123691-14-5Relevant articles and documents
Methods for restoring cognitive function following systemic stress
-
, (2008/06/13)
The invention provides methods for treating cognitive decline that is associated with systemic stress.
Phosphinic acid analogues of GABA. 2. Selective, orally active GABA(B) antagonists
Froestl,Mickel,Von Sprecher,Diel,Hall,Maier,Strub,Melillo,Baumann,Bernasconi,Gentsch,Hauser,Jaekel,Karlsson,Klebs,Maitre,Marescaux,Pozza,Schmutz,et al.
, p. 3313 - 3331 (2007/10/02)
In 1987, 25 years after the synthesis of the potent and selective GABA(B) agonist baclofen (1), Kerr et al. described the first GABA(B) antagonist phaclofen 2. However, phaclofen and structurally similar derivatives 3-5 did not cross the blood-brain barrier and hence were inactive in vivo as central nervous system agents. As a consequence, the therapeutic potential of GABA(B) antagonists remained unclear. In exploring GABA and baclofen derivatives by replacing the carboxylic acid residue with various phosphinic acid groups, we discovered more potent and water soluble GABA(B) antagonists. Electrophysiological experiments in vivo demonstrated that some of the new compounds were capable of penetrating the blood-brain barrier after oral administration. Neurotransmitter release experiments showed that they interacted with several presynaptic GABA(B) receptor subtypes, enhancing the release of GABA, glutamate, aspartate, and somatostatin. The new GABA(B) antagonists interacted also with postsynaptic GABA(B) receptors, as they blocked late inhibitory postsynaptic potentials. They facilitated the induction of long-term potentiation in vitro and in vivo, suggesting potential cognition enhancing effects. Fifteen compounds were investigated in various memory and learning paradigms in rodents. Although several compounds were found to be active, only 10 reversed the age-related deficits of old rats in a multiple-trial one-way active avoidance test after chronic treatment. The cognition facilitating effects of 10 were confirmed in learning experiments in Rhesus monkeys. The novel GABA(B) antagonists showed also protective effects in various animal models of absence epilepsy.
Substituted propane-phosphinic acid compounds
-
, (2008/06/13)
Compounds of the formula I STR1 wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms, and wherein one of the groups R1, R2 and R3 represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another one of R1, R2 and R3 is hydrogen or, in the case of R1 and R2, is hydroxy, and the remaining one of R1, R2 and R3 is hydrogen, and their salts have GABAB -antagonistic properties and can be used as GABAB -antagonists. They are obtained when in a compound of formula II STR2 in which R, R1, R2 and R3 have their previous significances, Z represents --NH2 and R4 denotes a hydroxy-protective group R5 or, when R1 and R3 denote hydrogen and R2 denotes hydrogen or alkyl, denotes an alkali metal or ammonium ion R6, or Z represents a protected or latent amino group Z0 and R4 deontes hydrogen or a hydroxy-protective group R5, any group R5 or R6 is replaced by hydrogen, and/or any group Z0 is converted into --NH2.
Substituted propane-phosphinic acid compounds
-
, (2008/06/13)
Compounds of the formula I STR1 wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms, and wherein one of the groups R1, R2 and R3 represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another one of R1, R2 and R3 is hydrogen or, in the case of R1 and R2, is hydroxy, and the remaining one of R1, R2 and R3 is hydrogen, or wherein R denotes methyl, R1 denotes hydrogen or hydroxy, R2 denotes an aromatic radical and R3 represents hydrogen, and their salts have GABAB -antagonistic properties and can be used as GABAB -antagonists. They are obtained when in a compound of formula II STR2 in which R, R1, R2 and R3 have their previous significances, Z represents --NH2 and R4 denotes a hydroxy-protective group R5 or, when R1 and R3 denote hydrogen and R2 denotes hydrogen or alkyl, denotes an alkali metal or ammonium ion R6, or Z represents a protected or latent amino group Z0 and R4 denotes hydrogen or a hydroxy-protective group R5, any group R5 or R6 is replaced by hydrogen, and/or any group Z0 is converted into --NH2.
Substituted propane-phosphinic acid compounds
-
, (2008/06/13)
Compounds of the formula I STR1 wherein R denotes an aliphatic, cycloaliphatic, cycloaliphatic-aliphatic or araliphatic radical having 2 or more carbon atoms, and wherein one of the groups R1, R2 and R3 represents hydrogen or an aliphatic, cycloaliphatic, araliphatic or aromatic radical, another one of R1, R2 and R3 is hydrogen or, in the case of R1 and R2, is hydroxy, and the remaining one of R1, R2 and R3 is hydrogen, or wherein R denotes methyl, R1 denotes hydrogen or hydroxy, R2 denotes an aromatic radical and R3 represents hydrogen, and their salts have GABAB -antagonistic properties and can be used as GABAB -antagonists. They are obtained when in a compound of formula II STR2 in which R, R1, R2 and R3 have their previous significances, Z represents --NH2 and R4 denotes a hydroxy-protective group R5 or, when R1 and R3 denote hydrogen and R2 denotes hydrogen or alkyl, denotes an alkali metal or ammonium ion R6, or Z represents a protected or latent amino group Z° and R4 denotes hydrogen or a hydroxy-protective group R5, any group R5 or R6 is replaced by hydrogen, and/or any group Z° is converted into --NH2.
