Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

Deutsch, Howard M.; Shi, Qing; Gruszecka-Kowalik, Ewa; Schweri, Margaret M.

doi:10.1021/jm950697c

Cited by 101 publications

(134 citation statements)

References 34 publications

(60 reference statements)

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“…The most active enantiomer of Ritalin has been marketed as an independent therapeutic agent 34 . Its synthesis using conventional functional group manipulations requires multiple steps 35,36 . The C-H functionalization approach to Ritalin, conversely, is direct 37,38 .…”

Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

2,174

812

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Novel reactions that can selectively functionalize carbon-hydrogen bonds are of intense interest to the chemical community because they offer new strategic approaches for synthesis. A very promising 'carbon-hydrogen functionalization' method involves the insertion of metal carbenes and nitrenes into C-H bonds. This area has experienced considerable growth in the past decade, particularly in the area of enantioselective intermolecular reactions. Here we discuss several facets of these kinds of C-H functionalization reactions and provide a perspective on how this methodology has affected the synthesis of complex natural products and potential pharmaceutical agents.I n 2006, 31 new chemical entities were introduced to the world pharmaceutical market and 2,075 molecules were in phase I or II of clinical development 1 . The majority of these were smallmolecule (relative molecular mass ,1,000) organic compounds 2 . As knowledge about the specific interactions of drugs in vivo increases, often so does the structural complexity of new drug targets. A major obstacle to the development of such drugs is the difficulty associated with synthesizing large quantities in an economical fashion, because complex multi-step syntheses are usually required. In the general media, it is often overlooked that the accessibility of the components required for these new treatments will often govern their eventual success or failure. Likewise, a design element of any pharmaceutical agent is the expectation that the target compounds can be made economically. Therefore, new strategies for synthesis can become enabling technologies, making available new targets and materials that would have been previously out of range. For example, new methodologies such as metal-catalysed crosscoupling 3 and olefin metathesis 4-6 have rapidly become central transformations in the synthesis of new pharmaceutical agents. Selective C-H functionalization is a class of reactions that could lead to a paradigm shift in organic synthesis, relying on selective modification of ubiquitous C-H bonds of organic compounds instead of the standard approach of conducting transformations on pre-existing functional groups. The reactive sites in each type of transformation are very different, as illustrated in Fig. 1.The many opportunities associated with C-H functionalization has made this field an active area of research. Organometallic chemists have focused much attention on developing 'C-H activation' strategies, whereby a highly reactive metal complex inserts into a C-H bond, activating the system for subsequent transformations 7-9 . One of the major challenges associated with this chemistry has been to render it catalytic in the metal complex 10 . A partial solution to this problem has been to use neighbouring functionality to direct less reactive metal complexes to the site for functionalization. Numerous reviews have been written about this method for C-H functionalization [11][12][13][14][15][16][17] . Here, however, we highlight another approach, in which a divalent c...

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Section: C-h Functionalization By Metal Carbenoidsmentioning

confidence: 99%

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Davies

Manning

2008

Nature

2,174

812

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“…In this way, a set of available tertiary amines as bases was investigated. In all cases a variable ratio of compounds 2 and 5 was observed ( Table 1, entries [8][9][10][11][12][13][14] and the use of KOt-Bu furnished the compound 5 as a major product (entry 15). Interestingly, the best yield of compound 2 (60%) was achieved when DBU was employed in the absence of a thiophile (Table 1, entry 14) in which thiazolidinone 5 was not isolated.…”

Section: Thementioning

confidence: 99%

“…3 The activity of Ritalin ® promotes an enhancement of the cognitive performance in both adults and children diagnosed with AD/HD. 4 Although Ritalin ® is available in the market as the racemate, the (2R,2%R)-(+)-threo-methylphenidate has been reported to be up to 38 times 5 more active than (2S,2%S)-(−)-threo-methylphenidate and several racemic [6][7][8][9] and chiral [10][11][12][13] synthesis of threo-methylphenidate were reported previously.…”

Section: Thementioning

confidence: 99%

A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

Russowsky

Neto

2003

Tetrahedron Letters

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Abstract-A concise and stereoselective synthesis of racemic erythro-methylphenidate (1) is described. The coupling reaction between piperidine-2-thione (3) and 2-bromo-2-phenylmethylacetate (4) afforded the b-enaminocarbonyl compound 2 in 60% yield by a modified Eschenmoser sulfide contraction reaction. In most cases the bicyclic thiazolidinone 5 was produced. Diastereoselective reduction of 2 in the presence of borohydrydes furnished the (+/−)-erythro-methylphenidate in good yields with dr >95%. © 2003 Elsevier Science Ltd. All rights reserved. The(+/−)-threo-methylphenidate hydrochloride (Ritalin ® ), is an indirect catecholamine agonist, 1 and is the drug treatment of choice for the attention deficit/ hyperactivity disorder (AD/HD), 2 one of the most common behavioral disorders of childhood which affects 5-10% of the general population. 3 The activity of Ritalin ® promotes an enhancement of the cognitive performance in both adults and children diagnosed with AD/HD. 4 Although Ritalin ® is available in the market as the racemate, the (2R,2%R)-(+)-threo-methylphenidate has been reported to be up to 38 times 5 more active than (2S,2%S)-(−)-threo-methylphenidate and several racemic 6-9 and chiral 10-13 synthesis of threo-methylphenidate were reported previously.Although the erythro-methylphenidate exhibits very few therapeutic properties and toxic hypertensive effects, 14 the stereoselective synthesis of the erythro-isomer can be helpful due to the possibility of resolution and epimerization of the erythro-isomer. 2,15 This approach was used early in the original synthesis of (+/−)-threomethylphenidate. Close to this, an enantioselective synthesis of (2S,2%S)-erythro-methylphenidate was recently published by Due to this fact and relating to our interest in the synthesis of b-aminocarbonyl compounds 17,18 we would like to communicate in this paper our approach to the synthesis of (+/−)-erythro-methylphenidate 1 applying a new concise stereoselective synthetic strategy.We envisaged obtaining 1 based on a stereoselective reduction of a b-enaminocarbonyl compound 2 which is readily accessible by the Eschenmoser sulfide contraction reaction 19,20 (Scheme 1).The needed piperidine-2-thione (3) was prepared in 91% yield after reaction of piperidine-2-one with Lawesson reagent. 21 The bromoester 4 was obtained by sterification and subsequent a-bromination 22 of 2-phenylacetic acid in 71% overall yield after purufication by horizontal destilation at reduced pressure. Next, the condensation reaction of compounds 3 and 4 was carried out under the Eschenmoser sulfide contraction reaction Scheme 1. The retrosynthetic analysis of 1 based on the eschemoser sulfide contraction reaction.

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“…Pharmacological data is limited with records of 4Me-TMP as one of the analogues of methylphenidate investigated in the treatment of cocaine dependence. It was found to be slightly more potent than methylphenidate at inhibiting the binding of [ 3 H]-WIN35 428, a cocaine analogue used in research on the dopamine transporter [16,17].…”

Section: Fig 1 the Structures Of Commonly Encountered Psychostimulantsmentioning

confidence: 99%

An overview of emerging and new psychoactive substances in the United Kingdom

Beharry

Gibbons

2016

Forensic Science International

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The purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug fora and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review the 'user reviews' on drugs fora were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were use alone were considered. Each of the classes contained drugs that are modelled on existing illegal materials and are now covered by the UK New Psychoactive Substances Bill in 2016. AbstractThe purpose of this review is to identify emerging or new psychoactive substances (NPS) by undertaking an online survey of the UK NPS market and to gather any data from online drug fora and published literature. Drugs from four main classes of NPS were identified: psychostimulants, dissociative anaesthetics, hallucinogens (phenylalkylamine-based and lysergamide-based materials) and finally benzodiazepines. For inclusion in the review, the 'user reviewers' on drugs fora were selected based on whether or not the particular NPS of interest was used alone or in combination. NPS that were used alone were considered.Each of the classes contained drugs that are modelled on existing illegal materials and will be covered by the UK New Psychoactive Substances Bill in 2016.

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Synthesis and Pharmacology of Potential Cocaine Antagonists. 2. Structure−Activity Relationship Studies of Aromatic Ring-Substituted Methylphenidate Analogs

Cited by 101 publications

References 34 publications

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

Catalytic C–H functionalization by metal carbenoid and nitrenoid insertion

A concise and stereoselective synthesis of (+/−)-erythro-methylphenidate

An overview of emerging and new psychoactive substances in the United Kingdom

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