WO2008028060B1

WO2008028060B1 - Anti-tumor compounds for inhibiting cancer growth

Info

Publication number: WO2008028060B1
Application number: PCT/US2007/077273
Authority: WO
Inventors: Pui-Kwong Chan; May Sung Mak
Original assignee: Pacific Arrow Ltd
Current assignee: Pacific Arrow Ltd
Priority date: 2006-09-01
Filing date: 2007-08-30
Publication date: 2008-11-20
Anticipated expiration: 2009-03-01
Also published as: CN101553497B; WO2008028060A9; EP2061798A4; EP2061798A2; WO2008028060A2; CN101553497A; WO2008028060A3

Abstract

This invention provides a method for treating cancer by blocking the migration, metastasis of cancer cells, growth of cancers wherein the cancers comprise breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, renal cancer or cervix cancer. This invention provides uses of compositions comprising a triterpenoidal saponin, triterpenoid, triterpenoidal compound or sapongenin, comprising at least two side groups selected from the group consisting of angeloyl groups, tigloyl groups and senecioyl groups, wherein the side groups are attached to carbon 21, 22 or/and 28 of triterpenoidal sapogenin, triterpenoid, triterpenoidal compound or other sapongenin backbones.

Claims

AMENDED CLAIMS received by the International Bureau on 05 September 2008 (05/09/2008)What is claimed is:

1. A use of a composition for the preparation of medicament for inhibiting cancer growth, wherein the cancer cell is overexpressing aquaporin, for extending the life span of a cancer - bearing mammal, for reducing the size of tumor in a mammal, increasing the survived rate of cancer bearing mammal, for dissolving the cancer cell membrane, promoting cell apoptosis, increasing the inhibiting effect of

Paclitaxel on cancer cell, wherein the cancer is selected from the group consisting of breast cancer, leukocyte cancer, liver cancer, ovarian cancer, bladder cancer, prostate cancer, skin cancer, bone cancer, brain cancer, leukemia cancer, lung cancer, colon cancer, CNS cancer, melanoma cancer, and renal cancer, and wherein the composition comprises a compound having a formula:

named (1 B), or a salt, ester, metabolite or derivative thereof, wherein R1 comprises a group selected from hydrogen, angeloyl, tigloyl, senecioyl, alkyl, dibenzoyl, benzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl or derivatives thereof; R2 comprises a group selected from hydrogen, angeloyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl or derivative thereof; R4 comprises CH₂OR6 or COOR6, wherein R6 is selected from hydrogen, angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocyclic, heteroraryi or an acid with carbon 2-6, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl or derivative thereof; R3 is H or OH; R8 is OH; R5 comprises a hydrogen or sugar moiety, wherein the sugar moiety comprises one or more sugars including but not limited to glucose, galactose, rhamnose, arabinose, xylose, fucose, allose, altrose, gulose, idose, lyxose, mannose, psicose, ribose, sorbose, tagatose, talose, fructose, or alduronic acid: glucuronic acid, galacturonic acid, or derivatives thereof, or the combination thereof; wherein position C23, C24, C25, C26, C29 and C30 of the compound

68 independently comprise CH₃, CH₂OH, CHO, COOH, COOa-lkyl, COO-aryl, COO- heterocyclic, COO-heteroaryl, CH₂Oaryl, CH₂O- heterocyclic, CH₂O- heterσaryl, alkyls group, acetyl group, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl particularly CH₃, CH₂OH.

2. A use of composition of claim 1 , wherein the composition comprising a compound with at least two of R1 , R2, and R4 comprise groups selected from angeloyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic or heteroraryl or derivative thereof; or at least one of R1 , R2, and R4 comprises a sugar moiety comprising at least two groups selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocyclic, heteroraryl or an acyl with carbon 2-6, or a derivative thereof.

3. A use of composition of claim 1 , wherein the composition comprising a compound, wherein R4 comprises CH₂OR6 wherein R6 is H; wherein R1 and R2 independently comprise an angeloyl group, or at least two of R1 , R2 and R6 comprises angeloyl or at least one of R1 , R2 or R6 comprises a sugar moiety with two angeloyls I; wherein R5 comprises a sugar moiety wherein the sugar moiety is comprised glucose, galactose, arabinose, alduronic acid, glucuronic acid, galacturonic acid or derivative thereof, or the combination thereof.

4. A use of composition of Claim 1 , wherein the composition comprising a compound selected from the following: a) A compound comprising structure Xanifolia(Y),

or chemical name: 3-0-[β-D- galactopyranosyl (1 →2)]-α-L-arabinofuranosy (1 -»3)-β-D-glucuronopyranosyl~ 21 ,22-O-diangeloyl-3β, 15α, 16α, 21 β, 22α, 28-hexahydroxyolean-12-ene; b) A compound comprising structure Xanifolia (Y1),

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or chemical name: 3-O-[β-D- galactopyranosyl (1 →2)]-α-L-arabinofuranosyl (1 -»3)-β-D-glucuronopyranosyl-21 - O-(3,4-diangeloyl)-α-L-rhamnophyranosyl-22-O-acetyl-3β,16α, 21 β, 22α, 28- pentahydroxyolean-12-ene; c) A compound comprising structure Xanifolia (Y2),

or chemical name: 3-O-[β-D- glucopyranosyl-(1-→-2)]-α-L-arabinofuranosy (1->3)-β-D-glucuronopyranosyl-21,22- O-diangeloyl-3β, 15α, 16α, 21 β, 22α, 24β, 28-heptahydroxyolean-12-ene; d) A compound comprising structure Xanifolia (Y8),

or chemical name: 3-O-[β- glucopyranosyl (1->2)]-α-arabinofuranosyl (1→3)-^-glucuronopyranosyl-21 , 22-0- diangeloyl-3/?, 16α, 2ϊβ, 22a, 24/?, 28-hexahydroxyolean-12-ene; e) A compound comprising structure Xanifolia (Y9),

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chemical name: Z-O-[β- galactopyranosyl (1 ->2)]-o:-arabinofuranosyl (1 -»3)-/?-glucuronopyranosyl-21 -O- (3,4-diangeloyl)-α-rhamnopyranosyl-28-O-acetyl-3/?, 16α, 21/?, 22a, 28- pentahydroxyolean-12-ene; and f) A compound comprising structure Xanifolia (Y10),

or chemical name:

3-O-[/£-galactopyranosyl (i->2)]-α-arabinofuranosyl (1→3)-y-f-glucuronopyranosyl- 21 , 22-O-diangeloyl-3/?, 16«, 21^, 22a, 28-pentahydroxyolean-12-ene. g) A compound comprising structure Xanifolia (YO),

or chemical name: 3-0-[β-D- galactopyranosyl(1->2)]-α-L-arabinofuranosyl(1-»3)-β-D-glucuronopyranosyl-21-0- angeloyl, 22-O-(2-methylpropanoyl)-3β, 15α, 16α, 21β, 22α, 28-hexahydroxyolean- 12-ene, h) A compound comprising structure Xanifolia (X),

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or chemical name: Z-O-{[β-D- galactopyranosyl (1-»2)Hα-L-arabinofuranosyl (1->3)]-/?-D-glucuronopyranoside butyl ester}-21 -O-acetyl-22-O-angeloyl- 3β, 16α,21 β, 22or,28-pentahydroxyolean-12- ene. i) A compound comprising Compound (Y7),

or chemical name: 3-0-[β-D- galactopyranosyl-(1→2)]-α-L-arabinofuranosyl-(1→3)-^8-D-glucuronopyranosyl-21- 0-angeloyl-28-0-2-methylbutanoyl-3/3, 15 a, 16α, 2"\β, 22a, 28-hexahydroxyolean- 12-ene

5. A use of composition of Claim 1 , wherein the composition comprising a compound selected from the following: a) 3-O-[β-D-galactopyranosyl(1->2)]-α-L-arabinofuranosyl(1->3)-β-D- glucuronopyranosyl-21 ,22-0-diangeloyl-3β, 15α, 16α, 21 β, 22α, 28- hexahydroxyolean-12-ene; b) 3-O-[β-D-galactopyranosyl (1→2)]-α-L-arabinofuranosyl (1->3)-β-D- glucuronopyranosyl-21-0-(3,4-diangeloyl)-α-L-rhamnophyranosyl-22-0-acetyl- 3β,16α, 21 β, 22α, 28-pentahydroxyolean-12-ene; c) 3-0-[β-D-glucopyranosyl-(1->2)]-α-L-arabinofuranosyl (1→3)- β-D- glucuronopyranosyl-21 ,22-O-diangeloyl-3/?, 15α, 16α, 21/?, 22α, 24/?, 28- heptahydroxyolean-12-ene; d) 3-O-[/?-galactopyranosyl (1->2)]-α-arabinofuranosyl (1→3)-^ glucuronopyranosyi-21, 22-0-diangeloyl-3/?, 16a, 21/?, 22«, 28- pentahydroxyolean-12-ene;

72 e) 3-O-[y#-galactopyranosyl (1→2)]-«-arabinofuranosyl (1→3)-/?- glucuronopyranosyl-21-O-(3,4-diangeloyl)-a-rhamnopyranosyl-28-O-acetyl-3y9, 16«, 21/?, 22«, 28-pentahydroxyolean-12-ene; f) 3-O-[/?-galactopyranosyl (1→2)]-«-arabinofuranosyl (1→3)-/?- glucuronopyranosyl-21 , 22-O-diangeloyl-3/?, 16«, 21$ 22a, 28- pentahydroxyolean-12-ene; g) 3-O-[β-D-galactopyranosyl (1→2)]-α-L-arabinofuranosyl (1-»3)-β-D-glucuronopyranosyl-21 ,22-O-dibenzoyl-3β, 15α, 16α, 21 β, 22α, 28-hexahydroxyolean-12-ene; h)3-0-[β-D-galactopyranosyl(1→2)]-α-L arabinofuranosyl(1→3)-β-D- glucuronopyranosyl-21 -O-(3,4- dibenzoyl)-α-L-rhamnophyranosyl-22-0-acetyl-

3β,16α, 21 β,22α, 28-pentahydroxyoiean-12-ene; i)3-O-[β-D-glucopyranosyl-(1 →2)]-α-L-arabinofuranosyl (1 →3)-(-D- glucuronopyranosyl -21 ,22-0- dibenzoyl -3β, 15a, 16a, 21/?, 22a, 24/?, 28- heptahydroxyolean-12-ene; j) 3-O-[/?-galactopyranosyl (1→2)]-o;-arabinofuranosyl (1→3)-β- glucuronopyranosyl-21 , 22-0- dibenzoyl -3/?, 16«, 21/?, 22α, 28- pentahyd roxyolean- 12-ene ; k) 3-0-[/?-galactopyranosyl (1→2)]-α-arabinofuranosyl (1->3)-/?- glucuronopyranosyl-21-0-(3,4-dibenzoyl)-α-rhamnopyranosyl-28-0-acetyl-3/?, 16«,

21/?, 22«, 28-pentahydroxyolean-12-ene;

I) 3-O-[/?-galactopyranosyl (1->2)]-«-arabinofuranosyl (1->3)-^-glucuronopyranosyl

-21 , 22-0- dibenzoyl -3/?, 16«, 21/?, 22α, 28-pentahydroxyolean-12-ene; m) 3-0-[β-D-galactopyranosyl (1->2)]-β-D-xyopyranosyl (1->3)-β-D- glucuronopyranosyl-21 , 22-O-dibenzoyl-3β, 15α, 16α, 21 β, 22α, 28- hexahydroxyolean-12-ene; n) 3-O-[β-D-galactopyranosyl(1→2)]~ β-D-xyopyranosyl (1→3)-β-D- glucuronopyranosyl-21-0-(3,4-dibenzoyl)-α-L-rhamnophyranosyl-22-0-acetyl-

3β,16α, 21 β, 22α, 28-pentahydroxyolean-12-ene; o) 3-0-[β-D-glucopyranosyl-(iH>2)]-β-D-xyopyranosyl (1->3)- β-D- glucuronopyranosyl-21 , 22-0- dibenzoyl -3/?, 15«, 16«, 21/?, 22«, 24/?, 28- heptahydroxyolean-12-ene;

73 p) 3-O-[/?-D-galactopyranosyl (1→2)]- β- D-xyopyranosyl (1-»3)-/?- D- glucuronopyranosyl-21 , 22-0- dibenzoyl -3β, 16a, 21 β, 22a, 28- pentahydroxyolean-12-ene; q) 3-O-[/?-galactopyranosyl (1-»2)]- β- xyopyranosyl (1→3)-y9-glucuronopyranosyl- 21-O-(3,4- dibenzoyl)-a-rhamnopyranosyl-28-O-acetyl-3/?, 16a, 21/?, 22a, 28- pentahydroxyolean-12-ene; r) 3-0-[/?-galactopyranosyl (1→2)]-β- xyopyranosyl (1->3)-/?-glucuronopyranosyl-

21 , 22-0- dibenzoyl -3β, 16a, 21/?, 22α, 28-pentahydroxyolean-12-ene; s) 3-0-[β-D-galactopyranosyl (1→2)] - β- D-xyopyranosyl (1→3)-β-D- glucuronopyranosyl-21 , 22-0-diangeloyl-3β, 15α,16α, 21 β, 22α, 28- hexahydroxyolean-12-ene; t) 3-O-[β-D-galactopyranosyl (1->2)] - β- D-xyopyranosyl (1->3)-β-D- glucuronopyranosyl-21-O-(3, 4-diangeloyl)-α-L-rhamnophyranosyl-22-0-acetyl-

3β,16α, 21 β, 22α, 28-pentahydroxyolean-12-ene; u) 3-O-[β-D-glucopyranosyl-(1->2)] - β- D-xyopyranosyl (1->3)- β-D- glucuronopyranosyl-21 , 22-O-diangeloyl-3/?, 15a, 16a, 21,5, 22α, 24/?, 28- heptahydroxyolean-12-ene; v) 3-O-[/?-galactopyranosyl (1→2)] - β- D-xyopyranosyl (1→3)-β- glucuronopyranosyl-21 , 22-O-diangeloyl-3^, 16a, 21^, 22a, 28- pentahydroxyolean-12-ene; w) 3-O-[/?-galactopyranosyl (1→2)] - β- D-xyopyranosyl {1→3)-β- glucuronopyranosyl-21-O- (3, 4-diangeloyl)-α- rhamnopyranosyl-28-O-acetyl-3/?,

16α, 21/?, 22cc, 28- pentahydroxyolean-12-ene; x) 3-O-[^-D-galactopyranosyl (1→2)] - β- D-xyopyranosyl (1→3)-β-O- glucuronopyranosyl-21 , 22-O-diangeloyl-3/?, 16a, 21/?, 22α, 28- pentahydroxyolean-12-ene; and

Y) A compound comprising chemical name: 3-O-[^-galactopyranosyl (1→2)]- α-arabinofuranosyl (1→3)-/?- glucuronopyranosyl-21 -O-(3, 4-diangeloyl)-α- fucopyranosyl -28-O-acetyl-3/?, 16a, 21^, 22α, 28-pentahydroxyolean-12-ene

6. The use of any one of claims 1-5, wherein the medicament is effective for extending the life span of a cancer-bearing mammal, or reducing the size of tumor in a mammal.

7. The use of any one of claims 1-6, wherein the compound is a triterpenoid saponin with at least two groups, selected from angeloyl, acetyl, tigloyl, senecioyl, alkyl, benzoyl, dibenzoyl, alkanoyl, alkenoyl, benzoyl alkyl substituted alkanoyl, aryl, acyl, heterocylic, heteroraryl, cycloalkyl, cycloalkanoyl, cycloalkenoyl, aryloyl, heteroaryloyl, acyl with carbon 2-6 or derivative thereof; or particularly wherein the compound comprise angeloyl groups

8 The use of any one of claims 1-7, wherein a medicament is intravenous injection or intravenous drip; wherein a medicament is intravenous drip: 0.05-0.2mg/kg medicine dissolved in 250ml of 10% glucose solution or in 250ml of 0.9% NaCI solution; or wherein a medicament is intravenous injection: 0.05-0.2mg/kg/day medicine dissolved in 10-2OmI of 10% glucose solution or of 0.9% NaCI solution; or wherein a medicament is intravenous drip: 0.1-0.2mg/kg/day medicine dissolved in 250ml of 10% glucose solution or in 250ml of 0.9% NaCI solution; or wherein a medicament is intravenous injection: 0.1-0.2mg/kg/day medicine dissolved in 10-

20ml of 10% glucose solution or of 0.9% NaCI solution; or wherein a medicament is intraperitoneal (IP.): 2.5mg/kg/day medicine dissolved in 10% glucose solution or of 0.9% NaCI solution; or wherein a medicament is administered orally wherein the dosage of mammal is 1-10mg/Kg. ; or wherein a medicament is administered orally wherein the dosage is 10-30mg/Kg; or wherein a medicament is administered orally wherein the dosage is 30-60mg/Kg; or wherein a medicament is administered orally wherein the dosage is 60-90mg/Kg ; or wherein a medicament is administered by intravenous injection or intravenous drip wherein the dosage of mammal is 0.01- 0.1mg/Kg, or wherein the dosage is 0.1-0.2mg/Kg, or wherein the dosage is 0.2 - 0.4mg/Kg, or wherein the dosage is 0.4 - 0.6 mg/Kg; or a medicament is administered by intraperitoneal (IP.) wherein the dosage of mammal is 1-3mg/Kg, or wherein the dosage is 3-5mg/Kg, or wherein the dosage is 4-6mg/Kg, or wherein the dosage is 6-10mg/Kg.

9. The use of any one of claims 1-8, wherein the cancer comprises cells overexpressing aquaporin.

10. The use of any one of claims 1-9, wherein the medicament is capable of interacting or regulating the protein on the surface of a cell or altering the functional properties of intracellular membranes or regulating the fluid passage through the cell wall or destroying the cell membranes.

75 The use of any one of claims 1-8, wherein the medicament is also capable of treating chronic venous insufficiency, peripheral edema, antilipemic, chronic venous disease, varicose vein disease, varicose syndrome, venous stasis, Expectorant, peripheral vascular disorders, cerebro-organic convulsion, cerebral circulation disorder, cerebral edema, psychoses, dysmenorrhea!, hemorrhoids, episiotomies, haemonhoids, peripheral oedema formation or postoperative swelling; for reducing symptoms of leg pain; for treating pruritis, lower leg volume, thrombosis, thromophlebitis; for preventing gastric ulcers antispasmotic, for antithrombotic, anti-oedematous or anti inflammatory treatment, for regulating the release of PGF2, antagonism to 5-HT and histamine; or for reducingcatabolism of tissue mucopolysaccharides, for AntiMS, antianeurysm, antiasthmatic, antibradykinic, anticapillarihemorrhagic, anticephalagic, anticervicobrachialgic, antieclamptic, antiedemic, antiencaphalitic, antiepiglottitic, antiexudative, antiflu, antifracture, antigingivitic, antihematomic, antiherpetic, antihistaminic, antihydrathritic, antimeningitic, antioxidant, antiperiodontic, antiphlebitic, antipleuritic, antiraucedo, antirhinitic, antitonsilitic, antiulcer, antivaricose, antivertiginous, cancerostatic, corticosterogenic, diuretic, fungicide, hemolytic, hyaluronidase inhibitor, lymphagogue, natriuretic, pesticide, pituitary stimulant, thymolytic, vasoprotective, venotonic treatment, for curing enuresis, frequent micturition, urinary incontinence, for curing disease by mechanisms related to increasing hemolytic activities or blood circulation or reducing the formation of blood clots.

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