Hexahydropentaleno derivatives, preparation method and use in medicine thereof

Patent metadata

Field	Value
Publication number	US-9567300-B2
Application number	US-201314378975-A
Country	US
Kind code	B2
Filing date	Jun 25, 2013
Priority date	Jun 25, 2012
Publication date	Feb 14, 2017
Grant date	Feb 14, 2017

Abstract

The invention relates to hexahydropentaleno derivatives, the preparation method and use in medicine thereof, and in particular to hexahydropentaleno derivatives or stereo-isomers or pharmaceutically acceptable salts thereof as shown in general formula (I), and to the preparation method therefor and pharmaceutical compositions comprising the derivatives, and to the use thereof as a therapeutical agent, especially as a DPP-IV inhibitor. The definition of each substituent in formula (I) is the same as the definition in the description.

First claim

What is claimed is:

1. A compound having formula (I), or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

wherein each of R 1 and R 1a is independently H, F, Cl or C 1-4 alkyl;
each of R 2 and R 2a is independently H or C 1-4 alkyl; when each of R 2 and R 2a is H, each of R 1 and R 1a is independently H or F, or
R 2 and R 1a , together with the carbon atoms to which they are attached, form a 3-6 membered ring; each of R 1 and R 2a is H, wherein the 3-6 membered ring optionally contains one or more heteroatoms independently selected from N, O and S, and wherein the 3-6 membered ring is optionally substituted with one or more substituents independently selected from H, C 1-4 alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkyamino, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclyl, carboxy, —C(═O)O—C 1-4 alkyl, F, Cl, Br and I, or
R 1 and R 1a , together with the carbon atom to which they are attached, form a 3-6 membered ring, and R 2 and R 2a , together with the carbon atom to which they are attached, form a 3-6 membered ring, wherein each of the 3-6 membered rings optionally and independently contains one or more heteroatoms independently selected from N, O and S, and wherein each of the 3-6 membered rings is optionally and independently substituted with one or more substituents independently selected from C 1-4 alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclyl, carboxy, —C(═O)O—C 1-4 alkyl, F, Cl, Br and I;
wherein R 3 is C 1-4 alkyl;
each of R 4 , R 5 , R 6 and R 7 is independently H, hydroxy, C 1-4 alkyl, cycloalkyl or heterocyclyl, and wherein optionally each of the C 1-4 alkyl, cycloalkyl and heterocyclyl is substituted with one or more substituents independently selected from H, C 1-4 alkyl, F, Cl, Br, I, aryl, hydroxy, nitro, cyano, amino, C 1-3 alkylamino, R 14 C(═O)NH—, alkoxy, aryloxy, heterocyclyl, carboxy and —C(═O)O—C 1-4 alkyl;
wherein each of R 8 and R 9 is independently H or methyl;
wherein each of R 10 and R 11 is independently H, hydroxy, C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) r -aryl, —(CH 2 ) r O-aryl, —(CH 2 ) r -heteroaryl, —(CH 2 ) r O—heteroaryl, alkenyl, alkynyl, cyano, —OR 14 , —(CH 2 ) p C(═O)OR 14 , —(CH 2 ) p OC(═O)R 14 , —(CH 2 ) p C(═O)NR 14 R 15 , —(CH 2 ) p OC(═O)NR 14 R 15 , —C(═O)R 14 , —N(R 14 )C(═O)R 15 , —N(R 15 )C(═O)OR 15 , —OC(═O)OR 14 , —OC(═O)NR 14 R 15 or —NR 14 R 15 , and wherein each of the C 1-6 alkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, —(CH 2 ) r -aryl, —(CH 2 ) r O-aryl, —(CH 2 ) r -heteroaryl, —(CH 2 ) r O-heteroaryl, alkenyl and alkynyl is optionally substituted with one or more substituents independently selected from H, C 1-6 alkyl, aryl, heteroaryl, haloalkyl, haloalkoxy, hydroxy, amino, alkylamino, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, cyano, alkoxy, aryloxy, aminoalkyl, hydroxyalkyl, heterocyclyl, carboxy, —C(═O)O—C 1-4 alkyl, halogen and —NR 12 R 13 , or
R 10 and R 11 , together with the carbon atom to which they are attached, form a 3-8 membered ring, wherein the 3-8 membered ring optionally contains one or more heteroatoms independently selected from N, O and S, and wherein the 3-8 membered ring is optionally substituted with one or more substituents independently selected from H, C 1-4 alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amino, alkylamino, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, cyano, aminoalkyl, hydroxyalkyl, heterocyclyl, trifluoromethyl, carboxy, —C(═O)O—C 1-4 alkyl and —NR 12 R 13 ;
wherein each R 12 , R 13 , R 14 and R 15 is independently H, C 1-6 alkyl, —(CH 2 ) p —C 3-6 cycloalkyl, aryl, heteroaryl or heterocyclyl, and wherein each of the C 1-6 alkyl, —(CH 2 ) p —C 3-6 cycloalkyl, aryl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents independently selected from H, C 1-4 alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amino, alkylamino, cyano, aminoalkyl, hydroxyalkyl, heterocyclyl, heterocycloalkoxy, trifluoromethyl, carboxy, —C(═O)O—C 1-4 alkyl and —NR 12 ′R 13 ′, or
R 12 and R 13 , together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring; R 14 and R 15 , together with the nitrogen atom to which they are attached, form a 3-8 membered heterocyclic ring, wherein each of the 3-8 membered heterocyclic rings optionally and independently contains one or more heteroatoms independently selected from N, O and S, and wherein each of the 3-8 membered heterocyclic rings is optionally and independently substituted with one or more substituents independently selected from H, C 1-4 alkyl, cycloalkyl, aryl, heteroaryl, alkoxy, cycloalkoxy, aryloxy, heteroaryloxy, halogen, hydroxy, amino, alkylamino, cyano, aminoalkyl, hydroxyalkyl, heterocyclyl, trifluoromethyl, carboxy and —C(═O)O—C 1-4 alkyl;
wherein each of R 12 ′ and R 13 ′ is independently H, C 1-4 alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl;
wherein r is 1, 2, 3 or 4; and
wherein p is 0, 1, 2, 3 or 4.

2. The compound of claim 1 having formula (IA) or a stereoisomer, a geometric isomer, a tautomer, a racemate, an N-oxide, a hydrate, a solvate, or a pharmaceutically acceptable salt thereof,

wherein each of R 1 and R 1a independently H, F, Cl or C 1-4 alkyl;
each of R 2 and R 2a is independently H or C 1-4 alkyl; when each of R 2 and R 2a is H, each of R 1 and R 1a is independently H or F, or
R 2 and R 1a , together with the carbon atoms to which they are attached, form a 3-6 membered ring; each of R 1 and R 2a is H, wherein the 3-6 membered ring optionally contains one or more heteroatoms independently selected from N, O and S, and wherein the 3-6 membered ring is optionally substituted with one or more substituents independently selected from H, C 1-4 alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, amino, C 1-3 alkyamino, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, cyano, C 1-3 alkoxy, C 6-10 aryloxy, C 1-3 aminoalkyl, C 1-3 hydroxyalkyl, C 2-5 heterocyclyl, carboxy, —C(═O)O—C 1-4 alkyl, F, Cl, Br and I, or
R 1 and R 1a , together with the carbon atom to which they are attached, form a 3-6 membered ring, and R 2 and R 2a , together with the carbon atom to which they are attached, form a 3-6 membered ring, wherein each of the 3-6 membered rings optionally and independently contains one or more heteroatoms independently selected from N, O and S, and wherein each of the 3-6 membered rings is optionally and independently substituted with one or more substituents independently selected from H, C 1-4 alkyl, C 6-10 aryl, C 1-9 heteroaryl, C 1-3 haloalkyl, C 1-3 haloalkoxy, hydroxy, amino, C 1-3 alkylamino, R 14 C(═O)NH—, R 14 R 15 NC(═O)—, cyano, C 1-3 alkoxy, C 6-10 aryloxy, C 1-3 aminoalkyl, C 1-3 hydroxyalkyl, C 2-5 heterocyclyl, carboxy, —C(═O)O—C 1-4 alkyl, F, Cl, Br and I;
wherein R 3 is C 1-4 alkyl;
each of R 4 and R 5 is independently H, hydroxy, C 1-4 alkyl, C 3-6 cycloalkyl or C 2-5 heterocyclyl, and wherein each of the C 1-4 alkyl, C 3-6 cycloalkyl and C 2-5 heterocyclyl is optionally substituted with one or more substituents independently selected from H, C 1-4 alkyl, F, Cl, Br, I, C 6-10

Assignees

• Sunshine Lake Pharma Co Ltd

Inventors

• Gu Zheng
• Qiu Guanpeng
• Wu Wuyong
• Kang Panpan
• Zhang Zongyuan
• Chen Gang
• Lan Chengsheng
• Wei Yonggang
• Wen Jiaping
• Zhu Guozhi
• Lu Yonghua
• Wang Heran
• Wang Yincai
• Yuan Mingyun
• Ye Kangzhi
• Su Guizhuan
• Tang Pengcho

Classifications

• A61P3/10

  for hyperglycaemia, e.g. antidiabetics · CPC title

• A61P9/12

  Antihypertensives · CPC title

• A61P9/10

  for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis · CPC title

• A61P3/06

  Antihyperlipidemics · CPC title

• A61P5/50

  for increasing or potentiating the activity of insulin · CPC title