JPH09249623A - New tricyclic compound and medicine composition containing the same - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a new tricyclic compound having β3 operation activity, blood sugar lowering action and lipolytic activity, useful for treating and preventing diseases related to β3, such as diabetes, obesity and hyperlipemia. SOLUTION: This compound is shown by formula I (R is H or methyl; R<1> is H, a halogen, a hydroxyl group, benzyloxy, etc.; R<2> is H, hydroxymethyl, nitro, etc.; R<6> is H or a lower alkyl; X is a secondary nitrogen atom, an oxygen atom, a sulfur atom or methylene; when X is a secondary nitrogen atom, an oxygen atom or a sulfur atom, R<9> is H, one of R<7> and R<8> is H and the other is H, amino, etc., and when X is methylene, R<7> and R<8> are H and R<9> is H, amino, acetylamino or a hydroxyl group; *1 is an asymmetrical carbon atom; *2 is an asymmetric carbon atom when R<6> is the lower alkyl) or its salt. The compound of formula I is obtained by reacting a compound of formula II (R<1> ' is H, a halogen, etc.; R<2> ' is H, nitro, etc.; A' is a hydroxyl-protecting group; B is Br or I) with a compound of formula III (Y is H; R<7> ' to R<9> ' are each are shown for R<7> to R<9> ) and deprotecting each protecting group.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a novel tricyclic compound and a pharmaceutical composition containing the tricyclic compound.

[0002]

2. Description of the Related Art Conventionally, β-adrenergic receptors are
It has been considered that it is classified into two types, i.e., β1 and β2, and that stimulation of β1 increases the number of beats and stimulation of β2 induces relaxation of smooth muscle tissue to lower blood pressure. Arch, etc. have β1,
A compound having a very small β2 action and promoting lipolysis of adipocytes was found, and the existence of the third receptor was clarified (Nature, 1984, 309, 163, Nature 309, p163-165 (198).
4)). After that, its primary structure became clear (Emo
Line et al. Science, 1989, 245, 11
18, p. Science 1989, vol. 245,
p1118-1121), and was named β3. More recently, compounds having β3 agonistic activity have been shown to be useful as prophylactic / therapeutic agents for diabetes, obesity, hyperlipidemia, digestive system diseases, and depression (Int. J. Obe.
site 8 (Suppl. 1), p93-102 (1
984), Nature 309, p163-165.
(1984), USP 5120766, Brit. J.
Pharmacol. 103, p1351-1356
(1991), Eur. J. Pharmacol. 21
9, p193-201 (1992)). Conventional compounds related to β3 are EP023385 and the literature (Drugs).
ofthe future vol. 16, p79
7-800 (1991)), the following structural formula

[0003]

Embedded image Having a compound (BRL37344), and EP045
5006 and references (J. Med. Chem. Vol. 3).
5, p3081-3084 (1992)).

[0004]

Embedded image Having a compound (CL316, 243), or WO9
The following structural formula described in 492290

[0005]

Embedded image And various compounds are described in EP0659737. For example, in the specification example 1 thereof, the following structural formula is shown.

[0006]

Embedded image Is exemplified. However, they clearly differ in structure from the compounds of the present invention. In addition, as a compound having a heart rate increasing action, a myocardial contractile force enhancing action and an antiobesity action, the following structural formula described in EP171702

[0007]

Embedded image Although a compound having ## STR3 ## is known, this compound is a compound that acts on the heart, and differs from the compounds of the present invention in that it has a strong structure and a strong action on the heart. Further, compounds having an α, β blocking action, that is, a blood pressure lowering action are disclosed in JP-A-55-53262 and JP-A-58-41.
The following structural formula described in No. 860

[0008]

Embedded image Are known, and as a compound having a vasodilatory action, the following structural formula described in German Patent DE2651572 is given.

[0009]

Embedded image There is a compound having the formula (1), which is different in structure and use from the compound of the present invention.

[0010]

SUMMARY OF THE INVENTION There has been a long-felt need to provide a novel and useful pharmaceutical agent for treating and preventing β3-related diseases such as diabetes, obesity, and hyperlipidemia.

[0011]

[Means for Solving the Problems] In order to solve the above problems, the present inventors synthesized various compounds and studied the activity thereof. As a result, a novel compound represented by the following general formula (I)
It was confirmed that the cyclic compound has β3 agonistic activity, and has a blood glucose lowering action and a lipolytic action, and completed the present invention. That is, the present invention provides a compound represented by the general formula (I):

[0012]

Embedded image[In the formula, R represents a hydrogen atom or a methyl group, and R¹Is water
Elementary atom, halogen atom, hydroxyl group, benzyloxy group,
R represents a mino group or a hydroxymethyl group, R^TwoIs hydrogen field
Child, hydroxymethyl group, NHR^Three , SO_TwoNR^FourR^Four'
Alternatively, it represents a nitro group. Where R^ThreeIs a hydrogen atom, methyl
Base, SO_TwoR^Five, Formyl group or CONHR^{6 '}Shows
Then R^FiveIs a lower alkyl group, benzyl group or NR^FourR
^Four'Is shown. Also, R^FourAnd R^Four'Are the same or each other
To a hydrogen atom, a lower alkyl group or
Indicates a benzyl group. R^{6 '}Is hydrogen atom or lower alk
Represents a hydroxyl group. Also, R⁶Is hydrogen atom or lower alk
Represents a hydroxyl group. X is a secondary nitrogen atom, oxygen atom, sulfur atom
Or a methylene group, and X is a secondary nitrogen atom or oxygen atom
Or in the case of a sulfur atom, R⁹Is a hydrogen atom, R⁷is there
Iha R⁸One of them is a hydrogen atom and the other is a hydrogen atom.
Represents a child, amino group, acetylamino group or hydroxyl group.
When X is a methylene group, R⁷And R⁸Yes
This is also a hydrogen atom, R ⁹Is a hydrogen atom, amino group, acetyl
Indicates an amino group or a hydroxyl group. * 1 is an asymmetric carbon atom
, * 2 is R⁶Is a lower alkyl group
It means a carbon atom. ] Or its compound
Salt.

In the present invention, the halogen atom is
A fluorine atom, a chlorine atom, a bromine atom or an iodine atom can be mentioned, and among these, a fluorine atom and a chlorine atom are preferred. Further, the "lower" of the lower alkyl group means a linear or branched saturated hydrocarbon containing a carbon atom having 1 to 4 carbon atoms, such as methyl, ethyl and n.
-Propyl, i-propyl, n-butyl, i-butyl,
Examples thereof include s-butyl and t-butyl. R is preferably a hydrogen atom. It is also preferable that R is a methyl group because it has more selectivity. R ¹ is a hydrogen atom, a halogen atom, a hydroxyl group, benzyloxy group, but is an amino group or a hydroxymethyl group, the inner R ¹
Preferred examples include compounds of the general formula (I) in which is a hydrogen atom. Further, a compound of the general formula (I) in which R ¹ is an amino group or a hydroxymethyl group is mentioned as a preferable example. In addition, compounds of the general formula (I) in which R ¹ is a halogen atom, a hydroxyl group or a benzyloxy group are also preferred examples.

Further, R ² is a hydrogen atom, a hydroxymethyl group, is a _{^{NHR 3, SO 2 NR 4 R}} 4 ' or nitro group, compounds of general formula (I) the inner R ² is a hydrogen atom As a preferable example. Further, a compound of the general formula (I) in which R ² is a hydroxymethyl group or a nitro group is mentioned as a preferable example. In addition, R ² is NHR
Preferred examples include compounds of general formula (I) which are ³ or SO ₂ NR ⁴ R ^{4 ′} . R ³ is a hydrogen atom in the NHR ^3, methyl, SO ₂ R ^5, is a formyl group or CONHR ^{6 ',} a particularly NHR ^3, N
H ₂ , NHMe, NHSO ₂ R ⁵ , NHCHO or N
It can be mentioned as preferred examples of HCONHR ^{6 ',}
Of these, NHSO ₂ R ⁵ is a more preferable example. R ⁵ in NHSO ₂ R ⁵ is a lower alkyl group, a benzyl group, or NR ⁴ R ^{4 '.} R ⁴ and R ^{4 ′} are hydrogen atoms, lower alkyl groups or benzyl groups, which may be the same or different from each other.
It is also preferable that either one of ⁴ and R ^{4 ′} is a hydrogen atom.

Specifically, NR^FourR^Four'As an amino group,
Methylamino group, ethylamino group, propylamino group,
Benzylamino group, dimethylamino group, diethylamino
Group, dipropylamino group, methylethylamino group, methyl
Rupropylamino group or methylbenzylamino group, etc.
, Of which a methylamino group or dimethyl group
A mino group is mentioned as a more preferable example. Therefore, N
HSO_TwoR^FiveThe preferred specific examples of NHSO are:_Two
Me, NHSO_TwoEt, NHSO_TwoCH_TwoPh, NHS
O_TwoNH_Two, NHSO_TwoNHMe, NHSO_TwoNHE
t, NHSO_TwoNMe_Two, NHSO_TwoNEt_Two, NHS
O_TwoNMeEt or NHSO_TwoNMeCH_TwoPh, etc.
No. Also, NHCONHR^{6 '}R in^{6 '}Is
A hydrogen atom or a lower alkyl group is shown. NHCONH
R^{6 '}Specifically, NHCONH_Two, NHCON
HMe, NHCONHEt or NHCONHPr etc.
Is exemplified. R^TwoSO in_TwoNR^FourR^Four'about
Is R^FourAnd R^Four'Is the same as described above, and R^Four
And R^Four'May be the same or different from each other
A hydrogen atom, a lower alkyl group or a benzyl group,
R^FourAnd R^Four'When either one of is a hydrogen atom
Is also preferred. Therefore, SO_TwoNR^FourR^Four'As a concrete
SO_TwoNH_Two, SO_TwoNHMe, SO_TwoNHE
t, SO_TwoNMe _Two , SO_TwoNEt_Two, SO_TwoNHCH
_TwoPh or SO_TwoNMeCH_TwoPh and the like are exemplified.

R ⁶ represents a hydrogen atom or a lower alkyl group. Preferred examples include a hydrogen atom, a methyl group and an ethyl group. Furthermore, a hydrogen atom is mentioned as a preferable example. X is a secondary nitrogen atom, an oxygen atom, a sulfur atom or a methylene group, and a compound in which X is a secondary nitrogen atom (that is, the tricyclic group is the skeleton of a carbazole group) is preferred. . R ⁷ , R ⁸ and R ⁹ are as described above. In the above general formula (I), * 1 is an asymmetric carbon atom, and when R ⁶ is a lower alkyl group, * 2 is also an asymmetric carbon atom. In that case, the compound of general formula (I) has four isomers, namely (R, R), (R, S), (S, S).
And (S, R) (displayed in the order * 1, * 2). Further, when R ⁶ is a hydrogen atom, two isomers exist. Not only optically pure isomers, but also mixtures of any two isomers, mixtures of any three isomers, or mixtures of all four isomers are included within the scope of the present invention. From the viewpoint of expression of pharmacological activity, the absolute configuration of the ethanol amino chain asymmetric carbon (* 1) is the absolute configuration R. Especially, regarding the asymmetric carbon (* 1) of N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide, An R-hydroxy body is mentioned as a preferable example.

In the present invention, various groups are recognized as being extremely preferable by combining the respective substituents. Unless otherwise specified below, R ⁶ , X and R are represented.
⁷ , R ⁸ , R ⁹ , * 1 and * 2 mean the same as above. In the compound of the present invention represented by the general formula (I), R ² is a hydroxymethyl group, NHR ³ , SO ₂ NR
⁴ For R 4 ^'or nitro group, the substitution position of R ¹ is 4-position or 5-position is preferred. Furthermore, the substitution position of R ¹ is more preferably the 4-position. When R ² is a hydrogen atom, the substitution position of R ¹ is more preferably the 2-position. In the present invention, the combination of the respective substituents of the general formula (I) is as follows: [R represents a hydrogen atom, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a benzyloxy group, an amino group or a hydroxymethyl group. Shows,
R ² is a hydrogen atom, hydroxymethyl group, NHR ³ , SO
Shows a ₂ NR ⁴ R ^{4 'or} nitro. However, R ³ is hydrogen atom, methyl group, SO ₂ R ⁵ , formyl group or CON
'Indicates, R ⁵ is a lower alkyl group, a benzyl group, or NR ⁴ R ^4' HR ⁶ shows the. R ⁴ and R ^{4 ′} represent the same or different hydrogen atom, lower alkyl group or benzyl group. R ⁶ 'has the same meaning as described above. ] Or a salt thereof is a preferred example.

The present invention also relates to each unit of the above general formula (I).
The combination of substituents is [R represents a hydrogen atom, R¹Is water
Elemental atom, fluorine atom, chlorine atom, hydroxyl group or benzyl
Represents an oxy group, R^TwoIs a hydrogen atom, hydroxymethyl
Group, NHR^Three , SO_TwoNR^FourR ^Four'Or indicates a nitro group
You. Where R^ThreeIs hydrogen atom, methyl group, SO_TwoR^Five, E
Rumil group or CONHR⁶'. R^FiveIs lower alk
Group, benzyl group or dimethylamino group. Ma
R^FourAnd R^Four'Is one of the hydrogen atoms
And the other is hydrogen atom, lower alkyl group or benzyl group
Is shown. Also, R⁶'Has the same meaning as above. ]
A compound or its salt is also mentioned as a preferable example. Ma
Further, the present invention provides a combination of each substituent of the above general formula (I).
Sega, [R represents a hydrogen atom, R¹Is hydrogen atom, halogen
R atom, hydroxyl group or benzyloxy group, R
^TwoIs a hydroxymethyl group, NHR^Three , SO_TwoNR^FourR
^Four'Alternatively, it represents a nitro group. Where R^ThreeIs a hydrogen atom,
Lu group, SO_TwoR^Five, Formyl group or CONHR⁶Indicates'
Then R^FiveIs a lower alkyl group, benzyl group or NR^FourR
^Four'Is shown. Also, R^FourAnd R^Four'Are the same or each other
To a hydrogen atom, a lower alkyl group or
Indicates a benzyl group. Also, R⁶'Means the same as above
You. ] Or a salt thereof is a preferable example.
I can do it.

Further, in the present invention, the combination of the respective substituents of the general formula (I) is as follows: [R represents a hydrogen atom, R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom, a hydroxyl group or a benzyloxy group. , R ² is a hydroxymethyl group, NHR
³ , SO ₂ NR ⁴ R ^{4 ′} or a nitro group is shown. However, R
³ represents a hydrogen atom, a methyl group, SO ₂ R ⁵ , a formyl group or a CONHR ⁶ ′, one of R ⁴ and R ⁴ ′ is a hydrogen atom, and the other is a hydrogen atom, a lower alkyl group or a benzyl group. Indicates. R ⁵ represents a lower alkyl group, a benzyl group or a dimethylamino group. Also,
R ⁶ 'has the same meaning as described above. ] Or a salt thereof is also preferred. In the present invention, the combination of the respective substituents of the general formula (I) is as follows: [R and R ¹ represent a hydrogen atom, R ² is a hydroxymethyl group,
NHR ³ or SO ₂ NR ⁴ R ^{4 ′} , R ³ is hydrogen atom, methyl group, SO ₂ R ⁵ , formyl group or CONH
'Indicates, R ⁵ is a lower alkyl group, a benzyl group, or NR ⁴ R ^4' R ⁶ illustrates a. R ⁴ and R ⁴ 'represent a hydrogen atom, a lower alkyl group or a benzyl group, which may be the same or different. R ⁶ 'has the same meaning as described above. ] Or a salt thereof is a preferred example.

The present invention also relates to each substitution of the above general formula (I)
The combination of groups is [R and R¹Represents a hydrogen atom,
R^TwoIs a hydroxymethyl group, NHR^Three Or SO_TwoN
R^FourR^Four'Is shown. Where R^ThreeIs a hydrogen atom, a methyl group, S
O_TwoR^Five, Formyl group or CONHR⁶'Indicates R^Four
And R^Four'Is either a hydrogen atom and the other is
A hydrogen atom, a lower alkyl group or a benzyl group is shown. Ma
R^FiveIs a lower alkyl group, benzyl group or dimethyl
Indicates an amino group. Also, R⁶'Means the same as above
You. ] Or a salt thereof is a preferred example.
I can do it. In addition, the present invention provides each substitution of the above general formula (I).
The combination of groups is [R represents a hydrogen atom, R¹Is halo
R represents a gen atom or hydroxyl group^TwoIs NHSO_TwoR^Five
Or SO_TwoNR^FourR^Four'And R^FiveIs lower alkyl
Group, benzyl group or NR^FourR^Four'And R^Fourand
R^Four'Is a hydrogen source which may be the same or different from each other
Represents a child, a lower alkyl group or a benzyl group. ]
A compound or its salt is mentioned as a preferable example. Ma
Further, the present invention provides a combination of each substituent of the above general formula (I).
Sega, [R represents a hydrogen atom, R¹Is a fluorine atom, chlorine
R represents an atom or a hydroxyl group^TwoIs NHSO _TwoR^FiveAlso
Is SO_TwoNR^FourR^Four'And R^FourAnd R^Four'Is either
One is a hydrogen atom and the other is a hydrogen atom or a lower alkyl group.
Or benzyl group. Also, R^FiveIs a lower alkyl group,
A benzyl group or a dimethylamino group is shown. ] Is
Compounds or salts thereof are also preferred examples.

In the present invention, the combination of the respective substituents of the general formula (I) is such that [R and R ² both represent a hydrogen atom, and R ¹ represents a hydrogen atom, a halogen atom or a hydroxyl group. ] Or a salt thereof is a preferred example. Further, in the present invention, the combination of the respective substituents of the general formula (I) is such that [R and R ² both represent a hydrogen atom, and R ¹ represents a hydrogen atom, a fluorine atom, a chlorine atom or a hydroxyl group. ] Or a salt thereof is also preferred. In the present invention, the combination of the respective substituents of the general formula (I) is such that [R represents a hydrogen atom, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a hydroxymethyl group, and R ² represents NHR ³ or SO ₂ N
R ⁴ shows R ^{4 ′} . However, R ³ represents SO ₂ R ⁵ . R ⁵
Represents a lower alkyl group, a benzyl group or NR ⁴ R ^{4 ′} . R ⁴ and R ⁴ 'may hydrogen atom be different same or another, a lower alkyl group or a benzyl group. ] Or a salt thereof is a preferred example. In the present invention, the combination of the respective substituents of the general formula (I) is such that [R represents a methyl group, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, a benzyloxy group, an amino group or a hydroxymethyl group. R ² is a hydrogen atom, a hydroxymethyl group, NHR ³ or SO ₂ NR ⁴
R4 ^' or a nitro group is shown. Provided that R ³ represents a hydrogen atom, a methyl group, SO ₂ R ⁵ , a formyl group or CONHR ^{6 ′} , and R ⁵ represents a lower alkyl group, a benzyl group or NR ⁴
R ^4'is shown. R ⁴ and R ⁴ 'represent a hydrogen atom, a lower alkyl group or a benzyl group, which may be the same or different. R ⁶ 'has the same meaning as described above. ] Or a salt thereof is a preferred example.

The present invention also relates to each substitution of the above general formula (I).
The combination of groups is [R represents a methyl group, R¹Is hydrogen
Atom, fluorine atom, chlorine atom, hydroxyl group or benzyl group
A xy group;^TwoIs a hydrogen atom, a hydroxymethyl group,
NHR^Three , SO_TwoNR^FourR^Four'Alternatively, it represents a nitro group. However
Then R^ThreeIs hydrogen atom, methyl group, SO_TwoR^Five, Holmill
Group or CONHR^{6 '}Is shown. R^FiveIs a lower alkyl group,
Benzyl group or NR ^FourR^Four'Is shown. Also, R^Fourand
R^Four'Is either a hydrogen atom and the other is a hydrogen atom.
Represents a child, a lower alkyl group or a benzyl group. Also, R
⁶'Has the same meaning as above. ] Or a compound thereof
Salt is also mentioned as a preferable example. The present invention also provides
The combination of the respective substituents of the general formula (I) is [R is methyl
And R represents¹Is a hydrogen atom, halogen atom, hydroxyl group
Or benzyloxy group, R^TwoIs hydroxymethy
Ru group, NHR^Three , SO_TwoNR^FourR^Four'Or indicates a nitro group
You. Where R^ThreeIs hydrogen atom, methyl group, SO_TwoR^Five, E
Rumil group or CONHR^{6 '}And R^FiveIs lower alk
Group, benzyl group or NR^FourR^Four'Is shown. Also, R^Four
And R^Four'May be the same or different from each other
A hydrogen atom, a lower alkyl group or a benzyl group is shown. Ma
R⁶'Has the same meaning as above. ] Which is also
The salt thereof is also preferred. In addition, the present invention
Is a combination of the substituents of the above general formula (I) is [R
Represents a methyl group, R¹Is hydrogen atom, fluorine atom, chlorine
An atom, a hydroxyl group or a benzyloxy group, R^TwoIs
Hydroxymethyl group, NHR^Three , SO_TwoNR^FourR^Four'Also
Represents a nitro group. Where R^ThreeIs a hydrogen atom, a methyl group,
SO_TwoR^Five, Formyl group or CONHR^{6 '}And R
^FourAnd R^Four'Is one of the hydrogen atoms and the other
Represents a hydrogen atom, a lower alkyl group or a benzyl group.
Also, R^FiveIs a lower alkyl group, benzyl group or dimethy
Represents a ruamino group. Also, R⁶'Means the same as above
You. ] Or a salt thereof is a preferable example.
I can do it.

The present invention also relates to each unit of the above general formula (I).
The combination of the substituents is [R represents a methyl group, R¹Is water
Indicates elementary atom, R^TwoIs a hydroxymethyl group, NHR
^Three , SO_TwoNR^FourR^Four'And R^ThreeIs a hydrogen atom, methyl
Base, SO_TwoR^Five, Formyl group or CONHR^{6 '}Shows
Then R^FiveIs a lower alkyl group, benzyl group or NR^FourR
^Four'Is shown. Also, R^FourAnd R^Four'Are the same or each other
To a hydrogen atom, a lower alkyl group or
Indicates a benzyl group. Also, R⁶'Means the same as above
You. ] Or a salt thereof is a preferred example.
I can do it. In addition, the present invention provides each substitution of the above general formula (I).
The combination of groups is [R represents a methyl group, R¹Is hydrogen
Represents an atom, R^TwoIs a hydroxymethyl group, NHR^Three Ma
Or SO_TwoNR^FourR^Four'Is shown. Where R^ThreeIs a hydrogen atom,
Methyl group, SO_TwoR^Five, Formyl group or CONHR^{6 '}
And R^FourAnd R^Four'Is either a hydrogen atom
And the other is hydrogen atom, lower alkyl group or benzyl.
Represents a group. Also, R ^FiveIs a lower alkyl group, benzyl group
Or dimethylamino group. Also, R⁶'Is the same as above
Show meaning. ] Or a salt thereof is preferred
It is listed as. The present invention also provides the above general formula (I).
And the combination of each substituent of [R is a methyl group, R
¹Represents a halogen atom or a hydroxyl group, R^TwoIs NHS
O_TwoR^FiveOr SO_TwoNR^FourR^Four'And R^FiveIs a lower class
Rukyl group, benzyl group or NR^FourR^Four'And R^FourYou
And R^Four'Is water that may be the same or different from each other
An elementary atom, a lower alkyl group or a benzyl group is shown. ]so
A compound or a salt thereof is mentioned as a preferable example.
You. The present invention also provides a group of each substituent of the above general formula (I).
The combination is [R represents a methyl group, R¹Is fluorine
Child, chlorine atom or hydroxyl group, R^TwoIs NHSO _Two
R^FiveOr SO_TwoNR^FourR^Four'And R^FourAnd R^Four'Is
One is a hydrogen atom, the other is a hydrogen atom
A kill group or a benzyl group is shown. Also, R^FiveIs lower al
A kill group, a benzyl group or a dimethylamino group is shown. ]
And a salt thereof is also preferred.
You.

In the present invention, the combination of the respective substituents of the general formula (I) is such that [R represents a methyl group, R ¹ represents a hydrogen atom, a halogen atom or a hydroxyl group, and R ² represents a hydrogen atom. Show. ] Or a salt thereof is a preferred example. The present invention also provides the above general formula (I).
And the combination of each substituent of [R is a methyl group, R
¹ represents a hydrogen atom, a fluorine atom, a chlorine atom or a hydroxyl group, and R ² represents a hydrogen atom. ] Or a salt thereof is also preferred. Further, in the present invention, the combination of the respective substituents of the general formula (I) is such that [R represents a methyl group, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group,
Represents an amino group or a hydroxymethyl group, and R ² is NH
Shows the R ³ or SO ₂ NR ⁴ R ^{4 '.} However, R ³ is SO
₂ R ⁵ is shown. R ⁵ represents a lower alkyl group, a benzyl group, or NR ⁴ R ^{4 '.} R ⁴ and R ⁴ 'may hydrogen atom be different same or another, a lower alkyl group or a benzyl group. ] Or a salt thereof is a preferred example.

Further, specific compounds of the compound of the present invention represented by the general formula (I) include the following compounds. (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; (S) -N- [ 5- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methane Sulfonamide; N- [5- [2- [2- (3-hydroxy-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5 -[2- [2-
(3-amino-9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2
-[2- (6-Amino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2
-Hydroxyphenyl] methanesulfonamide;

N- [5- [2- [2- (6-hydroxy-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; (R)- N- [3- [2-
[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; (S) -N- [3- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] phenyl] methanesulfonamide; N- [3- [2- [2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N-methyl-3
-[2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] benzenesulfonamide; N-methyl- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-Hydroxyethyl] -2-hydroxy] benzenesulfonamide; (R) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl ] Methanesulfonamide; (S) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5 -[2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazole-
2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] methanesulfonamide;

N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide; N- [5- [2- [ 2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide; N
-[3- [2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [5- [2- [2-
(7-Acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2-
[2- (7-Aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [3- [2-
[2- (7-Acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [3- [2- [2-
(7-Aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1 -Hydroxyethyl] -2-hydroxyphenyl] formamide; N
-[3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] formamide; N- [3- [2-[[1- (9H
-Carbazol-2-yloxy) propan-2R-yl] amino] -1-hydroxyethyl] phenyl] methanesulfonamide;

2- [N- [2- (9H-carbazole-
2-yloxy) ethyl] amino] -1- (4-hydroxy-3-nitrophenyl) ethanol; 2- [N-
[2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (3-amino-4-hydroxyphenyl) ethanol; N- [5- [2- [2- (9H-carbazol-2-yloxy) ) Ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl]
Urea; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] urea; N- [5-
[2- [2- (9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] formamide; N ′-[5-
[2- [2- (9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] -N, N-dimethylsulfamide; N ′-[5- [2- [2- (9H-carbazole-
2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; 2- [N- [2- (9H-carbazole-
2-yloxy) ethyl] amino] -1- [3- (methylamino) -4- (benzyloxy) phenyl] ethanol; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3- (methylamino) -4-hydroxyphenyl] ethanol; N- [5
-[2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -2-propanesulfonamide;

2- [N- [2- (9H-carbazole-
2-yloxy) ethyl] amino] -1- (3-nitrophenyl) ethanol; N ′-[3- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-hydroxyethyl] phenyl] -N, N-dimethylsulfamide; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (3-aminophenyl) ethanol; 2 -[N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1-
[3- (Hydroxymethyl) -4-hydroxyphenyl] ethanol; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -3-hydroxyphenyl] N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [3- [2 -[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -4-hydroxyphenyl] methanesulfonamide;

(R) -N '-[5- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] -2-hydroxyphenyl]-
N, N-dimethylsulfamide; (S) -N '-[5-
[2- [2- (9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; N-
[3- [2- [2- (6-acetylamino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N-
[5- [2- [2- (6-Acetylamino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; (R) -N- [5 -[2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Hydroxyethyl] -2-fluorophenyl] methanesulfonamide; (S) -N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Hydroxyethyl] -2-fluorophenyl] methanesulfonamide; (R) -N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Hydroxyethyl] -2-chlorophenyl] methanesulfonamide;

(S) -N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Hydroxyethyl] -2-chlorophenyl] methanesulfonamide; N, N-dimethyl- [5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide; N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Hydroxyethyl] -2-iodophenyl] methanesulfonamide; N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl]- N, N-dimethylsulfamide; N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] -N, N-dimethyl Sulfamide; (R) -N-methyl- [5- [2
-[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide; (R) -N- [5- [2
-[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (hydroxymethyl) phenyl] methanesulfonamide; (R)-
N- [3- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N '-[5- [2- [2-
(Dibenzofuran-3-yloxy) ethylamino]-
1-hydroxyethyl] -2-hydroxyphenyl]-
N, N-dimethylsulfamide; (R) -N '-[5-
[2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; (S)-
N '-[5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2
-Hydroxyphenyl] -N, N-dimethylsulfamide; N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl]-
2-Fluorophenyl] methanesulfonamide; N- [5
-[2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide; N- [5- [2- [2
-(Dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N '-[5- [2- [2-
(Dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide;

N- [3- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; (R)-
N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl]-
2-Hydroxyphenyl] methanesulfonamide; N-
[5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-
Fluorophenyl] methanesulfonamide; N- [5-
[2- [2- (dibenzothiophen-3-yloxy)
Ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide; N- [5- [2-
[2- (7-Aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N ′-[5- [2-
[2- (7-Acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide;
N '-[5- [2- [2- (9H-carbazole-2-
Iloxy) ethylamino] -1-hydroxyethyl]
2-Aminophenyl] -N-benzyl-N-methylsulfamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- Aminophenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxymethylphenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxy Ethyl] -2-bromophenyl] methanesulfonamide;
N '-[5- [2- [2- (9H-carbazole-2-
Iloxy) ethylamino] -1-hydroxy; cyethyl] -2-hydroxyphenyl] -N-benzyl-N-
Methylsulfamide; N '-[5- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] -2-hydroxyphenyl]-
N, N-diethylsulfamide; N- [5- [2- [2
-(9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-aminophenyl] methanesulfonamide; N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Methoxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide

Specific compounds in which R ¹ and R ² are hydrogen atoms include the following compounds. 2- [N
-[2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (4-hydroxyphenyl) ethanol; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino]- 1- (2-Fluorophenyl) ethanol; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (2-hydroxyphenyl) ethanol; (R, R)-[2 −
[N- [1- (9H-carbazol-2-yloxy)
Propan-2-yl] amino] -1-phenyl] ethanol; [2- [N- [2- (9H-carbazole-2-
(R)-[2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl] ethanol; (S)- [2- [N- [2- (9H-
Carbazol-2-yloxy) ethyl] amino] -1
-Phenyl] ethanol; [2- [N- [2- (3-acetylamino-9H-carbazol-2-yloxy)
Ethyl] amino] -1-phenyl] ethanol; [2-
[N- [2- (3-amino-9H-carbazole-2-
Iloxy) ethyl] amino] -1-phenyl] ethanol; [2- [N- [2- (3-hydroxy-9H-carbazol-2-yloxy) ethyl] amino] -1-
Phenyl] ethanol; [2- [N- [2- (6-amino-9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl] ethanol; [2- [N- [2
-(6-Acetylamino-9H-carbazol-2-yloxy) ethyl] amino] -1-phenyl] ethanol; [2- [N- [1- (9H-carbazol-2-yloxy) propan-2-yl] Amino] -1-phenyl] ethanol; [2- [N- [2- (dibenzofuran-3-yloxy) ethyl] amino] -1-phenyl]
ethanol;

Further, examples of compounds in which R is a methyl group include the following. N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (Dibenzothiophen-3-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazole-
2-yloxy) ethylamino] -1-methoxyethyl] -2-aminophenyl] methanesulfonamide; N
-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-
Chlorophenyl] methanesulfonamide; general formula (I)
The compound can be produced, for example, by the following method. (Production method A) General formula (II)

[0035]

[Chemical 21] [Wherein R ¹ 'represents a hydrogen atom, a halogen atom, a hydroxyl group protected by a protective group A, an amino group protected by an acetyl group or a hydroxymethyl group protected by an acetyl group,
R ² ′ represents a hydrogen atom, a hydroxymethyl group protected by a hydroxyl-protecting group A ′ ″, NHR ^{3 ′} , SO ₂ NR ⁴ R 4 ′ or a nitro group. However, R ³ 'represents an amino-protecting group, a methyl group, SO ₂ R ⁵ , formyl group or CONHR ^6' , and R ⁵ is a lower alkyl group, benzyl group or NR ⁴ R
Indicates ^{4 '} . R ⁴ and R ⁴ 'represent a hydrogen atom, a lower alkyl group or a benzyl group, which may be the same or different. R ⁶ 'represents a hydrogen atom or a lower alkyl group. R ⁶ represents a hydrogen atom or a lower alkyl group. A'represents a hydroxyl-protecting group, B means a bromine atom or an iodine atom, and * 1 means an asymmetric carbon atom. ] And the compound represented by the general formula (III)

[0036]

Embedded image [In the formula, Y represents a hydrogen atom, and R ⁶ represents a hydrogen atom or a lower alkyl group. X represents a secondary nitrogen atom, oxygen atom, sulfur atom or methylene group, and when X is a secondary nitrogen atom, oxygen atom or sulfur atom, R ⁹ 'is a hydrogen atom and R ⁷ ' or R ⁸ ' One of them is a hydrogen atom, and the other is a hydrogen atom, an acetylamino group or a hydroxyl group protected by a protective group A ″. When X is a methylene group, R ⁷ 'and R ⁸ ' are both hydrogen atoms, and R ⁹ 'is a hydrogen atom, an acetylamino group or a hydroxyl group protected by a protective group A''. * 2 means an asymmetric carbon atom when R ⁶ is a lower alkyl group. ] The protective group A (provided that R ¹ is a benzyloxy group and the protective group A is a benzyl group does not deprotect the protective group A), A '. , A ″, A ′ ″ and R
^By deprotecting the protecting group for amino group in ³ '(only when present) or the acetyl protecting group in R ¹ ', the compound of the general formula (I) [wherein R represents a hydrogen atom and R ¹ represents Represents a hydrogen atom, a halogen atom, a hydroxyl group, a benzyloxy group, an amino group or a hydroxymethyl group, and R ² represents a hydrogen atom, a hydroxymethyl group, NHR ³ ,
Shows the SO ₂ NR ⁴ R ⁴ 'or nitro. However, R ³ is a hydrogen atom, a methyl group, SO ₂ R ⁵ , a formyl group or C
ONHR ^{6 ′} is shown, and R ⁵ is a lower alkyl group, benzyl group or NR ⁴ R ⁴ ′. R ⁴ and R ⁴ 'represent a hydrogen atom, a lower alkyl group or a benzyl group, which may be the same or different. R ⁶ 'represents a hydrogen atom or a lower alkyl group. ] Compound is obtained.

The protective group for the hydroxyl group is not particularly limited as long as it is commonly used. For example, A is a benzyl group or t-butyldimethylsilyl group as a protective group that can be easily and selectively deprotected. Examples of A ′ and A ′ ″ include a triethylsilyl group, and examples of A ″ include a methyl group and a benzyl group. A known method is used for introducing these hydroxyl-protecting groups. For example, for introducing the benzyl group, 1 to 2 moles of benzyl bromide and 1.1 times the molar amount of benzyl bromide in a solvent such as dimethylformamide are used. Double molar sodium iodide is added and reacted at room temperature. Further, the introduction of the triethylsilyl group is carried out in a solvent such as pyridine and a silylating agent such as 1.2 to 2 moles of triethylsilyl chloride at 0 ° C.
The method of reacting at 1 to 3 hours at 30 to 30 ° C is exemplified. The amino group-protecting group for R ³ 'is not particularly limited as long as it is a group commonly used as a protecting group for aniline, and among them, an acetyl group is preferable. An example of the acetylation method is reaction with acetic anhydride in a solvent such as pyridine. The coupling reaction between the general formula (II) and the amine of the general formula (III) is carried out by reacting the general formula (III) with the halide of the general formula (II) in a polar solvent such as dimethylformamide, dimethylacetamide or dimethylsulfoxide. 1 to 1.5 times the molar amount of the amine of 1) is used, and the mixture is heated at room temperature to 90 ° C., preferably 60 ° C. for 5 to 10 hours in the presence of an amine such as triethylamine or diisopropylethylamine as a proton trapping agent.

Deprotection may be carried out sequentially or collectively, but preferably A ″, A ′, A ′ ″ and R ³ ′.
The amino group-protecting group in step A and A may be performed in this order. As a deprotection condition, the benzyl groups of the protecting groups A and A ″ are deprotected by hydrogenolysis in a solvent such as methanol using a catalyst such as palladium or nickel. However, when R ^{1 of} the general formula (I) is a benzyloxy group,
The benzyl group of the protecting group A may not be deprotected. Alternatively, the benzyl group or methyl group of the protective groups A and A ″ is deprotected by treatment with a Lewis acid such as boron tribromide in a solvent such as methylene chloride. Further, deprotection of the acetyl-protected hydroxymethyl group in R ¹ 'is carried out by using known ester hydrolysis conditions. As a specific example, there is a method of heating from room temperature to the reflux temperature of the solvent using an alkali in alcohol. In addition, the protecting groups A ′, A ′ ″
The triethylsilyl group and the like can be deprotected by adding acetic acid and 3 to 5 moles of tetrabutylammonium fluoride in tetrahydrofuran and treating at room temperature for 30 minutes to 5 hours. In the case of an amino-protecting group in R ³ ′, for example, an acetyl group or an acetyl-protected amino group in R ^{1 ′} , it is treated with hydrochloric acid in a solvent such as methanol at room temperature or heated with an alkali in a solvent such as water or methanol. It can be deprotected. The compound represented by the general formula (II) has the general formula (V)

[0039]

Embedded image [In the formula, R ¹ 'and R ² ' have the same meanings as described above. ] By reducing the compound represented by the following method,
When the substituent B is an iodine atom, it can be obtained by substituting the bromine atom with iodine and then protecting the hydroxyl group. That is, reduction of the compound represented by the general formula (V) can be obtained by using a reducing agent such as borane when the steric (* 1) of the hydroxyl group of the compound represented by the general formula (II) is racemic. . Further, regarding * 1 in the general formula (II), when an optical isomer of R or S is to be obtained, the compound represented by the general formula (V
I)

[0040]

Embedded image It may be carried out using a chiral auxiliary such as. That is, it can be obtained by reducing the compound represented by the general formula (V) with borane in the presence of the above chiral auxiliary. The above reduction reaction is preferably performed in a solvent such as tetrahydrofuran. The preparation of these chiral auxiliaries and their reactions are described in the literature (EJ Corey et al., Journal of Organic Chemistry (J. Org.
Chem) 56, 442, 1991). When it is necessary to replace the bromine atom (bromine form) with an iodine atom after the reduction of the compound represented by the general formula (V), the compound obtained by the above reduction is further added to a solvent such as acetone. An example is a method of heating at a reflux temperature for 1 to 3 hours with an iodizing agent such as sodium iodide in an amount of 3 to 10 times that of the bromide. Then, the compound of the general formula (II) can be obtained by further protecting the hydroxyl group with a protecting group such as a triethylsilyl group by the above-mentioned method for protecting the hydroxyl group. The compound represented by the general formula (V) is known, and is disclosed in literatures (for example, A. Larsen et al., Journal of Medicinal Chemistry (J. Med. Chem.) 1
967, vol. 10, p. 462 or Kaiser (CK
aiser) et al., Journal of Medicinal Chemistry (J. Med. Chem.) 1974, 1
Vol. 7, p. 49). on the other hand,
The compound of the general formula (III) has the general formula (VII)

[0041]

Embedded image [Wherein Y represents an amine protecting group, R ⁶ and * 2
Have the same meanings as described above. ] And the compound represented by the general formula (VIII)

[0042]

Embedded image [In the formula, X, R ⁷ ′, R ⁸ ′ and R ⁹ ′ have the same meanings as described above. ] It is obtained by reacting with a compound represented by Y is an amine-protecting group and is not particularly limited as long as it is a group usually used as an amine-protecting group. Group, or an acetyl group or a trifluoroacetyl group. The reaction of the general formula (VII) with the general formula (VIII) is exemplified to be carried out in an organic solvent, usually in the presence of a base, from room temperature to the reflux temperature of the selected solvent. Examples of the solvent include dimethylformamide, dimethylacetamide, acetonitrile, diglyme, and tetrahydrofuran, and examples of the base include potassium carbonate, sodium carbonate, sodium hydroxide, potassium hydroxide, triethylamine, pyridine, sodium hydride, sodium methoxide, and the like. It is preferable to use 1 to 10 times the molar amount of (VIII). When the reaction is slow, the Brutein Chemical Society
Japan 1982, 55, 2504 (Bul
l. Chem. Soc. Jpn. , 55, 2504), or by using a modified method thereof, general formula (III) (Y represents a protecting group for amine) can be synthesized. As an example, in dimethylformamide or acetonitrile, the compound of the general formula (VII) is 2 to 5 times mol, 40% potassium fluoride-alumina is 5 to 10 times mol to alcohol, and as an improved method, potassium iodide is further added. 0.1 to 0.5 equivalent is added, and the mixture is reacted at room temperature to 90 ° C.

Furthermore, by deprotecting the protecting group Y of the amine, the compound of the general formula (III) (Y represents a hydrogen atom)
The amine compound of Deprotection can be carried out by a conventional method, for example, by hydrogenolysis in a solvent such as methanol using palladium-carbon as a catalyst or treatment with hydrogen bromide-acetic acid. When the protecting group Y is an acetyl group or a trifluoroacetyl group, it is treated with an alkali in a solvent such as methanol to obtain the general formula (III) (Y means a hydrogen atom). The compound of general formula (VII) is
First, a commercially available amino alcohol having R ⁶ * 2 is
It can be synthesized by protecting the amine with a protecting group Y and then bromating the hydroxyl group by a conventional method. In addition, if there is an easily accessible aminobromide, it can be obtained by protecting the amine with the protecting group Y. As an example, commercially available 2-bromoethylamine HB
It is exemplified that the r salt is reacted with benzyloxycarbonyl in methylene chloride in the presence of triethylamine under ice cooling. In the compound of general formula (VIII), X is a secondary nitrogen atom,
In the case of an oxygen atom or a sulfur atom and the case of X being a methylene group, they can be produced by the following methods. First, X
Is a secondary nitrogen atom, an oxygen atom or a sulfur atom, R ⁸ 'and R ⁹ ' are hydrogen atoms, and R ⁷ 'is a hydrogen atom, a acetylamino group or a hydroxyl group protected by a protecting group A''. Can be manufactured by the following method.

That is, commercially available 2-hydroxycarbazole, 3-methoxydibenzofuran or 3-hydroxydibenzothiophene (H. Kudo et a.
1, J .; Heterocycl. Chem. , 22
(1), 215-218, 1985) are used as starting materials to obtain the compound of general formula (VIII). When R ⁷ 'is a substituent other than a hydrogen atom, for example, commercially available 2-
After benzylating the hydroxyl group of hydroxycarbazole, it is nitrated (introduced at the position of the substituent R ⁷ ′) and subsequently reduced to an amino group. Acetylate the amino group,
Alternatively, diazotization, introduction of a hydroxyl group, protection with a hydroxyl-protecting group A ″, deprotection of the benzyl group, and reaction with the general formula (VI
The compound of II) is obtained. The nitration can be carried out by a conventional method described in the chemical literature, and as an example, it is exemplified that it is carried out at room temperature to 60 ° C. using an equivalent amount of fuming nitric acid diluted with benzyl-protected compound in acetic acid. Furthermore, the reduction reaction of the nitro group is carried out by a commonly used method, for example, hydrogenation at room temperature in the presence of a catalyst of platinum oxide in a solvent such as methanol, or using hydrochloric acid in the presence of iron powder or divalent tin. Reduce from room temperature to reflux temperature. The amine thus formed is acetylated with acetyl chloride in a solvent such as methylene chloride at 0 ° C. to room temperature, or the amine is diazotized with sodium nitrite and the resulting diazonium salt is thermally decomposed in an acidic aqueous solution to form a hydroxyl group. It is introduced, protected by the protective group A ″ by the above-mentioned hydroxyl group protection method, and finally the benzyl group is deprotected. Next, in the case where X is a secondary nitrogen atom, oxygen atom or sulfur atom, R ⁷ 'and R ⁹ ' are hydrogen atoms and R ⁸ 'is protected with a hydrogen atom, an acetylamino group or a protective group A''. In the case of a hydroxyl group, it can be produced by the following method. That is, the general formula (IX)

[0045]

Embedded image [In the formula, X means a secondary nitrogen atom, an oxygen atom or a sulfur atom. ] A known compound represented by the formula: 2-acetylcarbazole (J. B. Kyziol et al, Te
trahedron, 36, 3017-3019, 19
80), 3-acetyldibenzofuran (MI She
vchuk et al, Zh. Obshch. Khi
m. , 40 (8), 1717-1725, 1970) or 3-acetyldibenzothiophene (Phospho
rus, Sulfur Silicon Relat.
Elem. , 72 (1-4), 13-31, 1992 and E.I. Camazine et al. Hetero
cycle. Chem. , 6 (4), 517-522,
1969) as a starting material. When R ⁸ 'is a substituent other than a hydrogen atom, for example, 2-acetylcarbazole is nitrated (introduced at the position of the substituent R ⁸ '), and then the nitro group is reduced to an amino group. The amino group is acetylated or diazotized, a hydroxyl group is introduced, and the hydroxyl group is protected with a protective group A ″.

A compound having an acetyl group thus obtained
To obtain the compound of general formula (VIII) (ie acetyl
To make the group a hydroxyl group), for example, carbazole
The acetyl group at the 2-position is oxidized with peracid to form an acetyloxy group.
And then hydrolyzed. Acid the acetyl group with peracid
Except for the reaction of forming and hydrolyzing^{7 '}Introduction of
It can be done according to the method. Oxidation with peracid is methylene chloride, etc.
-Chloroperbenzoic acid and sodium hydrogen phosphate in the solvent
Water at room temperature in a water-ethanol mixed solvent.
Hydrolyze with sodium oxide. In addition, in the general formula (VIII)
In the compound, when X is a methylene group (fluorene)
Is R⁷'And R⁸'Is a hydrogen atom, R⁹'Is hydrogen
Compounds of acetylamino group are known (as commercial products
Are, for example, manufactured by Sailor.
You. ). Also, R⁹Water protected by'protecting group A '
In the case of acid group, the hydroxyl group of fluorene is protected with a benzyl group
To deprotect the acetyl group of the acetylamino group,
Diazotized amine, and then converted to hydroxy via the diazonium salt.
Introduce a group, protect with a hydroxyl protecting group A '', and finally
It is obtained by deprotecting the benzyl group. These series of reactions are
It can be performed by the method described above. Furthermore, the general formula (III)
In the compound of⁷', R⁸', R⁹'Is either protected
Another method for obtaining a compound having a hydroxyl group protected by a group A ″
Then, the following method can be given. That is, the general formula (III)
(Y represents a protecting group for amine, and R represents R depending on X. ⁷', R⁸'
And R⁹'Represents an acetylamino group, R⁶You
And * 2 have the same meanings as described above. )
Hydrolyze the acetyl group of the acetylamino group of the compound
And an amino group. The amino group is diazotized and the hydroxyl group
To protect the hydroxyl group with a protecting group A ''
By deprotecting the protective group Y, the general formula (III) (Y is water
Means elementary atom. ) Are obtained. Moreover,
Alternatively, the general formula (IV)

[0047]

Embedded image [In the formula, Y'means a hydrogen atom or an amine protecting group. ^{R 1 ', A', R} 6, X, R 7 ', R 8', R 9 ', * 1 and * 2 have the same meanings respectively as defined above. ] The compound represented by the general formula is used as an important synthetic intermediate.
(I) (R means a hydrogen atom) can be used. In producing the compound represented by the general formula (IV), the above general formula (II) (R ² 'represents a nitro group) and the general formula (III) (Y represents a hydrogen atom). .) And the amine of the product of the reaction are protected if necessary.
The amine protecting group in the substituent Y ′ of the general formula (IV) is the same as the amine protecting group in the substituent Y described above, and the introduction and deprotection thereof can be similarly performed. General formula (I
Examples of the method for obtaining the general formula (I) using the compound represented by V) as a synthetic intermediate include the following methods. That is, first, the compound represented by the general formula (IV) is reduced (that is, the nitro group of the compound is reduced) to give the general formula (X)

[0048]

Embedded image [In formula, Y'means the protecting group of an amine. R ¹ ', A'
, R ⁶ , X, R ⁷ ′, R ⁸ ′, R ⁹ ′, * 1 and * 2 have the same meanings as described above. ] The compound shown by these is obtained. In this reduction, when the substituent Y ′ in the general formula (IV) is a hydrogen atom, it is preferable to make it an amine protecting group in advance, and the reduction reaction can be carried out in a solvent such as methanol, Hydrogenation in the presence of platinum oxide catalyst, or in the presence of iron powder or divalent tin,
It can be performed in a system using hydrochloric acid. Then R ³
If necessary, the compound represented by the general formula (X) can be converted to various substituents in the literature (Kaiser (C. Ka.
Iser) et al., Journal of Medicinal Chemistry (J. Med. Chem.) 1974, 17
Vol., P. 49), using the method described in Vol.
By carrying out formylation, sulfonation, and urea formation of the general formula (XI)

[0049]

Embedded image [Wherein Y ′, R ¹ ′, A ′, R ³ , R ⁶ , X, R ⁷ ′, R
⁸ ′, R ⁹ ′ and * 1 and * 2 have the same meanings as described above. ] A compound represented by the following formula is prepared, and among the amine protecting groups in the hydroxyl protecting groups A, A ′, A ″ and Y ′, the existing protecting groups are deprotected by the above-mentioned deprotection method, A compound represented by formula (I) (R means a hydrogen atom) is obtained. The above-mentioned formylation can be carried out, for example, by heating the general formula (X) in ethyl formate ester, or by reacting in a formic acid-acetic anhydride system at ice-cooling to room temperature. Examples of the sulfonation include reacting R ⁵ -substituted sulfonic acid chloride in a solvent such as pyridine of the compound of general formula (X) from ice-cooling to room temperature. Examples of the urea formation include a method of reacting with sodium cyanate (NaOCN) in a water-acetic acid mixed solvent represented by the general formula (X) at room temperature or under heating, for example, at 60 ° C. As an alternative method, a method of obtaining a racemate by a short process using general formula (V) instead of general formula (II) can be mentioned. That is, the general formula (V)

[0050]

Embedded image [Wherein R ¹ 'and R ² ' have the same meanings as described above, respectively. ] The compound represented by the general formula (III) (Y means a hydrogen atom) is reacted, and the ketoamine produced is subsequently reduced to give a protective group A (provided that R ¹ is a benzyloxy group and is protected). When the group A is a benzyl group, the protecting group A is not deprotected.), A ″, A ′ ″ and R ³ ′ are protected by deprotecting the amino group by the above-mentioned method. Formula (I) (wherein R represents a hydrogen atom,
R ¹ , R ² , R ⁶ , X, R ⁷ , R ⁸ , R ⁹ and * 1,
* 2 has the same meaning as above. ) Are obtained. The reaction between the general formula (V) and the general formula (III) is described in the literature (AA Larsen et al., Journal of Medicinal Chemistry (J. Med. C)).
hem. ) 1967, vol. 10, p. 462), the method of acetonitrile, dimethylformamide,
In a polar solvent such as dimethylacetamide or dimethylsulfoxide, the reaction is carried out at 60 ° C. in the presence or absence of an amine as an acid trapping agent under ice cooling, and then the carbonyl group is reacted with sodium borohydride, sodium cyanoborohydride, etc. The product is reduced with a reducing agent under ice-cooling at room temperature to deprotect the protecting group. In this reaction, * 1 becomes a racemic mixture, and optical resolution by the method described later is required to obtain an optically active substance. (Production method B) As an alternative to the production method A, a method using an epoxy body can be mentioned as a method for obtaining an optically active substance and a racemic body. That is, the general formula (XII)

[0051]

Embedded image [Wherein R ¹ ′, R ² ′ and * 1 have the same meanings as described above, respectively. ] And a compound of the general formula (III) (Y represents a hydrogen atom, and X, R ⁶ , R ⁷ ′, R ⁸ ′, R ⁹ ′ and * 2 have the same meanings as described above). The compound is reacted with a protective group A (provided that when R ¹ is a benzyloxy group and the protective group A is a benzyl group, the protective group A is
Will not be deprotected. ), A ″, A ′ ″ and the protecting group for the amino group in R ³ ′ or the acetyl protecting group in R ¹ ′ are deprotected by the method described in the production method A to give a compound of the general formula (I) , R represents a hydrogen atom, and R ¹ , R ² , R
⁶ , X, R ⁷ , R ⁸ , R ⁹ and * 1 and * 2 have the same meanings as described above. Method of preparing the compound).

The reaction of the compound represented by the general formula (XII) with the compound represented by the general formula (III) can be carried out by a conventional medium such as dimethylsulfoxide, a linear or cyclic ether,
It can be carried out in an organic solvent such as dimethylformamide or dimethylacetamide. The compound represented by the general formula (XII) and the compound represented by the general formula (III) are often used in equimolar amounts, but it is preferable to use an excessive amount of the compound represented by the general formula (III). Be seen. The reaction temperature is appropriately selected, but usually the reflux temperature of the solvent selected from room temperature is exemplified. The reaction time can be appropriately selected depending on the reaction conditions and the like, and usually the reaction may be terminated when the yield is maximized. Further, in the reaction, it was reported that the addition of trimethylsilylacetamide (TMSA), [N, O-bis (trimethylsilylacetamide), hexamethyldisilazane (HMDS), and bis (trimethylsilyl) urea shortened the reaction time and improved the yield. (Tetrahedron Letters, 1986, 27, 2451)
Therefore, this method can be appropriately selected. The compound of the general formula (XII) is known and can be synthesized by a conventional method described in the chemical literature. As an example, the compound of the general formula (XII) is obtained by oxidizing styrene or substituted styrene with a peracid (for example, metachloroperbenzoic acid), or by using Journal of American Chemical Society (J. Am. Chem. Soc.), 87, 1956
Vol. 1, page 1353, and a method of reacting dimethylsulfonium methyl imide or dimethyl sulfoxonium methyl ylide with a corresponding benzaldehyde substituted with R ¹ ′ or R ² ′.

The preparation of the optically active general formula (XII) is carried out by reacting the compound of general formula (II) or a substituted mandelic acid derivative in which the α-carbon atom (* 1) is in the desired absolute configuration with the corresponding glycol derivative. Of the primary alcohol produced by tosylation or mesylation or halogenation of the resulting primary alcohol, and the resulting compound is subjected to a strong reaction such as an alkali metal hydroxide under the conditions of a usual intramolecular nucleophilic substitution reaction. Obtained by cyclization with a base. (Production Method C) As an alternative to Production Method A, a compound of the general formula (XIII)

[0054]

Embedded image[Wherein, R¹', R^Two'Has the same meaning as above
You. ] And phenylglyoxal represented by the general formula (II
I) (Y means a hydrogen atom, X, R⁶, R⁷', R⁸', R
⁹'And * 2 have the same meanings as described above. )so
Condensation reaction with the indicated amine and reduction of the resulting product
In the method consisting of the original reaction, the protecting group A (however, R¹But
A benzyloxy group, and the protective group A is a benzyl group
In some cases, the protecting group A is not deprotected. ), A ″, A ′ ″
And R^ThreeProtecting group for amino group in R or R¹To '
Deprotecting the acetyl protecting group by the method described in Production method A
By the general formula (I) (wherein R represents a hydrogen atom).
Then R¹, R^Two, R⁶, X, R ⁷, R⁸, R⁹and*
1 and * 2 have the same meanings as described above. ) Compound
Things are obtained.

This reaction is usually carried out in a medium, and is first carried out in the presence of a suitable reducing agent capable of further reducing the Schiff base obtained by the condensation reaction and at the same time reducing the oxo group to a hydroxy group. . Examples of the reducing agent include sodium borohydride, sodium cyanoborohydride, lithium cyanoborohydride and the like. The amount of phenylglyoxal used is 1 to 3 times mol, preferably 1 to 1.5 times mol, of the amine. The reaction temperature is appropriately selected, but usually the reflux temperature of the solvent selected from room temperature is exemplified. The reaction time can be appropriately selected depending on the reaction conditions and the like, and usually the reaction may be terminated when the yield is maximized. As an example, these reactions are carried out in an alcoholic solvent such as methanol, ethanol, preferably at low temperature in the presence of sodium borohydride. The compound of the general formula (XIII) is prepared by oxidizing R ¹ ′, R ² ′ -substituted acetophenones with water or an organic solvent such as cyclic ether such as dioxane or tetrahydrofuran with an oxidizing agent such as selenium dioxide. By doing so, it can be easily obtained. Another method is the Journal of American Chemical Society (J. Am. Chem. Soc.), 1957, 79.
Volume, page 6562. (Production method D) As an alternative to the production methods A, B and C, a compound of the general formula (XIV)

[0056]

Embedded image [Wherein R ¹ ′, R ² ′ and * 1 have the same meanings as described above. ] With an amine represented by the general formula (XV)

[0057]

Embedded image [Wherein R ⁶ , X, R ⁷ ′, R ⁸ ′, R ⁹ ′ and * 2 have the same meanings as described above, and Z is a leaving group. ] The reaction with the compound represented by
When R ¹ is a benzyloxy group and the protecting group A is a benzyl group, the protecting group A is not deprotected. ), A '',
Protecting group or R a amino group in A '''and R ^3'
By deprotection by the method described of acetyl protecting group at ^{1 'in} Process A, the general formula (I) (wherein, R represents a hydrogen ^{atom, R 1, R 2, R} 6, X, R 7 , R ⁸ , R ⁹ and * 1, * 2 have the same meanings as described above.)
Is obtained. The coupling reaction with an amine is carried out in an organic solvent, if necessary, in the presence of a proton acceptor such as a tertiary amine (eg triethylamine),
A compound of general formula (I) is obtained. The leaving group means a group capable of leaving in the above reaction such as chlorine, bromine, iodine or a sulfonate such as mesyl group and tosyl group. As an example of reaction conditions, the amount of the amine of the general formula (XIV) used is 1 to 10 times mol of the compound of the general formula (XV). Since this reaction is slow, it is preferably carried out in an autoclave, and examples of the solvent used include alcohols such as methanol, ethanol and butanol, hydrogen halides such as methylene chloride and chloroform, tetrahydrofuran and dioxane. . The reaction temperature is generally 10 to 150 ° C, preferably 70 ° C to 130 ° C. The reaction time is generally 5 to 100 hours.

The compound of the general formula (XIV) can be obtained by hydrogenating a substituted mandelonitrile substituted by R ¹ 'and R ² ', for example, by reacting it in the presence of a catalyst such as Raney nickel. Substituted mandelonitrile is obtained as a racemate from the reaction of substituted benzaldehyde with hydrogen cyanide or sodium cyanide with sodium bisulfite,
The optically active isomer can be easily separated by forming a salt of a diastereoisomer with an appropriately selected optically active acid according to a commonly used method and technique. Further, the optically active compound of the general formula (XIV) is obtained by reacting an optically active carboxylic acid obtained by hydrolyzing an optically active substituted mandelonitrile with ammonia in the presence of a commonly used condensing agent, It is obtained by subsequent reduction. The compound of the general formula (XV) is a compound represented by the general formula (VIII) and the general formula (XVI)

[0059]

Embedded image [Wherein R ⁶ and * 2 have the same meanings as described above,
B'is a halogen atom. ] Or a compound represented by the general formula (XVII)

[0060]

Embedded image [In the formula, R ⁶ and * 2 have the same meanings as described above. ] The compound represented by the formula [III] is reacted under the conditions for synthesizing the compound of the general formula (III) described in the production method A, and the alcohol produced by the reaction with the compound of the general formula (XVI) is tosylated by a conventional method. It is obtained by mesylation. (Production Method E) The compound of the general formula (I) (R represents a methyl group) produced by the production method A, B, C or D has the general formula (I) (R represents a hydrogen atom). The compound (1) can be produced by a method of methylating an alcohol under a commonly used acidic condition. For example, by heating a compound of the general formula (I) (R means a hydrogen atom) in methanol with hydrogen chloride from room temperature to the boiling point temperature of the solvent, the compound of the general formula (I) (R is a methyl group) is heated. Can be produced. In the general formula (I), the amine compound (in the case where there is a hydroxyl-protecting group A ', deprotected by the above-mentioned method) formed in the process of producing a compound in which R is a hydrogen atom is replaced with the amine-protecting group Y'. Protected general formula (XVIII)

[0061]

Embedded image [Wherein R ¹ ′, R ² ′, R ⁶ , Y ′, X, R ⁷ ′, R ⁸ ′, R
⁹ 'and * 1, * 2 are the respectively the same meaning. ] The compound represented by
Methylate alcohol. Using the deprotection method described above, the amine protecting group Y'and then the protecting group A (provided that
When R ¹ is a benzyloxy group and the protecting group A is a benzyl group, the protecting group A is not deprotected. ), A '',
By deprotecting the protecting group for amino group in A ″ ′ and R ³ ′ (however, if present) or the acetyl protecting group in R ¹ ′, a compound of the general formula (I) (in the formula,
R represents a methyl group, and R ¹ , R ² , R ⁶ , X, R ⁷ , R
⁸ , R ⁹ and * 1 and * 2 have the same meanings as described above. ) Are obtained.

Specific examples of the methylation of alcohol include alcohol and 1 to 5 equivalents of methyl iodide or methyl bromide in the presence of a base such as potassium carbonate, triethylamine, sodium hydroxide or sodium hydride.
The reaction may be carried out in a solvent such as dimethyl sulfoxide, dimethylformamide, dimethoxyethane or tetrahydrofuran at a temperature ranging from room temperature to the reflux temperature of the solvent. As another method, 2 to 10 equivalents of dimethyl sulfate are added to an alkaline solution of alcohol such as sodium hydroxide or potassium hydroxide (water or methanol is used as a solvent), and the reaction is performed at room temperature to the reflux temperature of the solvent. Is mentioned. Various compounds described in the present invention include
It may be purified if necessary, and can be carried out using various commonly known chromatography (column, flash column, thin layer, high-performance liquid) using, for example, the Rf value in the present specification as an index.

As mentioned above, the compound of the general formula (I) is
It may exist as one or two different isomers. The process of the invention can give both pure isomers and racemic mixtures. The reactions described above do not change the stereochemistry involved. Therefore, starting from compounds of general formula (V) or general formula (XIII) having no asymmetric carbon, or starting from compounds of general formula (II), (XII) or (XIV) as racemates Alternatively, starting from a compound of general formula (III) or (XV) as a racemate, a mixture of isomers (R, R), (R, S), (S,
S) and (S, R) are obtained. Similarly, the general formula (II
Pure isomers of compounds of I) or (XV), for example starting from the R isomer of general formula (III), a mixture of only two isomers (R, R) and a mixture of (S, R) If the optically active isomer of the compound of general formula (II), (XII) or (XIV) is used, the pure isomer is obtained.

Alternatively, when a mixture of 4 or 2 isomers is obtained, fractional crystallization is carried out as an addition salt with an optically active acid such as camphor sulfonic acid, mandelic acid or substituted mandelic acid. Can be separated by a suitable method. Fractional crystallization is carried out in a suitable solvent, preferably a lower alkanol (eg ethanol, isopropanol and mixtures thereof).
Can be done using Each set of enantiomers can be separated into pure isomers by formation of diastereomeric salts, chromatography using optically active columns or other means. If one of the starting materials is optically active, the mixture of diastereomers thus obtained is separated into the pure isomers by the procedure described above. By separating and purifying the optically active isomer, only the higher active isomer can be used to improve the effect or dissociate side effects, which is preferable as a medicine.

Examples of the salt of the compound of the general formula (I) in the present invention include known salts such as hydrochloride, hydrobromide, sulfate, hydrogen sulfate, dihydrogen phosphate and citric acid. Salt, maleate, tartrate, fumarate, gluconate, methanesulfonate or camphor sulfonate,
An addition salt with an optically active acid such as mandelic acid or substituted mandelic acid is included, but a pharmaceutically acceptable salt is particularly preferable. When the compound of the general formula (I) is converted to a salt thereof, the compound of the general formula (I) is dissolved in an alcohol such as methanol or ethanol, and an equivalent amount or several times amount of an acid component is added to obtain a salt thereof. Acid addition salts can be obtained. Examples of the acid component used include pharmaceutically acceptable minerals such as hydrochloric acid, hydrobromic acid, sulfuric acid, hydrogen sulfate, dihydrogen phosphate, citric acid, maleic acid, tartaric acid, fumaric acid, gluconic acid and methanesulfonic acid. Mention may be made of acids or organic acids.

INDUSTRIAL APPLICABILITY The tricyclic compound of the present invention and a pharmaceutically acceptable salt thereof are useful as a medicine without showing toxicity and have, for example, β3 agonist activity, and therefore, they are useful for treating and preventing β3 related diseases. It can be used as a medicine used in. The β3-related disease is a general term for diseases that can be ameliorated by agonistic activity mediated by β3-adrenergic receptor, and examples thereof include diabetes, obesity, hyperlipidemia, digestive system diseases (preferably abnormal movement or ulcer of digestive system). ), And depression. Particularly in the present invention, diabetes, obesity, and hyperlipidemia are mentioned as preferable examples. That is, since it exhibits a blood glucose lowering action, it is useful as a preventive and / or therapeutic drug for diabetes.
Further, since it exhibits a lipolytic action, it is useful as a prophylactic / therapeutic drug for hyperlipidemia and a therapeutic drug for obesity. In producing the medicament of the present invention, a pharmaceutically acceptable carrier is optionally added to an effective amount of the tricyclic compound represented by the general formula (I) or a salt thereof to form a pharmaceutical composition. Is preferred. Examples of the pharmaceutically acceptable carrier include excipients, binders such as carboxymethyl cellulose, disintegrants, lubricants, additives and the like. When the compound of the present invention is administered to humans, it can be orally administered in the form of tablets, powders, granules, capsules, dragees, solutions, syrups and the like. In addition, parenteral administration such as injection is also possible. The dose varies depending on the age, weight, and degree of symptoms of the patient, but is generally 0.01 to 2000 mg per day for an adult.
Is administered once or in several divided doses. The administration period is generally several days to several months, and is generally daily. However, the daily dose and the administration period can be increased or decreased depending on the symptoms of the patient.

[0067]

BEST MODE FOR CARRYING OUT THE INVENTION The present invention will be further described by the following examples, but the present invention is not limited thereto. Thin layer chromatography (TLC) is based on Preco
arated silica gel 60 F254 (ME
RCK) was used. After development with chloroform: methanol (100: 1 to 4: 1) or ethyl acetate: n-hexane (100: 0 to 1:10), UV (2
(54 nm) irradiation and coloration with ninhydrin. The Rf value of TLC indicates the value of free amine. Drying the organic solvent used anhydrous magnesium sulfate or anhydrous sodium sulfate. Column chromatography is performed using silica gel (Wako-gel C-200: manufactured by Wako Pure Chemical Industries, Ltd.).
Flash column chromatography using s
ilica gel 60 (230-400 mesh;
MERCK) was used. Preparative thin layer chromatography (PTLC) is precoated silica
a gel 60 F254 20 × 20cm 2mm
(Manufactured by MERCK) was used. Elution with chloroform:
It was carried out with methanol = 1: 1. For the measurement of nuclear magnetic resonance spectrum (NMR), Gemini-300 (FT-
NMR, Varian). Unless otherwise specified, deuterated chloroform was used as the solvent, tetramethylsilane (TMS) was used as the internal standard for the chemical shift, and δ
(Ppm) and the coupling constant is shown in J (Hz). Mass spectrum (MS) is JEOL-JMS-SX102
Using a fast electron collision mass spectrum (FAB-M
S). The measurement results are shown in Tables 1 to 3.

Example 1 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide hydrochloride Salt A. Synthesis of 2-benzyloxycarbonylamino-1-bromoethane (Intermediate 0) 2-Bromoethylamine hydrochloride (25 g, manufactured by Tokyo Kasei) and a solution of triethylamine (34 ml) in methylene chloride (450 ml) were added to benzyl under ice-cooling stirring. Oxycarbonyl chloride (19 ml) was added dropwise over 20 minutes, and the mixture was stirred at room temperature for 19 hours. The reaction mixture was washed successively with water, saturated aqueous sodium hydrogen carbonate and saturated brine, and the organic layer was dried and the solvent was evaporated under reduced pressure. The residue was ice-cooled, the crystals were collected by filtration and washed with hexane to give the title compound (29.4 g). Rf: 0.
58 (chloroform)

B. Synthesis of 9H-2- (2-benzyloxycarbonylaminoethoxy) carbazole (Intermediate 1) Intermediate 2 was added to a solution of 2-hydroxycarbazole (252 mg, Aldrich) and potassium carbonate (292 mg) in dimethylformamide (4 ml). (452 mg) was added and the mixture was heated at 70 ° C. for 72 hours. Ethyl acetate and water were added, the mixture was extracted and washed with water, the organic layer was dried, and the solvent was distilled off under reduced pressure.
Purify by column chromatography (methanol: chloroform = 1: 100) to give the title compound (184.7 m
g) was obtained. Rf: 0.77 (methanol: chloroform = 1: 10) C.I. Synthesis of 2- (9H-carbazol-2-yloxy) ethylamine (Intermediate 2) Intermediate 1 (620 mg) was added with a 30% hydrobromic acid solution (5
ml) was added and the mixture was stirred at room temperature for 1.5 hours. Diethyl ether was added under ice cooling, and the deposited precipitate was collected by filtration. After adjusting the pH to 10 by adding water and NaOH, the mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (311.3 mg). Rf: 0.08 (methanol: chloroform = 1: 10)

D. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide hydrochloride Intermediate 2 (500 mg) in a mixed solvent of anhydrous acetonitrile (40 ml) -anhydrous dimethylformamide (4 ml).
Solution of 2-bromo-1- [4-benzyloxy-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 3) in anhydrous acetonitrile (10 ml) (A. A. Larsen et al. , J. Med. Ch.
em. , Pp. 462-472 (1967)) (617 mg, 70% pure) was added at 0 ° C. under an argon atmosphere and stirred for 83 minutes. The mixture was then warmed to room temperature (~ 22 ° C), 7
Stir for 9 minutes. Absolute ethanol (30m
A solution of sodium borohydride (352 mg) in 1) was added at room temperature. After stirring for 81 minutes, the reaction was stopped with 1.0 N hydrochloric acid (pH 4), and then ethanolamine (0.89 g) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate (100 ml), the organic layer was washed with saturated brine (100 ml × 3), dried and concentrated under reduced pressure to give 1.09 g of a crude product. This was purified by column chromatography (ethyl acetate-1 / 8: methanol / chloroform) to give the free amine of the title compound (195 m
g) was obtained. Rf: 0.41 (methanol: chloroform = 1: 10) 0.1N hydrogen chloride / a part (46 mg)
Add ethanol (1.1 eq.) Hydrochloride (title compound)
The solvent was distilled off under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure at 50 ° C. to give the title compound (48.5 m
A powder of g) was obtained.

Example 2 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride The hydrochloride salt of the compound of Example 1 (753 mg) was treated with 1% hydrogen under 10% palladium / carbon (Merck) (40).
6 mg) and methanol (85 ml) were used for hydrogenolysis (room temperature, 2.5 hours). The catalyst was filtered through Celite and washed with chloroform and methanol. The filtrate and the washing solution were combined, and the solvent was evaporated under reduced pressure to give the title compound (520 mg) as a pale yellow powdery solid. R
f: 0.11 (methanol: chloroform = 1: 10)

Example 3 (±) -N- [5- [2- [2- (dibenzofuran-3
-Yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide A. Synthesis of 3-hydroxydibenzofuran In a solution of 3-methoxydibenzofuran (SALOR, 1 g) in methylene chloride (5 ml) under an ice-cooled argon atmosphere,
1M Boron tribromide / methylene chloride solution (10.2 ml)
Was added dropwise. The mixture was stirred under ice cooling for 30 minutes, then warmed to room temperature and stirred for 35 minutes. Water (26 ml) was added all at once under ice cooling, and the temperature was raised to room temperature over 30 minutes with vigorous stirring. The organic layer was separated and the aqueous layer was extracted twice with methylene chloride. The combined organic layers were washed with saturated brine, dried and concentrated under reduced pressure to give the title compound (663.1 mg).

B. Synthesis of 3- (2-benzyloxycarbonylaminoethoxy) dibenzofuran (Intermediate 4) Using the method described in Step B of Example 1, 3-hydroxydibenzofuran (321.3 mg), intermediate 0 (541).
mg) and potassium carbonate (1.2 g) were reacted in dimethylformamide (4.5 ml). Ethyl acetate and water were added, the mixture was extracted and washed with water, the organic layer was dried, and the solvent was distilled off under reduced pressure.
Purify by column chromatography (chloroform),
The title compound (574.2 mg) was obtained. Rf: 0.40
(Chloroform) C.I. Synthesis of 2- (dibenzofuran-3-yloxy) ethylamine (Intermediate 5) Using the method described in Step C of Example 1, Intermediate 4 (55
4.7 mg) and 30% hydrobromic acid acetic acid solution (7 ml) were added, and the mixture was stirred at room temperature for 1 hr. Diethyl ether was added under ice cooling, and the deposited precipitate was collected by filtration. Add water and NaOH p
After adjusting to H10, the mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (224.6 mg). Rf: 0.13 (methanol: chloroform =
1:10)

D. (±) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-
Synthesis of Hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide Using a modification of the method described in Step D of Example 1, anhydrous acetonitrile (4 ml) -anhydrous dimethylacetamide (1 m
l) To a solution of intermediate 5 (91.6 mg) in a mixed solvent,
Intermediate 3 (227 m in anhydrous acetonitrile (2 ml)
g, 70% pure) at 0 ° C. under an argon atmosphere, then triethylamine (56.3 μl) was added and the mixture was warmed to room temperature (-22 ° C.) and stirred for 50 minutes. Sodium borohydride (80 m
A solution of g) in absolute ethanol (4 ml) was added at room temperature. After stirring for 77 minutes, the reaction was stopped with 1N hydrochloric acid (p
H4) was added, followed by ethanolamine (123 μl). After stirring for 10 minutes, the mixture was diluted with ethyl acetate, the organic layer was washed three times with saturated brine, dried and concentrated under reduced pressure to give a crude product. Column chromatography (chloroform to 3/100: methanol / chloroform)
The title compound (52.4 mg) was obtained. Rf:
0.37 (methanol: chloroform = 3: 100)

Example 4 (±) -N- [5- [2- [2- (dibenzofuran-3
-Yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride Using the method of Example 2, the compound of Example 3 (52.4m
g) under 1 atm of hydrogen, 10% palladium / carbon (30
mg) and methanol (6.4 ml), acetic acid (4.7
(1 μl) for hydrogenolysis (room temperature, 1 hour). The catalyst was filtered through Celite and washed with chloroform and methanol. The filtrate and the washing solution were combined, and the solvent was distilled off under reduced pressure. Ethyl acetate and saturated aqueous sodium hydrogen carbonate were added to the residue for extraction, the organic layer was dried, and the solvent was evaporated under reduced pressure. 0.1 normal hydrogen chloride /
Ethanol (1.1 equivalent) was added to give the hydrochloride salt, and the title compound (43.3 mg) was obtained as a slightly orange powdery solid.
Rf: 0.07 (methanol: chloroform = 1: 1)
0)

Example 5 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride 2-Bromo-1- [4-fluoro-3-[(methylsulfonyl) amino] phenyl] ethanone was prepared according to the synthetic method of Intermediate 3 (steps A, B, C, D below). A. Synthesis of 1- [4-fluoro-3-nitrophenyl] ethanone (Intermediate 6) 4'-Fluoroacetophenone (Tokyo Kasei Co., Ltd., 13.8)
g) in fuming nitric acid (100 ml) cooled to -10 ° C,
It was added in two portions with stirring. After warming to room temperature 4
Stirred for hours. The mixture was poured into ice-water (1.0 l) and extracted with ethyl acetate (500 ml). After drying the organic layer, the solvent was distilled off under reduced pressure. This was purified twice by column chromatography (9/1 to 4/1: n-hexane / ethyl acetate) to obtain the title compound (4.16 g). Rf:
0.50 (chloroform)

B. Synthesis of 1- [3-amino-4-fluorophenyl] ethanone (Intermediate 7) Platinum oxide (anhydrous, 189.7 m) was added to a solution of argon-substituted Intermediate 6 (4.16 g) in methanol (305 ml).
g) was added and reduction was carried out at room temperature with 1 atm of hydrogen. After stirring for 6 hours, the atmosphere was replaced with argon, diluted with chloroform and filtered. The solvent was distilled off under reduced pressure to obtain the title compound (3.52 g). Rf: 0.47 (ethyl acetate: n-hexane = 1:
1) C.I. Synthesis of 1- [4-fluoro-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 8) A solution of intermediate 7 (3.48 g) in pyridine (100 ml) was added at room temperature to methanesulfonyl chloride (1). .93m
l) was added. After stirring for 2.5 days, it was poured into a saturated ammonium chloride solution and extracted with ethyl acetate (200 ml). The organic layer was washed with saturated brine (100 ml × 3), dried and concentrated under reduced pressure to give a crude product. This was purified by column chromatography (1/1: n-hexane / ethyl acetate) to obtain the title compound (3.9 g). Rf: 0.23
(Ethyl acetate: n-hexane = 1: 1)

D. 2-Bromo-1- [4-fluoro-3-
Synthesis of [(methylsulfonyl) amino] phenyl] ethanone (Intermediate 9) Intermediate 8 (3.9 g) in 1,4-dioxane (50
bromine (2.83 g) was added to the mixture (ml) under stirring. The mixture was warmed to 60 ° C. and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue and the precipitate was crushed and collected by filtration. This was washed with cold ethanol, dried and recrystallized from ethanol to obtain the title compound (3.69 g). R
f: 0.30 (ethyl acetate: n-hexane = 1: 2,3
E.) E. Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride Example 1 Using a modification of the method described in Step D, anhydrous acetonitrile (20 ml) -anhydrous dimethylformamide (2
ml) to a solution of intermediate 2 (226 mg) in a mixed solvent,
Intermediate 9 (310 m) in anhydrous acetonitrile (3 ml)
The solution of g) was added at 0 ° C. under an argon atmosphere, then triethylamine (103 μl) was added, the mixture was warmed to room temperature (-22 ° C.) and stirred for 50 minutes. A solution of sodium borohydride (189 mg) in absolute ethanol (15 ml) was added to this mixture at room temperature. After stirring for 77 minutes, the reaction was stopped with 1N hydrochloric acid (pH 4), and then ethanolamine (479 μl) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate, the organic layer was washed three times with saturated brine, dried and concentrated under reduced pressure to give a crude product. This was purified by column chromatography (chloroform to 3/100: methanol / chloroform),
This gave the free amine of the title compound (239.8 mg).
0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was collected by filtration,
It was washed with hot ethanol and dried under reduced pressure at 50 ° C. to obtain the powder of the title compound (121.1 mg). Rf: 0.37
(Methanol: chloroform = 1: 6)

Example 6 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide hydrochloride 2 -Bromo-1- [4-chloro-3-[(methylsulfonyl) amino] phenyl] ethanone was prepared in the same manner as Steps A, B, C and D of Example 5 according to the synthetic method of Intermediate 3. did. A. Synthesis of 1- [4-chloro-3-nitrophenyl] ethanone (Intermediate 10) 4'-chloroacetophenone (Tokyo Chemical Co., Ltd., 15.5)
g) in fuming nitric acid (100 ml) cooled to -10 ° C,
It was added in two portions with stirring. After warming to room temperature 4
Stirred for hours. The mixture was poured into ice-water (1.61) and extracted with ethyl acetate (800ml). After drying the organic layer, the solvent was distilled off under reduced pressure. This was purified by column chromatography (9/1 to 4/1: n-hexane / ethyl acetate) to obtain the title compound (1.2 g). Rf: 0.5
2 (chloroform) B.I. Synthesis of 1- [3-amino-4-chlorophenyl] ethanone (Intermediate 11) A solution of Intermediate 10 (1.2 g) in methanol (260 ml) was added with tin (II) chloride (7.63 g) and concentrated hydrochloric acid (5). .4
8 ml) was added, and the mixture was stirred at room temperature for 3.5 hours. The mixture was concentrated, washed with saturated aqueous sodium hydrogen carbonate, and extracted with ethyl acetate.
The organic layer was concentrated under reduced pressure to give the title compound (970 mg). Rf: 0.49 (ethyl acetate: n-hexane = 1:
1)

C. 1- [4-chloro-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 12)
Synthesis of Intermediate 11 (970 mg) in pyridine (50 ml) at room temperature, methanesulfonyl chloride (487 μl)
Was added. After stirring for 2.5 days, it was poured into a saturated ammonium chloride solution and extracted with ethyl acetate (100 ml). The organic layer was washed with saturated brine (50 ml × 3), dried and concentrated under reduced pressure to give a crude product. This was purified by column chromatography (n-hexane / ethyl acetate: 3/2 to 1/1) to obtain the title compound (890 mg). Rf: 0.
41 (ethyl acetate: n-hexane = 1: 1) D.I. 2-Bromo-1- [4-chloro-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 13)
Synthesis of Intermediate 12 (890 mg) in 1,4-dioxane solution (10 ml) was added bromine (605 mg) with stirring. The mixture was warmed to 60 ° C. and stirred for 1 hour. After cooling to room temperature, the mixture was concentrated under reduced pressure. Water was added to the residue and the precipitate was crushed and collected by filtration. This was washed with cold ethanol, dried and recrystallized from ethanol to obtain the title compound (620 mg). Rf: 0.39 (ethyl acetate: n-hexane =
1: 1)

E. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-Hydroxyethyl] -2-chlorophenyl] methanesulfonamide hydrochloride Using a modification of the method described in Example 1, Step D, an intermediate in a mixed solvent of anhydrous acetonitrile (20 ml) -anhydrous dimethylformamide (2 ml). To a solution of body 2 (226 mg) was added intermediate 13 (3
27 mg) solution at 0 ° C. under an argon atmosphere,
Triethylamine (103 μl) was then added and the mixture was warmed to room temperature (-22 ° C) and stirred for 50 minutes.
A solution of sodium borohydride (189 mg) in absolute ethanol (15 ml) was added to this mixture at room temperature. 7
After stirring for 7 minutes, stop the reaction with 1N hydrochloric acid (pH
4) then ethanolamine (479 μl) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate, the organic layer was washed three times with saturated brine, dried and concentrated under reduced pressure to give a crude product. Column chromatography (1
/ 9 to 1/6: methanol / chloroform),
This gave the free amine of the title compound (129.8 mg).
Rf: 0.36 (methanol: chloroform = 1: 6) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was collected by filtration, recrystallized from ethanol and dried under reduced pressure at 50 ° C. to obtain a powder of the title compound (34.1 mg).

Example 7 (±) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride Anhydrous acetonitrile (20 ml) ) -Anhydrous dimethylformamide (2 ml) in a mixed solvent of intermediate 2 (219.5 m)
g) to a solution of 2- in anhydrous acetonitrile (5 ml).
Bromo-1- [3- (methylsulfonyl) aminophenyl] ethanone (Intermediate 14) (Lacene (AA La
rsen) et al., J. Med. Chem. , 9, 88-9
7 (1966) prepared by the method reported by (1) (1
A solution of 63.6 mg) was added at 0 ° C. under an argon atmosphere and stirred for 83 minutes. The mixture is then allowed to come to room temperature (~ 2
2 ° C.) and stirred for 79 minutes. To this mixture was added sodium borohydride (110 mg) in absolute ethanol (1
0 ml) solution was added at room temperature. After stirring for 81 minutes, 1.
The reaction was stopped with 0N hydrochloric acid (pH 4), and then ethanolamine (0.28 ml) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate (30 ml), the organic layer was washed three times with saturated brine, dried and concentrated under reduced pressure to 39
9 mg of crude product was obtained. This was recrystallized from ethyl acetate to remove the starting amine, the filtrate was concentrated, and the resulting residue was PTLC (developed with methanol / chloroform: 1/8)
And purified to give a free amine (48.3 mg). R
f: 0.32 (methanol: chloroform = 1: 4) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the precipitated precipitate was recrystallized from ethanol and dried under reduced pressure at 50 ° C to give the title compound (3
8.7 mg) of powder was obtained.

Example 8 (±) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] phenylmethanesulfonamide hydrochloride A. Synthesis of 1- [3- (benzylsulfonylamino) phenyl] ethanone (Intermediate 15) According to the method for synthesizing intermediate 14 of Example 7, 3'-aminoacetophenone (Tokyo Kasei Co., Ltd., 300 mg), benzylsulfonyl chloride ( Manufactured by Tokyo Kasei (427 mg),
719 mg of the title compound was prepared from pyridine (3 ml). B. Synthesis of 2-Bromo-1- [3- (benzylsulfonylamino) phenyl] ethanone (Intermediate 15-1) According to the method of Example 7, a solution of Intermediate 15 (700 mg) in 1,4-dioxane (6.8 ml). ) To bromine (130
μl) and reacted to give a fraction containing the title compound (786
mg). ¹ H-NMR (300 MHz, CDCl
_{In 3} ), mono-Br body 29%, di-Br body 58%, raw material 13
The integral ratio of% was shown. The mixture was used as it was in the next reaction. C. Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] phenylmethanesulfonamide hydrochloride Anhydrous acetonitrile (40 ml) -anhydrous Intermediate 2 (400 mg) in dimethylformamide (4 ml) mixed solvent
15-1 (465 mg, 58% pure) in intermediate solution
Anhydrous acetonitrile (10 ml) solution of was added at 0 ° C. under an argon atmosphere and stirred for 80 minutes.

The mixture was then warmed to room temperature (~ 22 ° C) and stirred for 70 minutes. To this mixture was added sodium borohydride (244 mg) in absolute ethanol (20 ml).
The solution was added at room temperature. After stirring for 60 minutes, the reaction was stopped with 1.0 N hydrochloric acid (pH 4), and then ethanolamine was added. After stirring for 10 minutes, the mixture was mixed with ethyl acetate (6
After diluting with (0 ml) and washing with water (60 ml), the organic layer was washed twice with saturated brine, dried and concentrated under reduced pressure to obtain a crude product. PTLC (methanol / chloroform: 1 /
(Developed in 8) to obtain a free amine (66 mg). Rf: 0.16 (methanol: chloroform = 1:
10) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the precipitated precipitate was washed with diethyl ether and dried under reduced pressure at 46 ° C to give the title compound (6
0 mg) of powder was obtained.

Example 9 (±) -N- [3- [2- [2- (dibenzofuran-3
-Yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride Intermediate 5 (224.6 mg) according to the method of Example 7.
And the title compound was synthesized from Intermediate 14 (170 mg) (however, the following modifications were made: dimethylformamide was not added, and the crude product was purified by chromatography (methanol / chloroform: 1/20 to 1/10). I went there twice). 0.1 N free amine (98.4 mg)
Hydrochloric acid / ethanol (1.1 equivalent) was used to form the hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was washed with diethyl ether and dried under reduced pressure at 46 ° C to obtain a powder of the title compound. Rf: 0.27 (methanol: chloroform = 1:
10)

Example 10 (±) -N- [3- [2- [2- (9H-7-acetylaminofluoren-2-yloxy) ethylamino]-
1-Hydroxyethyl] phenyl] methanesulfonamide hydrochloride A. N- [7- [2-[(benzyloxycarbonyl)
Synthesis of Amino] ethoxy] -9H-fluoren-2-yl] acetamide (Intermediate 16) According to Step B of Example 1, dimethylformamide (3m
2-acetamide-7-hydroxyfluorene (300 mg, manufactured by SALOR), intermediate 0 (485.
5 mg) and potassium carbonate (241.2 mg) were reacted (heated at 70 ° C. for 24 hours). Ethyl acetate and water were added, the mixture was extracted and washed with water, the organic layer was dried, and the solvent was distilled off under reduced pressure.
Purify by column chromatography (methanol: chloroform = 1: 20) to give the title compound (431.9 mg).
I got Rf: 0.47 (methanol: chloroform =
1:10)

B. Synthesis of N- [9H-7- (2-aminoethoxy) fluorene] -2-acetamide (Intermediate 17) According to step C of Example 1, intermediate 16 (572.9m).
To g) was added a 30% hydrobromic acid acetic acid solution (5 ml), and the mixture was stirred at room temperature for 1 hour. Diethyl ether was added under ice cooling,
The deposited precipitate was collected by filtration. Add water and NaOH to pH 10
After adjustment to, the mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (256.7 mg).
Rf: 0.06 (methanol: chloroform = 1: 5) C.I. Synthesis of (±) -N- [5- [2- [2- (9H-7-acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride According to Example 7. The title compound was synthesized from Intermediate 17 (253.2 mg) and Intermediate 14 (154.1 mg) (however, the following modifications were made. That is, dimethylformamide was not added, and the crude product was purified by chromatography (methanol). / Chloroform: 1/10) and PTLC
(Methanol / chloroform: developed at 1/5). The free amine (52.3 mg) was converted to the hydrochloride (title compound) with 0.1N hydrogen chloride / ethanol (1.1 equivalent), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was washed with diethyl ether and dried under reduced pressure at 46 ° C to give a powder of the title compound (45.1).
mg). Rf: 0.40 (methanol: chloroform = 1: 5).

Example 11 (±) -N- [3- [2-[[1- (9H-carbazol-2-yloxy) propan-2R-yl] amino]
-1-Hydroxyethyl] phenyl] methanesulfonamide hydrochloride A. Synthesis of (R)-[1- (9H-carbazol-2-yloxy) propan-2-yl] amine (Intermediate 18) (R)-(−)-2-amino-1-propanol (4.
82 g, manufactured by Aldrich Co., is used as tetrahydrofuran (1
57 ml) and di-tert-butyl-at room temperature.
Di-carbonate (13.84g) was added and stirred for 18 hours. The solvent was evaporated under reduced pressure to give a white solid (11 g).
The above white solid (10.3 g) and triphenylphosphine (17.76 g) were added to methylene chloride (147 ml).
Dissolved in N-chlorosuccinimide under ice cooling (9.3
g) was added little by little, and the mixture was stirred at room temperature for 23 hours. The reaction mixture was washed successively with aqueous sodium hydroxide solution and saturated brine, dried and evaporated under reduced pressure. The residue was purified by silica gel chromatography (R) -2- (N-tert-butoxycarbonyl) amino-1-chloropropane (5.89).
g) was obtained. Rf = 0.89 (methanol: chloroform = 1: 9)

2-hydroxycarbazole (734 m
g) and a solution of the above compound (815.6 mg) in dimethylformamide (9.6 ml) at room temperature with anhydrous potassium carbonate (1588 mg) and potassium iodide (190 m).
g) was added, and the reaction and treatment were carried out by the method according to the synthesis method of Step B of Example 1 to give (R) -2- (N-te.
rt-Butoxycarbonylamino-1-propyloxy) carbazole (597 mg) was obtained. Rf = 0.8
1 (methanol: chloroform = 1: 9) 30% hydrobromic acid acetic acid solution (10 ml) was added to the above compound (597 mg) to carry out reaction and treatment by a method according to the synthesis method of Step C of Example 1 to give an intermediate. 18 (25
8 mg) was obtained. Rf: 0.06 (methanol: ethyl acetate = 1:10) B.I. Synthesis of (±) -N- [3- [2-[[1- (9H-carbazol-2-yloxy) propan-2R-yl] amino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride Example According to 7, Intermediate 18 (120 mg) and Intermediate 1
4 (190 mg) was reacted and treated to synthesize the title compound (however, the following changes were made.
In the coupling step, triethylamine (72 μl, 1 eq) was used as the base catalyst. Purification of the crude product is PTLC (developed with methanol / ethyl acetate: 1/9)
I went there). Free amine (87.5 mg) 0.1N
Hydrochloric acid / ethanol (1.1 equivalent) was used to form the hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the precipitated precipitate was washed with diethyl ether and dried under reduced pressure at 46 ° C. to give the title compound powder (8
0.5 mg) was obtained. Rf: 0.19 (methanol: ethyl acetate = 1: 10)

Example 12 (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride A. Synthesis of (R) -2-bromo-1- [3-nitro-4- (benzyloxy) phenyl] ethanol (Intermediate 19) 2-Bromo-1- [3-nitro-4 under an argon atmosphere.
-(Benzyloxy) phenyl] ethanone (Kaiser
(Prepared by the method reported by (C. Kaiser) et al., J. Med. Chem., 17, 49 (1974)) (1.01 g, 70% purity) and (R) -3,3-diphenyl-1- Methyltetrahydro-1H, 3H-pyrrolo [1,2-c] [1,3,2] oxazaborol (100 mg, manufactured by Tokyo Chemical Industry Co., Ltd., hereinafter referred to as asymmetric catalyst, provided that there is (R) or (S) form. 2) borane-dimethyl sulfide complex-tetrahydrofuran solution (2.1
6 ml, manufactured by Aldrich) was added dropwise over 5 minutes, and the mixture was stirred at the same temperature for 2 hours. Then, the mixture was diluted with ethyl acetate, washed successively with saturated ammonium chloride solution and saturated brine, dried and the solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: n-hexane = 1: 2-1: 1).
Purification in 1) gave the title compound (1.015 g). R
f: 0.41 (ethyl acetate: n-hexane = 1: 1) retention time: 35.7 minutes, analysis condition: column: chiralcel O
B (4.6 mm * 25 cm) (manufactured by Daicel); mobile phase: n-hexane / 2-propanol = 7/3; flow rate:
0.5 ml / min; detection wavelength: 254 nm; temperature: 35 ° C

B. (R) -3-Nitro-4-benzyloxy- [2-iodo-1- (triethylsilyloxy)
Synthesis of ethyl] benzene (intermediate 20) Intermediate 19 (695.6 mg) in acetone (30 m
l) Sodium iodide (2.96 g, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the solution, and the mixture was heated under reflux for 2 hours. After cooling to room temperature, the mixture was filtered and the filtrate was evaporated under reduced pressure. Chloroform and water were added to the residue, the organic layer was washed with a saturated sodium thiosulfate solution, dried and the solvent was evaporated under reduced pressure. The obtained oil (0.78 g) and imidazole (408.5 m)
g) and dimethylaminopyridine (24.4 mg) in dimethylformamide (5 ml), and triethylsilane chloride (452 mg) was added under ice cooling. It was immediately warmed to room temperature and stirred for 1.5 hours. Diluted with ethyl acetate, water,
Wash sequentially with 2% copper sulfate solution, water, then saturated saline solution,
After drying, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 3) to obtain the title compound (915 mg). Rf: 0.76
(Ethyl acetate: n-hexane = 1: 1)

C. (R) -N, N-[[2- (9H-carbazol-2-yloxy) ethyl]-[2- (triethylsilyloxy) -2- [3-nitro-4- (benzyloxy) phenyl]] ethyl ] Amine (Intermediate 2
Synthesis of 1) Intermediate 20 (289 mg), Intermediate 2 (165 m)
A solution of g) and Hunig's base (0.51 ml, Aldrich) in dimethylacetamide (1.5 ml) was stirred at 60 ° C. for 8 hours. Ethyl acetate (40m)
l) and water (40 ml) were added for extraction, and the aqueous layer was further extracted 3 times with ethyl acetate. After drying the combined organic layers,
The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (chloroform-methanol: chloroform = 1: 4).
Purification in 9) gave the title compound (173 mg). R
f: 0.60 (methanol: chloroform = 1: 9)

D. (R) -N, N, N-[(benzyloxycarbonyl)-[2- (9H-carbazole-2-
Iloxy) ethyl]-[2- (triethylsilyloxy) -2- [3-nitro-4- (benzyloxy) phenyl]] ethyl] amine (Intermediate 22) Synthesis of the above amine (173 mg) in methylene chloride (2 ml). ), Triethylamine (45 μl) was added, and benzyl chloroformate (43 μl, Aldrich) was added under ice-cooling stirring. After stirring for 30 minutes, the mixture was stirred at room temperature for 8 hours. The mixture was diluted with ethyl acetate, washed successively with water and saturated brine, dried and evaporated under reduced pressure. The residue was subjected to column chromatography (ethyl acetate: normal hexane = 1: 5).
~ 1: 3) to obtain the title compound (200 mg). Rf: 0.55 (ethyl acetate: n-hexane = 1:
2) Retention time: 14.7 minutes, analysis conditions: column: Chiralcel OJ-R (4.6 mm ¢ x15 cm) (manufactured by Daicel); mobile phase: 0.5M NaClO4 / CH3CN = 2
0/80; Flow rate: 0.7 ml / min; Detection wavelength: 254n
m; temperature: 30 ° C

E. (R) -N, N, N-[(benzyloxycarbonyl)-[2- (9H-carbazole-2-
Iloxy) ethyl]-[2- (triethylsilyloxy) -2- [3-amino-4- (benzyloxy) phenyl]] ethyl] amine (Intermediate 23) Synthesis of Argon-Substituted Nitro Compound (200 mg) Platinum oxide (anhydrous, 5 ml) was added to a methanol (14 ml) solution under ice cooling.
mg, manufactured by Wako Pure Chemical Industries, Ltd.) was added and the mixture was reduced with 1 atm of hydrogen. After stirring for 6 hours, the atmosphere was replaced with argon, diluted with chloroform and filtered. The solvent was distilled off under reduced pressure and the title compound (183 m
g) was obtained. Rf: 0.32 (ethyl acetate: n-hexane = 1: 3) F.I. (R) -N- [5- [2- [benzyloxycarbonyl- [2- (9H-carbazol-2-yloxy)
Synthesis of ethyl] amino] -1- (triethylsilyloxy) ethyl] -2- (benzyloxy) phenyl] methanesulfonamide (Intermediate 24) To a solution of the amine compound (183 mg) in pyridine (1 ml) at room temperature, Methanesulfonyl chloride (20 μl) was added, the mixture was stirred for 1 hour, water was added, the mixture was stirred for 3 hours, cooled with ice, and the deposited precipitate was collected by filtration. It was dissolved in ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give the title compound (192 mg). Rf: 0.44 (ethyl acetate:
n-hexane = 1: 2)

G. (R) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride According to the procedure of Example 1, step C, the above methanesulfonamide compound (192 mg) was added to a 30% hydrobromic acid acetic acid solution (4 m
The benzyloxycarbonyl group and the triethylsilyl group were removed by l). Then, according to the procedure of Example 1 Step E, 10% palladium / carbon (71 m
g, manufactured by Merck & Co., Inc.) was used to hydrogenolyze the benzyl group, followed by hydrochloric acid salification by a conventional method to obtain the title compound. Retention time: 40.6 minutes, Analytical conditions: Column: Chiralcel OJ-R (manufactured by Daicel); Mobile phase: 0.5M NaC
10 / CH3CN = 77/23; flow rate: 0.5 ml /
Min; detection wavelength: 254 nm; temperature: 40 ° C

Example 13 (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride Other than using the (S) -form asymmetric catalyst (manufactured by Tokyo Kasei),
The reaction and treatment were carried out in the same manner as in Example 12. A. (S) -2-Bromo-1- [3-nitro-4- (benzyloxy) phenyl] ethanol Retention time: 47.3 minutes, Analytical conditions: Column: Chiralcel OB (manufactured by Daicel); Mobile phase: n- Hexane / 2-propanol = 7/3; flow rate: 0.5 ml / min; detection wavelength: 254 nm; temperature: 35 ° C. D.I. (S) -N, N, N-[(benzyloxycarbonyl)-[2- (9H-carbazol-2-yloxy)
Ethyl]-[2- (triethylsilyloxy) -2-
Synthesis of [3-nitro-4- (benzyloxy) phenyl]] ethyl] amine Retention time: 9.8 minutes, analytical condition: column: chiralcel O
JR (manufactured by Daicel); mobile phase: 0.5M NaCl
O4 / CH3CN = 2/8; flow rate: 0.7 ml / min; detection wavelength: 254 nm; temperature: 30 ° C. G.I. Synthesis of (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride Retention time: 47 .5 minutes. Analytical conditions: Column: Chiralcel OJ-R (manufactured by Daicel); Mobile phase: 0.5M NaC
10 / CH3CN = 77/23; flow rate: 0.5 ml /
Min; detection wavelength: 254 nm; temperature: 40 ° C

Example 14 (R) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride The following Example 12 It was synthesized according to the procedure described in. However, in Example 12 Step G, hydrogenolysis with 10% palladium / carbon was not performed. A. (R) -2-Bromo-1- (3-nitrophenyl)
Synthesis of ethanol (intermediate 25) 2-Bromo-1- (3′-nitrophenyl) ethanone (769 mg) and the above asymmetric catalyst (R form, 100 mg, manufactured by Tokyo Kasei) in anhydrous tetrahydrofuran (20 ml, prepared at the time of use) ) Add 2M borane-
Dimethyl sulfide complex-tetrahydrofuran solution (2.16 ml, manufactured by Aldrich) was added dropwise over 5 minutes, reacted and treated to give the title compound (768 m
g) was obtained. Rf: 0.72 (ethyl acetate: n-hexane = 1: 1) Retention time: 9.02 minutes, analysis condition: Column: Chiralcel AD (manufactured by Daicel); Mobile phase: n-hexane / ethanol = 1/1 Flow rate: 0.5 ml / min; detection wavelength: 25
4 nm; temperature: 35 ° C.

B. Synthesis of (R) -3- [2-iodo-1 (triethylsilyloxy) ethyl] -nitrobenzene (Intermediate 26) Acetone (30 ml) of Intermediate 25 (768 mg) above
Sodium iodide (2.96 g, manufactured by Wako Pure Chemical Industries, Ltd.) was added to the solution for reaction and treatment. Obtained iodide (79
5 mg), imidazole (408.5 mg) and dimethylaminopyridine (24.4 mg) in dimethylformamide (5 ml), triethylsilane chloride (452 mg) was added under ice-cooling, and the mixture was reacted and treated to give the title compound (9
94 mg) was obtained. Rf: 0.43 (ethyl acetate: n-
Hexane = 1: 3) C.I. (R) -N, N-[[2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl]-[2- (triethylsilyloxy) -2- (3-nitrophenyl)] ethyl] amine Intermediate 26 (451 mg), Intermediate 2 (330 m)
g) and Hunig's base (1.02 ml, Aldrich) in dimethylformamide (2 ml) were reacted and treated to give the title compound (217 mg).

D. (R) -N, N, N-[(benzyloxycarbonyl)-[2- (9H-carbazole-2-
Synthesis of (yloxy) ethyl]-[2- (triethylsilyloxy) -2- (3-nitrophenyl)] ethyl] amine (Intermediate 27) The above amine (217 mg) was dissolved in methylene chloride (2 ml) to give triethylamine ( 66 μl), and benzyl chloroformate (63 μl, manufactured by Aldrich) under ice-cooling stirring, reacted and treated to give the title compound (261
mg). Rf: 0.32 (ethyl acetate: n-hexane = 1: 2) E.I. (R) -N, N, N-[(benzyloxycarbonyl)-[2- (9H-carbazol-2-yloxy)
Ethyl]-[2- (triethylsilyloxy) -2-
Synthesis of (3-aminophenyl)] ethyl] amine Platinum oxide (anhydrous, anhydrous) was added to a solution of the nitro compound (261 mg) substituted with argon in methanol (5.5 ml) under ice cooling.
5 mg, manufactured by Wako Pure Chemical Industries, Ltd.) was added and reduced with hydrogen at 1 atm.
Workup gave the title compound (236 mg).

F. (R) -N- [3- [2- [benzyloxycarbonyl- [2- (9H-carbazole-2-
Synthesis of (yloxy) ethyl] amino] -1- (triethylsilyloxy) ethyl] phenyl] methanesulfonamide (Intermediate 28) To a solution of the above amine derivative (236 mg) in pyridine (1 ml), at room temperature, methanesulfonyl chloride (30 μl) was added. ) Was added, and the mixture was reacted and treated to obtain the title compound (253 mg). Rf: 0.25 (ethyl acetate: n-hexane = 1:
2) G. Synthesis of (R) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride Following the procedure of Example 1, Step C. , 30% hydrobromic acid acetic acid solution (5 m
1) was added, and the reaction and treatment were carried out to obtain the title compound. Retention time: 29.3 minutes, Analytical conditions: Column: Chiralcel OJ
-R (manufactured by Daicel); mobile phase: 0.5M NaClO
4 / CH3CN = 7/3; Flow rate: 0.5 ml / min; Detection wavelength: 254 nm; Temperature: 30 ° C

Example 15 (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride Other than using the (S) -form asymmetric catalyst (manufactured by Tokyo Kasei),
The reaction and treatment were carried out in the same manner as in Example 14. A. (S) -2-Bromo-1- (3-nitrophenyl)
Ethanol retention time: 8.18 minutes, analysis conditions: column: Chiralcel AD (manufactured by Daicel); mobile phase: n-hexane / ethanol = 1/1; flow rate: 0.5 ml / min; detection wavelength: 25
4 nm; temperature: 35 ° C. G.I. (S) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride retention time: 25.3 minutes, analysis conditions : Column: Chiralcel OJ-R (manufactured by Daicel); Mobile phase: 0.5M NaC
10 / CH3CN = 7/3; flow rate: 0.5 ml / min; detection wavelength: 254 nm; temperature: 30 ° C.

Example 16 (±) -N-Methyl-3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] benzenesulfonamide hydrochloride A. Synthesis of N-methyl-3-acetylbenzenesulfonamide To a solution of 3-acetylbenzenesulfonyl fluoride (2 g, manufactured by Across Co.) in pyridine (20 ml) was added 4 at room temperature.
0% methylamine / methanol (2.02 ml, manufactured by Wako Pure Chemical Industries, Ltd.) was added and stirred for 2 hours. Furthermore, 40% methylamine / methanol (2.02 ml) was added, and 40%
Stirred for minutes. The reaction was stopped by adding 5N hydrochloric acid and water (about 40 ml) (pH 4), and the mixture was extracted with ethyl acetate. The organic layer was separated, dried and evaporated under reduced pressure to give the title compound (996 mg). Rf: 0.64 (methanol: chloroform = 1: 10). B. Synthesis of N-methyl-3- (2-bromoacetyl) benzenesulfonamide (Intermediate 29) 1,4-dioxane (1 of the above compound (990 mg)
5.8 ml) solution, bromine (769 mg) was added,
The mixture was stirred at 0 ° C for 1 hour. The mixture was concentrated under reduced pressure, water (18 ml) was added to the residue, and the mixture was vigorously stirred under ice cooling. The resulting precipitate was crushed, collected by filtration and washed with water. Dried under reduced pressure at room temperature,
The title compound (1.18 g) was obtained. Rf: 0.63 (methanol: chloroform = 1: 10)

C. (±) -N-methyl-3- [2- [2
Synthesis of-(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] benzenesulfonamide hydrochloride According to the procedure described in Example 1, Step D, the above Intermediate 29 was used.
(0.59 g), HBr salt of Intermediate 2 (0.59 g),
By reacting and treating sodium borohydride (0.39 g) and ethanolamine (1 ml),
The title compound (227.8 mg) was obtained (however, the following changes were made. As a base catalyst, triethylamine (0.
56 ml, 2 equivalents) were used. Purification was performed by column chromatography (methanol: ethyl acetate = 1: 5),
Then, PTLC (methanol: ethyl acetate = 1: 5) was used. Rf: 0.28 (methanol: ethyl acetate =
1: 5)

Example 17 (±) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] formamide hydrochloride A. Synthesis of 1- (3-formylaminophenyl) ethanone A solution of 1- (3-aminophenyl) ethanone (2 g, manufactured by Tokyo Chemical Industry Co., Ltd.) in dimethylformamide (15 ml) was stirred under ice cooling with formic acid (15 ml) and acetic anhydride. A mixture of (5 ml) was added and stirred for 2.5 hours. Then at room temperature 15
After stirring for an hour, additional formic acid (3 ml) and acetic anhydride (1
(ml) and the mixture was stirred at room temperature for 8 hours. Water (150 ml) and ethyl acetate (150 ml) were added to the mixture for extraction. The organic layer was washed twice with water, dried and evaporated under reduced pressure to give the title compound (1.69 g). R
f: 0.65 (methanol: chloroform = 1: 10)

B. (±) -N- [3- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] phenyl] formamide hydrochloride To a solution of 1- (3-formylaminophenyl) ethanone (1.6 g) in 1,4-dioxane (33.4 ml), bromine (1.63 g) was added. The mixture was stirred at 60 ° C for 1 hour. The mixture was concentrated under reduced pressure and the residue was washed with water (40 m
1) was added and the mixture was vigorously stirred under ice cooling. Ethyl acetate was added to this mixture for extraction, the organic layer was dried, and the solvent was evaporated under reduced pressure. Chloroform and methanol were added to the residue, and the deposited precipitate was filtered. The solvent was distilled off from the filtrate under reduced pressure to obtain a mixture containing 2-bromo-1- (3-formylaminophenyl) ethanone (975 mg). Following the procedure described in Example 1, Step D, a mixture containing the above bromo compound (300 m
g), HBr salt of Intermediate 2 (363 mg), sodium borohydride (239 mg) and ethanolamine (0.6 ml) were reacted and treated to obtain the title compound (73 mg) (provided that The base catalyst was triethylamine (0.34 m).
1, 2 equivalents) were used. For purification, PTLC (methanol: ethyl acetate = 1: 3) was used, and then the hydrochloride was added.
This was done by precipitating impurities from methanol-ethyl acetate and filtering). Rf: 0.26 (methanol: ethyl acetate = 1: 3)

Example 18 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (4-hydroxy-3-nitrophenyl)] ethanol hydrochloride A. Synthesis of (±)-[2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (3-nitro-4- (benzyloxy) phenyl) ethanol Example 1 Step D Anhydrous acetonitrile (25.5 ml) -anhydrous dimethylformamide (2
HBr salt of Intermediate 2 (435 m
g) in a solution of triethylamine (409 μl) and 2-bromo-1- in anhydrous acetonitrile (6.4 ml).
[3-Nitro-4- (benzyloxy) phenyl] ethanone (Carl Kaiser et al., J. M.
ed. Chem. , 17, 49-57 (1974)) (0.52 g, 70% pure), a solution of sodium borohydride (287 mg) in absolute ethanol (13 ml) was added sequentially to react. Workup gave the title compound (61.8 mg). Rf:
0.24 (methanol: chloroform = 1: 10) B.I. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- (4-hydroxy-3-nitrophenyl) ethanol hydrochloride

A solution of the compound of step A (127.6 mg) in dichloromethane (10 ml) was added with a 1M solution of boron tribromide in dichloromethane (0.69 ml, manufactured by Aldrich Co.) over 2 minutes while cooling with a dry ice-acetone refrigerant. Dropped. The mixture was stirred for 1 hour as it was, and further stirred for 5 minutes under ice cooling. Methanol (10 ml) was added to the reaction mixture to stop the reaction, the pH was adjusted to 8-9 with saturated aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and the solvent was distilled off under reduced pressure. The residue was triturated with ethyl acetate and collected by filtration to give the free base of the title compound (87.6 mg).
I got This was made into the hydrochloride (93.0 mg) as the title compound using 0.1 N HCl / ethanol. R
f: 0.33 (methanol: chloroform = 1: 10)

Example 19 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (3-amino-4
-Hydroxyphenyl) ethanol dihydrochloride The compound of Example 18 (15 mg) was used in Example 12, Step E.
According to the procedure described in 1, dissolve a mixed solvent of methanol (1 ml) -tetrahydrofuran (1 ml), and under ice cooling,
Platinum oxide (anhydrous, 1.1 mg, manufactured by Wako Pure Chemical Industries, Ltd.) was added,
The reaction was performed to obtain the title compound (10.2 mg). R
f: 0.15 (methanol: ethyl acetate = 1: 3)

Example 20 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] urea hydrochloride Salt Following the procedure described in Example 1, Step D, anhydrous acetonitrile (26 ml) -anhydrous dimethylformamide (10 m
l) To a solution of the HBr salt of Intermediate 2 (435 mg) in a mixed solvent was added 2-bromo-1- [4- (4-ml) in triethylamine (409 μl) and anhydrous acetonitrile (6.4 ml).
(Benzyloxy) -3-ureidophenyl] ethanone (Carl Kaiser et al., J. Med. Chem., 17, 49.
~ 57 (1974) prepared by the method)
A solution of (0.54 g) and a solution of sodium borohydride (287 mg) in absolute ethanol (13 ml) were sequentially added and the reaction was performed to obtain the title compound (59.3 mg). Rf: 0.15 (methanol: chloroform = 1:
10)

Example 21 Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] urea hydrochloride Following the procedure described in Example 2, the compound of Example 20 (40 mg, solution in methanol (5.3 ml)) was added to 10
Hydrogenolysis using% palladium / carbon (25 mg) gave the title compound (29.8 mg). Rf: 0.0
8 (methanol: chloroform = 1: 10)

Example 22 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] formamide hydrochloride Salt Synthesis Following the procedure described in Example 1, Step D, anhydrous acetonitrile (22 ml) -anhydrous dimethylformamide (6 m
l) To a solution of the HBr salt of Intermediate 2 (435 mg) in a mixed solvent was added 2-bromo-1- [3- (formylamino) -4- (benzyloxy) triethylamine (409 μl) and anhydrous acetonitrile (10 ml). ) Phenyl] ethanone (Carl Kaiser et al., J. Med. Chem.
17, 49-57 (prepared by the method reported by 1974) (0.52 g), absolute ethanol (1
A solution of sodium borohydride (287 mg) in 3 ml) was added sequentially and the reaction was worked up to give the title compound (57.0).
mg). Rf: 0.18 (methanol: chloroform = 1: 10)

Example 23 Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] formamide hydrochloride Following the procedure described in Example 2, 10 mg of the compound of Example 22 (40 mg, solution in methanol (5.8 ml)) was added.
Hydrogenolysis using% palladium on carbon (27 mg) gave the title compound (28.1 mg). Rf: 0.0
8 (methanol: chloroform = 1: 10)

Example 24 (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl]- N, N
-Synthesis of dimethylsulfamide hydrochloride According to the procedure described in Example 1, Step D, anhydrous acetonitrile (26 ml) -anhydrous dimethylformamide (10 m
l) To a solution of the HBr salt of Intermediate 2 (435 mg) in mixed solvent was added 2-Bromo-1- [4-
(Benzyloxy) -3- (dimethylsulfamoylamino) phenyl] ethanone (Carl Kaiser)
Et al., J. Med. Chem., 17, 49-57 (1974)) (0.64 g).
A solution of sodium borohydride (287 mg) in absolute ethanol (15 ml) was sequentially added and the reaction was performed to obtain the title compound (70.5 mg). Rf: 0.17 (methanol: chloroform = 1: 10)

Example 25 (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N -Synthesis of dimethylsulfamide hydrochloride According to the procedure described in Example 2, the compound of Example 24 (40 mg, solution in methanol (5.1 ml)) 10
Hydrogenolysis using% palladium / carbon (24 mg) gave the title compound (38.3 mg). Rf: 0.3
8 (methanol: ethyl acetate = 1: 3)

Example 26 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- [3- (methylamino) -4- (benzyloxy) phenyl] ethanol.dihydrochloride, Kaiser, et al., J. Am. Med.
Chem. , 17, 49-57 (1974).
0 mg, Wako Pure Chemical Industries, Ltd. tetrahydrofuran (2 m
l) In suspension, with stirring, the compound of Example 22 (500 m
A solution of g) in tetrahydrofuran (1 ml) was added dropwise, and the mixture was reacted and treated to obtain the title compound (381 mg). R
f: 0.13 (methanol: chloroform = 1: 10)

Example 27 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- [3- (methylamino) -4-hydroxyphenyl] ethanol dihydrochloride According to the procedure described in Example 2, the compound of Example 26 (200 mg, methanol (25 ml) solution). To 10
Hydrogenolysis using% palladium on carbon (100 mg) gave the title compound (153 mg). Rf: 0.09
(Methanol: chloroform = 1: 10)

Example 28 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (2-fluorophenyl) ethanol hydrochloride A. (±) -2-Fluorostyrene oxide (Intermediate 3
Synthesis of 0) 2-Fluorostyrene (5.00 g, Aldrich)
To a methylene chloride (200 ml) solution of was added metachloroperbenzoic acid (17.7 g, manufactured by Kanto Chemical Co., Inc.) and disodium phosphate (18.6 g) under ice cooling, and the mixture was stirred to room temperature for 20 hours. After cooling with ice, the precipitated crystals were separated by filtration twice, and the residue was washed with an aqueous sodium thiosulfate solution (180 ml).
After drying the organic layer, the solvent was evaporated under reduced pressure and the residue was purified by column chromatography (ethyl acetate: n-hexane = 1: 19) to obtain the title compound (0.38 g). Rf: 0.5
7 (ethyl acetate: n-hexane = 1: 5) B.I. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- (2-fluorophenyl) ethanol hydrochloride Under an argon atmosphere, dimethyl sulfoxide (1.6 ml) and N, O-bis (trimethylsilyl) were added to Intermediate 2 (452.6 mg). ) Acetamide (1.06 ml, 25% acetonitrile solution, manufactured by Tokyo Kasei) was added, and the mixture was stirred at room temperature for 30 minutes. Then Intermediate 30 (290 mg) was added,
The mixture was stirred at 70 ° C for 70 hours. Next, the mixture was cooled to room temperature, 6N hydrochloric acid (2 ml) was added, the mixture was stirred for 5 minutes, made basic with 5N sodium hydroxide solution, extracted with ethyl acetate, the organic layer was dried, the solvent was evaporated under reduced pressure, Column chromatography (chloroform-methanol: chloroform = 3: 1)
00-7: 100) to give the free amine of the title compound. Rf: 0.20 (methanol: chloroform = 1: 9) 0.1N hydrochloric acid-ethanol solution was used to obtain the title compound (268 mg).

Example 29 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (4-hydroxyphenyl) ethanol hydrochloride A. Synthesis of 2-bromo-1- (4-benzyloxy) phenylethanone (Intermediate 31) Copper (II) bromide (7.4 g) was suspended in ethyl acetate (100 ml) under an argon atmosphere and heated under reflux with stirring. Below, 1-
A solution of (4-benzyloxy) phenylethanone (5 g, manufactured by Transworld) in chloroform (100 m) was added. After refluxing for 5.5 hours, the mixture was cooled to 62 ° C. and diluted with chloroform (100 ml), and then the suspension was hot filtered and concentrated under reduced pressure. The residue was suspended in isopropyl alcohol, the precipitate was collected by filtration, washed with cold isopropyl alcohol and dried to give the title compound (4.52 g) as pale yellow crystals. B. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- [4- (benzyloxy) phenyl] ethanol (Intermediate 32)

Intermediate 31 (400 mg) and Intermediate 2 (5
34 mg) was reacted and treated according to the procedure of Step D of Example 1 to obtain the title compound (120 mg). However, the crude product was purified by column chromatography (ethyl acetate: methanol = 8: 1). C. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- (4-hydroxyphenyl) ethanol Intermediate 32 (120 mg) was added to dimethylformamide (1
5 ml), add acetic acid (100 μl), then 1
0% Palladium / carbon (110 mg) was rinsed with dimethylformamide (2 ml), and hydrogenolysis was performed for 50 minutes under a hydrogen atmosphere at 1 atm. Treatment according to the method of Example 2 gave the title compound (88 mg). Rf: 0.31
(Methanol: ethyl acetate = 1: 3)

Example 30 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (2-hydroxyphenyl) ethanol acetate A. Synthesis of 2-bromo-1- (2-benzyloxy) phenylethanone Under an argon atmosphere, copper (II) bromide (14.6 g) was suspended in ethyl acetate (175 ml) and heated under reflux with stirring.
(2-benzyloxy) phenylethanone (6.35
g, manufactured by Transworld) chloroform (175
m) The solution was added. Treatment according to step A of example 29 gave a fraction containing the title compound (9.32 g). It was used for the next reaction without further purification. B. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- [2- (benzyloxy) phenyl] ethanol (Intermediate 33) The above compound (442 mg) and Intermediate 2 (400 mg) were prepared according to the procedure of Step D of Example 1. After reaction and treatment, the title compound (31.9 mg) was obtained. However, the crude product was subjected to column chromatography (methanol: chloroform =
1:20). D. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- (2-hydroxyphenyl) ethanol acetate Intermediate 33 (31.9 mg) was added to methanol (4.7 m).
It was dissolved in 1), acetic acid (4 μl) was added, and hydrogenolysis was performed using 10% palladium / carbon (22.3 mg) under hydrogen at 1 atm (room temperature, 5 hours). The catalyst was filtered through Celite and washed with chloroform and methanol. The filtrate and the washing solution were combined, and the solvent was evaporated under reduced pressure to give the title compound (18.5 mg) as a powdery solid. Rf: 0.
13 (methanol: chloroform = 1: 10)

Example 31 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1-phenylethanol hydrochloride To a solution of intermediate 2.HBr salt (140 mg) and triethylamine (110 μl) in methanol (5 ml) was added phenylglyoxal (92.0 mg), and the mixture was placed on a water bath for 4 minutes.
Heated for minutes. After cooling, sodium borohydride (12
0 mg) was added in 2 portions every 10 minutes, and 2 mg at room temperature was added.
Stirred for 0 hours. The solvent was evaporated under reduced pressure, ethyl acetate and water were added, the organic layer was separated, the organic solvent was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (methanol: chloroform = 1: 25) to give the title compound. (116.3m
g) was obtained. Rf: 0.34 (methanol: chloroform = 1: 10) was recrystallized from ethanol to obtain 93.8 mg.

Example 32 (R) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1-phenylethanol hydrochloride Intermediate 2 (200 mg) was added to dimethyl sulfoxide (0.
5 ml) and (R)-(+)-styrene oxide (102
μl, manufactured by Aldrich) was added, and the mixture was stirred at 70 ° C. for 70 hours. Basify with water and sodium hydrogen carbonate, extract with ethyl acetate, dry the organic layer, evaporate the solvent under reduced pressure, and perform column chromatography (methanol: chloroform =
1:20) and the title compound (93.4 mg) was obtained. Rf: 0.34 (methanol: chloroform = 1:
10) Optical purity is Chiralcel OD-R (4.6 mmφ
High-performance liquid chromatography using x25 cm (manufactured by Daicel Chemical Industries, Ltd.) revealed that it was almost 100% R-form. The analysis was conducted using a mobile phase of 0.5M NaClO4 / CH3CN = 1/1.
The flow rate was 0.5 ml / min, the detection wavelength was 254 nm, and the column temperature was 25 ° C., and the retention times were 33.2 and 32.4 minutes for the R and S bodies, respectively. A hydrochloride (70 mg) was obtained using a hydrochloric acid ethanol solution.

Example 33 (S) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1-phenylethanol hydrochloride Intermediate 2 (70.4 mg) was added with dimethyl sulfoxide (0.3 ml) and (S)-(−)-styrene oxide (36 μl, Aldrich). 70 at 70 ° C
Stirred for hours. Basify with water and sodium bicarbonate,
Extract with ethyl acetate, dry the organic layer, evaporate the solvent under reduced pressure, and remove PTLC (chloroform: methanol = 10: 1).
The title compound (22.4 mg) was obtained. Rf:
The optical purity of 0.34 (methanol: chloroform = 1: 10) was analyzed by the high performance liquid chromatography of Example 32 under the same conditions, and as a result, it was about 100% S isomer, and the retention time was 32.4. It was a minute. The hydrochloride salt (15 mg) was obtained using a hydrochloric acid ethanol solution.

Example 34 (±) -2- [N- [2- (dibenzofuran-2-yloxy) ethyl] amino] -1-phenylethanol hydrochloride Intermediate 5 · HBr salt (105 mg) and triethylamine (105 μl) Phenylglyoxal (69 mg) was added to a methanol (5 ml) solution of and the reaction and treatment were carried out according to the synthetic method of Example 31 to obtain the title compound (63.6 mg). Rf: 0.48 (methanol: chloroform = 1: 10) was used as a hydrochloric acid-ethanol solution to obtain a hydrochloride (40 mg).

Example 35 (R, R) -2- [N- [1- (9H-carbazole-
2-yloxy) propan-2-yl] amino] -1-
Phenylethanol hydrochloride 2- (N-tert) synthesized according to the method of Example 11
-Butoxycarbonylamino-1-propyloxy) 9
30% hydrobromic acid acetic acid solution (10 ml) was added to H-carbazole (597 mg), and the mixture was reacted and treated according to a method similar to the synthesis method of Example 32 to give the title compound (258
mg). Rf = 0.47 (methanol: chloroform = 1: 9) The optical purity was analyzed by using the high performance liquid chromatography of Example 32 under the same conditions except that the optical purity was almost 100% (R, R). ) Body and the retention time was 27.3 minutes. Hydrochloric acid (2
80 mg).

Example 36 (±) -2- [N- [2-[(9H-3-aminocarbazol) -2-yloxy] ethyl] amino] -1-phenylethanol dihydrochloride A. Synthesis of N- [2- (9H-carbazol-2-yloxy) ethyl] acetamide (Intermediate 34) Intermediate 2 (1 g) and triethylamine (0.93 ml,
Acetyl chloride (0.4 ml, manufactured by Wako Pure Chemical Industries) in a dichloromethane (5 ml) solution of Wako Pure Chemical Industries, Ltd. under ice-cooling stirring.
In dichloromethane (2 ml) was added. Under ice cooling 2.
Stir for 5 hours, then warm to room temperature. Ethyl acetate and water were added, the organic layer was separated, washed with saturated brine and dried, and the solvent was evaporated under reduced pressure. After drying under reduced pressure at room temperature, the title compound (1.16 g) was obtained. Rf: 0.47 (methanol:
Chloroform = 1: 9)

B. Synthesis of N- [2-[(9H-3-nitrocarbazol) -2-yloxy] ethyl] acetamide (Intermediate 35) At 60 ° C, the intermediate 34 (500 mg) of acetic acid (2
0 ml) solution was added 20% nitric acid (0.4 ml) with stirring. After 1 minute, ice-water (20 ml) was added and stirred, water was further added, and the mixture was extracted with ethyl acetate. Wash the organic layer with water and
The pH was adjusted to 8 with a specified sodium hydroxide solution and washed with saturated saline. After drying, the solvent was distilled off under reduced pressure, and the residue was
Purify by column chromatography (methanol: chloroform = 1: 50) to give the title compound (271.2 mg).
I got Rf: 0.50 (methanol: chloroform =
1: 9, expanded twice) C. N- [2-[(9H-3-nitrocarbazole)-
Synthesis of 2-yloxy] ethyl] amine (Intermediate 36) Intermediate 35 (100 mg) was suspended in 2.5N hydrochloric acid,
After stirring at room temperature for 10 days, the mixture was stirred at 100 ° C. for 4 hours. Add ethyl acetate, adjust to pH 10 with 5N sodium hydroxide solution, extract and dry, then evaporate the solvent under reduced pressure.
The title compound (71.2 mg) was obtained. Rf: 0.11
(Methanol: chloroform = 1:10, developed 3 times)

D. (±) -2- [N- [2-[(9H-
3-Nitrocarbazol) -2-yloxy] ethyl]
Amino] -1-phenylethanol hydrochloride (Intermediate 3
Synthesis of 7) Intermediate 36 (71.2 mg), phenylglyoxal (52.8 mg, manufactured by Tokyo Kasei) and triethylamine (54.8 μl) were dissolved in methanol (5 ml),
The mixture was heated and stirred at 70 ° C for 4 minutes. Then, the mixture was ice-cooled, and sodium borohydride (79 mg) was added with stirring. The mixture was stirred for 21 hours while gradually warming to room temperature. Ethyl acetate and water were added and the mixture was stirred for 15 minutes, the organic layer was separated, dried and the solvent was evaporated under reduced pressure. Column chromatography of the residue (112.1 mg) (methanol: chloroform = 1: 25)
The title compound (17.1 mg) was obtained. Rf:
0.34 (methanol: chloroform = 1: 10)

E. (±) -2- [N- [2-[(9H-
3-Aminocarbazol) -2-yloxy] ethyl]
Amino] -1-phenylethanol dihydrochloride In a solution of the compound of Intermediate 37 (71.8 mg) in methanol (3.7 ml), concentrated hydrochloric acid (0.16 ml) and iron powder (68.6 mg, manufactured by Kanto Chemical Co., Inc.) ) Were sequentially added, and the mixture was stirred at room temperature for 3.5 hours and then at 40 ° C. for 5 minutes.
The pH was adjusted to 9 with water and 5N sodium hydroxide solution, extracted with ethyl acetate, dried, and the solvent was evaporated under reduced pressure. 0.1N hydrogen chloride / ethanol (4 ml) was added to the residue,
The solvent was distilled off under reduced pressure and recrystallized from ethanol-ethyl acetate. The crystals were collected by filtration, washed successively with ethyl acetate and diethyl ether, and dried under reduced pressure to give the title compound (29 mg). Rf: 0.14 (free form) (methanol: chloroform = 1: 10)

Example 37 (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide / hydrochloric acid Salt A. Synthesis of 3- (2-benzyloxycarbonylaminoethoxy) dibenzothiophene (Intermediate 38) 3-hydroxydibenzothiophene (370.6 mg,
References (H. Kudo, J. Heterocycl. Ch.
em. , 22 (1), 215-218, 1985) and potassium carbonate (768 mg).
In a solution of dimethylformamide (4 ml) in
(720 mg) was added and the mixture was heated at 60 ° C. for 30 hours. Ethyl acetate and water were added, and after extraction and washing with water, the organic layer was dried, the solvent was evaporated under reduced pressure, and the residue was purified by column chromatography (methanol: chloroform = 1: 100) to obtain the title compound (637 mg). Rf: 0.17 (ethyl acetate:
n-hexane = 1: 5)

B. Synthesis of 2- (dibenzothiophen-3-yloxy) ethylamine (Intermediate 39) To intermediate 38 (637 mg) was added a 30% hydrobromic acid solution (12 ml), and the mixture was stirred at room temperature for 2.5 hours. Diethyl ether was added under ice cooling, and the deposited precipitate was collected by filtration. After adjusting the pH to 10 by adding water and NaOH, the mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (334.2 mg). Rf: 0.10 (methanol: chloroform = 1: 10) C.I. Synthesis of (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide hydrochloride

Intermediate 3 (334.2 mg) in anhydrous acetonitrile (14 ml) was added with Intermediate 3 (780 m).
g, 70% purity) in anhydrous acetonitrile (7 ml) and triethylamine (210 μl) were added at 0 ° C. under an argon atmosphere, and the mixture was removed from the ice bath and stirred for 83 minutes. Then to this mixture was added a solution of sodium borohydride (270 mg) in absolute ethanol (14 ml) at room temperature. After stirring for 6.5 hours, the reaction was stopped with 1.0 N hydrochloric acid (pH 4), and then ethanolamine (0.7 g)
Was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give 1.09 g of a crude product. This was purified by column chromatography (methanol: chloroform = 3:
100), the free amine of the title compound (240.6 m
g) was obtained. Rf: 0.38 (methanol: chloroform = 1: 10). 0.1 N hydrogen chloride / ethanol (1.1 equivalent) was added to a portion (46 mg) to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure at 50 ° C. to give the title compound (48.5).
mg).

Example 38 (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride The compound of Example 37 (43 mg) was treated with 1 atm of hydrogen and 1
0% Palladium / Carbon (Merck) (30 mg)
And hydrogenolysis with methanol (5 ml) (room temperature, 4 hours). The catalyst was filtered and washed with chloroform, methanol and then hot methanol. The filtrate and the washing solution were combined, and the solvent was evaporated under reduced pressure to give the title compound (3
2.5 mg) was obtained as a white powdery solid. Rf: 0.
08 (methanol: chloroform = 1: 10)

Example 39 (±) -N '-[5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -N, N -Dimethylsulfamide / hydrochloride A. 2-Bromo-1- [4-benzyloxy-3-
Synthesis of [(dimethylsulfamoyl) amino] phenyl] ethanone (Intermediate 40) Similar to Intermediate 3, it was prepared from 4-hydroxyacetophenone (manufactured by Tokyo Kasei) in 4 steps. (Larsen (A.
A. Larsen) et al. Med. Chem. , 1
0,462-472 (1967)). However, the bromination step was performed in the same manner as in the method described in Example 29, Step A. Rf: 0.37 (chloroforom)

B. (±) -N '-[5- [2- [2-
Synthesis of (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide hydrochloride Intermediate 39 (462 mg) in anhydrous acetonitrile (20
(ml) solution, a solution of intermediate 40 (470 mg) in anhydrous acetonitrile (10 ml) was added at 0 ° C under an argon atmosphere, and the mixture was removed from the ice bath and stirred for 110 minutes. Then, a solution of sodium borohydride (215 mg) in absolute ethanol (20 ml) was added to this mixture at room temperature. 70
After stirring for 1 minute, the reaction was stopped with 1N hydrochloric acid (pH 4),
Then ethanolamine (0.54 g) was added. 10
After stirring for 1 minute, the mixture was diluted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give a crude product. This was purified by column chromatography (eluting with methanol: chloroform = 3: 100) to obtain a free amine (200.2 mg) of the title compound. Rf: 0.3
7 (methanol: chloroform = 1: 10). To this, 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to form the hydrochloride (title compound), the solvent was distilled off under reduced pressure, and diethyl ether was added to the residue to distill off twice. It was dried to obtain the title compound (210.8 mg).

Example 40 (±) -N '-[5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N- Dimethylsulfamide hydrochloride The compound of Example 39 (210.8 mg) was hydrolyzed with 10% palladium / carbon (107 mg) and methanol (22.5 ml) under hydrogen at 1 atm (room temperature, 4 time). The catalyst was filtered and washed with hot methanol. The filtrate and the washing solution were combined, and the solvent was evaporated under reduced pressure to give the title compound (137.9 mg). Rf: 0.
26 (methanol: chloroform = 1: 10)

Example 41 (±) -N- [3- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride Intermediate 39 (462 mg) ) Anhydrous acetonitrile (20
ml) solution, a solution of intermediate 14 (320.2 mg) in anhydrous acetonitrile (10 ml) at 0 ° C. under an argon atmosphere.
, And the mixture was removed from the ice bath and stirred for 115 minutes. This mixture was then added to sodium borohydride (215m
A solution of g) in absolute ethanol (20 ml) was added at room temperature. After stirring for 75 minutes, the reaction was stopped with 1.0 N hydrochloric acid (pH 4), and then ethanolamine (0.54 g) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure. This was purified by column chromatography (eluting with methanol: ethyl acetate = 1: 7) to obtain a fraction containing the free amine of the title compound (251.3 mg). This was further purified by PTLC (elution with methanol: ethyl acetate = 1: 7) to obtain the free amine (134.7 mg) of the title compound. Rf: 0.50 (methanol: ethyl acetate = 1:
7). To this was added 0.1N hydrogen chloride / ethanol (1.1 equivalents), and the precipitated hydrochloride (title compound) was collected by filtration, washed successively with ethanol, ethyl acetate and then diethyl ether, and dried under reduced pressure at 50 ° C to give the title. Compound (93.9 mg)
I got

Example 42 (±) -N '-[5- [2- [2- (dibenzofuran-
3-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide A. Synthesis of (±) -N- [5- [2-Bromo-1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 41) Ice-cooled Intermediate 40 (15 0.1 g) in a solution of anhydrous tetrahydrofuran (197 ml) in argon, and a solution of borane-tetrahydrofuran complex in 1M tetrahydrofuran (6
(1.9 ml, Aldrich) was added all at once, and the mixture was stirred at the same temperature for 75 minutes. The mixture was diluted with 500 ml of ethyl acetate, saturated aqueous ammonium chloride was added little by little, and the organic layer was washed twice. The organic layer was separated, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Further, it was dried under reduced pressure with a vacuum pump overnight to obtain the title compound (14.91 g). R
f: 0.27 (ethyl acetate: n-hexane = 1: 2)

B. (±) -N- [5- [2-iodo-1
Synthesis of-(triethylsilyloxy) ethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 42) Intermediate 41 (14.9 g) in acetone (212.9 m)
l) Add sodium iodide (58.09 g) to the solution and add 1
Heated to reflux for 05 minutes. After cooling to room temperature and filtering, the solvent was distilled off under reduced pressure. The residue was partitioned between dichloromethane (240 ml) and water (240 ml) and the organic layer was 23.5% (w / w).
%) Aqueous sodium bisulfite solution was washed twice, washed with water and then with saturated brine, dried and evaporated under reduced pressure. Further, it was dried under reduced pressure with a vacuum pump for 2 hours to obtain a brown tar-like substance (iodine product, 15.51 g). This was dissolved in dimethylformamide (75.6 ml), and imidazole (6.1 g) and 4-dimethylaminopyridine (346 m at room temperature).
g) was added, followed by chlorotriethylsilane (5.83).
ml) was added. After stirring for 35 minutes, ethyl acetate (250 m
1) and n-heptane (100 ml) and diluted with water (12
5 ml), saturated copper sulfate solution (125 ml, twice), water (125 ml), and saturated saline (125 ml), and the extract was dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography, and the target product (15.41 g) was obtained as a slightly brown solid from the fraction eluted with n-hexane. R
f: 0.86 (ethyl acetate: n-hexane = 1: 1)

C. (±) -N '-[5- [2- [2-
(Dibenzofuran-3-yloxy) ethylamino]-
Synthesis of 1- (triethylsilyloxy) ethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 43) Intermediate 42 (150 mg), Intermediate 5 (71.6 mg)
And a solution of Hunig's base (0.44 ml, Aldrich) in dimethylacetamide (0.5 ml) 60
The mixture was stirred at 0 ° C for 12 hours. Ethyl acetate (40m)
l) and water (40 ml) were added for extraction, and the aqueous layer was further extracted 3 times with ethyl acetate. After drying the combined organic layers,
The solvent was distilled off under reduced pressure. The residue was subjected to column chromatography (chloroform-methanol: chloroform = 1: 4).
Purification in 9) gave the title compound (173 mg). R
f: 0.74 (methanol: chloroform = 1: 10)

D. (±) -N '-[5- [2- [2-
(Dibenzofuran-3-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide To a solution of intermediate 43 (60.1 mg) in anhydrous tetrahydrofuran (2.9 ml) was added acetic acid (36.8 μl) and tetrabutyl. 1M solution of ammonium in tetrahydrofuran (57
4 μl) was added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography, and the title compound (50.0 mg) was obtained from the fraction eluted with methanol: chloroform = 7: 100.
I got Rf: 0.39 (methanol: chloroform =
1:10)

Example 43 (±) -N '-[5- [2- [2- (dibenzofuran-
3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide.hydrochloride The compound of Example 42 was dissolved in methanol (5.9 ml) to give 0.1N. Hydrogen chloride / ethanol (0.92 ml),
10% Pd-carbon (27.6 mg) was added, and the mixture was stirred under hydrogen at 1 atm for 2.5 hours. The catalyst was filtered, washed with hot methanol, and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether and collected by filtration. The solid was dried under reduced pressure at 50 ° C. for 2 hours to obtain the title compound (24.7 mg) as a pale brown amorphous substance. Rf: 0.25 (methanol: chloroform =
1:10)

Example 44 (±) -N '-[5- [2- [2- (9H-7-acetylaminofluoren-2-yloxy) ethylamino]
-1-Hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide A. (±) -N '-[5- [2- [2- (9H-7-acetylaminofluoren-2-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-
Synthesis of benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 44) In the same manner as in Intermediate 43 in Step C of Example 42,
Intermediate 42 (486 mg), Intermediate 17 (290.4 m
g) and a solution of Hunig's base (1.44 ml, Aldrich) in dimethylacetamide (1.3 ml) were stirred at 60 ° C. for 16 hours. Ethyl acetate and water were added to the reaction solution for extraction, and the aqueous layer was further extracted with ethyl acetate three times. After the combined organic layers were dried, the solvent was distilled off under reduced pressure. The residue was purified by column chromatography (chloroform-methanol: chloroform = 1: 49) to obtain the title compound (75.3 mg). Rf: 0.51 (methanol: chloroform = 1: 10)

B. (±) -N '-[5- [2- [2-
Synthesis of (9H-7-acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide Anhydrous of Intermediate 44 (75.3 mg) To a tetrahydrofuran (3.3 ml) solution, acetic acid (43 μl) and tetrabutylammonium 1M tetrahydrofuran solution (667 μm)
1) was added, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated with ethanol to give the title compound (4
7.1 mg) was obtained as a white powder. Rf: 0.25
(Methanol: chloroform = 1: 10)

Example 45 (±) -N '-[5- [2- [2- (9H-7-acetylaminofluoren-2-yloxy) ethylamino]
-1-Hydroxyethyl] -2-hydroxyphenyl]
-N, N-Dimethylsulfamide hydrochloride: The compound of Example 44 was dissolved in methanol (4.8 ml) to prepare 0.1N hydrogen chloride / ethanol (0.78 ml),
10% Pd-carbon (25 mg) was added, and the mixture was stirred under 1 atm of hydrogen for 2.2 hours. The catalyst was filtered, washed with hot methanol, and the solvent was distilled off under reduced pressure. The residue was triturated with diethyl ether and collected by filtration. It was dried under reduced pressure at 50 ° C. for 2 hours to obtain the title compound (40.6 mg). Rf: 0.05 (methanol: chloroform = 1: 10)

Example 46 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (3-nitrophenyl)] ethanol · hydrochloride hydrochloride HBr salt of intermediate 2 (678.6 mg) and triethylamine (371 μl) in anhydrous acetonitrile (45 ml)
In a mixed solution of anhydrous dimethylformamide (4.5 ml), 2-bromo-1- (3-nitrophenyl) ethanone (AA Larsen et al., J. Med.
Chem. , 9,88-97 (1966)) (539 mg) in anhydrous acetonitrile (20 ml) was added at 0 ° C. under an argon atmosphere and stirred for 1 hour. In addition, the mixture is allowed to come to room temperature (~ 22
(° C) and stirred for 2 hours. To this mixture was added sodium borohydride (434 mg) in absolute ethanol (20 m).
l) The solution was added at room temperature. After stirring for 1 hour, the reaction was stopped with 1.0 N hydrochloric acid (pH 4), and ethanolamine (1.1 ml) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate and the organic layer was washed 3 times with saturated saline,
After drying, it was concentrated under reduced pressure to obtain 0.93 g of a crude product. This was recrystallized from ethyl acetate / ethanol to remove the starting amine, the filtrate was concentrated, and the resulting residue was purified by PTLC (developed with methanol / chloroform: 1/10).
Free amine (77.4 mg) was obtained. Rf: 0.32
(Methanol: chloroform = 1: 10) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was recrystallized from ethanol and dried under reduced pressure at 50 ° C. to obtain a powder of the title compound.

Example 47 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- (3-aminophenyl)] ethanol · hydrochloride hydrochloride of the compound of Example 46 (43.9 mg) (2
ml) solution, iron powder (38.3 mg) and concentrated hydrochloric acid (90 μ)
1) was added, and the mixture was stirred at room temperature for 4 hours. The mixture was diluted with water, adjusted to pH 10 with 5N NaOH and extracted with ethyl acetate. The organic layer was dried and then concentrated under reduced pressure to obtain 50 mg of a crude product. This was PTLC (methanol / ethyl acetate:
The product was purified by 1/4) to obtain a free amine (16 mg). Rf: 0.30 (methanol: ethyl acetate = 1:
4) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was recrystallized from ethanol and dried under reduced pressure at 50 ° C. to obtain a powder of the title compound.

Example 48 (±) -N '-[3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] -N, N-dimethylsulfamim De
Hydrochloride 2-Bromo-1- [3-[(dimethylsulfamoyl))
Amino] phenyl] ethanone (AALarsen)
Example 4 except that (710 mg) prepared according to the method reported by J. Med. Chem., 9, 88-97 (1966) was used.
The reaction and treatment were performed in the same manner as in 6, and the obtained residue was purified by PTLC (developed with methanol / ethyl acetate: 1/4) to obtain a free amine (111.2 mg). Rf: 0.52
(Methanol: ethyl acetate = 1: 3) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was recrystallized from ethanol and dried under reduced pressure at 50 ° C to give the title compound (9
3.2 mg) of powder was obtained.

Example 49 (±) -N- [5- [2- [2- (9H-7-acetylaminofluoren-2-yloxysi) ethylamino]]
-1-Hydroxyethyl] -2-benzyloxyphenyl] methanesulfonamide hydrochloride In accordance with the method described in Example 1, Intermediate 17 (500 m
g) and intermediate 3 (1.06 g, 70% purity) by coupling reaction, followed by sodium borohydride (359 m
g) and subjected to a reduction reaction, and the reaction mixture was subjected to silica gel column chromatography (methanol: chloroform =
1: 9) to give the free amine of the title compound (245
mg). Rf: 0.24 (methanol: chloroform = 1: 10) A part (97 mg) was made into hydrochloride (100 mg) with 0.1 N hydrogen chloride / ethanol.

Example 50 (±) -N- [5- [2- [2- (9H-7-acetylaminofluoren-2-yloxysi) ethylamino]
-1-Hydroxyethyl] -2-hydroxyphenyl]
Methanesulfonamide hydrochloride The compound of Example 49 (100 mg) was dissolved in methanol (10.5 ml) according to the method described in Example 2 to obtain 10
A hydrogenolysis reaction was carried out using Pd-C (49.5 mg). After stirring at room temperature for 2.5 hours, the catalyst was filtered through Celite, and the catalyst was washed with hot methanol. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure to obtain the title compound (77.5 mg). Rf: 0.03 (methanol: chloroform =
1:10)

Example 51 (±) -N- [5- [2- [2- (9H-7-Aminofluoren-2-yloxysi) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] methane Sulfonamide hydrochloride The free amine of Example 49 (72.1 mg) was dissolved in 10% hydrogen chloride / methanol (10 ml) and allowed to stand at room temperature for 41
Stirred for hours. The precipitate was collected by filtration, washed with diethyl ether, and dried under reduced pressure at 50 ° C. (40 minutes) to give the title compound (49
mg). Rf: 0.27 (methanol: chloroform = 1: 10)

Example 52 (±) -N- [5- [2- [2- (9H-7-Aminofluoren-2-yloxysi) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfone Amide / hydrochloride The compound of Example 51 (49 mg) was dissolved in methanol (5.4 ml) according to the method described in Example 2 to give 10% P.
A hydrogenolysis reaction was carried out using d-C (25.9 mg). After stirring at room temperature for 3 hours, the catalyst was filtered through Celite, and the catalyst was washed with hot methanol. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure to obtain the title compound (43.1 mg). R
f: 0.22 (methanol: ethyl acetate = 1: 3)

Example 53 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -2-propane Sulfonamide / hydrochloride A. 2-Bromo-1- [4-benzyloxy-3-
Synthesis of [(Isopropylsulfonyl) amino] phenyl] ethanone (Intermediate 45) Same as Intermediate 3 except isopropylsulfonyl chloride was used in place of methanesulfonyl chloride (however, the bromination was carried out in Example 29 Step A). According to the method described.) From 1- (3-amino-4-benzyloxyphenyl) ethanone (2 g), the title intermediate (2.
03g, about 70% pure) was prepared. Rf: 0.19
(Chloroform)

B. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-benzyloxyphenyl] -2-propanesulfonamide hydrochloride Intermediate 45 (1.43 g, 70% purity) and Intermediate 2 (6
86 mg) was subjected to a coupling reaction according to the method described in Example 1, followed by reduction reaction with sodium borohydride (650 mg) under hydrogen, and purification by silica gel chromatography (methanol: chloroform = 11:89 mixed solvent elution). The title compound (369 mg) was obtained. Rf: 0.
49 (methanol: chloroform = 1: 5) Hydrochloric acid salt was prepared with 0.1N hydrogen chloride / ethanol.

Example 54 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -2-propanesulfone Amide / hydrochloride The compound of Example 53 (369 mg) was dissolved in methanol (39.9 ml) according to the method described in Example 2 to give 10
A hydrogenolysis reaction was performed using Pd-C (190 mg). After stirring at room temperature for 5 hours, the catalyst was filtered through Celite, and the catalyst was washed with hot methanol. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure to obtain the title compound (267 mg). R
f: 0.27 (methanol: ethyl acetate = 1: 3)

Example 55 (±) -N- [5- [2- [2- (dibenzofuran-3
-Iloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride A. Synthesis of (±) -N- [5- [2-iodo-1- (triethylsilyloxy) ethyl] -2-fluorophenyl] methanesulfonamide (Intermediate 46) As described in Steps A and B of Example 42. Reaction and treatment are carried out according to the method, and Intermediate 9 (7.48 g) to the title compound (1
0.22 g) was obtained. Rf: 0.36 (ethyl acetate: n
-Hexane = 1: 3) B.I. Of (±) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-fluorophenyl] methanesulfonamide (Intermediate 47) Synthesis Reaction and treatment were carried out according to the method described in Step C of Example 42 to give Intermediate 46 (819 mg) and Intermediate 5 (500 m
The title compound (648 mg) was obtained from g). Rf: 0.
44 (methanol: chloroform = 1: 10)

C. (±) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-
Synthesis of Hydroxyethyl] -2-Fluorophenyl] methanesulfonamide Hydrochloride Intermediate 47 (648 mg) in tetrahydrofuran (30
4) hydrogen chloride / dioxane solution (2.
(15 ml) was added, and the mixture was stirred at room temperature for 1 hr, diethyl ether (30 ml) was added, and the crystals were filtered and dried under reduced pressure to give the title compound (408.8 mg). Rf: 0.61
(Methanol: ethyl acetate = 1: 3)

Example 56 (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide
Hydrochloride A. (±) -N- [5- [2- [2- (Dibenzothiophen-3-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-fluorophenyl] methanesulfonamide (Intermediate 48) The reaction and treatment were conducted according to the method described in Step C of Example 42 to give Intermediate 46 (811 mg) and Intermediate 39 (500
The title compound (581.8 mg) was obtained from (mg). R
f: 0.52 (methanol: chloroform = 1: 10) B.I. Synthesis of (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride Intermediate 48 (581) (8 mg) in tetrahydrofuran (30 ml), 4N hydrogen chloride / dioxane solution (1.88 ml) was added, the mixture was stirred at room temperature for 1 hr, diethyl ether (30 ml) was added, and the crystals were filtered and dried under reduced pressure. A compound (412 mg) was obtained. Rf: 0.50
(Methanol: ethyl acetate = 1: 3)

Example 57 (±) -N- [5- [2- [2- (dibenzofuran-3
-Iloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide hydrochloride A. Synthesis of (±) -N- [5- [2-iodo-1- (triethylsilyloxy) ethyl] -2-chlorophenyl] methanesulfonamide (Intermediate 49) The method described in Steps A and B of Example 42. The reaction and treatment were carried out according to (1), and the title compound (1.24 g) was obtained from Intermediate 13 (1.72 g). Rf: 0.65 (ethyl acetate:
n-hexane = 1: 2) B.I. Synthesis of (±) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-chlorophenyl] methanesulfonamide (Intermediate 50) Reaction and treatment were carried out according to the method described in Step C of Example 42 to give Intermediate 49 (873 mg) and Intermediate 5 (500 m
The title compound (544 mg) was obtained from g). Rf: 0.
49 (methanol: chloroform = 1: 10) C.I. Synthesis of (±) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride Intermediate 50 (544 mg) Tetrahydrofuran (30
4) hydrogen chloride / dioxane solution (1.
75 ml) was added, and the mixture was stirred at room temperature for 1 hr, diethyl ether (30 ml) was added, and the crystals were filtered and dried under reduced pressure to give the title compound (296.8 mg). Rf: 0.67
(Methanol: ethyl acetate = 1: 3)

Example 58 (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide
Hydrochloride A. Of (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-chlorophenyl] methanesulfonamide (Intermediate 51) Synthesis Reaction and treatment were carried out according to the method described in Step C of Example 42 to give Intermediate 49 (480 mg) and Intermediate 39 (29
The title compound (122 mg) was obtained from 4.8 mg). R
f: 0.45 (ethyl acetate: hexane = 2: 1) B.I. Synthesis of (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide hydrochloride Intermediate 51 (122 mg) Tetrahydrofuran (6m
l) solution, 4N hydrogen chloride / dioxane solution (0.3
(8 ml) and after stirring at room temperature for 1 hour, diethyl ether was added, and the crystals were filtered and dried under reduced pressure to give the title compound (8
6.7 mg) was obtained. Rf: 0.76 (methanol: ethyl acetate = 1: 3)

Example 59 (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] -N, N -Dimethylsulfamide / hydrochloride A. Synthesis of 1- [4-fluoro-3-[(dimethylsulfamoyl) amino] phenyl] ethanone (intermediate 52) A solution of intermediate 7 (1 g) in pyridine (7.2 ml) was added to dimethylaminosulfonyl at room temperature. Chloride (708μ
l) was added. After stirring for 3 days, pour into water (50 ml),
Extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give a crude product. Further, the reaction and treatment were carried out again under the same conditions as above, and the crude product was purified by column chromatography (2/1: n-hexane / ethyl acetate) to obtain the title compound (1.1 g). R
f: 0.21 (ethyl acetate: n-hexane = 1: 2)

B. 2-Bromo-1- [4-fluoro-3-
Synthesis of [(dimethylsulfamoyl) amino] phenyl] ethanone (intermediate 53) Intermediate 52 (1.1 g) in 1,4-dioxane (1
Bromine (229 μl) was added to 0 ml) with stirring. The mixture was warmed to 60 ° C. and stirred for 2.5 hours. After cooling to room temperature, water was added and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give the title compound as a crude product (1.588 g). Rf: 0.52
(Ethyl acetate: n-hexane = 1: 1) C.I. (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] -N, N-dimethylsulfamide hydrochloride Synthesis of Salt Using a modification of the method described in Step D of Example 1, Intermediate 2
(632 mg) in anhydrous acetonitrile (30 ml) -anhydrous dimethylformamide (15 ml) mixed solution was added to intermediate 53 (1.58 g) in anhydrous acetonitrile (15 ml).
The solution was added at 0 ° C. under an argon atmosphere, then triethylamine (824 μl) was added and the mixture was warmed to room temperature (-22 ° C.) and stirred for 50 minutes.

To this mixture was added sodium borohydride (9
A solution of 03 mg) in absolute ethanol (30 ml) was added at room temperature. After stirring for 70 minutes, the reaction was stopped with 1N hydrochloric acid (pH 4), and then ethanolamine (1.35 m
l) was added. After stirring for 10 minutes, the mixture was diluted with ethyl acetate (200 ml), the organic layer was washed three times with saturated brine, dried and concentrated under reduced pressure to give a crude product. This was subjected to column chromatography (methanol / chloroform:
1/20) to give the free amine of the title compound (27
6 mg). Rf: 0.66 (concentrated ammonia water 10
% -Containing methanol: ethyl acetate = 1: 4) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Ethanol-ethyl acetate was added to the residue, and the precipitated precipitate was collected by filtration and dried under reduced pressure at 50 ° C. to give the title compound (188.2 m
A powder of g) was obtained.

Example 60 (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] -N, N- Dimethylsulfamide / hydrochloride A. Synthesis of 1- [4-chloro-3-[(dimethylsulfamoyl) amino] phenyl] ethanone (Intermediate 54) A solution of Intermediate 11 (1 g) in pyridine (6.5 ml) was added,
Dimethylsulfamoyl chloride (640μ at room temperature)
1) was added and stirred for 28 hours. Furthermore, 65 at 40 ℃
After heating for an hour, the mixture was poured into water and extracted with chloroform. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give a crude product. This was purified by column chromatography (n-hexane / ethyl acetate: 4/1) to give the title compound (86
5 mg) was obtained. Rf: 0.24 (ethyl acetate: n-hexane = 1: 2) B.I. Synthesis of 2-bromo-1- [4-chloro-3-[(dimethylsulfamoyl) amino] phenyl] ethanone (Intermediate 55) Stirring in a solution of Intermediate 54 (860 mg) in 1,4-dioxane (9 ml). Below, bromine (168 μl) was added. The mixture was warmed to 60 ° C. and stirred for 1.5 hours. After cooling to room temperature, water was added and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give the title compound (1.05 g) as a crude product. Rf: 0.5
5 (ethyl acetate: n-hexane = 1: 1)

C. (±) -N '-[5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl]
Synthesis of —N, N-Dimethylsulfamide Hydrochloride Intermediate 2 (4) was prepared according to the method described in Step C of Example 59.
47 mg) and Intermediate 55 (1.05 g) were reacted and treated, purified by column chromatography (methanol / chloroform: 1/20), and further purified by PTLC (concentrated aqueous ammonia 10% in methanol / ethyl acetate: 1/4). ), The free amine of the title compound (251.1 mg)
I got Rf: 0.67 (methanol / ethyl acetate: 1/4 containing 10% concentrated aqueous ammonia) 0.1N hydrogen chloride / ethanol (1.1 equivalents) was added to make a hydrochloride (title compound), and the solvent was removed under reduced pressure. Distilled off. Diethyl ether was added to the residue, and the deposited precipitate was collected by filtration,
It was dried under reduced pressure at 50 ° C. to obtain a powder of the title compound (253.9 mg).

Example 61 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -3-benzyloxyphenyl] methanesulfonamide A ． Synthesis of 1- (3,5-dinitrophenyl) ethanone (Intermediate 56) 0.92 M methylmagnesium bromide was added to a solution of dimethyl malonate (8 ml) in anhydrous tetrahydrofuran (70 ml) at -10 ° C or lower under an argon atmosphere. / Tetrahydrofuran (78 ml, Aldrich) was added dropwise over 30 minutes. After further stirring for 15 minutes, a chloroform (35 ml) solution of 3,5-dinitrobenzoyl chloride (8.0 g, manufactured by Tokyo Chemical Industry Co., Ltd.) was added dropwise over 15 minutes. The reaction solution was returned to room temperature and stirred for 59 hours. The solvent was distilled off under reduced pressure to obtain a yellow amorphous product (36.72 g), which was converted to acetic acid (42
ml) -water (35 ml) mixed solution and concentrated sulfuric acid (5 m
1) was added and the mixture was stirred with heating under reflux for 5 hours. The reaction mixture was poured into 300 ml of ice and the precipitated solid was collected by filtration. This was washed with water, dried under reduced pressure at room temperature (6.35 g) and recrystallized from ethanol (5 ml) to obtain the title compound (2.1 g). Rf: 0.79 (ethyl acetate: n-hexane = 1:
2)

B. Synthesis of 1- (3-amino-5-nitrophenyl) ethanone (intermediate 57) Stirred intermediate 56 (503 mg) in acetic acid (10 ml).
Stannous chloride (1.43 g,
A solution of anhydrous) in concentrated hydrochloric acid (5 ml) was added dropwise over 5 minutes.
The cold bath was removed, and the mixture was stirred for 3 hours while gradually returning to room temperature. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate (100 ml), the aqueous saturated sodium bicarbonate solution was added to adjust the pH to 8, and the mixture was extracted with ethyl acetate (50 ml × 3). The organic layer was washed with saturated brine, dried and evaporated under reduced pressure to remove the title compound (160 mg).
I got Rf: 0.51 (ethyl acetate: n-hexane =
1: 2) C.I. Synthesis of 1- (3-hydroxy-5-nitrophenyl) ethanone (Intermediate 58) Intermediate 57 (350 mg) was dissolved in 10 ml of sulfuric acid (prepared by adding 5 ml of concentrated sulfuric acid to 5 ml of water) and stirred under ice-cooling. An aqueous solution (5 ml) of sodium nitrate (140 mg) was added dropwise over 5 minutes. After further stirring for 25 minutes, the above sulfuric acid solution (10 ml) was added, and the mixture was stirred at 120 ° C for 30 minutes while refluxing under heating. After cooling to room temperature, ethyl acetate (40 ml x 2)
Extracted. After drying the organic layer, the solvent was distilled off under reduced pressure to obtain a crude product (293 mg). This was purified by silica gel chromatography (chloroform-methanol: chloroform = eluting 3: 97-5: 95) to obtain the title compound (154 mg). Rf: 0.40 (methanol:
Chloroform = 1: 9) D.I. 1- (3-benzyloxy-5-nitrophenyl)
Synthesis of Ethanone (Intermediate 59)

Intermediate 58 (154 mg) was dissolved in anhydrous dimethylformamide (5 ml), and anhydrous potassium carbonate (360 mg) and benzyl bromide (0.22 m) were added at room temperature.
l) and sodium iodide (130 mg) were sequentially added 1
Stir for 1.5 hours. To the reaction mixture, 10 ml of water was added to stop the reaction, 50 ml of water was added, and ethyl acetate (50 ml
× 2). The organic layer was washed successively with water (100 ml) and saturated brine, dried and evaporated under reduced pressure to give a crude product (277 mg). This was purified by silica gel chromatography (eluted with ethyl acetate: n-hexane = 1: 9) to obtain the title compound (140 mg). Rf: 0.
91 (methanol: chloroform = 1: 9) E.I. 1- (3-amino-5-benzyloxyphenyl)
Synthesis of Ethanone (Intermediate 60) Intermediate 59 (140 mg) was dissolved in methanol (20 ml), platinum oxide (5 mg) was added under an argon atmosphere, and the inside of the reaction system was replaced with hydrogen by cooling with ice. The mixture was stirred under ice cooling for 11.5 hours, the reaction system was replaced with argon, and chloroform (20 m
l) was added. The catalyst was filtered off, and the filtrate was evaporated under reduced pressure to give the title compound (116 mg). Rf: 0.82
(Methanol: chloroform = 1: 9)

F. 1- [3-benzyloxy-5-
Synthesis of [(Methylsulfonyl) amino] phenyl] ethanone (Intermediate 61) A. Larsen et al., J. Am. Med. C
hem. , 10, 462-472 (1967), the reaction and treatment are carried out according to the method described in Intermediate 60.
(116 mg) and methanesulfonyl chloride (40μ
l) to silica gel chromatography (methanol:
The title compound (142 mg) was obtained after purification with chloroform = 5:95 elution. Rf: 0.47 (methanol:
Chloroform = 1: 9) G.I. 2-Bromo-1- [3-benzyloxy-5-
Synthesis of [(methylsulfonyl) amino] phenyl] ethanone (Intermediate 62) Intermediate 6 was prepared in the same manner as in the method described in Step A of Example 29.
The title compound (172 mg) was obtained from 1 (140 mg) and cupric bromide (223 mg). Rf: 0.78 (ethyl acetate: n-hexane = 1: 1)

H. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-Hydroxyethyl] -3-benzyloxyphenyl] methanesulfonamide Intermediate 62 (17) according to the method described in Example 1, Step D.
0 mg) and intermediate 2 (95 mg) to give the title compound (55
mg). Rf: 0.28 (methanol: chloroform = 1: 9)

Example 62 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -3-hydroxyphenyl] methanesulfonamide / hydrochloric acid Salt According to the method described in Example 2, the compound of Example 61 (5
5 mg) was hydrolyzed with 10% palladium / carbon (27.5 mg) to obtain the title compound (30.6 mg).
However, after converting the crude product into a hydrochloride by a conventional method, methanol-
Recrystallized from ethyl acetate. Rf: 0.05 (methanol: chloroform = 1: 9)

Example 63 (±) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide / hydrochloric acid Salt A. Synthesis of 1- (2-hydroxy-3-nitrophenyl) ethanone (intermediate 63), 1- (2-hydroxy-5-nitrophenyl) ethanone (intermediate 64) 2-hydroxyacetophenone (13.2 g, Aldrich) (Made by) was dissolved in concentrated sulfuric acid (140 ml) under ice cooling, and potassium nitrate (9.66 g) was added. Stir for 105 minutes at 10 ° C to 15 ° C and further potassium nitrate (total 2.8 g)
Was added in 3 portions over 8 hours until the raw material was consumed. After further ice cooling and stirring for 14 hours, the reaction mixture was iced.
Pour into a mixture of water (2 L) and extract with ethyl acetate (500 m
1 × 2), the organic layer was washed with saturated brine, dried and evaporated under reduced pressure to give a crude product (19.23 g). This was purified by silica gel chromatography to obtain an intermediate 64 (6.0 g) from a fraction eluted with a mixed solvent of ethyl acetate: n-hexane = 1: 9, and ethyl acetate: n-hexane =
Intermediate 63 (9.5 g) was obtained from the 1: 4 mixed solvent elution fraction. (Intermediate 63) Rf: 0.19 (ethyl acetate: n-hexane = 1: 4) (Intermediate 64) Rf: 0.49 (ethyl acetate: n-hexane = 1: 4)

B. Synthesis of 1- (2-methoxy-3-nitrophenyl) ethanone (Intermediate 65) Intermediate 63 (2.29 g) was dissolved in anhydrous dimethylformamide (20 ml), and anhydrous potassium carbonate (5.2 g) was added at room temperature. , Methyl iodide (1.56 ml) were sequentially added, and the mixture was stirred for 18 hours. 50 ml of water was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate (50 ml × 6). The organic layer was washed with saturated brine, dried and evaporated under reduced pressure to give a crude product (2.29 g). This was further dried under reduced pressure with a vacuum pump to obtain the title compound (1.87 g). Rf:
0.58 (ethyl acetate: n-hexane = 1: 2) C.I. Synthesis of 1- (3-amino-2-methoxyphenyl) ethanone (Intermediate 66) Intermediate 65 (1.87 g) was added to methanol (150 ml).
Was dissolved in and was added with platinum oxide (90 mg) under an argon atmosphere, and the inside of the reaction system was replaced with hydrogen by cooling with ice. The mixture was stirred at room temperature for 5 hours, the reaction system was replaced with argon, and chloroform (50 m
l) was added. The catalyst was filtered off and the filtrate was evaporated under reduced pressure to give the title compound (1.59 g). Rf: 0.74
(Methanol: chloroform = 1: 9)

D. 1- [2-methoxy-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 6
7) Synthesis of A. Larsen et al. Med. C
hem. Prepared from intermediate 66 (1.59 g) and methylsulfonyl chloride (750 μl) according to the method reported by Chem., 10, 462-472 (1967). However, the following changes were made in the purification from the reaction mixture.
The reaction was stopped with water (50 ml), stirred for 12 hours, extracted with ethyl acetate (50 ml × 1, 30 ml × 2), the organic layer was washed successively with 1N hydrochloric acid (25 ml × 2) and saturated brine, and dried. And the solvent was distilled off under reduced pressure to give the title compound (1.9
3 g) was obtained. Rf: 0.55 (methanol: chloroform = 1: 19)

E. Synthesis of 1- [2-methoxy-3- [N-benzyl-N- (methylsulfonyl) amino] phenyl] ethanone (Intermediate 68) Intermediate 67 (1.93 g) was dissolved in anhydrous dimethylformamide (15 ml). At room temperature, anhydrous potassium carbonate (3.32 g), benzyl bromide (1.9 ml) and sodium iodide (1.2 g) were sequentially added, and the mixture was stirred for 14 hours.
Water (50 ml) was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate (40 ml × 3). The organic layer is water (50m
1 × 2) and a saturated saline solution were successively washed, dried and the solvent was distilled off under reduced pressure to obtain a crude product (3.04 g). This was subjected to silica gel chromatography (ethyl acetate: n-hexane =
The product was purified by elution with 1: 4 to 1: 2), and the fractions containing the desired product were concentrated and recrystallized from ethyl acetate-n-hexane to obtain the title compound (2.00 g). Rf: 0.75 (methanol: chloroform = 1: 19)

F. 2-Bromo-1- [2-methoxy-3
-[N-benzyl-N- (methylsulfonyl) amino]
Synthesis of Phenyl] ethanone (Intermediate 69) Intermediate 6 was prepared in the same manner as described in Example 29 Step A.
The title compound (438 mg) was obtained from 8 (333 mg) and cupric bromide (491 mg). Rf: 0.36 (ethyl acetate: n-hexane = 1: 2) G.I. (±) -N-benzyl-N- [3- [2- [2-
Synthesis of (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-methoxyphenyl] methanesulfonamide (Intermediate 70) Intermediate 69 (according to the method described in Example 1, Step D). 43
8 mg) and intermediate 2 (215 mg) to give the title compound (1
50 mg). Rf: 0.74 (methanol: chloroform = 1: 9)

H. (±) -N-benzyl-N- [3-
[2- [2- (9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride (Intermediate 7
Synthesis of 1) Intermediate 70 (100 mg) in anhydrous dichloromethane (10
ml) solution, a 1M dichloromethane solution of boron tribromide (0.60 ml, manufactured by Aldrich) was added dropwise under cooling with a dry ice-acetone refrigerant. The mixture was stirred for 30 minutes as it was, and further stirred for 30 minutes under ice cooling. Saturated aqueous sodium hydrogen carbonate was added to the reaction mixture to stop the reaction, and the mixture was extracted with ethyl acetate (30 ml × 4). The organic layer was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue was chromatographed on silica gel (chloroform: ethyl acetate: concentrated aqueous ammonia 10%).
Contained methanol = eluted from 16: 3: 1 to 6: 3: 1)
The free amine (69 mg) of the title compound was obtained. Rf: 0.47 (methanol: chloroform = 1:
9)

This was converted to a hydrochloride using 0.1N HCl / ethanol and recrystallized from methanol-ethyl acetate to obtain the title compound (28 mg). At this time, the title compound (38 mg) was obtained from the filtrate. I. Synthesis of (±) -N- [3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride Example 2 Intermediate 71 and the filtrate recovery product (total 55 mg) were treated with 10% palladium / carbon (55 m
g) and hydrogenolysis for 13 hours to give a crude product (25 m
g) was recrystallized from methanol-ethyl acetate to obtain the title compound (17.3 mg). Rf: 0.41 (methanol: chloroform = 1: 9)

Example 64 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -4-hydroxyphenyl] methanesulfonamide / hydrochloric acid Salt A. Synthesis of 1- (2-methoxy-5-nitrophenyl) ethanone (Intermediate 72) Intermediate 63 (2.36 g) of Example 63 Step A was reacted and treated according to Example 63 Step B to give the title. A compound (2.50 g) was obtained. Rf: 0.37 (ethyl acetate:
n-hexane = 1: 2) B.I. Synthesis of 1- (5-amino-2-methoxyphenyl) ethanone (Intermediate 73) Intermediate 72 (2.50 g) was reacted and treated according to Example 63 Step C to give the title compound (2.13 g). Got
Rf: 0.38 (methanol: chloroform = 1: 1)
9) C.I. 1- [2-methoxy-5-[(methylsulfonyl)
Synthesis of Amino] phenyl] ethanone (Intermediate 74) Intermediate 73 (2.13 g) was reacted and treated according to Example 63 Step D to obtain the title compound (2.656 g). Rf: 0.35 (methanol: chloroform = 1:
19)

D. Synthesis of 1- [2-methoxy-5- [N-benzyl-N- (methylsulfonyl) amino] phenyl] ethanone (Intermediate 75) Intermediate 74 (2.65 g) was reacted according to Example 63 Step E. -Processing was performed to obtain a crude product (4.29 g). This was subjected to silica gel chromatography (ethyl acetate: n-
Hexane = 1: 4-1: 1-2: 2: 3)),
The fraction containing the desired product was concentrated and recrystallized from ethyl acetate-n-hexane to obtain the title compound (2.553 g). R
f: 0.68 (methanol: chloroform = 1: 19) E.I. Synthesis of 2-Bromo-1- [2-methoxy-5- [N-benzyl-N- (methylsulfonyl) amino] phenyl] ethanone (Intermediate 76) In a manner similar to that described in Example 29 Step A, Intermediate 7
The title compound (436 mg) was obtained from 5 (333 mg) and cupric bromide (491 mg). Rf: 0.28 (ethyl acetate: n-hexane = 1: 2) F.I. (±) -N-benzyl-N- [5- [2- [2-
Synthesis of (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -4-methoxyphenyl] methanesulfonamide (Intermediate 77) Intermediate 76 (according to the method described in Step D of Example 1). 43
6 mg) and intermediate 2 (215 mg) to give the title compound (7
0 mg). Rf: 0.52 (methanol: chloroform = 1: 9)

G. (±) -N-benzyl-N- [5-
[2- [2- (9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -4-hydroxyphenyl] methanesulfonamide hydrochloride (Intermediate 7
Synthesis of 8) Intermediate 77 (70 mg) was reacted and treated according to Example 63 Step H, and subjected to silica gel chromatography (chloroform: ethyl acetate: concentrated aqueous ammonia 10% in methanol = 16: 3: 1 to 6 :). Purification by elution (3: 1) gave the free base (39 mg) of the title compound. Rf:
0.50 (methanol: chloroform = 1: 9) This was made into a hydrochloride using 0.1N hydrogen chloride / ethanol and recrystallized from methanol-ethyl acetate to obtain the title compound (17 mg). At this time, 16 mg of a crude product containing the title compound was obtained from the filtrate. H. Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -4-hydroxyphenyl] methanesulfonamide hydrochloride In Example 2 According to the method described, the intermediate 78 and the filtrate recovery product (total 30 mg) were treated with 10% palladium / carbon (30 m
g) was used for hydrogenolysis for 13 hours and the crude product was triturated from diethyl ether, filtered and collected to give the title compound (9
mg). Rf: 0.34 (methanol: chloroform = 1: 9)

Example 65 (±) -N-methyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxy] benzenesulfonamide A. Synthesis of N-methyl- (2-benzyloxy-4-acetylbenzene) sulfonamide (Intermediate 80) 1- (3-Amino-4-benzyloxyphenyl) ethanone (2.41 g) (Rasen (A.A. Larse
n) et al. Med. Chem. , 10,462-47
2 (prepared by the method reported by 1967)) was dissolved in acetic acid (5 ml) and 5 ml of concentrated hydrochloric acid was added. -10 ° C
An aqueous solution of sodium nitrite (1.0 g) (7
ml) was added over 50 minutes. The mixture was stirred for another 28 minutes under ice cooling, and thionyl chloride (3.5 ml) was added to acetic acid (6.5 ml).
The solution and an aqueous solution (3 ml) of cupric chloride dihydrate (720 mg) were sequentially added, and the mixture was stirred for 6 hours while returning to room temperature. The precipitate was collected by filtration, dissolved in chloroform, washed with water, dried, and concentrated to 50 ml under reduced pressure to give 2-benzyloxy-5-.
A chloroform solution of acetylbenzenesulfonyl chloride (Intermediate 79) was prepared. A 40% methylamine aqueous solution (1.0 ml) was added thereto, and the mixture was stirred at room temperature for 16.5 hours. Water (50 ml) was added to the reaction mixture, and the organic layer was separated. The aqueous layer was extracted once with chloroform (50 ml), and the combined organic layers were washed with saturated brine, dried and evaporated under reduced pressure. Purification by silica gel chromatography (chloroform-methanol: chloroform = 1: 19) gave the title compound (200 mg). Rf: 0.05 (chloroform)

B. N-methyl- [2-benzyloxy-
Synthesis of 4- (2-bromoacetyl) benzene] sulfonamide (Intermediate 81) Intermediate 8 was prepared in a manner similar to that described in Example 29, Step A.
The title compound (248 mg) was obtained from 0 (200 mg) and cupric bromide (310 mg). Rf: 0.83 (ethyl acetate: n-hexane = 1: 1) C.I. (±) -N-methyl- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Synthesis of Hydroxyethyl] -2-benzyloxy] benzenesulfonamide As described in Example 1, Step D, except silica gel chromatography (methanol: ethyl acetate = 1: 19 to 1: 9) was used to purify the crude product. Intermediate 81 (2
The title compound (118 mg) was obtained from 48 mg) and the intermediate body 2 (136 mg). Rf: 0.55 (methanol:
Chloroform = 1: 9)

Example 66 (±) -N-methyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide Hydrochloride According to the method described in Example 2, the compound of Example 65 (1
10 mg) was hydrolyzed with 10% palladium / carbon (55 mg) for 1 hour, hydrochloric acid-chlorinated and recrystallized from methanol-ethyl acetate to obtain the title compound (39 mg). Rf: 0.08 (methanol: chloroform = 1:
9)

Example 67 (±) -2- [N- [2- (9H-carbazole-2-
Iloxy) ethyl] amino] -1- [4-hydroxy-3- (hydroxymethyl) phenyl] ethanol.hydrochloride A. Synthesis of 2-benzyloxy-5-acetylbenzoic acid methyl ester (Intermediate 82) 5-Acetylsalicylic acid methyl ester (1.94 g,
Anhydrous dimethylformamide (manufactured by AVOCADO) (1
5 ml) and dissolved at room temperature in anhydrous potassium carbonate (4.2
g), benzyl bromide (2.5 ml) and sodium iodide (3.3 g) were sequentially added, and the mixture was stirred for 60 hours. 50 ml of water was added to the reaction mixture to stop the reaction, and the mixture was ice-cooled and stirred. The precipitate was collected by filtration, washed with water, and dried under reduced pressure at 50 ° C. (2.83).
g). This was recrystallized from toluene-n-hexane to obtain the title compound (2.54g). Rf: 0.32 (ethyl acetate: n-hexane = 1: 2) B.I. 2-benzyloxy-5- (2-bromoacetyl)
Synthesis of Benzoic Acid Methyl Ester (Intermediate 83) Intermediate 8 was prepared in the same manner as in Example 29 Step A.
2 (1.42g) and cupric bromide (2.46g) reacted
Workup gave the title compound (566 mg). Rf: 0.
71 (methanol: chloroform = 1: 19)

C. (±)-[5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Synthesis of Hydroxyethyl] -2-benzyloxy] benzoic acid methyl ester (Intermediate 84) Intermediate 2 (154) according to the method described in Example 1, Step D.
mg), triethylamine (150 μl), intermediate 83
(191 mg) and sodium borohydride (151
The title compound (80 mg) was obtained from (mg). Rf: 0.
24 (methanol: chloroform = 1: 9) D.I. (±) -2- [N- [2- (9H-carbazole-
Synthesis of 2-yloxy) ethyl] amino] -1- [4-benzyloxy-3- (hydroxymethyl) phenyl] ethanol (Intermediate 85) Lithium aluminum hydride (2 mg) in anhydrous tetrahydrofuran (5 ml) suspension. , Ice-cooled intermediate 84 (3
A solution of 4 mg) in anhydrous tetrahydrofuran (5 ml) was added. After stirring for 30 minutes, the reaction was stopped by adding ethyl acetate (1 ml) and 1N hydrochloric acid (1 ml), the pH of the aqueous layer was adjusted to 10, and the mixture was extracted with ethyl acetate (20 ml × 2). After drying the organic layer, the solvent was evaporated under reduced pressure, and the residue (28 mg) was subjected to silica gel chromatography (methanol: chloroform = 1: 1).
9 to 1: 7) to give the title compound (24 mg). Rf: 0.05 (methanol: chloroform = 1:
9)

E. (±) -2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1-
Synthesis of [4-Hydroxy-3- (hydroxymethyl) phenyl] ethanol Hydrochloride According to the procedure described in Example 2, Intermediate 85 (24 m
g) was added to methanol (5 ml) and 10% palladium /
Hydrogenolysis was performed for 2.5 hours using carbon (12 mg), followed by hydrochloric acid chloride according to a conventional method and trituration from ethyl acetate to obtain the title compound (8.9 mg). Rf: 0.21 (methanol: chloroform = 1: 7)

Example 68 (±) -N- [3- [2- [2- [9H-6- (Acetylamino) carbazol-2-yloxy] ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide -Hydrochloride A. (±) -N- [3- (2-Bromo-1-hydroxyethyl) phenyl] methanesulfonamide (Intermediate 8
Synthesis of 6) Intermediate 14 (45 g) was reacted and treated according to the synthesis method of Intermediate 41 to obtain the title compound (50.76 g).
Rf: 0.27 (methanol: chloroform = 1: 1)
0) B. (±) -N- [3- [2-Iodo-1- (triethylsilyloxy) ethyl] phenyl] methanesulfonamide (Intermediate 87) Synthesis of Intermediate 86 (50. 1g)
Was dissolved in dry acetone (944 ml), sodium iodide (257.57 g) was added, and the mixture was stirred with heating under reflux for 2.5 hr. After cooling to room temperature and filtration, the filtrate was concentrated to dryness under reduced pressure. The residue was mixed with dichloromethane (720 ml) and water (720 ml).
The organic layer was washed with a 23.5 (w / w)% sodium hydrogen sulfite aqueous solution (twice), water and saturated saline in this order, dried and the solvent was distilled off under reduced pressure. Further, it was dried under reduced pressure with a vacuum pump to obtain a starch syrup (51.61 g). This was dissolved in anhydrous dimethylformamide (351 ml) at room temperature, imidazole (28.3 g) and 4-dimethylaminopyridine (1.61 g) were added, and the mixture was stirred for 15 minutes. Chlorotrimethylsilane (27.04 ml) was added all at once, and the mixture was stirred at room temperature for 40 minutes. Ethyl acetate (840 ml) and n
-Diluted with heptane (336 ml) and water (420 ml),
2% copper sulfate aqueous solution (420 ml x 2), water (420 m
1) and then washed successively with saturated saline (420 ml), dried and evaporated under reduced pressure to give the title compound (68.25 g). Rf: 0.48 (methanol: chloroform = 1:
10)

C. Synthesis of 4-Acetylaminocyclohexanone (Intermediate 88) Chromium trioxide (9.28 g) was added to a suspension of trans-4-acetamidocyclohexanol (20.85 g) in water (21.6 ml) under ice cooling. ), Concentrated sulfuric acid (8.1m
1), Jones's reagent prepared from water (33.4 ml) was added over 8 minutes. The mixture was stirred for 5 hours under ice cooling and left in the refrigerator for 2 nights. Add this to chloroform (70 ml x 1
It was extracted with 0), washed with saturated aqueous sodium hydrogen carbonate, dried, and the solvent was distilled off under reduced pressure. Further dried under reduced pressure at room temperature, the title compound (8.
45 g) was obtained. Rf: 0.40 (methanol: chloroform = 1: 10) D.I. (±) -3-Acetylamino-7-methoxy-1,
2,3,4-Tetrahydrocarbazole (Intermediate 89)
Synthesis of 3-methoxyphenylhydrazine hydrochloride (9.77 g,
ACROS) and intermediate 88 (8.58 g) were dissolved in ethanol (83 ml) to prepare 4N hydrogen chloride / 1,4-
Dioxane (35 ml, manufactured by Aldrich) was added and the mixture was heated under reflux for 3 hours. The mixture was cooled to room temperature, the precipitate was filtered off, and the filtrate was evaporated under reduced pressure. Ethanol-n-heptane was added to the residue, concentrated to dryness, dissolved in a small amount of ethanol, water was added to triturate the precipitate, and the precipitate was collected by filtration, washed with water, and dried under reduced pressure at 42 ° C. This was triturated with a small amount of ethanol, crystallized from ethyl acetate (200 ml), collected by filtration, washed with ethyl acetate, and dried under reduced pressure at room temperature to give the title compound (5.
188 g (primary crystal) was obtained. Rf: 0.45 (methanol: chloroform = 1: 10)

E. Synthesis of 9H-6-acetylamino-2-methoxycarbazole (Intermediate 90) Intermediate 89 (5.188 g) and 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (9) under an argon atmosphere. (.459 g, 97%) was heated to reflux in benzene for 7.5 hours. The reaction mixture was filtered while hot and the residue was washed with hot benzene. The filtrate and the washing solution were combined and the solvent was distilled off under reduced pressure. Ethanol was added to the residue and the precipitate was collected by filtration to give the title compound (269 mg, primary crystal). Rf: 0.3
9 (methanol: chloroform = 1: 10) F.I. Synthesis of 9H-6-acetylamino-2-hydroxycarbazole (Intermediate 91) Intermediate 90 (269 mg) was melted at 180 ° C. Pyridine hydrochloride (from 5 ml of pyridine and 5 ml of concentrated hydrochloric acid to 18).
It was heated and dehydrated at 0 ° C. for 1.5 hours and prepared), and stirred for 4 hours under heating under reflux. It was poured into 100 ml of ice and extracted with ethyl acetate. The aqueous layer was adjusted to pH 7 and extracted with ethyl acetate. The organic layers were combined, washed with saturated brine, dried, and the solvent was evaporated under reduced pressure. The obtained residue (182.1 mg) was dissolved in pyridine (5 ml), acetic anhydride (1 ml) was added, and the mixture was stirred at room temperature for 12 hr. The mixture was diluted with water (50 ml), extracted with ethyl acetate, washed with water, washed with saturated brine, dried and evaporated under reduced pressure. The residue obtained is treated with methanol (4 m
1, MS3A product), water (1 ml) and 5N sodium hydroxide solution (0.5 ml) were added, and the mixture was stirred at room temperature for 45 minutes.
Stirred for minutes. Dilute with water (40 ml) and p with 1N hydrochloric acid.
It was adjusted to H3 and extracted three times with ethyl acetate. The organic layer was washed with saturated brine, dried and evaporated under reduced pressure to give the title compound (163.8 mg). Rf: 0.10 (methanol: chloroform = 1: 10)

G. 9H-6-acetylamino-2- (2
Synthesis of -benzyloxycarbonylaminoethoxy) carbazole (Intermediate 92) Intermediate 91 (16) according to the method described in Example 1, Step B.
1 mg) and potassium carbonate (470 mg) in dimethylformamide (1.7 ml) was added with Intermediate 0 (520 m).
g) was added, and the mixture was stirred at room temperature for 11.5 hours and further heated and stirred at 50 ° C. for 8 hours. Ethyl acetate and water were added, and the mixture was extracted twice with ethyl acetate, washed with water, washed with saturated brine, dried, and evaporated under reduced pressure to remove the solvent, followed by column chromatography (methanol: chloroform = 3: 100 to 6: 100). Purification gave the title compound (105.8 mg). Rf: 0.
37 (methanol: chloroform = 1: 10) 2- (9H-6-acetylaminocarbazole-2
Synthesis of -yloxy) ethylamine (Intermediate 93) To intermediate 92 (105.8 mg) was added 30% hydrobromic acid acetic acid solution (2.1 ml), and the mixture was stirred at room temperature for 1.5 hours.
Diethyl ether (50 ml) was added, and the deposited precipitate was collected by filtration. After dissolving in water and adjusting the pH to 10 by adding aqueous NaOH, the mixture was extracted with ethyl acetate, the organic layer was dried, and the solvent was evaporated under reduced pressure to give the title compound (80.1 mg). Rf:
0.05 (methanol: chloroform = 1: 5)

I. (±) -N- [3- [2- [2- [9
Synthesis of H-6- (acetylamino) carbazol-2-yloxy] ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride Intermediate 87 (117.5 mg) and Intermediate 93 (80.1).
mg) was dissolved in anhydrous dimethylacetamide (0.5 ml), Hunig's base (493 μl) was added, and the mixture was stirred at 60 ° C. for 27 hours under an argon atmosphere. The mixture was cooled to room temperature, diluted with ethyl acetate, washed successively with water (twice) and saturated brine and dried, and the solvent was evaporated under reduced pressure. The residue was dissolved in ethyl acetate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. This was roughly purified by silica gel chromatography (methanol: chloroform = 5: 100 to 1:10). The obtained fractions containing the ninhydrin positive product were combined and concentrated under reduced pressure to dryness. The obtained viscous product (49.6 mg) was dissolved in anhydrous tetrahydrofuran (2.7 ml) and acetic acid (35 μm) was added.
1) and 1M tetrabutylammonium fluoride / tetrahydrofuran (535 μl) were added and the mixture was tightly closed and at room temperature 1
Stirred for hours. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate, washed with saturated brine, dried, and the solvent was evaporated under reduced pressure. The residue was chromatographed on silica gel (methanol: chloroform = 1: 10, low polar impurities eluted, concentrated ammonia water: methanol: chloroform = 1: 9: 50).
The free amine (30.5 mg) of the title compound was obtained. This was hydrochloric acid-chlorinated by a conventional method, dissolved in a small amount of methanol, diluted with ethyl acetate, crystallized and collected by filtration to obtain the title compound (2
9.5 mg) was obtained. Rf: 0.14 (methanol: chloroform = 1: 5)

Example 69 (R) -N- [5- [2- [2- (dibenzofuran-3
-Yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride In accordance with the method described in Example 12, Intermediate 19 (220 m)
g) and intermediate 5 (121.7 mg) to give the title compound (3
7.6 mg) was obtained. Retention time: R body 36.3 minutes, (S body 41.7 minutes); Analysis conditions: Column: 4.6 mm ID x 150 mm CHIR
Two ALCEL OJ-R (Daicel); mobile phase 0.
5M NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 70 (R) -N- [3- [2- [2- (dibenzofuran-3
-Yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide hydrochloride In accordance with the method described in Example 14, Intermediate 26 (815m)
g) and intermediate 5 (455 mg) to give the title compound (16
7.0 mg) was obtained. Retention time: R body 28.7 minutes, (S body 25.4 minutes); Analysis conditions: Column: 4.6 mm ID x 150 mm CHIR
ALCEL OJ-R (Daicel); Mobile phase 0.5M
NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 254
nm; temperature 40 ° C

Example 71 (R) -N- [3- [2- [2- (9H-7-acetylaminofluoren-2-yloxy) ethylamino]-
1-Hydroxyethyl] phenyl] methanesulfonamide hydrochloride In accordance with the method described in Example 14, Intermediate 26 (815 m
The title compound (55.5 mg) was obtained from g) and intermediate 17 (564.6 mg). Retention time: R body 77.6 minutes, (S body 64.7 minutes); Analysis conditions: Column: 4.6 mm ID x 150 mm CHIR
Two ALCEL OJ-R (Daicel); mobile phase 0.
5M NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (8: 2); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 72 (R) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride Intermediate 19 (642 m according to the method described in Example 12)
g) and intermediate 39 (380 mg) to give the title compound (22
3.2 mg) was obtained. Retention time: R body 36.3 minutes, (S body 38.6 minutes); Analysis conditions: Column: 4.6 mm ID x 150 mm CHIR
Two ALCEL OJ-R (Daicel); mobile phase 0.
5M NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 73 (R) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N -Dimethylsulfamide / hydrochloride A. (R) -N '-[5- (2-Bromo-1-hydroxyethyl) -2-benzyloxyphenyl] -N, N-
Synthesis of dimethylsulfamide Intermediate 40 (1.058) was prepared according to the synthetic method of Intermediate 19.
The title compound (925.7 mg) was obtained from g). Retention time: R body 19.6 minutes, (S body 17.4 minutes); Analysis conditions: Column: 4.6 mm ID x 250 mm CHIR
ALCEL OJ (Daicel); mobile phase: ethanol / n-hexane (1: 1); flow rate 0.7 ml / min; detection 254 nm; T.

B. (R) -N '-[5- [2-iodo-
Synthesis of 1- (triethylsilyloxy) ethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 94) Similar to the synthesis of Intermediate 42 (racemic), the above Intermediate (92
The title compound (1.27 g) was obtained in 2 steps from 5 mg). C. (R) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-benzyloxyphenyl] -N, N- Dimethylsulfamide (Intermediate 9
Synthesis of 5) Intermediate 94 (590 mg), similar to the synthesis of Intermediate 43,
From Intermediate 2 (294 mg) to the title compound (262.2 m
g) was synthesized. Rf: 0.54 (methanol: chloroform = 1: 10)

D. (R) -N '-[5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 9
Synthesis of 6) The title compound (83.7 mg) was obtained from Intermediate 95 (120 mg) according to the method described in the synthesis of Example 42. E. FIG. (R) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide hydrochloride Synthesis of Salt Intermediate 96 (82 mg) was reacted and treated according to the method described in Example 25 to obtain the title compound (75.6 mg). Retention time: R form 38.0 minutes, (S form 47.7 minutes); Analysis conditions: Column: 4.6 mm ID x 150 mm CHIR
Two ALCEL OJ-R (Daicel); mobile phase 0.
5M NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 74 (S) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N -Dimethylsulfamide / hydrochloride A. (S) -N '-[5- (2-Bromo-1-hydroxyethyl) -2-benzyloxyphenyl] -N, N-
Synthesis of dimethylsulfamide Intermediate 40 (1.05 g) was prepared according to the synthetic method of Intermediate 19.
To the title compound (928.
1 mg) was obtained. Retention time: (R body 19.6 minutes), S body 17.4 minutes; analysis conditions: column 4.6 mm ID x 250 mm CHIRA
LCEL OJ (Daicel); Mobile phase ethanol: n
-Hexane (1: 1); flow rate 0.7 ml / min; detection 25
4 nm; temperature R.I. T.

B. (S) -N '-[5- [2-iodo-
Synthesis of 1- (triethylsilyloxy) ethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 97) Similar to the synthesis of Intermediate 42 (racemic), the above Intermediate (86
The title compound (1.18 g) in 2 steps from 8.1 mg)
I got C. (S) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1- (triethylsilyloxy) ethyl] -2-benzyloxyphenyl] -N, N- Dimethylsulfamide (Intermediate 9
Synthesis of 8) Intermediate 97 (300 mg), similar to the synthesis of Intermediate 43,
From Intermediate 2 (144 mg) to the title compound (120.8 m
g) was obtained.

D. (S) -N '-[5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxyphenyl] -N, N-dimethylsulfamide (Intermediate 9
Synthesis of 9) Intermediate 98 (120.8 mg) was prepared according to the method described in the synthesis of the compound of Example 42 to give the title compound (65.8 mg).
I got E. FIG. (S) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide hydrochloride Synthesis of Salt Intermediate 99 (65.8 mg) was reacted and treated according to the method described in Example 25 to obtain the title compound (42.3 mg). Retention time: (R body 38.5 minutes), S body 47.7 minutes; analysis conditions: column: 4.6 mm ID x 150 mm CHIR
Two ALCEL OJ-R (Daicel); mobile phase 0.
5M NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 75 (R) -N '-[5- [2- [2- (dibenzofuran-
3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide.hydrochloride Intermediate 94 (240 m) according to the method described in Example 73.
g) and intermediate 5 (115.4 mg) to give the title compound (3
2.9 mg) was obtained. Retention time: R body 18.3 minutes, (S body 21.5 minutes); Analysis conditions: Column: 4.6 mm ID x 150 mm CHIR
Two ALCEL OJ-R (Daicel); mobile phase 0.
5M NaClO4-HClO4 buffer (pH 2.0) / acetonitrile (6: 4); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 76 (S) -N '-[5- [2- [2- (dibenzofuran-
3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide.hydrochloride Intermediate 97 (240 m) according to the method described in Example 74.
g) and intermediate 5 (114.4 mg) to give the title compound (3
9.6 mg) was obtained. Retention time: (R body 18.3 minutes), S body 21.5 minutes; analysis conditions; column 4.6 mm ID x 150 mm CHIRA
LCEL OJ-R (Daicel) 2; mobile phase 0.5
MNaClO4-HClO4 buffer (pH 2.0) / acetonitrile (6: 4); flow rate 0.5 ml / min; detection 25
4 nm; temperature 40 ° C

Example 77 (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide
Hydrochloride A. Synthesis of (R) -N- [5- [2-Bromo-1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide (Intermediate 100) Intermediate 9 (1.53 g) was synthesized as Intermediate 19. The reaction treatment was carried out according to the procedure described above to give the title compound (1.79 g). Retention time: R body 31.1 minutes, (S body 33.3 minutes); Analysis conditions: Column 4.6 mm ID x 250 mm CHIRA
LPAK AD (Daicel); mobile phase ethanol: n
-Hexane (1: 1); flow rate 0.3 ml / min; detection 25
4 nm; temperature R.I. T. B. (R) -N- [5- [2-
Iodo-1-[(triethylsilyl) oxy] ethyl]
Synthesis of 2-fluorophenyl] methanesulfonamide (Intermediate 101) Intermediate 100 (1.78 g) was reacted and treated according to the method of synthesizing Intermediate 20 to obtain the title compound (2.29 g).

C. (R) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-[(triethylsilyl) oxy] ethyl] -2-fluorophenyl] methanesulfonamide (Intermediate 102)
Synthesis of Intermediate 101 (445 mg) and Intermediate 2 (294 mg)
Was reacted and treated according to the method for synthesizing intermediate 21 to obtain the title compound (243.0 mg). Rf: 0.50 (methanol: chloroform = 1: 10) D.I. Synthesis of (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride Intermediate 102 ( 243 mg) was dissolved in anhydrous terrahydrofuran (15 ml), 4N hydrogen chloride / 1,4-dioxane (1 ml) was added, and the mixture was stirred at room temperature for 1 hr. The precipitate was collected by filtration, washed with tetrahydrofuran, and dried under reduced pressure at 40 ° C to obtain the title compound (96.8 mg). Retention time: R body 42.1 minutes, (S body 38.5 minutes); analysis conditions: column 4.6 mm ID x 150 mm CHIRA
LCEL OJ-R (Daicel) 2; mobile phase 0.5
MNaClO4-HClO4 buffer (pH 2.0): acetonitrile (7: 3); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 78 (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide
Hydrochloride A. Synthesis of (S) -N- [5- [2-Bromo-1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide (Intermediate 103) Intermediate 9 (1.53 g) was synthesized as Intermediate 19. According to the above, the S-form was used as an asymmetric catalyst for reaction and treatment to obtain the title compound (1.36 g). Retention time: (R body 31.1 minutes), S body 33.3 minutes; analysis conditions: column 4.6 mm ID x 250 mm CHIRA
LPAK AD (Daicel); mobile phase ethanol: n
-Hexane (1: 1); flow rate 0.3 ml / min; detection 25
4 nm; temperature R.I. T. B. (S) -N- [5- [2-
Iodo-1-[(triethylsilyl) oxy] ethyl]
Synthesis of 2-fluorophenyl] methanesulfonamide (Intermediate 104) Intermediate 103 (1.36 g) was subjected to a reaction treatment according to a method for synthesizing Intermediate 20 to give the title compound (1.85).
g) was obtained. C. (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-[(triethylsilyl) oxy] ethyl] -2-fluorophenyl] methanesulfonamide (intermediate Synthesis of body 105) Intermediate 104 (445 mg) and intermediate 2 (294 mg)
Was reacted and treated according to the method for synthesizing intermediate 21 to obtain the title compound (198.2 mg).

D. (S) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide hydrochloride Intermediate 105 (154.8 mg) was dissolved in anhydrous terrahydrofuran (6.8 ml) to prepare 4N hydrogen chloride / 1,4-
Dioxane (430 μl) was added, and the mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with tetrahydrofuran and 40 ° C.
After drying under reduced pressure, the title compound (109.0 mg) was obtained. Retention time: (R body 42.1 minutes), S body 38.5 minutes; analysis conditions; column 4.6 mm ID x 150 mm CHIRA
LCEL OJ-R (Daicel) 2; mobile phase 0.5
MNaClO4-HClO4 buffer (pH 2.0): acetonitrile (7: 3); flow rate 0.5 ml / min; detection 25
4 nm; temperature 40 ° C

Example 79 (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide
Hydrochloride A. Synthesis of (R) -N- [5- [2-Bromo-1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide (Intermediate 106) Intermediate 13 (800 mg) was prepared according to the method for synthesizing Intermediate 19. The reaction was processed to obtain the title compound (880 mg). Retention time: R body 14.1 minutes, (S body 16.8 minutes); Analysis conditions: Column 4.6 mm ID x 250 mm CHIRA
LPAK AD (Daicel); mobile phase ethanol: n
-Hexane (4: 1); flow rate 0.5 ml / min; detection 25
4 nm; temperature R.I. T. B. (R) -N- [5- [2-iodo-1-[(triethylsilyl) oxy] ethyl] -2-chlorophenyl]
Synthesis of Methanesulfonamide (Intermediate 107) Intermediate 106 (880 mg) was treated according to the method of synthesizing Intermediate 20 to obtain the title compound (1.24 g). C. (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-[(triethylsilyl) oxy] ethyl] -2-chlorophenyl] methanesulfonamide (intermediate 108) Intermediate 107 (489.4 mg) and Intermediate 2 (294 m
g) was reacted and treated according to the method for synthesizing intermediate 21 to obtain the title compound (135.9 mg). Rf: 0.57
(Methanol: chloroform = 1: 10)

D. (R) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide hydrochloride Intermediate 108 (73.2 mg) was dissolved in anhydrous terrahydrofuran (4.2 ml) and 4N hydrogen chloride / 1,4-dioxane (240 μl) was added. ) Was added and the mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with tetrahydrofuran and 40 ° C.
After drying under reduced pressure, the title compound (36.3 mg) was obtained. Retention time: R body 61.7 minutes, (S body 58.4 minutes); Analysis conditions: Column 4.6 mm ID x 150 mm CHIRA
LCEL OJ-R (Daicel) 2; mobile phase 0.5
MNaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 2
54nm; temperature 40 ° C

Example 80 (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide
Hydrochloride A. Synthesis of (S) -N- [5- [2-Bromo-1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide (Intermediate 109) Intermediate 13 (780 mg) was prepared according to the synthetic method of Intermediate 19. , S-isomer asymmetric catalyst was used for the reaction and treatment to obtain the title compound (753.4 mg). Retention time: (R body 14.1 minutes), S body 16.8 minutes; analysis conditions: column 4.6 mm ID x 250 mm CHIRA
LPAK AD (Daicel); mobile phase ethanol: n
-Hexane (4: 1); flow rate 0.5 ml / min; detection 25
4 nm; temperature R.I. T. B. (S) -N- [5- [2-iodo-1-[(triethylsilyl) oxy] ethyl] -2-chlorophenyl]
Synthesis of Methanesulfonamide (Intermediate 110) Intermediate 109 (753 mg) was subjected to a reaction treatment according to a method for synthesizing Intermediate 20 to obtain the title compound (1.06 g).

C. (S) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-[(triethylsilyl) oxy] ethyl] -2-chlorophenyl] methanesulfonamide (Intermediate 111)
Synthesis of Intermediate 110 (490 mg) and Intermediate 2 (294 mg)
Was reacted and treated according to the method of synthesizing intermediate 21 to obtain the title compound (111.2 mg). D. Synthesis of (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide hydrochloride Intermediate 111 (111) 0.2 mg) was dissolved in anhydrous terrahydrofuran (6.3 ml) and 4N hydrogen chloride / 1,4-
Dioxane (360 μl) was added and the mixture was stirred at room temperature for 1 hour. The precipitate is collected by filtration, washed with tetrahydrofuran and 40 ° C.
After drying under reduced pressure, the title compound (70.4 mg) was obtained. Retention time: (R body 61.7 minutes), S body 58.4 minutes; analysis conditions: column 4.6 mm ID x 150 mm CHIRA
LCEL OJ-R (Daicel) 2; mobile phase 0.5
MNaClO4-HClO4 buffer (pH 2.0) / acetonitrile (7: 3); flow rate 0.5 ml / min; detection 25
4 nm; temperature 40 ° C

Example 81 (R) -N-Methyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide Hydrochloride A. Synthesis of (R) -N-methyl- [5- (2-bromo-1-hydroxyethyl) -2-benzyloxy] benzenesulfonamide (Intermediate 112) Intermediate 81 (800 mg) was used to synthesize Intermediate 19. The reaction and treatment were conducted according to the above procedure to give the title compound (752.2 mg).
Rf: 0.15 (ethyl acetate: n-hexane = 1: 2) B.I. (R) -N-methyl- [5- (2-iodo-1-
Synthesis of [(triethylsilyl) oxy] ethyl] -2-benzyloxy] benzenesulfonamide (Intermediate 113) Intermediate 112 (462.8 mg) was reacted and treated according to the synthesis method of Intermediate 20 to give the title compound ( 587.9 mg) was obtained. Rf: 0.53 (ethyl acetate: n-hexane =
1: 2) C.I. (R) -N-methyl- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Synthesis of [(triethylsilyl) oxy] ethyl] -2-benzyloxy] benzenesulfonamide (Intermediate 114) Intermediate 113 (587.9 mg) and Intermediate 2 (295 m).
g) was reacted and treated according to the method for synthesizing intermediate 21 to obtain the title compound (265.3 mg). Rf: 0.45
(Methanol: chloroform = 1: 10)

D. (R) -N-methyl- [5- [2-
Synthesis of [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxy] benzenesulfonamide (Intermediate 115) Intermediate 114 (265.3 mg) in anhydrous tetrahydrofuran (13 (39.6 ml) solution, acetic acid (169.6 μl) and tetrabutylammonium 1M tetrahydrofuran solution (2.65 ml) were added, and the mixture was stirred at room temperature for 1 hr.
The reaction mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate and then saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was triturated from ethanol and collected by filtration to give the title compound (111.3 mg). Further, the residue obtained by concentrating the filtrate was purified by silica gel chromatography (methanol: chloroform = 7: 100) to obtain the title compound (59 mg). E. FIG. (R) -N-methyl- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Synthesis of Hydroxyethyl] -2-hydroxy] benzenesulfonamide hydrochloride According to the method described in Example 2, the intermediate 115 (166.
3 mg) was reacted and treated to give the title compound (136.3 m
g) was obtained. Retention time: R body 117.8 minutes, (S body 132.6 minutes);
Analysis conditions: Column 4.6 mm ID x 150 mm CHI
RALCEL OJ-R (Daicel) two; mobile phase 0.5M NaClO4-HClO4 buffer (pH 2.
0): acetonitrile (78:22); flow rate 0.5 ml
/ Min; Detection 254 nm; Temperature 40 ° C

Example 82 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-aminophenyl] methanesulfonamide
Hydrochloride A. 1- (4-acetylamino-3-nitrophenyl)
Synthesis of Ethanone (Intermediate 116) To a cooled acetic anhydride (4.5 ml), fuming nitric acid (0.5 ml) was added in 5 batches with stirring. 4-acetamido acetophenone (350
mg, Lancaster) acetic acid (1.8 ml) solution was added dropwise over 7 minutes. After stirring at 5 ° C for 38 minutes, water (10 ml) and ethyl acetate (10 ml) were added to separate the organic layer. The aqueous layer was further extracted with ethyl acetate (10 ml), and the combined organic layers were poured into saturated aqueous sodium hydrogen carbonate (200 ml) and stirred for 30 minutes. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (50 ml). The combined organic layers were dried and the solvent was evaporated under reduced pressure to give the title compound (0.41 g). Rf:
0.67 (methanol: chloroform = 1: 19) B.I. 1- (3-amino-4-acetylaminophenyl)
Synthesis of Ethanone (Intermediate 117) Intermediate 116 (410 mg) in methanol (40 ml)
Platinum oxide (20 mg) was added to the solution under an argon atmosphere, and the inside of the reaction system was replaced with hydrogen by cooling with ice. At room temperature 12.5
After stirring for an hour, the reaction system was replaced with argon and chloroform (20 ml) was added. The catalyst was filtered off and the filtrate was evaporated under reduced pressure. The residue was purified by silica gel chromatography (ethyl acetate: n-hexane = 3: 7-eluted with ethyl acetate only) to obtain the title compound (0.29 g). Rf:
0.06 (methanol: chloroform = 1: 19)

C. 1- [4-acetylamino-3-
Synthesis of [(Methylsulfonyl) amino] phenyl] ethanone (Intermediate 118) Larsen et al., J. Am. Med. C
hem. Prepared from intermediate 117 (290 mg) and methanesulfonyl chloride (118.5 μl) according to the method reported by Chem., 10, 462-472 (1967). However, the following changes were made in the purification from the reaction mixture. The reaction was quenched with water (10 ml), adjusted to pH 4 with 1N hydrochloric acid, and extracted with ethyl acetate (30 ml × 4). The organic layer was washed with saturated brine, dried and the solvent was distilled off under reduced pressure. The residue was purified by silica gel chromatography (methanol: chloroform = 3: 97) to obtain the title compound (315 mg). Rf: 0.37 (methanol:
Chloroform = 1: 19) D.I. 2-Bromo-1- [4-acetylamino-3-
Synthesis of [(methylsulfonyl) amino] phenyl] ethanone (Intermediate 119) Performed except that silica gel chromatography (ethyl acetate: n-hexane = 7: 13-eluted only with ethyl acetate) was performed in the purification from the reaction mixture. Example 29 In a manner similar to the method described in Step A of Intermediate 118 from Intermediate 118 (310 mg) and cupric bromide (570 mg), the title compound (267 m) was obtained.
g) was obtained. Rf: 0.68 (ethyl acetate: n-hexane = 1: 1)

E. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-acetylaminophenyl] methanesulfonamide (Intermediate 120) Carried out except that silica gel chromatography (methanol: chloroform = 5: 95 to 15:85) was used for purification of the crude product. Intermediate 1 according to the method described in Example 1, Step D
The title compound (53 mg) was synthesized from 19 (147 mg) and Intermediate 2 (90.5 mg). Rf: 0.17 (methanol: chloroform = 1: 9) F.I. Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-aminophenyl] methanesulfonamide hydrochloride Intermediate 120 ( 70 mg of 1,4-dioxane (8 m
1), concentrated hydrochloric acid (2 ml) was added, and the mixture was stirred with heating under reflux for 1 hour. The residue obtained by concentrating to dryness under reduced pressure (60
(mg) was recrystallized from methanol-ethyl acetate to obtain the title compound (13 mg). Rf: 0.05 (water: methanol: chloroform = 1: 15: 25)

Example 83 (±) -N-methyl-N-benzyl- [5- [2- [2
-(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide hydrochloride A. N-methyl-N-benzyl- (2-benzyloxy-5-acetyl) benzenesulfonamide (Intermediate 12
Synthesis of 1) In the same manner as in the method described in Step A of Example 65, 1- (3
Prepared from -amino-4-benzyloxyphenyl) ethanone. However, instead of adding 40% methylamine aqueous solution, N-methylbenzylamine (0.2 ml) and triethylamine (0.7 ml) were added to dichloromethane (10 m).
l) The reaction was carried out in the solvent for 31.5 hours. Water (10 ml) was added to the reaction mixture, and the organic layer was separated. The organic layer was washed with 1N hydrochloric acid and saturated brine, dried and evaporated under reduced pressure to give the title compound (398 mg). Rf: 0.36 (ethyl acetate: n-hexane = 1: 2)

B. Synthesis of N-methyl-N-benzyl- [2-benzyloxy-5- (2-bromoacetyl)] benzenesulfonamide (Intermediate 122) Silica gel chromatography (ethyl acetate: n-hexane = 1: 9 to 1: 1). Example 2 except that it was purified according to 4)
In the same manner as in the method described in 9th step A, the intermediate 121 (2
The title compound (228 mg) was obtained from 05 mg) and cupric bromide (246 mg). Rf: 0.50 (ethyl acetate:
n-hexane = 1: 2) C.I. (±) -N-methyl-N-benzyl- [5- [2-
Synthesis of [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-benzyloxy] benzenesulfonamide (Intermediate 123) Silica gel chromatography (first methanol : Chloroform = 5:95 elution, second time according to the method described in Step D of Example 1 except that methanol: ethyl acetate = 1: 19) was used.
mg) and Intermediate 2 (102 mg) to give the title compound (0.
20 g) was obtained. Rf: 0.25 (methanol: chloroform = 1: 19) D.I. (±) -N-methyl-N-benzyl- [5- [2-
[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy]
Synthesis of Benzenesulfonamide Hydrochloride Intermediate 123 (0.20) according to the method described in Example 2.
g) with 10% palladium / carbon (100 mg) 1
The product was hydrolyzed for a period of time, hydrochloric acid was salified, and recrystallized from methanol-ethyl acetate to obtain the title compound (62 mg). R
f: 0.31 (methanol: chloroform = 1: 9)

Example 84 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (hydroxymethyl) phenyl] methanesulfone Amide / hydrochloride A. Synthesis of 1- [4- (ethoxycarbonyl) phenyl] ethanone ethylene acetal (Intermediate 124) Under argon atmosphere, ethyl 4-acetylbenzoate (9.
61 g, Wako Pure Chemical Industries, Ltd. was dissolved in toluene (200 ml), ethylene glycol (20 ml) and p-toluenesulfonic acid hydrate (200 mg) were added, and Dean-Stark was added.
The mixture was heated under reflux for 24 hours while dehydrating with an apparatus. After cooling to room temperature, the toluene layer was washed successively with water (100 ml × 2) and saturated saline (100 ml), dried and then concentrated to dryness under reduced pressure to give the title compound (12.76 g). Rf: 0.58
(Ethyl acetate: n-hexane = 1: 2)

B. Synthesis of 1- [4- (hydroxymethyl) phenyl] ethanone (Intermediate 125) Under an argon atmosphere, lithium aluminum hydride (1.
90 g) was suspended in anhydrous tetrahydrofuran (120 ml), and a solution of intermediate 124 (12.76 g) in anhydrous tetrahydrofuran (40 ml) was added dropwise over 15 minutes under ice cooling, followed by stirring for 90 minutes. Ethyl acetate (100m
1) was gradually added over 25 minutes to stop the reaction, and then 1N sulfuric acid (100 ml) was added over 30 minutes.
The mixture was stirred at room temperature for 45 minutes, 100 ml of water was added, and the organic layer was separated. The aqueous layer was extracted with ethyl acetate (100 ml × 2), the organic layers were combined, washed successively with water (100 ml) and saturated brine (100 ml), dried and evaporated under reduced pressure. The residue (12.25 g) was dissolved in acetone (200 ml), p-toluenesulfonic acid hydrate (200 mg) was added, and the mixture was stirred at room temperature for 20 hours. After confirming the completion of the reaction by ¹ H-NMR, the acetone solvent was distilled off under reduced pressure. The residue was partitioned between ethyl acetate (50 ml) and water (50 ml), the organic layer was separated, washed with saturated brine, dried and evaporated under reduced pressure to give the title compound (6.688 g). . Rf:
0.19 (ethyl acetate: n-hexane = 1: 2)

C. Synthesis of 1- [4- (acetoxymethyl) phenyl] ethanone (Intermediate 126) Intermediate 125 (6.67 g) was added to pyridine (7.3 ml).
Dissolve in and add acetic anhydride (6.3 ml) at room temperature.
Stir for 5 hours. The reaction was stopped by adding water (300 ml), and the mixture was extracted with ethyl acetate (50 ml). The aqueous layer was extracted with ethyl acetate (50 ml x 2), and the organic layers were combined and water (1
(00 ml), 1N hydrochloric acid (50 ml) and then saturated brine (50 ml), which was dried, and the solvent was evaporated under reduced pressure to give the title compound (8.27 g). Rf: 0.56
(Ethyl acetate: n-hexane = 1: 1) D.I. Synthesis of 1- [3-nitro-4- (acetoxymethyl) phenyl] ethanone (Intermediate 127) Fuming nitric acid (80 ml) was cooled with ice-salt cryogen to give Intermediate 12
6 (8.09 g) was added all at once. After stirring for 10 minutes while maintaining the same temperature, a mixture of ice and water (300
ml). The mixture was extracted with ethyl acetate (80 ml × 3), the organic layer was washed successively with water (100 ml × 3), saturated aqueous sodium hydrogen carbonate and saturated brine, dried and the solvent was evaporated under reduced pressure. The residue (9.70 g) was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the title compound (8.41 g). Rf: 0.36 (ethyl acetate:
n-hexane = 1: 2)

E. Synthesis of 1- [3-amino-4- (acetoxymethyl) phenyl] ethanone (Intermediate 128) Intermediate 127 (1.97 g) was added to methanol (358 m).
l) and dissolved in stannous chloride (10.
55 g) and concentrated hydrochloric acid (7.5 ml) were added, and the mixture was stirred at room temperature for 2 hours. Saturated sodium hydrogen carbonate solution (200 ml) was added and the mixture was stirred at room temperature for 7
After stirring for 5 minutes, the precipitated inorganic salt was removed by filtration through Celite, and the filtrate was concentrated under reduced pressure to about 200 ml. Ethyl acetate (300
(ml), the extract was washed with saturated brine, dried, and the solvent was distilled off under reduced pressure. The residue (1.32 g) was purified by silica gel chromatography (ethyl acetate: n-hexane = 1: 2) to obtain the title compound (0.56 g). Rf: 0.31
(Ethyl acetate: n-hexane = 1: 2) F.I. 1- [3- (methylsulfonyl) amino-4- (acetoxymethyl) phenyl] ethanone (Intermediate 129)
Synthesis of Intermediate 128 (0.56 g) in pyridine (3.6 ml)
, Methanesulfonyl chloride (215 μl) was added under an argon atmosphere, and the mixture was stirred at room temperature for 26 hours. Water (5 ml) was added, the mixture was extracted with ethyl acetate (20 ml × 3), the organic layer was washed successively with 1N hydrochloric acid (50 ml × 2) and saturated brine, dried and evaporated under reduced pressure to remove the title compound (0.
58 g) were obtained. Rf: 0.39 (ethyl acetate: n-hexane = 1: 1)

G. 2-Bromo-1- [3- (methylsulfonyl) amino-4- (acetoxymethyl) phenyl]
Synthesis of Ethanone (Intermediate 130) Intermediate 1 was prepared in the same manner as described in Example 29 Step A.
The title compound (430 mg) was prepared from 29 (285 mg) and cupric bromide (491 mg, manufactured by Kanto Chemical Co., Inc.). R
f: 0.44 (ethyl acetate: n-hexane = 1: 2) (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (acetoxymethyl) phenyl] methanesulfonamide (Intermediate 131) Synthesis of the crude product was performed by silica gel chromatography (first time methanol: ethyl acetate = 1: 9 to 1: 4, second time concentrated ammonia water 10% in methanol: chloroform =
2:25) was used according to the method described in Example 1, step D, except that the intermediate 130 (405 mg) and intermediate 2 were used.
The title compound (68 mg) was obtained from (226 mg). R
f: 0.18 (methanol containing 10% concentrated aqueous ammonia:
Chloroform = 1: 9)

I. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2- (hydroxymethyl) phenyl] methanesulfonamide hydrochloride To a solution of Intermediate 131 (68 mg) was added 2N sodium hydroxide solution (10 ml), and the mixture was stirred at room temperature for 2.5 hours. The mixture was diluted with water (30 ml), saturated brine (50 ml) was added, and the mixture was extracted with ethyl acetate (3 over 50 ml). After drying the organic layer, the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography (methanol: ethyl acetate = 1: 9 containing 10% concentrated aqueous ammonia) to give the free base of the title compound. This was converted to a hydrochloride by a conventional method and then crystallized from methanol-ethyl acetate to obtain the title compound (22 mg). R
f: 0.11 (methanol containing 10% concentrated aqueous ammonia:
Chloroform = 1: 9)

Example 85 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-bromophenyl] methanesulfonamide
Hydrochloride 2-Bromo-1- [4-bromo-3-[(methylsulfonyl) amino] phenyl] ethanone was prepared according to the synthetic method of Intermediate 13 in the same manner as in Steps B, C and D of Example 6. Prepared. A. Synthesis of 1- [3-amino-4-bromophenyl] ethanone 4-Bromo-3-nitroacetophenone (5.0 g, manufactured by Lancaster) was added to a solution of tin (II) chloride (19) in a solution of methanol (890 ml). .4
g) and concentrated hydrochloric acid (17 ml) were added, and the mixture was stirred at room temperature for 3.5 hours. Saturated aqueous sodium hydrogen carbonate (470 ml) was added, and the deposited precipitate was filtered and extracted with ethyl acetate. The organic layer was dried and concentrated under reduced pressure to give the title compound (3.97 g). R
f: 0.43 (ethyl acetate: n-hexane = 1: 2)

B. 1- [4-bromo-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 13
Synthesis of 2) A solution of the above compound (3.97 g) in pyridine (21 ml) was added to methanesulfonyl chloride (1.8 ml) at room temperature.
Was added, and the mixture was stirred for 1 hour and then poured into water (142 ml). After stirring overnight, the deposited precipitate was filtered off and dissolved with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give a crude product (4.08 g). Rf: 0.41 (ethyl acetate: n-hexane = 1: 1) C.I. 2-Bromo-1- [4-bromo-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 13
Synthesis of 3) Bromine (0.75 ml) was added to a solution of Intermediate 132 (4.08 g) in 1,4-dioxane (40 ml) with stirring under an argon atmosphere. The mixture was warmed to 60 ° C. and stirred for 1.5 hours. After cooling to room temperature, water was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give a crude product (6.28 g). To this, a mixed solution of ethyl acetate: n-hexane = 1: 1 was added,
After heating and cooling, the precipitate was collected by filtration to obtain the title compound (4.0 g). Rf: 0.54 (ethyl acetate: n-hexane = 1:
1)

D. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-hydroxyethyl] -2-bromophenyl] methanesulfonamide hydrochloride According to the method described in Step D of Example 1, Intermediate 2 · HB
r salt (452.5 mg) and intermediate 133 (742.1 m)
The reaction / treatment was carried out from g) and the product was purified by PTLC (developed with methanol / chloroform: 1/10) to obtain the free amine (191.6 mg) of the title compound. Rf: 0.5
8 (methanol: ethyl acetate = 1: 3) 0.1N hydrogen chloride / ethanol (1.1 equivalent) was added to give a hydrochloride (title compound), and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue, and the deposited precipitate was collected by filtration, recrystallized from ethanol and dried under reduced pressure at 50 ° C. to obtain a powder of the title compound (112.6 mg).

Example 86 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-iodophenyl] methanesulfonamide
Hydrochloride 2-Bromo-1- [4-iodo-3-[(methylsulfonyl) amino] phenyl] ethanone was prepared in analogy to Steps A, B, C, D of Example 6. A. Synthesis of 1- [4-iodo-3-nitrophenyl] ethanone (Intermediate 134) 4′-Iodoacetophenone (20 g, manufactured by Tokyo Chemical Industry Co., Ltd.) was added to ice-salt-cooled fuming nitric acid (130 ml).
After stirring for 1 minute, the mixture was poured into ice-water (1 L) and ethyl acetate (1 L) was added.
Extracted. The organic layer was dried and concentrated under reduced pressure to give the title compound (20.7 g). Rf: 0.19 (ethyl acetate:
n-hexane = 1: 5)

B. Synthesis of 1- [3-amino-4-iodophenyl] ethanone (Intermediate 135) Intermediate 134 (14.3 g) in methanol (2134 m)
l) Chloride (II) chloride (46.5 g) and concentrated hydrochloric acid (40.8 ml) were added to the solution, and the mixture was stirred at room temperature for 4.75 hours. Saturated aqueous sodium hydrogen carbonate (1100 ml) was added, the deposited precipitate was filtered, and the filtrate was partially concentrated and extracted with ethyl acetate.
The organic layer was dried and concentrated under reduced pressure to give the title compound (11.87).
g) was obtained. Rf: 0.67 (methanol: chloroform = 1: 10) C.I. Synthesis of 1- [4-iodo-3-[(methylsulfonyl) amino] phenyl] ethanone (Intermediate 136) Intermediate 135 (11.87 g) in pyridine (50 ml).
The solution was added with methanesulfonyl chloride (3.55) at room temperature.
ml) was added, and the mixture was stirred for 2.5 hours and then poured into water (250 ml). The deposited precipitate was filtered off and dissolved with ethyl acetate. The organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give a crude product. Ethyl acetate: n-hexane =
A 1: 1 solvent was added, and the precipitated crystals were filtered and dried to give the title compound (10.44 g). Rf: 0.14 (ethyl acetate: n-hexane = 1: 3)

D. 2-Bromo-1- [4-iodo-3-
Synthesis of [(methylsulfonyl) amino] phenyl] ethanone (Intermediate 137) Bromine (1.66 ml) was added to a solution of Intermediate 136 (10.4 g) in 1,4-dioxane (102 ml) under argon atmosphere with stirring. Was added. The mixture was warmed to 60 ° C. and stirred for 1.5 hours. After cooling to room temperature, water was extracted with ethyl acetate, the organic layer was washed with saturated brine, dried and concentrated under reduced pressure to give the title crude product (11.77 g). Rf: 0.25 (ethyl acetate: n-hexane = 1:
2) E. Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-iodophenyl] methanesulfonamide hydrochloride

Reaction and treatment were carried out according to the method described in Step D of Example 1 to give Intermediate 2 (500 mg) and Intermediate 13.
From 7 (1.385 g), the obtained residue was roughly purified by column chromatography (6.3% methanol-chloroform), and further PTLC (developed with concentrated ammonia water 10% -containing methanol / ethyl acetate: 1/4). Refined in
The free amine (211.5 mg) of the title compound was obtained. R
f: 0.49 (concentrated aqueous ammonia 10% in methanol:
Ethyl acetate = 1: 4) 0.1N hydrogen chloride / ethanol (1.1 equivalents) was added to give the hydrochloride (title compound), and the solvent was distilled off under reduced pressure at 50 ° C.
After drying under reduced pressure, a powder of the title compound (218 mg) was obtained.

Example 87 (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N-methyl -N
-Benzylsulfamide / hydrochloride A. Synthesis of N-methyl-N-benzylsulfamoyl chloride Sulfuryl chloride (3.0
ml) in dichloromethane (50 ml), N-methyl-N-benzylamine (6.45 ml) and triethylamine (7.0 ml) were added over 15 minutes. After stirring for 15 minutes, water (50 ml) was added to stop the reaction, the organic layer was separated, washed with 1N hydrochloric acid (50 ml), dried and the solvent was distilled off under reduced pressure. N-Hexane (100 m) was added to the residue (8.35 g).
l) was added and cooled, and the precipitate was filtered off. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound (5.30 g). Rf: 0.6
4 (ethyl acetate: n-hexane = 1: 4)

B. 1- [4-benzyloxy-3-
Synthesis of [(N-methyl-N-benzylsulfamoyl) amino] phenyl] ethanone (Intermediate 138) From the above intermediate (880 mg) and 1- (3-amino-4-benzyloxyphenyl) ethanone (482 mg). The title compound (671 mg) was prepared (Larsen (A.
A. Larsen) et al. Med. Chem. , 1
0,462-472 (1967). ). However, in the reaction, a pyridine-dichloromethane mixed solvent (7 ml, 2: 5) was used, and the mixture was first stirred at room temperature for 66 hours, and further stirred for 2 hours under heating under reflux.
Water (20 ml) and ethyl acetate (50 ml) for purification
The organic layer was washed with 1N hydrochloric acid (30 ml). The combined aqueous layers were further extracted with ethyl acetate (30 ml × 2), and the combined organic layers were washed with saturated brine, dried and evaporated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate: n-hexane = 1: 3) Rf: 0.4.
7 (methanol: chlorophorm = 1: 19)

C. Synthesis of 2-Bromo-1- [4-benzyloxy-3-[(N-methyl-N-benzylsulfamoyl) amino] phenyl] ethanone (Intermediate 139) Similar to the method described in Example 29 Step A. Then, Intermediate 1
The title compound (810 mg, about 80% pure) was prepared from 38 (670 mg) and cupric bromide (780 mg). R
f: 0.41 (ethyl acetate: n-hexane = 1: 2) D.I. (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] -N
-Methyl-N-benzylsulfamide (Intermediate 140)
The reaction and treatment were carried out according to the method described in Example 1, step D, and intermediate 2 (400 mg), triethylamine (28
0 μl), silica gel chromatography (methanol: ethyl acetate = 1: 9) from intermediate 139 (805 mg).
(Eluted with) to obtain the title compound (251 mg). R
f: 0.47 (methanol: chloroform = 1: 9)

E. (±) -N '-[5- [2- [2-
Synthesis of (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N-methyl-N-benzylsulfamide hydrochloride Following the procedure described in Example 2, the intermediate 140 (250
mg) was added to methanol (50 ml), hydrogenolysis was performed using 10% palladium / carbon (122 mg), hydrochloric acid was chlorided according to a conventional method, and recrystallized from methanol-ethyl acetate to obtain the title compound (46 mg). Rf: 0.33 (methanol: chloroform = 1: 9)

Example 88 (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N -Diethylsulfamide-hydrochloride A. Synthesis of N, N-diethylsulfamoyl chloride According to the method described in Example 87, step A, N, N-diethylamine (2 0.07 ml) and triethylamine (2.8 ml) were added over 2 hours. After stirring for 1 hour, water (20 ml) was added to stop the reaction, the organic layer was separated, and 1N hydrochloric acid (20 ml) was added.
After washing with water and drying, the solvent was distilled off under reduced pressure. N-Hexane (30 ml) was added to the residue and cooled, and the precipitate was filtered off. The filtrate was concentrated to dryness under reduced pressure to obtain the title compound (2.19 g). R
f: 0.59 (ethyl acetate: n-hexane = 1: 4)

B. 1- [4-benzyloxy-3-
Synthesis of [(N, N-diethylsulfamoyl) amino] phenyl] ethanone (Intermediate 141) The title compound from the above intermediate (686 mg) and 1- (3-amino-4-benzyloxyphenyl) ethanone (482 mg). (513 mg) was prepared (Larsen (A.
A. Larsen) et al. Med. Chem. , 1
0,462-472 (1967). However, in the reaction, a pyridine-dichloromethane mixed solvent (7 ml, 2: 5) was used, and the mixture was first stirred at room temperature for 66 hours, and further stirred for 2 hours under heating under reflux. In the purification, it was extracted from water (20 ml) and ethyl acetate (20 ml), and the organic layer was washed with 1N hydrochloric acid (30 ml).
The combined aqueous layers were further extracted with ethyl acetate (30 ml × 2), and the combined organic layers were washed with saturated brine, dried and evaporated under reduced pressure. The residue was chromatographed on silica gel (ethyl acetate: n-hexane = 1: 3) Rf: 0.42 (ethyl acetate: n-hexane = 1: 2).

C. Synthesis of 2-Bromo-1- [4-benzyloxy-3-[(N, N-diethylsulfamoyl) amino] phenyl] ethanone (Intermediate 142) In a manner similar to that described in Example 29 Step A. , Intermediate 1
The title compound (693 mg, about 70% purity) was prepared from 41 (500 mg) and cupric bromide (670 mg). R
f: 0.64 (ethyl acetate: n-hexane = 1: 2) D.I. (±) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl]-
Synthesis of N, N-diethylsulfamide (Intermediate 143) Reaction and treatment were carried out according to the procedure described in Step D of Example 1, Intermediate 2 (390 mg), triethylamine (28
0 μl), silica gel chromatography (methanol: ethyl acetate = 1: 9) from intermediate 142 (673 mg).
(Eluted with) to obtain the title compound (256 mg). R
f: 0.46 (methanol: chloroform = 1: 9)

E. (±) -N '-[5- [2- [2-
Synthesis of (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-diethylsulfamide hydrochloride Intermediates were prepared according to the method described in Example 2. 143 (250
mg) to methanol (50 ml) and hydrogenolysis using 10% palladium / carbon (120 mg), followed by hydrochloric acid chloride according to a conventional method and recrystallization from methanol-ethyl acetate to obtain the title compound (85 mg). Rf: 0.32 (methanol: chloroform = 1: 9)

Example 89 (±) -N, N-dimethyl- [5- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] -2-hydroxy] benzenesulfonamide / hydrochloride A. N, N-dimethyl- [2-benzyloxy-5-
Synthesis of (2-bromoacetyl) benzene] sulfonamide (Intermediate 144) 1- (3- as in the method described in Example A, Steps A, B.
Amino-4-benzyloxyphenyl) ethanone (AA Larsen et al., J. Med. Che.
m. , 10,462-472 (1967)) was prepared from the title compound (705 mg). However, instead of adding N-methylbenzylamine, N, N-dimethylamine was reacted. Rf:
0.33 (ethyl acetate: n-hexane = 1: 2)

B. N, N-dimethyl- [2-benzyloxy-5- [2-iodo-1-[(triethylsilyl)
[Oxy] ethyl]] benzenesulfonamide (Intermediate 1
Synthesis of 45) Intermediate 144 (700 mg) was reacted and treated according to the method for synthesizing Intermediate 42 to obtain the title compound (407 mg). Rf: 0.74 (ethyl acetate: n-hexane = 1:
1) C.I. (±) -N, N-dimethyl- [5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-[(triethylsilyl) oxy] ethyl]-
Synthesis of 2-benzyloxy] benzenesulfonamide (Intermediate 146) Intermediate 145 was prepared according to the method for synthesizing Intermediate 43 except that silica gel chromatography (methanol: chloroform = 1: 25) was used to purify the crude product. (398 mg)
And Intermediate 2 (193 mg) from the title compound (138 m
g) was obtained. Rf: 0.43 (methanol: chloroform = 1: 10)

D. (±) -N, N-dimethyl- [5-
[2- [2- (9H-carbazol-2-yloxy)
Synthesis of ethylamino] -1-hydroxyethyl] -2-benzyloxy] benzenesulfonamide (Intermediate 147) Intermediate 146 (135 mg) was dissolved in anhydrous tetrahydrofuran (7 ml) and acetic acid (38.2 μl) and 1M tetrabutyl were added. An ammonium fluoride / tetrahydrofuran solution (314 μl) was added, and the mixture was stirred at room temperature for 14.5 hours.
The mixture was diluted with ethyl acetate, washed with saturated brine, dried and the solvent was distilled off under reduced pressure. The residue was purified by PTLC (methanol:
Chloroform = 1:10 developed and the title compound (4.9m)
g) was obtained. Rf: 0.23 (methanol: chloroform = 1:10) The hydrochloride salt (7.7 mg) was prepared by a conventional method. E. FIG. (±) -N, N-dimethyl- [5- [2- [2-
Synthesis of (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide hydrochloride Intermediate 147 (7.7 m) according to the method described in Example 2.
g) was hydrolyzed with 10% palladium / carbon (4 mg) for 2 hours, the catalyst was filtered off and the solvent was evaporated under reduced pressure to give the title compound (5.0 mg). Rf: 0.31 (methanol: chloroform = 1: 9)

Example 90 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide / hydrochloric acid Salt A. Synthesis of (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-benzyloxyphenyl] methanesulfonamide (Intermediate 148) The compound of Example 1 (120 mg) was stirred in 10% hydrogen chloride / methanol (10 ml) for 24 hours while heating under reflux.
The mixture was further stirred at room temperature for 3 days. The reaction mixture was concentrated to dryness under reduced pressure, saturated aqueous sodium hydrogen carbonate was added, and the mixture was extracted with ethyl acetate (20 ml × 2). After drying, it was concentrated under reduced pressure and the residue was purified by silica gel chromatography (methanol: chloroform = 1: 19) to obtain the title compound (72 mg). Rf: 0.55 methanol: chloroform = 1: 9)

B. (±) -N- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
Synthesis of 1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride According to the method described in Example 2, Intermediate 148 (70 m
g) was hydrolyzed with 10% palladium / carbon (30 mg) for 1 hour, hydrochloric acid-chlorinated, dried and triturated from diethyl ether to obtain the title compound (60 mg). Rf: 0.40 (methanol: chloroform = 1:
9)

Example 91 (±) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide hydrochloride The compound of Example 38 (28 mg) was suspended in 10% hydrogen chloride / methanol (3 ml), and the mixture was stirred with heating under reflux for 3 days and nights. Further, 10% hydrogen chloride / methanol (10 ml) was added, and the mixture was stirred for 2 days. The reaction mixture was concentrated to dryness under reduced pressure, dissolved in methanol, and purified by PTLC (developed with methanol: chloroform = 1: 10). This was chewed in diethyl ether and collected by filtration to give the title compound (11.8).
mg). Rf: 0.38 (methanol: chloroform = 1: 10)

Example 92 (±) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-aminophenyl] methanesulfonamide / hydrochloric acid Salt Intermediate 120 (35 mg) was added to 10% hydrogen chloride / methanol (5 ml), and the mixture was stirred with heating under reflux for 2 hours. It was concentrated to dryness under reduced pressure to obtain the title compound (37 mg). Rf:
0.29 (methanol: chloroform = 1: 9)

Test Example 1 Human β3 agonistic activity Human β3 agonistic activity was determined by using the human β3 gene as pcDNA3.
It was carried out using CHO (Chinese hamster ovary) cells transfected with the one inserted in (in vitrogen). The human β3 gene was first identified by the primer for β3 (Krief et al., J. Clin. Invest.
vol. 91, p344-349 (1993)) and PCR using human adipose tissue cDNA (Clontech)
Then, a human β3 fragment was obtained, and using this as a probe, a full-length human β3 gene was obtained from a human genomic library (Clontech). These cells were treated with 10% fetal bovine serum, 400 μg / ml Geneticin (GibcoBR
L), 100 U / ml penicillin, and 100 μg / ml streptomycin were cultured in Ham's F-12 medium.
The cells were placed in a 6-well plate at 5 × 10 ⁵ , cultured for 24 hours, and then allowed to stand in serum-free Ham's F-12 medium for 2 hours. Ham F-containing 1 mM isobutylmethylxanthine, 1 mM ascorbic acid after first dissolving the compound in DMSO
The cells were diluted with 12, diluted 10-fold to 10 ^-5 -10 ^-12 M, and added to the cells.

After culturing for 30 minutes, the medium was removed and 1N N
0.5 ml of aOH was added and left for 20 minutes. 0.5 ml of 1N acetic acid was added, and the mixture was stirred and then centrifuged, and cAMP was quantified using a cAMPEIA kit (manufactured by Cayman). Table 4 shows the internal activity and ED ₅₀ of 65 compounds of Examples 1-92. BRL37344 is published in the literature (Dr
ugs of the future vol. 16,
p797-800 (1991)),
CL316 and 243 are described in the literature (J. Med. Chem.
vol. 35, p3081-3084 (1992), isoproterenol was synthesized by RBI (Re
search BiochimicalsIntern
national) company. From the results in Table 4, these compounds were found to have BRL37344, CL316,24.
It was more active than 3.

Test Example 2 Action on the Heart The heart was excised from a male guinea pig weighing 180-250 g, a right atrium sample was prepared, and an organ bath containing Krebs solution aerated with a 5% CO ₂ /95% O ₂ mixed gas was used. Set to. The automatic function is a polygraph (Nihon Kohden MR-600
0) Isometric Transducer (Nihon Kohden)
(TB-611T). ED ₅₀ of the compound of Example is higher than that ED ₅₀ of .beta.3, these compounds are selective, very little to increase the heart rate, it was expected side effects is small.

Test Example 3 Lipolytic activity of canine adipocytes Mesenteric adipose tissue was collected from dogs, shredded, washed and
3 ml of Krebs-Ringer buffer containing 1 mg / ml collagenase (Sigma) and 1% bovine serum albumin was added to 1 g of the tissue. Shaking this 3
After incubating at 7 ° C for 30 minutes, undigested tissue was removed with a nylon filter to obtain adipocytes. The adipocytes were washed 4 times with Krebs-Ringer buffer, and then the Krebs-Ringer buffer containing 4% bovine serum albumin was used to adjust the cell concentration to 2 × 10 ⁵ cells / ml, and 300 μl of the cells were dispensed into an Eppendorf tube. . 300 μl of a medium containing the compound was added to each tube, and the mixture was kept at 37 ° C. for 1 hour while shaking. Stop the stimulation with ice cooling,
After centrifugation, adipocytes were removed by an aspirator, and free glycerol was separated by F-kit glycerol (Boehringer
(Mannheim). As shown in Table 5, since the compounds of Examples exhibited lipolytic activity in vitro, it was expected that lipolysis would occur in vivo.

Test Example 4 Hypoglycemic action and lipolytic action 6-week-old male ddy mouse (manufactured by Charles River Japan) was subcutaneously administered with 2 g / kg of glucose (manufactured by Wako Pure Chemical Industries, Ltd.) and 0.3% carboxymethylcellulose. The test compound suspended in (Junsei Kagaku Co., Ltd.) was used in an amount of 0.
It was orally or intraperitoneally administered at a dose of 1 ml. One hour later, blood was collected from the abdominal aorta and serum was separated to obtain a sample.

Blood glucose lowering action The above-mentioned sample was subjected to measurement of serum glucose concentration in the sample by an autoanalyzer (SUPER Z manufactured by MC Medical Co., Ltd.). Glucose II in the measurement kit
HA test Wako (manufactured by Wako Pure Chemical Industries, Ltd.) was used [blood glucose decrease (%) = (A-B) / (A-C) x 100,
A: glucose concentration during glucose load, B: glucose concentration during drug administration, C: glucose concentration under normal conditions]. The compound of Example 31 was orally administered at 100 mg / kg,
The compound of Example 2 showed 34.5% lowering of blood glucose, and
Intraperitoneal administration of mg / kg showed a decrease in blood glucose of 77.1%. Therefore, it was shown to be useful as a preventive / therapeutic drug for diabetes.

Lipolytic action For the amount of free fatty acid in serum of the above sample, the amount of free fatty acid in the sample was measured by NEFA HA Test Wako (manufactured by Wako Pure Chemical Industries, Ltd.). The compounds of Examples 31 and 7 are 30, 1
Oral administration of 00 mg / kg gives 32.4 and 47.7, respectively.
% Increased. The compound of Example 2 was 10 mg /
Intraperitoneal administration of kg increased the free fatty acid concentration by 67.2%. These compounds are shown to have lipolytic activity. Therefore, it was shown to be useful as a preventive / therapeutic drug for hyperlipidemia and a therapeutic drug for obesity, respectively.

Test Example 5 Toxicity Test Each compound of Examples 7 and 31 was orally administered to 6-week-old male ddy mice (manufactured by Charles River Japan) at 100 mg / kg, and all of 8 mice died. Of course, the same was true for the other compounds, indicating that the compounds of the present invention have low toxicity.

[0256]

The compound of the present invention is a novel compound,
It is useful as a pharmaceutical composition used for the treatment and prevention of β3-related diseases such as diabetes drugs, obesity drugs and hyperlipidemia drugs.

[0257]

[Table 1]

[0258]

[Table 2]

[0259]

[Table 3]

[0260]

[Table 4]

[0261]

[Table 5]

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Internal reference number FI Technical display location C07C 217/24 7457-4H C07C 217/24 217/94 7457-4H 217/94 219/30 7457- 4H 219/30 233/25 9547-4H 233/25 237/30 9547-4H 237/30 275/28 9451-4H 275/28 311/37 7419-4H 311/37 317/32 7419-4H 317/32 C07D 209/88 C07D 209/88 307/91 307/91 333/76 333/76 // C07M 7:00

Claims (18)

[Claims] 1. A compound of the general formula (I)[In the formula, R represents a hydrogen atom or a methyl group, and R¹Is water
Elementary atom, halogen atom, hydroxyl group, benzyloxy group,
R represents a mino group or a hydroxymethyl group, R^TwoIs hydrogen field
Child, hydroxymethyl group, NHR^Three, SO_TwoNR^FourR^Four'
Alternatively, it represents a nitro group. Where R^ThreeIs a hydrogen atom, methyl
Base, SO_TwoR^Five, Formyl group or CONHR^{6 '}Shows
Then R^FiveIs a lower alkyl group, benzyl group or NR^Four R
^Four'Is shown. Also, R^FourAnd R^Four'Are the same or each other
To a hydrogen atom, a lower alkyl group or
Indicates a benzyl group. R^{6 '}Is hydrogen atom or lower alk
Represents a hydroxyl group. Also, R⁶Is hydrogen atom or lower alk
Represents a hydroxyl group. X is a secondary nitrogen atom, oxygen atom, sulfur atom
Or a methylene group, and X is a secondary nitrogen atom or oxygen atom
Or in the case of a sulfur atom, R⁹Is a hydrogen atom, R⁷is there
Iha R⁸One of them is a hydrogen atom and the other is a hydrogen atom.
Represents a child, amino group, acetylamino group or hydroxyl group.
When X is a methylene group, R⁷And R⁸Yes
This is also a hydrogen atom, R ⁹Is a hydrogen atom, amino group, acetyl
Indicates an amino group or a hydroxyl group. * 1 is an asymmetric carbon atom
, * 2 is R⁶Is a lower alkyl group
It means a carbon atom. ] Or its compound
salt. 2. A compound represented by the general formula (I):[In the formula, R represents a hydrogen atom,¹Is hydrogen atom, halogen
Group atom, hydroxyl group, benzyloxy group, amino group or
Represents a droxymethyl group, R^TwoIs a hydrogen atom, hydroxy
Methyl group, NHR^Three , SO_TwoNR^Four R^Four'Or nitro group
Is shown. Where R ^ThreeIs hydrogen atom, methyl group, SO_TwoR
^Five , Formyl group or CONHR^{6 '}And R^FiveIs low
Alkyl group, benzyl group or NR^FourR^Four'Is shown. Ma
R^FourAnd R^Four'Are the same or different from each other
Optionally a hydrogen atom, a lower alkyl group or a benzyl group
Show. R^{6 '}Represents a hydrogen atom or a lower alkyl group.
Also, R ⁶Represents a hydrogen atom or a lower alkyl group.
X is a secondary nitrogen atom, oxygen atom, sulfur atom or methyl
X is a secondary nitrogen atom, an oxygen atom or a sulfur atom.
R for child⁹Is a hydrogen atom, R⁷Or R⁸No
One of them is a hydrogen atom, the other is a hydrogen atom, an amino group,
Indicates an acetylamino group or hydroxyl group. Also, X is meth
In the case of a len group, R⁷And R⁸Are all hydrogen atoms
And R⁹Is a hydrogen atom, amino group, acetylamino group or
Represents a hydroxyl group. * 1 indicates an asymmetric carbon atom, * 2
Is R⁶Is a lower alkyl group, an asymmetric carbon atom
Means ] The compound according to claim 1 represented by
Is its salt. 3. A compound represented by the general formula (I):[In the formula, R represents a hydrogen atom,¹Is a hydrogen atom, fluorine
Indicates an atom, chlorine atom, hydroxyl group or benzyloxy group
Then R^TwoIs a hydrogen atom, hydroxymethyl group, NHR ^Three ,
SO_TwoNR^FourR^Four'Alternatively, it represents a nitro group. Where R^ThreeIs
Hydrogen atom, methyl group, SO_TwoR^Five , Formyl group or C
ONHR^{6 '}And R^FourAnd R^Four'Either one is hydrogen source
And the other is a hydrogen atom, a lower alkyl group or
Represents a benzyl group. Also, R^FiveIs a lower alkyl group, benz
R group or dimethylamino group, R^{6 '}Is a hydrogen atom
Or a lower alkyl group. Also, R⁶Is a hydrogen atom
Or a lower alkyl group. X is a secondary nitrogen atom, acid
Represents an elementary atom, a sulfur atom or a methylene group, and X is a secondary nitrogen atom.
In the case of elementary atom, oxygen atom or sulfur atom, R⁹Is hydrogen
Atom, R⁷Or R⁸One of is a hydrogen atom
And the other is hydrogen atom, amino group, acetylamino group or
Represents a hydroxyl group. When X is a methylene group, R⁷
And R⁸Is a hydrogen atom, R⁹Is a hydrogen atom,
Indicates a mino group, an acetylamino group or a hydroxyl group. * 1
Is an asymmetric carbon atom, * 2 is R⁶Is lower alkyl
When it is a group, it means an asymmetric carbon atom. ]
The compound according to claim 2 or a salt thereof. 4. A compound represented by the general formula (I): [Wherein R represents a hydrogen atom, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group or a benzyloxy group, and
² is a hydroxymethyl group, NHR ³ , SO ₂ NR ⁴ R
^{4 'or} a nitro group. Provided that R ³ represents a hydrogen atom, a methyl group, SO ₂ R ⁵ , a formyl group or CONHR ^{6 ′} , and R ⁵ represents a lower alkyl group, a benzyl group or NR ⁴ R
Indicates ^{4 '} . R ⁴ and R ^{4 ′} represent the same or different hydrogen atom, lower alkyl group or benzyl group. R ^6'represents a hydrogen atom or a lower alkyl group. R ⁶ represents a hydrogen atom or a lower alkyl group. X represents a secondary nitrogen atom, an oxygen atom, a sulfur atom or a methylene group, and when X is a secondary nitrogen atom, an oxygen atom or a sulfur atom, R ⁹ is a hydrogen atom, and either R ⁷ or R ⁸ One is a hydrogen atom and the other is a hydrogen atom, an amino group, an acetylamino group or a hydroxyl group.
When X is a methylene group, R ⁷ and R ⁸ are both hydrogen atoms, and R ⁹ is a hydrogen atom, amino group, acetylamino group or hydroxyl group. * 1 represents an asymmetric carbon atom, and * 2 means an asymmetric carbon atom when R6 is a lower alkyl group. ] The compound or its salt of Claim 2 shown by these. 5. In the general formula (I), R and R ¹ both represent a hydrogen atom, R ² is a hydroxymethyl group, N 2
HR ³ or SO ₂ NR ⁴ R ^{4 ′} is represented by R ³ being a hydrogen atom, a methyl group, SO ₂ R ⁵ , a formyl group or CONH.
R ^{6 ′} and R ⁵ are lower alkyl group, benzyl group or NR
The compound or salt thereof according to claim 2, wherein ⁴ R ^{4 ′} is shown, and R ⁴ and R ^{4 ′} are the same or different from each other, a hydrogen atom, a lower alkyl group or a benzyl group. 6. In the general formula (I), R is a hydrogen atom.
And R¹Represents a halogen atom or a hydroxyl group, R^TwoIs
NHSO_TwoR^FiveOr SO_TwoNR^FourR^Four'And R^FiveIs
Lower alkyl group, benzyl group or NR^Four R^Four'Indicates that
R^FourAnd R ^Four'Can be the same or different
A good hydrogen atom, lower alkyl group or benzyl group
The compound according to claim 2 or a salt thereof. 7. The compound is (R) -N- [5- [2-
[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; (S) -N- [5-
[2- [2- (9H-carbazol-2-yloxy)
Ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2
-[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2-
[2- (3-Hydroxy-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl]-
2-Hydroxyphenyl] methanesulfonamide; N-
[5- [2- [2- (3-Amino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [ 2- (6-amino-9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (6-hydroxy- 9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; (R) -N- [3- [2-
[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; (S) -N- [3- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] phenyl] methanesulfonamide; N- [3- [2- [2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N-methyl-3
-[2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] benzenesulfonamide; N-methyl- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-Hydroxyethyl] -2-hydroxy] benzenesulfonamide; (R) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl ] Methanesulfonamide; (S) -N- [5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5 -[2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazole-
2-yloxy) ethylamino] -1-hydroxyethyl] -2- (benzyloxy) phenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino]- 1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide; N
-[3- [2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [5- [2- [2-
(7-Acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2-
[2- (7-Aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [3- [2-
[2- (7-Acetylaminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [3- [2- [2-
(7-Aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1 -Hydroxyethyl] -2-hydroxyphenyl] formamide; N
-[3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] formamide; N- [3- [2-[[1- (9H
-Carbazol-2-yloxy) propan-2R-yl] amino] -1-hydroxyethyl] phenyl] methanesulfonamide; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1 -(4-
Hydroxy-3-nitrophenyl) ethanol; 2-
[N- [2- (9H-carbazol-2-yloxy)
Ethyl] amino] -1- (3-amino-4-hydroxyphenyl) ethanol; N- [5- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] -2- (benzyloxy) phenyl] urea; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] Urea; N-
[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-
(Benzyloxy) phenyl] formamide; N'-
[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-
(Benzyloxy) phenyl] -N, N-dimethylsulfamide; N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy Phenyl] -N, N-dimethylsulfamide; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3-
(Methylamino) -4- (benzyloxy) phenyl]
Ethanol and 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3-
(Methylamino) -4-hydroxyphenyl] ethanol N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl]-
2-Hydroxyphenyl] -2-propanesulfonamide; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (3-nitrophenyl) ethanol; N '-[3- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] -N, N-dimethylsulfamide; 2- [N- [2- (9H-carbazole-2 −
Iloxy) ethyl] amino] -1- (3-aminophenyl) ethanol; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1- [3-
(Hydroxymethyl) -4-hydroxyphenyl] ethanol; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -3-hydroxyphenyl] methanesulfonamide N- [3- [2- [2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [3- [2- [2- (9H-carbazole-2
-Yloxy) ethylamino] -1-hydroxyethyl] -4-hydroxyphenyl] methanesulfonamide; (R) -N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-Hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; (S) -N '-[5- [2- [2
-(9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; N- [3- [2
-[2- (6-acetylamino-9H-carbazole-
2-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N- [5- [2
-[2- (6-acetylamino-9H-carbazole-
2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-Hydroxyethyl] -2-fluorophenyl] methanesulfonamide; (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl]- 2-Fluorophenyl] methanesulfonamide; (R) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] methanesulfonamide (S) -N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-quat; N-N-dimethyl- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxy] benzenesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-iodophenyl] methanesulfonamide;
N '-[5- [2- [2- (9H-carbazole-2-
Iloxy) ethylamino] -1-hydroxyethyl]
-2-Fluorophenyl] -N, N-dimethylsulfamide; N '-[5- [2- [2- (9H-carbazole-
2-yloxy) ethylamino] -1-hydroxyethyl] -2-chlorophenyl] -N, N-dimethylsulfamide; (R) -N-methyl- [5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-hydroxyethyl] -2-hydroxy] benzenesulfonamide; (R) -N- [5- [2- [2- (9H
-Carbazol-2-yloxy) ethylamino] -1
-Hydroxyethyl] -2- (hydroxymethyl) phenyl] methanesulfonamide; (R) -N- [3- [2
-[2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] phenyl] methanesulfonamide; N '-[5- [2- [2- (dibenzofuran-3-yloxy) ethylamino] -1 -Hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; (R) -N '-[5- [2- [2-
(Dibenzofuran-3-yloxy) ethylamino]-
1-hydroxyethyl] -2-hydroxyphenyl]-
N, N-dimethylsulfamide; (S) -N '-[5-
[2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-dimethylsulfamide; N- [5
-[2- [2- (Dibenzofuran-3-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide; N- [5- [2- [2
-(Dibenzofuran-3-yloxy) ethylamino]
-1-Hydroxyethyl] -2-chlorophenyl] methanesulfonamide; N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methane Sulfonamide; N '-[5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N, N-
Dimethylsulfamide; N- [3- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1
-Hydroxyethyl] phenyl] methanesulfonamide; (R) -N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfone. Amide; N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl] -2-fluorophenyl] methanesulfonamide;
N- [5- [2- [2- (dibenzothiophen-3-yloxy) ethylamino] -1-hydroxyethyl]-
2-chlorophenyl] methanesulfonamide; N- [5
-[2- [2- (7-Aminofluoren-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] methanesulfonamide; N '-[5
-[2- [2- (7-acetylaminofluorene-2-
Iloxy) ethylamino] -1-hydroxyethyl]
2-Hydroxyphenyl] -N, N-dimethylsulfamide; N '-[5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-amino Phenyl] -N-benzyl-N-
Methylsulfamide; N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
Hydroxyethyl] -2-aminophenyl] methanesulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxymethylphenyl] methane Sulfonamide; N- [5- [2- [2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-bromophenyl] methanesulfonamide; N '-[5- [2 -[2- (9H-carbazol-2-yloxy) ethylamino] -1-hydroxyethyl] -2-hydroxyphenyl] -N-benzyl-N
-Methylsulfamide; N '-[5- [2- [2- (9
H-carbazol-2-yloxy) ethylamino]-
1-hydroxyethyl] -2-hydroxyphenyl]-
The compound or its salt according to claim 2, which is a compound selected from the group consisting of N, N-diethylsulfamide. 8. A compound represented by the general formula (I):[In the formula, R represents a hydrogen atom,¹Is hydrogen atom, halogen
R represents a hydrogen atom or a hydroxyl group, and R^TwoRepresents a hydrogen atom,
R⁶Represents a hydrogen atom or a lower alkyl group. X is
Secondary nitrogen atom, oxygen atom, sulfur atom or methylene group
And X is a secondary nitrogen atom, oxygen atom or sulfur atom
If R⁹Is a hydrogen atom, R⁷Or R ⁸Any of
One is a hydrogen atom, the other is a hydrogen atom, amino group, acetyl
Indicates a luamino group or a hydroxyl group. In addition, X is a methylene group
In case of, R⁷And R⁸Is a hydrogen atom, R⁹
Is a hydrogen atom, amino group, acetylamino group or hydroxyl group
Is shown. * 1 indicates an asymmetric carbon atom, * 2 indicates R⁶Is low
When it is a primary alkyl group, it means an asymmetric carbon atom.
You. ] The compound of Claim 2 shown by these or its
salt. 9. The compound is 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1-.
(4-hydroxyphenyl) ethanol; 2- [N-
[2- (9H-carbazol-2-yloxy) ethyl] amino] -1- (2-fluorophenyl) ethanol; 2- [N- [2- (9H-carbazol-2-yloxy) ethyl] amino] -1 -(2-Hydroxyphenyl) ethanol; (R, R) -2- [N- [1- (9
H-carbazol-2-yloxy) propan-2-yl] amino] -1-phenylethanol; 2- [N-
[2- (9H-carbazol-2-yloxy) ethyl] amino] -1-phenylethanol; (R) -2-
[N- [2- (9H-carbazol-2-yloxy)
Ethyl] amino] -1-phenylethanol; (S)-
[2- [N-2- (9H-carbazol-2-yloxy) ethyl] amino] -1-phenylethanol; 2-
[N- [2- (3-Acetylamino-9H-carbazol-2-yloxy) ethyl] amino] -1-phenylethanol; 2- [N- [2- (3-amino-9H-carbazol-2-yloxy) ) Ethyl] amino] -1-
Phenylethanol; 2- [N- [2- (3-hydroxy-9H-carbazol-2-yloxy) ethyl] amino] -1-phenylethanol; 2- [N- [2-
(6-amino-9H-carbazol-2-yloxy)
Ethyl] amino] -1-phenylethanol; 2- [N
-[2- (6-acetylamino-9H-carbazole-
2-yloxy) ethyl] amino] -1-phenylethanol; 2- [N- [1- (9H-carbazole-2-
It is a compound selected from the group consisting of yloxy) propan-2-yl] amino] -1-phenylethanol and 2- [N- [2- (dibenzofuran-3-yloxy) ethyl] amino] -1-phenylethanol. The compound according to claim 8 or a salt thereof. 10. A compound represented by the general formula (I): [In the formula, R represents a methyl group, R ¹ represents a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a hydroxymethyl group, and R ² represents NHR ³ or SO ₂ NR ⁴ R ^{4 ′} .
However, R ³ represents SO ₂ R ⁵ . R ⁵ represents a lower alkyl group, a benzyl group, or NR ⁴ R ^{4 '.} R ⁴ and R ^{4 ′} represent the same or different hydrogen atom, lower alkyl group or benzyl group. R ⁶
Represents a hydrogen atom or a lower alkyl group. X represents a secondary nitrogen atom, an oxygen atom, a sulfur atom or a methylene group, and when X is a secondary nitrogen atom, an oxygen atom or a sulfur atom, R ⁹ is a hydrogen atom, and either R ⁷ or R ⁸ One is a hydrogen atom and the other is a hydrogen atom, an amino group, an acetylamino group or a hydroxyl group. When X is a methylene group, R ⁷ and R ⁸ are both hydrogen atoms, and R ⁹ is a hydrogen atom, amino group, acetylamino group or hydroxyl group. * 1 represents an asymmetric carbon atom, and * 2 means an asymmetric carbon atom when R ⁶ is a lower alkyl group. ] The compound or its salt of Claim 1 shown by these. 11. The compound is N- [5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2-
(Dibenzothiophen-3-yloxy) ethylamino] -1-methoxyethyl] -2-hydroxyphenyl] methanesulfonamide; N- [5- [2- [2-
(9H-carbazol-2-yloxy) ethylamino] -1-methoxyethyl] -2-aminophenyl] methanesulfonamide; N- [5- [2- [2- (9H-
Carbazol-2-yloxy) ethylamino] -1-
A compound selected from the group consisting of methoxyethyl] -2-chlorophenyl] methanesulfonamide.
The compound according to 0 or a salt thereof. 12. A medicine comprising the compound according to claim 1 or a salt thereof as an active ingredient. 13. The medicament according to claim 12, which is a pharmaceutical composition comprising the compound according to claim 1 or a salt thereof as an active ingredient, and the active ingredient and a pharmaceutically acceptable carrier. 14. The medicine according to claim 12, which is a therapeutic or prophylactic agent for diabetes, obesity, or hyperlipidemia. 15. A compound represented by the general formula (II):[Wherein, R^{1 '}Is a hydrogen atom, a halogen atom, or a protective group A.
Protected hydroxyl group, amino group protected by acetyl group,
Represents a hydroxymethyl group protected by an acetyl group,
R^{2 '}Is a hydrogen atom, a hydroxyl group protecting group A '' 'protected
Droxymethyl group, NHR^{3 '}, SO_TwoNR^FourR^Four'Or
Indicates a nitro group. Where R^{3 '}Is an amino-protecting group, methyl
Lu group, SO_TwoR^Five, Formyl group or CONHR^{6 '}Shows
Then R^FiveIs a lower alkyl group, benzyl group or NR^FourR
^Four'Is shown. Also, R^FourAnd R^Four'Are the same or each other
To a hydrogen atom, a lower alkyl group or
Indicates a benzyl group. R^{6 '}Is hydrogen atom or lower alk
Represents a hydroxyl group. Also, R⁶Is hydrogen atom or lower alk
Represents a hydroxyl group. A'represents a hydroxyl-protecting group, B is bromine
Child or iodine atom, * 1 means asymmetric carbon atom
You. ] And a compound represented by the general formula (III):[Wherein Y represents a hydrogen atom, R⁶Is a hydrogen atom
Represents a lower alkyl group. X is a secondary nitrogen atom, oxygen source
Child, sulfur atom or methylene group, and X is a secondary nitrogen atom
In the case of a child, oxygen atom or sulfur atom, R^{9 '}Is a hydrogen atom
And R^{7 '}Or R^{8 '}One of is a hydrogen atom and the other is
One should be protected by hydrogen atom, acetylamino group or protective group A ''.
Shows protected hydroxyl groups. When X is a methylene group
Is R^{7 '}And R^{8 '}Is a hydrogen atom, R^{9 '}Is hydrogen
Protected by atom, acetylamino group or protecting group A ''
Indicates a hydroxyl group. * 2 is R⁶Is a lower alkyl group
When used together, it means an asymmetric carbon atom. ] And the compound
To react with the protective group A (provided that R¹Is a benzyloxy group
And when the protective group A is a benzyl group, the protective group A
Will not be deprotected. ), A ′, A ″, A ′ ″ and R^{3 '}
Protecting group for amino group or R^{1 '}Asset in
Of the general formula (I), characterized in that the protecting group is deprotected.[In the formula, R represents a hydrogen atom,¹Is hydrogen atom, halogen
Group atom, hydroxyl group, benzyloxy group, amino group or
Represents a droxymethyl group, R^TwoIs a hydrogen atom, hydroxy
Methyl group, NHR^Three , SO_TwoNR^FourR^Four'Or nitro group
Is shown. Where R ^ThreeIs hydrogen atom, methyl group, SO
_TwoR^Five, Formyl group or CONHR^{6 '}Is shown. Also,
X is a secondary nitrogen atom, oxygen atom, sulfur atom or methyl
X is a secondary nitrogen atom, an oxygen atom or a sulfur atom.
R for child⁹Is a hydrogen atom, R⁷Or R⁸No
One of them is a hydrogen atom, the other is a hydrogen atom, an amino group,
Indicates an acetylamino group or hydroxyl group. Also, X is meth
In the case of a len group, R⁷And R⁸Are all hydrogen atoms
And R⁹Is a hydrogen atom, amino group, acetylamino group or
Represents a hydroxyl group. R^Four, R^Four', R^Five, R⁶, R^{6 '}, * 1
And * 2 have the same meanings as described above. ]
Of producing a compound or a salt thereof. 16. A compound represented by the general formula (II): [Wherein R ^{1 ′} represents a hydrogen atom, a halogen atom, a hydroxyl group protected by a protective group A, an amino group protected by an acetyl group or a hydroxymethyl group protected by an acetyl group,
R ^{2 'is} SO ₂ NR ⁴ R ^4' indicates a or a nitro group. A 'represents a protecting group for a hydroxyl group, R ⁴ and R ^4' are the same or different from each other have also good hydrogen atom, a lower alkyl group or benzyl group, B is bromine atom or an iodine atom, * 1 Means an asymmetric carbon atom. ] The compound shown by these. 17. A compound represented by the general formula (III): [In the formula, Y represents a hydrogen atom or an amine protecting group, and R ⁶ represents a hydrogen atom or a lower alkyl group. X
Represents a secondary nitrogen atom, an oxygen atom, a sulfur atom or a methylene group, and when X is a secondary nitrogen atom, an oxygen atom or a sulfur atom, R ^{9 ′} is a hydrogen atom and R ^{7 ′} or R ^{8 ′} One of them is a hydrogen atom and the other is a hydrogen atom, an acetylamino group or a hydroxyl group protected by a protective group A ″. When X is a methylene group, R ^{7 ′} and R ^{8 ′} are both hydrogen atoms, and R ^{9 ′} is a hydrogen atom, an acetylamino group or a hydroxyl group protected by the protective group A ″. * 2 is R ⁶
Is a lower alkyl group, it means an asymmetric carbon atom. ] The compound shown by these. 18. A compound represented by the general formula (IV): [Wherein R ^{1 ′} represents a hydrogen atom, a halogen atom, a hydroxyl group protected by a protective group A, an amino group protected by an acetyl group or a hydroxymethyl group protected by an acetyl group,
R ⁶ represents a hydrogen atom or a lower alkyl group. Y'means a hydrogen atom or an amine protecting group, X represents a secondary nitrogen atom, an oxygen atom, a sulfur atom or a methylene group,
When X is a secondary nitrogen atom, oxygen atom or sulfur atom,
R ^{9 ′} is a hydrogen atom, one of R ^{7 ′ and} R ^{8 ′} is a hydrogen atom, and the other is an acetylamino group or a protective group A ″.
Shows a hydroxyl group protected by. When X is a methylene group, R ⁷ 'and R ⁸ ' are both hydrogen atoms, and R ⁹ 'is a hydrogen atom, an acetylamino group or a hydroxyl group protected by a protective group A''.A'represents a hydroxyl-protecting group, * 1 means an asymmetric carbon atom, and * 2 means an asymmetric carbon atom when R ⁶ is a lower alkyl group. ] The compound shown by these.