# US 2016/0355478 A1 · Therapeutic agents

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- Number: US 2016/0355478 A1
- Document ID: US20160355478A1
- Status: Published application
- Kind: A1
- Application number: 15/150,947
- Filed: 2016-05-10
- Published: 2016-12-08
- Earliest claimed: 2008-06-25
- Assignees: Cancer Research Technology Limited
- Applicants: Cancer Research Technology Limited
- Inventors: Bernard Thomas GOLDING; Christiane RIEDINGER; Roger John GRIFFIN; Ian Robert HARDCASTLE; Eric VALEUR; Anna Frances WATSON; Martin NOBLE
- Web page: https://patentgrep.com/patent/US20160355478A1

## CPC

- C07D 209/49: and having in the molecule an acyl radical containing a saturated three-membered ring, e.g. chrysanthemumic acid esters
- A61K 31/4035: Isoindoles, e.g. phthalimide
- A61K 31/4402: only substituted in position 2, e.g. pheniramine, bisacodyl
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07D 209/48: with oxygen atoms in positions 1 and 3, e.g. phthalimide
- C07D 401/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 403/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS

## Abstract

A compound of formula (I) or a compound of formula (II) or pharmaceutically acceptable salts thereof, wherein R1-R7 and X are as defined in the description, and the use of these compounds in therapy, in particular in treating cancer or as an inhibitor of the interaction of the MDM2 protein with p53.

## Claims

### Claim 1

A compound of formula I:
or a pharmaceutically acceptable salt thereof, wherein:
X is O;
R1 is selected from substituted aralkyl and substituted heteroaralkyl;
R2 is substituted or unsubstituted alkylamine;
R3 is 4-chlorophenyl; and
R4-R7 represents groups R4, R5, R6 and R7 which are independently selected from hydrogen, halo, hydroxy, substituted or unsubstituted alkyl, substituted or unsubstituted hydroxyalkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heteroaralkyl, substituted or unsubstituted alkylamine, substituted or unsubstituted alkoxy, trifluoromethyl, amino, nitro, carboxyl, carbonylmethylsulfone, trifluoromethylsulfone, cyano and substituted or unsubstituted sulfonamide.

### Claim 2 (depends on 1)

A compound according to claim 1, wherein R1 is substituted aralkyl.

### Claim 3 (depends on 1)

A compound according to claim 1, wherein R1 is substituted benzyl

### Claim 4 (depends on 1)

A compound according to claim 1, wherein R1 is substituted 1-ethylphenyl, 4-nitrobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-iodobenzyl.

### Claim 5 (depends on 4)

A compound according to claim 4, wherein the substituted 1-ethylphenyl is the S-enantiomer.

### Claim at position 6

6-11. (canceled)

### Claim 12 (depends on 1)

A compound according to claim 1, wherein R4-R7 are all hydrogen or at least one of R4-R7 is a chlorine atom.

### Claim 13

(canceled)

### Claim 14 (depends on 1)

A compound according to claim 1, wherein, where a moiety is substituted, substituent functional groups are selected from: halo, hydroxyl, hydroxyalkyl, acyl, acetamide, carboxyl, cyano, carboxamide (carbamoyl), sulfonamide, sulfone, sulfoxide, amino, alkoxy and silico ligand, and combinations thereof.

### Claim 15 (depends on 1)

A pharmaceutical composition comprising an effective amount of at least one compound according to claim 1 and a pharmaceutically acceptable carrier.

### Claim 16 (depends on 1)

A method of treating osteosarcoma, colorectal carcinoma, neuroblastoma, or uterus chorion cancer in a mammal comprising administering to the mammal a therapeutically effective amount of a compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 17 (depends on 1)

A method of treating cancer in a mammal comprising administering a therapeutically effective amount of a compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 18 (depends on 1)

A method of inhibiting the interaction of MDM2 protein with p53 comprising administering a therapeutically effective amount of a compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof.

### Claim 19 (depends on 1)

A kit comprising at least one compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof, and instructions for use.

### Claim 20 (depends on 1, 19)

A kit according to claim 19, further comprising a second compound of Formula I according to claim 1 or a pharmaceutically acceptable salt thereof.

### Claim 21 (depends on 17)

A method according to claim 17, wherein the cancer is selected from breast cancer, advanced solid tumor, leukemia, acute myeloid leukemia (AML), sarcoma, acute lymphocytic leukemia (ALL), chronic myelogenous leukemia (CML), liposarcoma, lung cancer, and soft tissue sarcoma.

### Claim 22 (depends on 21)

A method according to claim 21, wherein the cancer is leukemia.

### Claim 23 (depends on 21)

A method according to claim 21, wherein the cancer is AML.

### Claim 24 (depends on 21)

A method according to claim 21, comprising administering, in addition to the therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, a therapeutically effective amount of at least one additional anticancer agent.

### Claim 25 (depends on 16)

A method according to claim 16, comprising administering, in addition to the therapeutically effective amount of a compound of Formula I or pharmaceutically acceptable salt thereof, a therapeutically effective amount of at least one additional anticancer agent.

### Claim 26 (depends on 1)

A method of manufacturing a medicament comprising, combining a compound of Formula I as defined in claim 1, or a pharmaceutically acceptable salt thereof, with a carrier that comprises one or more accessory ingredients.

### Claim 27 (depends on 14)

A compound according to claim 14, wherein R1 is substituted 1-ethylphenyl, 4-nitrobenzyl, 4-cyanobenzyl, 4-chlorobenzyl, 4-bromobenzyl or 4-iodobenzyl.