Saturday, 31 January 2015

Antimalarial Drug TCMDC 123812 and 123794

Synthesis of Analogs of Arylpyrrole Antimalarial Drug Leads


Malaria continues to be one of the most widespread infectious diseases and with recent focus on global eradication and the continual evolution of drug resistant parasitic strains, the search for potent new antimalarials has gained momentum. In contrast to rational drug design approaches, the high-throughput screening of large compound libraries for potency against the parasite in whole cell assays has identified the Arylpyrrole series as a promising chemical lead. Before looking to comprehend the complex modes of biological action, the evaluation of analogs within this new drug class and the validation of their organic synthesis may act to identify specific compounds with increased potency or chemical moieties that lend themselves to the optimisation of the drug synthesis process. The collaborative efforts of open source drug discovery may help to identify potent compounds with a high-yielding and cost effective manufacturing process and thus accelerate the development of a promising candidate for integration into clinical practice.


Malaria is a widespread tropical infectious disease caused by a number of species of the protozoan parasite of the genus plasmodium, most notably P. falciparum, which are transmitted through the saliva of the anopheles mosquito. Per year, more than 240 million people suffer from the disease and approximately 40% of the global population live in countries where Malaria is endemic.[1] As both a consequence of and a great contributor towards poverty, Malaria costs sub-Saharan Africa alone US$12 billion in productivity every year and while an approximate cost limitation for one antimalarial treatment is US $1[1], current estimates suggest that many may only be able to afford 10 cents per treatment.[2] Thus with the majority of sufferers of a poor socioeconomic background, drug design should focus on the cost-effective synthesis of highly potent compounds, in order to minimise the quantities administered.

Driven by a knowledge of the biology of the parasite, conventionally rational drug design deduces leads based on first identifying a possible molecular target and the potential mechanisms of drug action at that target. However through reversing this process, a high-throughput screening for potent compounds in whole cell assays can act to expedite the lead identification process.[3] By this approach a single compound may be applicable to many ambiguous or poorly understood, more complex biological targets, decreasing the chances of a parasitic strain evolving resistance mechanisms at every target. Ultimately this approach will allow the rapid identification of leads which, because of their capacity to act on complex targets, may result in more effective prophylactic or therapeutic drugs which retain their activity for longer.

Recently the data from the high-throughput screening of a two million compound library was released by GlaxoSmithKline (GSK), identifying 13, 533 compounds, which inhibited the intra-erythrocytic cycle of multidrug resistant strains of P. falciparum by more than 70%. This identified several promising classes of compounds which retained low cytotoxicity to human cell lines.[4] [5] Among these, the arylpyrrole series has been isolated and the resynthesis and validation of a number of lead compounds within this series are being conducted using open source science. Disseminating information over many online mediums has encouraged collaborative efforts within the international scientific community and this free exchange of data and ideas between organisations, individuals and academic institutions may stimulate faster optimisation and development of leads.

Initial validation of arylpyrrole leads involved the resynthesis of two known series compounds, that is TCMDC 123812 and TCMDC 123794, as high quality starting points for lead optimisation with reasonable druggability.[6] Following evaluation of two possible synthesis pathways to these final compounds, slight changes were introduced to the chemical substructures and synthesis re-evaluated. Based on knowledge of the in vivo functionality of certain moieties, analogs were identified that may influence synthesis or beneficially contribute to the overall drug profile and efficacy.

Modifications to the para-position of aryl ring were evaluated, with hydrogen, methyl and trifluoromethyl groups being chosen to substitute the fluorine present in the original compounds. The introduction of bonds weaker than the original carbon-fluorine bond at that position may influence metabolic stability, influencing the affinity of the drug to para-hydroxylation.[7] However, and especially in the instance of a hydrogen in that position, a null result may be invaluable in enabling the prioritisation of other more stable functional groups. Thus antiplasmodial activity and cytotoxicity may be impacted upon as variations may influence the modes of action, changing the in vivo efficacy of the drug. Resultant changes in the physical or chemical properties of analogs may affect the potential for developing high-yielding, efficient and cost effective synthesis strategies. However ramifications of these chemical modifications on the ease of organic synthesis are hard to predict and thus the viability of the synthesis of a range of analogs must be evaluated as primary steps in the lead optimisation process.

Two potential synthesis pathways were identified for obtaining the carboxylic acid which then undergoes the addition of an amide group through a coupling reaction to achieve the final compound.[6] The first relied on a Paal Knorr cyclisation reaction between a dicarbonyl compound and a para-substituted aniline resulting in the arylpyrrole core. A Vilsmeier-Haack reaction then employed the use of phosphoryl chloride and dimethylformamide to form a Vilsmeier reagent or chloroimminium ion, which when substituted onto the pyrrole ring acts as a formylating agent to produce an aldehyde, once hydrolysed at a low pH. A second synthesis pathway involved synthesis of an ester, initially involving alkylation using a reactive enolate ion to form an intermediate before continuing with a condensation reaction into the characteristic arylpyrrole core. This report will describe the synthesis of each analog via these two alternative synthesis pathways. (Fig. 1)
Figure 1: Synthesis Strategy initially proposed for lead compounds: TCMDC 123812 and  123794

Figure 1: Synthesis Strategy initially proposed for lead compounds: TCMDC 123812 and 123794

Materials and Methods

1. Paal Knorr Synthesis of 2,5-dimethyl-1H-phenyl-pyrrole
Figure 2: Paal Knorr Synthesis of 2,5-dimethyl-1H-phenyl-pyrrole

Figure 2: Paal Knorr Synthesis of 2,5-dimethyl-1H-phenyl-pyrrole

2. Paal Knorr synthesis of 2,5-dimethyl-1H-(p-tolyl)- pyrrole
Figure 3: Paal Knorr synthesis of 2,5-dimethyl-1H-(p-tolyl)- pyrrole

Figure 3: Paal Knorr synthesis of 2,5-dimethyl-1H-(p-tolyl)- pyrrole

3. Paal Knorr Synthesis of 2,5-dimethyl -1H-(p-trifluoromethyl)phenyl-pyrrole
Figure 4: Paal Knorr synthesis of 2,5-dimethyl -1H-(p-trifluoromethyl)phenyl-pyrrole

Figure 4: Paal Knorr synthesis of 2,5-dimethyl -1H-(p-trifluoromethyl)phenyl-pyrrole

4. Vilsmeier-Haack synthesis of 2,5-dimethyl-1H-phenyl pyrrole-3-carboxaldehyde
Figure 5: Vilsmeier-Haack synthesis of 2,5-dimethyl-1H-phenyl pyrrole-3-carboxaldehyde

Figure 5: Vilsmeier-Haack synthesis of 2,5-dimethyl-1H-phenyl pyrrole-3-carboxaldehyde

5. Vilsmeier-Haack Synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde.
Figure 6: Vilsmeier-Haack synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde

Figure 6: Vilsmeier-Haack synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde

6. Synthesis of ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate
Figure 7: Synthesis of ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate

Figure 7: Synthesis of ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate
7. Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate
Figure 8: Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate

Figure 8: Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate

8. Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate
Figure 9: Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

Figure 9: Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate

General Reaction Mechanisms

Figure 10: Mechanism: Paal-Knorr cyclisation and Vilsmeier-Haack Synthesis to Aldehyde

Figure 10: Mechanism: Paal-Knorr cyclisation and Vilsmeier-Haack Synthesis to Aldehyde
Figure 11: Mechanism: Alkylation of ethyl acetoacetate with chloroacetone and condensation to Ester

Figure 11: Mechanism: Alkylation of ethyl acetoacetate with chloroacetone and condensation to Ester


1. Paal-Knorr Synthesis of 2,5-dimethyl-1H-phenyl-pyrrole
Yield: 6.2 g (60.4%)
Comment: Product crystallised easily. Reasonably pure red brown granular substance after recrystallization.

2. Paal-Knorr synthesis of 2,5-dimethyl-1H-(p-tolyl)- pyrrole
Yield: 8.3 g (74.5%)
Comment: Crystallisation required use of activated charcoal. Recrystallisation produced ochre-coloured sand-like, relatively pure compound at a reasonable yield.

3. Paal-Knorr Synthesis of 2,5-dimethyl -1H-(p-trifluoromethyl)phenyl-pyrrole
Yield: 6.08g (60%)
Comment: Reaction took slightly longer. Recrystallisation produced a relatively pure red-brown sand-like compound.

4. Vilsmeier-Haack synthesis of 2,5-dimethyl-1H-phenyl pyrrole-3-carboxaldehyde
Yield: 407 mg (64%)
Comment: Vilsmeier reaction completed reasonably quickly. Pure compound that crystallised easily produced after recrystallization. (grey/beige free-flowing powder)

5. Vilsmeier-Haack Synthesis of 2,5-dimethyl-1H-(p-tolyl)-pyrrole-3-carboxaldehyde.
Yield: 423 mg (71%)
Comment: Recrystallised fairly easily producing a fairly pure grey/brown lumpy powder.

6. Synthesis of ethyl 2,5-dimethyl-1-(p-tolyl)-1H-pyrrole-3-carboxylate
Yield: 1.8 g (45.6%)
Comment: Upon the use of both activated charcoal and column chromatography, product crystallised easily to a relatively pure bright yellow powder.

7. Synthesis of ethyl 2,5-dimethyl-1-phenyl-1H-pyrrole-3-carboxylate
Yield: 952 mg (approximate yield 37%)
Comment: Lack of separation between product and impurity in column chromatography resulted in product not crystallising.

8. Synthesis of ethyl 2,5-dimethyl-1-[p-(trifluoromethyl)phenyl]-1H-pyrrole-3-carboxylate
Yield: 1.85 g (55%)
Comment: Crystallised easily following column chromatography to form a pale yellow powder.


Synthesis via each reaction pathway was viable for most analogs however procedures need to be optimised and due to the nature of the corresponding reactions to the carboxylic acid, synthesis via the ester could be considered the most favourable.

The synthesis of the aldehyde via a Vilsmeier Haack synthesis following a Paal Knorr cyclisation was viable and the products synthesised achieved moderate yields and a reasonable level of purity with minimal purification steps. While viable, procedures could still be optimised further, however the oxidation of the aldehyde to obtain the carboxylic acid has proved problematic for the original resynthesis using the p-fluoro-phenyl-pyrrole-carbaldehyde. Unless a forgiving oxidation reaction becomes apparent, the simple base-hydrolysis via saponification necessary for the ester could prove a more favourable approach. For this reason only two aldehydes were synthesised with this strategy.

Although the ester exists in the correct oxidation state which acts to mitigate further issues with the synthesis of the carboxylic acid, complications in purification steps need to be overcome before the synthesis of analogs could be considered practical using this pathway. Potassium carbonate acts to remove a labile hydrogen off the alpha carbon of ethyl acetoacetate, which forms a reactive enolate ion. Sodium iodide substitutes the chlorine of the chloroacetone, which becomes susceptible to nucleophilic attack and an alkylation reaction follows to form a reactive intermediate. Enolate ion formation is susceptible to side reactions such as alkylation at the oxygen and while alkylation of the alpha carbon is preferential, the synthesis of the intermediate may need to be refined to ensure minimal side products and impurities. Additionally immediate condensation of the crude intermediate with the aniline derivatives may minimise formation of further side products. All three analogs required column chromatography, resulting in a significant amount of product loss and diminishing from the simplicity and practicality required for large-scale drug manufacture. It must be noted, however, this condensation reaction proved forgiving in the resynthesis of the original compounds, achieving a reasonable yield with minimal purification steps.[8] Thus appropriate optimisation of the synthesis procedures could affirm this as the most practical pathway for each analog.

Given synthesis complications and a likely propensity for para-hydroxylation, it may be unlikely that the N-phenyl analogs present promising drug leads, however further synthesis trials and testing against the parasite are required to conclusively determine this. Aqueous extraction of the final ester was problematic as a result of increased miscibility with dilute citric acid, and unsuccessful separation of product and impurity in column chromatography prevented crystallisation. It is unclear at this stage whether the parasubstituted methyl or trifluoromethyl groups retain any steric, inductive or other effects that contribute to any physicochemical properties that lend themselves to improving organic synthesis or in vivo drug targeting. The synthesis strategies require optimisation to eliminate time consuming and costly purification steps and the proceeding hydrolysis and coupling reactions need validation before testing the in vivo efficacy of the drugs in whole cell assays. Alternative reaction conditions, reagents, solvents or even new synthesis pathways should be tested to achieve optimisation as, irrespective of the drug’s antiplasmodial activity, it is crucial that cost-effective simple procedures be conserved so that large-scale production and distribution to impoverished nations remains possible.

Following the validation and testing of current analogs, additional analogs may be evaluated based on informed decisions of the potential advantages of specific chemical groups and the success of similar moieties. Once a promising lead has been identified and validated, the mode of action and how the drug acts to mediate host parasite-interactions on a molecular level may be researched and the drug tailored for that specific functionality. Mechanisms of action have already been postulated for related arylpyrroles, informing the choice of analogs and pursuit of specific lead compounds.[9]

Open source science has contributed significantly to the rapid identification of promising drug leads. Contributions from a variety of fields of expertise allow both synthetic and biological concerns for these lead compounds to be addressed, giving a more holistic view of the nature of drug design goals. Stimulating discussion and participation, this free exchange of ideas enables involvement of the wider scientific community, accelerating research and development so that it may be possible to find an effective solution to a devastating problem as soon as possible.


  1. Wells, T.N.C., Alonso, P.L.and Gutteridge, W.E. “New Medicines to improve control and contribute to the eradication of Malara”, Nature Reviews,2009, Vol. 8, pp879-891 
  1. Panosian, CB. “Economic access to effective drugs for falciparum malaria”, Clinical Infectious Diseases, 2005, Vol. 40, no. 5, pp. 713-717 
  1. Wells T.N.C “Is the tide turning for New Malaria Medicines”, Science, 2010, Vol. 329 pp.1153-1154 
  1. Francisco-Javier, G., Sanz, LM., Jaume, V. “Thousands of chemical starting points for antimalarial lead identification”, Nature, 2010, Vol. 465, no. 7296, pp305-U56 
  1. Calderon, F., Barros, D., Beuno Jose, M. et al. “An Invitation to Open Innovation in Malaria Drug Discovery: 47 Quality Starting Points from the TCAMS”, ACS Chemistry Letters, 2011, Vol.2, no.10, pp741-746 
  1. The Synaptic Leap – Malaria Research Community (Updated 2011) 
  1. Todd, M., Ylioja, P. (2011). Open Source Drug Discovery – Malaria. Open wet ware. 
  1. Lab Blog: blog (Updated 2011) 

  1. Lee, BH., Lee, MJ., Park, S,. Oh, DC,. Elsasser, S,. Chen, PC,. Gartner, C,. Dimova, N,. Hanna, J,. Gygi, SP,. Wilson, SM,. King, RW,. Finley, D. “Enhancement of proteasome activity by a small-molecule inhibitor of USP14”, Nature, 2010, Vol. 467, pp179-184 

Thursday, 29 January 2015

LY-156735 (TIK-301, PD-6735)….for the treatment of sleep latency in patients with primary insomnia

LY-156735 (TIK-301, PD-6735)….for the treatment of sleep latency in patients with primary insomnia

TIK-301 structure
LY-156735 (TIK-301PD-6735) is a melatonin MT1 and MT2 agonist which is under development for the treatment of insomnia and other sleep disorders.[1]
Beta-methyl-6-chloromelatonin (PD-6735) is a melatonin MT1 and MT2 agonist which had been in phase II trials at Phase 2 Discovery for the treatment of sleep latency in patients with primary insomnia, however, no recent development has been reported.
The melatonin agonist exhibits high selectivity and provides a novel mode of action different from that of benzodiazepine receptor ligands currently on the market.
Furthermore, the drug candidate is believed to be non-addicting, therefore, offering an advantage over marketed sleep medications. Originally discovered by Lilly, PD-6735 was licensed to Phase 2 Discovery in 2002 for further development.
Orphan drug designation has been assigned in the U.S. for the treatment of circadian rhythm sleep disorders in blind people with no light perception and for the treatment of neuroleptic-induced tardive dyskinesia in schizophrenia patients.
In 2007, the product candidate was licensed to Tikvah Therapeutics by Phase 2 Discovery for worldwide development and commercialization for the treatment of sleep disorder, depression and circadian rhythm disorder.
beta -alkylmelatonins as ovulation inhibitors [US4997845]1991-03-05
BETA-ALKYLMELATONINS [EP0281242]1988-09-07 GRANT1992-08-12
The condensation of 6-chloro-5-methoxy-1H-indole (I) with Meldrum’s acid (II) and acetaldehyde (III) catalyzed by L-proline in acetonitrile gives the adduct (IV), which is treated with Cu and ethanol in refluxing pyridine to yield 3-(6-chloro-5-methoxy-1H-indol-3-yl)butyric acid ethyl ester (V). The reaction of (V) with hydrazine at 140 C affords the hydrazide (VI), which is treated with NaNO2 and Ac-OH to provide the corresponding azide that, without isolation, is thermolyzed and rearranged in toluene at 80?C to give 7-chloro-6-methoxy-4-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (VII). The cleavage of the lactam ring of (VII) with KOH in refluxing ethanol/water yields 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (VIII). The decarboxylation of (VIII) by means of refluxing aq. 3M HCl affords 3-(2-amino-1-methylethyl)-6-chloro-5-methoxy-1H-indole (IX), which is finally acylated with acetic anhydride and pyridine in toluene to provide the target 6-chloromelatonin as a racemic compound.
Example 3
    Preparation of β-Methyl-6-chloromelatonin
  • Following the procedure of Example 1, a solution of 10.0 g (0.055 mole) of 5-methoxy-6-chloroindole, 3.1 ml (2.44 g, 0.055 mole) of acetaldehyde, and 7.94 g (0.055 mole) of Meldrum’s acid in 90 ml of acetonitrile was stirred for 48 hours. The solvent was removed under vacuum, and the adduct thus prepared was recrystallized by dissolving in warm toluene and immediately cooling. The adduct was obtained as slightly pink crystals; m.p. = 145°C; yield = 16.5 g (85%). The elemental analysis of the product showed a slightly elevated percentage of carbon. However, the NMR spectrum indicated that the product was pure and had the indicated structure.
    Analysis calc. for C₁₇H₁₈NO₅Cl
    C, 58.04; H, 5.16; N, 3.98; Cl, 10.08
    Found :
    C, 59.34; H, 5.15; N, 3.84; Cl, 9.69
  • The solvolysis and decarboxylation of the adduct (11.0 g; 31.3 mmoles) using ethanol, pyridine, and copper dust was carried out by the procedure of Example 1. The yield of 3-(5-methoxy-6-chloro-1H-indol-3-yl)pentanoic acid ethyl ester, a pale yellow oil, after chromatography over silica gel using 10% EtOAc/90% toluene was 8.68 g (94%).
    Analysis calc. for C₁₅H₁₈NO₃Cl
    C, 60.91; H, 6.13; N, 4.74; Cl, 11.99
    Found :
    C, 60.67; H, 5.86; N, 4.93; Cl, 11.73
  • A mixture of 8.68 g (29.3 mmoles) of the above ethyl ester and 6 ml of hydrazine hydrate was heated at 140°C under nitrogen in a flask fitted with an air cooled condensor. After 6½ hours, the excess hydrazine hydrate was removed under vacuum. The 2-methyl-2-(5-methoxy-6-chloro-3-indolyl)-propionhydrazide thus prepared was recrystallized from ethyl acetate; Yield = 7.13 g (86%); m.p. = 154-155°C.
    Analysis calc. for C₁₃H₁₆N₃O₂Cl
    C, 55.42; H, 5.72; N, 14.91; Cl, 12.58
    Found :
    C, 55.14; H, 5.51; N, 14.49; Cl, 12.78
  • The above hydrazide (7.13 g, 25 mmoles) was converted to the corresponding acyl azide, the azide thermolyzed and rearranged at 80° in toluene, and the rearranged product cyclized with HCl according to the procedure of Example 1. The yield of crude, light tan, lactam, 1-oxo-4-methyl-6-methoxy-7-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole, product, (m.p. = 249-252°C) was 4.77 g (72%).
    Analysis calc. for C₁₃H₁₃N₂O₂Cl
    C, 58.99; H, 4.95; N, 10.58
    Found :
    C, 59.45; H, 4.77; N, 10.72
  • The crude lactam (4.77 g, 18 mmoles) was hydrolyzed with aqueous ethanolic KOH as described in Example 1. The yield of crude amino acid, 2-carboxy-3-(1-amino-2-propyl)-5-methoxy-6-chloroindole, was 3.98 g (78%). The crude product (3.0 g; 10.6 mmoles) was decarboxylated, using the procedure of Example 1, by refluxing in 100 ml of 3M HCl overnight. The acidic solution was decolorized with activated carbon and was then basified with 5M NaOH. The amine was extracted into diethyl ether. After drying the ether extract over Na₂SO₄, the diethyl ether was removed in vacuoleaving as a residue the crystallized tryptamine, 3-(1-amino-2-propyl)-5-methoxy-6-chloroindole; m.p. 133-4°C. The yield, after recrystallization from toluene/hexane, was 1.62 g (64%).
    Analysis calc. for C₁₂H₁₅N₂OCl
    C, 60.38; H, 6.33; N, 11.74; Cl, 14.85
    Found :
    C, 60.11; H, 6.05; N, 11.93; Cl, 15.06
  • A solution of 1.51 g (6.3 mmoles) of the above tryptamine in 10 ml of toluene and 2.5 ml of pyridine was treated with 1.5 ml of acetic anhydride. After allowing the reaction mixture to stand for three hours at room temperature, the volatile materials were removed under vacuum. The residue was dissolved in ethyl acetate, and washed with aqueous NaHCO₃, and brine. The ethyl acetate solution was dried over Na₂SO₄, and the solvent removed by evaporation. The residual oil was crystallized from toluene/hexane yielding 6-chloro-β-methylmelatonin, (m.p. = 133-5°C; 1.09 g, 61%).
    Analysis calc. for C₁₄H₁₇N₂O₂Cl
    C, 59.89; H, 6.10; N, 9.98; Cl, 12.63
    Found :
    C, 60.03; H, 6.22; N, 9.75; Cl, 12.92
The intermediate diazonium salt (XIII) has been obtained as follows: the hydrogenation of 3-chloro-4-methoxynitrobenzene (XI) with H2 over Pt/Al2O3 in toluene gives the corresponding aniline (XII), which is diazotized with NaNO2/HCl and treated with sodium tetrafluoroborate to yield the target diazonium salt intermediate (XIII). The reduction of pulegone (I) with H2 over Pd/C gives the menthol (II), which is oxidized with CrO3/H2SO4 to yield 3(R),7-dimethyl-6-oxooctanoic acid (IV), which can also be obtained by direct oxidation of (l)-menthol (III) under the same conditions.
The oxidation of (IV) with trifluoroperacetic acid (trifluoroacetic anhydride/H2O2) in dichloromethane yields the 3(R)-methylhexanedioic acid isopropyl monoester (V), which is treated with NaOEt in ethanol to obtain the corresponding ethyl monoester (VI). The reaction of (VI) with diethyl carbonate, EtONa, and “Adogen 464″ (a phase transfer catalyst) in ethanol affords 5,5-bis(ethoxycarbonyl)-3(S)-methylpentanoic acid (VII), which is treated with oxalyl chloride to provide the expected acyl chloride (VIII). The reaction of (VIII) with sodium azide and benzyl alcohol gives the intermediate azide that rearranges to the benzyl carbamate (IX).
The reductive cyclization of (IX) with H2 over Pd/C in ethanol yields 5(R)-methyl-2-oxopiperidine-3-carboxylic acid ethyl ester (X), which is condensed with the intermediate diazonium salt (XIII) to afford the hydrazono derivative (XIV). The cyclization of (XIV) in hot formic acid provides 7-chloro-6-methoxy-4(R)-methyl-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indol-1-one (XV), which is treated with KOH In refluxing ethanol/water to cleave the lactam ring, yielding 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole-2-carboxylic acid (XVI). The decarboxylation of (XVI) by means of refluxing 3M HCl affords 3-(2-amino-1(R)-methylethyl)-6-chloro-5-methoxy-1H-indole (XVII), which is finally acylated with Ac2O and pyridine in toluene to provide the target 6-chloromelatonin as a pure enantiomer.
Example 7
    Preparation of S-(-)-β-methyl-6-chloromelatonin and R-(+)-β-methyl-6-chloromelatonin
  • A solution of 4.0 g (21 mmoles) of 3-chloro-4-methoxynitrobenzene in 200 ml of toluene was hydrogenated over 0.4 g of 5% platinum on alumina. The catalyst was removed by filtration and the solvent evaporated from the filtrate. The crude 3-chloroanisidine prepared was placed in solution in diethyl ether and treated with ethereal HCl to produce the hydrochloride salt, which was collected and dried; weight = 2.48 g (61% yield).
  • A mixture of 2.40 g (12.4 mmoles) of 3-chloroanisidine hydrochloride in 7 ml of 4M HCl was treated, at 0°C, with 0.86 g (12.5 mmoles) of sodium nitrite in 5 ml of water. After stirring at 0°C for an hour the solution was filtered and the filtrate added slowly to an ice cold solution of 2.6 g (24 mmoles) of sodium fluoroborate in 8 ml of water. After stirring at 0°C for an hour the salt was collected and washed successively with, cold 5% sodium fluoroborate solution, cold methanol, and ether. The dried 3-chloro-4-methoxybenzene diazonium fluoroborate thus prepared weighed 2.2 g (69% yield).
  • A mixture of 2.03 g (11.0 mmole) of (R)-(-)-3-ethoxycarbonyl-5-methyl-2-piperidone and 30 ml of 0.75M NaOH was stirred at room temperature (24°C) overnight. The solution was cooled to 0°C and the pH lowered to 3.5 with 3M hydrochloric acid. The diazonium salt (2.8 g, 10.9 mmoles) was added in small portions and the reaction mixture cooled to about 0°C overnight. The product, R-(-)-3-(3-chloro-4-methoxy)phenylhydrazono-5-methyl-2-piperidone, was collected, washed with water, and dried; weight = 2.30 g (75% yield); m.p. = 205°C. A small sample was further purified by chromatography over a short silica gel column using ethyl acetate as the eluant. [α]²⁵ = -58° (c = 10, MeOH).
    Analysis calc. for C₁₃H₁₆N₃O₂Cl
    C, 55.42; H, 5.72; N, 14.91; Cl, 12.58
    Found :
    C, 55.79; H, 5.78: N, 14.72; Cl, 12.69
  • A mixture of 2.20 g (7.8 moles) of the R-(-) hydrazone and 20 ml of 90% formic acid was heated at 85° for three hours then slowly diluted with an equal volume of water. The mixture was allowed to cool and then chilled overnight. The dark precipitate was collected, washed with water, then recrystallized from acetone/water, yielding 1.20 g (60% yield) of S-(-)-1-oxo-4-methyl-6-methoxy-7-chloro-1,2,3,4-tetrahydro-9H-pyrido[3,4-b]indole; m.p. = 248°C. [α]²⁵ = -12.2° (c = 10, MeOH).
    Analysis calc. for C₁₃H₁₃N₂O₂Cl
    C, 58.99; H, 4.95; N, 10.58; Cl, 13.39
    Found :
    C, 59.16; H, 4.88; N, 10.80; Cl, 13.15
  • The conversion of (S)-(-)-lactam to (S)-(-)-6-chloro-β-methylmelatonin was carried out as described previously in Example 3. The product, S-(-)-β-methyl-6-chloromelatonin, was spectroscopically identical to the racemate, but gave an optical rotation of [α]²⁵ = -13.2° (c = 10, MeOH).
  • (R)-(+)-6-chloro-β-methylmelatonin was synthesized from (S)-(+)-3-ethoxycarbonyl-5-methyl-2-piperidone in the same manner as described above. The stereoisomer was identical to the (S)-(-) material except for the sign of rotation.
CAS NUMBER118702-11-7 Yes




Abstract Image
Acetamide, N-​[2-​[7-​(cyclohexylmethyl)​-​1,​6-​dihydro-​2H-​indeno[5,​4-​b]​furan-​8-​yl]​ethyl]​-
339.47, C22 H29 N O2
cas 1287785-08-3
Melatonin MT2 Agonists
Treatment of Sleep Disorders,
  • Melatonin (N-acetyl-5-methoxytryptamine), which is a hormone synthesized and secreted principally in the pineal gland, increases in dark circumstances and decreases in light circumstances. Melatonin exerts suppressively on pigment cells and the female gonads, and acts as a synchronous factor of biological clock while taking part in transmittance of photoperiodic code. Therefore, melatonin is expected to be used for the therapy of diseases related with melatonin activity, such as reproduction and endocrinic disorders, sleep-awake rhythm disorders, jet-lag syndrome and various disorders related to aging, etc.
  • Recently, it has been reported that the production of melatonin melatonin could reset the body’s aging clock (see Ann. N. Y. Acad. Sci., Vol. 719, pp. 456-460 (1994)). As previously reported, however, melatonin is easily metabolized by metabolic enzymes in vivo (see Clinical Examinations, Vol. 38, No. 11, pp. 282-284 (1994)). Therefore, it cannot be said that melatonin is suitable as a pharmaceutical substance.
  • Various melatonin agonists and antagonists such as those mentioned below are known.
    • (1) EP-A-578620 discloses compounds of:

      • Figure 00020001
      • (2) EP-A-420064 discloses a compound of:
        Figure 00020002
      • (3) EP-A-447285 discloses a compound of:
        Figure 00020003
      • (4) EP-A-662471 discloses a compound of:
        Figure 00020004
      • (5) EP-A-591057 discloses a compound of:
        Figure 00020005
      • (6) EP-A-527687 discloses compounds of:
        Figure 00030001
        X=S, 0, Y=CH
        X=0, NH, Y=N
      • (7) EP-A-506539 discloses compounds of:
        Figure 00030002
    • Tricyclic or more poly-cyclic compounds with a cyclic ether moiety, such as those mentioned below, are known.
      • (1) Compounds of:
        Figure 00030003
        are disclosed in Tetrahedron Lett., Vol. 36, p. 7019 (1995).
      • (2) Compounds of:
        Figure 00040001
        Figure 00040002
        are disclosed in J. Med. Chem., Vol. 35, p. 3625 (1992).
      • (3) Compounds of:
        Figure 00040003
        are disclosed in Tetrahedron, Vol. 48, p. 1039 (1992).
      • (4) Compounds of:
        Figure 00040004
        are disclosed in Tetrahedron Lett., Vol. 32, p. 3345 (1991).
      • (5) A compound of:
        Figure 00050001
        is disclosed in Bioorg. Chem., Vol. 18, p. 291 (1990).
      • (6) A compound of:
        Figure 00050002
        is disclosed in J. Electroanal. Chem. Interfacial Electrochem., Vol. 278, p. 249 (1990).


Highly Potent MT2-Selective Agonists

J. Med. Chem.201154 (9), pp 3436–3444
DOI: 10.1021/jm200221q
N-{2-[7-(Cyclohexylmethyl)-1,6-dihydro-2H-indeno[5,4-b]furan-8-yl]ethyl}acetamide (15)
By a similar procedure that described for 815 (79%) was obtained as a white solid; mp 133−134 °C (EtOAc/hexane).
1H NMR (CDCl3) δ 0.82−1.03 (2H, m), 1.06−1.32 (3H, m), 1.42−1.78 (6H, m), 1.96 (3H, s), 2.32 (2H, d, J = 7.2 Hz), 2.74 (2H, t, J = 7.2 Hz), 3.26 (2H, s), 3.32−3.52 (4H, m), 4.59 (2H, t, J= 8.6 Hz), 5.60 (1H, s), 6.59 (1H, d, J = 7.9 Hz), 7.11 (1H, d, J= 7.9 Hz).
MS (ESI) m/z 340 (M + H)+. Anal. (C22H29NO2) C, H, N.