JPH09278750A - Alicyclic amine derivative - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain the subject compound useful as a medicine for treating or preventing thrombotic diseases, arteriosclerotic diseases, hyperlipemic diseases, etc. SOLUTION: An alicyclic amine derivative of formula I[R<1> is a 3-6 membered cyclic saturated heterocyclyl (e.g. pyrrolidinyl) containing one or two heterogeneous atoms selected from N, O, S; R<2> a, R<2> b, R<2> c are each H, methyl, etc.; R<3> a, R<3> b, R<3> c R<3> d are each H, a 1-6C alkyl, etc.; A is a single bond or a 1-6C alkylene] or its pharmacologically permissible salt, e.g. 2-[2-(4-fluoro-2-(2- phenylethyl) phenoxy]ethyl]-4-hydroxy-1-methylpyrodien. The compound of formula I is obtained by reacting a compound of formula II with a compound of the formula: Z-A-R<1> a (R<1> a is a 5-6C membered cyclic saturated heterocyclyl in R<1> ; Z is hydroxy, etc.) in the presence of a base in inactive solvent usually at 0-100 deg.C for 30 min to 48hr, and subsequently removing a hydroxy-protecting group contained in e.g. the group of R<1> a from the obtained compound of formula III. Therein, the removal reaction is performed e.g. in the presence of a catalytic reduction catalyst in an inactive solvent at p-100 deg.C for 30min to 47hr.

Description

Detailed Description of the Invention

[0001]

The present invention relates to an excellent serotonin 2
A cycloaliphatic amine that has both receptor antagonism and squalene synthase inhibitory action and is useful as a therapeutic or prophylactic agent for cardiovascular disease (thrombotic disease, arteriosclerotic disease or hyperlipidemic disease, especially thrombotic disease) Derivatives or pharmacologically acceptable salts thereof or serotonin 2 receptor antagonists, squalene synthase inhibitors or cardiovascular diseases containing them as active ingredients (thrombotic diseases, arteriosclerotic diseases or hyperlipidemic diseases, especially thrombotic (Disease).

[0002]

BACKGROUND OF THE INVENTION Serotonin is classically classified as an autacoid and is also known as a neurotransmitter. In the living body, serotonin exhibits various physiological actions through various receptors. It is known that there are subtypes of this serotonin receptor, but in the circulatory system, receptors classified as serotonin 2 receptors are distributed on vascular endothelial cells and platelets, and constriction of blood vessels and It is deeply involved in platelet aggregation [for example, S. J. Peroutka et al .; Federation Proceedings, Vol. 42, p. 213 (1
983): SJ Peroutka et. Al., Fed. Proc., 4
2 , 213 (1983)], its antagonists are useful in preventing vasoconstriction and inhibiting platelet aggregation. Currently, ketanserin is known as a serotonin 2 receptor antagonist [eg, Jay IS Robertson; Current Opinion in Cardiology, Volume 3, p. 702 (1
1988): JIS Robertson, Curr. Opinion Card
iol., 3 , 702 (1988)], this drug is adrenaline α1.
It was developed as an antagonist and has the drawback of showing a strong hypotensive effect. Also, recently, a diallyl alkane derivative has been known as a platelet aggregation inhibitor having a weak adrenergic α1 antagonism and an excellent serotonin 2 receptor antagonism [for example, Journal of Medicinal Chemistry, No. 35. Volume, p. 189 (1992
33), 1818 (1990), etc .: J. Med. Ch.
em., 35 , 189 (1992), ibid., 33 , 1818 (1990), JP 6-234736 A, JP 6-306025 A, etc.], these compounds have a squalene synthase inhibitory action Not known at all. On the other hand, hyperlipidemia is one of the three major risk factors for ischemic heart disease such as arteriosclerosis, and it has been recognized that lowering high blood cholesterol level can prevent heart disease. . Squalene synthase is located several steps downstream of HMG-CoA reductase in the cholesterol synthesis system, and after this stage, the cholesterol synthesis system separates the pathway from other isoprene-derived compound synthesis systems. That is, when squalene synthase is inhibited, it is possible to suppress the biosynthesis of cholesterol without inhibiting the biosynthesis of ubiquinone, dolichol and the like [eg, Nature, vol. 343, p. 425 (1990); Nature]. , 343 , 425 (1990)], and squalene synthase inhibitors are extremely useful as therapeutic agents for hyperlipidemia. Incidentally, as a squalene synthase inhibitor, until now, isoprenoid (phosphinylmethyl)
Phosphate, Zaragozic Acids having a basic skeleton of dioxabicyclooctane ring, etc. are known (U.S. Pat.No. 4,871,721, U.S. Pat.No. 5,10).
2,907 etc.). Therefore, a compound having both a serotonin 2 receptor antagonistic action and a squalene synthase inhibitory action is not only based on the antihyperlipidemic action, but not only prevents or prevents the development and progress of arteriosclerosis, but also is based on the serotonin 2 receptor antagonistic action. By preventing thrombus formation in the arteriosclerotic plexus and suppressing vasoconstriction, circulatory dynamics are improved, and preventive and curative actions for these diseases are expected.

[0003]

DISCLOSURE OF THE INVENTION The present inventors have conducted extensive studies for a long time on the pharmacological activity of alicyclic amine derivatives, and as a result, these compounds have serotonin 2 receptor antagonistic activity and squalene synthase inhibitory activity. And their effects are persistent, they are useful as therapeutic or preventive agents for thrombotic diseases and arteriosclerotic diseases based on inhibition of platelet aggregation, and hyperlipidemia and arteriosclerosis based on cholesterol lowering effects. By being useful as a therapeutic or preventive agent for sexually transmitted diseases and having both serotonin 2 receptor antagonistic action and cholesterol lowering action,
They have found that they are useful as excellent therapeutic or preventive agents for arteriosclerotic diseases, and have completed the present invention. The present invention provides treatment of an alicyclic amine derivative or a pharmacologically acceptable salt thereof, and a cardiovascular disease (thrombotic disease, arteriosclerotic disease or hyperlipidemic disease, particularly thrombotic disease) containing them as an active ingredient. Agent or prophylactic agent.

[0004]

The alicyclic amine derivative of the present invention has the general formula

[0005]

Embedded image

[0006] has.

In the above formula, R ¹ is a substituted 3- to 6-membered cyclic saturated heterocyclyl group containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms. substituents on the carbon atoms is required, it as a hydroxy group, C ₁ -C ₂₀ alkoxycarbonyloxy group, C ₁ -C ₂₀ alkanoyloxy group, C ₂ -C ₇ alkanoyloxy group substituted by a carboxy ,
Carbamoyloxy group or mono- or di-C ₁ -C
₆ alkylcarbamoyloxy group, the substituents on the nitrogen atom being optional, which may be substituted by C ₁ -C ₆ alkyl groups, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen. C ₁ -C ₆ substituted with also good C ₆ -C ₁₀ aryl alkyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆ alkoxy or halogen with an optionally substituted C ₆ -C even though ₁₀ aryl group Alternatively, it represents a C ₁ -C ₉ alkoxycarbonyloxy group. ), R ² a,
R ² b and R ² c are the same or different and represent a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano group or a nitro group, and R ^{3 a, R 3 b, R} 3 c and R ³ d is the same or different, a hydrogen atom, C ₁ -C ₆ alkyl group, Harogeno C ₁ -C ₆ alkyl groups, C ₂ -C ₆ alkenyl groups, C ₂ -C ₆ alkynyl group, hydroxy group, C ₁ -C ₆
Alkoxy group, halogeno C ₁ -C ₆ alkoxy group, C
₁ -C ₆ alkoxycarbonyloxy group, C ₁ -C ₆ alkanoyloxy group, carbamoyloxy group, mono - or di -C ₁ -C ₆ alkylcarbamoyl group,
It represents a halogen atom, a cyano group, a nitro group, a C ₁ -C ₆ alkyl group, a C ₁ -C ₆ alkoxy group or a C ₆ -C ₁₀ aryl group which may be substituted with halogen, and A represents a single bond or C _1-. shows a C ₆ alkylene group. Where R ¹
Is attached to the group having the formula -A- at its carbon atom,
One of R ² a, R ² b and R ² c represents a group other than a hydrogen atom.

In the above general formula (I), saturated heterocyclyl of 3- to 6-membered cyclic saturated heterocyclyl group containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur atoms substituted with R ^1. The moieties are, for example, aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl, thiomorpholinyl,
It may be an imidazolidinyl, pyrazolidinyl, triazinyl or tetrazolidinyl group, preferably an azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl or thiomorpholinyl group, more preferably 2-pyrrolidinyl, 3-pyrrolidinyl, 2-piperidinyl, 3- A piperidinyl, 4-piperidinyl, 1-piperazinyl, 2-morpholinyl or 3-morpholinyl group, and even more preferably 2-pyrrolidinyl, 3-
It is a pyrrolidinyl, 2-piperidinyl, 3-piperidinyl or 4-piperidinyl group, particularly preferably a 2-pyrrolidinyl group or a 3-piperidinyl group, and most preferably a 2-pyrrolidinyl group.

[0009] Mono included in C ₁ -C ₆ alkyl group or R ¹ and the like are included in R ¹ or the like - or di -C ₁ -C ₆ alkylamino group, mono - or di -C ₁ -C ₆ alkylcarbamoyl Group, C ₁ -C ₆ alkoxy group or C ₁ -C
C ₁ -C ₆ alkyl moiety, such as ₆ alkoxycarbonyl group, for example, be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, s- butyl, t- butyl, pentyl, hexyl, preferably, C an ₁ -C ₄ alkyl group, more preferably a methyl group or an ethyl group, particularly preferably a methyl group.

[0010] C ₁ -C ₂₀ alkoxy moieties of C ₁ -C ₂₀ alkoxycarbonyloxy group contained in R ^1, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s- butoxy, t-butoxy, Pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy, decyloxy, undecyloxy, dodecyloxy, tridecyloxy,
Tetradecyloxy, pentadecyloxy, hexadecyloxy, heptadecyloxy, octadecyloxy,
Nonadecyloxy, eicosyloxy group, preferably C ₁ -C ₆ or C ₈ -C ₁₈ alkoxy group,
More preferably, it is a C ₁ -C ₄ or C ₈ -C ₁₈ alkoxy group, even more preferably an ethoxy, isopropoxy, t-butoxy, octyloxy, hexadecyloxy or octadecyloxy group, and More preferably, it is an ethoxy group, isopropoxy group, t-butoxy, octyloxy or hexadecyloxy group, and particularly preferably an octyloxy group.

C which is a substituent of the nitrogen atom contained in R ^1.
C ₁ -C ₉ alkoxy moieties of ₁ -C ₉ alkoxycarbonyl group, for example, methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy, s-
It may be butoxy, t-butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy, nonyloxy group, preferably C ₁ -C ₄ alkoxy group, heptyloxy group or octyloxy group, more preferably , C ₁ -C ₂ alkoxy group or octyloxy group, particularly preferably methoxy group.

The C ₁ -C ₂₀ alkanoyl moiety of the C ₁ -C ₂₀ alkanoyloxy group contained in R ¹ is, for example, the C ₁ -C ₆ alkanoyl group described later, heptanoyl, octanoyl, nonanoyl, decanoyl, lauroyl, myristoyl, It may be palmitoyl, stearoyl, eicosanoyl, docosanoyl group, preferably C ₂ -C ₅ alkanoyl group or C ₁₀ -C ₁₈ alkanoyl group,
More preferably, C ₂ -C ₃ alkanoyl or C ₁₀ -C
₁₆ Alkanoyl group, more preferably decanoyl group, lauroyl group, myristoyl group or palmitoyl group, particularly preferably decanoyl group or lauroyl group.

C substituted with carboxy contained in R ¹
_{The 2-} C ₇ alkanoyl group may be, for example, a malonyl, succinyl, glutaryl, adipoyl, pimeloyl, suberoyl group, preferably a C ₃ -C ₆ alkanoyl group, particularly preferably a succinyl or glutaryl group. is there.

The halogen atom contained in R ³ a or the like may be, for example, a fluorine, chlorine, bromine or iodine atom, and preferably,
It is a fluorine, chlorine or bromine atom, more preferably a fluorine or chlorine atom.

The C ₁ -C ₆ alkyl group substituted by the C ₆ -C ₁₀ aryl contained in R ¹ is 1 to 3 C ₆ -C.
₁₀ Aryl may be substituted with an alkyl group, for example, benzyl, methylbenzyl, methoxybenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl, 5-phenylpentyl, 6 -Phenylhexyl, benzhydryl, methylbenzhydryl, methoxybenzhydryl, fluorobenzhydryl, chlorobenzhydryl, difluorobenzhydryl, dichlorobenzhydryl, trityl group, preferably benzyl, methylbenzyl , Methoxybenzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, phenethyl or benzhydryl group, particularly preferably benzyl group.

[0016] C ₆ -C ₁₀ aryl group C ₆ -C ₁₀ an aryl group, or R ³ a included in R ^1, for example, phenyl, methylphenyl, methoxyphenyl, fluorophenyl, chlorophenyl, bromophenyl, naphthyl, It may be a methylnaphthyl or methoxynaphthyl group, preferably phenyl, methylphenyl, methoxyphenyl,
It is a fluorophenyl, chlorophenyl or naphthyl group, particularly preferably a phenyl group.

The halogeno C ₁ -C ₆ alkyl group such as R ³ a is, for example, fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, bromomethyl, iodomethyl, 2-fluoroethyl, 2-chloroethyl, 2-
Bromoethyl, 2-iodoethyl, 3-fluoropropyl, 4-fluorobutyl, 5-fluoropentyl, 6-
It may be a fluorohexyl group, preferably a fluoromethyl, difluoromethyl, trifluoromethyl, chloromethyl, 2-fluoroethyl or 2-chloroethyl group, more preferably a fluoromethyl, difluoromethyl, trifluoromethyl , 2-fluoroethyl or 2-
A chloroethyl group, particularly preferably a trifluoromethyl group.

C ₂ -C ₆ alkenyl groups such as R ³ a are, for example, vinyl, allyl, methallyl, 2-butenyl, 2-
Pentenyl, which may be a 2-hexenyl group;
A ₃ -C ₄ alkenyl group, more preferably an allyl group or a methallyl group, particularly preferably an allyl group.

The C ₂ -C ₆ alkynyl group such as R ³ a may be, for example, ethynyl, propargyl, 2-butynyl, 2-pentynyl, 2-hexynyl group, preferably C _3-.
It is a C ₄ alkynyl group, and particularly preferably a propargyl group.

[0020] Harogeno C ₁ -C ₆ alkoxy group such as ^{R 3} a, for example, fluoromethoxy, difluoromethoxy, trifluoromethoxy, chloromethoxy, bromomethoxy, iodomethoxy, 2-fluoroethoxy, 2-
It may be a chloroethoxy, 2-bromoethoxy, 2-iodoethoxy, 3-fluoropropoxy, 4-fluorobutoxy, 5-fluoropentyloxy, 6-fluorohexyloxy group, preferably fluoromethoxy, difluoromethoxy, tri-. Fluoromethoxy, 2-fluoroethoxy or 2-chloroethoxy group, more preferably fluoromethoxy, difluoromethoxy, trifluoromethoxy, 2-fluoroethoxy or 2-chloroethoxy group, particularly preferably difluoro. It is a methoxy group or a 2-fluoroethoxy group.

The C ₁ -C ₆ alkanoyl moiety of the C ₁ -C ₆ alkanoyloxy group such as R ³ a is, for example, formyl,
Acetyl, propionyl, butyryl, isobutyryl, valeryl, pivaloyl, be a hexanoyl group obtained, preferably a C ₂ -C ₅ alkanoyl group, more preferably, an acetyl group or a propionyl group, a particularly preferred, It is an acetyl group.

The C ₁ -C ₆ alkylene group of A is, for example,
It may be a methylene, ethylene, propylene, trimethylene, tetramethylene, pentamethylene or hexamethylene group, preferably a C ₁ -C ₄ alkylene group, more preferably a methylene, ethylene or trimethylene group, and It is more preferably a methylene or ethylene group, and particularly preferably an ethylene group.

The substituent on the ring of the 5- to 6-membered cyclic saturated heterocyclyl group of R ¹ is preferably a hydroxy group, C ₁ -C ₆ or C ₈ as a substituent on the carbon atom.
-C ₁₈ alkoxycarbonyloxy group, C ₁ -C ₂₀ alkanoyloxy group, C ₃ -C ₇ substituted by carboxy
An alkanoyloxy group, a carbamoyloxy group or a mono- or di-C ₁ -C ₂ alkylcarbamoyloxy group, more preferably a hydroxy group, a C ₁ -C ₄
Or a C ₈ -C ₁₈ alkoxycarbonyloxy group, C
₂ -C ₅ alkanoyloxy group, a C ₁₀ -C ₁₈ alkanoyloxy group, C ₃ -C ₆ alkanoyloxy group substituted with carboxy, carbamoyloxy group or a mono- or di-C ₁ -C ₂ alkylcarbamoyl group, Even more preferably, hydroxy, methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, t-butoxycarbonyloxy, octyloxycarbonyloxy, decyloxycarbonyloxy, hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, acetoxy, Propionyloxy, butyryloxy, valeryloxy, pivaloyloxy, decanoyloxy, undecanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, steer Yloxy, succinyloxy,
A glutaryloxy, carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy or N, N-dimethylcarbamoyloxy group, and even more preferably hydroxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, t- Butoxycarbonyloxy, octyloxycarbonyloxy, hexadecyloxycarbonyloxy, decanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, stearoyloxy, succinyloxy,
A carbamoyloxy or N, N-dimethylcarbamoyloxy group, particularly preferably hydroxy, ethoxycarbonyloxy, t-butoxycarbonyloxy, octyloxycarbonyloxy, hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, decanoyloxy. A lauroyloxy, myristoyloxy, palmitoyloxy or stearoyloxy group, most preferably a hydroxy, decanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy or stearoyloxy group, and a substituent on the nitrogen atom. as, preferably a C ₁ -C ₄ alkyl group or a methyl, methoxy, phenyl group which may be substituted with fluoro or chloro, more preferably, methyl, ethyl or off A group, particularly preferably a methyl group.

Furthermore, R ¹ Nitrogen, oxygen or sulfur
Specific examples of the 5- or 6-membered cyclic saturated heterocyclyl group containing an atom
Typical examples are hydroxypyrrolidinyl and methoxine.
Cycarbonyloxypyrrolidinyl, ethoxycarbonyl
Oxypyrrolidinyl, propoxycarbonyloxypyro
Lysinyl, isopropoxycarbonyloxypyrrolidini
L, butoxycarbonyloxypyrrolidinyl, t-but
Xycarbonyloxypyrrolidinyl, pentyloxyca
Lubonyloxypyrrolidinyl, hexyloxycarboni
Luoxypyrrolidinyl, Octyloxycarbonyl Oki
Cypyrrolidinyl, nonyloxycarbonyloxypyrroli
Dinyl, decyloxycarbonyloxypyrrolidinyl,
Undecyloxycarbonyloxypyrrolidinyl, dode
Syloxycarbonyloxypyrrolidinyl, tridecyl
Oxycarbonyloxypyrrolidinyl, pentadecyl
Xycarbonyloxypyrrolidinyl, hexadecyl oxy
Cycarbonyloxypyrrolidinyl, heptadecyloxy
Carbonyloxypyrrolidinyl, octadecyloxyca
Rubonyloxypyrrolidinyl, formyloxypyrrolidinyl
Nyl, acetoxypyrrolidinyl, propionyloxypi
Loridinyl, butyryloxypyrrolidinyl, valeryl
Xypyrrolidinyl, pivaloyloxypyrrolidinyl,
Xanoyloxypyrrolidinyl, 3,3-dimethylbutyrate
Ryloxypyrrolidinyl, heptanoyloxypyrrolidinyl
Nyl, octanoyloxypyrrolidinyl, nonanoylo
Xypyrrolidinyl, decanoyloxypyrrolidinyl, u
Ndecanoyloxypyrrolidinyl, lauroyloxypi
Loridinyl, myristoyloxypyrrolidinyl, palmi
Toyloxypyrrolidinyl, stearoyloxypyrroli
Dinyl, eicosanoyloxypyrrolidinyl, docosano
Iloxypyrrolidinyl, succinyloxypyrrolidinyl
, Glutaryloxypyrrolidinyl, adipoyloxy
Pyrrolidinyl, pimeloyloxypyrrolidinyl, carba
Moyloxypyrrolidinyl, N-methylcarbamoylo
Xypyrrolidinyl, N-ethylcarbamoyloxypyro
Lysinyl, N, N-dimethylcarbamoyloxypyrrolid
Dinyl, N, N-diethylcarbamoyloxypyrrolidi
Nyl, N-methyl-N-ethylcarbamoyloxypyro
Lysinyl, 1-methyl-hydroxypyrrolidinyl, 1-
Methyl-methoxycarbonyloxypyrrolidinyl, 1-
Methyl-ethoxycarbonyloxypyrrolidinyl, 1-
Methyl-propoxycarbonyloxypyrrolidinyl, 1
-Methyl-isopropoxycarbonyloxypyrrolidini
1-methyl-butoxycarbonyloxypyrrolidinyl
1-methyl-t-butoxycarbonyloxypyrroli
Dinyl, 1-methyl-pentyloxycarbonyloxy
Pyrrolidinyl, 1-methyl-hexyloxycarbonyl
Oxypyrrolidinyl, 1-methyl-heptyloxycal
Bonyloxypyrrolidinyl, 1-methyl-octyloxy
Cicarbonyloxypyrrolidinyl, 1-methyl-nonyl
Oxycarbonyloxypyrrolidinyl, 1-methyl-de
Syloxycarbonyloxypyrrolidinyl, 1-methyl
-Undecyloxycarbonyloxypyrrolidinyl, 1
-Methyl-dodecyloxycarbonyloxypyrrolidini
1-methyl-tridecyloxycarbonyloxypi
Loridinyl, 1-methyl-pentadecyloxycarboni
Leoxypyrrolidinyl, 1-methyl-hexadecyloxy
Cycarbonyloxypyrrolidinyl, 1-methyl-hepta
Decyloxycarbonyloxypyrrolidinyl, 1-methyl
L-octadecyloxycarbonyloxypyrrolidini
1-methyl-formyloxypyrrolidinyl, 1-methyl
Tyl-acetoxypyrrolidinyl, 1-methyl-propio
Nyloxypyrrolidinyl, 1-methyl-butyryloxy
Pyrrolidinyl, 1-methyl-valeryloxypyrrolidinyl
1-methyl-pivaloyloxypyrrolidinyl, 1-
Methyl-hexanoyloxypyrrolidinyl, 1-methyl
-3,3-dimethylbutyryloxypyrrolidinyl, 1-
Methyl-heptanoyloxypyrrolidinyl, 1-methyl
-Octanoyloxypyrrolidinyl, 1-methyl-nona
Noyloxypyrrolidinyl, 1-methyl-decanoylo
Xypyrrolidinyl, 1-methyl-undecanoyloxy
Pyrrolidinyl, 1-methyl-lauroyloxy pyrrolidi
Nil, 1-methyl-myristoyloxypyrrolidinyl,
1-methyl-palmitoyloxypyrrolidinyl, 1-me
Tyl-stearoyloxypyrrolidinyl, 1-methyl-
Eicosanoyloxypyrrolidinyl, 1-methyl-doco
Sanoyloxypyrrolidinyl, 1-methyl-succinyl
Oxypyrrolidinyl, 1-methyl-glutaryloxypi
Loridinyl, 1-methyl-adipoyloxypyrrolidini
1-methyl-pimeloyloxypyrrolidinyl, 1-
Methyl-carbamoyloxypyrrolidinyl, 1-methyl
-N-methylcarbamoyloxypyrrolidinyl, 1-me
Tyl-N-ethylcarbamoyloxypyrrolidinyl, 1
-Methyl-N, N-dimethylcarbamoyloxypyrrolid
Dinyl, 1-methyl-N, N-diethylcarbamoyl
Xypyrrolidinyl, 1-methyl-N-methyl-N-ethyl
Lucarbamoyloxypyrrolidinyl, 1-ethyl-hydride
Roxypyrrolidinyl, 1-ethyl-methoxycarbonyl
Oxypyrrolidinyl, 1-ethyl-ethoxycarbonyl
Oxypyrrolidinyl, 1-ethyl-propoxycarbonyl
Luoxypyrrolidinyl, 1-ethyl-isopropoxyca
Lubonyloxypyrrolidinyl, 1-ethyl-butoxyca
Rubonyloxypyrrolidinyl, 1-ethyl-t-butoxy
Cycarbonyloxypyrrolidinyl, 1-ethyl-pentyl
Luoxycarbonyloxypyrrolidinyl, 1-ethyl-
Hexyloxycarbonyloxypyrrolidinyl, 1-E
Tyl-heptyloxycarbonyloxypyrrolidinyl,
1-ethyl-octyloxycarbonyloxypyrrolidone
Nyl, 1-ethyl-nonyloxycarbonyloxypyro
Lysinyl, 1-ethyl-decyloxycarbonyloxy
Pyrrolidinyl, 1-ethyl-hexadecyloxycarbo
Nyloxypyrrolidinyl, 1-ethyl-octadecyl io
Xycarbonyloxypyrrolidinyl, 1-ethyl-acetate
Toxypyrrolidinyl, 1-ethyl-propionyloxy
Pyrrolidinyl, 1-ethyl-butyryloxypyrrolidini
1-ethyl-valeryloxypyrrolidinyl, 1-E
Tyl-pivaloyloxypyrrolidinyl, 1-ethyl-o
Cutanoyloxypyrrolidinyl, 1-ethyl-nonanoi
Luoxypyrrolidinyl, 1-ethyl-decanoyloxy
Pyrrolidinyl, 1-ethyl-undecanoyloxypyro
Lysinyl, 1-ethyl-lauroyloxypyrrolidini
1-ethyl-myristoyloxypyrrolidinyl, 1
-Ethyl-palmitoyloxypyrrolidinyl, 1-ethyl
L-stearoyloxypyrrolidinyl, 1-ethyl-su
Cusinyloxypyrrolidinyl, 1-ethyl-glutaryl
Oxypyrrolidinyl, 1-ethyl-adipoyloxypi
Loridinyl, 1-ethyl-pimeloyloxypyrrolidini
1-ethyl-carbamoyloxypyrrolidinyl, 1
-Ethyl-N-methylcarbamoyloxypyrrolidini
1-ethyl-N, N-dimethylcarbamoyloxy
Pyrrolidinyl, hydroxypiperidinyl, methoxycal
Bonyloxypiperidinyl, ethoxycarbonyloxy
Piperidinyl, isopropoxycarbonyloxypiperi
Dinyl, t-butoxyoxycarbonyloxypiperidini
L, octyloxycarbonyloxypiperidinyl, no
Nyloxycarbonyloxypiperidinyl, decyl oki
Cycarbonyloxypiperidinyl, hexadecyloxy
Carbonyloxypiperidinyl, octadecyloxyca
Rubonyloxypiperidinyl, acetoxypiperidini
L, propionyloxy piperidinyl, butyryloxy
Piperidinyl, valeryloxypiperidinyl, pivalloy
Oxypiperidinyl, decanoyloxypiperidinyl,
Lauroyloxypiperidinyl, myristoyloxypi
Peridinyl, palmitoyloxypiperidinyl, steer
Royloxypiperidinyl, succinyloxypiperidin
Nil, glutaryloxypiperidinyl, carbamoylo
Xypiperidinyl, N-methylcarbamoyloxypipe
Lysinyl, N-ethylcarbamoyloxypiperidini
L, N, N-dimethylcarbamoyloxypiperidinini
1-methyl-hydroxypiperidinyl, 1-methyl
-Methoxycarbonyloxypiperidinyl, 1-methyl
-Ethoxycarbonyloxypiperidinyl, 1-methyl
-Isopropoxycarbonyloxypiperidinyl, 1-
Methyl-t-butoxycarbonyloxypiperidinyl,
1-methyl-octyloxycarbonyloxypiperidi
Nyl, 1-methyl-nonyloxycarbonyloxypipe
Lysinyl, 1-methyl-decyloxycarbonyloxy
Piperidinyl, 1-methyl-hexadecyloxycarbo
Nyloxypiperidinyl, 1-methyl-octadecyl io
Xycarbonyloxypiperidinyl, 1-methyl-acetate
Toxypiperidinyl, 1-methyl-propionyloxy
Piperidinyl, 1-methyl-butyryloxypiperidinini
1-methyl-valeryloxypiperidinyl, 1-me
Tyl-pivaloyloxypiperidinyl, 1-methyl-de
Canoyloxypiperidinyl, 1-methyl-lauroyl
Oxypiperidinyl, 1-methyl-myristoyloxy
Piperidinyl, 1-methyl-palmitoyloxypiperi
Dinyl, 1-methyl-stearoyloxypiperidinini
1-methyl-succinyloxypiperidinyl, 1-
Methyl-glutaryloxypiperidinyl, 1-methyl-
Carbamoyloxypiperidinyl, 1-methyl-N-me
Tylcarbamoyloxypiperidinyl, 1-methyl-N
-Ethylcarbamoyloxypiperidinyl, 1-methyl
-N, N-dimethylcarbamoyloxypiperidinyl,
1-ethyl-hydroxypiperidinyl, 1-ethyl-eth
Toxycarbonyloxypiperidinyl, 1-ethyl-ii
Sopropoxycarbonyloxypiperidinyl, 1-ethyl
L-t-butoxycarbonyloxypiperidinyl, 1-
Ethyl-octyloxycarbonyloxypiperidini
1-ethyl-nonyloxycarbonyloxypiperi
Zinyl, 1-ethyl-decyloxycarbonyloxypi
Peridinyl, 1-ethyl-hexadecyloxycarboni
Luoxypiperidinyl, 1-ethyl-octadecyloxy
Cycarbonyloxypiperidinyl, 1-ethyl-aceto
Xypiperidinyl, 1-ethyl-propionyloxypi
Peridinyl, 1-ethyl-butyryloxypiperidinini
1-ethyl-valeryloxypiperidinyl, 1-E
Tyl-pivaloyloxypiperidinyl, 1-ethyl-de
Canoyloxypiperidinyl, 1-ethyl-lauroyl
Oxypiperidinyl, 1-ethyl-myristoyloxy
Piperidinyl, 1-ethyl-palmitoyloxypiperi
Dinyl, 1-ethyl-stearoyloxypiperidini
1-ethyl-acroyloxypiperidinyl, 1-
Ethyl-succinyloxypiperidinyl, 1-ethyl-
It may be a glutaryloxypiperidinyl group, preferably
Hydroxypyrrolidinyl, methoxycarbonyloxypi
Loridinyl, ethoxycarbonyloxypyrrolidinyl,
Isopropoxycarbonyloxypyrrolidinyl, t-bu
Toxycarbonyloxypyrrolidinyl, octyloxy
Carbonyloxypyrrolidinyl, nonyloxycarboni
Luoxypyrrolidinyl, decyloxycarbonyloxy
Pyrrolidinyl, hexadecyloxycarbonyloxypi
Loridinyl, octadecyloxycarbonyloxypyro
Ridinyl, acetoxypyrrolidinyl, propionyl oki
Cypyrrolidinyl, valeryloxypyrrolidinyl, pivalo
Iloxypyrrolidinyl, decanoyloxypyrrolidini
Le, undecanoyloxypyrrolidinyl, lauroyl
Xypyrrolidinyl, myristoyloxypyrrolidinyl,
Palmitoyloxypyrrolidinyl, stearoyloxy
Pyrrolidinyl, succinyloxypyrrolidinyl, gluta
Ryloxypyrrolidinyl, carbamoyloxypyrrolidinyl
Nil, N-methylcarbamoyloxypyrrolidinyl,
N, N-dimethylcarbamoyloxypyrrolidinyl, 1
-Methyl-hydroxypyrrolidinyl, 1-methyl-meth
Xycarbonyloxypyrrolidinyl, 1-methyl-eth
Xycarbonyloxypyrrolidinyl, 1-methyl-iso
Propoxycarbonyloxypyrrolidinyl, 1-methyl
-T-butoxycarbonyloxypyrrolidinyl, 1-me
Tyl-octyloxycarbonyloxypyrrolidinyl,
1-methyl-nonyloxycarbonyloxypyrrolidini
1-methyl-decyloxycarbonyloxypyrroli
Dinyl, 1-methyl-hexadecyloxycarbonyl o
Xypyrrolidinyl, 1-methyl-octadecyloxyca
Rubonyloxypyrrolidinyl, 1-methyl-acetoxy
Pyrrolidinyl, 1-methyl-propionyloxypyrrolid
Dinyl, 1-methyl-valeryloxypyrrolidinyl, 1
-Methyl-pivaloyloxypyrrolidinyl, 1-methyl
-Decanoyloxypyrrolidinyl, 1-methyl-unde
Canoyloxypyrrolidinyl, 1-methyl-lauroyl
Oxypyrrolidinyl, 1-methyl-myristoyloxy
Pyrrolidinyl, 1-methyl-palmitoyloxypyrrolid
Dinyl, 1-methyl-stearoyloxypyrrolidini
1-methyl-succinyloxypyrrolidinyl, 1-
Methyl-glutaryloxypyrrolidinyl, 1-methyl-
Carbamoyloxypyrrolidinyl, 1-methyl-N-meth
Tylcarbamoyloxypyrrolidinyl, 1-methyl-
N, N-dimethylcarbamoyloxypyrrolidinyl, 1
-Ethyl-hydroxypyrrolidinyl, 1-ethyl-meth
Xycarbonyloxypyrrolidinyl, 1-ethyl-eth
Xycarbonyloxypyrrolidinyl, 1-ethyl-iso
Propoxycarbonyloxypyrrolidinyl, 1-ethyl
-T-butoxycarbonyloxypyrrolidinyl, 1-E
Tyl-octyloxycarbonyloxypyrrolidinyl,
1-ethyl-nonyloxycarbonyloxypyrrolidini
1-ethyl-decyloxycarbonyloxypyrroli
Dinyl, 1-ethyl-hexadecyloxycarbonylo
Xypyrrolidinyl, 1-ethyl-octadecyloxyca
Rubonyloxypyrrolidinyl, 1-ethyl-acetoxy
Pyrrolidinyl, 1-ethyl-propionyloxypyrroli
Dinyl, 1-ethyl-valeryloxypyrrolidinyl, 1
-Ethyl-pivaloyloxypyrrolidinyl, 1-ethyl
-Lauroyloxypyrrolidinyl, 1-ethyl-myris
Toyloxypyrrolidinyl, 1-ethyl-palmitoyl
Oxypyrrolidinyl, 1-ethyl-stearoyloxy
Pyrrolidinyl, 1-ethyl-succinyloxypyrrolidinide
Nil, 1-ethyl-glutaryloxypyrrolidinyl, 1
-Ethyl-carbamoyloxypyrrolidinyl, hydroxy
Cipiperidinyl, methoxycarbonyloxypiperidinyl
, Ethoxycarbonyloxypiperidinyl, isopro
Poxycarbonyloxypiperidinyl, t-butoxyca
Rubonyloxypiperidinyl, octyloxycarboni
Luoxypiperidinyl, decyloxycarbonyloxy
Piperidinyl, hexadecyloxycarbonyloxypi
Peridinyl, octadecyloxycarbonyloxypipe
Ridinyl, acetoxypiperidinyl, propionyl oki
Cipiperidinyl, valeryloxypiperidinyl, pivalo
Iloxypiperidinyl, decanoyloxypiperidinyl
Le, undecanoyloxypiperidinyl, lauroyl
Xypiperidinyl, myristoyloxypiperidinyl,
Palmitoyloxy piperidinyl, stearoyloxy
Piperidinyl, succinyloxypiperidinyl, gluta
Ryloxypiperidinyl, carbamoyloxypiperidin
Nil, N-methylcarbamoyloxypiperidinyl,
N, N-dimethylcarbamoyloxypiperidinyl, 1
-Methyl-hydroxypiperidinyl, 1-methyl-meth
Xycarbonyloxypiperidinyl, 1-methyl-eth
Xycarbonyloxypiperidinyl, 1-methyl-iso
Propoxycarbonyloxypiperidinyl, 1-methyl
-T-butoxycarbonyloxypiperidinyl, 1-me
Tyl-octyloxycarbonyloxypiperidinyl,
1-methyl-decyloxycarbonyloxypiperidinini
1-methyl-hexadecyloxycarbonyloxy
Piperidinyl, 1-methyl-octadecyloxycarbo
Nyloxypiperidinyl, 1-methyl-acetoxypipe
Lysinyl, 1-methyl-propionyloxypiperidinini
1-methyl-valeryloxypiperidinyl, 1-me
Tyl-pivaloyloxypiperidinyl, 1-methyl-de
Canoyloxypiperidinyl, 1-methyl-undecano
Iloxypiperidinyl, 1-methyl-lauroyl oxy
Cipiperidinyl, 1-methyl-myristoyloxypipe
Lysinyl, 1-methyl-palmitoyloxypiperidini
1-methyl-stearoyloxypiperidinyl, 1
-Methyl-succinyloxypiperidinyl, 1-methyl
-Glutaryloxypiperidinyl, 1-methyl-carba
Moyloxypiperidinyl, 1-methyl-N, N-dime
Tylcarbamoyloxypiperidinyl, 1-ethyl-hi
Droxypiperidinyl, 1-ethyl-methoxycarbonyl
Luoxypiperidinyl, 1-ethyl-ethoxycarbonyl
Luoxypiperidinyl, 1-ethyl-isopropoxyca
Rubonyloxypiperidinyl, 1-ethyl-t-butoxy
Cycarbonyloxypiperidinyl, 1-ethyl-octyl
Luoxycarbonyloxypiperidinyl, 1-ethyl-
Decyloxycarbonyloxypiperidinyl, 1-ethyl
L-Hexadecyloxycarbonyloxypiperidini
1-ethyl-octadecyloxycarbonyloxy
Piperidinyl, 1-ethyl-acetoxypiperidinyl,
1-ethyl-propionyloxypiperidinyl, 1-e
Tyl-valeryloxypiperidinyl, 1-ethyl-piva
Royloxypiperidinyl, 1-ethyl-decanoylo
Xypiperidinyl, 1-ethyl-lauroyloxypipe
Lysinyl, 1-ethyl-myristoyloxypiperidini
1-ethyl-palmitoyloxypiperidinyl, 1
-Ethyl-stearoyloxypiperidinyl, 1-ethyl
Ru-succinyloxypiperidinyl, 1-ethyl-glu
Taryloxypiperidinyl or 1-ethyl-carbamoy
A ruoxypiperidinyl group, more preferably 4-hydroxy
Droxy-2-pyrrolidinyl, 4-ethoxycarbonyl
Oxy-2-pyrrolidinyl, 4-isopropoxycarbo
Nyloxy-2-pyrrolidinyl, 4-t-butoxycal
Bonyloxy-2-pyrrolidinyl, 4-octyloxy
Carbonyloxy-2-pyrrolidinyl, 4-decyloxy
Cycarbonyloxy-2-pyrrolidinyl, 4-hexade
Syloxycarbonyloxy-2-pyrrolidinyl, 4-
Octadecyloxycarbonyloxy-2-pyrrolidini
4-acetoxy-2-pyrrolidinyl, 4-propio
Nyloxy-2-pyrrolidinyl, 4-valeryloxy-
2-pyrrolidinyl, 4-pivaloyloxy-2-pyrroli
Dinyl, 4-decanoyloxy-2-pyrrolidinyl, 4
-Lauroyloxy-2-pyrrolidinyl, 4-myristo
Iloxy-2-pyrrolidinyl, 4-palmitoyl oki
Cy-2-pyrrolidinyl, 4-stearoyloxy-2-
Pyrrolidinyl, 4-succinyloxy-2-pyrrolidini
L, 4-glutaryloxy-2-pyrrolidinyl, 4-carb
Lubamoyloxy-2-pyrrolidinyl, 4-N-methyl
Carbamoyloxy-2-pyrrolidinyl, 4-N, N-
Dimethylcarbamoyloxy-2-pyrrolidinyl, 1-
Methyl-4-hydroxy-2-pyrrolidinyl, 1-methyl
Lu-4-ethoxycarbonyloxy-2-pyrrolidini
1-methyl-4-isopropoxycarbonyloxy
-2-Pyrrolidinyl, 1-methyl-4-t-butoxyca
Rubonyloxy-2-pyrrolidinyl, 1-methyl-4-
Octyloxycarbonyloxy-2-pyrrolidinyl,
1-methyl-4-decyloxycarbonyloxy-2-
Pyrrolidinyl, 1-methyl-4-hexadecyloxyca
Rubonyloxy-2-pyrrolidinyl, 1-methyl-4-
Octadecyloxycarbonyloxy-2-pyrrolidini
1-methyl-4-acetoxy-2-pyrrolidinyl,
1-methyl-4-propionyloxy-2-pyrrolidini
1-methyl-4-valeryloxy-2-pyrrolidini
1-methyl-4-pivaloyloxy-2-pyrrolidi
Nyl, 1-methyl-4-decanoyloxy-2-pyrroli
Dinyl, 1-methyl-4-lauroyloxy-2-pyrro
Lysinyl, 1-methyl-4-myristoyloxy-2-
Pyrrolidinyl, 1-methyl-4-palmitoyloxy-
2-pyrrolidinyl, 1-methyl-4-stearoyloxy
Cy-2-pyrrolidinyl, 1-methyl-4-succinyl
Xypyrrolidinyl, 1-methyl-4-glutaryloxy
-2-pyrrolidinyl, 1-methyl-4-carbamoylo
Xy-2-pyrrolidinyl, 1-methyl-4-N-methyl
Carbamoyloxy-2-pyrrolidinyl, 1-methyl-
4-N, N-dimethylcarbamoyloxy-2-pyrroli
Dinyl, 1-ethyl-4-hydroxy-2-pyrrolidini
1-ethyl-4-ethoxycarbonyloxy-2-
Pyrrolidinyl, 1-ethyl-4-isopropoxycarbo
Nyloxy-2-pyrrolidinyl, 1-ethyl-4-t-
Butoxycarbonyloxy-2-pyrrolidinyl, 1-E
Cyl-4-octyloxycarbonyloxy-2-pyro
Lysinyl, 1-ethyl-4-hexadecyloxycarbo
Nyloxy-2-pyrrolidinyl, 1-ethyl-4-octyl
Tadecyloxycarbonyloxy-2-pyrrolidinyl,
1-ethyl-4-acetoxy-2-pyrrolidinyl, 1-
Ethyl-4-decanoyloxy-2-pyrrolidinyl, 1
-Ethyl-4-lauroyloxy-2-pyrrolidinyl,
1-ethyl-4-myristoyloxy-2-pyrrolidini
1-ethyl-4-palmitoyloxy-2-pyrroli
Dinyl, 1-ethyl-4-stearoyloxy-2-pi
Loridinyl, 1-ethyl-4-succinyloxy-2-
Pyrrolidinyl, 4-hydroxy-2-piperidinyl or
1-methyl-4-hydroxy-2-piperidinyl group
And even more preferably 4-hydroxy-2-pyrrolididy
Nil, 4-ethoxycarbonyloxy-2-pyrrolidinyl
4-isopropoxycarbonyloxy-2-pyrroli
Dinyl, 4-t-butoxycarbonyloxy-2-pyrro
Lysinyl, 4-octyloxycarbonyloxy-2-
Pyrrolidinyl, 4-hexadecyloxycarbonyloxy
Cy-2-pyrrolidinyl, 4-octadecyloxycarbo
Nyloxy-2-pyrrolidinyl, 4-acetoxy-2-
Pyrrolidinyl, 4-pivaloyloxy-2-pyrrolidini
4-decanoyloxy-2-pyrrolidinyl, 4-la
Uroyloxy-2-pyrrolidinyl, 4-myristoyl
Oxy-2-pyrrolidinyl, 4-palmitoyloxy-
2-pyrrolidinyl, 4-stearoyloxy-2-pyro
Ridinyl, 4-succinyloxy-2-pyrrolidinyl,
4-carbamoyloxy-2-pyrrolidinyl, 4-N,
N-dimethylcarbamoyloxy-2-pyrrolidinyl,
1-methyl-4-hydroxy-2-pyrrolidinyl, 1-
Methyl-4-ethoxycarbonyloxy-2-pyrrolidi
Nyl, 1-methyl-4-isopropoxycarbonyloxy
Cy-2-pyrrolidinyl, 1-methyl-4-t-butoxy
Carbonyloxy-2-pyrrolidinyl, 1-methyl-4
-Octyloxycarbonyloxy-2-pyrrolidini
1-methyl-4-hexadecyloxycarbonyl o
Xy-2-pyrrolidinyl, 1-methyl-4-octadecyl
Luoxycarbonyloxy-2-pyrrolidinyl, 1-me
Cyl-4-acetyloxy-2-pyrrolidinyl, 1-me
Tyl-4-pivaloyloxy-2-pyrrolidinyl, 1-
Methyl-4-decanoyloxy-2-pyrrolidinyl, 1
-Methyl-4-lauroyloxy-2-pyrrolidinyl,
1-methyl-4-myristoyloxy-2-pyrrolidini
1-methyl-4-palmitoyloxy-2-pyrroli
Dinyl, 1-methyl-4-stearoyloxy-2-pi
Loridinyl, 1-methyl-4-succinyloxy-2-
Pyrrolidinyl, 1-methyl-4-carbamoyloxy-
2-pyrrolidinyl or 1-methyl-4-N, N-dimethyl
A rucarbamoyloxy-2-pyrrolidinyl group,
And more preferably 4-hydroxy-2-pyrrolidini
4-ethoxycarbonyloxy-2-pyrrolidini
4-isopropoxycarbonyloxy-2-pyrroli
Dinyl, 4-t-butoxycarbonyloxy-2-pyrro
Lysinyl, 4-octyloxycarbonyloxy-2-
Pyrrolidinyl, 4-hexadecyloxycarbonyloxy
Cy-2-pyrrolidinyl, 4-octadecyloxycarbo
Nyloxy-2-pyrrolidinyl, 4-acetoxy-2-
Pyrrolidinyl, 4-decanoyloxy-2-pyrrolidini
L, 4-lauroyloxy-2-pyrrolidinyl, 4-mi
Listoyloxy-2-pyrrolidinyl, 4-palmitoy
Luoxy-2-pyrrolidinyl, 4-stearoyloxy
-2-Pyrrolidinyl, 4-succinyloxy-2-pyro
Lysinyl, 4-carbamoyloxy-2-pyrrolidini
1-methyl-4-hydroxy-2-pyrrolidinyl,
1-methyl-4-ethoxycarbonyloxy-2-pyrro
Lysinyl, 1-methyl-4-isopropoxycarbonyl
Oxy-2-pyrrolidinyl, 1-methyl-4-t-buto
Xycarbonyloxy-2-pyrrolidinyl, 1-methyl
-4-octyloxycarbonyloxy-2-pyrrolidi
Nyl, 1-methyl-4-hexadecyloxycarbonyl
Oxy-2-pyrrolidinyl, 1-methyl-4-octade
Syloxycarbonyloxy-2-pyrrolidinyl, 1-
Methyl-4-acetoxy-2-pyrrolidinyl, 1-methyl
Lu-4-decanoyloxy-2-pyrrolidinyl, 1-me
Cyl-4-lauroyloxy-2-pyrrolidinyl, 1-
Methyl-4-myristoyloxy-2-pyrrolidinyl,
1-methyl-4-palmitoyloxy-2-pyrrolidini
1-methyl-4-stearoyloxy-2-pyrroli
Dinyl or 1-methyl-4-succinyloxy-2-pi
A loridinyl group, particularly preferably 4-hydroxy-
2-pyrrolidinyl group, 4-ethoxycarbonyloxy-
2-pyrrolidinyl group, 4-t-butoxycarbonyloxy
Cy-2-pyrrolidinyl group, 4-octyloxycarboni
Luoxy-2-pyrrolidinyl group, 4-hexadecyloxy
Cycarbonyloxy-2-pyrrolidinyl group, 4-octa
Decyloxycarbonyloxy-2-pyrrolidinyl group,
4-decanoyloxy-2-pyrrolidinyl group, 4-laur
Royloxy-2-pyrrolidinyl group, 4-myristoyl
Oxy-2-pyrrolidinyl group, 4-palmitoyloxy
-2-Pyrrolidinyl group, 4-stearoyloxy-2-
Pyrrolidinyl group, 1-methyl-4-hydroxy-2-pi
Loridinyl group, 1-methyl-4-ethoxycarbonylo
Xy-2-pyrrolidinyl group, 1-methyl-4-t-but
Xycarbonyloxy-2-pyrrolidinyl group, 1-methyl
Ru-4-octyloxycarbonyloxy-2-pyrroli
Dinyl group, 1-methyl-4-hexadecyloxycarbo
Nyloxy-2-pyrrolidinyl group, 1-methyl-4-o
Cutadecyloxycarbonyloxy-2-pyrrolidinyl
Group, 1-methyl-4-decanoyloxy-2-pyrrolidi
Nyl group, 1-methyl-4-lauroyloxy-2-pyrro
Lysinyl group, 1-methyl-4-myristoyloxy-2
-Pyrrolidinyl group, 1-methyl-4-palmitoyloxy
Cy-2-pyrrolidinyl group or 1-methyl-4-stearo
An yloxy-2-pyrrolidinyl group, most preferably
Is a 4-hydroxy-2-pyrrolidinyl group, 4-decano
Iloxy-2-pyrrolidinyl group, 4-lauroyloxy
Cy-2-pyrrolidinyl group, 4-myristoyloxy-2
-Pyrrolidinyl group, 4-palmitoyloxy-2-pyro
Lysinyl group, 4-stearoyloxy-2-pyrrolidini
Group, 1-methyl-4-hydroxy-2-pyrrolidinyl
Group, 1-methyl-4-decanoyloxy-2-pyrrolidi
Nyl group, 1-methyl-4-lauroyloxy-2-pyrro
Lysinyl group, 1-methyl-4-myristoyloxy-2
-Pyrrolidinyl group, 1-methyl-4-palmitoyloxy
Cy-2-pyrrolidinyl group or 1-methyl-4-stearo
It is an yloxy-2-pyrrolidinyl group.

The compound (I) of the present invention can be converted into a corresponding pharmacologically acceptable acid addition salt by treating with an acid according to a conventional method. Examples of such acid addition salts include, for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid, and organic acids such as acetic acid, benzoic acid, oxalic acid, maleic acid, fumaric acid, tartaric acid, and citric acid. Acid, methanesulfonic acid,
Addition salts with sulfonic acids such as benzenesulfonic acid, p-toluenesulfonic acid and the like. Furthermore, when an asymmetric carbon atom is present in the molecule of compound (I), it includes racemates and optically active isomers (preferably (2R, 4R) isomers), and includes compound (I) or a salt thereof. A hydrate is also included.

In the compound having the general formula (I), (1) R ¹ is preferably a substituted pyrrolidinyl group,
A piperidinyl group, a morpholinyl group, a thiomorpholinyl group or a piperazinyl group (the substituent is a substituent on a carbon atom which is essential, and a hydroxy group, C ₁ -C
₆ or C ₈ -C ₁₈ alkoxycarbonyloxy group,
C ₁ -C ₂₀ alkanoyloxy group, carboxy-substituted C ₃ -C ₆ alkanoyloxy group, carbamoyloxy group or mono- or di-C ₁ -C ₂ alkylcarbamoyloxy group, wherein the substituent on the nitrogen atom is desired. Which is a C ₁ -C ₄ alkyl group or a phenyl group optionally substituted by methyl, methoxy, fluorine or chlorine. ) Is (2) R ¹ is
A substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (wherein the substituent is a substituent on a carbon atom, which is a hydroxy group, C ₁ -C ₄ or C ₈ -C ₁₈ alkoxycarbonyloxy group, C ₂ -C ₅ alkanoyloxy group, C ₁₀ -
C ₁₈ alkanoyloxy group, C substituted with carboxy
₃ -C ₆ alkanoyloxy group, a carbamoyloxy group or a mono- or di-C ₁ -C ₂ alkylcarbamoyl group, the substituents on the nitrogen atom is desired,
As it is a C ₁ -C ₄ alkyl group. And (3) R ¹ is a substituted pyrrolidinyl group,
A piperidinyl group, a morpholinyl group or a thiomorpholinyl group (wherein the substituent is a substituent on a carbon atom, which is essentially hydroxy, methoxycarbonyloxy,
Ethoxycarbonyloxy, isopropoxycarbonyloxy, t-butoxycarbonyloxy, octyloxycarbonyloxy, decyloxycarbonyloxy,
Hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, acetoxy, propionyloxy, butyryloxy, valerioloxy, pivaloyloxy, decanoyloxy, undecanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, stearoyloxy, succinyloxy, glutaryl. Oxy, carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy or N, N-
Dimethylcarbamoyloxy, the substituent on the nitrogen atom being desired, which is a C ₁ -C ₂ alkyl group. ) Is (4) R ¹ is substituted,
A pyrrolidinyl group, a piperidinyl group or a morpholinyl group (the substituent is a substituent on a carbon atom which is essential and includes hydroxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, t-butoxycarbonyloxy, octyloxycarbonyloxy. , Hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, decanoyloxy, lauroyloxy,
It is a palmitoyloxy, stearoyloxy, succinyloxy, carbamoyloxy or N, N-dimethylcarbamoyloxy group, the substituent on the nitrogen atom of which is desired and is a C ₁ -C ₂ alkyl group. )
And (5) R ¹ is 4-hydroxy-2-pyrrolidinyl group, 4-ethoxycarbonyloxy-2-pyrrolidinyl group, 4-isopropoxycarbonyloxy-
2-pyrrolidinyl group, 4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 4-octyloxycarbonyloxy-2-pyrrolidinyl group, 4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-octadecyloxycarbonyloxy- 2-pyrrolidinyl group,
4-acetoxy-2-pyrrolidinyl group, 4-decanoyloxy-2-pyrrolidinyl group, 4-lauroyloxy-
2-pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 4-succinyloxy-2-pyrrolidinyl group, 4-
Carbamoyloxy-2-pyrrolidinyl group, 1-methyl-4-hydroxy-2-pyrrolidinyl group, 1-methyl-
4-ethoxycarbonyloxy-2-pyrrolidinyl group,
1-methyl-4-isopropoxycarbonyloxy-2
-Pyrrolidinyl group, 1-methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-
Octyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octadecyloxycarbonyloxy-2-pyrrolidinyl group, 1
-Methyl-4-acetoxy-2-pyrrolidinyl group, 1-
A methyl-4-decanoyloxy-2-pyrrolidinyl group,
1-methyl-4-lauroyloxy-2-pyrrolidinyl group, 1-methyl-4-myristoyloxy-2-pyrrolidinyl group, 1-methyl-4-palmitoyloxy-2-
A compound which is a pyrrolidinyl group, a 1-methyl-4-stearoyloxy-2-pyrrolidinyl group or a 1-methyl-4-succinyloxy-2-pyrrolidinyl group, (6) R ¹
Is a 4-hydroxy-2-pyrrolidinyl group, a 4-ethoxycarbonyloxy-2-pyrrolidinyl group, a 4-t-butoxycarbonyloxy-2-pyrrolidinyl group, a 4-octyloxycarbonyloxy-2-pyrrolidinyl group,
4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-octadecyloxycarbonyloxy-
2-pyrrolidinyl group, 4-decanoyloxy-2-pyrrolidinyl group, 4-lauroyloxy-2-pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4
-Palmitoyloxy-2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 1-methyl-4
-Hydroxy-2-pyrrolidinyl group, 1-methyl-4-
Ethoxycarbonyloxy-2-pyrrolidinyl group, 1-
Methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 1- Methyl-4-octadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-decanoyloxy-2-pyrrolidinyl group, 1-methyl-4-lauroyloxy-2-pyrrolidinyl group, 1-methyl-4-
Myristoyloxy-2-pyrrolidinyl group, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl group or 1
-Methyl-4-stearoyloxy-2-pyrrolidinyl group, (7) R ¹ is 4-hydroxy-2-
A pyrrolidinyl group, a 4-decanoyloxy-2-pyrrolidinyl group, a 4-lauroyloxy-2-pyrrolidinyl group,
4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 1-methyl-4-hydroxy-2-pyrrolidinyl group, 1-methyl-4-deca Noyloxy-2-pyrrolidinyl group, 1-methyl-4-
Lauroyloxy-2-pyrrolidinyl group, 1-methyl-
4-myristoyloxy-2-pyrrolidinyl group, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl group or 1-methyl-4-stearoyloxy-2-pyrrolidinyl group, (8) R ² a and R ² a compound in which b is the same or different and is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a cyano group or a nitro group, and R ² c is a hydrogen atom, (9) R ² a and R
² b are the same or different and each is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom or a bromine atom, and R ² c
Is a hydrogen atom, (10) R ² a and R ² b are
The same or different, a compound which is a hydrogen atom, a fluorine atom or a chlorine atom, and R ² c is a hydrogen atom, (11) R ² a
Is a fluorine atom and R ² b and R ² c are hydrogen atoms, and (12) R ³ a, R ³ b and R ³ c are the same or different and are a hydrogen atom, C ₁ -C ₄ Alkyl group, halogeno-C
₁ -C ₂ alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -
C ₄ alkynyl group, hydroxy group, C ₁ -C ₄ alkoxy group, Harogeno C ₁ -C ₂ alkoxy group, C ₁ -C ₄
Alkoxycarbonyl group, C ₂ -C ₅ alkanoyloxy group, a carbamoyl group, mono- or di-C ₁ -C ₂
A compound in which an alkylcarbamoyl group, a halogen atom, a cyano group, a nitro group, a C ₁ -C ₂ alkyl, a C ₁ -C ₂ alkoxy or a phenyl group which may be substituted with a halogen, and R ³ d is a hydrogen atom, (13) R ³ a, R
³ b and R ³ c are the same or different and are a hydrogen atom, C ₁ -C
₂ Alkyl groups, fluoro or chloro-C ₁ -C ₂
Alkyl group, allyl group, propargyl group, hydroxy group, C ₁ -C ₂ alkoxy group, fluoromethoxy group, difluoromethoxy group, chloromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, C ₁ -C ₂ alkoxy carbonyl group, C ₂ -C ₃ alkanoyloxy group,
A carbamoyl group, a methylcarbamoyl group, a dimethylcarbamoyl group, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a nitro group or a phenyl group which may be substituted with methyl, methoxy, fluorine or chlorine, and R ³ d is A compound which is a hydrogen atom, (14) R ³ a, R ³ b and R ³ c are:
The same or different, a hydrogen atom, a C ₁ -C ₂ alkyl group,
Fluoromethyl group, trifluoromethyl group, chloromethyl group, hydroxy group, C ₁ -C ₂ alkoxy group, fluoromethoxy group, difluoromethoxy group, 2-fluoroethoxy group, fluorine atom, chlorine atom, bromine atom, cyano group,
A compound which is a carbamoyl group or a phenyl group and R ³ d is a hydrogen atom, (15) R ³ a and R ³ b are the same or different, and are a hydrogen atom, a methyl group, a hydroxy group, a methoxy group or an ethoxy group. A fluoromethoxy group, a difluoromethoxy group, a fluorine atom, a chlorine atom, a bromine atom or a cyano group, and R ³ c and R ³ d are hydrogen atoms, (1
6) A compound in which R ³ a and R ³ b are the same or different and each is a hydrogen atom, a methoxy group or a fluorine atom, R ³ c and R ³ d are hydrogen atoms, and (17) A is a single bond. Or C ₁ -C ₄
A compound which is an alkylene group, a compound (18) A is a single bond, a methylene group, an ethylene group or a trimethylene group, and a compound (20) A whose (19) A is a single bond, a methylene group or an ethylene group is Is an ethylene group. In the same group of variables, the larger the item number, the more suitable the variable.

Further, (1)-(7), (8)-(11),
A combination of those arbitrarily selected from the group consisting of (12)-(16) and (17)-(20) is also suitable, and examples thereof include the following. (2
1) R ¹ is a substituted pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group or piperazinyl group (wherein the substituent is a substituent on a carbon atom, and a hydroxy group, C ₁ -C ₆ or C ₈ -C ₁₈ alkoxycarbonyloxy group, C ₁ -C ₂₀
Alkanoyloxy group, C ₃ substituted by carboxy -
C ₆ alkanoyloxy group, carbamoyloxy group or mono- or di-C ₁ -C ₂ alkylcarbamoyloxy group, wherein the substituent on the nitrogen atom is desired, as C ₁ -C ₄ alkyl group or methyl, A phenyl group which may be substituted with methoxy, fluorine or chlorine is shown. ), R ² a and R ² b are the same or different and each is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom, a cyano group or a nitro group, and R ² c
There is a hydrogen atom, R ³ a, R ³ b and R ³ c are the same or different, a hydrogen atom, C ₁ -C ₄ alkyl group, a halogeno -C ₁ -C ₂ alkyl group, C ₃ -C ₄ Alkenyl group, C
₃ -C ₄ alkynyl group, hydroxy group, C ₁ -C ₄ alkoxy group, Harogeno C ₁ -C ₂ alkoxy group, C ₁ -
C ₄ alkoxycarbonyl group, C ₂ -C ₅ alkanoyloxy group, a carbamoyl group, mono- or di C ₁ -
A C ₂ alkylcarbamoyl group, a halogen atom, a cyano group, a nitro group, a C ₁ -C ₂ alkyl, a C ₁ -C ₂ alkoxy or a phenyl group which may be substituted with a halogen, and R ³ d is a hydrogen atom. , A is a single bond or C
A compound which is a _1- C ₄ alkylene group, (22) R ¹ is
A substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (wherein the substituent is a substituent on a carbon atom, which is a hydroxy group, C ₁ -C ₄ or C ₈ -C ₁₈ alkoxycarbonyloxy group, C ₂ -C ₅ alkanoyloxy group, C ₁₀ -
C ₁₈ alkanoyloxy group, C substituted with carboxy
₃ -C ₆ alkanoyloxy group, a carbamoyloxy group or a mono- or di-C ₁ -C ₂ alkylcarbamoyl group, the substituents on the nitrogen atom is desired,
As it is a C ₁ -C ₄ alkyl group. ) And R ² a and R ² b are the same or different and each represents a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a bromine atom
A cyano group or a nitro group, R ² c is a hydrogen atom, and R ³ a, R ³ b and R ³ c are the same or different and are a hydrogen atom, a C ₁ -C ₄ alkyl group, a halogeno-C ₁ -C ₂ alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -C ₄ alkynyl group, hydroxy group, C ₁ -C ₄ alkoxy group, Harogeno C ₁ -C ₂ alkoxy group, C ₁ -C ₄ alkoxycarbonyl group, C ₂ -C ₅ alkanoyloxy group, a carbamoyl group, mono- or di-C ₁ -C ₂ alkylcarbamoyl group, a halogen atom, a cyano group, a nitro group or a C
An ₁ -C ₂ alkyl, C ₁ -C ₂ alkoxy or phenyl group which may be substituted with halogen, R ³ d is hydrogen atom, A is a single bond or a C ₁ -C ₄ alkylene group The compound, (23) R ^1, is a substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (wherein the substituent is a substituent on a carbon atom, and hydroxy, methoxycarbonyloxy , Ethoxycarbonyloxy, isopropoxycarbonyloxy, t-butoxycarbonyloxy, octyloxycarbonyloxy, decyloxycarbonyloxy, hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, acetoxy, propionyloxy, butyryloxy, valerioloxy, pivaloyloxy, De Noyloxy, undecanoyloxy, lauroyloxy, myristoyloxy, palmitoyloxy, stearoyloxy, succinyloxy, glutaryloxy, carbamoyloxy, N-methylcarbamoyloxy, N-ethylcarbamoyloxy or N, N-dimethylcarbamoyloxy , A substituent on the nitrogen atom is desired, which includes C ₁ -C
_{2 is} an alkyl group. ), R ² a and R ² b are the same or different and each is a hydrogen atom, a methyl group, a methoxy group, a fluorine atom, a chlorine atom or a bromine atom, R ² c is a hydrogen atom, and R ³ a, R ³ b and R ³ c are the same or different and each is a hydrogen atom, a C ₁ -C ₂ alkyl group, a fluoro- or chloro-C ₁ -C ₂ alkyl group, an allyl group, a propargyl group, a hydroxy group, C ₁ -C ₂ alkoxy group, fluoromethoxy group, difluoromethoxy group, chloromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group,
C ₁ -C ₂ alkoxycarbonyl group, C ₂ -C ₃ alkanoyloxy group, carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, fluorine atom, chlorine atom, bromine atom, cyano group, nitro group or methyl, methoxy, fluorine or A compound which is a phenyl group which may be substituted with chlorine, R ³ d is a hydrogen atom and A is a single bond, a methylene group, an ethylene group or a trimethylene group, (2
4) R ¹ is a substituted pyrrolidinyl group, piperidinyl group or morpholinyl group (wherein the substituent is a substituent on a carbon atom, which is essentially hydroxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, t-butoxycarbonyloxy, octyloxycarbonyloxy, hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, decanoyloxy, lauroyloxy, palmitoyloxy, stearoyloxy, succinyloxy, carbamoyloxy or N, N-dimethylcarbamoyloxy groups Yes,
Substituents on the nitrogen atom are desirable and include C ₁
-C is a _2-alkyl group. ) And R ² a and R ² b are
The same or different, a hydrogen atom, a fluorine atom or a chlorine atom, R ² c is a hydrogen atom, R ³ a, R ³ b and R ³ c
Are the same or different, and are a hydrogen atom, a C ₁ -C ₂ alkyl group, a fluoromethyl group, a trifluoromethyl group, a chloromethyl group, a hydroxy group, a C ₁ -C ₂ alkoxy group, a fluoromethoxy group, a difluoromethoxy group, 2-fluoroethoxy group, fluorine atom, chlorine atom, bromine atom, cyano group, carbamoyl group or phenyl group, R ³ d is hydrogen atom, A is a single bond, methylene group, ethylene group or trimethylene group A compound of (25) R ¹ is 4
-Hydroxy-2-pyrrolidinyl group, 4-ethoxycarbonyloxy-2-pyrrolidinyl group, 4-isopropoxycarbonyloxy-2-pyrrolidinyl group, 4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 4-octyloxycarbonyloxy -2-pyrrolidinyl group,
4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-octadecyloxycarbonyloxy-
2-pyrrolidinyl group, 4-acetoxy-2-pyrrolidinyl group, 4-decanoyloxy-2-pyrrolidinyl group, 4
-Lauroyloxy-2-pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 4-succinyloxy-2-pyrrolidinyl group, 4 -Carbamoyloxy-2-pyrrolidinyl group, 1-methyl-4-hydroxy-2-pyrrolidinyl group, 1-methyl-4-ethoxycarbonyloxy-2
-Pyrrolidinyl group, 1-methyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4
-T-butoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4 -Octadecyloxycarbonyloxy-2-
Pyrrolidinyl group, 1-methyl-4-acetoxy-2-pyrrolidinyl group, 1-methyl-4-decanoyloxy-2
-Pyrrolidinyl group, 1-methyl-4-lauroyloxy-2-pyrrolidinyl group, 1-methyl-4-myristoyloxy-2-pyrrolidinyl group, 1-methyl-4-palmitoyloxy-2-pyrrolidinyl group, 1-methyl- 4-
A stearoyl-2-pyrrolidinyl group or a 1-methyl-4-succinyloxy-2-pyrrolidinyl group, R ² a and R ² b are the same or different, a hydrogen atom, a fluorine atom or a chlorine atom, R ² c is a hydrogen atom,
R ³ a and R ³ b are the same or different and each is a hydrogen atom, a methyl group, a hydroxy group, a methoxy group, an ethoxy group, a fluoromethoxy group, a difluoromethoxy group, a fluorine atom, a chlorine atom, a bromine atom or a cyano group. , R ³ c and R ³ d are hydrogen atoms, A is a single bond, a methylene group or an ethylene group, (26) R ¹ is 4-hydroxy-2
-Pyrrolidinyl group, 4-ethoxycarbonyloxy-2
-Pyrrolidinyl group, 4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 4-octyloxycarbonyloxy-2-pyrrolidinyl group, 4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-octadecyloxycarbonyloxy-2 -Pyrrolidinyl group, 4
-Decanoyloxy-2-pyrrolidinyl group, 4-lauroyloxy-2-pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-
2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 1-methyl-4-hydroxy-2-pyrrolidinyl group, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-t -Butoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octadecyl group Oxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-decanoyloxy-2-pyrrolidinyl group, 1-methyl-4-lauroyloxy-2-pyrrolidinyl group, 1-methyl-4-myristoyloxy-2
- pyrrolidinyl group, a 1-methyl-4-palmitoyloxy-2-pyrrolidinyl group or a 1-methyl-4-stearoyl-2-pyrrolidinyl group, R ² a is a fluorine atom, R ² b and R ² c is a hydrogen atom, R ³ a and R ³ b are the same or different and are a hydrogen atom, a methoxy group or a fluorine atom, and R ³ c and R ³ d are a hydrogen atom,
A is an ethylene group, (27) R ¹ is 4-
Hydroxy-2-pyrrolidinyl group, 4-decanoyloxy-2-pyrrolidinyl group, 4-lauroyloxy-2-
Pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 1
-Methyl-4-hydroxy-2-pyrrolidinyl group, 1-
A methyl-4-decanoyloxy-2-pyrrolidinyl group,
1-methyl-4-lauroyloxy-2-pyrrolidinyl group, 1-methyl-4-myristoyloxy-2-pyrrolidinyl group, 1-methyl-4-palmitoyloxy-2-
Pyrrolidinyl or be 1-methyl-4-stearoyl-2-pyrrolidinyl group, R ² a is a fluorine atom, R ² b and R ² c is hydrogen atom, R ³ a and R ³ b
Are the same or different and each is a hydrogen atom, a methoxy group or a fluorine atom, R ³ c and R ³ d are hydrogen atoms, and A is
A compound that is an ethylene group.

Specific examples of suitable compounds in formula (I) include the compounds shown in Table 1 below. In addition, the compound of the following formula 3 is a compound in which R ² c and R ³ d are hydrogen atoms in the compound (I).

[0029]

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[0030]

[Table 1] ──────────────────────────────────── Example Compound No. R ¹ -AR ^Two a & R ^Two b R ^Three a, R ^Three b & R ^Three c ──────────────────────────────────── 1 CH _Two CH _Two (2-Pyr) 4-FH 2 CH _Two CH _Two (1-Me-2-Pyr) 4-FH 3 CH _Two CH _Two (1-Et-2-Pyr) 4-FH 4 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-FH 5 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-FH 6 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 4-FH 7 CH _Two CH _Two (1-Bz-4-OH-2-Pyr) 4-FH 8 CH _Two CH _Two (1-Boc-4-OH-2-Pyr) 4-FH 9 CH _Two CH _Two (1-EtOCO-4-OH-2-Pyr) 4-FH 10 CH _Two CH _Two (4-OH-2-Pyr) 4-FH 11 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4-FH 12 CH _Two CH _Two (1-Me-4-OPrp-2-Pyr) 4-FH 13 CH _Two CH _Two (1-Me-4-OBur-2-Pyr) 4-FH 14 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4-FH 15 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-FH 16 CH _Two CH _Two (1-Me-4-OHex-2-Pyr) 4-FH 17 CH _Two CH _Two (1-Me-4-OHep-2-Pyr) 4-FH 18 CH _Two CH _Two (1-Me-4-OOct-2-Pyr) 4-FH 19 CH _Two CH _Two (1-Me-4-ODec-2-Pyr) 4-FH 20 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-FH 21 CH _Two CH _Two (1-Me-4-OMyr-2-Pyr) 4-FH 22 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-FH 23 CH _Two CH _Two (1-Me-4-OSte-2-Pyr) 4-FH 24 CH _Two CH _Two (1-Me-4-OMal-2-Pyr) 4-FH 25 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-FH 26 CH _Two CH _Two (1-Me-4-OGlu-2-Pyr) 4-FH 27 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 4-FH 28 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-FH 29 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 4-FH 30 CH _Two CH _Two (1-Me-4-OCO _Two tBu-2-Pyr) 4-FH 31 CH _Two CH _Two (1-Me-4-OCO _Two Oc-2-Pyr) 4-FH 32 CH _Two CH _Two (1-Me-4-OCO _Two Dc-2-Pyr) 4-FH 33 CH _Two CH _Two (1-Me-4-OCO _Two DoD-2-Pyr) 4-FH 34 CH _Two CH _Two (1-Me-4-OCO _Two TetD-2-Pyr) 4-FH 35 CH _Two CH _Two (1-Me-4-OCO _Two HxD-2-Pyr) 4-FH 36 CH _Two CH _Two (1-Me-4-OCO _Two OcD-2-Pyr) 4-FH 37 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4-FH 38 CH _Two CH _Two (1-Me-4-OCONHMe-2-Pyr) 4-FH 39 CH _Two CH _Two (1-Me-4-OCONHEt-2-Pyr) 4-FH 40 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4-FH 41 CH _Two CH _Two (1-Me-4-OCONMeEt-2-Pyr) 4-FH 42 CH _Two CH _Two (1-Me-4-OMe-2-Pyr) 4-FH 43 CH _Two CH _Two (1-Me-4-OEt-2-Pyr) 4-FH 44 CH _Two CH _Two (1-Me-4-OiPr-2-Pyr) 4-FH 45 CH _Two CH _Two (1-Me-4-Cl-2-Pyr) 4-FH 46 CH _Two CH _Two (1-Me-4-Br-2-Pyr) 4-FH 47 CH _Two CH _Two (1-Me-4-NH2-2-Pyr) 4-FH 48 CH _Two CH _Two (1-Me-4-NHMe-2-Pyr) 4-FH 49 CH _Two CH _Two (1-Me-4-NHEt-2-Pyr) 4-FH 50 CH _Two CH _Two (1-Me-4-NMe _Two -2-Pyr) 4-FH 51 CH _Two CH _Two (1-Me-4-NEtMe-2-Pyr) 4-FH 52 CH _Two CH _Two (4-OAc-2-Pyr) 4-FH 53 CH _Two CH _Two (4-OPiv-2-Pyr) 4-FH 54 CH _Two CH _Two (4-OOct-2-Pyr) 4-FH 55 CH _Two CH _Two (4-ODec-2-Pyr) 4-FH 56 CH _Two CH _Two (4-OLau-2-Pyr) 4-FH 57 CH _Two CH _Two (4-OPal-2-Pyr) 4-FH 58 CH _Two CH _Two (4-OSuc-2-Pyr) 4-FH 59 CH _Two CH _Two (4-OAdp-2-Pyr) 4-FH 60 CH _Two CH _Two (4-OCO _Two Et-2-Pyr) 4-FH 61 CH _Two CH _Two (4-OCO _Two iPr-2-Pyr) 4-FH 62 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 4-FH 63 CH _Two CH _Two (4-OCO _Two Dc-2-Pyr) 4-FH 64 CH _Two CH _Two (4-OCO _Two HxD-2-Pyr) 4-FH 65 CH _Two CH _Two (4-OCO _Two OcD-2-Pyr) 4-FH 66 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 4-FH 67 CH _Two CH _Two (4-OCONHMe-2-Pyr) 4-FH 68 CH _Two CH _Two (4-OCONMe _Two -2-Pyr) 4-FH 69 CH _Two CH _Two (4-OMe-2-Pyr) 4-FH 70 CH _Two CH _Two (4-NH _Two -2-Pyr) 4-FH 71 CH _Two CH _Two (4-NMe _Two -2-Pyr) 4-FH 72 CH _Two CH _Two (1-Et-4-OAc-2-Pyr) 4-FH 73 CH _Two CH _Two (1-Et-4-OOct-2-Pyr) 4-FH 74 CH _Two CH _Two (1-Et-4-OLau-2-Pyr) 4-FH 75 CH _Two CH _Two (1-Et-4-OPal-2-Pyr) 4-FH 76 CH _Two CH _Two (1-Et-4-OSuc-2-Pyr) 4-FH 77 CH _Two CH _Two (1-iPr-4-OVal-2-Pyr) 4-FH 78 CH _Two CH _Two (1-iPr-4-OLau-2-Pyr) 4-FH 79 CH _Two CH _Two (1-iPr-4-OPal-2-Pyr) 4-FH 80 CH _Two CH _Two (1-iPr-4-OSuc-2-Pyr) 4-FH 81 CH _Two CH _Two (2-Pip) 4-FH 82 CH _Two CH _Two (1-Me-2-Pip) 4-FH 83 CH2 (3-Pip) 4-FH 84 CH _Two (1-Me-3-Pip) 4-FH 85 CH _Two CH _Two (1-Me-3-Pip) 4-FH 86 CH _Two CH _Two (3-Pip) 4-FH 87 CH _Two (1-Et-3-Pip) 4-FH 88 CH _Two (2-Mor) 4-FH 89 CH _Two (4-Me-2-Mor) 4-FH 90 CH _Two (2-TMor) 4-FH 91 CH _Two (4-Me-2-TMor) 4-FH 92 4-Pip 4-FH 93 1-Me-4-Pip 4-FH 94 2-Pir 4-FH 95 1,4-diMe-2-Pir 4-FH 96 1-Me-4-Et-2-Pir 4-FH 97 1-Me-4-Ph-2-Pir 4-FH 98 CH _Two CH _Two (2-Pyr) 4-F 3-OMe 99 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-OMe 100 CH _Two CH _Two (1-Boc-2-Pyr) 4-F 3-OMe 101 CH _Two CH _Two (1-Et-2-Pyr) 4-F 3-OMe 102 CH _Two CH _Two (1-iPr-2-Pyr) 4-F 3-OMe 103 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-OMe 104 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 4-F 3-OMe 105 CH _Two CH _Two (1-Bz-4-OH-2-Pyr) 4-F 3-OMe 106 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3-OMe 107 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4-F 3-OMe 108 CH _Two CH _Two (1-Me-4-OBur-2-Pyr) 4-F 3-OMe 109 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-F 3-OMe 110 CH _Two CH _Two (1-Me-4-OHex-2-Pyr) 4-F 3-OMe 111 CH _Two CH _Two (1-Me-4-OOct-2-Pyr) 4-F 3-OMe 112 CH _Two CH _Two (1-Me-4-ODec-2-Pyr) 4-F 3-OMe 113 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 3-OMe 114 CH _Two CH _Two (1-Me-4-OMyr-2-Pyr) 4-F 3-OMe 115 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F 3-OMe 116 CH _Two CH _Two (1-Me-4-OSte-2-Pyr) 4-F 3-OMe 117 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F 3-OMe 118 CH _Two CH _Two (1-Me-4-OGlu-2-Pyr) 4-F 3-OMe 119 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 4-F 3-OMe 120 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 3-OMe 121 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 4-F 3-OMe 122 CH _Two CH _Two (1-Me-4-OCO _Two Oc-2-Pyr) 4-F 3-OMe 123 CH _Two CH _Two (1-Me-4-OCO _Two DoD-2-Pyr) 4-F 3-OMe 124 CH _Two CH _Two (1-Me-4-OCO _Two TetD-2-Pyr) 4-F 3-OMe 125 CH _Two CH _Two (1-Me-4-OCO _Two HpD-2-Pyr) 4-F 3-OMe 126 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4-F 3-OMe 127 CH _Two CH _Two (1-Me-4-OCONHMe-2-Pyr) 4-F 3-OMe 128 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4-F 3-OMe 129 CH _Two CH _Two (1-Me-4-OMe-2-Pyr) 4-F 3-OMe 130 CH _Two CH _Two (1-Me-4-Cl-2-Pyr) 4-F 3-OMe 131 CH _Two CH _Two (1-Me-4-NH _Two -2-Pyr) 4-F 3-OMe 132 CH _Two CH _Two (1-Me-4-NHMe-2-Pyr) 4-F 3-OMe 133 CH _Two CH _Two (1-Me-4-NMe _Two -2-Pyr) 4-F 3-OMe 134 CH _Two CH _Two (4-OAc-2-Pyr) 4-F 3-OMe 135 CH _Two CH _Two (4-OPiv-2-Pyr) 4-F 3-OMe 136 CH _Two CH _Two (4-OOct-2-Pyr) 4-F 3-OMe 137 CH _Two CH _Two (4-OLau-2-Pyr) 4-F 3-OMe 138 CH _Two CH _Two (4-OPal-2-Pyr) 4-F 3-OMe 139 CH _Two CH _Two (4-OSuc-2-Pyr) 4-F 3-OMe 140 CH _Two CH _Two (4-OCO _Two Et-2-Pyr) 4-F 3-OMe 141 CH _Two CH _Two (4-OCO _Two iPr-2-Pyr) 4-F 3-OMe 142 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 4-F 3-OMe 143 CH _Two CH _Two (4-OCO _Two Dc-2-Pyr) 4-F 3-OMe 144 CH _Two CH _Two (4-OCO _Two OcD-2-Pyr) 4-F 3-OMe 145 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 4-F 3-OMe 146 CH _Two CH _Two (4-OCONHMe-2-Pyr) 4-F 3-OMe 147 CH _Two CH _Two (4-OCONMe _Two -2-Pyr) 4-F 3-OMe 148 CH _Two CH _Two (4-OMe-2-Pyr) 4-F 3-OMe 149 CH _Two CH _Two (4-NH _Two -2-Pyr) 4-F 3-OMe 150 CH _Two CH _Two (4-NMe _Two -2-Pyr) 4-F 3-OMe 151 CH _Two CH _Two (1-Et-4-OAc-2-Pyr) 4-F 3-OMe 152 CH _Two CH _Two (1-Et-4-OLau-2-Pyr) 4-F 3-OMe 153 CH _Two CH _Two (1-Et-4-OPal-2-Pyr) 4-F 3-OMe 154 CH _Two CH _Two (1-Et-4-OSuc-2-Pyr) 4-F 3-OMe 155 CH _Two CH _Two (1-iPr-4-OPrp-2-Pyr) 4-F 3-OMe 156 CH _Two CH _Two (1-iPr-4-OLau-2-Pyr) 4-F 3-OMe 157 CH _Two CH _Two (1-iPr-4-OSuc-2-Pyr) 4-F 3-OMe 158 CH _Two CH _Two (2-Pip) 4-F 3-OMe 159 CH _Two CH _Two (1-Me-2-Pip) 4-F 3-OMe 160 CH2 (3-Pip) 4-F 3-OMe 161 CH2 (1-Me-3-Pip) 4-F 3-OMe 162 CH2 CH2 (1- Me-3-Pip) 4-F 3-OMe 163 CH _Two CH _Two (3-Pip) 4-F 3-OMe 164 CH2 (1-Et-3-Pip) 4-F 3-OMe 165 CH2 (2-Mor) 4-F 3-OMe 166 CH2 (4-Me-2- Mor) 4-F 3-OMe 167 CH2 (4-Et-2-Mor) 4-F 3-OMe 168 CH2 (2-TMor) 4-F 3-OMe 169 CH2 (4-Me-2-TMor) 4 -F 3-OMe 170 4-Pip 4-F 3-OMe 171 1-Me-4-Pip 4-F 3-OMe 172 2-Pir 4-F 3-OMe 173 1,4-diMe-2-Pir 4 -F 3-OMe 174 1,4-diEt-2-Pir 4-F 3-OMe 175 1-Me-4-Ph-2-Pir 4-F 3-OMe 176 CH _Two CH _Two (2-Pyr) 4-F 4-F 177 CH _Two CH _Two (1-Me-2-Pyr) 4-F 4-F 178 CH _Two CH _Two (1-Et-2-Pyr) 4-F 4-F 179 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-F 180 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-F 4-F 181 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 4-F 4-F 182 CH _Two CH _Two (1-Boc-4-OH-2-Pyr) 4-F 4-F 183 CH _Two CH _Two (4-OH-2-Pyr) 4-F 4-F 184 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4-F 4-F 185 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4-F 4-F 186 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-F 4-F 187 CH _Two CH _Two (1-Me-4-OOct-2-Pyr) 4-F 4-F 188 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 4-F 189 CH _Two CH _Two (1-Me-4-OMyr-2-Pyr) 4-F 4-F 190 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F 4-F 191 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F 4-F 192 CH _Two CH _Two (1-Me-4-OGlu-2-Pyr) 4-F 4-F 193 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 4-F 4-F 194 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 4-F 195 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 4-F 4-F 196 CH _Two CH _Two (1-Me-4-OCO _Two Oc-2-Pyr) 4-F 4-F 197 CH _Two CH _Two (1-Me-4-OCO _Two Dc-2-Pyr) 4-F 4-F 198 CH _Two CH _Two (1-Me-4-OCO _Two DoD-2-Pyr) 4-F 4-F 199 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4-F 4-F 200 CH _Two CH _Two (1-Me-4-OCONHMe-2-Pyr) 4-F 4-F 201 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4-F 4-F 202 CH _Two CH _Two (1-Me-4-OMe-2-Pyr) 4-F 4-F 203 CH _Two CH _Two (1-Me-4-Cl-2-Pyr) 4-F 4-F 204 CH _Two CH _Two (1-Me-4-NH _Two -2-Pyr) 4-F 4-F 205 CH _Two CH _Two (1-Me-4-NEt _Two -2-Pyr) 4-F 4-F 206 CH _Two CH _Two (1-Me-4-NPrMe-2-Pyr) 4-F 4-F 207 CH _Two CH _Two (4-OOct-2-Pyr) 4-F 4-F 208 CH _Two CH _Two (4-OLau-2-Pyr) 4-F 4-F 209 CH _Two CH _Two (4-OPal-2-Pyr) 4-F 4-F 210 CH _Two CH _Two (4-OSuc-2-Pyr) 4-F 4-F 211 CH _Two CH _Two (4-OCO _Two iPr-2-Pyr) 4-F 4-F 212 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 4-F 4-F 213 CH _Two CH _Two (4-OCO _Two Dc-2-Pyr) 4-F 4-F 214 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 4-F 4-F 215 CH _Two CH _Two (4-OMe-2-Pyr) 4-F 4-F 216 CH _Two CH _Two (4-NH _Two -2-Pyr) 4-F 4-F 217 CH _Two CH _Two (1-Et-4-OAc-2-Pyr) 4-F 4-F 218 CH _Two CH _Two (1-Et-4-OPrp-2-Pyr) 4-F 4-F 219 CH _Two CH _Two (1-Et-4-OLau-2-Pyr) 4-F 4-F 220 CH _Two CH _Two (1-Et-4-OSuc-2-Pyr) 4-F 4-F 221 CH _Two CH _Two (1-iPr-4-OBur-2-Pyr) 4-F 4-F 222 CH _Two CH _Two (1-iPr-4-OPal-2-Pyr) 4-F 4-F 223 CH _Two CH _Two (1-iPr-4-OSuc-2-Pyr) 4-F 4-F 224 CH _Two CH _Two (2-Pip) 4-F 4-F 225 CH _Two CH _Two (1-Me-2-Pip) 4-F 4-F 226 CH _Two (3-Pip) 4-F 4-F 227 CH _Two (1-Me-3-Pip) 4-F 4-F 228 CH _Two CH _Two (1-Me-3-Pip) 4-F 4-F 229 CH _Two CH _Two (3-Pip) 4-F 4-F 230 CH _Two (1-Et-3-Pip) 4-F 4-F 231 CH _Two (2-Mor) 4-F 4-F 232 CH _Two (4-Me-2-Mor) 4-F 4-F 233 CH _Two (2-TMor) 4-F 4-F 234 CH _Two (4-Me-2-TMor) 4-F 4-F 235 4-Pip 4-F 4-F 236 1-Me-4-Pip 4-F 4-F 237 2-Pir 4-F 4-F 238 1,4-diMe-2-Pir 4-F 4-F 239 1,4-diEt-2-Pir 4-F 4-F 240 1-Me-4-Et-2-Pir 4-F 4-F 241 CH _Two CH _Two (2-Pyr) 4-F 3-OMe, 4-F 242 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-OMe, 4-F 243 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-OMe, 4-F 244 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-F 3-OMe, 4-F 245 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3-OMe, 4-F 246 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4-F 3-OMe, 4-F 247 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4-F 3-OMe, 4-F 248 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-F 3-OMe, 4-F 249 CH _Two CH _Two (1-Me-4-ONon-2-Pyr) 4-F 3-OMe, 4-F 250 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 3-OMe, 4-F 251 CH _Two CH _Two (1-Me-4-OMyr-2-Pyr) 4-F 3-OMe, 4-F 252 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F 3-OMe, 4-F 253 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F 3-OMe, 4-F 254 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 4-F 3-OMe, 4-F 255 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 3-OMe, 4-F 256 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 4-F 3-OMe, 4-F 257 CH _Two CH _Two (1-Me-4-OCO _Two Dc-2-Pyr) 4-F 3-OMe, 4-F 258 CH _Two CH _Two (1-Me-4-OCO _Two DoD-2-Pyr) 4-F 3-OMe, 4-F 259 CH _Two CH _Two (1-Me-4-OCO _Two TetD-2-Pyr) 4-F 3-OMe, 4-F 260 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4-F 3-OMe, 4-F 261 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4-F 3-OMe, 4-F 262 CH _Two CH _Two (1-Me-4-OMe-2-Pyr) 4-F 3-OMe, 4-F 263 CH _Two CH _Two (1-Me-4-Cl-2-Pyr) 4-F 3-OMe, 4-F 264 CH _Two CH _Two (1-Me-4-NH _Two -2-Pyr) 4-F 3-OMe, 4-F 265 CH _Two CH _Two (1-Me-4-NEt _Two -2-Pyr) 4-F 3-OMe, 4-F 266 CH _Two CH _Two (4-OAc-2-Pyr) 4-F 3-OMe, 4-F 267 CH _Two CH _Two (4-OPal-2-Pyr) 4-F 3-OMe, 4-F 268 CH _Two CH _Two (4-OSuc-2-Pyr) 4-F 3-OMe, 4-F 269 CH _Two CH _Two (4-OCO _Two Et-2-Pyr) 4-F 3-OMe, 4-F 270 CH _Two CH _Two (4-OCO _Two iPr-2-Pyr) 4-F 3-OMe, 4-F 271 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 4-F 3-OMe, 4-F 272 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 4-F 3-OMe, 4-F 273 CH _Two CH _Two (4-OMe-2-Pyr) 4-F 3-OMe, 4-F 274 CH _Two CH _Two (4-NH _Two -2-Pyr) 4-F 3-OMe, 4-F 275 CH _Two CH _Two (1-Et-4-OLau-2-Pyr) 4-F 3-OMe, 4-F 276 CH _Two CH _Two (1-Et-4-OPal-2-Pyr) 4-F 3-OMe, 4-F 277 CH _Two CH _Two (1-iPr-4-OLau-2-Pyr) 4-F 3-OMe, 4-F 278 CH _Two CH _Two (1-iPr-4-OSuc-2-Pyr) 4-F 3-OMe, 4-F 279 CH _Two CH _Two (2-Pip) 4-F 3-OMe, 4-F 280 CH _Two CH _Two (1-Me-2-Pip) 4-F 3-OMe, 4-F 281 CH _Two (3-Pip) 4-F 3-OMe, 4-F 282 CH _Two (1-Me-3-Pip) 4-F 3-OMe, 4-F 283 CH _Two CH _Two (1-Me-3-Pip) 4-F 3-OMe, 4-F 284 CH _Two CH _Two (3-Pip) 4-F 3-OMe, 4-F 285 CH _Two (1-Et-3-Pip) 4-F 3-OMe, 4-F 286 CH _Two (2-Mor) 4-F 3-OMe, 4-F 287 CH _Two (4-Me-2-Mor) 4-F 3-OMe, 4-F 288 CH _Two (2-TMor) 4-F 3-OMe, 4-F 289 CH _Two (4-Me-2-TMor) 4-F 3-OMe, 4-F 290 4-Pip 4-F 3-OMe, 4-F 291 1-Me-4-Pip 4-F 3-OMe, 4- F 292 2-Pir 4-F 3-OMe, 4-F 293 1,4-diMe-2-Pir 4-F 3-OMe, 4-F 294 1,4-diEt-2-Pir 4-F 3- OMe, 4-F 295 1-Me-4-Ph-2-Pir 4-F 3-OMe, 4-F 296 CH _Two CH _Two (2-Pyr) 4-F 2-OMe 297 CH _Two CH _Two (1-Me-2-Pyr) 4-F 2-OMe 298 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2-OMe 299 CH _Two CH _Two (4-OH-2-Pyr) 4-F 2-OMe 300 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4-F 2-OMe 301 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-F 2-OMe 302 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 2-OMe 303 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F 2-OMe 304 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 2-OMe 305 CH _Two CH _Two (2-Pip) 4-F 2-OMe 306 CH _Two CH _Two (1-Me-2-Pip) 4-F 2-OMe 307 CH _Two (3-Pip) 4-F 2-OMe 308 CH _Two (1-Me-3-Pip) 4-F 2-OMe 309 CH _Two CH _Two (1-Me-3-Pip) 4-F 2-OMe 310 CH _Two CH _Two (3-Pip) 4-F 2-OMe 311 CH _Two (1-Et-3-Pip) 4-F 2-OMe 312 CH _Two (2-Mor) 4-F 2-OMe 313 CH _Two (4-Me-2-Mor) 4-F 2-OMe 314 CH _Two (2-TMor) 4-F 2-OMe 315 CH _Two (4-Me-2-TMor) 4-F 2-OMe 316 4-Pip 4-F 2-OMe 317 1-Me-4-Pip 4-F 2-OMe 318 2-Pir 4-F 2-OMe 319 1,4-diMe-2-Pir 4-F 2-OMe 320 CH _Two CH _Two (2-Pyr) 4-F 4-OMe 321 CH _Two CH _Two (1-Me-2-Pyr) 4-F 4-OMe 322 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-OMe 323 CH _Two CH _Two (4-OH-2-Pyr) 4-F 4-OMe 324 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4-F 4-OMe 325 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 4-OMe 326 CH _Two CH _Two (1-Me-4-OSte-2-Pyr) 4-F 4-OMe 327 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F 4-OMe 328 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 4-OMe 329 CH _Two CH _Two (2-Pip) 4-F 4-OMe 330 CH _Two CH _Two (1-Me-2-Pip) 4-F 4-OMe 331 CH _Two (3-Pip) 4-F 4-OMe 332 CH _Two (1-Me-3-Pip) 4-F 4-OMe 333 CH _Two CH _Two (1-Me-3-Pip) 4-F 4-OMe 334 CH _Two CH _Two (3-Pip) 4-F 4-OMe 335 CH _Two (1-Et-3-Pip) 4-F 4-OMe 336 CH _Two (2-Mor) 4-F 4-OMe 337 CH _Two (4-Me-2-Mor) 4-F 4-OMe 338 CH _Two (2-TMor) 4-F 4-OMe 339 CH _Two (4-Me-2-TMor) 4-F 4-OMe 340 4-Pip 4-F 4-OMe 341 1-Me-4-Pip 4-F 4-OMe 342 2-Pir 4-F 4-OMe 343 1,4-diMe-2-Pir 4-F 4-OMe 344 CH _Two CH _Two (2-Pyr) 4-F 3,4-diF 345 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3,4-diF 346 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3,4-diF 347 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-F 3,4-diF 348 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3,4-diF 349 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4-F 3,4-diF 350 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-F 3,4-diF 351 CH _Two CH _Two (1-Me-4-ONon-2-Pyr) 4-F 3,4-diF 352 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 3,4-diF 353 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F 3,4-diF 354 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F 3,4-diF 355 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 4-F 3,4-diF 356 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 3,4-diF 357 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 4-F 3,4-diF 358 CH _Two CH _Two (1-Me-4-OCO _Two Dc-2-Pyr) 4-F 3,4-diF 359 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4-F 3,4-diF 360 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4-F 3,4-diF 361 CH _Two CH _Two (1-Me-4-OEt-2-Pyr) 4-F 3,4-diF 362 CH _Two CH _Two (1-Me-4-Br-2-Pyr) 4-F 3,4-diF 363 CH _Two CH _Two (1-Me-4-NMe _Two -2-Pyr) 4-F 3,4-diF 364 CH _Two CH _Two (4-OPal-2-Pyr) 4-F 3,4-diF 365 CH _Two CH _Two (4-OSuc-2-Pyr) 4-F 3,4-diF 366 CH _Two CH _Two (4-OCO _Two Et-2-Pyr) 4-F 3,4-diF 367 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 4-F 3,4-diF 368 CH _Two CH _Two (1-Et-4-OPal-2-Pyr) 4-F 3,4-diF 369 CH _Two CH _Two (2-Pip) 4-F 3,4-diF 370 CH _Two CH _Two (1-Me-2-Pip) 4-F 3,4-diF 371 CH _Two (3-Pip) 4-F 3,4-diF 372 CH _Two (1-Me-3-Pip) 4-F 3,4-diF 373 CH _Two CH _Two (1-Me-3-Pip) 4-F 3,4-diF 374 CH _Two CH _Two (3-Pip) 4-F 3,4-diF 375 CH _Two (1-Et-3-Pip) 4-F 3,4-diF 376 CH _Two (2-Mor) 4-F 3,4-diF 377 CH _Two (4-Me-2-Mor) 4-F 3,4-diF 378 CH _Two (2-TMor) 4-F 3,4-diF 379 CH _Two (4-Me-2-TMor) 4-F 3,4-diF 380 4-Pip 4-F 3,4-diF 381 1-Me-4-Pip 4-F 3,4-diF 382 2-Pir 4 -F 3,4-diF 383 1,4-diMe-2-Pir 4-F 3,4-diF 384 CH _Two CH _Two (2-Pyr) 4-F 2-Me 385 CH _Two CH _Two (1-Me-2-Pyr) 4-F 2-Me 386 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2-Me 387 CH _Two CH _Two (4-OH-2-Pyr) 4-F 2-Me 388 CH _Two CH _Two (2-Pip) 4-F 2-Me 389 CH _Two CH _Two (1-Me-2-Pip) 4-F 2-Me 390 CH _Two (3-Pip) 4-F 2-Me 391 CH _Two (1-Me-3-Pip) 4-F 2-Me 392 CH _Two CH _Two (1-Me-3-Pip) 4-F 2-Me 393 CH _Two CH _Two (3-Pip) 4-F 2-Me 394 CH _Two (1-Et-3-Pip) 4-F 2-Me 395 CH _Two (2-Mor) 4-F 2-Me 396 CH _Two (4-Me-2-Mor) 4-F 2-Me 397 CH _Two (2-TMor) 4-F 2-Me 398 CH _Two (4-Me-2-TMor) 4-F 2-Me 399 4-Pip 4-F 2-Me 400 1-Me-4-Pip 4-F 2-Me 401 2-Pir 4-F 2-Me 402 1,4-diMe-2-Pir 4-F 2-Me 403 CH _Two CH _Two (2-Pyr) 4-F 3-Me 404 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-Me 405 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-Me 406 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3-Me 407 CH _Two CH _Two (2-Pip) 4-F 3-Me 408 CH _Two CH _Two (1-Me-2-Pip) 4-F 3-Me 409 CH _Two (3-Pip) 4-F 3-Me 410 CH _Two (1-Me-3-Pip) 4-F 3-Me 411 CH _Two CH _Two (1-Me-3-Pip) 4-F 3-Me 412 CH _Two CH _Two (3-Pip) 4-F 3-Me 413 CH _Two (1-Et-3-Pip) 4-F 3-Me 414 CH _Two (2-Mor) 4-F 3-Me 415 CH _Two (4-Me-2-Mor) 4-F 3-Me 416 CH _Two (2-TMor) 4-F 3-Me 417 CH _Two (4-Me-2-TMor) 4-F 3-Me 418 4-Pip 4-F 3-Me 419 1-Me-4-Pip 4-F 3-Me 420 2-Pir 4-F 3-Me 421 1,4-diMe-2-Pir 4-F 3-Me 422 CH _Two CH _Two (2-Pyr) 4-F 4-Me 423 CH _Two CH _Two (1-Me-2-Pyr) 4-F 4-Me 424 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-Me 425 CH _Two CH _Two (4-OH-2-Pyr) 4-F 4-Me 426 CH _Two CH _Two (2-Pip) 4-F 4-Me 427 CH _Two CH _Two (1-Me-2-Pip) 4-F 4-Me 428 CH _Two (3-Pip) 4-F 4-Me 429 CH _Two (1-Me-3-Pip) 4-F 4-Me 430 CH _Two CH _Two (1-Me-3-Pip) 4-F 4-Me 431 CH _Two CH _Two (3-Pip) 4-F 4-Me 432 CH _Two (1-Et-3-Pip) 4-F 4-Me 433 CH _Two (2-Mor) 4-F 4-Me 434 CH _Two (4-Me-2-Mor) 4-F 4-Me 435 CH _Two (2-TMor) 4-F 4-Me 436 CH _Two (4-Me-2-TMor) 4-F 4-Me 437 4-Pip 4-F 4-Me 438 1-Me-4-Pip 4-F 4-Me 439 2-Pir 4-F 4-Me 440 1,4-diMe-2-Pir 4-F 4-Me 441 CH _Two CH _Two (2-Pyr) 4-F 2-Cl 442 CH _Two CH _Two (1-Me-2-Pyr) 4-F 2-Cl 443 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2-Cl 444 CH _Two CH _Two (4-OH-2-Pyr) 4-F 2-Cl 445 CH _Two CH _Two (2-Pip) 4-F 2-Cl 446 CH _Two CH _Two (1-Me-2-Pip) 4-F 2-Cl 447 CH _Two (3-Pip) 4-F 2-Cl 448 CH _Two (1-Me-3-Pip) 4-F 2-Cl 449 CH _Two CH _Two (1-Me-3-Pip) 4-F 2-Cl 450 CH _Two CH _Two (3-Pip) 4-F 2-Cl 451 CH _Two (1-Et-3-Pip) 4-F 2-Cl 452 CH _Two (2-Mor) 4-F 2-Cl 453 CH _Two (4-Me-2-Mor) 4-F 2-Cl 454 CH _Two (2-TMor) 4-F 2-Cl 455 CH _Two (4-Me-2-TMor) 4-F 2-Cl 456 4-Pip 4-F 2-Cl 457 1-Me-4-Pip 4-F 2-Cl 458 2-Pir 4-F 2-Cl 459 1,4-diMe-2-Pir 4-F 2-Cl 460 CH _Two CH _Two (2-Pyr) 4-F 3-Cl 461 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-Cl 462 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-Cl 463 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3-Cl 464 CH _Two CH _Two (2-Pip) 4-F 3-Cl 465 CH _Two CH _Two (1-Me-2-Pip) 4-F 3-Cl 466 CH _Two (3-Pip) 4-F 3-Cl 467 CH _Two (1-Me-3-Pip) 4-F 3-Cl 468 CH _Two CH _Two (1-Me-3-Pip) 4-F 3-Cl 469 CH _Two CH _Two (3-Pip) 4-F 3-Cl 470 CH _Two (1-Et-3-Pip) 4-F 3-Cl 471 CH _Two (2-Mor) 4-F 3-Cl 472 CH _Two (4-Me-2-Mor) 4-F 3-Cl 473 CH _Two (2-TMor) 4-F 3-Cl 474 CH _Two (4-Me-2-TMor) 4-F 3-Cl 475 4-Pip 4-F 3-Cl 476 1-Me-4-Pip 4-F 3-Cl 477 2-Pir 4-F 3-Cl 478 1,4-diMe-2-Pir 4-F 3-Cl 479 CH _Two CH _Two (2-Pyr) 4-F 4-Cl 480 CH _Two CH _Two (1-Me-2-Pyr) 4-F 4-Cl 481 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-Cl 482 CH _Two CH _Two (4-OH-2-Pyr) 4-F 4-Cl 483 CH _Two CH _Two (2-Pip) 4-F 4-Cl 484 CH _Two CH _Two (1-Me-2-Pip) 4-F 4-Cl 485 CH _Two (3-Pip) 4-F 4-Cl 486 CH _Two (1-Me-3-Pip) 4-F 4-Cl 487 CH _Two CH _Two (1-Me-3-Pip) 4-F 4-Cl 488 CH _Two CH _Two (3-Pip) 4-F 4-Cl 489 CH _Two (1-Et-3-Pip) 4-F 4-Cl 490 CH _Two (2-Mor) 4-F 4-Cl 491 CH _Two (4-Me-2-Mor) 4-F 4-Cl 492 CH _Two (2-TMor) 4-F 4-Cl 493 CH _Two (4-Me-2-TMor) 4-F 4-Cl 494 4-Pip 4-F 4-Cl 495 1-Me-4-Pip 4-F 4-Cl 496 2-Pir 4-F 4-Cl 497 1,4-diMe-2-Pir 4-F 4-Cl 498 CH _Two CH _Two (2-Pyr) 4-F 2-Br 499 CH _Two CH _Two (1-Me-2-Pyr) 4-F 2-Br 500 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2-Br 501 CH _Two CH _Two (4-OH-2-Pyr) 4-F 2-Br 502 CH _Two CH _Two (2-Pip) 4-F 2-Br 503 CH _Two CH _Two (1-Me-2-Pip) 4-F 2-Br 504 CH _Two (3-Pip) 4-F 2-Br 505 CH _Two (1-Me-3-Pip) 4-F 2-Br 506 CH _Two CH _Two (1-Me-3-Pip) 4-F 2-Br 507 CH _Two CH _Two (3-Pip) 4-F 2-Br 508 CH _Two (1-Et-3-Pip) 4-F 2-Br 509 CH _Two (2-Mor) 4-F 2-Br 510 CH _Two (4-Me-2-Mor) 4-F 2-Br 511 CH _Two (2-TMor) 4-F 2-Br 512 CH _Two (4-Me-2-TMor) 4-F 2-Br 513 4-Pip 4-F 2-Br 514 1-Me-4-Pip 4-F 2-Br 515 2-Pir 4-F 2-Br 516 1,4-diMe-2-Pir 4-F 2-Br 517 CH _Two CH _Two (2-Pyr) 4-F 3-Br 518 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-Br 519 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-Br 520 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3-Br 521 CH _Two CH _Two (2-Pip) 4-F 3-Br 522 CH _Two CH _Two (1-Me-2-Pip) 4-F 3-Br 523 CH _Two (3-Pip) 4-F 3-Br 524 CH _Two (1-Me-3-Pip) 4-F 3-Br 525 CH _Two CH _Two (1-Me-3-Pip) 4-F 3-Br 526 CH _Two CH _Two (3-Pip) 4-F 3-Br 527 CH _Two (1-Et-3-Pip) 4-F 3-Br 528 CH _Two (2-Mor) 4-F 3-Br 529 CH _Two (4-Me-2-Mor) 4-F 3-Br 530 CH _Two (2-TMor) 4-F 3-Br 531 CH _Two (4-Me-2-TMor) 4-F 3-Br 532 4-Pip 4-F 3-Br 533 1-Me-4-Pip 4-F 3-Br 534 2-Pir 4-F 3-Br 535 1,4-diMe-2-Pir 4-F 3-Br 536 CH _Two CH _Two (2-Pyr) 4-F 4-Br 537 CH _Two CH _Two (1-Me-2-Pyr) 4-F 4-Br 538 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-Br 539 CH _Two CH _Two (4-OH-2-Pyr) 4-F 4-Br 540 CH _Two CH _Two (2-Pip) 4-F 4-Br 541 CH _Two CH _Two (1-Me-2-Pip) 4-F 4-Br 542 CH _Two (3-Pip) 4-F 4-Br 543 CH _Two (1-Me-3-Pip) 4-F 4-Br 544 CH _Two CH _Two (1-Me-3-Pip) 4-F 4-Br 545 CH _Two CH _Two (3-Pip) 4-F 4-Br 546 CH _Two (1-Et-3-Pip) 4-F 4-Br 547 CH _Two (2-Mor) 4-F 4-Br 548 CH _Two (4-Me-2-Mor) 4-F 4-Br 549 CH _Two (2-TMor) 4-F 4-Br 550 CH _Two (4-Me-2-TMor) 4-F 4-Br 551 4-Pip 4-F 4-Br 552 1-Me-4-Pip 4-F 4-Br 553 2-Pir 4-F 4-Br 554 1,4-diMe-2-Pir 4-F 4-Br 555 CH _Two CH _Two (2-Pyr) 4-Cl H 556 CH _Two CH _Two (1-Me-2-Pyr) 4-Cl H 557 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Cl H 558 CH _Two CH _Two (4-OH-2-Pyr) 4-Cl H 559 CH _Two CH _Two (2-Pip) 4-Cl H 560 CH _Two CH _Two (1-Me-2-Pip) 4-Cl H 561 CH _Two (3-Pip) 4-Cl H 562 CH _Two (1-Me-3-Pip) 4-Cl H 563 CH _Two (4-Me-2-Mor) 4-Cl H 564 4-Pip 4-Cl H 565 1-Me-4-Pip 4-Cl H 566 CH _Two CH _Two (2-Pyr) 4-Cl 4-OMe 567 CH _Two CH _Two (1-Me-2-Pyr) 4-Cl 3-OMe 568 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Cl 3-OMe 569 CH _Two CH _Two (4-OH-2-Pyr) 4-Cl 3-OMe 570 CH _Two CH _Two (2-Pip) 4-Cl 2-OMe 571 CH _Two CH _Two (1-Me-2-Pip) 4-Cl 4-OMe 572 CH _Two (3-Pip) 4-Cl 3,4-diOMe 573 CH _Two (1-Me-3-Pip) 4-Cl 3-OMe 574 CH _Two (4-Me-2-Mor) 4-Cl 3-OMe, 4-Cl 575 4-Pip 4-Cl 3-Me 576 1-Me-4-Pip 4-Cl 3-OMe 577 CH _Two CH _Two (2-Pyr) 4-Cl 2-F 578 CH _Two CH _Two (1-Me-2-Pyr) 4-Cl 4-F 579 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Cl 2-Cl, 4-F 580 CH _Two CH _Two (4-OH-2-Pyr) 4-Cl 3-Me, 4-F 581 CH _Two CH _Two (2-Pip) 4-Cl 3-F 582 CH _Two CH _Two (1-Me-2-Pip) 4-Cl 3,4-diF 583 CH _Two (3-Pip) 4-Cl 3-OMe, 4-F 584 CH _Two (1-Me-3-Pip) 4-Cl 2-Me, 4-F 585 CH _Two (4-Me-2-Mor) 4-Cl 3-Cl, 4-F 586 4-Pip 4-Cl 3-OH, 4-F 587 1-Me-4-Pip 4-Cl 2,4-diF 588 CH _Two CH _Two (2-Pyr) 4-Br H 589 CH _Two CH _Two (1-Me-2-Pyr) 4-Br H 590 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Br H 591 CH _Two CH _Two (4-OH-2-Pyr) 4-Br H 592 CH _Two CH _Two (1-Me-2-Pip) 4-Br H 593 CH _Two (3-Pip) 4-Br H 594 CH _Two (1-Me-3-Pip) 4-Br H 595 CH _Two (4-Me-2-Mor) 4-Br H 596 4-Pip 4-Br H 597 1-Me-4-Pip 4-Br H 598 2-Pir 4-Br H 599 1,4-diMe-2- Pir 4-Br H 600 CH _Two CH _Two (2-Pyr) 4-Br 3-OMe 601 CH _Two CH _Two (1-Me-2-Pyr) 4-Br 3-OMe 602 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Br 3-OMe 603 CH _Two CH _Two (4-OH-2-Pyr) 4-Br 3-OMe 604 CH _Two CH _Two (2-Pip) 4-Br 3,4-diOMe 605 CH _Two CH _Two (1-Me-2-Pip) 4-Br 3-OMe, 4-Cl 606 CH _Two (3-Pip) 4-Br 4-OMe 607 CH _Two (1-Me-3-Pip) 4-Br 3-OH 608 CH _Two (4-Me-2-Mor) 4-Br 3-Me 609 4-Pip 4-Br 3-Br 610 1-Me-4-Pip 4-Br 3-OMe, 4-OH 611 CH _Two CH _Two (2-Pyr) 4-Br 3,4-diF 612 CH _Two CH _Two (1-Me-2-Pyr) 4-Br 4-F 613 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Br 4-F 614 CH _Two CH _Two (4-OH-2-Pyr) 4-Br 4-F 615 CH _Two CH _Two (2-Pip) 4-Br 3-OMe, 4-F 616 CH _Two CH _Two (1-Me-2-Pip) 4-Br 3-Cl, 4-F 617 CH _Two (3-Pip) 4-Br 2-F 618 CH _Two (1-Me-3-Pip) 4-Br 3-F 619 CH _Two (4-Me-2-Mor) 4-Br 3-Me, 4-F 620 4-Pip 4-Br 2,4-diF 621 1-Me-4-Pip 4-Br 3-OH, 4-F 622 CH _Two CH _Two (2-Pyr) 5-Cl H 623 CH _Two CH _Two (2-Pyr) 6-Cl H 624 CH _Two CH _Two (1-Me-2-Pyr) 5-Cl H 625 CH _Two CH _Two (1-Me-2-Pyr) 3-Cl H 626 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Cl H 627 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-Cl H 628 CH _Two CH _Two (4-OH-2-Pyr) 5-Cl H 629 CH _Two CH _Two (4-OH-2-Pyr) 3-Cl H 630 CH _Two CH _Two (1-Me-2-Pip) 3-Cl H 631 CH _Two CH _Two (1-Me-2-Pip) 5-Cl 3,4-diCl 632 CH _Two (3-Pip) 5-Cl H 633 CH _Two (1-Me-3-Pip) 3-Cl H 634 CH _Two (1-Me-3-Pip) 5-Cl 3-Cl 635 CH _Two (1-Me-3-Pip) 6-Cl H 636 CH _Two (4-Me-2-Mor) 5-Cl 3-OH 637 4-Pip 5-Cl H 638 2-Pir 5-Cl H 639 1,4-diMe-2-Pir 6-Cl 3-Br 640 1, 4-diMe-2-Pir 5-Cl H 641 1-Me-4-Pip 5-Cl H 642 2-Pir 3-Cl H 643 CH _Two CH _Two (2-Pyr) 5-Cl 3-OMe 644 CH _Two CH _Two (1-Me-2-Pyr) 6-Cl 3-OMe 645 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Cl 3-OMe 646 CH _Two CH _Two (4-OH-2-Pyr) 5-Cl 3-OMe 647 CH _Two CH _Two (2-Pip) 5-Cl 3,4-diOMe 648 CH _Two CH _Two (1-Me-2-Pip) 5-Cl 3-OMe, 4-Cl 649 CH _Two (3-Pip) 3-Cl 4-OMe 650 CH _Two (1-Me-3-Pip) 3-Cl 3-OH 651 CH _Two (4-Me-2-Mor) 5-Cl 3-Me 652 4-Pip 6-Cl 3-Cl 653 1-Me-4-Pip 5-Cl 3-OMe, 4-OH 654 CH _Two CH _Two (2-Pyr) 6-Cl 3,4-diF 655 CH _Two CH _Two (1-Me-2-Pyr) 5-Cl 4-F 656 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Cl 4-F 657 CH _Two CH _Two (4-OH-2-Pyr) 5-Cl 4-F 658 CH _Two CH _Two (2-Pip) 5-Cl 3-OMe, 4-F 659 CH _Two CH _Two (1-Me-2-Pip) 3-Cl 3-Cl, 4-F 660 CH _Two (3-Pip) 5-Cl 2-Br 661 CH _Two (1-Me-3-Pip) 5-Cl 3-F, 4-Cl 662 CH _Two (4-Me-2-Mor) 5-Cl 3-Me, 4-F 663 4-Pip 6-Cl 2,4-diF 664 1-Me-4-Pip 5-Cl 3-OH, 4-F 665 CH _Two CH _Two (2-Pyr) 5-Br H 666 CH _Two CH _Two (1-Me-2-Pyr) 5-Br H 667 CH _Two CH _Two (1-Me-2-Pyr) 6-Br H 668 CH _Two CH _Two (1-Et-2-Pyr) 5-Br H 669 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-Br H 670 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Br H 671 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-Br H 672 CH _Two CH _Two (4-OH-2-Pyr) 5-Br H 673 CH _Two CH _Two (1-Me-2-Pip) 5-Br H 674 CH _Two CH _Two (1-Et-2-Pip) 5-Br H 675 CH _Two (3-Pip) 5-Br H 676 CH _Two (1-Me-3-Pip) 3-Br H 677 CH _Two (1-Me-3-Pip) 5-Br H 678 CH _Two (1-Me-3-Pip) 5-Br 3-Br 679 CH _Two (4-Me-2-Mor) 5-Br 3-Cl 680 4-Pip 5-Br H 681 1-Me-2-Pir 5-Br H 682 1,4-diMe-2-Pir 6-Br H 683 1-Me-4-Et-2-Pir 5-Br H 684 1-Me-4-Pip 5-Br 3-OMe 685 2-Pir 3-Br 4-F 686 CH _Two CH _Two (2-Pyr) 5-Br 3-OMe 687 CH _Two CH _Two (1-Me-2-Pyr) 6-Br 3-OMe 688 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Br 3-OMe 689 CH _Two CH _Two (4-OH-2-Pyr) 5-Br 3-OMe 690 CH _Two CH _Two (2-Pip) 5-Br 3,4-diMe 691 CH _Two CH _Two (1-Me-2-Pip) 5-Br 3-Br, 4-Cl 692 CH _Two (3-Pip) 5-Br 3,4-diOMe 693 CH _Two (1-Me-3-Pip) 3-Br 3-Cl 694 CH _Two (4-Me-2-Mor) 5-Br 3-OMe, 4-F 695 4-Pip 6-Br 3-Cl 696 1-Me-4-Pip 5-Br 3-OMe, 4-OH 697 CH _Two CH _Two (2-Pyr) 6-Br 3,4-diF 698 CH _Two CH _Two (1-Me-2-Pyr) 5-Br 4-F 699 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Br 4-F 700 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Br 3,4-diF 701 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Br 3-OMe, 4-F 702 CH _Two CH _Two (1-Me-2-Pip) 3-Br 3-Cl, 4-F 703 CH _Two (3-Pip) 5-Br 2-Cl 704 CH _Two (1-Me-3-Pip) 5-Br 4-F 705 CH _Two (4-Me-2-Mor) 5-Br 3-Me, 4-F 706 4-Pip 5-Br 3,4-diF 707 1-Me-4-Pip 5-Br 3-OMe, 4-F 708 CH _Two CH _Two (2-Pyr) 5-OMe H 709 CH _Two CH _Two (2-Pyr) 5-OMe 3-OMe 710 CH _Two CH _Two (2-Pyr) 6-OMe 3,4-diF 711 CH _Two CH _Two (1-Me-2-Pyr) 5-OMe 4-F 712 CH _Two CH _Two (1-Me-2-Pyr) 3-OMe H 713 CH _Two CH _Two (1-Me-2-Pyr) 4-OMe H 714 CH _Two CH _Two (1-Me-2-Pyr) 4-OMe 3-OMe 715 CH _Two CH _Two (4-OH-2-Pyr) 5-OMe 3-OMe 716 CH _Two CH _Two (4-OH-2-Pyr) 6-OMe H 717 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-OMe H 718 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-OMe H 719 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-OMe H 720 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-OMe H 721 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-OMe 3-OMe, 4-F 722 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-OMe 3-OMe 723 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-OMe 3-OMe 724 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-OMe 3-OMe 725 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-OMe 4-F 726 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-OMe 4-F 727 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-OMe 3,4-diF 728 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-OMe 3-OMe, 4-F 729 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 5-OMe H 730 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 5-OMe H 731 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-OMe H 732 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 5-OMe H 733 4-Pip 5-OMe 3,4-diF 734 4-Pip 4-OMe H 735 1-Me-4-Pip 5-OMe 4- F 736 CH _Two (3-Pip) 3-OMe 2-Cl 737 CH _Two (3-Pip) 5-OMe H 738 CH _Two (3-Pip) 5-OMe 3,4-diOMe 739 CH _Two (1-Me-3-Pip) 4-OMe H 740 CH _Two (1-Me-3-Pip) 5-OMe 4-F 741 CH _Two (1-Me-3-Pip) 3-OMe 3-Br 742 CH _Two (1-Me-3-Pip) 6-OMe 3-OMe 743 CH _Two (1-Et-3-Pip) 3-OMe H 744 CH _Two CH _Two (2-Pip) 3-OMe H 745 CH _Two CH _Two (2-Pip) 5-OMe 3,4-diMe 746 CH _Two CH _Two (2-Pip) 4-OMe H 747 CH _Two CH _Two (3-Pip) 6-OMe H 748 CH _Two CH _Two (1-Me-2-Pip) 4-OMe H 749 CH _Two CH _Two (1-Me-2-Pip) 3-OMe 3-Cl, 4-F 750 CH _Two CH _Two (1-Me-2-Pip) 6-OMe 3-OMe, 4-Cl 751 CH _Two CH _Two (1-Me-2-Pip) 3-OMe H 752 CH _Two CH _Two (1-Me-2-Pip) 4-OMe H 753 CH _Two CH _Two (1-Me-3-Pip) 6-OMe H 754 2-Pir 3-OMe 4-F 755 2-Pir 4-OMe H 756 1-Me-2-Pir 5-OMe H 757 1,4-diMe- 2-Pir 6-OMe H 758 1,4-diMe-2-Pir 3-OMe H 759 1,4-diEt-2-Pir 4-OMe H 760 1-Me-4-Et-2-Pir 5-OMe H 761 1-Me-4-Ph-2-Pir 4-OMe H 762 CH _Two (4-Me-2-Mor) 5-OMe H 763 CH _Two (4-Me-2-Mor) 3-OMe 3-OMe, 4-F 764 CH _Two (4-Me-2-Mor) 5-OMe 3-Cl 765 CH _Two (4-Me-2-Mor) 5-OMe 3-OMe, 4-F 766 CH _Two (4-Me-2-TMor) 4-OMe H 767 CH _Two CH _Two (2-Pyr) 4-Me H 768 CH _Two CH _Two (2-Pyr) 5-Me 3-OMe 769 CH _Two CH _Two (1-Me-2-Pyr) 6-Me 3,4-diF 770 CH _Two CH _Two (1-Me-2-Pyr) 4-Me H 771 CH _Two CH _Two (1-Me-2-Pyr) 5-Me H 772 CH _Two CH _Two (1-Me-2-Pyr) 5-Me 4-F 773 CH _Two CH _Two (1-Me-2-Pyr) 4-Me 3-OMe 774 CH _Two CH _Two (4-OH-2-Pyr) 5-Me H 775 CH _Two CH _Two (4-OH-2-Pyr) 5-Me 3-OMe 776 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-Me 4-Br 777 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Me H 778 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Me H 779 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-Me H 780 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Me 4-F 781 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Me 3-OMe 782 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Me 3-OMe 783 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Me 4-Cl 784 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Me 3,4-diF 785 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-Me 3-OMe, 4-F 786 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-Me 3-OMe, 4-F 787 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 5-Me H 788 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 4-Me H 789 4-Pip 4-FH 790 1-Me-4-Pip 5-Me 3-OMe 791 CH _Two (3-Pip) 4-Me H 792 CH _Two (1-Me-3-Pip) 4-Me H 793 CH _Two (1-Me-3-Pip) 5-Me 4-F 794 CH _Two (1-Me-3-Pip) 3-Me 3-Cl 795 CH _Two (1-Et-3-Pip) 5-Me 3-Me 796 CH _Two CH _Two (2-Pip) 5-Me H 797 CH _Two CH _Two (1-Me-2-Pip) 4-Me H 798 2-Pir 5-Me 4-F 799 1,4-diMe-2-Pir 6-Me H 800 CH _Two (4-Me-2-Mor) 5-Me 3-OMe, 4-F 801 CH _Two (4-Me-2-Mor) 5-Me 3-Cl 802 CH _Two CH _Two (2-Pyr) 4-CN 3-OMe 803 CH _Two CH _Two (1-Me-2-Pyr) 5-CN 4-F 804 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-CN H 805 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-CN H 806 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-CN H 807 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-CN 3-OMe 808 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-CN 4-F 809 1-Me-4-Pip 5-CN 3-OMe 810 CH _Two (3-Pip) 5-CN H 811 CH _Two (1-Me-3-Pip) 4-CN H 812 1-Me-2-Pir 5-CN H 813 1,4-diMe-2-Pir 4-CN H 814 CH _Two (4-Me-2-Mor) 4-CN H 815 CH _Two CH _Two (2-Pyr) 4-NO _Two H 816 CH _Two CH _Two (2-Pyr) 5-NO _Two 3-OMe 817 CH _Two CH _Two (2-Pyr) 6-NO _Two 3,4-diF 818 CH _Two CH _Two (1-Me-2-Pyr) 4-NO _Two H 819 CH _Two CH _Two (1-Me-2-Pyr) 5-NO _Two H 820 CH _Two CH _Two (1-Me-2-Pyr) 4-NO _Two 3-OMe 821 CH _Two CH _Two (4-OH-2-Pyr) 5-NO _Two 3-OMe 822 CH _Two CH _Two (4-OH-2-Pyr) 5-NO _Two H 823 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-NO _Two H 824 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-NO _Two H 825 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-NO _Two H 826 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-NO _Two 4-F 827 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-NO _Two 3-OMe 828 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-NO _Two 3,4-diF 829 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-NO _Two 3-OMe, 4-F 830 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 6-NO _Two H 831 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-NO _Two 4-F 832 4-Pip 4-NO _Two H 833 4-Pip 5-NO _Two 3,4-diF 834 1-Me-4-Pip 4-NO _Two H 835 CH _Two (3-Pip) 5-NO _Two H 836 CH _Two (1-Me-3-Pip) 5-NO _Two 4-F 837 CH _Two CH _Two (1-Me-2-Pip) 4-NO _Two H 838 1-Me-2-Pir 5-NO _Two H 839 1,4-diMe-2-Pir 4-NO _Two H 840 CH _Two (4-Me-2-Mor) 5-NO _Two 3-Cl 841 CH _Two (4-Me-2-Mor) 4-NO _Two H 842 CH _Two CH _Two (2-Pyr) 3-FH 843 CH _Two CH _Two (1-Me-2-Pyr) 3-FH 844 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-FH 845 CH _Two CH _Two (4-OH-2-Pyr) 3-FH 846 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 3-FH 847 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 3-FH 848 CH _Two CH _Two (1-Me-4-OSte-2-Pyr) 3-FH 849 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 3-FH 850 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 3-FH 851 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 3-FH 852 CH _Two CH _Two (1-Me-4-OCO _Two OcD-2-Pyr) 3-FH 853 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 3-FH 854 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 3-FH 855 CH _Two CH _Two (4-OPal-2-Pyr) 3-FH 856 CH _Two CH _Two (4-OSuc-2-Pyr) 3-FH 857 CH _Two CH _Two (4-OCO2Et-2-Pyr) 3-FH 858 CH _Two (3-Pip) 3-FH 859 CH _Two (1-Me-3-Pip) 3-FH 860 CH _Two (4-Me-2-Mor) 3-FH 861 4-Pip 3-FH 862 1-Me-4-Pip 3-FH 863 CH _Two CH _Two (2-Pyr) 5-FH 864 CH _Two CH _Two (1-Me-2-Pyr) 5-FH 865 CH _Two CH _Two (1-Pr-2-Pyr) 5-FH 866 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-FH 867 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 5-FH 868 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 5-FH 869 CH _Two CH _Two (4-OH-2-Pyr) 5-FH 870 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 5-FH 871 CH _Two CH _Two (1-Me-2-Pip) 3-FH 872 CH _Two CH _Two (1-Me-4-OPrp-2-Pyr) 5-FH 873 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 5-FH 874 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 5-FH 875 CH _Two CH _Two (1-Me-4-OHep-2-Pyr) 5-FH 876 CH _Two CH _Two (1-Me-4-OOct-2-Pyr) 5-FH 877 CH _Two CH _Two (1-Me-4-ODec-2-Pyr) 5-FH 878 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 5-FH 879 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 5-FH 880 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 5-FH 881 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 5-FH 882 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 5-FH 883 CH _Two CH _Two (1-Me-4-OCO _Two Oc-2-Pyr) 5-FH 884 CH _Two CH _Two (1-Me-4-OCO _Two HxD-2-Pyr) 5-FH 885 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 5-FH 886 CH _Two CH _Two (1-Me-4-OCONHEt-2-Pyr) 5-FH 887 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 5-FH 888 CH _Two CH _Two (1-Me-4-OCONMePr-2-Pyr) 5-FH 889 CH _Two CH _Two (1-Me-4-OMe-2-Pyr) 5-FH 890 CH _Two CH _Two (1-Me-4-OiPr-2-Pyr) 5-FH 891 CH _Two CH _Two (1-Me-4-Cl-2-Pyr) 5-FH 892 CH _Two CH _Two (1-Me-4-NH _Two -2-Pyr) 5-FH 893 CH _Two CH _Two (1-Me-4-NHMe-2-Pyr) 5-FH 894 CH _Two CH _Two (1-Me-4-NHiPr-2-Pyr) 5-FH 895 CH _Two CH _Two (1-Me-4-NMe _Two -2-Pyr) 5-FH 896 CH _Two CH _Two (4-OAc-2-Pyr) 5-FH 897 CH _Two CH _Two (4-OPiv-2-Pyr) 5-FH 898 CH _Two CH _Two (4-OLau-2-Pyr) 5-FH 899 CH _Two CH _Two (4-OPal-2-Pyr) 5-FH 900 CH _Two CH _Two (4-OSuc-2-Pyr) 5-FH 901 CH _Two CH _Two (4-OCO _Two Pr-2-Pyr) 5-FH 902 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 5-FH 903 CH _Two CH _Two (4-OCO _Two Dc-2-Pyr) 5-FH 904 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 5-FH 905 CH _Two CH _Two (4-OCONMe _Two -2-Pyr) 5-FH 906 CH _Two CH _Two (1-Me-2-Pip) 5-FH 907 CH _Two (3-Pip) 5-FH 908 CH _Two (1-Me-3-Pip) 5-FH 909 CH _Two (1-iPr-3-Pip) 5-FH 910 CH _Two (4-Et-2-Mor) 5-FH 911 4-Pip 5-FH 912 1-Me-4-Pip 5-FH 913 1,4-diMe-2-Pir 5-FH 914 CH _Two CH _Two (1-Me-2-Pyr) 6-FH 915 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-FH 916 CH _Two CH _Two (4-OH-2-Pyr) 6-FH 917 CH _Two CH _Two (1-Me-4-OOct-2-Pyr) 6-FH 918 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 6-FH 919 CH _Two CH _Two (1-Me-4-OSte-2-Pyr) 6-FH 920 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 6-FH 921 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 6-FH 922 CH _Two CH _Two (1-Me-4-OCO _Two Dc-2-Pyr) 6-FH 923 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 6-FH 924 CH _Two CH _Two (1-Me-4-OCONHMe-2-Pyr) 6-FH 925 CH _Two CH _Two (1-Me-4-NH _Two -2-Pyr) 6-FH 926 CH _Two CH _Two (1-Me-4-NMe _Two -2-Pyr) 6-FH 927 CH _Two CH _Two (4-OPiv-2-Pyr) 6-FH 928 CH _Two CH _Two (4-OPal-2-Pyr) 6-FH 929 CH _Two CH _Two (4-OSuc-2-Pyr) 6-FH 930 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 6-FH 931 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 6-FH 933 CH _Two (1-Me-3-Pip) 6-FH 934 CH _Two (4-Me-2-Mor) 6-FH 935 4-Pip 6-FH 936 1-Me-4-Pip 6-FH 937 1-Me-4-Ph-2-Pir 6-FH 938 CH _Two CH _Two (2-Pyr) 4,5-diF H 939 CH _Two CH _Two (1-Me-2-Pyr) 4,5-diF H 940 CH _Two CH _Two (1-Et-2-Pyr) 4,5-diF H 941 CH _Two CH _Two (1-iPr-2-Pyr) 4,5-diF H 942 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4,5-diF H 943 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4,5-diF H 944 CH _Two CH _Two (1-iPr-4-OH-2-Pyr) 4,5-diF H 945 CH _Two CH _Two (1-Bzl-4-OH-2-Pyr) 4,5-diF H 946 CH _Two CH _Two (1-Boc-4-OH-2-Pyr) 4,5-diF H 947 CH _Two CH _Two (1-EtOCO-4-OH-2-Pyr) 4,5-diF H 948 CH _Two CH _Two (4-OH-2-Pyr) 4,5-diF H 949 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4,5-diF H 950 CH _Two CH _Two (1-Me-4-OPrp-2-Pyr) 4,5-diF H 951 CH _Two CH _Two (1-Me-4-OBur-2-Pyr) 4,5-diF H 952 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4,5-diF H 953 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4,5-diF H 954 CH _Two CH _Two (1-Me-4-OHex-2-Pyr) 4,5-diF H 955 CH _Two CH _Two (1-Me-4-OHep-2-Pyr) 4,5-diF H 956 CH _Two CH _Two (1-Me-4-OOct-2-Pyr) 4,5-diF H 957 CH _Two CH _Two (1-Me-4-ODec-2-Pyr) 4,5-diF H 958 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4,5-diF H 959 CH _Two CH _Two (1-Me-4-OMyr-2-Pyr) 4,5-diF H 960 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4,5-diF H 961 CH _Two CH _Two (1-Me-4-OSte-2-Pyr) 4,5-diF H 962 CH _Two CH _Two (1-Me-4-OMal-2-Pyr) 4,5-diF H 963 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4,5-diF H 964 CH _Two CH _Two (1-Me-4-OGlu-2-Pyr) 4,5-diF H 965 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 4,5-diF H 966 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4,5-diF H 967 CH _Two CH _Two (1-Me-4-OCO _Two iPr-2-Pyr) 4,5-diF H 968 CH _Two CH _Two (1-Me-4-OCO _Two Bu-2-Pyr) 4,5-diF H 969 CH _Two CH _Two (1-Me-4-OCO _Two Oc-2-Pyr) 4,5-diF H 970 CH _Two CH _Two (1-Me-4-OCO _Two Dc-2-Pyr) 4,5-diF H 971 CH _Two CH _Two (1-Me-4-OCO _Two UnD-2-Pyr) 4,5-diF H 972 CH _Two CH _Two (1-Me-4-OCO _Two PnD-2-Pyr) 4,5-diF H 973 CH _Two CH _Two (1-Me-4-OCO _Two HxD-2-Pyr) 4,5-diF H 974 CH _Two CH _Two (1-Me-4-OCO _Two HpD-2-Pyr) 4,5-diF H 975 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4,5-diF H 976 CH _Two CH _Two (1-Me-4-OCONHMe-2-Pyr) 4,5-diF H 977 CH _Two CH _Two (1-Me-4-OCONHEt-2-Pyr) 4,5-diF H 978 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4,5-diF H 979 CH _Two CH _Two (1-Me-4-OCONMeEt-2-Pyr) 4,5-diF H 980 CH _Two CH _Two (1-Me-4-OMe-2-Pyr) 4,5-diF H 981 CH _Two CH _Two (1-Me-4-OEt-2-Pyr) 4,5-diF H 982 CH _Two CH _Two (1-Me-4-Cl-2-Pyr) 4,5-diF H 983 CH _Two CH _Two (1-Me-4-NH _Two -2-Pyr) 4,5-diF H 984 CH _Two CH _Two (1-Me-4-NHMe-2-Pyr) 4,5-diF H 985 CH _Two CH _Two (1-Me-4-NMe _Two -2-Pyr) 4,5-diF H 986 CH _Two CH _Two (1-Me-4-NiPrMe-2-Pyr) 4,5-diF H 987 CH _Two CH _Two (4-OAc-2-Pyr) 4,5-diF H 988 CH _Two CH _Two (4-OiBur-2-Pyr) 4,5-diF H 989 CH _Two CH _Two (4-OOct-2-Pyr) 4,5-diF H 990 CH _Two CH _Two (4-OLau-2-Pyr) 4,5-diF H 991 CH _Two CH _Two (4-OPal-2-Pyr) 4,5-diF H 992 CH _Two CH _Two (4-OSuc-2-Pyr) 4,5-diF H 993 CH _Two CH _Two (4-OAdp-2-Pyr) 4,5-diF H 994 CH _Two CH _Two (4-OCO _Two Et-2-Pyr) 4,5-diF H 995 CH _Two CH _Two (4-OCO _Two iPr-2-Pyr) 4,5-diF H 996 CH _Two CH _Two (4-OCO _Two Oc-2-Pyr) 4,5-diF H 997 CH _Two CH _Two (4-OCO _Two Dc-2-Pyr) 4,5-diF H 998 CH _Two CH _Two (4-OCO _Two TrD-2-Pyr) 4,5-diF H 999 CH _Two CH _Two (4-OCO _Two OcD-2-Pyr) 4,5-diF H 1000 CH _Two CH _Two (4-OCONH _Two -2-Pyr) 4,5-diF H 1001 CH _Two CH _Two (4-OCONMe _Two -2-Pyr) 4,5-diF H 1002 CH _Two CH _Two (4-OMe-2-Pyr) 4,5-diF H 1003 CH _Two CH _Two (4-NH _Two -2-Pyr) 4,5-diF H 1004 CH _Two CH _Two (1-Et-4-OLau-2-Pyr) 4,5-diF H 1005 CH _Two CH _Two (1-Et-4-OPal-2-Pyr) 4,5-diF H 1006 CH _Two CH _Two (1-iPr-4-OLau-2-Pyr) 4,5-diF H 1007 CH _Two CH _Two (1-Pr-4-OPal-2-Pyr) 4,5-diF H 1008 CH _Two CH _Two (1-Et-4-OSuc-2-Pyr) 4,5-diF H 1009 CH _Two CH _Two (1-Me-2-Pip) 4,5-diF H 1010 CH _Two (3-Pip) 4,5-diF H 1011 CH _Two (1-Me-3-Pip) 4,5-diF H 1012 CH _Two CH _Two (1-Me-3-Pip) 4,5-diF H 1013 CH _Two (1-Et-3-Pip) 4,5-diF H 1014 CH _Two (2-Mor) 4,5-diF H 1015 CH _Two (4-Me-2-Mor) 4,5-diF H 1016 CH _Two (4-Me-2-TMor) 4,5-diF H 1017 4-Pip 4,5-diF H 1018 1-Me-4-Pip 4,5-diF H 1019 1,4-diMe-2-Pir 4 , 5-diF H 1020 CH _Two CH _Two (2-Pyr) 4,6-diF H 1021 CH _Two CH _Two (1-Me-2-Pyr) 3,5-diF H 1022 CH _Two CH _Two (1-Me-2-Pyr) 4,6-diF H 1023 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3,5-diF H 1024 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3,6-diF H 1025 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3,4-diF H 1026 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4,6-diF H 1027 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5,6-diF H 1028 CH _Two CH _Two (4-OH-2-Pyr) 3,4-diF H 1029 CH _Two CH _Two (4-OH-2-Pyr) 4,6-diF H 1030 CH _Two CH _Two (1-Me-4-OVal-2-Pyr) 4,6-diF H 1031 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 3,4-diF H 1032 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 3,4-diF H 1033 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4,6-diF H 1034 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 3,4-diF H 1035 CH _Two CH _Two (4-OAc-2-Pyr) 3,5-diF H 1036 CH _Two CH _Two (4-OLau-2-Pyr) 3,6-diF H 1037 CH _Two CH _Two (4-OPal-2-Pyr) 4,6-diF H 1038 CH _Two CH _Two (4-OSuc-2-Pyr) 3,4-diF H 1039 CH _Two CH _Two (1-Me-2-Pip) 4,6-diF H 1040 CH _Two (3-Pip) 3,4-diF H 1041 CH _Two (1-Me-3-Pip) 4,6-diF H 1042 CH _Two (1-Me-3-Pip) 3,6-diF H 1043 CH _Two (1-Me-3-Pip) 3,5-diF H 1044 CH _Two (1-Me-3-Pip) 5,6-diF H 1045 4-Pip 4,6-diF H 1046 1-Me-4-Pip 4,6-diF H 1047 CH _Two CH _Two (2-Pyr) 3-Cl, 4-FH 1048 CH _Two CH _Two (2-Pyr) 4-F, 5-Br H 1049 CH _Two CH _Two (2-Pyr) 4-F, 5-OMe 3-OMe, 4-F 1050 CH _Two CH _Two (1-Me-2-Pyr) 4-F, 5-OMe H 1051 CH _Two CH _Two (1-Me-2-Pyr) 4-F, 5-Me 3,4-diF 1052 CH _Two CH _Two (1-Me-2-Pyr) 4-F, 6-Me H 1053 CH _Two CH _Two (1-Me-2-Pyr) 3-Me, 4-F 3-Br 1054 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F, 5-OMe 3,4-diF 1055 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F, 6-OMe H 1056 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F, 5-Me H 1057 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 3-Cl, 4-F 3-OMe, 4-F 1058 CH _Two CH _Two (4-OH-2-Pyr) 4-F, 5-OMe 4-F 1059 CH _Two CH _Two (4-OH-2-Pyr) 3-OMe, 4-F 3-OMe, 4-F 1060 CH _Two CH _Two (4-OH-2-Pyr) 4-F, 6-Cl 3-OMe 1061 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F, 5-OMe H 1062 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F, 5-Cl 3-OMe 1063 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F, 5-Cl H 1064 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F, 5-Cl 3-OMe 1065 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4-F, 5-OMe 4-F 1066 CH _Two CH _Two (4-OAc-2-Pyr) 4-F, 5-Cl 3,4-diF 1067 CH _Two CH _Two (4-OLau-2-Pyr) 4-F, 5-OMe H 1068 CH _Two CH _Two (4-OPal-2-Pyr) 3-Me, 4-F 4-F 1069 CH _Two CH _Two (4-OSuc-2-Pyr) 4-F, 5-Cl H 1070 CH _Two CH _Two (2-Pip) 4-F, 6-OMe H 1071 CH _Two CH _Two (1-Me-2-Pip) 4-F, 5-OMe H 1072 CH _Two CH _Two (1-Me-2-Pip) 4-F, 5-Cl H 1073 CH _Two (3-Pip) 3-Br, 4-F 3,4-diF 1074 CH _Two (1-Me-3-Pip) 4-F, 5-Cl 4-F 1075 CH _Two (1-Me-3-Pip) 4-F, 5-Me 3,4-diF 1076 CH _Two (1-Me-3-Pip) 3-Me, 4-FH 1077 CH _Two (4-Me-2-Mor) 4-F, 6-Cl H 1078 CH _Two (4-Me-2-Mor) 4-F, 5-OMe H 1079 4-Pip 4-F, 5-Br H 1080 1-Me-4-Pip 4-F, 5-Cl 4-F 1081 1- Me-4-Pip 3-Br, 4-FH 1082 1,4-diMe-2-Pir 4-F, 5-Me 4-F 1083 CH _Two CH _Two (2-Pyr) 4-F 3,4,5-triCl 1084 CH _Two CH _Two (1-Me-2-Pyr) 4-F 2,4,5-triCl 1085 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3,4,5-triCl 1086 CH _Two CH _Two (1-Me-2-Pyr) 4-F, 5-Br 3,4,5-triOMe 1087 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3,4,5-triCl 1088 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3,4,5-triF 1089 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2,4,5-triF 1090 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F, 5-Cl 2,3,4-triF 1091 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2,4-diCl, 5-F 1092 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4,6-di-F 2-Cl, 4,5-diF 1093 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-Br, 4,5-diOMe 1094 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 5-Br, 3,4-diOMe 1095 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2,4-diOMe, 3-Me 1096 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2,4-diOMe, 5-OH 1097 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2,6-diOMe, 4-OH 1098 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4,6-diOMe, 2-OH 1099 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3,5-diCl, 4-OH 1100 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3,5-diCl, 2-OH 1101 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3,5-diBr, 4-OH 1102 CH _Two CH _Two (1-Et-4-OH-2-Pyr) 4-F 2,4,6-triF 1103 CH _Two CH _Two (4-OH-2-Pyr) 4,5-diF 2,4,6-triMe 1104 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 4-F 2,3,4-triOMe 1105 CH _Two CH _Two (1-Me-4-OPiv-2-Pyr) 4-F 3,4,5-triOMe 1106 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 3,4,5-triF 1107 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F 2,4,6-triOMe 1108 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4,5-diF 3,4,5-triF 1109 CH _Two CH _Two (4-OAc-2-Pyr) 4-F 3,4,5-triF 1110 CH _Two CH _Two (4-OLau-2-Pyr) 4-F 2,4,6-triF 1111 CH _Two CH _Two (4-OSuc-2-Pyr) 4-F 2,4,6-triCl 1112 CH _Two CH _Two (1-Me-2-Pip) 4-F 3,5-diCl, 4-OH 1113 CH _Two (3-Pip) 4-F 2,4,6-triOMe 1114 CH _Two (1-Me-3-Pip) 4-F 3,4,5-triF 1115 CH _Two (1-Me-3-Pip) 4-F 3,5-diCl, 4-OH 1116 CH _Two (4-Me-2-Mor) 4-F 3,5-diCl, 2-OH 1117 4-Pip 4-F 2,4,5-triF 1118 1-Me-4-Pip 4-F 3,4, 5-triF 1119 CH _Two CH _Two (2-Pyr) 4-F 4-OH 1120 CH _Two CH _Two (2-Pyr) 3-F 3-CN 1121 CH _Two CH _Two (2-Pyr) 4-F 4-NO _Two 1122 CH _Two CH _Two (2-Pyr) 4-F 3-OCF _Three 1123 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-OCHF _Two 1124 CH _Two CH _Two (1-Me-2-Pyr) 4-F 3-OH 1125 CH _Two CH _Two (1-Me-2-Pyr) 4-F 4-CF _Three 1126 CH _Two CH _Two (1-Me-2-Pyr) 5-F 3-CN 1127 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-F 3-OCF _Three 1128 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-OCHF _Two 1129 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-OCHF _Two 1130 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 5-F 4-CF _Three 1131 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-CN 1132 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2-OH 1133 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-OH 1134 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4,5-diF 3-OCCl _Three 1135 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-CCl _Three 1136 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 4-Ph 1137 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 2-NO _Two 1138 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 6-F 4-OAc 1139 CH _Two CH _Two (1-Me-4-OH-2-Pyr) 4-F 3-OCONH _Two 1140 CH _Two CH _Two (4-OH-2-Pyr) 4-F 3-OCHF _Two 1141 CH _Two CH _Two (1-Me-4-OAc-2-Pyr) 5-F 3-CCl _Three 1142 CH _Two CH _Two (1-Me-4-OLau-2-Pyr) 4-F 4-OH 1143 CH _Two CH _Two (1-Me-4-OPal-2-Pyr) 4-F 3-OCHF _Two 1144 CH _Two CH _Two (1-Me-4-OSuc-2-Pyr) 4,5-diF 4-CH _Two CH = CH _Two 1145 CH _Two CH _Two (1-Me-4-OAdp-2-Pyr) 5-F 3-OCHF _Two 1146 CH _Two CH _Two (1-Me-4-OCO _Two Et-2-Pyr) 4-F 4-Ph 1147 CH _Two CH _Two (1-Me-4-OCONH _Two -2-Pyr) 4-F 4-OH 1148 CH _Two CH _Two (1-Me-4-OCONMe _Two -2-Pyr) 4-F 4-CCl _Three 1149 CH _Two CH _Two (4-OAc-2-Pyr) 4-F 3-OCHF _Two 1150 CH _Two CH _Two (4-OLau-2-Pyr) 4-F 3-OCHCl _Two 1151 CH _Two CH _Two (4-OPal-2-Pyr) 4-F 4-CH _Two C ≡ CH 1152 CH _Two CH _Two (4-OSuc-2-Pyr) 4,6-diF 4-OCONMe _Two 1153 CH _Two CH _Two (4-OCO _Two Et-2-Pyr) 4-F 4-OH 1154 CH _Two CH _Two (1-Me-2-Pip) 4-F 3-OCHF _Two 1155 CH _Two (3-Pip) 4,5-diF 4-OCF _Three 1156 CH _Two (1-Me-3-Pip) 4-F 4-OH 1157 CH _Two (4-Me-2-Mor) 3-F 4-CF _Three 1158 4-Pip 4-F 4-OCHF _Two 1159 1-Me-4-Pip 4-F 3-OCHF _Two 1160 2-Pir 6-F 4-OPiv 1161 1,4-diMe-2-Pir 3-F 4-OCHCl _Two ──────────────────────────────────.

In the above table, the abbreviations have the following meanings. Ac: acetyl group Adp: adipoyl group Boc: t-butoxycarbonyl group Bu: butyl group tBu: t-butyl group Bur: butyryl group iBur: isobutyryl group Bz: benzyl group Dc: decyl group Dec: decanoyl group DoD: dodecyl group Et : Ethyl group Glu: Glutaryl group Hep: Heptanoyl group Hex: Hexanoyl group HpD: Heptadecyl group HxD: Hexadecyl group Lau: Lauroyl group Mal: Malonyl group Me: Methyl group Mor: Morpholinyl group Myr: Myristoyl group Non: Nonanoyl group Oc: Octanoyl group Group OcD: Octadecyl group Oct: Octanoyl group Pal: Palmitoyl group PnD: Pentadecyl group Ph: Phenyl group Pip: Piperidinyl group Pir: Piperazinyl group Piv: Pivaloyl group Pr: Propyl group iPr: Isopropyl group Prp: Propionyl group Pyr Ste: Pyrrolidyl group : Stearoyl group Suc: Succinyl group TetD Tetradecyl group TrD: tridecyl Tmor: thiomorpholinyl group UnD: undecyl Val: valeryl group.

Of these compounds, compound numbers 4, 5, 10, 11, 15, 20, 22, 25, 29, 31, 37, 4 are preferred.
0, 56, 58, 103, 113, 117, 179, 183, 190, 191
, 243, 245, 250, 253, 346, 348, 352, 353
, 354, 462, 463, 481, 482, 519, 557, 568
, 590, 626, 645, 656, 718, 719, 720, 777
, 778, 779 and 915, and more preferably compound numbers 4, 10, 20, 22, 25, 3
1, 103, 113, 117, 179, 183, 190, 191, 243, 24
5, 250, 253, 346, 348, 352, 354, 462, 481
, 519, 557, 568, 590, 645, 656, 718, 719
, 720, 777, 778, 779, and 915, and even more preferably, compound numbers 4, 10,
20, 22, 25, 103, 113, 117, 179, 183, 190, 191
, 243, 245, 250, 253, 346, 348, 352, 354
, 481, 568 and 718 compounds,
Particularly preferably, compound No. 4: 2- [2- [4-fluoro-2- (2-
Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, compound number 10: 2- [2- [4-fluoro-2- (2
-Phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine, compound number 20: 2- [2- [4-fluoro-2- (2
-Phenylethyl) phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine, compound number 25: 2- [2- [4-fluoro-2- (2
-Phenylethyl) phenoxy] ethyl] -1-methyl-4-succinyloxypyrrolidine, compound number 103: 2- [2- [4-fluoro-2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
Ethyl] -4-hydroxy-1-methylpyrrolidine, compound number 113: 2- [2- [4-fluoro-2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
Ethyl] -4-lauroyloxy-1-methylpyrrolidine, compound No. 117: 2- [2- [4-fluoro-2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
Ethyl] -1-methyl-4-succinyloxypyrrolidine, compound number 179: 2- [2- [4-fluoro-2-
[2- (4-Fluorophenyl) ethyl] phenoxy]
Ethyl] -4-hydroxy-1-methylpyrrolidine, compound number 183: 2- [2- [4-fluoro-2-
[2- (4-Fluorophenyl) ethyl] phenoxy]
Ethyl] -4-hydroxypyrrolidine, compound number 190: 2- [2- [4-fluoro-2-
[2- (4-Fluorophenyl) ethyl] phenoxy]
Ethyl] -1-methyl-4-palmitoyloxypyrrolidine, compound number 191: 2- [2- [4-fluoro-2-
[2- (4-Fluorophenyl) ethyl] phenoxy]
Ethyl] -1-methyl-4-succinyloxypyrrolidine, compound number 243: 2- [2- [4-fluoro-2-
[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, compound number 245: 2- [2- [4-fluoro-2-
[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine, compound number 250: 2- [2- [4-fluoro-2-
[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1
-Methylpyrrolidine, compound number 253: 2- [2- [4-fluoro-2-
[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methyl-4-succinyloxypyrrolidine, compound number 346: 2- [2- [2- [2- (3,4-
Difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, compound number 348: 2- [2- [2- [2- (3,4-
Difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxypyrrolidine, compound number 352: 2- [2- [2- [2- (3,4-
Difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine and compound No. 354: 2- [2- [2- [2- (3,4-
A compound of difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -1-methyl-4-succinyloxypyrrolidine may be mentioned.

[0033]

BEST MODE FOR CARRYING OUT THE INVENTION Is the compound having the general formula (I) of the present invention produced according to a known method (for example, JP-A-6-234736 and JP-A-6-306025), or Is easily manufactured according to the following method.

[0034]

Embedded image

In the above formula, R ¹ , R ² a, R ² b, R ² c, R
³ a, R ³ b, R ³ c, R ³ d and A have the same meanings as defined above, and R ¹ a is a substituted hetero atom selected from the group consisting of nitrogen, oxygen and sulfur atoms. 5- to 6-membered cyclic saturated heterocyclyl group containing 1 to 2 atoms (the substituent is a substituent on a carbon atom, which includes a protected hydroxy group, a C ₁ -C ₂₀ alkoxycarbonyloxy group). group, C ₁ -C ₂₀ alkanoyloxy group, a carbamoyloxy group or a mono -. a or di C ₁ -C ₆ alkylcarbamoyl group, also indicates that the nitrogen atom of the ring is protected), R ⁴ a, R ⁴ b, R ⁴ c and R ⁴ d are not only hydroxy-protected but also R ³ a, R ³ b and
R ³ c and R ³ d have the same meanings, Z is a hydroxy group, a halogen atom (preferably chlorine, bromine or iodine atom),
C ₁ -C ₆ alkanesulfonyloxy group or C ₁ -C ₆
Alkyl a C ₁ -C ₆ alkoxy or optionally C ₆ -C optionally substituted with halogen ₁₀ arylsulfonyloxy group.

Examples of the protective group for the hydroxy group such as R ¹ a, R ⁴ a, R ⁴ b, R ⁴ c and R ⁴ d include cyclic ether groups such as tetrahydrofuranyl and tetrahydropyranyl groups, and methoxymethyl group. , methoxymethoxymethyl group, C ₆ - C ₁₀ aryl - methyl, C ₆ -C ₁₀ aryl - be a methyloxy carbonyl group, preferably, tetrahydropyranyl, methoxymethyl, benzyl, p- methoxybenzyl, p -Brombenzyl, benzyloxycarbonyl,
p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl groups.

The protecting group such as nitrogen atom, amino group, mono-C ₁ -C ₆ alkylamino group of the heterocyclyl ring of R ¹ a is, for example, C ₁ -C ₆ alkoxycarbonyl group, C ₁
-C ₅ alkanoyl group, C ₆ -C ₁₀ aryl-methyl group, C ₆ -C ₁₀ aryl-methyloxycarbonyl group, preferably t-butoxycarbonyl, acetyl, benzyl, p-methoxybenzyl, p -Brombenzyl, benzyloxycarbonyl, p-methoxybenzyloxycarbonyl and p-bromobenzyloxycarbonyl groups.

Method A is a method for producing compound (I).
Step A1 is a step of producing a compound having the general formula (IV) and is achieved by reacting a compound having the general formula (II) with a compound having the general formula (III).

When Z represents a halogen atom, a C ₁ -C ₆ alkanesulfonyloxy group or a C ₆ -C ₁₀ arylsulfonyloxy group, this reaction is carried out in an inert solvent in the presence of a base.

The base used is preferably an alkali metal carbonate such as sodium carbonate or potassium carbonate, an alkali metal bicarbonate such as sodium bicarbonate or potassium bicarbonate, sodium fluoride or potassium fluoride. Alkali metal fluorides such as sodium hydride, potassium hydride, lithium hydride such as alkali metal hydrides, sodium methoxide, sodium ethoxide, potassium t-butoxide, alkali metal alkoxides such as lithium methoxide, Pyridine, picoline, triethylamine, N
Organic amines such as -methylmorpholine, 4-dimethylaminopyridine, more preferably alkali metal carbonate, alkali metal fluoride, alkali metal hydride or alkali metal alkoxide.

The inert solvent used is not particularly limited as long as it does not participate in the reaction, and examples thereof include hydrocarbons such as hexane, benzene and toluene, halogens such as dichloromethane, chloroform and 1,2-dichloroethane. Hydrocarbons, ethers, ethers such as tetrahydrofuran and dioxane, acetone, ketones such as methyl ethyl ketone, nitriles such as acetonitrile, N, N-dimethylacetamide, N, N-dimethylformamide, N-methylpyrrolidone , Amides such as hexamethylphosphoramide, sulfoxides such as dimethyl sulfoxide, or a mixed solvent thereof, and preferably ethers, ketones, amides or sulfoxides. The reaction temperature varies depending on the type of the starting compounds (II) and (III), the solvent and the base, but is usually from 0 ° C to 100 ° C (preferably from 10 ° C to 80 ° C). The time varies from 30 minutes to 48 hours (preferably 1 to 24 hours).

When Z represents a hydroxy group, the reaction is
It is carried out in an inert solvent in the presence of triphenylphosphine and an azodicarboxylic acid diC ₁ -C ₄ alkyl ester such as dimethyl azodicarboxylic acid and diethyl azodicarboxylic acid. The inert solvent used may be the same as those mentioned above, but aromatic hydrocarbons, halogenated hydrocarbons or ethers are preferable. The reaction temperature is usually −20 ° C. to 100 ° C. (preferably 10 ° C. to 80 ° C.), though it varies depending on the starting compounds (II) and (III), the solvent and the type of base, and the reaction time is the reaction temperature. The time is 30 minutes to 48 hours (preferably 1 to 24 hours), although it varies depending on the conditions. After completion of the reaction, the target compound (IV) of this reaction is collected from the reaction mixture according to a conventional method. For example, if insoluble matter is present, filter it off as appropriate,
By distilling off the solvent under reduced pressure or after distilling off the solvent under reduced pressure, water is added to the residue, the mixture is extracted with a water-immiscible organic solvent such as ethyl acetate, dried over anhydrous magnesium sulfate, etc., and the solvent is distilled off. It can be obtained by removing it, and if necessary, it can be further purified by a conventional method such as recrystallization or column chromatography.

The step A2 is an optional step, and the hydroxy protecting group contained in the reaction (a): R ¹ a, R ⁴ a, R ⁴ b, R ⁴ c and / or R ⁴ d is removed. Reaction, Reaction (b): Reaction of alkylating, acylating or carbamoylating the hydroxy group formed by the reaction (a) Reaction (c): Removing a protective group such as nitrogen atom and amino group contained in R ¹ a. Reaction Reaction (d): Reaction for converting hydroxy group to amino group Reaction (e): Reaction for converting alkoxycarbonyl group contained in R ¹ a to methyl group or alkanoyl group to alkyl group Reaction (f): R ¹ and a reaction (g): a method of converting a cyano group into a carbamoyl group, which is carried out in an appropriate order.

Reaction (a): R ¹ a, R in reaction (a)
⁴ a, R ⁴ b, removal of the protecting group of hydroxy included in R ⁴ c / or R ⁴ d reaction, the reaction to remove the protecting group varies depending on the kind of the protecting group, well known in synthetic organic chemistry Is done in the same way.

When the hydroxy-protecting group is an arylmethyl group or an arylmethyloxycarbonyl group, an inert solvent (preferably methanol, ethanol,
Alcohols such as isopropanol, diethyl ether
Ethers such as tellurium, tetrahydrofuran and dioxane, aromatic hydrocarbons such as toluene, benzene and xylene, aliphatic hydrocarbons such as hexane and cyclohexane, esters such as ethyl acetate and butyl acetate, A catalytic reduction catalyst (preferably palladium-carbon, Raney-nickel, platinum oxide, platinum black, rhodium-aluminum oxide, palladium-barium sulfate) in a fatty acid such as acetic acid or a mixed solvent of these organic solvents and water) Etc.) in the presence of the corresponding compound with hydrogen (usually 1 to 10 atm, preferably 1 to 3 atm). The reaction temperature is generally 0 ° C to 100 ° C (preferably 2 ° C).
The reaction time is usually 30 minutes to 48 hours (preferably 1 to 24 hours), although it varies depending on the reaction temperature and the like.

When the hydroxy-protecting group is a methoxymethyl group, a methoxymethoxymethyl group or a cyclic ether group, for example, an inert solvent (hydrocarbons such as hexane and benzene, methylene chloride, chloroform and the like) can be used. Halogenated hydrocarbons, esters such as ethyl acetate, ketones such as acetone and methyl ethyl ketone, alcohols such as methanol and ethanol, ethers such as ether, tetrahydrofuran and dioxane.
Tellurium or a mixed solvent of these organic solvents and water,
Preferred are esters, ethers, and halogenated hydrocarbons. ) In an acid (for example, an inorganic acid such as hydrogen chloride, nitric acid, hydrochloric acid, sulfuric acid, an acetic acid, an organic acid such as trifluoroacetic acid, methanesulfonic acid, p-toluenesulfonic acid, or boron trifluoride). Lewis acid such as, a strong acid cation exchange resin such as Dowex 50W (registered trademark), and the like, preferably an inorganic acid and an organic acid,
More preferred are hydrochloric acid, sulfuric acid and trifluoroacetic acid. ) Is performed. The reaction temperature is generally -10 ° C to 100 ° C (preferably -5 ° C to 50 ° C).
° C), and the reaction time varies depending on the reaction temperature and the like.
It is usually from 5 minutes to 48 hours (preferably from 30 minutes to 10 hours).

Further, R ¹ a, R ⁴ a, R can be changed by changing the kind of the protecting group of the hydroxy group and selecting the reaction condition.
⁴ b, it is possible to selectively remove the protecting group of hydroxy included in R ⁴ c / or R ⁴ d.

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an organic solvent immiscible with water such as ethyl acetate is added, and after washing with water, the solvent is distilled off. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Reaction (b): The reaction of alkylating, acylating or carbamoylating the hydroxy group in the reaction (b) is carried out by a method well known in synthetic organic chemistry. For example, inert solvents (preferably aromatic hydrocarbons such as benzene and toluene, halogenated hydrocarbons such as dichloromethane, chloroform, esters such as ethyl acetate, ethers such as tetrahydrofuran and dioxane, Acetone, ketones such as methyl ethyl ketone, amides such as N, N-dimethylacetamide)
In the presence or absence of a base (a base is preferably triethylamine, pyridine, diethylisopropylamine,
It is carried out by reacting an organic tertiary amine such as 4-dimethylaminopyridine), an alkylating agent, an acylating agent or a carbamoylating agent. Alkylation used,
Examples of the acylating or carbamoylating agent include C ₁ -C ₆ alkyl halides such as methyl iodide, ethyl iodide, propyl iodide, butyl iodide, pentyl iodide and hexyl iodide, formyloxymethyl chloride, acetoxymethyl. Like chloride, acetoxymethyl iodide, propionyloxymethyl iodide, butyryloxymethyl iodide, valeryloxymethyl iodide, pivaloyloxymethyl chloride, pivaloyloxymethyl bromide, pivaloyloxymethyl iodide C ₁ -C ₆ alkanoyloxy C ₁ -C ₆
Alkyl halide, methyl chlorocarbonate, methyl bromocarbonate, ethyl chlorocarbonate, propyl chlorocarbonate, isopropyl chlorocarbonate, butyl chlorocarbonate, t-chlorocarbonate
Butyl, pentyl chlorocarbonate, hexyl chlorocarbonate, heptyl chlorocarbonate, octyl chlorocarbonate, nonyl chlorocarbonate, decyl chlorocarbonate, undecyl chlorocarbonate, dodecyl chlorocarbonate, tridecyl chlorocarbonate, tetradecyl chlorocarbonate C ₁ -C ₁₄ alkyls,
Phenyl chlorocarbonate, chlorocarbonate tolyl chlorocarbonate fluorophenyl chlorocarbonate chlorophenyl chlorocarbonate methoxyphenyl, halogeno carbonate C ₆ -C ₁₀ aryl such as chlorocarbonate naphthyl, acetyl chloride, propionyl chloride, butyryl chloride, butyryl bromide , Isobutyryl chloride, valeryl chloride, pivaloyl chloride, hexanoyl chloride, 3,3-dimethylbutyryl chloride, heptanoyl chloride, octanoyl chloride, nonanoyl chloride, decanoyl chloride, lauroyl chloride, myristoyl chloride, Palmitoyl chloride, stearoyl chloride, eicosanoyl chloride, docosanoyl chloride, acryloyl chloride, methacryloyl chloride Ride, crotonoyloxy chloride, Reno Lero yl black good C ₂ -C ₂₀ alkanoyl halides may have a double bond, such as chloride, mixed acid anhydride of formic acid and acetic acid, acetic anhydride, propionic anhydride, butanoic anhydride , Valeric anhydride, pivalic anhydride, hexanoic anhydride, heptanoic anhydride, octanoic anhydride, nonanoic anhydride,
Decanoic anhydride, lauric anhydride, myristic anhydride, palmitic anhydride, acrylic anhydride, methacrylic acid, crotonic acid anhydride, optionally C ₂ -C also have a double bond, such as anhydrous linoleic acid ₂₀ C such as carboxylic acid anhydride, benzoic acid chloride, benzoic acid bromide, benzoic acid iodide, methylbenzoic acid chloride, methoxybenzoic acid chloride, fluorobenzoic acid chloride, chlorobenzoic acid chloride, naphthylcarboxylic acid chloride
_6- C ₁₀ arylcarboxylic acid halide, benzoic anhydride,
C ₆ -C ₁₀ arylcarboxylic acid anhydrides such as methylbenzoic anhydride, methoxybenzoic anhydride, fluorobenzoic anhydride, chlorobenzoic anhydride, naphthylcarboxylic anhydride,
Cyclic anhydrides such as succinic anhydride, glutaric anhydride, adipic anhydride, pimelic acid, suberic acid anhydride, isocyanic acid, methyl isocyanate, ethyl isocyanate, propyl isocyanate, butyl isocyanate, pentyl isocyanate, hexyl isocyanate, etc. C ₁ -C ₆ alkyl isocyanate, phenyl isocyanate, tolyl isocyanate, methoxyphenyl isocyanate, fluorophenyl isocyanate, chlorophenyl isocyanate, C ₆ -C ₁₀ aryl isocyanates such as naphthyl isocyanate,
N, N-dimethylcarbamoyl chloride, N, N-diethylcarbamoyl chloride, N, N-dipropylcarbamoyl chloride, N, N-dibutylcarbamoyl chloride, N, N-dipentylcarbamoyl chloride, N, N
-Di-C _1- , such as dihexylcarbamoyl chloride
Mention may be made of C ₆ alkylcarbamoyl halides.

The reaction for acylating a hydroxy group can also be carried out by reacting the corresponding hydroxy compound with a carboxylic acid (for example,
Acetic acid, propionic acid, butanoic acid, valeric acid, hexanoic acid,
3,3-dimethylbutanoic acid, heptanoic acid, octanoic acid,
Nonanoic acid, decanoic acid, lauric acid, myristic acid, palmitic acid, stearic acid, eicosanoic acid, docosanoic acid,
Acrylic acid, methacrylic acid, crotonic acid, double good C ₂ -C be combined to have ₂₀ aliphatic carboxylic acids, such as linolenic acid, t- butyl malonate, t- butyl succinic acid, t- butyl Glutaric acid, t-butyl adipic acid, t
- Buchirupimerin acid, t-Buchirusuberin dicarboxylic acid monoalkyl or benzoic acid, such as, methyl benzoate, methoxybenzoic acid, fluorobenzoic acid, chlorobenzoic acid, C ₆ -C ₁₀ aryl carboxylic acids such as naphthyl carboxylic acid Etc.) in the same manner as in the case where Z in the A1 step is a hydroxy group. Further, the obtained t-butyl ester compound can be treated with an acid to give the desired carboxy-substituted C ₂ -C ₇ alkanoyloxy compound as in the case of the reaction (a) in the present step. .

The reaction temperature is usually -10 ° C to 50 ° C (preferably 0 ° C to 30 ° C), and the reaction time is usually 15 minutes to 20 hours (preferably, although it varies depending on the reaction temperature and the like). 30 minutes to 10 hours).

After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method. For example, when an insoluble matter is present, it is appropriately filtered, and when the reaction solution is acidic or alkaline, it is appropriately filtered. After the neutralization, the same operation as the method of collecting the compound of the step A1 described above is performed.

Reaction (c): The reaction for removing the protecting group of the nitrogen atom contained in R ¹ a in the reaction (c) depends on the kind of the protecting group and is carried out by a method well known in synthetic organic chemistry. . When the protecting group for the nitrogen atom is an arylmethyl group or an arylmethoxycarbonyl group, the reaction is performed in the same manner as in the reaction (a) in the above step A2 when the hydroxy protecting group is an arylmethyl group.

When the nitrogen-protecting group is a t-butoxycarbonyl group, it is carried out in the same manner as the removal reaction when the hydroxy-protecting group in the reaction (a) in the above step (a) is a methoxymethyl group or the like.

Further, when the protecting group of the nitrogen atom is an alkoxycarbonyl residue, an inert solvent (preferably,
In a base (preferably lithium hydroxide, sodium hydroxide or potassium hydroxide) With an alkali metal hydroxide or an alkali metal carbonate such as sodium carbonate or potassium carbonate), and the corresponding protecting group is removed by hydrolysis.

The reaction temperature varies depending on the solvent and the like, but is ordinarily 0 ° C. to 100 ° C. (preferably room temperature to 60 ° C.), and the reaction time is usually 30 depending on the reaction temperature and the like.
Minutes to 24 hours (preferably 1 hour to 16 hours). After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method. For example, the reaction is performed by the same operation as in the method of the above-mentioned method A for collecting the compound of this step.

Reaction (d): The reaction for converting a hydroxy group into an amino group in the reaction (d) is performed by converting a hydroxy group into a sulfonyloxy group and converting a sulfonyloxy group into an azido group, or converting the hydroxy group into a halogen atom. (Preferably, chlorine, bromine or iodine) is converted, the halogen atom is converted into an azide group, and then the azide group is reduced.

The reaction for converting a hydroxy group to a sulfonyloxy group is carried out in the presence or absence of a base by a sulfonylating agent (for example, C such as methanesulfonyl chloride, methanesulfonyl bromide, ethanesulfonyl chloride, butanesulfonyl chloride). ₁ -C ₄ alkanesulfonyl halides, benzenesulfonyl chloride,
Benzenesulfonyl bromide, C ₆ -C ₁₀ arylsulfonyl halide such as p-toluenesulfonyl chloride, naphthalenesulfonyl chloride, etc., preferably methanesulfonyl chloride, benzenesulfonyl chloride or p-toluenesulfonyl chloride)
And is carried out in the same manner as in the reaction (b) of this step.

The reaction for converting a hydroxy group into a halogen atom is carried out in the presence or absence of a base in the presence of a halogenating agent (eg, thionyl chloride, thionyl halide such as thionyl bromide, phosphorus oxychloride, phosphorus oxybromide). Phosphorus halides such as phosphorus oxyhalide, phosphorus trichloride, phosphorus tribromide, phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide,
Triphenylphosphine dichloride, triphenylphosphine dibromide, triphenylphosphine C ₆ -C ₁₀ arylphosphine dihalide such as diiodide, tri C ₆ -C ₁₀ arylphosphine and carbon tetrachloride as triphenylphosphine, four Carbon bromide, mixtures of carbon tetrahalides such as carbon tetraiodide, tri-C ₆ -C ₁₀ arylphosphines such as triphenylphosphine and N-chlorosuccinimides, N-halogenenoes such as N-bromosuccinimides. Mixtures of succinimides, preferably thionyl halide, phosphorus halide or C ₆
—C ₁₀ arylphosphine dihalides, particularly preferably,
Thionyl chloride, phosphorus trichloride, phosphorus tribromide, triphenylphosphine dichloride, triphenylphosphine dibromide or triphenylphosphine diiodide) is allowed to act, and the reaction is carried out in the same manner as in the reaction (b) of the present step.

The reaction for converting a sulfonyloxy group or a halogen atom into an azido group is carried out in an inert solvent (preferably ethers such as tetrahydrofuran and dioxane, amides such as dimethylformamide and dimethylacetamide). The compound and an alkali metal azide (preferably sodium azide, potassium azide) at 0 ° C to 150 ° C (preferably room temperature to 100 ° C) for 30 minutes to 20 hours (preferably 1 hour to 10 hours). It is carried out by reacting.

The reaction for reducing an azido group is carried out by removing the protecting group by catalytic reduction when the protecting group for the hydroxy group in the reaction (a) in the above step is an arylmethyl group or the reaction in the following step ( The same is done as in e). After completion of the reaction, the product of each reaction can be collected from the reaction mixture by a conventional method, for example, the same operation as the method for collecting the compound of Step A1 described above.

Reaction (e): The reaction for converting the alkoxycarbonyl group contained in R ⁶ a into a methyl group or the alkanoyl group into an alkyl group in the reaction (e) is carried out in an inert solvent (preferably ether, tetrahydrofuran, It is carried out by reacting with a reducing agent (preferably an alkali metal aluminum hydride such as lithium aluminum hydride) in ethers such as dioxane). The reaction temperature varies depending on the solvent and the like, but is usually 0 ° C to 100 ° C.
° C (preferably from room temperature to 80 ° C), and the reaction time varies depending on the reaction temperature and the like, but is usually from 30 minutes to 24 hours (preferably from 1 hour to 16 hours). After completion of the reaction, the reaction product can be collected from the reaction mixture by a conventional method, for example, the same operation as the method for collecting the compound of Step A1 described above.

Reaction (f): The reaction for alkylating the ═NH group contained in R ¹ a in the reaction (f) is carried out by using methyl iodide, ethyl iodide, propyl iodide, butyl iodide as an alkylating agent. A C ₁ -C ₆ alkyl halide such as pentyl iodide or hexyl iodide can be converted into a base (for example,
Alkali metal carbonates such as potassium carbonate and sodium carbonate; alkali metal hydrides such as sodium hydride)
Is carried out in the same manner as in the reaction (b) in the present step.

Reaction (g): The reaction for converting the cyano group into a carbamoyl group in the reaction (g) is carried out by using an inert solvent (for example, water-containing alcohols such as water-containing methanol and water-containing ethanol, water-containing ether). , Water-containing tetrahydrofuran, water-containing ethers such as water-containing dioxane, or water, preferably water-containing alcohols, the corresponding compound is a base (for example, alkali metal water such as sodium hydroxide or potassium hydroxide). It is an alkali metal carbonate such as an oxide, sodium carbonate or potassium carbonate, and is preferably carried out by reacting with an alkali metal hydroxide). The reaction temperature is usually 10 ° C to 200 ° C (preferably 50 ° C).
The reaction time varies depending on the reaction temperature and the like, but is usually 30 minutes to 48 hours (preferably 1 hour to 20 hours).

After completion of the reaction, the target compound of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, an organic solvent immiscible with water such as ethyl acetate is added, and after washing with water, the solvent is distilled off. can get. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

Compound (I) can be converted into a pharmaceutically acceptable salt by treating with an acid according to a conventional method. For example, in an inert solvent (preferably ethers such as ether, tetrahydrofuran and dioxane, alcohols such as methanol and ethanol, halogenated hydrocarbons such as methylene chloride and chloroform) and the corresponding acid at room temperature. For 5 minutes to 1 hour, and the solvent can be distilled off under reduced pressure. The hydrochloride can be obtained by adsorbing compound (I) or an acid addition salt thereof on an acidic resin column [for example, CM-Sephadex C-25 (registered trademark) or the like] and eluting dilute hydrochloric acid. . The starting compound (II) is known or is produced according to a known method (for example, JP-A-55-20740, JP-A-2-304022, JP-A-6-206).
234736, JP-A-6-306025, etc.).

Compound (I) has almost no adrenergic α ₁ antagonism, has serotonin 2 receptor antagonism and squalene synthase inhibitory activity, and since these actions are persistent and weakly toxic (1 ) A therapeutic or prophylactic agent (preferably a therapeutic agent) for thrombotic diseases and arteriosclerotic diseases based on the inhibition of platelet aggregation by blocking the serotonin 2 receptor distributed in vascular endothelial cells and platelets, or due to these diseases Which are useful as therapeutic or preventive agents (preferably therapeutic agents) for various diseases such as coronary artery disease and cerebrovascular disease, and (2) hyperlipidemia and arteriosclerotic diseases based on cholesterol lowering action. Useful as a therapeutic or prophylactic agent. (3) Excellent arteriosclerosis by combining serotonin 2 receptor antagonistic action and cholesterol lowering action. It is useful as a therapeutic or preventive agent for sexually transmitted diseases (preferably, a therapeutic agent).

When the compound (I) of the present invention and a pharmacologically acceptable salt thereof are used as a therapeutic or prophylactic agent for the above-mentioned diseases, itself or a suitable pharmacologically acceptable excipient. , A diluent, etc., and can be administered orally by tablets, capsules, granules, powders, syrups, etc. or parenterally by injections, etc. These preparations may contain excipients (e.g., sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; starch derivatives such as corn starch, potato starch, α-starch, dextrin, carboxymethyl starch; crystalline cellulose). Cellulose derivatives such as low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, and internally cross-linked sodium carboxymethylcellulose; gum arabic; dextran; pullulan; light anhydrous silicic acid, synthetic aluminum silicate, magnesium aluminate metasilicate Phosphate derivatives such as calcium phosphate;
Carbonate derivatives such as calcium carbonate; sulfate derivatives such as calcium sulfate; binders (eg, the above-mentioned excipients; gelatin; polyvinylpyrrolidone; magrogol; etc.); disintegrants (eg, the above-described excipients) Agents; croscarmellose sodium, sodium carboxymethyl starch, chemically modified starch such as cross-linked polyvinyl pyrrolidone, starch, cellulose derivatives, etc.), lubricants (eg, talc; stearic acid; calcium stearate;
Metal stearates such as magnesium stearate; colloidal silica; Luxs such as bee gum and gallow; boric acid; glycols; carboxylic acids such as fumaric acid and adipic acid; sodium carboxylic acid salts such as sodium benzoate; sulfuric acid. Sulfates such as sodium;
Leucine; lauryl sulfates such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acids such as silicic anhydride and silicic acid hydrate; starch derivatives in the above-mentioned excipients); stabilizers (eg, methyl paraben, propyl paraben) Paraoxybenzoic acid esters; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride;
Phenols such as phenol and cresol; thimerosal; acetic anhydride; sorbic acid, etc.), flavoring agents (eg, commonly used sweeteners, sour agents, flavors, etc.), diluents, solvents for injections (eg, Water, ethanol, glycerin and the like) are used and manufactured by a known method. The dosage varies depending on symptoms, age, etc., but in the case of oral administration, the lower limit is 1 mg per day (preferably 10 mg
g), an upper limit of 2000 mg (preferably 400 mg)
In the case of intravenous administration, the lower limit is 0.1 mg (preferably 1 mg) and the upper limit is 500 mg (preferably 300 mg per day).
mg) is desirably administered to an adult 1 to 6 times a day depending on the symptoms. Below, Examples, Reference Examples,
The present invention will be described in more detail by showing Test Examples and Formulation Examples, but the scope of the present invention is not limited thereto.

[0069]

【Example】

Example 1 (2R, 4R) -2- [2- [4-fluoro-2- [2
-(3-Methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -1-ethoxycarbonyl-2-
[2- [4-Fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine 4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenol 399 mg Dissolved in 8 ml of N, N-dimethylacetamide, and under ice cooling, 363 mg of potassium t-butoxide and (2S, 4R) -2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine 718m.
g was added and stirred at 40 ° C. for 5 hours. 50 ml of ethyl acetate was added to the reaction solution, which was successively washed with water and brine.
The ethyl acetate layer was dehydrated with anhydrous magnesium sulfate,
It was concentrated under reduced pressure. The obtained oily substance was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3.
/ 7) to give 535 mg of the title compound (yield: 76
%) As a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1 to 1.3
5 (3H, m), 1.75-2.3 (3H, m), 2.3-2.6 (1H, m), 2.75
~ 3.0 (4H, m), 3.4 ~ 3.8 (1H, m), 3.45 (1H, dd, J = 4.
3 and 11.9Hz), 3.79 (3H, s), 3.9-4.3 (5H, m), 4.3
5-4.5 (1H, m), 6.8-6.9 (6H, m), 7.15-7.25 (1H,
m). (B) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -2- [2- [4] obtained in the step (a).
-Fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-ethoxycarbonyl-
4-Hydroxypyrrolidine (201 mg) was dissolved in tetrahydrofuran (4 ml), added dropwise to a mixture of lithium aluminum hydride (53 mg) and tetrahydrofuran (4 ml) under ice-cooling and stirring, and heated to reflux for 30 minutes. Thereafter, the reaction solution was ice-cooled and sodium sulphate decahydrate was added to decompose excess hydride. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (eluent: methylene chloride / methanol = 4/1) to give 139 mg of the title compound as a colorless oil (yield 80
%) Was obtained. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.75 ~
2.2 (3H, m), 2.2-2.4 (1H, m), 2.40 (1H, dd, J = 4.5
And 10.8Hz), 2.51 (3H, s), 2.75 -3.05 (5H, m), 3.
62 (1H, dd, J = 6.0 and 10.8Hz), 3.79 (3H, s), 3.9-
4.1 (2H, m), 4.4-4.55 (1H, m), 6.7-6.9 (6H, m), 7.
15-7.25 (1H, m). (C) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- obtained in the same manner as in the above step (b).
246 mg of [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine in 5 ml of ethyl acetate
In 4N hydrogen chloride-ethyl acetate solution 0.25m
1 was added and left at room temperature. The precipitated crystals are collected by filtration,
After drying in vacuum, 210 mg of the title compound (78% yield)
Was obtained as colorless crystals. Melting point: 128-129 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.0-2.2
(1H, m), 2.3-2.65 (2H, m), 2.33 (1H, dd, J = 5.9 and 13.8Hz), 2.75-3.0 (4H, m), 2.89 (3H, s), 2.99 (1
H, d, J = 12.3Hz), 3.78 (3H, s), 3-8-4.2 (4H, m), 4.
55-4.7 (1H, m), 6.65-6.8 (4H, m), 6.8-6.9 (2H, m),
7.21 (1H, t, J = 7.8Hz).

Example 2 (2R, 4R) -2- [2- [4-fluoro-2- [2
-(4-Fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -1-t-butoxycarbonyl-
4-t-butyldimethylsilyloxy-2- [2- [4
-Fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] pyrrolidine 4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenol 248 mg was dissolved in N, N-dimethylacetamide 10 ml. Then, under ice cooling, 125 mg of potassium t-butoxide and 405 mg of (2S, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy-2- (2-chloroethyl) pyrrolidine were added, and the mixture was kept at room temperature for 3 hours. It was stirred. Ethyl acetate 150
Then, the mixture was washed successively with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4 /
Purified in 1), 433 mg of the title compound (yield 73%)
Was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 0.02 (3
H, s), 0.03 (3H, s), 0.84 (9H, s), 1.46 (9H, s), 1.
7-1.9 (2H, m), 2.0-2.15 (1H, m), 2.25-2.5 (1H, m),
2.75-2.95 (4H, m), 3.3-3.7 (2H, m), 3.9-4.2 (3H,
m), 4.25-4.4 (1H, m), 6.7-7.0 (5H, m), 7.05-7.2 (2
H, m). (B) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (4-Fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -1-t-butoxycarbonyl-4-t- obtained in the above step (a). Butyldimethylsilyloxy-
2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] pyrrolidine 3
98 mg of tetrahydrofuran was dissolved in 10 ml of tetrahydrofuran, and the mixture was added dropwise to a mixed solution of 81 mg of lithium aluminum hydride and 10 ml of tetrahydrofuran under ice-cooling stirring, and the mixture was heated under reflux for 1 hour. After that, the reaction solution was ice-cooled, and sodium sulfate
Decahydrate was added to decompose excess hydride. The insoluble material was filtered off, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 7/3) to give 151 mg of the title compound as a colorless oil (yield 59%). ) Got. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.6-1.8
(1H, m), 1.8-2.0 (2H, m), 2.1-2.3 (2H, m), 2.34 (3
H, s), 2.6-2.75 (1H, m), 2.8-2.95 (4H, m), 3.49 (1
H, dd, J = 6.3 and 10.2Hz), 3.85-4.05 (2H, m), 4.35
-4.5 (1H, m), 6.7-6.9 (3H, m), 6.9-7.0 (2H, m), 7.0
5-7.2 (2H, m). (C) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (4-Fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [4] obtained in step (b) above.
138 mg of -fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine is dissolved in 4 ml of ethyl acetate,
4N hydrogen chloride-ethyl acetate solution (0.15 ml) was added and the mixture was concentrated. The oily substance obtained was dissolved in 5 ml of ethyl acetate and allowed to stand at room temperature. The precipitated crystals were collected by filtration and dried in vacuum to obtain 66 mg (yield 43%) of the title compound as colorless crystals. Melting point: 70-73 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.0-2.2
(1H, m), 2.25-2.65 (3H, m), 2.78 (4H, s), 2.84 (3H,
s), 2.99 (1H, d, J = 12.4Hz), 3.7-3.9 (1H, m), 3.9-
4.2 (3H, m), 4.55-4.7 (1H, m), 6.7-7.05 (5H, m),
7.05-7.2 (2H, m).

Example 3 (2R, 4R) -2- [2- [4-fluoro-2- [2
-(4-Fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride (a) (2R, 4R) -1-t-butoxycarbonyl-
2- [2- [4-Fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine 4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenol 687 mg was dissolved in 12 ml of N, N-dimethylacetamide, 212 mg of potassium t-butoxide was added under ice cooling, and the mixture was stirred for 10 minutes. (2S, 4R) -2- (2-chloroethyl) -1 was added to the resulting solution.
687 mg of -t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine was added, and the mixture was stirred at room temperature for 14 hours. In the reaction solution, potassium t-butoxide 13
After adding 5 mg and stirring at 40 ° C. for 4 hours, 300 ml of ethyl acetate was added to the reaction solution, and the mixture was washed successively with water and brine. The ethyl acetate layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/3) to give 571 mg of the title compound.
(74% yield) as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.45 (9H,
s), 1.7-2.05 (2H, m), 2.1-2.25 (1H, m), 2.3-2.55
(1H, m), 2.85 (4H, s), 3.4-3.7 (1H, m), 3.42 (1H, d
d, J = 4.4 and 11.9Hz), 3.9-4.05 (2H, m), 4.1-4.25
(1H, m), 4.35-4.5 (1H, m), 6.7-6.9 (3H, m), 6.9-7.
0 (2H, m), 7.05-7.2 (2H, m). (B) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (4-Fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride (2R, 4R) -1-t-butoxycarbonyl-2- [2- [obtained in the above step (a). 4-fluoro-2- [2- (4-
Fluorophenyl) ethyl] phenoxy] ethyl] -4
-570 mg of hydroxypyrrolidine in 5 ml of ethyl acetate
The resulting mixture was dissolved in, 5 ml of 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was stirred at room temperature for 30 minutes. The precipitated crystals were collected by filtration, washed with ethyl acetate and dried in vacuum to give the title compound 381m.
g (78% yield) as colorless crystals. Melting point: 186-187 [deg.] C. NMR spectrum (270MHz, CD ₃ SOCD ₃ ) δ ppm: 1.65
1.85 (1H, m), 2.0-2.4 (3H, m), 2.82 (4H, s), 3.01
(1H, d, J = 12.2Hz), 3.3-3.45 (1H, m), 3.8-4.0 (1H,
m), 4.06 (2H, t, J = 6.1Hz), 4.35-4.45 (1H, m), 5.41
(1H, d, J = 3.0 Hz), 6.9-7.15 (5H, m), 7.2-7.3 (2H,
m).

Example 4 (2R, 4R) -2- [2- [4-fluoro-2- [2
-(4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -1-ethoxycarbonyl-2-
[2- [4-Fluoro-2- [2- (4-fluoro-3
-Methoxyphenyl) ethyl] phenoxy] ethyl]-
622 mg of 4-hydroxypyrrolidine 4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenol was added to N, N-
Dissolve in 7 ml of dimethylacetamide and add potassium t-
343 mg butoxide and (2S, 4R) -2- (2
-Chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine (678 mg) was used, Example 1 (a)
It reacted and extracted like the process. The obtained oily substance was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/3) to give the title compound 552.
mg (52% yield) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.7-1.95 (1H, m), 1.96 (1H, dd, J = 4.9 and 7.2Hz), 2.05-2.25 (1H, m), 2.25-2.65 (1H, m), 2.7
5-2.95 (4H, m), 3.45 (1H, dd, J = 4.3 and 12.0Hz),
3.45-3.8 (1H, m), 3.83 (3H, s), 3.85-4.05 (1H, m),
4.05-4.3 (3H, m), 4.35-4.5 (1H, m), 6.6-6.9 (5H,
m), 6.96 (1H, dd, J = 8.0 and 11.3Hz). (B) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -1-ethoxycarbonyl-2- obtained in the above step (a). [2- [4-fluoro-2- [2- (4
-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine 551 mg,
Using 20 ml of tetrahydrofuran and 140 mg of lithium aluminum hydride, the reaction was carried out in the same manner as in step (b) of Example 1 and post-treatment was carried out. The obtained concentrate is subjected to silica gel column chromatography (elution solvent: methylene chloride /
Purification using methanol = 3/2) gave 405 mg (yield 84%) of the title compound as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.65-2.1
(3H, m), 2.1-2.3 (1H, m), 2.25 (1H, dd, J = 5.2 and 10.3Hz), 2.39 (3H, s), 2.6-2.8 (1H, m), 2.8-3.0
(4H, m), 3.50 (1H, dd, J = 6.2 and 10.3Hz), 3.84 (3
H, s), 3.85-4.05 (2H, m), 4.35-4.5 (1H, m), 6.65-
7.05 (6H, m). (C) (2R, 4R) -2- [2- [4-fluoro-2
-[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [4
399 mg of -fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine was added to ethyl acetate 5
dissolved in 4 ml hydrogen chloride-ethyl acetate solution 0.3
When 8 ml was added, crystals precipitated. The solvent was removed under reduced pressure, and the obtained solid was dissolved in a small amount (about 0.5 ml) of methylene chloride, 5 ml of ethyl acetate was added, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (359 mg, yield 82%) as colorless crystals. Melting point: 128-130 ° C. NMR spectrum (400 MHz, CD ₃ SOCD ₃ + D ₂ O) δ ppm: 1.
8-2.0 (1H, m), 2.0-2.2 (1H, m), 2.20 (1H, dd, J = 6.
0 and 13.7Hz), 2.4-2.55 (1H, m), 2.7-3.0 (4H, m),
2.89 (3H, s), 2.97 (1H, d, J = 12.5Hz), 3.6-3.9 (2H,
m), 3.80 (3H, s), 3.95-4.15 (2H, m), 4.3-4.45 (1H,
m), 6.7-6.8 (1H, m), 6.9-7.15 (5H, m).

Example 5 (2R, 4R) -2- [2- [4-fluoro-2- (2
-Phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride (a) (2R, 4R) -1-t-butoxycarbonyl-
4-t-butyldimethylsilyloxy-2- [2- [4
-Fluoro-2- (2-phenylethyl) phenoxy]
Ethyl] pyrrolidine 4-fluoro-2- (2-phenylethyl) phenol 1090 mg, (2S, 4R) -2- (2-bromoethyl) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine 1870 mg and Using 566 mg of potassium t-butoxide, the reaction was carried out in 10 ml of N, N-dimethylacetamide in the same manner as in step (a) of Example 2 and extraction was performed. The obtained oily substance was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/1) to give 2090 mg of the title compound.
(Yield 84%) was obtained as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 0.02 (3
H, s), 0.03 (3H, s), 0.84 (9H, s), 1.45 (9H, s), 1.
7-1.95 (2H, m), 2.0-2.15 (1H, m), 2.25-2.5 (1H,
m), 2.8-2.95 (4H, m), 3.3-3.65 (1H, m) 3.35 (1H, d
d, J = 4.5 and 11.0Hz), 3.85-4.2 (3H, m), 4.25-4.4
(1H, m), 6.7-6.9 (3H, m), 7.15-7.35 (5H, m). (B) (2R, 4R) -2- [2- [4-fluoro-2
-(2-phenylethyl) phenoxy] ethyl] -4-
Hydroxypyrrolidine hydrochloride (2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy- obtained in the above step (a).
600 mg of 2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine was dissolved in 5 ml of dioxane, 5 ml of 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 1 hour. The solid obtained by removing the solvent under reduced pressure was dissolved in a small amount of a mixed solution of methylene chloride and methanol, 10 ml of ethyl acetate was added, and the mixture was left standing. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (270 mg, yield 67%) as colorless crystals. Melting point: 151-152 ° C. NMR spectrum (270MHz, CD ₃ OD) δ ppm: 1.8-2.0
(1H, m), 2.1-2.4 (3H, m), 2.8-3.0 (4H, m), 3.22 (1
H, d, J = 12.4Hz), 3.46 (1H, dd, J = 4.1 and 12.4Hz),
4.0-4.2 (3H, m), 4.5-4.6 (1H, m), 6.8-7.0 (3H,
m), 7.1-7.3 (5H, m).

Example 6 (2R, 4R) -2- [2- [4-fluoro-2- (2
-Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -1-t-butoxycarbonyl-
2- [2- [4-Fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine (2R, 4R) -1-t-butoxycarbonyl-obtained in the step of Example 5 (a). 1490 mg of 4-t-butyldimethylsilyloxy-2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine was dissolved in 15 ml of tetrahydrofuran, and 0.79 ml of tetrabutylammonium fluoride was added. The mixture was stirred at room temperature for 0.5 hours. The reaction solution was concentrated under reduced pressure, and the oily concentrate was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give the title compound 111.
5 mg (95% yield) was obtained as a colorless solid. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.45 (9
H, s), 1.7-2.05 (2H, m), 2.05-2.25 (1H, m), 2.3-2.5
5 (1H, m), 2.88 (4H, s), 3.4-3.75 (1H, m), 3.42 (1
H, dd, J = 4.4 and 11.9 Hz), 3.9-4.05 (2H, m), 4.05
-4.25 (1H, m), 4.3-4.45 (1H, m), 6.7-6.9 (3H, m),
7.1-7.35 (5H, m). (B) (2R, 4R) -2- [2- [4-fluoro-2
-(2-phenylethyl) phenoxy] ethyl] -4-
Hydroxy-1-methylpyrrolidine (2R, 4R) -1-t-butoxycarbonyl-2- [2- [4-fluoro-2- (2-
Phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine 1115 mg, tetrahydrofuran 20 m
1 and 200 mg of lithium aluminum hydride were reacted and post-treated in the same manner as in the step of Example 1 (b).
The obtained concentrate was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol = 5/1) to obtain 540 mg (yield 61%) of the title compound as a colorless solid. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.65-2.3
(4H, m), 2.30 (1H, dd, J = 4.8 and 10.5Hz), 2.44
(3H, s), 2.7-2.95 (1H, m), 2.88 (4H, s), 3.55 (1H,
dd, J = 6.1 and 10.5Hz), 3.85-4.1 (2H, m), 4.35-4.
5 (1H, m), 6.7-6.9 (3H, m), 7.1-7.25 (5H, m). (C) (2R, 4R) -2- [2- [4-fluoro-2
-(2-phenylethyl) phenoxy] ethyl] -4-
Hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [4
-Fluoro-2- (2-phenylethyl) phenoxy]
Ethyl] -4-hydroxy-1-methylpyrrolidine 54
0 mg was dissolved in 5 ml of ethyl acetate, and 4N hydrogen chloride-
0.60 ml of ethyl acetate solution was added. The precipitated crystals were collected by filtration and dried in vacuum to give 515 mg of the title compound (yield 8
6%) as colorless crystals. Melting point: 121-122 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.0-2.15
(1H, m), 2.25-2.6 (2H, m), 2.33 (1H, dd, J = 5.8 and 13.9Hz), 2.85 (4H, s), 2.87 (3H, s), 3.00 (1H,
d, J = 12.5Hz), 3.7-4.2 (4H, m), 4.5-4.65 (1H, m),
6.7-6.9 (3H, m), 7.1-7.35 (5H, m).

Example 7 (2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine Hydrochloride (a) (2R, 4R) -1-t-butoxycarbonyl-
4-t-butyldimethylsilyloxy-2- [2- [2
-[2- (3,4-difluorophenyl) ethyl] -4
-Fluorophenoxy] ethyl] pyrrolidine 2- [2- (3,4-difluorophenyl) ethyl]-
4-fluorophenol 400 mg, (2S, 4R)-
2- (2-bromoethyl) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxypyrrolidine 6
90 mg and 208 mg of potassium t-butoxide were reacted in 5 ml of N, N-dimethylacetamide in the same manner as in step (a) of Example 2 and extracted. The obtained oil was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/1) to obtain 580 mg (yield 63%) of the title compound as a colorless oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 0.02 (3
H, s), 0.04 (3H, s), 0.84 (9H, s), 1.45 (9H, s), 1.
7-1.95 (2H, m), 1.95-2.15 (1H, m), 2.2-2.55 (1H,
m), 2.7-3.0 (4H, m), 3.25-3.65 (2H, m), 3.85-4.05
(2H, m), 4.05-4.25 (1H, m), 4.25-4.4 (1H, m), 6.7-
7.1 (6H, m). (B) (2R, 4R) -1-t-butoxycarbonyl-
2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4
-Hydroxypyrrolidine (2R, 4R) -1-t-butoxycarbonyl-4-t-butyldimethylsilyloxy- obtained in the above step (a).
580 mg of 2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] pyrrolidine was dissolved in 5 ml of tetrahydrofuran, 0.31 ml of tetrabutylammonium fluoride was added, and the mixture was stirred at room temperature. It was stirred for 1 hour. The reaction solution was concentrated under reduced pressure, and the oily concentrate was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to obtain 280 mg (yield 61%) of the title compound as a colorless solid. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.46 (9
H, s), 1.7-2.0 (2H, m), 2.05-2.3 (1H, m), 2.3-2.55
(1H, m), 2.84 (4H, s), 3.4-3.7 (1H, m), 3.43 (1H,
dd, J = 4.2 and 11.9Hz), 3.85-4.05 (2H, m), 4.05-
4.25 (1H, m), 4.35-4.5 (1H, m), 6.7-7.1 (6H, m). (C) (2R, 4R) -2- [2- [2- [2- (3,
4-Difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -1-t-butoxycarbonyl-2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy]
Ethyl] -4-hydroxypyrrolidine (280 mg), tetrahydrofuran (5 ml) and lithium aluminum hydride (50 mg) were used for a reaction and post-treatment in the same manner as in Example 1 (b). The obtained concentrate was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol = 10/1) to obtain 140 mg (yield 63%) of the title compound as a colorless solid. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.75-2.5
(4H, m), 2.41 (1H, dd, J = 4.3 and 10.8Hz), 2.51
(3H, s), 2.8-3.05 (1H, m), 2.84 (4H, s), 3.64 (1H,
dd, J = 6.0 and 10.8Hz), 3.85-4.1 (2H, m), 4.4-4.5
5 (1H, m), 6.8-6.9 (4H, m), 6.9-7.1 (2H, m). (D) (2R, 4R) -2- [2- [2- [2- (3,
4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [2] obtained in the above step (c).
-[2- (3,4-difluorophenyl) ethyl] -4
-Fluorophenoxy] ethyl] -4-hydroxy-1
-Methylpyrrolidine (140 mg) was dissolved in ethyl acetate (5 ml), and 4N hydrogen chloride-ethyl acetate solution (0.15 ml) was added. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (113 mg, yield 73%) as colorless crystals. Melting point: 93-94 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.05-2.25
(1H, m), 2.25-2.7 (3H, m), 2.83 (4H, s), 2.9-3.15
(1H, m), 2.91 (3H, s), 3.75-4.3 (4H, m), 4.55-4.75
(1H, m), 6.7-7.15 (6H, m).

Example 8 (2R, 4R) -2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4-hydroxypyrrolidine hydrochloride Example (2R, 4R) -1-t-Butoxycarbonyl-2- [2- [2- [2- (2,3,4-difluorophenyl) ethyl] -4-fluorophenoxy] obtained in 7 (b).
83 mg of ethyl] -4-hydroxypyrrolidine was dissolved in 2 ml of dioxane, 2 ml of a 4N hydrogen chloride-dioxane solution was added, and the mixture was allowed to stand at room temperature for 1 hour. The precipitated crystals were collected by filtration and dried in vacuum to give 55 mg of the title compound (yield 77
%) As colorless crystals. Melting point: 170-171 ° C. NMR spectrum (270 MHz, CD ₃ OD) δ ppm: 1.75-1.9
5 (1H, m), 2.15-2.35 (2H, m), 2.35-2.55 (1H, m), 2.
85 (4H, s), 3.24 (1H, d, J = 12.6Hz), 3.49 (1H, dd, J
= 4.4 and 12.6Hz), 3.95-4.2 (3H, m), 4.5-4.6 (1H,
m), 6.7-7.15 (6H, m).

Example 9 (2R, 4R) -2- [2- [4-chloro-2- (2-
Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (a) (2R, 4R) -2- [2- [4-chloro-2-
(2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrrolidine 4-chloro-2- (2-phenylethyl) phenol 5
00 mg was dissolved in 10 ml of N, N-dimethylacetamide, and 270 mg of potassium t-butoxide and (2
Using 520 mg of S, 4R) -2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine, the reaction was carried out in the same manner as in step (a) of Example 1 and extraction was performed.
The obtained oil was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to obtain 260 mg (yield 29%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.75-2.0 (2H, m), 2.05-2.55 (2H, m), 2.85
(4H, s), 3.4-3.75 (1H, m), 3.41 (1H, dd, J = 4.2 and 11.9Hz), 3.9-4.3 (5H, m), 4.3-4.4 (1H, m), 6.7
3 (1H, d, J = 8.6 Hz), 7.05-7.35 (7H, m). (B) (2R, 4R) -2- [2- [4-chloro-2-
(2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -2- [2- [4
-Chloro-2- (2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrrolidine (260 mg), tetrahydrofuran (10 ml) and lithium aluminum hydride (70 mg) were used and reacted in the same manner as in Example 1 (b). And post-treated. The obtained concentrate was purified by silica gel silica gel column chromatography (eluting solvent: methylene chloride / methanol = 5/1) to obtain 103 mg (yield 46%) of the title compound as a colorless solid. Melting point: 65-68 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.7-2.05
(3H, m), 2.15-2.4 (1H, m), 2.31 (1H, dd, J = 4.9 and 10.5 Hz), 2.44 (3H, s), 2.75-2.95 (1H, m), 2.86
(4H, s), 3.55 (1H, dd, J = 6.1 and 10.5 Hz), 3.85-
4.1 (2H, m), 4.35-4.5 (1H, m), 6.74 (1H, d, J = 8.4H
z), 7.05-7.35 (7H, m).

Example 10 (2R, 4R) -2- [2- [4-bromo-2- (2-
(Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (a) (2R, 4R) -2- [2- [4-bromo-2-
(2-Phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrrolidine 4-bromo-2- (2-phenylethyl) phenol 5
00 mg was dissolved in 10 ml of N, N-dimethylacetamide, and 220 mg of potassium t-butoxide and (2
S, 4R) -2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine (440 mg) was reacted in the same manner as in Step (a) of Example 1 and extracted to obtain an oil. This was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to obtain 280 mg (yield 34%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.75-2.6 (4H, m), 2.85 (4H, s), 3.4-3.75
(1H, m), 3.42 (1H, dd, J = 4.2 and 11.9Hz), 3.9-4.3
(5H, m), 4.3-4.45 (1H, m), 6.69 (1H, d, J = 8.5 H
z), 7.15-7.35 (7H, m). (B) (2R, 4R) -2- [2- [4-bromo-2-
(2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -2- [2- [4
-Bromo-2- (2-phenylethyl) phenoxy] ethyl] -1-ethoxycarbonyl-4-hydroxypyrrolidine (280 mg), tetrahydrofuran (10 ml) and lithium aluminum hydride (70 mg).
The concentrated product obtained by the reaction and post-treatment in the same manner as in the step (b) was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 5/1) to give 113 mg of the title compound as a colorless solid ( Yield 46%) was obtained. Melting point: 63-66 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.7-2.05
(3H, m), 2.1-2.35 (1H, m), 2.29 (1H, dd, J = 4.9 and 10.4Hz), 2.42 (3H, s), 2.7-2.95 (1H, m), 2.86 (4
H, s), 3.52 (1H, dd, J = 6.1 and 10.4Hz), 3.9-4.05
(2H, m), 4.35-4.5 (1H, m), 6.70 (1H, d, J = 8.4Hz),
7.15-7.35 (7H, m).

Example 11 (2R, 4R) -4-Hydroxy-1-methyl-2-
[2- [5-Methyl-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine hydrochloride (a) (2R, 4R) -1-ethoxycarbonyl-4-
Benzyloxy-2- [2- [5-methyl-2- (2-
Phenylethyl) phenoxy] ethyl] pyrrolidine 5-methyl-2- (2-phenylethyl) phenol 1
000 mg was dissolved in N, N-dimethylacetamide 10 ml and potassium t-butoxide 580 mg and (2S, 4R) -4-benzyloxy-2- (2-chloroethyl) -1-ethoxycarbonylpyrrolidine 162 were dissolved.
0 mg was used and reacted in the same manner as in step (a) of Example 2,
Extraction gave an oil. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 /
1) to give 1680 mg of the title compound (yield 73
%) As an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.75-2.1 (2H, m), 2.15-2.6 (2H, m), 2.32
(3H, s), 2.86 (4H, s), 3.42 (1H, dd, J = 4.7 and
11.9Hz), 3.55-4.3 (7H, m), 4.44 (2H, s), 6.6-6.75
(2H, m), 6.99 (1H, d, J = 7.4Hz), 7.1-7.4 (10H, m). (B) (2R, 4R) -1-ethoxycarbonyl-4-
Hydroxy-2- [2- [5-methyl-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-benzyloxy-2 obtained in the step (a). -[2- [5-Methyl-2- (2-phenylethyl) phenoxy] ethyl]
1680 mg of pyrrolidine was dissolved in 15 ml of ethanol, 200 mg of 10% palladium-carbon catalyst was added, and the mixture was stirred at 60 ° C. for 1.5 hours under normal pressure of hydrogen. The catalyst was filtered off, and the reaction solution was concentrated under reduced pressure. The obtained product was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2) to give the title compound 11
50 mg (yield 85%) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.7-2.25 (3H, m), 2.25-2.65 (1H, m), 2.32
(3H, s), 2.86 (4H, s), 3.4-3.8 (1H, m), 3.44 (1H,
dd, J = 4.4 and 11.9Hz), 3.95-4.3 (3H, m), 4.01 (2
H, t, J = 5.9Hz), 4.3-4.45 (1H, m), 6.6-6.75 (2H,
m), 6.99 (1H, d, J = 7.5Hz), 7.1-7.35 (5H, m). (C) (2R, 4R) -4-hydroxy-1-methyl-
2- [2- [5-methyl-2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [5-methyl-) obtained in the step (b).
2- (2-Phenylethyl) phenoxy] ethyl] pyrrolidine (1150 mg), tetrahydrofuran (18 ml) and lithium aluminum hydride (330 mg) were reacted in the same manner as in Step (b) of Example 1 and the concentrate obtained by the post-treatment was used as a silica gel column. Purify using chromatography (elution solvent: methylene chloride / methanol = 10/1),
776 mg (yield 80%) of the title compound was obtained as a colorless solid. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.6-1.8
(1H, m), 1.85-2.0 (2H, m), 2.15-2.35 (1H, m), 2.20
(1H, dd, J = 5.4 and 10.0Hz), 2.33 (3H, s), 2.38 (3
H, s), 2.6-2.8 (1H, m), 2.87 (4H, s), 3.47 (1H, d
d, J = 6.4 and 10.0Hz), 3.9-4.1 (2H, m), 4.35-4.5
(1H, m), 6.6-7.75 (2H, m), 7.00 (1H, d, J = 7.4Hz),
7.15-7.35 (5H, m). (D) (2R, 4R) -4-hydroxy-1-methyl-
2- [2- [5-methyl-2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine hydrochloride (2R, 4R) -4-hydroxy-1-methyl-2- [2- [5-methyl-2- (2-phenylethyl) phenoxy] ethyl obtained in step (c) above. ] Pyrrolidine 776
mg was dissolved in 10 ml of ethyl acetate, and 4N hydrogen chloride-
0.57 ml of ethyl acetate solution was added. The solvent was removed under reduced pressure, the obtained solid was dissolved in a small amount (about 0.5 ml) of methylene chloride, 5 ml of ether was added, and the mixture was left standing. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (788 mg, yield 92%) as colorless crystals. Melting point: 97-100 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.0-2.2
(1H, m), 2.25-2.65 (3H, m), 2.33 (3H, s), 2.84 (4H,
s), 2.85 (3H, s), 2.98 (1H, d, J = 12.6Hz), 3.75-4.
1 (3H, m), 4.1-4.25 (1H, m), 4.55-4.65 (1H, m), 6.
66 (1H, s), 6.73 (1H, d, J = 7.4Hz), 7.01 (1H, d, J =
7.4Hz), 7.1-7.35 (5H, m).

Example 12 (2R, 4R) -4-Hydroxy-1-methyl-2-
[2- [4-Methyl-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine hydrochloride (a) (2R, 4R) -1-ethoxycarbonyl-4-
Benzyloxy-2- [2- [4-methyl-2- (2-
Phenylethyl) phenoxy] ethyl] pyrrolidine 4-methyl-2- (2-phenylethyl) phenol 1
200 mg was dissolved in 10 ml of N, N-dimethylacetamide and 700 mg of potassium t-butoxide and (2S, 4R) -4-benzyloxy-2- (2-chloroethyl) -1-ethoxycarbonylpyrrolidine 160 were dissolved.
Using 0 mg, the reaction was carried out in the same manner as in step (a) of Example 2 and extraction was performed. The obtained oil was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to obtain 1820 mg (yield 73%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.7-2.1 (2H, m), 2.2-2.6 (2H, m), 2.26 (3
H, s), 2.87 (4H, s), 3.42 (1H, dd, J = 4.7 and 11.
9Hz), 3.55-4.3 (7H, m), 4.44 (2H, s), 6.72 (1H, d,
J = 7.8Hz), 6.9-7.0 (2H, m), 7.1-7.4 (10H, m). (B) (2R, 4R) -1-ethoxycarbonyl-4-
Hydroxy-2- [2- [4-methyl-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-benzyloxy-2 obtained in the step (a). -[2- [4-Methyl-2- (2-phenylethyl) phenoxy] ethyl]
1 in 20 ml of ethanol solution of 1820 mg of pyrrolidine
200 mg of 0% palladium-carbon catalyst was added, and the mixture was stirred under normal pressure of hydrogen at 60 ° C. for 2 hours. The product obtained by filtering off the catalyst and concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2).
1410 mg of the title compound (yield 95
%) As an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.75-2.3 (3H, m), 2.25 (3H, s), 2.3-2.6
(1H, m), 2.86 (4H, s), 3.4-3.8 (1H, m), 3.42 (1H, d
d, J = 4.4 and 11.9Hz), 3.98 (2H, t, J = 5.9Hz), 4.0
5-4.3 (1H, m), 4.12 (2H, q, J = 7.1Hz), 4.3-4.45 (1H,
m), 6.72 (1H, d, J = 7.9Hz), 6.9-7.0 (2H, m), 7.15-
7.35 (5H, m). (C) (2R, 4R) -4-hydroxy-1-methyl-
2- [2- [4-methyl-2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [4-methyl-) obtained in step (b) above.
2- (2-Phenylethyl) phenoxy] ethyl] pyrrolidine (1410 mg), tetrahydrofuran (20 ml) and lithium aluminum hydride (400 mg) were used for a reaction and post-treatment in the same manner as in Example 1 (b). The obtained concentrate was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 5/1) to give 884 mg of the title compound as a colorless solid (yield 73%).
I got NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.55-1.8
(1H, m), 1.8-2.0 (2H, m), 2.15-2.3 (1H, m), 2.20
(1H, dd, J = 5.5 and 10.1Hz), 2.26 (3H, s), 2.38 (3
H, s), 2.6-2.8 (1H, m), 2.87 (4H, s), 3.47 (1H, d
d, J = 6.3 and 10.1Hz), 3.9-4.1 (2H, m), 4.35-4.5
(1H, m), 6.74 (1H, d, J = 8.9Hz), 6.9-7.0 (2H, m),
7.15-7.35 (5H, m). (D) (2R, 4R) -4-hydroxy-1-methyl-
2- [2- [4-methyl-2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine hydrochloride (2R, 4R) -4-hydroxy-1-methyl-2- [2- [4-methyl-2- (2-phenylethyl) phenoxy] ethyl obtained in step (c) above. ] Pyrrolidine 884
mg was dissolved in 10 ml of ethyl acetate, and 4N hydrogen chloride-
0.65 ml of ethyl acetate solution was added. The solvent was removed under reduced pressure, the obtained solid was dissolved in a small amount of methylene chloride, 10 ml of ethyl acetate was added, and the mixture was left standing at room temperature. The precipitated crystals were collected by filtration, dried in vacuo and the title compound 905
mg (yield 92%) was obtained as colorless crystals. Melting point: 136-138 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.0-2.2
(1H, m), 2.25-2.65 (3H, m), 2.27 (3H, s), 2.83 (3H,
s), 2.86 (4H, s), 2.94 (1H, d, J = 12.7Hz), 3.7-3.9
(1H, m), 3.9-4.1 (2H, m), 4.1-4.25 (1H, m), 4.55-
4.65 (1H, m), 6.73 (1H, d, J = 7.9Hz), 6.95-7.05 (2
H, m), 7.1-7.35 (5H, m).

Example 13 (2R, 4R) -4-Hydroxy-1-methyl-2-
[2- [6-Methyl-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine hydrochloride (a) (2R, 4R) -1-ethoxycarbonyl-4-
Benzyloxy-2- [2- [6-methyl-2- (2-
Phenylethyl) phenoxy] ethyl] pyrrolidine 6-methyl-2- (2-phenylethyl) phenol 1
200 mg was dissolved in 10 ml of N, N-dimethylacetamide and 700 mg of potassium t-butoxide and (2S, 4R) -4-benzyloxy-2- (2-chloroethyl) -1-ethoxycarbonylpyrrolidine 160 were dissolved.
0 mg was used and reacted in the same manner as in step (a) of Example 2,
Extraction gave an oil. This was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 3 /
1) and 2260 mg of the title compound (yield 90
%) As an oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.23 (3
H, t, J = 7.0Hz), 1.75-2.1 (2H, m), 2.2-2.6 (2H, m),
2.28 (3H, s), 2.90 (4H, s), 3.42 (1H, dd, J = 4.5 and 11.9Hz), 3.55-3.9 (3H, m), 4.05-4.3 (2H, m),
4.12 (2H, q, J = 7.0Hz), 4.35-4.6 (2H, m), 6.9-7.1
(3H, m), 7.1-7.4 (10H, m). (B) (2R, 4R) -1-ethoxycarbonyl-4-
Hydroxy-2- [2- [6-methyl-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-benzyloxy-2 obtained in the step (a). -[2- [6-Methyl-2- (2-phenylethyl) phenoxy] ethyl]
1 part of a solution of 2260 mg of pyrrolidine in 20 ml of ethanol
300 mg of 0% palladium-carbon catalyst was added, and the mixture was stirred at 60 ° C. for 1.5 hours under normal pressure of hydrogen. The product obtained by filtering off the catalyst and concentrating the reaction solution under reduced pressure was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 1 /
Purification using 2) gave 1840 mg (quantitative) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.15-1.2
(3H, m), 1.75-2.05 (2H, m), 2.05-2.25 (1H, m), 2.2
8 (3H, s), 2.35-2.6 (1H, m), 2.90 (4H, s), 3.4--3.
9 (3H, m), 3.42 (1H, dd, J = 4.2 and 11.9Hz), 4.0-
4.25 (3H, m), 4.3-4.45 (1H, m), 6.9-7.1 (3H, m), 7.
05-7.35 (5H, m). (C) (2R, 4R) -4-hydroxy-1-methyl-
2- [2- [6-methyl-2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2- [6-methyl- obtained in the above step (b).
2- (2-Phenylethyl) phenoxy] ethyl] pyrrolidine (1840 mg), tetrahydrofuran (20 ml) and lithium aluminum hydride (530 mg) were used for a reaction and post-treatment in the same manner as in the step of Example 1 (b). The obtained concentrate was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol = 5/1) to give 1050 mg of the title compound as a colorless solid (yield 67
%) Was obtained. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.55-1.7
5 (1H, m), 1.8-2.0 (2H, m), 2.18 (1H, dd, J = 5.6 and 10.0Hz), 2.2-2.35 (1H, m), 2.30 (3H, s), 2.37 (3
H, s), 2.6-2.75 (1H, m), 2.91 (4H, s), 3.43 (1H, d
d, J = 6.3 and 10.0Hz), 3.78 (2H, t, J = 6.6Hz), 4.3-
4.55 (1H, m), 6.95 (1H, dd, J = 6.0 and 8.6Hz), 7.0
-7.1 (2H, m), 7.15-7.35 (5H, m). (D) (2R, 4R) -4-hydroxy-1-methyl-
2- [2- [6-methyl-2- (2-phenylethyl)
Phenoxy] ethyl] pyrrolidine hydrochloride (2R, 4R) -4-hydroxy-1-methyl-2- [2- [6-methyl-2- (2-phenylethyl) phenoxy] ethyl obtained in step (c) above. ] Pyrrolidine 105
0 mg was dissolved in 10 ml of ethyl acetate, and 0.77 ml of 4N hydrogen chloride-ethyl acetate solution was added. The solvent was removed under reduced pressure, 20 ml of ethyl acetate was added to the obtained solid, and the mixture was left standing. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (1024 mg, yield 88%) as colorless crystals. Melting point: 114-115 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 2.0-2.1
(1H, m), 2.25-2.45 (1H, m), 2.27 (3H, m), 2.35 (1H,
dd, J = 5.7 and 13.7Hz), 2.45-2.65 (1H, m), 2.7-3.
1 (5H, m), 2.90 (3H, s), 3.7-4.0 (3H, m), 4.0-4.2
(1H, m), 4.5-4.65 (1H, m), 6.9-7.1 (3H, m), 7.15-7.
35 (5H, m).

Example 14 (2R, 4R) -4-Hydroxy-2- [2- [4-methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (a) (2R , 4R) -1-Ethoxycarbonyl-4-
Hydroxy-2- [2- [4-methoxy-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine 4-methoxy-2- (2-phenylethyl) phenol 1130 mg and N, N-dimethylacetamide 10 ml
And potassium tert-butoxide (610 mg) and (2S, 4R) -2- (2-chloroethyl) -1-ethoxycarbonyl-4-hydroxypyrrolidine (1000 m).
g was used to react in the same manner as in the step (a) of Example 2 and extracted to obtain an oily substance. Silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/2)
The title compound (448 mg, yield 24%) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.1-1.35
(3H, m), 1.7-2.1 (2H, m), 2.1-2.25 (1H, m), 2.25-
2.6 (1H, m), 2.88 (4H, s), 3.44 (1H, dd, J = 4.4 and 11.9Hz), 3.45-3.75 (1H, m), 3.73 (3H, s), 3.97
(2H, t, J = 6.1Hz), 4.05-4.3 (3H, m), 4.35-4.5 (1H,
m), 6.65-6.85 (3H, m), 7.1-7.35 (5H, m). (B) (2R, 4R) -4-hydroxy-2- [2-
[4-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine (2R, 4R) -1-ethoxycarbonyl-4-hydroxy-2- [2-] obtained in the step (a). [4-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] pyrrolidine (448 mg), tetrahydrofuran (10 ml) and lithium aluminum hydride (120 mg) were reacted in the same manner as in Example 1 (b) and post-treated to obtain the compound. Silica gel column chromatography (eluting solvent:
Purify using methylene chloride / methanol = 5/1),
144 mg (37% yield) of the title compound were obtained as a colorless solid. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.6-1.8
(1H, m), 1.85-2.0 (2H, m), 2.1-2.3 (1H, m), 2.22
(1H, dd, J = 5.1 and 10.2Hz), 2.39 (3H, s), 2.6-2.8
(1H, m), 2.88 (4H, s), 3.48 (1H, dd, J = 6.3 and
10.2Hz), 3.74 (3H, s), 3.85-4.05 (2H, m), 4.35-4.5
(1H, m), 6.65-6.85 (3H, m), 7.1-7.35 (5H, m). (C) (2R, 4R) -4-hydroxy-2- [2-
[4-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (2R, 4R) -4-hydroxy-2- [2- [4-] obtained in the step (c). Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine 14
Dissolve 4 mg in 5 ml of ethyl acetate and prepare 4N hydrogen chloride-
0.10 ml of ethyl acetate solution was added. The solvent was removed under reduced pressure, the obtained oily substance was dissolved in 1 ml of methylene chloride, ether was added until it became cloudy, and the mixture was allowed to stand at room temperature. The precipitated crystals were collected by filtration and dried to give the title compound (137 mg)
(Yield 86%) was obtained as colorless crystals. Melting point: 63-65 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.05-2.2
(1H, m), 2.30 (1H, dd, J = 5.8 and 13.9Hz), 2.35-
2.65 (2H, m), 2.8-3.0 (1H, m), 2.85 (3H, s), 2.87
(4H, s), 3.74 (3H, s), 3.7-4.2 (4H, m), 4.55-4.65
(1H, m), 6.65-6.85 (2H, m), 6.72 (1H, s), 7.1-7.35
(5H, m).

Example 15 (2R, 4R) -4-Hydroxy-2- [2- [5-methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (a) (2R , 4R) -4-Dimethylcarbamoyloxy-2- [2- [5-methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-octyloxycarbonylpyrrolidine 5-methoxy-2- (2-phenylethyl) ) 670 mg of phenol was dissolved in 10 ml of N, N-dimethylacetamide, and 360 mg of potassium t-butoxide and 1000 mg of (2S, 4R) -2- (2-chloroethyl) -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine were used. Then, the reaction was carried out in the same manner as in step (a) of Example 2 and extraction was performed to obtain an oil. This was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 1500 mg of the title compound.
(Yield 99%) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.8-0.95
(3H, m), 1.15-1.45 (10H, m), 1.5-1.75 (2H, m), 1.7
5-2.15 (2H, m), 2.25-2.8 (2H, m), 2.7-3.0 (4H, m),
2.83 (6H, s), 3.5-3.9 (1H, m), 3.53 (1H, dd, J = 4.3
And 12.6Hz), 3.78 (3H, s), 3.9-4.3 (5H, m), 5.1-
5.25 (1H, m), 6.35-6.5 (2H, m), 6.98 (1H, d, J = 8.1H
z), 7.1-7.3 (5H, m). (B) (2R, 4R) -4-hydroxy-2- [2-
[5-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine (2R, 4R) -4-dimethylcarbamoyloxy-2- [2- [5-] obtained in the step (a). Methoxy-2-
(2-Phenylethyl) phenoxy] ethyl] -1-octyloxycarbonylpyrrolidine (1500 mg), tetrahydrofuran (25 ml) and lithium aluminum hydride (310 mg) were reacted in the same manner as in step (b) of Example 1 and obtained by post-treatment. The concentrate was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol = 5/1) to give the title compound 3 as a colorless solid.
85 mg (41% yield) was obtained. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.6-1.8
(1H, m), 1.8-2.0 (2H, m), 2.15-2.3 (1H, m), 2.20
(1H, dd, J = 5.5 and 10.1Hz), 2.38 (3H, s), 2.6-2.7
5 (1H, m), 2.84 (4H, s), 3.46 (1H, dd, J = 6.4 and
10.1Hz), 3.79 (3H, s), 3.9-4.1 (2H, m), 4.35-4.5 (1
H, m), 6.35-6.5 (2H, m), 7.00 (1H, d, J = 8.0Hz), 7.0
5-7.35 (5H, m). (C) (2R, 4R) -4-hydroxy-2- [2-
[5-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (2R, 4R) -4-hydroxy-2- [2- [5-] obtained in the step (c). Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine 38
5 mg was dissolved in 5 ml dioxane, and 4N hydrogen chloride-
0.27 ml of dioxane solution was added. The solvent was removed under reduced pressure, and the obtained oily substance was dissolved in 10 ml of ethyl acetate and allowed to stand. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (385 mg, yield 91%) as colorless crystals. Melting point: 108-110 ° C. NMR spectrum (270MHz, CDCl ₃₎
δ ppm: 2.0-2.2 (1H, m), 2.3-2.65 (2H, m), 2.31
(1H, dd, J = 5.9 and 13.8Hz), 2.83 (4H, s), 2.84 (3
H, s), 2.96 (1H, d, J = 12.3Hz), 3.75-3.9 (1H, m), 3.
79 (3H, s), 3.9-4.2 (3H, m), 4.55-4.65 (1H, m), 6.4
-6.5 (2H, m), 7.01 (1H, d, J = 7.9 Hz), 7.1-7.35 (5H,
m).

Example 16 (2R, 4R) -4-Hydroxy-2- [2- [6-methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (a) (2R , 4R) -4-Dimethylcarbamoyloxy-2- [2- [6-methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-octyloxycarbonylpyrrolidine 6-methoxy-2- (2-phenylethyl) ) Phenol 670 mg was dissolved in N, N-dimethylacetamide 10 ml and potassium t-butoxide 360 mg and (2S, 4R) -2- (2-chloroethyl) -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine 1000 mg were used. Then, the reaction was carried out in the same manner as in step (a) of Example 2 and extraction was performed to obtain an oily substance. This was subjected to silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to give 1500 mg of the title compound.
(Yield 99%) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.8-0.95
(3H, m), 1.15-1.45 (10H, m), 1.5-1.7 (2H, m), 1.75
-2.05 (1H, m), 2.05-2.2 (1H, m), 2.25-2.6 (2H, m),
2.75-3.0 (4H, m), 2.90 (6H, s), 3.5-3.9 (1H, m),
3.55 (1H, dd, J = 4.3 and 12.6Hz), 3.83 (3H, s),
3.9-4.3 (5H, m), 5.1-5.25 (1H, m), 6.7-6.8 (2H, m),
6.96 (1H, t, J = 7.9Hz), 7.1-7.35 (5H, m). (B) (2R, 4R) -4-hydroxy-2- [2-
[6-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine (2R, 4R) -4-dimethylcarbamoyloxy-2- [2- [6--obtained in the step (a). Methoxy-2-
(2-Phenylethyl) phenoxy] ethyl] -1-octyloxycarbonylpyrrolidine (1500 mg), tetrahydrofuran (25 ml) and lithium aluminum hydride (300 mg) were reacted in the same manner as in step (b) of Example 1 and obtained by post-treatment. The concentrate was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol = 5/1) to give the title compound 5 as a colorless solid.
52 mg (yield 59%) was obtained. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.55-1.7
5 (1H, m), 1.8-2.0 (2H, m), 2.15-2.4 (1H, m), 2.18
(1H, dd, J = 5.4 and 10.1Hz), 2.37 (3H, s), 2.6-
2.75 (1H, m), 2.8-3.0 (4H, m), 3.45 (1H, dd, J = 6.4
And 10.1Hz), 3.84 (3H, s), 3.85-4.05 (2H, m), 4.
3-4.45 (1H, m), 6.7-6.85 (2H, m), 6.97 (1H, t, J = 7.
8Hz), 7.1-7.35 (5H, m). (C) (2R, 4R) -4-hydroxy-2- [2-
[6-Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (2R, 4R) -4-hydroxy-2- [2- [6-] obtained in the step (c). Methoxy-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine 55
2 mg was dissolved in 10 ml of ethyl acetate, and 0.39 ml of 4N hydrogen chloride-ethyl acetate solution was added. The solvent was removed under reduced pressure, and the obtained oily substance was dissolved in 10 ml of ethyl acetate and allowed to stand. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound (424 mg, yield 70%) as colorless crystals. Melting point: 70-72 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.05-2.2
(1H, m), 2.2-2.6 (2H, m), 2.44 (1H, dd, J = 5.7 and 13.9Hz), 2.8-3.1 (1H, m), 2.89 (4H, s), 2.93 (3
H, s), 3.75-3.9 (1H, m), 3.84 (3H, s), 3.9-4.2 (3
H, m), 4.55-4.65 (1H, m), 6.75-6.85 (2H, m), 7.01
(1H, t, J = 7.9Hz), 7.1-7.35 (5H, m).

Example 17 (2R, 4R) -2- [2- [5-chloro-2- (2-
Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -2- [2- [5-chloro-2-
(2-Phenylethyl) phenoxy] ethyl] -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine 5-chloro-2- (2-phenylethyl) phenol 6
80 mg was dissolved in 10 ml of N, N-dimethylacetamide, 360 mg of potassium t-butoxide was added under ice cooling, and the mixture was stirred for 10 minutes. In the reaction solution (2S, 4R) -2-
(2-chloroethyl) -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine 1000
mg was added and reacted in the same manner as in step (a) of Example 2 and extracted to obtain an oily substance. Silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1)
The title compound (1.38 g, yield 91%) was obtained as an oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 0.8-1.0
(3H, m), 1.15-1.45 (10H, m), 1.45-1.7 (2H, m), 1.75-2.
15 (2H, m), 2.25-2.7 (2H, m), 2.7-3.0 (4H, m), 2.85
(3H, s), 2.87 (3H, s), 3.53 (1H, dd, J = 4.1 and 12.6Hz),
3.6-3.9 (1H, m), 3.9-4.3 (5H, m), 5.1-5.3 (1H, m),
6.7-6.9 (2H, m), 6.97 (1H, d, J = 7.9Hz), 7.1-7.35 (5H,
m). (B) (2R, 4R) -2- [2- [5-chloro-2-
(2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -2- [2- [5
-Chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine 1380 mg, lithium aluminum hydride 450 mg, tetrahydrofuran 2
Using 0 ml, the same reaction as in Example 1 (b),
The concentrate obtained by the post-treatment was subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 5 /
256 m of the title compound as a colorless solid after purification using 1).
g (30% yield). NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.6-1.8
(1H, m), 1.8-2.05 (2H, m), 2.1-2.3 (1H, m), 2.22 (1H, d
d, J = 5.4 and 10.1Hz), 2.39 (3H, s), 2.6-2.75 (1H, m),
2.8-2.95 (4H, m), 3.48 (1H, dd, J = 6.3 and 10.1Hz), 3.9
-4.1 (2H, m), 4.35-4.5 (1H, m), 6.75-6.9 (2H, m), 6.99
(1H, d, J = 7.8Hz), 7.1-7.35 (5H, m). (C) (2R, 4R) -2- [2- [5-chloro-2-
(2-Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [5] obtained in the step (c).
-Chloro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine 256
mg was dissolved in 5 ml of ethyl acetate, and 0.18 ml of a 4N hydrogen chloride-ethyl acetate solution was added. The solvent was removed under reduced pressure and the resulting oil was dissolved in 10 ml of ethyl acetate,
It was left still. The precipitated crystals were collected by filtration and dried in vacuo to give the title compound (183 mg, yield 65%) as colorless crystals. Melting point: 99-102 ° C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.05-2.25
(1H, m), 2.31 (1H, dd, J = 5.9 and 13.8Hz), 2.35-2.65
(2H, m), 2.8-3.0 (5H, m), 2.86 (3H, s), 3.7-3.9 (1H,
m), 3.9-4.25 (3H, m), 4.55-4.7 (1H, m), 6.82 (1H, d, J
= 1.9Hz), 6.85-7.0 (1H, m), 7.02 (1H, d, J = 8.0Hz), 7.1
-7.35 (5H, m).

Example 18 (2R, 4R) -2- [2- [6-fluoro-2- (2-
(Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -4-dimethylcarbamoyloxy-2- [2- [6-fluoro-2- (2-phenylethyl) ) Phenoxy] ethyl] -1-octyloxycarbonylpyrrolidine 6-fluoro-2- (2-phenylethyl) phenol 5
20 mg was dissolved in 10 ml of N, N-dimethylacetamide, potassium t-butoxide 300 mg, (2S, 4
R) -2- (2-Chloroethyl) -4-dimethylcarbamoyloxy-1-octyloxycarbonylpyrrolidine (820 mg) was reacted in the same manner as in Example 2 (a) and extracted to give an oily substance. This was purified using silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1) to give 984 mg of the title compound.
(81% yield) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.8-0.95
(3H, m), 1.15-1.45 (10H, m), 1.55-1.7 (2H, m), 1.7-2.0
(1H, m), 2.0-2.15 (1H, m), 2.25-2.6 (2H, m), 2.75-3.
0 (4H, m), 2.89 (6H, s), 3.54 (1H, dd, J = 4.3 and 12.5H
z), 3.6-3.9 (1H, m), 3.95-4.25 (5H, m), 5.1-5.3 (1H,
m), 6.8-7.0 (3H, m), 7.1-7.3 (5H, m). (B) (2R, 4R) -2- [2- [6-fluoro-2-
(2-Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (2R, 4R) -4-dimethylcarbamoyloxy-2- [2- [6-fluoro-2] obtained in the step (a). -(2
-Phenylethyl) phenoxy] ethyl] -1-octyloxycarbonylpyrrolidine 984 mg, lithium aluminum hydride 200 mg, tetrahydrofuran 20
Using ml, the reaction was carried out in the same manner as in step (b) of Example 1, and the concentrate obtained by post-treatment was subjected to silica gel column chromatography (elution solvent: methylene chloride / methanol = 5/1).
Was purified using 319 mg of the title compound (yield 53
%) As an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.55-1.75
(1H, m), 1.8-2.0 (2H, m), 2.15-2.35 (1H, m), 2.19 (1
H, dd, J = 5.4 and 10.1Hz), 2.37 (3H, s), 2.6-2.75 (1H,
m), 2.8-3.0 (4H, m), 3.45 (1H, dd, J = 6.3 and 10.1Hz),
3.95-4.15 (2H, m), 4.35-4.45 (1H, m), 6.85-7.0 (3H,
m), 7.15-7.35 (5H, m). (C) (2R, 4R) -2- [2- [6-fluoro-2-
(2-Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [6] obtained in the step (c).
-Fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine 319
mg was dissolved in 10 ml of ethyl acetate, and 4N hydrogen chloride-
0.23 ml of ethyl acetate solution was added. The solvent was removed under reduced pressure and the resulting oil was recrystallized from ethyl acetate, filtered and dried in vacuo to give 320 mg of the title compound.
(Yield 91%) was obtained as colorless crystals. Melting point: 136-138 [deg.] C. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 2.0-2.2
(1H, m), 2.2-2.6 (3H, m), 2.8-3.1 (5H, m), 2.92 (3H,
s), 3.8-4.25 (4H, m), 4.55-4.7 (1H, m), 6.85-7.05 (3
H, m), 7.1-7.4 (5H, m).

Example 19 2- [2- [4-Fluoro-2- (2-phenylethyl)]
Phenoxy] ethyl] -1-methylpyrrolidine hydrochloride (a) 2- [2- [4-Fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine 4-fluoro-2- (2- Phenylethyl) phenol 1
75 mg was dissolved in 5 ml of N, N-dimethylacetamide, and 130 mg of potassium t-butoxide was added under stirring with ice cooling. 220 mg of 2- (2-chloroethyl) pyrrolidine hydrochloride was added to the reaction solution, and the mixture was stirred at room temperature for 5 hours and then at 55 ° C.
For 6 hours. The reaction solution was cooled, diluted with ethyl acetate, and washed successively with water and brine. The extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil. Silica gel column chromatography (elution solvent:
Purification with methylene chloride / methanol = 5/1) gave 83.8 mg (yield 32%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.5-1.9
(4H, m), 1.9-2.1 (1H, m), 2.1-2.7 (3H, m), 2.36 (3H,
s), 2.8-2.95 (4H, m), 3.05-3.15 (1H, m), 3.85-4.1 (2
H, m), 6.7-6.9 (3H, m), 7.1-7.35 (5H, m).

(B) 2- [2- [4-fluoro-2- (2
-Phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine hydrochloride 2- [2- [4-fluoro-2- obtained in the above step (a).
(2-Phenylethyl) phenoxy] ethyl] -1-methylpyrrolidine (83.8 mg) was dissolved in a small amount of ethyl acetate, and 4N hydrogen chloride-ethyl acetate solution (0.06 ml) was added. The precipitated crystals were allowed to stand still, filtered, and dried in vacuum to obtain 68.9 mg (yield 74%) of the title compound as colorless crystals. Melting point: 149-151 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.9-2.15
(2H, m), 2.15-2.35 (2H, m), 2.35-2.6 (2H, m), 2.7-3.0
(5H, m), 2.74 (3H, s), 3.1-3.25 (1H, m), 3.8-4.05 (2H,
m), 4.1-4.25 (1H, m), 6.7-6.95 (3H, m), 7.05-7.35 (5
H, m).

Example 20 3- [4-Fluoro-2- (2-phenylethyl) phenoxy] methyl-1-methylpiperidine hydrochloride (a) 1-t-butoxycarbonyl-3- [4-fluoro-2- (2-Phenylethyl) phenoxy] methylpiperidine 4-fluoro-2- (2-phenylethyl) phenol 1
75 mg was dissolved in 5 ml of N, N-dimethylacetamide, 100 mg of potassium t-butoxide was added under stirring with ice cooling, and the mixture was stirred for 10 minutes. 330 m of 1-t-butoxycarbonyl-3-tosyloxymethylpiperidine was added to the reaction solution.
g was added, and the mixture was stirred at room temperature for 3 days. The reaction solution was diluted with ethyl acetate, washed successively with water and brine, the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give an oil. This was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to obtain 291 mg (yield 87%) of the title compound as an oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 1.3-1.8
(3H, m), 1.43 (9H, s), 1.8-2.1 (2H, m), 2.7-3.1 (6H,
m), 3.78 (2H, d, J = 6.0Hz), 3.85-4.0 (1H, m), 4.0-4.2
(1H, m), 6.65-6.9 (3H, m), 7.1-7.35 (5H, m). (B) 3- [4-fluoro-2- (2-phenylethyl)
Phenoxy] methyl-1-methylpiperidine 1-t-butoxycarbonyl-3 obtained in the step (a)
-[4-Fluoro-2- (2-phenylethyl) phenoxy] methylpiperidine (291 mg), lithium aluminum hydride (100 mg) and tetrahydrofuran (10 ml) were reacted in the same manner as in step (b) of Example 1 and post-treated to obtain the compound. The concentrated product was purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 10/1) to give 89.8 mg of the title compound (yield 39
%) As an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.05-1.3
(1H, m), 1.6-2.05 (5H, m), 2.1-2.3 (1H, m), 2.30 (3H,
s), 2.6-2.95 (5H, m), 2.95-3.05 (1H, m), 3.7-3.9 (2
H, m), 6.7-6.9 (3H, m), 7.15-7.35 (5H, m). (C) 3- [4-fluoro-2- (2-phenylethyl)
Phenoxy] methyl-1-methylpiperidine hydrochloride 89.8 mg of 3- [4-fluoro-2- (2-phenylethyl) phenoxy] methyl-1-methylpiperidine obtained in the above step (c) was added to a small amount of ethyl acetate. After dissolution, 0.07 ml of 4N hydrogen chloride-ethyl acetate solution was added. The precipitated crystals were collected by filtration and dried in vacuum to give the title compound 81.
7 mg (yield 82%) was obtained as colorless crystals. Melting point: 193-196 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.3-1.7
(1H, m), 1.85-2.05 (2H, m), 2.2-2.9 (8H, m), 2.72 (3
H, s), 3.35-3.6 (2H, m), 3.7-4.0 (2H, m), 6.65-6.8 (1
H, m), 6.8-6.95 (2H, m), 7.1-7.35 (5H, m).

Example 21 (2R, 4R) -2- [2- [4-fluoro-2- [2-
(4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -2- [2- [4-fluoro-2-
[2- (4-Fluoro-3-methoxyphenyl) ethyl]
Phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine (2R, 4R) -2- [2-] obtained in the step of Example 4 (b).
[4-Fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (513 mg) and pyridine (10)
It was dissolved in ml and 652 mg of lauric anhydride was added at room temperature. To this, 48 mg of 4-dimethylaminopyridine was added, and the mixture was stirred at room temperature for 30 minutes and then at 40 ° C for 1 hour. The reaction solution was diluted with ethyl acetate, washed twice with 1N-hydrochloric acid and then washed with brine, and the extract was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The obtained oily substance was purified by silica gel column chromatography (eluting solvent: methylene chloride / methanol = 5/1) to obtain 684 mg (yield 91%) of the title compound as a colorless oily substance. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H,
t, J = 6.6Hz), 1.15-1.4 (16H, m), 1.45-1.85 (3H, m), 1.8
5-2.1 (2H, m), 2.15-2.3 (2H, m), 2.22 (2H, t, J = 7.6H
z), 2.38 (3H, s), 2.55-2.7 (1H, m), 2.7-3.0 (4H, m),
3.60 (1H, dd, J = 6.6 and 10.7Hz), 3.83 (3H, s), 3.85-
4.05 (2H, m), 5.05-5.2 (1H, m), 6.6-7.05 (6H, m). (B) (2R, 4R) -2- [2- [4-fluoro-2-
[2- (4-Fluoro-3-methoxyphenyl) ethyl]
Phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [4] obtained in the step (a).
-Fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine 684 mg was dissolved in dioxane 10 ml, and 4N hydrogen chloride-dioxane solution 0 0.45 ml was added and the mixture was concentrated under reduced pressure. Hexane was added to this to crystallize, which was collected by filtration and dried in vacuo to obtain 485 mg (yield 67%) of the title compound as colorless crystals. Melting point: 49-53 [deg.] C. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H,
t, J = 6.6Hz), 1.1-1.4 (16H, m), 1.4-1.7 (2H, m), 2.21
(2H, t, J = 7.6Hz), 2.3-2.5 (2H, m), 2.5-2.7 (2H, m), 2.75
-3.0 (5H, m), 2.86 (3H, s), 3.45-3.7 (1H, m), 3.83 (3
H, s), 3.9-4.05 (1H, m), 4.1-4.25 (1H, m), 4.25-4.45
(1H, m), 5.3-5.4 (1H, m), 6.55-7.05 (6H, m). Example 22 (2R, 4R) -2- [2- [4-fluoro-2- [2-
(3-Methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine hydrochloride (a) (2R, 4R) -2- [2- [4-fluoro-2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
Ethyl] -4-lauroyloxy-1-methylpyrrolidine (2R, 4R) -obtained in the same manner as in Example 1 (b).
2- [2- [4-Fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine (1.13 g) was added to pyridine (20 m).
It was dissolved in 1 and 1.50 g of lauric anhydride was added at room temperature. 4-Dimethylaminopyridine (0.11 g) was added thereto, reacted in the same manner as in step (a) of Example 21, extracted, and purified by silica gel column chromatography (elution solvent: methylene chloride / methanol = 5/1). The title compound (1.34 g, yield 80%) was obtained as a colorless oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H,
t, J = 6.6Hz), 1.15-1.4 (16H, m), 1.45-1.8 (3H, m), 1.85
-2.1 (2H, m), 2.15-2.3 (2H, m), 2.21 (2H, t, J = 7.6Hz),
2.39 (3H, s), 2.6-2.75 (1H, m), 2.75-3.0 (4H, m), 3.
62 (1H, dd, J = 6.6 and 10.8Hz), 3.78 (3H, s), 3.85-4.1
(2H, m), 5.05-5.2 (1H, m), 6.7-6.9 (6H, m), 7.15-7.25
(1H, m). (B) (2R, 4R) -2- [2- [4-fluoro-2-
[2- (3-methoxyphenyl) ethyl] phenoxy]
Ethyl] -4-lauroyloxy-1-methylpyrrolidine hydrochloride (2R, 4R) -2- [2- [4] obtained in step (a) above.
-Fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1
-Methylpyrrolidine (1.34 g) was dissolved in dioxane (15 ml) and 4N hydrogen chloride-dioxane solution (0.90 ml)
Was added and concentrated under reduced pressure. Hexane was added to this, and after stirring, decantation was repeated 3 times, and the precipitate was dried in vacuum.
1.39 g (yield 97%) of the title compound was obtained as a colorless oil. IR spectrum (film) cm ^-1 : 1739, 1601, 1584,
1499, 1468, 1456, 1258, 1216, 1156. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 0.88 (3H,
t, J = 6.6Hz), 1.1-1.4 (16H, m), 1.4-1.8 (2H, m), 2.15
(2H, t, J = 7.5Hz), 2.25-2.5 (2H, m), 2.5-2.7 (2H, m),
2.75-3.0 (5H, m), 2.86 (3H, s), 3.6-3.85 (1H, m), 3.7
8 (3H, s), 3.85-4.05 (1H, m), 4.1-4.3 (1H, m), 4.35
(1H, dd, J = 5.7 and 13.6Hz), 5.3-5.4 (1H, m), 6.65-7.0
(6H, m), 7.21 (1H, t, J = 7.8Hz).

Reference Example 1 5-Methoxy-2- (2-phenylethyl) phenol 2-hydroxy-4-methoxybenzaldehyde 3.0
g was dissolved in 30 ml of acetonitrile, 9.2 g of benzyltriphenylphosphonium chloride was added, and the mixture was heated to 80 ° C.
For 30 minutes. To this, 1,8-diazabicyclo [5.4.
3.53 ml of 0] -7-undecene (DBU) was added, and the mixture was heated under reflux for 1 hour. The reaction solvent was removed under reduced pressure, ethyl acetate and water were added to the residue, and the layers were separated. The ethyl acetate layer was concentrated under reduced pressure, purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1), and then 4.
37 g of solid was obtained. This was dissolved in 50 ml of ethanol, 0.5 g of 5% palladium black was added, and the mixture was mixed with hydrogen under atmospheric pressure to give 6
Stirred at 0 ° C. for 2 hours. The catalyst was filtered off under reduced pressure, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to give 1.60 g (yield 36%) of the title compound as a colorless solid. Obtained. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 2.75-2.9
5 (4H, m), 3.74 (3H, s), 4.87 (1H, s), 6.33 (1H, d,
J = 2.5Hz), 6.42 (1H, dd, J = 2.5 and 8.3Hz), 6.97
(1H, d, J = 8.3Hz), 7.15-7.35 (5H, m).

Reference Example 2 4-bromo-2- (2-phenylethyl) phenol 2-hydroxy-5-bromobenzaldehyde 6.0 g
Was dissolved in 70 ml of acetonitrile, 13.9 g of benzyltriphenylphosphonium chloride was added, and the mixture was heated to 80 ° C.
For 15 minutes. To this, 5.3 ml of DBU was added, and the mixture was heated under reflux for 1 hour. Remove the reaction solvent under reduced pressure,
Ethyl acetate and water were added to the residue and the layers were separated. The ethyl acetate layer was concentrated under reduced pressure and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to obtain 7.44 g of a solid. This is ethanol 150
0.8 ml of tris (triphenylphosphine) rhodium (I) chloride was added and the mixture was dissolved in 50 ml of hydrogen under atmospheric pressure.
Stirred at C for 24 hours. An aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the mixture was stirred and then filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/1) to obtain 7.13 g (yield 86%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.75-3.
0 (4H, m), 5.13 (1H, s), 6.61 (1H, d, J = 8.5Hz), 7.1
-7.35 (7H, m).

Reference Example 3 4-fluoro-2- (2-phenylethyl) phenol Benzaldehyde (0.91 g), 5-fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride (4.00 g) and DBU (1.28 ml) were used, and 40 ml of acetonitrile was used. In the same manner as in Reference Example 2, after-treatment, purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 10/1),
2.04 g of oil was obtained. 2.03 g of this was mixed with 12 ml of a 1: 2 (v / v) mixture of benzene and ethanol.
And tris (triphenylphosphine) rhodium (I) chloride (0.30 g) were added, and the mixture was heated to 60 ° C. under normal pressure of hydrogen.
For 8 hours. The reaction solution was filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 10/1). Dissolve this in 10 ml of ethyl acetate, and under ice cooling, 4
10 ml of a normal hydrogen chloride-ethyl acetate solution was added, and the mixture was allowed to stand at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (elution solvent: hexane /
Purified with ethyl acetate = 5/1), 1.45 g of the title compound.
(79% yield) was obtained as a solid. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 2.8-3.0
(4H, m), 4.43 (1H, s), 6.6-6.9 (3H, m), 7.15-7.35
(5H, m).

Reference Example 4 4-Fluoro-2- [2- (3-methoxyphenyl) ethyl] phenol 2-hydroxy-5-fluorobenzaldehyde 312
mg, 3-methoxybenzyltriphenylphosphonium chloride 1110 mg and DBU 0.37 ml were reacted in 20 ml of acetonitrile in the same manner as in Reference Example 2, post-treated, and subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2). / 1) to obtain 526 mg of solid. This was dissolved in 12 ml of a 1: 2 (v / v) mixture of benzene and ethanol, 52 mg of tris (triphenylphosphine) rhodium (I) chloride was added, and the mixture was stirred at room temperature for 7 hours under normal pressure of hydrogen.
An aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the mixture was stirred, then filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (eluting solvent: hexane /
Purify with ethyl acetate = 2/1) to give the title compound 404m
g (75% yield) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.88 (4
H, s), 3.78 (3H, s), 4.52 (1H, s), 6.65-6.85 (6H,
m), 7.21 (1H, t, J = 7.5Hz).

Reference Example 5 4-Fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenol (a) Methoxymethyl [4-fluoro-2- [2- (4
-Fluoro-3-methoxyphenyl) ethyl] phenyl] ether 4-fluoro-3-methoxybenzaldehyde 547m
g, 5-fluoro-2-methoxymethoxybenzyl triphenylphosphonium chloride 1990 mg and DB
U of 0.58 ml was reacted in 30 ml of acetonitrile in the same manner as in Reference Example 2, post-treated, and purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give 948 mg of an oily substance. Got 936 mg of this is benzene and ethanol 1: 2
This was dissolved in 9 ml of the (v / v) mixed solution, 155 mg of tris (triphenylphosphine) rhodium (I) chloride was added, and the mixture was stirred at 60 ° C. for 14 hours under normal pressure of hydrogen. An aqueous sodium hydrogen sulfite solution was added to the reaction solution, and the mixture was stirred and then filtered using diatomaceous earth. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 4/1) to obtain 785 mg (yield 73%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.75-3.0
(4H, m), 3.47 (3H, s), 3.84 (3H, s), 5.12 (2H, s),
6.65-6.75 (2H, m), 6.75-6.9 (2H, m), 6.9-7.1 (2H,
m). (B) 4-fluoro-2- [2- (4-fluoro-3-
Methoxyphenyl) ethyl] phenol Methoxymethyl [4-fluoro-2- [2] of the above (a)
770 mg of-(4-fluoro-3-methoxyphenyl) ethyl] phenyl] ether was dissolved in 4 ml of ethyl acetate, and 4 ml of 4N hydrogen chloride-ethyl acetate solution was added under ice cooling.
In addition, it was allowed to stand at room temperature for 2 hours. The reaction solution is concentrated under reduced pressure,
The concentrate was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 3/2) to obtain 631 mg (yield 96%) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.87 (4
H, s), 3.83 (3H, s), 4.60 (1H, s), 6.6-6.85 (5H,
m), 6.98 (1H, dd, J = 8.5 and 11.3Hz).

Reference Example 6 4-Fluoro-2- [2- (4-fluorophenyl) ethyl] phenol (a) Methoxymethyl [4-fluoro-2- [2- (4
-Fluorophenyl) ethyl] phenyl] ether 4-fluorobenzaldehyde 950 mg, 5-fluoro-2-methoxymethoxybenzyl triphenylphosphonium chloride 3860 mg and DBU 1.26 ml.
Was reacted in 60 ml of acetonitrile in the same manner as in Reference Example 2, post-treated, and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 9/1) to obtain 2030 mg of an oily substance. . 19 of these
80 mg was dissolved in 12 ml of a 1: 2 (v / v) mixture of benzene and ethanol, 155 mg of tris (triphenylphosphine) rhodium (I) chloride was added, and the mixture was stirred at 60 ° C. for 20 hours under normal pressure of hydrogen. The reaction solution was filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 9
/ 1) to give 1816 mg of the title compound (yield 87
%) As an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.75-3.0
(4H, m), 3.47 (3H, s), 5.11 (2H, s), 6.75-6.9 (2H,
m), 6.9-7.2 (5H, m). (B) 4-Fluoro-2- [2- (4-fluorophenyl) ethyl] phenol Methoxymethyl [4-fluoro-2- [2] of the above (a)
1-85 mg of-(4-fluorophenyl) ethyl] phenyl] ether was dissolved in 8 ml of ethyl acetate, and the mixture was cooled with ice.
8 ml of 4N hydrogen chloride-ethyl acetate solution was added, and the mixture was allowed to stand at room temperature for 2 hours. The reaction solution was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 4/1) to give the title compound 1483.
mg (yield 99%) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.75-3.0
(4H, m), 4.57 (1H, s), 6.6-6.85 (3H, m), 6.9-7.05
(2H, m), 7.05-7.2 (2H, m).

Reference Example 7 2- [2- (3,4-difluorophenyl) ethyl]-
4-fluorophenol 3,4-difluorobenzaldehyde 610 mg, 5-
Fluoro-2-methoxymethoxybenzyl triphenylphosphonium chloride 2000 mg and DBU 0.6
Reference Example 2 using 4 ml in 20 ml of acetonitrile
The same reaction as above, post-treatment, and silica gel column chromatography (elution solvent: hexane / ethyl acetate = 15 /
Purification in 1) gave 1230 mg of oil. This was dissolved in 10 ml of ethanol, 300 mg of tris (triphenylphosphine) rhodium (I) chloride was added, and the mixture was stirred at 60 ° C. for 14 hours under normal pressure of hydrogen. The reaction solution was filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, adsorbed on a silica gel column, allowed to stand for a while, and then slowly eluted (eluting solvent: hexane / ethyl acetate = 4/1),
An eluate containing the title compound was obtained. This was concentrated under reduced pressure and dried in vacuum to give 1010 mg of the title compound (yield 93%).
Was obtained as a solid. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.86 (4
H, s), 4.60 (1H, s), 6.6-7.15 (6H, m).

Reference Example 8 5-Fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride (a) 5-Fluoro-2-hydroxybenzyl alcohol 1.98 g of lithium aluminum hydride was added to 50 ml of tetrahydrofuran, and 5-fluorosalicylic acid was added at room temperature. A solution of 5.44 g of tetrahydrofuran (50 ml) was added dropwise, and then the mixture was heated under reflux for 1 hour. After cooling, sodium sulfate decahydrate was added to decompose excess hydride, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure. This was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 2/1) to give the title compound 4.
72 g (95% yield) was obtained as a solid. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 1.69 (1
H, t, J = 3.2Hz), 4.82 (2H, d, J = 3.2Hz), 6.7-7.0 (3H,
m), 7.17 (1H, s). (B) 5-Fluoro-2-methoxymethoxybenzyl alcohol 4.71 g of 5-fluoro-2-hydroxybenzyl alcohol obtained in the step (a) was dissolved in 100 ml of N, N-dimethylacetamide, and potassium t-butoxide 3 was added. 0.72 g was added under ice cooling, and the mixture was stirred at the same temperature for 10 minutes. To the resulting solution was added methoxymethyl chloride 2.74.
ml was added at the same temperature, and the mixture was stirred at room temperature for 1 hour. Water (60 ml) and ethyl acetate (300 ml) were added to the reaction mixture to separate it. The ethyl acetate layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This was subjected to silica gel column chromatography (elution solvent: hexane /
Ethyl acetate = 3/2) and the title compound 4.25.
g (69% yield) was obtained as an oil. NMR spectrum (270MHz, CDCl ₃ ) δ ppm: 2.30 (1
H, t, J = 6.2Hz), 3.49 (3H, s), 4.67 (2H, d, J = 6.2H
z), 5.19 (2H, s), 6.85-7.0 (1H, m), 7.0-7.15 (2H,
m). (C) 5-Fluoro-2-methoxymethoxybenzyl chloride 4.15 g of 5-fluoro-2-methoxymethoxybenzyl alcohol obtained in the above step (b) was dissolved in 70 ml of tetrahydrofuran to give 6.86 g of carbon tetrachloride and triphenyl. 11.69 g of phosphine was sequentially added, and 1 was added at room temperature.
The mixture was stirred for an hour and heated under reflux for an additional 5 hours. Then, the insoluble matter was removed by filtration, the filtrate was concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography (elution solvent: hexane / ethyl acetate = 9/1) to give 3.27 g of the title compound (yield 71%). Was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.50 (3
H, s), 4.62 (2H, s), 5.21 (2H, s), 6.9-7.05 (1H,
m), 7.05-7.2 (2H, m). (D) 5-Fluoro-2-methoxymethoxybenzyltriphenylphosphonium chloride 3.25 g of 5-fluoro-2-methoxymethoxybenzyl chloride obtained in the above step (c) is dissolved in 50 ml of toluene to obtain 6.25 g of triphenylphosphine. In addition,
The mixture was refluxed for 6 hours. The reaction solution was cooled, and the resulting crystals were collected by filtration and dried under vacuum to give 5.16 g of the title compound (yield 70
%) Was obtained. Further, the filtrate was concentrated, and the precipitated crystals were collected by filtration to obtain 0.75 g of the title compound (total yield: 80).
%). NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.18 (3
H, s), 4.51 (2H, s), 5.60 (2H, d, J = 14.6Hz), 6.85-
6.95 (2H, m), 7.05-7.15 (1H, m), 7.55-7.8515H,
m).

Reference Example 9 5-chloro-2- (2-phenylethyl) phenol benzaldehyde 1.10 g, 4-chloro-2-methoxymethoxybenzyltriphenylphosphonium chloride 6.02 g, DBU 1.85 ml and acetonitrile 2
0 ml was used, reacted in the same manner as in Reference Example 2, post-treated,
Purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 10/1), 2.85 g
Oil was obtained. Dissolve this in 50 ml of ethanol,
0.40 g of tris (triphenylphosphine) rhodium (I) chloride was added, and the mixture was stirred at 50 ° C. for 14 hours under hydrogen normal pressure. The reaction solution was filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/1). This was dissolved in 10 ml of ethyl acetate, 10 ml of 4N hydrogen chloride-ethyl acetate solution was added under ice cooling, and the mixture was allowed to stand at room temperature for 1 hour. The reaction solution was concentrated under reduced pressure, and the concentrate was subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate =
5/1) to obtain 2.40 g (quantitative) of the title compound as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.75-3.0
(4H, m), 6.7-6.9 (2H, m), 6.96 (1H, d, J = 8.1Hz), 7.1-
7.35 (5H, m).

Reference Example 10 6-Fluoro-2- (2-phenylethyl) phenol 3-Fluoro-2-hydroxybenzaldehyde 3.00
g, benzyltriphenylphosphonium chloride 9.9
9 g, DBU 3.83 ml and acetonitrile 30 ml
Was reacted in the same manner as in Reference Example 2, post-treated, and purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 5/1) to obtain 4.58 g of a colorless solid. This was dissolved in 50 ml of ethanol, 0.50 g of tris (triphenylphosphine) rhodium (I) chloride was added, and the mixture was stirred at 50 ° C. for 48 hours under normal pressure of hydrogen. The reaction solution was filtered using diatomaceous earth, the filtrate was concentrated under reduced pressure, and silica gel column chromatography (eluting solvent:
Purification with hexane / ethyl acetate = 5/1) gave 3.15 g (yield 68%) of the title compound as a colorless solid. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 2.8-3.05
(4H, m), 6.65-7.0 (3H, m), 7.1-7.35 (5H, m).

Reference Example 11 4-Chloro-2-methoxymethoxybenzyltriphenylphosphonium chloride (a) 4-Chloro-2-hydroxybenzyl alcohol 1.65 g of lithium aluminum hydride was added to 100 ml of tetrahydrofuran, and the mixture was stirred under ice-cooling for 4 minutes. A solution of 5.00 g of chlorosalicylic acid in tetrahydrofuran (50 ml) was added dropwise, and the mixture was heated under reflux for 1 hour. After cooling,
Sodium sulfate decahydrate was added to decompose excess hydride, insoluble materials were removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained solid was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 1/1) to obtain 4.00 g (yield 87%) of the title compound as a solid. NMR spectrum (270 MHz, DMSO-d ₆ ) δ ppm: 4.43 (2
H, s), 6.75-6.9 (2H, m), 7.28 (1H, d, J = 8.0Hz). (B) 4-Chloro-2-methoxymethoxybenzyl alcohol 4.00 g of 4-chloro-2-hydroxybenzyl alcohol obtained in the step (a) was dissolved in 80 ml of N, N-dimethylacetamide, and potassium t-butoxide 2 was added. .8
3 g was added under ice cooling and stirred for 10 minutes. 2.09 ml of methoxymethyl chloride was added dropwise to the obtained solution at the same temperature, and the mixture was stirred at room temperature for 1 hour. Water (60 ml) and ethyl acetate (300 ml) were added to the reaction mixture to separate it. The ethyl acetate extract layer was washed with brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. This is subjected to silica gel column chromatography (elution solvent: hexane / ethyl acetate = 2/1).
The title compound (4.69 g, yield 92%) was obtained as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.48 (3H,
s), 4.65 (2H, s), 5.20 (2H, s), 6.98 (1H, dd, J = 1.9 and
8.2Hz), 7.12 (1H, d, J = 1.9Hz), 7.24 (1H, d, J = 8.2Hz)
. (C) 4-Chloro-2-methoxymethoxybenzyl chloride 4.69 g of 4-chloro-2-methoxymethoxybenzyl alcohol obtained in the step (b) was dissolved in 80 ml of tetrahydrofuran to give 7.11 g of carbon tetrachloride and triphenyl. 12.14 g of phosphine was sequentially added, and the mixture was stirred at room temperature for 1 hour. The mixture was heated under reflux for another 2.5 hours. The insolubles were removed by filtration, and the filtrate was concentrated under reduced pressure. The concentrate was purified by silica gel column chromatography (eluting solvent: hexane / ethyl acetate = 10/1) to give 3.38 g of the title compound (yield 6
6%) as an oil. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.50 (3H,
s), 4.61 (2H, s), 5.24 (2H, s), 6.98 (1H, dd, J = 2.0 and
8.2Hz), 7.14 (1H, d, J = 2.0Hz), 7.26 (1H, d, J = 8.2Hz)
. (D) 4-Chloro-2-methoxymethoxybenzyltriphenylphosphonium chloride 3.38 g of 4-chloro-2-methoxymethoxybenzyl chloride obtained in the above step (c) is dissolved in 50 ml of toluene, and 6.02 g of triphenylphosphine is dissolved. Add 1
The mixture was heated under reflux for 5.5 hours. The reaction solution was cooled, the resulting crystals were collected by filtration and dried in vacuum to obtain 6.02 g (yield 82%) of the title compound. NMR spectrum (270 MHz, CDCl ₃ ) δ ppm: 3.19 (3H,
s), 4.52 (2H, s), 5.58 (2H, d, J = 14.3Hz), 6.8-6.9 (1H,
m), 6.9-6.95 (1H, m), 7.39 (1H, dd, J = 3.0 and 8.2Hz),
7.6-7.9 (15H, m).

Test Example 1 Vasoconstriction Experiment The smooth muscle contraction reaction was measured by Van Neuten et al. (J. Pharmacol. Exp.
Ther., 218 , 217-230, 1981).
SD male rats weighing about 500 g were exsanguinated to death, and the tail artery was excised. The artery was removed (2 ×
A spiral specimen of 20 mm) was prepared. Tyor
The suspension was suspended in a Magnus tube maintained at 37 ° C. containing 10 ml of the ode solution, mixed gas (95% O ₂ , 5% CO ₂ ) was aerated, and left for 1 hour. 0 as initial tension.
5 g was loaded and the tension was recorded isometrically using a transducer. Serotonin 3x10 as vasoconstrictor
^-6 M was added to the Magnus tube, and after the contraction reaction was stabilized, each test solution was added cumulatively. Finally, papaverine 10 ^-4 M was added.
Was added. The tension was set to 100% before the addition of the test drug, and the tension was set to 0% 5 minutes after the addition of papaverine. The concentration of the test drug required to reduce the tension to 50% was defined as an IC ₅₀ value, and was calculated using a least squares regression line. The results are shown in Table 2.

[0103]

[Table 2] ────────────────────────────────── Compound IC ₅₀ nM ───────── ────────────────────────── Compound of Example 1 1.9 Compound of Example 2 2.0 Compound of Example 4 2.3 Compound of Example 6 2.2 The compound of Example 7 2.6 ───────────────────────────────────.

Test Example 2 Receptor Binding Experiment This was carried out according to the method of Leysen et al. (Mol. Pharmacol., 21, 301-314, 1982). Male Wistar rats (weight 280-
320 g) was used. After decapitation, the removed cerebral cortex and striatum were frozen on dry ice and stored at -80 ° C until measurement. The cerebral cortex was used as the serotonin receptor. Membrane preparation was prepared by homogenizing frozen brain tissue with 50 mM Tris-HCI buffer (pH 7.7) (Polytron PT-20),
It was centrifuged at 49,000 g for 10 minutes. The precipitate was suspended in Tris buffer, centrifuged again, and then suspended in Tris buffer. The membrane preparation obtained was quantified with protein and then with Tris buffer.
It was adjusted to 0.57 mg / protein / ml and stored at -80 ° C. In the receptor binding experiment, 440 μl of the membrane preparation was added to a test tube containing 50 μl of ³ H-ligand and 10 μl of a test compound (dissolved in DMSO) to start the reaction. After incubation for 1 hour at 30 ° C, the reaction was incubated with Whatman GF
It was stopped by vacuum filtration with a / B glass filter. After washing the filter with ice-cold Tris buffer (4 ml x 2 times), ACS-II was added and the radioactivity of the filter was measured with a liquid scintillation counter. Non-specific binding was determined by 20 μM atropine. The binding inhibition rate (%) was determined from the binding rate in the presence of the test drug, and the concentration required to inhibit the binding by 50% was taken as the IC ₅₀ value, which was determined from the least-squares regression line. Table 3 shows the results.

[0105]

[Table 3] ────────────────────────────────── Compound IC ₅₀ nM ───────── ────────────────────────── Compound of Example 1 1.0 Compound of Example 2 0.8 Compound of Example 4 0.65 Compound of Example 6 3.4 The compound of Example 7 0.75 ───────────────────────────────────.

Test Example 3 Squalene synthase inhibitory activity Squalene synthase inhibitory activity was determined by the method described in the literature [US Pat. No. 5,102,907, Anal. Biochem. 203 , 310 (19).
92) etc.]. That is, under anaerobic conditions, 16
Reactions were performed in x110 mm Spitz tubes. The composition of the reaction solution is shown below. 50 mM KH in 100 μl reaction 1 assay
₂ PO ₄ / K ₂ HPO ₄ (pH 7.5: potassium dihydrogen phosphate-dipotassium hydrogen phosphate buffer, 10 mM NaF (sodium fluoride)
, 10 mM MgCl ₂ (magnesium chloride), 2 mM DTT (dithiothreitol), 50 mM ascorbic acid, 20 units / ml ascorbate oxidase, 1 mM NADPH (nicotinamide adenine dinucleotide phosphate), 10 μM (4-
¹⁴ C] -FPP (farnesyl pyrophosphate; 58 μCi / μmo
l), containing 60 μg / ml rat liver microsome suspension and inhibitor solution (5 μl of test compound in methanol or aqueous solution). The rat liver microsome suspension was added last to initiate the reaction. The reaction was carried out in a thermostat at 37 ° C. After incubation for 20 minutes, the reaction was stopped by adding 100 μl of a 1: 1 mixture of 40% KOH (hydrous potassium hydroxide) and 95% EtOH (hydrous ethanol). did. This is further heated at 65 ° C. for 30
After heating for 1 minute, the mixture was cooled, and squalene was extracted by adding 2 ml of hexane. Take 1 ml of the hexane layer and add 10 ml
And the radioactivity was measured with a liquid scintillation counter. The inhibitory activity of the test compound was determined by co-incubating a test sample containing the test compound with an enzyme preparation and a substrate in the enzyme reaction solution, and measuring the inhibitory activity on the enzyme activity. The 50% inhibitory concentrations (IC ₅₀ ) of the preferred test compounds are shown in Table 4.

[0107]

[Table 4] ───────────────────────────── Compound IC ₅₀ μM ────────────── ──────────────── Compound of Example 4 1.6 Compound of Example 5 0.74 Compound of Example 6 1.1 Compound of Example 12 1.5 ────────── ───────────────────.

Formulation Example 1 Capsule Compound of Example 4 20.0 mg Lactose 158.7 Corn starch 70.0 Magnesium stearate 1.3 250 mg The powders of the above formulation were mixed and passed through a 60 mesh sieve, and then 250 mg of this powder No. 3 was mixed. Put in a gelatin capsule to make a capsule.

Formulation Example 2 Tablets Compound of Production Example 4 20.0 mg Lactose 154.0 Corn starch 25.0 Magnesium stearate 1.0 200 mg The powders of the above formulation are mixed and tableted with a tableting machine to give tablets of 200 mg each.

The tablets may be sugar-coated as needed.

[0111]

The compound (I) has both serotonin 2 receptor antagonism and squalene synthase inhibitory activity,
Because their action is persistent and their toxicity is weak, (1)
A therapeutic or prophylactic agent for thrombotic diseases and arteriosclerotic diseases (preferably therapeutic agents) that block the serotonin 2 receptor distributed in vascular endothelial cells and platelets and are based on platelet aggregation inhibition
Alternatively, it is useful as a therapeutic or preventive agent (preferably a therapeutic agent) for various diseases caused by these diseases, for example, coronary artery disease, cerebrovascular disorder, etc. (2) Hyperlipidemia based on cholesterol lowering action And a useful therapeutic or preventive agent for arteriosclerotic diseases. (3) An excellent therapeutic or preventive agent for arteriosclerotic diseases (suitably having a serotonin 2 receptor antagonistic action and a cholesterol lowering action) , A therapeutic agent).

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location A61K 31/54 A61K 31/54 C07D 207/08 C07D 207/08 207/14 207/14 211/22 211/22 241/04 241/04 265/30 265/30 279/12 279/12 // C12N 9/99 C12N 9/99 (72) Inventor Takeshi Ogawa 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Teiichiro Koga 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock Company (72) Inventor Tatsuo Tanimoto 1-258 Hiromachi, Shinagawa-ku, Tokyo Sankyo Stock In-company (72) Inventor Fumio Tsujita, Sanctuary, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. (72) In-house Hiroyuki Koike, 1-2-58, Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd. In the company

Claims (25)

[Claims] 1. A compound of the general formula [In the formula, R ¹ is a substituted 3- to 6-membered cyclic saturated heterocyclyl group containing 1 to 2 heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur atoms (the substituent is a carbon atom; The substituent is essential and includes a hydroxy group, a C ₁ -C ₂₀ alkoxycarbonyloxy group, a C _1
1 -C ₂₀ alkanoyloxy group, a carboxy substituted with a C ₂ -C ₇ alkanoyloxy group, a carbamoyloxy group or a mono - indicates or di -C ₁ -C ₆ alkylcarbamoyl group, the substituent on the nitrogen atom desired and, as it, C ₁ -C ₆ alkyl, C ₁ -C ₆
C substituted with alkyl, C ₁ -C ₆ alkoxy or C ₆ -C ₁₀ aryl optionally substituted with halogen
₁ -C ₆ alkyl group, C ₁ -C ₆ alkyl, C ₁ -C ₆
C optionally substituted with alkoxy or halogen
₆ -C showing a ₁₀ aryl group or a C ₁ -C ₉ alkoxycarbonyl group. ) Shows a, R ² a, R ² b and R ² c is the same or different, a hydrogen atom, a methyl group, an ethyl group, a methoxy group, an ethoxy group, a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, a cyano represents a group or a nitro ^{group, R 3 a, R 3 b} , R 3 c and R ³ d are the same or different and each represents a hydrogen atom, C ₁ -C ₆ alkyl group, Harogeno C ₁ -C ₆
Alkyl groups, C ₂ -C ₆ alkenyl groups, C ₂ -C ₆ alkynyl group, hydroxy group, C ₁ -C ₆ alkoxy group, Harogeno C ₁ -C ₆ alkoxy group, C ₁ -C ₆ alkoxycarbonyloxy groups, C ₁ -C ₆ alkanoyloxy group, carbamoyloxy group, mono - or di -C ₁ -
C ₆ alkylcarbamoyl group, a halogen atom, a cyano group, a nitro group or a C ₁ -C ₆ alkyl, C ₁ -C ₆
C optionally substituted with alkoxy or halogen
It indicates ₆ -C ₁₀ aryl group, A is a single bond or a C ₁ -C ₆ alkylene group. However, R ¹ is bound to a group having the formula -A- at its carbon atoms, one of R ² a, R ² b and R ² c represents a group other than a hydrogen atom. ] Is shown. ] The alicyclic amine derivative which has these, or its pharmacologically acceptable salt. 2. The alicyclic amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a substituted pyrrolidinyl group, piperidinyl group, morpholinyl group, thiomorpholinyl group or piperazinyl group (the substituent group). Are essential substituents on the carbon atom, such as a hydroxy group, C ₁ -C ₆ or C ₈ -C ₁₈ alkoxycarbonyloxy group, C ₁ -C ₂₀
Alkanoyloxy group, C ₃ substituted by carboxy -
C ₆ alkanoyloxy group, carbamoyloxy group or mono- or di-C ₁ -C ₂ alkylcarbamoyloxy group, wherein the substituent on the nitrogen atom is desired, as C ₁ -C ₄ alkyl group or methyl, A phenyl group which may be substituted with methoxy, fluorine or chlorine is shown. ) Is a compound. 3. The alicyclic amine derivative or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ is a substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (wherein the substituent is a carbon atom). Substituents on atoms are essential and include
Hydroxy groups, C ₁ -C ₄ or C ₈ -C ₁₈ alkoxycarbonyloxy group, C ₂ -C ₅ alkanoyloxy group, C ₁₀ -C ₁₈ alkanoyloxy group, C ₃ -C ₆ alkanoyloxy group substituted by a carboxy , A carbamoyloxy group or a mono- or di-C ₁ -C ₂ alkylcarbamoyloxy group, the substituent on the nitrogen atom being desired, which is a C ₁ -C ₄ alkyl group. ) Is a compound. 4. The alicyclic amine derivative or pharmacologically acceptable salt thereof according to claim 1, wherein R ¹ is a substituted pyrrolidinyl group, piperidinyl group, morpholinyl group or thiomorpholinyl group (wherein the substituent is a carbon atom). Substituents on atoms are essential and include
Hydroxy, methoxycarbonyloxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, t-
Butoxycarbonyloxy, octyloxycarbonyloxy, decyloxycarbonyloxy, hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, acetoxy, propionyloxy, butyryloxy, valerioloxy, pivaloyloxy, decanoyloxy, undecanoyloxy, lauroyloxy, Myristoyloxy, palmitoyloxy, stearoyloxy, succinyloxy, glutaryloxy,
Carbamoyloxy, N-methylcarbamoyloxy,
N-ethylcarbamoyloxy or N, N-dimethylcarbamoyloxy, the substituent on the nitrogen atom being desired, which is a C ₁ -C ₂ alkyl group. )
A compound that is 5. The alicyclic amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein R ¹ is a substituted pyrrolidinyl group, piperidinyl group or morpholinyl group (wherein the substituent is on a carbon atom). Substituents are essential and include hydroxy, ethoxycarbonyloxy, isopropoxycarbonyloxy, t
-Butoxycarbonyloxy, octyloxycarbonyloxy, hexadecyloxycarbonyloxy, octadecyloxycarbonyloxy, decanoyloxy,
A lauroyloxy, palmitoyloxy, stearoyloxy, succinyloxy, carbamoyloxy or N, N-dimethylcarbamoyloxy group, the substituent on the nitrogen atom of which is desired, as it is C ₁ -C ₂
It is an alkyl group. ) Is a compound. 6. The alicyclic amine derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-hydroxy-2-pyrrolidinyl group, 4-ethoxycarbonyloxy-2-pyrrolidinyl group, 4- An isopropoxycarbonyloxy-2-pyrrolidinyl group,
4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 4-octyloxycarbonyloxy-2-pyrrolidinyl group, 4-hexadecyloxycarbonyloxy-
2-pyrrolidinyl group, 4-octadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-acetoxy-2-
A pyrrolidinyl group, a 4-decanoyloxy-2-pyrrolidinyl group, a 4-lauroyloxy-2-pyrrolidinyl group,
4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 4-succinyloxy-2-pyrrolidinyl group, 4-carbamoyloxy-2
-Pyrrolidinyl group, 1-methyl-4-hydroxy-2-
Pyrrolidinyl group, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-isopropoxycarbonyloxy-2-pyrrolidinyl group, 1-
Methyl-4-t-butoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 1- Methyl-4-octadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-acetoxy-2-pyrrolidinyl group, 1-methyl-4-decanoyloxy-2-pyrrolidinyl group, 1-methyl-4-lauroyloxy -2-pyrrolidinyl group, 1-methyl-4-myristoyloxy-2-pyrrolidinyl group, 1-methyl-
A compound which is a 4-palmitoyloxy-2-pyrrolidinyl group, a 1-methyl-4-stearoyloxy-2-pyrrolidinyl group or a 1-methyl-4-succinyloxy-2-pyrrolidinyl group. 7. The alicyclic amine derivative according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-hydroxy-2-pyrrolidinyl group, 4-ethoxycarbonyloxy-2-pyrrolidinyl group, 4- t
-Butoxycarbonyloxy-2-pyrrolidinyl group, 4
-Octyloxycarbonyloxy-2-pyrrolidinyl group, 4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-octadecyloxycarbonyloxy-2-pyrrolidinyl group, 4-decanoyloxy-2-
Pyrrolidinyl group, 4-lauroyloxy-2-pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-pyrrolidinyl group, 4
-Stearoyloxy-2-pyrrolidinyl group, 1-methyl-4-hydroxy-2-pyrrolidinyl group, 1-methyl-4-ethoxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-t-butoxycarbonyloxy-
2-pyrrolidinyl group, 1-methyl-4-octyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-
4-hexadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-octadecyloxycarbonyloxy-2-pyrrolidinyl group, 1-methyl-4-decanoyloxy-2-pyrrolidinyl group, 1-methyl-4
-Lauroyloxy-2-pyrrolidinyl group, 1-methyl-4-myristoyloxy-2-pyrrolidinyl group, 1-
A compound which is a methyl-4-palmitoyloxy-2-pyrrolidinyl group or a 1-methyl-4-stearoyloxy-2-pyrrolidinyl group. 8. The alicyclic amine derivative of claim 1 or a pharmaceutically acceptable salt thereof, wherein R ¹ is 4-hydroxy-2-pyrrolidinyl group, 4-decanoyloxy-2-pyrrolidinyl group, 4- Lauroyloxy-2-pyrrolidinyl group, 4-myristoyloxy-2-pyrrolidinyl group, 4-palmitoyloxy-2-
Pyrrolidinyl group, 4-stearoyloxy-2-pyrrolidinyl group, 1-methyl-4-hydroxy-2-pyrrolidinyl group, 1-methyl-4-decanoyloxy-2-pyrrolidinyl group, 1-methyl-4-lauroyloxy- 2-
A compound which is a pyrrolidinyl group, a 1-methyl-4-myristoyloxy-2-pyrrolidinyl group, a 1-methyl-4-palmitoyloxy-2-pyrrolidinyl group or a 1-methyl-4-stearoyloxy-2-pyrrolidinyl group. 9. The alicyclic amine derivative or a pharmacologically acceptable salt thereof according to claim 1 to 8, R ² a and R ² b are the same or different, a hydrogen atom, a methyl group, a methoxy group, fluorine A compound which is an atom, a chlorine atom, a bromine atom, a cyano group or a nitro group, and R ² c is a hydrogen atom. 10. The method of claim 1 to 8 cycloaliphatic amine derivative or a pharmacologically acceptable salt thereof of, R ² a and R ² b are the same or different, a hydrogen atom, a methyl group, a methoxy group, fluorine A compound which is an atom, a chlorine atom or a bromine atom, and R ² c is a hydrogen atom. 11. The alicyclic amine derivative or pharmacologically acceptable salt thereof according to claim 1, wherein R ² a and R ² b are the same or different and each is a hydrogen atom, a fluorine atom or a chlorine atom. , R ² c is a hydrogen atom. 12. A compound in which R ² a is a fluorine atom and R ² b and R ² c are hydrogen atoms in the alicyclic amine derivative or the pharmaceutically acceptable salt thereof according to claim 1. . 13. The method of claim 1 to 12 alicyclic amine derivatives or a pharmacologically acceptable salt thereof of, R ³ a, R ³ b and R ³ c are the same or different, a hydrogen atom,
C ₁ -C ₄ alkyl group, a halogeno -C ₁ -C ₂ alkyl group, C ₃ -C ₄ alkenyl group, C ₃ -C ₄ alkynyl group, hydroxy group, C ₁ -C ₄ alkoxy group, Harogeno C ₁ -C ₂ alkoxy group, C ₁ -C ₄ alkoxycarbonyl group, C ₂ -C ₅ alkanoyloxy group, carbamoyl group, mono- or di-C ₁ -C ₂ alkylcarbamoyl group, halogen atom, cyano group, nitro group or C ₁
A compound which is a phenyl group which may be substituted with -C ₂ alkyl, C ₁ -C ₂ alkoxy or halogen, and R ³ d is a hydrogen atom. 14. The method of claim 1 to 12 alicyclic amine derivatives or a pharmacologically acceptable salt thereof of, R ³ a, R ³ b and R ³ c are the same or different, a hydrogen atom,
C ₁ -C ₂ alkyl group, fluoro or chloro-C
_1- C ₂ alkyl group, allyl group, propargyl group, hydroxy group, C ₁ -C ₂ alkoxy group, fluoromethoxy group, difluoromethoxy group, chloromethoxy group, 2-fluoroethoxy group, 2-chloroethoxy group, C ₁ -C ₂
Alkoxycarbonyl group, C ₂ -C ₃ alkanoyloxy group, a carbamoyl group, methylcarbamoyl group, dimethylcarbamoyl group, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a nitro group or a methyl, methoxy, substituted by fluorine or chlorine A phenyl group which may be R ³ d
Is a compound in which is a hydrogen atom. 15. The alicyclic amine derivative or pharmacologically acceptable salt thereof according to claim 1, wherein R ³ a, R ³ b and R ³ c are the same or different and each is a hydrogen atom,
C ₁ -C ₂ alkyl group, fluoromethyl group, trifluoromethyl group, chloromethyl group, hydroxy group, C ₁ -C
_{2 A} compound in which an alkoxy group, a fluoromethoxy group, a difluoromethoxy group, a 2-fluoroethoxy group, a fluorine atom, a chlorine atom, a bromine atom, a cyano group, a carbamoyl group or a phenyl group, and R ³ d is a hydrogen atom. 16. The method of claim 1 to 12 alicyclic amine derivatives or a pharmacologically acceptable salt thereof of, R ³ a and R ³ b are the same or different, a hydrogen atom, a methyl group, hydroxy group, methoxy A group, an ethoxy group, a fluoromethoxy group, a difluoromethoxy group, a fluorine atom, a chlorine atom, a bromine atom or a cyano group, and R ³ c and R ³ d are hydrogen atoms. 17. cycloaliphatic amine derivative or a pharmacologically acceptable salt thereof of claims 1 to 12, R ³ a and R ³ b are the same or different, a hydrogen atom, a methoxy group or a fluorine atom , R ³ c and R ³ d are hydrogen atoms. 18. A compound of the alicyclic amine derivative or pharmacologically acceptable salt thereof according to claim 1, wherein A is a single bond or a C ₁ -C ₄ alkylene group. 19. The alicyclic amine derivative according to any one of claims 1 to 17 or a pharmacologically acceptable salt thereof, wherein A is a single bond, a methylene group, an ethylene group or a trimethylene group. 20. A compound of the alicyclic amine derivative or the pharmaceutically acceptable salt thereof according to claim 1, wherein A is a single bond, a methylene group or an ethylene group. 21. A compound in which A is an ethylene group in the alicyclic amine derivative or the pharmaceutically acceptable salt thereof according to any one of claims 1 to 17. 22. 2- [2- [4-fluoro-2- (2-
Phenylethyl) phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, 2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-hydroxypyrrolidine, 2- [2- [4-Fluoro-2- (2-phenylethyl) phenoxy] ethyl] -4-lauroyloxy-1
-Methylpyrrolidine, 2- [2- [4-fluoro-2- (2-phenylethyl) phenoxy] ethyl] -1-methyl-4-succinyloxypyrrolidine, 2- [2- [4-fluoro-2- [ 2- (3-Methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, 2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl ] -4-Lauroyloxy-1-methylpyrrolidine, 2- [2- [4-fluoro-2- [2- (3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methyl-4-succinyloxypyrrolidine, 2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, -[2- [4-Fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine, 2- [2- [4-fluoro-2- [2- (4- Fluorophenyl) ethyl] phenoxy] ethyl] -1-methyl-4-palmitoyloxypyrrolidine, 2- [2- [4-fluoro-2- [2- (4-fluorophenyl) ethyl] phenoxy] ethyl] -1- Methyl-4-succinyloxypyrrolidine, 2- [2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxy-1-methylpyrrolidine, 2 -[2- [4-Fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-hydroxypyrrolidine, 2- [ 2- [4-fluoro-2- [2- (4-fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -4-lauroyloxy-1-methylpyrrolidine, 2- [2- [4-fluoro-2] -[2- (4-Fluoro-3-methoxyphenyl) ethyl] phenoxy] ethyl] -1-methyl-4-succinyloxypyrrolidine, 2- [2- [2- [2- (3,4-difluorophenyl)) Ethyl] -4-fluorophenoxy] ethyl] -4
-Hydroxy-1-methylpyrrolidine, 2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4
-Hydroxypyrrolidine, 2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -4
-Lauroyloxy-1-methylpyrrolidine and 2- [2- [2- [2- (3,4-difluorophenyl) ethyl] -4-fluorophenoxy] ethyl] -1
An alicyclic amine derivative selected from the group consisting of -methyl-4-succinyloxypyrrolidine or a pharmacologically acceptable salt thereof. 23. A therapeutic or prophylactic agent for thrombotic diseases, which comprises the alicyclic amine derivative according to any one of claims 1 to 22 or a pharmacologically acceptable salt thereof as an active ingredient. 24. A therapeutic or prophylactic agent for arteriosclerotic diseases, which comprises the alicyclic amine derivative according to any one of claims 1 to 22 or a pharmacologically acceptable salt thereof as an active ingredient. 25. A therapeutic or prophylactic agent for hyperlipidemic diseases, which comprises the alicyclic amine derivative according to any one of claims 1 to 22 or a pharmacologically acceptable salt thereof as an active ingredient.