrifuge tube, and D-glucose-6-phosphate dehydrogenase (final concentration: 1 unit / ml) and chloride were added thereto. Phosphate buffer (pH 7.0) containing magnesium (final concentration: 5 mM)
(4, final concentration: 100 mM) 290 μl and a test compound solution 10 μl were added and stirred. After treating the obtained mixture in the same manner as the above reaction solution, HPLC
And a calibration curve was created from the measurement results.

Based on this calibration curve, immediately after the start of the reaction (after 0 minute), 3 minutes, 5 minutes, 10 minutes,
The concentration of the test compound at 0 and 60 minutes was determined and used as an index of metabolic stability.

HPLC was performed under the following conditions <Measurement conditions> Column: L-column ODS (4.6 × 250 mm) (Chemical Inspection Association) Column temperature: 40 ° C. Eluent: 50% acetonitrile / 10 mM phosphoric acid Buffer solution (pH 7.4) Flow rate: 1 ml / min Wavelength: 215 nm Injection volume: 50 μl.

The compounds of the present invention show excellent antagonism against NK ₁ receptor, NK ₂ receptor and NK ₃ receptor,
Furthermore, it showed high stability against drug metabolism.

[0214]

The compound of the present invention having the general formula (I)
Is NK₁Receptor, NK_TwoReceptor and NK _ThreeAll of the receptors
Has excellent antagonism against
Furthermore, its excellent pharmacokinetics makes it useful as a medicine.
Especially chronic obstructive pulmonary disease, asthma and / or bronchi
Preventive agent for inflammation, rhinitis, allergy, urinary incontinence, ulcerative colitis
Or it is useful as a therapeutic agent.

──────────────────────────────────────────────────続 き Continued on the front page (51) Int.Cl. ⁷ Identification symbol FI Theme coat ゛ (Reference) A61P 11/00 A61P 11/00 17/00 17/00 19/02 19/02 21/00 21/00 25 / 00 25/00 25/28 25/28 25/32 25/32 27/02 27/02 29/00 29/00 37/00 37/00 37/08 37/08 43/00 111 43/00 111 C07D 401/14 C07D 401/14 413/10 413/10 413/14 413/14 471/10 101 471/10 101 491/107 491/107 495/10 495/10 498/10 498/10 S (72) Invention Person Takeshi Yamaguchi 1-258 Hiromachi, Shinagawa-ku, Tokyo F-term in Sankyo Co., Ltd. 4C063 AA01 AA03 BB06 CC25 CC41 CC42 CC47 CC52 CC54 DD03 DD10 DD25 DD41 DD42 DD47 EE01 4C065 AA16 AA18 BB04 BB09 CC01 DD02 EE02 HH05 JJ01 KK01 LL04 PP03 PP09 PP13 4C071 AA04 AA07 BB01 BB05 CC01 CC21 DD19 EE13 FF06 GG05 HH08 JJ01 JJ05 JJ08 LL01 4C072 AA04 AA06 BB02 BB06 CC01 CC11 EE06 FF07 GG07 HH01 HH07 UU01 4C086 AA01 AA02 AA03 BC21 BC60 BC62 BC64 CB22 CB29 MA01 MA04 NA14 ZA02 ZA08 ZA16 ZA18 ZA20 ZA33 ZA36 ZA59 ZA66 ZA67 ZA68 ZA81 ZA89 ZA94 ZA96 ZB05 ZB ZBZ ZB08

Claims (22)

[Claims] 1. A compound having the following general formula (I) or a pharmacologically acceptable salt, ester or other derivative thereof: In the formula, R ¹ represents a lower alkyl group; R ² is a 5-membered heteroaryl group containing at least one nitrogen atom, which is substituted with 1 to 3 groups selected from a substituent group α. A 5-membered heteroaryl group containing at least one nitrogen atom, a 5-membered heteroaryl group containing at least one nitrogen atom
A 3-membered heterocyclyl group or a 5-membered heterocyclyl group containing at least one nitrogen atom, which is substituted by 1 to 3 groups selected from a substituent group α, and R ³ represents an aryl group or a substituent group α 1 in the selected group
Represents an aryl group, a heteroaryl group, or a heteroaryl group substituted by 1 to 3 groups selected from a substituent group α, A represents a carbonyl group or a sulfonyl group, and E represents , A methylene group, an oxygen atom or a sulfur atom, and the cyclic group G is a cycloalkane ring having 5 to 8 carbon atoms, a carbon group having 5 to 8 carbon atoms substituted by 1 or 2 groups selected from a substituent group α. 8 cycloalkane rings, C5 to C8 cycloalkene rings, C5 to C8 cycloalkene rings substituted by 1 or 2 groups selected from substituent group α, 5 to 8 members A ring-saturated heterocyclic ring, or a 5- to 8-membered saturated heterocyclic ring substituted by one or two groups selected from a substituent group α, wherein a cyclic group Ar is an aryl ring, a heteroaryl ring, a substituent group Ali substituted by 1 to 3 groups selected from α Shows Le or heteroaryl ring 1 is three substituent groups selected from substituent group alpha. m represents 1 or 2, and n represents an integer of 2 to 4. ｝. [Substituent group α] halogen atom, lower alkyl group, halogeno lower alkyl group, lower alkoxy group, lower alkoxycarbonyl group, carboxy group, hydroxyl group, lower aliphatic acyl group, lower aliphatic acylamino group, amino group, and cyano Base. 2. The compound according to claim 1, wherein R ¹ is methyl, ethyl or n-propyl, or a pharmaceutically acceptable salt, ester or other derivative thereof. 3. The method according to claim 1, wherein
² is imidazolyl, triazolyl, tetrazolyl, pyrrolidinyl, or a compound that is imidazolyl, triazolyl, tetrazolyl or pyrrolidinyl substituted with 1 to 3 groups selected from the substituent group α, or a pharmaceutically acceptable salt, ester or Other derivatives. 4. The method according to claim 1, wherein
^2, 1-imidazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl, 1-pyrrolidinyl, or 1 to which is three substituted with a group selected from Substituent group alpha 1
-A compound which is imidazolyl, 2-triazolyl, 1-tetrazolyl, 2-tetrazolyl or 1-pyrrolidinyl, or a pharmaceutically acceptable salt, ester or other derivative thereof. 5. The method according to claim 1, wherein
A compound wherein ² is 1-tetrazolyl, or a pharmaceutically acceptable salt, ester or other derivative thereof. 6. A method selected from claims 1 to 5.
In any one of the terms, R ^ThreeIs selected from the substituent group α
Group substituted by 1 to 3 groups, heteroaryl
1 to 3 groups selected from the group consisting of
Compounds that are substituted heteroaryl groups or pharmacologically
Acceptable salts, esters or other derivatives. 7. Selection from the claims 1 to 5
In any one of the terms, R ^ThreeIs selected from the substituent group α
Or an aryl group substituted by 1 to 3 groups
Is a pharmacologically acceptable salt, ester or other
Derivatives. 8. A method selected from claims 1 to 5.
In any one of the terms, R ^ThreeIs one to three halogen sources
Or a pharmacologically acceptable compound which is an aryl group substituted with
Acceptable salts, esters or other derivatives. 9. The compound according to any one of claims 1 to 8, wherein A is carbonyl, or a pharmaceutically acceptable salt, ester or other derivative thereof. 10. The compound according to any one of claims 1 to 9, wherein E is an oxygen atom and m is 2, or a pharmacologically acceptable salt, ester or other derivative thereof. 11. The method according to any one of claims 1 to 9, wherein E is a methylene group, and m is 1
Or a pharmacologically acceptable salt, ester or other derivative thereof. 12. The compound according to any one of claims 1 to 9, wherein n is 2 or 3, or a pharmacologically acceptable salt, ester or other derivative thereof. 13. The method according to claim 1, wherein the cyclic group G has 5 to 6 carbon atoms.
Cycloalkane ring, a cycloalkane ring having 5 to 6 carbon atoms, substituted with 1 or 2 carbon atoms by a group selected from the substituent group α, a 5- to 6-membered saturated heterocyclic ring, or a substituent group α. Or a 5- or 6-membered saturated heterocyclic ring substituted by one or two groups, or a pharmaceutically acceptable salt, ester or other derivative thereof. 14. The method according to claim 1, wherein the cyclic group G is substituted with one or two groups selected from the substituent group α and has 5 to 6 carbon atoms. Or a 5- or 6-membered saturated heterocyclic ring, or a 5- or 6-membered saturated heterocyclic ring substituted by one or two groups selected from the substituent group α, or a pharmacologically acceptable compound thereof. Salts, esters or other derivatives. 15. A cycloalkane ring having 5 to 6 carbon atoms, wherein the cyclic group G is substituted with one or two hydroxyl groups, or a cyclic group G according to any one of claims 1 to 12, or A compound having a 5- or 6-membered saturated heterocycle or a pharmacologically acceptable salt, ester or other derivative thereof. 16. The method according to any one of claims 1 to 15, wherein the cyclic group Ar is an aryl ring,
A compound or a pharmacologically acceptable salt, ester or other derivative thereof, which is a heteroaryl ring or an aryl ring substituted with one to three substituents selected from the substituent group α. 17. The method according to any one of claims 1 to 15, wherein the cyclic group Ar is an aryl ring,
Or a compound which is an aryl ring substituted by 1 to 3 groups selected from the substituent group α, or a pharmaceutically acceptable salt, ester or other derivative thereof. 18. The method according to any one of claims 1 to 15, wherein the cyclic group Ar is a benzene ring,
Or a compound which is a benzene ring substituted by 1 to 3 groups selected from the substituent group α, or a pharmacologically acceptable salt, ester or other derivative thereof. 19. The method according to claim 1, wherein the partial structure (II) in the general formula (I) is as follows: But, Or a pharmacologically acceptable salt, ester or other derivative thereof. 20. The compound according to any one of claims 1 to 15, wherein the following partial structure (II) in the general formula (I): Is Or a pharmacologically acceptable salt, ester or other derivative thereof. 21. The compound according to claim 1, wherein the compound is selected from the following, or a pharmacologically acceptable salt, ester or other derivative thereof: 1- {2-[(3R)-(3,4-dichlorophenyl)- 1- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) pyrrolidin-3-yl] ethyl {spiro [((2S) -hydroxy) indan-1,4'-
Piperidine], 1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-yl) benzoyl) pyrrolidin-3-yl] ethyl} -3 -Oxo-3,4-dihydrospiro [isoquinoline-1 (2H), 4'-piperidine], 1- {2-[(3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5 -(Tetrazole-1-
Yl) benzoyl) pyrrolidin-3-yl] ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,4′-piperidine], 1- {2-[( 3R)-(3,4-dichlorophenyl) -1- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) pyrrolidin-3-yl] ethyl} spiro [benzo [c] thiophene-1 (3H), 4'-piperidine]-(2S) -oxide; 1- {2-[(2R)-(3 , 4-Dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [((2S) -hydroxy) indane-1,4'-
1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-)
Yl) benzoyl) morpholin-2-yl] ethyl}-
3-oxo-3,4-dihydrospiro [isoquinoline-
1 (2H), 4'-piperidine], 1- {2-[(2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [1,4-dihydrobenzo [d] [1.3] oxazin-2-one-1,4′-piperidine]; and 1- {2- [ (2R)-(3,4-dichlorophenyl) -4- (2-methoxy-5- (tetrazol-1-
Yl) benzoyl) morpholin-2-yl] ethyl {spiro [benzo [c] thiophen-1 (3H), 4'-piperidine]-(2S) -oxide. 22. A medicament comprising as an active ingredient a compound according to any one of claims 1 to 21 or a pharmacologically acceptable salt, ester or other derivative thereof.