JPH0741496A - Steroid derivative - Google Patents

Abstract

PURPOSE:To provide a steroid derivative for preventing and treating diseases such as prostatic hypertrophy, prostatic cancer, etc., caused by excessive 5alpha- dihydrotestosterone, having excellent inhibitory action on testosterone 5alpha-reductase, comprising a steroid derivative. CONSTITUTION:A corticosterone of formula I (Z is oxo, H and OH or H and 1-5C aliphatic acyloxy) is dissolved in dioxane, mixed with a hot aqueous solution of sodium periodate and stirred at 50 deg.C for 1 day. The reaction solution is filtered, a water layer of the filtrate is acidified with hydrochloric acid, extracted with methylene chloride and treated with diazomethane to give an ester derivative of formula II (R<5> is a carboxyl-protecting group). Then, the ester derivative is treated with dimethyl cyanophosphate, hydrolyzed, reacted with an amine of the formula HNR<1>R<2> [R<1> is H, 1-6C alkyl, etc.; R<2> is a (substituted)alkyl, etc.] to give a compound of formula III. Further this compound is hydrolyzed or reduced to give the steroid derivative of formula IV [R<3> is a (protected) COOH or (substituted)alkyl, etc.].

Description

Detailed Description of the Invention

[0001]

[Object of the Invention]

[0002]

FIELD OF THE INVENTION The present invention relates to testosterone-5α.
-Regarding a steroid derivative having a reductase inhibitory action and a pharmacologically acceptable salt thereof, it is useful as a preventive agent and / or a therapeutic agent for a disease caused by an excess of 5α-dihydrotestosterone. Examples of such diseases include benign prostatic hyperplasia, acne, male baldness, hirsutism of females, and the like. In particular, the steroid derivative of the present invention and a pharmacologically acceptable salt thereof are benign prostatic hyperplasia. It is useful as a prophylactic or / and therapeutic agent and a prophylactic or / and therapeutic agent for prostate cancer.

[0003]

PRIOR ART Conventionally, compounds having a testosterone-5α-reductase inhibitory activity and useful as therapeutic agents for benign prostatic hyperplasia include, for example, the following compounds A, B, C and D:
Etc. are known [JP-A-3-169890 (EP-
A427434, US 5041433)].

[0004]

[Chemical 2]

[0005]

However, the action of these compounds cannot be said to be satisfactory in terms of their potency and the like, and it is desired to develop a compound having a new structure and having stronger potency. It was The present inventors have extensively studied for many years about the synthesis of a compound having testosterone-5α-reductase inhibitory activity and its pharmacological action. As a result, a novel steroid derivative having a specific substituent at the 17-position is excellent. It has been found that the compound has testosterone-5α-reductase inhibitory activity, and is particularly useful as a preventive agent and / or therapeutic agent for benign prostatic hypertrophy and a preventive agent and / or therapeutic agent for prostate cancer. .

[0006]

The steroid derivative of the present invention has the general formula (1)

[0007]

[Chemical 3]

[Wherein R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkyl group substituted by one or more groups selected from the substituent group A, R ²
Is a C ₁ -C ₆ alkyl group substituted by one or more groups selected from Substituent group A (further optionally, it may have a carboxy group or a hydroxyl group as a substituent), or Represents a diarylamino group, R ³ is a carboxy group, a protected carboxy group, or a group represented by the formula —C
A group having ONHSO ₂ R ⁴ (wherein R ⁴ is C ₁ -C
₆ alkyl group or a C ₁ -C ₆ alkyl group substituted by one or more groups selected from Substituent group A is shown. )
And Z is an oxo group, a hydrogen atom and a hydroxyl group, or
A hydrogen atom and C ₁ -C ₅ aliphatic acyloxy group. ] And preferably in the above, (2) R ¹
But a hydrogen atom, C ₁ -C ₄ alkyl group, or, C ₁ -C substituted by one or more groups selected from Substituent group A
₄ alkyl group, steroid derivative, (3) R ¹
Is a hydrogen atom, a C ₁ -C ₄ alkyl group, or a C ₁ -substituted by one or more groups selected from the substituent group A ′.
A steroid derivative, which is a C ₄ alkyl group, (4) R ¹
But a hydrogen atom, C ₂ -C ₄ alkyl group, or a methyl group substituted by one or more groups selected from Substituent group A ', a steroid derivative, have (5) R ^1, a hydrogen atom, A C ₂ -C ₄ alkyl group or a methyl group substituted with one or more groups selected from the substituent group A ″,
Steroid derivative, (6) R ¹ is hydrogen atom, carbon number 3
An alkyl group, a benzyl group, a benzyl group substituted with one or more groups selected from the substituent group B, a furylmethyl group or a thienylmethyl group, a steroid derivative,
(7) A steroid derivative, wherein R ¹ is a hydrogen atom, an isopropyl group, a benzyl group, a benzyl group substituted with one or more groups selected from Substituent group C, or a thienylmethyl group, (8) The above (1) ) To (7), R ²
Is a C ₁ -C ₄ alkyl group substituted with one or more groups selected from the substituent group A, or a diarylamino group, (9) In the above (1) to (7), A steroid derivative in which R ² is a C ₁ -C ₄ alkyl group substituted with one or more groups selected from the substituent group A ′, or a diarylamino group,
(10) In the above (1) to (7), R ² is C substituted with one or more groups selected from the substituent group A ″.
₁ -C ₄ alkyl group, or a diarylamino group, a steroid derivative, (11) (1) to (7)
In, R ² is a C ₁ -C ₄ alkyl group substituted by 1 or 2 substituents (the substituent is a phenyl group, a phenyl group substituted by one or more groups selected from Substituent group B). , A furyl group, a thienyl group, a C ₁ -C ₄ alkyl-substituted thienyl group, a C ₁ -C ₄ alkyl-substituted furyl group), a diarylamino group or a substituent group B. Steroid derivative which is a diarylamino group substituted by the above groups, (12) In the above (1) to (7), R ² is a C ₁ -C ₄ alkyl group substituted by 1 or 2 substituents. (The substituent is a phenyl group, a phenyl group substituted with one or more groups selected from the substituent group C, a furyl group, a methyl-substituted furyl group, a thienyl group or a methyl-substituted thienyl group.), Diphenylamino Or diphenylamino group substituted by one or more groups selected from Substituent group C, a steroid derivative, in (13) above (1), R ¹ and R ² are the same or different, benzyl or A steroid derivative which is a benzyl group substituted with one or more groups selected from the substituent group C, (14) In the above (1), R ¹ and R ² are the same or different,
A steroid derivative which is a benzyl group or a substituted benzyl group (the substituent on the ring is a methyl group, a methoxy group, a fluorine atom, a chlorine atom, a dimethylamino group or a hydroxyl group), (15) above (1). ), R ¹ is a hydrogen atom, and R ² is a C ₁ -C ₄ alkyl group substituted by 1 to 2 substituents (the substituents are selected from a phenyl group and a substituent group C). A phenyl group, a furyl group or a thienyl group substituted with one or more groups), a diphenylamino group or a diphenylamino group substituted with one or more groups selected from Substituent Group C, a steroid derivative, (16) In the above (1), R ¹ is a hydrogen atom, and R ² is a C ₁ -C ₄ alkyl group substituted with 1 to 2 substituents (the substituent is a phenyl group,
A phenyl group, a furyl group or a thienyl group substituted with one or more groups selected from the substituent group D. ), A diphenylamino group or a diphenylamino group substituted with one or more groups selected from Substituent group D, (17) In the above (1), R ¹ is a hydrogen atom, and R is ² is a C ₁ -C ₃ alkyl group substituted by 1 to 2 substituents [the substituent is a phenyl group, a substituted phenyl group (the substituent is a methyl group, a methoxy group, a fluorine atom, chlorine An atom or a hydroxyl group.),
A furyl group or a thienyl group. ] In the above (1) to (17), R is
³ is a carboxy group, a protected carboxy group (the protecting group is a C ₁ -C ₆ alkyl group; a halogeno “C ₁ -C ₆ alkyl group”; a hydroxy “C ₁ -C ₆ alkyl group”;
"Alkoxy" - "C ₁ -C ₆ alkyl group" or "alkoxy" - "alkoxy" - "C ₁ -C ₆ alkyl group"; phenacyl group; ( "alkoxy" carbonyl)
- "C ₁ -C ₆ alkyl group", cyano, "C ₁ -C ₆ alkyl group"; ( "C ₁ -C ₆ alkyl" thio) methyl group;
"Aryl" thiomethyl group which can be substituted by halogen ( "C ₁ -C ₆ alkyl" sulfonyl) - "C ₁ -C ₆
Alkyl group ";(" aryl "sulfonyl) -" C ₁
-C ₆ alkyl group ";" aryl "-" C ₁ -C ₆ alkyl group ";" aryl group "; group (wherein having the formula ^{-SiR a R b R c, R} a, R b and R ^c , The same or different, and represent a "C ₁ -C ₆ alkyl group" or an "aryl group", except when all represent an "aryl group"); (C ₁ -C ₆ alkanoyloxy)- "C _1-
C ₆ alkyl group "; (C ₆ -C ₇ cycloalkanoyloxy) -" C ₁ -C ₆ alkyl group ";(" alkoxy "
Carbonyloxy) - "C ₁ -C ₆ alkyl group"; (C
_5- C ₆ cycloalkoxycarbonyloxy)-“C ₁
-C ₆ alkyl group ";[5" aryl "oxo-1,3-dioxolen-4-yl] methyl group; [5-
“C ₁ -C ₆ alkyl” -2-oxo-1,3-dioxolen-4-yl] methyl group or phthalidyl group,
Steroid derivative, (19) A steroid derivative, wherein in the above (1) to (17), R ³ is a carboxy group, a methoxycarbonyl group or an ethoxycarbonyl group.
(20) In the above (1) to (19), Z is a steroid group, and (21) In the above (1) to (19), Z is an α-hydrogen atom and a β-hydroxyl group. , Steroid derivatives, and (22) above (1)
To (19), Z is an α-hydrogen atom and β-
(C ₁ -C ₅ aliphatic acyloxy group), which is a steroid derivative, while the testosterone 5α of the present invention is
-The reductase inhibitor contains the steroid derivative or the pharmacologically acceptable salt thereof described in the item 1 selected from the above (1) to (22), and is also a preventive agent for prostatic hypertrophy of the present invention Or / and the therapeutic agent contains the steroid derivative described in one item selected from the above (1) to (22) or a pharmacologically acceptable salt thereof, and
The prophylactic and / or therapeutic agent for prostate cancer of the present invention contains the steroid derivative or the pharmaceutically acceptable salt thereof described in the item (1) to (22) above.

[Substituent Group A] An aryl group and a 5- to 6-membered cyclic heteroaryl group.

[Substituent group A '] aryl group and 5-membered cyclic heteroaryl group.

[Substituent group A ″] phenyl group, furyl group and thienyl group.

[Substituent Group B] C ₁ -C ₄ alkyl group, C
₁ -C ₄ alkoxy group, a halogen atom, an amino group, mono- or di (C ₁ -C ₄ alkyl) amino group, a hydroxyl group,
C ₂ -C ₅ alkoxycarbonyl group, and, C ₁ -C ₅
Aliphatic acylamino group.

[Substituent Group C] C ₁ -C ₄ Alkyl Group, C
₁ -C ₄ alkoxy group, a halogen atom, mono- or di (C ₁ -C ₄ alkyl) amino group, and a hydroxyl group.

[Substituent Group D] Methyl group, methoxy group, fluorine atom, chlorine atom, dimethylamino group, hydroxyl group and acetylamino group.

In the general formula (I), R ¹ and R ⁴
In the definition of “C ₁ -C ₆ alkyl group”, and R
“C ₁ -C ₆ alkyl group” of “C ₁ -C ₆ alkyl group substituted by one or more groups selected from substituent group A” in the definitions of ¹ , R ² and R ⁴ is, for example, Methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, s-butyl, tert-butyl, n-pentyl, isopentyl, 2-methylbutyl, neopentyl, 1-ethylpropyl, n-hexyl, isohexyl, 4-methyl Pentyl, 3-methylpentyl, 2-methylpentyl, 1-methylpentyl, 3,3-dimethylbutyl, 2,2-dimethylbutyl, 1,1-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethyl A linear or branched alkyl group having 1 to 6 carbon atoms such as butyl, 2,3-dimethylbutyl, 2-ethylbutyl, preferably 1 to 4 carbon atoms A chain or branched alkyl group, and more preferably with respect to R ^1, 2 to carbon atoms is 4 linear or branched alkyl group, and more preferably with respect to R ^2, the carbon number 1 to 3 linear or branched alkyl groups, more preferably 2 to 3 carbon linear or branched alkyl groups, and even more preferably 3 carbon atoms. A straight chain or branched chain alkyl group, and most preferably an isopropyl group.

“C ₁ -C ₄ alkyl group” in the definitions of [Substituent group B] and [Substituent group C], and one or more groups selected from “Substituent group A ′” in the definition of R ^2. C ₁ -C substituted by ₄ alkyl group ", C ₁ substituted by one or more groups selected from" substituent group a "-
"C ₄ alkyl group", "C ₁ -C ₄ alkyl group substituted by 1 or 2 substituents", "C ₁ -C ₄ alkyl substituted thienyl group" and "C ₁ -C ₄ alkyl substituted" The “C ₁ -C ₄ alkyl group” of the “provided furyl group” is
Among the above-mentioned "C ₁ -C ₆ alkyl group", a straight or branched chain alkyl group having 1 to 4 carbon atoms is shown, and preferably,
It is a linear or branched alkyl group having 1 to 3 carbon atoms.

The "C ₁ -C '1 to 2 C ₁ -C ₃ alkyl group substituted by a substituent group" in the definition of R ²
_The “ ₃ alkyl group” means, in the description of the “C ₁ -C ₆ alkyl group”, a straight chain or branched chain alkyl group having 1 to 3 carbon atoms and a straight chain or branched chain alkyl group having 1 to 3 carbon atoms. And is preferably a linear or branched alkyl group having 2 to 3 carbon atoms, more preferably a linear or branched alkyl group having 3 carbon atoms, and most preferably , An isopropyl group.

The "halogen atom" in the definitions of [Substituent group B] and [Substituent group C] is, for example, a fluorine atom, a chlorine atom, a bromine atom or an iodine atom, and preferably a fluorine atom or a chlorine atom. Atoms and bromine atoms.

“Aryl group” in the definitions of [Substituent group A] and [Substituent group A ′], and one or more selected from “Diarylamino group” and “Substituent group B” in the definition of R ² . Diarylamino group substituted by a group "
The “aryl group” is an aryl group having 6 to 14 carbon atoms, and includes, for example, phenyl, indenyl, naphthyl,
Examples thereof include groups such as phenanthrenyl and anthracenyl, and a phenyl group is preferable. The "aryl group" may be condensed with a cycloalkyl group having 3 to 10 carbon atoms, and examples thereof include a group such as 2-indanyl. Further, the aryl ring may have 1 to 4 (preferably 1 to 2) substituents, which are the above-mentioned "C ₁ -C ₆ alkyl group" (preferably C ₁ -C ₆ alkyl group). ₁ -C ₄ alkyl group); for example, methoxy, ethoxy, n- propoxy, isopropoxy, n-butoxy, isobutoxy, s- butoxy, tert- butoxy, n
-Pentoxy, isopentoxy, 2-methylbutoxy,
Neopentoxy, n-hexyloxy, 4-methylpentoxy, 3-methylpentoxy, 2-methylpentoxy, 3,3-dimethylbutoxy, 2,2-dimethylbutoxy, 1,1-dimethylbutoxy, 1,2- A straight-chain or branched "alkoxy group" having 1 to 6 carbon atoms such as dimethylbutoxy, 1,3-dimethylbutoxy, and 2,3-dimethylbutoxy (preferably a straight chain having 1 to 4 carbon atoms). A chain or branched alkoxy group); said "halogen atom";
An amino group; for example, a mono- or di-(“C- (C- _1- C ₆ alkyl ”) amino group (preferably mono or di (“ C ₁ alkyl ”)
-C ₄ alkyl ") amino group), a hydroxyl group, the above-mentioned" alkoxy group "is bonded to a carbonyl group," alkoxycarbonyl group "(preferably, C ₂ -C ₅ alkoxycarbonyl group, more preferably, C ₂ -C ₃ alkoxycarbonyl group); or; formylamino, acetylamino, propionylamino, butyrylamino, isobutyrylamino,
“C ₁ -C ₆ aliphatic acylamino group” such as pentanoylamino, pivaloyloxy, valerylamino, isovalerylamino, preferably C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halogen Atom, amino group, mono- or di (C ₁ -C ₄ alkyl) amino group,
Hydroxyl, C ₂ -C ₃ alkoxycarbonyl group and C ₁ -
C ₃ aliphatic acylamino group, more preferably, methyl group, ethyl group, methoxy group, ethoxy group, fluorine atom,
Chlorine atom, bromine atom, amino group, methylamino group, ethylamino group, dimethylamino group, diethylamino group, methylethylamino group, hydroxyl group, methoxycarbonyl group,
An ethoxycarbonyl group, a formylamino group and an acetylamino group are preferred, and a methyl group, a methoxy group, a fluorine atom, a chlorine atom and a hydroxyl group are particularly preferred.

The "5- or 6-membered cyclic heteroaryl group" in the definition of Substituent group A has 1 to 3 nitrogen atoms, oxygen atoms or sulfur atoms, for example, furyl, thienyl,
Pyridyl, pyrrolyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrazinyl, pyrimidyl, pyridazinyl, preferably,
Furyl, thienyl, pyridyl, more preferably,
Furyl and thienyl, and particularly preferably thienyl. Further, the heteroaryl ring may have 1 to 2 substituents, which may be the above-mentioned "C ₁ -C ₆ alkyl group" or the above "halogen atom", and preferably, C
₁ -C ₄ alkyl group, a fluorine atom, a chlorine atom, more preferably a methyl or ethyl group, particularly preferably a methyl group.

The "5-membered cyclic heteroaryl group" in the definition of [Substituent group A '] is a group having a 5-membered ring in the above description of "5- to 6-membered cyclic heteroaryl group".

The “C ₁ -C ₄ alkoxy group” in the definitions of [Substituent group B] and [Substituent group C] is, for example, methoxy, ethoxy, n-propoxy, isopropoxy,
A straight-chain or branched-chain alkoxy group having 1 to 4 carbon atoms such as n-butoxy, isobutoxy, s-butoxy, and tert-butoxy is shown, preferably a straight-chain or branched chain having 1 to 3 carbon atoms. It is an alkoxy group.

In the definitions of [Substituent group B] and [Substituent group C], "mono- or di (C ₁ -C ₄ alkyl) amino group" means the above-mentioned "mono- or di-" C ₁ -C ₆ alkyl ". In the description of "amino group", a group corresponding to 1 to 4 carbon atoms is shown.

“C ₂ -C” in the definition of [Substituent group B]
_{The “5} alkoxycarbonyl group” refers to a group in which the above “C ₁ -C ₄ alkoxy group” is bonded to a carbonyl group.

The "protecting group" of the "protected carboxy group" in the definition of R ³ is a protecting group generally widely known in synthetic organic chemistry or an ester which can be pharmacologically converted into a carboxy group in vivo. Means a residue. Examples of such a protecting group include the above-mentioned “C ₁ -C ₆ alkyl group”; halogeno “C ₁ -C ₆ alkyl group” (eg, trifluoromethyl, 2,2,2-trifluoroethyl, 2,2,2). 2-trichloroethyl, 2-fluoroethyl, 2-chloroethyl, 2-iodoethyl, 3-chloropropyl, 4-fluorobutyl, 6-iodohexyl, etc., preferably 2,2,2-trichloroethyl, 2-chloroethyl ); Hydroxy “C ₁ -C ₆ alkyl group”
(For example, 2-hydroxyethyl, 2,3-dihydroxypropyl, 3-hydroxypropyl, 3,4-dihydroxybutyl, 4-hydroxybutyl and the like, preferably 2
-Hydroxyethyl); "alkoxy"-"C ₁ -C ₆
"Alkyl group" or "alkoxy"-"alkoxy"
- "C ₁ -C ₆ alkyl group" (e.g., methoxymethyl, 2-methoxyethyl, 2-ethoxyethyl, 2-methoxyethoxymethyl, etc., preferably methoxymethyl); phenacyl group; ( "alkoxy" carbonyl) −
"C ₁ -C ₆ alkyl group" (e.g., methoxycarbonylmethyl, etc.), cyano "C ₁ -C ₆ alkyl group" (e.g., cyanomethyl, 2-cyanoethyl, etc.); ( "C ₁ -
C ₆ alkyl ”thio) methyl group (eg, methylthiomethyl, ethylthiomethyl, etc.);“ Aryl ”thiomethyl group (eg, phenylthiomethyl, naphthylthiomethyl, etc.); optionally substituted with halogen (“ C _1- C ₆ alkyl "sulfonyl) -" C ₁ -C ₆ alkyl group "(e.g., 2-methanesulfonyl-ethyl, 2-trifluoromethanesulfonyl ethyl group, etc.); (" aryl "sulfonyl) -" C ₁ -C ₆ alkyl group (Eg, 2-benzenesulfonylethyl, 2-toluenesulfonylethyl group, etc.); “Aryl”-“C ₁ -C ₆ alkyl group” (eg, benzyl, naphthylmethyl, diphenylmethyl, trityl, 6-phenylhexyl, 4-methylbenzyl,
2,4,6-trimethylbenzyl, 3,4,5-trimethylbenzyl, 4-methoxybenzyl, 4-chlorobenzyl, 4-bromobenzyl group, preferably phenyl-
"C ₁ -C ₆ alkyl group", and more preferably, benzyl, 4-methylbenzyl, 4-chlorobenzyl, 4-bromobenzyl group); the "aryl group"; Formula -SiR ^a
A group having R ^b R ^c (wherein R ^a , R ^b and R ^c are
Identical to or different from a "C ₁ -C ₆ alkyl group" or "aryl group". However, the case where all are "aryl groups" is excluded. For example, trimethylsilyl, triethylsilyl, isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl, methyldi-t
-Butylsilyl, triisopropylsilyl, methyldiphenylsilyl, isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilyl group,
Preferably, trimethylsilyl, t-butyldimethylsilyl, methyldiphenylsilyl group); (C ₁ -C ₆ alkanoyloxy)-“C ₁ -C ₆ alkyl group” (eg,
Formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, valeryloxymethyl, isovaleryloxymethyl, hexanoyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1 -Propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, 1-valeryloxyethyl, 1-isovaleryloxyethyl, 1-hexanoyloxyethyl, 2-formyloxyethyl, 2- Acetoxyethyl, 2-propionyloxyethyl, 2-butyryloxyethyl, 2-pivaloyloxyethyl, 2-valeryloxyethyl, 2-isovaleryloxyethyl, 2-hexanoyloxyethyl, 1-formyloxy Propyl, 1-acetoxyp Pills, 1-propionyloxy-propyl, 1-butyryloxy-propyl, 1-pivaloyloxymethyl-propyl, 1-valeryl propyl, 1-
Isovaleryloxypropyl, 1-hexanoyloxypropyl, 1-acetoxybutyl, 1-propionyloxybutyl, 1-butyryloxybutyl, 1-pivaloyloxybutyl, 1-acetoxypentyl, 1-propionyloxypentyl, 1-butyryloxypentyl,
1-pivaloyloxypentyl, 1-pivaloyloxyhexyl group and the like, preferably formyloxymethyl, acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1-formyloxyethyl, 1-acetoxyethyl, 1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl, more preferably acetoxymethyl, propionyloxymethyl, butyryloxymethyl, pivaloyloxymethyl, 1 -Acetoxyethyl,
1-propionyloxyethyl, 1-butyryloxyethyl, 1-pivaloyloxyethyl groups, particularly preferably,
Pivaloyloxymethyl, 1-pivaloyloxyethyl group); (C ₆ -C ₇ cycloalkanoyloxy)-“C
₁ -C ₆ alkyl group "(e.g., cyclopentadiene pivaloyloxymethyl, cyclohexanol pivaloyloxymethyl, 1-cyclopropyl pentanoyloxy ethyl, 1-cyclohexanoyl oxyethyl, 1-cyclopropyl pentanoyloxy propyl, 1-cyclohex Noyloxypropyl, 1-cyclopentanoyloxybutyl, 1-cyclohexanoyloxybutyl group, preferably cyclopentanoyloxymethyl, cyclohexanoyloxymethyl, 1-cyclopentanoyloxyethyl, 1-cyclohexanoyl Oxyethyl group); ("alkoxy" carbonyloxy)
- "C ₁ -C ₆ alkyl group" (e.g., methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,
Propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, pentyloxycarbonyloxymethyl, hexyloxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1- Propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1-
Pentyloxycarbonyloxyethyl, 1-hexyloxycarbonyloxyethyl, 2-methoxycarbonyloxyethyl, 2-ethoxycarbonyloxyethyl, 2-propoxycarbonyloxyethyl, 2-isopropoxycarbonyloxyethyl, 2-butoxycarbonyloxyethyl, 2-isobutoxycarbonyloxyethyl, 2-pentyloxycarbonyloxyethyl, 2-hexyloxycarbonyloxyethyl, 1-
Methoxycarbonyloxypropyl, 1-ethoxycarbonyloxypropyl, 1-propoxycarbonyloxypropyl, 1-isopropoxycarbonyloxypropyl, 1-butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl, 1-pentyloxycarbonyloxypropyl, 1-hexyloxycarbonyloxypropyl, 1-methoxycarbonyloxybutyl, 1-ethoxycarbonyloxybutyl, 1-
Propoxycarbonyloxybutyl, 1-isopropoxycarbonyloxybutyl, 1-butoxycarbonyloxybutyl, 1-isobutoxycarbonyloxybutyl, 1-methoxycarbonyloxypentyl, 1-ethoxycarbonyloxypentyl, 1-methoxycarbonyloxyhexyl, 1 -Ethoxycarbonyloxyhexyl group and the like, preferably methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl. , 1-ethoxycarbonyloxyethyl, 1
-Propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1-butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl, 1-methoxycarbonyloxypropyl, 1-ethoxycarbonyloxypropyl, 1-propoxycarbonyloxypropyl, 1-isopropoxycarbonyloxypropyl, 1-butoxycarbonyloxypropyl, 1-isobutoxycarbonyloxypropyl, 1-
Methoxycarbonyloxybutyl, 1-ethoxycarbonyloxybutyl, 1-propoxycarbonyloxybutyl, 1-isopropoxycarbonyloxybutyl, 1
-Butoxycarbonyloxybutyl, 1-isobutoxycarbonyloxybutyl group, more preferably methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, propoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, butoxycarbonyloxymethyl, isobutoxycarbonyloxy. Methyl, 1-
Methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-propoxycarbonyloxyethyl, 1-isopropoxycarbonyloxyethyl, 1
-Butoxycarbonyloxyethyl, 1-isobutoxycarbonyloxyethyl group, particularly preferably methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl, isopropoxycarbonyloxymethyl, 1-methoxycarbonyloxyethyl, 1-ethoxycarbonyloxyethyl, 1-isopropoxycarbonyloxy ethyl group); (C ₅ -C ₆ cycloalkoxy-carbonyloxy) - "C ₁ -C ₆ alkyl group" (e.g., cyclopentyloxycarbonyl oxymethyl, cyclohexyloxycarbonyloxy, 1- cyclopentyloxy Carbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl, 1-cyclopentyloxycarbonyloxypropyl, 1-cyclohexyloxycarbonyloxyp Ropil, 1-cyclopentyloxycarbonyloxybutyl, 1-cyclohexyloxycarbonyloxybutyl group, preferably cyclopentyloxycarbonyloxymethyl, cyclohexyloxycarbonyloxymethyl, 1-cyclopentyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl group); [5- ( "aryl" - or 5 - ( "C ₁ -C ₆ alkyl") -2-oxo-1,
3-Dioxolen-4-yl] methyl group [for example, (5
-Phenyl-2-oxo-1,3-dioxolen-4-
Yl) methyl, [5- (4-methylphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5
-(4-Methoxyphenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, [5- (4-fluorophenyl) -2-oxo-1,3-dioxolen-4-
Yl] methyl, [5- (4-chlorophenyl) -2-oxo-1,3-dioxolen-4-yl] methyl, (5
-Methyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-ethyl-2-oxo-1,3-dioxolen-4-yl) methyl, (5-propyl-2-oxo-1) , 3-Dioxolen-4-yl) methyl, (5
-Isopropyl-2-oxo-1,3-dioxolene-
4-yl) methyl, (5-butyl-2-oxo-1,3)
-Dioxolen-4-yl) methyl group and the like, preferably
(5-phenyl-2-oxo-1,3-dioxolene-
4-yl) methyl, (5-methyl-2-oxo-1,3
-Dioxolen-4-yl) methyl, (5-ethyl-2)
-Oxo-1,3-dioxolen-4-yl) methyl group, particularly preferably (5-methyl-2-oxo-1,3
-Dioxolen-4-yl) methyl group]; or a phthalidyl group.

A suitable protecting group is C₁ -C_Four Archi
Group, benzyl group, methyl, ethyl, methoxy, etoki
A benzyl group substituted with ci, fluoro or chloro,
Diphenylmethyl group, naphthylmethyl group, (C₁ -C_Five 
Alkanoyloxy) C₁ -C_Four Alkyl group, (C₆ −
C₇ Cycloalkanoyloxy) C₁ -C_Four Alkyl
Group, (C₁ -C_Four Alkoxycarbonyloxy) C₁ −
C_Four Alkyl group, (C_Five-C₆ Cycloalkoxy carbo
Nyloxy) C₁ -C_Four Alkyl group, [5-phenyl-
Or 5- (C₁ -C_Four Alkyl) -2-oxo-
1,3-Dioxolen-4-yl] methyl group or lid
A lysyl group, more preferably C₁ -C_Four Alkyl
Group, benzyl group, (C₁ -C_Five Alkanoyloxy) C
₁ -C₂ Alkyl group, (C₆ -C₇ Cycloalkanoyl
Oxy) C₁ -C₂ Alkyl group, (C ₁ -C_Four Arcoki
Cicarbonyloxy) C₁ -C₂ Alkyl group, (C_Five −
C₆ Cycloalkoxycarbonyloxy) C₁ -C₂ A
Alkyl group, [5-phenyl- or 5- (C₁ -C₂ 
Alkyl) -2-oxo-1,3-dioxolen-4-
And] are particularly preferred.
Is C₁ -C₂ Alkyl group, pivaloyloxymethyl
Group, ethoxycarbonyloxymethyl group, 1- (ethoxy
Cycarbonyloxy) ethyl group, isopropoxycarbo
Nyloxymethyl group, 1- (isopropoxycarbonyl
(Oxy) ethyl group, (5-methyl-2-oxo-1,3)
-Dioxolen-4-yl) methyl group or phthalidyl group
Is.

“C ₁ -C” in the definition of [Substituent group B]
₅ "Aliphatic acylamino group" and "C in the definition of Z
Examples of the “C ₁ -C ₅ aliphatic acyl” in the “ _1- C ₅ aliphatic acyloxy group” include formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, and preferably,
C ₁ -C ₃ aliphatic acyl group, more preferably formyl or acetyl group.

Formula -NR ¹ R ² With preferred groups having
For example, benzylamino, (2-methylbenzi
) Amino, (3-methylbenzyl) amino, (4-me
Cylbenzyl) amino, (2-methoxybenzyl) ami
No, (3-methoxybenzyl) amino, (4-methoxy
Benzyl) amino, (2-fluorobenzyl) amino,
(3-Fluorobenzyl) amino, (4-fluoroben
Dil) amino, (2-chlorobenzyl) amino, (3-
(Chlorobenzyl) amino, (4-chlorobenzyl) ami
No, phenethylamino, (2-methylphenethyl) ami
No, (3-methylphenethyl) amino, (4-methylphenethyl)
(Ethenyl) amino, (2-methoxyphenethyl) ami
No, (3-methoxyphenethyl) amino, (4-methoxy)
Ciphenethyl) amino, (2-fluorophenethyl) a
Mino, (3-fluorophenethyl) amino, (4-flu
Orophenethyl) amino, (2-chlorophenethyl) a
Mino, (3-chlorophenethyl) amino, (4-chloro
Phenethyl) amino, (3-phenylpropyl) ami
No, (1-methyl-1-phenylethyl) amino, [1
-Methyl-1- (2-methylphenyl) ethyl] ami
No, [1-methyl-1- (3-methylphenyl) ethyl
L] amino, [1-methyl-1- (4-methylphenyl)
Lu) ethyl] amino, [1-methyl-1- (2-methoxy)
Cyphenyl) ethyl] amino, [1-methyl-1- (3
-Methoxyphenyl) ethyl] amino, [1-methyl-
1- (4-methoxyphenyl) ethyl] amino, [1-
Methyl-1- (2-fluorophenyl) ethyl] ami
No, [1-methyl-1- (3-fluorophenyl) ethyl
L] amino, [1-methyl-1- (4-fluorophenyl)
Lu) ethyl] amino, [1-methyl-1- (2-chloro)
(Phenyl) ethyl] amino, [1-methyl-1- (3-
Chlorophenyl) ethyl] amino, [1-methyl-1-
(4-chlorophenyl) ethyl] amino, [1-methyl
-1- (2-hydroxyphenyl) ethyl] amino,
[1-methyl-1- (3-hydroxyphenyl) ethyl
L] amino, [1-methyl-1- (4-hydroxyphene
Nyl) ethyl] amino, [1-methyl-1- (2-ami
Nophenyl) ethyl] amino, [1-methyl-1- (3
-Aminophenyl) ethyl] amino, [1-methyl-1
-(4-Aminophenyl) ethyl] amino, [1-methyl
L-1- (2-methylaminophenyl) ethyl] ami
No, [1-methyl-1- (3-methylaminophenyl)
Ethyl] amino, [1-methyl-1- (4-methylami
Nophenyl) ethyl] amino, [1-methyl-1- (2
-Ethylaminophenyl) ethyl] amino, [1-methyl
L-1- (3-ethylaminophenyl) ethyl] ami
No, [1-methyl-1- (4-ethylaminophenyl)
Ethyl] amino, [1-methyl-1- (2-dimethyla
Minophenyl) ethyl] amino, [1-methyl-1-
(3-Dimethylaminophenyl) ethyl] amino, [1
-Methyl-1- (4-dimethylaminophenyl) ethyl
Lu] amino, {1-methyl-1- [3,5-bis (dim
Cylamino) phenyl] ethyl} amino, [1-methyl
-1- (2-acetamidophenyl) ethyl] amino,
[1-Methyl-1- (3-acetamidophenyl) ethyl
L] amino, [1-methyl-1- (4-acetamidophosphine)
Phenyl) ethyl] amino, [1-methyl-1- (2,3
-Dimethoxyphenyl) ethyl] amino, [1-methyl
-1- (2,4-dimethoxyphenyl) ethyl] ami
No, [1-methyl-1- (2,5-dimethoxyphenyl
Ru) ethyl] amino, [1-methyl-1- (2,6-di
Methoxyphenyl) ethyl] amino, [1-methyl-1
-(3,4-dimethoxyphenyl) ethyl] amino,
[1-Methyl-1- (3,5-dimethoxyphenyl) e
Tyl] amino, [1-methyl-1- (3,6-dimethoxy)
Cyphenyl) ethyl] amino, [1-methyl-1-
(3,4,5-Trimethoxyphenyl) ethyl] ami
No, [1-methyl-1- (2,4,6-trimethoxyphenol
Phenyl) ethyl] amino, (1,1-dimethyl-2-phenyl)
Phenylethyl) amino, [1,1-dimethyl-2- (2
-Methylphenyl) ethyl] amino, [1,1-dimethyl]
Ru-2- (3-methylphenyl) ethyl] amino,
[1,1-dimethyl-2- (4-methylphenyl) ethyl
Lu] amino, [1,1-dimethyl-2- (2-methoxy
Phenyl) ethyl] amino, [1,1-dimethyl-2-
(3-Methoxyphenyl) ethyl] amino, [1,1-
Dimethyl-2- (4-methoxyphenyl) ethyl] ami
No, [1,1-dimethyl-2- (2-fluorophenyl
Ru) ethyl] amino, [1,1-dimethyl-2- (3-
Fluorophenyl) ethyl] amino, [1,1-dimethyl]
Ru-2- (4-fluorophenyl) ethyl] amino,
[1,1-dimethyl-2- (2-chlorophenyl) ethyl
L] amino, [1,1-dimethyl-2- (3-chlorofluoro)
Phenyl) ethyl] amino, [1,1-dimethyl-2-
(4-chlorophenyl) ethyl] amino, benzhydrido
Luamino, (2,2'-dimethylbenzhydryl) ami
No, (2,3'-dimethylbenzhydryl) amino,
(2,4'-Dimethylbenzhydryl) amino, (3,4
3'-Dimethylbenzhydryl) amino, (3,4'-
Dimethylbenzhydryl) amino, (4,4'-dimethyl)
Rubenzhydryl) amino, (2,2'-dimethoxybenzoyl)
Nzhydryl) amino, (2,3'-dimethoxybenz)
Hydryl) amino, (2,4'-dimethoxybenzhydride)
(Ryl) amino, (3,3'-dimethoxybenzhydri)
) Amino, (3,4'-dimethoxybenzhydryl)
Amino, (4,4'-dimethoxybenzhydryl) ami
No, (2,2'-difluorobenzhydryl) amino,
(2,3'-difluorobenzhydryl) amino,
(2,4'-difluorobenzhydryl) amino,
(3,3′-difluorobenzhydryl) amino,
(3,4'-difluorobenzhydryl) amino,
(4,4'-difluorobenzhydryl) amino,
(2,2'-dihydroxybenzhydryl) amino,
(2,3'-dihydroxybenzhydryl) amino,
(2,4'-dihydroxybenzhydryl) amino,
(3,3'-dihydroxybenzhydryl) amino,
(3,4'-dihydroxybenzhydryl) amino,
(4,4'-dihydroxybenzhydryl) amino,
(2,2'-Diaminobenzhydryl) amino, (2
3'-diaminobenzhydryl) amino, (2,4'-
Diaminobenzhydryl) amino, (3,3′-diami
Nobenzhydryl) amino, (3,4'-diaminoben)
Tsuhydryl) amino, (4,4'-diaminobenzhydride
Ryl) amino, [2,2′-di (dimethylamino) ben
Tsuhydryl] amino, [2,3′-di (dimethylamido)
No) Benzhydryl] amino, [2,4′-di (dimethy)
Luamino) benzhydryl] amino, [3,3′-di
(Dimethylamino) benzhydryl] amino, [3
4'-di (dimethylamino) benzhydryl] amino,
[4,4'-Di (dimethylamino) benzhydryl]
Mino, (2-methylbenzhydryl) amino, (3-me
Cylbenzhydryl) amino, (4-methylbenzhydride)
(Ryl) amino, (2-methoxybenzhydryl) ami
No, (3-methoxybenzhydryl) amino, (4-me
Toxibenzhydryl) amino, (2-fluorobenz
Hydryl) amino, (3-fluorobenzhydryl) a
Mino, (4-fluorobenzhydryl) amino, (2-
Chlorobenzhydryl) amino, (3-chlorobenzhydryl)
Drill) amino, (4-chlorobenzhydryl) ami
No, (2-hydroxybenzhydryl) amino, (3-
Hydroxybenzhydryl) amino, (4-hydroxy
Benzhydryl) amino, (2-aminobenzhydryl)
Amino), (3-aminobenzhydryl) amino,
(4-Aminobenzhydryl) amino, (2-dimethyl
Aminobenzhydryl) amino, (3-dimethylamino)
Benzhydryl) amino, (4-dimethylaminobenz)
Hydryl) amino, (1,1-diphenylethyl) ami
No, (1,2-diphenylethyl) amino, [2- (2
-Methylphenyl) -1-phenylethyl] amino,
[2- (3-methylphenyl) -1-phenylethyl]
Amino, [2- (4-methylphenyl) -1-phenyl
Ethyl] amino, [2- (2-methoxyphenyl) -1
-Phenylethyl] amino, [2- (3-methoxyphen)
Nyl) -1-phenylethyl] amino, [2- (4-me
Toxyphenyl) -1-phenylethyl] amino, [2
-(2-Fluorophenyl) -1-phenylethyl] a
Mino, [2- (3-fluorophenyl) -1-phenyl
Ethyl] amino, [2- (4-fluorophenyl) -1
-Phenylethyl] amino, [2- (2-chlorophenyl)
) -1-Phenylethyl] amino, [2- (3-chloro)
Rophenyl) -1-phenylethyl] amino, [2-
(4-Chlorophenyl) -1-phenylethyl] ami
No, [1- (2-fluorophenyl) -2- (2-full
Orophenyl) ethyl] amino, [1- (2-fluoro
Phenyl) -2- (3-fluorophenyl) ethyl] a
Mino, [1- (2-fluorophenyl) -2- (4-phenyl)
Luorophenyl) ethyl] amino, [1- (3-fluor
Rophenyl) -2- (2-fluorophenyl) ethyl]
Amino, [1- (3-fluorophenyl) -2- (3-
Fluorophenyl) ethyl] amino, [1- (3-full
Orophenyl) -2- (4-fluorophenyl) eth
Ru] amino, [1- (4-fluorophenyl) -2-
(2-Fluorophenyl) ethyl] amino, [1- (4
-Fluorophenyl) -2- (3-fluorophenyl)
Ethyl] amino, [1- (4-fluorophenyl) -2
-(4-Fluorophenyl) ethyl] amino, [1-
(2-chlorophenyl) -2- (2-chlorophenyl)
Ethyl] amino, [1- (2-chlorophenyl) -2-
(3-chlorophenyl) ethyl] amino, [1- (2-
Chlorophenyl) -2- (4-chlorophenyl) eth
Ru] amino, [1- (3-chlorophenyl) -2- (2
-Chlorophenyl) ethyl] amino, [1- (3-chloro)
Rophenyl) -2- (3-chlorophenyl) ethyl] a
Mino, [1- (3-chlorophenyl) -2- (4-chloro)
Rophenyl) ethyl] amino, [1- (4-chlorophe
Nil) -2- (2-chlorophenyl) ethyl] amino,
[1- (4-chlorophenyl) -2- (3-chlorophene
Nyl) ethyl] amino, [1- (4-chlorophenyl)]
-2- (4-chlorophenyl) ethyl] amino, [1-
(2-chlorophenyl) -2- (2-methoxyphenyl)
Ru) ethyl] amino, [1- (2-chlorophenyl)-
2- (3-methoxyphenyl) ethyl] amino, [1-
(2-chlorophenyl) -2- (4-methoxyphenyl)
Ru) ethyl] amino, [1- (3-chlorophenyl)-
2- (2-methoxyphenyl) ethyl] amino, [1-
(3-chlorophenyl) -2- (3-methoxyphenyl)
Ru) ethyl] amino, [1- (3-chlorophenyl)-
2- (4-methoxyphenyl) ethyl] amino, [1-
(4-chlorophenyl) -2- (2-methoxyphenyl)
Ru) ethyl] amino, [1- (4-chlorophenyl)-
2- (3-methoxyphenyl) ethyl] amino, [1-
(4-chlorophenyl) -2- (4-methoxyphenyl)
Ru) ethyl] amino, [1- (2-methylphenyl)-
2- (2-methylphenyl) ethyl] amino, [1-
(2-methylphenyl) -2- (3-methylphenyl)
Ethyl] amino, [1- (2-methylphenyl) -2-
(4-Methylphenyl) ethyl] amino, [1- (3-
Methylphenyl) -2- (2-methylphenyl) eth
L] amino, [1- (3-methylphenyl) -2- (3
-Methylphenyl) ethyl] amino, [1- (3-methyl)
Ruphenyl) -2- (4-methylphenyl) ethyl] a
Mino, [1- (4-methylphenyl) -2- (2-methyl)
Ruphenyl) ethyl] amino, [1- (4-methylphene)
Nil) -2- (3-methylphenyl) ethyl] amino,
[1- (4-methylphenyl) -2- (4-methylphene)
Nyl) ethyl] amino, [1- (2-hydroxyphenyl)
L) -2- (2-hydroxyphenyl) ethyl] ami
No, [1- (2-hydroxyphenyl) -2- (3-hi)
Droxyphenyl) ethyl] amino, [1- (2-hydr
Roxyphenyl) -2- (4-hydroxyphenyl) e
Cyl] amino, [1- (3-hydroxyphenyl) -2
-(2-hydroxyphenyl) ethyl] amino, [1-
(3-hydroxyphenyl) -2- (3-hydroxyphenyl)
Phenyl) ethyl] amino, [1- (3-hydroxyphene
Nyl) -2- (4-hydroxyphenyl) ethyl] ami
No, [1- (4-hydroxyphenyl) -2- (2-hi
Droxyphenyl) ethyl] amino, [1- (4-hydr
Roxyphenyl) -2- (3-hydroxyphenyl) d
Cyl] amino, [1- (4-hydroxyphenyl) -2
-(4-hydroxyphenyl) ethyl] amino, [1-
(2-Aminophenyl) -2- (2-aminophenyl)
Ethyl] amino, [1- (2-aminophenyl) -2-
(3-Aminophenyl) ethyl] amino, [1- (2-
Aminophenyl) -2- (4-aminophenyl) eth
L] amino, [1- (3-aminophenyl) -2- (2
-Aminophenyl) ethyl] amino, [1- (3-ami
Nophenyl) -2- (3-aminophenyl) ethyl] a
Mino, [1- (3-aminophenyl) -2- (4-ami
Nophenyl) ethyl] amino, [1- (4-aminophen
Nil) -2- (2-aminophenyl) ethyl] amino,
[1- (4-aminophenyl) -2- (3-aminophen
Nyl) ethyl] amino, [1- (4-aminophenyl)]
-2- (4-aminophenyl) ethyl] amino, [1-
(2-Dimethylaminophenyl) -2- (2-dimethyl
Aminophenyl) ethyl] amino, [1- (2-dimethyl)
Luaminophenyl) -2- (3-dimethylaminophenyi
Ru) ethyl] amino, [1- (2-dimethylaminophen)
Nyl) -2- (4-dimethylaminophenyl) ethyl]
Amino, [1- (3-dimethylaminophenyl) -2-
(2-Dimethylaminophenyl) ethyl] amino, [1
-(3-Dimethylaminophenyl) -2- (3-dimethyl)
Luminophenyl) ethyl] amino, [1- (3-dimme
Cylaminophenyl) -2- (4-dimethylaminophen)
Nyl) ethyl] amino, [1- (4-dimethylaminophenyl)
Phenyl) -2- (2-dimethylaminophenyl) eth
L] amino, [1- (4-dimethylaminophenyl)-
2- (3-dimethylaminophenyl) ethyl] amino,
[1- (4-dimethylaminophenyl) -2- (4-di
Methylaminophenyl) ethyl] amino, [2- (2-
Fluorophenyl) -1- (2-methylphenyl) eth
Lu] amino, [2- (2-fluorophenyl) -1-
(3-Methylphenyl) ethyl] amino, [2- (2-
Fluorophenyl) -1- (4-methylphenyl) eth
Ru] amino, [2- (3-fluorophenyl) -1-
(2-Methylphenyl) ethyl] amino, [2- (3-
Fluorophenyl) -1- (3-methylphenyl) eth
Ru] amino, [2- (3-fluorophenyl) -1-
(4-Methylphenyl) ethyl] amino, [2- (4-
Fluorophenyl) -1- (2-methylphenyl) eth
Lu] amino, [2- (4-fluorophenyl) -1-
(3-Methylphenyl) ethyl] amino, [2- (4-
Fluorophenyl) -1- (4-methylphenyl) eth
L] amino, 2- (2-fluorophenyl) -1- (2
-Methoxyphenyl) ethyl] amino, 2- (2-fur
Orophenyl) -1- (3-methoxyphenyl) eth
L] amino, 2- (2-fluorophenyl) -1- (4
-Methoxyphenyl) ethyl] amino, 2- (3-full
Orophenyl) -1- (2-methoxyphenyl) eth
L] amino, 2- (3-fluorophenyl) -1- (3
-Methoxyphenyl) ethyl] amino, 2- (3-full
Orophenyl) -1- (4-methoxyphenyl) eth
L] amino, 2- (4-fluorophenyl) -1- (2
-Methoxyphenyl) ethyl] amino, 2- (4-full
Orophenyl) -1- (3-methoxyphenyl) eth
L] amino, 2- (4-fluorophenyl) -1- (4
-Methoxyphenyl) ethyl] amino, [2- (2-hi
Droxyphenyl) -1-phenylethyl] amino,
[2- (3-hydroxyphenyl) -1-phenylethyl
Lu] amino, [2- (4-hydroxyphenyl) -1-
Phenylethyl] amino, [2- (2-aminophenyl
) -1-Phenylethyl] amino, [2- (3-ami
Nophenyl) -1-phenylethyl] amino, [2-
(4-Aminophenyl) -1-phenylethyl] ami
No, [2- (2-dimethylaminophenyl) -1-phen
Nylethyl] amino, [2- (3-dimethylaminophen
Nyl) -1-phenylethyl] amino, [2- (4-di
Methylaminophenyl) -1-phenylethyl] ami
No, [1- (2-methoxyphenyl) -2-phenylene
Cyl] amino, [1- (3-methoxyphenyl) -2-
Phenylethyl] amino, [1- (4-methoxyphenyl)
) -2-Phenylethyl] amino, (1-methyl-
1,2-diphenylethyl) amino, (2,2-diphe
Nylethyl) amino, [2- (2-methylphenyl)-
2- (2-methylphenyl) ethyl] amino, [2-
(2-methylphenyl) -2- (3-methylphenyl)
Ethyl] amino, [2- (2-methylphenyl) -2-
(4-Methylphenyl) ethyl] amino, [2- (3-
Methylphenyl) -2- (3-methylphenyl) eth
Ru] amino, [2- (3-methylphenyl) -2- (4
-Methylphenyl) ethyl] amino, [2- (4-methyl)
Ruphenyl) -2- (4-methylphenyl) ethyl] a
Mino, [2- (2-methoxyphenyl) -2- (2-me
Toxyphenyl) ethyl] amino, [2- (2-methoxy)
Cyphenyl) -2- (3-methoxyphenyl) ethyl]
Amino, [2- (2-methoxyphenyl) -2- (4-
Methoxyphenyl) ethyl] amino, [2- (3-meth)
Xyphenyl) -2- (3-methoxyphenyl) eth
Ru] amino, [2- (3-methoxyphenyl) -2-
(4-Methoxyphenyl) ethyl] amino, [2- (4
-Methoxyphenyl) -2- (4-methoxyphenyl)
Ethyl] amino, (1-benzyl-4-phenylbuty
) Amino, (1,1-diphenylethyl) amino,
[1- (2-fluorophenyl) -1- (2-fluoro
Phenyl) ethyl] amino, [1- (2-fluorophene
Nyl) -1- (3-fluorophenyl) ethyl] ami
No, [1- (2-fluorophenyl) -1- (4-full
Orophenyl) ethyl] amino, [1- (3-fluoro
Phenyl) -1- (3-fluorophenyl) ethyl] a
Mino, [1- (3-fluorophenyl) -1- (4-phenyl)
Luorophenyl) ethyl] amino, [1- (4-fluor
Rophenyl) -1- (4-fluorophenyl) ethyl]
Amino, [1- (2-methylphenyl) -1- (2-me
Tylphenyl) ethyl] amino, [1- (2-methylphenyl) ethyl]
Phenyl) -1- (3-methylphenyl) ethyl] ami
No, [1- (2-methylphenyl) -1- (4-methyl
Phenyl) ethyl] amino, [1- (3-methylphenyl)
) -1- (3-Methylphenyl) ethyl] amino,
[1- (3-methylphenyl) -1- (4-methylphene)
Nyl) ethyl] amino, [1- (4-methylphenyl)]
-1- (4-methylphenyl) ethyl] amino, [1-
(2-Methoxyphenyl) -1- (2-methoxyphenyl)
Ru) ethyl] amino, [1- (2-methoxyphenyl)]
-1- (3-methoxyphenyl) ethyl] amino, [1
-(2-Methoxyphenyl) -1- (4-methoxyphen)
Nyl) ethyl] amino, [1- (3-methoxyphenyl)
) -1- (3-Methoxyphenyl) ethyl] amino,
[1- (3-methoxyphenyl) -1- (4-methoxy
Phenyl) ethyl] amino, [1- (4-methoxyphen)
Nyl) -1- (4-methoxyphenyl) ethyl] ami
No, [1- (2-hydroxyphenyl) -1-phenyl
Ethyl] amino, [1- (3-hydroxyphenyl)-
1-phenylethyl] amino, [1- (4-hydroxy)
Phenyl) -1-phenylethyl] amino, [1- (2
-Aminophenyl) -1-phenylethyl] amino,
[1- (3-aminophenyl) -1-phenylethyl]
Amino, [1- (4-aminophenyl) -1-phenyl
Ethyl] amino, [1- (2-dimethylaminophenyl
) -1-Phenylethyl] amino, [1- (3-dime
Tylaminophenyl) -1-phenylethyl] amino,
[1- (4-dimethylaminophenyl) -1-phenyl
Ethyl] amino, tritylamino, 2,2 ', 2 ",-
Trimethyltritylamino, 2,2 ', 3 ",-trimethyl
Tiltlytylamino, 2,2 ', 4 ",-Trimethylto
Litylamino, 2,3 ', 3 ",-trimethyltrityl
Amino, 2,3 ', 4 ",-trimethyltritylami
No, 2,4 ', 4 ",-trimethyltritylamino,
3,3 ′, 3 ″,-trimethyltritylamino, 3,
3 ', 4 ",-trimethyltritylamino, 3,4',
4 ″,-trimethyltritylamino, 4,4 ′, 4 ″,
-Trimethyltritylamino, 2,2 ', 2 "-trif
Luorotritylamino, 2,2 ', 3 "-trifluoro
Tritylamino, 2,2 ', 4 "-trifluorotriti
Luamino, 2,3 ', 3 "-trifluorotritylami
No, 2,3 ', 4 "-trifluorotritylamino,
2,4 ', 4 "-trifluorotritylamino, 3,
3 ', 3 "-trifluorotritylamino, 3,3',
4 "-trifluorotritylamino, 3,4 ', 4"-
Trifluorotritylamino, 4,4 ', 4 "-trif
Luorotritylamino, (1-benzyl-2-phenyl
Ethyl) amino, [1- (2-fluorobenzyl) -2
-(2-Fluorophenyl) ethyl] amino, [1-
(2-Fluorobenzyl) -2- (3-fluorophenyl)
Ru) ethyl] amino, [1- (2-fluorobenzyl)]
-2- (4-fluorophenyl) ethyl] amino, [1
-(3-Fluorobenzyl) -2- (2-fluorophene
Nyl) ethyl] amino, [1- (3-fluorobenzyl
) -2- (3-Fluorophenyl) ethyl] amino,
[1- (3-fluorobenzyl) -2- (4-fluoro
Phenyl) ethyl] amino, [1- (4-fluoroben
Dil) -2- (2-fluorophenyl) ethyl] ami
No, [1- (4-fluorobenzyl) -2- (3-full
Orophenyl) ethyl] amino, [1- (4-fluoro)
Benzyl) -2- (4-fluorophenyl) ethyl] a
Mino, (1-benzyl-1-methyl-2-phenylethyl)
Ru) amino, [1- (2-chlorobenzyl) -2- (2
-Chlorophenyl) ethyl] amino, [1- (2-chloro)
Robenzyl) -2- (3-chlorophenyl) ethyl] a
Mino, [1- (2-chlorobenzyl) -2- (4-chloro)
Rophenyl) ethyl] amino, [1- (3-chloroben
Dil) -2- (2-chlorophenyl) ethyl] amino,
[1- (3-chlorobenzyl) -2- (3-chlorophene
Nyl) ethyl] amino, [1- (3-chlorobenzyl)]
-2- (4-chlorophenyl) ethyl] amino, [1-
(4-chlorobenzyl) -2- (2-chlorophenyl)
Ethyl] amino, [1- (4-chlorobenzyl) -2-
(3-chlorophenyl) ethyl] amino, [1- (4-
(Chlorobenzyl) -2- (4-chlorophenyl) eth
Lu] amino, [1- (2-fluorobenzyl) -2-
(2-Fluorophenyl) -1-methylethyl] ami
No, [1- (2-fluorobenzyl) -2- (3-full
Orophenyl) -1-methylethyl] amino, [1-
(2-Fluorobenzyl) -2- (4-fluorophenyl)
) -1-methylethyl] amino, [1- (3-fluor
Robenzyl) -2- (2-fluorophenyl) -1-me
Cylethyl] amino, [1- (3-fluorobenzyl)]
-2- (3-Fluorophenyl) -1-methylethyl]
Amino, [1- (3-fluorobenzyl) -2- (4-
Fluorophenyl) -1-methylethyl] amino, [1
-(4-Fluorobenzyl) -2- (2-fluorophene
Nyl) -1-methylethyl] amino, [1- (4-full
Orobenzyl) -2- (3-fluorophenyl) -1-
Methylethyl] amino, [1- (4-fluorobenzyl
) -2- (4-Fluorophenyl) -1-methylethyl
L] amino, [1-methyl-2- (2-methylphenyl)
) -3- (2-Methylphenyl) propyl] amino,
[1-methyl-2- (2-methylphenyl) -3- (3
-Methylphenyl) propyl] amino, [1-methyl-
2- (2-methylphenyl) -3- (4-methylphenyl)
) Propyl] amino, [1-methyl-2- (3-methyl)
Ruphenyl) -3- (2-methylphenyl) propyl]
Amino, [1-methyl-2- (3-methylphenyl)-
3- (3-methylphenyl) propyl] amino, [1-
Methyl-2- (3-methylphenyl) -3- (4-methyl)
Ruphenyl) propyl] amino, [1-methyl-2-
(4-methylphenyl) -3- (2-methylphenyl)
Propyl] amino, [1-methyl-2- (4-methylphenyl)
Phenyl) -3- (3-methylphenyl) propyl] ami
No, [1-methyl-2- (4-methylphenyl) -3-
(4-Methylphenyl) propyl] amino, [2- (2
-Fluorophenyl) -3- (2-fluorophenyl)
-1-methylpropyl] amino, [2- (2-fluoro
Phenyl) -3- (3-fluorophenyl) -1-methyl
Lupropyl] amino, [2- (2-fluorophenyl)
-3- (4-fluorophenyl) -1-methylpropy
Lu] amino, [2- (3-fluorophenyl) -3-
(2-Fluorophenyl) -1-methylpropyl] ami
No, [2- (3-fluorophenyl) -3- (3-full
Orophenyl) -1-methylpropyl] amino, [2-
(3-Fluorophenyl) -3- (4-fluorophenyl)
) -1-methylpropyl] amino, [2- (4-full
Orophenyl) -3- (2-fluorophenyl) -1-
Methylpropyl] amino, [2- (4-fluorophenyl)
) -3- (3-Fluorophenyl) -1-methylpro
Pill] amino, [2- (4-fluorophenyl) -3-
(4-Fluorophenyl) -1-methylpropyl] ami
No, (1,3-diphenylpropyl) amino, [1-
(2-Methylphenyl) -3- (2-methylphenyl)
Propyl] amino, [1- (2-methylphenyl) -3
-(3-Methylphenyl) propyl] amino, [1-
(2-Methylphenyl) -3- (4-methylphenyl)
Propyl] amino, [1- (3-methylphenyl) -3
-(2-methylphenyl) propyl] amino, [1-
(3-Methylphenyl) -3- (3-methylphenyl)
Propyl] amino, [1- (3-methylphenyl) -3
-(4-methylphenyl) propyl] amino, [1-
(4-methylphenyl) -3- (2-methylphenyl)
Propyl] amino, [1- (4-methylphenyl) -3
-(3-Methylphenyl) propyl] amino, [1-
(4-methylphenyl) -3- (4-methylphenyl)
Propyl] amino, [1- (2-methoxyphenyl)-
3- (2-methoxyphenyl) propyl] amino, [1
-(2-Methoxyphenyl) -3- (3-methoxyphen)
Nyl) propyl] amino, [1- (2-methoxyphenyl)
) -3- (4-Methoxyphenyl) propyl] ami
No, [1- (3-methoxyphenyl) -3- (2-meth)
Xyphenyl) propyl] amino, [1- (3-methoxy)
Cyphenyl) -3- (3-methoxyphenyl) propyi
L] amino, [1- (3-methoxyphenyl) -3-
(4-Methoxyphenyl) propyl] amino, [1-
(4-methoxyphenyl) -3- (2-methoxyphenyl)
) Propyl] amino, [1- (4-methoxyphenyl)
) -3- (3-Methoxyphenyl) propyl] ami
No, [1- (4-methoxyphenyl) -3- (4-meth)
Xyphenyl) propyl] amino, (1,4-dipheny
Rubutyl) amino, [1- (2-chlorophenyl) -4
-(2-chlorophenyl) butyl] amino, [1- (2
-Chlorophenyl) -4- (3-chlorophenyl) buty
Lu] amino, [1- (2-chlorophenyl) -4- (4
-Chlorophenyl) butyl] amino, [1- (3-chloro)
Rophenyl) -4- (2-chlorophenyl) butyl] a
Mino, [1- (3-chlorophenyl) -4- (3-chloro)
Rophenyl) butyl] amino, [1- (3-chlorophene
Nyl) -4- (4-chlorophenyl) butyl] amino,
[1- (4-chlorophenyl) -4- (2-chlorophene
Nyl) butyl] amino, [1- (4-chlorophenyl)
-4- (3-chlorophenyl) butyl] amino, [1-
(4-chlorophenyl) -4- (4-chlorophenyl)
Butyl] amino, [1- (2-methoxyphenyl) -4
-(2-Methoxyphenyl) butyl] amino, [1-
(2-methoxyphenyl) -4- (3-methoxyphenyl)
Ru) butyl] amino, [1- (2-methoxyphenyl)]
-4- (4-methoxyphenyl) butyl] amino, [1
-(3-Methoxyphenyl) -4- (2-methoxyphen)
Nyl) butyl] amino, [1- (3-methoxyphenyl)
) -4- (3-Methoxyphenyl) butyl] amino,
[1- (3-methoxyphenyl) -4- (4-methoxy)
Phenyl) butyl] amino, [1- (4-methoxyphen)
Nyl) -4- (2-methoxyphenyl) butyl] ami
No, [1- (4-methoxyphenyl) -4- (3-meth)
Xyphenyl) butyl] amino, [1- (4-methoxy
Phenyl) -4- (4-methoxyphenyl) butyl] a
Mino, (1-methyl-3,3-diphenylpropyl) a
Mino, [3- (2-fluorophenyl) -3- (2-phenyl)
Luorophenyl) -1-methylpropyl] amino, [3
-(2-Fluorophenyl) -3- (3-fluorophene
Nyl) -1-methylpropyl] amino, [3- (2-phenyl)
Luorophenyl) -3- (4-fluorophenyl) -1
-Methylpropyl] amino, [3- (3-fluorophene
Nyl) -3- (3-fluorophenyl) -1-methylpropyl
Ropil] amino, [3- (3-fluorophenyl) -3
-(4-Fluorophenyl) -1-methylpropyl] a
Mino, [3- (4-fluorophenyl) -3- (4-phenyl)
Luorophenyl) -1-methylpropyl] amino, [1
-Methyl-3- (2-methylphenyl) -3- (2-me
Cylphenyl) propyl] amino, [1-methyl-3-
(2-methylphenyl) -3- (3-methylphenyl)
Propyl] amino, [1-methyl-3- (2-methylphenyl)
Phenyl) -3- (4-methylphenyl) propyl] ami
No, [1-methyl-3- (3-methylphenyl) -3-
(3-Methylphenyl) propyl] amino, [1-methyl
Le-3- (3-methylphenyl) -3- (4-methylphenyl)
Phenyl) propyl] amino, [1-methyl-3- (4-
Methylphenyl) -3- (4-methylphenyl) propyi
L] amino, N-benzyl-N-methylamino, N-beta
N-ethyl-N-ethylamino, N-benzyl-N-isop
Ropylamino, N-benzyl-N-isobutylamino,
N-benzyl-Nt-butylamino, N- (2-fur
Orobenzyl) -N-isopropylamino, N- (3-
Fluorobenzyl) -N-isopropylamino, N-
(4-fluorobenzyl) -N-isopropylamino,
N- (2-chlorobenzyl) -N-isopropylamido
No, N- (3-chlorobenzyl) -N-isopropyla
Mino, N- (4-chlorobenzyl) -N-isopropyl
Amino, N- (2-methylbenzyl) -N-isopropylate
Lumino, N- (3-methylbenzyl) -N-isopro
Pyramino, N- (4-methylbenzyl) -N-isop
Ropyramino, N- (2-methoxybenzyl) -N-i
Sopropylamino, N- (3-methoxybenzyl) -N
-Isopropylamino, N- (4-methoxybenzyl)
-N-isopropylamino, N- (2-hydroxyben
Dil) -N-isopropylamino, N- (3-hydroxy
Cibenzyl) -N-isopropylamino, N- (4-hi
Droxybenzyl) -N-isopropylamino, N, N
-Dibenzylamino, N-benzyl-N- (2-methoxy)
Cibenzyl) amino, N-benzyl-N- (3-methoxy)
Cibenzyl) amino, N-benzyl-N- (4-methoxy)
Cibenzyl) amino, N- (2-fluorobenzyl)-
N- (2-fluorobenzyl) amino, N- (2-full
Orobenzyl) -N- (3-fluorobenzyl) ami
No, N- (2-fluorobenzyl) -N- (4-fluor
Robenzyl) amino, N- (3-fluorobenzyl)-
N- (3-fluorobenzyl) amino, N- (3-full
Orobenzyl) -N- (4-fluorobenzyl) ami
No, N- (4-fluorobenzyl) -N- (4-fluor
Robenzyl) amino, N- (2-methylbenzyl) -N
-(2-methylbenzyl) amino, N- (2-methylbenzyl)
N-)-N- (3-methylbenzyl) amino, N-
(2-methylbenzyl) -N- (4-methylbenzyl)
Amino, N- (3-methylbenzyl) -N- (3-methyl
Rubenzyl) amino, N- (3-methylbenzyl) -N
-(4-methylbenzyl) amino, N- (4-methylbenzyl)
N-)-N- (4-methylbenzyl) amino, N-
(2-Methoxybenzyl) -N- (2-methoxybenzyl
L) amino, N- (2-methoxybenzyl) -N- (3
-Methoxybenzyl) amino, N- (2-methoxyben)
Dil) -N- (4-methoxybenzyl) amino, N-
(3-Methoxybenzyl) -N- (3-methoxybenzyl
L) amino, N- (3-methoxybenzyl) -N- (4
-Methoxybenzyl) amino, N- (4-methoxyben)
Dil) -N- (4-methoxybenzyl) amino, N-
(2-hydroxybenzyl) -N- (2-hydroxy ester)
), N- (2-hydroxybenzyl) -N
-(3-hydroxybenzyl) amino, N- (2-hydr
Roxybenzyl) -N- (4-hydroxybenzyl) a
Mino, N- (3-hydroxybenzyl) -N- (3-hi
Droxybenzyl) amino, N- (3-hydroxyben)
Dil) -N- (4-hydroxybenzyl) amino, N-
(4-Hydroxybenzyl) -N- (4-hydroxy ester)
), N- (2-aminobenzyl) -N-
(2-aminobenzyl) amino, N- (2-aminoben
Dil) -N- (3-aminobenzyl) amino, N- (2
-Aminobenzyl) -N- (4-aminobenzyl) ami
No, N- (3-aminobenzyl) -N- (3-aminobe
N-di) amino, N- (3-aminobenzyl) -N-
(4-aminobenzyl) amino, N- (4-aminoben
Dil) -N- (4-aminobenzyl) amino, N- (2
-Dimethylaminobenzyl) -N- (2-dimethylamido)
Nobenzyl) amino, N- (2-dimethylaminobenzyl
) -N- (3-Dimethylaminobenzyl) amino, N
-(2-Dimethylaminobenzyl) -N- (4-dimethyl)
Luaminobenzyl) amino, N- (3-dimethylamino)
Benzyl) -N- (3-dimethylaminobenzyl) ami
No, N- (3-dimethylaminobenzyl) -N- (4-
Dimethylaminobenzyl) amino, N- (4-dimethyl
Aminobenzyl) -N- (4-dimethylaminobenzyl
A) amino, N-benzyl-N-phenylethylami
No, N-benzyl-N- (1-phenylethyl) ami
No, N-benzyl-N- (1-methyl-1-phenylene
Cyl) amino, N, N-diphenylethylamino, N,
N-bis (1-phenylethyl) amino, N-benzyl
-N- (3-phenylpropyl) amino, (2-furyl
Methyl) amino, (3-furylmethyl) amino, (2-
Thienylmethyl) amino, (3-thienylmethyl) ami
No, (2-pyridylmethyl) amino, (3-pyridylme
(Cyl) amino, (4-pyridylmethyl) amino, (2-
Methyl-3-furyl) methylamino, (5-methyl-2)
-Furyl) methylamino, (5-methyl-3-furyl)
Methylamino, (2-methyl-3-thienyl) methyla
Mino, (5-methyl-2-thienyl) methylamino,
(5-methyl-3-thienyl) methylamino, [2-
(2-Furyl) ethyl] amino, [2- (3-furyl)]
Ethyl] amino, [2- (2-thienyl) ethyl] ami
No, [2- (3-thienyl) ethyl] amino, [3-
(2-furyl) propyl] amino, [3- (3-free
Ru) propyl] amino, [3- (2-thienyl) propyi
L] amino, [3- (3-thienyl) propyl] ami
No, [bis (2-furyl) methyl] amino, [bis (3
-Furyl) methyl] amino, [bis (2-thienyl) meth
Cyl] amino, [bis (3-thienyl) methyl] ami
No, [1,1-bis (2-furyl) ethyl] amino,
[1,1-bis (3-furyl) ethyl] amino, [1,
1-bis (2-thienyl) ethyl] amino, [1,1-
Bis (3-thienyl) ethyl] amino, [(2-methyl
-3-furylmethyl) (2-methyl-3-furylmethyl
)] Amino, [(2-methyl-3-furylmethyl)]
(5-Methyl-2-furylmethyl)] amino, [(2-
Methyl-3-furylmethyl) (5-methyl-3-furyl
Methyl)] amino, [(5-methyl-2-furylmethyi)
(2-methyl-3-furylmethyl)] amino,
[(5-Methyl-2-furylmethyl) (5-methyl-2
-Furylmethyl)] amino, [(5-methyl-2-free)
Rumethyl) (5-methyl-3-furylmethyl] amino,
[(5-Methyl-3-furylmethyl) (2-methyl-3
-Furylmethyl)] amino, [(5-methyl-3-free
L-methyl) (5-methyl-2-furylmethyl)] ami
No, [(5-methyl-3-furylmethyl) (5-methyl
-3-furylmethyl] amino, [(2-methyl-3-thi
(Enylmethyl) (2-methyl-3-thienylmethyl)]
Amino, [(2-methyl-3-thienylmethyl) (5-
Methyl-2-thienylmethyl)] amino, [(2-methyl
L-3-thienylmethyl) (5-methyl-3-thienyl
Methyl)] amino, [(5-methyl-2-thienylmethyi)
(2-methyl-3-thienylmethyl)] amino,
[(5-Methyl-2-thienylmethyl) (5-methyl-
2-thienylmethyl)] amino, [(5-methyl-2-
Thienylmethyl) (5-methyl-3-thienylmethyl
)] Amino, [(5-methyl-3-thienylmethyl)]
(2-Methyl-3-thienylmethyl)] amino, [(5
-Methyl-3-thienylmethyl) (5-methyl-2-thi
[Ethylmethyl)] amino, [(5-methyl-3-thienyl)
L-methyl) (5-methyl-3-thienylmethyl)] ami
No, [1- (2-furyl) -1-methylethyl] ami
No, [1- (3-furyl) -1-methylethyl] ami
No, [1- (2-thienyl) -1-methylethyl] ami
No, [1- (3-thienyl) -1-methylethyl] ami
No, [1- (2-methyl-3-thienyl) -1-methyl
Ethyl] amino, [1- (5-methyl-2-thienyl)
-1-Methylethyl] amino, [1- (5-methyl-3
-Thienyl) -1-methylethyl] amino, [1- (2
-Furyl) -2- (2-furyl) ethyl] amino, [1
-(2-furyl) -2- (3-furyl) ethyl] ami
No, [1- (3-furyl) -2- (2-furyl) eth
Lu] amino, [1- (3-furyl) -2- (3-free
Ru) ethyl] amino, [1- (2-methyl-3-free)
) -1-Methylethyl] amino, [1- (5-methyl
-2-furyl) -1-methylethyl] amino, [1-
(5-Methyl-3-furyl) -1-methylethyl] ami
No, [1- (2-thienyl) -2- (2-thienyl) e
Tyl] amino, [1- (2-thienyl) -2- (3-thi
(Enyl) ethyl] amino, [1- (3-thienyl) -2]
-(2-thienyl) ethyl] amino, [1- (3-thiet
Nyl) -2- (3-thienyl) ethyl] amino, [1-
(2-furyl) -2-phenylethyl] amino, [1-
(3-furyl) -2-phenylethyl] amino, [1-
(2-Furyl) -2- (2-methylphenyl) ethyl]
Amino, [1- (2-furyl) -2- (3-methylphene
Nyl) ethyl] amino, [1- (2-furyl) -2-
(4-Methylphenyl) ethyl] amino, [1- (3-
Furyl) -2- (2-methylphenyl) ethyl] ami
No, [1- (3-furyl) -2- (3-methylphenyl)
Ru) ethyl] amino, [1- (3-furyl) -2- (4
-Methylphenyl) ethyl] amino, [2-phenyl-
1- (2-thienyl) ethyl] amino, [2-phenyl
-1- (3-thienyl) ethyl] amino, [1-phenyl
Lu-2- (2-thienyl) ethyl] amino, [1-phen
Nyl-2- (3-thienyl) ethyl] amino, [2-
(2-Methylphenyl) -1- (2-thienyl) eth
Ru] amino, [2- (3-methylphenyl) -1- (2
-Thienyl) ethyl] amino, [2- (4-methylphene)
Nil) -1- (2-thienyl) ethyl] amino, [2-
(2-Methylphenyl) -1- (3-thienyl) eth
Ru] amino, [2- (3-methylphenyl) -1- (3
-Thienyl) ethyl] amino, [2- (4-methylphene)
Nil) -1- (3-thienyl) ethyl] amino, [2-
(2-chlorophenyl) -1- (2-thienyl) eth
Ru] amino, [2- (3-chlorophenyl) -1- (2
-Thienyl) ethyl] amino, [2- (4-chlorophene
Nil) -1- (2-thienyl) ethyl] amino, [2-
(2-chlorophenyl) -1- (3-thienyl) eth
Ru] amino, [2- (3-chlorophenyl) -1- (3
-Thienyl) ethyl] amino, [2- (4-chlorophene
Nil) -1- (3-thienyl) ethyl] amino, [2-
(2-Fluorophenyl) -1- (2-thienyl) eth
Ru] amino, [2- (3-fluorophenyl) -1-
(2-thienyl) ethyl] amino, [2- (4-fluor
Lophenyl) -1- (2-thienyl) ethyl] amino,
[2- (2-fluorophenyl) -1- (3-thieni
Ru) ethyl] amino, [2- (3-fluorophenyl)
-1- (3-thienyl) ethyl] amino, [2- (4-
Fluorophenyl) -1- (3-thienyl) ethyl] a
Mino, [2- (2-methoxyphenyl) -1- (2-thio)
(Enyl) ethyl] amino, [2- (3-methoxyphenyl)
L) -1- (2-thienyl) ethyl] amino, [2-
(4-Methoxyphenyl) -1- (2-thienyl) eth
Ru] amino, [2- (2-methoxyphenyl) -1-
(3-thienyl) ethyl] amino, [2- (3-methoxy)
Cyphenyl) -1- (3-thienyl) ethyl] amino,
[2- (4-methoxyphenyl) -1- (3-thieni
Ru) ethyl] amino, N- (2-furylmethyl) -N-
(2-furylmethyl) amino, N- (3-furylmethyl)
) -N- (2-furylmethyl) amino, N- (3-fur
Rylmethyl) -N- (3-furylmethyl) amino, N-
(2-thienylmethyl) -N- (2-thienylmethyl)
Amino, N- (3-thienylmethyl) -N- (2-thiet
Nylmethyl) amino, N- (3-thienylmethyl) -N
-(3-thienylmethyl) amino, [1- (2-fluor
Lophenyl) -2- (2-thienyl) ethyl] amino,
[1- (3-fluorophenyl) -2- (2-thieni
Ru) ethyl] amino, [1- (4-fluorophenyl)
-2- (2-thienyl) ethyl] amino, [1- (2-
Fluorophenyl) -2- (3-thienyl) ethyl] a
Mino, [1- (3-fluorophenyl) -2- (3-thio)
(Enyl) ethyl] amino, [1- (4-fluorophenyl)
L) -2- (3-thienyl) ethyl] amino, N-ben
Dil-N- (2-furylmethyl) amino, N-benzyl
-N- (3-furylmethyl) amino, N-benzyl-N
-(2-thienylmethyl) amino, N-benzyl-N-
(3-thienylmethyl) amino, (2-hydroxy-
1,2-diphenylethyl) amino, N ', N'-diph
Phenylhydrazino, N '-(2-methylphenyl)-
N'-phenylhydrazino, N '-(3-methylpheny
) -N'-phenylhydrazino, N '-(4-methyl
Phenyl) -N'-phenylhydrazino, N '-(2-
Methoxyphenyl) -N'-phenylhydrazino, N '
-(3-Methoxyphenyl) -N'-phenylhydrazide
No, N '-(4-methoxyphenyl) -N'-phenyl
Hydrazino, N '-(2-chlorophenyl) -N'-f
Phenylhydrazino, N '-(3-chlorophenyl)-
N'-phenylhydrazino, N '-(4-chloropheny
) -N'-phenylhydrazino, N '-(2-fluor
Rophenyl) -N'-phenylhydrazino, N '-(3
-Fluorophenyl) -N'-phenylhydrazino,
N '-(4-fluorophenyl) -N'-phenylhydr
Radino, N '-(2-hydroxyphenyl) -N'-fu
Phenylhydrazino, N '-(3-hydroxyphenyl)
-N'-phenylhydrazino, N '-(4-hydroxy
Phenyl) -N'-phenylhydrazino, N '-(2-
Aminophenyl) -N'-phenylhydrazino, N'-
(3-aminophenyl) -N'-phenylhydrazino,
N '-(4-aminophenyl) -N'-phenylhydra
Dino, N '-(2-dimethylaminophenyl) -N'-
Phenylhydrazino, N '-(3-dimethylaminophen
Nyl) -N'-phenylhydrazino, N '-(4-dime
Tilaminophenyl) -N'-phenylhydrazino,
N '-(2-acetamidophenyl) -N'-phenyl
Hydrazino, N '-(3-acetamidophenyl)-
N'-phenylhydrazino, N '-(4-acetamide
Phenyl) -N'-phenylhydrazino, N '-(2-
Methylphenyl) -N '-(2-methylphenyl) hydr
Radino, N '-(3-methylphenyl) -N'-(2-
Methylphenyl) hydrazino, N '-(3-methylphene
Nyl) -N '-(3-methylphenyl) hydrazino,
N '-(4-methylphenyl) -N'-(2-methylphenyl)
Phenyl) hydrazino, N '-(4-methylphenyl)-
N '-(3-methylphenyl) hydrazino, N'-(4
-Methylphenyl) -N '-(4-methylphenyl) hi
Dorazino, N '-(2-methoxyphenyl) -N'-
(2-methoxyphenyl) hydrazino, N '-(2-me
Toxyphenyl) -N '-(3-methoxyphenyl) hi
Dorazino, N '-(2-methoxyphenyl) -N'-
(4-Methoxyphenyl) hydrazino, N '-(3-me
Toxyphenyl) -N '-(3-methoxyphenyl) hi
Dorazino, N '-(3-methoxyphenyl) -N'-
(4-Methoxyphenyl) hydrazino and N'-
(4-Methoxyphenyl) -N '-(4-methoxyphen)
Nil) Hydrazino.

More preferably, (1-methyl-1-phenyl)
Ruethyl) amino, [1-methyl-1- (2-methylphenyl)
Phenylethyl] amino, [1-methyl-1- (3-methyl
Luphenylethyl] amino, [1-methyl-1- (4-
Methylphenylethyl] amino, [1-methyl-1-
(2-Methoxyphenyl) ethyl] amino, [1-methyl
Ru-1- (3-methoxyphenyl) ethyl] amino,
[1-Methyl-1- (4-methoxyphenyl) ethyl]
Amino, [1-methyl-1- (2-fluorophenyl)
Ethyl] amino, [1-methyl-1- (3-fluorophenyl)
Phenyl) ethyl] amino, [1-methyl-1- (4-phenyl)
Luorophenyl) ethyl] amino, [1-methyl-1-
(2-Chlorophenyl) ethyl] amino, [1-methyl
-1- (3-chlorophenyl) ethyl] amino, [1-
Methyl-1- (4-chlorophenyl) ethyl] amino,
[1-methyl-1- (2-hydroxyphenyl) ethyl
L] amino, [1-methyl-1- (3-hydroxyphene
Nyl) ethyl] amino, [1-methyl-1- (4-hydr
Roxyphenyl) ethyl] amino, [1-methyl-1-
(2-Aminophenyl) ethyl] amino, [1-methyl
-1- (3-aminophenyl) ethyl] amino, [1-
Methyl-1- (4-aminophenyl) ethyl] amino,
[1-methyl-1- (2-dimethylaminophenyl) e
Cyl] amino, [1-methyl-1- (3-dimethylamido)
Nophenyl) ethyl] amino, [1-methyl-1- (4
-Dimethylaminophenyl) ethyl] amino, {1-me
Cyl-1- [3,5-bis (dimethylamino) phenyl
Ru] ethyl} amino, [1-methyl-1- (2-aceto
Amidophenyl) ethyl] amino, [1-methyl-1-
(3-acetamidophenyl) ethyl] amino, [1-
Methyl-1- (4-acetamidophenyl) ethyl] a
Mino, [1-methyl-1- (2,3-dimethoxyphenyl
Ru) ethyl] amino, [1-methyl-1- (2,4-di
Methoxyphenyl) ethyl] amino, [1-methyl-1
-(2,5-dimethoxyphenyl) ethyl] amino,
[1-Methyl-1- (2,6-dimethoxyphenyl) e
Cyl] amino, [1-methyl-1- (3,4-dimethoxy)
Cyphenyl) ethyl] amino, [1-methyl-1-
(3,5-dimethoxyphenyl) ethyl] amino, [1
-Methyl-1- (3,6-dimethoxyphenyl) ethyl
L] amino, [1-methyl-1- (3,4,5-trime
Toxyphenyl) ethyl] amino, [1-methyl-1-
(2,4,6-Trimethoxyphenyl) ethyl] ami
No, (1,1-dimethyl-2-phenylethyl) ami
No, benzhydrylamino, (2,2'-dimethylben
Tsuhydryl) amino, (2,3'-dimethylbenzhydride
(Ryl) amino, (2,4'-dimethylbenzhydryl)
Amino, (3,3'-dimethylbenzhydryl) ami
No, (3,4'-dimethylbenzhydryl) amino,
(4,4'-Dimethylbenzhydryl) amino, (2,4
2'-dimethoxybenzhydryl) amino, (2,3 '
-Dimethoxybenzhydryl) amino, (2,4'-di
Methoxybenzhydryl) amino, (3,3'-dimeth)
Xybenzhydryl) amino, (3,4'-dimethoxy)
Benzhydryl) amino, (4,4'-dimethoxyben)
Tsuhydryl) amino, (2,2'-dihydroxybenz
Hydryl) amino, (2,3'-dihydroxybenzhi)
Drill) amino, (2,4'-dihydroxybenzhydride
(Ryl) amino, (3,3'-dihydroxybenzhydrido)
Lu) amino, (3,4'-dihydroxybenzhydri)
Lu) amino, (4,4'-dihydroxybenzhydri)
Le) amino, (2,2'-diaminobenzhydryl) a
Mino, (2,3'-diaminobenzhydryl) amino,
(2,4'-diaminobenzhydryl) amino, (3,
3'-diaminobenzhydryl) amino, (3,4'-
Diaminobenzhydryl) amino, (4,4'-diami
Noventhydryl) amino, [2,2'-di (dimethyl)
Amino) benzhydryl] amino, [2,3'-di (di
Methylamino) benzhydryl] amino, [2,4'-
Di (dimethylamino) benzhydryl] amino, [3
3'-di (dimethylamino) benzhydryl] amino,
[3,4'-Di (dimethylamino) benzhydryl]
Mino, [4,4'-di (dimethylamino) benzhydrido]
]] Amino, (2-methylbenzhydryl) amino,
(3-methylbenzhydryl) amino, (4-methylbenzyl)
Amino, (2-methoxybenzhydryl)
Amino), (3-methoxybenzhydryl) amino,
(4-methoxybenzhydryl) amino, (2-fluor
Lobenzhydryl) amino, (3-fluorobenzhydride
Ryl) amino, (4-fluorobenzhydryl) ami
No, (2-chlorobenzhydryl) amino, (3-chloro
Lobenzhydryl) amino, (4-chlorobenzhydryl)
Le) amino, (2-hydroxybenzhydryl) ami
No, (3-hydroxybenzhydryl) amino, (4-
Hydroxybenzhydryl) amino, (2-aminoben
Tsuhydryl) amino, (3-aminobenzhydryl) a
Mino, (4-aminobenzhydryl) amino, (2-di
Methylaminobenzhydryl) amino, (3-dimethyl
Aminobenzhydryl) amino, (4-dimethylamino)
Benzhydryl) amino, (1,1-diphenylethyl)
) Amino, (1,2-diphenylethyl) amino,
[2- (2-chlorophenyl) -1-phenylethyl]
Amino, [2- (3-chlorophenyl) -1-phenyl
Ethyl] amino, [2- (4-chlorophenyl) -1-
Phenylethyl] amino, [2- (2-fluorophenyl)
) -1-Phenylethyl] amino, [2- (3-full
Orophenyl) -1-phenylethyl] amino, [2-
(4-Fluorophenyl) -1-phenylethyl] ami
No, [2- (2-methylphenyl) -1-phenylethyl
Lu] amino, [2- (3-methylphenyl) -1-phen]
Nylethyl] amino, [2- (4-methylphenyl)-
1-phenylethyl] amino, [2- (2-methoxyphenyl)
Phenyl) -1-phenylethyl] amino, [2- (3-
Methoxyphenyl) -1-phenylethyl] amino,
[2- (4-methoxyphenyl) -1-phenylethyl
Lu] amino, [1- (2-fluorophenyl) -2-
(2-Fluorophenyl) ethyl] amino, [1- (2
-Fluorophenyl) -2- (3-fluorophenyl)
Ethyl] amino, [1- (2-fluorophenyl) -2
-(4-Fluorophenyl) ethyl] amino, [1-
(3-Fluorophenyl) -2- (2-fluorophenyl)
Ru) ethyl] amino, [1- (3-fluorophenyl)]
-2- (3-Fluorophenyl) ethyl] amino, [1
-(3-Fluorophenyl) -2- (4-fluorophene
Nyl) ethyl] amino, [1- (4-fluorophenyl)
) -2- (2-Fluorophenyl) ethyl] amino,
[1- (4-fluorophenyl) -2- (3-fluoro
Phenyl) ethyl] amino, [1- (4-fluorophene
Nyl) -2- (4-fluorophenyl) ethyl] ami
No, [1- (2-chlorophenyl) -2- (2-chloro
Phenyl) ethylamino, [1- (2-chlorophenyl)
) -2- (3-chlorophenyl) ethylamino, [1
-(2-chlorophenyl) -2- (4-chlorophenyl
Ru) ethylamino, [1- (3-chlorophenyl) -2
-(2-chlorophenyl) ethylamino, [1- (3-
Chlorophenyl) -2- (3-chlorophenyl) ethyl
Amino, [1- (3-chlorophenyl) -2- (4-chloro)
Lolophenyl) ethylamino, [1- (4-chlorophene
Nil) -2- (2-chlorophenyl) ethylamino,
[1- (4-chlorophenyl) -2- (3-chlorophene
Nyl) ethylamino, [1- (4-chlorophenyl)-
2- (4-chlorophenyl) ethylamino, [1- (2
-Chlorophenyl) -2- (2-methoxyphenyl) e
Cyl] amino, [1- (2-chlorophenyl) -2-
(3-Methoxyphenyl) ethyl] amino, [1- (2
-Chlorophenyl) -2- (4-methoxyphenyl) e
Cyl] amino, [1- (3-chlorophenyl) -2-
(2-Methoxyphenyl) ethyl] amino, [1- (3
-Chlorophenyl) -2- (3-methoxyphenyl) e
Cyl] amino, [1- (3-chlorophenyl) -2-
(4-Methoxyphenyl) ethyl] amino, [1- (4
-Chlorophenyl) -2- (2-methoxyphenyl) e
Cyl] amino, [1- (4-chlorophenyl) -2-
(3-Methoxyphenyl) ethyl] amino, [1- (4
-Chlorophenyl) -2- (4-methoxyphenyl) e
Cyl] amino, [1- (2-methylphenyl) -2-
(2-Methylphenyl) ethyl] amino, [1- (2-
Methylphenyl) -2- (3-methylphenyl) eth
L] amino, [1- (2-methylphenyl) -2- (4
-Methylphenyl) ethyl] amino, [1- (3-methyl)
Ruphenyl) -2- (2-methylphenyl) ethyl] a
Mino, [1- (3-methylphenyl) -2- (3-methyl)
Ruphenyl) ethyl] amino, [1- (3-methylphene
Nyl) -2- (4-methylphenyl) ethyl] amino,
[1- (4-methylphenyl) -2- (2-methylphene
Nyl) ethyl] amino, [1- (4-methylphenyl)]
-2- (3-methylphenyl) ethyl] amino, [1-
(4-methylphenyl) -2- (4-methylphenyl)
Ethyl] amino, [1- (2-hydroxyphenyl)-
2- (2-hydroxyphenyl) ethyl] amino, [1
-(2-hydroxyphenyl) -2- (3-hydroxy
Phenyl) ethyl] amino, [1- (2-hydroxyphenyl)
Phenyl) -2- (4-hydroxyphenyl) ethyl] a
Mino, [1- (3-hydroxyphenyl) -2- (2-
Hydroxyphenyl) ethyl] amino, [1- (3-hi
Droxyphenyl) -2- (3-hydroxyphenyl)
Ethyl] amino, [1- (3-hydroxyphenyl)-
2- (4-hydroxyphenyl) ethyl] amino, [1
-(4-hydroxyphenyl) -2- (2-hydroxy
Phenyl) ethyl] amino, [1- (4-hydroxyphenyl)
Phenyl) -2- (3-hydroxyphenyl) ethyl] a
Mino, [1- (4-hydroxyphenyl) -2- (4-
Hydroxyphenyl) ethyl] amino, [1- (2-a
Minophenyl) -2- (2-aminophenyl) ethyl]
Amino, [1- (2-aminophenyl) -2- (3-a
Minophenyl) ethyl] amino, [1- (2-aminophenyl)
Phenyl) -2- (4-aminophenyl) ethyl] ami
No, [1- (3-aminophenyl) -2- (2-amino
Phenyl) ethyl] amino, [1- (3-aminophenyl)
) -2- (3-aminophenyl) ethyl] amino,
[1- (3-aminophenyl) -2- (4-aminophen
Nyl) ethyl] amino, [1- (4-aminophenyl)]
-2- (2-aminophenyl) ethyl] amino, [1-
(4-aminophenyl) -2- (3-aminophenyl)
Ethyl] amino, [1- (4-aminophenyl) -2-
(4-Aminophenyl) ethyl] amino, [1- (2-
Dimethylaminophenyl) -2- (2-dimethylamino)
Phenyl) ethyl] amino, [1- (2-dimethylamido)
Nophenyl) -2- (3-dimethylaminophenyl) e
Cyl] amino, [1- (2-dimethylaminophenyl)
-2- (4-Dimethylaminophenyl) ethyl] ami
No, [1- (3-dimethylaminophenyl) -2- (2
-Dimethylaminophenyl) ethyl] amino, [1-
(3-Dimethylaminophenyl) -2- (3-dimethyl
Aminophenyl) ethyl] amino, [1- (3-dimethyl)
Luaminophenyl) -2- (4-dimethylaminophenyl)
Lu) ethyl] amino, [1- (4-dimethylaminophen)
Nyl) -2- (2-dimethylaminophenyl) ethyl]
Amino, [1- (4-dimethylaminophenyl) -2-
(3-Dimethylaminophenyl) ethyl] amino, [1
-(4-Dimethylaminophenyl) -2- (4-dimethyl)
Luminophenyl) ethyl] amino, [2- (2-full
Orophenyl) -1- (2-methylphenyl) ethyl]
Amino, [2- (2-fluorophenyl) -1- (3-
Methylphenyl) ethyl] amino, [2- (2-fluor
Rophenyl) -1- (4-methylphenyl) ethyl] a
Mino, [2- (3-fluorophenyl) -1- (2-me
Tylphenyl) ethyl] amino, [2- (3-fluoro
Phenyl) -1- (3-methylphenyl) ethyl] ami
No, [2- (3-fluorophenyl) -1- (4-methyl)
Ruphenyl) ethyl] amino, [2- (4-fluorophenyl)
Phenyl) -1- (2-methylphenyl) ethyl] ami
No, [2- (4-fluorophenyl) -1- (3-methyl)
Ruphenyl) ethyl] amino, [2- (4-fluorophenyl)
Phenyl) -1- (4-methylphenyl) ethyl] ami
No, [2- (2-fluorophenyl) -1- (2-meth)
Xyphenyl) ethyl] amino, [2- (2-fluoro
Phenyl) -1- (3-methoxyphenyl) ethyl] a
Mino, [2- (2-fluorophenyl) -1- (4-me
Toxyphenyl) ethyl] amino, [2- (3-fluor
Rophenyl) -1- (2-methoxyphenyl) ethyl]
Amino, [2- (3-fluorophenyl) -1- (3-
Methoxyphenyl) ethyl] amino, [2- (3-full
Orophenyl) -1- (4-methoxyphenyl) eth
Lu] amino, [2- (4-fluorophenyl) -1-
(2-Methoxyphenyl) ethyl] amino, [2- (4
-Fluorophenyl) -1- (3-methoxyphenyl)
Ethyl] amino, [2- (4-fluorophenyl) -1
-(4-Methoxyphenyl) ethyl] amino, [2-
(2-Hydroxyphenyl) -1-phenylethyl] a
Mino, [2- (3-hydroxyphenyl) -1-phenyl
Ruethyl] amino, [2- (4-hydroxyphenyl)]
-1-Phenylethyl] amino, [2- (2-aminophen
Phenyl) -1-phenylethyl] amino, [2- (3-
Aminophenyl) -1-phenylethyl] amino, [2
-(4-Aminophenyl) -1-phenylethyl] ami
No, [2- (2-dimethylaminophenyl) -1-phen
Nylethyl] amino, [2- (3-dimethylaminophen
Nyl) -1-phenylethyl] amino, [2- (4-di
Methylaminophenyl) -1-phenylethyl] ami
No, [1- (2-methoxyphenyl) -2-phenylene
Cyl] amino, [1- (3-methoxyphenyl) -2-
Phenylethyl] amino, [1- (4-methoxyphenyl)
) -2-Phenylethyl] amino, (1-methyl-
1,2-diphenylethyl) amino, (2,2-diphe
Nylethyl) amino, (1,1-diphenylethyl) a
Mino, [1- (2-fluorophenyl) -1- (2-phenyl)
Luorophenyl) ethyl] amino, [1- (2-fluor
Rophenyl) -1- (3-fluorophenyl) ethyl]
Amino, [1- (2-fluorophenyl) -1- (4-
Fluorophenyl) ethyl] amino, [1- (3-full
Orophenyl) -1- (3-fluorophenyl) eth
Ru] amino, [1- (3-fluorophenyl) -1-
(4-Fluorophenyl) ethyl] amino, [1- (4
-Fluorophenyl) -1- (4-fluorophenyl)
Ethyl] amino, [1- (2-methylphenyl) -1-
(2-Methylphenyl) ethyl] amino, [1- (2-
Methylphenyl) -1- (3-methylphenyl) eth
Lu] amino, [1- (2-methylphenyl) -1- (4
-Methylphenyl) ethyl] amino, [1- (3-methyl)
Ruphenyl) -1- (3-methylphenyl) ethyl] a
Mino, [1- (3-methylphenyl) -1- (4-methyl)
Ruphenyl) ethyl] amino, [1- (4-methylphene)
Nil) -1- (4-methylphenyl) ethyl] amino,
[1- (2-methoxyphenyl) -1- (2-methoxy
Phenyl) ethyl] amino, [1- (2-methoxyphen)
Nyl) -1- (3-methoxyphenyl) ethyl] ami
No, [1- (2-methoxyphenyl) -1- (4-meth)
Xyphenyl) ethyl] amino, [1- (3-methoxy
Phenyl) -1- (3-methoxyphenyl) ethyl] a
Mino, [1- (3-methoxyphenyl) -1- (4-me
Toxyphenyl) ethyl] amino, [1- (4-methoxy)
Cyphenyl) -1- (4-methoxyphenyl) ethyl]
Amino, [1- (2-hydroxyphenyl) -1-phen
Nylethyl] amino, [1- (3-hydroxyphenyl)
) -1-Phenylethyl] amino, [1- (4-hydr
Roxyphenyl) -1-phenylethyl] amino, [1
-(2-Aminophenyl) -1-phenylethyl] ami
No, [1- (3-aminophenyl) -1-phenylethyl
Lu] amino, [1- (4-aminophenyl) -1-phen]
Nylethyl] amino, [1- (2-dimethylaminophen
Nyl) -1-phenylethyl] amino, [1- (3-di
Methylaminophenyl) -1-phenylethyl] ami
No, [1- (4-dimethylaminophenyl) -1-phen
Nylethyl] amino, tritylamino, (1-benzyl
-2-Phenylethyl) amino, (1-benzyl-1-)
Methyl-2-phenylethyl) amino, N-benzyl-
N-methylamino, N-benzyl-N-ethylamino,
N-benzyl-N-isopropylamino, N-benzyl
-N-isobutylamino, N-benzyl-Nt-butyl
Luamino, N- (2-fluorobenzyl) -N-isop
Ropyramino, N- (3-fluorobenzyl) -N-i
Sopropylamino, N- (4-fluorobenzyl) -N
-Isopropylamino, N- (2-chlorobenzyl)-
N-isopropylamino, N- (3-chlorobenzyl)
-N-isopropylamino, N- (4-chlorobenzyl
) -N-isopropylamino, N- (2-methylben
Dil) -N-isopropylamino, N- (3-methyl ester
N-)-N-isopropylamino, N- (4-methyl
Benzyl) -N-isopropylamino, N- (2-meth
Xybenzyl) -N-isopropylamino, N- (3-
Methoxybenzyl) -N-isopropylamino, N-
(4-methoxybenzyl) -N-isopropylamino,
N- (2-hydroxybenzyl) -N-isopropyla
Mino, N- (3-hydroxybenzyl) -N-isopro
Pyramino, N- (4-hydroxybenzyl) -N-i
Sopropylamino, N, N-dibenzylamino, N-beta
And N- (2-methoxybenzyl) amino, N-beta
N-N- (3-methoxybenzyl) amino, N-beta
And N- (4-methoxybenzyl) amino, N-
(2-Fluorobenzyl) -N- (2-fluorobenzyl
Ru) amino, N- (2-fluorobenzyl) -N- (3
-Fluorobenzyl) amino, N- (2-fluoroben
Dil) -N- (4-fluorobenzyl) amino, N-
(3-Fluorobenzyl) -N- (3-fluorobenzyl
Ru) amino, N- (3-fluorobenzyl) -N- (4
-Fluorobenzyl) amino, N- (4-fluoroben
Dil) -N- (4-fluorobenzyl) amino, N-
(2-Methylbenzyl) -N- (2-methylbenzyl)
Amino, N- (2-methylbenzyl) -N- (3-methyl
Rubenzyl) amino, N- (2-methylbenzyl) -N
-(4-methylbenzyl) amino, N- (3-methylpropyl)
N-)-N- (3-methylbenzyl) amino, N-
(3-Methylbenzyl) -N- (4-methylbenzyl)
Amino, N- (4-methylbenzyl) -N- (4-methyl
Rubenzyl) amino, N- (2-methoxybenzyl)-
N- (2-methoxybenzyl) amino, N- (2-meth
Xybenzyl) -N- (3-methoxybenzyl) ami
No, N- (2-methoxybenzyl) -N- (4-methoxy)
Cibenzyl) amino, N- (3-methoxybenzyl)-
N- (3-methoxybenzyl) amino, N- (3-meth
Xybenzyl) -N- (4-methoxybenzyl) ami
No, N- (4-methoxybenzyl) -N- (4-methoxy)
Cibenzyl) amino, N- (2-hydroxybenzyl)
-N- (2-hydroxybenzyl) amino, N- (2-
Hydroxybenzyl) -N- (3-hydroxybenzyl
L) amino, N- (2-hydroxybenzyl) -N-
(4-hydroxybenzyl) amino, N- (3-hydro
Xybenzyl) -N- (3-hydroxybenzyl) ami
No, N- (3-hydroxybenzyl) -N- (4-hydr
Roxybenzyl) amino, N- (4-hydroxybenzyl)
L) -N- (4-hydroxybenzyl) amino, N-
(2-Aminobenzyl) -N- (2-aminobenzyl)
Amino, N- (2-aminobenzyl) -N- (3-ami
Nobenzyl) amino, N- (2-aminobenzyl) -N
-(4-aminobenzyl) amino, N- (3-aminobe
N-)-N- (3-aminobenzyl) amino, N-
(3-Aminobenzyl) -N- (4-aminobenzyl)
Amino, N- (4-aminobenzyl) -N- (4-ami
Nobenzyl) amino, N- (2-dimethylaminobenzyl
) -N- (2-Dimethylaminobenzyl) amino, N
-(2-Dimethylaminobenzyl) -N- (3-dimethyl)
Luaminobenzyl) amino, N- (2-dimethylamino)
Benzyl) -N- (4-dimethylaminobenzyl) ami
No, N- (3-dimethylaminobenzyl) -N- (3-
Dimethylaminobenzyl) amino, N- (3-dimethyl
Aminobenzyl) -N- (4-dimethylaminobenzyl
) Amino, N- (4-dimethylaminobenzyl) -N
-(4-Dimethylaminobenzyl) amino, [bis (2
-Furyl) methyl] amino, [bis (3-furyl) methyl]
Ru] amino, [bis (2-thienyl) methyl] amino,
[Bis (3-thienyl) methyl] amino, [1,1-bi
Sus (2-thienyl) ethyl] amino, [1,1-bis
(3-thienyl) ethyl] amino, [2- (2-methyl
-3-thienyl) ethyl] amino, [2- (5-methyl
-2-thienyl) ethyl] amino, [2- (5-methyl
-3-thienyl) ethyl] amino, [(2-methyl-3
-Thienyl) methyl] amino, [(5-methyl-2-thi
(Enyl) methyl] amino, [(5-methyl-3-thienyl)
Ru) methyl] amino, [1- (2-thienyl) -1-me
Cylethyl] amino, [1- (3-thienyl) -1-me
Cylethyl] amino, [1- (2-methyl-3-thienyi
) -1-Methylethyl] amino, [1- (5-methyl
-2-thienyl) -1-methylethyl] amino, [1-
(5-Methyl-3-thienyl) -1-methylethyl] a
Mino, [1- (2-furyl) -1-methylethyl] ami
No, [1- (3-furyl) -1-methylethyl] ami
No, [1- (2-methyl-3-furyl) -1-methyl ether
Cyl] amino, [1- (5-methyl-2-furyl) -1
-Methylethyl] amino, [1- (5-methyl-3-fluoro)
Ryl) -1-methylethyl] amino, [1- (2-free
Ru) -2- (2-furyl) ethyl] amino, [1- (2
-Furyl) -2- (3-furyl) ethyl] amino, [1
-(3-furyl) -2- (2-furyl) ethyl] ami
No, [1- (3-furyl) -2- (3-furyl) eth
L] amino, [1- (2-thienyl) -2- (2-thiene)
Nyl) ethyl] amino, [1- (3-thienyl) -2-
(2-thienyl) ethyl] amino, [1- (2-thienyl)
) -2- (3-thienyl) ethyl] amino, [1-
(3-thienyl) -2- (3-thienyl) ethyl] ami
No, [1- (2-furyl) -2-phenylethyl] ami
No, [1- (3-furyl) -2-phenylethyl] ami
No, [2-phenyl-1- (2-thienyl) ethyl] a
Mino, [2-phenyl-1- (3-thienyl) ethyl]
Amino, [1-phenyl-2- (2-thienyl) ethyl
L] amino, [1-phenyl-2- (3-thienyl) e]
Cyl] amino, [2- (2-methylphenyl) -1-
(2-thienyl) ethyl] amino, [2- (3-methyl
Phenyl) -1- (2-thienyl) ethyl] amino,
[2- (4-methylphenyl) -1- (2-thienyl)
Ethyl] amino, [2- (2-methylphenyl) -1-
(3-thienyl) ethyl] amino, [2- (3-methyl
Phenyl) -1- (3-thienyl) ethyl] amino,
[2- (4-methylphenyl) -1- (3-thienyl)
Ethyl] amino, [2- (2-chlorophenyl) -1-
(2-thienyl) ethyl] amino, [2- (3-chloro
Phenyl) -1- (2-thienyl) ethyl] amino,
[2- (4-chlorophenyl) -1- (2-thienyl)
Ethyl] amino, [2- (2-chlorophenyl) -1-
(3-thienyl) ethyl] amino, [2- (3-chloro
Phenyl) -1- (3-thienyl) ethyl] amino,
[2- (4-chlorophenyl) -1- (3-thienyl)
Ethyl] amino, [2- (2-fluorophenyl) -1
-(2-thienyl) ethyl] amino, [2- (3-fur
Orophenyl) -1- (2-thienyl) ethyl] ami
No, [2- (4-fluorophenyl) -1- (2-thie
Nyl) ethyl] amino, [2- (2-fluorophenyl)
L) -1- (3-thienyl) ethyl] amino, [2-
(3-Fluorophenyl) -1- (3-thienyl) eth
Lu] amino, [2- (4-fluorophenyl) -1-
(3-thienyl) ethyl] amino, [2- (2-methoxy)
Cyphenyl) -1- (2-thienyl) ethyl] amino,
[2- (3-methoxyphenyl) -1- (2-thienyl)
Ru) ethyl] amino, [2- (4-methoxyphenyl)]
-1- (2-thienyl) ethyl] amino, [2- (2-
Methoxyphenyl) -1- (3-thienyl) ethyl] a
Mino, [2- (3-methoxyphenyl) -1- (3-thio)
(Enyl) ethyl] amino, [2- (4-methoxyphenyl)
L) -1- (3-thienyl) ethyl] amino, N- (2
-Thienylmethyl) -N- (2-thienylmethyl) ami
No, N- (2-thienylmethyl) -N- (3-thienyl)
Methyl) amino, N- (3-thienylmethyl) -N-
(3-thienylmethyl) amino, [1- (2-fluoro
Phenyl) -2- (2-thienyl) ethyl] amino,
[1- (3-fluorophenyl) -2- (2-thieni
Ru) ethyl] amino, [1- (4-fluorophenyl)
-2- (2-thienyl) ethyl] amino, [1- (2-
Fluorophenyl) -2- (3-thienyl) ethyl] a
Mino, [1- (3-fluorophenyl) -2- (3-thio)
(Enyl) ethyl] amino, [1- (4-fluorophenyl)
Ru) -2- (3-thienyl) ethyl] amino, N ′,
N'-diphenylhydrazino, N '-(2-methylphene
Nyl) -N'-phenylhydrazino, N '-(3-methyl
Ruphenyl) -N'-phenylhydrazino, N '-(4
-Methylphenyl) -N'-phenylhydrazino, N '
-(2-Methoxyphenyl) -N'-phenylhydrazide
No, N '-(3-methoxyphenyl) -N'-phenyl
Hydrazino, N '-(4-methoxyphenyl) -N'-
Phenylhydrazino, N '-(2-chlorophenyl)-
N'-phenylhydrazino, N '-(3-chlorophenyl
) -N'-phenylhydrazino, N '-(4-chloro
Phenyl) -N'-phenylhydrazino, N '-(2-
Fluorophenyl) -N'-phenylhydrazino, N '
-(3-Fluorophenyl) -N'-phenylhydrazide
No, N '-(4-fluorophenyl) -N'-phenyl
Hydrazino, N '-(2-hydroxyphenyl) -N'
-Phenylhydrazino, N '-(3-hydroxypheni
) -N'-phenylhydrazino, N '-(4-hydro
Xyphenyl) -N'-phenylhydrazino, N'-
(2-aminophenyl) -N'-phenylhydrazino,
N '-(3-aminophenyl) -N'-phenylhydra
Dino, N '-(4-aminophenyl) -N'-phenyl
Hydrazino, N '-(2-dimethylaminophenyl)-
N'-phenylhydrazino, N '-(3-dimethylamido
Nophenyl) -N'-phenylhydrazino, N '-(4
-Dimethylaminophenyl) -N'-phenylhydrazide
No, N '-(2-acetamidophenyl) -N'-phen
Nylhydrazino, N '-(3-acetamidophenyl)
-N'-phenylhydrazino, N '-(4-acetamii
Dephenyl) -N'-phenylhydrazino, N '-(2
-Methylphenyl) -N '-(2-methylphenyl) hi
Dorazino, N '-(2-methylphenyl) -N'-(3
-Methylphenyl) hydrazino, N '-(2-methylphenyl)
Phenyl) -N '-(4-methylphenyl) hydrazino,
N '-(3-methylphenyl) -N'-(3-methylphenyl
Phenyl) hydrazino, N '-(3-methylphenyl)-
N '-(4-methylphenyl) hydrazino, N'-(4
-Methylphenyl) -N '-(4-methylphenyl) hi
Dorazino, N '-(2-methoxyphenyl) -N'-
(2-methoxyphenyl) hydrazino, N '-(2-me
Toxyphenyl) -N '-(3-methoxyphenyl) hi
Dorazino, N '-(2-methoxyphenyl) -N'-
(4-Methoxyphenyl) hydrazino, N '-(3-me
Toxyphenyl) -N '-(3-methoxyphenyl) hi
Dorazino, N '-(3-methoxyphenyl) -N'-
(4-Methoxyphenyl) hydrazino and N '-(4-
Methoxyphenyl) -N '-(4-methoxyphenyl)
It's a hydrazino.

Even more preferably, (1-methyl-1-phenylethyl) amino, [1-methyl-1- (2-methylphenyl) ethyl] amino, [1-methyl-1- (3
-Methylphenyl) ethyl] amino, [1-methyl-1
-(4-methylphenyl) ethyl] amino, [1-methyl-1- (2-methoxyphenyl) ethyl] amino,
[1-Methyl-1- (3-methoxyphenyl) ethyl]
Amino, [1-methyl-1- (4-methoxyphenyl)
Ethyl] amino, [1-methyl-1- (3,4-dimethoxyphenyl) ethyl] amino, [1-methyl-1-
(3,5-dimethoxyphenyl) ethyl] amino, [1
-Methyl-1- (3,4,5-trimethoxyphenyl)
Ethyl] amino, [1-methyl-1- (2,4,6-trimethoxyphenyl) ethyl] amino, [1-methyl-
1- (2-fluorophenyl) ethyl] amino, [1-
Methyl-1- (3-fluorophenyl) ethyl] amino, [1-methyl-1- (4-fluorophenyl) ethyl] amino, [1-methyl-1- (2-chlorophenyl) ethyl] amino, [1- Methyl-1- (3-chlorophenyl) ethyl] amino, [1-methyl-1- (4-
Chlorophenyl) ethyl] amino, [1-methyl-1-
(2-Hydroxyphenyl) ethyl] amino, [1-methyl-1- (3-hydroxyphenyl) ethyl] amino, [1-methyl-1- (4-hydroxyphenyl) ethyl] amino, [1-methyl-1 -(2-Dimethylaminophenyl) ethyl] amino, [1-methyl-1- (3
-Dimethylaminophenyl) ethyl] amino, [1-methyl-1- (4-dimethylaminophenyl) ethyl] amino, {1-methyl-1- [3,5-bis (dimethylamino) phenyl] ethyl} amino, (1,1-dimethyl-2-phenylethyl) amino, benzhydrylamino, (2,2′-dimethylbenzhydryl) amino,
(2,3'-Dimethylbenzhydryl) amino, (2,3'-
4'-Dimethylbenzhydryl) amino, (3,3'-
Dimethylbenzhydryl) amino, (3,4'-dimethylbenzhydryl) amino, (4,4'-dimethylbenzhydryl) amino, (2,2'-dimethoxybenzhydryl) amino, (2,3 ′ -Dimethoxybenzhydryl) amino, (2,4′-dimethoxybenzhydryl)
Amino, (3,3′-dimethoxybenzhydryl) amino, (3,4′-dimethoxybenzhydryl) amino,
(4,4'-dimethoxybenzhydryl) amino,
(2,2'-difluorobenzhydryl) amino,
(2,3'-difluorobenzhydryl) amino,
(2,4'-difluorobenzhydryl) amino,
(3,3′-difluorobenzhydryl) amino,
(3,4'-difluorobenzhydryl) amino,
(4,4'-difluorobenzhydryl) amino,
(2,2'-dichlorobenzhydryl) amino, (2,2 '
3'-dichlorobenzhydryl) amino, (2,4'-
Dichlorobenzhydryl) amino, (3,3'-dichlorobenzhydryl) amino, (3,4'-dichlorobenzhydryl) amino, (4,4'-dichlorobenzhydryl) amino, (2-methyl Benzhydryl) Amino,
(3-Methylbenzhydryl) amino, (4-methylbenzhydryl) amino, (2-methoxybenzhydryl) amino, (3-methoxybenzhydryl) amino,
(4-Methoxybenzhydryl) amino, (2-fluorobenzhydryl) amino, (3-fluorobenzhydryl) amino, (4-fluorobenzhydryl) amino, (2-chlorobenzhydryl) amino, (3-Chlorobenzhydryl) amino, (4-chlorobenzhydryl) amino, (2-hydroxybenzhydryl) amino, (3-hydroxybenzhydryl) amino, (4-
Hydroxybenzhydryl) amino, (2-dimethylaminobenzhydryl) amino, (3-dimethylaminobenzhydryl) amino, (4-dimethylaminobenzhydryl) amino, (1,1-diphenylethyl) amino, (1,2-diphenylethyl) amino, [2- (2
-Chlorophenyl) -1-phenylethyl] amino,
[2- (3-chlorophenyl) -1-phenylethyl]
Amino, [2- (4-chlorophenyl) -1-phenylethyl] amino, [2- (2-fluorophenyl) -1
-Phenylethyl] amino, [2- (3-fluorophenyl) -1-phenylethyl] amino, [2- (4-fluorophenyl) -1-phenylethyl] amino, [2
-(2-Methylphenyl) -1-phenylethyl] amino, [2- (3-methylphenyl) -1-phenylethyl] amino, [2- (4-methylphenyl) -1-phenylethyl] amino, [- 2- (2-methoxyphenyl)
-1-Phenylethyl] amino, [2- (3-methoxyphenyl) -1-phenylethyl] amino, [2- (4
-Methoxyphenyl) -1-phenylethyl] amino,
N, N-dibenzylamino, N- (2-fluorobenzyl) -N- (2-fluorobenzyl) amino, N- (2
-Fluorobenzyl) -N- (3-fluorobenzyl)
Amino, N- (2-fluorobenzyl) -N- (4-fluorobenzyl) amino, N- (3-fluorobenzyl) -N- (3-fluorobenzyl) amino, N- (3
-Fluorobenzyl) -N- (4-fluorobenzyl)
Amino, N- (4-fluorobenzyl) -N- (4-fluorobenzyl) amino, N- (2-methylbenzyl)
-N- (2-methylbenzyl) amino, N- (2-methylbenzyl) -N- (3-methylbenzyl) amino, N
-(2-Methylbenzyl) -N- (4-methylbenzyl) amino, N- (3-methylbenzyl) -N- (3-
Methylbenzyl) amino, N- (3-methylbenzyl)
-N- (4-methylbenzyl) amino, N- (4-methylbenzyl) -N- (4-methylbenzyl) amino, N
-(2-Methoxybenzyl) -N- (2-methoxybenzyl) amino, N- (2-methoxybenzyl) -N-
(3-Methoxybenzyl) amino, N- (2-methoxybenzyl) -N- (4-methoxybenzyl) amino, N
-(3-Methoxybenzyl) -N- (3-methoxybenzyl) amino, N- (3-methoxybenzyl) -N-
(4-methoxybenzyl) amino, N- (4-methoxybenzyl) -N- (4-methoxybenzyl) amino,
[1- (2-thienyl) -1- (2-thienyl) methyl] amino, [1- (2-thienyl) -1- (3-thienyl) methyl] amino, [1- (3-thienyl) -1 −
(3-thienyl) methyl] amino, [2-phenyl-1
-(2-thienyl) ethyl] amino, [2-phenyl-
1- (3-thienyl) ethyl] amino, [1-methyl-
1- (2-thienyl) ethyl] amino, [1-methyl-
1- (3-thienyl) ethyl] amino, [1-methyl-
1- (2-methyl-3-thienyl) ethyl] amino,
[1-Methyl-1- (5-methyl-2-thienyl) ethyl] amino, [1-methyl-1- (5-methyl-3-thienyl) ethyl] amino, [1-methyl-1- (2- Furyl) ethyl] amino, [1-methyl-1- (3-furyl) ethyl] amino, [1-methyl-1- (5-methyl-2-furyl) ethyl] amino, N ′, N′-diphenylhydra Dino, N '-(2-methoxyphenyl) -N'
-Phenylhydrazino, N '-(3-methoxyphenyl) -N'-phenylhydrazino, N'-(4-methoxyphenyl) -N'-phenylhydrazino, N '-(2
-Fluorophenyl) -N'-phenylhydrazino,
N '-(3-fluorophenyl) -N'-phenylhydrazino, N'-(4-fluorophenyl) -N'-phenylhydrazino, N '-(2-methoxyphenyl)-
N '-(2-methoxyphenyl) hydrazino, N'-
(2-Methoxyphenyl) -N '-(3-methoxyphenyl) hydrazino, N'-(2-methoxyphenyl)-
N '-(4-methoxyphenyl) hydrazino, N'-
(3-Methoxyphenyl) -N '-(3-methoxyphenyl) hydrazino, N'-(3-methoxyphenyl)-
N '-(4-methoxyphenyl) hydrazino, and
It is N '-(4-methoxyphenyl) -N'-(4-methoxyphenyl) hydrazino.

Particularly preferably, (1-methyl-1-phenylethyl) amino, [1-methyl-1- (2-methylphenyl) ethyl] amino, [1-methyl-1- (3-methylphenyl) Ethyl] amino, [1-methyl-1-
(4-Methylphenyl) ethyl] amino, [1-methyl-1- (2-methoxyphenyl) ethyl] amino, [1
-Methyl-1- (3-methoxyphenyl) ethyl] amino, [1-methyl-1- (4-methoxyphenyl) ethyl] amino, [1-methyl-1- (3,4-dimethoxyphenyl) ethyl] amino , [1-methyl-1- (3,
5-dimethoxyphenyl) ethyl] amino, [1-methyl-1- (3,4,5-trimethoxyphenyl) ethyl] amino, [1-methyl-1- (2,4,6-trimethoxyphenyl) ethyl ] Amino, [1-methyl-1-
(2-fluorophenyl) ethyl] amino, [1-methyl-1- (3-fluorophenyl) ethyl] amino,
[1-Methyl-1- (4-fluorophenyl) ethyl]
Amino, [1-methyl-1- (2-chlorophenyl) ethyl] amino, [1-methyl-1- (3-chlorophenyl) ethyl] amino, [1-methyl-1- (4-chlorophenyl) ethyl] amino, [1-methyl-1- (2-
Hydroxyphenyl) ethyl] amino, [1-methyl-
1- (3-hydroxyphenyl) ethyl] amino, [1
-Methyl-1- (4-hydroxyphenyl) ethyl] amino, [1-methyl-1- (2-dimethylaminophenyl) ethyl] amino, [1-methyl-1- (3-dimethylaminophenyl) ethyl] amino , [1-methyl-1
-(4-dimethylaminophenyl) ethyl] amino,
{1-methyl-1- [3,5-bis (dimethylamino)
Phenyl] ethyl} amino, (1,1-dimethyl-2-
Phenylethyl) amino, benzhydrylamino,
(2,2'-Dimethylbenzhydryl) amino, (2,2 '
3'-Dimethylbenzhydryl) amino, (2,4'-
Dimethylbenzhydryl) amino, (3,3′-dimethylbenzhydryl) amino, (3,4′-dimethylbenzhydryl) amino, (4,4′-dimethylbenzhydryl) amino, (2,2 ′ -Dimethoxybenzhydryl) amino, (2,3′-dimethoxybenzhydryl)
Amino, (2,4'-dimethoxybenzhydryl) amino, (3,3'-dimethoxybenzhydryl) amino,
(3,4'-dimethoxybenzhydryl) amino,
(4,4'-dimethoxybenzhydryl) amino,
(2,2'-difluorobenzhydryl) amino,
(2,3'-difluorobenzhydryl) amino,
(2,4'-difluorobenzhydryl) amino,
(3,3′-difluorobenzhydryl) amino,
(3,4'-difluorobenzhydryl) amino,
(4,4'-difluorobenzhydryl) amino,
(2,2'-dichlorobenzhydryl) amino, (2,2 '
3'-dichlorobenzhydryl) amino, (2,4'-
Dichlorobenzhydryl) amino, (3,3'-dichlorobenzhydryl) amino, (3,4'-dichlorobenzhydryl) amino, (4,4'-dichlorobenzhydryl) amino, (2-methyl Benzhydryl) Amino,
(3-Methylbenzhydryl) amino, (4-methylbenzhydryl) amino, (2-methoxybenzhydryl) amino, (3-methoxybenzhydryl) amino,
(4-Methoxybenzhydryl) amino, (2-hydroxybenzhydryl) amino, (3-hydroxybenzhydryl) amino, (4-hydroxybenzhydryl)
Amino, (1,1-diphenylethyl) amino, [1-
Methyl-1- (2-thienyl) ethyl] amino, [1-
Methyl-1- (3-thienyl) ethyl] amino, [1-
Methyl-1- (2-methyl-3-thienyl) ethyl] amino, [1-methyl-1- (5-methyl-2-thienyl) ethyl] amino, [1-methyl-1- (5-methyl-3) -Thienyl) ethyl] amino, [1-methyl-1-
(2-Furylethyl)] amino, [1-methyl-1-
(3-furylethyl)] amino, [1-methyl-1-
(2-Methyl-3-furyl) ethyl] amino, [1-methyl-1- (5-methyl-2-furyl) ethyl] amino, and [1-methyl-1- (5-methyl-3-furyl) ) Ethyl] amino.

The compounds of the general formula (I) according to the invention are
If necessary, it can be converted into a pharmacologically acceptable salt.
As such a salt, when it has an acidic group such as a carboxy group, an alkali metal salt such as sodium salt, potassium salt or lithium salt, an alkaline earth metal salt such as calcium salt, barium salt or magnesium salt. , Aluminum salts, iron salts, zinc salts, copper salts, nickel salts, cobalt salts and other metal salts; inorganic salts such as ammonium salts, t-octylamine salts, dibenzylamine salts, morpholine salts, glucosamine salts, phenylglycine. Alkyl ester salt, ethylenediamine salt, N-methylglucamine salt, guanidine salt, diethylamine salt, triethylamine salt, dicyclohexylamine salt, chlorin salt, N, N′-dibenzylethylenediamine salt, chloroprocaine salt, procaine salt, diethanolamine salt, N-benzyl-phenethylamine salt, pipera Examples thereof include amine salts (preferably alkali metal salts, particularly preferably sodium salts) such as organic salts such as gin salt, tetramethylammonium salt, and tris (hydroxymethyl) aminomethane salt.
When it has a basic group such as an amino group, a hydrohalide such as a hydrofluoride, a hydrochloride, a hydrobromide or a hydroiodide, a nitrate or a perchlorate. Inorganic acid salts such as sulfates, phosphates; lower alkane sulfonates such as methanesulfonate, trifluoromethanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, etc. Aryl sulfonate, acetic acid,
Organic acid salts such as malic acid, fumarate, succinate, citrate, tartrate, oxalate and maleate; and glycine salt, lysine salt, arginine salt, ornithine salt, glutamate, asparagine. Mention may be made of addition salts of amino acid salts such as acid salts.

In the compound (I), optical isomers based on an asymmetric carbon atom exist, but the present invention includes such stereoisomers and mixtures thereof.

As the compound having the above general formula (I) of the present invention, preferably, (1) the protecting group of the "protected carboxy group" of R ³ is a C ₁ -C ₄ alkyl group; a benzyl group; Benzyl group substituted with methyl, ethyl, methoxy, ethoxy, fluorine atom or chlorine atom; naphthylmethyl group; diphenylmethyl group; (C ₁ -C ₅ alkanoyloxy) C ₁ -C ₄ alkyl group; (C ₆ -C ₇ cycloalkanoyloxy) C ₁ -C ₄ alkyl group; (C ₁ -C
₄ alkoxycarbonyloxy) C ₁ -C ₄ alkyl group; (C ₅ -C ₆ cycloalkoxycarbonyloxy)
C ₁ -C ₄ alkyl group; (5-phenyl-2-oxo-
1,3-dioxolen-4-yl) methyl group; [5-
A compound which is a (C ₁ -C ₄ alkyl) -2-oxo-1,3-dioxolen-4-yl] methyl group or a phthalidyl group, (2) the protecting group of the “protected carboxy group” of R ³ is C ₁ -C ₄ alkyl group, benzyl group, (C ₁ -C
₅ alkanoyloxy) C ₁ -C ₂ alkyl group, (C ₆
-C ₇ cycloalkanoyloxy) C ₁ -C ₂ alkyl group, (C ₁ -C ₄ alkoxycarbonyloxy) C ₁ -
C ₂ alkyl group, (C ₅ -C ₆ cycloalkoxycarbonyloxy) C ₁ -C ₂ alkyl group, (5-phenyl-
2-oxo-1,3-dioxolen-4-yl) methyl group, [5- (C ₁ -C ₂ alkyl) -2-oxo-1,
A compound that is a 3-dioxolen-4-yl] methyl group or a phthalidyl group, (3) the protecting group of the “protected carboxy group” of R ³ is a methyl group, an ethyl group, a pivaloyloxymethyl group, or ethoxycarbonyl. Oxymethyl group, 1-
(Ethoxycarbonyloxy) ethyl group, isopropoxycarbonyloxymethyl group, 1- (isopropoxycarbonyloxy) ethyl group, (5-methyl-2-oxo-1,3-dioxolen-4-yl) methyl group or phthalidyl group Is (4) a compound in which the protecting group of the "protected carboxy group" of R ³ is a methyl group or an ethyl group, (5) when R ³ has the formula CONHSO ₂ R ⁴ , R ⁴ Is a C ₁ -C ₄ alkyl group,
(6) When R ³ has the formula CONHSO ₂ R ⁴ , R ^3
A compound in which ⁴ is a methyl group or an ethyl group, (7) R ³
When the formula CONHSO ₂ R ⁴ is present, a compound in which R ⁴ is a methyl group can be mentioned.

Specific compounds of the present invention include, for example, the compounds shown in the following [Table 1] and [Table 2].

The compound having the general formula (I-1) and the compound having the general formula (I-2) correspond to [Table 1] and [Table 2], respectively.

[0037]

[Chemical 4]

[0038]

[Table 1] ────────────────────────────────── Compound R ¹ R ² R No. ³ ─── ─────────────────────────────── 1-1 H 1,2-diPhEt CO ₂ H 1-2 H Bzhy CO ₂ H 1-3 H 1,1-diPhEt CO ₂ H 1-4 Bz Bz CO ₂ H 1-5 H 1,2-di (2-Thi) Et CO ₂ H 1-6 H 1,2-bis (4 -FPh) Et CO ₂ H 1-7 H 1,2-bis (4-MePh) Et CO ₂ H 1-8 H 1,2-bis (4-MeOPh) Et CO ₂ H 1-9 H 1,2 -bis (4-ClPh) Et CO ₂ H 1-10 H di (2-Thi) CH- CO ₂ H 1-11 H 1,2-di (2-Thi) Et CO ₂ Me 1-12 H bis ( 4-FPh) CH- CO ₂ H 1-13 H bis (4-MePh) CH- CO ₂ H 1-14 H bis (4-MeOPh) CH- CO ₂ H 1-15 H 2- (4-MeOPh) -1- (2-Thi) Et CO ₂ H 1-16 H 2- (4-FPh) -1- (2-Thi) Et CO ₂ H 1-17 H 2- (4-MePh) -1- ( 2-Thi) Et CO ₂ H 1-18 H 2- (4-ClPh) -1- (2-Thi) Et CO ₂ H 1-19 H 1- (2-Fur) -2-PhEt CO ₂ H 1 -20 H 2-Ph-1- (2-Thi) Et CO ₂ H 1-21 H di (3-Thi) CH- CO ₂ H 1-22 H 2- (4-MePh) -1-PhEt CO ₂ H 1-23 H 2- ( 4-FPh) -1- (4-MePh) Et CO ₂ H 1-24 H 2- (4-MeOPh) -1-PhEt CO ₂ H 1-25 H 2- (4-FPh) -1- (4 -MeOPh) Et CO ₂ H 1-26 H 1-Bz-4-PhBu CO ₂ H 1-27 H 4-ClBzhy CO ₂ H 1-28 H 4-MeOBzhy CO ₂ H 1-29 H 4-FBzhy CO ₂ H 1-30 H 4-F-4'-MeOBzhy CO ₂ H 1-31 H 4-MeBzhy CO ₂ H 1-32 H 2-Ph-1- (2-Thi) Et CO ₂ Me 1-33 H 2 -Ph-1- (2-Thi) Et CO 2 CH 2 OCOBu t 1-34 H 2-Ph-1- (2-Thi) Et CO 2 CH (Me) OCO 2 Et 1-35 H 2-Ph- 1- (2-Thi) Et CO ₂ Mod 1-36 H 2-Ph-1- (2-Thi) Et CO ₂ Na 1-37 H 1,1-diBzEt CO ₂ H 1-38 H 1,1- di (2-Thi) Et CO 2 H 1-39 H 1,1-di (2-Thi) Et CO 2 Me 1-40 H 1,1-di (2-Thi) Et CO 2 CH 2 OCOBu t 1 −41 H 1,1-di (2-Thi) Et CO ₂ CH (Me) OCO ₂ Et 1-42 H 1,1-di (2-Thi) Et CO ₂ Mod 1-43 H 1,1-di _{(2-Thi) Et CO 2} Na 1-44 H Bzhy CO 2 Me 1-45 H Bzhy CO 2 CH 2 OCOBu t 1-46 H Bzhy CO 2 CH (Me) OCO 2 Et 1-47 H Bzhy CO 2 Mod _{1-48 H Bzhy CO 2 Na 1-49 H} 1,2-diPhEt CO 2 Et 1-50 H 1,2-diPhEt CO 2 CH 2 OCOBu t 1-51 H 1,2-diPhEt CO 2 CH (Me) OCO ₂ Et 1 _{52 H 1,2-diPhEt CO 2 Mod} 1-53 H 1,2-diPhEt CO 2 Na 1-54 H 1,2-diPhEt CO 2 Phth 1-55 H 1,1-diPhEt CO 2 Me 1-56 H _{1,1-diPhEt CO 2 Et 1-57 H} 1,1-diPhEt CO 2 CH 2 OCOBu t 1-58 H 1,1-diPhEt CO 2 CH (Me) OCO 2 Et 1-59 H 1,1-diPhEt CO ₂ Mod 1-60 H 1,1-diPhEt CO ₂ Phth 1-61 H 1,1-diPhEt CO ₂ Na 1-62 H 1-Bz-1-PhEt CO ₂ H 1-63 H 1,2-diPhPr CO ₂ H 1-64 4-HOBz 4-HOBz CO ₂ H 1-65 4-FBz 4-FBz CO ₂ H 1-66 H 1-Me-1-PhEt CO ₂ H 1-67 H 1-Me-1 -(2-Thi) Et CO ₂ H 1-68 H 1-Me-1- (2-Thi) Et CO ₂ Me 1-69 H 1-Me-1- (2-Thi) Et CO ₂ CH ₂ OCOBu ^t 1-70 H 1-Me-1- (2-Thi) Et CO ₂ CH (Me) OCO ₂ Et 1-71 H 1-Me-1- (2-Thi) Et CO ₂ Mod 1-72 H 1 _{-Me-1-PhEt CO 2 Me} 1-73 H 1-Me-1-PhEt CO 2 CH 2 OCOBu t 1-74 H 1-Me-1-PhEt CO 2 CH (Me) OCO 2 Et 1-75 H 1-Me-1-PhEt CO ₂ Mod 1-76 H 1,1-diMe-2-PhEt CO ₂ H 1-77 H 1-Me-1- (4-HOPh) Et CO ₂ H 1-78 H 1 -Me-1- (4-FPh) Et CO ₂ H 1-79 H 1-Me-1- (4-NMe ₂ Ph) Et CO ₂ Na 1-80 H di (2-Fur) CH- CO ₂ H 1 −81 H 4,4'-diHOBzhy CO ₂ H 1-82 H 1,2-bis (4-HOPh) Et CO ₂ H 1-83 H 1,2-bis (4-HOPh) -1-MeEt CO ₂ H 1-84 i Pr Bz CO ₂ H 1-85 Et Bz CO ₂ H 1-86 Me Bz CO ₂ H 1-87 i Bu Bz CO ₂ H 1-88 i Pr 4-FBz CO ₂ H 1-89 i Pr 4-ClBz CO ₂ H 1-90 i Pr 4-MeBz CO ₂ H 1-91 i Pr 4-MeOBz CO ₂ H 1-92 i Pr 4-HOBz CO ₂ H 1-93 2-ThiMe 2-ThiMe CO _{2 H 1-94 2-ThiMe Bz CO} 2 H 1-95 H Bzhy CO 2 Et 1-96 H Bzhy CO 2 CH 2 OCOBu t 1-97 H Bzhy CO 2 CH (Me) OCO 2 Et 1-98 H Bzhy CO ₂ Mod 1-99 H Bzhy CO ₂ Na 1-100 Bz Bz CO ₂ Me 1-101 Bz Bz CO ₂ Et 1-102 H di (2-Thi) CH- CO ₂ Me 1-103 H di (2- _{Thi) CH- CO 2 Et 1-104 H} di (2-Thi) CH- CO 2 CH 2 OCOBu t 1-105 H di (2-Thi) CH- CO 2 CH (Me) OCO 2 Et 1-106 H di (2-Thi) CH- CO ₂ Mod 1-107 H di (2-Thi) CH- CO ₂ Na 1-108 H 2- (4-MePh) -1-PhEt CO ₂ Me 1-109 H 2- (4-MePh) -1-PhEt CO 2 Et 1-110 H 2- (4-MePh) -1-PhEt CO 2 CH 2 OCOBu t 1-111 H 2- (4-MePh) -1-PhEt CO 2 CH (Me) OCO ₂ Et 1-112 H 2- (4- MePh) -1-PhEt CO ₂ Mod 1-113 H 2- (4-MePh) -1-PhEt CO ₂ Na 1-114 H 1,1-diPhEt CO ₂ Me 1-115 H 1-Me-1-PhEt _{CO 2 Et 1-116 H 1-Me} -1-PhEt CO 2 CH 2 OCOBu t 1-117 H 1-Me-1-PhEt CO 2 CH (Me) OCO 2 Et 1-118 H 1-Me-1- PhEt CO ₂ Mod 1-119 H 1-Me-1-PhEt CO ₂ Na 1-120 H 1-Me-1- (2-Thi) Et CO ₂ Et 1-121 H 1-Me-1- (2- _{Thi) Et CO 2 CH 2 OCOBu} t 1-122 H 1-Me-1- (2-Thi) Et CO 2 CH (Me) OCO 2 Et 1-123 H 1-Me-1- (2-Thi) Et CO ₂ Mod 1-124 H 1-Me-1- (2-Thi) Et CO ₂ Na 1-125 H 1,1-diMe-2-PhEt CO ₂ Me 1-126 H 4,4'-diMeOBzhy CO _{2 Me 1-127 H 4-HOBzhy CO 2} H 1-128 H 4-HOBzhy CO 2 Me 1-129 H 4-HOBzhy CO 2 Et 1-130 H 4-HOBzhy CO 2 CH 2 OCOBu t 1-131 H 4- HOBzhy CO ₂ CH (Me) OCO ₂ Et 1-132 H 4-HOBzhy CO ₂ Mod 1-133 H 4-HOBzhy CO ₂ Na 1-134 H 4-MeOBzhy CO ₂ Et 1-135 H 4-MeOBzhy CO ₂ Na _{1-136 H 4-MeOBzhy CO 2 Me} 1-137 H 4-MeOBzhy CO 2 CH 2 OCOBu t 1-138 H 4-MeOBzhy CO 2 CH (Me) OCO 2 Et 1-139 H 4-MeOBzhy CO 2 Mod 1 −140 H 4-ClBzh y CO ₂ H 1-141 H 4-ClBzhy CO ₂ Me 1-142 H 1- (4-MeOPh) -1-MeEt CO ₂ H 1-143 H 1- (4-MeOPh) -1-MeEt CO ₂ Me 1-144 H 1- (4-MeOPh) -1-MeEt CO 2 Et 1-145 H 1- (4-MeOPh) -1-MeEt CO 2 CH 2 OCOBu t 1-146 H 1- (4-MeOPh) -1-MeEt CO ₂ CH (Me) OCO ₂ Et 1-147 H 1- (4-MeOPh) -1-MeEt CO ₂ Mod 1-148 H 1- (4-MeOPh) -1-MeEt CO ₂ Na 1 −149 H 1- (3,5-diMeOPh) -1-MeEt CO ₂ H 1-150 H 1- (3,5-diMeOPh) -1-MeEt CO ₂ Me 1-151 H 1- (4-FPh) _{-1-MeEt CO 2 Et 1-152 H} 1- (4-FPh) -1-MeEt CO 2 CH 2 OCOBu t 1-153 H 1- (4-FPh) -1-MeEt CO 2 CH (Me) OCO ₂ Et 1-154 H 1- (4-FPh) -1-MeEt CO ₂ Mod 1-155 H 1- (4-FPh) -1-MeEt CO ₂ Na 1-156 H 1- (4-FPh)- 1-MeEt CO ₂ Me 1-157 H 1- (4-AcNHPh) -1-MeEt CO ₂ H 1-158 H 1- (4-AcNHPh) -1-MeEt CO ₂ Me 1-159 H Ph ₂ N- _{CO 2 H 1-160 H Ph 2 N-} CO 2 Me 1-161 H Ph 2 N- CO 2 Et 1-162 H Ph 2 N- CO 2 CH 2 OCOBu t 1-163 H Ph 2 N- CO 2 CH _{(Me) OCO 2 Et 1-164 H} Ph 2 N- CO 2 Mod 1-165 H Ph 2 N- CO 2 Na 1-166 H 1-Me-1- (3-MeOPh) Et CO 2 H -167 H 1-Me-1- ( 3-MeOPh) Et CO 2 Me 1-168 H 1-Me-1- (2-MeOPh) Et CO 2 H 1-169 H 1-Me-1- (2- MeOPh) Et CO ₂ Me 1-170 H 2,2-diPhEt CO ₂ H 1-171 H 3,3-diPhPr CO ₂ H 1-172 H Bzhy CO ₂ Et 1-173 H Bzhy CO ₂ Me 1-174 H ^{_{Bzhy CO 2 CH 2 OCOBu t 1-175}} H Bzhy CO 2 CH (Me) OCO 2 Et 1-176 H Bzhy CO 2 Mod 1-177 H Bzhy CO 2 Na 1-178 H 1-Me-1- (2- Fur) Et CO ₂ H 1-179 H 1-Me-1- (2-Fur) Et CO ₂ Me 1-180 H 1-Me-1-PhEt CONHSO ₂ Me 1-181 H 1-Me-1- ( 2-Thi) Et CONHSO ₂ Me 1-182 H 1-Me-1- (4-MeOPh) Et CONHSO ₂ Me 1-183 H 1-Me-1- (3-Thi) Et CONH S O ₂ Me 1- 184 H 1-Me-1- (4-NMe ₂ Ph) Et CONHSO ₂ Me 1-185 H 1-Me-1- (4-FPh) Et CONHSO ₂ Me 1-186 H 1-Me-1- (4 -MePh) Et CONHSO ₂ Me 1-187 H 1-Me-1- (4-ClPh) Et CONHSO ₂ Me 1-188 H Bzhy CONHSO ₂ Me 1-189 H Bzhy CONHSO ₂ Et 1-190 H 1-Me- 1- (4-NMe ₂ Ph) Et CO ₂ H 1-191 H 1-Me-1- (3-Thi) Et CO ₂ H 1-192 H 1-Me-1- (3,4-diOMePh) Et CO ₂ H 1-193 H 1-Me-1- (4-ClPh) Et CO ₂ H 1-194 H 1-Me-1- (4-OEtPh) Et C O ₂ H 1-195 H 1-Et-1-PhPr CO ₂ H 1-196 H 1-Me-1- (4-MePh) Et CO ₂ H 1-197 H 1-Me-1- (3,4 , 5-triMeOPh) Et CO ₂ Me 1-198 H 1- (CH ₃ OH) -1- (4-MeOPh) Et CO ₂ H 1-199 H 1- (COOH) -1- (4-MeOPh) Et CO ₂ H 1-200 H 1-Me-1- (3,4,5-triMeOPh) Et CO ₂ H 1-201 H 1-Me-1- (3,5-diNMe ₂ Ph) Et CO ₂ H ─ ───────────────────────────────────

[0039]

[Table 2] ────────────────────────────────── Compound R ¹ R ² R No. ³
────────────────────────────────── 2-1 H 1,2-diPhEt CO ₂ H 2-2 H Bzhy CO ₂ H 2-3 H 1,1-diPhEt CO ₂ H 2-4 Bz Bz CO ₂ H 2-5 H 1,2-di (2-Thi) Et CO ₂ H 2-6 H 1,2- bis (4-FPh) Et CO ₂ H 2-7 H 1,2-bis (4-MePh) Et CO ₂ H 2-8 H 1,2-bis (4-MeOPh) Et CO ₂ H 2-9 H 1,2-bis (4-ClPh) Et CO ₂ H 2-10 H di (2-Thi) CH- CO ₂ H 2-11 H 1,2-di (2-Thi) Et CO ₂ Me 2-12 H bis (4-FPh) CH- CO ₂ H 2-13 H bis (4-MePh) CH- CO ₂ H 2-14 H bis (4-MeOPh) CH- CO ₂ H 2-15 H 2- (4 -MeOPh) -1- (2-Thi) Et CO ₂ H 2-16 H 2- (4-FPh) -1- (2-Thi) Et CO ₂ H 2-17 H 2- (4-MePh)- 1- (2-Thi) Et CO ₂ H 2-18 H 2- (4-ClPh) -1- (2-Thi) Et CO ₂ H 2-19 H 1- (2-Fur) -2-PhEt CO ₂ H 2-20 H 2-Ph-1- (2-Thi) Et CO ₂ H 2-21 H di (3-Thi) CH- CO ₂ H 2-22 H 2- (4-MePh) -1- PhEt CO ₂ H 2-23 H 2- (4-FPh) -1- (4-MePh) Et CO ₂ H 2-24 H 2- (4-MeOPh) -1-PhEt CO ₂ H 2-25 H 2 -(4-FPh) -1- (4-MeOPh) Et CO ₂ H 2-26 H 1-Bz-4-PhBu CO ₂ H 2-2 7 H 4-ClBzhy CO ₂ H 2-28 H 4-MeOBzhy CO ₂ H 2-29 H 4-FBzhy CO ₂ H 2-30 H 4-F-4'-MeOBzhy CO ₂ H 2-31 H 4-MeBzhy _{CO 2 H 2-32 H 2-Ph} -1- (2-Thi) Et CO 2 Me 2-33 H 2-Ph-1- (2-Thi) Et CO 2 CH 2 OCOBu t 2-34 H 2- Ph-1- (2-Thi) Et CO ₂ CH (Me) OCO ₂ Et 2-35 H 2-Ph-1- (2-Thi) Et CO ₂ Mod 2-36 H 2-Ph-1- (2 -Thi) Et CO ₂ Na 2-37 H 1,1-diBzEt CO ₂ H 2-38 H 1,1-di (2-Thi) Et CO ₂ H 2-39 H 1,1-di (2-Thi _{) Et CO 2 Me 2-40 H 1,1} -di (2-Thi) Et CO 2 CH 2 OCOBu t 2-41 H 1,1-di (2-Thi) Et CO 2 CH (Me) OCO 2 Et 2-42 H 1,1-di (2-Thi) Et CO ₂ Mod 2-43 H 1,1-di (2-Thi) Et CO ₂ Na 2-44 H Bzhy CO ₂ Me 2-45 H Bzhy CO ^{_{2 CH 2 OCOBu t 2-46 H Bzhy}} CO 2 CH (Me) OCO 2 Et 2-47 H Bzhy CO 2 Mod 2-48 H Bzhy CO 2 Na 2-49 H 1,2-diPhEt CO 2 Et 2-50 _{H 1,2-diPhEt CO 2 CH 2} OCOBu t 2-51 H 1,2-diPhEt CO 2 CH (Me) OCO 2 Et 2-52 H 1,2-diPhEt CO 2 Mod 2-53 H 1,2- diPhEt CO ₂ Na 2-54 H 1,2-diPhEt CO ₂ Phth 2-55 H 1,1-diPhEt CO ₂ Me 2-56 H 1,1-diPhEt CO _{2 Et 2-57 H 1,1-diPhEt CO} 2 CH 2 OCOBu t 2-58 H 1,1-diPhEt CO 2 CH (Me) OCO 2 Et 2-59 H 1,1-diPhEt CO 2 Mod 2-60 H 1,1-diPhEt CO ₂ Phth 2-61 H 1,1-diPhEt CO ₂ Na 2-62 H 1-Bz-1-PhEt CO ₂ H 2-63 H 1,2-diPhPr CO ₂ H 2-64 4-HOBz 4-HOBz CO ₂ H 2-65 4-FBz 4-FBz CO ₂ H 2-66 H 1-Me-1-PhEt CO ₂ H 2-67 H 1-Me-1- (2-Thi) _{Et CO 2 H 2-68 H 1-} Me-1- (2-Thi) Et CO 2 Me 2-69 H 1-Me-1- (2-Thi) Et CO 2 CH 2 OCOBu t 2-70 H 1 -Me-1- (2-Thi) Et CO ₂ CH (Me) OCO ₂ Et 2-71 H 1-Me-1- (2-Thi) Et CO ₂ Mod 2-72 H 1-Me-1-PhEt _{CO 2 Me 2-73 H 1-Me} -1-PhEt CO 2 CH 2 OCOBu t 2-74 H 1-Me-1-PhEt CO 2 CH (Me) OCO 2 Et 2-75 H 1-Me-1- PhEt CO ₂ Mod 2-76 H 1,1-diMe-2-PhEt CO ₂ H 2-77 H 1-Me-1- (4-HOPh) Et CO ₂ H 2-78 H 1-Me-1- ( 4-FPh) Et CO ₂ H 2-79 H 1-Me-1- (4-NMe ₂ Ph) Et CO ₂ Na 2-80 H di (2-Fur) CH- CO ₂ H 2-81 H 4, 4'-diHOBzhy CO ₂ H 2-82 H 1,2-bis (4-HOPh) Et CO ₂ H 2-83 H 1,2-bis (4-HOPh) -1-MeEt CO ₂ H 2-84 i Pr Bz CO ₂ H 2-85 Et B z CO ₂ H 2-86 Me Bz CO ₂ H 2-87 i Bu Bz CO ₂ H 2-88 i Pr 4-FBz CO ₂ H 2-89 i Pr 4-ClBz CO ₂ H 2-90 i Pr 4- MeBz CO ₂ H 2-91 i Pr 4-MeOBz CO ₂ H 2-92 i Pr 4-HOBz CO ₂ H 2-93 2-ThiMe 2-ThiMe CO ₂ H 2-94 2-ThiMe Bz CO ₂ H 2- _{95 H Bzhy CO 2 Et 2-96 H} Bzhy CO 2 CH 2 OCOBu t 2-97 H Bzhy CO 2 CH (Me) OCO 2 Et 2-98 H Bzhy CO 2 Mod 2-99 H Bzhy CO 2 Na 2-100 _{Bz Bz CO 2 Me 2-101 Bz Bz} CO 2 Et 2-102 H di (2-Thi) CH- CO 2 Me 2-103 H di (2-Thi) CH- CO 2 Et 2-104 H di (2 _{-Thi) CH- CO 2 CH 2 OCOBu} t 2-105 H di (2-Thi) CH- CO 2 CH (Me) OCO 2 Et 2-106 H di (2-Thi) CH- CO 2 Mod 2-107 H di (2-Thi) CH- CO ₂ Na 2-108 H 2- (4-MePh) -1-PhEt CO ₂ Me 2-109 H 2- (4-MePh) -1-PhEt CO ₂ Et 2- 110 H 2- (4-MePh) -1-PhEt CO 2 CH 2 OCOBu t 2-111 H 2- (4-MePh) -1-PhEt CO 2 CH (Me) OCO 2 Et 2-112 H 2- ( 4-MePh) -1-PhEt CO ₂ Mod 2-113 H 2- (4-MePh) -1-PhEt CO ₂ Na 2-114 H 1,1-diPhEt CO ₂ Me 2-115 H 1-Me-1 -PhEt CO ₂ Et 2-116 H 1-Me-1-P ^{_{hEt CO 2 CH 2 OCOBu t 2-117}} H 1-Me-1-PhEt CO 2 CH (Me) OCO 2 Et 2-118 H 1-Me-1-PhEt CO 2 Mod 2-119 H 1-Me-1 _{-PhEt CO 2 Na 2-120 H 1-} Me-1- (2-Thi) Et CO 2 Et 2-121 H 1-Me-1- (2-Thi) Et CO 2 CH 2 OCOBu t 2-122 H 1-Me-1- (2-Thi) Et CO ₂ CH (Me) OCO ₂ Et 2-123 H 1-Me-1- (2-Thi) Et CO ₂ Mod 2-124 H 1-Me-1- (2-Thi) Et CO ₂ Na 2-125 H 1,1-diMe-2-PhEt CO ₂ Me 2-126 H 4,4'-diMeOBzhy CO ₂ Me 2-127 H 4-HOBzhy CO ₂ H 2- _{128 H 4-HOBzhy CO 2 Me} 2-129 H 4-HOBzhy CO 2 Et 2-130 H 4-HOBzhy CO 2 CH 2 OCOBu t 2-131 H 4-HOBzhy CO 2 CH (Me) OCO 2 Et 2-132 H 4-HOBzhy CO ₂ Mod 2-133 H 4-HOBzhy CO ₂ Na 2-134 H 4-MeOBzhy CO ₂ Et 2-135 H 4-MeOBzhy CO ₂ Na 2-136 H 4-MeOBzhy CO ₂ Me 2-137 _{H 4-MeOBzhy CO 2 CH 2} OCOBu t 2-138 H 4-MeOBzhy CO 2 CH (Me) OCO 2 Et 2-139 H 4-MeOBzhy CO 2 Mod 2-140 H 4-ClBzhy CO 2 H 2-141 H 4-ClBzhy CO ₂ Me 2-142 H 1- (4-MeOPh) -1-MeEt CO ₂ H 2-143 H 1- (4-MeOPh) -1-MeEt CO ₂ Me 2-144 H 1- (4 -MeOPh) -1-Me _{Et CO 2 Et 2-145 H 1- (} 4-MeOPh) -1-MeEt CO 2 CH 2 OCOBu t 2-146 H 1- (4-MeOPh) -1-MeEt CO 2 CH (Me) OCO 2 Et 2 -147 H 1- (4-MeOPh) -1-MeEt CO ₂ Mod 2-148 H 1- (4-MeOPh) -1-MeEt CO ₂ Na 2-149 H 1- (3,5-diMeOPh) -1 -MeEt CO ₂ H 2-150 H 1- (3,5-diMeOPh) -1-MeEt CO ₂ Me 2-151 H 1- (4-FPh) -1-MeEt CO ₂ Et 2-152 H 1- ( 4-FPh) -1-MeEt CO 2 CH 2 OCOBu t 2-153 H 1- (4-FPh) -1-MeEt CO 2 CH (Me) OCO 2 Et 2-154 H 1- (4-FPh) - 1-MeEt CO ₂ Mod 2-155 H 1- (4-FPh) -1-MeEt CO ₂ Na 2-156 H 1- (4-FPh) -1-MeEt CO ₂ Me 2-157 H 1- (4 -AcNHPh) -1-MeEt CO ₂ H 2-158 H 1- (4-AcNHPh) -1-MeEt CO ₂ Me 2-159 H Ph ₂ N- CO ₂ H 2-160 H Ph ₂ N- CO ₂ Me _{2-161 H Ph 2 N- CO 2 Et} 2-162 H Ph 2 N- CO 2 CH 2 OCOBu t 2-163 H Ph 2 N- CO 2 CH (Me) OCO 2 Et 2-164 H Ph 2 N- CO ₂ Mod 2-165 H Ph ₂ N- CO ₂ Na 2-166 H 1-Me-1- (3-MeOPh) Et CO ₂ H 2-167 H 1-Me-1- (3-MeOPh) Et CO ₂ Me 2-168 H 1-Me-1- (2-MeOPh) Et CO ₂ H 2-169 H 1-Me-1- (2-MeOPh) Et CO ₂ Me 2-170 H 2,2-diPhEt CO ₂ H _{2-171 H 3,3-diPhPr CO 2 H} 2-172 H Bzhy CO 2 Et 2-173 H Bzhy CO 2 Me 2-174 H Bzhy CO 2 CH 2 OCOBu t 2-175 H Bzhy CO 2 CH (Me) OCO ₂ Et 2-176 H Bzhy CO ₂ Mod 2-177 H Bzhy CO ₂ Na 2-178 H 1-Me-1- (2-Fur) Et CO ₂ H 2-179 H 1-Me-1- (2 -Fur) Et CO ₂ Me 2-180 H 1-Me-1-PhEt CONHSO ₂ Me 2-181 H 1-Me-1- (2-Thi) Et CONHSO ₂ Me 2-182 H 1-Me-1- (4-MeOPh) Et CONHSO ₂ Me 2-183 H 1-Me-1- (3-Thi) Et CONH S O ₂ Me 2-184 H 1-Me-1- (4-NMe ₂ Ph) Et CONHSO ₂ Me 2-185 H 1-Me-1- (4-FPh) Et CONHSO ₂ Me 2-186 H 1-Me-1- (4-MePh) Et CONHSO ₂ Me 2-187 H 1-Me-1- ( 4-ClPh) Et CONHSO ₂ Me 2-188 H Bzhy CONHSO ₂ Me 2-189 H Bzhy CONHSO ₂ Et 2-190 H 1-Me-1- (4-NMe ₂ Ph) Et CO ₂ H 2-191 H 1 -Me-1- (3-Thi) Et CO ₂ H 2-192 H 1-Me-1- (3,4-diOMePh) Et CO ₂ H 2-193 H 1-Me-1- (4-ClPh) Et CO ₂ H 2-194 H 1-Me-1- (4-OEtPh) Et CO ₂ H 2-195 H 1-Et-1-PhPr CO ₂ H 2-196 H 1-Me-1- (4- MePh) Et CO ₂ H 2-197 H 1-Me-1- (3,4,5-triMeOPh) Et CO ₂ Me 2-198 H 1- (CH ₃ OH) -1- (4-MeOPh) Et CO ₂ H 2-199 H 1- (COOH) -1- (4-MeOPh) Et CO ₂ H 2-200 H 1-Me-1- (3,4,5- triMeOPh) Et CO ₂ H 2-201 H 1-Me-1- (3,5-diNMe ₂ Ph) Et CO ₂ H ────────────────────── ────────────── The abbreviations used in the table have the following meanings.

Ac: acetyl, Bu: butyl, Bz: benzyl, Bzhy: benzhydryl, Et: ethyl, Fur: furyl, Me: methyl, Mod: (5-methyl-2-oxo-1,3-dioxolen-4-). Yl) methyl group, Ph: phenyl, Phth: phthalidyl, Pr: propyl, i-Pr: isopropyl, Thi: thienyl.

Of the above-exemplified compounds, preferred compounds include 1-1, 1-2, 1-4, 1-5, 1-8, 1-
9, 1-12, 1-13, 1-14, 1-16, 1-1
7, 1-19, 1-22, 1-27, 1-28, 1-2
9, 1-31, 1-33, 1-45, 1-48, 1-5
0,1-64,1-66,1-67,1-69,1-7
3,1-76,1-78,1-79,1-82,1-8
6, 1-88, 1-127, 1-130, 1-140,
1-142, 1-145, 1-149, 1-152, 1
-157, 1-159, 1-166, 1-168, 1-
178, 1-180, 1-182, 1-190, 1-1
91, 1-192, 1-193, 1-194, 1-19
5,1-196,1-197,1-200,1-20
1,2-1,2-2,2-4,2-5,2-8,2-
9, 2-12, 2-13, 2-14, 2-16, 2-1
7, 2-19, 2-22, 2-27, 2-28, 2-2
9,2-3,1,2,33,2-45,2-48,2-5
0,2-64,2-66,2-67,2-69,2-7
3,2-76,2-78,2-79,2-82,2-8
6,2-88,2-127,2-130,2-140,
2-142, 2-145, 2-149, 2-152, 2
-157, 2-159, 2-166, 2-168, 2-
178, 2-180, 2-182, 2-190, 2-1
91,2-192,2-193,2-194,2-19
5,2-196,2-197,2-200 and 2-20
One compound may be mentioned.

Further, as preferable compounds, 1-1,1
-2, 1-4, 1-5, 1-12, 1-13, 1-1
4, 1-16, 1-17, 1-22, 1-27, 1-2
8, 1-29, 1-31, 1-64, 1-66, 1-6
7, 1-76, 1-78, 1-127, 1-140, 1
-142, 1-145, 1-149, 1-159, 1-
166, 1-168, 1-178, 1-190, 1-1
92,1-194,1-197,2-1,2-2,2-
4, 2-5, 2-12, 2-13, 2-14, 2-1
6, 2-17, 2-22, 2-27, 2-28, 2-2
9, 2-31, 2-64, 2-66, 2-67, 2-7
6,2-78,2-127,2-140,2-142,
2-145, 2-149, 2-159, 2-166, 2
-168, 2-178, 2-190, 2-192, 2-
The compounds of 194 and 2-197 and the like can be mentioned.

The most preferred compounds are 1-1,1-
2, 1-5, 1-12, 1-13, 1-14, 1-1
6, 1-27, 1-28, 1-29, 1-31, 1-1
27, 1-140, 1-149, 1-159, 1-16
6, 1-168, 1-178, 2-1, 2-2, 2-
5, 2-12, 2-13, 2-14, 2-16, 2-2
7,2-28,2-29,2-3,1,127,2-
140, 2-149, 2-159, 2-166, 2-1
The compounds of 68 and 2-178 may be mentioned.

The compound (I) of the present invention can be easily produced according to the following method.

[0045]

[Chemical 5]

[Method A] In the above formula, R ¹ , R ² , R ³ and Z have the same meanings as described above, and R ⁵ is the above-mentioned carboxy-protecting group [preferably C ₁ -C ₆ alkyl group, or, where -SiR ^a R ^b R ^c (wherein, R ^a, R
^b and R ^c have the same meanings as described above. Group having a).

Method A is a method for producing the target compound (I).

The step A1 is carried out by adding a known compound (II) [eg, Journal of Medicinal Chemistry, Vol. 33, page 943, 1990] in a solvent.
This is a step of producing a 17-carboxy derivative by oxidizing with an oxidizing agent and then protecting the produced carboxy group with a protecting group to produce a compound having the general formula (III).

The oxidizing agent used in the first step is, for example, an alkali metal perhalogen acid such as sodium perchlorate, sodium periodate, potassium periodate; sodium permanganate, potassium permanganate, etc. An alkali metal permanganate; or a lead such as lead tetraacetate, preferably an alkali metal perhalogen acid, an alkali metal perhalogen acid-alkali metal permanganate mixture, or a lead. More preferably, it is an alkali metal periodate or a lead. The reaction is preferably carried out in the presence of an alkali such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate. The solvent used in the first step is not particularly limited as long as it does not participate in the reaction, and examples thereof include water; ethers such as tetrahydrofuran, dioxane and diethyl ether; aromatic hydrocarbons such as benzene and toluene; methanol. , Alcohols such as ethanol and t-butanol; halogenated hydrocarbons such as methylene chloride, chloroform and carbon tetrachloride; or a mixture thereof, preferably an alkali metal periodate as an oxidizing agent. If used, it is water-t-butanol. Although the reaction temperature in the first step varies depending on the oxidizing agent and the like, it is usually −
78 ° C. to 150 ° C. (preferably 0 ° C. to 100 ° C. when using alkali metal periodate), and reaction time is 15 minutes to 24 hours (preferably 30 minutes to 15 hours). Is.

The raw material compounds include those in which Z is a hydrogen atom or a hydroxyl group as a raw material.
Since it has a hydroxyl group at the terminal of the substituent at the position, if desired,
A compound in which these hydroxyl groups are protected can also be used.
The protective group for the hydroxyl group is, for example, an aliphatic acyl group such as acetyl or propionyl; or a tri (C ₁ -C ₄ alkyl) silyl group such as trimethylsilyl, triethylsilyl or t-butyldimethylsilyl, and preferably , An aliphatic acyl group. The protection of the hydroxyl group is carried out by protecting the compound in the presence of a base in an inert solvent (for example, aromatic hydrocarbons such as benzene and toluene; halogenated hydrocarbons such as methylene chloride and chloroform) (for example, pyridine). , Triethylamine, tertiary amines such as dimethylaniline, etc.), corresponding halides (eg, acetyl chloride, propionyl chloride, propionyl bromide, trimethylsilyl chloride, triethylsilyl chloride, t-butyldimethylsilyl chloride, t-butyldimethylsilyl bromide). Etc.) or a corresponding acid anhydride (for example, acetic anhydride, propionic anhydride, etc.), and -2
1 at 0 ° C to 100 ° C (preferably 0 ° C to 50 ° C)
5 minutes to 10 hours (preferably 30 minutes to 5 hours)
It is carried out by reacting.

Further, these protecting groups are removed by treatment with an alkali metal (C ₁ -C ₄ alkoxide) in a solvent. The alkali metal (C ₁ -C ₄ alkoxide) used is, for example, sodium methoxide, sodium ethoxide, potassium ethoxide, sodium propoxide, sodium butoxide, potassium t-butoxide, preferably sodium methoxide. , Sodium ethoxide. The solvent used is not particularly limited so long as it does not participate in the reaction, and examples thereof include alcohols such as methanol and ethanol; tertiary amines such as pyridine and triethylamine; ethers such as ether and tetrahydrofuran; benzene. , Aromatic hydrocarbons such as toluene and xylene; halogenated hydrocarbons such as methylene chloride and chloroform; or a mixed solvent thereof, preferably a mixed solvent of alcohols and pyridine. The reaction temperature will differ depending on the starting compounds and the like, but is ordinarily 0 ° C to 100 ° C (preferably 20 ° C to 80 ° C), and the reaction time is 30 minutes to 6 hours (preferably 1 hour to 4 hours). Time).

The reaction of protecting the produced carboxy group, which is the latter step, is usually carried out using a base by a method well known in synthetic organic chemistry. For example, an inert solvent (preferably water; tetrahydrofuran, dioxane,
Ethers such as diethyl ether; aromatic hydrocarbons such as benzene and toluene; amides such as N, N-dimethylformamide, N, N-dimethylacetamide; alcohols such as methanol, ethanol and t-butanol A halogenated hydrocarbon such as methylene chloride, chloroform, carbon tetrachloride; or a mixture thereof), an alkali metal salt such as a sodium salt or potassium salt of a corresponding carboxylic acid is added to a compound represented by the formula R ⁵ —Y ( IV) (In the formula, R ⁵ is “C ₁ -C ₆ alkyl group”, halogeno “C ₁ -C ₆ alkyl group”, hydroxy “C ₁ -C ₆ alkyl group”, “alkoxy”-“C _1- C ₆ alkyl group "or" alkoxy "-" alkoxy "-" C ₁
—C ₆ alkyl group ”, phenacyl group, (“ alkoxy ”
Carbonyl) - "C ₁ -C ₆ alkyl group", cyano, "C
₁ -C ₆ alkyl group "," C ₁ -C ₆ alkyl "thiomethyl group," aryl "thiomethyl group which may be substituted by halogen (" C ₁ -C ₆ alkyl "sulfonyl) -
"C ₁ -C ₆ alkyl group", ( "aryl" sulfonyl) - "C ₁ -C ₆ alkyl group", "aryl" - "C
₁ -C ₆ alkyl group "," aryl group ", the formula -SiR ^a
A group having R ^b R ^c (wherein R ^a , R ^b and R ^c are
It has the same meaning as described above. ), (C ₁ -C ₆ alkanoyloxy)-"C ₁ -C ₆ alkyl group", (C _6-
C ₇ cycloalkyl alkanoyloxy) - "C ₁ -C ₆ alkyl group", ( "alkoxy" carbonyloxy) - "C ₁
-C ₆ alkyl group ", (C ₅ -C ₆ cycloalkoxy-carbonyloxy) -" C ₁ -C ₆ alkyl group ", [5-
"Aryl" -2-oxo-1,3-dioxolen-4
-Yl] methyl group, [5- "C ₁ -C ₆ alkyl" -2
-Oxo-1,3-dioxolen-4-yl] methyl group or phthalidyl group, Y is a chlorine atom, a bromine atom,
It represents a halogen atom such as iodine atom or a leaving group such as sulfonyloxy group such as methanesulfonyloxy, ethanesulfonyloxy, p-toluenesulfonyloxy and trifluoromethanesulfonyloxy. ), When protected with an alkyl group, the corresponding carboxylic acid is a di "C ₁ -C ₆ alkyl" sulfate such as dimethylsulfate, diethylsulfate or diazomethane, diazoethane, diazo. It is carried out by reacting with a diazo C ₁ -C ₆ alkane such as propane. The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably alkali metal carbonates such as sodium carbonate, potassium carbonate and lithium carbonate; sodium hydrogen carbonate. Alkali metal hydrogen carbonates such as potassium hydrogen carbonate and lithium hydrogen carbonate; Alkali metal hydrides such as lithium hydride, sodium hydride and potassium hydride; Sodium hydroxide, potassium hydroxide, barium hydroxide, water Alkali metal hydroxides such as lithium oxide; inorganic bases such as alkali metal fluorides such as sodium fluoride and potassium fluoride; sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium Alkali metal alkoxides such as t-butoxide and lithium methoxide Mercaptan alkali metals such as methyl mercaptan sodium and ethyl mercaptan sodium; N-methylmorpholine, triethylamine, tripropylamine, tributylamine, diisopropylethylamine, dicyclohexylamine, N-methylpiperidine, pyridine, 4-pyrrolidinopyridine , Picoline, 4- (N, N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline,
N, N-diethylaniline, 1,5-diazabicyclo [4.3.0] non-5-ene (DBN), 1,4-diazabicyclo [2.2.2] octane (DABCO),
1,8-diazabicyclo [5.4.0] undec-7-
Mention may be made of organic bases such as ene (DBU) or organic metal bases such as butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide. The reaction temperature is usually -20 ° C to 5 ° C.
The temperature is 0 ° C. (preferably 0 ° C. to 30 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but 5 minutes to 1
It is 0 hours (preferably 5 minutes to 5 hours). After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent under reduced pressure, water was added to the residue and the mixture was extracted with a water-immiscible organic solvent such as ethyl acetate,
It can be obtained by drying over anhydrous magnesium sulfate and the like, and then distilling off the solvent, and if necessary, further purification can be carried out by a conventional method such as recrystallization or column chromatography.

The step A2 is a step for producing a compound having the general formula (V) in the presence of an alkali metal cyanide in an inert solvent and a compound having the general formula (III) and di (C ₁ -C _{1 6} ) It is carried out by reacting an alkyl or diaryl phosphoric acid cyanide and reacting the obtained phosphoric acid ester with an acid. The alkali metal cyanide used can be, for example, lithium cyanide, sodium cyanide, potassium cyanide, preferably lithium cyanide.

The di (C ₁ -C ₆ alkyl) or diaryl phosphoric acid cyanide used can be, for example, dimethyl cyano phosphoric acid, diethyl cyano phosphoric acid, diphenyl cyano phosphoric acid, ditolyl cyano phosphoric acid, preferably , Diethyl cyanophosphoric acid and diphenyl cyanophosphoric acid.
The acid used can be, for example, a Lewis acid such as boron trifluoride, boron trifluoride-ether complex, zinc chloride, aluminum chloride, tin tetrachloride, preferably boron trifluoride, trifluoride. It is a boron-ether complex. The inert solvent used is not particularly limited as long as it does not participate in the reaction, for example, benzene, toluene, aromatic hydrocarbons such as xylene, ether, tetrahydrofuran,
It may be ethers such as dioxane, halogenated hydrocarbons such as methylene chloride and chloroform, preferably ethers in the first reaction, and aromatic hydrocarbons in the second reaction. is there. In the first-step reaction, the reaction temperature is usually -20 ° C to 50 ° C.
(Preferably 0 ° C. to 30 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but is 5 minutes to 5 hours (preferably 10 minutes to 1 hour). The reaction temperature is usually -50 ° C to 50 ° C (preferably -20 ° C to 30 ° C), and the time required for the reaction varies depending on the reaction temperature and the like, but is 30 minutes to 10 minutes.
Time (preferably 1 to 5 hours). After completion of the reaction, the target compound in the first and second steps is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent under reduced pressure, adding water to the residue, extracting with a water-immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate, etc., and then distilling off the solvent. If necessary, it can be further purified by a conventional method such as recrystallization or column chromatography.

The step A3 is a step for producing a compound having the general formula (VI), which is carried out by reacting the compound (V) with a base in an inert solvent and hydrolyzing it.
The base used may be, for example, an alkali metal hydroxide such as lithium hydroxide, sodium hydroxide or potassium hydroxide, or an alkali metal carbonate such as lithium carbonate, sodium carbonate or potassium carbonate, preferably , An alkali metal hydroxide. The inert solvent used is not particularly limited as long as it does not participate in the reaction, for example, tetrahydrofuran, ethers such as dioxane, alcohols such as methanol, ethanol, butanol, ethylene glycol, propylene glycol, ethylene glycol dimethyl ether. Glycol or its ethers such as, water or a mixture of these solvents,
Alcohols are preferred. Reaction temperature is usually 0 ° C
To 150 ° C. (preferably 30 ° C. to 100 ° C.), and the time required for the reaction is 1 hour to 50 hours (preferably 3 hours to 20 hours), depending on the reaction temperature and the like. After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent under reduced pressure, acidic water such as dilute hydrochloric acid is added to the residue to make it acidic, and the mixture is extracted with a water-immiscible organic solvent such as methylene chloride, dried over anhydrous magnesium sulfate and the like. It can be obtained by distillation, and if necessary, it can be further purified by a conventional method such as recrystallization or column chromatography.

If desired, the steps A2 and A3 can be performed in different orders.

Step A4 is a step of producing a compound having the general formula (VIII) using the compound (VI) or a reactive derivative thereof and the compound having the general formula (VII), which is a conventional step in peptide synthesis. Method, for example, an acid halide method, an azide method, an active ester method, a mixed acid anhydride method or a condensation method, and the active ester method is preferable.

In the above method, the acid halide method is carried out, for example, by reacting compound (VI) with a halogenating agent in an inert solvent and then treating with amine compound (VII). -145669 gazette (E
It is carried out according to the method described in P-4949A).

In the azide method, an acid hydrazide produced by reacting compound (VI) or an ester thereof with hydrazine in an inert solvent (eg, dimethylformamide) at around room temperature is reacted with a nitrite compound, After conversion into an azide compound, it is carried out by treating with an amine compound (VII). Examples of the nitrite compound used include alkali metal nitrites such as sodium nitrite or alkyl nitrites such as isoamyl nitrite. The reaction is preferably carried out in an inert solvent, and examples of the solvent used include amides such as dimethylformamide and dimethylacetamide, sulfoxides such as dimethylsulfoxide, and N.
Mention may be made of pyrrolidones, such as methylpyrrolidone. The two steps of this method are usually carried out in one reaction solution, and the reaction temperature is from -50 ° C to 0 ° C in the first stage and from -10 ° C to 10 ° C in the second stage. The time is 5 minutes to 1 hour in the first stage and 10 minutes in the second stage.
Time to 5 days.

In the active ester method, the compound (VI) is reacted with an active esterifying agent to produce an active ester,
By reacting with an amine compound (VII), for example, JP-A-2-172999 (EP-4780).
66A), JP-A-4-288096 (EP-36).
7502A) or European Patent Publication No. 85301122.
It is performed according to the description of the issue. Both reactions are preferably carried out in an inert solvent, examples of the solvent used include:
Aromatic hydrocarbons such as benzene, toluene, xylene, halogenated hydrocarbons such as methylene chloride, chloroform, ethers, ethers such as tetrahydrofuran, amides such as dimethylformamide, dimethylacetamide, acetonitrile, etc. Examples thereof include nitriles, pyridine, and amines such as triethylamine. Examples of the active esterifying agent used include N-hydroxysuccinimide, 1-hydroxybenzotriazole, N-hydroxy-5-norbornene-2,3-dicarboximide and the like N-.
Mention may be made of hydroxy compounds or disulfide compounds such as dipyridyl disulfide, with dipyridyl disulfide being preferred. The active esterification reaction is
It is preferably carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole or triphenylphosphine. The reaction temperature is −10 ° C. to 100 ° C. in the active esterification reaction, is around room temperature in the reaction of the active ester compound and the amine compound (VII), and the time required for the reaction is 30 minutes to 8 minutes in both reactions.
It's 0 hours. Moreover, this reaction can also be performed in the coexistence of dimethylaminopyridine.

The mixed acid anhydride method is carried out by preparing a mixed acid anhydride of compound (VI) and then reacting it with an amine compound (VII). The reaction for producing the mixed acid anhydride is carried out in an inert solvent (for example, the above-mentioned halogenated hydrocarbons, amides, ethers) in a mixed acid anhydride agent such as ethyl chlorocarbonate and isobutyl chlorocarbonate. Carbonic acid (C ₁ -C ₆ ) alkyl carbonate, (C ₂ -C ₅ ) alkanoyl halide such as pivaloyl chloride or di (C ₁ -C ₆ ) alkyl such as diethylcyanophosphoric acid, diphenylcyanophosphoric acid Alternatively, it can be achieved by reacting compound (IV) with diaryl cyanophosphoric acid or the like. The reaction is preferably carried out in the presence of an organic amine such as triethylamine, N-methylmorpholine, N, N-dimethylaminopyridine, the reaction temperature is -10 ° C to 50 ° C, and the time required for the reaction is Is 3
It is from 0 minutes to 20 hours. The reaction between the mixed acid anhydride and the amine compound (VII) is preferably carried out in the presence of the above organic amine in an inert solvent (for example, the above amides and ethers), and the reaction temperature is 0. C. to 80.degree. C., and the time required for the reaction is 1 hour to 30 hours. This reaction is also carried out in the presence of compound (VI), compound (VII) and a mixed acid anhydride agent.

In the condensation method, the compound (VI) and the amine compound (VII) are directly reacted in the presence of a condensing agent such as dicyclohexylcarbodiimide, carbonyldiimidazole, 1-methyl-2-chloro-pyridinium iodide-triethylamine. Is done by doing. This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

In an inert solvent, a base and the general formula
A sulfonyl compound having R ^d SO ₂ X, or
A sulfonyl compound having the general formula (R ^d SO ₂ ) ₂ O (wherein R ^d is a C ₁ -C ₆ alkyl group, a trifluoromethyl group, a camfanyl group, an isocyano group or a C _1-
C ₆ alkyl, C ₁ -C ₆ alkoxy or a C ₆ -C ₁₀ aryl group which may be substituted with halogen is shown, and X is
Represents a halogen atom. ) In the presence of compound (VI)
The compound (VIII) can be easily produced by reacting the compound (VIII) with the amine (VII) with good yield. Examples of the inert solvent used include hydrocarbons such as hexane, benzene, toluene and xylene, halogenated hydrocarbons such as methylene chloride, chloroform and dichloroethane, ether, tetrahydrofuran, dioxane and dimethoxyethane. Ethers, dimethylformamide, dimethylacetamide, amides such as hexamethylphosphorotriamide, sulfoxides such as dimethylsulfoxide, and preferably halogenated hydrocarbons. Also,
A liquid amine such as triethylamine or pyridine can also be used in a large excess also as a solvent. Examples of the base used include triethylamine, tripropylamine, tributylamine, diisopropylethylamine, N, N-dimethylaniline, N, N-diethylaniline, pyridine, 4- (N, N-dimethylamino) pyridine, quinoline. , 1,5-diazabicyclo [4.3.
0] nona-5-ene (DBN), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU), which may be an organic amine, preferably triethylamine,
N, N-diethylaniline and pyridine. Also, 2
It is also possible to use more than one amine at the same time.

The sulfonyl compound itself having the general formula R ^d SO ₂ X is preferably methanesulfonic acid chloride, methanesulfonic acid bromide, ethanesulfonic acid chloride, propanesulfonic acid chloride, benzenesulfonic acid chloride, toluenesulfonic acid chloride. , 2, 4,
6-trimethylbenzenesulfonic acid chloride, chlorobenzenesulfonic acid chloride, bromobenzenesulfonic acid chloride, methoxybenzenesulfonic acid chloride, camphorsulfonic acid chloride or chlorosulfonylisocyanate, more preferably methanesulfonic acid chloride, benzenesulfonic acid chloride , Toluene sulfonic acid chloride, camphor sulfonic acid chloride or chlorosulfonyl isocyanate.

The sulfonyl compound itself having the general formula (R ^d SO ₂ ) ₂ O is preferably methanesulfonic anhydride, trifluoromethanesulfonic anhydride, ethanesulfonic anhydride, benzenesulfonic anhydride, toluene. Sulfonic acid anhydride, chlorobenzenesulfonic acid anhydride or camphorsulfonic acid anhydride, more preferably methanesulfonic acid anhydride, trifluoromethanesulfonic acid anhydride, benzenesulfonic acid anhydride or toluenesulfonic acid anhydride. .

The reaction temperature will differ depending on the starting compounds used, the type of base, etc., but is usually -70 ° C to 50 ° C, preferably -50 ° C to 30 ° C, and the time required for the reaction is Although it varies depending on the reaction temperature and the like, it is usually 15 minutes to 20 hours, and preferably 30 minutes to 10 hours.

In this reaction, more preferably, the compound (VI) and 1 to 10 equivalents of a base are added to an inert solvent, and then 1 to 5 equivalents of a sulfonyl compound are added.
Further, 1 to 5 equivalents of the amine compound (VII) is added to react, or the compound (VI) and 1 to 10 equivalents of the base are added in an inert solvent, and then 1 to 5 equivalents of the compound (VII). ) Is added, and 1 to 5 equivalents of a sulfonyl compound is further added, and the mixture is reacted.

Even if a Vilsmeier reagent such as dimethylformamide-phosphorus oxychloride or chloromethylenedimethyliminium chloride is used instead of the sulfonyl compound, the corresponding amide compound can be obtained by the same reaction as above. At this time, it is preferable to add the compound (VI) and 1 to 5 equivalents of Vilsmeier reagent in an inert solvent, and then add 1 to 10 equivalents of the base and 1 to 5 equivalents of the amine compound (VII). It is carried out by reacting.

When the amine compound (VII) containing a carboxy group is used in the above reaction, preferably,
A compound in which a carboxy group is protected, and examples of the protecting group include t-butyl, benzhydryl, p
-Methylbenzhydryl, p-methoxybenzhydryl group, which protecting group is removed by treating with an acid in an inert solvent after completion of the above reaction. The acid used is, for example, a halogen acid such as hydrochloric acid, hydrobromic acid or hydroiodic acid, an organic acid such as trifluoroacetic acid, trichloroacetic acid or trifluoromethanesulfonic acid (preferably,
The organic solvent is an organic solvent, and examples of the inert solvent used include ethers such as anisole and diphenyl ether, aromatic hydrocarbons such as benzene, toluene and xylene, and halogenated hydrocarbons such as methylene chloride and chloroform. Or a mixed solvent thereof (preferably an ether, a halogenated hydrocarbon or a mixed solvent thereof). The reaction temperature is -20 ° C to 50 ° C (preferably -10 ° C to room temperature), and the time required for the reaction is
It is 30 minutes to 20 hours (preferably 1 hour to 10 hours).

Step A5 is a step for producing the compound (I) of the present invention, which comprises hydrolyzing the compound (VIII),
If desired, (1) when Z is a compound showing a hydrogen atom and a hydroxyl group, the hydroxyl group is oxidized to be converted into an oxo group, and (2) when Z is an oxo group, the oxo group is converted. Reducing the group to a hydroxyl group, (3) acylating the hydroxyl group in the case where Z represents a hydrogen atom and a hydroxyl group, (4) protecting the carboxy of the obtained carboxylic acid, and / Alternatively, (5) it is carried out by sulfonylamidating the obtained carboxylic acid.

The hydrolysis is carried out by reacting the compound (VI) in an inert solvent.
It is carried out by reacting II) with a base. The base and inert solvent used are essentially the same as those in step A3 above, but suitable inert solvents are glycols. The reaction temperature is usually 50 ° C. to 250 ° C. (preferably 100 ° C. to 200 ° C.), and the time required for the reaction varies depending on the reaction temperature and the like, but is 3 hours to 50 hours (preferably 6 hours to 6 hours). 20 hours). After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, after distilling off the solvent under reduced pressure, acidic water such as dilute hydrochloric acid is added to the residue to make it acidic, and the mixture is extracted with a water-immiscible organic solvent such as methylene chloride, dried over anhydrous magnesium sulfate and the like. It can be obtained by distillation, and if necessary, it can be further purified by a conventional method such as recrystallization or column chromatography.

When the alkanoylamino groups contained in R ¹ and R ² are simultaneously hydrolyzed during the above hydrolysis, the corresponding amino compound can be alkanoylated if desired. The alkanoylation reaction is carried out by converting the corresponding amino compound into an alkanoyl halide such as acetyl chloride, acetyl bromide, propionyl chloride, butyryl chloride, isobutyryl chloride or an acid anhydride of formic acid and acetic acid, acetic anhydride, propionic anhydride,
The reaction is performed in the same manner as the reaction between the acid anhydride such as butanoic anhydride and isobutanoic anhydride, the mixed acid anhydride in step A4 and the amine.

Further, in the above hydrolysis, when the alkoxycarbonyl groups contained in R ¹ and R ² are simultaneously hydrolyzed, the corresponding carboxylic acid can be alkyl-esterified if desired. The esterification reaction is carried out in the same manner as in the reaction for protecting the carboxy group described below, and can be produced by using about 1 equivalent of esterification and separating the obtained mixture.

In the case where Z is a compound having a hydrogen atom and a hydroxyl group, which is a desired step, the compound having a hydrogen atom and a hydroxyl group is converted into an oxo group by oxidizing the hydroxyl group. Oxidation in active solvents (eg aromatic hydrocarbons such as benzene and toluene, ketones such as acetone and methyl ethyl ketone, amines such as pyridine and quinoline, halogenated hydrocarbons such as dichloromethane and chloroform) Agent (eg, chromium oxide, Collins reagent, Jones reagent, etc.) and -78 ° C to 70 ° C
(Preferably, when using a chromium oxide or Collins reagent, 0 ° C. to 50 ° C., when using a Jones reagent, −78 ° C. to 0 ° C.) for 15 minutes to 24 hours (preferably 30 ° C.). It is achieved by reacting for 1 minute to 15 hours).

In the case of a compound in which Z is an oxo group, which is a desired step, in the step of reducing the oxo group to a hydroxyl group, the compound in which Z is an oxo group is treated in an inert solvent (for example, methanol). , Alcohols such as ethanol,
Ethers, ethers such as tetrahydrofuran, methylene chloride, halogenated hydrocarbons such as chloroform, benzene, aromatic hydrocarbons such as toluene), reducing agents (eg, sodium borohydride, sodium cyanoborohydride) , Lithium aluminum hydride, etc.) and -20 ° C to 50 ° C (preferably near room temperature)
For 15 minutes to 10 hours (preferably 30 minutes to 5 hours).
Time).

When Z is a compound showing a hydrogen atom and a hydroxyl group, which is a desired step, the step of acylating the hydroxyl group is carried out by treating the compound in which Z is a hydrogen atom and a hydroxyl group in an inert solvent (for example, , Ethers, ethers such as tetrahydrofuran, methylene chloride, halogenated hydrocarbons such as chloroform, benzene, aromatic hydrocarbons such as toluene), in the presence of a base (eg, pyridine, triethylamine, dimethylaniline). Tertiary amines such as), corresponding halides (eg acetic anhydride,
It can be achieved by reacting with propionic anhydride or the like) at −20 ° C. to 100 ° C. (preferably 0 ° C. to 50 ° C.) for 15 minutes to 10 hours (preferably 30 minutes to 5 hours).

The reaction of protecting the carboxy group, which is a desired step, is usually accomplished by a method well known in synthetic organic chemistry and using a base in accordance with the description of step A1.

The desired step, the sulfonylamidation reaction, involves reacting the corresponding carboxylic acid with an active esterifying agent to produce an active ester, and then reacting with the compound of formula MHNSO ₂ R ⁴ (IX) (wherein R ⁴ Represents the same meaning as described above, and M represents
Indicates an alkali metal such as sodium or potassium. )
By reacting with a compound having

The reaction for producing the active ester is carried out in analogy to the corresponding reaction of step A4 above. Also,
Compound (IX) can be prepared by a conventional method, for example, in an inert solvent described below with a corresponding sulfonamide and an alkali metal alkoxide such as sodium methoxide, sodium ethoxide or potassium t-butoxide at room temperature for about 10 minutes or longer. It is produced by reacting for 3 hours. The reaction of the active ester with the compound (IX) can be carried out by using an inert solvent (preferably N, N-dimethylformamide, N, N-dimethylacetamide, amides such as hexamethylphosphoramide, dimethyl sulfoxide, etc.). Both compounds in sulphoxides, ethers such as tetrahydrofuran and dioxane) at -20 ° C to 100 ° C (preferably
0 ° C to 50 ° C for 5 minutes to 10 hours (preferably,
It is carried out by reacting for 10 minutes to 3 hours). After completion of the reaction, the target compound is collected from the reaction mixture according to a conventional method. For example, it can be obtained by distilling off the solvent under reduced pressure, adding water to the residue, extracting with a water-immiscible organic solvent such as ethyl acetate, drying over anhydrous magnesium sulfate, etc., and then distilling off the solvent. , If necessary, conventional method,
For example, it can be further purified by recrystallization, column chromatography and the like.

[0080]

[Chemical 6]

[Method B] In the above formula, R ¹ , R ² and Z are
It has the same meaning as described above.

[0082] Method B, the compound of the A4 step of Method A (VI
This is a method of separately producing II).

Step B1 is a step of producing a compound having the general formula (X), and is accomplished by reacting a compound having the general formula (III ′) with an amine compound (VII). The reaction is performed in the same manner as in the reaction in Method A, Step A4.

Step B2 is a step for producing compound (VIII) and is accomplished by cyanating compound (X), and this reaction is carried out in the same manner as the corresponding reaction of Step A2 of Method A above. ..

The expression

[0086]

[Chemical 7]

(In the formula, Z has the same meaning as described above, and R and R ′ are the same or different and each represents a hydrogen atom or the above “C ₁
Shows a -C ₆ alkyl group ". (VII) having
I ′) is a compound having the compound (III ′) and the formula HNRR ′ (VII ′) (wherein R and R ′ have the same meanings as described above) as a raw material, and the B1 step of Method B and It is produced by carrying out a reaction similar to Step B2, while hydrolyzing in a manner similar to the corresponding reaction of Step A5 of Method A to give a compound of formula

[0088]

[Chemical 8]

(Wherein R and R ′ have the same meanings as described above), and can be converted into the compound (XI), which is a useful intermediate for producing the compound (XI). still,
In the compound (VIII ′), preferably, R is a hydrogen atom, R ′ is a C ₁ -C ₄ alkyl group, or R and R ′ are the same or different and are a C ₁ -C ₄ alkyl group. And more preferably, R is a hydrogen atom and R ′ is a t-butyl group, or R and R ′ are the same and are an ethyl group or isopropyl. be able to.

[Method C]

[0091]

[Chemical 9]

In the above formula, R ¹ , R ² , R ³ and Z have the same meanings as described above.

Method C is a method for separately producing compound (I) of the present invention from compound (VIII).

The step C1 is a step for producing the compound (XIII) by converting the cyano group of the compound (VIII) into an aldehyde group by a reduction reaction.

The reducing agent used is not particularly limited as long as it is usually used in the reduction reaction, but preferably di (isobutyl) aluminum hydride and di (methoxyethoxy) aluminum sodium dihydride. The organoaluminum hydride-based reducing agents such as The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aliphatic hydrocarbons such as hexane and heptane; benzene, toluene and xylene. Aromatic hydrocarbons such as; halogenated hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, dichloroethane;
Examples thereof include ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide. The reaction temperature is -100 ° C to 3
It is carried out at 0 ° C, preferably -10 ° C to 20 ° C. The reaction time mainly depends on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but usually,
30 minutes to 10 hours. After completion of the reaction, the target compound (XIII) of this reaction is collected from the reaction mixture according to a conventional method. For example, water is added to the reaction mixture to hydrolyze, then neutralized or acidified as appropriate, and if insoluble matter is removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added. After washing with water, the organic layer containing the target compound is separated, dried over anhydrous magnesium sulfate or the like, and the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In Step C2 , the aldehyde group of compound (XIII) is converted into a carboxy group by an oxidation reaction,
If desired, the resulting carboxy group is treated according to the step A5 to produce the compound (I) of the present invention.

The oxidizing agent to be used is not particularly limited as long as it is usually used in an oxidation reaction for converting an aldehyde group into a carboxy group, but it is preferably potassium permanganate or manganese dioxide. Manganese oxides;
Ruthenium oxides such as ruthenium tetroxide; Zelen compounds such as Zelen dioxide; Iron compounds such as iron chloride;
Osmium compounds such as osmium tetroxide; silver compounds such as silver oxide; chromic acid compounds such as potassium chromate, chromic anhydride-sulfuric acid, chromic anhydride-pyridine complexes, such as ammonium cerium nitrate (CAN) Inorganic metal oxidizers such as cerium compounds; halogen molecules such as chlorine molecules, bromine molecules and iodine molecules; periodic acids such as sodium periodate; ozone; hydrogen peroxide solution; nitrite compounds such as nitrous acid; Chlorite compounds such as potassium chlorite and sodium chlorite; inorganic oxidizing agents such as potassium persulfate and persulfate compounds such as sodium persulfate, and the like, and more preferably potassium chromate, Chromic anhydride-sulfuric acid, chromic acid compounds such as chromic anhydride-pyridine complex, ammonium cerium nitrate (CAN) Inorganic metal oxidizing agent cerium compound such as; potassium chlorite, chlorite compounds such as sodium chlorite; and a silver compound such as silver oxide. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as chloroform; ethers such as ether, tetrahydrofuran, dioxane, dimethoxyethane; dimethylformamide, dimethylacetamide,
Amides such as hexamethylphosphorotriamide; sulfoxides such as dimethyl sulfoxide; methano-
, Ethanol, n-propanol, isopropanol
Alcohols such as alcohol, n-butanol, isobutanol and isoamyl alcohol; dilute acids such as sulfuric acid;
Dilute base such as sodium hydroxide water; water; acetone,
Mention may be made of ketones such as methyl ethyl ketone; organic bases such as pyridine or nitriles such as acetonitrile. The reaction temperature is -10 ° C to 30 ° C, preferably 0 ° C to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but is usually 10 minutes to 1 minute.
It's 0 hours. In the above oxidation reaction, the reaction may be accelerated by adding an interlayer transfer catalyst such as triethylbenzylammonium chloride or tributylbenzylammonium bromide.

After completion of the reaction, the desired compound (I) is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized or acidified, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and after washing with water, the organic compound containing the target compound is added. The layers are separated, dried over anhydrous magnesium sulfate and the like, and then the solvent is distilled off. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

[Method D]

[0100]

[Chemical 10]

[0102] In the above ^{formulas, R 1, R 2, R} 3, Y and Z
Represents the same meaning as described above, and R ^{5 ′} represents the same group as the “C ₁ -C ₆ alkyl group” in the definition of R ⁵ .

Method D is a method for separately producing compound (I) of the present invention from carbonyl compound (X).

In step D1 , the carbonyl group of compound (X) is substituted with leaving group Y in the presence of a base to give compound (XI
This is a step of manufacturing V).

Examples of the reagent used for introducing the Y group include trifluoromethane sulfonating agents such as trifluoromethanesulfonic anhydride, N, N-di (trifluoromethanesulfone) anilide, phosphorus trichloride, and trichloride. Phosphorus bromide, phosphorus trihalides such as phosphorus triiodide, phosphorus pentachloride, phosphorus pentabromide, phosphorus pentahalides such as phosphorus pentaiodide, organic acid chlorides such as oxalyl chloride or Phosphorus oxychloride,
Examples thereof include phosphorus oxyhalides such as phosphorus oxybromide and phosphorus oxyiodide, and a trifluoromethane sulfonating agent is preferable. The base used is not particularly limited as long as it is used as a base in a usual reaction, but preferably triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N , N-dimethylamino) pyridine, 2,6-di (t-butyl) -4-methylpyridine, quinoline, N, N-dimethylaniline, N,
N-diethylaniline, 1,5-diazabicyclo [4.
3.0] nona-5-ene, 1,4-diazabicyclo [2.2.2] octane (DABCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DB
There may be mentioned organic bases such as U) or organic metal bases such as butyllithium, lithium diisopropylamide, lithium bis (trimethylsilyl) amide. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Chloroform,
Halogenated hydrocarbons such as carbon tetrachloride, dichloroethane; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, dioxane, dimethoxyethane, diethylene glycol dimethyl ether; formamide, dimethylformamide, dimethylacetamide, hexamethyl Mention may be made of amides such as phosphorotriamide. The reaction temperature is -50 ° C to 30 ° C, preferably 0 ° C to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but it is usually 1
It is from 0 minutes to 8 hours. After completion of the reaction, the target compound (XIV) of this reaction is collected from the reaction mixture according to a conventional method. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. It is obtained by separating, drying over anhydrous magnesium sulfate and the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In Step D2 , the substituent Y of the compound (XIV) is substituted with a protected carboxy group to give a compound (XIV).
V) is a step of producing V), which is achieved by reacting a palladium catalyst (which can coexist with phosphines, if necessary) and carbon monoxide in the presence of a base in an alcohol solvent. , European Publication No. 0465-
No. 123 publication, European Publication No. 0465-141 publication, or Journal of Medicinal Chemistry,
It is carried out according to the method described in Vol. 33, page 943 (1990).

Examples of the palladium catalyst to be used include palladium catalysts such as tetrakistriphenylphosphine palladium, bistriphenylphosphine palladium (II) diacetate and palladium chloride, preferably bistriphenylphosphine palladium. (II) It is diacetate. Examples of the phosphines used include triphenylphosphine,
Mention may be made of phosphines such as tributylphosphine, preferably triphenylphosphine.
The palladium catalyst and the phosphine are used at the same time to form a complex and participate in the reaction. For example,
When palladium (II) diacetate is used as the palladium catalyst and triphenylphosphine is used as the phosphine, it is involved in the reaction as bis (triphenylphosphine) palladium (II) diacetate. The base used is not particularly limited as long as it is used as a base in a normal reaction,
Preferably, triethylamine, tributylamine, diisopropylethylamine, N-methylmorpholine, pyridine, 4- (N, N-dimethylamino) pyridine, N, N
-Dimethylaniline, N, N-diethylaniline, 1,
5-diazabicyclo [4.3.0] non-5-ene,
1,4-diazabicyclo [2.2.2] octane (DA
BCO), 1,8-diazabicyclo [5.4.0] undec-7-ene (DBU) or organic metal bases such as butyllithium or lithium diisopropylamide. In addition, in order to carry out the reaction effectively, a quaternary compound such as benzyltriethylammonium chloride or tetrabutylammonium chloride is used.
It is also possible to add quaternary ammonium salts, crown ethers such as dibenzo-18-crown-6, and the like.

[0107] As the solvent to be used, the origin of the R 5 ^'group, methanol -, ethanol - Le, n- propanol - le, isopropanol - Le, n- butanol - le, isobutanol - le, t
-Butanol, isoamyl alcohol, octanol,
Alcohols such as cyclohexanol are essential, and the alcohol alone or a mixed solvent of the alcohol and the solvent described in the step D1 is used. The reaction temperature is -10 ° C to 50 ° C, preferably 0 ° C to room temperature. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but it is usually 2 hours to 50 hours. After completion of the reaction, the target compound (XV) of this reaction is prepared according to a conventional method.
Taken from the reaction mixture. For example, the reaction mixture is appropriately neutralized, and if insolubles are present, they are removed by filtration, water and an immiscible organic solvent such as ethyl acetate are added, and the mixture is washed with water to form an organic layer containing the target compound. It is obtained by separating, drying over anhydrous magnesium sulfate and the like, and distilling off the solvent. If necessary, the obtained target compound can be further purified by a conventional method, for example, recrystallization, reprecipitation or chromatography.

In Step D3 , the protected carboxy group of compound (XV) is hydrolyzed according to Step A3 to produce a carboxy group, and the carboxy group obtained is, if desired, added to Step A5. This is a step of producing the compound (I) of the present invention by treating in a similar manner.

By treating the compound (XIV) with a base and then reacting it with carbon dioxide, a compound having a free carboxy group, which corresponds to the compound (XV), can be produced. The compound (I) of the present invention can also be produced by treatment according to Step A5.

The base used is not particularly limited as long as it is a base used when generating an anion in a usual reaction, but n-butyllithium, s-butyllithium and t-butyl are preferred. Organometallic bases such as butyl lithium and lithium diisopropylamide can be mentioned. The solvent used is not particularly limited as long as it does not inhibit the reaction and dissolves the starting material to some extent, but preferably, aromatic hydrocarbons such as benzene, toluene and xylene; methylene chloride, Halogenated hydrocarbons such as chloroform, carbon tetrachloride, dichloroethane; diethyl ether, diisopropyl ether
Examples thereof include ethers such as tellurium, tetrahydrofuran, dioxane, dimethoxyethane, and diethylene glycol dimethyl ether; amides such as formamide, dimethylformamide, dimethylacetamide, and hexamethylphosphorotriamide. The reaction temperature is −
It is carried out at 100 ° C to 30 ° C, preferably -78.
The temperature is from 0 ° C to 0 ° C. The reaction time varies depending mainly on the reaction temperature, the starting compound, the reaction reagent or the type of solvent used, but it is usually 1 hour to 10 hours.

The amine compound (VII) is a known compound or a known method (for example, Synthesis, 593 (1976); JO.
rg.Chem., 36 , 305 (1971); Angew.Chem., 82 , 138 (197
0); Synthesis, 24 (1978); Synthetic Commun., 18 , 77
7 (1988); Snythetic Commun., 18 , 783 (1988); Organic
Reaction, 3 , 337 (1946); Org. Synthesis, 51 , 48 (197
1); Tetrahedron, 30 , 2151 (1974); J.Org.Chem., 37 , 1
88 (1972)], for example, a compound of the general formula H ₂ N—CH (R ⁶ ) (R
^The compound having ⁷ ) is

[0112]

[Chemical 11]

(In the above formula, R ⁶ and R ⁷ are the same or different and represent the same group as the “aryl group” in the definition of R ^2. ) As in the above formula, titanium trichloride is used. , Synthetic Communications,
It is produced according to the method described in Vol. 18, page 777 (1988).

[0114]

[Chemical 12]

In the above formula, R ⁶ has the same meaning as defined above,
R ⁸ is “C ₁ -C ₆ alkyl group” in the definition of R ^1.
The same group as above is shown.

The starting compound of the present invention, which has the general formula H
_The compound having 2N—C (R ⁶ ) (R ⁸ ) (R ⁸ ) is
As shown in the above formula, it is produced according to the method described in Synthesis, page 24 (1978) by Grignard reaction, hydroxyl group azidation reaction, and reduction reaction.

[0117]

[Chemical 13]

In the above formula, R ⁶ and R ⁸ have the same meanings as described above.

The compound of the general formula H
_The compound having 2N—C (R ⁶ ) (R ⁸ ) (R ⁸ ) is
In addition, separately, as shown in the above formula, active carbonate formation reaction,
By the acid azide production reaction, the isocyanate production reaction, and the hydrolysis reaction of the isocyanate, the journal of
Organic Chemistry (Journal of Organic Chemi
stry), 45, 415 (1980).

The amine compound (VII) in which R ² represents a carboxy group or an alkyl group having a hydroxyl group can be similarly produced by using the corresponding starting materials.

[0121]

【The invention's effect】

[0122]

[Test Example 1] (1) Preparation of 5α-reductase from rat prostate After cutting the abdominal lobe of prostate of adult male rat (300-350 g: Sprague-Dawley) into small pieces with scissors, about 5 times amount of buffer of tissue was buffered. Liquid [0.33 M sucrose, 1 mM dithiothreitol,
50 μM nicotinamide adenine dinucleotide phosphate-reductant (NADPH), containing 0.001% phenylmethylsulfonyl fluoride (PMSF) 20
mM potassium phosphate buffer (pH 7.4)] was added, followed by polytron (KINEMATICA, GmbH) and then Teflon.
Homogenized with a glass homogenizer. Centrifuge homogenized prostate tissue suspension (140,000 x
g, 60 minutes), the above buffer is added to the sediment in an amount of about 5 times the volume of the tissue, and the suspension is suspended and centrifuged again (140,000 × g, 6).
For 0 minutes) and washed. This precipitate was used as rat 5α-reductase, and the above-mentioned buffer solution was added to adjust the protein amount to 30-4.
After adjusted to 0 mg / ml, it was frozen and stored at -80 ° C. The protein content was measured using the Bio-Rad protein analysis method (Bio-R
ad Protein Assay) and bobain γ-globulin (Cohn Fraction II, Sigma) was used as a protein standard.

(2) Rat 5α-reductase inhibition test Rat 5α-reductase (protein mass: 1 mg), 1 μ
5 ml of a test substance dissolved in dimethyl sulfoxide or ethanol in 0.5 ml of 40 mM potassium phosphate buffer (pH 6.5) containing M [ ¹⁴ C] testosterone, 1 mM dithiothreitol and 500 μM NADPH (final concentration of test compound: 10 ⁻⁸ M) at 37 ° C for 15
Incubated for ~ 30 minutes. Only the solvent was added to the control group. After that, 2 ml of ethyl acetate containing 10 μg of testosterone, 5α-dihydrotestosterone, androstendaion, 10 μg each, was added to stop the reaction,
After centrifugation (1400 × g, 5 minutes), the ethyl acetate fraction was transferred to another test tube and evaporated to dryness under a nitrogen gas spray. The steroid was dissolved in 40 μl of ethyl acetate, spotted on a thin layer chromatography plate (LK5DF silica plate, Whatman), and developed twice with a mixed solution of ethyl acetate: cyclohexane (1: 1) at room temperature. The steroid fraction was identified by heat staining using ultraviolet rays and a 1% cesium sulfate / 10% sulfuric acid aqueous solution. The radioactivity on the thin layer chromatoplate was measured using a bio image analyzer (Fuji Photo Film Co., Ltd.). Enzyme activity was displayed with the added ^[14 C] ratio became ^[14 C] 5α- dihydrotestosterone of testosterone (conversion rate (%)). The rat 5α-reductase inhibitory activity of the sample is
It was calculated using the following formula. Inhibitory activity = (conversion rate of sample addition group) / (conversion rate of control group) × 100 (%) As described above, the novel steroid derivative and the pharmacologically acceptable salt thereof of the present invention are excellent in testosterone-5α.
-Has reductase inhibitory activity and has low toxicity,
It is useful as a prophylactic and therapeutic agent for diseases caused by excess 5α-dihydrotestosterone. Examples of such diseases include benign prostatic hyperplasia, acne, male baldness, hirsutism of females, and the like. In particular, the steroid derivative of the present invention and a pharmacologically acceptable salt thereof are benign prostatic hyperplasia. It is useful as a prophylactic or / and therapeutic agent and a prophylactic or / and therapeutic agent for prostate cancer.

Examples of the administration form of the compound (I) of the present invention include oral administration by tablets, capsules, granules, powders or syrups, and parenteral administration by injections or suppositories. , These formulations are excipients (eg, sugar derivatives such as lactose, sucrose, glucose, mannitol, sorbitol; corn starch, potato starch, α starch, dextrin, carboxymethyl starch starch derivatives; crystalline cellulose , Low-substituted hydroxypropylcellulose, hydroxypropylmethylcellulose, carboxymethylcellulose, carboxymethylcellulose calcium, cellulose derivatives such as internally crosslinked sodium carboxymethylcellulose; gum arabic; dextran; organic excipients such as pullulan And silicate derivatives such as light anhydrous silicic acid, synthetic aluminum silicate, and magnesium aluminometasilicate; phosphates such as calcium phosphate; carbonates such as calcium carbonate; inorganic compounds such as sulfates such as calcium sulfate. Shape forming agents), lubricants (eg, stearic acid metal salts such as stearic acid, calcium stearate, magnesium stearate; talc; colloidal silica; waxes such as bee gum and gay wax; boric acid; Adipic acid; sulfate such as sodium sulfate; glycol; fumaric acid; sodium benzoate; DL leucine; sodium salt of fatty acid; lauryl sulfate such as sodium lauryl sulfate and magnesium lauryl sulfate; silicic acid anhydride, silicic acid hydrate, etc. Examples thereof include silicic acids; and the above starch derivatives.) , Binders (eg, polyvinylpyrrolidone, macrogol, and compounds similar to the above-mentioned excipients), disintegrants (eg, compounds similar to the above-mentioned excipients,
And chemically modified starch / celluloses such as croscarmellose sodium, sodium carboxymethyl starch, cross-linked polyvinylpyrrolidone. ), Stabilizers (paraoxybenzoic acid esters such as methylparaben, propylparaben; alcohols such as chlorobutanol, benzyl alcohol, phenylethyl alcohol; benzalkonium chloride;
Phenols, phenols such as cresol; thimerosal; dehydroacetic acid; and sorbic acid. ), Flavoring agents (eg, commonly used,
Examples thereof include sweeteners, acidulants, and flavors. ), A diluent or the like, and a known method. Although the amount used varies depending on symptoms, age, administration method, etc., for example, the minimum amount is 0.01 mg per day, preferably,
0.1 mg, maximum amount 1000 mg, preferably 1
00 mg can be administered to an adult once a day or in several divided doses.

Next, the present invention will be described more specifically with reference to Examples and Reference Examples.

[0126]

Example 1 17β- (N-diphenylmethylcarbamoyl) -11
β-hydroxyandrosta-3,5-diene-3-ca
Rubonic acid

[0127]

Example 1a Methyl 11β-hydroxy-3-oxo-4-and
Rosten-17β-carboxylate 18 g of commercially available corticosterone was added to 400 m of dioxane.
200 ml of 20 g of sodium periodate dissolved in 1
A hot aqueous solution was added, and the mixture was stirred at 50 ° C for 1 day. Sodium periodate precipitated from the reaction solution was filtered, and chloroform-
It was washed with a mixed solvent of methanol. The aqueous layer of the filtrate was acidified with hydrochloric acid, extracted with methylene chloride, washed with water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was dissolved in 100 ml of methylene chloride, an ether solution of diazomethane was added, and the mixture was left for 30 minutes. After distilling off the solvent under reduced pressure, the residue was purified by column chromatography using 400 g of silica gel (eluting solvent: hexane / ethyl acetate = 3/2 to 1/1) and crystallized from ether-methanol. , 6.5 g of the target compound was obtained. NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, s), 0.96
-2.57 (18H, m), 1.45 (3H, s), 3.68 (3H, s), 4.39 (1H, dd, J =
2.9,6.4Hz), 5.68 (1H, s) IR spectrum ν _max cm ^-1 (KBr): 3546, 2906, 283
2, 1722, 1662, 1615,1434

[0128]

Example 1b Methyl 3-cyano-11β-hydroxyandrosta
3.70 g of 3,3,5 -diene-17β-carboxylate methyl 11β-hydroxy-3-oxo-4-androstene-17β-carboxylate was dissolved in 80 ml of dry tetrahydrofuran, and lithium cyanide 1 was added under a nitrogen stream. 0.07 g and 4.90 ml of diethyl cyanophosphate were added, and the mixture was stirred at room temperature for 30 minutes. The solvent was distilled off from the reaction solution under reduced pressure, the residue was dissolved in 100 ml of a benzene-ethyl acetate (1: 1) mixed solution, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was reduced in pressure. I distill off. The residue was dissolved in 80 ml of dried benzene, 0.5 ml of boron trifluoride / ether complex was added, and the mixture was stirred at room temperature for 4 hours. Water was added to the reaction solution, which was extracted with ethyl acetate, washed with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using 100 g of silica gel (elution solvent: hexane / ethyl acetate = 7/3) and crystallized from ether,
3.15 g of the desired compound was obtained. NMR spectrum (CDCl ₃ ) δppm: 0.93 (3H, s), 1.10
-2.55 (16H, m), 1.16 (3H, s), 3.69 (3H, s), 4.40 (1H, dd, J =
3.4,6.3Hz), 5.69 (1H, t, J = 3.9Hz), 6.62 (1H, s) IR spectrum ν _max cm ^-1 (KBr): 3543, 2937, 220
5, 1716, 1640, 1440

[0129]

Example 1c 3-Cyano-11β-hydroxyandrosta-3,5
-Diene- 17β-carboxylate methyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-carboxylate 3.10
g was dissolved in 80 ml of methanol, an 8 ml aqueous solution of 1.5 g of potassium hydroxide was added, and the mixture was heated under reflux for 18 hours under a nitrogen atmosphere. After evaporating the solvent under reduced pressure, the mixture was acidified with dilute hydrochloric acid, extracted with methylene chloride, washed with water and saturated brine, dried over anhydrous sodium sulfate, and then the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using 80 g of silica gel (elution solvent: methylene chloride / acetone = 3/22 to 1/1) and crystallized from ether to obtain 2.42 g of the target compound. NMR spectrum (CDCl ₃ ) δppm: 1.01 (3H, s), 1.10
-2.55 (16H, m), 1.16 (3H, s), 4.42 (1H, dd, J = 3.2,6.6Hz),
5.69 (1H, t, J = 3.7Hz), 6.62 (1H, s) IR spectrum ν _max cm ^-1 (KBr): 3578, 3240, 291
3, 2198, 1733, 1697, 1640, 1604, 1392

[0130]

Example 1d S-2-Pyridyl 3-cyano-11β-hydroxya
Androsta-3,5-diene-17β-thiocarboxy
Rate 3-cyano-11β-hydroxyandrosta-3,5
1.0 g of -diene-17β-carboxylic acid was dissolved in 15 ml of dry toluene to give triphenylphosphine 1.
57 g and dipyridyl disulfide 1.30 g were added, and the mixture was stirred at room temperature for 1 day. The reaction solution was directly purified by column chromatography using 50 g of silica gel (elution solvent: hexane / ethyl acetate = 7/3 to 3/2) and crystallized from ether to obtain 1.12 g of the target compound. . NMR spectrum (CDCl ₃ ) δppm: 1.02 (3H, s), 1.04
-2.55 (16H, m), 1.16 (3H, s), 2.69 (1H, t, J = 8.8Hz), 4.46
(1H, dd, J = 3.4,6.3Hz), 5.69 (1H, t, J = 3.7Hz), 6.62 (1H,
s), 7.28-7.34 (1H, m), 7.61-7.65 (1H, m), 7.74-7.81 (1H,
m), 8.61-8.65 (1H, m) IR spectrum ν _max cm ^-1 (KBr): 3495, 3314, 291
5, 2876, 2204, 1704, 1636, 1603, 1573, 1450, 1422

[0131]

Example 1e N-diphenylmethyl-3-cyano-11β-hydroxy
Cyandroster-3,5-diene-17β-carboxa
Mido 3-cyano-11β-hydroxyandrosta-3,5
100 mg of -diene-17β-carboxylic acid was suspended in 3 ml of dry methylene chloride, and triethylamine 10 was added.
0 μl, diethyl cyanophosphate 90 μl and diphenylmethylamine 100 μl were added, and the mixture was stirred at room temperature for 1 day. The reaction mixture was poured into diluted hydrochloric acid, extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using 7 g of silica gel (eluting solvent: hexane / ethyl acetate = 7/3 to 3/2).
And purified to give 130 mg of the desired compound. NMR spectrum (CDCl ₃ ) δppm: 0.94 (3H, s), 1.05
-2.55 (16H, m), 1.14 (3H, s), 4.36 (1H, dd, J = 3.4,6.3Hz),
5.68 (1H, t, J = 3.7Hz), 5.90 (1H, d, J = 7.8Hz), 6.29 (1H, d, J
= 7.8Hz), 6.61 (1H, s), 7.20-7.40 (10H, m) IR spectrum ν _max cm ^-1 (KBr):
3444, 3356, 2964, 2916,
2203, 1656, 1602, 1494, 14
55

[0132]

Example 1f 17β- (N-diphenylmethylcarbamoyl) -11
β-hydroxyandrosta-3,5-diene-3-ca
Rubonic acid N-diphenylmethyl-3-cyano-11β-hydroxyandrosta-3,5-diene-17β-carboxamide 115 mg was dissolved in 1,4-dioxane 1 ml and ethylene glycol 8 ml, and 30% potassium hydroxide aqueous solution 3 ml was used. Was added, and the mixture was heated under reflux for 1 day under a nitrogen atmosphere.
The reaction solution is poured into diluted hydrochloric acid, extracted with methylene chloride, water,
The extract was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by column chromatography using 6 g of silica gel (eluting solvent: acetone / methylene chloride = 4/96 to 3/7) and crystallized from ether to give 95 mg of the desired compound. NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, s), 1.10
-2.65 (16H, m), 1.14 (3H, s), 4.41 (1H, d, J = 2.9Hz), 5.77
(1H, t, J = 3.7Hz), 5.90 (1H, d, J = 7.8Hz), 6.30 (1H, d, J = 7.8Hz
Hz), 7.10 (1H, s), 7.20-7.45 (10H, m) IR spectrum ν _max cm ^-1 (KBr): 3444, 3340, 293
9, 2914, 1674, 1636,1615, 1495

[0133]

Example 2 17β- (N-diphenylmethylcarbamoyl) -11
-Oxoandrosta-3,5-diene-3-carvone
Chromium trioxide (VI) 60 mg, dissolved by heating in pyridine 3 ml, under a nitrogen stream at room temperature and stirred for 30 minutes. 17β
A solution of 45 mg of-(N-diphenylmethylcarbamoyl) -11β-hydroxyandrosta-3,5-diene-3-carboxylic acid in 1 ml of pyridine was added, and the mixture was stirred at room temperature for 3 hours. The reaction solution was poured into diluted hydrochloric acid, extracted with methylene chloride, washed with water and saturated saline, dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The residue was purified by column chromatography using 4 g of silica gel (eluting solvent: acetone / methylene chloride = 3/17 to 2/3) and crystallized from ether to give 30 mg of the desired compound. NMR spectrum (CDCl ₃ ) δppm: 0.68 (3H, s), 0.85
-2.75 (16H, m), 1.10 (3H, s), 5.79-5.88 (2H, m), 6.26 (1H,
d, J = 7.8Hz), 7.08 (1H, s), 7.20-7.65 (10H, m) IR spectrum ν _max cm ^-1 (KBr): 3324, 2963, 292
1, 1705, 1667, 1645, 1520, 1495

[0134]

Example 3 17β- [N- (1-methyl-1-phenylethyl) carb
Lubamoyl] -11β-hydroxyandrosta-3,
5-diene-3-carboxylic acid

[0135]

Example 3a N- (1-methyl-1-phenylethyl) -3-cyano
-11β-Hydroxyandrosta-3,5-diene-
100 mg of 17β-carboxamide S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate was suspended in 2 ml of dry methylene chloride to prepare 1-methyl-1-phenylethylamine. 160
mg was added, and the mixture was stirred at room temperature for 3 days. The reaction mixture was poured into diluted hydrochloric acid, extracted with methylene chloride, washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using 8 g of silica gel (elution solvent:
Purified with ethyl acetate / hexane = 1/3 to 2/3),
80 mg of the desired compound was obtained. NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, s), 1.05
-2.55 (16H, m), 1.16 (3H, s), 1.71 (3H, s), 1.74 (3H, s),
4.40 (1H, dd, J = 3.4,6.4Hz), 5.57 (1H, s), 5.68 (1H, t, J = 3.
7Hz), 6.62 (1H, s), 7.20-7.45 (5H, m) IR spectrum ν _max cm ^-1 (KBr): 3441, 2970, 291
7, 2203, 1661, 1635, 1602, 1509, 1496

[0136]

Example 3b 17β- [N- (1-methyl-1-phenylethyl) carb
Lubamoyl] -11β-hydroxyandrosta-3,
5-Diene-3-carboxylic acid N- (1-methyl-1-phenylethyl) -3-cyano-11β-hydroxyandrosta-3,5-diene-
Using 17β-carboxamide and in the same manner as in Example 1f, the target compound was obtained in a yield of 88%. NMR spectrum (CDCl ₃ ) δppm: 0.96 (3H, s), 1.05
-2.65 (16H, m), 1.15 (3H, s), 1.72 (3H, s), 1.74 (3H, s),
4.45 (1H, d, J = 2.4Hz), 5.57 (1H, s), 5.78 (1H, t, J = 3.9Hz),
7.10 (1H, s), 7.20-7.44 (5H, m) IR spectrum ν _max cm ^-1 (KBr): 3441, 2966, 291
5, 1665, 1634, 1608, 1508, 1496

[0137]

Example 4 17β- [N- (1-methyl-1-phenylethyl) carb
Lubamoyl] -11-oxoandrosta-3,5-di
Ene-3-carboxylic acid 17β- [N- (1-methyl-1-phenylethyl) carbamoyl] -11β-hydroxyandrosta-3,
The same procedure as in Example 2 was carried out using 5-diene-3-carboxylic acid to obtain the target compound in a yield of 55%. NMR spectrum (CDCl ₃ ) δppm: 0.68 (3H, s), 0.80
-2.80 (16H, m), 1.12 (3H, s), 1.71 (3H, s), 1.74 (3H, s),
5.49 (1H, s), 5.81 (1H, br.s), 7.08 (1H, s), 7.20-7.42 (5
H, m) IR spectrum ν _max cm ^-1 (KBr): 3361, 2965, 292
4, 1706, 1675, 1637, 1509, 1496

[0138]

Example 5 17β- [N- (4,4′-dimethoxydiphenylmethy !
) Carbamoyl] -11β-hydroxyandrosta
-3,5-Diene-3-carboxylic acid 3-cyano-11β-hydroxyandrosta -3,5
-Diene-17β-carboxylic acid and 4,4'-dimethoxydiphenylmethylamine were carried out in the same manner as in Example 1e and then in Example 1f to give 65% of the target compound.
It was obtained in a yield of. NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, s), 1.05
-2.65 (16H, m), 1.14 (3H, s), 3.788 (3H, s), 3.794 (3H, s),
4.41 (1H, d, J = 2.9Hz), 5.77 (1H, t, J = 3.7Hz), 5.83 (1H, d,
J = 7.8Hz), 6.19 (1H, d, J = 7.8Hz), 6.82-6.89 (4H, m), 7.09
-7.19 (5H, m) IR spectrum ν _max cm ^-1 (KBr): 3446, 2938, 291
2, 1664, 1636, 1611, 1511, 1247

[0139]

Example 6 17β- [N- (1,2-diphenylethyl) carbamo
Ill] -11β-hydroxyandrosta-3,5-di
Ene-3-carboxylic acid 3-cyano-11β-hydroxyandrosta-3,5
Example 1e followed by Example 1 using -diene-17β-carboxylic acid and 1,2-diphenylethylamine.
Target compound was obtained in a yield of 77% by carrying out in the same manner as in f. NMR spectrum (CDCl ₃ + CD ₃ OD) δppm: 0.65 and 0.
76 (total 3H, each s), 0.95-2.65 (16H, m), 1.10 and 1.12 (total 3
H, each S), 2.90-3.30 (2H, m), 4.22 and 4.36 (total 1H, each d,
Each J = 3Hz), 5.28 and 5.41 (total 1H, t and dd, J = 7.1Hz and
3.4Hz), 5.73 (1H, d, J = 3.4Hz), 7.04-7.37 (11H, m) IR spectrum ν _max cm ^-1 (KBr): 3494, 3436, 293
4, 2913, 1671, 1632, 1606, 1497, 1455, 1421

[0140]

Example 7 17β- {N- [1- (4-methoxyphenyl) -1-
Methylethyl] carbamoyl} -11β-hydroxya
Androsta-3,5-diene-3-carboxylic acid S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate and 1- (4-methoxyphenyl) -1- Example 3a, then Example 1 using methylethylamine
Target compound was obtained in a yield of 61% by carrying out in the same manner as in f. NMR spectrum (CDCl ₃ ) δppm: 1.10-2.65 (16H,
m), 1.15 (3H, m), 1.70 (3H, s), 1.73 (3H, s), 3.79 (3H, s),
4.45 (1H, d, J = 2.9Hz), 5.52 (1H, s), 5.78 (1H, t, J = 3.7H
z), 6.86 (2H, d, J = 9Hz), 7.10 (1H, s), 7.34 (2H, d, J = 9Hz) IR spectrum ν _max cm ^-1 (KBr): 3432, 2970, 291
6, 1669, 1633, 1611, 1514, 1497

[0141]

Example 8 17β- [N- (4,4′-dimethoxydiphenylmethy !
Le) carbamoyl] -11-oxoandrosta-3,
5-diene-3-carboxylic acid 17β- [N- (4,4′-dimethoxydiphenylmethyl) carbamoyl] -11β-hydroxyandrosta-3,5-diene-3-carboxylic acid was used in Example 2
Target compound was obtained in a yield of 67%. NMR spectrum (CDCl ₃ ) δppm: 0.69 (3H, s), 0.80
-2.75 (16H, m), 1.11 (3H, s), 3.79 (3H, s), 3.80 (3H, s),
5.76-5.82 (2H, m), 6.15 (1H, d, J = 7.8Hz), 6.83-6.90 (4H,
m), 7.08-7.16 (5H, m) IR spectrum ν _max cm ^-1 (KBr): 3340, 2963, 293
9, 1707, 1664, 1635, 1611, 1511

[0142]

Example 9 17β- [N- (1,2-diphenylethyl) carbamo
Il] -11-oxoandrosta-3,5-diene-
3-Carboxylic acid 17β- [N- (1,2-diphenylethyl) carbamoyl] -11β-hydroxyandrosta-3,5-diene-3-carboxylic acid was used and carried out in the same manner as in Example 2, The target compound was obtained in a yield of 33%. NMR spectrum (CDCl ₃ ) δppm: 0.48 (3H, s), 0.75
-2.75 (16H, m), 1.08 and 1.10 (total 3H, each s), 3.00-3.20 (2
H, m), 5.20-5.35 (1H, m), 5.47 and 5.55 (total 1H, each d, J = 7.
8Hz), 5.80 (1H, br.s), 7.08-7.36 (11H, m) IR spectrum ν _max cm ^-1 (KBr): 3332, 2964, 294
1, 1706, 1675, 1638, 1497

[0143]

Example 10 17β- {N- [1- (4-methoxyphenyl) -1-
Methylethyl] carbamoyl} -11-oxoandro
Star-3,5-diene-3-carboxylic acid 17β- {N- [1- (4-methoxyphenyl) -1-
Methylethyl] carbamoyl} -11β-hydroxyandrosta-3,5-diene-3-carboxylic acid was used and carried out in the same manner as in Example 2 to obtain the target compound in a yield of 40%. NMR spectrum (CDCl ₃ ) δppm: 0.67 (3H, s), 0.80
-2.85 (16H, m), 1.12 (3H, s), 1.70 (3H, s), 1.72 (3H, s),
3.79 (3H, s), 5.44 (1H, s), 5.82 (1H, br.s), 6.87 (2H, d, J =
8.3Hz), 7.08 (1H, s), 7.33 (2H, d, J = 8.3Hz) IR spectrum ν _max cm ^-1 (KBr): 3366, 2964, 292
5, 1706, 1678, 1660, 1614, 1514, 1456

[0144]

Example 11 17β- [N- (4,4′-difluorodiphenylmethyi ]
) Carbamoyl] -11β-hydroxyandrosta
-3,5-Diene-3-carboxylic acid 3-cyano-11β-hydroxyandrosta -3,5
-Diene-17β-carboxylic acid and 4,4'-difluorodiphenylmethylamine were used and carried out in the same manner as in Example 1e and then Example 1f to give 24% of the target compound.
It was obtained in a yield of. NMR spectrum (CDCl ₃ ) δppm: 0.95 (3H, s), 1.10
-2.65 (16H, m), 1.14 (3H, m), 4.42 (1H, d, J = 2.9Hz), 5.77
(1H, t, J = 3.9Hz), 5.81 (1H, d, J = 7.8Hz), 6.25 (1H, d, J = 7.8
Hz), 7.00-7.27 (9H, m) IR spectrum ν _max cm ^-1 (KBr):
3440, 3370, 2940, 2915,
1667, 1634, 1606, 1509, 14
22

[0145]

Example 12 17β- (N, N-Dibenzylcarbamoyl) -11β
-Hydroxyandrosta-3,5-diene-3-cal
Boronic acid 3-cyano-11β-hydroxyandrosta-3,5
-Diene-17β-carboxylic acid and N, N-dibenzylamine were used and carried out in the same manner as in Example 1e and then Example 1f to obtain the target compound in a yield of 58%. NMR spectrum (CDCl ₃ ) δppm: 0.85-2.75
(16H, m), 1.15 (3H, s), 1.17 (3H, s), 3.85 (1H, d, J = 15Hz),
4.21 (1H, d, J = 17Hz), 4.40 (1H, d, J = 2.9Hz), 4.84 (1H, d, J
= 17Hz), 5.37 (1H, d, J = 15Hz), 5.76 (1H, t, J = 3.9Hz), 7.08-
7.40 (11H, m) IR spectrum ν _max cm ^-1 (KBr): 3468, 2940, 291
8, 1702, 1676, 1634, 1496, 1423

[0146]

Example 13 17β- {N- [α- (4-hydroxyphenyl) ben
Zil] carbamoyl} -11β-hydroxyandross
3,5-diene-3-carboxylic acid 3-cyano-11β-hydroxyandrosta -3,5
-Diene-17β-carboxylic acid and α- (4-hydroxyphenyl) benzylamine were used to perform the same procedure as in Example 1e and then in Example 1f to give 61
Obtained in% yield. NMR spectrum (CDCl ₃ + CD ₃ OD) δppm: 0.94 (3H,
s), 1.05-2.60 (16H, m), 1.14 (3H, s), 4.39 (1H, br.s), 5.
73 (1H, t, J = 3.9Hz), 6.19 (1H, d, J = 3.4Hz), 6.74-6.82 (2H,
m), 7.03-7.10 (3H, m), 7.21-7.37 (5H, m) IR spectrum ν _max cm ^-1 (KBr): 3328, 2966, 291
7, 1674, 1636, 1615,1514, 1496

[0147]

Example 14 17β- {N- [α- (4-chlorophenyl) benzyl
]] Carbamoyl} -11 β-hydroxyandrosta
-3,5-Diene-3-carboxylic acid 3-cyano-11β-hydroxyandrosta -3,5
Example 1e using -diene-17β-carboxylic acid and α- (4-chlorophenyl) benzylamine hydrochloride.
Then, the same procedure as in Example 1f was carried out to obtain 9
Obtained in a yield of 0%. NMR spectrum (CDCl ₃ ) δppm: 0.94 and 0.95 (total
3H, each S), 1.10-2.65 (16H, m), 1.14 and 1.15 (total 3H, each
S), 4.35-4.45 (1H, m), 5.78 (1H, br.s), 5.82-5.88 (1H,
m), 6.23-6.28 (1H, m), 7.09 (1H, s), 7.15-7.40 (9H, m) IR spectrum ν _max cm ^-1 (KBr): 3441, 3370, 296
3, 2938, 2914, 1668, 1634, 1609, 1490

[0148]

Example 15 17β- (N, N-Dibenzylcarbamoyl) -11-
Oxoandrosta -3,5-diene-3-carboxylic acid 17β- (N, N-dibenzylcarbamoyl) -11β
-Hydroxyandrosta-3,5-diene-3-carboxylic acid was used and carried out in the same manner as in Example 2 to obtain the target compound in a yield of 50%. NMR spectrum (CDCl ₃ ) δppm: 0.85-2.70 (15H,
m), 0.87 (3H, s), 1.12 (3H, s), 2.95 (1H, t, J = 8.8Hz), 3.8
2 (1H, d, J = 15Hz), 4.21 (1H, d, J = 18Hz), 4.72 (1H, d, J = 18H
z), 5.38 (1H, d, J = 15Hz), 5.80 (1H, br.s), 7.08-7.41 (11
H, m) IR spectrum ν _max cm ^-1 (KBr): 2924, 2855, 170
6, 1672, 1638, 1496, 1423

[0149]

Example 16 17β- {N- [1- (2-methoxyphenyl) -1-
Methylethyl] carbamoyl} -11β-hydroxya
Androsta-3,5-diene-3-carboxylic acid S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate and 1- (2-methoxyphenyl) -1- Example 3a, then Example 1 using methylethylamine
Target compound was obtained in a yield of 85% by carrying out in the same manner as in f. NMR spectrum (CDCl ₃ ) δppm: 0.90 (3H, s), 1.10
-2.65 (16H, m), 1.14 (3H, s), 1.77 (3H, s), 1.81 (3H, s),
3.85 (3H, s), 4.43 (1H, d, J = 2.9Hz), 5.78 (1H, t, J = 3.7Hz),
5.99 (1H, s), 6.87-6.98 (2H, m), 7.10 (1H, s), 7.20-7.27
(1H, m), 7.38-7.42 (1H, m) IR spectrum ν _max cm ^-1 (KBr): 3450, 2937, 290
5, 1664, 1635, 1606, 1515, 1490, 1453, 1435

[0150]

Example 17 17β- {N- [1- (3,5-dimethoxyphenyl)
-1-Methylethyl] carbamoyl} -11β-hydro
Xiandrosta- 3,5-diene-3-carboxylic acid S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate and 1- (3,5-dimethoxyphenyl) ) -1-
Using methylethylamine, the procedure of Example 3a and then Example 1f was repeated to give the target compound in 70% yield. NMR spectrum (CDCl ₃ ) δppm: 0.97 (3H, s), 1.10
-2.65 (16H, m), 1.15 (3H, s), 1.70 (6H, s), 3.79 (6H, s),
4.45 (1H, d, J = 2.9Hz), 5.56 (1H, s), 5.78 (1H, t, J = 3.9Hz),
6.34 (1H, t, J = 2.4Hz), 6.57 (2H, d, J = 2.4Hz), 7.11 (1H,
S) IR spectrum ν _max cm ^-1 (KBr): 3440, 2939, 291
5, 1674, 1635, 1608, 1595, 1507, 1457, 1424

[0151]

Example 18 17β- {N- [α- (4-chlorophenyl) benzyl
]] Carbamoyl} -11-oxoandrosta-3,
Using 5-diene-3-carboxylic acid 17.beta. {N-[alpha-(4-chlorophenyl) benzyl] carbamoyl} 11? - hydroxy-androsta-3,5-diene-3-carboxylic acid, Example 2
Target compound was obtained in a yield of 36%. NMR spectrum (CDCl ₃ ) δppm: 0.68 (3H, s), 0.85
-2.75 (16H, m), 1.11 and 1.12 (total 3H, each s), 5.79-5.90 (2
H, m), 6.19-6.25 (1H, m), 7.07-7.37 (10H, m) IR spectrum ν _max cm ^-1 (KBr): 3328, 2962, 292
3, 1706, 1672, 1491

[0152]

Example 19 17β- {N- [1- (4-methylphenyl) -1-me
Cylethyl] carbamoyl} -11β-hydroxyan
Drosta-3,5-diene-3-carboxylic acid S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate and 1- (4-methylphenyl) -1- Example 3a, then Example 1f, using methylethylamine.
Target compound was obtained in a yield of 60%. NMR spectrum (CDCl ₃ ) δppm: 0.96 (3H, s), 1.10
-2.65 (16H, m), 1.15 (3H, s), 1.70 (3H, s), 1.73 (3H, s),
2.32 (3H, s), 4.45 (1H, d, J = 2.9Hz), 5.54 (1H, s), 5.78 (1
H, t, J = 3.7Hz), 7.10 (1H, s), 7.14 (2H, d, J = 8.1Hz), 7.30
(2H, d, J = 8.1Hz) IR spectrum ν _max cm ^-1 (KBr): 3492, 3451, 296
0, 2930, 2915, 1672,1637, 1611, 1497, 1454, 1430

[0153]

Example 20 17β- [N- (4,4′-difluorodiphenylmethyi ]
Le) carbamoyl] -11-oxoandrosta-3,
5-diene-3-carboxylic acid 17β- [N- (4,4′-difluorodiphenylmethyl) carbamoyl] -11β-hydroxyandrosta-3,5-diene-3-carboxylic acid was used in Example 2
Target compound was obtained in a yield of 40%. NMR spectrum (CDCl ₃ ) δppm: 0.67 (3H, s), 0.80
-2.70 (16H, m), 1.11 (3H, s), 5.76 (1H, d, J = 7.4Hz), 5.81
(1H, br.s), 6.22 (1H, d, J = 7.4Hz), 7.00-7.08 (5H, m), 7.1
5-7.21 (4H, m) IR spectrum ν _max cm ^-1 (KBr): 3322, 2960, 292
4, 2854, 1703, 1669, 1647, 1607, 1509

[0154]

Example 21 17β- [N-Diphenylaminocarbamoyl] -11
β-hydroxyandrosta-3,5-diene-3-ca
Rubonic acid

[0155]

Example 21a N-diphenylamino-3-cyano-11β-hydroxy
Cyandroster-3,5-diene-17β-carboxa
A procedure similar to that of Example 3a was carried out using amide S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate and 1,1-diphenylhydrazine hydrochloride. 75% target compound
It was obtained in a yield of. NMR spectrum (CDCl ₃ ) δppm: 0.95-2.55 (16H,
m), 0.98 (3H, s), 1.15 (3H, s), 4.38 (1H, dd, J = 2.9,6.4H
z), 5.69 (1H, t, J = 3.6Hz), 6.62 (1H, s), 6.99-7.35 (10H,
m), 7.51 (1H, s) IR spectrum ν _max cm ^-1 (KBr): 3540, 3273, 291
9, 2882, 2202, 1672,1630, 1591

[0156]

Example 21b N-diphenylamino-3-formyl-11β-hydro
Xyandrosta-3,5-diene-17β-carboxy
200 mg of the compound obtained in Samide Example 21a was suspended in 5 ml of dry toluene, 1.4 ml of a 1M diisobutylaluminum hydride-toluene solution was added at 0 ° C under a nitrogen stream, and the mixture was stirred for 30 minutes. The reaction solution was brought to room temperature, a 12 ml aqueous solution of 0.6 g of L-tartaric acid was added, and the mixture was stirred for 2 hours. The reaction solution is poured into water, extracted with methylene chloride, water,
The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using 20 g of silica gel (elution solvent: hexane /
Purification with ethyl acetate = 3/2) gave 60 mg of the desired compound. NMR spectrum (CDCl ₃ ) δppm: 0.88-2.28 (14H,
m), 0.92 (3H, s), 1.12 (3H, s), 2.45-2.58 (2H, m), 4.32
(1H, br.s), 5.89 (1H, t, J = 3.6Hz), 6.74 (1H, s), 6.94-7.
32 (10H, m), 8.14 (1H, br.s), 9.44 (1H, s) IR spectrum ν _max cm ^-1 (CHCl ₃ ): 3260, 3015, 2
920, 1662, 1625, 1590

[0157]

Example 21c 17β- [N-diphenylaminocarbamoyl] -11
β-hydroxyandrosta-3,5-diene-3-ca
Rubonic acid 55 mg of the compound obtained in Example 21b was treated with 2-methyl-2.
-Dissolved in 1.2 ml of propanol, 2-methyl-2
0.3 m of butene 0.15 ml and sodium dihydrogen phosphate dihydrate 90 mg and sodium chlorite 180 mg
1 aqueous solution was added, and the mixture was stirred at room temperature for 1 hour. The reaction solution was poured into 1N hydrochloric acid, extracted with methylene chloride, washed successively with an aqueous solution of sodium thiosulfate, water and saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was subjected to column chromatography using 5 g of silica gel (elution solvent: methylene chloride / acetone = 4/1 to 7 /
Purified in 3) and crystallized from ether to give 25 mg of the desired compound. NMR spectrum (CDCl ₃ ) δppm: 0.85-2.62 (16H,
m), 0.97 (3H, s), 1.13 (3H, s), 4.41 (1H, br.s), 5.77 (1
H, br.s), 6.99-7.32 (11H, m), 7.67 (1H, br.s) IR spectrum ν _max cm ^-1 (CHCl ₃ ): 3460, 3260, 3
010, 2920, 1675, 1630, 1590

[0158]

Reference Example 1 17β- (Nt-butylcarbamoyl) -11β-hi
Droxyandrosta-3,5-diene-3-carvone
Example 3a, using the acid S-2-pyridyl 3-cyano-11β-hydroxyandrosta-3,5-diene-17β-thiocarboxylate and t-butylamine.
Then, the same procedure as in Example 1f is carried out to obtain the target compound 6
Obtained in a yield of 5%. NMR spectrum (CDCl ₃ + CD ₃ OD) δppm: 0.95 (3H,
s), 1.05-2.60 (16H, m), 1.15 (3H, s), 1.36 (9H, s), 4.43
(1H, d, J = 2.9Hz), 5.74 (1H, t, J = 3.9Hz), 7.05 (1H, s) IR spectrum ν _max cm ^-1 (KBr): 3450, 2963, 294
4, 1663, 1633, 1608, 1514

[0159]

Reference Example 2 17β- (Nt-butylcarbamoyl) -11-oxy
Soandrosta-3,5-diene-3-carboxylic acid 17β- (Nt-butylcarbamoyl) -11β-hydroxyandrosta-3,5-diene-3-carboxylic acid was carried out in the same manner as in Example 2. Thus, the target compound was obtained in a yield of 40%. NMR spectrum (CDCl ₃ ) δppm: 0.69 (3H, s), 0.85
-2.75 (16H, m), 1.12 (3H, s), 1.35 (9H, s), 5.82 (1H, br.
s), 7.08 (1H, s) IR spectrum ν _max cm ^-1 (KBr):
3396, 2962, 2923, 2854,
1705, 1662, 1635, 1609, 15
09

Continuation of front page (51) Int.Cl. ⁶ Identification number Reference number within the agency FI Technical indication location C07J 33/00 9051-4C 43/00 9051-4C (72) Inventor Horikoshi Ohno Hiromachi, Shinagawa-ku, Tokyo Sanchome Co., Ltd. 1-258 (72) Inventor Takakazu Hamada 1-25-2 Hiromachi, Shinagawa-ku, Tokyo Sankyo Co., Ltd.

Claims (25)

[Claims] 1. A general formula: [In the formula, R ¹ represents a hydrogen atom, a C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkyl group substituted by one or more groups selected from the substituent group A, and R ² represents A C ₁ -C ₆ alkyl group substituted by one or more groups selected from the substituent group A (further optionally having a carboxy group or a hydroxyl group as a substituent) or a diaryl. An amino group, R ³ is a carboxy group, a protected carboxy group, or a group having the formula —CONHSO ₂ R ⁴ (wherein R ⁴ is
C ₁ -C ₆ alkyl group, or a C ₁ -C ₆ alkyl group substituted by one or more groups selected from Substituent group A. And Z represents an oxo group, a hydrogen atom and a hydroxyl group, or a hydrogen atom and a C ₁ -C ₅ aliphatic acyloxy group. ] And a pharmaceutically acceptable salt thereof. [Substituent Group A] An aryl group and a 5- to 6-membered cyclic heteroaryl group. 2. The method according to claim 1, wherein R ¹ is a hydrogen atom or C
₁ -C ₄ alkyl group, or one or more by a group which is substituted C ₁ -C ₄ alkyl group, steroid derivatives and pharmacologically acceptable salts thereof selected from the substituent group A. 3. The method according to claim 1, wherein R ¹ is a hydrogen atom or C
₁ -C ₄ alkyl group, or one or more by a group which is substituted C ₁ -C ₄ alkyl group, steroid derivatives and pharmacologically acceptable salts thereof selected from the substituent group A '. [Substituent Group A ′] An aryl group and a 5-membered cyclic heteroaryl group. 4. The method according to claim 3, wherein R ¹ is a hydrogen atom or C
A steroid derivative and a pharmaceutically acceptable salt thereof, which is a _2- C ₄ alkyl group or a methyl group substituted with one or more groups selected from the substituent group A ′. 5. The method according to claim 1, wherein R ¹ is a hydrogen atom or C
Steroid derivatives and their pharmaceutically acceptable salts, which are _2- C ₄ alkyl groups or methyl groups substituted by one or more groups selected from Substituent group A ″. [Substituent group A ″] Phenyl group, furyl group and thienyl group. 6. The benzyl group and furylmethyl group according to claim 1, wherein R ¹ is a hydrogen atom, an alkyl group having 3 carbon atoms, a benzyl group, a benzyl group substituted by one or more groups selected from the substituent group B. Or a steroid derivative having a thienylmethyl group and a pharmacologically acceptable salt thereof. [Substituent Group B] C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, a halogen atom, an amino group, mono- or di (C ₁ -C ₄ alkyl) amino group, a hydroxyl group, C ₂ -C ₅
Alkoxycarbonyl group, and, C ₁ -C ₅ aliphatic acylamino groups. 7. The steroid derivative according to claim 1, wherein R ¹ is a hydrogen atom, an isopropyl group, a benzyl group, a benzyl group substituted with one or more groups selected from the substituent group C, or a thienylmethyl group. And their pharmacologically acceptable salts. [Substituent group C] C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halogen atom, mono or di (C ₁ -C ₄
Alkyl) amino group and hydroxyl group. 8. An item is selected from claims 1 to 7, R ² is, C ₁ -C ₄ alkyl group substituted by one or more groups selected from Substituent group A, or, diarylamino A steroid derivative and a pharmacologically acceptable salt thereof which are groups. [Substituent Group A] An aryl group and a 5- to 6-membered cyclic heteroaryl group. 9. The C ₁ -C ₄ alkyl group as defined in claim 1, wherein R ² is substituted with one or more groups selected from the substituent group A ′, or a diaryl. A steroid derivative and a pharmacologically acceptable salt thereof which are amino groups. [Substituent Group A ′] An aryl group and a 5-membered cyclic heteroaryl group. 10. An item is selected from claims 1 to 7, R ² is, C ₁ -C ₄ alkyl group substituted by one or more groups selected from Substituent group A ", or, diaryl Steroid derivatives and pharmaceutically acceptable salts thereof which are amino groups [Substituent group A ″] phenyl group, furyl group and thienyl group. 11. The method according to claim 1, wherein R ² is C substituted with 1 to 2 substituents.
_1- C ₄ alkyl group (wherein the substituent is a phenyl group, a phenyl group substituted with one or more groups selected from the substituent group B, a furyl group, a thienyl group, and a C ₁ -C ₄ alkyl group) A thiol group, a C ₁ -C ₄ alkyl-substituted furyl group), a diarylamino group or a diarylamino group substituted by one or more groups selected from Substituent Group B, and steroid derivatives and them A pharmacologically acceptable salt of. [Substituent Group B] C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, a halogen atom, an amino group, mono- or di (C ₁ -C ₄ alkyl) amino group, a hydroxyl group, C ₂ -C ₅
Alkoxycarbonyl group, and, C ₁ -C ₅ aliphatic acylamino groups. 12. The method according to claim 1, wherein R ² is C substituted with 1 to 2 substituents.
_1- C ₄ alkyl group (wherein the substituent is a phenyl group, a phenyl group substituted with one or more groups selected from the substituent group C, a furyl group, a methyl-substituted furyl group, a thienyl group or a methyl-substituted thienyl group. A), a diphenylamino group or a diphenylamino group substituted with one or more groups selected from Substituent Group C, and a pharmaceutically acceptable salt thereof. [Substituent group C] C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halogen atom, mono or di (C ₁ -C ₄
Alkyl) amino group and hydroxyl group. 13. A steroid derivative or a compound thereof according to claim 1, wherein R ¹ and R ² are the same or different and each is a benzyl group substituted with one or more groups selected from the substituent group C. A pharmacologically acceptable salt of. [Substituent group C] C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halogen atom, mono or di (C ₁ -C ₄
Alkyl) amino group and hydroxyl group. 14. The benzyl group or substituted benzyl group according to claim 1, wherein R ¹ and R ² are the same or different (the substituent on the ring is a methyl group, a methoxy group, a fluorine atom or a chlorine atom). , A dimethylamino group or a hydroxyl group.)
And a pharmaceutically acceptable salt thereof. 15. The C according to claim 1, wherein R ¹ is a hydrogen atom and R ² is substituted with 1 or 2 substituents.
₁ -C ₄ alkyl group (said substituent is a phenyl group, a phenyl group substituted by one or more groups selected from Substituent group C, furyl group or thienyl group.), A diphenylamino group or a substituent A steroid derivative and a pharmaceutically acceptable salt thereof, which is a diphenylamino group substituted with one or more groups selected from Group C. [Substituent group C] C ₁ -C ₄ alkyl group, C ₁ -C ₄ alkoxy group, halogen atom, mono or di (C ₁ -C ₄
Alkyl) amino group and hydroxyl group. 16. The C according to claim 1, wherein R ¹ is a hydrogen atom and R ² is substituted with 1 to 2 substituents.
₁ -C ₄ alkyl group (said substituent is a phenyl group, a phenyl group substituted by one or more groups selected from Substituent group D, furyl group or thienyl group.), A diphenylamino group or a substituent A steroid derivative and a pharmacologically acceptable salt thereof, which is a diphenylamino group substituted with one or more groups selected from Group D. [Substituent Group D] Methyl group, methoxy group, fluorine atom, chlorine atom, dimethylamino group, hydroxyl group and acetylamino group. 17. The C according to claim 1, wherein R ¹ is a hydrogen atom and R ² is substituted with 1 to 2 substituents.
_1- C ₃ alkyl group [the substituent is a phenyl group, a substituted phenyl group (the substituent is a methyl group, a methoxy group,
It is a fluorine atom, a chlorine atom or a hydroxyl group. ), A furyl group or a thienyl group. ] The steroid derivative and those pharmacologically acceptable salt which are these. 18. The method according to claim 1, wherein R ³ is a carboxy group or a protected carboxy group (wherein the protecting group is a C ₁ -C ₆ alkyl group; halogeno “C”).
₁ -C ₆ alkyl group ";hydroxy" C ₁ -C ₆ alkyl group ";" alkoxy "-" C ₁ -C ₆ alkyl group "or" alkoxy "-" alkoxy "-" C ₁ -C ₆
Alkyl group "; phenacyl group; (" alkoxy "carbonyl) -" C ₁ -C ₆ alkyl group ", cyano," C ₁ -C
₆ alkyl group ";(" C ₁ -C ₆ alkyl "thio) methyl group;" aryl "thiomethyl group; optionally substituted with halogen (" C ₁ -C ₆ alkyl "sulfonyl)-" C ₁
-C ₆ alkyl group ";(" aryl "sulfonyl) -
"C ₁ -C ₆ alkyl group";"aryl" - "C ₁ -C
“ ₆ alkyl group”; “aryl group”; formula —SiR ^a R ^b R
a group having ^c (in the formula, R ^a , R ^b and R ^c are the same or different and represent a “C ₁ -C ₆ alkyl group” or an “aryl group”, provided that all are “aryl groups”; Unless otherwise indicated); (C ₁ -C ₆ alkanoyloxy)-“C
₁ -C ₆ alkyl group "; (C ₆ -C ₇ cycloalkanoyloxy) -" C ₁ -C ₆ alkyl group ";(" alkoxy "carbonyloxy) -" C ₁ -C ₆ alkyl group ";
(C ₅ -C ₆ cycloalkyl alkoxycarbonyloxy) -
"C ₁ -C ₆ alkyl group"; [5 "aryl" 2-
Oxo-1,3-dioxolen-4-yl] methyl group;
[5- "C ₁ -C ₆ alkyl" -2-oxo-1,3-
A steroid derivative and a pharmacologically acceptable salt thereof, which is a dioxolen-4-yl] methyl group or a phthalidyl group. 19. A steroid derivative or a pharmacologically acceptable salt thereof according to claim 1, wherein R ³ is a carboxy group, a methoxycarbonyl group or an ethoxycarbonyl group. 20. A steroid derivative and a pharmacologically acceptable salt thereof according to claim 1, wherein Z is an oxo group. 21. A steroid derivative and a pharmacologically acceptable salt thereof according to claim 1, wherein Z is an α-hydrogen atom and a β-hydroxyl group. 22. The steroid derivative and the pharmacologically acceptable thereof according to claim 1, wherein Z is α-hydrogen atom and β- (C ₁ -C ₅ aliphatic acyloxy group). Salt. 23. A testosterone 5α-reductase inhibitor containing the steroid derivative according to claim 1 or a pharmacologically acceptable salt thereof selected from claims 1 to 22. 24. A prophylactic and / or therapeutic agent for benign prostatic hyperplasia, which comprises the steroid derivative or the pharmaceutically acceptable salt thereof described in any one of claims 1 to 22. 25. A prophylactic or / and therapeutic agent for prostate cancer, which comprises the steroid derivative or the pharmaceutically acceptable salt thereof described in any one of claims 1 to 22.