# US 8,772,299 B2 · Phenyl piperazine compounds, pharmaceutical composition including the same and use thereof

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- Number: US 8,772,299 B2
- Document ID: US8772299B2
- Status: Granted
- Kind: B2
- Application number: 13/015,717
- Filed: 2011-01-28
- Published: 2011-05-19
- Granted: 2014-07-08
- Earliest claimed: 2008-05-29
- Assignees: SK Biopharmaceuticals Co., Ltd.
- Applicants: Yonggil Kim; Nahmryune Cho; Yunhee Kim; Joon Heo; Seonmin Dong; Mi Kyung Ji; Man-Young Cha; Kiho Lee
- Inventors: Yonggil Kim; Nahmryune Cho; Yunhee Kim; Joon Heo; Seonmin Dong; Mi Kyung Ji; Man-Young Cha; Kiho Lee
- Web page: https://patentgrep.com/patent/US8772299B2

## CPC

- A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
- A61K 31/5377: not condensed and containing further heterocyclic rings, e.g. timolol
- A61P 25/22: Anxiolytics
- A61P 25/24: Antidepressants
- C07D 231/54: condensed with carbocyclic rings or ring systems
- C07D 233/58: with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring nitrogen atoms
- C07D 235/08: Radicals containing only hydrogen and carbon atoms
- C07D 249/04: 1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
- C07D 249/08: 1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
- C07D 257/04: Five-membered rings
- C07D 261/14: Nitrogen atoms
- C07D 285/135: Nitrogen atoms
- C07D 295/088: to an acyclic saturated chain
- C07D 295/096: with the ring nitrogen atoms and the oxygen or sulfur atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings
- 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 novel piperazine derivatives or pharmaceutically acceptable salts thereof, a process for preparing the same, and in particular, a high binding for Serotonin 1A(5-hydroxytryptamine; 5-HT1A) receptor, a pharmaceutical composition for treatment and/or prevention of depression and anxiety including an effective amount of the piperazine compound, and a method of treating depression, anxiety and other conditions related to 5-HT1A receptor in a mammal.

## Claims

### Claim 1

A method for treating at least one of depression and anxiety in a mammal comprising administering to a mammal in need thereof an effective amount of a piperazine compound represented by Formula (I):
or pharmaceutically acceptable salts thereof,
wherein
n is an integer from 2 to 6;
R1 and R2 are the same or different and are independently selected from the group consisting of hydrogen, a hydroxyl group, a halogen, nitrogen dioxide, a straight or branched chain-alkyl group with 1 to 4 carbon atoms, and a straight or branched chain alkoxy group with 1 to 4 carbon atoms;
R3 is a C1-C2 alkylene; and
R4 is selected from the group consisting of:
(a) a C2-C6 dialkylamine,
(b) a 5 to 9-membered aromatic amine wherein the ring is independently substituted with at least one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and a halogen,
(c) a 5 to 9-membered heteroaromatic amine comprising at least a nitrogen atom as a ring constituent wherein the ring is independently substituted with at least one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and a halogen,
(d) a 5 to 9-membered heterocyclic ring comprising at least a nitrogen atom as a ring constituent wherein the ring is independently substituted with at least one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and a halogen, and
(e) a 5 to 9-membered heteroaromatic ring comprising at least a nitrogen atom as a ring constituent wherein the ring is independently substituted with at least one of hydrogen, a C1-C6 aliphatic alkyl, a C3 to C10 cyclic alkyl, a C6-C10 aryl group and a halogen; and
R4 is connected to R3 group through a nitrogen atom therein,
wherein R4 is not morpholine.

### Claim 2 (depends on 1)

The method of claim 1, wherein R4 is dimethylamine or diethylamine.

### Claim 3 (depends on 1)

The method of claim 1, wherein R4 is connected to R3 through a nitrogen atom in an amino group of the 5 to 9-membered aromatic amine or heteroaromatic amine.

### Claim 4 (depends on 3)

The method of claim 3, wherein R4 is a 5 or 6-membered aromatic amine substituted with at least one of hydrogen, a C1-C6 alkyl, and a halogen.

### Claim 5 (depends on 4)

The method of claim 4, wherein R4 is a 6-membered aromatic amine substituted with hydrogen.

### Claim 6 (depends on 3)

The method of claim 3, wherein R4 is a 5 or 6-membered heteroaromatic amine substituted with at least one of a C1-C6 alkyl and a halogen, wherein the heteroaromatic amine comprises at least two heteroatoms as ring constituents where a first heteroatom is N and a second heteroatom is independently selected from the group consisting of N, O, and S.

### Claim 7 (depends on 6)

The method of claim 6, wherein R4 is a 5-membered heteroaromatic amine having a structure (II) selected from the group consisting of:

### Claim 8 (depends on 1)

The method of claim 1, wherein R4 is connected to R3 through a nitrogen atom contained in a ring as a heteroatom of the 5 to 9-membered heterocyclic ring or heteroaromatic ring.

### Claim 9 (depends on 8)

The method of claim 8, wherein R4 is a 5 or 6-membered heterocyclic ring having a structure (III) selected from the group consisting of:

### Claim 10 (depends on 8)

The method of claim 8, wherein R4 is an azole selected from the group consisting of diazole, triazole, tetraazol, benzotriazole, imidazole, pyrazole, benzimidazloe, and indazole.

### Claim 11 (depends on 10)

The method of claim 10, wherein the azole has a structure (IV) selected from the group consisting of:

### Claim 12 (depends on 1)

The method of claim 1, wherein R1 and R2 are independently selected from the group consisting of hydrogen, a halogen, a straight or branched chain alkyl group with 1 to 4 carbon atoms, and a straight or branched chain alkoxy group with 1 to 4 carbon atoms.

### Claim 13 (depends on 1)

The method of claim 1, wherein said compound is selected from the group consisting of:
1-[4-(4-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine, 1-(2-methoxy-phenyl)-4[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-methoxy-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine;
1-[4-(3-imidazol-1-ylmethyl-phenoxy)-butyl]-4-(2-methoxy-phenyl)-piperazine-hydrochloride;
1-(2-methoxy-phenyl)-4-[4-(3-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine hydrochloride;
1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-1-ylmethyl-phenoxy)-butyl]-piperazine hydrochloride;
1-(2-methoxy-phenyl)-4-[4-(3-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine hydrochloride;
1-(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzoimidazole;
1-(2-Methoxy-phenyl)-4-{4-[4-(2-methyl-imidazol-1-ylmethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-methoxy-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-indazole;
1-(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-1H-benzotriazole;
1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(5-phenyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine;
(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine di-hydrochloride;
1-(2-methoxy-phenyl)-4-[4-(4-piperidin-1-ylmethyl-phenoxy)-butyl]-piperazine;
(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-phenyl-amine;
(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-thiazol-2-yl-amine;
1-(2-chloro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-methoxy-phenyl)-4-[[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-Methoxy-phenyl)-4-[4-(3-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-methoxy-phenyl)-4-{4-[3-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine;
(3-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine;
1-{4-[4-(4,5-dichloro-imidazol-1-ylmethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine;
1-(2-chloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine;
(4-{4-[4-(2-Chloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine;
1-(3-fluoro-phenyl)-4-[4-(4-[1,2,4]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2,3-dichloro-phenyl)-4-[4-(4-tetrazol-2-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-1-ylmethyl)-phenoxy]-butyl}-piperazine;
1-(2,3-Dichloro-phenyl)-4-{4-[4-(5-methyl-tetrazol-2-ylmethyl)-phenoxy]-butyl}-piperazine;
(4-{4-[4-(2,3-dichloro-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-dimethyl-amine;
1-(2-methoxy-phenyl)-4-[4-(4-4-methylpiperazine-1-ylmethyl-phenoxy)-butyl]-piperazine;
1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-[1,3,4]thiadiazol-2-yl-amine;
1-(2,3-dichloro-phenyl)-4-[4-(4-[1,2,3]triazol-1-ylmethyl-phenoxy)-butyl]-piperazine;
(4-{4-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine;
(4-{4-[4-(2-methoxy-phenyl)-piperazin-1-yl]-butoxy}-benzyl)-(5-methyl-isoxazol-3-yl)-amine;
1-{4-[4-(2-imidazol-1-yl-ethyl)-phenoxy]-butyl}-4-(2-methoxy-phenyl)-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,4]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(2-[1,2,3]triazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-2-yl-ethyl)-phenoxy]-butyl}-piperazine;
1-(2-methoxy-phenyl)-4-{4-[4-(2-tetrazol-1-yl-ethyl)-phenoxy]-butyl}-piperazine;
1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-1-yl)-ethyl]-phenoxy}-butyl)-piperazine;
1-(2-Methoxy-phenyl)-4-(4-{4-[2-(5-methyl-tetrazol-2-yl)-ethyl]-phenoxy}-butyl)-piperazine;
2-{4-[4-(4-[1,2,3]-triazol-1-ylmethyl-phenoxy)-butyl]-piperazin-1-yl}-benzonitrile; and
1-(2-chloro-phenyl)-4-[4-(4-[1,2,3]triazol-2-ylmethyl-phenoxy)-butyl]-piperazine.

### Claim 14 (depends on 1)

The method of claim 1, wherein the piperazine compound represented by Formula (I) is administered in a pharmaceutical composition, wherein the pharmaceutical composition further comprises a pharmaceutically acceptable carrier or excipient.