WO1999064408A1

WO1999064408A1 - Prodrugs of estrogen antagonist

Info

Publication number: WO1999064408A1
Application number: PCT/JP1999/003117
Authority: WO
Inventors: Akira Okamachi; Takahiro Hatanaka; Kiyohiko Sugano; Yoshiki Hayashi
Original assignee: C & C Research Laboratories
Priority date: 1998-06-12
Filing date: 1999-06-11
Publication date: 1999-12-16
Also published as: WO1999064408A8; KR20010052673A; AU4165299A

Abstract

Compounds represented by general formula (I) or pharmaceutically acceptable salts thereof wherein ------ represents a single or double bond; R1 and R2 are each independently hydrogen, lower alkyl, aralkyl, alkenyl, alkynyl, acyl or the like, provided the cases wherein both R1 and R2 are simultaneously hydrogen or lower alkyl are excepted; R3 is hydrogen or methyl; X is O or S; and A is a group represented by, e.g., the general formula (a): -(CH2)m-(NH)nS(O)p(NH)q-R4 wherein R4 is alkyl or haloalkyl; m is an integer of 3 to 10; n is 0 or 1; p is 0, 1 or 2; q is 0 or 1; and r is an integer of 1 to 6.

Description

Specification

Prodrugs for estrogen angiogonist

The present invention relates to a compound of the general formula (I) having an excellent estrogen-pure anti-gonist effect which can be orally administered.

(Where

Represents a single bond or a double bond. And R ₂ are the same or different and are each a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, or an alkenyl which may have a substituent Represents an alkynyl group which may have a substituent, an acyl group which may have a substituent, an amide group which may have a substituent, a phosphate group, or a saccharide linked by a glycosidic bond. However, and R ₂ are not simultaneously hydrogen atoms or simultaneously unsubstituted lower alkyl groups. R ₃ represents a hydrogen atom or a methyl group. X represents 〇 or S. A represents the equations (a), (b) and (c),

■ (CH ₂ ) m— (NH) nS (0) p (NH) q R ₄ (a)

(CH ₂ ) m—— O— (CH ₂ ) r-S (〇) p- R ₄ (b) r— S (0) p-

Here, R ₄ represents an alkyl group or a halogenated alkyl group, m is an integer of 3 to 10, n is 0 or 1, p is 0, 1 or 2, and Q is 0 or 1. Yes, r Is an integer from 1 to 6. ) Or a pharmaceutically acceptable salt thereof. Background art

In the treatment of various diseases caused by steroid hormones, it is very important to inhibit the function of the hormone itself, and several methods have been tried so far. One approach is to reduce the amount of steroids that work at the receptor site, and another is to inhibit the receptor that transmits sex hormones. For example, administration of an aroma inhibitor can reduce the amount of estrogen in the body below the level required to induce hormonal activity at receptor. However, it is difficult to sufficiently suppress the effects caused by estrogen with this method. Therefore, steroid hormone antagonists are attracting attention as an excellent treatment. However, even in the method using an antagonist, in many cases, the gonist is weak in itself but shows activity as an agonist, and there is a problem that the function of the receptor cannot be completely inhibited. Therefore, there is a demand for the development of angiogonist (herein referred to as "pure antagonist") that can completely inhibit the action of estrogen receptor. Numerous antiestrogens have already been developed, for example, US Patents 4,760,061,4,732,912,4,904,661 and 5,395,842, International Patent Application Publication W 〇 Various anti-estrogenic agents are disclosed in 96Z22092 and the like. Also, as an estrogen receptor antagonist, evening moxifen is the most widely used estrogen-like effect in some organs (M. Harper and A. Walpole, J. Reprod. Fertil. , 1967, 13, 101). Further, a non-steroidal angonist is disclosed in WO 93/10741 (Endorecherche), in which compounds represented by the following structural formulas are shown as typical compounds, and these compounds are also estrogen receptors. It does not completely hinder one's work.

On the other hand, as a pure antagonist, a compound having a substituent (— (CH ₂ ) ₁₀ CONMe Bu) at the 7-position of estradiol is disclosed in European Patent Application 0 1 3850 4., US Pat. No. 4,659,516. Further, a compound having a substituent (— (CH ₂ ) _g SO (CH ₂ ) ₃ C ₂ F ₅ ) at the 7-position of estradiol is shown in the literature (Wakeling et a Cancer Res., 1991, 51, 3867). Have been. By the way, these compounds are expected to have a considerable effect when administered intravenously or subcutaneously, but their effects are greatly reduced in oral administration compared to intravenous administration or subcutaneous administration. Therefore, considering the convenience of prescribing a drug, it is highly desirable to develop a pure antagonist that shows a sufficient effect by oral administration. Disclosure of the invention

None of the estrogen-pure gonists developed to date have shown sufficient efficacy with oral administration. In view of the above, an object of the present invention is to provide a compound having a strong estrogen-pure anti-gonist effect which can be orally administered and is very useful in a medical setting.

In the present invention, a method has been found in which a compound exhibiting an estrogen-pure gonist action is prodruged to increase absorption from the digestive tract and to lead to a compound exhibiting a sufficiently high effect by oral administration. That is, the present invention relates to a benzopyran derivative represented by the following general formula (I).

(Where

Represents a single bond or a double bond. R and R ₂ are the same or different and each may be a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a group which may have a substituent. Good alkenyl group, alkynyl group which may have a substituent, acyl group which may have a substituent, amide group which may have a substituent, phosphoric acid group, saccharide linked by a glycosidic bond Or a polyethylene glycol bonded by an ester bond, a carbonate bond, a urethane bond, an ether bond, an acetal bond or a thiocarbonate bond, provided that R and R ₂ are simultaneously a hydrogen atom or simultaneously an unsubstituted lower alkyl group. There is no.

R ₃ represents a hydrogen atom or a methyl group. X represents 〇 or S. A represents the equations (a), (b) and (c),

― (CH ₂ ) m― (NH) nS (0) p (NH) q―― R ₄ (a) ― (CH ₂ ) m-O― (CH ₂ ) r― S (0) p― R ₄ ( b)

— (CH ₂ ) m— O ~ ^^ ~ 〇ichi (CH ₂ ) r— S (〇) p— R ₄ (c) where R ₄ represents an alkyl group or a halogenated alkyl group, and m is from 3 10 is an integer, n is 0 or 1, ρ is 0, 1 or 2, Q is 0 or 1, and r is an integer from 1 to 6. ) Or a pharmaceutically acceptable salt thereof.

Unless otherwise specified in the present invention, each term has the following meaning. The term "lower alkyl group" means a linear or branched alkyl group having 1 to 6 carbon atoms, such as a methyl group, an ethyl group, an n_propyl group, an i-propyl group, an n-butyl group, s-butyl group, i-butyl group, t-butyl group, pentyl group, hexyl group and the like.

“Alkenyl group” means a linear or branched unsaturated hydrocarbon having 2 to 9 carbon atoms and having a double bond in a side chain, and includes a vinyl group, an aryl group and an i-propenyl group. , n-butenyl group, i-butenyl group, s-butenyl group, pentenyl group, hexenyl group and the like.

The “alkynyl group” is a linear or branched unsaturated hydrocarbon having 2 to 9 carbon atoms and having a triple bond in a side chain. Examples thereof include an ethynyl group, a propargyl (propynyl) group, and a butynyl group. And the like.

“Aryl group” is a monocyclic or polycyclic monovalent group obtained by removing one hydrogen atom from an aromatic hydrocarbon, such as phenyl, tolyl, xylyl, naphthyl, biphenyl Group, anthryl group, phenanthryl group and the like.

The term "acyl group" refers to a group represented by the general formula RCO (where R represents an arbitrary atom or group), for example, formyl group, acetyl group, propionyl group, butyryl group, isoptyryl group, valeryl group, isovaleryl Group, pivaloyl group, propyl group, lauroyl group, myristoyl group, palmitoyl group, stearoyl group, hydratroboyl group, cyclohexanecarbonyl group, saturated alkylcarbonyl group such as phenylacetyl group, 4-methoxyphenylacetyl group, acryloyl group, propioylyl Group, methacryloyl group, crotonyl group, isocrotonyl group, oleoyl group, elideyl group, at-open boil group, cinnamoyl group, etc., unsaturated alkyl group, benzoyl group, 4-nitrobenzoyl group, 4-nitrobenzoyl group, 4-cyclobenzoyl group, Four Tokishibenzoiru group, naphthoyl group, toluoyl group, 3-furoyl, 2-te Noiru group, Nikochinoiru group, etc. § reel carbonyl group such Isonikochinoiru group.

The “halogen atom” includes a fluorine atom, a chlorine atom, a bromine atom and an iodine atom.

In the definition of the compound of the present invention, the `` lower alkyl group optionally having substituent (s) '' in the definition of and R ₂ means a hydroxyl group, a carboxyl group, an amino group, a sulfonic acid group, a halogen atom, A linear or branched alkyl group having 1 to 6 carbon atoms which may be substituted with a cyano group, a nitro group or the like. In addition to the above examples of the lower alkyl group, for example, a hydroxymethyl group, Hydroxyethyl group, 2,

Examples include a 3-dihydroxypropyl group, a carboxymethyl group, a 2-carboxyethyl group, an aminomethyl group, a 2-aminoethyl group, and a sulfoxymethyl group. In addition, in this specification, "lower" means 1-6 carbon atoms.

The “aralkyl group optionally having substituent (s)” in the definitions of R ₁ and R _{2 is} a group in which the above alkyl group is substituted with an aryl group, and the aryl group and / or the alkyl moiety The substituent may be substituted with one or more of a hydroxyl group, a carboxyl group, an amino group, a sulfonic acid group, a halogen atom, a lower alkyl group, an alkenyl group, a cyano group, a nitro group and the like. For example, benzyl, diphenylmethyl, tritylmethyl, trityl, phenethyl, naphthylmethyl, 4,4'-dimethoxytrityl, 4-carboxybenzyl, 3-carboxybenzyl, 2-carboxybenzyl , 4-carboxyphenethyl, 3-hydroxybenzyl, 2-aminobenzyl, 3,4-dihydroxybenzyl, 4-amino-3-hydroxybenzyl, 4-sulfoxybenzyl and the like. Can be

"Alkenyl group optionally having substituent (s)" in the definition of R ₁ and R ₂ means a substituent such as a hydroxyl group, a carboxyl group, an amino group, a sulfonic acid group, a halogen atom, a cyano group, a nitro group, etc. Means a linear or branched alkenyl group having 2 to 9 carbon atoms, preferably 2 to 6 carbon atoms, which may be substituted. In addition to the examples of the above alkenyl groups, for example, 3-hydroxypropyl-1-propenyl Group, 3-propoxy-2-propenyl group, 3-propoxy-1-methyl-2-propenyl group, 3-carboxy-2-methyl-2-propenyl group, 4-carboxy-1-butenyl group , 4-carboxy-2-butenyl group, 4-carboxy-1 monomethyl-2-butenyl group, 4-carboxy-

3-Methyl_2-butenyl group, 4-carboxy-1,3-butenyl group, 4-carboxy-1 —methyl-1,3-butenyl group, 3-hydroxy-1-propyl group, 3-hydroxy — 2-Propenyl group, 3-hydroxy-1-methyl-2-propenyl group, 3-hydroxy-2-methyl-2-propenyl group, 4-hydroxy-l-butenyl group, 4-hydroxy — 2-butenyl group, 4-hydroxy-1-methyl-2-butenyl group, 4-hydroxy-3-methyl-2-butenyl group,

4-hydroxy-1, 3-butagenyl group, 4-hydroxy-1-methyl-1,

3-butadienyl group, 2-aminovinyl group, 3-amino-1-propenyl group, 3

—Amino-2-propenyl group, 3-amino-1 monomethyl—2—propenyl group, 3 2-amino-2-propenyl group, 4-amino-1-butenyl group, 4-amino-2-butenyl group, 4-amino-1-methyl-2-butenyl group, 4-amino-3-methyl-2 -Butenyl group, 4-amino-1,3-butenyl group, 4-amino-1-methyl-1,3, -butenyl group, 2-sulfoxyvinyl group, 3-sulfoxy-1-propenyl group, 3-sulfoxy — 2-propenyl group, 3-sulfoxy-1-methyl-2 —propenyl group, 3 —sulfoxy-2-methyl-2 —propanol group, 4-sulfoxy-1-butenyl group, 4-sulfoxy-2 —Butenyl, 4-monosulfoxy— 1-methyl-2-butenyl, 4-sulfoxy-3-methyl-2-butenyl, 4-sulfoxy-1,3 —butenyl, 4-sulfoxy1-methyl — 1, 3 —Butajenyl group And the like.

The `` alkynyl group which may have a substituent '' in the definition of R ₁ and R ₂ is a hydroxyl group, a carbonyl group, an amino group, a sulfonic acid group, a halogen atom, a cyano group, a nitro group, etc. It means a linear or branched alkynyl group having 2 to 9, preferably 2 to 6 carbon atoms which may be substituted. In addition to the above-mentioned alkynyl groups, for example, carboxyl group, 3-carboxy-2 —Propynyl group, 4-butoxyl 1-butynyl group, 4-butyrupoxy—2-butynyl group, 4-butyroloxy—3-butynyl group, 4—butoxyloxy 1 —methyl-2-butynyl group, 4 _carboxy _ 2 —Ethyl-3 —butynyl group, 4-carboxy-1,3-butanedinyl group, 5-carboxy-2,4_pentendinyl group, 3-hydroxy-1 —propynyl group, 3-hydroxy-2 Propynyl group, 4-hydroxy-1 monobutyl group, 4-hydroxy-2-butynyl group, 4-hydroxy-3-butynyl group, 4-hydroxy xy-1-methyl-2-butynyl group, 4-hydroxy-2- Ethyl-3-butynyl group, 4-hydroxy-1,3-butanediynyl group, 5-hydroxy-2,4—pentanedinyl group, aminoethynyl group, 3-amino-1-propynyl group, 3-amino-1-propynyl group, 4 -Amino-1 -butynyl group, 4-amino-1 -butynyl group, 4-amino-3 -butynyl group, 4-amino-1 -methyl-2-butynyl group, 4-amino-2-ethyl-3-butynyl group , 4-amino-1,3-butanediynyl group, 5-amino-2,4-pentanedinyl group, sulfoxethinyl group, 3-sulfoxy-1-propynyl group, 3-sulfoxy-2-pro Group, 4-sulfoxy-1-butynyl, 4-sulfoxy-2-butynyl, 4-sulfoxy-13-butynyl, 4-sulfoxy-1-methyl-2-butynyl, 4-sulfoxy-2-ethyl-3-butynyl, 4-Sulfoxy-1,3-butanedinyl group, 5-sulfoxy-2,4-pentendinyl group and the like.

And `` optionally substituted acyl group '' in the definition of R ₂ include a hydroxyl group, a carboxyl group, an amino group, a sulfonic acid group, a halogen atom, a cyano group, a nitro group, etc. And is preferably a group of CO--Y (where Y is a lower alkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, An aralkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group, an alkenyl group optionally having a hydroxyl group, a carboxyl group, an amino group or an sulfonic acid group, and a hydroxyl group as a substituent Alternatively, an alcohol which may have a carboxyl group, an amino group, or a sulfonic acid group Which represents a quinyl group). Specifically, in addition to the above-mentioned examples of the acyl group, for example, a hydroxymethylcarbonyl group, a 2-hydroxyethylcarbonyl group, a carboxymethylcarbonyl group, a 2-hydroxypropyloxycarbonyl group, an aminomethylcarbonyl group, 2,3 —Dihydroxypropylcarbonyl group, sulfoxymethylcarbonyl group and the like.

The `` optionally substituted amide group '' in the definition of R ₁ and R ₂ is a hydroxyl group, a carboxyl group, an amino group, a sulfonic acid group, a halogen atom, a cyano group, a nitro group, etc. Means an amide group which may be substituted, wherein the amide group is one of the groups CONR ₅ , R ₆ , (where R ₅ and R ₆ are the same or different and each represents a hydrogen atom, an alkyl group, an aralkyl group; Alkenyl group or alkynyl group). Specifically, a carbamoyl group, an N-methylamide group, an N-ethylamide group, an N-hydroxymethylamide group, an N-hydroxypropylamide group, an N-2-hydroxypropylamide group, an N-1-carboxy group And an ethylamido group.

And the "conjugated saccharide by glycosidic bonds" in the definitions of R _2, glucose linked by α or / 3-glycosidic linkages, galacto Ichisu, Ribot And sugars such as fructose.

And in the definition of R ₂ the term "ester bond, carbonate bond, urethane binding, ether bond, polyethylene glycol attached by Asetaru bond or Chio carbonate bond", molecular weight 2 0 0-5 0 0 0 0, preferably 2 It means a group in which polyethylene glycol of 5,000 to 500 is bonded by an ester bond, a carbonate bond, a urethane bond, an ether bond, an acetal bond or a thiocarbonate bond.

The term "a lower alkyl group optionally having a hydroxyl group or a carboxyl group or an amino group or a sulfonic acid group as a substituent" in the definition of R ₁ and R ₂ means one or more hydroxyl groups or carboxyl groups as a substituent. Alternatively, it is a straight-chain or branched lower alkyl group having 1 to 6 carbon atoms which may have an amino group or a sulfonic acid group. Lower alkyl group "which may be mentioned.

R, and "hydroxyl group or a carboxyl Motoa Rui substituents are Amino group or substituted lower Ararukiru group optionally having a sulfonic acid group" in the definition of R ₂ and one or more hydroxyl groups or force Rupokishiru as a substituent And an aralkyl group optionally having an amino group or a sulfonic acid group, and specific examples include the examples shown in the above-mentioned "aralkyl group optionally having a substituent". .

In the definition of R ₁ and R ₂ , “an alkenyl group optionally having a hydroxyl group, a carboxyl group, or an amino group or a sulfonic acid group as a substituent” means one or more hydroxyl groups or alkoxyl groups as a substituent. Alternatively, it is a linear or branched alkenyl group having 2 to 9, preferably 2 to 6 carbon atoms which may have an amino group or a sulfonic acid group. Alkenyl group which may have a group ".

In the definition of R ₁ and R ₂ , “an alkynyl group optionally having a hydroxyl group, a carboxyl group, or an amino group or a sulfonic acid group as a substituent” means one or more hydroxyl groups or alkoxyl groups as a substituent. Alternatively, it is a linear or branched alkynyl group having 2 to 9 carbon atoms, preferably 2 to 6 carbon atoms, which may have an amino group or a sulfonic acid group. Has a group Alkynyl group which may be mentioned ".

The “alkyl group” for R ₄ is an alkyl group having 1 to 9 carbon atoms, preferably 3 to 6 carbon atoms, particularly preferably 5 carbon atoms, and specifically includes a pentyl group and the like.

The “halogenated alkyl group” for R ₄ is an alkyl group substituted with one or more halogen atoms, and specific examples include 4, 4, 5, 5, 5-pentenefluoropentyl group and the like. Can be

The compound represented by the general formula (I) of the present invention can be converted to a pharmaceutically acceptable base addition salt by treating with a base, if necessary. Examples of such a salt include a sodium salt, a potassium salt, a calcium salt, a magnesium salt, a cerium salt, a samarium salt, a tin salt, a zinc salt and the like, and preferably a sodium salt and the like.

Furthermore, the compound represented by the general formula (I) or a salt thereof according to the present invention has an asymmetric carbon in the molecule, and there are stereoisomers having an R configuration and an S configuration, respectively. Alternatively, any of these compounds in any proportions are encompassed by the present invention. In the compound of the present invention represented by the general formula (I), A is

-(CH ₂ ) „-(title) _n S (〇) p (NH) _q -R ₄ (a) is preferable, and among them, a compound in which m is from 8 to 10, particularly preferably 9; Compounds in which p is 1 or 2, particularly preferably 1, and compounds in which R ₃ is a methyl group are particularly preferred compounds.

As representative compounds of the present invention, for example, the compounds described in Table 1 can be exemplified, but the present invention is not limited to these compounds.

1

Table 1 (continued)

1 —60 S 1 — CH ₂ CH ₂ NMe ₂ — CH ₂ CH ₂ Ne ₂

1 —61 〇 1 H — CH ₂ CH ₂ NMe ₂

1 —62 S 1 H — CH ₂ CH ₂ NMe ₂

1 —63 〇 1 — CH ₂ CH ₂ NMe ₂ H

1 —64 S 1 — CH ₂ CH ₂ Ne ₂ H

1 —65 〇 1 H -CONH (CH ₂ ) ₂ C0 ₂ H

1 —66 S 1 H -CONH (CH2) ₂ C0 ₂ H

1 —67 〇 1 -CONH (CH ₂ ) 2C0 ₂ HH

1 —68 S 1 -CONH (CH2) 2C0 ₂ HH

BEST MODE FOR CARRYING OUT THE INVENTION

The benzopyran derivative represented by the general formula (I) can be produced, for example, according to the method of the following reaction formula 1 and reaction formula 5.

(T

.lI € 0 / 66dT / lDd 80Ϊ 9/66 ΟΛ \ (Reaction formula 2)

One z c "

o ェ

one

〇

In the chemical formulas described in the above production method, X represents 〇 or S. (Reaction formula 3)

In the chemical formulas described in the above production methods, and R ₂ have the same meanings as described above, that is, R and R ₂ are the same or different and are a hydrogen atom, a hydroxyl group or a carboxyl group as a substituent, an amino group or A lower alkyl group optionally having a sulfonic acid group, a hydroxyl group, a carboxyl group, an amino group or an aralkyl group optionally having a sulfonic acid group as a substituent, a hydroxyl group, a carboxyl group, an amino group, or a sulfone as a substituent; An alkenyl group which may have an acid group, an alkynyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, (where R and R ₂ are hydrogen atoms at the same time, Never). R ₇ and R ₈ are a hydroxyl group protected by a protecting group, a carboxyl group, an amino group or a lower alkyl group which may have a sulfonic acid group as a substituent, a hydroxyl group protected by a protecting group, a carboxyl group or An aralkyl group optionally having an amino group or a sulfonic acid group as a substituent, a hydroxyl group or a carboxyl group protected by a protecting group, an alkenyl group optionally having an amino group or a sulfonic acid group as a substituent Alternatively, it represents an alkynyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group protected by a protecting group, or a hydrogen atom. The above-mentioned production method includes a deprotecting group and an operation of separation and purification as necessary.

1 f

₃ C ₂ F ₅

R _Y C0 ₂ H ', HATU, iPr _£ NB

IV 111

In the chemical formulas described in the above production method, and R ₂ have the same meanings as described above, that is, R 1 and R ₂ are the same or different and each represents a hydrogen atom, one CO—Y (Y is a hydroxyl group as a substituent. Or a lower alkyl group optionally having a carboxyl group, an amino group or a sulfonic acid group, a hydroxyl group as a substituent, or an aralkyl group optionally having a carboxyl group, an amino group or a sulfonic acid group, An alkenyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, and a group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent Rukiel group) (however, R, and R ₂ are not simultaneously hydrogen atoms). R ₉ is a hydroxyl group protected by a protecting group or a lower alkyl group which may have an amino group or an amino group or a sulfonic acid group as a substituent; a hydroxyl group or a carboxyl group protected by a protecting group as a substituent Or an aralkyl group which may have an amino group or a sulfonic acid group, a hydroxyl group or a hydroxyl group protected by a protecting group as a substituent, or an alkenyl group which may have an amino group or a sulfonic acid group Alternatively, it represents an alkynyl group optionally having a hydroxyl group, a propyloxyl group, an amino group or a sulfonic acid group protected by a protecting group as a substituent. The above-mentioned production method includes a deprotecting group and an operation of separation and purification as necessary.

₃ C ₂ F ₅

III

IV

In the chemical formulas described in the above process, R 1 and R ₂ have the same meanings as described above, that is, R 1 and R ₂ are the same or different and each represents a hydrogen atom, one CO-NR ₅ R ₆ (R ₅ and R ₆ are independently a hydrogen atom or a lower alkyl group which may have a carboxyl group, an amino group or a sulfonic acid group as a substituent; a hydroxyl group, a hydroxyl group or an amino group as a substituent. Or an aralkyl group optionally having a sulfonic acid group, a hydroxyl group or an alkenyl group optionally having an amino group or a sulfonic acid group as a substituent, or a hydroxyl group or an alkoxy group optionally having a sulfonic acid group group or an amino group § Rui alkynyl which may have a sulfonic acid group) (wherein, R ,, R ₂ is a hydrogen atom at the same time Representing a it is not) and. R _1Q and R _n are a hydroxyl group protected by a protecting group, a carboxyl group, an amino group or a lower alkyl group which may have a sulfonic acid group as a substituent; a hydroxyl group protected by a protecting group; It may have a xyl group, an amino group or a sulfonic acid group as a substituent, and may have a aralkyl group, a hydroxyl group protected by a protecting group, a hydroxyl group, an amino group or a sulfonic acid group as a substituent. An alkenyl group or a alkenyl group which may have a hydroxyl group protected by a protecting group, a hydroxyl group, an amino group or a sulfonic acid group as a substituent, a hydrogen atom (provided that R ₁₀ , R R Are not simultaneously hydrogen atoms).

In the step represented by Reaction Scheme 3, the metal salt of compound (IV) obtained by mixing compound (IV) and a base in an inert solvent is reacted with compound (V) in an inert solvent. This is achieved by:

The inert solvent used is not particularly limited as long as it does not participate in the reaction.Examples include: ether, tetrahydrofuran, dioxane, dimethoxyethane, benzene, toluene, xylene, quinoline, benzene, acetonitrile, and dicyclohexane. It can be chloromethane, chloroform, carbon tetrachloride, cyclohexane, dimethylsulfoxide, dimethylacetamide, dimethylimidazolidinone, dimethylformamide, N-methylpyrrolidone, ethyl acetate, preferably ether, tetraethyl Ethers such as lahydrofuran and dioxane, more preferably tetrahydrofuran. The bases used are metal alkoxides such as sodium alkoxide, potassium hydroxide, metal hydrides such as sodium hydride, potassium hydride, calcium hydride, methyllithium, ethyllithium, n-butyllithium. , Lithium bis (trimethylsilyl) amide, sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, metal amides such as lithium diisopropylamide, and preferably hydrogen. Sodium chloride. The reaction temperature of the reaction of the compound (IV) with the base and the reaction of the metal salt of the compound (IV) with the compound (V) are usually from 18 ° C. to 50 ° C., preferably 10 ° C. C to 30 ° C. The reaction time varies depending on the reaction temperature, but is usually 1 hour to 100 hours (preferably 1 hour to 20 hours) for both reactions.

The step represented by Reaction Scheme 4 is a reaction for condensing compound (IV) with compound (VI) in an inert solvent. This reaction is performed by an acid condensation method, an active ester method, or a condensation method.

The acid condensation method is achieved by reacting compound (IV) with compound (VI) in the presence of an acid. The acid used is usually used as an acid and is not particularly limited as long as it does not inhibit the reaction. Preferably, an inorganic acid such as hydrochloric acid, sulfuric acid, phosphoric acid, or hydrobromic acid is used. And particularly preferably sulfuric acid. The reaction temperature is generally 0 ° C. to 100 ° C., preferably 50 ° C. to 100 ° C. The reaction time varies depending on the reaction temperature and the like, but is usually from 10 minutes to 48 hours, preferably from 5 hours to 48 hours.

In the active esterification method, the compound (VI) is converted into an active esterification agent (for example, N-hydroxysuccinimide, N-hydroxysuccinimide, N-hydroxysuccinimide, N-hydroxysuccinimide, N-hydroxysuccinimide). —An N-hydroxy compound such as hydroxybenzotriazole) to produce an active ester, and reacting this active ester with compound (IV). The reaction for producing the active ester is preferably carried out in an inert solvent, and the inert solvent used is, for example, an ether-based solvent such as ether, tetrahydrofuran, dioxane, dimethoxyethane. Halogens such as dichloromethane, chloroform, carbon tetrachloride It can be a solvent, dimethylformamide, ethyl acetate, acetonitrile and the like, preferably dichloromethane, acetonitrile, ethyl acetate and the like. The reaction temperature varies depending on the type of solvent such as, in the active esterification reaction, usually an 20 ° C to 50 ° C (The good suitable one 10 ^D C to 30 ° C), an active ester compound In the reaction with the compound (IV), the temperature is -20 ° C to 50 ° C (preferably -10 ° C to 30 ° C). The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 15 hours) for both reactions.

The condensation method is carried out by reacting compound (IV) with compound (IV) in the presence of a condensing agent [for example, dicyclohexylcarbodiimide, carbonyldiimidazole, 11- (N, N-dimethylaminopropyl) -13-ethylcarbodiimide hydrochloride, etc.] This is carried out by directly reacting (VI). This reaction is carried out in the same manner as the above-mentioned reaction for producing an active ester.

In the step represented by the reaction formula 5, the compound (IV) is reacted with the compound (IV) in an inert solvent with a 4-nitrophenyl 1-chloroform (4-nitrophenyl) 1 ch 1 oroformate. And then reacting with the compound (VII). The reaction of the compound (IV) with 412 trifluorochloroformate is preferably carried out in an inert solvent, and the inert solvent used is, for example, ether, tetrahydrofuran, dioxane, dimethoxetane or the like. Ether solvents, dichloromethane, chloroform, halogen solvents such as carbon tetrachloride, dimethylformamide, ethyl acetate, acetonitrile and the like, preferably dichloromethane, acetonitrile, ethyl acetate and the like. The reaction temperature varies depending on the type of the solvent and the like, but is usually from 20 ° C to 50 ° C (preferably from 10 ° C to 30 ° C). The reaction temperature of the reaction between the carbonate of compound (IV) and compound (VII) differs depending on the type of the solvent and the like as in the previous reaction. To 50 ° C (preferably 10 ° C to 30 ° C). The reaction time varies depending on the reaction temperature and the like, but is usually 15 minutes to 24 hours (preferably 30 minutes to 15 hours) for both reactions. Example Hereinafter, the present invention will be described specifically with reference to Examples and Reference Examples, but the present invention is not limited thereto. Example 1

(3RS, 4RS)-(7-carboxymethyloxy) — 3- (4-carboxymethyloxyphenyl) — 3-methyl-4 _ {9-(4, 4, 5, 5, 5—pen

■ Tafluolopentyl) sulfiernonyl} Thiochroman (Compounds 1-2)

(3 RS, 4RS) —7-Hydroxy-3- (4 _carboxymethyloxyphenyl) — 3-Methyl-4_ {9-(4,4,5,5,5_pentafluorofluoropentyl) sulfinylnonyl} Thiochroman (Compounds 1-4)

(3 RS, 4RS)-(7-potoxymethyloxy) — 3- (4-hydroxyphenyl) _ 3_methyl— 4— {9-(4, 4, 5, 5, 5—pennofluor) Pentyl) sulfiernonyl} thiochroman (compounds 1-6)

(3RS, 4RS)-(7-Hydroxy-1- (4-hydroxyphenyl) —3-methyl-4-({9- (4,

4, 5, 5, 5—pentafluoropentyl) sulfinylnonyl

55.6 mg was dissolved in lm1 of DMF, 8 mg of 60% NaH was added under ice cooling, and the mixture was stirred at room temperature for 30 minutes. Subsequently, under ice-cooling, 0.012 ml of ethyl bromoacetate was added to the reaction solution, and the mixture was stirred at room temperature for another 17 hours. An aqueous solution of citrate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous citric acid, aqueous sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue is subjected to silica gel column chromatography (elution solvent: chloroform Z methanol)

= 20/1), and the solvent was distilled off under reduced pressure. The obtained crude product was dissolved in 2 ml of ethanol, 0.2 ml of 1M aqueous solution of Na〇H was added, and the mixture was stirred at room temperature for 30 minutes. The reaction solution was acidified with hydrochloric acid and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The resulting et the residue, Asetonitoriru - H ₂ 0 was separated and purified by reverse-phase H PLC of (0. 1% TFA-containing) system, and lyophilized, as a colorless oil, (3RS, 4RS) i (7- 1- (4-carboxymethyloxyphenyl) -3 —Methyl— 4- {9- (4,4,5,5,5_pentyfluoropentyl) sulfinylnonyl} thiochroman (compounds 1-2) 22.8 mg and

(3 RS, 4 RS) — 7-Hydroxy-3- (4-Carboxymethyloxyphenyl) -1-Methyl_4- {9- (4,4,5,5,5_Pentatefluoropentyl) Sulfinyl Nonyl} Thiochroman (Compounds 1-4)

(3 RS, 4RS) ― (7 carboxymethyloxy) — 3- (4-hydroxyphenyl) -1-3-methyl-4- {9-(4, 4, 5, 5, 5-pentafluorofluoropentyl) ) 23.0 mg of a mixture of sulfinylnonyl} thiochroman (compounds 1-6) was obtained.

(3 RS, 4 RS) — (7-potoxymethyloxy) — 3— (4-potoxymethyloxyphenyl) — 3-methyl-4 — {9-(4, 4, 5, 5 , 5-pentafluoropentyl) sulfinyl nonyl} thiochroman; 'H-NMR (270 MHz, CDC 13 + CD3OD): δ 7.31 (d, J = 8.9 Hz, 2 H), 6. 94 (d, J = 8.3Hz, 1H), 6.93 (d, J = 8.9Hz, 2H), 6.74 (d, J = 2.6Hz, 1H), 6. 6 1 (dd, 1 = 2.6 Hz, 8.3 Hz, 1 H), 4.63 (s, 2 H), 4.58 (s, 2H), 3.63 (d, J = 11.5Hz, 1H), 2.98 (d, J = ll.5Hz, 1H), 2.87-2.66 (m, 5H), 2.36-1. 9 9 (m, 4H), 1.80—1.62 (m, 2H), 1.48-0.95 (m, 17H); MS (ESI) m / z = 7 2 3 6 (M + H) ⁺ : MS / MS: 70.5.3, 67.7.3.

(3 RS, 4RS) _ 7—Hydroxy-1 3— (4

Nil) — 3-methyl- 4— {9-(4, 4, 5,

Le) sulfinylnonyl}

(3 RS, 4RS) — (7-carboxymethyloxy) — 3— (4-hydroxyphenyl) 1-3 _methyl-14 4-1 {9-(4, 4, 5, 5, 5, 5—pentafluorofluoropentyl) ) Sulfinyl nonyl} a mixture of thiochromans; '2-NMR (270MHMH, CDC 13 + CD3OD): δ 7.33-6.50 (m, 7H), 4.63

-4.58 (s, 2H), 3.65 (d, J = 11.5 Hz, 1H), 2.97

(d, J = 11.5Hz, 1H), 2.82-2.64 (m, 5H), 2.36 -1.99 (m, 4H), 1.78-1.65 (m, 2H), 1.46—1.000 (m, 17H); MS (ESI) m / z -6 65.9 (M + H) ÷: MS / MS:

647. 3, 5 7 1.2. Example 2

(3 RS, 4RS)--(7-Dalisiloxy) -1-3- (4-Glysiloxyphenyl)-3-methyl-.4-1 (9- • (4,4,5,5,5-Pentafluorene) Le) Sulfinyl noni: le}-2,3-dihydro-4H-benzopyran (Compound 1

7)

(3 RS, 4RS) _ 7-Hydroxy-3- (4-Glycyloxyphenyl)-3 _Methyl-4-1 {9-1 (4,4,5,5,5 _Pentate fluoropentyl) sulfinylnonyl} -2,3-dihydro-4H-benzopyran (compounds 11-9) (3 RS, 4RS) 1 (7-glycyroxy) — 3— (4-hydroxyphenyl) 1 3—methyl 1-4 1 {9-( 4,4,5,5,5-pentylfluoropentyl) sulfinirnonyl}-2,3-dihydro_4H-benzopyran (compound 111) synthesized according to reaction formula 2 (X = 0) ( 3 RS, 4RS) — 7-Hydroxy-3- (4-Hydroxyphenyl) -1-Methyl-4- {9- (4,4,5,5,5-Pentylfluoropentyl) sulfinylnonyl}-2,3 —Dihydro— 4H —Benzopyran 46.6 mg was dissolved in 0.5 ml of DMF, and under ice-cooling, 151 mg of EDC, 19 mg of DMAP and 138 mg of B0c—G1y were added. Overnight at room temperature It was. An aqueous solution of citrate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous citric acid, aqueous sodium bicarbonate, and saturated saline, and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 72 mg of an oily crude product. In the above, DMF means N, N-dimethylformamide, £ 0 (: means 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride, and DMAP means 4-dimethylaminopyridine.

47.3 mg of crude B0c-G1y form was added with 1 ml of 95% TFAZt ^ O and stirred for 30 minutes under ice-cooling. The solvent was distilled off under reduced pressure, the obtained residue, Asetonitoriru - H ₂ 0 was separated and purified by reverse-phase H PLC of (0. 1% TFA-containing) system, and lyophilized, As a colorless oil, (3RS, 4RS)-(7-glycyloxy) —3— (4-glycyloxyphenyl) —3-methyl—4-1 {9-(4, 4, 5, 5, 5, 5- ぺ) Fluorinopenyl) sulfinylnonyl} -2,3-Dihydro-4H-benzopyran (TFA salt) (Compound 1-7) 26.8 mg and (3RS, 4RS) -7-hydroxy-3- (4-glycylicoxyf Enyl) —3-Methyl-4-— {9-I (4,4,5,5,5-pentylfluoropentyl) sulfinylnonyl)-1,2,3-Dihydro_4H-benzopyran (TFA salt) (Compounds 1-9 ) And (3RS, 4RS) 1- (7-glycyroxy) —3- (4-hydroxyphenyl) 1-3-methyl 4- 1 9- (4,4,5,5,5-pentylfluoropentyl) sulfinyl nonyl 8.4 mg of a mixture of -2,3-dihydro-4H-benzopyran (TFA salt) (compound 111) was obtained.

(3RS, 4RS)-(7-Glycyloxy) —3- (4-Glycyloxyphenyl) -3-methyl-4— {9- (4,4,5,5,5-Pentate fluoropentyl) sulfinylnonyl } -2,3-dihydro-1 4H-benzopyran; ¹ H—NM R (270 MHz, CD ₃ OD): δ 7.35 (d, J = 8.7 Hz, 2 H), 7.23 (d, J = 8.7 Hz, 2 H), 7.16 (d, J = 8.3 Hz, 1 H), 6.72-6.64 (m, 2 H), 4.65 (d, J = 1 OH z, 1 H), 4.39 (d, J = 10 Hz, 1H), 4.16 (s, 2 H), 4.12 (s, 2 H), 2.95-2.73 (m, 5H), 2.46-2.26 (m, 2H), 2.15-2.02 (m, 2H), 1.79-1.68 (m, 2H), 1.48-1.06 (m MS (ES I) m / z- 705.3 (M + H) ⁺ : MS / MS: 648. 2, 591.2.

(3RS, 4RS) 1 7-Hydroxy-3- (4 -Glycyloxyphenyl) 1

3-Methyl-4-1 {9- (4,4,5,5,5-Pentafluoropentyl) sulfinylnonyl} -1 2,3-Dihydro-4H-benzopyran and (3RS, 4RS) -1 (7-Glysiloxy) -1 3- (4-hydroxyphenyl) -3-methyl-4

― {9-(4, 4, 5, 5, 5—pennofluoropentyl) sulfinylnonyl}

Mixture of -2,3-dihydro-1 4H-benzopyran; ¹ H-NMR (270MHζ,

_{_{CDC 1 3 + CD 3 OD)}} : δ 7. 40 - 6. 28 (m, 7 H), 4. 60- 4. 5 3 (m, 1 H), 4.30-4.11 (m, 3 H), 2.94—2.70 (m, 5H), 2.45-1.94 (m, 3H) 4H), 1.77—1.60 (m, 2H), 1.45-1.00 (m, 17H); MS (ESI) mZ z = 648.3 (M + H ) +: MS No. MS: 59.1.2. Example 3

(3 RS, 4RS)-7-(a- D-ricinyloxy) 1 3-(4-(Hi-I- D- ricinyl) oxyphenyl)-3-methyl- 4 _ {9-(4, 4, 5, 5, 5 -Pennofluoropentyl) sulfinylnonyl} thiochroman (Compounds 1-114) (3 RS, 4 RS) synthesized according to Reaction Schemes 1 and 2 (X = S)-7-hydroxy-3- (4-hydroxyphenyl)- 3-Methyl-4- (9- (4,4,5,5,5-pentyfluoropentyl) sulfinylnonyl) Thiochroman 59.5 mg was dissolved in 1.5 ml of DMF and 373 mg under ice-cooling HATU, 0.239m1 diisopropylethylamine and Boc_D_Lys (Boc) (5.18mg Boc—D—Lys (Boc) DCHA (Without salt) and stirred overnight at room temperature. In the above, HA TU is 1- (7-azabenzotriazole_1-yl) _1,1,3,3-tetramethylperonium hexafluorophosphate, and DCHA is dicyclohexane. Hexylamine respectively.

An aqueous solution of citrate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous citric acid, aqueous sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by silica gel column chromatography (elution solvent: n-hexane / ethyl acetate = 1Z2), and the solvent was distilled off under reduced pressure.

To the resulting crude product, a 9 5% TF AZH ₂ 〇 of 2. 5 m 1 was added, under ice-cooling, followed by stirring for 3 0 minutes. The solvent was distilled off under reduced pressure, the obtained residue, Asetonitoriru one H ₂ 0 (0.

Separation and purification by reversed-phase HP LC containing 1% TFA) and lyophilization give a colorless oil as a colorless oil (3RS, 4RS) — 7— (Hiichi D-ricinyloxy) 1-3_ (4— (a

— D-lysinyl) oxyphenyl) — 3-methyl— 4-1 {9-(4, 4, 5, 5, 5)

5-Pentate fluoropentyl) sulfinylnonyl} thiochroman (4TFA salt) (Compound 1-114) 58.3 mg was obtained.

(3 RS, 4 RS)-7-(α- D-ricinyloxy) — 3— (4— (a-D-ricinyl) oxyphenyl) _ 3 _methyl—4— {9-(4, 4, 5, 5 , 5-pentafluoropentyl) sulfinyl nonyl} Thiochroman: MS (ESI) m / z = 863.5 (M + H) ⁺ : MS / MS: 735.3. Example 4

(3 RS, 4RS) ― (7-Ripoxymethylcarbamoyloxy) — 3 -— (4 Ripoxymethylcarbamoyloxyphenyl) -1-3-methyl-4 _ {9-(4, 4, 5 , 5,5-Pennofluoropentyl) sulfinylnonyl} Thiochroman (Compounds 1-144)

(3 RS, 4 RS)-(7-carboxymethylcarbamoyloxy) — 3- (4-hydroxyphenyl) —3-methyl-4-1 {9-(4, 4, 5, 5, 5_pen Fluoropentyl ) Sulfinyl nonyl} Thiochroman (Compound 1-146) (3RS, 4 RS) _7-hydroxy-3- (4-carboxymethylcarbamoyloxyphenyl) — 3-methyl_4_ {9-(4, 4, 5, 5, 5) —Pentafluoropentyl) sulfinylnonyl} Thiochroman (Compounds 1-148)

(3 RS, 4RS) -7-hydroxy-13- (4-hydroxyphenyl) -13-methyl-4-1 {9- (4,4,5) synthesized according to Reaction Schemes 1 and 2 (X = S) 5,5-Pentayl fluoropentyl) sulfinylnonyl} Thiochroman 59.5 mg is dissolved in 2 ml of methylene chloride, and under ice-cooling, 0.075 ml of disopropylethylamine and 47 mg of p-ditrophenylclo mouth are dissolved. The foam was added and stirred for 40 minutes. To the reaction solution, 164 mg of glycine-t-butyl ester hydrochloride and 0.17 lm 1 of diisopropylethylamine were added, and the mixture was further stirred under ice-cooling for 2 hours. An aqueous solution of citrate was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with aqueous citric acid, aqueous sodium bicarbonate, and saturated saline, dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by silica gel column chromatography (eluent: chloroform / methanol = 20Z1), and the solvent was distilled off under reduced pressure. To the obtained crude product, 2 ml of 95% TFAZH20 was added, and the mixture was stirred for 90 minutes under ice cooling. The solvent was distilled off under reduced pressure, and the obtained residue was separated and purified by reversed phase HPLC using acetonitrile _H ₂ 〇 (containing 0.1% TFA), and lyophilized to give a colorless oil, (3RS, 4RS) — (7_Carboxymethylcarbamoyloxy) —3— (4L-loxymethylcarbamoyloxyphenyl) 1 3-methyl—4 1 {9 1 (4,4,5,5,5—pen Fluoropentyl) sulfinylnonyl} thiochroman (compounds 1-44) 61. Omg and (3RS, 4RS)-(7-carboxymethylcarbamoyloxy) -13- (4-hydroxyphenyl) -13-methyl- 4- {9- (4,4,5,5,5-pentafluorofluoropentyl) sulfinyl nonyl} thiochroman (compounds 1-46) and (3RS, 4RS) — 7-hydroxy-3- (4-carboxymethyl Carbamoyloxyphenyl) — 3—methyl 4-—9— (4, 4, 5, 5, 5, 5—pen Ruoropenchiru) a mixture of sulfinyl nonyl} Chiokuroman (Compound 1-48) 2. give 8 mg.

(3 RS, 4RS)-(7-carboxymethylcarbamoyloxy) —3— (4—carboxymethylcarbamoyloxyphenyl) -1-methyl-4 — {9-(4, 4, 5, 5, 5 —Penfufluoropentyl) sulfinylnonyl} thiochroman: MS (ES I) m / z = 809.5 (M + H) ⁺ : MS / MS: 708.1, 607.3. —Hydroxyphenyl) -3-methyl-4-1- {9- (4,4,5,5,5-pentenefluoropentyl) sulfinylnonyl} thiochroman and

(3 RS, 4 RS) —7-Hydroxy-3- (4-carboxymethylcarbamoyloxyphenyl) —3-methyl-4- {9- (4,4,5,5,5-pentafluoropentyl) sulfinylnonyl} Thiochroman Mix: MS (ES I) m / z = 708.6 (M + H) ⁺ : MS / MS: 607.3.

The following compound of Example 5 was produced in the same manner as in Example 2. Example 5

(3 RS, 4RS) 1 (7-Grosyloxy) —3— (4-Glysiloxyxe) Nyl) 1-3-Methyl-4-1- {9- (4,4,5,5,5-Pentafluoropentyl) sulfinylnonyl} thiochroman (Compounds 1-8)

MS (ESI) m / z = 721.3 (M + H) +: MS / MS: 664.2, 607.2.

In the same manner as in Example 3, the following compounds of Examples 6 to 10 were produced. Example 6

(3 RS, 4 RS)-(7-ricinyloxy) 1 3 _ (4-ricinyloxyphenyl) — 3— chill 4 — {9-(4, 4, 5, 5, 5—pentylfluoropentyl) ) Sulfinyl nonyl} Thiochroman (Compounds 11-14)

MS (ESI) m / z = 83.5 (M + H) ⁺ : MS / MS: 73.5.2. Example 7

(3 RS, 4 RS)-(7-(a—L—daltamyl) oxy) — 3— (4— (a — L_daltamyl) oxyphenyl) — 3—methyl—4— {9 — (4, 4, 5,5,5-Pentate fluoropentyl) sulfinylnonyl} Thiochroman (Compound 1-20)

MS (ESI) m / z = 865.3 (M + H) ⁺ : MS / MS: 847.1, 829.2. Example 8

(3 RS, 4 RS)-(7-(a— L—gluminyl) oxy) 1 3— (4— (—L1gluminyl) oxyphenyl) 1 3—methyl—4— {9-(4 , 4,5,5,5-Pentanylfluoropentyl) sulfinylnonyl} Thiochroman (Compound 1-54)

MS (ESI) m / z = 863.4 (M + H) ⁺ , 885.4 (M + Na) ⁺ : MS / MS: 846.2, 829.4. Example 9 (3 RS 4 RS) 1 (7-N, N-dimethyldaricillo: si) 1 3— (4— N,

N-dimethylglycyl :: xyphenyl) 1 3-methyl-4-{9 4 4 5,

5,5-pentylfluorene copentyl) sulfinylnonyl} thiochroman (compound

1—2 6)

MS (ESI) m / z == 7 77.5 (M + H) +; 7 99.5 (M + Na) ⁺ , 8 22.4 (M + 2Na) ⁺ : MS / MS: 6 0 3.3 Example 10

z Xyphenyl) 1-3-Methyl-4- {9- (4 4,5,5 5-Pennofluoropentyl) sulfinirnonyl} Thiochroman (Compounds 11-28) and (3RS,

4RS)-(71-NN-dimethyldaricyloxy) — 3 _ (4-hydroxyphenyl) — 3-methyl —4- {9- (4 45,55-ntaffluoropentyl) sulfinylnonyl} thiochroman ( Compound (1)

MS (ES I) m / z = 6 92.5 (M + H) + 7 1 3.4 (M + Na) + 7

37.3 (M + 2Na) ⁺ : MS / MS: 603.2

The following compounds of Examples 11 to 14 were produced in the same manner as in Example 4.Example 11

(3 RS, 4RS)-{7-(2-Hydroxyethylcarbamoyl) oxy}-3-{4- (2-Hydroxyethylcarbamoyl) oxyphenyl} 1-3-methyl- 4-1-9-( 4 4, 5 5, 5 _ Pennofluoropentyl) Sulfinyl nonyl} Thiochroman (Compound 1-32)

Ή-NMR (2 7 0MHz, CDC 1 3): δ 7. 3 7 (d, J = 8. 6H z,

2H), 7.13 (d, J = 8.6 Hz, 2H), 7.00-6.966 (m, 2

H), 6.79 (dd, J = 2.0 Hz, 8.2 Hz, 1 H), 6.25-6.

1 1 (m 1 H), 5 5 7—5, 5 1 (m 1 H), 3.79 (q, J = 4.

8Hz 4H), 3.69 (d, J = 11.7 Hz, 1H), 3.47--3.4

2 (m 4H), 2.97 (d, J = 1 1.7 Hz, 1H 2.87-2.6 1 (m, 4H), 2.35-2.10 (m, 4H), 1.80-1.65 (m, 2H), 1.40-0.90 (m, 17 H); MS (ESI) m / z = 781.3 (M + H ", 803.3 (M + Na) ⁺ : MS / MS: 694.1, 607.2. Example 1 2

(3 RS, 4RS) 1 7-Hydroxy-3 _ {4_ (2-Hydroxyethylcarbamoyl) oxyphenyl} 1-3-Methyl-41 {9-(4, 4, 5, 5, 5-Pen Fluoropentyl) sulfinylnonyl} thiochroman (compounds 1-34) and (3RS, 4RS)-{7- (2-hydroxyethylcarbamoyl) oxy} -3- (4-hydroxyphenyl) —3-methyl-4 — {9-(4,4,5,5,5—pentylfluoropentyl) sulfinylnonyl} a mixture of thiochromans (compounds 1-36)

MS (ESI) m / z = 694.4 (M + H), 71.6.4 (M + Na) ⁺ : MS / MS: 56.3, 50.6.4. Example 13

(3 RS, 4 RS)-{7-(2 _ morpholinoethylcarbamoyl) oxy} 1 3-{4- (2 _ morpholinoethylcarbamoyl) oxyphenyl} — 3 -methyl 4-{9-(4 , 4,5,5,5-Pentate fluoropentyl) sulfinyl nonyl} Thiochroman (Compounds 1-138)

Ή-NMR (2 7 0MHz, CDC 1 3): δ 7. 3 6 (d, J = 8. 4Hz,

2H), 7.14 (d, J = 8.4 Hz, 2H), 7.00-6.966 (m, 2

H), 6.80 (dd, 1 = 2.0 Hz, 8.2 Hz, 1 H), 5.89—5.65 (m, 2H), 3.73 (t, J = 4. 3Hz, 8H), 3.65 (d, J

= 1 1.5 Hz, 1 H), 3.42-3.35 (m, 4H), 2.99 (d, J

= 11.5Hz, 1H), 2.80-2.50 (m, 17H), 2.35-2.

0 9 (m, 4 H), 1.78-1.67 (m, 2 H), 1.45-0.95 (m,

MS (ES I) m / z = 9 20.0 (M + H) +, 941.5 (M + N a) ⁴ : MS / MS: 785.2. Example 14

(3 RS, „4RS) 1 7-hydroxy-3- 3- {4- (2-morpholinoethylcarbamoyl) oxyphenyl} 1 3-methyl-4- (9- (4,4,5,5,5— Pennofluoropentyl) sulfinylnonyl} thiochroman (compounds 1-140) and (3RS, 4RS)-{{7- (2-morpholinoethylcarbamoyl) oxy}} — 3- (4-hydroxyphenyl) —3-methyl- 4 one {9-(4, 4, 5,

5,5-pentylfluoropentyl) sulfinylnonyl} thiochroman (compound

1-42) mixture

MS (ES I) m / z = 763.7 (M + H) +: MS / MS: 607.1, 60

3. 4, 553.3.

In the same manner as in Example 1, the following compounds of Examples 15 to 16 were produced. Example 15

(3RS, 4RS) ― (7— (2-dimethylaminoethyloxy) — 3— (4— (2-dimethylaminoethyloxyphenyl) -1-3-methyl-14— {9-(4,

4, 5, 5, 5—pentafluoropentyl) sulfinylnonyl} Thiochroman (Compounds 1-160)

Ή-NMR (270 MHz, CD ₃ OD): δ 7.43 (d, J = 8.9 Hz, 2H), 7.05-7.02 (m, 3 H), 6.83 (d, J = 2 3 Hz, 1 H), 6.70 (dd, J = 2.3 Hz, 8.3 Hz, 1 H), 4.38 -4.30 (m, 4 H), 3.69-3.56 (m , 5H), 3.07-2.75 (m, 18H), 2.46-2.25 (m, 2H), 2.13-2.04 (m, 2H), 1 78-1.69 (m, 2 H), 1.48—0.98 (m, 17 H); MS (ESI) m / z = 749.4 (M + H) ⁺ : MS / MS: 57 1.2, 539.2. Example 16

(3 RS, 4RS) — 7-Hydroxy-3- (4- (2-Dimethylaminoethyl Oxyphenyl) _ 3-methyl- 4- {9- (4,4,5,5,5-pentafluorofluoropentyl) sulfinylnonyl} thiochroman (compounds 1-162) and (3RS, 4RS)-(7- ( 2-Dimethylaminoethyloxy) -1-3- (4-hydroxyphenyl) -3-methyl-4--1- {9- (4,4,5,5,5-pentafluoropentyl) sulfinylnonyl} thiochroman (Compound 1 64-NMR (270 MHz, CD ₃ OD): δ7.43—6.44 (m, 7H), 4.38-4.29 (m, 2H), 3.67-3 55 (m, 3 H), 3.02 -2.72 (m, 12 H), 2.46-2.25 (m, 2 H), 2.14-2.04 (m, 2H), 1.78-1.68 (m, 2H), 1.49-1.00 (m, 17H); MS (ES I) m / z = 678.3 (M + H) ⁺ : MS / MS: 5 1 8. 1, 468. 2. Industrial Possibility

The compound represented by the above general formula (I) and a pharmaceutically acceptable salt thereof exhibit a sufficiently high effect as an estrogen pure antagonist when orally administered due to high absorption from the digestive tract. Therefore, the above compounds and pharmaceutically acceptable salts thereof are very useful in medical practice.

Claims

-General formula (I)

Blue

(Where

Represents a single bond or a double bond. R and R ₂ are the same or different, and

Substituent, lower alkyl group optionally having substituent (s), aralkyl group optionally having substituent (s), alkenyl group optionally having substituent (s), optionally having substituent (s) Alkynyl group, optionally substituted acyl group, optionally substituted amide group, phosphate group, saccharide linked by glycosidic bond, or ester bond, carbonate bond, urethane bond, ether bond Represents polyethylene glycol linked by an acetal bond or a thioca-ponate bond, provided that R 1 and R ₂ are not simultaneously a hydrogen atom or a simultaneously unsubstituted lower alkyl group. R ₃ represents a hydrogen atom or a methyl group. X represents 〇 or S. A represents equations (a), (b), and (c),

—— (CH ₂ ) m—— (NH) nS (0) p (NH) q—— R ₄ ( ^a )

— (CH ₂ ) m—— O— (CH ₂ ) r—S (0) p—R ₄ (b)

Here, R ₄ represents an alkyl group or a halogenated alkyl group, m is an integer of 3 to 10, n is 0 or 1, p is 0, 1 or 2, and Q is 0 or 1. And r is an integer from 1 to 6. Or a pharmaceutically acceptable salt thereof.

2.

Is a single bond, and R ₃ is a methyl group, or a pharmaceutically acceptable salt thereof.

3.

Is a single bond, R ₃ is a methyl group, and X is O, or a pharmaceutically acceptable salt thereof.

Four.

Is a single bond, R ₃ is a methyl group, and X is S, or a pharmaceutically acceptable salt thereof.

Five .

Is a single bond, R ₃ is a methyl group, X is 〇, and R and R ₂ are the same or different and are a hydrogen atom, a hydroxyl group or a carboxyl group, a amino group or a sulfonic acid group as a substituent. A lower alkyl group which may have a substituent, a hydroxyl group, a carboxyl group or an aralkyl group which may be substituted with an amino group or a sulfonic acid group as a substituent; and a hydroxyl group, a carboxyl group or an amino group or a sulfone as a substituent. An alkenyl group which may be substituted with an acid group, an alkynyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a saccharide linked by a glycosidic bond, an ester bond, a carbonate bond, Urethane bond, ether bond, acetal bond or Polyethylene glycol or a phosphate group bonded by a thiocarbonate bond (provided that R 1 and R ₂ are a hydrogen atom at the same time, The compound according to claim 1, which is not an alkyl group) or a pharmaceutically acceptable salt thereof.

6.

Is a single bond, R ₃ is a methyl group, X is S, and R and R ₂ are the same or different and each represents a hydrogen atom, a hydroxyl group or a carboxyl group, an amino group, or a sulfonic acid group as a substituent. A lower alkyl group which may be substituted, a hydroxyl group, a carboxyl group, an amino group or an aralkyl group which may be substituted with a sulfonic acid group as a substituent, and a hydroxyl group, a hydroxyl group or an amino group as a substituent. Or an alkenyl group which may be substituted with a sulfonic acid group, an alkynyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a saccharide bonded by a glycosidic bond, One-ponate bond, urethane bond, ether bond, acetal bond or Okapone Ichito polyethylene da recall or phosphoric acid groups linked by bonds (wherein, R, and R ₂ does not represent a hydrogen atom at the same time or simultaneously unsubstituted lower alkyl group) The compound according to claim 1, or a Pharmaceutically acceptable salts.

7.

Is a single bond, R ₃ is a methyl group, X is 〇, and R and R ₂ are the same or different and are a hydrogen atom, a phosphate group, a saccharide linked by a glycosidic bond, one CO—Y (Y is a lower alkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, and a hydroxyl group or a carboxyl group, an amino group or a sulfonic acid group as a substituent. An aralkyl group, an alkenyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent; and a hydroxyl group, a carboxyl group, an amino group or an amino group or a sulfonic acid group as a substituent. hand Or an optional alkynyl group) or one CO—NR ₅ R ₆ (R ₅ and R ₆ may independently have a hydrogen atom or a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent. A lower alkyl group, an aralkyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, or a aralkyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent A good alkenyl group or a alkynyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, provided that R and R ₂ are simultaneously a hydrogen atom or (It is not a substituted lower alkyl group.) Acceptable salts are the pharmaceutically.

8.

Is a single bond, R ₃ is a methyl group, X is S, R and R ₂ are the same or different, and are a hydrogen atom, a phosphate group, a saccharide linked by a glycosidic bond, one CO—Y (Y is a lower alkyl group which may have a hydroxyl group, a hydroxyl group or an amino group or a sulfonic acid group as a substituent, and a hydroxyl group or a carboxyl group or an amino group or a sulfonic acid group as a substituent. An aralkyl group, an alkenyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent; and a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent. It is shown also an alkynyl group optionally) one CO- NR _₅ R ₆ (R ₅ and R ₆ are independently water atom or location A lower alkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a group, and a hydroxyl group or a carboxyl group, an amino group or a sulfonic acid group as a substituent. An aralkyl group, an alkenyl group which may be substituted with a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent; or a hydroxyl group, a carboxyl group, an amino group, or an sulfonic acid group which may be substituted as a substituent. (Indicating an alkynyl group) (provided that R 1 and R ₂ are hydrogen The compound or a pharmaceutically acceptable salt thereof according to claim 1, which is not an atom or simultaneously an unsubstituted lower alkyl group.

9. General formula (I I)

(In the formula, R 1 and R ₂ are the same or different and each may be a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a group which may have a substituent. Good alkenyl group, optionally substituted alkynyl group, phosphate group, saccharide or ester bond bonded by glycosidic bond, carbonate bond, ゥ resin bond, ether bond, acetal bond or thiocarbonate bond Wherein R and R ₂ are not a hydrogen atom or an unsubstituted lower alkyl group at the same time, R ₄ is an alkyl group or a halogenated alkyl group, and X is O or S M is an integer from 3 to 10, n is 0 or 1, p is 0, 1 or 2, and Q is 0 or 1. Acceptable salts are the pharmaceutically.

10. The compound according to claim 9, wherein X is 0, or a pharmaceutically acceptable salt thereof.

11. The compound according to claim 9, wherein X is S, or a pharmaceutically acceptable salt thereof.

12.X is 0, m is an integer of 8 to 10, n is 0 or 1, p force is 0, 1 or 2, Q is 0 or 1, or the compound according to claim 9 or a pharmaceutically acceptable compound thereof. Vine.

13. The compound according to claim 9, wherein X is S, m is an integer of 8 to 10, n is 0 or 1, p is 0, 1 or 2, and q is 0 or 1, or a pharmaceutically acceptable compound thereof. Vine salt.

14. X is 0, R and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a substituent Hydroxyl or carboxyl groups as Or an aralkyl group optionally having an amino group or a sulfonic acid group, a hydroxyl group or a carboxyl group as a substituent, or an alkenyl group optionally having an amino group or a sulfonic acid group, or a hydroxyl group or a carboxyl group as a substituent. Alkynyl group optionally having an amino group or a sulfonic acid group, phosphorus

5 groups, glycosidic bonds by linked sugars or ester bond, carbonate binding, a urethane bond, an ether bond, a polyethylene glycol attached by Asetaru bond or Chio carbonate bond (and伹, and R ₂ or at the same time water atom It is not an unsubstituted lower alkyl group at the same time.) The compound of Claim 9 or a pharmaceutically acceptable salt thereof.

10 15. X is S, R and R ₂ are the same or different and each is a hydrogen atom, a lower alkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, An aralkyl group which may have a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a group, a hydroxyl group, a hydroxyl group, an amino group, or a sulfonic acid group as a substituent

An alkenyl group optionally having 15, an alkynyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a phosphoric acid group, a saccharide or an ester bond bonded by a glycosidic bond, a carbonate Polyethylene glycol linked by a bond, urethane bond, ether bond, acetal bond or thiocarbonate bond (provided that R and R ₂ are water

20. A compound according to claim 9 or a pharmaceutically acceptable salt thereof.

16. X is 〇, and R ₂ is the same or different and is a hydrogen atom, a phosphate group, a saccharide linked by a glycosidic bond, one CO—Y (Y is a hydroxyl group or a hepoxyl group or an amino group as a substituent. Or even if it has a sulfonic acid group

25 A lower alkyl group, an aralkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, and a hydroxyl group, a carboxyl group, an amino group or an sulfonic acid group as a substituent An alkynyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent) or 1C 0-NR ₅ R ₆ (R ₅ and R ₆ are independently a hydrogen atom or a lower alkyl group which may have a carboxyl group, an amino group or a sulfonic acid group as a substituent, a hydroxyl group as a substituent Or an aralkyl group which may have a carboxyl group, an amino group or a sulfonic acid group, a hydroxyl group as a substituent or an alkenyl group which may have a carboxyl group, an amino group or a sulfonic acid group, and a substituent Represents an alkynyl group which may have a hydroxyl group, a hydroxyl group, an amino group or a sulfonic acid group (provided that R ₂ and R ₂ are not simultaneously a hydrogen atom or simultaneously an unsubstituted lower alkyl group) 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

17. X is S, and R ₂ is the same or different and is a hydrogen atom, a phosphate group, a saccharide linked by a glycosidic bond, one CO—Y (Y is a hydroxyl group or a hepoxyl group or an amino group as a substituent group) Alternatively, a lower alkyl group which may have a sulfonic acid group, a hydroxyl group, a carboxyl group, an amino group or an aralkyl group which may have a sulfonic acid group as a substituent, a hydroxyl group or a hepoxyl group as a substituent Or an alkenyl group optionally having an amino group or a sulfonic acid group, a hydroxyl group or a carbonyl group as a substituent, or an alkynyl group optionally having an amino group or a sulfonic acid group), or one CO— hydroxyl Oh Rui as NR ₅ R ₆ (R ₅ and R ₆ are independently hydrogen atom or a substituent group is force Rupokishiru group Is a lower alkyl group optionally having an amino group or a sulfonic acid group, a hydroxyl group or a carboxyl group or an aralkyl group optionally having an amino group or a sulfonic acid group as a substituent, and a hydroxyl group or a carboxyl group as a substituent. Or an alkenyl group optionally having an amino group or a sulfonic acid group, or a hydroxyl group, a carboxyl group, an amino group or an alkynyl group optionally having a sulfonic acid group as a substituent (provided that R and R ₂ is not a hydrogen atom or an unsubstituted lower alkyl group at the same time.) 10. The compound according to claim 9, or a pharmaceutically acceptable salt thereof.

1 8. General formula (III)

(Wherein and R ₂ are the same or different and each may be a hydrogen atom, a lower alkyl group which may have a substituent, an aralkyl group which may have a substituent, or a substituent Alkenyl group, alkynyl group which may have a substituent, phosphate group, saccharide or ester bond bonded by a glycosidic bond, carbonate bond, ゥ -ray bond, ether bond, acetate bond or thiol force Represents a polyethylene glycol linked by a one-ponate bond, provided that R and R ₂ are not simultaneously a hydrogen atom or a simultaneously unsubstituted lower alkyl group, X is 〇 or S, and m is 8 to 10 And p is 0, 1 or 2. A compound represented by the formula: or a pharmaceutically acceptable salt thereof.

19. The compound according to claim 18, wherein X is 〇, or a pharmaceutically acceptable salt thereof.

20. The compound according to claim 18, wherein X is S, or a pharmaceutically acceptable salt thereof.

21. X is 〇, R _t and R ₂ are the same or different and each represents a hydrogen atom, a lower alkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a substituent An aralkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group, an alkenyl group optionally having a hydroxyl group, a hydroxyl group, an amino group or a sulfonic acid group as a substituent, and a substituent Alkynyl group which may have hydroxyl group, carboxyl group, amino group or sulfonic acid group, phosphoric acid group, saccharide or ester bond bonded by glycosidic bond, carbonate bond, urethane bond, ether bond, base bond Bonded by bond or thiocarbonate bond And polyethylene glycol (wherein, R, and R ₂ is never at the same time water atom or simultaneously unsubstituted lower alkyl group) according to claim 1 8 title compound or acceptable salts their pharmaceutically mounting.

22. X is S, R i and R ₂ are the same or different, and a hydrogen atom, a substituent A lower alkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group, an aralkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group, or a substituent group A hydroxyl group, a hepoxyl group, an amino group, or a sulfonic acid group

An alkenyl group optionally having 5; an alkynyl group optionally having a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent; a phosphoric acid group; a saccharide or an ester bond bonded by a glycosidic bond; Polyethylene glycol linked by a bond, urethane bond, ether bond, acetal bond or thiocarbonate bond (provided that and R ₂ are water

10. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, which is not a hydrogen atom or an unsubstituted lower alkyl group at the same time.

23. X is 〇, and R and R ₂ are the same or different and each represents a hydrogen atom, a phosphate group, a saccharide linked by a glycosidic bond, -CO—Y (Y is a hydroxyl group, a carboxyl group, or an amino group Group or sulfonic acid group

15 Good lower alkyl group, aralkyl group which may have hydroxyl group or hydroxyl group or amino group or sulfonic acid group as substituent, and hydroxyl group, carboxyl group, amino group or sulfonic acid group as substituent. An alkenyl group which may have a hydroxyl group, a carboxyl group, an amino group or an alkynyl group which may have a sulfonic acid group as a substituent) or 1C

20 0 -NR ₅ R ₆ (R ₅ and R ₆ are independently a hydrogen atom or a lower alkyl group which may have a carboxyl group, an amino group or a sulfonic acid group as a substituent, or a substituent An aralkyl group which may have a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group, or a hydroxyl group or a hydroxyl group, an amino group, or a sulfonic acid group as a substituent.

An alkenyl group, or a alkynyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent (provided that R and R ₂ are not hydrogen atoms at the same time) 20. The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

24. X is S, R and R ₂ are the same or different and each is a hydrogen atom, a phosphoric acid A saccharide linked via a glycosidic bond, —CO—Y (Y is a lower alkyl group optionally having a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group as a substituent, and a hydroxyl group, a carboxyl group or an amino group as a substituent. An aralkyl group optionally having a hydroxyl group or a sulfonic acid group, a hydroxyl group or a hydroxyl group as a substituent or an alkenyl group optionally having an amino group or a sulfonic acid group, or a hydroxyl group or a carboxyl group as a substituent Or an alkynyl group optionally having an amino group or a sulfonic acid group) or

〇— NR ₅ R ₆ (R ₅ and R ₆ are independently a hydrogen atom or a lower alkyl group which may have a hydroxyl group or a hydroxyl group as a substituent, an amino group or a sulfonic acid group, or a substituent An aralkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group; an alkenyl group optionally having a hydroxyl group or a carboxyl group, an amino group or a sulfonic acid group; And a alkynyl group optionally having a hydroxyl group, a hydroxyl group, an amino group or a sulfonic acid group (wherein and R ₂ are not hydrogen atoms at the same time). Or a pharmaceutically acceptable salt thereof.

25. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein X is O, m is an integer of 8 to 10, and p is 0, 1 or 2.

26. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein X is S, m is an integer of 8 to 10, and p power is 0, 1 or 2.

27. X is O, m is an integer from 8 to 10, p is 1 or 2, and R ₂ is the same or different and is a hydrogen atom, a hydroxyl group or a propyloxyl group or an amino group as a substituent. A lower alkyl group which may have a sulfonic acid group or a sulfonic acid group, a hydroxyl group or a carboxyl group or an aralkyl group which may have an amino group or a sulfonic acid group as a substituent, and a hydroxyl group or hydroxyl as a substituent Alkenyl group which may have a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group, a phosphate group, a glycoside Saccharide or ester bond, carbonate bond, urethane bond, 19. A poly (ethylene diol) alcohol linked by a tell bond, an acetate bond or a thiocarbonate bond (provided that and R ₂ are not simultaneously a hydrogen atom or an unsubstituted lower alkyl group). Or a pharmaceutically acceptable salt thereof.

2 8. X is 〇, m is an integer from 8 to 10, p is 1 or 2, R and R ₂ are the same or different and each represents a hydrogen atom or one CO—Y (Y is substituted It may have a hydroxyl group, a carboxyl group, an amino group or a lower alkyl group which may have a sulfonic acid group as a group, and may have a hydroxyl group, a hydroxyl group or an amino group or a sulfonic acid group as a substituent. An aralkyl group, an alkenyl group optionally having a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent; and a hydroxyl group, a carboxyl group, or an amino group, or a sulfonic acid group as a substituent. a shows the alkynyl group) (wherein, R, and R ₂ are not hydrogen atoms at the same time) a compound or a pharmaceutically claims 1 8 Symbol mounting Acceptable salt thereof.

29. X is 〇, m is an integer from 8 to 10, p is 1 or 2, and R ₂ is the same or different and is a hydrogen atom or one CO—NR ₅ R ₆ (R ₅ And R ₆ are independently a hydrogen atom or a lower alkyl group optionally having a hydroxyl group or a carboxyl group or an amino group or a sulfonic acid group as a substituent; a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent. An aralkyl group which may have a group, an alkenyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent; a hydroxyl group, a hydroxyl group or an amino group or a sulfonic acid group as a substituent the have also shown a good alkynyl group) (wherein, and R ₂ are not hydrogen atoms at the same time) Motomeko 1 8 compound or a pharmaceutically acceptable Cormorants Ru salt according.

30. X is 〇, m is an integer from 8 to 10, p is 1 or 2,

19. The method according to claim 18, wherein R ₁ and R ₂ are the same or different and are a saccharide linked by a hydrogen atom, a phosphate group or a glycosidic bond (however, R 1 and R ₂ are not simultaneously hydrogen atoms). A compound or a pharmaceutically acceptable salt thereof.

31. X is S, m is an integer of 8 to 10, p is 1 or 2, and R ₂ is the same or different and is a hydrogen atom, a hydroxyl group or a hydroxyl group as a substituent, or an amino group. A lower alkyl group optionally having a sulfonic acid group or a sulfonic acid group; an aralkyl group optionally having a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group as a substituent; and a hydroxyl group or a sulfoxyl group as a substituent. Alkenyl group which may have a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group, a phosphate group, a glycoside Saccharide or ester bond, carbonate bond, urethane bond, ether bond, acetate Le is a bond or Poryechi glycol linked by Chio carbonate bond (provided that, and R ₂ are not hydrogen atom at the same time or simultaneously unsubstituted lower alkyl group) according to claim 1 8 A compound according or a pharmacy on Acceptable salts.

3 2. X is S, m is an integer from 8 to 10, p is 1 or 2, R and R ₂ are the same or different and each represents a hydrogen atom or one CO—Y (Y is substituted It may have a hydroxyl group, a hydroxyl group, an amino group or a lower alkyl group which may have a sulfonic acid group as a group, and may have a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group as a substituent. An aralkyl group, an alkenyl group optionally having a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent; and a hydroxyl group, a carboxyl group, or an amino group, or a sulfonic acid group as a substituent. (Indicating an alkynyl group) (provided that and R ₂ are not simultaneously hydrogen atoms) or a pharmaceutically acceptable compound thereof. Acceptable salt.

33. X is S, m is an integer from 8 to 10, p is 1 or 2, R and R ₂ are the same or different, and represent a hydrogen atom or one CO—NR ₅ R ₆ ( R ₅ and R ₆ are independently a hydrogen atom or a lower alkyl group which may have a hydroxyl group or a carboxyl group or an amino group or a sulfonic acid group as a substituent; a hydroxyl group, a carboxyl group or an amino group which may have a substituent. An aralkyl group which may have a sulfonic acid group, a hydroxyl group or a carboxyl group as a substituent Or an alkenyl group optionally having an amino group or a sulfonic acid group, or a hydroxyl group or a carbonyl group as a substituent, or an alkynyl group optionally having an amino group or a sulfonic acid group. 19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R ₂ is not simultaneously a hydrogen atom.

3 4. X is S, m is 1 0 integer from is 8, p is 1 or 2, and R ₂ are the same or different and each represents a hydrogen atom, a saccharide bonded by phosphate or glycosidic bond 19. The compound according to claim 18, wherein R ₁ and R ₂ are not hydrogen atoms at the same time, or a pharmaceutically acceptable salt thereof.

35. The compound according to claim 18, wherein X is O, m is 9, and p is 1 or 2, or a pharmaceutically acceptable salt thereof.

36. X is O, m is 9, p is 1 or 2, R and R ₂ are the same or different and each represents a hydrogen atom, a hydroxyl or carboxyl group or an amino group or a sulfonic acid as a substituent. A lower alkyl group which may have a group, a hydroxyl group or a carbonyl group as an substituent, an aralkyl group which may have an amino group or a sulfonic acid group, a hydroxyl group, a propyloxyl group or an amino group as a substituent. An alkenyl group optionally having a sulfonic acid group, an alkynyl group optionally having a hydroxyl group or a carbonyl group, an amino group or an optionally substituted sulfonic acid group, a phosphoric acid group, a saccharide linked by a glycosidic bond, or Ester bond, carbonate bond, urethane bond, ether bond, acetate bond or Is a polyethylene glycol linked by a thiocarbonate bond (provided that and R ₂ are not simultaneously hydrogen atoms or unsubstituted lower alkyl groups) or a pharmaceutically acceptable compound thereof. Salt.

37. X is O, m is 9, p is 1 or 2, R and R ₂ are the same or different, and each represents a hydrogen atom or one CO—Y (Y is a hydroxyl group or Is a lower alkyl group which may have a hydroxyl group, an amino group or a sulfonic acid group, an aralkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, and a substituent Hydroxyl group Or an alkenyl group optionally having a carboxyl group, an amino group or a sulfonic acid group, or an alkynyl group optionally having a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent. ,

R _t and R ₂ are not hydrogen atoms at the same time) a compound or acceptable salts their pharmaceutically according to claim 1 8, wherein.

38. X is O, m is 9, p is 1 or 2, R and R ₂ are the same or different and each represents a hydrogen atom or one CO—NR ₅ R ₆ (R ₅ and R ₆ Are independently a hydrogen atom or a lower alkyl group which may have a hydroxyl group, a carbonyl group, an amino group or a sulfonic acid group as a substituent; and a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent. An alkenyl group which may have a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent; a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid as a substituent. a represents an alkynyl group which may have a group) (wherein, R, and R ₂ are not Rukoto Oh simultaneously hydrogen atoms) according to claim 1 8 Compound or acceptable salts their pharmaceutically mounting.

39. X is 〇, m is 9, p is 1 or 2, R 1 and R 2 are the same or different and are saccharides linked by a hydrogen atom, a phosphate group or a glycosidic bond ( Provided that R 1 and R ₂ are not both hydrogen atoms at the same time.) The compound according to claim 18 or a pharmaceutically acceptable salt thereof.

40. The compound according to claim 18, wherein X is S, m is 9, and p is 1 or 2, or a pharmaceutically acceptable salt thereof.

41. X is S, m is 9, p is 1 or 2, and R ₂ is the same or different and is a hydrogen atom or a hydroxyl group, a carboxy group, an amino group, or a sulfonic acid group as a hydrogen atom or a substituent. A lower alkyl group optionally having a hydroxyl group, a carboxyl group, an amino group or an aralkyl group optionally having a sulfonic acid group as a substituent; a hydroxyl group, a carboxy group, an amino group or an sulfonic acid group as a substituent. An alkynyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a phosphate group, or a glycosidic bond. Polyethylene glycol linked by a saccharide or ester bond, a force bond, a urethane bond, an ether bond, an acetal bond or a thiocarbonate bond (provided that R and R ₂ are simultaneously hydrogen atoms or unsubstituted 19. The compound according to claim 18, or a pharmaceutically acceptable five salts thereof, which is not a lower alkyl group.

4 2. X is S, m is 9, p is 1 or 2, R and R ₂ are the same or different and each represents a hydrogen atom or one CO—Y (Y is a hydroxyl group or Is a lower alkyl group which may have a carboxyl group, an amino group or a sulfonic acid group, an aralkyl group which may have a hydroxyl group, a hydroxyl group or an amino 10 group or a sulfonic acid group as a substituent, a substituent Represents an alkenyl group optionally having a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group, and an alkynyl group optionally having a hydroxyl group, a hydroxyl group, an amino group, or a sulfonic acid group as a substituent) some (although and R ₂ are not hydrogen atoms at the same time) according to claim 1 8 compounds also 15 description acceptable its pharmaceutically .

4 3. X is S, m is 9, p is 1 or 2, R and R ₂ are the same or different and each represents a hydrogen atom or one CO—NR ₅ R ₆ (R ₅ and R ₆ Is independently a hydrogen atom or a lower alkyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a hydroxyl group, a hydroxyl group, an amino group or a sulfonic acid group as a substituent. An alkenyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a hydroxyl group, a hydroxyl group or an amino group as a substituent. (Indicating an alkynyl group which may have a sulfonic acid group.) (However, and R ₂ are not both hydrogen atoms at the same time). 8. The compound according to 8 or a pharmaceutically acceptable salt thereof.

4 4. X is S, m is 9, p is 1 or 2, R and R ₂ are the same or different and are saccharides bonded by hydrogen atom, phosphate group or glycosidic bond (Provided that R 1 and R ₂ are not hydrogen atoms at the same time). The compound according to claim 18 or a pharmaceutically acceptable salt thereof.

45. The compound according to claim 18, wherein X is O, m is 9, and p is 1, or a pharmaceutically acceptable salt thereof.

46. X is O, m is 9, p is 1, and R ₂ is the same or different and represents a hydrogen atom, a hydroxyl group, a carboxyl group, an amino group, or a sulfonic acid group as a substituent. A lower alkyl group which may have a hydroxyl group, a carbonyl group, an amino group or an aralkyl group which may have a sulfonic acid group as a substituent, and a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent. An alkenyl group, an alkynyl group, a phosphoric acid group, a phosphoric acid group, a saccharide or an ester bond bonded by a glycosidic bond, a Bonate bond, urethane bond, ether bond, acetal bond or thio bond Is a polyethylene glycol linked by sulfonate bond

(Provided that R 1 and R ₂ are not simultaneously a hydrogen atom or an unsubstituted lower alkyl group). The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

47. X is 0, m is 9, p is 1, and R and R ₂ are the same or different and each represents a hydrogen atom or one CO—Y (Y is a hydroxyl group or carboxyl as a substituent. A lower alkyl group optionally having a group, an amino group or a sulfonic acid group, a hydroxyl group or a carboxyl group as a substituent, an aralkyl group optionally having an amino group or a sulfonic acid group, and a hydroxyl group or a substituent as a substituent. An alkynyl group optionally having a ropoxyl group, an amino group or a sulfonic acid group, or an alkynyl group optionally having a hydroxyl group or a hepoxyl group or an amino group or a sulfonic acid group as a substituent) ( Provided that R 1 and R ₂ are not hydrogen atoms at the same time). 18. The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

4 8. X is O, m is 9, p is 1, R, and R ₂ are the same or different, a hydrogen atom or a CO- NR _₅ R ₆ (R ₅ and R ₆ Independently a hydrogen atom or a lower alkyl group which may have a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group as a substituent; and a hydroxyl group or a carbonyl group or an amino group or a sulfonic acid group as a substituent. You may Alkyl group, an alkenyl group which may have a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group as a substituent, and a hydroxyl group, a carbonyl group or an amino group or a sulfonic acid group which may have a substituent. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein R _t and R ₂ are not simultaneously a hydrogen atom.

4 9. X is O, m is 9, p is is 1, R! And are R ₂ are identical or different and are a hydrogen atom, Ru sugars der linked by a phosphate group or a glycosidic bond ( However, and R ₂ are not both hydrogen atoms at the same time.) The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

50. The compound according to claim 18, wherein X is S, m is 9, and p is 1, or a pharmaceutically acceptable salt thereof.

5 1. X is S, m is 9, p is 1, and R ₂ are identical or different and are a hydrogen atom, a hydroxyl group or a carboxyl group or a § amino group or sulfonic acid group as a substituent A lower alkyl group which may have a hydroxyl group, a carbonyl group, an amino group or an aralkyl group which may have a sulfonic acid group as a substituent, and a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent. An alkenyl group which may have, an alkynyl group which may have a hydroxyl group, a carboxyl group, an amino group or a sulfonic acid group as a substituent, a phosphoric acid group, a saccharide or an ester bond bonded by a glycosidic bond, a carbonate bond, Urethane bond, ether bond, acetal bond or thioker Is a polyethylene glycol linked by sulfonate bond

5 2. X is S, m is 9, p is 1, and R ₂ is the same or different and is a hydrogen atom or one CO—Y (Y is a hydroxyl group or a carboxyl group or A lower alkyl group optionally having an amino group or a sulfonic acid group, a hydroxyl group or a carboxyl group as a substituent, an aralkyl group optionally having an amino group or a sulfonic acid group, a hydroxyl group or a sulfoxyl group as a substituent Or an alkyl group optionally having an amino group or a sulfonic acid group. An alkynyl group which may have a hydroxyl group, a propyloxyl group, an amino group or a sulfonic acid group as a substituent. (However, R and R ₂ are not hydrogen atoms at the same time.) ) A compound according to claim 18 or a pharmaceutically acceptable salt thereof.

5 3. X is S, m is 9, p is 1, R and R ₂ are the same or different and each represents a hydrogen atom or one CO—NR ₅ R ₆ (R ₅ and R ₆ are Independently a hydrogen atom or a lower alkyl group which may have a hydroxyl group or a hydroxyl group or an amino group or a sulfonic acid group as a substituent, and a hydroxyl group, a carboxyl group or an amino group or a sulfonic acid group as a substituent. An alkenyl group which may have a hydroxyl group or a hydroxyl group or an amino group or an amino group or a sulfonic acid group as a substituent, a hydroxyl group or an alkyl group or an amino group or a sulfonic acid group as a substituent group the have also shown a good Al Kiniru group) (provided that and that R ₂ is a hydrogen atom at the same time have Na) compound of claim 1 8, wherein Or acceptable salts their pharmaceutically.

5 4. X is S, m is 9, p is 1, and R ₂ is or co - different, a hydrogen atom, Ru sugars der linked by a phosphate group or a glycosidic bond (provided that , R, and R ₂ are not simultaneously hydrogen atoms.) 18. The compound according to claim 18, or a pharmaceutically acceptable salt thereof.

55. X is S, m is 9, p is 1, and R ₂ is the same or different and is a hydrogen atom or an ester bond, a carbonate bond, a urethane bond, an ether bond, an acetal bond or a thiol bond. 19. The compound or a pharmaceutically acceptable salt thereof according to claim 18, wherein the compound is a polyethylene glycol bonded by a carbonate bond (provided that R 1 and R ₂ are not simultaneously hydrogen atoms).

56. X is S, m is 9, p is 1, and R and R ₂ are the same or different and each is a hydrogen atom or a phosphate group, provided that R and R ₂ are 19. The compound according to claim 18, which is not a hydrogen atom at the same time, or a pharmaceutically acceptable salt thereof.

57. X is S, m is 9, p is 1, R and R ₂ are the same or different and are saccharides bonded by a hydrogen atom or a glycosidic bond (provided that

R and R ₂ are not hydrogen atoms at the same time. Is a pharmaceutically acceptable salt thereof.

5 8 .X is .O, m is 9, p is 1, and R and R ₂ are the same or different and are a hydrogen atom or an ester bond, a carbonate bond, a urethane bond, an ether bond, an acetal 19. The compound according to claim 18 or a pharmaceutically acceptable salt thereof, wherein the compound or the pharmaceutically acceptable salt thereof is a polyethylene glycol bonded by a bond or a thiocarbonate bond (provided that R 1 and R ₂ are not simultaneously hydrogen atoms).

59. X is 〇, m is 9, p is 1, and R and R ₂ are the same or different and are a hydrogen atom or a phosphate group (provided that R and R ₂ are 19. The compound according to claim 18, which is not a hydrogen atom at the same time, or a pharmaceutically acceptable salt thereof.

60. X is O, m is 9, p is 1, and R and R ₂ are the same or different and are saccharides bonded by a hydrogen atom or a glycosidic bond (provided that R, and 19. The compound according to claim 18, or a pharmaceutically acceptable salt thereof, wherein R ₂ is not simultaneously a hydrogen atom.