Kojic acid derivatives as histamine H3 receptor ligands

Article abstract of DOI:10.1248/cpb.58.1353

The histamine H₃ receptor (H₃R) is a promising target in the development of new compounds for the treatment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced and some indications in the H₃R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripherally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H₃R antagonist/inverse agonist scaffold to investigate the bioisosteric potential of γ-pyranones with respect to the different moieties of the H₃R pharmacophore. The most affine compounds showed receptor binding in the low nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corresponding phenyl analogues (3-7) revealed that the newly integrated scaffold greatly influences chemical properties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong to the centrally acting diamine-based class of H₃R antagonist/inverse agonist, whereas kojic acid analogues 6 and 7 might act peripherally. The latter compounds state promising lead structures in the development of H₃R ligands with a modified profile of action.

Full text of DOI:10.1248/cpb.58.1353

October 2010
Regular Article
Chem. Pharm. Bull. 58(10) 1353—1361 (2010)
1353
Kojic Acid Derivatives as Histamine H3 Receptor Ligands
*
Kerstin SANDER, Tim KOTTKE, Lilia WEIZEL, and Holger STARK
Johann Wolfgang Goethe University, Institute of Pharmaceutical Chemistry, Biocenter, ZAFES/CMP/ICNF; Max-von-
Laue-Str. 9, 60438 Frankfurt/Main, Germany.
Received June 9, 2010; accepted July 12, 2010; published online July 13, 2010
The histamine H3 receptor (H3R) is a promising target in the development of new compounds for the treat-
ment of mainly centrally occurring diseases. However, emerging novel therapeutic concepts have been introduced
and some indications in the H3R field, e.g. migraine, pain or allergic rhinitis, might take advantage of peripher-
ally acting ligands. In this work, kojic acid-derived structural elements were inserted into a well established H3R
antagonist/inverse agonist scaffold to investigate the bioisosteric potential of g-pyranones with respect to the dif-
ferent moieties of the H3R pharmacophore. The most affine compounds showed receptor binding in the low
nanomolar concentration range. Evaluation and comparison of kojic acid-containing ligands and their corre-
sponding phenyl analogues (3—7) revealed that the newly integrated scaffold greatly influences chemical proper-
ties (S Log P, topological polar surface area (tPSA)) and hence, potentially modifies the pharmacokinetic profile
of the different derivatives. Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine ligands 3 and 4 belong
to the centrally acting diamine-based class of H3R antagonist/inverse agonist, whereas kojic acid analogues 6 and
7 might act peripherally. The latter compounds state promising lead structures in the development of H3R
ligands with a modified profile of action.
Key words histamine; G protein-coupled receptor; topological polar surface area; kojic acid; medicinal chemistry
Histamine is one of the most important chemical messen- required as basic pharmacophore to interact with the western
gers in the human (h) organism. It mediates its pleiotropic ef- part of the H3R binding pocket, the target allows for broader
fects via four known G protein-coupled receptors (GPCR), variation in the eastern part of the molecule. A second basic
the histamine receptors (H1R—H4R). H1R and H2R are moiety usually boosts H3R affinity as has been shown with
mainly associated with the development of allergy and ulcer, many compounds of the class of diamine-based ligands.7—9)
respectively, and the corresponding antagonists have reached Computational models support an additional ionic interaction
blockbuster status in the therapy of these widespread dis- with transmembrane domain 5.10,11) However, due to the
eases.1) The youngest member of the histamine receptor fam- strong receptor binding and their lipophilicity diamine-based
ily, H4R, is involved in inflammatory processes and takes an ligands tend to accumulate centrally, which as a result might
immunomodulatory role. The first ligands are currently eval- induce severe side effects and/or phospholipidosis.12) One
uated in an early stage of clinical studies.2) The H3R takes an aim of this study was to establish new lead structures that
exceptional role as an auto- and heteroreceptor that is mainly combine the second basic centre with increased hydrophilic-
but not exclusively expressed in the central nervous system ity to avoid potentially occurring side effects in an early state
(CNS). It controls the synthesis and liberation of the endoge- of compound development.
nous ligand histamine and hence, regulates its concentration
Due to high polarity and electron density g-pyranone de-
in the synaptic cleft. Located on non-histaminergic neurons, rivatives were tested as substitutes of the different elements
the H3R modulates the release of various other neurotrans- in the H3R pharmacophore. Kojic acid, 5-hydroxy-2-(hydroxy-
mitters and neuropeptides.3) By keeping a certain neurotrans- methyl)-4H-pyran-4-one, served as starting point for the
mitter balance in brain compartments with co-localized neu- preparation of a series of H3R ligands. This interesting scaf-
rons the H3R ensures different physiological functions like fold was first isolated from various fungi strains, e.g. Penicil-
vigilance, learning, attention, or feeding behaviour. In the lum, Gluconoacetobacter and especially Aspergillus oryzae,
peripheral nervous system (PNS) the receptor influences e.g. that is commonly called koji in Japanese. Koji malt has been
nerve and C fibers involved in the regulation of sympathetic used in the production of sake or soya sauce for a long time.
effector systems and pain sensation, respectively. Antago- A broad field of application is found in food and cosmetic in-
nists/inverse agonists of the H3R are able to increase the neu- dustries. Due to its antioxidant properties it is used to de-
rotransmitter content and may find their application in the colourize food or as depigmenting agent. The latter is sup-
therapy of cognitive diseases, sleep/wake disorders, epilepsy, ported by a strong inhibitory effect on the pigment-generat-
obesity, pain or allergic rhinitis. Several substances are pro- ing enzyme tyrosinase.13—15) For chemical purposes kojic
gressing in clinical trials.4,5)
acid consists of a 4H-pyran-4-one scaffold that is substituted
H3R antagonists/inverse agonists (Fig. 1) follow a general with a hydroxyl and a hydroxymethyl group in positions C-3
structural blueprint consisting of a basic moiety coupled via and C-5, respectively. The resulting enol moiety exhibits a
an alkyl spacer to a central core. This element constitutes a pKa value of 7.9—8.0 allowing for similar reactions as de-
hydrogen bond acceptor, which in most cases is connected to scribed for phenols. Kojic acid is a chelating agent that en-
an aromatic ring system, and might be substituted with a ables bidentate complexes with various metals that have been
variety of polar, lipophilic, basic or acidic moieties or their reported as radical scavengers (Fig. 2).16—18) Physicochemi-
combination.6) Whereas the amino-alkyl-acceptor fragment is cal properties of kojic acid and its application in consumer
∗ To whom correspondence should be addressed. e-mail: h.stark@pharmchem.uni-frankfurt.de
© 2010 Pharmaceutical Society of Japan

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Vol. 58, No. 10
Fig. 1. Reference H3R Antagonists/Inverse Agonists
boiling solvents (cesium carbonate in anhydrous N,N-di-
methylformamide (DMF) (a)25) and soda lye in methanol
(b),26,27) respectively). Although side processes like ring-
opening of the vinylogous lactone caused by the attack of the
aqueous alkali solution were expected,28) yields ranged be-
tween 50% and 60% in both approaches. Method (b) resulted
to be the more practicable one due to faster purification. Pre-
cursor P9 was prepared by chlorination in pure thionyl chlo-
ride resulting in 75% conversion to the product.29) The addi-
Fig. 2. Acidic (A) and Chelate Complexing (B) Properties of Kojic Acid
goods emphasize the safety of this scaffold.
The goal of this work was to combine the H3R antagonist/ tion of solvents like toluene to improve a usually quantitative
inverse agonist pharmacophore with kojic acid-derived ele- reaction minimized yields even further. P9 was subsequently
ments by integrated and spacer approaches to take advantage reduced using zinc/hydrochloric acid to obtain the methyl
of the physicochemical and pharmacological properties of derivative P10.30)
the g-pyranone scaffold and to modify the pharmacokinetic
properties of an existing H3R pharmacophore.
Benzyl kojic acid P8 was treated with acid P4 in a Mi-
tsunobu reaction31) giving compound 5. Diamine-containing
Chemistry Precursors containing the 1-(3-phenoxy- compounds 6—8 were obtained by nucleophilic substitution
propyl)piperidine pharmacophore were prepared as described of chlorokojic acid P9. Secondary amines 6 and 8 were syn-
before.9,19,20) Briefly, piperidine was alkylated with 3-chloro- thesized in tetrahydrofuran (THF) at ambient temperature,
propan-1-ol under basic conditions (Chart 1). The resulting whereas stronger conditions were required for the quantita-
alcohol precursor P1 was chlorinated (P2) and subsequently tive conversion into the tertiary amine 7. Microwave irradia-
transferred to phenol ether synthesis. Precursor compounds tion of the reagents in DMF led to the desired product forma-
P3 and P5 as well as final compounds 1 and 2 were prepared tion. Purification, especially of the diamine-based com-
by applying Williamson-like conditions combined with a pounds, by column chromatography had to occur under harsh
Finkelstein exchange.21,22) Derivatization of ester P3 and ni- conditions. Due to the high polarity of the compounds equi-
trile P5 led to carboxylic acid P4 and benzyl amine P6, re- voluminous mixtures of methylene chloride and ammoniacal
spectively.23) Hence, a series of precursor compounds con- methanol were regularly used. Compounds were usually
sisting of the H3R affine pharmacophore but differing func- crystallized as salts of oxalic acid. Polarity and hydrophilic-
tional moieties was designed as a molecular toolbox. Amine ity frequently resulted in the enclosure of water requiring
precursor P6 was the starting point in the preparation of di- repeated re-crystallization steps, which minimized overall
amine-based ligands. Benzyl amines 3 and 4 were prepared reaction yields.
in a one-pot approach by reductive amination of benzalde-
hyde using sodium triacetoxyborohydride as reducing plied to get methyl derivative 9. In contrast, the synthesis of
agent.24)
compounds 10 and 11 as well as the corresponding precur-
Williamson-like conditions, as described before, were ap-
Kojic acid (P7) was functionalized to obtain a variety of g- sors P11 and P12 was realized starting from kojic acid (P7)
pyranone-containing precursors (Charts 2, 3). Benzyl kojic due to a more convenient preparation and higher overall
acid P8 was synthesized under basic conditions using high- yields (Chart 3). After alkylation of the enol moiety of P7

October 2010
1355
Reagents and conditions: (i) 1. K2CO3, KI, acetone, reflux, 3 d; 2. HCl, 2-propanol; 79%. (ii) SOCl2, toluene, 0 °C→60 °C, 3 h; quantitative conversion. (iii)
Phenol (1)/4-(hydroxymethyl)phenol (2)/methyl 4-hydroxybenzoate (P3)/4-hydroxybenzonitrile (P5), K2CO3, KI, acetone, reflux, 2—3 d; 47—61%. (iv) KOH,
H2O, THF, MeOH, mW, 70 °C, 15 min; quantitative conversion. (v) Raney-Ni, MeOH/NH3, rt, 12 h, 10 bar; 94%. (vi) Benzaldehyde, Na(OAc)3, DCE, rt, 3.5 h; 1—
20.5%.
Chart 1. Synthesis of Precursors P1—P6 as well as Final Compounds 1—4
Reagents and conditions: (i) a) Benzyl bromide, Cs2CO3, DMF, rt, 24 h; 52%; b) Benzyl bromide, NaOH, MeOH, rf, 12 h; 57%. (ii) P4, DEAD, PPh3, THF, rt,
12 h; 4%. (iii) SOCl2, 0 °C→rt, 1 h; 75%. (iv) P6 (6)/3-(piperidin-1-yl)propan-1-amine (8), TEA, THF, rt, 12 h; 5—15%. (v) P6, DMF, mW, 30 min, 130 °C; 10%.
Chart 2. Synthesis of Precursors P8 and P9 as well as Final Compounds 5—8

1356
Vol. 58, No. 10
Reagents and conditions: (i) Zn, HCl, 70 °C, 3 h; 31%. (ii) P2, Cs2CO3, KI, DMF, 110 °C, 2 h; 11%. (iii) 1-Bromo-3-chloropropane, Cs2CO3, KI, DMF, 110 °C,
2 h; 72%. (iv) Piperidine, K2CO3, KI, acetone, 60 °C→rt, 14 h; 3—12%. (v) SOCl2, toluene, 70 °C, 3 h; quantitative conversion.
Chart 3. Synthesis of Precursors P10—P12 and Final Compounds 9—11
Table 1. hH3R Affinities and Selected Chemical Properties of Compounds
1—11 and References
the resulting 3-chloropropoxy derivative P11 was substituted
with piperidine to obtain a H3R pharmacophore-like scaffold
with exchanged central core (10). The hydroxymethyl group
of 10 was subsequently chlorinated (P12) and coupled with
piperidine resulting in a diamine-containing final compound
(11). First approaches to insert the two piperidine moieties in
one step by applying the activated dialcohol 3-(6-((methyl-
sulfonyloxy)methyl)-4-oxo-4H-pyran-3-yloxy)propyl meth-
anesulfonate failed due to compound polymerization.
Pharmacology All final compounds 1—11 as well as
reference inverse agonists thioperamide32) and pitolisant (for-
merly known as BF2.649 or tiprolisant)33) (cf. Fig. 1) were
evaluated with regard to their hH3R affinity using a mem-
brane preparation from HEK-293 cells stably expressing
hH3R. In a competition binding assay the displacement of
[3H]Na-methylhistamine by the respective test compound
was determined.33,34) Thioperamide and pitolisant exhibited
hH3R affinities in the nanomolar concentration range
(pKiϭ7.1 and 7.9, respectively), which is in accordance with
results from other experiments.33,35—37) The antagonist/in-
verse agonist efficacy of the 1-(3-phenoxypropyl)piperidine
scaffold was proven in several investigations of different
research groups, including ours.38)
Chemical Propertiesb)
hH3R affinity
Compound
Ki [nM]a)
S Log Pc)
tPSAc)
Thioperamide
Pitolisant
72.0Ϯ12.0
11.7Ϯ 2.5
1
2
3
4
5
6
7
8
9
307
123
2.3Ϯ 1.0
73.5Ϯ 5.1
34.3Ϯ12.5
31.5Ϯ 9.7
10.5Ϯ 0.4
1.52
1.28
4.72
4.11
3.49
0.74
0.94
Ϫ1.11
0.81
Ϫ0.22
Ϫ0.14
13.7
33.9
30.3
18.1
75.5
76.8
111.2
67.6
40.0
60.2
44.4
49671
11017
21975
596
10
11
a) [3H]Na-MeHA binding assay (HEK-293 cells expressing hH3R); values are
means of at least two experiments, each in triplicates, ϮS.D. (for Ki values Ͻ100 nM).
b) Values calculated for (di-)protonated compounds. c) Calculation with MOE soft-
ware suite (Molecular Operating Environment, version 2007.09, Chemical Computing
Group, Montreal, Canada, www.chemcomp.com).
compound 3, whereas the tertiary amine in ligand 4 is steri-
cally shielded by the benzyl rests.
Results and Discussion
Kojic acid derivatives were inserted into the pharma-
1-(3-Phenoxypropyl)piperidine (1) is the receptor-binding cophoric blueprint of H3R ligands aiming at the substitution
domain of many H3R antagonists/inverse agonists and incor- of either the benzyl moieties of compounds 3 and 4 in the
porates the most important structural elements that ensure re- eastern molecule part or the central phenoxy core of the
ceptor interactions, namely the tertiary amine and in a certain pharmacophore 1. In a first attempt, kojic acid was coupled
distance a polar moiety coupled to an aryl group. In the to carboxylic acid P4 and benzyl amine P6, respectively, re-
[3H]Na-MeHA displacement assay 1 showed moderate hH3R sulting in compounds 5—7. g-Pyranone analogues of com-
affinity (pKiϭ6.6; Table 1). Affinity was slightly improved by pounds 3 and 4, the diamines 6 and 7, exhibited good hH3R
insertion of the benzylic hydroxyl group in compound 2 affinities in the nanomolar concentration range (pKiϭ7.5 and
(pKiϭ6.9). The flexible benzyl amine 3 combines lipophilic 8.0, respectively) indicating that the hH3R binding pocket ac-
with hydrogen bond donor properties of a second basic moi- cepts these highly polar and electron withdrawing moieties in
ety in the eastern molecule part leading to a highly affine the eastern part of the ligand. The binding strength of the di-
compound with binding strength in the low nanomolar con- substituted derivative 7 is comparable to that of reference in-
centration range (pKiϭ8.6). The trisubstituted analogue 4 verse agonist pitolisant. Compared to its phenyl analogue 4
maintained affinity in the nanomolar concentration range compound 7 showed improved affinity (Fig. 3A). This may
(pKiϭ7.1) showing comparable receptor binding to thiop- be caused by additional polar interactions. Lipophilic, non-
eramide. Probably, affinity differences between 3 and 4 result aromatic residues with fixed points of high electron density,
from the improved accessibility of the second basic moiety in as seen in benzyl ester 5, were also well tolerated (pKiϭ7.5).

October 2010
1357
strength of compounds 6 and 7 is comparable to that of
phenyl-derived ligands 3 and 4.
In a first approximation of a compound’s drug-likeness
Lipinski’s rule of five considering size, number of donor and
acceptor groups and lipophilicity of a ligand is frequently ap-
plied.47) Extended guidelines include e.g. molar refractivity48)
and the topological polar surface area (tPSA) as helpful pa-
rameters to assess drug transport properties.49) The size of
the most affine compounds 3—7 and the arrangement of
donor and acceptor systems are in accordance with the gen-
eral rules. Physicochemical parameters calculated to evaluate
the CNS accessibility of these ligands are shown in Table 1.
Estimated SLogP values were calculated using the MOE
software suite (MOE, Molecular Operating Environment,
version 2007.09, Chemical Computing Group, Montreal,
Canada, www.chemcomp.com). This parameter reflects the
lipophilicity of the virtually protonated compounds. Deter-
mined values differ from the optimum of ca. 4.50,51) Only
phenyl derivatives 3 and 4 as well as kojic acid ester 5 fulfil
this requirement exhibiting S Log P values between 3.5 and
4.7, whereas S Log P values of the g-pyranones 6 and 7 (0.7
and 0.9, respectively) hint at a peripheral bioavailability. The
tPSA, which is based on the summation of surface contribu-
tions of polar fragments, should not exceed 120 Å2 to ensure
Fig. 3. Comparison of Phenyl and Pyran-4-one Moieties in the Eastern
Part (A) and in the Central Core (B) of H3R Ligands
Abbreviation: JNJϭJNJ-5207852.
Surprisingly, this compound exhibited receptor binding in the bioavailability. Compounds with tPSA values below 70 Å2
same range as diamine 6 did indicating that p interactions potentially pass the blood/brain barrier (BBB).52) Within the
evoked by the benzyl residue in 5 compensate ionic interac- presented series of compounds phenyl derivatives 3 and 4 ex-
tions resulting from the second basic moiety in 6. A smaller hibit tPSA values of 18.1 Å2 and 33.9 Å2, respectively. Re-
diamine-based ligand was designed with compound 8. How- garding the kojic acid analogues 5—7 this parameter ranges
ever, probably due to the missing hydrogen bond acceptor or between 75.5 Å2 and 111.2 Å2. The calculated chemical prop-
p donor in the central core of the ligand this approach led to erties indicate that phenyl derivatives 3 and 4 but not g-pyra-
a pronounced loss of receptor binding (pKiϭ4.3).
nones 5—7 are able to pass the BBB. Hence, the newly de-
The direct implementation of kojic acid instead of the cen- signed kojic acid derivatives offer new perspectives for the
tral phenyl ring of pharmacophore 1 was realized with com- development of H3R ligands with a modified pharmacoki-
pounds 9—11. Related scaffold-hopping approaches were netic and pharmacodynamic profile. At least partially periph-
followed by several research groups aiming at the discovery erally acting H3R antagonists/inverse agonists could be effec-
of new leads or at the differentiation of the pharmacody- tive in the therapy of different states of pain, obesity, or aller-
namic properties of H3R ligands (cf. Fig. 1). Abbott chemists gic rhinitis.53) Clinical studies (phase II for allergic rhinitis)54)
focused on the rigidification of the phenoxy core (e.g. ABT- of compounds like the H3R antagonist PF-365474655) or the
239),39,40) whereas researchers from Glaxo Smith Kline dual acting H1R/H3R antagonist GSK-10047235) corroborate
(GSK) published an ‘inverse’ aromatic core (e.g. GSK this approach.
189254).41) Scientists at Novo Nordisk increased anti-obesity
Despite an ambitious synthetic procedure the preparation
efficacy by using urea and cinnamic amide moieties as cen- of a series of kojic acid derivatives (5—11) was successfully
tral elements (e.g. NNC 38-1202).42,43) Comparable function- realized. Additionally, for reasons of comparison and evalua-
alities had already been used in imidazole-containing ligands tion, the corresponding phenyl analogues were prepared (1—
like thioperamide or clobenpropit and derivatives.44,45) The 4). Kojic acid as a scaffold was for the first time associated
advanced clinical candidate, pitolisant, contains an alkyl with H3R medicinal chemistry. It was integrated into a well
ether core.33) However, the application of this strategy, i.e. the established H3R antagonist/inverse agonist pharmacophore
direct implementation of kojic acid derivatives, did not suc- showing possibilities and limitations of kojic acid derivatives
ceed: compound 11 showed weak receptor binding in the as bioisosters of the different phenyl moieties existent in
submicromolar concentration range (pKiϭ6.2), whereas 9 compounds 3 and 4. The comparison of H3R affinities and
and 10 hardly exhibited hH3R affinity (pKiϭ5.0 and 4.7, re- calculated chemical properties of ligands 3 and 4 with those
spectively). The comparison between affinities of pyran-4- of compounds 6 and 7 indicates that the scaffold modifica-
ones 10 and 11 and the corresponding phenyl-substituted lig- tion allows for a new pharmacokinetic profile within the
ands 2 and JNJ-5207852,37,46) respectively, is diagrammed in class of diamine-based H3R antagonist/inverse agonists and
Fig. 3B. Results clearly show the limitations of kojic acid de- might determine the site of action. A comparable approach
rivatives as bioisosteric phenyl substitutes. Whereas kojic that was recently performed with lipophilic sandwich com-
acid-derived moieties as central core hardly show receptor plex-containing residues resulted in the design of centrally
interactions, they are well accepted as extension of the east- acting H3R pharmacological tools.56) In contrast, kojic acid
ern molecule part resulting in ligands with affinities in the derivatives 6 and 7 represent novel lead compounds offering
low nanomolar concentration range. Receptor binding promising possibilities for the development of peripherally

1358
Vol. 58, No. 10
13C-NMR (DMSO-d6) d: 21.53, 22.40, 23.24, 52.00, 53.27, 65.40, 114.24,
123.20, 131.30, 161.81, 166.91. ESI-MS m/z: 264.0 (Calcd for C15H21NO3:
263.15).
acting H3R antagonist/inverse agonists.
Experimental
4-(3-(Piperidin-1-yl)propoxy)benzonitrile (P5)9,20) Chloride P2 (3.0 g,
15.1 mmol), 4-hydroxybenzonitrile (2.0 g, 16.8 mmol), potassium carbonate
(9.0 g, 90.6 mmol) and potassium iodide (2.5 g, 15.1 mmol) were refluxed in
absolute acetone (100 ml) during 3 d. After cooling the inorganic salts were
filtered off and the filtrate was concentrated under reduced pressure. The re-
maining residue was taken up in soda lye (5 N) and extracted with methylene
chloride. The combined organic extracts were washed with brine and dried
over magnesium sulphate. The organic solvent was removed under reduced
pressure. The product was obtained as yellowish oil (1.7 g, 47%).
Chemical Formula: C15H20N2O. 1H-NMR (DMSO-d6) d: 1.35—1.37 (2H,
m), 1.43—1.50 (4H, m), 1.85 (2H, q), 2.30—2.37 (6H, m), 4.07 (2H, t,
Jϭ6.4 Hz), 7.10 (2H, dd, Jϭ11.5 Hz), 7.72 (2H, dd, Jϭ11.5 Hz). 13C-NMR
(DMSO-d6) d: 21.46, 22.61, 23.28, 52.12, 65.56, 102.99, 115.53, 119.05,
134.17, 164.42. ESI-MS m/z: 245.0 (Calcd for C15H20N2O: 244.16).
(4-(3-(Piperidin-1-yl)propoxy)phenyl)methanamine (P6)23) The nitr-
ile P5 (2.2 g, 8.8 mmol) was hydrogenated in an autoclave (10 bar) using
Raney nickel (nickel–aluminium alloy activated with sodium hydroxide pel-
lets) in ammoniacal methanol. After 12 h stirring at room temperature the
catalyst was removed by means of a filtration aid (Celite®) and the filtrate
concentrated under reduced pressure to give a yellowish oil (2.1 g, 94%).
Chemical Formula: C15H24N2O. 1H-NMR (DMSO-d6) d: 1.35—1.37 (2H,
m), 1.43—1.51 (4H, m), 1.74—1.86 (2H, m), 2.30—2.37 (6H, m), 3.72 (2H,
s), 4.07 (2H, t, Jϭ6.4 Hz), 6.88 (2H, d, Jϭ8.6 Hz), 7.24 (2H, d, Jϭ8.6 Hz).
13C-NMR (DMSO-d6) d: 24.12, 25.58, 26.32, 45.05, 54.09, 55.16, 65.81,
113.99, 128.02, 136.22, 157.02. ESI-MS m/z: 249.9 (Calcd for C15H24N2O:
248.19.
Chemistry. General Remarks Reagents and solvents were commer-
cially obtained from Merck, Sigma-Aldrich and ABCR. Melting points were
determined on a Büchi 510 melting point apparatus (Büchi, Switzerland)
and are uncorrected. 1H-NMR spectra were recorded on a Bruker AMX 300
1
(300 MHz) spectrometer (Bruker, Germany). H-NMR data are reported in
the following order: chemical shift (d) in ppm downfield from tetramethylsi-
lane as internal reference; multiplicity (br, broad; s, singlet; d, doublet; dd,
double doublet; t, triplet; m, multiplet; q, quintet); approximate coupling
constants (J) in Hertz (Hz). 13C-NMR spectra were recorded on a Bruker AC
200 (50 MHz) spectrometer (Bruker, Germany); all peaks resulted to be sin-
glets. Electrospray ionization (ESI)-MS was performed on a Fisons Instru-
ments VG Platform II (Manchester, Great Britain) in positive polarity. Data
(m/z) are listed as mass number ([MϩH]ϩ). Elemental analyses (C, H, N)
were measured on a CHN-Rapid (Heraeus, Germany) or on a ‘vario MICRO
cube’ (Elementar Analysensysteme GmbH, Germany) and were within
Ϯ0.4% of the theoretical values for all final compounds. Preparative column
chromatography was performed on silica gel 63—200 mM (Merck, Ger-
many). Hydrogenations were carried out on an autoclave model IV, 500 ml
(Roth, Germany). The microwave oven used was a Biotage Initiator 2.0
(Biotage, Sweden).
Reaction yields were not optimized and refer to the pure final products,
which in most cases were crystallized as salts.
3-(Piperidin-1-yl)propan-1-ol Hydrochloride (P1)9,19,20) Piperidine
(51.1 g, 0.6 mol), 3-chloropropan-1-ol (47.3 g, 0.5 mol), potassium carbonate
(74.3 g, 0.75 mol) and potassium iodide (8.3 g, 0.05 mol) were refluxed in
absolute acetone (300 ml) during 72 h. The mixture was allowed to cool to
room temperature, inorganic components were removed by filtration and the
filtrate was concentrated to dryness. Purification of the crude oil was
achieved by means of distillation (20 mbar, 95 °C). The oily product was
crystallized as hydrochloride from 2-propanol (white solid, 54.6 g, 79%).
1-(3-Phenoxypropyl)piperidine Hydrogenoxalate (1)9,20) Chloride P2
(2.2 g, 11.1 mmol), phenol (1.2 g, 12.2 mmol), potassium carbonate (9.2 g,
66.6 mmol) and potassium iodide (1.8 g, 11.1 mmol) were refluxed in ab-
solute acetone (100 ml) during 3 d. The crude was purified as described for
compound P3. The resulting yellow oil was crystallized as oxalic salt from
ethanol (1.6 g, 47%).
1
Chemical Formula: C8H17NO·HCl. H-NMR (DMSO-d6) d: 1.30—1.43
(1H, m), 1.64—1.88 (7H, m), 2.78—2.82 (2H, m), 2.95—3.02 (2H, m),
3.33—3.38 (2H, m), 3.44 (2H, t, Jϭ5.9 Hz), 4.42 (1H, s), 10.54 (1H, br s).
13C-NMR (DMSO-d6) d: 21.45, 22.27, 26.38, 51.95, 53.57, 57.98. ESI-MS
m/z: 143.8 (Calcd for C8H17NO: 143.13).
1
Chemical Formula: C15H21NO3·(COOH)2. H-NMR (DMSO-d6) d: 1.54
(2H, s), 1.75 (4H, s), 2.13 (2H, s), 3.13 (6H, s), 4.03 (2H, s), 6.95 (3H, s),
7.30 (2H, s). 13C-NMR (DMSO-d6) d: 21.48, 22.59, 23.51, 52.10, 53.47,
64.90, 114.44, 120.72, 129.62, 158.24, 164.62. ESI-MS m/z: 219.9 (Calcd
for C15H21NO3: 219.16). mp 185 °C. Anal. Calcd for C15H21NO3·(COOH)2:
C, 62.12; H, 7.49; N, 4.53. Found: C, 62.39; H, 7.75; N, 4.64.
1-(3-Chloropropyl)piperidine Hydrochloride (P2)9,19,20) Alcohol P1
(13.4 g, 0.08 mol) was suspended in toluene (100 ml). Under inert atmo-
sphere and at 0 °C an excess of thionyl chloride (11.6 ml, 0.16 mol) was
added dropwise. Once the exothermic reaction had decayed the mixture was
stirred for 3 h at 60 °C. Upon completion of the reaction thionyl chloride and
toluene were distilled off. The crude product was re-crystallized from
ethanol (beige solid, 14.8 g, quantitative conversion).
(4-(3-(Piperidin-1-yl)propoxy)phenyl)methanol Hydrochloride (2)9,20)
Chloride P2 (2.1 g, 10.5 mmol), 4-hydroxybenzyl alcohol (2.6 g, 21.0 mmol),
potassium carbonate (8.7 g, 63.0 mmol) and potassium iodide (1.7 g,
10.5 mmol) were refluxed in absolute acetone (100 ml) during 2 d. After pu-
rification (as described for compound P3) the resulting light solid was crys-
tallized as hydrochloride from 2-propanol (1.5 g, 50%).
1
Chemical Formula: C8H16ClN·HCl. H-NMR (DMSO-d6) d: 1.31—1.41
(1H, m), 1.65—1.87 (5H, m), 2.15—2.25 (2H, m), 2.77—2.89 (2H, m),
3.03—3.10 (2H, m), 3.35—3.40 (2H, m), 3.73 (2H, t, Jϭ6.4 Hz), 10.73 (1H,
br s). 13C-NMR (DMSO-d6) d: 21.34, 22.19, 26.13, 42.50, 51.94, 53.56.
ESI-MS m/z: 161.6 (Calcd for C8H16ClN: 161.10).
Chemical Formula: C15H23NO2·HCl. 1H-NMR (DMSO-d6) d: 1.34—1.38
(1H, m), 1.66—1.84 (5H, m), 2.13—2.22 (2H, m), 2.80—2.90 (2H, m),
3.09—3.16 (2H, m), 3.36—3.43 (2H, m), 4.01 (2H, t, Jϭ6.0 Hz), 4.40 (2H,
s), 5.10 (1H, br s), 6.89 (2H, d, Jϭ8.6 Hz), 7.20 (2H, d, Jϭ8.6 Hz), 10.70
(1H, br s). 13C-NMR (DMSO-d6) d: 21.39, 22.26, 23.47, 51.93, 53.36,
62.46, 65.06, 114.10, 127.88, 134.88, 157.11. ESI-MS m/z: 250.0 (Calcd for
C15H23NO2: 249.17). mp 167 °C. Anal. Calcd for C15H23NO2·HCl: C, 63.04;
H, 8.46; N, 4.90. Found: C, 62.92; H, 8.59; N, 4.68.
Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine Ligands
(3, 4)24) Under inert atmosphere at ambient temperature benzaldehyde
(0.6 g, 6.0 mmol) and amine P6 (1.0 g, 4.0 mmol) were coupled in 1,2-
dichloroethane (DCE) (20 ml) for 3 h. The resulting imine was reduced with
sodium triacetoxyborohydride (1.3 g, 6.0 mmol) during 30 min of stirring.
The reaction was quenched by adding a saturated solution of sodium carbon-
ate. The product was extracted with ethyl acetate. The organic layer was
washed with brine, dried over sodium sulphate, filtered and concentrated
under reduced pressure. Further purification was carried out by column
chromatography (methylene chloride : ammoniacal methanolϭ9.8 : 0.2→
9.5 : 0.5). Two fractions were eluted. Both colourless oils were crystallized
as salts of maleic and oxalic acid, respectively, resulting in white solids after
re-crystallization (3: 0.3 g, 20.5%; 4: 0.02 g, 1%). Especially 4 had to be re-
crystallized several times from acetonitrile due to incorporation of water and
stayed quite hygroscopic.
Methyl 4-(3-(Piperidin-1-yl)propoxy)benzoate (P3)9,20) Chloride P2
(3.0 g, 15.1 mmol), methyl 4-hydroxybenzoate (2.6 g, 16.8 mmol), potassium
carbonate (9.0 g, 90.6 mmol) and potassium iodide (2.5 g, 15.1 mmol) were
refluxed in absolute acetone (100 ml) during 3 d. The crude was taken up in
soda lye (2 N) and purified as described for compound P3. The resulting
product was a brown oil (2.6 g, 61%).
1
Chemical Formula: C16H23NO3. H-NMR (DMSO-d6) d: 1.38 (2H, br s),
1.45—1.58 (4H, m), 1.87 (2H, q), 2.31 (4H, br s), 2.36 (2H, t, Jϭ7.2), 3.81
(3H, s), 4.07 (2H, t, Jϭ6.4 Hz), 7.04 (2H, d, Jϭ8.8 Hz), 7.89 (2H, d,
Jϭ8.8 Hz). 13C-NMR (DMSO-d6) d: 24.11, 25.58, 26.12, 51.73, 54.07,
54.96, 66.31, 114.39, 121.65, 131.18, 162.54, 165.85. ESI-MS m/z: 277.9
(Calcd for C16H23NO3: 277.17).
4-(3-(Piperidin-1-yl)propoxy)benzoic Acid (P4)23) Ester P3 (2.0 g,
7.2 mmol) was dissolved in a mixture of THF (8 ml) and methanol (8 ml);
potassium hydroxide pellets (1.2 g, 21.6 mmol) were dissolved in water
(16 ml). Both solutions were transferred into a sealed vial and heated in the
microwave oven for 15 min at 70 °C. After cooling the organic solvents were
removed under reduced pressure and the aqueous solution neutralized with
hydrochloric acid (10 N). Reaching the isoelectric point of the product (close
to neutral pH value) it crystallized as a white solid (1.9 g, quantitative con-
version).
N-Benzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine Dihy-
drogenmaleate (3) Chemical Formula: C22H30N2O·2C4H4O4. 1H-NMR
(DMSO-d6) d: 1.43—1.78 (6H, m), 2.07—2.16 (2H, m), 2.91 (2H, br s),
3.19 (2H, t, Jϭ7.95 Hz), 3.45 (2H, br s), 4.05 (2H, t, Jϭ5.88 Hz), 4.35 (4H,
1
Chemical Formula: C15H21NO3. H-NMR (DMSO-d6) d: 1.53 (2H, br s),
1.77—1.81 (4H, m), 2.18—2.25 (2H, m), 3.08—3.12 (6H, m), 4.13 (2H, t,
Jϭ6.1 Hz), 7.03 (2H, d, Jϭ8.8 Hz), 7.88 (2H, d, Jϭ8.8 Hz), 11.66 (1H, br s).

October 2010
1359
br s), 3.44 (2H, br s), 3.96—4.10 (6H, m), 6.51 (1H, s), 6.95 (2H, d,
Jϭ8.07 Hz), 7.36 (2H, d, Jϭ7.89 Hz), 8.07 (1H, s). 13C-NMR (DMSO-d6) d:
21.31, 22.46, 23.30, 49.91, 52.02, 53.30, 59.94, 64.98, 114.04, 114.42,
125.56, 131.15, 139.88, 146.05, 158.34, 160.20, 163.25, 173.47. ESI-MS
m/z: 373.3 (Calcd for C21H28N2O4: 372.20). mp 190 °C. Anal. Calcd for
C21H28N2O4·3(COOH)2: C, 50.47; H, 5.33; N, 4.36. Found: C, 50.74; H,
5.48; N, 4.09.
6,6؅-(4-(3-(Piperidin-1-yl)propoxy)benzylazanediyl)bis(methylene)bis-
(3-hydroxy-4H-pyran-4-one) (7) Benzylamine P6 (0.5 g, 2.0 mmol) and
kojic acid chloride P9 (1.3 g, 8.0 mmol) were dissolved in DMF and heated
under microwave irradiation for 30 min. After cooling the solvent was re-
moved under reduced pressure. Purification was performed by column chro-
matography (methylene chloride : ammoniacal methanolϭ9.0 : 1.0〈1.0 : 1.0).
The product is a brown solid (0.1 g, 10%).
d, Jϭ5.73 Hz), 6.03 (4H, s), 7.00 (2H, d, Jϭ8.62 Hz), 7.26—7.45 (7H, m).
13C-NMR (DMSO-d6) d: 21.21, 22.63, 23.45, 49.65, 52.20, 53.36, 64.93,
114.53, 123.85, 128.68, 128.97, 129.87, 131.60, 131.84, 135.73, 158.70,
167.17. ESI-MS m/z: 339.1 (Calcd for C22H30N2O: 338.24). mp 133 °C.
Anal. Calcd for C22H30N2O·2C4H4O4: C, 63.14; H, 6.71; N, 4.91. Found: C,
62.89; H, 6.63; N, 4.77.
N,N-Dibenzyl-1-(4-(3-(piperidin-1-yl)propoxy)phenyl)methanamine
Dihydrogenoxalate Hydrate (4) Chemical Formula: C29H36N2O ·
2(COOH)2·1.5H2O. 1H-NMR (DMSO-d6) d: 1.38 (1H, br s), 1.73 (5H, br s),
2.06—2.12 (2H, m), 2.72 (2H, br s), 3.14 (2H, t, Jϭ7.91 Hz), 3.54 (4H, br s),
3.50 (4H, s), 4.00 (2H, t, Jϭ5.92 Hz), 6.92 (2H, d, Jϭ8.57 Hz), 7.21—7.39
(12H, m). 13C-NMR (DMSO-d6) d: 21.27, 22.48, 23.39, 52.04, 53.41, 56.16,
56.69, 64.82, 114.26, 126.99, 128.38, 129.78, 130.64, 138.69, 157.31,
162.53. ESI-MS m/z: 429.4 (Calcd for C29H36N2O: 428.28). mp 97 °C. Anal.
Calcd for C29H36N2O·2(COOH)2·1.5H2O: C, 62.35; H, 6.82; N, 4.41.
Found: C, 62.64; H, 6.79; N, 4.07%.
Chemical Formula: C27H32N2O7·2H2O. 1H-NMR (DMSO-d6) d: 1.37—
1.39 (2H, m), 1.48—1.52 (4H, m), 1.82—1.89 (2H, m), 2.42 (6H, br s), 3.54
(4H, s), 3.62 (2H, s), 3.96 (2H, t, Jϭ6.20 Hz), 6.35 (2H, s), 6.88 (2H, d,
Jϭ8.60 Hz), 7.20 (2H, d, Jϭ8.54 Hz), 8.01 (2H, s). 13C-NMR (DMSO-d6) d:
23.67, 25.05, 25.74, 53.75, 54.22, 54.86, 57.22, 65.61, 112.34, 114.29,
129.57, 129.83, 139.60, 145.77, 157.74, 165.03, 173.66. ESI-MS m/z:
497.6 (Calcd for C27H32N2O7: 496.22). mp 90 °C. Anal. Calcd for
C27H32N2O7·2H2O: C, 60.89; H, 6.81; N, 5.26. Found: C, 60.85; H, 6.38; N,
5.25.
5-Hydroxy-2-((3-(piperidin-1-yl)propylamino)methyl)-4H-pyran-4-
one Dihydrogenoxalate (8) Under inert atmosphere kojic acid chloride P9
(1.0 g, 6.2 mmol), 3-(piperidin-1-yl)propan-1-amine (1.8 g, 12.4 mmol),
TEA (0.8 ml, 6.2 mmol) and THF (20 ml) were stirred overnight at ambient
temperature. During this time the yellow solution turned brown. The solvent
was removed under reduced pressure and the crude product purified by col-
umn chromatography (methylene chloride : ammoniacal methanolϭ8.0 :
2.0→6.0 : 4.0). The crystallization of the product was performed with oxalic
acid in ethanol, while re-crystallization took place in acetonitrile to give a
light brown solid (0.4 g, 15%).
5-(Benzyloxy)-2-(hydroxymethyl)-4H-pyran-4-one (P8) (a)25) Under
inert atmosphere kojic acid (P7, 5 g, 35.2 mmol), cesium carbonate (11.5 g,
35.2 mmol), and benzyl bromide (12.5 ml, 105 mmol) were suspended in ab-
solute DMF (25 ml). The mixture was refluxed for 2 h. After cooling it was
purified by dry load column chromatography (methylene chloride : ammoni-
acal methanolϭ9.5 : 0.5) giving a light brown solid (4.2 g, 52%).
(b)26,27) Alternatively, a solution of P7 (5 g, 35.2 mmol) in methanol
(40 ml) was added to a solution of sodium hydroxide (1.6 g, 38.7 mmol) in
water (5 ml). This mixture was heated to reflux, benzyl bromide was added
dropwise and reflux was continued for 12 h. The solution was allowed to
cool to ambient temperature, the solvent removed by reduced pressure and
the resulting brown solid was washed with water (15 ml) and methanol
(10 ml). Re-crystallization in methanol led to beige crystal needles, which
were collected by filtration (4.6 g, 57%).
Chemical Formula: C13H12O4. 1H-NMR (DMSO-d6) d: 4.28 (2H, d,
Jϭ6.0 Hz), 4.93 (2H, s), 5.67 (1H, t, Jϭ6.1 Hz), 6.31 (1H, s), 7.24—7.42
(5H, m), 8.16 (1H, s). 13C-NMR (DMSO-d6) d: 59.31, 70.61, 111.19,
128.04, 128.11, 128.38, 136.17, 141.35, 146.59, 167.98, 173.20. ESI-MS
m/z: 232.8 (Calcd for C13H12O4: 232.07).
Chemical Formula: C14H22N2O3·2(COOH)2. 1H-NMR (DMSO-d6) d:
1.51 (2H, s), 1.71 (4H, s), 1.94 (2H, s), 2.82 (2H, s), 3.07 (6H, s), 3.90 (2H,
s), 6.49 (1H, s), 8.06 (1H, s), 8.23 (1H, br s). 13C-NMR (DMSO-d6) d:
21.29, 22.41, 40.29, 47.56, 51.96, 53.30, 113.50, 139.83, 146.00, 161.42,
164.11, 173.55. ESI-MS m/z: 267.1 (Calcd for C14H22N2O3: 266.34). mp
153—160 °C (carbonization). Anal. Calcd for C14H22N2O3·2(COOH)2: C,
48.43; H, 5.87; N, 6.28. Found: C, 48.63; H, 6.14; N, 6.20.
(5-(Benzyloxy)-4-oxo-4H-pyran-2-yl)methyl 4-(3-(Piperidin-1-yl)pro-
poxy)benzoate Hydrogenoxalate (5)31) A solution of benzyl kojic acid P8
(0.56 g, 2.4 mmol) and triphenylphosphine (0.42 g, 1.6 mmol) in THF (5 ml)
was added dropwise to another solution consisting of benzoic acid P4
(0.42 g, 1.6 mmol) and diethyl azodicarboxylate (DEAD) (0.28 g, 1.6 mmol)
in THF (5 ml). Under inert atmosphere the mixture was stirred overnight at
room temperature, filtered and purified by column chromatography (methyl-
ene chloride : ammoniacal methanolϭ9.5 : 0.5). The product is crystallized
with oxalic acid in ethanol and re-crystallized twice in acetonitrile (0.035 g,
4%).
5-Hydroxy-2-methyl-4H-pyran-4-one (P10)30) Chlorokojic acid P9
(1.0 g, 6.2 mmol) was suspended in water (5 ml) and heated to 50 °C. Zinc
powder (0.8 g, 12.45 mmol) and hydrochloric acid (2 ml) were added.
Whereas the mixture was kept at 70 °C for 3 h, the solids mostly dissolved.
After hot filtration the product was extracted with methylene chloride. The
combined organic extracts were dried over sodium sulphate and evaporated
to dryness. The crude was re-crystallized from 2-propanol affording a white
solid (0.24 g, 31%).
1
Chemical Formula: C28H31NO6·(COOH)2·0.5H2O. H-NMR (DMSO-d6)
d: 1.51 (2H, br s), 1.62—1.78 (4H, m), 2.12 (2H, br s), 2.98—3.18 (6H, m),
4.12 (2H, t, Jϭ5.46 Hz), 4.94 (2H, s), 5.18 (2H, s), 6.53 (1H, s), 7.08 (2H, d,
Jϭ8.78 Hz), 7.33—7.41 (5H, m), 7.94 (2H, d, Jϭ8.69 Hz), 8.27 (1H, s). 13C-
NMR (DMSO-d6) d: 21.63, 22.82, 23.54, 52.27, 53.38, 61.51, 65.50, 70.56,
113.67, 114.65, 128.09, 128.19, 128.41, 131.60, 141.55, 146.89, 161.78,
162.60, 164.41, 164.57, 172.85. ESI-MS m/z: 478.4 (Calcd for C28H31NO6:
477.22). mp 176 °C. Anal. Calcd for C28H31NO6·(COOH)2·0.5 H2O: C,
62.49; H, 5.94; N, 2.43. Found: C, 62.27; H, 5.94; N, 2.37.
1
Chemical Formula: C6H6O3. H-NMR (DMSO-d6) d: 2.23 (3H, s), 6.23
(1H, s), 7.96 (1H, s), 8.96 (1H, s). 13C-NMR (DMSO-d6) d: 19.03, 111.96,
139.26, 145.29, 165.20, 173.74. ESI-MS m/z: 126.7 (Calcd for C6H6O3:
126.03).
2-Methyl-5-(3-(piperidin-1-yl)propoxy)-4H-pyran-4-one Hydrogenox-
alate (9) Methyl derivative P10 (0.23 g, 1.8 mmol), chloride P2 (1.8 g,
9.0 mmol), cesium carbonate (2.9 g, 9.0 mmol) and potassium iodide (0.3 g,
1.8 mmol) were heated in DMF for 2 h. The crude product was purified by
means of column chromatography (methylene chloride : ammoniacal
methanolϭ9.5 : 0.5→9.0 : 1.0) and crystallized with oxalic acid in ethanol.
Re-crystallization of the beige solid was performed in acetonitrile (0.064 g,
11%).
2-(Chloromethyl)-5-hydroxy-4H-pyran-4-one (P9)29) Kojic acid (P7,
10 g, 70.4 mmol) was dissolved in thionyl chloride (40 ml) and stirred at
room temperature for 1 h. The product crystallized during this time and was
collected by filtration. The resulting residue was washed with petroleum
ether and re-crystallized from water giving a beige solid (8.4 g, 75%).
Chemical Formula: C6H5ClO3. 1H-NMR (DMSO-d6) d: 4.65 (2H, s), 6.56
(1H, s), 8.11 (1H, s), 9.30 (1H, s). 13C-NMR (DMSO-d6) d: 41.23, 113.23,
140.12, 146.02, 161.68, 173.72. ESI-MS m/z: 160.0 (Calcd for C6H5ClO3:
159.99).
1
Chemical Formula: C14H21NO3·(COOH)2. H-NMR (DMSO-d6) d: 1.51
(2H, br s), 1.70—1.74 (4H, m), 2.06 (2H, q), 2.24 (3H, s), 3.07—3.12 (6H,
m), 3.88 (2H, t, Jϭ5.79 Hz), 6.24 (1H, s), 8.11 (1H, s). 13C-NMR (DMSO-
d6) d: 18.96, 21.45, 22.49, 23.31, 52.14, 53.60, 67.15, 113.34, 141.74,
146.39, 164.45, 165.53, 173.22. ESI-MS m/z: 252.2 (Calcd for C14H21NO3:
251.15). mp 178 °C. Anal. Calcd for C14H21NO3·(COOH)2: C, 56.30; H,
6.79; N, 4.10. Found: C, 56.07; H, 6.79; N, 4.27.
5-Hydroxy-2-((4-(3-(piperidin-1-yl)propoxy)benzylamino)methyl)-4H-
pyran-4-one Dihydrogenoxalate (6) Benzylamine P6 (2.2 g, 9.0 mmol),
kojic acid chloride P9 (0.48 g, 3.0 mmol) and TEA (0.4 ml, 3.0 mmol) were
stirred in absolute THF (20 ml) overnight under inert atmosphere and at am-
bient temperature. After evaporation of the solvent the crude product was
purified by column chromatography (methylene chloride : ammoniacal
methanolϭ9.0 : 1.0→8.5 : 1.5). By adding oxalic acid the product was crys-
tallized as a brown solid and re-crystallized several times from acetonitrile
(0.1 g, 5%).
5-(3-Chloropropoxy)-2-(hydroxymethyl)-4H-pyran-4-one (P11) Kojic
acid (P7, 5 g, 35.2 mmol), cesium carbonate (11.5 g, 35.2 mmol), and potas-
sium iodide (5.8 g, 35.2 mmol) were suspended in absolute DMF (100 ml).
1-Bromo-3-chloropropane (17.3 ml, 176 mmol) was added via dropping fun-
nel. After refluxing (110 °C) the mixture for 2 h it was allowed to cool to
room temperature, filtered, and the dark brown solution was concentrated.
The residue was dissolved in methylene chloride (100 ml) and concentrated
Chemical Formula: C21H28N2O4·3(COOH)2. 1H-NMR (DMSO-d6)
d: 1.35—1.90 (6H, m), 2.11 (2H, m), 3.14 (2H, t, Jϭ6.29 Hz), 2.87 (2H,

1360
Vol. 58, No. 10
on silica gel to be submitted to dry load column chromatography (methylene
Acknowledgements The authors like to thank Prof. Dr. Dr. h.c. Jean-
chloride : ammoniacal methanolϭ9.5 : 0.5). The product was evaporated to Charles Schwartz, Bioprojet, Saint-Grégoire, France, for the kind donation
dryness to give an orange solid (5.5 g, 72%). of the hH3R cell line. The calculation of S Log P and tPSA values of all final
1
Chemical Formula: C9H11ClO4. H-NMR (DMSO-d6) d: 2.07—2.15 (2H, compounds was performed by Janosch Achenbach and Dr. Ewgenij
m), 3.74 (2H, t, Jϭ6.43 Hz), 3.93 (2H, t, Jϭ6.02 Hz), 4.28 (2H, s), 5.69 (1H, Proschak, both Goethe University Frankfurt, and is greatfully acknowl-
br s), 6.30 (1H, s), 8.16 (1H, s). 13C-NMR (DMSO-d6) d: 31.63, 41.82, edged.
59.33, 65.87, 111.05, 140.78, 146.88, 168.02, 173.08. ESI-MS m/z: 218.6
(Calcd for C9H11ClO4: 218.03).
This work was partly supported by the ESF COST action BM0806 ‘Re-
2-(Hydroxymethyl)-5-(3-(piperidin-1-yl)propoxy)-4H-pyran-4-one cent advances in histamine receptor H4 research’ as well as the Hessia
Hydrogenoxalate (10) Chloride P11 (2 g, 9.2 mmol), piperidine (1.1 ml,
11 mmol), potassium carbonate (1.9 g, 13.8 mmol) and potassium iodide
(0.15 g, 0.9 mmol) were heated in absolute acetone (20 ml) for 2 h and
stirred overnight at room temperature. After cooling, filtration and concen-
tration steps the crude was purified by column chromatography (methylene
chloride : ammoniacal methanolϭ9.5 : 0.5). 0.2 g of the isolated brown oil
(0.66 g, 27%) were crystallized with oxalic acid in ethanol and re-crystal-
lized from acetonitrile (beige solid, 0.4 g, 12%).
LOEWE programs LiFF and NeFF.
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2175 (2009).
1
Chemical Formula: C14H21NO4·(COOH)2. H-NMR (DMSO-d6) d: 1.51
(2H, br s), 1.71—1.74 (4H, m), 2.03—2.12 (2H, m), 3.07—3.12 (6H, m),
3.89 (2H, t, Jϭ5.92 Hz), 4.29 (2H, s), 6.31 (1H, s), 7.26 (1H, br s), 8.15 (1H,
s). 13C-NMR (DMSO-d6) d: 21.44, 22.58, 23.32, 52.14, 53.57, 59.28, 67.20,
111.09, 141.56, 146.69, 164.58, 168.31, 173.26. ESI-MS m/z: 268.0 (Calcd
for C14H21NO4: 267.15). mp 143 °C. Anal.. Calcd for C14H21NO4·(COOH)2:
C, 53.78; H, 6.49; N, 3.92%. Found: C, 53.52; H, 6.35; N, 3.89.
2-(Chloromethyl)-5-(3-(piperidin-1-yl)propoxy)-4H-pyran-4-one (P12)
Under inert atmosphere alcohol 10 (0.35 g, 1.0 mmol) was chlorinated with
thionyl chloride (0.21 ml, 3.0 mmol) in toluene (10 ml) as described for com-
pound P2 to give a yellow solid (0.32 g, quantitative conversion).
Chemical Formula: C14H20ClNO3·HCl. 1H-NMR (DMSO-d6) d: 1.41—
1.48 (1H, m), 1.74—1.96 (5H, m), 2.17—2.28 (2H, m), 2.90—2.95 (2H, m),
3.15—3.23 (2H, m), 3.41—3.53 (2H, m), 4.01 (2H, t, Jϭ5.91 Hz), 4.75 (2H,
s), 6.65 (1H, s), 8.36 (1H, s), 10.37 (1H, br s). 13C-NMR (DMSO-d6) d:
21.32, 22.30, 23.04, 41.08, 51.98, 53.38, 67.05, 114.43, 141.93, 146.89,
161.92, 172.94. ESI-MS m/z: 286.0 (Calcd for C14H20ClNO3: 285.11).
5-(3-(Piperidin-1-yl)propoxy)-2-(piperidin-1-ylmethyl)-4H-pyran-4- 10) Axe F. U., Bembenek S. D., Szalma S., J. Mol. Graph. Model., 24,
one (11) Chloride P12 (0.3 g, 0.93 mmol), piperidine (0.14 ml, 1.4 mmol),
potassium carbonate (0.64 g, 4.7 mmol) and potassium iodide (0.16 g,
0.93 mmol) were refluxed in absolute acetone (20 ml) for 8 h. After filtration
of the inorganic salts and concentration of the filtrate the remaining residue
was dissolved in soda lye (2 N) and the product extracted with methylene
456—464 (2006).
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chloride. The resulting oil was purified by column chromatography (methyl- 13) Kobayashi K., Kayahara H., Tadasa K., Tanaka H., Bioorg. Med.
ene chloride : ammoniacal methanolϭ9.0 : 1.0) and crystallization with ox-
alic acid. The white solid was re-crystallized in acetonitrile (0.015 g, 3%).
Chemical Formula: C19H30N2O3·2(COOH)2·0.5H2O. 1H-NMR (DMSO-
Chem. Lett., 6, 1303—1308 (1996).
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d6) d: 1.40 (2H, s), 1.54 (6H, s), 1.74 (4H, s), 2.08 (2H, m), 2.53 (8H, m), 15) Rho H. S., Baek H. S., You J. W., Kim S., Lee J. Y., Kim D. H., Chang
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s). 13C-NMR (DMSO-d6) d: 21.30, 22.52, 23.05, 23.20, 24.80, 52.13, 53.39, 16) Niwa Y., Akamatsu H., Inflammation, 15, 303—315 (1991).
53.62, 58.20, 67.11, 114.70, 141.87, 146.79, 163.16, 163.60, 173.01. ESI- 17) Vajragupta O., Boonchoonga P., Sumanonta Y., Watanabe H.,
MS: 335.1 (Calcd for C19H30N2O3: 334.23). mp 166 °C. Anal. Calcd for
C19H30N2O3·2(COOH)2·0.5H2O: C, 52.77; H, 6.74; N, 5.35. Found: C,
52.42; H, 6.37; N, 5.21.
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