WO1999051623A1 - DEPRESSANT FOR PRODUCTION OF TGF-$g(b) - Google Patents

Abstract

A medicine composition comprising, as an active component, an oleanane derivative represented by formula (1), wherein Me represents methyl, with respect to X, Y and Z; any of (1), (2), (3) and (4) is selected: (1) X and Z together represents a bonding and Y represents hydrogen; (2) X and Y together represents an oxo and Z represents hydrogen; (3) X represents hydroxy and each of Y and Z represents hydrogen; (4) Y represents hydroxy and each of X and Z represents hydrogen; R1 represents (1) hydroxy, (2) a substituted or unsubstituted monoalkylamino, (3) a substituted or unsubstituted cyclic amino, (4) a substituted or unsubstituted alkoxy, or the like; R2 represents (1) hydroxy, (2) a substituted or unsubstituted sulfoxy, (3) a substituted or unsubstituted phosphoxy, (4) a substituted or unsubstituted acyloxy, or the like; R3 represents (1) hydrogen, (2) hydroxy, (3) a substituted or unsubstituted sulfoxy, (4) a substituted or unsubstituted phosphoxy, (5) a substituted or unsubstituted acyloxy, or the like; or a pharmaceutically acceptable salt thereof. The medicine composition is useful as a depressant for production of TGF-β.

Description

 Specification

 TG F— production inhibitor

 Technical field

 The present invention relates to a TGF-β (transforming growth factor-j3) production inhibitor comprising an oleanan derivative or a pharmaceutically acceptable salt thereof as an active ingredient. The TGF- / 3 production inhibitor is useful for the prevention or treatment of diseases characterized mainly by fibrotic proliferative, scarring, or sclerotic lesions involving TGF-] 3.

 Background technology

 TGF-i3 is an important cytokine that regulates cell proliferation, differentiation, repair and regeneration after tissue injury. TGF-] 3 promotes angiogenesis during repair of injured tissue, and also enhances the production and deposition of extracellular matrix (laminin Bl, fibronectin, collagen, tenascin, and proteodalican, etc.) .

 The production and deposition of extracellular matrix by TGF-] 3 consists of the following three mechanisms. First, TGF-3 promotes extracellular matrix protein gene expression and increases extracellular matrix protein synthesis and secretion. Second, TGF-β inhibits the synthesis of proteases that degrade the synthesized extracellular matrix, and at the same time increases the synthesis of protease inhibitors. Third, TGF-3 adds integrin, a receptor for the extracellular matrix, and promotes the deposition of pericellular matrix.

 Thus, TGF- regulates the proliferation and differentiation of various cells including fibroblasts, which are the main constituent cells of fibrous tissue, and regulates the production and deposition of extracellular matrix, which is essential for wound healing. It has a very important role for living organisms. However, once any excess TGF- / 3 production or hyperactivity occurs and persists for some reason, it is a systematic, organ or systemic fibrotic reproductive, scarring, or sclerotic lesion Causes diseases characterized by sexual lesions.

Therefore, in order to improve the above-mentioned diseases in which TGF- / 3 is involved, it is essential to suppress excessive TGF-] 3 production or increase in activity (Border, WA et al., J Clin. Invest., (90), 1-7, 1992), and drugs having these effects can be therapeutic drugs for the above diseases. Until now, it has not been known that oleanan derivatives have a TGF-β production inhibitory action.

 Disclosure of the invention

 An object of the present invention is to provide a novel TGF- production inhibitor.

 The present inventors have sought for such a compound and have been conducting research. As a result, the present inventors have found that an oleanan derivative achieves the above object, and have completed the present invention. The present invention relates to a compound represented by the following formula [1], wherein the oleanane derivative is any of the following (A), (Β), or (C): A TGF-production inhibitor comprising a chemically acceptable salt (hereinafter, referred to as the compound of the present invention) as an active ingredient.

In the formula, Me represents methyl.

 (A)

 X and Z together represent a bond. Y represents hydrogen.

R ¹ represents O Rll or N RUR ¹² . R ^u and R ¹² are the same or different and are (1) hydrogen, (2) alkyl which may have a substituent,) cycloalkyl which may have a substituent, (4) substituent (5) alkynyl optionally having a substituent, (6) aryl which may have a substituent, or (7) optionally having a substituent Represents an aromatic heterocyclic group.

RU, Anorekiru represented by R ^12, cycloalkyl Anore keno les, Anorekeninore, Anorekininore, Ariru, substituents which may be possessed by the aromatic heterocyclic渌基is, (a) halogen,

(b) ORl ³ , (c) OCOR ¹³ , (d) COORl3, (e) cyano, (f) NR ¹³ R ¹⁴ , (g) cycloalkyl, (h) halogen, alkyl, hydroxy or amino Phenyl and (i) substituted with halogen, alkyl, hydroxy or amino Selected from the group consisting of aromatic heterocyclic groups which may be substituted.

 Ri3 and R "are the same or different and denote (1) hydrogen or (2) anolequinole which may be substituted with hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino.

R ² and R ³ are the same or different and are (1) hydroxy, (2) optionally substituted alkoxy, (3) optionally substituted cycloalkyloxy, (4 ) Optionally substituted alkenyloxy, (5) optionally substituted alkynyloxy, (6) optionally substituted monoalkyl rubamoyloxy, (7) (8) alkoxycarbonyloxy optionally having a substituent, (9) alkylcarbonyloxy optionally having a substituent, or (9) alkylcarbonyloxy optionally having a substituent. 10) represents arylcarboxy which may have a substituent. Or R ² and R ³ together represent carbonyl.

2, alkoxy represented by R ^3, cycloalkyl O alkoxy, Arukeniruokishi, § Honoré yn Honoré oxy monoalkyl Kano lever Moi Honoré O carboxymethyl, di § Honoré kills Kano lever Moi Honoré Okishi, § Honoré Koki Shikano repo Nino les Substituents which oxy, anolequinolecanoleponinoleoxy, and arylene force may have are ( _a ) halogen, (b) OR ¹⁵ ,

^{(c) OCORl 5, (d} ) COORl 5, (e) ^{Shiano, (f) NR l5 R 16} , (g) cycloalkyl, (h) halogen, alkyl, optionally substituted with human Dorokishi or Amino Ari And (i) an aromatic compound, which may be substituted with halogen, alkyl, hydroxy or amino.

R ¹⁵ and R ¹⁶ are the same or different and represent (1) hydrogen or (2) alkyl optionally substituted with hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino.

 (B)

 X, Y, and Ζ are any of the following cases (1) to (4).

 (1) x and ζ together represent a bond. γ represents hydrogen.

 (2) X and Υ together represent oxo. Ζ represents hydrogen.

 (3) X represents hydroxy. Υ and Ζ each represent hydrogen.

(4) Υ represents hydroxy. X and Ζ each represent hydrogen. R ¹ represents any of the following substituents (1) to (4).

 (1) hydroxy,

 (2) monoalkylamino (the alkyl moiety of the monoalkylamino is selected from the group consisting of hydroxy, alkoxy, anoreoxycarbonyl, cyclic amino, anolequinolecarbonylamino, and alkylcarbonyloxy) May be substituted by one substituted group.),

 (3) cyclic amino (such cyclic amino may be replaced by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy),

(4) Alkoxy (The alkoxy may be substituted by one substituent selected from the group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, diamino, and alkylcarbonyloxy. The alkylcarbonyloxy may be substituted with an alkylcarbonylamino or an arylalkyloxy in which the aryl moiety may be substituted with an alkoxy.), And R ² represents the following (1) to (1) Represents any of the substituents of 4).

 (1) hydroxy,

(2) O S0 ₂ R ⁷ ,

(3) OP (= 0) (OR ⁸ ) (OR ⁹ ),

(4) OC (= 0) R 6.

R ³ represents any of the following substituents (1) to (5).

 (1) hydrogen,

 (2) hydroxy,

(3) OS0 ₂ R ^7,

 (4) O P (= 0) (O R8) (O R9),

 (5) OC (= 0) R6.

R ⁷ represents hydroxy, alkyl, or aryl.

R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, or aryl. R ⁶ represents the following substituents ① to ⑤.

① aryl substituted with alkyl substituted with N (R ⁴⁰ ) (R ⁴¹ ) R ⁴⁰ and R ⁴¹ are the same or different and each is hydrogen or alkyl (wherein such alkyl is one substituent selected from the group consisting of hydroxy, unsubstituted amino, monoalkylamino, and dialkylamino) Or R 40 and R 41, together with the adjacent N, represent N- (R ⁴⁰ ) (R ⁴¹ ) a linear amino. Such a cyclic amino may be substituted with an alkyl or heterocyclic group. ]

② Alkylene which may have one or both of substituents R ⁴² and R ⁴³ [The R ⁴² and R ⁴³ may be the same or different and are hydroxy, alkylthio, alkylsulfiel, alkylsulfonyl , Unsubstituted amino, carboxy, alkynolecarboninoleamino, alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy is one substituent selected from the group consisting of hydroxy, and unsubstituted amino) Or alkoxy (the alkoxy may be substituted by 1 to 2 aryls, and the aryl may be substituted by the alkoxy.) . ]

 (3) Cycloalkyl which may be substituted with aminoalkyl,

 ④ a heterocyclic group (the heterocyclic group may be substituted by one substituent selected from the group consisting of an alkyl optionally substituted by hydroxy, and a heterocyclic group);

 {Circle around (1)} 1 or 2 identical or different aminos optionally substituted by hydroxy, optionally substituted by alkyl.

Or, R ² and R ³ together represent the following formula:

R ²¹ and R ³¹ are the same or different and each represent hydrogen, alkyl, aryl, or a heterocyclic group; or R 21 and R SI together represent alkylene which may be substituted with alkyl.

X, Z are together a bond, Y is hydrogen, R 1 is hydroxy, monoalkylamino (the alkyl portion of such a monoalkylamino is a hydroxy, anoreoxy, Alkylcarboninoleoxy and anoreoxycarbonyl It may be substituted by one substituent selected from the group consisting of: ) Or alkoxy (such alkoxy may be substituted by one substituent selected from the group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, and unsubstituted alkylcarbonyloxy) R ^{2 is} hydroxy or OC (-0) R ⁶ , R ³ is chromium, hydroxy, or 0C (= 0) R ⁶ , and R ⁶ is the following (a ) Or (b>).

(a) alkyl which may have one or both of the substituents R ⁴² and R 4S (such R ⁴² and R ⁴³ may be the same or different and are hydroxy, unsubstituted amino, carboxy, anolequino Lecanolebonyloxy (the anorealkyl moiety of such anorealkylcarboninoleoxy may be substituted by hydroxy or unsubstituted amino), or unsubstituted alkoxy. ]

 (b) 1- or 2 identical or different aminos which may be substituted by an alkyl which may be substituted by a hydroxy.

 (C)

 X and Z together represent a bond. Y represents hydrogen.

R ¹ represents OR81 or N (R ⁸¹ ) (R ⁸² ).

R ⁸¹ and R ⁸² are the same or different and represent any of the following (1) to (7).

 (1) hydrogen,

 (2) an alkyl which may have a substituent,

 (3) cycloalkyl optionally having a substituent,

 (4) optionally substituted alkenyl,

 (5) alkynyl optionally having a substituent,

 (6) aryl which may have a substituent,

 (7) An aromatic heterocyclic group which may have a substituent.

The substituents that the alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and aromatic heterocyclic groups represented by R ⁸¹ and R ⁸² may have are the following substituents (a) to (i) 1-3 identical or different substituents selected from the group consisting of:

 (a) halogen,

(b) OR83, (c) O (C = 0) R ⁸³ ,

(d) COOR ⁸³ ,

 (e) Siano,

(f) N ( ^R83 ) ( ^R84 ),

 (g) cycloalkyl,

 (h) aryl, optionally substituted by one to three identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;

 (i) an aromatic heterocyclic group which may be substituted by 1 to 3 identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino.

R ⁸³ and R 84 are the same or different,

 ① Hydrogen or

 (2) represents an alkyl selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino, which may be substituted by one substituent.

R ² represents any of the following (1) to (10).

 (1) hydroxy,

 (2) an alkoxy optionally having a substituent,

 (3) a cycloalkyloxy which may have a substituent,

 (4) alkenyloxy optionally having a substituent,

 (5) alkynyloxy optionally having a substituent,

 (6) monoanolequinolecarbamoinoleoxy optionally having a substituent,

 (7) dialkyl power rubamoyloxy optionally having a substituent,

 (8) an alkoxycarbonyloxy optionally having a substituent,

 (9) an alkylcarbonyloxy optionally having a substituent,

 (10) aryl optionally substituted;

Alkoxy, cycloalkyloxy, alkenyloxy, alkyne / reoxy, monoalkyl rubamoyloxy, dialkyl rubamoinole represented by R ² The substituents which the oxy, anorecoxy propylonyloxy, alkylcanoleboninoleoxy and the aryl propylonoxy may have may be 1 to 3 substituents selected from the group consisting of the following substituents (a) to (i): Are the same or different substituents.

 (a) norogens,

(b) OR ⁸⁵ ,

(c) O (C = 0) R ⁸⁵ ,

(d) COOR ⁸⁵ ,

 (e) Siano,

(f) N ( ^R85 ) ( ^R86 ),

 (g) cycloanolequil,

 (h) aryl, optionally substituted by one to three identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;

 (i) An aromatic heterocyclic group which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino.

R ⁸⁵ and R ⁸⁶ are the same or different,

 ① Hydrogen or

 ② Represents an alkyl selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino, which may be substituted by one substituent.

R ³ represents hydrogen.

Where X and Z are together a bond, Y is hydrogen, R ^{1 is} hydroxy, R ² is unsubstituted alkylcarbonyloxy, and R ³ is hydrogen. Excludes Hereinafter, the present invention will be described in detail.

The “alkyl” in the present invention is a straight-chain or branched anoalkyl having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, and Sobutinole, sec-butynole, tert-butynole, n-pentynole, isopentynole, n-hexynole, isohexyl, n-heptyl, and isoheptyl.

 "Monoalkyl power rubamoyloxy", "dialkylcarpamoyloxy", "alkoxy canoleponinoleoxy J", "monoalkylamino", "dialkylamino", "alkynolecanoleponyloxy", "aryl carbonyl" Examples of the alkyl moiety of "oxy", "alkylthio", "alkylsulfinyl", "alkylsulfonyl", "aminoalkyl", "arylalkyloxy" and "alkylcarbonylamino" include the above-mentioned alkyl. .

 “The alkylene J includes alkylene having 4 to 7 carbon atoms, for example, tetramethylene, pentamethylene, hexamethylene, and heptamethylene.

 “Cycloalkyl” includes cyclic alkyl having 3 to 7 carbon atoms, for example, cyclopropynole, cyclobutynole, cyclopentynole, cyclohexynole, and cycloheptinol.

 Examples of the cycloalkyl moiety of “cycloalkyloxy” and “cycloalkylcarbonyloxy” include the above-mentioned cycloalkyl.

 "Γalkoxy" includes linear or branched alkoxy having 1 to 7 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert. -Butoxy, n-pentynoleoxy, isopentynoleoxy, n-hexyloxy, isohexyloxy, n-heptyloxy and isoheptyloxy.

 Examples of the alkoxy moiety of “alkoxycarbonyl” include the aforementioned alkoxy.

 The “alkenyl” includes straight or branched ones having 2 to 7 carbon atoms, for example, vinylinole, 1-propeninole, isopropenyl, arinole, 1-buteninole, 3-buteninole, 1 4-penteninole, 1-hexeninole, 5-hexeninole, 1-heptenyl, 6-heptenyl.

The alkenyl moiety of “alkenyloxy” includes the aforementioned alkenyl. “Alkynyl” includes straight-chain or branched-chain ones having 2 to 7 carbon atoms, for example, ethininole, 1-f. Robininole, 2-propyninole, 1-butininole, 3-butininole, 1 1 Pentininole, 4-pentininole, 1-hexininole, 5-hexininole, 1-heptinole, 6-heptinyl.

 The alkynyl moiety of "alkynyloxy" includes the above-mentioned alkynyl. “Aryl” includes those having 6 to 10 carbon atoms, for example, phenyl, 1-naphthyl and 2-naphthyl.

 The aryl part of "aryl alkyloxy J" and "arylcarbonyloxy" includes the above aryl.

 "Acil" means "alkylcarbonyl" and "arylcarbonyl". The alkyl part of "alkylcarbonyl" represents the above-mentioned alkyl. The aryl part of "aryl carponyl" represents the above aryl. Examples of “acyl” include acetyl, propionyl, butyryl, isobutyryl, benzoyl, 1-naphthyl, and 2-naphthyl.

 Examples of the “heterocyclic group” include a saturated or unsaturated 5- to 7-membered ring group containing 1 to 4 identical or different nitrogen atoms, oxygen atoms or sulfur atoms as ring-constituting atoms. Examples include pyrrolidine-111, pyrrolidine-1-yl, pyrrolidine-3-yl, furan-2-yl, furan-3-inore, and thiophen-2-inole. , Thiophene 1-yl, piperidine 1-inole, piperidine 1-inole, piperidine 1 3-inlet, piperidine 1-inole, monoreholin 1-inole, monoreholin 1 3-yl, morpholin 4-inole, thiomonoleline 1 2—inole, thiomorpholin 1 3—inole, thiomonoleolin 4—inole, pirazin 1 1—inore, pirazin 1 2—inore, homopyrazin 1 1-inole , Hexamethyleneimine 1-inole, Pyridine-1-yl, Pyridine-3-yl, Pyridine-4-yl, Imidazole-1-yl, Pyrimidin-12-yl, Pirimi Gin-4-yl and pyrimidine-5-yl.

The “aromatic heterocyclic group” means a 5- to 6-membered aromatic ring group having 1 to 4 identical or different hetero atoms, selected from a nitrogen atom, an oxygen atom and a sulfur atom, and includes, for example, 1-ru, 1-pyro, 1-pyro, 2-ino-, 3-pyro-no-nore, Fran 2-yl, Fran-3-1-yl, Ciofen 2-yl, Thiophen-3-1-ino, Oxazonole 2 —Innore, Thiazonore 2 —Innore, 1 H—1,2,4—Triazonole 1—Ill, 1 H—Te Trazonore 1-5—Ill, Pyridin 1 2—Innore, Pi Lysine-1-pyr, pyridin-4-yl, pyrimidine-2-yl, pyrimidine-1-yl, pyrazine-1-yl, 1,3,5-triazine-1-yl No.

 “Cyclic amino” may include, in addition to the nitrogen atom forming a bond, one or two nitrogen atoms, oxygen atoms or sulfur atoms, the same or different, as ring-constituting atoms And a saturated or unsaturated 5- to 7-membered ring group. Examples include pyrrolidine-1-1-inole, piperidine-1-1-inole, piperazine-1-1-inole, monoleforin-4-1-inole, thiomonoleforin-4-1-inole, thiomonoleforin-1-1, 1-dioxydo-41-yl, Imidazole-1-yl, thiazolidine-3-yl, homopyrazine-11-yl and hexamethyleneimine-1-yl.

 “Halogen” includes, for example, fluorine, chlorine, bromine, and iodine. Preferred examples of the compound of the present invention include the following compounds (1) to (3).

 (1)

 X and Z are linked together and Y is hydrogen.

R ¹ is a monoalkylamino (the alkyl portion of such a monoalkylamino is substituted with alkoxy).

R ² represents any of the following substituents (a) to (f).

 (a) hydroxy,

 (b) phosphoxy,

 (c) Alkyl alkenyloxy (the alkyl part of the alkyl alkenyloxy is hydroxy, unsubstituted amino, alkoxy substituted by 1 to 2 identical aryls, alkylcarbonyl optionally substituted by unsubstituted aminos) It may be substituted by one or two same or different substituents selected from the group consisting of oxy, and alkylcarbonylamino. ]

(d) arylcarbonyloxy substituted with alkyl (the alkyl moiety of arylcarbonyloxy substituted with such alkyl is amino substituted with one or two hydroxyalkyl, and cyclic amino) Is substituted by one substituent selected from the group consisting of:), (e) a cycloalkylcarbonyloxy substituted with an unsubstituted aminoalkyl,

(f) alkoxy.

R ³ represents any of the following substituents (a) to (g).

 (a) hydrogen,

 (b) hydroxy,

 (c) phosphoxy,

 (d) anolyalkylcarbonyloxy (the alkyl moiety of such an alkylcarbonyloxy is substituted by hydroxy, unsubstituted amino, alkoxy substituted by one or two identical aryls, unsubstituted amino) May be substituted by one or two same or different substituents selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. ]

 (e) arylcarbonyl substituted with alkyl (the alkyl moiety of arylcarbonyl substituted with alkyl is composed of amino substituted with one or two hydroxyalkyl, and cyclic amino Substituted by one substituent selected from the group :),

 (f) a cycloalkylcarbonyloxy substituted with an aminoalkyl,

 (g) alkoxy.

Or, R ² and R ^{3 taken} together are isopropylidenedioxy.

 (2)

 X and Z are linked together and Y is hydrogen.

R ¹ represents any of the following substituents (a) to (c).

 (a) monoalkylamino (the alkyl part of such monoalkylamino is substituted with pyridyl or dialkylamino),

 (b) cyclic amino (such cyclic amino is replaced by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy),

 (c) alkoxy (the alkyl part of such alkoxy is substituted by alkylcarbonyloxy substituted by hydroxy).

R2, R ³ are the same or different, human Dorokishi, alkoxy, or alkyl Cal Bonyloxy.

 (3)

 X and Y are together oxo, and z is hydrogen.

R ¹ represents the following substituent (a) or (b).

 (a) monoalkylamino (the alkyl moiety of such monoalkylamino is substituted with alkoxy),

 (b) alkoxy (such alkoxy is substituted with alkylcarbonyloxy).

R ² and R ³ are each hydroxy. Among the compounds of the present invention, more preferred compounds include, for example, the following compounds (4) to (9).

 ( Four )

 X and Z are linked together and Y is hydrogen.

R ¹ is monoalkylamino (the alkyl part of such monoalkylamino is substituted with alkoxy).

R ² represents hydroxy.

 R3 represents any of the following substituents (a) to (f).

 (a) hydrogen,

 (b) Hydroxy

 (c) phosphoxy,

 (d) anorealkyl carboxy / reoxy (the alkyl moiety of such anolequinolecanolevonyloxy is substituted by hydroxy, unsubstituted amino, alkoxy substituted by two identical aryls, unsubstituted amino) May be substituted with one substituent selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. Alternatively, such alkyl moieties may be substituted by both hydroxy and unsubstituted amino substitutions. ]

(e) arylcarbonyl substituted with alkyl (the aryloxy moiety of arylcanolebonyloxy substituted with alkyl is; It is substituted by one substituent selected from the group consisting of amino substituted by alkyl, and cyclic amino. ),

 (f) Cyclic alkylcarbonyloxy substituted with aminoalkyl.

 ( Five )

 X and Z are together a bond, and Y is hydrogen.

 R l is monoalkylamino (the alkyl portion of such monoalkylamino is substituted with alkoxy).

R ² represents the following substituent (a) or (b).

 (a) alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyl group is one substituent selected from the group consisting of hydroxy, unsubstituted amino, and alkylcarbonyloxy substituted with unsubstituted amino) Has been replaced by Or, such an alkyl moiety is substituted by both substitution of hydroxy and unsubstituted amino. ]

 (b) alkoxy.

R ³ represents hydroxy.

 (6)

 X and Z are together a bond, and Y is hydrogen.

R ¹ is monoalkylamino (the alkyl portion of such monoalkylamino is substituted with alkoxy).

R ² and R ³ are for the following cases (a) to ().

 (a) R2 and R3 are each a phosphoxy.

(b) R ² and R ³ are each an alkylcarbonyloxy, wherein the alkyl moiety of the alkylcarbonyloxy is substituted by an alkylcarbonyloxy; ].

 (c) R2 and R3 together are isopropylidenedioxy.

 (7)

 X and Z are together a bond, and Y is hydrogen.

R ¹ represents the following substituent (a) or (b).

(a) Cyclic amino (such cyclic amino is substituted with hydroxy and hydroxy) Substituted by one substituent selected from the group consisting of optionally substituted alkyl. ),

 (b) alkoxy (the alkyl portion of such alkoxy is substituted with alkylcarbonyloxy substituted with hydroxy).

R ² and R ³ each represent hydroxy.

 (8)

 X and Z are together a bond, and Y is hydrogen.

Rl, R ² is the case of the following (a) or (b).

(a) R ¹ is monoalkylamino (where the alkyl portion of such monoalkylamino is substituted with pyridyl or dialkylamino), and R ² is hydroxy.

(b) R ¹ is a cyclic amino (such amino is substituted by hydroxy), and R ² is hydroxy or alkylcarbonyloxy.

R ³ represents alkoxy.

 (9)

 X and Y together are oxo, and z is hydrogen.

R ¹ represents the following substituent (a) or (b).

 (a) monoalkylamino (the alkyl moiety of such monoalkylamino is substituted with alkoxy),

 (b) alkoxy (such alkoxy is substituted with alkylcarbonyloxy).

R ² and R ³ are each hydroxy. Among the compounds of the present invention, particularly preferred compounds include, for example, the following compounds (1) to (38).

 (1) N- (2-Methoxyxetil) 1/3 / 3—Hydroxy 2 3 (4α) —Hydroxy acetoxolean 1 2—En 1 28—Amid

(2) Ν-(2—methoxin) 1 2 3 (4 α) —hydroxy 3) 3—hydroxy 2 1-28 1-amide (3) N- (2—methoxhetil) 1 2 3 (4α) —acetoxy 3 j3—hydroxyl 1 1 2—en 1 2 8—amide

 (4) N- (2-Methoxyxetil) — 3β, 2 3 (4α) —Bis (acetoxyacetoxy) orean 1 2 —en 1 2 8—amide

(5) Ν- (2-Methoxyxetil) 1 2 3 (4α) -acetoxy-acetoxy 3; 3—Hydroxylean 1 1 2

 (6) Ν- (2—methoxil) 1 2 3 (4α) —benzhydryloxytoxy 1/3 / 3—hydroxylorean 1 2—en 1 2 8—amide

 (7) Ν-(2-methoxyxyl) 1 3) 3-Hydroxy 2 3 (4α)-(3-Hydroxypropionyloxy) Orean 1 2-En 2-Amide

 (8) Ν- (2—Methoxyxetil) 1 3 j3—Hydroxy 1 2 3 (4α)-((S) -2-Hydroxypropioninoleoxy) Orean 1 1 2—En 1 2 8 — Amid

 (9) Ν- (2—methoxhetyl) 1/3 / 3—hydroxy 2 3 (4α) 1 [4 1 (Molenorehori Nomethinole) Benzoinoleoxy] Orean 1 1 2 —En 1 2 8 —Ami Do

(10) Ν— (2-methoxethyl) 1 2 3 (4α) 1 [4— (bis (2-hydroxyshethyl) aminomethyl) benzoyloxy] 1 3] 3—Hydroxylean 1—12-ene 1 2 8—Amid

 (11) N— (2-Methoxyxethyl) 1 3; 3—Hydroxy2 3 (4o!) — [4 — ((2—Hydroxitytyl) aminomethyl) benzoinoleoxy] olean 1 1—2 1 2 8—Amid

 (12) N— (2-Methoxyxetil) 1/3 / 3—Hydroxy2 3 (4H)-[4- (thiomorpholinomethyl) benzoyloxy]

(13) N— (2—Methoxyxetil) 1 2 3 (4a) —Dali siloxy 3) 3—Hydroxylean 1 2—En 1 2 8—Amid

(14) N— (2-Methoxyxetil) 1/3 / 3—Glycyloxy1 2 3 (4α) —Hydroxylean 1 2—En-28—Amid

 (15) Ν— (2-methoxetil) 1 3/3 —hydroxy 2 3 (4α) 1 (L-seryloxy) orean 1 2 —en 1 2 8—amide

(16) Ν— (2-methoxil) 1 2 3 (4 α) —hydroxy 1 3/3 — (L— Liloxy) Orean 1 1 2—En 1 2 8 — Amid

 (17) N- (2—Methoxyxetil) 1 2 3 (4a) —Glycyloxyacetoxy 3—Hydroxylean 1 1—2—1—2 8—Amide

 (18) N— (2-Methoxyxetil) 1 3) 3—Glycyloxyacetoxy 1 2 3 (4a) —Hydroxylean 1 1—2—2—8—Amide

 (19) N- (2-Methoxyxetil) 13β-Hydroxy23 (4α) -Phosphoroxylean12_12-28-Amid

 (20) Ν- (2—Methoxyxetil) 1 2 3 (4α) 1 ((S) —2—acetoxypropionyloxy) 1 3 j3—Hydroxylean 1 1 2—En 1 2 8—Amid (21) N- (2-Methoxyxetil) 1 2 3 (4α)-(Ν-Acetylglycyloxy) 1 3β-Hydroxylean 1 12-En-28-Amide

 (22) Ν— [21- (Jetylamino) ethyl] -1 3] 3-Hydroxy-1 2 3 (4α) -Methoxyl-an 1 12-en _28—Amid

 (23) 1 [3 β, 2 3 (4 α) —dihydroxylone 1 1 2 — 2 2 8 — — 4-methylbiperazine

 (24) N- (2-Methoxyxetil) 1 2 3 (4α)-(trans -4- 4-aminomethyl phenol

 (25) 1 — [3/3, 2 3 (4 α) —dihydroxy-1-orane 1 2 —en 1 28 —oil] — 3—hydroxypyrrolidine

 (26) 1 — [3 β, 2 3 (4 α) —dihydroxylone 1 1 2 — 2 2 8 — yl] — 4 1 (2 —hydroxypropyl) piverazine

 (27) 2— (Hydroxyacetoxy) ethyl 3] 3,2 3 (4α) —dihydroxy ore 1 1 2—2 1 2

(28) 1 — [3-Hydroxy 2 3 (4 α) —Methoxyl-an 1 12—2—28—Oil] 1-3—Hydroxypyrrolidine

 (29) Ν-[2 — (4-pyridyl) ethyl] — 3-hydroxy-1 2 3 (4 α) 1-methoxyl-an 1 2-en- 1 28-amide

(30) Ν- (2-Methoxyshethyl) 1 2 3 (4α) -Hydroxy 1 3 1-Methoxy Orean 1 1 2—Ann 2 8—Amide

 (31) [3 β, 4 a, 1 3 (Η)] — Ν— (2 — methoxyxetil) 1 S, 23 3 -dihydroxy 1 2 — Oxosolean 1 28 — Amide

 (32) 2 —acetoxityl [3,4a, 1 3 β (Η)] -3,2 3—dihydroxy _12—Oxosolean 1 28—Ooate

 (33) Ν— (2-methoxethyl) 1/3/3, 23 (4α)-(isopropylidenedioxy) orean 1 2—en 1 2 8—amide

 (34) 1-[3) 3 —acetoxy 1 2 3 (4 α) —methoxolean 1 2 —ene 2 8 —oilinole — 3 —hydroxypyrrolidine

(35) Ν-(2-Methoxyxetil) 1 3] 3—Hydroxylean 1 1 2—No 28—Amid

 (36) 3 β, 2 3 (4 α) —dihydroxylean 1 1 2 —en 1 2 8 —Oic acid

 (37) 2—acetoxitytil 3 3, 2 3 (4 α—dihydroxylean 1 1—2—2 2 1

(38) Ν— (2-methoxitytyl) 1/3/3, 23 (4α) dihydroxylorean 1 2 1 1 2 1 —amide The compound of the present invention represented by the above formula [1] is It may be prepared by any of the methods described in International Publication WO96 / 002 ³⁶ No., or International published No. W098 / 58946.

 Among the compounds of the present invention, compounds having an acidic group (carboxy, sulfoxy, phosphoxy, etc.) can be used as a medicament as a free acid, but can be converted into pharmaceutically acceptable salts by a known method. Can also be used. Examples of such a salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.

 For example, a mono-alkali metal salt can be obtained by adding one equivalent of sodium hydroxide, potassium hydroxide, or the like to an oleanan derivative, preferably in an alcohol solvent.

The dialkali metal salt of an oleanan derivative having a phosphoxy group is It can be obtained by adding 2 equivalents of sodium hydroxide or hydroxylated water to the body, preferably in an alcoholic solvent.

 The alkaline earth metal salt of an oleanean derivative can be obtained by dissolving the alkaline earth metal salt produced by the above method in water, methanol, ethanol, or a mixed solvent thereof, and adding one equivalent of calcium chloride or the like. Can be.

 Among the compounds of the present invention, compounds having a basic group (such as unsubstituted or substituted amino or piperazyl, pyridyl or pyrrolidyl) can be used as a free base as a medicament, but can be pharmaceutically acceptable by known methods. It can be used in the form of a salt. Examples of such salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and formic acid, acetic acid, quinic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, and benzenesulfonic acid. Acids and salts of organic acids such as methanesulfonic acid.

 For example, a hydrochloride of an oleanan derivative can be obtained by dissolving the oleanan derivative in an alcohol solution of hydrogen chloride or a methylene chloride solution.

 The compound of the present invention has an excellent TGF-) 3 production inhibitory activity as shown in the test examples described later, and has low toxicity, so that diseases involving TGF-] 3, such as hepatic fibrosis, Biliary fibrosis, cirrhosis, pulmonary fibrosis, adult respiratory distress syndrome, myelofibrosis, scleroderma, systemic sclerosis, renal sclerosis, renal auditory fibrosis, diabetic nephropathy, intraocular proliferative Disease, proliferative vitreoretinopathy, cataract, heart fibrosis after infarction, restenosis after angioplasty, arteriosclerosis, connective tissue hyperplasia after wounding such as surgical incision, trauma, burn (abdominal adhesions) , Scars, keloids), fibrosis after radiation therapy, chronic spleenitis, fibrotic tumors, nasal polyps, periodontal ulcerative colitis, and sclerosing Hodgkin's disease.

When the compound of the present invention is administered as a medicament, the compound of the present invention is used as it is or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.1 to 99.5%, preferably 0.5 to 90%. % Can be administered to mammals, including humans. As the carrier, one or more solid, semi-solid or liquid diluents, fillers and other auxiliaries for formulation are used. Preferably, the pharmaceutical compositions are administered in dosage unit form. The pharmaceutical composition of the present invention can be administered by intravenous administration, oral administration, It can be administered rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred.

 Oral administration is performed in solid or liquid dosage units, such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other forms be able to.

 Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added. Capsules are manufactured by first filling powdered powders, powders, or granules as described in the section on powders as described above into a capsule shell such as a gelatin capsule. Is done. Lubricants and glidants, such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed into a powder and then filled Operations can also be performed. Disintegrators and solubilizers, such as carboxymethyl cellulose, carboxymethyl cellulose canolesum, low-substituted hydroxypropyl cenorellose, cros-canolemelose sodium, canoleboximetinorestar sodium, calcium carbonate, sodium carbonate If added, the effectiveness of the medicine when the capsule is taken can be improved.

Also, the fine powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped in a gelatin sheet to form a soft capsule. Tablets are made by adding an excipient, forming a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and compressing. The powder mixture is prepared by mixing the appropriately powdered material with the diluents and bases described above and, if necessary, a binder (e.g., sodium canolepoxymethylcellulose, methylcellulose, hydroxypropynolemethinolecellulose, Gelatin, polyvinylinopyrrolidone, polyvinyl alcohol, etc.), dissolution retarders (eg, paraffin), resorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, dicalcium phosphate) Etc.). The powder mixture is first prepared with a binder such as syrup, It can be moistened with powder paste, gum arabic, cellulose solution or polymer solution, mixed with stirring, dried and pulverized to obtain granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules.

 The granules thus produced can be prevented from adhering to one another by adding stearic acid, stearates, talc, mineral oil and the like as lubricants. The lubricated mixture is then tableted. The uncoated tablets thus manufactured can be coated with a film-coated sugar coating.

 Alternatively, the drug may be directly tableted after mixing with a fluid inert carrier without going through the granulating and slagging steps as described above. Transparent or translucent protective coatings consisting of a sealed shellac coating, coatings of sugar or polymeric materials, and polish coatings made of wax may also be used.

 Other oral dosage forms such as solutions, syrups, elixirs and the like can also be made in dosage unit form so that a given quantity contains a fixed amount of the drug. Syrups are prepared by dissolving the compound in a suitable aqueous flavor solution, and elixirs are prepared through the use of a non-toxic alcoholic carrier. Suspensions are formulated by dispersing the compound in a non-toxic carrier. Solubilizers and emulsifiers (eg, ethoxylated isostearyl alcohols, polyoxetylene sorbitol esters), preservatives, flavor enhancers (eg, palmit oil, saccharin) and others It can be added as needed.

 Where necessary, dosage unit formulations for oral administration may be encapsulated in a mic mouth. The formulations can also provide for prolonged action or sustained release by coating or embedding in polymeric waxes and the like.

Administration into tissues can be carried out by using liquid dosage unit forms for subcutaneous, intramuscular or intravenous injection, for example, solutions and suspensions. These are accomplished by suspending or dissolving an aliquot of the compound in a non-toxic liquid vehicle suitable for injection, such as an aqueous or oily vehicle, and then sterilizing the suspension or solution. Manufactured. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives, and emulsifiers can be used in combination. For rectal administration, the compounds are soluble or insoluble in low-melting water, such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol®), higher esters (such as myristyl palmitate). And suppositories produced by dissolving or suspending in a mixture thereof.

 The dose of the TGF-3 production inhibitor should be set in consideration of the nature and severity of the disease, the patient's condition such as age and weight, and the route of administration. The amount of the active ingredient of the compound of the present invention is generally in the range of 0.1 to 100 mg / day, preferably 1 to 500 mgZ per day.

 In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in 12 to 3 divided doses.

 BEST MODE FOR CARRYING OUT THE INVENTION

 Hereinafter, the present invention will be described in more detail with reference to Test Examples and Formulation Examples, but the present invention is not limited thereto.

 In Test Examples and Formulation Examples, Compound 1 represents N- (2-methoxethyl) -13β, 23 (4α) -dihydroxylorane-12-en-28-amide, and Compound 2 Stands for Ν— (2-methoxhetyl) -1 33-hydroxy-1 23 (4α) 1-hydroxyacetoxylean 12-en-28-amide, and compound 3 has 3 / 3, 2 3 (4α) Represents dihydroxolean 1 12 — 1 1 2 8 — eutectic.

Test example 1

Inhibition of TGF- / 3 production by cultured rat lung lung fibroblasts

 Fibroblasts were isolated from rat lungs and subcultured to obtain cultured fibroblasts. The fibroblasts were seeded on a plate, cultured for 36 hours in the presence of serum, and then cultured for 3 hours under bloodless conditions to make the cells quiescent. The test drug was added thereto, and the cells were cultured in the presence of blood for 5 days, and the culture supernatant was collected. The amount of TGF-J3 in the culture was measured using an enzyme immunoassay (法 method). . The protein content of the cells was measured using a Bio-Rad Protein Assay kit (Bradford,., Anal. Biochem., 72, 248, 1976) according to the method of Bradford.

The TGF-production inhibition rate and the protein protein inhibition rate by the test drug were as follows. It was calculated by a mathematical formula.

 TGF—) 3 Production inhibition rate = 100 X [1 (T 2 / P 2) / (T 1 / P 1)] Cell protein inhibition rate = 100 XC 1-(P 2 / P 1)]

 In the formula, P1 represents the protein amount (g) of the cells in the control group. T1 represents the amount (pg) of TGF—] 3 in the control group. P2 represents the protein amount g> of the cells in the test drug group. T2 represents TGF- / 3 amount (pg) in the test drug group. Table 1 shows the results. Table 1 Inhibitory effect of TGF-β production in cultured rat lung fibroblasts Test drug addition concentration TGF-β production inhibition rate Inhibition rate of cellular protein

 (k μ g / ml) (%) (%) Compound 1 1.0 16.7 -8.9

 Compound 1 3.0 41.1 11.1 Compound 2 0.1 5.9-1.5

 Compound 2 1.0 40.2 1.3 It is apparent that the compound of the present invention has an inhibitory effect on TGF-0 production in cultured rat fibroblasts. In addition, since the protein content of the cells is not significantly reduced, it is understood that the TGF-β production inhibitory effect of the compound of the present invention is not based on cell growth inhibition or cell damage by the test drug.

Test example 2

Acute toxicity test

 A suspension of the test drug was orally administered to mice at a dose of 2 g / kg, and general symptoms were observed up to one week later. Compound 1, compound 2 and compound 3 were administered as test drugs, respectively.

 As a result, there were no deaths and no abnormal findings in any of the treatment groups.

Formulation Example 1

Tablets (oral tablets) Prescription 1 tablet in 80mg

 Compound 1 5.Omg

 4 モ .6mg corn starch

 SB cell mouth "S 24. Omg

 Methynoresenorelose 4. Omg

 Magnesium stearate 0.4 mg

 The mixed powder in this ratio is tableted and made into an internal tablet.

Formulation Example 2

Tablets (oral tablets)

 Prescription 1 tablet in 80mg

 Compound 2 5.Omg

 Corn starch 46.6 nig

 Crystalline Senorelose 24. Omg

 Methynoresenorelose 4. Omg

 Magnesium stearate 0.4 mg

 The mixed powder in this ratio is tableted and made into an internal tablet.

Formulation Example 3

Tablets (oral tablets)

 Prescription 1 tablet in 80mg

 Compound 3 5.Omg

 46.6 mg corn starch

 Microcrystalline cellulose 24.Omg

 Methynoresenorelose 4. Omg

 Magnesium stearate 0.4 mg

 The mixed powder in this ratio is tableted and made into an internal tablet.

 Industrial applicability

 As described above, the compound of the present invention has an excellent TGF-) 3 production inhibitory activity and is a safe compound with low toxicity. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient is Is useful as a TGF-production inhibitor for mammals, including mammals.

Claims

The scope of the claims

 1. A compound represented by the following formula [1], which is any of the following (A), (B) or (C), or a pharmaceutically acceptable salt thereof: A TGF-j3 production inhibitor containing as an active ingredient.

In the formula, Me represents methyl.

 (A)

 X and Z together represent a bond. Y represents hydrogen.

R ¹ represents OR ¹¹ or NR ^U R ^12. RU and R ¹² are the same or different and are (1) hydrogen, (2) alkyl which may have a substituent, (3) cycloalkyl which may have a substituent, (4) substitution Alkenyl optionally having a group, (5) alkynyl optionally having a substituent, (6) aryl which may have a substituent, or (7) optionally having a substituent Represents a good aromatic heterocyclic group.

The substituents which the alkyl, cycloalkyl, alkenyl, alkynyl, aryl, and aromatic heterocyclic groups represented by R ¹¹ and R ¹² may have are (a) halogen,

^{(b) ORl 3, (c} ) OCOR 13, (d) COORl3, (e) Shiano, (f) NR 3Rl4, ( g) a cycloalkyl, (h) halogen, alkyl, substituted arsenide Dorokishi or Amino And (i) an aromatic heterocyclic group which may be substituted with a nitrogen, an alkyl, a hydroxy or an amino.

R ¹³ and R ¹⁴ are the same or different and represent (1) hydrogen or (2) alkyl optionally substituted with hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino.

R ² and R ³ are the same or different and each may have (1) hydroxy, (2) a substituent Alkoxy, (3) cycloalkyloxy optionally having a substituent, (4) alkenyloxy optionally having a substituent, (5) alkynyloxy optionally having a substituent, (6) monoalkyl-capable rubamoyloxy optionally having a substituent; (7) dialkyl-capable rubamoyloxy optionally having a substituent; ( ⁸ ) alkoxycarbonyloxy optionally having a substituent. And (9) an alkylcarbonyloxy optionally having a substituent, or (10) an arylcarbonyloxy optionally having a substituent. Or R ² and R ³ together represent carbonyl.

Alkoxy, cycloalkyloxy, alkenyloxy, alkynyloxy, monoalkyl rubamoyloxy, dialkyl rubamoyloxy, alkoxycarbonyloxy, alkylcarbonyloxy, arylno rubonyoxy represented by R ² and R ³ substituent group optionally has, _(a) halogen, (b) ORl ^5,

(c) OCOR ¹⁵ , (d) COOR ¹⁵ , (e) cyano, (f) NR ¹⁵ R ¹⁶ , (g) cycloalkyl, (h) halogen optionally substituted with alkyl, hydroxy or amino And (i) an aromatic heterocyclic group which may be substituted with halogen, alkyl, hydroxy or amino.

R ¹⁵ and R ¹⁶ are the same or different and represent (1) hydrogen or (2) alkyl optionally substituted with hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino.

 (B)

 X, Y, and Ζ are any of the following cases (1) to (4).

 (1) X and Ζ together represent a bond. Υ represents hydrogen.

 (2) X and Υ together represent oxo. Ζ represents hydrogen.

 (3) X represents hydroxy. Υ and Ζ each represent hydrogen.

 (4) Υ represents hydroxy. X and Ζ each represent hydrogen.

R ¹ represents any of the following substituents (1) to (4).

 (1) hydroxy,

(2) monoalkylamino (wherein the alkyl moiety of the monoalkylamino is one substituent selected from the group consisting of hydroxy, alkoxy, alkoxycarbonyl, cyclicamino, alkylcarbonylamino, and alkylcarbonyloxy) It may be substituted by a substituent. ),

 (3) cyclic amino (such cyclic amino may be replaced by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy),

(4) Alkoxy (The alkoxy is optionally substituted by one substituent selected from the group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, cyclic amino, and alkylcarbonyloxy. The carbonyloxy may be substituted by an alkylcarbonylamino or an arylalkyloxy in which the aryl moiety may be substituted by an alkoxy.) And R ² are the following (1) to (4) ) Represents any of the substituents.

 (1) hydroxy,

₍₂₎ OS0 2 R ^7,

(3) OP (= 0) (O R8) (OR ⁹ ),

(4) OC (= 0) R ⁶ .

R ³ represents any of the following substituents (1) to (5).

 (1) hydrogen,

 (2) hydroxy,

(3) OS0 ₂ R ^7,

(4) OP (= 0) (O R8) (OR 9),

(5) OC (= 0) R ⁶ .

R ⁷ represents hydroxy, alkyl, or aryl.

R ⁸ and R ⁹ are the same or different and represent hydrogen, alkyl, or aryl. R ⁶ represents the following substituents ① to ⑤.

① N (R ⁴⁰⁾ Ariru substituted with alkyl substituted by (R ⁴¹⁾ [such R40, R ⁴ 1 are the same or different, hydrogen or alkyl (such alkyl is, human de port alkoxy, unsubstituted amino , Monoalkylamino, and dialkylamino, which may be S-substituted by one substituent.) Or R40 and R41 are taken together with the adjacent N And N (R40) (R41) represents a cyclic amino. Such a cyclic amino may be substituted with an alkyl or heterocyclic group. ] (2) Alkyl which may have one or both of substituents R ⁴² and R ⁴³ [the R ⁴² and R ⁴³ may be the same or different and are hydroxy, alkylthio, alkylsphenol, alkyl, Sulfonyl, unsubstituted amino, carboxy, alkynole canoleboninoleamino, alkylcarbonyloxy (the alkyl portion of such alkynolecanoleponinoleoxy is one selected from the group consisting of hydroxy, and unsubstituted amino; Or alkoxy (such an alkoxy may be substituted with 1 to 2 aryls, and such aryls may be substituted with an alkoxy). Represent. ]

 (3) Cycloalkyl which may be substituted with aminoalkyl,

 ④ a heterocyclic group (the heterocyclic group may be substituted by one substituent selected from the group consisting of an alkyl optionally substituted by hydroxy, and a heterocyclic group);

 {Circle around (1)} 1 or 2 identical or different aminos optionally substituted by hydroxy, optionally substituted by alkyl.

Or, R ² and R ³ together represent the following formula:

R ²¹ and R ³¹ are the same or different and each represent a hydrogen, an alkyl, an aryl or a heterocyclic group, or R ²¹ and R ³¹ together represent an alkylene which may be g-substituted by an alkyl.

Wherein X and Z are taken together to form a bond, Y is hydrogen, and Rl is hydroxy, monoalkylamino (the alkyl portion of such monoalkylamino is hydroxy, alkoxy, An alkylcarboninoleoxy, and an alkanoloxycarboninole, which may be substituted by one substituent.) Or an alkoxy (such alkoxy is hydroxy, aryl, R ² may be substituted with one substituent selected from the group consisting of alkoxy, alkoxycarbonyl, and unsubstituted alkylcarbonyloxy. = 0) and R ^6, R ³ is hydrogen, arsenate Dorokishi, or OC (= 0) R6 der Except that R ⁶ is a substituent of the following (a) or (b):

(a) alkyl which may have one or both of substituents R ⁴² and R ⁴³ (such R ⁴² and R ⁴³ may be the same or different and are hydroxy, unsubstituted amino, carboxy, phenolic Quinolecarbonyloxy (the alkyl moiety of such acrequinolecarbonyloxy may be substituted with hydroxy or unsubstituted amino) or unsubstituted alkoxy. ]

 (b) One or two identical or different aminos optionally substituted by alkyls optionally substituted by hydroxy.

 (C)

 X and Z together represent a bond. Y represents hydrogen.

R ¹ is, OR, or N (R ⁸ 1) represents the (R ^82>.

 R81 and RS2 are the same or different and represent any of the following (1) to (7).

 (1) hydrogen,

 (2) an alkyl which may have a substituent,

 (3) cycloalkyl optionally having a substituent,

 (4) optionally substituted alkenyl,

( ⁵ ) alkynyl optionally having a substituent,

( ⁶ ) aryl which may have a substituent,

 (7) An aromatic heterocyclic group which may have a substituent.

The substituents which may be possessed by the alkyl, cycloalkyl, alkenyl, anorecynyl, aryl, and aromatic heterocyclic groups represented by R ⁸¹ and R82 are selected from the following substituents (a) to (i). 1-3 identical or different substituents selected from the group consisting of:

( _a ) halogen,

 (b) OR83,

(c) O (C = 0) R ⁸³ ,

 (d) COOR83,

 (e) Siano,

 (f) N (R83) (R84),

(g) Alkyl alkyl, (h) aryl, optionally substituted by one to three identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;

 (i) An aromatic heterocyclic group which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of halogen, alkynole, hydroxy, and unsubstituted amino.

R ⁸³ and R ⁸⁴ are the same or different,

 ① Hydrogen or

 ② Represents an alkyl selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino, which may be substituted by one substituent.

R ² represents any of the following (1) to (10).

 (1) hydroxy,

 (2) an alkoxy optionally having a substituent,

 (3) a cycloalkyloxy which may have a substituent,

 (4) alkenyloxy optionally having a substituent,

 (5) alkynyloxy optionally having a substituent,

 (6) an optionally substituted monoalkyl group rubamoyloxy,

 (7) dialkyl power rubamoyloxy optionally having a substituent,

 (8) an alkoxycarbonyloxy optionally having a substituent,

 (9) an alkylcarbonyloxy optionally having a substituent,

 (10) arylcarbonylcarbonyl optionally having a substituent;

Alkoxy, cycloalkyloxy, alkenyloxy, anolequininoleoxy, monoanolekyl rubamoyloxy, dianolekyl rubamoyloxy, alkoxycarbonyloxy, alkylcarbonyloxy, arylyl ruponyloxy represented by R ² have Possible substituents are one to three identical or different substituents selected from the group consisting of the following substituents (a) to (i).

 (a) halogen,

(b) OR ^85, (c) O (C = 0) R ⁸⁵ ,

(d) COOR ⁸⁵ ,

 (e) Siano,

(f) N ( ^R85 ) ( ^R86 ),

 (g) cycloalkyl,

 (h) aryl, optionally substituted by one to three identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;

 (i) An aromatic heterocyclic group which may be substituted by 1 to 3 identical or different substituents selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino.

 R85 and R86 are the same or different,

 ① Hydrogen or

 ② Represents an alkyl that may be substituted with one substituent selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino.

R ³ represents hydrogen.

X, Z are together a bond, Y is hydrogen, R ^{1 is} hydroxy, R ² is unsubstituted alkylcarbonyloxy, and R ³ is hydrogen Excludes cases.

 2. A TGF-production inhibitor comprising, as an active ingredient, the T-oreane derivative or the pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of the following compounds (1) to (3).

 (1)

 X and Ζ are together a bond, and Υ is hydrogen.

R ¹ is a monoalkylamino (the alkyl portion of such a monoalkylamino is substituted with alkoxy).

R ² represents any of the following substituents (a) to (f).

(a) hydroxy, (b) phosphoxy,

 (c) alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy may be substituted with hydroxy, unsubstituted amino, alkoxy substituted with 1 to 2 identical aryls, unsubstituted amino It may be substituted by one or two same or different substituents selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. ]

 (d) arylcarbonyl substituted with alkyl (the alkyl moiety of arylcarbonyl substituted with alkyl is composed of amino substituted with one or two hydroxyalkyl, and cyclic amino Substituted by one substituent selected from the group:),

 (e) a cycloalkylcarbonyloxy substituted with an unsubstituted aminoalkyl,

(f) alkoxy.

R ³ represents any of the following substituents (a) to (g).

 (a) hydrogen,

 (b) hydroxy,

 (c) phosphoxy,

 (d) alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy may be substituted with hydroxy, unsubstituted amino, alkoxy substituted with 1 to 2 identical aryls, unsubstituted amino) It may be substituted by one or two same or different substituents selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. ]

 (e) arylcarbonyl substituted with alkyl (the alkyl moiety of arylcarbonyl substituted with alkyl is composed of amino substituted with one or two hydroxyalkyl, and cyclic amino Substituted by one substituent selected from the group:),

 (f) a cycloalkylcarbonyloxy substituted with an aminoalkyl,

 (g) alkoxy.

Or, R ² and R ³ together are isopropylidenedioxy.

(2) X and Z are together a bond, and Y is hydrogen.

R ¹ represents any of the following substituents (a) to (c).

 (a) monoalkylamino (the alkyl portion of such monoalkylamino is substituted with pyridyl or dialkylamino),

 (b) cyclic amino (such cyclic amino is replaced by one S-substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy);

 (c) alkoxy (the alkyl part of such alkoxy is substituted by alkylcarbonyloxy substituted by hydroxy).

R ² and R ³ are the same or different and are hydroxy, alkoxy, or alkylcarboninoleoxy.

 (3)

 X and Y are oxo together, and Z is hydrogen.

R ¹ represents the following substituent (a) or (b).

 (a) monoalkylamino (the alkyl portion of such monoalkylamino is substituted with alkoxy.)

 (b) alkoxy (such alkoxy is substituted with alkylcarbonyloxy).

R ² and R ³ are each hydroxy.

 3. A TGF-β production inhibitor comprising, as an active ingredient, the oleananane derivative or a pharmaceutically acceptable salt thereof according to claim 1, selected from the group consisting of the following compounds (4) to (9).

 ( Four )

 X and Ζ are together a bond, and Υ is hydrogen.

R ¹ is a monoalkylamino (the alkyl portion of such a monoalkylamino is substituted with alkoxy).

 R2 represents hydroxy.

 R3 represents any of the following substituents (a) to (f).

(a) hydrogen, (b) Hydroxy

 (c) phosphoxy,

 (d) alkylcarbonyloxy (the alkyl moiety of such alkylcarbonyloxy is hydroxy, unsubstituted amino, alkoxy substituted by two identical aryls, alkylcarbonyl optionally substituted by unsubstituted amino) And it may be substituted by one substituent selected from the group consisting of oxy, and alkylcarbonylamino. Alternatively, such alkyl moieties may be substituted by both hydroxy and unsubstituted amino substitutions. ]

( _e ) arylcarbonyl substituted with alkyl (the alkyl moiety of arylcarbonyl substituted with alkyl is composed of amino substituted with one or two hydroxyalkyl, and cyclic amino Substituted by one substituent selected from the group:),

 (f) Cyclic alkylcarbonyloxy substituted with aminoalkyl.

 ( Five )

 X and Z are together a bond, and Y is hydrogen.

R ¹ is monoalkylamino (the alkyl part of such monoalkylamino is substituted with alkoxy).

R ² represents the following substituent (a) or (b).

 (a) an alkyl moiety of the carbonyl group, wherein the alkyl moiety of the alkynolecarponinoleoxy is one substituted group selected from the group consisting of hydroxy, unsubstituted amino, and alkylcarbonyloxy substituted with unsubstituted amino. Substituted by a group. Or, such an alkyl moiety is substituted by substitution of both hydroxy and unsubstituted amino. ]

 (b) alkoxy.

R ³ represents hydroxy.

 (6)

 X and Z are together a bond, and Y is hydrogen.

R ¹ is monoalkylamino (the alkyl part of such monoalkylamino is substituted with alkoxy). R2 and R3 are for the following cases ( _a ) to ().

(a) R ² and R ³ are each a phosphoxy.

(b) R ² and R ³ are each alkynolecarboninoleoxy (the anoreky moiety of such anolequinolecarbonyloxy is substituted by alkylcarbonyloxy). ].

(c) R ² and R ³ together are isopropylidenedioxy.

 (7)

 X and Z are linked together and Y is hydrogen.

 Rl represents the following substituent (a) or <b).

 (a) ァ -amino (such cyclic amino is replaced by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy),

 (b) alkoxy (the alkyl portion of such alkoxy is substituted with alkylcarbonyloxy substituted with hydroxy).

R ² and R ³ each represent hydroxy.

 (8)

 X and Z are linked together and Y is hydrogen.

RR ² is for the following cases (a) or (b).

(a) Rl is monoalkylamino (alkyl moiety of such monoalkyl § amino is substituted with pyridyl or dialkyl § amino.) a, R ² is a human de proxy.

(b) Rl is a cyclic amino (such cyclic amino is substituted by human Dorokishi.) a, R ² is a human Dorokishi or alkylcarbonyl O alkoxy.

R ³ represents alkoxy.

 (9)

 X and Y together are oxo, and Z is hydrogen.

 Rl represents the following substituent (a) or (b).

(a) monoalkylamino (the alkyl part of such monoalkylamino is substituted with alkoxy), (b) alkoxy (such alkoxy is substituted with alkylcarbonyloxy).

R ² and R ³ are each hydroxy.

 4. A TGF-jS production inhibitor comprising, as an active ingredient, an oleanan derivative selected from the group consisting of the following compounds (1) to (38) or a pharmaceutically acceptable salt thereof.

 (1) N-(2-methoxyxetil) 1 3/3-hydroxy 1 2 3 (4a)-hydroxy 1-2-1-2-amide

 (2) N-(2-methoxethyl) 1 2 3 (4α)-hydroxy 1 3 β-hydroxy 1-2- 1-8-amide

(3) Ν- (2—methoxil) 1 2 3 (4α) -acetoxy 3 j9—Hydroxy Sorean 1 2—No 2 28—Amid

 (4) N- (2-Methoxyxetil) 13,23 (4α) -Bis (acetoxyacetoxy) orean-1 2—En-28-Amid

 (5) Ν- (2—methoxil) 1 2 3 (4α) —acetoxyacetoxy 1 3) 3—Hydroxylean 1 1 2—en 1 2 8 _amide

 (6) Ν-(2-methoxicil) 1 2 3 (4α) 1 benzylhydroxylate 3 3-hydroxyrean 1 2-1-2 8-amid

 (7) Ν- (2-Methoxyxetil) 1 3) 3—Hydroxy-1 2 3 (4α) -1 (3—Hydroxypropioninoleoxy) Orean 1 2 —En 1 2 8 —Amid

(8) Ν— (2-Methoxyxetil) 1 3) 3—Hydroxy-1 2 3 (4α) — ((S) -2-Hydroxypropionyloxy) Orean 1 2—Yen 2 8—Ami Do

 (9) Ν- (2—Methoxyxetil) 1 3 j9—Hydroxy 1 2 3 (4α) — [4— (Morpholinomethyl) benzoyloxy] Orean 1 1 2—En 1 2 8—Amide

(10) Ν— (2—methoxyl) 1 2 3 (4α) — [4— (bis (2—hydroxy)) Amino methinole) benzoinoleoxy] —3—hydroxylean

1 2—Yen 2 8—Amid

(11) Ν— (2-Methoxyxetil) -1 3 J3—Hydroxy2 3 (4 οί) — [4 -— ((2—Hydroxyxetil) aminomethyl) benzoyloxy] Amid

(12) N- (2-Methoxyxetil) 1/3 / 3-Hydroxy2 3 (4H) 1 [4 (1) (benzoinoleoxy) benzoinoleoxy] Orean 1 1 2 2 8—Amid

(13) N— (2-Methoxyxetil) 1 2 3 (4α) —Dalisiloxy 1 3 J3—Hydroxylean 1 1 2—En 2 28—Amid

(14) N-(2-methoxil) 1/3/3-Glysiloxy 2 3 (4α)-Hydroxylean 1 2-1-2 8-Amid

 (15) Ν— (2—methoxhetil) 1/3 / 3—hydroxy 2 3 (4α) 1 (L-ceryloxy) orean 1 2—en 1 2 8—amide

 (16) Ν-(2-methoxyxetil) 1 2 3 (α)-hydroxy 3/3-(L-seryloxy) orean 1 2-1-2 8-amide

 (17) Ν— (2-methoxethyl) 1 2 3 (4 α) —glycyloxyacetoxy — 3 β —hydroxylone 1 12 — ene _ 28 — amide

 (18) Ν— (2—Methoxyxetil) 1-3-Glycyloxyacetoxy 2 3 (4a) —Hydroxylean 1 12—Ien 1 28—Amid

(19) N- (2-Methoxyxetil) 1 3 J3—Hydroxy 1 2 3 (4α) 1 Phosphoxylene 1 1 2—En 2 28—Amide

 (20) Ν- (2—methoxethyl) 1 2 3 (4α) 1 ((S) —2—acetoxypropioninoleoxy) 1/3 / 3—Hydroxylean 1 1—2—2—Amide

 (21) Ν-(2 -methoxil) — 2 3 (4 α)-(Ν-acetyldarisiloxy) 1 3/3 —hydroxylorean 1 2 —en 1 2 8 —amide

 (22) Ν— [2- (Jetylamino) ethyl] — 3 j8—Hydroxy2 3 (4α) —Methoxylean 1 1—2—2 2—Amid

 (23) 1-[3, 2 3 (4 α) —dihydroxylone 1 2 — 1 1 2 8 — yl] — 4 — Methylbiperazine

(24) Ν— (2-methoxethyl) 1 2 3 (4α)-(trans 1-aminomethyl hexylcarbonylhexyl 3 1-hydroxyloxyan 1 12-en-28-amide

(25) 1 [3 β, 23 (4 α) -dihydroxy-lean- 1 -2-en- 28 -oil]-1-3-hydroxypyrrolidine

(26) 1-[30, 23 (α) dihydroxylean 1 2 -en- 28 -oil] — 4 — (2 -hydroxypropyl) piperazine

 (27) 2 — (Hydroxyacetoxy) ethynole 3 β, 23 (4 α)

 (28) 1 — [3 J3 —hydroxy 2 3 (4 α) — methoxylean 1 2 — 1 2 — 2 8 — oil] 1 3 — hydroxypyrrolidine

 (29) Ν— [2— (4 —pyridyl) ethyl] 1/3 / 3—hydroxy 1 2 3 (4 α) — methoxylean 1 1 2 —en 2 28 —amide

 (30) Ν— (2—methoxyl) 1 2 3 (4α) -hydroxyl 3 jS—methoxyl ore 1 2—en 1 2 8—amide

 (31) [3/3, 4 a, 1 3 β (Η)] — Ν— (2 — methoxyxetil) 1, 2, 3-dihydroxy 1-2-oxosolean 1 28-amide

 (32) 2-acetoxityl [3/3, 4h, 1 3/3 (Η)]-3, 23-dihydroxy 1 2—oxorean 1 2 8—et

 (33) Ν— (2-methoxethyl) 1/3/3, 2 3 (4α) 1 (isopropylidenedioxy) Orean 1 2—en-28—amide

 (34) 1 — [3) 3 —acetoxy 1 2 3 (4 α) -methoxolean 1 2 —ene 1 2 8 -oil] — 3—hydroxypyrrolidine

 (35) Ν- (2—methoxil) 1 3—Hydroxylean 1 1 2—No 28—Amid

 (36) 3) 3,2 3 (4α) —dihydroxylone 1 1—2—2 8—Oic acid

 (37) 2—acetoxityl 3 β 2 3 (4 α) —dihydroxyloleane 1 2 _en 28 2—oate

 (38) Ν— (2-Methoxyxetil)-3 β, 2 3 (4 α) dihydroxylean 12 2 —