This Account describes the design and development of a scalable synthesis for the drug molecule A... more This Account describes the design and development of a scalable synthesis for the drug molecule AR-A2 (1) starting from the discovery route originating in medicinal chemistry. Special emphasis is placed on the introduction of the correct (R) stereochemistry on C2, which was ultimately achieved in a diastereoselective imine-reducing step applying NaBH4. After optimization, this transformation was operated on a large pilot-plant scale (2000 L), offering the desired product (11) in 55% yield and 96% diastereomeric excess at a 100 kg batch size. From a synthesis strategy point of view, the choice of (S)-1-phenylethylamine (9) was crucial not only for its role as a provider of the NH2 functionality and the stereo-directing abilities but also as an excellent protecting group in the subsequent N-arylation reaction, according to the Buchwald-Hartwig protocol. As one of the very first examples in its kind, the latter step was scaled up to pilot manufacturing (125 kg in 2500 L vessel size), delivering an outstanding isolated yield of 95%. This consecutive series of chemical transformations was completed with an environmentally friendly removal of the phenethyl appendage. In addition, an elegant method to synthesize the tetralone substrate 6, as well as a novel and robust procedure to use imidazole as a buffer for the selective formation of the mono-HBr salt of AR-A2, will be briefly described.
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine ... more Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
Journal of Chemical Information and Computer Sciences, Jul 28, 1997
... Chemistry, Biomedical Centre, Uppsala University, Box 574, S-751 23 Uppsala, Sweden, Medicina... more ... Chemistry, Biomedical Centre, Uppsala University, Box 574, S-751 23 Uppsala, Sweden, Medicinal and Computational Chemistry Section, Karo Bio AB ... The resulting binding pockets can subsequently be used for de novo design of new compounds 10,11 and for searching 3D ...
A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesi... more A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, P... more 1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, Pharmacology, and Modeling of 5-HT1A Receptor Interactions. -Novel aporphines, e.g. (IV) and (VI), and noraporphines, e.g. (XIV) and (XV), are synthesized following recently described methods. Structure-activity relationship evaluation shows that reference compound (I) has a 7-fold higher affinity for the serotonin 5-HT1A receptor in vitro but is less efficacious in vivo than (XV) while compound (XIV) displays weak dopamine receptor agonism. -(HEDBERG, M. H.; JANSEN, J. M.; NORDVALL, G.; HJORTH, S.; UNELIUS, L.; JOHANSSON, A. M.; J.
2,6-Pipecoloxilidide (PPX) is an important intermediate for the synthesis of mepivacaine, ropivac... more 2,6-Pipecoloxilidide (PPX) is an important intermediate for the synthesis of mepivacaine, ropivacaine and bupivacaine, which are frequently used local anesthetics of the amide type for several purposes in medicine[1]. Based on its chiral nature, an enantioseparation of PPX is needed to exclude additional negative side effects from the counter-enantiomer. By combining three different techniques, chromatography, enantioselective crystallization and racemization, an improved process with a higher yield was achieved in comparison to the use of a single full-separation process. All 3 unit operations were executed within a jointly used solvent system with full recycling (counter-enantiomer of PPX and solvents) including a minimum requirement of solvent exchanges / removals. The target molecule was obtained with an enantiopurity of >99.5% in multi-gram scale. Within this contribution the design of the integrated process is presented with a focus on the final enantioselective crystalliza...
1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, P... more 1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, Pharmacology, and Modeling of 5-HT1A Receptor Interactions. -Novel aporphines, e.g. (IV) and (VI), and noraporphines, e.g. (XIV) and (XV), are synthesized following recently described methods. Structure-activity relationship evaluation shows that reference compound (I) has a 7-fold higher affinity for the serotonin 5-HT1A receptor in vitro but is less efficacious in vivo than (XV) while compound (XIV) displays weak dopamine receptor agonism. -(HEDBERG, M. H.; JANSEN, J. M.; NORDVALL, G.; HJORTH, S.; UNELIUS, L.; JOHANSSON, A. M.; J.
AstraZeneca R&D S€ odert€ alje, Pharmaceutical Development, 15185 S€ odert€ alje, Sweden b S Supp... more AstraZeneca R&D S€ odert€ alje, Pharmaceutical Development, 15185 S€ odert€ alje, Sweden b S Supporting Information
To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS... more To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS) patients by assessing the levels of fecal calprotectin, to study levels of serum calprotectin in AS, and to correlate the concentrations of calprotectin in feces and serum with reported gastrointestinal symptoms, medication, and measures of disease activity. All patients fulfilling the Modified New York criteria of AS at the study centers were invited to participate. The patients answered questionnaires concerning medication, symptoms, and disease activity. Physical examination was performed, including back mobility tests. Samples of stools and blood were collected and analyzed for fecal and serum calprotectin. Elevated levels of fecal calprotectin (>50 mg/kg) was found in 140 of 205 AS patients (68%). Levels of fecal calprotectin were associated with increasing age, disease duration, ESR, CRP, and serum calprotectin, but not with gastrointestinal symptoms. Fecal calprotectin was higher in patients using NSAIDs, salicylates, and proton pump inhibitors, but lower in patients using methotrexate and infliximab. Serum calprotectin levels were normal or low in 98% of AS patients and not different from the levels in healthy blood donors. Serum calprotectin levels were positively associated with ESR, CRP, WBC, and PLT. Two-thirds of AS patients had elevated levels of fecal calprotectin, without associated gastrointestinal symptoms. Serum calprotectin was mostly normal in AS, in contrast to various other inflammatory rheumatic diseases. We suggest that fecal calprotectin may be a marker for subclinical intestinal inflammation in AS and should be measured after stopping NSAIDs, but further endoscopic studies are needed.
R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natura... more R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious ~-H T~A receptor agonist. In contrast, 2 is a partial 5-HTu receptor agonist of low potency which has affinity also for central DI and DM receptors. The differences in pharmacological profiles were rationalized by modeling use of in vitro and in vivo test systems. The differences in pharmacological profiles have been rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HTu and DM receptor binding site. The results indicate that 3 is a potent, selective, and efficacious B-HT~A receptor agonist. In contrast, 2 is a partial B-HTIA receptor agonist of low potency which has affinity also for central D1 and D u receptors. The selective and pronounced serotonergic effects of 3 can be rationalized by the B-HT~A binding site model in which the C10-methyl group is accommodated by a lipophilic pocket, which is not present in the Du binding site.
This Account describes the design and development of a scalable synthesis for the drug molecule A... more This Account describes the design and development of a scalable synthesis for the drug molecule AR-A2 (1) starting from the discovery route originating in medicinal chemistry. Special emphasis is placed on the introduction of the correct (R) stereochemistry on C2, which was ultimately achieved in a diastereoselective imine-reducing step applying NaBH4. After optimization, this transformation was operated on a large pilot-plant scale (2000 L), offering the desired product (11) in 55% yield and 96% diastereomeric excess at a 100 kg batch size. From a synthesis strategy point of view, the choice of (S)-1-phenylethylamine (9) was crucial not only for its role as a provider of the NH2 functionality and the stereo-directing abilities but also as an excellent protecting group in the subsequent N-arylation reaction, according to the Buchwald-Hartwig protocol. As one of the very first examples in its kind, the latter step was scaled up to pilot manufacturing (125 kg in 2500 L vessel size), delivering an outstanding isolated yield of 95%. This consecutive series of chemical transformations was completed with an environmentally friendly removal of the phenethyl appendage. In addition, an elegant method to synthesize the tetralone substrate 6, as well as a novel and robust procedure to use imidazole as a buffer for the selective formation of the mono-HBr salt of AR-A2, will be briefly described.
Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine ... more Derivatives of the selective serotonin 5-HT1A receptor agonist (R)-11-hydroxy-10-methylaporphine (2) having various substituents in the C10-position or at the nitrogen have been synthesized from natural morphine or 6-O-acetylcodeine, respectively. The C10-substituents were introduced using efficient Stille or Suzuki cross-coupling reactions. The compounds were evaluated for their affinities to 5-HT1A and dopamine (DA) D1 and D2A receptors in vitro. All compounds tested displayed low (micromolar) affinities to D1 and D2A receptors. In addition, changes in steric bulk and/or electronic properties of the C10-substituent as compared to a C10-methyl group, as well as substitution of the N-methyl group for a hydrogen or a larger N-alkyl group, produced a marked decrease in the affinities to 5-HT1A receptors. Selected compounds that displayed moderate to high affinities to 5-HT1A receptors were evaluated for their ability to stimulate 5-HT1A receptors in vivo. The evaluated compounds behaved as agonists at 5-HT1A receptors, except for the N-propyl analogue of 2, (R)-11-hydroxy-10-methyl-N-propylnoraporphine (23), which displayed weak DA receptor agonism at the doses tested. Hence, the substitution pattern of 2 (a C10-methyl, a C11-hydroxy, and an N-methyl group) appears to be optimal for potent interaction of 10,11-disubstituted (R)-aporphines with 5-HT1A receptors. Modeling of ligand-5-HT1A receptor interactions was performed in an attempt to rationalize the observed affinity data. The binding site model suggests the presence of a "methyl pocket" in the 5-HT1A receptor binding ste. The C11-methoxy-substituted aporphines appear to have a different binding mode compared to 2, implying a different accessibility of these compounds to the "methyl pocket".
Journal of Chemical Information and Computer Sciences, Jul 28, 1997
... Chemistry, Biomedical Centre, Uppsala University, Box 574, S-751 23 Uppsala, Sweden, Medicina... more ... Chemistry, Biomedical Centre, Uppsala University, Box 574, S-751 23 Uppsala, Sweden, Medicinal and Computational Chemistry Section, Karo Bio AB ... The resulting binding pockets can subsequently be used for de novo design of new compounds 10,11 and for searching 3D ...
A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesi... more A series of C11-substituted (R)-aporphines and C11-oxygenated (R)-noraporphines has been synthesized and evaluated for central serotonergic and dopaminergic effects in vitro and in vivo. The various C11-substituents were introduced using efficient nickel- and palladium-catalyzed reactions of the corresponding triflate (R)-11-[[(trifluoromethyl)sulfonyl]oxy]aporphine (6). Several compounds display high affinity to serotonin 5-HT1A receptors in spite of major differences in steric bulk and electronic properties of the various C11-substituents. A change of the N-methyl group of the nonselective 3 to H [23, (R)-11-hydroxynoraporphine] or propyl [2, (R)-11-hydroxy-N-propylnoraporphine] increases the selectivity for 5-HT1A receptors (100-fold) and dopamine D2A receptors (3-fold), respectively. Compounds 3 and 23 have similar affinities to 5-HT1A receptors, whereas the propyl substituent of 2 not only enhances the selectivity for D2A receptors but also increases the D2A affinity. Modeling of ligand-receptor binding site interactions yielded an interaction site model for the 5-HT1A receptor that describes a gradual change in binding mode for C11-hydroxy, -methoxy-, and -phenyl-substituted derivatives. Hydrogen bonding is hereby gradually replaced by van der Waals interactions involving a relatively large lipophilic pocket. The derived D2A receptor model can accommodate both the N-propyl substituent of 2 and the C11-ethyl substituent of 11 [(R)-11-ethylaporphine].
1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, P... more 1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, Pharmacology, and Modeling of 5-HT1A Receptor Interactions. -Novel aporphines, e.g. (IV) and (VI), and noraporphines, e.g. (XIV) and (XV), are synthesized following recently described methods. Structure-activity relationship evaluation shows that reference compound (I) has a 7-fold higher affinity for the serotonin 5-HT1A receptor in vitro but is less efficacious in vivo than (XV) while compound (XIV) displays weak dopamine receptor agonism. -(HEDBERG, M. H.; JANSEN, J. M.; NORDVALL, G.; HJORTH, S.; UNELIUS, L.; JOHANSSON, A. M.; J.
2,6-Pipecoloxilidide (PPX) is an important intermediate for the synthesis of mepivacaine, ropivac... more 2,6-Pipecoloxilidide (PPX) is an important intermediate for the synthesis of mepivacaine, ropivacaine and bupivacaine, which are frequently used local anesthetics of the amide type for several purposes in medicine[1]. Based on its chiral nature, an enantioseparation of PPX is needed to exclude additional negative side effects from the counter-enantiomer. By combining three different techniques, chromatography, enantioselective crystallization and racemization, an improved process with a higher yield was achieved in comparison to the use of a single full-separation process. All 3 unit operations were executed within a jointly used solvent system with full recycling (counter-enantiomer of PPX and solvents) including a minimum requirement of solvent exchanges / removals. The target molecule was obtained with an enantiopurity of >99.5% in multi-gram scale. Within this contribution the design of the integrated process is presented with a focus on the final enantioselective crystalliza...
1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, P... more 1996 alkaloids alkaloids U 0600 52 -255 10-Substituted 11-Oxygenated (R)-Aporphines: Synthesis, Pharmacology, and Modeling of 5-HT1A Receptor Interactions. -Novel aporphines, e.g. (IV) and (VI), and noraporphines, e.g. (XIV) and (XV), are synthesized following recently described methods. Structure-activity relationship evaluation shows that reference compound (I) has a 7-fold higher affinity for the serotonin 5-HT1A receptor in vitro but is less efficacious in vivo than (XV) while compound (XIV) displays weak dopamine receptor agonism. -(HEDBERG, M. H.; JANSEN, J. M.; NORDVALL, G.; HJORTH, S.; UNELIUS, L.; JOHANSSON, A. M.; J.
AstraZeneca R&D S€ odert€ alje, Pharmaceutical Development, 15185 S€ odert€ alje, Sweden b S Supp... more AstraZeneca R&D S€ odert€ alje, Pharmaceutical Development, 15185 S€ odert€ alje, Sweden b S Supporting Information
To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS... more To investigate indirectly the prevalence of intestinal inflammation in ankylosing spondylitis (AS) patients by assessing the levels of fecal calprotectin, to study levels of serum calprotectin in AS, and to correlate the concentrations of calprotectin in feces and serum with reported gastrointestinal symptoms, medication, and measures of disease activity. All patients fulfilling the Modified New York criteria of AS at the study centers were invited to participate. The patients answered questionnaires concerning medication, symptoms, and disease activity. Physical examination was performed, including back mobility tests. Samples of stools and blood were collected and analyzed for fecal and serum calprotectin. Elevated levels of fecal calprotectin (>50 mg/kg) was found in 140 of 205 AS patients (68%). Levels of fecal calprotectin were associated with increasing age, disease duration, ESR, CRP, and serum calprotectin, but not with gastrointestinal symptoms. Fecal calprotectin was higher in patients using NSAIDs, salicylates, and proton pump inhibitors, but lower in patients using methotrexate and infliximab. Serum calprotectin levels were normal or low in 98% of AS patients and not different from the levels in healthy blood donors. Serum calprotectin levels were positively associated with ESR, CRP, WBC, and PLT. Two-thirds of AS patients had elevated levels of fecal calprotectin, without associated gastrointestinal symptoms. Serum calprotectin was mostly normal in AS, in contrast to various other inflammatory rheumatic diseases. We suggest that fecal calprotectin may be a marker for subclinical intestinal inflammation in AS and should be measured after stopping NSAIDs, but further endoscopic studies are needed.
R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natura... more R)-11-Hydroxyaporphine (2) and (R)-11-hydroxy-10-methylaporphine (3) were synthesized from natural morphine by using new, short, and efficient synthetic sequences. The dopaminergic and serotonergic effects of 2 and 3 were evaluated by use of in vitro and in vivo test systems. The results indicate that 3 is a potent, selective, and efficacious ~-H T~A receptor agonist. In contrast, 2 is a partial 5-HTu receptor agonist of low potency which has affinity also for central DI and DM receptors. The differences in pharmacological profiles were rationalized by modeling use of in vitro and in vivo test systems. The differences in pharmacological profiles have been rationalized by modeling of ligand-receptor interactions using homology-based receptor models of the 5-HTu and DM receptor binding site. The results indicate that 3 is a potent, selective, and efficacious B-HT~A receptor agonist. In contrast, 2 is a partial B-HTIA receptor agonist of low potency which has affinity also for central D1 and D u receptors. The selective and pronounced serotonergic effects of 3 can be rationalized by the B-HT~A binding site model in which the C10-methyl group is accommodated by a lipophilic pocket, which is not present in the Du binding site.
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