Pyrimidinone derivative having autotaxin-inhibitory activity

Patent metadata

Field	Value
Publication number	US-10183949-B2
Application number	US-201715441385-A
Country	US
Kind code	B2
Filing date	Feb 24, 2017
Priority date	Aug 29, 2014
Publication date	Jan 22, 2019
Grant date	Jan 22, 2019

Abstract

A compound according to any one of formula (Ia) to (Ic), or its pharmaceutically acceptable salt:

wherein R 1 , R 2 , R 3 , R 4a , R 4c , R 5 are as defined in the description.

First claim

The invention claimed is:

1. A compound of formula (Ia), or a pharmaceutically acceptable salt thereof:

wherein:
R 1 is hydrogen,
R 2 is a group represented by the formula:

wherein:
X is a single bond or O,
Ring B is a benzene ring, a 6-membered aromatic heterocycle, a 6-membered non-aromatic carbocycle or a 6-membered non-aromatic heterocycle,
R 6 is halogen, cyano, or substituted or unsubstituted alkyloxy,
R 7 is each independently, substituted or unsubstituted alkyl, substituted or unsubstituted amino, substituted or unsubstituted alkylcarbonyl, substituted or unsubstituted alkenylcarbonyl, substituted or unsubstituted alkynylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted carbamoyl, substituted or unsubstituted sulfamoyl, substituted or unsubstituted alkylsulfinyl, substituted or unsubstituted alkenylsulfinyl, substituted or unsubstituted alkynylsulfinyl, substituted or unsubstituted alkylsulfonyl, substituted or unsubstituted alkenylsulfonyl or substituted or unsubstituted alkynylsulfonyl,
n is integer of 0 to 4,
R 4a is substituted or unsubstituted alkyl,
R 5 is a group represented by formula: R 11 —(C(R 10a )(R 10b ))m-,
wherein
R 10a is each independently hydrogen, halogen or substituted or unsubstituted alkyl,
R 10b is each independently hydrogen, halogen or substituted or unsubstituted alkyl,
m is integer of 1 to 6,
R 11 is substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyl, substituted or unsubstituted non-aromatic heterocyclyl, substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl, or substituted or unsubstituted sulfamoyl.

2. The compound according to claim 1 , wherein R 4a is alkyl optionally substituted with one or more substitutent(s) selected from Substituent group α, alkenyl optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkynyl optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkylamino optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkenylamino optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkynylamino optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkyloxy optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkenyloxy optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkynyloxy optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkylthio optionally substituted with one or more substitutent(s) selected from the Substituent group α, alkenylthio optionally substituted with one or more substitutent(s) selected from the Substituent group α, or alkynylthio optionally substituted with one or more substitutent(s) selected from the Substituent group α,
wherein the one or more substitutent(s) of Substituent group α is selected from the group consisting of cyano, halogen, substituted or unsubstituted alkyloxy, substituted or unsubstituted alkenyloxy, substituted or unsubstituted alkynyloxy, substituted or unsubstituted non-aromatic carbocyclylalkyloxy, substituted or unsubstituted aromatic carbocyclylalkyloxy, substituted or unsubstituted non-aromatic heterocyclylalkyloxy and substituted or unsubstituted aromatic heterocyclylalkyloxy,
or its pharmaceutically acceptable salt.

3. The compound according to claim 1 , wherein R 11 is substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl, or its pharmaceutically acceptable salt.

4. The compound according to claim 1 , wherein R 11 is substituted or unsubstituted aromatic carbocyclylcarbonyl, substituted or unsubstituted aromatic heterocyclylcarbonyl, substituted or unsubstituted non-aromatic carbocyclylcarbonyl, substituted or unsubstituted non-aromatic heterocyclylcarbonyl, substituted or unsubstituted alkyloxycarbonyl, substituted or unsubstituted alkenyloxycarbonyl, substituted or unsubstituted alkynyloxycarbonyl, substituted or unsubstituted aromatic carbocyclyloxycarbonyl, substituted or unsubstituted aromatic heterocyclyloxycarbonyl, substituted or unsubstituted non-aromatic carbocyclyloxycarbonyl, substituted or unsubstituted non-aromatic heterocyclyloxycarbonyl, substituted or unsubstituted carbamoyl or substituted or unsubstituted sulfamoyl, or its pharmaceutically acceptable salt.

5. The compound according to claim 1 , wherein R 11 is carbamoyl optionally substituted with one or more substitutent(s) selected from the group consisting of substituted or unsubstituted alkyl, substituted or unsubstituted alkenyl, substituted or unsubstituted alkynyl, substituted or unsubstituted aromatic carbocyclyl, substituted or unsubstituted aromatic heterocyclyl, substituted or unsubstituted non-aromatic carbocyclyl and substituted or unsubstituted non-aromatic heterocyclyl, or its pharmaceutically acceptable salt.

6. A pharmaceutical composition comprising the compound according to claim 1 or its pharmaceutically acceptable salt as an active ingredient and a pharmaceutical additive.

7. A method for the treatment of a disease related to autotaxin, comprising administering an effective amount of the compound according to claim 1 or a pharmaceutically acceptable salt thereof to a patient in need thereof,
wherein the disease is selected from the group consisting of urinary extraction failure, chronic kidney disease, renal fibrosis, interstitial pneumonitis, pulmonary fibrosis, scleroderma, pain, fibromyalgia, rheumatoid arthritis, angiogenesis, cancer, formation, growth and propagation of tumor, arteriosclerosis, an ocular disease, choroidal neovascularization, diabetic retinopathy, an inflammatory disease, arthritis, neurodegeneration, restenosis, wound healing, transplant rejection and endometriosis.

8. A pharmaceutical composition comprising the compound according to claim 2

Assignees

• Univ Tokyo
• Univ Tohoku
• Shionogi & Co

Inventors

• Nagano Tetsuo
• Okabe Takayoshi
• Kojima Hirotatsu
• Kawaguchi Mitsuyasu
• Nureki Osamu
• Ishitani Ryuichiro
• Nishimasu Hiroshi
• Aoki Junken
• Tanaka Nobuyuki
• Kanda Yasuhiko
• Kioi Yoshiyuki
• Tateno yusuke
• Kida Shiro
• Yamane Junji

Classifications

• C07D471/08

  Bridged systems · CPC title

• C07D409/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D403/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title

• C07D405/12

  linked by a chain containing hetero atoms as chain links · CPC title

• C07D413/06

  linked by a carbon chain containing only aliphatic carbon atoms · CPC title