# US 10,766,873 B2 · Zuclopenthixol hydrochloride derivatives and Ebselen derivatives as ErbB2 inhibitors

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- Number: US 10,766,873 B2
- Document ID: US10766873B2
- Status: Granted
- Kind: B2
- Application number: 16/069,049
- Filed: 2017-01-11
- Published: 2019-01-31
- Granted: 2020-09-08
- Earliest claimed: 2016-01-11
- Assignees: Centre National de la Recherche Scientifique (CNRS); Institut National De La Sante Et De La Recherche Medicale (Inserm); Universite Paris Descartes
- Applicants: Centre National de la Recherche Scientifique (CNRS); Institut National de la Sante et de la Recherche Medicale (INSERM); Universite Paris Descartes
- Inventors: Sandrine Bourdoulous; Camille Faure
- Web page: https://patentgrep.com/patent/US10766873B2

## CPC

- C07D 335/20: with hydrocarbon radicals, substituted by amino radicals, directly attached in position 9
- A61K 31/41: having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
- A61K 31/497: containing further heterocyclic rings
- A61P 35/00: Antineoplastic agents
- C07D 275/04: condensed with carbocyclic rings or ring systems
- C07D 279/24: with hydrocarbon radicals, substituted by amino radicals, attached to the ring nitrogen atom
- C07D 293/12: Selenazoles; Hydrogenated selenazoles
- C07D 405/06: linked by a carbon chain containing only aliphatic carbon atoms
- C07D 409/06: 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

The present invention relates to compounds of the following general formula (I) or (II): or a pharmaceutically acceptable salt and/or solvate thereof, for use in the treatment and/or in the prevention of ErbB2 dependent cancers, and pharmaceutical compositions containing such compounds.

## Claims

### Claim 1

A method of inhibiting ErbB2 activation in an ErbB2 dependent cancer patient, the method comprising:
selecting an ErbB2 dependent cancer patient that overexpresses ErbB2; and
administering to the ErbB2 dependent cancer patient an effective amount of a compound of formula (I), or a pharmaceutically acceptable salt and/or solvate thereof for inhibiting ErbB2 activation;
wherein compound (I) has the general formula:
wherein:
the symbol represents a bond in cis or trans configuration;
X is a sulfur atom;
R1 is hydrogen atom, halo, —CN, —NO2, —NO, —CHO, —NR7R8, —CO2R9, —SO2R10, —SO2NR11R12, —OR13, —COR14, —SR15, —CONR16R17, —SO2(O)R18 or a group selected from saturated (C1-C6)alkyl, unsaturated (C1-C6)alkyl and aryl, said group being optionally substituted with one or several groups selected from halo, —CF3, —CN and —SO2NR19R20;
R2 and R3 form together with the nitrogen atom to which they are chemically linked a piperazinyl group substituted with one or several groups selected from halo, —CO2R21 and a (C1-C6)alkyl group, the (C1-C6)alkyl group being optionally substituted with one or several groups selected from halo, —OR22, —SR23, —S(O)R24, —SO2R25, —SO2NR26R27, —OC(O)R28, —NR29COR30, —NR31CONR32R33, —NR34C(O)OR35, —CO2R36, —CONR37R38, —OCO2R39, —OCONR40R41, —COR42, —NO2, CF3, and —CN;
R4, R5 and R6 are, independently of one another, hydrogen atom, halo, —CN, —NO2, —NO, —CHO, —NR43R44, —CO2R45, —S(O)R46, —SO2R47, —SO2NR48R49, —OCOR50, —NR51COR52, —NR53CO(O)R54, —NR55CONR56R57, —CO2R58, —OR59, —COR60, —SR61, —CONR62R63, —OCONR64R65, —SO2(O)R66, or a group selected from saturated (C1-C6)alkyl, unsaturated (C1-C6)alkyl and aryl, said group being optionally substituted with one or several groups selected from halo, —CF3, —CN, and —SO2NR67R68;
R7 to R68 are, independently of one another, a hydrogen atom or a (C1-C10)alkyl, aryl or aryl(C1-C6)alkyl group, said group being optionally substituted with one or several groups selected from halo, —OH, —CF3, —CN and SO2NR69R70; with the proviso that R21 is not an hydrogen atom;
R69 and R70 are independently of one another, a hydrogen atom or a (C1-C10)alkyl, aryl or aryl(C1-C6)alkyl group; and
n is an integer selected from 1 to 6.

### Claim 2 (depends on 1)

The method according to claim 1, wherein R1 is hydrogen atom, halo, —CN, —NO2, —NO, —CHO, —NR7R8, —CO2R9, —SO2R10, —SO2NR11R12, —COR14, —CONR16R17, —SO2(O)R18 or a group selected from saturated (C1-C6)alkyl, unsaturated (C1-C6)alkyl and aryl, said group being optionally substituted with one or several groups selected from halo, —CF3, —CN and —SO2NR19R20; R7 to R12, R14 and R16 to R20 being as defined in claim 1.

### Claim 3 (depends on 1)

The method according to claim 1, wherein R1 is hydrogen atom, halo, —CN, —SO2NR11R12 or —CF3; R11 and R12 being as defined in claim 1.

### Claim 4 (depends on 1)

The method according to claim 1, wherein R2 and R3 form together with the nitrogen atom to which they are chemically linked a piperazinyl group, substituted with one or several (C1-C6)alkyl group optionally substituted with one or several groups selected from —OR22, —SR23, —S(O)R24, —SO2R25, —SO2NR26R27, —OC(O)R28, —NR29COR30, —NR31CONR32R33, —NR34C(O)OR35, —CO2R36, —CONR37R38, —OCO2R39, —OCONR40R41, —COR42, —NO2 and —CN; R22 to R42 being as defined in claim 1.

### Claim 5 (depends on 1)

The method according to claim 1, wherein R2 and R3 form together with the nitrogen atom to which they are chemically linked a piperazinyl group, substituted with one (C1-C6)alkyl group optionally substituted with one or several groups selected from —OR22, —SR23, —S(O)R24, —SO2R25, —SO2NR26R27, —OC(O)R28, —OCO2R39 and —COR42; and wherein R22 to R28, R39 and R42 are, independently of one another, a hydrogen atom or a (C1-C10)alkyl group.

### Claim 6 (depends on 1)

The method according to claim 1, wherein R2 and R3 form together with the nitrogen atom to which they are chemically linked a piperazinyl group, substituted with one (C1-C6)alkyl group optionally substituted with one group selected from —OR22 and —OC(O)R28;
and wherein R22, R28, and R31 to R33 are, independently of one another, a hydrogen atom or a (C1-C6)alkyl group.

### Claim 7 (depends on 1)

The method according to claim 1, wherein R4, R5 and R6 are, independently of one another, hydrogen atom, halo or (C1-C6)alkyl.

### Claim 8 (depends on 1)

The method according to claim 1, wherein the compound is of following general formula (Ia):

### Claim 9 (depends on 1)

The method according to claim 1, wherein said compound is selected from the following compounds:
and pharmaceutically acceptable salt and/or solvate thereof.

### Claim 10 (depends on 1)

The method according to claim 1, wherein the ErbB2 cancer patient that overexpresses ErbB2 is a patient with metastases.

### Claim 11 (depends on 1)

The method according to claim 1, wherein said ErbB2 dependent cancer is lung cancer, ovarian cancer, stomach cancer, bladder cancer, uterine cancer, pancreas cancer, liver cancer, kidney cancer, gastroeosophageal cancer, gastric cancer, colorectal cancer, female genital tract cancer, endometrial cancer, anal cancer, breast cancer or neurofibroma.

### Claim 12 (depends on 11)

The method according to claim 11, wherein said ErbB2 dependent cancer is ovarian cancer, pancreas cancer, gastroeosophageal cancer, gastric cancer, colorectal cancer, endometrial cancer, anal cancer or neurofibroma.

### Claim 13 (depends on 11)

The method according to claim 11, wherein said ErbB2 dependent cancer is ovarian cancer, gastric cancer or breast cancer.

### Claim 14 (depends on 3)

The method according to claim 3, wherein halo is Cl or F.