IP Library › Granted Patent US 10,252,992

Granted Patent B2

US 10,252,992 · App. 16/011,050 · Granted Apr 9, 2019

Urea derivative or pharmacologically acceptable salt thereof

Inventors: Hiroyasu Takahashi (Kirihara, JP); Yoshifumi Saito (Shimotsuga-gun, JP); Kosuke Tsuda (Shimotsuga-gun, JP); Mitsuhito Shibasaki (Shimotsuga-gun, JP); Kohei Ohata (Shimotsuga-gun, JP)

Assignee: Kyorin Pharmaceutical Co., Ltd.

C07D207/273 C07D207/22 C07D209/54 C07D401/04 C07D401/06 C07D401/12 C07D403/04 C07D403/12 C07D405/04 C07D405/12 C07D405/14 C07D409/04 C07D409/12 C07D409/14 C07D413/06 C07D413/12 C07D413/14 C07D417/12

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Quick Facts

Patent No.: US 10,252,992
App. No.: 16/011,050
Granted: Apr 9, 2019
Kind: B2

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Abstract

Provided is a compound having a formyl peptide receptor like 1 (FPRL1) agonist effect. The present invention relates to a compound represented by the general formula (I) or a pharmacologically acceptable salt thereof. The present invention also relates to a pharmaceutical composition containing the compound represented by the general formula (I) or a pharmacologically acceptable salt thereof.

Claims (95)

1. A method of treating an inflammatory disease, a chronic airway disease, cancer, septicemia, a circulatory disorder, neuroinflammation, a nervous disorder, pain, a prion disease, amyloidosis, an immune disorder, or COPD in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a compound, or a pharmacologically acceptable salt thereof, wherein said compound is

(−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(3,4-difluorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(4-chlorophenyl)-3-[(3S*,4R*)-4-(4-methoxyphenyl)- 1 -methyl-2-oxopyrrolidin-3 -yl]urea,

(−)-1-(4-fluorophenyl)-3 -[(3S*,4R*)-4-(4-methoxyphenyl)- 1 -methyl-2-oxopyrrolidin-3 -yl]urea,

(−)-1-[(3S*,4R*)-4-(3-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

1-[(3S*,4R*)-4-(2-chloro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-(4-fluorophenyl)-3-[(3S*,4R*)-4-(4-methoxy-2-methylphenyl)-2-oxopyrrolidin-3 -yl]urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(2,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(3,5-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*, 4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(3-fluoro-5-methoxypyridin-2-yl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-(4-fluorophenyl)-3-[(3S*, 4R*)-4-(5-methoxythiophen-2-yl)-2-oxopyrrolidin-3 -yl]urea,

(−)-1-(4-fluorophenyl)-3-[(3S*, 4R*)-4-(4-methylthiophenyl)-2-oxopyrrolidin-3 -yl]urea,

(−)-1-(4-chlorophenyl)-3 -[(3S*, 4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(4-cyanophenyl)-3-[(3S*, 4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-methoxyphenyl)urea,

(−)-1-(5-chlorothiazol-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(6-chloropyridin-3-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]urea,

(−)-1-(5-chloropyridin-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-(benzo[b]thiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(5-methylthiophen-2-yl)urea,

(−)-1-(4-fluorophenyl)-3 -[(3S*,4R*, 5S*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea,

(−)-1-(4-fluorophenyl)-3-[(3S*,4R*,5R*)-4-(4-methoxyphenyl)-5-methyl-2-oxopyrrolidin-3-yl]urea,

(+)-1-(4-chlorophenyl)-3-[(3R*,4S*)-2-oxo-4-phenylpyrrolidin-3-yl]urea,

(±)-trans- 1-(4-chlorophenyl)-3- [4-(4-methoxyphenyl)- 1-methyl-2-oxopyrrolidin-3-yl]urea,

(±)-trans-1-(4-fluorophenyl)-3- [4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(±)-trans-1-(4-chlorophenyl)-3- [4-(4-methoxyphenyl)- 1-methyl-2-oxopyrrolidin-3 -yl]urea,

(−)-1-[(3 S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]-3[4-(trifluoromethoxy)phenyl]urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]-3-fluorophenyl)urea,

(−)- 1-[(3 S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]-3-(4-phenoxyphenyl)urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]-3 -(3 -fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]-3 -(3,4-difluorophenyl)urea,

(−)- 1-(5 -chlorothiophen-2-yl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(p-tolyl)urea,

(−)-1-[(3S*,4R*)- 1-ethyl-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-(4-fluorophenyl)-3 -[(3S*,4R*)-1-(1-hydroxy-2-methylpropan-2-yl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(±)-trans-1-(4-chlorophenyl)-3-[ 1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]urea,

(+)-trans-1-(4-chlorophenyl)-3-[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-trans- 1-(4-chlorophenyl)-3 -[1-(2-hydroxyethyl)-4-(4-methoxyphenyl)-2-oxopyrrolidin-3-yl]urea,

(−)-2-{(3S*,4R*)-3 -[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin- 1-yl }-N-methylacetamide,

(−)-2-{ (3S*,4R*)-3-[3-(4-fluorophenyl)ureido] -4-(4-methoxyphenyl)-2-oxopyrrolidin- 1-yl}propionic acid (isomer A),

(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin- 1-yl}-N-methylpropionamide (isomer A),

(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin- 1-yl}propionic acid (isomer B),

(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin- 1-yl}-N-methylpropionamide (isomer B),

(−)-2-{(3S*,4R*)-3-[3-(4-fluorophenyl)ureido]-4-(4-methoxyphenyl)-2-oxopyrrolidin-1-yl}-N,2-dimethylpropionamide,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-methyl-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(2-fluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3 -y1]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(+)-1-(4-fluorophenyl)-3-[(3R*,4S*)-1-methoxy-4-(4-methoxyphenyl)-2-oxopyrrolidin-3 -yl]urea,

(−)-3,5-difluoro-4-{(3R*,4S*)-443-(4-fluorophenyl)ureido]-5-oxopyrrolidin-3-y1Ibenzamide,

(−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(methoxyimino)-4-(4-methoxyphenyl)pyrrolidin-3 -yl]urea,

(−)-1-[(3S*,4R*,Z)-4-(2-fluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3 -yl]-3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methoxyimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-(4-fluorophenyl)-3-{ (3S*,4R*,Z)-2-[(2-hydroxyethoxy)imino]-4-(4-methoxyphenyl)pyrrolidin-3-yl }urea,

(−)-1-{ (3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl } -3-(4-fluorophenyl)urea,

(−)-1-[(3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-(methylimino)pyrrolidin-3-yl]-3-(4-fluorophenyl)urea,

(−)-1-(4-fluorophenyl)-3-[(3S*,4R*,Z)-2-(2-hydroxyimino)-4-(4-methoxyphenyl)pyrrolidin-3-yflurea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(3-hydroxy-4-methylphenyl)urea,

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yl]-3-(4-fluoro-3-hydroxyphenyl)urea,

(−)-1-(4-chloro-3-hydroxyphenyl)-3-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)-2-oxopyrrolidin-3-yflurea,

(−)-1-(4-cyanophenyl)-3-[(3S*,4R*)-4-(6-fluoro-2,3-dihydrobenzofuran-5-yl)-2-oxopyrrolidin-3-yflurea,

(−)-1-{ (3S*,4R*,Z)-4-(2,6-difluoro-4-methoxyphenyl)-2-[(2-hydroxyethoxy)imino]pyrrolidin-3-yl}-3-(p-tolyl)urea, or

(−)-1-[(3S*,4R*)-4-(2,6-difluoro-4-methoxyphenyl)- 1-(2-hydroxyethyl)-2-oxopyrrolidin-3-yl]-3-phenylurea.

2. The method of claim 1 , wherein the immune disorder is an allergic symptom or HIV retrovirus infection.

3. A method of treating an inflammatory disease, a chronic airway disease, cancer, septicemia, a circulatory disorder, neuroinflammation, a nervous disorder, pain, a prion disease, amyloidosis, an immune disorder, or COPD in a patient in need of treatment comprising administering to the patient a therapeutically effective amount of a compound, or a pharmacologically acceptable salt thereof, wherein said compound is

4. The method of claim 3 , wherein the immune disorder is an allergic symptom or HIV retrovirus infection.

5. The method of claim 3 , wherein said compound is