Notch inhibitors for use in the treatment of t-cell acute lymphoblastic leukemia

Patent metadata

Field	Value
Publication number	US-11104657-B2
Application number	US-201716473986-A
Country	US
Kind code	B2
Filing date	Dec 20, 2017
Priority date	Dec 29, 2016
Publication date	Aug 31, 2021
Grant date	Aug 31, 2021

Abstract

Compounds of formula (I) in the capacity of compounds with anti-tumor activity for the treatment of T-cell acute lymphoblastic leukemia (T-ALL).

First claim

The invention claimed is:

1. A method of treating T-cell acute lymphoblastic leukemia (T-ALL) in a subject, comprising administering to the subject a compound of formula (I), the compound of formula (I) being an inhibitor of Notch signaling,

wherein
X and Y are carbon atoms bound by a single or double bond having, independently, an E or Z configuration;
R 1′ is hydrogen, halogen, OR A , C(═O)R A , C(═O)OR A , OC(═O)R A , SR A , SO 2 R A , SO 3 R A , OSO 2 R A , OSO 3 R A , N(R A ) 2 , NHC(═O)R A , C(═O)N(R A ) 2 , or C(R A ) 3 ;
R 2′ , R 3′ , R 1 , R 2 , R 3 are the same or different and independently selected from: hydrogen; halogen; OR B ; C(═O)R B ; C(═O)OR B ; OC(═O)R B ; SR B ; SO 2 R B ; SO 3 R B ; OSO 2 R B ; OSO 3 R B ; N(R B ) 2 ; NHC(═O)R B ; C(═O)N(R B ) 2 ; C(R B ) 3 ; a linear or branched, saturated or unsaturated C 1-7 acyclic aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl; a C 5-7 heterocyclic group;
wherein at each occurrence RA and RB are independently selected from: hydrogen; a linear or branched, saturated or unsaturated C 1-7 aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl group; a C 5-7 heterocyclic group;
and pharmaceutically acceptable salts thereof,
wherein the compound is selected from:
2′,3,4,4′-tetramethoxychalcone (1);
2′-hydroxy-3,4,4′-trimethoxychalcone (2);
2′-hydroxy-4,4′-dimethoxychalcone (3);
2′,4,4′-trimethoxychalcone (4);
2′,3-dihydroxy-4,4′-dimethoxychalcone (5);
2′-hydroxy-3,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (7a);
2′,4-dihydroxy-3,4′-dimethoxychalcone (7);
2′-hydroxy-4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (8a);
2′,4-dihydroxy-4′-methoxychalcone (8);
2′-hydroxy-4′-methoxychalcone (9);
2′-hydroxy-3,4′-dimethoxychalcone (10);
2′-hydroxy-4′-methoxy-3-(tetrahydropyran-2-yloxy)chalcone (11a);
2′,3-dihydroxy-4′-methoxychalcone (11);
2,2′-dihydroxy-4′-methoxychalcone (12);
2′-hydroxy-2,4′-dimethoxychalcone (13);
2′-hydroxy-4-(tetrahydropyran-2-yloxy)chalcone (14a);
2′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (15a);
4-hydroxy-2′-methoxychalcone (15);
2′,4′-dimethoxy-4-(tetrahydropyran-2-yloxy)chalcone (16a);
4-hydroxy-2′,4′-dimethoxychalcone (16);
4′-methoxy-4-(tetrahydropyran-2-yloxy)chalcone (17a); and
4-hydroxy-4′-methoxychalcone (17).

2. The method according to claim 1 , wherein X and Y are carbon atoms bound by a double bond having, independently, an E or Z configuration.

3. A method of treating T-cell acute lymphoblastic leukemia (T-ALL) in a subject, comprising administering to the subject a compound of formula (I), the compound of formula (I) being an inhibitor of Notch signaling,

wherein
X and Y are carbon atoms bound by a single or double bond having, independently, an E or Z configuration;
R 1′ is hydrogen, halogen, OR A , OC(═O)R A , SR A , SO 2 R A , SO 3 R A , OSO 2 R A , OSO 3 R A , C(R A ) 3 ;
R 2′ , R 3′ , R 1 , R 2 , R 3 are the same or different and independently selected from: a linear or branched, saturated or unsaturated C 1-7 acyclic aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl group; a C 5-7 heterocyclic group; and
wherein R A is selected from: hydrogen; a linear or branched, saturated or unsaturated C 1-7 aliphatic group optionally containing up to three heteroatoms independently selected from nitrogen, oxygen or sulfur; a C 5-7 cycloalkyl group; a phenyl group; a C 5-7 heterocyclic group;
and pharmaceutically acceptable salts thereof.

Assignees

• Univ Degli Studi Di Roma “La Sapienza”
• Fondazione St Italiano Tecnologia

Inventors

• Botta Bruno
• Screpanti Isabella
• Tottone Luca
• Zhdanoskaya Nadezda
• Ingallina Cinzia
• Giulimondi Francesca
• Quaglio Deborah
• Palermo Rocco
• Mori Mattia
• Ghirga Francesca

Classifications

• C07D309/12

  only hydrogen atoms and one oxygen atom directly attached to ring carbon atoms, e.g. tetrahydropyranyl ethers · CPC title

• C07C49/835

  having unsaturation outside an aromatic ring · CPC title

• C07C49/248

  having unsaturation outside the aromatic rings · CPC title

• A61P35/02

  specific for leukemia · CPC title

• C07C49/84

  containing ether groups, [IMAGE cpc-sch-C07C-0958.gif] groups,[IMAGE cpc-sch-C07C-0959.gif] groups, or[IMAGE cpc-sch-C07C-0960.gif] groups · CPC title