JP2003238413A - Steroid sulfatase inhibitor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a steroid sulfatase inhibitor containing a thiophosphate derivative or its pharmacologically permissible salt as an active component. <P>SOLUTION: The steroid sulfatase inhibitor contains a thiophosphate derivative of formula (I) (R<SP>1</SP>and R<SP>2</SP>are each independently H or a substituted or unsubstituted lower alkyl; and O-R<SP>3</SP>is a monocyclic alcohol residue or a polycyclic alcohol residue) or its pharmacologically permissible salt as an active component. For example, the active component is a thiophosphate derivative of formula I wherein R<SP>1</SP>and R<SP>2</SP>are each hydrogen atom and R<SP>3</SP>is a group of formula A or a pharmacologically permissible salt of the derivative. <P>COPYRIGHT: (C)2003,JPO

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to a steroid sulfatase inhibitor containing a thiophosphate derivative or a pharmacologically acceptable salt thereof as an active ingredient. The present invention also relates to a thiophosphate derivative or a pharmaceutically acceptable salt thereof, which has a steroid sulfatase inhibitory action and is useful, for example, in the treatment and / or prevention of steroid hormone-dependent diseases.

[0002]

BACKGROUND OF THE INVENTION In post-menopausal women, the level of estrogen in breast cancer is at least 10 times higher than that in plasma, and the high estrogen level in breast cancer is that estrone sulfate is stimulated by steroid sulfatase (estron sulfatase). It is believed that this is due to the fact that it is hydrolyzed to. Therefore, steroid sulfatase inhibitors are effective therapeutic agents in the treatment of estrone-dependent breast cancer, and diseases in which other estrones may be involved, such as endometrial cancer, ovarian cancer, endometriosis and uterine adenomyosis. It is also considered to be effective in the prevention or treatment of diseases and the like. Further, since steroid sulfatase is involved in the process of androgen biosynthesis, it is considered to be effective in preventing or treating diseases in which androgens are considered to be involved, such as prostate cancer.

Estrone-3-sulfamate (EMAT
E) has been reported as a representative inhibitor of steroid sulfatase [International Journal of Cancer
r), 63, 106 (1995), US Pat. No. 5,616,574
No.], EMATE has been shown not to be useful for the treatment of estrone-dependent diseases due to its estrogenic effect [Cancer Researc
h), 56, 4950 (1996)].

In addition, a number of nonsteroidal steroid sulfatase inhibitors have been found so far [Expert Opinion on Therapeutics.
Patents (Expert opinion on therapeutic patent
s), vol. 9, p. 1083 (1999)]. Specific examples thereof include, for example, tyramine derivatives [Cancer Research, Volume 57, page 702 (1997), The Journal of Steroids Biochemistry and Molecular Biology (The Journalof St
eroid Biochemistry and Molecular Biology), Volume 59,
Page 41 (1996), The Journal of Steroids
Bio Chemistry and Molecular Biology (The Journal of Steroid Biochemistry and Mole
cular Biology), 68, 31 (1999), The Journal of Steroids and Biochemistry and Molecular Biology (The Journal of Stero
id Biochemistry and Molecular Biology), 69, 227
Page (1999), US Pat. No. 5,567,831], cinnamic acid derivative (US Pat. No. 6,011,024), diethylstilboestrol derivative [The Journal of Steroids Biochemistry and Molecular Biology (The Journal of Steroid Biochemistry and Molecul
ar Biology), 69, 227 (1999)] and the like. Moreover, several steroid sulfatase inhibitors have recently been disclosed (WO01 / 04086, WO01 / 02349).

Further, estrone-3-methylthiophosphonate, estrone-3-methylphosphonate, estrone-3-phenylphosphonothioate, estrone-
3-Phenylphosphonate [Cancer Research (Ca
ncer Research), 53, 298 (1993), Bioorganic & Medicinal Chemistry Letters (Bi
oorganic & Medicinal Chemistry Letters), Volume 3, 313
Page (1993), US Pat. No. 5,604,215], and 3-monoalkylthiophosphate derivatives [compound (A1)] are disclosed as steroid sulfatase inhibitors (WO91 / 13083).

[0006]

[Chemical 9]

(In the formula, R ^a1 represents lower alkyl;
bcd represents a substituted or unsubstituted saturated or substituted or unsubstituted unsaturated steroid nucleus). Steroid sulfamate and tyramine derivatives are known to have a memory-enhancing effect (US Pat. No. 5,556). , 84
No. 7, No. 5,763,492). On the other hand, as reported in WO99 / 33858, a compound having not only a steroid sulfatase inhibitory action but also an anti-estrogen action (inhibition of estrogen action or estrogen biosynthesis) is a steroid hormone-dependent disease. It is considered to be more useful for the treatment or prevention of the above, and it is also considered that the phenol derivative produced by hydrolysis in vivo has an anti-estrogen action.

[0008]

SUMMARY OF THE INVENTION An object of the present invention is to provide a steroid sulfatase inhibitor containing a thiophosphate derivative or a pharmacologically acceptable salt thereof as an active ingredient. Another object of the present invention is to provide a thiophosphate derivative or a pharmacologically acceptable salt thereof which has a steroid sulfatase inhibitory action and is useful, for example, in the treatment and / or prevention of steroid hormone-dependent diseases.

[0009]

Means for Solving the Problems The present invention includes the following (1) to
Regarding (28). (1) Formula (I)

[0010]

[Chemical 10]

(Wherein R ¹ and R ² are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl, and —O—R ³ is a residue of a monocyclic alcohol or a polycyclic group). A steroid sulfatase inhibitor containing, as an active ingredient, a thiophosphate derivative represented by (representing an alcohol residue) or a pharmaceutically acceptable salt thereof. (2) The monocyclic alcohol and the polycyclic alcohol in the residue of the monocyclic alcohol and the residue of the polycyclic alcohol are sulfate compounds corresponding to these [thiophosphate group of the compound represented by the formula (I) To a sulfate group] is a monocyclic alcohol or a polycyclic alcohol that serves as a substrate for a steroid sulfatase enzyme, and the steroid sulfatase inhibitor according to (1) above.

(3) The steroid sulfatase inhibitor according to the above (1) or (2), wherein -O-R ³ is a residue of a substituted or unsubstituted sterol. (4) -O-R ³ is the is the residue of a substituted or unsubstituted 3- sterols (1) or (2) a steroid sulfatase inhibitor according. (5) The steroid sulfatase inhibitor according to (4) above, wherein the 3-sterol is estrone or dehydroepiandrosterone.

(6) R ³ is represented by the formula (A)

[0014]

[Chemical 11]

(Wherein the ring system ABCD represents a substituted or unsubstituted, saturated or unsaturated steroid nucleus), a formula
(B)

[0016]

[Chemical 12]

<Wherein Q is an oxygen atom, a sulfur atom or
-N (-Z)-(In the formula, Z is a hydrogen atom or a substituted or non-substituted
Represents a substituted lower alkyl), Y¹, Y², Y³, Y^FourOh
And Y^FiveAre the same or different and are a hydrogen atom, a halogen,
Nitro, cyano, azido, substituted or unsubstituted lower alkyl
Alkyl, substituted or unsubstituted cycloalkyl, substituted also
Or unsubstituted lower alkenyl, substituted or unsubstituted
Lower alkynyl, substituted or unsubstituted aryl, substituted
Or an unsubstituted heterocyclic group, -C (= X¹) R^Four[Where X
¹Represents an oxygen atom or a sulfur atom, R^FourIs the hydrogen source
Child, substituted or unsubstituted lower alkyl, substituted or
Unsubstituted cycloalkyl, substituted or unsubstituted lower alkyl
Lucenyl, substituted or unsubstituted lower alkynyl, substituted
Or unsubstituted aryl, substituted or unsubstituted complex
Ring group, -NR^FiveR⁶(In the formula, R^FiveAnd R⁶Are the same or different
Is a hydrogen atom, substituted or unsubstituted lower alkyl,
Substituted or unsubstituted cycloalkyl, substituted or unsubstituted
Substituted lower alkenyl, substituted or unsubstituted aryl
Or a substituted or unsubstituted heterocyclic group), -OR⁷
(In the formula, R⁷Is a hydrogen atom, a substituted or unsubstituted lower
Alkyl, substituted or unsubstituted cycloalkyl, substituted also
Or unsubstituted lower alkenyl, substituted or unsubstituted
Represents an aryl or a substituted or unsubstituted heterocyclic group)
Or −SR⁸(In the formula, R⁸Is the R⁷Is synonymous with)
], -NR⁹R^Ten{In the formula, R⁹And R^TenAre the same or different
Becomes a hydrogen atom, substituted or unsubstituted lower alkyl
Group, substituted or unsubstituted cycloalkyl, substituted or
Is an unsubstituted lower alkenyl, a substituted or unsubstituted ari
, A substituted or unsubstituted heterocyclic group, -C (= X²) R
¹¹(In the formula, X²And R¹¹Are each X¹And R^FourWhen
Synonymous) or -SO₂R¹²[In the formula, R¹²Replace if
Or unsubstituted lower alkyl, substituted or unsubstituted
Alkyl, substituted or unsubstituted lower alkenyl, position
A substituted or unsubstituted aryl, a substituted or unsubstituted compound
Substrate, -NR¹³R¹⁴(In the formula, R¹³And R¹⁴Respectively
The R^FiveAnd R⁶Synonymous with) or -OR¹⁵(In the formula, R
¹⁵Is the R⁷Synonymous with)]], -OR¹⁶
[In the formula, R¹⁶Is a hydrogen atom, substituted or unsubstituted lower
Alkyl, substituted or unsubstituted cycloalkyl, substituted
Or unsubstituted lower alkenyl, substituted or unsubstituted
Aryl, substituted or unsubstituted heterocyclic group or --SO
₂R¹⁷(In the formula, R¹⁷Is the R¹²Synonymous with)],
−S (O)_mR¹⁸(In the formula, m represents an integer of 0 to 1, and R¹⁸Is before
Note R⁷Synonymous with) or -SO₂R¹⁹(In the formula, R¹⁹Is before
Note R¹²Synonymous with) or Y¹And Y²Together
Become-(CH₂)_n-(In the formula, n represents an integer of 4 to 9)
Form> or formula (C)

[0018]

[Chemical 13]

[Wherein Y ⁶ is a hydrogen atom, substituted or unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted lower alkenyl, substituted or unsubstituted lower alkynyl, substituted or unsubstituted Aryl, substituted or unsubstituted heterocyclic group, -C (= X ^1A ) R
^4A (in the formula, X ^1A and R ^4A have the same meanings as the above X ¹ and R ⁴ , respectively),-(CH ₂ ) _na -NR ^9A R ^10A (in the formula, na is 0 to
Represents an integer of 5, R ^9A and R ^10A are the same as the above R ⁹ and R ¹⁰ , respectively, -OR ^16A (wherein R ^16A is the above R
Synonymous with ¹⁶ ), -S (O) _ma R ^18A (wherein ma and R ^18A
Are respectively as defined above for m and R ⁷ ) or —SO ₂
R ^19A (in the formula, R ^19A has the same ^{meaning as} R ¹² )]
The steroid sulfatase inhibitor according to (1) above, which is

(7) The above (1) or (2), wherein R ³ is the formula (A)
The steroid sulfatase inhibitor described. (8) The steroid sulfatase inhibitor according to the above (1) or (2), wherein R ³ is the formula (B). (9) The steroid sulfatase inhibitor according to the above (1) or (2), wherein R ³ is the formula (C).

(10) The steroid sulfatase inhibitor according to the above (9), wherein Y ⁶ is a substituted or unsubstituted heterocyclic group. (11) The steroid sulfatase inhibitor according to (7) above, wherein ring A is a benzene ring or a cyclohexene ring. (12) R ³ is a substituted or unsubstituted 3-estra-1,
3,5 (10) -trien-17-on-3-yl or substituted or unsubstituted (3β) -3-androst-
The above (1) which is 5-en-17-on-3-yl, or
(2) The steroid sulfatase inhibitor according to the above.

(13) The above, wherein R ¹ and R ² are hydrogen atoms
The steroid sulfatase inhibitor according to any one of (1) to (12). (14) Formula (IA)

[0023]

[Chemical 14]

{Wherein R ^3A is the formula (A)

[0025]

[Chemical 15]

(Wherein the ring system ABCD is as defined above), formula (B)

[0027]

[Chemical 16]

(Wherein Q, Y ¹ , Y ² , Y ³ , Y ⁴ and Y ⁵ are as defined above) or formula (D)

[0029]

[Chemical 17]

[Where Y^6AIs a substituted or unsubstituted low
Alkenyl, substituted or unsubstituted aryl, -C (=
X^1A) R^4A(In the formula, X^1AAnd R^4AAre each X¹And
And R^FourSynonymous with),-(CH₂)_nb-NR^9AR^10A(Where nb
Represents 0 or an integer of 2 to 5 and R^9AAnd R^10AIs it
Each R above⁹And R^TenSynonymous with), -OR^16A(In the formula,
R ^16AIs the R¹⁶Synonymous with), -S (O)_maR^18A(formula
Medium, ma and R^18AAre m and R respectively⁷Synonymous with
Yes) or −SO₂R^19A(In the formula, R^19AIs the R¹²Synonymous with
, But with a substituted or unsubstituted vinyl
A thiophosphate derivative
Or a pharmaceutically acceptable salt thereof.

(15) The thiophosphate derivative according to the above (14), wherein R ^3A is formula (A), or a pharmaceutically acceptable salt thereof. (16) The thiophosphate derivative or the pharmaceutically acceptable salt thereof according to (15) above, wherein ring A is a benzene ring or a cyclohexene ring. (17) R ^3A is a substituted or unsubstituted 3-estra
1,3,5 (10) -trien-17-on-3-yl or substituted or unsubstituted (3β) -3-androst-5-en-17-on-3-yl (14) The thiophosphate derivative or a pharmaceutically acceptable salt thereof described.

(18) The thiophosphate derivative according to the above (14), wherein R ^3A is the formula (B), or a pharmaceutically acceptable salt thereof. (19) The thiophosphate derivative according to the above (14), wherein R ^3A is formula (D), or a pharmaceutically acceptable salt thereof. (20) The thiophosphate derivative or the pharmaceutically acceptable salt thereof according to (19), wherein Y ^6A is a substituted or unsubstituted heterocyclic group.

(21) The thiophosphate derivative or the pharmaceutically acceptable salt thereof according to (19) above, wherein Y ^6A is a substituted or unsubstituted pyrazolyl or a substituted or unsubstituted oxazolyl. (22) A therapeutic agent for breast cancer, endometrial cancer, ovarian cancer or prostate cancer, which comprises the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of (14) to (21) as an active ingredient. And / or a prophylactic agent.

(23) An antitumor agent containing the thiophosphate derivative according to any one of (14) to (21) or a pharmaceutically acceptable salt thereof as an active ingredient. (24) A therapeutic and / or prophylactic agent for a disease involving steroid sulfatase, which comprises, as an active ingredient, the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any of (14) to (21).

(25) A therapeutic agent and / or prophylaxis for a steroid hormone-dependent disease containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of (14) to (21) as an active ingredient Agent. (26) A medicament containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of (14) to (21) as an active ingredient.

(27) The thiophosphate derivative according to any one of the above (14) to (21) or a pharmacological method thereof, which produces a phenol derivative having an anti-estrogen action by hydrolysis of the thiophosphate moiety in the molecule in vivo. A steroid sulfatase inhibitor containing an acceptable salt as an active ingredient. (28) -O-R ³ is a residue of a monocyclic alcohol or polycyclic alcohol in which the sulfate compound of R ³ -OH serves as a substrate for a steroid sulfatase enzyme (14) to (21)
A steroid sulfatase inhibitor containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of 1.

[0037]

BEST MODE FOR CARRYING OUT THE INVENTION Hereinafter, the compound represented by the formula (I) is referred to as a compound (I). The same applies to compounds having other formula numbers. In the definition of each group of the formula (I), (i) the monocyclic alcohol and the polycyclic alcohol in the residue of the monocyclic alcohol and the residue of the polycyclic alcohol include a monocyclic alcohol or a polycyclic alcohol. There is no particular limitation as long as it is an alcohol, and examples thereof include those in which a corresponding sulfate compound [compound (I) in which a thiophosphate group is converted to a sulfate group] serves as a substrate for a steroid sulfatase enzyme. Which, when incubated with an enzyme having steroid sulfatase activity at pH 7.4 and 37 ° C., provides a Km value of less than 50 μmol / L.

As the monocyclic alcohol, for example, a substituted or unsubstituted heterocyclic ring having hydroxy as one of the substituents (the heterocyclic ring is a heterocyclic group (xi) having a hydrogen atom
And the substituents other than hydroxy in the substituted heterocycle are the substituents (x
ii)), a substituted or unsubstituted phenol (the substituent in the substituted phenol has the same meaning as the substituent (xii) in the substituted heterocyclic group described later), and the like. Specific examples include tyramine amide derivatives and hydroxycinnamic acid derivatives.

Examples of the polycyclic alcohol include, for example, a substituted or unsubstituted C 6-60, preferably C 6-30, hydroxy group as one of the substituents.
A fused ring of a bicyclic to pentacyclic ring in which a ring of 8 to 8 members is fused, each ring system may be saturated or unsaturated, and may contain an atom such as a nitrogen atom, an oxygen atom or a sulfur atom. . Specific examples thereof include a substituted or unsubstituted sterol, a tetrahydronaphthol derivative, a coumarin derivative having a hydroxy as one of the substituents, a chroman derivative or an isoflavone derivative, and a 4-hydroxy tamoxifen derivative.

Examples of (ii) sterols include 3-sterols such as estrone, estradiol, estriol and dehydroepiandrosterone. (iii) Substituted sterols include, for example, 2-hydroxyestrone, 2-methoxyestrone, 4-hydroxyestrone, 6α-hydroxyestrone, 1α-hydroxyestrone, 15α-hydroxyestrone, 1
Substituted estrone such as 5β-hydroxy estrone, 2-
Hydroxy-17β-estradiol, 2-methoxy-17β-estradiol, 4-hydroxy-17β
-Estradiol, 6α-hydroxy-17β-estradiol, 7α-hydroxy-17β-estradiol, 16α-hydroxy-17α-estradiol, 16β-hydroxy-17α-estradiol,
16β-hydroxy-17β-estradiol, 17
α-estradiol, 17β-estradiol, 1
Substituted estradiol such as 7α-ethynyl-17β-estradiol, 2-hydroxyestriol, 2-
Substituted estriols such as methoxy estriol, 4-hydroxy estriol, 6α-hydroxy estriol, 7α-hydroxy estriol, 6α-hydroxydehydroepiandrosterone, 7α-hydroxydehydroepiandrosterone, 16α-hydroxydehydroepiandrosterone , 16β-hydroxydehydroepiandrosterone and other substituted dehydroepiandrosterone and other substituted 3-sterols and the like.

(Iv) As the saturated or unsaturated steroid nucleus, for example, the corresponding hydroxy form is the sterol
Some examples are synonymous with (ii). (v) Examples of lower alkyl include, for example, linear or branched alkyl having 1 to 20 carbon atoms, specifically, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, se
c-butyl, tert-butyl, pentyl, isopentyl,
Neopentyl, hexyl, heptyl, octyl, isooctyl, decyl, undecyl, dodecyl, tridecyl,
Examples thereof include tetradecyl, pentadecyl, eicosyl and the like.

Examples of (vi) lower alkenyl include linear or branched alkenyl having 2 to 8 carbon atoms, specifically vinyl, allyl, 1-propenyl, butenyl, pentenyl, hexenyl, heptenyl, octenyl and the like. To be (vii) Examples of lower alkynyl include linear or branched alkynyl having 2 to 8 carbon atoms, specifically ethynyl,
Examples include propynyl, butynyl, pentynyl, hexynyl, heptynyl, octynyl and the like.

Examples of (viii) cycloalkyl include cycloalkyl having 3 to 8 carbon atoms, specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
Examples include cycloheptyl and cyclooctyl. Examples of (ix) aryl include C 6-14, specifically, phenyl, naphthyl, anthranyl and the like.

(X) Halogen represents each atom of fluorine, chlorine, bromine and iodine. Examples of the (xi) heterocyclic group include an aliphatic heterocyclic group and an aromatic heterocyclic group. As the aliphatic heterocyclic group, for example, a 5-membered or 6-membered monocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom is condensed with a 3- to 8-membered ring. And a bicyclic or tricyclic condensed heterocyclic aliphatic heterocyclic group containing at least one atom selected from a nitrogen atom, an oxygen atom and a sulfur atom, and specific examples thereof include tetrahydropyranyl, pyranyl and tetrahydrofuran. Nyl, pyrrolidinyl, piperidino, piperidinyl, perhydroazepinyl, perhydroazocinyl, morpholino, morpholinyl, thiomorpholino, thiomorpholinyl, piperazinyl, homopiperazinyl, oxazolinyl, dioxolanyl, imidazolidinyl, imidazolinyl-1, pyrazolidinyl, pyrazolidinyl, pyrazolidinyl, pyrazolidinyl. 3-dihydroisoindolyl, 1, - dioxo-1,3-dihydroisoindolyl, 1,1-dioxo-2,3-dihydro-benzo [d] isothiazolyl, 1,1,3-trioxo -
2,3-dihydrobenzo [d] isothiazolyl, 2-pyrrolinyl, 2-pyrrolidonyl, 3-pyrrolidonyl, 2-
Piperidonyl, 3-piperidonyl, 4-piperidonyl,
Perhydro-2-azepinonyl, perhydro-3-azepinonyl, perhydro-4-azepinonyl, 2-thiazolidonyl, 4-thiazolidonyl, 2-oxazolidonyl, 4-oxazolidonyl, succinimide, phthalimide, glutarimide, maleimide, hydantoinyl,
Examples thereof include thiazolidine dionyl and oxazolidine dionyl.

The aromatic heterocyclic group is, for example, at least one selected from nitrogen atom, oxygen atom and sulfur atom.
5-membered or 6-membered monocyclic aromatic heterocyclic group containing 4 atoms, at least 1 selected from a nitrogen atom, an oxygen atom and a sulfur atom, which is a bicyclic or tricyclic condensed with a 3- to 8-membered ring.
And a condensed aromatic heterocyclic group containing 6 atoms, specifically, furyl, thienyl, pyrrolyl, imidazolyl,
Pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl,
1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,3
-Thiadiazolyl, 1,2,4-thiadiazolyl, 1,
3,4-thiadiazolyl, flazanyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, quinolyl, isoquinolyl, quinazolinyl, phthalazinyl, purinyl, indolyl, isoindolyl, 2-pyridonyl, 4-pyridonyl, urasilyl, benzofuryl, benzothienyl,
Examples thereof include benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl and benzisothiazolyl.

(Xii) Saturated or unsaturated substituted sterloy
The same as the substituents on the ring and the substituted heterocyclic group.
Or, differently, for example, a halogen or nitrite having 1 to 3 substitutions
B, cyano, azido, substituted or unsubstituted lower alkyl
Group, substituted or unsubstituted cycloalkyl, substituted or
Is unsubstituted lower alkenyl, substituted or unsubstituted lower
Alkynyl, substituted or unsubstituted aryl, substituted if
Or an unsubstituted heterocyclic group, -C (= X^1B) R^4B[Where X^1BIs acid
Represents an elementary atom or a sulfur atom, R^4BIs a hydrogen atom,
Or unsubstituted lower alkyl, substituted or unsubstituted
Chloroalkyl, substituted or unsubstituted lower alkenyl,
Substituted or unsubstituted lower alkynyl, substituted or unsubstituted
Substituted aryl, substituted or unsubstituted heterocyclic group, -NR
^5BR^6B(In the formula, R^5BAnd R^6BAre the same or different,
Hydrogen atom, substituted or unsubstituted lower alkyl, substituted
Or unsubstituted cycloalkyl, substituted or unsubstituted
Lower alkenyl, substituted or unsubstituted aryl or
Represents a substituted or unsubstituted heterocyclic group), -OR^7B(formula
Medium, R^7BIs a hydrogen atom, a substituted or unsubstituted lower alkyl
Kill, substituted or unsubstituted cycloalkyl, substituted if
Or unsubstituted lower alkenyl, substituted or unsubstituted
Represents a reel or a substituted or unsubstituted heterocyclic group) or
Or-SR^8B(In the formula, R^8BIs the R^7B(Synonymous with)
], -NR^9BR^10B{In the formula, R^9BAnd R^10BAre the same or
Is different from a hydrogen atom, substituted or unsubstituted lower alkyl
Kill, substituted or unsubstituted cycloalkyl, substituted if
Or unsubstituted lower alkenyl, substituted or unsubstituted
Reel, substituted or unsubstituted heterocyclic group, -C (= X^2B) R
^11B(In the formula, X^2BAnd R^11BAre each X^1BAnd R
^4BSynonymous with) or -SO₂R^12B[In the formula, R^12BIs
Substituted or unsubstituted lower alkyl, substituted or unsubstituted
Cycloalkyl, substituted or unsubstituted lower alkene
Group, substituted or unsubstituted aryl, substituted or unsubstituted
Heterocyclic group, -NR^13BR ^14B(In the formula, R^13BAnd R
^14BAre each R^5BAnd R^6BSynonymous with)
Is -OR^15B(In the formula, R^15BIs the R^7BIs synonymous with)
]], -OR^16B[In the formula, R^16BIs a hydrogen atom,
Substituted or unsubstituted lower alkyl, substituted or unsubstituted
Cycloalkyl, substituted or unsubstituted lower alkene
Group, substituted or unsubstituted aryl, substituted or unsubstituted
A heterocyclic group or --SO₂R^17B(In the formula, R^17BIs the R^12B
Synonymous with)], -S (O)_mcR^18B(Where mc is 0
Represents an integer from 1 to R^18BIs a hydrogen atom, substituted or non-substituted
Substituted lower alkyl, substituted or unsubstituted cycloalkyl
Group, substituted or unsubstituted lower alkenyl, substituted or
Is an unsubstituted aryl or a substituted or unsubstituted heterocycle
Represents a group), -SO₂R^19B(In the formula, R ^19BIs the R^12BSynonymous with
It is).

The halogen, lower alkyl, cycloalkyl, lower alkenyl, lower alkynyl, aryl and heterocyclic group shown here are the halogen (x), lower alkyl (v), cycloalkyl (viii) and lower alkenyl (respectively). vi), lower alkynyl (vii), aryl (ix) and heterocyclic group (xi), which have the same meaning as substituted lower alkyl, substituted lower alkenyl and substituted lower alkynyl, and substituted cycloalkyl, substituted aryl and substituted heterocyclic group. The substituents are the substituents (x) in the substituted lower alkyl, the substituted lower alkenyl and the substituted lower alkynyl, respectively, which will be described later.
iii) and the substituent (xvi) in the substituted cycloalkyl and the substituted aryl.

(Xiii) Substituents in the substituted lower alkyl, the substituted lower alkenyl and the substituted lower alkynyl are the same or different and have, for example, the number of substitutions of 1 to 3, halogen, nitro, cyano, azido, lower alkenyl, lower alkadienyl, lower Alkatrienyl, lower alkynyl, lower alkoxy lower alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted aryl,
A substituted or unsubstituted heterocyclic group, -C (= X ^1C ) R ^4C [wherein, X ^1C represents an oxygen atom or a sulfur atom, R ^4C represents a hydrogen atom, a lower alkyl, a substituted or unsubstituted cycloalkyl group; Alkyl, lower alkenyl, lower alkynyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group,
Substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, -NR ^5C R ^6C (in the formula, R ^5C and R ^6C are the same or different, a hydrogen atom, a lower alkyl, a substituted or unsubstituted cycloalkyl, Lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl or substituted or unsubstituted heteroarylalkyl), -OR ^7C (wherein R ^7C is a hydrogen atom) , Lower alkyl,
Represents a substituted or unsubstituted cycloalkyl, lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl or substituted or unsubstituted heteroarylalkyl)
Or -SR ^8C (in the formula, R ^8C has the same ^{meaning as} the above R ^7C )], -NR ^9C R ^10C (in the formula, R ^9C and R ^10C are the same or different, a hydrogen atom, a lower alkyl, Substituted or unsubstituted cycloalkyl, lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, -C (= X ^2C ). R ^11C (in the formula, X ^2C
And R ^11C have the same ^meanings as the above X ^1C and R ^4C respectively) or —SO ₂ R ^12C [wherein R ^12C is lower alkyl,
Substituted or unsubstituted cycloalkyl, lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl, -NR ^13C R
^14C (In the formula, R ^13C and R ^14C are respectively the above R ^5C and
^{Has the same meaning} as R ^6C ) or —OR ^15C (wherein R ^15C is the same as the above R).
Represents the same as ^7C ]], -OR ^16C [in the formula, R
^16C is a hydrogen atom, lower alkyl, substituted or unsubstituted cycloalkyl, lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl, substituted or unsubstituted heteroarylalkyl Or --SO ₂ R ^17C (wherein R ^17C is the above R
Represents the ^12C and is synonymous)], - S (O) md R 18C ( wherein, md
Represents an integer of 0 to 1, R ^18C represents a hydrogen atom, lower alkyl,
Substituted or unsubstituted cycloalkyl, lower alkenyl, substituted or unsubstituted aryl, substituted or unsubstituted heterocyclic group, substituted or unsubstituted aralkyl or substituted or unsubstituted heteroarylalkyl), -SO ₂ R ^19C (in the formula, R ^19C has the same ^{meaning as} the above R ^12C ) and the like.

The halogen, lower alkyl, lower alkenyl, lower alkynyl, cycloalkyl, aryl and heterocyclic group shown here are the same as the halogen (x), lower alkyl (v), lower alkenyl (vi) and lower alkynyl, respectively.
(vii), cycloalkyl (viii), aryl (ix) and heterocyclic group (xi), and lower alkadienyl (xiv) includes, for example, alkadienyl having 4 to 8 carbon atoms, specifically 1,3 -Pentadienyl, 1,3-hexadienyl, 2,4-hexadienyl, 1,3-octadienyl and the like, and examples of the lower alkatrienyl (xv) include, for example, alkatrienyl having 6 to 8 carbon atoms, specifically 1,
3,5-hexatrienyl, 1,3,5-octatrienyl and the like are mentioned, and the lower alkyl part of the lower alkoxy lower alkoxy has the same meaning as the above lower alkyl (v), and the lower alkoxy lower alkoxy, aralkyl and The alkylene portion of heteroarylalkyl has the same meaning as the definition of lower alkyl (v) above with one hydrogen removed, and the aryl portion of aralkyl is the same as aryl (ix) above.
The heteroaryl moiety in the heteroarylalkyl has the same meaning as the aromatic heterocyclic group in the definition of the heterocyclic group (xi).

Further, the substituted cycloalkyl shown here,
Substituted aryl, substituted heterocyclic group, substituted aralkyl and position
Substituents on the substituted heteroarylalkyl are as described below.
Substituents in cycloalkyl and substituted aryl (xv
Synonymous with i). (xvi) Substituted cycloalkyl and substituted
The substituents on the aryl may be the same or different.
For example, lower alkyl, halogen, and nit having 1 to 3 substitutions
B, cyano, azide, lower alkenyl, lower alkadie
Nyl, lower alkatrienyl, lower alkynyl, lower alkenyl
Lucoxy lower alkoxy, cycloalkyl, aryl,
4-sulfamoyloxybenzyl, heterocyclic group, -C (=
X^1D) R^4D[Where X^1DRepresents an oxygen atom or a sulfur atom.
Then R^4DIs a hydrogen atom, lower alkyl, cycloalkyl
Ru, lower alkenyl, lower alkynyl, aryl, hetero
Ring group, -NR^5DR^6D(In the formula, R^5DAnd R^6DAre the same or
Differently, hydrogen atom, lower alkyl, cycloalkyl,
Represents a lower alkenyl, aryl or heterocyclic group),-
OR^7D(In the formula, R^7DIs a hydrogen atom, lower alkyl, cyclo
Alkyl, lower alkenyl, aryl or heterocyclic group
Represents) or −SR^8D(In the formula, R^8DIs the R^7DSynonymous with
)], -NR^9ER^10E{In the formula, R^9DAnd R^10DIs
The same or different, hydrogen atom, lower alkyl, cyclo
Alkyl, lower alkenyl, aryl, heterocyclic group, -C
(= X^{2 D}) R^11D(In the formula, X^2DAnd R^11DAre each X
^1DAnd R^4DSynonymous with) or -SO₂R^12D[In the formula, R
^12DIs lower alkyl, cycloalkyl, lower alkenyl
Ru, aryl, heterocyclic group, -NR^13DR^14D(In the formula, R^13DOh
And R^14DAre each R^5DAnd R^6DIs synonymous with)
Or −OR^15D(In the formula, R^15DIs the R^7DIs synonymous with)
Represents]], -OR^16D[In the formula, R^16DIs a hydrogen atom,
Lower alkyl, cycloalkyl, lower alkenyl, ari
Group, heterocyclic group or --SO₂R^17D(In the formula, R ^17DIs the R
^12DSynonymous with)], -S (O)_meR^18D(In the formula, me
Represents an integer of 0 to 1, R^18DIs a hydrogen atom, lower alk
Ru, cycloalkyl, lower alkenyl, aryl or
Represents a heterocyclic group), -SO₂R^19D(In the formula, R^19DIs the R^12D
Is synonymous with) and the like.

The halogen, lower alkyl, lower alkenyl, lower alkadienyl, lower alkatrienyl, lower alkynyl, cycloalkyl, aryl and heterocyclic groups shown here are the same as the halogen (x), lower alkyl (v) and lower, respectively. Alkenyl (vi), lower alkadienyl (xi
v), lower alkatrienyl (xv), lower alkynyl (vi
i), cycloalkyl (viii), aryl (ix) and heterocyclic group (xi), and the lower alkyl part of lower alkoxy lower alkoxy has the same meaning as lower alkyl (v) above, and lower alkoxy lower alkoxy The lower alkylene moiety of is the same as the definition of the lower alkyl (v) above with one hydrogen removed.

In the formulas (C) and (D), the substitution positions of the respective substituents Y ⁶ and Y ^6A are not particularly limited, but the para position is preferable. The pharmacologically acceptable salt of the compound (I), for example, a pharmacologically acceptable acid addition salt, a metal salt,
It includes ammonium salts, organic amine addition salts, amino acid addition salts and the like. Examples of the acid addition salt include inorganic acid salts such as hydrochloride, sulfate, and phosphate, acetate, maleate, fumarate, tartrate, citrate, lactate, aspartate, glutamate, Examples thereof include organic acid salts such as succinate, and examples of metal salts include alkali metal salts such as sodium salts and potassium salts, alkaline earth metal salts such as magnesium salts and calcium salts, aluminum salts, zinc salts and the like. Examples of the ammonium salt include ammonium and salts of tetramethylammonium,
Examples of the organic amine addition salt include addition salts such as morpholine and piperidine, and examples of the amino acid addition salt include:
Examples thereof include addition salts of lysine, glycine, phenylalanine and the like.

Next, the method for producing the compound (I) will be described. In the production method shown below, when the defined group changes under the conditions of the method for implementation or is inappropriate for performing the method, introduction or elimination of a protecting group commonly used in synthetic organic chemistry is carried out. Method [eg Protective Groups in Organic Synthesis (Protective Group
s in Organic Synthesis), Green (TW Greene)
[John Wiley & Sons Inc. (1981)] and the like can be used to obtain the target compound. Moreover, the order of the reaction steps can be changed as necessary.

Production Method 1 Compound (I) is a commercially available compound (M) or a known method [WO98
/ 24802, WO98 / 32763, WO98 / 11124, WO99 / 27935, WO98 / 4
2729, WO99 / 27936, WO99 / 03876, WO99 / 33858, WO97 / 300
41, WO01 / 02349, WO01 / 04086, WO97 / 32872, WO99 / 5289
0, WO97 / 06793, etc.] or from a compound (M) obtained according to them, or the like, by the following reaction step.

[0055]

[Chemical 18]

(Wherein R ¹ , R ² and R ³ have the same meanings as defined above) Step 1 In the compound (I), the compound (Ia) in which both R ¹ and R ² are hydrogen atoms is (M) can be obtained by reacting (M) with thiophosphoryl chloride [P (= S) Cl ₃ ] in a solvent in the presence or absence of a base, and then treating the reaction solution with an aqueous alkali solution or an aqueous acid solution. it can.

The compound (Ib) in which R ¹ and R ² are the same or different and is a substituted or unsubstituted lower alkyl among the compounds (I) can be prepared by reacting the compound (M) in a solvent in the presence of a base with thiophosphoryl chloride. After reacting with [P (= S) Cl ₃ ],
^{Treated with 1b} OH (wherein R ^1b represents a substituted or unsubstituted lower alkyl having the same meaning as described above) and R ^2b OH (wherein R ^2b represents a substituted or unsubstituted lower alkyl having the same meaning as described above) It can be obtained by

Compound (Ic) in which one of R ¹ and R ² is a hydrogen atom in compound (I) can be prepared by reacting compound (M) in a solvent in the presence of a base with thiophosphoryl chloride [P ( = S) Cl
₃ ] and then treating the reaction solution with an aqueous alkali solution or an aqueous acid solution and R ^1b OH or R ^2b OH. Examples of the reaction solvent include tetrahydrofuran (THF), N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DM
A), 1,3-dimethyl-2-imidazolidinone, toluene, dichloromethane, chloroform, 1,2-dichloroethane, 1-methyl-2-piperidone and the like,
They can be used alone or as a mixture thereof.

Examples of the base include sodium hydride,
Potassium carbonate, sodium carbonate, sodium hydrogen carbonate,
Cesium carbonate, lithium hydroxide, potassium tert-butoxide, 2,6-di (tert-butyl) -4-methylpyridine, pyridine, 2,6-di (tert-butyl) pyridine, 2,6-lutidine, triethylamine,
Diisopropylethylamine, 4- (dimethylamino)
Pyridine or the like is used, and pyridine is preferable. When the base is a liquid, it can also be used as a solvent.

As the alkaline aqueous solution, for example, sodium hydroxide aqueous solution, sodium hydrogen carbonate aqueous solution, potassium hydroxide aqueous solution, sodium carbonate aqueous solution and the like are used.
As the acid aqueous solution, for example, hydrochloric acid, hydrobromic acid or the like is used. Thiophosphoryl chloride [P (= S) Cl ₃ ] is a compound (M)
Used in an amount of 1 to 20 equivalents.

The base is used in 0.1 to 20 equivalents relative to compound (M). R ^1b OH and R ^2b OH are 1 with respect to the compound (M).
~ 100 equivalents are used. The alkaline aqueous solution and the acid aqueous solution are
Relative to the compound (M), 0.5 to 1.5 equivalents in the case of either of R ¹ and R ² to obtain a compound which is a hydrogen atom, when R ¹ and R ² get together represent hydrogen atom 2-1
Used at 00 equivalents.

The reaction is usually carried out at a temperature between -78 ° C and 120 ° C, preferably at a temperature between -20 ° C and 60 ° C, and is completed in 5 minutes to 72 hours. Production Method 2 Of the compound (I), the compound (Ib) in which R ¹ and R ² are the same or different and are substituted or unsubstituted lower alkyl,
It can also be obtained from the compound (M) by the following reaction step.

[0063]

[Chemical 19]

(Wherein R ^1b , R ^2b and R ³ are as defined above) Step 2 Compound (Ib) is prepared by reacting compound (M) in a solvent in the presence of a base (R
^1b O) (R ^2b O) P (═S) Cl (in the formula, R ^1b and R ^2b each have the same meaning as described above).

As the solvent, for example, THF, DMF, D
MA, 1,3-dimethyl-2-imidazolidinone, toluene, dichloromethane, chloroform, 1,2-dichloroethane, 1-methyl-2-piperidone, and the like,
They can be used alone or as a mixture thereof. Examples of the base include sodium hydride, potassium carbonate,
Sodium carbonate, sodium hydrogen carbonate, cesium carbonate,
Lithium hydroxide, potassium tert-butoxide, 2,
6-di (tert-butyl) -4-methylpyridine, pyridine, 2,6-di (tert-butyl) pyridine,
2,6-lutidine, triethylamine, diisopropylethylamine, 4- (dimethylamino) pyridine and the like are used, and pyridine is preferable. When the base is a liquid, it can be used also as a solvent, and the base is used in 0.1-30 equivalents, preferably 1-20 equivalents, relative to compound (M). (R ^1b O) (R ^2b O) P (= S) Cl is 1 relative to the compound (M).
-30 equivalents, preferably 1-20 equivalents are used.

The reaction is usually carried out at a temperature between -78 ° C and 120 ° C, preferably at a temperature between -20 ° C and 60 ° C, and is completed in 5 minutes to 72 hours. In compound (I) and starting compounds
R ^1, conversion of R ² or R ³ and R ^1, the conversion of functional groups contained in the substituents R ² or R ³ are other methods known in addition to the above process [for example, Comprehensive Organic Transformations (Comprehensive Organic Tran
sformations), RC Larock, (1989
Year)] etc.

A compound having a desired functional group at a desired position can be obtained by appropriately combining the above methods and the like.
(I) can be obtained. Isolation and purification of the product in the above production method can be carried out by appropriately combining methods used in ordinary organic synthesis such as filtration, extraction, washing, drying, concentration, crystallization and various chromatographies.
In addition, the intermediate may be subjected to the next reaction without being particularly purified.

Although some isomers such as positional isomers, geometric isomers and optical isomers may exist in the compound (I), all possible isomers including these isomers and any of these isomers are possible. Mixtures in ratios can also be used in the steroid sulfatase inhibitors of the present invention. Compound
When it is desired to obtain the salt of (I), when the salt of compound (I) is obtained, it may be purified as it is, and when the compound (I) is obtained in a free form, the compound (I) is used in a suitable manner. It may be dissolved or suspended in a solvent and added with an acid or a base to form a salt.

The compound (I) or a pharmaceutically acceptable salt thereof may exist in the form of an adduct with water or various solvents, and these adducts are also included in the steroid sulfatase inhibitor of the present invention. Can be used. Compound
Table 1 shows specific examples of (I).

[0070]

[Table 1]

Next, the pharmacological activity of the representative compound (I) will be described with reference to test examples. Test Example 1: Steroid sulfatase inhibition test 4-methylumbelliferyl sulfate (4-methylum)
belliferyl sulfate, final concentration: 0.3 mmol / L), recombinant human estrone sulfatase (recombinant human)
estrone sulfatase, 7.8 ng / well) and each test concentration of compound (I) [compound (I) was dissolved in 0.001 mL of dimethyl sulfoxide (DMSO)] at 0.28 mol / L sucrose and 0.04 It added to the phosphate buffer (pH 7.5, final volume; 0.1 mL) containing mol / L nicotinamide, and performed the enzyme reaction at 37 degreeC for 1 hour. As the recombinant human estrone sulfatase, the human estrone sulfatase gene was introduced into CHO (Chinese Hamster Ovary) cells and expressed, and then partially purified and used. After completion of the enzymatic reaction, 2 mol / L glycine-sodium hydroxide aqueous solution (pH 10.3, 0.13 mL) was added and stirred, and the produced 4-methylumbelliferone (4-methylumbelliferone) was used using a fluorescence plate reader (Cyto FluorII). ) Fluorescence intensity was measured. The measurement was performed once by duplicate, and the intra-assay variation was 10% or less.
An enzymatic reaction in the absence of the test compound was also performed at the same time. The estrone sulfatase inhibitory activity at each concentration of the test compound was calculated by the following formula. A: Amount of 4-methylambelliferone produced in the presence of the test compound B: Amount of 4-methylambelliferone produced in the absence of the test compound

[0072]

[Equation 1]

The estrone sulfatase inhibitory activity of the compound (I) is such that the estrone sulfatase activity is half that of the case where the test compound is not added.
It can be expressed by the concentration (IC ₅₀ ) of (I). The results obtained in Test Example 1 are shown in Table 2.

[0074]

[Table 2]

According to Table 2, Compound (I) exhibits a steroid sulfatase inhibitory action and is considered to be useful as a therapeutic agent and / or preventive agent for steroid hormone-dependent diseases. The compound (I) or a pharmaceutically acceptable salt thereof is orally or parenterally administered as it is or as various pharmaceutical compositions. Examples of the dosage form of such a pharmaceutical composition include tablets, powders, granules, injections and the like.

For the formulation of the above-mentioned dosage form, a generally known method is applied. For example, the obtained formulation is various excipients, lubricants, binders, disintegrating agents, suspending agents, isotonic agents. , An emulsifier, an absorption promoter, etc. may be contained. Examples of the carrier used in the pharmaceutical composition include water, distilled water for injection, physiological saline, glucose, fructose, sucrose, mannitol, lactose, starch, corn starch, cellulose, methyl cellulose, carboxymethyl cellulose, hydroxypropyl cellulose. , Polyvinyl alcohol, alginic acid, talc, sodium citrate, calcium carbonate,
Examples thereof include calcium hydrogen phosphate, magnesium stearate, urea, silicone resin, sorbitan fatty acid ester, glycerin fatty acid ester and the like, and these are appropriately selected depending on the type of preparation.

The dose and frequency of administration of the compound (I) used for the above purpose may vary depending on the desired therapeutic or prophylactic effect, administration method, treatment period, age, body weight, etc., but it may be orally or parenterally administered. Administration (eg injection)
Therefore, the usual daily dose for an adult is 0.01 to 20 mg / kg, once or several times a day.

[0078]

EXAMPLES Examples will be described below. ¹ H-NMR used in the examples was measured at 270 MHz, and in the parentheses after the δ value of each signal, the observed multiplicity, coupling constant (unit: Hz), proton The numbers are shown in order. Example 1 (Compound 1) Raw material compound 1 obtained according to the method described in WO00 / 43408
a (300 mg, 0.884 mmol) was dissolved in pyridine (3 mL), thiophosphoryl chloride (0.359 mL, 3.54 mmol) was added, and the mixture was stirred at room temperature for 3 hours. 3 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified by preparative thin layer chromatography (chloroform / methanol = 4/1) to give compound 1
(145 mg, yield 56%) was obtained. ESI-MS m / z: 434 [MH] ^- . ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.84 (t, J = 7.4 Hz, 3H),
0.92 (s, 3H), 1.37-1.56 (m, 7H), 1.87 (m, 1H), 2.
03 (m, 1H), 2.27 (m, 4H), 2.81 (m, 2H), 3.04 (m, 2
H), 6.35 (s, 1H), 6.85 (s, 1H), 6.91 (d, J = 8.9 H
z, 1H), 7.23 (d, J = 8.6 Hz, 1H), 7.27 (t, J = 5.6
Hz, 1H).

Example 2 (Compound 2) Starting material compound 2a (300 mg, 0.786 mmol) and thiophosphoryl chloride (0.319 mL, 3.14 mmol) obtained according to the method described in WO00 / 43408 according to Example 1 were used. ) From compound 2
(134 mg, yield 36%) was obtained. FAB-MS m / z:. 500 [M + Na] + 1 H-NMR (DMSO-d 6) δ (ppm): 0.98 (s, 3H), 1.03-1.63
(m, 17H), 1.79 (m, 1H), 2.04 (m, 1H), 2.75 (br s, 2
H), 3.35 (br s, 2H), 5.63 (s, 1H), 6.75-7.00 (m, 3
H).

Example 3 (Compound 3) Starting material compound 3a (200 mg, 0.506 mmol) obtained according to the method described in WO99 / 03876 according to Example 1 and thiophosphoryl chloride (0.206 mL, 2.02 mmol) ) From compound 3
(29 mg, yield 12%) was obtained. FAB-MS m / z:. 514 [M + Na] + 1 H-NMR (DMSO-d 6) δ (ppm): 0.85 (t, J = 6.8 Hz, 3H),
0.90 (s, 3H), 1.41-1.50 (m, 15H), 1.83 (m, 1H),
2.03 (m, 1H), 2.24 (m, 4H), 2.76 (m, 2H), 3.07 (m,
2H), 6.31 (s, 1H), 6.87 (s, 1H), 6.95-7.07 (m, 2
H), 7.68 (t, J = 5.8 Hz, 1H).

Example 4 (Compound 4) Step 4-1 Tetrahedron Letters, 2
3-Methoxyestra-1,3,5 (10), 16-tetraene-17-carboxylic acid (68.6 mg, 0.220 mmol) obtained according to the method described in Volume 6, page 1109 (1985).
Was dissolved in dichloromethane (4 mL), oxalyl chloride (0.075 mL, 0.88 mmol) was added under ice cooling, the temperature was raised to room temperature, and the mixture was stirred at the same temperature for 1 hr. The solvent was distilled off from the reaction solution under reduced pressure to give 3-methoxyestradi-1,3,5 (1
0), 16-Tetraene-17-carboxylic acid chloride was obtained as a concentrated residue. The obtained residue was dissolved in dichloromethane (4 mL), and piperidine (0.087 mL, 0.88 mmo
l) was added, and the mixture was stirred at room temperature for 5 hours. 1 mol / L hydrochloric acid was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (chloroform → chloroform / methanol = 100/1). The obtained solid was dissolved in dichloromethane (5 mL), and 1.0 mol / L boron tribromide solution in dichloromethane (0.40 mL, 0.40 mmol) under ice cooling.
Was added and the mixture was stirred at the same temperature for 2 hours. The reaction solution was warmed to room temperature and further stirred for 1 hour. Methanol (10m
L) was added, the mixture was stirred at room temperature for 1 hr, water was added, and the mixture was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was evaporated to give the starting compound 4a (106 mg) as a crude product. TOF-MS m / z: 366 [M + H] ^{+ 1} H-NMR (CDCl ₃ ) δ (ppm): 1.08 (s, 3H), 1.30-1.76 (m,
12H), 1.86-2.40 (m, 5H), 2.72-3.00 (m, 2H), 3.40-
3.70 (m, 4H), 5.76 (dd, J = 1.3, 3.0 Hz, 1H), 6.61
(d, J = 2.3 Hz, 1H), 6.65 (dd, J = 2.3, 8.3 Hz, 1
H), 7.11 (d, J = 8.3 Hz, 1H).

Step 4-2 According to Example 1, starting material compound 4 obtained in step 4-1
a (70.6 mg, 0.193 mmol) and thiophosphoryl chloride (0.0
From 78 mL, 0.77 mmol), compound 4 (25 mg, yield 28%)
Got APCI-MS m / z: 460 [MH] ^- . ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.99 (s, 3H), 1.47-1.58
(br, 11H), 1.80 (m, 1H), 2.07 (m, 1H), 2.26 (m, 4
H), 2.76 (m, 2H), 3.48 (br s, 4H), 5.74 (s, 1H),
6.88 (br s, 2H), 7.06 (d, J = 9.4 Hz, 1H).

Example 5 (Compound 5) Step 5-1 According to Step 4-1 of Example 4, chloride of 3-methoxyestra-1,3,5 (10), 16-tetraene-17-carboxylic acid was prepared. The product was reacted with 2- (aminomethyl) -5-methylpyrazine and then treated with a dichloromethane solution of 1.0 mol / L boron tribromide to obtain the starting compound 5a. ESI-MS m / z: 404 [M + H] ^{+ 1} H-NMR (DMSO-d ₆ ) δ (ppm): 0.92 (s, 3H), 1.36-1.57
(m, 5H), 1.84 (m, 1H), 2.06 (m, 1H), 2.10-2.31 (m,
4H), 2.51 (s, 3H), 2.75 (m, 2H), 4.41 (d, J = 5.9 H
z, 2H), 6.44 (d, J = 2.3 Hz, 1H), 6.49 (m, 2H), 7.
03 (d, J = 8.6Hz, 1H), 8.39-8.45 (m, 3H), 8.98 (s,
1H).

Step 5-2 According to Example 1, raw material compound 5 obtained in step 5-1
a (150 mg, 0.372 mmol) and thiophosphoryl chloride (0.15
Compound 5 (17 mg, yield 9%) was obtained from 1 mL, 1.49 mmol). APCI-MS m / z: 498 [MH] ^- . ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.93 (s, 3H), 1.30-1.59
(m, 5H), 1.88 (m, 1H), 2.06 (m, 1H), 2.28 (m, 4H),
2.75 (m, 2H), 4.41 (d, J = 5.3 Hz, 2H), 6.49 (s, 1
H), 6.88 (s, 1H), 7.01 (br s, 1H), 7.07 (d, J = 8.
9 Hz, 1H), 8.40 (s, 1H), 8.43 (m, 1H), 8.46 (s, 1
H).

Example 6 (Compound 6) Step 6-1 4-acetoxybenzoic acid (1.04 g, 6.04 mmol) was dissolved in dichloromethane (30 mL) and triethylamine (1.0
1 mL, 7.25 mmol) and ethyl chloroformate (0.572 mL,
7.25 mmol) was added and the mixture was stirred at room temperature for 10 minutes. A dichloromethane solution (30 mL) of tyramine (1.24 g, 9.06 mmol) was added to the reaction solution, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure to give 4- [2- (4-hydroxyphenyl) ethylcarbamoyl] phenylacetate (869 mg, yield 48% ) Got. ¹ H-NMR (CDCl ₃ ) δ (ppm): 2.31 (s, 3H), 2.86 (t, J =
6.9 Hz, 2H), 3.68 (m, 2H), 5.10 (br s, 1H), 6.06 (b
rs, 1H), 6.80 (d, J = 8.6 Hz, 2H), 7.09 (d, J =
8.6 Hz, 2H), 7.14 (d, J = 8.6 Hz, 2H), 7.71 (d, J
= 8.6 Hz, 2H).

Step 6-2 4- [2- (4-hydroxyphenyl) ethylcarbamoyl] phenylacetate (250
mg, 0.835 mmol), triphenylphosphine (262 mg,
1.00 mmol) and 1-pentanol (0.109 mL, 1.00
mmol) in THF (7.5 mL), and 40% diethyl azodicarboxylate solution in toluene (0.500 mL, 1.10) under ice cooling.
mmol) was added and the mixture was stirred at room temperature for 3 hours. A saturated aqueous ammonium chloride solution was added to the reaction solution, and the mixture was extracted with ethyl acetate.
The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was added to methanol (5.
It was dissolved in 0 mL), 28% sodium methoxide in methanol (0.300 mL) was added, and the mixture was stirred at room temperature for 1.5 hours. A saturated ammonium chloride aqueous solution was added to the reaction solution, and the mixture was extracted with chloroform. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue is subjected to silica gel column chromatography (chloroform /
Purified with methanol = 20/1), starting compound 6a {N-
[2- (4-pentyloxyphenyl) ethyl] -4-
Hydroxybenzamide} (218 mg, yield 80%) was obtained. ¹ H-NMR (CDCl ₃ ) δ (ppm): 0.93 (t, J = 6.9 Hz, 3H),
1.37-1.44 (m, 4H), 1.78 (m, 2H), 2.86 (t, J = 6.6 H
z, 2H), 3.66 (t, J = 6.9 Hz, 2H), 3.94 (t, J = 6.6
Hz, 2H), 5.71 (br s, 1H), 6.05 (br s, 1H), 6.84
(d, J = 8.6 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 7.1
3 (d, J = 8.6 Hz, 2H), 7.59 (d, J = 8.6Hz, 2H).

Step 6-3 According to Example 1, raw material compound 6 obtained in Step 6-3
a (300 mg, 0.916 mmol) and thiophosphoryl chloride (0.37
From 2 mL, 3.66 mmol), compound 6 (127 mg, yield 33%)
Got APCI-MS m / z: 447 [MH] ^- . ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 0.89 (t, J = 7.1 Hz, 3H),
1.36 (m, 4H), 1.67 (m, 2H), 2.74 (t, J = 7.4 Hz,
2H), 3.39 (m, 2H), 3.90 (t, J = 6.4 Hz, 2H), 6.78
(d, J = 8.6 Hz, 2H), 6.83 (d, J = 8.6 Hz, 2H), 7.1
2 (d, J = 8.6 Hz, 2H), 7.68 (d, J = 8.9 Hz, 2H),
8.26 (t, J = 5.4 Hz, 1H).

Example 7 (Compound 7) In accordance with Example 1, starting material compound 7a (4′-nitrobiphenyl-4-ol) (200 mg, 0.929 mmol) and thiophosphoryl chloride (0.377 mL, 3.72 mmol) were used. , Compound 7
(87 mg, yield 30%) was obtained. APCI-MS m / z: 310 [MH] ^- . ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 7.37 (d, J = 8.6 Hz, 2H),
7.74 (d, J = 8.9 Hz, 2H), 7.94 (d, J = 8.9 Hz, 2
H), 8.28 (d, J = 8.9 Hz, 2H).

Example 8 (Compound 8) Starting compound 8a (3-hydroxy-8,9,1) obtained according to the method described in WO97 / 30041 according to Example 1.
From 0,11-tetrahydro-7H-cyclohepta [c] chromen-6-one) (300 mg, 1.30 mmol) and thiophosphoryl chloride (0.396 mL, 3.90 mmol), compound 8 (10
1 mg, yield 24%) was obtained. ¹ H-NMR (DMSO-d ₆ ) δ (ppm): 1.51 (m, 2H), 1.60 (m, 2
H), 1.82 (m, 2H), 2.79 (m, 2H), 2.97 (m, 2H), 7.19
(br d, J = 8.9 Hz, 1H), 7.22 (br s, 1H), 7.82 (d,
J = 8.9 Hz, 1H). Table 3 shows the structures of the raw material compounds 1a to 8a used in the examples.

[0090]

[Table 3]

Formulation Example 1 (tablets) A tablet having the following composition is prepared by a conventional method. Compound 1 5 mg Lactose 60 mg Potato starch 30 mg Polyvinyl alcohol 2 mg Magnesium stearate 1 mg Tar dye Formulation example 2 (granules) A granule having the following composition is prepared by a conventional method. Compound 2 5 mg Lactose 280 mg

[0092]

INDUSTRIAL APPLICABILITY The present invention provides a steroid sulfatase inhibitor containing a thiophosphate derivative or a pharmacologically acceptable salt thereof as an active ingredient. The present invention also provides a thiophosphate derivative or a pharmaceutically acceptable salt thereof, which has a steroid sulfatase inhibitory action and is useful, for example, in the treatment and / or prevention of steroid hormone-dependent diseases.

─────────────────────────────────────────────────── ─── Continuation of front page (51) Int.Cl. ⁷ Identification code FI theme code (reference) C07J 41/00 C07J 41/00 43/00 43/00 F term (reference) 4C086 AA01 AA02 AA03 DA36 DA38 EA19 MA01 NA14 ZB26 ZC03 ZC10 ZC11 ZC20 4C091 AA02 BB03 BB04 BB07 BB11 CC01 DD01 EE03 FF01 GG01 HH01 JJ01 KK01 LL01 MM01 NN01 PA02 PA12 PA13 QQ01

Claims (28)

[Claims] 1. Formula (I): (In the formula, R ¹ and R ² are the same or different and each represents a hydrogen atom or a substituted or unsubstituted lower alkyl,
-R ³ is thiophosphate derivative or a steroid sulfatase inhibitor containing a pharmacologically acceptable salt thereof as an active ingredient represented by monocyclic represents the residue or polycyclic residue of an alcohol of the alcohol). 2. The monocyclic alcohol and the polycyclic alcohol in the residue of the monocyclic alcohol and the residue of the polycyclic alcohol are the sulfate compounds corresponding to these compounds, and the thiol of the compound represented by the formula (I). The compound obtained by converting a phosphate group into a sulfate group] is a monocyclic alcohol or a polycyclic alcohol serving as a substrate for a steroid sulfatase enzyme, and the steroid sulfatase inhibitor according to claim 1. 3. The steroid sulfatase inhibitor according to claim 1, wherein -O-R ³ is a residue of a substituted or unsubstituted sterol. 4. —O—R ³ is a substituted or unsubstituted 3-
The steroid sulfatase inhibitor according to claim 1 or 2, which is a residue of sterol. 5. The steroid sulfatase inhibitor according to claim 4, wherein the 3-sterol is estrone or dehydroepiandrosterone. 6. R³Is the formula (A) [Chemical 2] (Wherein the ring system ABCD is a substituted or unsubstituted saturated
Represents an unsaturated steroid nucleus), formula (B) [Chemical 3] <In the formula, Q is an oxygen atom, a sulfur atom or -N (-Z)-
(In the formula, Z is a hydrogen atom or a substituted or unsubstituted lower
Represents alkyl), Y¹, Y², Y³, Y^FourAnd Y^FiveIs
The same or different, hydrogen atom, halogen, nitro,
Ano, azide, substituted or unsubstituted lower alkyl, position
Substituted or unsubstituted cycloalkyl, substituted or unsubstituted
Substituted lower alkenyl, substituted or unsubstituted lower alkyl
Nyl, substituted or unsubstituted aryl, substituted or non-substituted
Substituted heterocyclic group, -C (= X¹) R^Four[Where X ¹Is an oxygen atom
Or represents a sulfur atom, R^FourIs a hydrogen atom, substituted or
Unsubstituted lower alkyl, substituted or unsubstituted cycloalkyl
Alkyl, substituted or unsubstituted lower alkenyl, also substituted
Or unsubstituted lower alkynyl, substituted or unsubstituted
Aryl, substituted or unsubstituted heterocyclic group, -NR^FiveR
⁶(In the formula, R^FiveAnd R⁶Are the same or different and
Child, substituted or unsubstituted lower alkyl, substituted or
Unsubstituted cycloalkyl, substituted or unsubstituted lower alkyl
Also alkenyl, substituted or unsubstituted aryl or substituted
Or an unsubstituted heterocyclic group), -OR⁷(In the formula, R
⁷Is a hydrogen atom, substituted or unsubstituted lower alkyl,
Substituted or unsubstituted cycloalkyl, substituted or unsubstituted
Substituted lower alkenyl, substituted or unsubstituted aryl
Or represents a substituted or unsubstituted heterocyclic group) or-
SR⁸(In the formula, R⁸Is the R⁷Synonymous with)], -N
R⁹R^Ten{In the formula, R⁹And R^TenAre the same or different, water
Elementary atom, substituted or unsubstituted lower alkyl, substituted if
Or unsubstituted cycloalkyl, substituted or unsubstituted low
Primary alkenyl, substituted or unsubstituted aryl, substituted also
Or an unsubstituted heterocyclic group, -C (= X²) R¹¹(In the formula, X²And
And R¹¹Are each X¹And R^FourSynonymous with)
Is -SO₂R¹²[In the formula, R¹²Is a substituted or unsubstituted lower
Alkyl, substituted or unsubstituted cycloalkyl, substituted
Or unsubstituted lower alkenyl, substituted or unsubstituted
Aryl, substituted or unsubstituted heterocyclic group, -NR¹³R
¹⁴(In the formula, R¹³And R¹⁴Are each R^FiveAnd R⁶When
Are synonymous) or -OR¹⁵(In the formula, R¹⁵Is the R⁷Same as
Represents the meaning of]], -OR¹⁶[In the formula, R¹⁶Is
Hydrogen atom, substituted or unsubstituted lower alkyl, substituted
Or unsubstituted cycloalkyl, substituted or unsubstituted
Lower alkenyl, substituted or unsubstituted aryl, substituted
Or an unsubstituted heterocyclic group or --SO₂R¹⁷(In the formula, R¹⁷
Is the R¹²Synonymous with)], -S (O)_mR¹⁸(formula
Inside, m represents an integer of 0 to 1, R¹⁸Is the R⁷Synonymous with
) Or −SO₂R¹⁹(In the formula, R¹⁹Is the R¹²Synonymous with
Or Y¹And Y²Together,-(CH₂)_n
-(Wherein n represents an integer of 4 to 9)> or
Expression (C) [Chemical 4] [Where Y⁶Is a hydrogen atom, a substituted or unsubstituted lower
Alkyl, substituted or unsubstituted cycloalkyl, substituted also
Or unsubstituted lower alkenyl, substituted or unsubstituted
Lower alkynyl, substituted or unsubstituted aryl, substituted
Or an unsubstituted heterocyclic group, -C (= X^1A) R^4A(In the formula, X^1A
And R^4AAre each X¹And R^FourSynonymous with
), − (CH₂)_na-NR^9AR^10A(In the formula, na is an integer from 0 to 5
Represents R^9AAnd R^10AAre each R⁹And R^TenWhen
Synonyms), -OR^16A(In the formula, R^16AIs the R¹⁶Synonymous with
, -S (O)_maR^18A(Where ma and R^18AIs it
M and R above⁷Synonymous with) or -SO₂R^19A(formula
Medium, R^19AIs the R¹²Is synonymous with)]
The steroid sulfatase inhibitor according to claim 1. 7. The steroid sulfatase inhibitor according to claim 1, wherein R ³ is formula (A). 8. The steroid sulfatase inhibitor according to claim 1, wherein R ³ has the formula (B). 9. The steroid sulfatase inhibitor according to claim 1, wherein R ³ is formula (C). 10. The steroid sulfatase inhibitor according to claim 9, wherein Y ⁶ is a substituted or unsubstituted heterocyclic group. 11. The steroid sulfatase inhibitor according to claim 7, wherein ring A is a benzene ring or a cyclohexene ring. 12. R ³ is a substituted or unsubstituted 3-oestra-1,3,5 (10) -trien-17-one-3.
-Yl or a substituted or unsubstituted (3β) -3-androst-5-en-17-one-3-yl, The steroid sulfatase inhibitor according to claim 1 or 2. 13. The steroid sulfatase inhibitor according to claim 1, wherein R ¹ and R ² are hydrogen atoms. 14. Formula (IA) [Chemical 5] {In the formula, R^3AIs the formula (A) [Chemical 6] (Wherein the ring system ABCD is as defined above), formula (B) [Chemical 7] (Where Q, Y¹, Y², Y³, Y^FourAnd Y^FiveAre the above and
Synonymous) or formula (D) [Chemical 8] [Where Y^6AIs a substituted or unsubstituted lower alkenyl
Group, substituted or unsubstituted aryl, -C (= X^1A) R
^4A(In the formula, X^1AAnd R^4AAre each X¹And R^FourWhen
Synonyms),-(CH₂)_nb-NR^9AR^10A(In the formula, nb is 0 or
Or represents an integer of 2 to 5, R^9AAnd R^10ARespectively before
Note R⁹And R^TenSynonymous with), -OR^16A(In the formula, R
^16AIs the R¹⁶Synonymous with), -S (O)_maR^18A(In the formula,
ma and R^18AAre m and R respectively⁷Synonymous with
) Or −SO₂R^19A(In the formula, R^19AIs the R¹²Synonymous with
A) but with a substituted or unsubstituted vinyl
A thiophosphate derivative of
Is a pharmacologically acceptable salt thereof. 15. The thiophosphate derivative according to claim 14, wherein R ^3A is formula (A), or a pharmaceutically acceptable salt thereof. 16. The thiophosphate derivative according to claim 15, wherein ring A is a benzene ring or a cyclohexene ring, or a pharmaceutically acceptable salt thereof. 17. R ^3A is a substituted or unsubstituted 3-oestra-1,3,5 (10) -trien-17-one-
The thiophosphate derivative or a pharmaceutically acceptable salt thereof according to claim 14, which is 3-yl or a substituted or unsubstituted (3β) -3-androst-5-en-17-on-3-yl. 18. The thiophosphate derivative according to claim 14, wherein R ^3A is formula (B), or a pharmaceutically acceptable salt thereof. 19. The thiophosphate derivative according to claim 14, wherein R ^3A is formula (D), or a pharmaceutically acceptable salt thereof. 20. The thiophosphate derivative according to claim 19, wherein Y ^6A is a substituted or unsubstituted heterocyclic group, or a pharmaceutically acceptable salt thereof. 21. The thiophosphate derivative or a pharmaceutically acceptable salt thereof according to claim 19, wherein Y ^6A is substituted or unsubstituted pyrazolyl or substituted or unsubstituted oxazolyl. 22. A therapeutic agent for breast cancer, endometrial cancer, ovarian cancer or prostate cancer, containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of claims 14 to 21 as an active ingredient, and / Or preventive agent. 23. An antitumor agent containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of claims 14 to 21 as an active ingredient. 24. A therapeutic and / or prophylactic agent for a disease involving steroid sulfatase, which comprises the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of claims 14 to 21 as an active ingredient. 25. A therapeutic and / or prophylactic agent for a steroid hormone-dependent disease containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of claims 14 to 21 as an active ingredient. 26. A medicine containing the thiophosphate derivative or the pharmaceutically acceptable salt thereof according to any one of claims 14 to 21 as an active ingredient. 27. The thiophosphate derivative according to any one of claims 14 to 21 or a pharmaceutically acceptable derivative thereof, which produces a phenol derivative having an anti-estrogen action by hydrolysis of the thiophosphate moiety in the molecule in vivo. A steroid sulfatase inhibitor containing a salt as an active ingredient. 28. -O-R ^3A is, in any one of claims 14 to 21 sulfate compound of R ^3A -OH is a residue of a monocyclic alcohol or polycyclic alcohols as a substrate for steroid sulfatase enzyme A steroid sulfatase inhibitor containing the thiophosphate derivative or the pharmacologically acceptable salt thereof as an active ingredient.