Synthesis and evaluation of 1-arylsulfonyl-3-piperazinone derivatives as factor Xa inhibitors V. A series of new derivatives containing a spiro[imidazo[1,2-a]pyrazine-2(3H),4'-piperidin]-5(1H)-one scaffold.
We have already reported unique compounds containing a N,O-spiro acetal structure as an orally active factor Xa (FXa) inhibitor. This time, we described a N,N-spiro acetal structure as an analogue of the N,O-spiro acetal structure for an orally active FXa inhibitor. The synthesis of these analogues could be achieved in a similar fashion to the N,O-spiro acetal synthesis. Consequently, FXa inhibitory activity was increased and more active compounds could be found (M58163: IC50 = 0.61 nM, M58169: IC50 = 0.58 nM). Additionally, the absolute configuration could be determined by X-ray crystallography analysis (M58169: (R)-config.).
Saitoh
Fumihiko
F
Pharmaceutical Research Center, Mochida Pharmaceutical Co., Ltd, Gotemba, Shizuoka, Japan. fsaitoh@mochida.co.jp
Mukaihira
Takafumi
T
Nishida
Hidemitsu
H
Satoh
Tsutomu
T
Okano
Akihiro
A
Yumiya
Yasunobu
Y
Ohkouchi
Munetaka
M
Johka
Rumi
R
Matsusue
Tomokazu
T
Shiromizu
Ikuya
I
Hosaka
Yoshitaka
Y
Matsumoto
Miwa
M
Ohnishi
Shuhei
S
D018360:Crystallography, X-Ray; D065427:Factor Xa Inhibitors; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008958:Models, Molecular; D015394:Molecular Structure; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010881:Piperidones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D012680:Sensitivity and Specificity; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D065427:Factor Xa Inhibitors; C516638:M58163; C516637:M58169; D009281:Naphthalenes; D010879:Piperazines; D010881:Piperidones; D013141:Spiro Compounds; C516636:spiro(imidazo(1,2-a)pyrazine-2(3H),4'-piperidin)-5(1H)-one