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US 2023/0159436 A1Published application
Applications of amide analogs of triterpenes in cures of cancer and other diseases
AssigneePacific Arrow Limited
InventorsPui-Kwong CHAN, May Sung MAK
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Abstract
This invention provides a method of synthesizing new active compounds for pharmaceutical uses including cancer treatment, wherein the cancers comprise breast, leukocytic, liver, ovarian, bladder, prostatic, skin, bone, brain, leukemia, lung, colon, CNS, melanoma, renal, cervical, esophageal, testicular, splenic, kidney, lymphatic, pancreatic, stomach, eye and thyroid cancers. The active compounds are amine, sulfonamides, amide, and urea analogs of triterpene.
Claims19
A compound having the structure:
- diamine, amine, amide, sulfonamide or urea thereof, wherein R1, R2, R3, R5, R8, R9, R11, R12, R13, R14, R15, R16 are independently selected from the group of H, O, OH, NH2, CH3, CH2OH, and COOH;
- R17 and R18 are selected from NH-ethyl, NH—(Z)-(2-methylbut-2-en-1-yl), NH-(E)-(2-methylbut-2-en-1-yl), NH-(3-methylbut-2-en-1-yl, NH-(E)-(but-2-en-1-yl, NH-cinnamyl, NH-pent-4-en-1-yl, NH-(E)-3-((4-(dimethylamino)but-2-en-1-yl, NH-acetyl, NH-angeloyl, NH-tigloyl, NH-senecioyl, NH-Crotonoyl, NH-Cinnamoyl, NH-Pentenoyl, NH-4-(dimethylamino)-2-methylbut-2-enoyl, NH-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl, NHSO2-ethyl, NHSO2-(Z)-(2-methylbut-2-en-1-yl), NHSO2-(E)-prop-1-enyl, NHSO2-(E)-2-phenylethenyl, NHSO2-but-3-enyl, NH—CO—NH-ethyl, NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-1-(3-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(but-2-en-1-yl), NH—CO—NH-1-cinnamyl, NH—CO—NH-1-(but-3-en-1-yl), NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl);
- or wherein the R17 and R18 are selected from NH-ethanyl, NH-propanyl, NH-propenyl, NH-butanyl, NH-butenyl, NH-pentanyl, NH-hexenyl, NH-heptanyl, NH-heptenyl, NH-octanyl, NH-octenyl, NH-nonanyl, NH-nonenyl, NH-decanyl, NH-decenyl, NH-alkyl, NH-haloalkyl, NH-alkenyl, NH-alkynyl, NH-hydroxyalkyl, NH-alkylene-O-alkyl, NH-aryl, NH-alkylene-aryl, NH-heteroaryl, NH-alkylene-heteroaryl, NH-cycloalkyl, NH-heterocyclyl, and NH-alkylene-heterocyclyl, NH-tigloyl, NH-angeloyl, NH-senecioyl, NH-acetyl, NH-Crotonoyl, NH-3,3-Dimethylartyloyl, NH-Cinnamoyl, NH-Pentenoyl, NH-Hexanoyl, NH-benzoyl, NH-Ethylbutyryl, NH-alkyl, NH-dibenzoyl, NH-benzoyl, NH-alkanoyl, NH-alkenoyl, NH-benzoyl alkyl substituted NH-alkanoyl, NH-alkanoyl substituted phenyl, NH-alkenoyl substituted phenyl, NH-aryl, NH-acyl, NH-heterocylic, NH-heteroraryl, NH-alkenylcarbonyl, NH-alkane, NH-alkene, NH-sugar moiety, NH-acid moiety, NH-ethanoyl, NH-propanoyl, NH-propenoyl, NH-butanoyl, NH-butenoyl, NH-pentanoyl, NH-hexenoyl, NH-heptanoyl, NH-heptenoyl, NH-octanoyl, NH-octenoyl, NH-nonanoyl, NH-nonenoyl, NH-decanoyl, NH-decenoyl, NH-propionyl, NH-2-propenoyl, NH-2-butenoyl, NH-Isobutyryl, NH-2-methylpropanoyl, NH-2-ethylbutyryl, NH-ethylbutanoyl, NH-2-ethylbutanoyl, NH-butyryl, NH-(E)-2,3-Dimethylacryloyl, NH-(E)-2-Methylcrotonoyl, NH-3-cis-Methyl-methacryloyl, NH-3-Methyl-2-butenoyl, NH-3-Methylcrotonoyl, NH-4-Pentenoyl, NH-(2E)-2-pentenoyl, NH-Caproyl, NH-5-Hexenoyl, NH-Capryloyl, NH-Lauroyl, NH-Dodecanoyl, NH-Myristoyl, NH-Tetradecanoyl, NH-Oleoyl, NH—C(2-18) Acyl,
- CH2NH-tigloyl, CH2NH-angeloyl, CH2NH-senecioyl, CH2NH-acetyl, CH2NH-Crotonoyl, CH2NH-3,3-Dimethylartyloyl, CH2NH-Cinnamoyl, CH2NH-Pentenoyl, CH2NH-Hexanoyl, CH2NH-benzoyl, CH2NH-Ethylbutyryl, CH2NH-alkyl, CH2NH-dibenzoyl, CH2NH-benzoyl, CH2NH-alkanoyl, CH2NH-alkenoyl, CH2NH-benzoyl alkyl substituted CH2NH-alkanoyl, CH2NH-alkanoyl substituted phenyl, CH2NH-alkenoyl substituted phenyl, CH2NH-aryl, CH2NH-acyl, CH2NH-heterocylic, CH2NH-heteroraryl, CH2NH-alkenylcarbonyl, CH2NH-alkane, CH2NH-alkene, CH2NH-sugar moiety, CH2NH-acid moiety, CH2NH-ethanoyl, CH2NH-propanoyl, CH2NH-propenoyl, CH2NH-butanoyl, CH2NH-butenoyl, CH2NH-pentanoyl, CH2NH-hexenoyl, CH2NH-heptanoyl, CH2NH-heptenoyl, CH2NH-octanoyl, CH2NH-octenoyl, CH2NH-nonanoyl, CH2NH-nonenoyl, CH2NH-decanoyl, CH2NH-decenoyl, CH2NH-propionyl, CH2NH-2-propenoyl, CH2NH-2-butenoyl, CH2NH-Isobutyryl, CH2NH-2-methylpropanoyl, CH2NH-2-ethylbutyryl, CH2NH-ethylbutanoyl, CH2NH-2-ethylbutanoyl, CH2NH-butyryl, CH2NH-(E)-2,3-Dimethylacryloyl, CH2NH-(E)-2-Methylcrotonoyl, CH2NH-3-cis-Methyl-methacryloyl, CH2NH-3-Methyl-2-butenoyl, CH2NH-3-Methylcrotonoyl, CH2NH-4-Pentenoyl, CH2NH-(2E)-2-pentenoyl, CH2NH-Caproyl, CH2NH-5-Hexenoyl, CH2NH-Capryloyl, CH2NH-Lauroyl, CH2NH-Dodecanoyl, CH2NH-Myristoyl, CH2NH-Tetradecanoyl, CH2NH-Oleoyl, CH2NH—C(2-18) Acyl,
- CH2NHCO-tigloyl, CH2NHCO-angeloyl, CH2NHCO-senecioyl, CH2NHCO-acetyl, CH2NHCO-Crotonoyl, CH2NHCO-3,3-Dimethylartyloyl, CH2NHCO-Cinnamoyl, CH2NHCO-Pentenoyl, CH2NHCO-Hexanoyl, CH2NHCO-benzoyl, CH2NHCO-Ethylbutyryl, CH2NHCO-alkyl, CH2NHCO-dibenzoyl, CH2NHCO-benzoyl, CH2NHCO-alkanoyl, CH2NHCO-alkenoyl, CH2NHCO-benzoyl alkyl substituted CH2NHCO-alkanoyl, CH2NHCO-alkanoyl substituted phenyl, CH2NHCO-alkenoyl substituted phenyl, CH2NHCO-aryl, CH2NHCO-acyl, CH2NHCO-heterocylic, CH2NHCO-heteroraryl, CH2NHCO-alkenylcarbonyl, CH2NHCO-alkane, CH2NHCO-alkene, CH2NHCO-sugar moiety, CH2NHCO-acid moiety, CH2NHCO-ethanoyl, CH2NHCO-propanoyl, CH2NHCO-propenoyl, CH2NHCO-butanoyl, CH2NHCO-butenoyl, CH2NHCO-pentanoyl, CH2NHCO-hexenoyl, CH2NHCO-heptanoyl, CH2NHCO-heptenoyl, CH2NHCO-octanoyl, CH2NHCO-octenoyl, CH2NHCO-nonanoyl, CH2NHCO-nonenoyl, CH2NHCO-decanoyl, CH2NHCO-decenoyl, CH2NHCO-propionyl, CH2NHCO-2-propenoyl, CH2NHCO-2-butenoyl, CH2NHCO-Isobutyryl, CH2NHCO-2-methylpropanoyl, CH2NHCO-2-ethylbutyryl, CH2NHCO-ethylbutanoyl, CH2NHCO-2-ethylbutanoyl, CH2NHCO-butyryl, CH2NHCO-(E)-2,3-Dimethylacryloyl, CH2NHCO-(E)-2-Methylcrotonoyl, CH2NHCO-3-cis-Methyl-methacryloyl, CH2NHCO-3-Methyl-2-butenoyl, CH2NHCO-3-Methylcrotonoyl, CH2NHCO-4-Pentenoyl, CH2NHCO-(2E)-2-pentenoyl, CH2NHCO-Caproyl, CH2NHCO-5-Hexenoyl, CH2NHCO-Capryloyl, CH2NHCO-Lauroyl, CH2NHCO-Dodecanoyl, CH2NHCO-Myristoyl, CH2NHCO-Tetradecanoyl, CH2NHCO-Oleoyl, CH2NHCO—C(2-18) Acyl,
- CH2NHCONH-tigloyl, CH2NHCONH-senecioyl, CH2NHCONH-acetyl, CH2NHCONH-Crotonoyl, CH2NHCONH-3,3-Dimethylartyloyl, CH2NHCONH-Cinnamoyl, CH2NHCONH-Pentenoyl, CH2NHCONH-Hexanoyl, CH2NHCONH-benzoyl, CH2NHCONH-Ethylbutyryl, CH2NHCONH-alkyl, CH2NHCONH-dibenzoyl, CH2NHCONH-benzoyl, CH2NHCONH-alkanoyl, CH2NHCONH-alkenoyl, CH2NHCONH-benzoyl alkyl substituted CH2NHCONH-alkanoyl, CH2NHCONH-alkanoyl substituted phenyl, CH2NHCONH-alkenoyl substituted phenyl, CH2NHCONH-aryl, CH2NHCONH-acyl, CH2NHCONH-heterocylic, CH2NHCONH-heteroraryl, CH2NHCONH-alkenylcarbonyl, CH2NHCONH-alkane, CH2NHCONH-alkene, CH2NHCONH-sugar moiety, CH2NHCONH-acid moiety, CH2NHCONH-ethanoyl, CH2NHCONH-propanoyl, CH2NHCONH-propenoyl, CH2NHCONH-butanoyl, CH2NHCONH-butenoyl, CH2NHCONH-pentanoyl, CH2NHCONH-hexenoyl, CH2NHCONH-heptanoyl, CH2NHCONH-heptenoyl, CH2NHCONH-octanoyl, CH2NHCONH-octenoyl, CH2NHCONH-nonanoyl, CH2NHCONH-nonenoyl, CH2NHCONH-decanoyl, CH2NHCONH-decenoyl, CH2NHCONH-propionyl, CH2NHCONH-2-propenoyl, CH2NHCONH-2-butenoyl, CH2NHCONH-Isobutyryl, CH2NHCONH-2-methylpropanoyl, CH2NHCONH-2-ethylbutyryl, CH2NHCONH-ethylbutanoyl, CH2NHCONH-2-ethylbutanoyl, CH2NHCONH-butyryl, CH2NHCONH-(E)-2,3-Dimethylacryloyl, CH2NHCONH-(E)-2-Methylcrotonoyl, CH2NHCONH-3-cis-Methyl-methacryloyl, CH2NHCONH-3-Methyl-2-butenoyl, CH2NHCONH-3-Methylcrotonoyl, CH2NHCONH-4-Pentenoyl, CH2NHCONH-(2E)-2-pentenoyl, CH2NHCONH-Caproyl, CH2NHCONH-5-Hexenoyl, CH2NHCONH-Capryloyl, CH2NHCONH-Lauroyl, CH2NHCONH-Dodecanoyl, CH2NHCONH-Myristoyl, CH2NHCONH-Tetradecanoyl, CH2NHCONH-Oleoyl, CH2NHCONH—C(2-18) Acyl, NHSO2-tigloyl, NHSO2-senecioyl, NHSO2-acetyl, NHSO2-Crotonoyl, NHSO2-3,3-Dimethylartyloyl, NHSO2-Cinnamoyl, NHSO2-Pentenoyl, NHSO2-Hexanoyl, NHSO2-benzoyl, NHSO2-Ethylbutyryl, NHSO2-alkyl, NHSO2-dibenzoyl, NHSO2-benzoyl, NHSO2-alkanoyl, NHSO2-alkenoyl, NHSO2-benzoyl alkyl substituted NHSO2-alkanoyl, NHSO2-alkanoyl substituted phenyl, NHSO2-alkenoyl substituted phenyl, NHSO2-aryl, NHSO2-acyl, NHSO2-heterocylic, NHSO2-heteroraryl, NHSO2-alkenylcarbonyl, NHSO2-alkane, NHSO2-alkene, NHSO2-sugar moiety, NHSO2-acid moiety, NHSO2-ethanoyl, NHSO2-propanoyl, NHSO2-propenoyl, NHSO2-butanoyl, NHSO2-butenoyl, NHSO2-pentanoyl, NHSO2-hexenoyl, NHSO2-heptanoyl, NHSO2-heptenoyl, NHSO2-octanoyl, NHSO2-octenoyl, NHSO2-nonanoyl, NHSO2-nonenoyl, NHSO2-decanoyl, NHSO2-decenoyl, NHSO2-propionyl, NHSO2-2-propenoyl, NHSO2-2-butenoyl, NHSO2-Isobutyryl, NHSO2-2-methylpropanoyl, NHSO2-2-ethylbutyryl, NHSO2-ethylbutanoyl, NHSO2-2-ethylbutanoyl, NHSO2-butyryl, NHSO2-(E)-2,3-Dimethylacryloyl, NHSO2-(E)-2-Methylcrotonoyl, NHSO2-3-cis-Methyl-methacryloyl, NHSO2-3-Methyl-2-butenoyl, NHSO2-3-Methylcrotonoyl, NHSO2-4-Pentenoyl, NHSO2-(2E)-2-pentenoyl, NHSO2-Caproyl, NHSO2-5-Hexenoyl, NHSO2-Capryloyl, NHSO2-Lauroyl, NHSO2-Dodecanoyl, NHSO2-Myristoyl, NHSO2-Tetradecanoyl, NHSO2-Oleoyl, NHSO2-C(2-18) Acyl,
- CH2NHSO2-tigloyl, CH2NHSO2-senecioyl, CH2NHSO2-acetyl, CH2NHSO2-Crotonoyl, CH2NHSO2-3,3-Dimethylartyloyl, CH2NHSO2-Cinnamoyl, CH2NHSO2-Pentenoyl, CH2NHSO2-Hexanoyl, CH2NHSO2-benzoyl, CH2NHSO2-Ethylbutyryl, CH2NHSO2-alkyl, CH2NHSO2-dibenzoyl, CH2NHSO2-benzoyl, CH2NHSO2-alkanoyl, CH2NHSO2-alkenoyl, CH2NHSO2-benzoyl alkyl substituted CH2NHSO2-alkanoyl, CH2NHSO2-alkanoyl substituted phenyl, CH2NHSO2-alkenoyl substituted phenyl, CH2NHSO2-aryl, CH2NHSO2-acyl, CH2NHSO2-heterocylic, CH2NHSO2-heteroraryl, CH2NHSO2-alkenylcarbonyl, CH2NHSO2-alkane, CH2NHSO2-alkene, CH2NHSO2-sugar moiety, CH2NHSO2-acid moiety, CH2NHSO2-ethanoyl, CH2NHSO2-propanoyl, CH2NHSO2-propenoyl, CH2NHSO2-butanoyl, CH2NHSO2-butenoyl, CH2NHSO2-pentanoyl, CH2NHSO2-hexenoyl, CH2NHSO2-heptanoyl, CH2NHSO2-heptenoyl, CH2NHSO2-octanoyl, CH2NHSO2-octenoyl, CH2NHSO2-nonanoyl, CH2NHSO2-nonenoyl, CH2NHSO2-decanoyl, CH2NHSO2-decenoyl, CH2NHSO2-propionyl, CH2NHSO2-2-propenoyl, CH2NHSO2-2-butenoyl, CH2NHSO2-Isobutyryl, CH2NHSO2-2-methylpropanoyl, CH2NHSO2-2-ethylbutyryl, CH2NHSO2-ethylbutanoyl, CH2NHSO2-2-ethylbutanoyl, CH2NHSO2-butyryl, CH2NHSO2-(E)-2,3-Dimethylacryloyl, CH2NHSO2-(E)-2-Methylcrotonoyl, CH2NHSO2-3-cis-Methyl-methacryloyl, CH2NHSO2-3-Methyl-2-butenoyl, CH2NHSO2-3-Methylcrotonoyl, CH2NHSO2-4-Pentenoyl, CH2NHSO2-(2E)-2-pentenoyl, CH2NHSO2-Caproyl, CH2NHSO2-5-Hexenoyl, CH2NHSO2-Capryloyl, CH2NHSO2-Lauroyl, CH2NHSO2-Dodecanoyl, CH2NHSO2-Myristoyl, CH2NHSO2-Tetradecanoyl, CH2NHSO2-Oleoyl, CH2NHSO2-C(2-18) Acyl, wherein the compound is in form in form of powder, liquid or crystal.
4 more elements
A Method for the preparation of compound of 24,28-diamine(E4D) with E4:
- 1) To a solution of triterpene or compound (E4)E4A (2 mmol) in tetrahydrofuran (THF, 10 mL) were added methanesulfonyl chloride (Ms-Cl, 2.2 mmol) and triethylamine (TEA, 3 mmol) at 0° C. and the resulting mixture was stirred for 2 hours;
- 2) The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in ethyl acetate (EtOAc) and washed with water;
- 3) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure;
- 4) The residue was dissolved in 10 mL of dimethylformamide (DMF), and then sodium azide (NaN3, 6 mmol) was added. After overnight stirring at 60° C., the reaction mixture was diluted with ethyl acetate and washed with water;
- 5) The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure;
- 6) Then, the obtained compound was dissolved in methanol (MeOH), and 10% palladium on carbon (Pd—C, 0.2 mmol) was added. After overnight stirring under hydrogen atmosphere, the reaction mixture was filtered, washed with methanol and concentrated under reduced pressure to provide the desired 24,28-diamine(E4D);
3 more elements
11:
- The method of claim 10, (E4D) with acetaldehyde, (Z)-2-methylbut-2-enal, (E)-2-methylbut-2-enal, 3-methylbut-2-enal, (E)-but-2-enal, cinnamaldehyde, pent-4-enal, (E)-4-(dimethylamino)but-2-enal gave the following compounds:
- wherein:
- 1) R1, R2, R3, R5, R8 are OH;
- R17, R18 are NH-ethyl;
- 2) R1, R2, R3, R5, R8 are OH;
- R17, R18 are NH—(Z)-(2-methylbut-2-en-1-yl);
- 3) R1, R2, R3, R5, R8 are OH;
- R17, R18 are NH-(E)-(2-methylbut-2-en-1-yl);
- 4) R1, R2, R3, R5, R8 are OH;
- R17, R18 are NH-(3-methylbut-2-en-1-yl;
- 5) R1, R2, R3, R5, R8 are OH;
- R17, R18 are NH-(E)-(but-2-en-1-yl;
- 6) R18, R2, R3, R5, R8 are OH;
- R17, R18 are NH-cinnamyl;
- 7) R18, R2, R3, R5, R8 are OH;
- R17, R18 are NH-pent-4-en-1-yl;
- 8) R18, R2, R3, R5, R8 are OH;
- R17, R18 are NH-(E)-3-((4-(dimethylamino)but-2-en-1-yl.
15 more elements
A method of treating cancer in a subject, comprising administering to the subject a therapeutically effective amount of a compound having the structure:
- wherein R1, R2, R5, R8 are OH;
- R17, R18 are selected from NH-acetyl, NH-angeloyl, NH-tigloyl, NH-senecioyl, NH-Crotonoyl, NH-Cinnamoyl, NH-Pentenoyl, NH-4-(dimethylamino)-2-methylbut-2-enoyl, NH-4-[(2-methoxyethyl)amino]-2-methyl-4oxobut-2-enoyl, NHSO2-ethyl, NHSO2-(Z)-(2-methylbut-2-en-1-yl), NHSO2-(E)-prop-1-enyl, NHSO2-(E)-2-phenylethenyl, NHSO2-but-3-enyl, NH—CO—NH-ethyl, NH—CO—NH—(Z)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(2-methylbut-2-en-1-yl), NH—CO—NH-1-(3-methylbut-2-en-1-yl), NH—CO—NH-(E)-1-(but-2-en-1-yl), NH—CO—NH-1-cinnamyl, NH—CO—NH-1-(but-3-en-1-yl), NH—CO—NH-(E)-1-(4-(dimethylamino)but-3-en-1-yl), NH-ethyl, NH—(Z)-(2-methylbut-2-en-1-yl), NH-(E)-(2-methylbut-2-en-1-yl), NH-(3-methylbut-2-en-1-yl, NH-(E)-(but-2-en-1-yl, NH-cinnamyl, NH-pent-4-en-1-yl, NH-(E)-3-((4-(dimethylamino)but-2-en-1-yl.
Dependencies are inferred from the claim text.