US2004097436A1PendingUtilityA1
Triterpenes having antibacterial activity
Est. expirySep 29, 2020(expired)· nominal 20-yr term from priority
A61K 31/56A61K 31/695Y02A50/30A61K 31/704C07J 63/008
58
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Claims
Abstract
Methods of treating a bacterial infection and of killing or inhibiting bacteria are disclosed. The methods use derivatives of triterpenes that are abundant in birch bark and other plants. The triterpenes include betulin, allobetulin, and lupeol.
Claims
exact text as granted — not AI-modifiedWhat is claimed is:
1 . A therapeutic method of treating a mammal afflicted with a bacterial infection comprising administering to the mammal an effective anti-bacterial amount of a triterpene of formula (I):
wherein
R 1 is hydrogen or hydroxy;
R 2 is a direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C 6 -C 10 )aryl, or (C 1 -C 6 )alkyl;
R 3 is hydrogen, hydroxy, (C 1 -C 6 )alkyl, O═P(OH) 2 , O═P(OH) 2 OP(O)(OH)—, (C 1 -C 5 )alkanoyl, Si(R) 3 wherein each R is H, phenyl or (C 1 -C 6 )alkyl, C(O)N(R) 2 , benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C 1 -C 4 )alkoxy](C 1 -C 4 )alkyl, or a glycoside;
R 4 is hydrogen, hydroxy, (C 1 -C 6 )alkyl, O═P(OH) 2 , O═P(OH) 2 OP(O)(OH)—, (C 1 -C 5 )alkanoyl, Si(R) 3 wherein each R is H, phenyl or (C 1 -C 6 )alkyl, C(O)N(R) 2 , benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C 1 -C 4 )alkoxy](C 1 -C 4 )alkyl, a glycoside, or amino; or R 4 and R 5 together are oxo or (═NOH); and
R 5 is direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C 6 -C 10 )aryl, or (C 1 -C 6 )alkyl; or R 4 and R 5 together are oxo or (═NOH);
wherein any alkyl can optionally be substituted with one or more halo, hydroxy, (C 6 -C 10 )aryl, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl or polyethyleneimine; —OP(═O)(OH) 2 ; or C(═O)OR 9 , wherein R 9 is hydrogen, (C 1 -C 6 )alkyl, or polyethyleneimine;
each of the bonds represented by—is independently absent or is present;
wherein any alkyl is optionally interrupted on carbon with one or more oxy, thio, sulfinyl, sulfonyl, polyethyleneimine, or poly(ethylene glycol);
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl or polyethyleneimine; or C(═O)OR 9 , wherein R 9 is hydrogen, (C 1 -C 6 )alkyl, or polyethyleneimine;
or a pharmaceutically acceptable salt thereof.
2 . The method of claim 1 wherein R 4 is not amino; R 4 and R 5 are not together (═NOH); and alkyl is not substituted with —OP(═O)(OH) 2 .
3 . The method of claim 1 wherein the bond between carbons 1 and 2 is a single bond.
4 . The method of claim 1 wherein the bond between carbons 1 and 2 is a double bond.
5 . The method of claim 1 wherein R 1 is hydrogen.
6 . The method of claim 1 wherein R 1 is hydroxy.
7 . The method of claim 1 wherein R 2 is a direct bond.
8 . The method of claim 7 wherein R 3 is (C 1 -C 6 )alkyl; wherein
any alkyl can optionally be substituted with one or more oxo, carboxy, amino, (C 6 -C 10 )aryl, or —OP(═O)(OH) 2 ,;
any alkyl is optionally interrupted on carbon with one or more oxy or thio;
any alkyl is optionally partially unsaturated; and
any aryl can optionally be substituted with one or more hydroxy or carboxy.
9 . The method of claim 8 wherein R 3 is 3-carboxypropenoyloxymethyl, aminoacetoxymethyl, (carboxymethoxy)acetoxymethyl, 4-carboxybutanoyloxymethyl, 2-carboxybenzoyloxymethyl, butanoyloxymethyl, or
—CH 2 OC(═O)OP(═O)(OH) 2 .
10 . The method of claim I wherein R 4 is (C 1 -C 6 )alkyl; wherein
any alkyl can optionally be substituted with one or more oxo, carboxy, amino, (C 6 -C 10 )aryl, or —OP(═O)(OH) 2 , (C 6 -C 10 )aryl; any alkyl is optionally interrupted on carbon with one or more oxy or thio; any alkyl is optionally partially unsaturated; and any aryl can optionally be substituted with one or more hydroxy or carboxy.
11 . The method of claim 1 wherein R 4 is 2-carboxybenzoyl, 2-amino-3-methylbutanoyl, 3-carboxypropenoyl, aminoacetyl, 4-carboxybutanoyl, (carboxymethoxy)acetyl, 3-(3,4-dihydroxyphenyl)propenoyl, carboxymethylenethioacetyl, 3-carboxy-3-methylbutanoyl, amino, —P(═O)(OH) 2 , oxo, or (═NOH).
12 . The method of claim 1 wherein R 5 is oxy or a direct bond.
13 . The method of claim 1 wherein
R 1 is hydrogen or hydroxy;
R 2 is a direct bond;
R 3 is (C 1 -C 5 )alkoxymethyl or hydroxymethyl;
R 4 is hydrogen, phosphono, sulfo, or (C 1 -C 6 )alkyl, and R 5 is oxy; or
R 4 is amino and R 5 is a direct bond; or
R 4 and R 5 together are oxo or (═NOH);
wherein any alkyl, or alkyl segment of an R group, is optionally interrupted on carbon with one or more oxy, thio, or imido;
wherein any alkyl, or alkyl segment of an R group, can optionally be substituted with one or more oxo, carboxy, amino, —OP(═O)(OH) 2 , or phenyl;
wherein phenyl can optionally be substituted with one or more hydroxy or carboxy.
14 . The method of claim 1 wherein
R 1 is hydrogen or hydroxy;
R 2 is a direct bond;
R 3 is 3-carboxypropenoyloxymethyl, aminoacetoxymethyl, (carboxmethox)acetoxymethyl, 4-carboxybutanoyloxymethyl, 2-carboxybenzoyloxymethyl, butanoyloxymethyl, or
—CH 2 OC(═O)OP(═O)(OH) 2 ;
R 4 is 2-carboxybenzoyl, 2-amino-3-methylbutanoyl, 3-carboxypropenoyl, aminoacetyl, 4-carboxybutanoyl, (carboxymethoxy)acetyl, 3-(3,4-dihydroxyphenyl)propenoyl, carboxymethylenethioacetyl, 3-carboxy-3-methylbutanoyl, amino, —P(═O)(OH) 2 , oxo, or (═NOH); and
R 5 is oxy or a direct bond.
15 . The method of claim 1 wherein the triterpene is betulin; betulin-3,28-diglycine; betulin-28-glycerol oxalate; betulin-28-glycine; betulin-28-oxalate; betulin arabinose galactan; betulin-3,28didiglycolate; betulin-3,28-diglycine; betulin-3-maleate; betulin-3,28-di-(L-glutamic acid γ-benzylester) ester; betulin-3,28-di-L-alanine; betulin-3,28-di-L-proline; betulin-3,28-dioxalate; betulin-1-ene-2-ol; betulin-3,28-diphenylalanine; betulin-3-28-dioxalate-polyethylene amine; betulin-3,38-diphosphate; betulin-3-caffeate; betulin-3,28-(3′,3′-dimethyl) glutarate; betulin-28-diglycolate; betulin-28-glutarate; betulin-28-maleate; betulin-28-phthalate; betulin-3,28-di(3′,3′-dimethyl)glutarate; betulin-3,28-didiglycolate; betulin-3,28-di(thiodiglycolate); betulin-3,28-diglutarate; betulin-3,28-dimaleate; betulin-3,28-diglycolate; betulin-3,28-diphthalate; betulin-3,28-di-L-phenylalanine; betulin-3,28—di-L-valine; betulin-28-succinate; betulin-3,28-disuccinate; betulin-3,28-di-(polyethylene glycol)-COOH (Mw=1448); betulin-3,28-di-(polyethylene glycol)-COOH (Mw=906 crude); betulin-3,28-di-(polyethylene glycol)-COOH (Mw=906 pure); betulinic acid; betulon-1-ene-2-ol; betulin-3,28-(dipoly(ethylene glycol)bis (carboxymethylester); allobetulin-3,28-(dipoly(ethylene glycol)bis (carboxymethyl allobetulin ester); hederin hydrate; lupeol; lupeol-3-glutarate; lupeol-3-succinate; lupeol-3-thiodiglycolate; lupeol-3-phthalate; oleanolic acid; ursolic acid; or uvaol.
16 . The method of claim 1 wherein the triterpene is betulin; betulin-28-glycerol oxalate; betulin-28-oxalate; betulin arabinose galactan; betulin-3,28-didiglycolate; betulin-3,28-diglycine; betulin-3,28-di-(L-glutamic acid γ-benzylester) ester; betulin3,28-di-L-proline ester; betulin-3,28-dioxalate; betulin-1-ene-2-ol; betulin-3,28-dioxalate-polyethylene amine; betulin-3,28-diphosphate; betulin-3-caffeate; betulin-28-diglycolate; betulin-28-glutarate; betulin-28-maleate; betulin-28-phthalate; betulin-3,28-dithiodiglycolate; betulin-3,28-diglutarate; betulin-3,28-dimaleate; betulin-3,28-diglycolate; betulin-3,28-diphthalate; betulin-3,28-di-L-phenylalanine; betulin-di-L-valine; betulin-28-succinate; betulin-3,28-disuccinate; betulin-3,28-di-(polyethylene glycol)-COOH (Mw=906 pure); betulinic acid; betulon-1-ene-2-ol; betulin-3,28-(dipoly(ethylene glycol)bis (carboxymethylester); hederin hydrate; lupeol-3-glutarate; lupeol-3-succinate; lupeol-3-thiodiglycolate; lupeol-3-phthalate; oleanolic acid; uvaol.
17 . The method of claim 1 wherein the triterpene is betulin-3-caffeate; betulin-28-diglycolate; betulin-3,28-diglutarate; betulin-3,28-diglycine; betulin-3,28-didiglycolate; betulin-3,28-dimaleate; betulin-3,28-diphosphate; betulin-3,28-diphthalate; betulin-3,28-di-L-valine; lupeol; lupeol-3-amine; lupeol-3-(3′,3′-dimethyl)succinate; lupeol-3-maleate; lupeol-3-phosphate; lupeol-3-thiodiglycolate; lupenone; lupenon-1,2-ene-2-ol; lupenon-3-oxime.
18 . The method of claim 1 wherein the bacterial infection is caused by Escherichia coli, Staphylococcus sp., Enterococcus faecalis, or a combination thereof.
19 . The method of claim 18 wherein the bacterial infection is caused by Staphylococcus aureus.
20 . A therapeutic method of treating a mammal afflicted with a bacterial infection comprising administering to the mammal an effective anti-bacterial amount of a triterpene of formula (II):
wherein
one of R 1 and R 2 is —O—Y and the other is hydrogen or (C 1 -C 6 )alkyl optionally substituted by hydroxy, (C 1 -C 6 )alkoxy, halo, halo(C 1 -C 6 )alkoxy or NR j R k wherein R j and R k are independently H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkonyl; or R 1 and R 2 together are oxo (═O);
R 3 is hydrogen, halo, carboxy, mercapto, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or —O—Y;
R 4 and R 5 are each independently hydrogen, (C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl;
R 6 is hydrogen or is absent when the adjacent—is a bond;
R 7 is hydrogen or (C 1 -C 6 )alkyl;
R 8 is hydrogen, (C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl and R 11 is hydrogen, (C 1 -C 6 )alkyl, carboxy, or hydroxy(C 1 -C 6 )alkyl; or R 8 and R 11 together are —O—C(═X)—;
R 9 and R 10 , are each independently hydrogen or (C 1 -C 6 )alkyl;
each of the bonds represented by—is independently absent or is present;
X is two hydrogens, oxo (═O) or thioxo (═S);
each Y is independently H, aryl, P(O)(Cl) 2 , (C 3 -C 8 )cycloalkyl, adamantyl, —SO 2 R a O═P(R b ) 2 , O═P(R c ) 2 OP(O)(R d )—, Si(R e ) 3 , tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and —N(R f )—; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(R g )(R h ), (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
R a is (C 1 -C 6 )alkyl or aryl;
R b , R c , and R d are each independently hydroxy, (C 1 -C 6 )alkoxy, hydroxy(C 2 -C 6 )alkoxy, adamantyloxy, adamantyl(C 1 -C 6 )alkoxy, norbornyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C 1 -C 6 )alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C 3 -C 8 )cycloalkyloxy, NR x R y , or aryloxy;
R e is H, aryl or (C 1 -C 6 )alkyl;
R f is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, phenyl or benzyl;
R g and R h are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, adamantyl, adamantyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, aminosulfonyl, (C 1 -C 6 )alkanoyl, aryl and benzyl; or R b and R c together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
R x and R y are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, aryl or benzyl;
wherein each aryl of Y, R a —R d , R g —R h , R x , and R y may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NR i R j , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, trifluoromethoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, or (C 1 -C 6 )alkanoyloxy; wherein R i and R j are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, phenyl, or benzyl;
wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol); and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
or a pharmaceutically acceptable salt thereof.
21 . The method of claim 20 wherein the triterpenoid is 3-β-acetoxy-19αH-19,28 lactone oleanan; allobetulin; allobetulin-3-succinate; allobetulin-3-glycine ester; allobetulin lactone; allobetulin lactone-3-acetate; allobetulin lactone-3-phosphate; allobetulin-3-L-alanine; allobetulin-3-L-valine; allobetulin-3-L-proline; allobetulin-3-succinate; allobetulin-3-diglycolate; allobetulin-3-glutarate; allobetulin-3-phthalate; allobetulin-3-methylenamine; allobetulin-3-ethanolamine; allobetulin-3-ethanolamine hydrochloride; allobetulin-3-glycolate; allobetulin-3-glutarate; allobetulin-28-glutarate; allobetulin-3-methylamine HCl; allobetulin-3-phosphate; allobetulin-3-(polyethylene glycol)-COOH (Mw=674); allobetulon; allobetulon lactone-1-ene-2-ol; allobetulon lactone-1-en-2-succinate; allobetulon-1-ene-2-ol; allobetulon-1-ene-2-diglycolate; 3-allobetulon-1-ene-2-succinate; or 3-allobetulon-1-ene-2-diglycolate.
22 . The method of claim 20 wherein the triterpenoid is 3-β-acetoxy-19αH-19,28 lactone oleanan; allobetulin; allobetulin-3-glycine ester; allobetulin lactone-3-phosphate; allobetulin-3-succinate; allobetulin-3-ethanolamine; allobetulin-3-glutarate; allobetulin-28-glutarate; allobetulin-3-methylamine HCl; allobetulin-3-phosphate; allobetulon; allobetulon lactone-1-ene-2-ol; 3-allobetulon-1-ene-2-succinate; or ursolic acid.
23 . A method of inhibiting or killing a bacterium, comprising contacting the bacterium with an effective antibacterial amount of a triterpene of formula (I):
wherein
R 1 is hydrogen or hydroxy;
R 2 is a direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C 6 -C 10 )aryl, or (C 1 -C 6 )alkyl;
R 3 is hydrogen, hydroxy, (C 1 -C 6 )alkyl, O═P(OH) 2 , O═P(OH) 2 OP(O)(OH)—, (C 1 -C 5 )alkanoyl, Si(R) 3 wherein each R is H, phenyl or (C 1 -C 6 )alkyl, C(O)N(R) 2 , benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C 1 -C 4 )alkoxy](C 1 -C 4 )alkyl, or a glycoside;
R 4 is hydrogen, hydroxy, (C 1 -C 6 )alkyl, O═P(OH) 2 , O═P(OH) 2 OP(O)(OH)—, (C 1 -C 5 )alkanoyl, Si(R) 3 wherein each R is H, phenyl or (C 1 -C 6 )alkyl, C(O)N(R) 2 , benzyl, benzoyl, tetrahydropyran-2-yl, 1-[(C 1 -C 4 )alkoxy](C 1 -C 4 )alkyl, a glycoside, or amino; or R 4 and R 5 together are oxo or (═NOH); and
R 5 is direct bond, carbonyl, oxy, thio, carbonyl oxy, oxy carbonyl, (C 6 -C 10 )aryl, or (C 1 -C 6 )alkyl; or R 4 and R 5 together are oxo or (═NOH);
wherein any alkyl can optionally be substituted with one or more halo, hydroxy, (C 6 -C 10 )aryl, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl or polyethyleneimine; —OP(═O)(OH) 2 ; or C(═O)OR 9 , wherein R 9 is hydrogen, (C 1 -C 6 )alkyl, or polyethyleneimine;
each of the bonds represented by - - - is independently absent or is present;
wherein any alkyl is optionally interrupted on carbon with one or more oxy, thio, sulfinyl, sulfonyl, polyethyleneimine, or poly(ethylene glycol);
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more halo, hydroxy, nitro, cyano, (C 1 -C 6 )alkoxy, trifluoromethyl, polyethyleneimine, poly(ethylene glycol), oxo, NR 7 R 8 , wherein R 7 and R 8 are each independently hydrogen, (C 1 -C 6 )alkyl or polyethyleneimine; or C(═O)OR 9 , wherein R 9 is hydrogen, (C 1 -C 6 )alkyl, or polyethyleneimine;
or a pharmaceutically acceptable salt thereof.
24 . The method of claim 23 wherein R 4 is not amino; R 4 and R 5 are not together (═NOH); and alkyl is not substituted with —OP(═O)(OH) 2 .
25 . The method of claim 23 wherein the bond between carbons 1 and 2 is a single bond.
26 . The method of claim 23 wherein the bond between carbons 1 and 2 is a double bond.
27 . The method of claim 23 wherein R 1 is hydrogen.
28 . The method of claim 23 wherein R 1 is hydroxy.
29 . The method of claim 23 wherein R 2 is a direct bond.
30 . The method of claim 29 wherein R 3 is (C 1 -C 6 )alkyl,
wherein any alkyl can optionally be substituted with one or more oxo, carboxy, amino, (C 6 -C 10 )aryl, or —OP(═O)(OH) 2 ,;
wherein any alkyl is optionally interrupted on carbon with one or more oxy or thio;
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more hydroxy or carboxy.
31 . The method of claim 30 wherein R 3 is aminoacetoxymethyl, (carboxymethoxy)acetoxymethyl, 4-carboxybutanoyloxymethyl, 2-carboxybenzoyloxymethyl, 3-carboxypropanoyloxymethyl, butanoyloxymethyl, or
—CH 2 OC(═O)OP(═O)(OH) 2 .
32 . The method of claim 23 wherein R 4 is (C 1 -C 6 )alkyl,
wherein any alkyl can optionally be substituted with one or more oxo, carboxy, amino, (C 6 -C 10 )aryl, or —OP(═O)(OH) 2 ,;
wherein any alkyl is optionally interrupted on carbon with one or more oxy or thio;
wherein any alkyl is optionally partially unsaturated;
wherein any aryl can optionally be substituted with one or more hydroxy or carboxy.
33 . The method of claim 23 wherein R 4 is 2-carboxybenzoyl, 2-amino-3-methylbutanoyl, 3-carboxypropenoyl, aminoacetyl, 4-carboxybutanoyl, (carboxymethoxy)acetyl, 3-(3,4-dihydroxyphenyl)propenoyl, carboxymethylenethioacetyl, 3-carboxy-3-methylbutanoyl, amino, —P(═O)(OH) 2 , oxo, or (═NOH).
34 . The method of claim 23 wherein R 5 is oxy or a direct bond.
35 . The method of claim 23 wherein
R 1 is hydrogen or hydroxy;
R 2 is a direct bond;
R 3 is (C 1 -C 5 )alkoxymethyl or hydroxymethyl;
R 4 is hydrogen, phosphono, sulfo, or (C 1 -C 6 )alkyl, and R 5 is oxy; or
R 4 is amino and R 5 is a direct bond; or
R 4 and R 5 together are oxo or (═NOH);
wherein any alkyl, or alkyl segment of an R group, is optionally interrupted on carbon with one or more oxy, thio, or imido;
wherein any alkyl, or alkyl segment of an R group, can optionally be substituted with one or more oxo, carboxy, amino, —OP(═O)(OH) 2 , or phenyl;
wherein phenyl can optionally be substituted with one or more hydroxy or carboxy.
36 . The method of claim 23 wherein
R 1 is hydrogen or hydroxy;
R 2 is a direct bond;
R 3 is aminoacetoxymethyl, (carboxmethox)acetoxymethyl, 4-carboxybutanoyloxymethyl, 2-carboxybenzoyloxymethyl, 3-carboxypropanoyloxymethyl, butanoyloxymethyl, or
—CH 2 OC(═O)OP(═O)(OH) 2 ;
R 4 is 2-carboxybenzoyl, 2-amino-3-methylbutanoyl, 3-carboxypropenoyl, aminoacetyl, 4-carboxybutanoyl, (carboxymethoxy)acetyl, 3-(3,4-dihydroxyphenyl)propenoyl, carboxymethylenethioacetyl, 3-carboxy-3-methylbutanoyl, amino, —P(═O)(OH) 2 , oxo, or (═NOH); and
R 5 is oxy or a direct bond.
37 . The method of claim 23 wherein the triterpene is betulin; betulin-3,28-diglycine; betulin-28-glycerol oxalate; betulin-28-glycine; betulin-28-oxalate; betulin arabinose galactan; betulin-3,28didiglycolate; betulin-3,28-diglycine; betulin-3-maleate; betulin-3,28-di-(L-glutamic acid γ-benzylester) ester; betulin-3,28-di-L-alanine; betulin-3,28-di-L-proline; betulin-3,28-dioxalate; betulin-1-ene-2-ol; betulin-3,28-diphenylalanine; betulin-3-28-dioxalate-polyethylene amine; betulin-3,38-diphosphate; betulin-3-caffeate; betulin-3,28-(3′,3′-dimethyl) glutarate; betulin-28-diglycolate; betulin-28-glutarate; betulin-28-maleate; betulin-28-phthalate; betulin-3,28-di(3′,3′-dimethyl)glutarate; betulin-3,28-didiglycolate; betulin-3,28-di(thiodiglycolate); betulin-3,28-diglutarate; betulin-3,28-dimaleate; betulin-3,28-diglycolate; betulin-3,28-diphthalate; betulin-3,28-di-L-phenylalanine; betulin-3,28-di-L-valine; betulin-28-succinate; betulin-3,28-disuccinate; betulin-3,28-di-(polyethylene glycol)-COOH (Mw=1448); betulin-3,28-di-(polyethylene glycol)-COOH (Mw=906 crude); betulin-3,28-di-(polyethylene glycol)-COOH (Mw=906 pure); betulinic acid; betulon-1-ene-2-ol; 3,28 (dipoly(ethylene glycol)bis (carboxymethylester); 3,28 (dipoly(ethylene glycol)bis (carboxymethyl allobetulin ester); hederin hydrate; lupeol; lupeol-3-glutarate; lupeol-3-succinate; lupeol-3-thiodiglycolate; lupeol-3-phthalate; lupeol-3-succinate; oleanolic acid; ursolic acid; or uvaol.
38 . The method of claim 23 wherein the triterpene is betulin; betulin-28-glycerol oxalate; betulin-28-oxalate; betulin arabinose galactan; betulin-3,28-didiglycolate; betulin-3,28-diglycine; betulin-3,28-di-(L-Glutamic acid r-benzylester) ester; betulin3,28-di-L-proline ester; betulin-3,28-dioxalate; betulin-1-ene-2-ol; betulin-3,28-dioxalate-polyethylene amine; betulin-3,28-diphosphate; betulin-3-caffeate; betulin-28-diglycolate; betulin-28-glutarate; betulin-28-maleate; betulin-28-phthalate; betulin-3,28-dithiodiglycolate; betulin-3,28-diglutarate; betulin-3,28-dimaleate; betulin-3,28-diglycolate; betulin-3,28-diphthalate; betulin-3,28-di-L-phenylalanine; betulin-di-L-valine; betulin-28-succinate; betulin-3,28-disuccinate; betulin-3,28-di-(polyethylene glycol)-COOH (Mw=906 pure); betulinic acid; betulon-1-ene-2-ol; betulin-3,28-(dipoly(ethylene glycol)bis (carboxymethylester); hederin hydrate; lupeol-3-glutarate; lupeol-3-succinate; lupeol-3-thiodiglycolate; lupeool-3-phthalate; oleanolic acid; uvaol.
39 . The method of claim 23 wherein the triterpene is betulin-3-caffeate; betulin-28-diglycolate; betulin-3,28-diglutarate; betulin-3,28-diglycine; betulin-3,28-didiglycolate; betulin-3,28-dimaleate; betulin-3,28-diphosphate; betulin-3,28-diphthalate; betulin-3,28-di-L-valine; lupeol; lupeol-3-amine; lupeol-3-(3′,3′-dimethyl)succinate; lupeol-3-maleate; lupeol-3-phosphate; lupeol-3-thiodiglycolate; lupenone; lupenon-1,2-ene-2-ol; lupenon-3-oxime.
40 . The method of claim 23 wherein the bacterium is Escherichia coli, Staphylococcus sp., Enterococcus faecalis, or a combination thereof.
41 . The method of claim 40 wherein the bacterium is Staphyloccoccus aureus.
42 . The method of claim 23 wherein the contacting is in vitro.
43 . The method of claim 23 wherein the contacting is in vivo.
44 . A method of inhibiting or killing a bacterium, comprising contacting the bacterium with an effective antibacterial amount of a triterpene of formula (II):
wherein
one of R 1 and R 2 is —O—Y and the other is hydrogen or (C 1 -C 6 )alkyl optionally substituted by hydroxy, (C 1 -C 6 )alkoxy, halo, halo(C 1 -C 6 )alkoxy or NR j R k wherein R j and R k are independently H, (C 1 -C 6 )alkyl or (C 1 -C 6 )alkonyl; or R 1 and R 2 together are oxo (═O);
R 3 is hydrogen, halo, carboxy, mercapto, (C 1 -C 6 )alkyl, (C 3 -C 8 )cycloalkyl, or —O—Y;
R 4 and R 5 are each independently hydrogen, (C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl;
R 6 is hydrogen or is absent when the adjacent—is a bond;
R 7 is hydrogen or (C 1 -C 6 )alkyl;
R 8 is hydrogen, (C 1 -C 6 )alkyl, or hydroxy(C 1 -C 6 )alkyl and R 11 is hydrogen, (C 1 -C 6 )alkyl, carboxy, or hydroxy(C 1 -C 6 )alkyl; or R 8 and R 11 together are —O—C(═X)—;
R 9 and R 10 , are each independently hydrogen or (C 1 -C 6 )alkyl;
each of the bonds represented by—is independently absent or is present;
X is two hydrogens, oxo (═O) or thioxo (═S);
each Y is independently H, aryl, P(O)(Cl) 2 , (C 3 -C 8 )cycloalkyl, adamantyl, —SO 2 R a O═P(R b ) 2 , O═P(R c ) 2 OP(O)(R d )—, Si(R e ) 3 , tetrahydropyran-2-yl, an amino acid, a peptide, a glycoside, or a 1 to 10 membered branched or unbranched carbon chain optionally comprising 1, 2, or 3 heteroatoms selected from non-peroxide oxy, thio, and —N(R f )—; wherein said chain may optionally be substituted on carbon with 1, 2, 3, or 4 oxo (═O), hydroxy, carboxy, halo, mercapto, nitro, —N(R g )(R h ), (C 3 -C 8 )cycloalkyl, (C 3 -C 8 )cycloalkyloxy, aryl, aryloxy, adamantyl, adamantyloxy, hydroxyamino, trifluoroacetylamino, a glycoside, an amino acid, or a peptide; and wherein said chain may optionally be saturated or unsaturated (e.g. containing one, two, three or more, double or triple bonds);
R a is (C 1 -C 6 )alkyl or aryl;
R b , R c , and R d are each independently hydroxy, (C 1 -C 6 )alkoxy, hydroxy(C 2 -C 6 )alkoxy, adamantyloxy, adamantyl(C 1 -C 6 )alkoxy, norbornyloxy, 1,1-di(hydroxymethyl)-2-hydroxyethoxy, carboxy(C 1 -C 6 )alkoxy, 2,3-epoxypropyloxy, benzyloxy, (C 3 -C 8 )cycloalkyloxy, NR x R y , or aryloxy;
R e is H, aryl or (C 1 -C 6 )alkyl;
R f is hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, phenyl or benzyl;
R g and R h are each independently selected from the group consisting of hydrogen, (C 1 -C 6 )alkyl, hydroxy(C 1 -C 6 )alkyl, adamantyl, adamantyl(C 1 -C 6 )alkyl, amino(C 1 -C 6 )alkyl, aminosulfonyl, (C 1 -C 6 )alkanoyl, aryl and benzyl; or R b and R c together with the nitrogen to which they are attached form a pyrrolidino, piperidino, or morpholino radical; and
R x and R y are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, aryl or benzyl;
wherein each aryl of Y, R a —R d , R g —R h , R x , and R y may optionally be substituted by 1, 2, or 3 aminosulfonyl, carboxy, NR i R j , (C 1 -C 6 )alkyl, (C 1 -C 6 )alkoxy, hydroxy, halo, nitro, cyano, mercapto, carboxy, hydroxy(C 1 -C 6 )alkyl, halo(C 1 -C 6 )alkyl, trifluoromethoxy, (C 1 -C 6 )alkanoyl, (C 1 -C 6 )alkoxycarbonyl, (C 1 -C 6 )alkylthio, or (C 1 -C 6 )alkanoyloxy; wherein R i and R j are each independently hydrogen, (C 1 -C 6 )alkyl, (C 1 -C 6 )alkanoyl, phenyl, or benzyl;
wherein any alkyl can optionally be substituted with one or more polyethyleneimine or poly(ethylene glycol); and wherein any alkyl can optionally be interrupted with one or more polyethyleneimine or poly(ethylene glycol);
or a pharmaceutically acceptable salt thereof.
45 . The method of claim 44 wherein the triterpenoid is 3-β-acetoxy-19αH-19,28 lactone oleanan; allobetulin; allobetulin-3-succinate; allobetulin-3-glycine ester; allobetulin lactone; allobetulin lactone-3-acetate; allobetulin lactone-3-phosphate; allobetulin-3-L-alanine; allobetulin-3-L-valine; allobetulin-3-L-proline; allobetulin-3-succinate; allobetulin-3-diglycolate; allobetulin-3-glutarate; allobetulin-3-phthalate; allobetulin-3-methylenamine; allobetulin-3-ethanolamine; allobetulin-3-ethanolamine hydrochloride; allobetulin-3-glycolate; allobetulin-3-glutarate; allobetulin-28-glutarate; allobetulin-3-methylamine HCl; allobetulin-3-phosphate; allobetulin-3-(polyethylene glycol)-COOH (Mw=674); allobetulon; allobetulon lactone-1-ene-2-ol; allobetulon lactone-1-en-2-succinate; allobetulon-1-ene-2-ol; allobetulon-1-ene-2-diglycolate; 3-allobetulon-1-ene-2-succinate; or 3-allobetulon-1-ene-2-diglycolate.
46 . The method of claim 44 wherein the triterpenoid is 3-β-acetoxy-19αH-19,28 lactone oleanan; allobetulin; allobetulin-3-glycine ester; allobetulin lactone-3-phosphate; allobetulin-3-succinate; allobetulin-3-ethanolamine; allobetulin-3-glutarate; allobetulin-28-glutarate; allobetulin-3-methylamine HCl; allobetulin-3-phosphate; allobetulon; allobetulon lactone-1-ene-2-ol; 3-allobetulon-1-ene-2-succinate; or ursolic acid.
47 . The method of claim 44 wherein the contacting is in vitro.
48 . The method of claim 44 wherein the contacting is in vivo.Join the waitlist — get patent alerts
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