Finasteride, the most widely used oral alopecia drug, shows several side effects such as hypoacti... more Finasteride, the most widely used oral alopecia drug, shows several side effects such as hypoactive sexual dysfunction or depression, whereas the topical drug minoxidil demonstrates unsatisfactory efficacy. Thus, there is an increasing need for new alopecia drugs and alternative delivery systems for future alopecia treatment. Researchers have developed dissolving microneedle (DMN), a transdermal drug delivery system, which can be used with minimal invasion. However, DMN has limited application for the alopecia treatment owing to its unsuccessful implantation on the hairy scalp. Here, it is suggested that TOP‐M119 (M119), a novel drug acting as a vasodilator in the scalp, and M119‐loaded DMN with a specially designed shape can be used for the alopecia treatment. This M119‐loaded DMN system is delivered using a newly designed applicator that supports patchless scalp implantation of DMN by microsized pillars designed to prevent accidental skin insertion. Enhanced hair follicle targeting drug delivery and superior alopecia treatment efficacy of specially designed shaped DMN and M119 has been demonstrated through in vitro and ex vivo studies. Moreover, M119‐loaded DMN system shows enhanced in vivo efficacy in mouse skin and through expression markers related to hair growth, such as β‐catenin, proliferating cell nuclear antigen, MECA 32, and versican.
Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs,... more Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs, which have a proven efficacy for the treatment of the target disease. In opposition to pro-drugs, DAD are activated in inflamed but not normal tissues. Due to the disease specific activation, the amount of locally released drug(s) should be related directly to the severity of
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ChemInform Abstract Das Enolat (IV) des Kondensationsproduktes (III) aus Prolin (Ia) und Pivaldeh... more ChemInform Abstract Das Enolat (IV) des Kondensationsproduktes (III) aus Prolin (Ia) und Pivaldehyd (II) gibt bei der Deuterolyse das Deuteroprolin (Ib); mit entsprechenden Halogeniden (V) werden die Verbindungen (VI) erhalten. Phenylierung [mit (BenzolHricarbonylchrom] bzw. Thiolierung (mit Diphenyldisulfid) führen zu den Derivaten (VII). Mit entsprechenden Aldehyden bzw. Ketonen werden aus (IV) die Verbindungen (VIIIa), (VIIIb) bzw. (VIIIc), (VIIId) gewonnen. Mit dein Cyclohexenon (IX) entstehen die beiden Addukte (Xa) (Xb); der Zusatz von z.B. HMPA unterdrückt dagegen die Bildung des Michael-Adduktes (Xb) fast vollständig. Die Addukte (Xc), (Xd) werdenähnlich gewonnen. Die angegebenen Verbindungen werden z.T. in hoher diastereomerer Reinheit erhalten.-Verschiedene Spaltungsreaktionen wie im Formelschema angegeben liefern die Produkte (XI), (XIII) bzw. (XIV).-Der Prozess der α-Alkylierung von Prolin (Ia) ohne Racemisierung, d. h. unter Konfigurationsretention, wird als Selbstreproduktion der Chiralität bezeichnet.
Results of an initial investigation are described, demonstrating for the first time the possibili... more Results of an initial investigation are described, demonstrating for the first time the possibility of achieving enantioselectivities (75‐95%) with a simple chiral controller ligand (III), obtainable in one step in either enantiomeric form from (+)‐ or (‐)‐ephedrine (I).
Dioxolanones 7 and 8a and oxazolinones 9a derived from pivalaldehyde and lactic acid, mandelic ac... more Dioxolanones 7 and 8a and oxazolinones 9a derived from pivalaldehyde and lactic acid, mandelic acid, and proline, respectively, furnish chiral enolates of type 3 by deprotonation with LDA. Reactions of these enolates with alkyl halides, aldehydes, and ketones (→ 8b, 9b, 11–13) are highly diastereoselective. Thus, the overall enantioselective α‐alkylation of chiral, non‐racemic α‐heterosubstituted carboxylic acids (4 → 6) is realized.
Steroselective Alkylation at C(α) of Serine, Clyceric Acid, Threonine, and Tartaric Acid Involvin... more Steroselective Alkylation at C(α) of Serine, Clyceric Acid, Threonine, and Tartaric Acid Involving Heterocyclic Enolates with Evocyelic Double BondsThe chiral, non‐racemic title acids are converted to methyl dioxolane‐(cf. 13), oxazoline‐(4) and oxazolidinecarboxylates (cf. 9). Deprotonation by Li(i‐Pr) 2N at dry‐ice temperature gives solutions of the lithium enolates A–D With exocyclic enolate double bonds. These are stable crough with respect to β‐elimination (Scheme 1) to be alkylated with or without cosolvents such as HMPA or DMPU The products are formed in good to excellent yields and, with the exception of the tartrate‐derived acetonlde (see Scheme 2), with diastereoselectivities above 90%. While the tartrate‐and threonine‐derived enolates (A and B, resp.) are chiral due to the second stereogenic center of the precursors, the serine‐ and glyceric‐acid‐derived enolates (Aand B, resp.) are chiral due to the second sterogenic center of the precursors, the serine‐nd glyceric‐acid‐derived enolates are non‐racemic due to a tert butyl‐substituted (pivalaldehyde‐derived) acetal center (C and D, resp.). The products of alkylation can be hydrolyzed to give α‐branched tartaric acid (Scheme 2), allothreonine (Scheme 3), serine (Scheme 4), and glyceric‐acid derivatives (Scheme 5) with quaternary stereogenic centers. The configurations of the products are determined by NOE‐NMR measurements and by chemical correlation. These show that the dioxolane‐derived enolates A and D are alkylated preferentially from that face of the ring which is already substituted (‘syn’‐attack), while the dihydrooxazol‐and oxazolidine‐derived enolates B and C are alkylated from the opposite face (‘anti’‐attack). The ‘syn’‐attack is postulated to arise from strong folding of the heterocyclic ring due to electronic repulsion between the enolate π‐system and non‐bonding electron pairs on the heteroatoms (see Scheme 6).
Ahatrad-a-Hydroxy-and a-mercaptwcarboxylic acids are condensed with pivalaidehyde to give 2-t-but... more Ahatrad-a-Hydroxy-and a-mercaptwcarboxylic acids are condensed with pivalaidehyde to give 2-t-butyl-S-substituted-l ,?l-dioxolanones or 1,3-oxathiolanones (2); the predominate cr&isomers are separateci by crystallization. The ci.rdisubstituted heterocycln 2 derived from lactic, mandeiic and malic acid furnish, after deprotonation with LDA, reaction with electrophiles such as alkyl halides, aldehydes and ketones, and hydrolysis a-branched a-hydroxy-carboxyhc acids (3,6,8,9,10). These result from an overall substitution of the proton in the a-CO position with retention of cot@uration. The optically active carboxylic acids are a-alkylated without racem& tion and without employment of a chiral auxiliary ("self-reproduction of chirality", Scheme 1). The diastereoselectivities (ds) are generally > 95% (Table 1, 2, and 29-25).
International Journal of Molecular Sciences, Jun 20, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
ChemInform Abstract Zahlreiche funktionelle Gruppen enthaltende Ester (I) werden mit Hilfe von Ti... more ChemInform Abstract Zahlreiche funktionelle Gruppen enthaltende Ester (I) werden mit Hilfe von Titan(IV)-alkoxiden in bekannter Weise umgeestert. tert.-Butylester entstehen so nur in geringer Ausbeute, Allylester gar nicht. (IR-, NMR-, MS-Daten).
Preparation of the Enantiomerically Pure cis‐ and trans‐Configurated 2‐(tert‐Butyl)‐3‐methylimida... more Preparation of the Enantiomerically Pure cis‐ and trans‐Configurated 2‐(tert‐Butyl)‐3‐methylimidazolidin‐4‐ones from the Amino Acids (S)‐Alanine, (S)‐Phenylalanine, (R)‐Phenylglycine, (S)‐Methionine, and (S)‐ValineIn contrast to α‐hydroxy and α‐mercapto carboxylic acids, simple α‐amino acids do not form acetal‐type derivatives (2, X = NH) with pivalaldehyde. For the generation of amino‐acid‐derived chiral, nonracemic enolates (cf. 3), and hence, for the α‐alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12–14 were prepared diastereoselectively. To this end, the methyl or ethyl esters of amino‐acid hydrochlorides were first converted to N‐methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides (11). These Schiff bases could be cyclized either to trans‐or to cis‐imidazolidinones (12, 14 and 13, respectively), which were obtained in enantiomerically pure form after recrystallization. The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by 1H‐NMR spectroscopy in the presence of chiral shift reagents. The configurations (cis, trans) were assigned by NOE measurements on 300‐ or 360‐MHz 1H‐NMR spectrometers.
Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infu... more Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 microgram/kg per min) for < 1 h. More prolonged infusion of rac-salbutamol induced a progressive susceptibility to inhaled antigen so that, by 48 h, animals collapsed and died following inhalation of antigen. In anaesthetized animals, acute infusion of rac-salbutamol (1.67 micrograms/kg per min) suppressed airway obstruction, an effect that can be attributed to beta 2-adrenoceptor activation by the eutomer (R-salbutamol). Acute intravenous infusion of the distomer (S-salbutamol) (1.67 micrograms/kg per min) induced hyperresponsiveness to histamine without having any effect upon airway calibre. It is suggested therefore that subcutaneous infusion of rac-salbutamol initially abrogates the bronchoconstrictor response to antigen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protection to susceptibility was not determined by reduced beta 2-adrenoceptor activation since animals could be protected from a lethal response to antigen by inhalation of rac-isoprenaline or by subcutaneous injection of rac-salbutamol. The seeming progressive loss of efficacy of R-salbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. The capacity of S-salbutamol to evoke hyperresponsiveness is shared by S-isoprenaline and S-terbutaline and, as has been shown previously for rac-isoprenaline, the capacity of S-salbutamol to elicit hyperresponsiveness was not evidenced following section of the vagus nerves. No mechanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.
Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite o... more Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite of improvements in standards of care there are no effective and safe treatments that promote new tissue formation and wound closure in ailments such as diabetic foot ulcer, pressure ulcer, venous leg ulcer or digital ulcer in systemic sclerosis. Endothelial dysfunction, which associates with impaired endogenous nitric oxide formation is assumed to be a main disease mechanism in chronic, non-healing wounds in diabetic and elderly patients as well as in digital ulcers in systemic sclerosis. To padur Pharma has invented small molecular weight nitric oxidereleasing PDE5 inhibitors, which by modulating a key enzyme system of intracellular signaling may address chronic non-healing wounds. The promising first drug candidate TOP-N53 is currently in early clinical development. Here we describe for the first time the design of TOP-N53 and the synthesis of the clinical GMP batch.
3‐Lithio‐1‐(trimethylsilyl)pyrrole (7, Schem 2), obtained by halogen‐metal interchange from the 3... more 3‐Lithio‐1‐(trimethylsilyl)pyrrole (7, Schem 2), obtained by halogen‐metal interchange from the 3‐bromo compound 2, reacted with various electrophilic reagents to provide products, which on fluoride ion desilylation, gave 3‐substituted pyrroles in good overall yields. One such pyrrole 13 (Schem 3), was converted into 2‐formyl‐3‐octadeclpyrrole (14), reputed to be a metabolite of the marine sponge Oscarella lobularis.3,4‐Dibromo‐1‐(triisopropylsityl)pyrrole (5) was efficiently transformed, by a process involving two consecutive bromine‐lithium exchange reactions (Scheme 4), into the antibiotic verrucarin E 17.
Finasteride, the most widely used oral alopecia drug, shows several side effects such as hypoacti... more Finasteride, the most widely used oral alopecia drug, shows several side effects such as hypoactive sexual dysfunction or depression, whereas the topical drug minoxidil demonstrates unsatisfactory efficacy. Thus, there is an increasing need for new alopecia drugs and alternative delivery systems for future alopecia treatment. Researchers have developed dissolving microneedle (DMN), a transdermal drug delivery system, which can be used with minimal invasion. However, DMN has limited application for the alopecia treatment owing to its unsuccessful implantation on the hairy scalp. Here, it is suggested that TOP‐M119 (M119), a novel drug acting as a vasodilator in the scalp, and M119‐loaded DMN with a specially designed shape can be used for the alopecia treatment. This M119‐loaded DMN system is delivered using a newly designed applicator that supports patchless scalp implantation of DMN by microsized pillars designed to prevent accidental skin insertion. Enhanced hair follicle targeting drug delivery and superior alopecia treatment efficacy of specially designed shaped DMN and M119 has been demonstrated through in vitro and ex vivo studies. Moreover, M119‐loaded DMN system shows enhanced in vivo efficacy in mouse skin and through expression markers related to hair growth, such as β‐catenin, proliferating cell nuclear antigen, MECA 32, and versican.
Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs,... more Disease activated drugs (DAD) are pro-drugs of one active principle or combinations of two drugs, which have a proven efficacy for the treatment of the target disease. In opposition to pro-drugs, DAD are activated in inflamed but not normal tissues. Due to the disease specific activation, the amount of locally released drug(s) should be related directly to the severity of
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ChemInform Abstract Das Enolat (IV) des Kondensationsproduktes (III) aus Prolin (Ia) und Pivaldeh... more ChemInform Abstract Das Enolat (IV) des Kondensationsproduktes (III) aus Prolin (Ia) und Pivaldehyd (II) gibt bei der Deuterolyse das Deuteroprolin (Ib); mit entsprechenden Halogeniden (V) werden die Verbindungen (VI) erhalten. Phenylierung [mit (BenzolHricarbonylchrom] bzw. Thiolierung (mit Diphenyldisulfid) führen zu den Derivaten (VII). Mit entsprechenden Aldehyden bzw. Ketonen werden aus (IV) die Verbindungen (VIIIa), (VIIIb) bzw. (VIIIc), (VIIId) gewonnen. Mit dein Cyclohexenon (IX) entstehen die beiden Addukte (Xa) (Xb); der Zusatz von z.B. HMPA unterdrückt dagegen die Bildung des Michael-Adduktes (Xb) fast vollständig. Die Addukte (Xc), (Xd) werdenähnlich gewonnen. Die angegebenen Verbindungen werden z.T. in hoher diastereomerer Reinheit erhalten.-Verschiedene Spaltungsreaktionen wie im Formelschema angegeben liefern die Produkte (XI), (XIII) bzw. (XIV).-Der Prozess der α-Alkylierung von Prolin (Ia) ohne Racemisierung, d. h. unter Konfigurationsretention, wird als Selbstreproduktion der Chiralität bezeichnet.
Results of an initial investigation are described, demonstrating for the first time the possibili... more Results of an initial investigation are described, demonstrating for the first time the possibility of achieving enantioselectivities (75‐95%) with a simple chiral controller ligand (III), obtainable in one step in either enantiomeric form from (+)‐ or (‐)‐ephedrine (I).
Dioxolanones 7 and 8a and oxazolinones 9a derived from pivalaldehyde and lactic acid, mandelic ac... more Dioxolanones 7 and 8a and oxazolinones 9a derived from pivalaldehyde and lactic acid, mandelic acid, and proline, respectively, furnish chiral enolates of type 3 by deprotonation with LDA. Reactions of these enolates with alkyl halides, aldehydes, and ketones (→ 8b, 9b, 11–13) are highly diastereoselective. Thus, the overall enantioselective α‐alkylation of chiral, non‐racemic α‐heterosubstituted carboxylic acids (4 → 6) is realized.
Steroselective Alkylation at C(α) of Serine, Clyceric Acid, Threonine, and Tartaric Acid Involvin... more Steroselective Alkylation at C(α) of Serine, Clyceric Acid, Threonine, and Tartaric Acid Involving Heterocyclic Enolates with Evocyelic Double BondsThe chiral, non‐racemic title acids are converted to methyl dioxolane‐(cf. 13), oxazoline‐(4) and oxazolidinecarboxylates (cf. 9). Deprotonation by Li(i‐Pr) 2N at dry‐ice temperature gives solutions of the lithium enolates A–D With exocyclic enolate double bonds. These are stable crough with respect to β‐elimination (Scheme 1) to be alkylated with or without cosolvents such as HMPA or DMPU The products are formed in good to excellent yields and, with the exception of the tartrate‐derived acetonlde (see Scheme 2), with diastereoselectivities above 90%. While the tartrate‐and threonine‐derived enolates (A and B, resp.) are chiral due to the second stereogenic center of the precursors, the serine‐ and glyceric‐acid‐derived enolates (Aand B, resp.) are chiral due to the second sterogenic center of the precursors, the serine‐nd glyceric‐acid‐derived enolates are non‐racemic due to a tert butyl‐substituted (pivalaldehyde‐derived) acetal center (C and D, resp.). The products of alkylation can be hydrolyzed to give α‐branched tartaric acid (Scheme 2), allothreonine (Scheme 3), serine (Scheme 4), and glyceric‐acid derivatives (Scheme 5) with quaternary stereogenic centers. The configurations of the products are determined by NOE‐NMR measurements and by chemical correlation. These show that the dioxolane‐derived enolates A and D are alkylated preferentially from that face of the ring which is already substituted (‘syn’‐attack), while the dihydrooxazol‐and oxazolidine‐derived enolates B and C are alkylated from the opposite face (‘anti’‐attack). The ‘syn’‐attack is postulated to arise from strong folding of the heterocyclic ring due to electronic repulsion between the enolate π‐system and non‐bonding electron pairs on the heteroatoms (see Scheme 6).
Ahatrad-a-Hydroxy-and a-mercaptwcarboxylic acids are condensed with pivalaidehyde to give 2-t-but... more Ahatrad-a-Hydroxy-and a-mercaptwcarboxylic acids are condensed with pivalaidehyde to give 2-t-butyl-S-substituted-l ,?l-dioxolanones or 1,3-oxathiolanones (2); the predominate cr&isomers are separateci by crystallization. The ci.rdisubstituted heterocycln 2 derived from lactic, mandeiic and malic acid furnish, after deprotonation with LDA, reaction with electrophiles such as alkyl halides, aldehydes and ketones, and hydrolysis a-branched a-hydroxy-carboxyhc acids (3,6,8,9,10). These result from an overall substitution of the proton in the a-CO position with retention of cot@uration. The optically active carboxylic acids are a-alkylated without racem& tion and without employment of a chiral auxiliary ("self-reproduction of chirality", Scheme 1). The diastereoselectivities (ds) are generally > 95% (Table 1, 2, and 29-25).
International Journal of Molecular Sciences, Jun 20, 2022
This article is an open access article distributed under the terms and conditions of the Creative... more This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY
ChemInform Abstract Zahlreiche funktionelle Gruppen enthaltende Ester (I) werden mit Hilfe von Ti... more ChemInform Abstract Zahlreiche funktionelle Gruppen enthaltende Ester (I) werden mit Hilfe von Titan(IV)-alkoxiden in bekannter Weise umgeestert. tert.-Butylester entstehen so nur in geringer Ausbeute, Allylester gar nicht. (IR-, NMR-, MS-Daten).
Preparation of the Enantiomerically Pure cis‐ and trans‐Configurated 2‐(tert‐Butyl)‐3‐methylimida... more Preparation of the Enantiomerically Pure cis‐ and trans‐Configurated 2‐(tert‐Butyl)‐3‐methylimidazolidin‐4‐ones from the Amino Acids (S)‐Alanine, (S)‐Phenylalanine, (R)‐Phenylglycine, (S)‐Methionine, and (S)‐ValineIn contrast to α‐hydroxy and α‐mercapto carboxylic acids, simple α‐amino acids do not form acetal‐type derivatives (2, X = NH) with pivalaldehyde. For the generation of amino‐acid‐derived chiral, nonracemic enolates (cf. 3), and hence, for the α‐alkylation of amino acids without racemization and without an external chiral auxiliary, the imidazolidinones 12–14 were prepared diastereoselectively. To this end, the methyl or ethyl esters of amino‐acid hydrochlorides were first converted to N‐methylamides of amino acids which in turn were condensed with pivalaldehyde to give (neopentylidenamino)amides (11). These Schiff bases could be cyclized either to trans‐or to cis‐imidazolidinones (12, 14 and 13, respectively), which were obtained in enantiomerically pure form after recrystallization. The enantiomeric purities were confirmed by HPLC with chiral stationary phases or by 1H‐NMR spectroscopy in the presence of chiral shift reagents. The configurations (cis, trans) were assigned by NOE measurements on 300‐ or 360‐MHz 1H‐NMR spectrometers.
Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infu... more Allergic bronchospasm in sensitized guinea-pigs was totally suppressed by acute subcutaneous infusion of rac-salbutamol (0.69 microgram/kg per min) for < 1 h. More prolonged infusion of rac-salbutamol induced a progressive susceptibility to inhaled antigen so that, by 48 h, animals collapsed and died following inhalation of antigen. In anaesthetized animals, acute infusion of rac-salbutamol (1.67 micrograms/kg per min) suppressed airway obstruction, an effect that can be attributed to beta 2-adrenoceptor activation by the eutomer (R-salbutamol). Acute intravenous infusion of the distomer (S-salbutamol) (1.67 micrograms/kg per min) induced hyperresponsiveness to histamine without having any effect upon airway calibre. It is suggested therefore that subcutaneous infusion of rac-salbutamol initially abrogates the bronchoconstrictor response to antigen because the bronchodilator action of the eutomer predominates over hyperreactivity attributable to the distomer. Conversion from protection to susceptibility was not determined by reduced beta 2-adrenoceptor activation since animals could be protected from a lethal response to antigen by inhalation of rac-isoprenaline or by subcutaneous injection of rac-salbutamol. The seeming progressive loss of efficacy of R-salbutamol may result from disproportionate accumulation of S-salbutamol if, as in man, there is stereospecific metabolism of R-salbutamol. The capacity of S-salbutamol to evoke hyperresponsiveness is shared by S-isoprenaline and S-terbutaline and, as has been shown previously for rac-isoprenaline, the capacity of S-salbutamol to elicit hyperresponsiveness was not evidenced following section of the vagus nerves. No mechanism has yet been established which might account for this property of S-salbutamol or for other S-enantiomers of sympathomimetics.
Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite o... more Chronic non-healing wounds impose a huge burden on patients and health care providers. In spite of improvements in standards of care there are no effective and safe treatments that promote new tissue formation and wound closure in ailments such as diabetic foot ulcer, pressure ulcer, venous leg ulcer or digital ulcer in systemic sclerosis. Endothelial dysfunction, which associates with impaired endogenous nitric oxide formation is assumed to be a main disease mechanism in chronic, non-healing wounds in diabetic and elderly patients as well as in digital ulcers in systemic sclerosis. To padur Pharma has invented small molecular weight nitric oxidereleasing PDE5 inhibitors, which by modulating a key enzyme system of intracellular signaling may address chronic non-healing wounds. The promising first drug candidate TOP-N53 is currently in early clinical development. Here we describe for the first time the design of TOP-N53 and the synthesis of the clinical GMP batch.
3‐Lithio‐1‐(trimethylsilyl)pyrrole (7, Schem 2), obtained by halogen‐metal interchange from the 3... more 3‐Lithio‐1‐(trimethylsilyl)pyrrole (7, Schem 2), obtained by halogen‐metal interchange from the 3‐bromo compound 2, reacted with various electrophilic reagents to provide products, which on fluoride ion desilylation, gave 3‐substituted pyrroles in good overall yields. One such pyrrole 13 (Schem 3), was converted into 2‐formyl‐3‐octadeclpyrrole (14), reputed to be a metabolite of the marine sponge Oscarella lobularis.3,4‐Dibromo‐1‐(triisopropylsityl)pyrrole (5) was efficiently transformed, by a process involving two consecutive bromine‐lithium exchange reactions (Scheme 4), into the antibiotic verrucarin E 17.
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