IP Library › Granted Patent US 8,314,142

Granted Patent B2

US 8,314,142 · App. 12/244,225 · Granted Nov 20, 2012

Dimers of artemisinin derivatives, preparation thereof and therapeutic use thereof

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Quick Facts

Patent No.: US 8,314,142
App. No.: 12/244,225
Granted: Nov 20, 2012
Kind: B2

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Abstract

The present invention relates to dimers of artemisinin derivatives, to processes for the preparation of such dimers, to methods of treatment comprising administration of such dimers, and to intermediates to such dimers.

Claims (58)

1. An compound compound of formula I:

wherein

A is a divalent group selected from the group consisting of S, SO, SO 2 , N(CH 3 ), N(CH 2 —C(O)O—CH 2 CH 3 ), N(CH 2 —COOH), (C 1 -C 6 )alkenylene, NHCO, 1,2,3-triazole, and NHSO 2 ;

B 1 and B 2 are both CF 3 ;

X 1 and X 2 are both O;

n 1 and n 2 are independently selected from the group consisting of 1, 2, 3 or 4; or pharmaceutically acceptable salt thereof, wherein the compound has less than 10 μM IC50 against HCT116 tumor line.

2. The compound of claim 1 or a hydrate, solvate, or pharmaceutically acceptable salt thereof, wherein n 1 and n 2 are identical and are selected from the group consisting of 2, 3 and 4.

3. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of N(CH 2 C(O)OCH 2 CH 3 , and N(CH 2 COOH) and n 1 and n 2 are both 2.

4. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is (C 1 -C 6 )alkenylene and n 1 and n 2 are both 1.

5. The compound of claim 1 , or pharmaceutically acceptable salt thereof, wherein A is selected from the group consisting of NHCO, and 1,2,3-triazole, and n 1 and n 2 are independently selected from the group consisting of 1 and 2.

6. A compound selected from the group consisting of:

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[thiobis(2,1-ethanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[sulfinylbis(2,1-ethanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[sulfonylbis(2,1-ethanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[thiobis(3,1-propanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[sulfinylbis(3,1-propanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[sulfonylbis(3,1-propanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[thiobis(4,1-butanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

2-[[(3R,5aS,6R,8aS,9R,10R,12R,12aR)-decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl]oxy]-N-[2-[[(3R,5aS,6R,8aS,9R,10R,12R,12aR)-decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepin-10-yl]oxy]ethyl]-N-methylethanamine;

ethyl N,N-bis(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)glycinate;

N,N-bis(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)glycine;

2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}-N-(2-{[(3S,5aS,6R,8aS,9R,10R,-12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)acetamide; 5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[(2E)-but-2-ene-1,4-diylbis(oxy)]bis[3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromene];

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[(2Z)-but-2-ene-1,4-diylbis(oxy)]bis[3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromene];

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[(2R,3R)-oxirane-2,3-diylbis(methyleneoxy)]bis[3,6,9-trimethyl-10-(trifluoromethyl)-decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromene];

(1-(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)deca-hydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)-4-({[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}methyl)-1H-1,2,3-triazole; and

1-(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)deca-hydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)-5-({[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)-1H-1,2,3-triazole

or pharmaceutically acceptable salt thereof.

7. A pharmaceutical composition comprising a compound of formula I:

wherein

A is a divalent group selected from the group consisting of S, SO, SO 2 , N(CH 3 ), N(CH 2 —C(O)O—CH 2 CH 3 ), N(CH 2 —COOH), (C 1 -C 6 )alkenylene, NHCO, 1,2,3-triazole, and NHSO 2 ;

B 1 and B 2 are both CF 3 ;

X 1 and X 2 are both O;

n 1 and n 2 are independently selected from the group consisting of 1, 2, 3 or 4; or a hydrate, solvate, or pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.

8. The pharmaceutical composition of claim 7 , wherein n 1 and n 2 are identical and are selected from the group consisting of 2, 3 and 4.

9. The pharmaceutical composition of claim 7 , wherein A is selected from the group consisting of, N(CH 2 C(O)OCH 2 CH 3 ), and N(CH 2 COOH, and n 1 and n 2 are both 2.

10. The pharmaceutical composition of claim 7 , wherein A is (C 1 -C 6 )alkenylene and n 1 and n 2 are both 1.

11. The pharmaceutical composition of claim 7 , wherein A is selected from the group consisting of NHCO and 1,2,3-triazole, and n 1 and n 2 are independently selected from the group consisting of 1 and 2.

12. The pharmaceutical composition of claim 7 , wherein the compound is selected from the group consisting of:

5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[thiobis(2,1-ethanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[sulfinylbis(3,1-propanediyloxy)]bis[decahydro-3,6,9-trimethyl-10-(trifluoromethyl)-3,12-epoxy-12H-pyrano[4,3-j]-1,2-benzodioxepine;

ethyl N,N-bis(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)glycinate;

N,N-bis(2-{[(3S,5aS,6R,8aS,9R,10R,12R,12aR)-3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromen-10-yl]oxy}ethyl)glycine;

(3S,5aS,6R,8aS,9R,10R,12R,12aR,3′S,5′aS,6′R,8′aS,9′R,10′R,12′R,12′aR)-10,10′-[(2E)-but-2-ene-1,4-diylbis(oxy)]bis[3,6,9-trimethyl-10-(trifluoromethyl)decahydro-3,12-epoxy[1,2]dioxepino[4,3-i]isochromene];

or pharmaceutically acceptable salt thereof.

13. A method for treating cancer in a patient in need thereof, comprising administering to such patient an effective amount of a compound of claim 1 or pharmaceutically acceptable salt thereof.

Assignments (2)

CHANGE OF NAME Recorded Jun 20, 2012

From: SANOFI-AVENTIS

To: SANOFI

Reel/Frame 028413/0927 →

ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Dec 18, 2008

From: COMMERCON, ALAIN; ZHANG, JIDONG; HITTINGER, AUGUSTIN

To: SANOFI-AVENTIS

Reel/Frame 022003/0079 →