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Novel compounds combining a 5-HT 1A moiety (3-aminochroman scaffold) and a 5-HT transporter (indole analogues) linked through a common basic nitrogen via an alkyl chain attached at the 1- or 3-position of the indole were evaluated for dual affinity at both the 5-HT reuptake site and the 5-HT 1A receptor. Compounds of most interest were found to have a 5-carbamoyl-8-fluoro-3-amino-3,4-dihydro-2 H-1-benzopyran linked to a 3-alkylindole (straight chain), more specifically substituted with a 5-fluoro (( R)-(-)- 35c), 5-cyano ((-)- 52a), or 5,7-difluoro ((-)- 52g). Several factors contributed to 5-HT 1A affinity, serotonin rat transporter affinity, and functional antagonism in vitro. Although most of our analogues showed good to excellent affinities at both targets, specific features such as cyclobutyl substitution on the basic nitrogen and stereochemistry at the 3-position of the chroman moiety seemed necessary for antagonism at the 5-HT 1A receptor. Branched linkers seemed to impart antagonism even as racemates; however, the potency of these analogues in the functional assay was not desirable enough to further pursue these compounds.

A process to prepare the four stereoisomers of the tricyclic 3‐aminotricyclo[2.2.1.0(2,6)] heptane‐1,3‐dicarboxylic acid, a potent selective inhibitor of the EAAT2 transporter, is described.

A pro-drug strategy to identify orally efficacious VLA-4 antagonists is described. Potential pro-drugs were evaluated for their physical chemical characteristics and in vitro properties, including solubility, stability, permeability and plasma stability. Based on this characterization, promising compounds were identified for in vivo pharmacokinetic evaluation. These studies resulted in the identification of a pro-drug that exhibited desirable blood levels in PK studies in several different species.

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of January through June 1998. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents that either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of July through December 1997. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of January through June 1997. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures, or claim relatively unexplored mechanisms for neuroprotection.

This patent update relates to agents for the treatment of neurodegenerative diseases, for both the peripheral and central nervous systems. Selected patent activities are described and summarised below for the period of January through June 1996. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. The patenting activity is described and summarised for the period between July and December 1995. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

This patent update relates to neurodegenerative diseases for both the peripheral and central nervous systems. The patenting activity is described and summarised for the period between July and December 1995. The newly disclosed agents are listed by their actual or proposed biological mechanism. While many patent applications include agents for the treatment of neurodegenerative diseases, this review cites only those patents which either disclose biological data to support potential activity, display novel structures or claim relatively unexplored mechanisms for neuroprotection.

2,3-Dihydro-2,2,9-trimethyl-1 H -pyrrolo[1,2- a ]indol-1-amine and its 1-(1-pyrrolidinyl) analog have been synthesized from the corresponding 1-ol via mesylation in pyridine followed by treatment with pyrrolidine. Mechanisms of the former, unexpected amination are briefly discussed. Evidence is presented that the pyridine ring serves as a masked amino group. The phenomenon is partly attributed to steric congestion. Similar preparation of 2-bromo-6,7,8,9-tetrahydro-8,8,10-trimethylpyridol[1,2- a ]indol-9-amine supports this notion.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

Previous studies with perzinfotel (1), a potent, selective, competitive NMDA receptor antagonist, showed it to be efficacious in inflammatory and neuropathic pain models. To increase the low oral bioavailability of 1 (3−5%), prodrug derivatives (3a−h) were synthesized and evaluated. The oxymethylene-spaced diphenyl analogue 3a demonstrated good stability at acidic and neutral pH, as well as in simulated gastric fluid. In rat plasma, 3a was rapidly converted to 1 via 2a. Pharmacokinetic studies indicated that the amount of systemic exposure of 1 produced by a 10 mg/kg oral dose of 3a was 2.5-fold greater than that produced by a 30 mg/kg oral dose of 1. Consistent with these results, 3a was significantly more potent and had a longer duration of activity than 1 following oral administration in a rodent model of inflammatory pain. Taken together, these results demonstrate that an oxymethylene-spaced prodrug approach increased the bioavailability of 1.

2,3-Dihydro-2,2,9-trimethyl-1H-pyrrolo[1,2-a]indol-1-amine and its 1-(1-pyrrolidinyl) analog have been synthesized from the corresponding 1-ol via mesylation in pyridine followed by treatment with pyrrolidine. Mechanisms of the former, unexpected amination are briefly discussed. Evidence is presented that the pyridine ring serves as a masked amino group. The phenomenon is partly attributed to steric congestion. Similar preparation of 2-bromo-6,7,8,9-tetrahydro-8,8,10-trimethylpyridol[1,2-a]indol-9-amine supports this notion.

A series of 2-amino-(phosphonoalkyl)-1H-benzimidazole-2-alkanoic acids was synthesized and evaluated for NMDA receptor affinity using a [3H]CPP binding assay. Functional antagonism of the NMDA receptor complex was evaluated in vitro using a stimulated [3H]TCP binding assay and in vivo by employing an NMDA-induced seizure model. Several compounds of the AP-6 type demonstrated potent and selective NMDA antagonistic activity both in vitro and in vivo. In particular, [R(-)]-2-amino-3-(5-chloro-1-phosphonomethyl-1H-benzoimidazol-2-yl)-propionic acid (1) displayed an IC(50) value of 7.1 nM in the [3H]CPP binding assay and an ED(50) value of 0.13 mg/kg (ip) in the NMDA lethality model. Compound 1, when administered intravenously as a single bolus dose of 3 mg/kg following permanent occlusion of the middle cerebral artery in the rat, reduced the volume of infarcted brain tissue by 45%. These results support a promising therapeutic potential for compound 1 as a neuroprotective agent.

Simplifications and modifications of the vincamine molecule led to the discovery of antihypertensive 1,2,3,4,4a,5,6,12b-octahydro-12-methylpyrazino[2',3':3,4]pyr ido[1,2-a] indoles. Stereoselective syntheses of both 4a,12b-cis and 4a,12b-trans isomers represent new annulation strategies for the construction of fused piperazines. Compounds of the trans series were at least 10 times more potent than the corresponding cis isomers. Antihypertensive activity and alpha 1-adrenoceptor blocking properties peaked with a simultaneous introduction of 4-methylethyl and 1-alkyl substituents. Compound 15j (AY-28,228; atiprosin), (4a, 12b-trans)-1-ethyl-1,2,3,4,4a,5,6, 12b-octahydro-12-methyl-4-(1-methylethyl)pyrazino[2',3':3,4]pyrido [1,2-a]indole, was chosen for a detailed preclinical evaluation.

Simplifications and modifications of the vincamine molecule led to the discovery of antihypertensive 1,2,3,4,4a,5,6,12b-octahydro-12-methylpyrazino[2',3':3,4]pyr ido[1,2-a] indoles. Stereoselective syntheses of both 4a,12b-cis and 4a,12b-trans isomers represent new annulation strategies for the construction of fused piperazines. Compounds of the trans series were at least 10 times more potent than the corresponding cis isomers. Antihypertensive activity and alpha 1-adrenoceptor blocking properties peaked with a simultaneous introduction of 4-methylethyl and 1-alkyl substituents. Compound 15j (AY-28,228; atiprosin), (4a, 12b-trans)-1-ethyl-1,2,3,4,4a,5,6, 12b-octahydro-12-methyl-4-(1-methylethyl)pyrazino[2',3':3,4]pyrido [1,2-a]indole, was chosen for a detailed preclinical evaluation.

Die aus 2,5-Dimethoxy-tetrahydrofuran (I), Ethylendiamin (II) und Carbonsauren (III) zuganglichen Pyrrol-amide (IV) konnen nach Umwandlung in die Amine (V) bzw. (VII) mit Aldehyden zu Pyrrolo-pyrazin-Derivaten (VI) bzw. (VIII) umgesetzt werden.