# US 2019/0167820 A1 · Novel aryl ethene derivative and pharmaceutical composition containing same as active ingredient

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- Number: US 2019/0167820 A1
- Document ID: US20190167820A1
- Status: Published application
- Kind: A1
- Application number: 16/313,360
- Filed: 2016-09-13
- Published: 2019-06-06
- Earliest claimed: 2016-06-27
- Applicants: Kemimedi Co.Ltd
- Inventors: Sung Yeoun HWANG; Sung Jin CHO; Jina KIM; Jungwook CHIN; Hayoung HWANG; In-Kyu LEE; Yong-Hyun JEON; Jaetae LEE; Jae-Han JEON; Sang Wook KIM
- Web page: https://patentgrep.com/patent/US20190167820A1

## CPC

- A61K 51/025: {inorganic Tc complexes or compounds}
- A61K 31/396: having three-membered rings, e.g. aziridine
- A61K 31/397: having four-membered rings, e.g. azetidine
- A61K 31/40: having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K 31/403: condensed with carbocyclic rings, e.g. carbazole
- A61K 31/404: Indoles, e.g. pindolol
- A61K 31/407: condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
- A61K 31/4192: 1,2,3-Triazoles
- A61K 31/445: Non condensed piperidines, e.g. piperocaine
- A61K 31/454: containing a five-membered ring with nitrogen as a ring hetero atom, e.g. pimozide, domperidone
- A61K 31/495: having six-membered rings with two {or more} nitrogen atoms as the only ring heteroatoms, e.g. piperazine {or tetrazines}(A61K31/48 takes precedence {; with three nitrogen atoms A61K31/53})
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/535: having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/695: Silicon compounds
- A61P 35/00: Antineoplastic agents
- C07D 203/08: with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring nitrogen atom
- C07D 241/04: having no double bonds between ring members or between ring members and non-ring members
- C07D 265/28: 1,4-Oxazines; Hydrogenated 1,4-oxazines
- 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
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to an aryl ethene derivative, for inhibiting an estrogen-related receptor gamma (ERRγ) activity, a prodrug of same, a solvate of same, a stereoisomer of same or pharmaceutically acceptable salts of same, and a pharmaceutical composition containing same as an active ingredient.

## Claims

### Claim 1

A pharmaceutical composition for treating thyroid cancer, comprising: the arylethene derivative represented by the following Chemical Formula 1:
wherein
L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20)fused heterocycle;
R1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH2)m—R11, —(CH2)m—R12, —NH—(CH2)m—R13, —NHCO—(CH2)n—R14, or —SiR16R17—(CH2)m—R15;
R11 to R15 are independently of one another (C3-C20)heterocycloalkyl;
R16 and R17 are independently of each other (C1-C20)alkyl;
m is an integer of 1 to 3; and
n is an integer of 0 or 1;
Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano, —NR21R22, (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SO2—R23, and —OSO2—R24;
R21 and R22 are independently of each other hydrogen, (C1-C20)alkylsulfonyl, or (C3-C20)cycloalkylsulfonyl;
R23 and R24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
R2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy;
the heterocycloalkyl or heteroaryl of R1 and the heterocycloalkyl of R11 to R15 may be further substituted by one or more selected from the group consisting of (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino, (C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl; and
the heterocycloalkyl and heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S, and the heterocycloalkyl is a saturated or unsaturated mono-, bi-, or spirocycle having a carbon atom or nitrogen atom in a ring as a binding site,
or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, as an effective component, and a pharmaceutically acceptable carrier, and being used in combination of radioactive iodine.

### Claim 2 (depends on 1)

The pharmaceutical composition of claim 1, wherein the thyroid cancer is analpastic thyroid cancer.

### Claim 3 (depends on 1)

The pharmaceutical composition of claim 1, wherein the arylethene derivative is an arylethene derivative represented by the following Chemical Formulae 2 to 5:
wherein denotes a single bond or a double bond; and R1, Ar and R2 are as defined in claim 1.

### Claim 4 (depends on 1)

The pharmaceutical composition of claim 1, wherein
R1 is (C3-CO1)heterocycloalkyl, (C3-C10)heteroaryl, —O—(CH2)m—R11, —(CH2)m—R12, —NH—(CH2)m—R13, —NHCO—(CH2)n—R14, or —SiR16R17—(CH2)m—R15;
R11 to R15 are independently of one another (C3-C10)heterocycloalkyl;
R16 and R17 are independently of each other (C1-C10)alkyl;
m is an integer of 1 to 3;
n is an integer of 0 or 1;
Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy;
R2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy; and
the heterocycloalkyl or heteroaryl of R1 and the heterocycloalkyl of R11 to R15 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C10)alkylamino(C1-C10)alkyl.

### Claim 5 (depends on 4)

The pharmaceutical composition of claim 4, wherein
R1 is (C3-C10)heterocycloalkyl or —O—(CH2)m—R11; R11 is (C3-C10)heterocycloalkyl; m is an integer of 1 to 3; and the heterocycloalkyl of R1 and R11 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C10)alkylamino(C1-C10)alkyl.

### Claim 6 (depends on 1)

The pharmaceutical composition of claim 1, wherein the heterocycloalkyl of R1 and R11 to R15 is independently of each other selected from the following structures:
wherein R31 and R32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.

### Claim 7 (depends on 3)

The pharmaceutical composition of claim 3, wherein the arylethene derivative is an arylethene derivative represented by the following Chemical Formula 6:
wherein
R1 is (C3-C10)heterocycloalkyl or —O—(CH2)m—R1;
R11 is (C3-C10)heterocycloalkyl;
m is an integer of 1 to 3;
the heterocycloalkyl of R1 and R11 may be further substituted by one or more selected from the group consisting of (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl;
Ar is (C6-C12)aryl or (C3-C12)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C10)alkyl, halo(C1-C10)alkyl, (C1-C10)alkoxy, nitro, cyano, amino, (C1-C10)alkylsulfonylamino, (C3-C10)cycloalkylsulfonylamino, di((C1-C10)alkylsulfonyl)amino, (C1-C10)alkylcarbonyloxy, (C1-C10)alkylcarbonylamino, guanidino, (C1-C10)alkylsulfonyl, (C1-C10)alkylsulfonyloxy, halo(C1-C10)alkylsulfonyloxy, and (C3-C10)cycloalkylsulfonyloxy; and
R2 is hydroxy, fluoro, (C1-C10)alkylcarbonyloxy, or (C1-C10)alkylsulfonyloxy.

### Claim 8 (depends on 7)

The pharmaceutical composition of claim 7, wherein R2 is hydroxy; and R1 is heterocycloalkyl selected from the following structures:
wherein R31 and R32 are independently of each other hydrogen, (C1-C10)alkyl, (C3-C10)cycloalkyl, (C2-C10)alkenyl, amidino, (C1-C10)alkoxycarbonyl, hydroxy(C1-C10)alkyl, or di(C1-C10)alkylamino(C1-C10)alkyl; and L is O or S.

### Claim 9 (depends on 7)

The pharmaceutical composition of claim 7, wherein R2 is hydroxy; R1 is —O—(CH2)m—R11; m is an integer of 1 or 2; and R11 is heterocycloalkyl selected from the following structures:
wherein R31 and R32 are independently of each other halogen, (C1-C100)alkyl, (C1-C10)alkoxycarbonyl, or hydroxy(C1-C10)alkyl; and L is O or S.

### Claim 10 (depends on 3)

The pharmaceutical composition of claim 3, wherein the arylethene derivative is selected from the following structures:

### Claim 11 (depends on 7)

The pharmaceutical composition of claim 7, wherein the arylethene derivative is selected from the following structures:

### Claim 12

A kit for treating thyroid cancer, comprising: an arylethene derivative represented by the following Chemical Formula 1:
wherein
L is (C6-C20)arylene, (C3-C20)heteroarylene, or (C3-C20)fused heterocycle;
R1 is (C3-C20)heterocycloalkyl, (C3-C20)heteroaryl, —O—(CH2)m—R11, —(CH2)m—R12, —NH—(CH2)m—R13, —NHCO—(CH2)n—R14, or —SiR16R17—(CH2)m—R15;
R11 to R15 are independently of one another (C3-C20)heterocycloalkyl;
R16 and R17 are independently of each other (C1-C20)alkyl;
m is an integer of 1 to 3;
n is an integer of 0 or 1;
Ar is (C6-C20)aryl or (C3-C20)heteroaryl, in which the aryl or heteroaryl of Ar may be further substituted by one or more selected from the group consisting of hydroxy, halogen, (C1-C20)alkyl, halo(C1-C20)alkyl, (C1-C20)alkoxy, nitro, cyano, —NR21R22, (C1-C20)alkylcarbonyloxy, (C1-C20)alkylcarbonylamino, guanidino, —SO2—R23 and —OSO2—R24;
R21 and R22 are independently of each other hydrogen, (C1-C20)alkylsulfonyl, or (C3-C20)cycloalkylsulfonyl;
R23 and R24 are independently of each other (C1-C20)alkyl, halo(C1-C20)alkyl, or (C3-C20)cycloalkyl;
R2 is hydroxy, halogen, (C1-C20)alkylcarbonyloxy, or (C1-C20)alkylsulfonyloxy;
the heterocycloalkyl or heteroaryl of R1 and the heterocycloalkyl of R11 to R15 may be further substituted by one or more selected from the group consisting of (C1-C20)alkyl, (C3-C20)cycloalkyl, (C2-C20)alkenyl, amidino, (C1-C20)alkoxycarbonyl, hydroxy, hydroxy(C1-C20)alkyl, and di(C1-C20)alkylamino(C1-C20)alkyl; and
the heterocycloalkyl and heteroaryl contains one or more heteroatoms selected from the group consisting of N, O and S, and the heterocycloalkyl is a saturated or unsaturated mono-, bi-, or spirocycle having a carbon atom or nitrogen atom in a ring as a binding site,
or a prodrug, solvate, stereoisomer, or pharmaceutically acceptable salt thereof, and radioactive iodine.