IP Library › Granted Patent US 8,742,121

Granted Patent B2

US 8,742,121 · App. 13/614,751 · Granted Jun 3, 2014

Process for the preparation of small molecule inhibitors of MDM2 and intermediates used therein

Inventors: Shaomeng Wang (Saline, MI); Ke Ding (Guangzhou, CN); Guoping Wang (Ann Arbor, MI)

Assignee: The Regents of the University of Michigan

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Quick Facts

Patent No.: US 8,742,121
App. No.: 13/614,751
Granted: Jun 3, 2014
Kind: B2

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Abstract

The invention relates to small molecules which function as inhibitors of the interaction between p53 and MDM2. The invention also relates to the use of these compounds for inhibiting cell growth, inducing cell death, inducing cell cycle arrest and/or sensitizing cells to additional agent(s).

Claims (115)

1. A compound selected from the group consisting of:

3-E-benzylidene-6-chloro-1,3-dihydro-indole-2-one;

3-E-benzylidene-6-bromo-1,3-dihydro-indol-2-one;

3-E-benzylidene-6-fluoro-1,3-dihydro-indol-2-one;

3-E-benzylidene-6-trifluoromethyl-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-bromo-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-methyl-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-methoxyl-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3,5-dichloro-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-bromo-3-(3-bromo-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-methyl-butylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(2-cyclohexyl-ethylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-pyridin-2-ylmethylene-1,3-dihydro-indol-2-one;

3-E-3-(6-chloro-pyridin-2-ylmethylene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-3-(3-chloro-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-3-(3-chloro-4-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one; and

3-E-3-(3-bromo-benzylidene)-6-trifluoromethyl-1,3-dihydro-indol-2-one.

2. The compound of claim 1 which is 3-E-3-(3-chloro-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one.

3. The compound of claim 1 which is 3-E-3-(3-chloro-4-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one.

4. A compound selected from the group consisting of:

3-E-6-chloro-3-(3-iodo-benzylidene)-1,3-dihydro-indol-2-one;

3-E-3-(3-bromo-benzylidene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-methoxy-benzylidene)-1,3-dihydro-indol-2-one;

3-E-3-(6-bromo-pyridin-2-ylmethylene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(1-methyl-1H-pyrrol-2-ylmethylene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-pyridin-4-ylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-pyridin-3-ylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-furan-3-ylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-furan-2-ylmethylene-1,3-dihydro-indol-2-one;

3-E-3-(3-bromo-benzylidene)-6-methoxy-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-fluoro-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(2,3-difluoro-benzylidene)-1,3-dihydro-indol-2-one;

3-E-3-(3-bromo-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-3-(3-chloro-2-fluoro-benzylidene)-6-methyl-1,3-dihydro-indol-2-one;

3-E-3-(3-bromo-2-fluoro-benzylidene)-6-methoxy-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-chloro-2-fluoro-benzylidene)-5-fluoro-1,3-dihydro-indol-2-one; and

3-E-3-(3-bromo-benzylidene)-6-chloro-5-fluoro-1,3-dihydro-indol-2-one.

5. A method of preparing a compound of Formula X:

wherein:

R 1 and R 5 are independently optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, CO 2 R′, OCOR′, CONR′R″, NR″COR′, NR′SO 2 R″, SO 2 NR′R″, (C═NR′)NR″R′″, or NR′R″;

R 7 is H;

each R 9 is independently selected from H, F, Cl, Br, I, OH, NO 2 , alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, OR′, CO 2 R′, OCOR′, CONR′R″, NR″COR′, NR′SO 2 R″, SO 2 NR′R″, (C═NR′)NR″R′″, or NR′R″;

t is 1, 2, 3, or 4;

R 10 and R 11 are independently H, OH or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heterocyclic, (CH 2 ) n —R′, (CH 2 ) n —NR′R″, (CH 2 ) n —NR′COR″, (CH 2 ) n —NR′SO 2 R″, (CH 2 ) n —NR′(C═NR″)NR′″, (CH 2 ) n —COOH, (CH 2 ) n —COOR′, (CH 2 ) n —CONR′R″, (CH 2 ) n —OR′, (CH 2 ) n —SR′, (CH 2 ) n —COR′, (CH 2 ) n —SO 2 H, (CH 2 ) n —SONR′R″, (CH 2 ) n —SO 2 NR′R″, (CH 2 CH 2 O) n —(CH 2 ) m —OH, (CH 2 CH 2 O) n —(CH 2 ) m —OR′, (CH 2 CH 2 O) n —(CH 2 ) m —COOR′, (CH 2 CH 2 O) n —(CH 2 ) m —CONR′R″, (CH 2 CH 2 O) n —(CH 2 ) m —NR′R″, (CH 2 CH 2 O) n —(CH 2 ) m —NR′COR″, (CH 2 CH 2 O) n —(CH 2 ) m —NR′(C═NR″)NR′″, (CH 2 CH 2 O) n —(CH 2 ) m —NR′SO 2 R″, (CH 2 ) p —(CH 2 CH 2 O) n —(CH2) m —OH, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —OR′, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —COOR′, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —CONR′R″, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —NR′R″, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —NR′COR″, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —NR′(C═NR″)NR′″, (CH 2 ) p —(CH 2 CH 2 O) n —(CH 2 ) m —NR′SO 2 R″, —CO—R′, —SOR′, or —SO 2 R′;

n, m, and p are each independently 1-6; and

each R′, R″ and R′″ is independently H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic; or

R′ and R″, or R″ and R′″, form a ring,

the process comprising condensing a compound of Formula I:

with R 1 CHO.

6. The method of claim 5 , wherein the condensation of Formula 1 with R 1 CHO gives a compound of Formula 3:

7. The method of claim 5 , wherein:

R 1 and R 5 are independently optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic;

each R 9 is independently selected from H, F, Cl, Br, alkyl, or OR′;

R 10 and R 11 are independently H or optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, or heterocyclic; and

R′ is alkyl.

8. The method of claim 7 , wherein:

R 1 is optionally substituted aryl;

R 5 is alkyl; and

each R 9 is independently selected from H, F, or Cl.

9. The method of claim 8 , wherein:

R 10 is hydrogen; and

R 11 is optionally substituted alkyl, aryl, or heterocyclic.

10. The method of claim 6 further comprising an asymmetric 1,3-dipolar cycloaddition reaction comprising the compound of Formula 3 as a reactant.

11. The method of claim 7 , wherein the compound of Formula 3 is selected from the group consisting of:

3-E-benzylidene-6-chloro-1,3-dihydro-indole-2-one;

3-E-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one;

3-E-benzylidene-6-bromo-1,3-dihydro-indol-2-one;

3-E-benzylidene-6-fluoro-1,3-dihydro-indol-2-one;

3-E-benzylidene-6-trifluoromethyl-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-bromo-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-methyl-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-methoxyl-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(4-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3,5-dichloro-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-bromo-3-(3-bromo-benzylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3,3-dimethyl-butylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-methyl-butylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(2-cyclohexyl-ethylidene)-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-cyclohexylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-cyclopentylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-thiophen-2-ylmethylene-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-pyridin-2-ylmethylene-1,3-dihydro-indol-2-one;

3-E-3-(6-chloro-pyridin-2-ylmethylene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-3-(3-chloro-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-3-(3-chloro-4-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one;

3-E-6-chloro-3-(3-chloro-5-fluoro-benzylidene)-1,3-dihydro-indol-2-one; and

3-E-3-(3-bromo-benzylidene)-6-trifluoromethyl-1,3-dihydro-indol-2-one.

12. The method of claim 11 , wherein the compound of Formula 3 is 3-E-3-(3-chloro-2-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one.

13. The method of claim 11 , wherein the compound of Formula 3 is 3-E-6-chloro-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one.

14. The method of claim 11 , wherein the compound of Formula 3 is 3-E-6-chloro-3-(4-chloro-benzylidene)-1,3-dihydro-indol-2-one.

15. The method of claim 11 , wherein the compound of Formula 3 is 3-E-3-(3-chloro-4-fluoro-benzylidene)-6-chloro-1,3-dihydro-indol-2-one.

16. The method of claim 6 , wherein the compound of Formula 3 is selected from the group consisting of:

3-E-6-chloro-3-(3-trifluoromethyl-benzylidene)-1,3-dihydro-indol-2-one;