# US 2013/0158022 A1 · Acrylamide Compounds And Use Thereof For Inhibiting Apoptosis

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- Number: US 2013/0158022 A1
- Document ID: US20130158022A1
- Status: Published application
- Kind: A1
- Application number: 13/697,810
- Filed: 2010-05-14
- Published: 2013-06-20
- Earliest claimed: 2010-05-14
- Assignees: Chinese Pla General Hospital
- Inventors: Kunlun He; Song Li; Wu Zhong; Juan Liu; Lili Wang; Xin Li; Guoliang Hu; Jie Wang; Long Long; Junhai Xiao; Zhibing Zheng; Wei Li; Ruijun Li; Chunlei Liu; Jie Tang
- Web page: https://patentgrep.com/patent/US20130158022A1

## CPC

- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61K 31/17: having the group >N—C(O)—N< or >N—C(S)—N<, e.g. urea, thiourea, carmustine (isoureas, isothioureas A61K31/155; sulfonylureas A61K31/64)
- A61K 31/381: having five-membered rings
- A61K 31/435: having six-membered rings with one nitrogen as the only ring hetero atom
- A61K 31/4453: only substituted in position 1, e.g. propipocaine, diperodon
- A61K 31/4709: Non-condensed quinolines and containing further heterocyclic rings
- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5375: 1,4-Oxazines, e.g. morpholine
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 9/00: Drugs for disorders of the cardiovascular system
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07C 335/12: the carbon skeleton containing six-membered aromatic rings
- C07D 295/194: Radicals derived from thio- or thiono carboxylic acids
- C07D 295/21: Radicals derived from sulfur analogues of carbonic acid
- C07D 333/24: Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
- C07D 409/12: linked by a chain containing hetero atoms as chain links
- 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
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07D: HETEROCYCLIC COMPOUNDS (macromolecular compounds C08)

## Abstract

The present invention relates to a compound of Formula I, or an isomer, pharmaceutically acceptable salt and solvate of the compound, and to a composition comprising the compound of Formula I, or the isomer, pharmaceutically acceptable salt and solvate thereof, and a pharmaceutically acceptable carrier, excipient or diluents. The present invention also relates to use of the compound of Formula I, or the isomer, pharmaceutically acceptable salt and solvate thereof for combating apoptosis, preventing or treating a disease or disorder associated with apoptosis; and especially use for protecting cardiomyocyte, and for preventing or treating a disease or disorder associated with cardiomyocyte apoptosis.

## Claims

### Claim 1

A compound of Formula I, or an isomer, pharmaceutically acceptable salt and solvate thereof,
wherein:
A represents ═S or —SR4;
X represents F, Cl, Br or I;
R1 represents thienyl or substituted thienyl, wherein said thienyl, thiazolyl is unsubstituted or substituted with 1-3 substituents selected from substituted: halogens, nitro, hydroxyl, amino, cyano, C1-C6 alkyl, C1-C6 alkoxy, and C1-C6 halogenated alkyl, and wherein said alkyl, alkoxy and halogenated alkyl is optionally substituted with hydroxy, —O—(C1-C4)-alkyl, oxo, amino, —NH—(C1-C4)-alkyl, or —N—[(C1-C6)-alkyl]2, or said alkyl, alkoxy and halogenated alkyl is optionally substituted with —O, S, NH, COO—;
R2, R3 each individually represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkyl, amino C1-C6 alkyl, mono-substituted or di-substituted amino C1-C6 alkyl, phenyl C1-C6 alkyl, substituted phenyl C1-C6 alkyl, heterocyclic group C1-C6 alkyl, phenyl, substituted phenyl, heterocyclic group or substituted heterocyclic group, wherein R2 and R3 may be attached together to form a saturated cyclic alkyl, nitrogen- or oxygen-containing heterocyclic group; and
R4 represents C1-C6 alkyl.

### Claim 2

A compound of Formula I, or an isomer, pharmaceutically acceptable salt and solvate thereof,
wherein
A represents ═S or —SR4;
X represents F, Cl, Br or I;
R1 represents thienyl or substituted thienyl;
R2, R3 each individually represent hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, substituted C3-C6 cycloalkyl, C1-C6 alkoxy, C1-C6 alkyl, amino C1-C6 alkyl, mono-substituted or di-substituted amino C1-C6 alkyl, phenyl C1-C6 alkyl, substituted phenyl C1-C6 alkyl, heterocyclic group C1-C6 alkyl, phenyl, substituted phenyl, heterocyclic group or substituted heterocyclic group, wherein R2 and R3 may be attached together to form a saturated cyclic alkyl, nitrogen- or oxygen-containing heterocyclic group; and
R4 represents methyl, ethyl, propyl, isopropyl, butyl, or pentyl.

### Claim 3

A compound of Formula I, or an isomer, pharmaceutically acceptable salt and solvate thereof.
wherein:
A represents ═S or —SR4;
X represents Cl;
R1 represents 2-thienyl or 3-thienyl;
R2, R3 each individually represent hydrogen, methyl, isopropyl, 2-methoxy ethyl, 3-isopropoxy propyl, 2-N,N-dimethyl ethyl, cyclohexyl, cycloheptyl, o-methoxy phenyl, o-fluorophenyl, o-chlorophenyl, p-chlorophenyl, benzyl or 8-quinolyl, wherein R2 and R3 may be attached together to form a piperidine ring, morpholine ring, or N-methyl piperazine ring; and
R4 represents methyl or ethyl.

### Claim 4 (depends on 1)

The compound according to claim 1 having any one of the following structures, or their isomers, pharmaceutically acceptable salts and solvates:
(1) (2E)-3-(2-thienyl)-N-[1-(8-quinolylamino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(2) (2E)-3-(3-thienyl)-N-[1-(8-quinolylamino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(3) (2E)-3-(2-thienyl)-N-[1-(4-tolylamino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(4) (2E)-3-(2-thienyl)-N-[1-(2-methoxyanilino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(5) (2E)-3-(2-thienyl)-N-(1-benzylaminothioformylamino-2,2,2-trichloroethyl)-2-acrylamide;
(6) (2E)-3-(2-thienyl)-N-(1-cyclohexylaminothioformylamino-2,2,2-trichloroethyl)-2-acrylamide;
(7) (2E)-3-(2-thienyl)-N-[1-isopropylaminothioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(8) (2E)-3-(2-thienyl)-N-[1-(2-fluoroanilino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(9) (2E)-3-(2-thienyl)-N-[1-(3-isopropoxypropylamino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(10) (2E)-3-(2-thienyl)-N-[1-(2-methoxyformylanilino)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(11) (2E)-3-(2-thienyl)-N-(1-cycloheptylaminothioformylamino-2,2,2-trichloroethyl)-2-acrylamide;
(12) (2E)-3-(2-thienyl)-N-[1-(1-morpholinyl)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(13) (2E)-3-(2-thienyl)-N-[1-(4-methylpiperazinyl)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(14) (2E)-3-(2-thienyl)-N-[1-(8-quinolylamino) methylthiomethenylamino-2,2,2-trichloroethyl]-2-acrylamide;
(15) (2E)-3-phenyl-[1-(1-morpholinyl)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide;
(16) (2E)-3-phenyl-[1-(1-piperidyl)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide; or
(17) (2E)-3-phenyl-[1-(3-methoxybenzyl)thioformylamino-2,2,2-trichloroethyl]-2-acrylamide.

### Claim 5 (depends on 1)

A pharmaceutical composition comprising a compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 1, and a pharmaceutically acceptable carrier, excipient or diluent.

### Claim 6 (depends on 1)

Use of the compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 1 in manufacture of a medicament for anti-apoptosis, or preventing or treating a disease or disorder associated with apoptosis.

### Claim 7 (depends on 1)

Use of the compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 1 in manufacture of a medicament for protecting cardiomyocyte, or preventing or treating a disease or disorder associated with cardiomyocyte apoptosis.

### Claim 8 (depends on 1)

A method for combating apoptosis, or preventing or treating a disease or disorder associated with apoptosis, the method comprising administering a subject in need thereof a therapeutically effective amount of a compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 1.

### Claim 9 (depends on 1)

A method for protecting cardiomyocyte, or preventing or treating a disease or disorder associated with cardiomyocyte apoptosis, the method comprising administering a subject in need thereof a therapeutically effective amount of a compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 1.

### Claim 10 (depends on 2)

A pharmaceutical composition comprising a compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 2, and a pharmaceutically acceptable carrier, excipient or diluent.

### Claim 11 (depends on 3)

A pharmaceutical composition comprising a compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 3, and a pharmaceutically acceptable carrier, excipient or diluent.

### Claim 12 (depends on 4)

A pharmaceutical composition comprising a compound or an isomer, pharmaceutically acceptable salt and solvate thereof according to claim 4, and a pharmaceutically acceptable carrier, excipient or diluent.