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WO1999051623A1 - Depresseur servant a la production du tgf-beta - Google Patents

Depresseur servant a la production du tgf-beta Download PDF

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Publication number
WO1999051623A1
WO1999051623A1 PCT/JP1999/001667 JP9901667W WO9951623A1 WO 1999051623 A1 WO1999051623 A1 WO 1999051623A1 JP 9901667 W JP9901667 W JP 9901667W WO 9951623 A1 WO9951623 A1 WO 9951623A1
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Prior art keywords
substituted
hydroxy
alkyl
alkoxy
substituent
Prior art date
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Ceased
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PCT/JP1999/001667
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English (en)
Japanese (ja)
Inventor
Hiroto Yoshifusa
Jun Segawa
Masato Matsuoka
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Nippon Shinyaku Co Ltd
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Nippon Shinyaku Co Ltd
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Priority to AU30541/99A priority Critical patent/AU3054199A/en
Publication of WO1999051623A1 publication Critical patent/WO1999051623A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C07J53/00—Steroids in which the cyclopenta(a)hydrophenanthrene skeleton has been modified by condensation with a carbocyclic rings or by formation of an additional ring by means of a direct link between two ring carbon atoms, including carboxyclic rings fused to the cyclopenta(a)hydrophenanthrene skeleton are included in this class
    • 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

  • the present invention relates to a TGF- ⁇ (transforming growth factor-j3) production inhibitor comprising an oleanan derivative or a pharmaceutically acceptable salt thereof as an active ingredient.
  • TGF- ⁇ transforming growth factor-j3 production inhibitor
  • the TGF- / 3 production inhibitor is useful for the prevention or treatment of diseases characterized mainly by fibrotic proliferative, scarring, or sclerotic lesions involving TGF-] 3.
  • TGF-i3 is an important cytokine that regulates cell proliferation, differentiation, repair and regeneration after tissue injury.
  • TGF-] 3 promotes angiogenesis during repair of injured tissue, and also enhances the production and deposition of extracellular matrix (laminin Bl, fibronectin, collagen, tenascin, and proteodalican, etc.) .
  • TGF-] 3 The production and deposition of extracellular matrix by TGF-] 3 consists of the following three mechanisms. First, TGF-3 promotes extracellular matrix protein gene expression and increases extracellular matrix protein synthesis and secretion. Second, TGF- ⁇ inhibits the synthesis of proteases that degrade the synthesized extracellular matrix, and at the same time increases the synthesis of protease inhibitors. Third, TGF-3 adds integrin, a receptor for the extracellular matrix, and promotes the deposition of pericellular matrix.
  • An object of the present invention is to provide a novel TGF- production inhibitor.
  • the present inventors have sought for such a compound and have been conducting research. As a result, the present inventors have found that an oleanan derivative achieves the above object, and have completed the present invention.
  • the present invention relates to a compound represented by the following formula [1], wherein the oleanane derivative is any of the following (A), ( ⁇ ), or (C): A TGF-production inhibitor comprising a chemically acceptable salt (hereinafter, referred to as the compound of the present invention) as an active ingredient.
  • Me represents methyl
  • X and Z together represent a bond.
  • Y represents hydrogen.
  • R 1 represents O Rll or N RUR 12 .
  • R u and R 12 are the same or different and are (1) hydrogen, (2) alkyl which may have a substituent,) cycloalkyl which may have a substituent, (4) substituent (5) alkynyl optionally having a substituent, (6) aryl which may have a substituent, or (7) optionally having a substituent Represents an aromatic heterocyclic group.
  • Ri3 and R are the same or different and denote (1) hydrogen or (2) anolequinole which may be substituted with hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino.
  • R 2 and R 3 are the same or different and are (1) hydroxy, (2) optionally substituted alkoxy, (3) optionally substituted cycloalkyloxy, (4 ) Optionally substituted alkenyloxy, (5) optionally substituted alkynyloxy, (6) optionally substituted monoalkyl rubamoyloxy, (7) (8) alkoxycarbonyloxy optionally having a substituent, (9) alkylcarbonyloxy optionally having a substituent, or (9) alkylcarbonyloxy optionally having a substituent. 10) represents arylcarboxy which may have a substituent. Or R 2 and R 3 together represent carbonyl.
  • R 15 and R 16 are the same or different and represent (1) hydrogen or (2) alkyl optionally substituted with hydroxy, alkoxy, amino, monoalkylamino, or dialkylamino.
  • 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).
  • monoalkylamino (the alkyl moiety of the monoalkylamino is selected from the group consisting of hydroxy, alkoxy, anoreoxycarbonyl, cyclic amino, anolequinolecarbonylamino, and alkylcarbonyloxy) May be substituted by one substituted group.
  • cyclic amino such cyclic amino may be replaced by one substituent selected from the group consisting of hydroxy and alkyl optionally substituted by hydroxy
  • Alkoxy (The alkoxy may be substituted by one substituent selected from the group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, diamino, and alkylcarbonyloxy.
  • the alkylcarbonyloxy may be substituted with an alkylcarbonylamino or an arylalkyloxy in which the aryl moiety may be substituted with an alkoxy.
  • R 2 represents the following (1) to (1) Represents any of the substituents of 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 40 and R 41 are the same or different and each is hydrogen or alkyl (wherein such alkyl is one substituent selected from the group consisting of hydroxy, unsubstituted amino, monoalkylamino, and dialkylamino) Or R 40 and R 41, together with the adjacent N, represent N- (R 40 ) (R 41 ) a linear amino. Such a cyclic amino may be substituted with an alkyl or heterocyclic group.
  • R 42 and R 43 may be the same or different and are hydroxy, alkylthio, alkylsulfiel, alkylsulfonyl , Unsubstituted amino, carboxy, alkynolecarboninoleamino, alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyloxy is one substituent selected from the group consisting of hydroxy, and unsubstituted amino) Or alkoxy (the alkoxy may be substituted by 1 to 2 aryls, and the aryl may be substituted by the alkoxy.) . ]
  • heterocyclic group (the heterocyclic group may be substituted by one substituent selected from the group consisting of an alkyl optionally substituted by hydroxy, and a heterocyclic group);
  • ⁇ Circle around (1) 1 or 2 identical or different aminos optionally substituted by hydroxy, optionally substituted by alkyl.
  • R 2 and R 3 together represent the following formula:
  • R 21 and R 31 are the same or different and each represent hydrogen, alkyl, aryl, or a heterocyclic group; or R 21 and R SI together represent alkylene which may be substituted with alkyl.
  • X, Z are together a bond
  • Y is hydrogen
  • R 1 is hydroxy, monoalkylamino (the alkyl portion of such a monoalkylamino is a hydroxy, anoreoxy, Alkylcarboninoleoxy and anoreoxycarbonyl It may be substituted by one substituent selected from the group consisting of: ) Or alkoxy (such alkoxy may be substituted by one substituent selected from the group consisting of hydroxy, aryl, alkoxy, alkoxycarbonyl, and unsubstituted alkylcarbonyloxy)
  • R 2 is hydroxy or OC (-0) R 6
  • R 6 is the following (a ) Or (b>).
  • alkyl which may have one or both of the substituents R 42 and R 4S (such R 42 and R 43 may be the same or different and are hydroxy, unsubstituted amino, carboxy, anolequino Lecanolebonyloxy (the anorealkyl moiety of such anorealkylcarboninoleoxy may be substituted by hydroxy or unsubstituted amino), or unsubstituted alkoxy.
  • substituents R 42 and R 4S such R 42 and R 43 may be the same or different and are hydroxy, unsubstituted amino, carboxy, anolequino Lecanolebonyloxy (the anorealkyl moiety of such anorealkylcarboninoleoxy may be substituted by hydroxy or unsubstituted amino), or unsubstituted alkoxy.
  • X and Z together represent a bond.
  • Y represents hydrogen.
  • R 1 represents OR81 or N (R 81 ) (R 82 ).
  • R 81 and R 82 are the same or different and represent any of the following (1) to (7).
  • R 81 and R 82 may have are the following substituents (a) to (i) 1-3 identical or different substituents selected from the group consisting of:
  • aryl optionally substituted by one to three identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;
  • an aromatic heterocyclic group which may be substituted by 1 to 3 identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino.
  • R 83 and R 84 are the same or different
  • (2) represents an alkyl selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino, which may be substituted by one substituent.
  • R 2 represents any of the following (1) to (10).
  • dialkyl power rubamoyloxy optionally having a substituent
  • the substituents which the oxy, anorecoxy propylonyloxy, alkylcanoleboninoleoxy and the aryl propylonoxy may have may be 1 to 3 substituents selected from the group consisting of the following substituents (a) to (i): Are the same or different substituents.
  • aryl optionally substituted by one to three identical or different substituents, selected from the group consisting of halogen, alkyl, hydroxy, and unsubstituted amino;
  • R 85 and R 86 are the same or different
  • alkyl selected from the group consisting of hydroxy, alkoxy, unsubstituted amino, monoalkylamino, and dialkylamino, which may be substituted by one substituent.
  • R 3 represents hydrogen
  • alkyl in the present invention is a straight-chain or branched anoalkyl having 1 to 7 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, and Sobutinole, sec-butynole, tert-butynole, n-pentynole, isopentynole, n-hexynole, isohexyl, n-heptyl, and isoheptyl.
  • the alkylene J includes alkylene having 4 to 7 carbon atoms, for example, tetramethylene, pentamethylene, hexamethylene, and heptamethylene.
  • Cycloalkyl includes cyclic alkyl having 3 to 7 carbon atoms, for example, cyclopropynole, cyclobutynole, cyclopentynole, cyclohexynole, and cycloheptinol.
  • cycloalkyl moiety of “cycloalkyloxy” and “cycloalkylcarbonyloxy” examples include the above-mentioned cycloalkyl.
  • alkoxy includes linear or branched alkoxy having 1 to 7 carbon atoms, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec-butoxy, tert. -Butoxy, n-pentynoleoxy, isopentynoleoxy, n-hexyloxy, isohexyloxy, n-heptyloxy and isoheptyloxy.
  • alkoxycarbonyl examples include the aforementioned alkoxy.
  • alkenyl includes straight or branched ones having 2 to 7 carbon atoms, for example, vinylinole, 1-propeninole, isopropenyl, arinole, 1-buteninole, 3-buteninole, 1 4-penteninole, 1-hexeninole, 5-hexeninole, 1-heptenyl, 6-heptenyl.
  • alkenyl moiety of “alkenyloxy” includes the aforementioned alkenyl.
  • Alkynyl includes straight-chain or branched-chain ones having 2 to 7 carbon atoms, for example, ethininole, 1-f. Robininole, 2-propyninole, 1-butininole, 3-butininole, 1 1 Pentininole, 4-pentininole, 1-hexininole, 5-hexininole, 1-heptinole, 6-heptinyl.
  • alkynyl moiety of "alkynyloxy” includes the above-mentioned alkynyl.
  • Aryl includes those having 6 to 10 carbon atoms, for example, phenyl, 1-naphthyl and 2-naphthyl.
  • aryl part of "aryl alkyloxy J" and “arylcarbonyloxy” includes the above aryl.
  • “Acil” means “alkylcarbonyl” and “arylcarbonyl”.
  • the alkyl part of “alkylcarbonyl” represents the above-mentioned alkyl.
  • the aryl part of “aryl carponyl” represents the above aryl.
  • Examples of “acyl” include acetyl, propionyl, butyryl, isobutyryl, benzoyl, 1-naphthyl, and 2-naphthyl.
  • heterocyclic group examples include a saturated or unsaturated 5- to 7-membered ring group containing 1 to 4 identical or different nitrogen atoms, oxygen atoms or sulfur atoms as ring-constituting atoms.
  • examples include pyrrolidine-111, pyrrolidine-1-yl, pyrrolidine-3-yl, furan-2-yl, furan-3-inore, and thiophen-2-inole.
  • the “aromatic heterocyclic group” means a 5- to 6-membered aromatic ring group having 1 to 4 identical or different hetero atoms, selected from a nitrogen atom, an oxygen atom and a sulfur atom, and includes, for example, 1-ru, 1-pyro, 1-pyro, 2-ino-, 3-pyro-no-nore, Fran 2-yl, Fran-3-1-yl, Ciofen 2-yl, Thiophen-3-1-ino, Oxazonole 2 —Innore, Thiazonore 2 —Innore, 1 H—1,2,4—Triazonole 1—Ill, 1 H—Te Trazonore 1-5—Ill, Pyridin 1 2—Innore, Pi Lysine-1-pyr, pyridin-4-yl, pyrimidine-2-yl, pyrimidine-1-yl, pyrazine-1-yl, 1,3,5-triazine-1-yl No.
  • Cyclic amino may include, in addition to the nitrogen atom forming a bond, one or two nitrogen atoms, oxygen atoms or sulfur atoms, the same or different, as ring-constituting atoms And a saturated or unsaturated 5- to 7-membered ring group.
  • Examples include pyrrolidine-1-1-inole, piperidine-1-1-inole, piperazine-1-1-inole, monoleforin-4-1-inole, thiomonoleforin-4-1-inole, thiomonoleforin-1-1, 1-dioxydo-41-yl, Imidazole-1-yl, thiazolidine-3-yl, homopyrazine-11-yl and hexamethyleneimine-1-yl.
  • Halogen includes, for example, fluorine, chlorine, bromine, and iodine.
  • Preferred examples of the compound of the present invention include the following compounds (1) to (3).
  • X and Z are linked together and Y is hydrogen.
  • R 1 is a monoalkylamino (the alkyl portion of such a monoalkylamino is substituted with alkoxy).
  • R 2 represents any of the following substituents (a) to (f).
  • Alkyl alkenyloxy (the alkyl part of the alkyl alkenyloxy is hydroxy, unsubstituted amino, alkoxy substituted by 1 to 2 identical aryls, alkylcarbonyl optionally substituted by unsubstituted aminos) It may be substituted by one or two same or different substituents selected from the group consisting of oxy, and alkylcarbonylamino. ]
  • arylcarbonyloxy substituted with alkyl (the alkyl moiety of arylcarbonyloxy substituted with such alkyl is amino substituted with one or two hydroxyalkyl, and cyclic amino) Is substituted by one substituent selected from the group consisting of:), (e) a cycloalkylcarbonyloxy substituted with an unsubstituted aminoalkyl,
  • R 3 represents any of the following substituents (a) to (g).
  • anolyalkylcarbonyloxy (the alkyl moiety of such an alkylcarbonyloxy is substituted by hydroxy, unsubstituted amino, alkoxy substituted by one or two identical aryls, unsubstituted amino) May be substituted by one or two same or different substituents selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. ]
  • 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 taken together are isopropylidenedioxy.
  • X and Z are linked together and Y is hydrogen.
  • R 1 represents any of the following substituents (a) to (c).
  • alkoxy (the alkyl part of such alkoxy is substituted by alkylcarbonyloxy substituted by hydroxy).
  • R2, R 3 are the same or different, human Dorokishi, alkoxy, or alkyl Cal Bonyloxy.
  • X and Y are together oxo, 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
  • R3 represents any of the following substituents (a) to (f).
  • anorealkyl carboxy / reoxy (the alkyl moiety of such anolequinolecanolevonyloxy is substituted by hydroxy, unsubstituted amino, alkoxy substituted by two identical aryls, unsubstituted amino) May be substituted with one substituent selected from the group consisting of alkylcarbonyloxy and alkylcarbonylamino. Alternatively, such alkyl moieties may be substituted by both hydroxy and unsubstituted amino substitutions. ]
  • arylcarbonyl substituted with alkyl (the aryloxy moiety of arylcanolebonyloxy substituted with alkyl is; It is substituted by one substituent selected from the group consisting of amino substituted by alkyl, and cyclic amino. ),
  • X and Z are together a bond, and Y is hydrogen.
  • R l is monoalkylamino (the alkyl portion of such monoalkylamino is substituted with alkoxy).
  • R 2 represents the following substituent (a) or (b).
  • alkylcarbonyloxy (the alkyl moiety of the alkylcarbonyl group is one substituent selected from the group consisting of hydroxy, unsubstituted amino, and alkylcarbonyloxy substituted with unsubstituted amino) Has been replaced by Or, such an alkyl moiety is substituted by both substitution of hydroxy and unsubstituted amino. ]
  • R 3 represents hydroxy
  • X and Z are together a bond, and Y is hydrogen.
  • R 1 is monoalkylamino (the alkyl portion of such monoalkylamino is substituted with alkoxy).
  • R 2 and R 3 are for the following cases (a) to ().
  • R2 and R3 are each a phosphoxy.
  • R 2 and R 3 are each an alkylcarbonyloxy, wherein the alkyl moiety of the alkylcarbonyloxy is substituted by an alkylcarbonyloxy; ].
  • X and Z are together a bond, 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).
  • R 2 and R 3 each represent hydroxy.
  • X and Z are together a bond, and Y is hydrogen.
  • Rl, R 2 is the case of the following (a) or (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 a cyclic amino (such amino is substituted by hydroxy), and R 2 is hydroxy or alkylcarbonyloxy.
  • R 3 represents alkoxy
  • X and Y together are oxo, 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.
  • particularly preferred compounds include, for example, the following compounds (1) to (38).
  • compounds having an acidic group can be used as a medicament as a free acid, but can be converted into pharmaceutically acceptable salts by a known method.
  • a salt include alkali metal salts such as sodium salt and potassium salt, and alkaline earth metal salts such as calcium salt.
  • a mono-alkali metal salt can be obtained by adding one equivalent of sodium hydroxide, potassium hydroxide, or the like to an oleanan derivative, preferably in an alcohol solvent.
  • the dialkali metal salt of an oleanan derivative having a phosphoxy group is It can be obtained by adding 2 equivalents of sodium hydroxide or hydroxylated water to the body, preferably in an alcoholic solvent.
  • the alkaline earth metal salt of an oleanean derivative can be obtained by dissolving the alkaline earth metal salt produced by the above method in water, methanol, ethanol, or a mixed solvent thereof, and adding one equivalent of calcium chloride or the like. Can be.
  • compounds having a basic group can be used as a free base as a medicament, but can be pharmaceutically acceptable by known methods. It can be used in the form of a salt.
  • salts include salts of mineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, and formic acid, acetic acid, quinic acid, tartaric acid, maleic acid, succinic acid, fumaric acid, p-toluenesulfonic acid, and benzenesulfonic acid.
  • Acids and salts of organic acids such as methanesulfonic acid.
  • a hydrochloride of an oleanan derivative can be obtained by dissolving the oleanan derivative in an alcohol solution of hydrogen chloride or a methylene chloride solution.
  • the compound of the present invention has an excellent TGF-) 3 production inhibitory activity as shown in the test examples described later, and has low toxicity, so that diseases involving TGF-] 3, such as hepatic fibrosis, Biliary fibrosis, cirrhosis, pulmonary fibrosis, adult respiratory distress syndrome, myelofibrosis, scleroderma, systemic sclerosis, renal sclerosis, renal auditory fibrosis, diabetic nephropathy, intraocular proliferative Disease, proliferative vitreoretinopathy, cataract, heart fibrosis after infarction, restenosis after angioplasty, arteriosclerosis, connective tissue hyperplasia after wounding such as surgical incision, trauma, burn (abdominal adhesions) , Scars, keloids), fibrosis after radiation therapy, chronic spleenitis, fibrotic tumors, nasal polyps, periodontal ulcerative colitis, and sclerosing Hodgkin's disease
  • the compound of the present invention is used as it is or in a pharmaceutically acceptable nontoxic and inert carrier, for example, 0.1 to 99.5%, preferably 0.5 to 90%. % Can be administered to mammals, including humans.
  • a pharmaceutically acceptable nontoxic and inert carrier for example, 0.1 to 99.5%, preferably 0.5 to 90%. %
  • 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 of the present invention can be administered by intravenous administration, oral administration, It can be administered rectally. Needless to say, it is administered in a dosage form suitable for these administration methods. Oral administration is particularly preferred.
  • Oral administration is performed in solid or liquid dosage units, such as powders, powders, tablets, dragees, capsules, granules, suspensions, solutions, syrups, drops, sublingual tablets, and other forms be able to.
  • Powders are prepared by comminuting the active substance to an appropriate degree. Powders are prepared by comminuting the active substance to a suitable fineness and then mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate such as starch, mannitol, and the like. If necessary, flavoring agents, preservatives, dispersing agents, coloring agents, flavors and the like may be added. Capsules are manufactured by first filling powdered powders, powders, or granules as described in the section on powders as described above into a capsule shell such as a gelatin capsule. Is done.
  • Lubricants and glidants such as colloidal silica, talc, magnesium stearate, calcium stearate, and solid polyethylene glycol are mixed into a powder and then filled Operations can also be performed.
  • Disintegrators and solubilizers such as carboxymethyl cellulose, carboxymethyl cellulose canolesum, low-substituted hydroxypropyl cenorellose, cros-canolemelose sodium, canoleboximetinorestar sodium, calcium carbonate, sodium carbonate If added, the effectiveness of the medicine when the capsule is taken can be improved.
  • the fine powder of this product can be suspended and dispersed in vegetable oil, polyethylene glycol, glycerin, and a surfactant, and wrapped in a gelatin sheet to form a soft capsule.
  • Tablets are made by adding an excipient, forming a powder mixture, granulating or slugging, then adding a disintegrant or lubricant and compressing.
  • the powder mixture is prepared by mixing the appropriately powdered material with the diluents and bases described above and, if necessary, a binder (e.g., sodium canolepoxymethylcellulose, methylcellulose, hydroxypropynolemethinolecellulose, Gelatin, polyvinylinopyrrolidone, polyvinyl alcohol, etc.), dissolution retarders (eg, paraffin), resorbents (eg, quaternary salts) and adsorbents (eg, bentonite, kaolin, dicalcium phosphate) Etc.).
  • a binder e.g., sodium canolepoxymethylcellulose, methylcellulose, hydroxypropynolemethinolecellulose, Gelatin, polyvinylinopyrrolidone, polyvinyl alcohol, etc.
  • dissolution retarders eg, paraffin
  • resorbents eg, quaternary salts
  • adsorbents eg, bentonit
  • the powder mixture is first prepared with a binder such as syrup, It can be moistened with powder paste, gum arabic, cellulose solution or polymer solution, mixed with stirring, dried and pulverized to obtain granules. Instead of granulating the powder in this way, it is also possible to first apply a tableting machine and then crush the imperfect slag obtained into granules.
  • a binder such as syrup
  • the granules thus produced can be prevented from adhering to one another by adding stearic acid, stearates, talc, mineral oil and the like as lubricants.
  • the lubricated mixture is then tableted.
  • the uncoated tablets thus manufactured can be coated with a film-coated sugar coating.
  • the drug may be directly tableted after mixing with a fluid inert carrier without going through the granulating and slagging steps as described above.
  • Transparent or translucent protective coatings consisting of a sealed shellac coating, coatings of sugar or polymeric materials, and polish coatings made of wax may also be used.
  • compositions such as solutions, syrups, elixirs and the like can also be made in dosage unit form so that a given quantity contains a fixed amount of the drug.
  • Syrups are prepared by dissolving the compound in a suitable aqueous flavor solution
  • elixirs are prepared through the use of a non-toxic alcoholic carrier.
  • Suspensions are formulated by dispersing the compound in a non-toxic carrier.
  • Solubilizers and emulsifiers eg, ethoxylated isostearyl alcohols, polyoxetylene sorbitol esters
  • preservatives eg, palmit oil, saccharin
  • flavor enhancers eg, palmit oil, saccharin
  • dosage unit formulations for oral administration may be encapsulated in a mic mouth.
  • the formulations can also provide for prolonged action or sustained release by coating or embedding in polymeric waxes and the like.
  • Administration into tissues can be carried out by using liquid dosage unit forms for subcutaneous, intramuscular or intravenous injection, for example, solutions and suspensions. These are accomplished by suspending or dissolving an aliquot of the compound in a non-toxic liquid vehicle suitable for injection, such as an aqueous or oily vehicle, and then sterilizing the suspension or solution. Manufactured. Non-toxic salts or salt solutions may be added to make the injection solution isotonic. Further, stabilizers, preservatives, and emulsifiers can be used in combination.
  • the compounds are soluble or insoluble in low-melting water, such as polyethylene glycol, cocoa butter, semi-synthetic fats and oils (such as Witebsol®), higher esters (such as myristyl palmitate). And suppositories produced by dissolving or suspending in a mixture thereof.
  • the dose of the TGF-3 production inhibitor should be set in consideration of the nature and severity of the disease, the patient's condition such as age and weight, and the route of administration.
  • the amount of the active ingredient of the compound of the present invention is generally in the range of 0.1 to 100 mg / day, preferably 1 to 500 mgZ per day.
  • lower doses may be sufficient, and conversely, higher doses may be required. It can also be administered in 12 to 3 divided doses.
  • Compound 1 represents N- (2-methoxethyl) -13 ⁇ , 23 (4 ⁇ ) -dihydroxylorane-12-en-28-amide, and Compound 2 Stands for ⁇ — (2-methoxhetyl) -1 33-hydroxy-1 23 (4 ⁇ ) 1-hydroxyacetoxylean 12-en-28-amide, and compound 3 has 3 / 3, 2 3 (4 ⁇ ) Represents dihydroxolean 1 12 — 1 1 2 8 — eutectic.
  • Fibroblasts were isolated from rat lungs and subcultured to obtain cultured fibroblasts.
  • the fibroblasts were seeded on a plate, cultured for 36 hours in the presence of serum, and then cultured for 3 hours under bloodless conditions to make the cells quiescent.
  • the test drug was added thereto, and the cells were cultured in the presence of blood for 5 days, and the culture supernatant was collected.
  • the amount of TGF-J3 in the culture was measured using an enzyme immunoassay ( ⁇ method). .
  • the protein content of the cells was measured using a Bio-Rad Protein Assay kit (Bradford,., Anal. Biochem., 72, 248, 1976) according to the method of Bradford.
  • the TGF-production inhibition rate and the protein protein inhibition rate by the test drug were as follows. It was calculated by a mathematical formula.
  • P1 represents the protein amount (g) of the cells in the control group.
  • T1 represents the amount (pg) of TGF—] 3 in the control group.
  • P2 represents the protein amount g> of the cells in the test drug group.
  • T2 represents TGF- / 3 amount (pg) in the test drug group.
  • Table 1 shows the results. Table 1 Inhibitory effect of TGF- ⁇ production in cultured rat lung fibroblasts Test drug addition concentration TGF- ⁇ production inhibition rate Inhibition rate of cellular protein
  • Compound 2 1.0 40.2 1.3 It is apparent that the compound of the present invention has an inhibitory effect on TGF-0 production in cultured rat fibroblasts. In addition, since the protein content of the cells is not significantly reduced, it is understood that the TGF- ⁇ production inhibitory effect of the compound of the present invention is not based on cell growth inhibition or cell damage by the test drug.
  • test drug A suspension of the test drug was orally administered to mice at a dose of 2 g / kg, and general symptoms were observed up to one week later.
  • Compound 1, compound 2 and compound 3 were administered as test drugs, respectively.
  • the mixed powder in this ratio is tableted and made into an internal tablet.
  • the mixed powder in this ratio is tableted and made into an internal tablet.
  • the mixed powder in this ratio is tableted and made into an internal tablet.
  • the compound of the present invention has an excellent TGF-) 3 production inhibitory activity and is a safe compound with low toxicity. Therefore, a pharmaceutical composition containing the compound of the present invention as an active ingredient is Is useful as a TGF-production inhibitor for mammals, including mammals.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique incluant, comme principe actif, un dérivé d'oléanane de la formule (1) dans laquelle Me est méthyle; et relativement à X, Y et Z, 1) X et Z forment ensemble une liaison et Y est hydrogène, ou 2) X et Y forment un ensemble oxo et Z est hydrogène, ou 3) X est hydroxy et Y et Z sont l'un et l'autre hydrogène, ou 4) Y est hydroxy et X et Z sont l'un et l'autre hydrogène; R1 est 1) hydroxy, 2) un monoalkylamino substitué ou insubstitué, 3) un amino cyclique substitué ou insubstitué, 4) un alcoxy substitué ou insubstitué, etc.; R2 est 1) hydroxy, 2) un sulfoxy substitué ou insubstitué, 3) un phosphoxy substitué ou insubstitué, 4) un acyloxy substitué ou insubstitué, etc.; R3 est 1) hydrogène, 2) hydroxy, 3) un sulfoxy substitué ou insubstitué, 4) un phosphoxy substitué ou insubstitué, 5) un acyloxy substitué ou insubstitué, etc., ou un sel pharmaceutiquement acceptable desdits composés. Cette composition pharmaceutique s'utilise comme dépresseur et sert à la production du TGF-bêta
PCT/JP1999/001667 1998-04-02 1999-03-31 Depresseur servant a la production du tgf-beta Ceased WO1999051623A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU30541/99A AU3054199A (en) 1998-04-02 1999-03-31 Depressant for production of tgf-beta

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP10/89745 1998-04-02
JP8974598 1998-04-02

Publications (1)

Publication Number Publication Date
WO1999051623A1 true WO1999051623A1 (fr) 1999-10-14

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Family Applications (1)

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PCT/JP1999/001667 Ceased WO1999051623A1 (fr) 1998-04-02 1999-03-31 Depresseur servant a la production du tgf-beta

Country Status (2)

Country Link
AU (1) AU3054199A (fr)
WO (1) WO1999051623A1 (fr)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265606A (zh) * 2013-05-31 2013-08-28 徐江平 一种常春藤皂苷元酰胺衍生物及其制备方法及其应用
CN105622704A (zh) * 2014-10-29 2016-06-01 思路迪（北京）医药科技有限公司 抗肿瘤药物x-toa的制备方法及其应用
CN113087758A (zh) * 2021-04-07 2021-07-09 西藏甘露藏药股份有限公司 源自蔓菁的碳环化合物的衍生物及其应用
CN117343122A (zh) * 2023-09-08 2024-01-05 安徽医科大学 一种治疗炎症免疫性疾病的齐墩果酸酰胺衍生物、其制备方法及其用途

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345650A (ja) * 1993-06-14 1994-12-20 Suntory Ltd ヘデラゲニン化合物を有効成分とする骨疾患の予防及び治療剤
JPH07316188A (ja) * 1994-05-23 1995-12-05 Shionogi & Co Ltd オレアノール酸誘導体の製造方法
JPH0859482A (ja) * 1994-08-26 1996-03-05 Res Inst For Prod Dev アルコール吸収抑制剤

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH06345650A (ja) * 1993-06-14 1994-12-20 Suntory Ltd ヘデラゲニン化合物を有効成分とする骨疾患の予防及び治療剤
JPH07316188A (ja) * 1994-05-23 1995-12-05 Shionogi & Co Ltd オレアノール酸誘導体の製造方法
JPH0859482A (ja) * 1994-08-26 1996-03-05 Res Inst For Prod Dev アルコール吸収抑制剤

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103265606A (zh) * 2013-05-31 2013-08-28 徐江平 一种常春藤皂苷元酰胺衍生物及其制备方法及其应用
CN103265606B (zh) * 2013-05-31 2015-04-01 徐江平 一种常春藤皂苷元酰胺衍生物及其制备方法及其应用
CN105622704A (zh) * 2014-10-29 2016-06-01 思路迪（北京）医药科技有限公司 抗肿瘤药物x-toa的制备方法及其应用
CN105622704B (zh) * 2014-10-29 2018-09-28 思路迪（北京）医药科技有限公司 抗肿瘤药物x-toa的制备方法及其应用
CN113087758A (zh) * 2021-04-07 2021-07-09 西藏甘露藏药股份有限公司 源自蔓菁的碳环化合物的衍生物及其应用
CN113087758B (zh) * 2021-04-07 2022-05-24 西藏甘露藏药股份有限公司 源自蔓菁的碳环化合物的衍生物及其应用
CN117343122A (zh) * 2023-09-08 2024-01-05 安徽医科大学 一种治疗炎症免疫性疾病的齐墩果酸酰胺衍生物、其制备方法及其用途

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