Benzene disulfonamide for the treatment of cancer

Patent metadata

Field	Value
Publication number	US-10913710-B2
Application number	US-201816477233-A
Country	US
Kind code	B2
Filing date	Jan 11, 2018
Priority date	Jan 12, 2017
Publication date	Feb 9, 2021
Grant date	Feb 9, 2021

Abstract

The present invention relates to novel substituted benzene disulfonamides, as well as pharmaceutical compositions containing at least one of these substituted benzene disulfonamides together with at least one pharmaceutically acceptable carrier, excipient and/or diluent. Said substituted benzene disulfonamides are binding to the prenyl binding pocket of PDE6δ and therefore, are useful for the prophylaxis and treatment of cancer by inhibition of the binding of PDE6δ to farnesylated Ras proteins and thereby, inhibition of oncogenic Ras signaling in cells.

First claim

What is claimed is:

1. A compound of the formula (I):

wherein
R 1 represents —CH 2 R 5 ;
R 2 represents —CH 2 —R 6 ;
R 3 represents —R 7 , —CH 2 —R 7 , or —CH 2 —CH 2 —R 7 ,
R 4 represents —R 8 , —CH 2 —R 8 , or —CH 2 —CH 2 —R 8 ;
R 5 represents

R 6 represents

R 7 represents

R 8 represents

R 9 -R 20 and R 9′ -R 20′ represent independently of each other
—H, —F, —Cl, —Br, —I, —OH, —CN, —NO 2 , —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2 , —C 4 H 9 , —CH 2 —CH(CH 3 ) 2 , —CH(CH 3 )—C 2 H 5 , —C(CH 3 ) 3 , -cyclo-C 3 H 5 , —CH 2 -cyclo-C 3 H 5 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —CH 2 Br, —CH 2 I, —CH 2 —CH 2 F, —CH 2 —CHF 2 , —CH 2 —CF 3 , —CH 2 —CH 2 Cl, —CH 2 —CH 2 Br, —CH 2 —CH 2 I, —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OCH(CH 3 ) 2 , —OC(CH 3 ) 3 , —OC 4 H 9 , —OCHF 2 , —OCF 3 , —OCH 2 CF 3 , —OC 2 F 5 , —OCH 2 OCH 3 , —O-cyclo-C 3 H 5 , —OCH 2 -cyclo-C 3 H 5 , —O—C 2 H 4 -cyclo-C 3 H 5 , —CHO, —COCH 3 , —COCF 3 , —COC 2 H 5 , —COC 3 H 7 , —COCH(CH 3 ) 2 , —COC(CH 3 ) 3 , —COOH, —COOCH 3 , —COOC 2 H 5 , —COOC 3 H 7 , —COOCH(CH 3 ) 2 , —COOC(CH 3 ) 3 , —OOC—CH 3 , —OOC—CF 3 , —OOC—C 2 H 5 , —OOC—C 3 H 7 , —OOC—CH(CH 3 ) 2 , —OOC—C(CH 3 ) 3 , —NH 2 , —NHCH 3 , —NHC 2 H 5 , —NHC 3 H 7 , —NHCH(CH 3 ) 2 , —NHC(CH 3 ) 3 , —N(CH 3 ) 2 , —N(C 2 H 5 ) 2 , —N(C 3 H 7 ) 2 , —N[CH(CH 3 ) 2 ] 2 , —N[C(CH 3 ) 3 ] 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 NHC 2 H 5 , —CH 2 N(CH 3 ) 2 , —CH 2 N(C 2 H 5 ) 2 , —NHCOCH 3 , —NHCOCF 3 , —NHCOC 2 H 5 , —NHCOC 3 H 7 , —NHCOCH(CH 3 ) 2 , —NHCOC(CH 3 ) 3 , —CONH 2 , —CONHCH 3 , —CONHC 2 H 5 , —CONHC 3 H 7 , —CONHCH(CH 3 ) 2 , —CONH-cyclo-C 3 H 5 , —CONHC(CH 3 ) 3 , —CON(CH 3 ) 2 , —CON(C 2 H 5 ) 2 , —CON(C 3 H 7 ) 2 , —CON[CH(CH 3 ) 2 ] 2 , —CON[C(CH 3 ) 3 ] 2 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHC 2 H 5 , —SO 2 NHC 3 H 7 , —SO 2 NHCH(CH 3 ) 2 , —SO 2 NH-cyclo-C 3 H 5 , —SO 2 NHC(CH 3 ) 3 , —SO 2 N(CH 3 ) 2 , —SO 2 N(C 2 H 5 ) 2 , —SO 2 N(C 3 H 7 ) 2 , —SO 2 N[CH(CH 3 ) 2 ] 2 , —SO 2 N[C(CH 3 ) 3 ] 2 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , —NHSO 2 C 2 H 5 , —NHSO 2 C 3 H 7 , —NHSO 2 CH(CH 3 ) 2 , —NHSO 2 C(CH 3 ) 3 , —CH═CH 2 , —CH 2 —CH═CH 2 , —C(CH 3 )═CH 2 , —CH═CH—CH 3 , —C≡CH, —C≡C—CH 3 , —CH 2 —C≡CH, -Ph, —O-Ph, —O—CH 2 -Ph, —OSi(CH 3 ) 3 , —OSi(C 2 H 5 ) 3 , —OSi(CH 3 ) 2 C(CH 3 ) 3 ,

R 23 -R 30 , R 23′ -R 26′ and R 28′ -R 30′ represent independently of each other
—H, —F, —Cl, —OH, —CN, —NO 2 , —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2 , —CF 3 , —OCH 3 , —OC 2 H 5 , —OC 3 H 7 , —OCH(CH 3 ) 2 , —OCF 3 , —OCH 2 OCH 3 , —O-cyclo-C 3 H 5 , —OCH 2 -cyclo-C 3 H 5 , —COOCH 3 , —COOC 2 H 5 , —OOC—CH 3 , —OOC—CF 3 , —OOC—C 2 H 5 , —OOC—C(CH 3 ) 3 , —NH 2 , —NHCH 3 , —NHC 2 H 5 , —NHCH(CH 3 ) 2 , —N(CH 3 ) 2 , —N(C 2 H 5 ) 2 , —CH 2 NH 2 , —CH 2 NHCH 3 , —CH 2 NHC 2 H 5 , —CH 2 N(CH 3 ) 2 , —CH 2 N(C 2 H 5 ) 2 , —NHCOCH 3 , —NHCOCF 3 , —CONH 2 , —CONHCH 3 , —CONHC 2 H 5 , —CON(CH 3 ) 2 , —CON(C 2 H 5 ) 2 , —SO 2 NH 2 , —SO 2 NHCH 3 , —SO 2 NHC 2 H 5 , —SO 2 N(CH 3 ) 2 , —SO 2 N(C 2 H 5 ) 2 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , or —NHSO 2 C 2 H 5 ;
R N1 , R N1′ , R N2 , and R N2″ represent independently of each other
—H, —CH 3 , —C 2 H 5 , —C 3 H 7 , —CH(CH 3 ) 2 , -cyclo-C 3 H 5 , —COCH 3 , —COCF 3 , —COC(CH 3 ) 3 , —OOC—CH 3 , —OOC—CF 3 , —OOC—C 2 H 5 , —OOC—C(CH 3 ) 3 , —SO 2 CH 3 , or —SO 2 CF 3 ;
or pharmaceutically acceptable salts thereof.

2. The compound according to claim 1 , wherein
R 5 is

R 6 is

and
R 9 -R 11 , R 9′ -R 11′ and R 18′ -R 20′ have the same meanings as defined in claim 1 .

3. The compound according to claim 1 , wherein
R 5 is

R 6 is

and
R 12 -R 14 and R 15 -R 17 have the same meanings as defined in claim 1 .

4. The compound according to claim 1 , wherein
R 5 is

R 6 is

and
R 9′ -R 11′ and R 15 -R 17 have the same meanings as defined in claim 1 .

5. The compound according to claim 1 , wherein
R 5 is

R 6 is

and
R 9′ -R 11′ and R 18 -R 20 have the same meanings as defined in claim 1 .

6. The compound according to claim 1 , wherein
R 3 is —R 7 , or —CH 2 —R 7 ; R 4 is —R 8 ;
R 7 is

R 8 is

and
R 23′ -R 24′ , R 25 -R 28 and R N1 -R N2 have the same meanings as defined in claim 1 .

7. The compound according to claim 1 , having any of the formulae (III-1) to (III-8):

wherein
R 3 represents —R 7 ;
R 4 represents —CH 2 —R 8 , or —CH 2 —CH 2 —R 8 ;
R 7 represents

R 8 represents

R 9 -R 20 , R 9′ -R 20′ , R 23 -R 26 , R 23′ -R 26′ , R 28′ -R 30′ and R N1′ -R N2′ have the same meanings as defined in claim 1 .

8. The compound according to claim 1 , having of the formula (V)

wherein
R 4 represents

R 15 represent —H, —F, —Cl, —Br, —CH 3 , —CH 2 F, —CHF 2 , —CF 3 , —CH 2 Cl, —OCHF 2 , —OCF 3 , —COOH, —COOCH 3 , —NH 2 , —NHCH 3 , —CONH 2 , —CONHCH 3 , —NHSO 2 CH 3 , —NHSO 2 CF 3 , —SO 2 NH 2 , —SO 2 NHCH 3 , or NHSO 2 CF 3 .

9. The compound according to claim 1 , selected from the group consisting of:
Compound 02: N1-(5-amino-2-bromobenzyl)-N4-(4-chlorobenzyl)-N4-cyclopentyl-N1-(piperidin-4-ylmethyl)benzene-1,4-disulfonamide,
Compound 04: tert-butyl 4-(((N-benzyl-4-(N-cyclopentyl-N-(3,5-dibromobenzyl)sulfamoyl)phenyl)sulfonamido)methyl)piperidine-1-carboxylate,
Compound 05: N1-((5-bromo-2-(methylamino)pyrimidin-4-yl)methyl)-

Assignees

• Max Planck Gesellschaft

Inventors

• Waldmann Herbert
• Martin-Gago Pablo Antonio
• Murarka Sandip
• Klein Christian
• Bastiaens Philippe
• Wittinghofer Alfred
• Fansa Eyad Kalawy

Classifications

• C07D239/42

  One nitrogen atom (nitro radicals C07D239/30) · CPC title

• C07D241/04

  having no double bonds between ring members or between ring members and non-ring members · CPC title

• C07D405/14

  containing three or more hetero rings · CPC title

• C07D213/42

  having hetero atoms attached to the substituent nitrogen atom (nitro radicals C07D213/26) · CPC title

• C07D401/12

  linked by a chain containing hetero atoms as chain links · CPC title