# US 8,785,405 B2 · Compounds for treating cancer and other diseases > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 8,785,405 B2 - Document ID: US8785405B2 - Status: Granted - Kind: B2 - Application number: 14/020,099 - Filed: 2013-09-06 - Published: 2014-01-23 - Granted: 2014-07-22 - Earliest claimed: 2010-07-16 - Assignees: Pacific Arrow Limited - Applicants: Pacific Arrow Limited - Inventors: Pui-Kwong Chan; May Sung Mak - Web page: https://patentgrep.com/patent/US8785405B2 ## CPC - C07J 63/008: {Expansion of ring D by one atom, e.g. D homo steroids} - A61K 31/704: attached to a condensed carbocyclic ring system, e.g. sennosides, thiocolchicosides, escin, daunorubicin {(digitoxin A61K31/7048)} - A61P 35/00: Antineoplastic agents - A61P 35/02: specific for leukemia - A61P 35/04: specific for metastasis - C07H 15/24: Condensed ring systems having three or more rings - C12N 5/0693: {Tumour cells; Cancer cells} - Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change - C07J: STEROIDS (seco-steroids C07C) - A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS - C07H: SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS (derivatives of aldonic or saccharic acids C07C, C07D; aldonic acids, saccharic acids C07C59/105, C07C59/285; cyanohydrins C07C255/16; glycals C07D; compounds of unknown constitution C07G; polysaccharides, derivatives thereof C08B; DNA or RNA concerning genetic engineering, vectors, e.g. plasmids, or their isolation, preparation or purification C12N15/00; sugar industry C13) - C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00) - Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE ## 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, spleenic, kidney, lymphatic, pancreatic, stomach and thyroid cancers. This invention is an anti adhesion therapy which uses the compound as a mediator or inhibitor of adhesion proteins and angiopoietins. It inhibits excess adhesion and inhibits cell attachment. It modulates angiogenesis. The compounds also use as mediator of cell adhesion receptor, cell circulating, cell moving and inflammatory diseases. ## Claims ### Claim 1 A compound having the structure: wherein R10 is selected from the group of CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, and CH2O-Ethylbutyryl; wherein R1, R2, R4, R5, and R8 are independently selected from the group of CH2OH, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, O-ethylbutyryl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-acetyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, and CH2O-ethylbutyryl; wherein R3 is OH or H; wherein R9, R11, R12, R13, R14, and R15 are CH3. ### Claim 2 (depends on 1) The compound of claim 1, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, or CH2O-Ethylbutyryl and at least 1 of R1, R2, R4, R5, R8, are O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, O-ethylbutyryl, —CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, or CH2O-Ethylbutyryl. ### Claim 3 (depends on 1) The compound of claim 1, wherein R1 is O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, or O-ethylbutyryl, and R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, CH2O-ethylbutyryl. ### Claim 4 (depends on 1) The compound of claim 1, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-Pentenoyl, CH2O-Hexanoyl, CH2O-benzoyl, CH2O-Ethylbutyryl. ### Claim 5 (depends on 1) The compound of claim 1, wherein R4 and R10 are independently—CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl. ### Claim 6 (depends on 1) The compound of claim 1, wherein the compound is selected from the following: a) An isolated, purified or synthesized compound having structure: or chemical name: 24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene b) An isolated, purified or synthesized compound having structure: or chemical name: 24-O-Tigloyl-3β,16α, 21β,22α, 24β,28-hexahydroxyolean-12-ene c) An isolated, purified or synthesized compound having structure: or chemical name: 22,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene d) An isolated, purified or synthesized compound having structure: or chemical name: 21,24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene e) An isolated, purified or synthesized compound having structure: or chemical name: 22,24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene f) An isolated, purified or synthesized compound having structure: or chemical name: 3,21,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene g) An isolated, purified or synthesized compound having structure: or chemical name: 21,24-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene. ### Claim 7 (depends on 1) The compound of claim 1, wherein the compound is attached one or more of the functional groups selected from the group consisting of angeloyl, tigloyl, senecioyl, acetyl, crotonoyl, dimethylartyloyl, cinnamoyl, pentenoyl, hexanoyl, benzoyl, ethylbutyryl, alkyl and phenyl; wherein the compound can be obtained by a method comprising the following steps: 1. Dissolving core compound, triterpenes, hydroxylated triterpenes core in pyridine; 2. Adding the functional group or acyl chloride; 3. Stirring the mixture for a length of time including 5 sec, 1 min, 2 min, 5 min, 10 min, 30 min, 1 hr, 2 hr, 18 hr, 2 days or 3 days at different temperature; 4. At the end of reaction, adding an aqueous solution of acid or base, or water to the reaction mixture; 5. Extracting the solution with ethyl acetate followed by lyophilization; 6. Dissolving the reaction product in acetonitrile with Trifluoroacetic acid or DMSO; 7. Testing the reaction product of mixtures and individual fractions with MTT cytotoxic assay; 8. Selecting the HPLC fractions for isolation according to the cytotoxic activity of the reaction product obtained at a specific reaction time; 9. Purifying the active esterification products with HPLC; 10. Collecting the products; and 11. Testing the products. ### Claim 8 A method for inhibiting cancer cell growth, inhibiting cancer cell invasion, inhibiting cancer cell metastasis, modulating cancer cell adhesion, or modulating cancer cell attachment, wherein the cancer is selected from the group of breast cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, melanoma cancer, cervical cancer, kidney cancer, pancreatic cancer, and mouth cancer, comprising contacting said cancer cell in a cell culture with an effective amount of compound, wherein the compound is selected from the structure: wherein R10 is selected from the group of CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, CH2O-ethylbutyryl; wherein R1, R2, R4, R5, R8, are independently selected from the group of CH2OH, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, O-ethylbutyryl, O-benzoyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, and CH2O-ethylbutyryl; R3 is H or OH; R9, R11, R12, R13, R14 and R15 are CH3; and R16 is H or R4 and R16 may together form —CH2-X—, CH(OH)—X— or C(═O)—X—, wherein the —X— may be O or NH or S. ### Claim 9 A method for inhibiting cancer cell growth, inhibiting cancer cell invasion, inhibiting cancer cell metastasis, modulating cancer cell adhesion, or modulating cancer cell attachment, wherein the cancer is selected from the group of breast cancer, liver cancer, ovarian cancer, bladder cancer, prostatic cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, melanoma cancer, cervical cancer, kidney cancer, pancreatic cancer, and mouth cancer, comprising contacting said cancer cell in vitro with an effective amount of compound selected from the structure: wherein R10 is selected from the group of CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, CH2O-ethylbutyryl; wherein R1, R2, R4, R5, R8, are independently selected from the group of CH2OH, hydroxyl, O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, O-ethylbutyryl, O-benzoyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, and CH2O-ethylbutyryl; R3 is H or OH; and R9, R11, R12, R13, R14 and R15 are CH3. ### Claim 10 (depends on 9) The method of claim 9, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; R1, R2, R5 and R8 are OH; and R4 is CH2OH. ### Claim 11 (depends on 9) The method of claim 9, wherein R10 and R4 are independently CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; and R1, R2, R5 and R8 are OH. ### Claim 12 (depends on 9) The method of claim 9, wherein R10 and R4 are independently CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, CH2O-ethylbutyryl; wherein R2, R5, R8, are OH; wherein R1 is O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, or O-ethylbutyryl. ### Claim 13 (depends on 9) The method of claim 9, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; R1 is O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, O-ethylbutyryl, or O-benzoyl; R2, R5 and R8 are OH; and R4 is CH2OH. ### Claim 14 (depends on 9) The method of claim 9, wherein R10 is CH2O-tigloyl; and R1, R2, R4, R5 and R8 are OH or CH2OH. ### Claim 15 (depends on 9) The method of claim 9, wherein R10 and R4 are CH2O-tigloyl; and R1, R2, R5 and R8 are OH. ### Claim 16 (depends on 8) The method of claim 8, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; and R1, R2, R4, R5 and R8 are OH or CH2OH. ### Claim 17 (depends on 8) The method of claim 8, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; R4 is CH2O-acetyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; and R1, R2, R5 and R8 are OH. ### Claim 18 (depends on 8) The method of claim 8, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; R4 is CH2O-acetyl, CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; R2, R5 and R8 are OH; and R1 is O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-benzoyl, or O-ethylbutyryl. ### Claim 19 (depends on 8) The method of claim 8, wherein R10 is CH2O-angeloyl, CH2O-tigloyl, CH2O-senecioyl, CH2O-crotonoyl, CH2O-3,3-dimethylartyloyl, CH2O-cinnamoyl, CH2O-pentenoyl, CH2O-hexanoyl, CH2O-benzoyl, or CH2O-ethylbutyryl; R1 is O-angeloyl, O-tigloyl, O-senecioyl, O-acetyl, O-crotonoyl, O-3,3-dimethylartyloyl, O-cinnamoyl, O-pentenoyl, O-hexanoyl, O-ethylbutyryl, or O-benzoyl; R2, R5 and R8 are OH; and R4 is CH2OH. ### Claim 20 (depends on 9) The method of claim 9, wherein the compound is selected from the following: a) A compound having structure: or chemical name: 24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene, b) A compound having structure: or chemical name: 24-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene, c) A compound having structure: or chemical name: 22,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene, d) A compound having structure: or chemical name: 21,24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene, e) A compound having structure: or chemical name: 22,24,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene, f) A compound having structure: or chemical name: 3,21,28-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene, g) A compound having structure: or chemical name: 21,24-O-Tigloyl-3β,16α,21β,22α,24β,28-hexahydroxyolean-12-ene.