WO2008070347A2 - Betulin-peptide conjugates - Google Patents

Abstract

The present invention provides for novel compounds of formula I, II, III and IV, as described herein. The present invention also provides for novel methods of manufacturing compounds of formula I, II and III from compounds of formula IV, that include contacting the compound of formula IV and an amino acid (or peptide). The present invention also provides for methods of killing or inhibiting a virus, bacteria and/or fungus. The methods include contacting a virus, bacteria and/or fungus, respectively, with a suitable amount of a compound of formula I, II or III. The present invention also provides for a method of treating a mammal afflicted with a viral infection, bacterial infection and/or fungal infection. The method includes administering to a mammal in need of such treatment an effective amount of a compound of formula I, II or III.

Description

TRITERPENES

Related Applications

This application claims priority to U.S. Provisional Patent Application Serial No. 60/854,951, filed October 27, 2006, which is incorporated herein by reference.

Summary of the Invention The present invention provides for novel compounds of formula I, II, III and

IV, as described herein below. The present invention also provides for novel methods of manufacturing compounds of formula I, II and III from compounds of formula IV, that include contacting a compound of formula IV and an amino acid (or peptide), to provide a compound of formula I, II or III. The present invention also provides for methods of killing or inhibiting a virus, bacteria and/or fungus. The methods include contacting a virus, bacteria and/or fungus, respectively, with a suitable amount of a compound of formula I, II or III, for a period of time effective to kill or inhibit the virus, bacteria and/or fungus. The present invention also provides for a method of treating a mammal afflicted with a viral infection, bacterial infection and/or fungal infection. The method includes administering to a mammal in need of such treatment an effective amount of a compound of formula I, II or III, for a period of time effective to treat the viral infection, bacterial infection and/or fungal infection.

Detailed Description of the Invention

Definitions

Unless stated otherwise, the following terms and phrases as used herein are intended to have the following meanings:

When tradenames are used herein, applicants intend to independently include the tradename product and the active pharmaceutical ingredient(s) of the tradename product. One diastereomer of a compound disclosed herein may display superior activity compared with the other. When required, separation of the racemic material can be achieved by HPLC using a chiral column or by a resolution using a resolving agent such as camphonic chloride as in Tucker et al., J. Med. Chem., 37:2437 (1994). A chiral compound described herein may also be directly synthesized using a chiral catalyst or a chiral ligand, e.g. Huffman et al., J. Org. Chem., 60:1590 (1995).

"Therapeutically effective amount" is intended to include an amount of a compound described herein, or an amount of the combination of compounds described herein, e.g., to treat or prevent the disease or disorder, or to treat the symptoms of the disease or disorder, in a host. The combination of compounds is preferably a synergistic combination. Synergy, as described for example by Chou and Talalay, Adv. Enzyme Regul.. 22:27 (1984), occurs when the effect of the compounds when administered in combination is greater than the additive effect of the compounds when administered alone as a single agent. In general, a synergistic effect is most clearly demonstrated at suboptimal concentrations of the compounds. Synergy can be in terms of lower cytotoxicity, increased activity, or some other beneficial effect of the combination compared with the individual components. As used herein, "treating" or "treat" includes (i) preventing a pathologic condition from occurring (e.g. prophylaxis); (ii) inhibiting the pathologic condition or arresting its development; (iii) relieving the pathologic condition; and/or (iv) diminishing symptoms associated with the pathologic condition.

"Stable compound" and "stable structure" are meant to indicate a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent. Only stable compounds are contemplated herein.

"Substituted" is intended to indicate that one or more hydrogens on the atom indicated in the expression using "substituted" is replaced with a selection from the indicated group(s), provided that the indicated atom's normal valency is not exceeded, and that the substitution results in a stable compound. Suitable indicated groups include, e.g., alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, acyloxy, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. When a substituent is keto (i.e., =0) or thioxo (i.e., =S) group, then 2 hydrogens on the atom are replaced.

"Interrupted" is intended to indicate that in between two or more adjacent carbon atoms, and the hydrogen atoms to which they are attached (e.g., methyl (CH₃), methylene (CH₂) or methine (CH)), indicated in the expression using "interrupted" is inserted with a selection from the indicated group(s), provided that the each of the indicated atoms' normal valency is not exceeded, and that the interruption results in a stable compound. Such suitable indicated groups include, e.g., with one or more non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(O)-), carboxy (-C(O)O-), carbonyldioxy (-OC(O)O-), carboxylato (-OC(O)-), imine (C=NH), sulfinyl (SO) and sulfonyl (SO₂).

Specific and preferred values listed below for radicals, substituents, and ranges, are for illustration only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents. "Alkyl" refers to a C i -C ] 8 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methyl (Me, -CH3), ethyl (Et, - CH2CH3), 1 -propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, - CH(CH3)2), 1 -butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-l -propyl Q-Bu, l-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3)CH2CH3), 2-methyl-2- propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2- pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (- C(CH3)2CH2CH3), 3-methyl-2-butyl

(-CH(CH3)CH(CH3)2), 3 -methyl- 1 -butyl (-CH2CH2CH(CH3)2), 2-methyl-l -butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2- methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (- CH(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentyl (-CH(CH3)CH2CH(CH3)2), 3- methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3 -pentyl (- CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3.

The alkyl can be a monovalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkylene). The alkyl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfϊnamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. The alkyl can optionally be interrupted with one or more non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(O)-), carboxy (-C(=O)O-), carbonyldioxy (-OC(=O)O-), carboxylato (-OC(=O)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO₂). Additionally, the alkyl can optionally be at least partially unsaturated, thereby providing an alkenyl.

"Alkenyl" refers to a C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon- carbon, sp² double bond. Examples include, but are not limited to: ethylene or vinyl (-CH=CH₂), allyl (-CH₂CH=CH₂), cyclopentenyl (-C₅H₇), and 5-hexenyl (-CH₂ CH₂CH₂CH₂CH-CH₂). The alkenyl can be a movalent hydrocarbon radical, as described and exemplified above, or it can be a divalent hydrocarbon radical (i.e., alkenylene).

The alkenyl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, the alkenyl can optionally be interrupted with one or more non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (- OCH₂O-), carbonyl (-C(=O)-), carboxy (-C(=O)O-), carbonyldioxy (-OC(=O)O-), carboxylato (-OC(O)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO₂). "Alkylidenyl" refers to a C] -C] 8 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms. Examples are methylidenyl (=CH2), ethylidenyl (=CHCH3), 1 -propyl idenyl (=CHCH2CH3), 2-propylidenyl (=C(CH3)2), 1-butylidenyl (=CHCH2CH2CH3), 2-methyl-l-propylidenyl (=CHCH(CH3)2), 2-butylidenyl (=C(CH3)CH2CH3), 1-pentyl (=CHCH2CH2CH2CH3), 2-pentylidenyl (=C(CH3)CH2CH2CH3), 3-pentylidenyl (=C(CH2CH3)2), 3-methyl-2-butylidenyl (=C(CH3)CH(CH3)2), 3-methyl-l- butylidenyl (=CHCH2CH(CH3)2), 2-methyl-l -butylidenyl

(=CHCH(CH3)CH2CH3), 1-hexylidenyl (=CHCH2CH2CH2CH2CH3), 2- hexylidenyl (=C(CH3)CH2CH2CH2CH3), 3-hexylidenyl (=C(CH2CH3)(CH2CH2CH3)), 3-methyl-2-pentylidenyl (=C(CH3)CH(CH3)CH2CH3), 4-methyl-2-pentylidenyl (=C(CH3)CH2CH(CH3)2), 2-methyl-3-pentylidenyl (=C(CH2CH3)CH(CH3)2), and 3,3-dimethyl-2-butylidenyl (=C(CH₃)C(CH₃)3. The alkylidenyl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, the alkylidenyl can optionally be interrupted with one or more non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(=O)-), carboxy (-C(=O)O-), carbonyldioxy (- OC(O)O-), carboxylato (-0C(=0)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO₂).

"Alkenylidenyl" refers to a C2-C18 hydrocarbon containing normal, secondary, tertiary or cyclic carbon atoms with at least one site of unsaturation, i.e. a carbon-carbon, sp² double bond. Examples include, but are not limited to: allylidenyl (=CHCH=CH₂), and 5-hexenylidenyl ^CHCH₂CH₂CH₂CH=CH₂). The alkenylidenyl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or C00R^x, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, the alkenylidenyl can optionally be interrupted with one or more non-peroxide oxy (-0-), thio (-S-), imino (-N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(=O)-), carboxy (-C(=O)O-), carbonyldioxy (- OC(O)O-), carboxylato (-OC(=O)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO₂).

"Alkylene" refers to a saturated, branched or straight chain or cyclic hydrocarbon radical of 1 -18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or different carbon atoms of a parent alkane. Typical alkylene radicals include, but are not limited to: methylene (-CH₂-) 1,2-ethyl (-CH₂CH₂-), 1,3-propyl (-CH₂CH₂CH₂-), 1,4-butyl (-CH₂CH₂CH₂CH₂-), and the like. The alkylene can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, the alkylene can optionally be interrupted with one or more non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (- OCH₂O-), carbonyl (-C(=O)-), carboxy (-C(=O)O-), carbonyldioxy (-OC(=O)O-), carboxylato (-OC(=O)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO₂). Moreover, the alkylene can optionally be at least partially unsaturated, thereby providing an alkenylene.

"Alkenylene" refers to an unsaturated, branched or straight chain or cyclic hydrocarbon radical of 2-18 carbon atoms, and having two monovalent radical centers derived by the removal of two hydrogen atoms from the same or two different carbon atoms of a parent alkene. Typical alkenylene radicals include, but are not limited to: 1,2-ethenylene (-CH=CH-). The alkenylene can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. Additionally, The alkenylene can optionally be interrupted with one or more non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(=O)-), carboxy (-Q=O)O-), carbonyldioxy (- OC(O)O-), carboxylato (-OC(O)-), imine (C=NH), sulfinyl (SO) or sulfonyl (SO₂).

The term "alkoxy" refers to the groups alkyl-O-, where alkyl is defined herein. Preferred alkoxy groups include, e.g., methoxy, ethoxy, «-propoxy, iso- propoxy, rø-butoxy, ter/-butoxy, seobutoxy, rø-pentoxy, rø-hexoxy, 1 ,2- dimethylbutoxy, and the like. The alkoxy can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy. The term "aryl" refers to an unsaturated aromatic carbocyclic group of from 6 to 20 carbon atoms having a single ring (e.g., phenyl) or multiple condensed (fused) rings, wherein at least one ring is aromatic (e.g., naphthyl, dihydrophenanthrenyl, fluorenyl, or anthryl). Preferred aryls include phenyl, naphthyl and the like. The aryl can optionally be a divalent radical, thereby providing an arylene.

The aryl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

The term "cycloalkyl" refers to cyclic alkyl groups of from 3 to 20 carbon atoms having a single cyclic ring or multiple condensed rings. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

The cycloalkyl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

The cycloalkyl can optionally be at least partially unsaturated, thereby providing a cycloalkenyl. Additionally, the cycloalkyl can optionally be a divalent radical, thereby providing a cycloalkylene.

The term "halo" refers to fluoro, chloro, bromo, and iodo. Similarly, the term "halogen" refers to fluorine, chlorine, bromine, and iodine.

"Haloalkyl" refers to alkyl as defined herein substituted by 1-4 halo groups as defined herein, which may be the same or different. Representative haloalkyl groups include, by way of example, trifluoromethyl, 3-fluorododecyl, 12,12,12- trifluorododecyl, 2-bromooctyl, 3-bromo-6-chloroheptyl, and the like.

The term "heteroaryl" is defined herein as a monocyclic, bicyclic, or tricyclic ring system containing one, two, or three aromatic rings and containing at least one nitrogen, oxygen, or sulfur atom in an aromatic ring, and which can be unsubstituted or substituted. The heteroaryl can optionally be a divalent radical, thereby providing a heteroarylene.

Examples of heteroaryl groups include, but are not limited to, 2H-pyrrolyl, 3H-indolyl, 4H-quinolizinyl, 4nH-carbazolyl, acridinyl, benzo[Z>]thienyl, benzothiazolyl, β-carbolinyl, carbazolyl, chromenyl, cinnaolinyl, dibenzo[b,d]furanyl, furazanyl, furyl, imidazolyl, imidizolyl, indazolyl, indolisinyl, indolyl, isobenzofuranyl, isoindolyl, isoquinolyl, isothiazolyl, isoxazolyl, naphthyridinyl, naptho[2,3-ό], oxazolyl, perimidinyl, phenanthridinyl, phenanthrolinyl, phenarsazinyl, phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrimidinyl, pyrrolyl, quinazolinyl, quinolyl, quinoxalinyl, thiadiazolyl, thianthrenyl, thiazolyl, thienyl, triazolyl, and xanthenyl. In one embodiment the term "heteroaryl" denotes a monocyclic aromatic ring containing five or six ring atoms containing carbon and 1, 2, 3, or 4 heteroatoms independently selected from the group non-peroxide oxygen, sulfur, and N(Z) wherein Z is absent or is Η, O, alkyl, phenyl or benzyl. In another embodiment heteroaryl denotes an ortho-fused bicyclic heterocycle of about eight to ten ring atoms derived therefrom, particularly a benz-derivative or one derived by fusing a propylene, or tetramethylene diradical thereto.

The heteroaryl can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

The term "heterocycle" refers to a saturated or partially unsaturated ring system, containing at least one heteroatom selected from the group oxygen, nitrogen, and sulfur, and optionally substituted with alkyl or C(=O)OR^b, wherein R^b is hydrogen or alkyl. Typically heterocycle is a monocyclic, bicyclic, or tricyclic group containing one or more heteroatoms selected from the group oxygen, nitrogen, and sulfur. A heterocycle group also can contain an oxo group (=0) attached to the ring. Non-limiting examples of heterocycle groups include 1,3- dihydrobenzofuran, 1,3-dioxolane, 1,4-dioxane, 1,4-dithiane, 2H-pyran, 2- pyrazoline, 4H-pyran, chromanyl, imidazolidinyl, imidazolinyl, indolinyl, isochromanyl, isoindolinyl, morpholine, piperazinyl, piperidine, piperidyl, pyrazolidine, pyrazolidinyl, pyrazolinyl, pyrrolidine, pyrroline, quinuclidine, and thiomorpholine. The heterocycle can optionally be a divalent radical, thereby providing a heterocyclene.

The heterocycle can optionally be substituted with one or more alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

Examples of nitrogen heterocycles and heteroaryls include, but are not limited to, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, morpholino, piperidinyl, tetrahydrofuranyl, and the like as well as N-alkoxy-nitrogen containing heterocycles. In one specific embodiment of the invention, the nitrogen heterocycle can be 3-methyl-5,6-dihydro- 4H-pyrazino[3,2,l-jk]carbazol-3-ium iodide.

Another class of heterocyclics is known as "crown compounds" which refers to a specific class of heterocyclic compounds having one or more repeating units of the formula [-(CH₂-)_aA-] where a is equal to or greater than 2, and A at each separate occurrence can be O, N, S or P. Examples of crown compounds include, by way of example only, [-(CH₂)₃-NH-]₃, [-((CH₂)₂-O)₄-((CH₂)2-NH)₂] and the like. Typically such crown compounds can have from 4 to 10 heteroatoms and 8 to 40 carbon atoms.

The term "alkanoyl" refers to C(=O)R, wherein R is an alkyl group as previously defined.

The term "acyloxy" refers to -O-C(=O)R, wherein R is an alkyl group as previously defined. Examples of acyloxy groups include, but are not limited to, acetoxy, propanoyloxy, butanoyloxy, and pentanoyloxy. Any alkyl group as defined above can be used to form an acyloxy group. The term "alkoxycarbonyl" refers to C(=O)OR, wherein R is an alkyl group as previously defined. The term "amino" refers to -NH₂, and the term "alkylamino" refers to -NR₂, wherein at least one R is alkyl and the second R is alkyl or hydrogen. The term "acylamino" refers to RC(=O)N, wherein R is alkyl or aryl.

The term "imino" refers to -C=NH. The imino can optionally be substituted with one or more alkyl, alkenyl, alkoxy, aryl, heteroaryl, heterocycle or cycloalkyl.

The term "carboxy" refers to -C(=O).

The term "carbonyl" refers to -C(=O)-.

The term "nitro" refers to -NO₂.

The term "trifluoromethyl" refers to -CF₃. The term "trifluoromethoxy" refers to -OCF₃.

The term "cyano" refers to -CN.

The term "hydroxy" or "hydroxyl" refers to -OH.

The term "oxy" refers to -O-.

The term "thio" refers to -S-. The term "thioxo" refers to (=S).

The term "keto" refers to (=0).

The term "isocyannato" refers to -NC.

The term "carboxyl" refers to -COOH.

As to any of the above groups, which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and/or synthetically non- feasible. In addition, the compounds of this invention include all stereochemical isomers arising from the substitution of these compounds.

Selected substituents within the compounds described herein are present to a recursive degree. In this context, "recursive substituent" means that a substituent may recite another instance of itself. Because of the recursive nature of such substituents, theoretically, a large number may be present in any given claim. One of ordinary skill in the art of medicinal chemistry and organic chemistry understands that the total number of such substituents is reasonably limited by the desired properties of the compound intended. Such properties include, by of example and not limitation, physical properties such as molecular weight, solubility or log P, application properties such as activity against the intended target, and practical properties such as ease of synthesis.

Recursive substituents are an intended aspect of the invention. One of ordinary skill in the art of medicinal and organic chemistry understands the versatility of such substituents. To the degree that recursive substituents are present in an claim of the invention, the total number will be determined as set forth above.

"Bioavailability" is the degree to which the pharmaceutically active agent becomes available to the target tissue after the agent's introduction into the body. Enhancement of the bioavailability of a pharmaceutically active agent can provide a more efficient and effective treatment for patients because, for a given dose, more of the pharmaceutically active agent will be available at the targeted tissue sites.

As used herein, "triterpene" or "triterpenoid" refers to a plant secondary metabolite that includes a hydrocarbon, or its oxygenated analog, that is derived from squalene by a sequence of straightforward cyclizations, functionalizations, and sometimes rearrangement. Triterpenes or analogues thereof can be prepared by methods known in the art, i.e., using conventional synthetic techniques or by isolation from plants. Suitable exemplary triterpenes and the biological synthesis of the same are disclosed, e.g., in R.B. Herbert, The Biosynthesis of Secondary Plant Metabolites, 2nd. ed. (London: Chapman 1989). The term "triterpene" refers to one of a class of compounds having approximately 30 carbon atoms and synthesized from six isoprene units in plants and other organisms. Triterpenes consist of carbon, hydrogen, and optionally oxygen. Most triterpenes are secondary metabolites in plants. Most, but not all, triterpenes are pentacyclic. Suitable classes of triterpenes include, e.g., lupanes and oleanes. Examples of triterpenes include betulin, allobetulin, lupeol, friedelin, and all sterols, including lanosterol, stigmasterol, cholesterol, β-sitosterol, and ergosterol. Additional examples of triterpenes include those described, e.g., in U.S. Patent Nos. 6,634,575; 6,369,101; 6,392,070; 6,768,016; 6,951,847; 5,750,578; 6,689,767; 6,642,217; 6,815,553; 6,232,481; as well as Published U.S. Patent Application Nos. 2004/0097436, 2002/0128210, 2004/0009242, and 2002/0119935; which are incorporated by reference herein. As used herein, "betulin" refers to 3β,28-dihydroxy-lup-20(29)-ene. Betulin is a pentacyclic triterpenoid derived from the outer bark of paper birch trees (Betula papyrifera, B. pendula, B. verucosa, etc.). The CAS Registry No. is 473-98-3. It can be present at concentrations of up to about 24% of the bark of white birch. Merck Index, twelfth edition, page 1236 (1996). Structurally, betulin is shown below:

As used herein, "betulinic acid" refers to 3(β)-hydroxy-lup-20(29)-ene-28- oic acid; 9-hydroxy-l-isopropenyl-5a,5b,8,8,l la-pentamethyl-eicosahydro- cyclopenta[a]chrysene-3a-carboxylic acid. The CAS Registry No. is 472-15-1. Structurally, betulinic acid is shown below:

As used herein, "betulin aldehyde" refers to 3(β)-hydroxy-lup-20(29)-en-28- al; Lup-20(29)-en-28-al, 3β-hydroxy- (8CI); Lup-20(30)-en-28-al, 3β-hydroxy- (7CI); 3aH-Cyclopenta[a]chrysene, lup-20(29)-en-28-al deriv.; Betulinaldehyde; Betulinic aldehyde; or Betunal. The CAS Registry Number is 13159-28-9. Structurally, betulin aldehyde is shown below:

As used herein, "lupeol" refers to 3(β)-hydroxy-lup-20(29)-ene. Lupeol is also found in birch bark and in other plant sources. Lupeol is present at concentrations of about 1.5-3% of the birch bark and at up to about 8.2% in Canavalia ensiformis, a plant widespread in the humid tropics of Asia and Africa. Structurally, lupeol is shown below: 30

As used herein, "belulonic acid" refers to a compound of the formula

As used herein, "betulonic aldehyde" refers to a compound of the formula

As used herein, "lupenone" refers to a compound of the formula

As used herein, "betulone" refers to a compound of the formula

As used herein, "amino acid" refers to the residues of the natural amino acids (e.g. Ala, Arg, Asn, Asp, Cys, GIu, GIn, GIy, His, HyI, Hyp, He, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and VaI) in D or L form, as well as unnatural amino acids (e.g. phosphoserine, phosphothreonine, phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid, octahydroindole-2- carboxylic acid, statine, l,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine, ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine, phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). The term also comprises natural and unnatural amino acids bearing a conventional amino protecting group (e.g. acetyl or benzyloxycarbonyl), as well as natural and unnatural amino acids protected at the carboxy terminus (e.g. as a (Ci-C₆)alkyl, phenyl or benzyl ester or amide; or as an α-methylbenzyl amide). Other suitable amino and carboxy protecting groups are known to those skilled in the art (See for example, T.W. Greene, Protecting Groups In Organic Synthesis; Third Edition, Wiley: New York, 1999, and references cited therein). The term includes alpha-amino acids, as well as beta-amino acids. The term also includes residues (i.e., radicals) of the amino acid. An amino acid can be linked, either directly or through a linker, to the triterpene through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of cysteine. Suitable amino acids are commercially available from, e.g., Sigma-Aldrich (Milwaukee, WI); and Bachem (Bubendorf, Switzerland).

The term "peptide" describes a sequence of 2 to about 25 amino acids (e.g. as defined hereinabove) or peptidyl residues. The sequence may be linear or cyclic. For example, a cyclic peptide can be prepared or may result from the formation of disulfide bridges between two cysteine residues in a sequence. A peptide can be linked, either directly or through a linker, to the triterpene through the carboxy terminus, the amino terminus, or through any other convenient point of attachment, such as, for example, through the sulfur of a cysteine. Specifically, the peptide can include 2 to 15, 2 to 10, or 2 to 5 amino acids. More specifically, the peptide can include 2 amino acids. Peptide derivatives can be prepared as disclosed in U.S. Patent Numbers 4,612,302; 4,853,371; and 4,684,620. Suitable peptides are commercially available from, e.g., Sigma-Aldrich (Milwaukee, WI); and Bachem (Bubendorf, Switzerland).

The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable benefit/risk ratio.

As used herein, "pharmaceutically acceptable salts" refer to compounds described herein, wherein the parent compound is modified by making acid or base salts thereof. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like. The pharmaceutically acceptable salts include the conventional non-toxic salts or the quaternary ammonium salts of the parent compound formed, for example, from non- toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.

The pharmaceutically acceptable salts of the compounds described herein can be synthesized from the parent compound, which contains a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA, (1985), 1418 the disclosure of which is hereby incorporated by reference.

Linking Group

The compounds described herein can optionally include a linking group. The reactive functional groups present on the triterpene and amino acid (or peptide) will typically influence the functional groups to be present on the linking group. The nature of the linking group is typically not critical, provided the compounds described herein possesses acceptable mechanical properties and release kinetics for the selected therapeutic application. The linking group is typically a divalent organic radical having a molecular weight of from about 25 daltons to about 400 daltons. More specifically, the linking group can have a molecular weight of from about 40 daltons to about 200 daltons.

The linking group is typically a divalent organic radical having a length of about 1 Angstrom to about 1,000 Angstroms. More specifically, the linking group can have a length of about 5 Angstroms to about 100 Angstroms, about 5 Angstroms to about 50 Angstroms, or about 5 Angstroms to about 20 Angstroms.

The resulting linking group may be biologically inactive, or may itself possess biological activity. The linking group can also include other functional groups (e.g., hydroxy, mercapto, amine, carboxylic acid, etc.) that can be used to modify the properties of the compounds described herein. Specifically, the linking group can include other functional groups that can be used, e.g., for changing the solubility of the compounds described herein, or for effecting the biodistribution of the compounds described herein.

Specifically, the linking group can be a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 50 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally interrupted with, e.g., one or more cycloalkyl, aryl, heteroaryl, substituted cycloalkyl, substituted aryl, substituted heteroaryl, non-peroxide oxy (-O-), thio (-S-), imino (- N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(=O)-), carboxy (-C(=O)O-), carbonyldioxy (-OC(=O)O-), carboxylato (-OC(=O)-), imine (C=NH), sulfinyl (SO), sulfonyl (SO₂) or (-NR-), wherein each R can independently be hydrogen, alkyl, cycloalkyl alkyl, or aryl alkyl.

The hydrocarbon chain of the linking group is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group of alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR^X, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

In a specific embodiment, the linking group L can itself be a divalent radical formed from a compound of the formula:

wherein

X_LG and Z_LG are each independently OR^X, NR^xR^y, SR^X or COOR^X;

Y_LG is a branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 50 carbon atoms, wherein one or more (e.g. 1, 2, 3, or 4) of the carbon atoms is optionally interrupted with, e.g., one or more cycloalkyl, aryl, heteroaryl, substituted cycloalkyl, substituted aryl, substituted heteroaryl, non- peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy (-OCH₂O-), carbonyl (-C(O)-), carboxy (-C(=0)0-), carbonyldioxy (-0C(=0)0-), carboxylato (-OC(O)-), imine (C=NH), sulfinyl (SO), sulfonyl (SO₂) or (-NR-), wherein each R can independently be hydrogen, alkyl, cycloalkyl alkyl, or aryl alkyl; wherein the hydrocarbon chain is optionally substituted on carbon with one or more (e.g. 1, 2, 3, or 4) substituents selected from the group of alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or C00R^x, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

In another specific embodiment, the linking group L can itself be a divalent radical formed from a compound of the formula:

wherein

XL_G and Z_LG are each independently OR^X, NR^xR^y, SR^X or COOR^X; Y_LG is one or more groups selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, substituted aryl, heterocycle, substituted heterocycle, heteroaryl and substituted heteroaryl; and

R^x and R^y are each independently hydrogen, alkyl, cycloalkyl alkyl, or aryl alkyl.

In a further specific embodiment, X_LG and Z_LG are each independently hydroxyl, amino, thio or carboxylic acid. In a further specific embodiment, Y_LG is alkyl. In another specific embodiment, Y_LG is alkyl cycloalkyl alkyl. In another specific embodiment, Y_LG is alkyl heterocycle alkyl. In another specific embodiment, Y_LG is alkyl aryl alkyl. In another specific embodiment, Y_LG is alkyl heteroaryl alkyl. In another specific embodiment, Y_LG is substituted alkyl. In another specific embodiment, the linking group L can itself be a divalent radical formed from polyethylene glycol (PEG).

R-L-T linkages

In the compound of formula R-L-T, the linking group L is optionally present. When the linking group is absent, L is a direct bond such that the amino acid or peptide, R, and the triterpene, T, are covalently bonded to one another to form a suitable linkage. When the linking group is present, the triterpene, R, is covalently bonded to the linking group L to form a suitable linkage, and the linking group L is also covalently bonded to the triterpene T to form another suitable linkage. Each of the covalent bonds can be formed from suitable functional groups present on each of the triterpene T, the amino acid or peptide R and the linking group L. Exemplary suitable functional groups include, e.g., hydroxyl (OH), carboxylic acid (COOH), thio (SH) and amino (NH). Exemplary suitable linkages include, e.g., carboxylic esters, amides, and thioesters. Suitable functional groups and linkages are shown in the tables I and II below.

Table I Suitable Functional Grou s and Linkages of Triter ene and Linking Group

Table II

Suitable Functional Groups and Linkages of Amino Acid or Peptide and

Linking Group

Pharmaceutical Formulations

The compounds described herein are formulated with conventional carriers and excipients, which will be selected in accord with ordinary practice. Tablets will contain excipients, glidants, fillers, binders and the like. Aqueous formulations are prepared in sterile form, and when intended for delivery by other than oral administration generally will be isotonic. All formulations will optionally contain excipients such as those set forth in the Handbook of Pharmaceutical Excipients, 5^th Ed.; Rowe, Sheskey, and Owen, Eds.; American Pharmacists Association; Pharmaceutical Press: Washington, DC, 2006. Excipients include ascorbic acid and other antioxidants, chelating agents such as EDTA, carbohydrates such as dextrin, hydroxyalkylcellulose, hydroxyalkylmethylcellulose, stearic acid and the like. The pH of the formulations ranges from about 3 to about 11, but is ordinarily about 7 to 10. While it is possible for the active ingredients to be administered alone it may be preferable to present them as pharmaceutical formulations. The formulations, both for veterinary and for human use, of the invention comprise at least one active ingredient, as above defined, together with one or more acceptable carriers therefor and optionally other therapeutic ingredients. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and physiologically innocuous to the recipient thereof.

The formulations include those suitable for the foregoing administration routes. The formulations may conveniently be presented in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy.

Techniques and formulations generally are found in Remington's Pharmaceutical Sciences, Mack Publishing Company, Easton, PA, (1985). Such methods include the step of bringing into association the active ingredient with the carrier which constitutes one or more accessory ingredients. In general the formulations are prepared by uniformly and intimately bringing into association the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product.

Formulations of the present invention suitable for oral administration may be presented as discrete units such as capsules, cachets or tablets each containing a predetermined amount of the active ingredient; as a powder or granules; as a solution or a suspension in an aqueous or non-aqueous liquid; or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion. The active ingredient may also be administered as a bolus, electuary or paste.

A tablet is made by compression or molding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine the active ingredient in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent, preservative, surface active or dispersing agent. Molded tablets may be made by molding in a suitable machine a mixture of the powdered active ingredient moistened with an inert liquid diluent. The tablets may optionally be coated or scored and optionally are formulated so as to provide slow or controlled release of the active ingredient therefrom.

For administration to the eye or other external tissues e.g., mouth and skin, the formulations are preferably applied as a topical ointment or cream containing the active ingredient(s) in an amount of, for example, 0.075 to 20% w/w (including active ingredient(s) in a range between 0.1% and 20% in increments of 0.1% w/w such as 0.6% w/w, 0.7% w/w, etc.), preferably 0.2 to 15% w/w and most preferably 0.5 to 10% w/w. When formulated in an ointment, the active ingredients may be employed with either a paraffinic or a water-miscible ointment base. Alternatively, the active ingredients may be formulated in a cream with an oil-in-water cream base.

If desired, the aqueous phase of the cream base may include, for example, at least 30% w/w of a polyhydric alcohol, i.e. an alcohol having two or more hydroxyl groups such as propylene glycol, butane 1,3-diol, mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400) and mixtures thereof. The topical formulations may desirably include a compound which enhances absorption or penetration of the active ingredient through the skin or other affected areas. Examples of such dermal penetration enhancers include dimethyl sulphoxide and related analogs. The oily phase of the emulsions of this invention may be constituted from known ingredients in a known manner. While the phase may comprise merely an emulsifier (otherwise known as an emulgent), it desirably comprises a mixture of at least one emulsifier with a fat or an oil or with both a fat and an oil. Preferably, a hydrophilic emulsifier is included together with a lipophilic emulsifier which acts as a stabilizer. It is also preferred to include both an oil and a fat. Together, the emulsifier(s) with or without stabilizer(s) make up the so-called emulsifying wax, and the wax together with the oil and fat make up the so-called emulsifying ointment base which forms the oily dispersed phase of the cream formulations.

Emulgents and emulsion stabilizers suitable for use in the formulation of the invention include Tween® 60, Span® 80, cetostearyl alcohol, benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodium lauryl sulfate. The choice of suitable oils or fats for the formulation is based on achieving the desired cosmetic properties. The cream should preferably be a non-greasy, non- staining and washable product with suitable consistency to avoid leakage from tubes or other containers. Straight or branched chain, mono- or dibasic alkyl esters such as di-isoadipate, isocetyl stearate, propylene glycol diester of coconut fatty acids, isopropyl myristate, decyl oleate, isopropyl palmitate, butyl stearate, 2-ethylhexyl palmitate or a blend of branched chain esters known as Crodamol CAP may be used, the last three being preferred esters. These may be used alone or in combination depending on the properties required. Alternatively, high melting point lipids such as white soft paraffin and/or liquid paraffin or other mineral oils are used.

Pharmaceutical formulations according to the present invention comprise one or more compounds described herein together with one or more pharmaceutically acceptable carriers or excipients and optionally other therapeutic agents. Pharmaceutical formulations containing the active ingredient may be in any form suitable for the intended method of administration. When used for oral use for example, tablets, troches, lozenges, aqueous or oil suspensions, dispersible powders or granules, emulsions, hard or soft capsules, syrups or elixirs may be prepared. Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents including sweetening agents, flavoring agents, coloring agents and preserving agents, in order to provide a palatable preparation. Tablets containing the active ingredient in admixture with non-toxic pharmaceutically acceptable excipient which are suitable for manufacture of tablets are acceptable. These excipients may be, for example, inert diluents, such as calcium or sodium carbonate, lactose, lactose monohydrate, croscarmellose sodium, povidone, calcium or sodium phosphate; granulating and disintegrating agents, such as maize starch, or alginic acid; binding agents, such as cellulose, microcrystalline cellulose, starch, gelatin or acacia; and lubricating agents, such as magnesium stearate, stearic acid or talc. Tablets may be uncoated or may be coated by known techniques including microencapsulation to delay disintegration and adsorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax may be employed.

Formulations for oral use may be also presented as hard gelatin capsules where the active ingredient is mixed with an inert solid diluent, for example calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, such as peanut oil, liquid paraffin or olive oil.

Aqueous suspensions of the invention contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients include a suspending agent, such as sodium carboxymethylcellulose, methylcellulose, hydroxypropyl methylcelluose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia, and dispersing or wetting agents such as a naturally occurring phosphatide {e.g., lecithin), a condensation product of an alkylene oxide with a fatty acid {e.g., polyoxyethylene stearate), a condensation product of ethylene oxide with a long chain aliphatic alcohol {e.g., heptadecaethyleneoxycetanol), a condensation product of ethylene oxide with a partial ester derived from a fatty acid and a hexitol anhydride {e.g., polyoxyethylene sorbitan monooleate). The aqueous suspension may also contain one or more preservatives such as ethyl or n-propyl p-hydroxy-benzoate, one or more coloring agents, one or more flavoring agents and one or more sweetening agents, such as sucrose or saccharin.

Oil suspensions may be formulated by suspending the active ingredient in a vegetable oil, such as arachis oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oral suspensions may contain a thickening agent, such as beeswax, hard paraffin or cetyl alcohol. Sweetening agents, such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an antioxidant such as ascorbic acid.

Dispersible powders and granules of the invention suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, a suspending agent, and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those disclosed above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.

The pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, such as olive oil or arachis oil, a mineral oil, such as liquid paraffin, or a mixture of these. Suitable emulsifying agents include naturally-occurring gums, such as gum acacia and gum tragacanth, naturally occurring phosphatides, such as soybean lecithin, esters or partial esters derived from fatty acids and hexitol anhydrides, such as sorbitan monooleate, and condensation products of these partial esters with ethylene oxide, such as polyoxyethylene sorbitan monooleate. The emulsion may also contain sweetening and flavoring agents. Syrups and elixirs may be formulated with sweetening agents, such as glycerol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative, a flavoring or a coloring agent. The pharmaceutical compositions of the invention may be in the form of a sterile injectable preparation, such as a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally acceptable diluent or solvent, such as a solution in 1,3-butane-diol or prepared as a lyophilized powder. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile fixed oils may conventionally be employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid may likewise be used in the preparation of injectables.

The amount of active ingredient that may be combined with the carrier material to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a time-release formulation intended for oral administration to humans may contain approximately 1 to 1000 mg of active material compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95% of the total compositions (weightweight). The pharmaceutical composition can be prepared to provide easily measurable amounts for administration. For example, an aqueous solution intended for intravenous infusion may contain from about 3 to 500 μg of the active ingredient per milliliter of solution in order that infusion of a suitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for administration to the eye include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, especially an aqueous solvent for the active ingredient. The active ingredient is preferably present in such formulations in a concentration of 0.5 to 20%, advantageously 0.5 to 10% particularly about 1.5% w/w.

Formulations suitable for topical administration in the mouth include lozenges comprising the active ingredient in a flavored basis, usually sucrose and acacia or tragacanth; pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia; and mouthwashes comprising the active ingredient in a suitable liquid carrier.

Formulations for rectal administration may be presented as a suppository with a suitable base comprising for example cocoa butter or a salicylate. Formulations suitable for intrapulmonary or nasal administration have a particle size for example in the range of 0.1 to 500 microns (including particle sizes in a range between 0.1 and 500 microns in increments microns such as 0.5, 1, 30 microns, 35 microns, etc.), which is administered by rapid inhalation through the nasal passage or by inhalation through the mouth so as to reach the alveolar sacs. Suitable formulations include aqueous or oily solutions of the active ingredient. Formulations suitable for aerosol or dry powder administration may be prepared according to conventional methods and may be delivered with other therapeutic agents such as compounds heretofore used in the treatment or prophylaxis of a given condition. Formulations suitable for vaginal administration may be presented as pessaries, tampons, creams, gels, pastes, foams or spray formulations containing in addition to the active ingredient such carriers as are known in the art to be appropriate.

Formulations suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents.

The formulations are presented in unit-dose or multi-dose containers, for example sealed ampoules and vials, and may be stored in a freeze-dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injection, immediately prior to use. Extemporaneous injection solutions and suspensions are prepared from sterile powders, granules and tablets of the kind previously described. Preferred unit dosage formulations are those containing a daily dose or unit daily sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredient.

It should be understood that in addition to the ingredients particularly mentioned above the formulations of this invention may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavoring agents. The invention further provides veterinary compositions comprising at least one active ingredient as above defined together with a veterinary carrier therefor.

Veterinary carriers are materials useful for the purpose of administering the composition and may be solid, liquid or gaseous materials which are otherwise inert or acceptable in the veterinary art and are compatible with the active ingredient. These veterinary compositions may be administered orally, parenterally or by any other desired route.

Compounds described herein can also be formulated to provide controlled release of the active ingredient to allow less frequent dosing or to improve the pharmacokinetic or toxicity profile of the active ingredient. Accordingly, the invention also provided compositions comprising one or more compounds described herein formulated for sustained or controlled release. Effective dose of active ingredient depends at least on the nature of the condition being treated, toxicity, whether the compound is being used prophylactically (lower doses), the method of delivery, and the pharmaceutical formulation, and will be determined by the clinician using conventional dose escalation studies. It can be expected to be from about 0.0001 to about 100 mg/kg body weight per day. Typically, from about 0.01 to about 10 mg/kg body weight per day. More typically, from about .01 to about 5 mg/kg body weight per day. More typically, from about .05 to about 0.5 mg/kg body weight per day. For example, the daily candidate dose for an adult human of approximately 70 kg body weight will range from 1 mg to 1000 mg, preferably between 5 mg and 500 mg, and may take the form of single or multiple doses.

Routes of Administration

One or more compounds described herein (herein referred to as the active ingredients) are administered by any route appropriate to the condition to be treated. Suitable routes include oral, rectal, nasal, topical (including buccal and sublingual), vaginal and parenteral (including subcutaneous, intramuscular, intravenous, intradermal, intrathecal and epidural), and the like. It will be appreciated that the preferred route may vary with for example the condition of the recipient.

Combination Therapy

Compounds described herein can also be used in combination with other active ingredients. Such combinations are selected based on the condition to be treated, cross-reactivities of ingredients and pharmaco-properties of the combination.

It is also possible to combine any compound described herein with one or more other active ingredients in a unitary dosage form for simultaneous (concurrent) or sequential administration to a patient. The combination therapy may be administered as a simultaneous (concurrent) or sequential regimen. When administered sequentially, the combination may be administered in two or more administrations. The combination therapy may provide "synergy" and "synergistic effect", i.e. the effect achieved when the active ingredients used together is greater than the sum of the effects that results from using the compounds separately. A synergistic effect may be attained when the active ingredients are: (1) co-formulated and administered or delivered simultaneously in a combined formulation; (2) delivered by alternation or in parallel as separate formulations; or (3) by some other regimen. When delivered in alternation therapy, a synergistic effect may be attained when the compounds are administered or delivered sequentially, e.g., in separate tablets, pills or capsules, or by different injections in separate syringes. In general, during alternation therapy, an effective dosage of each active ingredient is administered sequentially, i.e. serially, whereas in combination therapy, effective dosages of two or more active ingredients are administered together.

Pharmaceutical kits useful in the present invention, which include a therapeutically effective amount of a pharmaceutical composition that includes a compound of component (a) and one or more compounds of component (b), in one or more sterile containers, are also within the ambit of the present invention. Sterilization of the container may be carried out using conventional sterilization methodology well known to those skilled in the art. Component (a) and component (b) may be in the same sterile container or in separate sterile containers. The sterile containers or materials may include separate containers, or one or more multi-part containers, as desired. Component (a) and component (b), may be separate, or physically combined into a single dosage form or unit as described above. Such kits may further include, if desired, one or more of various conventional pharmaceutical kit components, such as for example, one or more pharmaceutically acceptable carriers, additional vials for mixing the components, etc., as will be readily apparent to those skilled in the art. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and/or guidelines for mixing the components, may also be included in the kit.

Methods of Making the Compounds of the Invention. The compounds described herein can be prepared by any of the applicable techniques of organic synthesis. Many such techniques are well known in the art. However, many of the known techniques are elaborated in Compendium of Organic Synthetic Methods (John Wiley & Sons, New York) Vol. 1, Ian T. Harrison and Shuyen Harrison (1971); Vol. 2, Ian T. Harrison and Shuyen Harrison (1974); Vol. 3, Louis S. Hegedus and Leroy Wade (1977); Vol. 4, Leroy G. Wade Jr., (1980); Vol. 5, Leroy G. Wade Jr. (1984); and Vol. 6, Michael B. Smith; as well as March, J., Advanced Organic Chemistry, 3rd Edition, John Wiley & Sons, New York (1985); Comprehensive Organic Synthesis. Selectivity, Strategy & Efficiency in Modern Organic Chemistry, In 9 Volumes, Barry M. Trost, Editor-in-Chief, Pergamon Press, New York (1993); Advanced Organic Chemistry, Part B:

Reactions and Synthesis, 4th Ed.; Carey and Sundberg; Kluwer Academic/Plenum Publishers: New York (2001); Advanced Organic Chemistry, Reactions, Mechanisms , and Structure, 2nd Edition, March, McGraw Hill (1977); Protecting Groups in Organic Synthesis, 2nd Edition, Greene, T. W., and Wutz, P.G.M., John Wi ley & Sons, New York ( 1991 ) ; and Comprehensive Organic Transformations, 2nd Edition, Larock, R.C., John Wiley & Sons, New York (1999).

Examples

Example 1 : Preparation of (3β)-Lup-20(29)-ene-3,28-diyl ditrifluoroacetate or betulin bis-trifluoromethyl acetate. Molecular Formula: C₃₄H₄₈F₆O₄. Molecular Weight: 634.733

In a 100 ml round bottom flask to a stirred suspension of 5 g (1 1.3 mmol) of Betulin and 50 ml CH₂Cl₂ at -30/- 40 ⁰C 5.2 g (24.86 mmol) Of(CF₃CO)₂O was added. The mixture was stirred for 10 min and then both the solvent and remaining trifluoromethylacetic acid was removed by vacuum evaporation at 10-15 ⁰C to obtain 7.17 g of white crystals. These were recrystallized from hexane to give white needles mp 172.4-174.7 ⁰C (dec).

Example 2: Preparation of (3β)-30-Bromolup-20(29)-ene-3,28- diyl ditrifluoroacetate or 30-Bromo-3,28-bis(trifluoroacetoxy)lup-20(29)-ene

A solution of betulin bis-trifluoromethyl acetate (5Og), NBS (28.04g), and carbon tetrachloride (IL) was heated to 4O⁰C and held for 23 hours. The reaction mixture was allowed to cool to room temperature and then washed twice with dilute NaHCO3 solution. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to an orange solid. NMR analysis indicated starting material remained present in the solid.

The solid was redissolved in carbon tetrachloride (IL) and NBS (7.88g) was added. The reaction was heated to 4O⁰C overnight. NMR analysis indicated the reaction was complete and was cooled to room temperature. The reaction was washed twice with bicarbonate solution (IL each) and dried over sodium sulfate. The dried solution was filtered and concentrated in vacuo to afford an orange solid. NMR analysis indicated pure product Example 3: Preparation of (3β)-30-Bromolup-20(29)-ene-3,28-diol or 30- Bromobetulin. Molecular Formula: C_3OH^BrO₂. Molecular Weight: 521.613

A mixture of 30-Bromo-3,28-bis(trifluoroacetoxy)lup-20(29)-ene (24 g, 0.0336 mol), potassium hydroxide (75.48 g, 1.345 mol), THF (1.14 L) and water (228 ml) was vigorously stirred at room temperature under nitrogen atmosphere. After 18 h, the aqueous layer was separated, extracted with THF (100 ml x2). The organics were combined, washed with brine, and the solvent was evaporated to dryness. The residue was triturated in a mortar. 250 ml of 5% aqueous AcOH was added; the residue was filtered off, dried and recrystallized from EtOAc (250 ml) to yield 30-Bromobetulin (1 1.86 g, 68%). M.p. 218-220 ⁰C.

Example 4: Preparation of (3β)-30N-Aspartamelup-20(29)-ene-3,28-diol (LK 121). Molecular Formula: C₄₄H₆₆N₂O₇. Molecular Weight: 735.004.

To solution of 0.1 g (0.4 mmol) aspartame in minimum amount of water,

0.033 g (0.4 mmol) NaHCO₃ precipitate was added. The solution was left for 30 min at room temperature and then was added to solution of 0.1 g (0.19 mmol) 30- bromobetulin in 6 ml DMAA. Reaction mixture was stirred at 60-70 °C overnight. Reaction was monitored by TLC and HPLC. Reaction mixture was diluted with 50 ml of water, NaCl was added and stirred for 3 hrs at room temperature Precipitate was filtered off, washed with water and dried. Then precipitate was stirred and refluxed for 4hrs in ether. After cooling to room temperature precipitate was filtered off and dried in vacuum. Yield 0.06 g (43%). M.p. 164-170 °C. IH NMR (CDC13+CD3OD, 300 MHz) δ 7.28 (m, 5H), 4.97 (s, IH), 4.84 (s, IH), 4.54 (m, 2H), 4.32 (m, IH), 4.16 (d, J = 10.8 Hz, IH), 3.76 (d, J = 1 1 Hz, IH), 3.50 (m, IH), 3.19 (m, 4H)₅ 2.98 (m, IH), 2.61 (d, J = 17.1 Hz, IH), 2.28 (m, IH), 2.18-0.66 (m, 42H).

Example 5: Biological activity

Biological activity of exemplary compounds described herein, wherein LK121 refers to (3β)-30N-Aspartamelup-20(29)-ene-3,28-diol and GW0004 refers to 3β-aminoactoxyallobetulin (see, Tables III and IV).

Table III

Table IV

All publications, patents, and patent applications are incorporated herein by reference. While in the foregoing specification this invention has been described in relation to certain preferred embodiments thereof, and many details have been set forth for purposes of illustration, it will be apparent to those skilled in the art that the invention is susceptible to additional embodiments and that certain of the details described herein may be varied considerably without departing from the basic principles of the invention.

Claims

Claims

1. A compound of formula (I)

R-L-T (I) or a pharmaceutically acceptable salt or solvate thereof wherein, R is a radical of an amino acid or a peptide; L is a diradical linking group or is a direct bond; and T is a radical of a triterpene.

2. The compound of claim 1, wherein R is a radical of a peptide.

3. The compound of claim 1, wherein R is a radical of a dipeptide.

4. The compound of claim 1, wherein R is a radical of aspartame, which is:

5. The compound of any one of claims 1-4, wherein L is a direct bond.

6. The compound of any one of claims 1-5, wherein T is a radical of betulin, betulinic acid, betulinic aldehyde, betulone, betulonic acid, betulonic aldehyde, lupeol, or lupenone.

7. The compound of any one of claims 1-6, wherein the triterpene is a lupane, and R-L is attached to the C-30 position of the triterpene.

8. The compound of any one of claims 1-7, wherein R-L is attached to the triterpene via an NR^ι-CR^rR^r linkage, wherein R¹ is hydrogen or alkyl and each R^r is independently hydrogen, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, NR^xR^y and/or COOR^X, wherein each R^x and R^y is independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy 1.

9. The compound of any one of claims 1-7, wherein R-L is attached to the triterpene via an NH-CH₂ linkage.

10. The compound of claim 1, which is 30-(N-aspartame)lup-20(30)-ene-3b,28- diol, which is a compound of formula (II):

(II).

11. A compound of formula (III)

(III)

or a pharmaceutically acceptable salt or solvate thereof wherein, the bond between C-20 and C-29 is a single bond or is a double bond; L is a suitable linking group or is a direct bond; R¹ is radical of an amino acid or peptide; R² is hydroxyl alkyl, CR^X1R^X2, or alkyl; R³ is H, or R³ and R⁴ together are keto (=0);

R⁴ is hydroxyl, or R³ and R⁴ together are keto (=0); R^X1 is keto (=0), thioxo (=S) or oxime (=N0H); R^X2 is H, hydroxy or alkoxy.

12. The compound of claim 1 1, wherein the bond between C-20 and C-29 is a single bond.

13. The compound of claim 11, wherein the bond between C-20 and C-29 is a double bond.

14. The compound of any one of claims 1 1-13, wherein R¹ is a radical of a peptide.

15. The compound of any one of claims 11-13, wherein R¹ is radical of a dipeptide.

16. The compound of any one of claims 11-13, wherein R¹ is a radical of aspartame, which is

17. The compound of any one of claims 11-16, wherein L is a divalent, branched or unbranched, saturated or unsaturated, hydrocarbon chain, having from 1 to 50 carbon atoms, wherein the 1 to 50 carbon atoms is optionally interrupted with one or more cycloalkyl, aryl, heteroaryl, substituted cycloalkyl, substituted aryl, substituted heteroaryl, non-peroxide oxy (-O-), thio (-S-), imino (-N(H)-), methylene dioxy

(-OCH₂O-), carbonyl (-C(=O)-), carboxy (-C(=O)O-), carbonyldioxy (-OC(=O)O-), carboxylato (-OC(=O», imine (C=NH), sulfinyl (SO), sulfonyl (SO₂) or (-NR-), wherein each R can independently be hydrogen, alkyl, cycloalkyl alkyl, or aryl alkyl; and wherein the hydrocarbon chain is optionally substituted on carbon with one or more substituents selected from the group of alkyl, alkenyl, alkylidenyl, alkenylidenyl, alkoxy, halo, haloalkyl, hydroxy, hydroxyalkyl, aryl, heteroaryl, heterocycle, cycloalkyl, alkanoyl, alkoxycarbonyl, amino, imino, alkylamino, acylamino, nitro, trifluoromethyl, trifluoromethoxy, carboxy, carboxyalkyl, keto, thioxo, alkylthio, alkylsulfϊnyl, alkylsulfonyl, cyano, acetamido, acetoxy, acetyl, benzamido, benzenesulfinyl, benzenesulfonamido, benzenesulfonyl, benzenesulfonylamino, benzoyl, benzoylamino, benzoyloxy, benzyl, benzyloxy, benzyloxycarbonyl, benzylthio, carbamoyl, carbamate, isocyannato, sulfamoyl, sulfinamoyl, sulfino, sulfo, sulfoamino, thiosulfo, NR^xR^y and/or COOR*, wherein each R^x and R^y are independently H, alkyl, alkenyl, aryl, heteroaryl, heterocycle, cycloalkyl or hydroxy.

18. The compound of any one of claims 11-16, wherein L is a direct bond.

19. The compound of any one of claims 11-18, wherein R² is CH₃, CH₂OH, COOH or CHO.

20. The compound of any one of claims 1 1-19, wherein R³ is H.

21. The compound of any one of claims 11-19, wherein R³ and R⁴ together are keto (=0).

22. The compound of any one of claims 11-19, wherein R⁴ is hydroxy.

23. The compound of any one of claims 11-22, wherein L- R¹ is attached to a radical of betulin, betulinic acid, betulinic aldehyde, betulone, betulonic acid, betulonic aldehyde, lupeol, or lupenone; at the C-30 position of the triterpene.

24. The compound of claim 23, wherein L is a direct bond.

25. The compound of any one of claims 23-24, wherein R¹ a radical of a peptide.

26. The compound of any one of claims 23-24, wherein R¹ is radical of a dipeptide.

27. The compound of any one of claims 23-24, wherein R^! is a radical of aspartame, which is:

28. A method for killing or inhibiting a virus, the method comprising contacting a virus with a suitable amount of the compound of any one of claims 1-27, for a period of time effective to inhibit or kill the virus.

29. The method of claim 28, wherein the contacting is in vitro.

30. The method of claim 28, wherein the contacting is in vivo.

31. The method of any one of claims 28-30, wherein the virus is human immunodeficiency virus (HIV), or is herpes virus.

32. A method for killing or inhibiting a bacteria, the method comprising contacting a bacteria with a suitable amount of the compound of any one of claims 1-27, for a period of time effective to inhibit or kill the bacteria.

33. The method of claim 32, wherein the contacting is in vitro.

34. The method of claim 32, wherein the contacting is in vivo.

35. A method for killing or inhibiting a fungus, the method comprising contacting a fungus with a suitable amount of the compound of any one of claims 1- 27, for a period of time effective to inhibit or kill the fungus.

36. The method of claim 35, wherein the contacting is in vitro.

37. The method of claim 35, wherein the contacting is in vivo.

38. A method of treating a mammal afflicted with a viral infection, the method comprising administering to a mammal in need of such treatment a suitable amount of the compound of any one of claims 1-27, for a period of time effective to treat the viral infection.

39. The method of claim 38, wherein the mammal is a human.

40. The method of any one of claims 38-39, wherein the virus is human immunodeficiency virus (HIV).

41. The method of any one of claims 39-40, wherein the virus is herpes virus.

42. The method of any one of claims 38-41, wherein the compound is formulated with a pharmaceutically acceptable carrier.

43. The method of claim 42, wherein the administering further comprises administering a second active ingredient.

44. The method of claim 43, wherein the compound of any one of claims 1-27, and the second active ingredient are concurrently administered.

45. The method of claim 43, wherein the compound of any one of claims 1-27, and the second active ingredient are sequentially administered.

46. A method of treating a mammal afflicted with a bacterial infection, the method comprising administering to a mammal in need of such treatment a suitable amount of the compound of any one of claims 1-27, for a period of time effective to treat the bacterial infection.

47. The method of claim 46, wherein the mammal is a human.

48. The method of any one of claims 46-47, wherein the compound is formulated with a pharmaceutically acceptable carrier.

49. The method of any one of claims 46-48, wherein the administering further comprises administering a second active ingredient.

50. The method of claim 49, wherein the compound of any one of claims 1-27, and the second active ingredient are concurrently administered.

51. The method of claim 46, wherein the compound of any one of claims 1 -27, and the second active ingredient are sequentially administered.

52. A method of treating a mammal afflicted with a fungal infection, the method comprising administering to a mammal in need of such treatment a suitable amount of the compound of any one of claims 1-27, for a period of time effective to treat the fungal infection.

53. The method of claim 52, wherein the mammal is a human.

54. The method of any one of claims 52-53, wherein the compound is formulated with a pharmaceutically acceptable carrier.

55. The method of claim 44, wherein the administering further comprises administering a second active ingredient.

56. The method of claim 55, wherein the compound of any one of claims 1-27, and the second active ingredient are concurrently administered.

57. The method of claim 55, wherein the compound of any one of claims 1-27, and the second active ingredient are sequentially administered.

58. A compound of formula (IV):

or a pharmaceutically acceptable salt or solvate thereof wherein, the bond between C-20 and C-29 is a single bond or is a double bond;

X^x is F, Cl, Br or I;

R² is hydroxyl alkyl, CR^X1R^X2, O- CR^X1R^X2 or alkyl;

R³ is H, or R³ and R⁴ together are keto (=0);

R⁴ is hydroxyl alkyl, CR^X1R^X2, or alkyl; or R³ and R⁴ together are keto (=0);

R^X1 is keto (=0), thioxo (=S) or oxime (=N0H);

R^x2 is H, hydroxyl, alkyl, trifluoromethyl or alkoxy.

59. A method of manufacturing a compound of any one of claims 1-27, the method comprising contacting the compound of claim 58, and an amino acid or a peptide, for a suitable time and temperature and under suitable conditions to provide the compound of any one of claims 1-27.