WO1998058946A1 - Derives triterpeniques et composition medicamenteuse - Google Patents

Derives triterpeniques et composition medicamenteuse Download PDF

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Publication number
WO1998058946A1
WO1998058946A1 PCT/JP1998/002779 JP9802779W WO9858946A1 WO 1998058946 A1 WO1998058946 A1 WO 1998058946A1 JP 9802779 W JP9802779 W JP 9802779W WO 9858946 A1 WO9858946 A1 WO 9858946A1
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Prior art keywords
hydroxy
substituted
amino
alkyl
alkoxy
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PCT/JP1998/002779
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English (en)
Japanese (ja)
Inventor
Jun Segawa
Masato Matsuoka
Hiroto Yoshifusa
Akio Nakamura
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Nippon Shinyaku Co., Ltd.
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Priority to AU80382/98A priority Critical patent/AU8038298A/en
Publication of WO1998058946A1 publication Critical patent/WO1998058946A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07J—STEROIDS
    • C07J63/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by expansion of only one ring by one or two atoms

Definitions

  • Triterpene derivative and pharmaceutical composition Triterpene derivative and pharmaceutical composition
  • 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.
  • 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)).
  • 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))).
  • 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).
  • 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.
  • Me represents methyl
  • X, Y, and ⁇ are any of the following cases (1) to (4).
  • ⁇ represents hydroxy.
  • X and ⁇ each represent hydrogen.
  • R 1 represents any of the following substituents (1) to (4).
  • cyclic amino (the cyclic amino may be substituted by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy),-
  • alkoxy (such alkoxy may be hydroxy, aryl, alkoxy, .
  • R 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.
  • R 2 represent any of the following substituents (1) to (4).
  • R 3 represents any of the following substituents (1) to (5).
  • 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.
  • 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.
  • alkoxy (the alkoxy may be substituted by 1 to 2 aryls, and the aryl may be substituted by the alkoxy.).
  • 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);
  • ⁇ Amino which may be substituted by 1 to 2 same or different, optionally substituted by hydroxyalkyl.
  • R 2 and R 3 together represent the following formula:
  • R21, R31 are the same or different and each represents hydrogen, alkyl, Ariru, or a heterocyclic group, or R 21, R 31 are such togetherconnection, the alkylene which may be substituted with alkyl.
  • Y is hydrogen
  • 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).
  • X and Z together represent a bond.
  • Y represents hydrogen.
  • RK R 2, R3 is any of the following cases (1) to (26).
  • R 1 is (2-methoxethyl) amino
  • R 2 is hydroxy
  • R 3 is hydroxyacetoxy
  • Ri is (2-methoxyxetil) amino
  • R 2 is hydroxyacetoxy
  • R 3 is hydroxy
  • Ri is (2-main Tokishechiru) Amino, R 2 Gahi Dorokishiase butoxy a R 3 Gahi Dorokishiase butoxy.
  • Ri is (2-methoxyxethyl) amino, R2 is hydroxy, and R3 is acetoxy.
  • Ri is (2-main Tokishechiru) Amino, R 2 turtles Tokishiase butoxy a R 3 turtles Tokishiase butoxy.
  • R 1 is (2-methoxethyl) amino
  • R 2 is hydroxy
  • R 3 is methoxyacetoxy
  • Ri is (2-main Tokishechiru) Amino
  • R 2 is ⁇ cell Tokishiase butoxy
  • R 3 is ⁇ cell Tokishiase Bok alkoxy.
  • Ri (2-main Tokishechiru) Amino is R2 Gahi Dorokishi, R 3 is ⁇ cell Tokishiase butoxy.
  • Ri (2-main Tokishechiru) Amino, R 2 Gahi Dorokishi, R3 is Etokishiase butoxy.
  • R 1 is (2-methoxethyl) amino
  • R 2 is glycyloxyacetoxy
  • R 3 is hydroxy
  • 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, -
  • R 3 is (S) -2-hydroxypropionyloxy.
  • R 1 is (2-methoxyl) amino
  • R2 is 3-carboxypropionyloxy
  • R3 is 3-carboxypropionyloxy
  • Ri is (2-methoxyshetyl) amino
  • R2 is hydroxy
  • R3 is ( S ) 12-acetoxypropionyloxy.
  • R 1 is (2-methoxethyl) amino
  • R 2 is hydroxy
  • R 3 is dimethylaminocarbonyloxy
  • R 1 is (2-methoxethyl) amino
  • R2 is glycyroxy
  • R3 is glycyroxy.
  • R 1 is (2-methoxethyl) amino
  • R2 is hydroxy
  • R 3 is glycyloxy.
  • Ri is (2-methoxyl) amino
  • R 2 is glycyroxy
  • 3 is hydroxy.
  • R 1 is (2-methoxethyl) amino
  • R 2 is hydroxy
  • R3 is L-alanyloxy
  • (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.
  • Ri is (2-methoxethyl) amino, R2 is hydroxy, and R3 is glycylooxyacetoxy.
  • R 1 is 2- (ethylamino) ethylamino
  • R2 is hydroxy
  • R 3 is methoxy
  • R 1 is 2- (4-pyridyl) ethylamino
  • R2 is hydroxy
  • methoxy
  • R 1 is (2-methoxyhexyl) amino, R 2 is methoxy, and R 3 is hydroxy.
  • 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).
  • 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.
  • aryl optionally substituted by one to three 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).
  • Dialkyl power rubamoyloxy which may have 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).
  • R 85 and R86 are the same or different
  • R 3 represents hydrogen
  • X and Z together represent a bond.
  • Y represents hydrogen.
  • R 1 represents the following substituent (1) or (2).
  • alkoxy (such alkoxy is alkoxy, alkylcarbonyl .
  • R 2 represents any of the following (1) to (10).
  • dialkyl power rubamoyloxy optionally having a substituent
  • 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;
  • R 85 and R 86 are the same or different
  • 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.
  • 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.
  • 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.
  • cycloalkyl portion of the “cycloalkylcarbonyloxy” examples include the 07 cycloalkyl.
  • Alkoxy includes linear or branched alkoxy having 1 to 7 carbon atoms, for example, methoxy, ethoxy, ⁇ -propoxy, isopropoxy, ⁇ -butoxy, isobutoxy, sec-butoxy, tert-butoxy , N-pentyloxy, isopentyloxy, n-hexyloxy, isohexyloxy, n-heptyloxy and isoheptyloxy.
  • alkoxycarbonyl examples 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.
  • 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.
  • aryl portion of “aryl alkyloxy” and “arylcarbonyloxy” examples include the above aryl.
  • 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, 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, imid
  • 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.
  • 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).
  • 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).
  • 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.
  • 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:),
  • R3 represents any of the following substituents (a) to (g).
  • 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. ]
  • 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:),
  • R 2 and R 3 together are isopropylidenedioxy.
  • X and Z are linked together and Y is hydrogen.
  • -R 1 represents any of the following substituents (a) to (c). .
  • 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.
  • X and Y are oxo together, and Z is hydrogen.
  • R 1 represents the following substituent (a) or (b).
  • alkoxy (such alkoxy is substituted with alkylcarbonyloxy).
  • R 2 and R 3 are each hydroxy.
  • more preferred compounds include, for example, the following compounds (4) to (9).
  • 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).
  • alkylcarbonyloxy (the alkyl moiety of such alkylcarbonyloxy is substituted by hydroxy, unsubstituted amino, two identical aryls) .
  • alkyl moieties may be substituted by both hydroxy and unsubstituted amino substitutions.
  • 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:),
  • X and Z are linked together and Y is hydrogen.
  • R 1 is monoalkylamino (the alkyl part of such monoalkylamino is substituted with alkoxy).
  • R2 represents the following substituent (a) or (b).
  • 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. ]
  • R3 represents hydroxy
  • X and Z are linked together and Y is hydrogen.
  • R 1 is monoalkylamino (the alkyl part of such monoalkylamino is substituted with alkoxy).
  • R2 and R3 are any of the following cases (a) to (c).
  • R2 and R3 are each a phosphoxy.
  • R2 and R3 are each an alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy is substituted by an alkylcarbonyloxy) .
  • X and Z are linked together and Y is hydrogen.
  • R 1 represents the following substituent (a) or (b).
  • alkoxy (the alkyl portion of such alkoxy is substituted with alkylcarbonyloxy substituted with hydroxy).
  • R2 and R3 each represent hydroxy.
  • X and Z are linked together and Y is hydrogen.
  • Rl and R2 are for the following cases (a) and (b).
  • R 1 is monoalkylamino (where the alkyl portion of such monoalkylamino is substituted with pyridyl or dialkylamino), and R 2 is hydroxy.
  • R 1 is ⁇ -amino (such ⁇ -amino is substituted by hydroxy), and R 2 is hydroxy or alkylcarbonyloxy.
  • R 3 represents alkoxy
  • X and Y are oxo together, and Z is hydrogen.
  • Rl represents the following substituent (a) or (b).
  • alkoxy (such alkoxy is substituted with alkylcarbonyloxy).
  • R2 and R3 are each hydroxy.
  • particularly preferred compounds include, for example, the following (1) to (35) .
  • 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.
  • R30 represents hydrogen or hydroxy.
  • the starting material 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
  • 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
  • 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
  • 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
  • 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.
  • R 2 is a substituent obtained by removing hydroxy from the definition of R 2
  • 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.
  • 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
  • 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 ”.
  • the Oreanan derivative [3] can be produced O Les Annan derivative [1 c] by reaction with a halide (4).
  • 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).
  • 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
  • halogenated hydrocarbon solvents such as chloroform, methylene chloride
  • hydrocarbon solvents such as benzene, toluene, and n-hexane, and mixtures thereof.
  • 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].
  • R2, R3, x, ⁇ , 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.
  • 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].
  • the oleanane derivative [1c] can be produced by reacting the oleanean derivative [6] with the alcohol [7].
  • 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. ]
  • 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].
  • an acid halide acid chloride, acid bromide, etc.
  • Alkyl ester methyl ester, ethyl ester, etc.
  • active ester p-nitrophenyl ester
  • 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.
  • 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.
  • 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].
  • the oleane derivative [1d] By reacting the oleane derivative [6] with the amine [8], the oleane derivative [1d] can be produced.
  • N (R71) (R72) represents monoalkyl ⁇ amino in the definition of said R 1, or cyclic Amino, or said N (R 81) (R 82 ).
  • 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].
  • O N-hydroxysuccinimide, 1-hydroxybenzoic acid
  • Lyazol 3-hydroxyl 4-oxo-1,3,4-dihydro 1,2,3-triazine, etc.
  • 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.
  • 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.
  • 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].
  • 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].
  • 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 ”.
  • the oleane derivative [1f] can be produced by reacting the oleane derivative [11a] with the halide [17].
  • 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].
  • R50 is COR6, and 13 ⁇ 46 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].
  • R R2, RlO, R11, x, ⁇ , 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].
  • 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.
  • a haloalkyl for example, 4-chloromethylbenzoyl chloride, (2-Bromoethyl) benzoyl chloride and 3- (3-bromopropyl) benzoyl chloride
  • 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.
  • a catalyst eg, platinum dioxide
  • 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.
  • 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.
  • 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].
  • 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.
  • the oleane derivative [ 1 i] can be produced.
  • 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].
  • an oleanan derivative of compound 4 shown in Examples described later can be produced.
  • 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].
  • 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.
  • an oleanan derivative [1 k] (the oleanan derivative of the formula [1], wherein R 3 is 0 S 03 H) can be produced.
  • 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].
  • the compound [lm] can be produced by reacting the oleane derivative [11b] with the halide [17].
  • 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].
  • R50 is c ⁇ 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].
  • 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].
  • 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.
  • an arylcarbonyl halide eg, 4-chloromethylbenzoyl chloride
  • 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.
  • 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.
  • 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]-.
  • a reactive derivative of a carboxylic acid corresponding to the carboxylic anhydride [20] for example, an active ester derivative ( ⁇ -nitrophenyl ester, ⁇ -chlorophenyl ester, etc.) or imidazolide is used.
  • an active ester derivative ⁇ -nitrophenyl ester, ⁇ -chlorophenyl ester, etc.
  • imidazolide imidazolide
  • R R3, R62, x, ⁇ , 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].
  • the oleane derivative [1r] can be produced by reacting the oleane derivative [11b] with a carbonylating agent and subsequently reacting with the amine [16].
  • R2 is Oreanan derivatives OS_ ⁇ 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.
  • 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.
  • the oleanan derivative [1t] can be produced by reacting the oleanane derivative [22] with the compound [19] in the presence of an acid catalyst.
  • 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].
  • 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.
  • X and Y are oxo together, and Z is a hydrogen compound (the oleane derivative [2a]), and (2) X is , Hydroxy, Y, ⁇ 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,
  • 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.
  • the epoxy compound [21] can be produced by reacting the oleane derivative [2d] with an oxidizing agent.
  • 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).
  • 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].
  • the oxo form [2a] can be produced by treating the epoxy form [21] with an acid.
  • 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.
  • 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
  • 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].
  • the oleanane derivatives [2b] and [2c] can be produced.
  • 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.
  • a metal hydride eg, borane, sodium borohydride, sodium cyanoborohydride, lithium borohydride, sodium aluminum hydride, lithium hydride.
  • 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].
  • 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.
  • the raw material 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.
  • a substituent for example, hydroxy, amino, carboxy, etc.
  • 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.
  • salts include alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts.
  • 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.
  • 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.
  • 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, ⁇ -toluenesulfonate, benzenesulfone Acids and salts of organic acids such as methanesulfonic acid can be mentioned.
  • hydrochloride of an oleanan derivative can be obtained by converting
  • 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.
  • 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.
  • 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.
  • the compound of the present invention 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.
  • a pharmaceutical composition it can be administered to animals, including humans.
  • the carrier one or more solid, semi-solid or liquid diluents, fillers and other auxiliaries for formulation are used.
  • 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.
  • 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.
  • 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.
  • the physical properties matched the values in Example 1- (1). Elemental analysis (as C 43 H 65 N0 7)
  • 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)
  • 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).
  • 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.
  • Example 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 )
  • Example 2 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
  • Example 3 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
  • a colorless amorphous product was obtained in the same manner as in Example 3, except that acetic acid was used instead of benzyloxyacetic acid.
  • 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
  • Example 10 Further elution (chloroform) was carried out by silica gel column chromatography in Example 10 to obtain a target substance as a colorless powder.
  • 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
  • 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
  • Example 16 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
  • 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
  • Example 24 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
  • a colorless amorphous target product was obtained in the same manner as in Example 24 except that morpholine was replaced with getylamine.
  • 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
  • Example 26 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
  • Example 26 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
  • 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.
  • 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
  • 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
  • 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
  • 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
  • N- (2-Methoxyxetyl) -1 23 (4 ⁇ )-[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.
  • 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.
  • 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.
  • 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.
  • 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.
  • 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 )
  • the desired product was obtained as a colorless powder by the same method as described above. Melting point 1 2 3 ° C
  • Example 49 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
  • 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.
  • Example 51 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.
  • Example 52 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.
  • Example 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.
  • Elemental analysis value (as C 33 H 54 NNa 0 7 S'7 / 2H 20 )
  • Example 62 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
  • 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
  • Example 3 and Example 41 (1) 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
  • step 1 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.
  • 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.
  • 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
  • Example 74 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
  • 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.
  • Example 80 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
  • 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
  • oleanolic acid 500 mg
  • WS CD 'HCl 420 mg
  • 1-Hydroxy-1H-Benzotriazo-1 (Hereinafter referred to as HOBt) (296 mg)
  • 2-methoxshetilamine 165 mg
  • 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.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
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  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
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Abstract

L'invention concerne des dérivés d'oléanane représentés par la formule générale (I) ci-après ou leurs sels pharmaceutiquement acceptables, ainsi qu'une composition médicamenteuse renfermant l'un quelconque des dérivés ci-dessus comme principe actif, formule dans laquelle Me représente méthyle; X, Y et Z sont l'une quelconque des combinaisons (1) à (4) ci-après, (1) X et Z combinés représentent une liaison et Y représente hydrogène. (2) X et Y combinés représentent oxo et Z représente hydrogène, (3) X représente hydroxy, et Y et Z représentent chacun hydrogène, (4) Y représente hydroxy, et X et Z représentent chacun hydrogène; R1 représente (1) hydroxy, (2) monoalkylamino éventuellement substitué, (3) amino cyclique éventuellement substitué, (4) alcoxy éventuellement substitué, etc.; R2 représente (1) hydroxy, (2) sulfoxy éventuellement substitué, (3) phosphoxy éventuellement substitué, (4) acyloxy éventuellement substitué, etc.; R3 représente (1) hydrogène, (2) hydroxy, (3) sulfoxy éventuellement substitué, (4) phosphoxy éventuellement substitué, (5) acyloxy éventuellement substitué, etc.. Lesdits composés sont efficaces pour le traitement de la néphrite.
PCT/JP1998/002779 1997-06-24 1998-06-19 Derives triterpeniques et composition medicamenteuse WO1998058946A1 (fr)

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007105015A3 (fr) * 2006-03-10 2008-03-27 York Pharma Plc DÉRIVES D'ACIDE 18ß-GLYCYRRHETINIQUE
CN102675406A (zh) * 2012-06-04 2012-09-19 福州大学 抗肿瘤活性的熊果酸含氮杂环类结构修饰物及其制备方法
CN106220706A (zh) * 2016-07-29 2016-12-14 烟台大学 一种α‑常春藤皂苷元衍生物及其制备方法和用途
CN109134585A (zh) * 2018-09-06 2019-01-04 昆明理工大学 一类三萜与直链氨基衍生物的偶联物及其应用

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56139416A (en) * 1980-04-01 1981-10-30 Minofuaagen Seiyaku Honpo:Goushi Antiulcer, anti-inflammatory and antiallergic agent, containing olean-12-ene-3beta, 3o-diol as main constituent, and having no side effect of glycylrrhetinic acid
JPH0399023A (ja) * 1989-09-11 1991-04-24 Minofuaagen Seiyaku Honpo:Goushi 経皮吸収促進剤及びこれを用いた経皮吸収型製剤
JPH08119866A (ja) * 1994-10-20 1996-05-14 Neos Co Ltd 抗腫瘍剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS56139416A (en) * 1980-04-01 1981-10-30 Minofuaagen Seiyaku Honpo:Goushi Antiulcer, anti-inflammatory and antiallergic agent, containing olean-12-ene-3beta, 3o-diol as main constituent, and having no side effect of glycylrrhetinic acid
JPH0399023A (ja) * 1989-09-11 1991-04-24 Minofuaagen Seiyaku Honpo:Goushi 経皮吸収促進剤及びこれを用いた経皮吸収型製剤
JPH08119866A (ja) * 1994-10-20 1996-05-14 Neos Co Ltd 抗腫瘍剤

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007105015A3 (fr) * 2006-03-10 2008-03-27 York Pharma Plc DÉRIVES D'ACIDE 18ß-GLYCYRRHETINIQUE
CN102675406A (zh) * 2012-06-04 2012-09-19 福州大学 抗肿瘤活性的熊果酸含氮杂环类结构修饰物及其制备方法
CN106220706A (zh) * 2016-07-29 2016-12-14 烟台大学 一种α‑常春藤皂苷元衍生物及其制备方法和用途
CN106220706B (zh) * 2016-07-29 2018-06-29 烟台大学 一种α-常春藤皂苷元衍生物及其制备方法和用途
CN109134585A (zh) * 2018-09-06 2019-01-04 昆明理工大学 一类三萜与直链氨基衍生物的偶联物及其应用
CN109134585B (zh) * 2018-09-06 2021-07-16 昆明理工大学 一类三萜与直链氨基衍生物的偶联物及其应用

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