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Heike Lorenz - One of the best experts on this subject based on the ideXlab platform.
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thermal deformations of crystal structures formed in the systems of malic acid enantiomers and l valine l isoleucine enantiomers
CrystEngComm, 2018Co-Authors: Elena N Kotelnikova, Anton I Isakov, Heike LorenzAbstract:The thermal behavior of discrete phases formed in the respective systems of malic acid enantiomers and L-enantiomers of the amino acids valine and isoleucine was studied using the temperature-resolved PXRD method. In the (S)-malic acid–(R)-malic acid system, thermal deformations in crystal structures of stable compounds (enantiomer S, Racemates RSI and RSII, and non-equimolar compound S3R) and polymorph transformations of metastable compounds (Racemate RSIII and non-equimolar compound 3S1R) were examined. In the L-valine–L-isoleucine system, thermal deformations in crystal structures of stable compounds L-Val and L-Ile and non-equimolar compound V2I were investigated. Thermal deformation analysis included plotting the temperature dependence of the unit cell parameters and volume, calculating thermal deformation tensors, plotting figures of thermal expansion coefficients (CTE), and estimating the extent of thermal deformation anisotropy. In all the cases studied, the maximal thermal expansion was observed in the direction of the weakest hydrogen (malic acid) or van der Waals (valine and isoleucine) intermolecular bonds, i.e. in the directions closest to that perpendicular to the dimer molecule chains (malic acid) or to molecular layers (valine and isoleucine). The strongest anisotropy of thermal deformations in monoclinic crystals was observed in the ac plane, in which the symmetrically unfixed angle β can vary.
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Effect of crystallization conditions on polymorphic diversity of malic acid RS — Racemate
Transactions of Tianjin University, 2013Co-Authors: Anton I Isakov, Elena N Kotelnikova, L. Y. Kryuchkova, Heike LorenzAbstract:Enantiomers (R(+) and S(−)), RS-Racemate (double compound) and (R+S)-conglomerate (mechanical mixture of enantiomers) of malic acid C4H6O5 have been investigated by means of X-ray diffractometry and high temperature X-ray diffraction method. The RS-Racemate was found to be able to form three polymorphic modifications, which we denominated as M1 (monoclinic, space group P21/c), M2 (monoclinic, space group Cc), and Tc (triclinic, space group P-1), the latter modification having been unknown before. Modification Tc was also described, and its Xray diffraction characteristics, including interplanar spacings d, hkl indices, unit cell parameters, were defined. In addition, X-ray diffraction characteristics for both reported earlier M1 and M2 monoclinic polymorphic modifications were measured with higher accuracy. The ability of RS-Racemate to form one of the above three modifications (M1, M2, and Tc) or their mixtures containing various proportions and combinations of the components (M1+M2, M1+Tc, or M2 +Tc) was found to depend on the type of crystallization medium (a melt, aqueous medium, ethanol or acetone solution), crystallization rate (from 2–3 minutes to 4 months), and crystallization temperature. Heating S-enantiomer and M1 RS-Racemate up to their respective melting points (100 °C and 124 °C, correspondingly) only made them undergo thermal deformations, while heating (R+S)-conglomerate in the temperature range of 96–110 °C resulted in its homogenization to form M2 RS-Racemate, which, near the melting point (118 °C), namely, in the range of 112–116 °C, was transformed into M1 RS-Racemate.
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effect of crystallization conditions on polymorphic diversity of malic acid rs Racemate
Transactions of Tianjin University, 2013Co-Authors: Anton I Isakov, Elena N Kotelnikova, L. Y. Kryuchkova, Heike LorenzAbstract:Enantiomers (R(+) and S(−)), RS-Racemate (double compound) and (R+S)-conglomerate (mechanical mixture of enantiomers) of malic acid C4H6O5 have been investigated by means of X-ray diffractometry and high temperature X-ray diffraction method. The RS-Racemate was found to be able to form three polymorphic modifications, which we denominated as M1 (monoclinic, space group P21/c), M2 (monoclinic, space group Cc), and Tc (triclinic, space group P-1), the latter modification having been unknown before. Modification Tc was also described, and its Xray diffraction characteristics, including interplanar spacings d, hkl indices, unit cell parameters, were defined. In addition, X-ray diffraction characteristics for both reported earlier M1 and M2 monoclinic polymorphic modifications were measured with higher accuracy. The ability of RS-Racemate to form one of the above three modifications (M1, M2, and Tc) or their mixtures containing various proportions and combinations of the components (M1+M2, M1+Tc, or M2 +Tc) was found to depend on the type of crystallization medium (a melt, aqueous medium, ethanol or acetone solution), crystallization rate (from 2–3 minutes to 4 months), and crystallization temperature. Heating S-enantiomer and M1 RS-Racemate up to their respective melting points (100 °C and 124 °C, correspondingly) only made them undergo thermal deformations, while heating (R+S)-conglomerate in the temperature range of 96–110 °C resulted in its homogenization to form M2 RS-Racemate, which, near the melting point (118 °C), namely, in the range of 112–116 °C, was transformed into M1 RS-Racemate.
John Caldwell - One of the best experts on this subject based on the ideXlab platform.
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Putting chirality to work: the strategy of chiral switches
Nature Reviews Drug Discovery, 2002Co-Authors: Israel Agranat, Hava Caner, John CaldwellAbstract:Chiral switches are chiral drugs that have already been claimed, approved and marketed as Racemates or as mixtures of stereoisomers, but have since been redeveloped as single enantiomers. The essential criterion of a chiral switch is a change in the status of chirality. There are still a significant proportion of racemic drugs among the recently approved new molecular entities. The patentability of single enantiomers in a chiral switch is an extreme case of a selection patent. The novelty of a single enantiomer is not negated by the prior-art disclosure of its Racemate. The strategy of enantiomeric pairs of patents of single enantiomers — E_1 and E_2 — in a chiral switch consists of two patents claiming simultaneously that E_1 and E_2 are pharmacologically superior to the racemic drug E_1,2. This strategy has been questioned. According to the US FDA, single enantiomers in chiral switches are not new molecular entities, and are therefore barred from five-years exclusivity. Such new products are treated as new derivatives of existing drugs or new formulations, on a case-by-case basis. Despite the regulatory acceptance of 'bridging strategies' from Racemate to single enantiomer, only a few successful switches have emerged from this route. Successful chiral switches emerge from racemic drugs that have efficacy and/or safety that can be enhanced, leading to significantly superior single enantiomers that are patentable and compete effectively with cheaper generic versions of the Racemates. Chiral switches are also eligible in cases in which the mechanisms of action of the single-enantiomer drugs involve achiral intermediates — for example, esomeprazole magnesium — and/or racemization. Paradoxically, a chiral switch can result in the increased use of the Racemate, this being a feature of the failure of the chiral switch of fenfluramine to dexfenfluramine and the 'fen–phen' fiasco. The timing of chiral switches of blockbuster drugs is crucial. The new single enantiomer should be launched ideally before the expiration of the patents that cover the Racemate, with extended exclusivity and before the incursions of the respective generic drugs. Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established Racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.
Kenji Mori - One of the best experts on this subject based on the ideXlab platform.
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mammalian blood odorant and chirality synthesis and sensory evaluation by humans and mice of the Racemate and enantiomers of trans 4 5 epoxy e 2 decenal
Tetrahedron-asymmetry, 2015Co-Authors: Kenji Mori, Kazumi Osada, Masayasu AmaikeAbstract:Abstract The Racemate and enantiomers of trans -4,5-epoxy-( E )-2-decenal 1 , an odorant with a metallic blood smell, were synthesized. The detection threshold for humans was 0.019 ppb for (2 E ,4 S ,5 S )-(−)- 1 and 0.62 ppb for (2 E ,4 R ,5 R )-(+)- 1 , respectively. The Racemate (±)- 1 made mice scared stiff at a dosage of approximately 1 mg, while the enantiomers were not significantly bioactive.
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pheromone synthesis part 253 synthesis of the Racemates and enantiomers of triglycerides of male drosophila fruit flies with special emphasis on the preparation of enantiomerically pure 1 monoglycerides
Tetrahedron, 2012Co-Authors: Kenji MoriAbstract:The Racemates and enantiomers of triglycerides 1a–e (2,3-ditigloyloxypropyl esters of palmitic, palmitoleic, stearic, oleic, and linoleic acids) of male Drosophila fruit flies were synthesized in three steps from the Racemate and enantiomers of 2,3-acetoneglycerol (2) via 1-monoglycerides 4a–e derived from the above fatty acids. Appropriate conditions were established for the preparation of enantiomerically pure 1-monoglycerides 4a–e, and their enantiomeric purities were determined by NMR analysis of the corresponding bis-(R)-MTPA esters.
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Pheromone synthesis. Part 244: Synthesis of the Racemate and enantiomers of (11Z,19Z)-CH503 (3-acetoxy-11,19-octacosadien-1-ol), a new sex pheromone of male Drosophila melanogaster to show its (S)-isomer and Racemate as bioactive ☆
Tetrahedron, 2010Co-Authors: Kenji Mori, Yasumasa Shikichi, Shruti Shankar, Joanne Y. YewAbstract:The enantiomers of (11Z,19Z)-3-acetoxy-11,19-octacosadien-1-ol were synthesized from the enantiomers of 3,4-epoxy-1-butanol PMB ether. Its Racemate was also synthesized. Its (S)-isomer and Racemate were shown to possess the same pheromone activity as CH503, a long-lived inhibitor of male courtship in Drosophila melanogaster, although the Racemate was less active.
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Synthetic Racemate and enantiomers of cytosporone E, a metabolite of an endophytic fungus, show indistinguishably weak antimicrobial activity.
Bioscience Biotechnology and Biochemistry, 2003Co-Authors: Tomoya Ohzeki, Kenji MoriAbstract:The Racemate and the enantiomers of cytosporone E [3-heptyl-4,5,6-trihydroxyphthalide (1)], a metabolite of the endophytic fungus, CR200 (Cytospora sp.), were synthesized. The key steps were (i) Sharpless asymmetric dihydroxylation of an alkene (8) and (ii) HPLC separation of the enantiomers of tert-butyldimethylsilyl ether (12) on a chiral stationary phase. The Racemate and enantiomers of cytosporone E showed only weak antimicrobial activity with no difference among them.
Elena N Kotelnikova - One of the best experts on this subject based on the ideXlab platform.
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thermal deformations of crystal structures formed in the systems of malic acid enantiomers and l valine l isoleucine enantiomers
CrystEngComm, 2018Co-Authors: Elena N Kotelnikova, Anton I Isakov, Heike LorenzAbstract:The thermal behavior of discrete phases formed in the respective systems of malic acid enantiomers and L-enantiomers of the amino acids valine and isoleucine was studied using the temperature-resolved PXRD method. In the (S)-malic acid–(R)-malic acid system, thermal deformations in crystal structures of stable compounds (enantiomer S, Racemates RSI and RSII, and non-equimolar compound S3R) and polymorph transformations of metastable compounds (Racemate RSIII and non-equimolar compound 3S1R) were examined. In the L-valine–L-isoleucine system, thermal deformations in crystal structures of stable compounds L-Val and L-Ile and non-equimolar compound V2I were investigated. Thermal deformation analysis included plotting the temperature dependence of the unit cell parameters and volume, calculating thermal deformation tensors, plotting figures of thermal expansion coefficients (CTE), and estimating the extent of thermal deformation anisotropy. In all the cases studied, the maximal thermal expansion was observed in the direction of the weakest hydrogen (malic acid) or van der Waals (valine and isoleucine) intermolecular bonds, i.e. in the directions closest to that perpendicular to the dimer molecule chains (malic acid) or to molecular layers (valine and isoleucine). The strongest anisotropy of thermal deformations in monoclinic crystals was observed in the ac plane, in which the symmetrically unfixed angle β can vary.
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Effect of crystallization conditions on polymorphic diversity of malic acid RS — Racemate
Transactions of Tianjin University, 2013Co-Authors: Anton I Isakov, Elena N Kotelnikova, L. Y. Kryuchkova, Heike LorenzAbstract:Enantiomers (R(+) and S(−)), RS-Racemate (double compound) and (R+S)-conglomerate (mechanical mixture of enantiomers) of malic acid C4H6O5 have been investigated by means of X-ray diffractometry and high temperature X-ray diffraction method. The RS-Racemate was found to be able to form three polymorphic modifications, which we denominated as M1 (monoclinic, space group P21/c), M2 (monoclinic, space group Cc), and Tc (triclinic, space group P-1), the latter modification having been unknown before. Modification Tc was also described, and its Xray diffraction characteristics, including interplanar spacings d, hkl indices, unit cell parameters, were defined. In addition, X-ray diffraction characteristics for both reported earlier M1 and M2 monoclinic polymorphic modifications were measured with higher accuracy. The ability of RS-Racemate to form one of the above three modifications (M1, M2, and Tc) or their mixtures containing various proportions and combinations of the components (M1+M2, M1+Tc, or M2 +Tc) was found to depend on the type of crystallization medium (a melt, aqueous medium, ethanol or acetone solution), crystallization rate (from 2–3 minutes to 4 months), and crystallization temperature. Heating S-enantiomer and M1 RS-Racemate up to their respective melting points (100 °C and 124 °C, correspondingly) only made them undergo thermal deformations, while heating (R+S)-conglomerate in the temperature range of 96–110 °C resulted in its homogenization to form M2 RS-Racemate, which, near the melting point (118 °C), namely, in the range of 112–116 °C, was transformed into M1 RS-Racemate.
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effect of crystallization conditions on polymorphic diversity of malic acid rs Racemate
Transactions of Tianjin University, 2013Co-Authors: Anton I Isakov, Elena N Kotelnikova, L. Y. Kryuchkova, Heike LorenzAbstract:Enantiomers (R(+) and S(−)), RS-Racemate (double compound) and (R+S)-conglomerate (mechanical mixture of enantiomers) of malic acid C4H6O5 have been investigated by means of X-ray diffractometry and high temperature X-ray diffraction method. The RS-Racemate was found to be able to form three polymorphic modifications, which we denominated as M1 (monoclinic, space group P21/c), M2 (monoclinic, space group Cc), and Tc (triclinic, space group P-1), the latter modification having been unknown before. Modification Tc was also described, and its Xray diffraction characteristics, including interplanar spacings d, hkl indices, unit cell parameters, were defined. In addition, X-ray diffraction characteristics for both reported earlier M1 and M2 monoclinic polymorphic modifications were measured with higher accuracy. The ability of RS-Racemate to form one of the above three modifications (M1, M2, and Tc) or their mixtures containing various proportions and combinations of the components (M1+M2, M1+Tc, or M2 +Tc) was found to depend on the type of crystallization medium (a melt, aqueous medium, ethanol or acetone solution), crystallization rate (from 2–3 minutes to 4 months), and crystallization temperature. Heating S-enantiomer and M1 RS-Racemate up to their respective melting points (100 °C and 124 °C, correspondingly) only made them undergo thermal deformations, while heating (R+S)-conglomerate in the temperature range of 96–110 °C resulted in its homogenization to form M2 RS-Racemate, which, near the melting point (118 °C), namely, in the range of 112–116 °C, was transformed into M1 RS-Racemate.
Israel Agranat - One of the best experts on this subject based on the ideXlab platform.
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The strategy of enantiomer patents of drugs
Drug Discovery Today, 2010Co-Authors: Israel Agranat, Silvya R. WainschteinAbstract:Enantiomer patents (ENPTs), constituents of chiral switches, claim single enantiomers of chiral drugs previously claimed as Racemates. In this article, the strategy of ENPTs and recent court decisions and trends in case law worldwide are highlighted. ENPTs are challenged frequently (e.g. anticipation, obviousness, double patenting and insufficient disclosure), even though the novelty of enantiomers is not destroyed by the description of Racemates. For establishing inventiveness (nonobviousness), the description in ENPTs should include superior pharmacological and/or pharmaceutical properties of enantiomer vis-a-vis Racemate, above the expected 2:1 ratio. ENPTs were ‘obvious-to-try’ (unless taught away) since the mid-1980s. General concern about evergreening by ENPTs is not justified. ENPTs should be evaluated on a case-by-case basis. ENPT litigations are especially susceptible to settlements.
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Putting chirality to work: the strategy of chiral switches
Nature Reviews Drug Discovery, 2002Co-Authors: Israel Agranat, Hava Caner, John CaldwellAbstract:Chiral switches are chiral drugs that have already been claimed, approved and marketed as Racemates or as mixtures of stereoisomers, but have since been redeveloped as single enantiomers. The essential criterion of a chiral switch is a change in the status of chirality. There are still a significant proportion of racemic drugs among the recently approved new molecular entities. The patentability of single enantiomers in a chiral switch is an extreme case of a selection patent. The novelty of a single enantiomer is not negated by the prior-art disclosure of its Racemate. The strategy of enantiomeric pairs of patents of single enantiomers — E_1 and E_2 — in a chiral switch consists of two patents claiming simultaneously that E_1 and E_2 are pharmacologically superior to the racemic drug E_1,2. This strategy has been questioned. According to the US FDA, single enantiomers in chiral switches are not new molecular entities, and are therefore barred from five-years exclusivity. Such new products are treated as new derivatives of existing drugs or new formulations, on a case-by-case basis. Despite the regulatory acceptance of 'bridging strategies' from Racemate to single enantiomer, only a few successful switches have emerged from this route. Successful chiral switches emerge from racemic drugs that have efficacy and/or safety that can be enhanced, leading to significantly superior single enantiomers that are patentable and compete effectively with cheaper generic versions of the Racemates. Chiral switches are also eligible in cases in which the mechanisms of action of the single-enantiomer drugs involve achiral intermediates — for example, esomeprazole magnesium — and/or racemization. Paradoxically, a chiral switch can result in the increased use of the Racemate, this being a feature of the failure of the chiral switch of fenfluramine to dexfenfluramine and the 'fen–phen' fiasco. The timing of chiral switches of blockbuster drugs is crucial. The new single enantiomer should be launched ideally before the expiration of the patents that cover the Racemate, with extended exclusivity and before the incursions of the respective generic drugs. Most of the new drugs reaching the market today are single enantiomers, rather than the racemic mixtures that dominated up to ten years ago. Many of the new single-enantiomer drugs were developed as such, but there are also important examples of new single-enantiomer drugs derived from 'chiral switches' of established Racemates. Indeed, a well-timed chiral switch can offer enhanced therapy and further profitability as a 'line extension' of a major racemic drug with patents that are expiring.
