WO1998058946A1

WO1998058946A1 - Triterpene derivatives and medicinal composition

Info

Publication number: WO1998058946A1
Application number: PCT/JP1998/002779
Authority: WO
Inventors: Jun Segawa; Masato Matsuoka; Hiroto Yoshifusa; Akio Nakamura
Original assignee: Nippon Shinyaku Co., Ltd.
Priority date: 1997-06-24
Filing date: 1998-06-19
Publication date: 1998-12-30
Also published as: AU8038298A

Abstract

Oleanane derivatives represented by general formula (I) or pharmacologically acceptable salts thereof; and a medicinal composition containing any of these as the active ingredient, wherein Me represents methyl; X, Y, and Z are any of the combinations (1) to (4): (1) X and Z in combination represent a bond, and Y represents hydrogen, (2) X and Y in combination represent oxo, and Z represents hydrogen, (3) X represents hydroxy, and Y and Z each represents hydrogen, (4) Y represents hydroxy, and X and Z each represents hydrogen; R1 represents (1) hydroxy, (2) optionally substituted monoalkylamino, (3) optionally substituted cyclic amino, (4) optionally substituted alkoxy, etc.; R2 represents (1) hydroxy, (2) optionally substituted sulfoxy, (3) optionally substituted phosphoxy, (4) optionally substituted acyloxy, etc.; and R3 represents (1) hydrogen, (2) hydroxy, (3) optionally substituted sulfoxy, (4) optionally substituted phosphoxy, (5) optionally substituted acyloxy, etc. The compounds are effective in the treatment of nephritis.

Description

^.

1 "Description

Triterpene derivative and pharmaceutical composition

Technical field

The present invention relates to an oleanan derivative useful as a medicament, a pharmaceutically acceptable salt thereof, and a pharmaceutical composition containing them as an active ingredient.

The compound of the present invention has a mesangial cell proliferation inhibitory effect and is useful for treating nephritis.

Background technology

Nephritis is classified into glomerulonephritis, interstitial nephritis, pyelonephritis, etc., depending on the location of the main lesion. A typical example is glomerulonephritis in which the glomerulus is the site of the lesion. Nephritis and glomerulonephritis are often used in the same sense (Latest Medical Dictionary, 1st edition, 570, ( 1987)).

Histopathological findings that are most frequent in human glomerulonephritis and are important in determining prognosis are the proliferation of mesangial cells and the deposition of substrates produced by mesangial cells (hereinafter referred to as mesangial substrates). The findings are common in most proliferative glomerulonephritis, such as IgA nephropathy, membranous proliferative glomerulonephritis and lupus nephritis (Iida, Kidney and Dialysis, 35, 505-509, ( 1993))). Then, as the proliferation of mesangial cells and the accompanying deposition of mesangial substrates progress, the glomeruli fall into glomerular sclerosis, which is the terminal image. Therefore, compounds that inhibit the proliferation of mesangial cells and the production of mesangial substrates are extremely useful as therapeutic agents for glomerulonephritis.

The present inventors have previously found that an oreanan derivative has a mesangial cell proliferation inhibitory effect and is useful for treating nephritis, and filed a patent application (International Publication W096 / 00236).

Disclosure of the invention

An object of the present invention is to provide a therapeutic agent for nephritis which has a higher absorbability at the time of oral administration than conventional oleanan derivatives and / or has a strong inhibitory action on mesangial cell proliferation. Has been repeated. As a result, the present inventors have found that a specific oleananane derivative achieves the above object and completed the present invention. did.

The present invention relates to a compound represented by the following formula [1], wherein the oleane derivative is any one of the following (A), (B) or (C): A pharmaceutical composition comprising an acceptable salt (hereinafter, referred to as the compound of the present invention) as an active ingredient, and a novel compound.

In the formula, Me represents methyl.

(A)

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 portion of the monoalkylamino is one substituent selected from the group consisting of hydroxy, alkoxy, alkoxycarbonyl, cyclic amino, alkylcarbonylamino, and alkylcarbonyloxy) May be substituted by a substituent.),

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

(4) alkoxy (such alkoxy may be hydroxy, aryl, alkoxy, .

3 It may be substituted by one substituent selected from the group consisting of alkoxycarbonyl, cyclic amino, and alkylcarbonyloxy. Such alkylcarbonyloxy may be substituted with alkylcarbonylamino or arylalkyloxy, where the aryl moiety may be substituted with alkoxy. ) And R ² represent any of the following substituents (1) to (4).

(1) hydroxy,

(2) 0 S 0 ₂ R ⁷ ,

(3) 0 P (= 0) (0R8) (0R9),

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

(1) hydrogen,

(2) hydroxy,

(4) 0 P (= 0) (0R8) (0R9),

(5) 0 C (= 0) R6 _O

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 (RiO) (Rll) [The R ¹⁰ and R ¹¹ are the same or different and are hydrogen or alkyl (the alkyl is a hydroxy, unsubstituted amino, mono May be substituted by one substituent selected from the group consisting of alkylamino and dialkylamino.) Or R ^{1 (} \ Rll together with adjacent N In other words, NiRlOHR ¹¹ ) 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 ¹² and R ¹³ [Such R ¹² and R ¹³ may be the same or different and are hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl Unsubstituted amino, carboxy, alkylcarbonylamino, alkylcarbonyloxy (the alkyl moiety of such alkylcarbonyloxy is selected from the group consisting of hydroxy, and unsubstituted amino, .

Four

It may be substituted by one substituent. ) Or alkoxy (the alkoxy may be substituted by 1 to 2 aryls, and the aryl may be substituted by the alkoxy.). ]

③ may be substituted by aminoalkyl ぃ cycloalkyl,

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);

ぃ Amino which may be substituted by 1 to 2 same or different, optionally substituted by hydroxyalkyl.

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

R ² 0- R3 —

R21, R31 are the same or different and each represents hydrogen, alkyl, Ariru, or a heterocyclic group, or R ^21, R ³¹ are such together connexion, the alkylene which may be substituted with alkyl.

Provided that X and Z are linked together, Y is hydrogen, R ^{1 is} hydroxy, monoalkylamino (the alkyl moiety of such monoalkylamino is hydroxy, alkoxy, Optionally substituted by one substituent selected from the group consisting of alkylcarbonyloxy and alkoxycarbonyl.) Or alkoxy (such alkoxy is hydroxy, aryl, alkoxy, alkoxy, alkoxy) Carbonyl, and optionally substituted by one substituent selected from the group consisting of unsubstituted alkylcarbonyloxy.), And R ^{2 is} hydroxy, or 0 C (= 〇) R 6 And R3 is hydrogen, hydroxy, or 0 C (= 〇) R ⁶ , except that R ⁶ is a substituent of the following (a) or (b).

(a) alkyl which may have one or both of the substituents R ¹² and R ¹³ (such R ⁱ² and R ¹³ may be the same or different and are hydroxy, unsubstituted amino, carboxy, alkylcarbonyl Oxy (the alkyl part of the alkylcarbonyloxy may be substituted by hydroxy or unsubstituted amino). -

5 is a substituted alkoxy. ]

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

(B)

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

RK R ^2, R3 is any of the following cases (1) to (26).

(1) R ¹ is (2-methoxethyl) amino, R ² is hydroxy, and R ^{3 is} hydroxyacetoxy.

(2) Ri is (2-methoxyxetil) amino, R ^{2 is} hydroxyacetoxy, and R ³ is hydroxy.

(3) Ri is (2-main Tokishechiru) Amino, R 2 Gahi Dorokishiase butoxy a R ³ Gahi Dorokishiase butoxy.

(4) Ri is (2-methoxyxethyl) amino, R2 is hydroxy, and R3 is acetoxy.

(5) Ri is (2-main Tokishechiru) Amino, R ² turtles Tokishiase butoxy a R ³ turtles Tokishiase butoxy.

(5) R ¹ is (2-methoxethyl) amino, R ² is hydroxy, and R ^{3 is} methoxyacetoxy.

(7) Ri is (2-main Tokishechiru) Amino, R 2 is § cell Tokishiase butoxy, R ³ is § cell Tokishiase Bok alkoxy.

(8) Ri is (2-main Tokishechiru) Amino is R2 Gahi Dorokishi, R ³ is § cell Tokishiase butoxy.

(9) Ri is (2-main Tokishechiru) Amino, R ² Gahi Dorokishi, R3 is Etokishiase butoxy.

(lO) R ¹ is (2-methoxethyl) amino, R ² is glycyloxyacetoxy, and R ³ is hydroxy.

(ll) R ¹ is (2-methoxethyl) amino, R ² is hydroxy, and R ³ is 3-hydroxypropionyloxy. -(lZ) R ¹ is (2-Methoxyxethyl) amino, R ² is hydroxy, -

6

R ³ is (S) -2-hydroxypropionyloxy.

(1S) R ¹ is (2-methoxyl) amino, R2 is 3-carboxypropionyloxy, and R3 is 3-carboxypropionyloxy.

(14) Ri is (2-methoxyshetyl) amino, R2 is hydroxy, and R3 is ( _S ) 12-acetoxypropionyloxy.

(15) R ¹ is (2-methoxethyl) amino, R ² is hydroxy, and R ³ is dimethylaminocarbonyloxy.

(1G) R ¹ is (2-methoxethyl) amino, R2 is glycyroxy, and R3 is glycyroxy.

() R ¹ is (2-methoxethyl) amino, R2 is hydroxy,

R ³ is glycyloxy.

(18) Ri is (2-methoxyl) amino, R ² is glycyroxy, and: 3 is hydroxy.

(l ^ R ¹ is (2-methoxethyl) amino, R 2 is hydroxy, and R3 is L-alanyloxy.

^ (^ R ¹ is (2-methoxethyl) amino, R 2 is L-alanyloxy, and R ³ is hydroxy.

(2DR ¹ is (2-methoxyxethyl) amino, R ² is hydroxy, and R3 is L-seryloxy.

(22) 1 ^ is (2-methoxethyl) amino, R ² is L-seryloxy, and R3 is hydroxy.

(23) Ri is (2-methoxethyl) amino, R2 is hydroxy, and R3 is glycylooxyacetoxy.

(24) R ¹ is 2- (ethylamino) ethylamino, R2 is hydroxy, and R ³ is methoxy.

(25) R ¹ is 2- (4-pyridyl) ethylamino, R2 is hydroxy, and is methoxy.

(26) R ¹ is (2-methoxyhexyl) amino, R ^{2 is} methoxy, and R ³ is hydroxy. --

7

(C)

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

R1 represents 0R81 or N (R81) (R82).

R81 and R82 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 R81 and R82 may have include the following substituents (a) to (i) 1-3 identical or different substituents selected from the group.

(a) halogen,

(b) OR83,

(c) 0 (C = 0) R83,

(d) COOR ⁸³ ,

(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, alkyl, hydroxy, and unsubstituted amino.

R83 and R84 are the same or different;-(1) hydrogen, or ② Represents an alkyl that may be substituted by one substituent selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino.

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

(1) hydroxy,

(2) an alkoxy optionally having a substituent,

(3) cycloalkyloxy optionally having 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 which may have a substituent,

(8) an alkoxycarbonyloxy optionally having a substituent,

(9) an alkylcarbonyloxy optionally having a substituent,

(10) arylcarbonyloxy optionally having a substituent;

Alkoxy, cycloalkyloxy, alkenyloxy, alkynyloxy, monoalkyl rubamoyloxy, dialkyl rubamoyloxy, alkoxycarbonyloxy, alkylcarbonyloxy, aryloxy represented by R ² have The optional substituents are 1 to 3 identical or different substituents selected from the group consisting of the following substituents (a) to (i).

(a) halogen,

(b) OR85,

(c) 0 (C = 0) R85,

(d) C 0◦ R ^85,

(e) Siano,

(f) N (R85) (R86),

(g) Alkyl alkyl,

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

9

R ⁸⁵ and R86 are the same or different,

① Hydrogen or

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

R ³ represents hydrogen.

Wherein X and Z are joined together, Y is hydrogen, R ^{1 is} hydroxy, R ² is unsubstituted alkylcarbonyloxy, and R ³ is hydrogen. Excludes The compound represented by the above formula [1], wherein the oleanane derivative in the case of (A) is a novel compound not described in the literature.

The compound represented by the formula [1], and the oleanan derivative in the case of (B), is not specifically disclosed in the above-mentioned International Publication WO096 / 00236.

It is not known that the compound represented by the formula [1] and which is the compound (C) is useful for treating nephritis.

The compound represented by the formula [1], and among the oleanan derivatives in the case of (C), the compound in the case of the following (D) is a novel compound not described in the literature.

(D)

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

R ¹ represents the following substituent (1) or (2).

(1) monoalkylamino (wherein the alkyl portion of the monoalkylamino is one selected from the group consisting of alkoxy, alkylcarbonyloxy, arylcarbonyl, and aromatic heterocarbonylcarbonyloxy) Has been replaced by a substituent of),-

(2) alkoxy (such alkoxy is alkoxy, alkylcarbonyl .

10 substituted with one substituent selected from the group consisting of xy, arylcarbonyl, and heteroaromatic carbonyloxy).

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

(1) hydroxy,

(2) an alkoxy optionally having a substituent,

(3) cycloalkyloxy optionally having a substituent,

(4) alkenyloxy which may have 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) arylcarbonyloxy optionally having a substituent;

Alkoxy, cycloalkyloxy, alkenyloxy, alkynyloxy, monoalkyl rubamoyloxy, dialkyl rubamoyloxy, alkoxycarbonyloxy, alkylcarbonyloxy, arylcarbonyl represented by R ² The optional substituents are 1 to 3 identical or different substituents selected from the group consisting of the following substituents (a) to (i).

(a) halogen,

(b) OR85,

(c) 0 (C = 〇) R85,

(d) COOR ⁸⁵ ,

(e) Siano,

(f) N (R85) (R86),

(g) cycloalkyl,

(h) aryl which may be substituted by 1 to 3 same or different substituents selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;

(i) the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino .

11. An aromatic heterocyclic group which may be substituted by 1 to 3 identical or different substituents selected from 11.

R 85 and R 86 are the same or different,

① Hydrogen or

R 3 represents hydrogen. The compound of the present invention has a higher absorbability at the time of oral administration than an oleanan derivative which is specifically disclosed as being useful for the treatment of nephritis in the International Publication W096 / 00236, and / or It has a strong inhibitory effect on mesangial cell proliferation and is useful for treating nephritis. This is a feature of the present invention.

Hereinafter, the present invention will be described in detail.

In the present invention, “alkyl” includes linear or branched alkyl having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl. -Butyl, n-pentyl, isopentyl, n-hexyl, isohexyl, n-heptyl and isoheptyl.

“Monoalkylamino”, “dialkylamino”, “alkylcarboxy”, “alkylthio”, “alkylsulfinyl”, “alkylsulfonyl”, “aminoalkyl”, “arylalkyloxy” and “ Examples of the alkyl portion of the “alkylcarbonylamino” include the aforementioned alkyl.

“Alkylene” 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, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl.

Examples of the cycloalkyl portion of the “cycloalkylcarbonyloxy” include the 07 cycloalkyl. -

12

"Alkoxy" includes linear or branched alkoxy having 1 to 7 carbon atoms, for example, methoxy, ethoxy, η-propoxy, isopropoxy, η-butoxy, isobutoxy, sec-butoxy, tert-butoxy , N-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy and isoheptyloxy.

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

“Alkenyl” includes straight-chain or branched-chain ones having 2 to 7 carbon atoms, for example, vinyl, 1-propenyl, isopropyl, aryl, 1-butenyl, 3-butenyl, 1-pentenyl , 4-pentenyl, 1-hexenyl, 5-hexenyl, 1-heptenyl and 6-heptenyl.

As the "alkynyl", a straight-chain or branched-chain one having 2 to 7 carbon atoms, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 3-butynyl, 1-pentynyl, 4-pentynyl, Examples include 1-hexynyl, 5-hexynyl, 1-heptynyl and 6-heptynyl.

“Aryl” includes those having 6 to 10 carbon atoms, for example, phenyl, 1-naphthyl, and 2-naphthyl.

Examples of the aryl portion of “aryl alkyloxy” and “arylcarbonyloxy” include the above aryl.

As the “heterocyclic group”, 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 can be mentioned. Examples include pyrrolidine-l-yl, pyrrolidine-l-yl, pyrrolidine-l-yl, furan-l-yl, furan-l-yl, thiophen-l-yl, and tiofen 1-yl, pyridine 1-yl, viridine 2-yl, biperidine 1 3-yl, viridine 4-yl, morpholine 1-yl, morpholine 1 3 — yl, morpholine 1 4 — yl, thiomorpholine 1 2 — yl, thiomorpholine 1 3 _ yl, thiomorpholine 1 4 — yl, biradizine 1 — yl, piradizine 1 2 — Yl, homopyrazine 1-1, hexamethylene diamine 1-1, pyridine-1 2 —yl, pyridine-1 3 —yl, pyridine-1 4 —yl, imidazole 1-1 1 , .

13 Pyrimidine-1 2 -yl, Pyrimidine-1 4 -yl, Pyrimidine-1 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. 1-ru 1-yl, Pillow 1-ru 2-yl, Virol 1- 3-yl, Franc- 2-il, Franc-3-1-yl, Ciophen 1- 2-yl, Ciophen 1- 3-yl, Oxazole-2-yl, thiazoyl 2-yl, 1H-1,2,4-triazole-1-yl, 1H-tetrazole-5-yl, pyridine-1 2- Yl, pyridin-1 3-yl, pyridine-1 yl, pyrimidine 1-2-yl, pyrimidine-1 _yl, pyrazine-1 2-yl, 1, 3, 5-triazine-1 2_ill.

The “cyclic amino” may include one or two nitrogen atoms, oxygen atoms, or sulfur atoms, the same or different, as ring-constituting atoms, in addition to the nitrogen atom that forms the bond. Or an unsaturated 5- to 7-membered ring group. Examples include pyrrolidine-1-1-yl, biradine-111-yl, piperazine-1-1-yl, morpholine-41-yl, thiomorpholine-4-yl, thiomorpholine-1-1 , 1-dioxy-do-yl, imidazo-l-yl, thiazolidine-l-yl, homobiradin-l-yl, and hexamethyleneimine-l-yl.

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

(1)

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

(a) hydroxy,

(b) phosphoxy,-

(c) alkylcarbonyloxy (alkyl of such alkylcarbonyloxy) .

The hydroxy moiety is selected from the group consisting of hydroxy, unsubstituted amino, alkoxy substituted by one or two identical aryls, alkylcarbonyloxy optionally substituted by unsubstituted amino, and alkylcarbonylamino. It may be substituted by 1-2 selected same or different substituents. ]

(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) cycloalkylcarbonyloxy substituted with unsubstituted aminoalkyl, (f) alkoxy.

R3 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 one or two 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) cycloalkylcarbonyloxy substituted with aminoalkyl,

(g) alkoxy.

Or, R ² and R ³ 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). .

Fifteen

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

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

(3)

X and Y are oxo together, 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 ² represents hydroxy.

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

(a) hydrogen,

(b) phosphoxy,

(c) alkylcarbonyloxy (the alkyl moiety of such alkylcarbonyloxy is substituted by hydroxy, unsubstituted amino, two identical aryls) .

And optionally substituted by one substituent selected from the group consisting of alkoxy, unsubstituted amino, alkylcarbonyloxy, and alkylcarbonylamino. Alternatively, such alkyl moieties may be substituted by both hydroxy and unsubstituted amino substitutions. ]

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

(e) cycloalkylcarbonyloxy substituted with aminoalkyl.

( Five )

X and Z are linked together and Y is hydrogen.

R2 represents the following substituent (a) or (b).

(a) alkylcarbonyloxy (where the alkyl moiety of such alkylcarbonyloxy 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.

R3 represents hydroxy.

(6)

X and Z are linked together and Y is hydrogen.

R2 and R3 are any of the following cases (a) to (c).

(a) R2 and R3 are each a phosphoxy.

(b) R2 and R3 are each an alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy is substituted by an alkylcarbonyloxy) .

17 ].

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

(7)

X and Z are linked together and Y is hydrogen.

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

(a) cyclic 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).

R2 and R3 each represent hydroxy.

(8)

X and Z are linked together and Y is hydrogen.

Rl and R2 are for the following cases (a) and (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 ァ -amino (such ァ -amino is substituted by hydroxy), and R ² is hydroxy or alkylcarbonyloxy.

R ³ represents alkoxy.

(9)

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

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

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

R2 and R3 are each hydroxy. -Among the compounds of the present invention, particularly preferred compounds include, for example, the following (1) to (35) .

18 compounds.

(1) N-(2-Methoxyxetil) 1/3/3-Hydroxy2 3 (4H)-Hydroxoxy 1-2-1-28-Amide

(2) N-(2-Methoxyxetil) 1 2 3 (4)-Hydroxy 1 3?-Hydroxoxy 1-2-1-28-Amide

(3) N- (2-Methoxyxetil) 1 2 3 (4a) —Acetoxy 1 3 / 5—Hydroxy Sorean 1 2—En 2 28—Amid

(4) N- (2-Methoxyxetil) 1/3/3, 2 3 (4h) 1bis (acetoxyacetoxy) Orean 1 12-en-1 28-amide

(5) N- (2-Methoxyxetil) — 2 3 (4) 1-Acetoxy-Acetoxy 1--3? —Hydroxy-lean 1 2 _

(6) N- (2-Methoxyxetil) 1 2 3 (4) Benzhydryl oxetate 3/3/3 Hydroxylene 1 1 2

(7) N- (2-Methoxyxetil) 1 3 / 5—Hydroxy 1 2 3 (4a) 1 (3—Hydroxypropionyloxy) Orean 1 2—Yen 1 2 8—Amide

(8) N— (2-Methoxyxetil) 1 3? —Hydroxy 2 3 (4 a)-((S) — 2—Hydroxypropionyloxy) Orean 1 1—2—1 2 8—Ami Do

(9) N- (2-Methoxyxetil) _3? —Hydroxy-1 23 (4a)-[4- (Morpholinomethyl) benzoyloxy] Orean 1 2 _ 2-28-Amide (10) N- (2-Methoxyxetil) 1 2 3 (4a)-[4— (Bis (2-hydroxyethyl) aminomethyl) benzoyloxy] — 3—Hydroxylean 1—12—2—8—Amide

(11) N— (2-Methoxyxetil) 1 3? —Hydroxy 2 3 (4) _ [4 — ((2 _Hydroxyxetyl) aminomethyl) Benzoyloxy] Orean 1 1 2—En 1 2 8 —Amid

(12) N- (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4) 1 [4— (thiomorpholinomethyl) benzoyloxy] Orean 1 1 2 — 1 1 2 8 — Amid

(13) N-(2-Methoxyxetil) 1 2 3 (4)-Glycyloxy 1 3 Byeon 'Roxylean 1 12-1-28-Amide .

19

(14) N- (2-Methoxyxetil) 1 3? —Glycyloxy 1 2 3 (4a) —Hydroxylean 1 2—Yen 2 8—Amide

(15) N-(2-methoxyxetil) 1 3 5-Hydroxy 2 3 (4)-(L-selyloxy) Orean 1 2--2-28-Amid

(16) N- (2—Methoxyxetil) 1 2 3 (4a) -Hydroxy-1 3? — (L—Ceryloxy) Orean 1 2—Yen 1 2 8—Amide

(17) N- (2—Methoxyxetil) 1 2 3 (4h) -Glycyloxyacetoxy 3? —Hydroxylean 1 1 2—En 1 2 8—Amid

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

(19) N— (2—Methoxyxetil) 1 3 / 5—Hydroxy 2 3 (4a) —Phosphoroxyl 1 1—2—1 2 8 _Amide

(20) N- (2-Methoxyxetil) 1 2 3 (4α) 1 ((S) —2—acetoxypropionyloxy) 1 3 / 5—Hydroxylean 1 1 2—En 2 28—Amide (21 ) Ν— (2—methoxyl) 1 2 3 (4a)-(N-acetylglycyloxy) 1 3? —Hydroxylean 1 1—2—28—Amid

(22) N— [2- (Jethylamino) ethyl] — 3? —Hydroxy-1 2 3 (4α) -Methoxyl-1 1 2-Yen-1 28-Amid

(23) 1 13/3, 2 3 (4) 1-doxy-l-oxylean 1 2

(24) Ν-(2-methoxethyl) 1 2 3 (4)-(trans 4-1 -aminomethylcyclohexancarbonyloxy 1-3--hydroxy-orean-1-2-en-28-amide

(25) 1 — [3/5, 2 3 (4) 1 ヒキシ — アン 1 2 ェ 1 — 2 8 — 才 — 3 3 3 3-Hydroxypyrrolidine

(26) 1-_ 3/3, 2 3 (4) Jihi-Droxylean 1 1 2 —Yen 2 8 —Yield] — 4— (2-Hydroxypropyl) pidazine

(27) 21- (Hydroxyacetoxy) ethyl 3/5, 23 (4H) (28) 1-[3? —Hydroxy 1 2 3 (4 H) 1-Methoxyl-an 1 1 2 -Yen 1 2 8—Oil] — 3—Hydroxypyrrolidine

(29) N- [2— (4-pyridyl) ethyl] — 3? —Hydroxy 2 3 (4 α) —methoxylean 1 12—one 1 28—amide

(30) Ν- (2-Methoxyxetil) 1 2 3 (4h) -Hydroxy 1 3? —Methoxy ore 1 1 2—Yen 1 2 8—Amide

(31) [3/5, 4 a, 1 3 β (Η)] -Ν- (2-Methoxyxetil) 1, 2,3-Dihydroxy 12-Oxosolean 1 28-Amid

(32) 2—acetoxityl [3 ^, 4 a, 1 3 β (Η)]-3,2,3-dihydrochloride 1 2—oxoxorean 1 2 8—oate

(33) Ν- (2-methoxethyl) 1 3 3, 2 3 (4α) 1 (isopropylidenedioxy) orean 1 2

(34) 1-[3-?-Acetoxy-1 2 3 (4) -Methoxyl-an-1 2 -Yen-1 28-Oil] — 3-Hydroxypyrrolidine

(35) N- (2-Methoxyxetil) 1 3—Hydroxylean 1 2—En 1 28—Amide

The compound of the present invention can be produced using an oleanan derivative represented by the following formula [2] as a starting material. The oleane derivative [2] has a carboxyl at position 28, a hydroxy group at position 3 and, in some cases, a hydroxy group at position 23, and these functional groups The compound of the present invention can be produced by utilizing the difference in the reactivity of the compounds.

(X, Y, and Z are the same as above. R30 represents hydrogen or hydroxy.) In the following production of the compound of the present invention, when the starting material has a substituent (for example, hydroxy, amino, carboxy, etc.) which is not desired to react, the starting material is protected by a known method in advance by a known method. It is generally used in reactions after protection with benzyl, 4-methoxybenzyl, 4,4,1-dimethoxytrityl, acetyl, tert-butoxycarbonyl, benzyloxycarbonyl, phthaloyl). After the reaction, the protecting group can be eliminated by a known method such as catalytic reduction, alkali treatment, or acid treatment.

R ¹ is a substituent obtained by removing hydroxy from the definition of R ¹ , R ² is hydroxy, and R ³ is hydrogen or hydroxy. [1] (hereinafter referred to as the “28-position derivative”) ) Can be produced from the oleanan derivative [2] using the following “1. Carboxy reaction”.

R ¹ is a substituent obtained by removing hydroxy from the definition of R ¹ , R ² is hydroxy, and R ³ is a substituent obtained by removing hydrogen and hydroxy from the definition of R ^3. Reanane derivatives [1] (hereinafter referred to as “23-position / 28-position derivatives”) can be produced from “28-position derivatives” using the following “2.2 3-position hydroxy reaction”. it can.

R ¹ is a substituent obtained by removing hydroxy from the definition of R ¹ above, R ² is a substituent obtained by removing hydroxy from the definition of R ² above, and R ³ is a substituent obtained by defining R ³ above. Oleanan derivatives [1] (hereinafter referred to as “33-positions / 23-positions / 28-position derivatives”), which are substituents excluding hydrogen and hydroxy, are converted from “23-position / 28-position derivatives” to “3. 3-5-hydroxylation ”.

R1 is hydroxy, R2 is hydroxy, and R3 is a substituent obtained by removing hydrogen and hydroxy from the definition of R3 above (1) (hereinafter referred to as “23-position derivative”). A protective group is introduced into the carboxy at position 28 of the oleanan derivative [2], and then the reaction is carried out using the following “2.23 Hydroxylation reaction”, followed by deprotection at position 28. Can be.

Is hydroxy, R ² is a substituent obtained by removing hydroxy from the definition of R ² , and R ³ is hydrogen or hydroxy. [1] (hereinafter referred to as “3-position derivative”) And the hydroxy at the 3-position of the oleanan derivative [2] .

A protective group can be introduced into the carboxy at the 22-position, and then the following "3.3-hydroxylation reaction" can be used, followed by deprotection at the 23- and 28-positions. However, when R ³ is hydrogen, introduction and deprotection of the protecting group at position 23 are unnecessary.

Wherein R ¹ Gahi Dorokishi, a substituent R ² is excluding the definition Karahi Dorokishi of said R ^2, a substituent R ³ is except hydrogen, the heat Dorokishi from the definition of the above R ³ O Reanane derivative [1] (hereinafter referred to as “3-position · 23-position derivative”) introduces a protecting group into the carboxy at position 28 of the oleanan derivative [2]. It can be produced by deprotecting the 28-position after using "3-hydroxyl reaction" and "3.3 5-hydroxyl reaction".

R ¹ is a substituent obtained by removing hydroxy from the definition of R ¹ , R ² is a substituent obtained by removing hydroxy from the definition of R ² , and R ³ is hydrogen or hydroxy. Derivative [1] (hereinafter referred to as the “3-position / 28-position derivative”) introduces a protecting group into the hydroxy at the 23-position of the “28-position derivative”. After using the 5-position hydroxy reaction, the 23-position can be deprotected to produce the 3-position '28 -position derivative '. However, when R ³ is hydrogen, introduction and deprotection of a protecting group at the 23-position are unnecessary.

The “28 position derivative” also introduces a protecting group into the 3-position hydroxy of the oleane derivative [2], and then uses the following “1. It can be manufactured even if deprotected.

The “28-position derivative” further introduces a protecting group into the hydroxyl group at the 23-position of the oleanan derivative [2], and then uses the following “1. Can also be produced by deprotection.

The “28-position derivative” further introduces a protecting group into the hydroxyl group at the 35-position and the hydroxyl group at the 23-position of the oleanan derivative [2], and then proceeds to the following “1. The reaction can be used to deprotect the 3-position and the 23-position.

The “3-position 23-position derivative” can also be produced from the oleanan derivative [2] using the following “4.3 Reaction of 3-position and 23-position dihydroxy”. '' “3 5 position · 2 3 position · 2 8 position derivative” means “2 8 position derivative” 3 / 5-position, 23-position reaction of dihydroxy ”.

1.2 Reaction of carboxy at the 8-position

(1-1) Reaction with halide

The Oreanan derivative [3], can be produced O Les Annan derivative [1 _c] by reaction with a halide (4).

[Wherein, R2, R3, X, γ, and Z are the same as above. R70 represents an alkyl moiety or R ⁸¹ of the alkoxy in the definition of said Rl. L represents halogen such as chlorine, bromine and iodine. ]

This reaction is usually carried out in a solvent-free or non-protonic solvent (for example, a polar solvent such as acetonitrile, N, N-dimethylformamide (DMF), or an ether-based solvent such as tetrahydrofuran (THF) or getyl ether). Bases (eg, potassium carbonate, sodium carbonate) in solvents, halogenated hydrocarbon solvents such as chloroform, methylene chloride, and hydrocarbon solvents such as benzene, toluene, and n-hexane, and mixtures thereof. In the presence of thorium, sodium bicarbonate, potassium bicarbonate, pyridine, 4-dimethylaminopyridine, triethylamine, sodium hydride, etc. -20 ~: 100

. (The reaction time varies depending on the type of the oleanane derivative [3] and the halide [4], and the reaction temperature, but is usually appropriate for 30 minutes to 24 hours. The amount to be used is preferably 1 to 1.2 times the molar amount of the oleanane derivative [3].

(1-2) Reaction with 0-alkylating agent

Can be produced Orea 'Na emission compound [1 _c] By Oreanan derivative [3] is reacted with 0-alkylating agent.

Wherein, R2, R3, x, γ , z s R 70 are as defined above. ]

This reaction can be usually performed without a solvent or in the same nonprotonic solvent as described above. As the 0-alkylating agent, diazoalkanes (eg, diazomethane, diazotane), trimethylsilyldiazomethane, orthoesters (eg, ethyl ethyl formate, ethyl ethyl orthoacetate) and the like can be used. The reaction temperature varies depending on the type of the 0-alkylating agent.In the case of diazoalkanes and trimethylsilyldiazomethans, it is appropriate to be -20 to 30 ° C, and in the case of orthoesters, it is 100 to 200 ° C. Is appropriate. The reaction time varies depending on the type of the oleanane derivative [3] and the 0-alkylating agent, and the reaction time, but usually 1 minute to 24 hours is appropriate. The amount of the 0-alkylating agent to be used is preferably 1 to 1.2 times the molar amount of the oleane derivative [3].

(1-3) Reaction with alcohol

The oleanane derivative [1c] can be produced by reacting the oleanean derivative [6] with the alcohol [7].

[Wherein, R ² , R ³ , X, Y, Z and R70 are the same as above. M is hydroxy or ha Rogen (chlorine, bromine, iodine, etc.), alkoxy (methoxy, etc.), aryloxy (p-nitrophenoxy, etc.), alkylsulfoxy (methanesulfoxy, etc.), arylsulfoxy (toluenesulfoxy, etc.) And a leaving group such as imidazolyl, alkylcarboxy or arylcarboxy. ]

Specifically, the oleanan derivative [1c] is an oleanane derivative [6] (when M is the above-mentioned leaving group other than hydroxy), for example, an acid halide (acid chloride, acid bromide, etc.) , Alkyl ester (methyl ester, ethyl ester, etc.), active ester (p-nitrophenyl ester, p-chlorophenyl ester, etc.), imidazolide or mixed anhydride (alkyl carbonic acid mixed anhydride, alkyl phosphoric acid A mixed acid anhydride) and an alcohol [7] as appropriate, or a condensing agent (1-ethyl-13_) with an oleanan derivative [6] (when M is hydroxy) and an alcohol [7]. (3-Dimethylaminopropyl) carbodiimide, dicyclohexyl carbodiimide, iodide 2-N-methylbiridinium, diphenyl The compound can be produced by a method in which the compound is directly bonded using a compound such as ruphosphoryl azide, getyl phosphoryl cyanide, or triphenylphosphine carbon tetrachloride.

In the case of using an acid halide (the oleanane derivative [6] in which M is a halogen), the oleanane derivative [1c] is used at -20 to 100 ° C. in the same non-protonic solvent as described above in the presence of the same base as above. It can be produced by carrying out a reaction with C. The reaction time varies depending on the type of the acid halide and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the alcohol [7] to be used is preferably 1 to 1: 1, 2 times the molar amount of the acid halide.

Such an acid halide is prepared by adding the oleane derivative [6] (when M is hydroxy) and a thionyl halide (eg, thionyl chloride, thionyl bromide) in the absence of a solvent or in the same non-protonic solvent as described above, It can be produced by reacting at -20 to 100 in the presence or absence of a base. The reaction time varies depending on the type of acid halide and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the halogenated thionyl used is at least 1 times the molar amount of the oleanane derivative [6], and a large excess such as 10 times the molar amount can be used. '' When a condensing agent is used, the oleanane derivative [1c] is the same nonprotonic solvent It can be produced by performing the reaction at -20 to 100 ° C in a medium in the presence or absence of the same base as described above. The reaction time varies depending on the type of the condensing agent and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the alcohol [7] and the condensing agent used is preferably 1 to 1.2 times the molar amount of the compound [6].

(1 -4) Reaction with amine

By reacting the oleane derivative [6] with the amine [8], the oleane derivative [1d] can be produced.

[Wherein, R2, R3, x, γ, z, and M are as defined above. N (R71) (R72) represents monoalkyl § amino in the definition of said R ^1, or cyclic Amino, or said ^{^{N (R 81) (R 82}} ). ]

Specifically, the oleanan derivative [1d] is an oleanane derivative [6] (when M is the above-mentioned leaving group other than hydroxy), for example, acid halide, alkyl ester, active ester, imidazolyl Or a mixed acid anhydride with an amine [8], or a condensing agent (1-ethyl-3- (3-) with an oleane derivative [6] (when M is hydroxy) and an amine [8]. Dimethylaminopropyl) carbodiimide, dicyclohexylcarbodiimide, diisopropyl carbodiimide, benzotriazole-1-yl tris (dimethylamino) phosphonidinehexafluorophosphoride, diphenylphosphoryl azide, propaneline Acid anhydride, etc.) and additives (N-hydroxysuccinimide, 1-hydroxybenzoic acid) Lyazol, 3-hydroxyl 4-oxo-1,3,4-dihydro 1,2,3-triazine, etc.) or by direct binding in the absence or presence of azine. O

When an acid halide (Oleanane derivative [6] in which M is a halogen) is used, the Oleanane derivative [1d] is used in the same non-protonic solvent as described above in the presence of the same base as above at -20 to 100 °. It can be produced by carrying out a reaction with C. The reaction time varies depending on the type of the acid halide and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the amine [8] used is preferably 1 to 1.2 times the molar amount of the acid halide. Amine [8] can be used in excess as a base.

When a condensing agent is used, the oleanane derivative (1d) is produced by performing the reaction in the same non-protonic solvent as described above in the presence or absence of the same base at -20 to 100 ° C. can do. The reaction time varies depending on the type of the condensing agent and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the amine [8] and the condensing agent is preferably 1 to 1.2 times the molar amount of the oreanan derivative [6] (when M is hydroxy). Amine [8] can be used in excess as a base.

In the aforementioned oleanane derivative [1], R ¹ is selected from the group consisting of optionally substituted monoalkylamino, optionally substituted dialkylamino, and optionally substituted cyclic amino. The oleanane derivative [1e], which is an alkoxy or monoalkylamino substituted by a substituent, can also be produced by reacting the oleane derivative [9] with an amine [10].

[Wherein, R ² , R ³ , X, Y, and Z are the same as described above. R73 represents haloalkylamino (for example, chloromethylamino, 2-bromoethylamino, 3-bromopropylamino), or haloalkoxy (for example, chloromethoxy, 2-bromoethoxy, 3'-bromopropoxy) Represent. R74 is a compound in which the halogen of R73 is N (R75) (R76) Represents a substituted group. R ^75, R ⁷⁶ are the same or different, represent hydrogen or optionally substituted alkyl, or R ⁷ 5, R76 is substituted with a together with the adjacent N connexion N (R75) (R76) Represents an optionally substituted cyclic amino. ]

This reaction can be carried out usually in the absence of a solvent or in the same nonprotonic solvent as described above, in the presence of the same base as above, at −20 to 100 ° C. The reaction time varies depending on the type of the oleanan derivative [9] and the amine [10] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the amine [10] used is preferably 1 to 1.2 times the molar amount of the oleanan derivative [9].

In this reaction, the oleanane derivative [9] used as a raw material is prepared by using the oleanan derivative [6] and a haloalkyl alcohol or a haloalkylamine, and the above-mentioned “reaction with (113) alcohol” or “(1— 4) Reaction with amine ”.

2. Reaction of hydroxy group at position 23

(2-1) Reaction with halide

The oleane derivative [1f] can be produced by reacting the oleane derivative [11a] with the halide [17].

[Wherein, R R2, X, Y, Z and L are as defined above. OR50 represents the aforementioned R ^3, except hydrogen, arsenide de port alkoxy. R ⁵⁰ represents a group obtained by removing a terminal oxygen atom from OR ⁵⁰ . ]

This reaction can be carried out in the same manner as in the above “(111) Reaction with halide”. The reaction time varies depending on the type of the oleanan derivative [11a] and the halide [17 '] and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. Haloge The amount of the compound [17] is preferably 1 to 1.2 times the molar amount of the oleane derivative [11a].

In the above-mentioned oleanane derivative (1 f), R50 is COR6, and 1¾6 is an aryl substituted with an alkyl substituted with ^^ (1 10) (R ¹¹ ). It can also be produced by reacting an oleane derivative [12a] with an amine [18].

[Wherein, R R2, RlO, R11, x, γ, and Z are as defined above. Ar ¹ represents aryl substituted with haloalkyl (chloromethyl, 2-bromoethyl, 3-bromopropyl, etc.). Ar ² is the halogen of Ar ¹

Represents a substituted group. ]

This reaction can be usually carried out without a solvent or in the same non-protonic solvent as described above, in the presence of the same base as above, at -20 to 100 ° C. The reaction time varies depending on the types of the oleanan derivative [12a] and the amine [18] and the reaction temperature, but is usually appropriate for 30 minutes to 24 hours. The amount of the amine [18] used is preferably 1 to 1.2 times the molar amount of the oleane derivative [12a].

In this reaction, the oleanane derivative [12a] used as a raw material is converted to an oleane derivative [11a] and an arylcarbonylcarbonyl halide substituted with a haloalkyl (for example, 4-chloromethylbenzoyl chloride, (2-Bromoethyl) benzoyl chloride and 3- (3-bromopropyl) benzoyl chloride) in the same manner as in “(2-1) Reaction with halide” above. Can be. In addition, among the above-mentioned oleanane derivatives [1: f], the oleanane derivative [1 h in which R ⁵⁰ is P (= 0) (OR ⁵² ) (〇R ⁵³ ), and R ⁵² and R ⁵³ are both hydrogen. Is Oreana [13a] by hydrogenolysis.

[Wherein, RR ² , X, Y, and Z are as defined above. Ph represents phenyl. This reaction can be carried out usually in a suitable solvent (eg, acetic acid, methanol, ethanol, ethyl acetate) in the presence of a catalyst (eg, platinum dioxide) at -20 to 100 ° C. and normal pressure. Depending on the type of the oleanan derivative [13a] and the solvent, pressure may be applied to accelerate the reaction. The reaction time varies depending on the oleanan derivative [13a], the type of catalyst, and the reaction temperature, but usually 30 minutes to 48 hours is appropriate. In this reaction, the oleanane derivative [13a] used as a raw material is prepared in the same manner as in the above “Reaction with (2-1) halide” using the oleanane derivative [11a] and diphenylphosphoryl chloride. Can be manufactured.

(2-2) Reaction with carboxylic anhydride

In Oreanan derivative [1 1 a] carboxylic anhydride [14] More Oreanan derivative is reacted with [1 i] [Equation (1), R3 is OC (= 0) R6, R 6 is a Group excluding the substituent bonded at the nitrogen atom from the definition of R ⁶ in (for example, ①

Or an aryl substituted with an alkyl substituted with or an alkyl optionally having one or both of the substituents R ¹² and R ¹³ )].

Me Me Me Me

(R ⁶¹ CO) ゥ O

CO-R ^J (14)

Mfe CH ₂ OH [11a] Me CH OCOR [Wherein, R R2, X, Y, and Z are as defined above. R61 is a group obtained by removing a substituent bonded by a nitrogen atom from the definition of R6 above (for example, (1) aryl substituted with alkyl substituted by N (RlO) (Rll), or (2) substituent R ^12, represents an alkyl) which may have any one or both of R ^13. ]

This reaction can be usually carried out without a solvent or at -20 to 100 ° C in the same manner as in the above-mentioned “(2-1) Reaction with halide”. The reaction time varies depending on the type of the oleanan derivative [11a] and the carboxylic acid anhydride [14], and the reaction temperature, but is usually 30 minutes to 24 hours. The amount of the carboxylic acid anhydride [14] to be used is preferably 1- to L2-fold the molar amount of the oleanane derivative [11a].

In this reaction, a reactive derivative of a carboxylic acid corresponding to the carboxylic anhydride [14], for example, an active ester derivative (p-nitrophenyl ester, p-chloro phenyl ester, etc.) or imidazolide is used. be able to.

(2-3) Reaction with carboxylic acid using condensing agent

By directly binding the oleane derivative [11a] and the carboxylic acid [15] using the condensing agent described in the above “(1-3) Reaction with alcohol”, the oleane derivative [ 1 i] can be produced.

_{Wherein, R R2 N X, Y,} Z, R61 are as defined above. ]

This reaction is usually carried out without a solvent or in the same non-protonic solvent as in "(2-1) Halide" above and in the same base as in "(2-1) Halide" above. In the presence of -20-100 ° C. The reaction time varies depending on the type of the oleanane derivative [11a] and the carboxylic acid [15], and the reaction temperature. 30 minutes to 24 hours is appropriate. The amount of the carboxylic acid [15] and the condensing agent to be used is preferably 1- to 1.2-fold the molar amount of the compound oleanane derivative [11a].

For example, N— (2-methoxicetil) 1/3 / 3,2 3 (4) obtained by the method described in International Publication WO096 / 00236, 1-dihydroxy-doxylean-12-2-28-amide ( Hereinafter, the compound is referred to as Compound A.) and p-methoxypentyioxyacetic acid are directly bonded using the above-mentioned condensing agent to produce an oleanan derivative of Compound 1 shown in Examples described later. can do. By hydrogenolysis of the obtained oleanan derivative, an oleanan derivative of compound 4 shown in Examples described later can be produced.

(Compound 1)

Hydrogenolysis

(Compound 4) (2-4) Reaction of 1,1, 1-carbonyldiimidazole and amine The oleane derivative [11a] is reacted with a carbonylating agent, and subsequently reacted with amine [16] to obtain the oleane derivative [1a]. j] can be produced.

[Wherein, R1, R2, X, Y and Z are the same as above. N (R77) (R78) is the same as defined above for R6, and is, for example, a substituent represented by ⑤ (1 to 2 identical or different, optionally substituted with alkyl which may be substituted by hydroxy) Represents a substituent bonded with a nitrogen atom, such as amino. ]

This reaction can be carried out usually in the absence of a solvent or in the same nonprotonic solvent as described above, in the presence of the same base as above, at −20 to 100 ° C. The reaction time varies depending on the type of the oleanan derivative [11a] and the amine [16], and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the amine [16] used is preferably 1 to 1.2 times the molar amount of the oleanan derivative [11a].

As the carbonylating agent, 1,1,1-carbonyldiimidazole, p-nitrochloroformate and the like can be used. The amounts of the carboxylating agent and the amine [16] used are preferably 1 to 1.2 moles per mol of the oleanan derivative [11a]. However, an excess of amine [16] can be used as the base.

(2-5) Reaction with sulfur trioxide-pyridine complex

By reacting the oleanan derivative [11a] with a sulfur trioxide-pyridine complex, an oleanan derivative [1 k] (the oleanan derivative of the formula [1], wherein R ₃ is 0 S 03 H) can be produced.

[Wherein, I ¹ , R 2, x, γ, and z have the same meanings as described above. ]

This reaction can be carried out usually at −20 to 100 ° C. in the same nonprotonic solvent as in the above “Reaction with (2-1) halide”. The reaction time varies depending on the type of the oleanane derivative [1 la] and the sulfur trioxide-pyridine complex, and the reaction temperature, but usually 30 minutes to 100 hours is appropriate. The amount of the sulfur trioxide-viridine complex to be used is preferably a 1- to 1.2-fold molar amount relative to the oreanan derivative [11a].

3. Reaction of 3-hydroxy group

(3-1) Reaction with halide

The compound [lm] can be produced by reacting the oleane derivative [11b] with the halide [17].

[Wherein, R ¹ R 3, X, Y, Z, L, and 50 are as defined above. ]

This reaction can be carried out in the same manner as the above-mentioned reaction for producing an oleanan derivative [1f] from an oleanan derivative [11a] and a halide [17].

In the above-mentioned oleanan derivative (1 m), R50 is c〇R6, and R6 is N (RH).

Oleanane derivatives that are aryls substituted with alkyls substituted with (R ¹¹ ) [1n] can also be produced by reacting an oleanan derivative [12b] with an amine [18].

^{^{Wherein, RR 3, R 10, R}} U, ArK Ar 2, X, Y, Z is Ru as defined above der. ]

This reaction can be carried out in the same manner as in the above-mentioned reaction for producing the oleanane derivative [1 g] from the oleanane derivative [12a] and the amine [18].

In this reaction, the oleanane derivative [12b] used as a raw material is converted into an oleane derivative [11b] and an arylcarbonyl halide (eg, 4-chloromethylbenzoyl chloride) substituted with haloalkyl. , 4- (2-bromoethyl) benzoyl chloride and 3- (3-bromopropyl) benzoyl chloride) in the same manner as in the above “Reaction with (3-1) halide”. can do. Further, in the above Oreanan derivative [lm], R50 is _P (= 〇) (OR52) (OR53), Oreanan derivative R ^52, R ⁵³ are both hydrogen [1 p] is Oreana down derivatives [13b] can be produced by hydrogenolysis.

[Wherein, R R3, X, Y, Z, and Ph are as defined above. -This reaction is similar to the above-mentioned reaction for hydrogenolyzing the oleane derivative [13a]. It can be carried out.

In this reaction, the oleanane derivative [13b] used as a raw material is prepared in the same manner as in the above-mentioned “reaction with (3-1) halide” using the oleanane derivative [11b] and diphenylphosphoryl chloride. Can be manufactured.

(3-2) Reaction with carboxylic anhydride

By reacting the oleane derivative [11b] with the carboxylic acid anhydride [20], the oleane derivative [1q] [in the formula [1], 112 is 〇〇 (= 0) 1 ^, or good alkylcarbonyl having substituent in the definition of R2 O carboxymethyl Wakashi Ku is a good § reel carbonyl O carboxymethyl be substituted, R ⁶ is defined in said R ⁶ A group excluding a substituent bonded with a nitrogen atom from (for example, aryl substituted with alkyl substituted with ①N (R ¹⁰ ) (R ¹¹ ), or ② any one of substituents R ¹² and R ¹³ Or an alkyl) which may have one or both of them.

[Wherein, R R3, X, Y, and Z are as defined above. R62 is a group obtained by removing a substituent bonded by a nitrogen atom from the definition of R6 described above (for example, (1) aryl substituted with alkyl substituted with N (RlO) (Rll), or (2) substituent R ^An alkyl optionally having one or both of the above), or an alkylcarbonyloxy optionally having a substituent in the above definition of R ² It represents a good alkyl moiety or an aryl moiety which may have a substituent of arylcarbonylcarbonyl which may have a substituent. ].

This reaction can be carried out in the same manner as the above-mentioned reaction for producing the oleanan derivative [1i] from the oleanane derivative [11a] and the carboxylic anhydride [14]-. In this reaction, a reactive derivative of a carboxylic acid corresponding to the carboxylic anhydride [20], for example, an active ester derivative (ρ-nitrophenyl ester, ρ-chlorophenyl ester, etc.) or imidazolide is used. Can be.

(3-3) Reaction with carboxylic acid using condensing agent

By using the same condensing agent as in the above “(2-3) Reaction with carboxylic acid using condensing agent”, the oleane derivative [11b] and the carboxylic acid [21] can be directly bonded to each other. Oleanan derivative [1q] can be produced.

[Wherein, R R3, R62, x, γ, and Z are as defined above. ]

This reaction can be carried out in the same manner as in the above-mentioned reaction for producing an oleanane derivative [1i] from the oleanane derivative [1la] and a carboxylic acid [15].

(3-4) Reaction with 1, 1, 1-carbonyldiimidazole and amine

The oleane derivative [1r] can be produced by reacting the oleane derivative [11b] with a carbonylating agent and subsequently reacting with the amine [16].

[Wherein, R3, X, Y, Z, and N (R77) (R78) are as defined above. ] This reaction can be carried out in the same manner as the reaction for producing an oleanan derivative [1j] by reacting an oleanan derivative [11a] with a carbonylating agent and subsequently reacting with an amine [16].

(3-5) Reaction with sulfur trioxide-pyridine complex

(In the formula [1] R2 is Oreanan derivatives OS_〇 ₃ H) More Oreanan derivative in which the Oreanan derivative [1 1 b] is reacted with sulfur trioxide one pyridine complex [ls] can be produced.

[Wherein, R R3, X, Y, and Z are as defined above. ]

This reaction can be usually carried out in the same manner as the reaction for producing the oleanan derivative [1k] by reacting the oleanane derivative [11a] with the sulfur trioxide-pyridine complex.

4.3 Reaction of 3-hydroxy and 23-dihydroxy

(4-1) Reaction with ketone

The oleanan derivative [1t] can be produced by reacting the oleanane derivative [22] with the compound [19] in the presence of an acid catalyst.

Me Me Me Me

HOH ₂ C Me .

39

[Wherein, R1, X, Y, Ζ, R21 and R31 have the same meanings as described above. ]

This reaction is usually carried out in the absence of a solvent or in the nonprotonic solvent described above, using an acid (for example, a mineral acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, or phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, or succinic acid). , Fumaric acid, p-toluenesulfonic acid, benzenesulfonic acid, and methanesulfonic acid) in the presence of -20 to 100 ° C. The reaction time varies depending on the types of the oleanan derivative [22] and the compound [19] and the reaction temperature, but is usually appropriate for 30 minutes to 24 hours. The compound [19] is preferably used in an amount of 1 to 10 times the molar amount of the oleanane derivative [22].

In the above “2.2 Reaction of 3-hydroxy group” or “3.3 / 5 Reaction of hydroxy group”, instead of the oleanan derivative [11a] or the oleanan derivative [11b], When using an oleanan derivative (2) having two hydroxy groups at positions 3 and 23, the reactants halide (17), carboxylic anhydride (14), carboxylic acid (15), The amount of the carboxylic acid anhydride [20], the carboxylic acid [21], the carbonylating agent, the amine [16] or the sulfur trioxide-pyridine complex to be used is 2 to 2.2 times the molar amount of the oleane derivative [2]. By using the compound in an appropriate amount, a 3-position or 23-position derivative having the same substituent at the 3-position and the 23-position can be produced.

A compound in which a substituent (eg, hydroxy, carboxyl, etc.) of the oleanane derivative [2] or the oleanane derivative [2], which is not to be reacted, used as a raw material in these reactions is protected by the above-mentioned protecting group, Halide [4], halide [17], alcohol [7], amine [8], amine [10], amine [16], amine [18], carboxylic anhydride [14] , Carboxylic anhydride [20], carboxylic acid [15], carboxylic acid [21], compound [19], and sulfur trioxide-bipyridine complex are known compounds or known methods. It can be manufactured according to the method described in Reference Example.

In the oleane derivative [2] used as a raw material, (1) X and Y are oxo together, and Z is a hydrogen compound (the oleane derivative [2a]), and (2) X is , Hydroxy, Y, Ζ are compounds each of which is hydrogen (oleanan derivative [2b]), (3) Y is hydroxy, and X, 、 are each hydrogen- (Oleanane derivative [2c]) is, for example, In the formula, X and Z are a bond together, and Y can be produced by a method shown below using a compound (oleanane derivative [2d]) which is hydrogen. Production of Oleanan Derivative [2a]

(Step 1) Production of Epoxy Compound [21] from Oleanan Derivative [2d]

The epoxy compound [21] can be produced by reacting the oleane derivative [2d] with an oxidizing agent.

[Wherein, R1, R2 and R3 are as defined above. ]

This reaction is usually carried out by oxidizing in a nonprotonic solvent or a protonic solvent (eg, an alcoholic solvent such as methanol, ethanol, or 2-propanol, water, or a mixed solvent thereof). Agents (for example, hydrogen peroxide, ozone, organic peroxides (t-butyl hydroperoxide, benzoyl peroxide, peracetic acid, perbenzoic acid, methyl peroxybenzoic acid, etc.), metal oxides (chromium oxide , Potassium permanganate, selenium dioxide, etc.)) in the presence of -20-100 ° C. The reaction time varies depending on the type of the oleanan derivative [2d], the oxidizing agent, and the reaction temperature, but is usually 30 minutes to 24 hours. The amount of the oxidizing agent to be used is preferably 1 to 10 times the molar amount of the oleanan derivative [2d].

(Step 2) Production of oxo form [2a] from epoxy form [2 1]

The oxo form [2a] can be produced by treating the epoxy form [21] with an acid.

[Wherein, R R2 and R 3 are as defined above. ]

This reaction is usually carried out in an acid such as a mineral acid such as hydrochloric acid, sulfuric acid, or phosphoric acid, formic acid, acetic acid, propionic acid, trifluoroacetic acid, p-toluene in the nonprotonic solvent or the protonic solvent described above. (Organic acid such as sulfonic acid) at −20 to 100 ° C. The reaction time varies depending on the type of the epoxy compound [21], the type of the acid, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the acid used is preferably a catalytic amount to an equimolar amount with respect to the oleanan derivative [21].

Production of Oleanane Derivatives [2b] and [2c]

By reducing the oleanane derivative [2a] with a metal hydride, the oleanane derivatives [2b] and [2c] can be produced.

-

42

[Wherein, R 1, R 2 and R 3 are as defined above. ]

This reaction is usually carried out in the above non-protonic solvent in a metal hydride (eg, borane, sodium borohydride, sodium cyanoborohydride, lithium borohydride, sodium aluminum hydride, lithium hydride). Can be carried out at −78 to 100 ° C. in the presence of aluminum. The reaction time varies depending on the type of the oleanan derivative [2a] and the reducing agent, and the reaction temperature, but usually 30 minutes to 24 hours is appropriate. The amount of the reducing agent used is preferably 1 to 1.5 times the molar amount of the oleanan derivative [2a].

The produced compound is a mixture of the oleane derivatives [2b] and [2c]. By using a separation and purification means such as fractional recrystallization and column chromatography from this mixture, the oleanean derivatives [2b] and [2c] can be isolated and purified.

In the production of the above-mentioned oleanan derivatives [2a], [2b], and [2c], when the raw material has a substituent (for example, hydroxy, amino, carboxy, etc.) which is not desired to react, the raw material is previously prepared. It is common to use in the reaction after protecting with the above protecting group by a known method. After the reaction, the protecting group can be removed by a known method such as catalytic reduction, alkali treatment, or acid treatment.

Compounds having an acidic group (such as carboxy, sulfoxy, and phosphoxy) among the oleanane derivatives according to the present invention can be used as a medicament as a free acid, but can be used in the form of a pharmaceutically acceptable salt by a known method. Can also be used. Examples of such salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts.

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

The dialkali metal salt of the phosphorenated oleanan derivative can be obtained by adding 2 equivalents of sodium hydroxide or potassium hydroxide to the oleanane derivative, preferably in an alcoholic solvent. '' The alkaline earth metal salt of the oleanean derivative is prepared by the above-described method. ,

43 It can be obtained by dissolving a metal salt in water, methanol, ethanol or a mixed solvent thereof and adding one equivalent of calcium chloride or the like.

Compounds having a basic group (such as unsubstituted or substituted amino or cyclic amino) among the oleanan derivatives according to the present invention can be used as a free base as a medicament, but are pharmaceutically acceptable by a known method. It can also 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 phosphoric acid, acetic acid, citric acid, tartaric acid, maleic acid, succinic acid, fumaric acid, ρ-toluenesulfonate, benzenesulfone Acids and salts of organic acids such as methanesulfonic acid can be mentioned.

For example, the hydrochloride of an oleanan derivative can be obtained by converting

-Or a methylene chloride solution.

The oleanane derivative according to the present invention can be obtained by using ordinary separation and purification means from the reaction mixture described above, for example, means such as extraction, concentration, neutralization, filtration, recrystallization, column chromatography, and thin layer chromatography. It can be isolated and purified. As shown in the test examples described below, the compound of the present invention is orally administered as compared to an oleanan derivative which is specifically disclosed as being useful for the treatment of nephritis in the aforementioned International Publication W096 / 00236. It has a high absorbency at the time and / or a strong inhibitory effect on mesangial cell proliferation. Further, the compound of the present invention has low toxicity. For this reason, the pharmaceutical composition of the present invention is useful as an excellent therapeutic agent for nephritis, and is effective for treating chronic glomerulonephritis, especially proliferative glomerulonephritis among nephritis.

When the compound of the present invention is administered as a medicament, the compound of the present invention contains 0.1 to 99.5%, preferably 0.5 to 90% as it is or in a pharmaceutically acceptable nontoxic and inert carrier. As a pharmaceutical composition, it can be administered to animals, 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 according to the present invention can be administered intravenously, orally, intraosseously, topically (such as transdermally) or rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred. '' The dosage of the pharmaceutical composition for the treatment of nephritis depends on the patient's condition, such as age and weight, It is desirable to set the dose taking into account the nature of the disease, the nature and degree of the disease, etc. A range is preferred, preferably in the range of l-500 mg / human.

In some cases, lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in divided doses two to three times a day.

BEST MODE FOR CARRYING OUT THE INVENTION

Hereinafter, the present invention will be described in more detail with reference to Examples, Test Examples, and Formulation Examples of the compound of the present invention.

Example 1— (1)

N- (2-Methoxyxetil) 1/3 / 3—Hydroxy2 3 (4a) 1-((4-Methoxybenzyloxy) acetoxy] Orean 1 2—1—2 8—Amide (Compound 1)

In accordance with the method of Example 8— (1) described in WO096 / 00236, N— (2-methoxecil) 13? 2,3 3 (4) Jihi-Droxylean 1 1—2—2 8-Amide (Compound A) was obtained.

Compound A (1 kg) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride in methylene chloride (20 L) under ice-cooling are shown as WS CD HC1. 36 g) and 4-dimethylaminoviridine (46 g) were dissolved. Under ice-cooling, a solution of p-methoxybenzyloxyacetic acid (370 g) in methylene chloride (1.5 L) was added dropwise to the solution, and the mixture was stirred for 4.5 hours. Under ice-cooling, WS CD HC1 (72 g) was added to the solution, and a solution of p-methoxybenzyloxyacetic acid (74 g) in methylene chloride (300 ml) was added dropwise. Stirred for hours.

After allowing the reaction solution to return to room temperature and stirring for 15 hours, WS CDHC1 (54 g) was added to the solution, and p-methoxybenzyloxyacetic acid (55 g) in methylene chloride (20 g) was added. 0 ml) solution was added dropwise and stirred for 2.5 hours. Water was added to the reaction solution, washed 1% HC 1 solution, 1% K ₂ C 0 ₃ solution, water, saturated saline in this order. The organic layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the residue was recrystallized three times from ethyl acetate to obtain the desired product (462 g) as a colorless powder. Mp 1 5 8~ 1 5 9 ° C " Elemental analysis (as C ₄₃ H ₆₅ N0 ₇₎ ,

45 Calculated value (%) C: 72.95 H: 9.25 N: 1.98

Observed value (%) C: 72.74 H: 9.14 N: 2.19

Example 11 (2)

N- (2-Methoxyxetil) 1/3 / 3—Hydroxy-1 2 3 (4a)-[(4-Methoxybenzyloxy) acetoxy] Orean 1 2—1—2 8—Ami Separate manufacturing method for compound (compound 1)

DMF (1 O ml) of compound A (5.0 g), 2-methyl-11-methylpyridinyl monoxide (3.6 g), p-methoxybenzyloxyacetic acid (2.8 g) Tritylamine (3.8 g) was added dropwise to the solution at 40 ° C or lower, and the mixture was further stirred at 30 to 40 ° C for 3 hours. After pouring the reaction solution into ice water, the resulting precipitate was collected by filtration and extracted with ethyl acetate. The organic layer is washed with water, a 5% aqueous hydrochloric acid solution, a 5% aqueous sodium hydrogen carbonate solution, and a 10% saline solution in that order, concentrated under reduced pressure until the volume becomes 10 ml, and cooled with ice (5 to 10 ° C). The precipitated crystals were collected by filtration. Yield 4.7 g. The crystals were suspended in ethyl acetate (9.5 ml), stirred at 50 ° C for 1 hour, cooled on ice, filtered to remove insolubles, and dried to obtain the desired product (4.2 g) as a colorless powder. Was. The physical properties matched the values in Example 1- (1). Elemental analysis (as C ₄₃ H ₆₅ N0 ₇₎

Calculated value (%) C: 72.95 H: 9.25 N: 1.98

Measured value (%) C: 72.67 H: 9.10 N: 2.21

Example 2

N- (2-Methoxyxetil) 1 2 3 (4) 1-Hydroxy-1 3? — [(4-Methoxybenzyloxy) acetoxy] Orean 1 12-En-28-Amide (Compound Object 2)

Example 1—The mother liquor of the recrystallization in (1) was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (methylene chloride, chloroform), and recrystallized three times from ethyl acetate to give the desired product (1). 3.8 g) was obtained as a colorless powder. Mp 1 9 0 ° C Elemental analysis (as C ₄₃ H ₆₅ N0 ₇₎

Calculated value (%) C: 72.95 H: 9.25 N: 1.98

Obtained value (%) C: 72.75 H: 9.21 N: 2.06 "Example 3 ,

46

Ν— (2-Methoxyxetil) 1 2 3 (4a) 1-benzyloxytoxin 3? — Hydroxylorean 1 12—1- 1 2 8—amide (Compound 3)

Compound A (26.5 g), WSCD · HC1 (11.5 g), 4-dimethylaminopyridine (1.2 g), benzyloxyacetic acid (100 ml) in methylene chloride (300 ml) .0 g) was added and the mixture was stirred at room temperature for 17 hours. The reaction mixture was washed with 5% hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and water, dried over magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1). ) To give a colorless oil of N- (2-methoxethyl) 13?, 23 (4h) -bis (benzyloxyacetoxy) orean-12-en-28-amide ( 5.0 g) and the desired product (15.5 g) as a colorless powder. Melting point 72 ° C Elemental analysis (C ₄₂ H ₆₃ N 0 ₆ '2H ₂₀ )

Calculated value (%) C: 70.65 H: 9.46 N: 1.96

Obtained value (%) C: 70.73 H: 8.97 N: 1.97

Example 4— (1)

N- (2-Methoxyxetil) 13 -Hydroxy-I 23 (4a) -Hydroxy-A-Sexy-Reo-I 12 -I-I-N-28-Amide (Compound 4)

Example 1 — The compound (100 g) obtained in (1) and 10% palladium on carbon (10 g) were suspended in 80% ethanol (1.5 L), and the suspension was subjected to normal pressure at 20 ° C. Hydrogenolysis was performed. After filtering the reaction solution, water (4 L) was added to the filtrate, and the mixture was extracted with ethyl acetate (5 L). The organic layer was washed twice with 5% saline (3 L) and once with saturated saline (3 L), dried over magnesium sulfate, and concentrated under reduced pressure at 30 ° C or lower. The residue was purified by silica gel column chromatography (methylene chloride / ethyl acetate) to give a colorless amorphous (85 g). This amorphous (82 g) is crushed in a mortar and sieved through an 80 mesh sieve, and the obtained powder (67 g) is heated at room temperature for 4 hours, at 65 ° C for 6 hours, and at 75 ° C for 6 hours. Drying under reduced pressure gave a colorless amorphous target product (62 g).

Elemental analysis value (as C ₃₅ H ₅₇ N0 ₆ '1 / 5H ₂₀ )

Calculated value (%) C: 71.08 H: 9.78 N: 2.37

Observed value (%) C-.70.87 H: 9.75 N: 2.41 "

: 0.79 (6H, s), 0.84-2.08 (25H, m), 0.91 (6H, s), 0.95 (3H, s), —-

47

1.15 (3H, s), 2.54 (lH, dd, J = 5Hz, 16Hz), 2.60 (lH, t, J = 5Hz), 3.20-3.60 (3H, m), 3.35 (3H 3 s), 3.98 (lH , d, J = llHz), 4.19 (2H, d, J = 5Hz), 4.28 (lH, d, J = llHz), 5.38 (lH, t 5 J = 3Hz)

Example 41 (2)

N- (2-Methoxyxetil) 13? -Hydroxy-1 2 3 (4) 1-Hydroxyacetoxylean 1 12-En- 28-Amide (Compound 4)

Example 11 The compound (30 g) obtained in step (1) and 10% palladium on carbon (3 g) were suspended in methanol (60 ml) and subjected to hydrogenolysis at 30 ° C. under normal pressure. The liquid was filtered under pressure. After washing the insolubles with methanol (30 ml), the washing solution was combined with the filtrate, water (23 ml) was added, and the mixture was washed three times with n-heptane (150 ml). The lower layer was filtered, and the filtrate was poured into water (430 ml) under ice-water cooling. After stirring for 30 minutes under ice water cooling, the precipitate was collected by filtration, washed with water, and dried under reduced pressure to obtain a colorless amorphous (24 g). This was added to methanol (60 ml), stirred, and filtered. The insolubles were washed with methanol (15 ml), and the washing solution and the filtrate were combined and poured into ice water (360 ml). After stirring for 30 minutes, the mixture was naturally returned to room temperature, cooled again (5 ° C), and further stirred for 30 minutes. The resulting precipitate was collected by filtration and dried under reduced pressure to obtain a colorless amorphous target product (23.5 g). The physical property values were the same as those in Example 41- (1).

Elemental analysis value (as C ₃₅ H ₅₇ N0 ₆ '1 / 5H ₂₀ )

Calculated value (%) C: 71.08 H: 9.78 N: 2.37

Measured value (%) C: 70.92 H-.9.69 N: 2.34

Example 41 (3)

N- (2-Methoxyxetil) 1/3 / 5—Hydroxy-1 2 3 (4a) —Hydroxyacetoxylean 1 2—Yen—28—Amide (Compound 4)

Using the compound obtained in Example 3, a colorless amorphous compound was obtained in the same manner as in Example 41- (1). The physical properties were the same as those in Example 4- (1). Elemental analysis value (as C ₃₅ H ₅₇ N0 ₆ '1 / 5H ₂₀ )

Calculated value (%) C: 71.08 H: 9.78 N: 2.37

Actual value (%) C: 71.04 H: 9.57 N: 2.54 'Example 5 —-

48

N- (2-Methoxyxetil) 1 2 3 (4) 1-Hydroxy 3? -Hydroxy-acetoxy-lean 1 12-Yen-1 28-Amide (Compound 5)

Using the compound (7.1 g) obtained in Example 2, the desired product (5.3 g) was obtained as a colorless powder in the same manner as in Example 4- (1). Melting point 1 3 8 ° C

Elemental analysis value (as C ₃₅ H ₅₇ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 70.43 H: 9.79 N: Z.35

Measured value (%) C: 70.65 H: 9.94 N: 2.30

Example 6

N- (2-Methoxyxetil) 13-3, 23 (4) Bis (hydroxyacetoxy) Orean 1 12-en-1 28-amide (Compound 6)

Using the compound obtained in Example 3, the desired product (3.1 g) was obtained as a colorless powder in the same manner as in Example 4- (1). Melting point 2 1 4 ° C

Elemental analysis (as C ₃₇ H ₅₉ N0 ₈₎

Calculated value (%) C: 68.81 H: 9.21 N: 2.17

Measured value (%) C: 68.53 H: 9.27 N: 2.14

Example Ί

Ν- (2-Methoxyxetil) 1 2 3 (4a) —Acetoxy 1 3 / 3—Hydroxylone 1 12—Ien 1 28—Amide (Compound 7)

A colorless amorphous product was obtained in the same manner as in Example 3, except that acetic acid was used instead of benzyloxyacetic acid.

IR (KBr): 3425, 2944, 1744, 1638, 1242 cm_l

Elemental analysis value (as C ₃₅ H ₅₇ N0 ₅ ' ⁷ / 3H ₂₀ )

Calculated value (%) C: 68.48 H: 10.13 N: 2.28

Observed value (%) C: 68.68 H: 9.16 N: 2.21

Example 8

N- (2-Methoxyxetil) 1 3 3,2 3 (4) 1-Bis (methoxyacetoxy) Orean 1 12-Ien 1 28-Amide (Compound 8)

Using methoxyacetic acid in place of benzyloxyacetic acid, the compound was synthesized in the same manner as in Example 3, and was subjected to silylation gel column chromatography. .-CTJ

49 Methanol = 100: 1) to give the target compound as a colorless powder. Mp 1 92 ° C Elemental analysis (as C ₃₉ H ₆₃ N0 ₈₎

Calculated value (%) C: 69.51 H: 9.42 N: 2.08

Observed value (%) C: 69.42 H: 9.41 N: 2.08

Example 9

N- (2-Methoxyxetil) 13-Hydroxy 23 (4a) -Methoxyacetoxylean 12 -N-28-Amide (Compound 9)

Further elution was carried out by silica gel column chromatography in Example 8 (closure form: methanol = 1100: 1) to obtain the target compound as a colorless powder.

Melting point 1 97 ° C

Elemental analysis (as C ₃₆ H ₅₉ N0 ₆₎

Calculated value (%) C.-71.84 H: 9.88 N: 2.33

Measured value (%) C: 71.64 H: 9.64 N: 2.27

Example 10

N- (2-Methoxyxethyl) 13/5, 23 (4α) Bis (acetoxyacetoxy) Orean 1 12-en-1-28-amide (Compound 10)

The compound was synthesized in the same manner as in Example 3 using acetic acid in place of benzyloxyacetic acid, and purified by silica gel column chromatography (form in chloroform) to obtain the target compound as a colorless powder. Melting point 5 9 ° C

Elemental analysis value (as C ₄₁ H ₆₃ N0 ₁₀ )

Calculated value (%) C: 67.46 H: 8.70 N: 1.92

Measured value (%) C: 67.50 H: 8.68 N: 1.98

Example 1 1

N- (2-Methoxyxetil) 1 2 3 (4) 1-Acetoxy-Acetoxy 3? -Hydroxy-lean 1 12-Yen-1 28-Amide (Compound 11)

Further elution (chloroform) was carried out by silica gel column chromatography in Example 10 to obtain a target substance as a colorless powder.

Melting point 8 1 ° C "Elemental analysis (as C ₃₇ H ₅₉ N 0 ₇ '1 / 4H ₂₀ ) .

50 Calculated value (%) C: 70.05 H: 9.45 N: 2.21

Observed value (%) C-.69.91 H: 9.22 N: 2.25

Example 1 2

N— (2 __- Methoxyxetil) 3? —Hydroxy2 3— (4) —Ethoxyacetoxylean 1 12—Ien 1 28—Amide (Compound 12)

The desired product was obtained as a colorless powder in the same manner as in Example 3 except that ethoxyacetic acid was used instead of benzyloxyacetic acid. Melting point 8 2 ° C

Elemental analysis value (as C ₃₇ H ₆₁ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 71.12 HilO.OO N: 2.24

Measured value (%) C: 70.98 H: 9.60 N: 2.28

Example 13

N- (2-Methoxyxetil) 1 2 3 (4) 1-Benzhydryloxyl ethoxy 3? -Hydroxylone 1 12-En 1 28-Amide (Compound 13)

The desired product was obtained as a colorless powder in the same manner as in Example 3 except for using benzylhydroxyacetic acid instead of benzyloxyacetic acid. Melting point 7 8 ° C

Elemental analysis value (as C ₄₈ H ₆₇ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 75.55 H: 8.98 N: 1.84

Obtained value (%) C: 75.54 H: 8.96 N: 1.86

Example 14

N- (2-Methoxyxetil) 1 2 3 (4) 1 (3-Benzyloxypropionyloxy) 1 3? -Hydroxylean 1 12-En 1 28-Amide (Compound 14) The desired product was obtained as a colorless powder in the same manner as in Example 3, except that 3-benzyloxypropionic acid was used instead of benzyloxyacetic acid. Melting point 1 3 3 ° C

Elemental analysis (as C ₄₃ H ₆₅ N0 ₆₎

Calculated value (%) C: 74.64 H: 9.47 N: 2.02

Measured value (%) C: 74.56 H: 9.52 N: 2.20

Example 15

N- (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4H)-(3—H! ^ Mouth xypropionyloxy) Orean 1 2—Yen 1 2 8—Amide (Compound 1 Five ) Using the compound obtained in Example 14, a colorless powdery target substance was obtained in the same manner as in Example 4- (1). Melting point 106 ~ 107 ° C

Elemental analysis value (as C ₃₆ H ₅₉ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 70.78 H: 9.90 N: 2.29

Measured value (%) C: 70.88 H: 9.69 N: 2.44

Example 16

N- (2-Methoxyxetil) 1 2 3 (4α)-((S) -2-benzyloxypropionyloxy) 1 3? -Hydroxylone 1 12-En-1-28-Amide (Compound Object 1 6)

Using (S) -2-benzyloxypropionic acid instead of benzyloxyacetic acid, the target compound was obtained as a colorless powder in the same manner as in Example 3. Melting point 7 1-7 2 ° C Elemental analysis value (as C ₄₃ H ₆₅ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 73.68 H: 9.49 N: 1.99

Measured value (%) C: 73.70 H: 9.44 N: 2.19

Example 17

N— (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4) — ((S) —2—Hydroxyb mouth pionyloxy) Orean 1 2—2—28—Amide (Compound 17)

Using the compound obtained in Example 16, the target compound was obtained as a colorless powder in the same manner as in Example 4- (1). Melting point 98 ~ 99 ° C

IR (KBr): 3400, 2945, 1934, 1638, 1129 cm— ¹

MS (m / z): 602 (M + + l)

Example 18

N- (2-Methoxyxetil) 13? -Hydroxy 23 (4)-(Methylthio) acetoxylean 12-Yen-28-Amide (Compound 18)

The desired product was obtained as a colorless powder in the same manner as in Example 3 except that methylthioacetic acid was used instead of benzyloxyacetic acid. Melting point 208 ° C

Elemental analysis _{_{_{(C 36 H 59 N0 5 S}}} ) ' Calculated (%) C: 69.97 H: 9.62 N: 2.27 Measured value (%) C: 69.65 H: 9.40 N: 2.49

Example 19

N— (2-Methoxyxetil) 13—Hydroxy 1 2 3 (4) 1 Mesylacetoxyl 1-12—Ien 1 28—Amide (Compound 19)

The compound (0.45 g) obtained in Example 18 was dissolved in methylene chloride (50 ml), and m-chloroperbenzoic acid (0.32 g) was added little by little at —18. After stirring for an hour, the temperature was raised to 0 C naturally. Water was poured into the reaction solution and partitioned. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform chloroform: methanol = 10: 1) to obtain the desired product (0.41 g) as a colorless powder. Was. Melting point 200 ° C

Elemental analysis _{_{_{(C 36 H 59 N0 7 S}}} )

Calculated value (%) C: 66.53 H: 9.15 N: 2.16

Measured value (%) C: 66.13 H: 8.90 N: 2.33

Example 20

N- (2-Methoxyxetil) 13?, 23 (4a) -Dinicotinyloxylean-12-En-28-Amide (Compound 20)

The compound was synthesized in the same manner as in Example 3 except that nicotinic acid was used in place of penziloxyacetic acid, and purified by silica gel column chromatography (form: methanol: 200: 1) to give the target compound as a colorless powder. Obtained. Mp 1 1 4~ 1 1 5 ° C Elementary analysis (as _{_{_{_{C 45 H 61 N 3 0 8}}}} '1 / 2H 2 0)

Calculated value (%) C: 72.16 H: 8.34 N: 5.61

Obtained value (%) C: 72.38 H: 8.52 N: 5.57

Example 2 1

N— (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4H) 1 Nicotinyloxylone 1 12—Yen _ 28 —Amide (Compound 21)

Further elution was carried out by silica gel column chromatography in Example 20 (chloroform: methanol = 200: 1) to obtain the target compound as a colorless powder.

Mp 2 2 8~ 2 2 9 ° C " Elemental analysis (as _{_{_{_{C 39 H 58 N 2 0 5}}}} ) -

53 Calculated value (%) C: 73.78 H: 9.21 N: 4.41

Measured value (%) C: 73.58 H: 9.38 N: 4.56

Example 22

N- (2-Methoxyxethyl) 23 (4) -dimethylaminocarbonyloxy13? -Hydroxylean-12-28-amide (Compound 22)

To a solution of compound A (0.60 g) in methylene chloride (30 ml) was added N, N-dimethylcarbamoyl chloride (0.13 g), and then sodium hydride (60%). (0.05 g) was added and stirred for 4 hours. The reaction solution was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to obtain the desired product (0.34 g) as a colorless powder. Melting point 19 7-19 8 ° C

Elemental analysis (as _{_{_{_{C 36 H 60 N 2 0 5}}}} '3 / 2H 2 0)

Calculated value (%) C: 68.86 H: 10.11 N: 4.46

Obtained value (%) C: 68.48 H: 9.80 N: 4.94

Example 23

N- (2-Methoxyxetil) 1 2 3 (4a) 1-[(4-Dimethylaminomethyl) benzoyloxy] 1/3 / 3-Hydroxylean 1 12-En-28-Amide hydrochloride (Compound 23)

To a solution of compound A (9.5 g) and pyridine (2.0 g) in methylene chloride (150 ml) was added dropwise 4-chloromethylbenzoyl chloride (10.2 g), and the mixture was allowed to stand at room temperature for 2 days. Stirred. After the precipitate was removed by filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: acetic acid I) = 1: 5 → 1: 2) to give N- (2- Methoxyxetil) 1 3? — (4-Chloromethylbenzoyloxy) —2 3 (4) 1-Hydroxylean 1 12—Oen 1 28-Amide (hereinafter referred to as Compound B. 1 5 7 g), followed by N— (2-Methoxyxetil) —23 (4h)-(4-Chloromethylbenzoyloxy) 1 3? —Hydroxylean 1 12—Yen—28— An amide (hereinafter, referred to as compound C. 3.57 g) was obtained. Under ice-cooling, Compound C (0.50 g), dimethylamine hydrochloride (0.24 g), triethylamine (0.30 g), and sodium iodide (0.44 g) were added in acetone. T .-

54

(30 ml), and then naturally returned to room temperature and stirred for 49 hours. The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to give N- (2-methoxethyl) 1 2 3 (4 (I) 1-((4-Dimethylaminomethyl) benzoyloxy) 135-hydroxylethane-12-28-amide (0.29 g) was obtained as a colorless amorphous. A 1 M hydrogen chloride-methanol solution (0.26 ml) was added dropwise to a solution of this amorphous (0.16 g) in getyl ether (10 ml) at room temperature, and the solvent was distilled off at room temperature under reduced pressure. . The residue was washed with getyl ether to give the desired product (0.16 g) as a colorless powder. Melting point 27 2 ~ 2 74 ° C

Elemental analysis (as _{_{_{_{C 43 H 86 N 2 0 5}}}} 'HC1'3 / 4H 2 0)

Calculated value (%) C: 69.70 Η: 9 · 31 Ν: 3.78

Measured value (%) C: 69.71 Η: 8.97 Ν: 3.84

Example 2 4

Ν— (2-Methoxyxetil) 13—Hydroxy 23 (4a) 1-1 “(Morpholinomethyl) benzoyloxy] Orean 12—12—28—Amide (Compound 24)

Compound C (0.776 g), morpholine (0.31 g), and sodium iodide (0.533 g) were added to acetone (50 ml) and stirred for 19 hours. . The reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with chloroform. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (form: ethyl acetate = 100: 1) to give the desired product (0.69 g). Was obtained as a colorless amorphous. Melting point 1 17 ~ 1 18 ° C

Elemental analysis (as _{_{_{_{C 45 H 68 N 2 0 6}}}} '1 / 2H 2 0)

Calculated value (%) C: 71.11 H: 9.42 N: 3.69

Measured value (%) C: 70.84 H: 9.29 N: 3.76

Example 2 5

N- (2-Methoxyxetil) 1 3? -Hydroxy 1 2 3 (4α)-"4- (Mole holinomethyl) benzoyloxy] _Olean 1 12-En-28- 8Mid Hydrochloric acid -

55 salt (Compound 25)

The compound (0.30 g) obtained in Example 24 was dissolved in a mixed solvent of geethylether (10 ml) and methylene chloride (1 ml), and a 1 M hydrogen chloride-methanol solution (0.3 ml) was dissolved. 9 ml) was added dropwise, and the solvent was distilled off under reduced pressure at room temperature. The residue was washed with getyl ether to obtain the desired product (0.29 g) as a colorless powder. Melting point 2 4 3 to 24 5 ° C

Elemental analysis (as _{_{_{_{C 45 H 68 N 2 0 6}}}} 'HC1'H 2 0)

Calculated value (%) C: 68.63 H: 9.09 N: 3.56

Measured value (%) C: 68.91 H: 9.22 N: 3.73

Example 26

N- (2-Methoxyxetil) 1 2 3 (4h)-[4- (Jetylaminomethyl) benzoyloxy] —3 / 3-Hydroxylean 1 12-En-1-28-Amide (Compound Object 2 6)

A colorless amorphous target product was obtained in the same manner as in Example 24 except that morpholine was replaced with getylamine.

IR (KBr): 3415, 2940, 1719, 1646, 1271, 1119 cm " ¹

Elemental analysis value (as C ₄₅ H ₇₀ N ₂ 0 ₅ '1 / 5H ₂ 0)

Calculated value (%) C: 74.79 H: 9.82 N: 3.88

Observed value (%) C: 74.49 H: 9.71 N: 4.04

Example 2 7

N- (2-Methoxyxetil) 1 2 3 (4) 1 [41- (Jetylaminomethyl) benzoyloxy] — 3? -Hydroxylean 1 12-En-28-Amide hydrochloride (Compound 27)

The desired product was obtained as a colorless powder in the same manner as in Example 25 using the compound obtained in Example 26. Melting point 2 16 ~ 2 18 ° C

Elemental analysis (as _{_{_{_{C 45 H 70 N 2 0 5}}}} 'HC1'H 2 0)

Calculated value (%) C-.69.87 H: 9.51 N: 3.62

Obtained value (%) C: 69.83 H: 9.26 N: 3.78 "Example 28 -

56

N- (2-Methoxyxetil) 1 2 3 (4a) 1- [4- (Getylaminomethyl) benzoyloxy] — 3 / 3—Hydroxylone 1 12-Yen-1 28-Amide Methanesulfonate (Compound 28)

Using the compound obtained in Example 26, methanesulfonic acid was used instead of hydrogen chloride, and the target product was obtained as a colorless powder in the same manner as in Example 25. Melting point 13 7 to 13 9 ° C

Elemental analysis value (as C ₄₅ H ₇₀ N ₂ 0 ₅ 'CH ₄ 0 ₃ S' ₃ H ₂ 0)

Calculated value (%) C: 63.56 H: 9.28 N: 3.22

Measured value (%) C: 63.61 H: 9.03 N: 3.30

Example 2 9

N- (2-Methoxyxetil) 1 2 3 (4α) 1- [41- (Jethylaminomethyl) benzoyloxy] 1 35-Hydroxylean 1 12-En-28-Amide Toluenesulfonate (Compound 2 9)

Using the compound obtained in Example 26, p-toluenesulfonic acid was used instead of hydrogen chloride, and the target product was obtained as a colorless powder in the same manner as in Example 25. Melting point 1 1 1 to 1 1 3; C

Elemental analysis _{_{_{(C 45 H 70 N 2 0}}} 5 · C 7 H 8 0 3 S · 3 / 2H 2 0)

Calculated value (%) C.-68.01 H: 8.89 N: 3.05

Measured value (%) C: 68.16 H: 8.67 N: 3.07

Example 30

N- (2-Methoxyxetil) 1 2 3 (4a) 1- [4— (Bis (2-hydroxyxethyl) aminomethyl) benzoyloxy 1—3? —Hydroxylean 1 2—Gen—2 8—Amin De hydrochloride (Compound 30)

The desired product was obtained as a colorless powder in the same manner as in Examples 24 and 25 except that morpholine was replaced with genoaluminamine. Mp 1 7 7~ 1 7 9 ° C Elemental analysis (as _{_{_{_{C 45 H 70 N 2 0 7}}}} 'HC1'2H 2 0)

Calculated value (%) C: 65.63 H: 9.18 N: 3.40

Measured value (%) C: 65.81 H: 8.82 N: 3.39 "Example 31 N— (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4)-[4 — ((2—Hydroxyxetyl) aminomethyl) Benzoyloxy 1 Orean 1 1—2—1 2 8—Amide Hydrochloride (Compound 31)

The desired product was obtained as a pale brown powder in the same manner as in Examples 24 and 25 using ethanolamine instead of morpholine. Melting point 18 1 ~ 1 8 3 ° C

Elemental analysis (as _{_{_{_{C 43 H 66 N 2 0 6}}}} -HC1'2H 2 0)

Calculated value (%) C: 66.26 H: 9.18 N: 3.59

Measured value (%) C: 66.66 H: 8.91 N: 3.78

Example 3 2

N— (2-Methoxyxetil) 1-3—Hydroxy-1 2 3 (4) — “4- (Pyridinomethyl) benzoyloxy] Orean—1—2—1—8—Amide Hydrochloride (Compound 32)

The desired product was obtained as a colorless powder in the same manner as in Examples 24 and 25 using piperidine instead of morpholine. Melting point 2 6 8 ~ 2 7 0 ° C

Elemental analysis (as _{_{_{_{C 46 H 70 N 2 0 5}}}} 'HC1)

Calculated value (%) C: 71.98 H: 9.32 N: 3.65

Measured value (%) C: 71.77 H: 9.35 N: 3.83

Example 3 3

N— (2-Methoxyxetil) 1-3? —Hydroxy-1 2 3 (4a)-[4-1 (thiomorpholinomethyl) benzoyloxy] orean 1-22-en-1-28-amide hydrochloride (Compound 3 3)

Using thiomorpholine instead of morpholine, the desired product was obtained as a colorless powder in the same manner as in Examples 24 and 25. 2 3 5 ° C (decomposition)

Elemental analysis (as _{_{_{_{C 45 H 68 N 2 0 5}}}} S'HC1'3 / 2H 2 0)

Calculated value (%) C: 66.51 H: 8.93 N: 3.45

Actual value (%) C: 66.55 H: 8.61 N: 3.51

Example 34

N- (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4)-[4— (Γ-midazolylmethyl) _ben-Viroxy] —Olean 1 2—En 1 —2 8—Amide -

58 Hydrochloride (Compound 34)

Using imidazole in place of morpholine, the desired product was obtained as a colorless powder in the same manner as in Examples 24 and 25. Melting point 200 ~ 210 ° C

Elemental analysis (as _{_{_{_{C 44 H 63 N 3 0 5}}}} 'HC1'2H 2 0)

Calculated value (%) C: 67.20 H: 8.71 N: 5.34

Measured value (%) C: 66.98 H: 8.77 N: 5.22

Example 3 5

N— (2-Methoxyxetil) 1/3 / 3—Hydroxy 1 2 3 (4H) 1- [4- (4-Methylbiperazine-1 1-ylmethyl) benzoyloxy “1 Orean 1 1—2—1 2 8 _ Amide dihydrochloride (Compound 35)

The desired product was obtained as a colorless powder in the same manner as in Examples 24 and 25 using 1-methylbiperazine instead of morpholine. Mp 1 9 9~2 0 0 ° C Elemental analysis (as _{_{_{_{C 46 H 71 N 3 0 5}}}} '2HC1'3H 2 0)

Calculated value (%) C: 63.28 H: 9.12 N: 4.81

Measured value (%) C: 63.16 H: 8.81 N: 4.91

Example 3 6

N- (2-Methoxyxetil) 1-3? -Hydroxy-1 2 3 (4-H) -1 "4- (1-Piperazinylmethyl) benzoyloxy-orean-1 12-En-28-Amid dihydrochloride (Compound 3 6)

The target product was obtained as a yellow powder in the same manner as in Example 24 and Example 25 using piperazine instead of morpholine. Melting point 2 3 3 to 2 35 ° C

Elemental analysis (as _{_{_{_{C 45 H 69 N 3 0 5}}}} '2HC1'3 / 2H 2 0)

Calculated value (%) C: 64.96 H: 8.96 N: 5.05

Actual value (%) C: 65.11 H: 9.08 N: 5.26

Example 37

N- (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4H) 1 [4— (4—1 (2-pyridyl) pyrazine 1 1-ylmethyl) Benzoyloxy] Orean 1 1 2—2 8-Amide trihydrochloride (compound 37) "Example 2 4 using 1- (2-pyridyl) pidazine instead of morpholine In the same manner as in Example 25, the desired product was obtained as a pale yellow powder. Melting point 2 32 ~ 233 ° C

Elemental analysis (as _{_{_{_{C 50 H 72 N 4 0 5}}}} '3HC1'2H 2 0)

Calculated value (%) C: 62.91 H: 8.34 N: 5.87

Measured value (%) C: 62.86 H: 8.56 N: 6.19

Example 38

N- (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4H) 1 [4-(4— (2—Birimidyl) piperazine 1 1-ylmethyl) benzoyloxy] orean 1 1 2 28-amide dihydrochloride (compound 38)

Using 11- (2-pyrimidyl) piperazine instead of morpholine, the target product was obtained as a colorless powder in the same manner as in Examples 24 and 25. Melting point 2 13 to 2 15 ° C

Elemental analysis (as _{_{_{_{C 49 H 71 N 5 0 5}}}} '2HC1'3H 2 0)

Calculated value (%) C: 62.80 H: 8.50 N: 7.47

Measured value (%) C: 62.99 H: 8.23 N: 7.57

Example 3 9

N- (2-Methoxyxetil) 1 2 3 (4) 1 [4-1 (Aminomethyl) benzoyloxy] — 3 ^ —Hydroxylean 1 1 2—1 1 2 8—Amide hydrochloride (Compound 3 9)

N- (2-Methoxyxetyl) -1 23 (4α)-[4-(4)-(Penzyloxycarbonylaminomethyl) benzoic acid was used instead of benzyloxyacetic acid in the same manner as in Example 3. Benzyloxycarbonylaminomethyl) benzoyloxy] —3 /? — Hydroxylyan-1-ene-1-28-amide was obtained as a colorless powder. This powder (1.08 g) was dissolved in methanol (30 m 1), 5% palladium carbon (0.20 g) was added, and hydrogenolysis was performed at normal temperature and normal pressure. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain a colorless amorphous (0.71 g). Using this amorphous material (0.22 g), the target product (0.18 g) was obtained as a colorless powder in the same manner as in Example 25. .

60 melting point 2 3 5 ° C (decomposition)

Elemental analysis (as _{_{_{_{C 41 H 62 N 2 0 5}}}} 'HC1)

Calculated value (%) C: 70.41 H: 9.08 N: 4.01

Measured value (%) C: 70.35 H: 9.17 N: 3.71

Example 40

N— (2-Methoxyxetil) 1 3 /? — Hydroxy 1 2 3 (4)-[3- (Morpholinomethyl) benzoyloxy] Orean 1 2—2—28—Amide (Compound 40)

Using 3-chloromethylbenzoyl chloride instead of 4-chloromethylbenzoyl chloride, N- (2-methoxethyl) was obtained in the same manner as in the preparation of compound C described in Example 23. One 23 (4-h) one (3-chloromethylbenzoyloxy) 13-hydroxyhydroxy-one 12-en-28-amide (hereinafter referred to as compound D) was obtained.

Using compound D instead of compound C, a colorless amorphous compound was obtained in the same manner as in Example 24.

IR (KBr): 3420, 2940, 1720, 1642, 1522, 1466, 1279 cm ~ l

Elemental analysis (as _{_{_{_{C 45 H 68 N 2 0 6}}}} )

Calculated value (%) C: 73.74 H: 9.34 N: 3.82

Actual value (%) C: 73.39 H: 9.08 N: 4.04

Example 4 1

N- (2-Methoxyxetil) 1 2 3 (4h)-[3— (Gethylaminomethyl) benzoyloxy] 13? -Hydroxylean 1 12-En-1-28-Amide (Compound 4 1)

A colorless amorphous target product was obtained in the same manner as in Example 24 using compound D in place of compound C and getylamine in place of morpholine.

IR (KBr): 3420, 2940, 1719, 1638, 1522, 1456, 1279 cm "!

Elemental analysis (as _{_{_{_{C 45 H 70 N 2 0 5}}}} )

Calculated value (%) C: 75.17 H: 9.81 N: 3.90 * Actual value (%) C: 74.68 H: 9.86 N: 4.12 .-

61 Example 4 2

N- (2-Methoxyxetil) 1 3? -Hydroxy 2 3 (4)-[3- (4-Methylbiperazine-1 1-ylmethyl) benzoyloxy "1 Orean 1 1 2"

28-amide (compound 42)

A colorless amorphous target product was obtained in the same manner as in Example 24, using compound D instead of compound C, and 1-methylbiperazine instead of morpholine.

IR (KBr): 3420, 2944, 1719, 1646, 1522, 1458, 1281 cm " ¹

Elemental analysis value (as C ₄₆ H ₇₁ N ₃₀ ₅ '1 / 2H ₂₀ )

Calculated value (%) C: 73.17 H: 9.61 N: 5.56

Measured value (%) C: 73.27 H: 9.26 N: 5.95

Example 43

N- (2-Methoxyxetil) 1 3? —Hydroxy-1 2 3 (4a) 1- [4- (N- (2-Dimethylaminoethyl) -1-N-methylaminomethyl) benzoyloxy] Orean 1 1—2 One 28-amide (compound 43)

Using N, N, N'-trimethylethylenediamine instead of morpholine, a colorless amorphous target product was obtained in the same manner as in Example 24.

IR (KBr): 3420, 2946, 1717, 1638, 1522, 1273, 1121 cm " ¹

Elemental analysis value (as C ₄₆ H ₇₃ N ₃ 0 ₅ 'H ₂₀ )

Calculated value (%) C: 72.12 H: 9.87 N: 5.48

Measured value (%) C: 71.84 H: 9.37 N: 5.52

Example 44

N- (2-Methoxyxetil) 1 3? —Hydroxy-1 2 3 (4a)-"4- (N- (2-Jetylaminoethyl) -1-N-ethylaminomethyl) benzoyloxy] orean _ 1 2 —1 2 8—Amide (Compound 44)

Using 無色, 物, Ν′-triethylethylenediamine instead of morpholine, a colorless amorphous target product was obtained in the same manner as in Example 24.

IR (KBr): 3420, 2945, 1717, 1640, 1522, 1273, 1121 cm— ¹

Elemental analysis _{_{_{(C 49 H 79 N 3 0}}} 5 - as 1 / 2H ₂ 0) - Calculated (%) C: 73.64 H: 10.09 N: 5.26 .-

62 Actual value (%) C: 73.56 H: 9.68 N: 5.64

Example 45

N- (2-Methoxyxetil) 1 3? _ [4- (Getylaminomethyl) benzoyloxy] — 2 3 (4) -Hydroxylone 1 12-en-28-amide (compound 45)

A colorless amorphous target product was obtained in the same manner as in Example 24, using Compound B in place of Compound C and getylamine in place of morpholine.

IR (KBr): 3420, 2945, 1717, 1650, 1522, 1277, 1119 cm— ¹

Elemental analysis (as _{_{_{_{C 45 H 70 N 2 0 5}}}} '1 / 2H 2 0)

Calculated value (%) C: 74.24 H: 9.83 N: 3.85

Measured value (%) C: 74.34 H: 9.60 N: 4.05

Example 46

N- (2-Methoxyxetil) 1, 2 3 (4) 1-Diethoxytoxylane 1 2-Yen-28-Amide (compound 46)

3/3, 2 3 (4h) 1-hydroxy-doxy-lean 1-2-ene-1 28-eupidine (hereinafter referred to as hederagenin) (2.08 g), acetic anhydride (7.64 g) Was added to pyridine (20 ml), and the mixture was stirred at 70 ° C. for 1 hour. Then, 1N hydrochloric acid (50 ml) was added dropwise at the same temperature, and the mixture was naturally returned to room temperature. After pouring the reaction solution into ice water, it was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1), and 3?, 23 3-diacetoxolean 1 22 一 1 オ 2 28-28-acid (1. 69 g) was obtained as a colorless powder. The obtained powder was added to thionyl chloride (28 ml), and the mixture was refluxed for 1 hour. Then, the reaction solution was concentrated under reduced pressure. The concentrated residue was dissolved in pyridine (14 ml), and 2-methoxethylamine was added dropwise at 10 ° C or lower, and the mixture was returned to room temperature and stirred for 3 hours. After water was poured into the reaction solution, extraction was performed with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was recrystallized from 70% methanol to obtain the desired product (1.23 g) as a pale yellow powder. Mp 1 97~ 1 9 8 ° C 'Elemental analysis (as C ₃₇ H ₅₉ N0 ₆₎ Calculated value (%) C: 72.39 H: 9.69 N: 2.28

Actual value (%) C: 72.17 H: 9.63 N: 2.38

Example 47

N- (2-Methoxyxetil) 1 3 2 3 (4a) 1-Bis (3-carboxypropionyloxy) orean 1 12-en-28-amide (compound 47)

Compound A (0.30 g) and succinic anhydride (0.29 g) were dissolved in dry tetrahydrofuran (3 ml), and 60% sodium hydride (0.19 g) was added little by little. I got it. The mixture was heated to reflux for 20 hours, allowed to warm to room temperature, neutralized with 1N hydrochloric acid, extracted with a mixture of chloroform-methanol (5: 1), and washed with water. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is purified by silica gel column chromatography (chloroform: methanol = 10: 1) to give the desired product (0.17 g) as a colorless amorphous As obtained.

IR (KBr): 3425, 2946, 1736, 1620, 1533, 1387, 1167 cm " ¹

Elemental analysis (as _{_{_{C 41 H 63 N0 10 'H}}} 2 0)

Calculated value (%) C: 65.84 H: 8.76 N: 1.87

Measured value (%) C: 65.66 H: 8.47 N: 2.04

Example 48

N- (2-Methoxyxetil) 1 2 3 (4)-((S) -2-acetoxypropionyloxy) 1 3? -Hydroxylean 1 12-Ien 1 28-Amide (compound 48)

The desired product as a colorless powder was obtained in the same manner as in Example 3 except that (S) -2-acetoxypropionic acid was used instead of benzyloxyacetic acid. Melting point 89-90 ° C Elemental analysis (as C ₃₈ H ₆₁ N 0 ₇ '1 / 2H ₂₀ )

Calculated value (%) C: 69.90 H: 9.71 N: 2.15

Actual value (%) C.-69.98 H: 9.49 N: 2.24

Example 4 9

N— (2-Methoxyxetil) 1 3?, 2 3 (4a) —Bis (N-acetylglycyloxy) orean—1 2—Ien 1 2 8—Amide (Compound 49)-Instead of benzyloxyacetic acid Same as in Example 3 using N-acetylglycine .-

The desired product was obtained as a colorless powder by the same method as described above. Melting point 1 2 3 ° C

Elemental analysis value (as C ₄₁ H ₆₅ N ₃ 0 ₈ '1 / 2H ₂₀ )

Calculated value (%) C-.66.82 H: 9.02 N: 5.70

Actual value (%) C: 66.77 H: 9.00 N: 5.67

Example 5 0

N- (2-Methoxyxetil) 1 2 3 (4h)-(N-Acetylglycyloxy) 1 3? -Hydroxylean 1 12-Ien 1 28-Amide (Compound 50)

Further elution (ethyl acetate) was carried out by the silica gel column chromatography in Example 49 to obtain the target compound as a colorless powder. Melting point 120 ° C

Elemental analysis (as _{_{_{_{C 37 H 60 N 2 0 6}}}} '2 / 3H 2 0)

Calculated value (%) C: 69.34 H: 9.65 N: 4.37

Measured value (%) C: 69.25 H: 9.52 N: 4.30

Example 5 1

N- (2-Methoxyxetil) 13 ?, 23 (4) Monobis (glycyroxy) orean 12-en-28-amide hydrochloride (compound 51)

(Process 1)

Using N-tert-butoxycarbonylglycine in place of benzyloxyacetic acid, N- (2-methoxethyl) 13?, 23 (4) -bis (N-tert-butoxycarbonyl) was obtained in the same manner as in Example 3. (Glycsiloxy) Orean 1 2—Gen 1 28—Amide was obtained.

(Process 2)

Dissolve the compound (1.02 g) obtained in Step 1 in methylene chloride (30 ml), blow in hydrogen chloride gas for 2 hours, and concentrate under reduced pressure to give the desired product (0.776 g) colorless Obtained as amorphous.

IR (KBr): 3400, 2946, 1748, 1632, 1526, 1244 cm "!

Elemental analysis (as _{_{_{_{C 37 H 61 N 3 0 6}}}} '2HC1'2H 2 0)

Calculated value (%) C: 60.48 H: 8.92 N: 5.72

Actual value (%) C: 60.29 H: 8.62 N: 5.82 "Example 5 2 -

65

N— (2-Methoxyxetil) 1 2 3 (4) -Glycyloxy 3 Hydroxysorean 1 12—Ien 1 28—Amide (Compound 52)

Further elution (chloroform) was carried out by silica gel column chromatography in Example 51, and N- (2-methoxethyl) 123 (4)-(N-tert-butoxycarbonylglycyroxy) 13- Hydroxyorean-1-2-en-28-amide was obtained. This compound was treated with hydrogen chloride in the same manner as in step 2 of Example 51, and then a 1% aqueous sodium hydrogen carbonate solution was injected, followed by extraction with ethyl acetate. The organic layer is dried over magnesium sulfate, concentrated under reduced pressure, and the residue is subjected to high performance liquid chromatography (column: YMC D-0DS-5-Bs-5 (250 x 30 mm id), eluate: 0.1% mesylate containing 40%). % Acetonitrile, elution rate: 10.0 ml / min., Detection: UV 210 nm) to obtain a colorless amorphous target product.

IR (KBr): 2940, 1735, 1640, 1520, 1465, 1390 cm " ¹

_{! H NMR (CDC1 3) (} 5: 0.63-2.10 (m, 41H), 2.55 (dd, 1H, J = 6, 13Hz),

2.92 (d, lH, J = 13Hz), 3.20-3.70 (m, 7H), 3.32 (d, 1H, J = 13Hz), 3.35 (s, 3H), 3.89 (d, lH, J = llHz), 4.25 (d, 1H, J = llHz), 5.38 (t, 1H, J = 3Hz), 6.3 (bs, lH) Example 5 3

N- (2-Methoxyxetil) 13-? Glycyloxy23 (4) -Hydroxysolean-12-One-28-Amide (Compound 53)

Further elution was carried out by high performance liquid chromatography in Example 52 (the eluate and elution rate were the same as in Example 52), and a colorless amorphous target product was obtained.

IR (KBr): 2940, 1735, 1640, 1520, 1465, 1390 cm " ¹

! HNR (CDCH ₃ ) 5: 0.63-2.10 (m, 41H), 2.55 (dd, lH, J = 6,13Hz),

2.92 (d, lH, J = 13Hz) ₅ 3.20-3.70 (m, 8H), 3.32 (d, 1H, J = 13Hz), 3.35 (s, 3H),

4.97 (dd, lH, J = 12Hz) ₃ 5.38 (t, 1H ₃ J = 3Hz), 6.3 (bs, lH)

Example 5 4

N- (2-Methoxyxetil) 1 2 3 (4h) 1-Glycyloxy-1 3 hydroxyxylean—12—2—28—Amide hydrochloride (compound 54A) and N— (2—Methoxyxetil) 1) 3-Glycyloxy 1 2 3 (4) 1-Hydroxyloreazine 1 2--2-28-amide hydrochloride (Compound 54B) .

66 Using the compound obtained in Example 52, in the same manner as in Step 2 of Example 51, a target mixture was obtained as a colorless amorphous.

Example 5 5

N- (2-Methoxyxetil) 1 2 3 (4H) 1 (L-alanyloxy) 13-Hydroxylean 12-Yen-28-Amide hydrochloride (compound 55A) and N- (2- (Methoxyxetil) 1 3? — (L-alanyloxy) 1 2 3 (4) -Hydroxylean 1 12—Yen—28—Amide hydrochloride (Compound 55B)

Using N-tert-butoxycarbonyl-L-alanine in place of benzyloxyacetic acid, a mixture of the desired product was obtained as a colorless amorphous in the same manner as in Step 2 of Example 3 and Example 51.

IR (KBr): 3400, 2946, 1744, 1636, 1244 cm- ¹

Elemental analysis (as _{_{_{_{C 36 H 60 N 2 0 5}}}} 'HC1'3 / 2H 2 0)

Calculated value (%) C: 65.08 H: 9.71 N: 4.22

Actual value (%) C: 65.26 H: 9.48 N: 4.37

Example 5 6,

Ν- (2-Methoxyxetil) 13-hydroxyl 23 (4)-(L-prolyloxy) orean- 12-en-28-amide hydrochloride (compound 56 6) and Ν— ( 2-Methoxyxetil) 1 2 3 (4) 1-Hydroxy 1 3? — (L-Prolyloxy) Olean 1 12-Yen-28-Amide hydrochloride (Compound 56) Instead of benzyloxyacetic acid Ν — Using tert-butoxycarbonyl L-proline, a mixture of the desired product was obtained as a colorless amorphous in the same manner as in Step 2 of Example 3 and Example 51.

IR (KBr): 3400, 2944, 1742, 1636, 1242 cm— ¹

Elemental analysis (as _{_{_{_{C 38 H 62 N 2 0 5}}}} 'HC1'4 / 3H 2 0)

Calculated value (%) C: 66.40 H: 9.63 N: 4.08

Actual value (%) C: 66.29 Η: 9 · 32 Ν: 4.38

Example 5 7

Ν— (2-Methoxyxetil) 13-Hydroxy 1 23 (4)-(L-celloxy) Orean-12-En 28-_ Amide hydrochloride (Compound 57 A) _ as well as -

67

N- (2-Methoxyxetil) 1 2 3 (4a) —Hydroxy 1 3? — (L-Ceryloxy) orean 1 12—Yen—28—Amide hydrochloride (Compound 57B)

Using N_tert-butoxycarbonyl-L-serine instead of benzyloxyacetic acid, a mixture of the target product was obtained as a colorless amorphous by the same method as in Step 2 of Example 3 and Example 51.

IR (KBr): 3400, 2944, 1748, 1653, 1238 cm- ¹

Elemental analysis (as _{_{_{_{C 36 H 60 N 2 0 6}}}} 'HC1'H 2 0)

Calculated value (%) C: 64.41 Η: 9 · 46 Ν: 4.17

Observed value (%) C: 64.35 H: 9.12 N: 4.44

Example 5 8

N- (2-Methoxyxetil) 1 2 3 (4) 1-Glycyloxyacetoxy 1 3 β-Hydroxyl-oren 1 2—Yen-1 28-Amide (Compound 58 Α) and Ν— ( 2-Methoxyxetil) 1 3 —Glycyloxyacetoxy 1 2 3 (4) 1-Hydroxysolean 1 1 2—Yen 1 2 8—Amide (Compound 58 8Β)

Using Ν- (benzyloxycarbonyl) glycylglycolic acid instead of benzyloxyacetic acid, the desired mixture was obtained in the same manner as in Example 3 and Example 4- (1).

IR (KBr): 4375, 2945, 1750, 1638, 1262 cm " ¹

Example 5 9

N- (2-Methoxyxetil) 1 2 3 (4) 1-Hydroxy 1 3? -Sulfoxylean 1 12-En-28-Amide (Compound 59)

Compound A (3.45 g) and iodopyridine trioxide complex (1.76 g) were added to N, N-dimethylformamide (35 ml), and the mixture was stirred for 68 hours. The reaction solution was concentrated under reduced pressure at 40 ° C. or lower, and the obtained residue was dissolved in water and acidified with concentrated hydrochloric acid. The precipitate was collected by filtration, extracted with a mixed solution of chloroform and methanol (5: 1), and washed with water. The organic layer was dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 10: 1) to obtain 0.82 g of a solid. This was recrystallized from 70% methanol to obtain the desired product (0.57) as a colorless powder. Melting point 2 2 2〜2 2 3 ° C .-

68 Elemental analysis (as _{_{_{_{C 33 H 55 N0 7 S'4H 2}}}} 0)

Calculated value (%) C: 58.12 H: 9.36 N: 2.05

Measured value (%) C: 58.36 H: 9.20 N: 2.23

Example 6 0

N— (2-Methoxyxetil) 13—Hydroxy 2 3 (4) 1-Sulfoxylean 12—1—28—Amide (Compound 60)

The solid (1.38 g) obtained by further elution (chloroform: methanol = 10: 1) by silica gel column chromatography in Example 59 was recrystallized from 70% methanol to obtain the desired compound ( 0.62 g) was obtained as a colorless powder.

Melting point 2 19-220 ° C

Elemental analysis value (as C ₃₃ H ₅₅ N 0 ₇ S'4H ₂₀ )

Calculated value (%) C: 58.12 H: 9.31 N: 2.05

Actual value (%) C: 57.97 H: 8.93 N: 2.19

Example 6 1

N— (2-Methoxyxetil) 1 3 5—Hydroxy 2 3 (4) 1-Sulfoxylean 1 2—Yen 1 2 8—Amide sodium salt (Compound 61)

A solution of sodium hydroxide (0.03 g) in methanol (3 ml) was added dropwise to a solution of the compound (0.39 g) obtained in Example 60 in methanol (5 ml), and the mixture was concentrated under reduced pressure. did. The residue was recrystallized from water to give the desired product (0.19 g) as a colorless powder. Melting point 187〜 188 ° C (decomposition)

Elemental analysis value (as C ₃₃ H ₅₄ NNa 0 ₇ S'7 / 2H ₂₀ )

Calculated value (%) C-.57.04 H: 8.85 N: 2.02

Measured value (%) C: 57.37 H: 8.70 N: 2.13

Example 6 2

N- (2-Methoxyxetil) 13-? Hydroxy-I 23 (4a) -Phossoxylean 12-I-one 28-Amide (Compound 62)

Compound A (5.0 g), 4-dimethylaminoviridine (2.76 g) and pyridine (1.80 g) in methylene chloride (150 ml) were added to a solution of diphenylphosphoryl chloride (150 g). 4.34 g) was added dropwise, and the mixture was stirred at room temperature for 6 hours. 5% salt solution After washing with an acid and saturated saline, the extract was dried over magnesium sulfate and concentrated under reduced pressure. The residue was washed with dimethyl ether, and the obtained solid was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain 固形 — (2-methoxyethyl) 13?. —Hydroxy 23 (4a) —diphenoxyphosphoryloxy-lean-1-2-en-28-amide (3.05 g) was obtained as a colorless powder. After dissolving this in acetic acid (150 ml), platinum dioxide (0.30 g) was added and hydrogenolysis was performed at 35 under normal pressure for 22 hours. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was washed with getyl ether to obtain a solid. This was purified by silica gel column chromatography (chloroform: methanol = 100: 1) to obtain the desired product (0.74 g) as a colorless amorphous.

IR (KBr): 3400, 2945, 1642, 1522, 1464, 1194, 1049 cm- ¹

Negative ion FAB-MS m / z: 608 [MH] - Elemental analysis (as _{_{_{_{C 33 H 56 N0 7 P'4H 2}}}} 0)

Calculated value (%) C: 58.13 H: 9.46 N: 2.05

Observed value (%) C: 57.92 H: 8.72 N: 2.07

Example 6 3

N- (2-Methoxyxetil) 1 2 3 (4a) —Hydroxy 3? —Phossoxylean 1 12—Ien 1 28—Amide (Compound 63)

The washing solution obtained in Example 62 was concentrated under reduced pressure, and the obtained residue was purified by silica gel gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain a colorless powder of N— ( 2-Methoxyxetil) 23 (4-h) -hydroxy-13-diphenoxyphosphoryloxyl-lean-12-en-28-amide was obtained. This was subjected to hydrogenolysis in the same manner as in Example 62 to obtain a colorless amorphous target product.

IR (KBr): 3375, 1636, 1387, 1242, 1196, 1034 cm " ¹

Elemental analysis (as _{_{_{C 33 H 56 N0 7 P'3 /}}} 2H 2 0)

Calculated value (%) C: 62.24 H: 9.34 N: 2.20

Obtained value (%) C: 62.33 H: 9.02 N: 2.09-Example 6 4 .

70

N— (2-Methoxyxetil) 1-3? —Hydroxy-1 2 3 (4) 1-Phosphoxylean 12-2-ene—28-Amido disodium salt (Compound 64)

The compound (2.88 g) obtained in Example 62 was dissolved in methanol (150 m 1), and a 1 N aqueous sodium hydroxide solution (9.4 m 1) was added dropwise at 50 C. . After stirring for 30 minutes, a small amount of insoluble matter was removed by filtration, and the filtrate was concentrated under reduced pressure. The obtained solid was washed with ethyl ether to obtain the desired product (2.16 g) as a colorless powder. Melting point 28 ◦ ~ 28 1 ° C

Elemental analysis (as _{_{_{_{C 33 H 54 NNa 2 0 7}}}} P'6H 2 0)

Calculated value (%) C: 52.03 H: 8.73 N: 1.84

Observed value (%) C: 52.02 H: 9.07 N: 1.89

Example 6 5

N— (2-Methoxyxetil) 1-3 ?, 23 (4a) diphosphoxylean-12-28—28-amide (compound 65)

To a solution of compound A (5.30 g), 4-dimethylaminopyridine (3.67 g) and pyridine (2.37 g) in methylene chloride (150 ml) was added diphenylphosphoryl chloride. (8.06 g) was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction solution was washed with 5% hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with dimethyl ether, and the resulting solid was purified by silica gel column chromatography (chloroform: methanol == 5: 1) to give N- (2-methoxethyl) 13?, 23 (4h) Monobis (diphenoxyphosphoryloxy) orean-12-en-28-amide (6.50 g) was obtained as a colorless powder. After dissolving this compound (6.0 g) in acetic acid (200 ml), platinum dioxide (0.20 g) was added, and hydrogenolysis was carried out at 30 ° 〇 for 24 hours under normal pressure. Was. After the reaction solution was filtered, the filtrate was concentrated under reduced pressure, and ethanol (10 ml) was added. After filtration of the insoluble matter, the filtrate was concentrated under reduced pressure to obtain the desired product (4.14 g) as a colorless powder. Melting point 2 3 1 ° C

Elemental analysis (as _{_{_{_{C 33 H 57 N0 10 P 2}}}} '3 / 2H 2 0)

Calculated value (%) C: 55.30 H: 8.44 N: 1.95

Actual value (%) C: 55.22 H: 8.20 N: 2.20-Example 6 6 .

71

N- (2-Methoxyxetil) 1 3 2 3 (4a) —Bis (methanesulfonyloxy) orean 1 2—2—28—Amide (Compound 66)

Compound A (3.0 g) was added to a pyridine (15 ml) solution. With C, methanesulfonyl chloride (1.94 g) was added dropwise and stirred for 1 hour. The reaction solution was poured into water, extracted with ethyl acetate, washed with 1N hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1 → 1: 2) to give the desired product (1.82 g) as a colorless amorphous.

IR (KBr): 2946, 1650, 1356, 1175 cm " ¹

Elemental analysis value (as C ₃₅ H ₅₉ N0 ₈ S ₂ )

Calculated value (%) C: 61.28 H: 8.67 N: 2.04

Measured value (%) C: 61.26 H: 8.53 N: 2.25

Example 6 7

N- (2-Methoxyxetil) 1-3 -Hydroxy-1 23 (4) 1-Diethoxyphosphoryloxylean 1 2-N-1 28-amide (Compound 67)

Under ice-cooling, getylphosphoryl chloride (0.26 g) was added dropwise to a pyridine (8 ml) solution of compound A (2.00 g), and the mixture was stirred for 1 hour. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was washed with n-hexane to obtain the desired product (0.52 g) as a colorless powder. Melting point 19 3 to 19 4 ° C

Elemental analysis value (as C ₃₇ H ₆₄ N 0 ₇ P'1 / 5H ₂₀ )

Calculated value (%) C: 66.38 H: 9.70 N: 2.09

Measured value () C: 66.18 H: 9.45 N: 2.34

Example 6 8

N- (2-Methoxyxyl) 13?, 23 (4H) Bis (diethoxyphosphoryloxy) orean- 12-en-28-amide (Compound 68)

Diethyl phosphoryl chloride (2.0 g) was added dropwise to a solution of the compound obtained in Example 67 (1.68 g) in pyridine (10 ml), and the mixture was added at 80 ° C for 3 hours. The mixture was heated and stirred. After the reaction mixture was concentrated under reduced pressure, the residue was subjected to silica gel column chromatography (salt The desired product (0.52 g) was obtained as a colorless amorphous. IR (KBr): 2946, 1650, 1356, 1175 cm " ¹

Elemental analysis value (as C ₃₅ H ₅₉ N0 ₈ S ₂ )

Calculated value (%) C: 61.28 H: 8.67 N: 2.04

Measured value (%) C: 61.26 H: 8.53 N: 2.25

Example 6 9

N— (2-Methoxyxetil) 1 3? —Hydroxy 2 3 (4) 1 (3-Methoxypropionyloxylean) 1 2—Yen 1 28—Amide (Compound 69) Replacement of benzyloxyacetic acid Using 3-methoxypropionic acid in the same manner as in Example 3, the target compound was obtained as a colorless powder, melting point: 178 to 179 ° C.

Elemental analysis value (as C ₃₇ H ₆₁ N0 ₆ -1 / 2H ₂₀ )

Calculated value (%) C: 71.12 H: 10.00 N: 2.24

Observed value (%) C: 71.09 H: 9.73 N: 2.31

Example 7 0

N- (2-Methoxyxetil) 1 2 3 (4α)-(trans 1-4-aminomethylcyclohexancarbonyloxy 1 3? -Hydroxylone 1 12-ene 1 28-amide (Compound 70 )

The same procedure as in Example 3 and Example 41 (1) was carried out except that benzyloxyacetic acid was used instead of benzyloxyacetic acid to obtain the target compound as a colorless powder. Melting point 1 2 1 to 1 2 2 ° C

Elemental analysis value (as C ₄₁ H ₆₈ N ₂ 0 ₅ 'H ₂ 0)

Calculated value (%) C: 71.68 H: 10.27 N: 4.08

Measured value (%) C: 71.45 H: 9.93 N: 4.35

Example 7 1

N- (2-Methoxyxetil) 1/3 / 3-Hydroxy2 3 (4H)-(Methanesulfonyloxy) Orean 1 12-En-1-28-Amide (Compound Ί1)

Using 1 equivalent of methyl sulfonyl chloride, the target compound was obtained as a colorless powder in the same manner as in Example 66. Mp 1 1 2 ~ 1 1 3 ° C - Elemental analysis (as C ₃₄ H ₅₇ N0 ₆ S) .

73 Calculated value (%) C: 67.18 H: 9.45 N: 2.30

Measured value (%) C: 66.89 H: 9.26 N: 2.34

Example 7 2

N- (2-Methoxyxetil) 1 3 3 -Hydroxy 1 2 3 (4α) -Dimethylaminocarboxyloxylean 1 1 2 -En 28 -Amide (Compound 72)

Compound A (0.60 g) and N, N-dimethylcarbamoyl chloride (0.13 g) were dissolved in 30 ml of methylene chloride, and sodium hydride (60%) (0. Was added and stirred for 4 hours. The reaction solution was poured into ice water and extracted with methylene chloride. The organic layer was washed with saturated saline and water in this order, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 1) to give the desired product as a colorless powder (0.34 g). Melting point 1997-198 ° C

Elemental analysis (as _{_{_{_{C 36 H 60 N 2 0 5}}}} -3 / 2H 2 0)

Calculated value (%) C: 68.86 H: 10.11 N: 4.46

Obtained value (%) C: 68.48 H: 9.80 N: 4.94

Example 7 3

N- (2-Methoxyxetil) _3? —Hydroxy2 3 (4)-(4-Piperidinobiliveridinocarbonyloxy) orean 1 2—2—28—Amide (Compound 73)

(Process 1)

N- (2-Methoxyxetil) 1 3?, 2 3 (4a)-(4—Methoxyphenylmethylenedioxy) Orean 1 12—1N 2 8—Amide

Compound A (30.0 g), anisaldehyde dimethyl acetate (10.9 g), and 10-camphorsulfonic acid (2.6 g) were added to 300 ml of dimethylformamide and added to 50 ° C. The mixture was stirred at C for 4 hours. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The organic layer was washed successively with saturated saline and water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to give the desired product (33.6 g ") as a colorless powder. ° C .

74 Elemental analysis value (as C ₄₁ H ₆₁ N0 ₅ '1 / 2H ₂₀ )

Calculated value (%) C: 74.96 H: 9.51 N: 2.13

Actual value (%) C: 75.02 H: 9.39 N: 2.24

(Process 2)

N- (2-Methoxyxetil) 1 2 3 (4a) Hydroxy 1 3 / 5— (4-Methoxy benzyloxy) Orean 1 2—Yen 1 2 8—Amide

The compound obtained in step 1 (9.80 g), sodium cyanoborohydride (3.00 g) and molecular sieves 3A were added to acetonitril (200 ml). Thereafter, a solution of chlorotrimethylsilane (4.88 g) in acetonitrile (80 ml) was added dropwise little by little under ice-cooling. The mixture was allowed to cool to room temperature and stirred for another 1 hour. The reaction solution was poured into a saturated aqueous solution of sodium hydrogen carbonate and extracted with ether. The organic layer was washed with a saturated aqueous solution of ammonium chloride, water, and saturated saline in this order, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 2: 1) to obtain the desired product (7.95 g) as a colorless powder. Melting point 102-103 ° C

Elemental analysis value (as C ₄₁ H ₆₃ N 0 ₅ '1 / 2H ₂₀ )

Calculated value (%) C: 74.73 H: 9.79 N: 2.13

Actual value (%) C: 74.37 H: 9.68 N: 2.40

(Process 3)

N- (2-Methoxyxetil) 1 3? — (4-Methoxybenzyloxy) 1 2 3 (4)-(4—Biperidinobiperidinocarbonyloxy) Orean 1 12—Ien 1 2 8 -Amid

To a solution of the compound (0.60 g) obtained in Step 2 in tetrahydrofuran (6 ml) was added 1,1, -carbonyldiimidazole (0.45 g), and the mixture was stirred for 1.5 hours. And 4-piperidinopiperidine (0.52 g) were added, and the mixture was stirred for 3 days. The reaction solution was poured into a saturated aqueous sodium hydrogen carbonate solution and extracted with ether. The organic layer was washed with brine and dried over magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (Cross-form: medium = 50: 1) under "T to give the target compound (0.55 g) as a colorless powder. Melting point 94-95 ° C Elemental analysis (as _{_{_{_{C 52 H 81 N 3 0 6}}}} '3 / 2H 2 0)

Calculated value (%) C: 71.69 H: 9.71 N: 4.82

Actual value (%) C: 72.01 H: 9.42 N: 4.98

(Process 4)

N— (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4H)-(4-Piperidino dipyridino carbonyloxy) Olean 1 12—Yen 1 2 8—Amide (Compound 7 3)

After dissolving the compound obtained in step 3 in methylene chloride (11 ml), water (0.6 g), 2,3-dichloro-1,5-dicyano 1,4,1-benzoquinone (0.3 g) was added and stirred overnight. The reaction solution was diluted with methylene chloride, poured into a saturated aqueous sodium hydrogen carbonate solution, and the organic layer was washed with a saturated aqueous sodium hydrogen carbonate solution, water, and saturated saline, and then dried over magnesium sulfate. The residue was purified by silica gel column chromatography (black form: methanol = 40: 1) to obtain the desired product (0.31 g) as a pale yellow powder. Melting point 105 ~ 106 ° C

Elemental analysis (as _{_{_{_{C 44 H 73 N 3 0 5}}}} 'H 2 0)

Calculated value (%) C: 71.22 Η: 10 · 19 Ν: 5.66

Obtained value (%) C: 70.98 H: 9.83 N: 5.41

Example 74

N— (2-Methoxyxetil) 1 3 g—Hydroxy 1 2 3 (4a)-(2—Hydroxyxetylaminocarbonyloxy) Orean 1 2—1—2 8—Amid ( (Compound 74)

Example 7 3 N- (2-Methoxyxetyl) 1-2 3 (4H) 1 (2-H) obtained by the same method as in Step 3 using monoethanolamine instead of piperidinopiperidine. Droxitylaminocarbonyloxy) 1/3 / 3— (4-Methoxybenziloxy) ore12—12—28-amide (0.6 g) is added to methanol (12 m1). The mixture was dissolved, 10% palladium-carbon (0.06 g) was added, and medium pressure reduction (5 atm) was performed at room temperature. After filtering the reaction solution, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (form: methanol = 30: 1) to give the target compound as a colorless powder (0.31 g) was obtained. Melting point 1 2 1 ~ 1 2 2 ° C .

76 Elemental analysis (as _{_{_{_{C 36 H 60 N 2 0 6}}}} '2H 2 0)

Calculated value (%) C: 68.10 H: 9.84 N: 4.41

Obtained value (%) C-.67.95 H: 9.54 N: 4.47

Example 7 5

N- (2-Methoxyxetil) 1-3? -Hydroxy2 3 (4α) -1 [bis (2-hydroxyxethyl) aminocarbonyloxy] orean 1-22-en-1 28-Amid ( Compound 75)

A colorless powder was obtained in the same manner as in Example 74, except that diethanolamine was used instead of monoethanolamine. Melting point 103-104 ° C

IR (KBr): 3300, 2945, 1750, 1685cm- ¹

Negative ion FAB-MS m / z: 659 [M-H]-Example 7 6

N- (2-Methoxyxetil) 1 3—Hydroxy 1 2 3 (4H)-(4-Methylpiperazinylcarbonyloxy) orean 1 2—Ien 1 28—Amide (Compound 76)

The same procedure as in Example 74 was carried out except for using 1-methylbiperazine instead of monoethanolamine, to obtain a target product as a colorless powder. Melting point 196-197 ° C

IR (KBr): 3300, 2950, 1700, 1650cm " ¹

Negative ion FAB-MS m / z: 654 [M-H]-Example Ί 7

2—acetoxityl 3 —hydroxy 1 2 3 (4)-(4—methoxybenziloxyacetoxy) ore 1 1 2—1 2 1—8-year-old (compound 77) International publication W09 6 / According to the method of Example 1 described in Japanese Patent Publication No. 023636, 2-acetoxicetyl 3 ?, 23 (4α) dihydroxylorean-1 2-ene-28-phosphate (hereinafter referred to as compound Ε). A colorless amorphous target product was obtained in the same manner as in Example 3 except that Compound E was used instead of Compound Α. IR (KBr): 2945, 1746, 1514, 1250, 1175 cm— ¹

Elemental analysis (as C ₄₄ H ₆₄ 0 ₉₎ - Calculated (%) C: 71.71 H: 8.75 -

77 Actual value (%) C: 71.52 H: 8.69

Example 7 8

2-acetoxitytyl 3 / 5—hydroxy 2 3 (4)-hydroxy 1-2 _ 28 _ 2-compound (compound 7 8)

Using compound 77, a colorless amorphous target was obtained in the same manner as in Example 41- (1).

IR (KBr): 3450, 2946, 1744, 1387, 1229 cm— ¹

Elemental analysis value (as C ₃₆ H ₅₆ 0 ₈ '1 / 2H ₂₀ )

Calculated value (%) C: 69.09 H: 9.18

Measured value (%) C: 68.98 H: 9.00

Example 7 9

2—acetoxitytil 2 3 () 1 (N—acetylglycyroxy) 1

3 3—Hydroxylean 1 1—2—2 1—8-year-old (compound 79)

A colorless amorphous target product was obtained in the same manner as in Example 77, except that N-acetylglycine was used instead of 4-methoxybenzyloxyacetic acid.

IR (KBr): 2948, 1744, 1656, 1229, 1177 cm— ¹

Elemental analysis value (as C ₃₈ H ₅₉ N0 ₈ 'H ₂₀ )

Calculated value (%) C: 67.52 H: 9.09 N: 2.07

Observed value (%) C.-67.23 H: 8.70 N: 2.07

Example 8 0

2 — (4-Methoxybenzyloxyacetoxy) ethyl 3?, 2 3 (4a) 1-hydroxyl-one 1 2-hydroxy-28-ether (compound 80)

Hederagenin (1.00 g), 2-bromoethyl 4-methoxybenzyloxycetate (1.92 g) and potassium hydrogen carbonate (0.63 g) were added to dimethyl formamide (5 ml). And stirred at 60 ° C. for 15 hours. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (chloroform: methanol = 200: 1) to give a colorless powder. (0.98 g)-was obtained. Melting point 108 ~: L 10 ° C Elemental analysis (as C ₄ 2H ₆₂ 0 ₈₎

Calculated value (%) C: 72.59 Η: 8 · 99

Observed value (%) C: 72.35 H: 8.99

Example 8 1

2-(Hydroxyacetoxy) ethyl 3/3, 2 3 (4h) 1-Hydroxyl-olean 1 2 -en-28-oate (compound 81)

Using the compound obtained in Example 80, a target product as a colorless powder was obtained in the same manner as in Example 41- (1). Melting point 1 5 7 to 1 5 8 ° C

Elemental analysis (as _{_{_{C 34 H 54 0 7 '1}}} / 5H 2 0)

Calculated value (%) C: 70.60 H: 9.48

Actual value (%) C: 70.47 H: 9.31

Example 82

2- (N-acetylglycyloxy) ethyl 3/5, 2 3 (4)

A target was obtained as a colorless powder in the same manner as in Example 80, except that 2-bromoethyl acetyl glycinate instead of 2-bromoethyl 4-methoxypentyl acetate was used. . Melting point 15 3-1 54 ° C

Elemental analysis value (as C ₃₆ H ₅₇ N 0 ₇ 'H ₂₀ )

Calculated value (%) C: 68.21 H: 9.38 N: 2.21

Actual value (%) 68.32 H: 9.14 N: 2.27

Example 83

N-(2-Methoxyxetil) 13-Hydroxolean 12-1-28-Amide (Compound 83)

3-Hydroxolean 1-2-1-2-Equivalent (hereinafter referred to as oleanolic acid) (500 mg), WS CD 'HCl (420 mg), 1-Hydroxy-1H-Benzotriazo-1 (Hereinafter referred to as HOBt) (296 mg) and 2-methoxshetilamine (165 mg) are suspended in DMF (2.5 ml) and stirred at 70 ° C for 1.5 hours. After cooling to room temperature, the mixture was poured into water. The resulting precipitate is collected by filtration, dried, and subjected to silylation gel column chromatography (black form: methanol). .

79

= 200: 1) to give a colorless powder. This was recrystallized from isopropyl ether to obtain the desired product (341 mg) as a colorless powder. Melting point 1 85 ° C

Elemental analysis (as C ₃₃ H ₅₅ N0 ₃₎

Calculated value (%) C77.14 H: 10.79 N: 2.73

Obtained value (%) C: 76.91 H: 10.82 N: 2.76

Example 84

N— (2-Methoxyxetil) 1 3? — [(4-Methoxybenzyl) oxyacetoxy] Orean 1 2—Ien 1 28—Amide (Compound 84)

A colorless amorphous target product was obtained in the same manner as in Example 11- (1), except that Compound 83 was used in place of Compound A.

Elemental analysis value (as C ₄₃ H ₆₅ N0 ₆ 'H ₂₀ )

Calculated value (%) C: 72.74 H: 9.51 N: 1.97

Obtained value (%) C: 72.71 H: 9.15 N: 2.13

IR (KBr): 2946, 1750, 1514, 1250, 1125cnrl

Example 85

N— (1-hydroxyhexyl) 1/3/3, 2 3 (4h) dihydroxoleorean 12—2—28—amide (compound 85)

To a solution of hederagenin (1.42 g), WS CDHC1 (0.86 g) and HOBt (0.61 g) in DMF (20 ml) was added 6-amino-11-hexanol ( 0.70 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 20: 1) to give the desired product (1.50 g) as a colorless powder. 234 ° C

Elemental analysis value (as C ₃₆ H ₆₁ N0 ₄ 'H ₂₀ )

Calculated value (%) C: 75.61 H: 10.75 N: Z.45

Obtained value (%) C: 75.34 H: 10.74 N: 2.63

Example 8 6-N— (2-fluoroethyl) -3 / 3, —2 3 (4) —Jihi _Droxylean .

80

1 2—28—Amide (Compound 86)

Using 2-fluoroethylamine and triethylamine instead of 6-amino-11-hexanol, the target compound as a colorless powder was obtained in the same manner as in Example 85. Melting point 206 ° C

Elemental analysis value (as C ₃₂ H ₅₂ FN 0 ₃ 'H ₂₀ )

Calculated value (%) C: 71.74 H: 10.16 N: 2.61

Measured value (%) C: 71.71 H-.10.il N: 2.72

Example 8 7

N- [2- (2-Hydroxyethoxy) ethyl] 13?, 23 (4α) -dihydroxylone 1-2-en-1-28-amide (compound 87)

Using 2- (2-aminoethoxy) phenol instead of 6-amino-1-hexanol, the target compound was obtained as a colorless powder in the same manner as in Example 85. Melting point 1 28 ° C Elemental analysis value (as C ₃₄ H ₅₇ N 0 ₅ '1 / 2H ₂₀ )

Calculated value (%) C: 71.79 H: 10.28 N: 2.46

Obtained value (%) C: 71.42 H: 10.29 N: 2.92

Example 8 8

N- (2-Acetylaminoethyl) 13/5, 23 (4a) dihydroxyl-olean 12-ene-28-amide (compound 88)

A target was obtained as a colorless powder in the same manner as in Example 85, except that N-acetylethylenediamine was used instead of 6-amino-11-hexanol. Melting point 170 ° C Negative ion FAB-MS m / z: 555 [MH]-IR (KBr): 1640, 2950, 3300cm— ¹

Example 8 9

N— [3 -— (imidazoyl-l-yl) propyl] —3,23 (4α) dihydroxolean-l-2-en-28-amide (compound 89)

A target was obtained as a colorless powder in the same manner as in Example 85 using 1- (3-aminopropyl) imidazole instead of 6-amino-11-hexanol. Mp 1 9 8 ° C Elemental analysis (as _{_{_{_{C 36 H 57 N 3 0 3}}}} -1 / 4H 2 0) - Calculated (%) C: 73.99 H: 9.92 N: 7.19 One.

81 Actual value (%) C: 73.90 H: 10.18 N: 7.16

Example 9 0

N- (1,3-dihydroxy-1--2-propyl) 13,23 (4α) -dihydroxyl-12-28-amide (compound 90)

Using 2-amino-1,3-propanediol instead of 6-amino-11-hexanol, the target compound was obtained as a colorless powder in the same manner as in Example 85. Melting point 2 85 ° C Negative ion FAB-MS m / z: 544 [-H] "

IR (KBr): 1628, 2944, 3400cm-1

Example 9 1

N- (3-Methylaminopropyl) 1-3 ?, 23 (4a) dihydroxyl-olean-12-ene28-amide (compound 91)

Using N-methyltrimethylenediamine instead of 6-amino-1-hexanol, the target compound was obtained as a colorless powder in the same manner as in Example 85. Melting point 1 19 ° C Negative ion FAB-MS m / z: 541 [Μ-Η] "

IR (KBr): 1630, 2944, 3400cm-l

Example 9 2

N-cyanomethyl-3?, 23 (4) 1-hydroxyl-one-l2-ene-28-amide (compound 92)

The target compound was obtained as a colorless powder in the same manner as in Example 85, except that aminoacetonitryl hydrochloride was used instead of 6-amino-11-hexanol. Melting point 17 1 ° C Elemental analysis value (as C ₃₂ H ₅₀ N ₂ 0 ₃ '3 / 4H ₂ 0)

Calculated value (%) C: 73.31 H: 9.90 N: 5.34

Obtained value (%) C.-73.38 H: 10.11 N: 5.67

Example 9 3

N- (2-morpholinoethyl) 1 3/5, 2 3 (4) Jihi-doxyreoan 1 12-en-28-amide (compound 93)

Using 4- (2-aminoethyl) morpholine instead of 6-amino-11-hexanol, the target compound was obtained as a colorless powder in the same manner as in Example 85. Mp 24 7 ^e C Elemental analysis (as _{_{_{_{C 36 H 60 N 2 0 4}}}} '2/3 H 2 0) .

82 Calculated value (%) C: 72.44 H: 10.36 N: 4.69

Observed value (%) C-.72.05 H: 10.00 N: 4.78

Example 94

N— [2- (2-pyridyl) ethyl] — 3?, 2 3 (4α) dihydroxolean 1 12—en—28—amide (compound 94)

A target was obtained as a colorless powder in the same manner as in Example 85, using 2- (2-aminoethyl) pyridine instead of 6-amino-11-hexanol. Melting point 8 7 ° C

EI- MS m / z: 576 [M] +

IR (KBr): 1636, 2950, 3400cm- ¹

Example 9 5

N— [2- (4-pyridyl) ethyl 1-3β, 23 (4α) —dihydroxyl-one-12-ene—28-amide (compound 95)

The desired product was obtained as a colorless powder in the same manner as in Example 85, except that 4- (2-aminoethyl) pyridine was used instead of 6-amino-11-hexanol. Melting point 84 ° C EI -MS m / z: 576 [M] ⁺

IR (KBr): 1609, 2950, 3400cm " ¹

Example 9 6

N- (3-pyridyl) methyl-13?, 23 (4a) dihydroxolean-12-ene-28-amide (compound 96)

A colorless powder was obtained in the same manner as in Example 85 using 3- (aminomethyl) pyridine instead of 6-amino-11-hexanol. Mp 2 2 7 ° C Elemental analysis (as _{_{_{_{C 36 H 54 N 2 0 3}}}} 'H 2 0)

Calculated value (%) C.-74.44 H: 9.72 N: 4.82

Observed value (%) C: 74.08 H: 9.45 N: 5.26

Example 9 7

1— “3?, 2 3 (4h) -dihydroxyl-orean 1 2—en—2 8—oil] -1 4—1 (2-hydroxylexetil) piperazine (compound 97)

The target compound was obtained as a colorless powder in the same manner as in Example 85 using 11- (2-hydroxyxethyl) biazine instead of 6-amino-1-hexanol. Melting point 1 6 8 ° C .

83 Elemental analysis value (as C ₃₆ H ₆₀ N ₂ 0 ₄ 'H ₂ 0)

Calculated value (%) C: 71.72 H: 10.37 N: 4.65

Measured value (%) C: 71.73 H: 10.01 N: 5.08

Example 9 8

3 β, 23 (4h) 1-doxytoxylene 1 2—en-28—oic acid (compound 98)

Acetic anhydride (30.63 g) was added to a solution of hederagenin (14.18 g) in pyridine (150 ml), and the mixture was stirred at 70 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to remove pyridin, poured into ice water, and extracted with ether. The organic layer was washed with dilute hydrochloric acid and saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-form) to obtain the desired product as a colorless powder (15.6 g). Melting point 1 6 1 ° C

Elemental analysis (as C ₃₄ H ₅₂ 0 ₆₎

Calculated value (%) C: 73.35 H: 9.41

Obtained value (%) C: 73.38 H: 9.64

Example 9 9

1— [3 / 3,2 3 (4h) diacetoxolean 1 2—1—28—oil] —4-methylbiperazine (compound 99)

A mixture of compound 98 (2.80 g) s thionyl chloride (2.88 g) was stirred at 8 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to remove excess thionyl chloride, benzene was added and the mixture was concentrated again to completely remove thionyl chloride. The residue was dissolved in pyridine (5 ml), 1-methylbiverazine (0.997 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. 30 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, diluted hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black-mouthed form) to obtain the desired product (1.56 g) as a colorless powder. Melting point 2 26 ° C

Positive ion FAB-MS m / z: 639 [M + H] +

IR (KBr): 1636,1740,2948,3400cm- ¹ "Example 100 .

84

1 1 [3 / g, 2 3 (4h) 1 drip droxylean 1 2-1-2 8-oil] 1

4-Methylbiperazine (Compound 100)

To a solution of compound 99 (1.0 g) in methanol (35 ml) was added dropwise a 1N aqueous solution of sodium hydroxide (15 ml), and the mixture was stirred at room temperature overnight. The reaction solution was concentrated under reduced pressure to remove methanol, 30 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was recrystallized from isopropyl ether to give the desired product as a colorless powder (0.333 g). Melting point 16 2 ° C Elemental analysis (as C ₃₅ H ₅₈ N ₂ 0 ₃ '2 / 3H ₂ 0)

Calculated value (%) C: 74.16 H: 10.55 N: 4.94

Observed value (%) C: 74.22 H: 10.45 N: 4.58

Example 10 1

4-"3?, 2 3 (4h) 1-D-Toxolean 1 2 2-- 1-28-Oil] morpholine (Compound 101)

Using morpholine in place of 1-methylbiperazine, the target compound was obtained as a colorless powder in the same manner as in Example 99. Melting point 1 1 9 ° C

Elemental analysis value (as C ₃₈ H ₅₉ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 71.89 H: 9.53 N: 2.21

Observed value (%) C: 71.78 H: 9.41 N: 2.23

Example 10

4— 3/3, 2 3 (4 a) —dihydroxy-1-orane 1 2—en 1 2 8—oil] morpholine (compound 102)

A compound of colorless powder was obtained in the same manner as in Example 100, except that compound 101 was used in place of compound 99. Melting point 1 5 5 ° C

Elemental analysis value (as C ₃₄ H ₅₅ N 0 ₄ '3 / 4H ₂₀ )

Calculated value (%) C: 73.54 H: 10.25 N: 2.52

Obtained value (%) C: 73.63 H: 10.21 N: 2.47

Example 1 0 3

1— “3/5, 2 3 (4 h) 1-doxy-toxolean 1 2—1—2 1—8—oil ——— 4—1 (2—hydroxyxethyl) biperazine -

85

A colorless powder of the target compound was obtained in the same manner as in Example 99 except that 1- (2-hydroxyxethyl) piperazine was used instead of 1-methylbiperazine. Mp 1 2 2 ° C Elemental analysis (as _{_{_{_{C 40 H 64 N 2 0 6}}}} '1 / 2H 2 0)

Calculated value (%) C: 70.86 H: 9.66 N: 4.13

Observed value (%) C: 71.07 H: 9.46 N: 4.30

Example 1 04

1— [3?, 2 3 (4h) 1-doxytoxolean 1 12—1—2 1—8—oil] —3—hydroxypyrrolidine (compound 104)

Using 3-pyrrolidinol instead of 1-methylbiperazine, the target compound was obtained as a colorless powder in the same manner as in Example 99. Melting point 13 1 ° C

Elemental analysis value (as C ₃₈ H ₅₉ N0 ₆ '3 / 2H ₂₀ )

Calculated value (%) C: 69.90 H: 9.57 N: 2.15

Obtained value (%) C: 69.73 H: 9.11 N: 2.35

Example 1 0 5

1— [3?, 2 3 (4h) 1 ヒ 2 1 キシ 2 キシ —2 18—oil] —

3-Hydroxybi mouth lysine (Compound 105)

A compound of colorless powder was obtained in the same manner as in Example 100, except that Compound 104 was used instead of Compound 99. Melting point 24 7 ° C

Elemental analysis value (as C ₃₄ H ₅₅ N0 ₄ 'H ₂₀ )

Calculated value (%) C: 7Z.95 H: 10.26 N: 2.50

Obtained value (%) C: 72.93 H: 9.95 N: 2.63

Example 1 0 6

1 [3?, 2 3 (4 h)-1-Toxiolean 1-2-1-2 8-Oil]-

4-(2-Hydroxityl) piperidine (Compound 106)

A colorless powder of the target compound was obtained in the same manner as in Example 99, except that 4- (2-hydroxyxethyl) piperidine was used instead of 1-methylbiperazine. Melting point 1 2 3 ° C Elemental analysis value (as C ₄₁ H ₆₅ N0 ₆ '2 / 3H ₂₀ )

Calculated value (%) C: 72.42 H: 9.83 N: 2.06 "Actual value (%) C: 72.34 H: 9.59 N: 2.18 .

86 Example 1 07

1 [3?, 23 (4) 1 dihydroxy 1-diene 28-oil] 1 4- (2-hydroxyxethyl) piperidine (compound 107)

A compound of colorless powder was obtained in the same manner as in Example 100, using compound 106 instead of compound 99. Melting point 1 8 1 ° C

Elemental analysis value (as C ₃₇ H ₆₁ N0 ₄ 'H ₂₀ )

Calculated value (%) C: 73.83 H: 10.54 N: 2.33

Obtained value (%) C: 73.50 H: 10.22 N: 2.49

Example 1 08

1 [3?, 23 (4h) 1 diacetoxylean 1 2-1-28-oil] 1-4- (2-hydroxypropyl) biazine (compound 108)

A colorless powder was obtained in the same manner as in Example 99 using 1- (2-hydroxypropyl) piperazine instead of 1-methylbiperazine. Mp 140 ° C Elemental analysis (as _{_{_{_{C 41 H 66 N 2 0 6}}}} '1 / 2H 2 0)

Calculated value (%) C: 71.16 H: 9.76 N: 4.05

Obtained value (%) C-.71.24 H: 9.58 N: 4.21

Example 1 09

1-13/3, 2 3 (4-H) -doxy-doxy-lean-l-2-ene-l-28-oil]-4-(2-hydroxyl-propyl) pidazine (compound 109)

A compound of colorless powder was obtained in the same manner as in Example 100, except that compound 108 was used instead of compound 9.9. Melting point 20 2 ° C

Elemental analysis (as _{_{_{_{C 37 H 62 N 2 0 4}}}} -2 / 3H 2 0)

Calculated value (%) C.72.74 H: 10.45 N: 4.59

Obtained value (%) C: 72.69 H: 10.27 N: 4.66

Example 1 1 0

4 1 13/3, 2 3 (4 h) 1 diacetoxolean 1 2-1-2 1 8-oil] thiomorpholine (compound 110)

The same procedure as in Example 99 was carried out except that thiomorpholine was used instead of 1-methylbiperazine, to obtain a colorless powder of the target compound. Melting point 1 27 ° C -

87 Elemental analysis value (as C ₃₈ H ₅₉ N0 ₅ S)

Calculated value (%) C: 71.10 H: 9.26 N: 2.18

Observed value (%) C: 71.11 H: 9.24 N: 2.22

Example 1 1 1

4-[3/3, 2 3 (4h) dihydrodroxylean 1 2-1-2 8-oil] thiomorpholine (compound 1 1 1)

A compound of colorless powder was obtained in the same manner as in Example 100, except that Compound 110 was used instead of Compound 9.9. Melting point 1 8 3 ° C

Elemental analysis value (as C ₃₄ H ₅₅ N0 ₃ S'1 / 2H ₂₀ )

Calculated value (%) C: 72.04 H: 9.96 N: 2.47

Obtained value (%) C: 71.82 H: 9.74 N: 2.49

Example 1 1 2

2-Bromoethyl 3/3, 2 3 (4a)

To a solution of hederagenin (10.59 g) in DMF (200 ml) was added 1,2-dibromoethane (2.1.04 g) and potassium hydrogen carbonate (11.2) at 60 ° C. A mixture of 1 g) and DMF (50 ml) was gradually added, and the mixture was stirred overnight at the same temperature. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform-form) to obtain a colorless amorphous target product (7.69 g).

Negative ion FAB-MS m / z: 577 [M-H] "

IR (KBr): 3400, 2946, 1730, 1387, 1159cm- ¹

Example 1 1 3

2—Fluoroethyl 3?, 2 3 (4 α) —Dihydroxylone 1 1 2 — 1 2 8 — Acetate (Compound 1 1 3)

A target was obtained as a colorless powder in the same manner as in Example 112, except that 1,1-bromo-12-fluoroethane was used instead of 1,2-dibromoethane. Mp 2 2 6~2 2 7 ° C_ Elemental analysis (as _{_{_{C 32 H 51 F0 4 '1}}} / 2H 2 0) -

88 Calculated value (%) C: 72.83 H: 9.93

Observed value (%) C: 73.08 H: 9.93

Example 1 1 4

2— (Jetylamino) ethyl 3/3, 2 3 (4 days)

A solution of compound 112 (0.30 g) getylamine (0.11 g) in DMF (3 ml) was stirred at room temperature overnight. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black-mouthed form) to obtain a colorless amorphous target substance (0.23 g).

IR (KBr): 3400, 2946, 1720, 1458, 1163cnrl

Elemental analysis value (as C ₃₆ H ₆₁ N0 ₄ ' ^1/3 H ₂₀ )

Calculated value (%) C: 74.82 H: 10.76 N: 2.42

Observed value (%) C: 74.88 H: 10.80 N: 2.43

Example 1 1 5

2- (morpholino) ethyl 2> β, 23 (4) dihydroxyolane 1 2— benzene 28-phosphate (compound 1 15)

A colorless amorphous target product was obtained in the same manner as in Example 114 using morpholine instead of getylamine.

Negative ion FAB- MS m / z'.SS ^ M-Hj- Il KBr ASO, 2946, 1725, 1458, 1119cm— ¹

Example 1 1 6

2- (4-Methyl-1-biperazinyl) ethyl 3 g, 2 3 (4) —Dihydroxylorean 1 2—1—2 8—age-acetate (Compound 1 16)

A colorless amorphous target product was obtained in the same manner as in Example 114 using 1-methylbiperazine instead of getylamine.

IR (KBr): 3400, 2944, 1725, 1458, 1167cm " ¹

Elemental analysis (as _{_{_{_{C 37 H 62 N 2 0 4}}}} '2H 2 0) - Calculated (%) C: 69.99 H: 10.48 N: 4.41 --

89 Actual value (%) C: 69.85 H: 9.70 N: 4.49

Example 1 1 7

2-(phthalimid) ethyl 3?, 2 3 (4) 1-hydroxy-doxylean 1 2--2-2-8-(compound 1 1 7)

A colorless amorphous target product was obtained in the same manner as in Example 114, except that fluoridium potassium salt was used instead of getylamine.

Negative ion FAB-MS m / z: 645 [M]-, 645 [M-H] ~

IR (KBr): 2946, 1717, 1395, 1364cffl-l

Example 1 1 8

2-Aminoethyl 3 6, 2 3 (4a) —Dihydroxylorean 1 2 — 2 — 2 8 — 4 (Compound 1 18)

To a solution of compound 117 (0.33 g) in ethanol (3 ml) was added hydrazine (0.08 g) at room temperature, and the mixture was stirred overnight at the same temperature. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous potassium carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization from ethyl acetate to give the desired product (0.13 g) as a colorless powder. Melting point 2 19-220 ° C

Elemental analysis value (as C ₃₂ H ₅₃ N 0 ₄ '4 / 5H ₂₀ )

Calculated value (%) C: 72.49 H: 10.38 N: 2.64

Obtained value (%) C: 72.43 H: 9.95 N: 2.76

Example 1 1 9

N- (2-Methoxyxetil) 13?, 23 (4H) 1-1 (cyclohexylidenedioxy) orean-12-en-28-amide (compound 111)

To a solution of compound A (1.18 g) in benzene (60 ml), add cyclohexanone (0.19 g) and p-toluenesulfonic acid (0.36 g) at room temperature, and heat overnight. Refluxed. After cooling the reaction solution, water was added thereto, and the mixture was partitioned. The organic layer was washed with an aqueous solution of sodium hydrogen carbonate and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black-mouthed form) to obtain the desired product (0.333 g) as a colorless powder. Mp 1 24~ 1 2 5 ° C - Elemental analysis (as _{_{_{C 39 H 63 N0 4 '1}}} / 2H20) -

90 Calculated value (%) C: 76.02 H: 10.37 N: 2.22

Measured value (%) C: 75.94 H: 10.65 N: 2.33

Example 1 2 0

N— (2-Methoxyxetil) 1-3 ?, 23 (4a)-(3-pyridylmethylenedioxy) orean-12-en-28-amide (compound 120)

The desired product was obtained as a colorless powder in the same manner as in Example 119, except that 3-pyridinecarbaldehyde was used instead of cyclohexanone. Melting point 1 2 1 to 1 2 2 ° C

IR (KBr): 3350, 2900, 1650cm- ¹

Example 1 2 1

N— (2-Methoxyxetil) 1-3 ?, 23 (4)-(3-pyridylmethylenedioxy) orean-12-ene-28-amide hydrochloride (compound 122)

To a solution of compound 120 (0.50 g) in ether (10 ml) was added 0.73 ml of a 1 M hydrochloric acid / ether solution at room temperature, and after stirring for 10 minutes, the precipitated crystals were collected by filtration. The residue was washed with ether and dried to obtain the desired product as a colorless powder. Melting point 13 0 to 13 1 ° C

Elemental analysis (as _{_{_{_{C 39 H 58 N 2 0 4}}}} 'HC1'2H 2 0)

Calculated value (%) C: 67.75 H: 9.18 N: 4.05

Obtained value (%) C: 67.80 H: 9.15 N: 4.31

Example 1 2 2

N— (2-Methoxyxetil) _ 3?, 23 (4a) 1 (isopropylidene dioxy) orean 1 12—en 1 28-amide (compound 122)

A solution of compound A (20 g) and a 10% aqueous solution of hydrochloric acid (10 ml) in acetone (400 ml) was stirred at 55 ° C. overnight. The reaction solution was concentrated to a total volume of about 100 ml, the solution was cooled with ice water, and the precipitated crystals were collected by filtration. The obtained crystals were washed with acetone and dried to obtain the desired product (16.0 g) as a colorless powder. Melting point 210 ° C

Elemental analysis (as C ₃₆ H ₅₉ N0 ₄₎

Calculated value (%) C: 75.88 H: 10.44 N: 2.46

Obtained value (%) C: 75.63 H: 10.24 N: 2.79

Example 1 2 3 -N —— (2-Methoxyxetil) 1 1 2H, 1 3H 1 Epoxy 1—3?, — 2 3_ (4H) 1 (Isopropylidenedioxy) ore-an 1 2 -en- 28 -amide (compound 123)

To a solution of compound 122 (5.70 g) in ether (60 ml) was added m-chloroperbenzoic acid (8.63 g), and the mixture was stirred at 50 ° C for 6 hours and refluxed. did. The reaction solution was cooled, 50 ml of water was added, and the mixture was extracted with ethyl acetate. The organic layer was washed with aqueous potassium carbonate solution, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by recrystallization from ethyl acetate to give the desired product (3.0 g) as a colorless powder. Melting point 299 ° C Positive ion FAB-MS M / Z: 586 [M + H] +

IR (KBr): 1736, 2948, 3500cm- ¹

Elemental analysis (as C ₃₆ H ₅₉ N0 ₅₎

Calculated value (%) C: 73.80 H: 10.15 N: 2.39

Obtained value (%) C: 74.06 H: 9.47 N: 2.40

Example 1 24

Benzyl 3?, 2 3 (4) 1-dihydroxy-doxy-lean 1 12-en-1 28-year-old

Add hederagenin (14, 18 g) and potassium bicarbonate (9.0) to DMF (150 ml), and stir at room temperature to dissolve benzylbutamate (15.4 g). The mixture was added dropwise and stirred overnight. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1 to 2: 1) to obtain the target compound (5.50 g) as a colorless powder. Melting point 15-9. C

Elemental analysis value (as C ₃₇ H ₅₄ 0 ₄ '1 / 5H ₂₀ )

Calculated value (%) C: 78.46 H: 9.68

Obtained value (%) C: 78.50 H: 9.47

Example 1 2 5

Benzyl 3-hydroxy- 1 2 3 (4) 1-Methoxyl-an 1 12-en- 1-28-oate (Compound 1 2 5)-Compound 1 24 (5.5 g), powdered hydroxide (1.92 g) dimethyl -

Methyl iodide (4.16 g) was slowly added dropwise to a solution of 92 sulfoxide (DMSO) (100 ml) while stirring at 5 ° C, and the mixture was stirred at room temperature overnight. Water (500 ml) was added to the reaction solution, extracted with ether, the organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 1: 0: 1 to 3: 1) to obtain a colorless powder (4.65 g). Melting point 1 6 2 ° C

Elemental analysis value (as C ₃₈ H ₅₆ 0 ₄ '1 / 4H ₂₀ )

Calculated value (%) C: 78.51 H: 9.80

Obtained value (%) C: 78.52 H: 9.72

Example 1 2 6

3 3—Hydroxy 2 3 (4a) 1-Methoxyl-an 1 2—1—2 8—Ouic acid (Compound 1 2 6)

A solution of compound 125 (4.65 g) and 5% palladium on carbon (0.465 g) in ethanol (100 ml) was placed at room temperature under a hydrogen gas atmosphere at normal pressure. Stirred. After confirming the absorption of the theoretical amount of hydrogen gas, the catalyst was removed by filtration from the reaction solution, and the filtrate was concentrated to obtain the desired product (3.40 g).

IR (KBr): 1698, 2946, 3450cm- ¹

Elemental analysis (as _{_{_{C 31 H 50 0 4 '1}}} / 2H 2 0)

Calculated value (%) C: 75.11 H: 10.37

Measured value (%) C: 75.28 HilO.Ol

Example 1 2 7

Benzyl 3 ^ —acetoxy 1 2 3 (4 a) —Methoxylean 1 2 — 1 1 2 8 — (Compound 1 2 7)

The desired product as a colorless powder was obtained in the same manner as in Example 98, except that compound 125 was used instead of heterogenin. Melting point 1 32 ° C

Elemental analysis (as C ₄₀ H ₅₈ 0 ₅₎

Calculated value (%) C: 77.63 H: 9.45

Obtained value (%) C: 77.51 H: 9.51-Example 1 2 8 -

93

3 / 3—Acetoxy 2 3 (4h) -Methoxorean 1 2—1—28—Ouic acid (Compound 1 28)

Using compound 127 instead of compound 125, the desired product was obtained as a colorless powder in the same manner as in Example 126. Melting point 2 32 ° C

Elemental analysis value (as C ₃₃ H ₅₂ 0 ₅ '2 / 3H ₂₀ )

Calculated value (%) C: 73.29 H: 9.94

Obtained value (%) C: 73.26 H: 9.83

Example 1 2 9

N- (2-Methoxyxetil) 1 3 ^ -Hydroxy-1 23 (4H) -Methoxyl-en- 12-Yen-28-Amide (Compound 12 29)

To a solution of Compound 126 (1.86 g), WSCDHC1 (1.47 g) and H0Bt (1.17 g) in DMF (30 ml) was added 2-methoxylamine. (0.573 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 5: 1) to give the desired product (1.00 g) as a colorless powder.

Melting point 100 ~ 101 ° C

Elemental analysis value (as C ₃₄ H ₅₇ N0 ₄ '1 / 2H ₂₀ )

Calculated value (%) C: 73.87 H: 10.57 N: 2.53

Actual value (%) C: 73.89 H: 10.43 N: 2.52

Example 1 30

N- [2— (Jethylamino) ethyl] — 3? —Hydroxy 1 2 3 (4h) 1-Methoxyl-an 1 2—1- 1 2 8—Amide (Compound 130)

A target product as a colorless powder was obtained in the same manner as in Example 12-29, except that N, N-getylethylenediamine was used in place of 2-methoxethylamine. Mp 6 5 ° C Elementary analysis (as _{_{_{_{C 37 H 64 N 2 0 3}}}} -H 2 0)

Calculated value (%) C: 73.71 H: 11.03 N: 4.65

Obtained value (%) C: 73.54 H: 10.82 N: 4.70-Example 1 31 -

94

N— (2-Fluoroethyl) 1 3? —Hydroxy 1 2 3 (4) -Methoxyl-an 1 2—Yen—28—Amide (Compound 131)

Using 2-fluoroethylamine hydrochloride instead of 2-methoxethylamine, the target compound was obtained as a colorless powder in the same manner as in Example 12-29. Melting point 83 ° C

Elemental analysis value (as C ₃₃ H ₅₄ FN0 ₃ '2H ₂₀ )

Calculated value (%) C: 69.80 H: 10.30 N: 2.47

Obtained value (%) C: 69.41 H: 9.73 N: 2.73

Example 1 3 2

N- (6-Hydroxyhexyl) 1/3 / 3—Hydroxyl23 (4α) —Methoxyolean—12—Yen—28—Amide (Compound 1332)

The desired product as a colorless powder was obtained in the same manner as in Example 12-29, except that 6-hydroxyhexylamine was used instead of 2-methoxyhexylamine. Melting point 8 7 ° C

Elemental analysis value (as C ₃₇ H ₆₃ N0 ₄ '3 / 2H ₂₀ )

Calculated value (%) C: 72.50 H: 10.85 N: 2.29

Obtained value (%) C: 72.60 H: 10.31 N: 2.78

Example 1 3 3

2 Fluoroethyl 3/3/3 Hydroxy 1 2 3 (4) -Methoxyl ian 1 2-2-28-Oate (Compound 1 3 3)

A compound was obtained as a colorless powder in the same manner as in Example 113, except that compound 126 was used instead of hederagenin. Melting point 6 9 ° C

Elemental analysis value (as C ₃₃ H ₅₃ N0 ₄ 'H ₂₀ )

Calculated value (%) C: 71.96 H: 10.06

Obtained value (%) C: 72.23 H: 9.64

Example 1 34

1- 1 [3 / 3-acetoxy 1 2 3 (4h) 1-methoxyl- 1 1 2-1-28-oil] ― 4-methylbiperazine (Compound 134)

A mixture of compound 128 (0.50 g) and thionyl chloride (1.13 g) was stirred at 80 ° C for 2 hours. The reaction mixture was concentrated under reduced pressure to remove excess thionyl chloride, benzene was added and the mixture was concentrated again to completely remove thionyl chloride. Residue in pyridine (3 ml) -

The mixture was dissolved in 95, 1-methylbiperazine (0.19 g) was added under ice cooling, and the mixture was stirred at room temperature for 2 hours. 3 Oml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, diluted hydrochloric acid and brine, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black-mouthed form) to obtain the desired product (0.36 g) as a colorless powder. Melting point 1 2 1 ° C

Elemental analysis value (as C ₃₈ H ₆₂ N ₂ 0 ₄ '3 / 2H ₂₀ )

Calculated value (%) C: 71.55 H: 10.27 N: 4.39

Observed value (%) C: 71.16 H: 9.61 N: 4.32

Example 1 35

1- [3? -Hydroxyl 23 (4) -methoxylean 1 2-ene-1 28-oil]-4-methylbiperazine (compound 13 35)

The desired product as a colorless powder was obtained in the same manner as in Example 100, using compound 134 in place of compound 9.9. Melting point 149 ° C

Elemental analysis value (as C ₃₆ H ₆₀ N ₂ 0 ₃ 'H ₂ 0)

Calculated value (%) C: 73.67 H: 10.65 N: 4.77

Obtained value (%) C: 73.54 H: 10.18 N: 4.65

Example 1 36

4-[3 / 5-acetoxy-1 23 (4 α)-methoxylean 1 2-1-2 1 8-oil] morpholine (compound 13 36)

Using morpholine instead of 1-methylbiperazine, a colorless powder of the desired product was obtained in the same manner as in Example 134. Melting point 1 36 ° C

Elemental analysis value (as C ₃₇ H ₅₉ N0 ₅ -1 / 4H ₂₀ )

Calculated value (%) C: 73.77 H: 9.96 N: 2.33

Obtained value (%) C: 73.65 H: 9.79 N: 2.35

Example 1 37

4-[3 / 5—hydroxyl 23 (4) 1 methoxyl 1 1 2-1 2 8-oil] morpholine (compound 1 37)

A compound was obtained as a colorless powder in the same manner as in Example 135, except that compound 136 was used instead of compound 134. Melting point 1 39 ° C .

96 Elemental analysis value (as C ₃₅ H ₅₇ N0 ₄ '1 / 2H ₂₀ )

Calculated value (%) C: 74.42 H: 10.35 N: 2.48

Observed value (%) C-.74.05 H: 9.98 N: 2.61

Example 1 3 8

1 [3? -Acetoxy 1 2 3 (4h) 1-Methoxyl-an 1 1 2-1-2 1 8-oil] — 3-Hydroxypyrrolidine (Compound 1 3 8)

Using 3-hydroxypyrrolidine instead of 1-methylbiperazine, the target compound was obtained as a colorless powder in the same manner as in Example 134. Melting point 1 6 8 ° C

Elemental analysis value (as C ₃₇ H ₅₉ N 0 ₅ 'H ₂₀ )

Calculated value (%) C: 72.16 H: 9.98 N: 2.27

Obtained value (%) C.-72.20 H: 9.79 N: 2.35

Example 1 3 9

1 “3? —Hydroxy 1 2 3 (4a) —Methoxyl 1 1—2—2 1—8—Oil] —3—Hydroxypyrrolidine (Compound 13 9)

The desired product as a colorless powder was obtained in the same manner as in Example 135, except that compound 138 was used instead of compound 134. Melting point 1 5 9 ° C

Elemental analysis value (as C ₃₅ H ₅₇ N0 ₄ 'H ₂₀ )

Calculated value (%) C: 73.26 H: 10.36 N: 2.44

Obtained value (%) C: 72.90 H: 9.94 N: 2.50

Example 1 4 0

1——Acetoxy 1 2 3 (4h) 1-Methoxyl-an 1 1—2—1—2 8—Oil] —4—1 (2—hydroxyxethyl) pidazine (Compound 1 40)

A target was obtained as a colorless powder in the same manner as in Example 134, using 1- (2-hydroxyxethyl) biperazine instead of 1-methylbiperazine. Mp 1 4 5 ° C Elementary analysis (as _{_{_{_{C 39 H 64 N 2 0 5}}}} 'H 2 0)

Calculated value (%) C: 71.09 H: 10.10 N: 4.25

Observed value (%) C: 71.02 H: 9.78 N: 4.27

Example 1 4 1-1 1-[3?-Hydroxy 2 3 _ (4) 1-Methoxylean 1-1 2 2 1-2 8-. .-

97 Oil] 1-41 (2-Hydroxityl) Piperazine (Compound 14 1)

Using compound 140 instead of compound 134, the desired product was obtained as a colorless powder in the same manner as in Example 135. Melting point 1 3 8 ° C

Elemental analysis value (as C ₃₇ H ₆₂ N ₂ 0 ₄ 'H ₂₀ )

Calculated value (%) C: 72.04 H: 10.46 N: 4.54

Actual value (%) C: 72.16 H: 10.23 N: 4.52

Example 1 4 2

N- [2- (4-pyridyl) ethyl] 13-acetoxy23 (4h) methoxylean-12-2-ene1-28-amide (compound 1442)

Using 4- (2-aminoethyl) pyridine instead of 1-methylbiperazine, the target compound was obtained as a colorless powder in the same manner as in Example 134. Melting point 107 ° C

Elemental analysis value (as C ₄₀ H ₆₀ N ₂ 0 ₄ '1 / 2H ₂ 0)

Calculated value (%) C-.74.84 H: 9.58 N: 4.36

Obtained value (%) C: 74.97 H: 9.42 N: 4.47

Example 1 43

N- [2- (4-pyridyl) ethyl] 1-3? -Hydroxy 23 (4-h) methoxylean 1 12-ene 1 28-amide (compound 144)

The desired product as a colorless powder was obtained in the same manner as in Example 135, using compound 142 instead of compound 134. Melting point 2 2 4 ° C

Elemental analysis value (as C ₃₈ H ₅₈ N ₂ 0 ₃ -1 / 4H ₂ 0)

Calculated value (%) C: 76.66 H: 9.90 N: 4.71

Measured value (%) C: 76.65 H: 9.82 N: 4.75

Example 1 44

2 3 (4 α) —hydroxy 1 3? —Methoxyl 1 1 2 —2 2 8 —Oic acid (Compound 144)

(Process 1)

Benzyl 2 3 (4α) 1 [di (4-methoxyphenyl) phenylmethoxy] 1 3? -Hydroxylean 1 2 1 -2 1 2 8 -oate-Compound 1 2 4 (10.7 g ) In a pyridine (100 ml) solution without stirring at room temperature. 4,4,1-Dimethoxytrityl chloride (6.0 g) was slowly added dropwise, and the mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with dilute hydrochloric acid and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 15: 1 to 10: 1) to obtain the target compound (13.5 g) as a colorless powder.

(Process 2)

Benzyl 2 3 (4a) 1 [di (4-methoxyphenyl) phenyl methoxy]-3? -Methoxylone 1 2-1-2 8-

To a solution of the compound obtained in step 1 (15.0 g) in dimethyl sulfoxide (DMSO) (30 ml) was added 60% sodium hydride (2.08 g) while stirring at room temperature. After stirring for 30 minutes, methyl iodide (7.39 g) was slowly added dropwise, and the mixture was stirred at room temperature overnight. Water was added to the reaction solution, which was extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure to obtain the desired product (9.6 g).

Process 3

2 3 (4 a) —hydroxy 3? —Methoxylean 1 2 ェ 2 82 8 オ oil (compound 144)

Concentrated hydrochloric acid (12 ml) was added to a THF (lOOml) solution of compound 165 (9.5 g) obtained in Step 2 while stirring at room temperature, and the mixture was stirred at room temperature for 1 hour. Water was added to the reaction solution, and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was dissolved in ethanol (100 ml), 5% palladium on carbon (0.955 g) was added, and the mixture was subjected to a hydrogenation reaction at room temperature under a normal pressure hydrogen gas atmosphere overnight. The catalyst was removed from the reaction solution by filtration, and the filtrate was concentrated. The obtained compound was washed with ethyl acetate to obtain a colorless amorphous target product (1.1 g).

Melting point> 300 ° C

Negative ion FAB-MS M / Z: 485 [M-H]-

IR (KBr): 2849, 1730, 1462, 1090cm— ¹

Elemental analysis (as C ₃₁ H ₅₀ 0 ₄₎ - Calculated (%) C: 76.50 H- .10.35 Actual value (%) C: 76.34 H: 9.99

Example 145

N- (2-Methoxyxetil) 1 2 3 (4) -Hydroxyl 3? -Methoxyl-an 1 2—Yen—28—Amide (Compound 144)

Using compound 144 instead of compound 126, the target compound was obtained as a colorless powder in the same manner as in Example 12-9. Melting point 1 15 ° C

IR (KBr): 2943, 1141 , 1103cm one ¹

Elemental analysis value (as C ₃₄ H ₅₇ N0 ₄ '1 / 2H ₂₀ )

Calculated value (%) C: 75.09 H: 10.56 N: 2.58

Obtained value (%) C: 73.50 H: 10.19 N: 2.69

Example 1 4 6

2-acetoxityl 2 3 (4) 1-hydroxyl 3? -Methoxyl-an 1 2-ene-1 28-oate (compound 1 4 6)

A mixture of compound 144 (0.20 g), 2-bromoethyl acetate (0.205 g) and potassium hydrogen carbonate (0.123 g) in DMF (3 ml) was added to Stirred overnight at ° C. After the reaction solution was concentrated under reduced pressure, water was added to the residue, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (black-mouthed form) to obtain the desired product (0.181 g) as a colorless powder. Melting point 73 ° C

Elemental analysis (as _{_{_{C 35 H 56 0 6 '1}}} / 2H 2 0)

Calculated value (%) C: 72.25 H: 9.87

Obtained value (%) C: 72.45 H: 9.67

Example 1 47

N— (2—Methoxyxetil) 1 2 3 (4a) —Acetoxy 3? —Methoxyl 1 1 2—Yen—28—Amide (Compound 147)

The desired product as a colorless powder was obtained in the same manner as in Example 98, except that compound 145 was used instead of hederagenin. Melting point 19 1 ° C

Elemental analysis (as C ₃₆ H ₅₉ N0 ₅ '1 / 2H ₂₀ )-Calculated (%) C: 72.69 H: 10.17 N: 2.35 Observed value (%) C: 73.07 H: 10.04 N: 2.36

Example 1 48

N- (2-Methoxyxetil) 1 2 3 (4) 1-Acetoxy-acetoxy 1-??-Methoxy-lean 1 2-N- 1-28-Amide (Compound 148)

A solution of compound 144 (0.30 g), WSCDHC1 (0.21 g), and dimethylaminoviridine (0.014 g) in methylene chloride (10 ml) was added to acetate. Acetic acid (0.13 g) was added, and the mixture was stirred at room temperature overnight. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the desired product (0.165 g) as a colorless powder. 80 ° C

Elemental analysis value (as C ₃₈ H ₆₁ N0 ₇ '1 / 2H ₂₀ )

Calculated value (%) C: 69.90 H: 9.57 N: 2.15

Measured value (%) C: 70.23 H: 9.35 N: 2.17

Example 1 4 9

N- (2-Methoxyxetil) 1 2 3 (4) 1-Hydroxyacetoxy 1 3 / 5-Methoxyl-an 1 12-Ien 1 28-Amide (Compound 14 9)

(Process 1)

N- (2-Methoxyxetil) 1 2 3 (4h)-(4-Methoxybenzyl) oxyacetoxy 1 3?

The desired product was obtained in the same manner as in Example 148, except that (4-methoxybenzyl) oxyacetic acid was used instead of acetoacetic acid.

(Process 2)

N— (2-Methoxyxetil) 1 2 3 (4a) —Hydroxyacetoxy 1 3 / 5—Methoxylean 1 12—Ien 1 28—Amide (Compound 14 9)

Using the compound obtained in step 1 instead of compound 125, the target compound was obtained as a colorless powder in the same manner as in Example 126. Melting point 210 ° C

Elemental analysis (as _{_{_{C 36 H 59 N0 6 '1}}} / 2H 2 0) - Calculated (%) C: 70.78 H: 9.90 N: 2.29 Measured value (%) C: 70.70 H: 9.79 N: 2.27

Example 15

N- (2-Methoxyxetil) 1 2 3 (4H) 1 "(S) 1 2—Hydroxypropionyl] oxy 1 3? -Methoxyolean 1 2 1 2 1 2 8—Amide (compound

1 5 0)

(Process 1)

N— (2-Methoxyxetil) 1 2 3 (4a)-“(S) 1—2 1-benzyloxypiponyl] oxy 1/3 / 3—Methoxyl-an 1 1—2—1-28—amide

The desired product was obtained in the same manner as in Example 148, except that (S) -2-benzyloxypropionic acid was used in place of acetoacetic acid.

(Process 2)

Ν— (2-Methoxyxetil) 1 2 3 (4a) 1 [(S) —2—Hydroxypropionyl] oxy 1 3? —Methoxy olean 1 2 —Yen 1 2 8 —Amide (Compound 15 0)

Using the compound obtained in step 1 instead of compound 125, the target compound was obtained as a colorless powder in the same manner as in Example 126. Melting point 9 7 ° C

IR (KBr): 2950, 1736, 1640, 1522cm— 1

Elemental analysis value (as C ₃₇ H ₆₁ N0 ₆ 'H ₂₀ )

Calculated value (%) C: 70.11 H: 10.02 N: 2.21

Observed value (%) C: 70.64 H: 9.62 N: 2.24

Example 1 5 1

N— (2-Methoxyxetil) 1 2 3 (4a)-(3—Hydroxypropionyl) oxy 1 3? —Methoxylone 1 2—Yen 1 28—Amide (Compound 15 1) ( Process 1)

N— (2-Methoxyxetil) 1 2 3 (4)-(3-Benzyloxypropionyl) oxy 1 3? —Methoxylone 1 1 2—Yen 1 2 8—Amide

The desired product was obtained in the same manner as in Example 148, except that 3-benzyloxypropionic acid was used instead of acetoacetic acid. -(Process 2) -

102

N- (2-Methoxyxetil) 1 2 3 (4) 1 (3-Hydroxypropionyl) oxy 3 3? -Methoxylone 1 12-Ien 1 28-Amide (Compound 15 1) Compound Using the compound obtained in step 1 in place of 125, a colorless powder of the target compound was obtained in the same manner as in Example 126. Melting point 95 ° C

IR (KBr): 3450, 2950, 1740, 1640cm " ¹

Elemental analysis value (as C ₃₇ H ₆₁ N0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 71.12 HilO.OO N: 2.24

Actual value (%) C: 70.99 H: 9.86 N: 2.25

Example 1 5 2

Benzyl [3?, 4h, 1 3/3 (H)] — 3,2,3-Diacetoxie 12 2-oxo-leo-one 28-oate (Compound 15 2)

(Process 1)

Benzyl 3?, 2 3 (4 α) —Diacetoxolean 1 2—1—2 8—Oate

The desired product as a colorless powder was obtained in the same manner as in Example 124, using compound 98 instead of hederagenin.

Melting point 69 ° C

Elemental analysis (as C ₄₁ H ₅₈ 0 ₆₎

Calculated value (%) C: 76.12 H: 9.04

Obtained value (%) C: 75.95 H: 8.95

(Process 2)

Benzyl 3?, 2 3 (4 α) —Diacetoxy 1 2 and 1 3

To a solution of the compound obtained in step 1 (6.30 g) in ether (6 Oml) was added perbenzoic acid (7.42 g), and the mixture was heated under reflux for 4 hours while stirring. The reaction solution was concentrated under reduced pressure, and extracted with ethyl acetate. The organic layer was washed with an aqueous sodium carbonate solution and saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. Melting point 87 ° C Negative ion FAB-MS m / z: 661 [M-H]--IR (KBr): 1698, 1730, 2950cm-i (Process 3)

Benzyl [3 4, 1 3? (H)] 3, 2 3—Diacetox — 1 2—Year

The compound (5.20 g) obtained in Step 2 was dissolved in a mixed medium of a 5% aqueous hydrochloric acid solution (30 ml) and THF (30 ml), and the mixture was refluxed at 80 ° C for 2 hours. The reaction solution was concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to obtain the desired product (2.60 g) as a colorless powder. Melting point 76 ° C

Elemental analysis value (as C ₄₁ H ₅₈ 0 ₇ -1 / 2H ₂₀ )

Calculated value (%) C: 73.Z9 H: 8.85

Observed value (%) C: 73.41 H: 8.56

Example 1 5 3

[3 / 5,4h, 1 3/3 (H)] — 3,23-diacetoxy- 1 2-oxooxolean-28-oic acid (compound 15 3)

The desired product as a colorless powder was obtained in the same manner as in Example 126 using Compound 152 in place of Compound 125. Melting point 1 75 ° C

Positive ion FAB-MS M / Z: 573 [M + H] +

IR (KBr): 1698, 1744, 2946cm— ¹

Elemental analysis value (as C ₃₄ H ₅₂ 0 ₇ 'H ₂₀ )

Calculated value (%) C-.69.12 H: 9.21

Found (%) C-.69.03 H: 8.81

Example 1 5 4

[3 / 3,4h, 13β (Η)]-Ν- (2-methoxethyl) 1-3,23-diacetoxy-1 12-oxosolean-28-amide (compound 15 4 )

Compound 15 3 (0.40 g), WSCDHC1 (0.29 g), HOBt (0.21 g) in DMF (4 ml) solution was added to 2-methoxethylamine ( 0.1 g) and stirred at 70 ° C for 2 hours. The reaction solution was concentrated under reduced pressure, 10 ml of water was added to the heavy fraction, and extracted with ethyl acetate. After washing the organic layer with saturated saline, It was dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by recrystallization from a mixed solvent of isopropyl ether and isopropanol to obtain the desired product as a colorless powder (0.322 g). Melting point 2 19 ° C

Elemental analysis value (as C ₃₇ H ₅₉ N 0 ₇ '1 / 4H ₂₀ )

Calculated value (%) C: 70.05 H: 9.45 N: 2.21

Obtained value (%) C: 69.91 H: 9.28 N: 2.45

Example 1 5 5

[34,13β (Η)]-Ν- (2-methoxethyl) 1,3,23-dihydroxy 12-oxo-orean-one 28-amide (compound 15 55)

The desired product as a colorless powder was obtained in the same manner as in Example 100, except that Compound 154 was used instead of Compound 99. Melting point 2 4 5 ° C

Elemental analysis value (as C ₃₃ H ₅₅ N 0 ₅ '1 / 4H ₂₀ )

Calculated value (%) C: 72.03 H: 10.17 N: 2.55

Observed value (%) C: 71.95 H: 10.07 N: 2.63

Example 1 5 6

1-[13/3, 4 a, 13/3 (H)]-3,2,3-Diacetoxy 1 2 -oxo-orean 1 8 -Oil] 13 -Hydroxypyrrolidine (Compound 1 56 )

A mixture of compound 153 (0.573 g) and thionyl chloride (1.19 g) was stirred at 80 ° C for 2 hours. The reaction solution was concentrated under reduced pressure to remove excess thionyl chloride, benzene was added and the mixture was concentrated again to completely remove thionyl chloride. The residue was dissolved in pyridine (5 ml), and 3-hydroxybi-mouth lysine (0.174 g) was added thereto under ice cooling, followed by stirring at room temperature for 2 hours. 30 ml of water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water, diluted hydrochloric acid, and brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (form: black form) to obtain the desired product (0.42 g) as a colorless powder. Melting point 1 48 ° C

IR (KBr): 1698, 1740, 2946, 3450cm- ¹

Example 1 5 7

1-[[3 / 3,4h, 1 30 (H)]]-3,2 -dihydroxy-1- 12-Ogisolean 28-oil "! 3-Hydroxypyrrolidine _ (compound 15 7) One The desired product as a colorless powder was obtained in the same manner as in Example 100, using Compound 156 instead of Compound 9.9. Melting point 2 4 2 ° C

IR (KBr): 1599, 1700, 2942, 3400cm— ¹

Elemental analysis value (as C ₃₄ H ₅₅ N 0 ₅ 'H ₂₀ )

Calculated value (%) C: 70.92 H: 9.98 N: 2.43

Observed value (%) C: 70.94 H: 9.32 N: 3.01

Example 1 5 8

1-[[3 / 3,4h, 1 3 3 (H)]]-3,2 3-diacetoxy 1 2-oxo-orean 1 2 8-oil]-4-1 (2-hydroxyxetil) piperazine (Compound 158)

Using 1- (2-hydroxyxethyl) piperazine instead of 3-hydroxypyrrolidine, the target compound was obtained as a colorless powder in the same manner as in Example 156. Melting point 1 5 5 ° C Elemental analysis (as C ₄₀ H ₆₄ N ₂ 0 ₇ 'H ₂ 0)

Calculated value (%) C: 68.34 H: 9.46 N: 3.99

Observed value (%) C: 68.12 H: 9.01 N: 4.04

Example 1 5 9

1 — [[3?, 4h, 1 3 (3 (H)]) — 3,2 3—dihydroxy 1 2—oxorean 1 2 8—oil] —4— (2—hydroxyl) Pirazine ( Compound 1 5 9)

The desired product as a colorless powder was obtained in the same manner as in Example 100, using Compound 158 instead of Compound 9.9. Melting point 110 ° C

Negative ion FAB-MS m / z: 599 [MH]-IR (KBr): 1690, 1698, 2944, 3400cm " ¹

Example 16

[3?, 4 a, 13 β (H)] 13, 23 -dihydroxy-1 12 -oxo-lean 28 -Euric acid (Compound 1660)

The desired product as a colorless powder was obtained in the same manner as in Example 100, except that Compound 153 was used instead of Compound 9.9. Melting point> 300 ° C 'IR (KBr): 1698, 2940, 3465cm- ¹ ―

106 Example 1 6 1

2-acetoxityl [3 g, 4, 13/3 (H)]-3,2,3-dihydroxy 12-oxo-orean 1 28-phosphate (compound 16 1)

A target compound was obtained as a colorless powder in the same manner as in Example 144, using compound 160 instead of compound 144. Melting point 9 1 ° C

Elemental analysis value (as C ₃₄ H ₅₄ 0 l / 2H ₂₀ )

Calculated value (%) C: 69.95 H: 9.50

Obtained value (%) C: 70.15 H: 9.38

Example 1 6 2

Benzyl [3?, 4h, 13β (Η)] — 3-acetoxy-l 23-methoxyl-l2-oxo-olean-l 28-oate (compound 162)

(Process 1)

Benzyl 3-acetoxy 1 2 3rd, 13th epoxy 1st 2 3 (4th) 1 methoxyl ore 1 2 8

The desired product as a colorless powder was obtained in the same manner as in Example 123, using Compound 127 instead of Compound 122. Melting point 54 ° C

IR (KBr): 1700, 1732, 2944cm " ¹

Elemental analysis value (as C ₄₀ H ₅₈ 0 ₆ 'H ₂₀ )

Calculated value (%) C: 73.58 H: 9.26

Actual value (%) C: 73.43 H: 8.74

(Process 2)

Benzyl [3?, 4h, 13β (Η)] — 3-acetoxy-l 23-methoxyl-l2-oxoxorean-l 28-oate (compound 162)

Example 15 2 The compound obtained in Step 1 was used in place of the compound obtained in Step 2 to obtain the target product as a colorless powder in the same manner as in Example 3, Step 2, Step 3. Melting point 5 8 ° C Elemental analysis value (as C ₄₀ H ₅₈ 0 ₆ 'H ₂₀ )

Calculated value (%) C: 73.58 H: 9.26

Obtained value (%) C: 73.83 H: 8.87-Example 16 3 "3?, 4h, 1 3? (H)] — 3-acetoxy-1 23 -methoxy 1 2 -oxosolean 1 28 -Oic acid (Compound 163)

The desired product as a colorless powder was obtained in the same manner as in Example 126, using compound 162 instead of compound 125. Melting point 15 1 ° C

Elemental analysis value (as C ₃₃ H ₅₂ 0 ₆ '1 / 2H ₂₀ )

Calculated value (%) C: 71.57 H: 9.65

Obtained value (%) C: 71.81 H: 9.40

Example 1 6 4

"3?, 4h, 1 3 3 (H)]-N— (2-Methoxyxyl) 1-3-Acetoxy 23-Methoxy 1 12-Oxorean 1-28-Amide (Compound 164)

The desired product as a colorless powder was obtained in the same manner as in Example 154, using compound 163 instead of compound 153. Melting point 2 4 6 ° C

Elemental analysis value (as C ₃₆ H ₅₉ N0 ₆ '1 / 3H ₂₀ )

Calculated value (%) C: 71.13 H: 9.89 N: 2.30

Observed value (%) C: 71.18 H: 9.68 N: 2.36

Example 1 6 5

"3?, 4h, 1 3 (H)]-N-- (2-Methoxyxetil) 1-3-Hydroxy 23-Methoxy 1 12 2-Oxosolean 28-Amide (Compound 1665)

The desired product as a colorless powder was obtained in the same manner as in Example 100, using compound 164 instead of compound 9.9. Melting point 1 2 3 ° C

Elemental analysis value (as C ₃₄ H ₅₇ N 0 ₅ ' ^2/3 H ₂₀ )

Calculated value (%) C-.71.41 H: 10.28 N: 2.45

Actual value (%) C: 71.34 H: 10.03 N: 2.38

Example 1 6 6

2-acetoxityl [3 / 3,4a, 13β (Η)]-3-acetoxy-l 23-methoxyl 12-oxo-lean-l 28-oate (compound 1666)

The desired product as a colorless powder was obtained in the same manner as in Example 144, using compound 163 instead of compound 144. Mp 7 8 ° C 'Elemental analysis (as C ₃₇ H ₅₈ 0 ₈₎ -

108 Calculated value (%) C: 70.44 H: 9.27

Measured value (%) C: 70.11 H: 9.14

Example 1 67

2—Hydroxitytil [3?, 4h, 1 3? (Η) Ί — 3—Hydroxy-1 23— Methoxy 1 2—Oxosolean 1 2 8—Wet (Compound 1 67)

The desired product as a colorless powder was obtained in the same manner as in Example 100, using compound 166 instead of compound 99. Melting point 1 2 1 ° C

Elemental analysis (as _{_{_{C 33 H 54 0 6 '1}}} / 2H 2 0)

Calculated value (%) C: 71.31 H: 9.97

Obtained value (%) C: 71.46 H: 9.93

Example 1 6 8

Benzyl [3?, 4 h, 12 h, 13 β (Η)] — 3,23-diacetoxy- 1 2 -hydroxyl-orean 1 -28-phosphate (compound 1 68 Α) and benzyl “3 ?, 4h, 1 2,3,1 3 3 (Η)]-3,2,3-Diacetoxy 1 2—Hydroxylean 1—28—phosphate (compound 16 8 Β)

Lithium borohydride (0.533 g) was added to a solution of compound 152 (10.8 g) in THF (11 Oml) under a stream of argon at -78 ° C, and the mixture was stirred at the same temperature for 2 hours. The temperature was naturally raised to room temperature, and the mixture was stirred at room temperature for 6 hours. 500 ml of water was added to the reaction solution, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (n-hexane: ethyl acetate = 10: 1) to give compound 168A (2.62 g) as a colorless powder.

Melting point 203 ° C

Elemental analysis (as C ₄₁ H ₆₀ 0 ₇₎

Calculated value (%) C: 74.06 H: 9.10

Observed value (%) C: 73.82 H: 9.05

The elution was further continued to obtain a colorless powder of compound 168B (2.73 g).

Mp 1 9 1 ° C 'Elemental analysis (as C ₄₁ H ₆₀ 0 ₇₎ Calculated value (%) C: 74.06 H: 9.10

Observed value (%) C: 73.83 H: 8.97

Example 1 6 9

[3?, 4h, 1 2?, 1 3 3 (H)]-3,2,3-Diacetoxy 12-Hydroxylean 1 28-Ouide Acid (Compound 1669)

The desired product as a colorless powder was obtained in the same manner as in Example 126 using Compound 168 8 in place of Compound 125. Melting point 270 ° C

Elemental analysis value (as C ₃₄ H ₅₄ 0 ₇ '1 / 2H20)

Calculated value (%) C: 69.95 H: 9.50

Actual value (%) C: 70.08 H: 9.30

Example 1 7 0

[3?, 4 a, 1 2 β, 1 3 β (])] — （— (2-Methoxyxetil) -1,3,23-diacetoxy 1 2 —Hydroxylean 1 2 8 —amide (Compound 17 0) The desired product as a colorless powder was obtained in the same manner as in Example 12 using Compound 169 in place of Compound 126. Melting point 2 32 ° C

Elemental analysis (as C ₃₇ H ₆₁ N0 ₇₎

Calculated value (%) C.-70.23 H: 9.73 N: 2.22

Obtained value (%) C: 69.97 H: 9.73 N: 2.36

Example 1 7 1

[3?, 4, 1 2?, 13? (Η)] — Ν— (2-Methoxyxetil) -1, 3, 12, 23—Trihydroxylean 1 28—amide (compound 17 1 丄)

A compound of colorless powder was obtained in the same manner as in Example 100, except that Compound 100 was used instead of Compound 99. Melting point 2 44 ° C

Elemental analysis value (as C ₃₃ H ₅₇ N 0 ₅ '3 / 2H ₂₀ )

Calculated value (%) C: 68.95 H.-10.52 N: 2.44

Obtained value (%) C: 68.51 H: 9.87 N: 2.61

Example 1 7 2

[3/5, 4 a, 1 2 5, 1 3/3 (H)]-3, 1, 2, 3-tridroxy-rean- 1 2 8-oil acid (compound 17 2) The desired product as a colorless powder was obtained in the same manner as in Example 100, except that compound 169 was used instead of compound 9.9. Melting point> 300 ° C

IR (KBr): 1698,2946,3400cm- ¹

Elemental analysis value (as C ₃₀ H ₅₀ 0 ₅ 'H ₂₀ )

Calculated value (%) C: 70.83 H: 10.30

Measured value (%) C: 70.87 H: 10.01

Example 1 7 3

2-acetoxityl [3?, 4h, 12?, 1/3/3 (H)] -3,12,23-trihdroxylean 1 28-oate (compound 1 73)

The desired product as a colorless powder was obtained in the same manner as in Example 144, using compound 172 instead of compound 144. Melting point 76 ° C

Elemental analysis value (as C ₃₄ H ₅₆ 0 ₇ '1 / 2H ₂₀ )

Calculated value (%) C: 69.71 H: 9.81

Obtained value (%) C: 69.70 H: 9.60

Example 1 74

[3 / 3,4,12,13 / 3 (H)]-3,23-Diacetoxy 1 2-Hydroxylean 1 28-Oxyacid (Compound 174)

The desired product as a colorless powder was obtained in the same manner as in Example 126 using Compound 168A instead of Compound 125. Melting point 2 7 8 ° C

IR (KBr): 1725, 1745, 2944, 3513cm- ¹

Elemental analysis value (as C ₃₄ H ₅₄ 0 ₇ '1 / 3H ₂₀ )

Calculated value (%) C: 70.31 H: 9.49

Measured value (%) C: 70.36 H: 9.44

Example 1 7 5

[3 / 3,4,12,13? (H)] — N— (2-Methoxyxetil) -1,3,23-diacetoxy 12 —Hydroxylean 1-2 8 —amide (compound 17 5) The desired product as a colorless powder was obtained in the same manner as in Example 1229, using Compound 174 instead of Compound 126. Melting point 93 ° C “Positive ion FAB-MS M / Z: 632 [M + H] ⁺ -

111

IR (KBr): 1636, 1745, 2946, 3400cm " ¹

Example 1 7 6

[3/3, 4 h, 12 h, 13? (Η)] — Ν— (2-Methoxyxetil) –3, 12, 23-Trihydroxylean 1-28-amide (Compound 1 76 )

The desired product as a colorless powder was obtained in the same manner as in Example 100, using compound 175 instead of compound 990. Melting point 1 6 7 ° C

Elemental analysis value (as C ₃₃ H ₅₇ N 0 ₅ 'H ₂₀ )

Calculated value (%) C: 70.05 H: 10.51 N: 2.48

Obtained value (%) C: 69.57 H: 9.92 N: 2.47

Example 1 7 7

N— (2-Methoxyxetil) 1 3 3—Hydroxyacetoxylean 1 12—Yen 1 28—Amide (Compound 1777)

The desired product as a colorless powder was obtained in the same manner as in Example 126, using Compound 84 in place of Compound 125. Melting point 1 8 4— 1 8 5 ° C

Elemental analysis (as _{_{_{C 35 H 57 N0 5 'H}}} 2 0)

Calculated value (%) C: 71.27 H: 10.08 N: 2.37

Obtained value (%) C: 71.45 H: 9.70 N: 2.44

Example 1 7 8

2-acetoxityl 3? -Hydroxyl-one 1 2-ene-1 28-oate (compound 1778)

The desired product was obtained as a colorless powder in the same manner as in Example 144, except that oleanolic acid was used instead of compound 144. Melting point 18 3-1 84 ° C

Elemental analysis value (as C ₃₄ H ₅₄ 0 ₅ '1 / 2H ₂₀ )

Calculated value (%) C: 74.01 H: 10.05

Obtained value (%) C.-74.11 H: 9.87

Example 1 7 9

2-acetoxitytyl 3-acetoxyacetoxylean 1 2-ene-28-oate (compound 179)-colorless powder in the same manner as in Example 10 using compound 17 8 instead of compound A Was obtained. Melting point 5 3 ~ 54 ° C

IR (KBr): 2950, 1750cm- ¹

Elemental analysis (as _{_{_{C 38 H 58 0 8 '1}}} / 4H 2 0)

Calculated value (%) C: 70.58 H: 9.11

Observed value (%) C: 70.58 H: 8.98

Example 1 8 0

2—acetoxityl 3? — [(2-hydroxyxethyl) aminocarbonyloxy] orean 1 2—en 1 28—oate (compound 180)

To a solution of compound 178 (0.50 g) in THF (10 ml) was added 1,1, -carbodiimidazole (0.448 g), and the mixture was stirred at room temperature for 5 hours, and then subjected to 2-aminoethylamine. Evening knol (0.169 g) was added, and the mixture was stirred for 5 days. The reaction solution was poured into ice water, extracted with ethyl acetate, and the organic layer was washed with saturated saline, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform: methanol = 200: 1) to obtain the desired product (0.248 g) as a colorless powder. Melting point 1 43-144 ° C

Elemental analysis value (as C ₃₇ H ₅₉ N 0 ₇ '1 / 2H ₂₀ )

Calculated value (%) C: 69.56 H: 9.47 N: 2.19

Obtained value (%) C: 69.60 H: 9.23 N: 2.16

Example 18 1

2-acetoxitytyl 3? — [(4-Methoxybenzyl) oxyacetoxy] orean 1 2—2—2 8—4 (compound 18 1)

A colorless amorphous target product was obtained in the same manner as in Example 1- (1), using compound 1-8 instead of compound A.

Elemental analysis (as _{_{_{C 43 H 62 0 r 5 /}}} 4H 2 0)

Calculated value (%) C: 72.39 H: 9.11

Obtained value (%) C: 72.43 H: 8.71

IR (KBr): 2950, 1750, 1735, 1515 cm " ¹

Example 1 8 2-2-acetoxityl-3/5-hydroxyacetoxylean 1 2-ene 1 2 .

113

8-Compound (compound 1 82)

The desired product as a colorless powder was obtained in the same manner as in Example 126, using Compound 181 in place of Compound 125. Melting point 153-154 ° C

IR (KBr): 3600, 2900, 1750, 1725cm- ¹

Elemental analysis (as C ₃₂ H ₅₂ 0 ₄₎

Calculated value (%) C: 76.75 H: 10.47

Observed value (%) C-.76.79 H: 10.49

The results of tests showing the usefulness of typical examples of the compounds of the present invention are shown below. Test example 1

Measurement of Compound A concentration in plasma after oral administration to rat

Among the oleanane derivatives according to the present invention, the compound used as a test drug in this test is described in International Publication W096 / 00236 as N- (2-methoxhetyl), which is described to be useful for the treatment of nephritis. It is metabolized to 3/3, 2 3 (4) 1-hydroxyl-oxylean 1-2-ene-28-amide (compound A). Compound A itself was administered as a control compound. By measuring the concentration of compound A in plasma after administration of the test drug, the absorbability of the oleanan derivative according to the present invention was evaluated.

The test drug was orally administered to 30 Wistar female rats (body weight: about 150 g) at a dose of 30 mg / kg per group. Blood was collected from the jugular vein at 0.5 and 2 hours after oral administration. After centrifugation of whole blood, the concentration of Compound A in the obtained plasma was quantified by HPLC. That is, 0.5 ml of plasma, 0.2 ml of 0.1N hydrochloric acid, 0.3 ml of H ₂ , a mixture of hexane / ether (1: 1) ml, and 0.05 ml of a methanol solution of an internal standard (10 μg / ml) were added. Shake for 10 minutes. After evaporating the organic layer to dryness, add the fluorescent derivatization reagent 1-antroyl cyanide in acetonitrile solution (4 mg / ml) 0.10 ml and quinuclidine in acetonitrile solution (20 mg / ml) 0.10 ml. And reacted at 60 ° C for 20 minutes. After the completion of the reaction, the fluorescent derivative of Compound A was purified using a solid phase column (Bond Elut NH ₂ (registered trademark)) and then injected into HPLC. HPLC conditions were as follows. Column: Capcell PakC18 (4.6xl50mm)

Column temperature: 40 ° C - mobile _{_{phase: CH 3 CN: 0.1¾H 3 P0}} 4 = 4: 1 Flow rate: l.Oml / min

Detector: Fluorescence detector

Measurement wavelength: Ex: 370nm, Em: 470nm

Table 1 shows the results. Table 1 Concentration of Compound A in plasma

a): not analyzed

54A.54B: Mixture of Compound 54A and Compound 54B

(57A, 57B) and (58A, 58B) also show that the plasma concentration of Compound A upon administration of the compound of the present invention is much higher than that upon administration of Compound A, similarly to the above.

Test example 2

Effects of anti-Thy-1 antibody on mesangial cell proliferation in nephritis rats

Anti-Thy-1 antibody nephritis is a model of glomerulonephritis that occurs through the reaction between antibodies and Thy-1 antigen, which is present as a membrane protein of mesangial cells, and activation of complement. In this model, mesangial cell injury and mesangial cell proliferative lesions are recognized.Most human chronic glomerulonephritis is proliferative glomerulonephritis mainly caused by proliferation of mesangial cells and deposition of matrix. -1 Antibody nephritis is a model of human proliferative glomerulonephritis, especially mesangial cell proliferative nephritis (Ishizaki .

115

(Ishizaki) et al., Acta. Pathol. Jpn., 36, 1191 (1986)).

(1) Experimental animals

Body weight 120-: A Wistar female rat of I40 g was used.

(2) Experimental materials

• Preparation of anti-Thy-1 antibody

The production of the antibody was carried out according to the method of Ishizaki et al. That is, an adjuvant suspension of rat thymocytes was prepared, and this was injected subcutaneously into rabbits for immunization. Blood was collected after two additional immunizations, and the obtained serum was subjected to inactivation and absorption procedures to obtain an antiserum (anti-Thy-1 antibody).

(3) Experimental method

A certain amount of antiserum was injected intravenously through the tail vein of the rat to induce nephritis. From the day after the injection, a suspension of the test drug was orally administered once a day for 7 days every day. Compound 4 was used as a test drug, and Compound A described above was used as a comparative control compound. On the 8th day after the start of administration, dissection was performed, and the kidney was removed. After fixing the kidney with Carnoy's fixative, paraffin sections were prepared according to a conventional method, subjected to periodate Schiff staining, and microscopically examined. For histopathological evaluation, the number of glomerular cells (mesangial cells) in each tissue specimen was counted using an optical microscope. Statistical tests were performed using Dunnett's method. The results are shown in Table 2. Table 2 Histopathological findings of renal glomeruli

Test drug dose Number of mice Number of glomerular cells ^a )

(mg / kg)

Nephritis control group Distilled water 5 76.4 ± 3.1

Compound A 10 5 67.0 ± 2.2

Compound A 30 5 66.3 ± 3.8 *

Compound 4 1 5 64.9 ± 1.2 *

Compound 4 3 5 60.7 ± 1.6 **

a) Number of cells (mesangial cells) per glomerulus

Mean soil standard error (The average number of cells in normal animals is 43.)

*: P-0.05, **: P-0.01 (Dunnett's method, vs. nephritis control group) In the anti-Thy-1 antibody nephritis rat, Compound 4 of the present invention showed significant mesa at ling / kg. It exhibited an inhibitory effect on proliferation of enzymatic cells. On the other hand, Compound A showed the same inhibitory effect on mesangial cell proliferation at 30 mg / kg. From this, it is clear that the compound of the present invention has a much stronger inhibitory action on mesangial cell proliferation than compound A. Test example 3

Effect of anti-Thy-1 antibody on the number of PCNA-positive cells in glomeruli in rats with nephritis

PCNA (Prolifative Cell Nucleic Acid) is a nuclear antigen expressed by cells in culture and is known as a marker of cell proliferation. In anti-Thy-1 antibody nephritis rats, a model of proliferative glomerulonephritis, the number of PCNA-positive cells is also used as an indicator of the proliferation of mesangial cells in the glomeruli (Kidney International, 40 (3 ), 477-488, 1991). Therefore, in this test, the degree of mesangial cell proliferation in the glomeruli was evaluated based on the degree of increase in the number of PCNA-positive cells.

An antiserum against Thy-1 antigen (anti-Thy-1 antibody) prepared in the same manner as in Test Example 2 was injected from the tail vein of the rat to induce nephritis. From the day after the injection, a suspension of the test drug was orally administered once a day for 4 days. Dissection was performed 5 hours after the last administration of the test drug, and the kidney was removed. After fixation in a 10% phosphate buffered formalin solution, PCNA immunohistochemical staining (PCNA antibody (mouse monoclonal antibody) and staining kit: Zymed Laboratories, Inc.) were performed using paraffin sections prepared according to a conventional method. Was given. Under a microscope, PCNA-positive cells were counted for 40 glomeruli per sample, and the average number of PCNA-positive cells per glomerulus was determined. The inhibition rate (%) of the number of PCNA-positive cells by the test drug was calculated by the following formula.

Inhibition rate of PCNA-positive cell count (¾) = 100 X [1— (PT—PN) / (PC—PN)] In the formula, PN is the average number of PCNA-positive cells per glomerulus in the normal group. Represent. PC represents the average number of PCNA-positive cells per glomerulus in the nephritis control group. PT represents the average number of PCNA-positive cells per glomerulus in the test group. The results are shown in Table 3. Table 3 Inhibition rate of the number of PCNA-positive cells in glomeruli in anti-Thy-1 antibody nephritis rats Test drug dose Number of PCNA-suppressed cells Number of PCNA-positive cells Good II 11 II 1 //. ;;匕匕 mg (mg / kg, po) (%)

Coupling Coupling Coupling Coupling

Object thing object thing thing thing thing thing 4 3 4 98.8

4 8 10 4 47.3

1 3 0 10 4 37.8

1 0 0 10 4 54.5 7 0 10 4 44.8

1 0 5 10 4 72.7

1 0 9 10 4 78.3 8 1 10 4 88.6

1 3 9 10 4 78.3

1 43 10 4 82.2

1 4 5 10 4 41.4

1 5 5 10 4 35.8 1 6 1 10 4 72.3

1 2 2 10 4 50.6

1 3 8 10 4 56.0

From the above results, it is clear that the compound of the present invention has an inhibitory effect on the increase in the number of PCNA-positive cells in glomeruli in an anti-Thy-1 antibody nephritis rat.

Test example 4

Acute toxicity

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 A and Compound 4 were administered as test drugs. 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 4 5.0mg

46.6mg corn starch

Microcrystalline cellulose 24.0mg-Methylcellulose 4.0mg .

118 Magnesium stearate 0.4mg

The mixture is mixed at this ratio, and the mixed powder is tableted to form an internal tablet.

Industrial applicability

As described above, the compound according to the present invention has a high absorbability upon oral administration and / or a strong inhibitory action on mesangial cell proliferation, and is therefore useful for treating nephritis.

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 pharmaceutical composition comprising, as an active ingredient.

In the formula, Me represents methyl.

(A)

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.

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

(1) hydroxy,

(2) monoalkylamino (wherein the alkyl portion of the monoalkylamino is one substituent selected from the group consisting of hydroxy, alkoxy, alkoxycarbonyl, cyclicamino, alkylcarbonylamino, and alkylcarbonyloxy) 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 a group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, cyclic amino, and alkylcarbonyloxy. And may be substituted by one substituent selected from Such alkylcarbonyloxy may be substituted with alkylcarbonylamino or arylalkyloxy, where the aryl moiety may be substituted with alkoxy. ) And represent any of the following substituents (1) to (4).

(1) hydroxy,

(2) 0 S 0 ₂ R7,

(3) 0 P (= 0) (0R8) (0R9),

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

(1) hydrogen,

(2) hydroxy,

(3) 0 S 0 ₂ R7,

(4) 0 P (= 0) (0 R8) (0R9),

R ⁷ represents hydroxy, alkyl, or aryl.

R8 and R9 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 NiRiO R ¹¹ ) [Such RiO and Rll are the same or different and are hydrogen or alkyl (such alkyl is hydroxy, unsubstituted amino, monoalkylamino, and selected from the group consisting of dialkyl § amino, one or represents may.) which may be substituted by a substituent, or, RLO, R ^11, such together with the adjacent N connexion, N (RLO ) (R1 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 ¹² and R ¹³ [Such R ¹² and R ¹³ may be the same or different, and may be hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, Substituted amino, carboxy, alkylcarbonylamino, alkylcarbonyloxy (wherein the alkyl portion of such alkylcarbonyloxy is selected from the group consisting of hydroxy, and unsubstituted amino;

It may be substituted by one substituent. ) Or alkoxy (such al The coxy may be substituted with one to two aryls, and such aryls may be substituted with aryloxy. ). ]

③ cycloalkyl optionally substituted with aminoalkyl,.

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

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

Provided that X and Z are linked together, Y is hydrogen, R ^{1 is} hydroxy, monoalkylamino (the alkyl moiety of such monoalkylamino is hydroxy, alkoxy, Optionally substituted by one substituent selected from the group consisting of alkylcarbonyloxy and alkoxycarbonyl.) Or alkoxy (such alkoxy is hydroxy, aryl, alkoxy, alkoxy, alkoxy) Carbonyl, and optionally substituted by one substituent selected from the group consisting of unsubstituted alkylcarbonyloxy.) And R ^{2 is} hydroxy, or 0 C (= 0) R 6 , and the except when R3 is hydrogen, arsenate Dorokishi, or 0C (= 0) R ⁶ der Ri, R6 is a substituent of the following (a) or (b).

(a) an alkyl optionally having one or both of the substituents R ¹² and R ¹³

[The R ^ and R13 are the same or different and each is a hydroxy, unsubstituted amino, carboxy, alkylcarbonyloxy (the alkyl part of the alkylcarbonyloxy is substituted with hydroxy or unsubstituted amino) Or non-substituted alkoxy. ] (b) one or two identical or different aminos, optionally substituted with an alkyl optionally substituted with a hydroxy.

(B)

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

RK R ² S R3 is any of the following cases (1) to (26).

(I) R ¹ is (2-methoxethyl) amino, R 2 is hydroxy, and R3 is hydroxyacetoxy.

(Z) R ¹ is (2-methoxethyl) amino, R 2 is hydroxyacetoxy, and R ³ is hydroxy.

(3) Rl is (2-main Tokishechiru) Amino, R 2 Gahi Dorokishiase butoxy a R ³ Gahi Dorokishiase butoxy.

(4) Ri is (2-methoxethyl) amino, R2 is hydroxy, and R3 is acetoxy.

(5) Rl is (2-main Tokishechiru) Amino is R2 turtles Tokishiase butoxy a R ³ turtles Tokishiasetokishi.

(6) Rl is (2-methoxethyl) amino, R2 is hydroxy, and R3 is methoxyacetoxy.

(7) Ri is (2-main Tokishechiru) Amino, R 2 is § cell Tokishiase butoxy, R ³ is § cell Tokishiase butoxy.

(8) Ri is (2-methoxyxethyl) amino, R 2 is hydroxy,

R3 is acetoacetoxy.

(9) 1 ^ is (2-Methoxyxetil) amino, R2 is hydroxy, and R3 is ethoxyacetoxy.

(10) Rl is (2-main Tokishechiru) Amino, R2 is glycyl O carboxymethyl § cell butoxy a R ³ Gahi Dorokishi.

(II) R ¹ is (2-methoxyl) amino, R 2 is hydroxy, and R 3 is 3-hydroxypropionyloxy.

(12) Ri is (2-methoxethyl) amino, R2 is hydroxy-, and R3 is (S) -2-hydroxypropionyloxy.

(13) Ri is (2-methoxyl) amino, R 2 is 3-carboxypropionyloxy, and R3 is 3-carboxypropionyloxy.

(M) R ¹ is (2-methoxethyl) amino, R2 is hydroxy, and R3 is (S) _2-acetoxypropionyloxy.

(15) 1 ^ is (2-Methoxyxethyl) amino, R 2 is hydroxy,

R ³ is dimethylaminocarbonyloxy.

(1S) R ¹ is (2-methoxyl) amino, R 2 is glycyroxy, and R ³ is glycyroxy.

(17) Ri is (2-main Tokishechiru) Amino is R2 Gahi Dorokishi, R ³ is Gurishiruokishi.

(18) Ri is (2-main Tokishechiru) Amino, R2 is Ri Ah in Gurishiruokishi a R ³ Gahi Dorokishi.

(19) Ri is (2-main Tokishechiru) Amino, R 2 Gahi Dorokishi, R ³ is L- Araniruokishi.

(20) 1 ^ is (2-methoxyl) amino, R2 is L-alanyloxy, and R3 is hydroxy.

(2DR ¹ is (2-methoxethyl) amino, R 2 is hydroxy, and R3 is L-seryloxy.

(22) R ¹ is (2-methoxyxethyl) amino, R 2 is L-seryloxy, and R ³ is hydroxy.

(23) R ¹ is (2-methoxethyl) amino, R 2 is hydroxy, and R ³ is glycyloxyacetoxy.

(24) Rl is 2- (Jechiruamino) Echiruamino a R2 Gahi Dorokishi a R ³ turtles butoxy.

(25) R ¹ is 2- (4-pyridyl) ethylamino, R ² is hydroxy, and R ³ is methoxy.

(26) R ¹ is (2-methoxyhexyl) amino, R ^{2 is} methoxy, and R3 is hydroxy. -(C) X and Z together represent a bond. Y represents hydrogen.

R1 represents 0R81 or N (R81) (R82).

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) phenyl which may have a substituent,

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

(a) halogen,

(b) OR83,

(c) 0 (C = 0) R83,

(d) C◦OR ⁸³ ,

(e) Siano,

(f) N (R83) (R84),

(g) cycloalkyl,

(i) optionally substituted by 1 to 3 identical or different substituents selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino

R83 and R84 are the same or different,

① Hydrogen or-

②Hydroxy, alkoxy, unsubstituted amino, monoalkylamino, And dialkylamino, which represents an alkyl 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) cycloalkyloxy optionally having a substituent,

(4) alkenyloxy which may have 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, alkynyloxy, monoalkyl rubamoyloxy, dialkyl rubamoyloxy, alkoxycarbonyloxy, alkylcarbonyloxy, aryl propyloxy represented by R ² have The substituents that may be substituted are one to three identical or different substituents selected from the group consisting of the following substituents (a) to (i).

(a) halogen,

(b) OR85,

(c) 0 (C = 0) ^R85 ,

(d) COOR ⁸⁵ ,

(e) Siano,

(f) N (R85) (R86),

(g) cycloalkyl,

(i) the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino An aromatic heterocyclic group optionally selected from 1 to 3 same or different substituents.

R85 and R86 are the same or different,

① Hydrogen or

R ³ represents hydrogen.

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

2. A pharmaceutical composition comprising, as an active ingredient, the oleananane derivative according to claim 1, selected from the group consisting of the following compounds (1) to (3), or a pharmaceutically acceptable salt thereof. (1)

X and Z are linked together and Y is hydrogen.

R2 represents any of the following substituents (a) to (f).

(a) hydroxy,

(b) phosphoxy,

(c) alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy may be substituted by hydroxy, unsubstituted amino, alkoxy substituted by 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) arylcarbonyloxy substituted with alkyl (the alkyl moiety of arylcarbonyloxy substituted with alkyl is an amino substituted with one or two hydroxyalkyl, and a 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) alkylcarbonyloxy (the alkyl moiety of such an alkylcarbonyloxy may be substituted by hydroxy, unsubstituted amino, alkoxy substituted by one or two 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. ]

(f) a cycloalkylcarbonyloxy substituted with an aminoalkyl,

(g) alkoxy.

Or, R ² and R ³ together are isopropylidenedioxy.

(2)

X and Z are linked together and Y is hydrogen.

Rl 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). -

R ² and R ³ are the same or different and are each a hydroxy, alkoxy, or alkyl Bonyloxy.

(3)

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

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

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

R2 and R3 are each hydroxy.

3. A pharmaceutical composition 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 Z are linked together and Y is hydrogen.

R2 represents hydroxy.

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

(a) hydrogen,

(b) phosphoxy,

(c) 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. ]

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

( Five)

X and Z are linked together and Y is hydrogen.

R2 represents the following substituent (a) or (b).

(a) alkylcarbonyloxy (where the alkyl moiety of the alkylcarbonyloxy is one substituent 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.

R3 represents hydroxy.

(6)

X and Z are linked together and Y is hydrogen.

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

R2, R ³ is either in the case of the following (a) ~ (c).

(a) R ² and R ³ are each a phosphoxy.

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

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

(7)

X and Z are linked together and Y is hydrogen.

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

(a) cyclic amino (such cyclic amino is replaced by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy); 130

R2 and R3 each represent hydroxy.

(8)

X and Z are linked together and Y is hydrogen.

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

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

R3 represents alkoxy.

(9)

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

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

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

R ² and R ³ are each hydroxy.

4. A pharmaceutical composition comprising, as an active ingredient, an oleanan derivative selected from the group consisting of the following compounds (1) to (35) or a pharmaceutically acceptable salt thereof.

(DN-(2—methoxetil) 1 3? —Hydroxy 1 2 3 (4α) —hydroxy 1 2 1—2 1—8—amide

(2) Ν-(2-Methoxyxetil) 1 2 3 (4) 1-Hydroxy 1 3?

(3) Ν-(2-methoxyxetil) 1 2 3 (4 α)-Acetoxy 1 3/3-Hydroxylene 1 2-1-2 8-Amid-

(4) Ν- (2-methoxetil) 1/3/3, 23 (4α) -bis Toxi) Orean 1 1 2—28—Amid

(5) N- (2-Methoxyxetil) 1 23 (4) 1-Acetoxy-Acetoxy 3 5—Hydroxy-lean 1 1 2—Ien 1 2 8—Amid

(6) N- (2-Methoxyxetil) 1 2 3 (4α) —Benzhydryl oxyacetoxy 1 3? —Hydroxylean 1 1 2—En 1 28—Amid

(7) Ν- (2-Methoxyxetil) 1 3 5—Hydroxy 2 3 (4a) 1 (3—Hydroxypropionyloxy) Orean 1 2—En 1 28—Amid

(8) N- (2-Methoxyxetil) 13-Hydroxy 23 (4a)-((S) -2-Hydroxypropionyloxy) Olean 1 12-En 1 28-Amide

(9) N— (2-Methoxyxetil) 1-3? -Hydroxy-23 (4α)-[41- (morpholinomethyl) benzoyloxy] orean-1 2-ene-1 28 _amide (10) Ν- ( 2—Methoxyxetil) 1 2 3 (4h) 1 [4— (Bis (2—hydroxyshethyl) aminomethyl) benzoyloxy] — 3—Hydroxylean 1—12—28—amide

(11) N— (2-Methoxyxetil) -1 3—Hydroxy-23 (4H) -1 [4 — ((2-Hydroxyethyl) aminomethyl) benzoyloxy] Orean _12-2-ene 28—Amid

(12) N- (2-Methoxyxetil) 1 3? —Hydroxy 1 2 3 (4a)-[4- (thiomorpholinomethyl) benzoyloxy] Orean 1 2—Yen 1 28—Amide (13 ) N- (2-Methoxyxetil) 1 2 3 (4) 1-Glycyloxy 1 3—Hydroxylean 1 2—Yen 1 2 8—Amide

(14) N- (2-Methoxyxetil) 1 3? —Glycyloxy 1 2 3 (4) 1 Hydroxylean 1 12—1 1 2 8—Amide

(15) N- (2-Methoxyxetil) 1 3 / 5—Hydroxy 2 3 (4) 1 (L-Selyloxy) Orean 1 2—En 1 28—Amid

(16) N- (2-Methoxyxetil) 1 2 3 (4a) —Hydroxy 1 3 5— (L—Ceryloxy) Orean 1 2—En-28—Amid

(17) N-(2-Methoxyxetil) 1 2 3 (4) 1-Glycyloxyacetic acid 3? -Hydroxylean 1 12-Ien 1 28-Amid (18) N— (2-Methoxyxetil) 1 3 / 5—Glysiloxyacetoxy 1 2 3 (4) -Hydroxylylene 1 12—En 1—28—Amid

(19) N-(2-Methoxyxetil) 13-Hydroxy 23 (4-H) Phosphoxylene 1 12-28-Amide

(20) N- (2-Methoxyxetil) 1 2 3 (4a)-((S) —2—Acetoxypropionyloxy) 1 3 5—Hydroxylean 1 12—1—2 28—Amide

(21) N— (2-Methoxyxetil) 1 2 3 (4a)-(N-Acetylglycyloxy) 1 3? —Hydroxylean 1 1—2—1 2 8—Amide

(22) N— [2-(Jethylamino) ethyl] 1 3? —Hydroxy 2 3 (4 α) -Methoxylair 1 1—2—1 2 8—Amide

(23) 1 1 [3/3, 2 3 (4) 1 2 3 1 2 3 4 1 2 1 2 3 4 1 2 1 2 1 2 3 4 4 4 4

(24) Ν- (2-methoxethyl) 1 2 3 (4a)-(trans 4-aminomethylcyclohexanecarbonyloxy 1/3 / 3-hydroxyl-oren 12-en-28-amide

(25) 1-13/3, 2 3 (4) 1-hydroxy-2-pyrrolidine 1 2-hydroxy-28-yl] 1-3-hydroxypyrrolidine

(26) 1-[3/3, 2 3 (4h) 1-doxy-doxylean 1 2-2-28-year-old]-41 (2-hydroxyprobiol) biradizine

(27) 2— (Hydroxyacetoxy) ethyl 3/5, 2 3 (4) 1-Hydroxy-orean 1 2

(28) 1— [3 / 5—hydroxy 1 2 3 (4h) -methoxyl 1 1 2—1 2 8—oil] — 3—hydroxypyrrolidine

(29) N- [2- (4-Pyridyl) ethyl] 1 3 ^ —Hydroxy 1 2 3 (4α) 1 Methoxyolane 1 2—Yen 2 8—Amide

(30) Ν— (2—methoxyl) 1 2 3 (4) 1—hydroxyl 3 5—methoxyl 1 12—2—28—amide

(31) [3?, 4 a, 13 β (Η)] — Ν— (2-Methoxyxetil) -1,3,2,3-Dihydroxy 1-12, Oxosolean 1,28—Amide (32) 2-acetoxityl [3,4h, 13β (Η)] 13, 23-dihydrochloride 1 2 -oxorean 1 2 8 1

(33) Ν- (2-Methoxyxetil) 13?, 23 (4a)-(Isopropylidenedioxy) orean 1 2-N-28-Amid

(34) 1- [3-Acetoxy 1 2 3 (4) 1-Methoxyl-an 1 12-en-28-oil] 13-Hydroxypyrrolidine

(35) N- (2-Methoxyxetil) 1 3—Hydroxylean 1 2—En 1 28-Amide

5. A pharmaceutical composition for treating nephritis, comprising the oleanan derivative according to claim 1 or a pharmaceutically acceptable salt thereof as an active ingredient.

6. A pharmaceutical composition for treating chronic glomerulonephritis, comprising the oleanan derivative or pharmaceutically acceptable salt thereof according to claim 1 as an active ingredient.

7. A pharmaceutical composition for treating proliferative glomerulonephritis, comprising as an active ingredient the oleanean derivative according to claim 1 or a pharmaceutically acceptable salt thereof.

8. A compound represented by the following formula [1], which is any of the following (A), (B) or (D), or a pharmaceutically acceptable salt thereof:

In the formula, Me represents methyl.

(A)

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

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

(1) 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.)

R2 represents any of the following substituents (1) to (4).

(1) hydroxy,

(2) 0 S〇 ₂ R ⁷ ,

(3) O P (= 0) (OR8) (〇R9),

(4) 0 C (= 0) R6 _O

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

(1) hydrogen,

(2) hydroxy,

(3) OS 0 ₂ R ⁷ ,

(4) 0 P (= 〇) (0R8) (0R9),

(5) O C (= 0) R6.

R7 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 (RlO) (Rll) [R ¹⁰ and R ¹¹ are the same or different and are hydrogen or alkyl (such alkyl is hydroxy, unsubstituted amino, mono) May be substituted by one substituent selected from the group consisting of alkylamino and dialkylamino.) Or R ¹⁰ and R ¹¹ are taken together with adjacent N In other words, N (R ¹⁰ ) (RU) 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 ¹² and R ¹³ [Such R ¹² and R ¹³ may be the same or different, and may be hydroxy, alkylthio, alkylsulfinyl, alkylsulfonyl, Substituted amino, carboxy, alkylcarbonylamino, alkylcarbonyloxy (wherein the alkyl portion of the alkylcarbonyl is substituted by 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 optionally substituted with aminoalkyl,

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

Or, R ² and R3 are taken together to 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 ³¹ together represent alkylene which may be substituted with alkyl.

Wherein X and Z are a bond together, Y is hydrogen, and Rl is hydroxy, monoalkylamino (the alkyl portion of such monoalkylamino is It may be substituted by one substituent selected from the group consisting of hydroxyl, alkoxy, alkylcarbonyloxy, and alkoxycarbonyl. ) Or alkoxy (such alkoxy may be substituted by one substituent selected from the group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, and unsubstituted alkylcarbonyloxy) .), and, R ² Gahi Doroki shea, or 〇 C (= 〇) R6, R3 is hydrogen, arsenate Dorokishi, or 〇 C (= 0) R6 der Ri, R 6 is the following _(a) Or the case where it is a substituent of (b) is excluded.

(a) alkyl which may have one or both of the substituents R ¹² and R ¹³ (such R ¹² and R ¹³ may be the same or different and are hydroxy, unsubstituted amino, carboxy, alkylcarbonyl Oxy (the alkyl part of such an alkylcarbonyloxy may be substituted by hydroxy or unsubstituted amino), or unsubstituted alkoxy. ]

(b) one or two identical or different aminos which may be substituted by an alkyl which may be substituted by a hydroxy.

(B)

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

RK R ² and R ³ are any of the following cases (1) to (26).

(1) R ¹ is (2-methoxyxethyl) amino,: 2 is hydroxy, and R ^{3 is} hydroxyacetoxy.

(2) Ri is (2-main Tokishechiru) Amino, R 2 Gahi Dorokishiase butoxy a R ³ Gahi Dorokishi.

(4) R is a (2-main Tokishechiru) Amino, R 2 Gahi Dorokishi, R ³ is § Se butoxy.

(5) Ri is (2-main Tokishechiru) Amino, R 2 turtles Tokishiase butoxy a R ³ turtles Tokishiase butoxy.

(6) Ri is (2-main Tokishechiru) Amino, Oh by R 2 Gahi Dorokishi a R ³ turtles Tokishiase butoxy. (7) Ri is (2-main Tokishechiru) Amino, R2 is § cell Tokishiase butoxy, R ³ is § cell Tokishiase butoxy.

(8) Ri is (2-methoxyxethyl) amino, R2 is hydroxy, and R3 is acetoacetoxy.

(9) Ri is (2-methoxyxethyl) amino, R 2 is hydroxy,

R3 is ethoxycetoxy.

(10) 1 ^ is (2 main Tokishechiru) Amino, R ² is glycyl O carboxymethyl § Se butoxy, R ³ is hydroxy.

(11) R ¹ is (2-methoxethyl) amino, R2 is hydroxy, and R ³ is 3-hydroxypropionyloxy.

(12) Ri is (2-main Tokishechiru) Amino is R2 Gahi Dorokishi, R ³ is (S) - 2-hydroxycarboxylic propionyl Ruo alkoxy.

(13) 1 ^ is (2-methoxyl) amino, R 2 is 3-carboxypropionyloxy, and R3 is 3-carboxypropionyloxy.

() R ¹ is (2-methoxethyl) amino, R2 is hydroxy,

1 ^ 3 is (5) -2-acetoxypropionyloxy.

(15) is 1 ^ is (2 main Tokishechiru) Amino is R2 Gahi Dorokishi, R ³ is dimethyl § iminocarbonyl O alkoxy.

(16) 1 ^ is (2-Methoxyxyl) amino, R ² is glycyloxy, and R ³ is glycyloxy.

(17) is 1 ^ is (2 main Tokishechiru) Amino is R2 Gahi Dorokishi, R ³ is Gurishiruokishi.

(18) 1 ^ is (2-Methoxyxyl) amino, is glycyloxy, and R ³ is hydroxy.

(19) R〗 is (2-methoxyxethyl) amino, R2 is hydroxy,

R3 is L-alaniloxy.

(20) 1 ^ is (2 main Tokishechiru) Amino, R ² is L Araniruokishi a R ³ Gahi Dorokishi.

(2DR ¹ is (2-methoxethyl) amino, R ² is hydroxy, R3 is L-seryloxy.

(22) Ri is (2-methoxyxethyl) amino, R2 is L-seroxy, and R3 is hydroxy.

(23) Ri is (2-main Tokishechiru) amino, R2 Gahi Dorokishi, R ³ is glycyl O carboxymethyl § Seto alkoxy.

(24) R ¹ is 2- (ethylamino) ethylamino, R 2 is hydroxy, and R3 is methoxy.

(25) R ¹ is 2- (4-pyridyl) ethylamino, R2 is hydroxy, and R ³ is methoxy.

(26) R ¹ is (2—methoxyxethyl) amino, R 2 is methoxy,

R3 is hydroxy.

(D)

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

Rl represents the following substituent (1) or (2).

(1) monoalkylamino (wherein the alkyl portion of the monoalkylamino is one selected from the group consisting of alkoxy, alkylcarbonyloxy, arylcarbonyl, and aromatic heterocyclic group carbonyloxy) Is replaced by a substituent of.),

(2) alkoxy (the alkoxy is substituted by one substituent selected from the group consisting of alkoxy, alkylcarbonyloxy, arylcarbonyloxy, and aromatic heterocyclic group carbonyloxy) ).

R2 represents any of the following (1) to (10).

(1) hydroxy,

(2) an alkoxy optionally having a substituent,

(3) cycloalkyloxy optionally having a substituent,

(4) alkenyloxy which may have 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) arylcarbonyloxy optionally having a substituent;

Alkoxy, cycloalkyloxy, alkenyloxy, alkynyloxy, monoalkyl rubamoyloxy, dialkyl rubamoyloxy, alkoxycarbonyloxy, alkylcarbonyloxy, arylcarbonyl represented by R ² The substituents which may be substituted are one to three identical or different substituents selected from the group consisting of the following substituents (a) to (i).

(a) halogen,

(b) OR85,

(c) 0 (C = 0) R85,

(d) C 00 R85,

(e) Siano,

(f) N (R85) (R86),

(g) Alkyl alkyl,

(h) aryl optionally 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 which may be substituted by one substituent selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino.

R3 represents hydrogen.

9. The method according to claim 8, wherein the compound is selected from the group consisting of the following compounds (1) to (3): or a pharmaceutically acceptable salt thereof. (1)

X and Z are linked together and Y is hydrogen.

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 identical or different substituents selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. ]

(e) cycloalkylcarbonyloxy substituted with unsubstituted aminoalkyl,

(f) alkoxy.

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

(a) hydrogen,

(b) hydroxy,

(c) phosphoxy,

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

(e) arylcarbonyl substituted with alkyl (the alkyl moiety of arylcarbonyl substituted with such alkyl is one to two hydroxyls) It is substituted by one substituent selected from the group consisting of amino substituted by alkyl, and cyclic amino. ),

(f) cycloalkylcarbonyloxy substituted with 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).

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

R2 and R3 are the same or different and are hydroxy, alkoxy, or alkylcarbonyloxy.

(3)

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

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

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

R ² and R ³ are each hydroxy.

10. The oleanan derivative or the pharmaceutically acceptable salt thereof according to claim 8, which is selected from the group consisting of 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.

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

(a) hydrogen,

(b) phosphoxy,

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

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

(e) Cycloalkylcarbonyloxy substituted with aminoalkyl.

( Five )

X and Z are linked together and Y is hydrogen.

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

(b) alkoxy. -R3 represents hydroxy. (6)

X and Z are linked together and Y is hydrogen.

R ² and R ³ are any of the following cases (a) to (c).

(a) R2 and R3 are each a phosphoxy.

(b) R2 and R3 are each an alkylcarbonyloxy (the alkyl moiety of such an alkylcarbonyloxy is substituted by an alkylcarbonyloxy; ].

(c) R2 and R3 are taken together to be isopropylidenedioxy.

(7)

X and Z are linked together and Y is hydrogen.

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

R2 and R3 each represent hydroxy.

(8)

X and Z are linked together and Y is hydrogen.

Ή.Κ R ² is for the following cases (a) or (b).

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

R3 represents alkoxy. -

(9) X and Y are oxo together, and Ζ is hydrogen.

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

(b) alkoxy (such alkoxy is substituted by alkylcarbonyloxy) o

R2 and R3 are each hydroxy.

11. An oleanan derivative or a pharmaceutically acceptable salt thereof selected from the group consisting of the following compounds (1) to (35).

(1) N-(2-Methoxyxetil) 1 3?-Hydroxy 1 2 3 (4a)-Hydroxy acid 1-2-1-28-Amide

(2) N-(2-Methoxyxetil) 1 2 3 (4α) — Hydroxy 1 3 — Hydroxy 1 2

(3) Ν-(2-methoxhetyl) 1 2 3 (4α)-acetoxin 1 3?

(4) Ν- (2—methoxil) 1 3/5, 2 3 (4h) 1 bis (acetoxyacetoxy) ore 1 1 2—en 2 28—amide

(5) Ν- (2-Methoxyxetil) 1 2 3 (4) 1-Acetoxy-Acetoxy 3 5—Hydroxy-lean 1 12-Ien 1 28-Amid

(6) Ν-(2-Methoxyxetil) 1 2 3 (4) 1-Hydroxyloxyacetic acid 3? —Hydroxylean 1 1 2—Yen 1 2 8—Amide

(7) Ν-(2-methoxyxetil)-3?-Hydroxy-1 2 3 (4)-(3- Hydroxypropionyloxy) Orean 1 2-1-28-Amide

(8) Ν— (2-Methoxyxetil) 1/3 / 3-hydroxy-23 (4) 1-1 ((S) —2-hydroxypropionyloxy)

(9) N- (2-Methoxyxetil) 1-3? -Hydroxy2 3 (4H) -1 [4- (Morpholinomethyl) benzoyloxy] Orean 1 12-En 1 28-Amid

(10) N— (2—methoxethyl) 1 2 3 (4) 1 [4 (bis (2—hydroxy-shethyl) aminomethyl) benzoyloxy] — 3 5—hydroxyl 12-28-Amide

(11) N— (2-Methoxyxetil) -1 3? —Hydroxy-1 2 3 (4) -1 [4-((2-hydroxyxethyl) aminomethyl) benzoyloxy] Orean 1 1—2—1 2 8- Amid

(12) N— (2-Methoxyxetil) 1 3 3—Hydroxy-1 2 3 (4) 1- [4— (thiomorpholinomethyl) benzoyloxy] Orean 1 2

(13) N- (2-Methoxyxetil) 1 2 3 (4) —Glycyloxy 1 3 Hydroxylean 1 12—Ien 1 28—Amide

(14) N- (2-Methoxyxetil) 1 3 Glycyloxy 1 2 3 (4a) Hydroxylean 1 2

(15) N- (2-Methoxyxetil) 1/3 / 3-Hydroxy2 3 (4H)-(L-Ceryloxy) Orean 1 2-N-28-Amid

(16) N- (2-Methoxyxetil) 1 2 3 (4a) —Hydroxy 3? — (L—Ceryloxy) Orean 1 2—En 1 28—Amid

(17) N- (2-Methoxyxetil) 1 2 3 (4) 1-Glycyloxy-acetoxy 1-??-Hydroxy-le-an 1 12-En--1 28-Amid

(18) N- (2-Methoxyxetil) 1 35-Glysiloxyacetoxy 1 2 3 (4a) —Hydroxylean 1 12—Ien 1 2 8—Amide

(19) N- (2-Methoxyxetil) 1/3 / 3-Hydroxy-1 2 3 (4) 1-Phosphoroxylean 1 2-Yen-1 28-Amide

(20) N- (2-Methoxyxetil) 1 2 3 (4a)-((S) — 2-Acetoxypropionyloxy) 1- 3-Hydroxy-lean 1 2-N-28-Amid

(2DN- (2-Methoxyxetil)) 1 2 3 (4a) ― (N-Acetylglycyloxy) 1 3 / 5—Hydroxylean 1 1 2—En 1 2 8—Amid

(22) N— [2- (Jethylamino) ethyl] —3? —Hydroxy2 3 (4h) -Methoxyolane 1 2—Yen 2 8—Amide

(23) 1-13/3, 2 3 (4 a) —dihydroxy-1,2-1,2,8-yl] — 4-methylbiperazine-

(24) N- (2-Methoxyxetil) 1 2 3 (4a)-(Trans 1 4-aminomethyl Lecyclohexanecarbonyloxy 3-Hydroxylene 1 12-1-28-Amide

(25) 1-13/3, 2 3 (4) Jihidroxylean 1 2 -en-28 -oil] — 3 -Hydroxypyrrolidine

(26) 1 1 [3/3, 2 3 (4) Jihidroxylorean 1 2-2-28-yl] 1 4 1 (2-hydroxypropyl) piperazine

(27) 2-(Hydroxyacetoxy) ethyl 3 ^, 2 3 (4) —dihydroxy ore 1 1 2 — 2 — 2 8 —

(28) 1— [3 / 3—Hydroxy 1 2 3 (4) 1-Methoxy ethoxy 1 1—2—1 2 8—Oil] 1—3—Hydroxypyrrolidine

(29) Ν- [2— (4-pyridyl) ethyl] — 3 / 5—hydroxy 1 2 3 (4) 1 methoxylean 1 2—en 2 28—amide

(30) N— (2-Methoxyxetil) 1 2 3 (4) 1 Hydroxy 3 5—Methoxy ore 1 1 2—En 2 28—Amide

(31) [3 / 3,4,13β (Η)] — Ν— (2-methoxethyl) 1,3,23-dihydroxy-1 12-oxolone 1 28-amide

(32) 2-acetoxyshethyl [3?, 4, 1 3 β (Η)]-3, 23 3-diethyl mouth x 12 1-oxolean 1 2 8 1

(33) Ν— (2-Methoxyxetil) 13?, 23 (4a)-(Isopropylidenedioxy) orean 1 12—28-amide

(34) 1— [3 / 3—acetoxy 1 2 3 (4a) 1-methoxy-2-an 1 28—oil] 1—3-hydroxypyrrolidine

(35) N- (2-Methoxyxetil) 1 3 Hydroxylean 1 2