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1. (WO2015002996) PRECISE DELIVERY OF THERAPEUTIC AGENTS TO CELL MITOCHONDRIA FOR ANTI-CANCER THERAPY
Anmerkung: Text basiert auf automatischer optischer Zeichenerkennung (OCR). Verwenden Sie bitte aus rechtlichen Gründen die PDF-Version.

CLAIMS

What is claimed is:

1. A compounds having Formula I:


where

TC is a mitochondria targeting moiety;

IM is an inhibitor moiety;

1 is from 1 to 10;

m is from 1 to 3 ;

n is from 0 to 20;

p is from 1 to 64;

X1 is -CO2-, -CO2CH2-, -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-;

X2 is -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-;

X3 is -CO2-, -OC(O)-, -NHR3-, -SO2-, -CO-, -S-, -O-, -1,2,3-triazole-; and

R1, R2, and R3 are, independently of one another, -H, -F, -CI, -Br, -OH, -C1-6 alkyl, or -OC(O)C1-6 alkyl, or a pharmaceutically acceptable salt thereof.

2. The compound of claim 1, wherein m is 1, 2, or 3, X1 is -CO2- or -CHR3-; X2 is - CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-; X3 is -CO2-; R1, R2, and R3 are each -H; p is 1; 1 is 1 to 5; and n is 0 to 3.

3. The compound of any one of the previous claims, wherein p is 1, 2, or 3, X1 is - CO2- or -CHR3-; X2 is -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-; X3 is - CO2-; R1, R2, and R3 are each -H; m is 1 ; 1 is 1 to 5; and n is 0 to 3.

4. The compound of any one of the previous claims, wherein TC is a cationic

rhodamine moiety or a Szeto-Shiller peptide.

5. The compound of any one of the previous claims, wherein TC is a

triphenyphosphonium moiety.

6. The compound of any one of the previous claims, wherein IM is lonidamine, dichloroacetate, alpha-tocopheryl succinate, methyl jasmonate, betulinic acid, and resveratrol, A-385358, ABT-263, ABT-737, AT-101, 2-amino-6-bromo-4-(1-cyano- 2-ethoxy-2-oxoethyl)-4H-chromene-3-carboxylate (HA14-1), LDH-A shRNA, orlistat, SB-204990, soraphen A, 4-(N-(s- glutathionylacetate)aminophenylarsenoxide (GSAO), clodronate, PK11195, menadione, beta-lapachone, CD437, gamitrinibs, 8-(2-chloro-3,4,5- trimethoxybenzyl)-2-fluoro-9-(pent-4-nyl)-9H-purin-6-amine (PU24Fcl), (8-(6- bromobenzo[d][1,3,]dioxyl-5-ylthio)-9-(pent-4-nyl)-9H-purin-6-amine (PUH58), 8- (6-iodobenzo[d][1,3,]dioxyl-5-ylthio)-9-(3-isopropylamino)propyl-9H-purin-6- amine (PUH71), shepherdin, 2 -methoxy estradiol, tetrathiomolybdate, buthionine sulphoximine, dimethylamino-parthenolide, parthenolide, imexons, magafodipir, menadione, motexafin gadolinium, PEITCs, elescomol (STA-4783), all trans- retinoic acid, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid, E-3-(4'-hydroxy-3'-adamantylbiphenyl-4yl)acrylic acid, 3-bromopyruvate, butyric acid, 2-deoxyD-glucose, arsenite trioxide, or betulinic acid.

7. The compound of any one of the previous claims, wherein IM is DCA.

8. The compound of any one of the previous claims, wherein the compound has

Formula II:


where

1 is from 1 to 10;

m is from 1 to 3;

n is from 0 too 20;

p is from 1 to 64;

X1 is -CO2-, -CO2CH2-, -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-;

X2 is -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-; and

R1, R2, and R3 are, independently of one another, -H, -F, -CI, -Br, -OH, -C1-6 alkyl, or -OC(O)C1-6 alkyl.

9. The compound of any one of the previous claims, wherein m is 1, 2, or 3, X1 is - CO2- or -CHR3- and X2 is -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-; R1, R2, and R3 are each -H; p is 1; 1 is 1 to 5; and n is 0 to 3.

10. The compound of any one of the previous claims, wherein p is 1, 2, or 3, X1 is - CO2- or -CHR3- and X2 is -CONR3-, -SO2NR3-, -CHR3-, -NHR3-, -CO-, or -O-; and R1, R2, and R3 are each -H; m is 1 ; 1 is 1 to 5; and n is 0 to 3.

11. The compound of any one of the previous claims, wherein m is 1, 2, or 3, X1 is - CH2- and X2 is -CONH-, and R1 and R2 are each -H; p is 1 ; 1 is 1 to 3; and n is 0.

12. The compound of any one of the previous claims, wherein p is 1, 2, or 3, X1 is - CH2- and X2 is -CONH-, and R1 and R2 are each -H; m is 1; 1 is 1 to 3; and n is 0.

13. The compound of any one of the previous claims, wherein the compound has

Formula IV or V:



where p is 1 to 64, and R1 is C1-3 alkyl or H.

14. The compound of any one of the previous claims, wherein the compound


or

or a pharmaceutically acceptable salt thereof.

15. A compound comprising from 4 to 64 triphenyl phosphenyl moieities and from 4 to 64 dichloroacetyl moieties.

16. The compound of claim 15 having the structure

17. The compound of claim 15 having the structure


.

18. The compound of claim 15 having the structure


.

19. A composition, comprising a compound of any one of claims 1-18 and a

pharmaceutically acceptable carrier

20. A nanoparticle comprising a hydrophobic core, a hydrophilic outer layer

surrounding the core, and a compound of any one of claims 1-18.

21. The nanoparticle of claim 20, wherein the core comprises poly(lactic-co-glycolic) acid.

22. The nanoparticle of claim 20 or 21, wherein the hydrophilic outer layer comprises polyethylene glycol and is attached to the core.

23. A method of treating or preventing cancer in a subject, comprising administering to the subject an effective amount of a compound or composition of any one of claims 1-18 or nanoparticle of any one of claims 20-22.

24. The method of claim 23, wherein the cancer is prostate cancer lung, breast, brain, ovarian, lymphoma, leukemia, head and neck, pancreatic, and cervical, colon and rectum, endrometrial, esophagous, liver, penile, skin-melanoma, skin-nonmelanoma, stomach, testicular, vaginal, uterine, vulvar, paranasal cancer, oropharyngeal and laryngeal cancers.

25. The method of any one of claims 23-24, further comprising administering a second compound or composition, wherein the second compound or composition includes an anticancer agent.

26. The method of any one of claims 23-25, further comprising administering an

effective amount of ionizing radiation to the subject.

27. A method of killing a tumor cell in a subject, comprising contacting the tumor cell with an effective amount of a compound or composition of any one of claims 1-18 or nanoparticle of any one of claims 20-22.